Imidazolopyrimidine modulators of TRPV1

A pharmaceutical composition for treating a disease, disorder, or medical condition mediated by TRPV1 activity, comprising:

• (a) an effective amount of at least one agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of said compounds of Formula (I):
• wherein:
• R1 is —H, —C1-6alkyl, —OC1-6alkyl, —NRaRb, —S—C1-6alkyl, or —SO2—C1-6alkyl;
• where Ra and Rb are each independently —H, —C1-6alkyl, or —CH2-pyridinyl;
• or, Ra and Rb taken together with the nitrogen of attachment in —NRaRb form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with a —C1-6alkyl substituent;
• R2 is —H, —C1-6alkyl, —OH, —OC1-6alkyl, —CN, —NO2, —N(Rh)Ri, —C(O)N(Rh)Ri, —N(Rh)C(O)Ri, —N(Rh)SO2C1-6alkyl, —N(SO2C1-6alkyl)2, —C(O)C1-6alkyl, —S(O)0-2—C1-6alkyl, —SO2CF3, —SO2N(Rh)Ri, —SCF3, halo, —CF3, —OCF3, —CO2H, —CO2C1-6alkyl, —C(Rj)2—CN, —C(Rj)2—CO2C1-4alkyl, —C(Rj)2—CO2H, —C(Rj)2—CON(Rh)Ri, —C(Rj)2—CH2N(Rh)Ri, or —C(Rj)2—OH;
• where Rh and Ri are each independently —H or —C1-6alkyl;
• or Rh and Ri taken together with their nitrogen of attachment in —NRhRi form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;
• where each Rj is independently-H or —C1-6alkyl;
• X and Z are each independently N or CRm, where Rm is —H, halo, or —CF3;
• R3 is —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rk)Rl, —C1-4alkyl-OH, —C1-4alkyl-N(Rk)Rl, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rk)Rl;
• where Rk and Rl are each independently —H or —C1-6alkyl;
• R4 is —H, —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rn)Ro, —C1-4alkyl-OH, —C1-4alkyl-N(Rn)Ro, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rn)Ro;
• where Rn and Ro are each independently —H or —C1-6alkyl;
• and
• R5 is —H or —CH3;
• and (b) a pharmaceutically acceptable excipient.

A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by TRPV1 activity, comprising administering to the subject an effective amount of at least one agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of said compounds of Formula (I):

• wherein:
• R1 is —H, —C1-6alkyl, —OC1-6alkyl, —NRaRb, —S—C1-6alkyl, or —SO2—C1-6alkyl;
• where Ra and Rb are each independently —H, —C1-6alkyl, or —CH2-pyridinyl;
• or, Ra and Rb taken together with the nitrogen of attachment in —NRaRb form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with a —C1-6alkyl substituent;
• R2 is —H, —C1-6alkyl, —OH, —OC1-6alkyl, —CN, —NO2, —N(Rh)Ri, —C(O)N(Rh)Ri, —N(Rh)C(O)Ri, —N(Rh)SO2C1-6alkyl, —N(SO2C1-6alkyl)2, —C(O)C1-6alkyl, —S(O)0-2—C1-6alkyl, —SO2CF3, —SO2N(Rh)Ri, —SCF3, halo, —CF3, —OCF3, —CO2H, —CO2C1-6alkyl, —C(Rj)2—CN, —C(R)2—CO2C1-4alkyl, —C(Rj)2—CO2H, —C(Rj)2—CON(Rh)Ri, —C(Rj)2—CH2N(Rh)Ri, or —C(Rj)2—OH;
• where Rh and Ri are each independently —H or —C1-6alkyl;
• or Rh and Ri taken together with their nitrogen of attachment in —NRhRi form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;
• where each Rj is independently —H or —C1-6alkyl;
• X and Z are each independently N or CRm, where Rm is —H, halo, or —CF3;
• R3 is —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rk)Rl, —C1-4alkyl-OH, —C1-4alkyl-N(Rk)Rl, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rk)Rl;
• where Rk and Rl are each independently —H or —C1-6alkyl;
• R4 is —H, —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rn)Ro, —C1-4alkyl-OH, —C1-4alkyl-N(Rn)Ro, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rn)Ro;
• where Rn and Ro are each independently —H or —C1-6alkyl;
• and
• R5 is —H or —CH3.

A process for the preparation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• comprising reacting a compound of formula (VIII):
• with an aromatic amine of formula (IX):
• to give a compound of Formula (I);
• wherein:
• R1 is —H, —C1-6alkyl, —OC1-6alkyl, —NRaRb, —S—C1-6alkyl, or —SO2—C1-6alkyl;
• where Ra and Rb are each independently —H, —C1-6alkyl, or —CH2-pyridinyl;
• or, Ra and Rb taken together with the nitrogen of attachment in —NRaRb form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with a —C1-6alkyl substituent;
• R2 is —H, —C1-6alkyl, —OH, —OC1-6alkyl, —CN, —NO2, —N(Rh)Ri, —C(O)N(Rh)Ri, —N(Rh)C(O)Ri, —N(Rh)SO2C1-6alkyl, —N(SO2C1-6alkyl)2, —C(O)C1-6alkyl, —S(O)0-2—C1-6alkyl, —SO2CF3, —SO2N(Rh)Ri, —SCF3, halo, —CF3, —OCF3, —CO2H, —CO2C1-6alkyl, —C(Rj)2—CN, —C(Rj)2—CO2C1-4alkyl, —C(Rj)2—CO2H, —C(Rj)2—CON(Rh)Rj, —C(Rj)2—CH2N(Rh)Ri, or —C(Rj)2—OH;
• where Rh and Ri are each independently —H or —C1-6alkyl;
• or Rh and Ri taken together with their nitrogen of attachment in —NRhRi form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl;
• where each Rj is independently —H or —C1-6alkyl;
• X and Z are each independently N or CRm, where Rm is —H, halo, or —CF3;
• R3 is —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rk)Rl, —C1-4alkyl-OH, —C1-4alkyl-N(Rk)Rl, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rk)Rl;
• where Rk and Rl are each independently —H or —C1-6alkyl;
• R4 is —H, —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rn)Ro, —C1-4alkyl-OH, —C1-4alkyl-N(Rn)Ro, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rn)Ro;
• where Rn and Ro are each independently —H or —C1-6alkyl;
• and
• R5 is —H or —CH3.

A compound of formula (VIII):

• wherein:
• R1 is —H, —C1-6alkyl, —OC1-6alkyl, —NRaRb, —S—C1-6alkyl, or —SO2—CR1-6alkyl;
• where Ra and Rb are each independently —H, —C1-6alkyl, or —CH2-pyridinyl;
• or, Ra and Rb taken together with the nitrogen of attachment in —NRaRb form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with a —C1-6alkyl substituent;
• R3 is —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rk)Rl, —C1-4alkyl-OH, —C1-4alkyl-N(Rk)Rl, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rk)Rl;
• where Rk and Rl are each independently —H or —C1-6alkyl;
• R4 is —H, —CF3, halo, —CN, —CO2H, —CO2C1-6alkyl, —C(O)N(Rn)Ro, —C1-4alkyl-OH, —C1-4alkyl-N(Rn)Ro, —S(O)0-2—C1-6alkyl, —SO2CF3, or —SO2N(Rn)Ro;
• where Rn and Ro are each independently —H or —C1-6alkyl;
• and
• R5 is —H or —CH3.