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 compound 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—, —C((C 1 -C 3 )alkyl) 2 -, or —C(O)—;
Y is a single bond, —CH—, —CHCH 2 —, —CH 2 CH—, —C═CH—, —CH═C—, —N—, —O—, —OCH 2 —, —S(O)—, or —S(O) 2 —;
if Y is a single bond, —O—, —OCH 2 —, —S(O)—, or —S(O) 2 —, then R 1 is absent;
R 1 is H, OH, (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≡CH,(C 1 -C 6 )alkylthio-, (C 1 -C 6 )mercaptoalkyl-, or —C(O)heterocyclyl;
Z is —CH—, —C(O)—, —C((C 1 -C 3 )alkyl)-, or —C(═CH 2 )—;
if Z is —C(O)—, then R 2 is absent,
R 2 is H, OH, 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≡CH, (C 1 -C 6 )alkylthio-, (C 1 -C 6 )mercaptoalkyl-, or —C(O)heterocyclyl;
or R 1 and R 2 , taken together with the intervening atoms, form a carbocyclic or heterocyclic ring;
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 compound of claim 1 , 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≡CH,(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≡CH, (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 sub stituents 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 .
3. The compound of claim 1 , wherein W is fluoro, chloro, bromo, methyl, or methoxy.
4. The compound of claim 1 , wherein R 6 is H or —OH.
5. The compound of claim 1 , wherein X is a single bond, —CH 2 —, or —C(O)—.
6. The compound of claim 1 , wherein Y is a single bond, —CH—, —N—, —O—, or —S(O) 2 —.
7. The compound of claim 1 , wherein Y is —CH— or —N—.
8. The compound of claim 7 , wherein R 1 is H or (C 1 -C 6 )alkyl.
9. The compound of claim 7 , wherein R 1 is —C(O)heterocyclyl selected from the group consisting
10. The compound 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 compound of claim 1 , wherein Z is —CH—.
12. The compound 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 compound 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 compound of claim 11 , wherein R 2 is —C(O)heterocyclyl selected from the group consisting
15. The compound of claim 1 represented by formula (I′):
16. The compound 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.
17. A compound represented by formula (II),
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—, —C((C 1 -C 3 )alkyl) 2 -, —C(O)—, —CH 2 O—, —CH 2 NH—, or —CH 2 N((C 1 -C 3 )alkyl)-, wherein when X is —CH 2 O—, —CH 2 NH—, or —CH 2 N((C 1 -C 3 )alkyl)-, then the O or N atom is covalently bonded to Ring A;
Ring A represents an optionally substituted aryl or heteroaryl ring;
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 sub stituents 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.
18. The compound of claim 17 , wherein W is fluoro, chloro, bromo, methyl, or methoxy.
19. The compound of claim 17 , wherein X is —CH 2 O—, —CH 2 NH—, or —CH 2 N((C 1 -C 3 )alkyl)-.
20. The compound of claim 17 , wherein Ring A represents a heteroaryl ring.
21. The compound of claim 17 , wherein Ring A represents an optionally substituted phenyl ring.
22. The compound of claim 1 selected from the group consisting of the following structural formulae:
23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 ; and a pharmaceutically acceptable carrier.
24. 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 subject in need thereof a therapeutically effective amount of at least one compound according to claim 1 .
25. A method for the therapeutic treatment of a disease, disorder, or condition associated with aberrant expression or activity of chitotriosidase, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound according to claim 1 .
26. The method of claim 24 , 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.
27. The compound of claim 1 of the following structural formulae: