ANTI-BACTERIAL COMPOUNDS BASED ON AMINO-GOLD PHOSPHINE COMPLEXES

Abstract

A compound of formula (I) for use in the prevention or treatment of a bacterial infection wherein: P.sup.X is selected from the group consisting of (P1), (P2) and (P3).

##STR00001##

Claims

1. A method of preventing or treating a bacterial infection by administering a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof: ##STR00191## wherein: P.sup.X is selected from the group consisting of (P1), (P2) and (P3); ##STR00192## wherein R.sup.P1 and R.sup.P2 are each independently selected from methyl, ethyl, isopropyl and phenyl; R.sup.P3 is selected from the group consisting of methyl and ethyl, isopropyl, t-butyl, cyclopentyl, phenyl, 4-membered or 5-membered heterocycloalkyl group linked to phosphorus via a carbon atom in the ring, including a single heteroatom independently selected from NR.sup.Z, O and S, CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CF.sub.2H, CH.sub.2CH.sub.2OR.sup.PB, CH.sub.2Q and (CH.sub.2).sub.2Q; wherein Q is a C.sub.5-6 heteroaryl group, optionally substituted with one or more groups R.sup.PA; R.sup.P4 is selected from methyl and ethyl; m is an integer selected from 1, 2 or 3; R.sup.M is one or more optional substituents on the ring independently selected from R.sup.PC when attached to a carbon atom adjacent the phosphorus atom, or OH, OC.sub.1-3alkyl and R.sup.PC, when attached to other ring carbons; -L.sup.B- is methylene, ethylene or is absent; when -L.sup.B- is present, R.sup.P4 is absent and R.sup.1 is selected from N, CH and CR.sup.PC; when -L.sup.B- is absent, R.sup.1 is selected from the group consisting of O, NR.sup.Z, SO.sub.2, CH.sub.2, CHF, CF.sub.2 and CHR.sup.PC; wherein R.sup.Z is selected from the group consisting of H, C.sub.1-3alkyl, COC.sub.1-3alkyl and SO.sub.2C.sub.1-3alkyl; R.sup.5 and R.sup.8 are each independently selected from H and R.sup.PC; R.sup.6 and R.sup.7 are each independently selected from H and R.sup.PC; wherein R.sup.PC is selected from the group consisting of C.sub.1-3alkyl, optionally substituted with one or more groups R.sup.PD; wherein R.sup.PA is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AL, F, Cl, Br, CN OH, OR.sup.PE, CF.sub.3, CF.sub.2H, COR.sup.PE, CH.sub.2OH, CH.sub.2OR.sup.PE, COOH, COOR.sup.PE, CONH.sub.2, CONHR.sup.PE, CONR.sup.PE.sub.2, OCOR.sup.PE, OCONH.sub.2, OCONHR.sup.PE, OCONR.sup.PE.sub.2, NH.sub.2, NHR.sup.PE, NR.sup.PE.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.PE.sub.2, SO.sub.2NR.sup.PE.sub.2, SO.sub.2R.sup.PE, NHCOH, NHCOR.sup.PE, NR.sup.PECOH and NR.sup.PECOR.sup.PE; and R.sup.PB is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AT, C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, C.sub.5-6cycloalkenyl or C.sub.5-6heterocycloalkenyl optionally substituted with one or more groups R.sup.AT, phenyl optionally substituted with one or more groups R.sup.AR, and C.sub.5-6heteroaryl optionally substituted with one or more groups R.sup.AR; R.sup.PE is selected from linear or branched C.sub.1-4alkyl optionally substituted with one or more groups R.sup.PD; and R.sup.PD is selected from the group consisting of F, OH and OC.sub.1-3alkyl; R.sup.A is selected from the group consisting of H; linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, C.sub.5-6cycloalkenyl and C.sub.5-6heterocycloalkenyl optionally substituted with one or more groups R.sup.AL, C.sub.5-6heteroaryl, optionally substituted with one or more groups R.sup.A1, C.sub.1-3alkyl substituted by phenyl or C.sub.5-6heteroaryl, which groups may optionally substituted with one or more groups R.sup.A1, R.sup.B is selected from COR.sup.A2 and SO.sub.2R.sup.A2; or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 5- or 6-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more groups selected from oxo, NH; phenyl optionally substituted with one or more groups R.sup.A1, R.sup.A2, and R.sup.A1; an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from oxo, NO.sub.2; C(O)N(R.sup.N1).sub.2, wherein each R.sup.N1 is independently selected from R.sup.N2 and OR.sup.N3, wherein R.sup.N2 and R.sup.N3 are each independently selected from linear unsubstituted C.sub.1-6alkyl; phenyl optionally substituted with one or more groups R.sup.A1, R.sup.A2 and R.sup.A1; with the proviso that when P.sup.X is P(C.sub.2H.sub.5).sub.3, NR.sup.AR.sup.B is not selected from the groups (X1) or (X6) ##STR00193## with the further proviso that when P.sup.X is PPh.sub.3, NR.sup.AR.sup.B is not selected from the groups (X15): ##STR00194## wherein R.sup.A1 is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AL, F, Cl, Br, CN OH, OR.sup.A2, CF.sub.3, CF.sub.2H, COR.sup.A2, CH.sub.2OH, CH.sub.2OR.sup.A2, CHR.sup.A2OH, CHR.sup.A2OR.sup.A2 COOH, COOR.sup.A2, CONH.sub.2, CONHR.sup.A2, CONR.sup.A2.sub.2, OCOR.sup.A2, OCONH.sub.2, OCONHR.sup.A2, OCONR.sup.A2.sub.2, NH.sub.2, NHR.sup.A2, NR.sup.A2.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.A2.sub.2, SO.sub.2NR.sup.A2.sub.2, SO.sub.2R.sup.A2, NHCOH, NHCOR.sup.A2, NR.sup.A2COH and NR.sup.A2COR.sup.A2; R.sup.A2 is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AT, C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, C.sub.5-6cycloalkenyl or C.sub.5-6heterocycloalkenyl optionally substituted with one or more groups R.sup.AT, phenyl optionally substituted with one or more groups R.sup.AR, and C.sub.5-10heteroaryl optionally substituted with one or more groups R.sup.AR; where N is substituted by 2 R.sup.A2 groups, the N and the R.sup.A2 groups may together form a N-containing C.sub.5-6 heterocycloalkyl group; R.sup.AL is selected from the group consisting of linear or branched C.sub.1-6alkyl optionally substituted with one or more groups R.sup.AT; F, CN OH, OR.sup.A2, CF.sub.3, CF.sub.2H, COR.sup.A2, COOH, COOR.sup.A2, CONH.sub.2, CONHR.sup.A2, CONR.sup.A2.sub.2, OCOR.sup.A2, OCONH.sub.2, OCONHR.sup.A2, OCONR.sup.A2.sub.2, NH.sub.2, NHR.sup.A2, NR.sup.A2.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.A2.sub.2, SO.sub.2NR.sup.A2.sub.2, SO.sub.2R.sup.A2, NHCOH, NHCOR.sup.A2, NR.sup.A2COH and NR.sup.A2COR.sup.A2; and wherein R.sup.AR is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AL, F, Cl, Br, CN OH, OR.sup.1A1, CF.sub.3, CF.sub.2H, COR.sup.1A1, CH.sub.2OH, CH.sub.2OR.sup.1A1, CHR.sup.1A1OH, CHR.sup.1A1OR.sup.1A1 COOH, COOR.sup.1A1, CONH.sub.2, CONHR.sup.1A1, CONR.sup.1A1.sub.2, OCOR.sup.1A1, OCONH.sub.2, OCONHR.sup.1A1, OCONR.sup.1A1.sub.2, NH.sub.2, NHR.sup.1A1, NR.sup.1A1.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1A1.sub.2, SO.sub.2NR.sup.1A1.sub.2, SO.sub.2R.sup.1A1, NHCOH, NHCOR.sup.1A1, NR.sup.1A1COH and NR.sup.1A1COR.sup.1A1; R.sup.AT is selected from the group consisting of F, CN OH, OC.sub.1-3alkyl, CF.sub.3, CF.sub.2H, COC.sub.1-3alkyl, COOH, COOC.sub.1-3alkyl, CONH.sub.2, CONHC.sub.1-3alkyl, CON(C.sub.1-3alkyl).sub.2, OCOC.sub.1-3alkyl, OCONH.sub.2, OCONHC.sub.1-3alkyl, OCON(C.sub.1-3alkyl).sub.2, NH.sub.2, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-3alkyl).sub.2, SO.sub.2N(C.sub.1-3alkyl).sub.2, SO.sub.2(C.sub.1-3alkyl), NHCOH, NHCO(C.sub.1-3alkyl), N(C.sub.1-3alkyl)COH and N(C.sub.1-3alkyl)CO(C.sub.1-3alkyl).

2. The method according to claim 1, wherein P.sup.X is P1, and either (a) both R.sup.P1 and R.sup.P2 are methyl; or (b) both R.sup.P1 and R.sup.P2 are ethyl; or (c) R.sup.P1 is methyl and R.sup.P2 is ethyl.

3-4. (canceled)

5. The method according to claim 2, wherein R.sup.P3 is selected from the group consisting of methyl, ethyl, oxetanyl, tetrahydrofuranyl, CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CF.sub.2H, CH.sub.2OCH R.sup.PB, where R.sup.PB is a linear or branched C.sub.1-6 alkyl; and CH.sub.2Q.

6-12. (canceled)

13. The method according to claim 1, wherein P.sup.X is P2, and the ring in P2 is not substituted.

14-16. (canceled)

17. The method according to claim 1, wherein P.sup.X is P3, -L.sup.B- is methylene or ethylene and either R.sup.1 is N; or R.sup.1 is CH; or R.sup.1 is CR.sup.PC, wherein R.sup.PC is unsubstituted C.sub.1-3 alkyl.

18-24. (canceled)

25. The method according to claim 1, wherein P.sup.X is selected from the group consisting of: ##STR00195##

26. The method according to claim 1, wherein R.sup.A is linear or branched C.sub.1-6alkyl optionally substituted with one or more groups R.sup.AL; and R.sup.B is selected from COR.sup.A2 and SO.sub.2R.sup.A2.

27-30. (canceled)

31. The method according to claim 1, wherein R.sup.A is C.sub.5-6heteroaryl, optionally substituted with one or more groups R.sup.A1; and R.sup.B is selected from COR.sup.A2 and SO.sub.2R.sup.A2.

32-38. (canceled)

39. The method according to claim 1, wherein NR.sup.AR.sup.B is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more groups selected from: oxo; phenyl optionally substituted with one or more groups R.sup.A1; R.sup.A2, and R.sup.A1.

40-50. (canceled)

51. The method according to claim 1, wherein NR.sup.AR.sup.B is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from: phenyl optionally substituted with one or more groups R.sup.A1; R.sup.A2, and R.sup.A1.

52. The method according to claim 51, wherein the 5- or 6-membered heteroaryl group contains up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of NR.sup.AR.sup.B.

53-58. (canceled)

59. The method according to claim 1, wherein NR.sup.AR.sup.B is an imidazolyl group, bearing a C substituent which is the group (B1) ##STR00196## wherein R.sup.B1 is selected from the group consisting of H, COR.sup.A2, CONR.sup.A2, CO.sub.2R.sup.A2, and SO.sub.2R.sup.A2; R.sup.B2 is selected from H, and linear or branched C.sub.1-4alkyl; and R.sup.B3 is selected from the group consisting of OH, OR.sup.A2, NH.sub.2, NHR.sup.A2 and NR.sup.A2.sub.2.

60. The method according to claim 1, wherein NR.sup.AR.sup.B is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from: oxo; phenyl optionally substituted with one or more groups R.sup.A1; R.sup.A2 and R.sup.A1.

61. The method according to claim 60, wherein the 8- to 10-membered heterobicyclyl group is a 9-membered heterobicyclyl group.

62-64. (canceled)

65. The method according to claim 1, wherein NR.sup.AR.sup.B is selected from ##STR00197## ##STR00198## ##STR00199## ##STR00200##

66-67. (canceled)

68. The method according to claim 1, wherein the bacterial infection prevented and/or treated is infection by one or more Gram-positive bacteria; or wherein the bacterial infection prevented and/or treated is infection by one or more Gram-negative bacteria.

69. (canceled)

70. A method for (a) reducing the biomass of a bacterial biofilm; (b) promoting the dispersal of microorganisms from a bacterial biofilm; (c) killing a microorganism within a bacterial biofilm: (d) sensitizing a microorganism in a bacterial biofilm to an antimicrobial agent; or (e) inhibiting the formation of a bacterial biofilm, the method comprising exposing the bacterial biofilm to an effective amount of a compound as described in claim 1; optionally wherein the bacteria are Gram positive bacteria; or optionally wherein the bacteria are Staphylococcus spp; or optionally wherein the bacteria are multi-drug resistant bacteria; or optionally wherein the bacteria are small colony variants.

71-86. (canceled)

87. The method according to claim 70, comprising further administering at least one additional antimicrobial agent.

88. (canceled)

89. A compound of formula (I): ##STR00201## and pharmaceutically acceptable salts and solvates thereof wherein: P.sup.X is selected from the group consisting of (P1), (P2) and (P3); ##STR00202## wherein R.sup.P1 and R.sup.P2 are each independently selected from methyl, ethyl, isopropyl and phenyl; R.sup.P3 is selected from the group consisting of methyl and ethyl, isopropyl, t-butyl, cyclopentyl, phenyl, 4-membered or 5-membered heterocycloalkyl group linked to phosphorus via a carbon atom in the ring, including a single heteroatom independently selected from NR.sup.Z, O and S, CF.sub.3, CH.sub.2CF.sub.3CH.sub.2CF.sub.2H, CH.sub.2CH.sub.2OR.sup.PB, CH.sub.2Q and (CH.sub.Z)Q; wherein Q is a C.sub.5-6 heteroaryl group, optionally substituted with one or more groups R.sup.PA; R.sup.P4 is selected from methyl and ethyl; m is an integer selected from 1, 2 or 3; R.sup.M is one or more optional substituents on the ring independently selected from R.sup.PC when attached to a carbon atom adjacent the phosphorus atom, or OH, OC.sub.1-3alkyl and R.sup.PC, when attached to other ring carbons; -L.sup.B- is methylene, ethylene or is absent; when -L.sup.B- is present, R.sup.P4 is absent and R.sup.1 is selected from N, CH and CR.sup.PC; when -L.sup.B- is absent, R.sup.1 is selected from the group consisting of O, NR.sup.Z, SO.sub.2, CH.sub.2, CHF, CF.sub.2 and CHR.sup.PC; wherein R.sup.Z is selected from the group consisting of H, C.sub.1-3alkyl, COC.sub.1-3alkyl and SOC.sub.1-3alkyl; R.sup.5 and R.sup.8 are each independently selected from H and R.sup.PC; R.sup.6 and R.sup.7 are each independently selected from H and R.sup.PC; wherein R.sup.PC is selected from the group consisting of C.sub.1-3alkyl optionally substituted with one or more groups R.sup.PD; wherein R.sup.PA is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.1-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AL, F, Cl, Br, CN OH, OR.sup.PE, CF.sub.3CF.sub.2H, COR.sup.PE, CH.sub.2OH, CH.sub.2OR.sup.PE, COOH, COOR.sup.PE, CONH.sub.2, CONHR.sup.PE, CONR.sup.PE.sub.2, OCOR.sup.PE, OCONH.sub.2, OCONHR.sup.PE, OCONR.sup.PE.sub.2, NH.sub.2, NHR.sup.PE, NR.sup.PE.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.PE.sub.2, SO.sub.2NR.sup.PE.sub.2, SO.sub.2R.sup.PE, NHCOH, NHCOR.sup.PE, NR.sup.PECOH and NR.sup.PECOR.sup.PE; and R.sup.PB is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AT, C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, C.sub.5-6cycloalkenyl or C.sub.5-6heterocycloalkenyl optionally substituted with one or more groups R.sup.AT, phenyl optionally substituted with one or more groups R.sup.AR, and C.sub.5-6heteroaryl optionally substituted with one or more groups R.sup.AR; R.sup.PE is selected from linear or branched C.sub.1-4alkyl optionally substituted with one or more groups R.sup.PD; and R.sup.PD is selected from the group consisting of F, OH and OC.sub.1-3alkyl; R.sup.A is selected from the group consisting of H; linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.4-6heterocycloalkyl, C.sub.5-6cycloalkenyl and C.sub.5-6heterocycloalkenyl optionally substituted with one or more groups R.sup.AL, C.sub.5-6heteroaryl, optionally substituted with one or more groups R.sup.A1, C.sub.1-3alkyl substituted by phenyl or C.sub.5-6heteroaryl, which groups may optionally substituted with one or more groups R.sup.A1, R.sup.B is selected from COR.sup.A2 and SOR.sup.A2; or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 5- or 6-membered heteroaryl, heterocycloalkyl or heterocycloalkenyl group optionally substituted with one or more groups selected from oxo, NH; phenyl optionally substituted with one or more groups R.sup.A1, R.sup.A2, and R.sup.A1; an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from oxo, NO.sub.2; C(O)N(R.sup.N1).sub.2, wherein each R.sup.N1 is independently selected from R.sup.N2 and OR.sup.N3, wherein R.sup.N2 and R.sup.N3 are each independently selected from linear unsubstituted C.sub.1-6alkyl; phenyl optionally substituted with one or more groups R.sup.A1, R.sup.A2 and R.sup.A1; with the proviso that when P.sup.X is P(C.sub.2H.sub.5).sub.3, NR.sup.AR.sup.B is not selected from the groups (X1) or (X6) ##STR00203## with the further proviso that when P.sup.X is PPh.sub.3, NR.sup.AR.sup.B is not selected from the groups (X15): ##STR00204## (X15) wherein R.sup.A1 is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AL, F, Cl, Br, CN OH, OR.sup.A2, CF.sub.3CF.sub.2H, COR.sup.A2, CH.sub.2OH, CH.sub.2OR.sup.A2, CHR.sup.A2OH, CHR.sup.A2OR.sup.A2 COOH, COOR.sup.A2, CONH.sub.2, CONHR.sup.A2, CONR.sup.A2.sub.2, OCOR.sup.A2, OCONH.sub.2, OCONHR.sup.A2, OCONR.sup.A2.sub.2, NH.sub.2, NHR.sup.2, NR.sup.A2.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.A2.sub.2, SO.sub.2NR.sup.A2.sub.2, SO.sub.2R.sup.A2, NHCOH, NHCOR.sup.A2, NR.sup.A2COH and NR.sup.A2COR.sup.A2; R.sup.A2 is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AT, C.sub.3-6cycloalkyl C.sub.4-6heterocycloalkyl C.sub.5-6cycloalkenyl or C.sub.5-6heterocycloalkenyl optionally substituted with one or more groups R.sup.AT, phenyl optionally substituted with one or more groups R.sup.AR, and C.sub.5-10heteroaryl optionally substituted with one or more groups R.sup.AR; where N is substituted by 2 R.sup.A2 groups, the N and the R.sup.A2 groups may together form a N-containing C.sub.5-6 heterocycloalkyl group; R.sup.AL is selected from the group consisting of linear or branched C.sub.1-6alkyl optionally substituted with one or more groups R.sup.AT; F, CN OH, OR.sup.A2, CF.sub.3, CF.sub.2H, COR.sup.A2, COOH, COOR.sup.A2, CONH.sub.2, CONHR.sup.A2, CONR.sup.A2.sub.2, OCOR.sup.A2, OCONH.sub.2, OCONHR.sup.A2, OCONR.sup.A2.sub.2, NH.sub.2, NHR.sup.A2, NR.sup.A2.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.A2.sub.2, SO.sub.2NR.sup.A2.sub.2, SO.sub.2R.sup.A2, NHCOH, NHCOR.sup.A2, NR.sup.A2COH and NR.sup.A2COR.sup.A2; and wherein R.sup.AR is selected from the group consisting of linear or branched C.sub.1-6alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl optionally substituted with one or more groups R.sup.AL, F, Cl, Br, CN OH, OR.sup.1A1, CF.sub.3, CF.sub.2H, COR.sup.1A1, CH.sub.2OH, CHOR.sup.1A1, CHR.sup.1A1OH, CHR.sup.1A1OR.sup.1A1 COOH, COOR.sup.1A1, CONH.sub.2, CONHR.sup.1A1, CONR.sup.1A1.sub.2, OCOR.sup.1A1, OCONH.sub.2, OCONHR.sup.1A1, OCONR.sup.1A1.sub.2, NH.sub.2, NHR.sup.1A1, NR.sup.1A1.sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1A1.sub.2, SO.sub.2NR.sup.1A1.sub.2, SO.sub.2R.sup.1A1, NHCOH, NHCOR.sup.1A1, NR.sup.1A1COH and NR.sup.1A1COR.sup.1A1; R.sup.AT is selected from the group consisting of F, CN OH, OC.sub.1-3alkyl, CF.sub.3, CF.sub.2H, COC.sub.1-3alkyl, COOH, COOC.sub.1-3alkyl, CONH.sub.2, CONHC.sub.1-3alkyl, CON(C.sub.1-3alkyl).sub.2, OCOC.sub.1-3alkyl, OCONH.sub.2, OCONHC.sub.1-3alkyl, OCON(C.sub.1-3alkyl).sub.2, NH.sub.2, NHC.sub.1-3alkyl, N(C.sub.1-3alkyl).sub.2, SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-3alkyl).sub.2, SO.sub.2N(C.sub.1-3alkyl).sub.2, SO.sub.2(C.sub.1-3alkyl), NHCOH, NHCO(C.sub.1-3alkyl), N(C.sub.1-3alkyl)COH and N(C.sub.1-3alkyl)CO(C.sub.1-3alkyl); with the provisos that when P.sup.X is P(CH.sub.3).sub.3, NR.sup.AR.sup.B is not selected from any of the groups (X1) to (X5), (X7) and (X12) to (X15); and when P.sup.X is P(C.sub.2H.sub.5).sub.3, NR.sup.AR.sup.B is not selected from the groups (X1), (X6) to (X11), (X13) and (X14); and when P.sup.X is PPh.sub.3, NR.sup.AR.sup.B is not selected from the groups (X2), (X12), (X14) and (X15): ##STR00205## ##STR00206##

90. A pharmaceutical composition comprising a compound according to claim 89 and a pharmaceutical acceptable diluent or excipient.

91-94. (canceled)

Description

EXAMPLES

Preparative HPLC Methods

[0580] Reverse Phase Preparative HPLC-MS: Mass-directed purification by preparative LC-MS using a preparative C-18 column (Phenomenex Luna C18 (2) 5 m, 10021.2 mm).

Generic Acidic Conditions:

[0581] A=water+0.1% formic acid; B=MeOH+0.1% formic acid; 20 C.; % B: 0.0 min Initial between 2% and 50%, 0.1 min % as per Initial, 7.0 min between 40% and 95%, 9.0 min 95%, 10.0 min 95%, 10.1 min back to Initial %; 12.0 min Initial %; 20.0 mL/min.

Generic Basic Conditions:

[0582] A=water pH 9 (Ammonium Bicarbonate 10 mM); B=MeOH; 20 C.; % B: 0.0 min Initial between 2% and 50%, 0.1 min % as per Initial, 7.0 min between 40% and 95%, 9.0 min 95%, 10.0 min 95%, 10.1 min back to Initial %; 12.0 min Initial %; 20.0 mL/min.

[0583] NMR was also used to characterise final compounds. NMR spectra were obtained Bruker Advance 400, Bruker DRX 400 or Jeol 400 ECS at room temperature unless otherwise stated. 1H NMR spectra are reported in ppm and referenced to either tetramethylsilane (0.00 ppm), DMSO-d6 (2.50 ppm), CDCl.sub.3 (7.26 ppm) or CD.sub.3OD (3.31 ppm).

Abbreviations Used

[0584] For the examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings. [0585] C. Degrees Centigrade [0586] aq. Aqueous [0587] br Broad [0588] d Doublet [0589] DABCO 1,4-Diazabicyclo[2.2.2]octane [0590] DavePhos 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl [0591] DCM Dichloromethane [0592] DIPEA N,N-Diisopropylethylamine [0593] DMF Dimethylformamide [0594] DMSO Dimethyl sulfoxide [0595] Et Ethyl [0596] EtOAc Ethyl acetate [0597] EtOH Ethanol [0598] Et.sub.2O Diethyl ether [0599] FA Formic acid [0600] g Gram [0601] h Hour(s) [0602] HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate [0603] .sup.iPr Isopropyl [0604] J Coupling constant [0605] LC-MS Liquid chromatography-mass spectrometry [0606] LiHMDS Lithium bis(trimethylsilyl)amide [0607] Me Methyl [0608] MeCN Acetonitrile [0609] MeOH Methanol [0610] mg Milligram [0611] min Minute(s) [0612] mL Milliliter [0613] mmol Millimole [0614] NaOMe Sodium methoxide [0615] O/N Overnight [0616] ppm Parts per million [0617] ppt Precipitate [0618] q Quartet [0619] quint Quintet [0620] rt Room temperature [0621] s Singlet [0622] sext sextet [0623] TEA Triethylamine [0624] THF Tetrahydrofuran [0625] TLC Thin layer chromatography [0626] t Triplet [0627] WIPE Water/isopropanol/Ethyl acetate (1:2:9)

Chemical Synthesis

[0628] Several of the requisite gold(I) phosphine chloride complexes III, necessary for coupling with precursors II, required synthesis from commercial starting materials. Other precursors used were commercially available.

Dimethylethylphosphine gold(I) chloride I-3

[0629] ##STR00054##

(a) Dimethylphosphine borane I-1

[0630] Cerium(III) chloride (25 g, 101.4 mmol) was suspended in THF (100 mL) and stirred at rt for 1 h. Sodium borohydride (3.8 g, 101.4 mmol) was then added and the suspension stirred at rt for a further 1 h. The reaction was cooled to 0 C. at which point dimethylphosphine oxide (2.6 g, 33.8 mmol) was added dropwise followed by lithium aluminium hydride (1M in THF, 40.7 mL, 40.7 mmol) also dropwise. The reaction was stirred at rt O/N before diluting with toluene (50 mL) then quenching with water (25 mL) and aqueous HCl (6N, 25 mL). The suspension was filtered through celite and the layers separated. The aqueous phase was extracted with DCM (340 mL) and the combined organic extracts washed with brine (140 mL) and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a yellow oil which was purified by column chromatography (Biotage Isolera Four, 25 g KP-Sil column eluting with isohexane to 20% EtOAc/isohexane to provide the title compound as a colourless oil (1.49 g, 19.6 mmol, 58%).

(b) Dimethylethylphosphine borane I-2

[0631] Dimethylphosphine borane I-1 (100 mg, 1.3 mmol) was dissolved in THF (3 mL) and the colourless solution cooled to 0 C. NaH (60% dispersion in mineral oil, 53 mg, 1.3 mmol) was added in one portion, whereupon effervescence was observed. The opaque reaction was stirred at rt for 10 min then cooled back down to 0 C. whereupon iodoethane (0.12 mL, 1.4 mmol) was added in one portion. When TLC had indicated completion of the reaction, water (10 mL) and Et.sub.2O (10 mL) were added and the phases separated. The aqueous phase was extracted with Et.sub.2O (215 mL) and the combined organic extracts washed with brine (120 mL) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material as a colourless gum. Purification by column chromatography (Biotage Isolera Four, 10 g KP-Sil column eluting with a gradient of isohexane to 20% EtOAc/isohexane provided the title compound as a white solid (122 mg, 1.1 mmol, 90%).

(c) Dimethylethylphosphine gold(I) chloride I-3

[0632] Dimethylethylphosphine borane I-2 (225 mg, 2.0 mmol) was dissolved in THF (5 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (640 mg, 6.0 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100 C. and stirred at this temperature for 4 h before cooling in an ice bath and adding a solution of chloro(tetrahydrothiophene)gold(I) (640 mg, 2.0 mmol) in DCM (5 mL). After stirring at rt O/N the reaction was diluted with DCM (10 mL) and water (10 mL) and the phases separated. The aqueous phase was extracted with DCM (220 mL) and the combined organic extracts washed with brine (20 mL) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a brown oil which was purified by column chromatography (Biotage SP1, 25 g KP-Sil eluting with 25% EtOAc/isohexane to 60% EtOAc/isohexane to provide the title compound as a white solid (265 mg, 0.82 mmol, 41%).

1-Methylphospholane gold(I) chloride I-5

[0633] ##STR00055##

(a) 1-Methylphospholaneborane I-4

[0634] The bis-Grignard reagent was prepared by treating magnesium (1.0 g, 0.04 mol) with 1,4-dibromobutane (4.3 g, 20 mmol) in dry THF (50 mL) at 65 C. for 3 h. The reaction mixture was cooled to 0 C. before adding a cooled (10 C.) solution of dichloromethyl phosphine (2.3 g, 20 mmol) in dry THF (25 mL) dropwise maintaining a temperature of 10 C. The mixture was stirred O/N at rt. Borane-THF complex (1.0M in THF, 20 mL, 20 mmol) was added dropwise and the reaction mixture stirred for additional 4 h. The reaction mixture was poured onto a mixture of ice (200 g) and aqueous HCl (2M, 100 mL) with vigorous stirring. The aqueous phase was extracted with DCM (3100 mL) and the combined organic extracts dried over MgSO.sub.4. Concentration in vacuo gave the crude product as a yellow oil which was purified by flash column chromatography (Biotage SP1, 50 g KP-Sil column, eluting with isohexane to DCM) to provide the title compound as a colourless oil (700 mg, 6.0 mmol, 30%).

(b) 1-Methylphospholane gold(I) chloride I-5

[0635] Procedure similar to that described for dimethylethylphosphine gold(I) chloride I-3 starting from 1-methylphospholaneborane I-4 (116 mg, 1.0 mmol) to provide the title compound as an off-white solid (200 mg, 0.6 mmol, 60%).

Diethylmethylphosphine gold(I) chloride I-7

[0636] ##STR00056##

(a) Diethylmethylphosphine borane I-6

[0637] To a cold (0 C.) solution of diethylchlorophosphine (1.0 g, 8.0 mmol) in THF (20 mL) under an inert atmosphere was slowly added methylmagnesium chloride (3M in THF, 2.7 mL, 8.1 mmol). After warming to rt and being stirred for 4 h, the reaction was cooled to 0 C. prior to the addition of borane-THF complex (1M in THF, 8 mL, 8.0 mmol). The reaction mixture was allowed to warm up to rt O/N, then was diluted with Et.sub.2O (30 mL) and water (20 mL). The phases were separated and the organic layer was washed with water (210 mL) and brine (10 mL) before being dried over MgSO.sub.4 and concentrated in vacuo to provide the title compound as a colourless oil (388 mg, 3.2 mmol, 40%).

(b) Diethylmethylphosphine gold(I) chloride I-7

[0638] Procedure similar to that described for dimethylethylphosphine gold(I) chloride I-3 starting from diethylmethylphosphine borane I-6 (385 mg, 3.2 mmol) to provide the title compound as a white solid (475 mg, 1.4 mmol, 44%).

4-Methyl-[1,4]oxaphosphinane gold(I) chloride I-9

[0639] ##STR00057##

(a) 4-Methyl-[1,4]oxaphosphinaneborane I-8

[0640] To a solution of diethyl methylphosphonate (1.5 g, 10.0 mmol) in dry THF (30 mL) was added lithium aluminium hydride (1M in THF, 15 mL, 15.0 mmol) at 00 C., and the mixture allowed to warm to rt and stirred for 4 h. The reaction mixture was cooled to 00 C. whereupon BuLi (1.6M in hexanes, 12.5 mL, 20 mmol) was added over 5 min and stirring continued at 00 C. for 45 min. 1-Bromo-2-(2-bromoethoxy)ethane (2.3 g, 10 mmol) was then added in one portion and the reaction mixture stirred for further 4 h. Borane-THF complex (1M in THF, 20 mL, 20 mmol) was added and the reaction mixture stirred at rt for an additional 72 h before being diluted with water (60 mL) and 2M HCl (aq., 160 mL) with vigorous stirring. The aqueous phase was extracted with DCM and the combined organic extracts dried over MgSO.sub.4. Concentration in vacuo gave the crude product which was purified by flash column chromatography (Biotage SP1, 25 g KP-Sil column, eluting with isohexane to EtOAc) to provide the title compound as a colourless oil (220 mg, 1.7 mmol, 17%).

(b) 4-Methyl-[1,4]oxaphosphinane gold(I) chloride I-9

[0641] Procedure similar to that described for dimethylethylphosphine gold(I) chloride I-3 starting from 4-methyl-[1,4]oxaphosphinaneborane I-8 (220 mg, 1.7 mmol) to provide the title compound as an off-white solid (186 mg, 0.5 mmol, 32%).

[0642] A number of the requisite precursors II, necessary for coupling with chloro(trialkyl phosphine) gold(I) complexes III, required synthesis from commercial starting materials. Other precursors used were commercially available.

7-Morpholin-4-yl-4H-benzo[1,4]oxazin-3-one I-10

[0643] ##STR00058##

[0644] 7-Bromo-4H-benzo[1,4]oxazin-3-one (300 mg, 1.3 mmol), morpholine (140 L, 1.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.9 mmg, 0.013 mmol) and DavePhos (15.3 mg, 0.039 mmol) were combined in THF (5 mL). The reaction was degassed with nitrogen and LiHMDS (3.3 mL, 3.3 mmol) was added and the reaction heated under nitrogen at 70 C. O/N. The reaction mixture was cooled to rt, diluted with saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (350 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a brown solid. The residue was purified by column chromatography (Biotage Isolera Four, 25 g, KP-Sil column, eluting with isohexane to EtOAc) to afford the title compound as a brown solid (125 mg, 0.53 mmol, 41%).

1H-Indazole-7-carboxylic acid dimethylamide I-11 and 1H-indazole-7-carboxylic acid diethylamide I-12

[0645] ##STR00059##

(a) 1H-Indazole-7-carboxylic acid dimethylamide I-11

[0646] 1H-Indazole-7-carboxylic acid (100 mg, 0.62 mmol) was suspended in anhydrous DCM (10 mL). DIPEA (430 L, 2.47 mmol) was added followed by HATU (281 mg, 0.74 mmol) and the reaction was stirred at rt for 20 min. Dimethylamine hydrochloride (100 mg, 1.23 mmol) was added and the reaction stirred at rt O/N. Additional dimethylamine hydrochloride (100 mg, 1.23 mmol), DIPEA (1 mL, 5.74 mmol) and HATU (281 mg, 0.74 mmol) were added and the reaction stirred for a further 18 h. The reaction was diluted with DCM and washed with water and saturated aqueous sodium hydrogen carbonate. The organic fraction was dried and concentrated in vacuo. Initial purification by column chromatography (Biotage Isolera Four, 10 g, KP-Sil column, eluting with isohexane to EtOAc) afforded impure title compound. Final purification by preparative HPLC (acidic conditions) afforded the title compound as a white solid, (43 mg, 0.23 mmol, 37%). An alternative procedure can be employed using 1H-indazole-7-carboxylic acid (198 mg, 0.62 mmol) and TEA (6.1 mmol) as base. The crude product was purified directly by preparative HPLC (basic conditions) to afford the title compound as a white solid, (108 mg, 0.57 mmol, 47%).

(b) 1H-Indazole-7-carboxylic acid diethylamide I-12

[0647] Procedure similar to that described for 1H-indazole-7-carboxylic acid dimethylamide I-11 starting from diethylamine (191 L, 1.85 mmol) to provide the title compound as a white solid (93 mg, 0.43 mmol, 49%).

1H-Benzoimidazole-2-carboxylic acid dimethylamide I-13 and 1H-benzoimidazole-2-carboxylic acid methoxy-methyl-amide I-14

[0648] ##STR00060##

(a) 1H-Benzoimidazole-2-carboxylic acid dimethylamide I-13

[0649] 1H-Benzoimidazole-2-carboxylic acid (150 mg, 0.93 mmol) was suspended in anhydrous DMF (10 mL). DIPEA (480 L, 2.76 mmol) was added followed by HATU (530 mg, 1.39 mmol) and the reaction was stirred at rt for 20 min. Dimethylamine hydrochloride (157 mg, 1.86 mmol) was added and the reaction stirred at rt O/N. The reaction was diluted with saturated aqueous sodium hydrogen carbonate and extracted with DCM. The organic fraction was dried and concentrated in vacuo. Purification by column chromatography (Biotage Isolera Four, 25 g KP-Sil column, eluting with isohexane to EtOAc) afforded impure title compound as a white solid, (80 mg, 0.42 mmol, 46%).

(b) 1H-benzoimidazole-2-carboxylic acid methoxy-methyl-amide I-14

[0650] Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from N-methyl,O-methyl hydroxylamine hydrochloride (181 mg, 1.86 mmol) to provide the title compound as an off-white solid (103 mg, 0.5 mmol, 54%).

1H-Imidazole-2-carboxylic acid dimethylamide I-15

[0651] ##STR00061##

[0652] Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from imidazole-2-carboxylic acid (218 mg, 2.67 mmol) to provide the title compound as a yellow oil (256 mg, 1.83 mmol, 54%).

1H-Indole-7-carboxylic acid dimethylamide I-16 and 1H-indole-7-carboxylic acid methoxy-methylamide I-17

[0653] ##STR00062##

(a) 1H-Indole-7-carboxylic acid dimethylamide I-16

[0654] Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from 7-indole carboxylic acid (200 mg, 1.24 mmol) to provide the title compound as a white solid (194 mg, 1.03 mmol, 83%).

(b) 1H-Indole-7-carboxylic acid methoxy-methylamide I-17

[0655] Procedure similar to that described for 1H-benzoimidazole-2-carboxylic acid dimethylamide I-13 starting from 7-indole carboxylic acid (200 mg, 1.24 mmol) and N-methyl,O-methyl hydroxylamine hydrochloride (240 mg, 2.45 mmol) to provide the title compound as a white solid (262 mg, 1.28 mmol, 100%).

[0656] Compounds of the formula I were synthesised via the coupling of gold(I) phosphine chloride complexes of formula III with nitrogen containing derivatives of general formula II:

Example 1

[0657] ##STR00063##

[0658] Method A:

[0659] To a stirred suspension of the appropriate nitrogen derivative II (0.16 mmol) and chlorophosphine gold(I) compound III (0.16 mmol) in MeOH (2 mL) was added dropwise NaOMe (0.5 M in MeOH, 0.18 mmol). The reaction was stirred at rt for 16 h before concentrating in vacuo to give a solid residue which was suspended in DCM (2 mL) and filtered. The filtrate was concentrated in vacuo giving an oily residue which after trituration with Et.sub.2O (3) and drying under high vacuum for 16 h, provided the title compound I.

[0660] Method B:

[0661] As Method A, except NaOH was used instead of NaOMe and EtOH instead of MeOH. The reaction was stirred at 0 C. for 75 min before the reaction mixture was concentrated in vacuo, re-suspended in water (10 mL) and extracted with DCM (310 mL). The combined organic extracts were passed through a phase separator cartridge (Biotage) and concentrated in vacuo to give a residue which was triturated with Et.sub.2O (3) to provide the title compound I.

[0662] Method C:

[0663] As Method A, except NaOH was used instead of NaOMe.

[0664] Method D:

[0665] As Method A except 2 equivalents of chlorophosphine gold(I) compound III and 2.2 equivalents of NaOMe were used.

[0666] Method E:

[0667] As Method A except the reaction mixture was heated at 50 C. for 18 h.

[0668] Method F:

[0669] As Method A except workup and isolation as Method B.

[0670] Method G:

[0671] As Method A except the order of addition of reagents was changed such that the base was added prior to addition of chlorophosphine gold(I) compound III.

[0672] Method H:

[0673] To a stirred solution of the appropriate nitrogen derivative II (0.1 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.1 mmol). The reaction mixture was stirred at rt for 15 min whereupon chlorophosphine gold(I) compound III (0.1 mmol) was added. The reaction mixture was stirred at rt for 18 h before concentrating in vacuo. The resulting residue was suspended in DCM (2 mL) and filtered. The filtrate was concentrated in vacuo, triturated with Et.sub.2O and isohexane, and dried under high vacuum for 16 h to provide the title compound I.

[0674] Method I:

[0675] As Method A except 2 equivalents of NaOMe were used and after 16 h, the reaction was concentrated in vacuo to afford the title compound I.

[0676] Method J:

[0677] As Method A except after 16 h, the reaction was concentration in vacuo, the resulting solid was triturated with DCM and then dissolved in MeOH. The solution was filtered, concentrated in vacuo and the resulting solid triturated further with Et.sub.2O and dried under high vacuum to provide the title compound I.

[0678] Method K:

[0679] To a stirred solution of the appropriate nitrogen derivative II (0.3 mmol) in EtOH (3 mL) was added aqueous K.sub.2CO.sub.3 (10% w/v, 1 mL) followed by chlorophosphine gold(I) compound III (0.3 mmol). The reaction mixture was stirred at RT for 18 h before it was diluted with water (10 mL) and extracted with EtOAc (330 mL). The combined organic extracts were passed through a phase separator cartridge (Biotage) and the solvent evaporated to provide the title compound I.

[0680] For compounds 94, 95, 96, and 98 the reaction was run in the dark by covering the reaction vessel in foil.

[0681] The solvent (or combination of solvents) used for trituration and isolation of target compounds I can be selected from the following: MeOH, EtOH, Et.sub.2O, EtOAc, isohexane, pentane or DCM.

[0682] Some of the compounds were prepared using methods in which minor modifications to the general methods were made; specifically, these methods involved small changes to the stoichiometry of reagents (1-2.2 equivalents), duration of reaction (1-86 h) and volume of solvent (2-6 mL). In some cases reactions were purged with nitrogen.

[0683] The following compounds were made using these methods:

TABLE-US-00002 TABLE 1 Compound Analytical Data Structure Number Method Physical appearance/Yield [00064] 1 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.84 (2H, s), 3.56 (2H, t, J = 4.7 Hz), 3.36 (2H, t, J = 4.7 Hz), 1.58 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.46 (s). Grey solid; 55 mg, 90% [00065] 2 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.29 (2H, t, J = 5.6 Hz), 2.03 (2H, t, J = 6.8 Hz), 1.47-1.65 (m, 13H). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.57 (s). White solid; 91 mg, 71% [00066] 3 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.84 (2H, s), 3.56 (2H, t, J = 4.5 Hz), 3.37 (2H, t, J = 4.5 Hz), 1.88 (6H, dq, J = 10.4, 7.6 Hz), 1.11 (9H, dt, J = 18.7, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 30.52 (s). Grey solid; 32 mg, 48% [00067] 4 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.29 (2 H, dq J = 7.2, 3.6 Hz), 1.92 (3H, s), 1.59 (9H, d, J = 11.4 Hz), 1.04 (3H, t, J = 7.2 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.70 (s). Dark grey solid; 35 mg, 60% [00068] 5 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.30 (2H, t, J = 7.6 Hz), 3.11 (2H, t, J = 7.6 Hz), 2.51 (3H, s), 1.57 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.08 (s) Grey solid; 51 mg, 85% [00069] 6 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.53-7.48 (2H, m), 7.24-7.18 (2H, m), 6.82 (1H, tt, J = 7.3, 1.1 Hz), 3.70 (2H, t, J = 7.6 Hz), 3.51 (2H, t, J = 7.6 Hz), 1.60 (9H, d, J = 1.14 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.11 (s) White solid; 62 mg, 88% [00070] 7 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 2.43 (4H, s), 1.62 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.80 (s) Off-white solid; 51 mg, 85% [00071] 8 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 4.11 (4H, s), 1.63 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.24 (s) Brown solid; 36 mg, 57% [00072] 9 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 4.09 (2H, t, J = 7.8 Hz), 3.49 (2H, t, J = 7.8 Hz), 1.59 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.21 (s). White solid; 57 mg, 98% [00073] 10 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.70-7.64 (4H, m), 1.67 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.61 (s) White solid; 53 mg, 74% [00074] 11 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.71-7.62 (4H, m), 1.98 (6H, dq, J = 18.9, 7.6 Hz), 1.15 (9H, dt, J = 18.9, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 31.65 (s) Grey solid; 20 mg, 25% [00075] 12 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.29 (1H, dd, J = 7.8, 1.8 Hz), 6.87-6.81 (2H, m), 6.74 (1H, m), 4.36 (2H, s), 1.66 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.47 (s) White solid; 58 mg, 84% [00076] 13 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.31 (1H, m), 7.14 (1H, ddd, J = 8.8, 6.6, 2.3 Hz), 6.14 (1H, dm, J = 9.1 Hz), 6.01 (1H, tt, J = 6.3, 1.3 Hz), 1.63 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.29 (s). Brown solid; 43 mg, 72% [00077] 14 A .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 2.51 (4H, t, J = 6.7 Hz), 1.92 (2H, quint, J = 6.6 Hz), 1.61 (9H, d, J = 11.1 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 11.40 (s) Brown solid; 47 mg, 76% [00078] 15 B .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 4.02 (1H, t, J = 8.1 Hz), 3.68 (1H, dt, J = 11.4, 7.1 Hz), 3.13 (1H, m), 2.14 (1H, m), 2.07-1.88 (2H, m), 1.76 (1H, m), 1.61 (9H, d, J = 11.1 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 11.25 (s) Pink solid; 27 mg, 28% [00079] 16 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.51 (2H, dd, J = 8.6, 1.0 Hz), 7.34 (2H, dd, J = 8.6, 7.6 Hz), 7.06 (1H, tt, J = 7.6, 1.0 Hz), 4.66 (1H, q, J = 6.8 Hz), 1.66 (9H, d, J = 11.6 Hz), 1.25 (3H, d, J = 6.8 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.10 (s) White solid; 73 mg, 97% [00080] 17 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 2.68 (3H, s), 1.62 (9H, d, J = 11.6 Hz), 1.18 (6H, s). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.10 (s) Off-white solid; 62 mg, 93% [00081] 18 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.98 (2H, t, J = 5.7 Hz), 3.32 (2H, t, J = 5.7 Hz), 1.70 (2H, quint, J = 5.7 Hz), 1.57 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.46 (s) Brown solid; 45 mg, 75% [00082] 19 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 2.70 (3H, s), 1.81-1.67 (8H, m), 1.62 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 10.12 (s). White solid; 60 mg, 85% [00083] 20 E .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.53 (1H, dt, J = 7.3, 1.0 Hz), 7.45-7.42 (2H, m), 7.37 (1H, m), 4.35 (2H, s), 1.64 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.58 (s). Off-white solid; 45 mg, 69% [00084] 21 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 2.82 (3H, d, J = 2.2 Hz), 2.62 (3H, s), 1.59 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.70 (s) Grey solid; 61 mg, 98% [00085] 22 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.71 (2H, s), 2.75 (3H, s), 1.62 (9H, d, J = 11.6 Hz). .sup.31P-NMR(162 MHz, DMSO- d6): ppm 9.99 (s) White solid; 52 mg, 83% [00086] 23 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.61-7.57 (2H, m), 7.34-7.28 (2H, m), 7.01 (1H, tt, J = 7.3, 1.0 Hz), 4.26 (2H, s), 1.65 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.93 (s) White solid; 53 mg, 73% [00087] 24 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.77-7.72 (2H, m), 7.52-7.48 (3H, m), 2.66 (3H, d, J = 2.0 Hz), 1.62 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.61 (s) Grey solid; 19 mg, 26% [00088] 25 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.77-7.73 (2H, m), 7.38-7.32 (2H, m), 7.09 (1H, tt, J = 7.6, 1.0 Hz), 6.77 (1H, dd, J = 2.8, 1.3 Hz), 6.29 (1H, dd, J = 2.8, 0.8 Hz), 1.64 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.33 (s) White solid; 43 mg, 61% [00089] 26 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.42-7.37 (2H, m), 6.83-6.78 (2H, m), 3.68 (3H, s), 3.68-3.62 (2H, m), 3.52-3.46 (2H, m), 1.59 (9H d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.80 (s) Brown solid; 54 mg, 71% [00090] 27 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.53-7.47 (2H, m), 7.08-7.01 (2H, m), 3.70- 3.65 (2H, m), 3.53-3.47 (2H, m), 1.59 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 9.91 (s) White solid; 51 mg, 68% [00091] 28 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.32 (2H, t, J = 6.6 Hz), 2.76-2.70 (2H, m), 2.20-2.12 (2H, m), 1.59 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.73 (s) White solid; 47 mg, 73% [00092] 29 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.39-3.33 (2H, m), 2.72-2.68 (2H, m), 1.98- 1.91 (2H, m), 1.58 (9H, d, J = 11.6 Hz), 1.49-1.42 (2H, m). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.24 (s) Off-white solid; 48 mg, 73% [00093] 30 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 1.65 (9H, d, J = 11.9 Hz), 1.37 (6H, s). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.01 (s) Grey solid; 59 mg, 91% [00094] 31 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.29 (2H, t, J = 6.6 Hz), 1.96-1.84 (4H, m), 1.57 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.28 (s) White solid; 51 mg, 88% [00095] 32 F .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.84 (1H, dd, J = 5.0, 1.5 Hz), 8.09 (1H, dd, J = 7.6, 1.5 Hz), 7.64 (1H, dd, J = 7.6, 5.0 Hz), 1.68 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.40 (s) White solid; 43 mg, 63% [00096] 33 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.45 (1H, app d, J = 7.3 Hz), 5.97 (1H, app d, J = 7.3 Hz), 1.64 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.17 (s) Brown solid; 32 mg, 53% [00097] 34* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.76 (2H, br s), 1.89 (6H, dq, J = 10.1, 7.6 Hz), 1.23 (9H, dt, J = 18.7, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 27.19 (br s) Colourless oil; 120 mg, 100% [00098] 35 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.65 (2H, br s), 6.39 (1H, t, J = 1.9 Hz), 1.86 (6H, dq, J = 10.1, 7.7 Hz), 1.23 (9H, dt, J = 18.7, 7.7 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 30.41 (br s) Colourless oil; 122 mg, 100% [00099] 36 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.45 (2H, brs), 6.19 (1H, t, J = 1.8 Hz), 1.64 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.88 (s) White solid; 161 mg, 98% [00100] 37* C .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 7.75 (2H, brs), 1.61 (9H, d, J = 11.1 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 12.29 (s) Beige solid; 101 mg, 97% [00101] 38* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.96 (2H, br s), 1.67 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.86 (s) White solid; 52 mg, 95% [00102] 39* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.70 (1H, br s), 7.42 (1H, d, J = 8.3 Hz), 7.08 (1H br s), 6.66 (1H, d, J = 8.3 Hz), 3.75 (3H, s), 1.71 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.20 (s) Yellow solid; 54 mg, 79% [00103] 40* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.74 (1H, brs), 1.71 (9H, d, J = 12.1 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.71 (s) White solid; 51 mg, 92% [00104] 41 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.83 (2H, s), 1.65 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.45 (s) Off-white solid; 36 mg, 55% [00105] 42* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.33 (1H, dd, J = 4.4, 2.8 Hz), 8.08 (1H, dd, J = 7.9, 1.5 Hz), 8.02 (1H, br s), 6.93 (1H, dd, J = 7.9, 4.4 Hz), 1.71 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.81 (s) Off-white solid; 46 mg, 73% [00106] 43 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.22 (1H, br s), 6.87 (2H, br s,), 1.64 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.16 (s) White solid; 49 mg, 86% [00107] 44 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.80 (1H, br s), 7.56 (2H, dd, J = 5.8, 3.1 Hz), 7.00 (2H, dd, J = 5.8, 3.1 Hz), 1.71 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.26 (s) White solid; 62 mg, 95% [00108] 45 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.43 (2H, br s), 6.91 (2H, br s), 2.48 (3H, s), 1.71 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 8.71 (s) Pale pink solid; 66 mg, 97% [00109] 46* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 2.17 (6H, brs), 1.65 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.21 (s) White solid; 40 mg, 67% [00110] 47 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 6.65 (2H, br s), 2.27 (3H, s), 1.64 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.57 (s) White solid; 61 mg, 100% [00111] 48 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.04 (2H, s), 1.68 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.69 (s) Grey solid; 61 mg, 92% [00112] 49** A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.59 (1H, br s), 6.85 (1H, br s), 1.66 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 11.23 (s) White solid; 48 mg, 80% [00113] 50* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.86 (1H, d, J = 1.0 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 2.3 Hz), 6.78 (1H, dd, J = 8.8, 2.3 Hz), 3.73 (3H, s), 1.69 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.17 (s) White solid; 42 mg, 62% [00114] 51* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.19 (1H, d, J = 4.5 Hz), 8.00 (1H, s), 7.92 (1H, dd, J = 7.8, 1.3 Hz), 7.04 (1H, dd, J = 7.8, 4.5 Hz), 1.72 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.00 (s) Yellow solid; 59 mg, 94% [00115] 52* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.34 (1H, dd, J = 4.5, 1.8 Hz), 8.08 (1H, ddd, J = 7.8, 1.8, 0.9 Hz), 8.03 (1H, d, J = 0.9 Hz), 6.94 (1H, dd, J = 7.8, 4.5 Hz), 2.01 (2H, dq, J = 11.4, 7.6 Hz), 1.70 (6H, d, J = 11.4 Hz), 1.91 (3H, dt, 20.2, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 3.01 (s) Brown oil; 34 mg, 54% [00116] 53* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 9.00 (1H, s), 8.73 (1H, s), 8.17 (1H, br s), 1.73 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.73 (s) Beige solid; 51 mg, 80% [00117] 54 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.13 (1H, dd, J = 4.5, 1.5 Hz), 7.79 (1H, app d, J = 8.1 Hz), 7.42 (1H, dd, J = 2.8, 0.8 Hz), 6.89 (1H, dd, J = 8.1, 4.5 Hz), 6.43 (1H, m), 1.69 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.17 (s) White solid; 45 mg, 71% [00118] 55 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.05 (1H, dd, J = 4.7, 1.6 Hz), 7.81 (1H, ddd, J = 7.7, 1.6, 0.8 Hz), 7.28 (1H, d, J = 2.8 Hz), 6.83 (1H, dd, J = 7.7, 4.7 Hz), 6.29 (1H, dd, J = 2.8, 1.3 Hz), 1.69 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.01 (s) White solid; 40 mg, 63% [00119] 56 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.74 (1H, m), 7.65 (1H, m), 7.36 (1H, dd, J = 2.5, 0.5 Hz), 7.09 (1H, ddd, J = 8.1, 6.8, 1.3 Hz), 7.00 (1H, ddd, J = 7.8, 6.8, 1.0 Hz), 6.51 (1H, m), 1.90 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.06 (s) Pale pink solid; 58 mg, 92% [00120] 57 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.60 (1H, s), 7.09 (2H, s), 3.75 (6H, s), 1.71 (9H, d,J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.08 (s) Off-white solid; 66 mg, 90% [00121] 58* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.39 (2H, m), 8.32 (1H, s), 1.72 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.54 (s) Off-white solid; 39 mg, 61% [00122] 59* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.98 (1H, app d, J = 8.1 Hz), 7.75 (1H, app d, J = 8.3 Hz), 7.24 (1H, m), 7.12 (1H, m), 3.85 (3H, s), 1.73 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.04 (s) White solid; 30 mg, 41% [00123] 60 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.39 (2H, s), 6.10 (1H, s), 1.95-1.86 (2H, m), 1.57 (6H, d, J = 10.6 Hz), 1.11 (3H, dt, J = 19.7, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 2.32 (s) Light brown solid; 36 mg, 57% [00124] 61* A .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 8.34 (1H, dd, J = 4.3, 1.5 Hz), 7.98 (1H, br s), 7.94 (1H, dd, J = 8.1, 1.5 Hz), 6.78 (1H, dd, J = 8.1, 1.5 Hz), 2.24-2.14 (2H, m,), 1.84-1.74 (6H, m), 1.63 (3H, d, J = 10.9 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 10.74 (s) Light brown solid; 28 mg, 67% [00125] 62* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.34 (1H, s), 7.31 (1H, m), 1.66 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.18 (s) White solid; 58 mg, 88% [00126] 63 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.04 (1H, ddd, J = 6.8, 1.5. 0.5 Hz). 6.89 (1H, ddd, J = 6.8, 1.5, 0.5 Hz), 6.83 (1H, td, J = 6.8, 1.5 Hz), 6.80 (1H, td, J = 6.8, 1.5 Hz), 3.23 (3H, s), 1.69 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz. DMSO-d6): ppm 9.19 (s). Cream solid; 59 mg, 87% [00127] 64 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.80 (1H, d, J = 7.6 Hz), 7.68 (1H, d, J = 7.8 Hz), 7.27-7.12 (2H, m), 1.75 (9H, d, J = 12.1 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.39 (s) Brown solid; 27 mg, 36% [00128] 65* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.85 (1H, d, J = 8.3 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.33 (1H, m), 7.20 (1H, m), 1.73 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.27 (s) White solid; 44 mg, 65% [00129] 66* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 9.18 (1H, s), 8.76 (1H, s), 8.26 (1H, s), 1.72 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.07 (s) White solid; 42 mg, 66% [00130] 67* A .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 8.20 (1H, br s), 7.92 (1H, br s), 7.52 (1H, app d, J = 7.1 Hz), 7.00 (1H, app t, J = 7.6 Hz), 1.66 (9H, d, J = 11.1 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 12.84 (s) Pale yellow solid; 39 mg, 52% [00131] 68 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.73 (1H, d, J = 7.6 Hz), 7.65 (1H, d, J = 8.1 Hz), 7.19 (1H, dd, J = 7.6, 7.1 Hz), 7.13 (1H, dd, J = 8.1, 7.1 Hz), 3.88 (3H, s), 1.74 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 10.96 (s) White solid; 23 mg, 32% [00132] 69 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.33 (1H, s), 8.24 (2H, br s), 1.72 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 10.04 (s) Brown solid; 58 mg, 91% [00133] 70 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 3.83 (2H, s), 3.55 (2H, t, J = 4.8 Hz), 3.35 (2H, t, J = 4.8 Hz), 1.87 (2H, dq, J = 10.8, 7.6 Hz), 1.54 (6H, d, J = 10.6 Hz), 1.10 (3H, dt, J = 19.9, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 3.1 (s) Brown oil; 42 mg. 74% [00134] 71 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.49 (1H, dd, J = 8.3, 2.0 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.34 (1H, d, J = 2.0 Hz), 4.46 (2H, s), 3.78 (3H, s), 1.68 (9H, d, J = 12.0 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.51 (s) White solid; 69 mg, 89% [00135] 72 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.83 (1H, dd, J = 5.1, 1.5 Hz), 7.17 (1H, ddd, J = 7.6, 1.5, 0.5 Hz), 6.76 (1H, dd, J = 7.6, 5.0 Hz), 4.46 (2H, s), 1.65 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.83 (s) Off-white solid; 40 mg, 59% [00136] 73 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.14 (1H, m), 6.48-6.44 (2H, m), 4.31 (2H, s), 3.71-3.68 (4H, m), 2.97-2.94 (4H, m), 1.65 (9H, d, J = 11.2 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.46 (s) Off-white solid; 66 mg, 80% [00137] 74 A .sup.1H-NMR (400 MHz, CD.sub.3OD): ppm 7.57 (2H, app d, J = 8.8 Hz), 6.64 (2H, app d, J = 8.8 Hz). 6.06 (1H, s), 5.50 (2H, s), 2.25 (3H, S), 1.68 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, CD.sub.3OD): ppm 11.50 (s) Beige solid; 82 mg, 96% [00138] 75 C .sup.1H-NMR (400 MHz, CD.sub.3CN): ppm 5.20 (1H, br s), 3.64 (2H, s), 2.86 (3H, s), 1.59 (9H, d, J = 11.4 Hz). .sup.31P-NMR(162 MHz, CD.sub.3CN): ppm 9.61 (s) Cream solid; 56 mg, 90 % [00139] 76 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.26 (1H, dd, J = 7.8, 1.5 Hz), 6.88-6.82 (2H, m), 6.78-6.72 (1H, m), 4.37 (2H, s), 2.05-1.90 (4H, m), 1.62 (3H, d, J = 10.9 Hz), 1.17 (6H, dt, J = 19.5, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 18.03 (s) Cream solid; 43 mg, 64% [00140] 77 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.07 (2H, br s), 6.68 (2H, br s), 5.57 (2H, br s), 1.69 (9H,d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 8.52 (s) White solid; 55 mg, 84% [00141] 78 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.73 (1H, s), 7.94 (1H, d, J = 5.6 Hz), 7.43 (1H, d, J = 5.6 Hz), 7.23 (1H, d, J = 2.5 Hz), 6.46 (1H, m), 1.70 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.30 (s) White solid; 26 mg, 41% [00142] 79 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.85 (1H, s), 7.85 (1H, d, J = 5.4 Hz), 7.40 (1H, d, J = 5.4 Hz), 7.38 (1H, d, J = 2.4 Hz), 6.38 (1H, m), 1.71 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.34 (s) Pale orange solid; 32 mg, 51 % [00143] 80 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.08 (1H, s), 7.06 (1H, s), 3.75 (3H, s), 1.67 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.97 (s) Pale pink solid; 60 mg, 93%. [00144] 81 I .sup.1H-NMR (400 MHz. DMSO-d6): ppm 6.85 (2H, br s), 1.63 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 13.17 (s) White solid; 67 mg, 89% [00145] 82 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.90 (2H, br s), 3.67 (3H, s), 1.65 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.43 (s) White solid; 61 mg. 95% [00146] 83 I .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.56 (1H, br s), 7.49 (1H, br s), 1.64 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.53 (s) White solid; 67 mg, 89% [00147] 84* A .sup.1H-NMR (400 MHz. DMSO-d6): ppm 8.16 (1H, s), 7.95 (1H, d, J = 7.6 Hz), 7.74 (1H, dd, J = 7.6, 1.0 Hz), 6.98 (1H, t, J = 7.6 Hz), 3.90 (3H, s), 1.69 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 13.04 (s) Off-white solid; 79 mg, 57% [00148] 85* J .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 8.44 (1H, dd, J = 4.4, 1.5 Hz), 8.01 (1H, br s), 7.99 (1H, dd, J = 7.8, 1.5 Hz), 6.88 (1H, dd, J = 7.8, 4.4 Hz), 4.06-4.01 (2H, m), 3.94-3.88 (2H, m), 2.31-2.21 (2H, m), 2.05-1.94 (2H, m), 1.72 (3H, d, J = 10.6 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 9.66 (s) Cream solid; 22 mg, 50% [00149] 86* I .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.19 (1H, d, J = 7.6 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.10 (1H, br s), 6.92 (1H, br s), 1.54 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 10.90 (s) Cream solid; 72 mg, 86% [00150] 87* I .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.91 (1H, s), 7.58 (1H, d, J = 7.6 Hz), 7.55 (1H, d, J = 7.6 Hz), 6.77 (1H, t, J = 7.6 Hz), 1.62 (9H, d, J = 11.1 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 14.42. (s) Yellow solid; 74 mg, 89% [00151] 88 I .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.60- 7.45 (2H, m), 7.05-6.90 (2H, m), 1.69 (9H, d, J = 11.1 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 12.17 (s) Cream solid; 72 mg. 87% [00152] 89 C. .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.70- 7.20 (2H, m), 6.19 (1H, s), 2.04-1.88 (4H, m), 1.61 (3H, d, J = 10.9 Hz), 1.16 (6H, dt, J = 19.2, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 16.12 (s) Brown gum; 17 mg. 31% [00153] 90* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.35 (1H, dd, J = 4.5, 1.5 Hz), 8.09 (1H, dd, J = 7.8, 1.5 Hz), 8.02 (1H, s). 6.94 (1H, dd. J = 7.8, 4.5 Hz), 2.10-1.95 (4H, m), 1.67 (3H, d, J = 10.9 Hz), 1.20 (6H, dt, J = 19.5, 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 16.63 (s) Cream solid; 26 mg, 42% [00154] 91* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.07 (1H, s), 7.69 (1H, dd, J = 7.8, 1.0 Hz), 6.98 (1H, dd, J = 6.8, 1.0 Hz), 6.92 (1H, dd, J = 7.8, 6.8 Hz), 3.07 (3H, s), 2.78 (3H, s), 1.68 (9H, d, J = 11.4 Hz). .sup.31P-NMR(162 MHz, DMSO-d6): ppm 11.61 (s) White solid; 62 mg, 83% [00155] 92* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.05 (1H, s), 7.67 (1H, dd, J = 6.1, 3.0 Hz), 6.95- 6.88 (2H, m), 3.60 (2H, br s), 3.14 (2H, q, J = 7.1 Hz), 1.66 (9H, d, J = 11.6 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.00 (3H, t, J = 7.1 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.89 (s) White solid; 68 mg, 86% [00156] 93 A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.81 (1H, dd, J = 8.8, 2.5 Hz), 7.64 (1H, d, J = 2.5 Hz), 7.43 (1H, d, J = 8.8 Hz), 4.55 (2H, s), 1.68 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.51 (s) Light brown solid; 24 mg, 32% [00157] 94 G .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.72- 7.60 (2H, m), 7.14-7.09 (2H, m), 3.86 (1.5H, s), 3.79 (1.5H, s), 3.62 (1.5H, s), 1.72 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 10.96 (s) Beige solid; 12 mg, 15% [00158] 95 G .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.48 (1H, d, J = 7.8 Hz), 7.19 (1H, d, J = 2.8 Hz), 6.81 (1H, dd, J = 7.8, 7.1 Hz), 6.71 (1H, dd, J = 7.1, 1.3 Hz), 6.38 (1H, dd, J = 2.8, 1.3 Hz), 3.05 (3H, s), 2.75 (3H, s), 1.65 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.88 (s) White solid; 65 mg, 87% [00159] 96 G .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.50 (1H, br dd, J = 7.3, 1.0 Hz), 7.19 (1H, d, J = 2.5 Hz), 6.81 (1H, dd, J = 7.3, 7.1 Hz), 6.78 (1H, dd, J = 7.1, 1.8 Hz), 6.38 (1H, dd, J = 2.5, 1.5 Hz), 3.33 (3H, br s), 3.19 (3H, br s), 1.65 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.51 (s) Beige solid; 43 mg, 58% [00160] 97* A .sup.1H-NMR (400 MHz, DMSO-d6): ppm 8.07 (1H, s), 7.68 (1H, d, J = 7.8 Hz), 7.00-6.90 (2H, m), 3.04 (3H, s), 2.77 (3H, s), 2.10-2.00 (2H, m), 2.10-2.00 (2H, m), 1.95-1.85 (4H, m), 1.61 (3H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.04 (s) Dark pink gum; 52 mg, 86% [00161] 98 G .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.66 (1H, d, J = 7.6 Hz), 7.60 (1H, d, J = 7.6 Hz), 7.13-7.05 (2H, m), 3.44 (3H, s), 3.04 (3H, s), 1.70 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.18 (s) Dark purple gummy solid; 25 mg, 34% [00162] 99 C .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 7.72-7.62 (6H, m), 7.53-6.44 (6H, m), 6.41 (1H, t, J = 2.0 Hz), 2.14 (3H, d, J = 10.1 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 17.24 (s) White solid, 126 mg, 88% [00163] 100* C .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 7.84-7.76 (2H, m), 7.70-7.63 (4H, m), 7.56-7.44 (6H, m) 2.17 (3H, d, J = 10.4 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 15.16 (s) Beige solid, 111 mg, 87% [00164] 101 K .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 7.80-7.73 (2H, m), 7.69 (2H, d, J = 2.0 Hz), 7.55-7.47 (3H, m), 6.41 (1H, t, J = 2.0 Hz), 1.87 (6H, d, J = 10.4 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 0.30 (s) White solid, 75 mg, 69% [00165] 102* K .sup.1H-NMR (400 MHz, CDCl.sub.3): ppm 7.84-7.74 (4H, m), 7.58-7.49 (3H, m), 1.89 (6H, d, J = 10.9 Hz). .sup.31P-NMR (162 MHz, CDCl.sub.3): ppm 1.37 (s) White solid, 93 mg, 86% [00166] 103 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.46 (2H, br s), 6.21 (1H, t, J = 1.8 Hz), 2.48-2.38 (3H, m), 1.28 (18H, dd, J = 16.2, 7.1 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 63.15 (s) White solid, 115 mg, 95% [00167] 104* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.67 (2H, br s), 2.50-2.43 (3H, m), 1.30 (18H, dd, J = 16.2, 7.1 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 62.53 (s) Brown solid, 101 mg, 97% [00168] 105 G .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.67- 7.53 (15H, m), 3.92 (2H, br s), 3.64-3.61 (2H, m), 3.55-3.51 (2H, m). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 31.60 (s) Grey solid, 80 mg, 89% [00169] 106 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.05 (1H, s), 6.99 (1H, s), 3.57 (3H, br s), 3.02 (3H, br s), 1.70 (9H, d, J = 11.4 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 12.68 (s) Brown oil; 33 mg, 90% [00170] 107 C .sup.1H-NMR (400 MHz. DMSO-d6): ppm 7.40 (1H, br s), 7.35 (1H, br s), 1.64 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 11.59 (s) White solid, 55 mg, 96% [00171] 108* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.39 (1H, s), 6.16 (1H, d, J = 1.8 Hz), 1.65 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 11.48 (s) White solid, 41 mg, 64% [00172] 109* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.05 (1H, s), 2.10 (3H, br s), 1.89 (3H, s), 1.64 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.67 (s) White solid, 75 mg, 93% [00173] 110 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 6.65 (2H, s), 2.60 (2H, t, J = 7.6 Hz), 1.71 (2H, sext, J = 7.6 Hz), 1.65 (9H, d, J = 11.6 Hz), 0.90 (3H, t, J = 7.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.54 (s) White solid, 59 mg. 64% [00174] 111* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.25 (1H, br s), 5.95 (1H, br s), 2.21 (3H, br s), 1.65 (9H, d, J = 11.4 Hz). .sup.31P-NMR(162 MHz, DMSO-d6): ppm 10.63 (s) White solid, 105 mg. 96% [00175] 112* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.52 (1H. m), 6.57 (1H, d, J = 1.8 Hz), 1.67 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO- d6): ppm 11.43 (s) Off-white solid. 85 mg, 66% [00176] 113* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.11 (1H, br s), 6.75 (1H, br s), 1.65 (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.40 (s) White solid, 85 mg, 76% [00177] 114* C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.68 (1H, d, J = 0.8 Hz), 7.41 (1H, d, J = 0.8 Hz), 1.67 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm -10.42 (s) Off-white solid, 92 mg, 79% [00178] 115* F .sup.1H-NMR (400 MHz, DMSO-d6): ppm 6.38 (1H, br.s), 2.25 (3H, s), 2.06 (3H, s), 1.65 (9H, d, J = 11.7 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.75 (s) Pale brown gum, 124 mg, 100% [00179] 116* F .sup.1H-NMR (400 MHz. DMSO-D6): ppm 6.35 (1H, s), 2.55 (2H, q, J = 7.4 Hz). 2.04 (3H, s), 1.61 (9H, d, J = 11.7 Hz), 1.18 (3H, t, J = 7.4 Hz). .sup.31P-NMR (162 MHz. DMSO-d6): ppm 8.54 (s) Pale brown gum, 127 mg, 100% [00180] 117 F .sup.1H-NMR (400 MHz. DMSO-D6): ppm 6.78 (2H, br s), 1.66 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.81 (s) Off-white solid, 117 mg. 95% [00181] 118 F .sup.1H-NMR (400 MHz, DMSO-D6): ppm 6.71 (2H, br s), 3.08 (1H, brs), 1.65 (9H, d, J = 11.9 Hz), 1.27 (6H, brs). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 8.08 (s) Pale orange gum, 130 mg, 100% [00182] 119 F .sup.1H-NMR (400 MHz, DMSO-D6): ppm 6.77 (2H, br s), 2.66 (2H, q, J = 7.5 Hz), 1.65 (9H, d, J = 11.4 Hz), 1.24 (3H, t, J = 7.5 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 8.65 (s) Pale yellow gum, 119 mg, 98% [00183] 120* C .sup.1H-NMR (400 MHz, DMSO-D6): ppm 7.04 (1H, br s), 6.55 (1H, s), 2.11 (3H, s), 1.64 (9H, d, J = 11.9 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.00 (s) Pale yellow gum, 109 mg, 96% [00184] 121 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.47 (1H, br s), 7.42 (1H, br s), 1.61 (9H, d, J = 11.5 Hz). .sup.31P-NMR (162 MHz. DMSO-d6): ppm 10.94 (s) White solid, 122 mg, 93% [00185] 122 C .sup.1H-NMR (400 MHz, DMSO-d6): ppm 7.33 (2H, br s), 4.44 (1H, br s), 4.32 (2H, s), 1.64 (9H, d, J = 11.5 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.48 (s) Yellow gum, 101 mg, 87% [00186] 123* C 1H-NMR (400 MHz, DMSO-d6): ppm 8.12 (1H. br s), 3.79 (3H, br s), 1.68 (9H, d, J = 12.3 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.42 (s) White powder, 91 mg, 69% [00187] 124* A 1H-NMR (400 MHz, DMSO-d6): ppm 7.73 (0.5H, br s), 7.61 (0.5H, br s) [the signals at 7.73 ppm and 7.61 ppm coalesce to a br s at 7.69 ppm on warming to 75 C.], 3.62 (0.5H br s), 3.43 (0.5H, br s) [the signals at 3.62 ppm and 3.43 ppm coalesce to a br s at 3.61 ppm on warming to 75 C.], 2.24 (4H, br s), 1.96 (1H, m), 1.84 (1H, m), 1.67, (9H, d, J = 11.6 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.75, 10.26 (s) [the two signals at 9.75 ppm and 10.26 ppm coalesce to a singlet at 9.86 ppm on warming to 75 C.]. Pink powder, 109 mg, 83% [00188] 125 C 1H-NMR (400 MHz, DMSO-d6): ppm 5.64 (1H, s), 2.05 (6H, br s), 1.57, (9H, d, J = 11.2 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.69 (s) White powder, 108 mg, 88% [00189] 126* C 1H-NMR (400 MHz, DMSO-d6): 7.30 (1H, br s), 2.25-2.06 (3H, m) (the signals at 2.25- 2.06 ppm coalesce to a br s at 2.15 ppm on warming to 75 C.]. .sup.31P-NMR (162 MHz, DMSO-d6): ppm 9.37, 10.26, 11.47 (s) [the three signals at 9.37 ppm, 10.26 ppm and 11.47 ppm coalesce to a br s at 10.11 ppm on warming to 75 C.] Grey solid, 49 mg, 94% [00190] 127 C 1H-NMR (400 MHz, DMSO-d6): 7.39-7.08 (2H, m), 1.97-1.88 (3H, m), 1.58 (9H, d, J = 11.5 Hz). .sup.31P-NMR (162 MHz, DMSO-d6): ppm 10.59 (s) *structural assignment to be confirmed: structure may be a regioisomer of this structure in which the Au is connected through a different N atom of the heterocyclic ring, or may represent a mixture of the possible regioisomers. **assigned on basis of X-ray crystallography experiments, although may represent a mixture of the possible regioisomers

Example 2

Growth Media

Tryptic Soy Broth

[0684]

TABLE-US-00003 Formula/Litre Pancreatic Digest of Casein 17.0 g Enzymatic Digest of Soybean 3.0 g Sodium Chloride 5.0 g Di-potassium hydrogen Phosphate 2.5 g Glucose 2.5 g

[0685] Directions for use: Dissolve 30 g of the medium in one litre of purified water, mix thoroughly, and then autoclave at 121 C. for 15 minutes.

Luria Broth

[0686]

TABLE-US-00004 Formula/Litre Tryptone 10.0 g Yeast Extract 5.0 g NaCl 5.0 g

[0687] Directions for use: Dissolve components in 1 litre of distilled or deionized water and sterilize by autoclaving at 121 C. for 15 minutes.

Mueller Hinton II Broth (Cation-Adjusted)

[0688]

TABLE-US-00005 Formula/Litre Beef Extract 3.0 g Acid Hydrolysate of Casein 17.5 g Starch 1.5 g *Adjusted and/or supplemented as required with appropriate salts to provide 20-25 mg/L of calcium and 10-12.5 mg/L of magnesium and as additionally required to meet performance criteria.

[0689] Directions for use: Dissolve components in 1 litre of distilled or deionized water and sterilize by autoclaving at 121 C. for 15 minutes.

Brain Heart Infusion Broth

[0690]

TABLE-US-00006 Formula/Litre Brain Heart Infusion solids 12.5 g Beef heart infusion solids 5 g Proteose peptone 10 g Glucose 2 g Sodium Chloride 5 g Di-sodium Phosphate 2.5 g

[0691] Directions for use: Dissolve components in 1 litre of purified water. Heat the mixture with frequent agitation to completely dissolve the medium, and sterilize by autoclaving at 121 C. for 15 minutes.

Growth Assay for S. aureus.

[0692] Stock solution of the test compounds (20 mg/ml) in dimethyl sulfoxide (DMSO) were serially diluted in DMSO and each diluted compound added in duplicate to a 96-well plate to a final DMSO concentration of 2% (v/v). An overnight culture of S. aureus (Oxford strain) grown in tryptic soy broth (TSB) was diluted to approximately 510.sup.7 cfu/ml and 150 l of this sample was added to each well of the 96-well plates. Control wells included an untreated control with bacteria in TSB in the presence of 2% DMSO and a negative sample (containing 150 l TSB growth media in the presence of 2% DMSO). Plates were incubated in a shaking incubator at 37 C. for 22-24 hours and bacterial growth assessed by absorbance at a wavelength of 595 nm. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of compound that inhibited growth compared to the no-treatment control.

Variation of growth assays for:

[0693] Klebsiella pneumoniae, Acinetobacter baumannnii or E. coli (ATCC 25922): use of 1/100 overnight dilution to set up assay, medium used: Luria broth (LB); incubation without shaking.

[0694] P. aeruginosa (ATCC 27853): use of 1/100 overnight dilution to set up assay, medium used: Cation adjusted Mueller Hinton broth (CaMHB); incubation without shaking.

TABLE-US-00007 S. aureus K. pneumoniae E. coli P. aeruginosa Com- MIC MIC MIC MIC pound (g/mL) (g/mL) (g/mL) (g/mL) 1 <0.8 3.1-6.3 3.1 12.5 2 <0.8 6.3 3.1-6.3 12.5 3 <0.8 12.5 12.5 25-50 4 <0.8 3.1 1.6 12.5 5 <0.8 3.1 6.3 12.5 6 <0.8 3.1-6.3 1.6 12.5 7 <0.8 3.1-6.3 6.3 6.3-12.5 8 <0.8 3.1-6.3 6.3 12.5 9 <0.8 6.3 3.1-6.3 12.5 10 0.8 1.6-3.1 1.6-3.1 11 0.8 12.5-25.sup. 12.5 12 1.6-3.1 1.6-3.1 13 3.1 1.6-3.1 14 <0.8 3.1 1.6 15 <0.8 3.1-6.3 1.6-3.1 16 0.8 3.1-6.3 3.1-6.3 17 <0.8 3.1-6.3 3.1 18 0.8 3.1 1.6-3.1 19 0.8 3.1-6.3 1.6-3.1 20 <0.8 3.1 1.6 21 .sup.0.8-1.6 3.1 1.6 22 1.6 3.1 1.6 23 0.8 1.6-3.1 1.6 24 .sup.0.8-1.6 3.1 1.6-3.1 25 <0.8 3.1 0.8-1.6 26 .sup.0.8-1.6 3.1 1.6 27 0.8 3.1 1.6 28 <0.8 3.1 0.8-1.6 29 .sup.0.8-1.6 3.1 1.6 30 <0.8 3.1 1.6 31 <0.8 3.1 0.8-1.6 32 <0.8 3.1 0.8-1.6 33 <0.8 3.1 1.6 34 1.6 12.5 6.3 12.5-25 35 1 6.3 6.3 12.5 36 <0.8 3.1 3.1-6.3 6.3-12.5 37 0.8 3.1-6.3 1.6 38 <0.8 3.1 3.1 6.3-12.5 39 <0.8 3.1-6.3 6.3 12.5 40 <0.8 3.1-6.3 3.1-6.3 12.5 41 1.6 3.1 1.6-3.1 42 0.8 1.6-3.1 1.6 43 <0.8 3.1 0.8-1.6 44 0.8 3.1 1.6 45 0.8 3.1 1.6 46 <0.8 3.1 0.8-1.6 47 <0.8 3.1 1.6-3.1 48 <0.8 1.6 49 <0.8 1.6-3.1 0.8-1.6 50 <0.8 3.1 1.6 51 .sup.0.8-1.6 3.1 0.8-1.6 52 <0.8 3.1 1.6 53 <0.8 3.1 1.6 54 <0.8 3.1 1.6 55 <0.8 3.1 1.6 56 <0.8 3.1-6.3 1.6-3.1 57 <0.8 3.1 1.6-3.1 58 <0.8 3.1 1.6 59 <0.8 3.1 1.6 60 <0.8 3.1-6.3 3.1 61 <0.8 3.1-6.3 3.1 62 <0.8 3.1 1.6 63 <0.8 1.6-3.1 1.6 64 <0.8 3.1 1.6 65 <0.8 3.1 1.6 66 <0.8 3.1 <0.8 67 <0.8 3.1 1.6 68 <0.8 3.1 1.6 69 <0.8 3.1 1.6 70 <0.8 3.1-6.3 1.6 71 0.8 1.6-3.1 3.1 25 72 0.8 1.6 3.1-6.3 12.5-25 73 0.8 1.6-3.1 3.1-6.3 25-50 74 0.8 1.6 3.1 25 75 0.8-1.6 0.8-3.1.sup. 1.6-3.1 25 76 0.8-1.6 1.6-25 3.1-25 12.5-25 77 0.8 0.8-1.6.sup. 1.6-3.1 12.5 78 0.8-1.6 0.8-3.1.sup. 1.6-3.1 25 79 0.8-12.5 0.8-1.6.sup. 1.6 25 80 0.8-12.5 0.8-1.6.sup. 1.6 25 81 0.8 1.6 1.6-3.1 12.5 82 0.8 1.6-3.1 3.1 12.5 83 0.8-1.6 1.6-3.1 3.1 12.5-25 84 0.8 0.8-3.1.sup. 1.6-3.1 12.5 85 .sup.1.6-3.1 1.6-6.3 6.3-12.5 25-50 86 0.8-3.1 0.8-3.1.sup. 3.1 6.3-25 87 0.8-3.1 0.8-3.1.sup. 3.1-6.3 12.5-25 88 0.8-3.1 0.8-3.1.sup. 1.6-3.1 6.3-12.5 89 0.8 3.1-6.3 6.3 12.5 90 0.8 3.1 6.3 12.5-25 91 0.8-1.6 0.8-1.6.sup. 3.1 12.5 92 0.8-1.6 1.6 3.1-6.3 6.3-12.5 93 0.8 0.8 <0.8-3.1 6.3-25 95 .sup.1.6-3.1 1.6-3.1 3.1-6.3 6.3-12.5 96 0.8-3.1 1.6-3.1 3.1-6.3 3.1-12.5 97 .sup.1.6-3.1 3.1 6.3 12.5 98 0.8-1.6 1.6-3.1 3.1 3.1-12.5 99 1.6 25-50 50-100 >100 100 .sup.1.6-3.1 37.5-50.sup. 100 >100 101 0.8-1.6 12.5-25.sup. 12.5-50.sup. 25 102 0.8-1.6 12.5-25.sup. 12.5-25.sup. 25 103 0.8-1.6 25-50 25-75 25 104 0.8-1.6 25-50 50-75 50 105 .sup.1.6-3.1 >100.sup. 100 100 106 0.8-3.1 1.6-3.1 3.1 12.5-25 107 0.8-1.6 3.1-6.3 3.1-6.3 12.5 108 0.8-1.6 3.1 3.1-6.3 12.5 109 0.8 3.1-6.2 1.6-3.1 25 110 0.8 1.6-6.2 1.6-3.1 12.5-25 111 .sup.0.4-0.8 3.1 1.6-3.1 12.5-25 112 .sup.0.4-1.6 1.6-3.1 1.6-3.1 25 113 .sup.0.8-1.6 1.6-6.2 1.6-3.1 25 114 0.2-0.8 1.6-3.1 1.6-3.1 25 115 .sup.0.4-0.8 3.1 1.6-3.1 12.5-25 116 .sup.0.8-1.6 3.1 3.1 12.5-25 117 0.8 3.1 1.6-3.1 25 118 .sup.0.4-0.8 3.1 1.6-3.1 25 119 .sup.0.4-0.8 3.1 1.6-3.1 25 120 0.8 3.1 3.1 25
Inhibition of Neisseria gonorrhoeae (NCTC 8375) Growth on Solid Media

[0695] N. gonorrhoeae was grown for 48 hours at 37 C. on Chocolate agar plates (BD Diagnostics). A culture loop-full of bacterial culture was picked from the plate and re-suspended in 50 l sterile phosphate buffered saline. The suspension was spread evenly onto the surface of a fresh chocolate agar plate and left to dry (approximately 5 minutes). Small discs of blotting paper were placed on the surface of the agar plate and 3 l of test compounds (at 20 mg/ml) were applied to the discs. The plates were incubated overnight at 37 C. and zones of clearance around the disc were measured.

HepG2 Cell Inhibition Assay

[0696] Cell counting kit-8 (Sigma, CCK-8) assays were performed to assess the effect of compounds on cell viability. The assay is based on the reduction of a water-soluble tetrazolium salt (WST-8) by cellular dehydrogenases to a formazan dye which can be detected spectroscopically. 96-well plates were seeded with the human hepatocyte cell line (HepG2) at approximately 810.sup.3 cells per well in Eagle's Minimum Essential Medium (EMEM) with Earle's salts and sodium bicarbonate supplemented with 10% heat-inactivated foetal bovine serum 2 mM glutamine and 1% non-essential amino acids (NEAA). The following day serial dilutions of compounds (dissolved and diluted in DMSO) were added to the cells in duplicates. Control wells included an untreated control where cells were grown in the presence of 1% DMSO and a medium only control (plus 1% DMSO). After 24 hours CCK-8 reagent (10 l) was added to each well and cell viability was assessed by measuring the absorbance at a wavelength of 450 nm after 2-3 h hours. Only living cells can reduce the tetrazolium salts into coloured formazan products. Results were expressed as 50% growth inhibition (TD.sub.50) values compared to untreated control.

TABLE-US-00008 HepG2 cell Compound TD.sub.50 (g/mL) 1 4 2 3 3 6 4 7 5 6 6 9 7 11 8 9 9 7 10 15 11 4 12 4 13 3 14 7 15 3 16 10 17 8 18 5 19 13 20 2 21 4 24 5 25 5 26 6 27 4 28 9 29 3 30 3 31 3 36 7.3 37 11.9 38 7 39 9 40 6 41 16 42 5 43 4 44 5 45 5 46 5 47 3.9 48 4 50 3 51 3
Efficacy Studies in the Galleria mellonella Model

[0697] G. mellonella larvae at 5.sup.th or 6.sup.th instar stage were purchased from a commercial supplier and used within 3 days. Prior to infection larvae were kept at room temperature. Larvae were infected with bacteria (various Gram positive and negative bacteria, including S. aureus, K. pneumoniae, E. coli and P. aeruginosa) using a sterile Hamilton syringe. Bacteria cultures were grown overnight, washed 3 in PBS and resuspended in PBS. Larvae were wiped with 70% ethanol and 10 l of bacteria solution (to cause 80%-100% death within 3-4 days) was injected into the bottom right proleg of the larvae. Larvae injected with 10 l of PBS were used as negative controls. Larvae were then placed in petri dishes (1 dish per condition) containing filter paper at the bottom of the dish at 37 C. After various time points post infection (1-6 h), larvae were taken from the incubator wiped again with 70% ethanol and injected with 10 l of various concentrations of compound, dissolved in either 5% dimethyl sulfoxide, 5% ethanol or 5% 1-methyl-2-pyrrolidinone into a proleg on the left hand-side. Control larvae received 10 l of 5% solvent. Ten larvae were injected for each condition. To assess the toxicity of the compound, larvae were injected with various concentrations of compound alone. Larvae were returned to a 37 C. incubator and checked daily. Larvae were considered dead when no movement occurred when touched with a blunt pair of forceps. Black or discoloured larvae which still showed movement were considered to be alive. Numbers of dead larvae were recorded each day.

Primary Cells Viability Assay

[0698] Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from venous blood obtained from healthy volunteers as previously described (Nauseef, Methods in Molecular Biology, 412 (2007), pp. 15-20). In brief, heparinised blood was diluted 1:1 with 3% Dextran-500 PBS solution (Sigma) to allow for erythrocyte sedimentation. Buffy coat was centrifuged over Hypaque-Ficoll (GE Lifescience) and PBMCs were carefully collected from the interface of the Hypaque-Ficoll and the upper liquid layer. Pelleted neutrophils were collected after hypotonic lysis of residing erythrocytes. Isolated cells were washed and suspended in culture media (RPMI+10% FBS) at 2106 cells/mL. Cell suspensions were transferred into 96-well plates containing compound in serially diluted (1% final volume). After 24 hours, the reaction was stopped and cells were stained with AnnexinV and 7-AAD. Results were determined by FACSCalibur and viability was defined for AnnexinV/7-AAD double negative cells population.

Biofilm Prevention Assay (S. aureus)

[0699] The effect of a test compound on the formation of a S. aureus biofilm was assessed using a biofilm prevention assay as described by Merritt et al. Current Protocols in Microbiology, 2011, 1B.1.1-1B1.18 with slight modifications. Briefly, S. aureus was grown overnight in tryptic soy broth (TSB) and diluted to 1/100 before 150 L was added to the wells of a flat bottomed 96-well plate. Three microliters of compound at the appropriate dilution in DMSO was added to the wells in duplicate. Controls included a positive control with bacteria alone in TSB with 2% DMSO and a negative (no bacteria) control with 150 L TSB containing 2% DMSO. Plates were sealed with AeraSeal and incubated at 37 C. for 24 hours. Plates were then washed three times with PBS, dried at 60 C. for 1 hour and stained with crystal violet for 1 hour. The plates were again washed three times with water, then dried 33% acetic acid was added to re-solubilize the crystal violet stain bound to the adherent cells. Absorbance was then measured at 595 nm and expressed as a percentage of the bacteria only control. A biofilm inhibitory concentration (BIC.sub.90) was determined as the concentration at which biofilm mass (measured by crystal violet staining) was reduced by at least 90% compared to untreated controls.

[0700] The effect of a test compound on preformed S. aureus biofilms can also be assessed. Briefly S. aureus was plated in 96-well plates as described in above and incubated at 37 C. for 24 hours. Biofilms were then washed 3 times with TSB and 150 L of fresh TSB and 3 L of compound at the appropriate dilution in DMSO was added to the wells in duplicate. Plates were again sealed with AeraSeal and reincubated at 37 C. for 24 hours. Biofilm was then detected as described above.

TABLE-US-00009 S. aureus BF dispersal Compound BIC.sub.90 (g/mL) 1 0.8 3 0.8 12 0.8 14 0.8 18 0.8 21 1.6 25 0.8 28 0.8 32 0.8 36 0.8 42 0.8 43 0.8 46 0.8 48 0.8 49 0.8 54 0.8 57 0.8
Biofilm Assay for A. baumannii

[0701] A. baumannii was grown overnight in LB broth and diluted 1/00-1/500 before 200 L was added to the wells of a flat bottomed 96-well plate with TSP 96 pins lid inserted. Plates with pins were incubated at 37 C. for 24 hours. Pins were washed with sterile phosphate buffered saline three times and exposed to compounds at pre-determined concentration in LB broth for 24 hours. Pins were washed again and either stained with crystal violet as described in the S. aureus biofilm assay, or incubated with LB media for 24 hours and the minimum biofilm eradication concentration (MBEC) was measured as the lowest concentration of compounds preventing further planktonic growth.

TABLE-US-00010 Compound Minimum biofilm eradication conc. (MBEC) g/mL 1 2.5-5.sup. 3 5-10 42 10-20 36 20 52 10 53 10 57 10 58 20 59 20 60 10 61 10 62 10 63 20 66 20 70 10 105 40 84 10

Persister Cell Assay

[0702] To determine whether S. aureus persister cells were susceptible to treatment with a test compound, a persister cell (or SCV) isolate hemB mutant of NCTC 8325-4 was used (Von Eiff et al., (1997) J Bacteriol 179:4706-4712). This persister cell variant displays varying resistance to erythromycin and the aminoglycosides gentamicin and kanamycin. Growth assays were performed essentially as described above with the bacteria being grown in TSB. Disc assays were also performed by plating bacteria on TSB agar. Discs impregnated with an amount of test compound were placed on top of the agar. The plates were incubated overnight at 37 C. and any zone of bacterial inhibition was observed.

Sensitivity of Multidrug Resistant Clinical Isolates

[0703] The activity of test compounds against multi-drug resistant bacterial strains was assessed by the disk diffusion assay; a standardised method to assess for the antimicrobial susceptibility of microorganisms (adapted from EUCAST, Version 5, January 2015). In brief, bacterial cultures were suspended in phosphate buffer and spread evenly onto blood agar plates. Cellulose disks (5 mm) were placed onto the agar plates and 3 l test compound (60 g/disk) were pipetted to the centre. A panel of standard antibiotics disks (Sigma) were used to control for the antimicrobial resistance profile of the individual strains (quantity as indicated in the table). The plates were then placed into a thermo-incubator and were cultured at 37 C. over-night. Activity was recorded by measuring the zone of clearance (mm) around the disks.

TABLE-US-00011 Size of clearance Size of clearance CDC Threat zone (mm) for 60 g zone (mm) for 60 g Clinical isolate classification level of Compound 35 of Compound 36 E. faecalis VRE Serious 12 20 DSM13591 A. baumannii MDRA Serious 7 11 NC13421 K. pneumoniae ESBL Serious 8 15 13368 E. coli 13400 ESBL Serious 11 ND

Comparative DataSize of Clearance of Zone (mm)

[0704]

TABLE-US-00012 Compund quantity E. faecalis A. baumannii K. pneumoniae E. coli Antibiotic (g) DSM13591 NC13421 13368 13400 Amoxycillin 2 17 R R R Azetronam 30 R R 11 23 Cefotaxime 30 R R R 18 Ceftriaxone 30 R R R R Colistin 10 N/A 11 9.5 12 Ertapenem 10 14 R R 30 Imipenem 10 26 R 18 29 Linezolid 10 22 N/A N/A N/A Meropenem 10 17 R 22 ND Piperacillin/Tazo 36 21 R 15 17 bactam Vancomycin 30 R N/A N/A N/A R = resistant N/A = strain not sensitive ND = not done

REFERENCES

[0705]

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