Isoquinoline, quinoline, and quinazoline derivatives as inhibitors of hedgehog signaling
The invention provides isoquinoline, quinoline, and quinazoline derivatives to treat a variety of disorders, diseases and pathologic conditions, and more specifically to the use of isoquinoline, quinoline, and quinazoline derivatives to inhibit the hedgehog signaling pathway and to the use of those compounds to the treatment of hyperproliferative diseases and pathologic angiogenesis.
1. A compound as shown in Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
B is N or CH;
R 1 represents hydrogen, halogen, hydroxyl, amino, nitro, cyano, alkyl, alkenyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylthio, sulfonyl, sulfinyl, cycloalkyl or a heterocycle;
L is oxygen, NR 3 , NR 3 CO, NR 3 SO, SO 2 NR 3 ; NR 3 CONH, NR 3 CSNH, CONR 3 , CSNR 3 , NR 3 CHR 4 , NR 3 PO or NR 3 PO(OH);
Ring A is aryl or heteroaryl;
R 2 represents hydrogen, hydroxyl, halogen, amino, nitro, cyano, acyl, alkyl, alkenyl, alkynyl, alkylthio, sulfonyl, sulfinyl, alkoxy, alkoxycarbonyl, carbamoyl, acylamine, sulfamoyl or sulfonamide;
or R 2 is aryl, heterocycle or heteroaryl that is optionally substituted with hydroxyl, halogen, amino, nitro, cyano, acyl, alkyl, alkanoyl, sulfonyl, sulfinyl, alkoxy, carbamoyl, acylamine, sulfamoyl and sulfonamide;
R 3 and R 4 are independently selected from hydrogen or an optionally substituted C1-4 alkyl group;
m is 0-4.
2. A compound as shown in Formula (Ia)
or a pharmaceutically acceptable salt thereof, wherein:
A, R 1 , R 2 , L, and m are as defined in claim 1 .
3. A compound as shown in Formula (Ib)
or a pharmaceutically acceptable salt thereof, wherein:
A, R 1 , R 2 , L, and m are as defined in claim 1 .
4. A compound as shown in Formula (A):
or a pharmaceutically acceptable salt thereof, wherein:
K is selected from NR 3 C(O), C(O)NR 3 , SO 2 NR 3 , and NR 4 C(O)NR 5 ;
A 1 is selected from aryl, heterocyclyl, and heteroaryl;
R 1 is selected from H, halo, nitro, —OR 4 , C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, and C 1 -C 6 haloalkyl;
m=0-4;
R 3 , R 4 , and R 5 are each independently selected from H and C 1 -C 6 alkyl;
W is selected from CH and N;
Z is selected from H, halo, and C 1 -C 6 alkyl, C 1 -C 6 alkylthio, —NR 4 R 5 , —OR 4 , and cyano.
5. A compound or pharmaceutically acceptable salt of claim 4 , wherein:
K is selected from NR 3 C(O), C(O)NR 3 , SO 2 NR 3 , and NR 4 C(O)NR 5 ;
A 1 is selected from phenyl and pyridyl;
R 1 is selected from H, halo, nitro, C 1 -C 6 alkylsulfonyl, and C 1 -C 6 alkyl;
m=0-4;
R 3 , R 4 and R 5 are each independently selected from H and C 1 -C 6 alkyl;
W is selected from CH and N;
Z is selected from H, halo, and C 1 -C 6 alkyl.
6. A compound as shown in Formula (B):
or a pharmaceutically acceptable salt thereof, wherein:
R 3 , R 4 , and R 5 are each independently selected from H and C 1 -C 6 alkyl;
R 7 is selected from heterocyclyl, haloalkyl, NR 3 C(O)R 4 , NR 3 C(O)NR 4 R 5 , NR 3 C(O)[C(R 3 )(R 4 )] n O[C(O)]pR 4 , (CH 2 ) n SO 2 R 3 , NR 3 SO 2 R 4 , NR 3 C(O)-Q-R 4 , and N(OR 3 )C(O)R 4 ;
n is 1-2;
p is 0 or 1;
Q is heterocyclyl;
U is selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkylthio, —NR 4 R 5 , —OR 4 , and cyano;
V is selected from CH and N;
W is selected from CH and N;
Z is selected from H, halo, and C 1 -C 6 alkyl.
7. A compound as shown in Formula (C):
or a pharmaceutically acceptable salt thereof, wherein:
R 3 , R 4 , and R 5 are each independently selected from H and C 1 -C 6 alkyl;
R 7 is selected from heterocyclyl, haloalkyl, NR 3 C(O)R 4 , NR 3 C(O)NR 4 R 5 , NR 3 C(O)[C(R 3 )(R 4 )] n O[C(O)]pR 4 , (CH 2 ) n SO 2 R 3 , NR 3 SO 2 R 4 , NR 3 C(O)-Q-R 4 , and N(OR 3 )C(O)R 4 ;
n is 1-2;
p is 0 or 1;
Q is heterocyclyl;
U is selected from H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkylthio, —NR 4 R 5 , —OR 4 , and cyano;
V is selected from CH and N;
Z is selected from H, halo, and C 1 -C 6 alkyl.
8. A compound having the structure shown in Formula (i):
9. The compound of claim 6 , wherein the compound is as shown in Formula (ii):
10. The compound of claim 6 , wherein the compound is as shown in Formula (iii):
11. The compound of claim 6 , wherein the compound is as shown in Formula (iv):
12. The compound of claim 6 , wherein the compound is as shown in Formula (v):
13. The compound of claim 6 , wherein the compound is as shown in Formula (vi):
14. The compound of claim 6 , wherein the compound is as shown in Formula (vii):
15. The compound of claim 6 , wherein the compound is as shown in Formula (viii):
16. The compound of claim 6 , wherein the compound is as shown in Formula (ix):
17. The compound of claim 6 , wherein the compound is as shown in Formula (x):
18. The compound of claim 6 , wherein the compound is as shown in Formula (xi):
19. The compound of claim 6 , wherein the compound is as shown in Formula (xii):
20. The compound of claim 6 , wherein the compound is as shown in Formula (xiii):
21. The compound of claim 6 , wherein the compound is as shown in Formula (xiv):
22. The compound of claim 7 , wherein the compound is as shown in Formula (xv):
23. A process for making a compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms, salts and individual diastereomers thereof.
24. A pharmaceutical composition comprising at least one compound of claim 1 or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms, salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier.