NK1 antagonists

A compound having the formula (I)

• 112
• or a pharmaceutically-acceptable salt thereof, where
• Ar1 and Ar2 are each independently selected from the group consisting of R17-heteroaryl- and
• 113
• X1 is —O—, —S—, —SO—, —SO2-, —NR18a—, —N(COR12)— or —N(SO2R15)—;
• X2 is C, S or SO;
• when X2 is C, then Y is O, S or NR11;
• when X2 is S or SO, then Y is O,
• when X1 is —SO—, —SO2—, —N(COR12)— or —N(SO2R15)—, then:
• R1 and R2 are each independently selected from the group consisting of H, —C1-C6 alkyl, hydroxy(C1-C3alkyl)-, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl, —CH2F, —CHF2 and —CF3;
• or
• R1 and R2, together with one another and the carbon to which they are both attached, form a C3-C6 alkylene ring;
• when X1 is —O—, —S— or —NR18a—, then:
• R1 and R2 are each independently selected from the group consisting of H, —C1-C6 alkyl, hydroxy(C1-C3alkyl)-, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl, —CH2F, —CHF2 and —CF3;
• or
• R1 and R2, together with one another and the carbon to which they are both attached, form a C3-C6 alkylene ring;
• or
• R1 and R2, together with one another and the carbon to which they are both attached, form a C═O group;
• R3 is selected from the group consisting of H, —C1-C6 alkyl, hydroxy(C1-C3 alkyl)-, —C3-C8 cycloalkyl, —CH2F, —CHF2 and —CF3;
• each R6 is independently selected from the group consisting of H, —C1-C6 alkyl, —OR13 and —SR18;
• each R7 is independently selected from the group consisting of H and C1-C6 alkyl;
• or
• R6 and R7, together with one another and the carbon to which they are both attached, form a C═O group;
• n2 is from 1 to 4;
• R4 and R5 are each independently selected from the group consisting of —(CR28R29)-G and —C(O)(CR28R29)n4-G,
• where,
• n1 is from 0 to 5;
• n4 is from 1 to 5;
• and
• G is H, —CF3, —CHF2, —CH2F, —OH, —O—(C1-C6 alkyl), —SO2R13, —O—(C3-C8 cycloalkyl), —NR13R14, —SO2NR13R14, —NR3SO2R15, —NR13COR12, —NR12(CONR13R14), —NR12COC(R12)2NR13R14, —CONR13R14, —COOR12, —C3-C8 cycloalkyl, (R19)raryl-, (R19)rheteroaryl-, —OC(O)R14, —OC(O)NR13R14,
• 114
• R4 and R5, together with one another and the carbon to which they are both attached, form a C═O or C═NR12 group;
• or
• R4 and R5, together with one another and the carbon to which they are both attached, form a 4- to 7-membered ring containing from 0 to 3 heteroatoms that are each independently selected from the group consisting of —O—, —S—, —S(O)—, —SO2— and —NR18-, the ring being optionally substituted with from 1 to 2 substituents that are independently selected from the group consisting of R30 and R31;
• or
• when R4 and R5 do not form a ring, and n2 is 1 or 2, then R4 and R6 or R4 and R7, which are on adjacent carbons, can form a bond;
• X3 is —NR20—, —N(CONR13R14)—, —N(CO2R13)—, —N(SO2R15)—, —N(COR12)—, —N(SO2NHR13)—, —O—, —S—, —S(O)—, —SO2—, —CH2—, —CF2— or —CR12F—;
• R8, R9 and R10 are each independently selected from the group consisting of H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —OR18, halogen, —CN, —NO2, —CF3, —CHF2, —CH2F, —CH2CF3, —OCF3, —OCHF2, —OCH2F, —OCH2CF3, —COOR12, —CONR21R22, —NR21 COR2, —NR21CO2R15, —NR21 CONR21R22, —NR21SO2R15, —NR21R22, —SO2NR21R22—S(O)n5R15 (R19)raryl- and (R19)rheteroaryl-;
• R11 is H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl, —NO2, —CN or —OR18;
• R12 is H, —C1-C6 alkyl, —C3-C8 cycloalkyl or —C4-C8 cycloalkylalkyl;
• R13 and R14 are each independently selected from the group consisting of H, —C1-C6 alkyl, —C3-C8 cycloalkyl or —C4-C8 cycloalkylalkyl;
• or
• R13 and R14, together with one another, form a —C3 to —C6 alkylene chain, and with the nitrogen to which they are both attached, form a 4- to 7-membered ring that is, optionally, substituted with —OR12, where one of the carbon atoms in the C3-C6 alkylene chain is, optionally, replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR18—;
• R15 is —C1-C6 alkyl, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl or —CF3;
• R17 is H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl, —COOR12, —CONR21R22, —NR21R22, —NR21 COR12, —NR2 CO21R12, —NR21CONR21R22, —NR21SO2R15 or —S(O)n5R15;
• each R18 is independently selected from the group consisting of H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl and —P(O)(OH)2;
• each R18a is independently selected from the group consisting of H, —C1-C6 alkyl, —C3-C8 cycloalkyl and —C4-C8 cycloalkylalkyl;
• each R19 is a substituent on the aryl or heteroaryl ring to which it is attached, and is independently selected from the group consisting of H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl, —C1-C6 alkoxy, —OH, halogen, —CN, —NO2, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, —O—(C1-C6 alkyl), —O—(C3-C8 cycloalkyl), —COOR12, —CONR21R22, —NR21R22—NR21 COR12, —NR21CO2R12, —NR21CONR21R22, —NR21SO2R15 and —S(O)n5R15;
• r is from 1 to 3;
• R20 is H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl or —(CH2)n6-heterocycloalkyl;
• R21 and R22 are each independently selected from the group consisting of H, —C1-C6 alkyl, —C3-C8 cycloalkyl, —C4-C8 cycloalkylalkyl and benzyl;
• or
• R21 and R22, together with one another, form a —C3-C6 alkylene chain, and with the nitrogen to which they are both attached, form a 4- to 7-membered ring, where one of the carbon atoms in the —C3-C6 alkylene chain is, optionally, replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR18—;
• R23 and R24 are each independently selected from the group consisting of H and —C1-C6 alkyl;
• or
• R23 and R24, together with one another and the carbon to which they are both attached, form a C═O or cyclopropyl group;
• R25 and R26 are each independently selected from the group consisting of H and —C1-C6 alkyl;
• or
• R25 and R26, together with one another and the carbon to which they are both attached, form a C═O or cyclopropyl group;
• R27 is H or —C1-C6 alkyl;
• R28 and R29 are each independently selected from the group consisting of H, —C1-C2alkyl, —CH2F, —CHF2 and —CF3;
• R30 and R31 are each independently selected from the group consisting of H, —C1-C2alkyl, —CH2F, —CHF2 and —CF3;
• or
• R30 and R31, together with one another and the carbon to which they are both attached, form a C═O or cyclopropyl group;
• n3 is from 1 to 5;
• n5 is from 0 to 2;
• and
• n6 is from 0 to 3;
• provided that, when n5 is 0, and R25 and R26 are each H, then X3 is —CH2—, —CF2— or —CR12F—;
• or a diastereomer, enantiomer, stereoisomer, regiostereomer, rotomer, tautomer or prodrug thereof.