US2008146574A1PendingUtilityA1
Heterocycle Substituted Carboxylic Acids
Assignee: INST PHARMACEUTICAL DISCOVERYPriority: Apr 30, 2003Filed: Feb 12, 2008Published: Jun 19, 2008
Est. expiryApr 30, 2023(expired)· nominal 20-yr term from priority
A61P 7/02A61P 9/12A61P 9/10A61P 5/50A61P 37/02A61P 43/00A61P 3/06A61P 7/04A61P 3/10C07D 417/12C07D 405/14A61P 35/00C07D 405/10C07D 417/10C07D 409/10C07D 401/14A61P 3/04C07D 405/12
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Claims
Abstract
The present invention relates to compounds and pharmaceutically acceptable salts of formula (I): which are useful in the treatment of metabolic disorders related to insulin resistance, leptin resistance, or hyperglycemia. Compounds of the invention include inhibitors of Protein tyrosine phosphatases, in particular Protein tyrosine phosphatase-1B (PTP-1B), that are useful in the treatment of diabetes and other PTP mediated diseases, such as cancer, neurodegenerative diseases and the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein,
R 1 is H, C 1 -C 6 alkyl, phenyl (C 1 -C 6 )alkyl, or C 3 -C 6 alkenyl;
L is a bond, —SO 2 —, —C(O)—, —O—(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkyl-O—, —C(O)—(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkyl-C(O)—, —O—, —S—, —SO—, —SO 2 —, or —(C 1 -C 4 )alkyl-,
L 2 is a bond, —NR 8 —, —O—, —S—, —SO—, —SO 2 —, —(C 1 -C 4 )alkyl-, —NR 8 C(O)—, or —C(O)NR 8 —;
L 3 is a bond, —(C 1 -C 4 )alkyl-O—, —O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-, C 2 -C 6 alkenyl, or C(O);
R 2 is H, halogen, arylalkoxy, aryl, arylalkyl, alkoxycarbonyl, C 1 -C 6 alkyl optionally substituted with phenyl, C 1 -C 6 alkoxy optionally substituted with phenyl, —(C 1 -C 4 )alkyl-C(O)NH 2 , —(C 1 -C 4 )alkyl-C(O)NH(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)N(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-S(O) b —(C 1 -C 4 )alkyl, —SO 2 -aryl, (C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkyl-heterocycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or OH,
wherein each heterocycloalkyl is optionally substituted with a total of 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —SO 2 —(C 1 -C 4 )alkyl;
wherein each aryl group within R 2 is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, or NO 2 ;
wherein b is 0, 1, or 2;
each R 6 and R 7 are independently H, C 1 -C 6 alkyl, aryl(C 1 -C 6 )alkyl, alkanoyl, arylalkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, heteroarylcarbonyl, heteroaryl, heterocycloalkylcarbonyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, or —SO 2 -aryl, wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NO 2 , OH, NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, haloalkyl or haloalkoxy;
R 8 at each occurrence is independently H or C 1 -C 6 alkyl;
R 20 , R 21 , R 22 , and R 23 are independently selected from H, arylalkoxy, arylalkyl, halogen, alkyl, OH, alkoxy, NO 2 , NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, NH-aryl, NHC(O)—(C 1 -C 4 )alkyl-aryl, N(C 1 -C 4 alkyl)C(O)—(C 1 -C 4 )alkyl-aryl, N(C 1 -C 4 )alkyl-aryl, —NHSO 2 -aryl, —N(C 1 -C 4 alkyl)SO 2 aryl, wherein the aryl group is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, OH, NO 2 , haloalkyl, haloalkoxy;
the A ring is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, haloalkyl, haloalkoxy, NO 2 , NH 2 , NH(C 1 -C 6 )alkyl, or N(C 1 -C 6 )alkyl (C 1 -C 6 )alkyl;
the B ring is heterocycloalkyl, or heteroaryl, wherein each is optionally substituted with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy, arylalkyl, arylalkoxy, halogen, alkoxycarbonyl, aryl, or OH;
Q is H, aryl, -aryl-carbonyl-aryl, -aryl-alkyl-aryl, -aryl-alkyl-heteroaryl, -aryl-heteroaryl, -heteroaryl-aryl, -aryl-heterocycloalkyl, heteroaryl, -heteroaryl-alkyl-aryl, or -heterocycloalkyl, wherein the aforementioned cyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, haloalkyl, haloalkoxy, NR 6 R 7 , or phenyl;
Y is selected from a bond, —O—(C 1 -C 6 alkyl)- optionally substituted with phenyl, —NHC(O)—(C 1 -C 4 )alkyl-, —N(C 1 -C 4 ) alkylC(O)—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl- optionally substituted with phenyl, —N(R 8 )C 1 -C 6 alkyl-, —C(O)—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C(O)—, —C(O)NR 8 —, —C(O)N(R 8 )—C 1 -C 6 alkyl, wherein the alkyl portion is optionally substituted with phenyl, —C(O)NR 8 , —NR 8 C(O)—, —C 1 -C 6 alkyl-NR 8 —, —SO 2 N(R 90 )—C 1 -C 4 alkyl-, or —NR 8 C(O)—; wherein
R 90 is H, C 1 -C 6 alkyl, phenyl, or —C 1 -C 4 alkyl-phenyl, wherein the phenyl groups are optionally substituted with 1,2 3, 4, or 5 groups that are independently alkyl, alkoxy, halogen, haloalkyl, CN, or haloalkyl, and
Z is absent or phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, or hydroxy.
2 . A compound according to claim 1 , wherein
R 1 is H, C 1 -C 6 alkyl, benzyl, or allyl; L 3 is a bond, —(C 1 -C 4 )alkyl —O—, —O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-, or C(O); R 2 is phenyl C 1 -C 4 alkoxy, phenyl, naphthyl, phenyl C 1 -C 4 alkyl, naphthyl C 1 -C 4 alkyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(C 1 -C 4 )alkyl-C(O)NH 2 , —(C 1 -C 4 )alkyl-C(O)NH(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)N(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-S(O) b —(C 1 -C 4 )alkyl, —SO 2 -phenyl, —SO 2 -naphthyl, (C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkyl-piperidinyl, —(C 1 -C 4 ) alkyl-pyrrolidinyl, —(C 1 -C 4 )alkyl-morpholinyl, or OH,
wherein the piperidinyl, pyrrolidinyl and morpholinyl rings are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —SO 2 —(C 1 -C 4 )alkyl;
wherein the phenyl and naphthyl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or NO 2 ;
wherein b is 0, 1, or 2;
R 8 is H or C 1 -C 6 alkyl;
R 20 , R 21 , R 22 , and R 23 are independently selected from H, phenyl C 1 -C 6 alkoxy, phenyl C 1 -C 6 alkyl, halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, NO 2 , NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, NH-phenyl, NHC(O)—(C 1 -C 4 )alkyl-phenyl, N(C 1 -C 4 alkyl)C(O)—(C 1 -C 4 )alkyl-phenyl, N(C 1 -C 4 )alkyl-phenyl, —NHSO 2 -phenyl, —N(C 1 -C 4 alkyl)SO 2 -phenyl, wherein the phenyl group is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, OH, NO 2 , C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy; the A ring is phenyl, indolyl, benzofuranyl, dibenzofuranyl, dibenzothienyl, thianthrenyl, thiazolyl, or isoindolyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, haloalkyl, haloalkoxy, NO 2 , NH 2 , NH(C 1 -C 6 )alkyl, or N(C 1 -C 6 )alkyl (C 1 -C 6 )alkyl; the B ring is pyrrolidinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, pyrrolidinonyl, pyrrolyl, thienyl, thiazolyl, pyrazolyl, thiazolidinyl, dihydroquinoxalinonyl, pyridinonyl, dihydroisoquinolinyl, indolyl, benzimidazolyl, quinolinyl, pyridinyl, or pyrimidinyl, wherein each is optionally substituted with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy, phenyl (C 1 -C 4 )alkyl, phenyl (C 1 -C 4 )alkoxy (benzyloxy), halogen, C 1 -C 6 alkoxycarbonyl, phenyl, or OH; Q is H, phenyl, -phenyl-carbonyl-phenyl, -phenyl-alkyl-phenyl, -phenyl-alkyl-benzofuranyl, -phenyl-pyridyl, -phenyl-benzofuranyl, -phenyl-piperidinyl, -phenyl-pyrrolidinyl, indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl, -pyridyl-phenyl, -pyrimidyl-phenyl, -benzofuranyl—C 1 -C 4 alkyl-phenyl, -pyridyl—C 1 -C 4 alkyl-phenyl, -piperidinyl, pyrrolidinyl, or indolinyl, wherein each aforementioned cyclic group is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, NR 6 R 7 , or phenyl; Y is selected from a bond, —NHC(O)—(C 1 -C 4 )alkyl-, —N(C 1 -C 4 ) alkyl-C(O)—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl- wherein the alkyl is optionally substituted with phenyl, —SO 2 N(R 8 )—C 1 -C 6 alkyl-, —C 1 -C 6 alkyl-SO 2 N(R 8 ), —N(R 8 )SO 2 N(R 8 )—C 1 -C 6 alkyl-, —C 1 -C 6 alkyl-N(R 8 )SO 2 —, —C(O)NR 8 —, or —NR 8 C(O)—; and Z is absent or phenyl optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, or hydroxy.
3 . A compound according to claim 2 ,
wherein R 22 and R 23 are both H; R 2 is benzyloxy, phenethyloxy, phenyl, phenyl C 1 -C 4 alkyl, —CH 2 -naphthyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(C 1 -C 4 )alkyl-C(O)NH 2 , —(C 1 -C 4 )alkyl-C(O)NH(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)N(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-S(O) b —(C 1 -C 4 )alkyl, —SO 2 -phenyl, (C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkyl-piperidinyl, —(C 1 -C 4 )alkyl-pyrrolidinyl, —(C 1 -C 4 ) alkyl-morpholinyl, or OH,
wherein the piperidinyl, pyrrolidinyl and morpholinyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —SO 2 —(C 1 -C 4 )alkyl;
wherein the phenyl and naphthyl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or NO 2 ;
each R 6 and R 7 are independently H, C 1 -C 6 alkyl, phenyl(C 1 -C 6 )alkyl, C 2 -C 6 alkanoyl, phenyl(C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, phenyl (C 1 -C 6 )alkoxycarbonyl, pyridylcarbonyl, pyridyl, piperidinyl, morpholinyl, pyrrolidinylcarbonyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, —C(O)N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, or —SO 2 -phenyl, wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NO 2 , OH, NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy, wherein b is 0, 1, or 2; and Z is absent.
4 . A compound according to claim 3 of the formula
wherein
the B ring is pyrrolidinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl, thiazolidinyl, dihydroquinoxalinonyl, pyridinonyl, or dihydroisoquinolinyl, wherein each is optionally substituted with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy, phenyl (C 1 -C 4 )alkyl (benzyl), phenyl (C 1 -C 4 )alkoxy (benzyloxy), halogen, C 1 -C 6 alkoxycarbonyl, phenyl, or OH;
Q is H, phenyl, -phenyl-alkyl-phenyl, -phenyl-pyridyl, -phenyl-benzofuranyl, -phenyl-piperidinyl, -phenyl-pyrrolidinyl, indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl, -pyridyl-phenyl, -benzofuranyl—C 1 -C 4 alkyl-phenyl, -pyridyl-C 1 -C 4 alkyl-phenyl, -piperidinyl, -pyrrolidinyl, -indolinyl, wherein the aforementioned cyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, NR 6 R 7 , or phenyl; wherein
each R 6 and R 7 are independently H, C 1 -C 6 alkyl, phenyl(C 1 -C 4 )alkyl, C 2 -C 6 alkanoyl, phenyl(C 1 -C 4 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, phenyl (C 1 -C 4 )alkoxycarbonyl, pyridylcarbonyl, or —SO 2 -phenyl, wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NO 2 , OH, NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy; and
Y is selected from a bond, —NHC(O)—(C 1 -C 4 )alkyl-, —N(C 1 -C 4 ) alkylC(O)—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl- wherein the alkyl is optionally substituted with phenyl, or —NHC(O)—.
5 . A compound according to claim 4 , wherein
R 1 is H or C 1 -C 4 alkyl; and R 2 is benzyloxy, phenethyloxy, phenyl, phenyl C 1 -C 4 alkyl, —CH 2 -naphthyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(C 1 -C 4 )alkyl-S(O) 2 —(C 1 -C 4 )alkyl, —SO 2 -phenyl, (C 1 -C 4 ) hydroxyalkyl, —(C 1 -C 4 )alkyl-piperidinyl, —(C 1 -C 4 )alkyl-pyrrolidinyl, —(C 1 -C 4 )alkyl-morpholinyl, or OH, wherein the piperidinyl, pyrrolidinyl and morpholinyl groups are optionally substituted with a total of 1, 2, or 3 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —SO 2 —(C 1 -C 4 )alkyl;
wherein the phenyl and naphthyl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or NO 2 .
6 . A compound according to claim 5 , wherein
R 20 , and R 21 are independently selected from H, benzyloxy, benzyl, halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, NO 2 , NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, NH-phenyl, N(C 1 -C 4 )alkyl-phenyl, wherein the phenyl group is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, OH, NO 2 , C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy; and the B ring is pyrrolidinyl, tetrahydroisoquinolinyl, piperidinyl, pyrrolidinonyl, thiazolidinyl, pyrrolyl, pyrazolyl, dihydroquinoxalinonyl, pyridinonyl, wherein each is optionally substituted with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy, benzyl, benzyloxy, halogen, C 1 -C 6 alkoxycarbonyl, phenyl, OH.
7 . A compound according to claim 6 , wherein
Q is H, phenyl, -phenyl-carbonyl-phenyl, -phenyl—C 1 -C 2 alkyl-phenyl, -phenyl-pyridyl, -phenyl-benzofuranyl, indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl, -benzofuranyl—C 1 -C 4 alkyl-phenyl, -pyridyl—C 1 -C 4 alkyl-phenyl, -piperidinyl, -pyrrolidinyl, -indolinyl, wherein the aforementioned cyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, CF 3 , OCF 3 , NR 6 R 7 , or phenyl; wherein R 6 and R 7 are independently H, C 1 -C 6 alkyl, benzyl, C 2 -C 6 alkanoyl, phenyl(C 1 -C 4 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, phenyl(C 1 -C 4 )alkoxycarbonyl, or —SO 2 -phenyl, wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NO 2 , OH, NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy.
8 . A compound according to claim 7 , of the formula
wherein
L 3 is a bond, or —(C 1 -C 4 )alkyl-;
R 1 is H or C 1 -C 4 alkyl;
R 2 is benzyloxy, phenyl, phenyl C 1 -C 4 alkyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —SO 2 -phenyl, (C 1 -C 4 )hydroxyalkyl or OH,
wherein the phenyl group is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or NO 2 .
R 20 , and R 21 are independently selected from H, benzyloxy, benzyl, halogen, C 1 -C 4 alkyl, OH, C 1 -C 4 alkoxy, and NO 2 ;
the B ring is pyrrolidinyl, tetrahydroisoquinolinyl, piperidinyl, pyrrolidinonyl, thiazolidinyl, pyrrolyl, pyrazolyl, dihydroquinoxalinonyl, pyridinonyl, wherein each is optionally substituted with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy, benzyl, benzyloxy, halogen, C 1 -C 6 alkoxycarbonyl, phenyl, or OH;
Q is H, phenyl, indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl, -benzofuranyl-CH 2 -phenyl, wherein the aforementioned cyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, CF 3 , OCF 3 , NR 6 R 7 , or phenyl; wherein
R 6 and R 7 are independently H, C 1 -C 6 alkyl, benzyl, C 2 -C 6 alkanoyl, phenyl(C 1 -C 4 )alkanoyl, or —SO 2 -phenyl, wherein the phenyl groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NO 2 , OH, NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, CF 3 or OCF 3 .
9 . A compound according to claim 8 , wherein
Y is a bond or —(C 1 -C 4 )alkyl-.
10 . A compound according to claim 8 ,
wherein Y is selected from —NHC(O)—(C 1 -C 4 )alkyl-, —N(C 1 -C 4 )alkyl C(O)—(C 1 -C 4 )alkyl-, —(C 1 -C 4 )alkyl- wherein the alkyl is optionally substituted with phenyl, or —NHC(O)—.
11 . A compound according to claim 1 , of the formula
wherein
R 1 is H, C 1 -C 4 alkyl, benzyl or allyl;
the B ring is indolyl, benzimidazolyl, quinolinyl, pyrrolyl, pyrazolyl, pyrimidinyl, or pyridinyl, wherein each is optionally substituted with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy, phenyl (C 1 -C 4 )alkyl, phenyl (C 1 -C 4 )alkoxy (benzyloxy), halogen, C 1 -C 6 alkoxycarbonyl, phenyl, OH.
12 . A compound according to claim 11 ,
wherein Q is H, phenyl, -phenyl-benzyl, -phenyl-pyridyl, -phenyl-benzofuranyl, -phenyl—C 1 -C 4 alkyl-benzofuranyl, -phenyl-piperidinyl, -phenyl-pyrrolidinyl, indolizinyl, benzofuranyl, indolyl, isoindolyl, quinolinyl, -benzofuranyl—C 1 -C 4 alkyl-phenyl, -pyridyl—C 1 -C 4 alkyl-phenyl, -piperidinyl, pyrrolidinyl, or indolinyl, wherein the aforementioned cyclic groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, NR 6 R 7 , or phenyl; wherein R 6 and R 7 are independently H, C 1 -C 6 alkyl, phenyl(C 1 -C 4 )alkyl, C 2 -C 6 alkanoyl, phenyl(C 1 -C 4 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, phenyl (C 1 -C 4 )alkoxycarbonyl, pyridylcarbonyl, or —SO 2 -phenyl, wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NO 2 , OH, NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy.
13 - 17 . (canceled)
18 . A method of treating type 1 or type 2 diabetes comprising administering a pharmaceutically acceptable amount of a compound of claim 1 to a patient in need thereof.
19 . A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable solvent, carrier, excipient or adjuvant.
20 . A compound according to claim 1 which is
1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}-4-(benzyloxy)proline;
4-(benzyloxy)-1-{[4′-(1-butylindolizin-2-yl)biphenyl-4-yl]sulfonyl}proline;
1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]sulfonyl}proline;
4-(benzyloxy)-1-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)proline;
1-({4′-[(2-butyl-1-benzofuran-3-yl)methyl]biphenyl-4-yl}sulfonyl)proline;
2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}piperidine-2-carboxylic acid;
1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}piperidine-3-carboxylic acid;
1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}proline;
(2-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid;
(1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}pyrrolidin-2-yl)acetic acid;
1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]carbonyl}-3-phenylproline;
(4R)-1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-4-(benzyloxy)-L-proline;
{1-benzyl-5-[4-(1H-indol-1-yl)phenyl]-1H-indol-3-yl}acetic acid;
1-{[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]methyl}-5-oxoproline;
[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1-(tert-butoxycarbonyl)-1H-indol-3-yl]acetic acid;
15-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1-[(4-methyl-3-nitrophenyl)sulfonyl]-1H-indol-3-yl]acetic acid;
3-{[5-{4-[(2-butyl-1-benzofuran-3-yl)methyl]phenyl}-2-(3-phenylpropoxy)pyridin-3-yl]amino}-3-oxopropanoic acid;
[5-[4-(1H-indol-1-yl)phenyl]-1-(2-naphthylmethyl)-1H-indol-3-yl]acetic acid;
(4R)-2-[4′-(2-benzyl-1-benzofuran-3-yl)biphenyl-4-yl]-1,3-thiazolidine-4-carboxylic acid;
(4R)-2-[4′-(1H-indol-1-yl)biphenyl-4-yl]-1,3-thiazolidine-4-carboxylic acid;
1-[4′-(2-benzyl-1-benzofuran-3-yl)-3-nitrobiphenyl-4-yl]-4-hydroxyproline;
{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}acetic acid;
{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}acetic acid;
3-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}propanoic acid;
4-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}butanoic acid;
4-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-phenyl-1H-benzimidazol-1-yl}butanoic acid;
4-[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-(2-phenylethyl)-1H-benzimidazol-1-yl]butanoic acid;
4-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}butanoic acid;
3-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}propanoic acid;
3-[5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-(2-phenylethyl)-1H-benzimidazol-1-yl]propanoic acid;
{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}acetic acid;
3-{1-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-2-yl}propanoic acid;
{1-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-2-yl}acetic acid;
2-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-hydroxy-1H-benzimidazol-1-yl}-3-phenylpropanoic acid;
2-{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2-methyl-1H-benzimidazol-1-yl}-3-phenylpropanoic acid;
2-{2-benzyl-5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-benzimidazol-1-yl}-3-phenylpropanoic acid;
[2-benzyl-7-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]acetic acid;
methyl 1-{[4-({[4-(4-chlorophenyl)-5-(4-ethylphenyl)-1,3-thiazol-2-yl]amino}carbonyl)phenyl]sulfonyl}prolinate;
{3-[4-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl]-1-benzofuran-2-yl}(phenyl)acetic acid
4-(benzyloxy)-1-{[4′-(5-methyl-1H-indol-1-yl)biphenyl-4-yl]carbonyl}-L-proline
{5-[4-(1H-indol-1-yl)phenyl]-1-[(4-methyl-3-nitrophenyl)sulfonyl]-2,3-dihydro-1H-indol-3-yl}acetic acid;
{5-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-1H-indol-3-yl}acetic acid;
[6-[4-(2-benzyl-1-benzofuran-3-yl)phenyl]-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl]acetic acid;
[4-(4-dibenzo[b,d]thien-4-ylphenyl)piperazin-1-yl](phenyl)acetic acid;
({4′-[10-(ethoxycarbonyl)pyrido[1,2-a]indol-3-yl]biphenyl-4-yl}oxy)(phenyl)acetic acid;
N-[5-[4-(2-Butyl-benzofuran-3-ylmethyl)-phenyl]-2-oxo-1-(3-phenyl-propyl)-1,2-dihydro-pyridin-3-yl]-malonamic acid;
N-[1-Benzyl-5-(4-dibenzofuran-4-yl-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-oxalamic acid;
[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid;
[5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetic acid;
{[1-benzyl-5-(4-dibenzo[b,d]furan-4-ylphenyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}(oxo)acetic acid;
4-{5-Chloro-1-[4-(dibenzofuran-4-ylamino)-benzyl]-1H-indol-3-yl}-4-oxo-butyric acid;
4-[5-Chloro-1-[4-(2-methoxy-dibenzofuran-3-ylamino)-benzyl]-1H-indol-3-yl]-4-oxo-butyric acid;
4-[5-Chloro-1-(4-thianthren-1-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyric acid;
4-[5-Chloro-1-(4-dibenzofuran-4-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyric acid;
4-[5-Chloro-1-(4-dibenzothiophen-4-yl-benzyl)-1H-indol-3-yl]-4-oxo-butyric acid;
4-{5-Chloro-1-[2-oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-1H-indol-3-yl}-4-oxo-butyric acid;
4-{5-Chloro-1-[2-(5-chloro-3-methyl-benzo[b]thiophen-2-yl)-2-oxo-ethyl]-1H-indol-3-yl}-4-oxo-butyric acid;
and pharmaceutically acceptable salts thereof.
21 . A compound of the formula
wherein
R 1 is H, C 1 -C 6 alkyl, or phenyl(C 1 -C 6 )alkyl;
L is a bond, —SO 2 —, —C(O)—, or —(C 1 -C 4 )alkyl-;
L 2 is a bond, C 1 -C 2 alkylene, —NR 8 C(O)—, or —C(O)NR 8 —, where R 8 is H or C 1 -C 6 alkyl;
R 2 is phenyl C 1 -C 4 alkoxy, phenyl, naphthyl, phenyl C 1 -C 4 alkyl, naphthyl C 1 -C 4 alkyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(C 1 -C 4 )alkyl-C(O)NH 2 , —(C 1 -C 4 )alkyl-C(O)NH(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)N(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkyl-S(O) b —(C 1 -C 4 )alkyl, —SO 2 -phenyl, —SO 2 -naphthyl, (C 1 -C 4 )hydroxyalkyl, —(C 1 -C 4 )alkyl-piperidinyl, —(C 1 -C 4 ) alkyl-pyrrolidinyl, —(C 1 -C 4 )alkyl-morpholinyl, or OH,
wherein the piperidinyl, pyrrolidinyl and morpholinyl rings are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or —SO 2 —(C 1 -C 4 )alkyl;
wherein the phenyl and naphthyl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or NO 2 ;
wherein b is 0, 1, or 2;
A is phenyl, benzofuranyl, or dibenzofuranyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, nitro, halogen, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, NR 6 R 7 , or phenyl; wherein
each R 6 and R 7 is independently H, C 1 -C 6 alkyl, phenyl(C 1 -C 4 )alkyl, C 2 -C 6 alkanoyl, phenyl(C 1 -C 4 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, phenyl (C 1 -C 4 )alkoxycarbonyl, pyridylcarbonyl, or —SO 2 -phenyl, wherein the cyclic groups are optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NO 2 , OH, NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy;
R 20 and R 21 are independently selected from H, benzyloxy, benzyl, halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, NO 2 , NH 2 , NH(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl, NH-phenyl, or N(C 1 -C 4 )alkyl-phenyl, wherein the phenyl group is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, OH, NO 2 , C 1 -C 4 haloalkyl, or C 1 -C 4 haloalkoxy;
the B ring is pyrrolidinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, pyrrolidinonyl, pyrazolyl, dihydropyrazolyl, thiazolidinyl, dihydroquinoxalinonyl, pyridinonyl, or dihydroisoquinolinyl, wherein each is optionally substituted with 1, 2, 3, or 4 groups that are independently alkyl, alkoxy, phenyl (C 1 -C 4 )alkyl (benzyl), phenyl (C 1 -C 4 )alkoxy (benzyloxy), halogen, C 1 -C 6 alkoxycarbonyl, phenyl, or OH; and
Y is a bond, —(C 1 -C 4 )alkyl- optionally substituted with phenyl, —NHC(O)—(C 1 -C 4 )alkyl-, —N(C 1 -C 4 )alkylC(O)—(C 1 -C 4 )alkyl-, or —NHC(O)—.
22 - 30 . (canceled)
31 . A compound according to claim 21 of the formula:
wherein
R 1 is H or C 1 -C 6 alkyl;
L is a bond or C 1 -C 2 alkylene;
L 2 is a bond or —CH 2 —;
A represents
where R 10 and R 10′ independently represent hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, haloalkyl, haloalkoxy, NO 2 , NH 2 , NH(C 1 -C 6 )alkyl, or N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl; and
Y is a bond, —NHC(O)— or —NHC(O) (C 1 -C 2 )alkyl-.
32 . A compound according to claim 31 , wherein R 10 is C 1 -C 6 alkyl.
33 . A compound according to claim 32 wherein the B ring is 1-dihydropyrazolyl, 1-pyridinonyl or 1-pyrazolyl, each of which is optionally substituted with 1 or 2 groups that are independently alkyl, alkoxy, benzyl, phenethyl, benzyloxy, halogen, C 1 -C 6 alkoxycarbonyl, phenyl, or OH.
34 - 37 . (canceled)
38 . A compound according to claim 31 , wherein R 10 is not hydrogen and R 10′ is hydrogen.Cited by (0)
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