US2009036454A1PendingUtilityA1
Compounds and Uses Thereof
Est. expiryDec 20, 2025(expired)· nominal 20-yr term from priority
A61P 9/00A61P 9/06A61P 43/00A61P 9/10A61P 9/12A61P 25/22A61P 25/18A61P 25/06A61P 25/14A61P 25/04A61P 25/28A61P 25/08A61P 25/16A61P 25/30A61P 25/24A61P 25/00A61P 25/36C07D 405/10C07D 409/04C07D 237/28C07D 401/10C07D 403/04C07D 405/14A61P 21/04C07D 403/10C07D 401/14C07D 401/04A61P 21/02C07D 405/12A61K 31/497
56
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
This invention relates to novel compounds having the structural formula I below: and their pharmaceutically acceptable salts, tautomers or in vivo-hydrolysable precursors, compositions and methods of use thereof. These novel compounds provide a treatment or prophylaxis of anxiety disorders, cognitive disorders, and/or mood disorders.
Claims
exact text as granted — not AI-modified1 . A compound of Formula J:
or a pharmaceutically acceptable salt, tautomer, atropisomer, or in vivo-hydrolysable precursor thereof, wherein:
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 R 7 ;
R 2 is H, C(═O)R b , C(═O)NR c R d , C(═O)OR a , S(═O) 2 R b , C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 8 ;
R 3 , R 4 and R 5 are each, independently, H, halo, Si(C 1-10 alkyl) 3 , CN, NO 2 , OR a , SR a , OC(═O)R a , OC(═O)OR b , OC(═O)NR c R d , C(═O)R a , C(═O)OR b , C(═O)NR c R d , NR c R d , NR c C(═O)R a , NR c C(═O)OR b , NR c S(═O) 2 R b , S(═O)R a , S(═O)NR c R d , S(═O) 2 R a , S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R 9 ;
R 6 is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1,2,3,4 or 5A 1 ;
R 7 , R 8 and R 9 are each, independently, halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
A 1 is halo, CN, NO 2 , OR a , SR a , C(═O)R b , C(═O)NR c R d , C(═O)OR a , OC(═O)R b , OC(═O)NR c R d , NR c R d , NR c C(═O)R d , NR c C(═O)OR a , NR c S(═O)R b , NR c S(═O) 2 R b , S(═O)R b , S(═O)NR c R d , S(═O) 2 R b , S(═O) 2 NR c R d , C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, aryl, cycloalkyl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R c′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O)R b′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
R a and R a′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R b and R b′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R c and R d are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c C and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
R c′ and R d′ are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
with the proviso that when R 2 , R 3 , R 4 and R 5 are each H, then R 6 is other than unsubstituted phenyl or unsubstituted cycloalkyl.
2 . A compound of claim 1 wherein R 1 is C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 R 7 .
3 . A compound of claim 1 wherein R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, C 3-5 heterocycloalkyl, or C 3-5 heterocycloalkyl-C 1-3 alkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, and C 2-8 dialkylamino.
4 . A compound of claim 1 wherein R 1 is C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, SH, —S-(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl) and S(═O) 2 NH(arylalkyl).
5 . A compound of claim 1 wherein R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, SH, —S-(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl) and S(═O) 2 NH(arylalkyl).
6 . A compound of claim 1 wherein R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)—(C 1-4 alkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl) and S(═O) 2 NH(arylalkyl).
7 . A compound of claim 1 wherein R 1 is C 1-6 alkyl or C 3-6 cycloalkyl.
8 . A compound of claim 1 wherein R 1 is C 1-6 alkyl or C 1-6 haloalkyl.
9 . A compound of claim 1 wherein R 1 is ethyl, n-propyl, cyclopropyl or cyclobutyl.
10 . A compound of claim 1 wherein R 1 is n-propyl.
11 . A compound of claim 1 wherein R 2 is H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, SH, —S-(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O—(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl) and S(═O) 2 NH(arylalkyl).
12 . A compound of claim 1 wherein R 2 is H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, SH, —S-(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl) and S(═O) 2 NH(arylalkyl).
13 . A compound of claim 1 wherein R 2 is H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl.
14 . A compound of claim 1 wherein R 2 is H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 or C 1-6 alkyl.
15 . A compound of claim 1 wherein R 2 is H, C(═O)—(C 1-4 alkyl), C(═O)-(aryl-C 1-3 alkyl), C(═O)O-(C 1-4 alkyl), C(═O)O-(aryl-C 1-3 alkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , or C 1-3 alkyl.
16 . A compound of claim 1 wherein R 2 is H.
17 . A compound of claim 1 wherein R 3 , R 4 and R 5 are each, independently, H, halo, C 1-3 alkyl, C 1-3 alkoxy, CN, NO 2 , OH, halogenated C 1-3 alkyl, or halogenated C 1-3 alkoxy.
18 . A compound of claim 1 wherein R 3 , R 4 and R 5 are each, independently, H, halo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, SH, —S-(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl), S(═O) 2 NH(arylalkyl), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, SH, —S-(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl) and S(═O) 2 NH(arylalkyl).
19 . A compound of claim 1 wherein R 3 , R 4 and R 5 are each, independently, H, halo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl) and S(═O) 2 NH(arylalkyl).
20 . A compound of claim 1 wherein R 3 , R 4 and R 5 are each, independently, H, C 1-4 alkoxy, halo, CN, C 1-6 alkyl or C 1-6 haloalkyl.
21 . A compound of claim 1 wherein R 3 , R 4 and R 5 are each, independently, H, C 1-4 alkoxy, halo, CN, or C 1-3 haloalkyl.
22 . A compound of claim 1 wherein R 3 , R 4 and R 5 are each, independently, H, C 1-4 alkoxy, CN, or halo.
23 . A compound of claim 1 wherein R 6 is phenyl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 substituents selected from halo, C 1-4 alkoxy, C 1-4 alkyl, halogenate C 1-4 alkyl, —OH, amino, C 1-4 alkylamino, C 2-8 dialkylamino and CN.
24 . A compound of claim 1 wherein R 6 is aryl optionally substituted by 1, 2, 3, 4 or 5 A 1 .
25 . A compound of claim 1 wherein R 6 is aryl substituted by 1, 2, 3, 4 or 5 A 1 .
26 . A compound of claim 1 wherein R 6 is heteroaryl optionally substituted by 1, 2, 3, 4 or 5 A 1 .
27 . A compound of claim 1 wherein R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents selected from halo, C 1-4 alkoxy, C 1-4 alkyl, halogenate C 1-4 alkyl, —OH, amino, C 1-4 alkylamino, C 2-8 dialkylamino and CN.
28 . A compound of claim 1 wherein R 6 is phenyl, 2-naphthyl, 3-pyridyl, 4-pyridyl, pyrimidin-5-yl, pyrazin-2-yl, pyrazol-3-yl, pyrazol-4-yl, 3-quinolyl, 6-quinolyl, or indol-5-yl, each optionally substituted by 1, 2, 3, 4 or 5 A 1 .
29 . A compound of claim 1 wherein:
R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each optionally substituted by 1, 2, 3, 4 or 5 halo, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, NR c R d , SH, —S—(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)NR c R d , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl), S(═O) 2 NH(arylalkyl), S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, R c′ R d′ , SH, —S-(C 1-4 alkyl), C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)R c′ R d′ , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl), S(═O) 2 NH(arylalkyl) and S(═O) 2 NR c′ R d′ ; R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and R c′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
30 . A compound of claim 1 wherein:
R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each optionally substituted by 1, 2, 3, 4 or 5 halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, NR c R d , C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)NR c R d , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl), S(═O) 2 NH(arylalkyl), S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; and R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
31 . A compound of claim 1 wherein:
R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each optionally substituted by 1, 2 or 3 halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, NR c R d , C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)NR c R d , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), OC(═O)H, OC(═O)—(C 1-4 alkyl), OC(═O)-(arylalkyl), OC(═O)NH 2 , OC(═O)NH(C 1-4 alkyl), OC(═O)NH-(arylalkyl), OC(═O)N(C 1-4 alkyl) 2 , NHC(═O)—(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHC(═O)O-(C 1-4 alkyl), NHC(═O)O-(arylalkyl), NHS(═O) 2 —(C 1-4 alkyl), NHS(═O) 2 -(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl), S(═O) 2 NH(arylalkyl), S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; and R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
32 . A compound of claim 1 wherein:
R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each optionally substituted by 1, 2 or 3 halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, NR c R d , C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)NR c R d , C(═O)OH, C(═O)O—(C 1-4 alkyl), C(═O)O-(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl), S(═O) 2 NH(arylalkyl), S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; and R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
33 . A compound of claim 1 wherein:
R 6 is phenyl substituted by 1, 2 or 3 substituents selected from halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, and C 1-6 haloalkyl.
34 . A compound of claim 1 wherein:
R 6 is naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each optionally substituted by 1, 2 or 3 halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, NR c R d , C(═O)H, C(═O)—(C 1-4 alkyl), C(═O)-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 , C(═O)NR c R d , C(═O)OH, C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), S(═O) 2 —(C 1-4 alkyl), S(═O) 2 -(arylalkyl), S(═O) 2 NH(C 1-4 alkyl), S(═O) 2 NH(arylalkyl), S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; and R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
35 . A compound of claim 1 wherein the compound has formula II
wherein:
R 1 is C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl;
R 2 is H, C(═O)—(C 1-4 alkyl), C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl), C(═O)NH 2 , C(═O)NH(C 1-4 alkyl), C(═O)N(C 1-4 alkyl) 2 or C 1-6 alkyl;
R 5 is H, C 1-4 alkoxy, halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each optionally substituted by 1, 2 or 3 substituents selected from halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, and C 1-6 haloalkyl.
36 . A compound of claim 35 wherein R 1 is ethyl, n-propyl, cyclopropyl or cyclobutyl.
37 . A compound of claim 35 wherein R 1 is n-propyl.
38 . A compound of claim 35 wherein R 2 is H, C(═O)—(C 1-4 alkyl), C(═O)O-(C 1-4 alkyl), C(═O)O-(arylalkyl) or C 1-6 alkyl.
39 . A compound of claim 35 wherein R 2 is H.
40 . A compound of claim 35 wherein R 5 is H, C 1-4 alkoxy, CN or halo.
41 . A compound of claim 35 wherein:
R 6 is phenyl substituted by 1, 2 or 3 substituents selected from halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, and C 1-6 haloalkyl.
42 . A compound of claim 35 wherein R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each substituted by 1, 2 or 3 substituents selected from halo, C 1-4 alkoxy and C 1-4 alkyl.
43 . A compound of claim 35 wherein R 6 is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl or indolyl, each substituted by 2 substituents selected from halo, C 1-4 alkoxy and C 1-4 alkyl.
44 . A compound of claim 41 , wherein R 1 is n-propyl and R 2 is H.
45 . A compound selected from:
4-amino-7-fluoro-8-phenyl-N-propyl-cinnoline-3-carboxamide;
4-amino-7-chloro-8-phenyl-N-propyl-cinnoline-3-carboxamide;
4-amino-7-methoxy-8-phenyl-N-propyl-cinnoline-3-carboxamide;
4-amino-7-chloro-8-(2,5-dimethylphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(5-methoxy-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-methoxypyrimidin-5-yl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3-fluoro-2-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-[4-methoxy-2-(trifluoromethyl)phenyl]-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,5-difluoro-4-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(5-fluoro-6-methoxy-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(5-chloro-6-methoxy-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,5-dichlorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,5-difluorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(5-azetidin-1-ylcarbonyl-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,3-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-dimethylaminophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3-methoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,4-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,5-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,3-difluorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,3-dichlorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(6-quinolyl)cinnoline-3-carboxamide;
4-amino-N-propyl-8-(3-quinolyl)cinnoline-3-carboxamide;
4-amino-8-(2-naphthyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(1H-indol-5-yl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-methoxy-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3-dimethylaminophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(3,4,5-trimethoxyphenyl)-cinnoline-3-carboxamide;
4-amino-8-(2,4-difluorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,4-difluorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(2,3,4-trimethoxyphenyl)-cinnoline-3-carboxamide;
4-amino-8-(2-methoxy-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,6-dimethoxy-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethylphenyl)-N-propyl-cinnoline-3-carboxamide;
3-[4-amino-3-(propylcarbamoyl)cinnolin-8-yl]benzoic acid;
4-amino-8-(3-azetidin-1-ylcarbonylphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-pyrazin-2-yl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(3-pyridyl)cinnoline-3-carboxamide;
4-amino-8-(3-methylsulfonylphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3-cyanophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(2-pyridyl)cinnoline-3-carboxamide;
4-amino-8-[3,5-bis(trifluoromethyl)phenyl]-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(1H-pyrazol-4-yl)cinnoline-3-carboxamide;
4-amino-8-[2-chloro-5-(trifluoromethyl)phenyl]-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-methoxy-5-methyl-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-[2-(trifluoromethyl)phenyl]-cinnoline-3-carboxamide;
4-amino-8-(5-chloro-2-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(4-pyridyl)cinnoline-3-carboxamide;
4-amino-8-(2,5-dichlorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,5-difluorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(1-methyl-1H-pyrazol-4-yl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-3-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethyl-2H-pyrazol-3-yl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-[2-fluoro-5-(trifluoromethyl)phenyl]-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-5-methyl-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-4-methyl-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(5-fluoro-2-methyl-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-fluoro-2-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3-fluoro-4-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-5-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(5-fluoro-2-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-methoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-fluorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-[4-(trifluoromethoxy)phenyl]-cinnoline-3-carboxamide;
4-amino-N-propyl-8-[3-(trifluoromethoxy)phenyl]-cinnoline-3-carboxamide;
4-amino-8-(6-methoxy-3-pyridyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-methoxy-3,5-dimethyl-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-methoxy-3-methyl-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-4-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(6-methylpyridin-3-yl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(4-methylpyridin-3-yl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(5-methoxy-2-methylphenyl)-N-propylcinnoline-3-carboxamide;
4-Amino-8-(2,4-dimethoxyphenyl)-7-fluoro-N-propylcinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-7-fluoro-N-propylcinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-7-fluoro-N-propylcinnoline-3-carboxamide;
4-amino-N-ethyl-8-(4-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-butyl-8-(2,5-dimethoxyphenyl)cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-ethylcinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-methylcinnoline-3-carboxamide;
4-amino-N-butyl-8-(2,4-dimethoxypyrimidin-5-yl)cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-ethylcinnoline-3-carboxamide;
4-Amino-8-(2,5-dimethoxy-phenyl)-cinnoline-3-carboxylic acid allylamide;
4-amino-N-(cyclopropylmethyl)-8-phenyl-cinnoline-3-carboxamide;
4-amino-8-(m-tolyl)-N-propyl-cinnoline-3-carboxamide;
4-Amino-8-(2-fluoro-6-methylpyridin-3-yl)-cinnoline-3-carboxylic acid propylamide;
4-Amino-7-fluoro-8-(5-fluoro-2-methoxyphenyl)-cinnoline-3-carboxylic acid propylamide;
4-Amino-8-(2-chloro-5-methoxyphenyl)-7-fluoro-cinnoline-3-carboxylic acid propylamide;
4-amino-N-cyclopropyl-8-(2,6-dimethoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2-methoxy-5-methyl-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2,4-dimethoxyphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2,4-dimethoxypyrimidin-5-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2,5-dimethoxyphenyl)cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(2-fluoro-6-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-7-fluoro-8-(2-fluoro-6-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-7-cyano-8-(2,4-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2-fluoro-6-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2-fluoro-6-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-8-(2-chloro-6-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-7-fluoro-8-(2-fluoro-3-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-7-fluoro-8-(3-fluoro-4-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,5-difluoro-2-methoxy-phenyl)-7-fluoro-N-propyl-cinnoline-3-carboxamide;
4-amino-7-fluoro-8-(4-fluoro-2-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-7-fluoro-8-(2-fluoro-4-methoxy-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-chlorophenyl)-7-fluoro-N-propyl-cinnoline-3-carboxamide;
4-amino-7-fluoro-8-(5-fluoro-2-methyl-phenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,3-dimethylphenyl)-7-fluoro-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-(3,3 ,3-trifluoropropyl)cinnoline-3-carboxamide;
4-amino-8-(2,5-difluorophenyl)-7-fluoro-N-propyl-cinnoline-3-carboxamide;
and a pharmaceutically acceptable salt thereof.
46 . A compound selected from:
4-amino-8-(3,5-dimethyl-1H-pyrazol-4-yl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,5-difluoro-2-methoxyphenyl)-N-propylcinnoline-3-carboxamide;
4-amino-8-[5-(azetidin-1-ylcarbonyl)-2-methoxyphenyl]-N-propylcinnoline-3-carboxamide;
4-amino-8-(6-methoxy-2-methylpyridin-3-yl)-N-propylcinnoline-3-carboxamide;
4-amino-N-propyl-8-(1,3,5-trimethyl-1H-pyrazol-4-yl)cinnoline-3-carboxamide;
4-amino-N-propyl-8-(2,4,6-trifluoro-3-methoxyphenyl)cinnoline-3-carboxamide;
4-amino-8-(2-fluoro-5-methylpyridin-3-yl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(1,3-dimethyl-1H-pyrazol-5-yl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(2-fluoro-4,6-dimethoxyphenyl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(3,5-difluoro-2-methoxyphenyl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(4,5-difluoro-2-methoxyphenyl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(1,3-benzodioxol-4-yl)-N-propylcinnoline-3-carboxamide;
4-amino-8-[5-(azetidin-1-ylcarbonyl)-2-methylphenyl]-N-propylcinnoline-3-carboxamide;
4-amino-8-(6-methoxy-4-methylpyridin-3-yl)-N-propylcinnoline-3-carboxamide;
4-amino-7-chloro-8-(4-methoxypyridin-3-yl)-N-propylcinnoline-3-carboxamide;
4-amino-7-fluoro-8-(4-methoxypyridin-3-yl)-N-propylcinnoline-3-carboxamide;
4-amino-7-chloro-8-(2-methoxy-5-methylphenyl)-N-propylcinnoline-3-carboxamide;
4-amino-7-fluoro-8-(2-methoxy-5-methylphenyl)-N-propylcinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-7-chloro-N-propylcinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-7-chloro-N-propylcinnoline-3-carboxamide;
4-amino-N-butyl-8-(4-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-8-(4-methoxypyridin-3-yl)-N-methylcinnoline-3-carboxamide;
4-amino-N-butyl-8-(2-methoxy-5-methylphenyl)cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(2-methoxy-5-methylphenyl)cinnoline-3-carboxamide;
4-amino-8-(2-methoxy-5-methylphenyl)-N-methylcinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-methylcinnoline-3-carboxamide;
4-amino-8-(4-methoxypyridin-3-yl)-N-(tetrahydrofuran-2-ylmethyl)cinnoline-3-carboxamide;
4-amino-N-isobutyl-8-(4-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-(2-hydroxypropyl)-8-(4-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-8-(2-methoxy-5-methylphenyl)-N-(tetrahydrofuran-2-ylmethyl)cinnoline-3-carboxamide;
4-amino-N-isobutyl-8-(2-methoxy-5-methylphenyl)cinnoline-3-carboxamide;
4-amino-N-(2-hydroxypropyl)-8-(2-methoxy-5-methylphenyl)cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-(tetrahydrofuran-2-ylmethyl)cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-isobutylcinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-(2-hydroxypropyl)cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-(tetrahydrofuran-2-ylmethyl)cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-isobutylcinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-(2-hydroxypropyl)cinnoline-3-carboxamide;
and a pharmaceutically acceptable salt thereof
47 . A compound selected from:
4-amino-8-(2,3-dimethylphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,5-dimethylphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethylphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(3,4-dimethylphenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(p-tolyl)cinnoline-3-carboxamide;
4-amino-8-(3-chlorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(4-chlorophenyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-8-(o-tolyl)-N-propyl-cinnoline-3-carboxamide;
4-amino-N-propyl-8-(3-thienyl)cinnoline-3-carboxamide;
4-amino-8-(2,6-dimethylphenyl)-N-propyl-cinnoline-3-carboxamide;
and a pharmaceutically acceptable salt thereof.
48 . (4-amino-8-(2,5-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide) or a pharmaceutically acceptable salt thereof
49 . A compound selected from:
4-amino-N-cyclobutyl-7-fluoro-8-(2-methoxy-5-methyl-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(5-fluoro-2-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(2-fluoro-6-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(2-fluoro-3-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,4-dimethoxyphenyl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(4-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,4-dimethoxypyrimidin-5-yl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,6-dimethoxypyridin-3-yl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(6-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(2-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(3,5-dimethylphenyl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,5-difluorophenyl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(3-methylphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,3-dimethoxyphenyl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-7-fluoro-8-(2-methoxyphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2-methoxy-5-methyl-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(5-fluoro-2-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2-fluoro-3-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(4-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,4-dimethoxypyrimidin-5-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,6-dimethoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(6-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(3,5-dimethylphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,5-difluorophenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(3-methylphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,3-dimethoxyphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2-methoxyphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(4-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,3,4-trimethoxyphenyl)cinnoline-3-carboxamide;
4-amino-8-(4-chlorophenyl)-N-cyclobutyl-cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(3,4-dimethoxyphenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2-fluoro-6-methyl-pyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(5-fluoro-6-methoxy-pyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(2-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(4-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(4-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2,6-dimethoxypyridin-3-yl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(6-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2,4-dimethoxypyrimidin-5-yl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2,5-dimethoxyphenyl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(5-fluoro-2-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(2-fluoro-6-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(2-methoxy-5-methyl-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2,4-dimethoxyphenyl)-7-fluoro-cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxyphenyl)-N-ethyl-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(2-fluoro-3-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(2-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(6-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(5-fluoro-6-methoxy-pyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(5-fluoro-2-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(4-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2-methoxy-5-methyl-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclobutyl-8-(2,4-dimethoxyphenyl)cinnoline-3-carboxamide;
4-amino-8-(2,6-dimethoxypyridin-3-yl)-N-ethyl-cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(5-fluoro-6-methoxy-pyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(2-fluoro-3-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-8-(6-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(5-fluoro-2-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxyphenyl)-N-ethyl-cinnoline-3-carboxamide;
4-amino-N-cyclopropyl-7-fluoro-8-(2-fluoro-3-methoxyphenyl)cinnoline-3-carboxamide;
4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-ethyl-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-ethyl-8-(4-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-ethyl-7-fluoro-8-(2-fluoro-6-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-8-(2,6-dimethoxypyridin-3-yl)-N-ethyl-7-fluoro-cinnoline-3-carboxamide;
4-amino-N-ethyl-7-fluoro-8-(5-fluoro-2-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-N-ethyl-7-fluoro-8-(5-fluoro-6-methoxy-pyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-ethyl-7-fluoro-8-(6-methylpyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-ethyl-7-fluoro-8-(2-methoxypyridin-3-yl)cinnoline-3-carboxamide;
4-amino-N-ethyl-7-fluoro-8-(2-fluoro-3-methoxy-phenyl)cinnoline-3-carboxamide;
4-amino-8-(2,5-dimethoxyphenyl)-N-ethyl-7-fluoro-cinnoline-3-carboxamide;
and a pharmaceutically acceptable salt thereof.
50 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
51 . A pharmaceutical composition comprising a compound of claim 48 .
52 . A method of treating or preventing an anxiety disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 .
53 . The method of claim 52 wherein the anxiety disorder is panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, or generalized anxiety disorder due to a general medical condition.
54 . The method of claim 52 wherein the mammal is a human.
55 . A method of treating or preventing an anxiety disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.
56 . A method of treating or preventing a cognitive disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 .
57 . The method of claim 56 wherein the cognitive disorder is Alzheimer's disease, dementia, dementia due to Alzheimer's disease, or dementia due to Parkinson's disease.
58 . The method of claim 56 wherein the mammal is a human.
59 . A method of treating or preventing a cognitive disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.
60 . A method of treating or preventing a mood disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claim 1 .
61 . The method of claim 60 wherein the mood disorder is a depressive disorder.
62 . The method of claim 61 wherein the depressive disorder is major depressive disorder, dysthymic disorder, bipolar depression and/or bipolar mania, bipolar I with or without manic, depressive or mixed episodes, bipolar II, cyclothymic disorder, mood disorder due to a general medical condition, manic episodes associated with bipolar disorder, or mixed episodes associated with bipolar disorder.
63 . The method of claim 60 wherein the mammal is a human.
64 . A method of treating or preventing a mood disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 and at least one cognitive enhancing agent, memory enhancing agent, or choline esterase inhibitor.
65 . A method of modulating activity of a GABAA receptor comprising contacting said GABAA receptor with a compound of claim 1 .
66 . A method of claim 65 , wherein said GABAA receptor is a GABAA1 receptor, GABAA2 receptor, GABAA3 receptor or GABAA5 receptor.
67 . A method of claim 65 , wherein said GABAA receptor is a GABAA2 receptor.
68 . A synthetic method of making a compound of formula I:
or a pharmaceutically acceptable salt, tautomer, or in vivo-hydrolysable precursor thereof, wherein:
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 R 7 ;
R 2 is H, C(═O)R b , C(═O)NR c R d , C(═O)OR a , S(═O) 2 R b , C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 8 ;
R 3 , R 4 and R 5 are each, independently, H, halo, Si(C 1-10 alkyl) 3 , CN, NO 2 , OR a , SR a , OC(═O)R a , OC(═O)OR a , OC(═O)NR c R d , C(═O)R a , C(═O)OR b , C(═O)NR c R d , NR c R d , NR c C(═O)R a , NR c C(═O)OR b , NR c S(═O) 2 R b , S(═O)R a , S(═O)NR c R d , S(═O) 2 R a , S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R 9 ;
R 6 is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 A 1 ;
R 7 , R 8 and R 9 are each, independently, halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
A 1 is halo, CN, NO 2 , OR a , SR a , C(═O)R b , C(═O)NR c R d , C(═O)OR a , OC(═O)R b , OC(═O)NR c R d , NR c R d , NR c C(═O)R d , NR c C(═O)OR a , NR c S(═O)R b , NR c S(═O) 2 R b , S(═O)R b , S(═O)NR c R d , S(═O) 2 R b , S(═O) 2 NR c R d , C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, aryl, cycloalkyl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O)R b′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
R a and R a′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R b and R b′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R c and R d are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
R c′ and R d′ are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
with the proviso that when R 2 , R 3 , R 4 and R 5 are each H, then R 6 is other than unsubstituted phenyl,
comprising reacting a compound of Formula III:
wherein X 1 is bromo or iodo,
with a compound of formula IV:
wherein:
R 10l and R 102 are each, independently, hydrogen or C 1-6 alkyl;
or R 101 and R 102 , together with the two oxygen atoms to which they are attached and the boron atom to which the two oxygen atoms are attached, form a 4-7 membered heterocyclic ring whose ring-forming atoms comprises B, O and C atoms and which is optionally substituted by 1, 2, 3, or 4 C 1-6 alkyl,
in the presence of a catalyst and a base for a time and under conditions sufficient to form the compound of Formula I.
69 . The method of claim 68 wherein R 101 and R 102 are each, independently, hydrogen.
70 . The method of claim 68 wherein the compound of formula IV has formula V:
71 . The method of claim 68 wherein said catalyst is a metal catalyst.
72 . The method of claim 68 wherein said catalyst is a palladium catalyst.
73 . The method of claim 72 wherein said palladium catalyst is bis(triphenylphosphine)palladium(II) dichloride.
74 . The method of claim 72 wherein said palladium catalyst is tetrakis(triphenylphosphine)palladium(0).
75 . The method of claim 68 wherein said base is an inorganic base.
76 . The method of claim 68 wherein said base is cesium carbonate, sodium carbonate or potassium phosphate.
77 . The method of claim 68 wherein said reacting is carried out in a solvent which comprises an organic solvent.
78 . The method of claim 77 wherein said organic solvent comprises a polar organic solvent.
79 . The method of claim 78 wherein said polar organic solvent comprises 1,2-dimethoxyethane, tetrahydrofuran or ethanol.
80 . The method of claim 77 wherein said solvent further comprises water.
81 . A synthetic method of making a compound of formula J:
or a pharmaceutically acceptable salt, tautomer, or in vivo-hydrolysable precursor thereof, wherein:
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 R 7 ;
R 2 is H, C(═O)Kb, C(═O)NR c R d , C(═O)OR a , S(═O) 2 R b , C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 8 ;
R 3 , R 4 and R 5 are each, independently, H, halo, Si(C 1-10 alkyl) 3 , CN, NO 2 , OR a , SR a , OC(═O)R a , OC(═O)OR b , OC(═O)NR c R d , C(═O)R a , C(═O)OR b , C(═O)NR c R d , NR c R d , NR c C(═O)R a , NR c C(═O)OR b , NR c S(═O) 2 R b , S(═O)R a , S(═O)NR c R d , S(═O) 2 R a , S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R 9 ;
R 6 is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 Al;
R 7 , R 3 and R 9 are each, independently, halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
A 1 is halo, CN, NO 2 , OR a , SR a , C(═O)R b , C(═O)NR c R d , C(═O)OR a , OC(═O)R b , OC(═O)NR c R d , NR c R d , NR c C(═O)R d , NR c C(═O)OR a , NR c S(═O)R b , NR c S(═O) 2 R b , S(═O)R b , S(═O)NR c R d , S(═O) 2 R b , S(═O) 2 NR c R d , C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, aryl, cycloalkyl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b″ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O)R b′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
R a and R a′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R b and R b′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R c and R d are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
R c′ and R d′ are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
with the proviso that when R 2 , R 3 , R 4 and R 5 are each H, then R 6 is other than unsubstituted phenyl,
comprising reacting a compound of Formula VI:
wherein X 2 is bromo or iodo, with a compound of R 6 -Sn(R 201 )(R 202 )(R 203 ), wherein R 201 , R 202 and R 203 are each, independently, C 1-6 alkyl, in the present of a catalyst, for a time and under conditions sufficient to form the compound of Formula I.
82 . The method of claim 81 wherein said catalyst comprises a metal catalyst.
83 . The method of claim 81 wherein said catalyst comprises a palladium catalyst.
84 . The method of claim 83 wherein said palladium catalyst comprises bis(triphenylphosphine)palladium(II) dichloride.
85 . The method of claim 83 wherein said palladium catalyst comprises tetrakis(triphenylphosphine)palladium(0).
86 . The method of claim 81 wherein said reacting is carried out in a solvent which comprises an organic solvent.
87 . The method of claim 86 wherein said organic solvent comprises a polar organic solvent.
88 . The method of claim 87 wherein said organic solvent comprises a polar aprotic organic solvent.
89 . The method of claim 88 wherein said polar aprotic organic solvent comprises N,N-dimethylformamide.
90 . The method of claim 81 wherein X 2 is bromo.
91 . A synthetic method of making a compound of formula J:
or a pharmaceutically acceptable salt, tautomer, or in vivo-hydrolysable precursor thereof, wherein:
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 R 7 ;
R 2 is H, C(═O)R b , C(═O)NR c R d , C(═O)OR a , S(═O) 2 R b , C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 8 ;
R 3 , R 4 and R 5 are each, independently, H, halo, Si(C 1-10 alkyl) 3 , CN, NO 2 , OR a , SR a , OC(═O)R a , OC(═O)OR b , OC(═O)NR c R d , C(═O)R a , C(═O)OR b , C(═O)NR c R d , NR c R d , NR c C(═O)R a , NR c C(═O)OR b , NR c S(═O) 2 R b , S(═O)R a , S(═O)NR c R d , S(═O) 2 R a , S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R 9 ;
R 6 is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 Al;
R 7 , R 8 and R 9 are each, independently, halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
A 1 is halo, CN, NO 2 , OR a , SR a , C(═O)R b , C(═O)NR c R d , C(═O)OR a , OC(═O)R b , OC(═O)NR c R d , NR c R d , NR c C(═O)R d , NR c C(═O)OR a , NR c S(═O)R b , NR c S(═O) 2 R b , S(═O)R b , S(═O)NR c R d , S(═O) 2 R b , S(═O) 2 NR c R d , C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, aryl, cycloalkyl, heterocycloalkylalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O)R b′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
R a and R a′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R b and R b′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R c and R d are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
R c′ and R d′ are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
with the proviso that when R 2 , R 3 , R 4 and R 5 are each H, then R 6 is other than unsubstituted phenyl, comprising reacting a compound of Formula VII:
wherein R 301 , R 302 and R 303 are each, independently, C 1-6 alkyl, with a compound of R 6 -X 3 wherein X 3 is bromo or iodo, in the present of a catalyst, for a time and under conditions sufficient to form the compound of Formula I.
92 . The method of claim 91 wherein said catalyst comprises a metal catalyst.
93 . The method of claim 91 wherein said catalyst comprises a palladium catalyst.
94 . The method of claim 93 wherein said palladium catalyst comprises bis(triphenylphosphine)palladium(II) dichloride.
95 . The method of claim 94 wherein said palladium catalyst comprises tetrakis(triphenylphosphine)palladium(0).
96 . The method of claim 91 wherein said reacting is carried out in a solvent which comprises an organic solvent.
97 . The method of claim 96 wherein said organic solvent comprises a polar organic solvent.
98 . The method of claim 96 wherein said organic solvent comprises a polar aprotic organic solvent.
99 . The method of claim 98 wherein said polar aprotic organic solvent comprises N,N-dimethylformamide.
100 . The method of claim 91 further comprising reacting a compound of Formula VIII:
wherein:
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 R 7 ;
R 2 is H, C(═O)R b , C(═O)NR c R d , C(═O)OR a , S(═O) 2 R b , C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R 8 ;
R 3 , R 4 and R 5 are each, independently, H, halo, Si(C 1-10 alkyl) 3 , CN, NO 2 , OR a , SR a , OC(═O)R a , OC(═O)OR b , OC(═O)NR c R d , C(═O)R a , C(═O)OR b , C(═O)NR c R d , NR c R d , NR c C(═O)R a , NR c C(═O)OR b , NR c S(═O) 2 R b , S(═O)NR c R d , S(═O) 2 NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R 9 ;
R 7 , R 8 and R 9 are each, independently, halo, C 1-4 alkyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(═O)R b′ , C(═O)NR c′ R d′ , C(═O)OR a′ , OC(═O)R b′ , OC(═O)NR c′ R d′ , NR c′ R d′ , NR c′ C(═O)R b′ , NR c′ C(═O)OR a′ , NR c′ S(═O) 2 R b′ , S(═O)R b′ , S(═O)NR c′ R d′ , S(═O) 2 R b′ , or S(═O) 2 NR c′ R d′ ;
X 4 is bromo or iodo;
R a and R a′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R b and R b′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
R c and R d are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
R c′ and R d′ are each, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or R c′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group,
with a compound of formula IX:
wherein R 301 , R 302 and R 303 are each, independently, in the present of a second catalyst, for a time and under conditions sufficient to form the compound of Formula VII.
101 . The method of 100 wherein said second catalyst is tetrakis(triphenylphosphine)palladium(0).
102 . A method of treating an anxiety disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of (4-amino-8-(2,5-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide) or a pharmaceutically acceptable salt thereof.
103 . A method of treating a cognitive disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of (4-amino-8-(2,5-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide) or a pharmaceutically acceptable salt thereof.
104 . A method of treating a depressive disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of (4-amino-8-(2,5-dimethoxyphenyl)-N-propyl-cinnoline-3-carboxamide) or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
Track US2009036454A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.