Macrocyclic inhibitors of myeloperoxidase

Patent metadata

Field	Value
Publication number	US-2019177340-A1
Application number	US-201716099010-A
Country	US
Kind code	A1
Filing date	Jun 26, 2017
Priority date	Jun 28, 2016
Publication date	Jun 13, 2019
Grant date	—

Abstract

The present invention provides compounds of Formula (I): wherein the substituents are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are myeloperoxidase (MPO) inhibitors and/or eosinophil peroxidase (EPX) inhibitors, and may be useful for for the treatment and/or prophylaxis of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

First claim

What is claimed is:

1 . The compound of the formula

wherein
ring A is pyrazole substituted with 0-1 R 1 ;
R 1 is C 1-4 alkyl, C 1-4 haloalkyl or halogen;
X 1 is CH 2 , or C 1-4 alkylene;
D is phenyl, pyridyl or pyrrolidinyl, all of which are substituted with 0-1 R 2 ,
R 2 is OH, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkyl;
X 2 is a bond, C 1-4 alkylene substituted with 0-2 R 3 , —O—, —OCH 2 —, —CH 2 O—, or —OCHR 3 —;
R 3 is C 1-4 alkyl;
E is selected from a bond, phenyl, pyridyl, C 3 -C 8 cycloalkyl or pyrrolidinyl, substituted with 0-2 R 4
R 4 is independently at each occurrence, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, phenyl or benzyl;
X 3 is a bond, C 1-4 alkyl substituted with 0-1 R 5 where R 5 is alkoxy, halogen, alkyl or hydroxyalkyl; or X 3 and NR z are taken together to form a pyrrolidinyl ring substituted with an aryl or aryl C 1-4 alkyl or group;
R z is H, CH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, or CH 2 CONH 2 ;

or a pharmaceutically acceptable salt, stereoisomer, tautomer or a solvate thereof.

2 . A compound according to claim 1 of the formula

wherein
X 1 is CH 2 , or C 1-4 alkylene;
D is phenyl, pyridyl or pyrrolidinyl, all of which are substituted with 0-1 R 2 ,
R 2 is OH, halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkyl;
X 2 is a bond, C 1-4 alkylene substituted with 0-1 R 3 , —O—, —OCH 2 —, —CH 2 O—, or —OCHR 3 —;
R 3 is C 1-4 alkyl;
E is selected from a bond, phenyl, pyridyl, C 3 -C 8 cycloalkyl or pyrrolidinyl, substituted with 0-2 R 4
R 4 is independently at each occurrence, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, phenyl or benzyl;
X 3 is a bond, C 1-4 alkyl substituted with 0-1 R 5 where R 5 is alkoxy, halogen, alkyl or hydroxyalkyl; or X 3 and NR z are taken together to form a pyrrolidinyl ring substituted with an aryl or aryl C 1-4 alkyl or group;
or X 3 and NR z are taken together to form a pyrrolidinyl ring substituted with an aryl or aryl C 1-4 alkyl or group;
R z is H, CH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, or CH 2 CONH 2 ;

or a pharmaceutically acceptable salt, stereoisomer, tautomer or a solvate thereof.

3 . A compound according to claim 2 wherein X 1 is CH 2 or CH 2 CH 2 —; D is phenyl; X 2 is C 1-4 alkylene, —O—, —OCH 2 — or —CH 2 O; E is a phenyl or C 3 -C 8 cycloalkyl, substituted with 0-2 R 4 ; R 4 is F, Cl, methoxy, CF 3 or benzyl; X 3 is a bond or C 1-2 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, tautomer or a solvate thereof.

4 . A compound selected from
7-{17-oxa-3,4,10-triazatetracyclo[16.3.1.1 3 , 6 .1 12 , 1 6 ]tetracosa-1(22),4,6(24),12,14,16(23), 18,20-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 13 , 1 7 ]pentacosa-1(23),4,6(25),13,15,17(24),19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 13 , 1 7 ]pentacosa-1(23),4,6(25),13,15,17(24),19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 13 , 1 7 ]pentacosa-1(23),4,6(25),13,15,17(24),19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{10-methyl-17-oxa-3,4,10-triazatetracyclo[16.3.1.1 3 , 6 .1 12 , 1 6 ]tetracosa-1(22),4,6(24),12,14,16(23), 18,20-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 12 , 1 6 ]pentacosa-1(23),4,6(25),12,14,16(24), 19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(17R)-18-phenyl-16-oxa-2,8,9-triazapentacyclo[16.2.2.1 1 , 1 7 .1 6 , 9 .1 11 , 1 5 ]pentacosa-6(25),7,11(24),12,14-pentaen-5-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(17S)-18-phenyl-16-oxa-2,8,9-triazapentacyclo[16.2.2.1 1 , 1 7 .1 6 , 9 .1 11 , 1 5 ]pentacosa-6(25),7,11(24),12,14-pentaen-5-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(3S,4S)-4-benzyl-2-oxa-6,12,13-triazatetracyclo[13.3.1.1 3 , 6 .1 1 0 , 13 ]henicosa-1(18),10(20),11,15(19), 16-pentaen-9-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{14-oxa-3,4,10-triazatricyclo[13.3.1.1 3 , 6 ]icosa-1(19),4,6(20), 15,17-pentaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{14′-oxa-3′,4′,10′-triazaspiro[cyclopropane-1,12′-tricyclo[13.3.1.1 3 , 6 ]icosane]-1′(19′),4′,6′(20′),15′,17′-pentaen-7′-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{14′-oxa-3′,4′,10′-triazaspiro[cyclopropane-1,12′-tricyclo[13.3.1.1 3 , 6 ]icosane]-1′(19′),4′,6′(20′),15′,17′-pentaen-7′-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{14′-oxa-3′,4′,10′-triazaspiro[cyclopentane-1,12′-tricyclo[13.3.1.1 3 , 6 ]icosane]-1′(19′),4′,6′(20′),15′,17′-pentaen-7′-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(3R,4S,6S,10R)-4-benzyl-2-oxa-7,13,14-triazatetracyclo[14.3.1.1 3 , 6 .1 11 , 1 4 ]docosa-1(19), 11(21),12,16(20), 17-pentaen-10-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(3R,4S,6S,10S)-4-benzyl-2-oxa-7,13,14-triazatetracyclo[14.3.1.1 3 , 6 .1 11 , 1 4 ]docosa-1(19),11(21),12,16(20), 17-pentaen-10-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{8,9,15-triazatetracyclo[16.3.1.1 2 , 6 .1 8 , 11 ]tetracosa-1(22),2,4,6(24),9,11(23),18,20-octaen-12-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{3-oxa-10,11,17-triazatetracyclo[16.2.2.1 4 , 8 .1 1 0 , 13 ]tetracosa-4,6,8(24),11,13(23)-pentaen-14-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{15,22-difluoro-18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 12 , 1 6 ]pentacosa-1(23),4,6(25),12,14,16(24), 19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(18S)-19-phenyl-17-oxa-2,8,9-triazapentacyclo[17.2.2.1 1 ,1 8 .1 6 , 9 .1 12 , 1 6 ]hexacosa-6(26),7,12(25), 13,15-pentaen-5-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{2-oxa-7,13,14-triazatetracyclo[14.3.1.1 3 , 6 .1 11 , 1 4 ]docosa-1(19),11(21),12,16(20),17-pentaen-10-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(17R)-17-methyl-18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 . 1 12 , 1 6 ]pentacosa-1(23),4,6(25),12,14,16(24), 19,21-octaen-7-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{17-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 12 , 1 6 ]pentacosa-1(23),4,6(25),12,14,16(24), 19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(11S,14R)-16-oxa-3,4,10-triazatetracyclo[15.3.1.1 3 , 6 .1 11 , 1 4 ]tricosa-1(21),4,6(23),17,19-pentaen-7-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, [(11S)-7-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 13 , 1 7 ]pentacosa-1(23),4,6(25),13,15,17(24),19,21-octaen-1-yl]methanol, 7-{14-fluoro-17-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 12 , 1 6 ]pentacosa-1(23),4,6(25), 12(24), 13,15,19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{15-fluoro-17-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 12 , 1 6 ]pentacosa-1(23),4,6(25), 12(24),13,15,19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{14-chloro-17-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 12 , 1 6 ]pentacosa-1(23),4,6(25), 12(24), 13,15,19,21-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-{18-oxa-3,4,10-triazatetracyclo[18.3.1.1 3 , 6 .1 13 , 1 7 ]hexacosa-1(24),4,6(26), 13(25),14,16,20,22-octaen-7-yl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(11R)-11-methyl-18-oxa-3,4,10-triazatetracyclo[17.3.1.1 3 , 6 .1 13 , 1 7 ]pentacosa-1(23),4,6(25),13,15,17(24), 19,21-octaen-7-yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[(11S)-11-methyl-i 8-oxa-3,4,10-triazatet

Assignees

• Bristol Myers Squibb Co

Inventors

• Smallheer Joanne M
• Kick Ellen K
• Valente Meriah Neissel
• Hu Carol Hui
• Halpern Oz Scott
• Jusuf Sutjano

Classifications

• A61P3/06

  Antihyperlipidemics · 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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title