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Tetrahydro-pyrimidoazepines as modulators of TRPV1

  • US 20070225275A1
  • Filed: 03/21/2007
  • Published: 09/27/2007
  • Est. Priority Date: 03/21/2006
  • Status: Active Grant
First Claim
Patent Images

1. A compound of Formula (I):

  • embedded image wherein;

    R1 is —

    H;



    NRaRb;



    OH;

    a —

    C1-6alkyl, —

    OC1-6alkyl, —

    O-(saturated monocyclic cycloalkyl), —

    OC1alkyl-(saturated monocyclic cycloalkyl), —

    O-(saturated monocyclic heterocycloalkyl), —

    O-phenyl, —

    O-benzyl, —

    S—

    C1-6alkyl, —

    S-(saturated monocyclic cycloalkyl), —

    SC1alkyl-(saturated monocyclic cycloalkyl), —

    S-(saturated monocyclic heterocycloalkyl), —

    S-phenyl, —

    S-benzyl, or —

    SO2

    C1-6alkyl group unsubstituted or substituted with one or two moieties independently selected from the group consisting of —

    C1-6alkyl, —

    OH, —

    OC1-4alkyl, —

    NReRf, and halo substituents;

    or a phenyl, monocyclic cycloalkyl, or monocyclic heteroaryl group unsubstituted or substituted with a —

    C1-6alkyl, —

    OH, —

    OC1-4alkyl, —

    NReRf, or halo substituent;

    where Ra and Rb are each independently —

    H;



    C1-6alkyl;

    a —

    C2-3alkyl group substituted with a —

    OH, —

    OC1-4alkyl, —

    NRcRd, or halo substituent;

    or a saturated monocyclic cycloalkyl, —

    C1alkyl-(saturated monocyclic cycloalkyl), saturated monocyclic heterocycloalkyl, —

    C1alkyl-(saturated monocyclic heterocycloalkyl), phenyl, benzyl, or —

    C1alkyl-(monocyclic heteroaryl) group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —

    C1-6alkyl, —

    OH, —

    OC1-4alkyl, —

    NRpRq, and halo substituents;

    or  

    Ra and Rb taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl or bridged bicyclic heterocycloalkyl group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —

    C1-6alkyl, —

    C1-4alkyl-OH, —

    C12alkyl-OC1-2alkyl, —

    OH, —

    OC1-4alkyl, —

    NRpRq, halo, —

    CO2H, and benzyl substituents;

    where Rc and Rd are each independently —

    H or —

    C1-6alkyl;

    or Rc and Rd taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl;

    where Rp and Rq are each independently —

    H or —

    C1-6alkyl;

    or Rp and Rq taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl;

    where Re and Rf are each independently —

    H or —

    C1-6alkyl;

    or Re and Rf taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl;

    R2 is —

    H or —

    C1-6alkyl;

    R3 is a monocyclic cycloalkyl, phenyl, benzyl, phenethyl, indanyl, thiazolyl, thiophenyl, pyridyl, pyridylmethyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl group unsubstituted or substituted with one, two, or three Rg substituents;

    where each Rg substituent is —

    C1-6alkyl;



    C1-4alkyl-OH unsubstituted or substituted with —

    CF3;

    saturated monocyclic cycloalkyl;



    OH;



    OC1-6alkyl;

    phenoxy;



    CN;



    NO2;



    N(Rh)Ri;



    C1-4alkyl-N(Rh)Ri;



    C(O)N(Rh)Ri;



    N(Rh)C(O)Ri;



    N(Rh)SO2C1-6alkyl;



    C(O)C1-6alkyl;



    S(O)0-2

    C1-6alkyl;



    SO2CF3;



    SO2N(Rh)Ri;



    SCF3;

    halo;



    CF3;



    OCF3;



    CO2H;



    CO2C1-6alkyl;



    C(Rj)(Rx)—

    CN;



    C(Rj)(Rx)—

    OH;



    C(Rj)(Rx)—

    CO2C1-6alkyl;



    C(Rj)(Rx)—

    CO2H;



    C(Rj)(Rx)—

    C(O)N(Rh)Ri;

    phenyl;

    or monocyclic heteroaryl;

    or two adjacent Rg substituents taken together form —

    OC1-2alkylO—

    ;

    where Rh and Ri are each independently —

    H or —

    C1-6alkyl;

    or Rhand Ri (when both are present) taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group;

    Rj is independently —

    H, —

    C1-6alkyl, or —

    CF3;

    Rx is —

    H or —

    C1-6alkyl;

    or Rj and Rx taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring;

    and Ar is a phenyl, pyridyl, imidazolyl, pyrimidinyl, pyridazinyl, or fused-bicyclic heteroaryl group unsubstituted or substituted with one, two, or three Rk substituents;

    where each Rk substituent is independently —

    C1-6alkyl, —

    C1-2alkyl-OH, —

    OH, —

    OC1-6alkyl, phenoxy, —

    CN, —

    NO2, —

    N(Rl)Rm, —

    C(O)N(Rl)Rm, —

    N(Rl)C(O)Rm, —

    N(Rl)SO2C1-6alkyl, —

    N(Rl)SO2CF3, —

    C(O)C1-6alkyl, —

    S(O)0-2

    C1-6alkyl, —

    SO2CF3, —

    SO2N(Rl)Rm, —

    SCF3, halo, —

    CF3, —

    OCF3, —

    CO2H, or —

    CO2C1-6alkyl;

    or two adjacent Rk substituents taken together form —

    OC1-2alkylO—

    ;

    where Rl and Rm are each independently —

    H, —

    C1-6alkyl, saturated monocyclic cycloalkyl, or —

    CF3;

    or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of such compound.

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