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Msg  4166 of 4336  at  9/17/2020 1:29:15 AM  by

JBWIN


Building IP: BMY Patent Application re "TRIAZOLOPYRIDINE INHIBITORS OF MYELOPEROXIDASE"

 
United States Patent Application20200291015
Kind CodeA1
Smallheer; Joanne M. ; et al.September 17, 2020

TRIAZOLOPYRIDINE INHIBITORS OF MYELOPEROXIDASE

Abstract

The present invention provides compounds of Formula (I). wherein A and Z are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are myeloperoxidase (MPO) inhibitors and may be useful for the treatment and/or prophylaxis of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. ##STR00001##


Inventors:Smallheer; Joanne M.; (Yardley, PA) ; HU; Carol Hui; (New Hope, PA) ; Valente; Meriah Neissel; (Bedminster, NJ) ; Shaw; Scott A.; (Lawrence Township, NJ) ; Vokits; Benjamin P.; (New York City, NY) ; Halpern; Oz Scott; (Robbinsville, NJ)
Applicant:
NameCityStateCountryType

Bristol-Myers Squibb Company

Princeton

NJ

US
Family ID:1000004866758
Appl. No.:16/083951
Filed:March 10, 2017
PCT Filed:March 10, 2017
PCT NO:PCT/US17/21807
371 Date:September 11, 2018

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62307723Mar 14, 2016

Current U.S. Class:1/1
Current CPC Class:C07D 471/04 20130101
International Class:C07D 471/04 20060101 C07D471/04

Claims



1. The compound of Formula (I): ##STR00154## wherein: Z is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxyalkyl, C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, hydroxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl NR.sup.z (CH.sub.2).sub.2--, heteroaryl C.sub.1-C.sub.6 alkyl-, aryl C.sub.3-C.sub.8 cycloalkyl NR.sup.z (CH.sub.2).sub.2--, aryl C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, bridged C.sub.6-C.sub.10 carbocyclyl NR.sup.z(CH.sub.2).sub.2--, heterocyclyl C.sub.1-C.sub.6 alkyl-, or C.sub.9-C.sub.10 bicyclic carbocyclyl NR.sup.z (CH.sub.2).sub.2--, any of which is substituted with 0-3 R.sup.2 groups; R.sup.z is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4 alkyl-,--C.sub.1-C.sub.4 alkyl CONH.sub.2 or hydroxy C.sub.2-C.sub.4 alkyl; R.sup.2 is, independently at each occurrence, one or more halogen, hydroxy, cyano, hydroxy C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl, --C.sub.3-6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.6 alkyl-, CONR.sup.xR.sup.y; said --C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.a, aryl substituted with 0-4 R.sup.a, and 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a; R.sup.a is, independently at each occurrence, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or C.sub.1-4 haloalkoxy; R.sup.x is hydrogen or C.sub.1-4 alkyl; R.sup.y is hydrogen or C.sub.1-4 alkyl; A is pyrazole, triazole, pyridine or dihydropyridinone optionally substituted with R1; R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6 alkyl-, halo C.sub.1-C.sub.6 alkyl-, heterocyclyl C.sub.1-C.sub.6 alkyl- or C.sub.3-C.sub.8 cycloalkyl, any of which is substituted with 0-4 R.sup.3 groups; R.sup.3 is, independently at each occurrence, one or more halogen, hydroxy, cyano, hydroxy C.sub.1-C.sub.4 alkyl, halo C.sub.1-C.sub.4 alkyl, halo C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.4 alkyl-, --COO C.sub.1-C.sub.4 alkyl, CONR.sup.xR.sup.y, --CO-heterocyclyl, --SO.sub.2-aryl or SO.sub.2-heteroaryl; or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

2. A compound according to claim 1 of Formula (II) ##STR00155## wherein Z is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, hydroxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkoxy-, aryl C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl-, aryl C.sub.1-C.sub.6 alkyl NR.sup.z alkyl-, heteroaryl C.sub.1-C.sub.6 alkyl-, aryl C.sub.3-C.sub.8 cycloalkyl NR.sup.z C.sub.1-C.sub.6 alkyl-, aryl C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.6 alkyl-, bridged carbocyclyl NR.sup.z C.sub.1-C.sub.6 alkyl- or heterocyclyl C.sub.1-C.sub.6 alkyl-, any of which is substituted with 0-3 R.sup.2 groups; R.sup.z is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4 alkyl-,--C.sub.1-C.sub.4 alkyl CONH.sub.2 or hydroxy C.sub.1-C.sub.4 alkyl; R.sup.2 is, independently at each occurrence, one or more halogen, hydroxy, cyano, hydroxy C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl, --C.sub.3-6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.6 alkyl-, --COO C.sub.1-C.sub.6 alkyl, CONR.sup.xR.sup.y, --CO-heterocyclyl, --SO.sub.2-aryl or SO.sub.2-heteroaryl; said --C.sub.3-6 cycloalkyl substituted with 0-3 R.sup.a, aryl substituted with 0-4 R.sup.a, and 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S; wherein said heterocycle is substituted with 0-3 R.sup.a; R.sup.a is, independently at each occurrence, OH, CN, --CONH.sub.2, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or C.sub.1-4 haloalkoxy; R.sup.x is hydrogen or C.sub.1-4 alkyl; R.sup.y is hydrogen or C.sub.1-4 alkyl; R.sup.1 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6 alkyl-, halo C.sub.1-C.sub.6 alkyl-, heterocyclyl C.sub.1-C.sub.6 alkyl- or C.sub.3-C.sub.8 cycloalkyl, any of which is substituted with 0-4 R.sup.3 groups; R.sup.3 is, independently at each occurrence, one or more halogen, hydroxy, cyano, hydroxy C.sub.1-C.sub.4 alkyl, halo C.sub.1-C.sub.4 alkyl, halo C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, aryl, aryloxy, aryl C.sub.1-C.sub.4 alkyl-, --COO C.sub.1-C.sub.4 alkyl, CONR.sup.xR.sup.y, --CO-heterocyclyl, --SO.sub.2-aryl or SO.sub.2-heteroaryl; or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

3. A compound according to claim 2 wherein: Z is Me, propyl, 3-phenylpropyl, 2-benzyloxyethyl, 3,3,-diphenylpropyl, 3-cyclohexylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 1-indanylpropyl, 2-(tetrahydro-2H-pyran-4-yl)ethyl, 2-phenoxyethyl, 3-(1,2,3,4-tetrahydroisoquinolin-1-yl)propyl, 2-benzylaminoethyl, ##STR00156## ##STR00157## R.sup.1 is H, benzyl, 4-chlorobenzyl, 3-difluoromethoxybenzyl, 3,5,-difluorobenzyl, 3-trifluoromethylbenzyl, 3-hydroxybenzyl, 3-hydroxyphenethyl, 3-(4-piperidinyl)benzyl, 1-naphthylmethyl, 3-pyridinylmethyl, 3-2-oxo-1,2-dihydropyridin-4-yl, cyclopropyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, 3,3-difluorocyclopentyl, 2,2-difluorocyclobutyl, 2,2,3-trifluorocyclobutyl, 3,3,3-trifluoropropyl, 3-pyridylmethyl, or 1,2,3,4-tetrahydroisoquinolin-6-yl)methyl.sub.[SJ1]; or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

4. A compound which is 7-(4-phenyl-1-(1-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyrazol-- 4-yl)butyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2 TFA, 7-{1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1H-pyrazol-4-yl]butyl}- -3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1H-pyrazol-4-yl]ethyl}- -3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-(3-(benzyloxy)-1-(1-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H-pyr- azol-4-yl)propyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{4,4-diphenyl-1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1H-pyrazo- l-4-yl]butyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2 TFA, 7-{4-cyclohexyl-1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1H-pyrazo- l-4-yl]butyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[4-(naphthalen-2-yl)-1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1H- -pyrazol-4-yl]butyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[4-(2,3-dihydro-1H-inden-1-yl)-1-[1-(1,2,3,4-tetrahydroisoquinolin-6-yl- methyl)-1H-pyrazol-4-yl]butyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[4-(Naphthalen-1-yl)-1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmeth- yl)-1H-pyrazol-4-yl]butyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[3-(Oxan-4-yl)-1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1H-pyraz- ol-4-yl]propyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{3-Phenoxy-1-[1-(1,2,3,4-tetrahydroisoquinolin-6-ylmethyl)-1H-pyrazol-4- -yl]propyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{4-Phenyl-1-[1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]butyl}-3H-[1,2,3]tr- iazolo[4,5-b]pyridin-5-amine, 2 TFA, 7-[4-Phenyl-1-(1-{[3-(piperidin-4-yl)phenyl]methyl}-1H-pyrazol-4-yl)butyl- ]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2 TFA, 7-[1-(1-Benzyl-1H-pyrazol-4-yl)-4-(1,2,3,4-tetrahydroisoquinolin-1-yl)but- yl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[3-(Benzylamino)-1-(1-methyl-1H-pyrazol-4-yl)propyl]-3H-[1,2,3]triazolo- [4,5-b]pyridin-5-amine, 2 TFA, 7-[1-(1-Benzyl-1H-pyrazol-4-yl)-3-[(4-phenylcyclohexyl)amino]propyl]-3H-[- 1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[1-(1-Benzyl-1H-pyrazol-4-yl)-3-[(2,3-dihydro-1H-inden-1-yl)amino]propy- l]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[1-(1-Benzyl-1H-pyrazol-4-yl)-3-{[trans-4-phenylcyclohexyl]-amino}propy- l]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-(1-{1-[(4-Chlorophenyl)methyl]-1H-pyrazol-4-yl}-3-{[trans-4-phenylcyclo- hexyl]amino}propyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[1-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-{[trans-4-phenylcyclohexyl]amino}pr- opyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{1-[1-(Cyclobutylmethyl)-1H-pyrazol-4-yl]-3-{[trans-4-phenylcyclohexyl]- amino}propyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[1-(1H-Pyrazol-4-yl)-3-{[trans-4-phenylcyclohexyl]amino}propyl]-3H-[1,2- ,3]triazolo[4,5-b]pyridin-5-amine, 2 TFA, 7-[1-(1-Cyclopentyl-1H-pyrazol-4-yl)-3-{[trans-4-phenylcyclohexyl]amino}p- ropyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{1-[1-(Naphthalen-1-ylmethyl)-1H-pyrazol-4-yl]-3-{[trans-4-phenylcycloh- exyl]amino}propyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[1-(1-{[3-(Difluoromethoxy)phenyl]methyl}-1H-pyrazol-4-yl)-3-{[trans-4-- phenylcyclohexyl]amino}propyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-(1-{1-[(3,5-Difluorophenyl)methyl]-1H-pyrazol-4-yl}-3-{[trans-4-p- henylcyclohexyl]amino}propyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{1-[1-(3,3-Difluorocyclopentyl)-1H-pyrazol-4-yl]-3-{[trans-4-phen- ylcyclohexyl]amino}propyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-{1-[1-(2,2-Difluorocyclobutyl)-1H-pyrazol-4-yl]-3-{[trans-4-phenylcyclo- hexyl]amino}propyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-(3-{[trans-4Pphenylcyclohexyl]amino}-1-[1-(2,2,3-trifluorocyclobutyl)-1- H-pyrazol-4-yl]propyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-(3-{[trans-4-Phenylcyclohexyl]amino}-1-[1-(3,3,3-trifluoropropyl)-1H-py- razol-4-yl]propyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-(3-{[trans-4-Phenylcyclohexyl]amino}-1-(1-{[3-(trifluoromethyl)phenyl]m- ethyl}-1H-pyrazol-4-yl)propyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7-[1-(1-Cyclopropyl-1H-pyrazol-4-yl)-3-{[trans-4-phenylcyclohexyl]a- mino}propyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 7(S)-[1-(1-{[3-(Difluoromethoxy)phenyl]methyl}-1H-pyrazol-4-yl)-3-{[trans- -4-phenylcyclohexyl]amino}propyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine- , 2TFA, 7(R)-[1-(1-{[3-(Difluoromethoxy)phenyl]methyl}-1H-pyrazol-4-yl)-3-- {[trans-4-phenylcyclohexyl]amino}propyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-- 5-amine, 2TFA, 7-[1-(Pyridin-3-yl)-3-{[trans-4-phenylcyclohexyl]amino}propyl]-3H-[1,2,3]- triazolo[4,5-b]pyridin-5-amine, 2TFA, 4-(1-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{[trans-4-phenylcy- clohexyl]amino}propyl)-1,2-dihydropyridin-2-one, 2TFA, 7-[1-(1H-Pyrazol-3-yl)-3-{[trans-4-phenylcyclohexyl]amino}propyl]-3H-[1,2- ,3]triazolo[4,5-b]pyridin-5-amine, 2TFA, 3-{[4-(1-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-({4-phenylbicy- clo[2.2.2]octan-1-yl}amino)propyl)-1H-pyrazol-1-yl]methyl}phenol, 2TFA, (2R)-4-[(3-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{1-[2-(3-hyd- roxyphenyl)ethyl]-1H-pyrazol-4-yl}propyl)amino]-1-phenylbicyclo[2.2.2]octa- n-2-ol, 2TFA, (2R)-4-[(3-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{1-[(3-hydro- xyphenyl)methyl]-1H-pyrazol-4-yl}propyl)(2-methoxyethyl)amino]-1-phenylbic- yclo[2.2.2]octan-2-ol, 2TFA, 2-[(3-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{1-[(3-hydroxyphe- nyl)methyl]-1H-pyrazol-4-yl}propyl) [(3R)-3-hydroxy-4-phenyl-bicyclo[2.2.2]octan-1-yl]amino]acetamide, 2TFA, 3-{[4-(1-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-[(2-hydroxyeth- yl)({4-phenylbicyclo[2.2.2]octan-1-yl})amino]propyl)-1H-pyrazol-1-yl]methy- l}phenol, 2TFA, 3-{[4-(1-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{[(1R,3R,4R)-3- -benzyl-4-hydroxycyclopentyl]amino}propyl)-1H-pyrazol-1-yl]methyl}phenol, 2TFA, (3R,4S)-1-(3-{5-Amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{1-[- (3-hydroxyphenyl)methyl]-1H-pyrazol-4-yl}propyl)-4-benzylpyrrolidin-3-ol, 2TFA, 7-[1-(5-fluoropyridin-3-yl)-3-{[(1r,4r)-4-phenylcyclohexyl]amino}pr- opyl]-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 7-[1-(6-fluoropyridin-3-yl)-3-{[(1r,4r)-4-phenylcyclohexyl]amino}propyl]-- 3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, 3-{[4-(1-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-(benzylamino)p- ropyl)-1H-pyrazol-1-yl]methyl}phenol, 3-{[4-(1-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}propyl)-1H-pyrazo- l-1-yl]methyl}phenol, 3-{[4-(1-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-({[3-(hydroxym- ethyl)phenyl]methyl}amino)propyl)-1H-pyrazol-1-yl]methyl}phenol, 3-{[4-(1-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{[(3-hydroxyph- enyl)methyl]amino}propyl)-1H-pyrazol-1-yl]methyl}phenol, 3-{2-[4-(1-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-({4-phenylbi- cyclo[2.2.2]octan-1-yl}amino)propyl)-1H-pyrazol-1-yl]ethyl}phenol, (2R)-4-[(3-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{1-[(3-hydro- xyphenyl)methyl]-1H-pyrazol-4-yl}propyl)amino]-1-phenylbicyclo[2.2.2]octan- -2-ol, (2S)-4-[(3-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{1-[(3- -hydroxyphenyl)methyl]-1H-pyrazol-4-yl}propyl)amino]-1-phenylbicyclo[2.2.2- ]octan-2-ol, 3-{2-[4-(1-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{[(1R,3S)-3-- benzylcyclopentyl]amino}propyl)-1H-pyrazol-1-yl]ethyl}phenol, 3-{2-[4-(1-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-{[(1S,3S,4S)- -3-benzyl-4-hydroxycyclopentyl]amino} propyl)-1H-pyrazol-1-yl]ethyl}phenol, 3-{5-amino-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl}-3-[1-({3-[(3-aminocyclo- pentyl)oxy]phenyl}methyl)-1H-pyrazol-4-yl]propan-1-ol, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

5. A compound according to claim 1, wherein the compound is selected from any one of Examples 1 to 55 or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.

6. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-5, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a solvate thereof.
Description



CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application Ser. No. 62/307,723, filed Mar. 14, 2016, which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel triazolopyridine compounds, which are myeloperoxidase (MPO) inhibitors, compositions containing them, and methods of using them, for example, for the treatment and/or prophylaxis of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

BACKGROUND OF THE INVENTION

[0003] Cardiovascular disease is a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack and stroke, and thereby the principal cause of death in the United States. Atherosclerosis is a complex disease involving many cell types and molecular factors (for a detailed review, see Weber et al., Nature Med, 17(11):1410-1422 (2011)).

[0004] MPO inhibitors have been suggested to reduce the atherosclerotic burden and/or the vulnerability of existing atherosclerotic lesions and thereby decrease the risk of acute myocardial infarction, unstable angina or stroke, and reduce ischemia-reperfusion injury during acute coronary syndrome and ischemic cerebrovascular events. Several lines of data support a role for MPO in atherosclerosis. MPO is expressed in the shoulder regions and necrotic core of human atherosclerotic lesions and active enzyme has been isolated from autopsy specimens of human lesions (Daugherty, A. et al., J. Clin. Invest., 94(1):437-444 (1994)). Moreover, HOCl-modified lipoproteins have been detected in advanced human atherosclerotic lesions (Hazell, L. J. et al., J. Clin. Invest., 97:1535-1544 (1996)). In eroded and ruptured human lesions, as compared to fatty streaks, an increased number of MPO expressing macrophages have been demonstrated, suggesting a particular role for MPO in acute coronary syndromes (Sugiyama, S. et al., Am. J. Pathol. 158(3):879-891 (2001); Tavora, F. R., BMC Cardiovasc. Disord., 9:27 (Jun. 23, 2009)).

[0005] Data accumulated during the last fifteen years indicate that the pro-atherogenic actions of MPO include oxidation of lipoproteins, induction of endothelial dysfunction via consuming nitric oxide and destabilization of atherosclerotic lesions by activation of proteases (Nicholls, S. J. et al., Arterioscler. Thromb. Vasc. Biol., 25(6):1102-1111 (2005); Nicholls, S. J. et al., JLR, S346-S351 (2009)). Several studies have focused on nitro- and chlorotyrosine modifications of LDL and HDL lipoproteins. Since chlorotyrosine modifications in vivo are generated by hypochlorous acid produced by MPO these modifications are regarded as specific markers of MPO activity (Hazen, S. et al., J. Clin. Invest., 99(9):2075-2081 (1997)).

[0006] ApoA-I isolated from atherosclerotic lesions is modified by reactive chlorine and nitrogen species as well as by reactive carbonyls (Pennathur, S. et al., J. Biol. Chem., 279:42977-42983 (2004); Shao, B. et al., J. Biol. Chem., 279:7856-7866 (2004); Zheng, L. et al., J. Clin. Invest., 114(4):529-541 (2004); Shao, B. et al., JBC in press (2012)). Chlorotyrosine modification of apoA1, the main apolipoprotein of HDL cholesterol, was associated with impaired cholesterol acceptor function (Bergt, C. S. et al., Proc. Natl. Acad. Sci. USA, 101(35):13032-13037 (2004); Zheng, L. et al., J. Clin. Invest., 114(4):529-541 (2004)). Thus, oxidation of apoA-I amino acid residues by the MPO-H.sub.2O.sub.2--Cl.sup.- system is one mechanism for loss of its biological activities.

[0007] The lipid and protein content of LDL are also targets for MPO oxidation and presence of chlorotyrosine in LDL extracted from human atherosclerotic tissues has been shown (Hazen, S. et al., J. Clin. Invest., 2075-2081 (1997)). LDL particles exposed to MPO in vitro become aggregated, leading to facilitated uptake via macrophage scavenger receptors and foam cell formation (Hazell, L. J. et al., Biochem. J., 290(Pt. 1):165-172 (1993); Podrez, E. A. et al., J. Clin. Invest. 105:1095-1108 (2000)). Thus, MPO appears to play a role in the generation of oxidized LDL, which contributes to atherosclerosis plaque development.

[0008] Further evidence implicating MPO in the pathophysiology of atherosclerosis comes from the study of hMPO transgenic mice crossed with LDL-R KO mice (Castelini L. W. et al., J. Lipid Res., 47:1366-1377 (2006)). These mice expressed MPO in lesions and developed significantly larger aortic lesions than control LDL-R KO mice.

[0009] Many clinical studies have implicated MPO in cardiovascular disease in human patients. Patients with established coronary artery disease have higher plasma and leukocyte MPO levels than healthy controls (Zhang, R. et al., JAMA, 286(17):2136-2142 (2001)). Moreover, in three large prospective studies plasma levels of MPO predicted the risk of future coronary events or revascularization (Baldus, S. et al., Circulation, 108(12):1440-1445 (2003); Brennan, M. et al., N. Engl. J Med., 349(17):1595-1604 (2003); Kohli, P. et al., Circulation, 122:A13175 (2010)). In two recent large nested case control prospective studies, the EPIC-Norfolk and MONICA-/KORA Augsburg studies, baseline MPO levels in these initially healthy populations turned out to be an excellent predictor of future risk of CAD and CHD respectively, showing that this inflammatory marker precedes the presentation of clinical symptoms of CVD (Meuwese, M. C. et al., J. Am. Coll. Cardiol., 50:159-165 (2007); Karakas et al., J. Int. Med., 271:43-50 (2011)). Interestingly, MPO deficient humans are less affected by cardiovascular disease than controls with normal MPO levels (Kutter, D. et al., Acta Haematol., 104:10-15 (2000)). A polymorphism in the MPO promoter affects expression leading to high and low MPO expressing individuals. In three different studies the high expression genotype has been associated with an increased risk of cardiovascular disease (Nikpoor, B. et al., Am. Heart J., 142(2):336-339 (2001); Makela, R. et al., Lab. Invest. 83(7):919-925 (2003); Asselbergs, F. W. et al., Am. J. Med., 116(6):429-430 (2004)).

[0010] MPO inhibitors are expected to preserve heart function and reduce heart failure burden in patients. In MPO null mice, preservation of left ventricular (LV) function has been observed in both a coronary artery ligation model (Askari, A. T. et al., J. Exp. Med., 197:615-624 (2003)) and an ischemia reperfusion model (Vasilyev, N. et al., Circulation, 112:2812-2820 (2005)), suggesting that MPO may provide a mechanistic link between inflammation, oxidant stress, and impaired cardiac remodeling. High circulating levels of MPO have also been linked to chronic heart failure in patients. Systemic MPO was increased in patients with established chronic systolic HF and correlated with diastolic dysfunction independent of age and plasma B-type natriuretic peptide (Tang, W. H. et al., Am. J. Cardiol., 98:796-799 (2006)). Studies also showed that systemic MPO in subjects with myocardial infarction (MI) (Mocatta, T. J. et al., J. Am. Coll. Cardiol., 49:1993-2000 (2007)) or chronic systolic HF (Tang, W. H. et al., J. Am. Coll. Cardiol., 49:2364-2370 (2007)) may predict long-term adverse clinical events.

[0011] Inhibitors of MPO may be used to treat other neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, and stroke as well as other inflammatory diseases or conditions like asthma, COPD, cystic fibrosis, inflammatory bowel disease, chronic kidney disease, renal glomerular damage and rheumatoid arthritis.

[0012] In these chronic inflammatory diseases, a role of MPO in the development of tissue injury has been suggested. In lesional tissues of patients with Alzheimer's disease, MPO protein was detected along with elevated levels of chlorotyrosine (Green, P. S. et al., J. Neurochem., 90:724-733 (2004)). In an animal model of Parkinson's disease, increased levels of chlorotyrosine and HOCl-modified proteins in brain tissues have been reported (Choi, D. K. et al., J. Neuroscience, 25(28):6394-6600 (2005)). In asthmatic patients the level of bromotyrosine, a molecular fingerprint of eosinophil-catalyzed oxidation was associated with symptom severity (Wedes, S. H. et al., J. Pediatr., 248-255 (2011)). Upon allergen challenge, a model that elicits primarily a strong eosinophilic response, lung segments of asthmatic subjects exhibit a >10 fold increase in bronchioalveolar lavage 3-bromotyrosine an indicator of eosinophil activity vs. a 3-fold increase in 3-chlorotyrosine characteristic of MPO activity (Wu, W. et al., JCI, 105:1455-1463 (2000)). The presence of HOCl-modified protein was also detected in patients with membranous glomerulonephritis (Grone et al., Lab. Invest., 82:5-14 (2002)). High MPO circulating levels have been implicated in the development of cardiovascular and chronic kidney disease in patients on hemodialysis (Honda, H. et al., Clin. J Am. Soc., Nephrol., 142-151 (2009). In addition MPO activity and 3-chlorotyrosine levels were also increased during hemodyalisis in patients with end-stage renal disease (Delporte, C et al., Talanta, 99:603-609 (2012)). Similarly, there is accumulation of neutrophils and eosinophils in conjunction with MPO and EPX seen in intestinal mucosa of patients with inflammatory bowel disease (Kruidenier, L. et al., J Pathol., 201:17-27 (2003); Carlson, M. et al., Am. J. Gastrol., 94(7):1876-1883 (1999)) and in synovial fluids of rheumatoid arthritis patients (Edwards, S. W. et al., Biochem. J., 250:81-85 (1988); Nucombe, H. L. et al., Ann. Rheum. Dis., 50:237-242 (1991)).

[0013] Thus, there is considerable evidence that MPO derived oxidants contribute to tissue injury in chronic inflammatory disorders. MPO inhibitors are anticipated to reduce the levels of oxidants and tissue injury associated with the progression of these diseases.

SUMMARY OF THE INVENTION

[0014] The present disclosure provides novel triazolopyridine compounds, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, which are useful as MPO inhibitors.

[0015] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0016] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.

[0017] The compounds of the invention may be used in the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO.

[0018] The compounds of the invention may be used in therapy.

[0019] The compounds of the invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of diseases or disorders associated with the activity of MPO.

[0020] Examples of diseases or disorders associated with the activity of MPO include, but are not limited to, atherosclerosis, coronary artery disease, acute coronary syndrome, dyslipidemias and the sequelae thereof, heart failure, lung diseases including asthma, COPD and cystic fibrosis, and neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, multiple system atrophy, and stroke, as well as chronic inflammatory diseases such as inflammatory bowel disease, renal glomerular damage and rheumatoid arthritis.

[0021] The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).

[0022] Other features and advantages of the invention will be apparent from the following detailed description and claims.


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