Benzo[b]thiophene compounds as STING agonists
View Patent ↗Compounds of general formula (Ia), compounds of general formula (Ia′), compounds of general formula (Ib), compounds of general formula (Ib′), compounds of general formula (I), compounds of general formula (I′), and their pharmaceutically acceptable salts, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , X 1 , X 2 , and X 3 are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds of the disclosure.
1. A method of inducing an immune response in a subject, said method comprising administering a therapeutically effective amount of a compound according to formula (I′) to the subject, wherein the compound of formula (I′) is
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
R 2 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 3 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 4 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
optionally R 3 and R 4 may be taken together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ) wherein said heterocyclic ring is optionally substituted with or more members of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 5 is selected from H, halogen, OR 6 , N(R 6 ) 2 , CN, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
each R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, wherein said C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl are optionally substituted with OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 haloalkyl);
X 1 is C(O);
X 2 is (C(R 8 ) 2 ) (1-3) ;
each R 8 is independently selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring;
optionally 2 R 8 on a single carbon atom may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle;
X 3 is selected from the group consisting of COOR 6 ,
C(O)SR 6 , C(S)OR 6 , SO 2 R 6 , and C(O)N(R 9 ) 2 ; and
each R 9 is independently selected from the group consisting of H, COOR 6 , and SO 2 R 6 .
2. A method of inducing an immune response in a subject, said method comprising:
(a) administering a therapeutically effective amount of a pharmaceutical composition to the subject, said pharmaceutical composition comprising a compound according to formula (I′) to the subject, wherein the compound of formula (I′) is
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
R 2 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 3 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 4 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
optionally R 3 and R 4 may be taken together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ) wherein said heterocyclic ring is optionally substituted with or more members of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 5 is selected from H, halogen, OR 6 , N(R 6 ) 2 , CN, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
each R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, wherein said C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl are optionally substituted with OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 haloalkyl);
X 1 is C(O);
X 2 is (C(R 8 ) 2 ) (1-3) ;
each R 8 is independently selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring;
optionally 2 R 8 on a single carbon atom may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle;
X 3 is selected from the group consisting of COOR 6 ,
C(O)SR 6 , C(S)OR 6 , SO 2 R 6 , and C(O)N(R 9 ) 2 ; and
each R 9 is independently selected from the group consisting of H, COOR 6 , and SO 2 R 6 .
3. A method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective amount of a compound according to formula (I′) to the subject, wherein the compound of formula (I′) is
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
R 2 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 3 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 4 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
optionally R 3 and R 4 may be taken together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ) wherein said heterocyclic ring is optionally substituted with or more members of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 5 is selected from H, halogen, OR 6 , N(R 6 ) 2 , CN, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
each R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, wherein said C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl are optionally substituted with OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 haloalkyl);
X 1 is C(O);
X 2 is (C(R 8 ) 2 ) (1-3) ;
each R 8 is independently selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring;
optionally 2 R 8 on a single carbon atom may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle;
X 3 is selected from the group consisting of COOR 6 ,
C(O)SR 6 , C(S)OR 6 , SO 2 R 6 , and C(O)N(R 9 ) 2 ; and
each R 9 is independently selected from the group consisting of H, COOR 6 , and SO 2 R 6 .
4. A method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject, said pharmaceutical composition comprising a compound according to formula (I′) to the subject, wherein the compound of formula (I′) is
or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
R 2 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 3 is selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SR 6 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 4 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
optionally R 3 and R 4 may be taken together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ) wherein said heterocyclic ring is optionally substituted with or more members of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 5 is selected from H, halogen, OR 6 , N(R 6 ) 2 , CN, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by SR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , C 1 -C 6 haloalkyl substituted by OR 6 , C 1 -C 6 haloalkyl substituted by SR 6 , and C 1 -C 6 haloalkyl substituted by N(R 6 ) 2 ;
each R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, wherein said C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl are optionally substituted with OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 haloalkyl);
X 1 is C(O);
X 2 is (C(R 8 ) 2 ) (1-3) ;
each R 8 is independently selected from the group consisting of H, halogen, CN, OR 6 , N(R 6 ) 2 , SR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 ), wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclic ring groups are optionally substituted by one or more substituents independently selected from the group consisting of CN, OR 6 , N(R 6 ) 2 , and SR 6 , and wherein said C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclic ring are each further optionally substituted with a member of the group consisting of C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring;
optionally 2 R 8 on a single carbon atom may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle;
X 3 is selected from the group consisting of COOR 6 ,
C(O)SR 6 , C(S)OR 6 , SO 2 R 6 , and C(O)N(R 9 ) 2 ; and
each R 9 is independently selected from the group consisting of H, COOR 6 , and SO 2 R 6 .
5. A method of claim 1 , wherein the compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. A method of claim 3 , wherein the compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.