Triazolopyridine and triazolopyrimidine inhibitors of myeloperoxidase

Patent metadata

Field	Value
Publication number	US-2017247396-A1
Application number	US-201515510168-A
Country	US
Kind code	A1
Filing date	Sep 9, 2015
Priority date	Sep 11, 2014
Publication date	Aug 31, 2017
Grant date	—

Abstract

The present invention provides compounds of Formula (I): wherein A and R 1 are each 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, which may be used as medicaments.

First claim

What is claimed is:

1 . The compound according to claim 1 of the formula (I)

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:
ring A is independently a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycle is substituted with 0-1 R 2 and 0-4 R 3 ;
X is independently CH or N;
R 1 is independently selected from: H, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
provided that ring A is other than thienyl substituted with halogen, when X is N and R 1 is H;
R 2 is independently selected from: SF 5 , —(CH 2 ) t OH, —(CH 2 ) n R 4 , and —(CH 2 ) n (X 1 ) n (CH 2 ) n R 5 ;
X 1 is independently selected from: O, S, CO and SO 2 ;
R 3 is, at each occurrence, independently selected from: halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NO 2 , CONH 2 , and SO 2 (C 1-4 alkyl);
R 4 is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, CN, CO 2 (C 1-4 alkyl), NO 2 , NR 6 R 7 , CONR 6 R 7 , NHCOR 8 , NHCO 2 R 8 , COR 10 , SO 2 NR 9 R 10 , and S(O) p R 8 ;
R 5 is independently selected from: C 3-10 carbocycle substituted with 0-2 R 11 , phenyl substituted with 0-3 R 11 and 0-1 R 12 , and 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ;

wherein said heterocycle is substituted with 0-2 R 11 and 0-1 R 13 ;
R 6 is, at each occurrence, independently selected from: H, C 1-4 haloalkyl, C 1-6 alkyl substituted with 0-2 R 15 , —(CH 2 ) t —(C 3-6 cycloalkyl substituted with 0-1 R 14 ), —(CHR b ) n -(phenyl substituted with 0-1 R 16 ), —(CH 2 ) t -(phenyl substituted with 0-1 R 16 ), —(CH 2 ) t -(a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p , wherein said heterocycle is substituted with 0-1 R 17 );
R 7 is, at each occurrence, independently selected from: H and C 1-4 alkyl substituted with R 11 ;
R 8 is, at each occurrence, independently selected from: C 1-4 alkyl, —(CH 2 ) t —C 3-6 cycloalkyl, and —(CH 2 ) t -phenyl;
R 9 is, at each occurrence, independently selected from: H and C 1-4 alkyl;
R 10 is, at each occurrence, independently selected from: R 8 and H;
R 11 is, at each occurrence, independently selected from: OH, NH 2 , halogen, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R 12 is independently selected from: halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylthio, OH, CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), NH 2 , CH 2 NH 2 , N(C 1-4 alkyl) 2 , CH 2 N(C 1-4 alkyl) 2 , CONH 2 , CON(C 1-4 alkyl) 2 , SO 2 NH 2 , SO 2 NH(C 1-4 alkyl), SO 2 N(C 1-4 alkyl) 2 , CONHPh, NHCOPh, —(CH 2 ) n —(C 3-6 carbocycle substituted with 0-2 R c ), (a 5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p , wherein said heterocycle is substituted with 0-2 R c ),

R 13 is independently selected from: R 12 and ═O;
R 14 and R 16 are, at each occurrence, independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, OH, CH 2 OH, N(C 1-4 alkyl) 2 , CONH 2 , CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , OCH 2 CONH 2 , NHCO(C 1-4 alkyl), NHCO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), —(CH 2 ) n -phenyl, —O—(CH 2 ) n -phenyl, and pyridylmethyl;
R 15 is, at each occurrence, independently selected from: OH, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, N(C 1-4 alkyl) 2 , CONH 2 , CONH(C 1-4 alkyl), and CON(C 1-4 alkyl) 2 ;
R 17 is independently selected from: R 14 and ═O;
R a is, at each occurrence, independently selected from the group consisting of H, C 1-4 alkyl, CO(C 1-4 alkyl), CO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), —(CH 2 ) n -(pyrrolidinyl substituted with 0-1 R c ), —(CH 2 ) n -(phenyl substituted with 0-1 R c ), and —CO(—(CH 2 ) n -phenyl substituted with 0-1 R c );
R b is, at each occurrence, independently selected from: H and C 1-4 alkyl;
R c is, at each occurrence, independently selected from: OH, NH 2 , C 1-4 alkyl, halogen, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, pyrrolidinyl, —(CH 2 ) n -piperidinyl, Ph, and OPh;
n is, at each occurrence, independently selected from: 0 and 1;
p is, at each occurrence, independently selected from: 0, 1 and 2; and
t is, at each occurrence, independently selected from: 0, 1, 2, 3 and 4.

2 . A compound according to claim 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein: R 2 is independently selected from: halogen, CN, CH 2 OH, C 1-4 alkyl, —CH 2 —C 1-4 alkoxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, SF 5 , CO 2 (C 1-4 alkyl), NR 6 R 7 , CONR 6 R 7 , —NHCO(C 1-4 alkyl), NO 2 , SO 2 NR 8 R 9 , SO 2 R 8 , —(O) 0-1 —(C 3-6 cycloalkyl), —(O) 0-1 —(CH 2 ) 0-1 -(phenyl substituted with 0-1 R 11 and 0-1 R 12 ), and —(CH 2 ) 0-1 -(a heterocycle substituted with 0-1 R 11 and 0-1 R 13 , wherein said heterocycle is a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S); R 6 is independently selected from: H, C 1-4 haloalkyl, and C 1-6 alkyl; R 12 and R 13 are, at each occurrence, independently selected from: halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CH 2 OH, CO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), C 3-6 cycloalkyl, CON(C 1-4 alkyl) 2 , SO 2 NH 2 , SO 2 NH(C 1-4 alkyl), SO 2 N(C 1-4 alkyl) 2 , Ph, Bn, CONHPh, NHCOPh, pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,

R 15 is, at each occurrence, independently selected from: OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, N(C 1-4 alkyl) 2 , CONH 2 , CONH(C 1-4 alkyl), and CON(C 1-4 alkyl) 2 ; and
R 16 is independently selected from: halogen, C 1-4 alkoxy, and SO 2 (C 1-4 alkyl).

3 . A compound according to claim 2 of formula (II)

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

4 . A compound according to claim 2 of the formula (IIa)

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, provided that ring A is other than thienyl substituted with halogen.

5 . A compound according to claim 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein: ring A is independently selected from:

 and a 5- to 10-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S; wherein each ring moiety is substituted with 0-1 R 2 and 0-2 R 3 ; provided that ring A is other than thienyl substituted with halogen, when X is N and R 1 is H in Formula (I);
R 2 is independently selected from: SF 5 , halogen, CN, CH 2 OH, C

Assignees

• Bristol Myers Squibb Co

Inventors

• Wurtz Nicholas R
• Viet Andrew Quoc
• Shaw Scott A
• Vokits Benjamin P
• Kick Ellen K
• Valente Meriah Neissel
• Dilger Andrew K
• Pabbisetty Kumar Balashanmuga
• Jusuf Sutjano

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title