Substituted condensed thiophenes as modulators of sting

Abstract

A compound of formula (I), wherein R.sup.1 is selected from (i) H, (ii) C.sub.3-6cycloalkyl, (iii) C.sub.3-7heterocyclyl optionally substituted with a group selected from: methyl and ester, and (iv) linear or branched C.sub.1-4alkyl optionally substituted with a group selected from: alkoxy, amino, amido, acylamido, acyloxy, alkyl carboxyl ester, alkyl carbamoyl, alkyl carbamoyl ester, phenyl, phosphonate ester, C.sub.3-7heterocyclyl 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, acetyl and boc; A.sup.1 is CR.sup.A or N; A.sup.2 is CR.sup.B or N; A.sup.3 is CR.sup.C or N; A.sup.4 is CR.sup.D or N; where no more than two of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 may be N; one or two of R.sup.A, R.sup.B, R.sup.C, and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and CH.sub.2NMe.sub.2; the remainder of R.sup.A, R.sup.B, R.sup.C, and R.sup.D, (if present) are H; Y is O, NH or CH.sub.2; R.sup.Y is selected from: (RYA) and (RYB).

Claims

1. A compound of formula I: ##STR00244## wherein: W is O or NH; R.sup.1 is selected from: (i) H; (ii) C.sub.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.sub.1-4 alkyl group, a 3-7 membered heterocyclyl, or a phenyl group; and (iv) linear or branched C.sub.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.sub.1-4 alkyl; —N(R″)C(═O)R′ wherein R′ and R″ are independently selected from H and C.sub.1-4 alkyl; —OC(═O)R, wherein R is selected from a C.sub.1-4 alkyl group, a 3-7 membered heterocyclyl, and a phenyl group; —OC(═O)O—C.sub.1-4 alkyl; —NHC(═O)O—C.sub.1-4 alkyl; —OC(═O)NR′R″ wherein R′ and R″ are independently selected from H and C.sub.1-4 alkyl; phenyl; —P(O)(OC.sub.1-4alkyl).sub.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.sub.3 and boc; A1 is CR.sup.A or N; A.sup.2 is CR.sup.B or N; A.sup.3 is CR.sup.C or N; A.sup.4 is CR.sup.D or N; where no more than two of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 may be N; one or two of R.sup.A, R.sup.B, R.sup.C, and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH; the remainder of R.sup.A, R.sup.B, R.sup.C, and R.sup.D, (if present) are H; Y is O, NH or CH.sub.2; R.sup.Y is selected from: (a) ##STR00245## wherein: Z.sup.1 is CR.sup.Z1 or N; Z.sup.2 is CR.sup.Z2 or N; Z.sup.4 is CR.sup.Z4 or N; Z.sup.5 is CR.sup.Z5 or N; where no more than two of Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 may be N; one or two of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OH, CH.sub.2OMe, C.sub.2-4 alkenyl, and 5-membered heterocyclyl; the remainder of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are H; (b) ##STR00246## where R.sup.12 is selected from H, F, Cl, Br, OMe, cyano and CF.sub.3; wherein each heterocyclyl comprises 1 or 2 heteroatoms selected from N and O; with the proviso that when A.sup.1 is CF; A.sup.2, A.sup.3 and A.sup.4 are CH; Y is O or NH; R.sup.Y is RYA, where Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are CH; R.sup.1 is not Et; and when A.sup.1 is CF; A.sup.2, A.sup.3 and A.sup.4 are CH; Y is NH; R.sup.Y is RYA, where Z.sup.1 and Z.sup.5 are CH, one of Z.sup.2 and Z.sup.4 is CF, and the other of Z.sup.2 and Z.sup.4 is CH; R.sup.1 is not Et.

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

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

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

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

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

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

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

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

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

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

12. A compound according to claim 1, wherein the compound is selected from compounds of formulae IIIb, IIIc, IIId and IIIe: ##STR00247##

13. A compound according to claim 1, wherein: R.sup.A (if present) is selected from Cl and Br; R.sup.B (if present) is H; R.sup.C (if present) is H; R.sup.D (if present) is selected from H, Me, F, Br, OMe.

14. A compound according to claim 11, wherein A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are selected from combinations 1-7: TABLE-US-00023 combination A.sup.1 A.sup.2 A.sup.3 A.sup.4 1 CCl CH CH CH 2 CCl CH CH CCH.sub.3 3 CCl CH CH CBr 4 CBr CH CH CH 5 CCl CH CH CF 6 CCl CH CH COCH.sub.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.sup.Y is RYA; and Z.sup.1 is CR.sup.Z1, Z.sup.2 is CR.sup.Z2, Z.sup.4 is CR.sup.Z4 and Z.sup.5 is CR.sup.Z5.

17. A compound according to claim 16, wherein: R.sup.Z1 is selected from H, F, and CH.sub.2OH; R.sup.Z2 is H; R.sup.Z4 is H; R.sup.Z5 is selected from H, F, and CH.sub.2OH.

18. A compound according to claim 16, wherein: R.sup.Z1 is F, R.sup.Z2 is H, R.sup.Z4 is H and R.sup.Z5 is F; or one of R.sup.Z1 and R.sup.Z5 is CH.sub.2OH, R.sup.Z2 is H, R.sup.Z4 is H and the other of R.sup.Z1 and R.sup.Z5 is F.

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

Description

FURTHER EMBODIMENTS

(1) R.sup.1

(2) In some embodiments, W is O and R.sup.1 is H. In these embodiments, the compounds are of formula Ia:

(3) ##STR00015##
where A.sup.1-A.sup.4, Y, and R.sup.Y are as defined above.

(4) In other embodiments, W is NH and R.sup.1 is H. In these embodiments, the compounds are of formula Ic:

(5) ##STR00016##
where A.sup.1-A.sup.4, Y, and R.sup.Y are as defined above.

(6) In other embodiments, W is O or NH and R.sup.1 is R.sup.1B. R.sup.1B is selected from C.sub.3-6cycloalkyl, optionally substituted C.sub.3-7heterocyclyl and optionally substituted linear or branched C.sub.1-4alkyl. In these embodiments, the compounds are of formula Ib:

(7) ##STR00017##

(8) where A.sup.1-A.sup.4, Y, and R.sup.Y are as defined above and R.sup.1B is selected from C.sub.3-6 cycloalkyl, optionally substituted C.sub.3-7heterocyclyl and optionally substituted linear or branched C.sub.1-4alkyl.

(9) In some embodiments R.sup.1/R.sup.1B is optionally substituted linear or branched C.sub.1-4alkyl. In some embodiments R.sup.1/R.sup.1B is unsubstituted C.sub.1-4alkyl. In some embodiments R.sup.1/R.sup.1B is substituted C.sub.1-4alkyl.

(10) When R.sup.1/R.sup.1B is C.sub.1-4 alkyl, in some of these embodiments R.sup.1/R.sup.1B is methyl. In other of these embodiments, R.sup.1/R.sup.1B is ethyl. In other of these embodiments, R.sup.1/R.sup.1B is propyl (e.g. iso-propyl, n-propyl). In other of these embodiments, R.sup.1/R.sup.1B is butyl (e.g. iso-butyl, sec-butyl, tert-butyl).

(11) In some embodiments, R.sup.1/R.sup.1B is C.sub.3-6 cycloalkyl. In some of these embodiments, R.sup.1/R.sup.1B is cyclopropyl. In other of these embodiments, R.sup.1/R.sup.1B is cyclobutyl. In other of these embodiments, R.sup.1/R.sup.1B is cyclopentyl. In other of these embodiments, R.sup.1/R.sup.1B is cyclohexyl.

(12) In some embodiments, R.sup.1/R.sup.1B is C.sub.3-7heterocyclyl. In some of these embodiments, the C.sub.3-7heterocyclyl has a single nitrogen ring atom. In some of these embodiments, R.sup.1/R.sup.1B is azetidinyl, pyrrolidinyl or piperidinyl. In some of these embodiments, R.sup.1/R.sup.1B is azetidinyl. In some of these embodiments, R.sup.1/R.sup.1B is piperidinyl.

(13) Substituents on R.sup.1

(14) In some embodiments, when R.sup.1/R.sup.1B is C.sub.3-7heterocyclyl, it is substituted with a group selected from methyl and ester. In some embodiments, when R.sup.1/R.sup.1B is C.sub.3-7heterocyclyl, it is substituted with methyl. In some embodiments, when R.sup.1/R.sup.1B is C.sub.3-7heterocyclyl, it is substituted with ester.

(15) In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with a group selected from alkoxy, amino, amido, acylamido, acyloxy, alkyl carboxyl ester, alkyl carbamoyl, alkyl carbamoyl ester, phenyl, phosphonate ester C.sub.3-7heterocyclyl optionally substituted with group selected from methyl and oxo, and a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc.

(16) In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with a group selected from acyloxy and phenyl. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with acyloxy, it is pivaloyloxymethyl; a group of formula:

(17) ##STR00018##

(18) In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with acyloxy, it is propanoyloxyisobutyl; a group of formula:

(19) ##STR00019##

(20) In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with phenyl, it is benzyl.

(21) In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with a naturally occurring amino acid, optionally N-substituted with a group selected from methyl, acetyl and boc. In some embodiments when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with a naturally occurring amino acid, the naturally occurring amino acid is valine. In some embodiments when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with a naturally occurring amino acid, the naturally occurring amino acid is N-methyl valine. In some embodiments when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with a naturally occurring amino acid, the naturally occurring amino acid is N-acetyl valine. In some embodiments when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with a naturally occurring amino acid, the naturally occurring amino acid is N-boc valine.

(22) In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with amino. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with amido. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with acylamido. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with acyloxy. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with alkyl carboxyl ester. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with alkyl carbamoyl. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with alkyl carbamoyl ester. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with phenyl. In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with phosphonate ester.

(23) In some embodiments, when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl, it is substituted with C.sub.3-7heterocyclyl, optionally substituted with a group selected from methyl and oxo. In some embodiments when R.sup.1/R.sup.1B is linear or branched C.sub.1-4alkyl substituted with C.sub.3-7heterocyclyl, the C.sub.3-7heterocyclyl is dioxole, optionally substituted with a group selected from methyl and oxo.

(24) The compounds of formula (Ib) and (Ic) are prodrugs of the acids of formula (Ia).

(25) In some embodiments, the compounds of formula I are compounds of formula II:

(26) ##STR00020##

(27) In some embodiments of compounds of formula II, R.sup.1 is H. In these embodiments, the compounds are of formula IIa:

(28) ##STR00021##

(29) In other embodiments of compounds of formula II, R.sup.1 is selected from Me, Et, iPr, benzyl and pivaloyloxymethyl. In these embodiments, the compounds are of formula IIb:

(30) ##STR00022##
where R.sup.1B is selected from Me, Et, iPr, benzyl and pivaloyloxymethyl. In some of these embodiments, R.sup.1/R.sup.1B may be Me. In other of these of these embodiments, R.sup.1/R.sup.1B may be Et. In other of these of these embodiments, R.sup.1/R.sup.1B may be iPr. In other of these embodiments, R.sup.1/R.sup.1B may be benzyl. In other of these embodiments, R.sup.1/R.sup.1B may be pivaloyloxymethyl.

(31) The esters of formula (IIb) are prodrugs of the acids of formula (IIa).

(32) A.sup.1-A.sup.4

(33) In some embodiments, A.sup.1 is CR.sup.A.

(34) In other embodiments, A.sup.1 is N.

(35) In some embodiments, A.sup.2 is CR.sup.B.

(36) In other embodiments, A.sup.2 is N.

(37) In some embodiments, A.sup.3 is CR.sup.C.

(38) In other embodiments, A.sup.3 is N.

(39) In some embodiments, A.sup.4 is CR.sup.D.

(40) In other embodiments, A.sup.4 is N.

(41) In some embodiments, two of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are N.

(42) In other embodiments, one of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are N.

(43) In other embodiments, none of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are N, i.e. A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are CR.sup.A, CR.sup.B, CR.sup.C, and CR.sup.D respectively.

(44) In some embodiments, the compound of formula I is selected from compounds of formulae (IIIa)-(IIIe):

(45) ##STR00023##

(46) R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if Present)

(47) In some embodiments, R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH.

(48) In some embodiments one of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH. The remainder (if present) are H.

(49) In other embodiments two of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH. The remainder (if present) are H.

(50) In some embodiments, one or two of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe. The remainder (if present) are H. In some of these embodiments, one or two of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3 and cyclopropyl. The remainder (if present) are H. In some of these embodiments, one or two of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me and CF.sub.3.

(51) In some embodiments R.sup.A and R.sup.D are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe; and R.sup.B and R.sup.C are H.

(52) In some embodiments R.sup.A is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt and CH.sub.2OMe. In some embodiments R.sup.A is selected from F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe. In some embodiments R.sup.A is selected from Cl and Br. In some embodiments R.sup.A is Cl. In some embodiments R.sup.A is Br.

(53) In some embodiments R.sup.D is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, CH.sub.2OH, CH.sub.2OMe and CH.sub.2NMe.sub.2. In some embodiments R.sup.D is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe. In some embodiments R.sup.D is selected from H, F, Br, Me and OMe. In some embodiments R.sup.D is H. In some embodiments R.sup.D is F. In some embodiments R.sup.D is Br. In some embodiments R.sup.D is Me. In some embodiments R.sup.D is OMe.

(54) In some embodiments, A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are selected from combinations 1-7 in the following table:

(55) TABLE-US-00001 Combination A.sup.1 A.sup.2 A.sup.3 A.sup.4 1 CCl CH CH CH 2 CCl CH CH CCH.sub.3 3 CCl CH CH CBr 4 CBr CH CH CH 5 CCl CH CH CF 6 CCl CH CH COCH.sub.3 7 CBr CH CH CF

(56) Y

(57) In some embodiments, Y is O.

(58) In other embodiments, Y is NH.

(59) In other embodiments, Y is CH.sub.2.

(60) In some preferred embodiments, Y is O or CH.sub.2.

(61) In some further preferred embodiments, Y is O.

(62) R.sup.Y

(63) In some embodiments, R.sup.Y is RYA:

(64) ##STR00024##

(65) In some embodiments R.sup.Y is RYA(I):

(66) ##STR00025##

(67) In other embodiments, R.sup.Y is RYB:

(68) ##STR00026##

(69) In some preferred embodiments R.sup.Y is RYA.

(70) In some further preferred embodiments R.sup.Y is RYA(I).

(71) In some yet further preferred embodiments R.sup.Y is selected from:

(72) ##STR00027##

(73) In some embodiments, R.sup.Y is:

(74) ##STR00028##

(75) In some embodiments, R.sup.Y is:

(76) ##STR00029##

(77) In some embodiments, R.sup.Y is:

(78) ##STR00030##

(79) Z.sup.1-Z.sup.5

(80) When R.sup.Y is RYA:

(81) In some embodiments, Z.sup.1 is CR.sup.Z1.

(82) In other embodiments, Z.sup.1 is N.

(83) In some embodiments, Z.sup.2 is CR.sup.Z2.

(84) In other embodiments, Z.sup.2 is N.

(85) In some embodiments, Z.sup.4 is CR.sup.Z4.

(86) In other embodiments, Z.sup.4 is N.

(87) In some embodiments, Z.sup.5 is CR.sup.Z5.

(88) In other embodiments, Z.sup.5 is N.

(89) In some embodiments, two of Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are N.

(90) In other embodiments, one of Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are N.

(91) In other embodiments, none of Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are N, i.e. Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are CR.sup.Z1, CR.sup.Z2, CR.sup.Z4 and CR.sup.Z5 respectively.

(92) In some embodiments, R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OMe, CH.sub.2OH, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl.

(93) In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OMe, CH.sub.2OH, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OH. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are selected from H, F, CH.sub.2OH. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are both F. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are both H. In some embodiments one of R.sup.Z1 and R.sup.Z5, (if present) is F and the other is CH.sub.2OH.

(94) In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OMe, CH.sub.2OH, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl, R.sup.Z2 and R.sup.Z4, (if present) are both H. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OH, R.sup.Z2 and R.sup.Z4, (if present) are both H. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are selected from H, F, CH.sub.2OH, R.sup.Z2 and R.sup.Z4, (if present) are both H. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are both F, R.sup.Z2 and R.sup.Z4, (if present) are both H. In some embodiments R.sup.Z1 and R.sup.Z5, (if present) are both H, R.sup.Z2 and R.sup.Z4, (if present) are both H. In some embodiments one of R.sup.Z1 and R.sup.Z5, (if present) is F and the other is CH.sub.2OH, R.sup.Z2 and R.sup.Z4, (if present) are both H.

(95) In some embodiments R.sup.Z2 and R.sup.Z4, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OMe, CH.sub.2OH, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl. In some embodiments R.sup.Z2 and R.sup.Z4, (if present) are selected from H, F, Cl, Br, Me, OMe, CF.sub.3, CH.sub.2OMe, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl. In some embodiments R.sup.Z2 and R.sup.Z4, (if present) are both H.

(96) In some embodiments one of R.sup.Z2 and R.sup.Z4, (if present) is selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OMe, CH.sub.2OH, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl; and the other is H. In some embodiments one of R.sup.Z2 and R.sup.Z4, (if present) is selected from H, F, Cl, Br, Me, OMe, CF.sub.3, CH.sub.2OMe, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl; and the other is H. In some embodiments one of R.sup.Z2 and R.sup.Z4, (if present) is selected from H, F, Br, OMe, CH.sub.2OMe, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl; and the other is H. In some embodiments one of R.sup.Z2 and R.sup.Z4, (if present) is selected from H and F; and the other is H.

(97) When R.sup.Y is RYA(I), in some embodiments Z.sup.4 is CR.sup.Z4. In other embodiments, Z.sup.4 is N.

(98) In some embodiments, one of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4, (if present) is selected from H, F, Cl, Br, Me, OMe, cyano and CF.sub.3.

(99) In other embodiments, two of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano and CF.sub.3.

(100) In some embodiments, one or two of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4, (if present) are selected from H, F, Cl, Br and Me. In some of these embodiments, one or two of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4 (if present) are selected from H, F and Cl.

(101) When R.sup.Y is RYB, R.sup.12 is selected from H, F, Cl, Br, OMe, cyano and CF.sub.3. In some embodiments, R.sup.12 is selected from H and F. In some of these embodiments, R.sup.12 is H. In other of these embodiments, R.sup.12 is F.

(102) In some embodiments, the compounds are of formula (II):

(103) ##STR00031##
wherein:
R.sup.1 is H, Me, Et, iPr, benzyl or pivaloyloxymethyl;
A.sup.1 is CR.sup.A or N;
one or two of R.sup.A (if present), R.sup.B, R.sup.C and R.sup.D are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe;
the remainder of R.sup.A (if present), R.sup.B, R.sup.C and R.sup.D are H;
Y is O, NH or CH.sub.2;
R.sup.Y is selected from:

(104) ##STR00032##
where Z.sup.4 is CR.sup.Z4 or N;
one or two of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4 (if present) are selected from H, F, Cl, Br, Me, OMe, cyano and CF.sub.3;
the remainder of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4 (if present) are H;

(105) ##STR00033##
where R.sup.12 is selected from H, F, Cl, Br, OMe, cyano and CF.sub.3;
with the proviso that when A.sup.1 is CF; R.sup.B, R.sup.C and R.sup.D are H; Y is O; R.sup.Y is RYA, where Z.sup.4 is CH, R.sup.2, R.sup.3 and R.sup.5 are H; R.sup.1 is not Et.

(106) In some embodiments R.sup.1 is H.

(107) In some embodiments R.sup.1 is selected from Me, Et, iPr, benzyl and pivaloyloxymethyl.

(108) In some embodiments R.sup.1 is Me.

(109) In some embodiments R.sup.1 is Et.

(110) In some embodiments R.sup.1 is iPr.

(111) In some embodiments R.sup.1 is benzyl.

(112) In some embodiments R.sup.1 is pivaloyloxymethyl.

(113) In some embodiments A.sup.1 is CR.sup.A.

(114) In some embodiments A.sup.1 is N.

(115) In some embodiments one of R.sup.A (if present), R.sup.B, R.sup.C and R.sup.D is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe.

(116) In some embodiments two of R.sup.A (if present), R.sup.B, R.sup.C and R.sup.D is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe.

(117) In some embodiments one or two of R.sup.A (if present), R.sup.B, R.sup.C and R.sup.D are selected from H, F, Cl, Br, Me, CF.sub.3 and cyclopropyl.

(118) In some embodiments one or two of R.sup.A (if present), R.sup.B, R.sup.C and R.sup.D are selected from H, F, Cl and CF.sub.3.

(119) In some embodiments Y is O.

(120) In some embodiments Y is NH.

(121) In some embodiments Y is CH.sub.2.

(122) In some embodiments R.sup.Y is RYA(I).

(123) In some embodiments Z.sup.4 is CR.sup.Z4.

(124) In some embodiments Z.sup.4 is N.

(125) In some embodiments one of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4 (if present) is selected from H, F, Cl, Br, OMe, cyano and CF.sub.3.

(126) In some embodiments two of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4 (if present) are selected from H, F, Cl, Br, OMe, cyano and CF.sub.3.

(127) In some embodiments one or two of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4 (if present) are selected from H, F, Cl, Br and Me.

(128) In some embodiments one or two of R.sup.Z1, R.sup.Z2, R.sup.Z5 and R.sup.Z4 (if present) are selected from H, F and Cl.

(129) In some embodiments R.sup.Y is RYB.

(130) In some embodiments R.sup.12 is selected from H and F.

(131) In some embodiments R.sup.12 is H.

(132) In some embodiments R.sup.12 is F.

EXAMPLES

(133) The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

(134) Acronyms

(135) For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), tert-butyl (tBu), phenyl (Ph), benzyl (Bn), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS), and acetyl (Ac).

(136) For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), deuterated methanol (MeOD-d.sub.4 or CD.sub.3OD) ethanol (EtOH), isopropanol (i-PrOH), ether or diethyl ether (Et.sub.2O), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), deuterated chloroform (CDCl.sub.3), diethylamine (DEA), deuterated dimethylsulfoxide (DMSO-d.sub.6), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl), meta-chloroperoxybenzoic acid (mCPBA), 1,1′-bis(diphenylphosphino)ferrocene (dppf), tert-butyloxycarbonyl (Boc, BOC), 2-(trimethylsilyl)ethoxymethyl (SEM), triethylamine (Et.sub.3N or TEA), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA or DIEA), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (II) (PdCl.sub.2(dppf)), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl.sub.2(PPh.sub.3).sub.2), tris(dibenzylideneacetone) dipalladium(0) (Pd.sub.2(dba).sub.3), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4), propylphosphonic anhydride (T3P), hexamethylphosphoramide (HMPA), 1,2-dichloroethane (DCE), chromium (VI) oxide (CrO.sub.3), n-bromosuccinimide (NBS), potassium hydroxide (KOH), benzoyl peroxide (BPO), carbon tetrachloride (CCl.sub.4), petroleum ether (Pet. Ether), potassium carbonate (K.sub.2CO.sub.3), sodium sulfate (Na.sub.2SO.sub.4), lithium diisopropylamine (LDA), azobisisobutyronitrile (AIBN), N-methylmorpholine N-oxide (NMO), benzoyl peroxide (BPO) and 1-hydroxybenzotriazole (HOBt).

(137) In addition, TLC refers to thin layer chromatography.

(138) General Experimental Details

(139) Unless otherwise stated the following generalisations apply. .sup.1H NMR spectra were recorded on a Bruker Ultrashield Plus (400 MHz) or a Bruker AVANCE III (400 MHz). The multiplicity of a signal is designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; td, triplet of doublets; ddd, doublet of doublet of doublets br, broad; m, multiplet. All observed coupling constants, J, are reported in Hertz.

(140) LCMS data was generated using the conditions described below. Chlorine isotopes are reported as .sup.35Cl, Bromine isotopes are reported as either .sup.79Br or .sup.81Br or both .sup.79Br/.sup.61Br.

(141) LCMS Method A (LCMS-A):

(142) Instrument: Agilent 6100 Series Single Quad LC/MS

(143) Agilent 1200 Series HPLC

(144) Pump: 1200 Series G1311A Quaternary pump

(145) Autosampler: 1200 Series G1329A Thermostatted Autosampler

(146) Detector: 1200 Series G1314B Variable Wavelength Detector

(147) LC conditions:

(148) Reverse Phase HPLC analysis

(149) Column: Luna C8 (2) 5 μm 50×4.6 mm 100 Å

(150) Column temperature: 30° C.

(151) Injection Volume: 5 μL

(152) Solvent A: Water 0.1% Formic Acid

(153) Solvent B: MeCN 0.1% Formic Acid

(154) Gradient: 5-100% solvent B over 10 min

(155) Detection: 254 nm or 214 nm

(156) MS conditions:

(157) Ion Source: Quadrupole

(158) Ion Mode: Multimode-ES

(159) Drying gas temp: 300° C.

(160) Vaporizer temperature: 200° C.

(161) Capillary voltage (V): 2000 (positive)

(162) Capillary voltage (V): 4000 (negative)

(163) Scan Range: 100-1000

(164) Step size: 0.1 sec

(165) Acquisition time: 10 min

(166) LCMS Method B (LCMS-B):

(167) Instrument: Agilent 1260 Infinity Series UPLC/MS

(168) Pump: 1260 Infinity G1312B Binary pump

(169) Autosampler: 1260 Infinity G1367E 1260 HiP ALS

(170) Detector: 1290 Infinity G4212A 1290 DAD

(171) LC conditions:

(172) Reverse Phase HPLC analysis

(173) Column: Poroshell 120 EC-C18 2.7 μm 50×3.0 mm

(174) Column temperature: 35° C.

(175) Injection Volume: 1 μL

(176) Solvent A: Water 0.1% Formic Acid

(177) Solvent B: MeCN 0.1% Formic Acid

(178) Gradient: 5-100% solvent B over 3.8 min

(179) Detection: monitored at 254 nm and 214 nm

(180) MS conditions:

(181) Ion Source: Quadrupole

(182) Ion Mode: API-ES

(183) Drying gas temp: 350° C.

(184) Capillary voltage (V): 3000 (positive)

(185) Capillary voltage (V): 3000 (negative)

(186) Scan Range: 100-1000

(187) Step size: 0.1 sec

(188) Acquisition time: 5 min

(189) LCMS Method C (LCMS-C):

(190) Instrument: Agilent 1200 (Pump type: Binary Pump, Detector type: DAD)

(191) MS model: Agilent G6110A Quadrupole

(192) LC Conditions

(193) LC: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm

(194) Column temperature: 30° C.

(195) Acquisition of wavelength: 214 nm, 254 nm

(196) Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

(197) TABLE-US-00002 MS: Ion source: ES+ (or ES−) MS range: 50-900 m/z Fragmentor: 60 Drying gas flow: 10 L/min Nebulizer pressure: 35 psi Drying gas temperature: 350° C. Vcap: 3.5 kV

(198) Gradient Table:

(199) TABLE-US-00003 Flow (mL/min) T (min) A (%) B (%) 0.5 0.0 70 30 0.5 0.2 70 30 0.5 1.8 5 95 0.5 2.4 5 95 0.5 2.6 70 30 0.5 3.5 70 30

(200) Sample Preparation

(201) The sample was dissolved in methanol, the concentration about 0.11˜1 mg/mL, then filtered through syringe filter with 0.22 μm (Injection volume: 1˜10 μL).

(202) LCMS Method D (LCMS-D):

(203) Instrument: Agilent 1200 (Pump type: Binary Pump, Detector type: DAD)

(204) MS model: Agilent G6110A Quadrupole

(205) LC Conditions:

(206) LC: Column: Xbridge-C18, 2.5 μm, 2.1×30 mm

(207) Column temperature: 30° C.

(208) Acquisition of wavelength: 214 nm, 254 nm

(209) Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

(210) TABLE-US-00004 MS: Ion source: ES+ (or ES−) MS range: 50-900 m/z Fragmentor: 60 Drying gas flow: 10 L/min Nebulizer pressure: 35 psi Drying gas temperature: 350° C. Vcap: 3.5 kV

(211) Gradient Table:

(212) TABLE-US-00005 Flow (mL/min) T (min) A (%) B (%) 0.5 0.0 70 30 0.5 0.3 70 30 0.5 0.6 50 50 0.5 0.9 40 60 0.5 1.2 30 70 0.5 3.2 5 95 0.5 3.5 5 95 0.5 4.0 70 30 0.5 5.0 70 30

(213) Sample Preparation

(214) The sample was dissolved in methanol, the concentration about 0.11˜1 mg/mL, then filtered through the syringe filter with 0.22 μm (Injection volume: 1˜10 μL).

(215) LC-MS method E (LCMS-E):

(216) Instrument: Waters 2695 alliance (Pump type: Quaternary Pump, Detector type: 2996

(217) Photodiode Array Detector)

(218) MS model: Micromass ZQ

(219) LC Conditions:

(220) LC Column: Xbridge-C18, 3.5 μm, 2.1×50 mm

(221) Column temperature: 30° C.

(222) Acquisition of wavelength: 214 nm, 254 nm

(223) Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

(224) TABLE-US-00006 MS: Ion source: ES+ (or ES−) MS range: 50-900 m/z Capillary: 3 kV Cone: 3 V Extractor: 3 V Drying gas flow: 600 L/hr Cone: 50 L/hr Desolvation temperature: 300° C.

(225) Source temperature: 100° C.

(226) Gradient Table:

(227) TABLE-US-00007 Flow (mL/min) T (min) A (%) B (%) 0.3 0.0 80 20 0.3 0.5 80 20 0.3 0.8 50 50 0.3 1.2 35 65 0.3 2.0 20 80 0.3 4.0 5 95 0.3 5.0 5 95 0.3 5.8 15 85 0.3 6.2 80 20 0.3 8.0 80 20

(228) Sample Preparation

(229) The sample was dissolved in methanol at a concentration of ˜0.11˜1 mg/mL, then filtered through a 0.22 μm syringe filter (injection volume: 1˜10 μL).

(230) LC-MS method F (LCMS-F):

(231) Instrument: Waters 2695 alliance (Pump type: Quaternary Pump, Detector type: 2996

(232) Photodiode Array Detector)

(233) MS model: Micromass ZQ

(234) LC conditions

(235) LC Column: Xbridge-C18, 2.5 μm, 2.1×30 mm

(236) Column temperature: 30° C.

(237) Acquisition of wavelength: 214 nm, 254 nm

(238) Mobile phase: A: 0.05% HCOOH aqueous solution, B: MeOH

(239) Run time: 5 min

(240) TABLE-US-00008 MS: Ion source: ES+ (or ES−) MS range: 50-900 m/z Capillary: 3.5kV Cone: 35 V Extractor: 3 V Drying gas flow: 350 L/hr cone: 50 L/hr Desolvation temperature: 300° C.

(241) Source temperature: 120° C.

(242) Run time: 5 min

(243) Gradient Table:

(244) TABLE-US-00009 Flow (mL/min) T (min) A (%) B (%) 0.5 0.0 70 30 0.5 0.3 70 30 0.5 0.6 50 50 0.5 0.9 40 60 0.5 1.2 30 70 0.5 3.2 5 95 0.5 3.5 5 95 0.5 4.0 70 30 0.5 5.0 70 30

(245) Sample Preparation

(246) The sample was dissolved in methanol at a concentration of ˜0.11˜1 mg/mL, then filtered through a 0.22 μm syringe filter (injection volume: 1˜10 μL).

(247) Preparative RP-HPLC:

(248) Instrument type: Varian 940-LC series;

(249) Pump type: Quaternary Pump;

(250) Detector type: Diode Array Detector

(251) HPLC conditions: Waters Sunfire prep C18 OBD, 5 μm 19×100 mm column, eluting with a gradient of MeOH in water with 0.07% TFA at a flow rate of 15 mL/min. Acquisition wavelength 214 nm, 254 nm.

(252) Analytical thin-layer chromatography was performed on Merck silica gel 60 F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or a basic KMnO.sub.4 dip or Ninhydrin dip.

(253) Preparative thin-layer chromatography (prep TLC) was performed using Tklst (China), grand grade: (HPTLC): 8±2 μm>80%; (TLC): 10-40 μm. Type: GF254. Compounds were visualised by UV (254 nm).

(254) Flash chromatography was performed using a Biotage Isolera purification system using either Grace or RediSep® silica cartridges.

(255) Column chromatography was performed using Tklst (China), grand grade, 100-200 meshes silica gel.

(256) Microwave irradiation was achieved using a CEM Explorer SP Microwave Reactor.

(257) Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods. Solutions of inorganic acids or bases where made up as aqueous solutions unless stated otherwise.

(258) Additional Cartridges used are as follows:

(259) Phase Separator:

(260) Manufacturer: Biotage

(261) Product: ISOLUTE® Phase Separator (3 mL unless otherwise stated)

(262) SCX and SCX-2 cartridges:

(263) Manufacturer: Biotage

(264) Product: ISOLUTE® SCX 1 g, (6 mL SPE Column unless otherwise stated)

(265) Manufacturer: Biotage

(266) Product: ISOLUTE® SCX-2 1 g (6 mL Column)

(267) Manufacturer: Silicycle

(268) Product: SCX-2 500 mg or 5 g

(269) Manufacturer: Agilent

(270) Product: Bond Elut® SCX 10 g

(271) Sample Extraction Cartridge:

(272) Manufacturer: Waters

(273) Product: Oasis® HLB 35 cc (6 g) LP extraction cartridge

(274) Solutions of hydrogen chloride, sodium hydroxide, potassium carbonate and sodium bicarbonate are aqueous, unless otherwise stated.

Intermediate Preparations

(i) Ethyl 3-methylbenzo[b]thiophene-2-carboxylate (I1)

(275) ##STR00034##

(276) To a solution of 3-methylbenzo[b]thiophene-2-carboxylic acid (800 mg, 4.16 mmol) in EtOH (40 mL) at 0° C. was added SOCl.sub.2 (30 mL) and the mixture was heated at 85° C. overnight then concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 30:1) to give the title product (754 mg, 82%) as a white solid. LCMS-C: rt 2.62 min; m/z 221.0 [M+H].sup.+.

(ii) Ethyl 3-(bromomethyl)-4-fluorobenzo[b]thiophene-2-carboxylate (I3)

(277) ##STR00035##

(278) (a) Ethyl 4-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I2) A solution of 1-(2,6-difluorophenyl)ethanone (5.0 g, 32.0 mmol), ethyl 2-mercaptoacetate (3.85 g, 32.0 mmol) and K.sub.2CO.sub.3 (6.63 g, 48.0 mmol) in DMF (150 mL) was heated at 100° C. overnight. The mixture was cooled to room temperature then poured into water and extracted twice with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by re-crystallization from EtOAc/Pet. Ether to give the title product (5.85 g, 76%) as a white solid. LCMS-C: rt 3.36 min; m/z 239.0 [M+H].sup.+, 260.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.81 (d, J=8.1 Hz, 1H), 7.52 (td, J=8.0, 5.0 Hz, 1H), 7.22 (dd, J=12.3, 8.0 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 2.84 (d, J=2.2 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H).

(b) Ethyl 3-(bromomethyl)-4-fluorobenzo[b]thiophene-2-carboxylate (I3)

(279) A solution of ethyl 4-fluoro-3-methylbenzo[b]thiophene-2-carboxylate 12 (5.10 g, 21.4 mmol), NBS (3.81 g, 21.4 mmol) and BPO (519 mg, 2.14 mmol) in CCl.sub.4 (250 mL) was heated at reflux for 1 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 50:1) to give the title product (6.24 g, 92%) as a white solid. LCMS-D: rt 3.26 min; m/z 338.8, 340.8 [M+Na].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.63 (dd, J=8.1, 0.6 Hz, 1H), 7.46 (td, J=8.0, 4.8 Hz, 1H), 7.18-7.10 (m, 1H), 5.36 (s, 2H), 4.47 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).

(iii) Ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate (I5)

(280) ##STR00036##

(281) (a) Ethyl 4-chloro-3-methylbenzo[b]thiophene-2-carboxylate (I4) A solution of 1-(2-chloro-6-fluorophenyl)ethanone (25.0 g, 145 mmol), ethyl 2-mercaptoacetate (17.4 g, 145 mmol) and K.sub.2CO.sub.3 (30.0 g, 217 mmol) in DMF (200 mL) was heated at 100° C. overnight. The mixture was allowed to cool to room temperature then poured into water (1.0 L) and EtOAc (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL×3). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by re-crystallization from Pet. Ether/EtOAc to give the title product (28.0 g, 76%) as a yellow solid. LCMS-C: rt 2.82 min; m/z 255.0 [M+H].sup.+.

(b) Ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate (I5)

(282) A suspension of ethyl 4-chloro-3-methylbenzo[b]thiophene-2-carboxylate 14 (28.0 g, 0.11 mol), NBS (19.6 g, 0.11 mol) and BPO (2.67 g, 0.011 mol) in CCl.sub.4 (200 mL) was heated at 115° C. for 1.5 h. The mixture was allowed to cool to room temperature then concentrated under reduced pressure and the residue was purified by re-crystallization from DCM/Pet. Ether to give the title product (26.0 g, 71%) as a purple solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (dd, J=8.0, 1.2 Hz, 1H), 7.46 (dd, J=7.6, 0.8 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 5.61 (s, 2H), 4.44 (q, J=7.1 Hz 2H), 1.44 (t, J=7.1 Hz, 3H).

(iv) 3-Aminobenzo[d]isoxazol-6-ol (I8)

(283) ##STR00037##

(a) 2-Fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzonitrile (I6)

(284) A mixture of 2-fluoro-4-hydroxybenzonitrile (5.42 g, 39.6 mmol), 3,4-dihydro-2H-pyran (7.20 mL, 79.1 mmol) and pyridinium p-toluenesulfonate (170 mg, 0.68 mmol) in DCM (100 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100/1 to 1/1) to give title product (7.8 g, 89%) as a white solid. LCMS-C: rt 1.874 min; m/z 221.9 [M+H].sup.+.

(b) 6-((Tetrahydro-2H-pyran-2-yl)oxy)benzo[d]isoxazol-3-amine (I7)

(285) To a solution of N-hydroxyacetamide (7.75 g, 103 mmol) in DMF (180 mL) was added t-BuOK (11.6 g, 103 mmol) portion-wise and the mixture was stirred at room temperature for 1 h. A solution of 2-fluoro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzonitrile 16 (7.6 g, 34 mmol) in DMF (30 mL) was then added and the resulting mixture was stirred at room temperature overnight. Water (200 mL) was added and the mixture was extracted with EtOAc (300 mL×3). The combined organic extracts were washed with water (500 mL×3), brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100/1 to 0/1) to give the title product (4.0 g, 49%) as a grey solid. LCMS-C: rt 1.291 min; m/z 235.0 [M+H].sup.+.

(286) To a solution of 6-((tetrahydro-2H-pyran-2-yl)oxy)benzo[d]isoxazol-3-amine 17 (1.37 g, 5.85 mmol) in MeOH (30 mL) was added aqueous 1 M HCl (10 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=100/1 to 30/1) to give the title product (600 mg, 68%) as a light yellow solid. LCMS-C: rt 0.78 min; m/z 151.0 [M+H].sup.+.

(v) 3-Chloro-4-hydroxybenzamide (I9)

(287) ##STR00038##

(288) A mixture of 3-chloro-4-hydroxybenzonitrile (300 mg, 1.96 mmol) and concentrated sulfuric acid (15 mL) was stirred at room temperature overnight. The mixture was poured slowly into water (200 mL) and extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title product (300 mg, 89%) as a pale yellow solid. LCMS-C: rt 0.99 min, m/z 172.0 [M+H].sup.+.

(vi) 4-Hydroxy-3,5-dimethoxybenzamide (I10)

(289) ##STR00039##

(290) To a solution of 4-hydroxy-3,5-dimethoxybenzoic acid (200 mg, 1.01 mmol) in DCM (2 mL) and THF (5 mL) at 0° C. was added oxalyl chloride (641 mg, 5.05 mmol) drop-wise followed by DMF (two drops) and the mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in THF (5 mL) and added drop-wise to a concentrated aqueous ammonia solution (20 mL). The mixture was stirred at room temperature for 20 min. The resulting precipitate was collected by filtration, washed with water (20 mL) and dried to give the title product (250 mg, 91%) as a light yellow solid. LCMS-C: rt 0.38 min, m/z 198.0 [M+H].sup.+.

(vii) 5-Hydroxypicolinamide (I11)

(291) ##STR00040##

(292) A suspension of 5-hydroxypicolinic acid (1 g, 7.2 mmol), NH.sub.4Cl (3.8 g, 72 mmol), HATU (3.3 g, 8.64 mmol) and DIPEA (2.8 g, 21.6 mmol) in DMF (20 mL) was stirred at room temperature overnight. Water (100 mL) was added and the mixture was extracted with

(293) EtOAc (50 mL×3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title product (65 mg, 7%) as a white solid. LCMS-C: rt 0.98 min, m/z 139.1 [M+H].sup.+.

(viii) 3,5-Dichloro-4-hydroxybenzamide (I12)

(294) ##STR00041##

(295) Prepared from 3,5-dichloro-4-hydroxybenzonitrile according to the procedure described for 3-chloro-4-hydroxybenzamide 19. LCMS-C: rt 1.13 min, m/z 205.9 [M+H].sup.+.

(ix) 4-Hydroxy-3-methoxybenzamide (I13)

(296) ##STR00042##

(297) Prepared from 4-hydroxy-3-methoxybenzonitrile according to the procedure described for 3-chloro-4-hydroxybenzamide 19. LCMS-C: rt 0.33 min, m/z 168.0 [M+H].sup.+.

(x) 3-Cyano-4-hydroxybenzamide (I14)

(298) ##STR00043##

(299) Prepared from 3-cyano-4-hydroxybenzoic acid according to the procedure described for 4-hydroxy-3,5-dimethoxybenzamide 110. LCMS-C: rt 0.34 min, m/z 162.9 [M+H].sup.+.

(xi) 2-Bromo-4-hydroxybenzonitrile (I15)

(300) ##STR00044##

(301) To a solution of 2-bromo-4-methoxybenzonitrile (1.0 g, 4.7 mmol) in DCM (15 mL) was added BBr.sub.3 (1 M solution in DCM, 14.2 mL, 14.2 mmol) and the mixture was heated at 50° C. overnight. The mixture was quenched with methanol and then poured into water and extracted with EtOAc (200 mL). The organic extract was washed with water (200 mL), brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=5:1) to give the title product (700 mg, 75%) as a white solid. LCMS-C: rt 0.93 min; m/z 197.9 [M+H].sup.+.

(xii) 3-Bromo-5-fluoro-4-hydroxybenzamide (I16)

(302) ##STR00045##

(303) 3-Fluoro-4-hydroxybenzonitrile (2.00 g, 14.6 mmol) was dissolved in acetic acid (20 mL) and bromine (0.785 mL, 15.3 mmol) was added dropwise. The mixture was stirred at room temperature for two hours then diluted with water (100 mL). The resulting precipitate was collected by filtration, washed with water (4×50 mL) and air dried. The precipitate was dissolved in DMSO (100 mL) and potassium carbonate (3.02 g, 21.9 mmol) was added. The mixture was stirred for five minutes then cooled with a room temperature water bath while 30% w/w aq. hydrogen peroxide (4.51 mL, 43.8 mmol) was added. The mixture was stirred at room temperature for two hours. Additional 30% w/w aq. hydrogen peroxide (4.51 mL, 43.8 mmol) was added and the mixture was stirred overnight. Another addition of 30% w/w aq hydrogen peroxide (4.51 mL, 43.8 mmol) was made and the mixture again stirred overnight. The mixture was added to water (500 mL) and the pH adjusted to ˜1 with aq. HCl (1 M). Brine (100 mL) was added and the mixture extracted with ethyl acetate (3×200 mL). The pooled ethyl acetate phases were washed with aq. HCl (0.5 M, 2×300 mL), brine (300 mL), dried over sodium sulfate and concentrated in vacuo. The residue was recrystallised from methanol to give the title compound as a white solid (0.716 g, 21% yield). LCMS-B rt 2.48 min; m/z 231.8 [M−H].sup.−.

(xiii) Ethyl 4-chloro-5-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I23) and Ethyl 4,7-difluoro-3-methylbenzo[b]thiophene-2-carboxylate (I24)

(304) ##STR00046##

(a) 1-(2-Chloro-3,6-difluorophenyl)ethan-1-ol (I21)

(305) To a solution of 2-chloro-3,6-difluorobenzaldehyde (5 g, 28 mmol) in dry THF (60 mL) at 0° C. under nitrogen was added methyl magnesium bromide (3 M solution in THF, 40 mL, 113 mmol) dropwise and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution (200 mL) was added and the mixture was extracted with EtOAc (150 mL×2). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (5.35 g, 98%) as a white solid. LCMS-C: rt 1.98 min; m/z 192.9 [M+H].sup.+.

(b) 1-(2-Chloro-3,6-difluorophenyl)ethan-1-one (I22)

(306) To a solution of 1-(2-chloro-3,6-difluorophenyl)ethan-1-ol 121 (5.35 g, 27.9 mmol) in acetone (150 mL) at 0° C. was added a solution of CrO.sub.3 (3.8 g, 38 mmol) and concentrated sulfuric acid (4 mL) in water (15 mL) dropwise over 1 h. Water (150 mL) was then added and the mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=1:0 to 100:1) to afford the title compound (4 g, 75%) as a pale yellow oil. LCMS-C: rt 0.98 min; m/z 191.0 [M+H].sup.+.

(c) Ethyl 4-chloro-5-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I23) and Ethyl 4,7-difluoro-3-methylbenzo[b]thiophene-2-carboxylate (I24)

(307) A suspension of 1-(2-chloro-3,6-difluorophenyl)ethan-1-one 122 (1.15 g, 6.05 mmol), ethyl 2-mercaptoacetate (727 mg, 6.05 mmol) and K.sub.2CO.sub.3 (1.26 g, 9.08 mmol) in DMF (20 mL) was heated at 50° C. overnight. The mixture was cooled to room temperature then poured into water and extracted with EtOAc (150 mL×2). The combined organic extracts were washed with water (150 mL×2), brine (150 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=1:0 to 100:1) followed by C18 reverse-phase chromatography (95% MeOH, 4% H.sub.2O, 1% TFA) to afford ethyl 4-chloro-5-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I23) (247 mg, 15%) as a white solid, LCMS-C: rt 2.89 min; m/z 272.9 [M+H].sup.+ and ethyl 4,7-difluoro-3-methylbenzo[b]thiophene-2-carboxylate (I24) (520 mg, 32%) as a white solid, LCMS-C: rt 2.89 min; m/z 256.9, [M+H].sup.+.

(xiv) 3,5-Difluoro-4-hydroxybenzamide (I25)

(308) ##STR00047##

(309) Prepared from 3,5-difluoro-4-hydroxybenzonitrile according to the procedure described for 3-chloro-4-hydroxybenzamide 19. LCMS-C: R10.34 min; m/z 174.0 [M+H].sup.+.

(xv) Ethyl 3-(bromomethyl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate (I29)

(310) ##STR00048##

(a) 1-(4-Bromo-2-methoxypyridin-3-yl)ethan-1-ol (I26)

(311) To a solution of diisopropylamine (2.9 g, 28.7 mmol) in dry THF (30 mL) at −78° C. under nitrogen was added n-BuLi (2.5 M solution in hexanes, 12.5 mL, 31.1 mmol) dropwise and the mixture was stirred at −78° C. for 45 min. The resulting LDA solution was then added slowly to a solution of 4-bromo-2-methoxypyridine (4.5 g, 23.9 mmol) in THF (30 mL) at −78° C. and the mixture was stirred at −78° C. for 1 h. A solution of acetaldehyde (3.2 g, 71.8 mmol) in THF (20 mL) was then added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. A saturated aqueous NH.sub.4Cl solution (150 mL) was added and the mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (3.70 g, 67%) as a yellow oil. LCMS-C: rt 1.32 min; m/z 233.9 [M+H].sup.+.

(b) 1-(4-Bromo-2-methoxypyridin-3-yl)ethan-1-one (I27)

(312) To a solution of 1-(4-bromo-2-methoxypyridin-3-yl)ethan-1-ol (I26) (3.70 g, 15.9 mmol) in dichloromethane (200 mL) was added MnO.sub.2 (13.9 g, 159 mmol) and the mixture was heated at reflux overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 80:1) to give the title compound (2.21 g, 60%) as a yellow oil. LCMS-C: rt 1.72 min; m/z 229.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.11 (d, J=5.5 Hz, 1H), 7.34 (d, J=5.5 Hz, 1H), 3.91 (s, 3H), 2.47 (s, 3H).

(313) A suspension of 1-(4-bromo-2-methoxypyridin-3-yl)ethan-1-one (I27) (2.21 g, 9.6 mmol), ethyl 2-mercaptoacetate (1.39 g, 11.5 mmol) and K.sub.2CO.sub.3 (3.98 g, 28.8 mmol) in DMF (50 mL) was stirred at room temperature under nitrogen overnight. The mixture was poured into water and extracted with EtOAc (350 mL×3). The combined organic extracts were washed with brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 80:1) to give the title compound (835 mg, 35%) as a white solid. LCMS-F: rt 3.46 min; m/z 252.1 [M+H].sup.+.

(d) Ethyl 3-(bromomethyl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate (I29)

(314) To a solution of ethyl 4-methoxy-3-methylthieno[3,2-c]pyridine-2-carboxylate (I28) (735 mg, 2.92 mmol) in 0014 (25 mL) was added NBS (531 mg, 2.98 mmol) and BPO (95 mg, 0.29 mmol) and the mixture was heated at reflux under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 40:1) to give the title compound (742 mg, 77%) as a white solid. LCMS-F: rt 3.47 min; m/z 330.0/332.0 [M+H].sup.+.

(xvi) Ethyl 7-bromo-3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate (I34)

(315) ##STR00049##

(a) 3-Bromo-6-chloro-2-fluorobenzaldehyde (I30)

(316) To a solution of 1-bromo-4-chloro-2-fluorobenzene (10.0 g, 47.8 mmol) in dry THF (300 mL) at −78° C. under nitrogen was added LDA (2.0 M solution in THF, 31 mL, 62.1 mmol) dropwise and the mixture was stirred at −78° C. for 15 min. DMF (7.00 g, 95.8 mmol) was added and the mixture was allowed to warm to room temperature. The reaction mixture was quenched with a saturated aqueous NH.sub.4Cl solution and the mixture was extracted with EtOAc (400 mL×3). The combined organic extracts were washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% Pet. Ether) to give the title compound (4.0 g, 35%) as a white solid, which was used directly in the next step.

(b) 1-(3-Bromo-6-chloro-2-fluorophenyl)ethan-1-ol (I31)

(317) To a solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (I30) (4.00 g, 16.8 mmol) in dry THF (48 mL) at 0° C. under nitrogen was added methyl magnesium bromide (3 M solution in THF, 7 mL, 20.5 mmol) dropwise and the mixture was allowed to warm to room temperature and stirred overnight. A saturated aqueous NH.sub.4Cl solution (40 mL) was added and the mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=200:1 to 5:1) to give the title compound (3.58 g, 84%) as a yellow oil. LCMS-C: rt 2.10 min; m/z 275.9/277.9 [M+H].sup.+.

(318) To a solution of 1-(3-bromo-6-chloro-2-fluorophenyl)ethan-1-ol (I31) (3.58 g, 14.1 mmol) in dichloromethane (200 mL) was added MnO.sub.2 (12.3 g, 141.2 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (2.0 g, 56%) as a yellow oil. LCMS-F: rt 2.59 min; m/z 250.9 [M+H].sup.+.

(d) Ethyl 7-bromo-4-chloro-3-methylbenzo[b]thiophene-2-carboxylate (I33)

(319) A suspension of 1-(3-bromo-6-chloro-2-fluorophenyl)ethan-1-one (I32) (2.0 g, 7.95 mmol), ethyl 2-mercaptoacetate (1.15 g, 9.57 mmol) and K.sub.2CO.sub.3 (3.3 g, 23.9 mmol) in DMF (160 mL) was stirred at room temperature under nitrogen overnight. The mixture was poured into water and extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (2.0 g, 76%) as a white solid, which was used directly in the next step.

(e) Ethyl 7-bromo-3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate (I34)

(320) A mixture of ethyl 7-bromo-4-chloro-3-methylbenzo[b]thiophene-2-carboxylate (I33) (2.0 g, 6.0 mmol), NBS (1.09 g, 6.12 mmol) and BPO (194 mg, 0.60 mmol) in 0014 (50 mL) was heated at reflux under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (2.20 g, 89%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.86 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 5.51 (s, 2H), 4.43 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).

(xvii) Ethyl 5-(bromomethyl)-4-methoxythieno[2,3-d]pyrimidine-6-carboxylate (I37)

(321) ##STR00050##

(a) Ethyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (I35)

(322) To a solution of 1-(4,6-dichloropyrimidin-5-yl)ethan-1-one (1.00 g, 5.24 mmol) in DMF (30 mL) was added ethyl 2-mercaptoacetate (755 mg, 6.29 mmol) and K.sub.2CO.sub.3 (2.17 g, 15.7 mmol) and the mixture was stirred at room temperature under nitrogen overnight. The mixture was poured into water and extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=200:1 to 40:1) to give the title compound (276 mg, 41%) as a white solid.

(323) LCMS-F: rt 3.12 min; m/z 257.0 [M+H].sup.+.

(b) Ethyl 4-methoxy-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (I36)

(324) A mixture of ethyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (I35) (576 mg, 2.24 mmol) and sodium methoxide (303 mg, 5.60 mmol) in THF (30 mL) was stirred at room temperature under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 50:1) to give the title compound (116 mg, 21%) as a white solid. LCMS-F: rt 3.15 min; m/z 253.1 [M+H].sup.+.

(325) To a solution of ethyl 4-methoxy-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (I36) (183 mg, 0.73 mmol) in 0014 (10 mL) was added NBS (132 mg, 0.75 mmol) and BPO (24 mg, 0.07 mmol) and the mixture was heated at reflux under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 50:1) to give the title compound (160 mg, 67%) as a white solid. LCMS-F: rt 3.15 min; m/z 330.9/332.9 [M+H].sup.+.

(xviii) Ethyl 3-(bromomethyl)-4-ethoxybenzo[b]thiophene-2-carboxylate (I40)

(326) ##STR00051##

(a) Ethyl 4-hydroxy-3-methylbenzo[b]thiophene-2-carboxylate (I38)

(327) To a solution of 1-(2-fluoro-6-hydroxyphenyl)ethan-1-one (2.0 g, 3.24 mmol) in DMF (20 mL) was added ethyl 2-mercaptoacetate (2.4 g, 4.86 mmol) and K.sub.2CO.sub.3 (3.6 g, 26.1 mmol) and the mixture was heated at 100° C. under nitrogen overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were washed with water (100 mL×3), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 10:1) to give the title compound (1.8 g, 60%) as a grey solid. LCMS-C: rt 2.64 min; m/z 259.0 [M+Na].sup.+.

(b) Ethyl 4-ethoxy-3-methylbenzo[b]thiophene-2-carboxylate (I39)

(328) A mixture of ethyl 4-hydroxy-3-methylbenzo[b]thiophene-2-carboxylate (I38) (300 mg, 1.27 mmol), K.sub.2CO.sub.3 (877 mg, 6.34 mmol) and ethyl iodide (6 mL) in DMF (10 mL) was stirred at room temperature in a sealed tube overnight. The mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 50:1) to give the title compound (230 mg, 68%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.50 (d, J=7.6 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 4.16 (q, J=6.9 Hz, 2H), 2.94 (s, 3H), 1.43 (t, J=6.9 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H).

(329) A suspension of ethyl 4-ethoxy-3-methylbenzo[b]thiophene-2-carboxylate (I39) (200 mg, 0.76 mmol), NBS (136 mg, 0.76 mmol) and AIBN (63 mg, 0.38 mmol) in 0014 (10 mL) was heated at reflux overnight. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (200 mg, 77%) as a white solid. LCMS-D: rt 3.38 min; m/z 364.9/366.9 [M+Na].sup.+.

(xix) Ethyl 3-(bromomethyl)-4-(methoxymethyl)benzo[b]thiophene-2-carboxylate (I46)

(330) ##STR00052##

(a) 1-Fluoro-3-(methoxymethyl)benzene (I41)

(331) To a solution of (3-fluorophenyl)methanol (15 g, 0.12 mol) in DMF (30 mL) at 0° C. was added NaH (60% dispersion in oil, 9.6 g, 0.24 mol) and the mixture was stirred for 30 min. Mel (15 mL, 0.24 mol) was then added and the mixture was allowed to warm to room temperature and stirred for 2 h. Water (300 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were washed with water (150 mL×3), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (7.3 g, 43%) as a colorless oil. LCMS-C: rt 1.98 min; m/z 163.0 [M+Na].sup.+.

(b) 2-Fluoro-6-(methoxymethyl)benzaldehyde (I42)

(332) To a solution of diisopropylamine (2.61 g, 25.8 mmol) in THF (20 mL) at −78° C. was added n-BuLi (2.5 M solution in hexanes, 11.2 mL, 28 mmol) and the mixture was stirred for 40 min. The resulting LDA solution was then added to a solution of 1-fluoro-3-(methoxymethyl)benzene (I41) (3.0 g, 21.5 mmol) in THF (20 mL) dropwise at −78° C. and the mixture was stirred for 1 h. A solution of DMF (2.1 mL, 25.8 mmol) in THF (10 mL) was then added dropwise and the mixture was stirred at −78° C. for a further 30 min. The reaction mixture was quenched with a saturated aqueous NH.sub.4Cl solution (30 mL) and the mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL×3). The combined organic extracts were washed with water (150 mL×3), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (400 mg, 11%) as a yellow oil. LCMS-C: rt 1.19 min; m/z 169.0 [M+H].sup.+.

(333) To a solution of 2-fluoro-6-(methoxymethyl)benzaldehyde (I42) (636 mg, 3.8 mmol) in dry THF (20 mL) at 0° C. was added methyl magnesium bromide (3.0 M solution in THF, 5.0 mL, 15.2 mmol) dropwise and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with a saturated aqueous NH.sub.4Cl solution (10 mL) and then extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 50:1) to give the title compound (550 mg, 79%) as a yellow oil. LCMS-C: rt 0.86 min; m/z 207.0 [M+Na].sup.+.

(d) 1-(2-Fluoro-6-(methoxymethyl)phenyl)ethan-1-one (I44)

(334) To a solution of 1-(2-fluoro-6-(methoxymethyl)phenyl)ethan-1-ol (I43) (550 mg, 3.0 mmol) in acetone (8 mL) at 0° C. was added a solution of CrO.sub.3 (420 mg, 4.2 mmol) and concentrated H.sub.2SO.sub.4 (1 mL) in water (3 mL) dropwise. The mixture was stirred at 0° C. for 1 h then diluted with water (5 mL) and extracted with EtOAc (100 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 50:1) to give the title compound (516 mg, 94%) as a yellow oil. LCMS-C: rt 1.43 min; m/z 205.0 [M+Na].sup.+.

(e) Ethyl 4-(methoxymethyl)-3-methylbenzo[b]thiophene-2-carboxylate (I45)

(335) A mixture of 1-(2-fluoro-6-(methoxymethyl)phenyl)ethan-1-one (I44) (516 mg, 2.84 mmol), ethyl 2-mercaptoacetate (517 mg, 4.2 mmol) and K.sub.2CO.sub.3 (785 mg, 5.68 mmol) in DMF (30 mL) was heated at 120° C. overnight. The mixture was allowed to cool to room temperature before being partitioned between water (300 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (365 mg, 49%) as a yellow oil. LCMS-C: rt 2.55 min; m/z 265.0 [M+H].sup.+.

(f) Ethyl 3-(bromomethyl)-4-(methoxymethyl)benzo[b]thiophene-2-carboxylate (I46)

(336) A suspension of ethyl 4-(methoxymethyl)-3-methylbenzo[b]thiophene-2-carboxylate (I45) (350 mg, 1.3 mmol), NBS (285 mg, 1.6 mmol) and BPO (32 mg, 0.13 mmol) in CCl.sub.4 (10 mL) was heated at reflux for 1.5 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (230 mg, 52%) as a white solid. LCMS-C: rt 2.78 min; m/z 342.9 [M+H].sup.+.

(xx) Ethyl 4-bromo-3-(bromomethyl)-7-fluorobenzo[b]thiophene-2-carboxylate (I52)

(337) ##STR00053##

(a) 6-Bromo-2,3-difluorobenzaldehyde (I47)

(338) To a solution of 4-bromo-1,2-difluorobenzene (5.0 g, 25.9 mmol) in dry THF (200 mL) at −78° C. under nitrogen was added LDA (2.0 M solution in THF, 17 mL, 33.7 mmol) dropwise and the mixture was stirred at −78° C. for 15 min. DMF (3.8 g, 51.8 mmol) was then added slowly and the mixture was allowed to warm to room temperature. The reaction mixture was quenched with a saturated aqueous NH.sub.4Cl solution and then extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% Pet. Ether) to give the title compound (1.3 g, 23%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.3 (t, J=1.2 Hz, 1H), 7.77-7.66 (m, 2H).

(b) 1-(6-Bromo-2,3-difluorophenyl)ethan-1-ol (I48)

(339) To a solution of 6-bromo-2,3-difluorobenzaldehyde (I47) (1.86 g, 8.46 mmol) in dry THF (25 mL) at 0° C. under nitrogen was added methyl magnesium bromide (3 M solution in THF, 3.5 mL, 10.3 mmol) dropwise before the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with 2 M aqueous HCl and then extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 5:1) to give the title compound (1.73 g, 93%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.48-7.43 (m, 1H), 7.37-7.28 (m, 1H), 5.57 (d, J=4.4 Hz, 1H), 5.20-5.11 (m, 1H), 1.44 (d, J=6.7, 1.0 Hz, 3H).

(340) A mixture of 1-(6-bromo-2,3-difluorophenyl)ethan-1-ol (I48) (1.73 g, 7.30 mmol) and MnO.sub.2 (6.34 g, 73.0 mmol) in dichloromethane (100 mL) was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=100:1 to 5:1) to give the title compound (850 mg, 49%) as a yellow oil, which was used directly in the next step. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63-7.51 (m, 2H), 2.59 (d, J=1.1 Hz, 3H).

(d) Ethyl 4-bromo-7-fluoro-3-hydroxy-3-methyl-2,3-dihydrobenzo[b]thiophene-2-carboxylate (I50)

(341) To a solution of 1-(6-bromo-2,3-difluorophenyl)ethan-1-one (I49) (855 mg, 3.64 mmol) in DMF (100 mL) was added ethyl 2-mercaptoacetate (525 mg, 4.37 mmol) and K.sub.2CO.sub.3 (1.50 g, 10.9 mmol) and the mixture was stirred at room temperature overnight. The mixture was poured into water (400 mL), extracted with EtOAc (400 mL×3) and the combined organic extracts were washed with brine (400 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 20:1) to give the title compound (726 mg, 63%) as a yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.36 (dd, J=8.7, 4.8 Hz, 1H), 7.12 (t, J=8.7 Hz, 1H), 6.27 (s, 1H), 4.75 (s, 1H), 4.26-4.16 (m, 2H), 1.44 (s, 3H), 1.24 (t, J=7.1 Hz, 3H).

(e) Ethyl 4-bromo-7-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I51)

(342) To a solution of ethyl 4-bromo-7-fluoro-3-hydroxy-3-methyl-2,3-dihydrobenzo[b]thiophene-2-carboxylate (I50) (950 mg, 2.84 mmol) in DMF (70 mL) was added K.sub.2CO.sub.3 (1.65 g, 11.9 mmol) and the mixture was heated at 75° C. for 2 h. The mixture was poured into water (300 mL) and extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (902 mg, 100%) as a white solid, which was used directly in the next step.

(f) Ethyl 4-bromo-3-(bromomethyl)-7-fluorobenzo[b]thiophene-2-carboxylate (I52)

(343) A mixture of ethyl 4-bromo-7-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I51) (1.0 g, 3.15 mmol), NBS (572 mg, 3.21 mmol) and BPO (102 mg, 0.32 mmol) in 0014 (50 mL) was heated at reflux under nitrogen for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 40:1) to give the title compound (660 mg, 53%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.85 (dd, J=8.5, 4.9 Hz, 1H), 7.46 (t, J=8.8 Hz, 1H), 5.55 (s, 2H), 4.42 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).

(xxi) Ethyl 3-(bromomethyl)-4-chloro-7-fluorobenzo[b]thiophene-2-carboxylate (I56)

(344) ##STR00054##

(a) 1-(6-Chloro-2,3-difluorophenyl)ethan-1-ol (I53)

(345) To a solution of 6-chloro-2,3-difluorobenzaldehyde (1.0 g, 5.67 mmol) in dry THF (30 mL) under nitrogen was added methyl magnesium bromide (3 M solution in THF, 7.6 mL, 22.7 mmol) dropwise and the mixture was allowed to warm to room temperature and stirred overnight. A saturated aqueous NH.sub.4Cl solution (100 mL) was added and the mixture was extracted with EtOAc (100 mL×2). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (1.44 g, >100%), which was used in the next step without further purification. LCMS-C: rt 1.22 min; m/z 192.9 [M+H].sup.+.

(b) 1-(6-Chloro-2,3-difluorophenyl)ethan-1-one (I54)

(346) To a solution of 1-(6-chloro-2,3-difluorophenyl)ethan-1-ol (I53) (1.44 g) in acetone (15 mL) at 0° C. was added a solution of CrO.sub.3 (1.01 g, 10.1 mmol) and concentrated sulfuric acid (2 mL) in water (7 mL) dropwise. The mixture was stirred at 0° C. for 1 h then diluted with water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 10:1) to give the title compound (960 mg, 89% over two steps) as a pale yellow oil. LCMS-C: rt 1.34 min; m/z 191.0 [M+H].sup.+.

(347) A suspension of 1-(6-chloro-2,3-difluorophenyl)ethan-1-one (I54) (480 mg, 2.53 mmol), ethyl 2-mercaptoacetate (305 mg, 2.53 mmol) and K.sub.2CO.sub.3 (524 mg, 3.79 mmol) in DMF (20 mL) was heated at 50° C. under nitrogen overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic extracts were washed with water (100 mL×3), brine (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (740 mg, >100%) as a pale yellow solid. The material was used in the next step without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.53 (dd, J=8.5, 4.7 Hz, 1H), 7.41 (t, J=8.7 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.98 (s, 3H), 1.33 (t, J=7.1 Hz, 3H).

(d) Ethyl 3-(bromomethyl)-4-chloro-7-fluorobenzo[b]thiophene-2-carboxylate (I56)

(348) A suspension of ethyl 4-chloro-7-fluoro-3-methylbenzo[b]thiophene-2-carboxylate (I55) (740 mg), NBS (581 mg, 3.27 mmol) and BPO (66 mg, 0.27 mmol) in 0014 (25 mL) was heated at reflux under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (840 mg, 95% over two steps) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.67-7.60 (m, 1H), 7.50 (t, J=8.7 Hz, 1H), 5.47 (s, 2H), 4.41 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H).

(xxii) Ethyl 3-(bromomethyl)-4-chlorothieno[3,2-c]pyridine-2-carboxylate (I60)

(349) ##STR00055##

(a) 1-(2,4-Dichloropyridin-3-yl)ethan-1-ol (I57)

(350) To a solution of diisopropylamine (4.1 g, 40.6 mmol) in dry THF (30 mL) at −78° C. under nitrogen was added n-BuLi (2.5 M solution in hexane, 17.6 mL, 43.9 mmol) dropwise and the mixture was stirred at −78° C. for 45 min. The resulting LDA solution was added slowly to a solution of 2,4-dichloropyridine (5.0 g, 33.8 mmol) in THF (30 mL) and the mixture was stirred at −78° C. for 1 h. A solution of acetaldehyde (4.5 g, 101 mmol) in THF (20 mL) was added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. A saturated aqueous NH.sub.4Cl solution (200 mL) was added and the mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with a saturated aqueous NH.sub.4Cl solution, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=100:1 to 10:1) to give the title compound (2.7 g, 42%) as a yellow oil. LCMS-C: rt 0.64 min; m/z 191.9/193.9 [M+H].sup.+.

(b) 1-(2,4-Dichloropyridin-3-yl)ethan-1-one (I58)

(351) Freshly activated 4 Å molecular sieves (3.5 g) and NMO (2.5 g, 21.2 mmol) were added to a solution of 1-(2,4-dichloropyridin-3-yl)ethan-1-ol (I57) (2.7 g, 14.1 mmol) in DCM (30 mL) and the mixture was stirred for 15 min. TPAP (248 mg, 0.71 mmol) was added and the mixture was stirred at room temperature for 2 h. The solids were removed by filtration and the filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 30:1) to give the title compound (2.4 g, 90%) as a pale yellow oil. LCMS-C: rt 1.17 min; m/z 189.9 [M+H].sup.+.

(352) A suspension of 1-(2,4-dichloropyridin-3-yl)ethan-1-one (I58) (400 mg, 2.12 mmol), ethyl 2-mercaptoacetate (255 mg, 2.12 mmol) and K.sub.2CO.sub.3 (440 mg, 3.18 mmol) in DMF (15 mL) was heated at 50° C. for 12 h and then at 70° C. overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic extracts were washed with water (100 mL×3), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (500 mg, 92%) as a white solid. LCMS-C: rt 2.42 min; m/z 255.9 [M+H].sup.+.

(d) Ethyl 3-(bromomethyl)-4-chlorothieno[3,2-c]pyridine-2-carboxylate (I60)

(353) A mixture of ethyl 4-chloro-3-methylthieno[3,2-c]pyridine-2-carboxylate (I59) (489 mg, 1.92 mmol), NBS (684 mg, 3.84 mmol) and BPO (47 mg, 0.2 mmol) in CCl.sub.4 (20 mL) was heated at reflux for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (500 mg, 78%) as a white solid. LCMS-C: rt 2.53 min; m/z 333.8 [M+H].sup.+.

(xxiii) Ethyl 4-bromo-3-(bromomethyl)benzo[b]thiophene-2-carboxylate (I62)

(354) ##STR00056##

(a) Ethyl 4-bromo-3-methylbenzo[b]thiophene-2-carboxylate (I61)

(355) A solution of 1-(2-bromo-6-fluorophenyl)ethanone (2.85 g, 13.1 mmol), ethyl 2-mercaptoacetate (2.37 g, 19.7 mmol) and K.sub.2CO.sub.3 (3.63 g, 26.3 mmol) in DMF (30 mL) was heated at 100° C. overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (200 mL×3). The combined organic extracts were washed with water (200 mL×3), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (1.85 g, 47%) as a white solid. LCMS-C: rt 2.23 min; m/z 299.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06 (dd, J=8.1, 1.0 Hz, 1H), 7.87-7.76 (m, 1H), 7.73 (dd, J=7.7, 1.0 Hz, 1H), 4.34 (q, J=8.0 Hz, 2H), 3.05 (s, 3H), 1.32 (t, J=8.0 Hz, 3H).

(b) Ethyl 4-bromo-3-(bromomethyl)benzo[b]thiophene-2-carboxylate (I62)

(356) A suspension of ethyl 4-bromo-3-methylbenzo[b]thiophene-2-carboxylate (I61) (1.82 g, 6.15 mmol), NBS (1.2 g, 6.77 mmol) and BPO (149 mg, 0.615 mmol) in 0014 (40 mL) was heated at reflux for 1.5 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc (200 mL×3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 100:1) to give the title compound (1.88 g, 82%) as a white solid. LCMS-C: rt 2.27 min; m/z 376.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (d, J=8.1 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 5.59 (s, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.8 Hz, 3H).

(xxiv) 3-Fluoro-4-hydroxy-5-(hydroxymethyl)benzamide (I69)

(357) ##STR00057##

(a) 5-Bromo-3-fluoro-2-hydroxybenzaldehyde (I63)

(358) To a solution of 3-fluoro-2-hydroxybenzaldehyde (3.43 g, 24.5 mmol) in acetonitrile (30 mL) under nitrogen was added NBS (4.36 g, 24.5 mmol) and ammonium acetate (189 mg, 2.45 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (5.0 g, 94%) as a white solid. LCMS-F: rt 3.70 min; m/z 217.0/219.0 [M−H].sup.−.

(b) 4-Bromo-2-fluoro-6-(hydroxymethyl)phenol (I64)

(359) To a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (I63) (5.0 g, 23.0 mmol) in MeOH (50 mL) at 0° C. was added NaBH.sub.4 (1.8 g, 45.9 mmol) portion-wise over 30 min. The mixture was then allowed to warm to room temperature and stirred overnight. The mixture was acidified with a 2 M aqueous HCl solution and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (6.5 g, >100%) as a brown solid, which was used in the next step without further purification. LCMS-F: rt 3.01 min; m/z 219.0/221.0 [M−H].sup.−.

(360) To a solution of 4-bromo-2-fluoro-6-(hydroxymethyl)phenol (I64) (5.35 g, 27.9 mmol) in DMF (300 mL) was added benzyl bromide (7.6 g, 44.3 mmol) and K.sub.2CO.sub.3 (12.3 g, 88.6 mmol) and the mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=20:1) to give the title compound (6.8 g, 74%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.49 (dd, J=10.8, 2.5 Hz, 1H), 7.45-7.32 (m, 6H), 5.45-5.40 (m, 1H), 5.04 (s, 2H), 4.45 (d, J=5.7 Hz, 2H).

(d) Methyl 4-(benzyloxy)-3-fluoro-5-(hydroxymethyl)benzoate (I66)

(361) A mixture of (2-(benzyloxy)-5-bromo-3-fluorophenyl)methanol (I65) (6.8 g, 21.9 mmol), Pd(dppf)Cl.sub.2 (800 mg, 1.1 mmol) and triethylamine (6.6 g, 65.6 mmol) in methanol (20 mL) was heated at 110° C. in a sealed tube under a carbon monoxide atmosphere overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=10:1) to give the title compound (2.0 g, 32%) as a yellow oil. LCMS-F: rt 3.92 min; m/z 313.1 [M+Na]+.sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.89 (s, 1H), 7.66 (dd, J=12.0, 2.1 Hz, 1H), 7.47-7.30 (m, 5H), 5.37 (t, J=5.5 Hz, 1H), 5.18 (s, 2H), 4.51 (d, J=4.4 Hz, 2H), 3.85 (s, 3H).

(e) 4-(Benzyloxy)-3-fluoro-5-(hydroxymethyl)benzoic acid (167)

(362) To a solution of methyl 4-(benzyloxy)-3-fluoro-5-(hydroxymethyl)benzoate (I66) ZXW-785-093 (2.0 g, 6.9 mmol) in THF/H.sub.2O (50 mL/25 mL) was added LiOH.H.sub.2O (867 mg, 20.7 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with water (30 mL), acidified to pH 4-5 with a 2 M aqueous HCl solution and the resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (1.8 g, 95%) as a white solid. LCMS-F: rt 2.25 min; m/z 299.0 [M+Na].sup.+.

(f) 4-(Benzyloxy)-3-fluoro-5-(hydroxymethyl)benzamide (I68)

(363) To a solution of 4-(benzyloxy)-3-fluoro-5-(hydroxymethyl)benzoic acid (167) (1.8 g, 6.0 mmol) in DMF (20 mL) was added NH.sub.4Cl (691 mg, 13.0 mmol) and the mixture was stirred at room temperature for 30 min. HATU (3.0 g, 7.8 mmol) and DIPEA (2.5 g, 19.5 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=20:1 to 10:1) to give the title compound (1.5 g, 83%) as a yellow oil. LCMS-F: rt 1.14 min; m/z 275.9 [M+H].sup.+.

(g) 3-Fluoro-4-hydroxy-5-(hydroxymethyl)benzamide (I69)

(364) A mixture of 4-(benzyloxy)-3-fluoro-5-(hydroxymethyl)benzamide (I68) (1.5 g, 5.5 mmol) and 10% Pd/C (wetted with ca. 55% water, 150 mg) in methanol (30 mL) was heated at 80° C. in a sealed tube under a hydrogen atmosphere overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=20:1 to 10:1) to give the title compound (900 mg, 90%) as a white solid. LCMS-F: rt 0.64 min; m/z 207.8 [M+Na].sup.+.

(xxvi) 4-Hydroxy-2-methoxybenzamide (I75)

(365) ##STR00058##

(a) Methyl 4-hydroxy-2-methoxybenzoate (I74)

(366) To a solution of 4-bromo-3-methoxyphenol (500 mg, 2.46 mmol) in MeOH (5 mL) was added Et.sub.3N (1.47 g, 9.85 mmol) and Pd(dppf)Cl.sub.2 (180 mg, 0.246 mmol) and the mixture was heated at 90° C. in a sealed tube under a CO atmosphere overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (100 mg, 22%) as a red solid. LCMS-F: rt 0.87 min; m/z 204.9 [M+Na].sup.+.

(b) 4-Hydroxy-2-methoxybenzamide (I75)

(367) To a solution of methyl 4-hydroxy-2-methoxybenzoate (I74) (100 mg, 0.55 mmol) in MeOH (6 mL) was added a 7% aqueous NH.sub.3 solution (4 mL), the flask was sealed and the mixture was heated at 90° C. overnight. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=5:1) to give the title compound (32 mg, 35%) as a white solid. LCMS-F: rt 0.67 min; m/z 167.9 [M+H].sup.+.

(xxvii) tert-Butyl (1-chloroethyl) carbonate (I76)

(368) ##STR00059##

(369) To a solution of 1-chloroethyl carbonochloridate (5.0 g, 35 mmol) in hexane (30 mL) at 0° C. was added a solution of pyridine (6.92 g, 87.4 mmol) in hexane (10 mL) dropwise. A white precipitate formed after complete addition. A solution of t-butanol (3.9 g, 52.4 mmol) in hexane (10 mL) was added and the mixture was stirred at 0° C. for 2 h then allowed to warm to room temperature and stirred for a further 1 h. The mixture was diluted with hexane and washed with a saturated aqueous NaHCO.sub.3 solution followed by water. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (900 mg, 14%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.50-6.41 (m, 1H), 1.73 (dd, J=5.7, 2.0 Hz, 3H), 1.45 (d, J=2.0 Hz, 9H).

(xxviii) tert-Butyl (chloromethyl) carbonate (I77)

(370) ##STR00060##

(371) To a solution of chloromethyl carbonochloridate (5 g, 39 mmol) in hexane (30 mL) at 0° C. was added a solution of pyridine (7.7 g, 97.0 mmol) in hexane (10 mL) dropwise. A white precipitate formed after complete addition. A solution of t-butanol (4.31 g, 58.2 mmol) in hexane (10 mL) was added and the mixture was stirred at 0° C. for 2 h then allowed to warm to room temperature and stirred for a further 1 h. The mixture was diluted with hexane and washed with a saturated aqueous NaHCO.sub.3 solution followed by water. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (2.5 g, 39%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 5.83 (s, 2H), 1.45 (s, 9H).

(xxviv) 1-Chloroethyl isopropyl carbonate (I78)

(372) ##STR00061##

(373) To a solution of 1-chloroethyl carbonochloridate (5 g, 35.0 mmol) in hexane (30 mL) at 0° C. was added a solution of pyridine (6.9 g, 87.4 mmol) in hexane (10 mL) dropwise. A white precipitate formed after complete addition. A solution of propan-2-ol (3.15 g, 52.5 mmol) in hexane (10 mL) was added and the mixture was stirred at 0° C. for 2 h then allowed to warm to room temperature and stirred for a further 1 h. The mixture was diluted with hexane and washed with a saturated aqueous NaHCO.sub.3 solution followed by water. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (3.0 g, 52%) as a pale yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.49 (q, J=5.7 Hz, 1H), 4.89-4.79 (m, 1H), 1.75 (d, J=5.7 Hz, 3H), 1.27-1.23 (m, 6H).

(xxvv) Chloromethyl (tert-butoxycarbonyl)-L-valinate (I79)

(374) ##STR00062##

(375) To a solution of (tert-butoxycarbonyl)-L-valine (7.9 g, 36 mmol) in DCM (20 mL) and water (20 mL) was added NaHCO.sub.3 (10.18 g, 121.2 mmol) and tetrabutylammonium hydrogen sulfate (1.03 g, 3.03 mmol) and the mixture was stirred at room temperature for 5 min, then cooled to 0° C. Chloromethyl sulfurochloridate (5 g, 30 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 2 h. Water (300 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (200 mL×2). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (4.8 g, 60%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.35 (d, J=8.0 Hz, 1H), 5.94 (d, J=6.2 Hz, 1H), 5.84 (d, J=6.2 Hz, 1H), 3.90 (dd, J=7.9, 6.5 Hz, 1H), 2.08-1.99 (m, 1H), 1.38 (s, 9H), 0.90-0.88 (m, 6H).

(xxvvi) 1-Chloroethyl acetate (I80)

(376) ##STR00063##

(377) To a solution of AlCl.sub.3 (2.04 g, 15.3 mmol) in DCM (40 mL) at 0° C. under a N.sub.2 atmosphere was added acetyl chloride (2.0 g, 25.5 mmol) and the mixture was stirred at 0° C. for 20 min. Acetaldehyde (5.0 M in THF, 5.1 mL, 25.5 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 h. The mixture was partitioned between water (300 mL) and DCM (300 mL), the layers were separated and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure at 35° C. to give the title compound as a pale red oil (final volume of 6 mL), which was used directly in the next step without further purification.

(xxvvii) 1-Chloroethyl isobutyrate (I81)

(378) ##STR00064##

(379) To a solution of AlCl.sub.3 (1.5 g, 11.3 mmol) in DCM (40 mL) at 0° C. under N.sub.2 atmosphere was added isobutyryl chloride (2.0 g, 18.8 mmol) and the mixture was stirred at 0° C. for 20 min. Acetaldehyde (5 M in THF, 3.75 mL, 18.8 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 h. The mixture was partitioned between water (300 mL) and DCM (300 mL), the layers were separated and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure at 30° C. to give the title compound as a pale yellow oil (final volume of 6 mL), which was used directly in the next step without further purification.

(xxvviii) Chloromethyl dimethylcarbamate (I82)

(380) ##STR00065##

(381) To a solution of chloromethyl carbonochloridate (1.0 g, 7.76 mmol) in DCM (10 mL) was added dimethylamine (2 M in THF, 3.9 mL, 7.76 mmol) and K.sub.2CO.sub.3 (3.2 g, 23.3 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (510 mg, 48%) as a yellow oil. LCMS-C: rt 0.64 min; m/z 138.0 [M+H].sup.+.

(xxvviv) Chloromethyl acetyl-L-valinate (I83)

(382) ##STR00066##

(383) To a solution of acetyl-L-valine (5.8 g, 36 mmol) in DCM (50 mL) and water (50 mL) was added NaHCO.sub.3 (10.2 g, 121.2 mmol) and tetrabutylammonium hydrogen sulfate (1.03 g, 3.03 mmol) and the mixture was stirred at room temperature for 5 min, then cooled to 0° C. Chloromethyl sulfurochloridate (5 g, 30 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 2 h. The layers were separated and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were washed with water (2×150 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give the title compound (2.5 g, 40%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.27 (d, J=7.6 Hz, 1H), 5.91 (d, J=6.2 Hz, 1H), 5.85 (d, J=6.2 Hz, 1H), 4.18 (dd, J=7.7, 6.2 Hz, 1H), 2.11-1.98 (m, 1H), 1.89 (s, 3H), 0.92-0.89 (m, 6H).

(xxvvv) Methyl 4-hydroxypiperidine-1-carboxylate (I84)

(384) ##STR00067##

(385) To a mixture of piperidin-4-ol (1.00 g, 9.88 mmol) and K.sub.2CO.sub.3 (2.73 g, 19.8 mmol) in DCM (40 mL) was slowly added methyl chloroformate (1.12 g, 11.9 mmol) and the mixture was stirred at room temperature overnight. The mixture was filtered and filtrate was concentrated under reduced pressure to give the title compound (1.40 g, 89%) as a colorless oil, which was used in the next step without further purification. LCMS-C: rt 0.33 min; m/z 160.0 [M+H].sup.+.

(xxvvvi) Ethyl 3-(bromomethyl)-4-chlorothieno[2,3-c]pyridine-2-carboxylate (I88)

(386) ##STR00068##

a) 1-(3-Chloro-5-fluoropyridin-4-yl)ethan-1-ol (I85)

(387) A solution of lithium diisopropylamide (titrated 2.0 M) in THF/heptane/ethylbenzene (13.1 mL, 18.2 mmol) was slowly added to a cooled (−78° C.) solution of 3-chloro-5-fluoro-pyridine (2.00 g, 15.2 mmol) in THF (30 mL). The mixture was stirred at −78° C. for 1 h before a solution of acetaldehyde (2.5 mL, 3 eq) in THF (2.5 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched under nitrogen by the addition of a saturated aqueous solution of NH.sub.4C1. The mixture was extracted with EtOAc (×3), washed with saturated NH.sub.4Cl.sub.(aq), brine and dried over MgSO.sub.4. The organics were filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography (24 g SiO.sub.2 cartridge, 0-30% EtOAc in petroleum benzine) to give the title compound (1.2 g, 44%) as a yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.32 (d, J=1.7 Hz, 1H), 5.44-5.24 (m, 1H), 2.56 (s, 1H), 1.61 (dd, J=6.8, 0.9 Hz, 3H). LCMS-B: rt 3.085 min, m/z 176.0 [M+H].sup.+.

b) 1-(3-Chloro-5-fluoropyridin-4-yl)ethan-1-one (I86)

(388) 1-(3-Chloro-5-fluoro-4-pyridyl)ethanol (I85) (0.56 g, 3.2 mmol) in anhydrous DCM (10 mL) was added to a stirred suspension of pyridinium chlorochromate (1.0 g, 4.7 mmol) and freshly activated 4 Å sieves in anhydrous DCM (10 mL) and the mixture was stirred overnight. The reaction mixture was taken-up in EtOAc/petroleum benzine (3:1) and filtered through a plug of silica. The silica was washed with EtOAc/petroleum benzine and the filtrate dried in vacuo. The residue was purified by column chromatography (12 g SiO.sub.2 cartridge, 0-30% EtOAc in petroleum benzine) to give the title compound (0.42 g, 77%) as a colourless liquid. .sup.1H-NMR (400 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.47 (s, 1H), 2.61 (d, J=1.0 Hz, 3H).

c) Ethyl 4-chloro-3-methylthieno[2,3-c]pyridine-2-carboxylate (I87)

(389) A high pressure tube was charged with 1-(3-chloro-5-fluoro-4-pyridyl)ethanone (0.711 g, 4.10 mmol) (186) (& (186b), not described), ethyl 2-mercaptoacetate (0.449 mL, 4.10 mmol), potassium carbonate (0.85 g, 6.1 mmol) and N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 70° C. overnight. Further portions of ethyl 2-mercaptoacetate (0.450 mL, 4.10 mmol) and DMF (5 mL) were added and the mixture stirred at 80° C. for 1 day. Water was added and the mixture extracted with EtOAc (3×35 mL). The combined organic layers were washed with water, brine, dried (MgSO.sub.4) and filtered. The filtrate was evaporated in vacuo and the residue purified by column chromatography (12 g SiO.sub.2 cartridge, 0-20% EtOAc in petroleum benzine) to give the title compound (0.28 g, 27% yield) as a white solid. LCMS-B: rt 3.727 min, m/z 255.9 [M+H].sup.+. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.97 (s, 1H), 8.47 (s, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.09 (s, 3H), 1.43 (t, J=7.1 Hz, 3H).

d) Ethyl 3-(bromomethyl)-4-chlorothieno[2,3-c]pyridine-2-carboxylate (I88)

(390) A solution of ethyl 4-chloro-3-methyl-thieno[2,3-c]pyridine-2-carboxylate (0.28 g, 1.1 mmol) (187), N-bromosuccinimide (0.387 g, 2.17 mmol), benzoyl peroxide (75%, remainder water, 0.11 g, 0.34 mmol) in 1,2-dichloroethane (30 mL) was stirred at reflux for 3 h. The mixture was concentrated and purified by column chromatography to give the title compound (0.34 g, 94%) as a pale yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 9.05 (s, 1H), 8.57 (s, 1H), 5.51 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). LCMS-A: rt 6.876 min, m/z=334.0 [M+H].sup.+ for .sup.79Br.

EXAMPLES

3-((4-Carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid (1)

(391) ##STR00069##

(392) To a solution of ethyl 3-((4-carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate A1 (200 mg, 0.53 mmol) in THF/H.sub.2O (5 mL/1 mL) was added LiOH.H.sub.2O (68 mg, 1.60 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with water (150 mL) and acidified to pH 4-5 with aq. 1 M HCl. The resulting precipitate was collected by filtration, washed with water and dried at 60° C. overnight to give the title product (150 mg, 81%) as a white solid. LCMS-D: rt 2.54 min; m/z 345.9 [M+H].sup.+, 367.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.93 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.7 Hz, 3H), 7.58 (td, J=8.0, 5.0 Hz, 1H), 7.28 (dd, J=11.9, 8.0 Hz, 1H), 7.20 (s, 1H), 7.08 (d, J=8.7 Hz, 2H), 5.72 (s, 2H), CO.sub.2H not observed.

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (2)

(393) ##STR00070##

(a) Ethyl 3-((4-cyano-2,6-difluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (A2)

(394) A mixture of ethyl 3-(bromomethyl)-4-fluorobenzo[b]thiophene-2-carboxylate 13 (25 mg, 0.079 mmol), 3,5-difluoro-4-hydroxybenzonitrile (0.013 g, 0.087 mmol) and cesium carbonate, 60-80 mesh (0.0385 g, 0.118 mmol) was stirred in DMF (0.5 mL) at room temperature. After 1.5 hours the mixture was added to ice water (10 mL) and the mixture filtered, the collected solids washed with water (2×1 mL) and air dried to give the title compound as an off-white solid (25.0 mg, 81% yield). LCMS-A rt 6.61 min; no product ions detected. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.64 (dd, J=8.2, 0.8 Hz, 1H), 7.46 (td, J=8.1, 4.8 Hz, 1H), 7.25-7.17 (m, 2H), 7.11 (ddd, J=11.7, 7.9, 0.8 Hz, 1H), 6.04 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H). .sup.19F NMR (376 MHz, CDCl.sub.3) δ −117.68 (t, J=4.1 Hz), −123.57 (d, J=4.1 Hz).

(b) Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (2)

(395) A mixture of ethyl 3-((4-cyano-2,6-difluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate A2 (20 mg, 0.051 mmol), DMSO (0.5 mL), potassium carbonate (0.0035 g, 0.026 mmol) and 30% aq. hydrogen peroxide (0.0047 mL, 0.15 mmol) was stirred at room temperature. After three hours additional 30% aq. hydrogen peroxide (0.0047 mL, 0.15 mmol) was added. After five hours the mixture was diluted with water (10 mL), filtered and the collected solid was washed with water (2×1 mL) and air dried to give the title compound as a white solid (16.8 mg, 80% yield). LCMS-B rt 3.41 min; m/z 409.8 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 7.76 (dd, J=8.2, 0.8 Hz, 1H), 7.56-7.49 (m, 1H), 7.51-7.44 (m, 2H), 7.19 (ddd, J=12.0, 7.9, 0.8 Hz, 1H), 5.98 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H). .sup.19F NMR (376 MHz, MeOD-d.sub.4) δ −119.08 (t, J=3.3 Hz), −127.78 (d, J=3.1 Hz).

Benzyl 3-((4-carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (3)

(396) ##STR00071##

(397) To a solution of 3-((4-carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid 1 (100 mg, 0.29 mmol) in benzyl alcohol (6 mL) was added conc. H.sub.2SO.sub.4 (4 drops) and the mixture was heated at 70° C. overnight. The mixture was cooled to room temperature and purified directly by silica gel chromatography (Pet. Ether/EtOAc=100:0 then 10:1 to 0:100) followed by re-crystallization from DCM/Pet. Ether to give the title product (20 mg, 15%) as a white solid. LCMS-C: rt 2.41 min; m/z 436.0 [M+H].sup.+, 458.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96 (d, J=8.1 Hz, 1H), 7.87-7.85 (m, 3H), 7.63-7.58 (m, 1H), 7.43 (dd, J=6.4, 2.8 Hz, 2H), 7.36-7.30 (m, 4H), 7.21 (s, 1H), 7.05 (d, J=8.7 Hz, 2H), 5.71 (s, 2H), 5.40 (s, 2H).

Isopropyl 3-((4-carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (4)

(398) ##STR00072##

(399) A mixture of 3-((4-carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid 1 (60 mg, 0.17 mmol), i-PrOH (104 mg, 1.74 mmol), EDCl.HCl (67 mg, 0.34 mmol) and DMAP (5 mg) in DMF (5 mL) was stirred at room temperature overnight. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was re-crystallized from DCM/Pet. Ether to give the title product (10 mg, 15%) as a white solid. LCMS-C: rt 2.34 min; m/z 388.0 [M+H].sup.+, 410.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95 (d, J=8.0 Hz, 1H), 7.88-7.86 (m, 3H), 7.60-7.59 (m, 1H), 7.32-7.27 (m, 1H), 7.26 (s, 1H), 7.14 (d, J=8.5 Hz, 2H), 5.75 (s, 2H), 5.16-5.13 (m, 1H), 1.33 (d, J=6.2 Hz, 6H).

(400) General Method A (Table 1)

(401) ##STR00073##

(402) Step (a)

(403) A solution of the appropriate ketone (1 equiv.), ethyl 2-mercaptoacetate (1 equiv.) and K.sub.2CO.sub.3 (1.5 equiv.) in DMF (0.1-0.3 M) was heated at 100° C. overnight. The mixture was cooled to room temperature then poured into water and extracted twice with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by re-crystallization from EtOAc/Pet. Ether to give the desired product.

(404) Step (b)

(405) A solution of the ethyl ester (1 equiv.), NBS (1 equiv.) and BPO (0.1 equiv.) in 0014 (0.08-0.1 M) was heated at reflux for 1 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=1:0 to 50:1) to give the desired product.

(406) Step (c)

(407) A solution of the alkyl bromide (1 equiv.), the appropriate phenol (1.05 equiv.) and Cs.sub.2CO.sub.3 (1.5 equiv.) in DMF (0.1-0.3 M) was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by re-crystallization from DCM/Pet. Ether to give the desired product.

(408) General Method B (Table 1)

(409) ##STR00074##

(410) To a solution of the ester (1 equiv.) in THF/H.sub.2O (5:1, 0.08-0.10 M) was added LiOH.H.sub.2O (3 equiv.) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with water and acidified to pH 4-5 with aqueous 1 M HCl. The resulting precipitate was collected by filtration, washed with water and dried at 60° C. overnight to give the desired product.

(411) General Method C (Table 1)

(412) ##STR00075##

(413) To a solution of the ester (1 equiv.) in MeOH/H.sub.2O (3:1, 0.01-0.05 M) was added KOH (4.9 equiv.) and the mixture was heated at 60° C. for 1 h. Most of the methanol was removed under reduced pressure and the aqueous residue was adjusted to pH 5 with aqueous 1 M HCl. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give the desired product.

(414) General Method D (Table 1)—Alternative Method to Step (c) of Method A

(415) The appropriate alkyl bromide (1 eq), the appropriate phenol (1.1 eq), finely ground cesium carbonate (60-80 mesh, 1.5 eq) and DMF (to 0.1-0.3M) were stirred at room temperature for two hours. The mixture was diluted with ice cold water, the resulting precipitate collected by filtration or centrifugation, washed with the minimum water and air dried to give the ether product.

(416) General Method E (Table 1)

(417) ##STR00076##

(418) The ester (1 eq), 2:1 THF:MeOH (to 0.05-0.1 M) and 2 M aq. lithium hydroxide (7 eq) were stirred at room temperature for three hours. The volatile solvents were removed with a current of air and the residue diluted with cold 3 M aq. HCl. The precipitate was collected by filtration or centrifugation, washed with the minimum water and air dried to give the acid product.

(419) The following examples were made according to the methods described in the general procedures:

(420) TABLE-US-00010 Starting LCMS Ex materials Name and structure data .sup.1H NMR data Method 5 I1 embedded image LCMS- C: rt 2.24 min; m/z 356.0 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.11-8.08 (m, 2H), 7.87-7.84 (m, 3H), 7.59-7.49 (m, 2H), 7.19 (s, 1H), 7.11 (d, J = 8.7 Hz, 2H), 5.79 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.29 (t, J= 7.1 Hz, 3H). A Steps (b) and (c) Ethyl 3-((4- carbamoylphenoxy)meth yl)benzo[b]thiophene-2- carboxylate 6 5 embedded image LCMS- C: rt 1.59 min; m/z 328.0 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.07 (d, J = 8.5 Hz, 2H), 7.85-7.78 (m, 3H), 7.56-7.47 (m, 2H), 7.19 (s, 1H), 7.11 (d, J =8.8 Hz, 2H), 5.82 (s, 2H), CO.sub.2H not observed. B Reacted at 30° C. overnight 3-((4- Carbamoylphenoxy)met hyl)benzo[b]thiophene-2- carboxylic acid 7 I5 embedded image LCMS- C: rt 2.33 min; m/z 390.0 [M + H].sup.+ .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.14 (d, J = 8.8 Hz, 1H), 7.88-7.84 (m ,3H), 7.20-7.18 (m, 2H), 7.19 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 5.86 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). A Step (c), purified by silica gel chromato- graphy (Pet. Ether/ EtOAc = 1:0 to 30:1) Ethyl 3-((4- carbamoylphenoxy)methyl)-4- chlorobenzo[b]thiophene- 2-carboxylate 8 7 0 embedded image LCMS- C: rt 1.86 min; m/z 362.0 [M + H].sup.+, 383.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.11 (d, J = 7.0 Hz, 1H), 7.87-7.85 (m, 3H), 7.56-7.50 (m, 2H), 7.18 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 5.89 (s, 2H), CO.sub.2H not observed. C 3-((4-Carbamoylphenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 9 1-(4-Chloro- 2-fluoro- phenyl)eth- anone embedded image LCMS- C: rt 2.41 min; m/z 390.0 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.29 (d, J = 1.3 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.86-7.84 (m, 3H), 7.57 (dd, J = 8.7, 1.5 Hz, 1H), 7.22 (s, 1H), 7.10 (d, J = 8.6Hz, 2H), 5.77 (s, 2H), 4.36 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). A Step b: Purified by re- crystal- lization from DCM/Pet. Ether Ethyl 3-((4- carbamoylphenoxy)methyl)-6- chlorobenzo[b]thiophene-2- carboxylate 10 9 embedded image LCMS- C: rt 2.06 min; m/z 361.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 14.0 (s, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.85-7.65 (m, 3H), 7.54 (dd, J = 8.8, 1.8 Hz, 1H), 7.20 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 5.80 (s, 2H). B 3-((4- carbamoylphenoxy)methyl)-6- chlorobenzo[b]thiophene-2- carboxylic acid 11 1-(3-Chloro- 2-fluoro- phenyl)eth- anone embedded image LCMS- C: rt 2.43 min; m/z 390.0 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.13 (d, J = 8.2 Hz, 1H), 7.87-7.84 (m, 3H), 7.74 (d, J = 7.7 Hz, 1H), 7.59-7.54 (m, 1H), 7.22 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 5.78 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). A Step b: Purified by recrystal- lization from DCM/Pet. Ether Ethyl 3-((4- carbamoylphenoxy)methyl)-7- chlorobenzo[b]thiophene-2- carboxylate 12 11 embedded image LCMS- C: rt 2.04 min; m/z 361.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d6) δ 14.2 (brs, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.8 Hz, 3H), 7.71 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.20 (s, 1H), 7.11 (d, J = 8.8 Hz, 2H), 5.81 (s, 2H). B 3-((4- Carbamoylphenoxy)methyl)-7- chlorobenzo[b]thiophene-2- carboxylic acid 13 1-(5-Chloro- 2-fluoro- phenyl)eth- anone embedded image LCMS- C: rt 2.36 min; m/z 390.0 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.18-8.14 (m, 2H), 7.87-7.85 (m, 3H), 7.63 (d, J = 8.4 Hz, 1H), 7.22 (s, 1H), 7.10 (d, J = 8.3 Hz, 2H), 5.77 (s, 2H), 4.36 (q, J = 6.9 Hz, 2H), 1.28 (t, J = 6.9 Hz, 3H). A Step b: Purified by recrystal- lization from DCM/Pet. Ether Ethyl 3-((4- carbamoylphenoxy)methyl)-5- chlorobenzo[b]thiophene-2- carboxylate 14 13 embedded image LCMS- C: rt 2.00 min; m/z 361.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.13-8.11 (m, 2H), 7.86-7.84 (m, 3H), 7.60 (dd, J = 8.7, 1.7 Hz, 1H), 7.20 (s, 1H), 7.10 (d, J = 8.7 Hz, 2H), 5.80 (s, 2H), CO.sub.2H not observed. B 3-((4- Carbamoylphenoxy)methyl)-5- chlorobenzo[b]thiophene-2- carboxylic acid 15 1-(2,3,6- Trifluoro- phenyl)eth- anone embedded image LCMS- C: rt 2.32 min; m/z 391.9 [M + H].sup.+, 413.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.88-7.85 (m, 3H), 7.55-7.50 (m, 1H), 7.40-7.34 (m, 1H), 7.21 (s, 1H), 7.09 (d, J = 8.9 Hz, 2H), 5.70 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). A Ethyl 3-((4- carbamoylphenoxy)methyl)-4,5- difluorobenzo[b]thiophene-2- carboxylate 16 15 embedded image LCMS- C: rt 1.84 min; m/z 363.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.87-7.85 (m, 3H), 7.51-7.46 (m, 1H), 7.36-7.40 (m, 1H), 7.20 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H), 5.71 (s, 2H), CO.sub.2H not observed. B 3-((4- Carbamoylphenoxy)methyl)-4,5- difluorobenzo[b]thiophene-2- carboxylic acid 17 1-(2-Chloro- 6-fluoro-3- methyl- phenyl)eth- anone embedded image LCMS- C: rt 2.43 min; m/z 403.9 [M + H].sup.+, 425.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.03 (d, J = 8.3 Hz, 1H), 7.92-7.80 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 5.89 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). A Step a: 1) reacted at 85° C. 2) Purified by chroma- tography (Pet. Ether) Step b: Stirred overnight Step c: Purified by prep-HPLC Ethyl 3-((4- carbamoylphenoxy)methyl)-4- chloro-5-methyl- benzo[b]thiophene-2- carboxylate 18 17 0 embedded image LCMS- C: rt 2.07 min; m/z 375.9 [M + H].sup.+, 397.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 14.0 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.86 (t, J = 7.7 Hz, 3H), 7.55 (d, J = 8.3 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.7 Hz, 2H), 5.91 (s, 2H), 2.45 (s, 3H). B Purified by prep-HPLC 3-((4- Carbamoylphenoxy)methyl)-4- chloro-5- methylbenzo[b]thiophene-2- carboxylic acid 19 1-(4-Chloro- 2,6-di- fluoro- phenyl)eth- anone embedded image LCMS- C: rt 2.41 min; m/z 407.9 [M + H].sup.+, 429.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.20 (d, J = 1.6 Hz, 1H), 7.87-7.85 (m, 3H), 7.55 (dd, J = 11.4, 1.6 Hz, 1H), 7.23 (s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 5.67 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). A Ethyl 3-((4- carbamoylphenoxy)methyl)-6- chloro-4-fluorobenzo[b]thiophene- 2-carboxylate 20 19 embedded image LCMS- C: rt 2.08 min; m/z 379.9 [M + H].sup.+, 401.8 [M + Na].sup.+ .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.15 (s, 1H), 7.86-7.84 (m, 3H), 7.50 (d, J = 11.2 Hz, 1H), 7.21 (s, 1H), 7.08 (d, J = 8.5 Hz, 2H), 5.71 (s, 2H), CO.sub.2H not observed. B 3-((4- Carbamoylphenoxy)methyl)-6- chloro-4- fluorobenzo[b]thiophene- 2-carboxylic acid 21 1-(2-Bromo- 6-fluoro- phenyl)eth- anone embedded image LCMS- C: rt 2.33 min; m/z 433.9 [M + H].sup.+, 455.8 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.20 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.8 Hz, 3H), 7.80 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.21 (s, 1H), 7.09 (d, J = 8.7 Hz, 2H), 5.88 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). A Step a and b: Crude products used in next step without purification Step c: Purified by chromato- graphy(Pet. Ether/EtOA c = 10:1 to 1:2) Ethyl 4-bromo-3-((4- carbamoylphenoxy)meth- yl)benzo[b]thiophene-2- carboxylate 22 21 embedded image LCMS- C: rt 1.95 min; m/z 405.8 [M + H].sup.+, 428.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.95 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 8.1 Hz, 3H), 7.60 (d, J = 7.0 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.14 (s, 1H), 7.07 (t, J = 7.0 Hz, 2H), 6.08 (s, 2H), CO.sub.2H not observed. B Purified by recrystal- lization from DCM/Pet. Ether 4-Bromo-3-((4- carbamoylphenoxy)meth- yl)benzo[b]thiophene-2- carboxylic acid 23 1-(3- Fluoro- pyridin-2- yl)ethanone embedded image LCMS- C: rt 1.78 min; m/z 356.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.85 (dd, J = 4.4, 1.4 Hz, 1H), 8.65 (dd, J = 8.3, 1.4 Hz, 1H), 7.87 (t, J = 5.8 Hz, 3H), 7.62 (dd, J = 8.3, 4.5 Hz, 1H), 7.20 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 5.68 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). A Step a: Purified by chromato- graphy(Pet. Ether/EtOA c = 1:0 to 50:1) Step c: Purified by recrystal- lization from DCM/Pet. Ether Ethyl 3-((4- carbamoylphenoxy)meth- yl)thieno[3,2-b]pyridine- 2-carboxylate 24 23 embedded image LCMS- C: rt 0.39 min; m/z 328.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 14.1 (s, 1H), 8.82 (s, 1H), 8.61 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.7 Hz, 3H), 7.59 (s, 1H), 7.34-6.96 (m, 3H), 5.69 (s, 2H). B Purified by recrystal- lization from DCM/Pet. Ether 3-((4- Carbamoylphenoxy)meth- yl)thieno[3,2-b]pyridine- 2-carboxylic acid 25 I5 embedded image LCMS- C: rt 2.42 min; m/z 407.9 [M + H].sup.+, 429.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.0, 2.0 Hz, 1H), 7.71 (t, J = 8.8 Hz, 1H), 7.62- 7.55 (m,2H),7.51 (s, 2H), 7.04-7.01 (m, 1H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H), 5.88 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-((4-carbamoyl-3- fluorophenoxy)methyl)- 4-chlorobenzo[b]thiophene-2- carboxylate 26 25 embedded image LCMS- C: rt 2.01 min; m/z 379.9 [M + H].sup.+, 401.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.17-8.09 (m, 1H), 7.70 (t, J = 8.8 Hz, 1H), 7.61-7.43 (m, 4H), 7.04 (dd, J = 12.9, 2.3 Hz, 1H), 6.95 (dd, J = 8.7, 2.3 Hz, 1H), 5.90 (s, 2H), CO.sub.2H not observed. C 3-((4-Carbamoyl-3- fluorophenoxy)methyl)- 4-chlorobenzo[b]thiophene-2- carboxylic acid 27 I5 embedded image LCMS- C: rt 2.38 min; m/z 425.9 [M + H].sup.+, 447.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.19-8.13 (m, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.64-7.51 (m, 2H), 6.93-6.91 (m, 2H), 5.86 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-((4-carbamoyl- 3,5-difluorophenoxy)methyl)- 4-chlorobenzo[b]thiophene-2- carboxylate 28 27 00 embedded image LCMS- C: rt 1.99 min; m/z 397.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.12 (dd, J = 7.4, 1.7 Hz, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.62-7.48 (m, 2H), 6.93 (d, J = 9.6 Hz, 2H), 5.88 (s, 2H), CO.sub.2H not observed. c 3-((4-Carbamoyl-3,5- difluorophenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 29 I5 and I13 01 embedded image LCMS- C: rt 2.28 min, m/z 419.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.18-8.13 (m, 1H), 7.89 (s, 1H), 7.61-7.52 (m, 3H), 7.47 (s, 1H), 7.25-7.18 (m, 2H), 5.85 (s, 2H), 4.39-4.29 (m, 2H), 3.71 (s, 3H), 1.27 (t, J = 6.0 Hz, 3H). A Step (c) Ethyl 3-((4-carbamoyl-2- methoxyphenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylate 30 29 02 embedded image LCMS- C: rt 1.81 min; m/z 391.9 [M + H].sup.+, 413.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.13-8.11 (m, 1H), 7.90 (s, 1H), 7.61-7.51 (m, 3H), 7.47 (d, J = 1.7 Hz, 1H), 7.23-7.20 (m, 2H), 5.87 (s, 2H), 3.71 (s, 3H), CO.sub.2H not observed. c 3-((4-Carbamoyl-2- methoxyphenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 31 1-(2,4,6- Trifluoro- phenyl)eth- an-1-one 03 embedded image LCMS- C: rt 2.32 min, m/z 391.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.98 (d, J = 8.3 Hz, 1H), 7.92-7.85 (m, 3H), 7.48-7.40 (m, 1H), 7.22 (s, 1H), 7.07 (d, J = 8.7 Hz, 2H), 5.67 (s, 2H), 4.34 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). A Ethyl 3-((4- carbamoylphenoxy)meth- yl)-4,6- difluorobenzo[b]thiophene- 2-carboxylate 32 31 04 embedded image LCMS- C: rt 1.82 min, m/z 363.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.93 (dd, J = 8.5, 2.0 Hz, 1H), 7.89-7.84 (m, 3H), 7.44- 7.36 (m, 1H), 7.19(s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 5.69 (s, 2H), CO.sub.2H not observed. C 3-((4- Carbamoylphenoxy)methyl)-4,6- difluorobenzo[b]thiophene-2- carboxylic acid 33 1-(2-Fluoro- 6-meth- oxy- phenyl)eth- an-1-one 05 embedded image LCMS- C: rt 2.32 min, m/z 407.9 [M + Na].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.93-7.80 (m, 3H), 7.62 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 7.9 Hz, 1H), 5.77 (s, 2H), 4.31 (q, J = 7.0 Hz, 2H), 3.68 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). A Ethyl 3-((4- carbamoylphenoxy)methyl)-4- methoxybenzo[b]thiophene-2- carboxylate 34 33 06 embedded image LCMS- C: rt 1.69 min, m/z 357.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 13.7 (s, 1H), 7.88-7.86 (m, 3H), 7.60 (d, J = 8.0 Hz, 1H), 7.52-7.44 (m, 1H), 7.18 (s, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 7.9 Hz, 1H), 5.79 (s, 2H), 3.64 (s, 3H). C 3-((4- Carbamoylphenoxy)methyl)-4- methoxybenzo[b]thiophene-2- carboxylic acid 35 1-(2-Fluoro- 6-(trifluoro- meth- yl)phenyl) ethan-1-one 07 embedded image LCMS- C: rt 2.30 min, m/z 423.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.53 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.87-7.85 (m, 3H), 7.79-7.72 (m, 1H), 7.22 (s, 1H), 7.05 (d, J = 7.9 Hz, 2H), 5.66 (s, 2H), 4.33 (q, J = 6.8 Hz, 2H), 1.23 (t, J = 6.8 Hz, 3H). A Ethyl 3-((4- carbamoylphenoxy)methyl)-4- (trifluoromethyl)benzo[b]thio- phene-2-carboxylate 36 35 08 embedded image LCMS- C: rt 1.97 min, m/z 395.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.50 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.86-7.84 (m, 3H), 7.73 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.05 (d, J = 8.8 Hz, 2H), 5.70 (s, 2H), CO.sub.2H not observed. C 3-((4- Carbamoylphenoxy)methyl)-4- (trifluoromethyl)benzo[b]thio- phene-2-carboxylic acid 37 I5 and I9 09 embedded image LCMS- C: rt 2.36 min, m/z 423.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.18-8.13 (m, 1H), 7.99-7.89 (m, 3H), 7.62-7.54 (m, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 5.95 (s, 2H), 4.36 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-((4-carbamoyl-2- chlorophenoxy)methyl)- 4-chlorobenzo[b]thiophene-2- carboxylate 38 37 0 embedded image LCMS- C: rt 2.04 min, m/z 395.8 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 7.96-7.90 (m, 2H), 7.89-7.84 (m, 2H), 7.50 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 6.9 Hz, 1H), 7.35-7.27 (m, 2H), 6.18 (s, 2H), CO.sub.2H not observed. C 3-((4-Carbamoyl-2- chlorophenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 39 I5 and I12 embedded image LCMS- C: rt 2.49 min, m/z 457.8 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.19 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.92 (s, 2H), 7.64- 7.53 (m, 3H), 6.14 (s, 2H), 4.12 (q,J = 7.1 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-((4-carbamoyl-2,6- dichlorophenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylate 40 39 embedded image LCMS- C: rt 2.21 min, m/z 429.8 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 13.8 (s, 1H), 8.14-8.05 (m, 2H), 7.88 (s, 2H), 7.62-7.50 (m, 3H), 6.18 (s,2H). C 3-((4-Carbamoyl-2,6- dichlorophenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 41 I5 and I10 LCMS- C: rt 2.31 min, m/z 449.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.06 (dd, J = 7.9, 1.0 Hz, 1H), 7.88 (s, 1H), 7.61-7.50 (m, 2H), 7.30 (s, 1H), 7.08 (s, 2H), 5.90 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.47 (s, 6H), 1.14 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-((4-carbamoyl-2,6- dimethoxyphenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylate 42 41 embedded image LCMS- C: rt 1.89 min, m/z 421.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.04 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.53-7.47 (m, 1H), 7.28 (s, 1H), 7.07 (s, 2H), 5.93 (s, 2H), 3.47 (s, 6H), CO.sub.2H not observed. C 3-((4-Carbamoyl-2,6- dimethoxyphenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 43 I5 and I14 embedded image LCMS- C: rt 2.25 min, m/z 414.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.27-8.21 (m, 2H), 8.17 (d,J = 6.7 Hz, 1H), 8.04 (s, 1H), 7.64-7.55 (m, 3H), 7.49 (s, 1H), 6.02 (s, 2H), 4.37 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-((4-carbamoyl-2- cyanophenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylate 44 43 embedded image LCMS- C: rt 1.78 min, m/z 386.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.23-8.17 (m, 2H), 8.05-7.95 (m, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.49-7.37 (m, 3H), 6.20 (s, 2H), CO.sub.2H not observed. C 3-((4-Carbamoyl-2- cyanophenoxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 45 I5 and I11 embedded image LCMS- C: rt 2.30 min, m/z 390.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.37 (d, J = 2.7 Hz, 1H), 8.17 (dd, J = 7.0, 2.0 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.73-7.68 (m, 1H), 7.62-7.55 (m, 2H), 7.51 (s, 1H), 5.96 (s, 2H), 4.35 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-(((6- carbamoylpyridin-3- yl)oxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylate 46 45 embedded image LCMS- C: rt 1.88 min, m/z 362.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.37 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.73-7.67 (m, 1H), 7.58-7.48 (m, 3H), 5.98 (s, 2H), CO.sub.2H not observed. C 3-(((6-Carbamoylpyridin- 3-yl)oxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 47 I5 and I8 embedded image LCMS- C: rt 2.46 min, m/z 402.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J = 6.9, 2.2 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.60-7.54 (m, 2H), 7.21- 7.19 (m, 1H), 6.90- 6.86 (m, 1H), 6.30 (s, 2H), 5.86 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). A Step (c) Ethyl 3-(((3- aminobenzo[d]isoxazol- 6-yl)oxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylate 48 47 0 embedded image LCMS- C: rt 2.11 min, m/z 374.9 [M + H].sup.+. .sup.1H NMR(400 MHz, DMSO-d.sub.6) δ 8.12 (dd, J = 7.1, 1.9 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.58- 7.51 (m, 2H), 7.20 (d, J = 1.7 Hz, 1H), 6.88 (dd, J = 8.7, 1.9 Hz, 1H), 6.30 (s, 2H), 5.89 (s, 2H), CO.sub.2H not observed. C 3-(((3- Aminobenzo[d]isoxazol- 6-yl)oxy)methyl)-4- chlorobenzo[b]thiophene-2- carboxylic acid 49 13 embedded image LCMS-B rt 3.67 min; m/z 407.7 [M + H].sup.+. D Ethyl 3-((4-carbamoyl-3- chlorophenoxy)methyl)-4- fluorobenzo[b]thiophene- 2-carboxylate 50 49 LCMS-A rt 5.65 min; m/z 379.7 [M + H].sup.+. E 3-((4-Carbamoyl-3- chlorophenoxy)methyl)- 4- fluorobenzo[b]thiophene- 2-carboxylic acid 51 13 LCMS-A rt 6.12 min; m/z 441.7 [M + H].sup.+. D Ethyl 3-((4-carbamoyl-3- (trifluoromethyl)phenoxy) methyl)-4- fluorobenzo[b]thiophene- 2-carboxylate 52 51 embedded image LCMS-A rt 5.73 min; m/z 413.7 [M + H].sup.+. E 3-((4-Carbamoyl-3- (trifluoromethyl)phenoxy) methyl)-4- fluorobenzo[b]thiophene- 2-carboxylic acid 53 I3 LCMS-B rt 3.64 min; m/z 387.8 [M + H].sup.+. D Ethyl 3-((4-carbamoyl-3- methylphenoxy)methyl)- 4-fluorobenzo[b]thiophene- 2-carboxylate 54 53 embedded image LCMS-A rt 5.63 min; m/z 359.8 [M + H].sup.+. E 3-((4-Carbamoyl-3- methylphenoxy)methyl)- 4- fluorobenzo[b]thiophene- 2-carboxylic acid 55 I3 and I16 LCMS-A rt 6.16 min; m/z 471.6 [M + H].sup.+. D Ethyl 3-((2-bromo-4- carbamoyl-6- fluorophenoxy)methyl)- 4- fluorobenzo[b]thiophene- 2-carboxylate 56 55 embedded image LCMS-B rt 3.38 min; m/z 441.6 [M + H].sup.+. E 3-((2-Bromo-4- carbamoyl-6- fluorophenoxy)methyl)- 4- fluorobenzo[b]thiophene- 2-carboxylic acid 57 2 LCMS-A rt 5.64 min; m/z 380.0 [M − H].sup.−. E 3-((4- Carbamoyl-2,6- difluorophenoxy)methyl)- 4- fluorobenzo[b]thiophene- 2-carboxylic acid

Ethyl 3-((4-carbamoyl-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (58) and 3-((4-carbamoyl-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid (59)

(421) ##STR00130##

(a) Ethyl 3-((4-cyano-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (A3)

(422) Ethyl 3-(bromomethyl)-4-fluorobenzo[b]thiophene-2-carboxylate 13 (0.050 g, 0.16 mmol), 3-fluoro-4-hydroxy-benzonitrile (0.024 g, 0.17 mmol) and cesium carbonate, 60-80 mesh (0.0770 g, 0.236 mmol) were stirred in DMF (0.5 mL) at room temperature. After 1.5 hours the mixture was diluted with water (10 mL) and the mixture was centrifuged. The solvent was decanted and the precipitate resuspended in water (3 mL). The mixture was filtered, the collected solids washed with water (2×1 mL) and air dried to give the title compound as an off-white solid (40.0 mg, 68% yield). LCMS-B rt 3.81 min; m/z 371.9 [M−H].sup.−. .sup.1H NMR (400 MHz, chloroform-d) δ 7.64 (dd, J=8.2, 0.8 Hz, 1H), 7.48-7.42 (m, 2H), 7.36 (dd, J=10.5, 2.0 Hz, 1H), 7.30-7.23 (m, peak obscured by solvent), 7.10 (ddd, J=11.6, 7.9, 0.8 Hz, 1H), 5.88 (s, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H). .sup.19F NMR (376 MHz, chloroform-d) δ −117.57, −130.69.

(b) Ethyl 3-((4-carbamoyl-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (58) and 3-((4-carbamoyl-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid (59)

(423) Ethyl 3-((4-cyano-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate A3 (0.035 g, 0.094 mmol) and potassium carbonate (0.0065 g, 0.047 mmol) were stirred in DMSO (0.5 mL) before 30% aq. hydrogen peroxide (0.096 mL, 0.28 mmol) was added dropwise. After two hours the mixture was added to iced water (5 mL) and stood for 15 minutes. The mixture was filtered, and the collected solid washed with water (2×1 mL) and air dried to give ethyl 3-((4-carbamoyl-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate 58 as a white solid (30.0 mg, 82% yield). LCMS-B rt 3.37 min; m/z 391.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01-7.91 (m, 2H), 7.80-7.73 (m, 1H), 7.71 (dd, J=12.4, 2.1 Hz, 1H), 7.61 (td, J=8.1, 4.9 Hz, 1H), 7.44 (t, J=8.6 Hz, 1H), 7.40-7.26 (m, 2H), 5.78 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) δ −118.06, −134.57.

(424) The combined filtrate and washings from the above filtration step was adjusted to pH 1 with aq. HCl (3 M) and stood at 4° C. overnight. The mixture was filtered, the collected solid washed with the minimum of aq. HCl (0.5 M) and air dried to give 3-((4-carbamoyl-2-fluorophenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid 59 as a white solid (3.8 mg, 11% yield). LCMS-B rt 3.37 min; m/z 363.8 [M+H].sup.+.

3-((4-Carbamoylphenoxy)methyl)-4-cyclopropylbenzo[b]thiophene-2-carboxylic acid (61)

(425) ##STR00131##

(a) Ethyl 3-((4-carbamoylphenoxy)methyl)-4-cyclopropylbenzo[b]thiophene-2-carboxylate (60)

(426) A solution of ethyl 4-bromo-3-((4-carbamoylphenoxy)methyl)benzo[b]thiophene-2-carboxylate 21 (150 mg, 0.34 mmol), cyclopropyl boronic acid (60 mg, 0.69 mmol), Pd(PPh.sub.3).sub.4 (40 mg, 0.034 mmol) and K.sub.2CO.sub.3 (144 mg, 1.03 mmol) in dioxane (10 mL) was heated at reflux under a N.sub.2 atmosphere overnight. The mixture was cooled to room temperature, EtOAc (60 mL) and water (50 mL) were added and the layers were separated. The organic layer was washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10:1 to 1:2) to give the title product (70 mg, 51%) as a white solid. LCMS-C: (ES-API): rt 2.40 min; m/z 396.0 [M+H].sup.+, 418.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96 (d, J=8.1 Hz, 1H), 7.89-7.86 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.26 (d, J=7.4 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J=8.7 Hz, 2H), 6.00 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 2.43-2.41 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 0.82-0.80 (m, 4H).

(b) 3-((4-Carbamoylphenoxy)methyl)-4-cyclopropylbenzo[b]thiophene-2-carboxylic acid (61)

(427) To a solution of ethyl 3-((4-carbamoylphenoxy)methyl)-4-cyclopropylbenzo[b]thiophene-2-carboxylate 60 (50 mg, 0.13 mmol) in THF/H.sub.2O (10 mL/3 mL) was added LiOH.H.sub.2O (30 mg, 0.71 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with water (15 mL) and acidified to pH 4-5 with aqueous 1 M HCl. The resulting precipitate was collected by filtration and purified by prep-HPLC to give the title product (3.0 mg, 7%) as a white solid. LCMS-C: (ES-API): rt 2.11 min; m/z 368.0 [M+H].sup.+, 389.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.92 (d, J=8.1 Hz, 1H), 7.87-7.85 (m, 3H), 7.44 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.4 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.7 Hz, 2H), 6.01 (s, 2H), 2.48-2.41 (m, 1H), 0.87-0.74 (m, 4H), CO.sub.2H not observed.

3-((4-Carbamoylphenoxy)methyl)-4-cyanobenzo[b]thiophene-2-carboxylic acid (63)

(428) ##STR00132##

(429) (a) Ethyl 3-((4-carbamoylphenoxy)methyl)-4-cyanobenzo[b]thiophene-2-carboxylate (62) A stirred solution of ethyl 4-bromo-3-((4-carbamoylphenoxy)methyl)benzo[b]thiophene-2-carboxylate 21 (140 mg, 0.32 mmol) and CuCN (144 mg, 1.61 mmol) in NMP (10 mL) was heated at 180° C. for 2 h then allowed to cool to room temperature, poured into water and extracted twice with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=1:0 to 0:1) to give the title product (90 mg, 73%) as a white solid. LCMS-C: (ES-API): rt 2.11 min; m/z 381.0 [M+H].sup.+, 402.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.54 (d, J=8.2 Hz, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.88-7.76 (m, 3H), 7.76 (t, J=7.8 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J=8.7 Hz, 2H), 5.88 (s, 2H), 4.44-4.31 (m, 2H), 1.30 (t, J=7.0 Hz, 3H).

(b) 3-((4-Carbamoylphenoxy)methyl)-4-cyanobenzo[b]thiophene-2-carboxylic acid (63)

(430) To a solution of ethyl 3-((4-carbamoylphenoxy)methyl)-4-cyanobenzo[b]thiophene-2-carboxylate 62 (85 mg, 0.22 mmol) in THF/H.sub.2O (8 mL/3 mL) was added LiOH.H.sub.2O (29 mg, 0.67 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with water and acidified to pH 4 with aqueous 1 M HCl. The resulting precipitate was collected by filtration and dried under reduced pressure to give the title product (70 mg, 89%) as a white solid. LCMS-C: (ES-API): rt 0.76 min; m/z 352.9 [M+H].sup.+, 374.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.51 (d, J=8.3 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 7.87-7.85 (m, 3H), 7.73 (t, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.09 (d, J=8.5 Hz, 2H), 5.90 (s, 2H), CO.sub.2H not observed.

3-((3-Bromo-4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (64)

(431) ##STR00133##

(a) Ethyl 3-((3-bromo-4-cyanophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (A4)

(432) A mixture of ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate 15 (200 mg, 0.6 mmol), 2-bromo-4-hydroxybenzonitrile 115 (131 mg, 0.66 mmol) and Cs.sub.2CO.sub.3 (391 mg, 1.2 mmol) in DMF (10 mL) was heated at 50° C. for 2 h. The mixture was poured into water and extracted with EtOAc (200 mL). The organic extract was washed with water (200 mL), brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=10:1) to give the title product (200 mg, 74%) as a white solid. LCMS-C: (ES-API): rt 2.95 min; m/z 472.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81-7.79 (m, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.47-7.39 (m, 2H), 7.33 (d, J=2.4 Hz, 1H), 6.00 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

(b) 3-((3-Bromo-4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (64)

(433) To a solution of ethyl 3-((3-bromo-4-cyanophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate A4 (100 mg, 0.22 mmol) in H.sub.2O.sub.2 (30% aqueous solution)/DMSO/EtOH (1 mL/1 mL/4 mL) was added a 5% aqueous NaOH solution (10 drops) and the resulting mixture was heated at 50° C. overnight. The mixture was acidified to pH 3-4 with aqueous 1 M HCl and extracted with EtOAc (100 mL). The organic extract was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title product (25 mg, 26%) as a white solid. LCMS-C: (ES-API): rt 2.03 min; m/z 439.8 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.92 (d, J=6.4 Hz, 1H), 7.52-7.48 (m, 3H), 7.34 (d, J=2.4 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 6.00 (s, 2H), CO.sub.2H and CONH.sub.2 protons not observed.

Ethyl 3-((3-bromo-4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (65)

(434) ##STR00134##

(435) To a solution of 3-((3-bromo-4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 64 (crude material from previous step, (50 mg, ˜50% purity, ˜0.057 mmol) in EtOH (15 mL) was added conc. H.sub.2SO.sub.4 (10 drops) and the mixture was heated at 90° C. overnight. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (100 mL). The organic extract was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=30:1) to give the title product (10 mg, 37%) as a yellow solid. LCMS-C: (ES-API): rt 2.46 min; m/z 467.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (dd, J=6.4, 2.0 Hz, 1H), 7.79 (s, 1H), 7.62-7.58 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.10 (dd, J=8.4, 2.0 Hz, 1H), 5.86 (s, 2H), 4.38 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).

3-((4-Carbamoyl-2,3-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (67)

(436) ##STR00135##

(a) Ethyl 4-chloro-3-((4-cyano-2,3-difluorophenoxy)methyl)benzo[b]thiophene-2-carboxylate (A5)

(437) A mixture of ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate 15 (0.030 g, 0.090 mmol), 2,3-difluoro-4-hydroxybenzonitrile (0.015 g, 0.099 mmol) and cesium carbonate, 60-80 mesh (0.044 g, 0.13 mmol) in DMF (0.3 mL) was stirred at room temperature for 2 hours. Water (˜15 mL) was added and the aqueous phase was extracted with EtOAc (3×25 mL). The organic extracts were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo to give the title compound (0.031 g, 85% yield) as a white solid. LCMS-B rt 3.892 min; m/z 405.7 [M−H].sup.−. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (dd, J=7.4, 1.8 Hz, 1H), 7.88-7.81 (m, 1H), 7.63-7.56 (m, 2H), 7.54-7.48 (m, 1H), 6.03 (s, 2H), 4.36 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).

(b) Ethyl 3-((4-carbamoyl-2,3-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (66)

(438) Hydrogen peroxide solution (30% w/w in H.sub.2O, 0.25 mL) was added to a mixture of ethyl 4-chloro-3-((4-cyano-2,3-difluorophenoxy)methyl)benzo[b]thiophene-2-carboxylate A5 (0.029 g, 0.071 mmol) and potassium carbonate (0.0049 g, 0.036 mmol) in DMSO (0.5 mL) at 0° C. The mixture was returned to room temperature and stirred for 30 minutes. An extra aliquot of hydrogen peroxide solution (30% w/w in H.sub.2O, 0.25 mL) was added and the mixture was stirred at room temperature for a further 2 hours. Water (˜10 mL) was added and the suspension was filtered and the solid washed with water and air dried to give the title compound as a white solid (0.012 g, 40% yield). LCMS-B rt 3.763 min; m/z 425.7 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (dd, J=7.4, 1.8 Hz, 1H), 7.68 (s, 1H), 7.65-7.50 (m, 4H), 7.37-7.29 (m, 1H), 5.97 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).

(439) An aqueous solution of lithium hydroxide monohydrate (2 M, 0.125 mL, 0.250 mmol) was added to ethyl 3-((4-carbamoyl-2,3-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 66 (0.011 g, 0.026 mmol) in THF:MeOH (2:1, 1 mL) and the mixture was stirred at room temperature for 48 hours. The volatiles were removed under reduced pressure and the residue was suspended in aqueous HCl (˜2 M). The suspension was filtered and the solid washed with water and air dried to give the title compound as a white solid (0.0043 g, 42% yield). LCMS-B rt 3.431 min; m/z 397.7 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (dd, J=7.7, 1.5 Hz, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.60-7.48 (m, 3H), 7.33 (t, J=8.2 Hz, 1H), 6.02 (s, 2H), CO.sub.2H proton not observed.

3-((4-Carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (69)

(440) ##STR00136##

(a) Ethyl 4-chloro-3-((4-cyano-2,6-difluorophenoxy)methyl)benzo[b]thiophene-2-carboxylate (A6)

(441) A mixture of ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate 15 (0.025 g, 0.075 mmol), 3,5-difluoro-4-hydroxybenzonitrile (0.013 g, 0.082 mmol) and cesium carbonate, 60-80 mesh (0.037 g, 0.11 mmol) in DMF (0.5 mL) was stirred at room temperature for 16 hours. Water (˜10 mL) was added and the precipitate was isolated by vacuum filtration. The precipitate was washed with water and air dried to give the title compound as a white solid (0.030 g, 98% yield). LCMS-A rt 6.701 min; product did not ionise. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=7.9, 1.2 Hz, 1H), 7.89-7.80 (m, 2H), 7.63 (dd, J=7.7, 1.2 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 6.18 (s, 2H), 4.28 (q, J=7.0 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).

(b) Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (68)

(442) A mixture of ethyl 4-chloro-3-((4-cyano-2,6-difluorophenoxy)methyl)benzo[b]thiophene-2-carboxylate A6 (0.023 g, 0.056 mmol), potassium carbonate (0.0039 g, 0.028 mmol) and hydrogen peroxide solution (30% w/w in H.sub.2O, 0.017 mL, 0.17 mmol) in DMSO (0.5 mL) was stirred at room temperature for 5 hours. Water (˜10 mL) was added and the precipitate was isolated by filtration, washed with water (2×1 mL) and air dried to give the title compound as a white solid (0.016 g, 65% yield). LCMS-B rt 3.607 min; m/z 447.7 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14-8.10 (m, 1H), 8.03 (s, 1H), 7.65-7.54 (m, 5H), 6.14 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H).

(443) A mixture of ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 68 (0.012 g, 0.028 mmol) and LiOH.H.sub.2O (2 M solution, 0.125 mL, 0.25 mmol) in

(444) THF:MeOH (2:1, 1 mL) was stirred at room temperature for 17 hours. The volatiles were removed by a stream of air and the residue was suspended in aq. HCl (2 M solution, ˜5 mL). The precipitate was filtered, washed with a minimum volume of water and air dried to give the title compound as a white solid (0.0030 g, 27% yield). LCMS-B rt 3.655 min; m/z 395.7 [M−H].sup.−. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.13-8.06 (m, 1H), 8.02 (s, 1H), 7.62-7.52 (m, 5H), 6.16 (s, 2H), CO.sub.2H proton not observed.

3-((2-Bromo-4-carbamoyl-6-fluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (71)

(445) ##STR00137##

(a) Ethyl 3-((2-bromo-4-carbamoyl-6-fluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (70)

(446) A mixture of 3-bromo-5-fluoro-4-hydroxybenzamide 116 (0.019 g, 0.082 mmol), ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate 15 (0.025 g, 0.075 mmol) and cesium carbonate, 60-80 mesh (0.037 g, 0.11 mmol) in DMF (0.5 mL) was stirred at room temperature for 16 hours. Water (˜10 mL) was added and the precipitate was isolated by vacuum filtration. The precipitate was washed with water and air dried to give the title compound as a white solid (0.029 g, 80% yield). LCMS-A RT 6.255 min; product did not ionise. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.12 (dd, J=8.1, 1.1 Hz, 1H), 8.06 (s, 1H), 7.92-7.89 (m, 1H), 7.75 (dd, J=12.0, 2.1 Hz, 1H), 7.63 (dd, J=7.7, 1.2 Hz, 1H), 7.59-7.54 (m, 2H), 6.16 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H).

(b) 3-((2-Bromo-4-carbamoyl-6-fluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (71)

(447) A mixture of ethyl 3-((2-bromo-4-carbamoyl-6-fluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 70 (0.022 g, 0.045 mmol) and LiOH.H.sub.2O solution (2 M, 0.125 mL, 0.25 mmol) in THF:MeOH (2:1, 1 mL) was stirred at room temperature for 17 hours. The volatiles were removed under a stream of air and the residue was suspended in aq. HCl (˜2 M, ˜3 mL). The mixture was filtered and the precipitate was washed with a minimum volume of water and air dried to give the title compound as a white solid (0.013 g, 63% yield). LCMS-B rt 3.753 min; m/z 455.6 [M−H].sup.−. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.90-7.85 (m, 2H), 7.72 (dd, J=12.5, 2.1 Hz, 1H), 7.49 (s, 1H), 7.43-7.39 (m, 1H), 7.33 (t, J=7.8 Hz, 1H), 6.38 (s, 2H), CO.sub.2H proton not observed.

3-((4-carbamoyl-2-methoxy-6-methylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (73)

(448) ##STR00138##

(a) Ethyl 4-chloro-3-((4-cyano-2-methoxy-6-methylphenoxy)methyl)benzo[b]thiophene-2-carboxlate (A7)

(449) A mixture of ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate 15 (0.030 g, 0.090 mmol), 4-hydroxy-3-methoxy-5-methyl-benzonitrile (0.016 g, 0.099 mmol) and cesium carbonate, 60-80 mesh (0.044 g, 0.13 mmol) in DMF (0.3 mL) was stirred at room temperature for 3 hours. Water (˜15 mL) was added and the precipitate was isolated by vacuum filtration and air dried to give the title compound as a white solid (0.021 g, 56% yield). LCMS-B rt 3.846 min; m/z 437.7 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (dd, J=7.9, 1.1 Hz, 1H), 7.62 (dd, J=7.6, 1.1 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.37-7.33 (m, 1H), 7.20-7.16 (m, 1H), 6.02 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 1.72 (s, 3H), 1.17 (t, J=7.1 Hz, 3H).

(b) Ethyl 3-((4-carbamoyl-2-methoxy-6-methylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (72) and 3-((4-carbamoyl-2-methoxy-6-methylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (73)

(450) A mixture of ethyl 4-chloro-3-((4-cyano-2-methoxy-6-methylphenoxy)methyl)benzo[b]thiophene-2-carboxylate A7 (0.019 g, 0.046 mmol), potassium carbonate (0.0095 g, 0.069 mmol) and hydrogen peroxide solution (30% w/w in H.sub.2O, 0.014 mL, 0.14 mmol) in DMSO (0.75 mL) was stirred for 16 hours at room temperature. An additional aliquot of hydrogen peroxide solution (30% w/w in H.sub.2O, 0.014 mL, 0.14 mmol) was added and the mixture was stirred at room temperature for a further 4 hours. A final aliquot of hydrogen peroxide solution (30% w/w in H.sub.2O, 0.014 mL, 0.14 mmol) was then added and the mixture was stirred at room temperature for a further 20 hours. Water (˜20 mL) was added and the aqueous phase was adjusted to pH ˜10 with aq. NaOH (2 M). The aqueous phase was extracted with EtOAc (3×20 mL) and the organic extracts were combined, washed with brine (3×20 mL), dried (MgSO.sub.4) and the solvent removed in vacuo to give ethyl 3-((4-carbamoyl-2-methoxy-6-methylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 72 as a tan coloured solid (0.008 g, 40% yield). LCMS-B RT 3.609 min; m/z 455.7 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.09 (dd, J=8.0, 1.1 Hz, 1H), 7.83 (s, 1H), 7.62 (dd, J=7.8, 1.2 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.37-7.31 (m, 1H), 7.24-7.17 (m, 2H), 5.98 (s, 2H), 4.14 (q, J=7.0 Hz, 2H), 3.74 (s, 3H), 1.70 (s, 3H), 1.14 (t, J=7.1 Hz, 3H);

(451) The aqueous phase was adjusted to pH ˜2 with aq. HCl (2 M) and extracted with EtOAc (3×20 mL). The organic extracts were combined, washed with brine, dried (MgSO.sub.4) and the solvent removed in vacuo to give 3-((4-carbamoyl-2-methoxy-6-methylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 73 as a white solid (0.011 g, 59% yield). LCMS-B RT 3.402 min; m/z 405.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06 (d, J=7.9 Hz, 1H), 7.82 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.21 (d, J=2.2 Hz, 2H), 6.02 (s, 2H), 3.76 (s, 3H), 1.72 (s, 3H), CO.sub.2H proton not observed.

(Pivaloyloxy)methyl 3-((4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (74)

(452) ##STR00139##

(453) A mixture of 3-((4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (8) (0.048 g, 0.13 mmol), sodium iodide (0.080 g, 0.53 mmol), cesium carbonate, 60-80 mesh (0.086 g, 0.27 mmol) and chloromethyl pivalate (0.076 mL, 0.53 mmol) in DMF (0.5 mL) was stirred at room temperature for 3.5 hours. Water (˜10 mL) was added and the precipitate was isolated by filtration. The solid was recrystallised from DCM/cyclohexane to give the title compound as a white powder (0.026 g, 41% yield). LCMS-B rt 3.892 min; m/z 475.8 [M+H].sup.+, m/z 497.7 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (dd, J=6.4, 2.8 Hz, 1H), 7.91-7.82 (m, 3H), 7.63-7.57 (m, 2H), 7.20 (s, 1H), 7.08 (d, J=8.7 Hz, 2H), 5.97 (s, 2H), 5.85 (s, 2H), 1.12 (s, 9H).

3-(((4-Carbamoylphenyl)amino)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (76)

(454) ##STR00140##

(a) Ethyl 3-(((4-carbamoylphenyl)amino)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (75)

(455) A solution of ethyl 3-(bromomethyl)-4-chlorobenzo[b]thiophene-2-carboxylate 15 (500 mg, 1.56 mmol), 4-aminobenzamide (213 mg, 1.56 mmol) and K.sub.2CO.sub.3 (865 mg, 6.26 mmol) in DMF (5 mL) was stirred at room temperature under a nitrogen atmosphere overnight. The mixture was diluted with water, extracted with EtOAc (50 mL) and the organic layer was washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=100:1 to 20:1) then re-crystallized (DCM/Pet. Ether) to give the title compound (500 mg) as a white solid. A 100 mg portion was further purified by preparative HPLC to give the title compound (5 mg) LCMS-C: rt 2.27 min; m/z 388.9 [M+H].sup.+, 410.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.09 (d, J=6.4 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.60-7.49 (m, 3H), 6.86 (s, 1H), 6.65 (d, J=7.6 Hz, 2H), 6.31 (s, 1H), 5.04 (s, 2H), 4.36-4.34 (m, 2H), 1.29 (t, J=6.4 Hz, 3H). The remaining material was used in the subsequent step without further purification.

(b) 3-(((4-Carbamoylphenyl)amino)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid (76)

(456) To a solution of ethyl 3-(((4-carbamoylphenyl)amino)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 75 (200 mg, 0.51 mmol) in MeOH (5 mL) was added NaOH (206 mg, 5.14 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with water (10 mL) and acidified to pH 4-5 with aq. 1 M HCl. The resulting precipitate was collected by filtration and purified by preparative HPLC to give the title compound (7 mg, 4%) as a white solid. LCMS-C: rt 1.79 min; m/z 360.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.07 (d, J=6.8 Hz, 1H), 7.66 (d, J=6.8 Hz, 2H), 7.55-7.51 (m, 3H), 6.86 (s, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.31 (br s, 1H), 5.05 (s, 2H).

Ethyl 3-((4-carbamoylphenoxy)methyl)-4-methylbenzo[b]thiophene-2-carboxylate (77)

(457) ##STR00141##

(458) A mixture of ethyl 4-bromo-3-((4-carbamoylphenoxy)methyl)benzo[b]thiophene-2-carboxylate 21 (400 mg, 0.92 mmol), methylboronic acid (221 mg, 3.68 mmol), Pd(PPh.sub.3).sub.4 (159 mg, 0.138 mmol) and K.sub.2CO.sub.3 (509 mg, 3.68 mmol) in dioxane (30 mL) was heated at 120° C. under a nitrogen atmosphere overnight. The mixture was cooled to room temperature, diluted with EtOAc (150 mL) and the organic phase was washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10:1 to 1:1) then re-crystallized (DCM/Pet. Ether) to give the title compound (200 mg) as a white solid. A 70 mg portion was purified further by preparative HPLC to give the title compound (40 mg, 12%). LCMS-C: rt 2.35 min; m/z 370.0 [M+H].sup.+, 391.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94-7.88 (m, 4H), 7.45 (t, J=7.2 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.21 (s, 1H), 7.12-7.10 (m, 2H), 5.79 (s, 2H), 4.33 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). The remaining material was used in the subsequent step without further purification.

Further Examples I

(459) The following examples were made according to the methods described in the general procedures:

(460) TABLE-US-00011 Starting Ex materials Name and structure LCMS data .sup.1H NMR data Method 78 77 embedded image LCMS-C: rt 1.98 min; m/z 342.0 [M + H].sup.+, 363.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.9 (s, 1H), 7.91- 7.87 (m, 4H), 7.42 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.20 (s, 1H), 7.12-7.10 (m, 2H), 5.82 (s, 2H), 2.65 (s, 3H). B Purified by preparative HPLC 3-((4- Carbamoylphenoxy) methyl)-4- methylbenzo[b]thiophene- 2-carboxylic acid 79 124 and 125 embedded image LCMS-C: rt 2.45 min; m/z 427.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 7.63- 7.48 (m, 4H), 7.44-7.35 (m, 1H), 5.84 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). A Steps (b) and (c) Ethyl 3-((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4,7-difluorobenzo[b]- thiophene-2-carboxylate 80 79 embedded image LCMS-C: rt 2.19 min; m/z 399.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.61- 7.54 (m, 3H), 7.52-7.46 (m, 1H), 7.41-7.34 (m, 1H), 5.88 (s, 2H), CO.sub.2H not observed. C 3-((4-Carbamoyl-2,6- difluorophenoxy)methyl)- 4,7-difluorobenzo[b] thiophene-2-carboxylic acid 81 124 embedded image LCMS-C: rt 2.41 min; m/z 391.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97-7.84 (m, 3H), 7.58-7.49 (m, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.23 (s, 1H), 7.07 (d, J = 8.5Hz, 2H), 5.68 (s, 2H), 4.36 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H). A Steps (b) and (c) Ethyl 3-((4- carbamoylphenoxy)- methyl)-4,7- difluorobenzo[b] thiophene-2-carboxylate 82 81 embedded image LCMS-C: rt 1.88 min; m/z 362.0 [M − H].sup.− .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90-7.80 (m, 3H), 7.39-7.31 (m, 1H), 7.28- 7.05 (m, 4H), 5.79 (s, 2H), CO.sub.2H not observed. C 3-((4- Carbamoylphenoxy)- methyl)-4,7- difluorobenzo[b]- thiophene-2-carboxylic acid 83 123 LCMS-C: rt 2.40 min; m/z 407.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23-8.17 (m, 1H), 7.90-7.87 (m, 3H), 7.69 (t, J = 9.1 Hz, 1H), 7.22 (s, 1H), 7.08 (d, J = 8.8Hz, 2H), 5.84 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). A Steps (b) and (c) Ethyl 3-((4- carbamoylphenoxy)- methyl)-4-chloro-5- fluorobenzo[b]- thiophene-2-carboxylate 84 83 embedded image LCMS-C: rt 2.14 min; m/z 379.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20-8.15 (m, 1H), 7.90-7.83 (m, 3H), 7.70- 7.63 (m, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.9 Hz, 2H), 5.87 (s,2H), CO.sub.2H not observed. C 3-((4- Carbamoylphenoxy) methyl)-4-chloro-5- fluorobenzo[b]- thiophene- 2-carboxylic acid 85 123 and 125 embedded image LCMS-C: rt 2.47 min; m/z 443.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.22-8.11 (m, 1H), 8.03 (s, 1H), 7.73-7.48 (m, 4H), 6.10 (s, 2H), 4.24 (q, J = 6.8Hz, 2H), 1.21 (t, J = 6.8 Hz, 3H). A Steps (b) and (c) Ethyl 3-((4- carbamoyl-2,6- difluorophenoxy)- methyl)-4-chloro-5- fluorobenzo[b]- thiophene- 2-carboxylate 86 85 0 embedded image LCMS-C: rt 2.17 min; m/z 415.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 8.00- 7.94 (m, 1H), 7.57 (m, 3H), 7.47 (m, 1H), 6.31 (s, observed. C 3-((4-Carbamoyl-2,6- difluorophenoxy)- methyl)-4-chloro-5- fluorobenzo[b]- thiophene- 2-carboxylic acid

3-(4-Carbamoylphenethyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid (88)

(461) ##STR00151##

(a) Ethyl (E)-3-(4-cyanostyryl)-4-fluorobenzo[b]thiophene-2-carboxylate A8

(462) Ethyl 3-(bromomethyl)-4-fluorobenzo[b]thiophene-2-carboxylate 13 (100 mg, 0.32 mmol) and triphenylphosphine (0.091 g, 0.35 mmol) were stirred in THF (1.5 mL) at 60° C. for 2.5 hours under a nitrogen atmosphere. The mixture was diluted with THF (3 mL) and cooled to 0° C. under a nitrogen atmosphere. Potassium tert-butoxide (0.039 g, 0.35 mmol) was added and the bright yellow mixture was stirred for 10 minutes. A solution of 4-cyanobenzaldehyde (45 mg, 0.35 mmol) in THF (1 mL) was added and the mixture stirred at room temperature for 3.5 hours. Water (50 mL) and brine (5 mL) were added and the mixture was extracted with DCM (4×25 mL). The pooled DCM extracts were washed with brine, dried over sodium sulfate and the solvent evaporated. The residue was purified by chromatography (4 g silica cartridge, 0-50% ethyl acetate/hexanes) and then recrystallised from toluene to give the title compound as an off-white solid (14.6 mg, 13% yield). LCMS-B rt 3.97 min; m/z 351.8 [M+H].sup.+. .sup.1H NMR (400 MHz, chloroform-d) δ 7.98 (dd, J=16.5, 0.8 Hz, 1H), 7.70-7.59 (m, 5H), 7.46 (td, J=8.0, 4.6 Hz, 1H), 7.15-7.01 (m, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H). .sup.19F NMR (376 MHz, Chloroform-d) δ −110.14.

(b) Ethyl 3-(4-cyanophenethyl)-4-fluorobenzo[b]thiophene-2-carboxylate A9

(463) Ethyl (E)-3-(4-cyanostyryl)-4-fluorobenzo[b]thiophene-2-carboxylate A8 (15 mg, 0.043 mmol), ethyl acetate (2 mL), ethanol (1 mL) and 10% Pd/C (53% wetted with water, 20 mg) were stirred vigorously under a hydrogen atmosphere for two hours. The mixture was filtered through an HPLC filter and concentrated in vacuo to give the title compound as a white solid (20.0 mg, >100% yield). The material was used in the next step without further purification assuming quantitative yield. LCMS-A rt 6.84 min; no products ions detected. .sup.1H NMR (400 MHz, chloroform-d) δ 7.69-7.55 (m, 3H), 7.50-7.36 (m, 3H), 7.07 (ddd, J=12.1, 7.9, 0.9 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.74-3.67 (m, 2H), 3.06-2.99 (m, 2H), 1.41 (t, J=7.1 Hz, 3H).

(464) Crude ethyl 3-(4-cyanophenethyl)-4-fluorobenzo[b]thiophene-2-carboxylate A9 (0.0427 mmol, quantitative yield assumed) was slurried in DMSO (0.75 mL) and treated in a fashion analogous to that of the preparation of 2 to give the title compound (8.10 mg, 51% yield, ˜85% purity by .sup.19F NMR). LCMS-B rt 3.54 min; m/z 371.8 [M+H].sup.+. .sup.1H NMR (400 MHz, methanol-d.sub.4) δ 7.84-7.75 (m, 2H), 7.72 (dd, J=8.1, 0.9 Hz, 1H), 7.49 (ddd, J=9.0, 7.5, 4.9 Hz, 1H), 7.33-7.28 (m, 2H), 7.20-7.09 (m, 1H), 4.34 (qd, J=7.1, 1.6 Hz, 2H), 3.77-3.68 (m, 2H), 3.06-2.96 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), CONH.sub.2 protons not observed. .sup.19F NMR (376 MHz, Methanol-d4) δ −120.17.

(d) 3-(4-Carbamoylphenethyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid 88

(465) Ethyl 3-(4-carbamoylphenethyl)-4-fluorobenzo[b]thiophene-2-carboxylate 87 (6.7 mg, 0.018 mmol) was dissolved in 2:1 THF:MeOH (1 mL) and a 2.0 M aqueous solution of lithium hydroxide monohydrate (0.125 mL, 0.250 mmol) was added. The mixture was stirred at room temperature for 2.5 hours before the volatile solvents were stripped with a stream of air. The aqueous residue was diluted with 1 M aqueous HCl (1 mL), the precipitate was collected by filtration, washed with aqueous 0.5 M HCl (2×0.5 mL) and air dried to give the title compound as a white solid (4.9 mg, 79% yield). LCMS-A rt 5.68 min; m/z 343.8 [M+H].sup.+.

Further Examples II

(466) The following examples were made according to the methods described in the general procedures:

(467) TABLE-US-00012 Starting LCMS Ex. materials Name and structure data .sup.1HNMR data Method 89 162 & 125 embedded image LCMS-C: rt 2.48 min; m/z 469.8/471.8 [M + H].sup.+, 491.8/493.8 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (dd, J= 8.1, 1.0 Hz, 1H), 8.02 (s, 1H), 7.83 (dd, J = 7.7, 1.0 Hz, 1H), 7.62-7.55 (m, 3H), 7.49 (t, J = 7.9 Hz, 1H), 6.18 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). A (step C): 1 eq phenol and 2 eq CS.sub.2CO.sub.3 used; Purified by column chromato- graphy (Pet. Ether/ EtOAc = 1:1) Ethyl 4-bromo-3-((4- carbamoyl-2,6- difluorophenoxy) methyl)benzo[b] thiophene- 2-carboxylate 90 89 embedded image LCMS-C: rt 2.12 min; m/z 441.8/443.8 [M + H].sup.+, 463.7/465.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (dd, J = 8.0, 0.4 Hz, 1H), 8.01 (s, 1H), 7.81 (dd, J = 7.7, 0.8 Hz, 1H), 7.61-7.54 (m, 3H), 7.46 (t, J = 7.9 Hz, 1H), 6.22 (s, 2H), CO.sub.2H not observed. B 4-Bromo-3-((4- carbamoyl-2,6- difluorophenoxy)- methyl)benzo[b]- thiophene-2- carboxylic acid 91 160 & 125 embedded image LCMS-C: rt 2.12 min; m/z 426.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.43 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H), 8.10 (s, 1H), 7.62 (d, J = 9.1 Hz, 2H), 7.60-7.56 (m, 1H), 6.10 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). A (step C): 1 eq phenol used; purified by column chromato- graphy (DCM/ MeOH = 100:0 to 100:1) Ethyl 3-((4- carbamoyl-2,6- difluorophenoxy)- methyl)-4- chlorothieno[3,2- c]pyridine-2- carboxylate 92 156 & 125 embedded image LCMS-C: rt 2.53 min; m/z 443.9 [M + H].sup.+, 465.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.07 (s, 1H), 7.68 (dd, J =8.5, 4.6 Hz, 1H), 7.64- 7.57 (m, 3H), 7.53 (t, J= 8.8 Hz, 1H), 6.10 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). A (step C): 1 eq phenol used; purified by column chromato- graphy (DCM/ MeOH = 100:0 to 80:1) Ethyl 3-((4- carbamoyl-2,6- difluorophenoxy)- methyl)- 4-chloro-7- fluorobenzo[b]- thiophene-2- carboxylate 93 92 embedded image LCMS-C: rt 2.17 min; m/z 415.9 [M + H].sup.+, 437.8 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.66 (dd, J = 8.5, 4.6 Hz, 1H), 7.62- 7.54 (m, 3H), 7.50 (t, J= 8.7 Hz, 1H), 6.13 (s,2H), CO.sub.2H not observed. C 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)- 4-chloro-7- fluorobenzo[b]- thiophene-2- carboxylic acid 94 140 & 125 embedded image LCMS-C: rt 2.52 min; m/z 457.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.68- 7.54 (m, 4H), 7.48 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.06 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 6.9 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 6.9 Hz, 3H). A (step C): 1 eq phenol and 2 eq CS.sub.2CO.sub.3 used; purified by column chromatogra- phy (Pet. Ether/ EtOAc = 2:1) Ethyl 3-((4- carbamoyl-2,6- difluorophenoxy) methyl)-4- ethoxybenzo[b]- thiophene- 2-carboxylate 95 94 embedded image LCMS-C: rt 2.15 min; m/z 429.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.65- 7.52 (m, 4H), 7.44 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.09 (s, 2H), 4.06 (q, J = 6.9 Hz, 2H), 1.11 (t, J= 6.9 Hz, 3H), CO.sub.2H not observed. B 3-((4- Carbamoyl-2,6- difluorophenoxy) methyl)-4- ethoxybenzo[b]- thiophene- 2-carboxylic acid 96 165 embedded image LCMS-C: rt 2.04 min; m/z 415.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.09 (s, 1H), 7.70- 7.60 (m, 2H), 7.53 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.20 (s, 2H), 3.55 (s, 3H), CO.sub.2H not observed. B 3-((4- Carbamoyl-2,6- difluorophenoxy) methyl)-4- methoxybenzo[b]- thiophene- 2-carboxylic acid 97 15 & 175 0 embedded image LCMS-C: rt 2.53 min; m/z 419.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.13 (dd, J = 7.1, 2.0 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.63-7.54 (m, 2H), 7.51 (s, 1H), 7.36 (s, 1H), 6.76 (dd, J = 8.6, 2.3 Hz, 1H), 6.71 (s, 1H), 5.89 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). A (step C): 1 eq phenol and 4 eq K.sub.2CO.sub.3 used; purified by column chromatogra- phy (DCM/ MeOH = 20:1) and Prep-RP- HPLC. Ethyl 3-((4- carbamoyl-3- methoxyphenoxy)- methyl)-4- chlorobenzo[b]- thiophene- 2-carboxylate 98 97 embedded image LCMS-C: rt 2.20 min; m/z 391.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08 (d, J = 7.1 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.63-7.46 (m, 3H), 7.33 (s, 1H), 6.74 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 5.92 (s, 2H), 3.88 (s, 3H), CO.sub.2H not observed. B: 10 eq NaOH used; MeOH used as solvent 3-((4-Carbamoyl-3- methoxyphenoxy)- methyl)-4- chlorobenzo[b]- thiophene- 2-carboxylic acid 99 134 & 125 embedded image LCMS-C: rt 2.78 min; m/z 503.8/505.8 [M + H].sup.+, 525.8/527.8 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.63-7.55 (m, 4H), 6.09 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). A (step C): 1.05 eq bromide, 1 eq phenol and 2 eq Cs.sub.2CO.sub.3 used; purified by trituration with MeOH Ethyl 7-bromo-3- ((4-carbamoyl-2,6- difluorophenoxy) methyl)-4- chlorobenzo[b]- thiophene- 2-carboxylate 100 99 embedded image LCMS-D: rt 4.10 min; m/z 497.8/499.7 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.80 (d, J= 8.2 Hz, 1H), 7.61-7.52 (m, 4H), 6.14 (s, 2H), CO.sub.2H not observed. B 7-Bromo-3-((4- carbamoyl-2,6- difluorophenoxy)- methyl)-4- chlorobenzo[b] thiophene- 2-carboxylic acid 101 144 embedded image LCMS-F: rt 2.85 min; m/z 434.0 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.62- 7.50 (m, 4H), 7.39 (d, J = 7.8 Hz, 1H), 6.16 (s, 2H), 2.52 (s, 3H), CO.sub.2H not observed. B 3-((4-Carbamoyl-2,6- difluorophenoxy)- methyl)-4-chloro-7- methylbenzo[b]- thiophene- 2-carboxylic acid 102 129 & 125 embedded image LCMS-F: rt 2.95 min; m/z 423.0 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (d, J = 5.7 Hz, 1H), 8.02 (s, 1H), 7.70 (d, J = 5.7 Hz, 1H), 7.64- 7.55 (m, 3H), 5.94 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.85(s, 3H), 1.26 (t, J = 7.1 Hz, 3H). A (step C): 1.05 eq bromide, 1 eq phenol and 2 eq CS.sub.2CO.sub.3 used; purified by column chromatogra- phy (Pet. Ether/ EtOAc = 100:1 to 1:1) Ethyl 3-((4- carbamoyl-2,6- difluorophenoxy)- methyl)-4- methoxythieno- [3,2-c]pyridine- 2-carboxylate 103 102 embedded image LCMS-F: rt 1.65 min; m/z 395.1 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.11 (d, J = 5.7 Hz, 1H), 8.02 (s, 1H), 7.67 (d, J = 5.7 Hz, 1H), 7.63- 7.53 (m, 3H), 5.96 (s, 2H), 3.82 (s, 3H), CO.sub.2H not observed. B 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4- methoxythieno- [3,2-c]pyridine- 2-carboxylic acid 104 145 embedded image LCMS-F: rt 1.30 min; m/z 427.8 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (s, 1H), 7.62- 7.53 (m, 4H), 7.50 (d, J = 7.9 Hz, 1H), 6.18 (s, 2H), 5.69 (t, J = 4.8 Hz, 1H), 4.76 (d, J = 3.9 Hz, 2H), CO.sub.2H not observed. B 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4-chloro-7- (hydroxymethyl)- benzo[b]- thiophene- 2-carboxylic acid 105 146 embedded image LCMS-F: rt 2.63 min; m/z 441.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.63- 7.53 (m, 4H), 7.50 (d, J = 7.8 Hz, 1H), 6.17 (s, 2H), 4.71 (s, 2H), 3.33 (s, 3H), CO.sub.2H not observed. B 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4-chloro-7- (methoxymethyl) benzo[b]- thiophene- 2-carboxylic acid 106 147 embedded image LCMS-D: rt 2.31 min; m/z 435.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.9 (s, 1H), 8.04 (s, 1H), 7.65-7.55 (m, 2H), 7.52 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.26 (s, 2H), CO.sub.2H not observed. B 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4-chloro-7- hydroxybenzo[b]- thiophene- 2-carboxylic acid 107 149 0 embedded image LCMS-F: rt 2.72 min; m/z 428.0 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (s, 1H), 7.58- 7.53 (m, 4H), 7.13 (d, J = 8.4 Hz, 1H), 6.14 (s, 2H), 4.01 (s, 3H), CO.sub.2H not observed. B 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4-chloro-7- methoxybenzo[b]- thiophene- 2-carboxylic acid 108 137 & 125 embedded image LCMS-D: rt 3.78 min; m/z 424.0 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.84 (s, 1H), 8.04 (s, 1H), 7.64-7.58 (m, 3H), 5.86 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). A (step C): 2 eq CS.sub.2CO.sub.3 used; purified by column chromatogra- phy (DCM/ MeOH = 100:1 to 20:1) 5-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4- methoxythieno- [2,3-d]pyrimidine- 6-carboxylic acid 109 108 embedded image LCMS-D: rt 3.60 min; m/z 396.0 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.82 (s, 1H), 8.04 (s, 1H), 7.66- 7.53 (m, 3H), 5.87 (s, 2H), 3.97 (s, 3H), CO.sub.2H not observed. B 5-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4- methoxythieno- [2,3-d]pyrimidine- 6-carboxylic acid 110 15 & 169 embedded image LCMS-D: rt 3.92 min; m/z 438.0 [M + H].sup.+, 460.0 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.13 (d, J = 7.9 Hz, 1H), 7.95 (s, 1H), 7.76 (s, 1H), 7.68-7.62 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.34 (s, 1H), 6.07 (s, 2H), 5.07 (brs, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 1.20 (t, J = 7.1 Hz, 3H). A (step C): 1.05 eq bromide, 1 eq phenol and 2 eq CS.sub.2CO.sub.3 used; purified by column chromato- graphy (Pet. Ether/ EtOAc = 1:1 to 1:3) (step C) Ethyl 3-((4- carbamoyl-2- fluoro-6- (hydroxymethyl)- phenoxy)methyl)- 4-chlorobenzo[b]- thiophene- 2-carboxylate 111 110 embedded image LCMS-D: rt 3.34 min; m/z 408.0 [M − H].sup.− .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.11 (dd, J= 7.9, 1.1 Hz, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 7.68-7.59 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.34 (s, 1H), 6.10 (s, 2H), 5.08 (brs, 1H), 4.17 (s, 2H), CO.sub.2H not observed. B 3-((4-Carbamoyl- 2-fluoro-6- (hydroxymethyl)- phenoxy)methyl)- 4-chlorobenzo[b]- thiophene- 2-carboxylic acid 112 151 embedded image LCMS-D: rt 3.35 min; m/z 426.0 [M − H].sup.− .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.7-13.3 (m, 2H), 8.12 (dd, J = 7.3, 1.9 Hz, 1H), 7.86 (s, 2H), 7.64 (s, 1H), 7.60-7.49 (m, 2H), 7.38- 7.23 (m, 2H), 7.13 (d, J = 2.5 Hz, 1H), 6.94 (dd, J = 8.4, 2.6 Hz, 1H), 5.89 (s, 2H). B 3-((4-Carbamoyl-3- (1H-pyrazol-4- yl)phenoxy)- methyl)-4- chlorobenzo[b]- thiophene- 2-carboxylic acid 113 150 embedded image LCMS-D: rt 3.59 min; m/z 406.0 [M + H].sup.+, 428.0 [M + Na].sup.+ .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.11 (dd, J = 7.0, 2.1 Hz, 1H), 7.68 (s, 1H), 7.60-7.49 (m, 3H), 7.23 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.98 (dd, J = 8.5, 2.7 Hz, 1H), 5.87 (s, 2H), 4.63 (s, 2H), 3.32 (s, 3H), CO.sub.2H not observed. B 3-((4-Carbamoyl-3- (methoxymethyl)- phenoxy)methyl)- 4-chlorobenzo[b]- thiophene- 2-carboxylic acid 114 142 embedded image LCMS-C: rt 2.35 min; m/z 425.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 7.89 (d, J= 8.1 Hz, 1H), 7.63-7.54 (m, 3H), 7.44 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 7A Hz, 1H), 6.24 (s, 2H), 2.85- 2.76 (m, 1H), 1.08-1.00 (m, 2H), 0.95-0.88 (m, 2H), CO.sub.2H not observed. B 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4- cyclopropyl- benzo[b]- thiophene- 2-carboxylic acid 115 146 & 125 embedded image LCMS-C: rt 2.49 min; m/z 458.0 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.09-8.03 (m, 2H), 7.66-7.50 (m, 5H), 6.00 (s, 2H), 4.98 (s, 2H), 4.28-4.14 (m, 2H), 3.30 (s, 3H), 1.29-1.16 (m, 3H). A (step C): Purified by column chromato- graphy (DCM/ MeOH = 100:0 to 50:1) Ethyl 3-((4- carbamoyl-2,6- difluorophenoxy)- methyl)-4- (methoxymethyl)- benzo[b]thiophene- 2-carboxylate 116 152 & 125 embedded image LCMS-D: rt 4.34 min; m/z 488.0 [M + H].sup.+, 509.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.87 (dd, J = 8.5, 4.9 Hz, 1H), 7.59 (d, J = 9.3 Hz, 2H), 7.57 (s, 1H), 7.47 (t, J = 8.8 Hz, 1H), 6.16 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.21 (t, J= 7.1 Hz, 3H). A (step C): 1.05 eq bromide, 1 eq phenol and 2 eq CS.sub.2CO.sub.3 used; purified by column chromato- graphy (Pet. Ether/ EtOAc = 100:0 to 1:1) Ethyl 4-bromo-3- ((4-carbamoyl-2,6- difluorophenoxy)- methyl)-7- fluorobenzo[b]- thiophene- 2-carboxylate 117 116 0 embedded image LCMS-F: rt 4.28 min; m/z 459.8 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.85 (dd, J = 8.5, 4.9 Hz, 1H), 7.59 (s, 1H), 7.57 (d, J = 2.9 Hz, 2H), 7.43 (t, J= 8.8 Hz, 1H), 6.19 (s, 2H), CO.sub.2H not observed. B 4-Bromo-3-((4- carbamoyl-2,6- difluorophenoxy) methyl)-7- fluorobenzo[b]- thiophene- 2-carboxylic acid 118 153 embedded image LCMS-F: rt 2.43 min; m/z 423.0 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.62- 7.53 (m, 3H), 6.16 (s, 2H), CO.sub.2H not observed. B: Purified the precipitate by Prep-HPLC 3-((4-Carbamoyl-2,6- difluorophenoxy) methyl)-4-chloro- 7-cyanobenzo[b]- thiophene- 2-carboxylic acid 121 129 & 169 embedded image LCMS-D: rt3.52 min; m/z 435.1 [M + H].sup.+, 457.1 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (d, J = 5.7 Hz, 1H), 7.95 (s, 1H), 7.78-7.76 (m, 1H), 7.74- 7.71 (m, 1H), 7.70-7.65 (m, 1H), 7.35 (s, 1H), 5.88 (s, 2H), 5.10 (t, J = 5.6 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.17 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). A (step C): 1.2 eq phenol and 3 eq CS.sub.2CO.sub.3 used; purified by prep-TLC (DCM/ MeOH = 10:1) Ethyl 3-((4- carbamoyl-2- fluoro-6- (hydroxymethyl)- phenoxy)methyl)-4- methoxythieno[3,2- c]pyridine-2- carboxylate

Further Examples III

(Pivaloyloxy)methyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-fluoro benzo[b]thiophene-2-carboxylate (122)

(468) ##STR00183##

(469) A suspension of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-fluoro benzo[b]thiophene-2-carboxylic acid 93 (50 mg, 0.12 mmol), chloromethyl pivalate (73 mg, 0.48 mmol), NaI (72 mg, 0.48 mmol) and 052003 (78 mg, 0.24 mmol) in DMF (5 mL) was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic extracts were washed with water (100 mL×3), brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (65 mg, 100%) as a white solid. LCMS-C: rt 2.76 min; m/z 529.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.11 (s, 1H), 7.70 (dd, J=8.6, 4.6 Hz, 1H), 7.68-7.54 (m, 4H), 6.10 (s, 2H), 5.90 (s, 2H), 1.12 (s, 9H).

(470) The following examples were prepared according to the procedure described for (122).

(471) TABLE-US-00013 Starting LCMS Ex materials Name and structure data .sup.1H NMRdata Comment 123 96 & Chloromethyl pivalate embedded image LCMS-C: rt 2.61 min; m/z 529.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.66-7.58 (m, 3H), 7.56 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H), 5.92 (s, 2H), 3.69 (s, 3H), 1.14 (s, 9H). (Pivaloyloxy)methyl 3- ((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4-methoxybenzo[b] thiophene-2-carboxylate 124 114 & Chloromethyl pivalate embedded image LCMS-C: rt 2.76 min; m/z 518.0 [M + H].sup.+, 540.0 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.63- 7.55 (m, 3H), 7.50 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 6.21 (s, 2H), 5.85 (s, 2H), 2.84-2.76 (m, 1H), 1.11 (s, 9H), 1.05-1.02 (m, 2H), 0.94- 0.90 (m, 2H). (Pivaloyloxy)methyl 3- ((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4-cyclopropylbenzo[b]- thiophene-2-carboxylate 125 69 & 1-Chloro-2- methylpropyl propionate embedded image LCMS-C: rt 2.74 min; m/z 547.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.8, 1.3 Hz, 1H), 8.01 (s, 1H), 7.67-7.54 (m, 5H), 6.66 (d, J = 4.9 Hz, 1H), 6.13 (s,2H), 2.39-2.30 (m, 2H), 2.07-1.97 (m, 1H), 1.02 (t, J= 7.5 Hz, 3H), 0.92-0.90 (m, 6H). Heated at 60° C. overnight; Purified by column chromato- graphy (Pet. Ether/ EtOAc = 10:1 to 0:1) 2-Methyl-1- (propionyloxy)propyl 3- ((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 126 69 & 4-(Chloro- methyl)- 5-methyl- 1,3-dioxol-2- one embedded image LCMS-C: rt 2.46 min; m/z 509.9 [M + Na].sup.+, 531.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.9, 1.3 Hz, 1H), 8.02 (s, 1H), 7.66-7.54 (m, 5H), 6.11 (s, 2H), 5.20 (s, 2H), 2.17 (s, 3H). Purified by column chromato- graphy (Pet. Ether/ EtOAc = 10:1 to 0:1) and recrystalliza- tion (Pet. Ether/DCM) (5-Methyl-2-oxo-1,3- dioxol-4-yl)methyl 3-((4- carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 127 69 & 2-Chloro- N,N- dimethyl- acetamide embedded image LCMS-C: rt 2.28 min; m/z 482.9 [M + H].sup.+, 504.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.8, 1.2 Hz, 1H), 8.01 (s, 1H), 7.68-7.52 (m, 5H), 6.14 (s, 2H), 5.01 (s, 2H), 2.94 (s, 3H), 2.82 (s, 3H). Purified by column chromato- graphy (Pet. Ether/ EtOAc = 10:1 to 0:1) then prep-HPLC 2-(Dimethylamino)-2- oxoethyl 3-((4- carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 128 90 & Chloromethyl pivalate embedded image LCMS-C: rt 2.67 min; m/z 555.9/ 557.9, [M + H].sup.+, 577.9/ 579.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (dd, J = 8.1, 1.0 Hz, 1H), 8.02 (s, 1H), 7.85 (dd, J = 7.7, 1.0 Hz, 1H), 7.63-7.54 (m, 3H), 7.51 (t, J = 7.9 Hz, 1H), 6.17 (s, 2H), 5.88 (s, 2H), 1.12 (s, 9H). Purified by column chromato- graphy (DCM/MeOH = 100:0 to 100:1) (Pivaloyloxy)methyl 4- bromo-3-((4-carbamoyl- 2,6- difluorophenoxy)methyl)- benzo[b]thiophene-2- carboxylate 129 69 & 176 0 embedded image LCMS-C: rt 2.69 min; m/z 563.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.9, 1.2 Hz, 1H), 8.02 (s, 1H), 7.67-7.54 (m, 5H), 6.73 (q, J = 5.4 Hz, 1H), 6.11 (app q, J = 11.3 Hz, 2H), 1.46 (d, J = 5.5 Hz, 3H), 1.40 (s, 9H). Purified by prep-TLC (DCM/ MeOH = 20:1) 1-((tert- Butoxycarbonyl)oxy)ethyl 3-((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 130 69 & 177 embedded image LCMS-C: rt 2.64 min; m/z 550.1 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (dd, J = 7.8, 1.3 Hz, 1H), 8.02 (s, 1H), 7.67-7.55 (m, 5H), 6.12 (s, 2H), 5.84 (s, 2H), 1.42 (s, 9H). Purified by column chromato- graphy (DCM/MeOH = 1:0 to 50:1) ((tert- Butoxycarbonyl)oxy)me thyl 3-((4-carbamoyl- 2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 131 117 & Chloromethyl pivalate embedded image LCMS-C: rt 2.74 min; m/z 595.8/ 597.8 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.89 (dd, J = 8.5, 4.9 Hz, 1H), 7.63-7.54 (m, 3H), 7.49 (t, J = 8.8 Hz, 1H), 6.15 (s,2H), 5.89 (s, 2H), 1.12 (s, 9H). Purified by column chromato- graphy (DCM/MeOH = 1:0 to 50:1) (Pivaloyloxy)methyl 4- bromo-3-((4-carbamoyl- 2,6- difluorophenoxy)methyl)- 7-chlorobenzo[b]- thiophene-2-carboxylate 132 69 & 178 embedded image LCMS-C: rt 2.64 min; m/z 549.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.9, 1.2 Hz, 1H), 8.02 (s, 1H), 7.69-7.52 (m, 5H), 6.77 (q, J = 5.4 Hz, 1H), 6.16-6.06 (m, 2H), 4.82-4.72 (m, 1H), 1.48 (d, J= 5.5 Hz, 3H), 1.23-1.20 (m, 6H). Purified by prep-TLC (DCM/ MeOH = 20:1) 1- ((Isopropoxycarbonyl)- oxy)ethyl 3-((4- carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 133 69 & 179 embedded image LCMS-C: rt 2.69 min; m/z 648.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (dd, J = 7.8, 1.3 Hz, 1H), 8.06-8.00 (m, 1H), 7.68-7.54 (m, 5H), 7.30 (d, Hz, 1H), 6.13 (s,2H), 5.97 (d, J = 6.1 Hz, 1H), 5.87 (d, J = 6.2 Hz, 1H), 3.86 (t, J = 7.0 Hz, 1H), 2.03- 1.92 (m, 1H), 1.34 (s, 9H), 0.85-0.82 (m, 6H). 3 eq. of XWH-744- 022 used; Purified by column chromato- graphy (DCM/ MeOH = 50:1) (((tert-Butoxycarbonyl)- L-valyl)oxy)methyl 3- ((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 134 69 & 180 embedded image LCMS-C: rt 2.52 min; m/z 505.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.9, 1.3 Hz, 1H), 8.04 (s, 1H), 7.68-7.55 (m, 5H), 6.86 (q, J = 5.4 Hz, 1H), 6.11 (s, 2H), 2.05 (d, J = 2.5 Hz, 3H), 1.46 (d, J= 5.5 Hz, 3H). Purified by column chromato- graphy (Pet. Ether/EtOAc = 10:1 to 1:1) then prep-TLC (EtOAc) 1-Acetoxyethyl 3-((4- carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 135 69 & 181 embedded image LCMS-C: rt 2.68 min; m/z 533.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.9, 1.2 Hz, 1H), 8.03 (s, 1H), 7.68-7.55 (m, 5H), 6.86 (q, J = 5.3 Hz, 1H), 6.15-6.07 (m, 2H), 2.59-2.52 (m, 1H), 1.47 (d, J = 5.5 Hz, 3H), 1.09-1.06 (m, 6H). Purified by column chromato- graphy (Pet. Ether/ EtOAc = 10:1 to 1:1) 1-(Isobutyryloxy)ethyl 3-((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 136 69 & 2-Chloro- N,N- dimethyl ethan-1- amine embedded image LCMS-D: rt 2.97 min; m/z 468.9 [M + H].sup.+ .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 7.93 (dd, J = 8.0, 1.2 Hz, 1H), 7.56-7.53 (m, 1H), 7.52-7.45 (m, 3H), 6.25 (s, 2H), 3.69 (t, J = 6.0 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.38 (s, 6H), CONH.sub.2 protons not observed. 2 eq. of 2- Chloro-N,N- dimethyleth- an-1-amine used; Purified by column chromato graphy (DCM/ MeOH = 10:1) 2-(Dimethylamino)ethyl 3-((4-carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 137 69 & 4-(2- Bromoethyl) morpholine embedded image LCMS-F: rt 2.23 min; m/z 511.1 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.13 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.66-7.54 (m, 5H), 6.14 (s, 2H), 4.33 (t, J = 5.7 Hz, 2H), 3.54-3.51 (m, 4H), 2.56 (t, J = 5.7 Hz, 2H), 2.42-2.40 (m, 4H). 2 eq. of 4-(2- Bromoethyl) morpholine and 3 eq. of CS.sub.2CO.sub.3 used; Heated at 60° C.; Purified by column chromato- graphy (DCM/ MeOH = 20:1) 2-Morpholinoethyl 3-((4- carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 138 69 & 182 embedded image LCMS-C: rt 2.37 min; m/z 498.9 [M + H].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (dd, J = 7.9, 1.3 Hz, 1H), 8.02 (s, 1H), 7.68-7.52 (m, 5H), 6.13 (s, 2H), 5.84 (s, 2H), 2.83 (s, 6H). Purified by column chromato- graphy (DCM/ MeOH = 50:1) ((Dimethylcarbamoyl)- oxy)methyl 3-((4- carbamoyl-2,6- difluorophenoxy)methyl)- 4-chlorobenzo[b]- thiophene-2-carboxylate 139 69 & 183 00 embedded image LCMS-C: rt 2.38 min; m/z 568.9 [M + H].sup.+, 590.9 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (d, J = 7.6 Hz, 1H), 8.17 (dd, J = 7.8, 1.3 Hz, 1H), 8.03 (s, 1H), 7.68-7.55 (m, 5H), 6.13 (s, 2H), 5.97 (d, J = 6.1 Hz, 1H), 5.88 (d, J = 6.0 Hz, 1H), 4.16 (dd, J = 7.6, 6.2 Hz, 1H), 2.05- 1.94 (m, 1H), 1.87 (s, 3H), 0.86-0.83 (m, 6H). Purified by prep-TLC (DCM/MeO H = 20:1) ((Acetyl-L- valyl)oxy)methyl 3- ((4-carbamoyl-2,6- difluorophenoxy)methyl) 4-chlorobenzo[b]- thiophene-2-carboxylate 140 117 & 1-Chloro-2- methylpropyl propionate 01 embedded image LCMS-D: rt 4.83 min; m/z 610.0/ 612.0 [M + Na].sup.+ .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (s, 1H), 7.89 (dd, J = 8.5, 4.9 Hz, 1H), 7.59 (d, J = 9.2 Hz, 2H), 7.57 (s, 1H), 7.50 (t, J = 8.7 Hz, 1H), 6.66 (d, J = 4.9 Hz, 1H), 6.16 (s, 2H), 2.43-2.27 (m, 2H), 2.10- 1.96 (m, 1H), 1.01 (t, J = 7.5 Hz, 3H), 0.90 (d, J= 6.8 Hz, 6H). Heated at 60° C.; Purified by column chromato- graphy (DCM/ MeOH = 100:1 to 30:1) 2-Methyl-1- (propionyloxy)propyl 4- bromo-3-((4-carbamoyl- 2,6- difluorophenoxy)methyl)- 7-fluorobenzo[b]- thiophene-2-carboxylate

Further Examples IV

Methyl 3-((4-carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylate (141)

(472) ##STR00202##

(473) To a solution of 3-((4-carbamoylphenoxy)methyl)-4-fluorobenzo[b]thiophene-2-carboxylic acid 1 (120 mg, 0.35 mmol) and Et.sub.3N (39 mg, 0.39 mmol) in THF (10 mL) at −15° C. was added a solution of ethyl chloroformate (40 mg, 0.37 mmol) in THF (2 mL). The mixture was then stirred at −5° C. for 30 min and filtered. The filtrate was diluted with acetonitrile (5 mL), (diazomethyl)trimethylsilane (2 M in hexanes, 0.35 mL, 0.70 mmol) was added and the mixture was stirred at 4° C. overnight. The mixture was diluted with EtOAc, washed with a 10% aqueous citric acid solution followed by a saturated aqueous NaHCO.sub.3 solution, then brine, then dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=5:1) to give the title compound (20 mg, 16%) as a white solid. LCMS-C: rt 2.12 min; m/z 359.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97 (d, J=8.2 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.85 (s, 1H), 7.65-7.57 (m, 1H), 7.34-7.26 (m, 1H), 7.19 (s, 1H), 7.07 (d, J=8.8 Hz, 2H), 5.71 (s, 2H), 3.89 (s, 3H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-cyclopropylbenzo[b]thiophene-2-carboxylate (142)

(474) ##STR00203##

(475) A solution of ethyl 4-bromo-3-((4-carbamoyl-2,6 difluorophenoxy)methyl)benzo[b]thiophene-2-carboxylate 114 (290 mg, 0.61 mmol), cyclopropyl boronic acid (159 mg, 1.85 mmol), Pd(PPh.sub.3).sub.4 (105 mg, 0.09 mmol) and K.sub.2CO.sub.3 (253 mg, 1.83 mmol) in 1,4-dioxane (10 mL) was heated at reflux under a N.sub.2 atmosphere overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. Ether/EtOAc=2:1) to give the title compound (137 mg, 52%) as a grey solid. LCMS-C: rt 2.56 min; m/z 453.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.62-7.55 (m, 3H), 7.47 (t, J=7.8 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 6.21 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.85-2.76 (m, 1H), 1.19 (t, J=7.1 Hz, 3H), 1.08-1.01 (m, 2H), 0.96-0.89 (m, 2H).

(Diethoxyphosphoryl)methyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (143)

(476) ##STR00204##

(477) To a solution of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (1.0 g, 2.5 mmol) in DMF (20 mL) was added diethyl (hydroxymethyl)phosphonate (1.27 g, 7.54 mmol), EDCl.HCl (964 mg, 5.03 mmol) and DMAP (61 mg, 0.50 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=50:1) to give the title compound (360 mg, 26%) as a yellow solid. LCMS-C: rt 2.35 min; m/z 547.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (d, J=7.8 Hz, 1H), 8.02 (s, 1H), 7.68-7.50 (m, 5H), 6.15 (s, 2H), 4.66 (d, J=8.4 Hz, 2H), 4.19-4.02 (m, 4H), 1.24 (t, J=7.0 Hz, 6H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-methylbenzo[b]thiophene-2-carboxylate (144)

(478) ##STR00205##

(479) A mixture of ethyl 7-bromo-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 99 (200 mg, 0.40 mmol), K.sub.2CO.sub.3 (164 mg, 1.19 mmol), methyl boronic acid (48 mg, 0.79 mmol) and Pd(PPh.sub.3).sub.4 (46 mg, 0.04 mmol) in 1,4-dioxane (15 mL) was heated at reflux under N.sub.2 overnight. The mixture was diluted with water, extracted with EtOAc and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (30 mg, 17%) as a white solid. LCMS-F: rt 3.42 min; m/z 440.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.65-7.53 (m, 4H), 7.43 (d, J=7.8 Hz, 1H), 6.14 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.23 (t, J=7.1 Hz, 3H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-(hydroxymethyl)benzo[b]thiophene-2-carboxylate (145)

(480) ##STR00206##

(a) (Tributylstannyl)methanol (I94)

(481) To a solution of diisopropylamine (2.1 g, 20.6 mmol) in THF (50 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M in hexanes, 8.2 mL, 20.6 mmol) dropwise and the mixture was stirred at −78° C. for 30 min. Tributylstannane (5.0 g, 17.2 mmol) was added and the mixture was allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was again cooled to −78° C. and paraformaldehyde (527 mg, 5.84 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (Pet. Ether/EtOAc=80:1) to give the title compound (3.0 g, 55%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.68 (s, 1H), 4.01 (s, 2H), 1.56-1.47 (m, 6H), 1.34-1.27 (m, 6H), 0.95-0.85 (m, 15H).

(b) Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-(hydroxymethyl)benzo[b]thiophene-2-carboxylate 145

(482) To a solution of ethyl 7-bromo-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 99 (100 mg, 0.198 mmol) and (tributylstannyl)methanol 194 (127 mg, 0.396 mmol) in 1,4-dioxane (6 mL) was added Pd(PPh.sub.3).sub.4 (23 mg, 0.02 mmol) and the mixture was heated at reflux under N.sub.2 overnight. The mixture was diluted with water, extracted with EtOAc and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15/1) to give the title compound (19 mg, 21%) as a white solid. LCMS-D: rt 3.69 min; m/z 478.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06 (s, 1H), 7.65-7.55 (m, 4H), 7.52 (d, J=7.8 Hz, 1H), 6.16 (s, 2H), 5.76 (t, J=5.6 Hz, 1H), 4.78 (d, J=5.6 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-(methoxymethyl)benzo[b]thiophene-2-carboxylate (146)

(483) ##STR00207##

(a) Tributyl(methoxymethyl)stannane (195)

(484) To a solution of diisopropylamine (765 mg, 7.56 mmol) in THF (20 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M in hexanes, 2.75 mL, 6.87 mmol) dropwise and the mixture was stirred at −78° C. for 30 min. Tributylstannane (2.0 g, 6.87 mmol) was added and the mixture was allowed to warm to 0° C. and stirred for 30 min. The mixture was again cooled to −78° C., chloro(methoxy)methane (554 mg, 6.87 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. Water was added and the mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100% Pet. Ether) to give the title compound (530 mg, 23%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.70 (s, 2H), 3.29 (s, 3H), 1.55-1.45 (m, 6H), 1.36-1.25 (m, 6H), 0.93-0.87 (m, 15H).

(b) Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-(methoxymethyl)benzo[b]thiophene-2-carboxylate (146)

(485) To a solution of ethyl 7-bromo-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 99 (100 mg, 0.198 mmol) and tributyl(methoxymethyl)stannane 195 (200 mg, 0.594 mmol) in 1,4-dioxane (6 mL) was added Pd(PPh.sub.3).sub.4 (23 mg, 0.02 mmol) and the mixture was heated at reflux under N.sub.2 overnight. The mixture was diluted with water, extracted with EtOAc and the organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (72 mg, 38%) as a white solid. LCMS-F: rt 3.27 min; m/z 469.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.66-7.52 (m, 5H), 6.15 (s, 2H), 4.74 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.34 (s, 3H), 1.24 (t, J=7.2 Hz, 3H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-hydroxybenzo[b]thiophene-2-carboxylate (147)

(486) ##STR00208##

(487) (a) Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-carboxylate (I96) A mixture of ethyl 7-bromo-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 99 (300 mg, 0.59 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (227 mg, 0.89 mmol), KOAc (175 mg, 1.78 mmol) and Pd(dppf)Cl.sub.2.DCM (49 mg, 0.06 mmol) in 1,4-dioxane (18 mL) was heated at reflux under N.sub.2 overnight. The mixture was diluted with water, extracted with EtOAc and the organic extract was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=100:1) to give the title compound (260 mg, 80%) as a grey solid. LCMS-F: rt 2.64 min; m/z 469.7 [M−C.sub.6H.sub.10+H].sup.+.

(b) Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-hydroxybenzo[b]thiophene-2-carboxylate (147)

(488) To a solution of ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-carboxylate 196 (60 mg, 0.109 mmol) in THF (4 mL) at 0° C. was added NaOH (5 mg, 0.109 mmol) and H.sub.2O.sub.2 (30% aqueous solution, 37 mg, 0.327 mmol) and the mixture was stirred at room temperature for 3 h. Ice cold water was added and the mixture was extracted with EtOAc. The organic extract was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=20:1) to give the title compound (25 mg, 52%) as a yellow solid. LCMS-F: rt 2.82 min; m/z 442.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.1 (s, 1H), 8.04 (s, 1H), 7.66-7.54 (m, 3H), 7.42 (d, J=8.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.10 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H).

N-(2-Amino-2-oxoethyl)-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxamide (148)

(489) ##STR00209##

(490) A mixture of 2-aminoacetamide hydrochloride (34 mg, 0.302 mmol), 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (100 mg, 0.251 mmol), HATU (144 mg, 0.377 mmol) and DIPEA (98 mg, 0.754 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc and the organic extract was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10:1) to give the title compound (30 mg, 26%) as a white solid. LCMS-C: rt 1.80 min; m/z 453.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65 (t, J=5.7 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.01 (s, 1H), 7.55-7.40 (m, 5H), 7.41 (s, 1H), 7.08 (s, 1H), 5.97 (s, 2H), 3.79 (d, J=5.7 Hz, 2H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-methoxybenzo[b]thiophene-2-carboxylate (149)

(491) ##STR00210##

(492) To a solution of ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-hydroxybenzo[b]thiophene-2-carboxylate 147 (70 mg, 0.158 mmol) and CH.sub.31 (34 mg, 0.238 mmol) in DMF (6 mL) was added K.sub.2CO.sub.3 (66 mg, 0.475 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc and the organic extract was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (36 mg, 50%) as a white solid. LCMS-F: rt 3.27 min; m/z 455.97 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.63-7.53 (m, 4H), 7.16 (d, J=8.5 Hz, 1H), 6.10 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 4.01 (s, 3H), 1.22 (t, J=7.1 Hz, 3H).

Ethyl 3-((4-carbamoyl-3-(methoxymethyl)phenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (150)

(493) ##STR00211##

(494) To a solution of ethyl 3-((3-bromo-4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 65 (200 mg, 0.427 mmol) and tributyl(methoxymethyl)stannane 195 (430 mg, 1.28 mmol) in 1,4-dioxane (15 mL) was added Pd(PPh.sub.3).sub.4 (50 mg, 0.043 mmol) and the mixture was heated at reflux under a N.sub.2 atmosphere overnight. The mixture was diluted with water, extracted with EtOAc and the organic extract was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10:1) to give the title compound (15 mg, 8%) as a white solid. LCMS-D: rt 4.17 min; m/z 434.1 [M+H].sup.+, 456.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=6.9, 2.0 Hz, 1H), 7.69 (s, 1H), 7.61-7.49 (m, 3H), 7.23 (s, 1H), 7.11 (d, J=2.6 Hz, 1H), 6.98 (dd, J=8.5, 2.7 Hz, 1H), 5.85 (s, 2H), 4.63 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.32 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).

Ethyl 3-((4-carbamoyl-3-(1H-pyrazol-4-yl)phenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (151)

(495) ##STR00212##

(496) To a solution of ethyl 3-((3-bromo-4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 65 (100 mg, 0.213 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (188 mg, 0.639 mmol) in 1,4-dioxane/water (10 mL/0.5 mL) was added Pd(PPh.sub.3).sub.4 (25 mg, 0.021 mmol) and K.sub.2CO.sub.3 (89 mg, 0.639 mmol) and the mixture was heated at reflux under a N.sub.2 atmosphere overnight. The mixture was diluted with water, extracted with EtOAc and the organic extract was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10:1) to give the title compound (15 mg, 13%) as a white solid. LCMS-D: rt 3.80 min; m/z 456.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.9 (s, 1H), 8.14 (dd, J=7.0, 2.2 Hz, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.62-7.53 (m, 2H), 7.32 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.13 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.5, 2.6 Hz, 1H), 5.87 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).

((L-Valyl)oxy)methyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate trifluoroacetate salt (152)

(497) ##STR00213##

(498) To a solution of (S)-((2-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)oxy)methyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 133 (60 mg, 0.096 mmol) in DCM (5 mL) was added TFA (2 mL) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give the title compound (30 mg, 60%) as a yellow oil. LCMS-C: rt 2.01 min; m/z 526.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (br s, 3H), 8.17-8.05 (m, 2H), 7.73-7.48 (m, 5H), 6.26-6.11 (m, 2H), 6.12-5.95 (m, 2H), 4.12-4.02 (m, 1H), 2.20-2.09 (m, 1H), 0.94-0.91 (m, 6H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chloro-7-cyanobenzo[b]thiophene-2-carboxylate (153)

(499) ##STR00214##

(500) A mixture of ethyl 7-bromo-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 99 (50 mg, 0.099 mmol) and CuCN (44 mg, 0.495 mmol) in NMP (5 mL) was heated at 180° C. under N.sub.2 for 16 h. The mixture was partitioned between water (15 mL) and EtOAc (15 mL), the layers were separated and the aqueous layer was extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (3.3 mg, 7%) as a white solid. LCMS-F: rt 3.12 min; m/z 451.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (d, J=8.1 Hz, 1H), 8.02 (s, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.66-7.53 (m, 3H), 6.12 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.24 (t, J=8.0 Hz, 3H).

Isopropyl 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylate (154)

(501) ##STR00215##

(502) To a solution of 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylic acid 34 (90 mg, 0.25 mmol) in DMF (5 mL) was added i-PrOH (151 mg, 2.52 mmol), EDCl.HCl (96 mg, 0.50 mmol) and DMAP (6 mg, 0.05 mmol) and the mixture was stirred at room temperature overnight. Water and 1 M aqueous HCl was added and the mixture was extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=10:1) to give the title compound (70 mg, 70%). LCMS-C: rt 2.50 min; m/z 400.0 [M+H].sup.+, 422.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.87 (d, J=8.4 Hz, 2H), 7.84 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.98 (d, J=7.9 Hz, 1H), 5.77 (s, 2H), 5.19-5.04 (m, 1H), 3.70 (s, 3H), 1.25 (d, J=6.3 Hz, 6H).

Cyclopentyl 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylate (155)

(503) ##STR00216##

(504) To a solution of 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylic acid 34 (90 mg, 0.25 mmol) in DMF (5 mL) was added cyclopentanol (108.4 mg, 1.26 mmol), EDCl.HCl (96.5 mg, 0.50 mmol) and DMAP (6.2 mg, 0.05 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=10:1) followed by prep-HPLC to give the title compound (70 mg, 65%) as a white solid. LCMS-C: rt 2.61 min; m/z 426.0 [M+H].sup.+, 448.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.87 (d, J=8.0 Hz, 2H), 7.84 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.97 (d, J=7.9 Hz, 1H), 5.74 (s, 2H), 5.36-5.27 (m, 1H), 3.69 (s, 3H), 1.92-1.80 (m, 2H), 1.76-1.65 (m, 2H), 1.62-1.50 (m, 4H).

Benzyl 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylate (156)

(505) ##STR00217##

(506) To a mixture of 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylic acid 34 (90 mg, 0.25 mmol) and benzyl alcohol (6 mL) was added conc. H.sub.2SO.sub.4 (2 drops) and the mixture was heated at 50° C. overnight. The mixture was purified by silica gel chromatography (DCM/MeOH=10:1) followed by prep-HPLC to give the title compound (3.2 mg, 3%) as a white solid. LCMS-C: rt 2.55 min; m/z 448.0 [M+H].sup.+, 470.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.93-7.83 (m, 3H), 7.64 (d, J=8.1 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.35-7.34 (m, 3H), 7.21 (s, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.99 (d, J=7.9 Hz, 1H), 5.80 (s, 2H), 5.37 (s, 2H), 3.68 (s, 3H).

2-Morpholinoethyl 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylate (157)

(507) ##STR00218##

(508) To a solution of 3-((4-carbamoylphenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylic acid 34 (90 mg, 0.25 mmol) in DMF (5 mL) was added 2-morpholinoethan-1-ol (99.1 mg, 0.76 mmol), EDCl.HCl (96.5 mg, 0.50 mmol) and DMAP (6 mg, 0.05 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=10:1) followed by prep-HPLC to give the title compound (5 mg, 4%) as a white solid. LCMS-D: rt 2.87 min; m/z 471.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (d, J=8.8 Hz, 2H), 7.85 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.97 (d, J=7.9 Hz, 1H), 5.78 (s, 2H), 4.38 (t, J=5.5 Hz, 2H), 3.67 (s, 3H), 3.51-3.48 (m, 4H), 2.60 (t, J=5.6 Hz, 2H), 2.41-2.39 (m, 4H).

2-Methoxyethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (158)

(509) ##STR00219##

(510) To a solution of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (150 mg, 0.38 mmol) in DMF (10 mL) was added 2-methoxyethanol (87 mg, 1.14 mmol), EDCl.HCl (146 mg, 0.76 mmol) and DMAP (10 mg, 0.076 mmol) and the mixture was stirred at room temperature for 3 h. Water (150 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were washed with water (3×150 mL), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=1:0 to 100:1) to give the title compound (60 mg, 35%) as a white solid. LCMS-C: rt 2.43 min; m/z 455.9 [M+H].sup.+, 477.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=7.9, 1.2 Hz, 1H), 8.08 (s, 1H), 7.66-7.54 (m, 5H), 6.14 (s, 2H), 4.38-4.30 (m, 2H), 3.59-3.53 (m, 2H), 3.25 (s, 3H).

2-Acetamidoethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (159)

(511) ##STR00220##

(512) To a solution of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (150 mg, 0.38 mmol) in DMF (8 mL) was added N-(2-hydroxyethyl)acetamide (78 mg, 0.76 mmol), EDCl.HCl (146 mg, 0.76 mmol) and DMAP (10 mg, 0.076 mmol) and the mixture was stirred at room temperature for 4 h. Water (150 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were washed with water (3×150 mL), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=1:0 to 100:1) to give the title compound (60 mg, 73%) as a white solid. LCMS-C: rt 2.22 min; m/z 482.9 [M+H].sup.+, 504.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=7.9, 1.2 Hz, 1H), 8.06-8.00 (m, 2H), 7.66-7.53 (m, 5H), 6.13 (s, 2H), 4.22 (t, J=5.6 Hz, 2H), 3.35 (t, J=5.6 Hz, 2H), 1.80 (s, 3H).

2-((Methoxycarbonyl)amino)ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (160)

(513) ##STR00221##

(a) Methyl (2-hydroxyethyl)carbamate (197)

(514) To a solution of 2-aminoethanol (2.0 g, 32.7 mmol) in DCM (20 mL) at 0° C. was added K.sub.2CO.sub.3 (13.6 g, 98.2 mmol) and the mixture was stirred for 10 min. Methyl chloroformate (3.1 g, 32.7 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (3.0 g, 77%), which was used directly in the next step. LCMS-C: rt 0.37 min; m/z 120.0 [M+H].sup.+.

(b) 2-((Methoxycarbonyl)amino)ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (160)

(515) To a solution of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (150 mg, 0.377 mmol) in DMF (5 mL) was added methyl (2-hydroxyethyl)carbamate 197 (135 mg, 1.131 mmol), EDCl.HCl (145 mg, 0.754 mmol) and DMAP (9.2 mg, 0.075 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=20:1) followed by prep-HPLC to give the title compound (8 mg, 4%) as a white solid. LCMS-C: rt 2.35 min; m/z 498.9 [M+H].sup.+, 520.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=7.9, 1.2 Hz, 1H), 8.02 (s, 1H), 7.67-7.54 (m, 5H), 7.36-7.27 (m, 1H), 6.13 (s, 2H), 4.22 (t, J=5.5 Hz, 2H), 3.51 (s, 3H), 3.28 (t, J=5.2 Hz, 2H).

2-((Methoxycarbonyl)(methyl)amino)ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (161)

(516) ##STR00222##

(a) Methyl (2-hydroxyethyl)(methyl)carbamate (198)

(517) To a solution of 2-(methylamino)ethanol (2.0 g, 26.6 mmol) in DCM (20 mL) at 0° C. was added K.sub.2CO.sub.3 (11.0 g, 80 mmol) and the mixture was stirred for 10 min. Methyl chloroformate (3.0 g, 32.0 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (3.0 g, 85%) which was used directly in the next step. LCMS-C: rt 1.24 min; m/z 134.0 [M+H].sup.+.

(b) 2-((Methoxycarbonyl)(methyl)amino)ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (161)

(518) To a solution of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (150 mg, 0.377 mmol) in DMF (5 mL) was added methyl (2-hydroxyethyl)(methyl)carbamate 198 (150 mg, 1.13 mmol), EDCl.HCl (145 mg, 0.754 mmol) and DMAP (9.2 mg, 0.075 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (80 mg, 41%) as a white solid. LCMS-C: rt 2.38 min; m/z 512.9 [M+H].sup.+, 534.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=7.9, 1.2 Hz, 1H), 8.02 (s, 1H), 7.66-7.54 (m, 5H), 6.14 (s, 2H), 4.33 (t, J=5.2 Hz, 2H), 3.56 (s, 3H), 3.52 (t, J=5.2 Hz, 2H), 2.87 (s, 3H).

3-Methoxypropyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (162)

(519) ##STR00223##

(520) To a solution of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (150 mg, 0.37 mmol) and 3-methoxypropan-1-ol (68 mg, 0.75 mmol) in DMF (10 mL) was added EDCl.HCl (144 mg, 0.75 mmol) and DMAP (9 mg, 0.07 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (53 mg, 30%). LCMS-C: rt 2.53 min; m/z 469.9 [M+H].sup.+, 491.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19-8.09 (m, 1H), 8.08-7.98 (m, 1H), 7.68-7.44 (m, 5H), 6.14 (s, 2H), 4.28-4.24 (m, 2H), 3.39-3.35 (m, 2H), 3.25 (s, 3H), 1.89-1.77 (m, 2H).

Methyl 4-((3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carbonyl)oxy)piperidine-1-carboxylate (163)

(521) ##STR00224##

(522) A mixture of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (100 mg, 0.25 mmol), methyl 4-hydroxypiperidine-1-carboxylate 184 (61 mg, 0.38 mmol), EDCl.HCl (96 mg, 0.50 mmol) and DMAP (24 mg, 0.05 mmol) in DMF (6 mL) was stirred at room temperature overnight. The mixture was poured into water, extracted with EtOAc and the organic extract was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=5:1) to give the title compound (4.3 mg, 3%) as a white solid. LCMS-C: rt 2.48 min; m/z 538.9 [M+H].sup.+, 560.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.12 (d, J=7.9 Hz, 1H), 8.03 (s, 1H), 7.62-7.55 (m, 5H), 6.14 (s, 2H), 5.11-5.01 (m, 1H), 3.60 (s, 3H), 3.54-3.45 (m, 2H), 3.42-3.36 (m, 2H), 1.88-1.77 (m, 2H), 1.61-1.47 (m, 2H).

1-Methylazetidin-3-yl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (164)

(523) ##STR00225##

(524) To a solution of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (100 mg, 0.25 mmol) and 1-methylazetidin-3-ol hydrochloride (47 mg, 0.38 mmol) in DMF (8 mL) was added EDCl.HCl (96 mg, 0.56 mmol) and DMAP (6 mg, 0.05 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=20:1) to give the title compound (10 mg, 9%) as a white solid. LCMS-C: rt 3.22 min; m/z 466.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=7.9, 1.2 Hz, 1H), 8.03 (s, 1H), 7.69-7.54 (m, 5H), 6.13 (s, 2H), 5.09-5.01 (m, 1H), 3.67-3.61 (m, 2H), 3.00-2.96 (m, 2H), 2.28 (s, 3H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylate (165)

(525) ##STR00226##

(a) Ethyl 4-methoxy-3-methylbenzo[b]thiophene-2-carboxylate (I99)

(526) To a solution of ethyl 2-mercaptoacetate (20 g, 167 mmol) in THF (350 mL) was added LiHMDS (1.0 M solution in THF, 166 mL, 166 mmol) and the mixture was stirred at room temperature for 40 min. 1-(2-Fluoro-6-methoxyphenyl)ethanone (7.0 g, 41.6 mmol) was then added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and 1 M aqueous HCl and extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give the title compound (2.5 g, 22%) as a yellow solid. LCMS-C: rt 2.65 min; m/z 251.0 [M+H].sup.+.

(b) Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-methoxybenzo[b]thiophene-2-carboxylate (165)

(527) To a solution of ethyl 4-methoxy-3-methylbenzo[b]thiophene-2-carboxylate 199 (2.0 g, 7.99 mmol) in 0014 (50 mL) was added NBS (1.7 g, 9.59 mmol) and BPO (194 mg, 0.8 mmol) and the mixture was heated at reflux overnight. Water was added and the mixture was extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give a 1:1 inseparable mixture of a mono-bromo and di-bromo products assigned by NMR spectroscopy to be ethyl 7-bromo-4-methoxy-3-methylbenzo[b]thiophene-2-carboxylate and ethyl 7-bromo-3-(bromomethyl)-4-methoxybenzo[b]thiophene-2-carboxylate (2.2 g) as a yellow solid. LCMS-C: rt 2.90 min; m/z 328.8 [M+H].sup.+ and 406.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 5.37 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 2.88 (s, 3H), 1.36 (t, J=8.0 Hz, 3H), 1.32 (t, J=8.0 Hz, 3H).

(528) To solution of the mixture of ethyl 7-bromo-4-methoxy-3-methylbenzo[b]thiophene-2-carboxylate and ethyl 7-bromo-3-(bromomethyl)-4-methoxybenzo[b]thiophene-2-carboxylate (152 mg) in DMF (10 mL) was added 3,5-difluoro-4-hydroxybenzamide 125 (80 mg, 0.462 mmol) and Cs.sub.2CO.sub.3 (301 mg, 0.924 mmol) and the mixture was stirred at room temperature overnight. Water was added and the resulting precipitate was collected by filtration to give a white solid (120 mg). LCMS-C: rt 2.55 min; m/z 521.8/523.8 [M+Na].sup.+. This material was dissolved in EtOH/THF (10 mL/10 mL), 10% Pd/C (63 mg, wetted with ca. 55% water) was added and the mixture was stirred at room temperature under H.sub.2 (20 KPa) overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=20:1) to give the title compound (15 mg, 6% over three steps) as a white solid. LCMS-C: rt 2.43 min; m/z 421.9 [M+H].sup.+, 443.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (s, 1H), 7.65-7.58 (m, 3H), 7.56 (s, 1H), 7.50 (t, J=8.0 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.00 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).

N-Benzyl-4-bromo-3-((4-carbamoylphenoxy)methyl)benzo[b]thiophene-2-carboxamide (166)

(529) ##STR00227##

(530) To a solution of ethyl 4-bromo-3-((4-carbamoylphenoxy)methyl)benzo[b]thiophene-2-carboxylate 21 (100 mg, 0.23 mmol) in EtOH (2 mL) was added benzylamine (123 mg, 1.2 mmol) and Et.sub.3N (70 mg, 0.69 mmol) and the mixture was heated at 150° C. under microwave irradiation for 30 min. The mixture was diluted with water, extracted with DCM and the combined organic extracts were concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15:1) followed by prep-HPLC to give the title compound (6 mg, 5%) as a white solid. LCMS-D: rt 3.86 min; m/z 495.0/497.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.26 (s, 1H), 8.17 (d, J=7.4 Hz, 1H), 7.94-7.81 (m, 3H), 7.75 (d, J=7.3 Hz, 1H), 7.49-7.37 (m, 1H), 7.34-7.16 (m, 6H), 7.02 (d, J=7.7 Hz, 2H), 5.63 (s, 2H), 4.47 (d, J=4.0 Hz, 2H).

4-Bromo-3-((4-carbamoylphenoxy)methyl)-N-phenethylbenzo[b]thiophene-2-carboxamide (167)

(531) ##STR00228##

(532) To a solution of ethyl 4-bromo-3-((4-carbamoylphenoxy)methyl)benzo[b]thiophene-2-carboxylate 21 (100 mg, 0.23 mmol) in EtOH (2 mL) was added 2-phenylethan-1-amine (140 mg, 1.15 mmol) and Et.sub.3N (70 mg, 0.69 mmol) and the mixture was heated at 150° C. under microwave irradiation for 30 min. The mixture was diluted with water, extracted with DCM and the combined organic extracts were concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15:1) followed by prep-HPLC to give the title compound (8 mg, 7%) as a white solid. LCMS-D: rt 3.95 min; m/z 509.0/511.0 [M+H].sup.+, 531.0/533.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.74 (t, J=5.6 Hz, 1H), 8.16 (dd, J=8.1, 0.8 Hz, 1H), 7.92-7.80 (m, 3H), 7.74 (dd, J=7.6, 0.8 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.30-7.12 (m, 6H), 7.01 (d, J=8.9 Hz, 2H), 5.55 (s, 2H), 3.52-3.47 (m, 2H), 2.82 (t, J=7.1 Hz, 2H).

Ethyl 3-((4-carbamoyl-3-vinylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (168)

(533) ##STR00229##

(534) A mixture of ethyl 3-((3-bromo-4-carbamoylphenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate 65 (100 mg, 0.213 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (66 mg, 0.426 mmol), K.sub.2CO.sub.3 (89 mg, 0.639 mmol) and tetrakis(triphenylphosphine)palladium (25 mg, 0.021 mmol) in 1,4-dioxane (8 mL) was heated at reflux under N.sub.2 overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10:1) to give the title compound (25 mg, 28%) as a white solid. LCMS-D: rt 4.29 min; m/z 416.0 [M+H].sup.+, 438.0 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (dd, J=7.0, 2.1 Hz, 1H), 7.72 (s, 1H), 7.61-7.54 (m, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.13 (dd, J=17.6, 11.1 Hz, 1H), 7.00 (dd, J=8.5, 2.6 Hz, 1H), 5.89 (s, 2H), 5.83 (d, J=17.7 Hz, 1H), 5.28 (d, J=11.0 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).

4-Bromo-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-7-fluorobenzo[b]thiophene-2-carboxamide (169)

(535) ##STR00230##

(536) A mixture of 4-bromo-3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-7-fluorobenzo[b]thiophene-2-carboxylic acid 117 (40 mg, 0.09 mmol), HATU (130 mg, 0.36 mmol) and DIPEA (34 mg, 0.27 mg) in NMP (5 mL) was stirred at room temperature for 0.5 h. A solution of conc. aqueous NH.sub.4OH (3 mL) was added and the mixture was stirred at room temperature for a further 16 h. The mixture was partitioned between water (15 mL) and EtOAc (15 mL), the layers were separated and the aqueous layer was extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=20:1) to give the title compound (13.8 mg, 35%) as a white solid. LCMS-F: rt 2.54 min; m/z 458.8/460.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.13 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.82 (dd, J=8.5, 4.9 Hz, 1H), 7.62-7.53 (m, 3H), 7.39 (t, J=8.8 Hz, 1H), 5.99 (s, 2H).

Ethyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorothieno[2,3-c]pyridine-2-carboxylate (170)

(537) ##STR00231##

(538) A suspension of 3,5-difluoro-4-hydroxy-benzamide 125 (0.089 g, 0.51 mmol), ethyl 3-(bromomethyl)-4-chloro-thieno[2,3-c]pyridine-2-carboxylate (0.17 g, 0.51 mmol) 188 and cesium carbonate (0.251 g, 0.771 mmol) in N,N-dimethylformamide (8 mL) was stirred at room temperature overnight. Water was added and the mixture extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO.sub.4) and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (MeOH/EtOAc) to give the title compound (0.100 g, 46%) as a white solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 8.58 (s, 1H), 7.42-7.30 (m, 2H), 6.20 (t, J=0.9 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 2.96 (s, 1H), 2.88 (d, J=0.5 Hz, 1H), 1.38 (t, J=7.1 Hz, 3H). LCMS-A: rt 6.040 min, m/z 427.1 [M+H].sup.+.

Lithium 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorothieno[2,3-c]pyridine-2-carboxylate (171)

(539) ##STR00232##

(540) To a solution of ethyl 3-[(4-carbamoyl-2,6-difluoro-phenoxy)methyl]-4-chloro-thieno[2,3-c]pyridine-2-carboxylate 170 (0.0300 g, 0.0703 mmol) in THF/Water/MeOH (3:2:1, 15 mL) was added lithium hydroxide monohydrate (0.0088 g, 0.21 mmol). The mixture was stirred at room temperature for 19 h. The solvent was removed in vacuo to give the lithium salt of the title compound (37 mg, quantitative yield) as a white solid. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.02 (s, 1H), 8.43 (s, 1H), 7.49-7.39 (m, 2H), 6.29 (s, 2H), CONH.sub.2 protons not observed. LCMS-A: rt 6.784, m/z 399.1 [M+H].sup.+ for the free acid.

3-((4-Carbamoyl-2-fluoro-6-(hydroxymethyl)phenoxy)methyl)-4-methoxythieno[3,2-c]pyridine-2-carboxylic acid (172)

(541) ##STR00233##

(542) To a solution of ethyl 3-((4-carbamoyl-2-fluoro-6-(hydroxymethyl)phenoxy)methyl)-4-methoxythieno[3,2-c]pyridine-2-carboxylate 121 (0.0080 g, 0.018 mmol) in tetrahydrofuran (3 mL), methanol (1 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.0155 g, 0.368 mmol). The reaction mixture was stirred at room temperature overnight before the solvent was removed in vacuo to give a white solid. The solid was taken up in water and acidified to pH 3 (citric acid), then extracted with EtOAc (×3). The organic layer was separated from the aqueous phase and the solvent removed in vacuo to give a white solid. The solid was purified by preparative RP-HPLC to give the title compound (0.60 mg, 8%) as a white solid. LCMS-B: rt 5.187 min, m/z=405.1 [M−H].sup.−. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.06 (d, J=5.8 Hz, 1H), 7.79-7.73 (m, 1H), 7.64 (dd, J=12.4, 2.2 Hz, 1H), 7.51 (d, J=5.8 Hz, 1H), 6.05 (s, 2H), 4.33 (s, 2H), 3.87 (s, 3H), exchangeable CO.sub.2H, CONH.sub.2 and OH protons not observed.

(Pivaloyloxy)methyl 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylate (173)

(543) ##STR00234##

(544) A mixture of 3-((4-carbamoyl-2,6-difluorophenoxy)methyl)-4-chlorobenzo[b]thiophene-2-carboxylic acid 69 (0.085 g, 0.21 mmol), sodium iodide (0.128 g, 0.855 mmol), cesium carbonate (60-80 mesh, 0.139 g, 0.427 mmol) and chloromethyl pivalate (0.12 mL, 0.85 mmol) in DMF (1 mL) was stirred at room temperature for 4 hours. Water (˜30 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The organic extracts were combined, washed with brine (3×30 mL), dried (MgSO.sub.4) and the solvent removed in vacuo. The solid was taken up in a minimum amount of DCM and the product was precipitated by the addition of cyclohexane. The precipitate was isolated by vacuum filtration and air dried to give the title compound (0.079 g, 72%) as an off-white solid. LCMS-B rt 4.318 min; m/z 511.8 [M+H].sup.+, 533.8 [M+Na].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (dd, J=7.9, 1.3 Hz, 1H), 8.02 (s, 1H), 7.68-7.54 (m, 5H), 6.13 (s, 2H), 5.89 (s, 2H), 1.12 (s, 9H).

(Pivaloyloxy)methyl 3-((4-carbamoylphenoxy)methyl)-4-chloro-5-methylbenzo[b]thiophene-2-carboxylate (174)

(545) ##STR00235##

(546) A mixture of 3-((4-carbamoylphenoxy)methyl)-4-chloro-5-methylbenzo[b]thiophene-2-carboxylic acid 18 (0.010 g, 0.027 mmol), chloromethyl pivalate (0.015 mL, 0.11 mmol), cesium carbonate (60-80 mesh, 0.017 g, 0.053 mmol) and sodium iodide (0.016 g, 0.11 mmol) in DMF (0.5 mL) was stirred at room temperature for 17 hours. Water (˜2 mL) was added and the precipitate was isolated by vacuum filtration to give the title compound (0.0040 g, 31%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06 (d, J=8.3 Hz, 1H), 7.91-7.83 (m, 3H), 7.61 (d, J=8.3 Hz, 1H), 7.19 (s, 1H), 7.12-7.04 (m, 2H), 5.96 (s, 2H), 5.87 (s, 2H), 2.45 (s, 3H), 1.12 (s, 9H). LCMS-B rt 3.625 min; m/z 489.9 [M+H].sup.+, m/z 511.9 [M+Na].sup.+.

(547) Assays

(548) Protein Production and Purification

(549) Biophysical experiments were performed with three different recombinant human STING protein variants designated according to allelic nomenclature of Yi et al., (2013). Codon optimized DNA sequences (for expression in Escherichia coli) encoding amino acid residues 149 to 345 (Swiss Prot Q86WV6) of human STING (WT), human STING (HAQ) and human STING (R232H) were synthesised by GenScript USA Inc (Piscataway, N.J., USA). These were ligated into a modified pET43a E. coli expression vector designed to encode N-terminal His tag followed by tobacco etch virus protease (TEV) cleavage site and a STING gene sequence. The resulting protein sequences for the three allelic variants are listed below:

(550) TABLE-US-00014 His-TEV-hSTING(WT) MGHHHHHHGTENLYFQGSE.sup.149KGNFNVAHGLAWSYYIGYLRLILPELQA RIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLP QQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYS QAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFS LSQEVLRHLRQEEKEEVTVGS.sup.345 His-TEV-hSTING(R232H) MGHHHHHHGTENLYFQGSE.sup.149KGNFNVAHGLAWSYYIGYLRLILPELQA RIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLP QQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYS QAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFS LSQEVLRHLRQEEKEEVTVGS.sup.345 His-TEV-hSTING(HAQ) MGHHHHHHGTENLYFQGSE.sup.149KGNFNVAHGLAWSYYIGYLRLILPELQA RIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLP QQTADRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYS QAGFSREDRLEQAKLFCQTLEDILADAPESQNNCRLIAYQEPADDSSFS LSQEVLRHLRQEEKEEVTVGS.sup.345

(551) To produce recombinant human STING proteins, expression plasmid encoding above-described constructs were transformed into E. coli BL21 DE3 strain and grown with shaking at 37° C. in 2×1 L volumes of Terrific broth (TB) supplemented with 100 μg/ml Ampicillin until OD.sub.600 of 0.8 was reached. Cultures were then cooled to 16° C. and protein expression induced by the addition of isopropyl β-D-1-thiogalactopyranoside to a final concentration of 0.5 mM and the cultures shaken overnight for further 16 hours. Following expression, cell cultures were centrifuged at 5000×g for 20 min and cell pellet stored frozen at −70° C.

(552) Protein purification was initiated by thawing the cell pellet in Lysis buffer (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 2 mM MgCl.sub.2, 10 mM imidazole, 0.5 mg/ml lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, complete protease inhibitor tablets EDTA-free [Roche]) using a ratio of 7 ml of buffer per 1 g of cells. Cells were further lysed by 3 passes through an ice cooled Avestin C5 cell crusher and then centrifuged at 48,000×g at 4° C. Supernatant (cell lysate) was filtered through a 5 μm filter and loaded onto 5 mL HiTrap IMAC Sepharose FF column (GE Healthcare) pre-equilibrated with IMAC wash buffer 1 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 10 mM imidazole) using Profinia Affinity chromatography purification system (Bio-Rad). The IMAC column was then sequentially washed with IMAC Wash buffer 1 and IMAC Wash buffer 2 (25 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 20 mM Imidazole) and bound His-TEV-hSTING protein eluted with IMAC Elution buffer (250 mM Tris-HCl pH 8.0, 300 mM NaCl, 5 mM DTT, 20 mM Imidazole). IMAC-eluted protein was further purified by passing through a HiLoad 26/60 Superdex 75 column pre-equilibrated in storage buffer (25 mM Tris-HCl pH 8.0, 150 mM NaCl, 5 mM DTT 0.02% [w/v] sodium azide). Finally, hSTING protein was concentrated to 2 mg/ml using Amicon Ultra centrifugal filter unit (Utra-15 MWCO 10 kDa), flash-frozen in liquid nitrogen and stored in −70° C. freezer.

(553) Differential Scanning Fluorimetry (DSF)

(554) Differential scanning fluorimetry (DSF) is a rapid screening method for identifying low-molecular-weight ligands that bind and, in doing so, stabilize (or sometimes destabilize) purified proteins (Niesen 2007). DSF monitors thermal unfolding of protein in the presence of a fluorescent dye and is typically performed using a real-time PCR instrument. The temperature at which a protein unfolds is measured by an increase in the fluorescence of a dye with affinity for hydrophobic parts of the protein that are gradually exposed during unfolding. The fluorescence of the dye is quenched in aqueous environments, but when the dye associates with hydrophobic sites on the unfolded protein, its fluorescence increases. The fluorescence intensity is plotted as a function of the temperature, generating a sigmoidal curve that can be described by a two-state transition. The inflection point of the transition curve (T.sub.m) is calculated using simple equations such as that of Boltzman.

(555) Thermal stability of STING protein (with and without bound ligand) was measured using previously described methodology (Seabrook & Newman 2013), with each experiment performed in triplicate using 96-well PCR microplates (AB Gene, ABGAB-0600/W). In a final volume of 20 μL, 1 μM protein in 1×HBS buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, pH 7.4) was mixed with SYPRO Orange dye (Sigma-Aldrich S5692, final reaction mix dilution 1:1200) and a compound (final concentration at 100 μM). Sealed plates were then placed into a Bio-Rad CFX96/C1000 thermocycler and FRET scanning mode (λ.sup.excitation of 490 nm and reads at λ.sup.emission of 570 nm) was used to measure fluorescence intensity. Melting curves were recorded from 20° C. to 100° C. in 0.5° C. increments every 30 seconds with a read at each increment. Data were analysed using “Meltdown analysis” protocol described by Rosa 2015. The melting point (T.sub.m) obtained for STING protein alone was subtracted from T.sub.m obtained for protein incubated with ligand to generate ΔT.sub.m values listed in the table below. DSF data was generated for each compound against 3 different STING protein variants-human STING (WT), human STING (HAQ) and human STING (R232H).

(556) TABLE-US-00015 DSF huSTING DSF huSTING DSF huSTING (HAQ) (WT) (R232H) Example ΔTm (° C.) ΔTm (° C.) ΔTm (° C.) 1 7.78 0.99 0.88 2 1.44 3 −0.47 4 0.13 5 −0.48 0.07 6 3.33 −1.15 −1.09 7 0.26 8 13.96 6 3.16 9 0.71 0.51 0.99 10 1.7 −2.34 −2.78 11 0.29 0.13 −0.57 12 9 3.29 −0.74 13 −0.15 −0.59 −0.46 14 0.09 −4.26 −4.88 16 10.12 3.49 2.82 18 6.29 −0.6 −1.89 20 5.83 −2.76 −2.03 22 17.08 7.61 6.33 24 0.6 −0.35 3.09 26 10.82 3.79 2.39 28 6.93 1.19 0.86 30 5.4 −0.32 0.01 32 7.23 0.63 0.56 34 10.07 3.76 1.94 36 12.31 5.96 5.79 38 6.02 −1.4 −3.47 40 9.91 3.66 −1.44 42 2.83 −0.64 −0.86 44 7.64 1.3 −1.24 46 7.26 1.77 −0.49 48 1.92 −4.63 −3.78 50 5.11 0.02 −2.74 52 −1.22 −2.15 −2.65 54 2.56 −1.28 −2.45 55 −1.03 56 4.48 −1.29 −1.75 57 10.74 3.43 1.27 58 0.43 59 7.31 0.54 −1.44 61 14.62 5.68 5.68 63 8.07 1.88 1.92 64 6.79 2.73 −0.59 67 11.14 3.04 −1.08 69 22.08 9.49 4.02 71 12.18 5.11 0.44 73 1.79 −1.03 −1.09 74 −0.31 −4.22 −4.25 76 2.43 −2.72 1.37 78 16 6.62 4.37 80 14.94 6.69 −0.9 82 9.29 3.15 −0.22 84 6.48 0.18 −1.24 86 10.1 3.33 −1.42 87 0.54 88 0.97 −1.07 −0.25

(557) Compounds where R.sup.1 is not H are not expected to show activity in these assays.

(558) These additional compounds were tested as described above, however the protein concentration was 2 μM.

(559) TABLE-US-00016 DSF huSTING DSF huSTING DSF huSTING (HAQ) (WT) (R232H) Example ΔTm (° C.) ΔTm (° C.) ΔTm (° C.) 90 26.56 12.18 5.32 93 30.34 17.91 8.35 95 8.16 1.63 −3.15 96 11.94 6.65 0.91 98 2.99 −1.42 −2.12 100 33.77 22.44 9.02 101 23.87 11.75 4.05 103 8.96 3.27 −0.17 104 6.94 2.46 −0.74 105 19.53 8.25 1.32 106 18.29 6.69 0.95 107 20.94 9.88 3.76 109 8.60 3.69 1.30 111 21.46 10.88 2.26 112 2.78 1.25 1.05 113 5.60 2.38 2.50 114 14.57 5.87 4.72 117 33.98 22.76 9.76 118 23.14 10.54 6.21 127 −2.52 −2.44 −3.55 136 17.97 5.53 −0.53 143 −2.10 −1.93 −2.44 148 −0.36 −0.37 −0.51 158 −1.58 −1.90 −2.57 159 −1.50 −1.02 −1.45 160 −0.84 −1.05 −1.57 161 −1.70 −1.76 −2.67 162 −1.45 −1.01 166 −3.01 −2.44 167 0.71 2.51 −0.03 169 1.67 1.69 0.37 171 9.33 3.92 0.25 172 0.56 −6.71 −6.07

(560) Surface Plasmon Resonance (SPR)

(561) Binding interactions of ligands with STING proteins were quantified using Surface Plasmon Resonance (SPR) with a minimally biotinylated STING protein immobilized on Streptavidin chip surface. In this manner highly active STING protein surfaces were obtained that were not compromised by a low pH required for amine coupling methods. Minimal biotinylation of purified huSTING protein was performed using a previously described methodology (Chabbra 2012). Briefly, approximately 20 nmol of recombinant STING protein in 1×TBS buffer (25 mM Tris-HCl, 150 mM NaCl, 5 mM DTT) was mixed with of EZ-LinkH Sulfo-NHS-LC-LC-Biotin (Thermofisher Scientific, cat #21338) at a molar ratio of 1 to 0.6 and then incubated on ice for 2 hours. To remove any unreacted biotin reagent, protein/biotin mixture was passed through a Superdex 75 (10/300 GL) column equilibrated with 10 mM HEPES pH 7.4, 150 mM NaCl, 5 mM DTT, 5% (v/v) glycerol. A protein peak containing biotinylated huSTING protein was collected and stored in aliquots at −80° C.

(562) Streptavidin was simultaneously immobilized in all four channels of a CM5 sensor chip docked in a Biacore instrument (either Biacore S200 or Biacore T200, GE Healthcare) as described previously (Zender 2013). Minimally biotinylated STING protein was captured onto Streptavidin coated chip surface at 25° C. in SPR binding buffer (50 mM HEPES pH 7.4, 150 mM NaCl, 2.5 mM TCEP, 2% (v/v) DMSO) gradually injected in a single channel at a constant flow-rate of 2 μL/min until SPR response increases were no longer observed resulting in typical capture levels of 5000 to 7000 RU (1 RU=1 μg/mm.sup.2).

(563) To determine binding affinity, compound interaction with immobilized STING protein was analysed using dose-response experiments. All binding experiments were performed at 25° C. in SPR binding buffer. Fresh 10 mM DMSO solutions of compound were diluted directly into SPR binding buffer to a final concentration of 10 μM and then further diluted either 2-fold or 3-fold aiming for either a 5- or 7-point concentration series range. Each ligand concentration series was injected at a constant flow rate of 60 μL/min with a 90 second association and a 180 second dissociation time.

(564) Scrubber 2 (www.biologic.com.au) was utilized for data processing and analysis. Thus, SPR signals were referenced against the blank surface (streptavidin+D-biotin) and further corrected for DMSO refractive index change and then “double-referenced” using a buffer-blank injection (Papalia 2006). To determine binding affinities (K.sub.D values) from dose-response experiments, binding responses at equilibrium were fit to either a 1:1 steady state affinity or to 1:1 binding kinetic models (both available within Scrubber software).

(565) TABLE-US-00017 SPR (HAQ) Example K.sub.D (μM) 1 32 3 3500 6 90 8 1.055 10 187 12 5.95 14 120 16 2.195 18 15.9 20 34 22 0.755 24 >10000 26 1.605 28 10.9 30 22.1 32 7.75 34 2.475 36 1.335 38 16.4 40 2.8 42 80.5 44 7.95 46 9.7 48 16.265 50 20.9 52 260 54 51 55 3700 56 29 57 9.05 58 >10000 59 15.19 61 0.83 63 9.15 64 6.2 69 0.0886 71 2.12 73 67 87 3000 88 532.67

(566) Binding experiments were also performed at 8° C. in SPR binding buffer (“SPR (HAQ) 8° C. K.sub.D (μM)”; “SPR (WT) 8° C. K.sub.D (μM)”; “SPR (R232H) 8° C. K.sub.D (μM)”). Fresh 10 mM DMSO solutions of compound were diluted directly into SPR binding buffer typically to a concentration of 50 μM and then further diluted 2-fold or 3-fold aiming for either a 5- or 7-point concentration series range. Each ligand concentration series was injected at a constant flow rate of 60 μL/min with a 90 second association and a 180 second dissociation time. These were modified for compounds with longer residence times, so that curves could reach steady-state, or so that compound would be fully dissociated before the subsequent injection. Where appropriate, tighter-binding compounds (roughly K.sub.D<1 uM) were tested using a single-cycle kinetics format (Karlsson 2006), with long association and dissociation times (typically 450 s and 1800 s, respectively).

(567) Scrubber 2 (www.biologic.com.au) was utilized for data processing, where signals were referenced against the blank surface (streptavidin+D-biotin) and further corrected for DMSO refractive index change and then “double-referenced” using a buffer-blank injection (Papalia 2006). To determine binding affinities (50% occupancy as a surrogate K.sub.D for the two binding events occurring) from dose-response experiments, binding responses at equilibrium were fit to a Hill equation, where the Hill coefficient was floated (≤2). For single-cycle kinetic experiments, sensorgrams were fit to a two-step kinetic model in which two analyte molecules bind sequentially (Biacore T200 or S200 Evaluation Software).

(568) TABLE-US-00018 SPR huSTING SPR huSTING SPR huSTING (HAQ) K.sub.D (WT) K.sub.D (R232H) K.sub.D Example at 8° C. (μM) at 8° C. (μM) at 8° C. (μM) 90 0.213 3.0 31 93 0.106 0.900 13.7 95 14.3 93 96 1.85 22 98 28.0 72 100 0.110 0.620 22.8 101 0.390 3.70 69 103 5.80 65 104 5.50 38 105 1.40 28 106 1.30 28 107 0.500 21 109 160 200 112 26 51 113 52 114 2.74 26 117 0.200 0.450 20.8 118 0.150 4.24 136 0.870 7.1 169 130 >1000 171 4.87 172 220

(569) THP-1 Reporter Cell Line Assays

(570) THP-1 STING Lucia ISG cells (Invivogen #thpl-isg) were cultured in RPMI-1640 containing 2 mM L-glutamine, 25 mM HEPES, 100 μg/mL Normocin and 10% HI-FBS. At a density of 7×10.sup.5 cells/mL, cells were seeded into a T175 flask and incubated at 37° C./5% CO.sub.2, and passaged every three (3) days (all media and supplements from Life Technologies). Selection pressure was maintained by the addition of 100 μg/mL Zeocin every second passage.

(571) Assay conditions: cells were harvested and resuspended at a concentration 5×10.sup.5 cells/mL in fresh growth media. To sterile 384-Culturplates (Perkin Elmer #6007688) was dispensed 20 μL of this cell preparation at a density of 1×10.sup.4 cells/well and the plates were incubated at 37° C./5% CO.sub.2 for 1 h whilst the compound plate was being prepared.

(572) 11 pt Concentration Response Curves (CRCs) of compounds (10 mM stocks) were prepared by serial dilution in DMSO as follows: 10, 5, 2.5, 1.25, 0.63, 0.31, 0.15, 0.08, 0.04, 0.02, 0.01 mM. Compounds were then diluted 1/40 in growth media by transferring 1.25 μL of each concentration into 48.75 μL growth media (working dose range: 250, 125, 62.5, 31.3, 15.63, 7.81, 3.9, 1.95, 0.98, 0.49, 0.24 μM). The addition of 5 μL of these compound stocks to the Culturplates containing 20 μL of cell suspension resulted in a further 1/5 dilution (final dose range: 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10, 0.05 μM) (0.5% DMSO final concentration). The plates were incubated for 24 h at 37° C./5% CO.sub.2.

(573) Following 24 h incubation, 10 μL of QUANTI-Luc (Invivogen #rep-qlc1) was added to the Culturplates. QUANTI-Luc is a coelenterazine-based substrate prepared in sterile reverse osmosis (RO) water and added directly to the cells. Plates were shaken for ten seconds on an orbital shaker and left in the dark at room temperature for two minutes, before being read on the EnSpire multimode reader (STING Luminescence protocol) (Perkin Elmer).

(574) Data analysis: presented as % activity of a 50 μM Aduro CDN (2′3′-cGsAsMP) positive control (HIGH) using 0.5% DMSO only wells as background controls (LOW).

(575) Aduro CDN (2′3′-cGsAsMP) is also known as ML RR-S2 CDA, which has the structure:

(576) ##STR00236##

(577) The following formula was used:
% activity=(unknown−LOW)/(HIGH−LOW)

(578) An identical method was used for the preparing and testing compounds against the THP-1-Dual KI-hSTING-R232 cells (Invivogen #thpd-r232) for assessing compound activity against the more prevalent human STING isoform, WT.

(579) “Cellular EC50 huSTING (HAQ) (μM)” data refers to assays performed with THP-1 STING Lucia ISG cells and “Cellular EC50 huSTING (WT) (μM)” refers to assays performed with THP-1-Dual KI-hSTING-R232 cells.

(580) TABLE-US-00019 Cellular EC.sub.50 Cellular EC.sub.50 huSTING huSTING Example (HAQ) (μM) (WT) (μM) 1 >50 >50 2 2.07 >50 3 2.943 >50 4 2.581 >50 5 8.219 >50 6 >50 >50 7 0.7049 8.936 8 >50 >50 9 >50 >50 10 >50 >50 11 16.16 25.6 12 >50 >50 13 >50 >50 14 >50 >50 15 2.399 2.568 16 >50 >50 17 14.75 >50 18 >50 >50 19 >50 >50 20 >50 >50 21 0.4741 0.5763 22 >50 41.03 23 7.611 16.87 24 >50 >50 25 1.598 1.417 26 >50 >50 27 >50 >50 28 >50 >50 29 2.685 6.499 30 36.28 >50 31 6.765 6.913 32 >50 >50 33 0.6654 0.8908 34 >50 >50 35 0.6553 1.283 36 >50 >50 37 3.844 4.766 38 >50 >50 39 1.484 1.783 40 >50 39.68 41 0.7976 2.458 43 1.352 3.775 45 12.88 24.67 46 >50 >50 47 18.67 >50 48 >50 >50 49 17.17 24.1 50 >50 >50 51 >50 >50 52 >50 >50 53 >50 >50 54 >50 >50 55 3.597 >50 56 >50 >50 57 >50 >50 58 9.194 27.72 59 >50 >50 60 0.8271 47.35 61 39.57 >50 62 0.9502 1.649 64 >50 >50 65 22.19 >50 66 8.029 >50 67 >50 >50 68 0.2597 1.627 69 16.5 42.7 71 21.37 40.37 72 7.441 >50 74 1.048 2.471 75 17.92 >50 76 2.683 0.2172 77 0.7021 3.219 78 >50 >50 79 0.1705 0.4739 80 38.57 >50 81 2.793 20.71 82 >50 >50 83 2.611 >50 84 >50 >50 85 1.634 >50 86 >50 >50 87 >50 >50 88 >50 >50

(581) The below data was collected using the same methodology as above, with the following modifications: (a) Compound concentration range was adjusted to ensure full curve definition resulting in final top concentration of 40 μM and ten (10) dilutions of 2-fold or 2.5-fold. (b) Stock solutions of compounds in DMSO were dispensed from sample plates using a pin tool directly to previously adhered cells to achieve above-mentioned concentrations. (c) Luminescence readouts measured on PerkinElmer EnVision plate readers.

(582) TABLE-US-00020 Cellular EC50 Cellular EC50 huSTING huSTING Example (HAQ) (μM) (WT) (μM) 89 0.016 0.148 90 4.34 12.55 91 0.270 0.862 92 0.050 0.163 93 2.05 6.36 94 0.390 1.69 95 >40 >40 96 21.64 >40 97 1.43 9.72 98 21.06 >40 99 0.022 0.135 100 1.23 5.32 101 3.93 >40 102 0.053 0.377 103 13.58 >40 104 >40 >40 105 18.30 >40 106 14.42 14.24 107 14.14 27.90 108 0.344 0.341 109 >40 >40 110 0.013 0.052 111 16.18 17.21 112 >40 >40 113 >40 >40 114 15.27 >40 115 0.635 1.51 116 0.024 0.076 117 2.26 4.89 118 9.80 31.94 121 0.059 0.580 122 0.036 0.156 123 0.049 0.335 124 0.278 1.43 125 0.086 0.529 126 0.039 0.187 127 0.026 0.229 128 0.068 0.210 129 0.119 1.58 130 0.060 0.687 131 0.044 0.057 132 0.097 0.916 133 0.120 0.806 134 0.042 0.217 135 0.064 0.334 136 0.068 0.497 137 0.021 0.226 138 0.014 0.242 139 0.036 0.291 140 0.046 0.160 141 1.77 3.34 142 0.181 3.12 143 0.018 0.381 144 0.023 0.925 145 0.746 3.84 146 0.041 2.15 147 0.065 1.62 148 4.07 >40 149 0.613 0.797 150 0.550 0.489 151 1.82 3.46 152 0.967 53.69 153 0.129 0.207 154 0.448 2.05 155 0.230 3.82 156 0.628 4.51 157 0.373 2.03 158 0.132 0.949 159 0.044 0.325 160 0.035 0.298 161 0.062 0.669 162 0.041 0.302 163 0.062 1.556 164 0.027 0.249 165 0.127 6.15 166 9.95 28.88 167 23.19 25.59 168 7.44 >40 169 0.216 0.596 170 0.189 0.450 171 >40 >40 172 >40 >40 173 0.055 0.208 174 4.72 25.61

STATEMENTS OF INVENTION

(583) 1. A compound of formula I:

(584) ##STR00237##
wherein:
W is O or NH;
R.sup.1 is selected from: (i) H; (ii) C.sub.3-6 cycloalkyl; (iii) C.sub.3-7heterocyclyl optionally substituted with a group selected from: methyl; and ester; and (iv) linear or branched C.sub.1-4alkyl optionally substituted with a group selected from: alkoxy; amino; amido; acylamido; acyloxy; alkyl carboxyl ester; alkyl carbamoyl; alkyl carbamoyl ester; phenyl; phosphonate ester; C.sub.3-7heterocyclyl 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, acetyl and boc; A.sup.1 is CR.sup.A or N; A.sup.2 is CR.sup.B or N; A.sup.3 is CR.sup.C or N; A.sup.4 is CR.sup.D or N;
where no more than two of A.sup.1, A.sup.2, A.sup.3, and A.sup.4 may be N;
one or two of R.sup.A, R.sup.B, R.sup.C, and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt, CH.sub.2OH, CH.sub.2OMe and OH;
the remainder of R.sup.A, R.sup.B, R.sup.C, and R.sup.D, (if present) are H;
Y is O, NH or CH.sub.2;
R.sup.Y is selected from:

(585) ##STR00238## wherein: Z.sup.1 is CR.sup.Z1 or N; Z.sup.2 is CR.sup.Z2 or N; Z.sup.4 is CR.sup.Z4 or N; Z.sup.5 is CR.sup.Z5 or N;
where no more than two of Z.sup.2, Z.sup.4 and Z.sup.5 may be N;
one or two of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, Cl, Br, Me, OMe, cyano, CF.sub.3, CH.sub.2OH, CH.sub.2OMe, C.sub.2-4 alkenyl, and C5heterocyclyl;
the remainder of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, present) are H;

(586) ##STR00239##
where R.sup.12 is selected from H, F, Cl, Br, OMe, cyano and CF.sub.3;
with the proviso that when A.sup.1 is CF; A.sup.2, A.sup.3 and A.sup.4 are CH; Y is O or NH; R.sup.Y is RYA, where
Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are CH; R.sup.1 is not Et; and
when A.sup.1 is CF; A.sup.2, A.sup.3 and A.sup.4 are CH; Y is NH; R.sup.Y is RYA, where Z.sup.1 and Z.sup.5 are CH, one of Z.sup.2 and Z.sup.4 is CF, and the other of Z.sup.2 and Z.sup.4 is CH; R.sup.1 is not Et.

(587) 2. A compound according to statement 1, wherein W is O.

(588) 3. A compound according to statement 1, wherein W is NH.

(589) 4. A compound according to any one of statements 1 to 3, wherein R.sup.1 is H.

(590) 5. A compound according to statement 1, wherein R.sup.1 is selected from C.sub.3-6 cycloalkyl, optionally substituted C.sub.3-7heterocyclyl, and optionally substituted linear or branched C.sub.1-4alkyl.

(591) 6. A compound according to any of statements 1 to 3 and statement 5, wherein R.sup.1 is C.sub.3-6 cycloalkyl.

(592) 7. A compound according to statement 6, wherein R.sup.1 is cyclopropyl.

(593) 8. A compound according to statement 6, wherein R.sup.1 is cyclobutyl.

(594) 9. A compound according to statement 6, wherein R.sup.1 is cyclopentyl.

(595) 10. A compound according to statement 6, wherein R.sup.1 is cyclohexyl.

(596) 11. A compound according to any of statements 1 to 3 and statement 5, wherein R.sup.1 is optionally substituted C.sub.3-7heterocyclyl.

(597) 12. A compound according to statement 11, wherein R.sup.1 is optionally substituted C.sub.3-7 cycloalkyl containing a single nitrogen ring atom.

(598) 13. A compound according to statement 12, wherein R.sup.1 is optionally substituted azetidinyl.

(599) 14. A compound according to statement 12, wherein R.sup.1 is optionally substituted pyrrolidinyl.

(600) 15. A compound according to statement 12, wherein R.sup.1 is optionally substituted piperidinyl.

(601) 16. A compound according to any of statements 11 to 15, wherein R.sup.1 is substituted with methyl.

(602) 17. A compound according to any of statements 11 to 15, wherein R.sup.1 is substituted with ester.

(603) 18. A compound according to any of statements 1 to 3 and statement 5, wherein R.sup.1 is optionally substituted linear or branched C.sub.1-4alkyl.

(604) 19. A compound according to statement 18, wherein R.sup.1 is optionally substituted methyl.

(605) 20. A compound according to statement 18, wherein R.sup.1 is optionally substituted ethyl.

(606) 21. A compound according to statement 18, wherein R.sup.1 is optionally substituted propyl.

(607) 22. A compound according to statement 18, wherein R.sup.1 is optionally substituted butyl.

(608) 23. A compound according to statement 18, wherein R.sup.1 is optionally substituted iso-propyl.

(609) 24. A compound according to statement 18, wherein R.sup.1 is optionally substituted sec-butyl.

(610) 25. A compound according to statement 18, wherein R.sup.1 is optionally substituted iso-butyl.

(611) 26. A compound according to statement 18, wherein R.sup.1 is optionally substituted tert-butyl.

(612) 27. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with alkoxy.

(613) 28. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with amino.

(614) 29. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with amido.

(615) 30. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with acylamido.

(616) 31. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with acyloxy.

(617) 32. A compound according to statement 31, wherein R.sup.1 is pivaloyloxymethyl.

(618) 33. A compound according to statement 31, wherein R.sup.1 is propanoyloxyisobutyl.

(619) 34. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with alkyl carboxyl ester.

(620) 35. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with alkyl carbamoyl.

(621) 36. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with alkyl carbamoyl ester.

(622) 37. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with phenyl.

(623) 38. A compound according to statement 37, wherein R.sup.1 is benzyl.

(624) 39. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with phosphonate ester.

(625) 40. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with

(626) C.sub.3-7heterocyclyl.

(627) 41. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with C.sub.3-7heterocyclyl substituted with methyl.

(628) 42. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with C.sub.3-7heterocyclyl substituted with oxo.

(629) 43. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with a naturally occurring amino acid.

(630) 44. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with a naturally occurring amino acid N-substituted with methyl.

(631) 45. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with a naturally occurring amino acid N-substituted with acetyl.

(632) 46. A compound according to any of statements 18 to 26, wherein R.sup.1 is substituted with a naturally occurring amino acid N-substituted with boc.

(633) 47. A compound according to any of statements 43 to 46, wherein the naturally occurring amino acid is valine.

(634) 48. A compound according to any of statements 1 to 47, wherein A.sup.1 is CR.sup.A.

(635) 49. A compound according to any of statements 1 to 47, wherein A.sup.1 is N.

(636) 50. A compound according to any of statements 1 to 47, wherein A.sup.2 is CR.sup.B.

(637) 51. A compound according to any of statements 1 to 47, wherein A.sup.2 is N.

(638) 52. A compound according to any of statements 1 to 47, wherein A.sup.3 is CR.sup.C.

(639) 53. A compound according to any of statements 1 to 47, wherein A.sup.3 is N.

(640) 54. A compound according to any of statements 1 to 47, wherein A.sup.4 is CR.sup.D.

(641) 55. A compound according to any of statements 1 to 47, wherein A.sup.4 is N.

(642) 56. A compound according to any of statements 1 to 47, wherein A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, A.sup.3 is CR.sup.C, and A.sup.4 is CR.sup.D.

(643) 57. A compound according to any of statements 1 to 47, wherein one of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are N.

(644) 58. A compound according to any of statements 1 to 47, wherein two of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are N.

(645) 59. A compound according to any of statements 1 to 47, wherein the compound is of formula IIIb:

(646) ##STR00240##

(647) 60. A compound according to any of statements 1 to 47, wherein the compound is of formula IIIc:

(648) ##STR00241##

(649) 61. A compound according to any of statements 1 to 47, wherein the compound is of formula IIId:

(650) ##STR00242##

(651) 62. A compound according to any of statements 1 to 47, wherein the compound is of formula IIIe:

(652) ##STR00243##

(653) 63. A compound according to any of statements 1 to 62, wherein two of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano and OMe, the remainder (if present) are H.

(654) 64. A compound according to any of statements 1 to 62, wherein two of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me, CF.sub.3 and cyclopropyl, the remainder (if present) are H.

(655) 65. A compound according to any of statements 1 to 62, wherein two of R.sup.A, R.sup.B, R.sup.C and R.sup.D, (if present) are selected from H, F, Cl, Br, Me and CF.sub.3, the remainder (if present) are H.

(656) 66. A compound according to any of statements 1 to 62, wherein: R.sup.A (if present) is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, OEt and CH.sub.2OMe; R.sup.B (if present) is H; R.sup.C (if present) is H; R.sup.D (if present) is selected from H, F, Cl, Br, Me, CF.sub.3, cyclopropyl, cyano, OMe, CH.sub.2OH and CH.sub.2OMe.

(657) 67. A compound according to any of statements 1 to 62, wherein: R.sup.A (if present) is selected from Cl and Br; R.sup.B (if present) is H; R.sup.C (if present) is H; R.sup.D (if present) is selected from H, Me, F, Br, OMe.

(658) 68. A compound according to statement 56, wherein: R.sup.A is Cl; R.sup.B is H; R.sup.C is H; R.sup.D is H.

(659) 69. A compound according to statement 56, wherein: R.sup.A is Cl; R.sup.B is H; R.sup.C is H; R.sup.D is Me.

(660) 70. A compound according to statement 56, wherein: R.sup.A is Cl; R.sup.B is H; R.sup.C is H; R.sup.D is Br.

(661) 71. A compound according to statement 56, wherein: R.sup.A is Br; R.sup.B is H; R.sup.C is H; R.sup.D is H.

(662) 72. A compound according to statement 56, wherein: R.sup.A is Cl; R.sup.B is H; R.sup.C is H; R.sup.D is F.

(663) 73. A compound according to statement 56, wherein: R.sup.A is Cl; R.sup.B is H; R.sup.C is H; R.sup.D is OMe.

(664) 74. A compound according to statement 56, wherein: R.sup.A is Br; R.sup.B is H; R.sup.C is H; R.sup.D is F.

(665) 75. A compound according to any of statements 1 to 74, wherein Y is selected from O and CH.sub.2.

(666) 76. A compound according to any of statements 1 to 75, wherein Y is O.

(667) 77. A compound according to any of statements 1 to 76, wherein R.sup.Y is RYA.

(668) 78. A compound according to statement 77, wherein Z.sup.1 is CR.sup.Z1.

(669) 79. A compound according to statement 77, wherein Z.sup.1 is N.

(670) 80. A compound according to statement 77, wherein Z.sup.2 is CR.sup.Z2.

(671) 81. A compound according to statement 77, wherein Z.sup.2 is N.

(672) 82. A compound according to statement 77, wherein Z.sup.4 is CR.sup.Z4.

(673) 83. A compound according to statement 77, wherein Z.sup.4 is N.

(674) 84. A compound according to statement 77, wherein Z.sup.5 is CR.sup.Z5.

(675) 85. A compound according to statement 77, wherein Z.sup.5 is N.

(676) 86. A compound according to statement 77, wherein Z.sup.1 is CR.sup.Z1, Z.sup.2 is CR.sup.Z2, Z.sup.4 is CR.sup.Z4 and Z.sup.5 is CR.sup.Z5.

(677) 87. A compound according to statement 77, wherein one of Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 is N.

(678) 88. A compound according to statement 77, wherein two of Z.sup.1, Z.sup.2, Z.sup.4 and Z.sup.5 are N.

(679) 89. A compound according to any of statements 77 to 88, wherein two of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, Cl, Me, OMe, cyano, CF.sub.3, CH.sub.2OMe, CH.sub.2OH, C.sub.2-4alkenyl and C.sub.3-7heterocyclyl; the remainder (if present) are H.

(680) 90. A compound according to any of statements 77 to 89, wherein two of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, Cl, OMe, CF.sub.3, CH.sub.2OMe and CH.sub.2OH; the remainder (if present) are H.

(681) 91. A compound according to any of statements 77 to 90, wherein two of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, CF.sub.3, CH.sub.2OMe and CH.sub.2OH; the remainder (if present) are H.

(682) 92. A compound according to any of statements 77 to 91, wherein two of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, and CH.sub.2OH;

(683) the remainder (if present) are H.

(684) 93. A compound according to any of statements 77 to 92, wherein one of R.sup.Z1; R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, Cl, Me, OMe, CF.sub.3, CH.sub.2OMe, CH.sub.2OH, C.sub.2-4 alkenyl and C.sub.3-7heterocyclyl; the remainder (if present) are H.

(685) 94. A compound according to any of statements 77 to 93, wherein one of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, Cl, OMe, CF.sub.3, CH.sub.2OMe and CH.sub.2OH; the remainder (if present) are H.

(686) 95. A compound according to any of statements 77 to 94, wherein one of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, CF.sub.3, CH.sub.2OMe and CH.sub.2OH; the remainder (if present) are H.

(687) 96. A compound according to any of statements 77 to 95, wherein one of R.sup.Z1, R.sup.Z2, R.sup.Z4 and R.sup.Z5, (if present) are selected from H, F, and CH.sub.2OH; the remainder (if present) are H.

(688) 97. A compound according to any of statements 77 to 96, wherein: R.sup.Z1 (if present) is selected from H, F, and CH.sub.2OH; R.sup.Z2 (if present) is H; R.sup.Z4 (if present) is H; R.sup.Z5 (if present) is selected from H, F, and CH.sub.2OH.

(689) 98. A compound according to statement 86, wherein: R.sup.Z1 is H; R.sup.Z2 is selected from H, OMe, C.sub.2-4 alkenyl, CH.sub.2OMe and C5heterocyclyl; R.sup.Z4 is selected from H, OMe, C.sub.2-4 alkenyl, CH.sub.2OMe and C5heterocyclyl; R.sup.Z5 is H; wherein one of R.sup.Z2 and R.sup.Z4 is H.

(690) 99. A compound according to statement 86, wherein: R.sup.Z1 is F; R.sup.Z2 is H; R.sup.Z4 is H;

(691) 100. A compound according to statement 86, wherein: R.sup.Z1 is CH.sub.2OH; R.sup.Z2 is H; R.sup.Z4 is H; R.sup.Z5 is F.

(692) 101. A compound according to statement 86, wherein R.sup.Z1 is H; R.sup.Z2 is H, R.sup.Z4 is H and R.sup.Z5 is H.

(693) 102. A compound according to any one of statements 1 to 76, wherein R.sup.Y is RYB.

(694) 103. A compound according to statement 102, wherein R.sup.12 is selected from H and F.

(695) 104. A compound according to statement 103, wherein R.sup.12 is H.

(696) 105. A compound according to statement 103, wherein R.sup.12 is F.

(697) 106. A compound as defined in any one of statements 1 to 105, including the compounds of the provisos, for use in a method of therapy.

(698) 107. A pharmaceutical composition comprising a compound as defined in any one of statements 1 to 105, including the compounds of the provisos, and a pharmaceutically acceptable excipient.

(699) 108. A method of treatment or prevention of a disease ameliorated by the modulation of STING, comprising administering to a patient in need of treatment, a compound as defined in any one of statements 1 to 105, including the compounds of the provisos, or a pharmaceutical composition according to statement 107.

(700) 109. The use of a compound as defined in any one of statements 1 to 105, including the compounds of the provisos, in the manufacture of a medicament for treating or preventing disease ameliorated by the modulation of STING.

(701) 110. A compound as defined in any one of statements 1 to 105, including the compounds of the provisos, or pharmaceutical composition thereof for use in the treatment or preventing of disease ameliorated by the modulation of STING.

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Substituted condensed thiophenes as modulators of sting

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GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

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