Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
View Patent ↗This application relates to derivatives of Formula I: and pharmaceutically acceptable salts thereof, which are inhibitors of PI3K, and compositions and methods of treatment related thereto.
1. A method of inhibiting an activity of a PI3Kδ kinase, comprising contacting the kinase with a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ar is:
R 1 is methyl;
R 2 is C 1-6 alkoxy, C 1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 3 is Cy or C(═O)NR c R d ;
provided that either (i) R 2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or (ii) R 3 is Cy;
R 4 is halo, C 1-4 alkyl, or C 1-4 haloalkyl;
R 5 is halo, CN, C 1-4 alkyl, or C 1-4 haloalkyl;
R 6 is H;
each Cy is independently selected from 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1 or 2 independently selected R 3b groups;
each R c and R d is independently selected from H and C 1-6 alkyl and each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(Cl 6 alkyl)carbamyl.
2. A method of treating a disease selected from idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, chronic lymphocytic leukemia (CLL), Non-Hodgkin lymphoma, hairy cell leukemia, Mantle cell lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma, monoclonal gammopathy of undetermined significance (MGUS), and B cell lymphoma in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ar is:
R 1 is methyl;
R 2 is C 1-6 alkoxy, C 1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 3 is Cy or C(═O)NR c R d ;
provided that either (i) R 2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or (ii) R 3 is Cy;
R 4 is halo, C 1-4 alkyl, or C 1-4 haloalkyl;
R 5 is halo, CN, C 1-4 alkyl, or C 1-4 haloalkyl;
R 6 is H;
each Cy is independently selected from 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1 or 2 independently selected R 3b groups;
each R c and R d is independently selected from H and C 1-6 alkyl; and
each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl.
3. The method of claim 2 , wherein the method is a method of treating idiopathic thrombocytopenic purpura (ITP) selected from relapsed ITP and refractory ITP.
4. The method of claim 2 , wherein the method is a method of treating vasculitis selected from Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease, central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis, Henoch-Schönlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, and anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV).
5. The method of claim 2 , wherein the method is a method of treating non-Hodgkin lymphoma (NHL) selected from relapsed NHL, refractory NHL, and recucurrent follicular NHL.
6. The method of claim 2 , wherein the method is a method of treating B cell lymphoma, wherein said B cell lymphoma is diffuse large B-cell lymphoma (DLBCL).
7. The method of claim 2 , wherein the method is a method of treating B cell lymphoma, wherein said 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.
8. The method of claim 2 , wherein the method further comprises administering to said patient a JAK1 and/or JAK2 inhibitor.
9. The method of claim 2 , wherein the disease is pemphigus.
10. The method of claim 2 , wherein the disease is autoimmune hemolytic anemia.
11. The method of claim 2 , wherein the disease is myelofibrosis.
12. The method of claim 2 , wherein R 2 is C 1-6 alkoxy or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.
13. The method of claim 2 , wherein R 3 is C(═O)NR c R d .
14. The method of claim 2 , wherein R 3 is Cy.
15. The method of claim 2 , wherein R 4 is C 1-4 alkyl or halo.
16. The method of claim 2 , wherein R 5 is halo, CN, or methyl.
17. The method of claim 2 , wherein:
Ar is:
R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;
each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl;
R 4 is C 1-4 alkyl or halo;
R 5 is halo; and
R 6 is H.
18. The method of claim 2 , wherein:
Ar is:
R 2 is C 1-6 alkoxy;
R 3 is 4-6 membered heterocycloalkyl;
R 4 and R 5 are each independently halo; and
R 6 is H.
19. The method of claim 2 , wherein:
Ar is:
R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;
each R 3b is di(C 1-6 alkyl)carbamyl;
R 4 is halo or C 1-4 alkyl;
R 5 is halo; and
R 6 is H.
20. The method of claim 2 , wherein the compound is selected from:
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-([1,3]thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl]phenyl}pyrrolidin-2-one;
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one;
5-{3-chloro-6-methoxy-2-methyl-5-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;
4-chloro-N-ethyl-3′,5′-difluoro-3-methyl-6-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]biphenyl-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
21. The method of claim 2 , wherein the compound is selected from:
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one; and
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
or a pharmaceutically acceptable salt thereof.
22. The method of claim 2 , wherein the compound is selected from:
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-([1,3]thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl]phenyl}pyrrolidin-2-one;
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one;
5-{3-chloro-6-methoxy-2-methyl-5-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;
4-chloro-N-ethyl-3′,5′-difluoro-3-methyl-6-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]biphenyl-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
23. The method of claim 2 , wherein the compound is selected from:
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one; and
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
or a pharmaceutically acceptable salt thereof.
24. A method of treating a disease selected from osteoarthritis, restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, inflammation, angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, and Sjögren's syndrome in a patient, wherein said disease is associated with abnormal expression or activity of a PI3Kδ kinase, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ar is:
R 1 is methyl;
R 2 is C 1-6 alkoxy, C 1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 3 is Cy or C(═O)NR c R d ;
provided that either (i) R 2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or (ii) R 3 is Cy;
R 4 is halo, C 1-4 alkyl, or C 1-4 haloalkyl;
R 5 is halo, CN, C 1-4 alkyl, or C 1-4 haloalkyl;
R 6 is H;
each Cy is independently selected from 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1 or 2 independently selected R 3b groups;
each R c and R d is independently selected from H and C 1-6 alkyl; and
each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl.
25. The method of claim 24 , wherein the method further comprises administering to said patient a JAK1 and/or JAK2 inhibitor.
26. The method of claim 24 , wherein R 2 is C 1-6 alkoxy or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.
27. The method of claim 24 , wherein R 3 is C(═O)NR c R d .
28. The method of claim 24 , wherein R 3 is Cy.
29. The method of claim 24 , wherein R 4 is C 1-4 alkyl or halo.
30. The method of claim 24 , wherein R 5 is halo, CN, or methyl.
31. The method of claim 24 , wherein:
Ar is:
R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;
each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl;
R 4 is C 1-4 alkyl or halo;
R 5 is halo; and
R 6 is H.
32. The method of claim 24 , wherein:
Ar is:
R 2 is C 1-6 alkoxy;
R 3 is 4-6 membered heterocycloalkyl;
R 4 and R 5 are each independently halo; and
R 6 is H.
33. The method of claim 24 , wherein:
Ar is:
R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;
each R 3b is di(C 1-6 alkyl)carbamyl;
R 4 is halo or C 1-4 alkyl;
R 5 is halo; and
R 6 is H.
34. The method of claim 24 , wherein the compound is selected from:
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-([1,3]thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl]phenyl}pyrrolidin-2-one;
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one;
5-{3-chloro-6-methoxy-2-methyl-5-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;
4-chloro-N-ethyl-3′,5′-difluoro-3-methyl-6-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]biphenyl-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
35. The method of claim 24 , wherein the compound is selected from:
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one; and
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
or a pharmaceutically acceptable salt thereof.
36. A method of treating an immune-based disease, cancer, or lung disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ar is:
R 1 is methyl;
R 2 is C 1-6 alkoxy, C 1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 3 is Cy or C(═O)NR c R d ;
provided that either (i) R 2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or (ii) R 3 is Cy;
R 4 is halo, C 1-4 alkyl, or C 1-4 haloalkyl;
R 5 is halo, CN, C 1-4 alkyl, or C 1-4 haloalkyl;
R 6 is H;
each Cy is independently selected from 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1 or 2 independently selected R 3b groups;
each R c and R d is independently selected from H and C 1 -6 alkyl; and
each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(Cl 6 alkyl)carbamyl.
37. The method of claim 36 , wherein said immune-based disease is rheumatoid arthritis, allergy, asthma, glomerulonephritis, lupus, or inflammation related to any of the aforementioned.
38. The method of claim 36 , wherein said immune-based disease is systemic lupus erythematosus or lupus nephritis.
39. The method of claim 36 , wherein said cancer is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, cancer of the uterus, cancer of the ovary, lung cancer, pancreatic cancer, renal cancer, gastric cancer, or a hematological cancer.
40. The method of claim 39 , wherein said hematological cancer is acute myeloblastic leukemia or chronic myeloid leukemia.
41. The method of claim 36 , wherein said lung disease is acute lung injury (ALI) or adult respiratory distress syndrome (ARDS).
42. The method of claim 36 , wherein the method further comprises administering to said patient a JAK1 and/or JAK2 inhibitor.
43. The method of claim 36 , wherein R 2 is C 1-6 alkoxy or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.
44. The method of claim 36 , wherein R 3 is C(═O)NR c R d .
45. The method of claim 36 , wherein R 3 is Cy.
46. The method of claim 36 , wherein R 4 is C 1-4 alkyl or halo.
47. The method of claim 36 , wherein R 5 is halo, CN, or methyl.
48. The method of claim 36 , wherein:
Ar is:
R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;
each R 3b is independently selected from halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, and di(C 1-6 alkyl)carbamyl;
R 4 is C 1-4 alkyl or halo;
R 5 is halo; and
R 6 is H.
49. The method of claim 36 , wherein:
Ar is:
R 2 is C 1-6 alkoxy;
R 3 is 4-6 membered heterocycloalkyl;
R 4 and R 5 are each independently halo; and
R 6 is H.
50. The method of claim 36 , wherein:
Ar is:
R 2 is C 1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R 3 is C(═O)NR c R d , 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein said 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted by 1, 2, or 3 independently selected R 3b groups;
each R 3b is di(C 1-6 alkyl)carbamyl;
R 4 is halo or C 1-4 alkyl;
R 5 is halo; and
R 6 is H.
51. The method of claim 36 , wherein the compound is selected from:
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-([1,3]thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl]phenyl}pyrrolidin-2-one;
4-{3-chloro-6-ethoxy-2-fluoro-5-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}pyrrolidin-2-one;
5-{3-chloro-6-methoxy-2-methyl-5-[(1S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;
4-chloro-N-ethyl-3′,5′-difluoro-3-methyl-6-[1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl]biphenyl-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
52. The method of claim 36 , wherein the compound is selected from:
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
(S)-4-(3-chloro-6-ethoxy-2-fluoro-5-((R)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one; and
(R)-4-(3-chloro-6-ethoxy-2-fluoro-5-((S)-1-(pyrido[3,2-d]pyrimidin-4-ylamino)ethyl)phenyl)pyrrolidin-2-one;
or a pharmaceutically acceptable salt thereof.