INHIBITORS OF BETA-SECRETASE

摘要

The present invention is directed to a compound represented by the following structural formula;;or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions and method of use of the compounds are also described.

主权项

1. A compound represented by the following Structural Formula:or a pharmaceutically acceptable salt thereof, wherein:
ring Het is a 5 membered monocyclic heterocycle or a 6 membered monocyclic heterocycle; X is —O—, —C(RaRb)—C(R3R4)—, —C(R3R4)—C(RaRb)— or —C(R3R4)—; Ra and Rb are each independently —H, -halogen, (C1-C4)alkyl, methoxy, fluoromethoxy, methoxy(C1-C4)alkyl and fluoro(C1-C4)alkyl; each R0 is independent selected from —H, ═O, ═S, ═NR15, (C1-C6)alkyl, halo(C1-C6)alkyl, —CN, —NO2, halogen, —OR5, —NR6R7, —S(O)iR5, —S(O)iNR12R13, —NR11S(O)iR5, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR(C═O)OR5, —O(C═O)NR12R13, —NR(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, —C(═O)R5, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C3)alkyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C3)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl, each of the (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C3)alkyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C3)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl group represented by R0 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C3)alkoxy(C1-C3)alkyl, (C3-C8)cycloalkyl, (C3-C9)heterocycloalkyl, aryl, heteroaryl, —NR6R7, —NR11S(O)iR5, —C(═O)NR12R13, —NR11C(═O)R5, —S(O)iR5—, —S(O)iNR12R13, —OR5, —C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —C(O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —O(C═O)NR12R13, —NR11(C═O)OR5, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13 and —C(═S)R5, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups in the substituents on the groups represented by R0 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R1 is —H, —OH, —(C1-C4)alkoxy, (C1-C6)alkyl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; wherein each alkyl, aryl and heteroaryl is optionally substituted with 1 to 5 substituents independently selected from halogen, —CN, —OH, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C3)alkoxy and halo(C1-C3)alkoxy; each R2 is independently selected from a) —H, -halogen, —CN, —NO2, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)iR5, —S(O)iNR12R13, C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, and —C(═O)R5; and b) (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl, and heteroaryl(C2-C6)alkynyl, wherein each of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C4-C8)cycloalkenyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl, and heteroaryl(C2-C6)alkynyl groups represented by R2 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -halogen, —CN, —NO2, —OR5, —SR5, —NR6R7, —S(O)iR5, —NR11S(═O)iR5, —S(O)iNR12R13, —C(═O)OR5, —OC(═O)R5, —C(═S)OR5, —OC(═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —C(═O)R5, —C(═S)R5, —OC(═O)OR5, —O(C═O)NR12R13, —NR11(C═O)OR5, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═O)R5, —C(═S)R5, (C1-C6)alkyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, (C3-C9)heterocycloalkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C6)alkoxy(C1-C3)alkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups in the substituents on the groups represented by R2 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R3 and R4 are each independently —H, -halogen, —CN, —NO2, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)iR5, —S(O)iNR12R13, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl or heteroaryl(C1-C6)alkynyl, wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl or heteroaryl(C1-C6)alkynyl represented by R3 and R4 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)iR5, —S(O)iNR12R13, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C6)alkoxy(C1-C3)alkyl, (C3-C8)cycloalkyl, (C3-C9)heterocycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups in the substituents on the groups represented by R3 and R4 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; or R3 and R4, together with the carbon to which they are attached, form ring A, which is a 3-14 membered monocyclic ring, 9-14 membered bicyclic ring or 9-14 membered polycyclic ring, wherein ring A optionally contains 1 to 3 heteroatoms independently selected from O, N, and S and when the heteroatom is nitrogen, the nitrogens is substituted with —H, (C1-C3)alkyl or halo(C1-C3)alkyl, and when the heteroatom is sulfur, the sulfurs is optionally mono or di-oxygenated; and ring A is optionally substituted with 1 to 4 substituents independently selected from the group consisting of -halogen, —CN, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)iR5, —S(O)iNR12R13, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, (C1-C3)alkylsulfonylamino(C1-C6)alkyl, cyano(C1-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C6)alkoxy(C1-C3)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl, and heteroaryl(C2-C6)alkynyl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups in the substituents on ring A are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R5 is —H, (C1-C6)alkyl, halo(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C3)alkoxy(C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl, each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl in the groups represented by R5 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, ═O, —NR6C(═NH)NR6R7, —C(═O)ORc, —ORc, —SRc, —C(═O)NR6R7, —C(═O)Rc, —S(O)iRc, —NO2, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and —NR6R7; Rc is —H, (C1-C3)alkyl, halo(C1-C3)alkyl or (C1-C3)alkoxy(C1-C3)alkyl; R6 and R7 are each independently —H, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl, or heteroaryl(C1-C6)alkyl, all of which groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R8 and R9, together with the carbon to which they are attached, form ring A, which is a 3-14 membered monocyclic ring, 9-14 membered bicyclic ring or 9-14 membered polycyclic ring, wherein ring A optionally contains 1 to 3 heteroatoms independently selected from O, N, and S and when the heteroatom is nitrogen, the nitrogen is substituted with —H, (C1-C3)alkyl or halo(C1-C3)alkyl, and when the heteroatom is sulfur, the sulfur is optionally mono or di-oxygenated; and ring A is optionally substituted with 1 to 4 substituents independently selected from the group consisting of from halogen, —CN, —OR5, —NR6R7, —S(O)iR5, —NR11S(O)iR5, —S(O)iNR12R13, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, (C1-C3)alkylsulfonylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C6)alkoxy(C1-C3)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl, and heteroaryl(C2-C6)alkynyl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups in the substituents on ring A are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; or when R3 and R4, together with the carbon to which they are attached, form a ring A, R8 and R9 are each independently —H, -halogen, —CN, —NO2, —OR5, —NR6R7, —S(O)iR5, —S(O)iNR12R13, —NR11S(O)iR5, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, and —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl or heteroaryl(C1-C6)alkynyl, wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C2-C6)alkynyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl(C2-C6)alkynyl, aryl, aryl(C1-C6)alkyl, aryl(C2-C6)alkynyl, heteroaryl, heteroaryl(C1-C6)alkyl or heteroaryl(C1-C6)alkynyl group represented by R8 and R9 is optionally substituted with 1 to 5 substituents independently selected from the group consisting of -halogen, —CN, —OR5, —NR6R7, —S(O)iR5, —S(O)iNR12R13, —NR11S(O)iR5, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR12R13, —NR11C(═O)R5, —C(═S)NR12R13, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR12R13, —NR11(C═S)OR5, —O(C═S)NR12R13, —NR11(C═O)NR12R13, —NR11(C═S)NR12R13, —C(═S)R5, —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C6)alkoxy(C1-C3)alkyl, (C3-C8)cycloalkyl, (C3-C9)heterocycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups in the substituents on the groups represented by R8 and R9 are each optionally substituted with 1 to 3 substituents independently selected from halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R11 is —H or (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 5 substituents independently selected from halogen, CN, (C1-C6)alkoxy, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C9)heterocycloalkyl, aryl and heteroaryl, wherein the (C1-C6)alkoxy, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C3-C9)heterocycloalkyl, aryl and heteroaryl groups are each optionally substituted with 1 to 3 substitutes independently selected from the group consisting of halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; R12 and R13 are each independently —H, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C3)alkylamino(C1-C6)alkyl, di(C1-C3)alkylamino(C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl or heteroaryl(C1-C6)alkyl, wherein the (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C9)heterocycloalkyl, (C3-C9)heterocycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heteroaryl and heteroaryl(C1-C6)alkyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -halogen, —CN, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C3)alkoxy(C1-C6)alkyl; or R12 and R13, together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —OR5, —NR6R7, —S(O)iR5, —S(O)iNR12R13, —NR11S(O)iR5, —C(═O)OR5, —OC(═O)OR5, —C(═S)OR5, —O(C═S)R5, —C(═O)NR6R7, —NR11C(═O)R5, —C(═S)NR6R7, —NR11C(═S)R5, —NR11(C═O)OR5, —O(C═O)NR6R7, —NR11(C═S)OR5, —O(C═S)NR6R7, —NR11(C═O)NR6R7, —NR11(C═S)NR6R7, —C(═S)R5, —C(═O)R5, (C1-C6)alkyl, (C2-C6)alkenyl, halo(C1-C6)alkyl, (C1-C3)alkylsulfonylaminoalkyl, hydroxy(C1-C6)alkyl, cyano(C1-C6)alkyl, (C1-C3)alkylcarbonylamino(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy and (C1-C6)alkoxy(C1-C3)alkyl, wherein the 3-8 membered ring optionally contains 1 to 3 additional heteroatoms, which are independently selected from O, N and S, wherein when the additional heteroatom is nitrogen, the nitrogen is substituted with —H, (C1-C3)alkyl or halo(C1-C3)alkyl, and when the additional heteroatom is sulfur, the sulfur is optionally mono or di-oxygenated; R15 is —H or (C1-C6)alkyl optionally substituted with 1 to 5-F. i is 0, 1 or 2; p is 1, 2, 3 or 4; and q is 1, 2 or 3.