2,4-disubstituted pyrimidines useful as kinase inhibitors
The present invention provides 2,4-disubstituted pyrimidine compounds useful as kinase inhibitors, pharmaceutically acceptable compositions thereof, and methods of using the same. In some embodiments, the present invention provides a compound of formula I-b: wherein each of Ring A, Ring B, W 1 , W 2 , R y , R v , R x , m, p, and R 1 is described herein.
1. A compound of formula I-b:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 1 is a warhead group -L-Y, or R 1 is selected from:
wherein R 1 is attached to Ring A at a position other than an atom adjacent to the atom attached to W 1 ;
L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)(C═N 2 )—, —NRC(O)(C═N 2 )C(O)—, —NRC(O)C(═CH 2 )CH 2 —, —CH 2 NRC(O)—, —CH 2 NRC(O)CH═CH—, —CH 2 CH 2 NRC(O)—, —CH 2 NRC(O)cyclopropylene-, —C(O)CH═C(CH 3 )—, —C(O)CH═CHCH 2 NH(CH 3 )—, —C(O)CH═CH—, —CH 2 C(O)CH═CH—, —CH 2 C(O)CH═C(CH 3 )—, —CH 2 CH 2 C(O)CH═CH—, —CH 2 CH 2 C(O)CH═CHCH 2 —, —CH 2 CH 2 C(O)CH═CHCH 2 N(CH 3 )—, —CH 2 CH 2 C(O)CH═C(CH 3 )—, —CH(CH 3 )OC(O)CH═CH—, —CH 2 OC(O)CH═CHCH 2 —, —CH 2 OC(O)CH═CH— or —CH(CH═CH 2 )OC(O)CH═CH—; wherein R is H or optionally substituted C 1-6 aliphatic; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN;
R y is hydrogen, halogen, —CN, —CF 3 , C 1-4 aliphatic, C 1-4 haloaliphatic, —OR, —C(O)R, or —C(O)N(R) 2 ;
each R group is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
W 1 is —O—;
W 2 is —NR 2 —;
R 2 is hydrogen, optionally substituted C 1-6 aliphatic, or —C(O)R;
m and p are independently 0, 1, 2, 3 or 4; and
R x is selected from —R, halogen, —OR, —O(CH 2 ) q OR, —NO 2 , —SO 2 R, —SO 2 N(R) 2 , —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 , wherein q is 1, 2, 3 or 4;
R v is selected from —R, halogen, —OR, —O(CH 2 ) q OR, —CN, —NO 2 , —SO 2 R, —SO 2 N(R) 2 , —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 , wherein q is 1, 2, 3 or 4; or:
R v and R 1 when concurrently present on Ring A are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with a warhead group and 0-3 groups independently selected from oxo, halogen, CN, or C 1-6 aliphatic.
2. The compound according to claim 1 , wherein Ring A is selected from:
3. The compound according to claim 1 , wherein Ring B is selected from:
4. The compound according to claim 1 , wherein said compound is of formula II-b:
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , wherein said compound is of formula III-b:
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 , wherein said compound is of formula IV-b:
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 , wherein R 1 is selected from:
8. The compound according to claim 1 , wherein Ring B is optionally substituted phenyl.
9. The compound according to claim 1 , wherein p is 0.
10. The compound according to claim 1 , wherein m is 2.
11. The compound according to claim 1 , wherein p is 0 and m is 2.
12. The compound according to claim 1 , wherein R 1 is
13. The compound according to claim 1 , wherein at least one R x is —OCH 3 .
14. The compound according to claim 1 , wherein one R x is R, wherein R is an optionally substituted morpholinyl, piperidinyl, or piperazinyl.
15. The compound according to claim 1 , wherein R y is —CF 3 .
16. The compound according to claim 1 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)C(═CH 2 )CH 2 —, or —CH 2 NRC(O)CH═CH—;
wherein R is H or optionally substituted C 1-6 aliphatic; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.
17. The compound according to claim 16 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)C(═CH 2 )CH 2 —, or —CH 2 NHC(O)CH═CH—.
18. The compound according to claim 1 , wherein R y is halogen.
19. The compound according to claim 18 , wherein R y is chloro.
20. The compound according to claim 18 , wherein R y is fluoro.
21. The compound according to claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.