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

Patent metadata

Field	Value
Publication number	US-9518064-B2
Application number	US-201314396831-A
Country	US
Kind code	B2
Filing date	Apr 24, 2013
Priority date	Apr 26, 2012
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

The present invention provides imidazothiadiazole compounds of Formula (I); Wherein W, Y, R 0 , R 2 , R 4 , R a , R b , 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 we claim 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 or R 1a ;
Y is S or —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 1a is independently selected from the group consisting of:
H,
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 1a , 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,
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, C 1 -C 6 alkyl, halo-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl, and C 1 -C 3 alkoxy-C 1 -C 3 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 phenyl or a 6-membered heteroaryl ring, at least one ring member of which is a nitrogen, which

ring is substituted with 0 to 2 R a groups;
B is selected from the group consisting of a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl containing carbon atoms and 1 to 4 additional heteroatoms selected from N, O, and S, and a C 3 -C 8 cycloalkyl which may contain unsaturation, all of which are substituted by 0 to 3 R b groups;
R a , at each occurrence, is independently selected from the group consisting of H, halo, halo-C 1 -C 4 alkoxy, OH, CN, NO 2 , NR 6 R 7 , COOH, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkoxycarbonyl, (C═O)NR 6 R 7 , C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, S(═O) 2 NR 6 R 7 , 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, phenyl, and C 1 -C 4 alkylthio;
R b , at each occurrence, is independently selected from the group consisting of H, halo, halo-C 1 -C 4 alkoxy, OH, CN, NO 2 , NR 6 R 7 , COOH, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkoxycarbonyl, (C═O)NR 6 R 7 , C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkyl sulfinyl, S(═O) 2 NR 6 R 7 , N(R 13 )(C═O)NR 6 R 7 , 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 6 R 7 , O(C═O)OR 14 , O(C═O)R 14 , (C═O)OR 14 , C 6 -C 10 aryl, 5-6-membered heteroaryl, 4- to 10-membered heterocyclyloxy 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, phenyl, C 1 -C 4 -alkoxyphenyl-C 1 -C 4 -alkoxy, 4- to 10-membered heterocyclyloxy and C 1 -C 4 alkylthio;
R 6 and R 7 are independently, at each occurrence, selected from the group consisting of:
H,
C 1 -C 4 alkyl,
halo-C 1 -C 4 -alkyl,
C 1 -C 4 alkyleneoxy-C 1 -C 4 -alkylene,
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 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,
di-C 1 -C 4 -alkylamino-C 1 -C 4 -alkyl,
C 1 -C 4 -alkylcarbonylamino-C 1 -C 4 -alkyl,
di-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl,
di-C 1 -C 4 -alkylaminophenyl,
hydroxy-C 1 -C 4 -alkyl,
cyano-C 1 -C 4 -alkyl,
C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl,
C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkyl,
C 1 -C 4 -alkoxycarbonyl,
C 1 -C 4 -alkylcarbonyl,
phenylcarbonyl;
C 1 -C 4 -alkoxycarbonylamino-C 1 -C 4 -alkylcarbonyl,
di-C 1 -C 4 -alkylamino-C 1 -C 4 -alkylcarbonyl,
amino-C 1 -C 4 -alkylcarbonyl,
4- to 10-membered-heterocyclyl-carbonyl, and

alternatively, R 6 and R 7 , when attached to the same nitrogen, combine to form a 4- to 8-membered heterocyclic ring containing carbon atoms substituted by 0 to 3 groups independently selected from the group consisting of halo, CF 3 , CHF 2 , OCF 3 , OCHF 2 , OCH 2 F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, and 0 to 2 additional heteroatoms selected from N, NR 13 , O and S(O) p ;
R 13 is independently, at each occurrence, selected from the group consisting of H, C 1 -C 6 alkyl and —(CH 2 )phenyl;
R 14 is independently, at each occurrence, selected from the group consisting of H, C 1 -C 6 alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonylamino, (C 6 -C 10 arylcarbonylamino), (a 5- to 10-membered heteroarylcarbonylamino) 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 -

Assignees

• Bristol Myers Squibb Co
• Univ Montreal

Inventors

• Martel Alain
• Tremblay François
• Marinier Anne
• Priestley Eldon Scott
• Posy Shoshana L
• Lawrence R Michael
• Miller Michael M

Classifications

• 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

• A61K31/433

  Thidiazoles · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/4439

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

• C07D513/04 Primary

  Ortho-condensed systems · CPC title