Substituted nitrogen containing compounds

Patent metadata

Field	Value
Publication number	US-10501449-B2
Application number	US-201815993683-A
Country	US
Kind code	B2
Filing date	May 31, 2018
Priority date	Jun 1, 2017
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

Disclosed are compounds of Formula (I)

or a salt thereof,

wherein R 1 is:

each W is independently NR 1b or O; Z is a bond or CHR 1d ; and R 1 , R 2 , R d , R 3a , R 3b , L 1 , B, V, Y, and n are defined 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:

each W is independently NR 1b or O;
Z is a bond or CHR 1d ;
X is independently N or CR 1a , wherein X is N at only 0, 1, or 2 positions;
each R 1a is independently H, F, Cl, —OH, —CN, 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 2-3 fluoroalkyl, C 3-6 cycloalkyl
R 1c is independently H, deuterium, 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;
Y is —C(R 6 ) 2 —, —C(R 6 ) 2 —C(R 6 ) 2 —, —C(O)—, —C(O)—C(R 6 ) 2 —, —C(R 6 ) 2 —C(O)—, or SO 2 —;
V is —O—, —NR 4 —, —CR 5 R 5 —, —S—, —S(O)—, —SO 2 —, or —C(O)—; wherein if V is —O—, —S—, —S(O)—, —SO 2 —, or —C(O)—, then Y is not —SO 2 —, and wherein if V is —O—, —S—, or NR 4 , then Y is not C(R 6 ) 2 , and wherein if V is —S(O)—, —SO 2 —, or C(═O)—, then Y is not —C(═O)—, —C(═O)—C(R 6 ) 2 —;
L 1 is —C(R) 2 —, —C(O)—, or —C(R) 2 —C(R) 2 —; wherein R is independently H, F, OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkyl; wherein R is not —OH or F if it is attached to a carbon atom that is adjacent to a nitrogen atom:
Ring B is phenyl, pyridinyl, pyrimidinyl, pyrrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazinyl, oxazolyl, pyridazinyl, pyrrolidinyl, or imidazolidinyl;
R 2 is a C 6-10 aryl, or a 5 to 10 membered heterocycle ring containing 1 to 4 heteroatoms selected from N, O, and S, the heterocycle ring optionally containing an oxo substitution, the aryl or heterocycle ring are substituted with 0-3 R 2a ;
R 2a is independently OH, ═O, CN, halo, C 1-4 alkyl, C 1-4 deuteroalkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, C 1-4 fluoroalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C(═O)NR 4b R 4b , C(═O)C 1-4 alkyl, SO 2 R e , NR 4b SO 2 R 4b , or a 4 to 6 membered heterocycle having 1, 2, 3, or 4 heteroatoms selected from O, S, and N, the heterocycle optionally containing an oxo substitution and is substituted with 0-3 R 2b ;
R 2b is independently C 1-3 alkyl, C 1-3 fluoralkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, or C 3-6 fluorocycloalkyl;
R 3a is H, halo, OH, CN, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, or C 3-6 cycloalkyl, wherein if V is —O—, —NR 4 —, —S—, —S(O)—, —SO 2 —, or —C(═O)—, then R 3a is not halo, and wherein if V is —O—, —NR 4 —, —S—, then R 3a is not OH, CN;
R 3b is H, ═O, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, or C 3-6 cycloalkyl;
R 4 is H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 2-3 hydroxyalkyl, CO 2 R 4a , C(O)R 4a , SO 2 R 4a , C(O)N(R 4b R 4b ), SO 2 N(R 4b R 4b ), or OH;
R 4a is C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from O, S, and N, the aryl or heterocycle being substituted with 0-3 R 4c ;
R 4b is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
alternatively, 2 R 4b s, along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring containing an additional 0-2 heteroatoms selected from O, S, and N;
R 4c is independently H, F, Cl, or C 1-3 alkyl;
R 5 is independently H, F, OH, C 1-3 alkoxy, C 1-3 fluoroalkoxy, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, NR 5b R 5b , O—R 5c , or 2 R 5 s are ═O; wherein if one R 5 is F, OH or NR 5b R 5b , then the other R 5 is not OH, or NR 5b R 5b ;
R 5b is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, C(O)R a , SO 2 R a , or C(O)NR b R b ;
alternatively, 2 R 5b s, along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring containing 0-2 heteroatoms selected from O, S, or N;
R 5c is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, or C(O)NR b R b ;
R 6 is independently H, OH, F, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 hydroxydeuteroalkyl, C 1-3 alkoxyalkyl, or C 1-3 fluoroalkoxyalkyl, or NR 6b R 6b ; wherein if one R 6 on one carbon atom is F, OH or NR 6b R 6b , then the other R 6 on the same carbon atom is not OH or NR 6b R 6b ;
R 6b is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, C(O)R a , SO 2 R a , or C(O)NR b R b ; alternatively, 2 R 6 s along with the same atom to which they are attached can form a 3 to 6 membered saturated ring containing 0-2 heteroatoms selected from O, S, and N;
R a is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3, or 4 heteroatoms selected from O, S, and N;
R b is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, C 6-10 aryl or a 4 to 10 membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from O, S, and N;
alternatively, 2 R b 's along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring, containing 0-2 heteroatoms selected from O, S, and N;
each R d is independently H, F, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, halo, OH, ═O, CN, OCF 3 , OCHF 2 , CHF 2 CF 3 , or C(O)NR e R e ;
each R e is independently H, C 1-3 alkyl, C 2-3 fluoroalkyl, C 3-6 cycloalkyl, C 2-3 hydroxyalkyl, C 2-3 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;
alternatively, 2 R e s along with the atom to which they are attached, join to form a 3 to 6 membered saturated ring, containing 0-2 heteroatoms selected from O, S, or N; and
n is 0, 1, or 2.

2. A compound of claim 1 , 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 independently H, deuterium, C 1-2 alkyl, or C 3-6 cycloalkyl; and
n is zero, 1, or 2.

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

4. A compound of claim 3 , or salt

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · CPC title

• 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

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title