Substituted amino triazoles useful as human chitinase inhibitors
Disclosed are amino triazole compounds substituted with a piperidinyl ring that is itself substituted with a heterocyclic ring. These compounds are inhibitors of acidic mammalian chitinase and chitotriosidase. Also disclosed are methods of using the compounds to treat asthma reactions caused by allergens, as well as acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer.
1. A method for the therapeutic treatment of a disease, disorder, or condition associated with aberrant expression or activity of acidic mammalian chitinase, comprising administering to a human in need thereof a therapeutically effective amount of a compound, wherein said compound is represented by formula (I):
wherein:
W is halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy-, or (C 1 -C 3 )alkylthio-;
X is a single bond, —CH 2 —, —CH 2 CH 2 —, —CH═CH—, or —C(O)—;
Y is a single bond, —CH—, —CHCH 2 —, —CH 2 CH—, —C═CH—, —CH═C—, —N—, —O—, —S(O)—, or —S(O) 2 —;
if Y is a single bond, —O—, —S(O)—, or —S(O) 2 —, then R 1 is absent;
R 1 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)aryl(C 1 -C 6 )alkyl, —C(O)heteroaryl(C 1 -C 6 )alkyl, —S(O) 2 (C 1 -C 6 )alkyl, —S(O) 2 aryl, —S(O) 2 heteroaryl, —S(O) 2 aryl(C 1 -C 6 )alkyl, —S(O) 2 heteroaryl(C 1 -C 6 )alkyl, —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(aryl(C 1 -C 6 )alkyl), —C(O)O(heteroaryl(C 1 -C 6 )alkyl), —C(O)NH 2 , —C(O)NHOH, —C(O)NHCN, —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl(C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) 2 , —C(O)N(C 1 -C 6 )alkyl)(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl)(aryl(C 1 -C 6 )alkyl), —C(O)NH((C 1 -C 6 )haloalkyl), —C(O)N((C 1 -C 6 )haloalkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NH(heteroaryl(C 1 -C 6 )alkyl), —S(O) 2 NH(heteroaryl), —S(O) 2 N((C 1 -C 6 )alkyl) 2 , —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —S(O) 2 NHC(O)aryl(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)heteroaryl, —S(O) 2 NHC(O)heteroaryl(C 1 -C 6 )alkyl, —NHS(O) 2 (C 1 -C 6 )alkyl, —NHS(O) 2 aryl, —NHS(O) 2 (C 1 -C 6 )haloalkyl, —NHS(O) 2 aryl(C 1 -C 6 )alkyl, —NHS(O) 2 heteroaryl, —NHS(O) 2 heteroaryl(C 1 -C 6 )alkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)(aryl(C 1 -C 6 )alkyl), —NHC(O)(heteroaryl), —NHC(O)(heteroaryl(C 1 -C 6 )alkyl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NH(aryl), —NHC(O)NH(aryl(C 1 -C 6 )alkyl), —NHC(O)NH(heteroaryl), —NHC(O)NH(heteroaryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 (C 1 -C 6 )alkyl, —C(O)NHS(O) 2 aryl, C(O)NHS(O) 2 ((C 1 -C 6 )haloalkyl), —C(O)NHS(O) 2 (aryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 heteroaryl, —C(O)NHS(O) 2 (heteroaryl(C 1 -C 6 )alkyl), —P(O)(OH) 2 , —((C 1 -C 6 )alkylene)C(O)OH, ((C 1 -C 6 )alkylene)C(O)O(C 1 -C 6 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NC, —CN, —C(S)NH 2 , —NHC(O)NH 2 , (C 1 -C 6 )alkylthio-, (C 1 -C 6 )mercaptoalkyl-, or —C(O)heterocyclyl;
Z is —CH—, —C(O)—, or —C((C 1 -C 3 )alkyl)-;
if Z is —C(O)—, then R 2 is absent,
R 2 is H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(aryl(C 1 -C 6 )alkyl), —C(O)O(heteroaryl(C 1 -C 6 )alkyl), —C(O)NHOH, —C(O)NHCN, —C(O)NH 2 , —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl(C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) 2 , —C(O)N(C 1 -C 6 )alkyl)(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl)(aryl(C 1 -C 6 )alkyl), —C(O)NH((C 1 -C 6 )haloalkyl), —C(O)N((C 1 -C 6 )haloalkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NH(heteroaryl(C 1 -C 6 )alkyl), —S(O) 2 NH(heteroaryl), —S(O) 2 NH(heteroaryl(C 1 -C 6 )alkyl), —S(O) 2 N((C 1 -C 6 )alkyl) 2 , —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —S(O) 2 NHC(O)aryl(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)heteroaryl, —S(O) 2 NHC(O)heteroaryl(C 1 -C 6 )alkyl, —NHS(O) 2 (C 1 -C 6 )alkyl, —NHS(O) 2 aryl, NHS(O) 2 (C 1 -C 6 )haloalkyl, —NHS(O) 2 aryl(C 1 -C 6 )alkyl, —NHS(O) 2 heteroaryl, —NHS(O) 2 heteroaryl(C 1 -C 6 )alkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)(aryl(C 1 -C 6 )alkyl), —NHC(O)(heteroaryl), —NHC(O)(heteroaryl(C 1 -C 6 )alkyl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —NHC(O)NH(aryl(C 1 -C 6 )alkyl), —NHC(O)NH(heteroaryl), —NHC(O)NH(heteroaryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 (C 1 -C 6 )alkyl, —C(O)NHS(O) 2 aryl, C(O)NHS(O) 2 ((C 1 -C 6 )haloalkyl), —C(O)NHS(O) 2 (aryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 heteroaryl, —C(O)NHS(O) 2 (heteroaryl(C 1 -C 6 )alkyl), —P(O)(OH) 2 , aryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl-, —NC, —CN, —C(S)NH 2 , —NHC(O)NH 2 , (C 1 -C 6 )alkylthio-, (C 1 -C 6 )mercaptoalkyl-, or —C(O)heterocyclyl;
R 3 is H, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, (C 1 -C 6 )haloalkyl, —NC, —CN, —C(S)NH 2 , —NHC(O)NH 2 , or —C≡CH;
R 4 is H, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl-, or (C 1 -C 4 )hydroxyalkyl;
R 5 is H, halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —OH, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkoxy, —SH, (C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, —NC, —C(S)NH 2 , —NHC(O)NH 2 , or —C≡CH; and
R 6 is H, halo, —OH, —NH 2 , or —SH; or
R 6 , taken together with the carbon atom bearing it, represents —C(O)—;
wherein:
any occurrence of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylene, heterocyclyl, cycloalkyl, alkoxy, alkylthio, haloalkyl, or hydroxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of —OH, halo, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —CN, —NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, —C(O)OH, —C(O)O(C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, and —C(O)N((C 1 -C 6 )alkyl) 2 ;
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or polymorph thereof.
2. The method of claim 1 , wherein the disease, disorder, or condition is selected from the group consisting of allergic diseases, acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, kidney diseases, skin diseases, polycystic ovary syndrome, endometriosis, fibrotic disorders, storage diseases, and cancer.
3. The method of claim 1 , wherein W is fluoro, chloro, bromo, methyl, or methoxy.
4. The method of claim 1 , wherein R 6 is H or —OH.
5. The method of claim 1 , wherein X is a single bond, —CH 2 —, or —C(O)—.
6. The method of claim 1 , wherein Y is a single bond, —CH—, —N—, —O—, or —S(O) 2 —.
7. The method of claim 1 , wherein Y is —CH— or —N—.
8. The method of claim 7 , wherein R 1 is H or (C 1 -C 6 )alkyl.
9. The method of claim 7 , wherein R 1 is —C(O)heterocyclyl selected from the group consisting of
10. The method of claim 7 , wherein R 1 is —CH 2 CO 2 H or —CH 2 C(O)O(C 1 -C 6 )alkyl.
11. The method of claim 1 , wherein Z is —CH—.
12. The method of claim 11 , wherein R 2 is H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(aryl(C 1 -C 6 )alkyl), —C(O)O(heteroaryl(C 1 -C 6 )alkyl), —C(O)NH 2 , —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl(C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) 2 , —C(O)N(C 1 -C 6 )alkyl)(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl)(aryl(C 1 -C 6 )alkyl), —C(O)NH((C 1 -C 6 )haloalkyl), —C(O)N((C 1 -C 6 )haloalkyl) 2 , aryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl-, or —C(O)heterocyclyl.
13. The method of claim 11 , wherein R 2 is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl.
14. The method of claim 11 , wherein R 2 is —C(O)heterocyclyl selected from the group consisting of
15. The method of claim 1 , wherein:
W is bromo or chloro;
X is a single bond, —CH 2 —, or —C(O)—;
Y is a single bond, —CH—, —N—, —O—, or —S(O) 2 —;
if Y is a single bond, —O—, or —S(O) 2 —, then R 1 is absent;
R 1 is H, methyl, isobutyl, methoxy, acetyl, methoxycarbonyl, methanesulfonyl, p-toluenesulfonyl, methoxycarbonylmethyl, or carboxymethyl;
Z is —CH—, —C(O)—, or —C(CH 3 )—;
if Z is —C(O)—, then R 2 is absent;
R 2 is H, methyl, ethyl, isopropyl, isobutyl, —C(O)NH 2 , —C(O)NHMe, —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 3 , —CO 2 H, —CO 2 CH 2 CH 3 , —OCH 3 , —F, —CH 2 -(p-chlorophenyl), or —CH 2 -cyclohexyl;
R 3 , R 4 , and R 5 are each H; and
R 6 is H or OH.
16. The method of claim 1 , wherein said compound is selected from the group consisting of:
17. The method of claim 16 , wherein the disease, disorder, or condition is selected from the group consisting of allergic diseases, acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, kidney diseases, skin diseases, polycystic ovary syndrome, endometriosis, fibrotic disorders, storage diseases, and cancer.
18. The method of claim 1 , wherein said compound is represented by:
19. The method of claim 18 , wherein the disease, disorder, or condition is selected from the group consisting of allergic diseases, acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, kidney diseases, skin diseases, polycystic ovary syndrome, endometriosis, fibrotic disorders, storage diseases, and cancer.
20. A method for the therapeutic treatment of a disease, disorder, or condition associated with aberrant expression or activity of chitotriosidase, comprising administering to a human in need thereof a therapeutically effective amount of a compound, wherein said compound is represented by formula (I):
wherein:
W is halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy-, or (C 1 -C 3 )alkylthio-;
X is a single bond, —CH 2 —, —CH 2 CH 2 —, —CH═CH—, or —C(O)—;
Y is a single bond, —CH—, —CHCH 2 —, —CH 2 CH—, —C═CH—, —CH═C—, —N—, —O—, —S(O)—, or —S(O) 2 —;
if Y is a single bond, —O—, —S(O)—, or —S(O) 2 —, then R 1 is absent;
R 1 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)aryl(C 1 -C 6 )alkyl, —C(O)heteroaryl(C 1 -C 6 )alkyl, —S(O) 2 (C 1 -C 6 )alkyl, —S(O) 2 aryl, —S(O) 2 heteroaryl, —S(O) 2 aryl(C 1 -C 6 )alkyl, —S(O) 2 heteroaryl(C 1 -C 6 )alkyl, —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(aryl(C 1 -C 6 )alkyl), —C(O)O(heteroaryl(C 1 -C 6 )alkyl), —C(O)NH 2 , —C(O)NHOH, —C(O)NHCN, —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl(C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) 2 , —C(O)N(C 1 -C 6 )alkyl)(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl)(aryl(C 1 -C 6 )alkyl), —C(O)NH((C 1 -C 6 )haloalkyl), —C(O)N((C 1 -C 6 )haloalkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NH(heteroaryl(C 1 -C 6 )alkyl), —S(O) 2 NH(heteroaryl), —S(O) 2 N((C 1 -C 6 )alkyl) 2 , —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —S(O) 2 NHC(O)aryl(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)heteroaryl, —S(O) 2 NHC(O)heteroaryl(C 1 -C 6 )alkyl, —NHS(O) 2 (C 1 -C 6 )alkyl, —NHS(O) 2 aryl, —NHS(O) 2 (C 1 -C 6 )haloalkyl, —NHS(O) 2 aryl(C 1 -C 6 )alkyl, —NHS(O) 2 heteroaryl, —NHS(O) 2 heteroaryl(C 1 -C 6 )alkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)(aryl(C 1 -C 6 )alkyl), —NHC(O)(heteroaryl), —NHC(O)(heteroaryl(C 1 -C 6 )alkyl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NH(aryl), —NHC(O)NH(aryl(C 1 -C 6 )alkyl), —NHC(O)NH(heteroaryl), —NHC(O)NH(heteroaryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 (C 1 -C 6 )alkyl, —C(O)NHS(O) 2 aryl, C(O)NHS(O) 2 ((C 1 -C 6 )haloalkyl), —C(O)NHS(O) 2 (aryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 heteroaryl, —C(O)NHS(O) 2 (heteroaryl(C 1 -C 6 )alkyl), —P(O)(OH) 2 , —((C 1 -C 6 )alkylene)C(O)OH, ((C 1 -C 6 )alkylene)C(O)O(C 1 -C 6 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NC, —CN, —C(S)NH 2 , —NHC(O)NH 2 , (C 1 -C 6 )alkylthio-, (C 1 -C 6 )mercaptoalkyl-, or —C(O)heterocyclyl;
Z is —CH—, —C(O)—, or —C((C 1 -C 3 )alkyl)-;
if Z is —C(O)—, then R 2 is absent,
R 2 is H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —CO 2 H, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(aryl(C 1 -C 6 )alkyl), —C(O)O(heteroaryl(C 1 -C 6 )alkyl), —C(O)NHOH, —C(O)NHCN, —C(O)NH 2 , —C(O)NH((C 1 -C 6 )alkyl), —C(O)N((C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl(C 1 -C 6 )alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl)((C 1 -C 6 )alkyl), —C(O)N(aryl) 2 , —C(O)N(C 1 -C 6 )alkyl)(aryl(C 1 -C 6 )alkyl), —C(O)N(aryl)(aryl(C 1 -C 6 )alkyl), —C(O)NH((C 1 -C 6 )haloalkyl), —C(O)N((C 1 -C 6 )haloalkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 NH((C 1 -C 6 )alkyl), —S(O) 2 NH((C 1 -C 6 )haloalkyl), —S(O) 2 NH(aryl), —S(O) 2 NH(heteroaryl(C 1 -C 6 )alkyl), —S(O) 2 NH(heteroaryl), —S(O) 2 NH(heteroaryl(C 1 -C 6 )alkyl), —S(O) 2 N((C 1 -C 6 )alkyl) 2 , —S(O) 2 NHC(O)(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)(C 1 -C 6 )haloalkyl, —S(O) 2 NHC(O)aryl, —S(O) 2 NHC(O)aryl(C 1 -C 6 )alkyl, —S(O) 2 NHC(O)heteroaryl, —S(O) 2 NHC(O)heteroaryl(C 1 -C 6 )alkyl, —NHS(O) 2 (C 1 -C 6 )alkyl, —NHS(O) 2 aryl, NHS(O) 2 (C 1 -C 6 )haloalkyl, —NHS(O) 2 aryl(C 1 -C 6 )alkyl, —NHS(O) 2 heteroaryl, —NHS(O) 2 heteroaryl(C 1 -C 6 )alkyl, —NHC(O)((C 1 -C 6 )alkyl), —NHC(O)((C 1 -C 6 )haloalkyl), —NHC(O)(aryl), —NHC(O)(aryl(C 1 -C 6 )alkyl), —NHC(O)(heteroaryl), —NHC(O)(heteroaryl(C 1 -C 6 )alkyl), —NHC(O)NH(C 1 -C 6 )alkyl, —NHC(O)NHaryl, —NHC(O)NH(aryl(C 1 -C 6 )alkyl), —NHC(O)NH(heteroaryl), —NHC(O)NH(heteroaryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 (C 1 -C 6 )alkyl, —C(O)NHS(O) 2 aryl, C(O)NHS(O) 2 ((C 1 -C 6 )haloalkyl), —C(O)NHS(O) 2 (aryl(C 1 -C 6 )alkyl), —C(O)NHS(O) 2 heteroaryl, —C(O)NHS(O) 2 (heteroaryl(C 1 -C 6 )alkyl), —P(O)(OH) 2 , aryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl-, —NC, —CN, —C(S)NH 2 , —NHC(O)NH 2 , (C 1 -C 6 )alkylthio-, (C 1 -C 6 )mercaptoalkyl-, or —C(O)heterocyclyl;
R 3 is H, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, (C 1 -C 6 )haloalkyl, —NC, —CN, —C(S)NH 2 , —NHC(O)NH 2 , or —C≡CH;
R 4 is H, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl-, or (C 1 -C 4 )hydroxyalkyl;
R 5 is H, halo, —NO 2 , —CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —OH, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkoxy, —SH, (C 1 -C 3 )alkylthio(C 1 -C 3 )alkyl, —NC, —C(S)NH 2 , —NHC(O)NH 2 , or —C≡CH; and
R 6 is H, halo, —OH, —NH 2 , or —SH; or
R 6 , taken together with the carbon atom bearing it, represents —C(O)—;
wherein:
any occurrence of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylene, heterocyclyl, cycloalkyl, alkoxy, alkylthio, haloalkyl, or hydroxyalkyl is optionally substituted with one or more substituents independently selected from the group consisting of —OH, halo, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —CN, —NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, aryl, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, —C(O)OH, —C(O)O(C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, and —C(O)N((C 1 -C 6 )alkyl) 2 ;
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or polymorph thereof.
21. The method of claim 20 , wherein:
W is bromo or chloro;
X is a single bond, —CH 2 —, or —C(O)—;
Y is a single bond, —CH—, —N—, —O—, or —S(O) 2 —;
if Y is a single bond, —O—, or —S(O) 2 —, then R 1 is absent;
R 1 is H, methyl, isobutyl, methoxy, acetyl, methoxycarbonyl, methanesulfonyl, p-toluenesulfonyl, methoxycarbonylmethyl, or carboxymethyl;
Z is —CH—, —C(O)—, or —C(CH 3 )—;
if Z is —C(O)—, then R 2 is absent;
R 2 is H, methyl, ethyl, isopropyl, isobutyl, —C(O)NH 2 , —C(O)NHMe, —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 3 , —CO 2 H, —CO 2 CH 2 CH 3 , —OCH 3 , —F, —CH 2 -(p-chlorophenyl), or —CH 2 -cyclohexyl;
R 3 , R 4 , and R 5 are each H; and
R 6 is H or OH.
22. The method of claim 20 , wherein said compound is selected from the group consisting of:
23. The method of claim 20 , wherein said compound is represented by: