Compounds and methods for CDK8 modulation and indications therefor

Patent metadata

Field	Value
Publication number	US-10703757-B2
Application number	US-201715851639-A
Country	US
Kind code	B2
Filing date	Dec 21, 2017
Priority date	Dec 23, 2016
Publication date	Jul 7, 2020
Grant date	Jul 7, 2020

Abstract

Disclosed are compounds of Formula I:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein R 4 , X 3 , X 4 , X 5 , X 6 , X 7 and Ring A are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.

First claim

What is claimed is:

1. A compound of Formula II(b), II(c), or II(d):

or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein:
R 3 is —B-L-T;
R 4 is one of (a1), (a2), (b1), (b2), (c) or (d):
(a1) saturated heterocycloalkyl substituted with 0-3 R 7 groups, wherein the saturated heterocycloalkyl is further optionally substituted with one R 8 group;
(a2) heterocycloalkenyl substituted with 0-3 R 7 groups, wherein the heterocycloalkenyl is further optionally substituted with one R 8 group;
(b1) saturated C 3 -C 6 cycloalkyl substituted with 0-3 R 7 groups, wherein the saturated C 3 -C 6 cycloalkyl is further optionally substituted with one R 8 group;
(b2) C 5 -C 6 cycloalkenyl substituted with 0-3 R 7 groups, wherein the C 5 -C 6 cycloalkenyl is further optionally substituted with one R 8 group;
(c) aryl or heteroaryl substituted with one R 10 group, wherein the aryl or heteroaryl is further optionally substituted with one R 1 group; or
(d) —C 2 -C 3 alkynylene substituted with R 12 ;

R 6 is H, -C1-C 6 alkyl, -C1-C 6 haloalkyl, —C 1 -C 6 alkylene-CN, —C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl;
each R 7 is independently —C 1 -C 6 alkyl, halogen, CN, hydroxyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 cyanoalkyl, or —C 1 -C 6 hydroxyalkyl optionally substituted with heteroaryl, provided that halogen and CN are not bonded to a heteroatom;
R 8 is CN, phenyl, 5-6 membered heterocycloalkyl or heteroaryl, —(CH 2 ) 0-2 —C(O)—N(H)—R 6 , —C(O)R 6 , —(CH 2 ) 0-2 C(O)OR 6 , —(CH 2 ) 0-2 S(O) 2 R 6 ; or

or R 7 and R 8 , when both are attached to the same carbon atom of the saturated heterocycloalkyl, join to form a heterocycloalkyl, oxoheterocycloalkyl, or dioxoheterocycloalkyl, wherein the heterocycloalkyl, oxoheterocycloalkyl, or dioxoheterocycloalkyl is optionally substituted with 1-2 —C 1 -C 6 alkyl groups, and wherein the oxoheterocycloalkyl is optionally fused to a phenyl or 5-6 membered heteroaryl;
B is a bond, arylene, heteroarylene, or heterocycloalkylene, wherein the arylene, heteroarylene, or heterocycloalkylene are each substituted with 0-3 G1 groups and 0-1 G2 groups;
L is a bond, —O—, —C(O)—, —N(H)—, —N(H)S(O) 2 —, —S(O) 2 —N(H)—, —S(O) 2 —, —S(O) 2 —C 1 -C 4 alkylene, —N(H)C(O)—C 1 -C 4 alkylene, —N(H)C(O)O—C 1 -C 4 alkylene, C 1 -C 4 alkylene-N(H)—C(O)—, —N(H)—(CH 2 ) 0-4 —, —C 1 -C 6 alkylene, —O—C 1 -C 6 alkylene, —O—C 1 -C 6 haloalkylene, —O—C 1 -C 6 alkylene-O—, or —O—C 1 -C 6 hydroxyalkylene;
T is heteroaryl, aryl, cycloalkyl, or heterocycloalkyl, wherein the heteroaryl, cycloalkyl, or heterocycloalkyl are each substituted with 0-3 G3 groups and 0-1 G4 groups;
or B-L is ethynylene and T is heteroaryl substituted with 0-3 G3 or G4 groups;
each G1 is independently halogen, —C 1 -C 4 alkyl, alkoxy, —C 1 -C 4 haloalkyl, hydroxyl, or —C 1 -C 4 hydroxyalkyl;
G2 is —C 0 -C 4 alkylene-S(O) 2 —C 1 -C 4 alkyl, —C 0 -C 4 alkylene-C(O)—NH 2 , or —N(H)C(O)—C 1 -C 4 alkyl;
each G3 is independently halogen, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkyl, hydroxyl, C 1 -C 6 hydroxyalkyl, or —C 0 -C 6 alkylene-CN;
G4, when attached to a carbon atom, is halogen, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkyl, hydroxyl, —C 1 -C 6 hydroxyalkyl, —C 0 -C 6 alkylene-CN, —C 0 -C 4 alkylene-S(O) 2 —C 1 -C 6 alkyl, —C 0 -C 4 alkylene-N(H)—S(O) 2 —C 1 -C 4 alkyl, —C 0 -C 4 alkylene-C(O)—NH 2 , —C 0 -C 4 alkylene-C(O)—N(H)—C 1 -C 4 alkyl, —N(H)—C(O)—C 1 -C 4 alkyl, —C 0 -C 4 alkylene-C(O)—N(C 1 -C 4 alkyl) 2 , —C 1 -C 6 alkylene-N—(C 1 -C 4 alkyl) 2 , —C 1 -C 6 alkylene-N(H)—(C 1 -C 4 alkyl), —C 1 -C 6 alkylene-NH 2 , —C 0 -C 4 alkylene-heterocycloalkyl, —C 0 -C 4 alkylene-C(O)O—C 1 -C 6 alkyl, or —C 0 -C 6 alkylene-cycloalkyl optionally substituted with CN, OH, —C 1 -C 4 alkyl, —C(O)O—C 1 -C 4 alkyl, —C(O)OH, or halogen;
or G4, when attached to a nitrogen atom, is —C 1 -C 6 alkyl, —C 1 -C 6 alkylene-C 1 -C 6 alkoxy, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —C 1 -C 6 alkylene-CN, —C 1 -C 4 alkylene-S(O) 2 —C 1 -C 6 alkyl, —C 1 -C 3 alkylene-N(H)—S(O) 2 —C 1 -C 4 alkyl, —C 1 -C 4 alkylene-C(O)—NH 2 , —C 1 -C 4 alkylene-C(O)—N(H)—C 1 -C 4 alkyl, —C 1 -C 4 alkylene-C(O)—N(C 1 -C 4 alkyl) 2 , —C 1 -C 6 alkylene-N—(C 1 -C 4 alkyl) 2 , —C 1 -C 6 alkylene-N(H)—(C 1 -C 4 alkyl), —C 1 -C 6 alkylene-NH 2 , —C 0 -C 4 alkylene-heterocycloalkyl, —C 0 -C 4 alkylene-C(O)O—C 1 -C 6 alkyl, —C 0 -C 4 alkylene-C(O)OH, or —C 1 -C 6 alkylene-cycloalkyl optionally substituted with CN, OH, C 1 -C 4 alkyl, —C(O)O—C 1 -C 4 alkyl, —C(O)OH, or halogen;
R 10 is —NHS(O) 2 —C 1 -C 5 alkyl, —S(O) 2 —C 1 -C 5 alkyl, —S(O) 2 -5-6 membered heterocycloalkyl, —S(O) 2 —N(H) C 1 -C 5 alkyl, —(CH 2 ) 0-1 —C(O)NH 2 , —(CH 2 ) 0-1 —O-phenyl, —(CH 2 ) 0-1 —O-(5-6 membered)heteroaryl, —(CH 2 ) 0-1 —NHC(O)O—C 1 -C 2 -alkylene-phenyl, —(CH 2 ) 0-1 —NHC(O)-5-6 membered heteroaryl, —(CH 2 ) 0-1 —NHC(O)-phenyl, —C 1 -C 5 alkylene-(5-6 membered)heterocycloalkyl, —C 2 -C 4 alkenyl, or CN;
R 11 is H, C3-C 7 cycloalkyl, C 5 -C 6 cycloalkenyl or 5-6 membered heterocycloalkyl;
R 12 is 3-6 membered cycloalkylene-R 13a , —C(O)NHR 6 , —Z 1 —(CH 2 ) 1-2 —Z 2 , —Z 1 —(C 1 -C 2 )haloalkylene-Z 2 , or —Z 1 —(C 1 -C 2 )hydroxyalkylene-Z 2 ;
each R 13a is halogen, hydroxyl, —C 1 -C 3 alkyl, —C 1 -C 3 hydroxyalkyl, —C 1 -C 3 haloalkyl or CN;
Z 1 is absent, —C 1 -C 3 alkylene, or —C 1 -C 3 haloalkylene; and
Z 2 is —C 1 -C 3 alkoxyl optionally substituted with hydroxyl, —N(H)—S(O) 2 —C 1 -C 3 alkyl, —N(H)—C(O)—C 1 -C 3 alkyl, —N(H)—C(O)—C 1 -C 3 haloalkyl, —C(O)—N(H)—C 1 -C 3 alkyl, —C(O)—N(H)—C 1 -C 3 haloalkyl or phenyl.

2. The compound according to claim 1 , wherein:
R 4 is one of (a1), (a2), (b1), (b2), (c), or (d):
(a1) saturated 5-6 membered heterocycloalkyl substituted with 0-1 R 7 groups, wherein the saturated heterocycloalkyl is further optionally substituted with one R 8 group;
(a2) 5-6 membered N-substituted heterocycloalkenyl substituted with 0-1 R 7 groups, wherein the six-membered N-substituted heterocycloalkenyl is further optionally substituted with one R 8 group;
(b1) cyclohexyl substituted with 1 R 7 group, wherein the cyclohexyl is further optionally substituted with one R 8 group;
(b2) cyclohexenyl substituted with 1 R 7 group, wherein the cyclohexenyl is further optionally substituted with one R 8 group;
(c) phenyl, pyridyl or pyrazolyl, wherein the phenyl, pyridyl or pyrazolyl is substituted with one R 10 group, and wherein the phenyl, pyridyl or pyrazolyl is further optionally substituted with one R 11 group; or
(d) ethynylene substituted with R 12 ;

R 6 is H, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 3 -C 4 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl;
each R 7 is independently —C 1 -C 4 alkyl, fluoro, chloro, bromo, CN, hydroxyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 cyanoalkyl, or —C 1 -C 4 hydroxyalkyl optionally substituted with heteroaryl, provided that fluoro, chloro, bromo, and CN are not bonded to a heteroatom;
R 8 is CN, phenyl, 5-6 membered heteroaryl, —C(O)—N(H)—R 6 , —C(O)OR 6 , —(CH 2 ) 0-1 —S(O) 2 R 6 ; or

or R 7 and R 8 , when both are attached to the same carbon atom of the saturated heterocycloalkyl, join to form a heterocycloalkyl, oxohe

Assignees

• Plexxikon Inc

Inventors

• Wu Guoxian
• Albers Aaron
• Buell John
• Burton Elizabeth A
• Pham Phuongly
• Powers Hannah
• Shi Songyuan
• Spevak Wayne
• Wu Jeffrey
• Zhang Jiazhong

Classifications

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title