Kinase inhibitors
Provided herein are compounds such as the compounds having the structure of Formula (XI) and methods of using the same, such as methods of inhibiting kinases.
1. A compound having the structure of Formula (XI):
wherein:
the dashed lines are optionally a bond;
y is an integer from 0 to 2;
j is an integer from 0 to 3;
f is 0 or 1;
Z 1 , Z 2 , and Z 3 are —N— or —CH—, provided that at least one and not more than two of Z 1 , Z 2 , and Z 3 are simultaneously N;
Ar is a monocyclic or fused bicyclic (C 6 -C 10 ) aryl, monocyclic or fused bicyclic 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, monocyclic (C 3 -C 10 )cycloalkyl or 4 to 8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S and is optionally fused to monocyclic aryl or heteroaryl as defined above and can contain one to two —CO— groups in the ring;
R 12 is hydrogen, (C 1 -C 6 ) unsubstituted saturated alkyl, hydroxy, unsubstituted saturated (C 1 -C 6 ) alkoxy, halogen, halo substituted (C 1 -C 6 ) saturated alkyl, or unsubstituted saturated (C 1 -C 6 ) haloalkoxy;
R 14 is hydrogen, (C 1 -C 6 ) unsubstituted saturated alkyl, hydroxy, —O(C 1 -C 6 ) unsubstituted saturated alkyl, halogen, unsubstituted saturated (C 1 -C 6 ) haloalkyl, or unsubstituted saturated (C 1 -C 6 ) haloalkoxy;
L 1 is —C(O)— or —SO 2 —;
L 4 is a bond, —O—, —NH—, or methylene;
ring A is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl optionally substituted with methyl or fluoro;
L 11 is —O—, —CO—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 15C —, —NR 15C CO—, —CONR 15C —, —NR 15C SO 2 —, —SO 2 NR 15C —, or —NR 15C CONR 15D —, wherein each R 15C and R 15D is independently hydrogen or C 1 -C 6 unsubstituted saturated alkyl;
R 23 is hydrogen, (C 1 -C 6 ) unsubstituted saturated alkyl, hydroxy, unsubstituted saturated (C 1 -C 6 ) alkoxy, halo, unsubstituted saturated (C 1 -C 6 ) haloalkyl, unsubstituted saturated (C 1 -C 6 ) haloalkoxy, carboxy, —COO—(C 1 -C 6 ) unsubstituted saturated alkyl, cyano, —CONH 2 , or —NR x R y where R x is hydrogen and R y is hydrogen, (C 1 -C 6 ) unsubstituted saturated alkyl, unsubstituted saturated (C 3 -C 6 ) cycloalkyl, unsubstituted saturated (C 3 -C 6 )cycloalkyl-(C 1 -C 6 ) unsubstituted saturated alkyl, —COR wherein R is (C 1 -C 6 ) unsubstituted saturated alkyl, or —SO 2 —(C 1 -C 6 ) unsubstituted saturated alkyl;
R 2 and R 3 are independently (C 1 -C 6 ) unsubstituted saturated alkyl, unsubstituted saturated (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) saturated alkyl which is substituted with one, two, or three substituents independently selected from hydroxyl, unsubstituted saturated (C 1 -C 6 ) alkoxy, carboxy, cyano, —COO—(C 1 -C 6 ) unsubstituted saturated alkyl, —S—(C 1 -C 6 ) unsubstituted saturated alkyl, —SO 2 —(C 1 -C 6 ) unsubstituted saturated alkyl, halo, —CONR″R′ or NR″R′ where each R″ is hydrogen, (C 1 -C 6 ) unsubstituted saturated alkyl, (C 3 -C 6 ) unsubstituted saturated cycloalkyl, (C 1 -C 6 ) saturated alkyl substituted with one, two, or three hydroxy or one to three unsubstituted saturated (C 1 -C 6 ) alkoxy and R′ is hydrogen, (C 1 -C 6 ) unsubstituted saturated alkyl, unsubstituted saturated (C 3 -C 6 ) cycloalkyl or 4 to 8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S and which is optionally substituted with one or two groups independently selected from (C 1 -C 6 ) unsubstituted saturated alkyl, hydroxyl, unsubstituted saturated (C 1 -C 6 ) alkoxy, —S—(C 1 -C 6 ) unsubstituted saturated alkyl, —SO 2 —(C 1 -C 6 ) unsubstituted saturated alkyl, or halo, or R 2 and R 3 together with the carbon atom to which they are attached form (C 3 -C 6 ) unsubstituted saturated cycloalkyl; and
R 4 is R 18 -substituted or unsubstituted alkyl, R 18 -substituted or unsubstituted heteroalkyl, R 18 -substituted or unsubstituted cycloalkyl, R 18 -substituted or unsubstituted heterocycloalkyl, R 18 -substituted or unsubstituted aryl, or R 18 -substituted or unsubstituted heteroaryl, wherein
R 18 is independently halogen, —CN, —OH, —SH, —NH 2 , —COOH, —NO 2 , —CONH 2 , —CF 3 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
2. The compound of claim 1 , wherein L 11 is —O—.
3. The compound of claim 2 , wherein R 12 is absent, methyl, fluoro, or trifluoromethyl.
4. The compound of claim 3 , wherein R 14 is independently absent, unsubstituted saturated (C 1 -C 6 ) alkyl, unsubstituted saturated (C 1 -C 6 ) alkoxy, halo, unsubstituted saturated (C 1 -C 6 ) haloalkyl or unsubstituted saturated (C 1 -C 6 ) haloalkoxy.
5. The compound of claim 4 , wherein R 23 is independently absent, unsubstituted saturated (C 1 -C 6 ) alkyl, unsubstituted saturated (C 1 -C 6 ) alkoxy, halo, unsubstituted saturated (C 1 -C 6 ) haloalkyl, unsubstituted saturated (C 1 -C 6 ) haloalkoxy, or cyano.
6. The compound of claim 5 , wherein L 4 is a bond or methylene.
7. The compound of claim 6 , wherein L 1 is —C(O)— and ring A is piperidinyl optionally substituted with methyl or fluoro.
8. The compound of claim 7 , wherein R 2 and R 3 are independently unsubstituted saturated C 1 -C 6 alkyl or together form (C 3 -C 6 ) unsubstituted saturated cycloalkyl.
9. The compound of claim 8 , wherein Ar is unsubstituted phenyl or phenyl substituted at least one of a meta or para position.
10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
11. A method for treating leukemia, multiple myeloma, lymphoma, non-small cell lung cancer, pancreatic cancer or rheumatoid arthritis, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .
12. The compound according to claim 1 , said compound selected from the group consisting of: