Granted Patent B2

US 12,421,197 · App. 17/328,240 · Granted Sep 23, 2025

Inventors: Brent Douty (Fallowfield, PA); Yanran Ai (West Chester, PA); David M. Burns (Plymouth Meeting, PA); Andrew P. Combs (Kennett Square, PA); Nikoo Falahatpisheh (Wilmington, DE); Daniel Levy (Philadelphia, PA); Padmaja Polam (Kennett Square, PA); Lixin Shao (Wilmington, DE); Stacey Shepard (Wilmington, DE); Artem Shvartsbart (Kennett Square, PA); Eddy W. Yue (Landenberg, PA); Andrew W. Buesking (Wilmington, DE)

Assignee: Incyte Corporation

C07D241/20C07D401/04C07D401/14C07D403/04C07D403/06C07D403/12C07D403/14C07D405/12C07D413/04C07D417/04C07D471/04C07D471/06C07D487/04

Abstract

Claims (105)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

X 1 is N or CR 1 ;

R 1 is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH and NH 2 ;

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, C 1-6 haloalkyl, 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, and NH 2 ;

or, alternatively, R 3 and R 3″ together form an oxo group;

R 4 , R 5 and R 6 are each independently selected from H, D, halo, CN, OH, NH 2 , and C 1-6 alkyl;

R 7 is selected from C 6-14 aryl and 5-14 membered heteroaryl, wherein the C 6-14 aryl and 5-14 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents;

R 8 and R 9 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and;

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 , SR a71 , NHOR a71 , C(O)R b71 , C(O)NR c71 R d71 , and BR j71 R k71 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, of R 7A are each optionally substituted with 1, 2, 3 or 4 independently selected R 7B substituents;

each R a71 , R b71 , R c71 , and R d71 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl

each R j71 and R k71 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;

or any R j71 and R k71 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

each R 7B 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 a72 , and SR a72 ;

each R a72 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and

each R b8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

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

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 3″ is H.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, D, halo, and C 1-6 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, D, halo, and C 1-6 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each H.

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

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

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

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

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and C(O)R b8 .

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

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R b8 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from phenyl and 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl of R 7 are each optionally substituted with 1 or 2 independently selected R 7A substituents; and

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 3-10 cycloalkyl, C 6-10 aryl, C(O)NR c71 R d71 , and BR j71 R k71 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and C 6-10 aryl of R 7A are each optionally substituted with 1 or 2 independently selected R 7B substituents.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from phenyl and 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl of R 7 are each optionally substituted with 1 or 2 independently selected R 7A substituents; and

each R 7A is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C(O)NR c71 R d71 , and B(OH) 2 , wherein the C 1-6 alkyl and C 3-10 cycloalkyl of R 7A are each optionally substituted with 1 or 2 independently selected R 7B substituents selected from CN, OH, C 1-3 alkoxy, and C 3-6 cycloalkyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, and pyrimidinyl, wherein the phenyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, and pyrimidinyl, of R 7 are each optionally substituted with 1 or 2 independently selected R 7A substituents;

each R 7A is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C(O)NR c71 R d71 , and B(OH) 2 , wherein the C 1-6 alkyl and C 3-10 cycloalkyl of R 7A are each optionally substituted with 1 or 2 independently selected R 7B substituents selected from CN, OH, C 1-3 alkoxy, and C 3-6 cycloalkyl; and

each R c71 and R d71 is independently selected from H and C 1-6 alkyl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt, wherein:

X 1 is N or CH;

R 2 is a C 1-6 haloalkyl, wherein each halogen of the C 1-6 haloalkyl is independently selected from F and C 1 ;

R 3 is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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, and NH 2 ;

or, alternatively, R 3 and R 3″ together form an oxo group;

R 4 is selected from H, D, halo, CN, OH, NH 2 , and C 1-6 alkyl;

R 5 is selected from H, D, halo, CN, OH, NH 2 , and C 1-6 alkyl;

R 6 is selected from H, D, halo, CN, OH, NH 2 , and C 1-6 alkyl;

R 7 is selected from phenyl and 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl of R 7 are each optionally substituted with 1 or 2 independently selected R 7A substituents;

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 3-10 cycloalkyl, C 6-10 aryl, C(O)NR c71 R d71 , and BR j71 R k71 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and C 6-10 aryl of R 7A are each optionally substituted with 1 or 2 independently selected R 7B substituents;

each R 7B is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo CN, OH, C 1-6 alkoxy, and C 3-6 cycloalkyl;

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;

R b8 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

each R c71 and R d71 is independently selected from H and C 1-6 alkyl; and

each R j71 and R k71 is independently selected from H and C 1-6 alkyl.

20. The compound of claim 1 , selected from:

2-(3-(5-amino-6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-methyl-1H-1,2,3-triazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

5-(3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)pyrazin-2-yl)-N-methylpicolinamide;

2-(3-(5-amino-6-(pyrimidin-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(6-methylpyridin-3-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(2-cyclopropylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(2-(hydroxymethyl)pyridin-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(4-(cyanomethyl)phenyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(4-(hydroxymethyl)phenyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

4-(3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)pyrazin-2-yl)-N-methylbenzamide;

2-(3-(5-amino-6-(3-isopropylphenyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(4-(2-hydroxypropan-2-yl)phenyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(4-cyclopropylphenyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1H-pyrazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxy-N-methylpropanamide;

2-(3-(5-amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxy-N,N-dimethylpropanamide;

2-(3-(5-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxy-N-methylpropanamide;

(4-(3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)pyrazin-2-yl)phenyl)boronic acid;

2-(3-(5-amino-6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3-difluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(1-methyl-1H-pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3-difluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3-difluoro-2-hydroxypropanamide;

2-(3-(5-amino-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3-difluoro-2-hydroxypropanamide;

N-(2-(3-(5-amino-6-(2-cyclopropylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropyl)formamide;

N-(2-(3-(5-amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropyl)formamide;

N-(2-(3-(5-amino-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropyl)acetamide;

N-(2-(3-(5-amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropyl)acetamide; and

3-amino-6-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(1-methyl-1H-pyrazol-5-yl)pyrazine-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

22. A method of inhibiting an activity of PI3Kγ kinase, comprising contacting the kinase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

23. The method of claim 22 , wherein said compound, or a pharmaceutically acceptable salt thereof, is a selective inhibitor for PI3Kγ over one or more of PI3Kα, PI3Kβ, and PI3Kδ.

24. A method of treating a disease or disorder in a patient, wherein said disease or disorder is associated with abnormal expression or activity of PI3Kγ kinase, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

25. The method of claim 24 , wherein the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xeroderma pigmentosum, keratoacanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma.

26. The method of claim 25 , wherein the diffuse large B cell lymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuse large B cell lymphoma.

27. The method of claim 24 , wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, asthma, allergy, allergic rhinitis, pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease, thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren's syndrome, osteoarthritis, restenosis, or atherosclerosis.

28. The method of claim 24 , wherein the disease or disorder is heart hypertrophy, cardiac myocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia, bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenia purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, or membranous nephropathy.

Assignments (1)

Continuity (6)

References Cited (400)