IP Library › Granted Patent US 10,730,849

Granted Patent B2

US 10,730,849 · App. 16/513,417 · Granted Aug 4, 2020

Benzo[b]thiophene compounds as STING agonists

Inventors: Michael D. Altman (Needham, MA); Brandon D. Cash (Stoughton, MA); Wonsuk Chang (Princeton, NJ); Jared N. Cumming (Winchester, MA); Andrew M. Haidle (Somerville, MA); Timothy J. Henderson (Natick, MA); James P. Jewell (Newton, MA); Matthew A. Larsen (Dedham, MA); Rui Liang (New Brunswick, NJ); Jongwon Lim (Lexington, MA); Min Lu (Brookline, MA); Ryan D. Otte (Natick, MA); Tony Siu (Brookline, MA); Benjamin Wesley Trotter (Medfield, MA); Sriram Tyagarajan (Edison, NJ)

Assignee: Merck Sharp & Dohme Corp.

C07D333/60 C07D333/62 C07D409/12 C07D498/04

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Quick Facts

Patent No.: US 10,730,849
App. No.: 16/513,417
Granted: Aug 4, 2020
Kind: B2

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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 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.

Claims (151)

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 COOH, COOC(CH 3 ) 3 , and

and

R 8 is selected from the group consisting of H, CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 OCH 3 , and cyclopropyl.

4. 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 4 is selected from the group consisting of H, F, C 1 -C 4 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 CHR 8 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

each 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 3 alkyl, and C 3 -C 6 cycloalkyl, and where optionally 2 R 8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring.

5. The compound of claim 4 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 CHR 8 CHR 8 ;

X 3 is selected from the group consisting of COOH, COOC(CH 3 ) 3 , and

and

each R 8 is selected from the group consisting of H and C 1 -C 4 alkyl.

6. The compound of claim 4 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 CHR 8 CHR 8 ;

X 3 is selected from the group consisting of COOH, COOC(CH 3 ) 3 , and

and

the 2 R 8 are taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring.

7. 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 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 C(R 8 ) 2 ;

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

each 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, and where optionally 2 R 8 are taken together, along with the atom to which they are attached, to form a 3- to 6-membered spirocycle.

8. The compound of claim 7 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 C(R 8 ) 2 ;

X 3 is selected from the group consisting of COOH, COOC(CH 3 ) 3 , and

and

each R 8 is selected from the group consisting of H, OH, and CH 3 .

9. The compound of claim 7 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 C(R 8 ) 2 ;

X 3 is selected from the group consisting of COOH, COOC(CH 3 ) 3 , and

and

the 2 R 8 are taken together, along with the atom to which they are attached, to form a 3- to 6-membered spirocycle.

10. A compound of formula (Ib′):

or a pharmaceutically acceptable salt thereof, wherein

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 ;

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

11. The compound according to claim 10 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 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.

12. The compound of claim 11 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 halogen, 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 COOH, COOC(CH 3 ) 3 , and

and

R 8 is selected from the group consisting of H, CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 OCH 3 , and cyclopropyl.

13. A pharmaceutical composition, said pharmaceutical composition comprising a compound according claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignments (2)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 16, 2020

From: 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

To: MERCK SHARP & DOHME CORP.

Reel/Frame 051532/0305 →