US2010240650A1PendingUtilityA1
Substituted pyrrolines as kinase inhibitors
Est. expiryJun 5, 2022(expired)· nominal 20-yr term from priority
Inventors:Han-Cheng ZhangBruce E. MaryanoffDavid F. MccomseyKimberly WhiteHong YeLeonard R. HeckerBruce ConwayKeith Demarest
A61P 9/10A61P 43/00A61P 37/02A61P 7/02A61P 37/06A61P 9/04A61P 9/00A61P 35/00A61P 3/10A61P 9/12A61P 37/00A61P 29/00A61P 27/02A61P 25/18A61P 25/24A61P 25/04A61P 25/02A61P 25/00A61P 25/28A61P 17/06C07D 417/14C07D 409/14A61P 13/12C07D 401/14A61P 11/06C07D 403/14A61P 17/14C07D 405/14A61P 17/00C07D 403/04
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Claims
Abstract
The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
wherein
R is selected from phenyl, naphthyl, thienyl, pyrimidinyl, benzothienyl or quinolinyl;
R 1 is selected from hydrogen, —C 1-8 alkyl-R 5 , —C 2-8 alkenyl-R 5 , —C 2-8 alkynyl-R 5 , -aryl-R 6 or -heteroaryl-R 6 ; wherein a heteroaryl ring carbon atom forms the point of attachment to the indole nitrogen atom;
R 5 is 1 to 2 substituents independently selected from hydrogen, —O—(C 1-8 )alkyl, —O—(C 1-8 )alkyl-OH, —O—(C 1-8 )alkyl-O—(C 1-8 )alkyl, —O—(C 1-8 )alkyl-NH 2 , —O—(C 1-8 )alkyl-NH(C 1-8 alkyl), —O—(C 1-8 )alkyl-N(C 1-8 alkyl) 2 , —O—(C 1-8 )alkyl-S—(C 1-8 )alkyl, —O—(C 1-8 )alkyl-SO 2 —(C 1-8 )alkyl, —O—(C 1-8 )alkyl-SO 2 —NH 2 , —O—(C 1-8 )alkyl-SO 2 —NH(C 1-8 alkyl), —O—(C 1-8 )alkyl-SO 2 —N(C 1-8 alkyl) 2 , —O—C(O)H, —O—C(O)—(C 1-8 )alkyl, —O—C(O)—NH 2 , —O—C(O)—NH(C 1-8 alkyl), —O—C(O)—N(C 1-8 alkyl) 2 , —O—(C 1-8 )alkyl-C(O)H, —O—(C 1-8 )alkyl-C(O)—(C 1-8 )alkyl, —O—(C 1-8 )alkyl-CO 2 H, —O—(C 1-8 )alkyl-C(O)—O—(C 1-8 )alkyl, —O—(C 1-8 )alkyl-C(O)—NH 2 , —O—(C 1-8 )alkyl-C(O)—NH(C 1-8 alkyl), —O—(C 1-8 )alkyl-C(O)—N(C 1-8 alkyl) 2 , —C(O)H, —C(O)—(C 1-8 )alkyl, —CO 2 H, —C(O)—O—(C 1-8 )alkyl, —C(O)—NH 2 , —C(NH)—NH 2 , —C(O)—NH(C 1-8 alkyl), —C(O)—N(C 1-8 alkyl) 2 , —SH, —S—(C 1-8 )alkyl, —S—(C 1-8 )alkyl-S—(C 1-8 )alkyl, —S(C 1-8 )alkyl-O—(C 1-8 )alkyl, —S—(C 1-8 )alkyl-O—(C 1-8 )alkyl-OH, —S—(C 1-8 )alkyl-O—(C 1-8 )alkyl-NH 2 , —S—(C 1-8 )alkyl-O—(C 1-8 )alkyl-NH(C 1-8 alkyl), —S—(C 1-8 )alkyl-O—(C 1-8 )alkyl-N(C 1-8 alkyl) 2 , —S—(C 1-8 )alkyl-NH(C 1-8 alkyl), —SO 2 (C 1-8 )alkyl, —SO 2 —NH 2 , —SO 2 —NH(C 1-8 alkyl), —SO 2 —N(C 1-8 alkyl) 2 , —N—R 7 , —(C 1-4 )alkyl-N—R 7 , cyano, (halo) 1-3 , hydroxy, nitro, oxo, -cycloalkyl-R 6 , —(C 1-4 )alkyl-cycloalkyl-R 6 , -heterocyclyl-R 6 , —(C 1-4 )alkyl-heterocyclyl-R 6 , -aryl-R 6 , —(C 1-4 )alkykaryl-R 6 , -heteroaryl-R 6 or —(C 1-4 )alkyl-heteroaryl-R 6 ;
R 6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —C 1-8 alkyl, —(C 1-8 )alkyl-(halo) 1-3 or —(C 1-8 )alkyl-OH;
with the proviso that, when R 6 is attached to a carbon atom, R 6 is further selected from —C 1-8 alkoxy, —NH 2 , —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , cyano, halo, —(C 1-8 )alkoxy-(halo) 1-3 , hydroxy or nitro;
R 7 is 2 substituents independently selected from hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, —(C 1-8 )alkyl-OH, —(C 1-8 )alkyl-O—(C 1-8 )alkyl, —(C 1-8 )alkyl-NH 2 , —(C 1-8 )alkyl-NH(C 1-8 alkyl), —(C 1-8 )alkyl-N(C 1-8 alkyl) 2 , —(C 1-8 )alkyl-S—(C 1-8 )alkyl, —C(O)—(C 1-8 )alkyl, —C(O)—O—(C 1-8 )alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-8 alkyl), —C(O)—N(C 1-8 alkyl) 2 , —SO 2 (C 1-8 )alkyl, —SO 2 —NH 2 , —SO 2 —NH(C 1-8 alkyl), —SO 2 —N(C 1-8 alkyl) 2 , —C(N)—NH 2 , -cycloalkyl-R 8 , —(C 1-8 )alkyl-heterocyclyl-R 8 , -aryl-R 8 , —(C 1-8 )alkyl-aryl-R 8 or —(C 1-8 )alkyl-heteroaryl-R 8 ;
R 8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —C 1-8 alkyl, —(C 1-8 )alkyl-(halo) 1-3 or —(C 1-8 )alkyl-OH;
with the proviso that, when R 8 is attached to a carbon atom, R 8 is further selected from —C 1-8 alkoxy, —NH 2 , —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , cyano, halo, —(C 1-8 )alkoxy-(halo) 1-3 , hydroxy or nitro;
R 2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen, —C 1-8 alkyl-R 5 , —C 2-8 alkenyl-R 5 , —C 2-8 alkynyl-R 5 , —C(O)H, —C(O)—(C 1-8 )alkyl-R 9 , —C(O)—NH 2 , —C(O)—NH(C 1-8 alkyl-R 9 ), —C(O)—N(C 1-8 alkyl-R 9 ) 2 , —C(O)—NH(aryl-R 8 ), —C(O)-cycloalkyl-R 8 , —C(O)-heterocyclyl-R 8 , —C(O)-aryl-R 8 , —C(O)-heteroaryl-R 8 , —CO 2 H, —C(O)—O—(C 1-8 )alkyl-R 9 , —C(O)—O-aryl-R 8 , —SO 2 —(C 1-8 )alkyl-R 9 , —SO 2 -aryl-R 8 , -cycloalkyl-R 6 , -aryl-R 6 or —(C 1-8 )alkyl-N—R 7 ;
with the proviso that, when R 2 is attached to a carbon atom, R 2 is further selected from —C 1-8 alkoxy-R 5 , —N—R 7 , cyano, halogen, hydroxy, nitro, oxo (wherein oxo is attached to a saturated carbon atom), -heterocyclyl-R 6 or -heteroaryl-R 6 ;
R 9 is 1 to 2 substituents independently selected from hydrogen, —C 1-8 alkoxy, —NH 2 , —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , cyano, (halo) 1-3 , hydroxy or nitro;
R 3 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C 1-8 alkyl-R 10 , —C 2-8 alkenyl-R 10 , —C 2-8 alkynyl-R 10 , —C 1-8 alkoxy-R 10 , —C(O)H, —C(O)—(C 1-8 )alkyl-R 9 , —C(O)—NH 2 , —C(O)—NH(C 1-8 alkyl-R 9 ), —C(O)—N(C 1-8 alkyl-R 9 ) 2 , —C(O)-cycloalkyl-R 8 , —C(O)-heterocyclyl-R 8 , —C(O)-aryl-R 8 , —C(O)-heteroaryl-R 8 , —C(NH)—NH 2 , —CO 2 H, —C(O)—O—(C 1-8 )alkyl-R 9 , —C(O)—O-aryl-R 8 , —SO 2 —(C 1-8 )alkyl-R 9 , —SO 2 -aryl-R 8 , —N—R 7 , —(C 1-8 )alkyl-N—R 7 , cyano, halogen, hydroxy, nitro, -cycloalkyl-R 8 , -heterocyclyl-R 8 , -aryl-R 8 or -heteroaryl-R 8 ;
R 4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C 1-8 alkyl-R 10 , —C 2-8 alkenyl-R 10 , —C 2-8 alkynyl-R 10 , —C 1-8 alkoxy-R 10 , —C(O)H, —C(O)—(C 1-8 )alkyl-R 9 , —C(O)—NH 2 , —C(O)—NH(C 1-8 alkyl-R 9 ), —C(O)—N(C 1-8 alkyl-R 9 ) 2 , —C(O)-cycloalkyl-R 8 , —C(O)-heterocyclyl-R 8 , —C(O)-aryl-R 8 , —C(O)-heteroaryl-R 8 , —C(NH)—NH 2 , —CO 2 H, —C(O)—O—(C 1-8 )alkyl-R 9 , —C(O)—O-aryl-R 8 , —SH, —S—(C 1-8 )alkyl-R 10 , —SO 2 —(C 1-8 )alkyl-R 9 , —SO 2 -aryl-R 8 , —SO 2 —NH 2 , —SO 2 —NH(C 1-8 alkyl-R 9 ), —SO 2 —N(C 1-8 alkyl-R 9 ) 2 , —N—R 7 , —(C 1-8 )alkyl-N—R 7 , cyano, halogen, hydroxy, nitro, -cycloalkyl-R 8 , -heterocyclyl-R 8 , -aryl-R 8 or -heteroaryl-R 8 ;
R 10 is 1 to 2 substituents independently selected from hydrogen, —NH 2 , —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , cyano, (halo) 1-3 , hydroxy, nitro or oxo;
X is selected from N or CR 11 ; and,
R 11 is selected from hydrogen, —C 1-8 alkyl-R 10 , —C 2-8 alkenyl-R 10 , —C 2-8 alkynyl-R 10 , —C 1-8 alkoxy-R 10 , -aryl-R 8 , -heteroaryl-R 8 or halogen;
provided that said compound is not a compound wherein:
R is phenyl or naphthyl;
R 1 is -heteroaryl-R 6 ;
X is CR 11 ; and
R 11 is hydrogen; and
provided that said compound is not a compound wherein:
R is phenyl or naphthyl;
R 1 is —C 1-8 alkyl-R 5 ;
R 4 is hydrogen;
R 5 is hydroxy; and
X is CR 11 ;
and pharmaceutically acceptable salts thereof.
2 . The compound of claim 1 wherein R is selected from phenyl, naphthyl, thienyl or benzothienyl.
3 . The compound of claim 1 wherein R 1 is selected from hydrogen, —C 1-6 alkyl-R 5 , —C 2-6 alkenyl-R 5 , —C 2-6 alkynyl-R 5 , -aryl-R 6 or -heteroaryl-R 6 ; wherein a heteroaryl ring carbon atom forms the point of attachment to the indole nitrogen atom.
4 . The compound of claim 1 wherein R 1 is selected from hydrogen, —C 1-4 alkyl-R 5 , —C 2-4 alkenyl-R 5 , —C 2-6 alkynyl-R 5 , -phenyl-R 6 , -naphthyl-R 6 , -pyridinyl-R 6 , -pyrimidinyl-R 6 , -quinolinyl-R 6 or -benzothienyl-R 6 ; wherein a pyridinyl, pyrimidinyl, quinolinyl or benzothienyl ring carbon atom forms the point of attachment to the indole nitrogen atom.
5 . The compound of claim 1 wherein R 5 is 1 to 2 substituents independently selected from hydrogen, —O—(C 1-4 )alkyl, —O—(C 1-4 )alkyl-OH, —O—(C 1-4 )alkyl-O—(C 1-4 )alkyl, —O—(C 1-4 )alkyl-NH 2 , —O—(C 1-4 )alkyl-NH(C 1-4 alkyl), —O—(C 1-4 )alkyl-N(C 1-4 alkyl) 2 , —O—(C 1-4 )alkyl-S—(C 1-4 )alkyl, —O—(C 1-4 )alkyl-SO 2 —(C 1-4 )alkyl, —O—(C 1-4 )alkyl-SO 2 —NH 2 , —O—(C 1-4 )alkyl-SO 2 —NH(C 1-4 alkyl), —O—(C 1-4 )alkyl-SO 2 —N(C 1-4 alkyl) 2 , —O—C(O)H, —O—C(O)—(C 1-4 )alkyl, —O—C(O)—NH 2 , —O—C(O)—NH(C 1-4 alkyl), —O—C(O)—N(C 1-4 alkyl) 2 , —O—(C 1-4 )alkyl-C(O)H, —O—(C 1-4 )alkyl-C(O)—(C 1-4 )alkyl, —O—(C 1-4 )alkyl-CO 2 H, —O—(C 1-4 )alkyl-C(O)—O—(C 1-4 )alkyl, —O—(C 1-4 )alkyl-C(O)—NH 2 , —O—(C 1-4 )alkyl-C(O)—NH(C 1-4 alkyl), —O—(C 1-4 )alkyl-C(O)—N(C 1-4 alkyl) 2 , —C(O)H, —C(O)—(C 1-4 )alkyl, —CO 2 H, —C(O)—O—(C 1-4 )alkyl, —C(O)—NH 2 , —C(NH)—NH 2 , —C(O)—NH(C 1-4 alkyl), —C(O)—N(C 1-4 alkyl) 2 , —SH, —S—(C 1-4 )alkyl, —S—(C 1-4 )alkyl-S—(C 1-4 )alkyl, —S—(C 1-4 )alkyl-O—(C 1-4 )alkyl, —S—(C 1-4 )alkyl-O—(C 1-4 )alkyl-OH, —S—(C 1-4 )alkyl-O—(C 1-4 )alkyl-NH 2 , —S—(C 1-4 )alkyl-O—(C 1-4 )alkyl-NH(C 1-4 alkyl), —S—(C 1-4 )alkyl-O—(C 1-4 )alkyl-N(C 1-4 alkyl) 2 , —S—(C 1-4 )alkyl-NH(C 1-4 alkyl), —SO 2 —(C 1-4 )alkyl, —SO 2 —NH 2 , —SO 2 —NH(C 1-4 alkyl), —SO 2 —N(C 1-4 alkyl) 2 , —N—R 7 , —(C 1-4 )alkyl-N—R 7 , cyano, (halo) 1-3 , hydroxy, nitro, oxo, -cycloalkyl-R 6 , —(C 1-4 )alkyl-cycloalkyl-R 6 , -heterocyclyl-R 6 , —(C 1-4 )alkyl-heterocyclyl-R 6 , -aryl-R 6 , —(C 1-4 )alkyl-aryl-R 6 , -heteroaryl-R 6 or —(C 1-4 )alkyl-heteroaryl-R 6 .
6 . The compound of claim 1 wherein R 5 is 1 to 2 substituents independently selected from hydrogen, —O—(C 1-4 )alkyl, —C(O)H, —N—R 7 , —(C 1-4 )alkyl-N—R 7 , hydroxy, -heterocyclyl-R 6 or —(C 1-4 )alkyl-heterocyclyl-R 6 .
7 . The compound of claim 1 wherein R 5 is 1 to 2 substituents independently selected from hydrogen, —O—(C 1-4 )alkyl, —C(O)H, —N—R 7 , —(C 1-4 )alkyl-N—R 7 , hydroxy, -pyrrolidinyl-R 6 , -morpholinyl-R 6 , -thiazolidinyl-R 6 , —(C 1-4 )alkyl-piperidinyl-R 6 or -piperazinyl-R 6 .
8 . The compound of claim 1 wherein R 6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —C 1-4 alkyl, —(C 1-4 )alkyl-(halo) 1-3 or —(C 1-4 )alkyl-OH;
with the proviso that, when R 6 is attached to a carbon atom, R 6 is further selected from —C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , cyano, halo, —(C 1-4 )alkoxy-(halo) 1-3 , hydroxy or nitro.
9 . The compound of claim 1 wherein R 6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen or —C 1-4 alkyl; with the proviso that, when R 6 is attached to a carbon atom, R 6 is further selected from halo.
10 . The compound of claim 1 wherein R 7 is 2 substituents independently selected from hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —(C 1-4 )alkyl-OH, —(C 1-4 )alkyl-O—(C 1-4 )alkyl, —(C 1-4 )alkyl-NH 2 , —(C 1-4 )alkyl-NH(C 1-6 alkyl), —(C 1-4 )alkyl-N(C 1-6 alkyl) 2 , —(C 1-4 )alkyl-S—(C 1-4 )alkyl, —C(O)—(C 1-4 )alkyl, —C(O)—O—(C 1-4 )alkyl, —C(O)—NH 2 , —C(O)—NH(C 1-6 alkyl), —C(O)—N(C 1-6 alkyl) 2 , —SO 2 —(C 1-4 )alkyl, —SO 2 —NH 2 , —SO 2 —NH(C 1-6 alkyl), —SO 2 —N(C 1-6 alkyl) 2 , —C(N)—NH 2 , -cycloalkyl-R 8 , —(C 1-4 )alkyl-heterocyclyl-R 8 , -aryl-R 8 , —(C 1-4 )alkyl-aryl-R 8 or —(C 1-4 )alkyl-heteroaryl-R 8 .
11 . The compound of claim 1 wherein R 7 is 2 substituents independently selected from hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —(C 1-4 )alkyl-OH, —(C 1-4 )alkyl-N(C 1-6 alkyl) 2 or —(C 1-4 )alkyl-heteroaryl-R 8 .
12 . The compound of claim 1 wherein R 7 is 2 substituents independently selected from hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —(C 1-4 )alkyl-OH, —(C 1-4 )alkyl-N(C 1-6 alkyl) 2 or —(C 1-4 )alkyl-furyl-R 8 .
13 . The compound of claim 1 wherein R 8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —C 1-4 alkyl, —(C 1-4 )alkyl-(halo) 1-3 or —(C 1-4 )alkyl-OH;
with the proviso that, when R 8 is attached to a carbon atom, R 8 is further selected from —C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , cyano, halo, —(C 1-4 )alkoxy-(halo) 1-3 , hydroxy or nitro.
14 . The compound of claim 1 wherein R 8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen or —C 1-4 alkyl.
15 . The compound of claim 1 wherein R 2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen, —C 1-4 alkyl-R 5 , —C 2-4 alkenyl-R 5 , —C 2-4 alkynyl-R 5 , —C(O)H, —C(O)—(C 1-4 )alkyl-R 9 , —C(O)—NH 2 , —C(O)—NH(C 1-4 alkyl-R 9 ), —C(O)—N(C 1-4 alkyl-R 9 ) 2 , —C(O)—NH(aryl-R 8 ), —C(O)-cycloalkyl-R 8 , —C(O)-heterocyclyl-R 8 , —C(O)-aryl-R 8 , —C(O)-heteroaryl-R 8 , —CO 2 H, —C(O)—O—(C 1-4 )alkyl-R 9 , —C(O)—O-aryl-R 8 , —SO 2 —(C 1-4 )alkyl-R 9 , —SO 2 -aryl-R 8 , -cycloalkyl-R 6 , -aryl-R 6 or —(C 1-4 )alkyl-N—R 7 ;
with the proviso that, when R 2 is attached to a carbon atom, R 2 is further selected from —C 1-4 alkoxy-R 5 , —N—R 7 , cyano, halogen, hydroxy, nitro, oxo (wherein oxo is attached to a saturated carbon atom), -heterocyclyl-R 6 or -heteroaryl-R 6 .
16 . The compound of claim 1 wherein R 2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen or —C 1-4 alkyl-R 5 ; with the proviso that, when R 2 is attached to a carbon atom, R 2 is further selected from —C 1-4 alkoxy-R 5 , halogen or hydroxy.
17 . The compound of claim 1 wherein R 2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen or —C 1-4 alkyl-R 5 ; with the proviso that, when R 2 is attached to a carbon atom, R 2 is further selected from —C 1-4 alkoxy-R 5 , bromine, iodine or hydroxy.
18 . The compound of claim 1 wherein R 9 is 1 to 2 substituents independently selected from hydrogen, —C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , cyano, (halo) 1-3 , hydroxy or nitro.
19 . The compound of claim 1 wherein R 9 is hydrogen.
20 . The compound of claim 1 wherein R 3 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C 1-4 alkyl-R 10 , —C 2-4 alkenyl-R 10 , —C 2-4 alkynyl-R 10 , —C 1-4 alkoxy-R 10 , —C(O)H, —C(O)—(C 1-4 )alkyl-R 9 , —C(O)—NH 2 , —C(O)—NH(C 1-4 alkyl-R 9 ), —C(O)—N(C 1-4 alkyl-R 9 ) 2 , —C(O)-cycloalkyl-R 8 , —C(O)-heterocyclyl-R 8 , —C(O)-aryl-R 8 , —C(O)-heteroaryl-R 8 , —C(NH)—NH 2 , —CO 2 H, —C(O)—O—(C 1-4 )alkyl-R 9 , —C(O)—O-aryl-R 8 , —SO 2 —(C 1-4 )alkyl-R 9 , —SO 2 -aryl-R 8 , —N—R 7 , —(C 1-4 )alkyl-N—R 7 , cyano, halogen, hydroxy, nitro, -cycloalkyl-R 8 , -heterocyclyl-R 8 , -aryl-R 8 or -heteroaryl-R 8 .
21 . The compound of claim 1 wherein R 3 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen or halogen.
22 . The compound of claim 1 wherein R 3 is hydrogen.
23 . The compound of claim 1 wherein R 4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C 1-4 alkyl-R 10 , —C 2-4 alkenyl-R 10 , —C 2-4 alkynyl-R 10 , —C 1-4 alkoxy-R 10 , —C(O)H, —C(O)-(C 1-4 )alkyl-R 9 , —C(O)—NH 2 , —C(O)—NH(C 1-4 alkyl-R 9 ), —C(O)—N(C 1-4 alkyl-R 9 ) 2 , —C(O)-cycloalkyl-R 8 , —C(O)-heterocyclyl-R 8 , —C(O)-aryl-R 8 , —C(O)-heteroaryl-R 8 , —C(NH)—NH 2 , —CO 2 H, —C(O)—O—(C 1-4 )alkyl-R 9 , —C(O)—O-aryl-R 8 , —SH, —S—(C 1-4 )alkyl-R 10 , —SO 2 —(C 1-4 )alkyl-R 9 , —SO 2 -aryl-R 8 , —SO 2 —NH 2 , —SO 2 —NH(C 1-4 alkyl-R 9 ), —SO 2 —N(C 1-4 alkyl-R 9 ) 2 , —N—R 7 , —(C 1-4 )alkyl-N—R 7 , cyano, halogen, hydroxy, nitro, -cycloalkyl-R 8 , -heterocyclyl-R 8 , -aryl-R 8 or -heteroaryl-R 8 .
24 . The compound of claim 1 wherein R 4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C 1-4 alkyl-R 10 or halogen.
25 . The compound of claim 1 wherein R 4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C 1-4 alkyl-R 10 or chlorine.
26 . The compound of claim 1 wherein R 10 is 1 to 2 substituents independently selected from hydrogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , cyano, (halo) 1-3 , hydroxy, nitro or oxo.
27 . The compound of claim 1 wherein R 10 is hydrogen.
28 . The compound of claim 1 wherein R 11 is selected from hydrogen, —C 1-4 alkyl-R 10 , —C 2-4 alkenyl-R 10 , —C 2-4 alkynyl-R 10 , —C 1-4 alkoxy-R 10 , -aryl-R 8 , -heteroaryl-R 8 or halogen.
29 . The compound of claim 1 wherein R 11 is hydrogen.
30 . The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ia):
Formula (Ia)
wherein R 1 , R 2 , R 4 and X are dependently selected from
R 1
R 2
R 4
X
—CH═CH 2
4-(—O—CH 2 CH(OH)CH 2 -
H
CH;
1-piperidinyl)
—CH═CH 2
3-(—O—CH 2 CH(OH)CH 2 —
H
CH;
N(CH 3 ) 2 )
—CH═CH 2
4-(—O—CH 2 CH(OH)CH 2 —
H
CH;
N(CH 3 ) 2 )
—CH═CH 2
2-(—O—CH 2 CH(OH)CH 2 —
H
CH;
N(CH 3 ) 2 )
—CH 2 CH(—OCH 2 CH 3 ) 2
2-(—OCH 3 )
H
CH;
—CH 2 C(O)H
2-(—OCH 3 )
H
CH;
—(CH 2 ) 2 —N(CH 3 )((CH 2 ) 2 —OH)
2-(—OCH 3 )
H
CH;
H
4-(—O—CH 2 CH 2 —NHCH 3 )
H
CH;
—(CH 2 ) 3 —N(CH 3 )(CH 2 C≡CH)
3-Br
H
CH;
5-hexyn-1-yl
3-Br
H
CH;
—(CH 2 ) 3 —NH(CH 3 )
3-Br
H
CH;
—(CH 2 ) 3 —N(CH 3 ) 2
4-(—O—CH 2 CH(OH)CH 2 —
H
CH;
N(CH 3 ) 2 )
—(CH 2 ) 3 —N(CH 3 ) 2
2-(—O—CH 2 CH(OH)CH 2 —
H
CH;
N(CH 3 ) 2 )
—(CH 2 ) 3 —N(CH 3 )(3-butyn-1-yl)
3-Br
H
CH;
—(CH 2 ) 3 —N(CH 3 )(3-butyn-1-yl)
2-I
H
CH;
H
2-Br-5-(—O—(CH 2 ) 3 —N(CH 3 ) 2 )
H
CH;
Ph
2-Br-5-(—O—(CH 2 ) 3 —N(CH 3 ) 2 )
H
CH;
—(CH 2 ) 3 —OH
H
H;
N;
—(CH 2 ) 3 —OH
H
2-O—CH 3 ;
N;
and pharmaceutically acceptable salts thereof.
31 . The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ib):
Formula (Ib)
wherein R 1 and R 2 are dependently selected from
R 1
R 2
—CH═CH 2
2-OH;
—CH═CH 2
2-(—O—CH 2 CH(OH)CH 2 —N(CH 3 ) 2 );
—(CH 2 ) 3 —N(CH 3 ) 2
H;
H
2-(—O—CH 2 CH(OH)CH 2 —N(CH 3 ) 2 );
—(CH 2 ) 2 —N(CH 2 CH 3 ) 2
H;
—(CH 2 ) 2 —N(CH 3 )(2-butyn-1-
H;
yl)
—(CH 2 ) 2 —N(CH 3 )(3-butyn-1-
H;
yl)
and pharmaceutically acceptable salts thereof.
32 . The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Ic):
Formula (Ic)
wherein R 1 and R 4 are dependently selected from
R 1
R 4
—(CH 2 ) 3 —N(CH 3 ) 2
5-Cl;
—(CH 2 ) 3 —N(CH 3 ) 2
H;
—(CH 2 ) 2 —N(CH 3 )(CH 2 C≡CH)
5-Cl;
—(CH 2 ) 2 —N(CH 3 )(2-butyn-1-yl)
5-Cl;
—(CH 2 ) 2 —N(CH 3 )(3-butyn-1-yl)
5-Cl;
—CH 2 CH(—O—CH 2 CH 3 ) 2
5-Cl;
—CH 2 C(O)H
5-Cl;
—(CH 2 ) 2 —N(CH 3 ) 2
5-Cl;
—(CH 2 ) 2 —N(CH 3 )((CH 2 ) 2 —N(CH 3 ) 2 )
5-Cl;
—(CH 2 ) 3 -1-(4-(CH 3 )-piperazinyl)
5-Cl;
—(CH 2 ) 2 —N(CH 3 )((CH 2 ) 2 —OH)
5-Cl;
—(CH 2 ) 2 -4-morpholinyl
5-Cl;
—(CH 2 ) 2 -1-pyrrolidinyl
5-Cl;
—(CH 2 ) 2 —N(CH 2 CH 3 ) 2
5-Cl;
—(CH 2 ) 2 —N(CH 3 )(CH 2 -2-furyl)
5-Cl;
—(CH 2 ) 2 -1-thiazolidinyl
5-Cl;
—(CH 2 ) 3 —N(CH 3 )(CH 2 CH═CH 2 )
5-Cl;
—(CH 2 ) 3 —OH
5-Cl;
—(CH 2 ) 3 —N(CH 3 ) 2
2,5-Cl 2 ;
—(CH 2 ) 3 —N(CH 3 )(CH 2 CH═CH 2 )
2,5-Cl 2 ;
(5-Br)-2-pyridinyl
5-Cl;
and pharmaceutically acceptable salts thereof.
33 . The compound of claim 1 wherein the compound of Formula (I) is selected from Formula (Id):
Formula (Id)
wherein R, R 1 and R 2 are dependently selected from
R
R 1
R 2
2-thienyl
3-pyridinyl
H;
and pharmaceutically acceptable salts thereof.
34 . A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
35 . A composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
36 . A method for preparing a composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.Cited by (0)
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