Heterocyclic compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10501460-B2
Application number	US-201715814179-A
Country	US
Kind code	B2
Filing date	Nov 15, 2017
Priority date	Mar 15, 2013
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

Heterocyclic compounds of formula (I), methods for their preparation, pharmaceutical compositions containing such a compound and their therapeutic uses.

First claim

What is claimed is:

1. A method for treating a subject suffering from a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound of formula (III),
wherein the disease or condition is breast cancer, midline carcinomas, acute myelogenous leukemia, chronic lymphocytic leukemia, non-small cell lung cancer, prostate cancer, or uveal melanoma,
wherein the compound of formula (III) has the following structure:

or a pharmaceutically acceptable salt, solvate, a tautomer, a stereoisomer, or a deuterated analog thereof,
Y 1 is N;
R 1 is deuterated C 1-6 alkyl, C 1-6 alkyl, aryl, aryl-C 1-4 alkyl, C 3-6 -cycloalkyl, C 3-6 - cycloalkylakyl, heteroaryl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, each of which is optionally substituted with from 1 - 3 R j groups,
R 2 is H;
R 3 is deuterated C 1-6 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 2-6 alkynyl, heterocycloalkyl, or heterocycloalkyl-C 1-4 alkyl, wherein each R 3 is optionally substituted with 1 - 3 substituents independently selected from CN, -OH, -NH 2 , -NO 2 , -C(O)OH, - C(S)OH,-C(O)NH 2 , -C(S)NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(NH)N H 2 , -CH═C(R n )(R n ), -OR n , -SR n , -OC(O)R n , -OC(S)R n , -P(═O)HR n , -P(═O)R n R n , -PH(═O)OR n , - P(═O)(OR n ) 2 , -OP(═O)(OR n ) 2 , -C(O)H, - O(CO)OR n , -C(O)R n , -C(S)R n , -C(O)OR n , -C(S)OR n , -S(O)R n , -S(O) 2 R n , -C(O)NHR n , -C(S)NHR n , -C(O)NR n R n , -C(S)NR n R n , -S(O) 2 NHR n , -S(O) 2 NR n R n , -C(NH)NHR n , -C(NH)NR n R n , -NHC(O)R n , -NHC(S)R n , -NR n C(O)R n , -NR n C(S)R n , -NHS(O) 2 R n , -NR n S(O) 2 R n , -NHC(O)NHR n , -NHC(S)NHR n , -NR n , -NR n C(O)NH 2 , -NR n C(S)NH 2 , -NR n C(O)NHR n , -NR n C(S)NHR n , -NHC(O)NR n R n , -NHC(S)NR n R n , -NR C(O)NR R n, -NR n C(S)NR n R n , -NHS(O) 2 NHR n , -NR n S(O) 2 NH 2 , -NR n S(O) 2 NHR n , -NHS(O) 2 NR n R n , -NR n S(O) 2 NR n R n , -NHR n , R n , and -NR n R n , wherein each R n is independently H, C 1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cyclaoalkylylalkyl; or two R n groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8- membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N, and S, wherein the nitrogen or sulfur ring atoms are optionally oxidized, wherein the aliphatic or aromatic portion of R n is further optionally substituted with from 1-3 R h ;
R 4 is H;
R 5 is:

each of which is optionally substituted with from 1-2 R 11 ;
wherein the wavy line indicates the point of attachment to the rest of molecule and each R 11 is independently D, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, or CN;
L is —C(R 6 )(R 7 )—, —C(O)—, —S(O)—, —S—, —P(O)(R a )—, —CH═C(R b )—, or —Si(R c )(R c );
R 6 is H or D;
R 7 is H, D, halogen, —OH, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, aryl-C 1-4 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, heterocycloalkyl, heterocycloalkyl-C 1-4 alkyl, heteroaryl, heteroarylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OR d , —NR d R d , —C(O)OR d , —OC(O)R d , —OC(O)OR d , —C(O)R d , —NHC(O)R d , —C(O)NR d R d , —SO 2 R d , —NHSO 2 R d , or —SO 2 NR d R d ,
wherein R 7 is further optionally substituted with from 1-3 R h groups;
R a is optionally substituted C 1-6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R b is H or C 1-6 alkyl;
each R c is independently C 1-6 alkyl or C 1-6 alkoxy;
each R d is independently H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, or aryl;
each R h is independently halogen, —CN, —OH, —NH 2 , —NO 2 , —CH═C(R k )(R k ), —C(O)OH, —C(S)OH, —C(O)NH 2 , —C(S)NH 2 , —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —C(NH)NH 2 , —OR i , —SR i , —OC(O)R i , —OC(S)R i , —P(═O)HR i , —P(═O)R i R i , —PH(═O)OR i , —P(═O)(OR i ) 2 , —OP(═O)(OR i ) 2 , —C(O)H, —O(CO)OR i , —C(O)R i , —C(S)R i , —C(O)OR i , —C(S)OR 1 , —S(O)R i , —S(O) 2 R i , —C(O)NHR i , —C(S)NHR i , —C(O)NR i R i , —C(S)NR i R i , —S(O) 2 NHR i , —S(O) 2 NR i R i , —C(NH)NHR i , —C(NH)NR i R i , —NHC(O)R i , —NHC(S)R i , —NR i C(O)R i , —NR i C(S)R i , —NHS(O) 2 R i , —NR i S(O) 2 R i , —NHC(O)NHR i , —NHC(S)NHR i , —NR i C(O)NH 2 , —NR i C(S)NH 2 , —NR i C(O)NHR i , —NR i C(S)NHR i , —NHC(O)NR i R i , —NHC(S)NR i R i , —NR i C(O)NR i R i , —NR i C(S)NR i R i , —NHS(O) 2 NHR i , —NR i S(O) 2 NH 2 , —NR i S(O) 2 NHR i , —NHS(O) 2 NR i R i , —NR i S(O) 2 NR i R i , R i , —NHR i , or —NR i R i ,
each R i is independently C 1-6 alkyl, aryl, aryl-C 1-2 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocycloalkyl, or heterocycloalkyl-C 1-4 alkyl;
R j is halogen, —CN, —OH, —NH 2 , —NO 2 , —C(O)OH, —C(S)OH, —C(O)NH 2 , —C(S)NH 2 , —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —C(NH)NH 2 , —CH═C(R k )(R k ), —OR k , —SR k , —OC(O)R k , —OC(S)R k , —P(═O)HR k , —P(═O)R k R k , —PH(═O)OR k , —P(═O)(OR k ) 2 , —OP(═O)(ORk)2, —C(O)H, —O(CO)OR k , —C(O)R k , —C(S)R k , —C(O)OR k , —C(S)OR k , —S(O)R k , —S(O) 2 R k , —C(O)NHR k , —C(S)NHR k , —C(O)NR k R k , —C(S)NR k R k , —S(O) 2 NHR k , —S(O) 2 NR k R k , —C(NH)NHR k , —C(NH)NR k R k , —NHC(O)R k , —NHC(S)R k , —NR k C(O)R k , —NR k C(S)R k , —NHS(O) 2 R k , —NR k S(O) 2 R k , —NHC(O)NHR k , —NHC(S)NHR k , —NR k C(O)NH 2 , —NR k C(S)NH 2 , —NR k C(O)NHR k , —NR k C(S)NHR k , —NHC(O)NR k R k , —NHC(S)NR k R k , —NR k C(O)NR k R k , —NR k C(S)NR k R k , —NHS(O) 2 NHR k , —NR k S(O) 2 NH 2 , —NR k S(O) 2 NHR k , —NHS(O) 2 NR k R k , —NR k S(O) 2 NR k R k , —NHR k , or —NR k R k ; and
each R k is independently H, C 1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, or cycloalkylalkyl; or two R k groups when attached to the same carbon or nitrogen atom are taken together to form a 3- to 6-membered carbocyclic ring or 3- to 8-membered heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N, and S, wherein the nitrogen or sulfur ring atoms are optionally oxidized, and wherein R k is optionally substituted with from 1-3 R h .

2. The method according to claim 1 , wherein the disease or condition mediated by a bromodomain is non-small cell lung cancer, midline carcinomas, or breast cancer.

3. The method of claim 1 , having formula (V):

4. The method of claim 1 , wherein
R 7 is D, halogen, —OH, C 1-6 alkyl, deuterated C 1-6 alkyl, aryl, aryl-C 1-4 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, heterocycloalkyl, heterocycloalkyl-C 1-4 alkyl, heteroaryl, heteroarylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OR d , —NR d R d , —C(O)OR d , —OC(O)R d , —OC(O)OR d , —C(O)R d , —NHC(O)R d , —C(O)NR d R d , —SO 2 R d , —NHSO 2 R d , or —SO 2 NR d R d .

5. The method of claim 1 , wherein L is a —C(O)—, —S—, —P(O)(C 1-6 alkyl)-, —P(O)(aryl)-, —CH(OH)—, —CHF—, —CH(C 1-6 alkyl)-, —CH(C 3-6 cycloalkyl)-, or —CH(C 1-6 haloalkyl)-.

6. The method of claim 1 , wherein:
L is —C(R 6 )(R 7 )—;
R 6 is H; and
R 7 is —OH, C 1-6 alkyl, aryl, C 3-6 cycloalkyl, hetero

Assignees

• Plexxikon Inc

Inventors

• Zhang Jiazhong
• Spevak Wayne

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title