Fused ring NK1 antagonists

A compound of Formula 1:

• or a pharmaceutically acceptable salt and/or or solvate thereof,
• Ar1 and Ar2 are each independently selected from the group consisting of (R7)n7-aryl- and (R8)n8-heteroaryl-;
• G is selected from the group consisting of —O—, —S—, —S(O)—, —S(O2)—, —N(R6)—, —N(C(O)R6)—, —N(S(O2)R6)—, —N(S(O)R6)—, —N(C(O)OR6)—, —N(C(O)N(R6)2)—, —N(R6)S(O2)—, —S(O2)N(R6)—, —N(R6)SO—, —S(O)N(R6)—, —N(R6)C(O)O—, —OC(O)N(R6)—, —N(R6)C(O)—, —C(O)N(R6)—, and —N(R6)C(O)N(R6)—;
• X is —(C(R6)2)n3-A-(C(R6)2)n4—, wherein n3 and n4 can be the same or different;
• Y is —(C(R6)2)n5-B-(C(R6)2)n6—, wherein n5 and n6 can be the same or different;
• A is selected from the group consisting of —O—, —S—, —C(R6)2—, and —N(R14)—;
• B is selected from the group consisting of —O—, —S—, —C(R6)2—, and —N(R14)—;
• n1, n2, n3, n4, n5, n6, and n8 are each independently an integer of from 0 to 3;
• n7 is an integer of from 0 to 5;
• n8 is an integer of from 1 to 3;
• n9 is an integer of from 0 to 2;
• n10 is an integer of from 1 to 5
• Z is selected from the group consisting of —C(O)—, —C(S)—, —S(O)—, —S(O2)—, —C(═NR6)—, —C(═NOR6)—, and —C(═NN(R6)2)—;
• R1 and R2 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, cycloalkyl, —CH2F, —CHF2, —CF3, and heterocycloalkyl, wherein each of said alkyl, cycloalkyl, or heterocycloalkyl can be unsubstituted or substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, —OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —N(R6)2, —C(O)R6, —C(O)OR6, —OC(O)R6, —C(O)N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR6, —N(R6)C(O)N(R6)2, —NO2, —CN, —S(O2)R6, and —S(O2)N(R6)2;
• or
• R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a carbonyl group with the proviso that G is selected from the group consisting of —O—, —S—, and —N(R6)—;
• or
• R1 and R2, taken together with the carbon to which they are shown to be attached in Formula 1, form a cycloalkylene ring, wherein said cycloalkylene ring can be unsubstituted or substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, —OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —N(R6)2, —C(O)R6, —C(O)OR6, —OC(O)R6, —C(O)N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR6, —N(R6)C(O)N(R6)2, —NO2, —CN, —S(O2)R6, and —S(O2)N(R6)2;
• R3 and R4 are independently selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl can be unsubstituted or substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, —OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —N(R6)2, —C(O)R6, —C(O)OR6, —OC(O)R6, —C(O)N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR6, —N(R6)C(O)N(R6)2, —NO2, —CN, —S(O2)R6, and —S(O2)N(R6)2;
• R5 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and —P(O)(OH)2, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl can be unsubstituted or substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of halogen, alkyl, haloalkyl, —OR6, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —N(R6)2, —C(O)R6, —C(O)OR6, —OC(O)R6, —C(O)N(R6)2, —N(R6)C(O)R6, —N(R6)C(O)OR6, —N(R6)C(O)N(R6)2, —NO2, —CN, —S(O2)R6, and —S(O2)N(R6)2;
• R6 is selected from the group consisting of H, —CN, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl can be unsubstituted or independently substituted with one or more substituents which can be the same or different, and the substituents are independently selected from the group consisting of halogen, —OH, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aryloxy, heteroaryl, and heteroaryloxy;
• each R7 is independently selected from the group consisting of H, alkyl, cycloalkyl, —OH, alkoxy, cycloalkoxy, halogen, —CN, —NO2, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, —C(O)OR1′, —C(O)NR9R1°, —N(R9)C(O)R11, —N(R9)C(O)OR12, —N(R9)C(O)NR9R10, —N(R9)S(O2)R12, —NR9R10—S(O2)NR9R1, —S(O)R12, —S(O2)R12, and (R15)n8-heteroaryl-;
• each R8 is independently selected from the group consisting of H, alkyl, cycloalkyl, —OH, halogen, —CN, —NO2, —C(O)CF3, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, alkoxy, cycloalkoxy, —C(O)OR11, —CONR9R10, —NR9R10, —NR9COR12, —NR9CO2R11, —NR9CONR9R10, —NR9SO2R12—S(O)R12 and —S(O2)R12;
• R9 and R10 are each independently selected from the group consisting of H, alkyl, cycloalkyl, and benzyl;
• or
• R9 and R10, taken together with the nitrogen to which they are attached, form a 4-7 membered heteroaryl ring containing from 0-3 additional heteroatoms selected from the group consisting of —O—, —S— and —N(R11)—;
• R11 is selected from the group consisting of H, alkyl, and cycloalkyl;
• R12 is selected from the group consisting of alkyl, cycloalkyl, and —CF3;
• each R13 is independently selected from the group consisting of —(C(R17)2)n7-D, wherein D is H, —CF3, —CHF2, —CH2F, —CN, —OH, —O-alkyl, —OCH2F, —OCHF2, —OCF3, —OCH2CF3, —O-cycloalkyl, —O-alkyl-cycloalkyl, —NR18R19, —SO2NR18R19, —NR11SO2R18, —NR11C(O)R19, —NR11C(O)OR18, —NR11 (C(O)NR18R19), —C(O)NR18R19, —C(O)OR18, -cycloalkyl, (R7)n7-aryl-(R8)n8-heteroaryl-, —OC(O)R19, —OC(O)NR18R19, —C(═NOR19)(R18), —C(O)R18, —C(OR11)(R18)(R19), heterocycloalkenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of R21 and R22,
• R14 is H, alkyl, haloalkyl, aryl, heteroaryl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, —S(O)R6, —S(O2)R6, —C(O)OR6, —C(O)R6, and —C(O)N(R6)2;
• R15 is H, alkyl, cycloalkyl, alkoxy, —OH, —CN, —NO2, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, cycloalkoxy, —C(O)OR11, —C(O)NR9R10, —N(R9)C(O)R11, —N(R9)C(O)OR12, —N(R9)C(O)NR9R10, —N(R9)S(O2)R12, —NR9R10, —S(O2)NR9R10, —S(O)R12, —S(O2)R12;
• each R17 is independently H or alkyl;
• R18 and R19 are each independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, —CH2CF3, aryl and heteroaryl;
• or
• R18 and R19, 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 —OR11, where one of the carbon atoms in the ring is optionally replaced by a heteroatom selected from the group consisting of —O—, —S— and —NR20—;
• R20 is H, alkyl, cycloalkyl, cycloalkylalkyl or hydroxyalkyl;
• R21 and R22, together with the carbon atom to which they are both attached, form —C(O)—, —C(S)—, a cyclopropyl ring or —C(NR23)—;
• R23 is H, alkyl, cycloalkyl, cycloalkylalkyl, —NO2, —CN or OR11;
• R24 and R25 are each independently selected from the group consisting of H and alkyl;
• or
• R24 and R25, together with the carbon atom to which they are both attached, form a —C(O)— or cyclopropyl group;
• R26 is H, —OH or alkyl;
• R27 is H, alkyl, cycloalkyl, cycloalkylalkyl, —P(O)(OH)2, allyl, hydroxyalkyl, alkoxyalkyl, —SO2R28 or —(CH2)2—N(R11)—SO2—R28;
• R28 is alkyl, cycloalkyl, —CF3 or —CH2CF3;
• R29 is 1 to 3 substituents independently selected from the group consisting of H, alkyl, —OH, alkoxy and halogen;
• X1 is —NR27—, —O—, —S—, —S(O)—, —S(O2)—, —CH2—, —CF2— or —CR11F—;
• and
• X2 is —NR20—, —N(C(O)NR18R19)—, —N(C(O)OR18)—, —N(S(O2)R28)—, —N(C(O)R11)—, —N(S(O2)NHR18)—, —O—, —S—, —S(O)—, —S(O2)—, —CH2—, —CF2— or —CR11F—.