BENZOMORPHAN COMPOUNDS AS OPIOID RECEPTORS MODULATORS

摘要

The present invention is directed to Benzomorphan Analog compounds of the Formula (I), Formula (IA), Formula (IB), Formula (IC), or Formula (ID) as shown below, wherein R1, R2a, R2b, R3, R4, Z, and G 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 the group consisting of —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C12)cycloalkyl, (C3-C12)cycloalkyl-(C1-C6)alkyl-, —(C3-C12)cycloalkenyl, (C3-C12)cycloalkenyl-(C1-C6)alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C1-C6)alkyl-, —(OCH2CH2)s—O—(C1-C6)alkyl, —(CH2CH2O)s—(C1-C6)alkyl, (C1-C10)alkoxy, C(halo)3, CH(halo)2, CH2(halo), C(O)R5, —C(O)O—(C1-C10)alkyl, and —(CH2)n—N(R6)2, each of which is optionally substituted by 1, 2 or 3 independently selected R9 groups; R2a and R2b are each independently selected from:
(a) —H; or(b) —(C1-C5)alkyl, —(C2-C5)alkenyl, or —(C2-C5)alkynyl; Z is absent or —(CH2)m—, optionally substituted with 1 or 2 independently selected —(C1-C6)alkyl; G is selected from the group consisting of:
a) a bond, —(C1-C6)alkylene, —(C2-C6)alkenylene; orb) O, —OCO—, —C(═O); orc) NR8; ord) S, SO, and SO2; R3 is selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C2-C12)alkenyl, —C(═O), C(═O)—(C1-C6)alkyl-, —C(═O)—(C1-C6)alkyl, —C(═O)-(6- to 14-membered)aryl, —C(═O)-(5- to 12-membered)heteroaryl, —(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-CONR5R6, —COOR7, —(C1-C6)alkyl-COOR7, —(C1-C6)alkoxy-COOR7, —C(═O)—(CH2)n—COOR7, —C(═O)—(CH2)n—CONR5R6, —(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-, -(6- to 14-membered)aryl, ((6- to 14-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 and naphthyl; each of which is optionally substituted with one, two, or three 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-, dihydroxy(C1-C6)alkyl-, —(C1-C6)alkoxy, ((C1-C6)alkoxy)-C(═O)—(C1-C6)alkoxy-, phenyl, benzyl, —NH2, —NR5R6, —NH(C1-C6)alkyl, —(C1-C6)alkyl-NH(C1-C6)alkyl-R14, —CN, —SH, —OR4, —CONR5R6, —(C1-C6alkyl)-C(═O)—NR5R6, —COOR7, —(C1-C6)alkyl-COOR7, —(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—C(═O)—(C1-C6)alkyl, —NH—C(═O)—NH2, —NH—C(═O)—NH—(C1-C6)alkyl, —NH—C(═O)-(6- to 14-membered)aryl, —NH—C(═O)—(C1-C6)alkyl-(6- to 14-membered)aryl, —NH—(C1-C6)alkyl-COOR7, —NH—C(═O)—(C1-C6)alkyl-COOR7, —NH—C(═O)—CH(NH2)—(C1-C6)alkyl-C(═O)—OR7, —(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, -(6- to 14-membered)aryl, -(6- to 14-membered)aryloxy, —(C1-C6)alkoxyC(O)NR5R6, —NH—(C1-C6)alkylC(O)—NR5R6, —C(O)NH—(C1-C6)alkyl-COOR7, ((6- to 14-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-; R4 is selected from
(a) —H, —OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo), COOH, or CONH2; or(b) —(C1-C5)alkyl, —(C2-C5)alkenyl, —(C2-C5)alkynyl, —(CH2)n—O—(CH2)n—CH3, or —(C1-C5)alkoxy, each of which is optionally substituted with 1, 2, or 3 independently selected R9 groups; R5 and R6 are each independently selected from
(a) hydrogen, —OH, halo, —C(halo)3, —CH(halo)2, —CH2(halo); or(b) —(C1-C6)alkyl, —(C2-C5)alkenyl, —(C2-C5)alkynyl, —(CH2)n—O—(CH2)n—CH3, —(C1-C6)alkoxy, each of which is optionally substituted with 1, 2, or 3 independently selected R9 groups; or(c) —(C3-C8)cycloalkyl, ((C3-C8)cycloalkyl)-(C1-C6)alkyl-, —COOR7, —(C1-C6)alkyl-COOR7, —CONH2, or (C1-C6)alkyl-CONH—; or(d) R5 and R6 together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle; R7 is selected from the group consisting of hydrogen, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C12)cycloalkyl, —(C4-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, and ((C4-C12)cycloalkenyl)-(C1-C6)alkyl-; R8 is selected from H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —(C3-C12)cycloalkenyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-, ((C3-C12)cycloalkenyl)-(C1-C6)alkyl-, —C(═O)(C1-C6)alkyl or SO2(C1-C6)alkyl; each R9 is independently selected from —OH, halo, —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C10)alkoxy, —(C3-C12)cycloalkyl, —CHO, —C(O)OH, —C(halo)3, —CH(halo)2, CH2(halo), or —(CH2)n—O—(CH2)n—CH3; each R14 is independently selected from the group consisting of —COOR7, —(C1-C6)alkyl-COOR7, —C(═O)—(C1-C6)alkyl-COOR7, —(C1-C6)alkyl-C(═O)—(C1-C6)alkyl-COOR7, CONH2, and —(C1-C6)alkyl-CONH; m is an integer 1, 2, 3, 4, 5, or 6; n is an integer 0, 1, 2, 3, 4, 5, or 6; s in an integer 1, 2, 3, 4, 5, or 6; and the pharmaceutically acceptable salts and solvates thereof; (i) provided that when R1, R2a, R2b are all methyl, and R4 is OH or methoxy, then Z-G-R3 is not OH; (ii) provided that when Z is absent and G is selected as —O, then R3 is not H, (C1-C10)alkyl, CH2CH2O—(C1-C6)alkyl), (C2-C12)alkenyl, (C2-C12)alkynyl, (6- to 14-membered)aryl-(C1-C6)alkyl, (7- to 12-membered)bicyclic ring system-(C1-C6)alkyl, or (7- to 12-membered)bicyclic aryl-(C1-C6)alkyl; (iii) provided that when Z is absent and G is selected as a bond, then R3 is not —(C1-C10)alkoxy, or OCH2CH2—O(C1-C6)alkyl; (iv) provided that when Z is absent and G is selected as —O, then R3 is not C(═O), (C═O)—(C1-C6)alkyl, or (C═O)-(6- to 14-membered aryl); (v) provided that when Z is absent and G is selected as a bond, then R3 is not H or phenyl; and (vi) provided that Z-G-R3 is not unsubstituted (C1-C6)alkyl.