Substituted bicycle heterocyclic derivatives useful as ROMK channel inhibitors

Patent metadata

Field	Value
Publication number	US-10723723-B2
Application number	US-201716344823-A
Country	US
Kind code	B2
Filing date	Nov 2, 2017
Priority date	Nov 3, 2016
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

Disclosed are compounds of Formula (I) or a salt thereof, wherein R 1 is (II) or (III); each W is independently NR 1b or O; Z is a bond or CHR 1d ; and R 1 , R 2 , R d , R 3 , L 1 , L 2 , R 1a , R 1b , R 1c , and n are define herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.

First claim

What is claimed is:

1. A compound having the structure of Formula (I)

or a salt thereof, wherein:
R 1 is

n is zero, 1 or 2;
each R 1a is independently H, F, Cl, —OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, or C 1-3 fluoroalkoxy;
each R 1b is independently H, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-6 cycloalkyl
R 1c is H, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl;
R 1d is H, C 1-3 alkyl, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl;
L 1 is —CHR b —, —CHR a CHR b —, —CH(R a )C(O)—, —C(R b ) 2 —, —C(R a ) 2 CH(R b )—, or —CH(R a )C(R b ) 2 —;
L 2 is —CH 2 —, —C(O)—, —CH 2 —CH 2 —, or —C(R) 2 —; wherein R is independently selected from hydrogen, F, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkyl;
R a is H, halo, —OH, C 1-4 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, alkoxy, OC(O)—C 1-4 alkyl substituted with 0-1 OH, halo or NH 2 , NR 1e R 1e , or C 1-3 fluoroalkoxy;
each R 1e is independently H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C(O)-alkyl, C(O)—C 1-6 fluoroalkyl, C(O)—C 3-6 cycloalkyl, C(O)heterocyclyl, C(O)O—C 1-6 alkyl, C(O)O—C 3-6 cycloalkyl, C(O)O—C 1-6 fluoroalkyl, C(O)O—C 3-6 fluorocycloalkyl, SO 2 —C 1-6 alkyl, SO 2 —C 3-6 cycloalkyl, SO 2 —C 3-6 fluoroalkyl, SO 2 —C 3-6 fluorocycloalkyl, C(O)NR e R e , wherein the heterocyclyl is 5 or 6 membered ring having 1, 2, 3, or 4 heteroatoms selected from O, S, and N, and the alkyl, cycloalkyl, or heterocyclyl is substituted with 0-1 of halo, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy; or two R 1e along with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms selected from O, S, and N, and being substituted with 0-1 halo, C 1-3 alkyl, or ═O;
R b is H, C 1-4 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkoxyalkyl;
Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, indolyl, indazolyl, thiazolyl, imidazolyl, pyridinonyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, pyrazinyl, oxazolyl, pyridazinyl, furanyl, thiophenyl, pyrrolyl, triazinyl, azaindolyl, benzimidazolyl, bezoxazolyl, bezothiazolyl, benzofuranyl, or benzothiophenyl;
R 2 is a C 6-10 aryl, or a 5 to 10 membered heteroaryl ring containing 1 to 4 heteroatoms selected from N, O, and S, the heteroaryl optionally containing an oxo substitution, and the heteroaryl and aryl being substituted with 0-3 R 2a ;
R 2a is OH, ═O, CN, halo, C(O)N(R) 2 , C(O)O—C 1-4 alkyl, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, SO 2 R e , or a 4 to 6 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms selected from O, S, and N, and wherein the heterocyclyl is substituted with 0-3 R d ;
each R 3 is independently H, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, C 3-6 cycloalkyl, —(CH 2 )—C 3-6 cycloalkyl, —(CH 2 )-heterocyclyl, —SO 2 R e , —C(O)R e , —C(O)OR e , or —C(O)NR e R e , wherein the heterocyclyl is a 5-6 membered ring have 1, 2, or 3 heteroatoms selected from N, O, and S;
each R d is independently H, C 1-3 alkyl, C 1-3 alkoxy, halo, OH, ═O, CN OCF 3 , OCHF 2 , CHF 2 and CF 3 , and
each R e is independently H, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, C 6-10 aryl, or a 5 to 10 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from O, S, and N; or two R e along with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms selected from O, S, and N.

2. A compound of claim 1 , or salt thereof, wherein:
R 2 is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-2(3H)-onyl, 1H-pyrazolo[4,3-b]pyridinyl, pyridin-2(1H)-onyl, 1H-pyrazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiazolyl, thiophenyl, 1H-1,2,3-triazolyl, 1H-benzo[d][1,2,3]triazolyl, [1,2,4]triazolo[4,3-b]pyridazinyl, 1H-benzo[d]imidazolyl, 1H-imidazolyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrrolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-tetrazolyl, 4H-1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyridazinyl, pyrimidinyl, or benzo[d]oxazol-2(3H)-only, each being substituted with with 0-3 R 2a .

3. A compound of claim 2 , or salt thereof, wherein:
R 2 is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-2(3H)-onyl, 1H-pyrazolo[4,3-b]pyridinyl, pyridin-2(1H)-onyl, 1H-pyrazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiophenyl, [1,2,4]triazolo[4,3-b]pyridazinyl, pyrazolo[1,5-a]pyrimidinyl, or benzo[d]oxazol-2(3H)-only, each being substituted with with 0-3 R 2a .

4. A compound of claim 3 , or salt thereof, wherein:
R 2 is phenyl, pyridinyl, indolyl, indazolyl, benzo[d]oxazol-2(3H)-onyl, 1H-pyrazolo[4,3-b]pyridinyl, or pyridin-2(1H)-onyl.

5. A compound of claim 4 , or salt thereof, wherein:
Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, indolyl, indazolyl, thiazolyl, imidizolyl, pyridinonyl, 1,2-dihydro-3H pyrazol-3-onyl, 1H-1,2,3-triazolyl, pyrazinyl or pyridazinyl, or oxazolyl.

6. A compound of claim 5 , or salt thereof, wherein:
Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, indolyl, or indazolyl.

7. A compound of claim 5 , or salt thereof, wherein:
R 1 is:

each R 1a is independently selected from F, Cl, C 1-3 alkyl, C 1-3 fluoroalkyl, and C 3-6 cycloalkyl;
R 1c is H, C 1-2 alkyl, or C 3-6 cycloalkyl;
n is zero, 1, or 2;
R a is H, F, —OH, C 1-2 alkyl, —CHF 2 , —CF 3 , —CH 2 OH, cyclopropyl, —OCH 3 , —OCHF 2 , or —OCF 3 ;
R b is H, C 1-2 alkyl, C 1-2 hydroxyalkyl, or cyclopropyl;
R c is H or —CH 3 ;
each R 3 is independently H, C 1-4 alkyl, —(CH 2 )—C 3-6 cycloalkyl, —(CH 2 )-heterocyclyl wherein the heterocyclyl is a 5-6 membered ring have 1, 2, or 3 heteroatoms selected from N, O, and S, or —C(O)—C 1-3 alkyl; and
each R e2 is independently H, —CH 3 , —CF 3 , or C 3-6 cycloalkyl.

8. The compound according to claim 7 , or a salt thereof, wherein:
R 1 is

R 1b is H or —CH 3 ;
L 1 is —CH 2 —, —CH 2 CH 2 —, —CH(CH 2 OH)—, or —CH(OH)CH 2 —;
R 3 is H.

9. The compound according to claim 8 , or salt thereof, wherein:
Ring B is phenyl, pyridinyl, pyrimidinyl, indolyl, or pyrrazolyl, indazolyl; and
R 2 is phenyl, indolyl, pyridinyl, benzo[d]oxazol-2(3H)-onyl, pyridin-2(1H)-onyl, or indazolyl.

10. A compound of claim 1 , or salt thereof, wherein the compound is selected from:
5-(5-(((2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)(methyl)amino)methyl)pyridin-2-yl)-3-methylbenzo[d]oxazol-2(3H)-one;
1-(5-(((2-hydroxy-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethy

Assignees

• Bristol Myers Squibb Co

Inventors

• Gunaga Prashantha
• Bhide Rajeev S
• Bora Rajesh Onkardas
• Panda Manoranjan
• Yadav Navnath Dnyanoba
• Priestley Eldon Scott
• Richter Jeremy

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title