Triazolopyridine and triazolopyrimidine inhibitors of myeloperoxidase

Patent metadata

Field	Value
Publication number	US-9920075-B2
Application number	US-201515510168-A
Country	US
Kind code	B2
Filing date	Sep 9, 2015
Priority date	Sep 11, 2014
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

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 of the formula (I)

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt 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: 0, 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, or a pharmaceutically acceptable salt 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, or a pharmaceutically acceptable salt thereof.

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

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

5. A compound according to claim 1
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt 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 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, —CH 2 (C 1-4 alkoxy), —(O)

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

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · 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

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title