IP Library › Granted Patent US 10,017,497

Granted Patent B2

US 10,017,497 · App. 15/308,428 · Granted Jul 10, 2018

Pyrrolidine GPR40 modulators for the treatment of diseases such as diabetes

Inventor: Chongqing Sun (East Windsor, NJ)

Assignee: Bristol-Myers Squibb Company

C07D401/14 A61K31/497 A61K45/06

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Quick Facts

Patent No.: US 10,017,497
App. No.: 15/308,428
Granted: Jul 10, 2018
Kind: B2

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Abstract

The present invention provides compounds of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.

Claims (80)

1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:

X is independently selected from: a bond, O, S, NH, N(C 1-4 alkyl), CH 2 , CH 2 CH 2 , CH(C 1-4 alkyl), OCH 2 , CH 2 O, OCH 2 CH 2 , and CH 2 CH 2 O;

ring B is independently a 4- to 7-membered saturated heterocycle containing carbon atoms, the nitrogen atom shown in the ring B and 0-1 additional heteroatom selected from N, O, and S; and ring B is substituted with 0-4 R 2 ;

R 1 is independently phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR 11 , O, and S; wherein said phenyl, benzyl, naphthyl and heteroaryl are each substituted with 0-3 R 6 ;

R 2 , at each occurrence, is independently selected from: ═O, OH, halogen, C 1-6 alkyl substituted with 0-1 R 12 , C 1-6 alkoxy substituted with 0-1 R 12 , C 1-4 haloalkyl substituted with 0-1 R 12 , C 1-4 haloalkoxy substituted with 0-1 R 12 , —(CH 2 ) m —C 3-6 carbocycle substituted with 0-1 R 12 , and —(CH 2 ) m -(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR 11 , O, and S); wherein said heteroaryl is substituted with 0-1 R 12 ;

when two R 2 groups are attached to two different carbon atoms, they may combine to form a 1- to 3-membered carbon atom bridge over ring B;

when two R 2 groups are attached to the same carbon, they may combine, together with the carbon atom to which they are attached, to form a 3- to 6-membered carbon atom containing spiro ring;

R 3 is independently selected from: H, halogen, CN, OH, CO 2 H, C 1-6 alkyl substituted with 0-1 R 10 , C 2-6 alkenyl substituted with 0-1 R 10 , C 2-6 alkynyl substituted with 0-1 R 10 , C 1-4 haloalkyl substituted with 0-1 R 10 , C 1-6 haloalkoxy substituted with 0-1 R 10 , —O(CH 2 ) 1-2 O(CH 2 ) 1-4 R 10 , OR 9 , SR 9 , C(O)OR 9 , CO 2 R 9 , S(O)R 9 , SO 2 R 9 , CONHR 9 , —(O) n —(CH 2 ) m -(phenyl substituted with 0-2 R 10 ), and —(O) n —(CH 2 ) m -(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR 11 , O, and S; wherein said heteroaryl is substituted with 0-2 R 10 );

R 4 and R 4a are independently selected from: H, halogen, C 1-6 alkyl, C 1-6 alkoxy, and —(CH 2 ) m —C 3-6 carbocycle;

R 5 , at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R 6 , at each occurrence, is independently selected from: halogen, OH, C 1-4 alkylthio, CN, SO 2 (C 1-2 alkyl), N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-8 alkyl substituted with 0-1 R 7 , C 1-6 alkoxy substituted with 0-1 R 7 , —(O) n —(CH 2 ) m —(C 3-10 carbocycle substituted with 0-2 R 7 ), and —(CH 2 ) m -(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR 11 , O, and S); wherein said heteroaryl is substituted with 0-2 R 7 ;

R 7 , at each occurrence, is independently selected from: halogen, OH, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, SCF 3 , CN, NO 2 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SO 2 (C 1-2 alkyl), and phenyl;

R 8 is independently selected from: H and C 1-4 alkyl;

R 9 , at each occurrence, is independently selected from: C 1-6 alkyl substituted with 0-1 R 10 , and C 1-4 haloalkyl substituted with 0-1 R 10 ;

R 10 , at each occurrence, is independently selected from: CN, C 1-4 alkoxy, C 1-4 haloalkoxy, CO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), and tetrazolyl;

R 11 , at each occurrence, is independently selected from: H, C 1-4 alkyl and benzyl;

R 12 , at each occurrence, is independently selected from: OH, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CO 2 (C 1-4 alkyl), and tetrazolyl;

m, at each occurrence, is independently 0, 1, or 2; and

n, at each occurrence, is independently 0 or 1.

2. A compound according to Formula I of claim 1 , wherein R 4 is hydrogen and R 8 is hydrogen, further characterized by Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:

X is independently selected from: O, N(CH 3 ), CH 2 , CH 2 O, and CH 2 CH 2 O;

ring B is independently a 4- to 7-membered saturated heterocycle containing carbon atoms and the nitrogen atom shown in ring B; and ring B is substituted with 0-4 R 2 ;

R 2 , at each occurrence, is independently selected from: ═O, OH, halogen, C 1-4 alkyl substituted with 0-1 R 12 , C 1-4 alkoxy substituted with 0-1 R 12 , C 1-4 haloalkyl, C 1-4 haloalkoxy, and benzyl;

when two R 2 groups are attached to two different carbon atoms, they may combine to form a 1- to 3-membered carbon atom bridge over ring B;

when two R 2 groups are attached to the same carbon, they may combine, together with the carbon atom to which they are attached, to form a 3- to 6-membered carbon atom containing spiro ring;

R 3 is independently selected from: C 1-6 alkyl substituted with 0-1 R 10 , C 1-6 alkoxy substituted with 0-1 R 10 , C 1-4 haloalkyl substituted with 0-1 R 10 , and C 1-4 haloalkoxy substituted with 0-1 R 10 , and —O(CH 2 ) 1-2 O(CH 2 ) 1-4 R 10 ;

R 4a is independently selected from: H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and —(CH 2 ) m —C 3-6 carbocycle;

R 5 , at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

R 6 , at each occurrence, is independently selected from: halogen, OH, C 1-4 alkylthio, CN, SO 2 (C 1-2 alkyl), N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-8 alkyl substituted with 0-1 R 7 , C 1-4 alkoxy substituted with 0-1 R 7 , —(O) n —(CH 2 ) m —(C 3-6 carbocycle substituted with 0-2 R 7 ), —(CH 2 ) m -(naphthyl substituted with 0-2 R 7 ), and —(CH 2 ) m -(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, O, and S; wherein said heteroaryl is substituted with 0-2 R 7 );

R 10 , at each occurrence, is independently selected from: CN, C 1-4 alkoxy, C 1-4 haloalkoxy, CO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), and tetrazolyl;

R 11 , at each occurrence, is independently selected from: H, C 1-4 alkyl and benzyl;

R 12 , at each occurrence, is independently selected from: halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CO 2 (C 1-4 alkyl), and tetrazolyl;

m, at each occurrence, is independently 0, 1, or 2; and

n, at each occurrence, is independently 0 or 1.

3. A compound of Formula (I) according the claim 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:

ring B is independently selected from:

R 1 is independently phenyl substituted with 0-3 R 6 or a heteroaryl substituted with 0-2 R 6 ; wherein said heteroaryl is selected from: furanyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl;

R 2 , at each occurrence, is independently selected from: OH, halogen, C 1-4 alkyl substituted with 0-1 CN, C 1-4 alkoxy, benzyl, and tetrazolylmethyl;

R 3 is independently selected from: C 1-4 alkyl substituted with 0-1 R 10 , C 1-4 alkoxy substituted with 0-1 R 10 , C 1-4 haloalkyl substituted with 0-1 R 10 , and C 1-4 haloalkoxy substituted with 0-1 R 10 ;

R 4a is independently selected from: H, halogen C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;

R 6 , at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl substituted with 0-2 C 1-4 alkyl, C 5-6 cycloalkenyl substituted with 0-2 C 1-4 alkyl, and benzyl; and

R 10 , at each occurrence, is independently selected from: CN, C 1-4 alkoxy, C 1-4 haloalkoxy, CO 2 (C 1-4 alkyl), and tetrazolyl.

4. A compound of Formula (I) according to claim 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:

ring B is independently selected from:

R 1 , at each occurrence, is independently phenyl substituted with 0-3 R 6 , pyridinyl substituted with 0-2 R 6 , pyrazinyl substituted with 0-2 R 6 , pyrimidinyl substituted with 0-2 R 6 , or thiazolyl substituted with 0-2 R 6 ; and

R 2 , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy and tetrazolylmethyl.

5. A compound of Formula (I) according to claim 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:

R 1 , at each occurrence, is independently phenyl substituted with 0-3 R 6 or pyridinyl substituted with 0-2 R 6 ;

R 3 , at each occurrence, is independently selected from: C 1-4 alkyl substituted with 0-1 C 1-4 alkoxy, C 1-4 alkoxy substituted with 0-1 C 1-4 alkoxy, and C 1-4 haloalkyl; and

6. A compound of Formula (III) or (IIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:

R 1 , at each occurrence, is independently phenyl substituted with 0-3 R 6 or pyridinyl substituted with 0-2 R 6 ;

R 2 , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, and C 1-4 alkoxy;

R 3 , at each occurrence, is independently: C 1-4 alkyl substituted with 0-1 C 1-4 alkoxy, C 1-4 alkoxy substituted with 0-1 C 1-4 alkoxy, and C 1-4 haloalkyl;

R 4a , at each occurrence, is independently selected from: H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and cyclopropyl; and

R 6 , at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituted with 0-2 C 1-4 alkyl, and C 5-6 cycloalkenyl substituted with 0-2 C 1-4 alkyl.

7. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof.

8. The pharmaceutical composition according to claim 7 , further comprising one or more other suitable therapeutic agents selected from: anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, and appetite suppressants.

9. The pharmaceutical composition according to claim 7 , further comprising a dipeptidyl peptidase-IV inhibitor and/or a sodium-glucose transporter-2 inhibitor.

10. A compound according to claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, for use in modulating or treating diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, and diabetic kidney disease.

11. A compound for use according to claim 10 , wherein the compound, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, is used simultaneously, separately or sequentially with one or more additional therapeutic agents.

12. A compound according to claim 1 , having the structure: