Aminopyrazine derivatives as PI3K-γ inhibitors

Patent metadata

Field	Value
Publication number	US-11046658-B2
Application number	US-201916458530-A
Country	US
Kind code	B2
Filing date	Jul 1, 2019
Priority date	Jul 2, 2018
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

This application relates to compounds of Formula (I):

or pharmaceutically acceptable salts thereof, which are inhibitors of PI3K-γ which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

First claim

What is claimed is:

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein:
R 2 is a C 1-6 haloalkyl, wherein each halogen is independently selected from F and Cl;
R 3 is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;
R 3″ is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;
or, alternatively, R 3 and R 3″ together form an oxo group;
R 6 is selected from H, D, halo, CN, OH, NH 2 , and C 1-6 alkyl;
R 7 is C(O)NR c7 R d7 ;
R 7 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R d7 is selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, and 4-8 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 4-8 membered heterocycloalkyl of R d7 are each optionally substituted with 1 or 2 independently selected R 7A substituents;
or, R c7 and R d7 , together with the N atom to which they are attached, form a 5-10 membered heteroaryl or a 4-12-membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-12 membered heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents;
R 8 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C(O)R b8 ;
R 9 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;
provided that either: (a) R 3 and R 3″ together form an oxo group; or (b) R 8 is C(O)R b8 ;
each R 7A is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR a71 , and SR a71 ;

each R a71 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R b8 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with 1, 2, 3 or 4 independently selected R 8A substituents; and
each R 8A is independently selected from D, halo, CN, NO 2 , OH, and SH.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CF 3 or CHF 2 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3″ is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is H.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 3″ together form an oxo group.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H or C(O)R b8 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R b8 is selected from methyl, fluoromethyl, cyanomethyl, and hydroxypropyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R c7 is H.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 7A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, CN, and OR a71 , wherein each R a71 is independently selected from H and C 1-6 alkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R d7 is selected from C 1-6 alkyl, hydroxyl-C 1-6 alkyl, cyano-C 1-6 alkyl, monocyclic C 3-6 cycloalkyl, bicyclic C 5-8 cycloalkyl, and 4-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, hydroxyl-C 1-6 alkyl, cyano-C 1-6 alkyl, monocyclic C 3-6 cycloalkyl, bicyclic C 5-8 cycloalkyl, and 4-6 membered heterocycloalkyl are each optionally substituted by 1 or 2 substituents R 7A independently selected from halo, OH, CN, C 1-3 alkoxy, and C 3-10 cycloalkyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R d7 is selected from ethyl, 2-cyanoethyl, 2,2,2-trifluoroethyl, 2-propyl, 1-(cyanomethyl)propyl, 2-methoxy-2-methylpropyl, 2-cyano-2,2-dimethylethyl, 2-hydroxy-2-methylprop-1-yl, 2-cyano-1-methylethyl, 2-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl, 1-cyanocycloprop-1-ylethyl, 1-cyanocyclobut-1-ylethyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4-hydroxy-4-methylcyclohexyl, 4-hydroxy-4-(trifluoromethyl)cyclohexyl, 4-(1-hydroxy-1-methylethyl)cyclohexyl, 4,4-difluorocyclohexyl, 3-cyanobicyclo[1.1.1]pentan-1-yl, 4-cyanobicyclo[2.1.1]hexan-1-yl, 4-cyanobicyclo[2.2.2]octan-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, wherein:
R 2 is a C 1-6 haloalkyl, wherein each halogen of the C 1-6 haloalkyl is independently selected from F and Cl;
R 3 is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and NH 2 ;
R 3″ is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and NH 2 ;
or, alternatively, R 3 and R 3″ together form an oxo group;
R 6 is selected from H, D, halo, CN, OH, NH 2 , and C 1-6 alkyl;
R c7 and R d7 are each independently selected H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and 4-8 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and 4-8 membered heterocycloalkyl of R c7 and R d7 are each optionally substituted with 1 or 2 independently selected R 7A substituents;
R 8 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C(O)R b8 ; provided that either: (a) R 3 and R 3″ together form an oxo group; or (b) R 8 is C(O)R b8 ;
R 9 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; each R 7A is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR a71 , and SR a71 ;
each R a71 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R b8 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R b8 are each optionally substituted with 1, 2, 3 or 4 independently selected R 8A substituents; and
each R 8A is independently selected from D, halo, CN, NO 2 , OH, and SH.

15. The compound of claim 1 , selected from:
3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(2-hydroxy-2-methylpropyl)pyrazine-2-carboxamide;
3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;
3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-((1r,4r)-4-hydroxycyclohexyl)pyrazine-2-carboxamide;
3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-((1-cyanocyclopropyl)methyl)pyrazine-2-carboxamide;
3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-isopropylpyrazine-2-carboxamide;
3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(4,4-dif

Assignees

• Incyte Corp

Inventors

• Douty Brent
• Ai Yanran
• Burns David M
• Combs Andrew P
• Falahatpisheh Nikoo
• Levy Daniel
• Polam Padmaja
• Shao Lixin
• Shepard Stacey
• Shvartsbart Artem
• Yue Eddy W
• Buesking Andrew W

Classifications

• C07D241/28 Primary

  in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D471/06

  Peri-condensed systems · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title