Buprenorphine analogs

摘要

The present invention is directed to Buprenorphine Analog compounds of the Formula (I), Formula (IA) or Formula (IB) shown below, wherein R1, R2, R8, R3a, R 3b, G, X, Z and Y are as defined herein. Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors.;

主权项

1. A compound of Formula I: Wherein
R1 is selected from hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, phenyl, and benzyl; any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (C1-C6)alkyl-, OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl-COOR7, —COOR7, NH2, —NH(C1-C6)alkyl, —NR9R10, —CN, —CONR9R10, —NR9COR10, —SR11, -(5- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl;R2 and R8 are each independently hydrogen, —(C1-C10)alkyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, —NH2, —NH(C1-C6)alkyl, CN, —CONR5R6, —(C1-C6)alkyl-CO—NR5R6, —COOR7, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, —(C6-C14)bicycloalkyl, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkyl, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, —(C7-C14)bicycloalkenyl, ((C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkenyl, ((C8-C20)tricycloalkenyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-, phenyl, benzyl or naphthyl; each of which is optionally substituted with one or two substituents independently selected from the group consisting of —OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, —(C1-C6)alkoxy, ((C1-C6)alkoxy)CO(C1-C6)alkoxy-, phenyl, benzyl, —NH2, —NH(C1-C6)alkyl, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, —CN, —SH, —OR4, —CONR5R6, —(C1-C6alkyl)-CO—NR5R6, —COOR7, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —NH—SO2(C1-C6)alkyl, —N(SO2(C1-C6)alkyl)2, —C(═NH)NH2, —NH—CO—(C1-C6)alkyl, —NH—CO—NH2, —NH—C(═O)—NH—(C1-C6)alkyl, —NH—C(═O)-(5- to 12-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(5- to 12-membered)aryl, —NH—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—CH(NH2)—(C1-C6)alkyl-CO—OR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, -(5- to 12-membered)aryloxy, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, —C(O)NH—(C1-C6)alkyl-COOR7, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-;at least one of R2 and R8 is —(C1-C10)alkyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, NH2, —NH(C1-C6)alkyl, CN, —CONR5R6, —(C1-C6)alkyl-CO—NR5R6, —COOR7, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, —(C6-C14)bicycloalkyl, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkyl, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, —(C7-C14)bicycloalkenyl, ((C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkenyl, ((C8-C20)tricycloalkenyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-, phenyl, benzyl, or naphthyl; each of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, —(C1-C6)alkoxy, ((C1-C6)alkoxy)CO(C1-C6)alkoxy-, phenyl, benzyl, NH2, —NH(C1-C6)alkyl, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, CN, SH, OR4, —CONR5R6, —(C1-C6alkyl)-CO—NR5R6, —COOR7, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —NH—SO2(C1-C6)alkyl, —N(SO2(C1-C6)alkyl)2, —C(═NH)NH2, —NH—CO—(C1-C6)alkyl, —NH—CO—NH2, —NH—C(═O)—NH—(C1-C6)alkyl, —NH—C(═O)-(5- to 12-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(5- to 12-membered)aryl, —NH—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—CH(NH2)—(C1-C6)alkyl-CO—OR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, -(5- to 12-membered)aryloxy, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, —C(O)NH—(C1-C6)alkyl-COOR7, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-;R3a and R3b are each independently selected from hydrogen, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C10)alkoxy, OH, hydroxy(C1-C6)alkyl-, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl-C(═O)—(C1-C6)alkoxy, —(C1-C6)alkoxy-C(═O)—(C1-C6)alkyl, —(C1-C6)alkyl-CN, —(C1-C6)alkyl-COOR7, —(C1-C6)alkoxy-COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, ((C4-C12)cycloalkenyl)-(C1-C6)alkoxy-, ((C4-C12)cycloalkenyl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, ((5- to 12-membered)aryl)-(C1-C6)alkoxy-, ((5- to 12-membered)aryl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-, ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-(C1-C6)alkyl-, or together form (═O);R4 is selected from —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —C(halo)3, —CH(halo)2, —CH2(halo), hydroxy(C1-C6)alkyl-, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C6-C14)bicycloalkyl, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkyl, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, —(C7-C14)bicycloalkenyl, ((C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkenyl, ((C8-C20)tricycloalkenyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, or ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-;R5 and R6 are each independently hydrogen, —(C1-C6)alkyl, —(C3-C8)cycloalkyl, ((C3-C8)cycloalkyl)-(C1-C6)alkyl-, —COOR7, —(C1-C6)alkyl-CO—OR7, —CONH2, or (C1-C6)alkyl-CONH—, or R5 and R6 together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle;R7 is selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, or ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-;R9 and R10 are each independently selected from hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —(C3-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, or ((C3-C12)cycloalkenyl)-(C1-C6)alkyl-;each R11 is independently selected from hydrogen, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C10)alkoxy, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, or ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-;R12 and R13 are each independently selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, —(C6-C14)bicycloalkyl, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkyl, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, —(C7-C14)bicycloalkenyl, ((C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, —(C8-C20)tricycloalkenyl, ((C8-C20)tricycloalkenyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)(C1-C6)alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-, phenyl, benzyl or naphthyl; each of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, (═O), halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkenyl, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, phenyl, benzyl, NH2, —NH(C1-C6)alkyl, CN, SH, OR4, —CONR5R6, —COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)-bicycloheterocycle)-(C1-C6)alkyl-;R14 is selected from —COOR7, —(C1-C6)alkyl-CO—OR7, —C(═O)—(C1-C6)alkyl-COOR7, —(C1-C6)alkyl-C(═O)—(C1-C6)alkyl-COOR7, —CONH2, or (C1-C6)alkyl-CONH—;G is O, —OCO—, —C(═O), NH, NR′, S, SO, or SO2;R′ is —C(═O)(C1-C6)alkyl or —SO2(C1-C6)alkyl;X is selected from OH, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, halogen, —NH2, —NR2(C═O)R12, —CONR12R13, —(C1-C6)alkyl-CONH2, —(C1-C6)alkyl-COOH, —COOH, —O—(C1-C6)alkyl-COOH, —O—(C1-C6)alkyl-CONH2, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(OCH2CH2)s—OH, —(CH2)pCHOHCH2OH, CN, —NH—SO2R9, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, ((5- to 12-membered)aryl)-(C1-C6)alkoxy-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, ((3- to 12-membered)heterocycle)-(C1-C6)alkoxy-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-, or ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkoxy-;Q is selected from OH, —(C1-C10)alkoxy, —(C1-C10)alkyl, —(C3-C12)cycloalkyl, -(5- to 12-membered)aryl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, —(OCH2CH2)s—OH, —O(C═O)R9, —O—(C1-C6)alkyl-COOR7, —NH—(C1-C6)alkyl-COOR7, —O—C(O)—(C1-C6)alkyl-C(O)OR7, —NH—C(O)—(C1-C6)alkyl-C(O)OR7, —O—(C1-C6)alkyl-C(O)NR9R10, —NH—(C1-C6)alkyl-C(O)NR9R10, —O—C(O)—(C1-C6)alkyl-C(O)NR9R10, —NH—C(O)—(C1-C6)alkyl-C(O)NR9R10, or R14;Z is —(CH2)m—, optionally substituted with 1 or 2 —(C1-C6)alkyl;Y is —(CH2)n—CH or a direct bond, provided that when Y is a direct bond then R8 is absent;m is an integer 1, 2, 3, 4, 5, or 6;n is 0, 1, or 2;p is 0, 1 or 2;s is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13;provided that when X is OH or —(C1-C6)alkoxy, Q is OMe, Z is unsubstituted, and G is O, then either: a) R1 is selected from
i. Hydrogen, or (C1-C10)alkoxy or tetrazolyl-(C1-C6)alkyl any of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —(C1-C6)alkyl, OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl-COOR7, —COOR7, NH2, —NH(C1-C6)alkyl, NR9R10, CN, —CONR9R10, —NR9COR10, SR11, -(5- to 12-membered)carbocyclic ring, -(5- to 12-membered)heterocycle, phenyl, and benzyl; orii. —(C1-C10)alkyl, —(C2-C12)alkenyl, —(C2-C12)alkynyl, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((3- to 12 membered)heterocycle)-, (5- to 12-membered)heteroaryl-(C1-C6)alkyl-, (3- to 12-membered)heterocycle-(C1-C6)alkyl-, phenyl, or benzyl; each of which is substituted with 1, 2, or 3 substituents independently selected from the group consisting of —(C1-C6)alkyl-COOR7, —COOR7, NR9R10, —CONR9R10, —NR9COR10, and SR11, provided that NR9R10 is other than NH2 or —NH(C1-C6)alkyl, and SR11 is other than SH; or b) at least one of R2 and R8 is:
i. —(C1-C10)alkoxy, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, or —(C1-C6)alkoxy-COOR7; each of which is optionally substituted with one or two substituents independently selected from the group consisting of OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C6)alkyl, halo(C1-C6)alkyl-, —(C2-C6)alkynyl, hydroxy(C1-C6)alkyl-, dihydroxy(C1-C6)alkyl-, —(C1-C6)alkoxy, ((C1-C6)alkoxy)CO(C1-C6)alkoxy-, phenyl, benzyl, NH2, —NH(C1-C6)alkyl, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, CN, SH, OR4, —CONR5R6, —(C1-C6alkyl)-CO—NR5R6, —COOR7, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —NH—SO2(C1-C6)alkyl, —N(SO2(C1-C6)alkyl)2, —C(═NH)NH2, —NH—CO—(C1-C6)alkyl, —NH—CO—NH2, —NH—C(═O)—NH—(C1-C6)alkyl, —NH—C(═O)-(5- to 12-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(5- to 12-membered)aryl, —NH—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—CH(NH2)—(C1-C6)alkyl-CO—OR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(5- to 12-membered)aryl, -(5- to 12-membered)aryloxy, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, —C(O)NH—(C1-C6)alkyl-COOR7, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-; orii. —(C1-C6)alkyl-COOR7, —(C3-C12)cycloalkyl, —((C3-C12)cycloalkyl)-(C1-C6)alkyl, —(C4-C12)cycloalkenyl, —(C6-C14)bicycloalkyl, —(C8-C20)tricycloalkyl, —(C7-C14)bicycloalkenyl, —(C8-C20)tricycloalkenyl, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, -(7- to 12-membered)bicyclic ring system, -(7- to 12-membered)bicyclic aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, -(7- to 12-membered)bicycloheterocycle, phenyl, benzyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, ((C6-C14)bicycloalkyl)-(C1-C6)alkyl-, ((C8-C20)tricycloalkyl)-(C1-C6)alkyl-, ((C7-C14)bicycloalkenyl)-(C1-C6)alkyl-, ((C8-C20)tricycloalkenyl)-(C1-C6)alkyl-, ((7- to 12-membered)bicyclic ring system)-(C1-C6)alkyl-, ((7- to 12-membered)bicyclic aryl)-(C1-C6)alkyl-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, ((7- to 12-membered)-bicycloheterocycle)-(C1-C6)alkyl-, or naphthyl; each of which is substituted with one or two substituents independently selected from the group consisting of —CONHR6, dihydroxy(C1-C6)alkyl-, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, —(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxy-COOR7, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —NH—SO2(C1-C6)alkyl, —N(SO2(C1-C6)alkyl)2, —C(═NH)NH2, —NH—CO—(C1-C6)alkyl, —NH—CO—NH2, —NH—C(═O)—NH—(C1-C6)alkyl, —NH—C(═O)-(5- to 12-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(5- to 12-membered)aryl, —NH—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—CH(NH2)—(C1-C6)alkyl-CO—OR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, —C(O)NH—(C1-C6)alkyl-COOR7-(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C1-C6)alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C1-C6)alkyl-; oriii. —(C1-C10)alkyl, or —(C2-C12)alkynyl, each of which is substituted with one or two substituents independently selected from the group consisting of —CONHR6, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, —(C1-C6)alkoxy-COOR7, —(OCH2CH2)s—O(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, ((C1-C6)alkyl)sulfonyl(C1-C6)alkyl-, —NH—SO2(C1-C6)alkyl, —N(SO2(C1-C6)alkyl)2, —C(═NH)NH2, —NH—CO—(C1-C6)alkyl, —NH—CO—NH2, —NH—C(═O)—NH—(C1-C6)alkyl, —NH—C(═O)-(5- to 12-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(5- to 12-membered)aryl, —NH—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—(C1-C6)alkyl-CO—OR7, —NH—C(═O)—CH(NH2)—(C1-C6)alkyl-CO—OR7, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, and —C(O)NH—(C1-C6)alkyl-COOR7; oriv. 2,3-dihydroxypropyl; orv. 4-isoxazolyl, 4-isoxazolyl(C1-C6)alkyl), 5-isoxazolyl, or 5-isoxazolyl(C1-C6)alkyl) substituted with one or two alkyl groups, orvi. —C(═O)NH2 or —(C1-C6)alkyl-C(═O)NH2; or c) at least one of R3a or R3b is independently selected from —(C7-C10)alkyl, —(C7-C10)alkenyl, —(C7-C10)alkynyl, —(C1-C10)alkoxy, —(C1-C6)alkyl-C(═O)—(C1-C6)alkoxy, —(C1-C6)alkoxy-C(═O)—(C1-C6)alkyl, —(C1-C6)alkyl-CN, —(C1-C6)alkyl-COOR7, —(C1-C6)alkoxy-COOR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-, ((C3-C12)cycloalkyl)-(C1-C6)alkoxy-(C1-C6)alkyl-, —(C4-C12)cycloalkenyl, ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-, ((C4-C12)cycloalkenyl)-(C1-C6)alkoxy-, ((C4-C12)cycloalkenyl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(5- to 12-membered)aryl, ((5- to 12-membered)aryl)-(C1-C6)alkyl-, ((5- to 12-membered)aryl)-(C1-C6)alkoxy-, ((5- to 12-membered)aryl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C1-C6)alkyl-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-, ((5- to 12-membered)heteroaryl)-(C1-C6)alkoxy-(C1-C6)alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C1-C6)alkyl-, ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-, or ((3- to 12 membered)heterocycle)-(C1-C6)alkoxy-(C1-C6)alkyl-; or provided that when X is OH or —(C1-C6)alkoxy, Q is OMe, R3a and R3b are both hydrogen, Z is substituted, G is O, and Y is a direct bond, then R2 is other than hydrogen;
or a pharmaceutically acceptable salt thereof.