Thioether triazolopyridine and triazolopyrimidine inhibitors of myeloperoxidase

Abstract

The present invention provides compounds of Formula (I): wherein A, X and Y 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, which may be used as medicaments.

What is claimed is: 
     
         1 . The compound according to the formula (I) 
       
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein: 
         ring A is independently phenyl substituted with 0-1 R 2  and 0-4 R 3 , or (a 5- to 6-membered heteroaryl 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 0-3 R 3 ); 
         X is independently CH or N; 
         Y is independently selected from: a hydrocarbon linker substituted with 0-1 R 1 , or a hydrocarbon-heteroatom linker substituted with 0-1 R 1 ; wherein said hydrocarbon linker has one to six carbon atoms and may be straight or branched; and said hydrocarbon-heteroatom linker has one to four carbon atoms and one group selected from O, S, NH, N(C 1-4  alkyl), CONH, and NHCO; 
         R 1  is independently selected from: CN, OH, —(C 1-4  alkyl substituted with 0-1 R 18 ), C 1-4  haloalkyl, Ph, Bn, COPh, CH(OH)Ph, CO 2 (C 1-4  alkyl), and CONHBn; 
         R 2  is independently selected from: —CH(NH 2 )CF 3 , —(CH 2 ) t OH, —O(CH 2 ) 2-3 N(C 1-4  alkyl) 2 , —(CH 2 ) n R 4 , and —(CH 2 ) n (X 1 ) n (CH 2 ) n R 5 ; 
         X 1  is independently selected from: C(Me) 2 , 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); 
         alternatively, R 2  and R 3 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-3 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R 19 ; 
         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 , COR 10 , —CONH(CH 2 ) 1-2 NR 9 R 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 ) n —(C 3-6  cycloalkyl substituted with 0-1 R 14 ), —(CH 2 ) n -(phenyl substituted with 0-1 R 16 ), —(CH 2 ) n -(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 ; 
         alternatively, R 6  and R 7 , together with the nitrogen atom to which they are attached, combine to form a 4- to 10-membered heterocyclic ring 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 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, 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 , CONH(C 1-4  alkyl), CONHCH 2 CH 2 (C 1-4  alkyl) 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 ), and (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 18  is independently selected from: OH, CN, NH 2 , N(C 1-4  alkyl) 2 , NHBn, imidazolyl and morpholinyl; 
         R 19  is independently selected from: halogen and CO 2 (C 1-4  alkyl); 
         R a  is, at each occurrence, independently selected from: 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 —C 3-6  cycloalkyl, —(CH 2 ) n -(phenyl substituted with 0-2 R c ), —CO(—(CH 2 ) n -phenyl), (a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR b , O, and S(O) p , wherein said heterocycle is substituted with 0-2 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, CN, C 1-4  alkyl, halogen, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, N(C 1-4  alkyl) 2 , —CH 2 N(C 1-4  alkyl) 2 , CONHCH 2 CH 2 N(C 1-4  alkyl) 2 , pyrrolidinyl, piperazinyl, and 
       
       
         
           
           
               
               
           
         
         n is, at each occurrence, independently selected from: 0, 1 and 2; 
         p is, at each occurrence, independently selected from: 0, 1 and 2; and 
         s is, at each occurrence, independently selected from: 1 and 2; 
         provided that 
       
       
         
           
           
               
               
           
         
       
       is excluded. 
     
     
         2 . A compound according to  claim 1   or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:   X is CH.   
     
     
         3 . A compound according to  claim 2   or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:   ring A is independently phenyl substituted with 0-1 R 2  and 0-3 R 3 , or a heteroaryl substituted with 0-1 R 2  and 0-2 R 3  selected from: oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, 1-R a -pyrazolyl, imidazolyl 1-R a -imidazolyl, triazolyl, 1-R a -triazolyl, pyridyl, and pyrimidinyl; and   alternatively, R 2  and R 3 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-3 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R 19 .   
     
     
         4 . A compound according to  claim 3   or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:   ring A is phenyl substituted with 1 R 2  and 0-3 R 3 ; and   alternatively, R 2  and R 3 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-3 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R 19 .   
     
     
         5 . A compound according to  claim 4   or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:   Y is independently selected from: CH 2 , CHR 1 , —CH 2 CH 2 —, —CH(C 1-4  alkyl)CH 2 —, —CH 2 CH(C 1-4  alkyl)-, —(CH 2 ) 1-3 O(CH 2 ) 0-1 —, —CH 2 CH 2 NH(CH 2 ) 1-3 —, —CH 2 CH 2 N(C 1-4  alkyl)CH 2 —, —CH 2 CH 2 NHCHBn-, —CH 2 CH 2 NHCH 2 CH(C 1-4  alkyl)-, —CH 2 CH 2 NHCH(C 1-4  alkyl)CH 2 —, —CH 2 CH 2 NHCH 2 C(OH)(C 1-4  alkyl)-, and —(CH 2 ) 1-2 CONH—;   R 1  is independently selected from: —(C 1-4  alkyl substituted with 0-1 R 18 ), C 1-4  haloalkyl, COPh, CH(OH)Ph, CO 2 (C 1-4  alkyl), and CONHBn;   R 2  is independently selected from: halogen, CN, —CH 2 CN, CH 2 OH, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, —CH(NH 2 )CF 3 , —CH 2 NHCF 3 , CO 2 (C 1-4  alkyl), SO 2 (C 1-4  alkyl), SO 2 Bn, SO 2 NH 2 , SO 2 NH(C 1-4  alkyl), —CH 2 SO 2 Ph, NH 2 , —CH 2 N(C 1-4  alkyl) 2 , —O(CH 2 ) 3 N(C 1-4  alkyl) 2 , CONH 2 , —CONHCH 2 CH 2 N(C 1-4  alkyl) 2 , CONH(1-C 1-4  alkyl-cyclopropyl), C 3-6  cycloalkyl substituted with 0-1 CN, —O—C 3-6  cycloalkyl, phenoxy, benzoxy, —(CH 2 ) 0-1 -(phenyl substituted with 0-2 R 11  and 0-1 R 12 ), pyrrolidinyl, pyrrolidinylmethyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, 1-C 1-4  alkyl-3-C 1-4  haloalkyl-pyrazo-5-yl, morpholinylmethyl, pyridyl, —O-pyridyl, 2-CN-pyrid-4-yl, 2-CONH 2 -pyrid-4-yl, 4-(pyrrolidinyl)-pyrid-3-yl, 4-(piperazinyl)-pyrid-3-yl, pyrimidinyl,   
       
         
           
           
               
               
           
         
         R 3  is, at each occurrence, independently selected from: halogen, CN, C 1-4  alkyl, C 1-4  alkoxy, and C 1-4  haloalkyl; 
         alternatively, R 2  and R 3 , together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-3 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R 19 ; 
         R 18  is independently selected from: OH, CN, N(C 1-4  alkyl) 2 , NHBn, imidazolyl and morpholinyl; 
         R 19  is independently selected from: halogen and CO 2 (C 1-4  alkyl); and 
         R a  is, at each occurrence, independently selected from: H, C 1-4  alkyl, —(CH 2 ) n —C 3-6  cycloalkyl, —(CH 2 ) n -(phenyl substituted with 0-1 R c ), (pyridyl substituted with 0-1 R c ), pyrazinyl, pyridazinyl, pyrimidinyl, and 
       
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound according to  claim 5  of formula (II) 
       
         
           
           
               
               
           
         
         or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein: 
       
       or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, within the scope of any of the above aspects; wherein:
 Y is independently selected from: CH 2 , CHR 1 , —CH 2 CH 2 —, —CH(C 1-4  alkyl)CH 2 —, —CH 2 CH(C 1-4  alkyl)-, —(CH 2 ) 1-3 O(CH 2 ) 0-1 —, —CH 2 CH 2 NH(CH 2 ) 1-3 —, —CH 2 CH 2 N(C 1-4  alkyl)CH 2 —, —CH 2 CH 2 NHCHBn-, —CH 2 CH 2 NHCH 2 CH(C 1-4  alkyl)-, —CH 2 CH 2 NHCH(C 1-4  alkyl)CH 2 —, —CH 2 CH 2 NHCH 2 C(OH)(C 1-4  alkyl)-, and —CH 2 CH 2 CONH—; 
 R 1  is independently selected from: —(C 1-4  alkyl substituted with 0-1 R 18 ), C 1-4  haloalkyl, COPh, CH(OH)Ph, CO 2 (C 1-4  alkyl), and CONHBn; 
 R 2  is independently selected from: halogen, CN, —CH 2 CN, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, —CH(NH 2 )CF 3 , —CH 2 NHCF 3 , CO 2 (C 1-4  alkyl), SO 2 (C 1-4  alkyl), SO 2 Bn, SO 2 NH 2 , SO 2 NH(C 1-4  alkyl), —CH 2 SO 2 Ph, —CH 2 N(C 1-4  alkyl) 2 , —O(CH 2 ) 3 N(C 1-4  alkyl) 2 , CONH 2 , —CONHCH 2 CH 2 N(C 1-4  alkyl) 2 , CONH(1-C 1-4  alkyl-cyclopropyl), C 3-6  cycloalkyl substituted with 0-1 CN, —O—C 3-6  cycloalkyl, 2-(SO 2 NH(C 1-4  alkyl))-Ph, Bn, phenoxyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, 1-C 1-4  alkyl-3-C 1-4  haloalkyl-pyrazo-5-yl, morpholinylmethyl, pyridyl, —O-pyridyl, 2-CN-pyrid-4-yl, 2-CONH 2 -pyrid-4-yl, 4-(pyrrolidinyl)-pyrid-3-yl, 4-(piperazinyl)-pyrid-3-yl, pyrimidinyl, 
 
       
         
           
           
               
               
           
         
         R 3  is, at each occurrence, independently selected from: halogen, CN, C 1-4  alkyl, C 1-4  alkoxy, and C 1-4  haloalkyl; and 
         R 18  is independently selected from: OH, CN, N(C 1-4  alkyl) 2 , NHBn, imidazolyl and morpholinyl. 
       
     
     
         7 . A compound according to  claim 1 , wherein the compound is selected from any one of Examples 1 to 166 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of any one of  claims 1  to  7 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.