Bicyclic heteroaryl compounds as GPR119 modulators

Patent metadata

Field	Value
Publication number	US-8940716-B2
Application number	US-201113696103-A
Country	US
Kind code	B2
Filing date	May 4, 2011
Priority date	May 6, 2010
Publication date	Jan 27, 2015
Grant date	Jan 27, 2015

Abstract

Novel compounds of structure Formula I: or an enantiomer, diastereomer, tautomer, prodrug or salt thereof, wherein A, D, Di, E, J, L, n, Q, R 2 and R 4 are defined herein, are provided which are GPR119 G protein-coupled receptor modulators. GPR119 G protein-coupled receptor modulators are useful in treating, preventing, or slowing the progression of diseases requiring GPR119 G protein-coupled receptor modulator therapy. Thus, the disclosure also concerns compositions comprising these novel compounds and methods of treating diseases or conditions related to the activity of the GPR119 G protein-coupled receptor by using any of these novel compounds or a composition comprising any of such novel compounds.

First claim

What is claimed is:

1. A compound of formula IIa:

or an enantiomer, diastereomer, tautomer or salt thereof wherein:

D is O or S;
G is CR 5 or N;
J is CH or N;
W is —S(═O) 2 —R 1 , —C(═O)—R 1 , —C(═O)—O—R 1 , or a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S and may be optionally substituted with one or more R 20 's;
L is —CR 1a R 1a —, or —O—; provided that L is —O— when A is

R 1a , at each occurrence, is independently hydrogen or (C 1 -C 8 )alkyl;
R 1 is (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 12 )-cycloalkyl, (C 6-10 )aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; all of which may be optionally substituted with one or more R 20 's;
R 4 is (C 1 -C 6 )-alkyl; which may be optionally substituted with one or more substituents selected from the group consisting of: halo, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 12 )-cycloalkyl, (C 1 -C 6 )-alkyloxy, cyano, nitro, —COOH, —CO(C 1 -C 6 )-alkyl, —CO 2 (C 1 -C 6 )-alkyl, —CONR 18 R 19 , —NR 18 R 19 , —O(C═O)—(C 1 -C 6 )-alkyl, —O(C═O)NR 18 R 19 , —(C 1 -C 6 )-alkylCOOH, —(C 1 -C 6 )-alkylOH, —(C 1 -C 6 )-alkyl(NH 2 )COOH, —(C 1 -C 6 )-alkylCONR 18 R 19 , —(C 1 -C 6 )-alkyl-CO 2 (C 1 -C 6 )-alkyl, (C 6-10 )aryl, heteroaryl, heterocyclo, dioxo-substituted heteroaryl, halo(C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyloxy; and wherein any heteroaryl and heterocyclo contains 4- to 10-members and 1-4 heteroatoms selected from N, O, and S; or
R 4 is (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, —CO(C 1 -C 6 )-alkyl, —CO(C 3 -C 12 )-cycloalkyl, —CO(C 6-10 )aryl, —CO-heteroaryl, —CO 2 (C 1 -C 6 )-alkyl, —CO 2 (C 3 -C 12 )-cycloalkyl, —CO 2 (C 6-10 )aryl, —SO 2 (C 1 -C 6 )-alkyl, —SO 2 (C 3 -C 12 )-cycloalkyl, —SO 2 (C 6-10 )aryl, —SO 2 -heteroaryl, (C 6-10 )aryl, heteroaryl or heterocyclo, wherein any alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo may be optionally substituted with one or more substituents selected from the group consisting of: halo, —OH, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 12 )-cycloalkyl, (C 1 -C 6 )-alkyloxy, cyano, nitro, —COOH, —CO(C 1 -C 6 )-alkyl, —CO 2 (C 1 -C 6 )-alkyl, —CONR 18 R 19 , —NR 18 R 19 , —O(C═O)—(C 1 -C 6 )-alkyl, —O(C═O)NR 18 R 19 , —(C 1 -C 6 )-alkylCOOH, —(C 1 -C 6 )-alkylOH, —(C 1 -C 6 )-alkyl(NH 2 )COOH, —(C 1 -C 6 )-alkylCONR 18 R 19 , —(C 1 -C 6 )-alkyl-CO 2 (C 1 -C 6 )-alkyl, (C 6-10 )aryl, heteroaryl, heterocyclo, dioxo-substituted heteroaryl, halo(C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyloxy; and wherein any heteroaryl and heterocyclo contains 4- to 10-members and 1-4 heteroatoms selected from N, O, and S;
R 5 , is independently H, halo, —OH or (C 1 -C 6 )-alkyl;
R 18 and R 19 , at each occurrence, are independently hydrogen or (C 1 -C 8 )alkyl, wherein the alkyl may be optionally substituted with one or more R 20 's;
or R 18 and R 19 are taken together with the nitrogen to which both are attached to form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S and be optionally substituted with one or more R 20 's;
R 20 , at each occurrence, is independently halo, —OH, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, —(C 3 -C 12 )-cycloalkyl, (C 1 -C 6 )-alkyloxy, cyano, nitro, —COOH, —CO(C 1 -C 6 )-alkyl, —CO 2 (C 1 -C 6 )-alkyl, —CONR 28 R 29 , —NR 28 R 29 ,—NR 28 COR 29 , —O(C═O)—(C 1 -C 6 )-alkyl, —O(C═O)NR 28 R 29 , —(C 1 -C 6 )-alkylCOOH, —(C 1 -C 6 )-alkylOH, —(C 1 -C 6 )-alkyl(NH 2 )COOH, —(C 1 -C 6 )-alkylCONR 28 R 29 , —(C 1 -C 6 )-alkyl-CO 2 (C 1 -C 6 )-alkyl, —O—P(═O)(OR 28 ) 2 , —O—CR 1a R 1a —P(═O)(OR 28 ) 2 , —P(═O)(OR 28 ) 2 , (C 6-10 )aryl, (C 6-10 )aryloxy, —SO 3 H, —SO 2 R 28 , —SO 2 NR 28 R 29 , —NR 28 —SO 2 —R 29 , a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; wherein any alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo may be optionally substituted with one or more substituents selected from the group consisting of: halo, —OH, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 1 -C 6 )-alkyloxy, cyano, nitro, —COOH, —CO(C 1 -C 6 )-alkyl, —CO 2 (C 1 -C 6 )-alkyl, —CONR 28 R 29 , —NR 28 R 29 , —O(C═O)—(C 1 -C 6 )-alkyl, —O(C═O)NR 28 R 29 , —(C 1 -C 6 )-alkylCOOH, —(C 1 -C 6 )-alkylOH, —(C 1 -C 6 )-alkyl(NH 2 )COOH, —(C 1 -C 6 )-alkylCONR 28 R 29 , —(C 1 -C 6 )-alkyl-CO 2 (C 1 -C 6 )-alkyl, (C 6-10 )aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S, a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; halo(C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyloxy; and
R 28 and R 29 , at each occurrence, are independently hydrogen or (C 1 -C 8 )alkyl, wherein the alkyl may be optionally substituted with one or more substituents selected from the group consisting of: halo, —OH, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 1 -C 6 )-alkyloxy, cyano, nitro, —COOH, —CO(C 1 -C 6 )-alkyl, —CO 2 (C 1 -C 6 )-alkyl, —O(C═O)—(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-alkylCOOH, —(C 1 -C 6 )-alkylOH, —(C 1 -C 6 )-alkyl(NH 2 )COOH, —(C 1 -C 6 )-alkylCONR 28 R 29 , —(C 1 -C 6 )-alkyl-CO 2 (C 1 -C 6 )-alkyl, (C 6-10 )aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S, a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; halo(C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyloxy;
or R 28 and R 29 are taken together with the nitrogen to which both are attached to form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S, wherein the ring may be optionally substituted with one or more substituents selected from the group consisting of: halo, —OH, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 1 -C 6 )-alkyloxy, cyano, nitro, —COOH, —CO(C 1 -C 6 )-alkyl, —CO 2 (C 1 -C 6 )-alkyl, —O(C═O)—(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-alkylCOOH, —(C 1 -C 6 )-alkylOH, —(C 1 -C 6 )-alkyl(NH 2 )COOH, —(C 1 -C 6 )-alkyl-CO 2 (C 1 -C 6 )-alkyl, (C 6-10 )aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S, a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; halo(C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyloxy.

2. The compound, enantiomer, diastereomer, tautomer or salt thereof, of claim 1 , wherein:

D is O or S;
G is CH or N;
J is CR 2 or N;
W is —S(═O) 2 —R 1 , —C(═O)—R 1 , —C(═O)—O—R 1 , or a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S and may be optionally substituted with one or more R 20 's;
L is a bond, —CR 1a R 1a —, or —O—; provided that L is —O— or —O—CR 1a R 1a — when A is

R 1a , at each occurrence, is independently hydrogen or (C 1 -C 8 )alkyl;
R 1 is (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 12 )-cycloalkyl, (C 6-10 )aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to 10

Assignees

• Ye Xiang-Yang
• Wacker Dean A
• Robl Jeffrey A
• Wang Ying
• Bristol Myers Squibb Co

Inventors

• Ye Xiang-Yang
• Wacker Dean A
• Robl Jeffrey A
• Wang Ying

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title