5 or 8-substituted imidazo[1,5-a]pyridines as indoleamine and/or tryptophane 2,3-dioxygenases
Disclosed herein are 5 or 8-substituted imidazo[1,5-a]pyridines and pharmaceutical compositions comprising at least one such 5 or 8-substituted imidazo[1,5-a]pyridines, processes for the preparation thereof, and the use thereof in therapy. Disclosed herein are certain 5 or 8-substituted imidazo[1,5-a]pyridines that can be useful for inhibiting indoleamine 2,3-dioxygenase and/or tryptophane 2,3-dioxygenase and for treating diseases or disorders mediated thereby.
1. A compound having the structure of Formula (IB):
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
n is 0, 1, 2, 3, or 4;
R a and R b are each independently hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 1 is hydrogen, halogen, C 1-8 alkyl or C 1-8 haloalkyl;
R 2 and R 3 are each independently hydrogen, halogen, OR 7 , NR 7 R 8 , COR 7 , SO 2 R 7 , C(═O)OR 7 , C(═O)NR 7 R 8 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with at least one substituent R 9 ;
R 4 , R 5 and R 6 are each independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, heteroaryl, —CN, —OR 7 , or —SR 7 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, and heteroaryl are each independently optionally substituted with at least one substituted R 9 ,
provided that at least one of R 4 and R 5 is not hydrogen;
R C is C 3-10 cycloalkyl, heterocyclyl or heteroaryl, each optionally substituted with at least one substituent R 9 ;
R 7 and R 8 are each independently hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one substituent R 9 ; or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring which optionally comprises a further hetero atom selected from nitrogen, oxygen or sulfur atom, and is optionally substituted with at least one substituent R 9 ;
R 9 is hydrogen, halogen, C 1-4 haloalkyl, C 1-4 alkyl, C 2-8 alkenyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —C 1-4 alkyl-NR′R″, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, nitro, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, NR′SO 2 R″, or —NR′SO 2 aryl, wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, and heterocyclyl group are each independently optionally substituted by one, two or three substituents selected from halo, hydroxyl, C 1-4 alkyl and C 1-4 haloalkyl; and
R′, R″, and R′″ are each independently H, C 1-4 haloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by one or more halogen, C 1-4 haloalkyl or C 1-4 alkyl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a ring selected from heterocyclyl optionally substituted by halogen, C 1-4 haloalkyl or C 1-4 alkyl and heteroaryl rings optionally substituted by halogen, C 1-4 haloalkyl or C 1-4 alkyl.
2. The compound of claim 1 , wherein:
n is 0, 1, 2, 3, or 4;
R a and R b are each independently hydrogen, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 1 is hydrogen, halogen, C 1-8 alkyl or C 1-8 haloalkyl;
R 2 and R 3 are each independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with at least one substituent R 9 ;
R 4 , R 5 and R 6 are each independently hydrogen, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, heteroaryl, or —OR 7 , wherein said C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, aryl, heterocyclyl, and heteroaryl are each independently optionally substituted with at least one substituted R 9 ,
provided that R 4 is not hydrogen;
R C is C 3-10 cycloalkyl optionally substituted with at least one substituent R 9 ;
R 7 is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with at least one substituent R 9 ;
R 9 is hydrogen, halogen, C 1-4 haloalkyl, C 1-4 alkyl, C 2-8 alkenyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —C 1-4 alkyl-NR′R″, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, nitro, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, NR′SO 2 R″, or —NR′SO 2 aryl, wherein said C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, and heterocyclyl group are each independently optionally substituted by one, two or three substituents selected from halo, hydroxyl, C 1-4 alkyl or C 1-4 haloalkyl; and
R′ and R″ are each independently selected from H, C 1-4 haloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by one or more halogen, C 1-4 haloalkyl or C 1-4 alkyl.
3. The compound of claim 1 , wherein n is 0, 1 or 2.
4. The compound of claim 1 , wherein R a and R b are hydrogen.
5. The compound of claim 1 , wherein R 1 is hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
6. The compound of claim 1 , wherein R 2 and R 3 are each independently hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
7. The compound of claim 1 , wherein R 4 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, heterocyclyl, aryl, heteroaryl, or —OC 1-6 alkyl, wherein said aryl and heteroaryl is independently optionally substituted with at least one R 9 independently selected from halogen, C 1-4 haloalkyl, or C 1-4 alkyl.
8. The compound of claim 7 , wherein R 4 is halogen; C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl; C 3-6 cycloalkyl; C 1-6 haloalkyl; phenyl optionally substituted with halogen, C 1-4 alkyl or C 1-4 haloalkyl; heteroaryl optionally substituted with halogen, C 1-4 alkyl or C 1-4 haloalkyl; or —OC 1-6 alkyl.
9. The compound of claim 7 , wherein R 4 is F, Cl, Br, I, methyl, isopropyl, propenyl, ethynyl, cyclopropyl, CF 3 , phenyl, dimethylisoxazolyl or methoxy.
10. The compound according to claim 7 , wherein R 6 is halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
11. The compound of claim 1 , wherein R 4 is not hydrogen, and R 5 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, heterocyclyl, aryl, heteroaryl, or —OC 1-6 alkyl, wherein said aryl and heteroaryl is independently optionally substituted with at least one R 9 independently selected from halogen, C 1-4 haloalkyl, or C 1-4 alkyl.
12. The compound of claim 11 , wherein R 5 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl or —OC 1-6 alkyl.
13. The compound according to claim 11 , wherein R 6 is halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
14. The compound according to claim 7 , wherein R 6 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, heterocyclyl, aryl, heteroaryl, or —OC 1-6 alkyl, wherein said aryl and heteroaryl is independently optionally substituted with at least one R 9 independently selected from halogen, C 1-4 haloalkyl, or C 1-4 alkyl.
15. The compound according to claim 11 , wherein R 6 is halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, heterocyclyl, aryl, heteroaryl, or —OC 1-6 alkyl, wherein said aryl and heteroaryl is independently optionally substituted with at least one R 9 independently selected from halogen, C 1-4 haloalkyl, or C 1-4 alkyl.
16. The compound of claim 1 , wherein R C is C 3-8 cycloalkyl optionally substituted with at least one substituent R 9 .
17. The compound of claim 1 , wherein R C is C 3-8 cycloalkyl optionally substituted with a phenyl.
18. The compound of claim 1 , wherein R C is C 3-8 cycloalkyl optionally substituted with halogen, C 1-4 haloalkyl, C 1-4 alkyl or —NR′COR″, wherein said C 1-4 haloalkyl and C 1-4 alkyl are optionally substituted with one or more halo or hydroxyl; wherein R′ and R″ are each independently H, C 1-4 haloalkyl, C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by one or more halogen, C 1-4 haloalkyl or C 1-4 alkyl.
19. The compound of claim 1 , wherein R C is unsubstituted cyclohexyl.
20. The compound of claim 1 , wherein n is zero, and R C is unsubstituted cyclohexyl or unsubstituted cyclopentyl.
21. The compound of claim 1 , wherein n is 1, and R C is unsubstituted cyclohexyl or unsubstituted cyclopentyl.
22. The compound of claim 1 , wherein n is 2, and R C is unsubstituted cyclohexyl or unsubstituted cyclopentyl.
23. The compound of claim 1 , wherein n is zero, and R C is unsubstituted bicyclo[2.2.1]heptan-2-yl.
24. The compound of claim 1 , wherein n is zero, and R C is 4-phenyl substituted cyclohexyl.
25. The compound of claim 1 , wherein the chiral α-carbon atom to which R 1 is bonded to is in an S-configuration.
26. A compound selected from:
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
27. A compound selected from:
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
29. A method for treating cancer responsive to inhibition of indoleamine 2,3-dioxygenase (IDO) and/or tryptophane 2,3-dioxygenase (TDO) comprising administering to a subject in need thereof a compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in an amount effective to inhibit said IDO and/or TDO;
wherein the cancer is melanomas, thyroid cancer, Barret's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, renal carcinoma, head and neck cancer, liver cancer, stomach cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematologic cancers, cancer of biliary tract, non-small cell lung cancer, endometrium cancer, blood cancer, large intestinal colon carcinoma, histiocytic lymphoma, or lung adenocarcinoma.