Imidazothiadiazole and imidazopyrazine derivatives as protease activated receptor4 (par4) inhibitors for treating platelet aggregation

A compound of Formula I:

• or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
• W is O or S;
• R0 is R1 or R1a;
• Y is S or —CR8═CR9—;
• R1 is independently selected from the group consisting of:
• halo,
• C1-C4 alkyl,
• C2-C3 alkenyl,
• C2-C3 alkynyl,
• C3-C4 cycloalkyl,
• C1-C4 alkoxy,
• C1-C2 alkoxy-C1-C2 alkyl,
• tetrahydrofuran-2-yl;
• C1-C4 alkylthio,
• C1-C4 alkylNH—,
• (C1-C4 alkyl)2N—,
• halo-C1-C2-alkyl, which contains 1 to 5 halogens, where halo is F or Cl,
• halo-C3-C4 cycloalkyl,
• halo-C1-C2 alkoxy, and
• halo-C1-C2 alkylthio;
• R1a is independently selected from the group consisting of:
• H,
• halo,
• C1-C4 alkyl,
• C2-C3 alkenyl,
• C2-C3 alkynyl,
• C3-C4 cycloalkyl,
• C1-C4 alkoxy,
• C1-C2 alkoxy-C1-C2 alkyl,
• tetrahydrofuran-2-yl;
• C1-C4 alkylthio,
• C1-C4 alkylNH—,
• (C1-C4 alkyl)2N—,
• halo-C1-C2-alkyl, which contains 1 to 5 halogens, where halo is F or Cl,
• halo-C3-C4 cycloalkyl,
• halo-C1-C2 alkoxy, and
• halo-C1-C2 alkylthio;
• R8 and R9 are independently selected from the group consisting of:
• H,
• halo,
• C1-C4 alkyl,
• C1-C4 alkoxy,
• halo-C1-C2 alkyl,
• halo-C1-C2 alkoxy,
• CN, and
• OH;
• provided that at least one of R1a, R8 and R9 is other than H;
• R2 is selected from the group consisting of:
• H,
• halo,
• C1-C4 alkyl,
• C1-C4 alkoxy, and
• cyano;
• X1 is selected from the group consisting of CH, N or CR10;
• X2, X3 and X4 are independently selected from CR3 or N;
• R3 is selected from the group consisting of H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 alkylthio, halo, OH, CN, OCF3, OCHF2, OCH2F, C1-C2-alkoxy-C1-C2-alkoxy, halo-C1-C3-alkyl, which contains 1 to 5 halogens, benzyloxy substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyclopropyl, CF3, OCF3, 5- or 6-membered heteroaryl, OH, OCHF2, di-C1-C4-alkylamino, and cyano, and —(CH2)n1-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyclopropyl, CF3, OCF3, 5- or 6-membered heteroaryl, OH, OCHF2, di-C1-C4-alkylamino, and cyano;
• R4 and R5 are independently selected from H and C1-C6 alkyl, or R4 and R5 can be taken together with the carbon to which they are attached to form a C3-C7 cycloalkyl ring;
• is a 5-membered heteroaryl ring containing at least one O, N or S atom;
• R6 is selected from the group consisting of H, halo, OCF3, OCHF2, OH, CN, NO2, NR11R12, COOH, C1-C4 alkoxycarbonyl, (C═O)NR11R12, C1-C4 alkylsulfonyl, S(═O)2NR11R12, and C1-C5 alkyl substituted by 0 to 7 groups independently selected from halo, CF3, OCF3, OH, hydroxy-C1-C4-alkyl, C1-C4 alkoxy, C1-C4 alkoxy-C1-C4 alkoxy, di-C1-C4-alkylaminophenyl-C1-C4-alkyl, (di-C1-C4-alkoxy-C1-C4-alkyl)-C1-C4-alkyl, di-C1-C4-alkylamino, C3-C6-cycloalkyl, and C1-C4 alkylthio, or
• R6 is B-D-, where D is a linker, which is selected from:
• a single bond,
• —O—,
• —S—,
• C1-C4 alkylene substituted by 0 to 4 groups independently selected from halo or OH,
• C1-C4 alkyleneoxy,
• C1-C4 alkylenethio,
• C1-C4 alkyleneoxy-C1-C4-alkylene,
• C1-C4-alkylenethio-C1-C4-alkylene,
• —S—C1-C4-alkylene,
• —O—C1-C4-alkylene,
• C2-C6 alkenylene, and
• B is selected from the group consisting of:
• C6-C10 aryl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, halo-C1-C4 alkoxy, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, cyano, nitro, NR11R12, OH, C1-C4-alkylcarbonyloxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, cyano-C1-C4-alkyl, COOR14, SO2R4, (C═O)NR11R12, SO2NR11R12, N(R13)(C═O)NR11R12, N(R13)(C═O)OR14, N(R13)(C═O)R14, NR13S(O)R14, NR13SO2R14, O(C═O)NR11R12, O(C═O)OR14, O(C═O)R14, (C═O)OR14, and 5-6-membered heteroaryl,
• 5- to 10-membered heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, halo-C1-C4 alkoxy, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, cyano, nitro, NR11R12, OH, C1-C4-alkylcarbonyloxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, COOR14, SO2R14, (C═O)NR11R12, SO2NR11R12, N(R13)(C═O)NR11R12, N(R13)(C═O)OR14, N(R13)(C═O)R14, NR13S(O)R14, NR13SO2R14, O(C═O)NR11R12, O(C═O)OR14, O(C═O)R14, (C═O)OR14, 5-6-membered heteroaryl, and (CH2)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, —(CHR13)n1-5- or 6-membered heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyclopropyl, CF3, OCF3, and CF2CH3;
• NR13S(O)R14, NR13SO2R14, —(CHR13)n1-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyclopropyl, CF3, OCF3, and CF2CH3;
• OH, hydroxy-C1-C4-alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, di-C1-C4-alkylamino-C1-C4-alkyl, NR11R12, cyano, C1-C4 alkyl, halo-C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C6 cycloalkyl-C1-C4-alkylcarbonyl, C6-C10 arylcarbonyl, C1-C4-alkylcarbonyloxy-C1-C4-alkyl, COOR14, SO2R14, (C═O)NR11R12, SO2NR11R12, N(R13)(C═O)NR11R12, N(R13)(C═O)OR14, N(R13)(C═O)R14, O(C═O)NR11R12, O(C═O)OR14, O(C═O)R14, (C═O)OR14, and C6-C10 aryl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyclopropyl, C1-C4-alkoxycarbonyl, (C═O)NR11R12, CF3, OCF3, and CF2CH3;
• C3-C6 cycloalkyl which may contain unsaturation, substituted by 0 to 3 groups independently selected from the group consisting of halo, CF3, OCF3, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C1-C4-alkyl, C6-C10 aryl, COOH, oxo, C1-C4-alkoxycarbonyl, (C═O)NR11R12, NR11R12 and C1-C4 alkyl;
• and
• C5-C11 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, CF3, OCF3, 5- or 6-membered heteroaryl, OH, hydroxy-C1-C4-alkyl, C6-C10 aryl, and C1-C4 alkyl;
• R11 and R12 are independently, at each occurrence, selected from the group consisting of:
• H,
• C1-C4 alkyl,
• halo-C1-C4-alkyl,
• C2-C4 alkenyl,
• C2-C4 alkynyl,
• —(CR14R14)n1-phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyclopropyl, CF3, OCF3, 5- or 6-membered heteroaryl, OH, OCHF2, di-C1-C4-alkylamino, and cyano,
• —(CHR13)n1—C3-C6-cycloalkyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF3, OCF3, 5- or 6-membered heteroaryl, OH, hydroxy-C1-C4-alkyl, and C1-C4 alkyl,
• —(CHR13)n1-4- to 10-membered-heterocyclyl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF3, OCF3, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C1-C4-alkyl, and C1-C4 alkyl,
• —(CHR13)n1-5- to 10-membered-heteroaryl substituted by 0 to 3 groups independently selected from the group consisting of halo, CF3, OCF3, 5- or 6-membered heteroaryl, OH, hydroxy-C1-C4-alkyl, and C1-C4 alkyl,
• di-C1-C4-alkylamino-C1-C4-alkyl,
• C1-C4-alkylcarbonylamino-C1-C4-alkyl,
• di-C1-C4-alkoxy-C1-C4-alkyl,
• di-C1-C4-alkylaminophenyl,
• hydroxy-C1-C4-alkyl,
• cyano-C1-C4-alkyl,
• C1-C4-alkoxy-C1-C4-alkyl,
• C1-C4-alkoxycarbonyl-C1-C4-alkyl,
• C1-C4-alkoxycarbonyl,
• C1-C4-alkylcarbonyl,
• phenylcarbonyl;
• C1-C4-alkoxycarbonylamino-C1-C4-alkylcarbonyl,
• di-C1-C4-alkylamino-C1-C4-alkylcarbonyl,
• amino-C1-C4-alkylcarbonyl,
• 4- to 10-membered-heterocyclyl-carbonyl, and
• alternatively, R11 and R12, 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, CF3, CHF2, OCF3, OCHF2, OCH2F, 5- or 6-membered heteroaryl, OH, oxo, hydroxy-C1-C4-alkyl, C1-C4 alkyl and C1-C4 alkoxy, and 0 to 2 additional heteroatoms selected from N, NR13, O and S(O)p;
• R13 is independently, at each occurrence, selected from the group consisting of H, C1-C6 alkyl and —(CH2)phenyl;
• R14 is independently, at each occurrence, selected from the group consisting of H, C1-C6 alkyl, halo-C1-C4-alkyl, C1-C4-alkoxycarbonylamino, (C6-C10 arylcarbonylamino), (a 5- to 10-membered heteroarylcarbonylamino) and —(CH2)n1phenyl substituted by 0 to 3 groups independently selected from the group consisting of halo, C1-C4 alkoxy, C1-C4 alkyl, cyclopropyl, CF3, OCF3, 5- or 6-membered heteroaryl, OH, OCHF2, di-C1-C4-alkylamino, and cyano,
• R7 is selected from the group consisting of H, halo, hydroxyl, oxo, C1-C4 alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, halo-C1-C4-alkyl, which contains 1 to 5 halogens, C1-C4-alkoxy, and halo-C1-C4-alkoxy;
• or R6 and R7 can be taken together with the carbons to which they attach to form a C6-C10 aryl ring;
• R10 is selected from the group consisting of C1-C4 alkyl, halo, C1-C4 alkoxy, and halo-C1-C2-alkyl, which contains 1 to 5 halogens, where halo is F or Cl;
• n1, at each occurrence, is selected from 0, 1, 2, 3, 4 or 5;
• and
• p, at each occurrence, is selected from 0, 1 and 2.