Imidazothiadiazole derivatives as protease activated receptor 4 (PAR4) inhibitors for treating platelet aggregation

Patent metadata

Field	Value
Publication number	US-9862730-B2
Application number	US-201314396807-A
Country	US
Kind code	B2
Filing date	Apr 24, 2013
Priority date	Apr 26, 2012
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

The present invention provides imidazothiadiazole compounds of Formula (I) wherein A, B, D, R x , R 1 , R 2 , R 3 , X 1 , X 2 and s are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments.

First claim

What is claimed is:

1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
R 10 is

wherein A, B and D are the same or different and are independently selected from N and C, provided that A, B and D represent at least 1 carbon atom and at most 2 N atoms;
X 1 is selected from O, S or NR 4 ;
X 2 is CR 5 ;
R 1 is selected from the group consisting of:
halo,
C 2 -C 3 alkenyl,
C 2 -C 3 alkynyl,
C 1 -C 4 alkoxy,
C 1 -C 4 alkylthio,
phenylthio,
C 1 -C 4 alkylNH,
C 1 -C 4 -alkylOC 1 -C 4 -alkyl,
(C 1 -C 4 alkyl) 2 N—,
C 3 -C 6 cycloalkyl,
4- to 10-membered heterocyclyl,
halo-C 1 -C 2 -alkyl, which contains 1 to 5 halogens, where halo is F or Cl,
halo-C 1 -C 2 -alkoxy, which contains 1 to 5 halogens, where halo is F or Cl,
C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkylthio, and
C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkoxy;

R 2 is selected from the group consisting of:
H,
halo,
C 1 -C 4 alkyl,
C 1 -C 4 alkoxy, and
cyano;

R x , at each occurrence, is independently selected from the group consisting of:
H,
halo which is F, Cl, Br or I,
NR 6 R 7 ,
NO 2 ,
cyano,
OH,
C 1 -C 4 alkoxy substituted with 0 to 3 R a1 groups,
C 1 -C 4 alkylthio substituted with 0 to 3 R a1 groups,
carboxy,
carbonyl,
C 1 -C 4 alkoxycarbonyl substituted with 0 to 3 R a1 groups,
C 1 -C 4 alkylcarbonyl substituted with 0 to 3 R a1 groups,
C(═O)NR 6 R 7 ,
C 1 -C 4 alkylsulfonyl substituted with 0 to 3 R a1 groups,
S(═O) 2 NR 6 R 7 ,
C 1 -C 4 alkyl substituted with 0 to 3 R a1 groups,
fluoro-C 1 -C 4 -alkyl, which contains 1 to 5 fluorines, or
fluoro-C 1 -C 4 -alkoxy, which contains 1 to 5 fluorines; or

R x is selected from Y-Z—, where:
Z is a linker which is selected from the group consisting of:
a single bond,
—O—,
—S—,

—NH—,
C 1 -C 4 alkyl which is independently substituted with 0 to 3 R a1 groups;
C 1 -C 4 alkyloxy wherein the alkyl portion is independently substituted with 0 to 3 R a1 groups;
C 1 -C 4 alkylthio wherein the alkyl portion is independently substituted with 0 to 3 R a1 groups;
C 1 -C 4 alkyloxy-C 1 -C 4 -alkyl wherein any alkyl portion is independently substituted with 0 to 3 R a1 groups;
C 1 -C 4 -alkylthio-C 1 -C 4 -alkyl wherein any alkyl portion is independently substituted with 0 to 3 R a1 groups;
—S—C 1 -C 4 -alkyl wherein the alkyl portion is independently substituted with 0 to 3 R a1 groups;
—O—C 1 -C 4 -alkyl wherein the alkyl portion is independently substituted with 0 to 3 R a1 groups; and
C 2 -C 6 -alkynyl which is substituted with 0 to 3 R a1 groups; and

Y is selected from the group consisting of:
C 1 -C 4 -alkyloxy-C 1 -C 4 -alkyl(C 1 -C 4 -alkyl),
C 6 -C 10 aryl substituted by 0 to 3 R a5 groups,
6- to 10-membered heteroaryl substituted by 0 to 3 R a5 groups,
4- to 10-membered heterocyclyl substituted by 0 to 3 R a5 groups or 0 to 1 R b5 groups, and
C 3 -C 10 cycloalkyl substituted by 0 to 3 R a5 groups;

R 3 , at each occurrence, is R 3a , R 3b or R 3d , each of which is independently selected from the group consisting of:
H,
Cl, F, I,
NR 6 R 7 ,
NO 2 ,
cyano,
CF 3 ,
OH,
C 2 -C 4 alkynyl substituted with 0 to 2 R a1 groups,
C 1 -C 4 alkoxy substituted with 0 to 2 R a1 groups,
C 1 -C 4 alkylthio substituted with 0 to 2 R a1 groups,
carboxy,
—OCH═O,
C 1 -C 4 alkoxycarbonyl substituted with 0 to 2 R a1 groups,
C 1 -C 4 alkylcarbonyl substituted with 0 to 2 R a1 groups,
C(═O)NR 6 R 7 ,
C 1 -C 4 alkylsulfonyl substituted with 0 to 2 R a1 groups,
S(═O) 2 NR 6 R 7 ,
NR 6 C(═O)R 7 ,
C 1 -C 4 alkyl substituted with 0 to 2 R a1 groups,
fluoro-C 1 -C 4 -alkyl, which contains 1 to 5 fluorines,
fluoro-C 1 -C 4 -alkoxy, which contains 1 to 5 fluorines,
phenyl, where phenyl is substituted with 0 to 2 R a5 groups,
phenyloxy, where phenyl is substituted with 0 to 2 R a5 groups,
phenyl-C 1 -C 4 -alkoxy, where phenyl is substituted with 0 to 2 R a5 groups,
5- to 10-membered heteroaryl-C 1 -C 4 -alkoxy, where heteroaryl is substituted with 0 to 2 R a5 groups, and
4- to 10-membered heterocyclo-C 1 -C 4 -alkoxy, where heterocyclo is substituted with 0 to 2 R a5 groups;

R 4 is independently selected from the group consisting of H and C 1 -C 4 alkyl;
R 5 is independently selected from the group consisting of H, halo and C 1 , C 3 or C 4 alkyl;
R 6 and R 7 are, at each occurrence, independently selected from the group consisting of:
H,
C 1 -C 4 alkyl substituted with 0 to 2 R a1 groups,
C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, or
—(CH 2 ) n -phenyl,

alternatively, R 6 and R 7 , when attached to the same nitrogen, combine to form a 4- to 6-membered heterocyclic ring containing carbon atoms and 1 to 2 additional heteroatoms selected from N, NR C , O, and S(O) p ;
R a1 is, at each occurrence, independently selected from the group consisting of:
H,
═O,
halo,
OCF 3 ,
CF 3 ,
OCHF 2 ,
C 1 -C 4 alkyl substituted with 1 to 5 fluorines,
C 1 -C 4 alkyl,
C 1 -C 4 alkoxy,
C 1 -C 4 alkylthio,
C 3 -C 6 cycloalkyl,
C 3 -C 6 cycloalkyloxy,
phenyl substituted by 0 to 3 R a5a groups independently selected from the group consisting of halo, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, CF 3 , OCF 3 , OCHF 2 , and cyano,
OH,
CN,
NO 2 ,
NR 6a R 7a ,
carboxy,
C 1 -C 4 alkoxycarbonyl,
C(═O)NR 6a R 7a ,
C 1 -C 4 alkylsulfonyl, and
S(═O) 2 NR 6a R 7a ;

R a5 is, at each occurrence, independently selected from the group consisting of:
H,
halo,
OCF 3 ,
CF 3 ,
OCHF 2 ,
C 1 -C 6 alkyl independently substituted with 1 to 5 fluorines, hydroxyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, or amino,
C 1 -C 4 alkyl,
C 1 -C 4 alkoxy,
C 1 -C 4 alkylthio,
C 3 -C 6 cycloalkyloxy,
OH,
CN,
NO 2 ,
NR 8a R 9a ,
carboxy,
C 1 -C 4 alkoxycarbonyl,
C(═O)NR 6a R 7a ,
C 6 -C 10 -arylcarbonylamino-C 1 -C 4 -alkyl(phenyl)carbonyl,
5- to 10-membered heteroarylcarbonylamino-C 1 -C 4 -alkyl(phenyl)carbonyl,
C 6 -C 10 arylcarbonyl substituted with 0 to 5 R a5a groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkoxy, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, NR 6a R 7a , OH, C 1 -C 4 -alkylcarbonyloxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, COOR 8a , SO 2 R 8a , (C═O)NR 6a R 7a , SO 2 NR 6a R 7a , N(R 8a )(C═O)NR 6a R 7a , N(R 8a )(C═O)OR 8a , N(R 8a )(C═O)R 8a , NR 8a S(O)R 8a , NR 8a SO 2 R 8a , O(C═O)NR 6a R 7a , O(C═O)OR 8a , O(C═O)R 8a , (C═O)OR 8a , and 5-6-membered heteroaryl,
C 1 -C 4 -alkyloxycarbonylamino-C 1 -C 4 -alkyl(phenyl)carbonyl,
C 1 -C 6 alkylsulfonyl,
S(═O) 2 NR 6a R 7a ,
phenyloxy, wherein the phenyl is substituted by 0 to 5 R a5a groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkoxy, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, cyano, nitro, NR 6a R 7a , OH, C 1 -C 4 -alkylcarbonyloxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, COOR 8a , SO 2 R 8a , (C═O)NR 6a R 7a , SO 2 NR 6a R 7a , N(R 8a )(C═O)NR 6a R 7a , N(R 8a )(C═O)OR 8a , N(R 8a )(C═O)R 8a , NR 8a S(O)R 8a , NR 8a SO 2 R 8a , O(C═O)NR 6a R 7a , O(C═O)OR 8a , O(C═O)R 8a , (C═O)OR 8a , and 5-6-membered heteroaryl,
phenylthio, wherein the phenyl is substituted by 0 to 5 R a5a groups independent

Assignees

• Bristol Myers Squibb Co
• Univ Montreal

Inventors

• Lawrence R Michael
• Miller Michael M
• Seiffert Dietmar Alfred
• Posy Shoshana L
• Wong Pancras C
• Banville Jacques
• Ruediger Edward H
• Deon Daniel H
• Martel Alain
• Tremblay François
• Guy Julia
• Lavallée Jean-François
• Gagnon Marc

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/4355

  the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom · CPC title