# US 10,479,803 B2 · Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors

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- Number: US 10,479,803 B2
- Document ID: US10479803B2
- Status: Granted
- Kind: B2
- Application number: 16/112,174
- Filed: 2018-08-24
- Published: 2019-03-21
- Granted: 2019-11-19
- Earliest claimed: 2014-06-11
- Assignees: Incyte Corporation
- Applicants: Incyte Corporation
- Inventors: Yun-Long Li; Andrew P. Combs
- Web page: https://patentgrep.com/patent/US10479803B2

## CPC

- C07D 513/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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.

## Claims

### Claim 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:
R1 is methyl;
R2 is C1-6 alkoxy, C1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
R3 is Cy or C(═O)NRcRd;
provided that either (i) R2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or (ii) R3 is Cy;
R4 is halo, C1-4 alkyl, or C1-4 haloalkyl;
R5 is halo, CN, C1-4 alkyl, or C1-4 haloalkyl;
R6 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 R3b groups;
each Rc and Rd is independently selected from H and C1-6 alkyl and each R3b is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, and di(Cl6 alkyl)carbamyl.

### Claim 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:
R1 is methyl;
R2 is C1-6 alkoxy, C1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
R3 is Cy or C(═O)NRcRd;
provided that either (i) R2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or (ii) R3 is Cy;
R4 is halo, C1-4 alkyl, or C1-4 haloalkyl;
R5 is halo, CN, C1-4 alkyl, or C1-4 haloalkyl;
R6 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 R3b groups;
each Rc and Rd is independently selected from H and C1-6 alkyl; and
each R3b is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, and di(C1-6 alkyl)carbamyl.

### Claim 3 (depends on 2)

The method of claim 2, wherein the method is a method of treating idiopathic thrombocytopenic purpura (ITP) selected from relapsed ITP and refractory ITP.

### Claim 4 (depends on 2)

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).

### Claim 5 (depends on 2)

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.

### Claim 6 (depends on 2)

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).

### Claim 7 (depends on 2)

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.

### Claim 8 (depends on 2)

The method of claim 2, wherein the method further comprises administering to said patient a JAK1 and/or JAK2 inhibitor.

### Claim 9 (depends on 2)

The method of claim 2, wherein the disease is pemphigus.

### Claim 10 (depends on 2)

The method of claim 2, wherein the disease is autoimmune hemolytic anemia.

### Claim 11 (depends on 2)

The method of claim 2, wherein the disease is myelofibrosis.

### Claim 12 (depends on 2)

The method of claim 2, wherein R2 is C1-6 alkoxy or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

### Claim 13 (depends on 2)

The method of claim 2, wherein R3 is C(═O)NRcRd.

### Claim 14 (depends on 2)

The method of claim 2, wherein R3 is Cy.

### Claim 15 (depends on 2)

The method of claim 2, wherein R4 is C1-4 alkyl or halo.

### Claim 16 (depends on 2)

The method of claim 2, wherein R5 is halo, CN, or methyl.

### Claim 17 (depends on 2)

The method of claim 2, wherein:
Ar is:
R2 is C1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R3 is C(═O)NRcRd, 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 R3b groups;
each R3b is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, and di(C1-6 alkyl)carbamyl;
R4 is C1-4 alkyl or halo;
R5 is halo; and
R6 is H.

### Claim 18 (depends on 2)

The method of claim 2, wherein:
Ar is:
R2 is C1-6 alkoxy;
R3 is 4-6 membered heterocycloalkyl;
R4 and R5 are each independently halo; and
R6 is H.

### Claim 19 (depends on 2)

The method of claim 2, wherein:
Ar is:
R2 is C1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R3 is C(═O)NRcRd, 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 R3b groups;
each R3b is di(C1-6 alkyl)carbamyl;
R4 is halo or C1-4 alkyl;
R5 is halo; and
R6 is H.

### Claim 20 (depends on 2)

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.

### Claim 21 (depends on 2)

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.

### Claim 22 (depends on 2)

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.

### Claim 23 (depends on 2)

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.

### Claim 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:
R1 is methyl;
R2 is C1-6 alkoxy, C1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
R3 is Cy or C(═O)NRcRd;
provided that either (i) R2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or (ii) R3 is Cy;
R4 is halo, C1-4 alkyl, or C1-4 haloalkyl;
R5 is halo, CN, C1-4 alkyl, or C1-4 haloalkyl;
R6 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 R3b groups;
each Rc and Rd is independently selected from H and C1-6 alkyl; and
each R3b is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, and di(C1-6 alkyl)carbamyl.

### Claim 25 (depends on 24)

The method of claim 24, wherein the method further comprises administering to said patient a JAK1 and/or JAK2 inhibitor.

### Claim 26 (depends on 24)

The method of claim 24, wherein R2 is C1-6 alkoxy or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

### Claim 27 (depends on 24)

The method of claim 24, wherein R3 is C(═O)NRcRd.

### Claim 28 (depends on 24)

The method of claim 24, wherein R3 is Cy.

### Claim 29 (depends on 24)

The method of claim 24, wherein R4 is C1-4 alkyl or halo.

### Claim 30 (depends on 24)

The method of claim 24, wherein R5 is halo, CN, or methyl.

### Claim 31 (depends on 24)

The method of claim 24, wherein:
Ar is:
R2 is C1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R3 is C(═O)NRcRd, 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 R3b groups;
each R3b is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, and di(C1-6 alkyl)carbamyl;
R4 is C1-4 alkyl or halo;
R5 is halo; and
R6 is H.

### Claim 32 (depends on 24)

The method of claim 24, wherein:
Ar is:
R2 is C1-6 alkoxy;
R3 is 4-6 membered heterocycloalkyl;
R4 and R5 are each independently halo; and
R6 is H.

### Claim 33 (depends on 24)

The method of claim 24, wherein:
Ar is:
R2 is C1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R3 is C(═O)NRcRd, 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 R3b groups;
each R3b is di(C1-6 alkyl)carbamyl;
R4 is halo or C1-4 alkyl;
R5 is halo; and
R6 is H.

### Claim 34 (depends on 24)

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.

### Claim 35 (depends on 24)

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.

### Claim 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:
R1 is methyl;
R2 is C1-6 alkoxy, C1-6 haloalkoxy, or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
R3 is Cy or C(═O)NRcRd;
provided that either (i) R2 is phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or (ii) R3 is Cy;
R4 is halo, C1-4 alkyl, or C1-4 haloalkyl;
R5 is halo, CN, C1-4 alkyl, or C1-4 haloalkyl;
R6 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 R3b groups;
each Rc and Rd is independently selected from H and C1-6 alkyl; and
each R3b is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, and di(Cl6 alkyl)carbamyl.

### Claim 37 (depends on 36)

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.

### Claim 38 (depends on 36)

The method of claim 36, wherein said immune-based disease is systemic lupus erythematosus or lupus nephritis.

### Claim 39 (depends on 36)

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.

### Claim 40 (depends on 39)

The method of claim 39, wherein said hematological cancer is acute myeloblastic leukemia or chronic myeloid leukemia.

### Claim 41 (depends on 36)

The method of claim 36, wherein said lung disease is acute lung injury (ALI) or adult respiratory distress syndrome (ARDS).

### Claim 42 (depends on 36)

The method of claim 36, wherein the method further comprises administering to said patient a JAK1 and/or JAK2 inhibitor.

### Claim 43 (depends on 36)

The method of claim 36, wherein R2 is C1-6 alkoxy or phenyl; wherein said phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

### Claim 44 (depends on 36)

The method of claim 36, wherein R3 is C(═O)NRcRd.

### Claim 45 (depends on 36)

The method of claim 36, wherein R3 is Cy.

### Claim 46 (depends on 36)

The method of claim 36, wherein R4 is C1-4 alkyl or halo.

### Claim 47 (depends on 36)

The method of claim 36, wherein R5 is halo, CN, or methyl.

### Claim 48 (depends on 36)

The method of claim 36, wherein:
Ar is:
R2 is C1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R3 is C(═O)NRcRd, 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 R3b groups;
each R3b is independently selected from halo, CN, C1-6 alkyl, C1-6 haloalkyl, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, C1-6 alkylsulfonyl, carbamyl, C1-6 alkylcarbamyl, and di(C1-6 alkyl)carbamyl;
R4 is C1-4 alkyl or halo;
R5 is halo; and
R6 is H.

### Claim 49 (depends on 36)

The method of claim 36, wherein:
Ar is:
R2 is C1-6 alkoxy;
R3 is 4-6 membered heterocycloalkyl;
R4 and R5 are each independently halo; and
R6 is H.

### Claim 50 (depends on 36)

The method of claim 36, wherein:
Ar is:
R2 is C1-6 alkoxy or phenyl, wherein said phenyl is optionally substituted by 1, 2, or 3 independently selected halo groups;
R3 is C(═O)NRcRd, 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 R3b groups;
each R3b is di(C1-6 alkyl)carbamyl;
R4 is halo or C1-4 alkyl;
R5 is halo; and
R6 is H.

### Claim 51 (depends on 36)

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.

### Claim 52 (depends on 36)

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.