IP Library › Granted Patent US 9,340,530

Granted Patent B2

US 9,340,530 · App. 14/383,176 · Granted May 17, 2016

Preparation and use of bicyclic himbacine derivatives as PAR-1 receptor antagonists

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Quick Facts

Patent No.: US 9,340,530
App. No.: 14/383,176
Granted: May 17, 2016
Kind: B2

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Abstract

The present invention relates to bicyclic himbacine derivatives of the formula or a pharmaceutically acceptable salt thereof, wherein: X is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)—; and Y is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)— and the remaining variables are described herein. The compounds of the invention are effective inhibitors of the PAR-1 receptor. The inventive compounds may be used for the treatment or prophylaxis of disease states such as ACS, secondary prevention of myocardial infarction or stroke, or PAD.

Claims (182)

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

X is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)—;

Y is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)—;

R is H, alkyl or —S(O) 2 —R 9

R 1 is H, alkyl or haloalkyl;

R 2 is H, alkyl or haloalkyl;

R 3 is —N 3 , —CN; halogen, —OR 12 , —N(R 25 )(R 26 ), —C(O)OR 12 , —C(O)N(R 25 )(R 26 ), —SO 2 (R 12 ), R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl or R 17 -heteroaryl;

R 4 is H, alkyl or haloalkyl;

R 5 is H, alkyl or haloalkyl;

R 6 is H or alkyl;

R 7 is H or alkyl;

R 8 independently is H or alkyl;

R 9 independently is H or alkyl;

R 10 is fluoro;

R 11 is fluoro;

R 12 independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

R 13 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

R 14 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, —C(O)R 12 , —S(O) 2 —R 12 , R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

or R 13 and R 14 taken together with the nitrogen atom to which they are attached are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —N(R 8 )—(CH 2 ) 2 —;

Het is a 5- or 6-membered heterocycloalkyl, heterocyclenyl or a heteroaryl ring containing 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of N, O or S, with the proviso that there are no adjacent oxygen or sulfur atoms present in said groups, and when Het is a N-containing heteraromatic group with one heteroatom present, then the ring nitrogen can form an N-oxide or a quaternary group with an alkyl group; wherein: 1) Het is attached to the double bond by a carbon atom ring member of Het; and 2) Het is substituted by 1 to 4 moieties, W,

where each W is independently hydrogen, alkyl, haloalkyl, R 17 -cycloalkyl, R 17 -heterocycloalkyl, R 16 -alkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -heteroarylalkyl, R 17 -heteroarylalkenyl, hydroxyalkyl, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl, alkoxy, -alkyl-SH, —S-alkyl, alkenyloxy, halogen, —NR 13 R 14 , —CN, —OH, —C(O)OR 12 , —COR 12 , —OS(O 2 )CF 3 , —CH 2 OCH 2 CF 3 , —C(O)NR 13 NR 14 , —OCHR 15 -phenyl, phenoxyalkyl, —NR 8 COR 12 , —NR 8 SO 2 R 12 , —C(O)NR 13 R 14 , —OC(R 15 ) 2 COOR 12 , —OC(R 15 ) 2 C(O)NR 13 R 14 , alkoxy optionally substituted by alkyl, amino or —NR 8 C(O)OR 12 , or alkyl optionally substituted with —NR 13 R 14 , —NR 13 COR 12 , —NR 8 CONR 13 R 14 , —NR 8 C(O)OR 12 , —NR 8 S(O) 2 NR 13 R 14 , —C(O)OR 12 , —CONR 13 R 14 or —OH;

R 15 independently is H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl or phenyl;

R 16 is 1 to 3 moieties and each R 16 is independently hydrogen, halogen, —OH, alkoxy, -alkyl-SH, —S-alkyl, R 24 -aryl, R 24 -heteroaryl, R 24 -heterocycloalkyl, R 24 -cycloalkyl, R 24 -cycloalkenyl, R 24 -heterocyclenyl, —OC(O)R 20 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 21 R 22 , —NR 21 R 22 , —NR 8 C(O)R 20 , —NR 8 C(O)NR 21 R 22 , —NR 8 SO 2 R 20 , —OC(O)NR 21 R 22 , R 23 -alkenyloxy, R 23 -alkynyloxy, R 23 -heterocycloalkyloxy, R 24 -cycloalkyloxy, R 24 -cycloalkenyloxy, R 24 -aryloxy, R 24 -heteroaryloxy, R 24 -cycloalkyl-NH—, —NR 8 SO 2 NHR 21 or —C(═NOR 18 )R 19 ;

R 17 is 1 to 3 moieties and each R 17 independently hydrogen, R 23 -alkyl, halogen, —CN, —NO 2 , —OH, R 23 -alkoxy, —OC(O)R 20 , —C(O)OR 20 , —C(O)R 20 , —C(O)NR 21 R 22 , —NR 21 R 22 , —NR 8 C(O)R 20 , —NR 8 C(O)NR 21 R 22 , —NR 8 SO 2 R 20 , —OC(O)NR 21 R 22 , —S(O)R 20 , —S(O) 2 R 20 , —SR 20 , —SO 2 NR 21 R 22 , —NHCOR 20 , —C(NH)—NH 2 , —C(O)NR 21 R 22 , R 23 -alkenyloxy, R 23 -alkynyloxy, R 24 -cycloalkyl, R 24 -cycloalkenyl, R 24 -heterocycloalkyl, R 24 -aryl, R 24 -heteroaryl, R 24 -heterocycloalkyloxy, R 24 -cycloalkyloxy, R 24 -cycloalkenyloxy, R 24 -aryloxy, R 24 -heteroaryloxy, R 24 -cycloalkyl-NH—, —NR 8 SO 2 NHR 21 or —C(═NOR 18 )R 19 ;

R 18 is H, alkyl, phenyl or benzyl;

R 19 is H, alkyl, phenyl or benzyl;

R 20 , R 21 and R 22 are independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl or alkoxyalkyl;

R 23 is 1 to 3 moieties and each R 23 is independently hydrogen, halogen, —OH, alkyl, haloalkyl, alkoxy, —CN, amino, alkylamino, dialkylamino, di(alkyl)amino, haloalkoxy, hydroxyalkyl, —CHO, —C(O)alkylamino, —C(O)alkylamino, —NHC(O)alkyl or —N(alkyl)C(O)alkyl;

R 24 is 1 to 3 moieties and each R 24 is independently hydrogen, halogen, —OH, alkyl, haloalkyl, alkoxy, —CN, amino, alkylamino, dialkylamino, di(alkyl)amino, haloalkoxy, hydroxyalkyl, —CHO, —C(O)alkylamino, C(O)alkylamino, NHC(O)alkyl or —N(alkyl)C(O)alkyl;

R 25 is H, R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, R 17 -aryl or R 17 -heteroaryl; and

R 26 is H, OH, —C(O)N(R 21 )(R 22 ), —C(S)N(R 21 )(R 22 ), —C(O)R 12 , —S(O) 2 R 12 ; R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, or R 17 -heteroaryl.

2. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula

wherein:

R 1 is H, alkyl or haloalkyl;

R 2 is H, alkyl or haloalkyl;

R 4 is H, alkyl or haloalkyl;

R 5 is H, alkyl or haloalkyl;

R 6 is H or alkyl;

R 7 is H or alkyl;

R 8 independently is H or alkyl;

R 10 is fluoro;

R 11 is fluoro;

R 12 independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

R 13 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

or R 13 and R 14 taken together with the nitrogen atom to which they are attached are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —N(R 8 )—(CH 2 ) 2 —;

W is independently hydrogen, alkyl, haloalkyl, R 17 -cycloalkyl, R 17 -heterocycloalkyl, R 16 -alkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -heteroarylalkyl, R 17 -heteroarylalkenyl, hydroxyalkyl, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl, alkoxy, -alkyl-SH, —S-alkyl, alkenyloxy, halogen, —NR 13 R 14 , —CN, —OH, —C(O)OR 12 , —COR 12 , —OS(O 2 )CF 3 , —CH 2 OCH 2 CF 3 , —C(O)NR 13 NR 14 , —OCHR 15 -phenyl, phenoxyalkyl, —NR 8 COR 12 , —NR 8 SO 2 R 12 , —C(O)NR 13 R 14 , —OC(R 15 ) 2 COOR 12 , —OC(R 15 ) 2 C(O)NR 13 R 14 , alkoxy optionally substituted by alkyl, amino or —NR 8 C(O)OR 12 , or alkyl optionally substituted with —NR 13 R 14 , —NR 13 COR 12 , —NR 8 CONR 13 R 14 , —NR 8 C(O)OR 12 , —NR 8 S(O) 2 NR 13 R 14 , —C(O)OR 12 , —CONR 13 R 14 or —OH;

R 15 independently is H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl or phenyl;

R 18 is H, alkyl, phenyl or benzyl;

R 19 is H, alkyl, phenyl or benzyl;

R 20 , R 21 and R 22 are independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl or alkoxyalkyl;

R 25 is H, R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, R 17 -aryl or R 17 -heteroaryl;

R 26 is H, OH, —C(O)N(R 21 )(R 22 ), —C(S)N(R 21 )(R 22 ), —C(O)R 12 , —S(O) 2 R 12 ; R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, or R 17 -heteroaryl; and

a is 1 or 2.

3. The compound as defined in claim 2 which has the structural formula

or a pharmaceutically acceptable salt thereof

wherein

W is optionally substituted phenyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl, wherein the optionally substitutents are halo, alkyl, haloalkyl, cyano, —OH, alkoxy, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl)(alkyl), haloalkoxy or heteroaryl, which is optionally substituted by alkyl or halogen,

and wherein

the heterocycloalkyl group is piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, oxetanyl, azetindinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiopyranyl or tetrahydrothiophenyl; and

the heteroaryl group is independently pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone, isoxazolyl, isothiazolyl, diazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyrimidyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl and indolyl.

4. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof wherein:

W is an optionally mono- or di substituted phenyl wherein the optional substituents are halogen, —CN, alkyl, haloalkoxy or R 17 -heteroaryl;

R 10 and R 11 are both fluoro;

R 3 is N 3 halogen; —OH, alkoxy, —C(O)OR 12 , —C(O)N(H)(R 26 ), —N(R 25 )(R 26 ), —SO 2 R 12 , R 17 -alkyl, R 17 -cycloalkyl, R 17 -phenyl, R 17 -heterocycloalkyl, or R 17 -heteroaryl;

R 12 is H, alkyl cycloalkyl, optionally substituted phenyl or optionally substituted heteroaryl and the optional substituents are halogen, alkyl, —CN, —NH 2 , —N(H)(alkyl) or —N(alkyl)(alkyl);

R 17 is 1 to 3 substituents and is independently H; halogen; —CN; —OH, alkoxy; —C(O)OR 20 ; —NH 2 ; —N(H)(alkyl); —N(alkyl)(alkyl); optionally substituted phenyl; optionally substituted heteroaryl, wherein the optional substituents are halogen, alkyl, NH 2 ; —N(H)(alkyl); —N(alkyl)(alkyl) or phenyl;

R 25 is H or alkyl;

R 22 is H, alkyl, hydroxyalkyl or cycloalkyl; and

R 26 is H, —OH; alkyl; R 17 -alkyl; cycloalkyl; —C(O)R 12 ; cycloalkyl; phenyl, heterocycloalkyl or heteroaryl; —C(S)N(H)(alkyl); —C(S)N(H)(cycloalkyl); —S(O) 2 alkyl or —C(O)N(H)(R 22 ).

5. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula

wherein:

R 1 is H, alkyl or haloalkyl;

R 2 is H, alkyl or haloalkyl;

R 3 is —N 3 , —CN, halogen, —OR 12 , —N(R 25 )(R 26 ), —C(O)OR 12 , —C(O)N(R 25 )(R 26 ), —SO 2 (R 12 ), R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl or R 17 -heteroaryl;

R 4 is H, alkyl, or haloalkyl;

R 5 is H, alkyl or haloalkyl;

R 6 is H or alkyl;

R 7 is H or alkyl;

R 8 independently is H or alkyl;

R 10 is fluoro;

R 11 is fluoro;

R 12 independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

R 13 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

or R 13 and R 14 taken together with the nitrogen atom to which they are attached are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —N(R 8 )—(CH 2 ) 2 —;

W is independently hydrogen, alkyl, haloalkyl, R 17 -cycloalkyl, R 17 -heterocycloalkyl, R 16 -alkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -heteroarylalkyl, R 17 -heteroarylalkenyl, hydroxyalkyl, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl, alkoxy, -alkyl-SH, —S-alkyl, alkenyloxy, halogen, —NR 13 R 14 , —CN, —OH, —C(O)OR 12 , —COR 12 , —OS(O 2 )CF 3 , —CH 2 OCH 2 CF 3 , —C(O)NR 13 NR 14 , —OCHR 15 -phenyl, phenoxyalkyl, —NR 8 COR 12 , —NR 8 SO 2 R 12 , —C(O)NR 13 R 14 , —OC(R 15 ) 2 COOR 12 , —OC(R 15 ) 2 C(O)NR 13 R 14 , alkoxy optionally substituted by alkyl, amino or —NR 8 C(O)OR 12 , or alkyl optionally substituted with —NR 13 R 14 , —NR 13 COR 12 , —NR 8 CONR 13 R 14 , —NR 8 C(O)OR 12 , —NR 8 S(O) 2 R 12 , —NR 8 S(O) 2 NR 13 R 14 , —C(O)OR 12 , —CONR 13 R 14 or —OH;

R 15 independently is H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl or phenyl;

R 18 is H, alkyl, phenyl or benzyl;

R 19 is H, alkyl, phenyl or benzyl;

R 20 , R 21 and R 22 are independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl or alkoxyalkyl;

R 25 is H; R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl; R 17 -aryl, or R 17 -heteroaryl;

R 26 is H, OH, —C(O)N(R 21 )(R 22 ), —C(S)N(R 21 )(R 22 ), —C(O)R 12 , —S(O) 2 R 12 , R 17 -alkyl, R 17 -cycloalkyl; R 17 -aryl; R 17 -heterocycloalkyl; R 17 -aryl or R 17 -heteroaryl; and

a is 1 or 2.

6. The compound as defined in claim 5 or a pharmaceutically acceptable salt thereof, wherein

R 10 is fluoro;

R 11 is fluoro;

W is R 17 -phenyl; and

R 17 is 1 to 2 moieties and each R 17 is independently halogen, —CN, alkyl, haloalkoxy or R 24 -heteroaryl.

7. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula

wherein:

R 1 is H, alkyl or haloalkyl;

R 2 is H, alkyl or haloalkyl;

R 3 is —N 3 , —CN; halogen, —OR 12 , —N(R 25 )(R 26 ), —C(O)OR 12 , —C(O)N(R 25 )(R 26 ), —SO 2 (R 12 ), R 17 -alkyl, R 17 -cycloalkyl; R 17 -aryl, R 17 -heterocycloalkyl, R 17 -aryl, or R 17 -heteroaryl;

R 4 is H, alkyl, or haloalkyl;

R 5 is H, alkyl or haloalkyl;

R 6 is H or alkyl;

R 7 is H or alkyl;

R 8 independently is H or alkyl;

R 10 is fluoro;

R 11 is fluoro;

R 12 independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

R 13 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

or R 13 and R 14 taken together with the nitrogen atom to which they are attached are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —N(R 8 )—(CH 2 ) 2 —;

W is independently hydrogen, alkyl, haloalkyl, R 17 -cycloalkyl, R 17 -heterocycloalkyl, R 16 -alkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -heteroarylalkyl, R 17 -heteroarylalkenyl; hydroxyalkyl; dihydroxyalkyl; aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl, alkoxy, -alkyl-SH, —S-alkyl, alkenyloxy, halogen, —NR 13 R 14 , —CN, —OH, —C(O)OR 12 , —COR 12 , —OS(O 2 )CF 3 , —CH 2 OCH 2 CF 3 , —C(O)NR 13 NR 14 , —OCHR 15 -phenyl, phenoxyalkyl, —NR 8 COR 12 , —NR 8 SO 2 R 12 , —C(O)NR 13 R 14 , —OC(R 15 ) 2 COOR 12 , —OC(R 15 ) 2 C(O)NR 13 R 14 , alkoxy optionally substituted by alkyl, amino or —NR 8 C(O)OR 12 , or alkyl optionally substituted with —NR 13 R 14 , —NR 13 COR 12 , —NR 8 CONR 13 R 14 , —NR 8 C(O)OR 12 , —NR 8 S(O) 2 R 12 , —NR 8 S(O) 2 NR 13 R 14 , —C(O)OR 12 , —CONR 13 R 14 or —OH;

R 15 independently is H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl or phenyl;

R 18 is H, alkyl, phenyl or benzyl;

R 19 is H, alkyl, phenyl or benzyl

R 20 , R 21 and R 22 are independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl or alkoxyalkyl;

R 25 is H, R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, R 17 -aryl or R 17 -heteroaryl;

R 26 is H, OH, —C(O)N(R 21 )(R 22 ), —C(S)N(R 21 )(R 22 ), —C(O)R 12 , —S(O) 2 R 12 , R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl or R 17 -heteroaryl; and

a is 1 or 2.

8. The compound as defined in claim 7 or a pharmaceutically acceptable salt thereof, wherein

R 19 is fluoro;

R 11 is fluoro;

W is R 17 -phenyl; and

R 17 is 1 to 2 moieties and each R 17 is independently halogen, —CN, alkyl, haloalkoxy or R 24 -heteroaryl.

9. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula

wherein:

R 1 is H, alkyl or haloalkyl;

R 2 is H, alkyl or haloalkyl;

R 3 is —N 3 , —CN, halogen, —OR 12 , —N(R 25 )(R 26 ), —C(O)OR 12 , —C(O)N(R 25 )(R 26 ), —SO 2 (R 12 ), R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl, R 17 -aryl, or R 17 -heteroaryl;

R 4 is H, alkyl or haloalkyl;

R 5 is H, alkyl or haloalkyl;

R 6 is H or alkyl;

R 7 is H or alkyl;

R 8 independently is H or alkyl;

R 9 independently is H or alkyl;

R 10 is fluoro;

R 11 is fluoro;

R 12 independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

R 13 is independently is H, R 16 -alkyl, R 16 -alkenyl, R 17 -cycloalkyl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -heteroarylalkyl or R 17 -heteroarylalkenyl;

or R 13 and R 14 taken together with the nitrogen atom to which they are attached are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 —N(R 8 )—(CH 2 ) 2 —;

W is independently hydrogen, alkyl, haloalkyl, R 17 -cycloalkyl, R 17 -heterocycloalkyl, R 16 -alkenyl, R 17 -aryl, R 17 -heteroaryl, R 17 -arylalkyl, R 17 -arylalkenyl, R 17 -heteroarylalkyl, R 17 -heteroarylalkenyl, hydroxyalkyl, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, di-(alkyl)-aminoalkyl, alkoxy, -alkyl-SH, —S-alkyl, alkenyloxy, halogen, —NR 13 R 14 , —CN, —OH, —C(O)OR 12 , —COR 12 , —OS(O 2 )CF 3 , —CH 2 OCH 2 CF 3 , —C(O)NR 13 NR 14 , —OCHR 15 -phenyl, phenoxyalkyl, —NR 8 COR 12 , —NR 8 SO 2 R 12 , —C(O)NR 13 R 14 , —OC(R 15 ) 2 COOR 12 , —OC(R 15 ) 2 C(O)NR 13 R 14 , alkoxy optionally substituted by alkyl, amino or —NR 8 C(O)OR 12 , or alkyl optionally substituted with —NR 13 R 14 , —NR 13 COR 12 , —NR 8 CONR 13 R 14 , —NR 8 C(O)OR 12 , —NR 8 S(O) 2 R 12 , —NR 8 S(O) 2 NR 13 R 14 —C(O)OR 12 , —CONR 13 R 14 or —OH;

R 15 independently is H, alkyl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl or phenyl;

R 18 is H, alkyl, phenyl or benzyl;

R 19 is H, alkyl, phenyl or benzyl

R 20 , R 21 and R 22 are independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl or alkoxyalkyl;

R 25 is H; R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl or R 17 -heteroaryl;

R 26 is H, OH, —C(O)N(R 21 )(R 22 ), —C(S)N(R 21 )(R 22 ), —C(O)R 12 , —S(O) 2 R 12 , R 17 -alkyl, R 17 -cycloalkyl, R 17 -aryl, R 17 -heterocycloalkyl or R 17 -heteroaryl; and

a is 1 or 2.

10. The compound as defined in claim 9 or a pharmaceutically acceptable salt thereof, wherein

R 10 is fluoro;

R 11 is fluoro;

W is R 17 -phenyl; and

R 17 is 1 to 2 moieties and each R 17 is independently are halogen, —CN, alkyl, haloalkoxy or R 24 -heteroaryl.

11. A pharmaceutical composition comprising an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition as defined in claim 11 , which further comprises a therapeutically effective amount of at least one additional cardiovascular agent.

13. The pharmaceutical composition as defined in claim 12 , wherein the at least one additional cardiovascular agent is aspirin or clopidogrel, wherein clopidogrel is its free base or pharmaceutically acceptable salt.

14. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

Assignments (1)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →