Thiophenes as glucagon receptor antagonists, compositions, and methods for their use

A compound or pharmaceutically acceptable salt thereof, having the general structure shown in Formula (A):

• wherein R1, R2, R3, R5, s, and Z are selected independently of each other and wherein:
• the * shown in the N* represents a valence optionally filled by R1, R2, or H;
• s is an integer from 1 to 5;
• R1 is selected from the group consisting of:
• (a) —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, —C(O)NR8R9, and —NR8R9;
• (b) alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
• wherein each of the alkyl, alkenyl and alkynyl portions of said alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
• halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, —OC(O)NR8R9, unsubstituted alkoxy, and alkoxy substituted with one or more groups independently selected from the group consisting of halo, perhaloalkoxy, OH, and —CO2R6;
• (c) —O-aryl, —S-aryl, arylalkyl-, —O-heteroaryl, —S-heteroaryl, heteroarylalkyl-, cycloalkyl, aryl-fused cycloalkyl-, cycloalkylalkyl-, —O-cycloalkyl, —S-cycloalkyl, heterocycloalkyl, aryl-fused heterocycloalkyl-, heterocycloalkylalkyl-, —O-heterocycloalkyl, —S-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —S-cycloalkenyl, heterocycloalkenyl, —O-heterocycloalkenyl, and —S-heterocycloalkenyl,
• wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl portions of said —O-aryl, —S-aryl, arylalkyl-, —O-heteroaryl, —S-heteroaryl, heteroarylalkyl-, cycloalkyl, aryl-fused cycloalkyl-, cycloalkylalkyl-, —O-cycloalkyl, —S-cycloalkyl, heterocycloalkyl, aryl-fused heterocycloalkyl-, heterocycloalkylalkyl-, —O-heterocycloalkyl, —S-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —S-cycloalkenyl, heterocycloalkenyl, —O-heterocycloalkenyl, and —S-heterocycloalkenyl, and the alkyl portions of said arylalkyl-, said heteroarylalkyl-, said cycloalkylalkyl-, and said heterocycloalkylalkyl-, are each independently unsubstituted or optionally independently substituted with 1 or more groups each independently selected from the group consisting of
• (i) halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR8—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9,
• (ii) -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
• wherein the alkyl, alkenyl and alkynyl portions of said -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
• halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9, and
• (iii) aryl, —O-aryl, —C(O)-aryl, heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, and heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (i) and (ii) above;
• and
• (d) aryl and heteroaryl,
• wherein said aryl and said heteroaryl are substituted with at least one group each independently selected from the group consisting of:
• (1) halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, —SF5, —Si(R7)3, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9,
• (2)-alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
• wherein each of the alkyl, alkenyl and alkynyl portions of said -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
• halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9, and
• (3) aryl, —O-aryl, —C(O)-aryl, heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, and heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above;
• R2 is selected from the group consisting of aryl, arylalkyl-, heteroaryl, and heteroarylalkyl-,
• wherein the aryl and heteroaryl, and the aryl and heteroaryl portions of said arylalkyl- and said heteroarylalkyl-, are substituted with 1 or more groups each independently selected from the group consisting of:
• (A) halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, —SF5, —Si(R7)3, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9,
• (B) -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
• wherein each of the alkyl, alkenyl and alkynyl portions of said -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
• halo, OH, —CO2R6, —C(O)R6, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9, and
• (C) aryl, —O-aryl, —C(O)-aryl, heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, and heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (A) and (B) above;
• R3 is selected from the group consisting of H and lower alkyl;
• Z is a moiety selected from —(C(R11)2)—(C(R12R13)), —C(O)OH, —(C(R11)2)—(C(R14)2)n—C(O)OH, from —(C(R11)2)—(C(R12R13))m—C(O)Oalkyl, —(C(R11)2)—(C(R14)2)n—C(O)Oalkyl,
• —(C(R11)2)—(C(R12R13))m-Q, and —(C(R11)2)—(C(R14)2)n-Q,
• wherein Q is a moiety selected from the group consisting of:
• m is an integer from 0 to 5;
• n is an integer from 0 to 5;
• p is an integer from 0 to 5;
• each R5 is independently selected from the group consisting of H, lower alkyl, hydroxy-substituted lower alkyl;
• each R6 is independently selected from the group consisting of H and alkyl;
• each R7 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl-;
• each R8 is independently selected from the group consisting of H and alkyl;
• each R9 is independently selected from the group consisting of H and alkyl,
• or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocyclic ring, or a 5-, 6-, or 7-membered unsaturated heterocyclic ring, which ring contains (including said nitrogen) from 1 to 2 ring heteroatoms each independently selected from the group consisting of N,N-oxide, O, S, S(O), or S(O)2,
• or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-membered heteroaromatic ring containing (including the nitrogen to which R8 and R9 are attached) from 1 to 3 ring nitrogens;
• each R10 is independently selected from the group consisting of H and alkyl;
• each R11 is independently selected from the group consisting of H and lower alkyl;
• each R12 is independently selected from the group consisting of H, lower alkyl, —OH, hydroxy-substituted lower alkyl;
• each R13 is independently selected from the group consisting of H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from the group consisting of hydroxyl and alkoxy, or R12 and R13 are taken together to form an oxo;
• and
• each R14 is independently selected from the group consisting of H and fluoro.

A compound or pharmaceutically acceptable salt thereof, having the general structure shown in Formula (VI):

• wherein R1, R2, R3, R5, s, and Z are selected independently of each other and wherein:
• R1 is selected from the group consisting of:
• phenyl and naphthyl,
• wherein said phenyl and said naphthyl are substituted with from 1 to 3 groups each independently selected from:
• halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
• R2 is selected from the group consisting of:
• phenyl and naphthyl,
• wherein said phenyl and said naphthyl are substituted with from 1 to 3 groups each independently selected from:
• halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
• R3 is selected from the group consisting of H and lower alkyl;
• R5 is selected from H and alkyl;
• s is 1-3;
• and
• Z is selected from the group consisting of —(CH2)—(CH(CH3))—C(O)OH, —(CH2)—(CH2)—(CH2)—C(O)OH, —(CH2)—C(CH3)2—C(O)OH, —(CH2)—C(CH3)(OH)—C(O)OH, —CH2—CH2—C(O)OH, —CH2—CH(OH)—C(O)OH, —CH(CH3)—CH2—C(O)OH, —CH2—CH(F)—C(O)OH, —CH2—CF2—C(O)OH, CH(CH3)—CF2—C(O)OH, —CH2—CH2—CF2—C(O)OH,