Substituted pyrrolopyridines as JAK inhibitors
The present invention relates to new pyrrolopyridine compounds having the structures of Formula (I)-(IV), wherein the R groups, A, B, C, D and n are as defined in the detailed description, and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of JAK kinase activity in a human or animal subject are also provided for the treatment diseases such as pruritus, alopecia, androgenetic alopecia, alopecia areata, vitiligo and psoriasis.
1. A compound, or a derivative thereof, of Formula (I):
wherein:
R 1 is selected from CN or a heteroaryl group and is optionally substituted at the one or more available nitrogen atoms with a group independently selected from H or C 1 -C 5 alkyl and at one or more available carbon atoms with substituents wherein each substituent is independently selected from H, halogen, CN, —C 1 —C 4 alkyl, —C 0 -C 6 alkylC 3 —C 6 cycloalkyl, —(C 0 -C 6 alkyl)C 3 -C 6 heterocycle, —OH, —SO 2 R 9 , —SOR 9 , —SR 9 , —NHSO 2 R 9 , —OSO 2 R 9 , —C 0 -C 6 alkylSO 2 R 9 , C 0 -C 6 alkylCOR 9 , C 0 -C 6 alkylNR 7 C(O)NR 7 R 8 , C 0 -C 6 alkylOC(O)NR 7 R 8 , C 0 -C 6 alkylNR 7 SO 2 R 9 , —C 0 -C 6 alkylNR 7 COR 9 -OC 1 -C 6 alkyl, —OC 0 -C 6 alkylC 3 -C 6 cycloalkyl, —OC 0 -C 6 alkylC 3 -C 6 heterocycle, —OC 0 -C 6 alkylNR 7 C(O)NR 7 R 8 , —OC 0 -C 6 alkylOC(O)NR 7 R 8 , —OC 0 -C 6 alkylNR 7 SO 2 R 9 , —OC 0 -C 6 alkylNR 7 COR 9 , —NR 7 R 8 , —NR 7 C 0 -C 6 alkylC 1 -C 6 alkyl, -NR 7 C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —NR 7 C 0 -C 6 alkylNR 7 C(O)NR 7 R 8 , —NR 7 C 0 -C 6 alkylOC(O)NR 7 R 8 , —NR 7 C 0 -C 6 alkylNR 7 SO 2 R 9 , —NR 7 C 0 -C 6 alkylNR 7 COR 9 , —NR 7 C 0 -C 6 alkylC 3 -C 6 heterocycle, aryl and heteroaryl wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is optionally substituted with one or more groups selected from: halogen, —OH, —C 0 -C 6 alkylNR 7 R 8 , —C 0 -C 6 alkylOH, —SO 2 R 9 , —SOR 9 , —NHSO 2 R 9 , —C 0 -C 6 alkylNR 7 R 4 , CN, —C 1 -C 5 alkylalkoxy, C 1 -C 5 alkoxy or —O-C 1 -C 5 alkyl;
R 2 is selected from H, —C 1 C 4 alkyl, —C 3 -C 6 cycloalkyl, or —C 1 -C 2 alkyl-C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups are optionally substituted with one or more groups selected from halogen, —OH, or —O- 1 -C 5 alkyl;
n is 2;
Ring A is substituted at one or more carbons with one, two, or three R 3 substituents wherein each R 3 substituent is independently selected from H, halogen, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —OH, or —O-C 1 -C 5 alkyl wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from: halogen, —OH, —C 1 -C 5 alkylalkoxy, or —O-C 1 -C 5 alkyl;
Two R 3 groups on the same or different carbon atoms of the ring A may be optionally joined to form a spirocyclic or bicyclic ring system with ring A;
R 4 is selected from —C(O)-R 6 , —CH 2 R 6 , —C(O)-C 1 -C 5 alkyl, or —C(O)-C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups may be optionally substituted with one or more groups selected from —OH, halogen, alkyne, or —CN;
R 5 is selected from —C 1 -C 5 alkyl, or —C 3 -C 6 cycloalkyl wherein the alkyl or cycloalkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, or —O-C 1 -C 5 alkyl;
R 6 is selected from —C 1 -C 5 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 5 alkyl-C 3 -C 6 cycloalkyl, —NR 7 R 8 , —O-aryl, —O-heteroaryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or heteroaryl groups can be optionally substituted by one or more groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl, —O-C 1 -C 5 alkyl, or —O-C 3 -C 6 cycloalkyl;
R 7 and R 8 are independently selected from H, —C 1 -C 5 alkyl, —C 1 -C 5 alkoxy, or —C 3 -C 5 cycloalkyl wherein the alkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, or —CN;
R 7 and R 8 may be optionally joined to form a ring to form a heterocycle such as piperidine, pyrrolidine, or with another heteroatom to form a ring such as morpholine wherein the heterocyclic ring may be optionally substituted by one or more groups selected from halogen, —OH, NH 2 , NHMe, NMe 2 , or —CN; and
R 9 is selected from H, —C 1 C 5 alkyl, —OC 1 C 5 alkyl, —C 3 -C 6 cycloalkyl, and NR 7 R 8 wherein the alkyl, heterocycle, or cycloalkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, NH 2 , NHMe, NMe 2 , or —CN.
2. The compound of claim 1 , wherein the compound is selected from the group consisting of:
3. A pharmaceutical composition comprising: a compound of claims 1 or 2 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.
4. The compound of claim 2 , wherein the compound, is
5. A pharmaceutical composition comprising: a compound of claim 4 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.
6. The compound of claim 2 , wherein the compound, is
7. A pharmaceutical composition comprising: a compound of claim 6 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.
8. The compound of claim 2 , wherein the compound, is
9. A pharmaceutical composition comprising: a compound of claim 8 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.
10. The compound of claim 2 , wherein the compound, is
11. A pharmaceutical composition comprising: a compound of claim 10 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.
12. The compound of claim 2 , wherein the compound, is
13. A pharmaceutical composition comprising: a compound of claim 12 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.
14. The compound of claim 2 , wherein the compound, is
15. A pharmaceutical composition comprising: a compound of claim 14 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.
16. The compound of claim 2 , wherein the compound, is
17. A pharmaceutical composition comprising: a compound of claim 16 , a derivative thereof, or a combination thereof; and a pharmaceutically acceptable excipient.