6-substituted and 7-substituted morphinan analogs and the use thereof

Abstract

The application is directed to compounds of Formula I or II: and pharmaceutically acceptable salts and solvates thereof, wherein R′, R″, R′″ R 1 , R 2 , R 3 , R 4 , R 4a , and R 20 are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I or II and the pharmaceutically acceptable salts and solvates thereof to treat disorders responsive to the modulation of one or more opioid receptors. Certain compounds of the invention are especially useful for treating pain.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R′, R″, R′″, and R″″ are each hydrogen, or 
 R 3  and R′ taken together form a double bond; or 
 R′ and R″ taken together form a double bond; or 
 R″ and R′″ taken together form a double bond; or 
 R′″ and R″″ taken together form a double bond; or 
 R 3  and R′ taken together form a double bond and R″ and R′″ taken together form a double bond; or 
 R 3  and R′ taken together form a double bond and R′″ and R″″ taken together form a double bond; or 
 R′ and R″ taken together form a double bond and R′″ and R″″ taken together form a double bond; 
 with the proviso that when R″ and R′″ taken together form a double bond or R′″ and R″″ taken together form a double bond, then R 20  is not —OH; 
 R 1  is selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 12 )cycloalkyl, (C 3 -C 12 )cycloalkyl-(C 1 -C 6 )alkyl-, —(C 3 -C 12 )cycloalkenyl, (C 3 -C 12 )cycloalkenyl-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, diphenyl(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, —(OCH 2 CH 2 ) s —O—(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, (C 1 -C 10 )alkoxy, C(halo) 3 , CH(halo) 2 , CH 2 (halo), C(O)R 5 , —C(O)O—(C 1 -C 10 )alkyl, and —(CH 2 ) n —NR 5 R 6 ; each of which is optionally substituted by 1, 2 or 3 independently selected R 9  groups; 
 R 3  is selected from the group consisting of hydrogen, OH, halo, —(C 1 -C 10 )alkoxy, and NR 17 R 18 ; any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, halo, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —(C 1 -C 10 )alkyl-(halo) w , —NR 17 R 18 , —COOH, —(C 1 -C 10 )alkoxy, —C(═O)—(C 1 -C 10 )alkoxy, -(5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, —(C 3 -C 12 )cycloalkyl, and —(C 4 -C 12 )cycloalkenyl; wherein the -(5- to 12-membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, —(C 3 -C 12 )cycloalkyl, and —(C 4 -C 12 )cycloalkenyl are optionally substituted with 1, 2, or 3 independently selected R 40  groups. 
 R 4  and R 4a  are each independently selected from:
 a) hydrogen, OH, halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —COOH, —C(═O)NH 2 ; 
 b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 2 -C 10 )alkenyloxy, —(C 2 -C 10 )alkynyloxy, any of which is optionally substituted with 1, 2, or 3 R 32  groups; or 
 c) —O-PG, wherein PG is a hydroxyl protecting group; 
 
 each R 32  is selected from:
 a) OH, halo, haloalkyl, NR 17 R 18 , COOH, —(C 1 -C 10 )alkoxy, alkoxycarbonyl; or 
 b) -(6- to 14-membered)aryl, -(5- to 12-membered)heteroaryl, -(3- to 12-membered)heterocycle, —(C 3 -C 12 )cycloalkyl, and —(C 3 -C 12 )cycloalkenyl, any of which is optionally substituted with 1, 2, or 3 R 40  groups; 
 
 each R 40  is independently selected from the group consisting of —OH, halo, —(C 1 -C 10 )alkyl, haloalkyl, —NO 2 , NR 17 R 18 , —COOH, —(C 1 -C 10 )alkoxy, and alkoxycarbonyl; 
 R 5  and R 6  are each independently selected from the group consisting of:
 a) hydrogen, —OH, halo, —C(halo) 3 , —CH(halo) 2 , and —CH 2 (halo); 
 b) —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and —(C 1 -C 6 )alkoxy, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from —OH, halo, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 3 -C 12 )cycloalkyl, —CHO, —COOH, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(CH 2 ) n —O—(CH 2 ) n —CH 3 , phenyl, and —CONR 5a R 6a ; 
 c) —(C 3 -C 8 )cycloalkyl, ((C 3 -C 8 )cycloalkyl)-(C 1 -C 6 )alkyl-, —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —CONH 2 , and (C 1 -C 6 )alkyl-CONH—; and 
 d) -(6- to 14-membered)aryl optionally substituted with 1, 2, or 3 independently selected R 30  groups;
 or R 5  and R 6  together with the nitrogen atom to which they are attached form a (3- to 12-membered)heterocycle optionally substituted with 1, 2, or 3 independently selected R 30  groups; 
 
 
 R 5a  and R 6a  are each independently selected from the group consisting of:
 a) hydrogen, —OH, halo, —C(halo) 3 , —CH(halo) 2 , and —CH 2 (halo); 
 b) —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and —(C 1 -C 6 )alkoxy, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from —OH, halo, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 3 -C 12 )cycloalkyl, —CHO, —COOH, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and phenyl; 
 c) —(C 3 -C 8 )cycloalkyl, ((C 3 -C 8 )cycloalkyl)-(C 1 -C 6 )alkyl-, —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —CONH 2 , and (C 1 -C 6 )alkyl-CONH—; and 
 d) -(6- to 14-membered)aryl optionally substituted with 1, 2, or 3 independently selected R 30  groups;
 or R 5a  and R 6a  together with the nitrogen atom to which they are attached form a (3- to 12-membered)heterocycle optionally substituted with 1, 2, or 3 independently selected R 30  groups; 
 
 
 each R 7  is independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 12 )cycloalkyl, —(C 4 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, and ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-; 
 each R 8  is independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 5 -C 12 )cycloalkyl, —(C 3 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, ((C 3 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —C(═O)(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-SO 2 —(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, —SO 2 -(6- to 14-membered)aryl, —NH 2 , and —(C 1 -C 6 )alkyl-NH 2 ; 
 each R 9  is independently selected from the group consisting of —OH, halo, —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 3 -C 12 )cycloalkyl, —CHO, —C(O)OH, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —(CH 2 ) n —O—(CH 2 ) n —CH 3 , phenyl, and CONR 5a R 6a ; 
 each R 11  is independently selected from the group consisting of —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , (6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, and (5- to 12-membered)heteroaryl, and ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-; each of which is optionally substituted with 1, 2, or 3 independently selected R 9  groups; 
 each R 14  is independently selected from —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkyl-C(═O)—(C 1 -C 6 )alkyl-COOR 7 , CONH 2 , or —(C 1 -C 6 )alkyl-CONH 2 ; 
 each R 17  and R 18  are independently selected from the group consisting of hydrogen and —(C 1 -C 10 )alkyl; 
 R 2  is hydrogen, OH, or Z 1 -G 1 -R 10a ; 
 or R 2  and R″ taken together with the carbon atom to which they are attached form: 
 
       
         
           
           
               
               
           
         
         Z 1  is (CH 2 ) m , which is optionally substituted with 1 or 2 —(C 1 -C 6 )alkyl; 
         G 1  is selected from:
 a) a bond, —(C 1 -C 6 )alkylene, —(C 2 -C 6 )alkenylene; 
 b) —O—, —O—C(═O), —C(═O), ═CH; or 
 c) NR 8 , —NH—C(═O), —NH—C(═NH), or ═N—NH; 
 
         R 10a  is selected from the group consisting of hydrogen, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —CH(═O), —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 2 -C 6 )alkenyl, —C(═O)-(6- to 14-membered)aryl, —C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, CN, NR 5 R 6 , —(C 1 -C 6 )alkyl-NR 5 R 6 , —CONR 5 R 6 , —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , —NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —CO—(CH 2 ) n —COOR 7 , —CO—(CH 2 ) n —CO—NR 5 R 6 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, —(C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, —(C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 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 , —CH 2 (halo), —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkoxy, ((C 1 -C 6 )alkoxy)-CO—(C 1 -C 6 )alkoxy-, phenyl, benzyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-NH(C 1 -C 6 )alkyl-R 14 , —NH—C(═NH)—NR 5 R 6 , —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —CN, —SH, —OR 11 , —CONR 5 R 6 , —(C 1 -C 6 alkyl)-C(═O)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-CO—OR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl)sulfonyl, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, —NH—SO 2 (C 1 -C 6 )alkyl, NH 2 —SO 2 (C 1 -C 6 )alkyl-, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—C(═O)—(C 1 -C 6 )alkyl, —NH—CO—NH 2 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 14-membered)aryl, —NH—C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —NH—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, -(6- to 14-membered)aryloxy, —(C 1 -C 6 )alkoxy-C(═O)NR 5 R 6 , —NH—(C 1 -C 6 )alkyl-C(═O)—NR 5 R 6 , —C(═O)NH—(C 1 -C 6 )alkyl-COOR 7 , ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
         R 20  is hydrogen, OH, or Z 2 -G 2 -R 10b ; 
         or R 20  and R′″ taken together with the carbon atom to which they are attached form: 
       
       
         
           
           
               
               
           
         
         provided that: 
         R 2  and R 20  are not both H; 
         Z 2  is (CH 2 ) m , which is optionally substituted with 1 or 2 —(C 1 -C 6 )alkyl; 
         G 2  is selected from:
 a) a bond, —(C 1 -C 6 )alkylene, —(C 2 -C 6 )alkenylene; 
 b) —O—, —O—C(═O), —C(═O), ═CH; or 
 c) NR 8 , —NH—C(═O), —NH—C(═NH), or ═N—NH; 
 
         R 10b  is selected from the group consisting of hydrogen, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —CH(═O), —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 2 -C 6 )alkenyl, —C(═O)-(6- to 14-membered)aryl, —C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, CN, NR 5 R 6 , —(C 1 -C 6 )alkyl-NR 5 R 6 , —CONR 5 R 6 , —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , —NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —CO—(CH 2 ) n —COOR 7 , —CO—(CH 2 ) n —CO—NR 5 R 6 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, —(C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, —(C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 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 , —CH 2 (halo), —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkoxy, ((C 1 -C 6 )alkoxy)-CO—(C 1 -C 6 )alkoxy-, phenyl, benzyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-NH(C 1 -C 6 )alkyl-R 14 , —NH—C(═NH)—NR 5 R 6 , —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —CN, —SH, —OR 11 , —CONR 5 R 6 , —(C 1 -C 6 alkyl)-C(═O)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-CO—OR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl)sulfonyl, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, —NH—SO 2 (C 1 -C 6 )alkyl, NH 2 —SO 2 (C 1 -C 6 )alkyl-, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—C(═O)—(C 1 -C 6 )alkyl, —NH—CO—NH 2 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 14-membered)aryl, —NH—C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —NH—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, -(6- to 14-membered)aryloxy, —(C 1 -C 6 )alkoxy-C(═O)NR 5 R 6 , —NH—(C 1 -C 6 )alkyl-C(═O)—NR 5 R 6 , —C(═O)NH—(C 1 -C 6 )alkyl-COOR 7 , ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
         or R 3  and R 20  can be taken together to form a —(C 1 -C 6 )alkylene bridge or —(CH 2 ) w —O—(CH 2 ) w ; 
         R 10c  is selected from the group consisting of hydrogen, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —CH(═O), —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 2 -C 6 )alkenyl, —C(═O)-(6- to 14-membered)aryl, —C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, CN, NR 5 R 6 , —(C 1 -C 6 )alkyl-NR 5 R 6 , —CONR 5 R 6 , —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , —NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —CO—(CH 2 ) n —COOR 7 , —CO—(CH 2 ) n —CO—NR 5 R 6 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, —(C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, —(C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 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 , —CH 2 (halo), —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkoxy, ((C 1 -C 6 )alkoxy)-CO—(C 1 -C 6 )alkoxy-, phenyl, benzyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-NH(C 1 -C 6 )alkyl-R 14 , —NH—C(═NH)—NR 5 R 6 , —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —CN, —SH, —OR 11 , —CONR 5 R 6 , —(C 1 -C 6 alkyl)-C(═O)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-CO—OR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl)sulfonyl, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, —NH—SO 2 (C 1 -C 6 )alkyl, NH 2 —SO 2 (C 1 -C 6 )alkyl-, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—C(═O)—(C 1 -C 6 )alkyl, —NH—CO—NH 2 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 14-membered)aryl, —NH—C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —NH—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, -(6- to 14-membered)aryloxy, —(C 1 -C 6 )alkoxy-C(═O)NR 5 R 6 , —NH—(C 1 -C 6 )alkyl-C(═O)—NR 5 R 6 , —C(═O)NH—(C 1 -C 6 )alkyl-COOR 7 , ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
         R 10d  is selected from the group consisting of hydrogen, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —CH(═O), —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 2 -C 6 )alkenyl, —C(═O)-(6- to 14-membered)aryl, —C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, CN, NR 5 R 6 , —(C 1 -C 6 )alkyl-NR 5 R 6 , —CONR 5 R 6 , —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , —NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH), —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —CO—(CH 2 ) n —COOR 7 , —CO—(CH 2 ) n —CO—NR 5 R 6 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, —(C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, —(C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 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 , —CH 2 (halo), —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkoxy, ((C 1 -C 6 )alkoxy)-CO—(C 1 -C 6 )alkoxy-, phenyl, benzyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-NH(C 1 -C 6 )alkyl-R 14 , —NH—C(═NH)—NR 5 R 6 , —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 , —CN, —SH, —OR 11 , —CONR 5 R 6 , —(C 1 -C 6 alkyl)-C(═O)—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-CO—OR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl)sulfonyl, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, —NH—SO 2 (C 1 -C 6 )alkyl, NH 2 —SO 2 (C 1 -C 6 )alkyl-, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—C(═O)—(C 1 -C 6 )alkyl, —NH—CO—NH 2 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 14-membered)aryl, —NH—C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —NH—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, -(6- to 14-membered)aryloxy, —(C 1 -C 6 )alkoxy-C(═O)NR 5 R 6 , —NH—(C 1 -C 6 )alkyl-C(═O)—NR 5 R 6 , —C(═O)NH—(C 1 -C 6 )alkyl-COOR 7 , ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered) heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-; 
         each R 30  is independently selected from —COOR 7 , —CONR 5a R 6a , —(C 1 -C 6 )alkyl, CN, -(3- to 12-membered)heteroaryl, ((3- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, NH 2 , halo, and ((6- to 14-membered)aryl)-(C 1 -C 6 )alkoxy-; 
         m is 0, 1, 2, 3, 4, 5, or 6; 
         n is 0, 1, 2, 3, 4, 5, or 6; 
         p is 0, 1, 2, 3, 4, 5, or 6; 
         s is 1, 2, 3, 4, 5, or 6; 
         w is 0, 1, or 2; 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , having Formula I-A: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , having Formula I-I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         6 . The compound of  claim 1 , having Formula I-J: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         7 - 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein R 2  is hydrogen or OH; or R 2  and R″ taken together form 
       
         
           
           
               
               
           
         
       
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The compound of  claim 1 , wherein R 2  is —Z 1 -G 1 -R 10a . 
     
     
         30 . The compound of  claim 29 , wherein R 10a  is selected from the group consisting of —(C 1 -C 10 )alkyl unsubstituted or substituted with OH; -(6- to 14-membered)aryl; ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-; -(3- to 12-membered)cycloalkyl; ((3- to 12-membered)cycloalkyl)-(C 1 -C 6 )alkyl-; —(C 1 -C 10 )alkoxy; -(3- to 12-membered)heterocycle; ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl; —COOR 7 ; —(C 1 -C 6 )alkyl-COOR 7 ; -(6-14-membered)aryl substituted with —NH—C(═NH)—NR 5 R 6 ; ((6-14-membered)aryl)-(C 1 -C 6 )alkyl-substituted with NH—C(═NH)—NR 5 R 6 ; —NR 5 R 6 ; —(C 1 -C 6 )alkyl-NR 5 R 6 ; and —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 ;
 wherein R 7  is hydrogen. 
 
     
     
         31 - 62 . (canceled) 
     
     
         63 . The compound of  claim 30 , wherein at least one of R 5  and R 6  is hydrogen or —(C 1 -C 6 )alkyl. 
     
     
         64 - 66 . (canceled) 
     
     
         67 . The compound of  claim 29 , wherein G 1  is a bond, —C(═O)—, —O—, —O—C(═O)—, —NR 8 , —NH—C(═O), or —NH—C(═NH); wherein R 8  is hydrogen. 
     
     
         68 - 69 . (canceled) 
     
     
         70 . The compound of  claim 29 , wherein Z 1  is (CH 2 ) m , wherein m is 0 or 1. 
     
     
         71 . The compound of  claim 1 , wherein R 20  is hydrogen or OH; or
 R 20  and R′″ are taken together to form   
       
         
           
           
               
               
           
         
       
     
     
         72 . (canceled) 
     
     
         73 . The compound of  claim 1 , wherein R 20  is —Z 2 -G 2 -R 10b . 
     
     
         74 . The compound of  claim 73 , wherein R 10b  is —(C 1 -C 10 )alkyl unsubstituted or substituted with OH; —(C 1 -C 10 )alkoxy; -(6- to 14-membered)aryl; -(6- to 14-membered)aryl substituted with —NH—C(═NH)—NR 5 R 6 ; ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-substituted with —NH—C(═NH)—NR 5 R 6 ; —NR 5 R 6 ; —(C 1 -C 6 )alkyl-NR 5 R 6 ; or —(C 1 -C 6 )alkyl-NH—C(═NH)—NR 5 R 6 . 
     
     
         75 - 96 . (canceled) 
     
     
         97 . The compound of  claim 73 , wherein G 2  is a bond, —C(═O)—, —O—, —O—C(═O)—, NR 8 , —NH—C(═O)—, or —NH—C(═NH)—; wherein R 8  is hydrogen. 
     
     
         98 - 99 . (canceled) 
     
     
         100 . The compound of  claim 73 , wherein Z 2  is (CH 2 ) m , wherein m is 0 or 1. 
     
     
         101 . The compound of  claim 1 , wherein R 1  is —(C 1 -C 10 )alkyl or ((C 3 -C 12 )cycloalkyl-(C 1 -C 6 )alkyl-. 
     
     
         102 . (canceled) 
     
     
         103 . The compound of  claim 1 , wherein R 4  is OH; R 3  is hydrogen or OH; R 4a  is hydrogen or OH; R′ is hydrogen, —(C 1 -C 3 )alkoxy, or —OH; R″ is hydrogen; and R 2  is hydrogen. 
     
     
         104 - 111 . (canceled) 
     
     
         112 . The compound of  claim 103 , wherein R 20  is —Z 2 -G 2 -R 10b , Z 2  is (CH 2 ) m , and m is 0. 
     
     
         113 . (canceled) 
     
     
         114 . A compound selected from the group consisting of:
 (4bR,6S,8aS,9R)-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthrene-6,8a-diol;   2-((4bS,6R,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)acetic acid;   (4bR,6S,8aS,9R)-11-(cyclopropylmethyl)-6-(dimethylamino)-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthrene-3,8a-diol;   (4bR,6R,8aS,9R)-6-((2-aminoethyl)amino)-11-(cyclopropylmethyl)-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthrene-3,8a-diol;   1-(2-(((4bR,6R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)amino)ethyl)guanidine;   (4bR,6R,8aS,9R)-6-((3-aminopropyl)amino)-11-(cyclopropylmethyl)-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthrene-3,8a-diol;   (4bR,6R,8aS,9R)-6-((4-aminobutyl)amino)-11-(cyclopropylmethyl)-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthrene-3,8a-diol;   1-(3-(((4bR,6R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)amino)propyl)guanidine;   1-(4-(((4bR,6R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)amino)butyl)guanidine;   N-((4bR,6R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)-2-guanidinoacetamide;   N-((4bR,6R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)-3-guanidinopropanamide;   N-((4bR,6R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)-4-guanidinobutanamide;   1-(4-(((4bR,6R,8aS,9R)-11-(cyclopropylmethyl)-3,8a-dihydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-6-yl)amino)phenyl)guanidine;   (4bS,8aS,9R)-11-(cyclopropylmethyl)-8a-hydroxy-3-methoxy-5,6,8,8a,9,10-hexahydro-7H-9,4b-(epiminoethano)phenanthren-7-one;   (4bS,9R)-11-(cyclopropylmethyl)-3-hydroxy-5,6,9,10-tetrahydro-7H-9,4b-(epiminoethano)phenanthren-7-one;   (4bS)-4-hydroxy-3,6-dimethoxy-11-methyl-9,10-dihydro-7H-9,4b-(epiminoethano)phenanthren-7-one;   (4bR,6R,8aS,9R)-6-(dimethylamino)-11-methyl-5,6,7,8,9,10-hexahydro-8aH-9,4b-(epiminoethano)phenanthrene-3,8a-diol (Compound 107);   (4bS,6R,8R,8aS,9R)-6-(2-hydroxyethoxy)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-8-ol (Compound 118);   (4bS,6S,8R,8aS,9R)-6-(2-hydroxyethoxy)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-8-ol (Compound 119);   (4bS,6R,8R,8aS,9R)-6-(2-hydroxyethoxy)-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3,8-diol (Compound 120); and   (4bS,6S,8R,8aS,9R)-6-(2-hydroxyethoxy)-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3,8-diol (Compound 121);   
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         115 . (canceled) 
     
     
         116 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         117 - 121 . (canceled) 
     
     
         122 . A method of treating pain in an animal, comprising administering to such animal in need thereof an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         123 - 131 . (canceled)