NK 1 antagonists

A compound having the formula (I):

• 227
• or a pharmaceutically-acceptable salt thereof, wherein
• Ar1 and Ar2 are each independently selected from the group consisting of R17-heteroaryl and
• 228
• X1 is —O—, —S—, —SO—, —SO2—, —NR34—, —N(COR12)— or —N(SO2R15)—;
• 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, —CH2F, —CHF2 and —CF3;
• or R1 and R2, together with the carbon atom to which they are both attached, form a C3 to C6 alkylene ring;
• or
• when X1 is —O—, —S— or —NR34—, then:
• R1 and R2 are each independently selected from the group consisting of H, C1-C6 alkyl, hydroxy(C1-C3alkyl), C3-C8 cycloalkyl, —CH2F, —CHF2 and —CF3;
• or R1 and R2, together with the carbon atom to which they are both attached, form a C3 to C6 alkylene ring;
• or R1 and R2, together with the carbon atom 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 and —OH;
• each R7 is independently selected from the group consisting of H and C1-C6 alkyl;
• n2 is 1 to 4;
• R4 and R5 are each independently selected from the group consisting of —(CR28R29)n1-G,
• where,
• n1 is 0 to 5;
• and
• G is H, —CF3, —CHF2, —CH2F, —OH, —O—(C1-C6 alkyl), —OCH2F, —OCHF2, —OCF3, —OCH2CF3, —O—(C3-C8 cycloalkyl), —O—(C1-C6)alkyl(C3-C8 cycloalkyl), —NR13R14, SO2NR13R14, —NR12SO2R13, —NR12C(O)R14, —NR12C(O)OR13, —NR12(C(O)NR13R14), —C(O)NR R13, —C(O)OR13, —C3-C8 cycloalkyl, (R19)r-aryl, (R19)r-heteroaryl, —OC(O)R14, —OC(O)NR13R14, —C(═NOR14)(R13), —C(O)R13, —C(OR12)(R13)(R14), heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of R30 and R31,
• 229
• R4 and R5 together are ═O, ═NOR12;
• or
• R4 and R5, together with the carbon atom to which they are both attached, form a 4- to 8-membered heterocycloalkyl or heterocycloalkenyl ring containing 1 to 3 groups independently selected from X2, provided that at least one X2 is —NR35—, —O—, —S—, —S(O)— or —SO2—, the ring being optionally substituted with from 1 to 6 substituents independently selected from the group consisting of R30 and R31;
• provided that R4 and R5 are not both selected from the group consisting of H, alkyl and cycloalkyl;
• further provided that, when one of R4 and R5 is —OH, then the other one of R4 and R5 is not alkyl or (R19)r-aryl;
• R8, R9 and R10 are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, —OR12, halogen, —CN, —NO2, —CF3, —CHF2, —CH2F, —CH2CF3, —OCF3, —OCHF2, —OCH2F, —OCH2CF3, —COOR12, —CONR21R22, —OC(O)NR21R22, —OC(O)R12, —NR21COR12, —NR21CO2R15, —NR21CONR21R22, —NR21SO2R15, —NR21R22, —S2NR21R22, —S(O)n6R15, (R19)r-aryl and (R19)r-heteroaryl;
• R12 is H, C1-C6 alkyl or C3-C8 cycloalkyl;
• R13 and R13 are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —CH2CF3, aryl and heteroaryl;
• or
• R13 and R14, together with the nitrogen atom to which they are both attached, form a 4- to 7-membered saturated or unsaturated ring that is optionally substituted with —OR12, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR34—;
• n6 is 0, 1 or 2;
• R15 is C1-C6 alkyl, C3-C8 cycloalkyl, —CF3 or —CH2CF3;
• R18 is H, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, hydroxy(C2-C6)alkyl or —P(O)(OH)2;
• 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, C1-C6 alkoxy, —OH, halogen, —CN, —NO2, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, —O—(C1-C6 alkyl), —O—(C3-C8 cycloalkyl), —COOR12, —CONR21R22, —OC(O)NR21R22, —OC(O)R12, —NR21R22, —NR21COR12, —NR21CO2R12, —NR21CONR21R22, —NR21SO2R15 and —S(O)n6R15;
• R21 and R22 are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl and benzyl;
• or
• R21 and R22, together with the nitrogen atom to which they are both attached, form a 4- to 7-membered saturated or unsaturated ring, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR34—;
• R23 and R24 are each independently selected from the group consisting of H and C1-C6 alkyl;
• or
• R23 and R24, together with the carbon atom to which they are both attached, form a C═O or cyclopropyl group;
• R27 is H, —OH or C1-C6 alkyl;
• R28 and R29 are each independently selected from the group consisting of H and C1-C2 alkyl;
• R30 and R31 are each independently selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl and —C(O)NR13R14;
• or
• R30 and R31, together with the carbon atom to which they are both attached, form ═O, ═S, a cyclopropyl ring or ═NR36;
• R32 and R33 are each independently selected from the group consisting of H and C1-C6 alkyl;
• R34 is H, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl or hydroxy(C2-C6)alkyl;
• R35 is H, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —P(O)(OH)2, allyl, hydroxy(C2-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, —SO2R15 or —(CH2)2—N(R12)—SO2—R15;
• R36 is H, C1-C6 alkyl, C3-C8 cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —NO2, —CN or OR12;
• R37 is 1 to 3 substituents independently selected from the group consisting of H, C1-C6 alkyl, —OH, C1-C6 alkoxy and halogen;
• r is 1 to 3;
• X2 is —NR35—, —O—, —S—, —S(O)—, —SO2—, —CH2—, —CF2— or —CR12F—;
• X3 is —NR34—, —N(CONR13R14)—, —N(CO2R13)—, —N(SO2R15)—, —N(COR12)—, —N(SO2NHR13)—, —O—, —S—, —S(O)—, —SO2—, —CH2—, —CF2— or —CR12F—;
• n3 is 1 to 5;
• and
• n5 is 1 to 3;
• or a diastereomer, enantiomer, stereoisomer, regiostereomer, rotomer, tautomer or prodrug thereof.