MAI MULTE A MINHA CUI ON TO A MAN UNION MINI

MAI MULTE A MINHA CUI ON TO A MAN UNION MINI US010053433B2

( 12 ) United States Patent England et al .

( 10 ) Patent No . : US 10 , 053 , 433 B2 ( 45 ) Date of Patent : Aug . 21 , 2018

( 54 ) ANDROGEN RECEPTOR ANTAGONISTS ( 56 ) References Cited U . S . PATENT DOCUMENTS @ ( 71 ) Applicant : THE REGENTS OF THE

UNIVERSITY OF CALIFORNIA , Oakland , CA ( US )

@ ( 72 ) Inventors : Pamela M . England , San Francisco , CA ( US ) ; Robert J . Fletterick , San Francisco , CA ( US ) ; Kristopher Kuchenbecker , San Francisco , CA ( US ) ; Felipe de Jesus Cortez , San Francisco , CA ( US )

4 , 636 , 505 A 7 , 709 , 517 32 8 , 110 , 594 B2 8 , 445 , 507 B2 8 , 802 , 689 B2 9 , 388 , 159 B2

2001 / 0012839 Al 2005 / 0209320 A1 2008 / 0057068 A1 2010 / 0185419 Al 2017 / 0014399 Al

1 / 1987 Tucker 5 / 2010 Sawyers et al . 2 / 2012 Jung et al . 5 / 2013 Jung et al . 8 / 2014 Jung et al . 7 / 2016 Jung et al . 8 / 2001 Miller et al . 9 / 2005 Miller et al . 3 / 2008 Dalton et al . 7 / 2010 Singh et al . 1 / 2017 Jung et al .

@ ( 73 ) Assignee : The Regents of the University of California , Oakland , CA ( US ) FOREIGN PATENT DOCUMENTS

( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 U . S . C . 154 ( b ) by 0 days .

WO WO WO

WO - 02 / 076177 A2 WO - 02 / 076177 A3

WO - 2006 / 124118 AL

10 / 2002 10 / 2002 11 / 2006

OTHER PUBLICATIONS ( 21 ) Appl . No . : 15 / 382 , 942 ( 22 ) Filed : Dec . 19 , 2016 ( 65 ) Prior Publication Data

US 2017 / 0101384 A1 Apr . 13 , 2017

Related U . S . Application Data ( 63 ) Continuation of application

PCT / US2015 / 036793 , filed on Jun . 19 , 2015 . No .

( 60 ) Provisional application No . 62 / 015 , 221 , filed on Jun . 20 , 2014

Blackledge , G . R . ( 1996 ) . “ Clinical progress with a new antiandrogen , Casodex ( bicalutamide ) , ” Eur Urol 29 Suppl 2 : 96 104 . Clegg , N . J . et al . ( Mar . 15 , 2012 , e - published Jan . 20 , 2012 ) “ ARN - 509 : a novel antiandrogen for prostate cancer treatment , ” Cancer Res 72 ( 6 ) : 1494 - 1503 . Feldman , B . J . et al . ( Oct . 2001 ) . “ The development of androgen independent prostate cancer , ” Nat Rev Cancer 1 ( 1 ) : 34 - 45 . Hara , T . et al . ( Jan . 1 , 2003 ) . “ Novel mutations of androgen receptor : a possible mechanism of bicalutamide withdrawal syn drome , ” Cancer Res 63 ( 1 ) : 149 - 153 . International Search Report dated Dec . 4 , 2015 , for PCT Applica tion No . PT / US2015 / 036793 , filed Dec . 4 , 2015 , 5 pages . Tran , C . et al . ( May 8 , 2009 , e - published Apr . 9 , 2009 ) . “ Develop ment of a second - generation antiandrogen for treatment of advanced prostate cancer , ” Science 324 ( 5928 ) : 787 - 790 . Tucker , H . et al . ( Apr . 1988 ) . “ Resolution of the nonsteroidal antiandrogen 4 - cyano - 3 - [ ( 4 - fluorophenyhsulfonyl ] - 2 - hydroxy - 2 methyl - 3 ' - ( trifluoromethyl ) - propionanilide and the determination of the absolute configuration of the active enantiomer , " J Med Chem 31 ( 4 ) : 885 - 887 . Tucker , H . et al . ( May 1988 ) . “ Nonsteroidal antiandrogens . Syn thesis and structure - activity relationships of 3 - substituted deriva tives of 2 - hydroxpropionanilides , " J Med Chem 31 ( 5 ) : 954 - 959 . Written Opinion dated Dec . 4 , 2015 , for PCT Application No . PT / US2015 / 036793 , filed Dec . 4 , 2015 , 6 pages . Yin , D . et al . ( Jan . 2003 ) . “ Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor , ” Mol Pharmacol 63 ( 1 ) : 211 - 223 .

( 51 ) Int . Cl . CO7D 213 / 74 ( 2006 . 01 ) C07D 239 / 42 ( 2006 . 01 ) C07D 241 / 26 ( 2006 . 01 ) A61K 31 / 44 ( 2006 . 01 ) A61K 31 / 495 ( 2006 . 01 ) CO7D 257 / 08 ( 2006 . 01 ) CO7K 14 / 72 ( 2006 . 01 ) CO7D 213 / 84 ( 2006 . 01 ) CO7D 237 / 24 ( 2006 . 01 ) CO7D 253 / 07 ( 2006 . 01 )

( 52 ) U . S . CI . CPC . . . . . . . . . C07D 257 / 08 ( 2013 . 01 ) ; C07D 213 / 74

( 2013 . 01 ) ; C07D 213 / 84 ( 2013 . 01 ) ; C07D 237 / 24 ( 2013 . 01 ) ; C07D 239 / 42 ( 2013 . 01 ) ;

C07D 241 / 26 ( 2013 . 01 ) ; C07D 253 / 07 ( 2013 . 01 ) ; C07K 14 / 721 ( 2013 . 01 )

( 58 ) Field of Classification Search None See application file for complete search history .

Primary Examiner — Zinna Northington Davis ( 74 ) Attorney , Agent , or Firm — Anson M . Nomura ; Mintz , Levin , Cohn , Ferris , Glovsky and Popeo , P . C . ( 57 ) ABSTRACT Disclosed herein are compositions and methods for modu lating the androgen receptor .

19 Claims , 19 Drawing Sheets

U . S . Patent Aug . 21 , 2018 Sheet 1 of 19 US 10 , 053 , 433 B2

412

Arg752

Cys784

FIG . 1

- -

0 : 00 0 +

ZX 0

* *

RR a : CDX : CDX

ON Cysyl 29 . 0 : 00 : 0 Kain

FIG . 2

atent Aug . 21 , 2018 Sheet 2 of 19 US 10 , 053 , 433 B2

Experimental ICs curves

100

Normalized Activity 8 cpx

4 , 037 03 . 077

. .

Umlanannnganggang ngayong mga pagmamangunan penyanyi lamang ang aga rin

100 0 . 001 0 . 01 0 . 1 1 . 0 10 log [ ligand ( UM ) ]

FIG , 3


Con graphs for AR LBD 100

Normalized Activity CDX

have 4 , 037 on 3 . 077 m 4 . 075 when 4 . 116 * 4 . 126

4 . 125 4 . 127 4 . 129 L Shopping ITTER 0 . 001 0 . 01 0 . 1 1 10 100

log [ ligand ( UM ) ]

FIG . 4


IC50 graphs for AR Full - length 100

po /

Normalized Activity 9 Cpx

4 , 037 3 . 077

within 4 . 075 wotein 4 . 116 * 4 . 126

4 . 125 4 . 127 4 . 129 Do

www . gogga g nangang p angangarang wwwgang

0 . 001 0 . 01 10 100 0 . 1 1 log [ ligand ( UM ) ]

FIG . 5


IC 50 graphs for Electrophilic Analogs ( LBD )

4 . 039 4 . 025 100 -

Normalized Activity U m nimmngingungongonpinguigpennommigninnunprigijgengrynjumangunanjoninging ang naging panguningannnynnigmpangganggapinningom tilbyrningumprising ang

0 . 001 0 . 01 0 . 1 10

log ( ligand ( UM ) ]

FIG . 6


IC se graphs for Electrophilic Analogs ( FL )

minimumin i oth 4 . 039

4 . 025 wimminpinoinninminininh wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww Normalized Activity

op

O grangggggggggggggningungen manggagawangun filmom 0 . 001 0 . 01 10 100 0 . 1 1

log [ ligand ( UM ) ]

FIG . 7


Gal AR LBD , 1nM DHT , HELA cells ng

www HE Amese HO persones stor

% Normalized fluoresence

CDX 4 , 037 4 . 116 4 . 126 3 . 077 4 . 075 4 . 125 4 . 127 4 . 129

UTDOO

10 100 0 0 . 0001 0 . 001 0 . 01 0 . 1 1 Conc ( MM )

FIG . 8A

Gal AR LBD , 1nM DHT , HELA cells CDX 4 . 037 4 , 116 . .

som

g

% Normalized fluoresence .

se ponaggagage 0000000000000000000000000000000oooooooooooooOOOOOOOOOOOOOOOOOOOOO

10 100 0 0 . 0001 0 . 001 0 . 01 0 . 1 1

Conc [ UM ] FIG . 8B


Gal AR LBD , 1nM DHT , HELA cells 150

1 * - 4 . 126 3 . 077 4 . 075 IA We care

% Normalized fluoresence 10 100 0 0 . 0001 0 . 001 0 . 01 0 . 1 1

Conc ( uM ) FIG . 8C

Gal AR LBD , 1nM DHT , HELA cells 150m * * * *

* * * * * * 3

4 . 125 4 . 127 4 . 129

8


Conc [ UM ] FIG . 8D


Gal AR LBD , 1nM DHT , HELA cells

- - CDX * * 4 , 037 soos sooo ARN - 509 * MDV3100

8

*

% Normalized fluoresence 50 * *

10 100 O 0 , 0001 0 . 001 0 . 01 0 . 1 1 Conc ( M )

igonist suiagonist e antagonist 7777

isgard binding asjonist

wwwwwww LED

OR &

FIG . 9


AR FL , 1nM DHT , HELA cells

1000 *

% Normalized fluoresence . CDX 4 . 037 4 . 116 4 . 126 3 . 077 4 . 075 4 , 125 4 . 127 4 , 129

Reg * * * * * * * * * * * *

100 0 0 . 0001 0 . 001 0 . 01 0 . 1 1 10 Conc ( UM )

FIG . 10A

AR FL , 1nM DHT , HELA cells CDX 4 . 037 4 , 116 www .

EESCHTETETE


Conc [ UM ] FIG . 10B


AR FL , 1nM DHT , HELA cells written moderni 4 . 126

3 . 077 4 . 075 A 10061

image TAT

% Normalized fluoresence fames an

Borang yang

thereby

10 100 0 0 . 0001 0 . 001 0 . 01 0 . 1 1 Conc ( um

FIG . 10C

AR FL , 1nM DHT , HELA cells 150 m

* * * *

* * * *

4 . 125 4 . 127 4 . 129

1000 * * * * * * * * * * * AHO * # $ $

% Normalized fluoresence e non sono

10 100 0 0 . 0001 0 . 001 0 . 01 0 . 1 1 Conc ( UM )

FIG . 10D


AR FL , 1nM DHT , HELA cells inwone won CDX w 4 . 037 crew other me ARN - 509

MDV3100 wwwwwwwwwwwwwww

% Normalized fluoresence Home JONAL Make

10 100 0 0 . 0001 0 . 001 0 . 01 0 . 1 1 ConcluM

?? $ ago ssilagoist

44464 * * * * * * * * * * isis

* * * * s

sganist om ligand binding site

ONS

FIG . 11


10 nM DHT on MMTV with LNCAP CDX 4 , 037 4 . 116 4 . 126

over eller om * * *

% Normalized 50 .

0 . 0001 0 . 001 0 . 01 0 . 1 Conc ( UM )

FIG . 12


10 nM DHT on MMTV with LNCAP 150 .

sense haveren CDX w 4 , 037 nou o ARN - 509 . . . MDV3100

pazijewON % bon 0 . 0001 0 . 001 0 . 01 0 . 1

Conc ( UM ) FIG . 13


Gal AR LBD , 1nM DHT , HELA cells 150mg

How - - 6 - - - CDX 4 . 010 4 . 015 4 . 025 4 . 039

0000000000000OOOOOK

% Normalized fluoresence - - *

- * * NE * * 4

* * * oppogon

0 . 001 0 . 01 100 0 . 1 1 10 Conc [ UM ]

FIG . 14


AR FL , 1nM DHT , HELA cells $ over phone

f

% Normalized fluoresence framfaraferenta dintre med Kapet

CDX CDX 4 . 010 4 . 015 4 . 025 4 . 039 eminine ta continua

O regon googoogagogos para o progoro

0 . 001 0 . 01

Conc ( UM ) FIG . 15


Transfection of Gal - AR LBD C784 mutants ( Hela cells ) 700000

802222

500000

Luc Activities 300000 o No hormone DHT ( INM ) 300000

200000

100000

- - - - - * * * * * - - - - - - - - - - * * * * * * - - - - * * * - - - * * * * * * - - - - - * *

Galt Gad AR 0784A 0784F C7844 0784 07849 0784V

FIG . 16


Western Blot of Gal - AR LBD C784 WT and Mutants ( Hela cells )

C784 WT Gal4 C784A 0704F 0784H C784L 07845 0784V 2105 W6920 C794A C784F 0784H 0784 C7848 0784V OHTIME

e - actin s - acin

Quantification of Gal AR LBD C784 W and mutants

Quantification of Gal AR LBD C784 WT and mutants

750 *

* * * * * * * * * 9a9398 www and 0155 07547 C7ML 075 07847 * Gm C784A OG 5734 * 07941 . c7945 079AV

M Hoone 213 in

FIG . 17


Western Blot of AR FL with compounds ( Hela cells )

? CMV LOON * No ligand to CDX 4 . 037 4 . 116 4 . 126 obe ARN - 509 * MDV3100

to - ole ole DHT ( 1nM ) AR FL

h

B - actin

Quantification of AR FL with compounds ehehehehehehhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh * * * *

Average of Density ?

? ?

?

? ! AR + ARICHT AR + OHT * CDXN AR + DHT + 4 . 037 N AR + DHT + 4 , 116 AR + OHT + 4 , 126 Af + DHT + ARN AR + DHT + MOV

FIG . 18

US 10 , 053 , 433 B2

ANDROGEN RECEPTOR ANTAGONISTS wherein Ring A is a heteroaryl ; Ring B is a phenyl or heteroaryl ; R ' is independently a

CROSS - REFERENCES TO RELATED halogen , CX°3 , CN , - S02C1 , SONR10 , APPLICATIONS SO , NRZR * , _ NHNH , LONR _ R * , _ NHC = ( 0 )

5 NHNH , NHC = ( O ) NR7R8 , N ( O ) , NR7R8 , This application is a continuation of International Patent C ( O ) R ” , C ( O ) - OR " , C ( O ) NRÖR , OR10 ,

Application No . PCT / US2015 / 036793 , filed Jun . 19 , 2015 , - NR7SO _ R10 , NR ? C = ( O ) R , NRC ( 0 ) OR ” , which claims the benefit of U . S . Provisional Patent Appli - NR OR ” , OCXC3 , OCHX “ , E , substituted or unsub cation No . 62 / 015 , 221 filed on Jun . 20 , 2014 , all of which stituted alkyl , substituted or unsubstituted heteroalkyl , sub are incorporated herein by reference in their entirety and for stituted or unsubstituted cycloalkyl , substituted or unsubsti all purposes . tuted heterocycloalkyl , substituted or unsubstituted aryl , or

substituted or unsubstituted heteroaryl ; two adjacent R REFERENCE TO A " SEQUENCE LISTING , ” A substituents may optionally be joined to form a substituted TABLE , OR A COMPUTER PROGRAM LISTING 16 or unsubstituted cycloalkyl , substituted or unsubstituted APPENDIX SUBMITTED AS AN ASCII FILE heterocycloalkyl , substituted or unsubstituted aryl , or sub

stituted or unsubstituted heteroaryl ; E is an electrophilic The Sequence Listing written in file 48536 moiety ; R2 is independently a halogen , CX 3 , CN ,

553C01US _ ST25 . TXT , created on Dec . 15 , 2016 , 8 , 258 SO , C1 , SO , R14 , SONR1R12 , bytes , machine format IBM - PC , MS Windows operating 20 - NHNH , , ONR1R12 , - NHC = ( O ) NHNH , system , is hereby incorporated by reference . NHC ( O ) NR ' R12 , N ( O ) , NR ' R12 , C ( O ) R13 ,

C ( O ) OR13 , C ( O ) NRIR12 , OR14 , NRISO , R14 , BACKGROUND NRC = ( O ) R13 , NRIC ( O ) OR13 , NRI ' OR13 , OCX 3 , OCHX " , substituted or unsubstituted alkyl ,

Androgen receptor ( AR ) is a member of the nuclear 25 substituted or unsubstituted heteroalkyl . substituted or hormone receptor family activated by androgens , such as unsubstituted cycloalkyl . substituted or unsubstituted het dihydrotestosterone ( DHT ) . AR is a prime therapeutic target erocycloalkyl , substituted or unsubstituted aryl , or substi for treating prostate cancer . Several compounds have been tuted or unsubstituted heteroaryl ; two adjacent R ? substitu developed as chemotherapy for prostate cancer . However , ents may optionally be joined to form a substituted or these compounds bind AR with affinities comparable to or 30 unsubstituted cycloalkyl , substituted or unsubstituted het less than the endogenous hormone and over time patients erocycloalkyl , substituted or unsubstituted aryl , or substi develop resistance to these drugs . Higher affinity and / or tuted or unsubstituted heteroaryl ; R * is independently an slower off - rate ligands ( e . g . covalent ligands ) are needed to

unsubstituted alkyl ; R ’ , R8 , Rº , R19 , R1 , R12 , R13 , and R 14 provide more effective therapies . Androgen receptor competitive antagonists ( antiandro - 35 are independently hydrogen , halogen , CX 3 , - CN ,

gens ) are drugs used to treat hormonal - based syndromes and OH , — NH2 , COOH , CONH2 , — NO2 , SH , prostate cancer . Current drugs for prostate cancer include _ SO , Cl , _ SO , H , JSOH , SO , NH , NHNH , flutamide , bicalutamide , nilutamide , enzalutamide and ONH , _ NHC = ( O ) NHNH , NHC ( 0 ) NHA , ARN - 509 . Each of these inhibitors binds to the hormone NHSO , H , NHC - ( 0 ) H , NHC ( O ) OH , NHOH , binding pocket ( HBP ) of the androgen receptor . This is the 40 OCX®3 , OCHX?2 , CF3 , OCF3 , OCHF2 , substi same site that the natural physiological steroids testosterone tuted or unsubstituted alkyl , substituted or unsubstituted ( TES ) and dihydrotestosterone ( DHT ) situate to produce an heteroalkyl , substituted or unsubstituted cycloalkyl , substi active conformation of the receptor that changes the cell ' s tuted or unsubstituted heterocycloalkyl , substituted or transcription program and cell fate . The drugs work by unsubstituted aryl , or substituted or unsubstituted heteroaryl ; competing with the natural hormones for binding to the 45 R7 and R8 substituents bonded to the same nitrogen atom pocket and , as a result , lessening activation of the receptor . may optionally be joined to form a substituted or unsubsti Of all these ligands , the steroids DHT and testosterone bind tuted heterocycloalkyl or substituted or unsubstituted het tightest to the receptor . Tighter binding and / or slower off eroaryl ; R11 and R12 substituents bonded to the same nitro rate drugs are desirable , along with the additional charac gen atom may optionally be joined to form a substituted or teristic that they encourage degradation of the receptor by 50 unsubstituted heterocycloalkyl or substituted or unsubsti components resident in cells and / or prevent formation of AR tuted heteroaryl ; al is independently an integer from 0 to 4 ; variants resistant to chemotherapy .

Disclosed herein are solutions to these and other problems b1 is independently an integer from 0 to 5 ; ml , m2 , v1 , and v2 are independently 1 or 2 ; nl and n2 are independently an in the art . integer from 0 to 4 ; X4 , Xb , and X° are independently — C1 ,

BRIEF SUMMARY — Br , — 1 , or — F . In another aspect is provided a pharmaceutical composi

In an aspect is provided a compound having the formula : tion including a compound as described herein , or a phar maceutically acceptable salt thereof , and a pharmaceutically

60 acceptable excipient . ( la ) In another aspect is provided an androgen receptor protein

covalently bound to a compound ( e . g . , a compound as ( R ' ) at A B + ( R2 ) 61 described herein ) .

In another aspect is provided a human androgen receptor IÓ R3 ó o 65 protein covalently bound to a compound as described herein ,

wherein the compound is covalently bound to Cys784 of the human androgen receptor protein .

IZ

US 10 , 053 , 433 B2

F

MT A

NC .

A

30

In another aspect is provided a method of treating cancer hormones . This allows endogenous ligands to competitively in a subject in need thereof , including administering to the activate the receptor , and selective pressure to drive escape subject a compound as described herein , or a pharmaceuti mechanisms . In embodiments , provided herein are new cally acceptable salt thereof . antiandrogens that bind tightly to AR .

In another aspect is provided a method of inhibiting 5 In embodiments , described herein are significantly more androgen receptor activity in a subject in need thereof , potent antiandrogens than previously characterized , which including administering to the subject a compound as can be designed based on the existing drug bicalutamide by described herein , or a pharmaceutically acceptable salt taking into account the chemical reactivity of the AR thiol thereof . side chain of Cys784 and the ability to improve the electro

philicity of bicalutamide . In embodiments , a compound BRIEF DESCRIPTION OF THE DRAWINGS more potent than bicalutamide is produced by replacing the CH atoms of the A ring with a nitrogen ( N ) atom , as FIG . 1 . Ligand binding domain of AR . Arg752 thought to described in more detail below . In embodiments , this change be important to ligand binding ; Increased affinity of ARN

509 compared to RD162 contrary to decreased point charge 15 15 results in a compound that binds more tightly ( e . g . 24 - Fold on CN ; Cys784 could contribute to binding affinity through more tightly ) than bicaluatmide in cellular transcription nucleophilic attack on — CN ; Crystal structures of wildtype assays . AR bound to DHT ( light gray sticks ) and AR mutant W741L bound to CDX ( dark gray sticks ) .

FIG . 2 . Proposed Mechanism of Action . Current mecha - 20 - nism of action : based on crystal structure of CDX bound to mutant AR ( W741L ) , Arg752 forms polar interaction with CN group ; proposed mechanism of action : CDX sits deeper F3C in the pocket , CN group forms reversible covalent bond with Cys784 . Addition of nitrogen in the A - ring increases the 25 Biculatamide electrophilicity of the CN group .

FIG . 3 . Androgen receptor activity in the presence of different compounds .

FIG . 4 . IC50 of compounds with ligand binding domain of androgen receptor .

FIG . 5 . IC50 of compounds with full length androgen HO CH3 0 0 receptor .

FIG . 6 . IC50 of select compounds with ligand binding domain of androgen receptor . In embodiment , the compounds provided here bind tight

FIG . 7 . IC50 of select compounds with full length andro - 35 and dro - 35 and with a slow off - rate and thereby outcompete binding of gen receptor . natural steroids to the androgen receptor . In embodiments ,

FIG . 8A - 8D . AR ligand binding domain ( LBD ) data . tighter binding and / or slower off - rates can be achieved by FIG . 9 . AR ligand binding domain ( LBD ) data compari - capitalizing on the reactivity of a resident amino acid

son to known compounds ( 4 . 037 = N - CDX ) . ( Cys784 ) in the AR receptor HBP with reactive electrophiles . FIG . 10A - D . AR full length data ( 4 . 037 = N - CDX ) . 40 In embodiments , this cysteine residue permits tighter bind FIG . 11 . AR full length data comparison to known com - ing to receptor antagonists containing reactive electrophiles ,

pounds ( 4 . 037 = N - CDX ) . such as aryl - cyano groups . FIG . 12 . AR activity in LNCap transformed with MMTV In embodiments , provided herein is a recognition and

data ( 4 . 037 = N - CDX ) . improvement of a chemical reaction occurring within the FIG . 13 . AR activity in LNCap transformed with MMTV 45 hormone - binding pocket , involving the formation of a cova

data comparison to known compounds ( 4 . 037 = N - CDX ) . lent bond between electrophilic moiety ( e . g , aryl - cyano ) FIG . 14 . Covalent bond forming compounds with AR containing inhibitors and a cysteine residue in the receptor

ligand binding domain ( LBD ) data ( 4 . 037 = N - CDX ) . hormone binding pocket . In embodiments , nucleophilic FIG . 15 . Covalent bond forming compounds with AR full attack of a thiol ( Cys784 ) on an electrophilic group ( e . g . ,

length data ( 4 . 037 = N - CDX ) . 50 aryl - cyano ) on the antagonist permits the design of tighter FIG . 16 . Transfection of Gal - AR LBD C784 mutants . binding and specific compounds that more effectively dis FIG . 17 . Western blot of Gal - AR LBD WT and C784 courage the binding of natural steroids .

mutants . Described herein are the recognition and improvement of FIG . 18 . Western blot of AR full length and compounds . a chemical reaction occurring within the hormone - binding

55 pocket , involving the formation of a covalent bond between DETAILED DESCRIPTION electrophilic moiety ( e . g , aryl - cyano ) containing inhibitors

and a cysteine residue in the receptor hormone binding The mainstay of current prostate cancer therapies are pocket . Specifically , nucleophilic attack of a thiol ( Cys784 )

drugs that directly inhibit androgen receptor ( AR ) function on an electrophilic group ( e . g . , aryl - cyano ) on the antagonist by competitively inhibiting the binding of hormones ( TES , 60 permits the design of tighter binding and specific com DHT ) to the receptor ( e . g . Casodex , Flutamide , MDV3100 , pounds that more effectively discourage the binding of ARN - 509 ) . However , tumor cells become resistant to many natural steroids . antiandrogens within a few years of treatment and the progression of prostate cancer subsequently resumes . We A . DEFINITIONS hypothesize that the limited efficacy of some current anti - 65 androgens is due in part to the fact that they bind AR with The abbreviations used herein have their conventional affinities weaker than or , at best , comparable to native meaning within the chemical and biological arts . The chemi

US 10 , 053 , 433 B2

cal structures and formulae set forth herein are constructed heteroatoms ( e . g . , O , N , S , Si , or P ) . A heteroalkyl moiety according to the standard rules of chemical valency known may include up to 8 optionally different heteroatoms ( e . g . , in the chemical arts . O , N , S , Si , or P ) . Where substituent groups are specified by their conven - Similarly , the term " heteroalkylene , ” by itself or as part of

tional chemical formulae , written from left to right , they 5 another substituent , means , unless otherwise stated , a diva equally encompass the chemically identical substituents that lent radical derived from heteroalkyl , as exemplified , but not would result from writing the structure from right to left , limited by , - CH2CH2S _ CH2CH2 – and CH – e . g . , CH20 is equivalent to OCH _ — . S CH2CH2 - NH CH2 — . For heteroalkylene groups ,

The term “ alkyl , ” by itself or as part of another substitu heteroatoms can also occupy either or both of the chain ent , means , unless otherwise stated , a straight ( i . e . , " termini ( e . g . , alkyleneoxy , alkylenedioxy , alkyleneamino , unbranched ) or branched non - cyclic carbon chain ( or car - alkylenediamino , and the like ) . Still further , for alkylene and bon ) , or combination thereof , which may be fully saturated , heteroalkylene linking groups , no orientation of the linking mono - or polyunsaturated and can include di - and multiva - group is implied by the direction in which the formula of the lent radicals , having the number of carbon atoms designated 15 linking group is written . For example , the formula - C ( O ) ( i . e . , C , - C10 means one to ten carbons ) . Examples of satu 2R ' — represents both C ( O ) 2R - and — WC ( 0 ) 2 — . As rated hydrocarbon radicals include , but are not limited to , described above , heteroalkyl groups , as used herein , include groups such as methyl , ethyl , n - propyl , isopropyl , n - butyl , those groups that are attached to the remainder of the t - butyl , isobutyl , sec - butyl , ( cyclohexyl ) methyl , homologs molecule through a heteroatom , such as C ( O ) R ' , C ( O ) and isomers of , for example , n - pentyl , n - hexyl , n - heptyl , 20 NR ' , - NR ' R " , - OR ' , SW , and / or — SO R ' . Where " het n - octyl , and the like . An unsaturated alkyl group is one eroalkyl ” is recited , followed by recitations of specific having one or more double bonds or triple bonds . Examples heteroalkyl groups , such as — NR ' R " or the like , it will be of unsaturated alkyl groups include , but are not limited to , understood that the terms heteroalkyl and — NR ' R " are not vinyl , 2 - propenyl , crotyl , 2 - isopentenyl , 2 - ( butadienyl ) , 2 , 4 - redundant or mutually exclusive . Rather , the specific het pentadienyl , 3 - ( 1 , 4 - pentadienyl ) , ethynyl , 1 - and 3 - propy - 25 eroalkyl groups are recited to add clarity . Thus , the term nyl , 3 - butynyl , and the higher homologs and isomers . An " heteroalkyl ” should not be interpreted herein as excluding alkoxy is an alkyl attached to the remainder of the molecule specific heteroalkyl groups , such as — NR ' R " or the like . via an oxygen linker ( 0 - ) . An alkyl moiety may be an The terms “ cycloalkyl ” and “ heterocycloalkyl , ” by them alkenyl moiety . An alkyl moiety may be an alkynyl moiety . selves or in combination with other terms , mean , unless An alkyl moiety may be fully saturated . 30 otherwise stated , non - aromatic cyclic versions of “ alkyl ”

The term “ alkylene , ” by itself or as part of another and “ heteroalkyl , ” respectively , wherein the carbons making substituent , means , unless otherwise stated , a divalent radi - up the ring or rings do not necessarily need to be bonded to cal derived from an alkyl , as exemplified , but not limited by , a hydrogen due to all carbon valencies participating in bonds - CH2CH2CH2CH2 – Typically , an alkyl ( or alkylene ) with non - hydrogen atoms . Additionally , for heterocy group will have from 1 to 24 carbon atoms , with those 35 cloalkyl , a heteroatom can occupy the position at which the groups having 10 or fewer carbon atoms being preferred in heterocycle is attached to the remainder of the molecule . the present invention . A " lower alkyl ” or “ lower alkylene ” is Examples of cycloalkyl include , but are not limited to , a shorter chain alkyl or alkylene group , generally having cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , 1 - cyclo eight or fewer carbon atoms . The term “ alkenylene , ” by hexenyl , 3 - cyclohexenyl , cycloheptyl , 3 - hydroxy - cyclobut itself or as part of another substituent , means , unless other - 40 3 - enyl - 1 , 2 , dione , 1H - 1 , 2 , 4 - triazolyl - 5 ( 4H ) - one , 4H - 1 , 2 , 4 wise stated , a divalent radical derived from an alkene . triazolyl , and the like . Examples of heterocycloalkyl

The term “ heteroalkyl , ” by itself or in combination with include , but are not limited to , 1 - ( 1 , 2 , 5 , 6 - tetrahydropyridyl ) , another term , means , unless otherwise stated , a stable 1 - piperidinyl , 2 - piperidinyl , 3 - piperidinyl , 4 - morpholinyl , straight or branched non - cyclic chain , or combinations 3 - morpholinyl , tetrahydrofuran - 2 - yl , tetrahydrofuran - 3 - yl , thereof , including at least one carbon atom and at least one 45 tetrahydrothien - 2 - yl , tetrahydrothien - 3 - yl , 1 - piperazinyl , heteroatom selected from the group consisting of O , N , P , Si , 2 - piperazinyl , and the like . A " cycloalkylene ” and a “ het and S , and wherein the nitrogen and sulfur atoms may erocycloalkylene , " alone or as part of another substituent , optionally be oxidized , and the nitrogen heteroatom may means a divalent radical derived from a cycloalkyl and optionally be quaternized . The heteroatom ( s ) O , N , P , S , and heterocycloalkyl , respectively . A heterocycloalkyl moiety Si may be placed at any interior position of the heteroalkyl 50 may include one ring heteroatom ( e . g . , O , N , S , Si , or P ) . A group or at the position at which the alkyl group is attached heterocycloalkyl moiety may include two optionally differ to the remainder of the molecule . Examples include , but are ent ring heteroatoms ( e . g . , O , N , S , Si , or P ) . A heterocy not limited to : - CH2 - CH2 - O - CH3 , - CH2 CH2 cloalkyl moiety may include three optionally different ring NH – CH , ?CH , CH?N ( CH ) CH , CH , S?A heteroatoms ( e . g . , O , N , S , Si , or P ) . A heterocycloalkyl CH2 CH3 , CH2 CH2 , - S ( O ) CH3 , CH2CH2 — 55 moiety may include four optionally different ring heteroa S ( O ) 2 - CH3 - CH = CH – O CH3 , Si ( CH3 ) 3 , toms ( e . g . , O , N , S , Si , or P ) . A heterocycloalkyl moiety may - CH2 - CH = N / OCH3 , - CH = CH - N ( CH3 ) CH3 , include five optionally different ring heteroatoms ( e . g . , O , N , - O CH3 , O CH2 CH3 , and CN . Up to two or S , Si , or P ) . A heterocycloalkyl moiety may include up to 8 three heteroatoms may be consecutive , such as , for example , optionally different ring heteroatoms ( e . g . , O , N , S , Si , or P ) . - CH2 - NH OCHZ and CH20 Si ( CH3 ) 3 . A het - 60 The terms “ halo ” or “ halogen , ” by themselves or as part eroalkyl moiety may include one heteroatom ( e . g . , O , N , S , of another substituent , mean , unless otherwise stated , a Si , or P ) . A heteroalkyl moiety may include two optionally fluorine , chlorine , bromine , or iodine atom . Additionally , different heteroatoms ( e . g . , O , N , S , Si , or P ) . A heteroalkyl terms such as “ haloalkyl ” are meant to include monoha moiety may include three optionally different heteroatoms loalkyl and polyhaloalkyl . For example , the term “ halo ( C , ( e . g . , O , N , S , Si , or P ) . A heteroalkyl moiety may include 65 C4 ) alkyl ” includes , but is not limited to , fluoromethyl , four optionally different heteroatoms ( e . g . , O , N , S , Si , or P ) . difluoromethyl , trifluoromethyl , 2 , 2 , 2 - trifluoroethyl , 4 - chlo A heteroalkyl moiety may include five optionally different robutyl , 3 - bromopropyl , and the like .

US 10 , 053 , 433 B2

The term “ acyl ” means , unless otherwise stated , - C ( O ) R optionally different ring heteroatoms ( e . g . , O , N , or S ) . An where R is a substituted or unsubstituted alkyl , substituted or aryl moiety may have a single ring . An aryl moiety may have unsubstituted cycloalkyl , substituted or unsubstituted het two optionally different rings . An aryl moiety may have eroalkyl , substituted or unsubstituted heterocycloalkyl , sub - three optionally different rings . An aryl moiety may have stituted or unsubstituted aryl , or substituted or unsubstituted 5 four optionally different rings . A heteroaryl moiety may have heteroaryl . one ring . A heteroaryl moiety may have two optionally

The term “ aryl ” means , unless otherwise stated , a poly different rings . A heteroaryl moiety may have three option unsaturated , aromatic , hydrocarbon substituent , which can ally different rings . A heteroaryl moiety may have four be a single ring or multiple rings ( preferably from 1 to 3 optionally different rings . A heteroaryl moiety may have five rings ) that are fused together ( i . e . , a fused ring aryl ) or linked 10 optionally different rings . covalently . A fused ring aryl refers to multiple rings fused A fused ring heterocyloalkyl - aryl is an aryl fused to a together wherein at least one of the fused rings is an aryl ring . The term " heteroaryl ” refers to aryl groups ( or rings ) heterocycloalkyl . A fused ring heterocycloalkyl - heteroaryl

is a heteroaryl fused to a heterocycloalkyl . A fused ring that contain at least one heteroatom such as N , O , or S , wherein the nitrogen and sulfur atoms are optionally oxi - 15 heterocycloalkyl - cycloalkyl is a heterocycloalkyl fused to a dized , and the nitrogen atom ( s ) are optionally quaternized . cycloalkyl . A fused ring heterocycloalkyl - heterocycloalkyl Thus , the term " heteroaryl ” includes fused ring heteroaryl is a heterocycloalkyl fused to another heterocycloalkyl . groups ( i . e . , multiple rings fused together wherein at least Fused ring heterocycloalkyl - aryl , fused ring heterocy one of the fused rings is a heteroaromatic ring ) . A 5 , 6 - Fused cloalkyl - heteroaryl , fused ring heterocycloalkyl - cycloalkyl , ring heteroarylene refers to two rings fused together , 20 or fused ring heterocycloalkyl - heterocycloalkyl may each wherein one ring has 5 members and the other ring has 6 independently be unsubstituted or substituted with one or members , and wherein at least one ring is a heteroaryl ring more of the substitutents described herein . Likewise , a 6 , 6 - fused ring heteroarylene refers to two rings The term " oxo , " as used herein , means an oxygen that is fused together , wherein one ring has 6 members and the double bonded to a carbon atom . other ring has 6 members , and wherein at least one ring is 25 The term “ alkylsulfonyl , " as used herein , means a moiety a heteroaryl ring . And a 6 , 5 - Fused ring heteroarylene refers having the formula S ( 02 ) R ' , where R ' is a substituted or to two rings fused together , wherein one ring has 6 members unsubstituted alkyl group as defined above . R ' may have a and the other ring has 5 members , and wherein at least one specified number of carbons ( e . g . , “ C , - C4 alkylsulfonyl ” ) . ring is a heteroaryl ring . A heteroaryl group can be attached Each of the above terms ( e . g . , " alkyl , " " heteroalkyl , ” , to the remainder of the molecule through a carbon or 30 " cycloalkyl ” , “ heterocycloalkyl ” , “ aryl , " and " heteroaryl ” ) heteroatom . Non - limiting examples of aryl and heteroaryl includes both substituted and unsubstituted forms of the groups include phenyl , 1 - naphthyl , 2 - naphthyl , 4 - biphenyl , indicated radical . Preferred substituents for each type of 1 - pyrrolyl , 2 - pyrroly1 , 3 - pyrrolyl , 3 - pyrazolyl , 2 - imidazolyl , radical are provided below . 4 - imidazolyl , pyrazinyl , 2 - oxazolyl , 4 - oxazolyl , 2 - phenyl Substituents for the alkyl and heteroalkyl radicals ( includ 4 - oxazolyl , 5 - oxazolyl , 3 - isoxazolyl , 4 - isoxazolyl , 5 - isox - 35 ing those groups often referred to as alkylene , alkenyl , azolyl , 2 - thiazolyl , 4 - thiazolyl , 5 - thiazolyl , 2 - Fury1 , 3 - Furyl , heteroalkylene , heteroalkenyl , alkynyl , cycloalkyl , hetero 2 - thienyl , 3 - thienyl , 2 - pyridyl , 3 - pyridyl , 4 - pyridyl , 2 - py cycloalkyl , cycloalkenyl , and heterocycloalkenyl ) can be rimidyl , 4 - pyrimidyl , 5 - benzothiazolyl , purinyl , 2 - benzimi one or more of a variety of groups selected from , but not dazolyl , 5 - indolyl , 1 - isoquinolyl , 5 - isoquinolyl , 2 - quinox limited to , - OR ' , = 0 , = NR ' , alinyl , 5 - quinoxalinyl , 3 - quinolyl , and 6 - quinolyl . 40 = N / OR ' , - NR ' R " , SR ' , - halogen , SiR ' R " R " " , OC Substituents for each of the above noted aryl and heteroaryl ( O ) R ' , - C ( O ) R ' , CO2R ' , CONR ' R " , OC ( O ) NR ' R " , ring systems are selected from the group of acceptable - NR " C ( O ) R ' , - NR - C ( O ) NR " R " " , NR " C ( O ) , R ' , substituents described below . An “ arylene ” and a “ het - NR - C ( NR ' R " R " ) = NR " " , - NR - C ( NR ' R " ) = NR " , eroarylene , ” alone or as part of another substituent , mean a - S ( O ) R ' , - S ( O ) R ' , - S ( O ) 2NR ' R " , NRSO , R ' , divalent radical derived from an aryl and heteroaryl , respec - 45 NR ' NR " R " " , ONR ' R " , NRC = ( O ) NR " NR " " R " , — CN , tively . Non - limiting examples of aryl and heteroaryl groups — NO , , in a number ranging from zero to ( 2m ' + 1 ) , where m ' include pyridinyl , pyrimidinyl , thiophenyl , thienyl , furanyl , is the total number of carbon atoms in such radical . R , R ' , R " , indolyl , benzoxadiazolyl , benzodioxolyl , benzodioxanyl , R ' ' , and R " each preferably independently refer to hydrogen , thianaphthanyl , pyrrolopyridinyl , indazolyl , quinolinyl , qui substituted or unsubstituted heteroalkyl , substituted or noxalinyl , pyridopyrazinyl , quinazolinonyl , benzoisox - 50 unsubstituted cycloalkyl , substituted or unsubstituted het azolyl , imidazopyridinyl , benzofuranyl , benzothienyl , ben - erocycloalkyl , substituted or unsubstituted aryl ( e . g . , aryl zothiophenyl , phenyl , naphthyl , biphenyl , pyrrolyl , substituted with 1 - 3 halogens ) , substituted or unsubstituted pyrazolyl , imidazolyl , pyrazinyl , oxazolyl , isoxazolyl , thi - heteroaryl , substituted or unsubstituted alkyl , alkoxy , or azolyl , furylthienyl , pyridyl , pyrimidyl , benzothiazolyl , thioalkoxy groups , or arylalkyl groups . When a compound purinyl , benzimidazolyl , isoquinolyl , thiadiazolyl , oxadiaz - 55 of the invention includes more than one R group , for olyl , pyrrolyl , diazolyl , triazolyl , tetrazolyl , benzothiadiaz example , each of the R groups is independently selected as olyl , isothiazolyl , pyrazolopyrimidinyl , pyrrolopyrimidinyl , are each R ' , R " , R ' " , and R " group when more than one of benzotriazolyl , benzoxazolyl , or quinolyl . The examples these groups is present . When R ' and R " are attached to the above may be substituted or unsubstituted and divalent same nitrogen atom , they can be combined with the nitrogen radicals of each heteroaryl example above are non - limiting 60 atom to form a 4 - , 5 - , 6 - , or 7 - membered ring . For example , examples of heteroarylene . A heteroaryl moiety may include - NR ' R " includes , but is not limited to , 1 - pyrrolidinyl and one ring heteroatom ( e . g . , O , N , or S ) . A heteroaryl moiety 4 - morpholinyl . From the above discussion of substituents , may include two optionally different ring heteroatoms ( e . g . , one of skill in the art will understand that the term “ alkyl ” O , N , or S ) . A heteroaryl moiety may include three option is meant to include groups including carbon atoms bound to ally different ring heteroatoms ( e . g . , O , N , or S ) . A heteroaryl 65 groups other than hydrogen groups , such as haloalkyl ( e . g . , moiety may include four optionally different ring heteroa - CF3 and - CH2CF3 ) and acyl ( e . g . , - C ( O ) CH3 , - C ( O ) toms ( e . g . , O , N , or S ) . A heteroaryl moiety may include five CF3 , - C ( O ) CH OCH3 , and the like ) .

US 10 , 053 , 433 B2 10

Similar to the substituents described for the alkyl radical , SO3H , SO H , SO NH , NHNH2 , ONH2 , substituents for the aryl and heteroaryl groups are varied and _ NHC = ( O ) NHNH , ?NHC = ( 0 ) NHÀ , are selected from , for example : _ OR ' , - NR ' R " , — SR ' , NHSO , H , _ NHC = ( O ) H , NHC ( O ) OH , - halogen , — SiR ' R " R " " , - OC ( O ) R ' , - C ( O ) R ' , — CO , R ' , — NHOH , OCF3 , OCHF2 , unsubstituted alkyl , - CONR ' R " , OC ( O ) NR ' R " , — NR " C ( O ) R ' , — NR - C 5 unsubstituted heteroalkyl , unsubstituted cycloalkyl , ( O ) NR " R ' " , — NR " C ( O ) R ' , — NR — C ( NR ' R " R " ) = NR " " , unsubstituted heterocycloalkyl , unsubstituted aryl , - NR - C ( NR ' R " ) NR ' " , S ( O ) R ' , - S ( O ) , R ' , unsubstituted heteroaryl , and - S ( O ) NR ' R " , — NRSO , R ' , NR ' NR " R " " , - ONR ' R " , ( B ) alkyl , heteroalkyl , cycloalkyl , heterocycloalkyl , aryl , NR ' C = ( O ) NR " NR ' ' R " , CN , - NO2 , - R ' , - N3 , CH heteroaryl , substituted with at least one substituent ( Ph ) 2 , fluoro ( CZ - C4 ) alkoxy , and fluoro ( C - C4 ) alkyl , in a 10 selected from : number ranging from zero to the total number of open ( i ) oxo , halogen , CF3 , CN , OH , NH2 , valences on the aromatic ring system ; and where R ' , R " , R ' ' , COOH , CONH2 , NO2 , SH , SO , C1 , and R " are preferably independently selected from hydro - SO3H , SOAH , SO2NH2 , NHNH2 , gen , substituted or unsubstituted alkyl , substituted or unsub JONH , NHC = ( O ) NHNH , NHC = ( O ) stituted heteroalkyl , substituted or unsubstituted cycloalkyl , 15 NHÀ , NHSOH , NHC = ( O ) H , NHC ( O ) substituted or unsubstituted heterocycloalkyl , substituted or OH , — NHOH , OCF3 , OCHF2 , unsubstituted unsubstituted aryl , and substituted or unsubstituted het alkyl , unsubstituted heteroalkyl , unsubstituted eroaryl . When a compound of the invention includes more cycloalkyl , unsubstituted heterocycloalkyl , unsubsti than one R group , for example , each of the R groups is tuted aryl , unsubstituted heteroaryl , and independently selected as are each R ' , R " , R ' " , and R " " 20 ( ii ) alkyl , heteroalkyl , cycloalkyl , heterocycloalkyl , groups when more than one of these groups is present . aryl , heteroaryl , substituted with at least one sub

Two or more substituents may optionally be joined to stituent selected from : form aryl , heteroaryl , cycloalkyl , or heterocycloalkyl ( a ) oxo , halogen , CF3 , CN , OH , NH , groups . Such so - called ring - forming substituents are typi COOH , CONH2 , — NO2 , — SH , SO , C1 , cally , though not necessarily , found attached to a cyclic base 25 SO3H , SO4H , SO2NH2 , NHNH2 , structure . In one embodiment , the ring - forming substituents ONH , _ NHC = ( O ) NHNH , _ NHC = ( 0 ) are attached to adjacent members of the base structure . For NH , NHSO , H , NHC = ( O ) H , — NHC ( O ) example , two ring - forming substituents attached to adjacent OH , — NHOH , OCF3 , OCHF2 , unsubstituted members of a cyclic base structure create a fused ring alkyl , unsubstituted heteroalkyl , unsubstituted structure . In another embodiment , the ring - forming substitu - 30 cycloalkyl , unsubstituted heterocycloalkyl , unsub ents are attached to a single member of the base structure . stituted aryl , unsubstituted heteroaryl , and For example , two ring - forming substituents attached to a ( b ) alkyl , heteroalkyl , cycloalkyl , heterocycloalkyl , single member of a cyclic base structure create a spirocyclic aryl , heteroaryl , substituted with at least one sub structure . In yet another embodiment , the ring - forming stituent selected from : oxo , substituents are attached to non - adjacent members of the 35 halogen , CF3 , CN , OH , - NH2 , COOH , base structure . CONH2 , - NO2 , SH , SO , C1 , S03H ,

Two of the substituents on adjacent atoms of the aryl or SOAH , SO2NH2 , — NHNH2 , ONH2 , heteroaryl ring may optionally form a ring of the formula - NHC = ( O ) NHNH , NHC = ( O ) NHA , - T - C ( O ) - ( CRR ' ) , U — , wherein T and U are indepen _ NHSO , H , ?NHC = ( O ) H , _ NHC ( O ) OH , dently — NR — , - 04 , - CRR - , or a single bond , and q 40 - NHOH , OCF3 , OCHF2 , unsubstituted is an integer of from 0 to 3 . Alternatively , two of the alkyl , unsubstituted heteroalkyl , unsubstituted substituents on adjacent atoms of the aryl or heteroaryl ring cycloalkyl , unsubstituted heterocycloalkyl , unsub may optionally be replaced with a substituent of the formula stituted aryl , unsubstituted heteroaryl . - A - ( CH2 ) , — B — , wherein A and B are independently " size - limited substituent ” or “ size - limited substituent — CRR - , - 06 , NR — , S , - S ( O ) - , - S ( O ) , — 45 group , " as used herein , means a group selected from all of - S ( O ) NR - , or a single bond , and ris an integer of from the substituents described above for a “ substituent group , " 1 to 4 . One of the single bonds of the new ring so formed wherein each substituted or unsubstituted alkyl is a substi may optionally be replaced with a double bond . Alterna tuted or unsubstituted C1 - C20 alkyl , each substituted or tively , two of the substituents on adjacent atoms of the aryl unsubstituted heteroalkyl is a substituted or unsubstituted 2 or heteroaryl ring may optionally be replaced with a sub - 50 to 20 membered heteroalkyl , each substituted or unsubsti stituent of the formula ( CRR ' ) . — X — ( C " R " R " ) tuted cycloalkyl is a substituted or unsubstituted Cz - C , where s and d are independently integers of from 0 to 3 , and cycloalkyl , each substituted or unsubstituted heterocy X ' is - O - , - NR - , - S - , - S ( O ) - , - S ( O ) 2 - , or cloalkyl is a substituted or unsubstituted 3 to 8 membered - S ( O ) , NR — The substituents R , R ' , R " , and R ' ' are heterocycloalkyl , each substituted or unsubstituted aryl is a preferably independently selected from hydrogen , substi - 55 substituted or unsubstituted C . - C1o aryl , and each substi tuted or unsubstituted alkyl , substituted or unsubstituted tuted or unsubstituted heteroaryl is a substituted or unsub heteroalkyl , substituted or unsubstituted cycloalkyl , substi stituted 5 to 10 membered heteroaryl . tuted or unsubstituted heterocycloalkyl , substituted or A “ lower substituent ” or “ lower substituent group , ” as unsubstituted aryl , and substituted or unsubstituted het - used herein , means a group selected from all of the sub eroaryl . 60 stituents described above for a “ substituent group , " wherein As used herein , the terms " heteroatom ” or “ ring heteroa - each substituted or unsubstituted alkyl is a substituted or

tom ” are meant to include , oxygen ( O ) , nitrogen ( N ) , sulfur unsubstituted C , - Cg alkyl , each substituted or unsubstituted ( S ) , phosphorus ( P ) , and silicon ( Si ) . heteroalkyl is a substituted or unsubstituted 2 to 8 membered

A “ substituent group , " as used herein , means a group heteroalkyl , each substituted or unsubstituted cycloalkyl is a selected from the following moieties : 65 substituted or unsubstituted Cz - C , cycloalkyl , each substi

( A ) oxo , halogen , — CF3 , CN , OH , NH , , tuted or unsubstituted heterocycloalkyl is a substituted or COOH , CONH2 , — NO2 , SH , S02C1 , unsubstituted 3 to 7 membered heterocycloalkyl , each sub

US 10 , 053 , 433 B2 12

stituted or unsubstituted aryl is a substituted or unsubstituted relatively nontoxic acids or bases , depending on the particu Co - C aryl , and each substituted or unsubstituted heteroaryl lar substituents found on the compounds described herein . is a substituted or unsubstituted 5 to 9 membered heteroaryl . When compounds of the present invention contain relatively

In some embodiments , each substituted group described acidic functionalities , base addition salts can be obtained by in the compounds herein is substituted with at least one 5 contacting the neutral form of such compounds with a substituent group . More specifically , in some embodiments , sufficient amount of the desired base , either neat or in a each substituted alkyl , substituted heteroalkyl , substituted suitable inert solvent . Examples of pharmaceutically accept cycloalkyl , substituted heterocycloalkyl , substituted aryl , able base addition salts include sodium , potassium , calcium , substituted heteroaryl , substituted alkylene , substituted het - ammonium , organic amino , or magnesium salt , or a similar eroalkylene , substituted cycloalkylene , substituted hetero - 10 salt . When compounds of the present invention contain cycloalkylene , substituted arylene , and / or substituted het - relatively basic functionalities , acid addition salts can be eroarylene described in the compounds herein are obtained by contacting the neutral form of such compounds substituted with at least one substituent group . In other with a sufficient amount of the desired acid , either neat or in embodiments , at least one or all of these groups are substi - a suitable inert solvent . Examples of pharmaceutically tuted with at least one size - limited substituent group . In 15 acceptable acid addition salts include those derived from other embodiments , at least one or all of these groups are inorganic acids like hydrochloric , hydrobromic , nitric , car substituted with at least one lower substituent group . bonic , monohydrogencarbonic , phosphoric , monohydrogen

In other embodiments of the compounds herein , each phosphoric , dihydrogenphosphoric , sulfuric , monohydro substituted or unsubstituted alkyl may be a substituted or gensulfuric , hydriodic , or phosphorous acids and the like , as unsubstituted C , - C20 alkyl , each substituted or unsubstituted 20 well as the salts derived from relatively nontoxic organic heteroalkyl is a substituted or unsubstituted 2 to 20 mem - acids like acetic , propionic , isobutyric , maleic , malonic , bered heteroalkyl , each substituted or unsubstituted benzoic , succinic , suberic , fumaric , lactic , mandelic , cycloalkyl is a substituted or unsubstituted C3 - C , cycloalkyl , phthalic , benzenesulfonic , p - tolylsulfonic , citric , tartaric , each substituted or unsubstituted heterocycloalkyl is a sub - methanesulfonic , and the like . Also included are salts of stituted or unsubstituted 3 to 8 membered heterocycloalkyl , 25 amino acids such as arginate and the like , and salts of each substituted or unsubstituted aryl is a substituted or organic acids like glucuronic or galactunoric acids and the unsubstituted C . - C , aryl , and / or each substituted or unsub - like ( see , e . g . , Berge et al . , Journal of Pharmaceutical stituted heteroaryl is a substituted or unsubstituted 5 to 10 Science 66 : 1 - 19 ( 1977 ) ) . Certain specific compounds of the membered heteroaryl . In some embodiments of the com - present invention contain both basic and acidic functional pounds herein , each substituted or unsubstituted alkylene is 30 ities that allow the compounds to be converted into either a substituted or unsubstituted C , - C20 alkylene , each substi - base or acid addition salts . Other pharmaceutically accept tuted or unsubstituted heteroalkylene is a substituted or able carriers known to those of skill in the art are suitable for unsubstituted 2 to 20 membered heteroalkylene , each sub - the present invention . Salts tend to be more soluble in stituted or unsubstituted cycloalkylene is a substituted or aqueous or other protonic solvents than are the correspond unsubstituted Cz - Ce cycloalkylene , each substituted or 35 ing free base forms . In other cases , the preparation may be unsubstituted heterocycloalkylene is a substituted or unsub - a lyophilized powder in 1 mM - 50 mM histidine , 0 . 1 % - 2 % stituted 3 to 8 membered heterocycloalkylene , each substi - sucrose , 2 % - 7 % mannitol at a pH range of 4 . 5 to 5 . 5 , that is tuted or unsubstituted arylene is a substituted or unsubsti - combined with buffer prior to use . tuted Co - C12 arylene , and / or each substituted or Thus , the compounds of the present invention may exist unsubstituted heteroarylene is a substituted or unsubstituted 40 as salts , such as with pharmaceutically acceptable acids . The 5 to 10 membered heteroarylene . present invention includes such salts . Examples of such salts

In some embodiments , each substituted or unsubstituted include hydrochlorides , hydrobromides , sulfates , methane alkyl is a substituted or unsubstituted C , - C , alkyl , each sulfonates , nitrates , maleates , acetates , citrates , fumarates , substituted or unsubstituted heteroalkyl is a substituted or tartrates ( e . g . , ( + ) - tartrates , ( - ) - tartrates , or mixtures thereof unsubstituted 2 to 8 membered heteroalkyl , each substituted 45 including racemic mixtures ) , succinates , benzoates , and salts or unsubstituted cycloalkyl is a substituted or unsubstituted with amino acids such as glutamic acid . These salts may be CZ - C , cycloalkyl , each substituted or unsubstituted hetero - prepared by methods known to those skilled in the art . cycloalkyl is a substituted or unsubstituted 3 to 7 membered The neutral forms of the compounds are preferably regen heterocycloalkyl , each substituted or unsubstituted aryl is a erated by contacting the salt with a base or acid and isolating substituted or unsubstituted Co - C1o aryl , and / or each substi - 50 the parent compound in the conventional manner . The parent tuted or unsubstituted heteroaryl is a substituted or unsub form of the compound differs from the various salt forms in stituted 5 to 9 membered heteroaryl . In some embodiments , certain physical properties , such as solubility in polar sol each substituted or unsubstituted alkylene is a substituted or vents . unsubstituted C , - C , alkylene , each substituted or unsubsti - Provided herein are agents ( e . g . compounds , drugs , thera tuted heteroalkylene is a substituted or unsubstituted 2 to 8 55 peutic agents ) that may be in a prodrug form . Prodrugs of the membered heteroalkylene , each substituted or unsubstituted compounds described herein are those compounds that read cycloalkylene is a substituted or unsubstituted Cz - C , ily undergo chemical changes under select physiological cycloalkylene , each substituted or unsubstituted heterocy conditions to provide the final agents ( e . g . compounds , cloalkylene is a substituted or unsubstituted 3 to 7 mem drugs , therapeutic agents ) . Additionally , prodrugs can be bered heterocycloalkylene , each substituted or unsubstituted 60 converted to agents ( e . g . compounds , drugs , therapeutic arylene is a substituted or unsubstituted Co - C , arylene , agents ) by chemical or biochemical methods in an ex vivo and / or each substituted or unsubstituted heteroarylene is a environment . Prodrugs described herein include compounds substituted or unsubstituted 5 to 9 membered heteroarylene . that readily undergo chemical changes under select physi In some embodiments , the compound is a chemical species ological conditions to provide agents ( e . g . compounds , set forth in the Examples section , figures , or tables below . 65 drugs , therapeutic agents ) to a biological system ( e . g . in a

The term “ pharmaceutically acceptable salts ” is meant to subject , in a cancer cell , in the extracellular space near a include salts of the active compounds that are prepared with cancer cell ) .

13 US 10 , 053 , 433 B2

14 Certain compounds of the present invention can exist in The symbol “ w ” denotes the point of attachment of a

unsolvated forms as well as solvated forms , including chemical moiety to the remainder of a molecule or chemical hydrated forms . In general , the solvated forms are equivalent formula . to unsolvated forms and are encompassed within the scope The terms “ a ” or “ an , " as used in herein means one or of the present invention . Certain compounds of the present 5 more . In addition , the phrase “ substituted with a [ n ] , ” as used invention may exist in multiple crystalline or amorphous herein , means the specified group may be substituted with forms . In general , all physical forms are equivalent for the one or more of any or all of the named substituents . For uses contemplated by the present invention and are intended example , where a group , such as an alkyl or heteroaryl to be within the scope of the present invention . group , is “ substituted with an unsubstituted C - C20 alkyl , or As used herein , the term " salt ” refers to acid or base salts 10 unsubstituted 2 to 20 membered heteroalkyl , ” the group may

of the compounds used in the methods of the present contain one or more unsubstituted C , - C20 alkyls , and / or one invention . Illustrative examples of acceptable salts are min - or more unsubstituted 2 to 20 membered heteroalkyls . eral acid ( hydrochloric acid , hydrobromic acid , phosphoric Moreover , where a moiety is substituted with an R substitu acid , and the like ) salts , organic acid ( acetic acid , propionic e nt , the group may be referred to as “ R - substituted . ” Where acid , glutamic acid , citric acid and the like ) salts , quaternary 15 a moiety is R - substituted , the moiety is substituted with at ammonium ( methyl iodide , ethyl iodide , and the like ) salts . least one R substituent and each R substituent is optionally

Certain compounds of the present invention possess different . asymmetric carbon atoms ( optical or chiral centers ) or Descriptions of compounds of the present invention are double bonds ; the enantiomers , racemates , diastereomers , limited by principles of chemical bonding known to those tautomers , geometric isomers , stereoisometric forms that 20 skilled in the art . Accordingly , where a group may be may be defined , in terms of absolute stereochemistry , as ( R ) - substituted by one or more of a number of substituents , such or ( S ) - or , as ( D ) - or ( L ) - for amino acids , and individual substitutions are selected so as to comply with principles of isomers are encompassed within the scope of the present chemical bonding and to give compounds which are not invention . The compounds of the present invention do not inherently unstable and / or would be known to one of ordi include those which are known in art to be too unstable to 25 nary skill in the art as likely to be unstable under ambient synthesize and / or isolate . The present invention is meant to conditions , such as aqueous , neutral , and several known include compounds in racemic and optically pure forms . physiological conditions . For example , a heterocycloalkyl or Optically active ( R ) - and ( S ) - , or ( D ) - and ( L ) - isomers may heteroaryl is attached to the remainder of the molecule via be prepared using chiral synthons or chiral reagents , or a ring heteroatom in compliance with principles of chemical resolved using conventional techniques . When the com - 30 bonding known to those skilled in the art thereby avoiding pounds described herein contain olefinic bonds or other inherently unstable compounds . centers of geometric asymmetry , and unless specified oth The terms “ treating ” or “ treatment ” refers to any indicia erwise , it is intended that the compounds include both E and of success in the treatment or amelioration of an injury , Z geometric isomers . disease , pathology or condition , including any objective or As used herein , the term “ isomers ” refers to compounds 35 subjective parameter such as abatement ; remission ; dimin

having the same number and kind of atoms , and hence the ishing of symptoms or making the injury , pathology or same molecular weight , but differing in respect to the condition more tolerable to the patient ; slowing in the rate of structural arrangement or configuration of the atoms . degeneration or decline ; making the final point of degen

The term “ tautomer , " as used herein , refers to one of two eration less debilitating ; improving a patient ' s physical or or more structural isomers which exist in equilibrium and 40 mental well - being . The treatment or amelioration of symp which are readily converted from one isomeric form to toms can be based on objective or subjective parameters ; another . including the results of a physical examination , neuropsy

It will be apparent to one skilled in the art that certain chiatric exams , and / or a psychiatric evaluation . For compounds of this invention may exist in tautomeric forms , example , certain methods herein treat diseases associated all such tautomeric forms of the compounds being within the 45 with androgen receptor activity . Certain methods described scope of the invention . herein may treat diseases associated with androgen receptor

Unless otherwise stated , structures depicted herein are activity ( e . g . , prostate cancer , benign prostatic hyperplasia , also meant to include all stereochemical forms of the struc - hypersexuality , acne , amenorrhea , seborrhea , hirsutism , ture ; i . e . , the R and S configurations for each asymmetric androgenic alopecia , hidradenitis suppurativa , or hyperan center . Therefore , single stereochemical isomers as well as 50 drogenism ) by inhibiting androgen receptor activity . Certain enantiomeric and diastereomeric mixtures of the present methods described herein may treat diseases associated with compounds are within the scope of the invention . androgen receptor activity by inhibiting ligand binding to Unless otherwise stated , structures depicted herein are androgen receptor . For example , certain methods herein treat

also meant to include compounds which differ only in the cancer . For example certain methods herein treat cancer by presence of one or more isotopically enriched atoms . For 55 decreasing a symptom of cancer . Symptoms of cancer would example , compounds having the present structures except be known or may be determined by a person of ordinary skill for the replacement of a hydrogen by a deuterium or tritium , in the art . The term “ treating ” and conjugations thereof , or the replacement of a carbon by 13C - or 14C - enriched include prevention of an injury , pathology , condition , or carbon are within the scope of this invention . disease .

The compounds of the present invention may also contain 60 An " effective amount ” is an amount sufficient to accom unnatural proportions of atomic isotopes at one or more of plish a stated purpose ( e . g . achieve the effect for which it is the atoms that constitute such compounds . For example , the administered , treat a disease , reduce enzyme activity , compounds may be radiolabeled with radioactive isotopes , increase enzyme activity , reduce protein function , reduce such as for example tritium ( H ) , iodine - 125 ( 1251 ) , or one or more symptoms of a disease or condition ) . An carbon - 14 ( 14C ) . All isotopic variations of the compounds of 65 example of an " effective amount ” is an amount sufficient to the present invention , whether radioactive or not , are encom - contribute to the treatment , prevention , or reduction of a passed within the scope of the present invention . symptom or symptoms of a disease , which could also be

15 US 10 , 053 , 433 B2

16 referred to as a " therapeutically effective amount . ” A “ reduc delaying activation , or inactivating , desensitizing , or down tion ” of a symptom or symptoms ( and grammatical equiva - regulating signal transduction or enzymatic activity or the lents of this phrase ) means decreasing of the severity or amount of a protein . frequency of the symptom ( s ) , or elimination of the As defined herein , the term “ activation ” , “ activate ” , “ acti symptom ( s ) . A “ prophylactically effective amount of a drug 5 vating ” and the like in reference to a protein - activator ( e . g . or prodrug is an amount of a drug or prodrug that , when agonist ) interaction means positively affecting ( e . g . increas administered to a subject , will have the intended prophy ing ) the activity or function of the protein relative to the lactic effect , e . g . , preventing or delaying the onset ( or activity or function of the protein in the absence of the reoccurrence ) of an injury , disease , pathology or condition , activator ( e . g . compound described herein ) . Thus , activation or reducing the likelihood of the onset ( or reoccurrence ) of 10 may include , at least in part , partially or totally increasing

stimulation , increasing or enabling activation , or activating , an injury , disease , pathology , or condition , or their symp sensitizing , or up - regulating signal transduction or enzy toms . The full prophylactic effect does not necessarily occur matic activity or the amount of a protein decreased in a by administration of one dose , and may occur only after disease . Activation may include , at least in part , partially or administration of a series of doses . Thus , a prophylactically 15 my 15 totally increasing stimulation , increasing or enabling acti effective amount may be administered in one or more vation , or activating , sensitizing , or up - regulating signal administrations . The exact amounts will depend on the transduction or enzymatic activity or the amount of a purpose of the treatment , and will be ascertainable by one protein . skilled in the art using known techniques ( see , e . g . , Lieber - The term “ modulator ” refers to a composition that man , Pharmaceutical Dosage Forms ( vols . 1 - 3 , 1992 ) ; 20 increases or decreases the level of a target molecule or the Lloyd , The Art , Science and Technology of Pharmaceutical function of a target molecule . In embodiments , a modulator Compounding ( 1999 ) ; Pickar , Dosage Calculations ( 1999 ) ; is an anti - cancer agent . In embodiments , a modulator is an and Remington : The Science and Practice of Pharmacy , androgen receptor antagonist . In embodiments , a modulator 20th Edition , 2003 , Gennaro , Ed . , Lippincott , Williams & is a hormone receptor antagonist . In embodiments , a modu Wilkins ) . 25 lator is an androgen receptor inhibitor . In embodiments , a

The term “ associated ” or “ associated with ” in the context m odulator is an androgen receptor covalent modifier . of a substance or substance activity or function associated “ Anti - cancer agent ” or “ anti - cancer drug " is used in with a disease ( e . g . cancer ) means that the disease is caused accordance with its plain ordinary meaning and refers to a by ( in whole or in part ) , or a symptom of the disease is composition ( e . g . compound , drug , antagonist , inhibitor , caused by ( in whole or in part ) the substance or substance 30 modulator ) having antineoplastic properties or the ability to activity or function . As used herein , what is described as inhibit the growth or proliferation of cells . In some embodi being associated with a disease , if a causative agent , could ments , an anti - cancer agent is a chemotherapeutic . In some be a target for treatment of the disease . For example , a embodiments , an anti - cancer agent is an agent approved by disease associated with androgen receptor activity may be the FDA or similar regulatory agency of a country other than treated with an agent ( e . g . compound as described herein ) 35 the USA , for treating cancer . Examples of anti - cancer agents effective for decreasing the level of androgen receptor include , but are not limited to , anti - androgens ( e . g . , Caso activity . dex , Flutamide , MDV3100 , or ARN - 509 ) , MEK ( e . g .

" Control ” or “ control experiment ” or “ standard control ” is MEK1 , MEK2 , or MEK1 and MEK2 ) inhibitors ( e . g . used in accordance with its plain ordinary meaning and XL518 , CI - 1040 , PD035901 , selumetinib / AZD6244 , refers to an experiment in which the subjects or reagents of 40 GSK1120212 / trametinib , GDC - 0973 , ARRY - 162 , ARRY the experiment are treated as in a parallel experiment except 300 , AZD8330 , PD0325901 , U0126 , PD98059 , TAK - 733 , for omission of a procedure , reagent , or variable of the PD318088 , AS703026 , BAY 869766 ) , alkylating agents experiment . In some instances , the control is used as a ( e . g . , cyclophosphamide , ifosfamide , chlorambucil , busul standard of comparison in evaluating experimental effects . fan , melphalan , mechlorethamine , uramustine , thiotepa ,

“ Contacting " is used in accordance with its plain ordinary 45 nitrosoureas , nitrogen mustards ( e . g . , mechloroethamine , meaning and refers to the process of allowing at least two cyclophosphamide , chlorambucil , meiphalan ) , ethylenimine distinct species ( e . g . chemical compounds including biomol and methylmelamines ( e . g . , hexamethlymelamine , thio ecules , or cells ) to become sufficiently proximal to react , tepa ) , alkyl sulfonates ( e . g . , busulfan ) , nitrosoureas ( e . g . , interact or physically touch . It should be appreciated , how carmustine , lomusitne , semustine , streptozocin ) , triazenes ever , that the resulting reaction product can be produced 50 ( decarbazine ) ) , anti - metabolites ( e . g . , 5 - azathioprine , leuco directly from a reaction between the added reagents or from vorin , capecitabine , fludarabine , gemcitabine , pemetrexed , an intermediate from one or more of the added reagents raltitrexed , folic acid analog ( e . g . , methotrexate ) , pyrimidine which can be produced in the reaction mixture . The term analogs ( e . g . , fluorouracil , floxouridine , Cytarabine ) , purine " contacting ” may include allowing two species to react , analogs ( e . g . , mercaptopurine , thioguanine , pentostatin ) , interact , or physically touch , wherein the two species may be 55 etc . ) , plant alkaloids ( e . g . , vincristine , vinblastine , vinorel a compound as described herein and a protein or enzyme . In bine , vindesine , podophyllotoxin , paclitaxel , docetaxel , some embodiments contacting includes allowing a com - etc . ) , topoisomerase inhibitors ( e . g . , irinotecan , topotecan , pound described herein to interact with a protein or enzyme . amsacrine , etoposide ( VP16 ) , etoposide phosphate , tenipo

As defined herein , the term “ inhibition " , " inhibit ” , “ inhib - side , etc . ) , antitumor antibiotics ( e . g . , doxorubicin , adriamy iting ” and the like in reference to a protein - inhibitor ( e . g . 60 ?in , daunorubicin , epirubicin , actinomycin , bleomycin , antagonist ) interaction means negatively affecting ( e . g . mitomycin , mitoxantrone , plicamycin , etc . ) , platinum - based decreasing ) the level of activity or function of the protein compounds ( e . g . cisplatin , oxaloplatin , carboplatin ) , anthra relative to the level of activity or function of the protein in cenedione ( e . g . , mitoxantrone ) , substituted urea ( e . g . , the absence of the inhibitor . In some embodiments inhibition hydroxyurea ) , methyl hydrazine derivative ( e . g . , procarba refers to reduction of a disease or symptoms of disease . 65 zine ) , adrenocortical suppressant ( e . g . , mitotane , aminoglu Thus , inhibition may include , at least in part , partially or tethimide ) , epipodophyllotoxins ( e . g . , etoposide ) , antibiotics totally blocking stimulation , decreasing , preventing , or ( e . g . , daunorubicin , doxorubicin , bleomycin ) , enzymes ( e . g . ,

17 US 10 , 053 , 433 B2

18 L - asparaginase ) , inhibitors of mitogen - activated protein ARRY334543 , ARRY - 380 , AG - 1478 , dacomitinib / kinase signaling ( e . g . U0126 , PD98059 , PD184352 , PF299804 , OSI - 420 / desmethyl erlotinib , AZD8931 , PD0325901 , ARRY - 142886 , SB239063 , SP600125 , BAY AEE788 , pelitinib / EKB - 569 , CUDC - 101 , W28040 , 43 - 9006 , wortmannin , or LY294002 ) , mTOR inhibitors , WZ4002 , W23146 , AG - 490 , XL647 , PD153035 , BMS antibodies ( e . g . , rituxan ) , 5 - aza - 2 ' - deoxycytidine , doxorubi - 5 599626 ) , sorafenib , imatinib , sunitinib , dasatinib , pyrrolo cin , vincristine , etoposide , gemcitabine , imatinib benzodiazepines ( e . g . tomaymycin ) , carboplatin , CC - 1065 ( Gleevec® ) , geldanamycin , 17 - N - Allylamino - 17 - and CC - 1065 analogs including amino - CBIs , nitrogen mus Demethoxygeldanamycin ( 17 - AAG ) , bortezomib , trastu tards ( such as chlorambucil and melphalan ) , dolastatin and zumab , anastrozole ; angiogenesis inhibitors ; antiandrogen , dolastatin analogs ( including auristatins : eg . monomethyl antiestrogen ; antisense oligonucleotides ; apoptosis gene 10 auristatin E ) , anthracycline antibiotics ( such as doxorubicin , modulators ; apoptosis regulators ; arginine deaminase ; BCR daunorubicin , etc . ) , duocarmycins and duocarmycin ana ABL antagonists ; beta lactam derivatives ; bFGF inhibitor ; logs , enediynes ( such as neocarzinostatin and cali bicalutamide ; camptothecin derivatives ; casein kinase cheamicins ) , leptomycin derivaties , maytansinoids and may inhibitors ( ICOS ) ; clomifene analogues ; cytarabine daclix tansinoid analogs ( e . g . mertansine ) , methotrexate , imab ; dexamethasone ; estrogen agonists ; estrogen antago - 15 mitomycin C , taxoids , vinca alkaloids ( such as vinblastine nists ; etanidazole ; etoposide phosphate ; exemestane ; fadro - and vincristine ) , epothilones ( e . g . epothilone B ) , camptoth zole ; finasteride ; fludarabine ; fluorodaunorunicin ecin and its clinical analogs topotecan and irinotecan , or the hydrochloride ; gadolinium texaphyrin ; gallium nitrate ; like . gelatinase inhibitors ; gemcitabine ; glutathione inhibitors ; “ Chemotherapeutic ” or “ chemotherapeutic agent ” is used hepsulfam ; immunostimulant peptides ; insulin - like growth 20 in accordance with its plain ordinary meaning and refers to factor - 1 receptor inhibitor ; interferon agonists ; interferons ; a chemical composition or compound having antineoplastic interleukins ; letrozole ; leukemia inhibiting factor ; leukocyte properties or the ability to inhibit the growth or proliferation alpha interferon ; leuprolide + estrogen + progesterone ; leupro of cells . relin ; matrilysin inhibitors ; matrix metalloproteinase inhibi “ Patient ” or “ subject in need thereof ” or “ subject ” refers tors ; MIF inhibitor ; mifepristone ; mismatched double 25 to a living organism suffering from or prone to a disease or stranded RNA ; monoclonal antibody ; mycobacterial cell condition that can be treated by administration of a com wall extract ; nitric oxide modulators ; oxaliplatin ; pound or pharmaceutical composition or by a method , as panomifene ; pentrozole ; phosphatase inhibitors ; plasmino provided herein . Non - limiting examples include humans , gen activator inhibitor ; platinum complex ; platinum com - other mammals , bovines , rats , mice , dogs , monkeys , goat , pounds ; prednisone ; proteasome inhibitors ; protein A - based 30 sheep , cows , deer , and other non - mammalian animals . In immune modulator ; protein kinase C inhibitor ; protein tyro - some embodiments , a patient is human . In some embodi sine phosphatase inhibitors ; purine nucleoside phosphory - ments , a subject is human . lase inhibitors ; ras farnesyl protein transferase inhibitors ; ras “ Disease " or " condition ” refer to a state of being or health inhibitors ; ras - GAP inhibitor ; ribozymes ; signal transduc - status of a patient or subject capable of being treated with a tion inhibitors ; signal transduction modulators ; single chain 35 compound , pharmaceutical composition , or method pro antigen - binding protein ; stem cell inhibitor ; stem - cell divi - vided herein . In some embodiments , the disease is a disease sion inhibitors ; stromelysin inhibitors ; synthetic gly . having the symptom of cell hyperproliferation . In some cosaminoglycans ; tamoxifen methiodide ; telomerase inhibi - embodiments , the disease is a disease having the symptom tors ; thyroid stimulating hormone ; translation inhibitors ; of an aberrant level of androgen receptor activity . In some tyrosine kinase inhibitors ; urokinase receptor antagonists ; 40 embodiments , the disease is a cancer . In some further steroids ( e . g . , dexamethasone ) , finasteride , aromatase instances , “ cancer ” refers to human cancers and carcinomas , inhibitors , gonadotropin - releasing hormone agonists sarcomas , adenocarcinomas , lymphomas , leukemias , etc . , ( GnRH ) such as goserelin or leuprolide , adrenocorticoster - including solid and lymphoid cancers , kidney , breast , lung , oids ( e . g . , prednisone ) , progestins ( e . g . , hydroxyprogester bladder , colon , ovarian , prostate , pancreas , stomach , brain , one caproate , megestrol acetate , medroxyprogesterone 45 head and neck , skin , uterine , testicular , glioma , esophagus , acetate ) , estrogens ( e . g . , diethlystilbestrol , ethinyl estradiol ) , and liver cancer , including hepatocarcinoma , lymphoma , antiestrogen ( e . g . , tamoxifen ) , androgens ( e . g . , testosterone including B - acute lymphoblastic lymphoma , non - Hodgkin ' s propionate , fluoxymesterone ) , antiandrogen ( e . g . , fluta - lymphomas ( e . g . , Burkitt ' s , Small Cell , and Large Cell mide ) , immunostimulants ( e . g . , Bacillus Calmette - Gurin lymphomas ) , Hodgkin ' s lymphoma , leukemia ( including ( BCG ) , levamisole , interleukin - 2 , alpha - interferon , etc . ) , 50 AML , ALL , and CML ) , or multiple myeloma . In embodi monoclonal antibodies ( e . g . , anti - CD20 , anti - HER2 , anti ments , the disease is prostate cancer . In embodiments , the CD52 , anti - HLA - DR , and anti - VEGF monoclonal antibod disease is hormone sensitive prostate cancer . In embodi ies ) , immunotoxins ( e . g . , anti - CD33 monoclonal antibody - ments , the disease is hormone refractory ( insensitive ) pros calicheamicin conjugate , anti - CD22 monoclonal antibody - tate cancer . pseudomonas exotoxin conjugate , etc . ) , 55 As used herein , the term " cancer ” refers to all types of radioimmunotherapy ( e . g . , anti - CD20 monoclonal antibody cancer , neoplasm or malignant tumors found in mammals conjugated to 11lIn , 90Y , or 1311 , etc . ) , triptolide , homohar - ( e . g . humans ) , including leukemia , carcinomas and sarco ringtonine , dactinomycin , doxorubicin , epirubicin , topote - mas . Exemplary cancers that may be treated with a com can , itraconazole , vindesine , cerivastatin , vincristine , deoxy - pound or method provided herein include cancer of the adenosine , sertraline , pitavastatin , irinotecan , clofazimine , 60 prostate , thyroid , endocrine system , brain , breast , cervix , 5 - nonyloxytryptamine , vemurafenib , dabrafenib , erlotinib , colon , head & neck , liver , kidney , lung , non - small cell lung , gefitinib , EGFR inhibitors , epidermal growth factor receptor melanoma , mesothelioma , ovary , sarcoma , stomach , uterus , ( EGFR ) - targeted therapy or therapeutic ( e . g . gefitinib Medulloblastoma , colorectal cancer , pancreatic cancer . ( IressaTM ) , erlotinib ( TarcevaTM ) , cetuximab ( ErbituxTM ) , Additional examples may include , Hodgkin ' s Disease , Non lapatinib ( TykerbTM ) , panitumumab ( VectibixTM ) , vande - 65 Hodgkin ' s Lymphoma , multiple myeloma , neuroblastoma , tanib ( CaprelsatM ) , afatinib / BIBW2992 , CI - 1033 / caner - glioma , glioblastoma multiforme , ovarian cancer , rhab tinib , neratinib / HKI - 272 , CP - 724714 , TAK - 285 , AST - 1306 , domyosarcoma , primary thrombocytosis , primary macro

US 10 , 053 , 433 B2 19 20

globulinemia , primary brain tumors , cancer , malignant pan - noma , Cloudman ' s melanoma , S91 melanoma , Harding creatic insulanoma , malignant carcinoid , urinary bladder Passey melanoma , juvenile melanoma , lentigo maligna cancer , premalignant skin lesions , testicular cancer , lympho - melanoma , malignant melanoma , nodular melanoma , sub mas , thyroid cancer , neuroblastoma , esophageal cancer , ungal melanoma , or superficial spreading melanoma . genitourinary tract cancer , malignant hypercalcemia , endo - 5 The term “ carcinoma ” refers to a malignant new growth metrial cancer , adrenal cortical cancer , neoplasms of the made up of epithelial cells tending to infiltrate the surround endocrine or exocrine pancreas , medullary thyroid cancer , ing tissues and give rise to metastases . Exemplary carcino medullary thyroid carcinoma , melanoma , colorectal cancer , mas that may be treated with a compound or method papillary thyroid cancer , hepatocellular carcinoma , or pros provided herein include , for example , medullary thyroid tate cancer . carcinoma , familial medullary thyroid carcinoma , acinar The term “ leukemia ” refers broadly to progressive , malig carcinoma , acinous carcinoma , adenocystic carcinoma , nant diseases of the blood - forming organs and is generally adenoid cystic carcinoma , carcinoma adenomatosum , carci characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone noma of adrenal cortex , alveolar carcinoma , alveolar cell marrow . Leukemia is generally clinically classified on the 15 carcinoma , basal cell carcinoma , carcinoma basocellulare , basis of ( 1 ) the duration and character of the disease - acute basaloid carcinoma , basosquamous cell carcinoma , bron or chronic ; ( 2 ) the type of cell involved ; myeloid ( myelog enous ) , lymphoid ( lymphogenous ) , or monocytic ; and ( 3 ) genic carcinoma , cerebriform carcinoma , cholangiocellular the increase or non - increase in the number abnormal cells in carcinoma , chorionic carcinoma , colloid carcinoma , comedo the blood - leukemic or aleukemic ( subleukemic ) . Exemplary 20 carcinoma , corpus carcinoma , cribriform carcinoma , carci leukemias that may be treated with a compound or method noma en cuirasse , carcinoma cutaneum , cylindrical carci provided herein include , for example , acute nonlymphocytic noma , cylindrical cell carcinoma , duct carcinoma , carci leukemia , chronic lymphocytic leukemia , acute granulocytic noma durum , embryonal carcinoma , encephaloid leukemia , chronic granulocytic leukemia , acute promyelo - carcinoma , epiermoid carcinoma , carcinoma epitheliale cytic leukemia , adult T - cell leukemia , aleukemic leukemia , 25 adenoides , exophytic carcinoma , carcinoma ex ulcere , car a leukocythemic leukemia , basophylic leukemia , blast cell cinoma fibrosum , gelatiniforni carcinoma , gelatinous carci leukemia , bovine leukemia , chronic myelocytic leukemia , noma , giant cell carcinoma , carcinoma gigantocellulare , leukemia cutis , embryonal leukemia , eosinophilic leukemia , glandular carcinoma , granulosa cell carcinoma , hair - matrix Gross ' leukemia , hairy - cell leukemia , hemoblastic leuke carcinoma , hematoid carcinoma , hepatocellular carcinoma , mia , hemocytoblastic leukemia , histiocytic leukemia , stem 30 Hurthle cell carcinoma , hyaline carcinoma , hypernephroid cell leukemia , acute monocytic leukemia , leukopenic leu carcinoma , infantile embryonal carcinoma , carcinoma in kemia , lymphatic leukemia , lymphoblastic leukemia , lym - situ , intraepidermal carcinoma , intraepithelial carcinoma , phocytic leukemia , lymphogenous leukemia , lymphoid leu - Krompecher ' s carcinoma , Kulchitzky - cell carcinoma , large kemia , lymphosarcoma cell leukemia , mast cell leukemia , cell carcinoma , lenticular carcinoma , carcinoma lenticulare , megakaryocytic leukemia , micromyeloblastic leukemia , 35 lipomatous carcinoma , lymphoepithelial carcinoma , carci monocytic leukemia , myeloblastic leukemia , myelocytic noma medullare , medullary carcinoma , melanotic carci leukemia , myeloid granulocytic leukemia , myelomonocytic noma , carcinoma molle , mucinous carcinoma , carcinoma leukemia , Naegeli leukemia , plasma cell leukemia , multiple muciparum , carcinoma mucocellulare , mucoepidermoid car myeloma , plasmacytic leukemia , promyelocytic leukemia , cinoma , carcinoma mucosum , mucous carcinoma , carci Rieder cell leukemia , Schilling ' s leukemia , stem cell leuke - 40 noma myxomatodes , nasopharyngeal carcinoma , oat cell mia , subleukemic leukemia , or undifferentiated cell leuke carcinoma , carcinoma ossificans , osteoid carcinoma , papil

lary carcinoma , periportal carcinoma , preinvasive carci The term " sarcoma ” generally refers to a tumor which is noma , prickle cell carcinoma , pultaceous carcinoma , renal

made up of a substance like the embryonic connective tissue cell carcinoma of kidney , reserve cell carcinoma , carcinoma and is generally composed of closely packed cells embedded 45 sarcomatodes , schneiderian carcinoma , scirrhous carci in a fibrillar or homogeneous substance . Sarcomas that may noma , carcinoma scroti , signet - ring cell carcinoma , carci be treated with a compound or method provided herein noma simplex , small - cell carcinoma , solanoid carcinoma , include a chondrosarcoma , fibrosarcoma , lymphosarcoma , spheroidal cell carcinoma , spindle cell carcinoma , carci melanosarcoma , myxosarcoma , osteosarcoma , Abemethy ' s noma spongiosum , squamous carcinoma , squamous cell sarcoma , adipose sarcoma , liposarcoma , alveolar soft part 50 carcinoma , string carcinoma , carcinoma telangiectaticum , sarcoma , ameloblastic sarcoma , botryoid sarcoma , chloroma carcinoma telangiectodes , transitional cell carcinoma , car sarcoma , chorio carcinoma , embryonal sarcoma , Wilms ' cinoma tuberosum , tuberous carcinoma , verrucous carci tumor sarcoma , endometrial sarcoma , stromal sarcoma , noma , or carcinoma villosum . Ewing ' s sarcoma , fascial sarcoma , fibroblastic sarcoma , The term " signaling pathway ” as used herein refers to a giant cell sarcoma , granulocytic sarcoma , Hodgkin ' s sar - 55 series of interactions between cellular and optionally extra coma , idiopathic multiple pigmented hemorrhagic sarcoma , cellular components ( e . g . proteins , nucleic acids , small immunoblastic sarcoma of B cells , lymphoma , immunoblas - molecules , ions , lipids ) that conveys a change in one com tic sarcoma of T - cells , Jensen ' s sarcoma , Kaposi ' s sarcoma , ponent to one or more other components , which in turn may Kupffer cell sarcoma , angiosarcoma , leukosarcoma , malig - convey a change to additional components , which is option nant mesenchymoma sarcoma , parosteal sarcoma , reticulo - 60 ally propagated to other signaling pathway components . cytic sarcoma , Rous sarcoma , serocystic sarcoma , synovial The term “ aberrant ” as used herein refers to different from sarcoma , or telangiectaltic sarcoma . normal . When used to describe enzymatic activity , aberrant

The term " melanoma ” is taken to mean a tumor arising refers to activity that is greater or less than a normal control from the melanocytic system of the skin and other organs . or the average of normal non - diseased control samples . Melanomas that may be treated with a compound or method 65 Aberrant activity may refer to an amount of activity that provided herein include , for example , acral - lentiginous results in a disease , wherein returning the aberrant activity melanoma , amelanotic melanoma , benign juvenile mela - to a normal or non - disease - associated amount ( e . g . by

mia .

US 10 , 053 , 433 B2 21

administering a compound or using a method as described gaps and the like . Preferably , identity exists over a region herein ) , results in reduction of the disease or one or more that is at least about 10 amino acids or 20 nucleotides in disease symptoms . length , or more preferably over a region that is 10 - 50 amino

“ Nucleic acid ” or “ oligonucleotide ” or “ polynucleotide ” acids or 20 - 50 nucleotides in length . As used herein , percent or grammatical equivalents used herein means at least two 5 ( % ) amino acid sequence identity is defined as the percent nucleotides covalently linked together . The term “ nucleic age of amino acids in a candidate sequence that are identical acid ” includes single - , double - , or multiple - stranded DNA , to the amino acids in a reference sequence , after aligning the RNA and analogs ( derivatives ) thereof . Oligonucleotides are sequences and introducing gaps , if necessary , to achieve the typically from about 5 , 6 , 7 , 8 , 9 , 10 , 12 , 15 , 25 , 30 , 40 , 50 maximum percent sequence identity . Alignment for pur or more nucleotides in length , up to about 100 nucleotides 10 poses of determining percent sequence identity can be in length . Nucleic acids and polynucleotides are a polymers achieved in various ways that are within the skill in the art , of any length , including longer lengths , e . g . , 200 , 300 , 500 , for instance , using publicly available computer software 1000 , 2000 , 3000 , 5000 , 7000 , 10 , 000 , etc . Nucleic acids such as BLAST , BLAST - 2 , ALIGN , ALIGN - 2 or Megalign containing one or more carbocyclic sugars are also included ( DNASTAR ) software . Appropriate parameters for measur within one definition of nucleic acids . 15 ing alignment , including any algorithms needed to achieve

A particular nucleic acid sequence also encompasses maximal alignment over the full - length of the sequences " splice variants . ” Similarly , a particular protein encoded by being compared can be determined by known methods . a nucleic acid encompasses any protein encoded by a splice For sequence comparisons , typically one sequence acts as variant of that nucleic acid . “ Splice variants , " as the name a reference sequence , to which test sequences are compared . suggests , are products of alternative splicing of a gene . After 20 When using a sequence comparison algorithm , test and transcription , an initial nucleic acid transcript may be reference sequences are entered into a computer , subse spliced such that different ( alternate ) nucleic acid splice quence coordinates are designated , if necessary , and products encode different polypeptides . Mechanisms for the sequence algorithm program parameters are designated . production of splice variants vary , but include alternate Preferably , default program parameters can be used , or splicing of exons . Alternate polypeptides derived from the 25 alternative parameters can be designated . The sequence same nucleic acid by read - through transcription are also comparison algorithm then calculates the percent sequence encompassed by this definition . Any products of a splicing identities for the test sequences relative to the reference reaction , including recombinant forms of the splice prod sequence , based on the program parameters . ucts , are included in this definition . A “ comparison window ” , as used herein , includes refer

Nucleic acid is “ operably linked ” when it is placed into a 30 ence to a segment of any one of the number of contiguous functional relationship with another nucleic acid sequence . positions selected from the group consisting of from 10 to For example , DNA for a presequence or secretory leader is 600 , usually about 50 to about 200 , more usually about 100 operably linked to DNA for a polypeptide if it is expressed to about 150 in which a sequence may be compared to a as a preprotein that participates in the secretion of the reference sequence of the same number of contiguous posi polypeptide ; a promoter or enhancer is operably linked to a 35 tions after the two sequences are optimally aligned . Methods coding sequence if it affects the transcription of the of alignment of sequences for comparison are well - known in sequence ; or a ribosome binding site is operably linked to a the art . Optimal alignment of sequences for comparison can coding sequence if it is positioned so as to facilitate trans - be conducted , e . g . , by the local homology algorithm of lation . Generally , “ operably linked ” means that the DNA Smith & Waterman , Adv . Appl . Math . 2 : 482 ( 1981 ) , by the sequences being linked are near each other , and , in the case 40 homology alignment algorithm of Needleman & Wunsch , J . of a secretory leader , contiguous and in reading phase . Mol . Biol . 48 : 443 ( 1970 ) , by the search for similarity However , enhancers do not have to be contiguous . Linking method of Pearson & Lipman , Proc . Natl . Acad . Sci . USA is accomplished by ligation at convenient restriction sites . If 85 : 2444 ( 1988 ) , by computerized implementations of these such sites do not exist , the synthetic oligonucleotide adap - algorithms ( GAP , BESTFIT , FASTA , and TFASTA in the tors or linkers are used in accordance with conventional 45 Wisconsin Genetics Software Package , Genetics Computer practice . Group , 575 Science Dr . , Madison , Wis . ) , or by manual

The terms “ identical ” or percent “ identity , ” in the context alignment and visual inspection ( see , e . g . , Current Protocols of two or more nucleic acids or polypeptide sequences , refer in Molecular Biology ( Ausubel et al . , eds . 1995 supple to two or more sequences or subsequences that are the same ment ) ) . or have a specified percentage of amino acid residues or 50 The phrase " selectively ( or specifically ) hybridizes to ” nucleotides that are the same ( i . e . , about 60 % identity , refers to the binding , duplexing , or hybridizing of a mol preferably 61 % , 62 % , 63 % , 64 % , 65 % , 66 % , 67 % , 68 % , ecule only to a particular nucleotide sequence with a higher 69 % , 70 % , 71 % , 72 % , 73 % , 74 % , 75 % , 76 % , 77 % , 78 % , affinity , e . g . , under more stringent conditions , than to other 79 % , 80 % , 81 % , 82 % , 83 % , 84 % , 85 % , 86 % , 87 % , 88 % , nucleotide sequences ( e . g . , total cellular or library DNA or 89 % , 90 % , 91 % , 92 % , 93 % , 94 % , 95 % , 96 % , 97 % , 98 % , 55 RNA ) . 99 % or higher identity over a specified region when com The phrase " stringent hybridization conditions ” refers to pared and aligned for maximum correspondence over a conditions under which a probe will hybridize to its target comparison window or designated region ) as measured subsequence , typically in a complex mixture of nucleic using a BLAST or BLAST 2 . 0 sequence comparison algo - acids , but to no other sequences . Stringent conditions are rithms with default parameters described below , or by 60 sequence - dependent and will be different in different cir manual alignment and visual inspection ( see , e . g . , NCBI cumstances . Longer sequences hybridize specifically at web site or the like ) . Such sequences are then said to be higher temperatures . An extensive guide to the hybridization " substantially identical . ” This definition also refers to , or of nucleic acids is found in Tijssen , Techniques in Biochem may be applied to , the compliment of a test sequence . The istry and Molecular Biology - Hybridization with Nucleic definition also includes sequences that have deletions and / or 65 Probes , “ Overview of principles of hybridization and the additions , as well as those that have substitutions . As strategy of nucleic acid assays ” ( 1993 ) . Generally , stringent described below , the preferred algorithms can account for conditions are selected to be about 5 - 10° C . lower than the

21 070 ,

23 US 10 , 053 , 433 B2

24 thermal melting point ( Tm ) for the specific sequence at a frequently be interchangeable , as can alanine ( A ) and valine defined ionic strength pH . The T , is the temperature ( under ( V ) . Methionine ( M ) , which is relatively hydrophobic , can defined ionic strength , pH , and nucleic concentration ) at frequently be interchanged with leucine and isoleucine , and which 50 % of the probes complementary to the target sometimes with valine . Lysine ( K ) and arginine ( R ) are hybridize to the target sequence at equilibrium ( as the target 5 frequently interchangeable in locations in which the signifi sequences are present in excess , at Tm , 50 % of the probes are cant feature of the amino acid residue is its charge and the occupied at equilibrium ) . Stringent conditions may also be differing pks of these two amino acid residues are not achieved with the addition of destabilizing agents such as significant . Still other changes can be considered “ conser formamide . For selective or specific hybridization , a positive vative ” in particular environments ( see , e . g . , BIOCHEMIS signal is at least two times background , preferably 10 times 10 TRY at pp . 13 - 15 , 2nd ed . Lubert Stryer ed . ( Stanford background hybridization . Exemplary stringent hybridiza - University ) ; Henikoff et al . , Proc . Nat ' l Acad . Sci . USA tion conditions can be as following : 50 % formamide , ( 1992 ) 89 : 10915 - 10919 ; Lei et al . , J . Biol . Chem . ( 1995 ) 5xSSC , and 1 % SDS , incubating at 42° C . , or , 5xSSC , 1 % 270 ( 20 ) : 11882 - 11886 ) . SDS , incubating at 65° C . , with wash in 0 . 2xSSC , and 0 . 1 % “ Polypeptide , " " peptide , " and " protein ” are used herein SDS at 65° C . 15 interchangeably and mean any peptide - linked chain of

Nucleic acids that do not hybridize to each other under amino acids , regardless of length or post - translational modi stringent conditions are still substantially identical if the fication . As noted below , the polypeptides described herein polypeptides which they encode are substantially identical . can be , e . g . , wild - type proteins , biologically - active frag This occurs , for example , when a copy of a nucleic acid is ments of the wild - type proteins , or variants of the wild - type created using the maximum codon degeneracy permitted by 20 proteins or fragments . Variants , in accordance with the the genetic code . In such cases , the nucleic acids typically disclosure , can contain amino acid substitutions , deletions , hybridize under moderately stringent hybridization condi - or insertions . The substitutions can be conservative or non tions . Exemplary “ moderately stringent hybridization con - conservative . ditions ” include a hybridization in a buffer of 40 % forma . Following expression , the proteins can be isolated . The mide , 1 M NaCl , 1 % SDS at 37° C . , and a wash in 1xSSC 25 term “ purified ” or “ isolated ” as applied to any of the proteins at 45° C . A positive hybridization is at least twice back described herein refers to a polypeptide that has been ground . Those of ordinary skill will readily recognize that separated or purified from components ( e . g . , proteins or alternative hybridization and wash conditions can be utilized other naturally occurring biological or organic molecules ) to provide conditions of similar stringency . Additional which naturally accompany it , e . g . , other proteins , lipids , guidelines for determining hybridization parameters are 30 and nucleic acid in a cell expressing the proteins . Typically , provided in numerous reference , e . g . , and Current Protocols a polypeptide is purified when it constitutes at least 60 ( e . g . , in Molecular Biology , ed . Ausubel , et al . at least 65 , 70 , 75 , 80 , 85 , 90 , 92 , 95 , 97 , or 99 ) % , by

Twenty amino acids are commonly found in proteins . weight , of the total protein in a sample . Those amino acids can be grouped into nine classes or An amino acid residue in a protein " corresponds ” to a groups based on the chemical properties of their side chains . 35 given residue when it occupies the same essential structural Substitution of one amino acid residue for another within the position within the protein as the given residue . For same class or group is referred to herein as a " conservative ” example , a selected residue in a selected protein corresponds substitution . Conservative amino acid substitutions can fre - to Cys784 of human androgen receptor when the selected quently be made in a protein without significantly altering residue occupies the same essential spatial or other structural the conformation or function of the protein . Substitution of 40 relationship as Cys 784 in human androgen receptor . In one amino acid residue for another from a different class or some embodiments , where a selected protein is aligned for group is referred to herein as a “ non - conservative ” substi maximum homology with the human androgen receptor tution . In contrast , non - conservative amino acid substitu - protein , the position in the aligned selected protein aligning tions tend to modify conformation and function of a protein . with Cys784 is said to correspond to Cys784 . Instead of a Example of Amino Acid Classification 45 primary sequence alignment , a three dimensional structural

Small / Aliphatic residues : Gly , Ala , Val , Leu , Ile alignment can also be used , e . g . , where the structure of the Cyclic Imino Acid : Pro selected protein is aligned for maximum correspondence Hydroxyl - containing Residues : Ser , Thr with the human androgen receptor protein and the overall Acidic Residues : Asp , Glu structures compared . In this case , an amino acid that occu Amide Residues : Asn , Gin 50 pies the same essential position as Cys784 in the structural Basic Residues : Lys , Arg model is said to correspond to the Cys784 residue . Imidazole Residue : His “ Pharmaceutically acceptable excipient ” and “ pharma Aromatic Residues : Phe , Tyr , Trp ceutically acceptable carrier ” refer to a substance that aids Sulfur - containing Residues : Met , Cys the administration of an active agent to and absorption by a

In some embodiments , the conservative amino acid sub - 55 subject and can be included in the compositions of the stitution comprises substituting any of glycine ( G ) , alanine present invention without causing a significant adverse ( A ) , isoleucine ( I ) , valine ( V ) , and leucine ( L ) for any other toxicological effect on the patient . Non - limiting examples of of these aliphatic amino acids ; serine ( S ) for threonine ( T ) pharmaceutically acceptable excipients include water , NaCl , and vice versa ; aspartic acid ( D ) for glutamic acid ( E ) and normal saline solutions , lactated Ringer ' s , normal sucrose , vice versa ; glutamine ( Q ) for asparagine ( N ) and vice versa ; 60 normal glucose , binders , fillers , disintegrants , lubricants , lysine ( K ) for arginine ( R ) and vice versa ; phenylalanine ( F ) , coatings , sweeteners , flavors , salt solutions ( such as Ring tyrosine ( Y ) and tryptophan ( W ) for any other of these er ' s solution ) , alcohols , oils , gelatins , carbohydrates such as aromatic amino acids ; and methionine ( M ) for cysteine ( C ) lactose , amylose or starch , fatty acid esters , hydroxymethy and vice versa . Other substitutions can also be considered cellulose , polyvinyl pyrrolidine , and colors , and the like . conservative , depending on the environment of the particu - 65 Such preparations can be sterilized and , if desired , mixed lar amino acid and its role in the three - dimensional structure with auxiliary agents such as lubricants , preservatives , sta of the protein . For example , glycine ( G ) and alanine ( A ) can bilizers , wetting agents , emulsifiers , salts for influencing

25 US 10 , 053 , 433 B2

26 osmotic pressure , buffers , coloring , and / or aromatic sub - ment , the formulations of the compositions of the present stances and the like that do not deleteriously react with the invention can be delivered by the use of liposomes which compounds of the invention . One of skill in the art will fuse with the cellular membrane or are endocytosed , i . e . , by recognize that other pharmaceutical excipients are useful in employing receptor ligands attached to the liposome , that the present invention . 5 bind to surface membrane protein receptors of the cell

The term “ preparation ” is intended to include the formu resulting in endocytosis . By using liposomes , particularly lation of the active compound with encapsulating material as where the liposome surface carries receptor ligands specific a carrier providing a capsule in which the active component for target cells , or are otherwise preferentially directed to a with or without other carriers , is surrounded by a carrier , specific organ , one can focus the delivery of the composi which is thus in association with it . Similarly , cachets and 10 tions of the present invention into the target cells in vivo . lozenges are included . Tablets , powders , capsules , pills , ( See , e . g . , Al - Muhammed , J . Microencapsul . 13 : 293 - 306 , cachets , and lozenges can be used as solid dosage forms 1996 ; Chonn , Curr . Opin . Biotechnol . 6 : 698 - 708 , 1995 ; suitable for oral administration . Ostro , Am . J . Hosp . Pharm . 46 : 1576 - 1587 , 1989 ) . The As used herein , the term “ administering ” means oral compositions of the present invention can also be delivered

administration , administration as a suppository , topical con - 15 as nanoparticles . tact , intravenous , parenteral , intraperitoneal , intramuscular , Pharmaceutical compositions provided by the present intralesional , intrathecal , intracranial , intranasal or subcuta invention include compositions wherein the active ingredi neous administration , or the implantation of a slow - release ent ( e . g . compounds described herein , including embodi device , e . g . , a mini - osmotic pump , to a subject . Adminis - ments or examples ) is contained in a therapeutically effec tration is by any route , including parenteral and transmu - 20 tive amount , i . e . , in an amount effective to achieve its cosal ( e . g . , buccal , sublingual , palatal , gingival , nasal , vagi - intended purpose . The actual amount effective for a particu nal , rectal , or transdermal ) . Parenteral administration lar application will depend , inter alia , on the condition being includes , e . g . , intravenous , intramuscular , intra - arteriole , treated . When administered in methods to treat a disease , intradermal , subcutaneous , intraperitoneal , intraventricular , such compositions will contain an amount of active ingre and intracranial . Other modes of delivery include , but are 25 dient effective to achieve the desired result , e . g . , reducing , not limited to , the use of liposomal formulations , intrave - eliminating , or slowing the progression of disease symptoms nous infusion , transdermal patches , etc . By “ co - administer ” ( e . g . symptoms of cancer or aberrant androgen receptor it is meant that a composition described herein is adminis - activity ) . Determination of a therapeutically effective tered at the same time , just prior to , or just after the amount of a compound of the invention is well within the administration of one or more additional therapies ( e . g . 30 capabilities of those skilled in the art , especially in light of anti - cancer agent ) . The compound of the invention can be the detailed disclosure herein . administered alone or can be coadministered to the patient . The dosage and frequency ( single or multiple doses ) Coadministration is meant to include simultaneous or administered to a mammal can vary depending upon a sequential administration of the compound individually or in variety of factors , for example , whether the mammal suffers combination ( more than one compound or agent ) . Thus , the 35 from another disease , and its route of administration ; size , preparations can also be combined , when desired , with other age , sex , health , body weight , body mass index , and diet of active substances ( e . g . to reduce metabolic degradation , to the recipient ; nature and extent of symptoms of the disease increase degradation of a prodrug and release of the drug , being treated ( e . g . symptoms of cancer ) , kind of concurrent detectable agent ) . The compositions of the present invention treatment , complications from the disease being treated or can be delivered by transdermally , by a topical route , for - 40 other health - related problems . Other therapeutic regimens or mulated as applicator sticks , solutions , suspensions , emul - agents can be used in conjunction with the methods and sions , gels , creams , ointments , pastes , jellies , paints , pow . compounds of Applicants ' invention . Adjustment and ders , and aerosols . Oral preparations include tablets , pills , manipulation of established dosages ( e . g . , frequency and powder , dragees , capsules , liquids , lozenges , cachets , gels , duration ) are well within the ability of those skilled in the syrups , slurries , suspensions , etc . , suitable for ingestion by 45 art . the patient . Solid form preparations include powders , tab - For any compound described herein , the therapeutically lets , pills , capsules , cachets , suppositories , and dispersible effective amount can be initially determined from cell cul granules . Liquid form preparations include solutions , sus ture assays . Target concentrations will be those concentra pensions , and emulsions , for example , water or water / tions of active compound ( s ) that are capable of achieving the propylene glycol solutions . The compositions of the present 50 methods described herein , as measured using the methods invention may additionally include components to provide described herein or known in the art . sustained release and / or comfort . Such components include As is well known in the art , therapeutically effective high molecular weight , anionic mucomimetic polymers , amounts for use in humans can also be determined from gelling polysaccharides and finely - divided drug carrier sub - animal models . For example , a dose for humans can be strates . These components are discussed in greater detail in 55 formulated to achieve a concentration that has been found to U . S . Pat . Nos . 4 , 911 , 920 ; 5 , 403 , 841 ; 5 , 212 , 162 ; and 4 , 861 , be effective in animals . The dosage in humans can be 760 . The entire contents of these patents are incorporated adjusted by monitoring compounds effectiveness and adjust herein by reference in their entirety for all purposes . The ing the dosage upwards or downwards , as described above . compositions of the present invention can also be delivered Adjusting the dose to achieve maximal efficacy in humans as microspheres for slow release in the body . For example , 60 based on the methods described above and other methods is microspheres can be administered via intradermal injection well within the capabilities of the ordinarily skilled artisan . of drug - containing microspheres , which slowly release sub - Dosages may be varied depending upon the requirements cutaneously ( see Rao , J . Biomater Sci . Polym . Ed . 7 : 623 - of the patient and the compound being employed . The dose 645 , 1995 ; as biodegradable and injectable gel formulations administered to a patient , in the context of the present ( see , e . g . , Gao Pharm . Res . 12 : 857 - 863 , 1995 ) ; or , as 65 invention should be sufficient to effect a beneficial thera microspheres for oral administration ( see , e . g . , Eyles , J . peutic response in the patient over time . The size of the dose Pharm . Pharmacol . 49 : 669 - 674 , 1997 ) . In another embodi - also will be determined by the existence , nature , and extent

US 10 , 053 , 433 B2 28

of any adverse side - effects . Determination of the proper GI : 349501065 . In embodiments , the androgen receptor has dosage for a particular situation is within the skill of the the nucleotide sequence corresponding to RefSeq practitioner . Generally , treatment is initiated with smaller NM _ 000044 . 3 . In embodiments , the androgen receptor has dosages which are less than the optimum dose of the the protein sequence corresponding to reference number compound . Thereafter , the dosage is increased by small 5 GI : 21322252 . In embodiments , the androgen receptor has increments until the optimum effect under circumstances is the nucleotide sequence corresponding to RefSeq reached NP _ 000035 . 2 . In embodiments , the androgen receptor has Dosage amounts and intervals can be adjusted individu the following amino acid sequence : ally to provide levels of the administered compound effec tive for the particular clinical indication being treated . This 10 will provide a therapeutic regimen that is commensurate MEVQLGLGRVYPRPPSKTYRGAFONLFQSVREVIQNPGPRHPEAASAAPP with the severity of the individual ' s disease state .

Utilizing the teachings provided herein , an effective pro GASLLLLQ000000000000000000QQETSPROQ000QGEDGSPQAHRR phylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to 15 GPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAP treat the clinical symptoms demonstrated by the particular patient . This planning should involve the careful choice of PDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAV active compound by considering factors such as compound

SEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVE potency , relative bioavailability , patient body weight , pres en ALEHLSPGEOLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKS

TEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGA

AAOCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGOLYGPCGG

YYFP POKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKOKYLCASRND

administration and the toxicity profile of the selected agent . The compounds described herein can be used in combi

nation with one another , with other active agents known to be useful in treating cancer , or with adjunctive agents that LDEAAAYOSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAA may not be effective alone , but may contribute to the efficacy 25 of the active agent .

In some embodiments , co - administration includes admin GGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPD istering one active agent within 0 . 5 , 1 , 2 , 4 , 6 , 8 , 10 , 12 , 16 , 20 , or 24 hours of a second active agent . Co - administration VWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPID includes administering two active agents simultaneously , 30 approximately simultaneously ( e . g . , within about 1 , 5 , 10 , 15 , 20 , or 30 minutes of each other ) , or sequentially in any order . In some embodiments , co - administration can be CTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTS accomplished by co - formulation , i . e . , preparing a single pharmaceutical composition including both active agents . In 35 PI on including both active acento In 25 PTEETTOKLTVSHIEGYECOPIFLNVLEAI EPGVVCAGHDNNQPDSFAAL

other embodiments , the active agents can be formulated LSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMG separately . In another embodiment , the active and / or adjunc tive agents may be linked or conjugated to one another . In WRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSCEFGWLQIT some embodiments , the compounds described herein may be combined with treatments for cancer such as radiation or 40 PQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPT surgery .

A " drug - resistant androgen receptor ” is a modified ( rela SCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEIIS tive to wildtype ) androgen receptor that is inhibited less

drug than a wildtype androgen receptor A V QVPKILSGKVKPIYFHTO " drug - resistant human androgen receptor ” is a modified 45 ( relative to wildtype ) human androgen receptor that is In embodiments , the androgen receptor is a mutant androgen inhibited less effectively by the drug than a wildtype human receptor . In embodiments , the mutant androgen receptor is androgen receptor . associated with a disease that is not associated with wildtype

The term “ androgen receptor ” or “ AR ” or “ NR3C4 ” androgen receptor . In embodiments , the androgen receptor refers to a nuclear receptor activated by binding of the 50 includes at least one amino acid mutation ( e . g . , 1 , 2 , 3 , 4 , 5 , androgenic hormone testosterone or dihydrotestosterone . 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , The term “ androgen receptor ” may refer to the nucleotide 23 , 24 , 25 , 26 , 27 , 28 , 29 , or 30 mutations ) compared to the sequence or protein sequence of human androgen receptor sequence above . ( e . g . , Entrez 367 , Uniprot P10275 , RefSeq NM _ 000044 , or The term “ electrophilic moiety ” is used in accordance RefSeq NP _ 000035 ) . The term “ androgen receptor ” 55 with its plain ordinary chemical meaning and refers to a includes both the wild - type form of the nucleotide sequences monovalent chemical group that is electrophilic . In embodi or proteins as well as any mutants thereof . In some embodi ments an electrophilic moiety is a monovalent chemical ments , “ androgen receptor ” is wild - type androgen receptor . In some embodiments , " androgen receptor " is one or more group capable of forming a covalent bond ( e . g . , reversible or mutant forms . The term “ androgen receptor ” XYZ refers to 60 irreversible ) with a Cys , Asp , Glu , Tyr , Ser , or Lys sidechain a nucleotide sequence or protein of a mutant androgen of a nuclear receptor ( e . g . , androgen receptor ) . In embodi receptor wherein the Y numbered amino acid of androgen ments an electrophilic moiety is a monovalent chemical receptor that normally has an X amino acid in the wildtype , group capable of forming a covalent bond ( e . g . , reversible or instead has a Z amino acid in the mutant . In embodiments , irreversible ) with a Cys residue . In embodiments an elec an androgen receptor is the human androgen receptor . In 65 trophilic moiety is a monovalent chemical group capable of embodiments , the androgen receptor has the nucleotide forming a covalent bond ( e . g . , reversible or irreversible ) sequence corresponding to reference number with an androgen receptor Cys residue .

US 10 , 053 , 433 B2 29 30

B . COMPOUNDS In embodiments , the compound has the formula

In an aspect is provided a compound , or a pharmaceuti cally acceptable salt thereof , having the formula : ( la )

5 ras ( R ) + A @ i ( B + @ e ( R2 ) 61 . ( 1 )

( R ' ) - as Qinam A

N

Quinoa NH

( II )

NH m2

HOR3 ó B + ( R ) b1

10 Ring A , Ring B , R1 , R2 , R3 , al , and b1 are as described HÓ R3 ? herein , including in embodiments ( e . g . , as for formula I and

embodiments thereof ) . Ring A is a heteroaryl ; Ring B is a phenyl or heteroaryl ; In embodiments , the compound has the formula

R ? is independently a hydrogen , halogen , CX°3 , CN , 15 - SO , C1 , SO R10 , SO , NR7RS , - NHNH , – ONR7R8 , - NHC = ( O ) NHNH , ( Ib ) ( Ib ) NHC = ( O ) NRR , N ( O ) I , NRZR * , C ( O ) Rº , ( Raita ) B + ( R2 ) b1 .

- C ( O ) - OR " , - C ( O ) NRÖR , OR10 , NR7SO , R10 , - NRC = ( O ) R ” , NRCO OR ” , NR OR ” , 20 - OCX?3 , OCHX°2 , E , substituted or unsubstituted alkyl , HO CH ; substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubstituted het - Ring A , Ring B , R1 , R2 , al , and b1 are as described herein , erocycloalkyl , substituted or unsubstituted aryl , or substi - including in embodiments ( e . g . , as for formula 1 and tuted or unsubstituted heteroaryl ; two adjacent Ri substitu heternarvl : two adiacent Rl substitu - 25 embodiments thereof ) . ents may optionally be joined to form a substituted or In embodiments , the compound has the formula unsubstituted cycloalkyl , substituted or unsubstituted het erocycloalkyl , substituted or unsubstituted aryl , or substi tuted or unsubstituted heteroaryl . E is an electrophilic moi - 30 ety . R² is independently a hydrogen , halogen , CX ' 3 , - CN , SO , C1 , SO - 2R14 , SONR1R12 , - NHNH , ( R ' 1 - A B + ( R2 ) bl . ONR ' R ' ? , NHC - ( O ) NHNHA ,

– NHC = ( O ) NR ' R ' ? , N ( O ) 2 , NR ' ' R ' ? , C ( O ) R3 , - C ( O ) - OR13 , - C ( O ) NR1R12 , - OR14 , - NRISO , R14 , 35 HOCH , Ó ! - NRC = ( O ) R13 , NRC ( O ) OR13 , NR ' ' OR13 , - OCX 3 , OCHX ' > , substituted or unsubstituted alkyl , Ring A , Ring B , R1 , R2 , al , and b1 are as described herein , substituted or unsubstituted heteroalkyl , substituted or including in embodiments ( e . g . , as for formula I , la , Ib , and unsubstituted cycloalkyl , substituted or unsubstituted het - embodiments thereof ) . erocycloalkyl , substituted or unsubstituted aryl , or substi - 40 In embodiments , Ring A is a 6 membered heteroaryl . Ring tuted or unsubstituted heteroaryl ; two adjacent R ? substitu - A may be ents may optionally be joined to form a substituted or unsubstituted cycloalkyl , substituted or unsubstituted het erocycloalkyl , substituted or unsubstituted aryl , or substi tuted or unsubstituted heteroaryl . R3 is independently an 45 unsubstituted alkyl . R " , R8 , R9 , R19 , R1 , R12 , R13 , and R14 are independently hydrogen , halogen , CX?3 , CN , - OH , - NH2 , COOH , CONH2 , — NO2 , SH , - SO , Cl , SO2H , SO _ H , SO NH , NHNH2 , ONH , NHC - ( O ) NHNH , NHC = ( O ) NHM , 50 II Ring A may be

– NHSO , H , NHC = ( 0 ) , _ NHC ( O ) OH , _ NHOH , - OCX°3 , OCHX°2 , substituted or unsubstituted alkyl , substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubstituted het erocycloalkyl , substituted or unsubstituted aryl , or substi - 55 tuted or unsubstituted heteroaryl ; R7 and R8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or Ring A may be substituted or unsubstituted heteroaryl ; R11 and R12 substitu ents bonded to the same nitrogen atom may optionally be 60 joined to form a substituted or unsubstituted heterocy cloalkyl or substituted or unsubstituted heteroaryl . The sym bol al is independently an integer from 0 to 4 . The symbol ( R ) a111 b1 is independently an integer from 0 to 5 . The symbols ml , m2 , v1 , and v2 are independently 1 or 2 . The symbols nl and 65 n2 are independently an integer from 0 to 4 . The symbols X " , X ” , and XC are independently Cl , Br , I , or - F .

( RalT

mui

7 ( R ' ) al ?

mu

US 10 , 053 , 433 B2 31 32

Ring A may be with al an integer from 0 to 2 . Ring A may be

( R ' ) al ( R ' ) a17 man with al an integer from 0 to 3 . Ring A may be with al an integer from 0 to 2 . Ring A may be

( R ' ) al

ma with al an integer from 0 to 3 . Ring A may be 20 with al an integer from 0 to 1 .

Ring A may be

( R ' ) al 25

( R ' ) al man with al an integer from 0 to 3 . Ring A may be

30

with al an integer from 0 to 3 . Ring A may be

35 ( R ' ) al

m

with al an integer from 0 to 3 . Ring A may be 40 with with al an integer from 0 to 3 . Ring A may be

NE 45 ( R ! ) al

mm with al an integer from 0 to 3 . Ring A may be

30 with al an integer from 0 to 3 . Ring A may be

( R ) 55 min

with al an integer from 0 to 3 . Ring A may be with al an integer from 0 to 3 . Ring A may be 60

( R ) al E

US 10 , 053 , 433 B2 34

with al an integer from 0 to 3 . Ring A may be with al an integer from 0 to 2 . Ring A may be

[ 1 ]

( R ' ) al | ( R al NVV? 1 with al an integer from 0 to 2 . Ring A may be


( R ) al EN

20 with al an integer from 0 to 2 . Ring A may be

with al an integer from 0 to 3 . Ring A may be ( R ' ) al w ?? 25 25

( Ryal

with al an integer from 0 to 2 . Ring A may be 30 "

with al an integer from 0 to 3 . Ring A may be ( R / al

x 3 35 [ l


N E = ;

( R ' ) il | | | ( R ' ) , ?? 45

?


| ( RJ ) ??? 55 ?? SLr )


E N

( R ' ) al yy ( R ) al - |

( 1 ] yyyy 65

US 10 , 053 , 433 B2 35 36

with al an integer from 0 to 2 . Ring A may be with al an integer from 0 to 1 . Ring A may be E .

( R ' ) al ( R ) a1 mu

with al an integer from 0 to 2 . Ring A may be 10

with al an integer from 0 to 1 . Ring A may be ( T )

( R ' ) , 1 EN N

mm with al an integer from 0 to 2 . Ring A may be with al an integer from 0 to 1 . Ring A may be

25

min with al an integer from 0 to 2 . Ring A may be 30 Ring A may be

E

( R ' ) a1 E

35 R ! mon


( R ' ) al

( 77


Ring A may be a 6 membered heteroaryl . Ring A may be 40 pyridinyl , pyrimidinyl , thiophenyl , thienyl , furanyl , indolyl , benzoxadiazolyl , benzodioxolyl , benzodioxanyl , thianaph thanyl , pyrrolopyridinyl , indazolyl , quinolinyl , quinoxali nyl , pyridopyrazinyl , quinazolinonyl , benzoisoxazolyl , imi dazopyridinyl , benzofuranyl , benzothienyl ,

45 benzothiophenyl , pyrrolyl , pyrazolyl , imidazolyl , pyrazinyl , oxazolyl , isoxazolyl , thiazolyl , furylthienyl , pyridyl , pyrim idyl , benzothiazolyl , purinyl , benzimidazolyl , isoquinolyl , thiadiazolyl , oxadiazolyl , pyrrolyl , diazolyl , triazolyl , tetra zolyl , benzothiadiazolyl , isothiazolyl , pyrazolopyrimidinyl ,

50 pyrrolopyrimidinyl , benzotriazolyl , benzoxazolyl , or qui nolyl . In embodiments , Ring A is a pyridinyl . In embodi ments , Ring A is a pyrimidinyl .

In embodiments , Ring A does not include a heteroatom ortho to the bond to the remainder of the compound includ

55 ing Ring B . In embodiments , Ring A does not include a nitrogen atom ortho to the bond to the remainder of the compound including Ring B . In embodiments , Ring A is a 6 membered heteroaryl . In embodiments , Ring A is not

( R ' ) al E N


EN

( R ' ) al . ( R ) al ?

my

ni e lager mon US 10 , 053 , 433 B2

37 with al an integer from 0 to 3 . In embodiments , Ring A is not cordian , was die

w

( R ) ai

10 with al an integer from 0 to 3 . In embodiments , Ring A is not o with al an integer from 0 to 3 . In embodiments , Ring A is na not w are the ones continen , kire

( R ' ) a w

( Ral 7

mu 20 with al an integer from 0 to 3 . In embodiments , Ring A is not

with al an integer from 0 to 3 . In embodiments , Ring A is not

25

( R ' ) al 1 ( R ' la

30 A este laget hen owns nebelion , kini dia with al an integer from 0 to 3 . In embodiments , Ring A is with al an integer from 0 to 3 . In embodiments , Ring A is not

not 35

E

40

m

with al an integer from 0 to 4 . In embodiments , Ring A is

arty : ex .

not 45 with al an integer from 0 to 3 . In embodiments , Ring A is not

( R ' ) al 7 50

d? with al an integer from 0 to 4 . In embodiments , Ring A is 35 not with al an integer from 0 to 3 . In embodiments , Ring A is

not may 60

( R ! ) 1 nex ( R ) al

65 with al an integer from 0 to 4 . In embodiments , Ring A is not with al an integer from 0 to 3 .

US 10 , 053 , 433 B2 39

In embodiments , Ring A is not

E Rhei min

with al an integer from 0 to 2 . In embodiments , Ring A is not with al an integer from 0 to 2 . In embodiments , Ring A is

not

( R ! ) , 2 ( R ' ) al w

20 with al an integer from 0 to 2 . In embodiments , Ring A is not with al an integer from 0 to 2 . In embodiments , Ring A is

not E

25

( R ' ) al i

( R1 ) , , mm mi 30


not 35 |

N

( R ) , 40 wi

with al an integer from 0 to 2 . In embodiments . Ring A is not

DX : DE . DX

with al an integer from 0 to 2 . In embodiments , Ring A is 45 not

VEN 50

with al an integer from 0 to 2 . In embodiments , Ring A is 55 with al an integer from 0 to 2 . In embodiments , Ring A is not not

E E 60

( R ' ) al ( R ! ) ai

65 with al an integer from 0 to 2 . In embodiments , Ring A is not

with al an integer from 0 to 2 . In embodiments , Ring A is not

US 10 , 053 , 433 B2

al ( R ) ai T ( R1

mu -

with al an integer from 0 to 1 . In embodiments , Ring A is with al an integer from 0 to 2 . In embodiments , Ring A is 10 not not

E

( R ' ) al ma ll


not

EN NEN 25

( R ' ) al ! ! no on see him on the

minn 32

NE

30 In embodiments , each R is independently a halogen , CXºz , CN , SO , CI , SONR10 ,

with al an integer from 0 to 2 . In embodiments , Ring A is SO , NR7R8 , _ NHNH , JONR7R8 , - NHC = ( 0 ) not NHNH , NHC = ( O ) NRZR® , ZN ( O ) , I , NRZR * ,

C ( O ) R " , C ( O ) OR , C ( O ) NR7RS , OR10 , - NR7SO _ R10 , NR ? C = ( O ) R , NRC ( O ) OR ” , - NR ’ OR ” , OCX " 3 , OCHXº2 , E , substituted or unsub

stituted alkyl , substituted or unsubstituted heteroalkyl , sub stituted or unsubstituted cycloalkyl , substituted or unsubsti

40 tuted heterocycloalkyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl ; two adjacent R substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl , substituted or unsubstituted

with al an integer from 0 to 1 . In embodiments , Ring A is heterocycloalkyl , substituted or unsubstituted aryl , or sub not 45 stituted or unsubstituted heteroaryl . E is an electrophilic

moiety . Each R ' may independently be - C1 , - F , - Br , - 1 , - CX4 , , - CN , NHNH , LONH , NHC - ( 0 ) NHNH , _ NHC = ( O ) NH , _ NO . , LNH ) , C ( 0 ) H , _ C ( O ) CH? , - C ( O ) - OH , - C ( O ) - OCHZ , - C ( O ) NH , , ( R ' ) a1 50 OH , _ NHC ( 0 ) H , NHC - ( ( ) CH , _ NHC ( 0 ) OH , - NHCONOCH , NHOH , NHOCH , . LOCX " , OCHX " , substituted or unsubstituted C , - C , alkyl , sub

stituted or unsubstituted 2 to 5 membered heteroalkyl , substituted or unsubstituted Cz - Co cycloalkyl , substituted or

with al an integer from 0 to 1 . In embodiments , Ring A is 55 unsubstituted 3 to 6 membered heterocycloalkyl , substituted or unsubstituted phenyl , or substituted or unsubstituted 5 to 6 membered heteroaryl . Each R may independently be E . Each Ri may independently be an optionally different E .

E Each Rl may independently be a — Cl , - F , - Br , — I , 60 CN , CX “ , - NO2 , OCX°3 , or - OCHX ̂ 2 . Each R ' may independently be C1 . Each Rl may independently be - F . Each R ? may independently be — Br . Each R ? may independently be — I . Each R may independently be CXºz . Each R ' may independently be CF3 . Each R !

65 may independently be CN . Each R ' may independently be with al an integer from 0 to 1 . In embodiments , Ring A is — NHNH . Each R may independently be — ONH2 . Each not R ! may independently be NHC = ( O ) NHNH2 . Each R ' may

i Na mu not

( R ) al

pour

US 10 , 053 , 433 B2 43 44

NH miny mi N N mm min tu

mm

to the mm

independently be NHC = ( O ) NH2 . Each Rl may indepen substituted or unsubstituted aldehyde moiety , substituted or dently be — NO2 . Each Ri may independently be — NH , . unsubstituted enone moiety , substituted or unsubstituted Each R ? may independently be - C ( O ) H . Each RI may diazomethylketone moiety , substituted or unsubstituted independently be - C ( O ) CH2 . Each Rl may independently diazomethylamide moiety , substituted or unsubstituted cya be - C ( O ) - OH . Each Rl may independently be - C ( O ) - 5 nocyclopropyl carboxamide moiety , substituted or unsubsti OCH , . Each R may independently be _ C ( O ) NH . . Each R1 tuted epoxide moiety , substituted or unsubstituted epoxyke may independently be OH . Each R ' may independently be tone moiety , substituted or unsubstituted epoxyamide - NHC = ( O ) H . Each R ' may independently be — NHC = moiety , substituted or unsubstituted dialdehyde moiety , sub

( O ) CHz . Each R ' may independently be — NHC ( O ) - OH . stituted or unsubstituted nitrogen mustard moiety , substi Each R ' may independently be NHC ( O ) OCHz . Each R 10 tuted or unsubstituted propargyl moiety , substituted or may independently be — NHOH . Each R ' may indepen unsubstituted propargylamide moiety , — CN , — NO2 , dently be — NHOCHZ . Each RI may independently be - OCX “ 3 . Each R ' may independently be - OCHX42 . Each Rl may independently be substituted or unsubstituted C , - C alkyl , substituted or unsubstituted 2 to 5 membered het - 15 eroalkyl , substituted or unsubstituted Cz - Cocycloalkyl , sub stituted or unsubstituted 3 to 6 membered heterocycloalkyl , substituted or unsubstituted phenyl , or substituted or unsub stituted 5 to 6 membered heteroaryl . Each Rl may indepen dently be unsubstituted C . - C , alkyl , unsubstituted 2 to 5 20 membered heteroalkyl , unsubstituted Cz - Co cycloalkyl , unsubstituted 3 to 6 membered heterocycloalkyl , unsubsti tuted phenyl , or unsubstituted 5 to 6 membered heteroaryl . Each R ' may independently be substituted C . - C , alkyl . Each R ? may independently be unsubstituted C , - C , alkyl . Each R ' 25 may independently be substituted 2 to 5 membered het eroalkyl . Each Rl may independently be unsubstituted 2 to 5 membered heteroalkyl . Each R ? may independently be substituted C3 - C6 cycloalkyl . Each R may independently be unsubstituted Cz - Cocycloalkyl . Each R may independently 30 be substituted 3 to 6 membered heterocycloalkyl . Each R may independently be unsubstituted 3 to 6 membered het erocycloalkyl . Each R ' may independently be substituted phenyl . Each R ' may independently be unsubstituted phe nyl . Each Rl may independently be substituted 5 to 6 35 membered heteroaryl . Each R ? may independently be unsub stituted 5 to 6 membered heteroaryl . In embodiments , two adjacent Rl substituents may be joined to form a substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl , or sub - 40 stituted or unsubstituted heteroaryl . In embodiments , two adjacent Ri substituents may be joined to form a substituted or unsubstituted C3 - Co cycloalkyl , substituted or unsubsti tuted 4 to 6 membered heterocycloalkyl , substituted or unsubstituted phenyl , or substituted or unsubstituted 5 to 6 45 membered heteroaryl . Two adjacent R ' substituents may be joined to form a substituted or unsubstituted Cz - C . cycloalkyl . Two adjacent R ' substituents may be joined to form a substituted or unsubstituted 4 to 6 membered het erocycloalkyl . Two adjacent Ri substituents may be joined 50 to form a substituted or unsubstituted phenyl . Two adjacent R ? substituents may be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl . Two adjacent R ! substituents may be joined to form an unsubstituted Cz - Co cycloalkyl . Two adjacent R ' substituents may be joined to 55 form an unsubstituted 4 to 6 membered heterocycloalkyl . Two adjacent Rl substituents may be joined to form an unsubstituted phenyl . Two adjacent R ' substituents may be joined to form an unsubstituted 5 to 6 membered heteroaryl .

In some embodiments , E includes a substituted or unsub - 60 stituted vinyl sulfone moiety , substituted or unsubstituted vinyl sulfonamide moiety , substituted or unsubstituted fluoro ( C / - C4 ) alkylketone moiety , substituted or unsubsti tuted chloro ( C1 - C4 ) alkylketone moiety , substituted or unsubstituted acrylamide moiety , substituted or unsubsti - 65 tuted disulfide moiety , substituted or unsubstituted thiol moiety , substituted or unsubstituted phosphonate moiety ,

win N Me

min mm Z

in R20

2 - 5

ima mu min til they mi mu NH

w

US 10 , 053 , 433 B2 45 46

- continued - continued CH3

HO mm CH3 Ž - Z CH3 this

tilaxed til the mu mi

CH2CH3

ma min CH3

Am CH3 ,

CHO = HOºH?

mimo mu min min mu man CH3 m mu HlaHias Har mm

- 30 ma Z

in OOH ZE mm m

O = o

m 35

HN noun mi man ZA minn Kith 40

mm mm mm mal 45 nem mu mum RO

im CH3 50

mm CZ U 55 mu min Het try CH3 mum mo ? R20 mu mi 60 * ??

99 mm min wan

US 10 , 053 , 433 B2 48 47

- continued - continued - CHz ,

OAC min R20 CH3 R20

mi mm min OEt , OH 10

HO 0

R20 NH2 , mm OEt , num ni R20

HO )

R20 NH2 , 3 mi mm

20 OF F

OMe P ( OR202 , mi mi mi 25 = o mi min R20 mim mm 30

HN the CF32 EN = N — R20 , = NH , 35 R20 m

R20 Attent Hotty

ti & Mike = N - R N = NH .

mm min min 40

OB w

win NH mo CC13 ( R20 ) 2 , NH mi 45

R20 XXV HN NH

R20 50

SH , CN , O = = min mu mm R20 B R20

55 55 minn , Or ' HS . min ma min OS CN

R20 most min

60 In some embodiments , E is a substituted or unsubstituted vinyl sulfone moiety , substituted or unsubstituted vinyl sulfonamide moiety , substituted or unsubstituted fluoro ( C , C2Jalkylketone moiety , substituted or unsubstituted chloro ( C , - C2Jalkylketone moiety , substituted or unsubstituted

65 acrylamide moiety , substituted or unsubstituted disulfide moiety , substituted or unsubstituted thiol moiety , substituted or unsubstituted phosphonate moiety , substituted or unsub

50 - continued

US 10 , 053 , 433 B2 49

stituted aldehyde moiety , substituted or unsubstituted enone moiety , substituted or unsubstituted diazomethylketone moi ety , substituted or unsubstituted diazomethylamide moiety , substituted or unsubstituted cyanocyclopropyl carboxamide moiety , substituted or unsubstituted epoxide moiety , substi tuted or unsubstituted epoxyketone moiety , substituted or unsubstituted epoxyamide moiety , substituted or unsubsti tuted dialdehyde moiety , substituted or unsubstituted nitro gen mustard moiety , substituted or unsubstituted propargyl moiety , substituted or unsubstituted propargylamide moiety , - CN , — NO ,

mi Me

N - Men mi mi

mon CN ma R20 ww NH wim mm mi

N 20 tyy mi wir tietila mu Me

25

min min R20 mm mu R20

mm mi " than til

mm mm NH V2

Me

te thote mo 0

mm mm Z

wvim DR , 45 OF N m

Me NH Xinje tyti , mu mm wn

mi mun ?? 10llllll wa mm mu min NH

tytis . www mi ma CF3

US 10 , 053 , 433 B2 51 52

- continued - continued - CH3 , tüntetit OAC

mm CHZ CH3

min HO min CH2CH3 HO

OEt , mm ??

Alantyleguir tlak . tayl Hiskia , tha Han tilfin

CHO = HOºH?

mm 20 min min F

www OMe .

CH3 25 : 0 mim mi whter that mm mm 30

H?c CCH , IZ NH

R20 xiak mum min 35

CF ( R20 ) 2 , Hito . this the minn OSS 40 wan = 0 man un * CC13 ( R20 ) 2 , HN mo 45 nan mu w

??3

CH3 nim 50 min HN OS R20 titor - R 2003

mi mia the tid 55

CH3 mi min 60 - R20

CH3 - R20

min mi 99 mi

53 T

- continued 20

R20 R20

min mm

US 10 , 053 , 433 B2 54

unsubstituted diazomethylamide moiety , unsubstituted cya nocyclopropyl carboxamide moiety , unsubstituted epoxide moiety , unsubstituted epoxyketone moiety , unsubstituted epoxyamide moiety , unsubstituted dialdehyde moiety ,

5 unsubstituted nitrogen mustard moiety , unsubstituted prop argyl moiety , or unsubstituted propargylamide moiety . In some embodiments , E is a cyano , an unsubstituted vinyl sulfone moiety , unsubstituted vinyl sulfonamide moiety , unsubstituted fluoro ( C1 - C4 ) alkylketone moiety , unsubsti

10 tuted chloro ( C , - C4 ) alkylketone moiety , unsubstituted acry lamide moiety , unsubstituted disulfide moiety , unsubstituted

NH2 , thiol moiety , unsubstituted phosphonate moiety , unsubsti tuted aldehyde moiety , unsubstituted enone moiety , unsub stituted diazomethylketone moiety , unsubstituted diazom ethylamide moiety , unsubstituted cyanocyclopropyl carboxamide moiety , unsubstituted epoxide moiety , unsub stituted epoxyketone moiety , unsubstituted epoxyamide moiety , unsubstituted dialdehyde moiety , unsubstituted nitrogen mustard moiety , unsubstituted propargyl moiety , or unsubstituted propargylamide moiety .

E may be CN . E may be — NO2 . E may be P ( OR20 ) 2 ,

- R20 vo mi R20

FO R20

NH2 , www R20 mm 20

= O

mum min 25

mi R20 min mi 30 20

E may be — CCH . E may be — CH CCH . E may be _ CHCH2 . E may be

= N = N — R20 , N = NH , min min 3 R20 35 35

NE N - R20 - N = NH , min ?? mm min 40 CN mm E may be

XY * tube XX XXV

E may be ?? mm R20

45 in

mi NH NH

R20

50 E may be SH , CN ,

mi mm mm N SH . 55 55 mi SH . , Or mi MW

CN E may be

Me -

In some embodiments , E comprises a cyano , an unsub - 60 stituted vinyl sulfone moiety , unsubstituted vinyl sulfona mide moiety , unsubstituted fluoro ( C , - C2 ) alkylketone moi ety , unsubstituted chloro ( C , CA Jalkylketone moiety , unsubstituted acrylamide moiety , unsubstituted disulfide moiety , unsubstituted thiol moiety , unsubstituted phospho - 65 nate moiety , unsubstituted aldehyde moiety , unsubstituted enone moiety , unsubstituted diazomethylketone moiety ,

wa

US 10 , 053 , 433 B2 55 56 56 E may be E may be

mi E may be NH

mi 10 E may be E may be

E may be

N wi Illu m

HN

20 E may be E may be

25

N min mi E may be 30 E may be

Me

35 Me . mi

E may be 40 E may be

w

HN 45

E may be E may be

50

Z

55 mum CF3

E may be E may be 60

Me -

min

US 10 , 053 , 433 B2 57 58

E may be E may be

w

mu E may be 10 E may be

Me

Me . mm mu E may be

20 E may be ? mi BIN

25 win E may be

30 E may be

E may be

35

mi in

m 40 E may be E may be

45 mm ZA mm E may be

E may be 50

noun 55 man


min 65 min

US 10 , 053 , 433 B2 59 60

E may be E may be

mim w


F F CH ; m man N CH3 .

CHZ

E may be 20 " E may be 20 E may be

m

25

tratado tlar

. tiada N .

CH3 . mu CH2CH3

30 EDO E may be E may be

CH3 35

CH3 . mu CH2CH = CH2 E may be 40

E may be

n IZ 45


min 55 min E may be

E may be 60

CH3

CH3 . mm 65

US 10 , 053 , 433 B2 61

E may be E may be

min mun HC CH2

10 E may be E may be

. ' S = O . mm NH

E may be E may be

20

CH3 mm NH CH3

E may be mm 25

E may be O =

30

E may be 35

E may be

s = .

mi min 40

E may be E may be

45

www wi 50

E may be E may be

55 CH3 min CH3


CN maan

US 10 , 053 , 433 B2 63 64

E may be E may be

OH

CN .

mi min 10

E may be E may be

CH3

ma O CH3


w F

OAc . 25

mm E may be

30 E may be

w

N . 35 ni OH OMe .


OEt . mm 45 mi E may be

E may be 50

HO O

ww OEt .

55

E may be E may be

8

nem OEt NH mm

US 10 , 053 , 433 B2 65 ? ( 66

E may be E may be

? ? 0

Muny CF3 SS E may be E may be

NNN TCF ( RI ) . unne 53 N

E may be E may be

25 * CC13 ? nnn

E may be ?? 30 ?

?

E may be NUMN TCCI ( R ) . s 35

E may be NH . 40 NANAN

0 R13

E may be ? Nin NH 45

E may be * NH 50 NNNNN ?

vs E may be ?

S5

E may be NH . Mus 60 Emay be

SH . ?? * NNNNN 6

US 10 , 053 , 433 B2 * E may be E may be

NAN NH ?? E may be 10 E may be

* NH SUS ????


SH . ?? N = NH .


?

30 HS ? NNNNA N = NH .


N = NH . AN 40

E may be E may be

- N = NH . 45 CN . NNNNN Anne

E may be 50 Emay be

nnnnw 55 ? NH

CN

E may be E may be A )

CN

* NAN

69 69 E may be

=

V

In embodiments , E is :

R 15

mi R16 R17

US 10 , 053 , 433 B2 70

substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl . R17 is independently hydrogen , halogen , CX17 _ CHX1 ) , , CH , X7 , CN , SO , 1R17 SO , NR174R17B , NHNR174R17B , ONR174R17B , NHC ( O ) NHNR174R17 . NHC ( O ) NR174R17B , N ( 0 ) 17 , NR174R17B , C ( O )

R17C , - C ( O ) - OR11C , - C ( O ) NR174R17B , - OR17D , - NR174SO R17D , NR17ACIÓ ) R17C , NR174C ( O ) OR17C , NR1740R17C , OCX13 , OCHX172 , substi tuted or unsubstituted alkyl , substituted or unsubstituted 10 heteroalkyl , substituted or unsubstituted cycloalkyl , substi tuted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl . R18 is independently hydrogen , — CX18 , CHX18 , CH , X18 , - C ( O ) R18C , - C ( O ) OR 18C , C ( O )

15 NR18?R18B , substituted or unsubstituted alkyl , substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl .

20 Each R154 , R15B , R15C , R150 , R164 , R16B , R16C , R16D . R174 , R17B , RITC , R17D , R184 , R18B , R18C , R18D , is inde pendently hydrogen , CX3 , CN , COOH , CONH2 , CHX , 4CH X , substituted or unsubstituted alkyl , sub

stituted or unsubstituted heteroalkyl , substituted or unsub stituted cycloalkyl , substituted or unsubstituted heterocy . cloalkyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl ; R154 and R15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl ; R164 and RIOB substituents

30 bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl ; R17A and R17B sub stituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocy

35 cloalkyl or substituted or unsubstituted heteroaryl ; R184 and R18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl . Each X , xl5 , x16 , xl7 and X18 is independently — F , C1 ,

40 - Br , or — I . The symbols n15 , n16 , n17 , v15 , v16 , and v17 , are independently and integer from 0 to 4 . The symbols m15 , m16 , and m17 are independently and integer between 1 and

R16 25

0 R15

mm 1 V Y R16 16 R 16

R17 0 R15

y R16 R16 m

ORI mim X ! ? , or

www R 16

OR 18 R17

NRSR 150 Im15 ,

L ' is a bond , 0 , - C ( O ) - , - S , SO , 15 S ( 0 ) 2 - , - N ( R96 ) , NR % C ( O ) , C ( O ) NR96

R15 is independently hydrogen , halogen , CX – SONR96 , NR9 So , - , OC ( O ) NR262 , NR96C - CHX15 , _ CH , X15 , CN , SO , R150 . ( O ) O - , - NR®°C ( O ) NR ” — , substituted or unsubstituted SO5NR154R15B , NHNR154R15B , ONR154R15B , alkylene , substituted or unsubstituted heteroalkylene , sub

– NHC = ( O ) NHNR154R158 , stituted or unsubstituted cycloalkylene , substituted or unsub _ _ NHC ONR15AR 15B _ N O ) _ NR 154R 15B CIO ) sostituted heterocycloalkylene , substituted or unsubstituted

su arylene , or substituted or unsubstituted heteroarylene . In R15C , C ( O ) OR15C , - C ( O ) NR 154R15B , OR150 , embodiments , L ' is a bond , 0 , - C ( O ) - , - S — , - NR154SO R15D , NR154C ( O ) R15C , NR154C ( O ) | SO2 , JS ( O ) , _ , LN ( H ) , - NHCO ) 2 , CO ) OR ' , JNR ' OR , OCX , OCHX2 , substi - NH , SO , NH , NHSO , , OC ( O ) NH NHC tuted or unsubstituted alkyl , substituted or unsubstituted ( O ) O - , - NHC ( O ) NH — substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substi - 55 alkylene , substituted or unsubstituted heteroalkylene , sub tuted or unsubstituted heterocycloalkyl , substituted or stituted or unsubstituted cycloalkylene , substituted or unsub unsubstituted aryl , substituted or unsubstituted heteroaryl . stituted heterocycloalkylene , substituted or unsubstituted R16 is independently hydrogen , halogen , CX163 , CHX16 , arylene , or substituted or unsubstituted heteroarylene . - CH , X16 , CN , SOR160 , SONR164R16B . In embodiments , Ll is a bond . In embodiments , L ' is - NHNR16AR16B , ONR16AR16B , NHC = ( 0 ) 60 — NH — . In embodiments , L ' is - N ( CH3 ) — . In embodi NHNR164R16B , NHCUONR164R16B , LN ( O ) , ments , L ' is - NR16AR 16B , - C ( O ) R16C , - C ( O ) - OR16C , C ( O ) NR164R16B , - OR16D , NR164SO , R16D , NR16ACTO ) R16C , NR164C ( O ) OR16C , NRI?AOR16C , OCX163 , - OCHX12 , substituted or unsubstituted alkyl , substituted 65 or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocycloalkyl ,

to?

US 10 , 053 , 433 B2 71 72

mimo R16

R17

R15

m

R17

Ring C is a substituted or unsubstituted heterocycloalky In embodiments , E is : lene or substituted or unsubstituted heteroarylene . In embodiments , Ring C is an R19 - substituted or unsubstituted heterocycloalkylene or R19 - substituted or unsubstituted het 0 R15 eroarylene . In embodiments , Ring C is an unsubstituted 5 heterocycloalkylene . In embodiments , Ring C is an unsub Y R 16 stituted heteroarylene .

In embodiments , Ring C is substituted heterocycloalky lene . In embodiments , Ring C is substituted heteroarylene . In embodiments , Ring C is an R19 - substituted heterocy - 10 heterocy , 10 and R15 , R16 , and R17 are independently hydrogen . In cloalkylene . In embodiments , Ring C is an R19 - substituted embodiments , E is : heteroarylene . In embodiments , Ring C is an R19 - substituted 5 to 7 membered heterocycloalkylene . In embodiments , Ring Cis an R19 - substituted 5 to 6 membered heteroarylene . In embodiments , Ring C is an unsubstituted 5 to 7 mem - , bered heterocycloalkylene . In embodiments , Ring C is an unsubstituted 5 to 6 membered heteroarylene .

In embodiments , R19 is independently hydrogen , oxo , halogen , CX93 , — CHX192 , - OCH , X " , - CN , OH , - NH2 , COOH , CONH2 , — NO2 , SH , SO , C1 , - SO3H , SO _ H , SO2NH2 , NHNH2 , ONH2 , 20 In embodiments , R15 , R16 , and R17 are independently hydro - NHC = ( O ) NHNH , NHC = ( O ) NH , NHSO , H , gen . NHC = ( O ) H , NHC ( O ) OH , NHOH , OCx1 , In embodiments , E is :

- OCHX192 , R90 - substituted or unsubstituted alkyl , Rºo . substituted or unsubstituted heteroalkyl , Rºº - substituted or unsubstituted cycloalkyl , R90 - substituted or unsubstituted 25 R 15 heterocycloalkyl , Rºº - substituted or unsubstituted aryl , or Rºº - substituted or unsubstituted heteroaryl . Xl9 is halogen . In embodiments , X19 is F .

Rºº is independently oxo halogen , CX9 , CHX9 , OCH , X ” , OCHX ” , 30 — CN , OH , — NH , , - COOH , — CONH2 , — NO2 , — SH , R15 is independently hydrogen : R16 is independently hydro _ SO , Cl , SO2H , SOAH , SO NH , NHNH , gen or CH2NR6AR16B ; R17 is independently hydrogen ; ONH , NHC = ( O ) NHNHA , _ NHC = ( O ) NH , and R164 and R16B are independently hydrogen or unsubsti

– NHSO , H , NHC = ( 0 ) , NHC ( O ) OH , NHOH , tuted alkyl . In embodiments , E is : - OCX°°3 , OCHX92 , R91 - substituted or unsubstituted 33 alkyl , Rºl - substituted or unsubstituted heteroalkyl , Rº substituted or unsubstituted cycloalkyl , Rºl - substituted or R15 unsubstituted heterocycloalkyl , R91 - substituted or unsubsti tuted aryl , or R91 - substituted or unsubstituted heteroaryl . X® is halogen . In embodiments , X9° is F . Rº is independently oxo

halogen , CX°13 , CHX9 _ , — OCH , X ” , - CN , OH , - NH2 , COOH , CONH2 , - NO2 , SH , SO , C1 , SOH , SOH , SONH , NHNH , LONH , In embodiments , R15 is independently hydrogen . In embodi

- NHC = ( O ) NHNH , NHC = ( O ) NH , NHSO , H , 45 45 ments , R 16 is independently hydrogen or — CH NR164R16B . – NHC = ( O ) H , NHCOOH , NHOH , OCXI In embodiments , R17 is independently hydrogen . In embodi - OCHX9 _ , Rº2 - substituted or unsubstituted alkyl , R92 ments , R16A and R16B are independently hydrogen or unsub

stituted alkyl . In embodiments , R16A and R16B are indepen substituted or unsubstituted heteroalkyl , Rº2 - substituted or unsubstituted cycloalkyl , Rº2 - substituted or unsubstituted dently unsubstituted methyl . heterocycloalkyl , Rº2 - substituted or unsubstituted aryl , or 50 In embodiments , E is : Rº2 - substituted or unsubstituted heteroaryl . Xº is halogen . In embodiments , Xºl is F .

In embodiments , E is :

R16

R17

40 R16

R17

RIS

R16 55

R17 my / 17 1 In embodiments , E is :

and Xl7 is Cl . In embodiments , E is : 60

w

R 16

In embodiments , X17 is Cl .

73 73

0 R15 mi R16 R17

R15

R16 R17

XL 17

US 10 , 053 , 433 B2 74

In embodiments , E is : ments , R15 is SOY15NR154R15B . In embodiments , R15 is - NHNR154R15B . In embodiments , R15 is ONR154R15B . In embodiments , R15 is — NHC = ( O ) NHNR154R15B . In embodiments , R15 is - NHC ( O ) NR154R15B . In embodi ments , R15 is — N ( O ) m15 . In embodiments , R15 is - NR154R15B . In embodiments , R15 is C ( O ) R15C . In embodiments , R15 is - C ( O ) - OR15C . In embodiments , R15 is — C ( O ) NR154R15B . In embodiments , R is OR150 . In embodiments , Ris is — NR154SO , R150 . In embodiments ,

In embodiments , E is : 10 R15 is NR154C ( O ) R15C . In embodiments , R15 is - NR154 C ( O ) OR15C . In embodiments , R15 is - NR154 OR15C . In embodiments , R15 is OCX153 . In embodiments , R15 is — OCHX152 . In embodiments , R15 is substituted or unsubstituted alkyl . In embodiments , R15 is substituted or unsubstituted heteroalkyl . In embodiments , R15 is substituted or unsubstituted cycloalkyl . In embodi ments , R15 is substituted or unsubstituted heterocycloalkyl . In embodiments , R15 is substituted or unsubstituted aryl . In embodiments , R15 is substituted or unsubstituted heteroaryl .

In embodiments , E is : 20 In embodiments , Ris is substituted alkyl . In embodiments , R is substituted heteroalkyl . In embodiments , R ' ) is sub stituted cycloalkyl . In embodiments , Ris is substituted het erocycloalkyl . In embodiments , Ris is substituted aryl . In embodiments , RS is substituted heteroaryl . In embodi

25 ments , Ris is unsubstituted alkyl . In embodiments , R15 is unsubstituted heteroalkyl . In embodiments , R15 is unsubsti tuted cycloalkyl . In embodiments , R15 is unsubstituted het

In embodiments , E is : erocycloalkyl . In embodiments , Rls is unsubstituted aryl . In embodiments , R is unsubstituted heteroaryl . In embodi

30 ments , R15 is unsubstituted methyl . In embodiments , R15 is 0 R15 unsubstituted ethyl . In embodiments , Ris is unsubstituted

propyl . In embodiments , RlS is unsubstituted isopropyl . In embodiments , R15 is unsubstituted butyl . In embodiments , R15 is unsubstituted tert - butyl .

35 In embodiments , R154 is unsubstituted hydrogen . In embodiments , R154 is CXz . In embodiments , R154 is

X may independently be F . X may independently be CN . In embodiments , R134 is — COOH . In embodiments , - Cl . X may independently be Br . X may independently R154 is CONH2 . In embodiments , R154 is CHX2 . In be — I . Xls may independently be — F . Xls may indepen embodiments , R154 is — CH X . In embodiments , R154 is dently be — Cl . X15 may independently be — Br . Xls may 40 unsubstituted methyl . In embodiments , R154 is unsubstituted independently be — I . X16 may independently be F . Xl6 ethyl . In embodiments , R154 is unsubstituted propyl . In may independently be — Cl . X16 may independently be embodiments , R154 is unsubstituted isopropyl . In embodi - Br . X16 may independently be - I . Xl7 may indepen - ments , R154 is unsubstituted butyl . In embodiments , R15A is

dently be - F . Xl7 may independently be Cl . Xl7 may unsubstituted tert - butyl . independently be Br . Xl7 may independently be — I . X18 45 In embodiments , R1SB is unsubstituted hydrogen . In may independently be F . X18 may independently be C1 . embodiments , R15B is CX3 . In embodiments , R15B is X18 may independently be — Br . X18 may independently be CN . In embodiments , R15B is – COOH . In embodiments , - I . n15 may independently be 0 . n15 may independently be R1SB is CONH2 . In embodiments , R15B is — CHX2 . In 1 . n15 may independently be 2 . n15 may independently be embodiments , R15B is — CH , X . In embodiments , R15B is 3 . n15 may independently be 4 . n16 may independently be 50 unsubstituted methyl . In embodiments , R15B is unsubstituted 0 . n16 may independently be 1 . n16 may independently be ethyl . In embodiments , R15B is unsubstituted propyl . In 2 . n16 may independently be 3 . n16 may independently be embodiments , RISB is unsubstituted isopropyl . In embodi 4 . n17 may independently be 0 . n17 may independently be ments , R15B is unsubstituted butyl . In embodiments , R15B is 1 . n17 may independently be 2 . n17 may independently be unsubstituted tert - butyl . 3 . n17 may independently be 4 . v15 may independently be 55 In embodiments , R15C is unsubstituted hydrogen . In 0 . v15 may independently be 1 . v15 may independently be embodiments , R15C is CXz . In embodiments , R15C is 2 . v15 may independently be 3 . v15 may independently be CN . In embodiments , R15C is COOH . In embodiments , 4 . v16 may independently be 0 . v16 may independently be R15C is CONH , . In embodiments , R15C is CHX , . In 1 . v16 may independently be 2 . v16 may independently be embodiments , R15C is — CH X . In embodiments , R15C is 3 . v16 may independently be 4 . m15 may independently be 60 unsubstituted methyl . In embodiments , R15C is unsubstituted 1 . m15 may independently be 2 . m16 may independently be ethyl . In embodiments , R15C is unsubstituted propyl . In 1 . m16 may independently be 2 . m17 may independently be embodiments , R15C is unsubstituted isopropyl . In embodi 1 . m17 may independently be 2 . ments , R15C is unsubstituted butyl . In embodiments , R15C is

In embodiments , R15 is hydrogen . In embodiments , R15 is unsubstituted tert - butyl . halogen . In embodiments , R15 is CX153 . In embodiments , 65 In embodiments , R15D is unsubstituted hydrogen . In R15 is CHX152 . In embodiments , R15 is – CH2X15 . In embodiments , R15D is CX3 . In embodiments , R15D is embodiments , R15 is CN , SOR , 15R15D . In embodi - CN . In embodiments , R15D is – COOH . In embodiments ,

XLINE R16 OR 18

R17 R17

US 10 , 053 , 433 B2 75 76

R15D is — CONH , . In embodiments , R15D is CHX , . In CN . In embodiments , R16C is – COOH . In embodiments , embodiments , R15D is CH X . In embodiments , R15D is R16C is CONH , . In embodiments , R16C is CHX , . In unsubstituted methyl . In embodiments , R15D is unsubstituted embodiments , R16C is _ CH _ X . In embodiments , R16C is ethyl . In embodiments , R15D is unsubstituted propyl . In unsubstituted methyl . In embodiments , R16C is unsubstituted embodiments , RSD is unsubstituted isopropyl . In embodi - 5 ethyl . In embodiments , R16C is unsubstituted propyl . In ments , R15D is unsubstituted butyl . In embodiments , R15D is embodiments , R16C is unsubstituted isopropyl . In embodi unsubstituted tert - butyl . ments , R16C is unsubstituted butyl . In embodiments , R16C is In embodiments , R16 is hydrogen . In embodiments , R16 is unsubstituted tert - butyl . halogen . In embodiments , R16 is CX163 . In embodiments , In embodiments , R16D is unsubstituted hydrogen . In R16 is CHX162 . In embodiments , R16 is CH X16 . In 10 embodiments , R16D is — CXz . In embodiments , R16D is embodiments , R16 is CN , SO 15R160 . In embodiments , CN . In embodiments , R16D is — COOH . In embodiments , R16 is SO 15NR164R16B . In embodiments , R16 is - NHNR16AR16B . In embodiments , R16 is ONR164R16B . R16D is — CONH . In embodiments , R16D is CHX , . In

In embodiments , R16 is NHC = ( O ) NHNR164R16B . In embodiments , R16D is CH X . In embodiments , R16D is is unsubstituted embodiments . R16 is _ NHC ( O NR16AR 16B In embodi - 15 unsubstituted methyl . In embodiments , R

ments , R16 is — N ( O ) m15 . In embodiments , R16 is ethyl . In embodiments , R16D is unsubstituted propyl . In NR16AR16B . In embodiments . R16 is _ C ( O ) R16C . In embodiments , R D is unsubstituted isopropyl . In embodi

embodiments , R16 is - C ( O ) - OR16C . In embodiments , R16 ments , RIP is unsubstituted butyl . In embodiments , RIP is is - C ( O ) NR16AR16B . In embodiments , R16 is - OR16D . In unsubstituted tert - butyl . embodiments , R16 is - NR16ASO , R16D . In embodiments , 20 In embodiments , R17 is hydrogen . In embodiments , R17 is R16 is - NR164C ( O ) R16C . In embodiments , R16 is halogen . In embodiments , R17 is CX173 . In embodiments , - NR164C ( O ) OR16C . In embodiments , R16 is R17 is — CHX172 . In embodiments , R17 is CH , X1 ? . In - NR16AOR16C . In embodiments , R16 is OCX163 . In embodiments , R17 is CN , SOL5R17D . In embodiments , embodiments , R16 is OCHX162 . In embodiments , R16 is R17 is — SO 15NR174R17B . In embodiments , R17 is substituted or unsubstituted alkyl . In embodiments , R16 is 25 — NHNR174R17B . In embodiments , R17 is ONR174R17B . substituted or unsubstituted heteroalkyl . In embodiments , In embodiments , R17 is NHC = ( O ) NHNR174R17B . In Rºis substituted or unsubstituted cycloalkyl . In embodi - embodiments , R17 is — NHC ( O ) NR174R17B . In embodi ments , R16 is substituted or unsubstituted heterocycloalkyl . ments , R17 is — N ( O ) m15 . In embodiments , R17 is In embodiments , R16 is substituted or unsubstituted aryl . In - NR174R17B . In embodiments , R17 is C ( O ) R17C . In embodiments , R16 is substituted or unsubstituted heteroaryl . 30 embodiments , R17 is C ( O ) - OR17C . In embodiments , R17 In embodiments , R16 is substituted alkyl . In embodiments , is C ( O ) NR174R17B . In embodiments , R17 is OR17D . In Rio is substituted heteroalkyl . In embodiments , Rio is sub - embodiments , R17 is NR174SO R17D . In embodiments , stituted cycloalkyl . In embodiments , R16 is substituted het - R17 is — NR174C ( O ) R17C . In embodiments , R17 is erocycloalkyl . In embodiments , R16 is substituted aryl . In - NR174C ( O ) OR17C . In embodiments , R17 is embodiments , R16 is substituted heteroaryl . In embodi - 35 NR1740R17C . In embodiments , R17 is - OCX ! ? 3 . In ments , R16 is unsubstituted alkyl . In embodiments , R16 is embodiments , R17 is OCHX172 . In embodiments , R17 is unsubstituted heteroalkyl . In embodiments , R16 is unsubsti - substituted or unsubstituted alkyl . In embodiments , R17 is tuted cycloalkyl . In embodiments , R1 is unsubstituted het - substituted or unsubstituted heteroalkyl . In embodiments , erocycloalkyl . In embodiments , R1 is unsubstituted aryl . In R17 is substituted or unsubstituted cycloalkyl . In embodi embodiments , R16 is unsubstituted heteroaryl . In embodi - 40 ments , R17 is substituted or unsubstituted heterocycloalkyl . ments , R is unsubstituted methyl . In embodiments , Rºis In embodiments , R is substituted or unsubstituted aryl . In unsubstituted ethyl . In embodiments , R16 is unsubstituted embodiments , R17 is substituted or unsubstituted heteroaryl . propyl . In embodiments , R16 is unsubstituted isopropyl . In In embodiments , R17 is substituted alkyl . In embodiments , embodiments , R1 is unsubstituted butyl . In embodiments , R17 is substituted heteroalkyl . In embodiments , R17 is sub R16 is unsubstituted tert - butyl . 45 stituted cycloalkyl . In embodiments , R17 is substituted het

In embodiments , R164 is unsubstituted hydrogen . In erocycloalkyl . In embodiments , R17 is substituted aryl . In embodiments , R164 is CX , . In embodiments , R164 is embodiments , R17 is substituted heteroaryl . In embodi - CN . In embodiments , R16A is — COOH . In embodiments , ments , R17 is unsubstituted alkyl . In embodiments , R17 is R164 is CONH , . In embodiments , R164 is — CHX , . In unsubstituted heteroalkyl . In embodiments , R17 is unsubsti embodiments , R10A is — CH , X . In embodiments , R164 is 50 tuted cycloalkyl . In embodiments , R17 is unsubstituted het unsubstituted methyl . In embodiments , R164 is unsubstituted erocycloalkyl . In embodiments , R17 is unsubstituted aryl . In ethyl . In embodiments , R164 is unsubstituted propyl . In embodiments , R17 is unsubstituted heteroaryl . In embodi embodiments , R16A is unsubstituted isopropyl . In embodi - ments , R17 is unsubstituted methyl . In embodiments , R17 is ments , R16A is unsubstituted butyl . In embodiments , R16A is unsubstituted ethyl . In embodiments , R17 is unsubstituted unsubstituted tert - butyl . 55 propyl . In embodiments , R17 is unsubstituted isopropyl . In

In embodiments , R16B is unsubstituted hydrogen . In embodiments , R17 is unsubstituted butyl . In embodiments , embodiments , R16B is — CXz . In embodiments , R16B is R17 is unsubstituted tert - butyl . - CN . In embodiments , R16B is - COOH . In embodiments , In embodiments , R174 is unsubstituted hydrogen . In

R16B is CONH , . In embodiments , R16B is CHX , . In embodiments , R174 is CX , . In embodiments , R174 is embodiments , R16B is - CH X . In embodiments , R16B is 60 CN . In embodiments , R174 is – COOH . In embodiments , unsubstituted methyl . In embodiments , R16B is unsubstituted R174 is CONH2 . In embodiments , R174 is — CHX2 . In ethyl . In embodiments , R16B is unsubstituted propyl . In embodiments , R17A is CH , X . In embodiments , R17A is embodiments , R16B is unsubstituted isopropyl . In embodi unsubstituted methyl . In embodiments , R174 is unsubstituted ments , R16B is unsubstituted butyl . In embodiments , R16B is ethyl . In embodiments , R174 is unsubstituted propyl . In unsubstituted tert - butyl . 65 embodiments , R174 is unsubstituted isopropyl . In embodi

In embodiments , R16C is unsubstituted hydrogen . In ments , R174 is unsubstituted butyl . In embodiments , R17A is embodiments , R16C is — CXz . In embodiments , R16C is unsubstituted tert - butyl .

m

77 US 10 , 053 , 433 B2

78 In embodiments , R17B is unsubstituted hydrogen . In embodiments , R18 is unsubstituted butyl . In embodiments ,

embodiments , R17B is CX , . In embodiments , R17B is R18 is unsubstituted tert - butyl . - CN . In embodiments , R17B is — COOH . In embodiments , In embodiments , R184 is unsubstituted hydrogen . In R17B is CONH , . In embodiments , R17B is — CHX2 . In embodiments , R184 is — CXz . In embodiments , R18A is embodiments , R17B is _ CH , X . In embodiments , R17B is 5 - CN . In embodiments , R18A is – COOH . In embodiments , unsubstituted methyl . In embodiments , R17B is unsubstituted R184 is CONH2 . In embodiments , R184 is CHX2 . In ethyl . In embodiments , R17B is unsubstituted propyl . In embodiments , R184 is CH X . In embodiments , R184 is embodiments , R17B is unsubstituted isopropyl . In embodi unsubstituted methyl . In embodiments , R18A is unsubstituted ments , R17B is unsubstituted butyl . In embodiments , R17B is ethyl . In embodiments , R184 is unsubstituted propyl . In

10 embodiments , R18A is unsubstituted isopropyl . In embodi unsubstituted tert - butyl . In embodiments , R17C is unsubstituted hydrogen . In ments , R18A is unsubstituted butyl . In embodiments , R18A is

unsubstituted tert - butyl . embodiments , R17C is — CXz . In embodiments , R17C is In embodiments , R18B is unsubstituted hydrogen . In CN . In embodiments , R17C is - COOH . In embodiments , embodiments , R18B is CXz . In embodiments , R18B is R17C is CONH2 . In embodiments , R17C is CHX . In 12 . 15 CN . In embodiments , R18B is – COOH . In embodiments , embodiments , R17C is — CH X . In embodiments , R17C is R18B is CONH , . In embodiments , R18B is — CHX , . In unsubstituted methyl . In embodiments , R ' ' is unsubstituted embodiments , R18B is - CH X . In embodiments , R18B is ethyl . In embodiments , R17C is unsubstituted propyl . In unsubstituted methyl . In embodiments , R18B is unsubstituted embodiments , R17C is unsubstituted isopropyl . In embodi ethyl . In embodiments , R18B is unsubstituted propyl . In ments , R17C is unsubstituted butyl . In embodiments , R17 is 20 embodiments , R18B is unsubstituted isopropyl . In embodi unsubstituted tert - butyl . ments , R18B is unsubstituted butyl . In embodiments , R18B is

In embodiments , R17D is unsubstituted hydrogen . In unsubstituted tert - butyl . embodiments , Ri7D is — CXz . In embodiments , R17D is In embodiments , R18C is unsubstituted hydrogen . In - CN . In embodiments , R17D is COOH . In embodiments , embodiments , R18C is — CXz . In embodiments , R18C is R17D is – CONH , . In embodiments , R17D is _ CHX , . In 25 CN . In embodiments , R18C is — COOH . In embodiments , embodiments , R17D is CH X . In embodiments , R17D is R18C is — CONH , . In embodiments , R18C is — CHX , . In unsubstituted methyl . In embodiments , R17D is unsubstituted embodiments , R18C is CH X . In embodiments , R18C is ethyl . In embodiments , R17D is unsubstituted propyl . In unsubstituted methyl . In embodiments , R18C is unsubstituted embodiments , R17D is unsubstituted isopropyl . In embodi ethyl . In embodiments , R18C is unsubstituted propyl . In ments , R17D is unsubstituted butyl . In embodiments , R17D is 30 embodiments , R18C is unsubstituted isopropyl . In embodi unsubstituted tert - butyl . ments , R18C is unsubstituted butyl . In embodiments , R18C is

In embodiments , R18 is hydrogen . In embodiments , R18 is unsubstituted tert - butyl . halogen . In embodiments , R18 is CX187 . In embodiments , In embodiments , R18D is unsubstituted hydrogen . In R18 is — CHX182 . In embodiments , R18 is CH , X18 . In embodiments , R18D is — CXz . In embodiments , R18D is embodiments , R18 is - CN , SO , R18D . In embodiments , 35 CN . In embodiments , R18D is – COOH . In embodiments , R18 is SO , 15NR18AR18B . In embodiments , R18 is R18D is CONH2 . In embodiments , R18D is CHX . In - NHNR18AR188 . In embodiments , R18 is ONR18AR18B . embodiments , R18D is CH X . In embodiments , R18D is In embodiments , R18 is — NHC = ( O ) NHNR184R 18B . In unsubstituted methyl . In embodiments , R18D is unsubstituted embodiments , R18 is — NHC ( O ) NR 184R18B . In embodi - ethyl . In embodiments , R18D is unsubstituted propyl . In ments , R18 is — N ( O ) 15 . In embodiments , R18 is 40 embodiments , R18D is unsubstituted isopropyl . In embodi - NR184R18B . In embodiments , R18 is - C ( O ) R18C . In ments , R18D is unsubstituted butyl . In embodiments , R18D is embodiments , R18 is - C ( O ) - OR18C . In embodiments , R18 unsubstituted tert - butyl . is - C ( O ) NR 184R 18B . In embodiments , R18 is OR18D . In Ring B may be phenyl . Ring B may be heteroaryl . Ring embodiments , R18 is - NR18ASO , R18D . In embodiments , B may be a 6 membered heteroaryl . Ring B may be R18 is — NR184C ( O ) R18C . In embodiments , R18 is 45 pyridinyl . Ring B may be pyrazinyl . Ring B may be pyrim

NR184C ( O ) OR18C . In embodiments , R18 is idinyl . Ring B may be pyridazinyl . Ring B may be triazinyl . - NR18AOR18C . In embodiments , R18 is _ OCX182 . In Ring B may be 1 , 2 , 3 - triazinyl . Ring B may be 1 , 2 , 4 , embodiments , R18 is — OCHX182 . In embodiments , R18 is triazinyl . Ring B may be 1 , 3 , 5 - triazinyl . substituted or unsubstituted alkyl . In embodiments , R18 is Ring B may be a 5 membered heteroaryl . In embodi substituted or unsubstituted heteroalkyl . In embodiments , 50 ments , Ring B is a pyridinyl , pyrimidinyl , thiophenyl , thie R18 is substituted or unsubstituted cycloalkyl . In embodi - nyl , furanyl , indolyl , benzoxadiazolyl , benzodioxolyl , ben ments , R18 is substituted or unsubstituted heterocycloalkyl . zodioxanyl , thianaphthanyl , pyrrolopyridinyl , indazolyl , In embodiments , R18 is substituted or unsubstituted aryl . In quinolinyl , quinoxalinyl , pyridopyrazinyl , quinazolinonyl , embodiments , R18 is substituted or unsubstituted heteroaryl . benzoisoxazolyl , imidazopyridinyl , benzofuranyl , benzoth In embodiments , R18 is substituted alkyl . In embodiments , 55 ienyl , benzothiophenyl , phenyl , pyrrolyl , pyrazolyl , imida R18 is substituted heteroalkyl . In embodiments , R18 is sub zolyl , pyrazinyl , oxazolyl , isoxazolyl , thiazolyl , furylthie stituted cycloalkyl . In embodiments , R18 is substituted het - nyl , pyridyl , pyrimidyl , benzothiazolyl , purinyl , erocycloalkyl . In embodiments , R18 is substituted aryl . In benzimidazolyl , isoquinolyl , thiadiazolyl , oxadiazolyl , pyr embodiments , R18 is substituted heteroaryl . In embodi - rolyl , diazolyl , triazolyl , tetrazolyl , benzothiadiazolyl , iso ments , R18 is unsubstituted alkyl . In embodiments , R18 is 60 thiazolyl , pyrazolopyrimidinyl , pyrrolopyrimidinyl , benzo unsubstituted heteroalkyl . In embodiments , R18 is unsubsti - triazolyl , benzoxazolyl , or quinolyl . tuted cycloalkyl . In embodiments , R18 is unsubstituted het . In embodiments , R2 is independently a erocycloalkyl . In embodiments , R18 is unsubstituted aryl . In halogen , CX3 , CN , SO , C1 , SO , R14 , embodiments , R18 is unsubstituted heteroaryl . In embodi - SONR1R12 , NHNH , , ONRI ' R1 ? , — NHC = ( 0 ) ments , R18 is unsubstituted methyl . In embodiments , R18 is 65 NHNH , , unsubstituted ethyl . In embodiments , R18 is unsubstituted NHC ( O ) NR ' R12 , N ( O ) , NR ' lR12 , CO ) R3 , propyl . In embodiments , R18 is unsubstituted isopropyl . In - C ( O ) OR13 , C ( O ) NRR ? , OR14 , - NRSO R14 ,

79 US 10 , 053 , 433 B2

80 NRIC ( O ) R13 , NRIC ( O ) OR13 , NRIOR13 , may independently be substituted 3 to 6 membered hetero

- OCX , OCHX " , substituted or unsubstituted alkyl , cycloalkyl . Each R ? may independently be unsubstituted 3 to substituted or unsubstituted heteroalkyl , substituted or 6 membered heterocycloalkyl . Each R may independently unsubstituted cycloalkyl , substituted or unsubstituted het be substituted phenyl . Each R ’ may independently be unsub erocycloalkyl , substituted or unsubstituted aryl , or substi - 5 stituted phenyl . Each R2 may independently be substituted 5 tuted or unsubstituted heteroaryl ; two adjacent R ? substitu - to 6 membered heteroaryl . Each R ? may independently be ents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heteroaryl . unsubstituted cycloalkyl , substituted or unsubstituted het - In embodiments , two adjacent R ? substituents may be erocycloalkyl , substituted or unsubstituted aryl , or substi - joined to form a substituted or unsubstituted cycloalkyl , tuted or unsubstituted heteroaryl . In embodiments , R2 is 10 substituted or unsubstituted heterocycloalkyl , substituted or independently a halogen , — CX " > , - C ( O ) NHCH? , substi - unsubstituted aryl , or substituted or unsubstituted heteroaryl . tuted or unsubstituted C , - C alkyl , substituted or unsubsti - In embodiments , two adjacent R2 substituents may be joined tuted 2 to 5 membered heteroalkyl , substituted or unsubsti - to form a substituted or unsubstituted C3 - Co cycloalkyl , tuted Cz - Co cycloalkyl , substituted or unsubstituted 3 to 6 substituted or unsubstituted 4 to 6 membered heterocy membered heterocycloalkyl , substituted or unsubstituted 15 cloalkyl , substituted or unsubstituted phenyl , or substituted phenyl , or substituted or unsubstituted 5 to 6 membered or unsubstituted 5 to 6 membered heteroaryl . Two adjacent heteroaryl . Each R2 may independently be — C1 , - F , - Br , R2 substituents may be joined to form a substituted or

I , C?T , C ( O ) NHCH , CN , NHNHA , ONH ) , unsubstituted C3 - C6 cycloalkyl . Two adjacent R ? substitu — NHC ( O ) NHNH , NHC = ( O ) NH , — NO2 , — NH2 , ents may be joined to form a substituted or unsubstituted 4 - C ( O ) H , C ( O ) CHz , - C ( O ) - OH , C ( O ) - OCHZ , 20 to 6 membered heterocycloalkyl . Two adjacent R ? substitu

C ( O ) NH , JOH , ?NHC = ( 0 ) , _ NHC ( O ) CH , , ents may be joined to form a substituted or unsubstituted - NHC ( O ) - OH , NHC ( O ) OCH3 , NHOH , phenyl . Two adjacent R² substituents may be joined to form — NHOCHZ . - OCX3 , OCHX® 2 , substituted or unsub - a substituted or unsubstituted 5 to 6 membered heteroaryl .

stituted C - Co alkyl , substituted or unsubstituted 2 to 5 Two adjacent R2 substituents may be joined to form an membered heteroalkyl , substituted or unsubstituted Cz - Co 25 unsubstituted Cz - Co cycloalkyl . Two adjacent R ? substitu cycloalkyl , substituted or unsubstituted 3 to 6 membered ents may be joined to form an unsubstituted 4 to 6 membered heterocycloalkyl , substituted or unsubstituted phenyl , or heterocycloalkyl . Two adjacent R2 substituents may be substituted or unsubstituted 5 to 6 membered heteroaryl . joined to form an unsubstituted phenyl . Two adjacent R ?

Each R ? may independently be a - C ( O ) NHCHZ , — C1 , substituents may be joined to form an unsubstituted 5 to 6 - F , - Br , - 1 , CX 3 , 4NO2 , OCX " 3 , or — OCHX " . 30 membered heteroaryl . Each R ? may independently be - C ( O ) NHCH3 . Each R2 In embodiments , R² is independently - C ( O ) NR1R12 , may independently be — C1 . Each R ? may independently be halogen , substituted or unsubstituted alkyl , or substituted or - F . Each R ? may independently be — Br . Each R2 may unsubstituted heteroalkyl . In embodiments , R2 is indepen independently be — I . Each R ? may independently be dently - C ( O ) NR ' R ' , halogen , substituted or unsubsti - CX 3 . Each R ’ may independently be CN . Each R ? may 35 tuted C - C , alkyl , or substituted or unsubstituted 2 to 8 independently be - NHNH2 . Each R ? may independently be membered heteroalkyl . In embodiments , R2 is independently - ONH . Each R² may independently be — NHC = ( 0 ) - C ( O ) NRI R12 halogen , substituted or unsubstituted C . - C , NHNH2 . Each R ? may independently be — NHC = ( O ) NH2 . alkyl , or substituted or unsubstituted 2 to 5 membered Each R2 may independently be — NO , . Each R2 may inde - heteroalkyl . In embodiments , R2 is independently - C ( O ) pendently be - NH2 . Each R ? may independently be - C ( O ) 40 NHR11 , halogen , substituted or unsubstituted C - Cz alkyl , or H . Each R ? may independently be - C ( O ) CHz . Each R ? may substituted or unsubstituted 2 to 5 membered heteroalkyl . In independently be _ C ( O ) OH . Each R ? may independently embodiments , R2 is independently - C ( O ) NHR11 , halogen , be - C ( O ) OCHz . Each R ? may independently be C ( O ) unsubstituted C . - C5 alkyl , or unsubstituted 2 to 5 membered NH , . Each R ? may independently be — OH . Each R ? may h eteroalkyl . In embodiments , R is independently - C ( O ) independently be — NHC = ( O ) H . Each R2 may indepen - 45 NHR11 , halogen , substituted C , - C , alkyl , or substituted 2 to dently be — NHC = ( O ) CH2 . Each R ? may independently be 5 membered heteroalkyl . In embodiments , R is indepen — NHC ( O ) OH . Each R ? may independently be — NHC ( O ) dently - C ( O ) NHR11 . In embodiments , R2 is independently OCHz . Each R ? may independently be — NHOH . Each R2 halogen . In embodiments , R2 is independently substituted or may independently be — NHOCHZ . Each R ? may indepen - unsubstituted C . - C , alkyl . In embodiments , R2 is indepen dently be OCX 3 . Each R2 may independently be 50 dently substituted or unsubstituted 2 to 5 membered het - OCHX 2 . Each R ? may independently be substituted or eroalkyl . unsubstituted C - C5 alkyl , substituted or unsubstituted 2 to In embodiments , R2 is independently C ( O ) NHR11 . In 5 membered heteroalkyl , substituted or unsubstituted C3 - C6 embodiments , R is independently substituted or unsubsti cycloalkyl , substituted or unsubstituted 3 to 6 membered tuted alkyl , substituted or unsubstituted heteroalkyl , substi heterocycloalkyl , substituted or unsubstituted phenyl , or 55 tuted or unsubstituted cycloalkyl , or substituted or unsub substituted or unsubstituted 5 to 6 membered heteroaryl . stituted heterocycloalkyl . In embodiments , R11 is Each R ? may independently be unsubstituted C , - C , alkyl , independently substituted or unsubstituted C - C , alkyl , sub unsubstituted 2 to 5 membered heteroalkyl , unsubstituted stituted or unsubstituted 2 to 8 membered heteroalkyl , C2 - Co cycloalkyl , unsubstituted 3 to 6 membered heterocy - substituted or unsubstituted Cz - C , cycloalkyl , substituted or cloalkyl , unsubstituted phenyl , or unsubstituted 5 to 6 mem - 60 unsubstituted 3 to 8 membered heterocycloalkyl . In embodi bered heteroaryl . Each R ? may independently be substituted ments , R11 is independently substituted or unsubstituted C , - C , alkyl . Each R may independently be unsubstituted C . - C , alkyl , substituted or unsubstituted 2 to 5 membered C - C , alkyl . Each R ? may independently be substituted 2 to heteroalkyl , substituted or unsubstituted C3 - C , cycloalkyl , 5 membered heteroalkyl . Each R ? may independently be substituted or unsubstituted 3 to 5 membered heterocy unsubstituted 2 to 5 membered heteroalkyl . Each R ? may 65 cloalkyl . In embodiments , Rll is independently substituted independently be substituted Cz - Cocycloalkyl . Each R may or unsubstituted C , - C , alkyl or substituted or unsubstituted independently be unsubstituted Cz - Co cycloalkyl . Each R2 2 to 5 membered heteroalkyl . In embodiments , R is inde

82

R21

R22

US 10 , 053 , 433 B2 81

pendently substituted or unsubstituted C . - C , alkyl . In embodiments , R21 is independently - C ( O ) NHR11 . In embodiments , Rl1 is independently substituted or unsubsti - embodiments , R2 is independently halogen . In embodi tuted C1 - C4 alkyl . In embodiments , R11 is independently ments , R21 is independently substituted or unsubstituted substituted or unsubstituted C . - C , alkyl . In embodiments , C1 - C5 alkyl . In embodiments , Rº is independently substi R11 is independently unsubstituted C . - C . alkyl , unsubsti - 5 tuted or unsubstituted 2 to 5 membered heteroalkyl . In tuted 2 to 5 membered heteroalkyl , unsubstituted C3 - C5 embodiments , R21 is independently hydrogen . In embodi cycloalkyl , or unsubstituted 3 to 5 membered heterocy ments , R2 . 1 is independently — F . In embodiments , R21 is cloalkyl . In embodiments , R11 is independently unsubsti independently Cl . In embodiments , R2 . 1 is independently

Br . In embodiments , R21 is independently — I . tuted CZ - C , alkyl or unsubstituted 2 to 5 membered het eroalkyl . In embodiments , R1 is independently 1 10 In embodiments , R2 . 2 is independently C ( O ) NRI ' R12 ,

halogen , substituted or unsubstituted alkyl , or substituted or unsubstituted C , - C , alkyl . In embodiments , R11 is indepen unsubstituted heteroalkyl . In embodiments , R2 . 2 is indepen dently unsubstituted C , - C4 alkyl . In embodiments , Rl is dently - C ( O ) NRTR12 , halogen , substituted or unsubsti independently unsubstituted C - Cz alkyl . In embodiments , tuted C , - C , alkyl , or substituted or unsubstituted 2 to 8 Rll is independently substituted C , - C , alkyl , substituted 2 to 15 membered heteroalkyl . In embodiments , R2 . 2 is indepen 5 membered heteroalkyl , substituted C3 - C , cycloalkyl , or dently - C ( O ) NR1R12 , halogen , substituted or unsubsti substituted 3 to 5 membered heterocycloalkyl . In embodi tuted C - C5 alkyl , or substituted or unsubstituted 2 to 5 ments , R11 is independently substituted C - Cs alkyl or sub membered heteroalkyl . In embodiments , R2 . 2 is indepen stituted 2 to 5 membered heteroalkyl . In embodiments , R11 dently — C ( O ) NHR11 , halogen , substituted or unsubstituted is independently substituted C1 - C5 alkyl . In embodiments , 20 C , - C , alkyl , or substituted or unsubstituted 2 to 5 membered R ! ! is independently substituted C , - C4 alkyl . In embodi heteroalkyl . In embodiments , R2 . 2 is independently C ( O ) ments , R is independently substituted C - Cz alkyl . NHR ' , halogen , unsubstituted C . - C . alkyl , or unsubstituted

In embodiments , the compound is 2 to 5 membered heteroalkyl . In embodiments , R2 . 2 is independently - C ( O ) NHR , halogen , substituted C . - C .

25 alkyl , or substituted 2 to 5 membered heteroalkyl . In embodiments , R2 . 2 is independently C ( O ) NHR11 . In embodiments , R2 is independently halogen . In embodi ments , R2 . 2 is independently substituted or unsubstituted C - C5 alkyl . In embodiments , R2 . 2 is independently substi ( RA 30 tuted or unsubstituted 2 to 5 membered heteroalkyl . In embodiments , R2 . 2 is independently hydrogen . In embodi

HO CH3 0 ments , R2 . 2 is independently — F . In embodiments , R2 . 2 is independently Cl . In embodiments , R2 . 2 is independently

wherein R ' , Ring A , and al are as described herein , includ - Br . In embodiments , R2 . 2 is independently — I . 35 In embodiments , R21 is independently - C ( O ) NHR11 . In ing in embodiments . In embodiments , the compound is embodiments , R2 . 2 is independently - C ( O ) NHR11 . In

embodiments , R11 is independently substituted or unsubsti tuted alkyl , substituted or unsubstituted heteroalkyl , substi tuted or unsubstituted cycloalkyl , or substituted or unsub

40 stituted heterocycloalkyl . In embodiments , R11 is independently substituted or unsubstituted Cz - C , alkyl , sub

( R ! ) a1 stituted or unsubstituted 2 to 8 membered heteroalkyl , substituted or unsubstituted Cz - Cg cycloalkyl , substituted or

HO CHz ? unsubstituted 3 to 8 membered heterocycloalkyl . In embodi 45 ments , R11 is independently substituted or unsubstituted

C - C5 alkyl , substituted or unsubstituted 2 to 5 membered wherein R1 , Ring A , and al are as described herein , includ - heteroalkyl , substituted or unsubstituted Cz - C , cycloalkyl , ing in embodiments . R2 . 1 and R2 . 2 are each an independent substituted or unsubstituted 3 to 5 membered heterocy R2 . In embodiments , R2 . 1 is as described herein for R2 cloalkyl . In embodiments , Rl is independently substituted including embodiments . In embodiments , R2 . 2 is as 50 or unsubstituted C , - C , alkyl or substituted or unsubstituted described herein for R2 including embodiments . 2 to 5 membered heteroalkyl . In embodiments , Rll is inde

In embodiments , R21 is independently C ( O ) NR1R12 , pendently substituted or unsubstituted C - C5 alkyl . In halogen , substituted or unsubstituted alkyl , or substituted or embodiments , R is independently substituted or unsubsti unsubstituted heteroalkyl . In embodiments , R2 . 1 is indepen - tuted C . - C . alkyl . In embodiments , R11 is independently dently - C ( O ) NRIR12 , halogen , substituted or unsubsti - 55 substituted or unsubstituted C - Cz alkyl . In embodiments , tuted C . - C , alkyl , or substituted or unsubstituted 2 to 8 Rll is independently unsubstituted C , - C alkyl , unsubsti membered heteroalkyl . In embodiments , R2 . 1 is indepen - tuted 2 to 5 membered heteroalkyl , unsubstituted Cz - C5 dently - C ( O ) NRR12 , halogen , substituted or unsubsti cycloalkyl , or unsubstituted 3 to 5 membered heterocy tuted C1 - C5 alkyl , or substituted or unsubstituted 2 to 5 cloalkyl . In embodiments , R11 is independently unsubsti membered heteroalkyl . In embodiments , R21 is indepen - 60 tuted C . - C , alkyl or unsubstituted 2 to 5 membered het dently - C ( O ) NHR11 , halogen , substituted or unsubstituted eroalkyl . In embodiments , R11 is independently C . - C , alkyl , or substituted or unsubstituted 2 to 5 membered unsubstituted C , - Cs alkyl . In embodiments , R11 is indepen heteroalkyl . In embodiments , R21 is independently C ( O ) dently unsubstituted C . - C4 alkyl . In embodiments , R11 is NHR " , halogen , unsubstituted C , - C , alkyl , or unsubstituted independently unsubstituted C , - C alkyl . In embodiments , 2 to 5 membered heteroalkyl . In embodiments , R2 . 1 is 65 R is independently substituted C , - C , alkyl , substituted 2 to independently C ( O ) NHR ! ! , halogen , substituted C - C5 5 membered heteroalkyl , substituted C3 - C , cycloalkyl , or alkyl , or substituted 2 to 5 membered heteroalkyl . In substituted 3 to 5 membered heterocycloalkyl . In embodi

R2 . 1

R

US 10 , 053 , 433 B2 83 84

NH

is

N

ments , Rll is independently substituted C - C5 alkyl or sub wherein R ' , X ” , Ring A , and al are as described herein , stituted 2 to 5 membered heteroalkyl . In embodiments , R11 including in embodiments . In embodiments , the compound is independently substituted C , - C , alkyl . In embodiments , R1 is independently substituted C . - C4 alkyl . In embodi ments , RlI is independently substituted C , - Cz alkyl . 5

In embodiments , R21 is independently hydrogen and R2 . 2 o is independently C ( O ) NHR11 and R11 is independently unsubstituted C , - Cz alkyl . In embodiments , R21 is indepen dently hydrogen and R2 . 2 is independently unsubstituted 10 ( R ) - + A C - C5 alkyl . In embodiments , R2 . 1 is independently hydro gen and R2 . 2 is independently unsubstituted C - Cz haloalkyl . In embodiments , R2 is independently hydrogen and R2 . 2 is HO CH? ? independently halogen . In embodiments , R21 is indepen dently hydrogen and R " is independently — F . In embodi - 15 wherein R ' , X ” , Ring A , and al are as described herein , ments , R “ is independently hydrogen and R - - is indepen - including in embodiments . In embodiments , the compound dently C , haloalkyl . In embodiments , R2 . 1 is independently hydrogen and R2 . 2 is independently methyl . In embodi ments , R2 . 1 is independently hydrogen and R2 . 2 is indepen dently CF3 . In embodiments , R21 is independently hydro - 20 gen and R2 . 2 is independently CHF2 . In embodiments , R21 is independently hydrogen and R2 . 2 is independently - CH , F .

In embodiments , R21 is independently halogen and R2 - 2 is independently - C ( O ) NHR11 and Rll is independently 25 ( R ' ) a - tA unsubstituted C . - C , alkyl . In embodiments , R21 is indepen dently halogen and R2 . 2 is independently unsubstituted HÓ CH3 0 C - C5 alkyl . In embodiments , R2 . 1 is independently halogen and R2 . 2 is independently unsubstituted C - C , haloalkyl . In embodiments , R21 is independently halogen and R2 . 2 is 30 wherein R ' , X ' , Ring A , and al are as described herein , independently halogen . In embodiments , R2 . 1 is indepen including in embodiments . In embodiments , the compound dently halogen and R2 . 2 is independently — F . In embodi - is ments , R21 is independently halogen and R2 . 2 is indepen dently C , haloalkyl . In embodiments , R21 is independently halogen and R2 . 2 is independently methyl . In embodiments , 35 R21 is independently halogen and R2 . 2 is independently - CFz . In embodiments , R21 is independently halogen and R2 . 2 is independently — CHF2 . In embodiments , R21 is independently halogen and R2 . 2 is independently — CH , F .

In embodiments , R21 is independently — F and R2 . 2 is 40 ( R ' ) aita independently - C ( O ) NHR11 and Rll is independently unsubstituted C - C , alkyl . In embodiments , R21 is indepen HO CH3 0 dently — F and R2 . 2 is independently unsubstituted C . - C , alkyl . In embodiments , R21 is independently — F and R2 . 2 is independently unsubstituted C , - Cz haloalkyl . In embodi - 45 wherein R ' , Xb , Ring A , and al are as described herein , ments , R21 is independently F and R2 . 2 is independently including in embodiments . In embodiments , Xb is - F . halogen . In embodiments , R21 is independently — F and R2 . 2 R3 may be an unsubstituted C , - C , , alkyl . R may be an is independently — F . In embodiments , R21 is independently unsubstituted C . - C , alkyl . Rºmay be an unsubstituted C - C6 — F and R2 . 2 is independently C , haloalkyl . In embodiments , alkyl . R ? may be an unsubstituted C , - C , alkyl . R™ may be an R21 is independently — F and R2 . 2 is independently methyl . 50 unsubstituted C , - C4 alkyl . R3 may be an unsubstituted C - C3 In embodiments , R21 is independently — F and R2 . 2 is alkyl . R3 may be an unsubstituted C , - C , alkyl . Rºmay be an independently CF3 . In embodiments , R2 . 1 is indepen - unsubstituted methyl . R3 may be an unsubstituted ethyl . R3 dently — F and R2 . 2 is independently CHF2 . In embodi - may be an unsubstituted propyl . R3 may be an unsubstituted ments , R21 is independently — F and R2 . 2 is independently butyl . R3 may be an unsubstituted pentyl . R3 may be an

CH , F . 55 unsubstituted C , - C5 alkenyl . In embodiments , the compound is Each R7 , R8 , RP , RIO , R1 , R2 , R13 , and R14 may

independently be hydrogen , halogen , CX®3 , CN , OH , - NH2 , COOH , CONH2 , — NO2 , SH , — SO , C1 , - SO3H , SO4H , SO NH2 , — NHNH2 , ONH2 ,

60 NHC = ( O ) NHNH , NHC - ( 0 ) NHA , _ NHSOH , - NHC = ( O ) H , _ NHC ( O ) OH , _ NHOH , OCX , OCHX® 2 , substituted or unsubstituted alkyl , substituted or ( R ' ) aita unsubstituted heteroalkyl , substituted or unsubstituted

cycloalkyl , substituted or unsubstituted heterocycloalkyl , HÓ CH3 © 65 substituted or unsubstituted aryl , or substituted or unsubsti

tuted heteroaryl . Each R ? , R8 , R9 , R10 , R1 , R12 , R13 , and R14 may independently be hydrogen , halogen , CF3 ,

IZ

au @ i

- F .

E E

US 10 , 053 , 433 B2 85 86

CN , OH , - NH2 , COOH , CONH2 , - NO2 , SH , The symbol al may be 0 . The symbol al may be 1 . The - S02Cl , SO2H , SO H , SO NH , NHNH2 , symbol al may be 2 . The symbol al may be 3 . The symbol ONH , NHC = ( O ) NHNH , NHC = ( O ) NHA , al may be 4 .

– NHSO , H , NHC = ( 0 ) H , NHC ( O ) OH , NHOH , The symbol b1 may be 0 . The symbol b1 may be 1 . The - OCF2 , - OCHF ) , substituted or unsubstituted alkyl , sub - 5 symbol b1 may be 2 . The symbol b1 may be 3 . The symbol stituted or unsubstituted heteroalkyl , substituted or unsub stituted cycloalkyl , substituted or unsubstituted heterocy b1 may be 4 . The symbol b1 may be 5 . cloalkyl , substituted or unsubstituted aryl , or substituted or The symbols ml may be 1 . The symbols ml may be 2 . unsubstituted heteroaryl . Each R ? , R8 , R9 , R19 , R1 , R12 , The symbols m2 may be 1 . The symbols m2 may be 2 . R ' s , and R ! 4 may independently be hydrogen , substituted or 10 The symbols v1 may be 1 . The symbols v1 may be 2 . The unsubstituted alkyl , substituted or unsubstituted heteroalkyl , symbols v2 may be 1 . The symbols v2 may be 2 . substituted or unsubstituted cycloalkyl , substituted or unsub stituted heterocycloalkyl , substituted or unsubstituted aryl , The symbol nl may be 0 . The symbol nl may be 1 . The or substituted or unsubstituted heteroarvl . Each R7 R8 R9 . symbol nl may be 2 . The symbol nl may be 3 . The symbol R10 , R11 , R12 R13 , and R14 may independently be hydrogen , 15 nl may be 4 . unsubstituted alkyl , unsubstituted heteroalkyl , unsubstituted The symbol n2 may be 0 . The symbol n2 may be 1 . The cycloalkyl , unsubstituted heterocycloalkyl , unsubstituted symbol n2 may be 2 . The symbol n2 may be 3 . The symbol aryl , or unsubstituted heteroaryl . Each R ? , R8 , R9 , R19 , R11 , yl . Each R ' , R , R , R , R . ; n2 may be 4 . R12 , R13 , and R14 may independently be hydrogen , substi tuted or unsubstituted C . - C , alkyl , substituted or unsubsti - 20 The symbol Xa may be Cl . The symbol Xa may be tuted 2 to 8 membered heteroalkyl , substituted or unsubsti - Br . The symbol X “ may be — I . The symbol X “ may be tuted Cz - C , cycloalkyl , substituted or unsubstituted 3 to 8 membered heterocycloalkyl , substituted or unsubstituted The symbol X may be Cl . The symbol X may be C . - C . aryl , or substituted or unsubstituted 5 to 10 mem - Br . The symbol X may be — I . The symbol X ” may be bered heteroaryl . Each R ' , R8 , R9 , R19 , R1 , R12 , R13 , and 25 F . R14 may independently be hydrogen , unsubstituted C . - C . The symbol X® may be — C1 . The symbol Xº may be — Br . alkyl , unsubstituted 2 to 8 membered heteroalkyl , unsubsti tuted Cz - C , cycloalkyl , unsubstituted 3 to 8 membered The symbol X® may be — I . The symbol Xº may be F . heterocycloalkyl , unsubstituted C . - C1o aryl , or unsubsti In embodiments , the compound is tuted 5 to 10 membered heteroaryl . Each R ? , R8 , R9 , R10 , 30 R ! ! , R12 , R13 , and R14 may independently be hydrogen , substituted or unsubstituted C . - C . alkyl , substituted or unsubstituted 2 to 6 membered heteroalkyl , substituted or unsubstituted C3 - Co cycloalkyl , substituted or unsubstituted 3 to 6 membered heterocycloalkyl , substituted or unsubsti - 35 tuted Co aryl , or substituted or unsubstituted 5 to 6 mem bered heteroaryl . Each R7 , R8 , R9 , R10 , R1 , R12 , R13 , and HÓ CHz ? R14 may independently be hydrogen , unsubstituted C , - C6 alkyl , unsubstituted 2 to 6 membered heteroalkyl , unsubsti tuted C . - C . cycloalkyl . unsubstituted 3 to 6 membered 40 wherein E is as described herein , including in embodiments . heterocycloalkyl , unsubstituted Co aryl , or unsubstituted 5 to In embodiments , the compound is 6 membered heteroaryl .

Each R7 and R8 substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl . 45 Each R7 and R8 substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocy cloalkyl or unsubstituted heteroaryl . Each R7 and R8 sub HO CH? ? stituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 4 to 6 membered het - 50 erocycloalkyl or 5 to 6 membered heteroaryl . Each R ' and wherein E is as described herein , including in embodiments . R $ substituents bonded to the same nitrogen atom may be In embodiments , the compound is joined to form an unsubstituted 4 to 6 membered heterocy cloalkyl or unsubstituted 5 to 6 membered heteroaryl .

Each R11 and R12 substituents bonded to the same nitro - 55 gen atom may be joined to form a substituted or unsubsti tuted heterocycloalkyl or substituted or unsubstituted het EN eroaryl . Each Rll and R12 substituents bonded to the same nitrogen atom may be joined to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl . Each Rll and 60 FC R12 substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted 4 to 6 mem HO CHz ? bered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl . Each R ' I and R12 substituents bonded to the same nitrogen atom may be joined to form an 65 unsubstituted 4 to 6 membered heterocycloalkyl or unsub - wherein E is as described herein , including in embodiments . stituted 5 to 6 membered heteroaryl . In embodiments , the compound is

F C NH

E F

Di F2C

- S = 0 N

U 1993 , 483 B2 US 10 , 053 , 433 B2 87 88

In embodiments , the compound is

E - R2 Dhoot . ama N Fac

10

wherein E is as described herein , including in embodiments . In embodiments , the compound is wherein E , R ' , and R2 are as described herein , including in

embodiments . In embodiments , the compound is 15

F E

( 1 )

N 20

F3C

HO CHz ?

wherein E , R ' , and R2 are as described herein , including in wherein E is as described herein , including in embodiments . 25 embodiments . Rl may be CF7 , - CC12 , F , C1 , Br , In embodiments , the compound is - I , CH3 , CHZF , CH , C1 , CHF2 , or CHC12 . R ?

may be CF3 , CC13 , — F , Cl , Br , — I , CH3 , CH F , CH , C1 , CHF2 , CHC12 , CONHCH3 , CONHCH2CH3 , CONHCH , CH , CH ,

30 – CONHCHCH2CH3 , — CONHC ( CH3 ) 3 , _ CONHCF3 , E CONHCH _ F , or CONHCHF2 . In embodiments , E is CN . E may be — CHCH2 . E may be CCH . In embodiments , the compound is fot ele F C

35 HOCHZ Ö

NC .

wherein E is as described herein , including in embodiments . In embodiments , the compound is F C 40

HO

R21 1 ( 1 ) - R2 . 2 R2 . 2 Halaman 45 In embodiments , the compound is

NC F . NH

HOCHZ ? s See

50 50 FC F C V N wherein E , R1 , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . R2 and R2 . 2 are embodiments of R2 . In embodiments , the compound is

» In embodiments , the compound is R21

F . EN - R2 . 2 F 60 NC ?? ?? HO CH3 0 F3C N

HO 65 CH

wherein E , R ? , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . ents .

US 10 , 053 , 433 B2 89

In embodiments , the compound is 90

The compound may be

E 5 NON Dhol . Dopo FzC N

IZ CH3 10 CH3

In embodiment , de compound is In embodiments , the compound is wherein E is as described herein , including in embodiments . The compound may be

15

NC

( 1 )

F C N 20

HO 0 F C CH3 N Dites . net yo y sa serta medias

N In embodiments , the compound is

25

wherein E is as described herein , including in embodiments . The compound may be NC N

30 F3C

HO NH

The compound may be 35 F C N N ?? .

NC

D e asemenea amesema wasiwasan 40 wherein E is as described herein , including in embodiments . The compound may be F3C N IZ

R2 . 1 45 The compound may be

FO

R1 NC . N 50 Dispod njeno CH

F3C N

CHZ wherein E , R1 , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . The compound may be

The compound may be E

NC 60 for . Det RIN IZ Fzc N NH HÓ CHz ?

CH3 65 wherein E , R ' , and R2 are as described herein , including in embodiments . The compound may be

US 10 , 053 , 433 B2 92

NC R2 . 1 She ainda E R2 . 2

FzC = 0

CH , ? HO CH? 0 0

The compound may be 10

FO wherein E , R ' , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . The compound may be

NC N In o 15 15 E NO

0 F3C

HOW CH ; 60 Rtv N HOCHZ Ó 20

The compound may be

wherein E , R1 , and R2 are as described herein , including in embodiments . The compound may be NC N

25 Demos Demo NC N

HO CHz Ó Fzc N

30 The compound may be HOCHZ CH ;

( T ) L

I s so grado como b o na volta

content on the road I n te The compound may be

35

F3C NH NC .

40

wherein E is as described herein , including in embodiments . The compound may be F3C N ? N HO CH , 0 %

The compound may be EN M = 0 D NC N F3C . Dita 50

F2C F3C ' N N HO CH ; 66 wherein E is as described herein , including in embodiments . The compound may be

55 The compound may be F

EN EN . NO - ????? NH 60 ?? F C F3C N

HOCHZ Ó

65 wherein E is as described herein , including in embodiments . The compound may be

wherein E is as described herein , including in embodiments . The compound may be

US 10 , 053 , 433 B2 93 94

The compound may be

EN 5 5 O

F3C N

US 1095 , 483 M2 * Dhant . The

hable to HO CH ; Ó6 HO CH?

wherein E is as described herein , including in embodiments . 10 The compound may be

The compound may be

F 15 15 NC EN /

0

Fac F3C N ? EZ HOCH , Ó ' CH3 20

wherein E is as described herein , including in embodiments . The compound may be wherein E is as described herein , including in embodiments .

The compound may be ande the so that same time i 25 R2 . 1

EN R2 . 2 ( 1 ) ??? . ???? AN

R1 N 30

F30 N HO HO

wherein E , R , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . The compound may be 35

wherein E is as described herein , including in embodiments . The compound may be bot 40

R1 N F

E

wherein E , R ' , and R2 are as described herein , including in 45 embodiments . The compound may be F C N À

HO CH? 0 0 NC

50

F C NH HO CH? 0 0


55

The compound may be

FO - R22 60 NC . 60

N 0 R1 N ?? ???? HO CH? F3C N ' N H?

wherein E , R1 , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . The compound may be

US 10 , 053 , 433 B2 95 95 96

P2

EN E ????? ???? R1 N

FzC N

wherein E , R ' , and R2 are as described herein , including in embodiments . The compound may be wherein E is as described herein , including in embodiments .

The compound may be NC N

15 EN F30 N R22

N? O HO CH? 0 0

R1 ' N 20

The compound may be HO CH , 0 .

F 0 wherein E , R1 , R2 . 1 and R2 . 2 are as described herein , includ sing in embodiments . The compound may be ing

NC N N o . 25

N

EN E P

FC CN7 CNC Ibu Ibu 0 H

30 RN ?

HO CHz ? The compound may be

NCAN wherein E , R ' , and R2 are as described herein , including in embodiments . The compound may be

NC . NCZN F3CNN H?

NO CH3 g 9 40

solo The compan D o sada acompanham e este mensen om

NH The compound may be

to one and a nto de

* The compound may be setores EY " IN o F O t FC CNC CN 50 NC CNN IN 0 .

wherein is as described herein , including in embodiments . The compound may be NH

HO CH , 0 % 55

The compound may be

N 60 NC . NC , N .

F C ' N

CH3 ? O HO CH? ? b 65


US 10 , 053 , 433 B2 97 97 98

The compound may be NC NC N

NEN NO A Ghos . Debemos HOCHZÓ

HO The compound may be 10 10


NC N 0

15

E IN O HO CHz ó o NH

N The compound may be HO CH? 0 0

NO Blood Diameter Minden

wherein E is as described herein , including in embodiments . 25 The compound may be

IZ FO F

30 The EV N = The compound may be 0 N

EN IN O 35

in de gaten i sense caden | HO a en CH? 0 wherein E is as described herein , including in embodiments . The compound may be

0 40

wherein E is as described herein , including in embodiments . The compound may be R2 . 1

R22 O and thos 45

N

HO CH? ? C s

50 HO CH? ?

wherein E , R ? , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . The compound may be wherein E is as described herein , including in embodiments .

The compound may be 55

P2 F

EN NN 60 N OU HO CH? 0 0 CH3

65 wherein E , R ' , and R2 are as described herein , including in embodiments . The compound may be


US 10 , 053 , 433 B2 99 99 100

P21

EN R22 NC . NH 5

NE N F3C NH HO CHI HO CHI

10 wherein E , R ' , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . The compound may be


N . R2 AN 15 ( NC . NC . AN i NH

HO CH3 0 F30 20 HO CH3 0 wherein E , R ' , and R2 are as described herein , including in embodiments . In embodiments , the compound is a com pound described herein , including in an aspect , embodiment , example , table , figure , or claim . The compound may be

, us 1993 , 435 about ork hos Sell

Daten que maison Dowloon

wherein E is as described herein , including in embodiments . The compound may be 25 25

NC F . R2 . 1

30 F3C NH

H? CH3 Ö

HO CH3 0 The compound may be 35

F 0

EN wherein E , R ' , R2 . 1 , and R2 . 2 are as described herein , including in embodiments . The compound may be

R2 NO di 40 - $ = 0 NH HO CH3 0 HO CHz

The compound may be 45 wherein E , R ' , and R2 are as described herein , including in

embodiments . The compound may be

NC . NC N 50

F3C

HO CH , HO CH3 0

55 The compound may be The composand may be The compound may be

NC NC FO F Ñ 60 NC , F3C F C

O HO CH? ? - S = IZ d

65 HO CH? ? wherein E is as described herein , including in embodiments . The compound may be

US 10 , 053 , 433 B2 102

wherein E , R ' , and R2 are as described herein , including in embodiments . The compound may be

Uus Maa on 101 o The compound may be

NC . O NC . Who Digest =

- S = EZ O HO CH3 O HO CH? ?

10

The compound may be The compound may be

E . N F FO F 15

HO CH3 0 IZ 20 HO CHI wherein E is as described herein , including in embodiments .

The compound may be The compound may be

25

NC . NC a

NH 30 H? CH3 6 HO CH3 O

The compound may be wherein E is as described herein , including in embodiments . . The compound may be 35

F 0

N 40 | HO CH? ?

HO CHz ? wherein E is as described herein , including in embodiments . The compound may be


Qbot about

satt . D internet

o a des

E R2 . 1 NH 50 EN R22

HO CH? ?

HO CH? ? 35 wherein E is as described herein , including in embodiments . wherein E , R1 , R2 . 1 , and R2 . 2 are as described herein , The compound may be including in embodiments . The compound may be

F 60

EN R2

N

HO CH3 0 65 HO CH , 4 o

5

- R22 Duo HO CHI | 0

( 1 )

US 10 , 053 , 433 B2 103 104

wherein E is as described herein , including in embodiments . of an androgen receptor . In embodiments , the compound The compound may be covalently ( e . g . , reversibly or irreversibly ) bonds to a Ser

residue of a nuclear receptor . In embodiments , the com pound covalently ( e . g . , reversibly or irreversibly ) bonds to a Ser residue of an androgen receptor . In embodiments , the compound covalently ( e . g . , reversibly or irreversibly ) bonds to a Thr residue of a nuclear receptor . In embodiments , the compound covalently ( e . g . , reversibly or irreversibly ) bonds to a Thr residue of an androgen receptor . In embodiments ,

10 the compound covalently ( e . g . , reversibly or irreversibly ) bonds to a Lys residue of a nuclear receptor . In embodi ments , the compound covalently ( e . g . , reversibly or irrevers ibly ) bonds to a Lys residue of an androgen receptor .

wherein E , R ' , and R2 . 2 are as described herein , including in In embodiments , the compound binds an androgen recep embodiments . The compound may be 15 tor with at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 ,

3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , 3000 , 4000 , 5000 , 6000 , 7000 , 8000 , 9000 , 10000 , 100000 - Fold stronger affin

20 ity than flutamide . In embodiments , the compound binds an androgen receptor with at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 ,

HOCHZ 1 . 7 , 1 . 8 , 1 . 9 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , 3000 , 4000 ,

wherein E , R ' , and R ’ are as described herein , including in 25 5000 , 6000 , 7000 , 8000 , 9000 , 10000 , 100000 - Fold stronger embodiments . affinity than bicalutamide . In embodiments , the compound

In embodiments , the compound is an antagonist of a binds an androgen receptor with at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , nuclear receptor . In embodiments , the compound is an 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , antagonist of an androgen receptor . In embodiments , the 15 , 16 , 17 , 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , compound is an antagonist of a human androgen receptor . In 30 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , embodiments , the compound is an antagonist of wildtype 3000 , 4000 , 5000 , 6000 , 7000 , 8000 , 9000 , 10000 , 100000 human androgen receptor . In embodiments , the compound is Fold stronger affinity than nilutamide . In embodiments , the an antagonist of a mutant human androgen receptor . In compound binds an androgen receptor with at least 1 . 1 , 1 . 2 , embodiments , the compound is an antagonist of a drug - 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , resistant human androgen receptor . In embodiments , the 35 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , compound is an antagonist of a casodex - resistant human 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , androgen receptor . In embodiments , the compound is an 1000 , 2000 , 3000 , 4000 , 5000 , 6000 , 7000 , 8000 , 9000 , antagonist of a Flutamide - resistant human androgen recep - 10000 , 100000 - Fold stronger affinity than enzalutamide . In tor . In embodiments , the compound is an antagonist of an embodiments , the compound binds an androgen receptor MDV3100 - resistant human androgen receptor . In embodi - 40 with at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 , 3 , 4 , ments , the compound is an antagonist of an ARN - 509 - 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . 20 , 25 , resistant human androgen receptor . In embodiments , the 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , compound forms a covalent bond with a nuclear receptor . In 600 , 700 , 800 , 900 , 1000 , 2000 , 3000 , 4000 , 5000 , 6000 , embodiments , the compound forms a covalent bond with an 7000 , 8000 , 9000 , 10000 , 100000 - fold stronger affinity than androgen receptor . In embodiments , the covalent bond is 45 ARN - 509 . reversible . In embodiments , the covalent bond is irrevers - In embodiments , the compound inhibits an androgen ible . In embodiments , the compound covalently ( e . g . , receptor with an IC50 at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 , 1 . 7 , reversibly or irreversibly ) bonds to Cys784 of human andro - 1 . 8 , 1 . 9 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , gen receptor . In embodiments , the compound covalently 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , ( e . g . , reversibly or irreversibly ) bonds to the residue corre - 50 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , 3000 , 4000 , sponding to Cys784 of human androgen receptor . In 5000 , 6000 , 7000 , 8000 , 9000 , 10000 , 100000 - Fold stronger embodiments , the compound covalently ( e . g . , reversibly or equivalent inhibition at a lower concentration of compound irreversibly ) bonds to a Cys residue of a nuclear receptor . In than the control ) than flutamide . In embodiments , the com embodiments , the compound covalently ( e . g . , reversibly or pound inhibits an androgen receptor with an IC50 at least irreversibly ) bonds to a Cys residue of an androgen receptor . 55 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , In embodiments , the compound covalently ( e . g . , reversibly 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , or irreversibly ) bonds to an Asp residue of a nuclear recep 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , tor . In embodiments , the compound covalently ( e . g . , revers 900 , 1000 , 2000 , 3000 , 4000 , 5000 , 6000 , 7000 , 8000 , 9000 , ibly or irreversibly ) bonds to an Asp residue of an androgen 10000 , 100000 - Fold stronger than bicalutamide . In embodi receptor . In embodiments , the compound covalently ( e . g . , 60 ments , the compound inhibits an androgen receptor with an reversibly or irreversibly ) bonds to a Glu residue of a nuclear IC50 at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 , 3 , 4 , receptor . In embodiments , the compound covalently ( e . g . , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . 20 , 25 , reversibly or irreversibly ) bonds to a Glu residue of an 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , androgen receptor . In embodiments , the compound cova 600 , 700 , 800 , 900 , 1000 , 2000 , 3000 , 4000 , 5000 , 6000 , lently ( e . g . , reversibly or irreversibly ) bonds to a Tyr residue 65 7000 , 8000 , 9000 , 10000 , 100000 - Fold stronger than nilu of a nuclear receptor . In embodiments , the compound cova - tamide . In embodiments , the compound inhibits an androgen lently ( e . g . , reversibly or irreversibly ) bonds to a Tyr residue receptor with an IC50 at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , 1 . 5 , 1 . 6 , 1 . 7 ,

US 10 , 053 , 433 B2 105 106

1 . 8 , 1 . 9 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , heterocycloalkyl , R23 - substituted or unsubstituted aryl , or 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , R23 - substituted or unsubstituted heteroaryl . 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , 3000 , 4000 , R23 is independently oxo , halogen , CF3 , CN , OH , 5000 , 6000 , 7000 , 8000 , 9000 , 10000 , 100000 - Fold stronger — NH , COOH , CONH , NO , SH , SO , C1 , than enzalutamide . In embodiments , the compound inhibits 5 - SO . H . - SOH . - SO . NH . . - NHNH . . _ ONH . . an androgen receptor with an IC50 at least 1 . 1 , 1 . 2 , 1 . 3 , 1 . 4 , NHC = ( O ) NHNH , , - NHC = ( 0 ) NHA , NHSOH , 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , NHC = ( 0 ) H , NHC ( O ) OH , NHOH , OCF , 15 , 16 , 17 , 18 , 19 . 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , - OCHF2 , R24 - substituted or unsubstituted alkyl , R24 - sub 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , stituted or unsubstituted heteroalkyl , R24 - substituted or 3000 , 4000 , 5000 , 6000 , 7000 , 8000 , 9000 , 10000 , 100000 - 10 unsubstituted cycloalkyl , R24 - substituted or unsubstituted Fold stronger than ARN - 509 . heterocycloalkyl , R24 - substituted or unsubstituted aryl , or In some embodiments of the compounds provided herein , R24 - substituted or unsubstituted heteroaryl . R ! is independently hydrogen , oxo , halogen , CF3 , CN , - OH , — NH , , - COOH , CONH , , — NO , , SH , R24 is independently oxo , halogen , CF3 , CN , OH , - S02C1 , SO3H , SO4H , SO2NH2 , - NHNH2 , 15NH2 , 15 . - NH2 , COOH , CONH2 , NO2 , SH , — SO , C1 , ONH , ?NHC = ( O ) NHNH , , NHC = ( O ) NHÀ , SO3H , — S04H , SO2NH2 , — NHNH2 , ONH2 ,

– NHSO , H , NHC = ( 0 ) H , — NHC ( O ) OH , NHOH , ~ NHC ( O ) NHNH , NHC ( 0 ) NHA , NHSOH , - OCF3 , OCHF2 , R20 - substituted or unsubstituted alkyl , _ NHC = ( O ) H , _ NHC ( O ) OH , _ NHOH , LOCF , , R20 - substituted or unsubstituted heteroalkyl , R20 - substituted OCHF2 , R? - substituted or unsubstituted alkyl , R » - sub or unsubstituted cycloalkyl , R20 - substituted or unsubstituted 20 stituted or unsubstituted heteroalkyl , R25 - substituted or heterocycloalkyl , R20 - substituted or unsubstituted aryl , or unsubstituted cycloalkyl , R25 - substituted or unsubstituted R20 - substituted or unsubstituted heteroaryl . heterocycloalkyl , R25 - substituted or unsubstituted aryl , or

R20 is independently hydrogen , oxo , halogen , CF3 , R25 - substituted or unsubstituted heteroaryl . CN , OH , - NH2 , COOH , CONH2 , - NO2 , SH , In some embodiments of the compounds provided herein ,

- SO , C1 , SO2H , SO4H , SO NH , NHNH2 , 25 R7 is independently hydrogen , halogen , CF3 , CN , JONH ) , – NHC = ( O ) NHNH , _ NHC = ( 0 ) NHA , JOH , – NH2 , COOH , CONH , _ NO . , JSH , – NHSO , H , NHC = ( 0 ) H , — NHC ( O ) OH , NHOH , SO , C1 , SO3H , SO H , SO2NH2 , NHNH2 , - OCF3 , OCHF2 , R21 - substituted or unsubstituted alkyl , ONH , NHC = ( O ) NHNH , NHC = ( O ) NHA , R21 - substituted or unsubstituted heteroalkyl , R21 - substituted _ NHSO , H , NHC = ( O ) H , NHC ( O ) OH , NHOH , or unsubstituted cycloalkyl , R21 - substituted or unsubstituted 30 OCF , OCHF , R38 - substituted or unsubstituted alkyl , heterocycloalkyl , R21 - substituted or unsubstituted aryl , or R38 - substituted or unsubstituted heteroalkyl , R38 - substituted R21 - substituted or unsubstituted heteroaryl . In embodi or unsubstituted cycloalkyl , R38 - substituted or unsubstituted ments , R20 is independently oxo , halogen , CF3 , CN , heterocycloalkyl , R38 - substituted or unsubstituted aryl , or - OH , - NH2 , COOH , CONH2 , — NO2 , SH , R38 - substituted or unsubstituted heteroaryl . - S02C1 , SO2H , SO H , SO2NH2 , — NHNH2 , 35 R38 is independently oxo , halogen , CF3 , CN , OH , JONH , _ NHC = ( O ) NHNH , _ NHC = ( O ) NHA , NHA , COOH , CONH , _ NO . , JSH , _ SOCI , – NHSOH , — NHC ( 0 ) H , — NHC ( O ) OH , NHOH , SOzH , SO H , SO NH , — NHNH2 , ONH2 , - OCF3 , OCHF2 , R21 - substituted or unsubstituted alkyl , _ NHC = ( O ) NHNH , NHC = ( O ) NHÀ , _ NHSOH , R21 - substituted or unsubstituted heteroalkyl , R21 - substituted _ NHC = ( O ) H , _ NHC ( O ) OH , _ NHOH , OCF , or unsubstituted cycloalkyl , R21 - substituted or unsubstituted 40 – OCHF2 , - S ( O ) , CHCH , NHS ( O ) CHCH , , R39 - sub heterocycloalkyl , R21 - substituted or unsubstituted aryl , or stituted or unsubstituted alkyl , R39 - substituted or unsubsti R21 - substituted or unsubstituted heteroaryl . In embodi - tuted heteroalkyl , R39 - substituted or unsubstituted ments , R20 is hydrogen . In embodiments , R20 is halogen . In cycloalkyl , R39 substituted or unsubstituted heterocy embodiments , R20 is CF3 . In embodiments , R20 is — CN . cloalkyl , R39 - substituted or unsubstituted aryl , or R39 - sub In embodiments , R20 is OH . In embodiments , R20 is 45 stituted or unsubstituted heteroaryl . - NH2 . In embodiments , R20 is - COOH . In embodiments , R39 is independently oxo , halogen , CF3 , CN , OH , R20 is CONH , . In embodiments , R20 is – CH2 . In NH , , COOH , CONH , , - NO , SH , SO , C1 , embodiments , R20 is unsubstituted alkyl . - SO3H , SO4H , SO2NH2 , NHNH2 , CONH2 ,

R21 is independently oxo , halogen , CF3 , CN , OH , _ NHC = ( O ) NHNH , _ NHC = ( 0 ) NHÀ , _ NHSO , H , – NH , COOH , _ CONH , _ NO . , JSH , SO Cl , 50 – NHC = ( O ) H , _ NHC ( O ) OH , _ NHOH , LOCF4 , - SO3H , SO _ H , SO2NH2 , — NHNH2 , ONH2 , OCHF2 , - S ( O ) 2CHCH2 , NHS ( O ) 2CHCH2 , R40 - sub – NHC = ( O ) NHNH , _ NHC = ( 0 ) NHÀ , _ NHSOH , stituted or unsubstituted alkyl , R40 - substituted or unsubsti – NHC = ( O ) H , NHC ( O ) OH , _ NHOH , OCF , tuted heteroalkyl , R40 - substituted or unsubstituted - OCHF2 , R22 - substituted or unsubstituted alkyl , R22 - sub cycloalkyl , R40 - substituted or unsubstituted heterocy stituted or unsubstituted heteroalkyl , R22 - substituted or 55 cloalkyl , R40 - substituted or unsubstituted aryl , or R40 - sub unsubstituted cycloalkyl , R22 - substituted or unsubstituted stituted or unsubstituted heteroaryl . heterocycloalkyl , R22 - substituted or unsubstituted aryl , or I n some embodiments of the compounds provided herein , R22 - substituted or unsubstituted heteroaryl . R $ is independently hydrogen , halogen , CF3 , CN ,

In some embodiments of the compounds provided herein , OH , NH2 , COOH , CONH2 , — NO2 , SH , R is independently hydrogen , oxo , halogen , CF3 , CN , 60 SO , C1 , SO3H , SO4H , SONH2 , - NHNH2 , - OH , NH , COOH , CONH2 , — NO , SH , JONH , , NHC = ( O ) NHNH , _ NHC ( 0 ) NHA , - S02C1 , SO2H , SO4H , SO NH2 , — NHNH2 , NHSO , H , NHC = ( 0 ) H , NHCOOH , _ NHOH , - ONH , NHC = ( O ) NHNH , NHC = ( 0 ) NH , _ OCF3 , OCHF2 , R41 - substituted or unsubstituted alkyl , — NHSO , H , — NHC = ( O ) H , — NHC ( O ) - OH , — NHOH , R41 - substituted or unsubstituted heteroalkyl , R41 - substituted - OCF3 , OCHF2 , R23 - substituted or unsubstituted alkyl , 65 or unsubstituted cycloalkyl , R41 - substituted or unsubstituted

R23 - substituted or unsubstituted heteroalkyl , R23 - substituted heterocycloalkyl , R41 - substituted or unsubstituted aryl , or or unsubstituted cycloalkyl , R23 - substituted or unsubstituted R41 - substituted or unsubstituted heteroaryl .

US 10 , 053 , 433 B2 107 108

R41 is independently oxo , halogen , CF3 , CN , OH , R47 is independently oxo , - NH2 , COOH , CONH2 , — NO2 , SH , SO , C1 , halogen , CF3 , CN , OH , - NH2 , COOH , _ SOZH , SO H , SO2NH2 , - NHNH2 , CONH2 , CONH2 , — NO2 , SH , SO2C1 , SO3H , SO4H , – NHC = ( O ) NHNH , NHC = ( 0 ) NHM , NHSO , H , SO NHA – NHNH , JONH , NHC = ( O ) NHNH , – NHC = ( O ) H , NHC ( O ) OH , NHOH , LOCF , 5 – NHC = ( 0 ) NHÀ , NHSO , H , NHC = ( O ) H , NHC OCHF2 , - S ( O ) 2CHCH2 , - NHS ( O ) 2CHCH2 , R42 - sub ( O ) - OH , — NHOH , _ OCF3 , OCHF2 , R48 - substituted

stituted or unsubstituted alkyl , R42 - substituted or unsubsti - or unsubstituted alkyl , R48 - substituted or unsubstituted het tuted heteroalkyl , R42 - substituted or unsubstituted eroalkyl , R48 - substituted or unsubstituted cycloalkyl , R48 cycloalkyl , R42 substituted or unsubstituted heterocy substituted or unsubstituted heterocycloalkyl , R48 - substi cloalkyl , R42 - substituted or unsubstituted aryl , or R42 - sub - 10 tuted or unsubstituted aryl , or R48 - substituted or unsubsti stituted or unsubstituted heteroaryl . tuted heteroaryl . R42 is independently oxo , halogen , CF3 , CN , OH , R48 is independently oxo ,

- NH2 , COOH , CONH2 , - NO2 , SH , S02C1 , halogen , CF3 , CN , OH , - NH2 , COOH , - SO2H , SO _ H , SO NH2 , — NHNH2 , CONH2 , 15 . CONH2 , — NO2 , SH , SO , C1 , SO2H , SO _ H , - NHC = ( O ) NHNH , ?NHC = ( O ) NHA – NHSO . H , SO , NH , — NHNH , LONH , NHC = ( O ) NHNHA , – NHC = ( O ) H , _ NHC ( O ) OH , _ NHOH , LOCF , _ NHC = ( 0 ) NHA , NHSO , H , NHC = ( O ) H , NHC - OCHF2 , S ( O ) 2CHCH2 , - NHS ( O ) CHCH2 , R43 - sub - ( 0 ) OH , — NHOH , OCF3 , OCHF2 , R49 - substituted stituted or unsubstituted alkyl , R43 - substituted or unsubsti - or unsubstituted alkyl , R49 - substituted or unsubstituted het tuted heteroalkyl , R43 - substituted or unsubstituted 20 eroalkyl , R49 - substituted or unsubstituted cycloalkyl , R49 cycloalkyl , R43 - substituted or unsubstituted heterocy - substituted or unsubstituted heterocycloalkyl , R49 - substi cloalkyl , R43 - substituted or unsubstituted aryl , or R43 - sub - tuted or unsubstituted aryl , or R49 - substituted or stituted or unsubstituted heteroaryl . unsubstituted heteroaryl .

In some embodiments of the compounds provided herein , In some embodiments of the compounds provided herein , Rº is independently hydrogen , halogen , CF3 , CN , 25 R " is independently hydrogen , oxo , halogen , - CF3 , — CN , - OH , — NH2 , COOH , CONH2 , — NO2 , SH , OH , — NH2 , COOH , CONH2 , — NO2 , — SH , SO C1 , SO3H , SO4H , SO2NH2 , - NHNH2 , SO C1 , SO3H , SO H , SO2NH , NHNH2 , ONH ) , – NHC ( O ) NHNHA , — NHC = ( 0 ) NHA , ONH , NHC = ( O ) NHNH , NHC = ( 0 ) NHA ,

– NHSO , H , — NHC = ( 0 ) H , — NHC ( O ) OH , NHOH , _ NHSO , H , NHC = ( 0 ) H , — NHC ( O ) OH , NHOH , - OCF3 , OCHF2 , R44 - substituted or unsubstituted alkyl , 3 1 30 OCF3 , OCHF2 , R56 - substituted or unsubstituted alkyl ,

R44 - substituted or unsubstituted heteroalkyl , R44 - substituted R56 - substituted or unsubstituted heteroalkyl , R $ 6 - substituted or unsubstituted cycloalkyl , R " - substituted or unsubstituted or unsubstituted cycloalkyl , R44 - substituted or unsubstituted

heterocycloalkyl , R44 - substituted or unsubstituted aryl , or heterocycloalkyl , R56 - substituted or unsubstituted aryl , or R56 - substituted or unsubstituted heteroaryl . R14 - substituted or unsubstituted heteroaryl . 172 35 R5 “ is independently oxo , R44 is independently oxo , halogen , CF3 , CN , OH , halogen , CF3 , CN , OH , - NH2 , COOH , — NH , , - COOH , CONH , , — NO , , SH , — SO , C1 , CONH2 , — NO2 , SH , SO2C1 , SO3H , SO _ H ,

– SOH , SOH , SOCNH – NHNH2 , CONH , SO , NH , NHNH , LONH , NHC = ( O ) NHNH , , – NHC = ( O ) NHNH , – NHC = ( O ) NH , NHSOH , NHC ( O ) NH , NHSO . H , NHC ( O ) H , NHC — NHC = ( OH , — NHC ( O ) OH , — NHOH , OCF3 , 40 ( 0 ) - OH , — NHOH , OCF , OCHF , , R57 - substituted - OCHF2 , R45 - substituted or unsubstituted alkyl , R45 - sub or unsubstituted alkyl , R57 - substituted or unsubstituted het

stituted or unsubstituted heteroalkyl , R45 - substituted or eroalkyl , R57 - substituted or unsubstituted cycloalkyl , RS7 unsubstituted cycloalkyl , Rus substituted or unsubstituted substituted or unsubstituted heterocycloalkyl , RS - substi heterocycloalkyl , R45 - substituted or unsubstituted aryl , or tuted or unsubstituted aryl , or R $ - substituted or unsubsti R45 - substituted or unsubstituted heteroaryl . 45 tuted heteroaryl .

R45 is independently oxo , R $ 7 is independently oxo , halogen , CF3 , CN , OH , - NH2 , COOH , halogen , CF3 , CN , OH , NH2 , COOH , - CONH2 , — NO2 , SH , S02C1 , SO3H , SO H , CONH2 , 4NO2 , SH , S02C1 , SO3H , SO H , – SO , NH , _ NHNH , JONH , — NHC = ( O ) NHNH , _ SO , NH , — NHNH , LONH , — NHC = ( O ) NHNH , - NHC = ( 0 ) NHÀ , NHSOH , NHC = ( 0 ) H , NHC 50 NHC = ( O ) NHA , NHSO , H , NHC = ( O ) H , NHC

( 0 ) OH , — NHOH , OCF3 , OCHF2 , R46 - substituted ( 0 ) - OH , — NHOH , _ OCF3 , OCHF2 , R38 - substituted or unsubstituted alkyl , R46 - substituted or unsubstituted het - or unsubstituted alkyl , R58 - substituted or unsubstituted het eroalkyl , R46 - substituted or unsubstituted cycloalkyl , R46 . eroalkyl , R58 - substituted or unsubstituted cycloalkyl , R58 . substituted or unsubstituted heterocycloalkyl , R46 - substi - substituted or unsubstituted heterocycloalkyl , R58 - substi tuted or unsubstituted aryl , or R46 - substituted or 55 tuted or unsubstituted aryl , or R58 - substituted or unsubstituted heteroaryl . unsubstituted heteroaryl .

In some embodiments of the compounds provided herein , In embodiments of the compounds provided herein , R12 is R10 is independently hydrogen , halogen , CF3 , CN , independently hydrogen , halogen , CF3 , CN , OH , - OH , NH , , COOH , CONH , , NO , , SH , NH , , - COOH , — CONH , , — NO , , SH , SO , C1 , - S02C1 , SO3H , SO4H , SO2NH2 , - NHNH2 , 60 SO2H , SO _ H , SO NH , NHNH2 , ONH2 , ONH , ?NHC = ( O ) NHNHA , NHC = ( O ) NHÀ , _ NHC = ( O ) NHNH , NHC = ( O ) NHÀ , _ NHSO , H , NHSO , H , NHC = ( 0 ) H , NHC ( O ) OH , — NHOH , NHC = ( 0 ) H , NHC ( O ) OH , NHOH , OCF ,

- OCF3 , OCHF2 , R47 - substituted or unsubstituted alkyl , _ OCHF2 , R59 - substituted or unsubstituted alkyl , R59 - sub R47 - substituted or unsubstituted heteroalkyl , R47 - substituted stituted or unsubstituted heteroalkyl , R59 - substituted or or unsubstituted cycloalkyl , R47 - substituted or unsubstituted 65 unsubstituted cycloalkyl , R " - substituted or unsubstituted heterocycloalkyl , R47 - substituted or unsubstituted aryl , or heterocycloalkyl , R59 - substituted or unsubstituted aryl , or R47 - substituted or unsubstituted heteroaryl . R59 - substituted or unsubstituted heteroaryl .

US 10 , 053 , 433 B2 109 110

R59 is independently oxo , R65 is independently oxo , halogen , CF3 , CN , OH , - NH2 , COOH , halogen , CF3 , CN , OH , - NH2 , COOH , - CONH2 , — NO2 , SH , SO2C1 , SO3H , SO4H , - CONH2 , — NO2 , SH , S02C1 , SO3H , SO4H , _ SO , NH , NHNH , LONH , NHC - ( ) NHNHA , SO , NH , — NHNH , LONH , , NHC = ( O ) NHNH , NHC ( O ) NH , NHSO , H , NHC - ( O ) H , NHC 5 – NHC = ( O ) NH – NHSOH , NHC = ( O ) H , NHC

( 0 ) OH , — NHOH , OCF3 , OCHF2 , R60 - substituted ( 0 ) OH , NHOH , OCF3 , OCHF2 , R66 - substituted or unsubstituted alkyl , Rø - substituted or unsubstituted het or unsubstituted alkyl , R " - substituted or unsubstituted het eroalkyl , R60 - substituted or unsubstituted cycloalkyl , R60 eroalkyl , R66 - substituted or unsubstituted cycloalkyl , RÓ6 substituted or unsubstituted heterocycloalkyl , Rø - substi substituted or unsubstituted heterocycloalkyl , RC - substi

arvl or R60 - substituted or 10 tuted tuted or aryl , or unsubstituted unsubstituted or R or - substituted unsubstituted heteroaryl . unsubstituted heteroaryl . R66 is independently oxo , R " is independently oxo , halogen , CF3 , CN , OH , - NH2 , COOH , halogen , CF3 , CN , OH , NH2 , COOH , CONH2 , — NO2 , — SH , SO , C1 , SO3H , SO _ H , CONH2 , — NO2 , ON 2 P2 : SH , ?H , P2 , SO , C1 , SO2H , P3 , SO4H , P4 , 15 – SO , NH , NHNH , LONH , NHC = ( O ) NHNHA , SO , NH , NHNH , JONH , _ NHC = ( O ) NHNH , NHC = ( O ) NHA , – NHSO , H , NHC = ( O ) H , NHC

– NHC = ( O ) NHA , _ NHSOH , NHC = ( 0 ) H , NHC ( 0 ) - OH , NHOH , OCF3 , OCHF2 , R67 - substituted ( 0 ) OH , — NHOH , OCF3 , OCHF2 , RØ1 - substituted or unsubstituted alkyl , R67 - substituted or unsubstituted het or unsubstituted alkyl , R61 - substituted or unsubstituted het - eroalkyl , R67 - substituted or unsubstituted cycloalkyl , Rº eroalkyl , R61 - substituted or unsubstituted cycloalkyl , R61 - 20 substituted or unsubstituted heterocycloalkyl , R67 - substi substituted or unsubstituted heterocycloalkyl , RÓl - substi - tuted or unsubstituted aryl , or R67 - substituted or tuted or unsubstituted aryl , or Rºt - substituted or unsubstituted heteroaryl . unsubstituted heteroaryl . In embodiments , Ris is independently hydrogen , oxo ,

In embodiments of the compounds provided herein , R13 is halogen , — CX153 , — CHX152 , OCH Xls , CN , — OH , independently hydrogen , halogen , CF3 , CN , - OH , 25 — NH2 , COOH , CONH2 , - NO2 , SH , SO2H , – NH2 , COOH , CONH , _ NO . , JSH , SOPCI , SOH , SO , NH , NHNH , LONH , NHC ( 0 ) – SO , H , JSOH , SO , NH , NHNH , LONH , NHNH , NHC = ( O ) NH , NHSO , H , NHC = ( 0 ) H , – NHC = ( O ) NHNHA – NHC = ( 0 ) NHA , NHSO , H , NHC ( O ) OH , NHOH , OCXl , OCHXl , R72 – NHC = ( O ) H , NHC ( 0 ) OH , NHOH , LOCF , substituted or unsubstituted alkyl , R72 - substituted or unsub - OCHF2 , R62 - substituted or unsubstituted alkyl , R62 - sub - 30 stituted heteroalkyl , R72 - substituted or unsubstituted stituted or unsubstituted heteroalkyl , R?2 - substituted or cycloalkyl , R72 - substituted or unsubstituted heterocy unsubstituted cycloalkyl , R62 - substituted or unsubstituted cloalkyl , R72 - substituted or unsubstituted aryl , or R72 - sub heterocycloalkyl , Rº2 - substituted or unsubstituted aryl , or stituted or unsubstituted heteroaryl . Xls is halogen . In R62 - substituted or unsubstituted heteroaryl . embodiments , X15 is F .

R62 is independently oxo , 35 R72 is independently oxo , halogen , CF3 , CN , OH , NH , - COOH , halogen , CX723 , CHX722 , OCH _ X7 ? , OCHX722 , - CONH2 , — NO2 , SH , S02C1 , SO3H , SOAH , CN , OH , - NH2 , COOH , CONH2 , - NO2 , SH , _ SO , NH , — NHNH , JONH , ?NHC = ( O ) NHNHA , SO3H , SOAH , SO2NH , NHNH2 , CONH2 , _ NHC = ( 0 ) NHA , NHSO , H , NHC = ( O ) H , NHC _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , NHSOH ,

( 0 ) OH , — NHOH , OCF3 , OCHF2 , R63 - substituted 40 NHC = ( O ) H , NHC ( O ) - OH , NHOH , OCX723 , or unsubstituted alkyl , R63 - substituted or unsubstituted het OCHX722 , R73 - substituted or unsubstituted alkyl , R73 eroalkyl , R63 - substituted or unsubstituted cycloalkyl , R63 - substituted or unsubstituted heteroalkyl , R73 - substituted or substituted or unsubstituted heterocycloalkyl , R63 - substi - unsubstituted cycloalkyl , R13 - substituted or unsubstituted tuted or unsubstituted aryl , or R $ 3 - substituted or heterocycloalkyl , R73 - substituted or unsubstituted aryl , or unsubstituted heteroaryl . 45 R73 - substituted or unsubstituted heteroaryl . X72 is halogen . R63 is independently oxo , In embodiments , X72 is F .

halogen , CF3 , CN , OH , NH , - COOH , R73 is independently oxo , - CONH2 , - NO2 , SH , SO , C1 , SO3H , SOAH , halogen , CX733 , CHX72 , OCH _ X73 , CN , OH , – SO , NH , — NHNH , LONH , _ NHC ( O ) NHNH ) , – NH2 , COOH , CONH , _ NO , SH , SO , H , - NHC = ( 0 ) NHÀ , NHSOH , NHC = ( 0 ) H , NHC 50 – SOH , SO , NH , NHNHA , ONH , — NHC = ( 0 )

( 0 ) OH , — NHOH , OCF3 , OCHF2 , R64 - substituted NHNH , NHC = ( O ) NH , NHSO , H , NHC = ( O ) H , or unsubstituted alkyl , R64 - substituted or unsubstituted het - NHC ( O ) OH , NHOH , OCX733 , OCHX732 , R74 eroalkyl , R64 - substituted or unsubstituted cycloalkyl , R64 - substituted or unsubstituted alkyl , R 74 - substituted or unsub substituted or unsubstituted heterocycloalkyl , R64 - substi stituted heteroalkyl , R74 - substituted or unsubstituted tuted or unsubstituted aryl , or R64 - substituted or 55 cycloalkyl , R74 - substituted or unsubstituted heterocy unsubstituted heteroaryl . cloalkyl , R74 - substituted or unsubstituted aryl , or R74 - sub

In some embodiments of the compounds provided herein , stituted or unsubstituted heteroaryl . X73 is halogen . In R14 is independently hydrogen , halogen , CF3 , CN , embodiments , X73 is F . - OH , — NH , , COOH , CONH , , — NO , , SH , In embodiments , R16 is independently hydrogen , oxo , - S02C1 , SO3H , SO _ H , SO2NH2 , — NHNH2 , 60 halogen , CX163 , CHX12 , OCH X1 , CN , OH , JONH ) , – NHC = ( O ) NHNH , – NHC = ( O ) NH?C – NH2 , COOH , CONH , – NO , SH , SOH , – NHSO , H , NHC = ( 0 ) , NHC ( O ) OH , NHOH , SOH , SO , NH , NHNH , LONH , NHC ( 0 ) - OCF3 , OCHF , R65 - substituted or unsubstituted alkyl , NHNH , , - NHC = ( O ) NH2 , — NHSO , H , NHC = ( O ) H ,

R65 - substituted or unsubstituted heteroalkyl , R65 - substituted NHC ( O ) OH , NHOH , OCX163 , OCHX162 , R75 or unsubstituted cycloalkyl , RÓS - substituted or unsubstituted 65 substituted or unsubstituted alkyl , R75 - substituted or unsub heterocycloalkyl , R65 - substituted or unsubstituted aryl , or stituted heteroalkyl , R75 - substituted or unsubstituted R “ 5 - substituted or unsubstituted heteroaryl . cycloalkyl , R7S - substituted or unsubstituted heterocy

111 US 10 , 053 , 433 B2

112 cloalkyl , R75 - substituted or unsubstituted aryl , or R75 - sub NHNH , NHC = ( O ) NH ) , NHSO , H , NHC = ( O ) H , stituted or unsubstituted heteroaryl . Xl6 is halogen . In - NHC ( O ) OH , NHOH , OCX183 , OCHX182 , R81 embodiments , x16 is F . substituted or unsubstituted alkyl , R81 - substituted or unsub

R7S is independently oxo , stituted heteroalkyl , R81 - substituted or unsubstituted halogen , — CX3 , — CHX2 , — OCH X ” , - OCHX 2 , 5 cycloalkyl , R81 - substituted or unsubstituted heterocy CN , OH , - NH2 , COOH , CONH2 , - NO2 , SH , cloalkyl , R & I - substituted or unsubstituted aryl , or R81 - sub - SO , H , SO H , SO , NH , NHNH , , ONH , , stituted or unsubstituted heteroaryl . X18 is halogen . In

– NHC = ( O ) NHNH , _ NHC = ( O ) NH – NHSO , H , embodiments , X18 is F . _ NHC = O ) H , NHC ( O ) OH , NHOH , OCX7 . LOCHX75 , R76 - substituted or unsubstituted alkyl , R ' ' - 10 halogen . R81 is independently oxo ,

CX81 - CHX81 , OCH , X81 , - OCHX12 , substituted or unsubstituted heteroalkyl , R70 - substituted or – CN , OH , - NH2 , COOH , CONH2 , - NO2 , SH , unsubstituted cycloalkyl , R76 - substituted or unsubstituted heterocycloalkyl , R76 - substituted or unsubstituted aryl , or SO2H , SO4H , SO2NH2 , - NHNH2 , ONH2 , R76 - substituted or unsubstituted heteroaryl . X75 is halogen . ~ NHC = ( O ) NHNH , , - NHC = ( O ) NH , _ NHSO , H , In embodiments , X75 is F . - NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX81

R76 is independently oxo , - OCHX12 , R82 - substituted or unsubstituted alkyl , R82 halogen , CX73 , CHX72 , OCH _ X76 , CN , OH substituted or unsubstituted heteroalkyl , R82 - substituted or - NH2 , COOH , CONH2 , NO2 , SH , SO3H , unsubstituted cycloalkyl , R82 - substituted or unsubstituted _ SO H , SO , NH , _ NHNH , LONH , _ NHC = ( 0 ) heterocycloalkyl , R82 - substituted or unsubstituted aryl , or NHNH? , — NHC = ( O ) NH , , — NHSO , H , — NHC = ( O ) H , 20 R82 - substituted or unsubstituted heteroaryl . XX1 is halogen . – NHC ( O ) OH , _ NHOH , OCX , OCHX7 , , R In embodiments , X8l is F .

substituted or unsubstituted alkyl , R ” - substituted or unsub R $ 2 is independently oxo , stituted heteroalkyl , R77 - substituted or unsubstituted halogen , — CX823 , — CHX82 _ , _ OCH , X82 , CN , OH , cycloalkyl , R77 - substituted or unsubstituted heterocy . - NH2 , COOH , CONH2 , — NO2 , SH , SO2H , cloalkyl , R ? ? - substituted or unsubstituted aryl , or R77 - sub - 25 SO H , SO NH , NHNH , , - ONH , , — NHC = ( 0 ) stituted or unsubstituted heteroaryl . X76 is halogen . In NHNH , NHC = ( O ) NH2 , NHSO , H , NHC = ( O ) H , embodiments , X76 is F . NHC ( 0 ) OH , NHOH , OCX82 , OCH3 * 2 , R83

In embodiments , R17 is independently hydrogen , oxo , substituted or unsubstituted alkyl , R83 - substituted or unsub halogen , CX173 , CHX12 , OCH _ X , CN , OH stituted heteroalkyl , R83 - substituted or unsubstituted - NH2 , COOH , CONH2 , — NO2 , SH , SO2H , 30 cycloalkyl , R83 - substituted or unsubstituted heterocy SOH , JSO , NH , NHNH , JONH , – NHC ( O ) cloalkyl , R83 - substituted or unsubstituted aryl , or R83 - sub

NHNH , NHC = ( O ) NH ) , – NHSO , H , NHC = ( O ) H , stituted or unsubstituted heteroaryl . X82 is halogen . In - NHC ( O ) - OH , — NHOH , OCX173 , OCHX17 , R78 . embodiments , X82 is F . substituted or unsubstituted alkyl , R78 - substituted or unsub - In embodiments , R154 is independently hydrogen , oxo , stituted heteroalkyl , R78 - substituted or unsubstituted 35 halogen , — CX1543 , _ CHX1542 , OCH - X154 , CN , cycloalkyl , R78 - substituted or unsubstituted heterocy OH , — NH , COOH , CONH2 , — NO2 , SH , cloalkyl , R78 - substituted or unsubstituted aryl , or R78 - sub - SO H , - SOAH , SO NH , NHNH , ONH2 , stituted or unsubstituted heteroaryl . xl7 is halogen . In _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , NHSOH , embodiments , xl7 is F . _ NHC = ( O ) H , NHC ( O ) OH , _ NHOH , OCX154 , ,

R78 is independently oxo , 40 – OCHX154 , R724 - substituted or unsubstituted alkyl , R724 halogen , — CX783 , — CHX782 , - OCH , X78 , OCHX78 , substituted or unsubstituted heteroalkyl , R724 - substituted or - CN , OH , - NH2 , COOH , CONH2 , - NO2 , SH , unsubstituted cycloalkyl , R724 - substituted or unsubstituted - SO3H , SO _ H , SO2NH2 , NHNH , , ONH2 , heterocycloalkyl , R724 - substituted or unsubstituted aryl , or – NHC = ( O ) NHNH , NHC = ( O ) NH , – NHSO , H , R724 - substituted or unsubstituted heteroaryl . x154 is halo — NHC = ( O ) H , — NHC ( O ) - OH , — NHOH , OCX783 , 45 gen . In embodiments , X154 is F . - OCHX782 , R79 - substituted or unsubstituted alkyl , R79 R724 is independently oxo , substituted or unsubstituted heteroalkyl , R79 - substituted or halogen , — CX7242 , CHX724 , OCH , X724 , unsubstituted cycloalkyl , R79 - substituted or unsubstituted OCHX724 , CN , OH , NH2 , COOH , CONH2 , heterocycloalkyl , R79 - substituted or unsubstituted aryl , or - NO2 , SH , - SO2H , SO H , SO NH , , - NHNH2 , R79 - substituted or unsubstituted heteroaryl . X78 is halogen . 50 – ONH , NHC = ( O ) NHNH , NHC = ( O ) NH2 , In embodiments , X78 is F . _ NHSO , H , NHC - ( 0 ) H , NHC ( O ) OH , NHOH ,

R79 is independently oxo , OCX7243 , OCHX7242 , R734 - substituted or unsubsti halogen , CX793 , CHX792 , OCH _ X79 , CN , OH , tuted alkyl , R134 - substituted or unsubstituted heteroalkyl , - NH2 , COOH , CONH2 , — NO , , — SH , SO2H , R734 - substituted or unsubstituted cycloalkyl , R734 - substi - SO H , SO NH , - NHNH , — ONH2 , — NHC = ( 0 ) 55 tuted or unsubstituted heterocycloalkyl , R734 - substituted or NHNH , , - NHC = ( O ) NH , NHSO , H , NHC = ( O ) H , unsubstituted aryl , or R734 - substituted or unsubstituted het - NHC ( O ) - OH , NHOH , OCX793 , OCHX792 , R80 eroaryl . X724 is halogen . In embodiments , X724 is F . substituted or unsubstituted alkyl , R80 - substituted or unsub R734 is independently oxo , stituted heteroalkyl , R80 - substituted or unsubstituted halogen , CX7343 , CHX7342 , _ OCH , X734 , CN , cycloalkyl , R80 - substituted or unsubstituted heterocy - 60 OH — NH2 , COOH , CONH2 , — NO2 , SH , cloalkyl , R80 - substituted or unsubstituted aryl , or R80 - sub - SO , H , SOAH , SO NH , NHNH , , ONH2 , stituted or unsubstituted heteroaryl . X79 is halogen . In — NHC = ( O ) NHNH , NHC = ( O ) NH2 , NHSO2H , embodiments , X79 is F . NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX734 ,

In embodiments , R18 is independently hydrogen , oxo , OCHX7342 , R 744 - substituted or unsubstituted alkyl , R743 - halogen , CX183 , CHX182 , OCH X18 , — CN , OH , 65 substituted or unsubstituted heteroalkyl , R744 - substituted or - NH2 , COOH , CONH2 , — NO2 , SH , SO2H , unsubstituted cycloalkyl , R 744 - substituted or unsubstituted - SO _ H , SO2NH2 , - NHNH2 , ONH2 , — NHC = ( 0 ) heterocycloalkyl , R744 - substituted or unsubstituted aryl , or

2 ;

9

US 10 , 053 , 433 B2 113 114

R744 - substituted or unsubstituted heteroaryl . X734 is halo NHC - ( 0 ) H , NHC ( O ) OH , NHOH , OCX79 . gen . In embodiments , X734 is F . OCHX794 , R804 - substituted or unsubstituted alkyl , R804

In embodiments , R164 is independently hydrogen , oxo , substituted or unsubstituted heteroalkyl , R804 - substituted or halogen , CX1643 , CHX1642 , OCH X16 , CN , unsubstituted cycloalkyl , R804 - substituted or unsubstituted - OH , — NH , COOH , CONH , NO2 , SH , 5 heterocycloalkyl , R804 - substituted or unsubstituted aryl , or - SO3H , SO H , SO NH , NHNH , ONH2 , R80A - substituted or unsubstituted heteroaryl . X794 is halo – NHC = ( O ) NHNH , ?NHC = ( O ) NH , _ NHSO , H , gen . In embodiments , X794 is F . – NHC = ( O ) H , NHCOOH , _ NHOH , OCX16 In embodiments , R18A is independently hydrogen , oxo , - OCHX1642 , R754 - substituted or unsubstituted alkyl , R754 . halogen , CX1843 , CHX184 , , _ OCH , X184 , CN , substituted or unsubstituted heteroalkyl , R754 - substituted or 10 – OH , — NH , COOH , CONH2 , — NO2 , SH , unsubstituted cycloalkyl , R754 - substituted or unsubstituted SO3H , SO _ H , SO2NH , NHNH2 , CONH2 , heterocycloalkyl , R754 - substituted or unsubstituted aryl , or _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , _ NHSOH , R754 - substituted or unsubstituted heteroaryl . X164 is halo _ NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX184 , gen . In embodiments , X16A is F . OCHX184 , R814 - substituted or unsubstituted alkyl , R814 R754 is independently oxo , 15 substituted or unsubstituted heteroalkyl , R $ 14 - substituted or

halogen , CX7543 , CHX754 , OCH , X754 , unsubstituted cycloalkyl , R814 - substituted or unsubstituted - OCHX7542 , CN , OH , - NH2 , COOH , CONH2 , heterocycloalkyl , R814 - substituted or unsubstituted aryl , or - NO2 , SH , SO2H , - SOAH , - SO2NH2 , - NHNH2 , R814 - substituted or unsubstituted heteroaryl . X184 is halo JONH4 – NHC = ( O ) NHNH , _ NHC = ( O ) NHA , gen . In embodiments , X184 is F . - NHSO , H , — NHC = ( O ) H , — NHC ( O ) - OH , — NHOH , 20 R814 is independently oxo , - OCX7543 , - OCHX7542 , R764 substituted or unsubsti halogen , CX8143 , CHX8142 , OCH , X814 ,

tuted alkyl , R764 - substituted or unsubstituted heteroalkyl , OCHX8142 , CN , OH , - NH2 , COOH , CONH , , R764 - substituted or unsubstituted cycloalkyl , R764 - substi NO2 , SH , SO2H , SO _ H , SO NH , NHNH , , tuted or unsubstituted heterocycloalkyl , R764 - substituted or ONH , NHC = ( O ) NHNH , — NHC = ( O ) NH , unsubstituted aryl , or R764 - substituted or unsubstituted het - 25 — NHSO , H , — NHC = ( O ) H , NHC ( O ) OH , — NHOH , eroaryl . X754 is halogen . In embodiments , X75A is F . - OCX8143 , - OCHX8142 , R824 - substituted or unsubsti

R764 is independently oxo , tuted alkyl , R824 - substituted or unsubstituted heteroalkyl , halogen , CX7643 , CHX7642 , OCH _ X764 , CN , R824 - substituted or unsubstituted cycloalkyl , R824 - substi - OH , — NH , COOH , CONH2 , - NO2 , SH , tuted or unsubstituted heterocycloalkyl , R824 - substituted or - SOZH , SOUH , SO NH , NHNH , ONH2 , 30 unsubstituted aryl , or R824 - substituted or unsubstituted het NHC = ( O ) NHNH , , - NHC = ( O ) NH , NHSO , H , eroaryl . X814 is halogen . In embodiments , X814 is F .

- NHC = ( O ) H , NHC ( 0 ) OH , _ NHOH , OCXA , R $ 24 is independently oxo , - OCHX7642 , R774 - substituted or unsubstituted alkyl , R774 halogen , CX8243 , - CHX8242 , OCH _ X824 , CN , substituted or unsubstituted heteroalkyl , R774 - substituted or OH , NH2 , COOH , CONH , , - NO2 , SH , unsubstituted cycloalkyl , R774 - substituted or unsubstituted 35 SO2H , SO4H , - SO2NH2 , — NHNH , ONH2 , heterocycloalkyl , R774 - substituted or unsubstituted aryl , or _ NHC = ( O ) NHNH , _ NHC = ( O ) NH – NHSOH , R77A - substituted or unsubstituted heteroaryl . X76A is halo - — NHC = ( O ) H , — NHC ( O ) - OH , — NHOH , OCX82 gen . In embodiments , X764 is F . - OCHX8242 , R834 - substituted or unsubstituted alkyl , R834

In embodiments , R17A is independently hydrogen , oxo , substituted or unsubstituted heteroalkyl , R834 - substituted or halogen , CX1743 , CHX17A , OCH , X174 , CN , 40 unsubstituted cycloalkyl , R834 - substituted or unsubstituted - OH , — NH2 , COOH , CONH2 , — NO2 , SH , heterocycloalkyl , R834 - substituted or unsubstituted aryl , or - SOZH , SO H SO NH , NHNH , ONH , R834 - substituted or unsubstituted heteroaryl . X824 is halo - NHC = ( O ) NHNH , NHC = ( O ) NH2 , NHSO2H , gen . In embodiments , X824 is F . – NHC = ( 0 ) H , NHC ( O ) OH , NHOH , OCX14 , In embodiments , R15B is independently hydrogen , oxo , OCHX1742 , R784 - substituted or unsubstituted alkyl , R784 - 45 halogen , — CX15B3 , CHX15B2 , _ OCH , X15B , CN ,

substituted or unsubstituted heteroalkyl , R784 - substituted or OH , — NH , COOH , CONH2 , — NO2 , SH , unsubstituted cycloalkyl , R784 - substituted or unsubstituted SO , H , SOH , JSO , NH , – NHNH , JONHA , heterocycloalkyl , R784 - substituted or unsubstituted aryl , or _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , NHSOH , R784 - substituted or unsubstituted heteroaryl . X174 is halo NHC = ( 0 ) H , NHC ( O ) OH , NHOH , OCX155 gen . In embodiments , X174 is F . 50 OCHX15B , R72B - substituted or unsubstituted alkyl , R72B

R784 is independently oxo , substituted or unsubstituted heteroalkyl , R72B - substituted or halogen , CX7843 : CHX7842 , OCH , X784 , unsubstituted cycloalkyl , R72B - substituted or unsubstituted - OCHX7842 , CN , OH , - NH2 , - COOH , CONH2 , heterocycloalkyl , R72B - substituted or unsubstituted aryl , or - NO2 , SH , SO2H , SO , H , SO NH2 , - NHNH2 , R72B - substituted or unsubstituted heteroaryl . X15B is halo ONH2 , — NHC = ( O ) NHNH , NHC = ( O ) NH2 , 55 gen . In embodiments , X15B is F . NHSO , H , — NHC = ( O ) H , NHC ( O ) OH , NHOH , R72B is independently oxo ,

- OCX7843 , OCHX7842 , R794 - substituted or unsubsti - halogen , CX72B3 , CHX72B2 , OCH _ X72B , tuted alkyl , R794 - substituted or unsubstituted heteroalkyl , OCHX72B2 , CN , - OH , - NH2 , COOH , CONH2 , R794 - substituted or unsubstituted cycloalkyl , R794 - substi - - NO2 , SH , SO3H , SO4H , SO NH2 , - NHNH2 , tuted or unsubstituted heterocycloalkyl , R794 - substituted or 60 - ONH , NHC = ( ONHNH , NHC = ( O ) NH , unsubstituted aryl , or R794 - substituted or unsubstituted het NHSO , H , – NHC = ( O ) H , NHC ( O ) OH , _ NHOH , eroaryl . X784 is halogen . In embodiments , X78A is F . - OCX72B3 , OCHX72B2 , R73B - substituted or unsubsti R794 is independently oxo , tuted alkyl , R73B - substituted or unsubstituted heteroalkyl ,

halogen , CX7943 , CHX7942 , OCH , X794 , CN , R73B - substituted or unsubstituted cycloalkyl , R73B - substi - OH , NH , COOH , — CONH2 , — NO2 , SH , 65 tuted or unsubstituted heterocycloalkyl , R73B - substituted or SO3H , SO _ H , SO NH , NHNH2 , CONH2 , unsubstituted aryl , or R73B - substituted or unsubstituted het

– NHC ( O ) NHNH – NHC = ( O ) NH – NHSOH , eroaryl . X72B is halogen . In embodiments , X72B is F .

cy17A

US 10 , 053 , 433 B2 115 116

R73B is independently oxo , tuted alkyl , R79B - substituted or unsubstituted heteroalkyl , halogen , CX73B3 , CHX73B2 , OCH , X73B , CN , R79B - substituted or unsubstituted cycloalkyl , R79B - substi OH , NH2 , COOH , CONH , NO2 , SH , tuted or unsubstituted heterocycloalkyl , R79B - substituted or

- SO3H , — SO H , SO2NH2 , — NHNH2 , ONH2 unsubstituted aryl , or R79B - substituted or unsubstituted het - NHC = ( O ) NHNH , NHC = ( O ) NH2 , - NHSO H , 5 eroaryl . X78B is halogen . In embodiments , X78B is F . NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX738 , R79B is independently oxo ,

- OCHX73B , R74B - substituted or unsubstituted alkyl , R74B halogen , CX79B3 , CHX79B2 , OCH _ X79B , CN , substituted or unsubstituted heteroalkyl , R74B - substituted or OH , NH2 , COOH , CONH2 , NO2 , SH , unsubstituted cycloalkyl , R74B - substituted or unsubstituted SO3H , SO4H , SO2NH2 , - NHNH2 , ONH2 , heterocycloalkyl , R74B - substituted or unsubstituted aryl , or 10 _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , _ NHSO , H , R748 - substituted or unsubstituted heteroaryl . X73B is halo – NHC = ( O ) H , NHC ( O ) OH , _ NHOH , OCX798 , gen . In embodiments , X73B is F . In embodiments , R16B is independently hydrogen , oxo , OCHX79B2 , R80B - substituted or unsubstituted alkyl , R 8OB

halogen , CX16B3 , CHX16B , OCH , X16B , CN , substituted or unsubstituted heteroalkyl , R80B - substituted or OH , — NH2 , COOH , CONH , NO2 , SH , 15 uns 15 unsubstituted cycloalkyl , R8OB - substituted or unsubstituted

_ SOTH , JSOH , JSO , NH , , - NHNH , ONHA , heterocycloalkyl , R8OB - substituted or unsubstituted aryl , or – NHC = ( O ) NHNH , NHC = ( O ) NH , NHSO , H , R8OB - substituted or unsubstituted heteroaryl . X79B is halo – NHC = ( O ) H , NHC ( O ) OH , _ NHOH , OCX168 gen . In embodiments , X79B is F . - OCHX16B2 , R75B - substituted or unsubstituted alkyl , R75B In embodiments , R18B is independently hydrogen , oxo ,

substituted or unsubstituted heteroalkyl , R75B - substituted or 20 halogen , CX1883 , CHX1852 , OCH X18B , CN , unsubstituted cycloalkyl , R7SB - substituted or unsubstituted OH , NH , COOH , CONH2 , NO , , SH , heterocycloalkyl , R75B - substituted or unsubstituted aryl , or _ SO , H , _ SO H , JSO , NH , _ NHNH , CONH , R75B - substituted or unsubstituted heteroaryl . X16B is halo NHC = ( O ) NHNH , _ NHC = ( O ) NH , _ NHSO , H , gen . In embodiments , X16B is F . NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX18

R75B is independently oxo , 25 OCHX18B , R81B - substituted or unsubstituted alkyl , R IB . halogen , CX75B3 - CHX75B2 , OCH , X75B , substituted or unsubstituted heteroalkyl , R81B - substituted or OCHX75B2 , CN , OH , NH2 , COOH , CONH , unsubstituted cycloalkyl , R & IB - substituted or unsubstituted NO2 , SH , SO2H , SO _ H , SO2NH2 , - NHNH , , heterocycloalkyl , R81B - substituted or unsubstituted aryl , or JONH , _ NHC - ( O ) NHNH , NHC - ( O ) NH , 1 = O ) NH2 R81B - substituted or unsubstituted heteroaryl . X18B is halo NHSO , H , — NHC = ( O ) H , NHC ( O ) OH , NHOH , 30 gen . In embodiments , X18B is F . - OCX75B3 , OCHX75B2 , R76B - substituted or unsubsti R81B is independently oxo , tuted alkyl , R76B - substituted or unsubstituted heteroalkyl , halogen , CX81B3 , CHX81B _ , _ OCH , X81B , R76B - substituted or unsubstituted cycloalkyl , R76B - substi OCHX81B2 , CN , OH , - NH2 , COOH , CONH2 , tuted or unsubstituted heterocycloalkyl , R76B - substituted or

unsubstituted aryl , or R76B - substituted or unsubstituted het - 35 5 - NO2 , SH , SO2H , SO4H , SO2NH2 , - NHNH , , eroaryl . X75B is halogen . In embodiments , X75B is F . JONH , _ NHC = O ) NHNH , _ NHC = ( O ) NH ,

R76B is independently oxo , _ NHSOH , NHC = ( O ) H , NHC ( O ) OH , NHOH , halogen , CX76B3 , CHX76B , OCH , X76B , CN , - OCX81B3 , OCHX81B2 , R82B - substituted or unsubsti - OH , NH , COOH , CONH , NO , , SH , tuted alkyl , R $ 2B - substituted or unsubstituted heteroalkyl , - SO , H , SO H , SO NH , , - NHNH , , - ONH , , 40 R82B - substituted or unsubstituted cycloalkyl , R82B - substi – NHC = ( O ) NHNH , NHC = ( O ) NH , NHSO , H , tuted or unsubstituted heterocycloalkyl , R82B - substituted or – NHC = ( O ) H , NHC ( O ) OH , _ NHOH , OCX768 , unsubstituted aryl , or R82B - substituted or unsubstituted het - OCHX76B2 , R77B - substituted or unsubstituted alkyl , eroaryl . X81B is halogen . In embodiments , X81B is F . R77B - substituted or unsubstituted heteroalkyl , R77B - substi R82B is independently oxo , tuted or unsubstituted cycloalkyl , R77B - substituted or unsub - 45 halogen , CX82B , CHX82B , OCH , X82B , CN , stituted heterocycloalkyl , R77B - substituted or unsubstituted OH , — NH , COOH , CONH2 , — NO2 , SH , aryl , or R77B - substituted or unsubstituted heteroaryl . X76B is SOzH , SO , H , SO NH , NHNH , CONH2 , halogen . In embodiments , X76B is F . _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , _ NHSO , H ,

In embodiments , R17B is independently hydrogen , oxo , _ NHC = ( ) H , NHC ( O ) OH , NHOH , OCX82 halogen , CX17B3 , CHX17B2 , OCH , X17B , CN , 50 OCHX82B2 , R83B - substituted or unsubstituted alkyl , R83B - OH , — NH2 , COOH , CONH2 , — NO2 , SH , substituted or unsubstituted heteroalkyl , R83B - substituted or - SO3H , SO _ H , SO2NH2 , — NHNH2 , ONH2 , unsubstituted cycloalkyl , R83B - substituted or unsubstituted – NHC = ( O ) NHNH , _ NHC = ( O ) NH – NHSO , H , heterocycloalkyl , R83B - substituted or unsubstituted aryl , or _ NHC — IOH . - NHC ( O ) - OH . NHOH . _ OCX17B . R83B - substituted or unsubstituted heteroaryl . X82B is halo - OCHX17B2 , R78B - substituted or unsubstituted alkyl , R78B - 55 gen . In embodiments , X82B is F . substituted or unsubstituted heteroalkyl , R78B - substituted or In embodiments , R15C is independently hydrogen , oxo , unsubstituted cycloalkyl , R78B - substituted or unsubstituted halogen , CX15C3 , CHX15C2 , OCH2X15C , CN , heterocycloalkyl , R78B - substituted or unsubstituted aryl , or OH , — NH2 , COOH , CONH2 , — NO2 , SH , R78B - substituted or unsubstituted heteroaryl . Xl7B is halo SO2H , SO4H , SO2NH2 , — NHNH2 , CONH2 , gen . In embodiments , X17B is F . 60 NHC = ( O ) NHNH , _ NHC = ( O ) NH – NHSOH , R78B is independently oxo , NHC ( O ) H , NHC ( O ) OH , _ NHOH , LOCX15C , .

halogen , CX78B3 , CHX78B2 , OCH _ X78B , OCHX15C2 , R72C - substituted or unsubstituted alkyl , - OCHX78B , CN , OH , - NH2 , COOH , CONH2 , R72C - substituted or unsubstituted heteroalkyl , R72C - substi - NO2 , SH , SO3H , SOAH , — SONH2 , — NHNH2 , tuted or unsubstituted cycloalkyl , R72C - substituted or unsub - ONH , NHC = ( O ) NHNH , NHC = ( O ) NH2 , 65 stituted heterocycloalkyl , R72C - substituted or unsubstituted NHSO , H , NHC = ( O ) H , — NHC ( O ) - OH , — NHOH , aryl , or R72C - substituted or unsubstituted heteroaryl . X15C is

_ OCX78B3 , OCHX782 2 , R79B - substituted or unsubsti - halogen . In embodiments , X15C is F .

2 .

3

US 10 , 053 , 433 B2 117 118

R72C is independently oxo , R78C - substituted or unsubstituted heteroalkyl , R78C - substi halogen , CX72C , CHX72C , OCH , X72C , tuted or unsubstituted cycloalkyl , R78C - substituted or unsub - OCHX72C2 , CN , OH , - NH2 , COOH , CONH2 , stituted heterocycloalkyl , R78C - substituted or unsubstituted — NO2 , — SH , — SO3H , — SO4H , — SO2NH2 , — NHNH2 , aryl , or R78C - substituted or unsubstituted heteroaryl . x17C is - ONH , NHC = ( O ) NHNH3 , NHC = ( O ) NH2 , 5 halogen . In embodiments , X17C is F . – NHSOH , NHC = ( O ) H , — NHCO ) OH , NHOH , R78C is independently oxo , OCX72C3 , OCHX72C2 , R73C - substituted or unsubsti halogen , CX78C3 , CHX78C2 , OCH2X78C , tuted alkyl , R73C - substituted or unsubstituted heteroalkyl , - OCHX78C2 , CN , OH , NH , , - COOH , CONH , , R73C - substituted or unsubstituted cycloalkyl , R73C - substi - NO2 , SH , - SOZH , - SO _ H , SO NH , , - NHNH , , tuted or unsubstituted heterocycloalkyl , R73C - substituted or 10 JONH , _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , unsubstituted aryl , or R73C - substituted or unsubstituted het NHSOH , NHC = ( O ) H , NHC ( O ) OH , NHOH , eroaryl . X72C is halogen . In embodiments , X72C is F . R73C is independently oxo , OCX78C3 , OCHX78C2 , R79C - substituted or unsubsti

halogen , CX73C3 , - CHX73C2 , _ OCH , X73C , CN , tuted alkyl , R79C - substituted or unsubstituted heteroalkyl , - OH , — NH2 , COOH , CONH , NO2 , SH SH , 15 K 15 R 79C - substituted or unsubstituted cycloalkyl , R79C - substi SO , H , SO H , SO NH , NHNH , , _ ONH . . tuted or unsubstituted heterocycloalkyl , R " - substituted or

– NHC = ( O ) NHNH , NHC = ( O ) NH , NHSO , H , unsubstituted aryl , or R79C - substituted or unsubstituted het – NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX73 , eroaryl . X78C is halogen . In embodiments , X78C is F . - OCHX73C , R74C - substituted or unsubstituted alkyl , R ' is independently oxo , R74C - substituted or unsubstituted heteroalkyl , R74C - substi - 20 halogen , CX7 % C3 , CHX19C2 , — OCH X79C , CN , tuted or unsubstituted cycloalkyl , R74C - substituted or unsub OH , NH , COOH , CONH2 , NO , , SH , stituted heterocycloalkyl , R74C - substituted or unsubstituted SO3H , SO _ H , SO NH , NHNH2 , _ ONH2 , aryl , or R74C - substituted or unsubstituted heteroaryl . X73C is NHC = ( O ) NHNH2 , - NHC = ( O ) NH2 , NHSO , H , halogen . In embodiments , X73C is F . NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX9C ,

In embodiments , R16C is independently hydrogen , oxo , 25 OCHX7°C , R80C - substituted or unsubstituted alkyl , halogen , CX16C3 , CHX16C2 , OCH X16C , CN , R80C - substituted or unsubstituted heteroalkyl , R80C - substi - OH , - NH2 , COOH , CONH2 , — NO2 , SH , tuted or unsubstituted cycloalkyl , R80C - substituted or unsub _ SOTH , JSOH , JSO , NH , , - NHNH , ONHA , stituted heterocycloalkyl , R80C - substituted or unsubstituted - NHC = ( O ) NHNH , NHC = ( O ) NH , NHSO , H , aryl , or R80C - substituted or unsubstituted heteroaryl . X79C is – NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX16C , 30 3 : 30 halogen . In embodiments , X79C is F . - OCHX16C2 , R75C - substituted or unsubstituted alkyl , In embodiments , R18C is independently hydrogen , oxo , R75C - substituted or unsubstituted heteroalkyl , R75C - substi halogen , CX18C3 , CHX18C , OCH , X18C , CN , tuted or unsubstituted cycloalkyl , R75C - substituted or unsub

stituted heterocycloalkyl , R75C - substituted or unsubstituted OH , — NH2 , COOH , CONH , NO2 , SH , aryl , or R75C - substituted or unsubstituted heteroaryl . X16C is 35 16C is 35 SO2H , SO4H , SO2NH2 , - NHNH , ONH2 , halogen . In embodiments , x16C is F . _ NHC = ( O ) NHNH – NHC = ( O ) NH – NHSO , H ,

R75C is independently oxo , _ NHC = ( O ) H , — NHCO ) OH , NHOH , OCX & CN , halogen , CX75C , CHX75C , - OCH , X75C , OCHX2 , Rº - substituted or unsubstituted alkyl , - OCHX75C2 , CN , OH , - NH2 , COOH , CONH2 , R81C - substituted or unsubstituted heteroalkyl , R & 1C - substi _ NO . — SH . — SO , H . — SO H . — SO . NH , NHNH , , 40 tuted or unsubstituted cycloalkyl , RI - substituted or unsub JONH , _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , stituted heterocycloalkyl , R81C - substituted or unsubstituted – NHSO , H , NHC = ( O ) H , NHC ( O ) OH , NHOH , aryl , or RS1C - substituted or unsubstituted heteroaryl . X18C is - OCX75C3 , OCHX75C2 , R76C - substituted or unsubsti - halogen . In embodiments , X18C is F . tuted alkyl , R76C - substituted or unsubstituted heteroalkyl , R & C is independently oxo , R76C - substituted or unsubstituted cycloalkyl , R76C - substi - 45 halogen , CX81C2 , CHX81C - OCH , X81C , tuted or unsubstituted heterocycloalkyl , R76C - substituted or OCHX81C2 , — CN , OH , - NH2 , — COOH , CONH2 , unsubstituted aryl , or R76C - substituted or unsubstituted het NO2 , SH , SO3H , SO H , SO NH , NHNH , , eroaryl . X75C is halogen . In embodiments , X75C is F . ONH , NHC = ( O ) NHNH , NHC - ( O ) NH ,

R76C is independently oxo , NHSO , H , NHC = ( 0 ) H , _ NHC ( O ) OH , NHOH , halogen , CX76C3 , CHX76C2 , - OCH , X76C , CN , 50 OCX81C3 , OCHX81C2 , R82C - substituted or unsubsti - OH , — NH2 , COOH , CONH , NO2 , SH , tuted alkyl , R82C - substituted or unsubstituted heteroalkyl , - SO3H , SO _ H , SO2NH2 , — NHNH2 , ONH2 , R $ 2C - substituted or unsubstituted cycloalkyl , R82C - substi – NHC = ( O ) NHNH , NHC = ( O ) NH , NHSO , H , tuted or unsubstituted heterocycloalkyl , R 82C - substituted or - NHC = ( 0 ) H , NHC ( O ) OH , NHOH , OCX7ºC , unsubstituted aryl , or R82C - substituted or unsubstituted het - OCHX76C2 , R77C - substituted or unsubstituted alkyl , 55 eroaryl . XXIC is halogen . In embodiments , XXIC is F . R77C - substituted or unsubstituted heteroalkyl , R77C - substi R82C is independently oxo , tuted or unsubstituted cycloalkyl , R77C - substituted or unsub - halogen , CX82C3 , CHX82C2 , OCH _ X82C , CN , stituted heterocycloalkyl , R77C - substituted or unsubstituted OH , NH2 , COOH , CONH , , - NO2 , SH , aryl , or R77C - substituted or unsubstituted heteroaryl . X76C is SO2H , SOH , SO NH , NHNH2 , ONH2 , halogen . In embodiments , X76C is F . 60 – NHC = O ) NHNH , _ NHC = O ) NH , _ NHSO , H ,

In embodiments , R17C is independently hydrogen , oxo , NHC = ( O ) H , — NHC ( O ) - OH , — NHOH , - OCX82C , halogen , — CX17C , CHX17C2 , OCH X17C , CN , OCHX82C2 , R83C - substituted or unsubstituted alkyl , - OH , — NH , COOH , CONH , NO2 , SH , R83C - substituted or unsubstituted heteroalkyl , R83C - substi - SO3H , SO H , SO NH , NHNH , ONH2 , tuted or unsubstituted cycloalkyl , R83C - substituted or unsub - NHC = ( O ) NHNH , NHC = ( O ) NH2 , - NHSO H , 65 stituted heterocycloalkyl , R83C - substituted or unsubstituted - NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX17M , aryl , or R83C - substituted or unsubstituted heteroaryl . X82C is - OCHX17C2 , R78C - substituted or unsubstituted alkyl , halogen . In embodiments , X82C is F .

31

US 10 , 053 , 433 B2 119 120

In embodiments , R15D is independently hydrogen , oxo , R77D - substituted or unsubstituted heteroalkyl , R77D - substi halogen , CX1503 , CHX15D2 , OCH X15D , CN , tuted or unsubstituted cycloalkyl , R77D - substituted or - OH , - NH2 , COOH , CONH2 , NO2 , SH , unsubstituted heterocycloalkyl , R77D - substituted or unsub - SO2H , SO4H , SO2NH2 , — NHNH2 , - ONH2 , stituted aryl , or R77D - substituted or unsubstituted heteroaryl . — NHC = ( O ) NHNH , NHC = ( O ) NH2 , — NHSO2H , 5 X76D is halogen . In embodiments , X76D is F . - NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX150 , In embodiments , R17D is independently hydrogen , oxo , OCHX15D2 , R72D - substituted or unsubstituted alkyl , tituted alkyl , halogen , CX17D3 , CHX17D2 , OCH X17D , CN , R72D - substituted or unsubstituted heteroalkyl , R72D - substi OH , - NH2 , COOH , CONH , , - NO2 , SH , tuted or unsubstituted cycloalkyl , R72D - substituted or SO3H , SOAH , SO2NH2 , — NHNH2 , CONH2 , unsubstituted heterocycloalkyl , R72D - substituted or unsub - 10 _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , _ NHSO , H , stituted aryl , or R72D - substituted or unsubstituted heteroaryl . NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX17M , X15D is halogen . In embodiments , X15D is F . R72D is independently oxo , OCHX17D2 , R78D - substituted or unsubstituted alkyl ,

halogen , CX72D3 , CHX72D2 , OCH _ X72D CH X72D R 78D - substituted or unsubstituted heteroalkyl , R78D - substi LOCHX72D - CN - OH . _ NH . COOH . _ CÔNH . . 15 tuted or unsubstituted cycloalkyl , R " - substituted or - NO2 , SH , SO2H , SO H , SO NH , NHNH , unsubstituted heterocycloalkyl , R78D - substituted or unsub - ONH , NHC ( O ) NHNH , , - NHC = ( O ) NH , stituted aryl , or R78D - substituted or unsubstituted heteroaryl . – NHSO . H , NHC = ( O ) H , NHC ( O ) OH , _ NHOH , X17D is halogen . In embodiments , X17D is F . - OCX72D , OCHX72D , R73D - Substituted or unsubsti - RiD is independently oxo , halogen , CX3 , tuted alkyl , R73D - substituted or unsubstituted heteroalkyl , 20 CHX78D2 , OCH _ X78D , OCHX78D2 , CN , OH , R73D - substituted or unsubstituted cycloalkyl , R73D - substi - NH2 , COOH , CONH2 , - NO2 , SH , SOZH , tuted or unsubstituted heterocycloalkyl , R73D - substituted or SOAH , SO NH , , - NHNH2 , — ONH2 , — NHC = ( O ) unsubstituted aryl , or R73D - substituted or unsubstituted het NHNH , NHC = ( O ) NH , NHSO , H , NHC = ( 0 ) H , eroaryl . X72D is halogen . In embodiments , X72D is F . - NHC ( O ) OH , NHOH , OCX780 , JOCHX780 ,

R73D is independently oxo , 25 R79D - substituted or unsubstituted alkyl , R19D - substituted or halogen , CX73D3 , CHX73D2 , OCH _ X73D , CN , unsubstituted he unsubstituted heteroalkyl , R79D - substituted or unsubstituted - OH , - NH2 , COOH , CONH2 , — NO2 , SH , cycloalkyl , R79D - substituted or unsubstituted heterocy _ SOTH , JSOH , JSO , NH , , - NHNH , ONHA , cloalkyl , R79D - substituted or unsubstituted aryl , or R79D – NHC = ( O ) NHNH , _ NHC = ( O ) NH – NHSO , H , substituted or unsubstituted heteroaryl . X78D is halogen . In - NHC = ( 0 ) H , NHC ( O ) OH , NHOH , OCX730 , 30 3º 30 embodiments , X78D is F . - OCHX73D2 , R74D - substituted or unsubstituted alkyl , R79D is independently oxo , R74D - substituted or unsubstituted heteroalkyl , R74D - substi halogen , CX79D , CHX79D , OCH , X79D , CN , tuted or unsubstituted cycloalkyl , R74D - substituted or

unsubstituted heterocycloalkyl , R74D - substituted or unsub OH , — NH , COOH , CONH2 , NO2 , SH , stituted aryl , or R74D - substituted or unsubstituted heteroaryl . 35 – SO , H , JSOH , JSO , NH , – NHNH , LONH , X73D is halogen . In embodiments , X73D is F . _ NHC = ( O ) NHNH – NHC = ( O ) NH – NHSOH ,

In embodiments , R16D is independently hydrogen , oxo , NHC = ( O ) H , — NHC ( O ) OH , NHOH , OCX7Ps , halogen , CX16D3 , CHX16D2 , OCH X16D , CN , OCHX79D2 , RSOD - substituted or unsubstituted alkyl , - OH . - NH . COOH . - CONH . . NO . . SH . ROD - substituted or unsubstituted heteroalkyl , RSOD - substi - SO , H , SO H , SO , NH NHNH , , ONH , , 40 tuted or unsubstituted cycloalkyl , R D - substituted or - NHC = ( O ) NHNH , NHC = ( O ) NH , NHSOH , unsubstituted heterocycloalkyl , R80D - substituted or unsub - NHC = ( O ) H , NHC ( O ) - OH , — NHOH , OCX16D3 , stituted aryl , or RSOD - substituted or unsubstituted heteroaryl . - OCHX16D2 , R75D - substituted or unsubstituted alkyl , X79D is halogen . In embodiments , X79D is F . R75D - substituted or unsubstituted heteroalkyl , R75D - substi In embodiments , R18D is independently hydrogen , oxo , tuted or unsubstituted cycloalkyl , R75D - substituted or 45 halogen , CX18D3 , CHX18D2 , OCH X18D , CN , unsubstituted heterocycloalkyl , R7SD - substituted or unsub OH , — NH2 , COOH , CONH2 , — NO2 , SH , stituted aryl , or R75D - substituted or unsubstituted heteroaryl . SO3H , SO H , SO NH2 , — NHNH , ONH2 , x16D is halogen . In embodiments , X16D is F . _ NHC = ( O ) NHNH , _ NHC = ( O ) NH , _ NHSO , H , R75D is independently oxo , _ NHC = ( O ) H , NHC ( 0 ) OH , NHOH , OCX8DT ,

halogen , CX7503 , CHX75D 2 , OCH , X75 , 50 OCHX18D2 , R81D - substituted or unsubstituted alkyl , - OCHX75D2 , CN , OH , - NH2 , COOH , CONH2 , R & ID - substituted or unsubstituted heteroalkyl , R & ID - substi - NO2 , SH , SO3H , SO H , SO NH2 , NHNH2 , tuted or unsubstituted cycloalkyl , R & ID - substituted or ONH , NHC = ( O ) NHNH , _ NHC = ( O ) NH , unsubstituted heterocycloalkyl , R & ID - substituted or unsub

– NHSO , H , NHC = ( 0 ) H , NHC ( O ) OH , NHOH , stituted aryl , or R & ID - substituted or unsubstituted heteroaryl . - OCX7503 , OCHX75D2 , R76D - substituted or unsubsti - 55 X18D is halogen . In embodiments , X18D is F .

tuted alkyl , R76D - substituted or unsubstituted heteroalkyl , R81D is independently oxo , R76D - substituted or unsubstituted cycloalkyl , R76D - substi halogen , CX81D3 , CHX81D2 , OCH _ X & ID , tuted or unsubstituted heterocycloalkyl , R76D - substituted or OCHX81D2 , CN , OH , - NH2 , COOH , CONH2 , unsubstituted aryl , or R76D - substituted or unsubstituted het - NO2 , SH , SO3H , - SO4H , - SO2NH2 , - NHNH2 , eroaryl . X75D is halogen . In embodiments , X75D is F . 60 ONH2 , — NHC = ( O ) NHNH2 , — NHC = ( O ) NH2 ,

R76D is independently oxo , – NHSO , H , NHC = ( O ) H , _ NHC ( O ) OH , — NHOH , halogen , CX7603 , CHX76D , OCH , X760 , CN , OCX81D3 , OCHX81D , R82D - substituted or unsubsti - OH , — NH , COOH , CONH , NO2 , SH , tuted alkyl , R82D - substituted or unsubstituted heteroalkyl , - SO3H , SOAH , SO NH2 , - NHNH2 , ONH2 , R82D - substituted or unsubstituted cycloalkyl , R82D - substi — NHC = ( O ) NHNH , NHC = ( O ) NH2 , — NHSO , H , 65 tuted or unsubstituted heterocycloalkyl , R $ 2D - substituted or - NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX768 , unsubstituted aryl , or R $ 2D - substituted or unsubstituted het - OCHX76D2 , R77D - substituted or unsubstituted alkyl , eroaryl . X & ID is halogen . In embodiments , X81D is F .

121

R9 . 30 ' R9 : 38 '

R100 R10 . 7

: R93 ' · R9 : 22 R933 ' ROL ROO R932 R $ 2 ' ROL ! R939 R 9 26 R9 . 18 Ruld R9 . 4 , R9 : 33 R 925 " ROI ) ; REO

R10 , R9 : 35 : R9 270 R 9 : 19 . ROLLS ROY R8 . 35 '

• RO ' R9 . 39 ' R931 R10 : R9 : 40 R108 ' R9 R10

R10 , R 10 . 3 . R937 ) R $ 29 ' R 9 : 2 , R9 . 13

R10 R10 R 10 : 20 : Rio ; R 10 . 1 R102 R936 ' R9 28 R9 : 20 Re

R 20 . 32 R10 R 1033 R 10 . 20 R 10 . 18 R 10 . 12

R 10 . 40 R112 R104 , R 10 . 30 : R 10 . 27 R 10 . 20 R 10 . 13 33 pios R10 . 27 R + 0 . 20 , R10 . 31

R10 . 38 ' 1 . R10 . 39

.

R 2015 "

· R10 . 30 : R10 . 20 R 10 . 22 R10 . 373 R 10 . 30 R 10 . 23 ?

R 11 . 10 R11 . 2 R 11 . 23 R11 . 18 R 11 . 9 ; R 11 . 1

R iL ' RIL Ri

-

i Rom

R 11 . 13 R 11 . 6°

R 11 . 275 R 11 . 20 R 11 . 20 R11 . 22 ' R11 . 35 ' R113 R 11 . 41 · R 11 . 34 R12 R 11 . 38 R 12 . 6 » R 11 . 403 R 11 . 33 R11 . 26 R 11 . 18 R 11 . 12

R 12 . 13 " R 12 . 14 R 12 . 2 25 R 122 , R 12 . 15 R 12 . 8 22 . 42 R 12 . 22 : R 12 . ia R 129 , R 12 . 1 R 12 . 20 R 12 . R 12 . 16 R72 . 2 , R 12 . 27 R 12 . 20

R 12 . 30 R 12 . 38 ' R 12 . 3 , ; R 12 . 40 R 1233 R12 . 20 R12 . 16 R 12 . 12 R125

R 124 ; R 12 . 34 R 13 . 4 R122 R1232 R12 26 Rilis R12 . 11

2 . 6 D * R 2 . 41 , R12 . 42 013 . : 42 , R13 . 10 . 13 RZ .

R12 . 21 ' R12 : 35 12 . 28 D , R12 . 36 '

M , R 13 . 3 "

US 10 , 053 , 433 B2 122

R82D is independently oxo , R7 . 22 , R7 . 23 , R7 . 24 , R7 . 25 , R7 . 26 , R7 . 27 , R7 . 28 , R7 . 29 , R7 . 30 , halogen , C # 82D3 , - CHX82D2 , OCH _ X82D , CN , R7 . 31 , R7 . 32 , R7 . 33 , R7 . 34 , R7 . 35 , R7 . 36 , R7 . 37 , R7 . 38 , R7 . 39 - OH , NH2 , COOH , CONH2 , NO2 , SH , R7 . 40 , R7 . 41 , R7 . 42 , R 8 . 1 , R8 . 2 , R8 . 3 , R8 . 4 , R8 . 5 , R8 . 6 , R87 , R8 . 8 , - SO H , SO H , SO NH , NHNH , , - ONH R8 . 9 , R8 . 10 , R8 . 11 , R8 . 12 , R8 . 13 , R8 . 14 , R8 . 15 , R8 . 16 , R8 . 17 , - NHC ( O ) NHNH , NHC ( O ) NH , NHSO , H , 5 R8 . 18 , R8 . 19 , R8 . 25 , R8 . 2í , R8 . 22 , R8 . 25 , R8 . 24 , R8 . 25 , R8 . 26 , NHC = ( O ) H , NHCO ) OH , NHOH , OCX80P , R8 . 27 R8 . 28 R8 . 29 R8 . 30 R8 . 31 R 8 . 32 R8 . 33 R8 . 34 R8 . 35

- OCHX82D , R83D - substituted or unsubstituted alkyl , R8 . 36 , R 8 . 37 , R 8 . 38 , R 8 . 39 , R8 . 40 , R8 . 41 , R8 . 42 , R9 . 1 , RP . 2 , R9 . 3 , R83D - substituted or unsubstituted heteroalkyl , R83D - substi - R9 . 4 tuted or unsubstituted cycloalkyl , R83D - substituted or R9 . 14 unsubstituted heterocycloalkyl , R83D - substituted or unsub - 10 R9 . 24 stituted aryl , or R83D - substituted or unsubstituted heteroaryl . X82D is halogen . In embodiments , X82D is F . R9 . 41 R9 . 42 R10 . 1 R10 . 2 R10 . 3 R 10 . 4 R10 . 5 R10 . 6 R 10 . 7

In embodiments , L ' is a Rº - substituted or unsubstituted R10 . alkylene . R96 - substituted or unsubstituted heteroalkylene , R10 . 16 , R10 . 17 . R10 . 18 . R10 . 19 . R10 . 20 . R10 . 21 . R10 . 22 R10 . 23 R96 - substituted or unsubstituted cycloalkylene , Rº6 - substi - 15 R10 . 2 tuted or unsubstituted heterocycloalkylene , R96 - substituted or unsubstituted arvlene , or R96 - substituted or unsubstituted R10 . 40 . R10 . 41 . R10 . 42 . R11 . 1 . R11 . 2 R11 . 3 . R11 . 4 R11 . 5 R 11 . 6 heteroarylene . R11 . 7 , R11 . 8 , R11 . 9 , R11 . 10 R11 . 11 , R11 . 12 , R11 . 13 , R11 . 14

R® is independently oxo , R11 . 15 R11 . 16 R 11 . 17 . R11 . 18 R11 . 19 R 11 . 20 R11 . 21 R11 . 22 halogen , CX % , CHX % , OCH , X96 , OCHX % , 20 R11 . 23 , R11 . 24 , R11 . 25 R11 . 26 R11 . 27 R11 . 28 R11 . 29 R11 . 30 - CN , OH , NH2 , COOH , CONH2 , - NO2 , SH , - SOH , SO H , SO NH , NHNH , , ONH , , R11 . 39 , R11 . 40 . R11 . 41 . R11 . 42 . R12 . 1 . R12 . 2 . R12 . 3 . R12 . 4 R 12 . 5 NHC ( O ) NHNH , NHC ( O ) NH , NHSOH , R12 . 6 , R127 , R12 . 8 , R12 . 9 , R12 . 10 , R12 . 11 , R12 . 12 , R12 . 13 .

- NHC = ( O ) H , NHC ( O ) OH , NHOH , OCX°g , - OCHX96 . R97 - substituted or unsubstituted alkyl . R97 - 25 R12 . 22 . R12 . 23 . R12 . 24 R12 . 25 R12 . 26 R12 . 27 R12 . 28 R12 . 29 substituted or unsubstituted heteroalkyl , Rº7 - substituted or unsubstituted cycloalkyl , Rº - substituted or unsubstituted R12 . 38 heterocycloalkyl , R97 - substituted or unsubstituted aryl , or R13 . 4 R13 . 4 , R13 . 5 , R13 . 6 , R13 . 7 , R13 . 8 , R13 . 9 , R13 . 10 , R13 . 11 , R13 . 12 , Rº7 - substituted or unsubstituted heteroaryl . X “ is halogen . arul X96 is halogen R13 . 1 R 13 . 13 R 13 . 14 R 13 . 15 R 13 . 16 R 13 . 17 R 13 . 18 R 13 . 19 R 13 . 20 In embodiments , X ” is F . 30 R13 . 21 R13 . 22 R13 . 23 . R13 . 24 R13 . 25 R13 . 26 R13 . 27 R13 . 28 Rº is independently oxo , R 13 . 29 R 13 . 30 R 13 . 31 R 13 . 32 R13 . 33 R13 . 34 R 13 . 35 R 13 . 36

halogen , CX ? ? , CHX ” , - OCH , X°F , CN , OH , R13 . 37 , R13 . 38 , R13 . 39 , R13 . 40 , R13 . 41 , R13 . 42 , R14 . 1 , R14 . 2 , - NH2 , COOH , CONH , , - NO2 , SH , SO2H , R14 . 3 , R14 . 4 , R 14 . 5 , R14 . 6 , R14 . 7 , R14 . 8 , R14 . 9 , R14 . 10 , R14 . 11 _ SOH , SO , NH , NHNH , LONH , NHC ( 0 ) R14 . 12 , R14 . 13 , R14 . 14 , R14 . 15 , R14 . 16 , R14 . 17 R14 . 18 R14 . 19 . NHNH , _ NHC = ( O ) NH , NHSO , H , NHC ( O ) H , 35 R14 . 20 , R14 . 21 , R14 . 22 , R14 . 23 , R14 . 24 , R14 . 25 , R14 . 26 , R14 . 27 . NHC ( O ) OH , NHOH , OCxºng , OCHxºng , Rºs R14 . 28 . R 14 . 29 . R 14 . 30 . R 14 . 31 R 14 . 32 . R 14 . 33 R14 . 34 R 14 . 35

substituted or unsubstituted alkyl , R98 - substituted or unsub R 14 . 36 R 14 . 37 R 14 . 38 R 14 . 39 R 14 . 40 R 14 . 41 R 14 . 42 xal ya2 stituted heteroalkyl , R98 - substituted or unsubstituted Xa3 , yaz ya4 yas yan yaz yas ya yalo yall yal2 yal3 cycloalkyl , R98 substituted or unsubstituted heterocy - Xal · xa15 yal6 yal7 yal8 yale ya20 xa21 ya22 ya23 cloalkyl , R98 - substituted or unsubstituted aryl , or R98 - sub - 40 Xa2 Xa25 Xa26 xa27 xa28 xa29 Xa30 Xa31 Xa32 xa33 stituted or unsubstituted heteroaryl . Xº7 is halogen . In xa35 xa36 xa37 xa38 xa39 xa46 xa4i xa42 xb1 embodiments , Xº7 is F . xb2 , xb3 , Xb4 , Xb5 , xb6 , x57 , Xb8 , xbº , xb10 , xbll xb12 ,

R22 , R25 , R40 , R43 , R46 , R49 , R58 , R61 , R64 , R67 , R74 , R77 , xb13 , xb14 , xb15 , xb16 , xb7 , xb8 , xb19 , xb20 , xb21 , xb22 R80 , R83 . R744 R77A , R804 , R 834 , R74B , R71B . R80B . R 83B . xb23 xb24 yb25 xb26 xb27 xb28 xb29 yb30 Xb31 xb32 R74C , R77C , R800 , R83C , R 74D , R77D , R 80D , R83D , RS6 , R 89 45 Xb33 , Xb34 , Xb35 , Xb36 , Xb37 , Xb38 , Xb39 , Xb40 X541 X542 , Rº2 , and R98 are independently hydrogen , oxo , halogen , XC1 , C2 , C3 , XC4 , X5 , XC6 , XC7 , Xc8 , XC9 , Xclo , xell , Xc12 ,

CF , CN , OH , – NH2 , COOH , CONH , Xc13 . xc14 Xc15 . xe16 ye17 . xc18 Xc19 Xc20 Xc21 - NO2 , SH , SO3H , SO H , SO2NH2 , NHNH2 , JONH , NHC ( O ) NHNH , , - NHC ( O ) NH , X2 , X34 NHSO , H , NHC = ( 0 ) H , NHC ( O ) OH , NHOH , 50 ml ' , ml ? , ml , ml * , ml , m2 ' , m2 ? , m2 , m2 * , m2 , n1 ' ,

- OCF3 , OCHF2 , unsubstituted alkyl , unsubstituted het n12 , n13 , n14 , n1 " , n2 , n22 , n23 , n24 , n2 " , vil , v1² , v13 , v14 , eroalkyl , unsubstituted cycloalkyl , unsubstituted heterocy - v1 " , v21 , v22 , v23 , v24 , v29 , R15 . 1 , R15 . 2 , R15 . 3 , R15 . 4 , R15 . 5 , cloalkyl , unsubstituted aryl , or unsubstituted heteroaryl .

In some embodiments , a compound as described herein R15 . 14 may include multiple instances of R1 , R2 , R7 , R8 , R9 , R10 , 55 R15 . 22 , R15 . 23 , R15 . 24 , R15 . 25 , R15 . 26 , R15 . 27 , R15 . 28 . R15 . 29 . R11 , R12 , R13 , R14 , xa Xb . x¢ , m1 , nl , vl . m2 , n2 , v2 , R15 , R15 . 30 . R15 . 31 . R15 . 32 R15 . 33 . R15 . 34 R15 . 35 R15 . 36 R15 . 37 R16 , R17 , R18 , x15 , x16 , x17 , X18 , E , m15 , n15 , v15 , m16 , R15 . 38 , R15 . 39 , R15 . 40 , R15 . 41 , R15 . 42 , R16 . 1 , R16 . 2 , R16 . 3 , n16 , v16 , m17 , n17 , v17 , m18 , n18 , v18 , and / or other R16 . 4 , R16 . 5 R16 . 6 , R16 . 7 , R16 . 8 , R16 . 9 , R16 . 10 , R16 . 11 R16 . 12 variables . In such embodiments , each variable may optional R16 . 13 . R16 . 14 . R16 . 15 . R16 . 16 . R16 . 17 . R16 . 18 R16 . 19 . R 16 . 20 be different and be appropriately labeled to distinguish each 60 R16 . 21 , R16 . 22 , R16 . 23 , R16 . 24 , R16 . 25 , R16 . 26 , R16 . 27 . R16 . 28 . group for greater clarity . For example , where each R1 , R2 , R16 . 29 , R16 . 30 , R16 . 31 , R16 . 32 , R16 . 33 , R16 . 34 R16 . 35 R16 . 36 . R ? , R8 , RP , R19 , R1 , R12 , R13 , R14 , X , X5 , Xº , m1 , n1 , vi , m2 , n2 , v2 , R15 , R16 , R17 , R18 , X15 . , X16 . , X17 . , E , m15 , n15 , R17 . 3 , R17 . 4 , R17 . 5 , R17 . 6 , R17 . 7 , R17 . 8 , R17 . 9 , R17 . 10 , R17 . 11 and / or v15 , is different , they may be referred to , for example , R17 . 12 , R17 . 13 , R17 . 14 , R17 . 15 , R17 . 16 , R17 . 17 , R17 . 18 , R17 . 19 . as R1 . 1 , R12 , R1 . 3 , R1 . 4 , R15 , R2 . 1 , R2 . 2 , R2 . 3 , R2 . 4 , R2 . 5 , R7 . 1 , 65 R17 . 20 , R17 . 21 , R17 . 22 , R17 . 23 , R17 . 24 , R17 . 25 , R17 . 26 , R17 . 27 , R7 . 2 , R7 . 3 , R7 . 4 , R7 5 , R7 . 6 , R7 . 7 , R7 . 8 , R19 , R7 . 10 , R7 . 11 , R7 . 12 , R17 . 28 . R17 . 29 R17 . 30 ' 217 . 31 ' . R7 . 13 , R7 . 14 , R 7 . 15 , R7 . 16 , R7 . 17 , R7 . 18 , R7 . 19 , R7 . 20 , R7 . 21 R17 . 36 , R17 . 37 , R17 . 38 , R17 . 39 , R17 . 40 , R17 . 41

R , R14 . 42 , Xal , yaz

8023 ? fold

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mal ; Pezo m22 R15 . 6 R 159 ' ,

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R 15 . 25° R 15 . 18 R 15 . 11 . R 15 . 38° R 153 , R15 . 22 R 15 . 1R75 . 10 13 . 20 Risc R 15 . 37 R 15 : 26 : R 15 . 1 . R 15 . 12 ; RISE · R15 . 4 ; R 15 . 34 R 15 . 270 R 15 . 20 R 15 . 194

R16 , 4 R 15 . 30 R 15 . 3 , R 16 . 1 ; R 10 . 5

; R 16 . 0 ; Rio ; R 15 . 383 R 15 . 209

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5 . 33 $ 15 . 26 , 115 . 30 v15 . 3 ? Vis ) , 815 . 27 X 5 . 20 X15 . 34 ,

15 . 37 ' . 30 , 115 . 38 ” . 1 , 815 . 32 ¥15 . 40 ' ° , 815 . 41 ' P15 . 4 ; 415 . 35 115 . 282845 . 21 '

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, X16 . 32 ' 15

; R 13 . 37 ' R 13 . 30 R73 . 23 '

R 14 . 20 R 14 . 265 R 14 . 18 R 14 . 12

R 14 . 32 R 14 . 38 R 14 . 27 R 14 . 30 : R 14 . 32 : R 14253 R 14 18 R 14 . 11

; R 14 . 40 R 14 . 4 , faz $ 70 . 15 , 116 . 8 ' 10 D

$ 16 . 10 Pale 824 v $ 16 . 76 $ 16 . is $ 16 . 20 476 . 13 $ 16 . 2 , 116 . 14 $ 16 . 22

416 . 20 $ 16 . 20 71637 116 . 39 $ 16 . 27

716 . 37 716 . 30 : $ 16 . 23 816 . 38 116 . 3 , 116 . 245 $ 16 . 4 ,

417 . 1 . 816 . 36 ' 116 . 20 $ 17 . 8 i 116 . 49 ; 116 . 32

$ 179 8177 1172 , 817 . ; , * 17 . 10477 . 2 7172 , 8172 . 4 81776 477 . 11 7 ' 7 . 3

PizzX 7 . 3 viz * ° : 38 Vlo , X17 . 12 629

23 i 7638 17 . 14 , 7177 217 . 159

81720 ; 4172 , Plz

817 . 36 ' 117 . 20 417 . 22 $ 18 . 7 : $ 17 . 4 , 717 . 34 417 . 270 117 . 20 877 . 13 1817876 . 40

418 . 11 818 118 . 27 : $ 18 . 15 878 . 9 3478 . 1 118 . 20 . | 181 , 478 . 10778 . 2

Pie $ 18 . 3 ,

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. 818 . 2 ,

$ 18 . 6 ' 20 No 178 . 14 % fc27 ' 1978

| 18 . 2 , $ 18 . 20 418 . 271 $ 18 . 28 418 . 13 $ 18 . 28

3182 i $ 18 . 30 ; 118 . 20 · 81837 718 . 30 ' $ 18 . 42 ; 818 . 35

US 10 , 053 , 433 B2 123 124

R18 . 2 , R18 . 3 , R18 . 4 , R18 . 5 , R18 . 6 , R18 . 7 , R18 . 8 , R18 . 9 , R13 . 11 , R13 . 12 , R13 . 13 , R13 . 14 , R13 . 15 , R13 . 16 , R13 . 17 , R13 . 18 , R18 . 11 , R18 . 12 , R18 . 13 , R18 . 14 , R18 . 15 , R18 . 16 , R18 . 17 , R18 . 18 R13 . 19 , R13 . 20 , R13 . 21 , R13 . 22 , R13 . 23 , R13 . 24 , R13 . 25 , R 13 . 26 , R18 . 19 , R18 . 20 . R18 . 21 . R18 . 22 . R18 . 23 . R18 . 24 R18 . 25 R18 . 26 R 13 . 27 R 13 . 28 R 13 . 29 R 13 . 30 R13 . 31 R13 . 32 R 13 . 33 R 13 . 34 R18 . 27 R18 . 28 R18 . 29 R18 . 30 R18 . 31 R18 . 32 R18 . 33 . R18 . 34 R 18 . 35 R 18 . 36 R 18 . 37 R18 . 38 R18 . 39 R18 . 40 R 18 . 41 R18 . 42 5 R14 is assumed by R14 . 1 , R14 . 2 , R14 . 3 , R14 . 4 , R14 . 5 , R14 . 6 . X15 . 1 , X15 . 2 , X15 . 3 , X15 . 4 x15 . 5 , X15 . 6 . / 15 . 7 x 15 . 6 , X15 . 10 . x15 . 11 . x15 . 12 x 15 . 13 x 15 . 14 y 15 . 15 x 15 . 16 X15 . 17 X15 . 18 X15 . 19 x 15 . 20 x 15 . 21 x 15 . 22 x15 . 23 x 15 . 24 x 15 . 25 R14 . 23 R 14 . 24 R14 . 25 R14 . 26 R14 . 27 R 14 . 28 R14 . 29 R14 . 30

R 14 . 31 , R14 . 32 , R14 . 33 , R14 . 34 , R14 . 35 , R14 . 36 , R 14 . 37 , R14 . 38 R 14 . 39 R 14 . 40 R14 . 41 R14 . 42 ; Xa is assumed by Xal , xa2 ,

x15 . 42 x16 . 1 , x16 . 2 , x16 . 3 , x16 . 4 , x16 . 5 , xl6 . 6 , x16 . 7 , xl6 . 8 Xa3 , xa4 , xas , xa6 , xa7 , xas , xa9 , xalo , xall , xa12 , xa13 , X16 . 9 x 16 . 10 x16 . 11 x16 . 12 x16 . 13 y 16 . 14 y 16 . 15 x16 . 16 Xalá , xais , xa16 , Xa17 , xal8 , xal9 xa20 xal xa22 xa23 x16 . 1 x16 . 1 x16 . 1 x16 . 2 x16 . 2 x16 . 23 x16 . 23 x16 . 24 ya24 ya25 ya26 ya27 ya28 ya29 ya30 ya31 ya32 ya33 ¥16 . 25 x16 . 26 x 16 . 27 x 16 . 28 x16 . 29 Xa34 xa35 xa36 xa37 xa38 xa39 xa40 xa41 xa42 : Xb is

: 15 assumed by Xbl . xb2 , Xb3 , Xb4 , Xb5 . Xb6 Xb7 xb8 yb9 X16 . 41 X16 . 42 X 17 . 1 X17 . 2 . X17 . 3 , X174 . x11 . 5 x17 . 6 . X17 . 1 xb10 , xb11xb12 , xb13 , xb4 , xb15 , xb16 , xb17 , xb18 , xb19 x 17 . 8 x17 . 9 x17 . 10 ' x17 . 11 x17 . 12 x17 . 13 x17 . 14 x17 . 15 ? Xb20 xb21 xb22 xb23 - 0 , X021 , Xb22 , Xb23 , Xb24 , Xb25 , X626 xb27 xb28

Xb30 Xb31 Xb32 Xb33 , Xb34 , Xb35 , Xb36 , Xb37 , Xb38 Xb39 X17 . 24 x 17 . 25 x17 . 26 X17 . 27 x 17 . 28 x17 . 29 x 17 . 30 x17 . 31 x640 x641 x642 : Xº is assumed by Xcl . xc2 . xc3 . Xc4 . xc5 x17 . 2 x17 . 5 x17 . 4 x 7 . 35 x17 . 36 x17 . 37 x17 . 38 x17 . 59 20 xcó , xe , xe , xe , xe10 , xcl1 , xci2 xci3 , xe14 , xe15 , xe16 X17 . 40 x17 . 41 x17 . 42 x18 . 1 , X18 . 2 X18 . 3 , X18 . 4 , X18 . 5 , X18 . 6 xe17 , xe18 , Xc19 , Xc20 , Xc21 , Xc22 , Xc23 , Xc24 , Xc25 Xc26 X18 . 7 x 18 . 8 x18 . 9 x18 . 10 x18 . 11 x18 . 12 x18 . 13 718 . 14 Xc28 Xc29 Xc30 Xc31 Xc32 , Xc33 , Xe34 Xc35 , Xc36 , X18 . 13 , 118 . 76 x18m x18 . is x18 . 19 118 . 2? x18 . 2 x18 . 22 Xc37 , Xc38 , Xe39 , XC40 , Xc41 , Xc42 ; ml is assumed by m1 " , X18 . 23 x18 . 24 x18 . 25 x18 . 26 ' x18 . 27 x18 . 28 x 18 . 29 x18 . 30 m1 ? , m1 , m14 , m1 ' ; nl is assumed by n1 ' , n1 ? , n13 , n14 , y18 . 31 y 18 . 32 y 18 . 33 y 18 . 34 ' x18 . 35 y18 . 36 y 18 . 37 " , 25 n1 ' ; v1 is assumed by v1 ' , vl ? , v1 , v14 , vl ; m2 is assumed X18 . 39 , X18 . 40 , X18 . 41 , X18 . 42 , E1 , E2 , E3 , E4 , E5 , m151 , m152 , by m2 ' , m2 , m2 , m24 , m2 ; n2 is assumed by n2 , n22 , m153 , m154 , m155 , n1 ' , n12 , n13 , n14 , n1 , n154 , n15² , n153 , n23 , n24 , n2º ; v2 is assumed by v21 , v22 , v23 , v24 , v2 ; R15 n154 , n155 , vl ! , vi ? , v13 , v14 , v1 , v151 , v152 , v153 , v154 , is assumed by R15 . 1 , R15 . 2 , R15 . 3 , R15 . 4 , R15 . 5 , R15 . 6 , R15 . 7 , v155 , m16 , m162 , m163 , m164 , m165 , n16 ' , n162 , n163 , R15 . 8 , R15 . 9 , R15 . 10 , R15 . 11 , R15 . 12 , R15 . 13 . R15 . 14 R15 . 15 n164 , n165 . v161 . v162 . v163 . v164 , v165 . m171 . m172 . 30 R15 . 16 . R15 . 17 . R15 . 18 . R15 . 19 . R15 . 20 . R15 . 21 R15 . 22 R15 . 23 m173 , m174 , m175 , n171 , n172 , n173 , n174 , n175 , v171 , R 15 . 24 R15 . 25 R15 . 26 R15 . 27 R15 . 28 R 15 . 29 R 15 . 30 R 15 . 31 v172 , v173 , v174 , v175 , m18 ' , m182 , m183 , m184 , m185 , R15 . 32 , R15 . 33 , R15 . 34 , R15 . 35 , R15 . 36 , R15 . 37 , R15 . 38 , R15 . 39 . n18 ' , n182 , n18 , n18 + , n185 , v18 ' , v18 , s18 , v18 + , v185 , R15 . 40 , R15 . 41 , R15 . 42 , R16 is assumed by R16 . 1 , R16 . 2 , R16 . 3 respectively , wherein the definition of R1 is assumed by R1 . 1 , R16 . 4 , R16 . 5 , R16 . 6 , R16 . 7 , R16 . 8 , R16 . 9 , R16 . 10 . R16 . 11 . R16 . 12 . R1 - 2 , R1 . 3 , R14 , R1 . 5 ; R2 is assumed by R2 . 1 , R2 - 2 , R2 . 3 , R2 . 4 , 35 R16 . 13 , R16 . 14 , R16 . 15 , R16 . 16 , R16 . 17 , R16 . 18 , R16 . 19 , R16 . 20 , R2 - 5 , R ? is assumed by R7 . 1 , R72 , R7 . 3 , R74 , R7 . 5 , R7 . 6 , R7 . 7 , R 16 . 21 R 16 . 22 R16 . 23 R 16 . 24 R 16 . 25 R16 . 26 R 16 . 27 R16 . 28 R7 . 8 , R7 . 9 , R7 . 10 , R7 . 11 , R7 . 12 , R7 . 13 , R7 . 14 , R7 . 15 , R 7 . 16 , R7 . 17 , R16 . 29 R16 . 30 R16 . 31 R16 . 32 R16 . 33 , R16 . 34 R16 . 35 R16 . 36 R7 . 18 , R7 . 19 , R1 . 20 , R7 . 21 , R7 . 22 , R 7 . 23 , R7 . 24 , R7 . 25 , R 7 . 26 R16 . 37 , R16 . 38 , R16 . 39 , R16 . 40 , R16 . 41 , R16 . 42 , R17 is assumed R7 . 27 R7 . 28 R7 . 29 R7 . 30 R7 . 31 R7 . 32 R7 . 33 R7 . 34 R7 . 35 . by R17 . 1 . R17 . 2 . R17 . 3 . R17 . 4 R17 . 5 . R17 . 6 . R17 . 7 . R17 . 8 . R17 . 9 . R7 . 36 , R7 . 37 , R7 . 38 , R7 . 39 , R7 . 40 , R7 . 41 , R7 . 42 ; R8 is assumed 40 R17 . 10 , R17 . 11 , R17 . 12 , R17 . 13 , R17 . 14 , R17 . 15 , R17 . 16 , R17 . 17 , by R8 . 1 , R8 . 2 , R8 . 3 , R8 . 4 , R8 . 5 , R8 . 6 , R8 . 7 , R8 . 8 , R8 . 9 , R8 . 10 , R 17 . 18 R 17 . 19 R17 . 20 R17 . 21 R17 . 22 R17 . 23 R17 . 24 R17 . 25 R8 . 11 . R8 . 12 , R8 . 13 R8 . 14 , R8 . 15 , R8 . 16 , R8 . 17 , R8 . 18 R8 . 19 , R17 . 26 , R17 . 27 , R17 . 28 R17 . 29 , R17 . 30 , R17 . 31 R17 . 32 R17 . 33 R8 . 20 , R8 . 21 , R8 . 22 , R8 . 23 , R8 . 24 , R8 . 25 , R8 . 26 , R8 . 27 , R8 . 28 R17 . 34 , R17 . 35 , R17 . 36 , R17 . 37 , R17 . 38 , R17 . 39 , R17 . 40 , R17 . 41 R8 . 29 R8 . 30 R8 . 31 R8 . 32 R8 . 33 , R8 . 34 , R8 . 35 R8 . 36 R8 . 37 R17 . 42 ; R18 is assumed by R18 . 1 , R18 . 2 , R18 . 3 . R18 . 4 . R18 . 5 . R8 . 38 , R8 . 39 , R8 . 40 , R8 . 41 , R8 . 42 ; Rº is assumed by Rº . 1 , R9 . 2 , 45 R18 . 6 , R18 . 7 , R18 . 8 , R18 . 9 , R18 . 10 , R18 . 11 , R18 . 12 , R9 . 3 , R9 : 4 , R9 . 5 , R9 . 6 , R9 . 7 , R9 . 8 , R9 . 9 , R9 . 10 , R9 . 11 , R9 . 12 ,

R9 . 14 R9 . 15 . R9 . 16 . , R9 . 17 . R9 . 18 R9 . 19 R9 . 20 R9 . 21 R18 . 22 R18 . 23 R18 . 24 R18 . 25 R18 . 26 R18 . 27 R18 . 28 R18 . 29 R9 : 22 , R9 . 23 , R9 . 24 , R9 . 25 , R9 . 26 , R9 . 27 , R9 . 28 , R9 . 29 , R9 . 30 R18 . 30 , R18 . 31 , R18 . 32 , R18 . 33 , R18 . 34 , R18 . 35 , R18 . 36 , R18 . 37 , R9 . 31 R9 . 32 R9 . 33 , R9 . 34 R9 . 35 R9 . 36 . R9 . 37 R9 . 38 R9 . 39 R18 . 38 R18 . 39 R18 . 40 R18 . 41 . R18 . 42 . x15 . is assumed by R9 . 40 , R9 . 41 , R9 . 42 : R10 is assumed by R10 . 1 , R10 . 2 , R10 . 3 , 50 X15 . 1 X15 . 2 . x15 . 3 X 15 . 4 x15 . 5 x15 . 6 x 15 . 7 x15 . 8 x15 . 5 . R10 . 4 R10 . 5 R10 . 6 . R10 . 7 . R10 . 8 . R10 . 9 . R10 . 10 . R10 . 11 R10 . 12 . x15 . 10 . x15 . 11 . x15 . 12 . x15 . 13 . x15 . 14 y 15 . 15 x 15 . 16 15 . 17 R 10 . 13 R10 . 14 R 10 . 15 R 10 . 16 R10 . 17 R 10 . 18 R10 . 19 R10 . 20 X15 . 18 X15 . 19 . X15 . 20 x15 . 21 x15 . 22 x 15 . 23 . x15 . 24 x 15 . 25

x15 . 26 x 15 . 27 x15 . 28 x 15 . 29 x15 . 30 x15 . 31 x15 . 32 x15 . 33 . R10 . 29 R10 . 30 R10 . 31 R10 . 32 , R10 . 33 R10 . 34 R10 . 35 R10 . 36 x15 . 34 x15 . 35 x15 . 36 , 115 . 37 x15 . 38 , x15 . 39 x15 . 40 x15 . 41 R10 . 37 R10 . 38 R10 . 39 R10 . 40 R10 . 41 R10 . 42 : R11 is assumed 55 x15 . 42 : X16 . is assumed by X16 . 1 , X16 . 2 , X16 . 3 , X16 . 4 , x16 . 5 , by R11 . 1 , R11 . 2 , R11 . 3 , R11 . 4 , R11 . 5 , R11 . 6 , R11 . 7 , R11 . 8 , R11 . 9 , x 16 . 6 X16 . 7 X16 . 8 x16 . 5 x16 . 10 x16 . 11 X16 . 12 716 . 13 R11 . 10 R11 . 11 R 11 . 12 R11 . 13 . R11 . 14 . R11 . 15 R11 . 16 R11 . 17 ¥16 . 14 x16 . 15 x16 . 16 x 16 . 17 x16 . 18 x16 . 19 716 . 20 x16 . 21° R11 . 18 R11 . 19 R11 . 20 , R11 . 21 , R11 . 22 , R11 . 23 R11 . 24 , R11 . 25 R11 . 26 R11 . 27 R11 . 28 R11 . 29 R11 . 30 R11 . 31 R11 . 32 R11 . 33 016 . 30 x16 . 31x16 . 32x16 . 33x16 . 34 x16 . 35 x16 . 36 016 . 37 R11 . 34 , R11 . 35 , R11 . 36 , R11 . 37 , R11 . 38 , R11 . 39 , R11 . 40 , R11 . 41 60 X16 . 38 , X16 . 39 , X16 . 40 , x16 . 41 , X16 . 42 , X17 . is assumed by R11 . 42 ; R12 is assumed by R12 . 1 , R12 . 2 , R12 . 3 , R12 . 4 , R12 . 5 , x17 . 1 X17 . 2 . X17 . 3 x17 . 4 . x17 . 5 . x17 . 6 X17 . 7 . x17 . 8 . x17 . 5 .

x17 . 10 x17 . 11 x17 . 12 x17 . 13 x17 . 14 x 17 . 15 x 17 . 16 x17 . 17 R12 . 14 R 12 . 15 R12 . 16 R 12 . 17 . R12 . 18 . R12 . 19 . R12 . 20 . R12 . 21 X17 . 18 x17 . 19 x17 . 20 y17 . 21

R 18 . 14 R 18 . 7 * , R18 . 15 . R18 . 16 0 . 18 . 17 R 18 . 21

R18 . 30 R93 , R 223 " ROLS R9 . 39 '

R 18 . 13 " ; R 18 . 40 R 18 . 375 R 18 . 261 R 18 . 16 R 18 . 12 ; R 18 . 5 "

; R 18 . 4 ; R 18 . 34 R 18 . 275 R 18 . 20

aby R10 . 1 $ 15 . 1 115 . 2

R10 . 21 ' " , R10 . 22 , R10 . 24 1 : 26 , R10 . 27 ' " , R10 . 28 0 . 30 pio

$ 16 . 22 ' , 627 , 716 . 28 ' 8 , x16 . 29

R12 R11 . 4 ,

$ 16 . 124 $ 16 . 16 416 . 12 16 . 18 176 . 11 . $ 16 . 20 $ 16 . 25

| 16 . 261 116 . 16 476 . 12 · 116 . 5 "

716 . 30 : $ 16 . 23 16 . 3 , 16 . 37 P16 . 30 ' , 716 . 4

816 . 8 ; 876 . 34 71627 $ 16 . 20 171 . 416 . 39 $ 16 . 39

17 . 2 ( 7 . 3 $ 17 . 10 2 . R12 . 7 , R 12 . 10 * * * * * * R 12 . 1 ' s R 72 . 8 R 12 . is R1211 R 12 . 22 < ? , R12 . 23 ' 23 , R12 . 24 26 , R12 . 27

7 . 34 , X 17 . 35 ' 17 . 30 : 717 . 3 , 417259

R12 . 30 R12 . 31 R12 . 32 R12 . 33 , R12 . 34 R12 . 35 R12 . 36 R12 . 37 R12 . 38 , R12 . 39 , R12 . 40 , R12 . 41 , R12 . 42 ; R13 is assumed by R13 . 1 R13 . 2 , R13 . 3 , R13 . 4 , R13 . 5 , R13 . 6 , R13 . 7 , R13 . 8 , R13 . 9 , R13 . 10

R12 . 29 ' $ 17 . 26 ' 26 , X17 . 27 S , R12 2 . 717 . 36 ed by R 13 . 1 ' 65 817 . 347 . 27 Y · R12 . 43 ; R1221 R 12 : 28 R 12 . 2 , ;

5 , 817 . 22 , X17 . 23 ' . 817 . 24 817 . 30 ' , X17 . 31 '

¥17 . 37 ' 39 viza X17 . 33 ' 717 . 40 ! , 717 . 41 X17 . 42 , X18 . is assumed X18 . 1 , X18 . 2 , X18 . 3 , X18 . 4 , X18 . 5 , x18 . 6 , X18 . 7 , X18 . 8 , X18 . 9 , X18 . 10 , X18 . 11 , X18 . 12 , X18 . 13 ,

R 13 . 2 % R 12 . 30 · R123 , R12 . 28

878 . 21 X18 . $ 18 . 28 a

- 22 , X18 . 23 ' Der X18 . 17 yil , x18 . 246 4 x18 . 25 ” 8 , x18 . 29

5

US 10 , 053 , 433 B2 125 126

X18 . 14 x18 . 15 x 18 . 16 x 18 . 17 x18 . 18 x18 . 19 x18 . 20 x18 . 21 compound , or pharmaceutically acceptable salt thereof , as described herein , including embodiments ( e . g . compound of 38 . 30 318 , 3 x18 . 32 38 . 3 8 . 34x18 . 35 x 8 . 30 318 , 37 formula I or II , or any embodiment thereof ; or in an X18 . 38 x18 . 39 x 18 . 40 , x18 . 41 , X18 . 42 ; E is assumed by E1 , E2 , example , table , figure , or claim ) . E ” , E4 , E > ; m15 is assumed by m151 , m152 , m153 , m154 , In embodiments of the pharmaceutical compositions , the

m155 ; n15 is assumed by n151 , n152 , n153 , n154 , n155 ; v15 compound , or pharmaceutically acceptable salt thereof , is is assumed by v151 , v15 ? , v153 , v154 , v15 % ; m16 is assumed by m161 , m162 , m163 , m164 , m16 ; n16 is assumed by n164 , included in a therapeutically effective amount .

In embodiments of the pharmaceutical compositions , the n16² , n16 , n164 , n16 " ; v16 is assumed by v16 % , v162 , v163 , v164 , v165 ; m17 is assumed by m171 , m172 , m173 , m174 , pharmaceutical composition includes a second agent ( e . g . m17 ) ; n17 is assumed by n17 ' , n172 , n172 , n174 , n17s ; n1z1 n172 n173 n174 n175 . 10 therapeutic agent ) . In embodiments of the pharmaceutical and / or v17 is assumed by v171 , v172 , v173 , v174 , v175 ; m18 compositions , the pharmaceutical composition includes a is assumed by m18 ! , m182 , m183 , m184 , m185 ; n18 is second agent ( e . g . therapeutic agent ) in a therapeutically assumed by n18 ' , n182 , n18 " , n184 , n189 ; and / or v18 is effective amount . In embodiments of the pharmaceutical assumed by v18 + , v182 , v183 , v184 , v18 % . The variables used compositions , the second agent is an agent for treating within a definition of R1 , R2 , R7 , R8 , R9 , R10 R11 , R12 , R13 , 15 cancer ( e . g . prostate cancer ) or an aberrant level of androgen R14 , X4 , X , X , ml , nl , vl , m2 , n2 , V2 , R15 , R17 , R7 , R18 , receptor activity or a disease associated with androgen X15 , X16 , X17 , X18 , E , m15 , n15 , v15 , m16 , n16 , v16 , m17 , receptor activity ( e . g . , prostate cancer , benign prostatic n17 , v17 , m18 , n18 , v18 , and / or other variables that appear hyperplasia , hypersexuality , acne , amenorrhea , seborrhea , at multiple instances and are different may similarly be hirsutism , androgenic alopecia , hidradenitis suppurativa , or appropriately labeled to distinguish each group for greater 20 hyperandrogenism ) . In embodiments , the second agent is an clarity . In some embodiments , the compound is a compound anti - cancer agent . In embodiments , the second agent is a described herein ( e . g . , in an aspect , embodiment , example , chemotherapeutic . In embodiments , the second agent is an claim , table , scheme , drawing , or figure ) . anti - prostate cancer agent . In embodiments , the second

agent is an agent for treating hormone - sensitive prostate C . NUCLEAR RECEPTORS 25 cancer . In embodiments , the second agent is an agent for

treating hormone - insensitive prostate cancer . In embodi In another aspect is provided a nuclear receptor protein ments , the second agent binds androgen receptor at a site

covalently bonded to a compound ( e . g . , an inhibitor or an that does not include the hormone binding site . In embodi AR inhibitor ) , for example a compound as described herein . ments , the second agent binds androgen receptor at a site

In embodiments , the compound is covalently bonded to a 30 that does is not the hormone binding site . In embodiments , cysteine residue of the nuclear receptor protein . In embodi - the second agent does not bind the ligand binding domain . ments , the compound is covalently bonded to an aspartate In embodiments , the second agent binds androgen receptor residue of the nuclear receptor protein . In embodiments , the at a site that is different from the site bound by a compound compound is covalently bonded to a glutamate residue of the described herein , including embodiments . In embodiments , nuclear receptor protein . In embodiments , the compound is 35 the second agent binds androgen receptor at a site that does covalently bonded to a tyrosine residue of the nuclear not overlap with the binding site of a compound described receptor protein . In embodiments , the compound is cova herein , including embodiments . In embodiments , the second lently bonded to a lysine residue of the nuclear receptor agent is a luteinizing hormone - releasing hormone analogue protein . In embodiments , the compound is covalently ( LHRH analogue or analog ) . In embodiments , the second bonded to a serine residue of the nuclear receptor protein . In 40 agent is a luteinizing hormone - releasing hormone agonist . In embodiments , the covalent bond is reversible . In embodi - embodiments , the second agent is a luteinizing hormone ments , the covalent bond is irreversible . In embodiments , releasing hormone analogue antagonist . In embodiments , the nuclear receptor is a human receptor . In embodiments , the second agent is a gonadotropin - releasing hormone ana the nuclear receptor is an androgen receptor . In embodi - logue ( GnRH analogue or analog ) . In embodiments , the ments , the androgen receptor is a human receptor . In 45 second agent is a gonadotropin - releasing hormone agonist . embodiments , the compound is covalently bonded to In embodiments , the second agent is a gonadotropin - releas Cys784 . In embodiments , the compound is covalently ing hormone analogue antagonist . In embodiments , the bonded to a residue corresponding to Cys784 of human second agent is leuprolide , goserelin , triptorelin , hisrelin , androgen receptor . In some embodiments , the covalently degarelix , or abiraterone . A luteinizing hormone - releasing modified nuclear receptor ( e . g . , androgen receptor ) has a 50 hormone analogue or gonadotropin - releasing hormone ana modulated activity relative to a control . In embodiments , the logue is a composition ( e . g . , peptide ) that interacts with nuclear receptor includes a mutation . In embodiments the ( binds ) the GnRH receptor and modulates the release of mutation includes a residue that covalently bonds the com - pituitary gonadotropins follicle - stimulating hormone and / or pound . In embodiments , the covalently modified nuclear luteinizing hormone . In embodiments , the second agent is receptor protein ( e . g . , androgen receptor , human receptor , 55 avorelin , buserelin , deslorelin , gonadorelin , goserelin , his human androgen receptor ) is in a subject . In embodiments , trelin , leuprorelin , lutrelin , nafarelin , peforelin , or triptore the covalently modified nuclear receptor protein ( e . g . , lin . In embodiments , the second agent is abarelix , cetrorelix , androgen receptor , human receptor , human androgen recep - degarelix , detirelix , ganirelix , iturelix , oxarelix , prazarelix , tor ) is in a sample extracted from a subject . In embodiments , ramorelix , or teverelix . the covalently modified nuclear receptor protein ( e . g . , 60 androgen receptor , human receptor , human androgen recep E . METHODS OF TREATMENT tor ) is from a subject .

In another aspect is provided a method of treating a D . PHARMACEUTICAL COMPOSITIONS nuclear receptor activity - associated disease in a subject in

65 need of such treatment , the method including administering In another aspect is provided a pharmaceutical composi - a compound , or a pharmaceutically acceptable salt thereof ,

tion including a pharmaceutically acceptable excipient and a as described herein , including embodiments ( e . g . compound

US 10 , 053 , 433 B2 127 128

of formula I or II , or any embodiment thereof ; or in an resistance ) . In embodiments , the method of treatment example , table , figure , or claim ) . includes a delay in drug resistance relative to the drug

In embodiments of the method , the compound , or phar resistance that develops with treatment using ARN - 509 maceutically acceptable salt thereof , is included in an effec - ( e . g . , average time to resistance ) . In embodiments , the tive amount . In embodiments of the method , the compound , 5 method of treatment includes a delay in drug resistance or pharmaceutically acceptable salt thereof , is included in a relative to the drug resistance that develops with treatment therapeutically effective amount . In embodiments of the using flutamide ( e . g . , average time to resistance ) . In embodi method , the compound , or pharmaceutically acceptable salt ments , the method of treatment includes a delay in drug thereof , is included in a prophylactically effective amount . resistance relative to the drug resistance that develops with

In embodiments , the method includes administering a 10 treatment using MDV3100 ( e . g . , average time to resistance ) . second agent ( e . g . therapeutic agent ) . In embodiments , the In embodiments , the method of treatment does not result in method includes administering a second agent ( e . g . thera - drug resistance for at least 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , peutic agent ) in a therapeutically effective amount . In 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , embodiments of the methods , the second agent is an agent 80 , 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , for treating cancer ( e . g . prostate cancer ) or an aberrant level 15 2000 , or 3000 days ( e . g . , average time to resistance ) . In of androgen receptor activity or a disease associated with embodiments , the method of treatment does not result in androgen receptor activity ( e . g . , prostate cancer , benign drug resistance for about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , prostatic hyperplasia , hypersexuality , acne , amenorrhea , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , seborrhea , hirsutism , androgenic alopecia , hidradenitis sup - 80 , 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , purativa , or hyperandrogenism ) . In embodiments , the sec - 20 2000 , or 3000 days ( e . g . , average time to resistance ) . In ond agent is an anti - cancer agent . In embodiments , the embodiments , the method of treatment does not result in second agent is a chemotherapeutic . In embodiments , the drug resistance for 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , second agent is an anti - prostate cancer agent . In embodi - 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , ments , the second agent is an agent for treating hormone - 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , or sensitive prostate cancer . In embodiments , the second agent 25 3000 days ( e . g . , average time to resistance ) . In embodi is an agent for treating hormone - insensitive prostate cancer . ments , the method of treatment does not result in drug In embodiments , the second agent binds androgen receptor resistance for at least 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , at a site that does not include the hormone binding site . In 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , embodiments , the second agent binds androgen receptor at 90 , 100 , 200 , 300 , 400 , 500 , or 600 weeks ( e . g . , average time a site that does is not the hormone binding site . In embodi - 30 to resistance ) . In embodiments , the method of treatment ments , the second agent does not bind the ligand binding does not result in drug resistance for about 1 , 2 , 3 , 4 , 5 , 6 , domain . In embodiments , the second agent binds androgen 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , receptor at a site that is different from the site bound by a 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , or 600 compound described herein , including embodiments . In weeks ( e . g . , average time to resistance ) . In embodiments , the embodiments , the second agent binds androgen receptor at 35 method of treatment does not result in drug resistance for 1 , a site that does not overlap with the binding site of a 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , compound described herein , including embodiments . In 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , embodiments , the second agent is a second agent described 500 , or 600 weeks ( e . g . , average time to resistance ) . In herein ( e . g . , in the pharmaceutical composition section embodiments , the method of treatment does not result in above ) . 40 drug resistance for at least 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 years

In embodiments , the nuclear receptor activity - associated ( e . g . , average time to resistance ) . In embodiments , the disease is cancer . In embodiments , the nuclear receptor method of treatment does not result in drug resistance for activity - associated disease is an androgen receptor activity - about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 years ( e . g . , average time associated disease . In embodiments , the androgen receptor to resistance ) . In embodiments , the method of treatment activity - associated disease is prostate cancer , benign pros - 45 does not result in drug resistance for 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , tatic hyperplasia , hypersexuality , acne , amenorrhea , sebor - or 10 years ( e . g . , average time to resistance ) . rhea , hirsutism , androgenic alopecia , hidradenitis suppura - In embodiments , the method of treatment is a method of tiva , or hyperandrogenism . In embodiments , the disease is prevention . In embodiments , the compounds set forth herein prostate cancer . In embodiments , the disease is hormone are provided as pharmaceutical compositions including the sensitive prostate cancer . In embodiments , the disease is 50 compound and a pharmaceutically acceptable excipient . hormone - insensitive prostate cancer . In embodiments , the In another aspect is provided a compound described cancer is drug - resistant cancer . In embodiments , the prostate herein , including embodiments ( e . g . compound of formula I cancer is drug - resistant prostate cancer . In embodiments , the or II , or any embodiment thereof ; or in an example , table , prostate cancer is casodex - resistant prostate cancer . In figure , or claim ) , for use in the treatment of a nuclear embodiments , the prostate cancer is Flutamide - resistant 55 receptor activity - associated disease in a subject in need of prostate cancer . In embodiments , the prostate cancer is such treatment . The use may include administering a com MDV3100 - resistant prostate cancer . In embodiments , the pound , or a pharmaceutically acceptable salt thereof , as prostate cancer is ARN - 509 - resistant prostate cancer . In described herein , including embodiments ( e . g . compound of embodiments , the subject is resistant to casodex , flutamide , formula I or II , or any embodiment thereof ; or in an MDV3100 , and / or ARN - 509 . In embodiments , the method 60 example , table , figure , or claim ) . of treatment includes a delay in drug resistance . In embodi - In another aspect is provided a compound described ments , the method of treatment includes a delay in drug herein , including embodiments ( e . g . compound of formula I resistance relative to the drug resistance that develops with or II , or any embodiment thereof ; or in an example , table , treatment using Casodex ( e . g . , average time to resistance ) . figure , or claim ) , for use in the treatment of cancer . The use In embodiments , the method of treatment includes a delay in 65 may include administering a compound , or a pharmaceuti drug resistance relative to the drug resistance that develops cally acceptable salt thereof , as described herein , including with treatment using enzalutimide ( e . g . , average time to embodiments ( e . g . compound of formula I or II , or any

129 US 10 , 053 , 433 B2

130 embodiment thereof ; or in an example , table , figure , or r hea , hirsutism , androgenic alopecia , hidradenitis suppura claim ) . In embodiments , the cancer is prostate cancer . In tiva , or hyperandrogenism . In embodiments , the disease is embodiments , the cancer is hormone - sensitive prostate can prostate cancer . In embodiments , the disease is hormone cer . In embodiments , the cancer is hormone - insensitive sensitive prostate cancer . In embodiments , the disease is prostate cancer . In embodiments , the cancer is drug - resistant 5 hormone - insensitive prostate cancer . In embodiments , the cancer . In embodiments , the prostate cancer is drug - resistant cancer is drug - resistant cancer . In embodiments , the prostate prostate cancer . In embodiments , the cancer is metastatic cancer is drug - resistant prostate cancer . In embodiments , the cancer . In embodiments , the cancer is metastatic prostate prostate cancer is casodex - resistant prostate cancer . In cancer . In embodiments , the cancer is castration - resistant embodiments , the prostate cancer is Flutamide - resistant prostate cancer . 10 prostate cancer . In embodiments , the prostate cancer is

In another aspect is provided a compound described MDV3100 - resistant prostate cancer . In embodiments , the herein , including embodiments ( e . g . compound of formula I prostate cancer is ARN - 509 - resistant prostate cancer . In or II , or any embodiment thereof ; or in an example , table , embodiments , the subject is resistant to casodex , flutamide , figure , or claim ) , for use as a medicament . MDV3100 , and / or ARN - 509 . In embodiments , the use

In another aspect is provided the use of a compound 15 includes a delay in drug resistance . In embodiments , the use described herein , including embodiments ( e . g . compound of includes a delay in drug resistance relative to the drug formula I or II , or any embodiment thereof ; or in an resistance that develops with treatment using Casodex ( e . g . , example , table , figure , or claim ) , in the manufacture of a average time to resistance ) . In embodiments , the use medicament for the treatment of a nuclear receptor activity includes a delay in drug resistance relative to the drug associated disease in a subject in need of such treatment . The 20 resistance that develops with treatment using enzalutimide use may include administering a compound , or a pharma - ( e . g . , average time to resistance ) . In embodiments , the use ceutically acceptable salt thereof , as described herein , includes a delay in drug resistance relative to the drug including embodiments ( e . g . compound of formula I or II , or resistance that develops with treatment using ARN - 509 any embodiment thereof ; or in an example , table , figure , or ( e . g . , average time to resistance ) . In embodiments , the use claim ) . 25 includes a delay in drug resistance relative to the drug

In embodiments , the compound , or pharmaceutically resistance that develops with treatment using flutamide ( e . g . , acceptable salt thereof , is included in an effective amount . In average time to resistance ) . In embodiments , the use embodiments , the compound , or pharmaceutically accept - includes a delay in drug resistance relative to the drug able salt thereof , is included in a therapeutically effective resistance that develops with treatment using MDV3100 amount . In embodiments , the compound , or pharmaceuti - 30 ( e . g . , average time to resistance ) . In embodiments , the use cally acceptable salt thereof , is included in a prophylacti - does not result in drug resistance for at least 1 , 2 , 3 , 4 , 5 , 6 , cally effective amount . 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 ,

In embodiments , the use includes a second agent ( e . g . 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , therapeutic agent ) . In embodiments , the use includes a 800 , 900 , 1000 , 2000 , or 3000 days ( e . g . , average time to second agent ( e . g . therapeutic agent ) in a therapeutically 35 resistance ) . In embodiments , the use does not result in drug effective amount . In embodiments , the second agent is an resistance for about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , agent for treating cancer ( e . g . prostate cancer ) or an aberrant 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , level of androgen receptor activity or a disease associated 90 , 100 , 200 , 300 , 400 , 500 , 600 , 700 , 800 , 900 , 1000 , 2000 , with androgen receptor activity ( e . g . , prostate cancer , benign or 3000 days ( e . g . , average time to resistance ) . In embodi prostatic hyperplasia , hypersexuality , acne , amenorrhea , 40 ments , the use does not result in drug resistance for 1 , 2 , 3 , seborrhea , hirsutism , androgenic alopecia , hidradenitis sup - 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , purativa , or hyperandrogenism ) . In embodiments , the sec - 30 , 35 , 40 , 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , ond agent is an anti - cancer agent . In embodiments , the 600 , 700 , 800 , 900 , 1000 , 2000 , or 3000 days ( e . g . , average second agent is a chemotherapeutic . In embodiments , the time to resistance ) . In embodiments , the use does not result second agent is an anti - prostate cancer agent . In embodi - 45 in drug resistance for at least 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , ments , the second agent is an agent for treating hormone 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , 60 , sensitive prostate cancer . In embodiments , the second agent 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , or 600 weeks ( e . g . , is an agent for treating hormone - insensitive prostate cancer . average time to resistance ) . In embodiments , the use does In embodiments , the second agent binds androgen receptor not result in drug resistance for about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , at a site that does not include the hormone binding site . In 50 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , embodiments , the second agent binds androgen receptor at 45 , 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , or 600 weeks a site that is not the hormone binding site . In embodiments , ( e . g . , average time to resistance ) . In embodiments , the use the second agent does not bind the ligand binding domain . does not result in drug resistance for 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , In embodiments , the second agent binds androgen receptor 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 25 , 30 , 35 , 40 , 45 , at a site that is different from the site bound by a compound 55 50 , 60 , 70 , 80 , 90 , 100 , 200 , 300 , 400 , 500 , or 600 weeks described herein , including embodiments . In embodiments , ( e . g . , average time to resistance ) . In embodiments , the use the second agent binds androgen receptor at a site that does does not result in drug resistance for at least 1 , 2 , 3 , 4 , 5 , 6 , not overlap with the binding site of a compound described 7 , 8 , 9 , or 10 years ( e . g . , average time to resistance ) . In herein , including embodiments . In embodiments , the second embodiments , the use does not result in drug resistance for agent is a second agent described herein ( e . g . , in the phar - 60 about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 years ( e . g . , average time maceutical composition section above ) . to resistance ) . In embodiments , the use does not result in

In embodiments , the nuclear receptor activity - associated drug resistance for 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10 years ( e . g . , disease is cancer . In embodiments , the nuclear receptor average time to resistance ) . activity - associated disease is an androgen receptor activity . In embodiments , the treatment is prevention . In embodi associated disease . In embodiments , the androgen receptor 65 ments , the compounds set forth herein are provided as activity - associated disease is prostate cancer , benign pros - pharmaceutical compositions including the compound and a tatic hyperplasia , hypersexuality , acne , amenorrhea , sebor pharmaceutically acceptable excipient .

US 10 , 053 , 433 B2 131 132

F . METHODS OF INHIBITING A NUCLEAR the same nitrogen atom may optionally be joined to form a RECEPTOR substituted or unsubstituted heterocycloalkyl or substituted

or unsubstituted heteroaryl ; R11 and R12 substituents bonded In another aspect is provided a method of inhibiting to the same nitrogen atom may optionally be joined to form

androgen receptor activity in a subject in need thereof , 5 a substituted or unsubstituted heterocycloalkyl or substituted including administering to the subject an effective amount of or unsubstituted heteroaryl ; al is independently an integer a compound as described herein , or a pharmaceutically from 0 to 4 ; b1 is independently an integer from 0 to 5 ; ml , acceptable salt thereof . m2 , v1 , and v2 are independently 1 or 2 ; nl and n2 are

In embodiments , the nuclear receptor is a human receptor . independently an integer from 0 to 4 ; X “ , X ” , and Xº are In embodiments , the nuclear receptor is an androgen recep - 10 independently - - C1 . — Br . — I . or — F . tor . In embodiments , the androgen receptor is a human receptor . 2p . The compound of embodiment 1p , having the formula :

G . ADDITIONAL EMBODIMENTS ( II ) 1p . A compound having the formula :

( RGA - ( R2 ) bl . ( 23 IZ

HO CH , o 20 20 as @ ya )

( R ' ) al

wa Or

( R ' ) al - A B + ( R2 ) b1 3p . The compound of one of embodiments 1p to 2p , wherein

HO CH3 0 Ring A is a 6 membered heteroaryl . 25 4p . The compound of one of embodiments 1p to 2p , wherein

wherein Ring A is a heteroaryl ; Ring B is a phenyl or Ring A is a 6 membered heteroaryl not comprising an ortho heteroaryl ; R ' is independently a heteroatom . halogen , CXC3 , CN , SO , C1 , SOnRlO , 5p . The compound of one of embodiments 1p to 2p , wherein – SONRZR * , NHNHA , ONRZR * , NHC = ( 0 ) Ring A is NHNH , NHC ( O ) NR7R8 , LN ( O ) . . . _ NR7R8 , 30 - C ( O ) R ” , - C ( O ) OR ” , - C ( O ) NR ’ RS , OR10 , - NR SO RO , NR ? C = ( O ) R , NR C ( 0 ) OR ” , - NRPOR " , OCX°3 , OCHX2 , E , substituted or unsub stituted alkyl , substituted or unsubstituted heteroalkyl , sub ( Rai stituted or unsubstituted cycloalkyl , substituted or unsubsti - 35 tuted heterocycloalkyl , substituted or unsubstituted aryl , or or substituted or unsubstituted heteroaryl ; two adjacent R ! substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl , or sub - 40 and al is an integer from 0 to 4 ; or stituted or unsubstituted heteroaryl ; E is an electrophilic moiety ; R2 is independently a halogen , — CX3 , CN ,

SO _ C1 , SO R14 , SONRR ! ? , NHNH , LONR ' R ' ? , NHC - ( O ) NHNH , NHC = O ) NR ' R2 , N ( O ) , NR ' R12 , C ( O ) R3 , 45

- C ( O ) - OR13 , - C ( O ) NRTR12 , - OR14 , - NRSO , R 14 , - NRIC ( O ) R13 , NRIC ( O ) OR13 , NRIOR13 , - OCX " 3 , OCHX 2 , substituted or unsubstituted alkyl , substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubstituted het - 50 erocycloalkyl , substituted or unsubstituted aryl , or substi tuted or unsubstituted heteroaryl ; two adjacent R2 substitu ents may optionally be joined to form a substituted or unsubstituted cycloalkyl , substituted or unsubstituted het erocycloalkyl , substituted or unsubstituted aryl , or substi - 55 tuted or unsubstituted heteroaryl ; R7 , R8 , RP , RIO , R1 , R12 , Istituted heteroamyl . R7 R8 R9 R10 R11 R12 and al is an integer from 0 to 3 .

R13 , and R14 are independently hydrogen , 6p . The compound of one of embodiments 1p to 2p , wherein halogen , CX3 , CN , OH , - NH2 , COOH , Ring A is CONH2 , — NO2 , — SH , SO , C1 , SO3H , SO4H ,

_ SO NHA , — NHNHA ONH , _ NHC = ( O ) NHNH , 60 – NHC = ( 0 ) NHÀ , — NHSOH , – NHC = ( 0 ) H , NHC

( 0 ) OH , — NHOH , OCX®z , OCHX2 , CF3 , - OCF3 , OCHF2 , substituted or unsubstituted alkyl , sub ( R ' ) al ( Rh ) a1

stituted or unsubstituted heteroalkyl , substituted or unsub stituted cycloalkyl , substituted or unsubstituted heterocy - 65 cloalkyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl ; R ' and R8 substituents bonded to

auch auf der ( R ' ) al man or

E

E ( ma

133 - continued

F E

US 10 , 053 , 433 B2 134

NHOH , NHOCHZ . - OCX°3 , OCHX°2 , substituted or unsubstituted C , - C , alkyl , substituted or unsubstituted 2 to 5 membered heteroalkyl , substituted or unsubstituted C3 - Co cycloalkyl , substituted or unsubstituted 3 to 6 mem

5 bered heterocycloalkyl , substituted or unsubstituted phenyl , or substituted or unsubstituted 5 to 6 membered heteroaryl . 10p . The compound of one of embodiments 1p to 9p , wherein Rl is independently C1 , F , Br , Br , I ,

CX “ 3 , CN , — NO2 , - OCX°3 , OCHX° 2 ,

( R ! ) , ,

or

10 and al is an integer from 0 to 3 ; or

( R ' ) a1 15 m

E E oors

20 11p . The compound of one of embodiments 1p to 10p , wherein said electrophilic moiety is — CN , — NO2 ,

( Ral ht mm NEN N . 25

( R ' ) a1 mi win Oors - , or

30

and al is an integer from 0 to 2 . 7p . The compound of one of embodiments 1p to 2p , wherein Ring A is

E

( Ral II min

12p . The compound of one of embodiments lp to 11p , wherein Ring B is a phenyl . 13p . The compound of one of embodiments lp to 11p , wherein Ring B is a heteroaryl . 14p . The compound of one of embodiments 1p to 11p , wherein Ring B is a 6 membered heteroaryl . 15p . The compound of one of embodiments lp to 14p , wherein R2 is independently a halogen , CX 3 , - C ( O ) NHCH3 , substituted or unsubstituted C , - C alkyl , substi tuted or unsubstituted 2 to 5 membered heteroalkyl , substi tuted or unsubstituted C3 - Co cycloalkyl , substituted or unsubstituted 3 to 6 membered heterocycloalkyl , substituted or unsubstituted phenyl , or substituted or unsubstituted 5 to

45 6 membered heteroaryl . 16p . The compound of embodiment 1p , wherein said com pound is

40 man - 177

SN ( R ' ) al

min mm or

NC . 50 NCN 50 and al is an integer from 0 to 3 . 8p . The compound of one of embodiments 1p to 2p , wherein Ring A is

HO CH3 55

17p . The compound of embodiment 2p , wherein said com pound is w

60 60 NC

Fac Tatto 9p . The compound of one of embodiments 1p to 8p , wherein R1 is a C1 , — F , Br , - I , CXºz , CN , - NHNH2 , ONH , NHC = ( O ) NHNH , NHC = ( O ) NH ,

- NO2 , — NH2 , C ( OH , C ( O ) CH3 , - C ( O ) - OH , 65 C ( 0 ) OCH2 , CO ) NH , JOH , _ NHC = ( O ) H ,

– NHC = ( O ) CH , NHC ( 0 ) OH , NHC ( O ) OCH ,

HO CHz ? O

10

US 10 , 053 , 433 B2 135 136

18p . The compound of one of embodiments 1p to 17p , unsubstituted cycloalkyl , substituted or unsubstituted het wherein said compound is an antagonist of a nuclear recep erocycloalkyl , substituted or unsubstituted aryl , or substi tor . tuted or unsubstituted heteroaryl ; two adjacent R ? substitu 19p . The compound of one of embodiments lp to 17p , ents may optionally be joined to form a substituted or wherein said compound is an antagonist of an androgen 5 unsubstituted cycloalkyl , substituted or unsubstituted het

erocycloalkyl , substituted or unsubstituted aryl , or substi receptor . 20p . A pharmaceutical composition comprising a compound tuted or unsubstituted heteroaryl ; R ? , R8 , R9 , R19 , R1 , R12 ,

R13 , and R 14 are independently hydrogen , of one of embodiments lp to 19p or a pharmaceutically halogen , CX?3 , CN , OH , - NH2 , COOH , acceptable salt thereof , and a pharmaceutically acceptable CONH , , - NO2 , — SH , SO , C1 , SO , H , SOAH , excipient . – SO , NH , _ NHNH , LONH , _ NHC = ( O ) NHNH , 21p . The pharmaceutical composition of embodiment 20p , NHC - ( 0 ) NHÀ , NHSO , H , NHC = ( O ) H , NHC comprising a therapeutically effective amount of said com ( 0 ) OH , — NHOH , OCX®3 , OCHX , CF3 , pound . OCF3 , OCHF2 , substituted or unsubstituted alkyl , sub 22p . An androgen receptor protein covalently bound to a stituted or unsubstituted heteroalkyl , substituted or unsub compound of one of embodiments 1p to 19p , wherein said 15 stituted cycloalkyl , substituted or unsubstituted heterocy compound is covalently bound to a cysteine residue of said cloalkyl , substituted or unsubstituted aryl , or substituted or androgen receptor protein . unsubstituted heteroaryl ; R7 and R8 substituents bonded to 23p . A human androgen receptor protein covalently bound to the same nitrogen atom may optionally be joined to form a a compound of one of embodiments lp to 19p , wherein said substituted or unsubstituted heterocycloalkyl or substituted compound is covalently bound to Cys784 of said human 20 or unsubstituted heteroaryl : R11 and R12 substituents bonded androgen receptor protein . to the same nitrogen atom may optionally be joined to form 24p . A method of treating cancer in a subject in need thereof , a substituted or unsubstituted heterocycloalkyl or substituted comprising administering to said subject an effective amount or unsubstituted heteroaryl ; al is independently an integer of a compound of one of embodiments lp to 19p , or a from 0 to 4 : b1 is independently an integer from 0 to 5 ; ml , pharmaceutically acceptable salt thereof . 25 m2 , v1 , and v2 are independently 1 or 2 ; nl and n2 are 25p . The method of embodiment 23p , wherein said cancer is independently an integer from 0 to 4 ; X “ , X ” , and XC are prostate cancer . independently — C1 , — Br , — I , or — F . 26p . The method of embodiment 23p , wherein said cancer is 2 . The compound of embodiment 1 , having the formula : associated with androgen receptor activity . 27p . A method of inhibiting androgen receptor activity in a 30 subject in need thereof , comprising administering to said subject an effective amount of a compound of one of embodiments 1p to 19p , or a pharmaceutically acceptable ( R ' ) a t A LB + ( R2 ) bl . salt thereof . 1 . A compound having the formula : 35

Bu Qi ( B7 ( Ryobi

( R ' ) al

or

( 1 ) 3 . The compound of one of embodiments 1 to 2 , wherein Ring A is a 6 membered heteroaryl .

( R2 ) 61 ; 40 4 . The compound of one of embodiments 1 to 2 , wherein Ring A is a 6 membered heteroaryl not comprising an ortho

HÓ CHz ? O heteroatom . 5 . The compound of one of embodiments 1 to 2 , wherein Ring A is

wherein ; Ring A is a heteroaryl ; Ring B is a phenyl or 45 heteroaryl ; R ' is independently a halogen , CXºz , — CN , - SO , CI , SO R10 , SO , NR7R® , NHNH , ONRZR * , NHC = ( O ) NHNH , , - NHC = ( O ) NRZR8 ,

- N ( O ) mi , - NR7RS , C ( O ) R ” , - C ( O ) - OR " , - C ( O ) ( RaTT NRÖR , OR10 , NR ’ SO , R10 , NR ? C = ( O ) R ” , 50 - NR?C ( O ) - OR ” , - NR ' OR ” , OCXºz , OCHX ̂ 2 , E , substituted or unsubstituted alkyl , substituted or unsubsti tuted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl ; 55 two adjacent Rl substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl ; E is an and al is an integer from 0 to 4 ; or electrophilic moiety ; R2 is independently a halogen , 60 - CX , CN , SO , CI , SO , R14 , SONR1R12 , – NHNH , ONR ' R ' ? , NHC ( O ) NHNH , – NHC ( ONR ' R12 , N ( O ) , NR ' SR12 , CO ) R13 , C ( O ) OR13 , C ( O ) NR1R12 , OR14 , NR ' SO , R14 ,

- NRC = ( O ) R13 , NRIC ( O ) OR13 , NRIOR13 , 65 - OCX " 3 , OCHX2 , substituted or unsubstituted alkyl , substituted or unsubstituted heteroalkyl , substituted or

totes ( R ) al ( R ) al TV 1L

w

US 10 , 053 , 433 B2 137

- continued 138

- continued ( R ' ) al

tant ( R ) al

minus ma 10

> or

and al is an integer from 0 to 3 ; or

and al is an integer from 0 to 3 ; or E N .

( R ! ) al ( R ' ) ai man ( Ral T Rial NS min 20 or . E

( R ! ) al and al an integer from 0 to 2 ; or ? , ( R ' ) al 25 wir wa

( R ' ) an meny en 30 S , N

!

h m

and al an integer from 0 to 1 . 6 . The compound of one of embodiments 1 to 2 , wherein 35 Ring A is

V = ( RD ) . QV wand tid

40 Nam Xxx EN ( R ' ) al ( R ' ) al man 45

N wim ( R ) al ( R or naro 1 ( R ' ) al 50

EN N = E $ ( R ' ) a1

- I 12 T

55

al

( R ' ) al ,

mo and al is an integer from 0 to 2 ; or 60

m

EN Or man ( 1 )

65 ( 1 )

US 10 , 053 , 433 B2 140

10 . The compound of one of embodiments 1 to 9 , wherein R is independently CL , - F , - Br , - I , CX°3 , CN , - NO2 , OCX “ 3 , OCHX “ 2 ,

US 10 . 053 , 433 p 139 - continued

E auf Seite weiteren ( Rh ) I ( R ' ) , 1 B . man 5 Or

and al is an integer from 0 to 1 ; or 10 min

E NEN 11 . The compound of one of embodiments 1 to 10 , wherein said electrophilic moiety is : mer is

Ris

Rio and al is 0 . 7 . The compound of one of embodiments 1 to 2 , wherein 20 Ring A is R17

D e dieren toegestaan om pa se samo oz . XLllL X . XX . XL

XL XL RIS

ma RIO R16 25

R17 RIZ an 0 mm E X17 Or

Rio 30 OR 18

R17 ( R ! ) al mm Fox > or 39

-

ma

wherein R15 is independently hydrogen , halogen , CX15 - CHX152 , CH , x15 , CN , SOm5R15D , SO , SNR 154R15B , NHNR154R15B , ONR154R15B , NHC = ( O ) NHNR15R15B , NHC ( O ) NR154R15B , N ( O ) mis , - NR 154R15B , C ( O ) ( R ' ) | R15C , - C ( O ) - OR15C , - C ( O ) NR154R15B , OR15D , NR15ASO , R150 , - NR154C ( O ) R15C , NR154C ( O )

40 OR15C , NR154 OR15C , OCX15 , OCHX15 , , substi tuted or unsubstituted alkyl , substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substi

and al is an integer from 0 to 3 . tuted or unsubstituted heterocycloalkyl , substituted or 8 . The compound of one of embodiments 1 to 2 , wherein unsubstituted aryl , substituted or unsubstituted heteroaryl ; Ring A is 45 R16 is independently hydrogen , halogen , CX163 , CHX12 ,

CH , X16 , CN , S0 , 16R16D , SONR16AR16AR16B , - NHNR164R168 , ONR165R16B NHC ( O

E NHNR164R16B — NHC ( O ) NR164R16B , — N ( O ) , 16 — NR16AR16B , - C ( O )

50 R16C , C ( O ) - OR16C , C ( O ) NR164R16B , OR16D , - NR16ASO , R16D , NR164C ( O ) R16C , NR164 C ( O ) OR16C , NR1640R16C , OCX1º3 , OCHX162 , substi tuted or unsubstituted alkyl , substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substi

9 . The compound of one of embodiments 1 to 8 , wherein R ' 55 tuted or unsubstituted heterocycloalkyl , substituted or is a _ C1 , - F , - Br , - I , CX°3 , CN , — NHNH2 , unsubstituted aryl , substituted or unsubstituted heteroaryl ; JONH , ?NHC = ( O ) NHNH , R17 is independently hydrogen , halogen , CX173 , CHX172 , NHC = ( O ) NH , NO2 , NHÀ , C ( O ) H , C ( O?CH , CH , x17 , CN , SO , R170 , LSO , NR174R178 ,

- C ( O ) OH , - C ( O ) - OCHZ , C ( O ) NH2 , OH , — NHNR174R17B , ONR174R17B , NHC = ( 0 ) NHC ( O ) H , NHC = ( O ) CH , NHC ( O ) OH , 60 NHNR174R978 ,

– NHC ( O ) OCH , _ NHOH , _ NHOCH , . _ OCC " , NHC ( O ) NR174R17B , N ( O ) , 7 , NR174R17B , CO ) - OCHXº2 , substituted or unsubstituted C . - C , alkyl , sub - R17C , - C ( O ) - OR17C , - C ( O ) NR174R17B , OR17D ,

stituted or unsubstituted 2 to 5 membered heteroalkyl , NR17ASO , R17D , NR174C ( O ) R17C , NR174C ( O ) substituted or unsubstituted Cz - Co cycloalkyl , substituted or OR17C , NR17AOR 17C , - OCX173 , OCHX12 , substi unsubstituted 3 to 6 membered heterocycloalkyl , substituted 65 tuted or unsubstituted alkyl , substituted or unsubstituted or unsubstituted phenyl , or substituted or unsubstituted 5 to heteroalkyl , substituted or unsubstituted cycloalkyl , substi 6 membered heteroaryl . tuted or unsubstituted heterocycloalkyl , substituted or

. Im16

Im17 , 1

R15

ma ! R17

US 10 , 053 , 433 B2 141 142

unsubstituted aryl , substituted or unsubstituted heteroaryl ; 14 . The compound of embodiment 11 , wherein E is : R18 is independently hydrogen , CX183 , CHX182 , CH , X1 $ , C ( O ) R18C , - C ( O ) OR18C , C ( O ) R15 NR184R18B , substituted or unsubstituted alkyl , substituted or

unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocycloalkyl , Y R16 ,

substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl ; each R154 , R15B , R15C , R150 , R16A , R16B , R16C , R16D , R174 , R17B , R17C , R17D , R184 , R18B , R18C , R18D , is 10 wherein R15 is independently hydrogen ; R16 is indepen independently hydrogen , CX3 , CN , - COOH , dently hydrogen or CH NR164R16B ; R17 is independently - CONH , CHX , CH . X . substituted or unsubstituted hydrogen ; and R 04 and RP are independently hydrogen or alkyl , substituted or unsubstituted heteroalkyl , substituted or unsubstituted alkyl .

15 . The compound of one of embodiments 1 to 10 , wherein unsubstituted cycloalkyl , substituted or unsubstituted het - 15 said electrophilic moiety is _ CN . NO . erocycloalkyl , substituted or unsubstituted aryl , or substi tuted or unsubstituted heteroaryl ; R154 and R 15B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl ; R164 and R16B sub stituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocy cloalkyl or substituted or unsubstituted heteroaryl ; R174 and R17B substituents bonded to the same nitrogen atom may 25 5 16 . The compound of one of embodiments 1 to 15 , wherein

Ring B is a phenyl . optionally be joined to form a substituted or unsubstituted 17 . The compound of one of embodiments 1 to 15 , wherein heterocycloalkyl or substituted or unsubstituted heteroaryl ; Ring B is a heteroaryl . R18A and R18B substituents bonded to the same nitrogen 18 . The compound of one of embodiments 1 to 15 , wherein atom may optionally be joined to form a substituted or Ring B is a 6 membered heteroaryl . unsubstituted heterocycloalkyl or substituted or unsubsti - 30 19 . The compound of one of embodiments 1 to 18 , wherein tuted heteroaryl ; each X , X15 , x16 , x17 and X18 is indepen R ? is independently a halogen , — CX z , - C ( O ) NHCHz , dently — F , Cl , Br , or — I ; n15 , n16 , n17 , v15 , v16 , and substituted or unsubstituted C - C alkyl , substituted or v17 , are independently and integer from 0 to 4 ; m15 , m16 , unsubstituted 2 to 5 membered heteroalkyl , substituted or

unsubstituted Cz - Co cycloalkyl , substituted or unsubstituted and m17 are independently an integer between 1 and 2 ; L 35 3 to 6 membered heterocycloalkyl , substituted or unsubsti is a bond , — N ( H ) - , - N ( CH3 ) - , or tuted phenyl , or substituted or unsubstituted 5 to 6 mem bered heteroaryl . 20 . The compound of embodiment 1 , wherein said com pound is

20 N min OI nom NH

C NC . NON

and Ring C is a substituted or unsubstituted heterocycloalky - 43 Ily . 45

lene or substituted or unsubstituted heteroarylene . HÓ CH3 6 12 . The compound of embodiment 11 , wherein E is :

21 . The compound of embodiment 2 , wherein said com 50 pound is

XL 817 . mm 1 NCAN 55 55 Ibon |

Fic and X17 is cl . 13 . The compound of embodiment 11 , wherein E is : H? CH3 0 0

0 R15

Y R16 ,

60 22 . The compound of one of embodiments 1 to 21 , wherein said compound is an antagonist of a nuclear receptor . 23 . The compound of one of embodiments 1 to 21 , wherein said compound is an antagonist of an androgen receptor . 24 . A pharmaceutical composition comprising a compound

65 of one of embodiments 1 to 23 or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable

R17

and R15 , R16 , and R17 are independently hydrogen . excipient .

5

OH

I | | . )

15

US 10 , 053 , 433 B2 143 144

25 . The pharmaceutical composition of embodiment 24 , TABLE 1 comprising a therapeutically effective amount of said com pound . Antiandrogens . 1st generation . Casodex : 42 - fold less potent than DHT .

2nd generation . RD162 , MDV3100 : changed B - ring of CDX , 26 . An androgen receptor protein covalently bound to a improved affinity 8 - fold . 3rd generation . compound of one of embodiments 1 to 23 , wherein said ARN - 509 : Added N to A - ring of RD162 , increased affinity 2 - fold . compound is covalently bound to a cysteine residue of said androgen receptor protein . 27 . A human androgen receptor protein covalently bound to a compound of one of embodiments 1 to 23 , wherein said 10 compound is covalently bound to Cys784 of said human androgen receptor protein . 28 . A method of treating cancer in a subject in need thereof , comprising administering to said subject an effective amount of a compound of one of embodiments 1 to 23 , or a Dihydrotestosterone ( DHT , IC50 = 3 . 8 nM ) pharmaceutically acceptable salt thereof .

NC 29 . The method of embodiment 28 , wherein said cancer is prostate cancer . 30 . The method of embodiment 29 , wherein said prostate 20 F3C cancer is hormone sensitive prostate cancer . 31 . The method of embodiment 29 , wherein said prostate cancer is hormone refractory prostate cancer . Casodex ( CDX , IC50 = 160 nM ) 32 . The method of embodiment 29 , wherein said prostate 25 cancer is resistant to casodex treatment . 33 . The method of embodiment 29 , wherein said prostate cancer is resistant to enzalutamide treatment . 34 . The method of embodiment 29 , wherein said prostate 30 cancer is resistant to ARN - 509 treatment . 35 . The method of embodiment 28 , wherein said cancer is associated with androgen receptor activity . MDV3100 ( IC50 = 21 . 4 nM ) 36 . A method of inhibiting androgen receptor activity in a 35 subject in need thereof , comprising administering to said subject an effective amount of a compound of one of embodiments 1 to 23 , or a pharmaceutically acceptable salt thereof .

= o

=

o

NC = Doyote

NC

40 40 H . EXAMPLES

45

Example 1 . Syntheses of Casodex Analogs RD162 ( IC50 = 30 . 9 nM ) 45

A New Strategy for Inhibiting Androgen Receptor Acti NC vation . The mainstay of current prostate cancer therapies are drugs that directly inhibit androgen receptor ( AR ) function by competitively inhibiting the binding of hormones ( TES ,

F C N ' N DHT ) to the receptor ( e . g . Casodex , Flutamide , MDV3100 , 50 ARN - 509 ) . However , tumor cells often become resistant to antiandrogens within a few years of treatment and the progression of prostate cancer subsequently resumes . We hypothesize that the limited efficacy of antiandrogens is due ARN - 509 ( IC50 = 16 . 0 nM ) in part to the fact that they bind AR with affinities weaker 55 - than or , at best , comparable to native hormones . This allows endogenous ligands to competitively activate the receptor , Casodex ( bicalutamide ) has been developed and utilized and selective pressure to drive escape mechanisms . Here we as chemotherapy for prostate cancer . Studies on bicaluta report the development of new antiandrogens , including one mide show it is well tolerated with very few side effects . differing by two atoms ( CH replaced by N ) from Casodex 60 However , over time many current treatments are rendered that binds over 24 - Fold more tightly to AR than the parent ineffective . Tran and coworkers evaluated 200 thiohydantoin compound . The improved affinity of the new antiandrogen is deriviatives and discovered MDV3100 and RD162 as lead attributed to a strategic substitution of a CH group by a N compounds . Compared to casodex , MDV3100 and RD162 atom in the A - ring of Casodex , designed to alter the elec - had 8 - Fold and 5 - Fold greater affinity , respectively . These tronics of the molecule . Even higher affinity ligands can be 65 compounds both contain the same A - ring as casodex but produced by capitalizing on this strategy , as described show drastic differences in the B - ring portion of the mol herein . ecule and link between the A and B rings . Recently , the

146 - continued

NC NC . N .

US 10 , 053 , 433 B2 145

development of a novel antiandrogen , ARN - 509 , which displayed 7 - to 10 - Fold greater affinity than casodex was reported . It also shows greater efficacy in xenograft model of human prostate cancer than MDV3100 and RD162 . Inter estingly , an atomistic comparison of ARN - 509 and RD162 5 F3CM shows that the two differ by the presence of a nitrogen in the A ring , which only leads to a 2 - Fold increase in its affinity . NC . NC Previously , it had been believed that increases in affinity largely come from changes in the B ring , while the A ring remained primarily the same .

FC

N

10

F NC . NC NC Wither . Theo NON N Finn NH HO

A - Ring Analogs

FC 4 . 037

F

NH FC 3 . 077

N

FIG . 1 displays an overlay of the crystal structures of wildtype AR bound to DHT ( light gray ) and AR mutant W741L bound to CDX ( dark gray ) . The mutation W741 is hypothesized to be responsible for casodex withdrawal syndrome . A cysteine is located in the ligand binding pocket that may interact with the cyano group of casodex . It is known that a nitrile can form a reversible covalent bond with a relative ( e . g . , active site ) cysteine and that this electrophi licity can be increased by the presence of an electron withdrawing heterocycle . We hypothesized that the presence of a pyridinyl moiety in casodex would increase in affinity /

30 efficacy of the compound due to reaction with Cys784 in the AR hormone binding pocket . To test this hypothesis , we synthesized multiple casodex analogs that contained a com bination of the aryl nitrile and pyridine , and tested their activity through in vitro assays of transcription . If this

35 hypothesis were true , it would expected that there would be an increase in affinity for the analog containing both a nitrile and pyridinyl moiety , while those lacking the aryl nitrile would exhibit little to no change .

A convergent approach was used in the synthesis of bicalutamide analogs by first synthesizing a carboxylic acid , based on the synthetic scheme found in Tucker and Ches terson , J Med Chem 1988 , 31 ( 4 ) , 885 - 887 . D - proline was reacted with methacryloyl chloride and triethylamine to arrive at the acryamide . Reaction with NBS in dimethylfor mamide to form the bromolactone , followed by acid cleav age of the proline auxiliary led to chiral carboxylic acid . Displacement of the alkyl bromide with 4 - Fluorothiophenol in sodium hydroxide and isopropanol gave a sulfide , which was followed by oxidation with peracetic acid to yield the desired carboxylic acid .

se na

NH FC 4 . 075

?

45

b

NH 50

F

NEtz II Baby 55

F ?? CH2Cl2 , 0° C .

NH

60 Baby ?? 1 . NBS . DMF z

2 . HCl , 100° C . F C N N N 65

US 10 , 053 , 433 B2 147

- continued 148

- continued H2SO4 , HNO3 sit as HS 5 F3C V NH2

?? ON - Br Br i - PrOH : NaOH

F30 V NH2 NH2 peracetic acid 10

HO to = EtoAc

carbo ID

= o

These anildes were then coupled with the late stage carboxylic acid through the reaction of the acid chloride formed by SOC1 , in dimethylacetamide to give casodex and

15 its analogues . The total list of analogues synthesized , along with their compound name , MW , ligand binding domain ( LBD ) IC50 , full length ( FL ) IC50 , and fold change ( in relationship to the experimental casodex data ) can be found in the tables below .

HO o =

|

20 Pete

X1 X2 With synthesis of the B ring portion of casodex complete ,

it was necessary to prepare the A ring of the analogues . The anilides used were either purchased or synthesized accord ing to literature precedent . Synthetic schemes for the anilides that were prepared in our lab are found below . N .

F

25 = o NH2 SOCl2 , R2 v DMA , - 10° C . HOT HO

HON o =

1 . NIS , CH3CN , 80° C . RiXj X20

2 . POC13 , DMF , 100°C . 30 =

= u = 0

FC YNH , NH2 À =

O Pd2 ( dba ) 3 , Xantphos , Meo RiX XI X2 - 35 NaOt - Bu , toluene , 130° C . FzCV

CIN O NH2 1 . Pd2 ( dba ) 3 , dppf , Zn ( CN ) 2 , DMF , 180° C .

= SOCI2 , RZ V

DMA , - 10° C . HO =

2 . TFA , CH2Cl2 1101 F3CV F3C NHPMB NHPMB 40 RiX X NCM O

= o

FO F3C F C F3CV NEL o =

AS 1 . NBS , CHCI : 2 . CuCN , DMF , 170°C . F C v NH ,

NC ' N

CDX R - CN , X = CH , X = CH , 4 . 116 RC = _ H , X = CH , X2 = CH 4 . 127 Ri = NO2 , X = CH , X2 = CH

50 4 . 037 R = _ CN , X = N , X2 = CH , 4 . 126 R , = H , X = N , X2 = CH 4 . 129 R = NO2 , X = CH , X2 = N 3 . 077 R - CN , X - CH , X = N , 4 . 125 R - _ H , X = CH , X2 = N

TABLE 2

F3C NH ,

LBD LBD MW IC50 ( g / mol ) ( M )

FL FL Fold IC50 LVCaP chg ( UM ) data ( LBD )

Fold chg ( FL ) Structure Cmpd

NC . 1 . 0 1 . 0 wer F Casodex ( CDX )

430 . 37 g / mol

0 . 36 0 . 02 ?M

1 . 00 I 0 . 24 UM

0 . 35 – 0 . 05 UM = o

F3C =

o

US 10 , 053 , 433 B2 149 150

TABLE 2 - continued LBD

MW IC50 ( g / mol ) ( UM )

FL Fold IC50 LVCaP chg ( UM ) data ( LBD )


0 . 19 24 . 0 5 . 3 431 . 06 g / mol

F FC 4 . 037 ( N CDX )

0 . 015 + 0 . 001 UM

0 . 14 $ 0 . 10 UM 0 . 06

?M o = u = 0

431 . 06 0 . 49 0 . 06

N / A 0 . 74 F FC 3 . 077

0 . 33 Not tested g / mo

?M = n = o

NH

NC F N / A N / A FC 4 . 075

364 . 06 g / mol

Not tested

IZ =

71 . 7 0 . 14 0 . 014 F FC 4 . 116

405 . 07 g / mol

2 . 53 1 . 16 UM

0 . 53 0 . 27 uM 512

UM

NH o = 6 =

0

F FC 4 . 126

12 . 4 0 . 23 0 . 08 406 . 06 g / mol

1 . 55 – 0 . 41

0 . 11 – 0 . 02 UM UM 14 . 2

?M F C o = = O

N / A 0 . 016 — FFC 4 . 125

406 . 06 g / mol

22 . 4 + 41 . 8

Not tested

UM

N

agres wyposa Dijo Bagyon

9

0 . 050 0 . 11 F FC 4 . 127

450 . 05 g / mol

7 . 26 £ 10 . 7

8 . 74 I 15 . 8

Not tested

2 UM ?M

o = • = o

8 . 61 0 . 19 0 . 12 F FC 4 . 129 O

451 . 05 g / mol

1 . 94 + 0 . 43

Not tested 17 UM 5 . 96

UM O = ú = o

19 . 5 0 . 14 0 . 05 MDV3100 464 . 09 g / mol

3 . 28 – 0 . 79

0 . 10 0 . 01

M UM 30 . 9 UM EZ

US 10 , 053 , 433 B2 151 151 152

TABLE 2 - continued LBD

MW IC50 ( g / mol ) ( UM )

FL Fold IC50 LVCP chg ( UM ) data ( LBD )


NCN 477 . 09 3 . 11 0 . 64

N / A ARN 509

0 . 30 0 . 12 + 0 . 02 g / mol

UM ?M F C

* * N / A means the compound was tested but IC50 could not be calculated .

15

Example 2 . IC50 Data and Quantum Mechanics calculation with the PCM method in water , to avoid over Calculations estimation of intramolecular H - bonds . Finally the equation

E ( adduct ) – E ( nitrile ) - E ( methanethiol ) is used to find the Density functional calculations to determine the electro reactivity in kcal / mol , listed in the tables below . Calcula philicity of the nitriles in our synthetic compounds were 20 tions were also performed to determine the charge on the performed as in Oballa et al . Bioorg Med Chem Lett 2007 , electronegative atom at the R1 position that is thought to 17 ( 4 ) , 998 - 1002 , discussing a method for assessing nitrile electrophilicity . Briefly , the free energy of thioimidate for interact with Arg752 . There is an obvious increase in elec mation from the reaction of the desired nitrile and meth trophilicity going from Casodex to Enzlutamide to ARN anethiol was calculated . The geometry of both reagents and 25 509 as well as a similar increase in 4 . 037 . Compound 4 . 075 the thioimidate was optimized in the gas phase with B3LYP / has the highest electrophilicity , yet lacking a — CF3 group , 6 - 311G ( d , p ) level of theory , followed by a single point which has been determined to be essential to binding .

TABLE 3 Electrophilicity and point charge calculations

Electrophilicity of — CN ( kcal / mol )

R1 Point charge Structure Name

NC F Casodex ( CDX ) - 5 . 647 - 0 . 562

= =

F Enzalutamide - 7 . 160 - 0 . 534

N

NH

ARN - 509 - 9 . 120 - 0 . 459

F3C N

F FC 4 . 037 - 7 . 641 - 0 . 486

= o

F3C NH o =

US 10 , 053 , 433 B2 153 154

TABLE 3 - continued

Electrophilicity and point charge calculations

Electrophilicity of — CN ( kcal / mol )

Ri Point charge Structure Name

NCA F FC 3 . 077 - 7 . 114 - 0 . 533 = o

F3C NH o = Theo * * * NC NC N F FC 4 . 075 - 12 . 422 - 0 . 460

O =

0

IZ = HO 0

F FC 4 . 116 n / a n / a

o = • = o

F FC 4 . 126 n / a n / a

F2C NH o = = o

F FC 4 . 125 F FC 4 . 125 n / a n / a n / a n / a

gyes agros Bagyar

to 11

able F FC 4 . 127 n / a - 0 . 461 , - 0 . 479

Fzc IZ o = h = o

ON F FC 4 . 129 n / a - 0 . 456 , - 0 . 471

? , IZ O = uEO

155 TABLE 4 .

US 10 , 053 , 433 B2 156

Example 3 . Characterization of Antiandrogens and Mechanism of Action

Compound characterization .

A . Kl = * 2

F 5 24 X2

= o

F3C F3C NH o =

10

P ILY Ri point charge

Electro philicity

( kcal / mol )

Addition of nitrogen ortho to CN increases affinity 5 24 - Fold , while addition of N in CDX analogs lacking CN

has no effect . It was noted that placing the nitrogen meta to the R1 caused a decrease in affinity . One explanation for this result can be found in the work by Tucker et al . J Med Chem 1988 , 31 ( 5 ) , 954 - 959 . Physiochemical studies show that the dominant configuration places the amide hydrogen coplanar to the hydroxyl group . This allows for the hydroxyl group to form an intramolecular H - bond and increase the proton donor ability of the hydroxyl proton . As supported by Yin et

is al . Mol Pharmacol 2003 , 63 ( 1 ) , 211 - 223 , replacing the hydroxyl group with an acetyl moiety obliterates the efficacy of this class of compounds . It is possible that having a nitrogen meta to the aryl nitrile allows for the tautomeric equilibrium of the amide to become perturbed . This weakens

20 the influence of the internal H - bond on the hydroxyl proton donor ability , lowering the affinity .

Nitrogen meta to CN decreases affinity , likely due to conformational change .

Experimental Fold IC50 ( uM change * Cmpd Ri Xi X

- 0 . 56 - 0 . 49 - 0 . 53

- 5 . 65 - 7 . 61 - 7 . 11

CDX 4 . 037 3 . 077 4 . 116 4 . 126 4 . 125 4 . 127 4 . 129

- CN CH CH 0 . 36 + 0 . 02 - CN N CH 0 . 015 + 0 . 001 - CN CH N 0 . 49 + 0 . 06

H CH CH 2 . 53 + 1 . 16 H N CH 1 . 55 + 0 . 41

CH N 22 . 4 + 41 . 8 — NO , CH CH 7 . 26 = 10 . 7 - NO , CH N 1 . 94 + 0 . 43

1 . 0 24 . 0 0 . 74 0 . 14 0 . 23 0 . 016 0 . 05 0 . 19

- 0 . 46 , - 0 . 48 - 0 . 46 , - 0 . 47 -

NC . F NC . NC N F OH

O - ???? 03 = ??? ??

Amide hydrogen increases proton donor ability . Confor mation change decreases proton donor ability

NC F NC IN OH

F3C ????

W 110

Conformation change decreases proton donor ability - Colegio una maneno 45 Example 4 . Additional Syntheses and Characterization of Compounds

Demonstrate cysteine - nitrile interaction through irrevers ible bond formation with electrophilic CDX analogs . We are

50 also making covalent analogs of casodex to show the interaction of Cys784 with the R1 position . Synthetically , 4 - nitro - 3 - ( trifluoromethyl ) aniline is coupled with carboxylic acid followed by oxidation to the sulfoxide . Reduction of the nitro group with SnCl , followed by reaction with the elec trophilic moiety precursor leades to four different electro philic casodex analogs . Their structures and IC50 data can be found in the table below .

F

1 . thionyl chloride , DMA 2 . O2N ??

Fac v NH2 3 . peracetic acid , EtOAC

US 10 , 053 , 433 B2 157 157 158

- continued O2N

1 . SnCl2 , HCI , MeOH , - 10° C .

F?c Y H 2 . Cysteine reactive group

F3C N O =

Ry = cysteine reactive group

= o

Wijo bo

Sa per saber vagonaster dit rod wit

F C F3C IZ o =

SO NH

Fac o = o = o

SO mi R1 =

N N s EO O =

LBD FL Fold Fold MW IC50 IC50 chg chg ( g / mol ) ( M ) ( UM ) ( LBD ) ( FL ) Structure Cmpd

NC Casodex ( CDX )

430 . 37 g / mol a gyerek 0 . 36 + 1 . 00

0 . 02 UM 0 . 24

?M o = ú = 0

FC 4 . 010 N / A N / A - 500 . 42 g / mol

F

= o

F C o =

US 10 , 053 , 433 B2 159 160

- continued LBD FL Fold

MW IC50 IC50 chg ( g / mol ) ( UM ) ( UM ) ( LBD )


FC 4 . 039 474 . 43 g / mol

0 . 48 - 0 . 75 N / A 0 . 26 UM

NH

F C O =

FC 4 . 015 N / A N / A - 496 . 86 g / mol

NH

Page Mango Sajjar

F C DEVE O = s = 0

FC 4 . 025 600 . 58 g / mol

0 . 62 0 . 78 0 . 58 + 1 . 29 0 . 11 – UM 1 . 29

?M

SO = O

F3C

* * N / A means the compound was tested but IC50 could not be calculated .

Show reversible cysteine - nitrile formation through IR experiments .

35 B - galactosidase activities were measured using the Luciferase Assay System ( Promega ) and Galacto - Light Plus - galactosidase reporter gene assay system ( Applied Bio systems ) , according to the manufacturer ' s instructions . Example 5 . Modulation of AR LBD

In order to test the effect of ligands on the AR ligand - 40 Example 6 . Modulation of Full Length AR binding domain ( AR LBD ) , a Gal4 - luciferase reporter assay was used . Briefly , the AR LBD is expressed as a fusion with In order to test the effect of antiandrogens on full length the Gal4 transcription factor , which binds to the Gal4 AR , a mm TV - luciferase reporter assay was used . An AR reporter DNA . Upon activation with agonist hormone 6 response element is contained within the mm TV sequence ( DHT ) , the Gal - AR LBD binds to the Gal4 reporter gene , and drives the expression of luciferase . The effect of anti which in turn drives the transcription ( and subsequently androgens ( competitive antagonists ) on this process is mea translation ) of the reporter luciferase . The effect of antian - sured by quantifying the amount of luciferase activity after drogens ( competitive antagonists ) on this process is mea - 24 hours in the presence of varying concentrations of sured by quantifying the amount of luciferase activity after 50 antiandrogens . From these values , an IC50 for each antago 24 hours in the presence of varying concentrations of nist is calculated . Experimentally , HeLa cells were main antiandrogens . From these values , an IC50 for each antago - tained in Dulbecco ' s modified Eagle ' s medium H - 21 4 . 5 g / L nist is calculated . Experimentally , Hela cells were main glucose , containing 10 % steroid depleted fetal bovine tained in Dulbecco ' s modified Eagle ' s medium H - 21 4 . 5 g / L serum , 50 units / mL penicillin . For transfection , ( 1x10° cells glucose , containing 10 % steroid depleted fetal bovine 55 per well were plated and incubated overnight . A mixture of serum , 50 units / mL penicillin . For transfection , ( 1x10° ) cells typically 200 ng of mm TV responsive luciferase reporter per well were plated and incubated overnight . A mixture of plasmid , 10 ng of ß - actin - B - galactosidase internal control , typically 200 ng of Gal4 responsive luciferase reporter 10 ng of AR full length CMV expression vector or empty plasmid , 10 ng of ß - actin - ß - galactosidase internal control , vector control , and 10 - 100 ng of ß - catenin or empty vector 10 ng of GAL - AR LBD or empty vector control , and 10 - 100 60 control were mixed with 0 . 5 uL of transfection reagent from ng of ß - catenin or empty vector control were mixed with 0 . 5 BioRad and incubated for 20 min and then plated in 24 well uL of transfection reagent from BioRad and incubated for 20 plate triplicates . Cells were induced with 1 nM DHT and 0 . 1 min and then plated in 24 well plate triplicates . Cells were nM - 30 UM compounds after 3 hrs and then incubated induced with 1 nM DHT and 0 . 1 nM - 30 uM test compounds overnight . Cells were collected , and pellets were lysed in after 3 hr and then incubated over night . Cells were col - 65 100 uL of 100 mM Tris - HCl ( pH 7 . 5 ) containing 0 . 1 % lected , and pellets were lysed in 100 uL of 100 mM Tris - HC1 Triton X - 100 . Luciferase and B - galactosidase activities were ( pH 7 . 5 ) containing 0 . 1 % Triton X - 100 . Luciferase and measured using the Luciferase Assay System ( Promega ) and

MAI MULTE A MINHA CUI ON TO A MAN UNION MINI

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