Substituted condensed thiophenes as modulators of sting

1. A compound of formula I:

wherein:

W is O or NH;

R 1 is selected from:

(i) H;

(ii) C 3-6 cycloalkyl;

(iii) 3-7 membered heterocyclyl optionally substituted with a group selected from:

methyl; and

—C(═O)OR, wherein R is selected from a C 1-4 alkyl group, a 3-7 membered heterocyclyl, or a phenyl group; and

(iv) linear or branched C 1-4 alkyl optionally substituted with a group selected from:

alkoxy;

amino;

—C(═O)N(R″)R′ wherein R′ and R″ are independently selected from H and C 1-4 alkyl;

—N(R″)C(═O)R′ wherein R′ and R″ are independently selected from H and C 1-4 alkyl;

—OC(═O)R, wherein R is selected from a C 1-4 alkyl group, a 3-7 membered heterocyclyl, and a phenyl group;

—OC(═O)O—C 1-4 alkyl;

—NHC(═O)O—C 1-4 alkyl;

—OC(═O)NR′R″ wherein R′ and R″ are independently selected from H and C 1-4 alkyl;

phenyl;

—P(O)(OC 1-4 alkyl) 2 ;

3-7 membered heterocyclyl optionally substituted with a group selected from methyl and oxo; and

a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, —C(O)—CH 3 and boc;

A1 is CR A or N;

A 2 is CR B or N;

A 3 is CR C or N;

A 4 is CR D or N;

where no more than two of A 1 , A 2 , A 3 , and A 4 may be N;

one or two of R A , R B , R C , and R D , (if present) are selected from H, F, Cl, Br, Me, CF 3 , cyclopropyl, cyano, OMe, OEt, CH 2 OH, CH 2 OMe and OH;

the remainder of R A , R B , R C , and R D , (if present) are H;

Y is O, NH or CH 2 ;

R Y is selected from:

(a)

wherein:

Z 1 is CR Z1 or N;

Z 2 is CR Z2 or N;

Z 4 is CR Z4 or N;

Z 5 is CR Z5 or N;

where no more than two of Z 1 , Z 2 , Z 4 and Z 5 may be N;

one or two of R Z1 , R Z2 , R Z4 and R Z5 , (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF 3 , CH 2 OH, CH 2 OMe, C 2-4 alkenyl, and 5-membered heterocyclyl;

the remainder of R Z1 , R Z2 , R Z4 and R Z5 , (if present) are H;

(b)

where R 12 is selected from H, F, Cl, Br, OMe, cyano and CF 3 ;

wherein each heterocyclyl comprises 1 or 2 heteroatoms selected from N and O;

with the proviso that when A 1 is CF; A 2 , A 3 and A 4 are CH; Y is O or NH; R Y is RYA, where Z 1 , Z 2 , Z 4 and Z 5 are CH; R 1 is not Et; and

when A 1 is CF; A 2 , A 3 and A 4 are CH; Y is NH; R Y is RYA, where Z 1 and Z 5 are CH, one of Z 2 and Z 4 is CF, and the other of Z 2 and Z 4 is CH; R 1 is not Et.

2. A compound according to claim 1 , wherein W is O.

3. A compound according to claim 1 , wherein R 1 is H.

4. A compound according to claim 1 wherein R 1 is selected from C 3-6 cycloalkyl, optionally substituted 3-7 membered heterocyclyl, and optionally substituted linear or branched C 1-4 alkyl.

5. A compound according to claim 1 , wherein R 1 is optionally substituted linear or branched C 1-4 alkyl.

6. A compound according to claim 5 , wherein R 1 is optionally substituted methyl.

7. A compound according to claim 5 , wherein R 1 is optionally substituted ethyl.

8. A compound according to claim 5 , wherein R 1 is optionally substituted iso-butyl.

9. A compound according to claim 5 , wherein R 1 is substituted with —OC(═O)R, wherein R is selected from a C 1-4 alkyl group, a 3-7 membered heterocyclyl group, and a phenyl group.

10. A compound according to claim 5 , wherein R 1 is pivaloyloxymethyl or propanoyloxyisobutyl.

11. A compound according to claim 1 , wherein A 1 is CR A , A 2 is CR B , A 3 is CR C , and A 4 is CR D .

12. A compound according to claim 1 , wherein the compound is selected from compounds of formulae IIIb, IIIc, IIId and IIIe:

13. A compound according to claim 1 , wherein:

R A (if present) is selected from Cl and Br;

R B (if present) is H;

R C (if present) is H;

R D (if present) is selected from H, Me, F, Br, OMe.

14. A compound according to claim 11 , wherein A 1 , A 2 , A 3 and A 4 are selected from combinations 1-7:

combination

A 1

A 2

A 3

A 4

1

CCl

CH

CH

CH

2

CCl

CH

CH

CCH 3

3

CCl

CH

CH

CBr

4

CBr

CH

CH

CH

5

CCl

CH

CH

CF

6

CCl

CH

CH

COCH 3

7

CBr

CH

CH

CF.

15. A compound according to claim 1 , wherein Y is O.

16. A compound according to claim 1 , wherein R Y is RYA; and

Z 1 is CR Z1 , Z 2 is CR Z2 , Z 4 is CR Z4 and Z 5 is CR Z5 .

17. A compound according to claim 16 , wherein:

R Z1 is selected from H, F, and CH 2 OH;

R Z2 is H;

R Z4 is H;

R Z5 is selected from H, F, and CH 2 OH.

18. A compound according to claim 16 , wherein:

R Z1 is F, R Z2 is H, R Z4 is H and R Z5 is F; or

one of R Z1 and R Z5 is CH 2 OH, R Z2 is H, R Z4 is H and the other of R Z1 and R Z5 is F.

19. A pharmaceutical composition comprising a compound as defined in claim 1 , and a pharmaceutically acceptable excipient.