W O 2010/017055 A3 A

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization IN International Bureau

(10) International Publication Number (43) International Publication Date

11 February 2010 (11.02.2010) PCT W O 2010/017055 A3

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C07D 487/14 (2006.01) A61P 3/10 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, C07D 487/12 (2006.01) A61P 29/00 (2006.01) DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, A61K 31/495 (2006.01) A61P 9/02 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K31/50 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,

ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (21) International Application Number: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,

PCT/US2009/051879 SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (22) International Filing Date: TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

27 July 2009 (27.07.2009) (84) Designated States (unless otherwise indicated, for every

(25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,

(26) Publication Language: English ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,

(30) Priority Data: TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,

61/086,687 6 August 2008 (06.08.2008) US ES, Fl, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,

61/151,036 9 February 2009 (09.02.2009) US MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM,

61/173,088 27 April 2009 (27.04.2009) US TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

(71) Applicant (for all designated States except US): LEAD THERAPEUTICS, INC. [US/US]; 999 Bayhill Drive, Declarations under Rule 4.17:

Suite 130, San Bruno, California 94066 (US). - as to applicant's entitlement to apply for and be granted

(72) Inventors; and a patent (Rule 4.17(ii))

(75) Inventors/Applicants (for US only): WANG, Bing [US/ - as to the applicant's entitlement to claim the priority of US]; 2041 Mandelay Place, San Jose, California 95138 the earlier application (Rule 4.17(iii)) (US). CHU, Daniel [US/US]; 3767 Benton Street, Santa Published Clara, California 95051 (US).

(74) Agents: WILSON SONSINI GOODRICH & ROSATI - with international search report (Art. 21(3))

et al.; 650 Page Mill Road, Palo Alto, California 94304 - before the expiration of the time limit for amending the

(US). claims and to be republished in the event of receipt of amendments (Rule 48.2(h))

(81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (88) Date of publication of the international search report:

27 May 2010

(54) Title: DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)

-.

00

A

r (57) Abstract: A compound having the structure set forth in Formula (I) and Formula (II) wherein the substituents Y, Z, A, B, Rl, O R2, R3, R4 and R5 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described

herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.

WO 2010/017055 PCT/US2009/051879

DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADPRIBOSE)POLYMERASE (PARP)

CROSS-REFERENCE

fOO01) This application claims the benefit of US. provisional application Ser. Nos. 61/173,088.

5 filed April 27, 2009; 61/151,036, filed February 9,2009. and 61/086,687, filed August 6, 2008, all

of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

100021 Described herein are compounds, methods of making such compounds, pharmaceutical

compositions and medicaments containing such compounds, and methods of using such compounds

10 to treat or prevent diseases or conditions associated with the enzyme poly(ADP-ribose)polymerase

(PARP).

BACKGROUND OF THE INVENTION

100031 The family of poly(ADP-ribose)polynerases (PARP) includes approximately 18 proteins;

which all display a certain level of homology in their catalytic domain but differ in their cellular

15 functions (Ame et al., Biolssays., 26(8), 882-893 (2004)). PARP-1 and PARP-2 are unique

members of the family, in that their catalytic activities are stimulated by the occurrence of DNA

strand breaks.

10004j PARP has been implicated in the signaling of DNA damage through its ability to recognize

and rapidly bind to DNA single or double strand breaks (DAmonurs, et a, Biochem. J., 342, 249

20 268 (1999)). It participates in a variety of DNA-related functions including gene amplification, cell

division, differentiation, apoptosis, DNA base excision repair as well as effects on telomere length

and chromosome stability (d'Adda di Fagagna, et aL, Nature Gen, 23(1), 76-80 (1999)).

SUMMARY OF THE INVENTION

100051 Provided herein are compounds, compositions and methods for modulating the activity of

25 PARP. Among the compounds that are provided herein, are compounds that are inhibitors of PARP.

Also described herein is the use of such compounds, compositions and methods for the treatment of

diseases, disorders or conditions associated with the activity of PARP.

100061 In some embodiments, compounds provided herein have the structure of Formula (1) and

Formula(lI) and pharmaceutically acceptable salts, solvates., esters, acids and prodrugs thereof. In

30 certain embodiments, provided herein are compounds having the structure of Formula (1) and

Formula (fl) that are inhibitors of the enzyme poly(ADP-ribose)polvmerase (PARP).

100071 Described herein are 8-B,Z-2-R4 -4-R -5 -R-6R-7R -9-AY-8,9-dihydro-2H-pyrido[4,3.2

deiphthalazin-3(71H)-ones, 8-B,Z-5-Rr-9-A\ ,Y- 8,9-dihydro-2H-pyrido[4,3,2-dejphthalazin-3(7H)~

ones in which A. B., Z, Y, k. R R1R, R4 and R5 are further described herein. In certain

WO 2010/017055 PCT/US2009/051879

embodiments, isomers including enantiomers and diastereoisomers, and chemically protected forms

of compounds having a structure represented by Formula (1) and Formula (U) are also provided.

100081 Formula (1) is as follows:

R4 I 0 N , N

R A

B R2 N Z

R, Rj

5 Formula (I)

wherein:

Y and Z are each independently selected from the group consisting of:

a) an aryl group optionally substituted with 1, 2, or 3 R; wherein each 1K is selected from

OH, NO2, CN, Br, Cl, F, 1. C1-Cialkyl, C cycloalkyl, C C<hterocycloalkyl; C

t0 Calkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, CrCalkynyl, aryIL

arylalkyl, Cr-CCycloalkyialkyl, haloalkoxy; haloalkyl, hydroxyalkylene, oxo, heteroary,

heteroarylalkoxy, heteroaryloxy, heteroarylthio heteroarylalkylthio, heterocyloalkoxy, C2

Cheterocycloalkylthio, heterocyclooxy, heterocyclothio., NR AR , (NfARB)C-Calkylene,

(NRAR)carbonv, (NR,\Rs)carbony lalkylene. (NRA Rl)sulfonyl, and

15 (NRADsulfonylalkxlene;

b) a heteroaryl group optionally substituted with 1, 2, or 3 R;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy

alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl,

20 alkylcarbony], aryIcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,

heteroarylsulfony, (NRARB)alkylene, (NRARB)carbonyl, (NRAR)carbony lalkylene;

(NRAR,)sulfonyl, and (NRARR)sulfonylalkylene;

RI, R, and. R3 are each independently selected from the group consisting of hydrogen, halogen,

alkenyl, alkoxy. alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano. haloalkoxy, haloalkyl, hydroxyl, 25 hydroxyalkylene, nitro, NRAR NRARaalkylene, and (NRARB)carbony ;

A and B are each independently selected from hydrogen, Br, Cl, F. 1, Off, C1-Qalkyl, C,Cscycloalkyl, alkoxy alkoxyalkyl wherein C-Cealkvl, C3 CcycloalkyL alkoxv, alkoxyalkyl are

optionally substituted with at least one substituent selected from OH, NO , CN, Br, Cl, F, 1, CQalkyl, and C3-Cscycloalkyl, wherein B is not OH;

30 RA. and Ra are independently selected from the group consisting of hydrogen, alky, cyloalkyI, and

alkylcarbonyl; or RA and R taken together with the atom to which they are attached form a 3-10

2

WO 2010/017055 PCT/US2009/051879

miembered heterocycle ring optionally having one to three heteroatoms or hetero functionalities

selected from the group consisting of -O-, -Nil, -N(Q-C-alkyl)-, -NCO(C-C 6-alkylp, -N(arvl)-,

N(anyl-Ct-C 6-alkyl-)-, -N(substituted-ary-C 1 Qalkyl-, -N(heteroaryl)-, -N(heteroary-C-C 6

alkyl-)-, -N(substituted-heteroaryi-Q-C 6 -alkyl-)-, and -S- or S(O)j-. wherein q is I or 2 and the 3

5 10 membered heterocycle ring is optionally substituted with one or more substituents;

R4 and RS are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl,

alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRAR 1)alkylene;

and isomers, salts, sol vates, chemically protected forms, and prodrugs thereof.

100091 Formula (11) is as follows:

0 N A

B

N Z 10 R2 H

Formula (II);

wherein:

Y is an ary I or heteroaryl group optionally substituted with at least one K Z is an aryl group optionally substituted with at least one R6 ;

[5 A and B are each independently selected from hydrogen, Br% Cl, F, 1 OH. CCalkyl, C3

Cscycloalkyl, alkoxy, alkoxyalkyl wherein Ci-Calkyl, C-Cacycloalkyl, alkoxy, alkoxyaikyl are

optionally substituted with at least one substituent selected from 01, NO, CN, Br, Cl, F, , Ci

Calkyl. and C3-C8Cycloalkyl, wherein B is not OH;

R6 is selected from OH, NO 7. CN, Br, Cl, F. I, C-Coalkyl. Cr-Cgcycloalkyl, C2-Cjheterocycloalkyl;

20 C2 C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl alkoxycarbonylalkyl, (>-Cralkynyl, aryl,

arlalkyl, CI-Qcycloalkylalkyl, hahoalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl,

hetcroarylalkoxy. heteroaryloxy, heteroarylthio, heteroarylalkyhhio, heterocycloalkoxy, C?

Cnheterocycloalkylthio, heterocyclooxy, heterocyclothio, NRAR13, (NRARa)CI-Calkylene,

(NRARS)carbonyl, (NRARB)carbonvlalkylene, (NRAR)sulfonyl, and (NRAR)sulfonvlaIkylene;

25 R? is selected from hydrogen, Br, Cl, I, or F;

Rk and Rg are independently selected from the group consisting of hydrogen. CrCoalkyl, C

Cscycloalkyl, and alkylcarbonyl; or RA and Rn taken together with the atom to which they are

attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or

hetero functionalities selected from the group consisting of -0- -N, -N(C1 -E 6alkyl)-. -NCO(C

30 Calkyl)-, -NCO(C,-Ccycloalkyl)- -N(aryl)-, -N(aryI-C -C6alkyl-)-, -N(substituted-aiy-C -Calk:'1y

), -N(heteroaryl)-. N(heteroary-CCsalkyI-)-, -N(substituted-heteroaryC CoalkyI, and -S- or

WO 2010/017055 PCT/US2009/051879

S(O.) . wherein q is I or 2 and the -10 membered heterocycle ring is optionally substituted with

one or more substituents or a pharmaceutically acceptable salt, solvate or prodrug thereof

100101 In certain embodiments are provided compounds of Formula (1) or a therapeutically

acceptable salt thereof wherein R, R2 R are independently selected fi-on a group consisting of

5 hydrogen, alkyl. and halogen; 1 is hydrogen and Rz is selected from the group consisting hydrogen,

alkyl, cycloalkyl. alkoxyalkyl, haloalkyl., hydroxyalkylene, and (NR AR)alkylene; R, and R5 are

independently selected from the group consisting of hydrogen. alkyl, cycloalkyl and alkylcarbonyl;

or RA and RB taken together with the atom to which they are attached form a 3-10 membered

heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from

10 the group consisting of -0-, -NH, -N(C1-C6-alkyl)-, -NCO(Cr 6-alkyl)-, N(ary- -N(aryl- C-Q

alkyl-)-, -N(substituted-aryl- C-Q-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- C-C-alkyl-)-

N(substituted-heteroaryl- C1 Qaikyl-) and -S- or S(O)\- wherein q is I or 2 and the 3-10

membered heterocycle ring is optionally substituted with one or more substituents.

100111 In one embodiment is a compound of Formula (1) wherein Y is an aryl group, In another

15 embodiment the aryl group is a. phenyl group. In yet another embodiment the phenyl group is

substituted with at least one R, selected from Br, Cl. F, or . In one embodiment R, is F. In one

embodiment the phenyl group is substituted with at least one R6 selected from (NRARn)CV

Calkylene, (NRAR)carbonyl, (NRAR)carbonvlalkylene, (NRAR)sulfonyl, and

(NRARI )sulfonvlalkylene. In one embodiment Re is (NRaRa)Cj-C(alkyene. in another

20 embodiment C Calkyl is selected from methylene, ethylene, n-propylene, iso-propylene, n

butylene, iso-butylene, and tert-butylene. In yet another embodiment C1-C-alkyl is methylene. In

yet a further embodiment RA and Rn are each independently hydrogen. C-Calkyl, or C3

Cgcycloalkyt In one embodiment C1 -C 6 alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n

butyl, iso-buty, and tert-butyl. In one embodiment C,-C(alkyl is methyl. In another embodiment

25 C1-C 6 alkyl is ethyl. In yet another embodiment C3 -Qcycloalkyl is cyclopropy cyclobutyl,

cyclopentyl, and cyclohexyl, In a further embodinent C3-Ccycloalkyl is cyclopropyl. In yet a

further embodiment IT is hydroxyalkylene. In one embodiment hydroxyalkylene is selected from

CH2oH, CH CHOR CH21CHC2CH21-1, CH(OH)CH3. CH(OlH)CH2CH, CH 2CH(OH)CH3, and

CH2CH-VCH-CH2OH. In another embodiment R and Rn taken together with the nitrogen to which

30 they are attached form a 6 membered heterocycle ring having I heteroatom or hetero functionality

selected from the group consisting of -0- -NH, or -N(C.-C 6alkyl). In yet another embodiment the

hetero functionality is --N(CICalkyl). In a further embodiment CI-Ctalkyl is selected from methyl., ethyl, n-propyl. iso-propyl, n-butyl, iso-butyl, and tert-butyl. In vet a further embodiment Cl

Calky] is methyl In one embodiment Y is a heteroaryl group optionally substituted with at least

35 one R,, in another embodiment the heteroaryl group is selected from furan, pyridine, pyrimidine.

pyrazine, imnidazole, thiazole, isothiazole, pyrazole, triazole. pyrrole, thiophene, oxazole, isoxazole,

4

WO 2010/017055 PCT/US2009/051879

12 4-oxadiazole, 1,3,4-oxadiazole, 1,2.4-triazine, indole, benzothiophene, benzoimidazole,

benzofuran, pyridazine, 1,3,5-triazine, thienothiophene., quinoxaline, quinoline, and isoquinoline. In

yet another embodiment the heteroaryl group is imidazole. In a further embodiment imidazole is

substituted with C-Calkyl selected from methyl, ethyl. n-propyl, iso-propyl, n-butyl, iso-butyl, and

5 tert-butyl. In yet a further embodiment C-Galkvi is methyl. In one embodiment.the heteroaryl

group is furan In another embodiment the heteroaryl group is thiazole. In yet another embodiment

the heteroaryl group is 1,3,4-oxadiazole. In a further embodiment heteroaryl group is substituted

with Cj7-Qalkvl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-ibutyl and tert-butyl.

In yet a further embodiment C-C-alkvl is methyl. i one embodiment Z is an aryl group. In

10 another embodimnent the aryl group is a phenyl group. In yet another embodiment the phenyl group

is substituted with at least one R selected from Br, Cl, F. or I In a further embodiment R, is F. In

yet a further embodiment Ra is Cl. In one embodiment the phenyl group is substituted with at least

one R, selected from (NRAR.)C, -GCalkylene, (NRIk)carbonyl, (NRAR)carbonylalkylene,

(NRAR)sulfonyl, and (NRARs)sulfonylalkylene. In another embodiment R6 is (NRARH)C;

15 Calkylene, In yet another embodiment C-Qalkyl is selected from methylene, ethylene n

propylene, iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet a further embodiment

Cl-Calkyl is methylene. In a further embodiment RA and Rn are each independently hydrogen, Cr

C6alkyl, or C-(Csycloalkyl In one embodiment C1 C-alkyl is selected from methyl, ethyl, n

propy iso-propyl, n-butyl, iso-butyl, and tert-butyl. in another embodiment C-Cealkyl is methyl.

20 In yet another embodiment RA and R5 taken together with the nitrogen to which they are attached

form a 6 membered heterocycle rine having I heteroatom or hetero functionality selected from the

group consisting of -O- . -NH, or -N(C-Calkyl). In a further embodiment the hetero functionality

is -N(C-C(alkyl). In one embodiment Cvbalkyl is selected from methyl, ethyl, n-propyl, iso

propyl, n-butyl, iso-butyl. and tert-butyL. In yet a further embodiment CrC 6alkyl is methyl. In one

25 embodiment Z is a heteroaryl group optionally substituted with at least one R In another

embodiment the heteroaryl group is selected from furan, pyridine, pyrimidine, pyrazine, imidazole,

thiazole. isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole,

1,3,4-oxadiazole, 1.2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran. pyridazine,

1,3,5-triazine. thienothiophene. quinoxaline, quinoline, and isoquinoline. In yet another

30 embodiment the heteroaryl group is imidazole. In a further embodiment imidazole is substituted

with C-Cjalkyl selected from methyl. ethyl, n-propyl, iso-propyl, n-butyl, iso-buty I and tert-butyl

In yet a further embodiment C-Calkyl is methyl. in one embodiment the heteroaryl group is furan.

In another embodiment the heteroaryl group is thiazole. In yet another embodiment the heteroaryl

group is 1,3,4-oxadiazole In a further embodiment heteroaryl group is substituted with C-Ctalkyl

35 selected from methyl, ethyl, n-propyl, iso-propyl. n-butyl. iso-butyl. and tert-butyl. In yet a further

WO 2010/017055 PCT/US2009/051879

embodiment C1-Ctalkyl is methyl, in another embodiment R) is hydrogen. In yet another

embodiment R- is selected from F, Cl, Br. and 1. In a further embodiment R) is F.

10012] in one embodiment is a compound Idof Formula (I) wherein A is hydrogen. In another

erbodiment A is CC 6alky. In a further embodiment; A is selected from methyl, ethyl, n-propyl,

5 iso-propyl, n-butyl, iso-butyl, tert-butyl. n-pentyl, and n-hexyl. In yet another embodiment, methyl.

ethyl, n-propyl, iso-propyl, n-butyl, iso-buty, tert-butyl, n-pentyl, and n-hexyl are optionally

substituted with OH, NO. ('N Br, Cl F, and 1, In a further embodiment A is methyl. In yet

another embodiment, A is selected from F, Cl, Br, and I, In another embodiment, A is C3

Cgcycloalkyl. In another embodiment, A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl In

10 one embodiment, A is substituted with OH, NO, or CN. In a further embodiment, B is C1 C-alkyl,

In a further embodiment, B is selected from methyl, ethyl, n-propyl. iso-propyl, n-butyl, iso-butyl,

ter-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl. n

butyl, iso-butyL tert-butyL, n-pentyL and n-hexyl are optionally substituted with Ol, NO2. CN, Br,

Cl, F, and 1. in one embodiment is a compound of Formula (I) wherein B is hydrogen. In a further

15 embodiment B is methyl. In yet another embodiment, B is selected from F, Cl, Br, and L In another

embodiment B is G C ycloalkyl. In another embodiment, B is cyclopropyl, cyclobutyl,

cyclopentyl, or cyclohexyl. In one embodiment, A is substituted with OH, NO, or CN. In a further

embodiment, is a compound of Formula (I) wherein A is hydrogen and B is selected from Br, Cl, F,

IL C1 C alkyl, C-Cscycloalky L, alkoxy, alkoxyalkyl wherein C-Calkyl, C3-Cacycioalkyl, alkoxy,

20 alkoxyalkyl are optionally substituted with at least one substituent selected from OH, NO. CN, Br,

Cf. F, L C3 C-alkyl, and C -C 8cycloalkyl. In another embodiment, is a compound of Formula (I)

wherein B is hydrogen and A is selected from Br, Cl, F, I C-Ctalkyl, C3-Cgcycloalky, alkoxy,

alkoxyalkyl wherein C aikyl, C~Ccycloalkyi, alkoxy, alkoxyalkyl are optionally substituted

with at least one substituent selected from OH NO 2, CN Br, Cl, F, 1. C-C(alkyl, and C

25 Ccvcloalkyl. In yet another embodiment, both A and B are hydrogen. In a further embodiment,

both A and B are selected from Br, Cl, F, I. C-Calkyl C-C 8cycloalkyl, alkoxy, alkoxyalkyl

wherein C1 C-alkyt Cr-Qcycloalkyl. alkoxy, alkoxyalkyl are optionally substituted with at least one

substituent selected from OH. NO2, CN. Br, Cl, F L C1-C6alkyl, and C-Ccycloalkvl.

100131 In one embodiment is a compound of Formula (II) wherein Y is an aryl group. In another

30 embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group is

substituted with at least one R, selected from Br, Cl, F, or L, In one embodiment R., is F. In one

embodiment the phenyl group is substituted with at least one R, selected from (NRAR)C

Coalkylene, (NRARt3)carbonyl, (NRARB)carbonvialkylene, (NRR 8)sulfonyl, and

(NRARa)sulfonylalkylene. In one embodiment R& is (NRAR)CJ-Csalkylene. In another

35 embodiment Cj-Cealkv is selected from methylene, ethylene, n-propylene. iso-propylene, n

butylene, iso-butylene, and tert-butylene. in yet another embodiment C-Calkylene is methylene.

6

WO 2010/017055 PCT/US2009/051879

In yet a further embodiment RA and RB are each independently hydrogen, C1-Calkyl. or Cr

CgcVcloalkyL in one embodiment C1 Calkvl is selected from methyl, ethyl, n-propyl, iso-propyl, n

butyl, iso-butyl, and tert-butyl. In one embodiment C-C 6alkyl is methyl. In another embodiment

C&Coalkyl is ethyl. In yet another embodiment C3 C8cycloalkyl is cyciopropyl, cyclobutyl,

5 cyclopentyl, and cyclohexyl. In a further embodiment C3-C8cycloalkyl is cyclopropyl In yet a

further embodiment Rk is hydroxyalkylene. In one embodiment hydroxyalkylene is selected from

CH2OHI, CIH. CH2H 01LC UCI 12H01, C1H(OHI)C13. CH(OH)CIJCI11, ClH2CH(0H)C-b. and

CHiC 2 CH2CFICH 1, In another embodiment RA and R8 taken together with the nitrogen to which

they are attached form a 6 membered heteroevele ring having I heteroatom or hetero functionality

10 selected from the group consisting of --O-j -NHl, or -N(CrC6alkyl), hI yet another embodiment the

hetero functionality is -N(CpCjalkv). In a further embodiment C1-Csalkyl is selected from methyl,

ethyl, n-propyl iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C

C6alkyl is methyl. in one embodiment Y is a heteroaryl group optionally substituted with at least

one R6. In another embodiment the heteroaryl group is selected from furan, pyridine, pyrimidine,

1.5 pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole, pyrrole- thiophene, oxazole, isoxazole,

1,2,4-oxadiazole, 1.3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole,

benzofuran, pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline, quinoline, and isoquinoline. In

yet another embodiment the heteroaryl group is imidazole. In a further embodiment imidazole is

substituted with -Crialkyl selected from methyl, ethyl. n-propyl, iso-propyl. n-buttyl, iso-butyl, and

20 tert-butyl. In y'et a further embodiment C1-C6alkvl is methyl.. In one embodiment the heteroaryl

group is furan. In another embodiment the heteroaryl group is thiazole. In yet another embodiment

the heteroaryl group is 1,3,4-oxadiazole. In a further embodiment heteroaryl group is substituted

with CC 6alkyl selected from methyl, ethyl, n-propyL iso-propyl, n-butyl, iso-butyl, and tert-butyl.

In yet a further embodiment C-Calkyl is methyl. In one embodiment Z is an aryl group. In

25 another embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group

is substituted with at least one R, selected from Br, Cl, F, or I. In a further embodiment 1% is F. in

yet a further embodiment Rb is Cl, In one embodiment the phenyl group is substituted with at least

one R selected from (NR&Ra)C -Coalkylene, (NRARj)carbonyl, (NRARB)carbonvlalkylene,

(NRARB)sulfonyl, and (NRARB)sulfonylaIkvlene. In another embodiment R6 is (NRAR3)C

30 Csalkylene. In yet another embodiment C1 -C6alkylene is selected from methylene, ethylene, n

propylene, iso-propylene, n-butylene, iso-butylene, and tert-butylene. In yet a further embodiment

C1-C6alkyl is niethylene, In a further embodiment RB and Rf are each independently hydrogen, C

Coalkyi, or Cr-CgcycloalkyL In one embodiment C1-C(alkyl is selected from methyl, ethyl, n

propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In another embodiment C-CalkyI is methyL

35 In vet another embodiment RA and R1 taken together with the nitrogen to which they are attached

form a 6 membered heterocycle ring having I heteroatom or hetero functionality selected from the

7

WO 2010/017055 PCT/US2009/051879

group consisting of -0-, -NH, or -N(C 1 -C6alkyl). In a further embodiment the hetero functionality

is -N(C-Calkyl). In one embodiment Q-Calkyl is selected from methyl, ethyl, n-propyl. iso

propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment CrC-alkyl is methyl In

another embodiment R, is hydrogen, In yet another embodiment R2 is selected from F, Cl, Br, and L

5 in a further embodiment R2 is F.

100141 In one embodiment is a compound of Formula (I1) wherein A is hydrogen. In another

embodiment A is C1 CalkyL In a further embodiment, A is selected from methyl, ethyl, n-propyl,

iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl. In yet another embodiment, methyl,

ethyl., n-propyl, iso-propyl, n-butyl iso-butyl, tert-butyl., n-pentyl, and n-hexyl are optionally

10 substituted with OH, NO. CN. Br, Cl, F, and I. In a further embodiment A is methyl. In yet

another embodiment. A is selected from F, Cl, Br, and . In another embodiment A is C

Ccvcloalkyl. In another embodiment A is cyclopropyl, eyelobutyl, cyclopentyl, or cyclohexyl. In

one embodiment, A. is substituted with OH, NO2, or CN. In one embodiment is a compound of

Fornula (11) wherein B is hydrogen. In a further embodiment, B is Cj-Cealky. In a further

15 embodiment, B is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n

pentyl, and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl, n-btyl iso

butyl, tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH, NO,, CN, Br, Cl, F, and 1.

In a further embodiment B is methyl. In yet another embodiment, B is selected from F, Cl, Br, and

1. In another embodiment, f is C-Ccycloalkyl In another embodiment, B is cyclopropyl.

20 cyclobutyl, cyclopentyl, or cyclohexyl In one embodiment. A is substituted with O-, NOJ, or CN.

In a further embodiment, is a compound of Formula (11) wherein A is hydrogen and B is selected

from Br, CI, F, 1, C1-Coalkyl, C3-Ccycloalkyl, alkoxy, alkoxyalkyl wherein C-Calkvl C

Cecycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected

from OH NO2. CN, Br. Cl, F, I, C.-Czalkyl, and C;C-cycloalkyl. In another embodiment, is a

25 compound of Formula (II) wherein B is hydrogen and A is selected from Br, Cl, F, 1, C1-COalkyl, C3

Cscvcloalkyl, alkoxy, alkoxyalkyl wherein C1 -Cfalkyl, C-Cecycloalkyl, alkoxy, alkoxyalkyl are

optionally substituted with at least one substituent selected from OHI, NO,. CN, Br, Cl, F, I, C1

C6alkyl. and C-Cgcycloalkyl. In yet another embodiment both A and B are hydrogen. In a further

embodiment, both A and B are selected from Br Cl F, 1, C-Calkyl, C-Cscycloalkyl, alkoxy,

30 alkoxyalkyl wherein -C6alkyl, C2-Cscycloalkyl, alkoxy, alkoxyalkyl are optionally substituted

with at least one substituent selected from OH, NC),, CN, Br, C. F 1, C, C-alkyl, and C

Cevcloalkyi.

10015] In yet a further aspect is a compound selected from:

8

WO 2010/017055 PCT/US2009/051879

H ,'<NH H H

,ut;~ IN7.. N' '.N N.1 N',

N'N - NN 7- F'.'

H H N.' H HH

N N N N' \< .'

NN itN

NN N N 0--\ N '

Y N

N A N HN iN

HY H F .NH 7

H FH N 11'o'~ N N>

(N and N N

or a phaimaceuticallvy acceptable salt, solvate or prodina thereof

100-161 i yet another aspect is a compound selected from:

WO 2010/017055 PCT/US2009/051879

NHNH' H N NHN N

N N N N NN

N H

NH -N HN N H HN/N r NH N

N-N N i sA

0N N 0H

NN

HN N/N N H N N

HN NH HN OHNN \ <N N N

N N N -N N NN

NN

N /N an

IO F

H AN AN H HN HNN'

01

N N

H ~ N~ H N N -,N H

00 NN0

/N 0 N N

H NN HNHO H A N N- N < FO -N.N A

\~/ N O/NH/NN n

N H

01

WO 2010/017055 PCT/US2009/051879

H HN' O N- HN-N HN-N

NO

F N NH N -NH HNN. N"-~/Q

H/ F F

NN H F FH

O H H 0N

N HHH H

N H

N ( NN F- N - N O 'N N Nkr N Nt.-Nt><"

N\H H H' N H H

N HN

H H

/4 "'N

'- N N IT

NN NH

NH~n ---- ~ if ) i

NN N N10 H H H

H

HN - HN >i NH o4 H9

N' H

"Li ~NH H H H.

0 N, NN,~~ NN " N N>

N H p, f o prodrugthereo

N N'X -0 .. X'N "O[> ~ 'N V HC H I -N N, N >.' HH H

HH N N

i N N H

HNr NN N ' H ----

N N, N~ 7/ -N A H N 0

[00181 In yet a further embodiment is a compound selected from:

11

WO 2010/017055 PCT/US2009/051879

0. N N N

0 N NH Nz K N' \ ,S

.AN~ 0 H- z\ NN

HN '<N N, H NH 'H

HH

HNN- N H NJ

O NN . H N NH N

H N>N w-- ~

or phrmcetcll accptbl sat sovl r rduiiee 1001,91~~~~~~ Nn ye ute n~oieti0acnPLn eetdfon

(8S.9R,-5-luoo-9-I-iietiylIH-iH >azo-'>Ny> -8peil89dhdo2-[pio2

deptaNzD- )(7-i> /

(8k\.) k-NH -J /\ 1-yrdo4,,'

orea phar ainc ucah acc)-oeptbeslslae rp duhro

(SSR)- -fior--9( 1metyl-iH-m iazo -2l) 8-peny-89-diydo-2H-pyrid4,32

5 ephthalazina-3(7Jf1)-one,

(8SR,9R)-5 -fluoro-9-( I,-mnethyl-I 1,-imiaz - -) -8-phei-8 ,9-ihd:-2H-pyrio[43 2

dejjphthalazin-3 (711)-one.

(SSR,9R.)-5 -iiuoro-8-(4 -ietloope- }-9,- i ,-tyl H-impizi,-2,-i -8,- d. dr-2--pvridoj3,2

delphthalazin-3(7H)-one,

10 (8K 595)-5-fluioro-8-(4-fluorophenyf)-9-(I -methyl-I H- Im24idazo--yl) -8,9-dihydro-2-id43

pdohthalazir-3c]hhJ~z'- (7/1)-onel

(88.9)- 8(j-fuoroheny1)-9( 1-mthylI Itmidaoi-2yi) 8,9-dihydro-2ioH3,

pdk[hthalaz-in-3(7h-oneli-)7H)oie

(SR.9 S- 8(4-h orpheyl)9-(i-mehyli Hmidzo12- )-S9divr-Nprdli

WO 2010/017055 PCT/US2009/051879

(8S,9R)- 8-(4-fluorophenyl)-9-(1 -methyl-1211-1 ,2,4-triazol-5-yl) -8,9-dihvdro-2H-pyrido[4A,,2

dite phthalazin-3(7H)-one,

(8R,9S)- 8-(4-fluorophenyl)-9-1-methyl-lH- ;2,4-triazol yl) -8,9-dihydro-2H-pyrido[4,3,2

deiphthalazin-3(7H)-one,

5 (8S.9R)-8-(4-((dimethylamino )methvl)phenyl)-5-fl uoro-9-(I -methyl-1H- 1,2,4-triazol-S-yl)-89

dihydro-2 ipyrido[4,3 2-de]phthalazin-3(7H)-one, and

(8R,9S)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9~(I-methyl Il,2/4-triazoiS-yl)~8,9~

dihvdro-21-prido[4.,3;2-de]phthalazin-3(7I)-one,

or a pharmaceutically acceptable salt, solvate or prodrug thereof

10 100201 In another aspect is a. pharmaceutical composition comprising a compound of Formula (I)

and Formula (II) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or

pharmaceutically acceptable prodrug and a pharmaceutically acceptable carrier, excipient, binder or

diluent thereof.

100211 In one aspect is a method of inhibiting poly(ADP-ribose)polymerase (PARP) in a subject in

15 need of PARP inhibition comprising administering to the subject a therapeutically effective amount

of a compound of Formula (1) and Formula (II).

100221 In another aspect is a method of treating a disease ameliorated by the inhibition of PARP

comprising administering to a subject in need of treatment a therapeutically effective amount of a

compound of Formula (1) and Formula (i1).

20 100231 In one embodiment the disease is selected from the group consisting of: vascular disease;

septic shock: ischaemic injury; reperfusion injury; neurotoxicity; hemorrhagic shock; inflammatory

diseases; multiple sclerosis; secondary effects of diabetes: and acute treatment of cytoxicity

following cardiovascular surgery.

100241 In another aspect is a method of treating cancer, comprising administering to a subject in

25 need of treatment a therapeutically effective amount of a compound of Formula (I) and Formula (Ui)

in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination

thereof

[0025] In one embodiment the compound of Formula (1) and Formula (11) is administered

simultaneously with ionizing radiation, one or more chemotherapeutic agents, or a combination

30 thereof In another embodiment the compound of Formula (I) and Formula (11) is administered

sequentially with ionizing radiation, one or more chemotherapeutic agents. or a combination thereof.

100261 In yet another aspect is a method of treating a cancer deficient in Homologous

Recombination (HR) dependent DNA double strand break (DSB) repair pathway, comprising

administering to a subject in need of treatment a therapeutically effective amount of a compound of

35 Frnula (1) and Formula (11).

13

WO 2010/017055 PCT/US2009/051879

100271 In one embodiment the cancer comprises one or more cancer cells having a reduced or

abrogated ability to repair DNA DSB by HR relative to normal cells. In another embodiment the

cancer cells have a BRCA1 or BRCA2 deficient phenotype. In yet another embodiment the cancer

cells are deficient in BRCA 1 or BRCA2. In a further embodiment the subject is heterozygous for a

5 mutation in a gene encoding a component of the fIR dependent DNA DSB repair pathway. In yet a

further embodiment the subject is heterozygous for a mutation in BRCA1 and/or BRCA2. In one

embodiment the cancer is breast, ovarian, pancreatic or prostate cancer. In another embodiment the

treatment further comprises administration of ionizing radiation or a chemotherapeutic agent.

100281 In one aspect is the use of a compound of Formula (I) and Formula (I) in the formulation of

10 a medicament for the treatment of a poly(ADP-ribose)polymnerase mediated disease or condition.

10029! In another aspect is an article of manufacture, comprising packaging material, a compound

of Formula (I) and Formula (f1), and a label, wherein the compound is effective for modulating the

activity of the enzyme poly(ADP-ribose)polymerase, or for treatment, prevention or amelioration of

one or more symptoms of a poly(ADP-ribose)polynerase-dependent or poly(ADP

15 ribose)polymerase-mediated disease or condition, wherein the compound is packaged within the

packaging material, and wherein the label indicates that the compound, or pharmaceutically

acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,

pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, or a

pharmaceutical composition comprising such a compound is used for modulating the activity of

20 poly(ADP-ribose)polyrerase, or for treatment, prevention or amelioration of one or more symptoms

of a poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polynerase-mediated disease or

condition.

DETAILED DESCRIPTION OF THE INVENTION

100301 PARP' has an essential role in facilitating DNA repair, controlling RNA transcription,

25 mediating cell death., and regulating immune response. PARP inhibitors demonstrate efficacy in

numerous models of disease particularly in models of ischemia reperfusion injury, inflammatory

disease, degenerative diseases, protection from above adverse effects of cytotoxic compounds, and

potentiation of cytotoxic cancer therapy. They are efficacious in the prevention of ischemia

reperfusion injury in models of myocardial infarction, stoke, other neural trauma, organ

30 transplantation, as well as reperfusion of the eye, kidney, gut and skeletal muscle, Inhibitors are

efficacious in inflammatory diseases such as arthritis, gout. inflammatory bowel disease, CNS

inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock,

pulmonary fibrosis, and uveitis. PARP inhibitors also show benefit in several models of

degenerative disease including diabetes and Parkinson's disease. PARP inhibitors ameliorate the

35 liver toxicity following acetaminophen overdose cardiac and kidney toxicities from doxorubicin and

platinum based antineoplastic agents, as well as skin damage secondary to sulfur custards. in

14

WO 2010/017055 PCT/US2009/051879

various cancer models, PARP inhibitors are shown to potentiate radiation and chemotherapy by

increasing apoptosis of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging

the survival of tumor-bearing animals,

[00311 In certain embodiments are provided compounds of Formula (I)

R4

IA 0 N N

R N Z

5 R Rs

Formula (1)

or a therapeutically acceptable salt thereof wherein It R2. and R3 are each independently selected

from the group consisting of hydrogen, halogen, alkenyl, aikoxy, alkoxycarbonyl, alkyl, cycloalkyl,

alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NRARB, NRARi3alkylene,

10 and (NRAR)carbonvl;

RA and RB are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and

alkylkarbony or RA and R, taken together with the atom to which they are attached form a 3-10

mnembered heterocycle ring optionally having one to three heteroatoms or hetero functionalities

selected from the group consisting of -O- -Nl. -N(C-C-alkyl)-, -NCO(C3-C6-alkyl)-, -N(aryl)-,

15 N(aryl-C 1 C--alkyl-), -N(substituted-aryl-Cr--alkyl-)-, -N(heteroaryl)-. -N(heteroaryl-Q-C>,

alkyl-)-N(substituted-heteroaryl-C-C,-alkvl-)-, and -S- or S(O)q- , wherein q is i or 2 and the 3

10 membered heterocycle ring is optionally substituted with one or more substituents; R4 and 1(5 are

each independently selected from the group consisting of hydrogen, alky, cycloalkyl, alkoxyalkyl,

haloalkyl, hydroxyalkylene, and (NRARB)alkylene;

20 A and B are each independently selected from hydrogen, Br, Cl, F, 1, 011, C,-Calkyl, C3

Cgcycloalkyl, alkoxy, alkoxyalkyl wherein CrCalkyl, C;-Cgcycloalkyl, alkoxy, alkoxyalkyl are

optionally substituted with at least one substituent selected from OH, NO2. CN, Br, Cl, F, I, C

Calkyl, and C-Cscycloalkyl, wherein B is not OL;


25 a) an aryl group optionally substituted with 1, 2, or 3 substituents 1; R6 is selected from OH,

NO,. CN, Br, C1, F, I, C1-C6alkyl, C-CgRcycloalkyl, C2-Cgheterocycloalkyl; C-Ckjalkenyl,

alkoxy, alkoxyalkyl, alkoxycarbonyl alkoxycarbonylalkyl, C3-Qalkynyl. aryl, arylalkyl,

C-C cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl,

heteroarylalkoxy, heteroaryloxy, heteroarylthio heteroarylalkylthio, heterocycloalkoxy,

30 C-Cheterocvcloalkylthio, heterocyclooxy, heterocyclothio., NRARB, (NR5AR)C

Calkylene, (NRARf)carbonv, (NRAR)carbonvlalkylene, (NRARI)sulfonvl. and

(NRARs)sulfonylalkylene;

15

WO 2010/017055 PCT/US2009/051879

b) a heteroaryl group optionally substituted with 1, 2. or 3 substituents R(; L is previously as

defined;

c) a substituent independently selected frorn the group consisting of hydrogen, alkenyl, alkoxy.

alkoxyalkyl, alkoxycarbonyl. alkoxycarbonylalkyl., alkyl alkyli. arylalkyl, cycloalkyl,

5 cycloalkylalkyl, haloalkyl. hydroxy alkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl,

alkylcarbonyL, aryicarbonyl, heteroarylcarbonyl alkylsulfonyl arysulfonyl,

heteroarysulfonyl, (NRR)alkylene, (NRkRn)carbonyl, (NRARFI)carbonylalkylene,

(NRARn)sulfonyl, and (NRARB)sulfonylalkylene; or a pharmaceutically acceptable salt,

solvate or prodrug thereof,

10 [0032] In certain embodiments are provided compounds of Formula (I) or a therapeutically

acceptable salt thereof wherein R1, R2, R- are independently selected from a group consisting of

hydrogen, alkyl, and halogen; R4 is hydrogen and R is selected from the group consisting hydrogen,

alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxvalkylene, and (NRAR 5)alkylene; RA, and Ra are

independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl;

15 or RA and Rn taken together with the atom to which they are attached form a 3-10 membered

heterocycle ring optionally having one to three heteroatoms or hetero functionalities selected from

the group consisting of-O-, -Nil1 -N(C 1-C6-alkyl)-, -NCO(C-C-alky)-, -N(aryl), -N(aryl- C-C,

alkyl-)-, -N(substituted-aryl- Cj-C 6-alky6+ -N(heteroaryl)-, -N(heteroaryl- -C6,-alkyl-)-

N(subsittuted-heteroaryl- CI-C;-alky1-)-, and -S- or S(O)- , wherein q is I or 2 and the 3-10

20 niembered heterocycle ring is optionally substituted with one or more substituents; A and B are each

independently selected from hydrogen. Br, Cl. F. 1, OH, C-C 6alkyI. C-Ccycloalkyl, alkoxy,

alkoxyalkyl wherein C-C-alkyl. C-Cscycloalkyl. alkoxy, alkoxyalkyl are optionally substituted

with at least one substituent selected from OH, NO2. CN, Br, Cl F, L C-Cealkyl, and C

Cicycloalkyl, wherein B is not 01-1 Y and Z are each independently selected from the group

25 consisting of:

a) an aryl group optionally substituted with 1, 2, or 3 Re ; wherein each R, is selected from OL,

NO, CN_ Br, Cl, F 1, C1-C-alkyl, C-Ccycloalkyl, Q-CQheterocycloalkyl; C-&alkenyl,

alkoxy, alkoxyalkyl, alkoxycarbonyl. alkoxycarbonylalkyl, CCalkynyl, aryl, arylalkyl, C2

Cgcycloalkylalkyl, haloalkoxy, haloalkyl. hydroxyalkylene, oxo, heteroaryl,

30 heteroarylalkoxy, beteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, Cr

Cgheterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARn, (NR tRa)Cj-Csalkylene,

(NRkR1)carbonyl, (NRARk3)carbonylalkyiene, (NRARB)sulfonyL and

(NRAR)sulfonylalkyiene;

b) a heteroary] group optionally substituted with 1, 2, or 3 R6;

35 c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy,

alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl. alkyI, alkynyl, arylalky], cycloalkyl,

16

WO 2010/017055 PCT/US2009/051879

cycloalkylalkyl, haloalkyL hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl,

alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsuIfonyl,

heteroarylsulfony (NRARB)alkylene, (NRARa)carbonyl, (NRARlf)carbonylalkylene;

(NRAR)sulfonyl, and (NRkRe)sulfonylalkylene; or a pharmaceutically acceptable salt,

5 solvate or prodrug thereof

100331 In certain embodiments are provided compounds of Formula (I) or a therapeutically

acceptable salt thereof wherein R R2, and R are independently selected from a group consisting of

hydrogen, alkyl, and halogen; R and R, are hydrogen; RA and Ra are independently selected from

the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RAand RB taken together

10 with the atom to which they are attached form a 3-10 membered heterocycle ring optionally having

one to three heteroatons or hetero functionalities selected from the group consisting of -0 -N.

N(C,-Q-alkylv), -NCO(C1 Cr-alkyl)-,, -N(aryl) ~N(aryl-C-C-alky1-)-, -N(substituted-aryI-CC

alkyl-)-. -N(heteroaryl)-, -N(heteroaryl--C (alk6yt )-. -N(substituted-heteroaryl-Q-CralkyI ), and

-S- or S(O),- , wherein q is I or 2 and the .3-10 rnembered heterocycle ring is optionally substituted

15 with one or more substituents; A and B are each independently selected from hydrogen, Br, Cl, F, 1,

C!-Calkyl, C3-Cgcycloalkyl, alkoxy, alkoxyalkyl wherein C1-Cialkyl, C-Cqcycloalkyl. alkoxy.

alkoxyalkyl are optionally substituted with at least one substituent selected from 011, NO2. CN. Br,

Cl, F, , C,-Calkyl. and C-Cscycloalkyl; Y and Z are each independently selected from the group

consisting of:

20 a) an aryl group optionally substituted with 1,2, or 3 Re; wherein each R is selected from

014, NO2. CN, Br, Cl, F, 1, C,-Calkyl, C3-Cgcycloalkyl, C -Csheterocycloalkyl; C

COalkenyl, alkoxy, alkoxyalkyl. alkoxycarbonyl, alkoxycarbonylalkyl Cr-Qalkynyl, aryl,

arylalkyl, CC 8cycloalkylalkyl, haloalkoxy. haloalkyl, hydroxyalkylene, oxo. heteroaryl,

heteroaryldaikoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C

25 Cgheterocycloalkylthio, heterocyclooxy, heterocyclothio, NRAR, (NRRa)C-C 6alkylene,

(NRARif)carbony, (NRxR8)carbonylalkylene. (NR1\Rg )sulfonyl, and (NRsR)sulfonylalkylene;

b) a heteroaryl group optionally substituted with 1, 2, or 3 R;

c) a substituent independently selected from the group consisting of hydrogen. alkenyl, alkoxy, 30 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl,

cycloalkylalkyl. haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl heterocycloalkylalkyl,

alkycarbonyl arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,

heteroary1sulfonyl, (NRAR)alkylene, (NR R1)carbonyl, (NRARB)carbonylalkylene.

(NRAR 2)sulfonyl, and (NR 5)sulfonyhdkylene; or a pharmaceutically acceptable salt,

35 solvate or prodrug thereof

17

WO 2010/017055 PCT/US2009/051879

100341 In certain embodiments are provided compounds of Formula (1) or a therapeutically

acceptable salt thereof wherein R1. R,, R3. R, and R5 are hydrogen; R, and RI are independently

selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or RA and R[

taken together with the atom to which they are attached form a 3-10 nembered heterocycle ring

5 optionally having one to three heteroatoms or hetero functionalities selected from the group

consisting of -O-1NH -N(C -C6--alkyl)-, -NCO(Q-C 6-alkyl)-, -N(aryl)- -Nfaryl- CI-C 6-alkyl-)-,

N(substituted-aryl- C1-Cr.--alkyl-)-, -N(heteroaryl) -N(heteroaryl- C1-C6-alkyl-)-. -N(substituted

heteroaryl- C-alkyl-) and -S- or S(O)- . wherein q is I or 2 and the 3-10 membered

heterocycle ring is optionally substituted with one or more substituents; A and B are each

10 independently selected from hydrogen, Br, Cl, F, 1, OH, C a-Calkyl, C2-Cacycloalkyk, alkoxy,

alkoxyalkyl wherein C1 -Cjalkyl. C-Cacycloalkyt alkoxy, alkoxyalkyl are optionally substituted

with at least one substituent selected from OH, NO, CN, Br. Cl, F, 1, CCralkyl, and C,

Ccycloalkyl, wherein B is not OH; Y and Z are each independently selected from the group

consisting of:

15 a) an aryl group optionally substituted with 1, 2, or 3 1.; wherein each RK is selected front

OH NO, CN, Br. Cl, F, I, C-Qalkyl, C,-Ccycloalkyl, C-Cheterocycloalkyl; C

C6alkenyk - alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonxylalkyl, Cr-Coalkynyl, ary,.

arylalkyl, CrCgcycloalkylalky I, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl

heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C

20 Csheterocycloalkylthio heterocyclooxy, heterocyclothio, NRARB, (NR ARa)C-Qalkylene,

(NRA R)carbonyl, (NRARa)carbonyialkyiene, (NRAR)sulfonyl, and

(NRARS)sulfonyalkylene;

b) a heteroaryl group optionally substituted with 1 2, or 3 R;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy,

25 alkoxy-alkyl, alkoxycarbonyl, aikoxycarbonylalkyl. alkyl, alkynyl, arylalkyl, cycloalkyl,

cycloalky lalkyl haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl,

alkylearbonyl, arylcarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,

heteroarylsulfonyl. (NRAR )alkylene, (N RAR)carbonyl, (NRARBs)carbonylalkylene,

(NRARS)sulfonyl, and (NRA4(a)sulfonylalkvlene; or a pharmaceutically acceptable salt,

30 solvate or prodrug thereof.

100351 In one embodiment is a compound of Formula (I) wherein R1, R.-, are each independently

selected from a group consisting of hydrogen. alkyl, and halogen: R4 is hydrogen and Rr is selected

from the group consisting hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and

(NRARB)alkylene; and isomers, salts, solvates, chemically protected forms, and prodrugs thereof.

Is

WO 2010/017055 PCT/US2009/051879

[00361 i another embodiment is a compound of Formula (I) wherein R1, R2 R, are each

independently selected from a group consisting of hydrogen, alkyl, and halogen; R4 and R are

hydrogen; and isomers, salts, solvates, chemically protected forms, and prodrugs thereof.

10037) In a further embodiment is a compound of Formula (I) wherein R, R2, R3, R, are each

5 hydrogen and R, is alkyl.

100381 In yet another embodiment is a compound of Formula (1) wherein R; R ,, R. R are each

hydrogen; and Rs is methyl.

[00391 In one embodiment is a compound of Formula (I) wherein R , R) and R, are each hydrogen.

100401 In another embodiment is a compound of Formula (1) wherein Y and 7 are each

10 independently selected from the group consisting of:

a) a phenyl group optionally substituted with 1, 2, or 3 R6

b) a pyridyl group optionally substituted with 1, 2, or 3 R% and

c) a substituent independently selected from the group consisting of hydrogen,

alkoxyalkyl, alkoxycarbonylalkyl, alkyl, arylalkyl, cycloalkytI cycloalkylalkyl,

15 haloalkyl, oxo, heterocycloalkyl, heterocycloalkylalkyl. alkylcarbonyl, arylcarbonyl,

heteroar'lcarbonyl, (NRAR)alkylene, (N'RARB)carbonyl, and

(NRaRn)carbonylalkylene.

10041] In a further embodiment is a compound of Formula (1) wherein Y and Z are each

independently selected from the group consisting of

20 a) a phenyl group optionally substituted with 1, 2, or 3 R

b) a imidazole group optionally substituted with 1, 2, or 3 Ra; and

c) a substituent independently selected from the group consisting of hydrogen,

alkoxyvalkylt alkoxycarbonylalkyl, alkyL ary'lalkyl, cycloalkyl, cycloalkylalkyl,

haloalkyL oxo, heterocycloalkyl, heterocycloalkylaikyL alkylcarbonyl,

25 arylcarbonyl, heteroarylcarbonyl, (NRARR)alkylene (NRAR)carbonyi, and

(NRAR 1 )carbonylalkylene.

[00421 hi a further embodiment is a compound of Formula (f) wherein Y and Z are each


d) a phenyl group optionally substituted with 1. 2, or 3 1(,

30 e) a triazole group optionally substituted with 1, 2, or 3 16; and

f) a substituent independently selected from the group consisting of hydrogen,

alkoxyalkv, alkoxycarbonylalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl,

haloalkyl, oxo, heterocycloalky!. hetercycloalkylalkyl, alkylcarbonyl,

arvlcarbonyli heteroarycarbonyl, (NR A1)alkylene (NR ARL)carbonyl, and

35 (NRARB)carbonylalkylene.

19

WO 2010/017055 PCT/US2009/051879

100431 In one embodiment is a compound of Formula (I) wherein R5 is hydrogen or an alkyl group.

In another embodiment, R, is hydrogen. In a further embodiment, R5 is C-C alkyl. In yet a further

embodiment, R is CH;. In another embodiment, Rj is CH 2CHJ3.

100441 In another embodiment is a compound of Formula (I) wherein R4 is hydrogen or an alkyl

5 group. In yet another embodiment, 1t is hydrogen.

100451 In one embodiment, R. is selected from the group consisting of hydrogen, halogen, alkenyl,

alkoxy, alkoxycarbonyl alkyl. cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl,

hydroxyalkylene, nitro, NRARS, NRARralkylene, and (NR AR)carbonyl. In a further embodiment

R is a halogen selected from F, Cl, Br, and In yet a further embodiment, RI is fluorine. In one

10 embodiment, R- is hydrogen,

100461 In another embodiment, R is selected from the group consisting of hydrogen, halogen,

alkenylt alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl,

hydroxyalkylene, nitro, NRR 2 , NRARjalkylene, and (NRAR)carbony L In a further embodiment,

Rt is hydrogen. In some embodiments, R, is selected from the group consisting of hydrogen,

15 halogen, alkenyl, alkoxy. alkoxycarbonyl, alkyl, cycloalkyl. alkynyl, cyano, haloalkoxy haloalkyl.

hydroxyl, hydroxyalkylene, nitro, NRARB. NRARnalkylene, and (NRARa)carbonyl. In a further

embodiment, R, is hydrogen.

100471 Also disclosed herein are compounds of Formula (f) wherein Z is an aryl group optionally

stbsthuted with v 2 or 3 Rt; wherein each Ra is selected from ORH, N02 CN, Br, Cl, F, 1, Cj

20 Calkyl, Cr-Cecycloalkyl, C-Csheterocycloalkyl; C Coalkenyl. alkoxy, alkoxyalkyl,

alkoxycarbonyl, alkoxycarbonylalkyl, CrC alkynyl, aryl arylalkyl, C3-Ccycloalkylalkyl,

haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryk heteroarylalkoxy, heteroaryloxv,

heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C2 -C8heterocycloalkylthio heterocyclooxy,

heterocyclothio, NRARB, (NRARB)CCalkvlene. (NRAR.B)carbonyl, (NRA R)carbonylalkvlene.

25 (NRARa)sufonyil, and (NRAR3)sulfonylalkylene. In one embodiment is a compound of Formula (i)

wherein Z is an optionally substituted phenyl group. In one embodiment, Z is a phenyl group. In

another embodiment, the phenyl group is optionally substituted with at least one R selected from

OH, NO,, CN. Br, Cl, F, I, C1 Calkyl C3-Cgcycloalkyl, C-Csheterocycoalkyi; C-C 6alkenylv

alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C-Ckalkyny1, aryl, arylalkyl, C

30 Cgcycloalkylalkyl, haloalkoxy, haloalkyl. hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxv,

heteroaryloxy, heteroarylthio. heteroarylalkylthio. heterocycloalkoxy, G-C 8heterocycloalkylthio,

heterocyclooxy, heterocyclothio. NR\Rp, (NR, R5)C[-Calkylene, (NRARB)carbonv,

(NRARB)carbonylalkylene, (NRARa)sulfonyl, and (NRARs)sulfonylalkylene. In another

embodiment, Rs is (NRARB)alkylene, In a further embodiment. R6 is CH(NRAR ). In a further

35 embodiment, R is CI-(NRARj) wherein NRAR3 is azetidine, pyrrolidine, piperidine or morpholine.

In yet a further embodiment, R, is H1 or alkyl. In another embodiment, RA is C1 C-alky. In yet

20

WO 2010/017055 PCT/US2009/051879

another embodiment RA is Cit. In another embodiment, R, is H or alkyl. In one embodiment, Ri

is QCCalkyl. In yet another embodiment RB is CH3 . In a further embodiment, Ri is CH2NHCFI.

In yet a further embodiment R6 is CIENCH3CH-L. In one embodiment, R6 is

(C=O)heterocycloalkyI(C=O)alkyl. In one embodiment R is (C=0)heterocycloalkyl(C'=O)alkyl

5 wherein the heterocycloalkyl group has at least one heteroatom selected from 0; N, and S. In

another embodiment, the heterocycloalkyl group has two N atoms. In a further embodiment, R6 is

(C>O)heterocycloalkyi(C=0)alkyi wherein alkyl is selected from methyl, ethyl, n-propyl, iso

propyl, cyclopropyl, n-butyl, iso-butyl, and t-butyl. In one embodiment, the alkyl group is

cyclopropyl. In another embodiment, the alkyl group is iso-propyL In one embodiment, R6 is

N N

10 0 . In another embodiment, R is 0

10048] Presented herein are compounds of Formula (1) wherein Z is an optionally substituted

heteroary l group. In one embodiment, the heteroaryl group is selected from pyridine, pyrimidine.

pyrazine, pyrazole, oxazole, thiazole, isoxazole, isothiazole. 1,3,4 ---oxadiazole, pyridazine. 1,3.5

trazine, I.2,4-triazine, quinoxaline, benzimidazole, benzotriazole. purine, IlH-[ ,2,3]triazolo[4,5

15 dlpyrimidine, triazole, imidazole. thiophene, furan. isobenzofuran, pyrrole, indolizine, isoindole,

indole, indazole, isoquinoline, quinoline. phthalazine, naphthyridine, quinazoline, cinnoline, and

pteridine. In one embodiment. Z is pyridine. In another embodiment, Z is optionally substituted

pyridine.

[0049] Also disclosed herein are compounds of Formula (I) wherein Y is an aryl group optionally 20 substituted with 1, 2. or 3 R6 ; wherein each R, is selected from OH, NO,, CN. Br, CL. F, I C

C6alkyl, C-Cscycloalkyi, C2-Csheterocycloalkyl; CA'Galkenvl. alkoxy, alkoxyalkyl.

alkoxycarbonyl. alkoxycarbonylalkyl C2 Calkynyl, aryl, arylalkyl, C3 Cacycloalkylalkyl,

haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, beteroaryloxy,

heteroarvlthio. heteroarylalkylthio, heterocycloalkoxy, Cr-Csheterocycloalkylthio, heterocyclooxy;

25 heterocyclothio, NRARa, (NRARB )C-Cfalkylene, (NRAR)carbonv (NRAR)carbonlialkylene,

(NRAR)sulfonyl, and (NR4R 8)sulfonylaIkylene, In one embodiment is a compound of Formula (I) wherein Y is an optionally substituted phenyl group. In one embodiment, Y is a phenvl group. In

another embodiment, the phenyl group is optionally substituted with at least one R selected from

OH, NO-, CN, Br, Cl, F, 1, C1-C6alkyl, C-Cecycloalkvl C2-Csheterocycloalkyl; C-C 6alkenyl, 30 alkoxy, alkoxyalkyl alkoxyearbonyl. alkoxycarbonylalkyl, C-Cealkynvl. aryl. arylalkyl, C;

Cscycloalkylalkvl, haloalkoxy, haloalky, hydroxyalkylene, oxo, heteroary, heteroarylalkoxy,

heteroaryloxy, heteroarylthio. heteroarylalkylthio, heterocycloalkoxy C-C 8heterocycloalkylthio,

heterocyclooxy, heterocyclothio, NRARB, (NRARP,)C-Qalkylene. (NRAR8 )carbonvl,

21

WO 2010/017055 PCT/US2009/051879

(NRARa)carbonylalkylene, (NRARu)si fonyl, and (NRARR)sulfonylalkylene. In a further

embodiment, R6 is CH(NRR3). In yet a further embodiment, RA is 1-I or alkyl, In another

embodiment, RA is Cj-%alkvt In yet another embodiment. R is CI In another embodiment, R8

is H or alkyl. In one embodiment R8 is C-C(a1kvl. In yet another embodiment, R3 is Cit In a

-S further embodiment I, is CHtNHCHIt In yet a further embodiment, R6 is CHZNCH 3CH;. In one

embodiment, R6 is (C=O)heterocycloalkvl(C=O)aiky. In one embodiment R is

(C=O)heterocycloakyl(C=0)alkyl wherein the heterocycloalkyl group has at least one heteroatom

selected from 0, N, and S, In another embodiment, the heterocycloalkyl group has two N atoms. In

a further embodiment, R, is (C=0)heterocycloalkyl(C=0)alkvl wherein alkyl is selected from

10 methyl, ethyl, n-propyl, iso-propyl. cyclopropyl, n-butyl, iso-butyl, and t-butyl. In one embodiment,

the alkyl group is cyclopropyl. In another embodiment, the alkyl group is iso-propyl. In one

N N r NN

embodiment, R is 0 , In another embodiment, R6 is 0

100501 Presented herein are compounds of Formula (1) wherein Y is an optionally substituted

heteroaryl group. In one embodiment, the heteroaryl group is selected from pyridine, pyrimidine,

15 pyrazine, pyrazole, oxazole, thiazole, isoxazole, isothiazole, I.3.4 -oxadiazole, pyridazine, 1,3,5trazine, 1,2,4-triazine, quinoxaline, benzimidazole, benzotriazole, purine, 1Ht-f I,2,3Jtriazolo[4,5

d]pyrimidine, triazole, imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine, isoindole,

indole. indazole, isoquinoline, quinoline, phthalazine, naphithyridine, quinazoline, cinnoline, and

pteridine. In one embodiment, Y is pyridine. in another embodiment, Y is optionally substituted

20 pyridine. In one embodiment, Y is imidazole, In another embodiment, Y is optionally substituted

imidazole. in one embodiment, Y is triazole. In another embodiment, Y is optionally substituted

triazole.

[00511 In one embodiment, Y is a substituent independently selected from the group consisting of

hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl,

25 arvlalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl,

heterocycloalkylalkyl alkylcarbonyl, arylcarbony, heteroarylearbonyl alky lsulfonyl, arylsulfonVI, heteroarylsulfonyl, (NRARB)alkylene,(NRARS)carbony, (NRARS)carbonylalkylene.

(NRsR.)sulfonyi, and (NRAR)sulfonylalkylene, In one embodiment, Y is alkyl. In another

erbodinient, Y is C1-C alkyl. In a further embodiment, Y is selected from methyl, ethyl, n-propyl

30 iso-propy, n-butyl, iso-butyl or tert-butyl. In another embodiment, Y is iso-propyl.

100521 Also disclosed herein are compounds of Formula (1) wherein Y is an optionally substituted

heterocycloalkyl group. In one embodiment, the heterocycloalkyl group is selected from

pyrrolidinvl, tetrabydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl.

22

WO 2010/017055 PCT/US2009/051879

dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino., thioxanyl,

piperazinyl, azetidinyl, oxetanyl, thietanyl, honopiperidinytl oxepanyl, thiepanyl, oxazepinyl,

diazepinvi, thiazepiny I 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 211

pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanvl. yrazolinl, dithianyl. dithiolanyl, dihydropyranyl, 5 dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazoliny , imidazolidinyl, 3

azabievyclo[3 1.0]hexanvl, 3-azabicyclo[4.1.0]heptanyl, 3H ndolyi and quinoliziny L In another

embodiment the heterocycloalkyl group is selected rom pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyL 1,3-oxathiolany, indolinyl,

isoindolinyl, morpholinyl, and pyrazolinylt In another embodiment, the heterocycloalkyl group is

tO piperidiny.

100531 In another aspect is a compound of Formula (IA):

R,

C) N,.

RI A

R N AR~

Formula (IA)

or a therapeutically acceptable salt, solvate or prodrug thereof wherein R, R-2, and R3 are each

15 independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl. cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, untro, NRARp, NRARealkylene, and (NRARL)carbonyl; RA. and R31 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and

alkylcarbonyl; or RA and RB taken together with the atom to which they are attached form a 3-10 20 membered heterocycle ring optionally having one to three heteroatoms or hetero fimctionalities

selected from the group consisting of-O-, -NH, -N(C-C 6C-alkvl)-, -NCO(Cj-C,--alkyl),N(aryi), N(ary-C-C 0-alIkvl-)-, -N(substituted-aryl-C C6-alkyl )-, -N(heteroaryl)-, -N(heteroaryl-C-Calkyl-)-, -N(substituted-heteroatyl-C-C,-alkyi-)-, and ---S- or S(O) wherein q is I or 2 and the 310 membered heterocycle ring is optionally substituted with one or more substituents; K, and R5 are

25 each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRAR13)alkylene;

A and B are each independently selected from hydrogen,. Br, C1, F, 1, 011, CI-Calkyl, Cr Cscycloalkyf, alkoxy, alkoxyalkyl wherein C,-Qalkyl, C3-Cxcycloalkyl, alkoxy. alkoxyalkyl are optionally substituted with at least one substituent selected from O-, NO>, CN, Br, CL, F, I, Ci

30 Cfalkyl and Q-Cscycloalkyl, wherein B is not OH;

Y is selected from the group consisting of:

23

WO 2010/017055 PCT/US2009/051879

a) an aryl group optionally substituted with 1, 2, or 3 substituents R; R( is selected from OH.

NO> CN, Br, CL. PR L, CP-Cbalkyl, CriCgcycloalkyl, CpCsheterocycloalkyl; C-Calkenvl,

alkoxy, alkoxyalkyl, akoxycarbonyl, alkoxycarbonylalkyl, C-Cjalkynyl, aryl, arylalkyl, C,

Cacycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl,

5 beteroarylalkoxy, heteroaryloxy, heteroarydthio. heteroarylalkylthio, heterocycloalkoxy, Cr

Cgheterocycloalkylthio, heterocyclooxy, heterocyclothio. NRARB, (NR AR8 )Cj -Calky lene,

(NRARB)carbonyl. (NRARE)earbony lalkylene., (NRR)sulfonyl, and

(NRARj)sulfonylalkylene;

b) a heteroaryl group optionally substituted with 1, 2, or 3 substituents 1%; R6 is selected

t0 independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl.

alkoxycarbonylalkyl, alkyl. alkynyl. aryl, arylalkyl, cycloalkyl, cycloalkylalkyli cyano,

haloalkoxy, haloalkyl, halogen, hydroxyl., hydroxyalkylene, nitro, oxo, heteroaryl.

heteroarylalkoxy, heteroaryloxy. heteroarylthio. heteroarylalkylthio, heterocycloalkyl,

heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocelothio, NRARB.

t5 (NRARJ)alkylene, (NRARj)carbonyl, (NRAR)carbonylalkylene, (NRAR )sulfonv. and

(NRAZ -sulfonylalkylene;

c) a substituent independently selected from the group consisting of hydrogen., alkenyl, alkoxy,

alkoxyalkyl, alkoxycarbonyl. alkoxycarbonylalkyl, alkyl, alkynyl arylalkyl cycloalky,

cycloalkylalkyl, haloalkyl. hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl,

20 alkylcarbonyl, arvicarbonyl, heteroarylcarbonyl alkylsulfonyl, arylsulfonyl,

heteroarylsulfonyl, (NR5 Rs)alkylene, (NR.,R,)carbonyl, (NRAR)carbonylalkylene,

(NRAR3)sulfonyl, and (NRaRn)sulfonvlalkylene; and

n is an integer from 0-4: or a pharmaceutically acceptable salt, solvate or prodrug thereof.

100541 In another embodiment is a compound of Formula (IA) having the structure:

14 R4

A N R, RY

B B R N

25 R rN R3 R

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

100551 In one embodiment is a compound of Formula (IA) wherein Y is an aryl group. In another

embodiment, Y is a heteroaryl group. In a further embodiment, the aryl group is a phenyl group. in

yet a further embodiment is a compound of Formula (IA) wherein the phenyl group is substituted

30 with at least one R . In yet another embodiment the phenyl group is substituted with at least one R,

selected from Br. Cl, F, or . In one embodiment K is F In one embodiment is a compound of

Formula (IA) wherein the phenyl group is substituted with at least one R6 selected from (NRARB)C

24

WO 2010/017055 PCT/US2009/051879

Cealkylene. (NRARn)carbonyI, (NRARB)carbonyilalkyl ene, (NRRn)sulfonyl, and

(NRAR)suifonylalkylene. In one embodiment R, is (NRAR)CrCalkvlene. In another

embodiment C-Calkylene is selected from methylene; ethylene, n-propylene, iso-propylene n

butylene, iso-butylene, and tert-butylene. In yet another embodiment C1-Calkylene is methylene.

5 In yet a further embodiment RA and R, are each independently hydrogen, C-Calkyl, or Cr

Cscycloalkyl. In one embodiment C-Calkyl is selected from methyl, ethyl, n-propyl, iso-propyl n

butyl, iso-butyl, and tert-butyl. In one embodiment C1-C6alkyl is methyl. In another embodinent

C-Calkyl is ethyl. In one embodiment is a compound of Formula (IA) wherein C-Ccycloalkyl is

cyclopropyl, cyclobutyL cyclopentyl, and cyclohexyL In a further embodiment CrCecvcloalkyl is

1o cyclopropyl, In one embodiment is a compound of Fornula (IA) wherein R is hydroxyalkvlene, In

one embodiment hydroxyalkylene is selected from CH2OH, CH12CHO, CH2CH 2CH2OH, CH(OH)CIFL, CH(OH)CHtCHL, CI±CH(OH)Ctt. and CICH2CItCHOHI. In another

embodiment R and R1 taken together with the nitrogen to which they are attached form a 6

membered heterocycle ring having I heteroatom or hetero functionality selected from the group

15 consisting of -O-, -NH, or -N(Q-C 6alkyl), In yet another embodiment the hetero functionality is

N(C-Calkyli) In a further embodiment C1-Cgalkyl is selected from methyl, ethyl, n-propyL iso

propyL n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C-C 6alkyl is methyl

100561 In one embodiment is a compound of Formula (IA) wherein Y is a heteroaryl group

optionally substituted with at least one R,. in another embodiment the heteroaryl group is selected

20 from furan, pyridine, pyrimidine, pyrazine, imidazole. thiazole, isothiazole, pyrazole, triazole,

pyrrole, thiophene, oxazole; isoxazole, I ,2,4-oxadiazole, I,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene, benzoimidazole, benzofuran., pyridazine, 1,3,5-triazine, thienothiophene, quinoxaline, quinoline, and isoquinoline. In yet another embodiment the heteroaryl group is

imidazole. In a further embodiment imidazole is substituted with C-C 6alkyl selected from methyl, 25 ethyl, n-propyl iso-propyl n-butyl iso-butyl, and tert-butyl. In yet a further embodiment C1

Calkyl is methyl. In one embodiment the heteroaryl group is furan. In another embodiment the

heteroaryl group is thiazole. In yet another embodiment the heteroaryl group is 1 3,4-oxadiazole. In a further embodiment heteroaryl group is substituted with C-CSalkyl selected from methyl, ethyl, npropyl, iso-propyl, n-butyl iso-butyl, and tert-buty] In yet a further embodiment C-Cfalkyl is

30 methyl.

100571 In one embodiment is a. compound of Formula (IA) wherein A and B are each independently selected from hydrogen, Br, ClF, 1, OH, C-Cjalkyl, C;-Cgcycloalk,, alkoxy., alkoxyalkyl wherein C -Calkyl, C-Cscycloalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one

substituent selected from OH, NO9. CN, Br; Cl, F, 1, C-CfalkyL and C-'Cgcvcloalkyl and B is not 35 OH.

100581 In yet another embodiment is a compound selected from:

25

WO 2010/017055 PCT/US2009/051879

NH <OH H N 1 HN H H HkN> N' ;0N , <N,

0 N N N > y 1 NMNNM~ .~ N 0

HX H NH Ni N

N

,.NrNN, A>, N H NN'

H NCN H CN 0 H 0 N H. N

Nq NNYN N

H .JN HH N'N

ANMW W N NOH

H H '1 0,N H NMAN

HN N H NNCMH XNN

N N,0Ai

,H F HN4MNN

HH K> H LV 0,,-,N, ~ N NX N H ,A

NN

O~N N,~ N0N N *A N< - H N H Nad~

F., N NNH

H~ HZ N'x% r NN

Y NN 0,

-NH H

or a pharmaceutically acceptable salt, solvate or prodmig thereof

100591 In one embodiment is a. compound of Formula (1) wherein Y is a heteroaryl group selected

from furan, pyridine, pyrimidine, pyrazi ne, imidazole, thiazole, isothiazole, pyrazole, triazole.

26

WO 2010/017055 PCT/US2009/051879

pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazoe, 1.3,4-oxadiazole, 1,2,4-triazine, indole,

benzothiophene, benzoimidazole. benzofuran, pyridazine, 13, 5triazine, thienothiophene,

quinoxaline, quinoline, and isoquinoline, In another embodiment, Y is an imidazole group. In yet

another embodiment, the nidazole group is substituted with a C1-C(alkvl group. In another

5 embodiment, the CC alkyl group is methyl. ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert

butyl. In a further embodiment CvC(alkyl is methyl. In another embodiment is a compound of

Formula (I) wherein Y is a substituted imidazole group and Z is selected from an aryl group or a

heteroaryl group. in a further embodiment, Z is an aryl group, In yet a further embodiment, the aryl

group is a phenyl group, In yet a further embodiment, the ard group is a phenyl group substituted by

10 a halogen. In yet a further embodiment Z is a heteroaryl group. In another embodiment, the

heteroaryl group is furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole,

triazole, pyrrole, thiophene, oxazole, isoxazole; 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine,

indole, benzoth iophene, benzoiimidazole. benzofuran, pyridazine, I ,3,5-triazine thienothiophene.

quinoxaline, quinoline, and isoquinoline. fn a further embodiment, the heteroaryl group is

15 imidazole. In another embodiment, the imidazole group is substituted with a C Calkvl group. In

another embodiment, the C1-C6alkyl group is methyl, ethyl. n-propyl, iso-propyl, n-butyf, iso-butyl,

and tert-butyi In a further embodiment QCalkyl is methyl

100601 In another embodiment is a compound of Formula (I) wherein Y is a triazole group. In yet

another embodiment, the triazole group is substituted with a C-Cealkyl group. In another

20 embodiment, the C-Calkyl group is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert

butyL In a further embodiment C1-Calkvl is methyl. In another embodiment is a compound of

Formula (1) wherein Y is a substituted triazole group and Z is selected from an aryl group or a

heteroaryl group. In a further embodiment, Z is an aryl group. In yet a further embodiment, the aryl

group is a phenyl group. In yet a further embodiment, the aryl group is a phenyl group substituted by

25 a halogen. In yet a further embodiment Z is a heteroaryl group. In another embodiment, the

heteroaryl group is furan, pyridine, pyrimidine, pyrazine, inidazole, thiazole, isothiazole pyrazole,

triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2.4-oxadiazole, 1,3,4-oxadiazole, 1,2.4-triazine,

indole, benzothiophene, benzoirnidazole, benzofuran, pyridazine, 1.3,5-triazine, thienothiophene,

quinoxaline, quinoline, and isoquinoline. In a further embodiment, the heteroaryl group is triazole.

30 In another embodiment, the triazole group is substituted with a CG-Cealkyl group In another

embodiment, the C-Cfbalkyl group is methyl, ethyl, n-propvl, iso-propyl, n-butyl, iso-butyl, and tert

butyl. In a further embodiment C-Calkyl is methyl.

27

WO 2010/017055 PCT/US2009/051879

100611 In another embodiment is a compound selected

I H N

or NN N

N N N N N N N 0

from H H or a pharmaceutically

acceptable salt, solvate or prodrug thereof,

100621 In one aspect is a compound of Formula (1I):

O N A

B N NZ

R2 H

Formula (II);

wherein:

Y is an aryl or heteroaryl group optionally substituted with at least one R6;

Z is an aryl group optionally substituted with at least one R6;

10 R6 is selected from OHd, NO 2, CN, Br. Cl, F,1, C-C-alkyl, C-Cgcycloalkyl, C7C 8heterocycloalkyl;

C-Coalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl alkoxycarbonvlalkyl, C-Calkvnyl, aryt, arylalkyl, C's-Ccycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl,

heteroarylalkoxy, heteroaryloxy, heteroarylthio, hetcroarylalkylthio, heterocycloalkoxy., C

Csheterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARn, (NRARB)C-Cfalkylene,

15 (NRAR,)carbonyl, (NRAR)carbonylalkylene, (NRARB)sulfonvl. and (NRxRs)sulfonvlalkylene;

R. is selected from hydrogen Br, Cl, , or F;

A aid B are each independently selected from hydrogen, Br, Cl, F, L OH, Cj-Cealkyl, C3

Cscycloalkyl, alkoxy, alkoxyalkyl wherein C-C-alkyl, C3-Ccycloalkyl, alkoxy, alkoxyalkyl are

optionally substituted with at least one substituent selected from OH, N0. CN Br, Cl, F, 1, Cj20 C6alkyL and C3-C9cVcioalkyl, wherein B is not OH

RA and R5 are independently selected from the group consisting of hydrogen, C1-Qalkyl., C;Cecycloalkyi. and alklcarbonyl; or RA and RBj taken together with the atom to which they are

attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or

hetero functionalities selected from the group consisting of -O~, -NH, -N(C1-C6alkyl)-, -NCO(C25 Calkyl)-, -NCO(C-C4cycloalkyl)- -N(arl)-, -N(aryl-CrC-alkvl, -N(su bstituted-aryl-C -Coalkvl

)-, -N(heteroaryl)-, -N(heteroaryl-C-C 6alkyl), - N(substituted-heteroaryl-C 1-Coalkyl-)-., and -S- or

28

WO 2010/017055 PCT/US2009/051879

S(O),, wherein q is I or 2 and the 3-10 membered heterocycle ring is optionally substituted with

one or more substituents; or a pharnaceutically acceptable salt, solvate or prodrug thereof.

100631 In one embodiment is a compound of Formula (11) wherein Y is an aryl group. In another

embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group is

5 substituted with at least one R6 selected from Br. Cl, F. or 1. In one embodiment R6 is F. In one

embodiment the phenyl group is substituted with at least one R6 selected from (NRAR)C+

Calkylene, (NRAR)carbonyl, (NRARB)carbonylalkylene, (NRAR)sulfonyl, and

(NRARB)sulfonylalkylene. In one embodiment R( is (NRAR)CI-Cfalkylene. In another

embodiment C-C-alkylene is selected from methylene, ethylene n-propylene, iso-propylene, n

10 butvlene. iso-butylene, and tert-butylene. In yet another embodiment C -Calkylene is methylene.

In yet a. further embodiment RA and RB are each independently hydrogen, C CalkyI or C3

CscycloalkyL In one embodiment C-Calkyl is selected from. methyl, ethyl, n-propyl, iso-propyl, n

butyl, iso-butyl, and tert-butyl. In one embodiment C1-Cfalkyl is methyl. In another embodiment

C1 Calkyl is ethyl, In yet another embodiment C%-Cqcycloalkyl is cyclopropyl cyclobutyl,

15 cyclopentyl. and cyclohexyl In a further embodiment C-Cacycloalkyl is cyclopropyl. In yet a

further embodiment R. is hydroxyalkylene. In one embodiment hydroxyalkylene is selected from

CIH2OH, CH11201 O CHICHCHC)F CH(OH)Cl, CIOlI)CIlCI CI-2CH(OH)CH, and

CIl 2CH 2CH CIOH In another embodiment RA and Ra taken together with the nitrogen to which

they are attached form a 6 membered heterocycle ring having I heteroatom or hetero functionality

20 selected from the group consisting of -0-, -Ni, or -N(CI-C 6alkyl). In yet another embodiment the

hetero functionality is ---N(C1 -C6aikyl). It a further embodiment C1-C6alkyl is selected from methyl,

ethyl, n-propyl, iso-propyl, n-butyl. iso-burtl, and tert-butyl In yet a further embodiment C:

Calkyl is methyl.

[00641 In one embodiment is a compound of Formula (II) wherein Y is a heteroaryl group

25 optionally substituted with at least one R(. In another embodiment the heteroaryl group is selected

from furan., pyridine, pyrimid ine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, triazole,

pyrrole, thiophene. oxazole, isoxazole, 1,2,4-oxadiazole. 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene., benzoimidazole, benzofuran. pyridazine, 1,35triazine, thienothiophene, quinoxaline, quinoline, and isoquinoline. In yet another embodiment the heteroaryl group is

30 imidazole. In a further embodiment imidazole is substituted with C-C 6alkyl selected from methyl,

ethyl, n-propyl. iso-propylI n-butvl, iso-butyl, and tert-butyl. In yet a further embodiment C

Calkyl is methyl. In one embodiment the heteroaryl group is furan. In another embodiment the

heteroaryl group is thiazole, in yet another embodiment the heteroaryl group is 1,3.4-oxadiazole. lIt a further embodiment heteroaryl group is substituted with C1-Cailkyl selected from methyl. ethyl, n

35 propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment Cj-C 6alkyl is

methyl.

29

WO 2010/017055 PCT/US2009/051879

100651 In one embodiment is a compound of Formula (II) wherein Z is an aryl group. In another

embodiment the aryl group is a phenyl group. In yet another embodiment the phenyl group is

substituted with at least one R6 selected from Br, Cl, F, or . In a further embodiment R is F. In yet

a further embodiment R is CL In one embodiment the phenyl group is substituted with at least one

5 Re selected from (NRARB)CI-Csalkylene, (NRRa)carbonvL (NRARS)carbonylalkylene,

(NRkRa)sulfonyl, and (NR Ra)sulfonylalkylene. In another embodiment 1k is (NRARB)Cv

Csalkylene. In yet another embodiment C1 Calkylene is selected from methylene, ethylene, n

propylene, iso-propylene, n-butylene. iso-butylene, and tert-butylene. In yet a further embodiment

CL-Calkylene is methylene. In a further embodiment RA and R1 are each independently hydrogen,

10 C1-Calkvl, or C3-CcycloalkyL In one embodiment C:-Calkyl is selected from methyl, ethyl. n

propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyJ. In another embodiment C-C 6alkyl is methyl.

In vet another embodiment Re and Rn taken together with the nitrogen to which they are attached

form a 6 membered heterocycle ring having I heteroatom or hetero functionality selected from the

group consisting of O- -NH. or -N(CI -COalkyl In a further embodiment the hetero functionality

15 is ---N(C;C-alkyl). In one embodiment C1 -Cbalkvl is selected from methyl, ethyl, n-propyl. iso

propyl n-butyl, iso-butyl, and tert-butyl. In yet a further embodiment C-Coalkyl is methyl. In a

further embodiment, Re is CH42(NRARR) wherein NR, ,R is azetidine, pyrrOlidine, piperidine or

morpholine. In another embodiment R2 is hydrogen. In yet another embodiment R2 is selected

from F, CL Br, and 1. In a further embodiment R) is F.

20 100661 In one embodiment is a compound of Formula (II) wherein A and B are hydrogen. In

another embodiment A and B are independently selected from hydrogen and CQalkyl.

10067] in a further embodiment is a compound of Fonula (II) wherein Z is ary and Y is


a) phenyl group optionally substituted with 1, 2, or 3 R6;

25 b) a imidazole group optionally substituted with 1, 2, or 3 R;

c) a triazole group optionally substituted with 1 2 or 3 R6; and

d) a substituent independently selected from the group consisting of hydrogen,

alkoxyalkyl, alkoxycarbonylalkyl, alkyl. arylalkyl, cycloalkyl. cycloalkylalkyl,

haloalkyl, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylearbonyl,

30 arylcarbonyl, heteroarylcarbonyl, (NRAR)alkylene (NRAR)carbonyL

[00681 In a further embodiment is a compound of Forntila (1I) wherein Z is phenyl and Y is


e) phenyl group optionally substituted with 1,2,or 3R 6 ;

f) a imidazole group optionally substituted with 1, 2, or 3 R6;

35 g) a triazole group optionally substituted with 1,2- or 3 R6 ; and

30

WO 2010/017055 PCT/US2009/051879

h) a substituent independently selected from the group consisting of hydrogen,

alkoxvalkyl, alkoxycarbonylalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl,

haloalkyl, oxo, heterocycloalkyl heterocycloalkylalkyl, alkylcarbonyl,

aryIcarbonyl, heteroarylcarbonyl, (NRARB)alkylene (NRAR)carbonyl.

100691 In a further embodiment is a compound of Formula (11) wherein Z is phenyl substituted with

1 2, or 3 R6 and Y is independently selected from the group consisting of

i) phenyl group optionally substituted with 1, 2, or 3 R6j;

j) a imidazole group optionally substituted with 1,2, or 3 R;

10 k) a triazole group optionally substituted with 1, 2, or 3 1I: and

1) a substituent independently selected from the group consisting of hydrogen,

alkoxyalkyl. alkoxycarbonylalkyl, alkyl, arylalkyl, cycloalkyl. cycloalkylalkyl,

haloalkyl, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl,

aryicarbony. beteroarvlcarbonyl. (NR.ARE)alkylene (NRAR)carbonvl.

15 100701 In a further embodiment, A is selected from methyl, ethy n-propyl, iso-propyl, n-butyl, iso

butyl tert-butyl.,n-pentyl, and n-hexyl. In yet another embodiment, methyl, ethyl, n-propyl, iso

propyl; n-butyl, iso-butyl, tert-butyl, ni-pentyl, and nihexyl are optionally substituted with OH, NO2. CN, Br, Cl, F, and . In a further embodiment A is methyl in yet another embodiment, A is

selected from F, Cl, Br. and I. In another embodiment, A is C3-Cgcvcloalkvl. In a further

20 embodiment, A is 01H. In another embodiment, A is cyclopropyl. cyclobutyl, cyclopentyl. or

cyclohexyl. In one embodiment, A is substituted with OHf, NO1. or CN. In a further embodiment, A is hydrogen. In a further embodiment, B is hydrogen. In a further embodiment, B is C[-C(,alkyl. In

a further embodiment, B is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert

butyl, n-pentyl, and n-hexyl In yet another embodiment, methyl, ethyl, n-propyl, iso-propyl, n

25 butyl, iso-butyl, tert-butyl, n-pentyl, and n-hexyl are optionally substituted with OH, NO , CN. Br, Cl, F. and 1. In a further embodiment B is methyl. In yet another embodiment, B is selected from F, Cl, Br, and 1. In another embodiment, B is CrsCcycloalkyl In another embodiment, B is

cyclopropyl, cyclobutyl, cyclopentyli, or cyclohexyl In one embodiment, A is substituted with OH, NO2 , or CN. In a further embodiment, is a compound of Formula (II) wherein .A is hydrogen and B

30 is selected from Br; Cl, F, 1. C1 C-alkyl, CrCscycloalkyl, alkoxy. alkoxyalkyl wherein Ce-Calkyl, -CCeycoalkyl, alkoxy, alkoxyalkyl are optionally substituted with at least one substituent selected

from OH NO-, CN, Br, Cl, F, 1, Cj-CalkyI, and CrCscycloalkyl In another embodiment, is a

compound of Formula (ft) wherein B is hydrogen and A is selected from Br, Cl, F, 1, CI-C(,alkyl, C3

C8cycioal kyl, alkoxy, alkoxyalkyl wherein C-C-alkyl, C,-Ccycloalkyt alkoxy, alkoxyalkyl are

35 optionally substituted with at least one substituent selected from OH, NO2. CN, Br, Cl F, LC, C6alkyl. and CrCscycloalkyl. in yet another embodiment, both A and B are hydrogen. In a further

3]

WO 2010/017055 PCT/US2009/051879

embodiment, both A and B are selected from Br, Cl, F 1, IOH, C-C-alkyl, C-Ccvcloalkyl. alkoxy,

alkoxyalkyl wherein C1 -Cbalkvl, CX-Cgcvcloalkyl, alkoxy, alkoxyalkyl are optionally substituted

with at least one substituent selected from OH, NO,, CN. Br,. Cl F, IL Cr-Qalkyl, and C,

C8cvcloalkvl wherein B is not OH.

5 [00711 Also described herein are stereoisomers of compounds of Formula (1), (IA), or (II), such as

enantiomers, diastereomers, and mixtures of enantioniers or diastereomers. In one embodiment is a

stereoisomer of a compound of Formula (11) having the structures:

H H H H 0. N~ N N- 0-N, ,,N 'N N N X A 4 ANrnA BY

J1 -i~ 'z >YINN 0 YNo NN

R H B R2 H 8 R HZ

wherein:

10 Y is an aryl or heteroaryl group optionally substituted with at least one R;

Z is an aryl group optionally substituted with at least one R;4

A and B are each independently selected from hydrogen, Br, Cl. F 1, OH C1-C6alkyl. C

Cscycloalkyl, alkoxy, alkoxyalkyl wherein CrCcalkyl, C3-Cgcycloalkyl. alkoxy, alkoxyalkyl are

optionally substituted with at least one substituent selected from OH, NO1 , CN.Br, Cl. F.!, C)

15 C6alkyl, and C3-Ccycloalkyl, wherein B is not. OH;

R6 is selected from 01], NO 2, CN, Br, CL F, I, C1CcalkyI, C3-Cgcycloalkyl, C-Csheterocycloalkyl;

C -Cralkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6alkynyI, aryl

arylalkyl, C-Cseycloalkylalkl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo heteroaryl,

heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C20 Cgheterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARR. (NRAR)CI-C 6alkylene,

(NRARB)carbonyl, (NRARS )carbonylalkylene, (NRARB)sulfonyl, and (NRARs)sulfonyilaIkylene;

R2 is selected from hydrogen, Br, Cl, 1, or F;

RA and R3 are independently selected from the group consisting of hydrogen. C1-C 6alkyI, C3

Cscycloalkyl, and alkylcarbonyl; or RA and R1 taken together with the atom to which they are

25 attached form a 3-10 membered heterocycle ring optionally having one to three heteroatoms or

hetero functionalities selected from the group consisting of -O, -NH, -N(Ct-Calky)-, -NCO(C

Csalkyl)-, NCO(C-,C, cycloalkyl')- -N(aryl)-, -N(arylCr-Cfalkyl-)-, --N(substituited-aryi-l-Cfalkyl

)- ~N(heteroaryl) -N(heteroaryl-QCalkyl-)- -N(substituted-heteroaryl-C-C 6 alkyl-)-, and -S- or

S(O),-, wherein q is I or 2 and the 3-10 membered heterocycle ring is optionally substituted with

30 one or more substituents; or a pharmaceutically acceptable salt. solvate or prodrug thereof

[00721 in one embodiment is the stereoisomer of the compound of Formula (i1) shown above, having the substituents shown above, wherein R2 isfluorine. In another embodiment is the

compound of Formula (11) shown above, having the substituents shown above, wherein Y is an

WO 2010/017055 PCT/US2009/051879

imidazole group, hi another embodiment is the compound of Formula (H) shown above, having the

substituents shown above, wherein the imidazole group of Y is substituted with a CI-Cbalkyl group.

In a further embodiment, the C1 -Calkyl is methyl. In yet another embodiment is a compound of

Formula (11), shown above, having the substituents shown above, wherein Y is a triazole group. In

5 another embodiment is the compound of Formula (II) shown above, having the substituents shown

above, wherein the triazole group of Y is substituted with a Cj-CalkyI group. in a further

embodiment, the C-Cjalkyl is methyl. In yet a further embodiment is the compound of Formula (II)

shown above, having the substituents above, wherein the Y group is an aryl group. In a further

embodiment is the compound of Fornula (II) shown above, having the substituents shown above,

10 wherein the aryl group of Y is a phenyl group, In a further embodiment, the phenyl group is

substituted with a halogen. In yet a further embodiment, the halogen is F. In yet another

embodiment the halogen is selected from Br, Cl, and L, In yet another embodiment, is the compound

of Formula (II) shown above, having the substituents shown above, wherein Z is an aryl group. In

yet another embodiment is the compound of Formula (11) shown above, having the substituents

5 shovn above, wherein the aryl group of Z is a phenyl group. In a further embodiment, the phenyl

group of Z is substituted with a halogen, selected from F, Br, Cl, and L In yet another embodiment,

the phenyl group of Z is substituted with F. In yet a further embodiment the phenyl group of Z is

substituted with CI-C6alkylene(NRARB). In yet a tirther embodiment, the CrC-alkylene group is

methylene. In yet another embodiment NRARB is azetidine.

20 {0073j In one embodiment is a compound selected from:

(8S,9.R)-5-fluoro-R-(4-fluorophenyl)-9-(-methyl-N-HI,2,4-triazol-5-y) -8,9-dihydro-211

pyridof4,3,2-de]phthalazin-3(7N)-one,

(8R;95-fl uoru-8-(4-fl uorophenyl)-9-(-methyl-IH-i1,2,4-triazol-5-yl) -8,9-dihydro-2H

pyrido[4,3,2-deiphthalazin-3(7J)-one,

25 (8S,9R)- 8-(4-fluoropheny )-9-(1-methyiH-imidazol-2-yl) -8,9-dihydro-2H-pyrido[4,2

de]phthalazin-3(7H--one,

(8R, 9S)- 8-(4-fluorophenyl)-9-(I -methyl-I H-imidazol-2-yi) -8,9-dihydro-2H-pyrido[4,3,2

de]phthalazin-3(711)-one,

(S,9.R)- 8-(4-fluorophenyl )-9-(1 -methyl-1 H-1 12,4-triazol-5-yl) -8,9-dihydro-2H-pyrido[4,3,2

30 de]phthalazin-3(7)-one.,

(8R,9S)- 8-(4-fluorophenyl)-9-(1-methyl- IH-1,2,4-triazol-5-yl) -8.9-dihydro-2H-pyrido[4,3,2

de]phthaiazin-3( 7H)-one,

(8S,9R)-5-fluoro-8-(4-fluoropheny l)-9-(1 -methyl- I -imidazol-2-yl) -8,9-dihydro-2I-pyrido[4,3,2

dejphthaiazin-3(7H)-one,

35 (8R,9S1-5-fluoro-8-(4-fluorophenyl)-9-( I -methyl- 1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[43,2

de]phthalazin-(7H)-one.

33

WO 2010/017055 PCT/US2009/051879

(85,9R)-5-fl uoro-9-( I Tf-ethyl- I -iinidazol-2-yi) -8-pheny I-8&9-dihydro-2J1-pyridot.4,2

de-pflaazn3(71/)-oue,

(SR.9 5)-5 -fluoro-9-( i-methy-il -I inidazol-2 -yl) -8-phienyl-8.9-dihiydro-211-pvrido[4,3

de]phthalazin-3(/1-1)-one,

5 (8S.9R)- 8-(4-(azetidin- 1-ylr-nethiyl)phienyb)-9-(4-fluoropheoyl)-8.9-dihvdro-2Hprido 1 4 32

de]phthalazin-3(7H.)-one, and

(SR-.9St- 8-(4-(azetidin- I-ylhnethiyl)pheniyI)-9-(4-tl~uoropheniyl)-8,9-dihydro-2H1--pyrido[4,3,2

delphthalazini-3 (VH-)-one., or a pharmiaceutically acceptable salt, solvate or prodig thereof.

[0741 lIn one aspect is acomipountd selected from:

10 9-diphenyl-8,9-diihydro-2H1-pvrido[4,3 .2-dielphithalazini-3(7Hi)-one:,

8,9-di(pvridini-4-yl)-S.,9-d ihyvdro-2R-pyrido[4,3 .2 -d Jphtialaz'i-3)(7'H-onie;

8,9-di(py ridini-3 -yI)-89-dihiydro-2H1-pvido[4,3,2--dejp~hthalqzini-3 (71)-one;

S 9-di(pvrNidini-2-yl)-S,9-dliydro-2H-I.-pyri dof4. 3 ,2-de]phithalazini-3 (711)-onie;

I S 9-isopro-pyl -S-pheniyl-S.9-dihydro-2-H-pyrido[4,3.,2-eiejphithalazin-3(7T-onie;

9-(4-(( methyl am ino)rnethi)pheniyl)-S-phienyl-8,9-diliydro-2H--pvrido[4 ,3.2'-d1c]phith-alazinl-3(7 N)

onle;

9-(4-((di nietlain)mtethyblphenx 19)-8-pheiy I-8.9-dihydro-ffHpvrido [4,3,2-dc j1phthalazin-3 (711)

20 9-(3-((moeth-vlanfiino)nwLthiyi)phienvi)-8-phienvi -S,9-d ~iydro-24H-pvridol4,3 ,2--Ie jphtlh-lazin-3( '7/fl

one.

S-(4-((methyiamino))iethvl)phenyi.)-9-pheny I-S,9-d ~ihydro-241-l-pyrido 4.3 ,2-dcjlphrializin-3( 711)

one',

S ,9-bis(3-((.methyli ino)rnethyl,-)phenyl)-S.9-dihdro-21-1'pyridio43,-eptaazn 7[loe

25 9-(4-(hydroxytncthyl )phieny I)-S-phenvl-SS- dihiydro-2H-pyridot)4,3 ,2-dlelplitbalazini-3(71:fl-one;c

dejphthiazin-3(7H-f)-onie;

8 ,9-bis( 3 -(4-i sobuty.rylIp iperazine - I -carbonvylphenyt) -8,9-di hyd ro-2H1--py-rido[4,3 .2-edc]phthalazinl

3(71f)-one;,

30 9-(piper-idin--3 -vl)-S-(pvridii-3 -yl)-8-9-d ihvdro-2H-pyridof4,3).2-dbjphthalazin-3(7111)--onIe:

9-(pipcridini-4-yi)-8-(pvridin-4-y)-8,9-dihvdro-11l-pyrido[4,3 ,-deicjphthialazin--3( 711)-onie;

S.,9-bis(4-((dimeiithyimino)mernhyl)plhenvl)-8-9-dihiydro-2H--pvrido{4.3 .2-dc jphrhalazii-3 (711)-one;

9-(4-(4-(cyclopropanecarhonttvl)piperazince- I -abnlpcy -- (mtyanu~ehlpey)

S,9-dihyvdro-2H- pyrido[4.3 ,2-dle]phth~alazin-3(7H-)-one;

3-5 9-(4-(4-(cyclopropanearbonvl )piperazine-lI -carb onvi)phelnyl)-8

34

WO 2010/017055 PCT/US2009/051879

8S-(4-(hy),droxyinethyl)phenyb)-9-(4-(4-isobuityvylpiperazine- I -carbonyf)pheniy)-8.9-d ihydro-211

pvrido[4,3 2--deiphthaiazini-3(71h)-one;I

8-(4-((dithyivlarino)rnethyl)pheniyl)-9-(4-(4-isobtvr ylpiperazine- I -catrbonvl)phienyl)-8,9-dihvdkro

211-pyridof4 3,2-d-ef phthalazin-3( 711)-one;

5 9-(4-(4-(eydlopropanecarbonvl)p iperazinie- I crnyph yl-peyi&9db ro2H

pyrido[4,3 ,2- llhthalazini-3(7Th,-one;-1

9-(3 -(4-(cyclopropaneea,,rboniyl)pipcriazinie- 1 -carboniyl )pheny 1)-8-pheniy!-8,9-J Iwdro-2 1-1

p ,rido[4,3 ,2-de] plialazini-3 (711)-onie;

9-(3 -((dimieth~ylarniino)miiethl jtpheinyf)-8-phenvi-8,,9-dihydro-211.I-py-rido [42 ),2-dcjephlthlaazin-3(7.F1)

HJ One;

one;

S-(4-(&jdimiethykzinnino)mievhy 1)phienyl.)-9-pheniyl-&,9-dibivdro-2H-pvrTido [4,3 ,2 -dlepldhlalaizin- 3(7t/.I)

15 S-(4-(niiorphiolinomethAy ,)phenvl)-9-phenvl-S 9-d ihydro-2H-pyrido{ 4,3 .,2-delphtbalazin-3(1f oe

S-(4-(hydroxyniietliyl )phei-.y)-9-pheinyl-8,9-dihydro)-2. tF-pyrido[4, 3Z' eephtiazin-3 (711)-on-.te;

9-(3 -(4-(cvelIopropanecarbonvf }pi perazi ne- 1-carbonyl~phenvl )-8-(4

((dimethylanino)rnethvi~lpheny1)-8,9-dihyidro-FJ-pyrido[4,3,2-dlelphthaazini-3(7H)-one;

9-( 3-(4-(eyclopropanec arbonyflIpiperazinie- I -carb~onyl )phel v)-8-(4-(hydroxvrnietbli)phenyl)-8,9

20 dihyda -2H-pyr-ido[4,3 ,2-dle]phithalazini-3(71-1)-one;c

9-(4-(4-isobtvrNyfpiperazinie- 1 -earbo()nyl)phienivl)-8-(4-((rnethiylarnino)rnethvi)pbeniyl)-&,9-dihvdro

2H--pyrido[4,3 ,2-dIejphthalazin-3 (7/1)-one;

9-(31 -4-isobuityr> I'piperaizine- I -earbonv1)phienyI)-8-(Ipyridin-4-y1 )-8 ,9-dihiydro-21I-pyrido[4,3,2-

deJphthalazin-3(71h)-one;,

25 9(3 -((dimeth-ylaminimethiyl)phienvi.)-8-(pyr-idin-4-vI)-8.,9-dilwd~ro)-2fl.-pyrido[4,3 2--dej phthalazinl

3(711)-one;

9(3 -((rnethvlarinito)rnethyl)pheny)-8-(pvridii-4-yfl)-8,9-dihvdr-o-2H-pv.rid of4,3.2- /e ]phthalzini

9-(44((dimieth-ylan ino)miethyi)phenvY;.)8 -(pyridin-4-yl)-&,9-dihydro-ZFI-pyrido 42 ,2-eiphthialazini

30 3(711)-one;

9i-(3 -(hydroxyinethvl.)phenyvl )-8-(pvridin--4-ylt)-8,9-dihydro-211-pvrido[43 ,-dcj.Iphthial~zini-3(7J1)

One,

9-(4-((methytIamiinotnefel~y1)pben-iv1)-8-( pvridini-4-yI )-&.9-dihyvdro-2 H-pvrido[4,3 ,2-/u]phthalazin

35 94(3 -((dirnethiy Iminio)miethyl)phenyl-8-(pyridi-n-3 -yD)-8,9-dihvdro-2H-pridoj-4..2-dj !phthalazi-

WO 2010/017055 PCT/US2009/051879

9-43 -((mrethylamino)inetyJ,,)pheniy1)-8-(pyridin-3 -yl)-8&9-dihyvdro-2H-pyrido 4,3,2-dce lphthalatin

3(7J11)-one;,

9-(4-ffdirncithiylarninio)m-etl v)phenyl)-8-(pvridin--yl)-89-dihydro-2H--pyrido4,3 ,2-Ic,]phlthalazin

3(711)-onie;

5 9-(4-(( miethlain ino)rnethybjphenlyl)-8-(pvridin-3 -yl)-4 9-dihyvdro-2H-pyr-idof4,3',2--de ,-phthabzCini

94(3-4hydroxynwiithl y)pher-iyl)- 8-(pyridiii-3 -yl)-8,9-dihydro-2H-pyridc4[4.3 .2-dc Jplhthahlizin-3 (711.)

one:

9-(3 -((dimethylarnino )methyl)phenvi)-8-(pv-ridini-2-yl )-&,9-dihydro-211-pyrido[4,3- ),2-dc]phfiaiazinl

10 370oe

9-(mt~ amn~ehIpey -- prdi- y>9ivr2t-yio4 2djhthalazin

-3(7th)-one;

9-(3 -(hydrox\ynwieti)pheni.)-8-(pyridin- -y-v 9-dyo- -pio[,32-]plhain(7

1 5 9-(4-((dimethyininto)miethiyl)phenyli)-8-(pxridi i-2 -yl)-8.9-d ih-vdr-o-2H-pvrido[4.3 2,'-de- phthalazinl

3 (7H)-ou e;

9-(4-((mieth-ylaminio~rnethyl)pheniy O-8-(pyridin-2'-yfl)-8,.9-dihydiro-2--H-pyridoj4..3 2-: e]phlthalazinl

3(711)-one;,

9-phieni- 8-(pyriini--vl)-8,9-d ihvdro-2H-pyrido[4,3 ,-de]phthialarini-3(70oe

20 9-phenvyl-8-(pyridin-3 -vi)-8,9-dihiydr-o-2Htvpridol4,3. 2-de.i~phthialazin-3 (711)-one;

9-pheniyl-8-(,pyridin-4-y1)-8,9-dihivdro-2H1-1pyridof4,,3 2-dc l'ph-thalazin-3)(7 11)-one;

9-(3 -((imieth~Ylamrio)miethv)pheniy)-5-fliuoro)-8-(pyridin-4-yi)-8,9-dihyvdrt>.2f-Ip).ridof4,3,2

dejphthalazin-3( 711-one;I

25S 5--fluoro-9-(3 -((miethivlarninto)rnOethyIv)phienyi )-8-(pvrTidin-4-')-8.9-dihydro-211[-pyrido[4,3 .,2

d 'Iphthalazin-3(711)-one;

9-(4-((dime~thylarnino)rnethvl')phenvl)-5-fluor-8 -(pyridini-4-y)-8,9-dihydro-2H-pvrido[4,3 .2

dejphithalazin-3 (711)-one:

5-fluotro-8,9-dipbeniyl-8,9-dihydro-2Hf-pyxrido[43 .2-d&]ph thalazinll-3(7 11)-one;

30 9-(4-((dime-ithvyainiio)1nte11w)phenv]-5-i~uoro-8-pheniy-8,9-dihiydroi-2I-1py)ridof4,3 ,2

dejphthaiazin-one

S-fl uoro-9-(4-((rniethylam ino)merncbvl)pheniyl)-8-phienx'1-8,9-dihv~dro-211-pyridio[4.3,2-dcj-phtlialazini

one.

9-(3 -((dimethylarniino)miethiyI)phienl},-5 -flutoro-8-phenvl-8,9-diiydro-211-pyrido [4,3,

35 delphthalazin-one;

36

WO 2010/017055 PCT/US2009/051879

dejphthalazin-one;

5-tkuoro-9-(3 -(Qinetiwlarnino)miethvl)pheniyl)-8-pheniyl -8,9-d iiydro-2H-pyrido[4,32" -die]phthialaizi n

one;

One;

7-ethiyl-8,9-diphenyl-8,9-di hydro-2H-pyrido[4,5 .2-dc Jphthaiazin-3 (71-h-one;

5-fl uoro-9-( I -methyl- IH1-imidazol.-2-yI)-8 -phenyl-8 ,9-dihydro)-2H1-pyriido[4,3 ,2--dc]phtialazin

10 3(WI)-one:

5-fluoro-8-(4-fluo(.ro phenyl)--9-( I -methyl- I H-imridazol-2-yl) -8,9-dihiydro-2H-pvrido)[4, 3,2

dcjphithalatin-3 (71j)-one:

8-( 4-((dimetthylamino)methyvl)phienvl.)-9-( '1-methyl-l1-f-imidazol-24-yl)- 8t9-d ihydro-21

pyridlo 4.3 ,2-dc]phthailazini-3(71fl-one;

15 9-(i -isopropy- iI H1-imidazol-5-vl)- 8-phenyl-8, 9-dlihyd ro-2H-py-rido[4,3 ,2-tie lphthalazin-3 (711)-one;

9-(4-methyl- I L-imiidazoi1-2-yl)- S-phenyl-8,9-d ihiydro-211-pyridofj.3,2-dcj phithakizini-3( 711)-onle;

8-phencjyl -9-(thiazoi5-yl)-8,.9-d ihvdro-2H1-pyridof4.3,2-de-]phithal azin-3 (7 [-one;

9-(furan-3 -yl)-8-phienvly-8,9-dihydro-2H-pyrido~[4.3 ,2-eephthalazini-3(7LJ)-one;

8-(4-((4-ethylpiperazin- I -yI)methyl)pli.enyi)-9-phei -8,9-dihyx-dro-2,!H-pyrido[4,3,2-delplialazini

20 3(7TH-one;

9-phenyl-8-(4-(piperazin- I -ylmnethvl)phenyvl)-8.9-dihydro)-2H-pyrido[.4,3 ,2-dle phthalazin-3( 7Th)one:.

8-( i-methyl- I 1/-imidazoi--ylv)-9-phenyvl-8,9-dihydro-2 /1-pyrido[4,3 ,2- Icjphthalazi n-3(711)-one;

9-( i-methyl- I 11-imid aw.l-2-x )-8-pheniyl-8,9-dihydro)-211-vrido 4.3.2-c] ph thalazin-'7J/)-one;I

25 8,9-bis( I --methyl- Il 1-mudazol 2-vl) -8&9-dihvdro2J1-I-pyrido432-kI]pthalazi-3(71-)-onie:

9-( llH-im idazoi-2-yi l) hn -.- ixr-1!pi o[, 2 cptaai- '1)oe

9-( .1 -ethyl]- IH- Im iclazol 2 x 1) -8-phenvl,-8,9-dihydro)-2Hl-pyr'idor43 ,2-d.clphthialaizin-3( (711-one;

S-phenivl-9-( i -pro~pyli I1--is-nidazoi-2 -yl) - 8.9-dihydro-2/1-pyrido [423 .2-dlejphthalazin -3(711)-onie;

9-( 1-miethyl-I H-im-ridazol-5 -yi) -8-pheniyl-8,9-dihiydro-2H- pyridoi[4,.3 2--dc]phthalazin-3 (711)-onie;

30 9-.(3 -((diethv laininio)znetll )pheny I)-8-(4-((diethylain)o)meth)lphenyl)-8.9-dihiydro-2H

Q-(3-((4-mecthlpiperazi-n-1I-yE) mnethybpheniyl )-8-phenvl,-R,9-dihydiro-2H-pvrido-[43,2?

dejphthalazin-3('7H)-one;

8-(4-(4-(cvclopr-opaniecarhonyl) piperazine- I -earbonvl.)phenyl)-9-pheny 1-8,9-dihydro-2H

335 pvr-idu[4,3' ,2 -dc]phthalazii-3 (7/11-one;,

9-phienyl- 8-(pvridlin-4-yI)-8 .9-dihvdro-2H-I-pyridoj4.3 .- dle-phthalazin-3-)(7-1)-one;

37

WO 2010/017055 PCT/US2009/051879

9-pheniyl-8-(piperidin-4-yvl)-8,9-dIihydro-2H.1-pyridio[4,3 ,2---tIlphthiaiazin-3t(7B1-tne

9-phienvi-8-(pyridini-2-vfi.-8,9-dihydro-2H-pyrido[4,3 2ccjhhlai-(7hoe

8-(4-((4-imthiylpiperazinl- I-yl,)nethyl)phienyl)-9-phienyl-8,9-dihiydro-2H-pyrido-[4 ,3 ,2-dejphithalazin

3(7Uf)-one;

5 ,9-bis(4-fl uorophenyI)- 8.9-d ihydro-211-pyrido [42 ,2--dlephthaiazinl-3 (7 [fl-one:

&.-dh dr-J-pvdro-11prd[,' )

8-(4-f1 uorophenyl}-9-( I -methyl-il!- inidazol-2-yl)- 8,-iyir - jpvio4,3i2-deit]piihtiazinl

10 8,9-bis(3-((dimethvianiino)miethvipey)y-ivr-I~yio42d~hhlzn3(1)oe

9-(3-((Qxyclopropylaxinao)miethvl)phdnyl)-&-phienyl-8,9-dihvdro-211.-pyridoj4,,3.2-dle]phlthialazinl

3N7II) one;

8-(3-k(dimethylamiitno)methiyl)phenyl Y9-pheonxl-&9-dihydro-21/-pyridc {14.3 2,' -dejphthnazini-3(7H/)

one,

15 8-(3 -(morphol inomnerhy Ithlem'! )-9-pheiinyt--8,9-dihydro -2l'pvrid4[4,3,3.2-delph)thalazin-3 (711%--onle:

8-(4-(a'zetidin- I -vlrneshyl)phenyhi.-9-(4-fl norojpheniyl)- 8,9-dihvdro--2H1-pyrido[4,3 .2-de]phthalazini

3(7H)-one:

20 f9uoo-8hlH-(4fluo renv]--lI 8-ethy-89-ih24-daol-5-1)-9ddo2-pyrido [,1,4,pltaln3 (1-ole

dphhiazin,-3 ),-epta-(7H)-one ;

8-(4-(jdim-ethiylamoino)methiyl)phenyli)-9-(titro( i -methy l- 1-1ra-5yb9dhdrZpyrido[4,3 ,2-dejphrhalazin-3(71-t)-onie;

258-(4-flutoropovl)-9-methyl -9-(: 1 metbv1- III- l.,2.4-triazoi-5S-yfl- 8,9-dihy dro-2l-pvido[4$3 2dejphthalazin-3 (711)oe

8-(4-fhuorophienvl)-9-( i,4. 5-trimethyi-l- 1-im nidazol-2-v b-8,9-dihvdro-2H1--pyr-ido[4, 3.2'

8-(4-fluorophenyl)-9-( 1 -methyl- H-1-i 1,2,3 "-tria.zoi-4-yl)-8,9-di hydro-2-)Ipxrido 473 ,2-dejphthliazi30 3(711)-one;

9-(4, 5-dimethvl --411- 1 ,2.4-triazol-3 -vl)-8-phen)yi-8.9-dihvdro-2 H-pvr-ido[4.3 ,2-de]phthalnzin-3 (711)one;

9-(4,5-diniiethiyl-411- I 2A-triazol-3 -d--4fnrpev)8,-iyr-1-yio432 dc-_,phth al azi n-3 (1 7Ifone;

35 8-(4-chlorophenyl)-9 -(.1 -methyl- I 11-timizo-2-vl)-8,9-d.ihvdro-2H1-pvidt; 3,2-de~phlth~aazini3(71f)-one;

38

WO 2010/017055 PCT/US2009/051879

9-( 1 -methyl.-I H-imnidazol-2-vl--)-S-(4-(triflutoromnethyl )phenyl)-8,9-dihvdro-2if-pyrido[4,3 2

8-(4-flutorophenyl)-9-(thiiazol-2-vl)-&,9-d ihydro-2H1-pyrido[ 4,32- /elphthialaztn-3(7 71)-one;

9-(1 i-ethyl- IH-imidazol -2-yl)-S-(4-fliorophlenyvl)-&0.-dihy dro-2H--p Tido [4,3 ,2-delphthalazinl-3(711)

5~ one;

8-(4-( (4 -ethyl -3 -methylpiperazin - I-yl)methyi1 phenyi)-9-phIenyl -8,9-diibydro-211-pyrido [4,2de]phthalazin-3 (711)-one;

8-(4-((4-ethiylpiperazin-v -yliethi)pheniyl)-9-(4-fl uorophien-yl)-8,9-dilwNdro-2H-,-pyrido[4,3 .-

de]pbthalazin-3(7Th-one;

10 9-(4-fluo~roplhenvl)-8-(4-((4-niethylpiperazin-1I-ylftnethy )phenyl)-8,9-dihvdro-211-pvrido [4,3,

9-(4-luor-ophienjy)-8-(4-(piperazii- I -ynIme thylI)phenybI-8,9-d ihydro-211-pyr id o [4,3 ,2-d-Ijphth al azin

3(711)-one;

9-(4-fluorophenyvl)-8-(4-((3 -ruetlpiperazin- 1 -yl.)mithiyflpbenyfl-8,9-clihydro)-2HI-pvrido[4,3 .2

15 deljphtbalatin-3()1-fl-one,

9-(4-fluorophenvI)- 8-(4 -(pyrroli dirt- I.-vlmiethy4}phenv,,,l)-&,9-d ihydro-2H-py rido[-4.3,2-de phihalazin.

3(711)-one;

9-phieiy l-8&.9-d ihydro-2 H-pyrido[4,3,A -dejphthialazin-3( 711)-onle:

8-(4-FI uorophenyl,)-9 -(4-miethlv-4H- 1.2,4-triazol-3 -yi)-&.9-dihydro-2H-pyrido )[4,3.2-ec jphthialazint

20 3(7Th)-one;

S-(4-fluorop~henvD)-9-( .imethyl-1 Fl-i.2',4-tr~iazol-5-vI)-8.9-dIihvdro-211-pyrido[42,3,-deephltlialazin.

3(71--one;

8-(4-fIuorophenvl)-9-( i-methyl.- ill1iiidazo[4 .5-cipyr-id'i--yi)- 8,9-dihyNdro-2H-pyrido[4,3 ,

tdclphthalazin-3(711)-one;

255-ch oro-9-( I -methyl- I11-irnidazol-2'-yl)-8 -pheny.1-8.9-dihvdro-211-pvr-ido[43' ),2-d&Jphthalazin

8-(4-((dimethylamino)mi~ethv l)phienyl)-5-filuoro-9-(4-fluotrophenivi.)-8,9-dihyd;(ro2 LH-pyrido[4.3 ,-de]phthala-iin-3( 71)-one;

8.9-bis(4-((dimnethlylainto)miethyl)phen '1)-S-fl uoro-K,9-dihydro,-21-I-pyrido{43.2'-- iplihalazinl30 3(71-1)-one;

8-(4-((dirnetrhylai-in iopnethivl)pheniyl -5 -fluor~io-9-pheniyl-8,9-dihydro,-2 FI-pvrido[4.3,2

dejphthalazin-3 (71-1)-one;

8-(4-((3 .4-dimethyl~piperazin- I -yl,)rnethivl)phen-yl)-9-(4-fluoroipheiy l)-8.9-dihydr-2-H-,pyrfdo[4,3.2dejphtbalazin-3(71fl-one;

3 8-4(3.-ictxpprzn -vl)mietlai- )pheniyl)-9-(4-fiuorophenyl)-8,9-dihyvdro-2Hl-pyrido[432.

39

WO 2010/017055 PCT/US2009/051879

9-phenyl -8-(4-(pvrrolidin- 1 -yltRnethyvl)phienvl )-8 ,9-dihvdro-2H-I-pvridof4,3 .2-Selplnh-alazi-3(711

9-_phenyl-8-(4-(pvrroiidin- I -ylmecth-yl)phens.')-S,9-d ihydro-2 YH-pyrido [4,3,2-deIiJphthaiazin-3(7 11)

one;

5 9-(lt-mnethyl-l .H-imidazol-2-yi)-8-(4-(pyrrol ilnti- I -yimiethi)phenyIi,])-8,9-dihydro-2H-pyrido[4,3 2

dejphthalazin-3(7H)-one:

9-(4dfluoroph.envl)-8-(quinolin-6-yl)-8,9-dihvdro)-2H1--pyrido [43 2-dc(]phithiazin-3(7H)-onc;

1 0 8-(4-((dimtyethylarn irno)methyl)phenxl)-9-p-tolvl-8,9-dihydkro -2 Ji-pyxido [4.3 ,2-dle]phvhttalaizin-3(7~h)

9-(4-ehloro)phenvI)-8-(4-((dimnerhilainlo)mietiy,-I')pbieni))-8,9-diyd-o-2H-py-ido[4,3 ,

tiejphthalazi n-3( 711)-one;

8-(4 -((dimiethiy lainto )meth-vl)phenyl)-9-(4-miethioxyphenyl)-S,9-d ihvdro-211-pyrido{4,.-15 dlejphtrhalazini-3(7H.)-one;

8-(4-((diethylamino)mcthiyl)ph-.eniv>9-phenvl -89-dihvdro-2H--pyrido[ 4L3 .2-dejpithalazini-3 (711)

one;

8-(4-((diethvlani io)mnethvl)pliyl)-9-(4-fl uoro~phienyl)-8,9-dihvdfro-2H-pvrido[4,32-tie~phithalazin3(7.1i)-one;

20 94(4-cdilo-ophienyF)- 8-( 4-((dietlhylamino)rnethyl)phenyl)-&9-dihydroc-2H-pyrido [4,3,2-diejphthialazin3(71Th-one;

(E)-6-fluoro-4-(( -methyl-i Hiiao--lmzyeemioioezfrn 3hoe

5-fl ioro--9-(4-fl uoropheniyl)-8-( I-miethyl- I H-i inidazol -2--iA )-8S9-dihvdcro-21-pylrido{4,3,2

dej(!phthia~ini-3(.7H)-onei;

25 S-(4-((dir-nethvla-n inos)methyl)phenivl)-9-(4-ethylpienvl)-&79-diliydro-21'-pyrido{4y,32

30 e]phthialaziin-3(7H1)-one;,

8-(4-((dieiylainiii~ o)ethy )phenIyt)9-(-opropvphcl)-89-di hydro-2UI-pvf-prido[4,3 .2-eeptlazi- )(1

one:,

9-(4-flutorophenivl)-8-(4-(I -m-ethylpvrrolidin-2-yl )phieny l)-8,9-dihvdr-o-2H-pyrido'4.3 ,2

dejphithalazin-3(7J1)-one;,

35 _- Bnrpex)8(4(y--ldi-- thnb&-ivr-Hprido[412d ptaazn-37U

40

WO 2010/017055 PCT/US2009/051879

8 -(4-fluorop henvyl)-9-.ethyi-94( i-methyl- -Iiidzl-y-8.9dh ro1-pid[3

dej]phthaazin-3(711)-orie;

9-(4-fluorop-heniyl)-8-( IH--im .idizol-2-yl)-8.9-dihydro-2Hf-pyrido[ 4,3.,2-Ic Ipbthialazini-3 (714 )-onez

5-iinoro-9-(] i-methylI - I .,4-triazol-$-y1 )-8-phenyl-8,9-dihydro-2Fl--pyrido[4.3 ,2-de lplithalazin

9-(4-±liuoro~phenyl)-9-hyvdroxy-8-( 1-methyl-l H-imnidazol-2-yl)-8,9-dihydro-2-H-pyrido(4,3,.-dejphthalazin-3(7f1-one;

(8S,910)-5 -tluoro-9-( 1-mi-ethyl-1 I 1i-midazol-2-yl) -8-phe.niyl-8,9-dihiydro-2HIl-pyriido[4,3 ,2

dejphithalazin-3(7H-1-one:

10 (81?,98)-5 -flnoro-9-( 1-ehliHiiao--l 8phnt89dhdo2-yio432

deiphthalazin-3( 7J-J-one;

(SS-,9R)-5 -tluoro-8-V4-fluorophenvl)-9-( I-methyl-- Iii-idazol-2--yl) -8,9-d ihydro-2H)I-pyr-ido[4,3 ,2

dejphthalazin-'3(71/)-one;

(8&< 95 )-S-fluoro-8-(4 -thitoropheniyl j-9-( i-methyl- I -irnildazol.-2-yl) -8,9-dihydrO-2 H-pyrido[4,3 .2

15 c/e] phthalazin-3(7Hf)-one;

(8S,9R)- 8-(4-fluorophI)Ienyl)-9-( 1-mnethiyl- IH-imyidazol-2-yI) -8,9-dihydr-2- 1 - 7 .43,

dcj]phthalaziin-3(71hi-one

(8?, 95>) 8-(4-flhoropheny I)-9-( I-methiyl-I 11-im iidazol1--yl) -8.,9-dihydro-21H-pyridlof4,3,2

de]phthalazin-3 ( 711)-onec;

20 (8S,9R.)-5-fluaoro-9-(l -methyl- I I- I 2,4-triazoi-5-yi.) - S-phen-.yl-8,9-dihvdtro-2H--pyrido[4,3 .

dejphthialazin-3(71H)-one;

(8R,%S'-5-fluoiro-9-( 1-methyl-] H-I ,2.4-triazol-5-vI) -8-phenvl-8,9-dihiydro-2H-pyr-ido )[4,3,2

delphithal azin-3(711h-one:

(8,9R)-S -fluor~o-8-(4-l uorophenyl)-9-( i-methyl- I H1- 1,2,4-triazol-5 -yh, -8,9-dihvdro--2H

25 pyriko[4,3 ,2-dIe] phthailazin-3(7Th-onie;

(8], 9)-5f~hro--(4florohen1)-.-(1-mthy- K-I,2,-trazo-S-l)-8,9-di tydro-211

pyrido[4,3,2-c] lphtha lazin 4-37TH-onie;

(85.1?)- 8-4furpes1 1-ehliHi.24tizi5y)-8,9-d ihvdro)-2,1f-pyrido[4,.3 .2e

delphthalazini-3(7Th OULc

30 (8R,98S)- 8-(4-fluorophex.1l) 9 (1-methyl-I H-i ,2,4-triazol)-5-v I) -&,9-dihiydro-2H-pvrido[4,3 -2

dc- jphthtalazin-3( 711)-onec;

(8S,9R)-8 -(4-((dimiiethy latmino)lmethyl )phenyl )-5-fluoro-9-( I -methyl- III11-1,,4-triazoi-5-vO)-89

dihydro-2H--pyrido[4,3 .2:-de(-,phthaiazin-3( 7th -onec: and

3,5 dihydro-2Hpro43,-e]hhizn3(1)oe

or a pharmaceutical acceptable salt soix'ate or prodrug therefore.

41

WO 2010/017055 PCT/US2009/051879

[00751 In some embodiments, provided herein is a pharmaceutical composition comprising of a

compound of Fornula (1), (IA) or (11) or stercoisomers, or a pharmaceutically acceptable salt, a

pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug thereof and a

pharmaceutically acceptable carrier, excipient, binder or diluent.

[00761 Certain embodiments provide a method of inhibiting PARP in a subject in, recognized need

of such treatment comprising administering to the subject a therapeutically acceptable amount of a

compound of Formula (1), (1A) or (11) or a therapeutically acceptable salt thereof,

[0077] In one embodiment, provided herein is a method of treating a disease ameliorated by the

inhibition of PARP comprising administering to a subject in need of treatment a therapeutically

10 effective amount of a compound of Formula (I)U (IA) or (11). In some embodiments, the disease is

selected from the group consisting of: vascular disease; septic shock; ischemic injury; reperfusion

injury; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis; secondary

effects of diabetes; and acute treatment of cytotoxicity following cardiovascular surgery,

100781 In certain embodiments, provided herein is a method for the treatment of cancer, comprising

15 administering to a subject in need of treatment a therapeutically-effective amount of a compound of

Formula (1), (IA) or (II).

100791 Certain embodiments provide a method of potentiation of cytotoxic cancer therapy in a

subject in recognized need of such treatment comprising administering to the subject a

therapeutically acceptable amount of a compound of Formula (I), (IA) or (II) or a therapeutically

20 acceptable salt thereof

100801 In some embodiments, provided herein is a method for the treatment of cancer, comprising

administering to a subject in need of treatment a therapeutically-effective amount of a compound of

Formula (1), (IA) or (Il) in combination with ionizing radiation or one or more chemotherapeutic

agents. In some embodiments, the compound described herein is administered simultaneously with

25 ionizing radiation or one or more chemotherapeutic agents, In other embodiments, the compound

described herein is administered sequentially with ionizing radiation or one or more

chemotherapeutic agents.

[00811 In certain embodiments, provided herein is a method for the treatment of cancer. which

includes administering to a subject in need of treatment a therapeutically-effective amount of a

30 compound of Formula (i) (IA) or (11) in combination with ionizing radiation and one or more

chemotherapeutic agents. In some embodiments, the compound described herein is administered

simultaneously with ionizing radiation and one or more chemotherapeutic agents. In other

embodiments, the compound described herein is administered sequentially with ionizing radiation

and one or more chenotherapeutic agents.

35 100821 Certain embodiments provide a method of treating leukemia, colon cancer, glioblastomas,

lymphonas. melanomas, carcinomas of breast, or cervical carcinomas in a subject in recognized

42

WO 2010/017055 PCT/US2009/051879

need of such treatment comprising administering to the subject a therapeutically acceptable amount

of a compound of Formula (1), (IA) or (I) or therapeutically acceptable salt thereof

100831 In some embodiments, provided herein is a method of treatment of a cancer deficient in

Homologous Recombination (HR) dependent DNA double strand break (DSB) repair pathway,

5 which includes administering to a subject in need of treatment a therapeutically-effective amount of

a compound of Formula (I), (IA) or (ii). In certain embodiments, the cancer includes one or more

cancer cells having a reduced or abrogated ability to repair DNA DSB by JHR relative to normal

cells. In some embodiments, the cancer cells have a BRCA I or BRCA2 deficient phenotype. In

some embodiments, the cancer cells are deficient in BRCA I or BRCA2. In some embodiments, the

10 methods provided herein involve treatment of an individual who is heterozygous for a mutation in a

gene encoding a component of the R dependent DNA DSB repair pathway, in certain embodiment,

the individual is heterozygous for a mutation in BRCAI and/or BRCA2. In some embodiments, the

method of treatment of a cancer includes treatment of breast, ovary, pancreas and/or prostate cancer

In some embodiments, the method of treatment of a cancer further includes administration of

15 ionizing radiation or a chemotherapeutic agent.

100841 The primary function of the DNA mismatch repair (MMR) system is to eliminate single

base mismatches and insertion-deletion loops that may arise during DNA replication. Insertion

deletion loops result from gains or losses of short repeat units within microsatellite sequences, also

known as microsatellite instability (MSI). At least six different MMR proteins are required. For

20 mismatch recognition, the MSFI2 protein forms a heterodimer with either MSH-i6 or MSI3

depending on the type of lesion to be repaired (MSI-16 is required for the correction of single-base

nispairs, whereas both MSH3 and MSHJ6 may contribute to the correction of insertion-deletion

loops). A heterodimer of MLI-l] and PMS2 coordinates the interplay between the mismatch

recognition complexand other proteins necessary for MMR. These additional proteins may include

25 at least exonuclease I (EXO 1), possibly helicase(s), proliferating cell nuclear antigen (PCNA),

single-stranded DNA-binding protein (RPA), and DNA polymerases S and c, In addition to PMS2,

MLII may heterodimerize with two additional proteins, MLII3 and PMSI. Recent observations

indicate that PMS2 is required for the correction of single-base mismatches, and PMS2 and MLI-3

both contribute to the correction of insertion-deletion loops. Additional homologs of the human

30 MMR proteins are known that are required for functions other than MMR These proteins include

MSH4 and MS15 that are necessary for neiotic (and possibly mitotic) recombination but are not

presumed to participate in MMR,

100851 Germline mutations of human MMR genes cause susceptibility to hereditary nonpolyposis

colon cancer (NNPCC). one of the most common cancer syndromes in humans. An excess of colon

35 cancer and a defined spectrum of extracolonic cancers, diagnosed at an early age and transmitted as

an autosomal dominant trait constitute the clinical definition of the syndrome. MS, the hallmark of

43

WO 2010/017055 PCT/US2009/051879

HNPCC, occurs in approximately 15% to 25% of sporadic tumors of the colorectum and other

organs as well, According to international criteria, a high degree of MS1 (MNSI-H) is defined as

instability at two or more of five loci or -30% to 40% of all mierosatellite loci studied, whereas

instability at fewer loci is referred to as MSI-low (MSiL), MSI occurs in a substantial proportion

5 (2% to 50% of tmnors) among non-HNPCC cancers (eg cancers of the breast, prostate, and lung).

On the basis of the proportion of unstable markers, categories MSS, MSI-L, and MSI-H can be

distinguished in these cancers in analogy to INPCC cancers. In one embodiment is a method for

treating a cancer deficient in mismatch DNA repair pathway. In another embodiment is a method

for treating a cancer demonstrating microsatellite instability due to reduced or impaired DNA repair

10 pathways. In another embodiment is a method for treating a cancer demonstrating genomic

instability due to reduced or impaired DNA repair pathways,

100861 Certain embodiments provide a method of treating ischenia reperfusion injury associated

with, but not limited to, myocardial infarction, stroke, other neural trauma, and organ

transplantation, in a subject in recognized need of such treatment comprising administering to the

I5 subject a therapeutically acceptable amount of a compound of Formula (1) (IA) or (11) or a

therapeutically acceptable salt thereof,

100871 Certain embodiments provide a method of treating reperfusion including, but not limited to,

reperfusion of the eye, kidney, gut, and skeletal muscle, in a subject in recognized need of such

treatment comprising administering to the subject a therapeutically acceptable amount of a

20 compound of Formula (1), (IA) or (IT) or a therapeutically acceptable salt thereof

100881 Certain embodiments provide a method of treating inflammatory diseases including, but not

limited to, arthritis, gout. inflammatorv bowel disease, CNS inflammation, multiple sclerosis,

allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis in a


25 therapeutically acceptable amount of a compound of Formula (I), (IA) or (II) or a therapeutically

acceptable salt thereof,

[00891 Certain embodiments provide a method of treating immunological diseases or disorders

such a rheumatoid arthritis and septic shock in a subject in recognized need of such treatment

comprising administering to the subject a therapeutically acceptable amount of a compound of

30 Formula (I), (IA) or (II) or a therapeutically acceptable salt thereof,

100901 Certain embodiments provide a method of treating degenerative diseases including, but not

limited to, diabetes and Parkinson's disease in a subject in recognized need of such treatment


Formula (1), (IA) or (11) or a therapeutically acceptable salt thereof.

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WO 2010/017055 PCT/US2009/051879

[00911 Certain embodiments provide a method of treating hypoglycemia in a subject in recognized

need of such treatment comprising administering to the subject a therapeutically acceptable amount

of a compound of Formula (1), (IA) or (11) or a therapeutically acceptable salt thereof.

[00921 Certain embodiments provide a method of treating retroviral infection in a subject in

5 recognized need of such treatment comprising administering to the subject a therapeutically

acceptable amount of a compound of Formula (I) (IA) or (11) or a therapeutically acceptable salt

thereof

100931 Certain embodiments provide a method of treating liver toxicity following acetaminophen

overdose in a subject in recognized need of such treatment comprising administering to the subject a

10 therapeutically acceptable amount of a compound of Formula (f), (IA) or (11) or a therapeutically

acceptable salt thereof

100941 Certain embodiments provide a method of treating cardiac and kidney toxicities from

doxorubicin and platinum based antineoplastic agents in a subject in recognized need of such


15 compound offormula (I), (IA) or (II) or a therapeutically acceptable salt thereof.

100951 Certain embodiments provide a method of treating skin damage secondary to sulfur

mustards in a subject in recognized need of such treatment comprising administering to the subject a



20 100961 Certain embodiments provide a use of a compound of Formula (1) (IA) or (11) or a

therapeutically acceptable salt thereof, to prepare a medicament for inhibiting the PARP enzyme in a

subject in recognized need of such treatment.

100971 Certain embodiments provide a use of a compound of Formula (I), (IA) or (II) or a

therapeutically acceptable salt thereof, to prepare a medicament for inhibiting tumor growth in a

25 subject in recognized need of such treatment,

10098] Certain embodiments provide a use of a compound of Formula (), (IA) or (II) or a

therapeutically acceptable salt thereof, to prepare a medicament for treating cancer in a subject in

recognized need of such treatment.

[00991 Certain embodiments provide a use of a compound of Formula (I) (IA) or (II) or a

30 therapeutically acceptable salt thereof, to prepare a medicament for treating leukemia. colon cancer.

glioblastomas, lymphomas in a subject in recognized need of such treatment.

1001001 Certain embodiments provide a method of treating degenerative diseases including, but not

limited to, diabetes and Parkinson's disease in a subject in recognized need of such treatment


35 Formula (I) (IA) or (II) or a therapeutically acceptable salt thereof.

45

WO 2010/017055 PCT/US2009/051879

[001011 Certain embodiments provide a use of a compound of Formula (I), (IA) or (II) or a

therapeutically acceptable salt thereof, to prepare a medicament for potentiation of cytotoxic cancer

therapy in a subject in recognized need of such treatment comprising administering to the subject a


5 acceptable salt thereof

100102] Certain embodiments provide a use of a compound of Formula (I). (IA) or (I) or a

therapeutically acceptable salt thereof, to prepare a medicament for treating ischemia reperfusion

injury associated with, but not limited to, myocardial infarction, stroke, other neural trauma, and

organ transplantation, in a subject in recognized need of such treatment comprising administering to

10 the subject a therapeutically acceptable amount of a compound of Formula (.) (IA) or (II) or a

therapeutically acceptable salt thereof

1001031 Certain embodiments provide a use of a compound of Formula (1), (IA) or (iI) or a

therapeutically acceptable salt thereof, to prepare a mnedicament for treating reperfusion including,

but not limited to, reperfusion of the eye, kidney, gut and. skeletal muscle, in a subject in recognized

15 need of such treatment comprising administering to the subject a therapeutically acceptable amount

of a compound of Formula (I), (IA) or (ii) or a therapeutically acceptable salt thereof

1001041 Certain embodiments provide a use of a compound of Formula (1), (IA) or (II) or a

therapeutically acceptable salt thereof, to prepare a medicament for treating inflammatory diseases

including, but not limited to, arthritis, gout, inflammatory bowel disease, CNS inflammation,

20 multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemorrhagic shock, puhnonary fibrosis.

and uveitis in a subject in recognized need of such treatment comprising administering to the subject

a therapeutically acceptable amount of a compound of Formula (1) (TA) or (11) or a therapeutically



25 therapeutically acceptable salt thereof, to prepare a medicament for treating immunological diseases

or disorders such as rheumatoid arthritis and septic shock in a mammal in recognized need of such


compound of Formula (I), (IA) or (II) or a therapeutically acceptable salt thereof

1001061 Certain embodiments provide a use of a compound of Formula (I), (IA) or (II) or a

30 therapeutically acceptable salt thereof, to prepare a medicament for treating hypoglycemia in a


therapeutically acceptable amount of a compound of Formula (I), (IA) or (I) or a therapeutically



35 therapeutically acceptable salt thereof, to prepare a medicament for treating retroviral infection in a


46

WO 2010/017055 PCT/US2009/051879

therapeutically acceptable amount of a compound of Formula ((1A) or (11) or a therapeutically

acceptable salt thereof,

1001081 Certain embodiments provide a use of a compound of Formula (1), (IA) or (I1) or a

therapeutically acceptable salt thereof, to prepare a medicament for treating liver toxicity following

5 acetaminophen overdose in a subject in recognized need of such treatment comprising administering

to the subject a therapeutically acceptable amount of a compound of Formula (1), (IA) or (II) or a

therapeutically acceptable salt thereof.

1001091 Certain embodiments provide a use of a compound of Formula (1) (IA) or (11) or a

therapeutically acceptable salt thereof to prepare a medicament for treating cardiac and kidney

10 toxieities from doxorubicin and platinum based antineoplastic agents in a subject in recognized need

of such treatment comprising administering to the mammal a therapeutically acceptable amount of a

compound of Formula (1), (IA) or (11) or a therapeutically acceptable salt thereof.

[001101 Certain embodiments provide a use of a compound of Formula (I), (IA) or (II) or a

therapeutically acceptable salt thereof, to prepare a medicament for treating skin damage secondary

15 to sulfur mustards in a subject in recognized need of such treatment comprising administering to the

manual a therapeutically acceptable amount of a compound of Formula (I), (IA) or (II) or a

therapeutically acceptable salt thereof

1001111 Articles of manufacture, comprising packaging material, a compound provided herein that is

effective for modulating the activity of the enzyme poly(ADP-ribose)polynerase, or for treatment,

20 prevention or amelioration of one or more symptoms of a poly(ADP-ribose)polvmerase-dependent

or poly(ADP-ribose)polyNierase-mediated disease or condition, within the packaging material, and a

label that indicates that the compound or composition, or pharmaceutically acceptable salt.

pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically

acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating the

25 activity of poly(ADP-ribose)polymerase, or for treatment, prevention or amelioration of one or more

symptoms of a poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polymerase-mediated

disease or condition, are provided.

1001121 Any combination of the groups described above for the various variables is contemplated

herein.

30 1001131 In one embodiment, disclosed herein is a pharmaceutical composition comprising a

compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,

pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically

acceptable solvate of any of the compounds disclosed herein. in some embodiments, the

pharmaceutical compositions further comprises a pharmaceutically acceptable diluent, excipient or

3S binder; In certain embodiments, the pharmaceutical composition further comprises a second

pharmiaceutically active ingredient,

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WO 2010/017055 PCT/US2009/051879

[00114] In one embodiment, the PARP mediated disease or condition in a patient, or the PARP

dependent disease or condition in a patient is cancer or a non-cancerous disorder. in some

embodiments, the disease or condition is iatrogenic.

[00115] In some embodiments are methods for reducing/inhibiting the activity of PARP in subject

5 that include administering to the subject at least once an. effective amount of a compound described

herein.

100116] Certain embodiments provided herein are methods for modulating, including reducing

and/or inhibiting the activity of PARR directly or indirectly, in a subject comprising administering

to the subject at least once an effective amount of at least one compound described herein.

10 1001171 in further embodiments are methods for treating PARP mediated conditions or diseases,

comprising administering to the subject at least once an effective amount of at least one compound

described herein.

too190 81 Some embodiments include the use of a compound described herein in the manufacture of a

medicament for treating a disease or condition in a subject in which the activity of at least one PARP

'u protein contributes to the pathology and/or symptoms of the disease or condition.

00l 191 In any of the aforementioned embodiments are further embodiments in which administration

is enteral, parenteral., or both, and wherein:

(a) the effective amount of the compound is systemically administered to the subject;

(b) the effective amount of the compound is administered orally to the subject;

20 (c) the effective amount of the compound is intravenously administered to the subject;

(d) the effective amount of the compound administered by inhalation;

(e) the effective amount of the compound is administered by nasal administration;

(f) the effective amount of the compound is administered by injection to the subject;

(g) the effective amount of the compound is administered topically (dermal) to the subject;

25 (5h) the effective amount of the compound is administered by ophthalmic administration:

and/or

(i) the effective amount of the compound is administered rectally to the subject.

1001201 In any of the aforementioned embodiments are further embodiments that include single

administrations of the effective amount of the compound, including further embodiments in which

30 the compound is administered to the subject (i) once; (ii) multiple times over the span of one day;

(iii) continually; or (iv) continuously.

1001211 In any of the aforementioned embodiments are further embodiments that include multiple

administrations of the effective amount of the compound, including further embodinents wherein:

(i) the compound is administered in a single dose;

35 (ii) the time between multiple administrations is every 6 hours;

(iii) the compound is administered to the subject every 8 hours.

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WO 2010/017055 PCT/US2009/051879

[001221 In further or alternative embodiments, the method includes a drug holiday, wherein the

administration of the compound is temporarily suspended or the dose of the compound being

administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is

resumed. In some embodiments, the length of the drug holiday varies from 2 days to 1 year,

5 1001231 In any of the aforementioned embodiments involving the treatment of proliferative

disorders, including cancer, are further embodiments that include administering at least one

additional agent selected from among alemtuzumab, arsenic trioxide, asparaginase (pegylated or

non-), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine,

dauanorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemituzumab,

10 methotrexate, paclitaxel, Taxoi@, temozolomide, thioguanine, and classes of drugs including

hormones (an antiestogen, an antiandrogen, or gonadotropin releasing hormone analogues,

interferons such as, for example, alpha interferon, nitrogen mustards such as, for example, busulfan,

melphalan or mechlorethamine, retinoids such as, for example, tretinoin, topoisomerase inhibitors

such as, for example, irinotecan or topotecan, tyrosine kinase inhibitors such as, for example,

15 gefinitinib or imatinib, and agents to treat signs or symptoms induced by such therapy including

allopurinol, filgrastim, granisetron/ondansetron/palonosetron, and dronabinoI.

1001241 Other objects, features and advantages of the compounds, methods and compositions

described herein will become apparent from the following description. It should be understood,

however, that the description and the specific examples, while indicating specific embodiments, are

20 given by way of illustration only, since various changes and modifications within the spirit and

scope of the present description will become apparent from this detailed description.

1001251 Described herein are compounds, methods of making such compounds, pharmaceutical

compositions and medicaments that include such compounds, and methods of using such

compounds to treat or prevent diseases or conditions associated with PARP activity.

25 1001261 Described herein are compounds having activity in inhibiting the enzyme poly(ADP

ribose)polymerase (PARP ). In some embodiments, the compounds have the structure set forth in

Formula (1), (IA) or (II)

[001271 The mammalian enzyme PARP-1 is a multidomain protein. PARP-l is implicated in the

signaling of DNA damage through its ability to recognize and rapidly bind to DNA single or double

30 strand breaks. D'Amours, et al., Biochem. J., 342, 249-268 (1999); and Virag et al.

Pharmacological Reviews, vol. 54, no. 3. 375-429 (2002) are hereby incorporated by reference for

such disclosure.

][001281 The family of poly(ADP-ribose)polymerases includes approximately 18 proteins, which all

display a certain level of homology in their catalytic domain but differ in their cellular functions.

35 PARP-1 and PARP-2 are unique members of the family, in that their catalytic activities are

49

WO 2010/017055 PCT/US2009/051879

stimulated by the occurrence of DNA strand breaks. Ame et at, BioEssays.. 26(8), 882-893 (2004)

is hereby incorporated by reference for such disclosure.

[001291 PARP-1 participates in a variety of DNA-related functions including gene amplification,

cell division, differentiation, apoptosis, DNA base excision repair as well as effects on telomere

5 length and chromosome stability. d'Adda di Fagagna, et al. Nature Gen, 23(1), 76-80 (1999) is

hereby incorporated by reference for such disclosure.

1001301 Studies on the mechanism by which PARP-I modulates DNA repair and other processes

identifies its importance in the formation of poly(ADP-ribose) chains within the cellular nucleus.

The DNA-bound., activated PARP-1. utilizes NAD- to synthesize poly(ADP-ribose) on a variety of

10 nuclear target proteins, including topoisomerases, histones and PARP itself. Althaus, F. R. and

Richter, C, ADP-Ribosylation of Proteins: Enzymology and Biological Significance, Springer

Verlag, Berlin (1987); and Rhun, et al, Biochem. Biophys. Res. Commnun., 245, 1-10 (1998) are

hereby incorporated by reference for such disclosure.

1001311 Poly(ADP-ribosyl)ation is also associated with malignant transformation. For example,

15 PARP-1 activity is higher in the isolated nuclei of SV4O-transformed fibroblasts, while both

leukemia cells and colon cancer cells show higher enzyme activity than the equivalent normal

leukocytes and colon rucosa. Furthermore. malignant prostate tumors have increased levels of

active PARP as compared to benign prostate cells, which is associated wit higher levels of genetic

instability. Miwa, e at, Arch. Biochem, Biophys, 181, 313-321 (1977); Burzio. eta., Proc. Soc.

20 Exp. Bil. Med., 149, 933-938 (1.975); Hirai, et al, Cancer Res., 43, 3441-3446 (1983); and

Mcnealy, et al., Anticancer Res., 23. 1473-1478 (2003) are hereby incorporated by reference for

such disclosure.

1001321 In cells treated with alkylating agents, the inhibition of PARP leads to a marked increase in

DNA-strand breakage and cell killing. PARP-1 inhibitors also enhance the effects of radiation

25 response by suppressing the repair of potentially lethal damage. PARP inhibitors are also effective

in radio-sensitizing hypoxic tumor cells. In certain tumor cell lines, chemical inhibition of PARP

activity is also associated with marked sensitization to very low doses of radiation.

[001331 Furthermore, PARP-1 knockout (PARP -/-) animals exhibit genomic instability in response

to alkylating agents and y-irradiation. Data indicates that PARP- and PARP-2 possess both

30 overlapping and non-redundant functions in the maintenance of genomic stability, making them both

interesting targets. Wang. et atl Genes Dev, 9, 509-520 (1995); Menissier de Murcia, el al, Proc.

Nat. Acad, Sci. USA, 94, 7303-7307 (1997); and Menissier de Murcia, el at, EMBO .L 22(9),

2255-2263 (2003) are hereby incorporated by reference for such disclosure.

1001341 There is also a role for PARPI-1 in certain vascular diseases, such as, for example, septic

35 shock ischaemic injury and neurotoxicity. Oxygen radical DNA damage that leads to strand breaks

in DNA, which are subsequently recognized by PA RP-1, is a major contributing factor to such

50

WO 2010/017055 PCT/US2009/051879

disease states as shown by PARP-1 inhibitor studies. PARP also plays a role in the pathogenesis of

hemorrhagic shock. Cantoni, et aL Blochim. Biophys. Acta. 1014, 1-7 (1989); Szabo, et al. J Clin,

invest, 100, 723-735 (1997); Cosi, et aL, J Neurosci. Res., 39, 3846 (1994); Said, et at, Proc. Nat[

Acad Sci USA., 93, 4688-4692 (1996); and Liaudet et a., Proc Nat Acad.Sc. USAi, 97(3),

5 10203-10208 (2000) are hereby incorporated by reference tr such disclosure.

[001351 Furthermore, efficient retroviral infection of mammalian cells is blocked by the inhibition of

PARP- I activity. Such inhibition of recombinant retroviral vector infections occurs in various

different cell types. In some embodiments, inhibitors of PARP-I are used in anti-viral therapies and

in cancer treatment. Oaken, et al I Virolc gv. 70(6). 3992-4000 (1996) is hereby incorporated by

10 reference for such disclosure.

1001361 Moreover, in certain embodiments; PARP1 inhibition delays the onset of aging

characteristics in human fibroblasts. While not intending to bound by any theory, this may be related

to the role that PARP plays in controlling telomere function. Rattan and Clark, Biochem. Biophrys.

Res. Comm., 201(2), 665-672 (1994): and d Adda di Fagagna, et al, Nature Gen, 23(1). 76-80

15 (1999) are hereby incorporated by reference for such disclosure.

1001371 In soine embodiments, PARP inhibitors are relevant to the treatment of inflammatory bowel

disease, ulcerative colitis and Crohn's disease. Szabo C., Role of Poly(ADP-Ribose) Polyimerase

Activation in the Pathogenesis of Shock and Inflammation, In PARP as a Therapeutic Target; Ed J.

Zhang, 2002 by CRC Press; 169-204; Zingarelli, B, e alt, Immunology. 113(4), 509-517 (2004);

20 and Jijon, H. B., et al, Am. J Phvsiol. Gastrointest. Liver Physiol, 279, G641-G651 (2000) are

hereby incorporated by reference for such disclosure,

1001381 In certain embodiments,. PARP inhibitors, such as those of Formula (I), (IA) or (11), have

utility in: (a) preventing or inhibiting poly(ADP-ribose) chain formation by, e g. inhibiting the

activity of cellular PARP (PARP-1 and/or PARP-2); (b) treating vascular disease; septic shock;

25 ischaemic injury, both cerebral and cardiovascular; reperfusion injury, both cerebral and

cardiovascular; neurotoxicity, including acute and chronic treatments for stroke and Parkinson's

disease; hemorrhagic shock; inflammatory diseases, such as arthritis, inflammatory bowel disease,

ulcerative colitis and Crohn's disease; multiple sclerosis: secondary effects of diabetes as well as the

acute treatment of cytotoxicity following cardiovascular surgery or diseases ameliorated by the

30 inhibition of the activity of PARP; (c) use as an adjunct in cancer therapy or for potentiating tumor

cells for treatment with ionizing radiation and/or chemotherapeutic agents.

1001391 In specific embodiments, compounds provided herein, such as, for example, Formula (f),

(IA) or (iik are used in anti-cancer combination therapies (or as adjuncts) along with alkylating

agents, such as methyl methanesulfonate (MMS), temozolomide and dacarbazine (DTIC), also with

35 topoisomerase- 1 inhibitors like Topotecan, Irinotecan, Rubitecan, Exatecan, Lurtotecan, Gimetecan,

Diflomotecan (homocamptothecins); as well as 7-substituted non-silatecans; the 7-silyl

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WO 2010/017055 PCT/US2009/051879

camptothecins, BNP 1350; and non-camptothecin topoisomerase-I inhibitors such as

indolocarbazoles also dual topoisomerase-I and I inhibitors like the bernzophenazines, XR

I I576/MLN 576 and benzopyridoindoles. In certain embodiments, such combinations are. given, for

example, as intravenous preparations or by oral administration as dependent on the method of

5 administration for the particular agent.

1001401 In some embodiments, PARP inhibitors, such as, for example, compounds of Formula (I), (IA) or (11), are used in the treatment of disease ameliorated by the inhibition of PARR, which

includes administering to a subject in need of treatment a therapeutically-effective amount of a

compound provided herein, and in one embodiment in the form of a pharmaceutical composition. In

to certain embodiments PARP inhibitors, such as, for example, compounds of Formula (1), (IA) or (UI).

are used in the treatment of cancer, which includes administering to a subject in need of treatment a

therapeutically-effective amount of a compound provided herein in combination, and in one

embodiment in the form of a pharmaceutical composition, simultaneously or sequentially with

radiotherapy (ionizing radiation) or chemotherapeutic agents.

15 1001411 In certain embodiments, PAIP inhibitors, such as, for example, compounds of Formula (I),

(IA) or (11), are used in the preparation of a medicament for the treatment of cancer which is

deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair

activity, or in the treatment of a patient with a cancer which is deficient in FIR dependent DNA DSB

repair activity, which includes administering to said patient a therapeutically-effective amount of the

20 compound.

[00142] The HR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA

via homologous mechanisms to reform a continuous DNA he ix, The components of the HR

dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051)4 RADS1

(NM 002875). RADS IL] (NM 002877). RAD51C (NM _002876), RAD51L 3 (NM 002878),

25 DMC I (NM 007068), XRCC2 (NM.005431), XRCC3 (NM 005432). RAD52 (NM_002879).

RAD54L (NM 003579), RADS4B (NM 012415), BRCAI (NM 007295). BRCA2 (NM 000059). RAD50 (NM 005732), MRVE I IA (NM005590) and NBS 1 (NM_002485). Other proteins involved

in the HR dependent DNA DSB repair pathway include regulatory factors such as EMSY, HR

components are also described in Wood, et al., Science, 291, 1284-1289 (2001), which is hereby

30 incorporated by reference for such disclosure. K. K Khanna and S. P. Jackson Nat. Gene. 27(3):

247-254 (2001'); and Ilughes-Davies, el al, Cell, 115; pp 523-535 are also incorporated herein by

reference for such disclosure.

1001431 In some embodiments. a cancer which is deficient in HR dependent DNA DSB repair

includes one or more cancer cells which have a reduced or abrogated ability to repair DNA DSBs

35 through that pathway, relative to normal cells, i.e. the activity of the HR dependent DNA DSB repair

pathway are reduced or abolished in the one or more cancer cells,

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WO 2010/017055 PCT/US2009/051879

1001441 In certain embodiments. the activity of one or more components of the IR dependent DNA

DSB repair pathway is abolished in the one or more cancer cells of an individual having a cancer

which is deficient in HR dependent DNA DSB repair. Components of the FIR dependent DNA DSB

repair pathway include the components listed above.

5 1001451 In some embodiments, the cancer cells have a BRCA1 and/or a BRCA2 deficient

phenotype, i.e. BRCA1 and/or BRCA2 activity is reduced or abolished in the cancer cells. In certain

embodiments, cancer cells with this phenotype are deficient in BRCAl and/or BRCA2, i.e.,

expression and/or activity of BRCA1 and/or BRCA2 is reduced or abolished in the cancer cells, for

example by means of mutation or polymorphism in the encoding nucleic acid, or by means of

10 amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the

EMSY gene which encodes a BRCA2 regulatory factor or by an epigenetic mechanism such as gene

promoter methylation.

1001461 BRCA 1 and BRCA2 are tumor suppressors whose wild-type alleles are frequently lost in

tumors of heterozygous carriers. BRCA I and/or BRCA2 mutations are associated with breast

15 cancer. Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is associated

with breast and ovarian cancer. Jasin M.. Oncogene 21(58) 8981-93 (2002); Tutt. et aL, Thends

Mt Med., 8(12), 571-6, (2002); and Radice, P. J., Exp C/in Cancer Res, 21(3 Suppl), 9-12 (2002)

are hereby incorporated by reference for such disclosure.

1001471 Carriers of mutations in BRCAI and/or BRCA2 are also at elevated risk of cancer of the

20 ovary, prostate and pancreas,

1001481 In some embodiments, the individual is heterozygous for one or more variations, such as

mutations and polymorphisms, in BRCA 1 and/or BRCA2 or a regulator thereof The detection of

variation in BRCA I and BRCA2 is described, for example in EP 699 754, EP 705 903, Neuhausen,

S. L. and Ostrander, E. A., Genet, Test, 1, 75-83 (1992); Janatova M., et a. Neoplasma, 50(4), 246

25 50 (2003), which is hereby incorporated by reference for such disclosure. Determination of

amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies, ei al.: Cell, Il 5,

523-535),

[001491 In certain instances, mutations and polymorphisms associated with cancer are detected at the

nucleic acid level by detecting the presence of a variant nucleic acid sequence or at the protein level

30 by detecting the presence of a variant (i.e. a mutant or allelic variant) polypeptide.

DEFINITIONS

1001501 Unless defined otherwise, all technical and scientific terms used herein have the standard

meaning pertaining to the claimed subject matter belongs. in the event that there are a plurality of

definitions for terms herein, those in this section prevaiL Where reference is made to a URL or other

35 such identifier or address, it understood that such identifiers can change and particular information

53

WO 2010/017055 PCT/US2009/051879

on the internet can come and go, but equivalent information can be found by searching the internet,

Reference thereto evidences the availability and public dissemination of such information.

[001511 It is to be, understood that the foregoing general description and the following detailed

description are exemplary and explanatory only and are not restrictive of any subject matter claimed,

5 In this application, the use of the singular includes the plural unless specifically stated otherwise. It

must be noted that, as used in the specification and the appended claims, the singular forms "a,"

"an" and "the" include plural referents unless the context clearly dictates otherwise, in this

application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term

"including" as well as other forms, such as "include", "includes," and "included," is not limiting.

10 1001521 Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC,

protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. Unless specific definitions are provided, the standard nomenclature employed in connection with,

and the standard laboratory procedures and techniques of, analytical chemistry, synthetic organic

chemistry, and medicinal and pharmaceutical chemistry are employed. In certain instances, standard

1 techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation,

formulation, and delivery, and treatment of patients. In certain embodiments, standard techniques

are used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation

(eg. electroporation, lipofection). In some embodiments, reactions and purification techniques are

performed e.g,, using kits of manufacturer's specifications or as commonly accomplished or as

20 described herein.

1001 51 As used throughout this application and the appended claims, the following terms have the

following meanings:

1001.541 The term "alkenyl" as used herein, means a straight, branched chain, or cyclic (in which

case, it would also be known as a "cycloalkenyl") hydrocarbon containing from 2-i40 carbons and

25 containing at least one carbon-carbon double bond formed by the removal of two hydrogens. In

some embodiments, depending on the structure, an alkenyl group is a monoradical or a diradical

(i.e., an alkenylene group). In some embodiments, alkenyl groups are optionally substituted.

Illustrative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2

propenyl, 3-butenyl, 4-pentenyl, 5-bexenyl, 2-heptenyl, 2-methyl-lI-heptenyl, and 3 -cecenyl

30 1001551 The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the

parent molecular moiety through an oxygen atom. Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy tert-butoxy, pentyloxy and hexyloxy.

1001561 The term "alkyl" as used herein, means a straight, branched chain, or cyclic (in this case, it

would also be known as "cycloalkyl") hydrocarbon. containing from 1- 10 carbon atoms. Illustrative

35 examples of alkyl include, but are not limited to, methyl, ethyl, n-propyt iso-propyl, n-butyl, sec

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WO 2010/017055 PCT/US2009/051879

butyl, tert-butyI, n-pentyl, isopentyl, neopentyl. n-hevy 3-methylihexyl, 2,2-dimethylpentyl, 2,3

dimethylhexyl, n-heptyl, n-octyl, n-nonyl. and n-decyL

1001571 The term "C-C-alkyl" as used herein, means a straight, branched chain, or cyclic (in this

case, it would also be known as "cycloalkyl") hydrocarbon containing from 1-6 carbon atoms.

5 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,

cyclopyl n-butyl, sec-butyl, terbutyl, cyclobutyl, n-pentyl, isopentyl. neopentyl, cyclopentyl, and

n-hexyl.

1001581 The term "cycloalkyi as used herein, means a monocyclic or polveyclic radical that

contains only carbon and hydrogen, and includes those that are saturated, partially unsaturated, or

10 fully unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative

examples of cyclic include but are not limited tot the following moieties:

OA O

15 . In some embodinents, depending

on the structure. a cycloalkyl group is a monoradical or a diradical (e.g., a cycloalkylene group),

100159l The term "cycloalkyl groups" as used herein refers to groups which are optionally

substituted with 1,2, 3. or 4 substituents selected from alkenyl, alkoxy, alkoxyalkyl

alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alky lthicialkyl, alkynyl, carboxy,

20 cyano, fornyl, haloalkoxy, haloalkyl,. halogen, hydroxyl, hydroxyalkylene, mercapto, oxo-NRJRA,

and (N~kR 1)carbonyl

1001601 The term "eycloalkylalkyl" as used herein, means a cycloalkyl group, as defined herein,

appended to the parent molecular moiety through an alkyl group, as defined herein. Representative

examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutvlethyL,

25 cyclopentylmethyl. cyclohexylmethyl and 4-cycloheptylbutyl.

1001611 The term "carbocyclic" as used herein, refers to a compound which contains one or more

covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon

atoms

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WO 2010/017055 PCT/US2009/051879

1001621 The term "carbocycle" as used herein, refers to a ring, wherein each of the atoms forming

the ring is a carbon atom. Carbocylic rings include those formed by three, four, five, six, seven,

eight, nine, or more than nine carbon atoms. Carbocycles are optionally substituted.

1001.631 The term "alkoxyalkyl" as used herein, means at least one alkoxy group, as defined herein,

5 appended to the parent molecular moiety through an alkyl group, as defined herein. Illustrative

examples of alkoxyalkyl include, but are not limited to, 2-methoxyethyl, 2-ethoxyethyl, tert

butoxyethyl and methoxymethyl.

[001641 The term "alkoxycarbonyl" as used herein, means an alkoxy group, as defined herein,

appended to the parent molecular moiety through a carbonyl group, as defined herein, Illustrative

10 examples of alkoxvcarbonyl include, but are not limited to, methoxycarbonyl. ethoxycarbonyl, and

tert-butoxycarbonyl.

1001651 The term "alkoxycarbonylalkyl" as used herein, means an alkoxycarbonyl group, as defined

herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[001661 The term "alkylcarbonyl" as used herein, means an alkyl group, as defined herein, appended

15 to the parent molecular moiety through a carbonyl group, as defined herein. Illustrative examples of

alkylcarbonyl include, but are not limited to, acetyl, 1 -oxopropyl, 2,2-dimethyl- I -oxopropyl, 1

oxobutyl., and 1-oxopentyl.

[001671 The term "alkylcarbonyloxy" as used herein, means an alkylcarbonyl group, as defined

herein, appended to the parent molecular moiety through an oxygen atom. illustrative examples of

20 alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylearbonyloxy, and tert

butylearbonyloxy.

1001681 The term "alkylthio" or "thioalkoxy" as used herein, means an alkyl group, as defined

herein, appended to the parent molecular moiety through a sulfur atom. Illostrative examples of

alkylthio include, but are not limited to, methylthio, ethylthio. butylthio, tert-butylthio, and

25 hexylthio.

[001691 The tern "alkylthioalkyl" as used herein, means an alkylthio group, as defined herein,

appended to the parent molecular moiety through an alkyl group, as defined herein. Illustrative

examples of alkylthioalkyl include, but are not limited to, methylthiomethyl, 2-(ethylthio)ethyl,

butylthiomethy1, and hexylthioethyl.

30 [00170] The term "alkynyi" as used herein, means a straight, branched chain hydrocarbon containing

from 2-10 carbons and containing at least one carbon-carbon triple bond. In some embodiments,

alkynyl groups are optionally substituted. Illustrative examples of alkynyl include, but are not

limited to, acetylenyl. 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and I -butynyl.

1001711 The term "aromatic" as used herein, refers to a planar ring having a delocalized r-,electron

35 system containing 4n+2 7 electrons, where n is an integer. In some embodiments, aromatic rings are

formed by five, six, seven, eight, nine, or more than nine atoms, In other embodiments, aromatics

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WO 2010/017055 PCT/US2009/051879

are optionally substituted. The term includes monocyclic or fused-ring polycyclic (ile. rings which

share adjacent pairs of carbon atoms) groups.

[001721 The term "aryl" as used herein, refers to an aromatic ring wherein each of the atoms forming

the ring is a carbon atom. In some embodiments, aryl rings are formed by five, six, seven, eight,

5 nine, or more than nine carbon atoms, Examples of aryl groups include, but are not limited to

phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl

1001731 In some embodiments, the term "aryl" as used herein means an aryl group that is optionally

substituted with one, two, three, four or five substituents independently selected from the group

consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alky I, alkylcarbonyl, alkylcarbonyloxy,

10 alkylthio, alkylthioalkyl, alkynyl, carbonyl, cyano, formyl, haloalkoxy. haloalkyl, halogen,

hydroxyl, hydroxyalkylene. mercapto, nitro, -NRARA, and (NRARa carbonyli.

[001741 The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the

parent molecular moiety through an alkyl group, as defined herein. Illustrative examples of arylalkyl

include, but are not limited to benzyL 2-phenylethyl, -ph enylpropyl, 1-methyl-3 -phenylpropyl, and

15 2-naphth-2-ylethyl.

[001751 The term "carbony" as used herein, means a -C(O)- group.

1001761 The term "carboxv" as used herein, means a -COOH group,

1001771 The term "cyano" as used herein, means a -CN group.

[001781 The term formall" as used herein, means a -C(O)H group.

20 1001791 The term "halo" or "halogen" as used herein, means a -Cl, -Br, -1 or -F.

1001801 The term "mercapto" as used herein, means a -SH group.

1001811 The term "nitro" as used herein, means a -NO 2 group,

[001821 The term "hydroxy" as used herein, means a -OH group,

1001831 The term "oxo" as used herein, means a =O group.

25 1001841 The term "bond" or "single bond" as used herein, refers to a chemical bond between two

atoms, or two moieties when the atoms joined by the bond are considered to be part of larger

substructure.

1001851 The terms "haloalkyl" "haloalkenyt" "haloalkynyi" and "haloalkoxy" as used herein,

include alkyl, alkenyl, alkynyl and alkoxy structures in which at least one hydrogen is replaced with

30 a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with

halogen atoms, the halogen atoms are all the same as one another, in other embodiments in which

two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the

same as one another.T he terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy

groups, respectively, in which the halo is fluorine, in certain embodiments, haloalkyls are optionally

35 substituted.

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WO 2010/017055 PCT/US2009/051879

[00186j The term "alkylamine" refers to the -N(alkyl)tHy group, where x and y are selected from

among x=1, y=1 and x=2, y=0. In some embodiments, when x=2, the alkyl groups, taken together

with the N atom to which they are attached, optionally form a cyclic ring system.

[001871 The term "amide" as used herein, is a chemical moiety with the formula -C(O)N.H-R or

5 -NHC(O)R, where R is selected from among hydrogen, alkyL cycloalkyl, aryl, heteroaryl (bonded

through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). In some embodiments,

an amide moiety forms a linkage between an amino acid or a peptide molecule and a compound

described herein, thereby forming a prodrug. In some embodiments, any amine, or carboxyl side

chain on the compounds described herein is amidified,

10 [001881 The term "ester" refers to a chemical moiety with formula -COOR, where R. is selected

from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl

(bonded through a ring carbon). In some embodiments, any hydroxy, or carboxyl side chain on the

compounds described herein is esterified

1001891 The terms "heteroalklv "heteroalkenyl' and "heteroalkynyf" as used herein, include

1 optionally substituted alkyl, alkenyl and alkynyl radicals in which one or more skeletal chain atoms

are selected from an atom other than carbon, e g oxygen, nitrogen, sulfur, silicon, phosphorus or

combinations thereof

[00190] The term "heteroatom" as used herein refers to an atom other than carbon or hydrogen.

Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen silicon and

20 phosphorus, but are not limited to these atoms In embodiments in which two or more heteroatoms

are present, the two or more heteroatoms are all the same as one another, or some or all of the two or

more heteroatoms are each different from the others.

1001911 The term "ring" as used herein, refers to any covalently closed structure. Rings include, for

example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and

25 heterocycloalkyls) aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and

heterocycloalkyls). in some embodiments, rings are optionally substituted. In some embodiments,

rings form part of a ring system.

1001921 As used herein, the term "ring system" refers to two or more rings, wherein two or more of

the rings are fused. The term "fused" refers to structures in which two or more rings share one or

30 more bonds.

1001931 The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that

includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An. N-containing

"heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the

skeletal atons of the ring is a nitrogen atom. In some embodiments, the polycyclic heteroaryl group

35 is fused or non-fused. Illustrative of heteroaryl groups include, but are nrot limited to, the following

moieties:

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N / NNH N~N

N N 9 N

N $ 0 O N S S

N 0N CN NN

N NNN

N

N 5 S . In some embodiments, depending on the structure, a.

heteroaryl groip is a monoradical or a diradical (i.e.., a heteroarylene group).

[001941 The tern "heteroaryl" means heteroaryl groups that are substituted with 0, 1, 21 3, or 4

substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl.

alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alynyl, carboxy, cyano, forml.

1o haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, -NRA, and

(NRAR 8)carbonyl.

100 1951 The term "heteroarylalkyl" as used herein, means a heteroaryl, as defined herein, appen ded

to the parent molecular moiety through an alkyl group, as defined herein. Illustrative examples of

heteroaryaIalkyl include, but are not limited to, pyridinyhnIethyl.

15 1001961 The term "heterocycloalkyl" or "non-aromatic heterocycle" as used herein, refers to a non

aromatic ring wherein one or more atoms forming the ring is a heteroatom. A "heteroceloalky" or

"non-aromatic heterocycle" group refers to a cycloalkyl group that includes at least one heteroatom

selected from nitrogen, oxygen and sulfur. In some embodiments, the radicals are fused with an aryl

or heteroarvl In some embodiments. heterocycloalkyl rings are formed by three, four, five, six, 20 seven, eight, nine, or more than nine atoms, In some embodiments, heterocycloalkyl rings are

optionally substituted. In certain embodiments, heterocycloalkyls contain one or more carbonyl or

thiocarbonyl groups such as, for example, oxo- and thio-containing groups, Examples of

heterocycloalkyls include, but are not limited to. lactams, lactones, cyclic imides, cyclic thioimides,

cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine 1,3-dioxin, 1,3

25 dioxane. 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane 1,4-oxathiin., 1,4-oxathiane, tetrahydro

1,4-thiazine, 211-1,2-oxazine , maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, diivdrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,

tetrahydrothiophene, tetrahydrofuran, pyrroline; pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,

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pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole. 1,3-dithiolane,

isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolid inone. thiazoline. thiazolidine, and 1,3

oxathiolane. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic

heterocycles, include, but are not limited to

0 0 O 0 0 0 0

S SN N t N O ON O N 0H NN N 00 0

5C , -N

NN O

H ~0 N0

ON N N H H H H

0 N O O0

The term heterocycloalkyl

also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides,

10 the disaccharides and the oligosaccharides.

1001971 The term "heterocycle" refers to heteroaryl and beterocycloalkyl used herein, refers to

groups containing one to four heteroatoms each selected from 0. S and N, wherein each heterocycle

group has from 4 to 10 atoms in its ring system, and with the proviso that the ring of said group does

not contain two adjacent 0 or S atoms. Herein, whenever the number of carbon atoms in a

I heterocycle is indicated (e.g., C1-C6 heterocycle), at least one other atom (the heteroatom) must be

present in the ring. Designations such as "C1-C4 heterocycle" refer only to the number of carbon

atoms in the ring and do not refer to the total number of atoms in the ring. In some embodiments, it

is understood that the heterocycle ring has additional heteroatoms in the ring. Designations such as

"4-6 membered heterocycle" refer to the total number of atoms that are contained in the ring (i.e., a

20 four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a

heteroatoin and the remaining two to four atoms are either carbon atoms or heteroatonis). In some

embodiments, in heterocycles that have two or more heteroatoms, those two or more heteroatorms

are the same or different from one another. In some embodiments, heterocycles are optionally

substituted, In some embodiments, binding to a heterocycle is at a heteroatom or via a carbon atom.

25 Heterocycloalkyl groups include groups having only 4 atoms in their ring system but heteroaryl

groups must have at least 5 atoms in their ring system. The heterocycle groups include benzo-fused

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ring systems. An example of a 4-membered heterocycle group is azetidinyl (derived from azetidine).

An example of a 5-membered heterocycle group is thiazolyl. An example of a 6-membered

heterocycle group is pyridyl, and an example of a I 0-membered heterocycle group is quinolinyl.

Examples of heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,

5 tetrahydrothienyl, tetrahydropyranyl, dilhydropyranyl. tetrahydrothiopyranyl, piperidino,

morpholino, thiomorpholino, thioxanyl. piperazinyl, azetidinvi. oxetanyl, thietanyl,

homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2.3,6

tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl. 4H-pyranyl, dioxanyl, 1,3

dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,

10 pyrazolidinyl, imidazolinyt imidazolidinyl 3-azabicyclo[3.L0]hexanyl, 3

azabicyclo[41.0]heptanylh 3H-indolyl and quinolizinyl. Examples of heteroaryl groups are

pyridinyl, imidazolyi pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyL thienyl,

isoxazolyl, thiazolyl oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,

benzimidazolyl, benzofuranyl. cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,

15 isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,

benzothiophenyl, benzothiazolyl, benzoxazolyl. quinazolinyl, quinoxalinyl, naphthyridiyl, and

furopyridinyl. in some embodiments, the foregoing groups, as derived from the groups listed above,

are C-attached or N-attached where such is possible. For instance. in some embodiments, a group

derived from pyrrole is pyrrol I-yi (N-attached) or pyrrol-3-yl (C-attached). Further, in some

20 embodiments, a group derived from imidazole is imidazol-l-yl or inidazol-3-yl (both N-attached) or

imidazol-2-yi, imidazol-4-yi or irmidazol-5-yl (all C-attached). 'he heterocycle groups inchide

benzo-fused ring systems and ring systems substituted with one or two oxo (=O) moieties such as

pyrrolidin-2-one, In some embodiments, depending on the structure. a heterocycle group is a

monoradical or a diradical (i e, a heterocyclene group).

25 [001981 The heterocycles described herein are substituted with 0, 1, 2 3, or 4 substituents

independently selected from alkenytl alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl. alkylcarbonyl,

alkylcarbonyloxy, alkylthio, alkylthioalkyl, alynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,

halogen, hydroxyl, hydroxyalkylene, mercapto, nitro NRARB, and -(NRARB)carbonyl

[001991 The term "heterocycloalkoxy" refers to a heterocycloalkyl group, as defined herein,

30 appended to the parent molecular moiety through an alkoxy group.

1002001 'The term "heterocycloalkylthio" refers to a heterocycloalkyl group, as defined herein,

appended to the parent molecular moiety through an alkyithio group,

1002011 The term "heterocyclooxy" refers to a heterocycloalkyl group, as defined herein, appended

to the parent molecular moiety through an oxygen atom.

35 1002021 The term "ieterocyclothio" refers to a heterocycloalkyl group, as defined herein, appended

to the parent molecular moiety through a sulfur atom.

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[002031 The term "heteroarvlalkoxy" refers to a heteroaryl group, as defined herein, appended to the

parent molecular moiety through an alkoxy group.

1002041 The term "heteroarylalkylthio" refers to a heteroaryl group, as defined herein, appended to

the parent molecular moiety through an alkylthio group.

5 1002051 The term "heteroaryloxy" refers to a heteroaryl group, as defined herein, appended to the

parent molecular moiety through an oxygen atom.

[002061 The term "heteroarvlthio" refers to a heteroaryl group, as defined herein, appended to the

parent molecular moiety through a sulfur atom.

[002071 In some embodiments, the term "menbered ring" embraces any cyclic structure. The term

10 "membered" is meant to denote the number of skeletal atoms that constitute the ring. Thus, for

example. cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole,

furan, and thiophene are 5-membered rings.

1002081 The term "non-aromatic 5, 6, 7, 8, 9, 10, 11 or 12- bicyclic heterocycle" as used herein,

means a heterocycloalkyl, as defined herein, consisting of two carbocyclic rings, fused together at

15 the same carbon atom (forming a spiro structure) or different carbon atoms (in which two rings share

one or more bonds), having 5 to 12 atoms in its overall ring system, wherein one or more atoms

forming the ring is a heteroatom. Illustrative examples of non-aromatic 5, 6, 7, 8, 9, 10t 11, or 12

bicyclic heterocycle ring include, but are not limited to, 2- azabicyclo[22.J]heptanyl, 7

azabicyclo[2 .2.jheptanyl, 2- azabicyclo[3 .2 .0]lheptanyl, 3- azabicyclo[3.2.0]heptanyl, 4

20 azaspiro[24]heptanyi 5- azaspiro[2.4]heptanyl, 2-oxa-5- azabicyclo[2.2.1 ]beptanyl, 4

azaspiroj2. 5joctanyl, 5- azaspiro[2.5 ]octanyl, 5- azaspiro[3 4]octanyl, 6- azaspiroj3 ,4]octanyl, 4

oxa-7- azaspiro{2.5]octanyl, 2- azabicyclo[2.22]octanyl. 1,3- diazabicyclo[2.2.2joctanyl, 5

azaspiro{3. 5]nonanyl, 6- azaspiro[3.5]nonanyl, 5-oxo- 8- azaspiro{3.5]nonanyl,

octahvdrocvclopentaf[c]pyrroly, octahydro-1 H-quinolizinyl. 2. .3,4,6,7,9a-hexahydro-ll-

25 quinolizinyl. decahydropyrido [1 ,2-alazepinyl decahydro- IH-pyrido[l,2-aazocinyl, I

azabicyc lof2 .2.1]heptany I azabicvclo[3 .3. 1]jnonanyl, quinuclidinyk and I

azabicyclo{4.4.0]decanyl.

1002091 The term hydroxyalkylene" as used herein, means at least one hydroxyl group, as defined

herein, is appended- to the parent molecular moiety through an alkylene group, as defined herein.

30 Illustrative examples of hydroxyalkylene include, but not limited to bydroxymethylene, 2-hydroxy

ethylene, 3 -hydroxypropylene and 4-hydroxyheptylene.

[002101 The tern "NRANR" as used herein, means two group, RA and R, which are appended to

the parent molecular moiety through a nitrogen atom. R and R5 are each independently hydrogen,

alkyl and alkylcarbonyi. Illustrative examples of NRkR- include, but are not limited to, amino,

35 methylamino, acetylamino, and acetymethylamino.

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WO 2010/017055 PCT/US2009/051879

[002111 The term "(NRANR)carbonvl" as used herein, means a RARa, group, as defined herein,

appended to the parent molecular moiety through a carbonyl group, as defined herein, Illustrative

examples of (N*RARB)carbonyl include, but are not limited to, aminocarbonyl

(methylamino)carbonyl, (dimethylamino)carbonyt, and (ethylmethylamnino)carbonvl.

5 1002121 The term "N&cNRn" as used herein, means two group, Re and R0 , which are appended to

the parent molecular moiety through a nitrogen atom. Re and RD are each independently hydrogen,

alkyl. and alkylcarbonyl. Illustrative examples of NRR 0 include, but are not limited to, amino,

methylamino, acetylamino, and acetylnethyl amino.

[00213] The term "(NRcNR 9)carbonyl" as used herein, means a ReR0 , group, as defined herein,

10 appended to the parent molecular moiety through a carbonyl group as defined herein. Illustrative

examples of (NRcRo)carbonvl include, but are not limited to, aminocarbonyl,

(inethylamino)carbonyl, (dimethylamino)carbonyl, and (ethvlmethylamino)carbonyl.

1002141 As used herein, the term "mercaptyl" refers to a (alkyl)S- group.

100215] As used herein, the term "moiety" refers to a specific segment or functional group of a

15 molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a

molecule.

1002161 As used herein, the term "sulfinyl" refers to a -S(=))-R, where R is selected from the group

consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl

(bonded through a ring carbon).

20 1002171 As used herein, the term "sulfonyl" refers to a -S(=O)-R., where R is selected from the

group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and

heterocycloalkyl (bonded through a ring carbon).

[002181 As used herein, the tern "0 carboxy" refers to a group of formula RC(0)0-.

1002191 As used herein, the term "C carboxy" refers to a group of formula -C(QO)OR.

25 [002201 As used herein, the term "acetyl" refers to a group of formula -C(=O)Cl;.

1002211 As used herein, the term "trihalomethanesulfonyl refers to a group of formula XCS(=O

where X is a halogen.

1002221 As used herein, the term "isocyanato" refers to a group of formula NCO

1002231 As used herein, the term "thiocyanato" refers to a group of formula -CNS,

30 1002241 As used herein, the term "isothiocyanato" refers to a group of formula -NCS.

1002251 As used herein, the term "S sulfonamido" refers to a group of formula -S(=O)NR.

1002261 As used herein, the term "N sulfonamido" refers to a group of formula RS(=O)NH-.

1002271 As used herein, the term "trihalomethanesulfonamido" refers to a group of formula

X3CS(=0)iNR

35 [002281 As used herein, the term "0 carbamyl' refers to a group of formula -OC(=0)NR2 .

[002291 As used herein, the term "N carbaryl" refers to a group of formula ROC(=0)NH-.

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WO 2010/017055 PCT/US2009/051879

[002301 As used herein, the term "O thiocarbamyl" refers to a group of formula -OC(=:S)NR 2.

1002311 As used herein, the term "N thiocarbamyl" refers to a group of formula ROC(=S)NH-.

1002321 As used herein, the term "C amido" refers to a group of formula -C(=O)NR.

1002331 As used herein, the term "N amido" refers to a group of formula RC(=Q)NH-.

5 [002341 As used herein, the substituent "R" appearing by itself and without a number designation

refers to a substituent selected from among from alkyl, cycloalkyl, aryl. heteroaryl (bonded through

a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).

100235] The tern "substituted" means that the referenced group is optionally substituted (substituted

or unsubstituted) with one or more additional group(s) individually and independently selected from

10 alkyl, cycloalkyl, anl. heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio,

arylthio, alkvlsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, carbonyl,

thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perifl uoroalkyl. silyl, and

amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. By

way of example an optional substituents is LsR8 , wherein each L, is independently selected from a

15 bond, -0-, -C(=O)-, -- , -S(=0)-, -S(=)r2-, -NI-, -NHC(0) -C(O)NfH S(=O)N-. -NiS(=0),

OC(O)NH-, -NHC(0)i0-. -(substituted or unsubstituted C-C, alkyl), or -(substituted or

unsubstituted Q-C alkenyl); and each R, is independently selected from HL, (substituted or

unsubstituted lower alkyl), (substituted or unsubstituted lower cycloalky), heteroaryl, or

heteroalkyl

20 [002361 The term "protecting group" refers to a removable group which modifies the reactivity of a

functional group, for example. a hydroxyl, ketone or amine, against undesirable reaction dorin

synthetic procedures and to be later removed. Examples of hydroxy-protecting groups include, but

not limited to, methyithiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as

inethoxymethyl. and esters including acetyl, benzoyl, and the like. Examples of ketone protecting

25 groups include, but not limited to, ketals, oximes; 0-substituted oximes for example O-benzyl

oxime, 0-phenylthiomethyl oxime, I -isopropoxycyclohexyl oxime, and the like. Examples of amine

protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc) and carbobenzyloxy

(Cbz).

1002371 The term "optionally substituted" as defined herein, means the referenced group is

30 substituted with zero, one or more substituents as defined herein.

[002381 The term "protected-hydroxy" refers to a hydroxy group protected with a hydroxy

protecting group, as defined above.

[00239] In some embodiments, compounds of the described herein exist as stereoisoners, wherein

asymmetric or chiral centers are present. Stereoisomers are designated (R) or (S) depending on the

35 configuration of substituents around the chiral carbon atom. The term (R) and (S) used herein are

configurations as defined in UPAC 1974 Recommendations for Section E, Fundamental

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WO 2010/017055 PCT/US2009/051879

Stereochemistry, Pure Appl. Chem., (1976), 45:13-30, hereby incorporated by reference. The

embodiments described herein specifically includes the various stereoisoners and mixtures thereof.

SterCoisomers include enantiomers., diastereomers; and rnixtures of enantiomers or diastereomers. In

some embodiinents, individual stereoisomers of compounds are prepared synthetically from

5 commercially available starting materials which contain asymmetric or chiral centers or by

preparation of racemic mixtures followed by resolution, These methods of resolution are

exemplified by (I) attachment of a mixture of enantiomers to a chiral axillary, separation of the

resulting mixture of diastereomers by recrystallization or chromatography and liberation of the

optically pure product from the auxiliary or (2) direct separation of the mixture of optical

10 enantiomers on chiral chromatographic column.

[00240] The methods and formulations described herein include the use of N-oxides. crystalline

forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described

herein, as well as active metabolites of these compounds having the same type of activity. In some

situations, compounds exist as tautomers. All tautomers are included within the scope of the

IS compounds presented herein. In some embodiments, the compounds described herein exist in

unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water,

ethanol, and the like. The solvated forms of the compounds presented herein are also considered to

be disclosed herein.

[00241 Throughout the specification, groups and substituents thereof are chosen, in certain

20 embodiments. to provide stable moieties and compounds.

Preparation of Compounds described herein

[002421 In certain embodiments, the compounds described herein are synthesized using any

synthetic techniques including standard synthetic techniques and the synthetic processes described

herein. In specific embodiments, the following synthetic processes are utilized,

25 Formation of Covalent Linkages by Reaction of an Electrophile with a Nucleophile

[002431 Selected examples of covalent linkages and precursor functional groups which yieid then

are given in the Table entitled "Examples of Covalent Linkages and Precursors Thereof" Precursor

functional groups are shown as electrophilic groups and nucleophilic groups. In certain

embodiments, a functional group on an organic substance is attached directly, or attached via any

30 useful spacer or linker as defined below.

Table 1: Examples of Covalent Linkages and Precursors Thereof

Co--alent ink-ge Prod.ctElectrophile Nueophile Carboxamides Activated esters amines/anilines Carboxan ides acyl azides amines/anilines Carboxamides acyl halides_ -------- aimnes/anidines

Esters acyl halides alcohols/phenols Esters acyl nitriles al o holsphennls

Carboxamides acylnitriles n amines,/anilines

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CovatMLinkage Product l_ ectrophile Nucleopheie imines Aldehydes amines anilines

i-"draiones aldehydes or ketones Hydrazines Oximes aldehvdes or ketones jydroxylamies

Alkyl amines alkyl halides amines/anilines Esters alkyl halides carboxvlic acids

Thioethers alky__ a l halides Thiols Ethers alyl halides.alcoholsphenols

Thioethers alkyl suilfonates Thiols Esters alkyl sulfonates carboxylic acids Ethers alky. slfonaies alcohols/phenols Esters Anhydrides alcohols/phenols

Carhoxamides Anydrides amines/anifines Thihenols aryl halides Thiols Aryl amines ary] halides Anines Thioethers Azindines Thiols

Boronate esters Boronates Glycols Carboxamides carboxylic acids amines/anilines

Esters carboxylic acids Alcohols hdrazines Hlydrazides carboxylic acids

N acylureas or Anhvdrides carbodiimides carboxylic acids Esters diazoalkanes carboxvlic acids

Thioethers Epoxides Thiols Thioethers haloacetamides Thiols

Ammotriazines halotriazines amines/anilines riazil ethers halotriazines alcohols/phenols

Amidines imido esters amines/aniines Lreas Isocyanates amines/anil ines

Urethanes Isocyanates alcohols/phenols Thioureas isothiocyanates amines/anilines Thioethers Maleimides Thiols

Phosphite esters phosphoramidies Alcohols

.---Silyl ethers .... silyl halides Alcohols Alkyl marines sulfonate esters amines/anilines Thioethers sulfonate esters Thiols

Esters sulfonate esters carboxylic acids Ethers sulfonate esters Alcohols

S ulfonamides sulfony halides amines/anilines Sulfonate esters sulfonyl halides p lnos/akchols

[00244I In general, carbon electrophiles are susceptible to attack by complementary nucleophiles,

including carbon nucleophiles, wherein an attacking nUcleophile brings an electron pair to the

carbon electrophile in order to form a new bond between the nucleophile and the carbon

5 electrophile.

1002451 Suitable carbon nucleophiles include, but are not limited to alkyl, alkenyl, aryl and alkynyl

Grignard, organolithium, organozine, alkyl-, alkenyl , aryl- and alkynyl-tin reagents

(organostannanes) alkyl-. alkenyl-, aryl- and alkynyl-borane reagents (organoboranes and

organoboronates); these carbon nucleophiles have the advantage of being kinetically stable in water

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or polar organic solvents. Other carbon nucleophiles include phosphorus yiids, enol and enolate

reagents; these carbon nucleophiles have the advantage of being relatively easy to generate from

precursors. Carbon nucleophiles, when used in conjunction with carbon electrophiles, engender new

carbon-carbon bonds between the carbon nucleophile and carbon electrophile.

5 [00246] Non-carbon nucleophiles suitable for coupling to carbon electrophiles include but are not

limited to primary and secondary amines, thiols, thiolates, and thioethers, alcohols. alkoxides,

aides, semicarbazides, and the like. These non-carbon nucleophiles, when used in conjunction with

carbon electrophiles, typically generate heteroatom linkages (C-X-C) wherein X is a heteroatom, e.

g, oxygen or nitrogen.

10 Use of Protecting Groups

1002471 The tern "protecting group" refers to chemical moieties that block some or all reactive

moieties and prevent such groups from participating in chemical reactions until the protective group

is removed. In specific embodiments, more than one protecting group is utilized. In more specific

embodiments, each protective group is removable by a different process. Protective groups that are

1.5 cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In

various embodiments, protective groups are removed by acid, base, or hydrogenolysis. Groups such

as trityl, dimetboxytrityl, acetal and t-butyldimethylsilyl are acid labile and are, in some

embodiments, used to protect carboxy and hydroxy reactive moieties in the presence of amino

groups protected with Chz groups, which are removable by hydrogenolysis. and Fmoc groups,

20 which are base labile. In some embodiments, carboxylic acid and hydroxy reactive moieties are

blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence

of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both

acid and base stable but hydrolytically removable.

1002481 In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with

25 hydrolytically removable protective groups such as the benzyl group, while, in some embodiments,

amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as

Fmoc. In various embodiments, carboxylic acid reactive moieties are protected by conversion to

simple ester derivatives as exemplified herein, or they are blocked with oxidatively-removable

protective groups such as 2,4-dimethoxybenzyl, while, in some embodiments, co-existing amino

30 groups are blocked with fluoride labile silyl carbamates.

1002491 in certain instances, allyl blocking groups are useful in the presence of acid- and base

protecting groups since the former are stable. hi some embodiments, such groups are subsequently

removed by metal or pi-acid catalysts. For example, in some embodiments, an allyl-blocked

carboxylic acid is deprotected with a Pd0-catalyzed reaction in the presence of acid labile t-butyl

35 carbamate or base-labile acetate amine protecting groups. In some embodiments, a protecting group

is a resin to which a compound or intermediate is attached. As long as the residue is attached to the

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resin, that functional group is blocked and cannot react. Once released from the resin, the functional

group is available to react.

[00250] In some embodiments, blocking/protecting groups are selected from, by way of non-limiting

example:

H2 H2 0

H c,.CN H 0 IC C C H C HC H2 U1 H2C' H2 Y

0 allyl Sn Cbz alloc Me

H2 H3C ,CH3 H2 0

H3C C (H3C)C' (H3CbC (CHy C, Si 0

Et t-butyl TBDMS Teoc

0 H2

(C HI)3C H C O (C H ) 3 C -~~ H C

Boc pMBn trityl acetyl Fmoc

1002511 Other protecting groups are described in Greene and Wuts, Protective Groups in Organic

Synthesis. 3rd Ed., John Wiley & Sons, New York, NY, 1999.

Compounds of Formula (I)

f002521 In certain embodiments, compounds of Formula (I) composing of Ta to If, are prepared in

10 various ways, as outlined in Synthetic Schemes I and 2. In each scheme, the variables (e.g., Rj. R',

R R4, I, Y, and Z) correspond to the same definitions as those recited above while R is alkyl and

Y is the same or different group defined by Y and ZT is the same or different group defined by Z. In

some embodiments, compounds are synthesized using methodologies analogous to those described

below by the use of appropriate alternative starting materials,

15 1002531 In certain embodiments. compounds of Formula (Ta, and Tb) wherein Y is identical to Z are

synthesized according to Synthetic Scheme _L Thus, the preparation of the intermediate 3 wherein RS

is hydrogen is achieved by condensation of 4-aminoisobenzofuran-l (311)-one 1 with an aldehyde 2

in the presence of a base preferably alkaline alkoxides in appropriate solvents such as ethyl acetate

or ethyl propionate at either ambient or elevated temperature. Compounds of Formula Ia wherein

20 R9 is hydrogen is prepared by treating the intermediate 3 with hydrazine hydrate at ambient or

elevated temperature. Compounds of Formula Ia wherein R. is alkyl or substituted alkyl is prepared

from compound of Formula Ia wherein RK is hydrogen by reductive amination reaction with R

C)O wherein R is alkyl, substituted alkyl. In some embodiments, the preparation of the

compounds in Formula Tb is accomplished by further modification of Ia. Through appropriate

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functional group transformations on the moiety of Y and Z, one affords the compounds of Formula

lb with different entities of V and Z' at 2- or 3-positions,

Synthetic Scheme 1

R2 1 E2 R~E2 'R,

R RONa ROH H2NNH2 $ Transforraation 0 + onN o ---- - - - ---------- o R -N 'N

NH2 2 Y SYz y V' 1 2 3 lb

5

[002541 In certain embodiments, compounds of Formula (it, and Id) are synthesized according to

_Syntiectie Scheme 2. For example, the intermediate 5 is prepared by condensation of the reagent I

with an aldehyde 4 in the presence of water absorbent such sodium sulfate or magnesium sulfate at

elevated temperature, A subsequent condensation reaction of this intermediate with another

10 aldehyde in the presence of a base preferably alkaline alkoxides in appropriate solvents such as ethyl

acetate or ethyl propionate at either ambient or elevated temperature gives the intermediate 6

wherein R5 is hydrogen. Compounds of Formula ITc wherein R5 is hydrogen is prepared by treating

the intermediate 6 with hydrazine hydrate at ambient or elevated temperature. Compounds of

Formula Ic wherein R5 is alkyl, substituted alkyi are prepared from compounds of Formula Ic

15 wherein RA is hydrogen by reductive amination reaction with R2-CI-O wherein RI is alkyl, or

substituted alkyl In some embodiments, the preparation of compounds of Formula Id are

accomplished by further modification of Ic. Through appropriate functional group transformations

on the moiety of Y and Z, one could afford the compounds of Formula Ic with different entities of

Y and Z' at 2- or 3-positions.

20 Synthetic Scheme 2

Rv R, R- RS, ES2 R.

S 4 5 6 1C Id Certain Pharmaceutical Terminology

002551 The term "acceptable" with respect to a formulation, composition or ingredient o as used

herein., means having no persistent detrimental effect on (te general health of the subject being

25 treated.

1002561 As used herein,the term "selective bindincompound"refers to a compoundthat

selectively binds to any portion of one or more target proteins.

[00257] As used herein, the term "selectively binds" refers to the ability of a selective binding

compound to bind to a target protein, such as, for example, PARP, with greater affinity than it binds

30 to a non-target protein In certain embodiments, specific binding refers to binding to a target with an

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affinity that is at least about 10, about 50, about 100, about 250, about 500, about 1000 or more

times greater than the affinity for a non-target.

j002581 As used herein, the term "target protein" refers to a molecule or a portion of a protein

capable of being bound by a selective binding compound. In certain embodiments, a target protein is

5 the enzyme poly(ADP-ribose)polymerase (PARP)

1002591 As used herein, the terms "treating" or "treatment" encompass either or both responsive and

prophylaxis nicasures, e.g.. designed to inhibit, slow or delay the onset of a symptom of a disease or

disorder, achieve a full or partial reduction of a symptom or disease state, and/or to alleviate,

ameliorate, lessen, or cure a disease or disorder and/or its symptoms.

10 1002601 As used herein, amelioration of the symptoms of a particular disorder by administration of a

particular compound or pharmaceutical composition refers to any lessening of severity, delay in

onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or

transient that can be attributed to or associated with administration of the compound or composition.

1002611 As used herein, the term "modulator" refers to a compound that alters an activity of a

15 molecule, For example, a modulator includes a compound that causes an increase or a decrease in

the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the

absence of the modulator. In certain embodiments. a modulator is an inhibitor, which decreases the

magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely

prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator;

20 which increases the magnitude of at least one activity of a molecule, In certain embodiments the

presence of a modulator results in an activity that does not occur in the absence of the modulator,

1002621 As used herein, the term "selective modulator" refers to a compound that selectively

modulates a target activity.

1002631 As used herein, the term "PART "refers to the family of the enzyme poly(ADP

25 ribose)polynierase which includes approximately 18 proteins, particularly poly(ADP

ribose)polymerase- 1. (PARP-I) and poly( ADP-ribose)polymerase-2 (PARP-2).

1002641 As used herein, the term "selective PARP modulator" refers to a compound that selectively

modulates at least one activity associated with the enzyme poly(ADP-ribose)polymerase (PARP). In

various embodiments, the selective modulator selectively modulates the activity of PARP -1, PARP

30 2, both PARP-1 and PARP-2 or several members of the family of the enzyme poly(ADP

ribose)polymerase (PARP).

[002651 As used herein, the term "method of inhibiting PARP" refers to a method of inhibiting the

activity of either one or more of the family of enzyme poly(ADP-ribose)polymerase (PARP), As

used herein, the term "inhibition of PARP" refers to inhibition of the activity of either one or more

35 of the family of enzyme poly(ADP-ribose)polymerase (PARP),

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1002661 As used herein, the term "modulating the activity of the enzyme poly(ADP

ribose)polymerase" refers to a modulating the activity of either one or more of the family of enzyme

poly(ADP-ribose)polynierase (PARP).

1002671 As used herein, the term "selectively modulates" refers to the ability of a selective

5 modulator to modulate a target activity to a greater extent than it modulates a non-target activity. in

certain embodiments the target activity is selectively modulated by, for example about 2 fold up to

more that about 500 fold, in some embodiments, about 2, 5, 10, 50, 100, 150, 200, 250, 300, 350,

400, 450 or more than 500 fold,

1002681 As used herein, the term "target activity" refers to a biological activity capable of being

10 modulated by a selective modulator. Certain exemplary target activities include, but are not limited

to, binding affinity, signal transduction, enzymatic activity tumor growth, inflammation or

inflammation-related processes, and amelioration of one or more symptoms associated with a

disease or condition.

1002691 As used herein, the term "agonist" refers to a compound, the presence of which results in a

15 biological activity of a protein that is the same as the biological activity resulting from the presence

of a naturally occurring ligand for the protein, such as, for example, PARP.

1002701 As used herein, the term "partial agonist" refers to a compound the presence of which

results in a biological activity of a protein that is of the same type as that resulting from the presence

of a naturally occurring ligand for the protein, but of a lower magnitude,

20 [002711 As used herein, the term "antagonist" or "inhibitor" refers to a compound, the presence of

which results in a decrease in the magnitude of a biological activity of a protein. In certain

embodiments, the presence of an antagonist results in complete inhibition of a biological activity of

a protein, such as, for example, the enzyme poly(ADP-ribose)polymerase (PARP),

1002721 As used herein, the IC% refers to an amount, concentration or dosage of a particular test

25 compound that achieves a 50% inhibition of a maximal response, such as modulation of PARP, in an

assay that measures such response.

[002731 As used herein, EC50 refers to a dosage, concentration or amount of a particular test

compound that elicits a dose-dependent response at 50% of maxinal expression of a particular

response that is induced, provoked or potentiated by the particular test compound.

30 1002741 The term "cancer", as used herein refers to an abnormal growth of cells which tend to

proliferate in an uncontrolled way and, in some cases, to metastasize (spread), The types of cancer

include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphonra), ovary, pancreas or other endocrine

organ (thyroid), prostate, skin (melanoma) or hematological tumors (such as the leukemias).

35 1002751 The term "carrier," as used herein, refers to relatively nontoxic chemical compounds or

agents that facilitate the incorporation of a compound into cells or tissues.

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[002761 The terms "co-administration" or the like, as used herein, are meant to encompass

administration of the selected therapeutic agents to a single patient. and are intended to include

treatment regimens in which the agents are administered by the same or different route of

administration or at the same or different time,

5 1002771 The term "diluent"refers to chemical compounds that are used to dilute the compound of

interest prior to delivery. Diluents include chemicals used to stabilize compounds because they

provide a more stable environment. Salts dissolved in buffered solutions (which also can provide p1H

control or maintenance) are utilized as diluents in certain embodiments, including, but not limited to

a phosphate buffered saline solution.

10 1002781 The terms "effective amount' or "therapeutically effective amount," as used herein, refer to

a sufficient amount of an agent or a compound being administered which will relieve to some extent

one or more of the symptoms of the disease or condition being treated. The result includes reduction

and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a

biological system. For example, an "effective amount" for therapeutic uses is the amount of the

15 composition comprising a compound as disclosed herein required to provide a clinically significant

decrease in disease symptoms. An appropriate "effective" amount in any individual case is

determined using any suitable technique, such as a dose escalation study.

1002791 The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in

potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents,

20 the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the

effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein.,

refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system,

[00280J The term "enzymatically cleavable tinker." as used herein refers to unstable or degradable

linkages which are degraded by one or more enzymes.

25 100281] The term "inflammatory disorders" refers to those diseases or conditions that are

characterized by one or more of the signs of pain (dolor, from the generation of noxious substances

and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation

and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid),

and loss of function (finctio laesa, which may be partial or complete. temporary or permanent). 30 Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more

of the following: acute, adhesive, atrophic, catarrhal., chronic, cirrhotic, diffuse, disseminated,

exudative, fibrinous, fibrosing, focal., granulomatous, hyperplastic, hypertrophic, interstitial.,

metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous,

pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute,

35 suppurative, toxic, traumatic, and/or ulcerative. Inflammatory disorders further include, without

being limited to those affecting the blood vessels (polyarteritis, temporal arteritis); joints (arthritis:

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crystalline, osteo, psoriatic, reactive, rheumatoid, Reiters); gastrointestinal tract (Chrohn's Disease,

ulcerative colitis); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).

1002821 The term "PARP-mediated", as used herein, refers to conditions or disorders that are

ameliorated by the one or more of the family of enzyme poly(ADP-ribose)polymerase (PARP),

5 1002831 The terms "kit" and "article of manufacture" are used as synonyms.

[002841 A "metabolite" of a compound disclosed herein is a derivative of that compound that is

formed when the compound is metabolized. The term "active metabolite" refers to a biologically

active derivative of a compound that is formed when the compound is metabolized. The term

"metabolized," as used herein, refers to the sum of the processes (including, but not limited to,

10 hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed

by an organism. Thus, in certain instances, enzymes produce specific structural alterations to a

compound. In some embodiments, metabolites of the compounds disclosed herein are identified

either by administration of compounds to a host and analysis of tissue samples from the host, or by

incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

15 1002851 The term "modulate," as used herein, means to interact with a target either directly or

indirectly so as to alter the activity of the target, including, by way of example only, to enhance the

activity of the target, to inhibit the activity of the target, to lmit the activity of the target, or to

extend the activity of the target.

1002861 By "pharmaceutically acceptable" or "therapeutically acceptable", as used herein, refers a

20 material, such as a carrier or diluent, which does not abrogate the biological activity or properties of

the compound, and is relatively nontoxic. In certain instances, nontoxic and non-abrogative

materials includes materials that when administered to an individual do not cause substantial,

undesirable biological effects and/or do not interact in a deleterious manner with any of the

components of the composition in which it is contained,

25 1002871 The term "pharmaceutically acceptable salt" or "therapeutically acceptable salt", refers to a

formulation of a compound that does not cause significant irritation to an organism. to which it is

administered and does not abrogate the biological activity and properties of the compound. in

certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described

herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric

30 acid, methanesulfonic acid, ethanesulfonic acid., p-toluenesulfonic acid, salicylic acid and the like. In

some instances, pharmaceutically acceptable salts are obtained by reacting a compound having

acidic group described herein with a base to form a salt such as an ammnonium salt, an alkali metal

salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a

magnesium salt. a salt of organic bases such as dicyclohexylamiine, N-methyl-D-gl ucamine,

35 tris(hydroxymnethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like,

or by other methods previously determined.

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1002881 The term "pharmaceutical combination" as used herein, means a product that results from

the mixing or combining of more than one active ingredient and includes both fixed and non-fixed

combinations of the active ingredients. The term "fixed combination" means that the active

ingredients, e.g. a compound described herein and a co-agent, are both administered to a patient

5 simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means

that the active ingredients, e~g. a compound described herein and a co-agent, are administered to a

patient as separate entities either simultaneously, concurrently or sequentially with no specific

intervening time limits, wherein such administration provides effective levels of the two compounds

in the body of the patient. The latter also applies to cocktail therapy. e.g. the administration of three

10 or more active ingredients.

1002891 The term "pharmaceutical composition" refers to a mixture of a compound described herein

with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending

agents, thickening agents, and/or excipients. The pharmaceutical composition fxcilitates

administration of the compound to an organism. Multiple techniques of administering a compound

15 exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic,

pulmonary and topical administration.

1002901 A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are

often useful because, in some situations. they are easier to administer than the parent drug. In certain

instances, a prodrug is bioavailable by oral administration whereas the parent is not, In some

20 instances, a prodrug has improved solubility in pharmaceutical compositions over the parent drug.

An example, without limitation, of a prodrug is a compound described herein, vhich is administered

as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is

detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active

entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug

25 might be a short peptide (polyaminoacid) bonded to an acid or amino group where the peptide is

metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a

prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active

form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or

more steps or processes to the biologically, pharmaceutically or therapeutically active form of the

30 compound, To produce a prodrug, a pharmaceutically active compound is modified such that the

active compound will be regenerated upon in vivo administration, In some embodiments, the

prodrug is designed to alter the metabolic stability or the transport characteristics of a drug, to mask

side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties

of a drug.

35 100291 I The term "subject" or "patient" encompasses mannmals and non-mammals. Examples of

mammals include, but are not limited to, any member of the Mammalian class: humans, non-human

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primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle,

horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals

including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals

include, but are not limited to, birds; fish and the like. in one embodiment of the methods and

5 compositions provided herein, the mammal is a human.

[002921 The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or

ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or

preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g.,

arresting the development of the disease or condition., relieving the disease or condition, causing

10 regression of the disease or condition, relieving a condition caused by the disease or condition, or

stopping the symptoms of the disease or condition either prophylactically and/or therapeutically,

Pharmaceutical Composition/Formulation

1002931 In certain embodiments, pharmaceutical compositions are formulated in any manner,

including using one or more physiologically acceptable carriers comprising excipients and/or

15 auxiliaries which facilitate processing of the active compounds into pharmaceutical preparations. In

some embodiments, proper formulation is dependent upon the route of administration chosen. in

various embodiments, any techniques, carriers, and excipients are used as suitable.

100294J Provided herein are pharmaceutical compositions that include a compound described herein

and a pharmaceutically acceptable diluent(s), excipient(s), and/or carrier(s). In addition, in some

20 embodiments, the compounds described herein are administered as pharmaceutical compositions in

which compounds described herein are mixed with other active ingredients. as in combination

therapy.

[002951 A pharmaceutical composition, as used herein, refers to a mixture of a compound described

herein with other chemical components. such as carriers, stabilizers, diluents, dispersing agents,

25 suspending agents, thickening agents, and/or excipients. In certain embodiments, a pharmaceutical

composition facilitates administration of the compound to an organism. In some embodiments,

practicing the methods of treatment or use provided herein, includes administering or using a

pharmaceutical composition comprising a therapeutically effective amount of a compound provided

herein. In specific embodiments, the methods of treatment provided for herein include

30 administering such a pharmaceutical composition to a mammal having a disease or condition to be

treated, in one embodiment, the manimal is a human, In some embodiments, the therapeutically

effective amount varies widely depending on the severity of the disease, the age and relative health

of the subject, the potency of the compound used and other factors. In various embodiments, the

compounds described herein are used singly or in combination with one or more therapeutic agents

35 as components of mixtures,

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1002961 In certain embodiments, the pharmaceutical compositions provided herein are formulated

for intravenous infections, hi certain aspects, the intravenous injection formulations provided herein

are formulated as aqueous solutions, and, in some embodiments, in physiologically compatible

buffers such as lank's solution, Ringer's solution, or physiological saline buffer. In certain

5 embodiments, the pharmaceutical compositions provided herein are formulated for transmucosal

administration In some aspects, transmucosal formulations inclu de penetrants appropriate to the

barrier to be permeated In certain embodiments, the pharmaceutical compositions provided herein

are formulated for other parenteral injections, appropriate formulations include aqueous or

nonaqueous solutions, and in one embodiment, with physiologically compatible buffers or

10 excipients.

100297J In certain embodiments, the pharmaceutical compositions provided herein are formulated

for oral administration. In certain aspects, the oral formulations provided herein comprise

compounds described herein that are formulated with pharmaceutically acceptable carriers or

excipients. Such carriers enable the compounds described herein to be formulated as tablets,

15 powders, pills, dragees, capsules, liquids, gels, syrups, elixirs. slurries, suspensions and the like, for

oral ingestion by a patient to be treated.

1002981 In some embodiments, pharmaceutical preparations for oral use are obtained by mixing one

or more solid excipient with one or more of the compounds described herein, optionally grinding the

resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if

20 desired, to obtain tablets or dragee cores. Suitable excipients include, in particular, fillers such as

sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example,

maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyleeilulose

microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others

such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating

25 agents are optionally added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone,

agar, or alginic acid or a salt thereof such as sodium alginate.

100299] In certain embodiments, provided herein is a pharmaceutical composition formulated. as

dragee cores with suitable coatings. in certain embodiments, concentrated sugar solutions are used

in forming the suitable coating, and optionally contain gumn arabic, talc, polyvinylpyrrolidone,

30 carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic

solvents or solvent mixtures. In some embodiments, dyestuffs and/or pigments are added to tablets,

dragees and/or the coatings thereof for, e.g., identification or to characterize different combinations

of active compound doses.

1003001 In certain embodiments, pharmaceutical preparations which are used include orally include

3n push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer,

such as glycerol or sorbitol. In some embodiments, the push-fit capsules contain the active

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ingredients in admixture with filler such as lactose. binders such as starches, and/or lubricants such

as talc or magnesium stearate and. optionally, stabilizers. In certain embodiments, in soft capsules,

the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid

paraffin, or liquid polyethylene glycols. In addition, stabilizers are optionally added. In certain

5 embodiments, the formulations for oral administration are in dosages suitable for such

administration.

1003011 In certain embodiments, the pharmaceutical compositions provided herein are formulated

for buccal or sublingual administration. In certain embodiments, buccal or sublingual compositions

take the form of tablets, lozenges, or gels formulated in a conventional manner. In certain

10 embodiments, parenteral injections involve bolus injection or continuous infusion. In some

embodiments, formulations for injection are presented in unit dosage form, e.g, in ampoules or in

multi-dose containers, with an added preservative. In some embodiments, the pharmaceutical

composition described herein is in a form suitable for parenteral injection as a sterile suspensions,

solutions or emulsions in oily or aqueous vehicles, and optionally contains formulatory agents such

15 as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral

administration include aqueous solutions of the active compounds in water-soluble form. In some

embodiments, suspensions of the active compounds are prepared as appropriate oily injection

suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or

synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain

20 embodiments, aqueous injection suspensions contain substances which increase the viscosity of the

suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the

suspensions also contain suitable stabilizers or agents which increase the sohibility of the

compounds to allow for the preparation of highly concentrated solutions. In alternative

embodiments, the active ingredient is in powder form for constitution with. a suitable vehicle, e.g.,

25 sterile pyrogen-free water, before use.

1003021 In some embodiments, the compounds described herein are administered topically. In

specific embodiments, the compounds described herein are formulated into a variety of topically

administrable compositions, such as solutions. suspensions. lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds optionally contain solubilizers,

30 stabilizers, tonicity enhancing agents, buffers and/or preservatives.

1003031 In certain embodiments the pharmaceutical compositions provided herein are formulated

for transdenral administration of compounds described herein. In some embodiments,

administration of such compositions employs transdermal delivery devices and transdermal delivery

patches. In certain embodiments., the compositions are lipophilic emulsions or buffered, aqueous

35 solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches include those

constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In some

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embodiments, transdermal delivery of the compounds described herein is accomplished by use of

iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled

delivery of the compounds provided herein, such as, for example, compounds of Formula (1), (IA) or

(T). In certain embodiments, the rate of absorption is slowed by using rate-controlling membranes or

5 by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers are

optionally used to increase absorption. Absorption enhancer and carrier include absorbable

pharmaceutically acceptable solvents that assist in passage of the compound through the skin. For

example, transdermal devices are in the form of a bandage comprising a backing member, a

reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to

10 deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged

period of time, and means to secure the device to the skin.

[003041 In certain embodiments, the pharmaceutical compositions provided herein are formulated

for administration by inhalation. In certain embodiments, in such pharmaceutical compositions

formulated for inhalation, the compounds described herein are in a form as an aerosol, a mist or a

15 powder. In some embodiments. pharmaceutical compositions described herein are conveniently

delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the

use of a suitable propellant, eag., dichlorodifluoromethane; trichlorofluoromethane,

dichlorotetralluoroethane, carbon dioxide or other suitable gas. In certain aspects of a pressurized

aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. In certain

20 embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an

inhaler or insufflator is formulated containing a powder mix of the compound described herein and a

suitable powder base such as lactose or starch.

1003051 In some embodiments, the compounds described herein are formulated in rectal

compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly

25 suppositories, or retention enemas. in certain embodiments, rectal compositions optionally contain

conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic

polymers such as polyvinylpyrrolidone, PEG, and the like. In certain suppository forms of the

compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides,

optionally in combination with cocoa butter is first melted.

30 100306] In various embodiments provided herein, the pharmaceutical compositions are formulated in

a conventional manner using one or more physiologically acceptable carriers comprising excipients

and auxiliaries which facilitate processing of the active compounds into pharmaceutically acceptable

preparations. In certain embodiments, proper formulation is dependent upon the route of

administration chosen. In various embodiments, any of the techniques, carriers, and excipients is

35 used as suitable. In some embodiments, pharmaceutical compositions comprising a compound

described herein are manufactured in a conventional manner, such as, by vav of example only, by

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means of conventional mixing, dissolving, granulating, dragee-making, levigating, einulsifying,

encapsulating, entrapping or compression processes.

1003071 in certain embodiments, the pharmaceutical compositions include at least one

pharmaceutically acceptable carrier, diluent or excipient and a compound described herein described

5 herein as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt

form. In addition. the methods and pharmaceutical compositions described herein include the use of

N-oxides crystalline forms (also known as polymorphs), as well as active metabolites of these

compounds having the same type of activity. In some situations, compounds described herein exist

as tautomers. All tautomers are included within the scope of the compounds presented herein.

10 Additionally, included herein are the solvated and unsolvated forms of the compounds described

herein. Solvated compounds include those that are solvated with pharmaceutically acceptable

solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein

are also considered to be disclosed herein. In some embodiments, the pharmaceutical compositions

described herein include other medicinal or pharmaceutical agents, carriers, adjuvants, such as

15 preserving, stabilizing wetting or emulsifying agents. solution promoters, salts for regulating the

osmotic pressure, and/or buffers. In additional embodiments, the pharmaceutical compositions

described herein also contain other therapeutically valuable substances.

[00308J Methods for the preparation of compositions containing the compounds described herein

include formulating the compounds with one or more inert, pharmaceutically acceptable excipients

20 or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to,

powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions

include solutions in which a compound is dissolved, emulsions comprising a compound. or a

solution containing liposones, micelles, or nanoparticles comprising a compound as disclosed

herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams., I

25 various embodiments, the compositions are in liquid solutions or suspensions, solid forms suitable

for solution or suspension in a liquid prior to use, or as emulsions. These compositions optionally

contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents. p-I

buffering agents, and so forth.

1003091 In some embodiments, a composition comprising a compound described herein takes the

30 form of a liquid where the agents are present in solution, in suspension or both, In some

embodiments, when the composition is administered as a solution or suspension a first portion of the

agent is present in solution and a second portion of the agent is present in particulate form, in

suspension in a liquid matrix. In sonic embodiments, a liquid composition includes a gel

formulation. In other embodiments, the liquid composition is aqueous.

35 1003101 Useful aqueous suspension optionally contain one or more polymers as suspending agents.

Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl

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methyicellulose, and water-insoluble polymers such as cross-linked carboxyi-containing polymers.

Useful compositions optionally comprise an mucoadhesive polymer, selected for example from

carboxymethyleellulose, carbomer (acrylic acid polymer), poly(methyhnethacrylate),

polyacrylanide, polyearbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

5 1003111 Useful compositions optionally include solubilizing agents to aid in the solubility of a

compound described herein. The term. "solubilizing agent" generally includes agents that result in

formation of a micellar solution or a true solution of the agent. Solubilizing agents include certain

acceptable nonionic surfactants, for example polysorbate 80, and ophithalmically acceptable glycols,

polyglycols, e g_ polyethylene glycol 400, and glycol ethers.

10 [003121 Useful compositions optionally include one or more pHi adjusting agents or buffering

agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases

such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate,

sodium lactate and tris-hvdroxymethylaminomethane; and buffers such as citrate/dextrose, sodium

bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount

15 required to maintain p11 of the composition in an acceptable range.

100313j Useful compositions optionally include one or more salts in an amount required to bring

osimolality of the composition into an acceptable range. Such salts include those having sodium,

potassium or ammonium nations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate,

sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride,

20 sodium thiosulfate, sodium bisulfite and ammonium sulfate.

1003141 Certain useful compositions optionally include one or more preservatives to inhibit

microbial activity. Suitable preservatives include mercury-containing substances such as merfen and

thioniersal; stabilized chlorine dioxide; and quaternary ammoniLm compounds such as

benzalkonium chloride, cetyitrimetylannonium bromide and cetylpyridinium chloride.

25 1003151 Some useful compositions optionally include one or more surfactants to enhance physical

stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid

glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and

polyoxyethylene alkylethers and alkylphenyl ethers, e g., octoxynol 10, octoxynol 40.

1003161 Certain useful compositions optionally one or more antioxidants to enhance chemical

30 stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and

sodium metabisulfite,

[003171 In some embodiments, aqueous suspension compositions are packaged in single-dose non

reclosable containers. In alternative embodiments, multiple-dose reclosable containers are used, in

which case it is typical to include a preservative in the composition.

35 1003181 In various embodiments, any delivery system for hydrophobic pharmaceutical compounds is

employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic

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drugs. In certain embodiments, certain organic solvents such as N-methylpyrrolidone are employed.

In some embodiments, the compounds are delivered using a sustained-release system, such as

semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various

sustained-release materials are utilized in the embodiments herein. In certain embodiments,

5 sustained-release capsules release the compounds for a few weeks up to over 100 days. In some

embodiments, depending on the chemical nature and the biological stability of the therapeutic

reagent, additional strategies for protein stabilization are employed,

[003191 In certain embodiments, the formulations or compositions described herein benefit from

and/or optionally comprise antioxidants, metal chelating agents, thiol containing compounds and

10 other general stabilizing agents. Examples of such stabilizing agents, include. but are not limited to:

(a) about 0.5% to about 2% w/v glycerol, (b) about 0:1% to about 1% w/v methionine, (c) about

0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01%

to about 2% w/v ascorbic acid, (1) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about

0.05% w/v. polysorbate 20, (h) arginirne (i) heparin, (j) dextran sulfate., (k) cyclodextrins. (1)

15 pentosan polysulfate and other heparinoids, (in) divalent nations such as magnesium and zinc; or (n)

combinations thereof.

Methods of Dosing and Treatment Regimens

1003201 In certain embodiments, the compounds described herein are used in the preparation or

manufacture of medicaments for the treatment of diseases or conditions that are mediated by the

20 enzyme pol(ADP-ribose)polymerase (PARP) or in which inhibition of the enzyme poly(ADP

ribose)polymerase (PARP) ameliorates the disease or condition. In some embodiments, a method fbr

treating any of the diseases or conditions described herein in a subject in need of such treatment,

involves administration of pharmaceutical compositions containing at least one compound described

herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,

25 pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically

acceptable solvate thereof; in therapeutically effective amounts to said subject,

1003211 In certain embodinents, the compositions containing the compound(s) described herein are

administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the

compositions are administered to a patient already suftring from a disease or condition, in an

30 amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. In

some embodiments, amounts effective for this use will depend on the severity and course of the

disease or condition, previous therapy; the patient's health status, weight, and response to the drugs.

and the judgment of the treating physician. In certain instances, it is considered appropriate for the

caregiver to determine such therapeutically effective amounts by routine experimentation (including,

35 but not limited to, a dose escalation clinical trial).

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1003221 In certain prophylactic applications, compositions containing the compounds described

herein are administered to a patient susceptible to or otherwise at risk of a particular disease,

disorder or condition. In some embodiments, the amount administere is defined to be a

"prophylactically effective amount or dose, In certain embodiments of this use, the precise amounts

5 of compound administered depend on the patient's state of health, weight, and the like. In some

embodiments, it is considered appropriate for the caregiver to determine such prophylactically

effective amounts by routine experimentation (e.g, a dose escalation clinical trial). in certain

embodiments, when used in a patient, effective amounts for this use will depend on the severity and

course of the disease, disorder or condition, previous therapy, the patienfs health status and response

10 to the drugs, and the judgment of the treating physician.

[00323] In certain instances, a patient's condition does not improve or does not significantly improve

following administration of a compound or composition described herein and, upon the doctor's

discretion the administration of the compounds is optionally administered chronically, that is, for an

extended period of time, including throughout the duration of the patient's life in order to ameliorate

15 or otherwise control or limit the symptoms of the patient's disease or condition.

1003241 In certain cases wherein the patient's status does improve or does not substantially improve,

upon the doctor's discretion the administration of the compounds are optionally given continuously;

alternatively, the dose of drug being administered is optionally temporarily reduced or temporarily

suspended for a certain length of time (i.e, a "drug holiday"). In certain embodinients, the length of

20 the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3

days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days,

70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days,

350 days, or 365 days. The dose reduction during a drug holiday includes a reduction from about

10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about

25 25%, about 30%, about 35%, about 40%, about 45%. about 50%, about 55%, about 60%, about

65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[00325] In certain embodiments, once improvement of the patient's conditions has occurred, a

maintenance dose is administered if necessary, In sone embodiments, the dosage, e.g., of the

maintenance dose, or the frequency of administration, or both, are reduced, as a function of the

30 symptoms. to a level at which the improved disease, disorder or condition is retained. In certain

embodiments, however, patients are optionally given intermittent treatment on a long-term basis

upon any recurrence of symptoms.

1003261 In certain embodiments, the amount of a given agent that corresponds to an effective

amount varies depending upon factors such as the particular compound., disease or condition and its

35 severity, the identity (e.g, weight) of the subject or host in need of treatment, In some

embodiments, the effective amount is, nevertheless, determined according to the particular

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circumstances surrounding the case, including, e.g., the specific agent that is administered, the route

of administration, the condition being treated, and the subject or host being treated. In certain

embodiments, however, doses employed for adult human treatment is in the range of about 0.02 to

about 5000 mg per day, in a specific embodiment about I to about 1500 mg per day. In various

5 embodiments, the desired dose is conveniently presented in a single dose or as divided doses

administered simultaneously (or over a short period of time) or at appropriate intervals, for example

as two, three, four or more sub-doses per day.

[003271 In some embodiments, the pharmaceutical compositions described herein are in a unit

dosage form suitable for single administration of precise dosages. In some instances, in unit dosage

10 form, the formulation is divided into unit doses containing appropriate quantities ofone or nmore

compound. In certain embodiments, the unit dosage is in the form of a package containing discrete

quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders

in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in

single-dose non-reclosable containers. In alternative embodiments, multiple-dose reclosable

15 containers are used, in which case it is typical to include a preservative in the composition. By way

of example only, formulations for parenteral. injection are, in some embodiments, presented in unit

dosage forn, which include, but are not limited to ampoules, or in multi-dose containers, with an

added preservative.

100328j In certain embodiments, the daily dosages appropriate for the compounds described herein

20 described herein are from about 0.01 to about 2.5 mg/kg per body weight. in some embodiments, an

indicated daily dosage in the larger subject, including, but not limited to, humans, is in the range

from about 0,5 mg to about 100 mg, conveniently administered in divided doses, including, but not

limited to, up to four times a day or in extended release form. In certain embodiments, suitable unit

dosage forms for oral administration comprise from about I to about 50 mg active ingredient. The

25 foregoing ranges are inerely suggestive, as the number of variables in regard to an individual

treatment regime is large, and considerable excursions from these recommended values are not

uncommon. In certain embodiments, the dosages are altered depending on a number of variables,

not limited to the activity of the compound used, the disease or condition to be treated, the mode of

administration, the requirements of the individual subject, the severity of the disease or condition

30 being treatedand the judgment of the practitioner.

1003291 In certain embodiments, toxicity and therapeutic efficacy of such therapeutic regimens are

determined by standard pharmaceutical procedures in cell cultures or experimental animals,

including, but not limited to, the determination of the LIDy) (the dose lethal to 50% of the population)

and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between

35 the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between

LD and EDz0. In certain embodiments, compounds exhibiting high therapeutic indices are

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preferred. in some embodiments, the data obtained from cell culture assays and animal studies is

used in formulating a range of dosage for use in human. In specific embodiments, the dosage of such

compounds lies within a range of circulating concentrations that include the ER 0 with minimal

toxicity. In certain embodiments, the dosage varies within this range depending upon the dosage

5 form employed and the route of administration utilized.

Combination Treatments

1003301 In certain instances, it is appropriate to administer at least one compound described herein in

combination with another therapeutic agent. By way of example only, if one of the side effects

experienced by a patient upon receiving one of the compounds herein is inflammation, then, in some

10 embodiments. it is appropriate to administer an anti -inflammatory agent in combination with the

initial therapeutic agent. In some embodiments, the therapeutic effectiveness of one of the

compounds described herein is enhanced by administration of an adjuvant (i.e., in some

embodiments, by itself the adjuvant has minimal therapeutic benefit, but in combination with

another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). In certain

15 embodiments, the benefit experienced by a patient is increased by administering one of the

compounds described herein with another therapeutic agent (which also includes a therapeutic

regimen) that also has therapeutic benefit. In some embodiments, regardless of the disease, disorder

or condition being treated, the overall benefit experienced by the patient as a result of a combination

treatment is additive or synergistic.

20 1003311 In certain embodiments, therapeutically-effective dosages vary when the drugs are used in

treatment combinations. In some embodiments, therapeutically-effective dosages of drugs and other

agents for use in combination treatment regimens is determined in any suitable manner, e'g., through

the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minnize toxic

side effects. In some embodiments, combination treatment regimen described herein encompass

25 treatment regimens in Which administration of a PARP inhibitor described herein is initiated prior

to, during, or after treatment with a second agent described above, and continues until any time

during treatment with the second agent or after termination of treatment with the second agent. It

also includes treatments in which a PARP inhibitor described herein and the second agent being

used in combination are administered simultaneously or at different times and/or at decreasing or

30 increasing intervals during the treatment period. Combination treatment further includes periodic

treatments that start and stop at various times to assist with the clinical management of the patient.

For example, in some embodiments, a PARP inhibitor described herein in the combination treatment

is administered weekly at the onset of treatment, decreasing to biweekly, and decreasing further as

appropriate.

35 1003321 In certain embodiments, compositions and methods for combination therapy are provided

herein. In accordance with one aspect, the pharmaceutical compositions disclosed herein are used to

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in a method of treating a PARP mediated disease or condition or a disease or condition that is

ameliorated by inhibition of PARP. In accordance with certain aspects, the pharmaceutical

compositions disclosed herein are used to treat vascular disease; septic shock; ischaemic injury;

reperfusion injury; neurotoxicity; hemorrhagic shock; inflammatory diseases; multiple sclerosis;

5 secondary effects of diabetes: and acute treatment of cytotoxicity following cardiovascular surgery.

In a certain aspect, the phannaceutical compositions disclosed herein are used in combination, either

simultaneously or sequentially, with ionizing radiation or one or more chemotherapeutic agents.

1003331 In certain embodiments, combination therapies described herein are used as part of a

specific treatment regimen intended to provide a beneficial effect from the co-action of a PARP

10 inhibitor described herein and a concurrent treatment. It is understood that the dosage regimen to

treat, prevent, or ameliorate the condition(s) for which relief is sought, is optionally modified. in

accordance with a variety of factors.

[003341 In certain combination therapies described herein, dosages of the co-administered

compounds vary depending on the type of co-drug employed, on the specific drug employed, on the

15 disease or condition being treated and so forth. In some embodiments, when co-administered with

one or more biologically active agents, the compound provided herein is administered either

simultaneously with the biologically active agentss, or sequentially. in certain aspects wherein the

agents are administered sequentially, the attending physician will decide on the appropriate

sequence of administering protein in combination with the biologically active agent(s). 20 1003351 In various embodiments, the multiple therapeutic agents (one of which is one of the

compounds described herein) are administered in any order Or even simultaneously. In certain

instances, administration is simultaneous and the multiple therapeutic agents are, optionally,

provided in a single, unified form, or in multiple forms (by way of example only, either as a single

pill or as two separate pills), in some embodiments, one of the therapeutic agents is given in

25 multiple doses, or both are given as multiple doses, in some instances, administration is not

simultaneous and the timing between the multiple doses varies, by way of non-limiting example,

from more than zero weeks to less than four weeks. In addition, the combination methods,

compositions and formulations are not to be limited to the use of only two agents; the use of

multiple therapeutic combinations are also envisioned.

30 1003361 In additional embodiments, the compounds described herein are used in combination with

procedures that provide additional or synergistic benefit to the patient. By way of example only,

patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein.

wherein pharmaceutical composition of a compound disclosed herein and/or combinations with

other therapeutics are combined with genetic testing to determine whether that individual is a carrier 35 of a mutant gene that is known to be correlated with certain diseases or conditions.

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1003371 In certain embodiments, the compounds described herein and combination therapies are

administered before, during or after the occurrence of a disease or condition. In certain

embodiments, the timing of administering the composition containing a compound varies. Thus, for

example, in some embodiments, the compounds are used as a prophylactic and are administered

5 continuously to subjects with a propensity to develop conditions or diseases in order to prevent the

occurrence of the disease or condition. In some embodiments, the compounds and compositions are

administered to a subject during or as soon as possible after the onset of the symptoms, in certain

embodiments, the administration of the compounds is initiated within the first 48 hours of the onset

of the symptoms. within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset

10 of the symptoms, The initial administration is achieved via any route practical, such as, for example,

an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule,

transdermal patch, buccal delivery, and the like, or combination thereof, in sonie embodiments. a

compound is administered as soon as is practicable after the onset of a disease or condition is

detected or suspected, and for a length of time necessary for the treatment of the disease, such as,

15 from about I month to about 3 months. In certain embodiments, the length of treatment varies for

each subject, and the length is determined using any criteria. In exemplay embodiments, a

compound or a formulation containing the compound is administered for at least 2 weeks, for about

I month to about 5 years. or for about 1 month to about 3 years.

Other Combination Therapies

20 [003381 In certain embodiments described herein, methods for treatment of PARP mediated

conditions or diseases, such as proliferative disorders, including cancer, include administration to a

patient compounds; pharmaceutical compositions, or medicaments described herein in combination

with at least one additional agent selected from the group consisting of alemtuzumab, arsenic

trioxide, asparaginase (pegylated or non-), bevacizumab. cetuximab, platinum-based compounds

25 such as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine, 5

fluorouracil, gemtuzumab, methotrexate, Padlitaxe taxol, temozolomide, thioguanine, or classes

of drugs including hormones (an antiestrogen, an antiandrogen, or gonadotropin releasing hormone

analogues, interferons such as alpha interferon, nitrogen mustards such as busulfan or melphalan or

mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecan or

30 topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents to treat signs or

symptoms induced by such therapy including allopurinol, filgrastim,

granisetron/ondansetron/palonosetron, and dronabinol.

Kits/Articles of Man ufacture

[003391 For use in the therapeutic applications described herein, kits and articles of manufacture are

35 also described herein. In various embodiments, such kits comprise a carrier, package, or container

that is compartmentalized to receive one or more containers such as vials tubes, and the like, each

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of the containers) comprising one of the separate elements to be used in a method described herein.

Suitable containers include, for example, bottles, vials, syringes, and test tubes. in some

embodiments, the containers are formed from a variety of materials such as glass or plastic.

j00340 In some entbodiments, the articles of manufacture provided herein contain packaging

5 materials. Packaging materials for use in packaging pharmaceutical products include, but are not

limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes botdes, and

any packaging material suitable for a selected formulation and intended mode of administration and

treatment.

1003411 In some embodiments, the container(s) described herein comprise one or more compounds

10 described herein, optionally in a composition or in combination with another agent as disclosed

herein. The container(s) optionally have a sterile access port (for example in some embodiments the

container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic

injection needle). Such kits optionally comprise a compound with an identifying description or label

or instructions relating to its use in the methods described herein,

15 [003421 In some embodiments, a kit will comprises one or more additional containers, each with one

or more of various materials (such as reagents, optionally in concentrated form, and/or devices)

desirable from a commercial and user standpoint for use of a compound described herein. Non

limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles,

syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for

20 use, and package inserts with instructions for use. A set of instructions is optionally included.

1003431 In certain embodiments, a label is on or associated with the container In some

embodiments, a label is on a container when letters, numbers or other characters forming the label

are attached, molded or etched into the container itself; a label is associated with a container when it

is present within a receptacle or carrier that also holds the container, e.g., as a package insert; In

25 certain embodiments, a label indicates that the contents are to be used for a specific therapeutic

application. In some embodiments, the label indicates directions for use of the contents, such as in

the methods described herein.

1003441 In certain embodinents, the pharmaceutical compositions are presented in a pack or

dispenser device which contains one or more unit dosage forms containing a compound provided

30 herein, In some embodiments, the pack contains a metal or plastic foil, such as a blister pack. The

pack or dispenser device is optionally accompanied by instructions for administration, In some

embodiments, the pack or dispenser is accompanied with a notice associated with the container in

form prescribed by a governmental agency regulating the manufacture, use, or sale of

pharmaceuticals- which notice is reflective of approval by the agency of the form of the drug for

35 human or veterinary administration. In certain embodiments, such notice is, for example, the

labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved

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product insert. In some embodiments, compositions containing a compound provided herein are

formulated in a compatible pharmaceutical carrier and are placed in an appropriate container labeled

for treatment of an indicated condition.

EXAMPLES

5 [003451 The following Examples are intended as an illustration of the various embodiments as

defined in the appended claims. In some embodiments, the compounds are prepared by a variety of

synthetic routes. All publications, patents, and patent applications cited herein are hereby

incorporated by reference for all purposes.

EXAMPLE I

10 Example la: Parenteral Composition

1003461 To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound described herein is dissolved in DMSO and

then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage init form

suitable for administration by injection.

15 Example I b: Oral Composition

[003471 To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound

described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage

unit for, such as a hard gelatin capsule, which is suitable for oral administration.

Example 1c: Sublingual (Hard Lozenge) Composition

20 1003481 To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, mix

100 mg of a compound described herein, with 420 mg of powdered sugar mixed, with 1 6 mL of

light corn syrup, 2.4 ml distilled water, and 0.42 mL mint extract. The mixture is gently blended

and poured into a mold to form a lozenge suitable for buccal administration.

Example Id: Inhalation Composition

25 1003491 To prepare a pharmaceutical composition for inhalation delivery, 20 rmg of a compound

described herein is mixed with 50 mg of anhydrous citric acid and 100 ml of 0.9% sodium. chloride

solution. The in ixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is

suitable for inhalation administration.

Example le: Rectal Gel Composition

30 1003501 To prepare a pharmaceutical composition for rectal delivery, 100 mig of a compound

described herein is mixed with 2.5 g of methylelluose (1500 mPa), 100 mg of methylparapen, 5 g

of glycerin and 100 mL of purified water. The resulting gel mixture is then incorporated into rectal

delivery units, such as syringes, which are suitable -for rectal administration.

Example I f: Topical Gel Composition

35 1003511 To prepare a pharmaceutical topical gel composition. 100 mg of a compound described

herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of

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isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then

incorporated into containers, such as tubes, which are suitable for topical administration.

Exaniple 1 g: Ophthalmic Solution Composition

1003521 To prepare a pharmaceutical ophthalmic solution composition, 100 ug of a compound

5 described herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2

micron filter. The resulting isotonic solution is then incorporated into ophthahnic delivery units,

such as eye drop containers, which are suitable for ophthalmic administration.

Example 2

8,9-Diphenyl-8,9-dihydro-2H-pyrido[4,3,2-d ejphthalazi n-3(711)-one

10 Example 2A

4-Nairoisobenzofuran-1(311)-one

1003531 A suspension of sodium borohydride (0.757 g, 20 mmol) in anhydrous tetrahydrofuran (120

mL) was cooled to 0 "C A solution of 4-nitrobenzofuran-1,3-dione (6.18 g, 32 mmol) in anhydrous

tetrahydrofuran (30 nL) was then added dropwise to the suspension. After the addition, the mixture

15 was allowed to stir at this temperature for 3 hr, The reaction was quenched with 3N hydrochloric

acid (to pH.=l). Water (40 nL) was added to the mixture and stirred for I hr. Tetrahydrofuran was

removed under reduced pressure. The residue was partioned between water (150 ml) and ethyl

acetate (150 mLx3). The combined organic layers were washed with brine, dried over anhydrous

sodium sulfate, concentrated to give crude product. The crude product was purified by

20 chromatography (silica gel, petroleum ether / ethyl acetate = 20:1 to 2:1) to give 4

nitroisobenzofuran-l (3H)-one (4.2 g, yield 73%) as a white solid. MS (ESI) n/z: 180(M+ 1) 1-1

NMR (400MHz, CDC 3) 5.77 (s, 31H1), 7.32-7.34 (d, J=84 Hz, I1H), 7.81-7.85 (t, J= 8.0 Hz 111), 8.29 (d, J= 8.0 Hz, H), 8,55 (dJ= 8.0 Hz, 11).

Example 2B

25 4-Arninoisobenzofuran- 1(31-)-one

1003541 A suspension of 4-nitroisobenzofurarn-1(311)-one (1.0 g, 5.58 nimol) and 10% Pd/C (0.1 g)

in ethyl acetate (30 mL) was purged in latm hydrogen and stirred at 25 "C for 3 hr. The mixture was

filtered, and the filtrate was concentrated to give 4-,aminoisobenzofuran-1(311)-one (0.8 g, yield

96%) as a off-white solid. MS (ESI) m/z: 150(M+) 'H-NMR (400 MHz, CDCLI) 6 3.82 (s, br 11),

30 5.19 (s, 311), 6.91-6.95 (n, 1H), 7.32-7.36 (m;211).

Example 2C

Methyl 4-oxo-2,3 -diphenyl- 1.2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-dipheny

1.,2.3.4-tetrahydroquinoline-5-carboxylate

1003551 A mixture of 4-aminoisobenzofuran-1 (31)-one (0.4 g. 2.68 mmol) and benzaldehyde (0 72

35 g, 6.7 inmol) in ethyl propionate (20 nL) was cooled to 0 "C. Then a solution of sodium methoxide

in methanol [sodiumn (248 ng, 10.72 minol) in methanol (20 mL)] was added dropwise. After the

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addition, the mixture was heated at reflux for 16 hr. The mixture was quenched with water (10I mL)

and solvent was removed in vacuum The residue was dissolved in water. acidified with IN

hydrochloric acid to pH = 6, then extracted with ethyl acetate (50 mL x3). The combined organic

layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude

5 product. The crude product was purified by prep-FIPLC to give methyl 4-oxo-2,3-diphenyl-1,2,3,4tetrahydroquinoline-5-carboxylate (256 mg, yield 27%) and ethyl 4-oxo-2,3-diphenyl- 1,2,3,4

tetrahvdroquinoline-5-carboxylate (140 mg, yield 14% ) as a light yellow solid. Methyl 4-oxo-2,3

dipheryl-1,2.3 4-tetrahydroquinoline-5-carboxyl ate: MS (ESI) m/z: 358(M+1)t . 'fH-NMR (400MHz,

CDC 3) 5 3.86 (s, 31-1), 395-3.98 (dJ= 16.4 Hz, iH) 4.81-4.84 (d J= 12.8 Hz 1-), 4.89 (s, br

10 11-1), 6.72-6.77 (m, 211), 6.90-6.93 (i, 21-1), 7.11-7.21 (m, 81-), 7.34-7.36 (t, J= 7.8 Hz, 1H).

Example 2D

8,9-Diphenyl-8,9-dihydro-2H-pyrido[4, 3 .2-delphthalazin-3(71f)-one

[003561 A mixture of methyl 4-oxo-2,3-diphenyl- 1, 2,3,4 -tetrahydroquinoline-5-carboxylate (100

mg. mmol) in hydrazine monohydrate (25 mL) was heated to reflux for 20 hr. The mixture was

15 diluted with water (30 mI. extracted with ethyl acetate (30 nLx 3). The combined organic layers

were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude

product. The crude product was purified by chromatography (silica get, petroleum ether / ethyl

acetate =20:1 to 8:1) to give 8,9-diphenyi1-8.9-dihydro-211-pyrido{4,3,2-de]phthalazin-3(7B1)-one

(15.6 mg, yield 16%) as a white solid. MS (ESI) in: 340(M1). 1-1-NMR (400 MHz, CDCI3 ) 8

20 4,2-4,25 (d, J= 9.6 Hz. PH), 4.66-4.69 (d, J= 9.6 Hz, IH), 7.02-7.06 (m. 3H), 7.16-7.26 (i, 811), 7.57-7.61 (t, J= 78 H z, 11H), 7.74-7.76 (d, J=7.6 Hz. IH), 9.82 (s, 1 11).

Example 3

8,9-Bis(4-((methylaiino)methyl)phenyl-8.,9-dihydro-2H-pyrido[4,3,2-dejphthalazin-3(7H)-one

Example 3A

25 Methyl 2,3-bis(4(-(diethoxvmethyl)phenyl)-4-oxof-1,2,3 ,4-tetrahydroquinoline-5 -carboxy late and

ethyl 2,3-bis(4(-(diethoxymethyli)henyl)-4-oxo- 1.2,3 .4-tetrahydroquinoine-5-carboxylate

100357] A mixture of 4-aminoisobenzofuran-l(3H)-one (298 ng 2 mmol) and 4

(diethoxymnethyl)benzaldehvde (1.04 g, 5 mmol) in ethyl propionate (15 mL) was cooled to 0 "C. A solution of sodium methoxide in methanol sodium (184 tug, 8 mmol) in methanol (15 mL)] was

30 then added dropwise. After the addition, the mixture was .stirred at 25 C for 16 hr The mixture was

quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in

water, and then extracted with ethyl acetate (50 mL:x3). The combined organic layers were washed

with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude

product was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 100:1 to 10:1) 35 to give methyl 2,3-bis(4(-(diethoxymethyl)pheiyl)-4-oxo- 1 ,23,4-tetrahydroquinoline-S-carboxylate

and ethyl 2,3-bis(4(-(diethoxvmethyl)phenyl)-4-oxo- 1,2,3 ,4-tetrahydroquinol ine-5-carboxylate (240

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WO 2010/017055 PCT/US2009/051879

mg together, yield 21%) as a light yellow solid. LC-MS (ESI) n/z: 562(M+l1f (methyl 2,3-bis(4(

(diethoxymethyl')phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate); 576(M-11)' (ethyl 2.3

bis(4(-(diethoxymethyl)phenyl)-4-oxo- 1,2,34 -tetrahydroquinol ine-5-carboxylate).

Example 3B

5 8.9-Bis(4-(diethoxymethyl)phenyl-8,9-dihydro-2HFf-pyrido[4.3,2-de]phthalazin-3 (71H)-one

[003581 A mixture of methyl 2,3-bis(4(-(diethoxy'methvl)phenyl)-4-oxo- 1,2,3.4-tetrahydroquinoline

5-carboxylate and ethyl 2,3-bis(4(-(diethoxymethyl)phenvl)-4-oxo- 1,2,3,4-tetrahydroquinoline-5

carboxylate (240 mg, 0.43 mmol) in hydrazine monohydrate (5 mL) and methanol (5 ml) was

stirred at 40 C for 2 hr. The mixture was cooled to room temperature and filtered to give the 8.9

10 bis(4-(diethoxymethyl)phenyl-89-dihydro-2H-pyrido[4,3,2-dejphthalazin-3(7H)-one (120 mg, yield

52%)as a light yellow solid. LC-MS (ESI) m/z: 544(M+ 1) MS (ESI) m/e 381 [M±Hf.

Example 3C

4,4'-(3-Oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-dejphthalazine-8.9-diyl )dibenzaldehyde

[003591 A mixture of 8.9-bis(4-(diethoxyrmethvl)phenyl-8,9-dihydro-2H-pyrido[4,3 ,2-de]phthalazin

15 3(714)-one (120 mg, 0.22 mmol) in 3N hydrochloric acid (5 mL) was stirred at room temperature for

3 hr. Then the mixture was neutralized (hasified) with potassium carbonate to pH1 8. The resulting

suspension was filtered to give 4,4'-(3 -oxo-3,7,8.9-tetrahydro-211-pyrido[4,3,2-de]phthalazine-8,9

diyl)dibenzaIdehyde (80 mg yield 97%) as a light yellow solid. LC-MS (ESI) m/z: 396(M+])',

Example 3D

20 8,9-Bis(4-((methvlam ino)methyl)phenyl-8,9-dihydro-2H-pyrido[43 2-de]phthalazin-(711)-one

1003601 A mixture of 4,4E'-(3-oxo-3 ,7 ,8,9-tetrahydro-211-pyrido[4,3,2 -de]phthalazine-8,9

diyl)dibenzaldehyde (80 mg, 0,21 mmol) and 27% methylamine alcohol solution (94 mg, 0.82

mmol) in methanol (10 mL) was stirred at room temperature for 40 min. The mixture was then

cooled to 0 'C, Sodium borohydride (24 ng, 0.64 mmol) was added. After the addition, the mixture

25 was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The

residue was washed with ethyl acetate and filtered, The filtrate was concentrated to give 8,9-bis(4

((methylamino)methyl)phenyl-8;9-dihydro-21-pyrido[4,3, 2-de]phthalazin-3 (714)-one (29.5 ng,

yield 33%) as a light yellow solid. 1H-NMR (400. M411z, DMSO-d6) 62.20 (d, 3::: 8.8 Hz ,61). 3.52

3,53 (d, J 2.4 liz, 4H), 4,31-4.33 (d, J 6.4 Hz, 111), 4.76-4.77 (d, J= 6.4 Hz, IH), 7.06-7.08 (]d,,

30 -6.4 H-z, 21H). 7,12-7.17 (m, 5F1), 7,35-7.38 (t,1= 6.4 Hiz 2) 7.49-7.57 (t, J= 10,0 Hz, IH); LCMS (ESI) m/z: 426(M+ I

Example 4

8,9-Di(pyridin-4-l)-89-dihydro-2H-pyrido[4,3;2-dejphthalazin-3(71)-one

Example 4A

35 Methyl 4-oxo-2,3-di(pyridin-4-yl)- 1,2,3,4-tetrahvdroquinoline-5 -carboxylate and ethyl 4-oxo-2,3

di(pyridin-4-yl)-1;2,3,4-tetrahy'droquinoline-5-carboxylate

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1003611 A mixture of 4-aminoisobenzofuran-1(3T)-one (149 mg, I mmol) and nicotinaldehyde (268

mng, 2.5 mmol) in ethyl propionate (10 nL) was cooled to 0 C. Then a solution of sodium

nethoxide in methanol. [sodium (93 mg, 4 mmol) in methanol (3 iL)] was added dropwise. After

the addition, the mixture was stirred at 25 *C for 16 hr. The mixture was quenched with water (5

5 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted

with ethyl acetate (50 mLx3). The combined organic layers were washed with brine, dried over

anhydrous sodium sufate, and concentrated to give crude product. The crude product was purified

by prep-HPLC to give methyl 4-oxo-2,3-di(pyridin-4 -y)-1,2,3 4-tetrahydroquinolie-5-carboxylate

(60 mg,yield 17%) and ethyl 4-oxo-2,3-di(pyridin-4-yl)- 1,2,3,4-tetrahydroquinoline-5 -carboxylate

10 (4 mg. yield I%) as a light yellow solid. LC~MS (ESI) m/z: 360(M+ I-f( methyl 4-oxo-2,3

di(pyridin-4-yl)-1,2.3 4-tetrahydroquinoline-5-carboxylate), 374(M+ I( ethyl 4-oxo-2 ,3-di(pyridin

4-y)-,2,3,4-tetrahydroquinoline-5-carboxylate).

Example 4B

8,9-Di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[43,2-de lphthalazin-3(7H)-one

15 1003621 A mixture of methyl 4-oxo-2,3-di(pyridin-4-vi)-1,2 34-tetrahydroquinoline-5-carboxylate

and ethyl 4-oxo-23 -d i(pyridin-4-y)- 1,2,3,4-tetrahydroquinoline-5-carboxylate (60 rmg, 0. 17 mmol)

in hydrazine nonohydrate (7 rL) was heated to reflux for 4 hr Then the mixture was cooled to

room temperature and solvent was removed in vacuum to give crude product. The crude product was

purified by pre-HPLC to give 8,9-di(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3 .2-delphthalazin

20 3(7H)-one (15 mg, yield 68%) as a light yellow solid. 'H-NMR (400 MHz, DMSO) i 4.46-4.48 (d, J= 8.A Hz 114) 4.90-4.92 (d, J= 8.4 Hz, Ili), 7. 16-7.20 (m 3.H) 7,32-7.34 (d, J= 5.2 Hz, 2H),

7.40-7,42 (d, J= 8.4 Hz. 1 H) 7.55 (s, 114)., 7.59-7.63 (t, i:= 8.0 Hz, I H), 8.40-8.40 (d, J= 5.2 Hz.

2H), 844-8.45 (d, J= 5.2 Hz, 2H). LC-MS (ESI) n/z: 342(M41)'.

Example 5

25 8,9-Di(pyridin-3y-'l)-8,9-dihydro-211-pyrido[4,3,2-delphthalazi-3(7H)-oie

Example 5A

methyl 4-oxo-2.3-di(pyridii-3-yl)-1,2,3,4-tetrahvdroquinoline-5-carboxylate and ethyl 4-oxo-2,3

di(pyridin-3 -y 1)- 1,2,3,4-tetrahydroquinoline-5 -carboxylate

1003631 A mixture of 4-aminoisobenzofuran-1(3H)-one (298 mg, 2 nimol) and nicotinaldehyde (535

30 rug, 5 mmol) in ethyl propionate (15 mL) was cooled to 0 *C. A solution of sodium niethoxide in

methanol [sodium (184 mg, 8 mmol) in methanol (15 mL)] was then added dropwise. After the

addition, the mixture was stirred at 25 TC for 16 hr. The mixture was quenched with water (10 mL)

and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with

ethyl acetate (50 mLx 3). The combined organic layers were washed with brine, dried over

35 anhydrous sodium sulfate, and concentrated to give crude product, The crude product was purified

by chromatography (silica gel, petroleum ether / ethyl acetate = 100:1 to 10:1) to give methyl 4-oxo

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2, 3-di(pyridin-3-yi)-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2,3-di(pyridin-3-Vl)

1,2,3,4-tetrahydroquinoline-5-carboxylate (480 mg together, yield 67%) as a light yellow solid. LC

MS (EST) m/z: 360 (M+1)*(methyl 4-oxo-2,3-di(pyridi n-3-y)-L2,3 4-tetrahydroquinoline-5

carboxylate); 374 (M+1)I j(ethyl 4-oxo-2,3-di(pyridina-3-yl )- 1,2,3,4-tetrahydroquinoline-5

5 carboxylate).

Example 5B

8,9-Di(pyridin-3-yl)-8.,9-dihydro-21pyrido[4,3 ,2-de]phthalazin-3(71)-one

{003641 A mixture of methyl 4-oxo-2,3-di(pyridin-3 -vl)- 1,2,3,4-tetrahvdroqu inoline-5-carboxylate

and ethyl 4-oxo-2,3-di(pyridin-3-yl)-,2 ,3 4-tetrahydroqu inoline-5 -carboxylate (480 mg, 1,34 mmol)

10 in hydrazine monohydrate (20 mL) and methanol (5 mL) was heated to reflux for 2 hr. The mixture

was then cooled to room temperature and filtered to give 8,9-di(pyridin-3-y1)-8,9-dihvdro-2H

pyrido[4,3,2-dcjphthalazin-3(7H)-one (320 mg, yield 68%)as a light yellow solid. 'H-NMR (400

MHz, DMSO-d6) 6 4.51-453 (d, J= 84 Hz, 1U), 4.89-4.91 (d, J= 8.4 Hz, I H), 7.18-7.20 (m, III),

7.24-7.27 (m, 11). 7.31-7.33 (m, IH), 7.43-7.44 (in 11H), 7.60 (s, 1H1), 7.58-7.63 (ni 2-1), 7.79-7.81

15 (m, Il), 8.32-8.34 (m, 211), 8,41-8,43 (m, 1 H), 8.45-8,46 (dJ= 1.6 Hz, 1 H); LC-MS (ESI) m/z:

342(M+1)

Example 6

8,9-Di(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3 .2-de]phthalazin-3(7H)-one

Example 6A

20 methyl 4-oxo-2,3-di(pyridin-2-yl)-I,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 4-oxo-2 3

di(pyrid in-2-yl)-1.231,3,4-tetrahvdroquinoline-5-carboxylate

[00365) A mixture of 4-aninoisobenzofuran- 1(3 H)-one (149 mg, 1 mmol) and nicotinaldehyde (268

mg, 2.5 mnol) in ethyl propionate (10 n.) was cooled to 0 C. A solution of sodium methoxide in

methanol [sodium (93 mg, 4 mmol) in methanol (3 nL)] was then added dropwise. After the

25 addition, the mixture was stirred at 25 "C for 16 hr. The mixture was quenched with water (5 mL)


ethyl acetate (50 mLx3). The combined organic layers were washed with brine, dried over

anhydrous sodium sulfate, and concentrated to give code product. The crude product was purified

by prep-HPLC to give methyl 4-oxo-2,3-di(pyridin-2-yI)-2,23,4-tetrahydroquinoline-5-carboxylate

30 (72 ig, yield 20%) and ethyl 4-oxo-2,3-di(pyridin-2-y])-1. 2, 3.4-tetrahydroquinoline-5-carboxylate

(14 mg, yield 3%) as a light yellow solid. LC-MS (ESI) nt/z: 360(M+I)(methyl 4-toxo-2,3di(pyridin-2-yl)-1,2 ,3,4-tetrahydroquitnoline-5-carboxylate); 374(M+1)' (ethyl 4-oxo-2,3di(pyridin

2-ydi- ,2;3,4-tetrahy droquinoline-5-carboxylate)

Example 6B

35 8,9-Di(pyridin-2-vl)-8,9-dihydro-2H-pyrido[42 "2-delphthalazin-3(711)-one

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WO 2010/017055 PCT/US2009/051879

[003661 A mixture of methyl 4-oxo-2,3-di(pyTidin-2-yl)- 1,2,3.4-tetrahydroquinoline-5-carboxylate

and ethyl 4-oxo-2i3-di(pyridin-2-yi)-1,2,3,4-tetrahydroquinoline-5-carboxylate (68 rmg, 0.19 inmol)

in hydrazine monohydrate (7 mL) was heated to reflux for 4 hr. Then the mixture was cooled to

room temperature and solvent was removed in vacuum to give crude product. The crude product was

5 purified by pre-HPLC to give 8,9-di(pyridin-2-yl)-8,9-d ihydro-2H-pyrido[4,3,2-de]phthalazin

3(71-I)~one (24 mg, yield 37%) as a light yellow solid. 1H-NMR (400 MHz, DMSO) 5,42-5.43 (d, J

= 5.2 Iz, 1H), 5.56-5.57 (d, J= 5,2 Hz. 111), 7.30-7.32 (d, .= 8.0 Hz,IH), 7.37-7.39 (d,J= 8.0 lz,

I H), 7.63-7.66 (t, J= 6.6 Hz. 1 H), 7.68-7.70 (m. 2H), 7.78-7.80 (d, J= 7.2 Hz,1 H), 7.87-7.89 (d, J=

8.0 Hz, li), 8,11-8.16 (m, 211). 8.66-8,67 (d, = 4.8 Hz, 11-). 8,74-8,76 (d, J= 5.6 Hz, I H); LC-MS

10 (ESI) mn/z: 342(M+ J).

Example 7

9-lsopropyl-8-phenyl-8,9-dihydro-2H-pyrido[4.3,2-de]phthalazin-3(7H)-one

Example 7A

(E)-4-(Benzylidenearnino)isobenzofuran- 1(311)-one

15 1003671 4-aminoisobenzofuran-d(3H)-one (600 mg, 4 mmol), benzaldehyde (427 mg. 4 nmol) were

added to methanol (20 mL) and stirred under reflux overnight, then the mixture was evaporated

under reduced pressure and the residue was dried in vacuum. 600 mg of crude product (E)-4

(benzylideneamino)isobenzofuran- 1(311)-one was obtained which was used for the next synthetic

step without further purification.

20 Example 7B

Methyl 3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate

[003681 4-(benzyl ideneamino)isobenzoftiran- 1(3 H)-one (237 ing, I mmol), isobutyraldehyde (216

mg,3 mmol), sodium methanolate (162 mg, 3 mnmol) and ethyl propionate (20 mL) were added and

the mixture was stirred at room temperature overnight. Then the resulting mixture was evaporated

25 under reduced pressure and extracted with ethyl acetate (100 mLx4) and concentrated. The crude

product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20:1 to

5:1). 35 rug of solid methyl-3-isopropyl-4-oxo-2-phenyl- 1;2,3 4-tetrahydroquinoline-5 -carboxylate

was obtained. (yield: 11%). LC-MS (ESI) m/z: 308(MH1)'.

Example 7C

30 9-sopropyl-8-phenyl-8,9-dihydro-2Hi-pyrido4.3 ,2-de]phthalazin-3(711)-one

1003691 Methyl 3-isopropyl-4-oxo-2-phenyl-1,2_.,3,4-tetrahydroquinoline-5-carboxylate (35 rmg, I

minmol) and hydrazine monohydrate (20 mL) were added and the mixture was stirred under 40 "C for

3 h. The resulting mixture was extracted with ethyl acetate (100 mLx4) and concentrated, purified

with prep-HPLC. 7 mg of solid 9-isopropyl-8-phenvl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin

35 3(711)-one was obtained (yield :15%). '1H-NMR (400 MHz I)MSO-d6): 6 0.82-0.83 (d, l= 5.2 lz,

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WO 2010/017055 PCT/US2009/051879

3H) 1. 15-1.17 (d, J= 5.2 Hz, 311), 1.89-1.93 (in, 11), 2.72-2.73 (d, J= 6,0 Hz, 1IH), 4-83 (s, lIH),

7.11-7.26 (m, 7H), 7:51-7,54 (, 211), 12-11 (s. 11l). ILC-MS (EST) m/z: 306 (M+1)

Example 8

9-(4-((Methylamino)methyl)phenvl)-8-phenyl-89-dihydro2R1-pyrido[4.3;2-de]phthalazin-3(7 T)5 one and 9-(4-((diinethylani no)miethyl)phenyl)-8-phenyl-8,9-dihydro-2I-pyrido[4.3,2

deJphthalazin-3(7.)-one

Example SA

1 -(4-(Diethoxymethyl)phenvl)-N-methyimethanamine

[003701 A mixture of 4-(diethoxymethl)benzaldehyde (1.04 g, 5 mmol) and methylamine (27-32 %

10 solution in methanol, 2.3 g 20 mmol) in methanol (20 mL) was stirred at room temperature for 40

mins. The mixture was cooled to 0 T, sodium borohydride (0, 284 g, 7.5 nmol) was added

portionwise. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was

removed under reduced pressure The residue was partitioned between water (50 mL) and ethyl

acetate (50 mL). The organic layer was separated. The aqueous layer was extracted with ethyl

15 acetate (50 mLx3). The combined organic layers were wvaslied with brine, dried over anhydrous

sodium sulfate, and concentrated to give crude i-(4-(diethoxymethyl)phenyl)-N

methyimethananine (11 g) as a light yellow oil which was used in the next step without further

purification LC-MS (ESI) m/z: 224(M+l) .

Example 8B

20 Benzyl 4-(diethoxymethyl)benzyl(nethyl)carbamate

1003711 To a stirred solution of l-(4-(diethoxymethl)phenyi)-N-methyimethanamine (1 g' 4.9

mml) and triethylamine (0.75 g, 735 mmol) in anhydrous dichloromethane (10 mL) was added

benzyl carbonochloridate (L g, 588 mmcol) at 0 C. After the addition, the mixture was allowed to

stir at room temperattire overnight. The mixture was diluted with dichloromethane (50 mL), washed

25 with water (50 mL 3), brine (50 nL), dried over anhydrous sodium sulfate, and concentrated to give

crude product which was purified by chromatography (silica gel, petroleum ether / ethyl acetate =

100:1 to 20:1) to give benzyl 4-(diethoxymethvl)benzyl(methyl)carbamate (L g; yield 57% for

two steps) as a light yellow oil. 1H-NMR (400 Mliz, CDCI3) 6: 3.82 (s, br H), 5.19 (s, 311), 6.916.95 (in, liH), 7,32-7.36 (i, 211); C-MS (ES1) m/z: 358(M+1).

30 Example 8C

Benzyl 4-formylbenzyl(imethyl)carbamate

100372] The mixture of benzyl 4-(diethoxymethvl)benzyl(methvl)carbaimate (1 .0 g 2.8 mmol) in

3N hydrochloric acid (50 ml) was stirring at room temperature for lb. Then the mixture was

neutralized with Potassium carbonate. The resulting mixture was extracted with ethyl acetate (100

35 mLx4), the organic phase was washed with water and saturated sodium bicarbonate, dried with

anhydrous sodium sulfate and concentrated to give benzyl 4-formylbenzyl(methyl)carbamate (730

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WO 2010/017055 PCT/US2009/051879

mg, 92%). 1H-NMR (400 MHz, CDC 3) 8: 2,94 (d, 314). 4.572 (d, 2H), 5.18 (d, 214)5 72.3-7,39 (in,

714). 7.84 (m, 21), 10,00(s, 111); LC-MS (ESI) m/iz: 284 (M+l)t

Example 8D

Methyl 3 -(4-(((benzyloxycarbonyl)(methyl)amino)methyl)pheny l)-4-oxo-2-phenyl- 1,2,3.4

5 tetrahydroquinoline-5-carboxylate

[003731 A mixture of benzyl 4-formylbenzyl(methyl)carbamate (566,11g, 2 rmol) and 4

(benzylideneamino) isobcnzofuran-1-one (474 mng, 2 mmnol) in ethyl propionate (15 mL) was cooled

to O *C, A solution of sodium methoxide in methanol [sodium (184 mg, 8 mmol) in methanol (15

mL)] was then added dropwise. After the addition, the mixture was stirred at 25 "T for 18 hr. The

10 mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was

dissolved in water, and then extracted with ethyl acetate (50 mLx3). The combined organic layers


product. The crude product was purified by chromatography (silica gel, petroleum ether / ethyl

acetate = 100:1 to 10:1) to give a mixture of methyl 3-(4

15 (((benzyloxvcarbonyl)(methyl)amino)iethyi)-phenyl)-4-oxo-2-phenyl-1 ,2,3 ,44etrahydroquinoline

5-carboxylate and ethyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-pheoyl)-4-oxo-2-phenyl

I,2,3.4-tetrahydroquinoline-5-carboxylate (220 mg, yield 20%) as a light yellow solid. LC-MS

(ES!) n/z: 535(M+1) and 549(M+I)

Example 8E

20 Benzyl niethyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3, 2-de]phthalazin-9

yl )benzyl)carbamate

1003741 A mixture of methyl 3 -(4-(((benzvloxycarbonyl)(nethyl)amino)methyl)phenyl)-4-oxo-2

phenyl- 1,2,3.,4-tetrahydroquinoline-5-carboxylate (220 mg 0.94 inniol) in hydrazine monohydrate

(50 ml) and methanol (5 mL) was stirred at 40 C for 24 hr. The mixture was cooled to room

25 temperature and filtered to give the crude product. The crude product was purified by

chromatography (silica gel, petroleum ether / ethyl acetate -3:1) to give bennl methy(4-(3-oxo-8

phenyl-3.7,89-tetrahydro-2H-pyrido[4,3,2-dejphthalazin-9-yl)benzyl)carbamate (80 mg. yield

16%) LC-MS (ES 1) n/z: 517(M+1).

Example 8F

30 9-(4-((Methvlamino)inethvl)phenyl)-8phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)

one and 9-(4-((dimethylam ino)methyl)phenyl)-S-phenyl-8,9-dihydro-211-pyrido[4.3,2

de]phthalazin-3(7H)-one

[003751 A mixture of benzyl methyl(4-(3-oxo-8-pheny-3.7,8,9-tetrahydro-2H-pyrido[4,3 .2

de]phthalazin-9-yl)benzyl)carbaniate (80 mg, 0.26 rrnol), 10% Pd/C (20 mg) of methanol (50 ml)

35 was stirring at room temperature for 4 h. The mixture solution was then filtered and evaporated

under reduced pressure. The residue was purified by prep-HPLC. 3 ing of 944

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((methylami no)methyl)phenvl)-8-phenv-8.9-d ihydro-2H-pyrido [4,3,2-deI]phthalazin-3(7H)-one and

6 mg of 9-(4-((dimethylamino)nethyl)phenyl)-8-phenyl-8,9-dihydro2LI-pyrido[4,3.2

dejphthalazin-3(7H)-one were obtained, yield 9%. For 9-(4-((methylamino)methyl)-phenyl)-8

phenyl-8,9-dihydro-2H-pyrido[4,3,2-dejphthalazin-3(7H1)-one: H-NMR (400 MIiz CD3OD) 6:

5 2.50 (s, 34), 3,87 (s, 21), 4,38 (d, 11), 4.75 (d. 111), 7.15-7.17 (m 2H) 7.19-7.25 (m, 51), 7,27

7.28 (m, 31), 7.57 (d, 111) 7.65 (t, 1-1). LC-MS (ESI) r/z: 383(M+1). For 9-(4

((dimethylainino)nethyl)phenyl)-8-phenyl-8,9-dihydro-2H9-pyrido[4,3 2-de]phthalazin-3(7H)-one:

'H-NMR (400 MHz, CD.OD) 6 2.31(s, 6H), 3.57 (s, 2H), 4.33 (d, 1N), 4.73 (d, 111), 7.10-712 (in,

21-1) 7.19- 721 (in, 614), 7.26-7.27 (n. 211), 7.58 (d, IH), 7.64 (t, I H). LCMS (ESI) n/z:

t0 397(M+1)*

Example 9

9-(3-((Methylamin o)imethyl)phenyl)-8-phenyl-8.9-dihydro-2H-pyrido[4;3,2-kphthalazin-3(7H1)

one

Example 9A

15 Methyl 3-(3-(diethoxynethyl)phenyl)-4-oxo-2-phenyl-l,2,3,4-tetrahydroquinoline-5-carboxylate

1003761 A mixture of (E)-4-(benzylideneainino)isobenzofuran- I(31)-one (474 ingn 2 mnimol) and 4

(diethoxyiethyl)benzaldehyde (418 mg, 2 nmol) in ethyl propionate (20 nL) was cooled to 0 *C,

Sodium methoxide in methanol solution [sodium (148 mg, 8 miol) in methanol (2 mL)] was then

added dropwise and the mixture was stirred at room temperature overnight. The resulting mixture

20 was evaporated under reduced pressure. The residue was extracted with ethyl acetate (100 mLx3)

and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and

concentrated to give crude product, The crude product was purified by column chromatography

(silica gel, petroleum ether/ethyl acetate z 50: to 5:1) to give methyl 3-(3-(diethoxvmethvl)phenyl)

4-oxo-2-phenyl-1 ,2,3,4-tetrahydroquinoLine-5-carboxylate (230 rug, yield 25%) as a yellow solid.

25 Example 9B

9-(3-(D iethoxymethvl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3 ,2-de]phthalazin-3(71)-one

[00377J Methyl 3-(3-(diethoxymethyl)phenyl)-4-oxo-2-phenvl-1,2,3,4-tetrahydroquinoline-5

carboxylate (300 mg, 0.65 mmol) in hydrazine monohydrate (20 mL) was stirred at 45 C -for 4 h.

The resulting mixture was filered to give 9-(3 -(diethoxymethyl)phenvl)-8-phenyl-8,9-dihy dro-2H

30 pyrido[4.3,2-di]phthalazin-3(71H)-one (95 mng, yield 33%) as a white solid. '-NMR (400 M -7,

DMSO-d6) 6-1 04-.08 (t, =J 7.0 Hz, 611), 3.27-3.31 (q, 4H); 434-4.36 (d, J = 8.8 Hz, 111), 4.74

4.76 (d, J= 8.8 Hz, 11), 5.34 (s, 1H), 7.08 (s, 1H), 7.14-7.24 (in 7H), 7.27-7.29 (m, 2H), 7.37-7.39

(d, J = 7.2 Hz, I H), 7.43 (sI 11), 7.56-7.60 (t, J- 8.0 Hz, 1H); 12.15 (s, 1l); LC-MS (ESI) n/z: 442

(M+ I).

35 Example 9C

3-( 3-Oxo-8-phenyl-3 ,7,8.9-tetrahydro-2ii-pyri do[4,3,2-de]phthalazin-9-yl)hbenzaIdehyde

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1003781 A mixture of 9-(3-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[43,2

de]phtbalazin-3(71h-)one (90 mg, 0.20 numol) in 3N hydrochloric acid (12 ml.) was stirred at room

temperature for 20 hr. Then the mixture was adjusted to pI=8 with potassium carbonate. The

resulting suspension was extracted with ethyl acetate to give 3-( 3-oxo-8-phenyl-3,7.8,9-tetrahydro

5 2H-pyrido3[4,3,2-de]phthalazin-9-vl)benzaldehyde (66 mg, yield 88%) as a light yellow solid. LC

MS (EST) m/z: 368(M+1)"

Example 9D

9-(3 -((Methylami no)methyl)pheny1)-8- pheny8,9-dihydro-2H-pyrido [4,3 ,2-de]phthalazin-3(711)

10 one

[003791 A mixture of 3-( 3-oxo-8-phenyl-3,7,8,9-tetrahydro-2HU-pyrido[4,3;.2-de]phthalazin-9

yl)benzaldehyde (66 mg, 0.18 minol) and 27% methylamine alcohol solution (83 mng, 0.72 mmol) in

methanol (15 miL) was stirred at room temperature for I h. The mixture was then cooled to 0 C and

sodium borohydride (I Img, 0.27 mmol) was added. After the addition, the mixture was stirred at

15 room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was purified

by prep-HIIPLC to give 9-(3-((methylamino)methl)phenyl)-8-phenyl-8,9-dihydro-2H-Ipyrido[4,3,2

de]phthalazin-3(71)-one (34 mg, yield 49%) as a light yellow solid. 3H-NMR (400 MHz, MeOD

d4) 8: 2.55 (s, 3H), 4.04-4.13 (q, 21), 4.36-4.38 (d, J:::: 9.6 Hz, 1H-), 4.74-4.76 (d. J= 8.8 Hz, 11),

7.18-7.24 (m 611). 7.25-735 (m, 41), 7.56-7.58 (d, J= 7.6 Hz, I III 7.62-7.66 (t,,J= 8 Hz, IH)

20 LC-MS (EST) m/z: 383(M+1)

Example 10

844-((Methy lamnino)methyl)phenvl)-9-phenvl-8,9-d ihydro-2H-pyrido[43 .2-de]phthalazini-3(711)

one

Example 1OA

25 (E)-4-(4-(diethoxymnethyl)benzyl ideneam ino)isobenzofuran-1(311)-one

[003801 4-Aminoisobenzofuran- 1(3H)-one (600 mg. 4 mmiol), 4-(ethoxv(methoxy)methvl)

benzaldehyde (1.6 g. 8 mmiol) and I g of magnesium sulfate were added into 40 m of

dichloromethane and stirred tinder reflux overnight, then the mixture was evaporated under reduced

pressure and the residue was dried in vacuum to give 600 tug of crude product (E)-4-(4

30 (diethoxymethy l)benzylideneamino)isobenzofuran-1(31)-one which without further purification

was used in next step.

Example 10B

Methyl 2-(4-(d i methoxymethyl)phenyl)-4-oxo-3 -phenyI - 1,2,3 ,4-tetrahydroquinoline-5 -carboxylate

[003811 (E)-4-(4-( diethoxvmethyl)benzylideneamino)isobenzofuranl-1(3 H)-one (600 mng, I imol),

35 benzaldehvde (616 mg, 3 mnol), sodium methanolate (414 mig, 7.6 mmol) and ethyl propionate (20

ml) were added and the mixture was stirred at room temperature overnight. The resulting mixture

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was then evaporated under reduced pressure and extracted with ethyl acetate (100 nLx4) and

concentrated. The crude product was purified by column chromatography (silica gel, petroleum

ether: ethyl acetate = 20:1 to 5:1) to yield 120 mg of solid of methyl 2-(4

(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2.3,4-tetrahydroquinoline-5-carboxylate (yield: 22

5 %). LC~MS (ES!) m/z: 432(M+1)

Example I OC

8-(4-(Dimethoxymethyl)phenyl)-9-piienvl-8,9-dihydro-2H-pyrido[4,3 ,2-de]phthalazin-3(71)-one

[003821 To methyl 2-(4-(dimethoxymethyi)phenyl)-4-oxo--3 -phenv-I,2,3,4-tetralydroquinoline-5

carboxylate (120 mg, 0.28 mmol) was added hydrazine ionohydrate (20 mL) and the mixture was

10 stirred under 40 C for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mi

and then Filtered, 89 mg of solid of 8-(4-(dimethoxynethyl)phenyl)-9-phenyl-8,9-diidro-2H

pyrido[4,3.2-de]phthalazin-3(7B)-one was obtained (yield: 78%). LC-MS (ESI) m/z: 414 (M4+1.

Example 1OD

4-( 3-Oxo-9-phenvl-3,7,8,9-tetrahydro-2H-pyrido[4,3.2-dce]phthalazin-8-yl)ben.zaldehyde

15 1003831 To 8-(4-(di methoxyiethyl)phenyl)-9-phenyl-89-d ihvdro-2Hf-pyrido[4,3,2-de]phthalazin

3(7H)-one (89 ing, 0.22 mmol) was added 20 ml of hydrochloric acid (3 mol/L) and the mixture was

stirred at room temperature for 2 h. The resulting mixture was evaporated under reduced pressure to

10 ml and then filtered, 59 mg of solid of 4-( 3-oxo-9-phenyl-3,7,8,9-tetrahydro-211-pyrido[4,3,2

de]phthalazin-8-yl)benzaldehyde was obtained; yield: 73%. LC-MS (ESI) n/z: 368 (M+l)O

20 Example 10 E

8-(4-((Methylamino)methyl)phenvl)-9-phenvl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)

one

[003841 To 4-( 3 -oxo-9-phenyl-3,7,8,9-tetrahvdro-2H1-pyrido[4, 3 ,2-de]phthalazin-8-yl)benzaldehyde

(59 mg, 0.16 mmol) was added methanamine (20 ml) and the mixture was stirred at room.

25 temperature for 2 h. Then 30 mg of sodium boroihydride was added and stirred for another 2 h, The

resulting mixture was evaporated under reduced pressure and purified by prep-HPLC. 11 .5 mg of 8

(4-((methvlamino)methyl)phenvl)-9-phenyl-8.9-dihydro-2H-pyrido[4,3,2-d/ejphthalazin-3(7H)-one

was obtained (yield: 19%). H -NMR (400 Mflz, CD3OD) 3: 2.66 (s, 314), 4.33-4.3 5 (d,,J= 8,Hz, 1Il), 4.83-4.85 (d, J= 7.6 Hz, IH), 7.10-7 12 (im, 211), 7.15-7.22 (in, 41H); 7.34-7.42 (m, 4H), 7.55

30 7.57 (m 11). 7,63-7.67 (in, IHi). LC-MS (EST) m/zi 383 (M+I).

Example 11

8,9-Bis(3-((iethylamino)methyl)phenyl)-8,9-dihydro-21H-pyrido[4,3 ,2-de'phthalazin-3(711)-one

Example 1 A

Methyl 2,3-bis(3-(diethoxymethvl)phenyl)-4-oxo-,2,3 ,4 -tetrahydroquinoline-5-carboxylate and

35 ethyl 2,3-bis(3-(diethoxymethy)phenyl)-4-oxo- 1,2,3,4-tetrahydroquinoline-5-carboxvlate

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WO 2010/017055 PCT/US2009/051879

100385] A mixture of 4-aminoisobenzofuran- 1(311)-one (298 mg, 2 mmol) and 3

(diethoxymethyl)benzalidehyde (0.83 g, 4 mmiol) in ethyl propionate (15 mL) was cooled to 0 *(.

Then a solution of sodium methoxide in methanol [sodium (184 mg, 8 mmol) in methanol (15 mL,)]

was added dropwise. After the addition, the mixture was stirred at 25 *C for 18 hr. The mixture was

5 quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in

water, and then extracted with ethyl acetate (50 mELx3). The combined organic layers were washed

with brine, dried over anhydrous sodium sulfate. and concentrated to give crude product, The crude

product was purified by chromatography (silica gel, petroleum ether / ethyl acetate= 100:1 to 1 0:1)

to give a mixture of methyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo- 1,2,3,4-tetrahydroquinoline-5

10 carboxylate and ethyl 2,3-bis(3-(diethoxvmethy l)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoine-5

carboxylate (370 mg; yield 33%) as a light yellow solid. LC-MS (ESI) m/z: 562(M+.1) and

5 76(M+ j)t

Example 118

8,9-Bis(3-4diethoxymethyl )phenyl)-8,9-dihydro-2H-pyrido[ 4,3;.2~dejphth alazi n~3(7H1)-one

15 1003861 A mixture of methyl 2,3-bis(3-(diethoxymnethyl)phenvl)-4-oxo-1,2,3,4-tetrahydroquinoline

5-carboxyl ate and ethyl 2, 3-bis(3-(diethoxymethyl)phenvl)-4-oxo-L 2,3,4-tetrahydroquinol ine-5

carboxylate (370 mg, 0.59 nimol) in hydrazine monohydrate (5 ml) and methanol (5 miL) was

stirred at 40 T for 2 hr. The mixture was cooled to room temperature and filtered to give 8,9-bis(3

(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-dephthalazin-3(711)-one (250 mg, yield

20 77%) as a light yellow solid. LC-MS (ESI) n/z: 544(M±] )

Example 11C

3.3'-( 3-Oxo-3 ,7,8.9-tetrahydro-2H-pyridof4,3,2-de]phtlalazin-8,9-diyl)dibenzaldehyde

1003871 A mixture of 8,9-bis(3-(diethoxymethyl)pheniyl)-8,9-dihydro-21-pyrido[4,3,2

dejphthalazin-3(71h)-one (120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at room

25 temperature for 3 hr. The mixture was then adjusted to p1 :8 with potassium carbonate. The

resulting suspension was filtered to give 3,3-( 3-oxo-3,7,8,9~tetrahydro-2H-pyrido[4,3,2

de}phthalazin-8,9-diyl)dihenzaldehyde (160 mg. yield 88%) as a light yellow solid. LC-MS (ESI)

in/z: 396(M+1)

Example II D

30 8.9-Bis(3-((methvlamino)methyl)phenyl)-8,9-dihydro-2H1-pyrido[4,3,2-de]phthalazin-3(7!)-one

1003881 A mixture of 33 '-( 3-oxo-3 ,7.8,9-tetrahydro-2H-pyrido[4,3 .2-de]phthalazin-8,9

diyl)dibenzaidehyde (100 mg, 0:25 mmol) and 27% methylamine alcohol solution (122 trig, 1.07

mmol) in methanol (15 ml) was stirred at room temperature for 40 min. The mixture was then

cooled to 0 ". Sodium borohydride (31 mg, 1.00 inmol) was added. After the addition, the mixture

35 was stirred at room temperature for 4 hr, Methanol was removed under reduced pressure. The

residue was washed with ethyl acetate and filtered. The filtrate was concentrated to give 8,9-bis(3

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((nethynlamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazi-n-3(7Hf)-one (20 mg, yield

19%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) 6; 2,62-2.63 (d,. J 4,0 Hz, 6H), 4.12

4.13 (d, J= 10.8 Hz, 411). 4,42-4.44 (d, f= 8.4 Hz, I H). 4.84-4.86 (d, J 8.4 Hz. I H), 7.20-7.24 (m,

2H). 7.29-7.33 (rn, 611), 7.52 (s, 1H), 7.57-7.60 (dd, J = 8.0 Hz, J 1.2 liz, IH), 7.65-769 (t, J

5 7.6 Iz, LH); LC-MS (ESI) ni/z: 426(M+l)V

Example 12

9-(4-(Hydroxymethyl)phenyl)-8-phenvl-8,9-dihydro-2HJ-pyrido[4,3,2-deJphthalazin-3(7H)-one

Example 12A

methyl 3 -(4-(diethoxymethyl )phenvl)-4-oxo-2-pheny -1.2,3 4-tetrahydroquinoli ne-5 -carboxylate

10 and ethyl 3-(4-(Diethoxymethyl)phenvl)4-oxo-2-phcn y1-1,2 3 4-tetrahydroquinoline-S-carboxylate

1003891 A mixture of (E)-4-(henzylideneaiino)isobenzofuran-1(311)-one (474 ng, 2 mnmol) and 4

(diethoxymethvl)benzaidehyde (0.40 g, 2.4 mmol) in ethyl propionate (15 mL) was cooled to 0 C,

A solution of sodium methoxide in methanol [sodium (184 mg, 8 minol) in methanol (15 m.L)j was

then added dropwise. After the addition, the mixture was stirred at 25 "C for 18 hr. The mixture was


water, and then extracted with ethyl acetate (50 mL3). The combined organic layers were washed

with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude

product was purified by chromatography (silica gel, petroleum ether/ethyl acetate= 100:1 to 10: 1) to

give methyl 3 -(4-(diethoxymethvl)phenil)-4-oxo-2-phenyl-12l,,3,4-tetrahydroquinoline-S.

20 carboxylate and ethyl 3-(4-(diethoxymethvl)phenyl)-4-oxo-2-phenykl 1,2,3,4-tetrahydroquinol ine-5

carboxylate (430 mg, yield: 47%) as a light yellow solid. LC-MS (ESI) m/z: 460(M+-l) and

474(M41)",

Example 121B

9-(4-(Diefthoxy'methyl)phenyl)-8-phenyi-&9-dihydro-211-pyrido[4,3 ,2-de]phlthalazin-3(711)-one

25 1003901 A mixture of methyl 3-(4-(dietloxymethyl)phenyl)-4-oxo-2-phenvl-1,2.3,4

tetrahydroqu inoline-5-carboxyl ate and ethyl 3-(4-(diethoxymethyl)phenyl )-4-oxo-2-phenyl- 1,2,3,4

tetrahydroquinoline-5-carboxylate (430 mg; 0.94 mmol) in hydrazine monohydrate (10 mL) and

methanol (5 i.L) was stirred at 40 C for 24 hr. The mixture was cooled to room temperature and

filtered to give the 9-(4-(diethoxynethyl)phenyl)-8-phenyl.8,9.dihvdro.-2H-pyrido[4,3,2

30 de]phthalazin-3(7H)-one (270 mg, yield: 65%) as a light yellow solid. LC-MS (ESI) m/z:

442(M+ I )

Example 12C

4-(3-Oxo-8-phenl-3,7,8,9-tetrahydro-2H-pyrido[4.3,2-dephthalazin-9-vl)benzaldehyde

1003911 A mixture of 9-(4-(dietloxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[ 4,3,235 de]phthaltzin-3(711)-one (270 mng, 0.61 nnol) in 3N hydrochloric acid (10 ml) was stirred at room

temperature for 3 hr. The mixture was then adjusted to pH = 8 with potassium carbonate. The

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resulting suspension was filtered to give 4-( 3-oxo-8-phenyl-3,7,8.,9-tetrahydro-2-11pyrido[4.3,2

dc]phthalazin-9-yl)benzaldehvde (140 rg, yield: 69%) as a light yellow solid,

Example 12D

9-(4-(-lydroxymethyl)phenyl)-8-phenyl-8,9-dihydro-21-pyrido[4.3,2-de]phthalazin-3(71)-one

5 [004921 A inixture of 4-( 3-oxo-8-phenyl-3 ,7, 8,9-tetrahydro-2H1-pyrido[4.3,2-de]phthalazii-9

yl)benzaldehyde (140 mgt 0.42 mmol) and 27% methylanine alcohol solution (194 mg, 1.69 mmol)

in methanol (15 ml) was stirred at room temperature for 40 min. Then the mixture was cooled to 0

"T. Sodium borohydride (48 mg, 1.26 mmol) was added. After the addition, the mixture was stirred

at room temperature for 4 hr. TLC (petroleum ether / ethyl acetate =2:1) show the reaction was

10 complete Methanol was removed under reduced pressure. The residue was washed with ethyl

acetate and filtered. The filtrate was concentrated to give 9-(4-(hydroxymethyl)phenyl)-8-phenyl

8,9-dihydro-2H-pyrido[4,32-de phthalazin-3(7H)- one (20 mg, yield: 13%) as a light yellow solid.

'H-NMR (400 Miz, CD 3OD) 6; 4.33-4.35 (d. J= 8.0 Hz,1 H). 4.53 (s, :2H). 4.74-4.76 (d, J= 80 Hz,

11 ) 7.08-7.1 0 (d, J= 8.0 Hz, 2H), 7.18-7.24 (m, 61). 7.27-7.29 (d, J= 6.8 Hz, 2H). 7.54-756 (d. .1

15 7.6 Hz 1-H), 7.62-7.66 (t, J= 8.0 Hz. 11H) LC-MS (EST) m/z: 370(M+)

Example 13

9-(3 -(4-isobutyrylpiperazine- 1 -carbonirw)phenvl)-8-phenyl-8,9-dihydro-217-pyrido[4,3 2

de]phthalazin-3(711)-one and 8,9-bis(3-(4-isobtityrylp iperazine- I -carbonyl)phenyl) -8,9-dihydro

2H1-pyrido[4 .3 ,2-dejphthialazin-3 (711)-one

20 Example 13A

tert-Butyl 4-isobutyrylpiperazine- I -carboxylate

1003931 To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrous dichloromethane (130

ml) was added triethylamine (8.33 g, 82.5 mmol), 1-hydroxybenzotriazole (10.125 g, 75 mrmol), followed by I -ethyl-3-(3-dimethylaminopropyl)carbodiim.ide hydrochloride (14.25 g; 75 minmol).

25 After the addition, the mixture was stirred at room temperature for 40 mins. The mixture was then

cooled to 0 *C, compound 1 (13.97 g, 75 mnol) was added portionwise. After the addition, the

mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane

(200 mnL), washed with saturated sodium bicarbonate (150 mL x2), 10% citric acid (150 ml), brine

(100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4

30 isobutyrylpiperazine-i -carboxylate (15 g, yield:78%) as a white solid, LC-MS (ESi) m/z:

257(M4)

Example 13B

2-Me thv-1-(piperazin-1-yl)propan-l-one

1003941 To a stirred mixture of teri-butyl 4 -isobutyrylpiperazine-1-carboxylate (6.8 g, 26.5 mmol)

35 in methanol (15 ml) was added hydrochloride/methanol (30 mL, 3M)) at 0 "C. After the addition,

the mixture was allowed to stir at room temperature overnight. The mixture was concentrated to give

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2-methyl-1-(piperazin-1-yl)propan- Ione (5.5 g. yield: 100%) as an off-white solid. 11-NMR (400

MHz, CDCl6) : 3.82 (brs, 11), 5.19 (s, 311), 6.91-6.95 (n. 11f), 7.32-7.36 (m, 21); LC-MS (EST)

rn/z: 157(M+1)

Example 13C

5 3-(4-Isobutyrylpiperazine- I -earbonyl)benzaldehyde

[003951 To a solution of 3-formyibenzoic acid (750 mg, 5 mmol) in anhydrous dichloromethane (15

rnL) was added triethylamine (1,263 g, 12.5 nmol), I -hydroxybenzotriazole (0,743 g, 5.5 mmol),

followed by I -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5,5 mmol).

After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was

10 cooled to 0 T, and 2-methyl-i-(piperazin-l--yl)propan-l-one (1.06 g, 5.5 mmol) was added

portionwise. After the addition, the mixture was stirred at room temperature overnight The mixture

was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (50 nmLx2).

10% citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to

give 3-(4-isobutyryipiperazine-1-carbonyl)benzaldehvde (1.44 g, yield: 95%) as a gum. LC-MS

15 (ES!) m/z: 289(M+1)

Example 13D

Methyl 3 -(3-(4-isobutyrylpiperazine-i-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3.4

tetrahydroquintoline-5-carboxylate and methyl 2 -bis(3-(4-isobutyryipiperazine- -carbonyl)phenyl)

4-oxo- 1.2,3,4-tetrahydroquinoline-5-carboxylate

20 1003961 A mixture of 3-(4-isobutyrylpiperazine- I -carbonyflbenzaldehyde (288 mg, 1 mmol) and 4

(benzylideneamino) isobenzofuran-1(3H)-one (237 mg, I mmol) in ethyl propionate (7,5 mL) was

cooled to 0 'C. Then a solution of sodium methoxide in methanol [sodium (92 mg, 4 minol) in

methanol (7.5 mL)] was added dropwise. After the addition, the mixture was stirred at 25 C for 18

hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue

25 was dissolved in water, and then extracted with ethyl acetate (50 mLx3). The combined organic



acetate = 10:1 to 1:10) to give methyl 3-(3-(4-isobutyrylpiperazine-I -carbonyl)phenyl)-4-oxo-2

phenyl-1,2,3.4-tetrahydroquinoline-5-carboxylate (110 mg, yield 20%) and methyl 2,3-bis(3-(4

30 isobutyrylpiperazine- I -carbonyl)phenyl)-4-oxo- 1, 2,3,4-tetrahvdroquinoline-5-carboxylate (90 mg,

yield 12%) as light yellow solids. LC-MS (ES!) m/z: 540(M+1) and 722(M+1) i

Example 13E

9-(3-(4-Isobut-rylpiperazine- I -carbony l)phenvl)-8-phenvl-8,9-d ihydro-211-pyridof[43 .2

delphthalazin-3(7iH-one

35 100397J A mixture of methyl 3 -(3-(4-isobutyiylpiperazi ne-i-carbonvl)phenvl)-4-oxo-2-pheny

1,2,3.4-tetrahydroquinoline-5-carboxyiate (110 ng, 0.20 nnmol) in hydrazine monohydrate (5 mL)

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and methanol (2 mL) was stirred at 25 *C for 4 hr, 'The mixture was extracted with ethyl acetate (50

mLx3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate,

and concentrated to give crude product. The crude product was purified by prep-FIPLC to give 9-(3

(4-isobutyrylpiperazi ne-l-carbonyl)phenyl)-8-phenyl-8.9-dihydro-2H-pyrido[4,3,2-de]phthalazin

5 3(711)-one (12 mg, yield: 11%) as a white solid. H-NMR (400 MHz, CDOD) 5; 0.96-0.98 (d, J=

6.8 Lz;6H), 2.68-295 (m, 2.), 3,28-3.55 (m, 7H.) 4,19-4.22 (d J= 10.0 Hz, 1 H), 4,54-4.57 (d, J=

10.4 Hz, 1), 7,03-7.20 (m, 10H), 7.40-7.50 (m, 2H); LC-MS (ESI) rn/z: 522(M+1) ,

Example 13F

8,9-Bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl) -8,9-dihydro-21i-pyrido[4,3 ,2-de]phthalazin

10 3(7H)-one

1003981 A mixture of methyl 2,3-bis(3 -(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-ox- 1.2,3,4

tetrahydroquinotine-5-carboxylate (90 mg. 0,12 mmol) in hydrazine monohydrate (5 mL) and

methanol (2 mL) was stirred at 25 C for 4 hr. The mixture was extracted with ethyl acetate (50

mLx 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, 15 and concentrated to give crude product. The crude product was purified by prep-HPLC to give 8,9

bis(3-(4-isobutyrylpiperazine-1-car bonyl)phenyl) -8,9-dihydro-211-pyrido[4.3;2-dejphthalazin

3(7H)-one (3.2 rmg. yield: 4%) as a white solid. tH-NMR (400MHz, CD 3OD) 6: 0.95-0.97 (q, 12H), 2.80-2.88 (m, 2H)t 2,98-308 (m, 311), 333-3,53 (11, 13H), 4.23-4.26 (d, J= 10.4 Hz, IH) 4.62-4.64

(d J-= 10.0 H, 1)7.02-7:46 (in, I 1H); LC-MS (ESI) m/z: 704(M+1).

20 Example 14

9-(Piperidin-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-dejphthalaziun-3(7TH-one

[003991 A suspension of 8,9-di(pyridin-3-yl)-8,9-d ihydro-2H-pyrido{4,3 .2-de]phthalazin-3(711)-one

(120 mng, 0.35 mrnol) and platinum (IV) oxide (60 mg) in methanol (20 ml) was purged in 20 atm

hydrogen and stirred at 50 *C for 24 hr. The mixture was filtered and the filtrate was concentrated to 25 give the crude product. 'he crude product was purified by prep-IPLC to give 9-(piperidin-3-yl)8

(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4;3,232de]phthalazin-3(7H)-one (4 mng, yield: 4%) as a light

yellow solid. 1H-NMR (400 MHz. CD3OD) 6 1L 19-1.32 (m, 2H), 160 -165 (in. 2H). 1.94-1.97 (d. J 10.0 Hz ,1H)2.31-2.43 (m, 2H), 2.82-2.85 (d, J= 12.4 Hz 1H), 3.02-3.05 (dJ= 12 HziH),

3,29-3.32 (dd, J, =2.8 Hz. J = 8.4 Hz,1-H), 4.25-4.26 (dJ 2.8 Hz, 1H), 7.02-7.05 (dd,.I = 0.8 lIz, 30 Jd = 8.8 H-z, IH), 7.22-7.25 (m, IH), 7.40-7.53 (in, 311), 8,25-829 (i, 211); LC-MS (ESI) in/z:

348(M+I).

Example 15

9-(Piperidin-4-yl)-8-(pvyridin-4-yl)-8,9-dihydro-2H-pyrido(4,3.2-de]phthalazin-3(7H)-one

[004001 A mixture of 8,9-di(pyridin-4-yl)-8,9-dihydro-2J-pyrido[4,3 ,2-de]phthalazin-3(7H-one

35 (120 mg, 0.35 mmol), platinum (IV) oxide (60 rug) and concentrate hydrochloric acid (0.3 mL) in methanol (20 mL) was stirred at SOT under 20 atm of hydrogen. The mixture was filtered out and

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the filtrate was concentrated to give crude product. The crude product was purified by prep-HPLC to

give 9~(piperidin-4-yl)-8-(pyTidin-4-yl)-89-dihydro-2H-pyrido[4.,3 ,2-dejphthalazin-3(7Hf)-one

(17.6 mg, yield: 16%) as a light yellow solid. 'H-NMR (400 MHz, CD301)) 1.25-139 (mn, Il-)

1.40-1.52 (mI 11H), 1.60-1.70 (nt 1H) 1.75-1.84 (i, IH.) 1 89-1.98 (in, 112.50-257 (, Ill)

5 2.60-2.66 (m, 1H). 3.09-3.21 (m, 211). 3.34-3.37 (dd, J;:= 8 Hz, J= 2.4 Hz, H), 4.24 (d =2 Hz,

1H), 7.02-7.04 (dd 4 8 Hz, J = 0.8 Hlz, 111), 7.09-7 11 (dd, J) 4.8 Hz = 1 .2 Hz 2H), 741

743 (dd,, = 7,6 Hz=J, 0.8 Hz, I H),7.50-7.54 (t, J= 8 Hz, H-), 8.30-8,32 (dd, Jj = 4.4 Hz,] J

.6 Hz, 21); LC-MS (ES!) m/z: 348(M+1)

Example 16

10 8,9-Bis(4-((d imethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3.2-dejphthalazin-3(71/)-one

Example 1 6A

1 -(4-(Diethoxymethyi)phenyl)-N ,ANdimethyhnethanamine

[004011 A mixture of 1-(4-(diethoxymethyl)benzaldehyde (2.08 g, 10 mmol) and diniethylamine

(33% aqueous solution. 2.74 g, 20 mmol) in methanol (20 inL) was stirred at room temperature for

15 40 mins. The mixture was cooled to 0 "C, sodium borohydride (0.57 g, 15 mmol) was added

portionwise. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was

removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl

acetate (50 ml,) The organic layer was separated. The aqueous layer was extracted with ethyl

acetate (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous

20 sodium sulfate, and concentrated to give 1-(4-(diethoxymethyl)phenvl.)-,N,-diniethylethanamine

(1.8 g) as a light yellow oil which was used in the next step without further purification. MS (EST)

m/z 237(M+ 1)

Example I 6B

4-((Dimethylauino)methlv)benzal dehyde

25 1004021 To a solution of 1-(4-(diethoxymethyl)phenl)-NN-dimeihylmethanamine (1.0 g, 4 miriol)

in methanol (5 mL), a hydrochloric acid m- ethanol solution (10 mrL) was added dropwise at 0 'C

The reaction solution was stirred at room temperature overnight. Then methanol was removed in

vacuo to give 4-((dimethylamino)methvl)benzaldehyde (0.68g yield 99%) as a light yellow oil .H

NMR (400 MHz, CDCl); 6 2,26 (s, 6H), 3.50 (s, 211), 7.49 (d, J -6.4 H.z, 21-1), 7.84 (dJ/-= 6.4 Hz

30 21-1) 10 (s, 111). LC-MS (ESI) m/z: 164(M1) t

Example 16C

Methyl 2,3~bis(4-((dimethylamino)methvl)phenyl)4-oxo-li2,3,4-tetrahydroquinoline-5-carboxylate

and ethyl 2,3-Bis(4-((dimethylamino)methyl)phenyi)-4-oxo 1,2,3,4-tetrahydroquinoiine-5

carhoxylate

35 1004031 A mixture of 4-((dimrethylanino)iethyl)benzaldehyde (539 mg, 3.3 mmol) and 4

aminoisobenzofuran-i(3H)~one (223 mg, 1.5 inmol) in ethyl propionate (14 mL) was cooled to 0 "C.

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A solution of sodium methoxide in methanol [sodium (138 ma, 6 mmol) in methanol (4 mL)] was

then added dropwise. After the addition, the mixture was stirred at room temperature for 20 hr. The

mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was

dissolved in water, and then extracted with ethyl acetate (50 mLx'3). The combined organic layers

5 were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude

product. The crude product was purified by chromatography (silica gel. petroleum ether / ethyl

acetate = I 00:1 to 10:1) to give a mixture of methyl 2,3-bis(4-((dimethylamino)methyl)phenyl)-4

oxo-1,2,3 ,4-tetrahvdroquinoline-5-carboxvlate and ethyl 2,3-bis(4-((dimethy lamino)methy I )phenyl)

4-oxo-1,2,3 , 4-tetrahydroquinoline-5-carboxvlate (165 mg) as a light yellow solid.

10 Example 16D

8,9-Bis(4-((dimethylam ino)methyl)phenyl)-8,9- dihvdro-21pyrido[4,3 ,2-de jphthalazin-3(?7 H))ne

[004041 A mixture of methyl 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4

tetrahvdroquinoline-5-carboxylate and ethyl 2,3-bis(4-{{dimethylamino)methyl)phenvl)-4-oxo

L.2,3.4-tetrahydroquinoline-5-carboxylate (165 mg, 0.34 mmol) in hydrazine monohydrate (12 mL)

15 and methanol (5 mL) was stirred at 40 T for 6 hrs. The mixture was filtered to give crude product.

The crude product was purified by prep-HPLC to give 8.9-bis(4-((dimethylamino)niethyl)phenvl)

8,9-dihydro-2H-pyrido[4.3,2-de]phthalazin-3(7H)-one (33.7 mign yield: 22%) as a light yellow solid.

'H-NMR (400MHz., CDOD) 6; 2.04 (s, 6H), 2.05 (s,61), 3.19420 (m 21H), 3.24-3.26 (in, 211), 4.09-4,11 (d, J= 8.8 Hz, I H). 4,52-4.54 (d, J= 8.8 Hz, 1 ), 6.88-6.90 (m, 211). 6.99-7.07 (m, 7E),

20 7.42-7.46 (m, 2H). LC-MS (ESI) n/z: 454(M41)*

Example 17

9-(4-(4-(Cyclopropanecarbonyl)piperazine- I -carbonyl)phenyl)-8(4((methylamino)niethyl)phenyl)

8,9-dihydro-211-pyrido[4,3 ,2-de]phthalazin-3(71)one

Example 17A

25 lert-Butyl 4-(cyclopropanecarbonyl)piperazine- I -carboxylate

[00405] A mixture of compound tert-butyl piperazine-Icarboxylate (3.725 g. 20 inmol) and

potassium carbonate (5.53 g, 40 inmol) in anhydrous dichloromethane (30 ml) was cooled to 0 C',

cyclopropanecarbonyl chloride (2.30 g, 22 nmol) was then added dropwise, After the addition, the

mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane

30 (100 nL), washed with 10% citric acid (50 mL), followed by saturated sodium bicarbonate (50 mlL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 4

(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, yield 73%) as a white solid. 'I-NMR (400

MI-zs CDCL) 6 (ppm): 0.76-0.81 (mn,2H-), 0.98-103 (m,. 2H1), 1.49 (s, 911), 1.69-1.75 (mn. IlH), 3.463.48 (in. 411), 3.63-3.65 (a, 4Hf); LC-MS (ESI) m/z: 255(M+1)'

35 Example 17B

Cyclopropyl(piperazin-1-yl)iethanone hydrochloride

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100406 To a stirred mixture of compound tert-butyI 4-(cyclopropanecarbonyl)piperazine-I

carboxylate (3.7 g, 14.5 mmol) in methanol (15 mL) was added hydrochloride/methaio (15 ml,

3M)) at 0 "C. After the addition, the mixture was allowed to stir at room temperature overnight, The

mixture was concentrated to give cyclopropyl(piperazin-I-yljmethanone hydrochloride (2.74 g,

5 yield 100%) as an off-white solid. IH-NMR (400 MHz, DMSO-(6) 8 (ppm): 0.71-0.76 (i, 4H),

1.96-2.03 (mn 1H), 3.04-316 (m, 4H), 3.69-4.08 (in, 41H), 9.58 (s, 21-) iLC-MS (ESI) miz:

Example 17C

4-( 4-(Cyclopropanecarbonyl)piperazine- -carbonvl)benzaldehyde

10 1004071 To a stirred mixture of 4-formylbenzoic acid (900 mg. 6 mmol) in anhydrous

dichloromethane (30 mL) was added triethylamine (1.52 ing, 15 mmol) I -hydroxybenzotriazole

(891 mg, 6.6 nmol) followed by I -ethyl-3-(3 -dimethylam mo propyl) carbodiimide hydrochloride

(1.254 g, 6,6 mmoi) After the addition, the mixture was stirred at room temperature for 40 miins.

Then the mixture was cooled to 0 C and cyclopropyl(piperazin-l -yi)methanone hydrochloride

15 (.259 g, 6.6 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at

room temperature overnight. The mixture was diluted with dichloromethane (50 ml.), washed with

saturated citric acid (100 mLx2) followed by saturated sodium bicarbonate (100 mLx2), brine (50

ml), dried over anhydrous sodium sulfate, and concentrated to give 4-( 4

(c)clopropanecarbonyl)piperazine- - carbonyl)benzaldehyde (810 mg, yield 80% ) as a light yellow

20 oil. 4HNMR (400 MHz, CDCI) 8 (ppm): 0.79-0.85 (in. 2H), 1.00-1.04 (in, 2H) 1.72-1,80 (m. IH), 3.41-3.81 (m. 811), 7.58-7.60 (d, J= 8.0 Hz, 111). 7,95-7.97 (d, J= 8.0 Hz, 1H), 10.07 (s, IH); LC

MS (ESI) nvz: 287 (M+-1)

Example 17D

4-(4-(Diethoxymethyl)benzylideneainino)isobenzofuran-1 -(3t)-one

25 1004081 To a stirred mixture of 4-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol) and anhydrous

sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (300 mi,) was added 4

aninoisobenzofuran-i(3-)-one (2.24 g, 15 mmol) at 0 "C. After the addition, the mixture was

stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with

dichloromethane (50 mLx3). The filtrate was concentrated to give crude product. The crude product

30 was washed with petroleum ether to give 4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran

1(311)-one (4.3 g; yield 84%) as a light yellow solid, LC-MS (EST) inz: 340(M+1)

Example 17E

Methyl 3 -( 4 -(4-(cyclopropanecarbonyl)piperazine- I - carbonyl)pheny)-2-(4

(diethoxymethyl)phenyl)-4-oxo-l,2,3 4-tetrahvdroquinoline-5-carboxylate

35 [004091 A mixture of 4-(4-(cvclopropanecarbonyl)piperazine-I- carbonyl)benzaldehyde (859 ing, 3

mmol) and 4-(4-(diethoxymethyl)benzylideneamino)isobenzofun-1(311)-one (1.018 g, 3 mmol) in

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ethyl propionate (40 mL) was cooled to 0 C. Then a solution of sodium methoxide in methanol

[sodium (276 mg, 12 numnl) in methanol (8 mL)] was added dropwise. After the addition, the

mixture was stirred at room temperature for 20 hr. The m ixture was quenched with water (10 mL)


5 ethyl acetate (100 mLx4). The combined organic layers were washed with brine, dried over

anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified

by chromatography (silica gel, petroleum ether / ethyl acetate = 10:1 to 1:10) to give methyl 3-(4-(4

(cyclopropanecarbonyl)piperazine- I - carbonyl)phenyl)-2-(4-(diethoxvmethyl)phenvl)-4-toxo

1,2,3,4-tetrahydroquinoline-5-carboxylate (500 mg, yield 26%). LC-MS (ESI) m/z: 640(M+1 )

10 Example 17F

9-(4-(4-(Cyclopropanecarbonyl)piperazine-I- carbonyl)phenyl)-8-(4-(diethoxymnethyl)phenyl)- 8,9

dihydro-211-pyrido[4,3,2-dejphthalazin-3(711)-one

1004101 A mixture of methyl 3-(4-(4-(cyclopropanecarbonyl)piperazine- l-carbonyl)phenyl)-2-(4

(d iethoxymethyl)phenyl)-4-oxo- 1 2,3 ,4-tetrahydroquinoline-5 -carboxylate (526 mg, 0.82 mmol) in

15 85% hydrazine monohydrate (4 nL) and methanol (3 niL) was stirred at 25 *C for 2 hr. The mixture

was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine,

dried over anhydrous sodium sulfate, and concentrated to give 9-(4-(4

(cyclopropanecarbonyl)piperazine-1- carbonyl)phenyl)-8-(4-(diethoxyiethyl )phenyl)- 8,9-dihydro

2 H-pyrido[4 3,2-dejphthalazin-3(7H)-one (330 mg, yield 65%) as a yellow solid. H-NMR (400

20 MHz, DMS-d6) S (ppm): 0.72-0.76 (m. 41) 1.09-1.12 (m, 6H), 1.99 (s. H11), 3.39-3.73 (m, 12H) 4.70 (s, 1-1), 5.40 (s, 11-1), 5.99 (s, 1 ),6.68-7.31 (m, 911), 7.41-7.61 (in, 31), 12.19 (s 11H); LC-MS (ESI) mz: 622(M+1).

Example 17G

4-(9-(4-(4-(Cvclopropanecarbonyl)piperazine- I - carbonyl)phenyl)-3-oxo-3 ,17.8,9-tetrahydro-2H

2 5 pyrido[4,3 .2-d e]phthalazin-8-yl)benzaldehyde

1004111 A mixture of 9-(4-(4cyclopropanecarbonyl)piperazine- I- carbonyl)phenyl)-8-(4

(diethoxymethyI)phenyi)- 8,9-dihydro-2H-pyrido[43.32-dejphtlialazin-3(71)-one (280 mg, 0.45

mimol) in 3N hydrochloric acid (10 niL) was stirred at room temperature for 3 hr. Then the mixture

was neutralized with potassium carbonate. The resulting suspension was filtered to give 4-(9-(4-(4

30 (cyclopropanecarbonvl)piperazine-1- carbonyl)phenyl)-3-oxo-3 ,7,8,9-tetrahydro-2HIJ-pyri do[4.,3 .2

de]phthalazin-8-vl)benzaldehyde (220 mng, yield 89%) as a light yellow solid. LC-MS (EST) n/z:

548 (M+1)

Example 171H

944-(4-(Cyclopropanecarbonyl.)piperazine- I -carbonyl)phenyl)-8-(4((nethylanilno)methyl)phenyl)

35 8 ,9-dihydro-2H-pyrido[4,3 ,2-de]phthalazin-3(711)-one

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1004121 A mixture of 4-(9-(4-(4-(cyclopropanecarbonyl)piperazine- -carbonyl)phenyl)-3-oxo

3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalauin-8-yl)benzaldehyde (80 mg, 0.15 mmol) and 27%

methylamine alcohol solution (50 mug, 0,44 mmol) in methanol (10 mL) was stirred at room

temperature for 40 min. Then the mixture was cooled to 0 'C. Sodium borohydride (8.3 mg, 0.23

5 mmoi) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol

was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1)

and filtered. The filtrate was concentrated to give the crude product. The crude product was purified

by prep-H-PLC to give 9-(4- (4-(cyclopropanecarbonyl)piperazine- I -carbonyl)phenyl)-8

(4((nethytamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]phthalazin-3(71f)-one (6A mg, 10 yield 7%) as a light yellow solid. H-NMR (400 MHz, CD 3OD) 5 (ppm): 0.83-0.91 (on, 41-), 1.94

2.03 (in, Il-). 2.66-2.68 (d, J= 6.0 Hz, 31H), 3.35-3.79 (in. 81), 4.11 (s, 2H); 4.42-4.44 (d7 J= 7.6

Hz, 1H), 4,88-4.90 (d, J= 7.2 Hzl H) 7,21-7.26 (m, 31) 7.29-7.36 (m, 4H1) 7.41-7.43 (d, J 8.4

Hz, 21), 7.55-7.57 (d, .J= 7,2 Hz, 11) 7.63-7.67 (t, J 8.0 Iz, I H); LC-MS (ESI) n/zi: 563(Ml+)

Example 18

15 9-(4-(4-(Cyclopropanecarbonyl)piperazine- I -carbonyl)phenyl)-8

(4((dimethylamino)methyl)phenvl)-8,9-dihydro-2JH-pyrido[4.3,2-delphthalazin -3(7t)-one

[00413] A. mixture of 4-(9-(4-(4-(cyclopropanecarbonvl)piperazine- I- carbonyl)phenyl)-3-oxo

3,7,8,9-tetrahvdro-2.U-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.15 imol) and 27%

dimethylamine solution (62 mig. 0.44 mnol) in methanol (10 mL) was stirred at room temperature 20 for 40 min. Then the mixture was cooled to 0 *C. Sodium borohydride (8.3 mg, 0.22 mmol) was

added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and

filtered. The filtrate was concentrated to give the crude product. The crude product was purified by

prep-HPLC to give 9-(4-(4-(cyclopropanecarbonyl)piperazine- I -carbonyl)phenyl)-8

25 (4((diiethylamino)iethyl)phenyl)-8,9-dihydro-2l-pyrido4,3 .2-dejphthalazin-3(7T)-one (4.2 mg, yield 5%) as a light yellow solid. 'H-INMR (400 MHz, CD3OD) 6 (ppm): 0.73-0.79 (i, 41), 1 84

(I, lH), 2.69 (s, 6H), 3.47-3.72 (m, 811), 4.14 (s 211), 4.31-4.33 (dJ= 8.0 liz, 1H), 7.12-7.35 (in,

9H), 7.47-7.58 (in, 2H); LC-MS (ESI) m/z: 577(M+1])

Example 1.9

30 8-(4~(Hydroxymethyl)phenyl)-9-(4-(4-isobutyry piperazine-1-carbonyl)phenyl}-8,9-dihydro-2H

pyrido[4,3, 2-de]phthalazin-3(7f)-one

Example 20

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-(4-isobutyrylpiperazine-1-carbonyil)phenyl)-8,9

dihydro-2Ht-pyrido[4,3,2-dcephthalazin-3(71H)-one

35 Example 1 9A

tert-Butyl 4-isobutyry ipiperazine- 1 -carboxylate

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[004141 To a solution of isobutyric acid (6.608 g, 75 mmol) in anhydrous dichloromethane (130

mL) was added triethylamine (8-33 g, 82.5 mmol), 1-hydroxybenzotriazole (10. 125 g75 mrnol).

followed by l -ethyl-3 -(3-dimnethylaminopropyl)carbodiimide hydrochloride (14.25 g. 75 mmol).


cooled to 0 C, and tert-butyl piperazine-l-carboxylate (13.97 g, 75 mmol) was added portion-wise.

After the addition, the mixture was stirred at room temperature overnight, The mixture was diluted

with dichloromethane (200 mL), washed with saturated sodium bicarbonate (150 mLx2). 10% citric

acid (150 mL). brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give tert

soby 4 utyrylpiperazine-I-carboxylate (15 g, yield 78%) as a white solid. 1H-NMR (400 M z,

10 CDCl,) 6 (ppm) 1.13- L14 (d, J= 6.81Hz, 6H), 1.47 (s, 9H), 2.75-2.82 (m, H), 3.43-3.58 (m.4H);

LC-MS (ESI) rn/z: 257(M+),

Example 19B

2-Methyl-I -(piperazin- I -yI)propan- i-one

[00415 To a stirred mixture of iert-butyl 4-isobutyrylpiperazine-l -carboxylate (6.8 g, 26.5 mmol) in

15 methanol (15 mL.) was added hydrochloride/methanol (30 mL. 3M)) at 0 C. After the addition. the

mixture was allowed to stir at room temperature overnight. The mixture was concentrated to give 2

methyl-I-(piperazin- -yl)propan-1 -one (5.5 g, yield 100%) as an off-white solid. 'H-NMR (400

MHz, DMSO-d6) 6 (ppm): 0.99-1.00 (d, J::: 6.4 Hz, 61), 2.84-2.89 (n, I)r 3,03-3,07 (d, 414).

3.68-3.74 (d, 411), 9.58 (s. 2H); LC-MS (ESI) ni/z: 157(M.1)

20 Example 19C

4-(44sobutyrylpiperazine- I -carbonvl)benzaldehyde

100416 To a stirred mixture of 4-formylbenzoic acid (1.5 g. 10 mmol) in anhydrous

dichloromerthane (30 ml.) was added triethylamine (2.52 g, 25 mmol), I -hydroxybenzotriazole (1.5

g, 1 I mmol), followed by l-ethyl-3-(3dimnethylanino propyl) carbodiimide hydrochloride (2.1 g, 11 25 mniol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the

mixture was cooled to 0 C and 2-methyl-I -(piperazin-l-yl)propan- I-one (2.1 2 g I1 mmtol) was

added in portion-wise. After the addition, the mixture was allowed to stir at room, temperature

overnight. The mixture was diluted with dichloromethane (50 ml,), washed with saturated citric acid

(100 mLx2), followed by saturated sodium bicarbonate (100 mLx2), brine (50 ml). dried over

30 anhydrous sodium sulfate, and concentrated to give 4-4-isobutyrylpiperazine- I

carbonyl)benzaldehyde (2 g, yield 70% ) as a light yellow oil. 'H-N MR (400 Ml, CDC13) 6 (ppm): 1.15 (d, 611), 2.80 (brs, I H)3.39-380 (n. 8H), 7.58 (d,.J= 8,0 Hz, 1 ), 7.95 (d, .J= 8.0 Hz,

11-1), 10.07 (s, 11); LC-MS (ESI) ni/z: 289(M+I)

Example 19D 35 Methyl 2-(4-(diethoxymethyl)phenyl)-3-(4-(4-isobutyrvlpiperazine- 1- carbonyl)phenyl)- 4-oxo

1,2;3,4-tetrahydroquinol ine-5-carboxylate

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10041,7 A mixture of 4-(4-isobutyrylpiperazine- 1 -carbony l)benzaldehyde (950 mg, 3.3 mmol) and

(E)-4-(4(dicthoxymethyl) benzyiideneamino)isobenzofuran-1(311)-one (1.018 g, 3 mmol) in ethyl

propionate (40 mL) was cooled to 0 C. Then a solution of sodium methoxide in methanol [sodium

(345 mg, 12 mmol) in methanol (8 mL)] was added dropwise. After the addition, the mixture was

5 stirred at room temperature for 24 hr. The mixture was quenched with water (10 niL) and solvent

was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate

(100 mLx4). The combined organic layers were washed with brine, dried over anhydrous sodium

sulfate, and concentrated to give crude product. The crude product was purified by chromatography

(silica gel, petroleum ether / ethyl acetate = 10:1 to 1:10) to give methyl 2-(4

10 (diethoxymethvl)phenyl)-3-(4-(4-isobutyryipiperazine- I - carbonyl)phenyl)- 4-oxo- 12,3,4

tetrahydroquinoline-5 -carboxyl ate (491 mg, yield 25%).

Example 19E

8-(4-(Diethoxynithyl)phenyl)-9-(4-(4-isobutyrylpiperazine- 1- carbonyl)phenyl)-8,9-dihydro-2H

pyrido[4,3 ,2-dejphthalazin-3(7)m-one

15 [00418J A mixture of methyl -(4-(diethoxymethyl)phenyil)-3-(4-(4-isobutyrylpiperazine- 1

carbonyl)phenyl)- 4-oxo12,3,4-tetrahydroquinoline-5-carboxylate (491 mg, 0.77 mmol) in 85%

hydrazine monohydrate (4 mL) and methanol (3 m) was stirred at 25 "C for overnight. The mixture

,was extracted with ethyl acetate (50 mLx 3). The combined organic layers were washed with brine.

dried over anhydrous sodium sulfate, and concentrated to give 8-(4-(diethoxymethyl)phenyl)-9-(4

20 (4-isobutyrylpiperazine-d- carbonvl)phenyl)-8,9-dihydro-2H-pyrido [4,3 ,2-dejphitalazin-3(7J1)-one

(365 mg, yield 77%) as a yellow solid,

Example 19F

4-( 9-(4-(4-(Isobutyrylpiperazine-I- carbonyl)phenvi)-3 -oxo-3,7,8,9-tetrahydro-2 H-pyrido(4,3.2

delphthalazin-8-yl)benzaldehyde

25 100419] A mixture of 8-(4-(diethoxymethyl)phenyl)-9-(4-(4-isobutyripiperazine- 1

carbonyl)phenyl )-8,9-dihydro-2L1-pyrido[4.3,2-dejphthalazin-3(7f)-one (365 mg, 0.59 mmol) in 3N

hydrochloric acid (10 mL) was stirred at room temperature for 3 hr. Then the mixture was

neutralized with potassium carbonate, The resulting suspension was filtered to give crude. The crude

product was punfied by prep-HPLC to give the 4-(9-( 4-(4-(isobutyrylpiperazine-

30 carbonyl)phenyl)-ouxo-3,7,8,9-tetrahydro-2Hi-pyrido[4.3,2-de]phthalazin-8-yl)benzaldeliyde (80

mg, yield 28%) as a light yellow solid. 'H-NMIR (400 MHz, CD3OD) 6 (ppm): 1. 11-1 13 (d, .= 6,8

Hz, 614), 295-3.14 (brs, III), 3.38-3.80 (m, 8H), 4.37-4.40 (d, = 7.2 H z, 11), 4.75-4,77 (d, J 7.6 Hz, I1-1) 7,20-7.33 (m, 9H), 7,57-7.59 (d, = 7.6 Hz, Hl)l, 7.60-7.76 (t,- 8.0 Hz. 1H), 9.92 (s, I); LC-MS (ESI) m/z: 550(M1-).

35 Examples 19G & 20

i I

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8-(4-(lydroxymnethyl)phetnyl)-9-(4-(4-isobutyrylpiperazine-Icarbonl)phenyl)-8,9-dihydro-2H

yrido{4,3&,2-de]phthalazin-3(7H-one & 8-(4-((dimethylamino)methyi phenyl)-9-4-(4isobutvrylpiperazine- I -carbonyl)phenyl)-8,9-dihydro-2H1-pyrido[4,3,2-dephthalazin-3(71)-one

1004201 A mixture of compound 7 (50 mg, 0.09 mmol) and 33% dimethylamine aq solution (25 mg,

5 0 18 mmol) in methanol (10 nL) was stirred at room temperature for 40 min. Then the mixture was

cooled to 0 "C, Sodium borohydride (5 mg, 0.13 mmol) was added After the addition, the mixture

was stirred at this temperature for 2 hr. TLC (petroleum ether / ethyl acetate = 2: 1) show the reaction

was complete. Methanol was removed under reduced pressure. The residue was washed with ethyl

acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The

10 crude product was purified by prep-HPLC to give 8-(4-((dimethy lamino)methyl)phenyl)-9-(4-(4

isobutyrylpiperazine-l-c arbonyl)phenyi l)-8,9-dihydro-2HU-pyrido[4.3,2-de]phthalazin-3(7H)-one (4

ing, yield 9%) and 8-(4-(hydroxynethyl)phenyl)-9-(4-( 4 -isobutyrylpiperazine- 1 -carbonyl)phenyl)

8.9-dihdro-2H-pyrido[4.3,2-dt]phthalazini3(7k)-one (16 mg, yield 36%) as light yellow solids. 8(4-((dimethylaiino )methyl)phenyl)-9-(4-(4-isobutyry Ipiperazine-1-carbonyl)phenyl)-8,9-dihydro

15 2H-pyrido[4,3,2-de]phthalazin-3(7)-one: --NMR (400 MHz, CD3QD) 3 (ppm):.01,12 (d, i

6.8 Hz, 6H), 2.80 (s, 614), 2.96-3.00 (brs, I H), 333-3.70 (in, 811), 4.12 (s, 211), 443-4,44 (d, J= 7.6

liz, 11), 4.89-4,91 (d, J= 7.6 Hz, 1-), 722-7.27 (in, 3H), 731-7.37 (in, 411), 7,42-744 (d,J= 8,0 Hz, 2 H), 7.56-7.58 (d, J - 72 Hz, 1 H). 7.64-7.68 (t ,= 8.0 Hz 1H); LC-MS (ESI) n/z: 579(M41)'.

8-(4-(hydroxymnethyl)phenyl )-9-(4-(4-i sobutyryipiperazine- carbonyl)phenyl)-8,9-dihydro-2H

20 pyrido(4,3,2-dephthalazin-3(7)-one: 'lt-NMR (400 MHz, CD3OD) 3 (ppm): 1. 10-1.12 (d, J= 6.4

Hz , 6H), 2.95 (brs, 1H4), 3.33-3.81 (m, 811), 4.39-4 41 (d, J= 8.2 liz 1H), 4.53 (s, 211) 4.77-4.79 (d. J= 7.6 Hz 114). 7.20-7.30 (m, 91) 7.55-7.57 (dd, J,= 8.0 Hz, J,= 1 0 Hz, IH), 7.63-7.67 (t, J=

8.0 lz, 114); LC-MS (ESI) i/z: 552(M 1)*.

Example 21

25 9-{4-(4-(Cyclopropanecarbonyl)piperazine I -carbonyl)phenvl)-8-phenvl-8,9-dihydro-21

pyrido[4,3,2-de]phthalazin-3(7h)-one

Example 21 A

(E)-4-(benzvlideneamino)isobenzofuran- I (3H)-one

1004211 To a stirred mixture of benzaldehyde (1.91 g, 18 imol) and anhydrous sodium sulfate (21.3

30 g, 150 minol) in anhydrous dichloromethane (100 mL) was added 4-aminoisobenzofuran-(31h-one

(2.24 g, 15 mmol) at 0 *C. After the addition, the mixture was stirred at room temperature for 6 days.

The mixture was filtered and the cake was washed with dichloromethane (50 nLx3). The filtrate

was concentrated to give crude product. The crude product was washed with petroleum ether to give

(E)-4-(benzylideneamino)isobenzofuran-(31-)-one (3.38 g, yield 95%) as a white solid. 'H-NMR

35 (400 MHz, CDCI3) A (ppm): 5.41 (s, 2H), 7.36-7.37 (dJ= 7.6 Hz, I 1), 7.49-7.59 (m, 411). 7777.8 (d, J= 7.6 Hz, I H) 7.92-794 (d, J: 8.0 Hz, 2H). 8,55 (s, 1H), LCMS (E1SI) m/t z: 238 (M+r)

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Example 2 1 B

Methyl 3-(4-(4-(cyclopropanecarbonyl)piperazine- 1- carbonyl)phenyl)~ 4-oxo-2-phenyl- 1,2,3,4

tetrahydroquinoline-5 -carboxylate

1004221 A mixture of compound 4-(4-(cyclopropanecarbonyl)piperazine-l-carbonyl) benzaldehyde

5 (429 mg. 1.5 inmol) and (E)-4-(benzylideneamino)isobenzofuran-31I)-one ((355,5 rmg, 15

mmol) in ethyl propionate (12 mL) was cooled to 0 *C. Then a solution of sodium methoxide in

methanol [sodium (138 mg, 6 mmol) in methanol (12 nL)] was added dropwise. After the addition.,

the mixture was stirred at 25 "C for 18 hr. The mixture was quenched with water (10 mL) and

solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl

10 acetate (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous

sodium sulfate, and concentrated to give crude product. The crude product was purified by

chromatography (silica gel, petroleum ether / ethyl acetate = 10:1 to 1:10) to give methyl 3-(4-(4

(cyclopropanecarbonyl )piperazine- I - carbonyl)phenyl)- 4-oxo-2-phenyl- 1;2,3,4

tetrahydroquinoline-5-carboxvlate (90 rmg, yield 11%). LC-MS (ESI) m/z: 538(M-+).

15 Example 21 C

9-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyi)phenyl)-8-phenl-89-dihydro.2H

pyrido[4,3,2-dejphthalazin-3(71)-one

-3(711)-one

[00423] A. mixture of methyl 3-(4-(4-(cyclopropanecarbonyl)piperazine- I - carbonyl)phenyl)- 4-oxo

20 2-phenyl- 1,233,4-tetrahydroquinoline-5-carboxylate (90 mg, 0. 16 mmol) in 85% hydrazine

monohydrate (5 ml) and methanol (2 rL) was stirred at 25 " for 4 hr. The mixture was extracted

with ethyl acetate (50 mILKx3). The combined organic layers were washed with brine, dried over


by prep-HPLC to give 9-(4-( 4-(cyclopropanecarbonyl)piperazine- I -carbonyl)phenyl)-8-phenyl-8,9

25 dihydro-2H-pyrido[43,2-cdephthalazinw3(7H)-one (18 mgt yield 22%) as a white solid. 'Ii-NMR

(400 MHz, CD30D) 8 (ppm): 0.86-0.94 (in, 41-), 2,00 (s, 111). 3.33-3.82 (i, 8H), 4.41-4,43 (dJ = 8.4 Hz, 1 H)4.78-4.80 (dJ= 8.4 Hz, i H), 7.21 -7.27 (m, 6H), 7.30-7.35 (i, 414) 7.58-7.60 (m, iH),

7.65-7.69 (t, J= 80 Hz. 41-); LC-MS (ESI) m/z: 520(M+1)

Example 22

30 9-(3-(4(Cvclopropanecarbonyl)piperazine- 1-carbonyl)phenyil)-8-phenyl-8.9-dihydro-21

pyrido[4,3,2.-dejphthalazin-3(71)-one

Example 22 A

Methyl 3-(3-(4-(cyclopropanecarbonvl)piperazine- - carbonyl)phenyl)- 4-oxo-2-phenyl- 2 3 4,

tetrahydroquinoline-5-carboxylate

35 [00424] A mixture of 3 -(4-(cyclopropanecarbonyl)piperazine-1-carbonyl) benzaldehyde (286 mg, I

mmol) and (E)-4-(benzylideneamino)isobezofuran- (31H)-one (237 rmg, I mmol) in ethyl

113

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propionate (7.5 mL) was cooled to 0 C. Then a solution of sodium methoxide in methanol [sodium

(92 .mg 4 mmol) in methanol (7.5 mL)] was added dropwise, After the addition, the mixture was

stirred at 25 'C for 1.8 hr. The mixture was quenched with water (10 mL) and solvent was removed

in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (50 mL-3

5 The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and

concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 10:1 to 1:10) to give methyl 3-(3-(4

(cyclopropanecarbonyl)piperazine-1- carbonyl)pheny1)- 4-oxo-2-phenyl-1,22,34

tetrahydroquinol ine-5-carboxylate (64 mg, yield 12%). LC-MS (ESI) mi/z: 538(M+)f.

to Example 22 B

9-(3-(4-(Cyclopropanecarbonvl)piperazine-I.-carbonyl)phenyl )-8-phenyl-8,9-dihydro-2H

pyrido[4,3 ,2-de]phthalazin-3(7R1)-one

[004251 A mixture of methyl 3-(3-(4-(cyclopropanecarbonvl)piperazine-I - carbonyi)phenyl)- 4-oxo

2-phenyl- 1,3 4-tetrahydroquinoline-5-carboxylate (64 mg, 0.12 mmol) in 85% hydrazine

15 monohydrate (5 mL) and methanol (2 niL) was stirred at 25 *C for 4 hr. The mixture was extracted

with ethyl acetate (50 mEx3). The combined organic layers were washed with brine, dried over


by prep-HPLC to give 9-(3 -(4-(cyclopropanecarbonyl)piperazine- I -carbonyl)phenyl)-8-phenyl-8,9

dihydro-211-pyrido[4.3,2-de]phth alazin-3(7)-one (8 mg, yield 13%) as a light yellow solid. 'H

20 NMR (400 MHz, CD3OD) 6 (ppm): 0.73-0.81 (mn, 41 1. 18-1.19 (i, I H), 3.20-3.71 (in, 811), 4.23

4.25 (d, J= 10.0 Hz I H), 4,59-4.61 (d, J= 8.4 Hz, 11), 7.08-7.26 (n, 1 O1), 7.45-7.54 (in, 214); LC

MS (PSI) m/z: 520(M.)*

Example 23

943 -((Dimethy lam ino)rnethvl)phenyl)-8-phenyl-8,9-dihydro-2-pyrido[4,3 .2-defphthalazin-3(7TH)

25 one

[004261 A mixture of 3-(3 -oxo-8-phenyl-3.7,8,9-tetrahydro-2Hapyrido[4,3,2-ieJphthalazin-9

yl)benzaldehyde (45 mg, 0. 12 nmol) and 33% dimethylamine solution (50.2 mg, 0366 mmol) in

methanol (5 mL) was stirred at room temperature for I h. Then the mixture was cooled to 0 "C, sodium borohydride (6,95 mg, 0.184 mmol) was added portionwise. After the addition, the mixture

30 was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure., The residue

was purified by prep-HPLC to give 9-3-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro

2fi-pyrido[4.3,2-de]phthalazin-3(7H)-one (21 mg, yield 44%) as a light yellow solid. H--NMR (400

MHz, CD 3OD) 6 (ppm): 2.59 (s, 311), 2.75 (s, 311), 41 1-4.27 (q, 211), 431-4.34 (d, J= 10.4 Hz,

1H), 4.68-4,71 (d, J=:x04 Hz, 1.), 7.17-7.30 (m, 911), 7.33-7.37 (t, J=7.6 Hz, 111), 7.56-7.58 (dJ

35 = 7.6 Hz. H), 7.60-7.64 (t. J-- 8.0 Hz, l1): IC-MS (ESI) m/z: 396(M+ 1).

Example 24

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8-(3-((Methylamino)methyl)phenyvl)-9-phenvy8l9-dihydro-2H-pyridot[4,3;2-delphthalazin-3( 71)

one

Example 24 A

(E-43-(Diethoxymethyl)benzylideneamino)isobenzofiran-1(3 H)-one

5 [00427J To a stirred mixture of 3-(diethoxymethvl)beTzaldehyde (3.75 g, 18 mmol) and anhydrous

sodium sulfate (21 .3 g, 150 mmol) in anhydrous dichloromethane (300 mL) was added 4

aminoisobenzofuran-1(31f)-one (224 g, 15 mmol) at 0 tC, After the addition, the mixture was


dichlorormethane (50 mL'3), The filtrate was concentrated to give crude product. The crude product

tO was washed with petroleum ether to give (E)-443

(diethoxymethyl)benzylideneanino)isobenzofuran-1(3H1)-one (3.1 g, yield 61%) as a white solid.

L-MS (ESI) m/z: 340 (M+1)

Example 24 B

Methyl 2-(3-(diethoxymethyl)phenyl}-4-oxo-3-phenyl- L2,3 ,4-tetrahydroquinoli ne-5 -carboxylate

15 and ethyl 2-(3-(diethoxymethvl)pheny l)-4-oxo-3-phenvl- 12.3 .4-tetrahvdroquinoline-5-carboxylite

3(71)-one

1004281 A mixture of (E)-4-(3-(d iethoxvmethyl)benzylideneamino)isobenzofuran-1(311)-one (678

mg, 2 mmol) and benzaldehyde (212 mg, 2.2 mmtol) in ethyl propionate (20 mL.) was cooled toO "C,

Then a solution of sodium methoxide in methanol [sodium (183 mg, 8 niol) in methanol (10 m.)]

20 was added dropwise. After the addition, the mixture was stirred at room temperature for 24 hr The

mixture was quenched with water (10 iL) and solvent was removed in vacuum. The residue was

dissolved in water, and then extracted with ethyl acetate (100 m Lx4). The combined organic layers



25 acetate = 10:1 to 1:10) to give a mixture of methyl 2-(3-(diethoxymethyl)phenyl)4-oxo-3-pheny

1 .23,4-tetrahydroquinoline-5-carboxylate and ethyl 2 (3(diehoxymethyl phenyl)-4-oxo-phenyl

1 ,2.3.4-tetrahydroquinoline-5-carboxyiate (160 mg, yield 17%b

Example 24 C

8-(3-(Dieth oxymethyl)phenyl.)-9-phenyl- 8,9-dihydro-2H-pyrido[4 3,2-de]phthalazin-3(7H)-one

30 1004291 A mixture of methyl 2-(3-(diethoxymethyl)phenyi)-4-oxo-3-phenyl- 1.2,3,4

tetrahydroquinoline-5-carboxylate and ethyl 2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl- 1.2,3,4

tetrahydroquinoline-5-carboxylate (160 mg, 0.36 mmol) in 85% hydrazine monohydrate (4 miL) and

methanol (3 ml) was stirred at 25 "C for overnight. The mixture was extracted with ethyl acetate (50

mLx3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate,

35 and concentrated to give the 8-(3-(diethoxymethyi)phenyl)-9phenyl- 8,9-dihvdro-2U-pyrido[4,3.2

deiphthalazin-3(7H)-one (90 mg, yield 58%) as a yellow solid. LC-MS (ESI) m/z: 442(M+If .

I1I3

WO 2010/017055 PCT/US2009/051879

Example 24 D

3-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-delphthalazin-8-yl)benzaldehyde

[004301 A mixture of 81(3-(diethoxyiethv)phenyl)-9-phenyl- 8,9-dihydro-2H-pyrido[4,3,2

dejphthalazin-37.H)-one (90 mg, 0.21 mmol) in 3N hydrochloric acid (10 mL) was stirred at room

5 temperature for 3 hr. Then the mixture was neutralized with potassium carbonate. The resulting

suspension was filtered to give 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2

de]phthalazin-8-yl)benzaldehyde (40 mg, yield 50%) as a light yellow solid. '4-NIMR (400 Mlz,

CDCI:) 8 (ppm): 4.24 (d, J= 7.6 Hz, 1H) 4,77 (d, J= 7.6 Hz, 111), 4.85 (brs, 11-I), 7.01-7.03 (m,

21i). 7.08-7.10 (mn, 11H), 7.21-7.24 (in, 311). 7.37-7.39 (m, 2H), 7.61-765 (m, 1 H) 7.74-75 (m,

10 21-1), 7.79-7.81 (m,. I H), 9.59 (brs, I H). 9.92 (s. 1,H). L-MS (ESI) m/z: 368 (M-1

Example 24 E

8-(3 -((Methylamino)tethvl)phenyl)-9phenyl-8,9-dihydro-2HLl-pyrido [4.3 ,2-de]phthalazin-3(71H)

one

1004311 A mixture of 3-(3-oxo-9-phenyl-3.7,8,9-tetrahvdro-2H-pyrido{4.3,2-de]phthalazin-8

15 yl)benzaldehyde (40 mg, 0.11 mmol) and 27% methylamine alcohol solution (28 mg, 0.23 mmol) in

methanol (10 miL) was stirred at room temperature for 40 min Then the mixture was cooled to 0 *C.

Sodium borohydride (7 mg. 0. 18 mmol) was added. After the addition, the mixture was stirred at

this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed

with ethyl acetate/hethanol (10/1) and filtered. The filtrate was concentrated to give the crude

20 product. The crude product was purified by prep-HPLC to give 8- 3-((methylamino)inethyl)phenyl)

9-phenyl-8,9-dihydro-2--pyTido[43,2-de]phthalazin-3(7TH-one (4 mg, yield 10%) as a light

yellow solid. 'H-NMR (400 MHz., CD3OD) 6 (ppm): 2.44 (s, 611), 3.99 (m, 21), 4.21 (m, 1H), 4.69

(i 111), 6.98-7.00 (d, J= 7.2 Hz, 114), 7.05-7.10 (m 4 H), 7.21-7.23 (n. 311), 7.31 (s. 11), 7,46

7.48 (d,J 8.0 Iz, I H), 751-7.53 (m, 1H). LC-MS (ESI) /i: 383 (MI+).

Example 25

8-(4-((Dimethylam ino)methyl)phenyl)-9-phenvl-8,9-dihydro-2H-pyrido[4,3,2 .-dejphthalazin-3(7H

one

Example 25 A

Methyl 2-(4-(dinethoxymethyl)phenvl)-4-oxo-3 -phenyl-1,2,3 ,4-tetrahydroquinoline-5-carboxvl ate 30 1004321 To a solution of (E)-4-(4-(dimethoxymethyl)benzylideneamino)isobenzofmani- 1(31)-one

(600 mg, I innol) and benzaldehyde (616 mg, 3 minol) in ethyl propionate (20 mL), sodium methanolate (414 mg, 7.6 nunol) were added and the mixture was stirred at room temperature

overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL\4) and concentrated. The crude product was purified by column

35 chromatography (silica gel, petroleum ether: ethyl acetate 20:1 to 5:1) to obtain a white solid of

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methyl 2 -(4-(dimetboxymethyl)phenyil)-4-oxo-3-phenyl- 1,2;3.4-tetrahydroquinoline-5-carboxvlate

(120 mg, yield 22%). LC-MS (ESI) n/z: 432 (M1)

Example 25 B

8-(4-(Diniethoxymethyl)phenyl)-9phenyl 8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(711)-one

5 [004331 Meihyl 2-(4-(dirmethoxymethyl)phenvl)~4-oxo-3-phenvl-4,2.3,4-tetrahydroqu inoline-5

carboxylate (120 mg, 0.28 mmol) and 85% hydrazine monohydrate (20 mL) were added and the

mixture was stirred tinder 40 "C for 3 h. The resulting mixture was evaporated under reduced

pressure to 10 nL and then filtered to give 8-(4-(diiethoxymethyl)phenyl)-9-phenyl- 8,9-dihydro

2 H-pyrido[4,3,2-de]phfthalazin-3(7)-one (89 mg, yield 78%), LC-MS (ESI) m/z- 414 (M+tJY.

10 Example 25 C

4-(3 -Oxo-9-phenyl1-3,7,8,9-tetrahvdro-2H-pvrido[4,3/2-dclphthalazin-8-vl)benzaldehyde

1004341 8-(4-(Dimethoxymethyl)phenyl)-9-phenyl- 8,9-dihydro-2H-pyrido[4,3.2-de]phlithalazin

3(71)-one (89 mg, 0.22 mmol) and 20 ml of 3 N hydrochloric acid were added and the mixture was

stirred at room temperature for 2 hi. The resulting mixture was neutralized with potassium carbonate

15 and then filtered to give 4-(3-oxo-9-phenyl-3 ,7.8,9-tetrahydro-2 H-pyrido[4,3,2-dje]phthalazin-8

yf)benzaldehyde (59, yield 73%). LC-MS (ESI) m/z: 368.

Example 25 D

8-(4-((Diiethylamino)methyl)pheny i)-9-phenyl -8,9-dihydro-2H-pyrido[4,3,2-dejphthalazin-3(7T)

one

20 [00435] 4-(3-Oxo-9-phenyl-3,7,8,9-tetrahydro-211-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde

(59 mg. 0.16 rmol) and dimethlyamine (5 mL) were added and the mixture was stirred at room

temperature for 2 h. Then 20 ig of sodium borohydride was added and stirred for another 2 h. The

resulting mixture was evaporated tinder reduced pressure and purified by prep-HPL.C to give 8-(4

((dimnethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2HU-pyrido[4,3 .2-de]plithalazin-3(7H-one

25 (20 mig, yield 32%). 'H--NMR (400 MHz, DMSO-d6) 6 (ppm): 2.18 (s, 61.), 4.28-4.30 (d, J= 8 Hz, 111), 4.72-4.74 (d, J= 8 Hz, 1), 7.06-7.08 (m, 2H), 7. 13-7.20(m. 611)7 7.23-7.25 (m. 211), 7.54-7.65 (m, 21). LC-MS (ESI) in/z: 397 (M+)

Example 26 & 27

8-(4-(Morpholinomethyl)phenvl)-9-phenyl-8,9-dihydro-2H-pvrido[4,3,2-de phthalazin-3(7B)-one

30 and

8-(4-( Hydroxymethvl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-dcIphthalazin-3(71)-one

1004361 4-(3-Oxo-9-phenyl-3 ,7. 8,9-tetrahydro-2HJi-pyrido[4,3,2-delphthalazin-8-vl)benzaldehyde

(59 mg. 0. 16 mmol) and morpholine (42 mg) were added and the mixture was stirred at room

temperature for 2 h. Then 20 mg of sodium borohydride was added and stirred for another 2 h. The

35 resulting mixture was evaporated under reduced pressure and purified by prep-HPLC to give 8-(4

(morphol inomethvl)phenyl)-9-phenvl-8,9-d ihydro-2H-pyrido[4,3,.2-delphlthalazin-3(7H)-one (8 mg,

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yield 11%) and 8-(4-(hydroxyiethyl)phenyl)~9-phenyl-8,9-dihydro-2 H-pyrido[423,-dejphthalazin

3(711)-one (7 mg, yield 12%). 8-(4-(morpholinomsethyl)phenyl)-9-phenyl-8,9-dihydro-2-I~

pyrido[4,3,2-dcjphthalazin-3(7H)-one : H-NMR (400 M, DMSO-d6) 6 (ppm): 2.31 (s. 411), 3.36

(s, 4H), 3.61-3.63 (m, 41), 415-4.17 (d, J= 10 Hz, 11H), 4.58-4,61 (d, J= 10 Hz, I H), 4.79 (s, III),

6.94-7,19 (m, 101 7.51-7.55 (m1H) 7.68-770 (mi i H) 7.63(s, I H). LC-MS (ESI) ma/z: 439

(Mt 1). 8-(4-(hydroxymethyl)pheny1)-9-phenyl-8,9-dihvdro-2H-pyrido[j4,3, 2-dc]phthalazi n-3(7H)

one H-N MR (400 MHz, DMSO-d6) 6 (ppm): 4,21-4.25 (m, 1l), 4.63-4.70 (in, 1H), 4,86 (s, 111.),

6.97-7.06 (m, 3dH). 7.11-7,26 (in, 7H), 7.58-7.62 (m, 114), 7.75-7.77 (m, 1H). LC-MS (ESI) m/z: 370

(M+ 1)

10 Examples 28 & 29

9-(3-(4-(Cyclopropanecarbonyl)piperazine-1 -carbonyl)phenyl)-8-(4

((dimethylanino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7l)-one and 9-(3

(4-(cyclopropanecarbonyl)piperazi ne-I -carbonyl)phenyl)-8-(4-(hydroxymethyl)plienyl)-8,9

dihydro-2H-pyrido[4,3 .2-de]phthalazin -3(7H1)-one

is Example 28 A

3-(4-(Cyclopropanecarbonyl)piperazine- I -carbonyl) benzaldehyde

[00437I To a stirred mixture of 3-formylbenzoic acid (450 mg, 3 mmiol) in anhydrous

dichloronethane (20 mL) was added triethylainie (758 mg, 7.5 mmol), 1-hydroxybenzotriazole

(466 ng, 3.45 mmol), followed by 1-ethyl-3-(3-dimethylanino propyl) carbodiimide hydrochloride

20 (629 mg, 3.45 mmol). After the addition, the mixture was stirred at room temperature for 40 nins.

Then the mixture was cooled to 0 C and cyelopropy(piperazin-I-yl)methanone hydrochloride (629

ig, 3.3 imml) was added in portion-wise. After the addition, the mixture was allowed to stir at

room temperature overnight. The mixture was diluted with dichloromethane (50 mL.), washed with

saturated citric acid (100 mLx2), followed by saturated sodium bicarbonate (100 mLx2), brine (50

25 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4

(cyclopropanecarbonyl)piperazine-l-carbonyl) benzaldehyde (810 mg, yield 94% ) as a light yellow

oil 'H-NMR (400 MHz, CDCL) 3 (ppm): 0.79-0.85 (in, 211), 1.00-1.04 (m, 211), 1.73-1.76 (mi, LH),

3.47-3.77 (m 8F1), 7.62-7.66 (t, J = 7.6 Hz, 1d), 7.70-7.72 (d, J= 76 Hz, i 111), 7.95-7.98 (m, 2H), 10.1 (s, iH); LC-MS (ESI) m/z: 287 (M-1)

30 Example 28 B

Methyl 3-(3 -(4 -(cyclopropanecarbonvl)piperazine- 1- carbonyl)phenyl)-2-(4

(diethoxymethyl)p henyl)-4-oxo-l,,34-tetrahydroquinoiine-5-carboxylate

[004381 A mixture of 3-(4-(cyclopropanecarbonvl)piperazine- 1 -carbonyl) benzaldehyde (940 mg,

3.3 mrol) and (E)-4-(4-(diethoxymethy) benzylideneamino)isobenzofuran- 1(3Bt)-one (1 01 8 g5 3

35 mmol) in ethyl propionate (40 miL) was cooled to 0 C. Then a solution of sodium methoxide in

methanol [sodium (345 ig, 15 mmol) in methanol (8 mL)] was added drop-wise. After the addition,

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the mixture was stirred at room temperature for 24 hr, The mixture was quenched with water ( 0

m1L) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted

with ethyl acetate (100 niL x4). The combined organic layers were washed with brine, dried over

anhydrous sodium sulfate, and concentrated to give crude product, The crude product was purified

5 by chromatography (silica gel, petroleum ether / ethyl acetate = 10:1 to 1:10) to give methyl 343 -(4.

(cyclopropanecarbonyl)piperazine- 1- carbonyl)phenyl)-2-(4-(diethoxymethyl)phenyl)-4-oxo

I, 2,3,4-tetrahydro quinoline-5-carboxylate (425 ig, yield 22%).

Example 28 C

9-(3-(4-(Cyclopropanecarbonyl)piperazine-I- carbonyl)phenyl )-8-(4-(diethoxymethyl)pheny1)- 8,9

I0 dihvdro-2H-pyrido[4,3,2-dejphthalazin-3(7l)-one

1004391 A mixture of methyl 3-(3-(4-(cyclopropanecarbonyl)piperazine-I- carbonyl)pheny1)-2-(4

(diethoxymethyl)phenyl)-4-oxo.1,2,3,4-tetrahydroquinoline-5- (425 mg, 0.67 mmol) in 85%

hydrazine monohydrate (4 mL) and methanol (3 nL) was stirred at 25 C for overnight The mixture

was extracted with ethyl acetate (50 mLx3) The combined organic layers were washed with brine,

15 dried over anhydrous sodium sulfate, and concentrated to give the 943-(4

(cyclopropanecarbonyl)piperazine-1- 'arbonyl)phenyl)-8(4-(diethox xymethyl)phenyl)- 8,9-dihydro

2H-pyrido[4,3,2-delphthalazin-3(7H)-one (290 ng, yield 70%) as a yellow solid.

Example 28 1)

4(9-(3 44-(Cyclopropanecarbonyl)piperazine-1- carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H~

20 pyrido[4,3,2-dejphthaiazin-8-yl)benzaldehyde

[004401 A mixture of 9-(3-(4-(cyclopropanecarbonyl)piperazine-1- carbonyl)phenyl)-8-(4

(diethoxvmethyl)phenyl)- 8,9-dihydro-2H-pyrido[4,3 2-dejlphthalazin-3(7.H)-one (290 mg, 0,48

mimol) in 3N hydrochloric acid (10 mL) was stirred at room temperature overnight. Then the

mixture was neutralized with potassium carbonate. The resulting suspension was filtered to give

25 crude, The crude product was purified by prep-HPLC to give the 4-(9-(3-(4

(cyclopropanecar bonyl)piperazine- 1- carbonyl )phenyl)-3-oxo-3.7.8,9-tetrahydro-2Hpyrido[4,3 ,2

dejphthalazin-8-yl)benzaldehyde (20 ig, yield 8%) as a light yellow solid. 'HNMR (400 MHz.

CD3OD) C (ppm): 0.83-0.91 (n, 4H.), 1.94-103 (in 11H), 318-3,23(m, 1H4). 3A6-3.82(n, 711), 4.42

(d,J=17.6 Hz, H). 4.87(d, J= 7.4 Hz, 11-1). 722-7,41 (in, 71), 7.52-7.54 (d, J= 8.0 Hz, 21-1). 7.60

30 (d, I H), 9.94 (s, 1H); LC-MS (EST) n/z: 548 (M+t I V

Examples 28E & 29 E

9-(3-(4-(Cyclopropanecarbonvl)piperazine-l-carbonyl)phenyl)-8(4

((dimaethylamnino)methyIl)pheny l)-8,9-dihydro-2U-pyrido[4,3,2-dejphthalazi.n-3(7H)-one and 9-(3

(4-(cyclopropanecarbonvl)piperazine-1-carbonyl)phenyl)-8-(4-(hydroxymethyi)phenyl)-8.9

35 dihydro-211-pyrido[4,3,2-de]phthalazin-3(71)-one

1.19

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1004411 A mixture of 4-(9-(3 -(4-(cyclopropanecarbonyl)piperazine- I-carbonyl)phenyl)-3-oxo

3,7,8,9-tetrahydro-21Hpyrido[4,32-de]phthalazin-8-yl)benzaldehyde (20 mg, 0.04 inol) and 33%

dinethylamine aq solution (10 mg, 0.07 mmol) in methanol (10 mL)) was stirred at room

temperature for 40 min. Then the mixture was cooled to 0 C. Sodium borohydride (2 mug, 0.06

5 mmol) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol

was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1)

and filtered. The filtrate was concentrated to give the crude product. The crude product was purified

by prep-HPLC to give the compound 9-(3 -(4-(cyclopropanecarbonyl )piperazine- 1 -carbonyl)phenyl)

8-(4-((dimethylamino)methyl)phenl)-8,9-dihydro2H-pyrido[43.2-de]phthalazin-3(7fl)-one (4

10 mg, yield 19%) and 9-(3-(4-(cyclopropanecarbonyl)piperazine-1 -carbonyl)phenyl)-8-(4

(hydroxymethy)phenyl)-8,9-dihydro-2H-pyri do[4, 3, 2-dclphthalazin-3(7.H..one (2 ig, yield 9%) as

light yellow solids. 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl )phenyl)-8-(4

((dinethylatnino)methyl)phenyl)-8,9-dihydro-2JI3-pyridof4,3.,2-de]phthalazin-3(7Ht)-one 4-NMR

(400 MHz, CD3OD) 6 (ppm): 0.83-091 (i 4H). 1.94-2.03 (m, 111) 2.81(s, 6H), 3.18-3,23(m, I H),

15 3.35-3.79 (m, 7H). 4.26 (s, 211), 4.40 (d, J 7.6 Hz, I Hl), 4.82 (d,.J= 7.2 Hz,11), 7.22-7.29 (m, 411). 7.3 1-7.33 (m, 11), 7.37-7.45 (m, 41). 7.58-7.60 (d. J= 8.0 Hz, 111), 7.64-7.68 (t, J:=: 8,0 Hz, I): LC-MS (ES!) niz: 577(M+1)". 9-(3-(4-(cyclopropanecarbonyl)piperazine-I-carbonyl)phenyl)

8-(4-(hydroxyinethyl)pbenyl)-8,9-dihydro-2H-.pyrido[4A,3,2-de]phthalaziin-3(7 H)-one : I-NMR

(400 MHz, CD;OD) 6 (ppm): 0.83-0.91 (m, 4H), 1.94-201 (n, 11-), 3.11-3.14 (in, 1H), 3.35-3.79

20 (i 7H), 437-440 (d, J= 10.0 Hz, I H), 4.55 (s, 2H), 4.38 (d, J= 7.6 Hz, 1 H), 4.73-4.76 (d J= 9.6

Hz, 111), 7.12 (s, I H). 7.20-7.30 (m, 71), 7.34-7.38 (t, J= 8.0 Hz, 11-1.7.56-7.58 (d, J= 7.6 Hz, 1H), 7.62-7.66 (t, J= 8.0 Hz, 1 H); LC-MS (ESI) im/z: 550(M+l)I

Example 30

9-(4-(4-Isobutytylpiperazine-I -carbonyl)phenyl)-8-(4-((methvlamino)methyli)pbeny l)-8,9-dihvdro

25 2IH-pyrido[4,3,2-delphthalazin-3(7-)-one

100442l A mixture of 4-(9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro

2H-pyridof4,3.2-de]phthalazin-8-yl)benzaldehyde (40 mg, 0.07 mmol) and 33% dimethylamine aq

solution (17 mg, 0. 14 mmol) in methanol (10 mI.) was stirred at room temperature for 40 min. Then

the mixture was cooled to 0 "C, Sodium borohydride (4 mg, 0. 11 mmnol) was added. After the

30 addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced

pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was

concentrated to give the crude product. The Crude product was purified by prep-HPLC to give the

compound 9-(4-(4-isobutyrylpiperazine -1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl)

8,9-dihydro-21-pyrido[4,3,2-de]phthalazin-3(71})-one (18 mg. yield 49%) as a light yelow solid.

35 'H-NMR (400 MHz, CDOD) 5 (ppm): 1.10-1.12 (d, J= 6.8 Hz, 61:1).2.67 (s, 3H), 2.81 (brs 1H), 3.33-3.70 (i, 811), 4.12 (s, 2H), .43-4.75 (d, J= 7.6 Hz, I1H), 4.88 (d, J= 74 iz, 1 -1), 7.22-7.27

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(m, 314) 7.31-7.37 (in, 41) 7.42-7.44 (d, J= 8.0 Hz, 2H), 7.56-7.58 (d, J= 7.2 Hz, IH). 7,64-7.68

(t,J= 8.0 Hz, 1H); LC-MS (ESI) miz: 579(M+i-1Y

Example 31

9-(3-(4-Isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2

5 de~phthaiazin-3(7/)-one

Example 31 A

3-(4-1sobutyrylpiperazine- 1 -carbonyl)benzaldehyde

1004431 To a solution of 3-formylhenzoic acid (750 mg, 5 mmol) in anhydrous dichloronethane (15

mL) was added triethvlamine (1.263 g, 12.5 mmol), 1-hydroxybenzotriazole (0,743 g, 5.5 mmol),

It0 followed by i-etlyl-3-(3-dimethylamino propyl)carbodiinide hydrochloride (L0 g, 5.5 mm,).


cooled to 0 C and 2-methyl- -(piperazin- -yl)propan-i-one hydrochloride (1.0 6 g, 55 mmol) was

added portionwise. After the addition, the mixture was stirred at room temperature overnight The

mixture was diluted with dichloromethane (50 mL). washed with saturated sodium bicarbonate (50

.15 mlix2), 10% citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and

concentrated to give 3-(4-isobutyrylpiperazine-l-carbonyl)benzaldehyde (1.44g, yield 95%) as a

gum iH-NMR (400 MHz, CDCI3) 3 (ppm): .13-1.14 (d, J= 6.8 Hz 61), 2.80 (s, 1H), 3.46-3.80

(mn, 8H),762~7.66 (t,1= 7.6 Hz, IH). 7.49-7.71 (d, Ji.6 Hz. lil) 7.94 (s, I H), 7.96~7.99 (dd..1,

7.6 Hz, J, = 1 .2 Hz, I H), 10,06 (s, 1H); LC-MS (ESI) mi/z: 289(M+1)*.

20 Example 31 B

(E)-4-(Pyridin -4-ylmethyleneamino)isobenzo.furan-1(311)-one

[00444] A mixture of 4-amnioisobenzofuran-1(3H)-one (894 mg, 6 mmol), isonicotinaldehyde

(2.568 g, 24 mmol) and anhydrous sodium sulfate (3.6 g) in anhydrous ethanol (70 mL) was heated

to reflux for two days. The mixture was cooled to room temperature and filtered. The filtrate was

25 concentrated to give the crude product. The crude product was washed with petroleum ether to give

(E)-4-(pyridin-4-ynethyleneaniino)isobenzofuran- 1(3TH-one (1.1 g, yield 77%) as a white solid.

'I-NMR (400 MHz, CDCI3 ) 3 (ppm): 5,44 (s, 1H)I 740-7.42 (d, J= 7.6 liz, 1H), 7.59-7.63 (tJ=

7.6 Hz, IN), 7.77-7.79 (d, J= 5.6 Hz, 21-1). 7.84-7.86 (d, J= 7.6 Hz 1H), 8.54 (s, 1H), 8.81-8.82 (d, J= 4.8 Hz, 11 ); LC-MS (ESI) ni/z: 239(M+ 1).

30 Example 31 C

Methyl 3-(3-(4-isobutyryl piperazine-1- carbonyl)phenyl )- 4-oxo-2 -(pyridin-4-y)-I 2,34


[004451 A mixture of 3-(4-isobutyrylpiperazine-I-carbonyl)benzaldehyde (288 mg. 1 mmol) and

(E)-4-(pyridin-4-ylmethyleneaiino)- isobenzofuran- I(311)-one (238 mg, I minol) in ethyl

35 propionate (7.5 mL) was cooled to 0 C. Then a solution of sodium methoxide in methanol [sodiumn

(92 mg, 4 mmol) in methanol (7.5 mi-fl was added drop-wise. After the addition, the mixture was

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stirred at 25 'C for 18 hr. The mixture was quenched with water (10 mL) and solvent was removed

in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (50 mL x3).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and

concentrated to give crude product. The crude product was purified by chromatography (silica gel,

5 petroleum ether /ethyl acetate = 10:1 to 1:10) to give methyl 3-(3-(4-isobutyryl piperazine-1

carbonyI)phenyl)- 4-oxo-2-(pyridin-4-y)- 12,3,4-tetrahy'droquinoline-5-carboxylate (140 mg, vield

26%), LC-MS (ESI) m/z: 541(M+ 1)

Example 3 1D

9-(3 -(4-isobutyry lpiperazine- I -carbonyl)phenyl)-8 -(pyridin-4-y')-8,9-d ihydro-2H-pyrido[4,3 ,2

10 de]phthalazin-3(7H)-one

[004461 A mixture of methyl 3-(3 -(4-isobutyryI piperazine-I- carbonyl)phenyl)- 4-oxo-2-(pyridin

4-yl)- 1,2,3,4-tetrahydroquinoline-5-carboxylate (140 rg, 0.26 minol) in 85% hydrazine

monohydrate (10 iL) and methanol (3 rL) was stirred at 25 "C for 4 hr. The mixture was extracted

with ethyl acetate (50 mLx3). The combined organic layers were washed with brine, dried over

15 anhydrous sodium sulfate, and concentrated to give crude product, The crude product was purified

by prep-IPLC to give compound 9-(3-(4-isobutyrylpiperazine- I -carbony )phenyl)-8-(pyridin-4-yl)

8,9-dihvdro-2H-pyrido[4,3.2-de]pthalazin-3(7L1)-one (11 Img, yield 8%) as a white solid. H

NMR (400 MHz, CD{)D) S (ppm): 1.11-1 13 (m, 611). 2.95-2,98 (m., 1H), 3.26-3.68 (i, 8H), 4.40

4.42 (d, J= 8.4 liz, 1H), 4.82-4.84 (d. J= 8.4 Hz, 1Hl), 7.19-7.32 (n, 411), 7.36-7.39 (in, 3H-), 7.59

20 7.68 (in, 2H), 8.41-8.42 (d, J= 6.0 Hz, 21); LC-MS (ES) mi/z: 523(M+1).

100447] Following the synthetic strategy outlined in Synthetic Scheme I and Synthetic Scheme II

and the appropriate experimental procedure as described in Examples 2 to Example 31 and using

different aldehydes 2 and appropriate 4-aminoisobenzofuran-1 (311)-one 1, the following compounds

are made.

25 Example 32

9-(3-((Diiethylainino)methyl)phenyl)-8-(pyridin-4-yi)-8,9-dihydro-2Hi-pyrido[4.32-de]phthalazin

3(711)-one

Example 33

9-(3-((Methylamino)methyl)phenyl)-8-(pyrid in-4-yl)-8,9-dihydro-2J1-pyrido[4,3,.2-dce]phthalazin

30 3(7-)-one

Example 34

9-(4-((Dimethyl amino)methyl)phenvl)-8-(pyridin-4-yl)-8,9-dilivdro-2H-pyrido[4,3,2-dejphthalazin

3(7H)-one

Example 35 35 943-(Iydroxymehl®)phenyl )-8-(pyridin -4-yl)-8,9-dihydro-2H-pyrido[4,3 2-dc]ph thalazin-3 (7/f)

one

122

WO 2010/017055 PCT/US2009/051879

Exmple 36

9-(4-((Mcetlwlam it)o)methyl)pheny9J-8-(pyridin-4-yD)-8,9-d ihydro-2 Ji-pyrido[4,3,2-deJphthala zmI

3(711)-one

Example 3 7

5 9-(3-((Diniiethiylaii-no)miethiyl)phenvl)-8-(pvridini-3 -yl)-8,9-dihydro-2HI)-pyridoj4,3 ,2"-dc]phtializinl

3(71-1)-one

Example 38 9-(3-(Qvlethylk~amni lo-)methyl)phlefyl)- 8-(pyridint-3"-yl}-8,9-dihydtro-2Hl-pvrido[4,3,2-de]phithalazii

3 (YEr-onle

Ito Example 39

9-(4-((Diinethiylamiino.)miethiyl)phenVl)-8-(pyr'1idinD-3 -yO-8.9-dihiydro-2H1-py.rido[4,3,2-delphthdiaazinl

3(711-one

Example 40

9-(4-((Methiyaninto)miethiyl)phienyl)-8-(pyridini-3 -yb)-8 9-dihivdr-o-211-pyrido)[4,3 ,2-dej,'phthia~azinl

i 5 3(7/1)-one

Example 41

9-(3 -(Hvdr-oxythtlyi.)phentyl)-8-(pvrid in-3 -yl)-8,9-dihy ,dro- !If-p yrido[4.3 ,24-dIcphthalazin-3 (7hone

Example 42

20 9-3-D mtyamnomt lptyI8-piin2yl 89dihdo2Iprd[432-ephtaain

3(7101-one

Example 43

9-( -~(Mthyami~hethl )he~l)8-py.,idin-2-yl)-8.9-dihvdro-2H-pyridof4,3d 3jl~phthalazi-n

3(711,)-one

25 Example 44

9-( 34-Hydroxym-etyl)phecnvl)-8-(pyridini--v1i)8,9)-dIihiyd-ro-2II-pvrido[4,3 2--dec ihthalazini-('7H1

one

Example 45

9-(4-((Di miethl ioito)myethyl,-)phenv I )-8-(pyrid in-2-yl }-8,9-dilhvdro-2H--p'Wi-do[4, 3 2-dej]phithalazini30 371-n

Example 46

9-(4-((Methylamino)m-nethyl)phienivl)-8-(pridin-2-yI)-8.9-dihiydro-2Hpyriao [43 .2,I-dipithalazinl

3(711)-one

Example 47

35 9-Phontiy l-8-(pyr-idin-2-vi)-8,9-dihvd,-ro-2.H-pyrido[43, .2-dc jphithialaz' n -3 (7TH-one

Example 48

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WO 2010/017055 PCT/US2009/051879

Example 49

9-Phen-y1-8-(py-ridini-4-y1)-&,9-dihiydro-2 )H-pyr.,ido-[43 .2-dlejphthialaz-in-3 (7th-one

Example 50

55-Fl uoro-9-phienIi-8-(pxrridini-4-yv)-,9-dilwdlro-2IZ-pvrido[4,3 ,-delphthalazin-3 (WiP-onie

Exam-ple 51

9-(3 -( (Dimethiylainio)miethyl)phienvl)-5-tuoro-8-(py ridin-4-l)-89-diivdro-11l-pyridof4,3 .

dejphithalazin-3(7Th-one

Example 52

10 5-Fiuoro-9-(3-((Jmethiviaminto)methiy1)phenvJ)-8-(p~yridin-4-y b-8,9-clihy ,dro-2 H-pyridoL[4,3,2

dejphthalazin-3(7th-one

Example 53

9-(4 -((Dimetb~ylai-no.)-nm~thyl)phenyl)-5--fl uoro.-8-(pyrid in-4-il )-8,9-dihiydro-2IJ-pyrido[4,3 2-

cle]phithalazin-3( 711-one

15 Example 54

5-Fiuioroi-8,9-diphenx i~l-8,9-dihiydro-2t11-pyrido[4.3.2-eiephthialai n-3(7Jfl-onei

Example 55

9-(4-((Dimethylamirio)rnethyl)phenyl)-5 -fluoro-8-pheniyl-8,9-dihiydro-2'H-py ,rido[4.3,2

de] phihalazi-n-one

20 Example 56

5-Fluioro-9-(4-((mnethvlam ino)methvl.)phenyb-8-phenyl,-8,9-dihvydro-2H l-pyrido [4,3 ,2-dIe]phthialazin

one

Examrple 57

9-(3 -((Dimethl-aminiio~rethiyl)phienvl)-5-fluioro-8-phienvly-8,9-dihv).dro-2H-pvr-ido[4,3 .,2

25 delphthalazin-one

Example 58

8-(4-((Dinielhyiainio)myethyl)phenvbI-5-flutoro-9-pheniyl-8,9-dihiydiro2-" 1pyrido[4,.3 2

dejphthalazin-one

Example 59

30 5-Fl uoro-9-(3 -((meThvianino)methyvl)phienvb)-8-phenvi-8 .9-dilwdro-2t1--pvrido[)14,-dej iphthalazin

one

Example 60

5Slor)8(-(ielyan-i~iely~lev.--liiy-,-iid~-f-y~dl432(eptazzll

one

35 [-Exaniple 61

7-Methyl -8,9-dipheniyl-8,9-dihvidro-2t1-pyr-ido[4,' ,2-dejphthiaazin-3(71-tfl-oe

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WO 2010/017055 PCT/US2009/051879

1004481 A solution of 8.9-dipheny-8,9-dihydro-2H-pyrido[4.3,2-delphthalazin-3(711)-one (1 04

mmol) in methanol (20 mL) is treated with formaldehyde (37 wt % in water, 270 pL, 3.61 mmol) at

roon temperature for overnight. Sodium cyanoborohydride (228 mug, 3.61 mmol) is added and the

solution is stirred at room temperature for 3 h. After concentration under reduced pressure, the

5 residue is dissolved in a mixture of trifluoroacetic acid and water and is purified by HPLC giving the

7-methyl-8,9-diphenyl-8.9-dihydro-211-pyrido[4,3,2-de]phthalazin-3(7H)-one in good yield,

Example 62

7-Ethyl-8,9-diphenyl-8,9-dihydro-2H-pyrido[4.,3,2-de]phthalazin-3(711)-one

1004491 Following the experimental conditions outlined in Example 61, replacing the formaldehyde

[0 with acetaldehyde, the title compound 7-etlyl-8,9-diphenyl-8,9-dihydro-211-pyrido[4,3,2

de]phthalazin-3(7h-one is made.

Example 63

5-Fluoro-9-( i-methylH-IH-im idazol-2-yl)-8-phenyl-8,9-dihydro-21-pyrido[4, .2-dejphthalazin

3(7H)-one

15 Example 63 A

Methyl 5-fluoro-2-methyl-3-nitrobenzoate

1004501 To a solution of conc. 112S04 (700 mL) was added portion-wise 5-fluoro-2-methylbenzoic

acid (80 g, 520 mmol) at -5~0 T Then a mixture of cone. HTNO; (60.4 g, 624 mmol) in conc. H2l:S0.

(60 mL) was added drop-wise at -5~0 "C in a period of about 1.5 hrs. After the addition, the mixture

20 was stirred at this temperature for 2 hrs. TLC (petroleum ether! EtOAe = 1:1) showed the reaction

was complete. The mixture was poured into crash ice with vigorous stirring and the precipitate was

collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over

anhydrous Na2 SO4, concentrated to give crude 5-fluoro-2-nmethyl-3-nitrobenzoic acid (54 g). A

solution of this crude 5-tluoro-2-nethyl-3-nitrobcnzoic acid (54 g) in dry methanol (500 mL) was

25 cooled to 0 C, SOC 2 (64.52 g, 542.3 mmoi) was added drop-wise. After the addition, the mixture

wvas heated to reflux for 16 hrs. TLC (petroleum ether/ EtOAc = 1:1) showed the reaction was

complete. Solvent was removed under reduced pressure to give crude product. The crude product

was purified by silica gel chromatography (petroleum ether to petroleum ether/ EtOAc= 50:1) to

give methyl 5-fluoro-2-methy-3-nitrobenzoate (28 g, yield 25% for two steps) as a white solid. '[H

30 NMR (400 MHz, CDCI3 ) 6 (ppm): 2.59 (s, 31])t 3.95 (s, 31), 760-7.63 (dd, 1H) 7.74-777 (dd, 1 H);

LC-MS (ESI) m/z: 214 (M+tl)* 216(M+3).

Example 63 B

6-Fltioro-4-nitroisobenzofuran-1(3H)-one

1004511 A mixture of methyl 5-fluoro-2-mcthyl-3-nitrobenzoate (28 g. 130.5 nmmol), NBS (27.8 g, 35 156.6 mmol) and BPO (3.13 g, 13.1 mmol) in CC14 (400 nmL) was heated to reflux overnight. TLC

(petroleum ether/ EtOAc = 15:1) showed the starting material was consumed completely. Water

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WO 2010/017055 PCT/US2009/051879

(200 mL) was added and CCL4 was removed under reduced pressure. The residue was extracted with

DCM (200 niL x 3). The combined organic layers were washed with brine, dried over Na2 SO4.

concentrated to give crude methyl 2-(bromomethyl)-5-fluoro-2-methyl-3 -nitrobenzoate (36 g, yield

94%) as a brown oil. A mixture of methyl 2-(bromomethyl)-5-fluoro-2-methy[-3-nitrobenzoate (36

5 g, 123 mmol) in 1, 4-dioxane (250 mL) and water (62.5 mL) was heated to reflux for 4 days. TLC

(petroleum ether / EtOAc= 15:1) showed the starting material was consumed completely. Dioxane

was removed under reduced pressure. The residue was extracted with EtOAc (300 mL x 4). The

combined organic layers were washed with brine, dried over NaSO, concentrated to give crude

product The crude product was purified by gel chromatography (petroleum ether to petroleum ether/

10 EtOAc =5:1) to give 6-fluoro-4-nitroisobenzofuran-l(3H)-one (19.2 g, yield 79%) as a white solid.

H-NMR (400 MHz, CDCL) d (ppm): 5.74 (s, 2H) 7.97-7:98 (dd 111), 8,24-8,27 (dd 11); LC-MS

(ES!) in/z: 198(M+1.f.

Example 63 C

4-Amino-6-fluoroisobenzofuran- (3H1)-one

15 [004521 A suspension of 6-fluoro-4-nitroisobenzofuran-1(3H)-one (9.6 g, 487 mmol) and Pd/C

(10%, 1 g) in EtOAc (300 mL) was stirred at 25 "C under I atmosphere of hydrogen for 12 hr. TLC

(petroleum ether! EtOAc= 2:1) showed the reaction was complete. The mixture was filtered., and the

cake was washed with EtOAc (100 mL x 3). The filtrate was concentrated to give 4-amino-6

fluoroisobenzofuran- 1(311)-one (7.5 g, yield 92%) as a white solid. 'H-NMR (400 MHz, CDCh) S

20 (ppm): 3.85 (br s, 211), 5.14-5.15 (d, 211). 6.62-6.65 (dd, 1H), 6,98-700 (ddi 1H); LC-MS (ESI) n/z:

168 (M+ 1)'.

Example 63 D

(E)-4-(Benzvlidencamino)-6-fluoroisobenzofuran-I (311)-one

1004531 To a stirred mixture of bentzaldehyde (4.125 g, 29.9 mmol) and anhydrous magnesium

25 sulfate (36 g, 299 mmol) in anhydrous acetonitrile (200 mL) was added 4-amino-6

flioroisobenzofuran- 1(3H1)-one (5 g 29 mmoi) at 0 'C. After the addition, the mixture was stirred

at room temperature for 6 days. The mixture was filtered and the cake was washed with ethyl acetate

(50 mLx3), The filtrate was concentrated to give crude product. The crude product was washed with

petroleum ether to give (E)-4-(benzyliden eamnino)-6-fluoroisobenzof uran- 1(31)-one (5 g, yield:

30 66%). 'H-NMR (400 Mliz, CDC 3) 6 (ppm):5.40 (s, 2); 7.11-7,14 (dd. 111), 7.44-7.46 (dd, 211),

7.53-7.59 (m, 311), 7.93-7.95 (m, 21). 8.54 (s, 11.); LC-MS (ESI) n/z: 256 (M+lY

Example 63 E

Ethyl 7-fluoro-3-(1-methyl-IHl-irnidazol-2-yl)-4-oxo-2-phenyl- I ,2,3,4-tetrahydroquiioline-5

carboxylate

35 1004541 A mixture of(E-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3 A)-one (2 g, 7.8 nmol)

and I-methyl-Il- imidazole-2-carbaldehyde (0.949 g, 8.63 imol) in ethyl propionate (50 mL) was

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WO 2010/017055 PCT/US2009/051879

cooled to 0 TC. Then a solution of sodium ethoxide in ethanol [sodium (722 mg, 31 .37mmol) in

ethanol (30 mL)] was added drop-wise. After the addition, the mixture was stirred at room

temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in

vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL x4) The

5 combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and


petroleum ether / ethyl acetate = 10:1 to 1:10) to give the ethyl 7-fluoro-3-( 1-methyl- I H-inidazol-2

yl)-4-oxo-2-phenyl- 1,2,3,4-tetrahydroquinol ine~5-carboxvlate (141 mg). 1 M-NMR (400 MHz,

DMSO-46) 6(ppm) 1.18-1,22 (t, 31), 331 (s, 31), 4.17-421 (q, 2M). 4.62 1-4.65 (d 211), 5.17-5.20

10 (d, 111), 6.48-6,51 (dd, I H), 6.70-6,73 (n 2), 6.86 (s, 111), 724-7.30 (m, 3 H), 7.42-7,44 (t 211)

7.76 (s, 1 H); LC-MS (ESI) 3/z:394 QV1).

Example 63 F

5-Fluoro-9-( 1-methyl-I H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3 .2-dejphthalazin

3(7H)-one

15 1004551 A mixture of ethyl 7-fluoro-3-(I-methyl-1 J-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4

tetrahydroquinoline-5-carboxylate (141 mg) in 85% hydrazine monohydrate (10 mL) and methanol

(10 mL) was stirred at 45 C for overnight. Methanol was removed under reduced pressure. The

mixture was filtered and washed with water to give 5-fluoro-9-(1i-methyl- 1H-iniidazol-2-yl)-8

phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (11 mg, yield: 9%). 'H-NMR (400

20 MHz, CDX)q) 6 (ppm): 3.34 (s, 311), 4.65 (d, J= 8.0 Hz, It), 4.94 (d, J 8.0 Hz, 1,H), 6.81(s, 1H)

6,88-7,02 (m, 2H), 7.18 (dd, I H), 7.28-7,29 (n. 3H), 7.34-7.36(m, 211); "'F-NMR(400 MHz,

CDOD) & -105.70 (s); LC-MS (ES!) mi/z: 362 (M+-)

Example 64

5-Fluoro-8-(4-fluorophenyl)-9-( 1-methyl-IH-imidazol-2-yl) -89-d ihydro-2H-pyrido[4,3,2


Example 64 A

(E)-6-FIuoro-4-(4-fluorobenzylideneam ino)isobenzofuran- 1(31)-one

1004561 4-anino-6-fluoroisobenzofuran-l(3H)-one (1 .5 g 8,98 mnmol), 4-fluorobenzaldehyde (1 67

g 13.47 nmol) and 12.75 g of MgSO4 were added into 40 ml of DCM and stirred under reflux

30 overnight, then the mixture was evaporated under reduced pressure and the residues was dried in

vacuum. 850 n.g of (E)-6-f1uoro-4-(4-tluorobenzylideneamino)isobenzofuran1(31)-one was

obtained. 1H-NMR (400 MHz, CDClI) 6 (ppm):5,37 (s, 2); 7.09-7.12 (dd, 11H), 7.19-7.23 (t, 211),

7:43-7.45 (dd. 111), 7.92-7.95 (m, 2H), 8.49 (s, 11); LC-MS (ES!) m/7: 274 (M+1)".

Example 64 B

35 Methyl 7-fluoro-2-(4-fiuorophenyl)-3-(I-methyl~1 H-imidazol-2-y )-4-oxo-1,2,3,4

tetrahydroquinolie-5 -carboxy late

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004571 (E)-6-Eluoro-4-(4-fluorobenzylideneam ino)isobenzofuran-1(3H)-one (850mg. 3.13 mmol),

I -nethyl- IH- imidazole-2-carbaldehyde (342 mug, 3.13 nunol), sodium methanolate (851 mg, 12.52

mamol) and ethyl propionate (50 in) were added and the mixture was stirred at room temperature

overnight, Then the resulting mixture was evaporated under reduced pressure and extracted with

5 EtOAc (4 x 100 mI) and concentrated. The crude product was purified by column chromatography

(silica gel, petroleum ether: EtOAc 20:1 to 5:1) 20 mg of methyl 7-fluoro-2-(4-fluorophenyl)-3-(1

methyl-I 1H-imidazol-2-vl)-4-oxo-1,2,3,4-tetrahydroquinol ie-5-carboxylate was obtained. LC-MS

(ESI) n/: 412 (M+1)

Example 64 C

10 5-Fluoro-8-(4-fluorophenyl)-9-( i-methylH-IH-i midazol-2-yl) -8,9-dihydro-2H-pyrido{4.3.2

de]phthalazin-3 (711)-one

[004581 Methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1HJ-imidazol-2-yl)-4-oxo-1,2,3 4

tetrahydroquinolie-5-carboxylate (20 mg, 0,048 mmol) and hydrazine (3 ml) were added MeOli (20

ml) and the mixture was stirred room temperature for 3 h. The resuming mixture was evaporated

15 under reduced pressure to 5 ml and then filtered: 5.6 mg of 5-fiuoro-8-(44-fiorophenyl)-9-(I -methyl

1H- inidazol-2-yl) -8.9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3 (7T)-one was obtained) H-NMR

(400 MHz, CD3OD) 8 (ppm):3.35 (s. 3H)5 4.65 (d, 11), 4,95 (d, 1H), 6.84 (s. IH), 6.87-6.91 (i,

21), 7.02 (t, 211) 7,17-7,20 (in, 1-), 7.37-7.40 (mAH). LC-MS (ESI) m/z: 380 (Mel.)

Example 65

20 8-(4-((Dimethylamino)mthyl)phenyl)-9-(1 -methyl-il H-imidazol-2-yl)- 8,9-dihydro-211

pyrido[4,3.2-de]phthalazin-3(711)-one

Example 65 A

Ethyl 2-(4-(diethoxyiethyl)phenyl) ~ 3-(1 -methyl- I H-inmidazol-2 -yl)-4-oxo- 1,23,4


25 [004591 A mixture of (E)-44diethoxymethyl)benzylidencamino)isobenzofuran-1.(311)-one (678

ing, 2 mmol), I-methyl-1 J1-imidazole-2-carbaldehyde (242 mg. 2.2 mmol), sodium ethanolate (544

mg, 8.0 mnol), and ethyl propionate (50 ml) was stirred at room temperature for 3hr. Then the

resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100

mLx4) and concentrated. The crude product was purified by column chromatography (silica gel, 30 petroleum ether: ethyl acetate =20:1 to 1L5:1) to give ethyl 2-(4-(diethoxymethyl)phenlv) -341

methyl-I H-imidazol-2-yi)-4-oxo-1 2 ,4-tetrahydroquinoline-5-carboxylate as solid (50 mg, yield

5%). LGM S (ESI) n/z: 478 (M+I)

Example 65 B

8-(4-(Diethoxyvniethyl)phenyl)-9-( 1-methyl-I 1H-imidazol-2-yl)- 8,9-dihydro-211-pyrido[4,3,2

35 de]phthalazin-3(7)-one

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WO 2010/017055 PCT/US2009/051879

[00460 A mixture of ethyl 2-(4-(diethoxynethyl)phenyl) -3-( -methyl-1 H-imidazol-2-yl)-4-oxo

1,2,3,4-tetrahydroquinoline-5-carboxylate (490 mg, 1,03 mmol) methanol (20 mL) and hydrazine

monohydrate (2 mL) was stirred under 25 'C for 3 hr. The resulting mixture was evaporated under

reduced pressure to 10 mil and then filtered, 250 mag of 8-(4-(dicthoxymethyl)phenyl)-9-(1-methyl

5 iJJ-imidazol-2-yi)- 8,9-dihydro-211-pyrido[4,3,2-de]phthalazin-3(7Th)-one as a solid vas obtained,

yield 55%. LC-MS (ESI) mr/z: 446 (M+l1)

Example 65 C

4-(9-(l -Methyl- I m-imidazol-2-yi)-3-oxo-3,7. 8,9-tetrahydro-2H-pyrido[43,2-de]phthalazin-8

yl)benzaldehyde

10 [004611 A mixture of 8-(4-(Diethoxymetlyl)phenyl)-9-( 1-methyl-I11iiiidazol-2-yl)- 8,9-dihydro

2-pyrido[432--de]phthalazin-3(7J)-one (50 mg, 0.11 mmol) and 2 nil of hydrochloric acid (3 N)

was stirred at room temperature for 2 hr. The reaction mixture wvas neutralized by ltCO3 to p1H=-7

and then filtered. 29 mg of 4-(9-( -methyl-lJH-imidazoi2-y)-3-oxo-3 27H8,9-tetrahydro-2H

pyrido[4,3,2-de]phthalazin-8-vl)benzaldehyde was obtained, yield 70% LCMS (ESI) m/z: 372

15 (M+1),

Example 65 D

8-4-((dimethylamino)methyl)phenyl)-9-(1-methyl-iH-imidazol-2-y)- 8,9-dihydro-21H

pyrido [4,3 ,2-dejphthalazin-3(7B)-one

[00462) A mixture of 4-(9-(1~methyi4R-imidazol-2-yl)-3-oxo-3 ,7,89-tetrahydro-2I-1prido[4,3,2

20 de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 amiol), acetic acid (60uL) and 27% dimethylamine

alcohol solution (2.5rnL 15 mmol) in acetonitrile (7 mL) was stirred at room temperature for 41.

Then the mixture was cooled to 0 C NaBH3 CN (36 mg, 0.67 umol) was added. After the addition,

the mixture was stirred at room temperature for 4 hr. Methanol was removed inder reduced

pressure. The residue was washed with ethyl acetate and filtered The filtrate was concentrated to

25 give 8-(4-((dimethylamino)methyl)pheny)-9-(1-methyl-I H-imidazol-2-yl)- 8,9-dihydro-2]H

pyrido(4,3,2-dle]phthalazin-3(71)-one (30 mg, yield 34%) as a white solid. 'H-NMR: (400MHz;

DMSO-I) 8 (ppm): 2.11 (s, 61H)13.36 (s, 211),3.37 (s, 3H), 4 65 (d, J= 10,4Hz, IH). 4.92 (d, I

10.4 Hz, 1HT), 6.76 (s, 1H-1), 7.20 (d,. J 7.6 iz; 311), 7.35 (d, J 8.0 Hz, 211), 7.43 (d, J= 6.8 Hz, 111), 7.62 (t, .J 7.8 Hz, 1-); LC-MS (PSI) mi/: 401 (M-4I).

30 Example 66

9-(I-isopropyl- 11-imidazol-5-yl)- 8-phenyl-S,9-dihydro-2H-pyrido[4,3 ;2-dc phthalazin-3(71)-one

Example 66 A

Ethyl 3-(I-isopropyl-1I -imidazol-5-yl)-4-oxo-2-phenyivl-I2.3.4-tetrahydroquinoline-5-carboxylate

[004631 A mixture of iH-imidazole-5-carbaldehyde (800 mg, 8.3 mmol), 2-iodopropane (1 .7 g, 10

35 mnmol) and potassium carbonate (1.4 g) in DMF (30 mL) was heated to 50 "C overnight. The

mixture was evaporated under reduced pressure, and then extracted with ethyl acetate (100 mL.;x4).

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WO 2010/017055 PCT/US2009/051879

The combined organic layers were dried over anhydrous sodium sulfate, concentrated to give I

isopropyl-1 H-imidazole-5-carbaldehyde (1.1 g), LC-MS (ESI) m/z: 139 (M+1) This compound

(11 g, 8.0 mmol) and (E)~4-(benzylideneamino)isobenzofuran- 1(3JH)-one (1.7 g ,7.2 mmol) were

added in ethyl propionate (50 mL) then sodium ethoxide was added under 0 *C The mixture was

5 stirred overnight at room temperature. The mixture was concentrated and the residue was extracted

with ethyl acetate (100 mL x4). The organic layer dried over anhydrous sodium sulfate, purified by

chromatography (silica gel, petroleum ether / ethyl acetate= 10:1 to 1:1) to give ethyl 3-(1

isopropyl- I J-imidazol5-yl)-4-oxo-2-pheny 121 .3,4-tetrahydroquinoline-5-carboxylate (770 mg,

yield 30%), LC-MS (ES.) m/z: 404 (M+1)1.

10 Example 66 B

9-(1-isopropyl-I H-imidazol-5-yl)- 8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

1004641 A suspension of ethyl 3-(1 -isopropyI- I 1-imidazol5 -yl)-4-oxo-2-phenyl- l,2,3,4

tetrahydroquinoline-5-carboxylate (770 mg, 1.9 mmol) aid hydrazine monohydrate (6 ml, 85%)

were added in methanol (10 mL) and stirred at 50 TC overnight, The mixture was filtered, and the

15 white solid was washed with methanol and dried to give 9-(1 -isopropyi-l-I -imidazol-5-yl)- 8

phenyl-8,9-dihydro-2H-pyrido[43 ,2-de]phthalazin-3(71H)-one (90 mg yield 13%). tH -NMR (400

MHz, DMS046) S (ppm) : 0.82-084 (d, J= 6.8 Hz, 3H), 1 27- L29 (d. J= 6.4 liz, 3H-) 3.30-3.33

(t;J =6.6 Hz, H), 4.67-4.70 (d, J= 1 1,2 Hz, 1-1), 4.92-4,95 (d,,J= 11.2 Hz, IH), 6.80 (s, 1H), 7.01 (s' I l). 7.16-7.18 (s, 1), 7.24-7.28 (m. 31H). 7.31 (s, 1H), 7.36-7.39 (m, 3H), 7.55-7.59 (mn., I l)

20 LC-MS (ESI) m/z: 3 72 (M+1

Example 67

9-(4-Methyl- 1 H-imidazol-2-y1)- 8-phenvl-8.9-dihydro-2H-pyrido[4,3,2-dejphthalazin-3(7H)-one

Example 67A

I -Benzyl-4-methyl- IH-imidazole-2-carbaldehyde

25 1004651 To a solution of 4-methyl-iH-imidazole (1g, 5.8 mmol) in 6 niL THE cooled to -50 'C was

added n-BuLi (2.9 mL, 625 imol), The mixture was stirred at -50 C ~- 40 T for 2h. Then cooled to

-78 C and added in DMF (0.87 mL) drop-wise. After addition the ice bath was removed, and the

mixture was stirred at room temperature 30 min. The resulting mixture was evaporated wider

reduced pressure to 10 mL and then filtered: the crude product was purified by column

30 chromatography to obtain 1-benzyl-4-methyl-IH-imidazole-2-carbaldehyde (450 mg, yield 38%).

LC-MS (ES1) m/z: 201( )M+

Example 67 B

Methyl 3-( Ibenzyl -4-nmethybl-iiJ-imidazol-2-vl)-4-oxo-2-phenyl-1,2,3.4-tetrahydroquinoi ine~5

carboxylate

35 1004661 A mixture of 1-benzyl-4-methyl -H-imidazole-2-carbaldehyde (450 ig, 2.25 nmol), (EL)

4-(benzvlideneamino)isobenzofuran- 1(31:)-one (640 mg, 2.7 nimol), sodium methanolate (207 mg,

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9 mnmol) and ethyl propionate (25 nL) were stirred at room temperature overnight. Then the

resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (4 x .100

mL) and concentrated to give methyl 3-(1 -benzyl-4-methyl- IH-imidazol2-vl)-4-oxo-2-phenyl

I 2,3,4-tetrahydroquinoline-5-carboxvlate (250 mg, yield 25%). LC-MS (ESI) m/z: 438 (MI+-1)

5 Example 67 C

9-(I-Benzyl-4-rnethyl- I H-imidazo-2-yl) 8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin

3(7H1)-one

[004671 A mixture of methyl 3-(1-benziyl-4 -methyl-I H-imidazo-2-yl)-4-oxo-2-phenyl- 12.3,4

tetrahydroquinoline-5-carboxylate (250 mg 0.57 mmol) and hydrazine monohydrate (3 mL) was

10 stirred room temperature for 5 b. The resulting mixture Was evaporated under reduced pressure to 15

ml and then filtered: the filtrate was concentrated to give 9-(1-benzyi-4-methyl- II1-imidazol-2-yi)

8-phenyl-8,9-dihydro-2Hpyrido[4,3,2-dejphthalazin-3(7h-one as a white solid (40 mg, yield

16%). L-MS (ESI) n/z: 434 (M-+J)'.

Example 67 D

15 9-(4-Methyl- I i-imidazol-2-yl)- 8-phenyl-8,9-dihydro-2 H-pyrido[4,3 ,2-cde/ phthalazin-3(7H)-one

1004681 A mixture of 9-(I-benzyl-4-methy 1-I H-imidazoi-2-yl)- 8-phenyl-8,9-dihydro-2H

pyrido{4,3,2-dephthailazin-3(7Hyone (40 ng, 0,09 mmol) and palladium hydroxide on carbon

catalyst (40 mg,20%wt) in anhydrous methanol (15 ml..) was purged with hydrogen (I bar) at room

temperature for 12 hr. The mixture was filtered and the filtrate was concentrated to give crude

20 product, which was purified by pre-HPLC to give 9-4-methxl ilHntidazol2-yl)- 8-phenyl-8,9

dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (27 mg, yield 87%).'1H-NMR (400 MHz, CD 3OD) 6 (ppm): 2.22 (dd,3H) 4,77-4.86 (m, 2H), 7.06(s, 1i1), 7.20 (d, I 1), 7,36 (t, 5H), 7.55 (d, I H), 7.62 (t, ifI): LC-MS (ESI) rm/z: 344(TM+l)

Example 68

25 8-Phenyl-9-(thiazol-5-yi)-8,9-dihydro-2H-pyrido(4,3,2-dejphthalazin-3(7H)-one

Example 68 A

Methyl 4-oxo-2-phenyl-3-(thiazol-5 -yl)-.2,3 ,4-tetrahydroquinoline-5-carboxylate

1004691 A mixture of thiazole-5-carbaldehyde (500 mg, 4 mmol), (E)-4

(benzylideneamino)isobenzofuran- (3h)-one (960 mug, 4 mmol), sodium methanolate (375 mg, 16.1

30 mmol) and ethyl propionate (30 mL) were stirred at room temperature overnight. Then the resulting

mixture was evaporated under reduced pressure and extracted with ethyl acetate (4 x 100 nL) and

concentrated. The crude product was purified by column chromatography (silica gel, petroleum

ether: ethyl acetate 10: 1 to 1:1) to give methyl 4-oxo-2 phenyl-3-(thiazol-5-yl)-1,2,3,4

tetrahydroquinoline-5-carboxylate (110 mg, yield 7%). LC-MS (ESI) rm/z: 379 (M+1).

35 Example 68 B

8-Pheny-9-(thiaol -yl)-8,9-dihydro-2H-pyrido[4,32-de]phtlhalazin-3(7)-one

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[004701 Methyl 4-oxo-2-phenyl-3-(thiazol-5 -l)-1,2 .34-tetrahydroquinol ine-5 -carboxylate (110 mg.

0.29 mmol) and hydrazine monohydrate (2 mL) were added to methanol (10 mL) and the mixture

was stirred room temperature for 4 h. The resulting mixture was evaporated under reduced pressure

to 10 ml. and then filtered; the filtrate was concentrated to give 8-phenv-9-( thiazol-5-yl)-8,9

5 dihydro-2H-pyrido[4,3,2-delphthalazin-3(7H1)-one (13 mg, yield 13%) as a white solid. Il-NiR

(400 MHz, CD3OD) 6 (ppm): 4.67 (d, IFH), 4.78 (d I H), 7.10-7.19 (m, 411), 7.24 (t; 2H), 7.45-.56

(m7 211), 8.76 (s, 1H); LC-MS (ESI) m/z: 347 (M+1.

Example 69

9-(Furan -3-yl)-8-phenyl-8.9-dihvdro-21H-pyrido[4,3 ,2-dejphthalazin-3(7/1)-one

10 Example 69 A

Ethyl 3 -(furan-3 -y)4-oxo-2-phenyl- 1,2,3 ,4-tetrahydroq uinoli ne-5 -carboxylate

1004711 A mixture of (E)-4-(benzylideneamino)isobenzofulran- 1(3H)-one (948 mg, 4 minol) and

furan-3-carbaldehyde (422 mg, 4.4 mmol) in ethyl propionate (30.mL) was cooled to 0 "T. Then a

solution of sodium ethanoxide in ethanol [sodium (368 mg, 16 mmol) in ethanol (20 mL)] was

5 added dropwise, After the addition, the mixture was stirred at room temperature for 2 hr The

mixture was quenched with water (10 mL.) and solvent was removed in vacuum The residue was

dissolved in water, and then extracted with ethyl acetate (100 niLx4). The combined organic layers



20 acetate= 10:1 to 1:1) to give ethyl 3-furan-3-yl)-4-oxo-2-pheny-i,2,3,4-tetrahydroquinone-5

carboxylate (80 rg, yield: 5%). LCMS (ESI) m/z: 362 (M+If)

Example 69 B

9-(Furan-3-yl)-8-phenyi-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(71f)-one

1004721 A mixture of ethyl 3-(furan-3-yl)-4-oxo-2-phenyl-l ,2,3,4-tetrahydroquinoline-5-carboxylate

25 (80 nig) in 85% hydrazine monohydrate (10 mL) and methanol (10 ml) was stirred at 45 'C

ovemight, Methanol was removed under reduced pressure. The crude product was purified by prep

HPLC to give 9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalizin-3 (7H)-one (5 img, yield 7%). I-l-NMR (400 MHz, CD3OD) 6 (ppm): 4.19 (d_ .f= 8.0 Hz, IH), 4.67 (d, -= 8.0 1-1z, I H), 6.26 (s, 1H), 7.07-7.21 (m, 7H-). 7.30 (s, 1)., 7.27 (i , 1H), 7.41 (d, 1H), 7.51 (m., IH); LC-MS

30 (ESI) m/z: 330 (MI-1

Example 70

8-(4-((4-Ethylpiperazin- 1-l)methyl)phenyi)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-dejphthalazin

3(7h)-one

1004731 To a stirred solution of 4-(3-oxo-9-phenyl-3, 7,8,9-tetrahydro-2H-pyrido[4,3,2

35 de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 immol) in dichloromethane (30 mL) was added

acetic acid (I ml..) followed by the addition of I -ethylpiperazine (121 mg. 1.63 mol). After the

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addition, the mixture was stirred at room temperature overnight, Then the mixture was cooled to 0

'C, NaBH (OAc)t (173 mg, 0.81 nrnol) was added, After the addition, the mixture was stirred at this

temperature for 12 hr. dichloromethane was removed under reduced pressure. The residue was

washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the

crude product. The crude product was purified by prep-HPLC to give 8-(4-((4-ethylpiperazin- I,

yl)methyl)phenvl)-9-phenvl-8,9-dihydro-2H-pyrido [4,3,2-de]phthalazin-3(711)-one (135 tmg, yield

47%) as white solid. 'H-NMR (400 MHz, DMSO-d6) 6 (ppm): 1.22 (t, 3H) 2.36-2.44 (in, 1HI),

2.74-3.11 (m, 8H) 4.01-4.10 (in, 314), 4.33 (dd, IH) 4.78 (dd. I), 7, 13-7.31 (i, IOH)t 7,37 (d.

1IH), 7.47 (s, 1), 7.58 (t, 311); LC-MS (ESI) m/z: 452(M+1)^.

10 Example 71

9-Phenyl-8-(4-(piperazin- I -ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3.2-dejphthalazin-3(7/)-one

1004741 A solution of 4-(3-oxo-9-phenyli-3,7,8,9-tetrahydro-2H-py rido[4,3,2-dejphthalazin-8

yl)benzaldehyde (200 mlg. 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (196 mug

15 3.24 nmol) and tert-butyl piperazine- 1 -carboxylate (304 mug, 1 .63 mmiol) at room temperature and

stirred overnight. Then NaBI (OAc)t (1~73 Tg, 0.81 mmol) was added to the mixture at 0 'C, stirred

for one day, The reaction mixture was quenched with aqueous sodium bicarbonate, extracted with

dichloromethane, The combined organic layer was washed by brine, dried over anhydrous sodium

sulfate, concentrated to give the crude product which was purified by flash chromatography to

20 obtain a solution. To the solution obtained (concentrated to about 50 mL) was added conc. HCI (10

mL) at room temperature and stirred overnight. The mixture was extracted with ethyl acetate for

three times, the aqueous phase was concentrated to give 9-phenyl-8-(4-(piperazin-I

ylmethy l)phenyl)-8,9-dihydro-2H-pvrido[4,3.2-de]phthalazin-3(7H)-one (1 27 tug, yield 46%). '11

NMR (400 MHz, DMSO-d6) 8 (ppm): 3.47(br s, 7H), 360 (m, 1H), 4.32 (s, 2H), 438 (d, 11), 4.83

25 (d, li), 5.41 (br s, 21). 7.19 (in, 611), 7.24 (m, 311), 7.55 (3na 4H), 9.87 (br s, 2H), 1220 (s. I H);

LC-MS (ESI) n/z: 438(M+t1) .

Example 72

8-(1-Methyl-1 H-i inidazol-2-yl )-9-phenyl-8,9-d ihydro-2H.pyrido[43 .2-dlephlthalazin-3(71)-one

Example 72 A

30 (E)-4-((1-Methyl-1 I--imidazol-2-yl)methyleneamino)benzoffiran-1(31)-one

1004751 To a stirred mixture of I -methyl H-imidazole-2-carbaldehyde (2 g, 23munol) and

anhydrous sodium sulfate (26.9 g, 190 mmol) in anhydrous dichloromethane (500 mL) was added 4

aminoisobenzofiran-1(3H)-cne (2.8 g, 19 mmol) at 0 "C. After the addition, the mixture was stirred

at room temperature for 6 days. The mixture was filtered and the cake was washed with

35 dichloromethane (50 mL x3). The filtrate was concentrated to give crude product. The crude product

was washed with petroleum ether to give (E)-4-((ln-ethyl- I Himidazol-2

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yl)methyleneamino)benzofuran-l(3 )-one (5 g, yield 98%) as a white solid. LC-MS (ESI) inz: 242

(M+1)>

Example 72 B

Methyl 2-( I -methyl- H-im idazo 1-2-yi)-4-oxo-3-pheny ,1-1 2,3,4-tetrahydroquinoline-5-carboxylate

5 and ethyl 2-(I -methyl- IH-im idazol -2-yi)-4-oxo-3 -pheny- l,2,3,4-tetrahydroquinoline-5-carboxylate

1004761 A mixture of (E)-4-((1-methyl-IH-inidazol-2-yl)methyleneamino)benzofuran-I(3H)-one

(241 mg, I mmol) and benzaldehyde (116mg, I1.1 mmol) in ethyl propionate (10 mL) was cooled to

O C. Then a solution of sodium methoxide in methanol [sodium (92 mg, 4 mmol) in methanol (5

mL)j was added drop-wise. After the addition, the mixture was stirred at room temperature for 2 hr.

10 The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue

was dissolved in water, and then extracted with ethyl acetate (100 mL:x4). The combined organic

layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a

crude product. The crude product was purified by chromatography (silica gel, petroleum ether / ethyl

acetate = 10:1 to 1:10) to give a mixture of methyl 2-(1-methyl-1 H-imidazol-2-yl)-4-oxo-3-phenyl

15 1,2,3 .4-tetrahydroquinol ine-5 -carboxylate and ethyl 2-(1-methyl-I H-imidazol2-yl)-4-oxo-3~

phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (87 mg yield: 24 %). LC-MS (ESI) i/z: 362

(M+l) 376 (M+1).

Example 72 C

8-(1-Methyl-IH-imidazol-2-yl)-9-pheny-8,9-dihydro-2H-pyrido[4.3 2-de]phthalazin-3(7HJ)-one

20 [004771 A mixture of methyl 2-(l-methyl-1I1-iiidazo-2-yl)-4-oxo-3 -phenyl-1,2,3 ,4

tetrahydroquinoline-5 -carboxylate aid ethyl 2-(I-methyl-I f-imidazol-2-yl)-4-oxo-3-phenyl

1,2,3.4-tetrahydroquinoline-5-carboxylate (87 mg) in 85% hydrazine monohydrate (4 mL) and

methanol (10 mL) was stirred at room temperature for overnight. he mixture was extracted with

ethyl acetate (50 m x3). The combined organic layers were washed with brine, dried over

25 anhydrous sodium sulfate, and concentrated to give the crude. The crude product was purified by

pre-HPEC to give 8-( 1I-methyl- IH-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyri do[4,3,2

de]phthalazin-3(71J)-one (34 mg, yield 42%) as a yellow solid. H-NMR (400 MHz, CD3 OD) 6

(ppm): 3.41 (s, 31-1), 4.49 (d, 1H1), 5.35 (d, IH), 7.18-7.20 (m, 2Ff). 7.26-7.29 (m, 114), 7.33-7.35 (in 3H), 7.40 (d, 1 ) 7.61 (d- 11) 7.71-7.75 (in, 211); LC-MS (ESI) m/z: 344 (M+1)*

30 Example 73

9- 1-Methyl- l1-im idazol-2-y1)-8-pheny8l-S9-dihydro-2U-pyrido[4,3,2-de] phthalazin-3(7H1)-one

Example 73 A

Ethyl 3-( i-methyl- I H-i mid azol-2-yl)-4-oxo-2-phenyl I ,2 ,3,4-tetrahydroquinoline-5-carboxylate

1004781 A mixture of (E)-4-(benzylideneamino)isobenzofuran~ I(3H-one (500 mg, 2.1 mmol) and

35 1-methyl-H J-imidazole-2- carbaldehvde (255 ig, 2.3 inmol) in ethyl propionate (20 mL) was

cooled to 0 C. Then a solution of sodium ethoxide in ethanol [sodium (194 mg 8.4 minol) in

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ethanol (10 nL)] was added drop-wise. After the addition, the mixture was stirred at room

temperature for 2.5 hr. The mixture was quenched with water (20 mL) and solvent was removed in

vacuum. The residue was dissolved in water, and filtered; the cake was washed by water, then ethyl

acetate to obtain ethyl 3-( -methvl-1H-imidazul-2-yl)-4-oxo-2-phenyl- V2,3 ,4-tetrahydroquinoline

5 5-carboxylate as a yellow solid. The solid was dried in vacuum at 50 'C (140 mg, yield 18%). I

NMR (400 MIHz, DMSO-d6) b (ppm): 1.18-1.21 (t,J= 7.2 Hz, 3H), 3.31 (s, 31-1), 4 16-4 19 (in, 2H),

4.56-4.59 (d., J= 13.2 liz, 111), 5.14-5.17 (d. = 13.2 Hz, 1H), 6.54-6.56 (dI. J= 7.2 Hz, 111), 6.72

(s, 111), 6.86 (s, 111), 6.98-6.99 (d, J= 4.8 Hz, I H), 7.24-7.29 (in, 3H), 7.34-7.38 (t., = 8.0 Hz, 11-),

7.42-7.44 (d, 1= 7.2 Hz. 2-H)r 7.49 (s, 111); LC-MS (ES!) n/z: 376 (M+1)

10 Example 73 B

9-(I-Methyl- IH-imidazol-2-vl)-8-phenvl-89-dihydro-21-pyrido4,3,2-delphthalazin-3(7H)-one

1004791 A mixture of ethyl 3-(1-methyl -imidazoi-2-yl-4-oxo-2-phenyl-1,2,3.4

tetrahvdroqu iioliie-5-carboxylate (140 mg) in 85% hydrazine monaohydrate (3 ml) and methanol (5

mL) was stirred at room temperature for 2 days. The resulting mixture was filtered and the residue

15 was washed with water (20 niL) and methanol (5 ml) to obtain a white solid. The solid was dried in

vacuum at 50 "C to obtain 9-(1-nethyl-iH-imidazol-2-vl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3.2

de]phthalazin-3 (7)f1-one (95 mg, yield 74%). 'H-NMR (400 MzI-l, DMSO-d4) 6 (ppm): 3.40 (s, 3H), 4.64-4.67 (d,J= 10.8 Hz, 11H), 4.92-4,94 (d,. J= 10.4 Hz, 111), 6.72 (sYBH), 6.87 (s.IH), 7.15

7.17 (d, J= 8.4 Hz, 21-), 7.26-7.30 (in 31H), 7.38 (s, 31). 7.55-7.59 (i. J= 7.6 z, 1H), 12.15 (s,

20 1 H); L-MS (ESI) rn/z: 344 (M-1)

Example 74

8,9-Bis( 1I-methyl- I 11-imidazol-2-yl) -8,9-dihydro-2H-pyrido[4,3 2-cdc]phthalazin-3(71-)-one

Example 74 A

Ethyl 2,3-bis(l -methyl-I1-H-i midazol-2-yl)-4-oxo- I,2,3,4-tetrahydroq uinoline-5 -carboxylate

25 100480J A mixture of 4-aminoisobenzofuran-1(31H)-one (298 mng, 2 mmoi) and 1-methyl-H

imidazole-2- carbaldehyde (440 ng 4 mnmol) in ethyl propionate (20 mL) was cooled to 0 "C Then

a solution of sodium ethoxide in ethanol [sodium (184 ng, 8 imol) in ethanol (10 mL)] was added

drop-wise, After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was

quenched with water (10 mL) and solvent was removed in vacuum, The residue was dissolved in

30 water, and then extracted with ethyl acetate (100 mLx4). The combined organic layers were washed

with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product The crude

product was purified by chromatography (silica geL petroleum ether / ethyl acetate = 5:1 to I, ethyl

acetate: -methanol=50:1 to 25:1 ammonia hydrate I mL) to give ethyl 2,3-bis(1-methyl

iiidazol-2-y4)-4-oxo-1,2 3,4-tetrahy droquinoline-5-carboxylate (120 mg, yield 16%). LC-MS (ES!)

35 n/z: 380 (M+1)

Example 74 B

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8,9-bis( 1-methyl-14H-nimidazol-2-yl) -8,9-dihydro-2H-pyrido[4,32-dephthaiazin3(7H)-one

[004811 A mixture of ethyl 2 3 -bis(1 -methyl- -i imidazol-2-yl)-4-oxo- I,2,3 4-tetrahydroquinoline

5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 rn) and methanol (3 mL) was stirred at

room temperature for 3 ,5 h. Evaporated the solvent and methanol (1 mL) was added, filtered and

5 washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50 C

to obtain 8,9-bis( -methylI Him idazoi-2-yI) 8.9-dihydro-2H-pyrido[4,3 ,2-de]phthalazin-3(7H)

one (45 ing, yield 41%). 'H-NMR (400 MHz, CD(OD) a (ppm): 3.46 (s, 3H). 3.49 (a, 311), 4.78

4.81 (d, J=: 12.0 Hz, 11-1), 5.08-5.11 (d, J = 12.0 Hz, 1H), 6.69 (s, ll), 6.76-6.79 (in, 3J), 6.99-7.02

(d,J= 7.6 Hz, 1H1) 7 42-7.49 (m, 21-1); LC-MS (ESI) m/z: 348 (M+l).

10 Example 75

9-(1 -limidazol-2-yl) -8-phenyl-8,9-dihydro-2H-pyrido[43 ,2-de]phthalazin-3(711)-one

Example 75 A

9-(l -Benzyl- I H-inidazol-2-yl) -8-phenyl-8,9 -dihydro-2H-pyrido[4,3 2-de]phthalazin-3(711)-one

1004821 Methyl 3-(1-benzy l- -imidazol-2-yl)-4-oxo-2-phenyi-I,2,3,4-tetrahydroquinoline-5

15 carboxylate (3.7 g, 8.46 mmol) in hydrazine monohydrate (25 mL) and methanol (100 mL) was

stirred at room temperature for 5 h. The resulting mixture was filtered to give 9-(1-benzyl-iH

imidazol-2-yl) -8-phenyl-8,9-dihydro-211-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid

(950 mg, yield 27%).AH-NMR (400 MHz, DMSO-d6) 6 (ppm) 4,61-4.64 (d,J= 11.2 Hz ,H),

4.99-5.12 (m. l H) 6.83-6.89 (m, 4H),7. 14-7.28 (m, I 1 H, 7.36-7.38 (d,.J = 7.6 Hz. I H), 7.54-7.58 20 (t,.J= 8.0 Hz, 71-1), 12.20 (s, IH). LC-MS (ESI) m/z: 420 (M+-1J)

Example 75 B

9-( 1Himidazol-2-yl) -8-phenyl-8,9-dihyd.ro-211-pyrido[4,3 ,2-de]phthalazin-3(7H)-one

[043 A mixture of 9-(1I-benzy 1-1U-imidazol-2..yl) -8-phenyl-8,9-dihydro~2H-pyrido[4,32

de]phthalazin-3(71I)-one (200 mg, 0.48 mmol), 20% Pd(OH)JC catalyst (100mg) in methanol (15

25 mL) was purged with I atn hydrogen and stirred at 40 0C over overnight. Then the mixture solution

was filtered and the filtrate was evaporated under reduced pressure. The residue was washed with

methanol to obtain 9-( 1 1-imidazol-2-yl) -8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-deJphthaiazin

3(71)-one as a light yellow solid (114 mg. yield 72%). 'H-NMR (400 MHz, DMSO-d6) a: 4.41

4.43 (dJ= 8.0 Hz,1H). 4.98-5.00 (d, J= 8.8 Hz, IH), 6.68-6,73 (in, 1H);6,86-6.97 (in, 1H). 7. 12

30 7.14 (d J -: 8.0 Hz, 1 H). 7,20-7.37 (m, 711), 7.54-7.58 (t, J= 8.0 Hz, IH), I 1,7 (s, 1H), 12.19 (s, 1H) LC-MS (ESI) m/z- 330 (M+It.

Example 76

9-(0Ethyl 1H-imidazoi2-yl) -8-plicnyil-8,9-dihydro-2l-pyrido[4,3 ,2-dejphthalazin-3(711)-one

Example 76 A

35 1 -Ethyl- 1H-Iimidazole-2- earbaldehyde

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WO 2010/017055 PCT/US2009/051879

1004841 To a suspension of I-imidazole-2-carbaldehyde (480 ng, 5 mno) and potassium

carbonate (936 mg, 6 mmol) in N. N-dimethylformamide (7 mL) was added iodoethane (829 mg,

6mmol) and the mixture was heated at 50 "C for 5 hrs. Solvent was removed under reduced pressure.

The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous layer

5 was extracted with ethyl acetate (20 niLx3). The combined organic layers were washed with brine,

dried over anhydrous sodium sulfate, and concentrated to give I-ethyl-1H-imidazole-2

carbaldehyde as light yellow oil (520 mug, yield 84%). 'HNMR (400 MHz., CDCI3 ) 5 (ppm): 1.42

1,46 (t, J= 7,2 Hz, 311), 4.42-4.47 (q, 2H), 7.19 (s, 1H3), 7.29 (s, 1M), 9.82 (s, 1H). LC-MS (ESI)

m/z: 125 (M+i)f

10 Example 76 B

Methyl 3-(I-ethyl-I H-imidazol-2-yl)-4-oxo-2-phenyl- 1,2 ,3.4-tetraldroquinoliine-5-carboxylate

[004851 To 1-ethyl-I H-imidazole-2- carbaldehyde (520 mg 4.19 mmol), (E)-4-(benzylideneamino)

isobenzofuran-1(3H)-one (994 mg, 4.19 mmol), sodium methanolate (385 mg, 16.8 mmol) and ethyl

propionate (15 nL) were added and the mixture was stirred at room temperature overnight. Then the

15 resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100

mLx4) and concentrated, Tihe crude product was purified by column chromatography (silica gel. petroleum ether/ethyl acetate= 20: 1 to 5:1), 190 mg of methyl 3-(1 -ethyl-1i-imidazol-2-yl)-4-oxo

2-phenyl-1,2,3,4-tetrahydroquinoline-5-earboxylate was obtained. LCIMS (ESI m/z: 390 (M+).

Example 76 C

20 9-(1 -Ethyl- I m-imidazol-2-yl) -8-phenyl-8,9-dihydro-2fl-pyridof4, 3 ,2-dejphthalazin-3(7H)-one

1004861 Methyl 3-(] -ethyl-I ii-imidazol-2-yl)-4-oxo-2-phenyl- 1,2,3,4-tetrahydroquinoline-5

carboxylate (190 mg. 0.49 inmol) and hydrazine monohydrate (2 mL) were added to methanol (1 5 mL) and the mixture was stirred room temperature for 3 hrs. Methanol was evaporated and then

filtered. The filtrate was concentrated to give 9-(] -ethyl- i H-i midazol-2-yl) -8-phenyl-8,9-dihydro

25 2H-pyrido[4,3,2-dejphthalazin-3(7H)-one as a white solid (50 mg, yield 28%). H.I NMR (400 MHz,

DMSO-d6) 5 (ppm); 0,96 (t, 31), 3.74-3;79 (m, 211), 4.61(d, I H) 4.95(d, I H), 6.78(dd I H), 6.91 (dd, i). 7.16 (d, 11) 7,23-7.31 (m,4H), 737 (s, 3H). 7.57(t, 1H). 1C-MS (ESI) mI/z 358 (M+1)'.

Example 77

8-PhenyI-9-(I propyl-1-imidazol-2-yi) -8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

30 Example 77 A

1 -propyl- I H-im idazole-2- carbaldehyde

1004871 iH-imidazole-2- carbaldehyde (800 mg, 8.3 mmol), I-iodopropane (1.7 g, 10 nimol) and

potassimn carbonate (1.4 g) were added in DMF (30 nL) and the mixture was heated to 50 T overnight. Then the mixture was evaporated under reduced pressure, and extracted with ethyl acetate

35 (100 mLx4). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to give 1-propyl-lif-iimidazole-2- carbaldehyde (1.1 g). LC-MS (ESI) m/z 139 (M-1).

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WO 2010/017055 PCT/US2009/051879

Example 77 B

Ethyl 4-oxo-2-phenyl-3-(I-propyl- i11-irnidazol -2-yl)-1,2A.3.4-tetrahydroquinoline-5-carboxylate

1004881 To the mixture of I -propyl-1H-imidazole-2- carbaldehyde (1 1 g, 8.0 mmol) and (ES)-4

(benzlideneamino) isobenzofuran- 1(3)-one (L7 g, 7.2 mmol) were added in ethyl propionate (50

5 mL)and then sodium methoxide was added under 0 ". The mixture was stirred overnight at room

temperature, The mixture was concentrated and the residue was extracted with ethyl acetate (100

mLx4). The organic layer dried over anhydrous sodium sulfate, purified by chromatography (silica

gelpetroleum ether / ethyl acetate = 10 :1 to 1:1) to give ethyl 4-oxo-2-phenyl-3-(I-propyl-1H

imidazol-2-yl)-1,2,3 ,4-tetrahydroquinoline-5-carboxylate (770 mg, yield 30%). LC-MS (ESI) mlz:

10 404 (M+1).

Example 77 C

8-Phenyl-9-(I -propyl- 1H-imidazol-2-yl) -8,9-dihvdro-211-pyrido[4,3,2-de phthalazin-3 (71H)-one

1004891 A suspension of ethyl 4-oxo-2-pheny-341 -propyl- I U1-imidazoi-2-yI)-1;2,3,4

tetrahydroquinoline-5-carboxylate (770 ing, 1 .9 mmol) and hydrazine monohydrate (6 ml.. 85%) 5 were added in methanol (10 mL) and stirred at 50 C overnight. The mixture was filtered, and the

white solid was washed with methanol and dried in vacuum to obtain 8-phenyl-9-(1 -propyl- 1I

imidazol-2-yl) -8,9-dihydro-2H-pyido[4,3,2-delphthalazin-3(7h)-one (260 mg, yield 37%). 'I

NMR (400 MHz, DMSO-d6) 6 (ppm): 0.59462 (t,J= 7.4 Hz, IfH), 1.23-1.40 (m, 2H), 3 62-3,72 (m, 2H), 4.58-4.61 (d,,J= 1 2Hz, IH) 4.97-4.9 (d,.J= 11.2 H z, IH). 6.79 (s, 1H), 6.89 (s, 1H4)

20 7.16-7,59 (m. 8H),12.15 (s, Ill); LC-MS (ESI) m/z: 372 (M+1)*.

Example 78

9-(I-Methyl~1-Il-imidazoi-5-yl) -8-phenyl -8,9-dihdro-2H-pyrido[4,3,2-d ejphthalazin-3 (7H1)-one

Example 78 A

Ethyl 3-(1-methyl-lIH-im idazol-5-y)- 4-oxo-2-phenyl- l,2,3,4-tetrahydroquinoli ne-5-carboxylate 25 1004901 A i ixture of (E-4-(benzylideneamnino) isobenzofuran-l(31l)-one (474 ing 2 mmol) and 1

methyl- .I-imidazole-5- carbaldehyde (220 mg, 2 mmol) in ethyl propionate (20 mlL) was cooled to

0 C. Then a solution of sodium ethoxide in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 mL)]

was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hr. The

mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was

30 dissolved in water, and then extracted with ethyl acetate (100 mLx4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude


acetate = 5:1 to 3:7) to give ethyl 3-(I-methyl-l H-imidazol-5-yl)- 4-oxo-2-phenyl- 12,34~ tetrai.ydroquinoline-5-carboxylate (170 mg, yield 23%). LC-MS (ESI) m/z: 376 (M+) I

35 Exanple 78 B

9-( 1-Methyl- 1H-imidazol-5-yl) -8-phenyl-8.9~dihydro-21J-pyrido[4,3,.2-deiphthalazin-3(713)-one

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WO 2010/017055 PCT/US2009/051879

[004911 A mixture of ethyl 3-( 1-methyl-I H-imidazol-5-vl)- 4-oxo-2-phenyl- 1,23,4

tetrahydroquinoline-5-carboxylate (170 tg) in 85% hydrazine monohydrate (3 mL) and methanol (3

m1L) was stirred at room temperature for 5 h. Filtered and washed the cake by methanol (2 mL) to

obtain a white solid. The solid was dried in vacuum at 50 C to obtain 9-(methyi-IH-irnidazoi-5~

5 yl) -8-phenyl-8,9-dihydro-2 H-pyrido[4/3,2-dejphthalazin-3(7H1)-one (70 mg. yield 46%). 'H-NMR

(400 MHz, DMSO-d6) 6 (ppm): 350 (s, 3H), 452-4.54 (d, J= 9.2 Hz, 11H1), 4.83-4.85 (d, J 9.2

Hz, 114), 6.66 (s, 114) 7.17-7.19 (d, J= 7.6 Hz, 111). 7.25-732 (in., 311). 7.36-7.44 (i, 514), 7.56

7.60 (t,J= 8.0 Hz,. IIH); LC-MS (ESI) m/z: 348 (M+1)

Example 79

10 9-(3-((Diethylamino)methyl)phenyl)-8-(4-((diethylaniino)methyl)phenvl)-8,9-dihvdro 21

pyrido[43 ,2-dejphthalazin-3(7H)-one

1004921 A mixture of 4,4' -(3-oxo-3 ,7,8.9-tetrahydro-2H-pvrido(4,3 .2-dejphthalazin-8,9

diyl)dibenzaldehyde (200 mng, 0.5 imol) and diethylamine (146 mg. 2.0 imol) in methanol (10

ml,) was stirred at room temperature for 40 min. Then the mixture was cooled to 0 'C. Sodium

15 borohydride (56 mg, 1.5 nmol) was added. After the addition, the mixture was stirred at room

temperature for 2 hr. Methanol was removed Under reduced pressure. The residue was washed with

ethyl acetate and filtered, The filtrate was concentrated to give the crude product. The crude product

was purified by prep-HPLC to give 943-(diethylamino)methyl)phenyl)-8-(4

((diet-hyilanino)methvl)phenyl )-8,9-dihvdro-2H-pyrido[4;3,2-de]phthalazin-3(711)-one as a white

20 solid (76 mg, yield 29%). tI-NMR (400 MHz, CD-OD) 6 (ppm): 1.28-1.33 (n, 1211), 3.13 -3.19 (m,

81), 4.27 (s, 4H). 4.40-442 (d, J= 7.6 Hz, 11-1), 4.84-4.86 (d, J= 7.6 lz, 114), 7.22-7.27 (m, 311),

7.38-7.41 (in, 6H), 7.56-7.65 (i, 2H); LC-MS (ESI) mn/z: 510 (M-1).

Example 80

9-(3-((4-Methylpiperazin-1 - yl) methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2

25 de]phthalazin-3(7H-one

[004931 To a stirred solution of 3-(3-oxo-8-pheny 1-3,7, 8,9-tetrahydro-2H-pyrido[4,3,2

de]phthalazin-9-yl)benzaldehyde (150 ing, 0.4 mmiol) in dryness dichloromethane (10 nil.) was

added acetic acid followed by I -methylpiperazine (121 ig, 1.2 mmol). After the addition, the

mixture was stirred at room temperature for I b ; Then the mixture was cooled to 0 '. Sodium

30 borohydride (130 mg, 0.2 mmol) was added. After the addition, the mixture was stirred at this

temperature for 3 hr. Dichioromethane was removed under reduced pressure. The residue was

washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the

crude product. The crude product was purified by pre-HPLC to give 9-(3-((4-inethylpiperazin- 1- yl)

methyl)phenvl)-8-phenyl -8,9-dihydro-2H-pyrido[43,2-delphthalazin-3(7H)-one as white solid (22

35 ng. yield 12%). 'H-NMR (400 MHz, CDOD) 6 (ppni): 2.31 (s, 31), 2.36-2.48 (m1, 8H), 3.37-3,48

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WO 2010/017055 PCT/US2009/051879

(dd., 211), 4.30 (dd, 1H), 4.71 (dd, 1N), 7.01 (s, 1I), 7.05 (dd, 11H)1 7.17-7.23 (m, 5H) 7.25-7.28 (in,

2H), 7.56 (dd. 1H), 7.61"7.65 (t, 1II); LC-MS (ESI) m/z: 452(M+i).

Example 81

8-(4-(4-(Cyclopropanecarbonyl) piperazine-1-carbonyl)phenvl)-9-phenvl-8,9-dihydro-2H

5 pyrido[4,3,2-de]phthalazin-3(7H)-one

Example 81 A

Methyl 2-(4-(4-(cyclopropanecarbonyl) piperazine-1 -carbonyl)phenyl) -4-oxo-3-phenyl- 1,2,3,4

tetrahydroquinoline-5-carboxy late

004941 4-Aminoisobenzofuran-1(311)-one (372.5 mg 2.5 mmol), 4-(4-(cyclopropanecarbonyl)

10 piperazine-i-carbonyl) benzaldehyde (645 mg. 2.5 miol) and 1 g ofMgSO4 were added into 40

mL of dichloromethane and stirred under reflux overnight, then the mixture was evaporated under

reduced pressure and the residues was dried in vacuum. 385 mg of (E)-4-(4-(4

(cyclopropanecarbonyl) piperazine-1-carbonyl)benzvlideneamino)isobenzofuran- 1 (3H)-one . A

mixture of (E)-4-(4-(4-(cyclopropanecarbonyI) piperazine-1

15 carbonyl)benzylideneamino~isobenzofuran-1(31)-one (385 mng, 0.92 mnol)., benzaldehyde (97.9

mg, 0.97 mmol). sodium methanolate (199 rmg, 3.68 mmol) and ethyl propionate (10 mL) was

stirred at room temperature overnight. Then the resulting n ixture was evaporated under reduced

pressure and extracted with ethyl acetate (100 mL x 4) and concentrated. The crude product was

purified by column chromatography (silica gel, petroleum ether: ethyl acetate 20:1 to 5:1) to give

20 300 mg of methyl 2-(4-(4-(cyclopropanecarbonyl) piperazine- 1 -carbonyl)phenyl) -4-oxo-3 -phenyl

1,2,3,4-tetrahvdroquinoiine-5-carboxylate. LC-MS (ESI) m/z: 538 (M+1)

Example 81 B

8-(4-(4-(Cyclopropanecarbonyl) piperazine- I -carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H

pyrido[43,2-delphthaiazin-3(7H)-one

25 [004951 A mixture of methyl 2-(4-(4-(cyclopropanecarbonyl) piperazine-I-earbo.nylphenyl) -4

oxo-3-phenyl-1,2,34-tetrahydroquinoline-5-carboxylate (300 mg, 0.55 mmol) and hydrazine

monohydrate (3 mL) was stirred room temperature for 3 h. The resulting mixture was evaporated

under reduced pressure to 10 mL and then filtered; the filtrate was concentrated to give the crude

product. The crude product was purified by pre-HPLC to give 8-(4(-4-(cyclopropanecarbonvl)

30 piperazine- I -carbonyl)phenyl)-9-phenyl-8,9-dihy dro-2H-pyrido(4,3,2-de]phtha lazin-3(7H)-one as a

white solid (4 mg, yield 19%), 'H-NMR (400 MHz, DMSO-d6) 6 (ppm); 0.71-0.74 (n, 4H), 1.97 (t, 1 ), 3.46-3.76 (i. 811), 4.36 (dd, 1H) 4.83 (dd, H), 7,13-7,23 (n, 6H), 7.30 (d. 211), 7.38 (t, 31-1), 7,47 (s, 1. H) 7.59 (t, IH), 12.17 (s I H): LC-MS (EST) m/z: 520(M4)1.

Example 82

35 9-Phenyl-8-(pyridin-4-vl)-8,9-dihydro-2H-pyrido(4,3,2-de phthalazin-3(7H)-one

Example 82 A

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Ethyl 4-oxo-3-phenyl-2-(pyridin-4-yl)-1,2,3.4-tetrahydroquinoline-5-carboxylate

1004961 A mixture of (E)-4-(pyridin-4-ylmethyleneamino) isobenzofuran-1(3H)-one ( L71 g, 7,18

mol) and benzaldehyde (837 mg, 7.9 nmol) in ethyl propionate (50 miL) was cooled to 0 "C. Then

a solution of sodium ethoxide in ethanol Isodium (660 mg, 28.7 irmol) in ethanol (35 inL)] was

5 added drop-wise. After the addition, the mixture was stirred at room temperature for 2 hr. The

mixture was quenched with water (20 mL) and solvent was removed in vacuum, The residue was

dissolved in water, and then extracted with ethyl acetate (150 mLx4). The combined organic layers

were washed with brine. dried over anhydrous sodium sulfate, and concentrated to give crude

product The crude product was purified by chromatography (silica gel, petroleum ether / ethyl

10 acetate = 5:1 to 1:1) to give ethyl 4-oxo-3-phenyl-2-(pyridin-4-y1)-1,2,3,4-tetrahydroquinoiine-5

carboxylate (340 mg, yield 13 %), LC-MS (ESI) n/z: 373 (M+1).

Example 82 B

9-Phenyl-8-(pyridin-4-yl)-8,9-dihydro-2J!-pyrido[4,3;.2-de]phthalazin-3(7H)-one

[004971 A mixture of ethyl 4-oxo-3-phenyl-2-(pyridin-4-yl)- ,2.3,4-tetrahydroquinoline-5

15 carboxylate (340 mg) in 85% hydrazine ionohydrate (6 rnL) and methanol (3 mL) was stirred at

room temperature for 2 h. After the evaporation of the solvent, water was added. Filtered and

washed the cake by water (5 mIL) then ethyl acetate to obtain a white solid. The solid was dried in

vacuum at 50 TC to obtain 9-phenyl8-(pyridin-4-vl)-8,9-dihydro-2H-pyrido 43,3 2-de] phthalazia

3(711)-one (150 mg, yield: 48 %). tH-NMR (400 MHz, DMSO-d6) 3 (ppm): 4.38-440(d. J = 7.6

20 liz, 111), 4.84-7.86 (d, J= 8.0 Hz, 1IH). 7.15-7.25 (m, 6Ff), 7.30-7.31 (m, 2H), 7.39-7.41 (d., J= 7.6

Hz, H), 7.51-7.52 (s, 111), 7.59-7.62 (tJ= 8.0 Hz, 11H), 8,43-8,44 (d J= 6.0 Hz 2H) 12.19 (s, 11); LC-MS (ESI) n/z: 341 (M+1).

Example 83

9-Phenyl -8-(pipcridin-4-yl)-8.9-dihydro-2HJI-pyrido[4,3.2-de]phthalazin-3(7H)-one

25 1004981 The mixture of 9-phenyl-8-(pyridin-4-vl)-8,9-dihydro-2H-pyrido[4,3,2-dc ]phthalazin

3(711)-one (150 mg, 0.4 inmol), con.-HC (0.6 mL) and Platinum (IV) oxide monohydrate (40 mg) in

methanol (30 mL) was purged with 50 atm of hydrogen at 50 "C for 18 h. Then the mixture was

filtered. The solvent was removed in vacuum to obtain a crude oil which was purified by prep

HPLC to give 9-phenyl-8-(piperidin-4-yl)-8,9-dihydro-2H-pyrido[43,2-de]phthalazin-3(7H)-one

30 (95 mg, yield 62%). 'H-NMR (400 MHz, DMSO-d6) 6 (ppm): 1.24-1 41 (m, 111). 1 49-1.59 (n,

1H), 1 69-1.78(m., 211), 1 98-2.01 (d. Jzz 13.2 Hz, 1-l), 2.67-2.86 (m, 211), 3.22-331 (m, 31),4,18

(s, 11), 7.05-7.08 (in, 311), 714-7.21 (m, 2H) 7.24-7.28 (m, 211), 7.31-7.33 (d, = 7.2 Hz, 1H).

7.52-7.56 (t, J= 8.0 Hz, 1H), 8.19-8.24 (n 1H1.). 8.54-8.56 (m, IN), 12.30 (s, 1 H); LC-MS (m/z) 347 (M+1).

35 Example 84

9-Phenyl-8-(pyridin-2-y)-8,9-dihydro-211-pyrido[4,3;2-de]iphthalazin-3(714)-one

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WO 2010/017055 PCT/US2009/051879

Example 84 A

Methyl 4-oxo-3 -phenyl-2-(pyridin-2-yl)- 1,2,3.4-tetrahydroquinoline-5-carboxylate

[004991 4-Aminoisobenzofiran-l(31f)-one (600 mg, 4 mmol.), picolinaldehyde (856 mg, 8 mmol)

and 1 g of MgSO 4 were added into 40 mail of dichloromethane and the mixture was stirred under

5 reflux overnight, then the mixture was evaporated under reduced pressure and the residues was dried

in vacuum. 476 rmg of (E)-4-(pyridin-2-vlmethyleneamino) isobenzoturan- I (31-)-one was obtained.

A mixture of (E)-4-(pyridirt-2-yimnethyleneamino) isobenzofuran-1(3/1)-one (476mg, 2 mmol),

benzaldehyde (212 mg, 2 mmol). sodium methanolate (432 mg 8 mmol) and ethyl propionate (40

mL) was stirred at room temperature overnight. Then the resulting mixture was evaporated under

10 reduced pressure and extracted with ethyl acetate (100 ml x 4) and concentrated. The crude product

was purified by column chromatography (silica gel, petroleum ether: ethyl acetate 20:1 to 5:1) to

give 30 ing of methyl 4-oxo-3-phenyl-2-(pyridin-2-yl )- 1,2 3 4-tetrahydroquinoline-5 -carboxylate;

yield 5%. LC-MS (ESI) m/z: 459 (Md)

Example 84 B

15 9-Phenyl-8-(pyridin-2-yi)-8,9-dihydro-2H-pyrido[4.3,2-de]phthalazin-3(719)-one

1005001 A mixture of methyl 4-oxo-3-phenyl-2-{pvridin- 2-yl)-1 ,3,4-tetrahy droquinoline-5

carboxylate (30 mg, 0.08 mmol) and hydrazine monohydrate (I mL) was stirred at room temperature

for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered, 10

mg of 9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[43.2-delphthalazin-3(7f)-ine was

20 obtained, yield 37%. 'H-NMR (400 MHz, CDCI3 ) 6 (ppm): 4.60 (d, 11). 4.86-4.88 (mil 5.21 (s' S11), 6.96 (dd, 11), 7,08-7.17 (in. 41), 7.22-7.28 (m, 311), 7.46-7.49 (m, 1H.) 7.60 (t, I1H), 7.73 (dd.

11H) 8.59 (d, 1H) 9.77(sIH); LC-MS (ESI) m/z: 341 (M+1).

Example 85

8-(4-((4-Methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-211-pyrido[43-2

25 de]phthadazin-3(7/1)-one

[005011 A mixture of 4-(3 -oxo-9-phenyl-3 ,7,8,9-tetrahydro-2H-pyrido[4,3,2-dejphthalazin-8

yl)benzaldehyde (150 mg, 0.4 mmol), -methyl-piperazine (123 mg, 1.2 mmol) and acetic acid (120

mg 1.2 imol) in methanol (50 mL) was stored at room temperature for 60 min. Then. the mixture

was cooled to 0 C. Sodium triacetoxyborohydride (130 mg, 0.6 mmol) was added. After the

30 addition, the mixture was stirred at room temperature for overnight. Methanol was removed under

reduced pressure. The crude product was purified by pre-HPLC to give 8-(4-((4-methylpiperazin- 1

yl)methyl)phenvl)-9-phenyl -8,9-d ihydro-2H-pyrido[43 3,2-de]phthalazin-3(71}-one (36 rmg, yield

19%). H-NMR (400 MHz, CDOD) 5 (ppm): 2.29 (s, 3-R), 2.12-2.73 (br s, 8H), 3.47 (s, 211), 4.30

(d,,J= 8.0 Hz, IH), 4.74 (d.sJ 8.0 liz, 11Il 7)08-7,10 (m, 2H), 7. 18-7.21 (m, 6 H), 7.23-7.25 (

35 211), 7.55-7.57 (d, J 8.0 Hz, 1 H); 7,62-7.64 (in, IH) . LC-MS (ESI) i/z; 452 (M+-)

Example 86

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WO 2010/017055 PCT/US2009/051879

8,9-Bis(4-fluorophenyl)- 8,9-dihydro-211-pyrido{4,3,2-delphthalazin-3(7J)-one

Example 86 A

Methyl 2-(4-(dimrethoxymethyl)phetiyl)-3~(44luorophenyl)-4-oxo- 1,2,3 4-tetrahydroquinoline-5

carboxylate, ethyl 2-(4-(dimethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-I ,2,3, 4

5 tetrahydroquinoline-5-carboxylate and methyl 2,3-bis-(4 -fluorophenyl)-4-oxo- 1 (,2,3,4

tctrahydroqui noline-5-carboxylate

[005021 A mixture of (E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran- I (3H),-one (1 36

g, 4 tmol), 4fluorobenzaidehyde (546 mg, 44 mmol). sodium methanolate (864 mg, 16 mmol) and

ethyl propionate(25 ml) was stirred at room temperature overnight. Then the resulting mixture was

10 evaporated under reduced pressure and extracted with ethyl acetate (100 mL x 4) and concentrated.

The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate

=20:1 to 1:1) to give 440 mg of a mixture of methyl 2-(4-(dimethoxymethl)phenyl)-3-(4

fluorophenyl)-4-oxo- 1,2,3,4-tetrahydroquinoline-5-carboxylate, ethyl 2-(4

(dimethoxnmethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxvlate and

15 methyl 2,3-bis-(4 -fluorophenyl)-4-oxo- I,2,3,4-tetrahydroquinoline-5-carboxylate.

Example 86 B

8,9-Bis(4-florophenyl)- 8,9-dihydro-2H-Bpyrido[4.3,2-de]phthalazin-3(7H)-one

1005031 A mixture of methyl 2-(4-(dimethoxymethyl)phenyl)-3-(4-fliorophenyl)-4-oxo- 1.2,3,4

tetrahydroquinoline-5-carboxylate, ethyl 2 -(4-(dimeithoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo

20 1,2.3,4-tetrahvdroquinoline-5-carboxylate and methyl 2,3-bis(4 -fluoropheny)-4-oxo-l,234

tetrahvdroqu inoline-5-carboxylate (440 mg) and hydrazine mionohydrate (20 mL) was stirred under

room temperature for overnight. The resulting mixture was evaporated under reduced pressure to 10

nL and then filtered, 400 mg of the crude products were obtained. To a solution of this crude

products (400 mg) in dichloromethane was added trifluoroacetic acid (Iml) at 0"C. The mixture was

25 stirred at room temperature for 1 hr. Then the mixture was neutralized with potassium carbonate.

The mixture was extracted with ethyl acetate (50 mL x3). The combined organic layers were washed

with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude. The crude

product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate 10:1 to

1:1) to give 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetraliydro-2H-pyrido[4,3 .2-de]phthalazin-8

30 yl)benzaldehyde (80 mg) and 8,9-bis(4-fluorophenyl)- 8,9-dihydro-21-I-pyrido[4,3,2-de]phthalazin

3(7.JfHyone (36mg). 4-(9-(4-fl uorophenty)-3-oxo-3.7,8,9-tetrahydro-2H-pyrido[4,3,2-de]ph.thalazin

8-yl)benzaldehyde: LC-MS (ESI) m/z: 368 (M+1) . 8,9-bis(4-fluorophenyl)- 8,9-dihydro-2H

pyrido[4,3.2-dejphthalazin-3(7H)-one: 'H-NMR (400 MHz, CD3OD) 6 (ppm); 4.29 (d, J= 8.0 14, 1H), 4,70 (d,. I= 8.0 -z, 1H) 6.92-7.00 (m, 4H), 7.08-7.10 (m, 211), 7.20-7.20 (i, IH), 7.28-732

35 (m 211). 7.59 (in, IH), 7.63-7.67 (i, I H). "F-NMR (400 MHz, CDOD) S (ppm): -116.77, -118.23; LC-MS (ESI) m/z: 376 (M+f-I. solid.

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Example 87

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)- 8,9-dihydro-211-pyrido[4;3,2

de]phthalazin-3(7)-one

1005041 A mixture of 4-(9-(4-fluorophenyl)-3 -oxo-3.7,8,9-tetrahydro-2H-pyrido[4,3,2

5 de]phthalazin-8-y)benzaldehyde (80 mg, 0,21 mmol), dimethlyaniine (47 mg, 1 04 mmol) and

acetic acid (62 mg, 1.04 mmol) in methanol (50 mL) was stirred at room temperature for 60 min,

Then the mixture was cooled to 0 'C. Sodium cyanoborohydride (20 mg, 0.3 munol) was added.

After the addition, the mixture was stirred at room temperature for overnight. Methanol was

removed under reduced pressure, The crude product was purified by pre-HJPLC to give 8-(4

10 ((diiethylamino)methyl)phenyl)-9-(4-fluorophenyl)- 8,9-di hydro-2-pyrido[4;3,2-delphthalazin

3(7)-one (21 mg, yield 24%). H-NMR (400 MHz, CD 3OD) 6 (ppm): 2.82 (s, 6H), 4.26(s, 2H),

4.32 (d, J= 8.0 Hz, [H). 4.77 (dJ= 8.0 Hz, 1i1), 6.93-6,95 (m. 211), 7.10-7.11 (m, 2 Hl). 7.23 (in,

I H), 7.40-7.41 (in. 4H.), 7.59 (d, ,= 8.0 H1z, 1H-), 7,65(t, J= 8.0 Hz., 1 H), F-NMR (400 MHz,

CD;OD) 6 (ppm): -77.09, -118.00; LC-MS (ESI) m/z: 415 (Mj.1)

15 Example 88

8-(4-Fluorophenyl)-9-( 1 -methyl-1.!- imidazol-2-yl)- 8,9-dihydro-211-pyridof4 3,2-del phthalazin

3(7h)-one

Example 88 A

Ethyl 2-(4-fiuorophenyl)-3-(i-methyl-i H- imidazol-2-yl)-4-oxo-1,2,3.4-tetrahydroquinoline-S

20 carboxylate

1005051 To a stirred mixture of 4-fluorobenzaldehyde (3 g, 20.4 mnol) and anhydrous sodium

sulfate (29 g, 20.4 mmol) in anhydrous dichloromethane (200 mL) was added 4

ainoisobenzofurani1(311)-one (3.04 g, 24.5 iniol) at 0 C. After the additions the mixture was


25 dichloromethane (50 niLx3). The filtrate was concentrated to give crude product. The crude product

was washed with petroleum ether to give (Eb-4~(4-lurobenzylideneamino)isobenzofuran-1(3H)

one (4.25 g. yield 81%); LC-MS (ES1) m/z: 256 (M+1). A mixture of (E)-4-(4

fluorobenzylideneamino)isobenzofuran- 1(31H)-one (2,53 g, 10 mmol) and 1 -methyl- 1 H- imidazole

2-carbaldehyde (1.21 g, 11 mmol) in ethyl propionate (50 mL) was cooled to 0 C. Then a solution

30 of sodium ethanoxide in ethanol [sodium (I g, 44 mmol) in ethanol (30 mL)] was added drop-wise,

After the addition, the in ixture was stirred at room temperature for 2 hr. The mixture was quenched

with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and

then extracted with ethyl acetate (100 mLx4). The combined organic layers were washed with brine,

dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was

35 purified by chromatography (silica gel, petroleum ether / ethyl acetate = 10-1 to 1:10) to give ethyl

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2-(4-fluorophenvl)-3-(l -methyl- 1H-- imidazol-2-vI)-4-oxo-1.2,3,4-tetrahydroquinoline-5-carboxylate

(210 mg, yield 5%). LC-MS (ESI) m/z: 394 (M+1).

Example 88 B

8-(4-Fluorophenyl)-9-(1 i-methyl- IH- imidazol-2-y)- 8,9-dihydro-2H-pyrido([4,3,2-de]phthailazin

3(71)-one

[005061 A mixture of ethyl 2-(4-fluorophenyl)-3 -(1-methyl-RI I- imidazol-2-yl)-4-oxo- 1,2,3,4

tetrahydroquinoline-5-carboxylate (210 mg) in 85% hydrazine monohydrate (10 m) and methanol

(10 mL) was stirred at 45 T for overnight. Methanol was removed under reduced pressure. The

mixture was filtered and washed with water to give 8-(4-fluorophenyi)-9-(1-tethvl- I H- imidazol-2

10 yl)- 8,9-dihydro-2H-pyrido[4,3,2.-de jphthalazin-3 (71-)-one 36 mg, yield 19%). 'H-NMR (400 MHz.

DMSO-d6) 8 (ppm): 3.42 (s, 3H). 4.66 (d. J= 8.0 Hz, 114), 4.95 (d, J= 8.0 Hz, 1 H), 6.72 (s, Hl),

6.89 (s, I H). 7.11-7.17 (m, 3Ff). 7.30 (s, 1H), 7,40 (d, I H), 7.43-7.44 (m. 2H), 7.58 (d. il), 12.17 (s,

I-); 19F-NMR (400 MHz, DMSO-d) 3 (ppm): -114.58: LC-MS (ESI) r/z: 362 (Mtl)'.

Example 89

15 8,9-Bis(3-((diimethylamino)methyb)phenyl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]phthalazin-3(71)--one

Example Example 89 A

3-(Diethoxymethvl)benzaldehyde

1005071 A mixture of isophthalaldehyde (21.44 g, 160 mmol), ammonium chloride (0.34 g, 6.38

mmol) in anhydrous ethanol (23.2 g 480 mmrol) was cooled to 0 C then triethyl orthoformate was

20 added drop-wise, After the addition, the mixture was warmed to 40 "C and stirred for two days. The

mixture was filtered and the filtrate was concentrated to give crude product. The crude product was

purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 200:1 to 100:1) to

give 3-(diethoxyrnethvl)benzaldehyde (25.4 g, yield 76%) as a colorless oil. 'H-NMR (400 MHz, CDCI3) 6 (ppm): 1.23-1.27 (m, 6H), 3,53-3.67 (in, 414), 5.58 (s I H). 7,52-7.56 (t, 1= 7.6 Hz, lIH),

25 7.74-7.77 (dd, J = 7.6 Hz, ?- 3.6 Hz, 11-), 8.00 (s, IH), 10.04 (s, lH); LC-MS (ESI) m/z: 209

(M+lf)

Example 89 B

Methyl 2,3-bis(3-(diethoxytethyl )phenyl)- 4-oxo- 1,2,3,4-tetrahydroquinoline-5 -carboxylate and

ethyl 2,3 -bis(3-(diethoxymethvl)phenyl)- 4-oxo-l,12,3,4-tetrahydroquinol ine-5-carboxylate 30 (005081 A mixture of 4-aminoisobenzofuran- 1(311)-one (298 mg, 2 mmol) and 3

(diethoxymethyl)benzaldehyde (0.83 g, 4 mol) in ethyl propionate (15 mL) was cooled to 0 'C.

Then a solution of sodium methoxide in methanol [sodium (184 rg, 8 mmol) in methanol (15 mL)]

was added drop-wise. After the addition, the mixture was stirred at 25 "C for 18 hr. The mixture was

quenched with water (10 ml.) and solvent was removed in vacuum. The residue was dissolved in

35 water. and then extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude

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product was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 100:1 to 10:1)

to give a mixture of methyl 2,3 -bis(3-(diethoxynmethyl)phenyl)- 4-oxo-1.2,3,4-tetrahydroquinoline

5-carboxylate and ethyl 2,3-bis(3-(diethoxymethyl)phenyl)- 4-oxo-1,2,3 4-tetrahydroquinoline-5

carboxylate (370 mg together, yield 33%) as light yellow solid. LC-MS (ESI) n/z: 562(M+1)f

5 576(M+I).

Example 89 C

8,9-Bis(3-(diethoxynethvl )phenyl)- 8,9-dihydro-2/1-pyrido[4,3,2-de]phthalazin-3(71H)-one

1005091 A mixture of methyl 2,3-bis(3-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4

tetrahydroquinoline-5-carboxylate and ethyl 2,3 -bis(3-(diethoxymethyl)phenyi)- 4-oxo- 1,23,4

10 tetrahydroqutinoline-5-carboxylate (370 mg, 0.59 mmol) in hydrazine monohydrate (5 mL) and

methanol (5 ml) was stirred at 50 "C for 2 hr The mixture was cooled to room temperature and

filtered to give 8,9-bis(3-(diethoxymethyl)phenyl)- 8,9-dihydro-2H-pyrido[4,3 ,2-dejphthalazin

3(7H)-one (250 mg, yield 77%) as a light yellow solid, H-NMR (400 MHz, DMSO0d6) 6 (ppm):

0.99-1.08 (m, 1211), 3.27-3.33 (m, 8H). 4.28-4.31 (d., J= 8.8 Hzi 11-i ), 4.74-4.76 (d, J= 8A Hz, I H)j

15 53 1-5,32 (d, = 6,8 Hz, 2H). 7.04 (s, 11), 7.121-7,26 (in, 7H), 7.31-7.43 (m, 31), 7.56-7.60 (t,.J=

8.0 Hz, 1iH); LC-MS (ESI) m/z: 544(M- ).

Example 89 D

3,3' (3 -(xo-3 ,89-tetrahyd ro-2H-pyrido [4,3 ,2-dejphthahazin-8,8-diyl)dibenzaldehyde

[005101 A mixture of 8 9-bis(3-(diethoxymethyl)phenyl)- 8,9-dihydro-2H-pyrido[4,3,2

20 de]phthalazin-3(71])-one (120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at room

temperature for 2 hr. Then the mixture was adjusted to pH=8 with potassium carbonate. The

resulting suspension was filtered to give 3,3'-(3-oxo-3,78,9-tetrahydro-21J-pyrido[4,3,2

de]phthalazin-8,8-diyl)dibenzaldehyde (160 mg, yield 88%) as a light yellow solid. H-NMR (400

MHz, DMSO-d6) 6 (ppm) 4.57-4.59 (d, J= 9.6 lIz, 111), 4.98-5.00 (d. J= 9.2 Hz, 111), 7.20-7.22

25 (dJ=7 6 Hz, 114). 7,42-7.52 (m, 5H), 7.60-7.77 (m, 5H), 7.89 (sI 1H)- 9.90 (s, 11), 9.93 (s, ilH,

12.08 (s, IH); LC-MS (ESI) nni: 396(M+1),

Example 89 E

8,9-Bis(3 -((dimethylaiino )methyl)phenyl)-8,9-dihydro-211-pyrido(4,3 ,2-deiphthalzin-3(71H)-one

1005111 A mixture of 3,3'-(3-oxo-3,7,8,9-tetrahydro-211-pyrido[4,3 , 2-dejphthalazin- 8;830 diyl)dibenzaldehyde (60 mg, 0.16 immol) and 32% dimethylamine solution (135 mg; 0.96 mmol) in

methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0 C.

Sodium borohydride (18.2 mg, 0.48 minmol) was added. After the addition, the mixture was stirred at

room temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed

with ethyl acetate and filtered. The filtrate was concentrated to give the crude product, The crude

35 product was purified by prep-HPLC to give 8,9-bis(3-((dimethylaniino)inethyl)phenyi)-8,9-dihydro

2H-pyrido[4,3,2-de]phthalazin-3(71)-one (18.6 mg, yield 26%) as a light yellow solid. 'I-NMR

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WO 2010/017055 PCT/US2009/051879

(400 MHz, CD3OD) 6 (ppm): 2.61-2.67 (m, 12H), 4.10-4.15 (m, 41), 4.25-4.27 (d, J= 9.6 H~z, I N),

4,67-4.69 (d, J= 10.0 Hz, 1 H), 7.05-7.29 (m, 71-1), 7.29-7.39 (m, 211). 7.49-7.54 (m, 211); LC-MS

(ESI) m/z: 454(M+I).

Example 90

S 9-(3-((Cyclopropylamino)methyl)phenyi)-8-phenyl-8,9-dihydro-2H-pyrido[4,3;.2-de]phthalazin

3(7H)-one

1005121 A mixture of 3 -(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2HU-pyrido[4,3 2- de]phthalazin-9

yl)benzaldehyde (70 mg, 0.19 mmol) and cyclopropanamine (32,55 mg, 0,57 mmol) in anhydrous

methanol (10 mL) was stirred at room temperature for L.5 h. Then the mixture was cooled to 0 C.

10 sodium borohydride (10.82 ing, 0,286 mnol) was added portion-wise. After the addition, the

mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The

residue was dissolved in ethyl acetate (50 mL), extracted with IN hydrochloric acid (20 nL), the

aqueous layer was separated. The organic layer was washed with IN hydrochloric acid (20 nL). The

combined aqueous layers were adj ousted to pH = 9 with potassium carbonate, extracted with ethyl

15 acetate (25 mLx4). The combined organic layers were dried over anhydrous sodium sulfate, and

concentrated to give 94-3-((cyclopropylamino)nethyl)phenyi)-8-phenyl-8,9-dihydro-2 H

pyrido[4,3,2-dephthalazin3(7HJ)-one (15 ing, yield 19%) as a light yellow solid. .H-NMR (400

MHz, CD.OD) S (ppm): 0.19-0.29 (i 411). 1.74-1.80 (mu, IH) 3.55 (s, 211), 4.16-4.19 (d J= 8.8

H4z, I N), 4.60-4.62 (d, J 8.8 Hz, 111), 688-6.90 (d, J::: 7.6 Hz, 1H), 6.95 (s, 111), 7.01-7.10 (m, 20 611), 7.13-7.15 (m, 2H), 7.42-7.44 (d, J=7.6 lHz, M), 7.48-7.75 (t, J= 8.0 Hz IH); LC-MS (ESI)

m/z: 408(M+1).

Example 91

8-(3-((Diimethylam ino)methyl )phenyl)-9-phenyl-8.9-d ihydro-2H-pyrido[4,.,2-dc) phthalazin-3 (711)

one

25 1095131 A mixture of 3-(3 -oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4.3,2-dejphthalazin-8

yl)benzaldehyde (50 mg, 0.14 mmtol) and I M dimethylanine methanol solution (0.5ml, 0.41 inmol)

in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0

C, Sodium cyanoborohydride (13 rg, 0.20 minmol) and acetic acid (40.8mg, 0.68mmol) was added.

After the addition, the mixture was stirred at 0"C for 2 hr. Methanol was removed under reduced

30 pressure. The residue was resolved with IN hydrochloric acid and washed with ethyl acetate. The

mother liquor was adjusted to p=1-8 and extracted with ethyl acetate. The solvent was removed to

give 8-(3-((dirmethylaindin)methvl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4.3,2-de]phthalazin

3(711)-one (34 rmg, yield 64%) as a light yellow solid. 'H-NMR (400 Mz, CDOD) 6 (ppm): 2.17

(s, 611), 3.17-3.41 (q, 211). 4.31 (dJ 8,0 Hz, INH), 4.74 (d,,J= 8.0 Hz, 111), 7.08-7,10 (i, 211).

35 7.13-7.25 (n, 81-1), 7.55-7.57 (d, J= 8.0 Hz IH), 7.61-7.65 (i, 14). LC-MS (E-SI) n/z: 397 (M+1)*

Example 92

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8-(3-(Morpholinomethy1)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,32delphthalazin-3(71-)-one

[00514] A mixture of 3-(3-oxo-9-phenyl-3 ,7,8,9-tetrahydro-2H-pyrido[4,3,2-dle]phthalazin-8

yl)benzaldehyde (40 mg, 0.11 ninol), morpholine (28mg, 0.33 mmol) and acetic acid (33mg,

0.55mmol) in methanol (50 mL) was stirred at room temperature for 40 min. Then the mixture was

5 cooled to 0 C. Sodium triacetoxyborohydride (35 tug, 0.16 mnmol) was added. After the addition,

the mixture was stirred at 0 C for 2 hr. Methanol was removed under reduced pressure. The residue

was resolved with IN hydrochloric acid and washed with ethyl acetate. The mother liquor was

adjusted to p-=8 and extracted with ethyl acetate. The solvent was removed to give 8-(3

(morpholintmethyl)pheny)-9-phenyl-8,9-dihydro-2H-pyrido[4.3,2-de]phthalazin-3(7Dh)-one (3 1

10 mg, yield 66%) as a light yellow solid. tH-NMR (400 MHz, CD3OD) 6 (ppm): 2,23-2.24 (i, 41),

3.32-3.43 (q, 211), 4.30 (d, J= 8 0 Hz, 1H), 4.74 (d, J= 8.0 HRz, 1H), 7.08-7.10 (mu. 2H)7 7.13-7.19

(ni, 6 1) 7.21-7.25 (m, 11) 7.31-7.33 (in, H), 7.55-7.57 (dJ: 8.0 Iz, 1 H), 7.62-764 (m, 1 H),

LC-MS (ESI) m/z: 439(M+1).

Example 93

15 8-(4-(Azetidin- l-yhnethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-211-pyrido[4,3,2-dejphithalazin

3( 7 H)-one

Example 93A

Ethyl 2-(4-(diethoxymethyl)pheny3l)~3-(4-fluorophenyl)-4-oxo- 1,2,3,4-tetrahydroquinoline-5

carboxylate

20 [005151 A solution of (F)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3 1)-one (10.8

g, 31.9 mmol) and 4-fluorobenzaldehyde (3.95 g, 31.9 nmmol) in ethyl propionate (150 mL) was

added sodium ethoxide (8.66 g, 127.4 mnol, in ethanol 60 ml) at 0 (C. Then the mixture was stirred

at room temperature for 5 hr. The resulting mixture was evaporated under reduced pressure and

extracted with ethyl acetate (100 mL x 4) and concentrated. The crde product was purified by

25 column chromatography (silica gel, petroleum ether: ethyl acetate =20: ito 1:1) to give the crude

product (4.2 g yield 26%). LC-MS (ESI) n/z: 492 (M+l).

Example 93B

8-(4-(Diethoxymethyl)phenyl)-9-(4-fluorophenyl)-89-dihvdro-2H l-pyridot4,3,2-dejphthalazin

3(714)-one

30 1005161 The crude compound ethyl 2-(4-(diethoxymethyl)phenyi)-3-(4-fluorophenyl)-4-oxo- 1;2,3,4

tetrahydroquinoline-5-carboxvlate (4.2 g. 8.54 mmol) and hydrazine monohydrate (5 niL) were

added in methanol (60 mL) and the mixture was stirred at room temperature for 16 hr, The resulting

mixture was concentrated under reduced pressure to a volume of 40 mL. and then filtered to obtain

the crude title compound (3.0 g, yield 76%). LC-MS (ESI) m/iz: 460 (M-i1)

35 Example 93C

4-(9-(4-Fluorophenyl)-3 -oxo-3,7.8,9-tetrahydro-2-l-pyrido[43,2-de]phthalaziu-8-yl)benzaldehyde

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[005171 To a solution of the crude 8-(14-(diethoxinethiy)phenyl)-9-(4-fluorophenyl)-8,9-dihydro

2H-pyrido[4,3,2-delphthalazin-3(7H)-one (3,0 g, 6,53 mmol) in water (10 aiL) was added

hydrochloric acid (IN, 50 mL ) at 0 ", The mixture was stirred at room temperature for 4 hr. Then

5 the mixture was neutralized with potassium carbonate, The mixture was extracted with ethyl acetate

(200 mL x 3), The combined organic layers were washed with brine, dried over anhydrous sodium

sulfate, and concentrated to give the crude title compound (2.5 g, yield 98%), LC-MS (ESI) rn/z:

386 (M+I)'.

Example 93 D

10 8-(4-(Azetidin-1 -ylmethyl)phenvy)-9-(4-fluorophenyl)-8,9-dihydro-211-pyrido[4,3.2-de]phthalazin

3(711)-one

1005181 To a stirred solution of the crude 4-(9-(4-fluorophenyl)-3-oxo-3,7,8.9-tetrahydro-2H

pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (930 mg 2,42 mrmol) in DCM (120 mL.) was added

acetic acid (0.3 mL) followed by azetidine (670 mg; 11.8 mmnol), after the addition, the mixture was

15 stirred at room temperature overnight. Then the mixture was cooled to 0 "C and NaBl(OAc), (764

mg, 3.62 minol) was added. After the addition, the mixture was stirred at this temperature for 6 hr.

DCM was removed under reduced pressure. The residue was added water followed by hydrochloric

acid (5 mL) at 25 *. The mixture was stirred at room temperature for 0,5 hr. The mixture was

extracted with ethyl acetate (100 nl. x 3). The water layer was neutralized with potassium carbonate

20 and filtered to obtain the title compound as a white solid (500 mg, yield 49%). LC-MS (ESI) m/z:

427 (M+). 'HI-NMR (400 MHz, DMSO-d6) 6 (ppm): 2.24-249 (_m, 2), 3.85-4.02 (in, 411), 4.25

(d, 2H). 4.38 (d, 1 H), 4.80 (d, IH) 7.03 (t, 211). 7.14-7.20 (m, 31), 7.36-7.39 (m, 51H) 7.47 (s, 1H).

7.59 (t, I H) 10.64 (s, I I), 12.18 (s, IH).

Example 94

25 5-fluoro-8-(4-fluorophenyl)-9-(I -methyl- I H-1.2,4-triazol-5-yl)-8,9-dihvdro-2H-pyrido[4,3,2


Example 94A

Ethyl 7-fl uoro-2-(4-fluorophenvl)3-( I-methyl- H1-1 2,4-triazoi-5-yl)4-xo-23,4


30

1005191 To a solution of (E)-6-fluoro-4-(4-fluorobenzyl ideneamino)isobenzofuran-1(311)-one (4 g,

14.6 mniol) and 1-methyl-lIZ-i1;2,4-triazole-5-carbaldehyde (4.1 g. 36.9 mol) in ethyl propionate

(220 mL) was added EtONa ((sodium 940 mg, 40.9 mmol), in 70 muL ethanol) at 37 C, then the

mixture was stirred at 40 (C for 6 hr. The resulting mixture was evaporated under reduced pressure

35 and extracted with ethyl acetate (100 mL x 4).The extract was concentrated to dryness to give a

crude product, which was purified by column chromatography (silica gel, dichloromethane:

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methanol= 200:1 to 100:1) to obtain a green solid (1.02 g, yield 14%). LC-MS (ESI) m/z: 413

(Me lV.

Example 94B

5-Fluoro8-(4-fluorophenyl)-9-(1-methylMH-1,2,4-triazol--yi)-8,9-dihydro-2H-pyrido[4,3,2

5 dejphthalazin-3(71)-one

1005201 To a solution of ethyl 7-fluoro-2-(4-fluorophenyl)-3-(i-methylIH4,2,4-triazol-5-y4

oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (840 mg, 204 inmol) in methanol (2 mL) was added

hydrazine monohydrate (l mL), and the mixture was stirred under 25 TC for 10 hr. Ihen the mixture

was filtered to obtain a white solid (650 mg; yield 84%). LC-MS (ESI) m/z: 381 (M+I)- ilNMR

10 (400 MHz, DMSO-d6) 6 (ppm): 3.66 (s, 311), 4.97-5.04 (m 2H), 6.91-6.94 (dd, J= 1 .2 H z J 2.4

Hz, 1H), 7.06-7.09 (dd, Ja= 8.8 H 214 Hz, I8), 7.14-7-18 (in, 31) 7.47-7.51 (m. 2H), 7.72 (s,

I11), 7.80 (s, 1H), 12.35 (s, 1 F)

Example 95

9-(1 -Methyl-I H-I ,2,4-triazol-5-yl)-8-pheny1-8,9-dihydro-2H-pyrido(4,3,2-dejphthaiazin-3 (711)-one

I5 Example 95A

Ethyl 3-(i-methyl-I l-i,2.4-triazol-5-yl)-4-oxo-2-phenyl-1,2,34-tetrahydroquinoline-5-carboxylate

[00521J To a solution of (E)-4-(benzvlideneamino)isobenzofuran-1(3H-one (1,78 g. 7,5 imol) and

1-inethyl-lH-1;2,4-triazole-5-carbaldehyde (1.01 g, 9.16 mmol) in ethyl propionate (110 mL) was

added EtONa (sodium (490 mg, 21 minmol) in 35 ml. ethanol) at 40 "C, then the mixture was stirred

20 at 41 T for 3 hr. The resulting mixture was evaporated under reduced pressure and extracted with

ethyl acetate (150 ml, x 4) and concentrated. The crude product was purified by column

chromatography (silica gel, dichloromethane: methanol =200:1 to 50:1) to obtain a green solid (400

mg, yield 14%), LC-MS (ESI) m/z: 377 (Meli

Example 95B

25 9-(l -Methyl-I H- .2,4-triazol-5-y, )-8-pheny I -8,9-dihydro-2H-pyrido[4.3 2-de]phthalazin-3 (7H)-one

[00522] To a solution of ethyl 3-( I-methyl-il-i,2,4-triazol-5-yl)-4-oxo-2-pheny-1,2,34

tetrahydroquinoline-5-carboxvlate (400 mg, 1 .06 mnmol) in methanol (8 mL) was added hydrazine

monohydrate (0.5 mL), and the mixture was then stirred at 25 C for 10 hr. The mixture was filtered

to obtain a vhite solid (1 10 mg, yield 30%). LC-MS (ESI) mu: 345 (M+1) Hl . l-NMR (400 MHz, 30 DMSO-d&) 6 (ppm): 3.77 (s, 3Ff), 4.48-4.49 (d, J= 6.4 Hz., 1H) 5.16-5.19 (d, J= 6.4 Hz, 1 )A 40

7.42 (n, 2H), 7.54-7.58 (t, 1 H), 7.74 (s, I H), 12.23 (s, 1H).

Example 96

8-(4-((Di methylamino)methyl)phenyl)-9-(I -methyl-Il-I ,2,4-triazol-5-yl)-8,9-dihydro-2H

pyrido[4,3,2-deJphthalazin-3(7H.)-one 35 Example 96A

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Ethyl 2-(4-((dimethylamino)imethyl)phenyl)-3-(1 -methyl-IH-1 2,4-triazol-5-vl)-4-oxo-1.2,3,4-

tetrahydroquinoline-S-carboxlate

1005231 To a solution of (E)-4-(4-((dimethylamino)methyl)benzvlideneami no)isobenzofuran- 1(31)

one (2.21 g, 7.5 mmol) and 1 -methyl-Il-B 1,2.4-triazole-5-carbaidehyde (LOi g, 9,16 mmol) in ethyl

5 propionate (110 ml) was added rapidly EtONa (sodium (490 mg, 21 mmol) in 35 mnL ethanol) at 40

T, then the mixture was stirred at 45 C for 3 hr. The resulting mixture was evaporated under

reduced pressure., extracted with ethyl acetate (200 mL x 3), and then concentrated the extract. The

crude product was purified by column chromatography (silica gel, dichloromethane: methanol

100:1 to 10:1) to obtain a green solid (510 mg, yield 16%). LC-MS (ESI) .m/z: 434(M+1).

10 Example 96B

8-(4-((Dimethylamino)methyl~phenyl1)-9-( I-methyl -IH-Il,2 .4-triazol-5-yl)-8,9-dihydro-2H

pyrido[4,3,2-dejph thalazin-3(7H)-one

1005241 To a solution of ethyl 2-(4-((dimethylam ino)methyl)phenyl)-3-(I -methyl-ill-I,2,4-triazol

5-yl)-4-oxo- 1,2,3,4-tetrahydroquinol ine-5-carboxylate (506 mg, 1.17 mmol) in methanol (3 ml.) was

15 added hydrazine monohydrate (I mL), and the mixture was stirred at 25 'C for 10 hrs. The mixture

was filtered to obtain a white solid (225 tug, yield 48%). LC-MS (ESI) m/z: 402 (M+') H-NMR

(400 MHz, DMSO-4) 6 (ppm): 2.10 (s, 6H), 333 (s 3 2)3.58 (s, 311), 4.88-4.92 (m, 2H), 7.20-722

(m, 314), 7.34-7.40 (in, 41) 7.54-7.62 (t, J= 8.4 Hz, 11H) 7.79 (s, 1-1), 12.20 (s, 1H-).

Example 97

20 8-(4-((Dimethylami no)methyl)phenyl)- 5-fl uoro-9-(1 imethyl-1liF-1,2,4-triazol-5-yI)-8,9-dihydro-2Hpyrido[4,3,2-de]phthalazin-3(7H)-one

Example 97A

Ethyl 2-(4-((dimethylamino)methy l)phenyl)-7-fluoro-3 -(i-methyl-I H- 1.2,4-triazol-5-vl)-4-oxo

I ;2,3,4-tetrahydroquinoiine-5-carboxylate

25 [005251 To a solution of (E)-4-(4-((dimethylamino)methyl)benzylideneaminc)-6

fluoroisobenzofuran-1(3H)-one (2.34 g, 7.5 mmol) and 1-methyl- 1-1H,2,4-triazole-S-carbaIdehyde

(1.0 1 g, 9.16 mmol) in ethyl propionate (110 mL) was added EtONa (sodium (500 mg, 21 mmiol) in

35 mL ethanol) at 40 ", then the mixture was stirred at 48 *C for 3 hr. The resulting mixture was

evaporated under reduced pressure, extracted with ethyl acetate (250 mL x 3), and concentrated. The

30 crude product was purified by column chromatography (silica gel dichloromethane: methanol

50:1 to 10:1) to obtain a green solid (160 mug, yield 4.7%). LC-MS (ESI) m/z: 452(M+1)'.

Example 97B

8-(4-((Dimethylamino)nethyl)phenyl)-5-fluoro-9-(I-methyl - IH-1,2,4-triazol-5-yl)-8 ,9-dihydro-2H.

pyrido[4,3,.2-dec phthalazin-3(7H)-one

35 [005261 To a solution of ethyl 2-(4-((dimethyiamino)metl)phenyl)-7-fluorc-3-(1-methyl-Il-I 2.4

triazol-5-yl)-4-oxo-l,2,3,4-tetrahycroquinoline-5-carboxylate (160 ng, 0,35 mnmo) in methanol (2

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mL) was added hydrazine monohydrate (0.5 mL), and the mixture was stirred at 25 C for 10 hr. The

mixture was filtered to obtain the title compound as a white solid (45 ig, yield 30%). LC-MS (ESI)

mz: 420 (M+1) . H-NMR (400 MHz, DMSO-d6) 6 (ppm): 2,10 (s, 6H), 3.36 (s, 2H), 3.59 (s, 3H),

4.91-4.99 (m. 2H) 6.91-6.95 (dd., Jj= 11. 2 Hz.J24 Hz, I1), 7.05-7.08 (dd, J=- 9.2 Hz, r 24

5 Hz, 1H), 7.20-7.23 (d, J= 8.0 Hz, 2H) 7,35-7.37 (d, J= 8,0 Hz. 2H, 7.72 (s, IH), 7.79 (s, 11),

12.33 (s, 1 l).

Example 98

8-(4-Fluorophenyl)-9-methyl-9-(I -methyl-I H-1,2,4-riazol-5-yl)-8 9-dihydro-2H-pyrido[4,3 .2de]phthalazin-3(7 1)-one

10 Example 98A

Ethyl 2-(4-fluoropheny l)-3-methyl-3-(1~methyl 1-1,2,4-triazol-5-yi)-4-oxo-1.2,3,4


[005271 A solution of ethyl 2-(4-luorophenvl)-3-(I-methyl -11-l;2,4-triazol-5-yl)-4-oxo-1 ,2,3.4

tetrahydroquinoline-5-carboxylate (100 mg, 0.25 mmol) aid potassium carbonate (70 mg; 0.51 15 mmol) in N.N-dimethylformamide (10 mL) was stirred at room temperature for 1 hr. Then the

solution was cooled to 0 C and a solution of iodomethane (0.1 mL) in YN-dimethylformamide (1

mL) was added dropwise at 0 C over I hr, stirred at room temperature overnight. The mixture was

quenched with water (30 nL), extracted with ethyl acetate, washed with brine, and then the

extraction was evaporated to get the crude product, which was used in next step without further

20 purification (80 mg, yield 77%). LC-MS (ESI) m/z: 409 (M+i).

Example 98B

8-(4-Fliorophenvl)-9-methyl-9-(1-methyl-111-1,2,4-triazol-5-yl)-8,9-dihydro-2 H-pyrido[4,3,2


1005281 A mixture of ethyl 2-(4-fluorophenyl)-3-methyl3-(i-methyli HI ,2,4-triazo-5-y1)4-oxo

25 1.2.3,4-tetrahydroquinoline-5-carboxylate (80 mg, 0.19 mmol) in 85% hydrazine monohydrate (5

raL) and methanol (1 mL) was stirred under reflux ovemight. The resulting solution was cooled and

filtered, washed the cake by methanol (2 rnL) to obtain a white solid, dried in vacuum at 55 *C to

obtain the title compound (40 mg, yield 54%). LC-MS (ESI) n/z: 377 (M-i)'; 'H-NMR (400 MHz,

DMSO-d6) 6 (ppm): 1.83 (s, 3Ff). 2.86 (s, 311), 4,61 (s, I H), 6,88-6.92 (m,2H), 7.11-7.169 (t, = 8. 8 30 Hz, 21-) 7.19-7.22 (d. J= 8.0 Hz, 11H), 7.41 (s, 111), 7.47-7,49 (mt 1-1). 7.60-7,64It,1= 8.0 Iz,

1i)t 7,72 (s, 11), 12.40 (s. 11H).

Example 99

8-(4-Fluorophenyl)-91-(4,5-trimethyl-I -I-imidazoI-2-v)-8.9-dihydro-2H-pyrido{4,3, 2delphthalazin-3(7H)-one

35 Example 99A

1,4,5-Trimethyl- l1-im idazole

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100529 To a cold suspension of formaldehyde (21 inL, 0.3 mol). methylamine hydrochloride (36.5

g. 540 mmol ) and ammonium hydroxide (150 niL) was added butandione (15.8 mL, 180 mmol) and

the mixture was then stirred at 100 C for 30 min. After cooled to room temperature the reaction

mixture was extracted with dichloromethane. The organic layers were dried with Na 2 SO and the

5 solvent was removed via rotary evaporation. The crude was purified by chromatography

(dichloromethane/methanol -100:1) to give 1,4,5-trimethyl-l H-imidazole. 'H-NNMR (400 MHz,

CDC) 6 (ppm): 2.11 (s, 3H)t 215 (s, 311), 349 (s, 3H), 7.28 (s, ITH).

Example 99B

I,4,5-Trimethyl- 1 14-imidazole-2-carbaldehyde

10 1005301 To a solution of 1,4;5-trimethyl-1H-imidazole (550 mg, 5 mmol) in dry tetrahydrofmtran (15

mL) was added dropwise n-BuLi (3 miL, 2.5 M in hexane) at -40 C. After stirring for 2 h at this

temperature, to the solution was added dried DMF (840 mg. 11.5 mmol) at -70 0C. 'he resulting

yellow suspension was stirred at -70 'C for I h. then at 0 "C for 0,5 h and quenched with ice-water.

The mixture was extracted with ethyl acetate, and the organic extracts were dried with Na 2SO

15 before evaporation to afford an oily residue. The residue was purified by silica colun (petroleum

ether: ethyl acetate = 3:1) to obtain 340 mg of white solid, yield: 50%, 'H-NMR (400 MHz, CDCb)

6 (ppm): 2.21 (s, I H), 2.25 (s, 111), 3.90 (s; I), 9.66 (s, It) LC-MS (ESI) m/z: 138(M+1)'

Example 99C

Ethyl 2-(4-fluorophenyl)-4-oxo-3-(14,.5-trimethyl-l H 1-imidazol-2-yl)-1,2,3 4-tetrahyd roquinoline-5

20 carboxy late

1005311 A mixture of compound (E)-4-(4-fliuorobenzylideneamino)isobenzoftiran- 1(3H)-one (510

mg, 2.0 mmol) and 1.4.5-trimethyl-lH-imidazole-2-carbadehy.de (304 mg, 2.2 mimol) in ethyl

propionate (20 mL) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol (sodium (184

mg, 8.0 mmol) in ethanol (10 niL)) was added dropwise. After the addition, the mixture was stirred

25 at room temperature for 2.5 hr. The mixture was quenched with water (20 mnL) and solvent was

removed under reduced. pressure. The residue was dissolved in water and extracted with ethyl

acetate (100 ml, x 3), then the extraction was washed with water, brine and evaporated, the crude

product was purified by chromatography to obtain a yellow solid (150 mig yield: 18%). LC-MS

(ESI) nz: 421 (M+lI)

30 Example 99D

8-(4-FI uorophenyl)-9-( 1.4,5-trimethyl-1im idazol-2-yl)~8,9-dihydro-2H-pyrido[4,3,2de]phthalazin-3(711)-one

1005321 A mixture of ethyl 2-(4-fluorophenyl)-4-oxo-3-(1.4,5-trimethyl-iH-imidazol-2-yl)- I2,3,4

tetrahydroquinoline-5-carboxylate (150 mg) in 85% hydrazine monohydrate (85%, 3 mL) and

35 methanol (5 mL) was stirred at room temperature for 2 days. The result suspension was filtered and

washed the water (20 m) and methanol (5 ml) to obtain a white solid. The solid was dried in

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vacuum at 50 "C to afford the title compound (90 mg, yield 65%) H4-MR (400 Mlz, DMSO-d6) 6

(ppm): 1,91-1.96 (dJ=H 18 Hz. 6H), 3.25 (s, 3H), 4.59-4.62 (d,.J= 10.8 Hz, 11H), 4,92-4.95 (d. J=

10.8 Iz, 11-), 7.09-7,15 (m,3H). 7,22 (sil), 7,36-7,38 (d, J= 7.6 lz, 1H), 7.43-7.46 (n, 211), 7.54

7,58 (t, J= 8 Hz, 1H), 12. 13 (s, 11); LC-MS (ESI) miz: 390 (M+ 1).

Example 100

8-(4-Fluorophenyl)-9-( 1-methyl-ll-I,2,3-triazol-4-yl)-8,9-dihydro-21]-pyTido[4,3,2-dejphthalazin

3(711)-one

Example I OA

(1 H-1 ,2,3-Triazol-4-yl)methanol

10 1005331 TMSN:, (24.8 a, 214 imnol) was added to a solution of CuT (1.4 g, 0,4 mol) and prop-2-yn

I-oi (8.0 g, 142.4 mmol) in DMF (160 mL) and methanol (20 mL) under nitrogen atmosphere. The

reaction mixture was stirred at 100 C for 12 h. Then the mixture was cooled to room temperature

and filtered through a short florisil and concentrated. The crude was purified by column

chromatography (silica gel, prev-washed with triethylamine, petroleum ether: ethyl acetate 1:3 to 1:5)

15 to give the title compound (12.7 g, 90%) as a yellow oil. 1 -INMR (400 MHz, DMSO-d6) 6 (ppm):

4.09 (n, 2H1) 4.48-4,10 (in, 1H), 5.21-5.24 (in, 1H). 7.62 (s, IH); LC-MS (ESI) Iz: 100 (M+ 1)

Example 100B

(I-Methyl- H-1,2.3-triazol-4-yl)methanol

1005341 To a solution of(lH-1 2,3-triazal4-y')methanol (5.0 g 51,5 mmol) and K2CO3 (8.5 g, 62

20 mmol) in MeCN (190 mL) was added methyl iodine (3.8 nil) dropwise at 0 'C. Then the reaction

was stirried at room temperature overnight, the reaction solution was filtrated, and adjusted to pH=

6 with acetic acid, then the solvent was evaporated to obtain the title compound (5.6 g, yield 98%)

as yellow oil and used in next step without further purification. LC-MS (ESI) m/z: 114 (M+1).

Example 100C

25 1 -Methyl I H-l,2,3-triazole-4-carbaldehyde

1005351 (1-Methyl-1li- ,2,3-triazol-4-yl)methanol (5,6 g, 50 minol) and activated manganese

dioxide (55 g, 65 mmol) was dissolved in acetone (130 mIL) and the solution was stirred at room

temperature for 3 h. Then the reaction mixture was filtered, the solvent was evaporated in vacuum.

The residue was purified by flash chromatography (silica gel, petroleum ether: ethyl acetate 5:1 to

30 2: 1) to obtain the title compound (1.1 g, yield 20%).'HI-NMR (400 MHz, DMSO-d6) 6 (ppm): 4 13

(i, 3H)- 8.81 (s, 1H), 10.02 (s, 1H-); LC-MS (ESI) m/z: 112 (M+-)

Example 100D

Ethyl 2-(4-fluorophenyl)-3-(I-methyl-IH-1, -triazo4-yl)- 4 -oxo-1,2;3,4-tetrahydroquinoline-5

carboxylate

35 [005361 A mixture of (E)-4-(4-fliuorobenzylideneami no)isobenzofiiran-1( 3 H)-one (698 mg 2.7

mtoI) and I.-methyl- 111-1,2.3-triazole-4-carbaldehyde (334 mg, 3 mimol) in ethyl propionate (35

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mL) was cooled to 0 "C. Then a solution of sodium ethanolate in ethanol (sodium (248 mg, 10.8

mmol) in ethanol (15 mnt) was added dropwise, After the addition, the mixture was stirred at room

temperature tot 4 hr. The mixture was quenched with water (10 mL) and solvent was removed in

vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL x 4).

5 The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and

concentrated to give crude product, which then was purified by chromatography (silica gel,

petroleum ether / ethyl acetate = 3:1 to 1:1) to give the title compound (426 mg, yield 39%). LC-MS

(ESI) m/z: 395 (M+l1).

Example 100 E

0 8-(4-Fluorophenyl)-9-( -methyl- IH-1.2.3 -triazol-4-yl)-8,9-dihydro-2 H-pyridof 4.3 2-de]phthalazin3(7th-one

[00537] A mixture of ethyl 2-(4-fluorophenyl)-3-(1 -methyl-IH- 1,2;3-triazol-4-yl)-4-oxo-1,23,4

tetrahydroquinoline-5-carboxylate (113 mg, 0.28 mmol) in 85% hydrazine monohydrate (4 mi )

stirred for 3 hr at room temperature. The mixture was filtered and washed with water, petroleum

15 ether and ethyl acetate to give the crude product, which was purified by prep-HPLC to give the title

compound (41 mg, yield 39%). H-NMR (400 MHz. DMSO-d46) 5 (ppm): 3,93 (s, 3H.), 4.50-4,52 (d,

J= 7.6 Hz, 111), 4.96-498 (d i= 7.6 Hz, 1H), 7.09-7.15 (m 311), 7.35-7.42 (i, 41), 7.55-7,57 (t, J

= 7.6 Htz, I l) 7.72 (s, I H); LC-MS (ES) m/z: 363 (M+l)

Example 101

20 NN-Dimethyl-4-(9-(1-lmethyl-IH-im idazol-2-yl)-3-oxo-3,7,89-tetrahydro-2H-pyrido[4,3,2

delphthalazin-8-yl)benzamide

Example 101 A

4-Formiyl.-N7,V-dimethylbenzam ide

1005381 To a suspension of 4-formylbenzoic acid (4.00 g, 26.7 minol) in dry DCM (8 mL) were

25 added thionyl chloride (2.92 g, 40.0 mmol) and DMF (0,6 mL) dropwise at ambient temperature

under nitrogen. The reaction mixture was refluxed for 2 h. After cooling, this mixture was added to

33% dimethylamine in water (10.5 mL, 72 mmol) dropwise over 15 min in an ice-water bath, and

the reaction mixture stirred for 1 h at the same temperature. The solvent was evaporated in vacuums.

The residue was purified by chromatography on silica gel to give the title compound (2.5 g, yield

30 53%) as a yellow solid. 'H-NMR (400 MHz, DMSO-d6) 8(ppm): 2.86 (s, 311), 330 (s, 311), 7,60 (d, J 7.6 Hz, 211), 7,95 (d, J= 7.6 Hz, 211), 10.04 (s. 1HI); LC-MS ([ES1) n/z: 178 (M4- )

Example 1011B

9)-N,N-dimethyl-4-((I-oxo-1,3-dihvdroisobenzofuran-4ylim ino)methyl)benzamide

1005391 4-Aminoisobezofuran-1(3H)-one (2.10 g, 14,1 mmol). 4-formyl-N-dimethylbenzamide 35 (2.50 g, 14.1 mmol) and dry MgSC (9.84 g, 82 mmol) were added to acetonitrile (170 ml) and

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stirred under refux overnight.The mixture was filtered, and the solvent was evaporated under

reduced pressure and the residue was re-crystallized to obtain 3.5 g of title compound as a pale solid.

4H-NMR (400 MHz. CDCh) S (ppm): 3.01 (s. 3M), 3.15 (s, 31H), 5.43 (s 2H)t 7.38-7.40 (d,.I= 7.6

Hz, I H), 7,55-7.61 (m. 3H), 7,80-7.82 (d, J= 7,6 lz, 1H) 7196-7.98 (d, J= 8 Iz 21)8.58 (s, Il);

5 LC-MS (ES11) nz: 308 (M+1)

Example 1OiC

Ethyl 2-(4-(dimethylcarbamoyl)phenyI)-3-(1 -methyl-i H-imidazol-2-yl)-4-oxo-1,2,3,4


[005401 (E)-N,N -Dimethy I -4-((1-Noxo- 1,3-dihydroisobenzofuran-4ylinino)methyl)benzamide (924

10 mg, 3,0 mmol) 1-methyl-IH-imidazole-2carbaidehyde (363 mg, 3.3 tumol), sodium (276 mg, 12

mmol) in ethanol (30 ml) and ethyl propionate (45 mL) were added and the mixture was stirred at

room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and

extracted with ethyl acetate (100 mL x 4) and concentrated. The crude product was purified by

column chromatography (silica gel, petroleum ether / ethyl acetate =20:1 to 1:2) to afford the title

15 compound as a yellow solid (500 mg, yield 37%). LC-M.S (ESI) m/z: 447 (M+-)

Example 1O1D

N,N-dimethyl-4-(9-( i-methyl-IHI-im idazol-2-vl)-3-oxo-3,7.8,9-tetrahydro-2H1-pyrido[4,3,2

de]plthalazin-8-yl)benzamide

Ethyl 2-(4-(dimethylearbamoyl)phenyl)-3-(I-methyll- H-imidazol-2-yl)-4-oxo-1,2,34

20 tetrahydroquinoline-5-carboxylate (500 mng, 1.12 mmol) and hydrazine monohydrate (8 niL) were

added and the mixture was stirred under 40 C for 3 h. Then the mixture was cooled to roon

temperature and filtered to give the title compound (90 mg, yield 19%) as a white solid. H--NMR

(400 MHz, DMSO-d6) S (ppm): 2.86 (s, 311), 2.96 (s, 311), 3.42 (s, 3H), 4.66-4.69 (d, J= 10.4 Hz;

11) 496-4.99 (d, J= 104 Hz, IH) 6,73 (s, 1H), 6.89 (s, IN), 7.16-7.19 (im .1= 7.6 Hz, I H)7.29

25 7 45 (m. 6H), 7.56-7.60 (t, J= 7.6 Hz IH1) 12.18 (s, I:H) LC-MS (ESI) m/z: 415 (M+.1).

Example 102

9-(4,5-Dimethvl-4Hl 1 ,2.4-triazol-3-yl)- 8-phenyl-8.9-dihydro-2H-pyrido[4,3;.2-dejphthalazin-3(7H)one

Example 102A

30 lisothiocyanatomethane

1005411 To a solution of methylamnine hydrochloride (61 g, 0.9 mot) in 100 ml. of water was added

carbon disulfide (68.5 g, 0.9 mol). The mixture was cooled to 10 C, a cold solution of sodium

hydroxide (72 g, 1.8 mol) in water (160 mL) was added dropwise over a period of 30 min. After the

addition, the internal temperature rise to 85 "C gradually. The solution was kept at this temperature

35 for 1.5 hr. The bright red solution was cooled to 35 'C - 40 C, and was added ethyl chlorocarbonate

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(98 g, 0.9 mol) over a period of I hr with stirring. The stirring was continued for 30 min after the

addition. The mixture was allowed to stand overnight. The organic layer was separated, dried over

Na2 SO4, and distilled under atmosphere pressure. The fraction, which boils at 115-120 C, was

collected as a colorless crystal (40 g, yield 61 %). 'H-NMR (400 M z, CDC],) 6 (ppm); 3.29 (s,

5 314).

Example 102B

2-Acety I-N -methylhydrazinecarbothioamide

1005421 To a stirred solution of acetohydrazide (3.7 g. 50 mmol) in methanol (30 mL) was added a

solution of compound isothiocyanatomethane (3.65 g, 50 nmol) in methanol (50 ml,) at 0 'C, After

10 the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated

to give crude product (7 g) as a white solid which was used in the next step without further

purification, LNMS (ES!) in/z: 148 (M+1)

Example 102C

3.4-Dimethyl- IH-1,2,4-triazole-5(4H)-thione

15 1005431 To a stirred solution of crude 2-acetyl-N-methylhydrazinecarbothioamide (7 g, 47.6 nnol)

in ethanol (100 miL) was added triethylamine (14-4 g, 143 mmol). After the addition, the mixture

was heated to reflux overnight and was then concentrated to give the title compound (4.2 g. yield

65% for two steps) as a white solid which was used in the next step without further purification. H

NMR (400 MHz, DMSO-d6) 6 (ppm): 2.28 (s, 3H), 3.38 (s, 31f 13.40 (s, I H). LC-MS (ESI) m/z:

20 130 (M+1)

Example 102D

3 ,4-Dimethyl-41-1,2,4-triazole

1005441 A suspension of 3,4-dimethy 1h,2.4-triazole-5(4H)thione (4.2 g, 32.5 mmol) in

dichloromethane (72 mL) was cooled to 0 'C A solution of 30% hydrogen peroxide (16.9 ml, 149.5

25 mmol) in acetic acid (44 mL) was added dropwise, After the addition, the mixture was allowed to

stir at room temperature overnight, The solvent was removed under reduced pressure. The residue

was dissolved with water (20 mL) treated with aqueous sodium hydroxide to p14 = 12, extracted

with dichloromethane (80 mL x 8). The combined organic layers were dried over anhydrous

NaSO4, concentrated to give the title compound (2.3 g, yield 73%) as a brown solid. H-1NMR (400

30 MHz, CDC) 6 (ppm): 2.47 (s, 311), 3.63 (s, 311), 8.09 (s, III). LC-MS (ES) m/z: 98 (M+1)

Example 102E

(4,5Dimethyl-4- 1,2,4.-triazol-3 -yl)methanol

1005451 A mixture of 3,4-dimet.hyl-4H-1 ,2,4-triazole (2.3 g, 23.7 mmol) and formalin (5 mL) was

heated to 90 C overnight. The mixture was concentrated to give crude product. The crude product

35 was purified by silica gel chromatography (dichloromethane/ methanol=200: 1 to 15:1) to give the

title compound (2.48 g, yield 82%) as a white solid. 11-NMR (400 MHz, DMSO-d6) 6 (ppm) 2.31

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(s, 31) 3.52 (s, 311), 4.52-4.54 (d,,J= 5.2 Hz, 211), 5,49-5.51 (t,1= 5.2 Hz, itt LC-MS (ESI) m/z;

128 (M+I)

Example 102F

4,5-Dimethyl-4H-1-1 ,2,4-triazole-3 -carbaldehyde

5 1005461 A mixture of (4,5-dimethyl-411-1,2,4-triazol-3-yl)methanol (2,48 g, 19.5 mmol) and

manganese (TV) oxide (17.8 g, 204.8 mmol) in dry tetrahydrofuran (72 mL) was stirred at room

temperature overnight. The mixture was filtered, and the cake washed with dichloromethane (100

mL x 3). The combined filtrate was concentrated to give the title compound (1.6 g, yield 66%) as a

while solid. I-NMR (400 MHz, DMSO-d6) 5 (ppm) 2.54 (s, 311). 3.89 (s, 31), 10.06 (s, 211), L.C

10 MS (ESi) m/z: 126 (M+1).

Example 102G

Ethyl 3 -(4,5-dinethyl-4H- L2.4-triazol-3-yl)-4-oxo-2-phenyl-1/2,3,4-tetrahydroqu inoline-5

carboxylate

1005471 A mixture of (E)-4-(benzvlideneamino)isobenzofuran-1(3/)-one (237 mg, I mmol) and

15 4,5-diniethyl-4H1-I,2,4-triazole-3- carbaldehyde (150 ing, 1.2 immol) in ethyl propionate (10 mL)

was cooled to 0 'C. Then a solution of sodium ethoxide in ethanol [sodium (92 mg, 4 mmol) in

ethanol (5 mL)] was added dropwise. After the addition, the mixture was stirred at 10 *C for 5 hr,

then 30 "C 2,5 hr. The mixture was quenched with water (10 mL) and solvent was removed in

vacuum The residue was dissolved in water, and then extracted with ethyl acetate (30 mLx4). The



petroleum ether / ethyl acetate = 5:1 then ethyl acetate /methanol= 15:1) to give the title compound

(60 mg, yield: 15 %). LC-MS (ESI) m/z: 391 (M+l)t

Example 1021H

25 9-(4,5-Dimethyl-411-1,2,4-triazol-3 -yl )-8-phenyl-8,9-dihydro-21-H-pyrido[4,3.2-dejphthalazin3(71H)-one

[00548] A mixture of ethyl 3-(4,5-d iniethyl-411-1,2,4-triazol-3-yl)-4-oxo-2-phenykl- ,2,3,4

tetrahydroquinoline-5-carboxylate (60 mg) in 85% hydrazine monohydrate (I mL) and methanol (3

mL) was stirred at 10 C for 2.5 h. The mixture was purified by prep-HIPLC to obtain the title

30 compound as a yellow solid (6 mg, yield: 11 %). 'H-NMR (400 MHz, CD3OD) 8 (ppm); 2.33 (s, 31),3.36 (s, 31), 4.79-4.81(dJ=: 11.6 Hz, IH), 4.99-5.02 (d.- 11.6 Hz, 1Ii), 7.21-7.23 (m, 211)., 7.3 1-733 (m, 21H), 7.45-7.48(n, 21), 7.59-7.67 (m, 211): LC-MS (ESI) m/z: 359 (M-4)"

Example 103

9-(4,5-Dimuethy1-411-1.2,4-triazol-3-yl )-8-(4-fluoropheny I)-8,9-dihydro-2H-pyrido[4,3,235 de]phth alazin-3(7/)-one

Example 103A

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Ethyl 3-(4,5-dimethyl-4H-1 2,4-triazol-3-yl)-2 -(4-fluorophenyi)-4-oxo-1.2.3,4-tetrahvdroquinoline

5-carboxylate

1005491 A mixture of (E)-4-(4-fluorobeizyideneamino)isobenzofuran-1 (311)-one (510 mg, 2 nmol)

and 4,5-dimethyl-4H- 1 ,2,4-triazole-3- carbaldehyde (275 mg, 22 mmol) in ethyl propionate (20

5 mL) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol (sodium (184 mng, 8 mmol)

in ethanol (10 mL)) was added dropwise. After the addition, the mixture was stirred at 10 'C for 2

hr, then 30 C for 4 hr. The mixture was quenched with water (10 mL) and solvent was removed in

vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (30 mL x 4), The

combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and

10 concentrated to give a crude product. The crude product was purified by chromatography (silica gel,

petroleum ether / ethyl acetate = 3:1 then ethyl acetate /methanol = 30:1) to afford the title

compound (170 mg, yield: 21%). LC-MS (ESI) m/z: 409 (M+1)'.

Example 103B

9-(4,5-Dimethyl-4H- 1,2,4-triazol-3-yl )-8-(4-fluorophenyl)-8.9-d ihydro-21-pyrido[4,3 .215 de]phthalazin-3 (7H)-one

100550j A mixture of ethyl 3-(4,5-dimethvl-4b1-,-2 ,4-4riazol-3-yl)-2-(4-fliuorophenyl)-4-oxo

1.2,3,4-tetrahydroquinoline-5-carboxylate (1~/0 mg) in 85% hydrazine monohydrate (1 mL) and

methanol (3 ml,) was stirred at 25 " for 3 h, The mixture was purified by prep-HPLC to obtain the

title compound as a yellow solid (40 mg. yield: 26%)'H-NMR (400 MHz. DMSO-d6) 3 (ppm): 2.23

20 (s, 3H),338 (s, 3 )11 4.784.80(dJ= 11.0 Hz, 11), 4.99-5,02 (d, J= 1 1.0 Hz., IH), 7.l1-7.18 (m, 3H), 7.35-7.40 (m 21), 7.47-7.51 (in, 2H) 7.57-7.61 (t. J= 7.6 l1. I t), 12.19 (s, IlH)-; LC-MS

(ESf) nOz: 377 (M4I)

Example 104

2-Fluoro-ANNdimethy-5 -(9-(1-methylH-imnidazol-2-y])-3-oxo~3,7,8.94tetrahydro-2H25 pyrido[4,3,2-dejphthalazin-8-yl)benzamide

Example 104A

5-(Diethoxymethyl)-2-fluorobenzonitrile

1005511 To a stirred solution of 2-fluoro-5-formlihenzonitrile (5.96 g, 40 mnol) in ethanol (5.6 g, 120 mmol) was added ammonium chloride (85.6 mg, 1.6 mmnol) After the addition, the mixture was

30 cooled to 0 "C and triethyl orthioformate (6.52 g, 44 mmol) was added dropwise. After the addition,

the mixture was stirred at room temperature overnight. The mixture was concentrated, then filtered

and the cake washed with ethyl acetate (20 mL x 2). The filtrate was concentrate to give the title

compound (8.8 g, yield 98%) as a colorless oil. 'H-NMR (400 MHz, CDCI3 ) 6 (ppm): 1.22-1.29 (m,

6H), 3.50-3.70 (in. 411), 5.50 (s. 11), 7.19-7.24 (t, J=- 8.8 Hz, 114), 7.70-7,74 (M, 11-), 7,76-7,78 35 (dd, J = 6.4 lz, 2= 2.4 Hz, 1-), LP-MS (ESI) m/z: 224 (M+'1)

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Example 104B

2-Fluoro-5-formylbenzoic acid

[005521 A mixture of 5-(diethoxymethyl)-2-fluorobenzonitrile (8.8 g, 39.5 mmol) in 3N aqueous

sodium hydroxide (100 ml,) was heated to 90 'C and stirred for 8 hr Then the mixture was cooled to

5 room temperature and acidified with 3N hydrochloric acid to pH -2. and then extracted with ethyl

acetate (200 mL x 4). The combined organic layers were dried over anhydrous Na2 SO 4 and

concentrated to give 2-fluoro-5-formylbenzoic acid (6.6 g, yield 99%) as a white solid. 1H-NMR

(400 MHz, CDClJ) 6 (ppm): 734-7.39 (dd,,J) = 10 Hz, J 84 Hz, iH), 8.14-8.18 (m. 1 H), 8.57

8,59 (dd, J, = 7,2 Hz W =2.4 Hz 1i), 10.04 (s, Id). LC-MS (ES1) m/z: 169 (M41).

10 Example I 04C

2-Fluoro-5-formyl-NN-diimethylbenzamide

1005531 The solution of 2-fluoro-5-formylbenzoic acid (3 g, 17.8 mmtol) in methylene chloride (10

mL) was added thionyl chloride (2.0 mL. 26.7 mmol ) slowly at 0 "C . Then the cold reaction

mixture was heated to reflux for 3 h. The solution wvas cooled to 0 *C, added dinethylamine (40

15 wt.% solution in water, 5mL) slowly, and then stirred at room temperature for Ih. The solution was

washed with water and brine, the organic layer was dried with NaSO41 and the solvent: was removed

to get the desired product (2.4 g, yield 76%), LC-MS (ES1) m/z: 196 (M+1)"

Example104D

(E)-2-fluoro-NN-dinethyl-5-(Il-oxo-1,3-dihvdroisobenzofuran-4-ylinino)methyl.)benzamide

20 100554] A solution of 2-fluoro-5-formyl-NNdimethylbenzamide (2.38 g, 12.2 mmol), 4

atninoisobenzofuran- 1(3)-one (1.82 g, 12.2 memol), anhydrous magnesium sulfate (14:67 g, 122

imol) in acetonitrile (100 ml) was heated to reflux for 2 days. The solution was filtered and

removed in vacuum. The crude product was re-crystal with isopropanol to give the title compound

(1.5 g, yield: 37%) HI.-NMR (400 MHz, DMSO-d6) 6 (ppm): 2,91-2.92 (d./= 0.4 Hz, 31-), 3.07 (s,

25 3H) 5.55 (s. 2H) 7.52-7.56 (L. J= 8.8 Hz. 11i), 7.67-7.70 (m,2H), 7.76-7.78 (mlt) 8.02-8.04 (m, IH), 8.10-8.14(m, 1H1), 8.83 (s, I H): LCEIS (ESI) miz: 327 (M+1).

Example 04E

Ethyl 2 -(3-(dinethylcarbamoyl)-4-fluorophenyl)-3-(I-methyl-lH-imidazol-2 -yi)-4-oxo-12,3,4

tetrahydroquinoline-s-carboxylate

30 [005551 A mixture of compound 1-methyl-1H-imidazole-2-carbaldehyde (110 mg 1.0 mmol) and

(E)-2-fluoro-N.dimethyl-5-((I-oxo-1,3-dihydroisobenzofuran-4-ylimino)methyl)benzamide (300

ing, 0.92 mmol) in ethyl propionate (10 niL) was cooled to 0 "C. Then a solution of sodium ethoxide

in ethanol (sodium (85 mg. 3.68 mimol) in ethanol (5 rL)) was added dropwise. After the addition,

tie mixture was stirred at room temperature for 2.5 hr. The mixture was quenched with water (20

35 mL) and solvent was removed in vacuum, The residue was dissolved in water and extracted with

ethyl acetate three times, washed by water, brine then the extraction was evaporated, the crude

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product was purified by chronatography to obtain a yellow solid. The solid was dried in vacuum at

50 T to give the title compound (130 mg, yield: 30%). LC-MS (ESI) m/z: 465 (M+1) .

Example I04F

2-Fluoro-N,N-dimehyl-5-(9-(1 -iethyl-IH-iimidazol -2-yl)-3-oxo-3,7,8,9-tetrahydro-2H

5 pyrido[4,3,.2-de]phthalazin-8-yl)benzaimide

[005561 A mixture of compound ethyl 2-(3 -(diimethylcarbainoyl)-4-fluorophenyl)-3-( I -methyl-l

imidazol-2-yl)-4-oxo- 1,2,3 .4-tetrahydroquinoline-5-carboxylate (130 mg) in hydrazine monohydrate

(85%, 2 mL) and methanol (5 nL) was stirred at room temperature for 4 h. The resulting mixture

was filtered and washed with water (20 ml) and methanol (5 ml) to obtain a white solid. The solid

10 was dried in vacuum at 50 "C to obtain the title compound (30.0 mg, yield 30%). H-NMR (400

MHz, DMS0-d6) 6 (ppm): 2,72 (s, 31), 2.97 (s, 311), 3.43 (s, 314) 4.67-470 (d, J= 10.8 Hz, I HJ), 4.

95-4,97 (d, J= 10.8 Hz,4 H), 6.72-6.73 (d, J 1.2 Hz,I1H) 6.89-6.89 (d,= 0.8 Hz, 1H) 7.15-7.23

(m 211), 7.34-7.41 (m, 3 H), 748-7.49 (m, H),7.56-7.60 (t .I8 Hz, 1iH), 12.17 (s, I H); LC-MS

(ESI) m/z: 433 (M+l)

15 Example 105

8-(4-Chiorophenyl)-9-( 1-methyl-IH-imidazol-2-yl)-8,9-dihydro-21-pyri do[4, 3,2-delphthalazin3(711)-one

Example IOSA

(E)-4-(4-Chlorobenzyl ideneamino)isobenzofuran- 1(3H)-one

20 {005571 To a stirred mixture of 4-chlorobenzaldehyde (2.3 g; 16.1 nmol) and anhydrous

magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 ml) was added 4

aminoisobenzofuran- I (31)-one (2 g, 1 3.4 mmol) at room temperature. After the addition, the

mixture was stirred at reflux for overnight. The mixture was filtered and the cake was washed with

ethyl acetate (50 mL x 3). The filtrate was concentrated to give crude product. The crude product

25 was washed with petroleum ether and re-crystallized from ethyl acetate to give the title compound (2

g, yield: 55%). LC-MS (ESI) ni/z: 272 (Ml1)

Example 105B

Ethyl 2-(4-chlorophenyl)-3-(i-methyl-i 1.H-imidazoi-2-yl)-4-oxo-I,2,3,4-tetrahydroquinoline-5

carboxylate

30 [005581 A mixture of (E)-4-(4-chlorobenzylideneamino)isobenzofuran-1(3/)-one (500 mg, 1.85

mmol) and N-methyl-2- imidazolecarbaldehyde (222 mg, 2.1 nnmol) in ethyl propionate (20 nL)

was cooled to 0 0C Then a solution of sodimn ethoxide in ethanol (sodium (174 mg, 7.4 mmol) in

ethanol (10 mL)) was added dropwise. After the addition, the mixture was stirred at room

temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in

35 vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL x 4).

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petroleum ether / ethyl acetate =1:1) to give the title compound (150 mg, yield 20%) s LC-MS (ES)

m/z: 410 (M+I)f

5 Example 105C

8-(4-Chlorophenyil)-9-( I methyl-iH-imidazoi-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-dejphthalazin

3(71)-one

100559] A mixture of ethyl 2-(4-chlorophenyl)-3-(-methyl-I iimidazol-2-yl)-4-oxo-i,234

tetrahydroquinoline-5-carboxylate (150 mg, 0.37 mmol) in 85% hydrazine monohydrate (4 ml) and

10 methanol (6 ml) was stirred at room temperature for 2W The mixture was filtered and washed with

water to give the title compound (89 ing, yield: 65%). l-NMR (400 MHz, DMSO-d6) 6 (ppm):

3.44 (s, 314), 4.69 (d, J= 10.8 Hz, 11), 4.96 (d, J = 10.8 Hz, 11) 6.76 (s, 11H), 6.93 (d I-H), 7.16 (d,

J=8 liz, 1H), 7.33-7,44 (mi, 6H), 7.56-7,60 (m, I H), 1219 (d, 1i); LC-MS (ESI) m/z: 378 (M+1-1)

Example 106

15 9-(I-Methyl-I Iiimidazol-2-yl)-8-(4-(trifiluoromethyl)phenyl)-8,9-dihydro-21-pyrido.[4,32die]phthal azin-3 (711)-one

Example 106A

(E)-4-(4-(Triflioromethyl)benzvlideneamino)isobenzofuran- I(311)-one

[005601 To a stirred mixture of 4-(trifliuoronetll)benzaldehyde (2.8 g, 16 1 imol) and anhydrous

20 Magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 mL) was added 4

aminoisobetizofuran-i(3H)-one (2 g, 13.4 mmol) at room temperature. After the addition, the

mixture was stirred at reflux for overnight. The mixture was filtered and the cake was washed with

ethyl acetate (50 ml x 3). The filtrate was concentrated to give crude product. The crude product

was washed with petroleum ether and re-crystallized from ethyl acetate to give the title compound

25 (2.8 g, yield: 68%). LC-MS (ESI) n/z 306 (M+1)

Example 106B

Ethyl 3-(1-methyl-1 H-imidazol-2-yI)-4~oxc-(4-(tifuoromethyl)phenyi)-1/2,3,4

tetrahydroqui nol inc-S-carboxylate

[00% 1 A mixture of (E)-4-( 4-(trifluoromethyl)benzylideneamino)isobenzofuran. 1(311)-one (i g, 30 3.28 mniol) and N-methyl-2- imnidazolecarbaldehyde (400 mg, 3.61 mmol) in ethyl propionate (40

mL) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol (sodium (31 mg, 13.l mmol)

in ethanol (10 mL)) was added dropwise. After the addition, the mixture was stirred at room

temperature for 2 hr. The mixture was quenched with water (10 miL) and solvent was removed in

vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL x 4). 35 The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and

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concentrated to give crude product. The crude product was purified by chromatography (silica gel.

petroleum ether / ethyl acetate =1:1) to give the title compound (150 mg, yield 8%). LC-MS (ESI)

m/z: 444 (M+ 1 )'

Example 106C

5 9-(I- Nethyl-lHimidazol-2-yIl)-8-(4-(trifluoromcthyl)phenyl)-8,9-dihydro-21-I-pyrido[4,3;2de]phthalazin-3(7H)-one

1005621 A mixture of ethyl 3-(1 i-methyl- I.Him idazol-2-yl)-4-oxo-2-(4-(trifluoromethyl)phenyl )

1,2.3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.34 nimol) in 85% hydrazine monohydrate (4

ml) and methanol (6 mL) was stirred at room temperature for 2h, The mixture was filtered and

10 washed with water to give the title compound (25 mg, yield: 18%). 'H-NMR (400 MIzDMSO-d6)

8 (ppm): 3,46 (s 31-), 4,81 (d, J= 10,8 Hz, 1H).5.07 (d, J= 10.8 H-z, I H), 6.82 (s, IH) 6.97 (d, 1H), 7.16 (d J 8 lHz, l H 7.41 (d,.J=7,6 1z 2H), 7.58-7.69 (in, 511), 12.22 (d, 114); LC-MS (ESI)

m/z: 412 (M+I-I

Example 107

15 8-(4-Fluoropheny)-9-(thiazoi-2-yi)-8,9-dihydro-2H-pyrido[4, ,2-de]phthalazin-3(71-J)-one

Example 107A

Ethyl 2-(4 -fluorophenyl)-4 -oxo-3 -(thiazol-2-vl)- 1,2,3 ,4-tetrahydroquinoline-5-carboxylate

100563] A mixture of (E)-4-(4-fl uorobenzylidencamino)isobenzofuran -1(3)Ii-one (L. 88 g 737

mmol) and thiazole-2-carbaldehyde (1 g, 8,8 mmnol) in ethyl propionate (50 ml) was cooled to 0 "C.

20 Then a solution of sodium ethoxide in ethanol (sodium (678 g, 29 mmol) in ethanol (30 mL)) was

added dropwise. After the addition, the mixture was stirred at room temperature for 2 hr. The

mixture was quenched with water (10 ml) and solvent was removed in vacuum. The residue was

dissolved in water, and then extracted with ethyl acetate (100 ml x 4). The combined organic layers


25 product. The crude product was purified by chromatography (silica gel, petroleum ether / ethyl

acetate = 10:1 to 1:10) to give the crude compound (180 mg). LC-MS (ES1) m/z: 397 (M+l).

Example 107B

8-(4- luorophenyl)-9-(thiazol-2-y I)-8;9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

[005641 A mixture of ethyl 2 -(4-fluorophenyl)-4-oxo-3 -(thiazol-2-yl)- 1,2,3.4-tetrahydroquinoline-5

30 carboxylate (180mg) in 85% hydrazine monohydrate (10 tt.) and methanol (10 mL) was stirred at

45 'C for overnight, Methanol was removed under reduced pressure. The mixture was filtered and

washed with water to give the title compound (3 mg, yield: 2%). H-NMR (400 MHz, CD01D) 6

(ppm): 4.88 (d, J= 8.0 Hz, 1H-), 5.09 (d,1J= 8.0 Hz, 11), 7.0(t, 21H), 7:21(d, 1 H), 7.36-7.40 (n,

21), 747 (d, 11), 7,59(d, 11-1), 7.65 (t, I 1-1), 7.74 (d, 11); 't-NMR(400 MHz, CDOD) 6(ppm): 35 116.36 (s); LC-MS (ESI) m/z: 365 (M+i)^

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Example 108

9-(I-Ethyl-IHtimidazol-2-yl)-8-(4-flucrophcnyl)-8,9-dihydro-2H-pvrido[4.3.2-e]phthalazin-3(7H)

one

5 Example 108A

Ethyl 3-(1 -ethyl- Himidazol-2-yl)-2-(4-fluorophenyl)-4-oxo -,2,3,4-tetrahydroquinoline-5

carboxylate

1005651 A mixture of (E)-4(4-fluorobenzvlideneamino)isobenzofuran-l(3H)-one (765 mg, 3 mmol)

and N-ethyl-2- imidazolecarbaldehyde (372 mg, 3 mmol) in ethyl propionate (45 mL) was cooled to

10 0 'C. Then a solution of sodium ethoxide (sodium (276 mg, 12 mmol) in ethanol (45 mL)) was

added dropwise. After the addition, the mixture was sirred at room temperature for 4 hr. The

mixture was quenched with water (10 mL) and solvent was removed in vacuu.n The residue was

dissolved in water, and then extracted with ethyl acetate (100 mL x 4). The combined organic layers


15 product The crude product was purified by chromatography (silica gel, petroleum ether /ethyl

acetate = 25:1 to 5:1) to give the title compound (90 mg, yield: 7%). LC-MS (ESI) m/z: 408 (M+ 1).

Example 108B

Synthesis of 9-( 1-Ethyl-1H-imidazol -2-vl)-8-(4-fluorophenyl)-8.9-dihydro-2H-pyrido[4,3,2

dejphthalazin-3(7H)-one

20 [00566) A mixture of ethyl 3-(i-ethyl-IJ-imidazol-2-yi)-2-(4-fluorophenyl)4-oxo- 1,2,3,4

tetrahydroq uincline-5-carboxylate (90 mg, 0.22 mmol) in 85% hydrazine monohydrate (4 mL) and

methanol (10 mL) was stirred for 4 h at room temperature. Methanol was removed under reduced

pressure. The mixture was filtered and washed with water to give the crude product. The crude

product was purified by prep-HPLC to give the title compound (38.5 mg, yield: 47%). I--NMR

25 (400 MHz, MeOD) 6(ppm): 1.06-1.09 (t,. j 7.2 Hz, 3H), 3.74-3.78 (m, 2H) 4.60-4.62 (d, J -= 11.6

Hz; 11), 4.98-5.01 (d. J=-- 11.6 Hz, 1H1), 6.91-7.02 (m, 411), 7.19-7.21 (m 1H.), 7.39-7.43 (in, 211). 7.56-7.64 (Im, 211); LC-MS (ES!) m/z: 376 (M+ 1)'.

Example 109

30 8-(4-((4-Ethyl-3-methylpiperazin-I--yi)methyl)phenyl)-9-ph.enyl-8.,9-dihydro-2H-pyrido[4,32dejphthalazin-3(711)-one

1005671 To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2

de]phthalazin-8-yl)benzaldehyde (86 mg 0,23 mmol) in dryness DCM (15 mL) was added HOAc

followed by I -ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was

35 stirred at room temperature overnight. Then the mixture was cooled to 0 'C. Sodium borohydride

(85 mg. 1,4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12

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hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol

(10/1) and filtered. The filtrate was concentrated to give the crude product. which was purified by

prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 'H-NMR (400 MHz.

DMSO-d6) 6 (ppm): 1.30 (t, 314)t 1.42 (in. 311). 3.23 (s, 11), 3.47-3.56 (n, 611), 3.80 (t, 211). 4,46

5 (m, 31H) 4.91 (m, 10H), 7.20-7.29 (mn, 3H.). 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H). 7.59(m, I ), 7.69

(t IM). LC-MS (EST) in/z: 552(M+±1)

Example 11 0

8-(4-((4-Ethylpiperazin-I -vl)nethyl)phenyl)-944-fluoro phenyl)-8,9-dihydro-21-pyrido[4,3,2


10 1005681 A mixture of 4~(3-oxo-9-phenyl-3,7,8,9-tetrahydro-21H-pyrido[4,3,2-dejphthalazin-8

yl)benzaldehyde (200 ing, 0.52 nimol), N-ethylpiperazine (209 mg, 1.56 minol) and acetic acid (156

mg; 2.6 nmol) in dichloromethane (30 nL) was stirred at room temperature overnight. Then the

mixture was cooled to 0 C and sodium triacetoxyborohydride (165 nig, 0.78 mmol) was added.

After the addition, the mixture was stirred at room temperature for 5 h, Dichloromethane was

15 removed under reduced pressure. The crude product was purified by pre-HIPLC to give the title

compound (96 ing, yield 33%). H-NMR (400 Mz, CD3OD) 6 (ppm): 1.37-1.41 (t, J=- 6.8 Hz

314), 3.30-3.34 (m, 211), 3.47-3.86 (m, 8H); 4.36-4.38 (d, J= 7 6 Hz, 1H), 4.46 (s 21). 4.80-4.82 (d, J 8.4 lz 11-1), 6.92-6,96 (m, 21), 7.1 1-7.15 (m. 2H), 7.21-7.23 (n, I H), 7.42-7.45 (m. 211), 7,51

7.56 (n, 3H), 7.63-7.67(m, IlH). LC-MS (ESI) m/z: 484 (M+H)

20 Example I 11

4-(9-(4-Fluorophenyl)-3 -oxo-3 78,9-tetrahydro-2H-pyrido[4.3,-delphthalazin-8-yl)-,N,

diiethylbenzamide

Example I I A

Ethyl 2-(4-(dimethylcarbamioyl)phenyl)-3-(4-fluoropheny l)-4-oxo-1.2,3,4-tetrahydroquinoline-5

carboxylate

1005691 Compound (E)-N-,dimethyl-4-((I-oxo-1.3-dihydroisobenzofuran-4

ylimi.no)iethyl)benzamide (1,36 g, 4.4 mniol) 4-fluorobenzaldehyde (600 mg, 4.84 mmol), sodium

(405 mg, 17.6 nmmol), ethanol (40 mL) and ethyl propionate (66 mL) were added and the mixture

was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced

30 pressure and extracted with ethyl acetate (100 mL x 4) and concentrated. The crude product was

purified by column chromatography (silica gel, petroleum ether/ ethyl acetate = 20:1 to 5:1) to give

the title compound as a solid (490 ng, yield 22%), LC-MS (ESI) m/z: 461(M+1)

Example I 1B

4-(9-(4-Fluorophenyyl)-3-oxo-3,7,8,9-tetrahydro-2H-pvrido[4,3,2-de)phthalazin-8-yl)-,N

35 dimnethylbenzamide

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1005701 A mixture of ethyl 2-(4-(dimethylearbamoyl)phenyl)-3-(4-fluorophenyl)-4-oxo- 1,2,3 .4tetrahydroquinoline-5-carboxylate (490 ing, I mmol) and hydrazine nionohydrate (15 mL) was

stirred at 40 T for 3 h. Then the mixture was cooled to room temperature and filtered to give the

title compound (110 mg, yield 24%) as a white solid. 'H-NMR (400 MHz, DMSO-d6) 6 (ppm): 2.82

5 (s, liH) 2.93 (s, 11H), 4.36-4.38 (d, J=: 9.2 Hz, lH). 4.78-4.80((d J= 9,2 Hz, 1H), 7,01-7.03 (m, 21H),

7.14-7.19 (m, 31H), 7.25-7:28 (im, 2H), 7.32-7.40 (i 3H), 7.45 (s, I H) 7,56-7.60 (t,.J= 8 Hz, iH),

12 17 (s, l); LC-MS (ESI) m/z: 429 (M+i)

Example 112

4-(8-(4-((Dimethylamino)methyl)plienvi)-3 -oxo-3,7. 8,9-tetrahydro-2H-pyrido[4, ,A2-de]phthalazin10 9-yl)-N ,N-dimethylbenzamiide

Example 1 12A

Ethyl 24-(4-(diethoxymethyl)pheny l)--(4-(dimethylcarbamoyl)phenyl)-4-oxo- 1,2,3,4


1005711 To a mixture of 4-formyl-N,N-dimethylbenzamide (960 mg.5.42 inmo, (E)-4-(4

15 (diethoxymethyl)benzylideneamino) isobenzofuran-1(3H)-one (1.84 g 5.42 imol) and sodium

methoxide (499 mg, 21 .7 mmol) was added to ethyl propionate (30 mL) and the mixture was stirred

at room temperature overnight, Then the resulting mixture was evaporated under reduced pressure

and extracted with EtOAe (100 mL x 4) and concentrated. This gave the crude product (250 lg).

LC-MS (ESI) m/z: 545 (M+1)z-1

20 Example 12B

4-(8-(4-(Diethoxymethyl)phenyl)-3 -oxo-3,7,8.9-tetralydro-21-pyrido(4,3 2-dephthalazin-9-vl)

N,N -dimethylbenzamnide

1005721 Ethyl 2-(4-(diethoxym ethyl)phenyl)-34(4-(dimethylcarbamoyl)phenyil)-4-oxo- 1,2,3,4

tetrahydroquinoline-5-carboxyl ate (250 mg, 0.46 mmol) and hydrazine monohydrate (85%, 5 mL) 25 were added in MeOH (15 ml) and the mixture was stirred room temperature for 5 h. The resulting

mixture was concentrated under reduced pressure to a volume of 15 mL., and then filtered: the filtrate

was evaporated to give the title compound as a white solid (180 mg, yield 76%). LC-MS (ESI) m/z:

513(M+1)

Example 11 2C

30 4-(8-(4-Formylphenyl)-3 -oxo-3, 7,8,9-tetrahydro-2Hpspyrido[4,3.2-depiithalazin-9-yl)-NN

dimethylbenzamide

{005731 To a solution of 4-(8-(4-(diethoxymethyl)phenvl)-3 -oxo-3,7,8.9-tetralhdro-211

pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (180 mg, 0.35 nmol) in acetonitrile (10

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maL) was added trifluoroacetic acid (5 mL), stirred for 30 min, Then the mixture was evaporated

under reduced pressure to get the title compound (140 g, yield 91%). LC-MS (ESI) m/z:

439(M+1) .

Example 1l2D

5 4-(8-(48((Diethylamino)niethiyl)phenyl)-3-oxo-3.7,8 9-tetrahydro-2H1-pyrido[4,3,2-del]phthalazin

9-yl)-NU,N-dimethylbenzam ide

[005741 To a stirred solution of 4-(8-(4-forniylphenyIl)-3-oxo-3,7,8,9-tetrahydro-2H-pyridof[4,3,2

de]phthalazia-9-yl)-N,N-dimethylbenzamide (140 mg. 0.32 miol) in dried DCM (20 ml) was

added acetic acid followed by diniethylamine (57 ig, 1.3 mmol). After the addition, the mixture

10 was stirred at room temperature overnight, Then the mixture was cooled to 0 "C. Sodium

borohydride (102 mg, 0.48 mmol) was added. After the addition, the mixture was stirred at this

temperature for 12 br. DCM was removed tinder reduced pressure. The residue was washed with

ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product,

which was purified by prep-HPLC to give the title compound as a white solid (15 mg, yield

15 10%).IH-NMR (400 MHz, CD4OD) d (ppm): 2.19 (dd, 6H-), 2.93 (s, 31H), 3,06 (s, 3H), 3.40 (dd,

2H). 4,34 (d, 1H), 4,16-7,19 (m E5H), 7.23-7.26 (M, 4H), 7.54 (d. 1H) 7.61 (t, Il1). LC-MS (ESI)

m/z: 468(M+1Y.

Example 113

9-(4-Fluorophenyl)-8-(4-((4-methylpiperazi n-I -yl)methyl)phenyl)-89-dihydro-211-pyrido[4,3;.2

20 de]phthalazin-3(711)-one

1005751 A mixture of 4-(9-(4-luorophenyl)-3 -oxo-3,7. 8,9-tetrahydro-2H-pyrido[4,3,2

delphthalaziti-8-yl)benzaldehyde (150 mg 0.39 mmol), N-methylpiperazine (117 rug, 1L 17 mniol)

and acetic acid (117 mg, 1.95 mmol) in dichloromethane (20 mnt) was stirred at room temperature

overnight. Then the mixture was cooled to 0 T and sodium triacetoxyborohydride (124 nig, 0.58

25 mmol) was added, After the addition, the mixture was stirred at room temperature for 5 h,

Dichloromethane was removed under reduced pressure. The crude product was purified by prep

HPLC to give the title compound (48 mg, yield 22%). 'H-NMR (400 MHz, CDOD) 5 (ppm): 3.02

(s, 3H), 3.60-3.81 (in, 81), 4.36-4-38 (d, = 7.6 Hz ,1 H), 4.47 (s, 2H), 4.80-4.82 (d,) = 7.6 Hz ,l11),

6.93-6,97 (in, 211). 7.12-7.15 (m, 21-), 7.22-7.24 (m, 18H), 7.43-7.45 (i, 21-1), 7.52-7.57 (m, 3H),

30 7,64-7,68(m, IH). LC-MS (ESI) i/z: 470 (M+ 1)"

Example 114

9-(4-Fliorophenyl)-8-(4-(piperazi-I -ylmethyl)phenvl)-8,9-dihydro -2Hf-pyrido[4,3,2-de}phthalaziii

3(711)-one

35 Example I l4A

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tert-Butyl 4-(4-(9-(4-fluorophenvl)-3-oxo-3 .7,8,9-tetrahydro-211-pyrido[4,3,2-dejphthalazin-8

yl)benzyl)piperazine-1 -carboxylate

1005761 A mixture of 4-(9-(4-fluorophenyl )-3-oxo-3,7;8,9-tetrahydro-21H-pyrido[4,3,2

ce]phthalazin-8-yl)benzaldehyde (150 mg, 0.39 mmol), tert-butyl piperazine-i-carboxylate (218 mug,

5 1. 17 mmiol), and acetic acid (117 mng, 1.95 mmol) in dichlorornethane (20 mL) was stirred at room

temperature overnight. Then the mixture was cooled to 0 "C and sodium triacetoxyborohydride (124

mg, 0.58 nmol) was added. After the addition, the mixture was stirred at room temperature for 5 h.

Dichloromethane was removed under reduced pressure. The crude product was purified by flash

chromatography to give the title compound (70 rug, yield 32%). LC-MS (ESI) tm/z: 556 (M+)if.

10 Example t 14B

9-(4-Fluorophenyl)-8-(4-(piperazin-1-ylietliyl)phenyl)-8,9-dihvdro-2H-pyrido[4;3, 2-dei]phthalazin

3(7TH)-one

[005771 The mixture of tert-buty 4-(4-(944-fl uorophenyl)- -oxo-3 ,7,8,9-tetrahydro-21

pyrido[4,3,2-de]phthalazin-8-yl)benzyl)piperazine- I -carboxylate (70 mg, 0.12 mmol) in a solution

15 of HCI(g) in acetonitrile (sat, 10 mL) was stirred for 3 hr at room temperature. Then the mixture was

filtered to give the crude product The crude product was purified by flash chromatography to give

the title compound as a hydrochloride salt (35 mg, yield 60%).H-NMR (400 M-.z, CDIOD) 6

(ppm): 2.63-264 (i 41), 3 19-3.21 (m 411), 3.54 (s, 2H), 4.29-4.31 (d, J= 8.0. Hz,1 H),4.69-4.71

(d. J= 8.4 H~z 11), 6.89-6.93 (m, 2H), 7.07-7.10 (in, 2H), 7.19-7.26 (n, 5H), 7.54-7.56 (m IlH), 20 7,61-7.65 (m, 111), LC-MS (ESI) m/z: 456 (M+1).

Example 115

9-(4-fluoropheny l)-8-(4-((3-methylpiperazin-I-y l)imethyl)phenyl)-8,9-dihvdro-2H-pyrido(4,3 .2


25 Example 115A

4-Beazyl 1-tert-butyl 2-methyipiperazine- 1,4-dicarboxylate

[005781 To the solution of 2-methyl-piperazine (2.0 g, 20 mmol) in methylene chloride (15 muL) at 0

TC was added benzylchloroformate (3.0 mL) dropwise. The mixture was stirred at 0 C for 1 hr and

then at room temperature for 2 hr. The mixture was then cooled to 0 C, and diisopropylethylamine

30 (4.5 mL) was added and followed by (Boc)2O (4.8 g, 22 unol). The mixture was stirred at room

temperature overnight, and then the solvent was removed by rotary evaporation. The residue was

dissolved in EtOAc, washed with water and brine, dried over Na 2 S0 4, and purified with column

chromatograph on silica gel (EtOAc: hexane =1 : 9) to give an oily intermediate (4.8 g, 72%). LC

MS (ESI) r/z: 357 (M+23).

35 Example 115B

tert-13utyl 2~iethylpiperazine-1-carboxylate

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[00579] A solution of 4-benzyl I -ter/-butyl 2-nethylpiperazine- 1,4-dicarboxylate (4.8 a, 14.4

minol) in methanol (25 mL) was added 480 rmg of 10% Pd/C and stirred at room temperature under

hydrogen overnight. Filtered and concentrated to give the title product (2.8 g, yield 97%) as

colorless oil. 1H-NMR (400 MHz, CDCh) 3 (ppm): 1L21 (d J= 6,8 Hz, 31), 1.46 (s, 9H), 2.64-2,70

5 (mH, 111274- 238 (n, 111), 188-3.01 (in, 311). 3.78 (d. J= 12.4 Hz, 111). 4.16 (m 1H-); LC-MS

(ESI) m/i: 201 (M+1)

Example 115C

tert-Butyl 4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-dephthalazin-8

yl)benzyl)-2-mn ethylpiperazine- 1 -carboxylate

1t 1005801 A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3;,7,8,9-tetrahydro-2H-pyrido[4,3 .2

de]phthalazin-8-vl.)benzaldehyde (200 mg, 0.52 inmol) and iert-butyl 2-methylpiperazine-1

carboxylate (311 mg. 1 ,56 inmol) in methylene chloride (10 mL) was stirred at room temperature

overnight, then NaBHCN (129 mg, 2.1 inmol) was added and the mixture was stirred for another 5

hours. Concentrated and the residue was purified by chromatography (silica gel, petroleum ether /

15 ethyl acetate = 3:1 to 1:1) to give the title compound (70 ng, yield 24%). LC-MS (ESI) r/z: 570

(M+1).

Example 115D

9-(4-Fluorophenyl)-8(4 -((3-nmethyipiperazin-1I-ybnmethy I)phenyl)-8.9-dihydro-2H-pyrido[4,3,2

delphthalazin-3(7H)-one

20 1005811 A mixture of iert-butyl 4-(44-(9-(4-fluoropheny)-3-oxo-3 7,8,9-tetrahydro-21-Hpyrido[4,3, 2

de]phthalazin-8-yI)benzyl)-2-methylpiperazine-1-carboxylate (70 mng. 0.123 mole) in 2 ml of HCl

acetonitrile was stined for 2 hours. Concentrated and the residue was purified by prep-HPLC to

afford the title produce as a white solid (30 mg. yield 52%), 'H-NMR (400 MIiz, DMSO-d6) S

(ppm): 0.87 (d,/= 6.4 Hz. 3H), 1.49 (t J= 10 Hz, I H), 1.83 (tr 1= 10 liz, 1H), 2,55 (i, 211), 2.64

25 (n, 2H), 2.75 (m. IHF), 3.32 (s, 3 H), 4.34 (d, J= 9.2 Utz, 1 ),, 4.72 (d, .J= 9.2 Hz, 1 H). 6.97- 7.01

(m, 2H), 7.13- 7.24 (n, 711). 7.37- 7.41 (i, 2H), 7.55- 7.59 (m, 114 12.15 (s, 1H); LC-MS (ESI) ivz: 470 (M+l1)

Example 116

4-(8-(4-Fluorophenyl)-3 -oxo-3,7, 8.9-tettrahydro-2H-pyrido[4,3,2 -de]phthalazin-9-yl)-MN

30 dimethylbenzamide

Example 116A

Ethyl 344-(dimethylcarbamoyil)phenyl)-2-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoiinc-5

carboxylate

[005821 Sodium (115mg; 5umol) was added to Et0H (10 mL) to afford sodium ethoxide. (E)-4-(435 fiuorobenzyiideneamino)isobenzofuran-l(31)-one (500mg, 1:96mmol) and 4-formyv-N,N

dimiethylbenzamide (382 mg. 2.16 Imol) were dissolved in ethyl propionate (10 miL) and the

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sodium ethoxide solution was added dropwise to the mixture at 0 "C then the mixture were heated

to 30 "C for I h. To the reaction mixture was added water and EtOAc, the organic phase was

separated, washed with water and brine, The organic phase was dried over anhydrous sodium sulfate

and then concentrated to afford the crude product. The crude product was purified by flash

5 chromatography (MeOH: DCM 1:25) to give the title compound (400 mg, yield 44%). LC~MS (EST)

mi/z: 461(M+ )*

Example 116B

4-(8(4-Fluoropheny])-3-oxo-3,7.8,9-tetrahydro-211-pyrido[4,3 ,2-dejphthalazin-9-yi)-N;N

dinethlbenzamide

10 [005831 A mixture of ethyl 3-(4-(dimethyicarbamoyl)phenyl)-2-(4-fluorophenyl)4-oxo-~I,2 3,4

tetrahydroquinoline-5-carboxylate (400 mg, 0.87 mmol) and hydrazine mnoohydrate (85% 10 TmL)

were dissolved in MeOH (20 mL), and stirred at 35 C for 2 h, The mixture was concentrated under

reduced pressure. The resulting mixture was filtered, the solid was washed with water and methanol

to obtain a white solid, and the solid was dried in vacuum at 40 "C to obtain the title compound (100

15 mg, yield 54%). 'H-NMR (400 MI-Hz, DMSO-d6) 6 (ppm): 2.85 (s, 3M), 2.94 (s, 3M), 4,37-4.40 (d,

IH), 4.80-4.82 (d, 1H), 7.17-7.25 (m, 5M1) 7.33-7.36 (m, 2H) 7.39-7.41 (d, l H) 7.45 (s, I), 7.57

7.61(t, 114) 12.19 (s, l.H); LC~MS (ESI) m/z: 429 (M+1)4

Example 117

9-(4-Fluorophenvl)-8-(4-(pyTrolidinb-I-yhnethyl)pheny l)-8,9-dihydro-2H-pyrido[4,3,2

20 deJphthalazin-3(71)-one

Example 117A

9-(4-Fluorophenyl)-8(4-(pyrrolidiny- Im -iethyl)phenyl)-8,9-dihydro-211-pyrido[4,3,2

de]phthalazin-3(7h)-one

1005841 To a stirred mixture of 4-(9-(4-1uorophenyl)-3-oxo-3 .7,8,9-tetrahydro-211-pyrido[4,3 2

2-5 clelplhtalazin-8-yl)benzaidehyde (0.1 g, 026 mmol) in anhydrous DCM (4 nil..) was added AcOll

(94 mg. 1 .56 mnol) at 25 "C for 0.5 h, then pyrrolidine (37 mg, 0.52 mniol) was added at 25 'C, stirred overnight. NaBH(OAc)3 was added at ice bath, and stirred for 5 h. The mixture was

concentrated to give the crude product. The crude product was dissolved in ethyl acetate and to this

solution was added 2N HCI (10 mL). The aqueous phase was separated and 20% NaOH (20 ml) was

30 added. The mixture was extracted witb ethyl acetate and the organic phase was separated to give the

title compound (30 mg yield 26%). LC-MS (ES!) m/z 441 (M+-1J)

Example I 1711

9-(4-Fhiorophenyl)-8-(4-(pyrrolidiny-I -hnlmethyl)phenvl)-8,9-dihydro-2H-pyrido[4,3.2


35 1005851 A mixture of 9-(4-fluorophenyl )-8-(4 (pyrrolidin-yl-vinethyl)phenyl)-8,9-dihvdro-2f

pyrido[4,3 ,2-dephthalazin-3(7C)-one (30 mg) in HCI / methanol solution (20 mL) was stirred at 25

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C for 0,5 h. Methanol was removed under reduced pressure. The mixture was filtered and washed

with water, dried overnight at 50 C to give the title compound (24 mg, yield 74%). 'H-NMR (400

MHz, CD;OD) 5 (ppm): 2.00 (sj 2H), 2,16 (s, 211). 3.14 (s,2H1), 3.41 (s, 21-) 4.32 (s,211), 4.35-4.38

(d, i) 4.78-4,80 (d 1 H), 6.91-6.95 (t, 2H), 7.10-7.13 (t,2Ht 7,22-7.24 (d, I H), 7.42 (m, 4H), 7.56

5 7.58 (d.2H). 7.64-7.70(11): 1C-MS (ES1) m/z: 441 (M4lj)

Example 118

9-Phenyi-8 9-dihydro-211-pyrido[4,3,2-de]phthalazin-3(7H)-one

Example I18A

2-Oxo-N-(1-oxo-1,3 -dihydroisobenzofuran-4-yl)-2-phenvlacetanide

10 1005861 To a solution of 4-aminoisobenztfuran-1(3H)-one (4.0 g, 26.8 mmol), 2-oxo-2

phenylacetic acid (4.1 g, 26.8 mmol), and HI3TU (15.2 g 40.2 mmoi) in dichloromethane (240 mL)

was added TEA (8 ml). The reaction mixture was stirred at room temperature overnight. The

resulting mixture was added water and adjusted to pH = 6-7 with 1% aq. HC, and then was filtered.

The filtrate was extracted with ethyl acetate. The ethyl acetate layer was evaporated and the crude

15 product was purified by gradient chromatography (silica gel, petroleum ether / ethyl acetate 6:1 to

3:1) to give the title compound (5.0 g yield 66%). LC-MS (ESI) m/z:282(M+1l).

Example 118B

N-(4-Methoxybenzyl)-2-oxo-N-( 1 -OXO- 1,3~-dihydroisobenzofuran-4-yl )-2-phenylacetamide

[005871 To a solution of 2-oxo-NV-(I-oxo- ,3 -dihydroisobenzofuran-4-yl)-2-phenylacetamide (S g, 20 1 17 nmol) in DMF (48 mL) was added NaH! (0.78 g, 19.5 mmol). The solution was stirring at room

temperature for 1.5 hr, followed by the addition of 1-(chloromethyl)-4-iethoxy-benzene (2.8 mL).

After stirred at 30 "C overnight, the resulting mixture was added water and adjusted to p! = 3~4

with 0.5 N aq. HCL Then ethyl acetate was added, concentrated and filtered, the filtrate was washed

by ethyl acetate, the combine ethyl acetate layer was washed with brine, dried over anhydrous

25 sodium sulfate, concentrated, and purified by flash chromatography on silica gel to obtain the

desired compound (4.7g yield 66%). LC-MS (ESI) miz: 402 (M I) 'H-NMR (400 MHz, DMSO

d6) 6 (ppm): 3.73 (s, 3H), 4.83-5.17 (m 41). 689-6.91 (d, J- 8.8 Hz 21H), 7.18-7.20 (m, 2$) 7.24

7.26 (m, 11H1). 7.38-7.42 (t, 1H), 7.52-7.56 (m, 21-1), 7.69-7.71 (n, 1f). 7.75-7.81 (n, 3H).

Example i18C

30 Ethyl 4-hydroxy-1-(4-methoxybenzyl)-2-oxo-3-phenyl-12-dihydroquinoline-5-carboxylate

100588] A mixture of N-(4-methoxybenzyl)-2-oxo-N-(I-oxo-J1,3-dihydroisobenzofuran-4-vl)-2

phenylacetamide (4.7 g 11.7 mmol) and anhydrous NaSO4 (16.6 g I 17 mmol) in anhydrous ethyl

propionate (120 mL) was cooled to 0 'C. Then a solution of sodium ethoxide in ethanol (sodium

(673 mg, 29.2 mmol) in anhydrous ethanol (70 niL)) was added dropwise. After the addition, the

35 mixture was stirred at room temperature for 18 hr. The mixture was quenched with water (100 ml.) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with

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ethyl acetate (250 mL x 4). The combined organic layers were washed with brine, dried over

anhydrous sodium sulfate, and concentrated to give product (4.02 g, yield 80%). LC-MS (ESI) n/z:

430 (MAY. 1H-NMR (400 MHz, DMSO-d6) 6 (ppm): 1.23-1,26 (t. = 6.8 Hz, 311), 3.69 (s. 311), 42 .-4.23 (m, 211), 5.46 (s, 11-), 6.86-6,88 (d,. 7.6 Hz., 211). 7.11-7.18 (m, 311), 7,36-7.55 (m,

5 711), 10.59 (s, I H).

Example11i8D

Ethyl 4-hydroxy-2-oxo-3-phenyl-1.2 -d ihydroquionoline-5-carxyl ate

1005891 A mixture of ethyl 4-hydroxy- I -(4-methoxybenzyl)-2-oxo-3-phenyl-l ,2-dihydroquinoline

5-carboxylate (298 mg. 2 mmol) in trifluoroacetic acid was heated to reflux for 48 h. After the

10 removal of the solvents, the residue was washed by ethyl acetate to obtain the title compound as a

white solid (250 mg, yield 32%). LC-MS (ESI) m/z: 3 10 (M+ 1). 'H-NMR (400 MHz, DMSO-d6) 6

(ppm): 1.25 (t,.I= 7.2 Hz, 3H), 4.23 (q, J= 7.2 Hz, 2H), 7.08 (d, J= 72 Hz. iH), 7.31-7.43 (i, 611), 7.52 (t, J-- 8 Hz, 111), 10,39 (s, 1 H) 11.64 (s, 1 H).

Example I8E

15 9-Phenv-2H-pyrido[4,3;2-le]phthalazine-3,8(7H,9H)-dione

[005901 Ethyl 4-hydroxy-2-oxo-3-phenyl-1,2-dihydroquinoline-5-carboxylate (330 mg, 1. 1 nimol)

was added to hydrazine monohydrate (1 mL) and methanol (2 mL), the mixture was stirred at 11.0 "C

for 2.5 h by microwave, Then the mixture was cooled to room temperature, the solvent was

evaporated in vacuum. The residue was washed with methanol, and then purified by column

20 chromatography (silica gel, dichloromethane / methanol: 300:1 to 50:1) to obtain a pale white solid

(148 mg, yield 53%), LCT-MS (ESI) m/z: 278 (M±1). 4H-NMR (400 MHz, DMSO-d6) 6 (ppm):

5.09 (s, 1 H), 7.1 7-7,40 (m, 614). 7.77-7.81 (m, 2H), 11. 10 (s, 1 H), 12,57 (s, 11).

Example 18F

9-Phenyl-8,9-dihydro-2H-pyrido[4,3;.2-dejphthalazin-3(7H)-one

25 [005911 A mixture of 9-phenyl-2IJ-pyrido[4,3,2-dejphthalazi ne-3,8(7.F9IH)-dione (80 ig, 2.2

nmmiol), Bl 3 (0.7 mL I mol/l in THF), dioxane (4 mL) in sealed tube was stirred for 2 h at 95 T

under nitrogen atmosphere. Then the mixture was treated with MeOH11-HCI (g) (0.2 iL-), stirred for

20 min at 95 C. Then the mixture was cooled and adjusted to pH =8 with EtaN. The solvent was

removed under vacuum and the crude was purified by column chromatography (silica gel, petroleum

30 ether / ethyl acetate = 20:1 to 1: 1) to obtain the title compound as a yellow solid( 18.3 mg, yield

24%). LC-MS (ESI) n/z: 264 (M+1) H -NMR (400 MiHz. CDOD) 6 (ppm): 3.60-3.64 (mn, 1H).

3.68-3.72 (i, 1H), 4.21 (t, J= 5.2 Hz, IFi), 7,09-7.11 (d, J= 8 liz, InH), 7.16-7.29 (in 5H), 7,537.61 (m, 211).

Example 119

35 8-(4-Fluorophenyil)-9-(4-methyl1-U4-1.2,4-triazol-3-y)-8,9-dihydro-2H-pyrido[4,3.2- de/phthalazin3 (7 H)-one

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Example 1 19A

Ethyl 2-(4-fluorophenyl)-3-(4-methy1-4H-1,2,4-triazol-3-yl)-4-oxo- 1,2,3 4-tetrahydroquinoline-5

carboxylate

100592 A. mixture of compound (E)-4-(4-fluorobenzylideineamino)isobenzofuran- 1(31-)-one (690

5 mg, 2.7nunol) and 4-methvl-4H-1.2,4-triazole-3-carbaldehyde (300 mg, 2.7 mmol) in ethyl

propionate (20 niL) was cooled to 0 "C. Then a solution of sodium ethoxide in ethanol [sodium (250

mg, 10.8 mmol) in ethanol (10 mL)] was added dropwise. After the addition the mixture was stirred

at room temperature for 2,5 hr, then was quenched with water (20 mL) and solvent was removed in

vacuum, The residue was dissolved in water and extracted with ethyl acetate three times, washed

10 with water and brine, and then evaporated to give the crude product, which was purified by

chromatography to obtain a yellow solid (120 mng, yield 11%). LC-MS (EST) m/z: 395 (M+1).

Example I19B

8-(4-Fluorophenyl )-9-(4-niethyl-4H- 1,2,4-triazol-3 yi)-8,9-dihydro2-pyrido[4,3,2~dejphthalazin

3(71H)-one

15 [005931 A mixture of ethyl 2-( 4-.fluorophenyl)-3-(4-mnethyl-4-f-1,2,4-triazol-3-yl)-4-oxo- 1,23,4

tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 nL) and methanol (5

mL) was stirred at room temperature for 4 h. Then the solution was evaporated, the crude product

was purified by prep-HPLC to obtain the title compound as a white solid (20 ng, yield 18%). LC

M.S (ESI) m/z: 363 (M+1). '11-NMR (400 MHz, DMSO-d6) 8 (ppm): 3 50 (s, 314). 4.83-4.86 (d, J

20 11.6 f Iz, IH)5.00-5.03 (d,,J= 11 .6 Hz,1H), 7.12-7.19 (m, 341), 7,39-7.42 (m, 2H) 747-7.51 (n,

214), 7.60-7.64 (t. J= 8 Hz, 1 H), 8.31 (s, IH-), 12.24 (s 1H).

Example 120

8-(4-Fluorophenyl)-9-( 1-methyl- 1f-1;2 4- -riazoi-5-yi)-8,9-dihydro-2H-pyrido[4,3, 2-dejphthalazin

3(7)1-one

25 Example 120A

Ethyl 2-(44uorophenyl)-3-(1 -methyl -1H- Il,2.4-triazol-5-yl)-4-oxo-I .2.-3,4-tetrahydroquinoline-5

carboxylate

1005941 To a solution of 4-(4-fluorobenzylideneamino) isobenzofuran- 1(311)-one (5.0 g, 19.6 mmol)

and 1-methyl-l H-il,2.4-triazole-5-carbaldehyde (2.8 g, 25.5 mmol) in ethyl propionate (310 il )

30 was added sodium ethoxide (1.26 g, 54.9 mmol) at room temperature under nitrogen. The mixture

was stirred at 55 "C for 2 hr. Then the resulting mixture was evaporated under reduced pressure and

extracted with ethyl acetate (150 mL x 4) and concentrated the extracts, The crude product was

purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 20:1 to 1.5:1), A solid product was obtained (24 g, yield 31%). L.C-MS (ES!) m/tz: 395 (M+).

35 Example 120B

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S-(4-Fluorophenyl)-9-(1 methylH-1 2,4-triazol-5-yl)-,9-dihydro-211pyrido[4 3 2-dephthalain

3{(7H)-one

1005951 A 100 mL round-bottom flask equipped with a thermometer and magenetic stirrer was

charged with ethyl 2-(4-fluorophenyl)-3-(i-methyl-1 H- 1.2 ,4-triazol-5-yl)-4-oxo-1,2.3.4

5 tetrahydroquinoline-5-carboxylate (1.72 g, 4.4 miol). methanol (15 mL), and NH2INI (4 mL,

85%). The mixture was stirred at 25 'C for 5 hr. The reaction was monitored by HPLC for

completion. The mixture was evaporated nuder reduced pressure and methanol was added to make

slurry. The suspension was filtered. The obtained solid was washed with 20 mL of methanol, and

was dried to afford the title compound (1.4 g, yield 90%). LC-MS (ESI) m1/z: 363 (M+1)". 1-H-NMR

10 (400 MHz, DMSO-d6) 8 (ppm): 365 (s, 3Ff), 4,93-4.97 (m, 211), 7.12-7,19 (m. 3}), 7.39-7.43 (m,

211), 7.47-7.50 (m, 2H), 7.58-7.60 (m, IH) 7.79 (s, 1 H). 12.22 (s, 3H).

Example 121

8-(4-Fluorophenvl)-9-(1 -methvl-iH-imidazo [4,5-c]pyridin-2-yl)-8,9-dihvdro-2Ri-pyridoc[4,3,2

15 de]phthalazin-3(7t)-one

Example 121A.

A-Methyl-3 -nitropyridin-4-amine

1005961 To a suspension of 4-chloro-3-nitropyridine (2 g, 12.6 minmol) in dichloromethane (15 mL)

was cautiously added methyl amine (25% solution in water, 10 mL, 63 mmol). The reaction mixture 20 was heated to 40 "C. After stirring for I h, the mixture was poured into water (20 mL), and the

precipitate was collected by filtration and dried in vacuo to afford the title compound (1,9 g, yield 98%) as a yellow solid LC-MS (ESI) m/z: 154 (M+1).

Example 121 B

N-4-methylpyridine-3 ,4-diamine

25 100597J The suspension of A-methyl-3-nitropyridin-4-amine (2.5 g, 16.3 mmol) and Pd/C (10 %, 500 mg) in methanol (50 mL) was hydrogenated at room temperature overnight. Then the mixture

was filtered and the filtrate was evaporated to give the product (1.2 g, yield 60%), LC-MS (ESI) m/z: 124 (M-l- I

Example 121 C

30 1,2-Dimethyl-IH-imidazo[4,5-cjpyridine

100598] The solution of N4-niethylpyridine-3,4-diamine (2.5 g,'20.3 mmol) in acetic anhydride (25

ml,) was refluxed overnight. Then acetic anhydride was evaporated under reduced pressure and I N hydrochloride acid was added. Then the mixture was extracted with dichloromethane (50 mL x 3), The aqueous layer was neutralized with sodium bicarbonate, and extracted with dichloromethane

35 (50 mL x 3). The organic layers were concentrated to give the title compound (1.9 g. yield 64%).

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LC-MS (ESI) m/z: 148 (M+ IX. 'H-NMR (40 MHz, CDCl3) 6 (ppm): 2.64 (s, 3H), 3.74 (s' 311),

7.23-7.24 (d, J= 5.2 Hz, I1l-) 8.39-8.41 (d, J= 5.2 Iz. iIx 8.98 (s, 1H).

Example 121D

1-Methyl-1iH-imidazo[4,5-c]pyridine-2-carbaldehyde

5 1005991 To a solution of 1,2-dimethyl- HiJ-imidazo[4,5-c]pyridine (500 mg, 3.40 mmol) in dry 1,4

dioxane (7.5 mL) was added selenium dioxide (665 tmg, 5. 10 mmol) , The mixture heated by

microwave at 130 'C for 5 min. Then the mixture was filtered and concentrated to give the crude

product, which was purified by column chromatography (silica gel, petroleum ether: DCM 10:1 to

1:1) to give the title compound (400 mg, yield 28%). LC-MS (ESI) ri/z: 162 (M+1) 'H-NMR (400

10 MHz, CD3OD) 6 (ppm): 3.61 (s, 311), 5.91 (s, 11-1), 7.67-7-70 (dK= 5.6 Hz,11H) 8.39-8.41 (d, J:

5.6 Hz, 1H), 8.93 (s, IH).

Example 121 E

Ethyl 2-(4-fluorophenyl)-3-(1-methyl-H-imidazo[4 -c]pyridin-2-yl)-4-oxo-1,2,3,4

tetrahydroquinoline-5-carboxvlate

15 1006001 To a solution of 1-methyl-IH-imi dazo[4.5-c]pyridine-2-carbaldehyde (400 mg, 2.48 mmol),

(E)-4-(4-fluorobenzylideneamino) isobenzofuran-1(3)-one (634 mg, 2.48 nmol) in ethyl

propionate (20 ml) were added a solution of sodium ethanoxide in ethanol [sodium(171 mg, 7.45

mmol) in ethanol(10 mL)] at 0 Then the mixture was stirred at room temperature overnight.

Then the mixture was quenched with water (10 mL.) and solvent was removed in vacuum. The

20 residue was extracted with ethyl acetate (100 mL.. x 4). The combined organic layers were washed

with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was

purified by chromatography (silica gel, petroleum ether / ethyl acetate = 25:1 to 5:1) to give the title

compound (150 mg. yield 14%). LC-MS (ESI) m/z: 445 (M+1).

Example 121F

25 8-(4-Fluorophenyl)-9-(I -m ethyl-HI-inidazo[4,5-c]pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,.3,2


(00601. The mixture of ethyl 2-(4-fluorophenvl)-3-(i-methyl 1H-imidazo[4, 5-c]pyridin-2-vl)-4

oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.34 mmol) and hydrazine monohydrate (2

ml,) in methanol (5 nL) was stirred at room temperature for 4 h. Then methanol was evaporated

30 under reduced pressure and the residue was extracted with ethyl acetate (20 mnL x 4). [he combined

organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to

give crude product, which was purified by chromatography (silica gel, DCM / MeOH = 25:1 to 1:1) to give the title compound (6.7 mg, yield 5%). LC-MS (ESI) m/z: 413 (M+1) H. 1 -NMR (400 MlIzi, CD;OD) 8 (ppm): 3.58 (s, 3H), 4,93-4.95 (dI.= 11.6 HziHl), 5.04-5.07 (d,IJ= 11.6 Hz,I H), 6.85

35 6.90 (t, J= 8.8 Hz, 2H), 7.12-7.14 (d, J= 8.0 Hz. 1Hi), 7.38-7.44 (m 3 H), 7.49-7.57 (m. 2H), 8.19

8.21 (d, ,- 5.6 Hz, 1H), 8.72 (s, IlH).

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Example 1

5-Chloro-9-( 1-methyl-i i-imidazol-2-yl)-8-phenyl-8,9-dihydro-2 U-pyrido[4,3,2-de]phthalazin

3(7H)-one

Example 122A

5 5-Chloro-2m-iethyl-3-nitrobenzoic acid

[00602] To a cone. H2S0 4 (90 ml.) was added portionwise 5-chloro-2-methylbenzoic acid (13.2 g,

77.6 mmol) at -J5 "C. Then a mixture of conc. HNO 3 (10.5 g7 1744 nnnol) in cone. H2SO4 (15 mnL)

was added dropwise at -5-0 "C over a period of about 1 .5 hr, After the addition, the mixture was

stirred at this temperature for 2 hr The mixture was poured into crashed ice with vigorous stirring

10 and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with

brine, dried over anhydrous NaSO4, and concentrated to give a crude title compound (13.2 g),

which was used in the next step without further purification.

Example 122B

Methyl 5-chloro-2-methyl-3-nitrobenzoate

15 1006031 A solution of crude 5-chioro~2-methyl3nitrobenzoie acid (13.2 g) in dry methanol (100

mL) was cooled to 0 'C (3 nL) was added conc. H1SO4 dropwise. After the addition, the mixture

was heated to reflux for 16 hr. After removal of solvents under reduced pressure, the crude product

was purified by silica gel chromatography (petroleum ether to petroleum ether/ EtOAe= 50:1) to

give the title compound (6.3 g, yield 35% for two steps) as a white solid. LC-MS (ESI) in/z 230

20 (M+1)% 231(M+2). 'H-NMR (400 MHz, CDC1L) 6 (ppm); 2.59 (s 3H), 3.95 (s, 3H), 7.84-7.85 (d,

1 H), 798-7,99 (d, INH).

Example 122C

Methyl 2-(bromomethyl)-5-chloro-3 -nitrobenzoate

1006041 A mixture of methyl 5-chloro-2-methyln-3-itrobcnzoate (6 g, 26.2 mmol), NBS (5.1 g, 28.8

25 mmol). and BPO (0.63 g, 2.6 mmol) in CC14 (50 mL) was heated to reflux overnight Water (200

mL) was added and CC14 was removed under reduced pressure. The residue was extracted with

DCM (200 mL x 3), The combined organic layers were washed with brine, dried over Na2 SO4, and

concentrated to give crude title compound (7 g yield 87%) as a brown oil which was used in the

next step without Purification.

30 Example 122D

6-Chloro-4-nitroisobenzofuranil(3H)-one

1006051 A mixture of methyl 2-(bromomethvl)-5-chloro-3-nitrobenzoate (7 g, 22.8 mmol) in 1, 4

dioxane (50 mt) and water (50 ml) was heated to reflux for 4 days. Dioxane was removed under

reduced pressure. The residue was extracted with EtOAc (300 mL x 4). The combined organic

35 layers were washed with brine, dried over Na 2SO 4, and concentrated to give crude product, which

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was purified by silica gel chromatography (petroleum ether to petroleum ether/ EtOAc = 5:1) to give

the title compound (4 g, yield 82%) as a white solid.

Example 1 22E

4-Amino-6-chloroisobenzofuran-1(3 11)-one

5 f006061 A suspension of 6-chloro-4-nitroisobenzofuran-i(3)-one (5 g, 23;5 mimi) and Pd/C

(10%, 500 mg) in EtOAc (250 mL) was stirred at 25 C under I atm of hydrogen for 12 hr. The

mixture was filtered, and the cake was washed with EtOAc (100 mL x 3). The filtrate was

concentrated to give the title compound (3.87 g, yield 90%) as a white solid, LC-MS (ESI) n/z: 184

(M+ 1)

10 Example 122F

(E)-4(Benzylideneam ino)-6-chloroisobenzoftiran- 1(3 1)-one

1006071 A mixture of 4-amino-6-chloroisobenzofuran- 1(3H11)-one (1 g, 5.46 mmol), benzaldehyde

(0.72 g, 6,79 mnol) and magnesium sulfiate (6 g) in dichloromethane (80 mL) was stirred at retux

overnight. The mixture was evaporated under reduced pressure and the residue was dried in

15 vacuum. A crude product was obtained (740 mg) and used in next step without further purification.

Example 122G

Ethyl 7-chloro-3-(1 -methyl- 1H-im idazol-2-vl)-4-oxo-2-phenyl-1 ,2,3 .4-tetrahydroquinoli ne-5

carboxylate

{006081 To a solution of (E)-4-(benzyliden eamino)-6-chloroisobenzofuran- 1(31)-one (720 mg 266

20 mmol) and 1-methyiiH-imidazole-2-carbaldehyde (330 mg 3 mmol) in ethyl propionate (40 mL)

was added sodium ethoxide (650 mg, 9.6 mmol), The mixture was stirred at room temperature for 3

hr. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl

acetate (100 ml x 4) and concentrated. The crude product was purified by column chromatography

(silica gel, petroleum ether: ethyl acetate = 20:1 to 15: 1) to give the title compound as a solid (170

25 ig, yield 15%).

Example 12211

5-Chloro-9-( I-methyl-1I fimidazol-2-yl)-8-phenyl-8,9-dihydro-2B pyrido[(4,3 ,2-de]phthalazin

3(71)-one

[006091 To a solution of ethyl 7-chloro-3-(1-methyl-l H-imidazol-2-yl)-4-oxo-2-phenyl-1.,2,3,4

30 tetrahydroquinoline-5-carboxyl ate (429 mg, 1.05 mmol) in methanol (15 mL) was added hydrazine

monohydrate (2 mL. The mixture was stirred at 25 'C for 5 br, The resulting mixture was

concentrated under reduced pressure to a volume of 10 ml and then filtered, giving 58 mg of solid

(yield 14%). LC-MS (ESI) m/z: 378 (M+]1- 379 (M2)4. 'H-NMR (400 MHz, DMSO-d 6 (ppm): 3.42 (s, 3H), 4.69 (d, J =10.0 Hz, I H), 4.98(d, J 10.4 Hz, I H) 5.76 (s, 11). 6.73 (s, 1-H), 6.89(s,

35 1H), 7.14 (s, 1l), 7.27 (dd, 4H), 7.38 (d, J= 6.4 Hz, 21-I), 7.62 (s, li), 12.36 (s, I H).

Example 123

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8-(4-((Dimethylanino)methyl)phenvl)-5-fluoro-9-(4-fl.uorophenvl)-8,9-dihydro-211-pyrido[4,3,2dephthalazin-3(7th-one

Example 123A

(E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-.1(311)-one

5 [00610] To a stirred mixture of 4-((diiethylamino)methyl)benzaldehyde (4 g, 24.5 mmol) and

anhydrous magnesium sulfate (15,8 g. 111.5 mmol) in anhydrous acetonitrile (100 mL) was added

4-amino-6-fluoroisobenz'ofuran-1(31:1)-one (4 g, 22.3 mmol) at 0 T. After the addition, the mixture

was stirred at reflux for 3 days, The mixture was filtered and the cake was washed with ethyl acetate

(50 mL x 3). The filtrate was concentrated to give crude product, which was re-crystallized with

10 isopropanol to give the title compound (3.7 g, yield 55%). LC-MS (ESI) N/z: 314 (M+l).

Example 123B

Ethyl 2-(4-(dimethylamino)methybphenyl)-7fluoro-3-(4-fluorophenyl)-4-oxo-1,2,3,4


1006111 A mixture of (E)-4-(4-((dimethylam ino)methyl)benzyl idencain mo)-6-fluoroisobenzofuran

15 1(31H)-one (500 mg, 1.6 mmol) and 4-fluorobenzaldehyde (218 mg, 176 mmol) in ethyl propionate

(10 mnL) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol (sodium (t110 mg, 4.8

mmol) in ethanol (5 ml,)) was added dropwise. After the addition the mixture was stirred at room

temperature for 3 hr. The mixture was quenched with water (10 niL) and solvent was removed in

vacuum. The residue was dissolved in water and then extracted with ethyl acetate (100 ml, x 4). The


concentrated to give crude product, which was purified by chromatography (silica gel, petroleum

ether / ethyl acetate = 1: 1) to give the title compound (100 mg, yield 13%). LC-MS (ESI) m/z: 462

(M+l).

Example 123C

25 8-(4-((Diethylaino)methyl)phenyl)-5-fluoro-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2

de~phthalazin-3 (711)-one

1006121 A mixture of ethyl 2-(4-((diinethvlamino)inethyl)phenyl )-7-fluoro-3-(4-fluorophenyl)-4

oxo-1,2 .3,4-tetrahvdroquinoline-5-carboxylate (100 mg) in 85% hydrazine monohydrate (0.5 mL)

and methanol (2 mL) was stirred at room temperature overnight, Methanol was removed under

30 reduced pressure. The crude was purified by prep-HPLC to give the title compound (35 mg, yield

37%). LC-MS (EST) m/z: 433 (M+1). 'H-NMR (400 MHz; CDOD) 6 (ppm): 2.12 (s, 31), 3.35 (s, 21-1), 4.21 (d, J= 8.0 Hz. 1 H). 4,64 (d, J=8.0 Hz, I1H), 6,81-6.85(m, 31H), 6.99-7.01 (in, 211), 7.137.19 (i, 51H): '9F-NMR(400 MHz, CD 3OD) 6 (ppm): -105.66 (s), -118.17 (s),

Example 124

35 89-Bis(4-((dimethylamino)iethyl)phenyl)-S-fl uoro-8.,9-dihydro-2HI-pyrido[4,3,2

de8phthalazin-3( 7])-one

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Example 124A

Ethyl 2 ,3-bis(4-((dimethylam ino)methyl)phenyl)-7-fluoro-4-oxo- 1 ,2,3,4-tetrahydroquinoline-5

carboxylate

{006131 A mixture of(E)-4-4-((dimethylamino)methyl)benzylideneamino)-6~fluoroisobenzofuran

5 1(311)-one (1 g 31.9 mmol) and 4 - (( dinethylamino) methyl) benzaldehyde (0.52 a, 31,9 mmol) in

ethyl propionate (50 ni.) was cooled to 0 'C. Then a solution of sodium ethoxide in ethanol (sodium

(220 mog, 95,8mmol) in ethanol (20 mL)) was added dropwise. After the addition, the mixture was

stirred at room temperature for 2 hr. The mixture was quenched. with water (10 mL..) and solvent was

removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100

10 iL 4). The combined organic layers were washed with brine, dried over anhydrous sodium

sulfate, and concentrated to give crude product, which was purified by chromatography (silica gel.

dichloromethane / methanol= 10:1 to 20:3) to give the title (520 mg, yield 33%). LC-MS (ESI) m/z:

503.

Example 124B

15 8.,9-Bis(4-((d imethylamino)nethyl)phenyl)-5-fluoro-8.9-dihydro-211-pyrido[4,3 .2-d e]phthalazin

3(7H-one

[006141 A mixture of ethyl 2,3-bis(4-((di methylamino)methyl)phenyl) 7-fluoro-4-oxo-1,2,3,4

tetrahydroquinoline-5-carboxylate (520 mg) in 85% hydrazine monohydrate (10 mL) and methanol

(50 mL) was stirred at 23 "C for overnight. Methanol was removed under reduced pressure. The

20 mixture was filtered and washed with water to give the title compound (II ng. yield 20%). LC-MS (EST) m/z: 472 (M.+1) 'I-NMR (400 Mliz, CD 301D) 6 (ppm): 2.09 (s, 12H), 3.31 (s, 4H4), 4.22 (d, J= 8.0 Hz, 111), 4,67 (dJ=: 8.0 Hz, 1H), 6.80 (dd, 14), 6.97-6.99 (m. 2H), 7.06-7.11 (m, 5H), 7_14

7.16 (i, 21); 'tNMk (400 MHz, CDAOD) C (ppm): -105.58 (s).

Example 125

2 8(4-((Dimethylaiino )methyl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2

de]phthalazin-3 (7h-one

Example 125A

4-(Dieth oxymethyl)benzaidehyde

1006151 A mixture of terephthalaldehyde (1.0 g, 74.55 mmol),amimonium chloride (160 nig, 3.0 30 minol) in ethanol (10.3 g, 223 .6 nmol) was added dropwise triethoxymethane (12.15 g, 82 mmol) at

0 'C. After the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated. the residue was purified by silica gel chromatography to give the title compound (7.0 g, yield 50%) as a white solid. LC-MS (ESI) m/z: 209 (M+l).

Example 125B

35 1-(4-(Diethoxymethvl)phenyl)-N,N-dimethylmethanamine

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[00616] A solution of 4-(diethoxymethyl)benzaldehyde (6.8 g, 32.69 mmol) and dimethylaminein

33 wt.% solution in water (9.25 g, 98 mrol) in methanol (200 mL) was stirred at room temperature

for overnight. Sodium borohydride (1.85 g, 49 mmol) was added by portions with ice cooling. After

the addition, the mixture was stirred at room temperature for 4 hr. The mixture was quenched with

5 water (100 mL) and extracted with ethyl acetate (100 ml x 3). The extract was dried over anhydrous

sodium sulfate and concentrated to give crude title compound (7.0 g, yield 90%). which was used in

the next step without further purification. LC-MS (ESI) n/z: 238 (M+l )

Example 125C

4-((Dinethylamino)imethyl )benzaldehyde

10 [00617j To the mixture of l-(4-(diethoxymethyl)pheny)-N.Vdimethylmethanamine (7.0 a, 29.

mmol) in hydrogen chloride (3M in water 30 mL) was stirred at room temperature for 5 hr, Then the

mixture was extracted with ethyl acetate ( 50 ml x 3).The aqueous layer was basified with sodiumn

carbonate to pH = 10., extracted with ethyl acetate ( 50 ml x 3). dried with anhydrous sodium sulfate,

and concentrated to give crude product (3.95 g, ield 82%). LC-MS (ESI) m/z: 164 (M+)*.

Is Example 125D

(IE)-4-(4-((Dimethylam ino)methyl)benzylideneamino)-6-fhiotoisobenzofuran-1(3H)-one

1006181 A solution of 4-((dimethylamino)methy)benzaldehyde (1.0 g, 6.13 nmiol), 4-amino-6

fluoroisobenzofuran-i(31b-one (1.024 g, 6.13 mmol) and anhydrous Inagnesium sulfate (7.356 g,

61.3 mmol) in acetonitrile (50 mi) was heated at reflux for 2 days. The solution was filtered and

20 concentrated in vacuum. The crude product was re-crystallized with isopropanol to obtain the title

compound (1 15 g. yield 60%). LC-MS (ESI) m/z: 313 (M-+1). 1H-NMR (400 MHz, CDCL) 8

(ppm): 2.28 (s, 611), 3.52 (s, 2H), 5.38-5.38 (m, 21HI). 7.09-7.12 (m, 11), 7.42-7,44 (m H-), 7.46-7.48

(d, J::8 Hz., 2H1) 787-7.89 (d, J = 8 Hz, 211), 8.51 (s, i1-).

Example 125E

25 Ethyl 2-(4-((dimethylamnino)methvl)phenyl )-7-fl uoro-4-oxo-3-phenyl-1.2,3 ,4-tetrahvdroquinoline-5

carboxylate

1006191 A mixture of compound benzaldehyde (75 mg; 0.705 mmol) and (E)-4-(4

((dimethylamino)methyl)benzylideneami no)-6-tluoroisobenzofuran-I(3H)-one (220 mg, 0.705

immol) in ethyl propionate (5 mL) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol

30 (sodium (65 mg, 2.82 mmol) in ethanol (3 nL)) was added dropwise. After the addition, the mixture

was stirred at room temperature for 2.5 hr. The mixture was quenched with water (20 muL) and

solvent was removed in vacuum. The residue was dissolved in water and extracted with ethyl acetate

for three times, The extract was washed with water and brine and then the solvent was evaporated.

The crude product was purified by chromatography to obtain the title compound as a yellow solid

35 (80 mg, yield 25%). LC-MS (ESI) ni/z: 447 (M+ 1)

Example 125F

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8-(4-((Dimethvlamino)methvl)phenyl)-5-fluoro-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2

dejphthalazin-3(7)-one

1006201 A mixture of compound ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-filuoro-4-oxo-

phenvl-1,2,3,4-tetrabydroquinoline-5-carboxylate (80 mg, 0.18 mol) in 85% hydrazine

5 monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The solvent was

removed in vacuum; the crude product was purified by chromatography to obtain the title compound

as a yellow solid (22 mg, yield 30%). LC-MS (ESI) m/z: 415 (M+1 1H-NMR (400 MHz, DMSO

d6) 6 (ppm): 2.14 (s, 6H) 3.36 (s, 2H), 4.18-4.21 (d, J = 8.8 Hz, I H), 4.674,69 (d, J= 9.2 Hz. 1 H),

6.81-6.84 (m. 11H.), 6.99-7. 01 (n, 214), 708-7 19 (m. 8H).

10 Example 126

8-(4-((3,4-Dimethylpiperazin- 1 -vi)imethyl)phenyl)-9-(4-fl uorophenyl)-8,9-dihydro-2Hpyrido{4,3,2 de]phthalazin-3(7H )1-one

Example 126A

tert-Butyl 3 -methylpiperazine- I -carboxylate

15 [006211 To a solution of 2-methyl-piperazine (2.0 g, 0.02 mol) and triethylamine (6 mL) in

methylene chloride (15 mL) at 0 C was added (Boc)$O (4.1.4 g, 0.019 mol) dropwise. The mixture

was stirred at room temperature for 1 hour, and then the solvent was removed by rotary evaporation.

The residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate and

brine, dried over Na'SO, and purified by column chromatography on silica gel (DCM: MeOH :EtN

20 75 1: 0.2) to give an white solid (1.65 g 42%). LC-MS (ESI) miz 201 (M+1).

Example 126B

tert-Butyl 3,4-dimethylpiperazine- 1 -carboxylate

[006221 ter/-Butyl-3-niethylpiperazine carboxylate (1.49 g, 7.45 minol) and paraformaldehyde (1.12

g,37.2 mmol) were dissolved in a mixture of MeOH and acetic acid (5: 1) on molecular sieves.

25 NaBCNH3 (1.88 g, 29.8 imol) was added to the suspension at 25 *C. The slurry was subsequently

heated to 80 'C for 10 hr. Then the mixture was cooled, filtered, and concentrated. The residue was

dissolved in dichloromethane and washed with saturated sodium bicarbonate. The organic solution

was dried over Na2 SO4. and concentrated to give a wh ite oily (1.2 g, 90%). LC-MS (ESI) m/z: 2 15

(M+l 1.

30 Example 126C

1,2-Dimethylpiperazine

Trifluoroacetic acid (7 mL) was added to a solution of tert-butyl-3,4-dimethylpiperazine-I

carboxylate (1 .7g, 7,94 mmol) in methylene chloride (15 mL) at room temperature, followed by

stirring for 1 hour. The residue obtained by removal of solvents by rotary evaporation under reduced

35 pressure to give the title compound. LC-M.S (ESI) m/z: 20i (M-+i. 1)*-H-NMR (400 MIz, CDC 3) 3

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(ppm): 1 21 (dJ= 6.8 Hz, 3H), 1.46 (s, 91-), 2.64-2.70 (n, I H) 2.74- 2,78 (m, 1H), 2.88-3.01 (m,

311), 3.78 (d, J= 12.4 Hz, 111), 4.16 (in, 11). Example 126D

8-(4-((3,4-Dimethylpiperazin- I -yl )methyl )phenyl)-9-(4-fluorophenyl)-8,9-dihvdro-2H-pyrido[4,3/2


5 [00623] A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pvrido[4,3,2

de]phthalazin-8-yl)benzaldehyde (200 mg., 0,52 minol), 1;2-dimethylpiperazine (311 mg, 1.56

inmol) in methylene chloride (10 mL.) was stirred at room temperature overnight, then NaBCNH;

(129 mg, 2.08 mnnole) was added and the mixture was stirred for another 5 hours. After removal of

solvents, the residue was purified by column chromatography (silica gel, petroleum ether / ethyl

10 acetate : 3:1 to 1:1) to give the title compound (70 mg 26%). LC-MS (ESI) n/z: 484 (M+i) H

NMR (400 MHz, CDC3) 6 (ppm): 1.43 (d,J - 5.2 H1z, 311), 2.84 (s, 3H), 3.29 (n, 1H4), 3.33-3.44

(m, 611), 4.03 (s. 2l) 422 (im 1H), 4.65 (in, I H) 6,91 (in, 111), 6.97 (m, 1H-), 7.00 (d, J= 8 iz,

2H), 7.23- 7.37 (i 41). 7.65 (in, 1H), 7.77 (d J= 7.2 Hz. 11H), 9.92 (s, 111).

Example 127

15 8-(4-((3,5-Dimethylpiperazin- 1 -yl)methyl)phenvl)-9-(4-fluoroplievl)-8.9-dihydro-2H-pyrido[43 ,2dejphihal azin-3(71-)-one

Example 127A

4-Benzyl 1-terl-butyI 2,6-dimethylpiperazine-1.4-4icarboxylate

[006241 To a solution of 2,6-diinethylpiperazine (2.,28 g20 iimol) in methylene chloride (15 iL)

20 at 0 C was added benzylchloroformate (3.0 mL) dropwise. The mixture was stirred at 0 "C for one

hour then at room temperature for 2 hours. The mixture was cooled to 0 "C, Diisopropylethylamine

(4.5 ml) was added and followed by (Boc)40 (4,8 g 22 mmol). The mixture was stirred at room

temperature overnight and then the solvent was removed by rotary evaporation. The residue was

dissolved in EtOAc, wa shed with water and brine, dried over Na SO,. and purified by column

25 chromatography on silica gel (EtOAc: hexane = : 9) to give an oily intermediate (4.8 g, 72%). LC

IS (EST) m/z: 361 (M+23)

Example 127B

tert-Butyl 2 6-dimethylpiperazine- I -carboxylate

[006251 A solution of 4-benzyl 1-tert-butyl 2,6-diimethylpiperazine-1,4-dicarboxylate (4.8 g, 30 0.0144mol) in methanol (25 mL) was added 480 mug of 10% Pd/C and stirred at room temperature

under 1-12 overnight, The resulting mixture was filtered and concentrated to give the title product (2.8 g, 97%) as colorless oil. LC-MS (ESI) m/z: 215 (M+1) 'l-l-NMR (400 MHz, CDC 3) 6 (ppm): 1 25

(d,,]:= 6.8 Hz. 3H), 1 46 (s. 9H). 1.64 (s, 1 H), 2.78- 2.87 (m, 411), 3.99-4,05 (m, 2H).

Example 127C

35 (2R,6R)-tert-ButyI 4-(4-(9-(4-fluorophenyl)-3-oxo -3,7,8,9-tetrahydro-2H-pyrido[4,3,2

de]phthalazin-8-yl)benzvl)-2,6-diinethylpiperazine- I -carboxylate

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1006261 A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H1-pyrido[4,3,2

dejphthalazin-8-yl)benzaldehyde (200 rmg, 520 mmol), tert-butyl 2,6-dimethylpiperazine-1I

carboxylate (335 mg, 1 .56 mmol) in methylene chloride (10 mL) was stirred at room temperature

overnight, then NaBCNIH: (129 mg, 2.08 mmol) vas added and the mixture was stirred for another 5

5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel,

petroleum ether / ethyl acetate = 3:1 to 1:1) to give the title compound (72 ng, 24%). LC-MS (ESI)

m/z: 584 (M+1).

Example 127D

8-(4-(3,.5-Dimethylpiperazin- I -yl)iethvl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-211-pyrido[43,

10 dejphthalazin-3(7H-one

[00627] A mixture of (2R,6R)-tert-butyl 4-(4-(9-(4-fluorophenyl)-3-oxo-3 ,7,8,9-tetrahvdro-2N

pyrido[4,3,2-de]phthalazin-8-yl)benzy l)-2,6-dimethylpiperazine-1 -carboxylate (72 mg,0. 12 mmol)

in HCI-CUICN (2 mL) was stirred for 2 hours. After removal of solvents, the residue was purified

by prep-H-IPLC to afford the title product as a white solid (33 mg 53%). LC-MS (ESI) m/z: 497

1i (M+1)'. L-NMR (400 MHz, DMSQ) 6 (ppm): 1.02-1.03 (d. 4 Hz, 611), 1.58 (t, J=::: 10 Hz,

1H-), 2,66 (d, J= 10 Hz, 1H), 2.91 (t.J= 6.8 Hz, 21-1), 3-41 (s, 2H). 4.20 (d, J= 10 Hz, 11) 4.58 (d.

J=- 10 iz, 114), 4,98 (s. I H), 6.97 (t, = 2.4 Hz, 2H), 7.04 (d, J= 8.0 Hz, 111), 7.09 (d,J= 2.4 Hz,

2H{), 7.16 (d, J= 2 4 Hz,211). 7.58 (t J= 7.6 Hz, 11), 7.73 (d.J= 7.6 Iz, 1H), 10.34 (s, 1H).

Example 128

20 9-Phenyl-8-(4-(pyrrolidin i-ylhnethyl)pheny 1)-8,9-d ihydro-2HF-pyrido[4,3,2-delphthalazin-3(7H)one

1006281 To a stirred solution of 4-(3-oxo-9-phenyli-3,78,9-tetrahydro-21-pyrido[4,3,2

dejphthalazin-8-yl)benzaldehyde (367 mg, i mmol) in dry DCM (15 muL) was added acetic acid (0.2

mL) followed by pyrrolidine (213 mg, 3 nmiol). After the addition, the mixture was stirred at room

25 temperature overnight. Then sodium borohydride (318 mg, 1. 5inmol) was added at 0TC . After the

addition. the mixture was stirred at this temperature for 12 hr, DCM was removed under reduced

pressure, The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was

concentrated to give the crude product, which was purified by prep-HPLC to give the title

compound (62 mg, yield 14%) as white solid. LC-MS (FSI) m/z: 423(M41)". 'H-NMR (400 MHz, 30 DMSO-d6) 3 (ppm): 1.82-.85 (in, 2H), 1.97 (s, 2Ff), 3.01-3.05 (m, 211) 3.26 (d, 2H) 4.27 (d, 21),

4.36 (d, 11). 4.84 (d, 11H), 7.13-7.23 (in, 611), 7.36-7.40 (m, 5.), 7.48 (s, 1H), 7.57-7.61 (t, I H), 12.18 (s, 11H).

Example 129

9-Phenvl-8-(4-(pyrrolidin-1-ylnethvl)phenyl)-8,9-dihydro-2/H-pyrido[4.3,2-de]phthalazin-3(7B)

35 one

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[006291 To a stirred solution of 4-(3-oxo-9-phenyl-3.7,8,9-tetrahvdro-2H-pyrido[42-2I

de]phthalazin-8-yl)benzaldehyde (150 mg, 0.41 mmol) in dry dichloromethane (20 mL) and MeOH

(2 mL) was added acetic acid (120 mg) followed by azetidine (70 mg, 1,23 mmol), After the

addition, the mixture was stirred at room temperature overnight. Then sodium triacetoxyborohydride

5 (131 mg, 0.62 miol) was added at 0 " After the addition, the mixture was stirred at this

temperature for 5 hr. DCM was removed under reduced pressure. The residue was washed with

ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product,

which was purified by column chromatography (silica ge, dichloromethane / methanol - 100;] to

15:1) to give the title compound (84 mg, yield 51%) as yellow solid. LC-MS (ESt) m/z: 409(M+i)

10 H-NMR (400 MHz; CD3OD) 6 (ppm): 2.38-2.43 (m, 21), 3.98 (tJ 8 Hz. 4H), 4.20 (s 21H), 4.27

(d,/= 8 Hz, 11-T) 4.77 (d, J= 8 Hz I H), 7.03-7.05 (n, 211), 7.10-717 (m 4H), 7.27-7.35 (mn 4H),

7.50-7.52 (m, 1,H), 757-7.62 (in, IH).

Example 130

9-(1-Methyl-i H-imidazol-2-yl)-8(4-(pyrrolidin-l-y lmethyl)phe.nyl)-8,9-dihydro-211-pyrido[4,3 2


1006301 A mixture of 4-(9-1-methyl-IH-imidazol-2-y1)-3-oxo-3;7.8,9-tetrahydro-2H-pyrido[4.3,2

de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), acetic acid (60 ul) and pyrrolidine (1.0 g,

15 mol) in acetonitrile (7 uL..) was stirred at room temperature for 4 hr. To this mixture was added

NaCNBH3 (36 ig, 0.67 mmol) at 0 C. After the addition, the mixture was stirred at room

20 temperature for 4 hr. Upon removal of solvents tinder reduced pressure, the residue was washed with

ethyl acetate and filtered. The filtrate was concentrated to give the title compound as a white solid

(21 mg, yield 22%). LC-MS (ESI) m/z: 427 (M+1 ) 'H-NMR: (400 MHz, DMSO-4 6&D2O) S

(ppm): 1.66 (d, J= 2.8 Hz, 4H); 2.37 (s, 41), 3.38 (s, 31H), 3.50(s,2H), 4.62 (dJ= 10Hz. 1,H) 4,90

(d, J = 10.4Hz, 11- ) 6.72 (s, I H), 6.87 (s, 1 H), 7.15-7,20 (in, 3 H), 7.29-7.32 (i, 3H1), 7.36-738 (m, 25 1 H) 7.54-7.58 (in, 1-), 12,15 (s, 1iH),

Example 131

9-(4-Fluorophenyl)-8-( 1-methyl-iH-nidazol-2-yl)-8,9-dihydro-2HJ-pyridof[4,3,2-de]phthalazin

3(711)-one

Example 131A

30 (f)-4-((1-methyl-1li1-imidazol-2-vl)methyleneamino)isobenzofuran-1(3H)-one

[006311 A solution of 1-methyl-1HIm-iidazole-2-carbaldehyde (680 mg, 6.18 mmol), 4

aminoisobenzofurand-1(31H)-one (920.8 mg. 6.18 mmol) and anhydrous magnesium sulfate (7.41 g.

61 .8 mnol) in acetonitrile (100 ml) was heated to reflux for two days. The mixture was filtered and

the solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to

35 get the title compound (1.49 g, yield 68%), IE-MS (ESI) n/z: 242 (M+ 1)H '-NMR (400 MHz,

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DMSO-d6); 4.06 (s, 31), 5.52 (s. 2H), 7.22 (s, 1H), 7.52 (s, 1H), 7.65-7.67 (mi, 114), 7.72-7.74 (i,

2 H), 8.66 (s, 1H).

Example 13I B

Ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-im idazol-2-yl)-4-oxo- 1,2A3,4-tetrahydroquinoline-5

5 carboxylate

1006321 A mixture of compound 4-fluorobenzaldehyde (248mg 2 mmol) and (E)-4-((1 -methyl-ll!

imidazol-2-yl)methyleamino)isobenzofian-l(3H)-one (482 mg, 2 mmol) in ethyl propionate (10

mnL) was cooled to 0 T . Then a solution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol)

in ethanol (5 mtL)) was added dropwise. After the addition, the mixture was stirred at room

10 temperature for 0.5 hr The mixture was quenched with water (20 mL) and solvent was removed in

vacuum. The residue was dissolved in water and extracted with ethyl acetate three times, washed

with water and brine, and then concentrated to give the crude product 'which was purified by

column chromatography to obtain a yellow solid (200 mg. yield 25%). LC-MS (ESi) m/z: 394

(M-I

15 Example 13 IC

9-(4-Fluorophenyl)-8-(1 -methyl-1H-i/m idazol -2-y i)-8,9-dihydro-21H'-pyrido[4.3 ,2-de]phth alazin

3(7R)-one

F006331 A mixture of ethyl 3-(4-fluorophenyl)-2-(1 -methyl-iH-imidazol-2-yl)-4-oxo- 1,2,3,4

tetrahydroquinoline-5-carboxylate (200 mg, 0.5 mmol) in 85% hydrazine monohydrate (1 mL) and

20 methanol (5 mL.) was stirred at room temperature for 4 h. The resulting mixture was filtered and

washed by water (20 mL) and methanol (5 mL) to obtain a white solid , which was dried in vacuum

at 50 "C to obtain the title compound (25 mg, yield 14%). LC-MS (ESI) m/z: 362(NM+1)" H-NMR

(400 MHz, DMSO-df) 6 (ppm): 3.58 (s, 3H), 4.52-4.54 (d,J= 7.2 iz, 11H), 4.94-4.97 (in. 1 ),

6,69-6,70 (m, I H), 6.96-6.97 (n, 11) 7.04-7.08 (mri 3f). 7.18-7,22 (i 211), 7.36-7.38 (m 2Ff),

25 7.51-7.55 (t. J=- 8,0 Hz; 1H>1), 12.2 (s, I H).

Example 132

9-(4-Fiuorophenyi)-8-(quinoilin-6-yl)-8,9-dihydro-211-pyrido[43 ,2-de]phthalazin-3( 711)-one

Example 132A

Quinoline-6-carbaldehyde

30 1006341 A mixture of SeO2 (10.89 g, 99 mmol) and 6-tnethylquinoline (12.87 g, 90 minol) was

heated to 150 "T and stirred for 16 h. Then it was cooled to room temperature and EtOAc (400 ml)

was added. After filtration, the filtrate was concentrated to obtain the crude compound, which was

purified by chromatography (silica gel, petroleum ether / EtOAc 5:1 to 2: 1. ) to afford the title

compound (2.87 g, yield 20%). LC-MS (ESI) miz: 158 (M+l)I.

35 Example 132B

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(E)-4-(quinolin-6-vlmethyleneamino)isobenzofuiran-1(3H)-one

100635 A solItion of quinoline-6-carbaldehyde (786 mg, 5.0 mmnol), 4-aminoisobenzofuran- 1(31)

one (745 mg. 5.0 mmol) and anhydrous magnesium sulfate (6,0 g, 50.0 inmol) in acetonitrile (100

ml) was heated at reflux for two days. The solution was filtered and removed in vacuum. The crude

5 product was re-crystallized from isopropanol to give the title compound (1.348 g. yield 93%) LC

MS (ES!) rn/z: 289 (M+1) ,H-NMR (400 MHz, DMSO-d6) 6 (ppm): 5.57 (s, 2H), 7.63-7.77 (nh

4-1), 8.14-8.16 (dJ= 8.8 Hz,1H), 8.39-8.42 (m, 11), 8.53-8.56 (m, 2H), 8,99-901 (Im, 2H).

Example 132C

Ethyl 3 (4-fluorophenyl)-2 (-methyl-1H-imidazol-2-yl)-4-oxo-l12,3,4-tetrahydroquioline-5

10 carboxylate

1006361 A mixture of compound 4-fluorobenzaldehyde (248 img. 2 mmol) and (E)-4-(quinolin6

vlmethyleneamino)isobenzofuran- 1(3H)-one (576 ing, 2 mmol) in ethyl propionate (10 mL) was

cooled to 0 TC. Then a solution of sodium ethoxide in ethanol (sodium (184 mg. 8 iniol) in ethanol

(5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 0.5

15 hr. The mixture was quenched with water (20 ruL) and solvent was removed in vacuum. The residue

was dissolved in water and extracted with ethyl acetate three times. After washed with water and

brine, the solvents were removed by rotary evaporation. The crude product was purified by

chromatography to obtain a yellow solid. The solid was dried in vacuum at 50 C to give the title

compound (260 mg, yield 29%). LC-MS (ESI) n/z: 441 (M+i I)

20 Example 132D

9-(4-Fl uorophenyl)-8-(quinol in-6-yl)-8,9-dihydro-211-pyrido[4,3,2-d'e]phthalazin-3(711)~one

1006371 A mixture of ethyl 3-(4-fluorophenyl)-2-(I-methyl-1Hlimidazol2-yl)-4-oxod ;2;3,4

tetrahydroquinoline-5-carboxylate (260 mgt 59 nmol) in 85% hydrazine monohydrate (I mL) and

methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and

25 washed by water (20 mL) and methanol (5 iL) to obtain the title compound as a white solid (61 mg,

yield 25%). LC-MS (ESI) mi/z: 409(M4t i. I H-NMR (400 MHz, DMSO-d6) 6 (ppm): 4.52-4.55 (d, J=9.6 HzI flH). 4.98-5.01 (dI= 9.6 Hz 1 H), 6,97-7.01 (m, 2H), 7. 19-7.22 (m, 3H), 7.41-7.43 (d, J

= 7.6 Hz. 111), 7.46-7.50 (n, 1 H) 7.54 (s, IH), 7.59-7.63 (t, J= 7.6 Hz, 11H), 7.77-7;79 (n. I H),

7.84 (s, 1IH), 7 .91-7.93(m. 11H). 8,24-8.26 (d, = 7.6 Hz, 1H) 8.85-8.86 (in, 1H), 12.20 (s. 1H)

30 Example 133

8-(4-((Dimethy lam ino)methy )phenyl)-9-p-tolyl-8.,9-dihydro-211-pyrido[4,3,2-de]phthalazin-3(7h)

one

Example 133A

Ethyl 2-(4-((dimiethylamino)methyl)phenv)-4-oxo-3-p-tolyl- 1,2,3,4-tetrahydroquinoiline-5

35 carboxylate

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WO 2010/017055 PCT/US2009/051879

1006381 A mixture of (E)-4~(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)

one (500 mg. 17 mmol) and 4-methylbenzaldehyde (204 mg, 1 .7 nmol) in ethyl propionate (30

mi) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol (sodium (1 56 mg, 6.8 mmol)

in ethanol (30 mi)) was added dropwise. After the addition, the mixture was stirred at 10 *C for 1

5 hr, then at 30 "C for 3 hr. The mixture was quenched with water (30 mL) and solvent was removed

in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (30 mL x 4).


concentrated to give crude product, which was purified by chromatography (silica gel,

dichloromethane / methanol = 100:1 to 10:1) to give the title compound (110 mg, yield: 15 %), LC

t0 MS (ESI) ink: 443 (M+41).

Example 133B

8-(4-((Dimethvlaminio)methyl )phenyl)-9-p-toiyl-8,9-dihydro-2H-pyridof43 ,2-dejphthalazin-3(7H)

one

1006391 A mixture of ethyl 2-(4-((dinethyiamino)methyl )phenyl)-4-oxo-3-p-toiyl- 1,2,3,4

15 tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine nonohydrate (I mL) and methanol (3

ml,) was stirred at 10 "C for 2.5 i The mixture was purified by prep-1-iPLC to obtain the title

compound as a white solid (14 tug, yield 11%). LC-MS (ESI) m/z: 411 (+1); 1H-NMR (400

MHz, CD 3OP) 3 (ppm): 2.18 (s, 31)2.31 (s. 6H), 3 .57 (s, 21) 4.25-4,27 (dJz- 8.4lz. .i) 4.72

4. 74 (di= 8.4 Hz, I H), 6.95-7.02 (in, 4F), 7.19-7.29 (in 511), 7.55-7.57 (m, 1N), 7.62-7-64 (t, J=

20 8 Hz, iI),

Example 134

9-(4-Ch loropheny l)-8-(4-((dimethylamino)methyl)phenyl1)-8,9-dihydro-21-pyrido[4,3,2


Example 134A

25 Ethyl 3-(4-chlorophenyl)-(4-((dimethylamino)methyi)phenyl)-4-oxo~1,2,3,4-tetrahydroquinoli ne

5-carboxylate

,1006401 A mixture of (E)-4-(4-((dimethylamino)methyl)benzylidenean ino)isoben zofuran- 1(31)

one (588 mg, 2 inmol) and 4-chlorobenzaldehyde (281 mg, 2 imol) in anhydrous ethyl propionate

(25 ml,) was cooled to 0 ". The sodium methoxide in methanol solution (sodium (115 mg; 5 mmol)

30 in anhydrous ethanol (10 ml)) was added dropwise and the mixture was stirred at 25 " for 3 hr.

The resulting mixture was quenched with water (5 nl.), and then evaporated under reduced

pressure. The residue was extracted with ethyl acetate (100 mL x 3) and the combined organic

layers were dried over anhydrous sodium sulfate and concentrated to give crude product, which was

purified by column chromatography (silica gel, dichloromethane to dichloromethane / methanol:

35 30:1) to give the title compound (260 mng, yield 28%) as a yellow solid. LC-MS (ESI) m/z: 463

(M1) Y.

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Example 1348

9-(4-Chliorophenyl) 8-(4-((dinethylamino)methyl)pheny l)-8,9-dihydro-2 Ji-pyrido[4,3,2

de]phthalazin-3(7h)-one

f006411 A mixture of ethyl 3-(4-chlorophenyl)-2-(4-(( dimyethyhunino)nethyl)phenyl)-4-oxo

5 1,2,3,4-tetrahvdroquinoline-5-carboxylate (260 mg, 0.56 mmol) and hydrazine monohydrate (3 mL)

in methanol (20 mL) was stirred at 30 C for 4 hr. The mixture was concentrated to give crude

product, which was purified by prep-MPLC to give the title compound (34 mg, yield 14%) as a

white solid of formic acid salt. LC-MS (ESI) m/z: 431 (M TI H-NMR (400 Ml-[z, DMSO-d6) 6

(ppm);2,66 (s, 6H) 4,20-4:21 (d, J= 4.8 Hz, 211) 4.39-4.42 (d, J= 8,8 Hz, 1H), 4.82-4.84 (d,.I=

10 8.8 Hz 1 H ). 7.15-7.20 (m, 4H) 7.25-7.27 (d 21I), 7 35-7,42 (mt 5H), 7.46(s, 11), 758-7.62(,1=

8.0Hz 1H), 9.74 (br s, I H), 12.18 (s, 14).

Example 135

8-(4-((Diinethylamino)ethyli)phenyl)-9-(4-methoxypheny)-8.9-dihvdro-2H-pyrid o[4,3,2de]phthalazin-3(7H)-one

15 Example 135A

Ethyl 2-(4-((dimethyiamino)methybphenyi)-3 -(4-methoxyphenyl)-4-oxo-,2,3,4tetrahydroquinol ine-S-c arboxylate

1006421 To a solution of 4-rnethoxybenzaldehyde (231 mng, 1.7 rmol) and (1)-4-(4

((dimethylamino)methyl)benzvlideneamino)isobenzofuran- I(3H)-one (500 rug, 1L7 umol) in ethyl

20 propionate (30 mL) was added sodium methanolate (120 mg, 5.2 nmol) and the mixture was stirred

at 25 C for 4 i. Then the resulting mixture was added water (10 niL) and evaporated tinder reduced

pressure, extracted vit EtOAc (4 x 100 ml), and concentrated to dryness. A crude product was

obtained (250 mg) and was used for next step reaction without father purification. LC-MS (ESI)

m/z: 459 (M-i-1.

Example 1351B

8-(4-((Diniethlamino)niethvl)pheny.-9~(4-methoxyphenvy)-8,9-dihy dro-21H-pyrido[4,3,2


[006431 A mixture of ethyl 2-(4-((dimethylamino)methyl)phenvl)-3-(4-methoxyphenyl)-4-oxo

I 2,3,4-tetrahvdroquinoline-5-carboxylate (70 mg, 0.15 mumol) and hydrazine monohydrate (1 mL.)

30 in methanol (5 ml) was stirred at room temperature for 5 hr. The resulting mixture was evaporated

under reduced pressure to a volume of I mL and then filtered, The filtrate was concentrated to give

the title compound as a white solid (26.5 mig). LC-MS (ESI) m/z: 427(M+ ). 'E-HNMR (400 MHz.

CDOD) 6 (ppm): 2.79 (s. 6H), 3.71 (s, 3H), 4.24 (s, 211), 4.26 (d, IH)., 4.77 (d, I H), 6.74 (d, 21H)

6.99 (d. 2H), 7,18-7.21(m, iiH), 7.35-7.43 (n, 41-), 7.55-7.57 (m, 1MH), 7.65 (t, 3H), 35 Example 136

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8-(4-((Dietlhylamino)methyli)phenyl-)9-phenyl-8,9-dihydro-211-pyrido[4,3,2-de]phthalazin-3(7H)

one

[006441 A mixture of 4-(3-oxo-9-phenyi-3,7 8.9-tetrahydro-2H-pyrido{4,3,2-dejphthalazin-8

yl)benzaldehyde (80 mg, 0.22 mmol), diethylamine (47mg, 0,65 mmol) and acetic acid (39 mg, 0.65

5 mmol) in dichloromethane (50 mL) was stirred at room temperature for 60 min. Upon cooling the

mixture to 0 C sodium triacetoxyborohydride ( mg, 0.33 mmol) was added. After the addition,

the mixture was stirred at room temperature overnight. Dichloromethane was removed under

reduced pressure. The crude product was purified by chromatography (silica gel, dichloromethane /

Methanol = 50:1) to give the title compound (34 mg, yield 36%), LC-MS (ESI) rn/z: 425 (M+HW

10 4-NMR (400 MHz, CD 3OD) 6 (ppm): 1.10 (t 614), 2.64 (q, 41), 3.70(s, 2H), 4.30 (d, = 8.0 Hz,

IH), 4.75 (d .J= 8.0 Hz, 111), 7.06-7.09 (in 21-H), 7.13-7.20 (m, 4 H), 7.22-7.29 (m, 411), 7,54-7.56

(dd, J= 8,0 Hz, IH). 7.62-7.64 (i, 1-l).

Example 137

8-(4-((Diethylami no)methyl)phenyl)-9(4-fluorophenyl)-8.9-dihvdro-2H-pvrido[4,3,215 de]phthalazin-3(7H1-one

[00645) To a stirred solution of 4-(9-(4-filuoophenl)-3-oxo-3,78,9-tetrahydro-2H-pyrido[4,3,2

dejphthalazin-8-y)beizaldehyde (260 mng, 0.68 mmol) in dryness DCM (15 mL) was added acetic

acid (0,2 mL) followed by diethylamine (148 mng, 2,03 nimol) After the addition, the mixture was

stirred at room temperature overnight. Then sodium borohydride (212 mg, 1.01 miol) was added to

20 the mixture at 0 "C. The mixture was stirred at this temperature for 12 hr. DCM was removed under

reduced pressure. The residue was washed with ethyl acetate / methanol (10/1) and filtered The

filtrate was concentrated to give the crude product, which was purified by flash chromatography to

give the title compound as white solid (27.3 mg, yield 9%). LC-MS (ESI) m/z: 442 (M+). H

NTMR (400 MHz, CD3OD) 6 (ppm): 312-3.17 (m, 4H), 4.27 (s, 21), 4.34 (d, 114), 4.78 (d, 1 H), 6.91

25 (t, 2H4), 7.09-7.12 (m, i H 7.38-7.45 (m, 41), 7.56-7.58(m, 11), 764(t, 1H).

Example 138

9-(4-Chlorophenyl)-8-(4-((diethylaimino)methyl )phenyl)-8.9-di.hvdro-2H-pyrido[4,3 ,2/e]phthalazin-3(71)-one

Example 138A

30 (E)-4-(4-((diethylami no)ncthyil)benzylideneamino)isobenzofuran-1(3H)-one

1006461 To a stirred mixture of 4-((diethvlaniino)methvl)benzaldehyde (3.7 g, 19.4 mmol) and

anhydrous magnesium sulfate (11.6 g, 96.8 mnmol) in anhydrous acetonitrile (100 mL) was added 4

aminoisobenzofuran- 1(314)-one (2,89 g, 19.4 mmol) at 0 C. After the addition the mixture was

stirred refluxed for 3 days. The mixture was filtered and the cake was washed with ethyl acetate (50

35 mL X 3). The filtrate was concentrated to give crude product, which was re-crystallized from

isopropanol to give the title compound (2,1 g, yield: 32 %). LCMS (ESI) m/z: 323 (M+l)'

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Example 138B

Ethyl 3-(4-chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)-4-oxo-1,2 3,4-tetrahydroquinoline-5

carboxylate

1006471 A mixture of (L)-4-(4(diethylamino)methy l)benzyl ideneamino)isobcnzofuran-1(3 11)-one

5 (500 mg, 1.55 mmol) and 4-chlorobenzaldehyde (218 mg,1.55 mmol) in ethyl propionate (10 mL)

was cooled to 0 TC Then a solution of sodium ethoxide in ethanol (sodium (107 mug, 4.66 mmol) in

ethanol (5 ml)) was added dropwise. After the addition, the mixture was stirred at room temperature

for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuumn. The

residue was dissolved in water, and then extracted with ethyl acetate (100 mL x 4) The combined

10 organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to

give crude product, which was purified by chromatography (silica gel, petroleum ether / ethyl

acetate = 11) to give the crude of the title compound (268 mg, yield 35%). LC-MS (ESI) n/z: 491

(M+i 1)

Example 138C

1 5 9-(4-Chlorophenyl)-8-(4-((diethylamino)methyl)phenyl)-8,9-d ihydro-2 H-pyrid4[4,3,2

deiphthalazin-3(711)-one

[00648] A mixture of ethyl 3-(4-chloroph.enyl)-2-(4-((diethylamino)methyi)phenyl)-4-oxo-1.,2,3,4

tetrahydroquinoline-5-carboxylate (268 mg) in 85% hydrazine monohydrate (0.5 mL) and methanol

(2 miL) was stirred at 23"C for overnight. Methanol was removed under reduced pressure. The crude

20 was purified by prep-HPLC to give the title compound (93 mg, yield 37%). LC-MS (ESI) m/z: 459

(M+1). ;HNMR (400 MHz DMSO-d6) S (ppm): 0.93 (t, 6H), 2.38 (q, 414), 3.44 (s, 21), 4,35 (d,

11-1), 4.73 (d, 1H) 71.13-7,19 (in, 51-) 7.22-7.25 (i 4 H), 7.38 (d, 214). 7.41 (s, 114), 7.56-7.59 (mn

1141).

25 Example 139

5-Fluoro-8~( 1-methyl- 1Him idazol 2-y l)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,.2-de]phthalazin

3(711)-one

Example 139A

(E)-6-Fluoro-4-((1-methyl-il H-imidazol-2-Iyl)methyleneamino)isohenzofuran- 1(3H11)-one

30 [006491 A solution of 1-methvl-IH-imidazole-2-carbaldehyde (659 mg, 6.0 mmol), 4-amino-6

fluoroisobenzofuran-1(3H)-one (1.0 g, 6.0 mmol), and anhydrous magnesium sulfate (7.2 g, 60.0

mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. The solution was filtered and the

solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to afford

the title compound (1.068 g, yield 68%) LC-MS (ESI) mz: 260 (M+1). '1I-NMR (400 MHz, 35 DMSO-d6) 6 (ppm): 4.04 (s 3m) 5,49 (s. 211), 724 (s, 114), 7.54-7.58 (m, 2H), 7.73-7.76 (i, 1H),

8.70 (s, 1H).

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Example 139B

Ethyl 7-fluoro-2-(i-methyl- 1 H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3 .4-tetrahydroquinoline-5

carboxylate

1006501 A mixture of benzaldehyde (212 ig. 2 mmol) and (E)-6-floro-4-((i-iethyl-lH-imidazo

5 2-yl)methyleneanino)isobenzofuran-1 (311)-one (518 mg. 2 mmol) in ethyl propionate (10 mL) was

cooled to 0 C. Then a solution of sodium ethoxide in ethanol (sodium (184 mg, 8 mmol) in ethanol

(5 ml,,)) was added dropwise. After the addition, the mixture was stirred at room temperature for 0.5

hr. The mixture was quenched with water (20 iL) and solvent was removed in vacuum. The residue

was dissolved in water and extracted with ethyl acetate three times. The combined organic layers

10 were washed by water and brine, and then evaporated to dryness, the crude product was purified by

chromatography to obtain a yellow solid. The solid was dried in vacuum at 50 'C to give the title

compound (250 mg, yield 32%). LC-MS (EST) n/z: 394 (M+1) t .

Example 139C

5-Fluoro-8-(1-methyl-IH-imidazol-2-yl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin

15 3(7T-one

[006511 A mixture of ethyl -fluoro-2-(1-methyl-ih-.aimidazol-2-yi)-4-oxo--phenyl-1,2,3,4

tetrahydroqujinoline-5-carboxylate (250 mg, 0.636 mmol) in 85% hydrazine monohydrate (1 mL)

and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture wax filtered and

washed water (20 nL) and methanol (5 mL) to obtain a white solid, which after dried in vacuum at

20 50 'C afforded the title compound (34.6 mg, yield 15%), LC-MS (ESI) m/z: 362(M+i)* 111-NMR

(400 Mliz, DMSO-d6) 6 (ppm): 3.56 (s, 31-l), 4.48-4.49 (d, J 6.0 Hz, 1H), 5.01-5.03 (in, 11H). 6.70-6.71 (in, Jil. 6.81-6.84 (, I M), 6.98-7.02 (m, 211)1 714-7.26 (in, 511), 7.66-7.67 (m, 1H1),

12.33 (s. 1H).

25 Example 140

5-Fluoro-9-(4-fluorophenyl)-8-(iethylI HJimidazol-2-yl)-8,9-dihydro-2J-pyrido[4,3,2~

de]phthaIazin-3 (71f)-one

Example 140A

Ethyl 7-fluoro-3-(4-fluorophenyi)-2-(1-methyl-Imf-iiidazol-2-yl)-4-oxo-1,2,3,4


1006521 A mixture of 4-fluorobenzaldehyde (248 ing, 2 Inmol) and (E)-6-fluoro-4-((l-methyl-l f

imidazol-2-yl)iethyleneamino)isobenzofiran-I(3H)-one (518 mg, 2 mmol) in ethyl propionate (10

mL) was cooled to 0 "C Then a solution ofsodium ethoxide in ethanol (sodium (184 mg, 8 mmol)

in ethanol (5 mL) was added dropwise. After the addition, the mixture was stirred at room

35 temperature for 0.5 hr. The mixture was quenched with water (20 mL) and solvents were removed in

vacuum. The residues were dissolved in water and extracted with. ethyl acetate three times. The

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combined organic layers were washed with water and brine. After the removal of solvents, the crude

product was purified by flash column chromatography to obtain a yellow solid, which was dried in

vacuum at 50 TC to give the title compound (200 mg, yield: 24%). LC-MS (ESI) m/z: 412 (M+1).

Example 140B

5 5-Fluoro-9-(4-fluorophenyl)-8-(I-methyl-1 H-imidazol-2-y)-8,9-dihydro-2H-pyrido[4,3,2

dejphthaiazin-3(7H)-one

1006531 A mixture of ethyl 7-fl uoro-3-(4-fluorophenyl)-2-( I -methyl.-1iH-irnidazol-2 -yl)-4-oxo

1 2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.486 mmol) in 85% hydrazine monohydrate (I

mL) and methanol (5 mL) was stirred at room temperature for 4 h, The resulting mixture was

to filtered and washed. by water (20 mL) and methanol (5 mL) to obtain a white solid, which was then

dried in vacuum at 50 C to obtain the title compound (25.4 mg, yield 14%). LC-MS (ESI) n/:

380(M+1)-i; 1H--NMR (400 MHz. DMSO-d6) 5 (ppm): 3.56 (s. 3ff), 452-453 (d. J= 6.8 Hz, i).

5,02-5.04 (m, li) 6.73 (s, 111), 682-6.85 (in, 11), 6.99-7.09 (in, 411), 7.18-7,22 (n 2H) 7.69 (s,

11), 12.34 (s, Ii),

15 Example 141

8-(4-((Dimethylamino)methyl)phenyl)9-(4-ethylphenyl)-8,9-dihydro-2H-pyrido[4,3,2de]phthalazin-3(7T)-one

Example 141A

Ethyl 2--(4 -((dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1 ,2,3,4-tetrahydroquinoi ine~5

20 carboxylate

[006541 A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3)

one (588 mg, 2 mmol) and 4-ethylbenzaldehyde (268 mg, 2 mmol) in ethyl propionate (15 mL) was

cooled to 0 C. Then a solution of sodium ethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol

(5 iL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 3

25 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum., The residue

was dissolved in water, and then extracted with ethyl acetate (.100 iL x 4). The combined organic


product, which was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 1:1) to

give the crude title compound (290 ng, yield 32%). LC-MS (ESI) m/z: 457 (M+1)

30 Example 1411B

8-(4-((Dimethylamnino)methybpheny)-9-(4-ethylphenyl)-8,9-dihydro-211-pyrido[4,3 .2

de]phthalazin-3 (71)-one

1006551 A mixture iof ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-ethylphenyl)-4-oxo-1,2.,4

tetrahydroquinoline-5-carboxylate (290 mg) in 85% hydrazine monohydrate (I mL) and methanol

35 (10 mL) was stirred at 30 C for overnight. Methanol was removed under reduced pressure. The

crude product was purified by chromatography (silica gel, Petroleum ether / ethyl acetate = 1:1) to

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give the title compound (112 mug, yield 42%). LC-MS (ESI) m/z: 425 (M+1). 'H-NMR (400 MHz,

CD:OD) 6 (ppm): 1.12 (L3t1), 2.10 (s. 611), 2.52 (q, 2H), 3.34 (s. 2H), 4.31 (d, J= 8.0 Hz, 11-1), 4,76

(d,J= 8.O Hz. II), 7.04 (in, 4H)t 7.15-7.20 (in, 31H), 7.25-727 (in, 2H), 7.38-7.41 (ma, 3H), 759

761 (m, IlH).

Example 142

8-(4-((Dinethylam ino)methyl)phenyl)-944-isopropylphenyl)-8,9-dihy dro-2H-pyrido[ 4,3,2deiphthalazin-3 (7H)-one

Example 142A

Ethyl 2-(4--((dimethylaimino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4


[006561 A mixture of (E)-4-(4-((dimethylanino)methyl)benzylideneaminno)isobenzofuran- 1 (3H1)-one

(588 mg, 2 nmol) and 4-isopropylbenzaldehyde (296 mug, 2 mimol) in ethyl propionate (15 mL) was

cooled to 0 "C Then a solution of sodium ethoxide in ethanol (sodium (138 ing, 6 mmol) in ethanol

(5 mi.)) was added dropwise. After the addition, the mixture was stirred at room temperature for 3

i5 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue

was dissolved in water. and then extracted with ethyl acetate (100 ml, x 4). The combined organic


product, which was then purified by column chromatography (silica gel, petroleum ether / ethyl

acetate = 1:1) to give the title compound (210 mg yield 22%), LC-MS (ESI) miz: 471 (M+ 1).

20 Example 142B

8-(4-((Dinethylamino)methyl)phenyl)-9-(4- isopropylphenl)9-8.-d ihydro-2.H-pyrido[4,3 .2


1006571 A mixture of ethyl 2-(4-((dimruethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo

1 2,3.4-tetrahvdroquinoline-5-carboxylate (210 mig) in 85% hydrazine monohydrate (I mL) and

25 methanol (10 m1.) was stirred at 23"C tor overnight Methanol was removed under reduced pressure.

The crude was purified by flash chromatography to give the title compound (72 mg, yield 37%). LC

MS (ESI) m/z: 439 (M+])' 'H-NMR (400 MHz, CDOD) 6 (ppm): 1 18 (d 31-1), 1.19 (d, 31), 2.26

(s, 6H), 2.79-2.83 (i, 1 H), 3.51 (d, 21-1), 4.27 (d, J= 8.0 Hz, 1H), 4.73 (d, ,= 8.0 Hz, I 1-, 6.98-7.00

(in, 2.H), 7.05-7.07 (m, 2H). 7.18-7,22 (n, 3 11) 7,25-7.27 (in, 2H-), 7.54-7.56 (m, 11), 7.56-7.59 (in, 30 111).

Example 143

8-(4-((Dimethyiamnino )methyl )phenyl)-9-44~(tri fiuoromnethyl)phenyl )-8,9-dihydro-2H1-pyrido{[4,3,2

delphthalazin-3(71f)-one

35 Example 143 A

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Ethyl 2(4-((dimethyIamino)methyl)phenyl)-4-oxo-344-(triloromethvl)phenyl) L2,3,4


1006581 A mixture of (f)-4-(4-((dimethylam ino)methyl)benzylideneamino)isobenzof uran-1I(31)

one (541 mg. 1.84 mmol) and 4-(trifluoromethyl)benzaldehyde (320 mg, 1.84 nmol) in anhydrous

5 ethyl propionate (25 mL) was cooled to 0 C, Then sodium ethoxide in methanol solution (sodium

(127 mg, 5.51 mmol) in anhydrous ethanol (10 rL)) was added dropwise and the mixture was

stirred at 25 "C for 4 hr. The resulting mixture was quenched with water (5 mL), and then

evaporated the solvents off under reduced pressure, The residue was extracted with ethyl acetate

(100 mL x 3) and the combined organic layers were dried over anhydrous sodium sulfate and

10 concentrated to give crude product, which was purified by column chromatography (silica gel,

dichloromethane to dichloromethane / methanol = 30:1) to give the title compound (150 mg, yield

16%) as a yellow solid. LC-MS (ESI) n/z: 497 (M+1).

Example 143B

8-(4-((Dimethylamino)methyl)phenyl)-9-(4-(trifluoromethyl)phenyl)-8,9-dihydro-2 H-pyrido[4,3,2


[006591 A. mixture of ethyl 2-(4-((dimethylamino)methivl)phenyi)-4-oxo-3 -(4

(trifl uoromethyl)phenyl) 1,2,3 .4-tetrahydroquinoline-5-carboxylate (150 mg, 0.30 mmol) and

hydrazine monohydrate (0.5 mL) in methanol (10 mL) was stirred at 30 "C overnight. Ihe mixture

was concentrated under reduced pressure to give crude product, which was purified by flash

20 chromatography to give the title compound (60 mg, yield 34,5%) as a white solid, LC-MS (ESt)

nz: 465 (M+l 7 1H-NMR (400 MHz, DMSO-d6) 6 (ppm): 2.64 (s, 3H) 2.65 (s, 314)5 4.19-4.20 (d,

J= 4.0 Hz, 2H), 4.534.55 (d. J= 9.2 Hz, lH), 4.88-4.90 (d, J= 9.2 Hz, 11 ), 7.20-7.22 (d, J= 7.6

Hz, 1H), 7-35-7.46 (i, 7.), 7.50 (s, 114), 7.56-7.63 (ni, 311), 9.69-971 (br s, I 11), 1.220 (s. 1H)

Example 144

25 8-(4-((Dietlylamino)methyl)phenyl)-9-p-tolvl-8,9-dihydro-2H-pyrido[4,3 ,2-dejphthalazin-3(711)one

Example 1.44A

Ethyl 2-(44(diethylanino)nethyl)phenyl)-4-oxo-3-p-tolyl-1,2;-23,4-tetrahydroquinoline-5

carboxylate

30 100660] A mixture of (E)-4-(4-((diethvlam ino)methyl)benzylideneamino)isobenzofuran- I(31H}1-one

(644 mg, 2 mmol) and 4-methylbenzaldehyde (240 mg, 2 mmol) in ethyl propionate (15 mL) was

cooled to 0 *C 'hen a solution of sodium ethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol

(5 ml..)) was added dropwise. After the addition, the mixture was stirred at room temperature for 3

hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue

35 was dissolved in water, and then extracted with ethyl acetate (100 mL x 4). The combined organic


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product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate

1:1) to give the title compound (320 ng, yield 34%). LC-MS (ESI) m/z: 471 (M-+1)K

Example 144B

8-(4-((Diethylainio)methyl)phenyl)-9-p-tolyl-8.9-d ihydro-211-pyrido(43,2-dejphthalazin-3(7H)

S One

1006611 A mixture of ethyl 2-(4-((diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl- 1,2,3,4

tetrahydroquinoline-5 -carboxylate (320 mug) in hydrazine monohydrate (2 mL 85%) and nethano

(10 mil) was stirred at 30 "C for overnight. Methanol was removed under reduced pressure. The

crude product was purified by chromatography (silica gel, petroleum ether / ethyl acetate= 1:1) to

10 give the title compound (85 mg, yield 29%). LC-MS (ESI) m/z: 439 (M4-l H-NMR (400 MHz,

DMSO-d6) S (ppm): 0.93 (t, 611), 2.20 (s, 311), 2.39 (q, 41]) 3.42 (d, 2H), 4.27 (d, J= 8.0 Hz, l1lH),

4.73 (d,] = 8.0 Hz, I1H), 6.98-7.00 (m, 4Ff), 7.15-7.17 (i, 3H1). 7.22-7.24 (in, 211), 7.35-7,38 (m,

2H), 7.54-7.56 (m, 111), 12.12 (s, IH).

15 Example 145

9-(4-Fluorophenyl)-8-(4-(I -methylpyrrolidin-2-yl)phenyl)-8,9-dihydro-2H-pyrido[4,3 2


Example 145A

tert-Butyl 2-oxopyrrolidine- I -carhoxylate

20 1006621 To a solution of 2-pyrrolidinone (10.82 g, 127 mnol) in acetonitrile (400 mL) was added

DMAP (.53 g, 12.6 mmol) followed by a solution of di-tert- butyldicarbonate (33.6 g, 77.1 minimol)

in acetonitrile (20 mL.. The reaction mixture was stirred at room temperature for I h. The resulting

mixture was concentrated in vacuo and the resulting oil was taken. up in diethyl ether. The mixture

was washed consecutively with I N HCI and brine. The organic phase was dried over sodium

25 sulfate, and concentrated in vacuo to afford the title compound as a yellow oil (15 g, 64%) which

was used directly in the next step.

Example 145-B

tert-Butyl 4-(4-broiophenyl)-4-oxobutylcarbamate

1006631 A thoroughly dried three-necked round-bottom flask was equipped with reflux condenser, 30 addition funnel and argon inlet. Then magnesium powder (7.5 g, 311 tmol, activated by iodine) and

dry THF (300 mL) were placed into this apparatus. A solution of 1, 4 - dibromobenzene (73,5 g, 311

mmol) in dry THF (200 mL) was slowly added at such a rate that the mixture maintained at reflux,

When the addition was completed the mixture was refluxed for additional 2 hrs. After cooling to

room temperature, the solution was added into a solution of tert-butyl 2-oxopyrrolidine- I

35 carboxyltte (48 g, 260 miol) in THF (320 mL) at -78 C and the mixture was stirred at -78 "C for

2 hrs. The solution was warmed to ambient temperature and stirred for another 10 hrs before

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quenching with water. Hydrochloric acid (1 N, 100 mL) was added and the mixture was stirred at

ambient temperature for 10 minutes. The mixture was concentrated and the residue was partitioned

between ethyl acetate and brine The organic phase was dried over magnesium sulfate and

concentrated in vacuo to afforded the crude product, which was purified by column chromatography

5 (EtOAc: DCM hexane 1 : 115) to give the title compound as a white solid (53 g, yield 60 %).

LC-MS (ESI) inz: 342 (M+A).

Example 145C

5-(4-Bromophenyl)-3,4-dihydro-2-lpyrrole

1006641 tert-Butyl 4-(4-bromophenyi)-4-oxobutylcarbaniate (3.42 g, 10 mmol) was stirred in TFA

10 (10 mL) for 6 hrs, Then 50 % NaOH solution was added to the mixture to make p11 13-14, the

white precipitate was filtrated, washed with water and dried to give the title compound as a white

solid (1 8 g. yield 80%). LC-MS (ESI) i/z: 224 (M+1)l.

Example 1451)

2-(4-Bromophenyl)pyrrolidine

15 [006651 NaiH4 (1.52 g, 40 mmol) was added to a solution of 5-(4-bromophenyl)-3,4-dihvdro-2iH

pyrrole (4.48 g, 20 mmol) in H?0/MeOH (30 mL, v/v 1: 4) at -41 'C. After stirred for 4 hrs. the

solution was allowed to warm to room temperature. Once the reaction was deemed complete by

TLC. the unreacted NaBlI was quenched by the addition of 2 N HCL The solution was then diluted

with water and ether, and separated two layers. The aqueous layer was washed with an additional

20 portion of ether, basified with 4 M. NaOHI (pH 12-13) and washed with ethyl acetate. The combined

organic extracts were washed with brine, and then dried over Na 2SO. Evaporation of the solvent

afforded the title crude product as a yellow oil (3.8 g, yield 84%), which was used directly in the

next step. hC-MS (ESI) m/z: 226 (M+ )

Example 145E

25 2-(4-Bromophenyl)-l -methylpyrrolidine

1006661 A mixture of 2-(4-bromophenvl)pyrrolidine (0,5 g, 2.2 minol); formic acid (0,11 mL 2.42

mmnol), formaldehyde (0.2 niL, 2.42 imol, 37 % in water), water (4 mL;) in a sealed tube was heated

to 150 C under microwave for 5 minutes. After cooling to room temperature the reaction mixture

was extracted with EtOAc (3 x 15 miL), the combined organic phase was washed consecutively with

30 saturated NaHCO3 (5 mt) and brine (5 miL), dried over Na2SO4 and concentrated in vacuo tn give

the crude product (0.48 g, 91 %), which was used directly in the next step. LC-MS (ESI) m/z: 240

(M+1)*,

Example 145F

4-(1 I-Methylpyrrolidin-2-yl)benzaldehyde

35 1006671 To a solution of 2-(4-bromophenyl)-m-niethylpyrrolidine (0.45 g, 2 mmol) in dry TU (10

mL) was added dropwise n-BuLi (0.88 mL, 2.2 nmmol, 2.5 mol/L in hexane) at -78 C, after the

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addition was completed the mixture was stirred for 1 h, then dry DMF (0,18 mL, 24 mmol) was

added to the reaction system and stirring was continued for another I hr. Then the reaction mixture

was partitioned between EtOAc and 1 N HCI. the aqueous solution was extracted with EtOAc (3 a

15 mL), The combined organic phase was washed with. brine, dried over Na2SO4, and concentrated

5 in vacuo to give crude product (0.28 g, yield 74 %) as a yellow oil. The product was used directly in

the next step without further purification. LC-MS (ESI) rn/z: 189 (M+1)Y

Example 145G

(E)-4-(41 -methylpyrrolidin-2-yi)benzylideneamnino)isoben zofuran- 1(311)-one

(00668] A mixture of 4-(1 -methylpTrolidin-2-y)benzaldehyde (1.89 g, 10 mmol) 4

10 aminoisobenzofuran-I (311)-one (1 .49 g, 10 mmol) and MgSO (12 g, 100 mmol) in CHCN (60 mL)

was refluxed at .120 "C for 4 days. After a hot filtration, CH3CN was partially removed under

reduced pressure and a white precipitate was appeared, the title compound was obtained by a direct

filtration (1.3 g, yield 41 %) as a white solid. LC-MS (ESI) m/z: 440 (M+1) .

Example 14511

15 Ethyl 3-(4-fluorophenyl)-2-(4-(1 -methylpyrrolidi-2 -y l)phenyl)-4-oxo-1,2,3 4-tetrahydroquinoline

5-carboxylate

1006691 A mixture of (E)-4-(4-(1-niethylpyrrolidin-2-yl)benzylideneamino)isobenzofuran-1(31)-one

(0.32 g, I mmol), 4-flourobenzenaldehyde (0.248 g, 2 mmol) was dissolved in dry ethyl propionate

(5 mL), EtONa (0.136 g, 2 mmol) in EtOH (5 mL) was added to this solution and the mixture was

20 stirred at room temperature until the starting material was disappeared as monitored by TLC, The

reaction was quenched with 0-5 mL of water, the resulting mixture was concentrated in vacuo. and

the residue was purified by column chromatography (MeOH: DCM = 1: 20) to give the title

compound (200 msg, yield 42 %) as a pale yellow solid. lC-MS (ESI) m/z: 472(M+1).

Example 145 1

25 9-(4-Fiuorophenyl)-8-(4-(I-mnethylpyrrolidin-2-yl)phenyl)-8,9-dihydro-2Htpyrido[4,3 2


[006701 To a stirred solution of ethyl 3-(4-fluorophenyl)-2-(4-(1 -methylpyrrolidin-2-yl)phenyl)-4

oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.42 mmol) in MeOH (20 ml) was added

N2Y14H1O (2 mL), the mixture was stirred for 4 hrs. and then concentrated in vacu:' and the residue

30 was purified by chromatography (MeOH: DCM= 1: 20) to give the title compound as a white solid

(45 mg, yield 24 %). LC-MS (ESI) n/z: 440 (M+l); 'H-NMR (400 MHz, CDCh) d (ppm): L671. 97 (m, 31), 2.11 (s 31H), 2.25 (m, I H), 2.17-2.30 (in, I ), 2,97-2.99 (m, 1H) 3.21-3.25 (in, 11), 4.19-4,22 (d. = 10.4 Hz, 111). 4,57-4.59 (dJ= 10A Hz; 1H), 4.90 (s, 11), 6.86-691 (m. 211), 6.95-6.97 (m, 211), 7.03-7.05 (d, := 7.6 Hz, I 1), 7.10-7-12 (d, J= 8 Hz, 2H), 7.20-7.22 (d, = 8 Hz.

35 211),7,57-7.61 (t, J=7,6 Hz, 1H), 7.74-7.76 (d, T= 7.6 Hz, IH), 9.94 (s, 114).

Example 146

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9-(4-Fluorophenyl)-8-(4-(pyrrolidin-2-yl)phenyl)-8;9-dihvdro-2H-pyrido[4,3.2-de iphthalazin

3(7T)-one

Example 146A

Benzyl 2-(4-bromophtenyl)pyrrolidine-I -carboxylate

5 1006711 A solution of 2-(4-bromophenyl)pyrrolidine (2.26 g 10 mniol) in dioxane (18 mL) and

water (12 nl.) was added potassium carbonate (5.52 g, 40 mol) and benzyl chloroformate (1.88 g,

II mmol) at ambient temperature and stirred overnight. Then the mixture was partitioned between

ethyl acetate and brine. The organic phase was concentrated in vacuo and the residue was purified

by colun chromatography (silica gel EtOAc: hexane = 1: 10) to give the title compound (2.95 g,

10 82 %) as a colorless oit L.C-MS (EST) n/z: 360 (M+1)

Example 14613

BenzyI 2-(4-formylphenyl)pyrrolidihne-i-carboxylate

[006721 To a 50 mL round-bottomed flask were placed Pd (PPh) 2C12 (70 mg, 0.1 inmol), and

sodium formate (510 mg, 7.5 mmol) and purged with carbon monoxide. DMF (7 mL) and benzyl 2

15 (4-bromophenyl)pyrrolidine-I -carboxylate (1 8 g, 5 mmol) were added via syringes. The mixture

was vigorously stirred at 100 "C under carbon monoxide atmosphere for 8 hrs. Then the reaction

mixture was cooled to room temperature and partitioned between ether (100 mL) and water (15 mL).

The organic phase was washed with water (3 x 15 mil,) dried over NaISO4, and concentrated in

vacuo. The residue was purified by column chromatography (silica gel, EtOAc : hexane = : 10) to

20 give the title compound (0.31 g, yield 20 %) as a colorless oil. LC-MS (ESI) m/z: 309 (M+1); H

NMR (400 MHz, DMSO-d6) 6 (ppm): 173-1.88(m. 31H), 2.3 1-2.41(m, IH 3,57-3.67(m, 2H.), 4.84

5.06 (m, 31.), 6.84-6.86(m, iH), 7.12-7.34(m, 41), 7.41-7.43(d, J= 8.0 Hiz, 21), 7.85-7.87(d, J=-

8.0 Iz 211), 9.98-9.99(d, ,J 6.0 Hz, 1H),

Example 146C

25 (E)-benzyl 2-(4-((1-oxo- I,3-dihvdroisobenzofiiran-4-vlimino)methyl)phenyl)pyrro idine-l

carboxylate

[00673] A mixture of benzyl 2-(4-fonylphenyb)pyrrolidne-1-carboxylate (0.62 g, 2 mmol), 4

aminoisobenzofuran-1 (3H)-one (0.298 g 2 mmol), MgSO (2.4 g, 20 mmol) in CH,4CN (20 maL) was

refluxed at 120 C for 4 days. After a hot filtration, the filtrate was concentrated in vacuo and the

30 residue was purified by column chromatography (EtOAc: DCM: hexane = 1: 1: 6) to give the title

compound (0.35 g, yield 30 %) as a white solid. LC-MS (ESI) m/z: 440 (M--i)

Example 146D

Ethyl 2-(4-(I-(benzyloxycarbonyl)pyrrolidin-2-l)phenyl)-3-(4-fluorophenyl)-4-oxo-i,2,3,4


35 [00674] A solution of (E)-benzyl 2-(4-((1 -oxo- 1,3-dihydroisobenzofuran-4

ylimino)methyl)phenyl)pyrrolidine-1-carboxylate (0.5 g, 1.14 mmol) and 4-flouro benzaldehyde

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(0.284 g, 2.28 mmol) in dry ethyl propionate (5 mL) was added EtONa (0. 155 g, 2.28 mmol) in

EtOH (6 mL), and the mixture was stirred at room temperature until the starting material was

disappeared as monitored by TILC. Then the reaction mixture was quenched with 0,5 niL of water,

the resulting mixture was concentrated in vacuo, and the residue was purified by column

5 chromatography to give the title compound (130 mg, yield 20 %) as a yellow solid. LC-MS (ESI)

n/z: 592(M+1)

Example 146E

Benzyl 2-(4-(9-(4-fluorophenyl)-3 -oxo-3,7,8,9-tetrahydro-2H-pyrido(4,3 ,2-de]phthalazin-8

yl)phenyl)pyrrolidine- 1 -carboxylate

10 1006751 To a stirred solution of ethyl 2(4-(h-(benzyloxycarbonvl)pyrrolidin-2-yl)phenvl)-3-(4

fluorophenyl)-4-oxo- 1,2,3,4-tetrahydroquinoline-a-carboxylate (130 mg, 0.22 mmol) in MeOH (20

mL) was added N 2HH4 . 20 (2 mL), the reaction was continued for 4 hrs, then mixture was

concentrated in vacuo and the residue was purified by chromatography (EtOAc : hexane 1 : 2) to

give the title compound (100 mg, yield 81 %) as a white solid, LC-MS (ES m/iz: 560 (M+1)''H

15 NMR (400 MHz, CDCl3) S (ppm): 1.77-1,90(nm 3H) 2,25(m, 1 H), 3 653.68(m, 21I). 4.10-423(m,

2H)t 4.59-4.61(d,'J= 10.0 Hz, 1Hl). 4.90-5.14(m, 2H) 6.82-7.09(m, 101-). 7.27-7.32(m, 2H), 737(s.

211), 7,60-7.64(m, I Hi), 7.77-7.79(m 1H), 9.61(s. 1H).

Example 146F

9-(4-Fl-uorophenyI)-8-(4-(pyrrolidin-2-yl)phenyl)- 8,9-dihydro-21-pyrido[4,3. 2-de jphthalazin.

20 3(71)-one

1006761 Benzyl 2-(4-(9-(4-fluorophenvl)-3 -oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-dejphthalazin

8-yl)phenyl)pyrrolidine-1-carboxylate (60 mg, 0.107 mmol) was dissolved in distilled methanol (15

mL), and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen in

the presence of a catalytic amount of palladium on carbon (II mg, 0.01 mimol) for 2 hrs. After the

25 reaction was completed, the catalyst was removed by filtration through a pad of Celite, and the

solvent was removed under reduced pressure. The residue was purified by preparative TLC (MeOH:

DCM = 1:10) to give the title compound (5 mg, yield 11 %) as a white foam. LC-MS (ESI) rn/iz:

426(M+I) H-NMR (400 MHz, CD1OD) 6 (ppm): 178-1.88 (m, 11H), 1.95-2.08 (in, 2H), 2.24-2.32

(in, 1), 3.05-3.12 (in 11-1), 3.21-3.27 (in, 11-), 417-4.21 (m, li-I), 4.34-4,36 (d, J=: 8,0 Hz, 11),

30 4.75-4.77 (d J - 8.0 Hz, IH), 6.91-6.95 (in, 211), 7,09-7.15 (i, 2H), 7.17-7.25 (in, L H), 7.22-7.25

(in, I H), 7.29-7.34 (ni. 411). 7,55-7.57 (i, 111), 7.63-7.67 (m, Il-1),

Example 147

8-(4-Fluorophenyl )-9-methyl-9-(I -methyl- 1H-inidazol-2-y l)-8,9-dihydro-2 H-pyrido[4,3,2


Example 147A

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Ethyl 2-(4-fiuorophenyl)-3-methy[3-1-methyl-1H-imidazo-2 y4-oxo-1,3,4


1006771 To a solution of ethyl 2-(4-fluorophenyl)-3 (1-methyl-l-imidazol-2-yl)-4-oxo- 1,23,4

tetrahydroquinoline-5-carboxylate (150 mg, 0.38 nmol) and cesium carbonate (268 mug, 0.76 mmol)

5 in DMF (10 mL) was added iodomethane (0.2 mL, 128 mmol) at 0 "C under N2. The reaction

mixture was stirred at 0 "C for 4. h and then at room temperature overnight. The resulting solution

was added 50 ml of water- and then extracted with ethyl acetate (100 mL x 3), The extracts were

concentrated to give the crude product as a yellow solid (145 mg, yield 90%), which was used in the

next step without further purification. LC-MS (ESI) m/z: 408 (M+14

to Example 147B

8 -(4-Fluorophenyl)-9-nethyl-9-( ntethylI -1H-imidazol-2-yl)-8,9-dihydro-211-pyrido[4,3,2

deJphthalazin-3(711)-one

[006781 Ethyl 2-4-fiuorophenyi)-3-methy -3-(1 -methyl-iH-imidazol-2-yl)-4-oxo-1,223.4

tetrahydroquinoline-5-carboxylate (70 mg, 0,18 rmmol) was added to hydrazine monohydrate (5 mL)

15 and the mixture was stirred at 67 "C for 10 hr, The resulting mixture was concentrated and purified

by prep-HPLC to obtain the title compound as a white solid (9 rg, yield 14%). LC-MS (ESI) m/z:

376 (I+). H -NMR (400 MHz, DMSO-d) 6 (ppm): 1,79 (s, 3H), 2.57 (s, 311), 4.50 (s, I H) 6.68

6,69 (dJ> 09 .Hz, IH). 6.78-6.82 (mn, 211), 6.84-6,85 (d, J= 0.9 Hz 1H), 7,05-7,09 (i, 2H), 7.16

7.18 (dd. J,- = 8.0 Hz, J,= 0.8 Hz., I H), 7.34 (s, I H), 7.43-745 (dd. 8.0 Hz; J,= 0.8 Hz. I H),

20 7.57-7.61 (t,J:zz 7.6 Hz, 11), 12.30 (s, 1l).

Example 148

9-(4-Fluorophenyl)-8-(I i-Iimidazol-2-yl)-8,9-dihydro-21H-pyrido[4,3 .2-del phthalazin-3(7H)-one

Example 148A

25 1 -Benzyl- nn11-iidazole-2-carbaldehyde {006791 To a solution of I1--imidazole-2-carbaldehyde (240 mg, 2.4 mmuiol) and potassium carbonate

(662 mg. 4.8 rmol) in acetonitrile (5 mL) at 0 C was added dropwise (bromomethyl)benzene (493

mg, 2.88 mmol). The mixture was stirred at 40 *C for 4 hr. Then the mixture was filtrated,

evaporated to remove the acetonitrile from the filtrate, added EtOAc to extract the residues, and

30 washed the extract with brine and water. The organic layer was dried with anhydrous Na 2SO 4

concentrated, and chromatographed on a silica gel column (EtOAc: hexane- 1: 9) to obtain the title

compound ( 430 mg, yield 95%). LC-MS (ESI) m/z: 187 (M+ 1)"

Example 148B

(Ef)-4-(( lenzyl- lH-Iim idazol-2-yl)methyleneamnino )isobenzofuran- 1(311)-one

335 1006801 The mixture of: -benzyl-iH-imridazole-2-carbaldehyde (430 mng, 1.48 mmol), 4

amioisobenzofuran1-3H)-one (221 mug, 1.48 rnmol) and magnesium sulfate (4.3 g) in acetonitrile

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was heated to reflux for 48 hr. Then the mixture was filtrated off and evaporated to remove the

solvent. The crude was re-crystallized from isopropanol to obtain the title compound (470 mg,

65%). LC-MS (ESI) m/z: 318 (M+1)4,

Example 148C

5 Ethyl 2-(1 -benzyl-11-im idazol-2-yi)-3 -(4-fl uorophenyl)-4-oxo- 1,2,3,4-tetrahydroquinoline-5

carboxylate

[006811 A solution of (E)-4-((I-benzykl -lH-imidazo4-2-yl)methvleneamino)isobenzofuran-1(3Lf)

one (470 mg, 1 .48 mmol) in ethyl propanate (5 mL) was added EtONa/EtOHI (136 mg of sodium in

5 mL of ethanol) and stirred at room temperature under N2 for 30 min. Then the mixture was

10 partitioned between water and ethyl acetate. The organic layer was separated, washed with water

and brine, dried with anhydrous Na 2SO 4 and chromatographed on a silica gel column (EtOAc:

hexane = 1: 9 to 1: 1) to obtain the title compound (280 mg, yield 40 %). LC-MS (ESI) mi/z: 470

(M+ 1)

Example 148D

15 8-(I-Benzyl- 1-Him idazol-2-yl)-9-(4-fluorophenyl )-8,9-dihydro-2I-pyrido[4,3 ,2-dejphthalazin

3(711)-one

100682] A mixture of ethyl 21-(-benzl -Hi-imidazol-2-yl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4

tetrahydroquinoline-5-carboxylate (280 mg, 0.59 mmol) and hydrazine monohydrate (2 mL, 85%) in

methanol (4 ml) was stirred at 40 T for 2 hr, and then evaporated to half of the original volume.

20 The mixture was filtrated and washed the solid with ethyl acetate to obtain the title compound (200

mg, yield 96%). LC-MS (ESI) m/z: 437 (M+1)

Example 148E

9-(4-Fluorophenyl)-8-( Iiimidazol-2-yl)-8,9-dihydro-2H-pyridof4,3,2-de]phthalazin -3(7H)-one

1006831 A mixture of 8-(I -benzyl- I H-imi dazol-2-yi)-9-(4-fliorophenyl)-8,9-dihydro-2H

25 pyrido[4,3,2-dejphthalazin-3(71H)-one (200 mg, 0.46 mmol) and palladium hydroxide (200 mg) in

methanol (4 mL) was purged with hydrogen and stirred at 60 "C for 18 hr. Then the mixture was

filtered, evaporated to remove the solvent, and washed the solid with ethyl acetate to obtain the title

compound (150 mg, yield 94%). LC~MS (ESI) m/z: 348 (M+1)". IH-NMR (400 MHz, DMSO-d6) 6

(ppm): 4.93 (d, J= 8.4 Hz, 11), 5,21 (d, J= 8.4 Hz, 1H1), 7.10 (t,, =8.4 Hz, 211), 7.21-7.30 (m, 30 31), 7.37 (s. 111), 7.45-7.49 (i, 31) 4.58 (d, J= 10 Iz,1H), 7.62-7,67 (m:, 1 V), 7.87 (s, 1H).

Example 149

5-Fluoro-9-(I -methyl-dH11-1,2.,4-triazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3 .2-de]phthalazin

3(711)-one

Example 149A

35 Ethyl 7-fluoro-3-(1 -methyl- litI ,2,4-triazoi-5-vl)-4-oxo-2-phenyl-1.2.3.4-tetrahvdroquinoline-5

carboxylate

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1006841 To a solution of (E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3B)-one (1.25 g, 4.9

inniol), anhydrous Na2SO3 (1.24 g, 9.82 mmol), anhydrous Na 2SO4 (2 g 14.7 mmol) and 1-methyl

1-Ji2,4-riazole-5-carbaldehvde (900 mg, 8. 1 mmol) in ethyl propionate (50 mL) was added

EtONa [(sodium 316 mg, 13.8 mmol) in 25 ml ethanol] at 40 "C. then the mixture was stirred at 40

5 C for 3 hr. The resulting mixture was evaporated under reduced pressure, extracted with ethyl

acetate (100 mL x 4) and concentrated to dryness The crude product was purified by column

chromatography (silica gel. dichloromethane: methanol = 200:1 to 50:1) to obtain the title

compound as a green solid (190 mg, yield 10%), LC-MS (ESI) mz: 395 (M+1I)

Example 149B

10 5-Fluoro-9-(I -methyl- 11-1 2,4-triazol-5-yl)-8-phenyl-8;9-dihy dro-2H-pyrido[4 .3,2-de]phthalazin

3(7H1)-one

100685) To a solution of ethyl 7-fluoro-3~(.41 methyl-l 1-1,2,4-triazo-5-yl)-4-oxo-2-phenyl-l 2,3,4

tetrahydroquinolinc-5-caI-boxylate (186 mg, 0.47 mmol) in methanol (1 ml) was added hydrazine

monohydrate (0.5 mL), and the mixture was stirred at 25 *C for 15 hr. Then the mixture was filtered

[5; to obtain a white solid (40 mg, yield 24%). LC-MS (ESI) mIz: 363 (M+1. l-NMR (400 MHz.

DMSO-dl6) 8 (ppm): 3.63 (s, 31) 4.94-5.03 (mn, 21-1)j 691-6.94 (dd., J= 11.6 Hz, J=24 Hz. 1 H)

7.05-7.08 (ddJ, j= 9.6 HzJ, = 2.4 Hz, 1H), 7-29-7.35 (m, 3H), 7.42-7,48 (m, 211), 7 .74 (s, 1H)T. 779

(s, 1-1), 12.34 (s, I H)

20 Example 150

9-(4-Fluorophenyl)-9-hydroxy-8-(I -methyl- I Ii-imidazol-2-yl)-8.9-dihydro-2H-pyrido[4,3,2dephthalazin-3(7/1)-one

Example 150A

Ethyl 3-(4-fluorophenyl)-3-hvdroxy-2-( 1-methyl-1 H-imidazol-2-yl)-4-oxo-1,2.3,4


J006861 T a mixture of (E)-4-((1-methyl-1HimidazoI-2-yI)methyieneamino)isobenzofiran-1(3H

one (590 mg, 2.4 mmol) and 4-fluorobenzaldehyde (300 mg 2.4 mmol) in ethyl propionate (20 mL)

was added a solution of sodium ethoxide in ethanol [sodium (220 mig, 9.6 rrnol) in ethanol (10

mL)1. Afler the addition, the mixture was stirred at room temperature overnight. The mixture was


water, and then extracted with ethyl acetate (100 mL x 4). The combined organic layers were

washed with brine, dried over anihydrous sodium sulfate, and concentrated to give a crude product,

which was purified by flash chromatography to give the title compound (100 mg, yield 10%). LC

MS (ESI) m/z: 4 10 (M-- 1) .

35 Example 150B

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9-(4-Fluoropheny)-9-hydroxy-8-( I-methyl- I H-imidazoi-2-yl)-8,9-dilhydro2H-pTido[4,3,2deiphthalazin-3(7Mh-one

100687) A mixture of ethyl 3(4-fluoropheny l)-3-hydroxy-2-(1-imethyl-IH-im idazo-2-yl)-4-o)xo

1,2,3.4-tetrahvdroquinoline-5-carboxylate (60 mg) in 85% hydrazine monohydrate (0.2 mL) and

5 methanol (2 mL) was stirred at room temperature for 1 hr; Then the solvent was removed under

reduced pressure. The residue was purified by prep-iTLC (methanol: dichloromethane = 1: 20) to

give the title compound (50 mg, yield 80%). LC-MS (ESI) iz: 378 (M1 ); 'H-NMR (400 MHz,

DMSO-d6); 3.44 (s, 3H) 5.24 (s, IfH), 6.84 (s, IH), 6.98-7.06 (m, 4H, 7.11-13 (d, J= 8.0 Hz,

1iH), 738-7.42 (m, 314), 7.46 (s, 1H1), 7,56-7.60 (t, J=8.0 Hz., 1i)

10 Example 151

-(4-Fluorophenvl)-8-methyl~9(-methylih


Example 151A

(E)-4-(I-(4-Fluorophenyl)ethylideneamino)isobenzofuran-I(3R)-one

5 [006881 To a solution of 4-aminoisobenzofuran-l (311)-one (I g, 6.7 mmol) and l-(4

fluorophenyl)ethanone (1 4 g, 10,1 nmol) in toluene (35 mL) was added anhydrous magnesium

sulfate (8.8 g3 73.7 mmol) and acetic acid (0.2 mL) at room temperature under N2. The reaction

mixture was then stirred at 120 "C for 36 hr. The reaction mixture was cooled to 90 C and filtered.

After filter cake was washed with acetonitrile, the filtrates were combined and evaporated to dryness

20 to obtain yellow solid, which was washed by petroleum ether to obtain the title compound as a white

solid (1.58 g, yield 88%). LC-MS (ES!) m/zi: 270(M+1) I-NMR (400 MHz., CDC13) 6 (ppm): 2,30

(s, 3H). 5.16 (s, 2H1). 7.00-7.02 (d, J= 7,6 Hz, 1i), 7.13-7.18 (in, 2H), 7.51-7,56 (tJ= 7.6 Hz, IHi),

7,66-7,69 (d, J= 7.6 Hz. III), 7.99-8.03 (in, 211).

Example 151 B

25 Ethyl 2-(4-fluorophenyl)-2-methyl-3-(m -ethyl-1H-imidazol-2-yl )-4-oxo-1,2,3.4


1006891 To a solution of I-methyl-I H-imidazole-2-carbaldehyde (580 mg, 5.2 mmol), and (E)-4-(1

(4-fluorophenyl)ethylideneamino)isobenzofnran-1(3H)-one (I g, 3.7 mmol) in ethyl propionate (20

ml) was added rapidly EtONa [sodium (340 mg, 14.8 mmol) in 8 mL ethanol] at 0 C. then the

30 mixture was stirred at 30 "C for 3 hr. The resulting mixture was added ethyl acetate (150 mL) and

washed with water (25 mL x 3), the organic layers were combined and evaporated to dryness to give

the crude product, which was purified by column chromatography (silica gel, dichloromethane:

methanol =200:1 to 50:1) to afford the title compound as a red solid (120 mg, yield 8%). LC-MS (PSI) m/z: 408 (M+1)*

35 Example 151C

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8-(4-Fluorophenyl)-8-methyl-9-(1-methyl- i1.H-im idazol-2-yi)-8,9-dihydro-2H-pyrido[4,3 ,2

deiphfhalazin-3(7H+-one

[006901 To a solution of ethyl 2-(4-fluorophenyl)-2-methy-3~(-methyli H-imidazol-2-y)-4-oxo

1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg.0.30 mmoil) in methanol (4 mL) was added

5 hydrazine monohydrate (0.7 mL) at room temperature, the mixture was stirred under 30 "C for 10 hr.

The solvent was evaporated to obtain crude solid, which was washed by 14 mL. of mixture of ethyl

acetate and methanol (13:1) to obtain the title compound as a green solid (40 mg, yield 36%), LC

MS (EST) m/z: 376 (M+1) . I-NMR (400 MHz, DMSO-d4) 4 (ppm): 1.39 (s, 314), 3.71 (s, 314)

4.74 (s, I H), 6,72 (s. 1 H), 7.03 (s, I H), 7.06-7,11 (in, 211), 7,16-7.19 (d, J= 8 Hz, lH), 7.25-7.28 (d,

10 J8 Hz., 111), 7149 (s. 1H1), 7.54-7.58 (in, 3H), 12.05 (s 1i).

Example 152

Racemate of (8R,9R)-8-(4-((dimethylamino)iethyl)phenyli)-5-fl uoro-9-(1 -methyl- 1H- 1,2,4-triazol

5-yi)-8.9-dihydro-2H-pyrido[4,3 .2-de]phthalazin-3(7H)-one and (8S,9S)-8-(4

((dimethylamino)nethvl)phenry)-5-fluoro-9-(1-methyl- i TI-i 2,4-triazol-5-yl)-8.9-dihydro-2kb

15 pyrido[4,3,2-dejphthalazin -3(7H)-one; and. racenate of (8S,9R)-8-(4

((dimethy lamninoi)methyl)pben yl-5-fluoro-9-(I1-methyl- l~1,2A-triazol5-yl)-8,9-dihydroP2H

pyrido[4,3,2-de]phthalazin-3(71)-one and (8R,9S)-844-((dimethylamino)methyi)phenyi)~5-fluoro

941n -ethy bl-i-l,2,4-triazol-5-yl)-8,9-dihydro-2HF-pyrido[4.3,2-de]phthalazin-3(71)-one

Example 152A

20 Ethyl 2-(4-((dimethylamino)mnethyl)phenyl)-7-fluoro-3 -(1 -methyl-I 1,2.4-triazo-5-yi)-4-oxo

1.2,3 4-tetrahydroquinoline -5-carboxylate

[006911 To a solution of (E)-4-(4-((dimethylamino)nethyi)benzylideneamino)-6

fluoroisobenzofran-1(311)-one (4.2 g, 13,5 mmol) and compound 1 -methyl- I H-1,2,4-triazole-5

carbaldehyde (3.0 g, 27 mmol) in ethyl propionate (150 mL) was added rapidly NaOEt [sodium (870 25 mg, 37.8 inmol) in 70 mL ethanol) at 40 "C. then the mixture was stirred at 48 C for 3 hr. The

resulting mixture was concentrated under reduced pressure and extracted with ethyl acetate (250 mL

x 3). The extract was evaporated to give a crude product, which was purified by column

chromatography (silica gel, dichloromethane: methanol = 50:1 to 10:1) to obtain the title compound

(560 mg, yield 9%) (a mixture of cis and trans isomers). LC-MS (ESI) mlz: 452(M+1)

30 Example 152B

Racemate of (8R,9R)-8-(4-(dimethylamino)methylphenyl)-5 -fluoro-9-(I-methy1l-,2.4-triazol

5-yl)-8,9~dihydro-2H-pyrido[4,3,2-dejphthalazin-3(7H)-one and (8S,9S)-8-(4((dimethylamino)methyl )phenyl)-5-fluoro-9-(I -methyl- lU-i,2,4-triazol-5-yl)-8,9-dihydro-2H

pyrido[4,3,2-d elphthalazin-3(7H)-one; and racemate of (8S,9R)-8-(4

35 ((dimethylamino)methy1)phenyl )-5 -fluoro-9-mehy U-1 ,2,4-triazol-5-yl)-8,9-dihydro-2H

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pyrido[4,3 ,2-de]phthalazin-3(71)-one and (8R,9S-(4-((dimethylamino)methyl)phenyb)-5-fluoro

9-(1 -methyl-i H-1,2,4-triazol-5 -yl)-8.9-dihydro-21I-pyrido[4,3,2-delphthalazin-3(7H)-one

100692J To a solution of ethyl 2-(4-((dimethyiaininolmethyl)phenyl )-7-floro-3-(I-methyl- 11H

1,.2,4-triazol-5-vi)-4-oxo-1,2,3,4-tetrahydroquinol ine-5 -carboxylate (560 mg, 1.24 mmol, a mixture

5 of cis and Irans isomers) in methanol (2 mL) was added hydrazine monohydrate (0.5 mL) and the

mixture was stirred under 25 T for 10 hr. The mixture was concentrated in vacuum and the residue

was purified by prep-ILC then prep-HPLC to obtain the two pairs of diastereomers as white solids

(racemate of (8R,9R)-8-(4-((dimethylamino)methyf)pheny l)-5-fluoro-9-(1-methyl-1H1-1.2,4-triazol

5-yI)-8,9-dihydro-2H-pyrido[4 3,2-dejphthalazin-3(7.H)-one and (8S&9S)-8-(4

10 ((diethylamino)methylI)phenyl)-5-fluoro-9-(1 -methyl- 1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H

pyrido[4,3,2-dephthalazin-3(7H)-one: 20 mg, yield 4%). LC-MS (ESI) mz: 420 (M+l) : 'H-NMR

(400 MHz, DMSO-d) 6 (ppm): 2.16 (s. 6H), 2.88 (s. 311), 3.34 (s, 2H) 4.73-4.74 (d,, J=4.0 Hz,

11-), 5.02-5.03 (d. =v" 4.0 Hz, 111), 6.92-6.95 (dd, J 10 8 Hz, J= 2.4 Hz, 11), 7,07-709 (dd. J

10.8 HzJ 2,4 Hz, IH), 7.04-7.06 (d,. = 7.6 Hz, 2H), 7.23-7.25 (dJ --7.6 Hz 2H), 756 (s, 114),

15 7.69 (s, 1H1)t 12.45 (s, I HI). Racemate of (8S,9R)-8-(4-((dimethylamino)methyl)phenyl)-5-fluoro-9

(1-methyl- 11-1,2 4-triazol-5-yl)-8,9-dihydro-2H-pyrido [4,3 ,2-dephthalazin-3 (7 H)-one and

(8R,9S)-8 -(4-((dimethylamino)methyl)phenyi)-5 -fluoro-9-( i-methyl- 11-I .2,4-triazol-5 -yi)-8,9

dihvdro-21-Jpyrido[4,3,2dephthalazin-3(7H)-onei 140 mg, yield 27%). LC-MS (ESI) m/z: 420

(M.+1)'; 1H-NMR (400 MHz, DMSO- 6) 6 (ppm): 2.10 (s. 6H), 3.36 (s, 211). 3.59 (s, 3H), 4.91-4,99

20 (m, 214). 6.91-6.95 (dd. J=2.4,2=1 L.2 Hz, 1H) 7.05-7.08 (dd, Jt=2,4, 12=9.2 Hz, I Fl), 7.20-7.23

(d,J=8.0 liz, 21), 7.35-7.37 (d f=8.0 liz, 2H), 7.72 (s, 114), 7.79 (s, 1H), 1233 (s, 1-1)

Example 153

Racemate of (8S,9S)-8-(4-fluorophenyl)-9-( 1-methyl-I H-i midazol-2-yl)-8,9-dihvdro-2H

pyrido[4,3;.2-de]phtha lazin-3 (7H)-one and (8R,9R)-8-(4--fluorophenyl)-9-(I -methyl- im-imidazol-2

25 yl)-8,9-dihydro-2H-pyrido[4,3 ,2-dejphthalazih-3 (711)-one

1006931 A racemate of (8R,.9S)-8-(4-fluorophenyl)-9-( 1-methyl-1 H-imidazol-2-yl)-8,9-dihydro-21

pyrido(4,3 ,2-de.phthalazin-3(71)-one and (8SR)-8-(4-fluorophenyl)-9-(l-methyM H-inidazol-2

yl)-8,9-dihydro-2H-pyrido[43.2-de]phthalazin-3(7H-one (600 mg, 1.67 minol) was added to 30%

NaOH (32 mL) at room temperature, the mixture was stirred at 85 "C for 3 hr. Then the solution wIs

30 cooled to 5 "C and filtered to obtain 555 mg of white solid, which was purified by prep-HPLO to

obtain the title compound as white solid (40 mg. yield 7%). LC-MS (ES) m/z: 362 (M+1) '1

NMR (400 Mlz, DMSO-I) 6 (ppm): 2.74 (s. 3H), 4.47 (d., J= 4 -z, i 1-), 4.90 (d, 1= 4 Hz, 11),

6.65 (s, 114), 6.81 (s, 11H), 7.07-7.17 (in, 61-1), 7.40-7.42 (d, J= 8 Hz, 11), 7.55-7.59 (t,,f= 8 Hz. 1H) 12 23 (s, 11)

35 Examples on Chiral Resolution

Example 154

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Enantiomers of (8R,9S)-8-(4-fliuorophenyl)-9-(1-methyl-i -imidazol-2-yl)-8,9-dihydro-2H

pyrido[4;3,2-delphthalazin-3(7H)-one and (8SQ9R)-8-(4-fluorophenyl)-9-( 1-methyl- I H-imidazoi-2

yl)-8-9-dilydro-2H-pyrido[4,3,2-dephthalazin-3(7H)-one

[006941 8-(4-Fluorophenvi)-9-( 1-methyl-lH-imidazoi-2~-l)-8,9-dihydro-2H-pyrido[4,3,2

5 de]phthalazin-3(71)-one was dissolved in DMF and chiral resolution was performed using super

fluid chromatography (SFC) with IA chiral column and methanol (30%) and CO2 (70%) as the

eluents.

Example 155

Enantiomers of (8R 9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-I -i12.4-triazol-5-yl)-8,9-dihydro

10 2Flpyrido[4.3,2-de]phthalazin-3(7H)-one and (8.S9R)-5-fluoro-8-(4-flnorophenvl)-9-(i -methyl- I If

1 .2.4-triazol-5-yl)-8.9-dihvdro-21-pvri do[4,3,2-de]phlthalazin-3(7H)-one

1006951 5-Fluoro-8-(4-fluorophenyl)-9-(i-methyl-1H-I,2,4-triazol-5-yl)-8,9-dihvdrc-2H

pyrido [4,32-de]phthalazin-3(7H,)-one was dissolved in DMF and chiral resolution was performed

using super-fluid chromatography (SFC) with IA chiral column and methanol (20%) and CO2 (80%) 15 as the eluents.

Example 156

(8R,9S)-5-Fhioro-8-(4-fluorophenyb)-9-(i-methyl-i 1-imidazol-2-yl)-8,9-dihydro-2/i-pyrido[4,3,2

de]phthalazin-3 (7f)-one and (8S,9R)-5-fluoro-8-(4-fluorophenvl)-9-( i-methyl-i himidazol-2-yl)

8,9-d ihydro-2H-pyrido[14,3 ,2-dejphthalazin-3(717)-one

20 f006961 5-Fioro-8-(4-fluorophenyl)-9-(1 -methyl-1H-iinidazol-2-yl)-8,9-d ihydro-2Ht-pyrido[4,3 ,2

de]phthalazin-3(7H)-one was dissolved in DMF and chiral resolution was performed using super

fluid chromatography (SFC) with IA chiral column and methanol (30%) and C02 (70%) as the

eluents.

Example 157

25 (8R,9S)-8-(4-Fhiorophenyl)-9-(1-methyl-I H-1,2.,4-triazol-5-yl )-8,9-dihydro-21-f-pyrido[4,3,2

cephthalazin-3 (711)-one and (8S,9R)-8-(4-fluorophenyl)-9-(1-methyl-IH-1,2,4-triazol-5-yl)-8,9

dihydro-2H-pyrido[4,32-dtephthaazin-3(71H)-one

[006971 8-(4-Fluorophenyl)-9-(1 -methyl- 1I l,2,4-triazol-5 -yl)-8 9-dihydro-2H-pyrido [4,3,2

dce]phthalazin-3(71H)-one was dissolved in DMF and chiral resolution was performed using super30 fluid chromatography (SFC) with IA chiral column and methanol (30%) and C02 (70%) as the

cluents,

Example 158

(8R,9S)-8-(4-(Azetidin-I -yl methyl)phenyl)-9-t4-fluorophenyl)-8,9-d ihydro-211-pyrido[4,3 2

de]phthalazin-3(7/1)-one and (8S.9R)-84-(azetidin-I-ylnethyl)phenyl)-9-(4-fluorophenyl)-8,9

35 dihydro-2t1-pyrido[4.3 ,2-dephthalazin-3(7H)-one

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1006981 8-(4-(Azetidin-I-vlmethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2 H-pyrido[4,3,2

dejphthalazin-3(7H)-one was dissolved in methanol and chiral resolution was performed using

super-fluid chromatography (SFC) with OJ-H chiral column and methanol (40%) and CO2 (60%) as

the eluents,

Example 159

(8R,9S)-8-(4-((Dimethylamino)methvl)phenyl)-5-fluoro-9-(I-Umethyl-1IH-i.24-triazol-5-yl)-8,9

dihydro-211-pyrido[4,3,2-de]phthalazin-3(711)-one and (8S,9R)-S(4

((dimethylamino)methvl)phenyl)-5-fluoro-9-(1-metiyl-1 -1-1,2,4-triazol-5 -y)-8,9-dihvdro-2H

pyrido[4,32-dejphthalazin-3(7-one

10 1006991 8-(4-((Dimethylanino)methyl)phenvl)-5-fluoro-9-(I -methyl-IH-1.2,4-triazol-5-yi )-8 9

dihydro-21H-pyrido4.,3,2-de]phthalazin-3(7H)-one was dissolved in methanol and chiral resolution

was performed using super-fluid chromatography (SFC) with AS-4 chiral column and methanol

(20%) and CO, (80%) as the eluents,

Biological Studies

15 [007001 Inhibitory effects of test compounds against human PARP I enzyme was assessed using

Trevigen's Universal Chemiluminescent PARP Assay Kit (Trevigen CAT44676-096-K) following

the manufacturer's recommended protocol.

1007011 Inmediately prior to performing the assay, the following reagents were prepared: A) 20x

PARP Assay Buffer was diluted to I x with dH2O; B) lOx PARP Cocktail, which contains a mixture

20 of NAD and biotinylated NAD wvas diluted by the addition of 1Ox Activated DNA and Ix PARP

Assay Buffer. Both the PARP Cocktail and Activated DNA are 1x after the dilution: C) al test

compounds were initially dissolved in DMSO. and subsequently serial diluted with I x PARP Assay

Buffer; D) recombinant human PARP I enzyme was diluted with I x PARP Assay Buffer to

generate 0.5 unit/i 5 p1; E) lOx Strep-Diluent was diluted to Ix with Ix PBS/0,I% Triton X-100; F)

25 Just before use, dilute Strep-HRP 500-fold with 1x Strep-Diluent.

[007021 The chemiluminescent assays for PARP activity were performed in white 96-well plates that

are pre-coated with histones. Briefly, strip wells were removed from the wrapper, 50 p1/well of I X

PARP Buffer was added to rehydrate the histones and incubation was allowed for 30 minutes at

room temperature. Removal of the IX PARP Buffer from the wells was accomplished by tapping

30 the strip wells on paper towel. Serial dilutions of the test compounds were added to duplicate wells

in 10 p1/well volume, Final assay concentrations of test compounds were typically bet ween I and

00001 tM. Subsequently, recombinant human PARP 1 enzyme was added to 0.5 unit of PARP I

enzyme/well in 15 lit/well volume. Combined volume of enzyme and inhibitor was 25 pI. incubate

the enzyme/inhibitor mixtures for 10 minutes at room temperature. To start the reaction, 25 pl/well

35 of the IX PARP Cocktail was added to all the wells. Controls included background wells with I x

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Assay Buffer alone (no PARP) and wells with no inhibitor for determining the maximum or 100%

PARP activity value. In all cases the final reaction volume was 50 d.

1007031 The reactions were allowed to proceed for I hour at room temperature. The plate was then

washed 4 times with 200 pI/well IX PBS/0.1% Triton X-1 00, using ELx50 Automated Strip Washer

5 (BIO-TEK). After washing, all wells were incubated for 60 minutes with 50 id/well Strep-HRP.

diluted 1:500 with Ix Strep-Diluent. The plate was washed 4 times with 200 pl/well IX PBS/0.1%

Triton X-100 using ELx50 Automated Strip Washer (BIO-TEK). After washing, dry the wells by

tapping plate onto paper towels. Mix equal volumes of PeroxyGlowTM A and B together and add 100

pi per well. The light output was immediately determined in a plate reader (EnVision, by Perkin

10 Elmer) set up for measuring chemilurinescence.

1007041 The % enzyme activity for each compound is then calculated using the following equation:

Activity Ctri X Acuntivi Iy Ctrl - Negative Ct01

[007051 [C5 values (the concentration at which 50% of the enzyme activity is inhibited) of each test

compound were calculated using GraphPad PrismS software.

15 100706 All of the compounds tested had or were expected to have enzymatic PNRP inhibitory

activity. Of the compounds tested, over 100 compounds had a PARP inhibitory activity in the

enzymatic assay of less than 50 nM, with approximately 60 of these compounds having an inhibitory

activity of less than 5 nM.

1007071 Chemosensitization assay determines the extent by which a PARP inhibitor enhances the

20 tunor cell-killing effect of cytotoxic drugs expressed as PF (potentiation factor at G )] 8000

LoVo cells were seeded into each well of a flat-bottomed 96-well microtiter plate in a volume of 50

pi and incubated in F12K containing 10% (v/v) FBS (medium) overnight at 37 'C, Cells were added

with 50 pl medium alone, medium containing 2 pM PARP inhibitor, medium containing increasing

concentration of Temozolomide (0-2000 pM), and medium containing 2 vM PARP inhibitor and

25 increasing concentration of Temozolomide (0-2000 MM), Final concentration range for

lemozolomide was 0-1000 M where applicable, final concentration of PARP inhibitor was 1pM

where applicable. Final concentration of DMSO was 1% in each well. Cells were allowed to grow

for 5 days before cell survival was determined by CelTiter Glo staining (Promega, Madison, WI, USA). Cell growth, determined after subtraction of time 0 values, was expressed as a percentage of

30 the control well that contained medium with 1% DMSO. G15o (concentration of drug that inhibited

growth by 50%) values were calculated from the computer generated curves (GraphPad Software, Inc. San Diego CA). The potentiation factor [PFSO (potentiation factor at Gbo)i was calculated as

G4L of Temozolomide alone / G150 of Temozolomide - PARP inhibitor. Reference: Thomas H.D

et al, (2007). Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical

35 trial. Molecular Cancer Therapy 6, 945-956.

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1007081 Most of the compounds tested had a PF50 of more than 2X.

Xenograft Studies

Antitumor in vivo animal efficacy study

1007091 Female athymic nu/nu mice (8-10 weeks old) were used for all in vivo xenograft studies.

5 Mice were quarantined for at least I week before experimental manipulation. Exponentially

growing cells or in vivo passaged tumor fragments were implanted subcutaneously at the right flank

of nude mice. Tumor-bearing mice were randomized according to tumor size into 6-8 mice/group in

each study (average tumor size .- 150 mm), Mice were observed daily for survival and tumors were

measured twice weekly by caliper in two dimensions and converted to tumor mass using the formula

10 for a prolate ellipsoid (V = 0.5 a x b2), where a and b are the long and short diameters of the tumor,

respectively, and assuming unit density (1 mm = mg).

[007101 Single agent activity: PARP inhibitors were evaluated in Capan- I and MX- xenografts for

single agent activities. Compounds were dosed orally (p.o.), once daily for 28 days in vehicle 10%

DMAc/6% Solutal/84% PBS, and the same vehicle was used as control. Mice were continuously

15 monitored for 10 more days after the last day of dosing.

1007111 Combination study: PARP inhibitory compounds described herein in vehicle 10%

DMAc/6% Solutal/84% P.BS, were either administered orally, once daily for 5 days with

Temozolonide (17mg/kg or 34 mg/kg, po,, qdx5. 30 min after each dose of compounds) in SW620

xenograft model or dosed orally, once daily for 8 days with 6 mg/kg Cisplatin (once by ip on day 3,

20 30 min after first dose of PARP inhibitors) in MX-I xenograft model. Mice were observed and

individual tumor was measured for 30 more days after the last dosing of PARP inhibitory

compounds.

1007121 In vivo animal study on a few potent PARP inhibitory compounds described in the

Examples section have demonstrated single agent activities in reducing both MX- I and Capan-I

25 tumor growth by themselves when administered orally for 28 days. A few compounds when

combined with DNA damaging agent Temozolomide significantly slowed tumor progression in

SW620 model. In the MX- 1 breast xenograft model, these compounds potentiated the platinum

drug Cisplatin causing regression of established tumors, whereas with comparable doses of cisplatin

or PARP inhibitor alone, only small to modest tumor inhibition was exhibited.

30 BRCA2-deficient V-C8 or BRCA2-complimented V-CS + B2 cells

1007131 BRCA2-deficient V-C8 or BRCA2-complimented V-C8 - B2 cells are implanted

intramuscularly into the thigh of 40 CD-1 nude mice. Treatments are initiated when tumors are of

measurable size (approximate leg diameter of I I mm). Animals receive either a compound of

Fornala (1), (IA) or (11) (two doses of 25 or 50 mg/kg in saline) or saline (10 mg/nl)

35 intraperitoneallly administered on days 1-5, and are monitored on a daily basis during treatment

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(tumor measurements, body weights and clinical evidence are recorded); and as required after the

last treatment.

ES-cell-derived tumors

1007141 ES-cell-derived tumors (teratomas) are produced by subcutaneous injection of 2 x 10 ES

5 cells into 6-8 week athymic BALB/c-nude (nu/nu) mice. 40 mice are injected with BRCA2-deficient

ES cells or isogenic wild-type cells. Two days after cell injection, treatment with a compound of

Formula (I), (IA) or (II) is initiated. For three consecutive days, two intraperitoneal doses of a

compoInd of Formula (I), (A) or (I1) or vehicle is administered, 6 h apart, each at a dosage of 15

mg/kg per animal. This treatment is stopped for 5 days and then re-initiated for another three

10 consecutive days. Growth of tumors is monitored from a minimum volume of 0.2 cmr

(007151 The in vitro assays disclosed herein, along with other known in vitro assays (Farmer el al,

Nature 2005: 434:913-7: clonogenic survival assay finding that a BRCA2-deficient cell line V-C8 compared with the BRCA2 wild type control exhibited sensitivity to AG1l4361, a PARP-1 inhibitor,

(Ki = 5nm) and NU 1025. a moderately potent PARP-1 inhibitor (Ki = 50nM); & Mcabe et al,

15 Cancer Biology & Therapy 2005; 4:9, 934-36; clonogenic survival assay using CAPAN-1 cells

maintained in DMEM supplemented with FCS (20% v/v), glutamine and antibiotics showing

sensitivity to PARP inhibition using KU0058684) demonstrates the activity of PARP-inhibitors in a

static test situation. Additionally, animal models have been used to analyze the relationship between

in vitro tests and parameters of in vivo efficacy; By way of example only. Farmer et at, has shown

20 in vivo efficacy in blocking the growth of BRCA2-deficient tumors using KU0058684, a PARP- I

inhibitor. Nature 2005; 434:913-7, This indicates that PARP-1 inhibition is a viable cancer treatment

for BRCA 1/2 mutation carriers. Furthermore, KU0059436, a PARP-1 inhibitor is currently in Phase

I clinical trials for patients with advanced solid tumors. Given this information, compounds of

Formula (1), (IA) or (11) which have shown in vitro inhibitory action are likely to show analogous in

25 vivo (mouse and human) efficacy.

Phase If Clinical Trial of the Safety and Efficacy of Compounds of Formula (1), (IA) or (II)

1007161 The purpose of this phase I trial is to study the side effects and best dose of a compound of

Formula (I), (IA) or (H) and to determine how well it works in treating patients with locally

advanced or metastatic breast cancer or advanced ovarian cancer.

30 Qbjectives Primary:

A. To determine the response rate to a compound of Formula (I). (IA) or (II) in patients with locally advanced or metastatic breast or advanced ovarian cancer shown to express the BRCA I or 2 mutations

35 B. To evaluate the toxicity of a compound of Formula (1), (IA) or (11) in these patients

Secondary A. To evaluate the time to progression and overall survival in patients treated with a compound of Formula (1), (IA) or (11)

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B. To study pharracokinetics of a compound of Formula (I), (IA) or (II) in these patients

C. To evaluate the Poly(ADP-ribose) polymerase (PARP) activity in peripheral blood lymphocytes from BRCA I and 2 beterozygotic patients

5 Tertiary: A. To evaluate PARP expression using quantitative western blotting imnumuno-assays B. To investigate pharmacogenomics, including CYP2D6 and CYP3A5, drug transport proteins, as well as polymorphisms in the genes coding for

10 the PARP enzymes themselves C. To analyze tumor biopsy samples (when possible) for BRCA mutation status, PARP activity, and PARP expression D. To analyze paraffin sections from original diagnostic biopsies/operative procedures (when available) for DNA repair enzyme status using

15 immunohistochemical techniques E. To analyze cells obtained from ascitic or pleural fluid (where available) for primary cell culture for DNA double strand break repair pathway function

Patients: Eligible subjects will be men and women 18 years and older 20 Criteria:

* Disease Characteristics: o Histologically confirmed locally advanced or metastatic breast cancer or

advanced ovarian cancer o Must meet I of the following criteria:

25 * Proven a carrier of a known mutation of BRCA I or BRCA 2 * Considered highly likely a carrier of BRCA I or 2 mutation (score of.

20 per Manchester criteria) o No more than 3 prior chemotherapy regimens for patients with breast or ovarian

cancer 30 More than 2 months since prior carboplatin- or cisplatin-containing

chemotherapy for ovarian cancer o Measurable disease, as defined by RECIST criteria and measured by x-ray, CT

scan, or MR N Patients with bone disease must have other measurable disease for

35 evaluation " Previously irradiated lesions cannot be used for measurable disease

o No known brain metastases o Hormone receptor status not specified

* Patient Characteristics: 40 o WHO performance status 0-1

o Life expectancy >. 12 weeks o Menopausal status not specified o Hemoglobin > 9 0 g'dL o Absohite neutrophils > 1;500/mm'

45 a Platelets > 100,000/mm o Serum bilirubin < 1.5 times tipper limit of normal (ULN) o ALT or AST s 2.5 times ULN (s 5 times ULN if due to tumor) 0 Glomerular filtration rate (GFR)> 50 mL/min o Not pregnant or nursing

50 o Negative pregnancy test o Fertile patients must use two highly effective forns of contraception (i.e., oral,

injected, or implanted hormonal contraception, intrauterine device, barrier method of condom plus spermicide, or are surgically sterile) 4 weeks prior to

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(females), during, and for 6 months after (males and females) completion of study therapy

o Able to cooperate with treatment and follow-up o No non-malignant systemic disease, including active uncontrolled infection

5 o No other concurrent malignancy, except adequately treated cone-biopsied carcinoma in situ of the uterine cervix, basal cell or squamous cell carcinoma of the skin, or breast and ovarian carcinoma

Cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years, and are

10 deemed at low risk for recurrence are eligible o No active or unstable cardiac disease or history of myocardial infarction within

the past 6 months s Patients with cardiovascular signs or symptoms should have a MUGA

scan or echocardiogram, and those with a left ventricular ejection 15 fraction (LVEF) below the institutional limit of normal should be

excluded o No other condition which, in the investigator's opinion, would. not make the

patient a good candidate for this study Prior Concurrent Therapv:

20 0 At least 4 weeks since prior radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy (6 weeks for nitrosoureas and mitomycin C)

0 At least 4 weeks since prior major thoracic and/or abdominal surgery and recovered * Concurrent radiotherapy for the control of bone pain or skin lesions allowed, but not

within 5 days of the last dose of study drug 25 * Concurrent bisphosphonates allowed provided the dose is stable and treatment was

started at least 2 weeks prior to recruitment * No unresolved toxicities (CTCAE > grade 1) from prior treatments (except for alopecia) * No concurrent anticancer therapy or investigational drugs * No concurrent tetracycline antibiotic therapy for prolonged periods (short courses [5-7

30 days] for treatment of infection are allowed)

[00717] Study Desin: This is a dose-escalation study followed by an open label multicenter study.

Patients will be stratified according to tumor type (breast vs ovarian) and mutation status ( BRCA I

vs BRCA 2). Patients will receive a compound of Formula (I) (IA) or (II) (at one of several possible

dosages) over 30 minutes once daily on days 1-5. Treatment repeats every 21 days for 12 courses in

35 the absence of disease progression or unacceptable toxicity. Patients who achieve stable or

responding disease may receive additional courses of treatment at the discretion of the chief

investigator or Drug Development Office (DDO). Patients will undergo blood sample collection

periodically for pharmacokinetic and pharmacodynamic studies. Samples will be analyzed for tumor

marker (CA 125 or CA 153) measurements, plasma levels of a compound of Formula (1), (IA) or

40 (H1) via liquid chromatography/mass spectrometry/mass spectrometry, PARP activity, and PARP

protein expression via western blotting imIunoassays. Paraffin embedded sections from original

diagnostic biopsy are also collected and analyzed for PARP protein expression via

iniunohistochemical technique. Pleural and ascitic fluid may be collected and analyzed for DNA

DS break repair proficiency via immunohistochemical technique. Some patients will also undergo

45 biopsy of tumors and samples will be analyzed for BRCA 2 mutation as well as PARP activity via

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validated PARP inmunoblotiting assay. After completion of the study treatment patients will be

followed for 28 days,

1007181 Primaiy Outcome Measures:

" Assessment of antitumor activity according to RECIST using tumor size measured

5 clinically or radiologically with CT scan, MRL plain x-ray, or other imaging techniques

* Safety profile

[00719 Secondary Outcome Measures:

* Time to progression and overall survival

* Plasma levels by Liquid Chromatography/Mass Spectrometry/Mass Spcctrometry

10 * Poly(ADP-ribose) polymerase (PARP) activity measured ex vivo using validated assays

* PARP expression using quantitative Western blotting i nmmuno-assays

* Pharmacogenomics including CYP2D6 and CYP3A5, drug transport proteins, as well as

polymorphisms in the genes coding for the PAR? enzymes themselves

" BRCA mutation status, PARP activity, and PARP expression in tumor biopsy samples

15 (when possible)

" DNA repair enzyme status using immumohistochemical techniques in paraffin sections

from original diagnostic biopsies/operative procedures (where available)

* DNA double strand break repair pathway function in cells obtained from ascitic or

pleural fluid (where available) for primary cell culture

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CLAIMS

WHAT IS CLAIMED IS:

1. A compound of Fornmula (I):

-R4

0 NN

R., A R Y

B

R 2 N Z

R R,

5 Formula (0)

wherein:


a) an aryl group optionally substituted with 1, 2 or 3 R6 ; wherein each RK is selected frmi

OH, NO2, CN, Br; Cl, F, 1, CrC-alkyl, C-Cscycloalkyl, C2-Cheterocycloalkyl; Cr

10 C6alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, CI-Coalkynyl, aryl,

arylalkyl, C3-Cscycloalkylalkyl, haloalkoxy, haloalkyl. hydroxyalkylene oxo heteroaryi,

heteroaryla.Ikoxy, heteroaryloxy, beteruarylthio, heteroarylalkylthio, heterocycloalkoxy, C

Cjheterocycloalkylthio, heterocyclooxy, heterocyclothio, NRARB, (NRARY)C IC alkylene,

(NRARR)carbonyl. (NRkRB)carbonvlalkylene, (NR R, )sulfonv and

15 (NLKRyj)sulfonylalkylene;

b) a heteroaryl group optionally substituted with 1, 2, or 3 R6;

c) a substituent independently selected from the group consisting of hydrogen, alkenyl. alkoxy,

alkoxyalkyl alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl,

cycloalkylakyvl, haloalkyl, hydroxyalkylene. oxo, heterocycloalkyl, heterocycloalkylalkyl.

20 alkylearbonyl, arylcarbonyl. heteroarylcarbonyl alkylsulfonyl, aryisulfonyl,

heteroarylsulfonyl, (NRARB)alkylene, (NRAR 13)carbonyl, (N R Ra)carbonylalkylene,

(NiRAR)sulfonyl. and (NRARB)sulfonylalkylene;

R I R, and R- are each independently selected from the group consisting of hydrogen, halogen,

aikenyl, alkoxy, alkoxycarbonyl. alkyl, cycloalkyl. alkynyi cyano, haloalkoxy haloalkyl. hydroxyl, 25 hydroxyalkylene, nitro, NRARB, NRARaalkylene, and (NRAR)carbonyl;

A and B are each independently selected from hydrogen, Br, Cl, F, 1, 01H, Cr-C6alkyl, C7

Ccycloalkyl alkoxy, alkoxyalkyl wherein C3-C6alkyl, C;-Cgcycloalkyl, alkoxy, alkoxyalkyl are

optionally substituted with at least one substituent selected from 011, NO, CN, Br, Cl, F, I, C

Calkyl, and CrC cycloalkyl, wherein B is not OH:

30 RA. and Rn are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl. and

alkylcarbonyl; or RA and Ra taken together with the atom to which they are attached form a 3-1(

214

WO 2010/017055 PCT/US2009/051879

membered heterocycle ring optionally having one to three heteroatoms or hetero functionalities

selected front the group consisting ofO-, -NH-, -N(C1 C,,-alkyl)r- -NCO(CI-Cb-alkyl)-, -N(aryl)-,

N(aryl-C1 -C6-alkyl-), -N(substituted-aryl-C -Q-alky i-)-, -N(heteroaryl)-, -N(heteroary i-C 1 -C>

alky-), -N(substituted-heteroary-C-alkyl-), and --S- or S(O),, , wherein q is 1 or 2 and the 3

5 10 membered heterocycle ring is optionally substituted with one or more substituents;

R4 and R5 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl.

alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NRAR)alkylene; or

a isomer, stereoisomer, enantiomer, salt, solvate, chemically protected form or prodrug thereof.

2, A compound of Formula (11):

10

0 N A

B N Z

R2H

Formula (II);

wherein:

Y is an aryl or heteroaryl group optionally substituted with at least one R,;

15 Z is an aryl group optionally substituted with at least one R6;

A and B are each independently selected from hydrogen, Br. Cl, F, L OH, C-C(,alkyl, C3

Cseycloalkyl, alkoxy. alkoxyalkyl wherein CrCfalkyl, Cr-Cgycloalkyl, alkoxy, alkoxyalkyl are

optionally substituted with at least one substituent selected from 01H, NOQ CN, Br, Cl, F, 1, CjC6alkyl, and C-Cscycloalkyl, wherein B is not 01H;

20 R is selected from 011, NO, CN. Br, CL F, 1. CI-C 6alkyl, Cr-Qcycloalkyl, C2-Csheterocycloalkyl;

C Calkenyl, alkoxy, alkoxyalkyIt, alkoxycarbonyl, alkoxycarbonylalkyl, C2 Calkynyl, ary, arylalkyl, CrGcycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylhio. heterocycloalkoxy, C

Csheterocycloalkylthio, heterocyclooxy, heterocyclothio, NRj R0, (NRARB)Cj-C 6alkyleIne, 25 (NRAR 8)carbonvt. (NRARa)carbonylalkylene, (NRAR)sulfony, and (NRAR4)sulfonylalkvlene;

R is selected from hydrogen, Br, Cl, L or F;

RA, and R are independently selected from the group consisting of hydrogen, C1-Ealkyl, C,

Cscycloalkyl, and alkylcarbonyl; or RA and RB taken together with the atom to which they are attached form a 3-10 mnembered heterocycle ring optionally having one to three heteroatoms or

30 hetero functionalities selected from the group consisting of 0-, -NFIL -N(C1-Calkyl)-. -NCO(C

Calkyl)-, -NCO(GrQcycloalkyl)-N(aryl)-, -N(aryl-C alkyl-)-, -N(substituted-ary l-Ci-Calkyl

) N(heteroaryl)-, -N(heteroaryl-C-Coalkyl1)-. -N(substituted-heteroaryC 1 C6Calkylj)-, and --S- or

215

WO 2010/017055 PCT/US2009/051879

S(O), , wherein q is I or 2 and the 3-10 membered heterocycle ring is optionally substituted with

one or more substituents; or

a isomer, stereoisomer, enantiomer, salt, solvate, chemically protected form or prodrug thereof

3 The compound of clain I or 2 wherein Y is an aryl group.

5 4. The compound of claim 1. 2 or 3 wherein the aryl group is a phenyl group.

5. The compound of any of claims 1- 4 wherein the phenyl group is substituted with at least one

R6 selected from Br, CL, F, or I,

6. The compound of any of claims 1-5 wherein R is F.

7. The compound of any of claims 1-4 wherein the phenyl group is substituted with at least one R(

10 selected from (NRARn)C -Cjalkylene, (NRAR)carbonyl, (NRAR3)carbonylalkylene,

(NRARB)sulfonyl, and (NRA R)sulfbnylalkvlene.

8. The compound of claim 7 wherein Rf is (NRAR)CJ-Cealkylene.

9. The compound of claim 8 wherein CrC-alkylene is selected from methylene, ethylene, n

propylene, iso-propylene, n-butylene, iso-butylene, and tert-butylene.

15 10, The compound of claim 9 wherein Cj-C 6alkylene is methylene.

11, The compound of any of claims 7-10 wherein RA and R0 are each independently hydrogen, C

Calkyl, or C-Cicyc loalkyl.

12, The compound of any of claims 7 - 11 wherein C-Calkvl is selected from methyl, ethyl, n

propyl, iso-propyl, n-butyl, iso-butyI. and tert-buty.

20 13. The compound of any of claims 7- 12 wherein C1 -C(alkyl is methyl.

14. The compound of any of claims 7 - 12 wherein C1-Calkyl is ethyl.

15. The compound of any of claims 7 - 11 wherein (NRA&) is azetidine, pyrrolidine, piperidine or

morpholine.

16, The compound of claim 7-1 1 wherein C3-Ccycloalkyl is cyclopropyL.

25 17. The compound of any of claims 1-3 wherein R6 is hydroxyalkylene.

18. The compound of claim 17 wherein hydroxyalkylene is selected from CH2OH, CH2CWOH,

CHCWCH2OH CH(OH)CIL, CH(OH)H 2CH CfCH(OH)CH3 , and CICIH CFOHI.

19. The compound of any of claims 7-11 wherein RA and Ra taken together with the nitrogen to

which they are attached form a 6 membered heterocycle ring having 1 heteroatom or hetero

30 functionality selected from the group consisting of--, -NH. or -N(C 1-C 6alkyl).

20. The compound of claim 19 wherein the hetero functionality is -N(C-Cealkyl).

21. The compound of claims 19 or 20 wherein C-C 6alkyl is selected from methyl, ethyl, n-propyl,

iso-propyl, n-butyl, iso-butyl, and tert-butyl,

22. The compound of any of claims 19-21 wherein C1-C6alkyl is methyl.

35 23. The compound of claim I wherein Y is a heteroaryl group optionally substituted with at least

one R .

216

WO 2010/017055 PCT/US2009/051879

24. The compound of claim 23 wherein the heteroaryl group is selected from furan, pyridine,

pyrimidine, pyrazine, imidazoie, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene,

oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, indole, benzothiophene,

benzoimidazole, benzofran, pyridazine 1,3,5-triazine, thienothiophene. quinoxaline, quinoline. and

5 isoquinoline.

25. The compound of claim 24 wherein the heteroaryl group is imidazole.

26. The compound of claim 25 wherein inidazole is substituted with C-C 6alkyl selected from

methyl., ethyi, n-propyl, iso-propyl, n-butyl. iso-butyl. and tert-butyl.

27. The compound of claim 26 wherein C-C.6alkyl is methyl.

10 28. The compound of claim 24 wherein the heteroaryI group is furan.

29. The compound of claim 24 wherein the heteroaryl group is thiazole.

30. The compound of claim 24 wherein the heteroatyl group is 1,3.4-oxadiazole.

31. The compound of any of claims 28~30 wherein heteroaryl group is substituted with C -Cealkvl

selected from methyl, ethyl n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

15 32, The compound of any of claims 28~31 wherein CrC-alkvl is methyl.

33. The compound of any of claims 1-32 wherein Z is an aryl group.

34. The compound of claim, 33 wherein the aryl group is a phenyl group,

35. The compound of any of claims 33-34 wherein the phenyl group is substituted with at least one

RP. selected from Br, Cl, F, or I

20 36. The compound of any of claims 33-35 wherein R , is F.

37. T he compound of any of claims 33-35 wherein R0 is Cl.

38. The compound of any of claims 33-34 wherein the phenyl group is substituted with at least one

R, selected from (NRA RB)C[C(alkylene, (NRAR3)carbonvl, (NRAR)carbonylalkylene,

(NRR 3 )sulfony, and (NRARI)sulfbnylalky lene.

25 39, The compound of claim 38 wherein R, is (NRARB)CI-Calkylene.

40, The compound of claim 39 wherein C-C 6alkylene is selected from methylene, ethylene, n

propylene, iso-propylene, n-butylene., iso-butylene, and tert-butylene.

41. The compound of claim 40 wherein Cl-Cbalkylene is methylene.

42. The compound of any of claims 38-41 wherein RA and Rn are each independently hydrogen,

30 C-Coalkyl. or Q-Ccycloalkvi.

43. The compound of any of claims 38-42 wherein C-Calkyl is selected from methyl, ethyl, n

propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl

44. The compound of any of claims38-43 wherein CICalkyl is methyl.

45, The compound of any of claims 38-41 wherein RA and RB taken together with the nitrogen to

35 which they are attached form a 6 membered heterocycle ring having I heteroatom or hetero

functionality selected from the group consisting of -0-, -NFi, or -N(C'-C alkyl).

217

WO 2010/017055 PCT/US2009/051879

46. 'The compound of claim 45 wherein the hetero functionality is -N(C-Cralkyl).

47. The compound of claims 45 or 46 wherein C-COalkyl is selected from methyl, ethyl, n-propyl,

iso- propyl, n-butyl, iso-butd, and tert-butyl.

48. The compound of any of claims 45-47 wherein QCbalkyl is methyl.

5 49. The compound of any of claims 1-48 wherein R. is hydrogen.

50. The compound of any of claims 1-48 wherein R is selected from F, Cl, Br, and 1.

51 . The compound of clahn 50 wherein R, is F.

52. A compound selected from:

9-diphenyl-8,9-dihvdro-2H-pyrido[4,32-d/e phthalazin-3(7f)-one.,

10 8,9-bis(4-((methyl amino)methvl)phenyl-8.9-d ihydro-2H-pyrido[442-de]phthalazi-3(7H)

one.

8.9-di(pyridin-4-yi)-8,9-dihydro-2H-pyrido[43 ,2-de]phthalazin-3 (711)-one.

8,9-di(pyridin-3-vl)-8,9-d ihydro-2H-pyrido[4, 3,2-dephthalazin-3(71)-one,

8,9-di(pyridin-2-vl)-8,9-dihydro-21-pyridof[4,3,2-de]phthalazin-3(711)-one,

9-isopropyl-8-phenyl -8,9-dihydro-211-pyrido[4,3 ,2-de]phthalazin-(71/)-one

9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihvdro-2H-Ipyrido[4,3,2-delphthalazin

3(711)-one,

9-(4-((dimethvlainino)methyl)phenyi)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-dce]phthalazin

3(711)-one,

20 9-(3 -((methylamino)methyl)phenyl)-8-phenyl-8 ,9-dihydro-2N~pyrido[4,3,2-dejphthalazia

3(711)-one,

8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[43,2-dce]phthalazin

3(7H)-one,

8,9-bi s(3-( (methylaminio)methyl)phenyl)-8,9-dihydro-2-pyrido[4,3 ,2-dejphthalazin-3(7HF

25 one,

9-(4-(hydroxymethvl)phenyl )-8-phenyI-8.9-dihydro-21-pyrido[4,32-de]phthalazin-3(T H)

one,

9-(3-(4-isobutyrylpiperazine- I -carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3, 2

dei phthakrzin-3(711)-one,

30 8,9-bis(3-(4-isobutyrylpiperazine- i-carbonyl)phenyl) -8.9-dihydro-211-pyrido[4,3,2

de]phthalazin-3(71H)-one,

9-(piperidine-3-yl)-8-(pyridin-3-yl)-8,9-dihydro-2H-pyrido[4.3.2-delphthalazin-3(7H)-one,

9-(piperidin-4-yl )-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-delphthalazin-3(7H)-one,

8,9-bis(4-((dimethvlamino)metlvl)phenyl )-8,9-dihvdro-211-pyrido[4,3 ,2-dejphthalazin

35 3(7H)-one.

2I8

WO 2010/017055 PCT/US2009/051879

9-(4-(4-(eyelopropanecarbonyblpiperazine- I -carbonyl)phenyb)-8

(4((mtieuhy Ianino)rthy Ilv)pbienyl)-8,9-dliydro-21-pyrido)[4,3 ,2-dle]phthialazini-3(7llb)one.,

9-(4-(4-(cyelopropniieearboniyl)piperazi-ne-lI-carbon)jylphen~yi)-8

(4((dirnethylarnino)mieflw)l,)phenvl)-8.9-d ihydro-211i-pyrido[4,3 ,2-dejphthaiazin-3(711)-one,

5 8-(4-(hydroxyrnethyl)phenyl,;)-9-(4 -(4-isobutyrylipiperaizine- I -carboniyl )pheiwyl)-&,9-dihiydr-o

211-pyrido[4,3 ,2-d1ejphtlialazin-3(1 H)-one,

8-(4 -((dimethiyla n ii o)methyl )phe nvl)-9-(4 -(4- isohutyrtylp iperazAnc- I-carbonv )pheniy])-8,9

dibkvdro-2l-1-pyrido)[4.3,2-deiphtalazin-3 (711>-one. 9-(4-(4-(cyc lopropaniecarbony I)piperazine- I-carbonvl)phenyl)-8-pbcnyl-8,9-dihlvdro-2J1,1

'10 pvr-idof 4,3 1,2-de-jphita lazin -3 (711)-onie,

9<3 -(4-(cyclopropani3ccarboniyi)piperazine-l1 carbonvyl)phenivl)-8-pheniyl-8,9-dihydro-2 11

pyirido[4,3 ,2-die]phthalazini-3 (711)-onie.

9-(3-((diniethylai niio)mlethivl)phieny I)-8 -pheny I -8,9-d ihyvdro-2-11-pyrido[ 4 .2-tklphthal azIII

3(711-one.

15 8-U -((methyla nino,)netbvl)plhenyl)-9-pbeniyl-8,9-dihiydro)-2HF-pyrido,[4,3 ,2-d--e]phitha]aziri-

3(711)-one,

8-(4-((dimiethvlamino)mt~ethvl)phieinyl)-9-phentvl-8,9-div)dro-21-pvrido[4,3 2-de]phithalazin

3(71f)-o-ne,

8-(4-(nioi'pholinomietbivl)pbeiyl )-9-pheniyi-8,9-ihly'dro-2H-pvridof4.3,..-dejphtialazin

20 3(711)-one,

8-(4-(hx'droxymiet-hvl)phenybl,-9-phertyi- 8,9-dihiydmi--2H--pvr'idof4,3,2-dejphithalain~t-3(7H-)

9-(3 -(4--(eye [opropanecarbony i)p iperazine- I -carbonybphecny 1)-8-(4

((dimetbylainiinio)rnethiybpheii)-89-dihv dro-2l.I'pyrido [4,3,)-delphithalazi-n-3 (71)-one,

2 5 9-(3 -(4-(cvclopr~opanecarbonvl)piperazine-- I -carbony i)phenyl)-8-(4

(hydroxyrnethylvl)henyl)-8,9-dihvd-ro-2H-pyi-ido[4.,3,2 -dejphthalazi n-3y (71)-one.

9-(4-(4-isobut.,yvp iperazinie- I -earbonyi)phieni)-8-(4-((methyiaInI ino)rnerlyl)phenyl)-8,9

dihydro-2H-pyrido)[4.3 ,2- (etphithalazii-3 (711)-onie,,

9-(3 '-(4-isobutvr-ty'lpiperazine-I -earl)omvIy)pbienv!I)-8-(pvnrdin-4-yl)-&9-dibvydro-21

30 pyridc[4t3 2-klejphthalazin-3 (711f)-one,

9-(3 -((drnethv.ilaiino)rnethly)phenyiv)-8-(pvridin-4-yI)-8,9-dihvdro,-2h)l-pyr-idof4.3,2

ck]phthalazinl-3(711)-onec,

Q-(3 -((rniethiylaiino)rneti )pbenvl)-8-(py'ridini-4-yl)-8,9-dihyN.dro-2 H-pyridio[4.3 2

de]phtbaiazin-3(711)-one.

3 5 9-(4-(dirnethv lam ino)rnethyl)pheniyh'-8-(pvridini-4-yl )-8 ,9"-,,dro-2H1-pvridof4,3,2

dejpbtbaazn-3Y(71/)-one;,

219

WO 2010/017055 PCT/US2009/051879

9-(3 -(hydroxN~ethiyl)phieny I)-8-(pyridin-4-vI])-8 ,9-dihyvdro-21/i-pyridof-4,3 ,2-de-phtbhalazin

9-(4-((rnethylarninio~inethyi)phenyvl)-8-(pyridini-4-J )-8-9-d ihydroc-2H--pyrido[4,32"

it] phlhalazin-3( 71f)-one.

5 ~9-( 3-((dirnethvlatn ino)r-nethvl)phieiyl )-8-(pyridin-3 -yl )- ,9-Ji hvdro -.Hpyridoj4,3 .2

de]phthalazin-_3(7H1)-one. 9-(4-((dinehlnio)ndhy)phewl)-8-(pyridi i-3 -l)-8,9-dihdro-2-pyrido[4-,3,.

9-(4-((dtiretylaninio)rnietyl)phenl)-8-(pyidi-3 -i)-89-dihy,-dro-211-pyrido4,3,

10 icIphthialnzin-3 (711)-one,

9-( (medrylanimethyie~l)h l-8-(yri d in-3 - -y8.9-2ihv ldo 4,1'py ide,- ltia

cit phtblan-37T-oe

159-(3 -(hdronethln)phli~envi)--(pyri i-3 yl--iv-21-pvrido[ 4,3$-depyphtoraazin

c/e(7thoane 7Mo~

S9-(3-((diretylami no)nethyihenvi} l--(pyridi-2-l)-8,9-dihyvdro-21-prido4,3 .2

tcphthalazin-3 (711)-one,

9-(3-(hyNclroxyretlhenPACvi)-8-(pyridin-2-yl)-8,9-d ihvdro-211-pyrido[4,3 .2-dielphthalazin

20 3(7th)-one.

9-(4-((diimne~thvlanino)methi)penl)-S-pyridin-2-yI )-8,9-dihvdr~o-2H--pvr-ido[43,2

dlelphthalazin-3(7 71)-one,

dcejphthialazin-3 (711)-one.

25 9-phenyl1-8-(pyridin-2-y'l)-8,9-dihvilro-2H1--py rido[4.3.2-dielphtiaI li- 3(711-one

9-phenvl-8-(pyridini-3 -yl)-8,9-dihydro-IJl-pyri dof4.3 2-diephtihalazi n-3 (711)-one.

9-.phenyi-Rg-4ydidin-4-vI)-8,9-dihydro-21-1-pyridio[4,. L2de~phlthalazini-3(7Th-o.ne, 5-~l uoro-9-phenyl-8-(pyridin-4-yI )-8.9-dihydro-2HI--pyridoj4,3 . -deji, phtliailaizn-3)( 711)-one.c

9-(3 -g dirnetlarninio i-nethvi)phenyl )-5 -tluoro-8-(pyridin-4-y]l)-8.,9-dhydro-2H [

30 pyrido[4,3 .2-dle Iphthalazin-3 (7H)-onte,

dle]phrhalazin-3 (711)-one.

9-(4-((dliinefhylarnino)rnethvi)phienyf-5,I)-fl uoro-8-(pyridin-4-yi}-8,9-dihlydro--2H

pyrido[4,3 ,2-delphthalazin-3 (7Th)-onie,

35 5-fti uoro-8,9-dipheniyi.-S,9-dihydro-2H-pyiido-[43 ,2-le jphithal azt11-3 (7Th-onie.

WO 2010/017055 PCT/US2009/051879

9-(4-((dimiethylamino))methyl)pheny)-5 -fluoi-ro-8-phienv-8.9-dih-ydtoc-2H-pvrido[4,3',2

de]phthalazin-one,

5-fluoro-9-(4-((nmetiyiaino)meithl!)phentyl)-8-plhenyl-8,9-dihiydr-o-2Ii-pyrido[43,2

delhthalaziin-one,

5 9-(3-((dimethl,ain~o)rnethiyl)pheinyi)-5 -fluioro-8-pheniy -8,9-dihydro-Hl-pyrido[43 ,2

delphthalazin-one.

8-(4-((diiniethylaniinoi)methyl)phieny1)-5 -fluotro-9-pheniyl-8$-diydro-11l-pyr.ido[4,3,2

ck~phthalazin-olne,

5-fluoro-9-( 3 -Qlnethylamino)m~iethyl')phenyl)-8-phbenyl-8,9-dihydro-Jf-py-id& 4,3,2

10 dejphthalazini-one.

5-fluoro- 8-(4-((miethiylam-ino)metiyl )phienyf)-9-phenvl-8,9-dihydro-211-pvrido44,2,

delphthalazin-one.

7-mtieth-yl-8,9-diphienvl- 8,9-dihydro-2H1-pyrkIdo{4.3 ,2-dej ph-thalazin-3(71-1)-onie,

7-eth~yl-8,9-diphenyl 1-8,9-dihvdr-o-2H--pyrido[4,3 .2-diclhthalazini-3(7Th)-one,

15 5-fl uoro-9-( I -methyl- lJJ-imidlazo1-2-v1)-8-phienv-8,9-d ihydro-2H-pvridof 4_3-",

delplithalazin-3(7Thl-one.

5 -tluoro-8-(4 -fluoropheny ,I)-9-( I-miethlv-IJl-imiidazol-2-yl) -8,9-dihvdro-2t1-pvrido[4,3,2

ckjplithalazin-3(Jtfi-one,

8-(4-((d imethyvlaminto.)m-ethiyi)pheniyi)-9-(1-i-ethiyl-lI H-imidazol-2-yI)- 8.,9-dihvdro-2Hf

20 pyridio[4,3 ,2-dlejphthialazin-3C711)-one,

9-(I -soropl- Hirnidaob5-4- -phienyi-&,9-dihvdro-2N-pyrido[4,3 ,-dejiphtializini

3(7Th)-one.

9-(4-mnethvl- IH-imidazol-2-yl)- S -phienyl-8,9-dihiydro-2 HT-pvridio[4.3 .2-d.eiphthalazini

3(7ff)-onie,

215 8-pheony1-9.-(h iawl -5-yI)-SS9-d ihvdro-2H-pyridof[4,3, 2-de--]phtlazii-3 (711)-onie,

9-(fuiran-3 -yi)-8-pheniyl-8,9-dihvdro-Q'-H-pyrTido[-43 ,-de]phthalazin-3(TH)-on[e,

8-(4-((4-ethylpiperazin- 1 -yl)methivl)pbeniyl)-9-pheinyl1-8,9-dihiydro-2-H-pyrido[4,3.2

9-phienvl-S-(4-(piperazin.- I.-yImeth-yI.)pheniy1)-8-,9-dihydro-2.H-pyrido)[4,3,2 -d-e]j hthiaawin

30 3(711)-one,

8-( 1-methyl- IH1-imiidazol1-2-l)-9-pieniyi-8,9-dihiydro-2H-.-pvrido,[4,3,2-dcsfphithalazin-3 (7.fl

one%,

9-(l 1-me thyl-I 11-i midazolI-2-yl)-8S-phe nyl-,- ilyr-'I.-yio4, )2dlpih a -1 -)

one,

35 &9bs -ehl Niiao~~ )-8.9-dihyd(]ro-211-pvrido[4,3.2-dIelphthiazin-3(7L-h-one,

9-( I H-imidazoi-2-yI) -8-phienvl-8,9-dihyd-ro- 2)H-pyrtido[4.3, -de~Jphithaiaziri-3(71fl-o~ne,

22 1

WO 2010/017055 PCT/US2009/051879

9-( 1 -ethy--I J-J-idazoi-2-yi) -S-phenyl-8,9-dIihydro-2 11-pyrido[4.3 ,2-deIcjphthialazin-3(7/H)

one0,

8-p-henyi1-9-( 1-propyl- I H1-imidazoi-2 -yl) -R,9-dihiydro-2H-pvrido-j4.3 ,2-c .jphthialazin-3( 711)

one,

5 9-( imethiyl-I H-imnidazol1-5 -yl) -8-phenctyl-&,9-d ihx'ydco-21:/I-pyridof 4,3,2-dic phthia~azin~

3(711)-one,

9-(3-((diethylirino)niethyi)ph~enyl)-8-(4-((diethyamin nt~y~he-y)-8 9-dihydro-2H

pyridoj 4,3 .2-c] phi halazin-3(7HJ1-onei,

9-(3-((4--methylpiperazin- 1- yl) mnethylI)pheny 1)-8-phenyl1-8,.9-dihydro-211-py ridof[4, 3,2

10 dclphathalazir -3(71-1)-one,

8-(4-(4-(cyclopro~paneearbonvyl) piperazi no-i -carbonyvlphienyl >9-phoniy]-8,9-d ihydro-21P1

pyridof 4,'3,2-dcj~phthialazin-3(7H)-onei,

9-phen-yl-8-(pyridini-4-y I)-&,9-dihydro-2H-pyrido[4.3,2-dcLithlalazin-3( 7th-one,

9-phenyl1-8 -(piperidin-4-vi.)-8,9-dihydro-211-pvrid o[4,3,2-dcle Iphth a]azin-3 (7H,)-onie,

I1S 9-phienyl-8-(pyridin-2-yl )-8,9-dihyvdro-2H-pyrido[4.3 ,2-dcl]plitlalazin-3 (7H/I-one,

8-(4-((4-nimethylpiperazin- I -yl)niethyl)phienyl)-9-phenvil-8&9-dihvydro-2H-pvrido[432

c/c phthalazin-3 (711)-one,

8,9-bis(4-41uorophenyl)- 8,9-ciydidr-2H--pyrido[ 4,3,2-elc]phrhaiazi n-3(7 11)-one,

S-(4-((dimnethy lam inio)methvi)pheniyl)-9-(4-fluioroplienyl)- 8,9-dihydro-2TH-pyridof4.3,2

20 citphthltaz7in-3( 7-1)-one,

R- 44hfliorophenyl )-9-{ I-miethyl-i.H- imidazol-2-yl)- 8&9-dihiydro-2t1-pyrido[4. 3,2

de]phthalazin-3(7H)-one,

8,9-bis(3 -Ud imiethylaminino)metrhyl)pheniyh-8,9-dihvdro-2HI-pyridlo[43',,2-dc~lphthalazin

3(711)-one,

25 9-(.3-((eyclopro-pyiauinto)miethvhlpheniy1)-8-phenvI-&,9-dihvidr.-2--pyTido[42 32

8-( 3-((dimethylamiiin lethiyl )pie-nv1)-9-ph-eniy-8.9-dih-ydro-2H-pvyridio[4,3,2-d-ljphthalazin

3(7th-one,

8-( 3-(morph~lol inomethvhl.'phen-Yl)-9-phenyl-8.9-dihvdiro-2t1-pvrido[4,3.,2-dc~lphthiaazini

30 3(711)-one,

8-(4-(azetidini- I-ylrnethyi.)pienvl)-9-(4-fhtiorophienvl)- 8,9-dihvdro-21-1-pv.rido[4 ,3 2

do] phthalazin-3 (71-1)-one,

5-fluoro -8-(4-fluior-ophbenyl )-9-( I-miethyl-I --I 2,4-triazoI-5-yi)-8,9-dihydro-21

pyridlo[4,3 .2-dejphthaiazin-1( 7H)-uwie

35 9-( 1-me-ithyl-Il-I ,2,4-triazoi-5-vhl-8-phienvl-8,9-diihvdro-2H--pyrido[4.3 .2-de]phthialazinl3(711)-one.

WO 2010/017055 PCT/US2009/051879

8 -(4-ftdhnethylamnino)miety'l)ph.envi )-9-( i-methyl- 1 1-1-1 ,2A4-triazoi-5 -yl)-8,9-dihiydro)- 1

pyrTido[4,3,2--dejphthalazin-3(7H4)-oi e,

8-(4-((dimnethyiamino)inetlv)phieny})-5 -11uoro-9-( i-methiyl- I H-I,2 ,4-triazol-5 -yl)-8,9dihvdro-211-pyrido[4.32-delph-thalazin--3('711)-onie,

pyiido74,3 ,2-delphithalazin-3(I 711)-one,

8-(4-fluioroiphienyl)-9-( I 4,5-rrimiethiyl - I H-im-idazol-2 -yi)-8,9-dihiydro-2H-pyrido 432 dejphthalazin-3 (711)-one,

0 tie]phthalazii-3)(7-)oe

9-(4,5-diniethyl-4H- I 2,4-triazol,-3 -yl)-8-p-heiinyl-8,9-dihiydro---f-pyridc4-2 deljphthaiazin-3(7_H)-one.

9-(4.5-dimecthy-411- 1 ,2,4-triaz.ol-3 -yI)-8-(4-Il uorophenyQl-8,9-dihvdr-H-pyfiridof[4,3-ckejphthalazin-3 (711)-one,

15 8-(4-chloropbhenyl)-9-(I -iiethyl-i H1-inidazol-2-y I )-8,9-dihydro-2H)I-pyrido[4,3,2de]phthalazin-3(7Th-one,

9-(1 1-methyl-IH-imidazol-2 -yI)-8-(4-Oriiflnoromiethyvl)phienvl)-8,9-dihiydro-2H-pvridof4,3 2'd~e]phthalazin-3(711)-one,

8-(4-.fluoropheayl ,')-9-(thiiazol-2-I)-8,9-dihdr-Hlpyridlof4,3 ,2-d.e~phthalazin-3(711)-one.

20 9-( 1 -ethyl- I H-imidazol-2-v i)-8-(4-fluo~ropheLnyfl-8,9-dihiydro-2H-pyrido[4.3 .2

&cjphthalazin-3 (711)-onie.

8-(4-t((4-eth~yl-3 -m~ethyipiperazin- I -y-)metiy i)phienyl)-9-phenvl-8,9-dih v dr)-2Hpyridof4,3 ,2-dIejphthialazini-3(711)-one,

8-(4-(4-ethylpiperazin- I -vl)methybphen)yl)-9-(4-f.I uoro~phenvl)-8,9-dihivdron-[

pvrTido[4,3 ,2'-dejlphithalazii-3 (711,)-one,

9-$4-fl uor~ophl,)-8-(4-((4-methyI-,piperazii- I -vl)nethyl.)pheniyl)-8 .9-dihivdro-2-

9-(4-ti uorophecnyl)-8-(i -(piperazin- 1 -ylmethv I)pheniyfl-8&9-dihy'dro-2-I11-pyrido[4 3,2

dejphthalaiin-3 (71-)-one,

30 9-(4-itoropenv)-8-(4-((3-miehiylpiperazin- I -y I)m-tethvyl)phenylI)-8,9-dihiydro-2-f

pyrido[ 4,3 -kphbain3(1)oe

9-(4-fluor-opheniyl)-8-(4-(pvrrolidin-'I -vlmnethyilphentyl)-8.9-d ihv dro-2H-pyrido 4.3,2

tIejphthaazint-3(711)-one,

9-phecny I-8..9-dihyvdro-2H'l-pyrido[4.3 ,2 -,ckeIphthialazin-3 (711)-on-e.,

2 - .

WO 2010/017055 PCT/US2009/051879

89-(4-Fluoropheniv)-9-(4-nethylx,-411- I .,4-tria,,zol-3 -yl)-8,9-dihydro- 21l-pyrido[4.,2

de]phtbaazin-3C 7R)--one,

8-(4-HuotiropheniiN-9-( I-thtlyl- 111- 1,2,4-triazol-5 -yl)-8 9-d ihydro-2H-pvrid4,14,3 .

dle]phthialazin-3(711)-o-ne,

5 8-(4-fluorophenyf)-9-(_ I -methyl- I Il-imiidazo)[4.5-clpvridin-2-yl)-8,9-d ihydro-2J1

pvrido)[4.3 .2-de]phflnlazini-3( 711)-onie,

5 -chloro-9-( I-me~thyl-I 11-i miida, zoi-2-yD,-8-phienvl-8,9-dihiydro-2Hl-pyrido[4J .,2

delp-thtazim-3( 711)-onie,

8-( 4-((dirnethvlam ini-tnethyl)-phenyvl)-5 -fluor-o-9-(4-fluiorophienyi)-8,9-dihiydro-2H10 pyrido [4,3, 2-de]phithalazin-3(711)-one.c

8.9-his(4-((dimethylam ino)miethvl)phAenvi)-5 -Iluoro-8,9-dihvdro-211-pvrido[4.2

8-(4-((dimethyla ininio)m-iethybphenyl)-5 -iiuoro-9-phenxd-8,9-dihydro -2Hl--pvriido[4,3 ,2

deiclphthalazini-3 (711)-onie,

15 8-(4-((3 .4-dimnethipiperazin- I -ybm:nethyl-)phecnvl)-9-(4-flutor-ophenyfli-8,9-dihiydro-ZHpyrido 4.3 ,2-de Jphthialazin-3(7H)-ooe,

8-(4-((3.S-direthiylpiperaizin- I -yI )methylIphbenTyl }-9-(4-fluoriopheniyl)-8,9-dihydro-211-pytido[4,3,2-c,,e~phtbtlal azini-3( 711)-one.,

9-phenyl-8-(4-(pvrrol idin-I1-lehbhnl- -iyr-Hprdt. 2d~hhlzn 20) 3(7/1)-one,

9-pheniyl-8-(4-(pyrro)iidin- I -ylm-eth 'i)pheniyl)-8jJ-dihydroc-2-H-pyrido[4,3 .2-do jpht alazini

3(7/1)-one,

9-( I-methyl-i H-iniidazol--ybl-8 -(4-(pyrrolidini-,y hne~ithyi)pheny 1)-8.-d ihydro-21t

pyridof-4,3, 2-tie]phthalazin-3(7 11)-one,

25 9-(4-fluoropheny1)-8-( I -mnethyl- I11-imidazol-2-x'It)-8 9-dihiydro-2H-pyridoi-)4,3,

do] phthalazin-3 (711)-one,

9-(-florpheyl)8-quiolin-6-vl)-8.9-dihydro-2H-pvrido[4,3,2 -de]phithalazini-3 (711)-one;,

8-(4-(( dimiethylaminio)metlhvI)phenyi)-9-p-toMy-8,9-dihvdo-2H--pyild,[4., .2-dephthalazin

3(710-onme.

309-(4-chlor-ophentvl)-8-( 4-((dimmiiehylamtino)methiyI)plhenx'ii)-8,9-dliydro-211-py'rido[4,3 2

del phth alazin-3 (1)oe

8-(4 -((dimiethyiainio)meithvl)pheiwvl)-9-(4-rniethoxypheIinx')-8,9.dihiydro-.Itpyi do[4 ,3,2delphithaazin.3(71f)-one.

8-(4-((dliethvlamino)m-.ethvl)phentyl )-9-pheniyl-8,9-dihy.d ro-211-pyr-ido[4,3'',2-dieJphithalaizil

35 3(711)-onte.

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8-(4-((diethyhaiinto)meihyi)phenyl)-9-(4-ftl orophienyl)- 8,9-dihydrdio-2H-pyrido[4 3,2fie jpthaiazin-3 (71f-orie.

9-(4-chbloropheny l)-8-(4 -((dIiethiyiain~io)methyl4 ~lienyfl-8,9-dIihydro-2 H-p yidoi[4,3 ,2die]pht nlazin-3 (7H)-one,

5 ~(EY-6-lluoro-4-(( I-methyl-i tI-imidazol-2-yl)miethyleneaminoflsobcnz.ofurian- I (31f)-one,

5-fluoro-9-(4-fluoriiophienyl)-8-( 1 -methyl- I Il-imid aizol-2-yI)-8,9-dihydro-2H--pyridof4.3.2

delplithalazin--3(7 f)-one,

8-(4 -((diiiethylainniii)rnyeth-yl)phenvil)-9-(4-ethiy phenvl)-8.9-dihydro-211-pvrido{4,3 .2delplithalazin-3(711)-one,

0 8-(4-((dimethylami no)miethyl)phienyl)-9-(4-is-,opropylpheniyl )-8,9-dihydro-2H1-pvridof[4.3.,2de]phtbalazin--3( 7TH-one,

8-(4-((iimethx'lam ino)rniethyl)phleniyl )-9-(4-(triftluoromietlwyl)phienv 1)-8,9-dibydro)-2H

pyridc4,2-dc] lphrihaiaii-3(7J1)-onec,

8-{4-((diethlam~inino)m-ethi)pleniyl )-9-p-Ioly 1-8.9-dihy dr-o-2H-pyrido[ 4,3,2-c jphithalazini15 3(711)-one,

9-(4-fluorophenyil)-8-(4-( 1 -methvipy'.vrrolidini-2-i)phienyl)-8.9-dihv.dro-2H- pyid.o[ 4.3 2

de]pbhtha~azin.-3(7I-)-ojne,

9-(4-fltuoro'phienvyl)-8-(4-(pyrrol idin-2-yl)pheniyl)-8.9-dihydro-AJI-pyrido[43 ,2

de]phthalazin-3 (7ff)-one.

20 8-(4-tiuoropheniyl)-0-methyl-9-(1-i.methyl-i 1J-imidazol-2-vl)-8&9-dihvdro(j-2H-pyridio[4,3,2

dejpithalazin-3(7U)-one,

9-(4-fluo)rophenx ij-8-( 1 H-im-idazol-2-yl)-8,9-dihiydlro-2F1-px) ridof4,3 ,2-de]phithalazin -3(714-I)

one,

5-flu-oro-9-( 1 -methyl-III-I ,2,4-triazol-5-vi.)-8-phenvl -8.94 ihvdrto-2H--pyrido[4,3.2

25 de]phthalazin-3(YH)-one,

9-(4-fi uorophenyl)-9-hiydroxv-8-( I -meth~yl- 1 U-imiidazol-2 -y b-8,9-dihy dro-2 U-pyrido[4.3,A

dclpihalazin.-one,

(8S,9R)-5 -fhioro-9-( 1-methyl-11H-imidazol-2-yl) -S-phienvl-8.9-dihiydro-2 tI-pyridof4,3'2

d&~phthalazin-3 (719)-one.

30 (81.9.9$-5-fl uoro-9-( I -methyl-i1J-iniidazoi-2-yl) -s -phienyi-8 ,9-dihydro-21-1-pvrtido[4,3,2

dIejphthla~lzmi-3(711 )-onie.

(882 9R'l-5-ltioro-8-(4 -fluoropheniyl)-9-( 1-miethiyil -im-nidazol-2-yl) -8,9-dihydro-2H

pyrido[4,3 ,2-dle]phthalazin-3 (711)-one,

(8R, 9S )-5-fluoro-8-(.4-fluioropieniyi)-9-( .-methyl- 1 U-imiidazo l-2-yl) -819-dihydro-2H1

35 pyrido(4,3.2-c ]phithalazin-3( 7th-onie,

225

WO 2010/017055 PCT/US2009/051879

(8S,9R)- 8-(4-fluorophenyl)-9-( I -methyl-iim-iiidazol-2-yl) -8,9-dihydro-2H-pyrido[4,3,2

dejphthalazin-3(71)-one,

(8R.9S)- 8-(4-fluorophenyl)-9-( 1-methyl-IH-imidazol-2-yi) -8,9-dihvdro-2H-pyrido[4,3,2

de]phthalazin-3(7HL)-one,

5 (8S,9R)-5-fluoro-9-( i-methyl- -1 ,4-triazol-5-yl) -8-phenvl-8.9-dihydro-2H

pyrido[4,3,2-dejphthalazin-3(7h)-one,

(8R,95)-5 -fiuoro-9-(I-methyl-IH-1, 2,4-triazoi-5-yl) -8-phenvl-8,9-dihydro-2H

pyrido[4,3. 2-dejphthalazin-3(7H)-one,

(8,9R)-5-tl uoro-8-(4-fluorophenyl)-9-(1 -methyl-I H-1,2,4-triazol-5-yl) -8,9-dihydro-211

10 pyrido[4,3,2-de]phthalazin-3(7TH-one,

(8,95)-5 fluoro-8-(4-fuorophenyl)-9-(i-methyl-i H-I ,2,4-triazol5-yl) 8,9-d ihydro~2H~

pyrido[4,3,2-dejphthalazin-3(7H)-one,

(8S,9R)- 8-(4-fluorophenvl)-9~(1-methyl-it H- 1,2,4-triazoi-5-yl) -89-dihydro-2

pyrido[4i3 2-dejjphthalazin-3(7H)}-one,

15 (8R,98)- 8-(4-fluorophenyl)-(1i-nmethyl-I H-Il,2,4-triazol-5-yl1) -8 9-dihydro-2H

pyrido[4,3,2-dcejphthalazi-3(7-)-one,

8,9-dihydro-2H-pyrido[43,2-c/e ]phthalazin-3( 7/f)-one, and

(8R.95)~8~(4-((d imethylamino)methyl)phenyb)-5-fluoro-9-( 1-methyl-ill-1,2,4-triazo-5 -yl)

20 8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(711)-one;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

53. A pharmaceutical composition comprising a compound of any of claims 1-52 or a

pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically

acceptable prodrug and a pharmaceutically acceptable carrier, excipient, binder or diluent thereof

25 54. A method of inhibiting poly(ADP-ribuse)polymerase (PARP) in a subject in need of PARP

inhibition, comprising administering to the subject a therapeutically effective amount of a compound

of any of claims 1-52.

55. A method of treating a disease ameliorated by the inhibition of PARP comprising administering

to a subject in need of treatment a therapeutically effective amount of a compound of any of claims

30 1-52.

56. The method according to claim 55, wherein the disease is selected from the group consisting of:

vascular disease; septic shock; ischaemic injury; reperfusion injury; neurotoxicity; hemorrhagic

shock; inflammatory diseases; multiple sclerosis; secondary effects of diabetes; and acute treatment

of cytoxicity following cardiovascular surgery.

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57. A method of treating cancer, comprising administering to a subject in need of treatment a

therapeutically effective amount of a compound of any of claims 1-52 in combination with ionizing

radiation, one or more chemotherapeutic agents, or a combination thereof.

58. The method of claim 57, wherein the compound according to any of claims 1-52 is

5 administered simultaneously with ionizing radiation, one or more chemotherapeutic agents, or a

combination thereof.

59. The method of claim 57, wherein the compound according to any of claims 1-52 is

administered sequentially with ionizing radiation, one or more chemotherapeutic agents, or a

combination thereof.

i) 60. A method of treating a cancer deficient in Homologous Recombination (H-R) dependent DNA

double strand break (DSB) repair pathway, comprising administering to a subject in need of

treatment a therapeutically effective amount of a compound of any of claims 1-52.

61 The method of claim 60, wherein the cancer comprises one or more cancer cells having a

reduced or abrogated ability to repair DNA DSB by HR relative to normal cells.

15 62. The method of claim 61, wherein the cancer cells have a BRCAI or BRCA2 deficient

phenotype.

63. The method of claim 62, wherein the cancer cells are deficient in BRCAI or BRCA2.

64. The method of claim 60, wherein the cancer comprises one or more cancer cells deficient in

proteins involved in DNA DSB repair by HR.

20 65. The method of claim 64, wherein the cancer cells are deficient in ATM Rad51 Rad52, Rad54,

Rad50, MRE 11, NBSI, XRCC2, XRCC3, cable, RPA CUP and MBC.

66. The method of claim 60 wherein the subject is heterozygous for a mutation in a gene encoding

a component of the HR. dependent DNA DSB repair pathway.

67. The method of claim 60 wherein the subject is heterozygous for a mutation in BR.CA 1 and/or

25 BRCA2.

68. The method of claim 60 wherein the cancer is breast, ovarian, pancreatic or prostate cancer.

69. The method of claim 60 wherein the treatment further comprises administration of ionizing

radiation or a chemotherapeutic agent.

70. A method of treating a cancer deficient in mismatch DNA repair pathway comprising

30 administering to a subject in need of treatment a therapeutically effective amount of a compound of

any of claims 1-52.

71. The method of claim 70 wherein the cancer cells are deficient in MutS, MutH and MutL

72. A. method of treating a cancer demonstrating microsatellite instability due to reduced or

impaired DNA repair pathways comprising administering to a subject in need of treatment a

35 therapeutically effective amount of a compound of any of claims -52.

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73. A method of treating a cancer demonstrating genomic instability due to reduced or impaired

DNA repair pathways comprising administering to a subject in need of treatment a therapeutically

effective amount of a compound of any of claims 1-52.

74. Use of a compound of any of claims 1-52 wherein the formulation of a medicament for the

5 treatment of a poly (ADP-ribose)polymerase mediated disease or condition.

75. An article of manufacture, comprising packaging material, a compound of any of claims 1-52

and a label, wherein the compound is effective for modulating the activity of the enzyme poly(ADP

ribose)polymerase, or for treatment, prevention or amelioration of one or more symptoms of a

poly(ADP-ribose)polymerase-dependent or poly(ADP-ribose)polyierase-mediated disease or

10 condition, wherein the compound is packaged within the packaging material, and wherein the label

indicates that the compound, or pharmaceutically acceptable salt, pharmaceutically acceptable N

oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or

pharmaceutically acceptable solvate thereoft or a pharmaceutical composition comprising such a

compound is used for modulating the activity of poly(ADP-ribose)polymerase, or for treatment,

15 prevention or amelioration of one or more symptoms of a poly(ADP-ribose)polymerase-dependent

or poly(ADP-ribose)polymerase-mediated disease or condition.

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