Substituted pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
A compound having the structure of below Formula(I), or pharmaceutically acceptable salts thereof, are useful as Janus kinase inhibitors, wherein R 1 and L 1 are as herein described.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
A is selected from C(R) or N;
L 1 is selected from a single bond, —C(═O)O—, —C(═O)—, —S(═O)—, —S(═O) 2 —, —C(═O)N(R)—, —N(R)C(═O)N(R)—, —N(R)—, —S(═O)N(R)—, —S(═O) 2 N(R)C(R) 2 — or —S(═O)N(R)C(R) 2 —;
R 1 is selected from H, CN, OH, NH 2 , halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R;
R is independently selected from H, CN, OH, NH 2 , halogen, C 1-6 alkyl or C 1-6 heteroalkyl, wherein the C 1-6 alkyl and C 1-6 heteroalkyl are independently and optionally substituted with 1, 2, 3 or 4 R′; and
R′ is selected from halogen, OH, NH 2 , CN, CH 3 , CH 2 CH 3 , CF 3 , CH 2 CF 3 , NHCH 3 or N(CH 3 ) 2 ;
wherein hetero is a heteroatom or a heterogroup selected from the group consisting of N, O, S, —C(═O)O—, —C(═O)—, —S(═O)— and —S(═O) 2 —, and the number of heteroatoms or heterogroups in any of the above conditions is independently selected from 1, 2 or 3.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is selected from a single bond, —C(═O)O—, —C(═O)—, —S(═O)—, —S(═O) 2 —, —C(═O)NH—, —NHC(═O)NH—, —NH—, —S(═O)NH—, —S(═O) 2 NHCH 2 — or —S(═O)NHCH 2 —.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H, CN, OH, NH 2 , C 1-3 alkyl, C 1-2 alkyl-N(CH 3 ) 2 , C 1-2 alkyl-N(CH 2 CH 3 ) 2 , C 1-2 alkyl-NHCH 3 , C 1-2 alkyl-NHCH 2 CH 3 , C 1-3 alkyl-S(═O) 2 —C 1-3 alkyl, C 1-3 alkyl-S(═O)—C 1-3 alkyl, C 4-5 cycloalkyl or 4-5 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-2 alkyl-N(CH 3 ) 2 , C 1-2 alkyl-N(CH 2 CH 3 ) 2 , C 1-2 alkyl-NHCH 3 , C 1-2 alkyl-NHCH 2 CH 3 , C 1-3 alkyl-S(═O) 2 —C 13 alkyl, C 1-3 alkyl-S(═O)—C 13 alkyl, C 4-5 cycloalkyl or 4-5 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CN, CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH 2 NHCH 3 , (CH 2 ) 2 —S(═O) 2 —CH 3 or cyclobutyl, wherein the CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH 2 NHCH 3 , (CH 2 ) 2 —S(═O) 2 —CH 3 or cyclobutyl is optionally substituted with 1, 2, 3 or 4 R.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CN, CH 3 , CH 2 CHF 2 , CH 2 CF 3 , (CH 2 ) 2 CN, (CH 2 ) 2 CHF 2 , CH 2 NHCH 3 , (CH 2 ) 2 —S(═O) 2 —CH 3 or 3,3-difluorocyclobutyl.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R is independently selected from H, CN, OH, NH 2 , halogen, CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , NHCH 3 , N(CH 3 ) 2 or NH(CH 3 ) 2 + , wherein the CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , NHCH 3 , N(CH 3 ) 2 and NH(CH 3 ) 2 + are independently and optionally substituted with 1, 2 or 3 R′.
7. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is selected from a single bond, —C(═O)O—, —C(═O)—, —S(═O)—, —S(═O) 2 —, —C(═O)NH—, —NHC(═O)NH—, —NH—, —S(═O)NH—, —S(═O) 2 NHCH 2 — or —S(═O)NHCH 2 —.
8. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H, CN, OH, NH 2 , C 1-3 alkyl, C 1-2 alkyl-N(CH 3 ) 2 , C 1-2 alkyl-N(CH 2 CH 3 ) 2 , C 1-2 alkyl-NHCH 3 , C 1-2 alkyl-NHCH 2 CH 3 , C 1-3 alkyl-S(═O) 2 —C 1-3 alkyl, C 1-3 alkyl-S(═O)—C 1-3 alkyl, C 4-5 cycloalkyl or 4-5 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-2 alkyl-N(CH 3 ) 2 , C 1-2 alkyl-N(CH 2 CH 3 ) 2 , C 1-2 alkyl-NHCH 3 , C 1-2 alkyl-NHCH 2 CH 3 , C 1-3 alkyl-S(═O) 2 —C 13 alkyl, C 1-3 alkyl-S(═O)—C 13 alkyl, C 4-5 cycloalkyl or 4-5 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R.
9. The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CN, CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH 2 NHCH 3 , (CH 2 ) 2 —S(═O) 2 —CH 3 or cyclobutyl, wherein the CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH 2 NHCH 3 , (CH 2 ) 2 —S(═O) 2 —CH 3 or cyclobutyl is optionally substituted with 1, 2, 3 or 4 R.
10. The compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from CN, CH 3 , CH 2 CHF 2 , CH 2 CF 3 , (CH 2 ) 2 CN, (CH 2 ) 2 CHF 2 , CH 2 NHCH 3 , (CH 2 ) 2 —S(═O) 2 —CH 3 or 3,3-difluorocyclobutyl.
11. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method for inhibiting Janus kinase activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .
15. The method according to claim 14 , wherein the subject has arthritis.
16. The method according to claim 15 , wherein the arthritis is rheumatoid arthritis.
17. A method for inhibiting Janus kinase activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 12 .
18. The method according to claim 17 , wherein the subject has arthritis.
19. The method according to claim 18 , wherein the arthritis is rheumatoid arthritis.
20. A process for the preparation of a compound of Formula (I):
wherein:
A is CH;
L 1 is —C(═O)NH—;
R 1 is selected from H, CN, OH, NH 2 , halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R;
R is independently selected from H, CN, OH, NH 2 , halogen, C 1-6 alkyl or C 1-6 heteroalkyl, wherein the C 1-6 alkyl and C 1-6 heteroalkyl are independently and optionally substituted with 1, 2, 3 or 4 R′; and
R′ is selected from halogen, OH, NH 2 , CN, CH 3 , CH 2 CH 3 , CF 3 , CH 2 CF 3 , NHCH 3 or N(CH 3 ) 2 ;
wherein hetero is a heteroatom or a heterogroup selected from the group consisting of N, O, S, —C(═O)O—, —C(═O)—, —S(═O)— and —S(═O) 2 —, and the number of heteroatoms or heterogroups in any of the above conditions is independently selected from 1, 2 or 3;
comprising the following steps:
(1) reacting a compound of the formula:
wherein:
A is CH;
L 1 is —C(═O)O—;
R 1 is H; and
PG is selected from benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, o-phthalyl, p-toluenesulfonyl, trifluoroacetyl, benzyl or p-methoxybenzyl;
with sodium hydroxide in the presence of tetrahydrofuran and a protic cosolvent, to provide a compound of the formula:
wherein:
A is CH;
L 1 is —C(═O)O—; and
R 1 is H; and
(2) reacting the compound of the formula:
wherein:
A is CH;
L 1 is —C(═O)O—; and
R 1 is H;
with a compound of the formula:
R 1 —NH 2
wherein:
R 1 is selected from H, CN, OH, NH 2 , halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R;
R is independently selected from H, CN, OH, NH 2 , halogen, C 1-6 alkyl or C 1-6 heteroalkyl, wherein the C 1-6 alkyl and C 1-6 heteroalkyl are independently and optionally substituted with 1, 2, 3 or 4 R′; and
R′ is selected from halogen, OH, NH 2 , CN, CH 3 , CH 2 CH 3 , CF 3 , CH 2 CF 3 , NHCH 3 or N(CH 3 ) 2 ;
wherein hetero is a heteroatom or a heterogroup selected from the group consisting of N, O, S, —C(═O)O—, —C(═O)—, —S(═O)— and —S(═O) 2 —, and the number of heteroatoms or heterogroups in any of the above conditions is independently selected from 1, 2 or 3;
in the presence of pyridine, to provide the compound of Formula (I) above.