Benzo[b]thiophene compounds as STING agonists

Patent metadata

Field	Value
Publication number	US-10730849-B2
Application number	US-201916513417-A
Country	US
Kind code	B2
Filing date	Jul 16, 2019
Priority date	Oct 4, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

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 R1, R2, R3, R4, R5, R6, R8, R9, X1, X2, and X3 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.

First claim

What is claimed is:

1. A compound of formula (Ia′):

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, —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), and 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 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 ;
wherein when X 1 -X 2 -X 3 is X 1 —CHR 8 —X 3 or X 1 —CHR 8 CH 2 -X 3 , at least one of R 2 and R 3 is not selected from the group consisting of halogen, OR 6 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is not H; and
wherein said compound is not

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of H, F, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;
R 2 is selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl, OH, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, N(C 1 -C 3 alkyl) 2 , NH(C 1 -C 3 alkyl), and SC 1 -C 3 alkyl;
R 3 is selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl, OH, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, N(C 1 -C 3 alkyl) 2 , NH(C 1 -C 3 alkyl), and SC 1 -C 3 alkyl;
R 4 is selected from the group consisting of H, F, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;
R 5 is selected from the group consisting of H, F, Cl, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;
each R 6 is independently selected from the group consisting of H, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl;
X 1 is C(O);
X 2 is CH 2 CHR 8 ;
X 3 is selected from the group consisting of COOR 6 ,

SO 2 R 6 , and C(O)N(R 9 ) 2 , where each R 9 is independently selected from the group consisting of H, COOR 6 , and SO 2 R 6 ; and
R 8 is selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by OH, C 1 -C 4 alkyl substituted by OC 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of H and F;
R 2 is selected from the group consisting of Br, Cl, F, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 F, CH═CH 2 , C≡CH, OH, OCH 3 , OCH 2 CH 3 , OCHF 2 , SCH 3 , and NHCH 3 ;
R 3 is selected from the group consisting of Br, Cl, F, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 F, CH═CH 2 , C≡CH, OH, OCH 3 , OCH 2 CH 3 , OCHF 2 , SCH 3 , and NHCH 3 ;
R 4 is selected from the group consisting of H and F;
R 5 is selected from the group consisting of H and Cl;
X 1 is C(O);
X 2 is CH 2 CHR 8 ;
X 3 is selected from the group consisting of CO

Assignees

• Merck Sharp & Dohme

Inventors

• Altman Michael D
• Cash Brandon D
• Chang Wonsuk
• Cumming Jared N
• Haidle Andrew M
• Henderson Timothy J
• Jewell James P
• Larsen Matthew A
• Liang Rui
• Lim Jongwon
• Lu Min
• Otte Ryan D
• Siu Tony
• Trotter Benjamin Wesley
• Tyagarajan Sriram

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61K31/381

  having five-membered rings · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/424

  condensed with heterocyclic ring systems, e.g. clavulanic acid · CPC title