Pyrimidine-4,6-diamine derivatives as PI3K inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 1-6 haloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from the group consisting of halo, OH, CN, NR 1a R 1b , C 1-6 alkoxy, and C 1-6 haloalkoxy;

R 2 is H, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -L 1 -(C 1-6 alkyl), or -L 1 -(C 1-6 haloalkyl), wherein said C 1-6 alkyl in said C 1-6 alkyl and -L 1 -(C 1-6 alkyl) is optionally substituted by 1, 2, 3, or 4 independently selected R 2a groups;

R 3 is Cy, —(CR 2b R 2c ) a -L 2 -(CR 2b R 2c ) b -Cy, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR b , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NR c R d , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 3a groups;

R 4 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 5 is halo, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 6 is H, halo, OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 7 is F, CN, C 1-3 haloalkyl, CONH 2 , C 1-4 alkyl-NHC(═O)— or (C 1-4 alkyl) 2 NC(═O)—;

R 8 is H, C 1-4 alkyl, C 1-4 haloalkyl, or C(O)R 4a ;

L 1 is O, NR B , S, S(O), S(O) 2 , C(O), C(O)NR B , S(O)NR B , or S(O) 2 NR B ;

L 2 is (CR C R D ) n , O, NR B , S, S(O), S(O) 2 , C(O), C(O)O, C(O)NR B , S(O)NR B , S(O) 2 NR B , OC(O)NR B , NR B C(O)NR B , C(═NR e ), C(═NR e )NR B , or NR B C(═NR e )NR B ;

R A , R B , R C , and R D are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-6 haloalkyl;

Cy is selected from the group consisting of C 3-7 cycloalkyl, 4-11 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, each of which is substituted with 0, 1, 2, 3, or 4 independently selected R 3a groups;

each R 1a and R 1b is independently selected from the group consisting of H and C 1-6 alkyl;

or any R 1a and R 1b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl;

each R 2a is independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R 2b and R 2c is independently selected from the group consisting of H, C 1-6 alkyl, and C 1-6 haloalkyl;

each R 3a is independently selected from the group consisting of halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4-11 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl, (4-11 membered heterocycloalkyl)-C 1-4 alkyl, (6-10 membered aryl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR b1 , NR c1 C(O)NR c1 R d1 , C(═NR e )R b1 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )NR c1 R d1 , NR S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4-11 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl, (4-11 membered heterocycloalkyl)-C 1-4 alkyl, (6-10 membered aryl)-C 1-4 alkyl, and (5-10 membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 groups independently selected from the group consisting of OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR b1 , NR c1 C(O)NR c1 R d1 , C(═NR e )R b1 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

R 4a is C 1-6 alkyl, C 3-7 cycloalkyl, 4-11 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl, (4-11 membered heterocycloalkyl)-C 1-4 alkyl, (6-10 membered aryl)-C 1-4 alkyl, and (5-10 membered heteroaryl)-C 1-4 alkyl;

each R a , R b , R c , and R d is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, amino sulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, amino sulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, amino carbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R e is independently selected from the group consisting of H, C 1-4 alkyl, CN, OH, C 1-4 alkoxy, C 1-4 alkylsulfonyl, carbamyl, C 1-4 alkylcarbamyl, di(C 1-4 alkyl)carbamyl, and C 1-4 alkylcarbonyl;

each R a1 , R b1 , R c1 , and R d1 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4-11 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl, (4-11 membered heterocycloalkyl)-C 1-4 alkyl, (6-10 membered aryl)-C 1-4 alkyl, and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4-11 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl, (4-11 membered heterocycloalkyl)-C 1-4 alkyl, (6-10 membered aryl)-C 1-4 alkyl, and (5-10 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, amino sulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, amino carbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, amino sulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, amino carbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

a is 0, 1, 2, 3, or 4;

b is 0, 1, 2, 3, or 4; and

n is 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 alkoxy.

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

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is Cy or —(CR 2b R 2c ) a -L 2 -(CR 2b R 2c ) b -Cy.

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

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is phenyl substituted with 0, 1, 2, 3, or 4 independently selected R 3a groups.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is 5-6 membered heteroaryl substituted with 0, 1, 2, 3, or 4 independently selected R 3a groups.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is pyridyl or pyrimidinyl substituted with 0, 1, 2, 3, or 4 independently selected R 3a groups.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently selected from the group consisting of halo, CN, C(O)NR c1 R d1 , NR c1 R d1 , and S(O) 2 R b1 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3a is independently selected from the group consisting of halo, CN, C(O)NR c1 R d1 , and S(O) 2 R b1 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is halo, CN, C 1-4 alkyl, or C 1-4 haloalkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is halo.

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

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

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

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is CN.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H.

18. The compound of claim 1 , having Formula II:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , having Formula III:

20. A compound of claim 1 selected from the group consisting of:

4-amino-6-[(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile (1);

4-amino-6-({1-[5-chloro-3-(5-cyanopyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}amino)-pyrimidine-5-carbonitrile (2);

4-amino-6-({1-[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-amino)pyrimidine-5-carbonitrile (3);

4-amino-6-({1-[5-chloro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}amino)pyrimidine-5-carbonitrile (4);

4-amino-6-[(1-{5-chloro-2-methoxy-4-methyl-3-[5-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}ethyl)-amino]pyrimidine-5-carbonitrile (5);

4-amino-6-({1-[5-chloro-3-(5-cyanopyridin-3-yl)-4-fluoro-2-methoxyphenyl]ethyl}-amino)pyrimidine-5-carbonitrile (6);

4-amino-6-({1-[5-chloro-4-fluoro-3-(5-fluoropyridin-3-yl)-2-methoxyphenyl]ethyl}-amino)pyrimidine-5-carbonitrile (7);

4-amino-6-[(1-{5-chloro-4-fluoro-2-methoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)amino]-pyrimidine-5-carbonitrile (8);

4-amino-6-({1-[5-chloro-6-fluoro-2-methoxy-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}amino) pyrimidine-5-carbonitrile (9);

4-amino-6-({1-[3-(2-aminopyrimidin-5-yl)-5-chloro-4-fluoro-2-methoxyphenyl]-ethyl}amino)pyrimidine-5-carbonitrile (10);

4-amino-6-[(1-{4,5-dichloro-2-methoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile (11);

4-amino-6-({1-[4,5-dichloro-3-(5-fluoropyridin-3-yl)-2-methoxyphenyl]ethyl}amino)pyrimidine-5-carbonitrile (12);

4-amino-6-({1-[5,6-dichloro-2-methoxy-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}amino)pyrimidine-5-carbonitrile (13); and

4-amino-6-({1-[3-(2-aminopyrimidin-5-yl)-4,5-dichloro-2-methoxyphenyl]ethyl}amino)pyrimidine-5-carbonitrile (14);

or a pharmaceutically acceptable salt thereof.

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

22. A method of inhibiting an activity of a PI3K kinase, comprising contacting the kinase with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

23. The method of claim 22 , wherein the PI3K is selected from the group consisting of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ.

24. A method of treating a disease selected from the group consisting of osteoarthritis, restenosis, atherosclerosis, arthritis, diabetic retinopathy, psoriasis, inflammation, angiogenesis, pancreatitis, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, and Sjögren's syndrome in a human patient, wherein said disease is associated with abnormal expression or activity of a PI3K kinase, comprising administering to said human patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

25. A method of treating an immune-based disease selected from the group consisting of rheumatoid arthritis, allergy, asthma, glomerulonephritis, lupus, and inflammation in a human patient, comprising administering to said human patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

26. A method of treating a cancer selected from is the group consisting of breast, prostate, colon, endometrial, brain, bladder, skin, uterus, ovary, lung, pancreatic, renal, gastric, and a hematological cancer in a human patient, comprising administering to said human patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

27. The method of claim 26 wherein said hematological cancer is acute myeloblastic leukemia, chronic myeloid leukemia, or B cell lymphoma.

28. A method of treating a lung disease selected from the group consisting of acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) in a human patient, comprising administering to said human patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

29. The method of claim 26 , wherein said hematological cancer is B cell lymphoma.

30. The method of claim 26 , wherein said hematological cancer is diffuse large B cell lymphoma.

31. The method of claim 22 , wherein said PI3K kinase is PI3Kδ.