US2009018147A1PendingUtilityA1
Compounds for modulating TRPV3 function
Est. expiryMay 10, 2027(~0.8 yrs left)· nominal 20-yr term from priority
Inventors:Jayhong A. ChongChristopher FangerGlenn R. LarsenMagdalene M. MoranHoward P. NgAmy RipkaDennis John UnderwoodManfred WeigeleXiaoguang Zhen
A61P 29/00A61P 25/00A61K 31/517A61K 31/519A61P 19/02A61P 17/00
61
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Claims
Abstract
The present application relates to compounds and methods for treating pain and other conditions related to TRPV3.
Claims
exact text as granted — not AI-modified1 . A method for inhibiting a TRPV3 mediated current, comprising contacting a cell with an effective amount of:
A) a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is a 5- or 6-membered heteroaryl;
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
or
B) a compound of Formula II or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is heteroaryl or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein A is not substituted or unsubstituted 2-pyridyl; or
C) a compound of Formula III or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is heteroaryl optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Ar′ is not substituted or unsubstituted 2-pyridyl when L is (CH 2 ) m CH═CH(CH 2 ) n ; or
D) a compound of Formula IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , or (CH 2 ) m C═N(CH 2 ) n ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4; or
E) a compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is an aryl or heteroaryl group;
R 1 is absent or represents one or more substituents;
A is an aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
Ar′ is
s is 0 or 1;
each Y is independently CH, CR 4 , or N;
Z is CH, CR 4 , or N when s is 1 or N, O, or S when s is 0;
R 10 is H, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
R 11 is alkyl;
Ar′ is further optionally substituted with 1-3 R 4 as valence permits;
each R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
L represents a linker having of 1-7 atoms in length, any of which may be optionally substituted by one or more hydrogens or R 5 as valence permits;
each R 3 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
and wherein the compound is not one of the following:
wherein said compound inhibits a TRPV3 mediated current with an IC 50 of 10 micromolar or less.
2 - 3 . (canceled)
4 . A method for treating or preventing a condition involving activation of TRPV3 or for which reduced TRPV3 activity can reduce the severity, comprising administering an effective amount of:
A) a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is a 5- or 6-membered heteroaryl;
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
B) a compound of Formula II or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is heteroaryl or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein A is not substituted or unsubstituted 2-pyridyl; or
C) a compound of Formula III or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is heteroaryl optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Ar′ is not substituted or unsubstituted 2-pyridyl when L is (CH 2 ) m CH═CH(CH 2 ) n ; or
D) a compound of Formula IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , or (CH 2 ) m C═N(CH 2 ) n ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl (e.g., haloalkyl, such as trifluoromethyl), C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4; or
E) a compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is an aryl or heteroaryl group;
R 1 is absent or represents one or more substituents;
A is an aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
Ar′ is
s is 0 or 1;
each Y is independently CH, CR 4 , or N;
Z is CH, CR 4 , or N when s is 1 or N, O, or S when s is 0;
R 10 is H, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
R 11 is alkyl;
Ar′ is further optionally substituted with 1-3 R 4 as valence permits;
each R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
L represents a linker having of 1-7 atoms in length, any of which may be optionally substituted by one or more hydrogens or R 5 as valence permits;
each R 3 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
and wherein the compound is not one of the following:
wherein said compound inhibits TRPV3 with an IC 50 of 10 micromolar or less.
5 . The method of claim 4 , wherein the compound is selected from one of the following:
6 . The method of claim 4 , used to prevent, treat or alleviate symptoms of a disorder or condition selected from acute or chronic pain, touch sensitivity, burns, inflammation, diabetic neuropathy, psoriasis, eczema, dermatitis, post-herpetic neuralgia (shingles), migraine, incontinence, fever, hot flashes, osteoarthritis, rheumatoid arthritis and cough, or is used as a depilatory to promote loss of or inhibit the growth of hair on a patient.
7 . The method of claim 4 , wherein the compound is administered conjointly with one or more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, anti-fungal agent, anti-viral agent, anti-septic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor.
8 . The method of claim 4 , wherein the compound has an IC 50 for TRPV3 inhibition, and when administered at that concentration, the compound does not cause QT interval elongation in the patient.
9 . A method for treating pain, comprising administering an effective amount of:
A) a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is a 5- or 6-membered heteroaryl;
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
B) a compound of Formula II or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is heteroaryl or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein A is not substituted or unsubstituted 2-pyridyl; or
C) a compound of Formula III or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is heteroaryl optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Ar′ is not substituted or unsubstituted 2-pyridyl when L is (CH 2 ) m CH═CH(CH 2 ) n ; or
D) a compound of Formula IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , or (CH 2 ) m C═N(CH 2 ) n ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4; or
E) a compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is an aryl or heteroaryl group;
R 1 is absent or represents one or more substituents;
A is an aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
Ar′ is
s is 0 or 1;
each Y is independently CH, CR 4 , or N;
Z is CH, CR 4 , or N when s is 1 or N, O, or S when s is 0;
R 10 is H, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
R 11 is alkyl;
Ar′ is further optionally substituted with 1-3 R 4 as valence permits;
each R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
L represents a linker having of 1-7 atoms in length, any of which may be optionally substituted by one or more hydrogens or R 5 as valence permits;
each R 3 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
and wherein the compound is not one of the following:
wherein said compound inhibits TRPV3 with an IC 50 of 10 micromolar or less.
10 - 14 . (canceled)
15 . The method of claim 4 , wherein said compound inhibits inward TRPV3-mediated current.
16 . The method of claim 4 , wherein said compound inhibits TRPV3 with an IC 50 at least one order of magnitude lower than its IC 50 for inhibition of at least one of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and HERG.
17 . The method of claim 4 , wherein said compound inhibits TRPV3 with an IC 50 at least two orders of magnitude lower than its IC 50 for inhibition of at least one of TRPV5, TRPV6, NaV 1.2, mitochondrial uniporter and HERG.
18 . The method of claim 4 , wherein said compound inhibits TRPV3 with an IC 50 at least one order of magnitude lower than its IC 50 for inhibition of TRPV1.
19 . The method of claim 4 , wherein said compound inhibits TRPV3 with an IC 50 at least two orders of magnitude lower than its IC 50 for inhibition of TRPV1.
20 . The method of claim 4 , wherein said compound inhibits TRPV3 with an IC 50 at least one order of magnitude more potent than its Ki for the AMPA receptor.
21 . The method of claim 4 , wherein said compound inhibits TRPV3 with an IC 50 of 1 uM or less.
22 . The method of claim 4 , wherein said compound inhibits TRPV3 with an IC 50 of 100 nM or less.
23 . The method of claim 4 , wherein the compound is administered orally.
24 . The method of claim 4 , wherein the compound is a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt.
25 . The method of claim 24 , wherein the compound is characterized by one or more of the following:
Q is a nitrogen-containing heteroaryl; Q is a six-membered nitrogen-containing heteroaryl; Q is pyridazyl; the compound of formula I is represented by a compound of formula (Ia) or (Ib):
wherein A, L, R 1 , and Ar′ are as defined above, and q is 0, 1, 2, or 3;
the compound of formula I is represented by a compound of formula (Ic)
wherein A, L, R 1 , and Ar′ are as defined above, and q is 0, 1, or 2;
Q is a 5-membered heteroaryl;
Q is a 5-membered heteroaryl comprising 1, 2, or 3 nitrogen atoms;
Q is a 5-membered heteroaryl comprising 1 nitrogen atom;
Q is a 5-membered heteroaryl comprising 2 nitrogen atoms;
Q is a 5-membered heteroaryl comprising 3 nitrogen atoms;
A is aryl or heteroaryl;
A is aryl;
A is phenyl;
A is substituted by 1-3 R 3 ;
A is substituted by two R 3 ;
A is
A is heteroaryl;
A is a nitrogen-containing heteroaryl;
A is a 5-membered nitrogen-containing heteroaryl;
A is a 6-membered nitrogen-containing heteroaryl;
A has 1, 2, 3, or 4 nitrogen atoms;
A is pyridyl;
A is pyridazyl;
A is
A is substituted by 1-3 R 3 ;
A is substituted by two R 3 ;
A is
at least one R 3 is alkyl;
each R 3 is independently alkyl;
at least one R 3 is C 1 -C 4 alkyl;
at least one R 3 is haloalkyl;
at least one R 3 is trifluoromethyl;
L is cyclopropyl;
L is (CH 2 ) m NR 2 C(O)(CH 2 ) n or (CH 2 ) m C(O)NR 2 (CH 2 ) n ;
m is 0 or 1, n is 0 or 1, and n and mare not both 1;
L is NR 2 C(O) or C(O)NR 2 ;
R 2 is H, C 1-6 alkyl, or arylalkyl;
R 2 is H;
L is (CH 2 ) m CH═CH(CH 2 ) n ;
L is trans ethenyl;
Ar′ is phenyl;
Ar′ is substituted with 1-3 R 4 ;
Ar′ is substituted with two R 4 ;
Ar′ is
each R 4 is independently hydroxy or alkoxy;
each R 4 is hydroxy;
Ar′ is
and R 4 is alkoxy;
Ar′ is heteroaryl;
Ar′ is a nitrogen-containing heteroaryl;
Ar′ is a 5- or 6-membered nitrogen-containing heteroaryl;
Ar′ has 1, 2, 3, or 4 nitrogen atoms;
Ar′ is a 6-membered nitrogen-containing heteroaryl;
Ar′ is pyridyl;
Ar′ is
optionally substituted with one or more R 4 ;
Ar′ is substituted with 1-3 R 4 ;
Ar′ is substituted with two R 4 ;
Ar′ is
or
each R 4 is independently hydroxyl or alkoxy.
26 . The method of claim 4 , wherein the compound is a compound of formula II or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt.
27 . The method of claim 26 , wherein the compound is characterized by one or more of the following:
A is heteroaryl; A is a nitrogen-containing heteroaryl; A is a 5-membered nitrogen-containing heteroaryl; A is a 6-membered nitrogen-containing heteroaryl; A has 1, 2, 3, or 4 nitrogen atoms; A is pyridyl; A is pyridazyl; A is
A is substituted with 1-3 R 3 ;
A is substituted by two R 3 ;
A is
at least one R 3 is alkyl;
each R 3 is independently alkyl;
at least one R 3 is C 1 -C 4 alkyl;
at least one R 3 is haloalkyl;
at least one R 3 is trifluoromethyl;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ), (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) m , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) m , (CH 2 ) m C═N(CH 2 ), or cyclopropyl;
L is cyclopropyl;
L is (CH 2 ) m NR 2 C(O)(CH 2 ) n or (CH 2 ) m C(O)NR 2 (CH 2 ) n ;
m is 0 or 1, n is 0 or 1, and n and mare not both 1;
L is NR 2 C(O) or C(O)NR 2 ;
R 2 is H, C 1-6 alkyl, or arylalkyl;
R 2 is H;
L is (CH 2 ) m CH═CH(CH 2 ) n ;
L is trans ethenyl;
Ar′ is substituted with 1-3 R 4 ;
Ar′ is substituted with two R 4 ;
Ar′ is phenyl;
Ar′ is
each R 4 is independently hydroxy or alkoxy;
each R 4 is hydroxy;
Ar′ is
and R 4 is alkoxy;
Ar′ is heteroaryl;
Ar′ is a nitrogen-containing heteroaryl;
Ar′ is a 5- or 6-membered nitrogen-containing heteroaryl;
Ar′ is a 6-membered nitrogen-containing heteroaryl;
Ar′ has 1, 2, 3, or 4 nitrogen atoms;
Ar′ is pyridyl;
Ar′ is
optionally substituted with one or more R 4 ;
Ar′ is
or
each R 4 is independently hydroxyl or alkoxy.
28 . The method of claim 4 , wherein the compound is a compound of Formula III or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt.
29 . The method of claim 28 , wherein the compound is characterized by one or more of the following:
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR(CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) m , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) m , (CH 2 ) m C═N(CH 2 ), or cyclopropyl; A is aryl or heteroaryl; A is aryl; A is phenyl; A is substituted by 1-3 R 3 ; A is substituted by two R 3 ; A is
A is heteroaryl;
A is a nitrogen-containing heteroaryl;
A is a 5-membered nitrogen-containing heteroaryl;
A is a 6-membered nitrogen-containing heteroaryl;
A has 1, 2, 3, or 4 nitrogen atoms;
A is pyridyl;
A is pyridazyl;
A is
A is substituted with 1-3 R 3 ;
A is substituted by two R 3 ;
A is
at least one R 3 is alkyl;
each R 3 is independently alkyl
at least one R 3 is C 1 -C 4 alkyl;
at least one R 3 is haloalkyl;
at least one R 3 is trifluoromethyl;
L is cyclopropyl;
L is (CH 2 ) m NR 2 C(O)(CH 2 ) n or (CH 2 ) m C(O)NR 2 (CH 2 ) n ;
m is 0 or 1, n is 0 or 1, and n and m are not both 1;
L is NR 2 C(O) or C(O)NR 2 ;
R 2 is H, C 1-6 alkyl, or arylalkyl;
R 2 is H;
L is (CH 2 ) m CH═CH(CH 2 ) n ;
L is trans ethenyl;
Ar′ is a nitrogen-containing heteroaryl;
Ar′ is a 5- or 6-membered nitrogen-containing heteroaryl;
Ar′ has 1, 2, 3, or 4 nitrogen atoms;
Ar′ is a 6-membered nitrogen-containing heteroaryl;
Ar′ is pyridyl;
Ar′ is
optionally substituted with one or more R 4 ;
Ar′ is substituted with 1-3 R 4 ;
Ar′ is substituted with two R 4 ;
Ar′ is
each R 4 is independently hydroxyl or alkoxy; or
each R 4 is hydroxyl.
30 . The method of claim 4 , wherein the compound is a compound of Formula IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt.
31 . The method of claim 30 , wherein the compound is characterized by one or more of the following:
A is aryl or heteroaryl; A is aryl; A is phenyl; A is substituted by 1-3 R 3 ; A is substituted by two R 3 ; A is
A is heteroaryl;
A is a nitrogen-containing heteroaryl;
A is a 5-membered nitrogen-containing heteroaryl;
A is a 6-membered nitrogen-containing heteroaryl;
A has 1, 2, 3, or 4 nitrogen atoms;
A is pyridyl;
A is pyridazyl;
A is
A is substituted with 1-3 R 3 ;
A is substituted by two R 3 ;
A is
at least one R 3 is alkyl;
each R 3 is independently alkyl;
at least one R 3 is C 1 -C 4 alkyl;
at least one R 3 is haloalkyl;
at least one R 3 is trifluoromethyl;
L is (CH 2 ) m NR 2 C(O)(CH 2 ) n or (CH 2 ) m C(O)NR 2 (CH 2 ) n ;
m is 0 or 1, n is 0 or 1, and n and m are not both 1;
L is NR 2 C(O) or C(O)NR;
R 2 is H, C 1-6 alkyl, or arylalkyl;
R 2 is H;
Ar′ is phenyl;
Ar′ is substituted with 1-3 R 4 ;
Ar′ is substituted with two R 4 ;
Ar′ is;
each R 4 is independently hydroxy or alkoxy;
each R 4 is hydroxy;
Ar′ is
and R 4 is alkoxy;
Ar′ is heteroaryl;
Ar′ is a nitrogen-containing heteroaryl;
Ar′ is a 5- or 6-membered nitrogen-containing heteroaryl;
Ar′ is a 6-membered nitrogen-containing heteroaryl;
Ar′ has 1, 2, 3, or 4 nitrogen atoms;
Ar′ is pyridyl;
Ar′ is
optionally substituted with one or more R 4 ;
Ar′ is substituted with 1-3 R 4 ;
Ar′ is substituted with two R 4 ;
Ar′ is
each R 4 is independently hydroxyl or alkoxy.
32 . The method of claim 4 , wherein the compound is a compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt.
33 . The method of claim 32 , wherein the compound is characterized by one or more of the following:
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 , R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl, each m and n is independently 0, 1, 2, or 3, p is 0, 1, or 2, and q is 0, 1, 2, 3, or 4; R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy; Q is a nitrogen-containing heteroaryl; Q is a six-membered nitrogen-containing heteroaryl; Q is pyridazyl; the compound of formula V is represented by a compound of formula (Va) or (Vb):
wherein A, L, R 1 , and Ar′ are as defined above, and q is 0, 1, 2, or 3;
the compound of formula V is represented by a compound of formula (Vc)
wherein A, L, R 1 , and Ar′ are as defined above, and q is 0, 1, or 2;
Q is a 5-membered heteroaryl;
Q is a 5-membered heteroaryl comprising 1, 2, or 3 nitrogen atoms;
Q is a 5-membered heteroaryl comprising 1 nitrogen atom;
Q is a 5-membered heteroaryl comprising 2 nitrogen atoms;
Q is a 5-membered heteroaryl comprising 3 nitrogen atoms;
Q is phenyl;
A is aryl or heteroaryl;
A is aryl;
A is phenyl;
A is substituted by 1-3 R 3 ;
A is substituted by two R 3 ;
A is
A is heteroaryl;
A is a nitrogen-containing heteroaryl;
A is a 5-membered nitrogen-containing heteroaryl;
A is a 6-membered nitrogen-containing heteroaryl;
A has 1, 2, 3, or 4 nitrogen atoms;
A is pyridyl;
A is pyridazyl;
A is
A is substituted with 1-3 R 3 ;
A is substituted by two R 3 ;
A is
at least one R 3 is alkyl;
each R 3 is independently alkyl;
at least one R 3 is C 1 -C 4 alkyl;
at least one R 3 is haloalkyl;
at least one R 3 is trifluoromethyl;
L is cyclopropyl;
L is (CH 2 ) m NR 2 C(O)(CH 2 ) n or (CH 2 ) m C(O)NR 2 (CH 2 ) n ;
m is 0 or 1, n is 0 or 1, and n and m are not both 1;
L is NR 2 C(O) or C(O)NR 2 ;
R 2 is H, C 1-6 alkyl, or arylalkyl;
R 2 is H;
L is (CH 2 ) m CH═CH(CH 2 ) n ;
L is trans ethenyl;
Ar′ is
Ar′ is
Ar′ is heteroaryl;
Ar′ is a nitrogen-containing heteroaryl;
Ar′ is a 5- or 6-membered nitrogen-containing heteroaryl;
Ar′ is a 6-membered nitrogen-containing heteroaryl;
Ar′ is pyridyl; or
Ar′ is
34 . A pharmaceutical preparation suitable for use in a human patient comprising an effective amount of a compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt, and one or more pharmaceutically acceptable excipients:
wherein
Q is an aryl or heteroaryl group;
R 1 is absent or represents one or more substituents;
A is an aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
Ar′ is
s is 0 or 1;
each Y is independently CH, CR 4 , or N;
Z is CH, CR 4 , or N when s is 1 or N, O, or S when s is 0;
R 10 is H, a pharmaceutically acceptable counterion, or a physiologically labile moiety;
R 11 is alkyl;
Ar′ is further optionally substituted with 1-3 R 4 as valence permits;
each R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
L represents a linker of 1-7 atoms in length, any of which may be optionally substituted by one or more hydrogens or R 5 as valence permits;
each R 3 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
and wherein the compound is not one of the following:
35 . The pharmaceutical preparation of claim 34 , wherein the compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt is characterized by one or more of the following:
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 , R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl, each m and n is independently 0, 1, 2, or 3, p is 0, 1, or 2, and q is 0, 1, 2, 3, or 4; R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy; Q is a nitrogen-containing heteroaryl; Q is a six-membered nitrogen-containing heteroaryl; Q is pyridazyl; the compound of formula V is represented by a compound of formula (Va) or (Vb):
wherein A, L, R 1 , and Ar′ are as defined above, and q is 0, 1, 2, or 3;
the compound of formula V is represented by a compound of formula (Vc)
wherein A, L, R 1 , and Ar′ are as defined above, and q is 0, 1, or 2;
Q is a 5-membered heteroaryl;
Q is a 5-membered heteroaryl comprising 1, 2, or 3 nitrogen atoms;
Q is a 5-membered heteroaryl comprising 1 nitrogen atom;
Q is a 5-membered heteroaryl comprising 2 nitrogen atoms;
Q is a 5-membered heteroaryl comprising 3 nitrogen atoms;
Q is phenyl;
A is aryl or heteroaryl;
A is aryl;
A is phenyl;
A is substituted by 1-3 R 3 ;
A is substituted by two R 3 ;
A is
A is heteroaryl;
A is a nitrogen-containing heteroaryl;
A is a 5-membered nitrogen-containing heteroaryl;
A is a 6-membered nitrogen-containing heteroaryl;
A has 1, 2, 3, or 4 nitrogen atoms;
A is pyridyl;
A is pyridazyl;
A is
A is substituted with 1-3 R 3 ;
A is substituted by two R 3 ;
A is
at least one R 3 is alkyl;
each R 3 is independently alkyl;
at least one R 3 is C 1 -C 4 alkyl;
at least one R 3 is haloalkyl;
at least one R 3 is trifluoromethyl;
L is cyclopropyl;
L is (CH 2 ) m NR 2 C(O)(CH 2 ) n or (CH 2 ) m C(O)NR 2 (CH 2 ) n ;
m is 0 or 1, n is 0 or 1, and n and mare not both 1;
L is NR 2 C(O) or C(O)NR 2 ;
R 2 is H, C 1-6 alkyl, or arylalkyl;
R 2 is H;
L is (CH 2 ) m CH═CH(CH 2 ) n ;
L is trans ethenyl;
Ar′ is
Ar′ is
Ar′ is heteroaryl;
Ar′ is a nitrogen-containing heteroaryl;
Ar′ is a 5- or 6-membered nitrogen-containing heteroaryl;
Ar′ is a 6-membered nitrogen-containing heteroaryl;
Ar′ is pyridyl; or
Ar′ is
36 . (canceled)
37 . A method of inhibiting TRPV3 in a patient, comprising administering an effective amount of:
A) a compound of Formula I or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is a 5- or 6-membered heteroaryl;
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
B) a compound of Formula II or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is heteroaryl or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) n , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein A is not substituted or unsubstituted 2-pyridyl; or
C) a compound of Formula III or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m NR 2 (CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m CH═CH(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , (CH 2 ) m C═N(CH 2 ) n , —N═N—, —C(O)N═N—, —N═N—C(O)—, or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 R 5 ;
Ar′ is heteroaryl optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4;
wherein Ar′ is not substituted or unsubstituted 2-pyridyl when L is (CH 2 ) m CH═CH(CH 2 ) n ; or
D) a compound of Formula IV or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
A is aryl, heteroaryl, arylalkyl, heteroarylalkyl, optionally substituted by 1-5 R 3 ;
L is (CH 2 ) m O(CH 2 ) n , (CH 2 ) m S(O) p (CH 2 ) n , (CH 2 ) m C(O)(CH 2 ) n , (CH 2 ) m NR 2 C(O)(CH 2 ) n , (CH 2 ) m C(O)NR 2 (CH 2 ) n , (CH 2 ) m NR 2 C(O)NR 2 (CH 2 ) n , (CH 2 ) m O—N═C(CH 2 ) n , (CH 2 ) m C═N—O(CH 2 ) n , (CH 2 ) m N═C(CH 2 ) n , or (CH 2 ) m C═N(CH 2 ) n ;
Ar′ is aryl or heteroaryl, optionally substituted by 1-5 R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
R 2 is H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, arylalkyl, cyano, hydroxyl, alkoxyl, hydroxyalkyl, or alkoxyalkyl;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 R 6 as valence permits;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4; or
E) a compound of Formula V or a salt thereof, or a solvate, hydrate, oxidative metabolite or prodrug of the compound or its salt:
wherein
Q is an aryl or heteroaryl group;
R 1 is absent or represents one or more substituents;
A is an aryl, heteroaryl, arylalkyl, or heteroarylalkyl, optionally substituted by 1-5 R 3 ;
Ar′ is
s is 0 or 1;
each Y is independently CH, CR 4 , or N;
Z is CH, CR 4 , or N when s is 1 or N, O, or S when s is 0;
R 10 is H, a pharmaceutically acceptable counterion or a physiologically labile moiety;
R 11 is alkyl;
Ar′ is further optionally substituted with 1-3 R 4 as valence permits;
each R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
L represents a linker having of 1-7 atoms in length, any of which may be optionally substituted by one or more hydrogens or R 5 as valence permits;
each R 3 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent substituents together represent —NHSO 2 NH— or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, or azido, or two adjacent R 4 groups are C 1 -C 4 alkylenedioxy;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
wherein Q is not substituted or unsubstituted thienyl or pyrazinyl, or is not selected to result in the following formulas
and wherein the compound is not one of the following:
wherein said compound inhibits TRPV3 with an IC 50 of 10 micromolar or less.Join the waitlist — get patent alerts
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