Sulfonamide compounds

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of formula (I):

• wherein
• X is C1-2alkyl or a bond;
• R1 is selected from the group consisting of
• a) naphthyl, phenyl, said phenyl optionally fused at two adjacent carbon atoms to Rf,
• Rf is a linear 3- to 5-membered hydrocarbon moiety-having 0 or 1 unsaturated bonds and having 0, 1 or 2 carbon members which is a carbonyl,
• b) Ar6—, where Ar6 is a 6-membered heteroaryl having carbon as a point of attachment, having 1 or 2 heteroatom members which are —N═ and optionally benzo or pyrido fused,
• c) Ar5—, where Ar5 is a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, having 0 or 1 additional heteroatom member which is —N═ and optionally benzo or pyrido fused,
• d) Ar6-6—, where Ar6-6 is phenyl having the point of attachment and fused to a 6-membered heteroaryl having 1 or 2 heteroatom members which are —N═,
• e) Ar6-5—, where Ar6-5 is phenyl or pyridyl having the point of attachment and fused to a 5-membered heteroaryl having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═,
• where each of a) to e) is substituted with 0, 1, 2, or 3 of Rq,
• Rq is independently selected from the group consisting of —C1-4alkyl, hydroxy, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, C1-4alkylO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, C1-4alkoxy, and C1-4alkylS—;
• R2 is selected from the group consisting of —H, —C1-4alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-7cycloalkyl, and —C3-7cycloalkenyl;
• Ra is, independently, selected from the group consisting of —C1-6alkyl, —C2-6alkenyl, —C3-6cycloalkyl, phenyl, furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC1-6alkyl, —OC3-6cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC1-6alkyl, —SC3-6cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(Ry)Rz (wherein Ry and Rz are independently —H, —C1-4alkyl, or C1-6cycloalkylC1-4alkyl), —(C═O)C1-4alkyl, —SCF3, halo, trifluoromethyl, —OCF3, and —COOC1-4alkyl, —COOH, or, alternatively, two adjacent Ra, may be taken together with the carbons of attachment to form a fused ring selected from the group consisting of phenyl, pyridyl, and pyrimidinyl;
• alternatively, R2 and one of Ra may be taken together as —CH2— or >C═O to form a fused ring to the phenyl;
• Rb is selected from the group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively, two adjacent Rb substituents at 2- and 3-positions may be taken together to form a five- or six-membered heterocyclic ring selected from the group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole, and pyrazine;
• Rc is independently selected from the group-consisting of hydrogen, —C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, —C0-2alkylCOOC1-4alkyl, —C0-2alkylCOOH, and —C0-2alkylCON(Rs)Rt;
• —COO—C0-2alkyl-ringA, and —COO—C1-2alkyl—CON(Rs)Rt;
• Rs and Rt are independently selected from the group consisting of —H, —C1-4alkyl, C1-6cycloalkylC1-4alkyl, phenyl, phenyl substituted with halo, benzyl, benzyl substituted with halo,
• or alternatively, Rs and Rt taken together with their nitrogen of attachment form pyrrolidine, piperidine, or morpholine;
• ringA is selected from the group consisting of
• i) a 6-membered heteroaryl having carbon as a point of attachment and having 1 or 2 heteroatom members which are —N═;
• ii) a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═;
• and
• iii) a 5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen as a point of attachment, having 1 or 2 heteroatoms selected from the group consisting of O, S, and N, having 0 or 1 double bonds, having 0 or 1 carbon member replaced by a carbonyl, and optionally substituted with —C1-4alkyl, —OH, or halo;
• Rd is independently selected from the group consisting of hydrogen, —C1-4alkyl, —OH, —OC1-6alkyl, HO—C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, and optionally substituted phenyl;
• or two Rd together can be ═O where at least one Rc is selected from the group consisting of —COOC1-4alkyl, —COO-ringA, —COOH, —CON(Rs)Rt, and —COOC1-2alkylCON(Rs)Rt;
• alternatively, one Rc and one Rd may be taken together to form a double bond;
• and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof.

A method for the treatment or prevention of pain, drug dependence, anxiety, panic attack, schizophrenia, pancreatic disorders, secretory disorders, gastrointestinal motility disorders, functional bowel disease, biliary colic, and cancer, eating disorders, reflux diseases, gastroduodenal ulcers, refluxesophagitis, peptic ulcers, Barrett's esophagus, antral G cell hyperplasia, pernicious anaemia, and Zollinger-Ellison syndrome, in mammals comprising the step of administering to a mammal suffering there from an effective amount of at least one compound of formula (I):

• wherein
• X is C1-2alkyl or a bond;
• R1 is selected from the group consisting of
• a) naphthyl, phenyl, said phenyl optionally fused at two adjacent carbon atoms to Rf,
• Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated bonds and having 0, 1 or 2 carbon members which is a carbonyl,
• b) Ar6—, where Ar6 is a 6-membered heteroaryl having carbon as a point of attachment, having 1 or 2 heteroatom members which are —N═ and optionally benzo or pyrido fused,
• c) Ar5—, where Ar5 is a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, having 0 or 1 additional heteroatom member which is —N═ and optionally benzo or pyrido fused,
• d) Ar6-6—, where Ar6-6, is phenyl having the point of attachment and fused to a 6-membered heteroaryl having 1 or 2 heteroatom members which are —N═,
• e) Ar6-5—, where Ar6-5 is phenyl or pyridyl having the point of attachment and fused to a 5-membered heteroaryl having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═,
• where each of a) to e) is substituted with 0, 1, 2, or 3 of Rq,
• Rq is independently selected from the group consisting of —C1-4alkyl, hydroxy, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, C1-4alkylO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, C1-4alkoxy, and C1-4alkylS—;
• R2 is selected from the group consisting of —H, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-7cycloalkyl, and —C3-7cycloalkenyl;
• Ra is, independently, selected from the group consisting of —C1-6alkyl, —C2-6alkenyl, —C3-6cycloalkyl, phenyl, furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC1-6alkyl, —OC3-6cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC1-6alkyl, —SC3-6cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(Ry)Rz (wherein Ry and Rz are independently —H, —C1-4alkyl, or C1-6cycloalkylC1-4alkyl), —(C═O)C1-4alkyl, —SCF3, halo, trifluoromethyl, —OCF3, and —COOC1-4alkyl, —COOH, or, alternatively, two adjacent Ra, may be taken together with the carbons of attachment to form a fused ring selected from the group consisting of phenyl, pyridyl, and pyrimidinyl;
• alternatively, R2 and one of Ra may be taken together as —CH2— or >C═O to form a fused ring to the phenyl;
• Rb is selected from the group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively, two adjacent Rb substituents at 2- and 3-positions may be taken together to form a five- or six-membered heterocyclic ring selected from the group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole, and pyrazine;
• Rc is independently selected from the group consisting of hydrogen, —C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1 4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, —C0-2alkylCOOC1-4alkyl, —C0-2alkylCOOH, and —C0-2alkyl-CON(Rs)Rt;
• —COO—C0-2alkyl-ringA, and —COO—C1-2alkyl—CON(Rs)Rt;
• Rs and Rt are independently selected from the group consisting of —H, —C1-4alkyl, C1-6cycloalkylC1-4alkyl, phenyl, phenyl substituted with halo, benzyl, benzyl substituted with halo,
• or alternatively, Rs and Rt taken together with their nitrogen of attachment form pyrrolidine, piperidine, or morpholine;
• ringA is selected from the group consisting of
• i) a 6-membered heteroaryl having carbon as a point of attachment and having 1 or 2 heteroatom members which are —N═;
• ii) a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═;
• and
• iii) a 5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen as a point of attachment, having 1 or 2 heteroatoms selected from the group-consisting of O, S, and N, having 0 or 1 double bonds, having 0 or 1 carbon member replaced by a carbonyl, and optionally substituted with —C1-4alkyl, —OH, or halo;
• Rd is independently selected from the group consisting of hydrogen, —C1-4alkyl, —OH, —OC1-6alkyl, HO—C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, and optionally substituted phenyl;
• or two Rd together can be ═O where at least one Rc is selected from the group consisting of —COOC1-4alkyl, —COO-ringA, —COOH, —CON(Rs)Rt, and —COOC1-2alkylCON(Rs)Rt;
• alternatively, one Rc and one Rd may be taken together to form a double bond;
• and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof.

A method for the treatment or prevention of pancreatic adenocarcinoma, pain, gastro-esophageal reflux disease, non-erosive reflux disease, anorexia, pancreatitis, gastroduodenal ulcers, reflux esophagitis, anxiety, colon cancer, peptic ulcers, pancreatic tumors and gastric tumors in mammals comprising the step of administering to a mammal suffering there from an effective amount of at least one compound of formula (I):

• wherein
• X is C1-2alkyl or a bond;
• R1 is selected from the group consisting of
• a) naphthyl, phenyl, said phenyl optionally fused at two adjacent carbon atoms to Rf,
• Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated bonds and having 0, 1 or 2 carbon members which is a carbonyl,
• b) Ar6—, where Ar6 is a 6-membered heteroaryl having carbon as a point of attachment, having 1 or 2 heteroatom members which are —N═ and optionally benzo or pyrido fused,
• c) Ar5—, where Ar5 is a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, having 0 or 1 additional heteroatom member which is —N═ and optionally benzo or pyrido fused,
• d) Ar6-6—, where Ar6-6 is phenyl having the point of attachment and fused to a 6-membered heteroaryl having 1 or 2 heteroatom members which are —N═,
• e) Ar6-5—, where Ar6-5 is phenyl or pyridyl having the point of attachment and fused to a 5-membered heteroaryl having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═,
• where each of a) to e) is substituted with 0, 1, 2, or 3 of Rq,
• Rq is independently selected from the group consisting of —C1-4alkyl, hydroxy, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, C1-4alkylO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, C1-4alkoxy, and C1-4alkylS—;
• R2 is selected from the group consisting of —H, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-7cycloalkyl, and —C3-7cycloalkenyl;
• Ra is, independently, selected from the group consisting of —C1-6alkyl, —C2-6alkenyl, —C3-6cycloalkyl, phenyl, furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC1-6alkyl, —OC3-6cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC1-6alkyl, —SC3-6cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(Ry)Rz (wherein Ry and Rz are independently —H, —C1-4alkyl, or C1-6cycloalkylC1-4alkyl), —(C═O)C1-4alkyl, —SCF3, halo, trifluoromethyl, —OCF3, and —COOC1-4alkyl, —COOH, or, alternatively, two adjacent Ra, may be taken together with the carbons of attachment to form a fused ring selected from the group consisting of phenyl, pyridyl, and pyrimidinyl;
• alternatively, R2 and one of Ra may be taken together as —CH2— or >C═O to form a fused ring to the phenyl;
• Rb is selected from the group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively, two adjacent Rb substituents at 2- and 3-positions may be taken together to form a five- or six-membered heterocyclic ring selected from the group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole, and pyrazine;
• Rc is independently selected from the group consisting of hydrogen, —C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, —C0-2alkylCOOC1-4alkyl, —C0-2alkylCOOH, and —C0-2alkylCON(Rs)Rt;
• —COO—C0-2alkyl-ringA, and —COO—C1-2alkyl—CON(Rs)Rt;
• Rs and Rt are independently selected from the group consisting of —H, —C1-4alkyl, C1-6cycloalkylC1-4alkyl, phenyl, phenyl substituted with halo, benzyl, benzyl substituted with halo,
• or alternatively, Rs and Rt taken together with their nitrogen of attachment form pyrrolidine, piperidine, or morpholine;
• ringA is selected from the group consisting of
• i) a 6-membered heteroaryl having carbon as a point of attachment and having 1 or 2 heteroatom members which are —N═;
• ii) a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═;
• and
• iii) a 5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen as a point of attachment, having 1 or 2 heteroatoms selected from the group consisting of O, S, and N, having 0 or 1 double bonds, having 0 or 1 carbon member replaced by a carbonyl, and optionally substituted with —C1-4alkyl, —OH, or halo;
• Rd is independently selected from the group consisting of hydrogen, —C1-4alkyl, —OH, —OC1-6alkyl, HO—C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, and optionally substituted phenyl;
• or two Rd together can be ═O where at least one Rc is selected from the group consisting of —COOC1-4alkyl, —COO-ringA, —COOH, —CON(Rs)Rt, and —COOC1-2alkylCON(Rs)Rt;
• alternatively, one Rc and one Rd may be taken together to form a double bond;
• and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof.

A method for the treatment or prevention of pancreatitis, non-erosive reflux disease, or gastroesophageal reflux disease in mammals comprising the step of administering to a mammal suffering there from an effective amount of at least one compound of formula (I):

• wherein
• X is C1-2alkyl or a bond;
• R1 is selected from the group consisting of
• a) naphthyl, phenyl, said phenyl optionally fused at two adjacent carbon atoms to Rf,
• Rf is a linear 3- to 5-membered hydrocarbon moiety having 0 or 1 unsaturated bonds and having 0, 1 or 2 carbon members which is a carbonyl,
• b) Ar6—, where Ar6 is a 6-membered heteroaryl having carbon as a point of attachment, having 1 or 2 heteroatom members which are —N═ and optionally benzo or pyrido fused,
• c) Ar5—, where Ar5 is a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, having 0 or 1 additional heteroatom member which is —N═ and optionally benzo or pyrido fused,
• d) Ar6-6—, where Ar6-6 is phenyl having the point of attachment and fused to a 6-membered heteroaryl having 1 or 2 heteroatom members which are —N═,
• e) Ar6-5—, where Ar6-5 is phenyl or pyridyl having the point of attachment and fused to a 5-membered heteroaryl having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═,
• where each of a) to e) is substituted with 0, 1, 2, or 3 of Rq,
• Rq is independently selected from the group consisting of —C1-4alkyl, hydroxy, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, cyano, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, C1-4alkylO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, C1-4alkoxy, and C1-4alkylS—;
• R2 is selected from the group consisting of —H, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —C3-7cycloalkyl, and —C3-7cycloalkenyl;
• Ra is, independently, selected from the group consisting of —C1-6alkyl, —C2-6alkenyl, —C3-6cycloalkyl, phenyl, furanyl, thiophenyl, benzyl, pyrrol-1-yl, —OH, —OC1-6alkyl, —OC cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC1-6alkyl, —SC3-6cycloalkyl, —Sphenyl, —Sbenzyl, cyano, nitro, —N(Ry)Rz (wherein Ry and Rz are independently —H, —C1-4alkyl, or C1-6cycloalkylC1-4alkyl), —(C═O)C1-4alkyl, —SCF3, halo, trifluoromethyl, —OCF3, and —COOC1-4alkyl, —COOH, or, alternatively, two adjacent Ra, may be taken together with the carbons of attachment to form a fused ring selected from the group consisting of phenyl, pyridyl, and pyrimidinyl;
• alternatively, R2 and one of Ra may be taken together as —CH2— or >C═O to form a fused ring to the phenyl;
• Rb is selected from the group consisting of 2,4-difluoro, 2,6-difluoro, or alternatively, two adjacent Rb substituents at 2- and 3-positions may be taken together to form a five- or six-membered heterocyclic ring selected from the group consisting of oxazole, thiazole, thiadiazole, [1,3]dioxole, and pyrazine;
• Rc is independently selected from the group consisting of hydrogen, —C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HO—C1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, —C0-2alkylCOOC1-4alkyl, —C0-2alkylCOOH, and —C0-2alkylCON(Rs)Rt;
• —COO—C0-2alkyl-ringA, and —COO—C1-2alkyl—CON(Rs)Rt;
• Rs and Rt are independently selected from the group consisting of —H, —C1-4alkyl, C1-6cycloalkylC1-4alkyl, phenyl, phenyl substituted with halo, benzyl, benzyl substituted with halo,
• or alternatively, Rs and Rt taken together with their nitrogen of attachment form pyrrolidine, piperidine, or morpholine;
• ringA is selected from the group consisting of
• i) a 6-membered heteroaryl having carbon as a point of attachment and having 1 or 2 heteroatom members which are —N═;
• ii) a 5-membered heteroaryl having carbon as a point of attachment, having 1 heteroatom member selected from the group consisting of O, S, >NH, and >NC1-4alkyl, and having 0 or 1 additional heteroatom member which is —N═;
• and
• iii) a 5- or 6-membered non-aromatic heterocycle having a carbon or nitrogen as a point of attachment, having 1 or 2 heteroatoms selected from the group consisting of O, S, and N, having 0 or 1 double bonds, having 0 or 1 carbon member replaced by a carbonyl, and optionally substituted with —C1-4alkyl, —OH, or halo;
• Rd is independently selected from the group consisting of hydrogen, —C1-4alkyl, —OH, —OC1-6alkyl, HO—C1-4alkyl, perhaloC1-4alkyl, mono- or di-haloC1-4alkyl, aminoC1-4alkyl, C1-4alkylaminoC1-4alkyl, diC1-4alkylaminoC1-4alkyl, HS—C1-4alkyl, C1-4alkylS—C1-4alkyl, and optionally substituted phenyl;
• or two Rd together can be ═O where at least one Rc is selected from the group consisting of —COOC1-4alkyl, —COO-ringA, —COOH, —CON(Rs)Rt, and —COOC1-2alkylCON(Rs)Rt;
• alternatively, one Rc and one Rd may be taken together to form a double bond;
• and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof.