Tetrahydroquinoline derivatives as antithrombotic agents

A compound of Formula (I):

• 81
• or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
• X is —NH—, —O—, —S—, —S(O)—, or —S(O)2—;
• ring A, including the two atoms of Ring B to which it is attached, is a phenyl ring;
• wherein, in addition to RA, ring A is substituted with 0-3 RAA;
• alternatively, ring A, including the two atoms of Ring B to which it is attached, is a 5-6 membered aromatic system consisting of carbon atoms and 1 or 2 nitrogen atoms, and ring A, in addition to RA, is substituted with 0-3 RAA;
• alternatively ring A and substituent RA, including the two atoms of Ring B to which ring A is attached, is a 5-6 membered heterocyclic ring selected from:
• 82 83
• alternatively ring A and substituent RA, including the two atoms of Ring B to which Ring A is attached, is a phenyl ring of formula:
• 84
• wherein RA is combined with RAA and two carbon atoms of Ring A to form a cyclic group selected from:
• 85 86
• RA is selected from F, Cl, Br, OH, OCH3, OCH2CH3, OCH(CH3)2,
• —OCH2CH2CH3, —OCF3, —CN, —NH2, —NH2NH3, C(=NR1)NR2R3,
• —NHC(=NR1)NR2R3, —NR2CH(=NR1), —C(O)NR2R3, —S(O)2NR2aR3,
• —NR2R3, —CH2NR2R3, —CH2CH2NR2R3, —CH(CH3)NR2R3,
• —CH2CH2CH2NR2R3, —CH2CH(CH3)NR2R3, —CH (CH2CH3)NR2R3,
• —CH(CH3)CH2NR2R3, —C(CH3)2NR2R3, —(C1-3 alkyl)CO2H,
• —O—(C1-3 alkyl)CO2H, —S—(C1-3 alkyl)CO2H, and
• —(C1-3 alkyl)CH(NH2)CO2H, —C(O)NHCH2CH2NH(C1-3 alkyl),
• —C(O)NHCH2CH2N(C1-3 alkyl)2, —CH2NCOO(C1-4 alkyl),
• 87
• R1 is selected from H, OH, —NH2, C1-6 alkyl, C1-6 alkoxy,
• phenylCH2—, and phenylCH2CH2—;
• R1a, at each occurrence, is selected from H and C14 alkyl;
• R1b is selected from H, Cl, C1-4 alkyl, NH2, and NHNH2;
• R1c is selected from H and C1-4 alkyl;
• R2, at each occurrence, is selected from:
• H, OH, C1-6 alkyl, C1-6 alkylcarbonyl,
• C1-4 alkoxycarbonyl, phenyl, phenyl(C1-3 alkyl)—,
• C6-10 aryloxy, C6-10 aryloxycarbonyl,
• C6-10 arylmethylcarbonyl,
• (C1-4 alkylcarbonyloxy)C1-4 alkoxycarbonyl,
• (C6-10 arylcarbonyloxy)C1-4 alkoxycarbonyl,
• C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and
• (phenyl)C1-4 alkoxycarbonyl;
• R2a, at each occurrence, is selected from H, C1-6 alkyl,
• —C(=NH)NH2, pyridinyl, pyrimidinyl, (CH3O)pyrimidinyl,
• (CH3O)2pyrimidinyl, oxazolyl, (CH3)oxazolyl, and
• (CH3)2oxazolyl;
• R3, at each occurrence, is selected from H, C1-6 alkyl,
• phenylCH2—, and phenylCH2CH2—;
• RAA is, at each occurrence, selected from:
• H, halo, C1-4 alkyl, C3-6 cycloalkyl—, —OH,
• C1-4 alkoxy, (C1-4 alkyl)S—, (C1-4 alkyl)S(O)—,
• (C1-4 alkyl)SO2—, —NH2, (C1-4 alkyl)2N—,
• (C1-4 alkyl)NH—, —CN, —NO2, (C1-4 alkyl)C(═O)—, HO2C—,
• (C1-4 alkyl)OC(═O)—, H2NC(═O)—, (C1-4 alkyl)NHC(═O)—,
• (C1-4 alkyl)C(═O)NH—, C1-4 haloalkyl, and
• C1-4 haloalkyloxy;
• RAAA is H, halo, or methyl;
• RB is a 5-10 membered ring system consisting of carbon atoms and 0, 1 or 2 heteroatoms selected from the group consisting of N, O, and S;
• wherein said ring system may be unsaturated, partially unsaturated or saturated;
• and RB is substituted with 0, 1, 2, 3, 4, or 5 substituents selected from Rb1, Rb2, Rb3, Rb4, and Rb5;
• alternatively RB is C1-4 alkyl substituted with 5-10 membered ring system consisting of carbon atoms and 0, 1 or 2 heteroatoms selected from the group consisting of N, O, and S;
• wherein said ring system may be unsaturated, partially unsaturated or saturated;
• and RB is substituted with 0, 1, 2, 3, 4, or 5 substituents selected from Rb1, Rb2, Rb3, Rb4, and Rb5;
• Rb1, Rb2, Rb3, Rb4, and Rb5 at each occurrence, are independently selected from
• H, F, Cl, Br, I, ═O, —CN, —NO2, OR12, SR12, NR12R13,
• C(O)H, C(O)R12, C(O)OR12, C(O)NR12R13, OC(O)NR12R13,
• NR14C(O)R12, OC(O)R12, CH(═NR14)NR12R13,
• NHC(═NR14)NR12R13, S(O)R12, S(O)2R12, S(O)H, S(O)2H,
• S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12,
• NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, NR12C(O)NHR15,
• (HO)2B—, C1-4 haloalkyl, C1-4 alkoxy, C2-4 alkenyloxy,
• C2-4 alkynyloxy, (C1-4 haloalkyl)oxy,
• C1-4 alkyl substituted with 0-3 R11,
• C2-4 alkenyl substituted with 0-3 R11,
• C2-4 alkynyl substituted with 0-3 R11,
• C1-4 alkoxy substituted with 0-3 R11,
• C3-10 carbocyclic residue substituted with 0-3 R31,
• aryl substituted with 0-5 R31, and
• 5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
• alternatively, Rb1 and Rb2, when substituents on adjacent carbons, or Rb2 and Rb3, when substituents on adjacent carbons, may be combined to form a methylenedioxy group;
• n is 1, 2, or 3;
• RC1, at each occurrence, is independently selected from
• H, halo, —CN, —NO2, OR12, SR12, NR12R13, C(O)H, C(O)R12,
• C(O)NR12R13, OC(O)NR12R13, NR14C(O)R12, NR14C(S)R12,
• C(O)OR12, OC(O)R12, OC(O)OR12, CH(═NR14)NR12R13,
• NHC(═NR14)NR12R13, S(O)R12, S(O)2R12, S(O)NR12R13,
• S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15,
• NR12C(S)R15, NR12C(O)OR15, NR12S(O)2R15, NR12C(O)NHR15,
• C1-4 haloalkyl, (C1-4 haloalkyl)oxy,
• C1-10 alkyl substituted with 0-3 RCC,
• C2-10 alkenyl substituted with 0-3 RCC,
• C2-10 alkynyl substituted with 0-3 RCC,
• C1-10 alkoxy substituted with 0-3 RCC,
• C3-6 carbocyclic residue substituted with 0-3 RCC,
• aryl substituted with 0-5 RCC, and
• 5-6 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 RCC;
• RC2 is selected from H, C1-4 alkyl, OH, CN, and C1-4 alkoxy;
• RCC, at each occurrence, is independently selected from
• H, halo, —CN, —NO2, OR12, SR12, NR12R13, C(O)H, C(O)R12,
• C(O)NR12R13, OC(O)NR12R13, NR14C(O)R12, NR14C(S)R12,
• C(S)NR12R13, C(O)OR12, OC(O)R12, OC(O)OR12,
• CH(═NR14)NR12R13, NHC(═NR14)NR12R13, S(O)R12, S(O)2R12,
• S(O)NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12,
• NR12C(O)R15, NR12C(S)R15, NR12C(O)OR15, NR12S(O)2R15,
• NR12C(O)NHR15, C1-4 haloalkyl, (C1-4 haloalkyl)oxy,
• C1-4 alkyl substituted with 0-3 R11,
• C2-4 alkenyl substituted with 0-3 R11,
• C2-4 alkynyl substituted with 0-3 R11,
• C1-4 alkoxy substituted with 0-3 R11,
• C3-6 carbocyclic residue substituted with 0-3 R31,
• aryl substituted with 0-5 R31, and
• 5-6 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
• ring D, including the two atoms of Ring C to which it is attached, is a 5-6 membered aromatic system consisting of carbon atoms and 0, 1 or 2 heteroatoms selected from the group consisting of N, O, and S;
• and ring D is substituted with 0-4 RD;
• RD, at each occurrence, is independently selected from
• H, halo, —CN, —NO2, OR16, SR16, NR16R16, C(O)H, C(O)R16,
• C(O)NR16R16, OC(O)NR16R16, NR14C(O)R16, C(O)OR16,
• OC(O)R16, OC(O)OR16, CH(═NR14)NR16R16, NHC(═NR14)NR16R16,
• S(O)R16, S(O)2R16, S(O)NR16R16, S(O)2NR16R16,
• NR14S(O)R16, NR14S(O)2R16, NR16C(O)R17, NR16C(O)OR17,
• NR16S(O)2R17, NR16C(O)NHR17, C1-4 haloalkyl, C1-4 alkoxy,
• (C1-4 haloalkyl) oxy,
• C1-4 alkyl substituted with 0-3 R31,
• C2-4 alkenyl substituted with 0-3 R31, and
• C2-4 alkynyl substituted with 0-3 R31;
• R11, at each occurrence, is independently selected from
• H, halo, —CN, —NO2, OR12, SR12, NR12R13, C(O)H, C(O)R12,
• C(O)NR12R13, OC(O)NR12R13, NR14C(O)R12, C(O)OR12,
• OC(O)R12, OC(O)OR12, CH(═NR14)NR12R13, NHC(═NR14)NR12R13,
• S(O)R12, S(O)2R12, S(O)NR12R13, S(O)2NR12R13,
• NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15,
• NR12S(O)2R15, NR12C(O)NHR15, C1-4 haloalkyl, C1-4 alkoxy,
• C2-4 alkenyloxy, C2-4 alkynyloxy, (C1-4 haloalkyl)oxy,
• C1-4 alkyl substituted with 0-3 R12a,
• C2-4 alkenyl substituted with 0-3 R12a,
• C3-6 carbocyclic residue substituted with 0-3 R31,
• aryl substituted with 0-5 R31, and
• 5-6 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
• R12, at each occurrence, is independently selected from H,
• C1-4 alkyl substituted with 0-1 R12a,
• C2-4 alkenyl substituted with 0-1 R12a,
• C2-4 alkynyl substituted with 0-1 R12a,
• C3-6 cycloalkyl substituted with 0-3 R31,
• aryl substituted with 0-5 R31;
• C3-10 carbocyclic residue substituted with 0-3 R31, and
• 5-10 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
• R12a, at each occurrence, is independently selected from phenyl substituted with 0-5 R31;
• C3-6 carbocyclic residue substituted with 0-3 R31, and
• 5-6 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R31;
• R13, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
• alternatively, R12 and R13 may be combined, along with the nitrogen to which they are attached, to form a 5- or 6-membered ring optionally substituted with —O— or —N(R14)—;
• R14, at each occurrence, is independently selected from H and C1-4 alkyl;
• R15, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
• R16, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and phenyl;
• R17, at each occurrence, is independently selected from H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
• R31, at each occurrence, is independently selected from
• H, F, Cl, Br, I, ═O, —CN, —NO2, OR32, SR32, NR32R33,
• C(O)H, C(O)R32, C(O)OH, C(O)OR32, C(O)NR32R33,
• OC(O)NR32R33, NR34C(O)R32, OC(O)R32, CH(═NR34)NR32R33,
• NHC(═NR34)NR32R33, S(O)R32, S(O)2R32, S(O)H, S(O)2H,
• S(O)3H, S(O)NR32R33, S(O)2NR32R33, NR34S(O)R32,
• NR34S(O)2R32, NR32C(O)R35, NR32C(O)OR35, NR32S(O)2R35,
• NR32C(O)NHR35, tetrazole, C1-4 haloalkyl, C1-4 alkoxy,
• C2-4 alkenyloxy, C2-4 alkynyloxy, (C1-4 haloalkyl)oxy,
• C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
• and
• R32, R33, R34, R35, at each occurrence, are independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and benzyl;
• provided when X is —O— and RB is phenyl, then RA is not methoxy;
• and
• provided when X is —NH— and RB is phenyl, then RA is not chloro or methoxy.