Substituted quinazolin-4-ylamine analogues

A compound of the formula:

• 989
• or a pharmaceutically acceptable salt thereof, wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkanone, C2-C8alkenyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently chosen from phenyl and 5- and 6-membered aromatic heterocycles, optionally substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and
• R7 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, mono- or di(C1-C8alkyl)amino or a 3- to 10-membered heterocycle, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, C1-C6alkyl, C1-C8alkoxy, C2-C8alkyl ether, haloC1-C8alkyl and haloC1-C8alkoxy.

A compound of the formula:

• 990
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono-and di-(C1-C6alkyl)amino;
• Ar1 and Ar2 are independently selected from phenyl and 5- to 7-membered aromatic heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• R3 and R4 are:
• (i) each independently selected from:
• (a) hydrogen;
• (b) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C1-C8alkoxy, C3-C8alkanone, C2-C8alkanoyl, C2-C8alkyl ether, C6-C10arylC0-C8alkyl, 5- to 10-membered heterocycleC0-C8alkyl and —(SO2)C1-C8alkyl, each of which is optionally substituted with from 1 to 9 substituents independently selected from Rb;
• and
• (c) groups that are joined to an R5 or R6 to form a 4- to 10-membered heterocyclic group that is unsubstituted or substituted with from 1 to 6 substituents independently selected from Rb;
• or
• (ii) joined to form, with the N to which they are bound, a 4- to 10-membered heterocyclic group that is unsubstituted or substituted with from 1 to 6 substituents independently selected from Rb, C1-C8alkanoyl, 4- to 7-membered heterocycloalkylC0-C4alkyl, and mono- and di-(C1-C6alkyl)aminoC1-C6alkyl;
• R5 and R6 are, independently at each occurrence:
• (i) each independently selected from:
• (a) hydrogen or hydroxy;
• (b) C1-C8alkyl, unsubstituted or substituted with 1 or 2 substituents independently selected from Rb;
• and
• (c) groups that are joined to R3 or R4 to form a 4- to 10-membered heterocyclic group that is unsubstituted or substituted with from 1 to 6 substituents independently selected from Rb;
• (ii) taken together to form a keto group;
• or
• (iii) joined to form a 3- to 7-membered carbocyclic or heterocyclic ring, unsubstituted or substituted with from 1 to 4 substituents selected from Rb;
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and
• n is 1, 2 or 3.

A method for reducing calcium conductance of a cellular capsaicin receptor, comprising contacting a cell expressing a capsaicin receptor with at least one compound or salt of the formula:

• 991
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and thereby reducing calcium conductance of the capsaicin receptor.

A method for inhibiting binding of vanilloid ligand to a capsaicin receptor in vitro, the method comprising contacting capsaicin receptor with at least one compound or salt of the formula:

• 992
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• under conditions and in an amount sufficient to detectably inhibit vanilloid ligand binding to capsaicin receptor.

A method for inhibiting binding of vanilloid ligand to capsaicin receptor in a patient, comprising contacting cells expressing capsaicin receptor with a compound or salt of the formula:

• 993
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—;
• —S(O)mNRx, and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• in an amount sufficient to detectably inhibit vanilloid ligand binding to cells expressing a cloned capsaicin receptor in vitro, and thereby inhibiting binding of vanilloid ligand to the capsaicin receptor in the patient.

A method for treating a condition responsive to capsaicin receptor modulation in a patient, comprising administering to the patient a capsaicin receptor modulatory amount of at least one compound or salt of the formula:

• 994
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and thereby alleviating the condition in the patient.

A method for treating pain in a patient, comprising administering to a patient suffering from pain a capsaicin receptor modulatory amount of at least one compound or salt of the formula:

• 995
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 1 0-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and thereby alleviating pain in the patient.

A method for treating itch in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or salt of the formula:

• 996
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X . is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 1 0-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and thereby alleviating itch in the patient.

A method for treating cough or hiccup in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or salt of the formula:

• 997
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and thereby alleviating cough or hiccup in the patient.

A method promoting weight loss in an obese patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or salt of the formula:

• 998
• wherein:
• V, X, W, Y and Z are each independently N or CR1, with the proviso that at least one of V and X is N;
• U is N or CR2, with the proviso that if V and X are N, then U is CR2;
• R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
• R2 is:
• (i) hydrogen, halogen or cyano;
• (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (iii) a group of the formula -Rc-M-A-Ry, wherein:
• Rc is C0-C3alkyl;
• M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
• A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
• and
• Ry and Rz, if present, are:
• (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• or
• (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
• wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, .each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
• L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
• wherein m is independently selected at each occurrence from 0, 1 and 2;
• and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
• Ra is independently selected at each occurrence from:
• (i) hydrogen, halogen, cyano and nitro;
• and
• (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
• and
• Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono-and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
• and thereby promoting weight loss in the patient.