Macrocyclic inhibitors of myeloperoxidase

Patent metadata

Field	Value
Publication number	US-10577383-B2
Application number	US-201716099010-A
Country	US
Kind code	B2
Filing date	Jun 26, 2017
Priority date	Jun 28, 2016
Publication date	Mar 3, 2020
Grant date	Mar 3, 2020

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 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 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-triazatetracyclo[17.3.1.1 3

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• A61P43/00

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

• 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

• A61P3/06

  Antihyperlipidemics · CPC title