Substituted pyridoindoles as serotonin agonists and antagonists

A compound of the formula (I):

• or stereoisomers or pharmaceutically acceptable salt forms thereof, wherein:
• b is a single bond or a double bond;
• X is —O—, —S—, —S(═O)—, —S(═O)2—, or —NR10—;
• R1 is selected from
• H,
• C(═O)R2,
• C(═O)OR2,
• C1-8 alkyl,
• C2-8 alkenyl,
• C2-8 alkynyl,
• C3-7 cycloalkyl,
• C1-6 alkyl substituted with Z,
• C2-6 alkenyl substituted with Z,
• C2-6 alkynyl substituted with Z,
• C3-6 cycloalkyl substituted with Z,
• aryl substituted with Z,
• 5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
• C1-3 alkyl substituted with Y,
• C2-3 alkenyl substituted with Y,
• C2-3 alkynyl substituted with Y,
• C1-6 alkyl substituted with 0-2 R2,
• C2-6 alkenyl substituted with 0-2 R2,
• C2-6 alkynyl substituted with 0-2 R2,
• aryl substituted with 0-2 R2, and
• 5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with 0-2 R2;
• Y is selected from
• C3-6 cycloalkyl substituted with Z,
• aryl substituted with Z,
• 5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with Z;
• C3-6 cycloalkyl substituted with —(C1-3 alkyl)-Z,
• aryl substituted with —(C1-3 alkyl)-Z, and
• 5-6 membered heterocyclic ring system containing at least one heteroatom selected from the group consisting of N, O, and S, said heterocyclic ring system substituted with —(C1-3 alkyl)Z;
• Z is selected from H,
• —CH(OH)R2,
• —C(ethylenedioxy)R2,
• —OR2,
• —NR2R3,
• —C(O)NR2R3,
• —NR3C(O)R2,
• —C(O)OR2,
• —OC(O)R2,
• —CH(═NR4)NR2R3,
• —NHC(═NR4)NR2R3,
• —S(O)2R2,
• —S(O)2NR2R3, and —NR3S(O)2R2;
• R2, at each occurrence, is independently selected from
• halo,
• C1-3 haloalkyl,
• C1-4 alkyl,
• C2-4 alkynyl,
• C2-4 alkynyl,
• C3-6 cycloalkyl,
• aryl substituted with 0-5 R42;
• C3-10 carbocyclic residue substituted with 0-3 R41, 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 R41;
• R3, at each occurrence, is independently selected from
• H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and
• C1-4 alkoxy;
• alternatively, R2 and R3 join to form a 5- or 6-membered ring optionally substituted with —O—or —N(R4)—;
• R4, at each occurrence, is independently selected from H and C1-4 alkyl;
• R5 is H or C1-4 alkyl;
• R6 is H or C1-4 alkyl;
• R7 and R9, at each occurrence, are independently selected from
• H, halo, —CF3, —OCF3, —OH, —CN, —NO2, —NR46R47,
• C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
• C3-10 cycloalkyl substituted with 0-2 R33,
• C1-4 alkyl substituted with 0-2 R11,
• C3-10 carbocyclic residue substituted with 0-3 R33,
• aryl substituted with 0-5 R33,
• 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;
• OR12, SR12, NR12R13, C(O)H, C(O)R12, C(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, and NR12C(O)NHR15;
• R8 is selected from
• H, halo, —CF3, —OCF3, —OH, —CN, —NO2,
• C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, (C1-4 haloalkyl)oxy,
• C3-10 cycloalkyl substituted with 0-2 R33,
• C1-4 alkyl substituted with 0-2 R11,
• C2-4 alkenyl substituted with 0-2 R11,
• C2-4 alkynyl substituted with 0-1 R11,
• C3-10 carbocyclic residue substituted with 0-3 R33,
• aryl substituted with 0-5 R33,
• 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;
• OR12, SR12, NR12R13, C(O)H, C(O)R12, C(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, and NR12C(O)NHR15;
• R10 is selected from H,
• C1-4 alkyl substituted with 0-2 R10A,
• C2-4 alkenyl substituted with 0-2 R10A,
• C2-4 alkynyl substituted with 0-1 R10A, and
• C1-4 alkoxy;
• R10A is selected from
• C1-4 alkoxy,
• C3-6 carbocyclic residue substituted with 0-3 R33,
• phenyl substituted with 0-3 R33, and
• 5-6 membered heterocyclic ring system containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and 5;
• substituted with 0-2 R44;
• R11 is selected from
• H, halo, —CF3, —CN, —NO2,
• C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-4 haloalkyl, C1-8 alkoxy, C3-10 cycloalkyl,
• C3-10 carbocyclic residue substituted with 0-3 R33,
• aryl substituted with 0-5 R33;
• 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;
• OR12, SR12, NR12R13, C(O)H, C(O)R12, C(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)2NR12R13, S(O)2NR12R13, NR14S(O)R12, NR14S(O)2R12, NR12C(O)R15, NR12C(O)OR15, NR12S(O)2R15, and NR12C(O)NHR15;
• R12 at each occurrence, is independently selected from
• 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 R33,
• aryl substituted with 0-5 R33;
• C3-10 carbocyclic residue substituted with 0-3 R33, 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 R33;
• C3-10 carbocyclic residue substituted with 0-3 R33, 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;
• R13, at each occurrence, is independently selected from
• H, C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl;
• alternatively, R12 and R13 join to form a 5- or 6-membered ring optionally substituted with —O—or —N(R14)—;
• alternatively, R12 and R13 when attached to N may be combined to form a 9- or 10-membered bicyclic heterocyclic ring system containing from 1-3 heteroatoms selected from the group consisting of N, O, and 5, wherein said bicyclic heterocyclic ring system is unsaturated or partially saturated, wherein said bicyclic heterocyclic ring system is substituted with 0-3 R16;
• 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, OH, halo, CN, NO2, CF3, SO2R45, NR46R47, —C(═O)H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-3 haloalkyl-oxy-, C1-3 alkyloxy-, and ═O;
• R31, at each occurrence, is independently selected from
• H, OH, halo, CF3, SO2R45, NR46R47, C1-4 alkyl, and ═O;
• R33 at each occurrence, is independently selected from
• H, OH, halo, CN, NO2, CF3, —OCF3, SO2R45, NR46R47,
• —C(═O)H, ═O, —C(═O)NH2, —C(═O)OCH3, phenyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
• C3-6 cycloalkyl,
• C1-4 haloalkyl, C1-4 haloalkyl-oxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(═O)—, C1-4 alkyl-OC(═O)—,
• C1-4 alkyl-C(═O)O—, C1-4 alkyl-C(═O)NH—,
• C1-4 alkyl-NHC(═O)—, (C1-4 alkyl)2NC(═O)—,
• C3-6 cycloalkyl-oxy-, C3-6 cycloalkylmethyl-oxy-;
• C1-6 alkyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, —SO2R45, —NR46R47, NR46R47C(═O)—, or (C1-4 alkyl)CO2—;
• and
• C2-6 alkenyl substituted with OH, methoxy, ethoxy, propoxy, butoxy, —SO2R45, —NR46R47, NR46R47C(═O)—, or (C1-4 alkyl)CO2—;
• R41, at each occurrence, is independently selected from
• H, CF3, halo, OH, CO2H, SO2R45, NR46R47, NO2, CN, ═O;
• C2-8 alkenyl, C2-8 alkynyl, C1-4 alkoxy, C1-4 haloalkyl
• C1-4 alkyl substituted with 0-1 R43,
• aryl substituted with 0-3 R42, 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 R44;
• R42 at each occurrence, is independently selected from
• H, CF3, halo, OH, CO2H, SO2R45, SOR45, SR45, NR46SO2R45, NR46SO2R45, NR46R47, NO2, CN, CH(═NH)NH2, NHC(═NH)NH2,
• C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C3-6 cycloalkyl,
• C1-4 alkyl substituted with 0-1 R43,
• aryl substituted with 0-3 R44, 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 R44;
• R43 is C3-6 cycloalkyl or aryl substituted with 0-3 R44;
• R44, at each occurrence, is independently selected from H, halo, —OH, NR46R47, CO2H, SO2R45,
• —CF3, —OCF3, —CN, —NO2, C1-4 alkyl, and C1-4 alkoxy;
• R45 is C1-4 alkyl;
• R46, at each occurrence, is independently selected from H and C1-4 alkyl;
• R47, at each occurrence, is independently selected from H, C1-4 alkyl, —C(═O)NH(C1-4 alkyl), —SO2(C1-4 alkyl),
• —C(═O)O(C1-4 alkyl), —C(═O)(C1-4 alkyl), and —C(═O)H;
• k is 1 or 2;
• m is 0 or 1;
• and
• n is 1 or 2;
• provided that when b is a double bond;
• n is 1;
• m is 1;
• k is 1;
• X is —O—, —S—, —S(═O)—, or —SO2—;
• and the three substituents of R7, R8, and R9, consist of i) three hydrogens, ii) two hydrogens and one chloro, or iii) two hydrogens and one methyl;
• then R1 must contain the substituent Z or Y.