US 7,601,752 B2
Pyrrolidine derivatives
Lilli Anselm, Binzen (Germany); Katrin Groebke Zbinden, Liestal (Switzerland); Wolfgang Haap, Loerrach (Germany); Hans Hilpert, Muenchenstein (Switzerland); Jacques Himber, Guebwiller (France); Bernd Kuhn, Liestal (Switzerland); Narendra Panday, Munich (Germany); Fabienne Ricklin, Hombourg (France); and Stefan Thomi, Basel (Switzerland)
Assigned to Hoffmann-La Roche Inc., Nutley, N.J. (US)
Filed on Nov. 06, 2006, as Appl. No. 11/593,821.
Claims priority of application No. 05110818 (EP), filed on Nov. 16, 2005.
Prior Publication US 2007/0112001 A1, May 17, 2007
Int. Cl. A61K 31/4025 (2006.01); C07D 409/12 (2006.01)
U.S. Cl. 514—423  [548/517; 548/527; 514/408; 514/422] 17 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of: (1) hydrogen, (2) optionally substituted C1-6-alkyl, (3) optionally substituted C3-7-cycloalkyl, (4) optionally substituted C3-7-cycloalkyl-C1-6-alkyl, (5) optionally substituted C2-6-alkenyl, (6) optionally substituted C2-6-alkynyl, (7) R4C(O)—, (8) R4OC(O)—, (9) N(R5,R6)C(O)—, (10) R4OC(O)—C1-6-alkyl, (11) N(R5,R6)C(O)—C1-6-alkyl, (12) R4—SO2—, (13) R4—SO2—C1-6-alkyl, (14) N(R5,R6)—SO2—, (15) N(R5,R6)—SO2—C1-6-alkyl, (16) heteroaryl, (17) heteroaryl-C1-6-alkyl, (18) aryl, and (19) aryl-C1-6-alkyl;
R2 is hydrogen or C1-6 alkyl; or
R1 and R2 form C1-6 alkylene, C2-7 alkenylene or C2-7 alkynylene, wherein one or two —CH2— groups may be independently replaced with —O—, —NH—, carbonyl or —S(O)n—, where n is 0, 1 or 2;
R3 is hydrogen or C1-6 alkyl;
R4 is hydrogen, optionally substituted C1-6-alkyl, optionally substituted C3-7 cycloalkyl, optionally substituted C3-7 cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl, heteroaryl or heteroaryl-C1-6-alkyl;
R5 and R6 independently from each other are selected from the group consisting of: (1) hydrogen, (2) optionally substituted C1-6-alkyl, (3) optionally substituted C3-7 cycloalkyl, (4) optionally substituted C3-7 cycloalkyl-C1-6-alkyl, (5) aryl, (6) aryl-C1-6-alkyl, (7) heteroaryl and (8) heteroaryl-C1-6-alkyl; or R5 and R6, together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolinyl and azetidinyl, said heterocyclic ring being optionally substituted by one or more substituents independently selected from the group consisting of C1-6-alkyl, halogen and hydroxy;
X is arylene, heteroarylene or heterocyclylene, said arylene, heteroarylene or heterocyclylene being optionally substituted by one or more substituents independently selected from the group consisting of : (1) C1-6 alkyl, (2) C3-7 cycloalkyl, (3) C3-7 cycloalkyl-C1-6-alkyl, (4) C1-6 alkoxy, (5) fluoro-C1-6 alkoxy, (6) carboxyl, (7) halogen, (8) cyano, (9) nitro, (10) amino, (11) —N(R′)—CO—(C1-6 alkyl optionally substituted by one or more fluorine atoms), wherein R′ is hydrogen, C1-6 alkyl or fluoro C1-6 alkyl, (12) —N(R′)—CO—O—(C1-6 alkyl optionally substituted by one or more fluorine atoms), wherein R′ is hydrogen, C1-6 alkyl or fluoro C1-6 alkyl, (13) —N(R′)—CO—N(R″) (R′″), wherein R′, R″ and R′″ are independently hydrogen, C1-6 alkyl or fluoro C1-6 alkyl, (14) —C(O)—N(R′)(R″), wherein R′ and R″ are independently hydrogen, C1-6 alkyl or fluoro C1-6 alkyl, or R′ and R″, together with the nitrogen atom to which they are attached, form heterocycyl, (15) —NR′R″, wherein R′ and R″ are independently hydrogen, C1-6 alkyl or fluoro C1-6 alkyl, or R′ and R″, together with the nitrogen atom to which they are attached, form heterocycyl, (16)

OG Complex Work Unit Drawing
 wherein R′ and R″ are independently C1-6 alkyl or fluoro C1-6 alkyl, or R′ and R″, together with the nitrogen atom to which they are attached, form heterocyclyl, (17)

OG Complex Work Unit Drawing
 wherein R′ and R″ are independently C1-6 alkyl or fluoro C1-6 alkyl, or R′ and R″, together with the nitrogen atom to which they are attached, form heterocyclyl, (18)

OG Complex Work Unit Drawing
 wherein R′ is fluoro C1-6 alkyl and (19)

OG Complex Work Unit Drawing
 wherein R′ is fluoro C1-6 alkyl, wherein one or two carbon atoms of said arylene, heteroarylene or heterocyclylene are optionally replaced with a carbonyl group;
Y is hydrogen, aryl, heteroaryl or heterocyclyl, said aryl, heteroaryl or heterocyclyl being optionally substituted by one or more substituents independently selected from the group consisting of: (1) C1-6 alkyl optionally substituted by one or more fluorine atoms, (2) C1-6 alkoxy optionally substituted by one or more fluorine atoms, (3) halogen, (4) cyano, (5) nitro, (6) amino, (7) mono- or di-C1-6 alkyl substituted amino, wherein said C1-6 alkyl is optionally substituted by one or more fluorine atoms, (8) mono- or di-C1-6 alkyl substituted amino-C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted by one or more fluorine atoms, (9) —SO2—C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted by one or more fluorine atoms, (10) —SO2—NH2, (11) —SO2—NH—C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted by one or more fluorine atoms, and (12) —SO2—N(C1-6 alkyl)2, wherein said C1-6 alkyl is optionally substituted by one or more fluorine atoms, and wherein one or two carbon atoms of said aryl, heteroaryl or heterocyclyl are optionally replaced with a carbonyl group.