Substituted nicotinimide inhibitors of BTK and their preparation and use in the treatment of cancer, inflammation and autoimmune disease
Compounds of Formula I, as shown below and defined herein: and pharmaceutically acceptable salts, syntheses, intermediates, formulations, and methods of treating diseases including cancer, inflammation, and autoimmune disease mediated at least in part by Bruton's Tyrosine Kinase (BTK).
1. A compound having a Formula IId, or a pharmaceutically acceptable salt or solvate thereof:
wherein X is
Z is N;
L 1 is selected from —C 1-2 alkylene-, —CR 5 R 6 —, —C 1-3 alkyl(R 5 )(OH)—, —C(O)—, —CH 2 O—, —OCH 2 —, —CF 2 —, —N(R 5 )—, —N(R 5 )C(O)—, —C(O)N(R 5 )—, —N(R 5 )C(O)N(R 6 )—, —O—, —S—, —S(O) m1 —, —N(R 5 )S(O) m1 —, or —S(O) m1 N(R 5 )—;
G 1 , G 2 , and G 3 are H, or optionally substituted with one or more substituents independently selected from the group consisting of D (deuterium), C 1-12 alkyl, halogen, CN, and CF 3 ;
R 2 and R 3 are each independently selected from the group consisting of H, D, C 1-12 alkyl, halogen, CN, and CF 3 , wherein C 1-12 alkyl is optionally substituted with NR 11 R 12 ;
R 4 is selected from the group consisting of H, D, C 1-12 alkyl, halogen, CN, and CF 3 ;
R 11 and R 12 are independently H or C 1-6 alkyl;
R 5 and R 6 are each independently selected from the group consisting of H, D, C 1-2 alkyl, wherein C 1-2 alkyl is optionally substituted with halogen; and
m1 is 1 or 2.
2. The compound according to claim 1 , wherein
wherein X is
3. The compound according to claim 1 , wherein L 1 is —C 1-2 alkylene-, —CH(OH)—, —CF 2 —, —N(CH 3 )—, —C(O)NH—, —O—, —S—, or —SO 2 —.
4. The compound according to claim 1 , wherein G 1 , G 2 , and G 3 are H, or optionally substituted with one or more halogen.
5. The compound according to claim 1 , wherein R 2 and R 3 are H or C 1-12 alkyl, wherein C 1-12 alkyl is optionally substituted with NR 11 R 12 , and R 11 and R 12 are H or CH 3 .
6. The compounds according to claim 1 , which are
7. The compound according to claim 3 , wherein L 1 is —C 1-2 alkylene, —CH(OH)—, or —CF 2 —.
8. A pharmaceutical composition comprising the compound according to claim 1 , and a pharmaceutically acceptable carrier.