Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor4 (PAR4) inhibitors for treating platelet aggregation

Patent metadata

Field	Value
Publication number	US-10822343-B2
Application number	US-201916538917-A
Country	US
Kind code	B2
Filing date	Aug 13, 2019
Priority date	Apr 26, 2012
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The present invention provides thiazole compounds of Formula I

wherein W, Y,

R 0 , R 2 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , X 3 and X 4 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester 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 for treating or preventing thromboembolic disorders.

First claim

What is claimed is:

1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
W is O or S;
R 0 is R 1 ;
Y is —CR 8 ═CR 9 —;
R 1 is independently selected from the group consisting of:
halo,
C 1 -C 4 alkyl,
C 2 -C 3 alkenyl,
C 2 -C 3 alkynyl,
C 3 -C 4 cycloalkyl,
C 1 -C 4 alkoxy,
C 1 -C 2 alkoxy-C 1 -C 2 alkyl,
tetrahydrofuran-2-yl;
C 1 -C 4 alkylthio,
C 1 -C 4 alkylNH—,
(C 1 -C 4 alkyl) 2 N—,
halo-C 1 -C 2 -alkyl, which contains 1 to 5 halogens, where halo is F or Cl,
halo-C 3 -C 4 cycloalkyl,
halo-C 1 -C 2 alkoxy, and
halo-C 1 -C 2 alkylthio;

R 8 and R 9 are independently selected from the group consisting of:
H,
halo,
C 1 -C 4 alkyl,
C 1 -C 4 alkoxy,
halo-C 1 -C 2 alkyl,
halo-C 1 -C 2 alkoxy,
CN, and
OH;

provided that at least one of R 1 , R 8 and R 9 is other than H;
R 2 is selected from the group consisting of:
H,
halo,
C 1 -C 4 alkyl,
C 1 -C 4 alkoxy, and
cyano;

X 1 is selected from the group consisting of CH, N or CR 10 ;
X 2 , X 3 and X 4 are independently selected from CR 3 or N;
R 3 is selected from the group consisting of H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo, OH, CN, OCF 3 , OCHF 2 , OCH 2 F, C 1 -C 2 -alkoxy-C 1 -C 2 -alkoxy, halo-C 1 -C 3 -alkyl, which contains 1 to 5 halogens, benzyloxy substituted by 0 to 3 groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyclopropyl, CF 3 , OCF 3 , 5- or 6-membered heteroaryl, OH, OCHF 2 , di-C 1 -C 4 -alkylamino, and cyano, and —(CH 2 ) n 1 -phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyclopropyl, CF 3 , OCF 3 , 5- or 6-membered heteroaryl, OH, OCHF 2 , di-C 1 -C 4 -alkylamino, and cyano;
R 4 and R 5 are independently selected from H and C 1 -C 6 alkyl, or R 4 and R 5 can be taken together with the carbon to which they are attached to form a C 3 -C 7 cycloalkyl ring;

 is a 5-membered heteroaryl ring containing at least one O, N or S atom;
R 6 is selected from the group consisting of H, halo, OCF 3 , OCHF 2 , OH, CN, NO 2 , NR 11 R 12 , COOH, C 1 -C 4 alkoxycarbonyl, (C═O)NR 11 R 12 , C 1 -C 4 alkylsulfonyl, S(═O) 2 NR 11 R 12 , and C 1 -C 5 alkyl substituted by 0 to 7 groups independently selected from halo, CF 3 , OCF 3 , OH, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, di-C 1 -C 4 -alkylaminophenyl-C 1 -C 4 -alkyl, (di-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl)-C 1 -C 4 -alkyl, di-C 1 -C 4 -alkylamino, C 3 -C 6 -cycloalkyl, and C 1 -C 4 alkylthio, or
R 6 is B-D-, where D is a linker, which is selected from:
a single bond,
—O—,
—S—,

C 1 -C 4 alkylene substituted by 0 to 4 groups independently selected from halo or OH,
C 1 -C 4 alkyleneoxy,
C 1 -C 4 alkylenethio,
C 1 -C 4 alkyleneoxy-C 1 -C 4 -alkylene,
C 1 -C 4 -alkylenethio-C 1 -C 4 -alkylene,
—S—C 1 -C 4 -alkylene,
—O—C 1 -C 4 -alkylene,
C 2 -C 6 alkenylene, and

B is selected from the group consisting of:
C 6 -C 10 aryl substituted by 0 to 3 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 11 R 12 , OH, C 1 -C 4 -alkylcarbonyloxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, cyano-C 1 -C 4 -alkyl, COOR 14 , SO 2 R 14 , (C═O)NR 11 R 12 , SO 2 NR 11 R 12 , N(R 13 )(C═O)NR 11 R 12 , N(R 13 )(C═O)OR 14 , N(R 13 )(C═O)R 14 , NR 13 S(O)R 14 , NR 13 SO 2 R 14 , O(C═O)NR 11 R 12 , O(C═O)OR 14 , O(C═O)R 14 , (C═O)OR 14 , and 5-6-membered heteroaryl,
5- to 10-membered heteroaryl substituted by 0 to 3 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 11 R 12 , OH, C 1 -C 4 -alkylcarbonyloxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, COOR 14 , SO 2 R 14 , (C═O)NR 11 R 12 , SO 2 NR 11 R 12 , N(R 13 )(C═O)NR 11 R 12 , N(R 13 )(C═O)OR 14 , N(R 13 )(C═O)R 14 , NR 13 S(O)R 14 , NR 13 SO 2 R 14 , O(C═O)NR 11 R 12 , O(C═O)OR 14 , O(C═O)R 14 , (C═O)OR 14 , 5-6-membered heteroaryl, and (CH 2 )phenyl,
4- to 10-membered heterocyclyl containing carbon atoms and 1 to 2 additional heteroatoms selected from N, O, and S, and substituted by 0 to 3 groups independently selected from the group consisting of halo, oxo, —(CHR 13 ) n 1 -5- or 6-membered heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyclopropyl, CF 3 , OCF 3 , and CF 2 CH 3 ; NR 13 S(O)R 14 , NR 13 SO 2 R 14 , —(CHR 13 ) n 1 -4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyclopropyl, CF 3 , OCF 3 , and CF 2 CH 3 ; OH, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkoxy, di-C 1 -C 4 -alkylamino-C 1 -C 4 -alkyl, NR 11 R 12 , cyano, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 6 cycloalkyl-C 1 -C 4 -alkylcarbonyl, C 6 -C 10 arylcarbonyl, C 1 -C 4 -alkylcarbonyloxy-C 1 -C 4 -alkyl, COOR 14 , SO 2 R 14 , (C═O)NR 11 R 12 , SO 2 NR 11 R 12 , N(R 13 )(C═O)NR 11 R 12 , N(R 13 )(C═O)OR 14 , N(R 13 )(C═O)R 14 , O(C═O)NR 11 R 12 , O(C═O)OR 14 , O(C═O)R 14 , (C═O)OR 14 , and C 6 -C 10 aryl substituted by 0 to 3 groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyclopropyl, C 1 -C 4 -alkoxycarbonyl, (C═O)NR 11 R 12 , CF 3 , OCF 3 , and CF 2 CH 3 ;
C 3 -C 6 cycloalkyl which may contain unsaturation, substituted by 0 to 3 groups independently selected from the group consisting of halo, CF 3 , OCF 3 , 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C 1 -C 4 -alkyl, C 6 -C 10 aryl, COOH, oxo, C 1 -C 4 -alkoxycarbonyl, (C═O)NR 11 R 12 , NR 11 R 12 and C 1 -C 4 alkyl; and

C 5 -C 11 spirocycloalkyl which may contain unsaturation and optionally containing 1 to 3 heteroatoms selected from O, N or S and substituted by 0 to 3 groups independently selected from the group consisting of halo, CF 3 , OCF 3 , 5- or 6-membered heteroaryl, OH, hydroxy-C 1 -C 4 -alkyl, C 6 -C 10 aryl, and C 1 -C 4 alkyl;
R 11 and R 12 are independently, at each occurrence, selected from the group consisting of:
H,
C 1 -C 4 alkyl,
halo-C 1 -C 4 -alkyl,
C 2 -C 4 alkenyl,
C 2 -C 4 alkynyl,
—(CR 14 R 14 ) n 1 -phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, cyclopropyl, CF 3 , OCF 3 , 5- or 6-membered heteroaryl, OH, OCHF 2 , di-C 1 -C 4 -alkylamino, and cyano,
—(CHR 13 ) n 1 —C 3 -C 6 -cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF 3 , OCF 3 , 5- or 6-membered heteroaryl, OH, hydroxy-C 1 -C 4 -alkyl, and C 1 -C 4 alkyl,
—(CHR 13 ) n 1 -4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF 3 , OCF 3 , 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C 1 -C 4 -alkyl, and C 1 -C 4 alkyl,
—(CHR 13 ) n 1 -5- to 10-membered-heteroaryl substituted by 0 to 3 groups inde

Assignees

• Bristol Myers Squibb Co
• Univ Montreal

Inventors

• Banville Jacques
• Remillard Roger
• Ruediger Edward H
• Deon Daniel H
• Gagnon Marc
• Dube Laurence
• Guy Julia
• Priestley Eldon Scott
• Posy Shoshana L
• Maxwell Brad D
• Wong Pancras C
• Lawrence R Michael
• Miller Michael M

Classifications

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/433

  Thidiazoles · CPC title

• A61K31/4355

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

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title