US 7,488,725 B2
Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase IV and methods
Stephen P. O'Connor, Stockton, N.J. (US); and Lawrence G. Hamann, North Grafton, Mass. (US)
Assigned to Bristol-Myers Squibb Co., Princeton, N.J. (US)
Filed on Oct. 30, 2006, as Appl. No. 11/589,409.
Claims priority of provisional application 60/731795, filed on Oct. 31, 2005.
Prior Publication US 2007/0099913 A1, May 03, 2007
Int. Cl. C07D 207/06 (2006.01); C07D 207/14 (2006.01); C07D 401/06 (2006.01); C07D 403/06 (2006.01); C07D 413/06 (2006.01); A61K 31/40 (2006.01); A61K 31/422 (2006.01); A61K 31/4709 (2006.01); A61K 31/538 (2006.01); A61K 31/55 (2006.01); A61P 3/00 (2006.01)
U.S. Cl. 514—213.01  [514/230.5; 514/312; 514/343; 514/378; 514/414; 514/423; 540/593; 544/105; 546/165; 548/247; 548/468; 548/540] 20 Claims
 
1. A compound of the formula

OG Complex Work Unit Drawing
wherein:
R1 is selected from aryl, heteroaryl or cycloheteroalkyl, wherein said aryl or heteroaryl may optionally be substituted with 1-5 substituents selected from the group consisting of halo, C1-6 alkyl, and C1-6 polyhaloalkyl, and said cycloheteroalkyl may optionally be substituted with 1-5 substituents selected from the group consisting of C1-6 alkyl, halo, oxo (═O) and C1-6 perhaloalkyl;
R2 and R2′ are each independently selected from hydrogen, C1-6 alkyl, and C1-6 perhaloalkyl;
R3 and R4 are each independently selected from hydrogen, OR6 and NR7R8, wherein at least one of R3 and R4 is not hydrogen;
R5 is selected from aryl and heteroaryl wherein said aryl and heteroaryl may optionally be substituted with 1-5 substituents selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkoxycarbonyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylakyl, hydroxy, C1-6 hydroxyalkyl, nitro, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, thiol, C1-6 alkylthio, aminocarbonyl, C2-6 alkynylaminocarbonyl, C1-6 alkylaminocarbonyl, C2-6 alkenylaminocarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, arylsulfonyl, heteroarylsulfonyl, and sulfonamido;
R6 is selected from hydrogen, C1-6 alkyl, and C3-6 cycloalkyl;
R7 and R8 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, —CO—(C1-6 alkyl), —CO-aryl, —CO-heteroaryl, —CONH2, —CONH(C1-6 alkyl), CON(C1-6 alkyl)2, —SO2(C1-6 alkyl), —SO2-aryl, and —SO2-heteroaryl;
X is a methylene group or a bond, wherein the methylene group may be optionally substituted with one or two fluorine atoms;
Y is a methylene group, wherein said methylene group may be optionally substituted with one or two fluorine atoms, or Y and Z together may optionally form a bond;
Z is selected from a bond, —NR6—, —O—, —SOn—, —N(R6)SO2— and —SO2N(R6)—, or Z and R5 may be taken together to form

OG Complex Work Unit Drawing
wherein A forms a 5 to 8 membered cycloheteroalkyl and B is a fused 5 to 7 member ring system selected from aryl and heteroaryl, wherein said ring system may be optionally be substituted with one to five groups selected from the group consisting of halo, C1-6 alkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkoxycarbonyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, C1-6 hydroxyalkyl, nitro, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, thiol, C1-6 alkylthio, aminocarbonyl, C2-6 alkynylaminocarbonyl, C1-6 alkylaminocarbonyl, C2-6 alkenylamino-carbonyl, C1-6 alkylcarbonyloxy, C1-6 alkylcarbonylamino, arylcarbonylamino; heteroarylcarbonylamino, C1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C1-6 alkylaminocarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and sulfonamido; and
n is 0-2.