Isoxazoline fibrinogen receptor antagonists

A compound of Formula (I):

• or a pharmaceutically acceptable salt form thereof wherein:
• R1 is selected from
• R2a(R3)N—V—,
• R2a(R3)N(CH2)q—,
• R2(R2b)N(R3N═)C—V—,
• R2(R2b)N(R3N═)C(CH2)q—,
• R2(R2b)N(R3N═)CNH—V—,
• R2(R11O) N (R3N═)C—V—,
• R2(R2b)N(R11ON═)C—V—,
• V is selected from:
• `(C1-C4 alkyl)-,
• `(C2-C4 alkenyl)-,
• `(C2-C4 alkynyl)-,
• `(phenyl), said phenyl substituted with 0-2 groups independently selected from R9,
• (pyridyl)-, said pyridyl substituted with 0-2 groups independently selected from R9, or
• (pyridazinyl)-, said pyridazinyl substituted with 0-2 groups independently selected from R9;
• Z is selected from:
• a bond, O, S, S(═O), and S(═O)2;
• R2a is R2 or R2(R2b)N(R3N═)C—;
• R2, R2b, and R3 are independently selected from:
• H, C1-C10 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C4 alkyl)-, C2-C7 alkylcarbonyl, C1-C4 haloalkyl, aryl, arylcarbonyl, aryl(C1-C4 alkyl)-, benzhydryl, benzhydry1(C1-C4 alkyl)-, heteroaryl, heteroaryl (C1-C5 alkyl)-, and
• a cleavable protecting group selected from:
• C1-C6 alkoxycarbonyl,
• C3-C11 cycloalkoxycarbonyl,
• C7-C11 bicycloalkoxycarbonyl,
• aryloxycarbonyl,
• aryl(C1-C10 alkoxy)carbonyl,
• (C1-C6 alkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
• arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
• (C3-C11 cycloalkyl)carbonyloxy(C1-C4 alkoxy)carbonyl,
• wherein at least one of R2, R2b, and R3 is H or a cleavable protecting group;
• wherein said aryl groups of R2, R2b, and R3 may be substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, —CN, —SO2(C1-C4 alkyl), —S(C1-C4 alkyl), —NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl;
• and
• said heteroaryl groups of R2, R2b, and R3 may be substituted with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SO2CH3, and —NR21R22;
• alternatively, R2 and R2b can be taken together with the nitrogen atom to which they are attached to form a 5-10 membered heterocyclic ring optionally containing one additional heteroatom selected from:
• N, O, or S;
• said heterocyclic ring being monocyclic or bicyclic;
• said heterocyclic ring being substituted with 0-2 R4;
• R4, when a substituent on carbon, is independently selected from:
• H, C1-C4 alkyl, aryl, and aryl(C1-C6 alkyl)-, wherein said aryl groups may be optionally substituted with 0-3 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SCH3, S(O)CH3, SO2CH3, —NR21R22, C1-C4 haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl;
• alternatively, when two R4 groups are attached to adjacent carbon atoms, they may be taken together with the atoms to which they are attached to form a fused 5-7 membered saturated, unsaturated or aromatic carbocyclic ring;
• alternatively, when R4 is attached to a saturated carbon atom, it may also be ═O or ═S;
• R4 when a substituent on nitrogen, is independently selected from:
• H, C1-C6 alkyl, C3-C6 alkenyl, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C4 alkyl)-, C3-C11 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, aryl, aryl(C1-C10 alkyl)-, benzhydryl, benzhydryl(C1-C4 alkyl)-, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, aryl(C1-C10 alkyl)sulfonyl, aryl(C2-C10 alkenyl)sulfonyl, aryl(C1-C10 alkoxy)carbonyl, heteroaryl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryl(C1-C10 alkyl)-, and heteroaryl(C1-C10 alkyl)carbonyl,
• wherein said aryl or heteroaryl groups may be additionally substitututed with 0-2 groups selected from hydroxy, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, SCH3, SOCH3, SO2CH3, or —NR21R22;
• R4 when a substituent on sulfur, may be ═O;
• X is —OCH2CH(Wa)—, —SCH2CH(Wa)—, —NHCH2CH(Wa)—, —OCH(Wb)—, —SCH(Wb)—, —NHCH(Wb)—, —OCH(Wb)CH2—, —SCH(Wb)CH2—, or —NHCH(Wb)CH2—;
• Y is selected from hydroxy,
• C1-C10 alkyloxy,
• C3-C11 cycloalkyloxy,
• C6-C10 aryloxy,
• C7-C11 arylalkyloxy,
• C2-C10 alkylcarbonyloxyalkyloxy,
• C2-C10 alkoxycarbonyloxyalkyloxy,
• C2-C10 alkoxycarbonylalkyloxy,
• C4-C10 cycloalkylcarbonyloxyalkyloxy,
• C4-C10 cycloalkoxycarbonyloxyalkyloxy,
• C4-C10 cycloalkoxycarbonylalkyloxy,
• C7-C11 aryloxycarbonylalkyloxy,
• C7-C12 aryloxycarbonyloxyalkyloxy,
• C7-C12 arylcarbonyloxyalkyloxy,
• C4-C10 alkoxyalkylcarbonyloxyalkyloxy,
• (5-(C1-C4 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
• (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
• (R28) (R29)N-(C1-C10 alkoxy)-;
• Wa is selected from:
• H,
• hydroxy,
• —NR16R20,
• —NR25R26,
• C1-C10 alkoxy,
• C1-C10 alkyl substituted with 0-3 R8, and
• aryl substituted with 0-3 R8,
• Wb is selected from:
• H,
• CH2OH,
• CH2OR12,
• CH2CO2R12,
• CH2C(═O)NHR18,
• CH2NR16R20,
• CH2NR25R26,
• C1-C8 alkyl substituted with 0-2 R8,
• C3-C6 alkenyl,
• C3-C10 cycloalkyl,
• C4-C11 cycloalkylmethyl,
• heteroaryl,
• heteroaryl(C1-C6 alkyl),
• aryl substituted with 0-3 R8, and
• aryl(C1-C6 alkyl), said aryl substituted with 0-3 R8;
• R5 and R6 are taken together to be C═O;
• R7 is H or C1-C4 alkyl substituted with 0-3 R8;
• R7a and R7b are independently selected from H, methyl, and ethyl;
• alternatively, when R7 and R7a occur on adjacent carbons R7 and R7a may be taken together to form a carbon-carbon double bond;
• alternatively, when R7a and R7b occur on adjacent carbons R7a and R7b may be taken together to form a six carbon aromatic ring;
• R8 is selected from:
• H, hydroxy, cyano, —CO2R12, —C(═O)R13, —OC(═O)R13, —OC(═O)OR14, —OR12, —OCH2CO2R12, —CO2CH2CO2R12, —OC(═O)NR23R24, —C(═O)NR23R24, —NR25R26, —NR27C(═O)R13, —NR27C(═O)OR14, —NR27SO2R14, —SR14, —SOR14, —SO2R14, —SO2NR23R24, C1-C10 alkoxy, C1-C10 alkylcarbonyl, C2-C6 alkenyl, C3-C10 cycloalkyl, C4-C11 cycloalkylmethyl,
• aryl, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or —NMe2,
• aryl(C1-C4 alkyl)-, wherein said aryl is substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, CO2R12, SO2Me, SOMe, SMe, or —NMe2, and
• a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, halo, CF3, CO2R12, SO2Me, SOMe, SMe or —NMe2;
• R9 is selected from H, halogen, CF3, CN, C1-C4 alkyl, or C1-C4 alkoxy;
• R10 is selected from:
• H, hydroxy, CN, carboxy, —NR25R26;
• C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C7-C14 bicycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, aryl, piperidinyl, morpholinyl, and pyridinyl;
• R11 is selected from:
• H, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
• R12 is selected from:
• H, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
• R13 is selected from:
• hydrogen, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
• R14 is selected from:
• C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
• R15 is selected from:
• H, OH, —OR12, —CO2R12, —C(═O)NR23R24, —OC(═O)NR23R24,
• C1-C10 alkoxycarbonyl substituted with 0-2 R8;
• C1-C10 alkyl substituted with 0-3 R8;
• C2-C10 alkenyl substituted with 0-3 R8;
• and
• C1-C10 alkoxy substituted with 0-3 R8;
• R16 is selected from:
• —C(═O)OR17, —C(═O)R18, —C(═O)NR17R18, —C(═O)NHSO2R17, —C(═O)NHC(═O)R17, —C(═O)NHC(═O)OR17, —C(═O)NHSO2NHR17, —SO2R17, —SO2NR17R18, and —SO2NHC(═O)OR17;
• R17 is selected from:
• C1-C8 alkyl substituted with 0-2 R19,
• C3-C8 alkenyl substituted with 0-2 R19,
• C3-C8 alkynyl substituted with 0-2 R19,
• C3-C8 cycloalkyl substituted with 0-2 R19,
• aryl substituted with 0-4 R19,
• aryl(C1-C6 alkyl)-substituted with 0-4 R19,
• a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19, and
• C1-C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19;
• R18 is selected from H or R17;
• R19 is selected from:
• H, halogen, CF3, CN, NO2, NR25R26, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C11 cycloalkyl, C3-C11 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, C1-C6 alkoxy, and C1-C4 alkoxycarbonyl;
• R20 is selected from:
• H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C3-C11 cycloalkyl(C1-C4 alkyl)-, aryl, and aryl(C1-C10 alkyl)-;
• R21 and R22 are each independently H, methyl, ethyl, propyl, or butyl;
• R23 is selected from:
• hydrogen, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, hydroxy, C1-C6 alkoxy, benzyloxy, aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, adamantylmethyl, and C1-C10 alkyl substituted with 1-2 R10;
• R24 is selected from:
• C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C4-C11 cycloalkylmethyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 1-2 R10;
• R25 and R26 are, independently, selected from:
• H, C1-C10 alkyl, C1-C10 alkoxycarbonyl, C1-C10 alkylcarbonyl, C1-C10 alkylsulfonyl, aryl, aryl(C1-C4 alkyl)-, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, aryl(C1-C10 alkoxy)carbonyl, aryl(C1-C10 alkyl)sulfonyl, aryl(C2-C10 alkenyl)sulfonyl, C2-C6 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C4 alkyl)-, C3-C10 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, and heteroaryl(C1-C4 alkyl)carbonyl,
• wherein said aryl groups are optionally substituted with 1-3 substituents selected from the group consisting of:
• C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and NO2;
• R27 is selected from H, methyl, ethyl, propyl, butyl, benzyl, phenethyl, cyclopropyl, and cyclopropylmethyl;
• R28 and R29 are independently selected from:
• H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• n is 0 or 1;
• q is 1, 2, 3, or 4;
• r is 0, 1, or 2;
• and
• s is 1, 2, 3, or 4.