Benzomorphan analogs and the use thereof

A compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:

• wherein
• R1 is —(C1-C10)alkyl optionally substituted by —(C3-C12)cycloalkyl;
• R2a and R2b, are each independently, hydrogen or —(C1-C5)alkyl;
• Z is —(CH2)m— optionally substituted with 1 or 2 independently selected —(C1-C5s)alkyl;
• G is selected from the group consisting of —N(Rd)—, —O—, —N(Ra)C(O)N(Ra)—, —C(O)—, —N(Ra)S(O)2N(Rb)—, and—C(O)N(Rc)—;
• R3 is selected from the group consisting of hydrogen, —(C1-C10)alkyl, —(C3-C12)cycloalkyl, —C(═O)—(C1-C6)alkyl, —C(═O)—(C3-C12)cycloalkyl, -(3- to 12-membered)heterocyclo, -(6- to 14-membered)aryl, —(C1-C6)alkyl-(6- to 14-membered)aryl, -(5- to 12-membered)heteroaryl, —(C1-C6)alkyl-(5- to 12-membered)heteroaryl, —S(O)2—(C1-C6)alkyl, —S(O)2—(C3-C12)cycloalkyl, —S(O)2—(6- to 14-membered)aryl, and -(7- to 12-membered)bicycloheterocyclo;
• each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of (═O), halo, —(C1-C6)alkyl, —(C1-C6)alkoxy, —COOR6, —NHC(O)(C1-C6)alkyl, —C(O)R5, —NH2, (alkyl)amino, (dialkyl)amino, —(C3-C12)cycloalkyl, —(C6-C14)bicycloalkyl, —(C1-C6)alkyl(C6-C14)bicycloalkyl, -(3- to 8-membered)-heterocyclo, -(6- to 14-membered)aryl, -(5- to 12-membered)heteroaryl, aryloxy, carboxamido, —C(O)NH(C1-C6)alkyl, —SO2NH2, —N(Ra)SO2(C1-C6)alkyl, —SO2N(Ra)(C1-C6)alkyl, —N(Ra)SO2-(6- to 14-membered)aryl, -(7- to 12-membered)bicycloheterocyclo, and —(C1-C6)alkyl-(7- to 12-membered)bicycloheterocyclo;
• wherein each of the —(C1-C6)alkyl, —(C3-C12)cycloalkyl, —(C6-C14)bicycloalkyl, —(C1-C6)alkyl(C6-C14)bicycloalkyl, -(3- to 8-membered)heterocyclo, -(6- to 14-membered)aryl, -(5- to 12-membered)heteroaryl, aryloxy, —N(Ra)SO2(C1-C6)alkyl, —SO2N(Ra)(C1-C6)alkyl, —N(Ra)SO2-(6- to 14-membered)aryl, -(7- to 12-membered)bicycloheterocyclo, and —(C1-C6)alkyl-(7- to 12-membered)bicycloheterocyclo is further optionally substituted by one or two substituents independently selected from the group consisting of —(C1-C3)alkyl, —(C1-C3)alkoxy, halogen, and carboxamido;
• or R3 and Rd, together with the nitrogen atom to which they are attached, form a (4- to 8-membered)heterocyclo, which is further optionally substituted by one to three independently selected R7 groups;
• Each of Ra independently is hydrogen, —(C1-C5)alkyl, or —(C3-C12)cycloalkyl;
• Rb, and Rc, each independently, are hydrogen, —(C1-C5)alkyl, or —(C3-C12)cycloalkyl;
• Rd is H or —(C1-C6)alkyl;
• or Rd and R3, together with the nitrogen atom to which they are attached, form a (4- to 8-membered)heterocyclo, which is further optionally substituted by one to three independently selected R7 groups;
• R4 is hydrogen, OH, halo, —(C1-C5)alkyl, —C(O)NH2, —(C1-C5)alkoxy, —(C2-C5)alkenyl, —(C2-C5)alkynyl, or —(CH2)n—O—(CH2)n-CH3;
• wherein each of the —(C1-C5)alkyl, —C(O)NH2, —(C1-C5)alkoxy, —(C2-C5)alkenyl, —(C2-C5)alkynyl, and —(CH2)n—O—(CH2)n—CH3, is optionally substituted by one to three independently selected R7 groups;
• R5 is selected from the group consisting of hydrogen, —OH, —NH2, —(C1-C6)alkyl, —(C2-C5)alkenyl, —(C2-C5)alkynyl, —(C1-C6)alkoxy, and —(C3-C8)cycloalkyl, each of —NH2, —(C1-C6)alkyl, —(C2-C5)alkenyl, —(C2-C5)alkynyl, —(C1-C6)alkoxy, and —(C3-C8)cycloalkyl is optionally substituted with 1, 2, or 3 independently selected R6 groups;
• or
• R6 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-;
• each R7 is independently selected from the group consisting of —OH, (═O), —NH2, halo, —(C1-C6)alkyl, —(C1-C6)alkyl-(6- to 14-membered)aryl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C1-C6)alkoxy, —(C3-C12)cycloalkyl, —C(O)OH, —C(O)O(C1-C6)alkyl, carboxamido, —C(O)NH(C1-C6)alkyl, —NHC(O)(C1-C6)alkyl, —S(O)2NH2, —(CH2)n—O—(CH2)n—CH3, -(3- to 8-membered)heterocyclo, -(7- to 12-membered)bicycloheterocyclo, and —N(Ra )SO2-(6- to 14-membered)aryl;
• wherein each of the —(C1-C6)alkyl, —(C1-C6)alkyl-(6- to 14-membered)aryl, -(3- to 8-membered)heterocyclo, -(7- to 12-membered)bicycloheterocyclo, and —N(Ra)SO2-(6- to 14-membered)aryl is optionally substituted by one to three substituents independently selected from the group of (═O), —(C1-C3)alkyl, —NH2, halogen, and phenyl optionally substituted by halogen;
• and wherein the -(3- to 8-membered)heterocyclo is further optionally fused together with a phenyl group;
• m is 1, 2, 3, 4, 5, or 6;
• and
• n is 0, 1, 2, 3, 4, 5, or 6;
• provided that
• (i) when G is —O—, and R3 is optionally-substituted -(5- to 12-membered)heteroaryl or optionally-substituted -(6- to 14-membered)aryl, then R1 is unsubstituted —(C1-C10)alkyl;
• (ii) when G is —O—, and R3 is H or —CH2Ph, then Z is —CH2CH2—;
• (iii) when -G-R3 is —C(O)NH2, then R1 is —(C1-C10)alkyl that is either unsubstituted or substituted by cyclobutyl;
• and
• (iv) when R1 is cyclopropylmethyl, R4 is methoxy, Z is —(CH2)2—, one of R2a and R2b is H, and the other is methyl, and G is —NHC(O)—, then
• R3 is —(C1-C6)alkyl, -(3- to 12-membered)heterocyclo, or —(C1-C6)alkyl-(6- to 14-membered)aryl;
• each of which is substituted with one, two, or three substituents independently selected from the group consisting of (═O), halo, —NH2, —(C1-C6)alkyl, -(C1-C6)alkoxy, —COOR6, —NHC(O)(C1-C6)alkyl, —C(O)R5, —(C3-C12)cycloalkyl, -(3- to 8-membered)-heterocyclo, -(6- to 14-membered)aryl, -(5- to 12-membered)heteroaryl, aryloxy, carboxamido, —C(O)NH(C1-C6)alkyl, —SO2NH2,—N(Ra )SO2(C1-C6)alkyl, —SO2N(Ra )(C1-C6)alkyl, —N(Ra)SO2-(6- to 14-membered)aryl, -(7- to 12-membered)bicycloheterocyclo, and —(C1-C6)alkyl-(7- to 12-membered)bicycloheterocyclo;
• wherein each of the —(C1-C6)alkyl, —(C3-C12)cycloalkyl, -(3- to 8-membered)heterocyclo, -(6- to 14-membered)aryl, -(5- to 12-membered)heteroaryl, aryloxy, —N(Ra )SO2(C1-C6)alkyl, —SO2N(Ra)(C1-C6)alkyl, —N(Ra)SO2-(6- to 14-membered)aryl, -(7- to 12-membered)bicycloheterocyclo, and —(C1-C6)alkyl-(7- to 12-membered)bicycloheterocyclo is further optionally substituted by one or two substituents independently selected from the group consisting of —(C1-C3)alkyl, —(C1-C3)alkoxy, halogen, and carboxamido;
• (v) when R1 is unsubstituted —(C1-C10)alkyl, then R1 is a straight —(C1-C10)alkyl chain;
• (vi) when G is —N(Rd)—, and R3 is —(C1-C10)alkyl optionally substituted by —(C1-C6)alkyl, then R4 is —OH;
• and
• (vii) when R1 is cyclopropylmethyl, Z is —(CH2)2—, and
• R3 is
• a) —(C1-C10)alkyl substituted by —NH2 or (dialkyl)amino;
• or
• b) —C(═O)—(C1-C6)alkyl substituted by —NH2 or (dialkyl)amino;
• then R4 is methoxy.