Cyanoindazole compounds and uses thereof

• US 10,722,495 B2
• Filed: 09/07/2018
• Issued: 07/28/2020
• Est. Priority Date: 09/08/2017
• Status: Active Grant

• Current Assignee: Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Vechorkin, Oleg, Atasoylu, Onur, Ye, Hai Fen, Liu, Kai, Zhang, Ke, Yao, Wenqing
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US16/125,084
• Publication Number:
  US 20190076401A1
• Time in Patent Office: 690 Days
• Field of Search: 5483611
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

Claims

1. A compound of Formula IIb2:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl;

wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

or

R¹ is selected from pyridin-4-yl and pyrimidin-4-yl;

wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁵.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl;

wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R¹⁰;

or

R¹ is selected from pyridin-4-yl and pyrimidin-4-yl;

wherein said pyridin-4-yl and pyrimidin-4-yl are each optionally substituted with 1 or 2 substituents independently selected from R¹⁵.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl;

wherein said phenyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazolyl, oxazolyl, isoxazolyl, and isothiazolyl are each optionally substituted with 1 or 2 substituents independently selected from R¹⁰;

or

R¹ is pyridin-4-yl;

wherein said pyridin-4-yl is optionally substituted with 1 or 2 substituents independently selected from R¹⁵.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from phenyl and pyrazolyl;

wherein said phenyl and pyrazolyl are each optionally substituted with 1 or 2 substituents independently selected from R¹⁰.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from pyridin-2-yl and pyridin-3-yl, wherein said pyridin-2-yl and pyridin-3-yl are optionally substituted with 1 or 2 substituents independently selected from R¹⁰;

or

R¹ is selected from pyridin-4-yl;

wherein said pyridin-4-yl is optionally substituted with R¹⁵.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰ is independently selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1 wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰ is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, C_3-10 cycloalkyl-C_1-3 alkylene, 4-10 membered heterocycloalkyl-C_1-3 alkylene, C_6-10 aryl-C_1-3 alkylene, halo, OR^a1, C(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, and S(O)₂R^b1;

wherein said C_1-6 alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, C_3-10 cycloalkyl-C_1-3 alkylene, 4-10 membered heterocycloalkyl-C_1-3 alkylene, and C_6-10 aryl-C_1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰ is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, C_3-10 cycloalkyl-C_1-3 alkylene, 4-10 membered heterocycloalkyl-C_1-3 alkylene, C_6-10 aryl-C_1-3 alkylene, halo, OR^a1, C(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, and S(O)₂R^b1;

wherein said C_1-6 alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, C_3-10 cycloalkyl-C_1-3 alkylene, 4-10 membered heterocycloalkyl-C_1-3 alkylene, and C_6-10 aryl-C_1-3 alkylene are each optionally substituted with 1 or 2 substituents independently selected from R¹¹.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰ is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, halo, OR^a1, C(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, and S(O)₂R^b1;

wherein said C_1-6 alkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, and C_6-10 aryl, are each optionally substituted with 1 or 2 substituents independently selected from R¹¹.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁵ is independently selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, D, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, and OC(O)NR^c1R^d1;

wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹¹.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁵ is C_1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from R¹¹.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹¹ is independently selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, D, CN, OR, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, NR^c3R^d3, NR^c3C(O)R^b3 NR^c3C(O)OR^a3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, and NR^c3S(O)₂NR^c3R^d3;

wherein said C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl, are each optionally substituted with 1, 2, or 3 substituents independently selected from R¹².

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹¹ is independently selected from C_1-6 alkyl, halo, CN, OR^a3, C(O)R^b3, and NR^c3R^d3;

wherein said C_1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from R¹².

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted with 1 or 2 substituents independently selected from:

—

CH₃, —

CH₂CH₃, —

OCH₃, cyclopropyl, —

CH₂CF₃, 2-chlorophenyl, —

CH(CH₃)₂, —

CH₂OH, —

C(O)NHCH₃, —

C(O)N(CH₃)₂, —

NHC(O)CH₃, —

CF₃, —

CH₂CN, —

F, —

SO₂CH₃, —

C(CH₃)₂CN, 1-cyanocyclopropyl, —

C(O)NHCH(CH₃)₂, —

Cl, —

SO₂CH(CH₃)₂, 4-methylpiperazin-1-yl, morpholinyl, 4-acetylpiperazin-1-yl, tetrahydro-2H-pyran-4-yl, —

C(CH₃)₂OH, 3-fluoropyrrolidin-1-yl, 4-hydroxypiperidin-1-yl, —

NHCH(CH₃)CH₂CH₃, 3-(hydroxymethyl)azetidin-1-yl, and 3-(dimethylamino)pyrrolidin-1-yl.

16. The compound of claim 1 selected from:

3-(1-Ethyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile;

3-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile;

3-(1-(2-Chlorophenyl)-1H-pyrazol-4-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(hydroxymethyl)phenyl)-1H-indazole-6-carbonitrile;

4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-N-methylbenzamide;

4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-N,N-dimethylbenzamide;

N-(4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl) phenyl)-1H-indazol-3-yl)phenyl)acetamide;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-p-tolyl-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(3-methoxyphenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-methoxyphenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)-1H-indazole-6-carbonitrile;

3-(4-Cyclopropylphenyl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile;

3-(4-(Cyanomethyl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile;

4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-2-fluoro-N-methylbenzamide;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-1H-indazole-6-carbonitrile;

3-(4-(2-Cyanopropan-2-yl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile;

3-(4-(1-Cyanocyclopropyl) phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl) phenyl)-1H-indazole-6-carbonitrile;

4-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)-2-fluoro-N,N-dimethylbenzamide;

3-Chloro-4-(6-cyano-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazol-3-yl)-N-isopropylbenzamide;

3-(3-Fluoro-4-(methylsulfonyl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile;

3-(2-Chloro-4-(methylsulfonyl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(isopropylsulfonyl)phenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-morpholinopyridin-3-yl)-1H-indazole-6-carbonitrile;

N-(5-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-indazol-3-yl)pyridin-2-yl)acetamide;

3-(6-(4-Acetylpiperazin-1-yl)pyridin-3-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-methylpyridin-4-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-methylpyridin-3-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-methoxypyrimidin-5-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(oxazol-5-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(isothiazol-4-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(isoxazol-4-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-methyloxazol-5-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-((S)-3-fluoropyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile;

3-(6-(((R)-sec-Butyl)amino)pyridin-3-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(3-(hydroxymethyl)azetidin-1-yl)pyridin-3-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl) phenyl)-3-(6-(4-hydroxypiperidin-1-yl)pyridin-2-yl)-1H-indazole-6-carbonitrile;

5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-indazole-6-carbonitrile; and

3-(6-((S)-3-(Dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-5-(2-fluoro-6-methyl-4-((methylamino) methyl)phenyl)-1H-indazole-6-carbonitrile;

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

21. A method of inhibiting HPK1 activity, said method comprising administering to a patient a compound of claim 1, or a pharmaceutically acceptable salt thereof.

17. A compound of Formula IIb2:

18. A compound of Formula IIb2:

19. A compound of Formula IIb2: