Triazole derivatives as tachykinin receptor antagonists

A compound selected from the group consisting of:

• [1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-(1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2yloxymethyl)-isoxazol-4-yl]-methanone, [1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-(1,2,3]triazol-4-yl-[5-(2-chloro-phenyl)-3-(2,2-dimethoxy-ethyl)-isoxazol 4-yl]methanone, [1-(3,5-bis-trifluoromethyl benzyl)5-phenyl-1H-[1,2,3]triazol-4-yl-(5-(2 chlorophenyl)-3-[1,3]dioxolan-2-ylmethyl-isoxazol-4-yl]-methanone,, [1-(3,5bis-trifluoromethyl-benzyl)-5-pyrazin-2-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3(tetrahydro-2-yloxymethyl)-isoxazol-4-yl]-methanone, {2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl]-1H-[1,2,3]triazole-carbonyl]2-chloro-benzyl)-amino]-ethyl]-carbamic acid tert-butyl ester, {2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-ethyl]-carbamic acid tert-butyl ester, (2-{[1-(3,5bis-trifluoromethyl-benzyl)-5-chloro 1H-[1,2,3]triazole-4 carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino})-ethyl)-carbamic acid tert-butyl ester, (2-[{1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1, 2,3]triazole-4—carbonyl]-[1-(2-chloro-phenyl)ethyl]-amino)ethyl)carbamic acid tert-butyl ester, {2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]ethyl}-carbamic acid tert-butyl ester, (2-{[1-(3,5-bis trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-(1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}ethyl)-carbamic acid tert-butyl ester, 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H]-1H-[1,2,3]triazol-4-carboxylic acid (2-amino-ethyl)-(2-chloro-benzyl)-amide dihydrochloride, 1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triaole-4-carboxylic acid (2amino-ethyl)-(2-chloro-benzyl)-amide hydrochloride, 1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholinyl)-1H-[1,2,3]triazole-4 catboxylic acid (2-amino-ethyl)-[1-(2-chloro-phenyl)-ethyl]-amide dihydrochloride, and 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid (2-amino-ethyl)-[1-(2-chloro-phenyl)-ethyl]-amide dihydrochloride.

A method for treating a condition associated with an excess of tachykinins, comprising:

• administering to a patient in need thereof an effective amount of a compound of Formula I:
• wherein:
• D is a C1-C3 alkane diyl;
• R1 is phenyl,
• which is optionally substituted with one to three substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, cyano, difluoromethyl, trifluoromethyl, and trifluoromethoxy,
• R4 is a radical selected from the group consisting of:
• wherein
• -A1-A2-A3-A4-, together with the atoms to which they are attached, form an aromatic carbocyclic or heterocyclic ring in which each of A1, A2;, A3, and A4 is independently —CR8—or nitrogen, wherein at least one of A1, A2, A3, and A4 must be —CR8—;
• -G1-G2-G3-, together with the atoms to which they are attached, form an aromatic heterocyclic ring in which each of G1, G2, and G3 is independently —CR8—, nitrogen, oxygen, or sulfur, wherein only one of G1, G2, and G3 can be oxygen or sulfur;
• -G4-G5-G6-, together with the atoms to which they are attached, form an aromatic heterocyclic ring in which each of G4, G5, and G6 is independently —CR8—, or nitrogen;
• each R8 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, substituted C1-C4 alkyl, C3-C6 cycloalkyl, —NR12R13, trifluoromethyl, and trifluoromethoxy;
• R12 and R13 are each independently hydrogen, C1-C4 alkyl, or —C(O)—CH3, or R12 and R13, together with the nitrogen to which they am attached, form a 4-7 membered ring;
• Q1, Q2, Q5, and Q6 arm each independently —CH—, or nitrogen;
• Q3 and Q4 are each independently oxygen or nitrogen, wherein at least one of Q3 and Q4 must be nitrogen;
• R6 is C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or pyridyl,
• which phenyl or pyridyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C1-4 alkyl, C1-C4 alkoxy, trifluoromethyl, trifluoromethoxy, morpholino, and —NR14R15;
• R14 and R15 are each independently hydrogen or C1-C4 alkyl, or R14 and R15, together with the nitrogen to which they m attached, form a 4-7 membered ring;
• X is a bond, C1-C3 alkane-diyl, —CH(OH)—, —C(O)—, —O—, —S(O)p—, or —C═N—OR9—;
• p is 0, 1, or 2;
• R9 is hydrogen, C1-C4 alkyl, or benzyl;
• Y is a bond, C1—C3 alkane-diyl, or —C(O);
• n is 0, 1, or 2;
• each R7 is independently C1-C4 alkyl;
• R5 is hydrogen, halo, trifluoromethyl, C1-C4 alkyl, C3-C6 cycloalkyl, furyl, thienyl, pyrrolyl, imidazolyl, NR16R17, pyridyloxy, phenyl, phenoxy, phenylthio, anilino,
• which phenyl, phenoxy, phenylthio, or anilino group may bc optionally substituted on the phenyl ring with one or two substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and —S(O)q(C1-C4 alkyl),
• or a radical selected from the group consisting of:
• wherein
• W is a bond, —CH2—, —O—, —NR11—, or —S(O)q—;
• q is 0, 1, or 2;
• R11 is selected from the group consisting of hydrogen, C1-C4 alkyl, acetyl, phenyl, benzyl, and —S(O)2CH3;
• Z1, Z2, and Z3 are each independently —CH— or nitrogen;
• R16 and R17 are each independently hydrogen Or C1-C4 alkyl;
• or a pharmaceutically acceptable salt thereof.

A method for treating depression, comprising:

• administering to a patient in need thereof an effective amount of a compound of Formula I:
• wherein:
• D is a C1-C3 alkane-diyl;
• R1 is phenyl,
• which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, cyano, difluoromethyl, trifluoromethyl, and trifluoromethoxy;
• R4 is a radical selected from the group consisting of:
• wherein
• —A1-A2-A3-A4-, together with the atoms to which they are attached, form an aromatic carbocyclic or heterocyclic ring in which each of A1, A2, A3, and A4 is independently —CR8— or nitrogen, wherein at least one of A1, A2, A3, and A4 must be —CR8—;
• -G1-G2-G3-, together with the atoms to which they are attached, form an aromatic heterocyclic ring in which each of G1, G2, and G3 is independently —CR8—, nitrogen, oxygen, or sulfur, wherein only one of G1, G2, and G3 can be oxygen or sulfur,
• -G4-G5-G6, together with the atoms to which they are attached, form an aromatic heterocyclic ring in which each of G4, G5, and G6 is independently —CR8—, or nitrogen;
• each R8 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, substituted C1-C4 alkyl, C3-C6 cycloalkyl, —NR12R13, trifluoromethyl, and trifluoromethoxy,
• R12 and R13 are each independently hydrogen, C1-C4 alkyl, or —C(O)—CH3, or R12 and R13, together with the nitrogen to which they are attached, form a 4-7 membered ring,
• Q1, Q2, Q5, and Q6 are each independently —CH—, or nitrogen;
• Q3 and Q4 are each independently oxygen or nitrogen, wherein at least one of Q3 and Q4 must be nitrogen;
• R6 is C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or pyridyl,
• which phenyl or pyridyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, trifluoromethoxy, morpholino, and —NR14R15;
• R14 and R15 are each independently hydrogen or C1-C4 alkyl, or R14 and R15, together with the nitrogen, to which they are attached, form a 4-7 membered ring;
• X is a bond, C1-C3 alkane-diyl, —CH(OH)—, —C(O)—, —O—, S(O)p—, or C═N—OR9—;
• p is 0, 1, or 2;
• R9 is hydrogen, C1-C4 alkyl, or benzyl;
• Y is a bond, C1-C3 alkane-diyl, or —C(O)—:
• n is 0, 1, or 2:
• each R7 is independently C1-C4 alkyl;
• R5 is hydrogen, halo, trifluoromethyl, C1-C4 alkyl, C3-C6 cycloalkyl, furyl, thienyl, pyrrolyl, imidazolyl, —NR16R17, pyridyloxy, phenyl, phenoxy, phenylthio, anilino,
• which phenyl, phenoxy, phenylthio, or anilino group may be optionally substituted on the phenyl ring with one or two substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and —S(O)q(C1-4 alkyl),
• or a radical selected from the group consisting of.
• wherein
• W is a bond, —CH2, —O—, —NR11—, or —S(O)q—;
• q is 0, 1, or 2;
• R11 is selected from the group consisting of hydrogen, Cl-Cd alkyl, acetyl, phenyl, benzyl, and —S(O)2CH3;
• Z1, Z2, and Z3 are each independently —CH— or nitrogen;
• R16 and R17 are each independently hydrogen or C1-4 alkyl;
• or a pharmaceutically acceptable salt thereof.

A method for treating anxiety, comprising:

• administering to a patient in need thereof an effective amount of a compound of Formula I:
• wherein:
• D is a C1-C3 alkane-diyl;
• R1 is phenyl,
• which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, cyano, difluoromethyl, trifluoromethyl, and trifluoromethoxy;
• R4 is a radical selected from the group consisting of:
• wherein
• -A1-A2-A3-A4-, together with the atoms to which they an attached, form an aromatic carbocyclic or heterocyclic ring in which each of A1, A2, A3, and A4 is independently —CR8— or nitrogen, wherein at least one of A1, A2, A3, and A1must be —CR8—;
• -G1-G2-G3-, together with the atoms to which they are attached, form an aromatic heterocyclic ring in which each of G1, G2, and G3 is independently —CR8—, nitrogen, oxygen, or sulfur, wherein only one of G1, G2, and G3 can be oxygen or sulfur;
• -G4-G5-G6-, together with the atoms to which they are attached, form an aromatic heterocyclic ring in which each of G4, G5, and G6 is independently —CR8—, or nitrogen;
• each R8 is independently selected from the group consisting of hydrogen, halo, C1-C4 alkyl, substituted C1-C4 alkyl, C3-C6 cycloalkyl, —NR12R13, trifluoromethyl, and trifluoromethoxy,
• R12 and R13 are each independently hydrogen, C1-C4 alkyl, or —C(O)—CH3, or R12 and R13, together with the nitrogen to which they are attached, from a 4-7 membered ring;
• Q1, Q2, Q5, and Q6 are each independently —CH—, or nitrogen;
• Q3 and Q4 are each independently oxygen or nitrogen, when at least one of Q2 and Q4 must be nitrogen;
• R6 is C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or pyridyl,
• which phenyl or pyridyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, C1-C4 aryl, C1-C4 alkoxy, trifluoromethyl, trifluoromethoxy, morpholino, and —NR14R15;
• R14 and R15 are each independently hydrogen or C1-C4 alkyl, or R14 and R15, together with the nitrogen to which they are attached, form a 4-7 membered ring,
• X is a bond, C1-C3 alkane-diyl, —CH(OH), —C(O)—, —O—, —S(O)p, or —C═N—OR9—;
• p is 0, 1, or 2;
• R9 is hydrogen, C1-C4 alkyl, or benzyl;
• Y is a bond, C1-C3 alkane-diyl, or —C(O)—;
• n is 0, 1, or 2;
• each R7 is independently C1-C4 alkyl;
• R5 is hydrogen, halo, trifluoromethyl, C1-C4 alkyl, C3-C6 cycloalky, furyl, thienyl, pyrrolyl, imidazolyl, NR16R17, pyridyloxy, phenyl, phenoxy, phenylthio, anilino,
• which phenyl, phenoxy, phenylthio, or amino group may be optionally substituted on the phenyl ring with one or two substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and S(O)q(C1-C4 alkyl),
• or a radical selected from the group consisting of:
• wherein
• W is a bond, —CH2—, —O—, NR11—, or —S(O)q—;
• q is 0, 1, or 2;
• R11 is selected from the group consisting of hydrogen, C1-C4 alkyl, acetyl, phenyl, benzyl, and S(O)2CH3;
• Z1, Z2, and Z3 are each independently —CH— or nitrogen;
• R16 and R17 are each independently hydrogen or C1-C4 alkyl;
• or a pharmaceutically acceptable salt thereof.