SUBSTITUTED AMINOTHIAZOLES AS DGKZETA INHIBITORS FOR IMMUNE ACTIVATION

Abstract

The present invention covers aminothiazole compounds of general formula (I): in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and/or prophylaxis of diseases, in particular of diacylglycerol kinase zeta (DGKζ) regulated disorders, as a sole agent or in combination with other active ingredients.

##STR00001##

Claims

1. A compound of formula (I): ##STR00275## wherein: R.sup.1 is a phenyl or 6-membered heteroaryl group optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, nitro, C.sub.1-C.sub.6-alkyl, (phenyl)-(C.sub.1-C.sub.3-alkyl)-, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, (phenyl)-(C.sub.1-C.sub.3-alkoxy)-, C.sub.1-C.sub.6-haloalkoxy, and —N(R.sup.5)(R.sup.6), wherein the phenyl groups in said (phenyl)-(C.sub.1-C.sub.3-alkyl)- and (phenyl)-(C.sub.1-C.sub.3-alkoxy)- groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, or two substituents attached to adjacent carbon atoms of said phenyl or 6-membered heteroaryl group together form a bivalent group selected from the group consisting of —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.2—O—, —(CH.sub.2).sub.3—O—, —CH.sub.2—O—CH.sub.2—, —(CH.sub.2).sub.2—O—CH.sub.2—, —O—CH.sub.2—O—, —O—CH.sub.2—CH.sub.2—O—, —O—CF.sub.2—O—, —O—CH.sub.2-CF.sub.2—O—, and —O—CF.sub.2—CF.sub.2—O—, or R.sup.1 is a 5-membered heteroaryl group optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C.sub.1-C.sub.3-alkyl, and C.sub.1-C.sub.3-alkoxy; R.sup.2 is ##STR00276## wherein “*” indicates the point of attachment to the nitrogen atom to which R.sup.2 is attached; R.sup.3 is methyl or —NH.sub.2; R.sup.4 is a 5-membered heteroaryl group optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C.sub.1-C.sub.6-alkyl, ((R.sup.9)O)—(C.sub.1-C.sub.3-alkyl)-, ((R.sup.10)(R.sup.11)N)—(C.sub.1-C.sub.3-alkyl)-, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)-, C.sub.3-C.sub.7-cycloalkyl, —OR.sup.9, —N(R.sup.10)(R.sup.11), —C(═O)—N(R.sup.15)(R.sup.16), —C(═O)—OR.sup.17, phenyl and 5- or 6-membered heteroaryl, wherein the phenyl group and the 5- or 6-membered heteroaryl group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl, ((R.sup.22)(R.sup.23)N)—C.sub.1-C.sub.3-alkyl, —OR.sup.9, —N(R.sup.10)(R.sup.11), and —C(═O)—N(R.sup.15)(R.sup.16); R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen atom, C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.4-cycloalkyl and (phenyl)-(C.sub.1-C.sub.3-alkyl)-, or R.sup.5 and R.sup.6, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, hydroxy, C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.4-cycloalkyl and C.sub.1-C.sub.4-alkoxy; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; R.sup.8 is selected from the group consisting of —C(═O)—NH.sub.2 and —S(═O).sub.2—NH.sub.2; R.sup.9 selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.6-alkyl, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)-, (phenyl)-(C.sub.1-C.sub.3-alkyl)-, (5- or 6-membered heteroaryl)-(C.sub.1-C.sub.3-alkyl)-, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.4-hydroxyalkyl, (C.sub.1-C.sub.3-alkoxy)-C.sub.2-C.sub.3-alkyl-, ((C.sub.1-C.sub.3-alkyl)-C(═O)—O)—C.sub.2-C.sub.3-alkyl-, —C(R.sup.18)(R.sup.19)—C(═O)—OR.sup.17, —C(R.sup.18)(R.sup.19)—C(═O)—N(R.sup.20)(R.sup.21), —C(═O)—N(R.sup.20)(R.sup.21), C.sub.3-C.sub.7-cycloalkyl, phenyl and 5- or 6-membered heteroaryl group, wherein C.sub.3-C.sub.7-cycloalkyl, and the C.sub.3-C.sub.7-cycloalkyl within said (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, oxo, cyano, C.sub.1-C.sub.2-alkyl and C.sub.1-C.sub.2-haloalkyl, and wherein the phenyl group within said (phenyl)-(C.sub.1-C.sub.3-alkyl)— group and said phenyl group itself, and the 5- or 6-membered heteroaryl group within said (5- or 6-membered heteroaryl)-(C.sub.1-C.sub.3-alkyl)— group and said 5- or 6-membered heteroaryl group itself, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy; R.sup.10 and R.sup.11 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.4-hydroxyalkyl, (C.sub.1-C.sub.3-alkoxy)-C.sub.2-C.sub.3-alkyl-, ((R.sup.22)(R.sup.23)N)—C.sub.2-C.sub.3-alkyl, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)-, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.7-cycloalkyl, (C.sub.3-C.sub.7-cycloalkyl)-C(═O)—, (phenyl)-(C.sub.1-C.sub.3-alkyl)-, (phenyl)-(C.sub.1-C.sub.3-alkyl)-C(═O)—, (phenyl)-(C.sub.1-C.sub.3-alkyl)-O—C(═O)—, phenyl, and a 5- or 6-membered heteroaryl group, wherein C.sub.3-C.sub.7-cycloalkyl, and the C.sub.3-C.sub.7-cycloalkyl within said (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)- and (C.sub.3-C.sub.7-cycloalkyl)-C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, C.sub.1-C.sub.2-alkyl and C.sub.1-C.sub.2-haloalkyl, and wherein said phenyl and said 5- or 6-membered heteroaryl group, and the phenyl groups within said (phenyl)-(C.sub.1-C.sub.3-alkyl)-, (phenyl)-(C.sub.1-C.sub.3-alkyl)-C(═O)—, and (phenyl)-(C.sub.1-C.sub.3-alkyl)-O—C(═O)— groups, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, or R.sup.10 and R.sup.11, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group or a bicyclic nitrogen containing 5- to 11-membered heterocycloalkyl group, which are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.7-cycloalkyl, C.sub.1-C.sub.4-alkoxy, —N(R.sup.22)(R.sup.23), and monocyclic 4- to 7-membered heterocycloalkyl; R.sup.15 and R.sup.16 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-hydroxyalkyl, (cyano)-C.sub.1-C.sub.4-alkyl-, (C.sub.1-C.sub.4-alkoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.1-C.sub.4-haloalkoxy)-C.sub.2-C.sub.3-alkyl-, (phenoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)-, C.sub.3-C.sub.7-cycloalkyl, bicyclic C.sub.5-C.sub.11-cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, (phenyl)-(C.sub.1-C.sub.3-alkyl)-, phenyl, and 5- or 6-membered heteroaryl, wherein C.sub.3-C.sub.7-cycloalkyl, the C.sub.3-C.sub.7-cycloalkyl within said (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)- group, the bicyclic C.sub.5-C.sub.11-cycloalkyl and the monocyclic 4- to 7-membered heterocycloalkyl groups are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, hydroxy, C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.4-cycloalkyl and C.sub.1-C.sub.4-alkoxy, and wherein the phenyl and the 5- or 6-membered heteroaryl groups, including the phenyl groups within said (phenoxy)-C.sub.2-C.sub.3-alkyl- and (phenyl)-(C.sub.1-C.sub.3-alkyl)- groups, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, or R.sup.15 and R.sup.16, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, hydroxy, C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.4-cycloalkyl and C.sub.1-C.sub.4-alkoxy; R.sup.17 represents a C.sub.1-C.sub.4-alkyl group; R.sup.18 and R.sup.19 are each independently a hydrogen atom or a C.sub.1-C.sub.4-alkyl group; R.sup.20 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.4-alkenyl, C.sub.3-C.sub.4-alkynyl, C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.7-cycloalkyl, bicyclic C.sub.5-C.sub.11-cycloalkyl, adamantyl, monocyclic 4- to 7-membered heterocycloalkyl, bicyclic 5- to 11-membered heterocycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl, wherein said C.sub.1-C.sub.6-alkyl group is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, C.sub.1-C.sub.3-alkoxy, —N(R.sup.22)(R.sup.23), C.sub.3-C.sub.7-cycloalkyl, bicyclic C.sub.5-C.sub.11-cycloalkyl, adamantyl, monocyclic 4- to 7-membered heterocycloalkyl, bicyclic 5- to 11-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl, said phenyl and 5- to 10-membered heteroaryl substituents themselves being optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, and wherein C.sub.3-C.sub.7-cycloalkyl, bicyclic C.sub.5-C.sub.11-cycloalkyl, adamantyl, monocyclic 4- to 7-membered heterocycloalkyl and bicyclic 5- to 11-membered heterocycloalkyl are optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C.sub.1-C.sub.4-alkyl, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.4-cycloalkyl and C.sub.1-C.sub.4-alkoxy, and wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl groups are optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-haloalkoxy, —N(R.sup.22)(R.sup.23) and —C(═O)—N(R.sup.24)(R.sup.25), R.sup.21 is a hydrogen atom or a C.sub.1-C.sub.4-alkyl group, or R.sup.20 and R.sup.21, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally benzocondensed, and which is optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, (phenyl)-(C.sub.1-C.sub.3-alkyl)-, (C.sub.1-C.sub.4-alkyl)-C(═O)—, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.3-haloalkoxy, —N(R.sup.22)(R.sup.23) and —C(═O)—N(R.sup.24)(R.sup.25); R.sup.22 and R.sup.23 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alky, and (C.sub.1-C.sub.2-alkyl)-C(═O)—, and R.sup.24 and R.sup.25 are each independently a hydrogen atom or a C.sub.1-C.sub.4-alkyl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound according to claim 1, wherein: R.sup.1 is a phenyl or pyridinyl group optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, nitro, C.sub.1-C.sub.4-alkyl, (phenyl)-(C.sub.1-C.sub.2-alkyl)-, C.sub.1-C.sub.4-halo alkyl, C.sub.1-C.sub.4-alkoxy, (phenyl)-(C.sub.1-C.sub.2-alkoxy)-, C.sub.1-C.sub.4-haloalkoxy, and —N(R.sup.5)(R.sup.6), wherein the phenyl groups in said (phenyl)-(C.sub.1-C.sub.2-alkyl)- and (phenyl)-(C.sub.1-C.sub.2-alkoxy)- groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, or two substituents attached to adjacent carbon atoms of said phenyl or pyridinyl group together form a bivalent group selected from the group consisting of —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —(CH.sub.2).sub.2—O—, —(CH.sub.2).sub.3—O—, —CH.sub.2—O—CH.sub.2—, —O—CH.sub.2—O—, —O—CH.sub.2—CH.sub.2—O—, and —I—CF.sub.2—O—, or R.sup.1 represents a pyrazolyl group optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C.sub.1-C.sub.2-alkyl, and C.sub.1-C.sub.2-alkoxy; R.sup.2 is ##STR00277## wherein “*” indicates the point of attachment to the nitrogen atom to which R.sup.2 is attached; R.sup.3 is methyl or —NH.sub.2; R.sup.4 is a 5-membered heteroaryl group selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and oxadiazolyl, optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, C.sub.1-C.sub.4-alkyl, ((R.sup.9)O)—(C.sub.1-C.sub.3-alkyl)-, ((R.sup.10)(R.sup.11)N)—(C.sub.1-C.sub.3-alkyl)-, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)-, C.sub.3-C.sub.7-cycloalkyl, —OR.sup.9,) —N(R.sup.10)(R.sup.11), —C(═O)—N(R.sup.15)(R.sup.16), —C(═O)—OR.sup.17, phenyl and 5- or 6-membered heteroaryl, wherein the phenyl group and the 5- or 6-membered heteroaryl group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, cyano, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-fluoroalkyl, —OR.sup.9, —N(R.sup.10)(R.sup.11) and —C(═O)—N(R.sup.15)(R.sup.16); R.sup.5 and R.sup.6 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl and (C.sub.1-C.sub.2-alkyl)-C(═O)—, or R.sup.5 and R.sup.6, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, oxo, hydroxy, C.sub.1-C.sub.2-alkyl and (C.sub.1-C.sub.2-alkyl)-C(═O)—; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; R.sup.8 is a —C(═O)—NH.sub.2 group; R.sup.9 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-, (phenyl)-(C.sub.1-C.sub.2-alkyl)-, C.sub.1-C.sub.4-haloalkyl, C.sub.2-C.sub.3-hydroxyalkyl, (C.sub.1-C.sub.2-alkoxy)-C.sub.2-alkyl-, ((C.sub.1-C.sub.2-alkyl)-C(═O)—O)—C.sub.2-alkyl-, —C(═O)—N(R.sup.20)(R.sup.21), C.sub.3-C.sub.7-cycloalkyl and phenyl, wherein C.sub.3-C.sub.7-cycloalkyl, and the C.sub.3-C.sub.7-cycloalkyl within said (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, oxo and methyl, and wherein the phenyl group within said (phenyl)-(C.sub.1-C.sub.2-alkyl)— group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, cyano, methyl, trifluoromethyl and methoxy; R.sup.10 and R.sup.11 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.2-C.sub.3-hydroxyalkyl, (C.sub.1-C.sub.2-alkoxy)-C.sub.2-alkyl-, ((R.sup.22)(R.sup.23)N)—C.sub.2-alkyl, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-, (C.sub.1-C.sub.2-alkyl)-C(═O)—, C.sub.3-C.sub.7-cycloalkyl, (C.sub.3-C.sub.7-cycloalkyl)-C(═O)—, (phenyl)-(C.sub.1-C.sub.2-alkyl)-, (phenyl)-(C.sub.1-C.sub.2-alkyl)-C(═O)—, and (phenyl)-(C.sub.1-C.sub.2-alkyl)-O—C(═O)—, wherein C.sub.3-C.sub.7-cycloalkyl, and the C.sub.3-C.sub.7-cycloalkyl within said (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)- and (C.sub.3-C.sub.7-cycloalkyl)-C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, C.sub.1-C.sub.2-alkyl and C.sub.1-C.sub.2-haloalkyl, and wherein the phenyl groups within said (phenyl)-(C.sub.1-C.sub.2-alkyl)-, (phenyl)-(C.sub.1-C.sub.2-alkyl)-C(═O)—, and (phenyl)-(C.sub.1-C.sub.2-alkyl)-O—C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, or R.sup.10 and R.sup.11, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group, or a bicyclic nitrogen containing 5- to 10-membered heterocycloalkyl group, which are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, (C.sub.1-C.sub.2-alkyl)-C(═O)—, C.sub.1-C.sub.2-alkoxy, —N(R.sup.22)(R.sup.23), and monocyclic 4- to 7-membered heterocycloalkyl; R.sup.15 and R.sup.16 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-hydroxyalkyl, (cyano)-C.sub.1-C.sub.4-alkyl-, (C.sub.1-C.sub.4-alkoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.1-C.sub.4-haloalkoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl), C.sub.3-C.sub.7-cycloalkyl, bicyclic C.sub.5-C.sub.11-cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, (phenyl)-(C.sub.1-C.sub.3-alkyl)-, phenyl and 5- or 6-membered heteroaryl, wherein C.sub.3-C.sub.7-cycloalkyl, the C.sub.3-C.sub.7-cycloalkyl within said (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.3-alkyl)- group, the bicyclic C.sub.5-C.sub.11-cycloalkyL and the monocyclic 4- to 7-membered heterocycloalkyl groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, C.sub.1-C.sub.2-alkyl, (C.sub.1-C.sub.2-alkyl)-C(═O)—, and cyclopropyl, and wherein the phenyl and the 5- or 6-membered heteroaryl groups, including the phenyl group within said (phenyl)-(C.sub.1-C.sub.3-alkyl)- group, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, or R.sup.15 and R.sup.16, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, C.sub.1-C.sub.2-alkyl, and (C.sub.1-C.sub.2-alkyl)-C(═O)—; R.sup.17 is a C.sub.1-C.sub.4-alkyl group; R.sup.20 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.7-cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein said C.sub.1-C.sub.6-alkyl group is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, C.sub.1-C.sub.3-alkoxy, —N(R.sup.22)(R.sup.23), C.sub.3-C.sub.7-cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein said phenyl and 5- to 6-membered heteroaryl substituents are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, and wherein C.sub.3-C.sub.7-cycloalkyl and monocyclic 4- to 7-membered heterocycloalkyl are optionally substituted one or two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C.sub.1-C.sub.2-alkyl, and (C.sub.1-C.sub.2-alkyl)-C(═O)—, and wherein said phenyl and 5- to 6-membered heteroaryl groups are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, C.sub.1-C.sub.2-alkoxy, C.sub.1-C.sub.2-haloalkoxy, —N(R.sup.22)(R.sup.23), and —C(═O)—N(R.sup.24)(R.sup.25), R.sup.21 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group, or R.sup.20 and R.sup.21, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-haloalkyl, (phenyl)-(C.sub.1-C.sub.2-alkyl)-, (C.sub.1-C.sub.2-alkyl)-C(═O)—, C.sub.3-C.sub.4-cycloalkyl, C.sub.1-C.sub.2-alkoxy, C.sub.1-C.sub.2-haloalkoxy, —N(R.sup.22)(R.sup.23) and —C(═O)—N(R.sup.24)(R.sup.25); R.sup.22 and R.sup.23 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alky, and (C.sub.1-C.sub.2-alkyl)-C(═O)—, and R.sup.24 and R.sup.25 are each independently a hydrogen atom or a C.sub.1-C.sub.2-alkyl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. The compound according to claim 1, wherein: R.sup.1 is a phenyl or pyridinyl group optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl, C.sub.1-C.sub.2-alkoxy, (phenyl)-(C.sub.1-C.sub.2-alkoxy)-, C.sub.1-C.sub.2-fluoroalkoxy and —N(R.sup.5)(R.sup.6), or two substituents attached to adjacent carbon atoms of said phenyl or pyridinyl group together form a bivalent group selected from the group consisting of —(CH.sub.2).sub.3—, —O—CH.sub.2—O— and —O—CF.sub.2—O—, or R.sup.1 is a pyrazolyl group optionally substituted with one methyl group, R.sup.2 is ##STR00278## wherein “*” indicates the point of attachment to the nitrogen atom to which R.sup.2 is attached; R.sup.3 is from methyl or —NH.sub.2; R.sup.4 is ##STR00279## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4a and R.sup.4b are each independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, C.sub.1-C.sub.4-alkyl, ((R.sup.9)O)—(C.sub.1-C.sub.2-alkyl)-, ((R.sup.10)(R.sup.11)N)—(C.sub.1-C.sub.2-alkyl)-, (C.sub.3-C.sub.7-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-, C.sub.3-C.sub.7-cycloalkyl, —OR.sup.9, —N(R.sup.10)(R.sup.11), —C(═O)—N(R.sup.15)(R.sup.16), —C(═O)—OR.sup.17, phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein the phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, C.sub.1-C.sub.2-alkyl, —OR.sup.9, —N(R.sup.10)(R.sup.11), and —C(═O)—N(R.sup.15)(R.sup.16); R.sup.5 and R.sup.6 are each a hydrogen atom or a C.sub.1-C.sub.2-alkyl group, or R.sup.5 and R.sup.6, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, hydroxy and C.sub.1-C.sub.2-alkyl; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; R.sup.8 is a —C(═O)—NH.sub.2 group; R.sup.9 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, benzyl, C.sub.1-C.sub.2-fluoroalkyl, C.sub.2-hydroxyalkyl, (C.sub.1-C.sub.2-alkoxy)-C.sub.2-alkyl-, ((C.sub.1-C.sub.2-alkyl)-C(═O)—O)—C.sub.2-alkyl-, —C(═O)—N(R.sup.20)(R.sup.21), and phenyl, wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano and methyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-fluoroalkyl, (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-(C.sub.1-C.sub.2-alkyl)-C(═O)—, C.sub.3-C.sub.7-cyclo alkyl, C.sub.3-C.sub.7-cycloalkyl-(C═O)—, (phenyl)-(C.sub.1-C.sub.2-alkyl)-, (phenyl)-(C.sub.1-C.sub.2-alkyl)-C(═O)—, and (phenyl)-(C.sub.1-C.sub.2-alkyl)-O—C(═O)—, wherein C.sub.3-C.sub.7-cycloalkyl, and the C.sub.3-C.sub.5-cycloalkyl within said (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)- and the C.sub.3-C.sub.7-cycloalkyl within the C.sub.3-C.sub.7-cycloalkyl-(C═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, C.sub.1-C.sub.2-alkyl and C.sub.1-C.sub.2-fluoroalkyl, and wherein the phenyl groups within said (phenyl)-(C.sub.1-C.sub.2-alkyl)-, (phenyl)-(C.sub.1-C.sub.2-alkyl)-C(═O)—, and (phenyl)-(C.sub.1-C.sub.2-alkyl)-O—C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom and a methyl group, or R.sup.10 and R.sup.11, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, oxo, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-fluoroalkyl and (C.sub.1-C.sub.2-alkyl)-C(═O)—; R.sup.15 and R.sup.16 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.3-fluoroalkyl, (cyano)-C.sub.1-C.sub.2-alkyl-, (C.sub.1-C.sub.4-alkoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.1-C.sub.2-fluoroalkoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-, C.sub.3-C.sub.5-cycloalkyl, phenyl, pyrazolyl, pyridinyl and pyrimidinyl, wherein C.sub.3-C.sub.5-cycloalkyl, and the C.sub.3-C.sub.5-cycloalkyl within said (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)— group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of methyl and cyclopropyl, and wherein the phenyl, pyrazolyl, pyridinyl and pyrimidinyl are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, methyl, trifluoromethyl and methoxy, or R.sup.15 and R.sup.16, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted once with a substituent selected from the group consisting of a fluorine atom, oxo, C.sub.1-C.sub.2-alkyl and CH.sub.3—C(═O)—; R.sup.17 is a C.sub.1-C.sub.2-alkyl group; R.sup.20 is a hydrogen atom, C.sub.1-C.sub.3-alkyl, or phenyl, wherein said C.sub.1-C.sub.3-alkyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, hydroxy, C.sub.1-C.sub.3-alkoxy and phenyl, said phenyl itself being optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group, and wherein said phenyl group is optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R.sup.21 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; or R.sup.20 and R.sup.21, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.2-fluoroalkyl, benzyl, (C.sub.1-C.sub.2-alkyl)-C(═O)—, and C.sub.3-C.sub.4-cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. The compound according to claim 1, wherein: R.sup.1 is a phenyl or pyridinyl group optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, difluoromethyl, trifluoromethyl, methoxy, benzyloxy, difluoromethoxy and trifluoromethoxy, or two substituents attached to adjacent carbon atoms of said phenyl or pyridinyl group together form a bivalent group —O—CF.sub.2—O—; R.sup.2 is ##STR00280## wherein “*” indicates the point of attachment to the nitrogen atom to which R.sup.2 is attached; R.sup.3 is methyl or —NH.sub.2; R.sup.4 is ##STR00281## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4a is selected from the group consisting of a chlorine atom, a bromine atom, ((R.sup.9)O)—(C.sub.1-C.sub.2-alkyl)-, ((R.sup.10)(R.sup.11)N)—(C.sub.1-C.sub.2-alkyl)-, (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-, C.sub.3-C.sub.5-cycloalkyl, —OR.sup.9, —C(═O)—N(R.sup.15)(R.sup.16), and phenyl, wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group, or R.sup.4 is ##STR00282## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4b is selected from the group consisting of C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, —C(═O)—N(R.sup.15)(R.sup.16), and phenyl, wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, C.sub.1-C.sub.2-alkyl, and —OR.sup.9; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; R.sup.8 is a —C(═O)—NH.sub.2 group; R.sup.9 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, benzyl, C.sub.1-C.sub.2-fluoroalkyl, (C.sub.1-C.sub.2-alkoxy)-C.sub.2-alkyl-, ((C.sub.1-C.sub.2-alkyl)-C(═O)—O)—C.sub.2-alkyl-, —C(═O)—N(R.sup.20)(R.sup.21) and phenyl, wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano and methyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-, C.sub.3-C.sub.7-cycloalkyl and (phenyl)-(C.sub.1-C.sub.2-alkyl)-O—C(═O)—, wherein C.sub.3-C.sub.7-cycloalkyl, and the C.sub.3-C.sub.5-cycloalkyl within said (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)— group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, methyl, and C.sub.1-fluoroalkyl, and wherein the phenyl group within said (phenyl)-(C.sub.1-C.sub.2-alkyl)-O—C(═O)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group, or R.sup.10 and R.sup.11, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, methyl, and C.sub.1-fluoroalkyl; R.sup.15 and R.sup.16 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl, (C.sub.1-C.sub.4-alkoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.1-C.sub.2-fluoroalkoxy)-C.sub.2-C.sub.3-alkyl-, (C.sub.3-C.sub.05-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)-, C.sub.3-C.sub.5-cycloalkyl, phenyl and pyridinyl, wherein C.sub.3-C.sub.5-cycloalkyl, and the C.sub.3-C.sub.5-cycloalkyl within said (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-C.sub.2-alkyl)— group are optionally substituted one or two times, wherein each substituent is independently a fluorine atom or a methyl group, and wherein the phenyl and pyridinyl groups are optionally substituted one or two times, wherein each substituent is independently elected from the group consisting of a fluorine atom, a chlorine atom, methyl, trifluoromethyl, and methoxy; R.sup.20 is benzyl or phenyl, wherein said phenyl group, and the phenyl group within said benzyl group, is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom and a methyl group, and R.sup.21 or a hydrogen atom or a methyl group, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

5. The compound according to claim 1, wherein: R.sup.1 is ##STR00283## wherein “**” indicates the point of attachment to the nitrogen atom to which R.sup.1 is attached; R.sup.2 is ##STR00284## wherein “*” indicates the point of attachment to the nitrogen atom to which R.sup.2 is attached; R.sup.3 is methyl or —NH.sub.2; R.sup.4 is ##STR00285## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4a is selected from the group consisting of ((R.sup.9)O)—(C.sub.1-alkyl)-, ((R.sup.10)(R.sup.11)N)—(C.sub.1-alkyl)-, (C.sub.3-C.sub.5-cycloalkyl)-(C.sub.1-alkyl)-, C.sub.3-C.sub.5-cycloalkyl, —OR.sup.9, —C(═O)—N(R.sup.15)(R.sup.16), and phenyl, wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from a fluorine atom, a chlorine atom, and a methyl group, or R.sup.4 is ##STR00286## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4b is selected from C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl and phenyl, wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, C.sub.1-C.sub.2-alkyl and —OR.sup.9; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; R.sup.8 is a —C(═O)—NH.sub.2 group; R.sup.9 is selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, benzyl, C.sub.1-C.sub.2-fluoroalkyl, (C.sub.1-C.sub.2-alkoxy)-C.sub.2-alkyl-, ((C.sub.1-C.sub.2-alkyl)-C(═O)—O)—C.sub.2-alkyl- and phenyl, wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, and methyl; R.sup.10 and R.sup.11 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, C.sub.3-C.sub.7-cycloalkyl, and (benzyl)-O—C(═O)—, wherein C.sub.3-C.sub.7-cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, methyl, and trifluoromethyl, and wherein the phenyl group within said (benzyl)-O—C(═O)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom and a methyl group, or R.sup.10 and R.sup.11, together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, methyl, and trifluoromethyl; R.sup.15 and R.sup.16 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.2-fluoroalkyl, (C.sub.1-C.sub.4-alkoxy)-C.sub.2-alkyl-, (C.sub.1-C.sub.2-fluoroalkoxy)-C.sub.2-alkyl-, C.sub.3-C.sub.5-cycloalkyl, phenyl, and pyridinyl, wherein C.sub.3-C.sub.5-cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom and a methyl group; Y.sup.1 is —C(H)═, —C(F)═, —C(Cl)═, —C(CN)═, or —N═, and R.sup.26 is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, difluoromethyl, trifluoromethyl, methoxy, benzyloxy, difluoromethoxy, and trifluoromethoxy, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6. The compound according to claim 1, wherein: R.sup.1 is ##STR00287## wherein “**” indicates the point of attachment to the nitrogen atom to which R.sup.1 is attached; R.sup.2 is ##STR00288## wherein “*” indicates the point of attachment to the nitrogen atom to which R.sup.2 is attached; R.sup.3 is methyl or —NH.sub.2; R.sup.4 is ##STR00289## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4a is selected from the group consisting of a chlorine atom, a bromine atom, ((R.sup.9)O)—(C.sub.1-alkyl)-, C.sub.3-C.sub.5-cycloalkyl, —OR.sup.9, and —C(═O)—N(R.sup.15)(R.sup.16), or R.sup.4 is ##STR00290## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4b is selected from the group consisting of C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, and phenyl, wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group; R.sup.7 is a hydrogen atom or a C.sub.1-C.sub.2-alkyl group; R.sup.8 is a —C(═O)—NH.sub.2 group; R.sup.9 is selected from the group consisting of C.sub.1-C.sub.2-alkyl, benzyl, C.sub.1-C.sub.2-fluoroalkyl, and phenyl, wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, and methyl; R.sup.15 and R.sup.16 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, C.sub.3-C.sub.5-cycloalkyl, phenyl, and pyridinyl, wherein C.sub.3-C.sub.5-cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom and a methyl group; Y.sup.1 is C(H)═, —C(F)═, —C(Cl)═ or —N═, and R.sup.26 is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, methoxy, benzyloxy, difluoromethoxy, and trifluoromethoxy, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

7. The compound according to claim 1, wherein: R.sup.1 is ##STR00291## wherein “**” indicates the point of attachment to the nitrogen atom to which R.sup.1 is attached; R.sup.2 is ##STR00292## wherein “*” indicates the point of attachment to the nitrogen atom to which R.sup.2 is attached; R.sup.3 is —NH.sub.2; R.sup.4 is ##STR00293## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4a selected from the group consisting of a chlorine atom, a bromine atom, ((R.sup.9)O)—(C.sub.1-alkyl)-, C.sub.3-C.sub.5-cycloalkyl, —OR.sup.9, and —C(═O)—N(R.sup.15)(R.sup.16), or R.sup.4 is ##STR00294## wherein “#” indicates the point of attachment to the carbonyl group to which R.sup.4 is attached, and wherein R.sup.4b is selected from the group consisting of C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.5-cycloalkyl, and phenyl, wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group; R.sup.7 is a methyl group; R.sup.8 is a —C(═O)—NH.sub.2 group; R.sup.9 is selected from the group consisting of C.sub.1-C.sub.2-alkyl, benzyl, C.sub.1-C.sub.2-fluoroalkyl, and phenyl, wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, and methyl; R.sup.15 and R.sup.16 are each independently selected from the group consisting of a hydrogen atom, C.sub.1-C.sub.2-alkyl, C.sub.3-C.sub.5-cycloalkyl, phenyl, and pyridinyl, wherein C.sub.3-C.sub.05-cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom and a methyl group; Y.sup.1 is C(H)═, —C(F)═, —C(Cl)═, or —N═, and R.sup.26 is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, methoxy, benzyloxy, difluoromethoxy, and trifluoromethoxy, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

8. The compound according to claim 1, which is selected from the group consisting of: rac-2-(N-[4-amino-5-[3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propenamide; rac-2-(N-[4-amino-5-(3-benzyloxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; (R)-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; (S)-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(2,4-dichlorophenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(4-chlorophenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro -anilino)propanamide; (R)-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro -anilino)propanamide; (S)-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro -anilino)propanamide; rac-2-(N-[4-amino-5-[3-(3-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(4-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-ethyl 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazole-3-carboxylate; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-phenyl-isoxazole-3-carboxamide; 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-[(cis)-2-fluorocyclopropyl]isoxazole-3-carboxamide (mixture of stereoisomers); rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylpyrazol-4-yl)isoxazole-3-carboxamide; rac-2-(N-[4-amino-5-[3-(morpholine-4-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-pyrimidin-5-yl-isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-cyclopropyl-isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(4-pyridyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2-difluoroethyl)isoxazole-3-carboxamide; rac-2-(N-[4-amino-5-[3-(azetidine-1-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(pyrrolidine-1-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3-pyridyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-cyclobutyl-isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(cyclopropylmethyl)isoxazole-3-carboxamide: rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2,2-trifluoroethyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-cyclopropylcyclopropyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2-tert-butoxyethyl)isoxazole-3-carboxamide; rac-2-(N-[4-amino-5-[3-(piperidine-1-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2-pyridyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-[2-(trifluoromethoxy)ethyl]isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide; (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide; (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-bicyclo[1.1.1]pentanyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide; (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide; (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide; 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers); rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-isopropyl-isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(cyanomethyl)isoxazole-3-carboxamide; 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2-methoxy-1-methyl-ethyl)isoxazole-3-carboxamide (mixture of stereoisomers); 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2-dimethylcyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers); 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(cis-3-fluorocyclobutyl)isoxazole-3-carboxamide (mixture of stereoisomers); rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclopentyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-[2-fluoro-1-(fluoromethyl)ethyl]isoxazole-3-carboxamide; 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2-difluoro-1-methyl-ethyl)isoxazole-3-carboxamide (mixture of stereoisomers); 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(trans-3-fluorocyclobutyl)isoxazole-3-carboxamide (mixture of stereoisomers); 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-dimethylcyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers); rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide; (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide; (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide; (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide; (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide; rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide; (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide; (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide; rac-2-(N-[4-amino-5-(3-cyclopentylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(difluoromethoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-isopropyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-phenylisothiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-methyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-tert-butyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(2-pyridyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(2,3-dimethylphenyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(1-methylpyrazol-4-yl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(3-cyclopentyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-[[cyclopentyl(methyl)amino]methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-[[(1-methylcyclopentyl)amino]methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-[(cyclopentylamino)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(1-piperidylmethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-[(4-cyanophenoxy)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(hydroxymethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl N-phenylcarbamate; rac-2-(N-[4-amino-5-[3-(2-fluorophenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(2-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-[4-(trifluoromethoxy)phenyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(2-methoxyphenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(6-methoxy-3-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-(1-phenyltriazole-4-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide: rac-2-(N-[4-amino-5-[3-[(3-fluoro azetidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-[(3,3-difluoroazetidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-[(4,4-difluoro-1-piperidyl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; 2-(N-[4-amino-5-[3-[(4,4-difluoro-3-methyl-1-piperidyl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers); 2-(N-[4-amino-5-[3-[(3-fluoropyrrolidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers); rac-2-(N-[4-Amino-5-(3-hydroxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2(N-[4-amino-5-[3-(cyclobutoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-amino-5-[3-(cyclobutylmethoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide; rac-2-(N-[4-Amino-5-[3-(4,4-difluorocyclohexoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propenamide; and rac-2-(N-[4-amino-5-(3-isopropoxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

9. A method of treatment or prophylaxis of a disease, comprising administering the compound of claim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, to a mammal in need thereof.

10. A pharmaceutical composition comprising the compound of claim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; and one or more pharmaceutically acceptable excipients.

11. A pharmaceutical combination comprising: the compound of claim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, and one or more immune checkpoint inhibitors.

12. The pharmaceutical combination according to claim 11, wherein the one or more immune checkpoint inhibitors comprise a aPD-1-L1 axis antagonist.

13. The pharmaceutical combination according to claim 11, wherein the one or more immune checkpoint inhibitors is an inhibitor of DGKα.

14.-15. (canceled)

16. The method of claim 9, wherein the disease is cancer, a condition with dysregulated immune response, or a disorder associated with aberrant DGKζ signaling.

17. The method of claim 9, wherein the mammal is a human.

18. The method of claim 16, wherein the disease is a liquid tumor.

19. The method of claim 16, wherein the disease is a solid tumor.

Description

DESCRIPTION OF FIGURES

[1199] FIG. 1: DGKz_hu_1 encoding human DGKζ M1 to V928 plus N-terminal Flag-Tag, as described under SEQ ID No. 1.

[1200] FIG. 2: SIINFEKL amino acid sequence, as described under SEQ ID No. 2.

[1201] FIG. 3: OVA-30 peptide sequence, as described under SEQ ID No. 3.

[1202] FIG. 4: FLAG-Tag, as described under SEQ ID No. 4.

[1203] FIG. 5: Kozak sequence for translation initiation, as described under SEQ ID No. 5.

[1204] FIG. 6: 50% thermal ellipsoids of Example 3.1

EXPERIMENTAL SECTION—GENERAL PART

[1205] NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The multiplicities are stated according to the signal form which appears in the spectrum, NMR-spectroscopic effects of a higher order were not taken into consideration. Multiplicity of the NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, br=broad signal, m=multiplet. NMR signals: shift in [ppm]. Combinations of multiplicity could be e.g. dd=doublet from doublet.

[1206] Chemical names were generated using software programs such as the ACDName batch version 14.05 from ACDLabs and BioVia Draw 2019 Version 19.1 NET, and chemical names were adapted if needed. In some cases generally accepted names of commercially available reagents were used in place of chemical names generated using abovementioned software programs.

[1207] All reagents the synthesis of which is not described in the experimental part were purchased commercially, or said reagents are known compounds or can be formed from known compounds by known methods by a person skilled in the art.

[1208] Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

TABLE-US-00001 TABLE 1 Abbreviations CDCl.sub.3 deuterochloroform DAD diode array detector SQD single quadrupole detector Azura UVD single variable wavelength UV detector for HPLC DMF N,N-dimethylformamide DMSO-d6 deuterated dimethyl sulphoxide DMSO dimethyl sulphoxide ELSD evaporative light scattering detector ESIpos electrospray ionization positive Expl. example HATU (7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC high-pressure liquid chromatography LC-MS liquid chromatography coupled with mass spectrometry mL milliliter min minute(s) MTBE methyl tert-butyl ether RP-HPLC reverse-phase high-pressure liquid chromatography Rt retention time rt room temperature sat. saturated THF tetrahydrofurane EtOAc ethyl acetate TLC thin layer chromatography rac racemic μM micromolar M molar UPLC Ultra high performance chromatography UPLC-MS Ultra high performance chromatography coupled with mass spectrometry BEH ethylene bridged hybrid CSH charged surface hybrid UV ultra violet CAS-RN chemical abstracts service registry number NMR nuclear magnetic resonance MHz Megahertz

Analytical UPLC-MS Standard Procedures

[1209] Method 1/Acidic Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50×2.1 mm; eluent A: water+0.1 vol % formic acid, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2 μL; DAD scan: 210-400 nm; ELSD

Method 2 .Basic

[1210] Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile;

[1211] gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2 μL; DAD scan: 210-400 nm; ELSD

Method 3/Basic

[1212] Instrument: Waters Acquity UPLC-MS SingleQuad; Column: Acquity UPLC CSH C18 1.7μm 50×2.1 mm; eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60° C.; DAD scan: 210-400 nm.

Method 4:

[1213] 5-95AB, Shimadzu

[1214] Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water+0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile+0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 mL/min; temperature: 50° C.; PDA: 220 nm & 254 nm.

Optical Rotation Optical rotations were measured with a JASCO Polarimeter 2000 using the solvent and concentration stated in each case at 20° C., wavelength 589 nm, integration time 10 s, layer 5 thickness 100 mm.

Compound Purification—General

[1215] The example compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexaneethyl acetate or dichloromethanemethanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier system equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[1216] In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

[1217] Specific methods are described below, and in the respective protocols describing the preparations of example compounds and intermediates.

Preparative HPLC

[1218] Instrument: pump: Labomatic HD-3000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 μm, 125×30 mm; eluent; gradient; UV-Detection. Eluent: solvent A: water+0.1 vol % formic acid (99%; acidic) or 0.2 vol % aqueous ammonia (32%, basic), solvent B: acetonitrile; flow 150 mL/min.

Gradients:

[1219] Method A: 0.00-0.50 min 1% B, 0.50-6.00 min 1-25% B, 6.00-6.10 min 25-100% B, 6.10-8.00 min 100% B

[1220] Method B: 0.00-0.50 min 10% B, 0.50-6.00 min 10-50% B, 6.00-6.10 min 50-100% B, 6.10-8.00 min 100% B

[1221] Method C: 0.00-0.50 min 15% B, 0.50-6.00 min 15-55% B, 6.00-6.10 min 55-100% B, 6.10-8.00 min 100% B

[1222] Method D: 0.00-0.50 min 30% B, 0.50-6.00 min 30-70% B, 6.00-6.10 min 70-100% B, 6.10-8.00 min 100% B

[1223] Method E: 0.00-0.50 min 40% B, 0.50-6.00 min 40-80% B, 6.00-6.10 min 80-100% B, 6.10-8.00 min 100% B

Method F:

[1224] Instrument: Waters autopurification system; column: Waters CSH C18 5 μ 100×30mm; eluent A: water+0.1 Vol-% aqueous ammonia (32%), eluent B: acetonitrile, DAD scan: 210-400 nm; MS Instrument: QDA (Waters); Collector-Trigger: DAD-MS flow rate: 60 mL/min

Chiral HPLC and Stereochemistry Assignments

[1225] Separations of stereoisomeric mixtures, such as racemic compounds, by chiral HPLC can result in the isolation of single stereoisomers without known configuration of the respective stereogenic centres in the isolated isomers. In the following, the full chemical names of all such separated isomers obtained from an isomeric mixture, including (R) and (S) configurations, are listed in alphabetical order together with all respective intermediate or example numbers, followed by the individual isomers with data on their analytics, isolation and yield, followed by descriptors such as “(enantiomer 1)”, “(stereoisomer 2)”, and the like. Likewise, example compounds obtained from starting materials being single stereoisomers of unknown absolute configuration are disclosed herein in an analogous fashion. The order of the full chemical names (including (R) and (S) configurations) cannot be construed as to encode for any correlation to the individual intermediate or example numbers.

Preparative Flash Chromatography

[1226] Instrument: Biotage Isolera Four; pump: Dual-Piston; flow rate: 1 to 200 mL/min; internal detector: 200-400 nm (variable UV detector); solvent inlets: 4; cartridges: Biotage SNAP Ultra™, sizes: 10 g, 25 g, 50 g, 100 g, 340 g, media: Biotage® HP-Sphere-25 micron 35 spherical silica, resolution: minimum 7000 N/m (plates per meter) typical 10 000 N/m; solvent A: hexane, solvent B: ethyl acetate, solvent C: dichlormethane, solvent D: ethanol; solvent E: methanol; UV collection modes: single/dual/λ-All wavelengths (variable UV); fractionation modes: volume, threshold, threshold with volume, low slope, medium slope, custom slope or via external detection

[1227] Method X: gradient with solvent A and B, λ-all

[1228] Method Y: gradient with solvent C and D, λ-all

[1229] Method Z: gradient with solvent C and E, λ-all

[1230] The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.

[1231] The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

Experimental Section—Preparation of Intermediates

Intermediate 1

[4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methanone

[1232] ##STR00093##

[1233] 1-fluoro-4-isothiocyanatobenzene (230 mg, 0.76 mmol) was dissolved in acetonitrile (6 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (116 mg, 0.76 mmol) and cyanamide (38.5 mg, 42 mmol). After stirring for 45 min at rt further 1,8-diazabicyclo(5.4.0)undec-7-ene (58 mg, 0.38 mmol) and 2-bromo-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanone (Intermediate 9, 230 mg, 0.76 mmol) were added. The reaction mixture was stirred at rt overnight followed by the addition of water and ethyl acetate. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine and filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product was purified by Biotage (method X) to give 26 mg (0.06 mmol, 8% yield) of the title compound.

[1234] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=7.24-7.28 (m, 2 H), 7.70-7.78 (m, 4H), 8.06 (d, J=8.62 Hz, 2H), 8.87 (br s, 1H), 8.97 (br s, 1H), 11.24 (s, 1H).

[1235] LC-MS (method 2) Rt=0.96 min; MS (ESlpos): m/z=416.3 [M+H].sup.+

[1236] The following intermediates were prepared from commercial starting or separately prepared materials as stated in Table 2, below, using the procedure as for Intermediate 1, followed by purification by chromatography if needed. If no purification is specified, the respective title compound was isolated as crude product.

[1237] The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (Biotage, methods X, Y or Z depending on polarity) if necessary. In case of a missing precipitation, the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and evaporated to dryness. The crude product was purified by chromatography as stated in Table 2.

TABLE-US-00002 TABLE 2 Intermediates 2-8 Inter- mediate Chemical structure number Compound name Starting materials Analytics/yield 2 [00094] 1-fluoro-4- isothiocyanatobenzene; 1-[3-(benzyloxy)- 1,2-oxazol-5-yl]-2- bromoethanone LC-MS (method 2) Rt = 0.99 min; MS (ESIpos): m/z = 411.1 [M + H].sup.+ 9% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- (3-benzyloxyisoxazol-5-yl)methanone 3 [00095] 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(3- phenyl-1,2-oxazol-5- yl)ethanone LC-MS (method 2) Rt = 0.99 min; MS (ESIpos): m/z = 381.2 [M + H].sup.+ 87% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- (3-phenylisoxazol-5-yl)methanone 4 [00096] 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[3- (2,4-dichlorophenyl)- 1,2-oxazol-5- yl]ethanone LC-MS (method 2) Rt = 1.14 min; MS (ESIpos): m/z = 449.2 [M + H].sup.+ 88% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- [3-(2,4-dichlorophenyl)isoxazol-5-yl]methanone 5 [00097] 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[3-(4- chlorophenyl)-1,2- oxazol-5- yl]ethanone .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 7.26 (m, 2 H), 7.62 (m, 2 H), 7.64 (s, 1 H), 7.69 (m, 2 H), 8.00 (m, 2 H), 8.61 (m, 1 H), 8.76 (m, 1 H), 11.10 (br s, 1 H) LC-MS (method 2) Rt = 1.13 min; MS (ESIpos): m/z = 415.2 [M + H].sup.+ 100% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- [3-(4-chlorophenyl)isoxazol-5-yl]methanone 6 [00098] 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-(3- bromoisoxazol-5- yl)ethanone LC-MS (method 2) Rt = 0.85 min; MS (ESIpos): m/z = 383.1 [M + H].sup.+ 70% yield [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5- yl](3-bromo-1,2-oxazol-5-yl)methanone 7 [00099] 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[3- (pyridin-3-yl)-1,2- oxazol-5- yl]ethanone (Intermediate 10) LC-MS (method 2) Rt = 1.04 min; MS (ESIpos): m/z = 382.2 [M + H].sup.+ 5% yield [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5- yl][3-(pyridin-3-yl)-1,2-oxazol-5-yl]methanone 8 [00100] 1-fluoro-4- isothiocyanatobenzene; 2-bromo-1-[3- (pyridin-4-yl)-1,2- oxazol-5- yl]ethanone (Intermediate 11) LC-MS (method 2) Rt = 0.75 min; MS (ESIpos): m/z = 382.3 [M + H].sup.+ 30% yield [4-amino-2-(4-fluoroanilino)thiazol-5-yl]- [3-(4-pyridyl)isoxazol-5-yl]methanone

Intermediate 9

2-bromo-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanone

[1238] ##STR00101##

[1239] 1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethenone (500 mg, 2.25 mmol) in THF (12.5 mL) at 0° C. was treated with phenyl trimethyl ammonium tribromide (844 mg, 2.25 mmol). The reaction mixture was stirred at rt overnight, diluted with water and extracted three times with dichloromethane. The combined organic phases were washed with brine, filtrated and 10 evaporated to dryness. The crude product was purified by Biotage (method X) to give 383 mg (1.27 mmol, 56% yield) of the title compound.

[1240] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=5.00 (s, 2H), 7.71 (d, J=8.7 Hz, 2H), 8.09 (d, J=8.7 Hz, 2H).

Intermediate 10

2-bromo-1-[3-(pyridin-3-yl)-1,2-oxazol-5-yl]ethanone

[1241] ##STR00102##

[1242] 1-[3-(3-pyridyl)isoxazol-5-yl]ethanone (100 mg, 0.53 mmol) and 1-bromopyrrolidine-2,5-dione (189 mg, 1.06 mmol) were solved in acetonitrile (2.5 mL) and treated with trimethyl silyl trifluormethane sulfonate (118 mg, 0.53 mmol, TMS-OTf). The reaction mixture was stirred for 9 h at 40° C. followed by the addition of further 1-bromopyrrolidine-2,5-dione (189 mg, 1.06 mmol). After stirring at 40° C. overnight, water was added to the reaction mixture followed by the extraction with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product (quant.) was used without further purification.

[1243] LC-MS (method 1): Rt=0.83 min; MS(ESlpos) m/z=266.9 [M+H].sup.+

Intermediate 11

2-bromo-1-[3-(pyridin-4-yl)-1,2-oxazol-5-yl]ethanone

[1244] ##STR00103##

[1245] 1-[3-(4-pyridyl)isoxazol-5-yl]ethanone (250 mg, 1.33 mmol) and 1-bromopyrrolidine-2,5-dione (473 mg, 2.66 mmol) were solved in acetonitrile (6 mL) and treated with trimethyl silyl trifluormethane sulfonate (295 mg, 1.33 mmol, TMS-OTD. The reaction mixture was stirred for 9 h at 40° C. followed by the addition of further 1-bromopyrrolidine-2,5-dione (473 mg, 2.66 mmol). After stirring at 40° C. for 4 h and rt for further 48 h, water was added to the reaction mixture followed by the extraction with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product (quant.) was used without further purification.

Intermediate 12

Ethyl 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylate

[1246] ##STR00104##

[1247] 1-fluoro-4-isothiocyanatobenzene (250 mg, 1.63 mmol) was dissolved in acetonitrile (15 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (248.5 mg, 1.63 mmol) and cyanamide (82.3 mg, 1.96 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (96 mg, 0.62 mmol) and ethyl 5-(bromoacetyl)-1,2-oxazole-3-carboxylate (124 mg, 0.81 mmol) dissolved in acetonitrile (6 mL) were added. The reaction mixture was stirred at rt overnight. The suspension was treated with water and the precipitate was isolated by filtration, washed with water and some ethyl acetate and dried by lyophilization to give 586 mg (1.25 mmol, 76%) of the title compound.

[1248] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=1.33 (t, J=7.10 Hz, 3H), 4.39 (q, J=7.10 Hz, 2H), 7.22-7.26 (m, 3H), 7.67-7.70 (m, 2H), 8.70-8.74 (m, 2H), 11.13 (s, 1H).

[1249] LC-MS (method 2): Rt=0.86 min; MS(ESlpos) m/z=377.3 [m+H].sup.+

Intermediate 13

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid

[1250] ##STR00105##

[1251] Ethyl 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylate (2.3 g, 6.1 mmol, Intermediate 12) was suspended in THF (60 mL) and treated with 1M aqueous sodium hydroxide (61 mL, 61 mmol). The reaction mixture was stirred overnight followed by the addition of 2M aqueous hydrochloric acid up to pH 4. The precipitate was filtered off, washed with water and dried to yield 1.73 g (4.96 mmol, 81%) of the title compound.

[1252] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=4.42 (br s, 1H), 7.23 (m, 3H), 7.68 (m, 2H), 8.70 (m, 2H), 11.12 (s, 1H).

[1253] LC-MS (method 1): Rt=0.84 min; MS(ESlpos) m/z=349.2 [M+H].sup.+

Intermediate 14

rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid

[1254] ##STR00106##

[1255] rac-Ethyl 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazole-3-carboxylate (1.99 g, 4.45 mmol, Example 9) was suspended in THF (42 mL) and treated with 1M aqueous sodium hydroxide (45 mL, 45 mmol). The reaction mixture was stirred overnight followed by the addition of 2M aqueous hydrochloric acid up to pH 5. The solution was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness to give 383 mg (21% yield) of the title compound.

[1256] LC-MS (method 1): Rt=0.74 min; MS(ESlpos) m/z=420.1 [M+H].sup.+

Intermediate 15

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(1-methylcyclopentypisoxazole-3-carboxamide

[1257] ##STR00107##

[1258] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and 1-methylcyclopentanamine (17.1 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 1 h, then evaporated to dryness in vacuo and triturated with isopropanol. The organic phase was filtrated and evaporated to dryness. The crude product was purified by RP-HPLC (method C, basic) to give 23 mg (37% yield) of the title compound.

[1259] LC-MS (method 2): Rt=0.95 min; MS(ESlpos) m/z=430.5 [m+H].sup.+

Intermediate 16

rac-5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(3,3-dimethylcyclopentypisoxazole-3-carboxamide

[1260] ##STR00108##

[1261] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and rac-3,3-dimethylcyclopentanamine (19.5 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 1 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacuo to yield 20 mg (50 μmol, 31%) of the title compound.

[1262] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 0.98 (s, 3H), 1.07 (s, 3H), 1.44 (m, 2H), 1.54 (m, 1H), 1.67 (m, 1H), 1.77 (m, 1H), 2.03 (m, 1H), 4.35 (m, 1H), 7.20 (s, 1H), 7.26 (t, J=8.87 Hz, 2H), 7.70 (m, 2H), 8.69 (m, 2H), 8.85 (d, J=7.60 Hz, 1H), 11.13 (m, 1H).

[1263] LC-MS (method 2): Rt=0.99 min; MS(ESlpos) m/z=444.4 [M+H].sup.+

Intermediate 17

rac-5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(2,2-dimethylcyclopentyl)isoxazole-3-carboxamide

[1264] ##STR00109##

[1265] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and rac-2,2-dimethylcyclopentanamine (19.5 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 1 h followed by the addition of water. The solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride solution, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product was purified by RP-HPLC (method C, basic) to give 13 mg (20% yield) of the title compound.

[1266] LC-MS (method 2): Rt=0.99 min; MS(ESlpos) m/z=444.5 [M+H].sup.+

Intermediate 18

rac-5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclopentyl)isoxazole-3-carboxamide

[1267] ##STR00110##

[1268] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and rac-3,3-difluorocyclopentanamine; hydrochloride (27.2 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 1 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacuo to yield 34 mg (70 μmol, 52%) of the title compound.

[1269] LC-MS (method 2): Rt=0.83 min; MS(ESlpos) m/z=452.3 [M+H].sup.+

Intermediate 19

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-isopropyl-isoxazole-3-carboxamide

[1270] ##STR00111##

[1271] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and propane-2-amine (10.2 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 48 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacuo to yield 11.9 mg (30 μmol, 21%) of the title compound.

[1272] LC-MS (method 2): Rt=0.76 min; MS(ESlpos) m/z=390.3 [M+H].sup.+

Intermediate 20

rac-5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(2-methoxy-1-methyl-ethyl)isoxazole-3-carboxamide

[1273] ##STR00112##

[1274] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and (2RS)-1-methoxypropan-2-amine (15.4 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 48 h followed by the addition of water. The solution was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride solution, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness to give 60 mg (quant., crude) of the title compound.

[1275] LC-MS (method 2): Rt=0.74 min; MS(ESlpos) m/z=420.3 [M+H].sup.+

Intermediate 21

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-[2-fluoro-1-(fluoromethypethyl]isoxazole-3-carboxamide

[1276] ##STR00113##

[1277] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and 1,3-difluoropropan-2-amine (16.4 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 48 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacua to yield 38.8 mg (91 μmol, 63%) of the title compound.

[1278] LC-MS (method 2): Rt=0.72 min; MS(ESlpos) m/z=424.3 [M+H].sup.+

Intermediate 22

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(cyanomethyl)isoxazole-3-carboxamide

[1279] ##STR00114##

[1280] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and aminoacetonitrile, hydrochloride (15.9 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 48 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacuo to yield 46.2 mg (119 μmol, 83%) of the title compound.

[1281] LC-MS (method 2): Rt=0.65 min; MS(ESlpos) m/z=387.2 [M+H].sup.+

Intermediate 23

rac-5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(2,2-difluoro-1-methyl-ethyl)isoxazole-3-carboxamide

[1282] ##STR00115##

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and (2RS)-1,1-difluoropropan-2-amine, hydrochloride (22.6 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 2 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacuo to yield 35.2 mg (83 μmol, 58%) of the title compound.

[1283] LC-MS (method 2): Rt=0.76 min; MS(ESlpos) m/z=426.3 [M+H].sup.+

Intermediate 24

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(cis-3-fluorocyclobutypisoxazole-3-carboxamide

[1284] ##STR00116##

[1285] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and cis-3-fluorocyclobutanamine (15.4 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 2 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacuo to yield 61.8 mg (quant.) of the title compound.

[1286] LC-MS (method 2): Rt=0.79 min; MS(ESlpos) m/z=420.3 [M+H].sup.+

Intermediate 25

5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]-N-(trans-3-fluorocyclobutypisoxazole-3-carboxamide

[1287] ##STR00117##

[1288] 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (50 mg, 144 μmol, Intermediate 13) and trans-3-fluorocyclobutanamine (15.4 mg, 173 μmol) were dissolved in dimethylformamide (1 mL). N,N-diisopropylethylamine (27.8 mg, 215 μmol) and HATU (65.5 mg, 173 μmol) were added. The reaction mixture was stirred at rt for 2 h followed by the addition of water. The precipitate was filtered off, washed with water and dried in vacuo to yield 46.1 mg (110 μM, 77%) of the title compound.

[1289] LC-MS (method 2): Rt=0.79 min; MS(ESlpos) m/z=420.3 [M+H].sup.+

Intermediate 26

Ethyl 5[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylate

[1290] ##STR00118##

[1291] 1,2-difluoro-4-isothiocyanatobenzene (3.27 g, 19 mmol) was dissolved in acetonitrile (60 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (2.9 g, 19 mmol) and cyanamide (0.96 g, 22.9 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (1.46 g, 9.5 mmol) and ethyl 5-(bromoacetyl)-1,2-oxazole-3-carboxylate (5 g, 19 mmol) dissolved in acetonitrile (28 mL) were added. The reaction mixture was stirred at rt overnight. The suspension was treated with water and the precipitate was isolated by filtration, washed with water and some ethyl acetate and dried by lyophilization to give 5.89 g (14.48 mmol, 76%) of the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=1.34 (t, J=7.1 Hz, 3H), 4.39 (q, J=7.1 Hz, 2H), 7.25 (s, 1H), 7.31 (m, 1H), 7.47 (dt, J=10.39, 9.12 Hz, 1H), 8.02 (ddd, J=12.86, 7.29, 2.41 Hz, 1H), 8.75 (br d, J=2.03 Hz, 2H), 11.28 (s, 1H).

[1292] LC-MS (method 2): Rt=0.81 min; MS(ESlpos) m/z=395.2 [M+H].sup.+

Intermediate 27

5-[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid

[1293] ##STR00119##

[1294] Ethyl 5-[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylate (3.64 g, 9.23 mmol, Intermediate 26) was suspended in THF (90 mL) and treated with 1M aqueous sodium hydroxide (92 mL, 92 mmol). The reaction mixture was stirred at rt for 3h followed by the addition of 2M aqueous hydrochloric acid up to pH 3. The organic solvent was evaporated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness to give 3.25 g (8.9 mmol, 96%) of the title compound.

[1295] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=7.18 (s, 1H), 7.32 (m, 1H), 7.47 (dt, J=10.39, 9.12 Hz, 1H), 8.02 (ddd, J=12.80, 7.35, 2.41 Hz, 1H), 8.74 (br s, 2H), 11.27 (s, 1H), 14.33 (m, 1H).

[1296] LC-MS (method 1): Rt=0.47 min; MS(ESlpos) m/z=367.2 .sup.[M+H].sup.+

Intermediate 28

5-{[4-amino-2-(3,4-difluoroanilino)-1,3-thiazol-5-yl]carbonyl}-N-cyclopentyl-1,2-oxazole-3-carboxamide

[1297] ##STR00120##

[1298] 5-[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (280 mg, 0.76 mmol, Intermediate 27) and cyclopentanamine (65.1 mg, 0.76 mmol) were dissolved in dimethyl sulfoxide (5.6 mL). N,N-diisopropylethylamine (148 mg, 1.15 mmol) and HATU (436 mg, 1.15 mmol) were added. The reaction mixture was stirred at rt for 2 h and then treated with water. The precipitate was filtered off, washed with water and dried in vacuo to give 228 mg (0.53 mmol, 69% yield) of the title compound.

[1299] LC-MS (method 2): Rt=0.88 min; MS(ESlpos) m/z=434.3 [M+H].sup.+

Intermediate 29

5[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide

[1300] ##STR00121##

[1301] 5-[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (250 mg, 0.68 mmol, Intermediate 27) and 1-methylcyclobutanamine; hydrochloride (83 mg, 0.68 mmol) were dissolved in dimethyl sulfoxide (5 mL). N,N-diisopropylethylamine (176 mg, 1.36 mmol) and HATU (389 mg, 1.0 mmol) were added. The reaction mixture was stirred at rt for 2 h and then treated with water. The precipitate was filtered off, washed with water and dried in vacuo to give 228 mg (0.66 mmol, 96% yield) of the title compound.

[1302] LC-MS (method 2): Rt=0.88 min; MS(ESlpos) m/z=434.3 [M+H].sup.+

Intermediate 30

5-[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide

[1303] ##STR00122##

[1304] 5-[4-amino-2-(3,4-difluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylic acid (250 mg, 0.68 mmol, Intermediate 27) and 3,3-difluorocyclobutanamine, hydrochloride (98 mg, 0.68 mmol) were dissolved in dimethyl sulfoxide (5 mL). N,N-diisopropylethylamine (176 mg, 1.36 mmol) and HATU (389 mg, 1.0 mmol) were added. The reaction mixture was stirred at rt for 2 h and then treated with water. The precipitate was filtered off, washed with water and dried in vacuo to give 288 mg (0.63 mmol, 93% yield) of the title compound.

[1305] LC-MS (method 2): Rt=0.79 min; MS(ESlpos) m/z=456.3 [M+H].sup.+

Intermediate 31

Ethyl 2-[4-amino-2-(4-fluoroanilino)thiazol-5-yl]-2-oxo-acetate

[1306] ##STR00123##

[1307] 1-fluoro-4-isothiocyanatobenzene (393 mg, 2.56 mmol) was dissolved in acetonitrile (12 mL) followed by the addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (390 mg, 2.57 mmol) and cyanamide (129.3 mg, 3.1 mmol). After stirring for 45 min at rt, further 1,8-diazabicyclo(5.4.0)undec-7-ene (195 mg, 1.28 mmol) and ethyl 3-bromopyruvate (500 mg, 2.56 mmol) dissolved in acetonitrile (4 mL) were added. The reaction mixture was stirred at rt overnight. The suspension was treated with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered off and evaporated to dryness. The residue was purified by column chromatography (method Y) to give 289 mg (0.93 mmol, 36%) of the title compound.

[1308] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=1.32 (m, 1H), 4.23 (d, J=7.10 Hz, 2H), 7.24 (t, J=8.87 Hz, 3H), 7.67 (m, 2H), 8.65 (s, 2H), 11.02 (s, 1H).

[1309] LC-MS (method 2): Rt=0.75 min; MS(ESlpos) m/z=310.2 [M+H].sup.+

Intermediate 32

4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(3-isopropyl-1,2,4-oxadiazol-5-yl)methanone

[1310] ##STR00124##

[1311] N-Hydroxyisobutyramidine (14 mg, 0.14 mmol) was solved in dry THF (1.5 mL) and treated with sodium hydride (60% in mineral oil, 6.5 mg, 0.16 mmol) for 1 h at rt followed by the addition of ethyl 2-[4-amino-2-(4-fluoroanilino)thiazol-5-yl]-2-oxo-acetate (50 mg, 0.16 mmol, Intermediate 31). The reaction mixture was stirred at 50° C. for 3 h, filtrated and purified by by RP-HPLC (method B, basic) to give 19 mg (34% yield) of the title compound.

[1312] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=1.31 (d, J=6.84 Hz, 6H) 3.10-3.21 (m, 1H) 7.17-7.30 (m, 2H) 7.63-7.75 (m, 2H) 8.73-8.96 (m, 2H) 11.10-11.20 (m, 1H).

[1313] LC-MS (method 2): Rt=0.84 min; MS(ESlpos) m/z=348.4 [M+H].sup.+

Intermediate 33

Methyl 3-(difluoromethoxy)-1,2-oxazole-5-carboxylate

[1314] ##STR00125##

[1315] To a mixture of methyl 3-hydroxy-1,2-oxazole-5-carboxylate (2.00 g, 14.0 mmol) in N,N-dimethylformamide (30 mL) were added chloro difluoro acetic acid sodium salt (5.31 g, 34.9 mmol) and potassium carbonate (2.9 g, 21.0 mmol) at room temperature. The mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate.

[1316] The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product as a white solid. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3: 1) to give methyl 3-(difluoromethoxy)-1,2-oxazole-5-carboxylate (1.60 g, 59% yield) as a white solid.

[1317] LC-MS (method 4): Rt=0.621 min; MS (ESlpos): m/z=193.7 [M+H].sup.+.

Intermediate 34

3-(difluoromethoxy)-1,2-oxazole-5-carboxylic acid

[1318] ##STR00126##

[1319] To a solution of methyl 3-(difluoromethoxy)-1,2-oxazole-5-carboxylate (1.60 g, 8.29 mmol, Intermediate 33) in methanol (24 mL) were added lithium hydroxide monohydrate (3.48 g, 82.9 mmol) and water (4.8 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. Concentrated hydrochloric acid was added to the reaction to adjust the pH=4. The mixture was concentrated in vacuo to give a residue as a white solid. The residue was diluted in water and filtered. The filter cake was dried in vacuo to give 3-(difluoromethoxy)-1,2-oxazole-5-carboxylic acid (1.40 g, 94% yield) as a white solid.

Intermediate 35

3-(difluoromethoxy)—N-methoxy-N-methyl-1,2-oxazole-5-carboxamide

[1320] ##STR00127##

[1321] To a solution of 3-(difluoromethoxy)-1,2-oxazole-5-carboxylic acid (700 mg, 3.91 mmol, Intermediate 34), N,N-diisopropylethylamine (2.0 mL, 12 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetrametyluronium hexafluorophosphate (1.78 g, 4.69 mmol) in N,N-dimethylformamide (14 mL) was added N-methoxymethanamine-hydrochloric acid salt (458 mg, 4.69 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydride sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue as a yellow solid. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1 then 3:1) to give 3-(difluoromethoxy)—N-methoxy-N-methyl-1,2-oxazole-5-carboxamide (300 mg, 35% yield) as a yellow solid.

[1322] LC-MS (method 4): Rt=0.686 min; MS (ESlpos): m/z=222.8 [M+H].sup.+.

Intermediate 36

1-[3-(difluoromethoxy)-1,2-oxazol-5-yl]ethan-1-one

[1323] ##STR00128##

[1324] To a mixture of 3-(difluoromethoxy)—N-methoxy-N-methyl-1,2-oxazole-5-carboxamide (300 mg, 1.35 mmol, Intermediate 35) in tetrahydrofuran (8.0 mL) was added methyl magnesium bromide (1.40 mL, 4.10 mmol, 3 M in diethyl ether) at −78° C. The mixture was stirred at −78° C. for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography on silica gel (300-400 mesh, petroleum ether:ethyl acetate=10:1) to give 1-[3-(difluoromethoxy)-1,2-oxazol-5-yl]ethanone (110 mg, 46% yield) as yellow oil.

Intermediate 37

Potassium N′-cyano-N-(4-fluorophenyl)carbamimidothioate

[1325] ##STR00129##

[1326] To a mixture of potassium hydroxide (1.73 g, 30.9 mmol) in ethanol (39 mL) were added cyanamide (1.30 g, 30.9 mmol) and 1-fluoro-4-isothiocyanatobenzene (4.74 g, 30.9 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was filtered. The filter cake was washed with ethanol (40.0 mL) and dried in vacuo to give potassium N′-cyano-N-(4-fluorophenyl)carbamimidothioate (4.90 g, 68% yield) as a white solid.

[1327] LC-MS (method 4): Rt=0.316 min; MS (ESlpos): m/z=195.7 [M+H].sup.+.

Intermediate 38

2-bromo-1-[3-(difluoromethoxy)-1,2-oxazol-5-yl]ethan-1-one

[1328] ##STR00130##

[1329] To a solution of 1-[3-(difluoromethoxy)-1,2-oxazol-5-yl]ethan-1-one (110 mg, 0.621 mmol, Intermediate 36) in dichloromethane (2.0 mL) were added bromine (0.064 mL, 1.2 mmol) and acetic acid (0.071 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=5:1) to give 2-bromo-1-[5-bromo-4-(3-bromo-4-methoxybenzyl)-4H-1,2,4-triazol-3-yl]ethan-1-one (130 mg, 82% yield) as yellow oil.

Intermediate 39

[4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(difluoromethoxy)-1,2-oxazol-5-yl]methanone

[1330] ##STR00131##

[1331] To a mixture of 2-bromo-1-[3-(difluoromethoxy)-1,2-oxazol-5-yl]ethan-1-one (130 mg, 0.508 mmol, Intermediate 38) in ethanol (2.0 mL) was added potassium N′-cyano-N-(4-fluorophenyl)carbamimidothioate (142 mg, 0.609 mmol, Intermediate 37) at room temperature. The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated in vacuo to give a residue as a brown solid. The residue was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=1:1) to give [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(difluoromethoxy)-1,2-oxazol-5-yl]methanone (60.0 mg, 32% yield) as a deep yellow solid.

[1332] LC-MS (method 4): Rt=0.898 min; MS (ESlpos): m/z=370.8 [M+H].sup.+.

Intermediate 40

N-(cyclopentylmethylidene)hydroxylamine

[1333] ##STR00132##

[1334] To a solution of cyclopentane carbaldehyde (3.00 g, 30.6 mmol) and hydroxylamine hydrogen chloride (1:1) (3.19 g, 45.9 mmol) in toluene (20 mL) was added potassium carbonate (3.17 g, 22.9 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated to remove the solvent. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to provide a crude product as colorless oil. The crude product was purified by column chromatography on silica gel (100-200 mesh, petroleum ether:ethyl acetate=1:0 then 10:1) to give N-(cyclopentyl methylene)hydroxylamine (3.0 g, 87% yield) as colorless oil.

Intermediate 41

N-hydroxy cyclopentane carboximidoyl chloride

[1335] ##STR00133##

[1336] To a solution of N-(cyclopentylmethylidene)hydroxylamine (3.00 g, 26.5 mmol, Intermediate 40) in dichloromethane (40 mL) were added N-chlorosuccinimide (3.72 g, 27.8 mmol) and N,N-dimethylformamide (2.0 mL) at 20° C. The reaction mixture was stirred at 20° C. for 3 hours. The reaction mixture was concentrated to give N-hydroxy cyclopentane carboximidoyl chloride (3.00 g, 77% yield) as yellow oil.

Intermediate 42

rac-1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-ol

[1337] ##STR00134##

[1338] To a solution of N-hydroxy cyclopentane carboximidoyl chloride (3.00 g, 20.3 mmol, Intermediate 41) and rac-but-3-yn-2-ol (1.50 g, 21.3 mmol) in dichloromethane (40 mL) was added triethylamine (5.7 mL, 41 mmol) at 0° C. The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated to give a residue as a yellow solid. The residue was purified by column chromatography on silica gel (100-200 mesh, petroleum ether:ethyl acetate=2:1) to give 1-(3-cyclopentyl-1,2-oxazol-5-yl)ethanol (2.40 g, 65% yield) as a yellow solid.

[1339] LC-MS (method 4): Rt=0.665 min; MS (ESlpos): m/z=182.1 [M+H].sup.+.

Intermediate 43

1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-one

[1340] ##STR00135##

[1341] To a solution of rac-1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-ol (2.40 g, 13.2 mmol, Intermediate 42) in dichloromethane (30 mL) was added 1,1,1-triacetoxy-1lambda5,2-benziodoxo1-3(1H)-one (11.2 g, 26.5 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a crude product as yellow oil. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1 then 3:1) to give 1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-one (2.00 g, 84% yield) as yellow oil.

[1342] LC-MS (method 4): Rt=0.74 min; MS (ESlpos): m/z=180.1 [M+H].sup.+.

Intermediate 44

2-bromo-1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-one

[1343] ##STR00136##

[1344] To a solution of 1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-one (200 mg, 1.12 mmol, Intermediate 43) in dichloromethane (2.0 mL) were added bromine (0.11 mL, 2.2 mmol) and acetic acid (0.13 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give 2-bromo-1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-one (200 mg, 69% yield) as yellow oil.

Intermediate 45

[4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopentyl-1,2-oxazol-5-yl)methanone

[1345] ##STR00137##

[1346] To a mixture of 2-bromo-1-(3-cyclopentyl-1,2-oxazol-5-yl)ethan-1-one (200 mg, 0.775 mmol, Intermediate 44) in ethanol (2.0 mL) was added potassium N′-cyano-N-(4-fluorophenyl) carbamimidothioate (217 mg, 0.930 mmol, Intermediate 37) at room temperature. The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated in vacuo to give a residue as a yellow solid. The residue was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=1:1) to give [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopentyl-1,2-oxazol-5-yl)methanone (100 mg, 35% yield) as a yellow solid.

[1347] LC-MS (method 4): R.sub.t=0.870 min; MS (ESlpos): m/z=373.1 [M+H].sup.+.

Intermediate 46

Ethyl (2,4-dichloro-1,3-thiazol-5-yl)(oxo)acetate

[1348] ##STR00138##

[1349] To a mixture of 2,4-dichloro-1,3-thiazole (5.00 g, 32.5 mmol) in tetrahydrofuran (100 mL) was added lithium diisopropylamide (24.0 mL, 49.0 mmol, 2 M in tetrahydrofuran-hexane solution) at −70° C. The mixture was stirred at −70° C. for 1 hour. Diethyl ethanedioate (9.49 g, 64.9 mmol) was added to the mixture at −70° C. The mixture was stirred at −70° C. for another 1 hour. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product as brown oil. The crude product was purified by column chromatography on silica gel (100-200 mesh, petroleum ether:ethyl acetate=5:1) to give ethyl (2,4-dichloro-1,3-thiazol-5-yl)(oxo)acetate (8.0 g, 97% yield) as a yellow solid.

Intermediate 47

Ethyl [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetate

[1350] ##STR00139##

[1351] A mixture of ethyl (2,4-dichloro-1,3-thiazol-5-yl)(oxo)acetate (7.00 g, 27.5 mmol, Intermediate 46) and 4-fluoroaniline (3.37 g, 30.3 mmol) in N,N-dimethylformamide (100 mL) was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacua to give a crude product as a yellow solid. The crude product was purified by column chromatography on silica gel (100-200 mesh, petroleum ether:ethyl acetate=5:1 then 1:1) to give ethyl [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetate (6.35 g, 68% yield) as a yellow solid.

[1352] LC-MS (method 4): Rt=0.1.162 min; MS (ESlpos): m/z=328.7 [m+H].sup.+.

[1353] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=9.48 (s, 1H), 7.44-7,39 (m, 2H), 7.18 (d, J=8.4 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

Intermediate 48

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetic acid

[1354] ##STR00140##

[1355] To a mixture of ethyl [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetate (2.00 g, 6.08 mmol, Intermediate 47) in tetrahydrofuran (30 mL) and water (10 mL) was added lithium hydroxide monohydrate (383 mg, 9.13 mmol) at 25° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The mixture was acidified by hydrochloric acid (2 M) to pH=4˜5. The mixture was filtered. The filter cake was washed with water and dried in vacuo to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetic acid (1.82 g, 95% yield) as a yellow solid.

[1356] LC-MS (method 4): Rt=0.793 min; MS (ESlpos): m/z=300.7 [M+H].sup.+.

Intermediate 49

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride

[1357] ##STR00141##

[1358] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetic acid (1.82 g, 6.05 mmol, Intermediate 48) in dichloromethane (20 mL) were added oxalyl chloride (0.79 mL, 9.1 mmol) and N,N-dimethylformamide (0.2 mL) at 25° C. The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (2.00 g, 43% purity, 45% yield) as a yellow solid.

Intermediate 50

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-phenyl-1,2,4-oxadiazol-5-yl)methanone

[1359] ##STR00142##

[1360] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (950 mg, 43% purity, 1.28 mmol, Intermediate 49) and N-hydroxybenzenecarboximidamide (192 mg, 1.41 mmol) in dichloromethane (5.8 mL) was added trimethylamine (0.36 mL, 2.6 mmol) at 25° C. The mixture was stirred at 40° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was washed with ethyl acetate (30 mL×2) to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-phenyl-1,2,4-oxadiazol-5-yl)methanone (300 mg, 58% yield) as a orange solid.

[1361] LC-MS (method 4): Rt=1.041 min; MS (ESlpos): m/z=400.8 [M+H].sup.+.

[1362] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=11.72 (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.69-7.63 (m, 5H), 7.32 (d, J=7.2 Hz, 2H).

Intermediate 51

rac-Ethyl N-[4-chloro-5-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-1,3-thiazol-2-yl]-N-(4-fluorophenyl)-alaninate

[1363] ##STR00143##

[1364] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-phenyl-1,2,4-oxadiazol-5-yl)methanone (200 mg, 0.499 mmol, Intermediate 50) in N,N-dimethylformamide (8.0 mL) were added potassium carbonate (138 mg, 0.998 mmol) and rac-ethyl-2-bromopropanoate (181 mg, 0.998 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=3: 1) to give rac-ethyl N-{4-chloro-5-[(3-phenyl-1,2,4-oxadiazol-5-yl)carbonyl]-1,3-thiazol-2-yl}-N-(4-fluorophenyl)alaninate (80 mg, 32% yield) as a yellow solid.

[1365] LC-MS (method 4): Rt=0.994 min; MS (ESlpos): m/z=501.1 [m+H].sup.+.

Intermediate 52

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-methyl-1,2,4-oxadiazol-5-yl)methanone

[1366] ##STR00144##

[1367] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetic acid (1.00 g, 3.33 mmol, Intermediate 48) and N-hydroxyethanimidamide (493 mg, 6.65 mmol) in N,N-dimethylformamide (10 mL) were added propane phosphonic anhydride (10.6 g, 16.6 mmol, 50% in ethyl acetate) and triethylamine (1.39 mL, 9.98 mmol) at 25° C. The mixture was stirred at 60° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product as brown oil. The crude product was purified by column chromatography on silica gel (100-200 mesh, petroleum ether:ethyl acetate=5:1 then 3:1) to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-methyl-1,2,4-oxadiazol-5-yl)methanone (150 mg, 13% yield) as a yellow solid.

[1368] LC-MS (method 4): R.sub.t=0.914 min; MS (ESlpos): m/z=338.7 [M+H].sup.+.

Intermediate 53

rac-Ethyl 2-(N-[4-chloro-5-(3-methyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanoate

[1369] ##STR00145##

[1370] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-methyl-1,2,4-oxadiazol-5-yl)methanone (110 mg, 0.325 mmol, Intermediate 52) and rac-ethyl-2-bromopropanoate (118 mg, 0.649 mmol) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (89.8 mg, 0.649 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product as a yellow solid. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=3:1) to give rac-ethyl N-{4-chloro-5-[(3-methyl-1,2,4-oxadiazol-5-yl)carbonyl]-1,3-thiazol-2-yl}—N-(4-fluorophenyl)alaninate (70.0 mg, 49% yield) as a yellow solid.

[1371] LC-MS (method 4): Rt=0.918 min; MS (ESlpos): m/z=439.1 [M+H].sup.+.

Intermediate 54

(3-tert-butyl-1,2,4-oxadiazol-5-yl)[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl]methanone

[1372] ##STR00146##

[1373] To a mixture of N-hydroxy-2,2-dimethylpropanimidamide (437 mg, 3.76 mmol) and N,N-diisopropylethylamine (2.2 mL, 12.5 mmol) in dichloromethane (9.4 mL) was added [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (1 g, 3.13 mmol, Intermediate 49) at 25° C. The mixture was stirred at 25° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product as brown oil. The crude product was purified by column chromatography on silica gel (100-200 mesh, petroleum ether:ethyl acetate=10:1 then 5:1) to give (3-tert-butyl-1,2,4-oxadiazol-5-yl)[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl]methanone (150 mg, 13% yield) as a yellow solid.

[1374] LC-MS (method 4): Rt=0.930 min; MS (ESlpos): m/z=381.1 [M+H].sup.+.

Intermediate 55

rac-Ethyl N-[5-(3-tert-butyl-1,2,4-oxadiazole-5-carbonyl)-4-chloro-1,3-thiazol-2-yl]-N-(4-fluorophenyl)-alaninate

[1375] ##STR00147##

[1376] To a mixture of (3-tert-butyl-1,2,4-oxadiazol-5-yl)[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl]methanone (150 mg, 0.394 mmol, Intermediate 54) in N,N-dimethylformamide (2.0 mL) were added potassium carbonate (109 mg, 0.788 mmol) and rac-ethyl-2-bromopropanoate (143 mg, 0.788 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=3: 1) to give rac-ethyl N-{5-[(3-tert-butyl-1,2,4-oxadiazol-5-yl)carbonyl]-4-chloro-1,3-thiazol-2-yl}-N-(4-fluorophenyl)alaninate (90.0 mg, 48% yield) as a yellow solid.

[1377] LC-MS (method 4): R.sub.t=1.088 min; MS (ESlpos): m/z=481.1 [M+H].sup.+.

Intermediate 56

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]nethanone

[1378] ##STR00148##

[1379] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetic acid (1.00 g, 3.33 mmol, Intermediate 48) and N-hydroxypyridine-2-carboximidamide (547 mg, 3.99 mmol) in N,N-dimethylformamide (10 mL) were added propane phosphonic anhydride (10.6 g, 16.6 mmol, 50% purity) and triethylamine (1.4 mL, 9.98 mmol) at 25° C. The mixture was stirred at 60° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was triturated with ethyl acetate (10.0 mL) to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]methanone (400 mg, 50% purity, 15% yield) as an orange solid.

[1380] LC-MS (method 4): R.sub.t=0.940 min; MS (ESlpos): m/z=401.8 [M+H].sup.+.

Intermediate 57

rac-Ethyl N-{4-chloro-5-[3-(pyridin-2-yl)-1,2,4-oxadiazole-5-carbonyl]-1,3-thiazol-2-yl}-N-(4-fluorophenyl)-alaninate

[1381] ##STR00149##

[1382] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]nethanone (350 mg, 50% purity, 0.436 mmol, Intermediate 56) and rac-ethyl-2-bromopropanoate (158 mg, 0.871 mmol) in N,N-dimethylformamide (3.5 mL) was added potassium carbonate (120 mg, 0.871 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give rac-ethyl N-(4-chloro-5-{[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]carbonyl}-1,3-thiazol-2-yl)—N-(4-fluorophenyl)alaninate (105 mg, 48% yield) as a yellow solid.

[1383] LC-MS (method 4): R.sub.t=1.009 min; MS (ESlpos): m/z=501.9 [M+H].sup.+.

Intermediate 58

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]methanone

[1384] ##STR00150##

[1385] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (1 g, 3.13 mmol, Intermediate 49) and triethylamine (1.75 mL, 12.5 mmol) in N,N-dimethylformamide (5.0 mL) was added 3-fluoro-N-hydroxybenzene-1-carboximidamide (580 mg, 3.76 mmol) at 0° C. The mixture was stirred at 20° C. for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate=3: 1) to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]methanone (300 mg, 23% yield) as yellow oil.

[1386] LC-MS (method 4): R.sub.t=0.957 min; MS (ESlpos): m/z=419.1 [M+H].sup.+.

Intermediate 59

rac-Ethyl N-{4-chloro-5-[3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carbonyl]-1,3-thiazol-2-yl}-N-(4-fluorophenyl)-alaninate

[1387] ##STR00151##

[1388] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]methanone (150 mg, 0.358 mmol, Intermediate 58) in N,N-dimethylformamide (2.0 mL) were added potassium carbonate (99.0 mg, 0.716 mmol) and rac-ethyl-2-bromopropanoate (130 mg, 0.716 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give rac-ethyl N-(4-chloro-5-{[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]carbonyl}-1,3-thiazol-2-yl)-N-(4-fluorophenyl)alaninate (80.0 mg, 43% yield) as brown oil.

[1389] LC-MS (method 4): R.sub.t=1.014 min; MS (ESlpos): m/z=519.2 [M+H].sup.+.

Intermediate 60

[3-(2,3-dimethylphenyl)-1,2,4-oxadiazol-5-yl][2-(4-fluoroanilino)-4-hydroxy-1,3-thiazol-5-yl]methanone

[1390] ##STR00152##

[1391] To a mixture of N-hydroxy-2,3-dimethylbenzene-1-carboximidamide (617 mg, 3.76 mmol) and N,N-diisopropylethylamine (2.18 mL, 12.5 mmol) in N,N-dimethylformamide (11 mL) was added [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (1.00 g, 3.13 mmol, Intermediate 49) at 25° C. The mixture was stirred at 25° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate=2:1) to give [3-(2,3-dimethylphenyl)-1,2,4-oxadiazol-5-yl][2-(4-fluoroanilino)-4-hydroxy-1,3-thiazol-5-yl]methanone (105 mg, 8% yield) as yellow oil.

[1392] LC-MS (method 4): R.sub.t=0.992 min; MS (ESlpos): m/z=411.1 [M+H].sup.+.

Intermediate 61

rac-Ethyl N-{5-[3-(2,3-dimethylphenyl)-1,2,4-oxadiazole-5-carbonyl]-4-hydroxy-1,3-thiazol-2-yl}-N-(4-fluorophenyl)-alaninate

[1393] ##STR00153##

[1394] To a mixture of [3-(2,3-dimethylphenyl)-1,2,4-oxadiazol-5-yl][2-(4-fluoroanilino)-4-hydroxy-1,3-thiazol-5-yl]methanone (105 mg, 0.256 mmol, Intermediate 60) in N,N-dimethylformamide (2.0 mL) were added potassium carbonate (70.7 mg, 0.512 mmol) and rac-ethyl-2-bromopropanoate (92.6 mg, 0.512 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give rac-ethyl N-(5-{[3-(2,3-dimethylphenyl)-1,2,4-oxadiazol-5-yl]carbonyl}-4-hydroxy-1,3-thiazol-2-yl)-N-(4-fluorophenyl)alaninate (80.0 mg, 61% yield) as a yellow solid.

[1395] LC-MS (method 4): R.sub.t=1.14 min; MS (ESlpos): m/z=511.1 [M+H].sup.+.

Intermediate 62

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopropyl-1,2,4-oxadiazol-5-yl)methanone

[1396] ##STR00154##

[1397] To a mixture of N-hydroxy cyclopropane carboximidamide (399 mg, 3.99 mmol) in dichloromethane (20 mL) were added N,N-diisopropylethylamine (2.89 mL, 16.6 mmol) and [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (1.06 g, 3.32 mmol, Intermediate 49) at 25° C. The mixture was stirred at 35° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1 then 5:1) to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopropyl-1,2,4-oxadiazol-5-yl)methanone (100 mg, 20% purity, 2% yield) as brown solid.

[1398] LC-MS (method 4): R.sub.t=0.987 min; MS (ESlpos): m/z=365.0 [M+H].sup.+.

Intermediate 63

rac-[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopropyl-1,2,4-oxadiazol-5-yl)methanone

[1399] ##STR00155##

[1400] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopropyl-1,2,4-oxadiazol-5-yl)methanone (100 mg, 20% purity, 0.0548 mmol, Intermediate 62) in N,N-dimethylformamide (2.0 mL) were added potassium carbonate (15.2 mg, 0.110 mmol) and rac-ethyl-2-bromopropanoate (19.9 mg, 0.110 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give rac-ethyl N-{4-chloro-5-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)carbonyl]-1,3-thiazol-2-yl}-N-(4-fluorophenyl)alaninate (10.0 mg, 84% purity, 18% yield) as a yellow solid.

[1401] LC-MS (method 4): R.sub.t=0.854 min; MS (ESlpos): rniz=464.9 [M+H].sup.+.

Intermediate 64

N-hydroxy-1-methyl-1H-pyrazole-4-carboximidamide

[1402] ##STR00156##

[1403] To a solution of 1-methyl-1H-pyrazole-4-carbonitrile (1.00 g, 9.34 mmol) in ethanol (10 mL) were added hydroxylamine hydrochloride (649 mg, 9.34 mmol) and sodium ethanolate (762 mg, 11.2 mmol) at 25° C. The reaction mixture was stirred at 90° C. for 16 hours. The mixture was filtered. The filtrate was concentrated in vacuo to give N-hydroxy-1-methyl-1H-pyrazole-4-carboximidannide (1.05 g, 80% yield) as light-yellow oil.

[1404] LC-MS (method 4): R.sub.t=0.150 min; MS (ESlpos): m/z=141.1 [M+H].sup.+.

Intermediate 65

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]methanone

[1405] ##STR00157##

[1406] To a mixture of N-hydroxy-1-methyl-1H-pyrazole-4-carboximidamide (527 mg, 3.76 mmol, Intermediate 64) and N,N-diisopropylethylamine (4.4 mL, 13 mmol, 50% purity) in dichloromethane (10 mL) was added [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (1.00 g, 3.13 mmol, Intermediate 49) at 25° C. The mixture was stirred at 25° C. for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]methanone (100 mg, 8% yield) as yellow oil.

[1407] LC-MS (method 4): R.sub.t=0.934 min; MS (ESlpos): m/z=404.8 [M+H].sup.+.

Intermediate 66

rac-[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]methanone

[1408] ##STR00158##

[1409] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]methanone (100 mg, 0.247 mmol, Intermediate 65) and rac-ethyl-2-bromopropanoate (89.4 mg, 0.494 mmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (68.3 mg, 0.494 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give rac-ethyl N-(4-chloro-5-{[3-(1-methyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]carbonyl}-1,3-thiazol-2-yl)-N-(4-fluorophenyl)alaninate (30.0 mg, 24% yield) as a yellow solid.

[1410] LC-MS (method 4): R.sub.t=0.993 min; MS (ESlpos): m/z=505.0 [M+H].sup.+.

Intermediate 67

N-hydroxy cyclopentane carboximidamide

[1411] ##STR00159##

[1412] To a solution of cyclopentane carbonitrile (1.00 g, 10.5 mmol) in ethanol (10.0 mL) were added hydroxylamine hydrochloride (803 mg, 11.6 mmol) and sodium ethanolate (858 mg, 12.6 mmol) at 25° C. The reaction mixture was stirred at 90° C. for 16 hours. The mixture was filtered, and 15 the filtrate was concentrated in vacuo to give N-hydroxy cyclopentane carboximidamide (1.00 g, 74% yield) as light yellow oil.

[1413] LC-MS (method 4): R.sub.t=0.149 min; MS (ESlpos): m/z=129.0 [M+H].sup.+.

Intermediate 68

[4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopentyl-1,2,4-oxadiazol-5-yl)methanone

[1414] ##STR00160##

[1415] To a mixture of N-hydroxy cyclopentane carboximidamide (145 mg, 1.13 mmol, Intermediate 67) and N,N-diisopropylethylamine (0.650 mL, 3.76 mmol) in dichloromethane (3.0 mL) was added [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](oxo)acetyl chloride (300 mg, 0.940 mmol, Intermediate 49) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopentyl-1,2,4-oxadiazol-5-yl)methanone (60.0 mg, 16% yield) as a yellow solid.

[1416] LC-MS (method 4): R.sub.t=1.045 min; MS (ESlpos): m/z=392.9 [M+H].sup.+.

Intermediate 69

rac-Ethyl N-[4-chloro-5-(3-cyclopentyl-1,2,4-oxadiazole-5-carbonyl)-1,3-thiazol-2-yl]-N-(4-fluorophenyl)-alaninate

[1417] ##STR00161##

[1418] To a mixture of [4-chloro-2-(4-fluoroanilino)-1,3-thiazol-5-yl](3-cyclopentyl-1,2,4-oxadiazol-5-yl)methanone (60 mg, 0.153 mmol, Intermediate 68) and rac-ethyl-2-bromopropanoate (55.3 mg, 0.305 mmol) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (42.2 mg, 0.305 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate=2:1) to give rac-ethyl N-{4-chloro-5-[(3-cyclopentyl-1,2,4-oxadiazol-5-yl)carbonyl]-1,3-thiazol-2-yl}-N-(4-fluorophenyl)alaninate (30 mg, 40% yield) as a yellow solid.

[1419] LC-MS (method 4): R.sub.t=1.008 min; MS (ESlpos): m/z=493.1 [M+H].sup.+.

Intermediate 70

1-[4-Amino-2-(4-fluoroanilino)thiazol-5-yl]prop-2-yn-1-one

[1420] ##STR00162##

[1421] 1-Fluoro-4-isothiocyanatobenzene (699 mg, 4.56 mmol) was dissolved in acetonitrile (28 mL) and cyanamide (230 mg, 5.48 mmol) was added at room temperature followed by DBU (0.68 mL, 4.56 mmol). The reaction mixture was stirred for 45 minutes then additional DBU (0.34 mL, 2.28 mmol) followed by 1-bromo-4-trimethylsilyl-but-3-yn-2-one (1.0 g, 4.56 mmol) as a solution in acetonitrile (14 mL) were added at room temperature. The reaction mixture was stirred for 3 h, then it was cooled with an ice bath and was diluted with water and a saturated aqueous solution of ammonium chloride. The precipitate was filtered off, washed with water and triturated with hexane, dried at high vacuum to give 810 mg (3.1 mmol, 68%) of the title compound which was employed in the next step without further purification.

[1422] LC-MS (method 2): Rt=0.70 min; MS(ESlpos) m/z=262.2 [M+H].sup.+

Intermediate 71

rac-2-(N-(4-Amino-5-prop-2-ynoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide

[1423] ##STR00163##

[1424] 1-[4-Amino-2-(4-fluoroanilino)thiazol-5-yl]prop-2-yn-1-one (570 mg, 2.18 mmol, Intermediate 70) and potassium carbonate (904 mg, 6.55 mmol) were mixed together in DMF (15 mL), then rac-2-bromopropanamide (497 mg, 3.27 mmol) was added portion wise and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water. After separation of the phases, the aqueous phase was extracted again three times with ethyl acetate, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue thus obtained was purified by automated flash column chromatography (method Z, methanol+2 Vol-% aqueous ammonia (33%)) to give 135 mg (0.37 mmol, 17%) of the title compound.

[1425] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.0-8.3 (br s, 1H), 7.7-8.0 (br s, 1H), 7.6-7.7 (m, 2H), 7.59 (s, 1H), 7.37 (t, 2H, J=8.7 Hz), 7.27 (s, 1H), 5.04 (br d, 1H, J=6.3 Hz), 4.37 (s, 1H), 1.16 (d, 3H, J=7.4 Hz).

[1426] LC-MS (method 2): Rt=0.85 min; MS(ESlpos) m/z=333.4 [m+H].sup.+.

Intermediate 72

2-Fluoro-N-hydroxy-benzimidoyl chloride

[1427] ##STR00164##

[1428] To a solution of 2-fluoro benzaldoxime (200 mg, 1.44 mmol) in DMF (1.4 mL), N-chlorosuccinimide (35 mg, 0.28 mmol) was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (176 mg, 1.3 mmol) was added portion wise over few minutes avoiding that the reaction temperature went above 40° C. The reaction mixture was stirred for three hours at room temperature, thin layer chromatography check (hexane:ethyl acetate 7:3) showed complete consumption of starting material and formation of a less polar spot. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.

Intermediate 73

N-Hydroxy-2-methoxy-benzimidoyl chloride

[1429] ##STR00165##

[1430] To a solution of o-anisaldehyde oxime (175 mg, 1.16 mmol) in DMF (1.1 mL), N-chlorosuccinimide (28 mg, 0.23 mmol) was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (142 mg, 1.04 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred for three hours at room temperature, thin layer chromatography check (hexane:ethyl acetate 7:3) showed complete consumption of starting material and formation of a less polar spot. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.

Intermediate 74

N-Hydroxypyridine-2-carboximidoyl chloride

[1431] ##STR00166##

[1432] To a solution of 2-pyridinecarbaldehyde oxime (182 mg, 1.49 mmol) in DMF (1.5 mL), N-chlorosuccinimide (38 mg, 0.28 mmol) was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (170 mg, 1.29 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred for three hours at room temperature. Thin layer chromatography (hexane:ethyl acetate 1:1) showed formation of a less polar spot but still mainly starting material present therefore the reaction was heated to 38° C. overnight. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.

Intermediate 75

N-Hydroxy-4-(trifluoromethoxy)benzimidoyl chloride

[1433] ##STR00167##

[1434] To a solution of p-trifluoromethoxybenzaldoxime (305 mg, 1.49 mmol) in DMF (1.5 mL), N-chlorosuccinimide (38 mg, 0.28 mmol) was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (170 mg, 1.29 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred at 36° C. overnight. The solution was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.

Intermediate 76

N-Hydroxy-6-methoxy-pyridine-3-carboximidoyl chloride

[1435] ##STR00168##

[1436] To a solution of 6-methoxypyridine-3-carbaldehyde oxime (257 mg, 1.69 mmol) in DMF (1.7 mL), N-chlorosuccinimide (43 mg, 0.32 mmol) was added to it in one portion to initiate the reaction. After few minutes, the remaining N-chlorosuccinimide (194 mg, 1.45 mmol) was added portion wise over few minute avoiding that the reaction temperature went above 40° C. The reaction was stirred at 36° C. overnight. In the morning thin layer chromatography check (hexane:ethyl acetate 1:1) showed still presence of starting material, therefore further N-chlorosuccinimide (237 mg, 1.77 mmol) was added portion wise and the reaction was stirred for an additional day at 36° C. The solution was then diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under vacuum to obtain an oily residue that was directly used in the next step without further purification.

Intermediate 77

[4-Amino-2-(4-fluoroanilino)thiazol-5-yl]-[3-(hydroxymethyl)isoxazol-5-yl]methanone

[1437] ##STR00169##

[1438] Ethyl 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylate (2.6 g, 6.9 mmol, Intermediate 12) was suspended in ethanol (44 mL) and THF (26 mL) under an inert atmosphere. The suspension was cooled with an ice bath and sodium borohydride (1.05 g, 27.6 mmol) was added portion wise. The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was then quenched by addition of a saturated aqueous solution of ammonium chloride and water causing the formation of a yellow precipitate that was collected by vacuum filtration. The solid was washed with water, triturated with hexane and left at high vacuum to give 2.15 g (6.43 mmol, 93%) of the title compound that was used in the next step without further purification.

[1439] LC-MS (method 1): Rt=0.88 min; MS(ESlpos) m/z=335.1 [M+H].sup.+.

Intermediate 78

rac-2-(N-[4-amino-5-(3-formylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

[1440] ##STR00170##

[1441] rac-2-(N-[4-amino-5-[3-(hydroxymethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (105 mg, 0.259 mmol, Example 65) was dissolved in DMSO (5 mL) and 2-iodoxybenzoic acid 45wt.% (322 mg, 0.517 mmol) was added portion wise to it. The reaction was stirred overnight and then was diluted with ethyl acetate, a saturated solution of sodium carbonate followed by a solution of sodium thiosulfate. The mixture was left stirring for few minutes, the organic phase was then washed with brine, dried over sodium sulfate and evaporated in vacua. The residue thus obtained was used in the next step without further purification.

[1442] LC-MS (method 2): Rt=0.80 min; MS(ESlpos) m/z=404.4 [M+H].sup.+.

Intermediate 79

rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl methanesulfonate

[1443] ##STR00171##

[1444] rac-2-(N-[4-amino-5-[3-(hydroxymethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (250 mg, 0.62 mmol, Example 65) was dissolved in pyridineTHF 1:1 (8 mL). The reaction mixture was cooled with an ice bath and methanesulfonyl chloride (57 μL, 0.74 mmol) was added to it. The reaction mixture was stirred at room temperature for 4 h and then it was diluted with ethyl acetate and HCI (0.01 N aqueous solution). The organic phase was washed with saturated aqueous sodium carbonate solution and brine, dried over sodium sulfate and reduced in vacuo. The residue thus obtained was used in the next step without further purification.

[1445] LC-MS (method 2): Rt=0.95 min; MS(ESlpos) m/z=484.5 [M+H].sup.+.

Intermediate 80

N-methoxy-N-methyl-3-phenyl-isothiazole-5-carboxamide

[1446] ##STR00172##

[1447] 3-phenyl-1,2-thiazole-5-carboxylic acid (250 mg, 1.22 mmol), N,O-dimethylhydroxylamine hydrochloride (238 mg, 2.44 mmol) were mixed in DMF (7.4 mL), then diisopropyl ethyl amine (0.85 mL, 4.87 mmol) and HATU (926 mg, 2.44 mmol) were added and the reaction mixture was stirred for one hour. The reaction mixture was poured in water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtrated and evaporated to dryness. The residue thus obtained was purified by automated flash column chromatography (method X) to give 262 mg (1.06 mmol, 87%) of the title compound.

[1448] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.46 (s, 1H) 8.04-8.13 (m, 2H) 7.41-7.55 (m, 3H) 3.87 (s, 3H) 3.36 (s, 3H).

[1449] LC-MS (method 1): Rt=1.18 min; MS(ESlpos) m/z=249.5 [M+H].sup.+.

Intermediate 81

2-bromo-1-(3-phenylisothiazol-5-yl)ethanone

[1450] ##STR00173##

[1451] N-methoxy-N-methyl-3-phenyl-isothiazole-5-carboxamide (100 mg, 0.40 mmol, Intermediate 80) was dissolved in THF (2 mL) under an inert atmosphere, dibromomethane (0.057 mL, 0.81 mmol) was added to it and the solution was cooled to -78° C. with an acetonedry ice bath. Methyl lithium solution 1.6 M in hexane (0.5 mL, 0.81 mmol) was then added to the cooled solution. After 15 min the reaction mixture was quenched by the addition of acetic acid, diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, filtrated and reduced under vacuum. The residue thus obtained was directly used in the next step without further purification.

[1452] .sup.1H NMR (Chloroform-d, 400 MHz) δ ppm=8.09 (s, 1H), 7.9-8.0 (m, 2H), 7.4-7.5 (m, 3H), 4.39 (s, 2H).

[1453] LC-MS (method 1): Rt=1.31 min; MS(ESlpos) m/z=282.0 [M+H].sup.+.

Intermediate 82

[4-amino-2-(4-fluoroanilino)thiazol-5-yl]-(3-phenylisothiazol-5-yl)methanone

[1454] ##STR00174##

[1455] 1-fluoro-4-isothiocyanatobenzene (57 mg, 0.37 mmol) was dissolved in acetonitrile (4.3 mL) and cyanamide (19 mg, 0.45 mmol) was added at room temperature followed by DBU (0.055 mL, 0.37 mmol). The reaction mixture was stirred for 45 minutes then additional DBU (0.028 mL, 0.19 mmol) followed by 2-bromo-1-(3-phenylisothiazol-5-yl)ethanone (105 mg, 0.37 mmol, Intermediate 81) as a solution in acetonitrile (1.9 mL) were added at room temperature. The reaction mixture was stirred for 2 h, then it was cooled with an ice bath and diluted with water and saturated aqueous ammonium chloride solution causing precipitation of the desired product that was collected by vacuum filtration. The solid was washed with water and triturated with hexane, dried at high vacuum to give 110 mg (0.28 mmol, 75%) of the title compound which was employed in the next step without further purification.

[1456] LC-MS (method 2): Rt=1.02 min; MS(ESlpos) m/z=397.2 [M+H].sup.+.

Intermediate 83

1-(3-allyloxyisoxazol-5-yl)-2-bromo-ethanone

[1457] ##STR00175##

[1458] Methyl 3-allyloxyisoxazole-5-carboxylate (synthesized as reported in the Eur. J. Org. Chem. 1998, 473-479) (535 mg, 2.92 mmol) was dissolved in THF (15 mL) under an inert atmosphere. Dibromomethane (0.37 mL, 5.26 mmol) was added and the solution was cooled to −78° C. with an acetonedry ice bath. Methyl lithium solution (1.6 M in hexane, 3.29 mL, 5.26 mmol) was then added to the cooled solution and the reaction was stirred for 15 minutes. The reaction mixture was quenched by addition of acetic acid, diluted with ethyl acetate, water and brine. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed with a saturated solution of sodium hydrogen carbonate, brine, dried over sodium sulfate and reduced under vacuum. The residue thus obtained was directly used in the next step without further purification.

[1459] .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm=6.65 (s, 1H) 5.99-6.12 (m, 1H) 5.41-5.50 (m, 1H) 5.36 (dd, J=10.39, 1.27 Hz, 1H) 4.81 (dt, J=5.77, 1.17 Hz, 2H) 4.37 (s, 2H).

[1460] LC-MS (method 1): Rt=1.10 min; MS(ESlpos) m/z=246.0 [M+H].sup.+.

Intermediate 84

(3-allyloxyisoxazol-5-yl)[4-amino-2-(4-fluoroanilino)thiazol-5-yl]methanone

[1461] ##STR00176##

[1462] 1-fluoro-4-isothiocyanatobenzene (399 mg, 2.61 mmol) was dissolved in acetonitrile (18 mL) and cyanamide (132 mg, 3.13 mmol) was added at room temperature followed by DBU (0.40 mL, 2.61 mmol). The reaction was stirred for 45 minutes, then additional DBU (0.18 mL, 1.29 mmol) followed by 1-(3-allyloxyisoxazol-5-yl)-2-bromo-ethanone (Intermediate 83, 642 mg, 2.61 mmol) as a solution in acetonitrile (9 mL) were added at room temperature. The reaction mixture was stirred for three hours, then cooled with an ice bath and diluted with water and saturated aqueous ammonium chloride solution causing precipitation of the desired product that was collected by vacuum filtration. The solid was washed with water and triturated with hexane, dried at high vacuum to give 650 mg (1.80 mmol, 65%) of the title compound as red solid that was employed in the next step without further purification.

[1463] LC-MS (method 2): Rt=0.89 min; MS(ESlneg) m/z=359.3 [M−H].sup.−.

Intermediate 85

rac-2-(N-[5-(3-allyloxyisoxazole-5-carbonyl)-4-amino-thiazol-2-yl]-4-fluoro-anilino)propanamide

[1464] ##STR00177##

[1465] (3-allyloxyisoxazol-5-yl)-[4-amino-2-(4-fluoroanilino)thiazol-5-yl]methanone (Intermediate 84, 650 mg, 1.81 mmol) and potassium carbonate (748 mg, 5.42 mmol) were mixed together in DMF (12 mL), then rac-2-bromopropanamide (329 mg, 2.17 mmol) was added portion wise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and brine and dried over sodium sulfate. The solvent was removed under vacuum distillation. The residue thus obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) to give 250 mg (0.58 mmol, 32%) of the title compound.

[1466] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.67 (br s, 1H) 8.46 (br s, 1H) 7.69 (dd, J=8.62, 5.07 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.87 Hz, 2H) 7.29 (s, 1H) 6.67 (s, 1H) 5.96-6.09 (m, 1H) 5.40 (dq, J=17.24, 1.52 Hz, 1H) 5.29 (dq, J=10.52, 1.31 Hz, 1H) 5.10 (br s, J=0.76 Hz, 1H) 4.71 (dt, J=5.58, 1.27 Hz, 2H) 3.17 (d, J=5.07 Hz, 1H) 1.19 (d, J=7.35 Hz, 3H).

[1467] LC-MS (method 2): Rt=1.11 min; MS(ESlpos) m/z=432.3 [N+H].sup.+.

Experimental Section—Preparation of Example Compounds

EXAMPLE 1

rac-2-(N-[4-amino-5-[3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1468] ##STR00178##

[1469] [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl][3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methanone (26 mg, 0.06 mmol; Intermediate 1) was dissolved in N,N-dimethylformamide (0.5 mL) followed by the addition of potassium carbonate (43 mg, 0.31 mmol) and rac-2-bromopropanamide (14 mg, 0.094 mmol). The reaction mixture was stirred at room temperature overnight followed by filtration and purification by RP-HPLC (method D, basic) to give 5 mg (16% yield) of the title compound.

[1470] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=1.20 (d, J=7.35 Hz, 3H), 5.14 (q, J=7.35 Hz, 1H), 7.30-7.34 (m, 1H), 7.39-7.41 (m, 2H), 7.62- 7.67 (m, 3H), 7.69-7.72 (m, 2H), 7.85-7.89 (m, 2H), 8.78-8.02 (m, 2H)

[1471] LC-MS (method 2) Rt=1.28 min MS (ESlpos): m/z=487.4 [M+H].sup.+

[1472] The following examples were prepared from the starting materials stated in Table 3, below, using the procedure as for Example 1.

[1473] The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

[1474] Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

TABLE-US-00003 TABLE 3 Example 2-8 Example Chemical structure Starting number Compound name materials Analytics/purification/yield 2 [00179] Intermediate 2, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 5.11 (m, 1 H), 5.24 (s, 2 H), 6.69 (s, 1 H), 7.29 (br s, 1 H), 7.40 (m, 7 H), 7.62 (br s, 1 H), 7.69 (dd, J = 8.62, 5.07 Hz, 2 H), 8.46 (br s, 1 H), 8.67 (br s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.20 min MS (ESIpos): m/z = 482.1 [M + H].sup.+ 42% yield rac-2-(N-[4-amino-5-(3-benzyloxyisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide 3 [00180] Intermediate 3, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.14 (m, 1 H), 7.30 (s, 1 H), 7.41 (dd, J = 8.87 Hz, 2 H), 7.52 (m, 4 H), 7.63 (br s, 1 H), 7.72 (m, 2 H), 7.91 (m, 2 H), 8.48 (m, 1 H), 8.74 (m, 1 H) LC-MS (method 2) Rt = 1.20 min MS (ESIpos): m/z = 452.3 [M + H].sup.+ 52% yield after trituration in DCM rac-2-(N-[4-amino-5-(3-phenylisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide 3.1 and (R)- 2-(N-[4-amino-5-(3-phenylisoxazole-5- 3.2 carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and (S)-2-(N-[4-amino-5-(3-phenylisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide 3.1 [00181] Example 3 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.14 (m, 1 H), 7.30 (s, 1 H), 7.41 (dd, J = 8.87 Hz, 2 H), 7.52 (m, 4 H), 7.63 (br s, 1 H), 7.72 (m, 2 H), 7.91 (m, 2 H), 8.48 (m, 1 H), 8.74 (m, 1 H) LC-MS (method 2) Rt = 1.20 min MS (ESIpos): m/z = 452.3 [M + H].sup.+ 2-(N-[4-amino-5-(3-phenylisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 3.1 HPLC separation of rac-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (370 mg, 0.82 mmol, Example 3 on a chiral column gave 160 mg (43% yield) of 2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10μ, 250 × 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 1.71 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 254 nm 3.1 [00182] Example 3.1 was determined to be (R)-2-(N-[4- amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]- 4-fluoro-anilino)propanamide, by means of X-ray crystal structure analysis. 3.2 [00183] Example 3 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.14 (m, 1 H), 7.30 (s, 1 H), 7.41 (dd, J = 8.87 Hz, 2 H), 7.52 (m, 4 H), 7.63 (br s, 1 H), 7.72 (m, 2 H), 7.91 (m, 2 H), 8.48 (m, 1 H), 8.74 (m, 1 H) LC-MS (method 2) Rt = 1.20 min MS (ESIpos): m/z = 452.3 [M + H].sup.+ 52% yield after trituration in DCM 2-(N-[4-amino-5-(3-phenylisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 3.2 HPLC separation of rac-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (370 mg, 0.82 mmol, Example 3 on a chiral column gave 90 mg (24% yield) of 2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 10μ, 250 × 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile + 0.1 vol % diethylamine; isocratic: 80% A + 20% B; flow: 100 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.01 min Instrument: Waters Alliance 2695; Column: YMC Amylose SA 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 80% A + 20% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 254 nm 4 [00184] Intermediate 4, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.13 (m, 1 H), 7.30 (s, 1 H), 7.31 (br s, 1 H), 7.40 (dd, J = 8.74 Hz, 2 H), 7.59 (dd, J = 8.36, 2.03 Hz, 1 H), 7.64 (br s, 1 H), 7.74 (m, 3 H), 7.86 (m, 1 H), 8.51 (m, 1 H), 8.73 (m, 1 H) LC-MS (method 2) Rt = 1.36 min MS (ESIpos): m/z = 520.2 [M + H].sup.+ 57% yield after trituration in MTBE rac-2-(N-[4-amino-5-[3-(2,4-dichlorophenyl)isoxazole- 5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 5 [00185] Intermediate 5, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.13 (q, J = 7.35 Hz, 1 H), 7.30 (br s, 1 H), 7.41 (dd, J = 8.74 Hz, 2 H), 7.58 (m, 3 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.74, 4.94 Hz, 2 H), 7.94 (m, 2 H), 8.50 (m, 1 H), 8.74 (m, 1 H) LC-MS (method 2) Rt = 1.30 min MS (ESIpos): m/z = 486.3 [M + H].sup.+ 51% yield after trituration in DCM rac-2-(N-[4-amino-5-[3-(4-chlorophenyl)isoxazole-5- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 6 [00186] Intermediate 6, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.10 (m, 1 H), 7.21 (s, 1 H), 7.30 (s, 1 H), 7.39 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.74, 4.94 Hz, 2H), 8.57 (br s, 1 H), 8.70 (br s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 454.2 [M + H].sup.+ 39% yield rac-2-(N-[4-amino-5-(3-bromoisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide 6.1 and (R)-2-(N-[4-amino-5-(3-bromoisoxazole-5- 6.2 carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide and (S)-2-(N-[4-amino-5-(3- bromoisoxazole-5-carbonyl)thiazol-2-yl]-4- fluoro-anilino)propanamide 6.1 [00187] Example 6 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.10 (m, 1 H), 7.21 (s, 1 H), 7.30 (s, 1 H), 7.39 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.74, 4.94 Hz, 2 H), 8.57 (br s, 1 H), 8.70 (br s, 1 H) LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 454.2 [M + H].sup.+ 49% yield 2-(N-[4-amino-5-(3-bromoisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (enantiomer 1) Chiral HPLC Example 6.1 HPLC separation of rac-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (150 mg, 0.33 mmol, Example 6) on a chiral column gave 76 mg (49% yield) of 2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-1; Column: YMC Cellulose SC 5μ, 250 × 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95% A + 5% B; flow: 50 mL/min; temperature: 25° C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.23 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 280 nm 6.2 [00188] Example 6 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.18 (d, J = 7.35 Hz, 3 H), 5.10 (m, 1 H), 7.21 (s, 1 H), 7.30 (s, 1 H), 7.39 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.74, 4.94 Hz, 2 H), 8.57 (br s, 1 H), 8.70 (br s, 1 H) LC-MS (method 2) Rt = 1.16 min MS (ESIpos): m/z = 454.2 [M + H].sup.+ 48% yield 2-(N-[4-amino-5-(3-bromoisoxazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (enantiomer 2) Chiral HPLC Example 6.2 HPLC separation of rac-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide (150 mg, 0.33 mmol, Example 6) on a chiral column gave 74 mg (48% yield) of 2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-1; Column: YMC Cellulose SC 5μ, 250 × 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95% A + 5% B; flow: 50 mL/min; temperature: 25° C.; UV: 280 nm Analytical chiral HPLC: Rt = 4.34 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 280 nm 7 [00189] Intermediate 7, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.60 Hz, 3 H), 5.06-5.19 (m, 1 H), 7.28-7.32 (m, 1 H), 7.38-7.45 (m, 2 H), 7.56 (ddd, J = 7.92, 4.88, 0.89 Hz, 1 H), 7.62-7.66 (m, 2 H), 7.69- 7.74 (m, 2 H), 8.27-8.32 (m, 1 H), 8.48-8.55 (m, 1 H), 8.70 (dd, J = 4.82, 1.52 Hz, 1 H), 8.72-8.79 (m, 1 H), 9.11 (dd, J = 2.28, 0.76 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.98 min MS (ESIpos): m/z = 453.3 [M + H].sup.+ 38% yield rac-2-(N-[4-amino-5-[3-(3-pyridyl)isoxazole-5- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 8 [00190] Intermediate 8, rac-2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.06-5.18 (m, 1 H), 7.28-7.32 (m, 1 H), 7.41 (dd, J = 8.87 Hz, 2 H), 7.60-7.66 (m, 1 H), 7.67 (s, 1 H), 7.69-7.75 (m, 2 H), 7.88- 7.91 (m, 2 H), 8.48-8.56 (br s, 1H), 8.73-8.75 (m, 3 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.97 min MS (ESIpos): m/z = 453.4 [M + H].sup.+ 2% yield rac-2-(N-[4-amino-5-[3-(4-pyridyl)isoxazole-5- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

EXAMPLE 9

rac-ethyl 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazole-3-carboxylate

[1475] ##STR00191##

[1476] Ethyl 5-[4-amino-2-(4-fluoroanilino)thiazole-5-carbonyl]isoxazole-3-carboxylate (585 mg, 1.55 mmol, Intermediate 12) was suspended in DMF (10 mL) and treated with rac-2-bromo propionamide (283.5 mg, 1.86 mmol) and potassium carbonate (1074 mg, 7.8 mmol). The reaction mixture was stirred for 48 h and then treated with water. After 30 min the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium hydrochloride solution, filtered through a water repellent filter circle (MN 617 WA) and evaporated to dryness. The crude product was purified by Biotage (method X) to give 43 mg (6% yield) of the title compound.

[1477] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=1.19 (d, J=7.35 Hz, 3H), 1.30 (t, J=7.10 Hz, 3H), 4.35 (q, J=7.10 Hz, 2H), 5.16 (m, 1H), 7.12 (s, 1H), 7.30 (s, 1H), 7.40 (t, J=8.87 Hz, 2H), 7.63 (m, 1H), 7.71 (dd, J=8.62, 5.07 Hz, 2H), 8.59 (m, 1H), 8.74 (m, 1H).

[1478] LC-MS (method 1): Rt=1.02 min; MS(ESlpos) m/z=448.4 [M+H].sup.+

EXAMPLE 10

rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-phenyl-isoxazole-3-carboxamide

[1479] ##STR00192##

[1480] rac-5-[4-Amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5 carbonyl]isoxazole-3-carboxylic acid (Intermediate 14, 50 mg, 0.12 mmol) and aniline (13 mg, 0.14 mmol) were solved in 1 mL DMF and treated with HATU (54 mg, 0.14 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol). The reaction mixture was stirred at rt for 3.5 h, filtrated and purified by RP-HPLC (method C) to yield 24 mg (0.05 mmol, 39%) of the title compound.

[1481] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=1.21 (d, J=7.35 Hz, 3H), 5.12 (m, 1H), 7.12-7.18 (m, 1H), 7.22 (s, 1H), 7.31 (br s, 1H), 7.34-7.44 (m, 4H), 7.64 (br s, 1H), 7.68-7.78 (m, 4H), 8.57 (br s, 1H), 8.70 (br s, 1H), 10.68 (s, 1H).

[1482] LC-MS (method 2): Rt=1.11 min; MS(ESlpos) m/z=495.2 [M+H].sup.+

[1483] The following examples were prepared from the starting materials stated in Table 4, below, using the procedure as for Example 10.

[1484] The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

[1485] Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

TABLE-US-00004 TABLE 4 Examples 11-32.2 Example Chemical structure number Compound name Starting materials Analytics/purification/yield 11 [00193] Intermediate 14, rac- (1R,2S)-2- fluorocyclopropanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.06-1.16 (m, 2H), 1.20 (d, J = 7.60 Hz, 3 H), 2.76-2.85 (m, 1 H), 4.63-4.86 (m, 1 H), 5.03-5.19 (m, 1 H), 7.10 (s, 1 H), 7.31 (br s, 1 H), 7.36-7.43 (m, 2 H), 7.63 (br s, 1 H), 7.67-7.75 (m, 2 H), 8.54 (br s, 1 H), 8.67 (br s, 1 H), 8.98 (d, J = 3.80 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.92 min MS (ESIpos): m/z = 477.4 [M + H].sup.+ 17% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-[(cis)-2- fluorocyclopropyl]isoxazole-3-carboxamide (mixture of stereoisomers) 12 [00194] Intermediate 14, 1- methyl-1H-pyrazol- 4-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.81 (s, 3 H), 5.03-5.20 (m, 1 H), 7.16 (s, 1 H), 7.31 (br s, 1 H), 7.40 (t, J = 8.87 Hz, 2 H), 7.57 (s, 1 H), 7.64 (br s, 1 H), 7.71 (dd, J = 8.62, 5.07 Hz, 2 H), 7.99 (s, 1 H), 8.56 (br s, 1 H), 8.68 (br s, 1 H), 10.92 (s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.89 min MS (ESIpos): m/z = 499.3 [M + H].sup.+ 17% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- methylpyrazol-4-yl)isoxazole-3-carboxamide 13 [00195] Intermediate 14, morpholine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.48-3.59 (m, 4 H), 3.59-3.70 (m, 4 H), 5.05-5.19 (m, 1 H), 7.05 (s, 1 H), 7.30 (br s, 1 H), 7.40 (br t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.71 (br dd, J = 8.49, 5.20 Hz, 2 H), 8.54 (br s, 1 H), 8.71 (br s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.92 min MS (ESIpos): m/z = 489.3 [M + H].sup.+ 34% yield rac-2-(N-[4-amino-5-[3-(morpholine-4- carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 14 [00196] Intermediate 14, pyrimidin-5-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.21 (d, J = 7.35 Hz, 3 H), 5.07-5.19 (m, 1 H), 7.24 (s, 1 H), 7.31 (br s, 1 H), 7.38-7.44 (m, 2 H), 7.64 (br s, 1 H), 7.72 (br dd, J = 8.74, 4.94 Hz, 2 H), 8.60 (br s, 1 H), 8.69 (br s, 1 H), 8.98 (s, 1 H), 9.15 (s, 2 H), 11.18 (br s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.73 min MS (ESIpos): m/z = 497.3 [M + H].sup.+ 34% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- pyrimidin-5-yl-isoxazole-3-carboxamide 15 [00197] Intermediate 14, cyclopropanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 0.53-0.61 (m, 2 H), 0.65- 0.73 (m, 2 H), 1.19 (d, J = 7.35 Hz, 3 H), 2.76-2.86 (m, 1 H), 5.04- 5.19 (m, 1 H), 7.05 (s, 1 H), 7.30 (br s, 1 H), 7.39 (t, J = 8.87 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (br dd, J = 8.62, 5.07 Hz, 2 H), 8.53 (br s, 1 H), 8.66 (br s, 1 H), 8.84 (d, J = 4.31 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.96 min MS (ESIpos): m/z = 459.3 [M + H].sup.+ 30% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- cyclopropyl-isoxazole-3-carboxamide 16 [00198] Intermediate 14, pyridin-4-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.05-5.19 (m, 1 H), 7.24 (s, 1 H), 7.31 (br s, 1 H), 7.37-7.45 (m, 2 H), 7.64 (br s, 1 H), 7.69-7.79 (m, 4 H), 8.47-8.53 (m, 2 H), 8.58 (br s, 1 H), 8.70 (br s, 1 H), 10.83- 11.13 (m, 1 H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 0.88 min MS (ESIpos): m/z = 496.2 [M + H].sup.+ 14% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- (4-pyridyl)isoxazole-3-carboxamide 17 [00199] Intermediate 14, 2,2- difluoroethanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.59-3.72 (m, 2 H), 5.04-5.19 (m, 1 H), 5.95-6.28 (m, 1 H), 7.11 (s, 1 H), 7.24-7.35 (m, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.67-7.74 (m, 2 H), 8.55 (br s, 1 H), 8.69 (br s, 1 H), 9.15-9.21 (m, 1 H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 0.95 min MS (ESIpos): m/z = 483.4 [M + H].sup.+ 21% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- (2,2-difluoroethyl)isoxazole-3-carboxamide 18 [00200] Intermediate 14, azetidine hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 2.22-2.31 (m, 2 H), 4.02-4.08 (m, 2 H), 4.40 (t, J = 7.60 Hz, 2 H), 5.04- 5.18 (m, 1 H), 6.98 (s, 1 H), 7.30 (br s, 1 H), 7.37-7.44 (m, 2 H), 7.63 (br s, 1 H), 7.71 (br dd, J = 8.49, 4.69 Hz, 2 H), 8.54 (br s, 1 H), 8.70 (br s, 1 H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 0.96 min MS (ESIpos): m/z = 459.3 [M + H].sup.+ 27% yield rac-2-(N-[4-amino-5-[3-(azetidine-1- carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 19 [00201] Intermediate 14, pyrrolidine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.81-1.87 (m, 4 H), 2.83- 2.87 (m, 4 H), 3.47 (t, J = 6.59 Hz, 3 H), 3.61 (t, J = 6.46 Hz, 2 H), 5.05- 5.18 (m, 1 H), 7.01 (s, 1 H), 7.30 (br s, 1 H), 7.37-7.43 (m, 2 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.87, 5.07 Hz, 2 H), 8.53 (br s, 1 H), 8.71 (br s, 1 H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 1.02 min MS (ESIpos): m/z = 473.3 [M + H].sup.+ 28% yield rac-2-(N-[4-amino-5-[3-(pyrrolidine-1- carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 20 [00202] Intermediate 14, pyridin-3-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.21 (d, J = 7.60 Hz, 3 H), 5.01-5.20 (m, 1 H), 7.18-7.28 (m, 1 H), 7.31 (br s, 1 H), 7.38-7.46 (m, 3 H), 7.64 (br s, 1 H), 7.68- 7.75 (m, 2 H), 8.15 (ddd, J = 8.36, 2.53, 1.52 Hz, 1 H), 8.36 (dd, J = 4.82, 1.52 Hz, 1 H), 8.57 (br s, 1 H), 8.69 (br s, 1 H), 8.91 (d, J = 2.03 Hz, 1 H), 10.95 (br s, 1 H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 0.91 min MS (ESIpos): m/z = 496.3 [M + H].sup.+ 42% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3- pyridyl)isoxazole-3-carboxamide 21 [00203] Intermediate 14, cyclobutanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 1.59-1.71 (m, 2 H), 1.99-2.11 (m, 2 H), 2.12-2.22 (m, 2 H), 4.29- 4.42 (m, 1 H), 5.06-5.17 (m, 1 H), 7.06 (s, 1 H), 7.30 (br s, 1 H), 7.40 (br t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (br dd, J = 8.62, 5.07 Hz, 2 H), 8.54 (br s, 1 H), 8.68 (br s, 1 H), 9.02 (d, J = 7.86 Hz, 1 H) RP-HPLC (method B basic) LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 473.3 [M + H].sup.+ 33% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- cyclobutyl-isoxazole-3-carboxamide 22 [00204] Intermediate 14, 1- cyclopropylmethanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 0.18-0.24 (m, 2 H), 0.38- 0.45 (m, 2 H), 0.96-1.06 (m, 1 H), 1.19 (d, J = 7.35 Hz, 3 H), 3.10 (t, J = 6.34 Hz, 2 H), 5.05-5.20 (m, 1 H), 7.07 (s, 1 H), 7.30 (s, 1 H), 7.36- 7.44 (m, 2 H), 7.64 (br s, 1 H), 7.71 (dd, J = 8.74, 5.20 Hz, 2 H), 8.55 (br s, 1 H), 8.67 (br s, 1 H), 8.90 (t, J = 5.70 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.03 min MS (ESIpos): m/z = 473.4 [M + H].sup.+ 15% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- (cyclopropylmethyl)isoxazole-3-carboxamide 23 [00205] Intermediate 14, 2,2,2- trifluoroethanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.99-4.12 (m, 2 H), 5.03-5.19 (m, 1 H), 7.14 (s, 1 H), 7.30 (br s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.62, 5.07 Hz, 2 H), 8.55 (br s, 1 H), 8.68 (br s, 1 H), 9.49 (br t, J = 6.08 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.01 min MS (ESIpos): m/z = 501.3 [M + H].sup.+ 19% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- (2,2,2-trifluoroethyl)isoxazole-3-carboxamide 24 [00206] Intermediate 14, [1,1′-bi(cyclopropyl)]- 1-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 0.12-0.19 (m, 2 H), 0.30- 0.37 (m, 2 H), 0.53-0.59 (m, 2 H), 0.62-0.68 (m, 2 H), 1.19 (d, J = 7.35 Hz, 3 H), 1.31-1.40 (m, 1 H), 5.03-5.18 (m, 1 H), 7.04 (s, 1 H), 7.29 (br s, 1 H), 7.35-7.43 (m, 2 H), 7.63 (br s, 1 H), 7.67-7.73 (m, 2 H), 8.57 (br s, 1 H), 8.66 (br s, 1 H), 9.02 (br s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.10 min MS (ESIpos): m/z = 499.4 [M + H].sup.+ 8% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- cyclopropylcyclopropyl)isoxazole-3-carboxamide 25 [00207] Intermediate 14, cyclopentanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.60 Hz, 3 H), 1.45-1.57 (m, 4 H), 1.66 (br s, 2 H), 1.84 (br d, J = 3.04 Hz, 2 H), 4.11-4.21 (m, 1 H), 5.04-5.20 (m, 1 H), 7.08 (s, 1 H), 7.24-7.36 (m, 1 H), 7.40 (t, J = 8.87 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.87, 5.07 Hz, 2 H), 8.53 (br s, 1 H), 8.65 (br s, 1 H), 8.70 (d, J = 7.35 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.12 min MS (ESIpos): m/z = 487.4 [M + H].sup.+ 48% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- cyclopentyl-isoxazole-3-carboxamide 26 [00208] Intermediate 14, 2- tert- butoxyethanamine hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 3.27-3.32 (m, 2 H), 3.37-3.42 (m, 2 H), 5.04-5.21 (m, 1 H), 7.06 (s, 1 H), 7.30 (s, 1 H), 7.39 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.66- 7.74 (m, 2 H), 8.47-8.59 (m, 1 H), 8.62-8.69 (m, 1 H), 8.72 (t, J = 5.70 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.08 min MS (ESIpos): m/z = 519.2 [M + H].sup.+ 63% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- (2-tert-butoxyethyl)isoxazole-3-carboxamide 27 [00209] Intermediate 14, piperidine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 1.44-1.65 (m, 6 H), 3.36-3.43 (m, 2 H), 3.58 (br t, J = 5.32 Hz, 2 H), 5.05-5.19 (m, 1 H), 7.03 (s, 1 H), 7.29 (br s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.71 (br dd, J = 8.62, 5.07 Hz, 2 H), 8.54 (br s, 1 H), 8.71 (br s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.07 min MS (ESIpos): m/z = 487.4 [M + H].sup.+ 27% yield rac-2-(N-[4-amino-5-[3-(piperidine-1- carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4- fluoro-anilino)propanamide 28 [00210] Intermediate 14, pyridin-2-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 5.05-5.21 (m, 1 H), 7.22 (ddd, J = 7.35, 4.82, 1.01 Hz, 1 H), 7.31 (s, 1 H), 7.34 (s, 1 H), 7.41 (t, J = 8.74 Hz, 2 H), 7.64 (br s, 1 H), 7.72 (dd, J = 8.74, 4.94 Hz, 2 H), 7.84-7.91 (m, 1 H), 8.10 (d, J = 8.36 Hz, 1 H), 8.40 (dt, J = 3.87, 0.98 Hz, 1 H), 8.58 (br s, 1 H), 8.72 (br s, 1 H), 10.94 (s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.04 min MS (ESIpos): m/z = 496.4 [M + H].sup.+ 24% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2- pyridyl)isoxazole-3-carboxamide 29 [00211] Intermediate 14, 2- (trifluoro- methoxy)ethanamine hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 3.55 (br d, J = 5.32 Hz, 2 H), 4.18 (t, J = 5.32 Hz, 2 H), 5.01-5.18 (m, 1 H), 7.07 (s, 1 H), 7.30 (s, 1 H), 7.39 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.74, 5.20 Hz, 2 H), 8.54 (br s, 1 H), 8.62-8.72 (m, 1 H), 9.05 (t, J = 5.70 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 531.1 [M + H].sup.+ 65% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-[2- (trifluoromethoxy)ethyl]isoxazole-3-carboxamide 30 [00212] Intermediate 14, 1- methylcyclobutanamine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.60 Hz, 3 H), 1.43 (s, 3 H), 1.73-1.84 (m, 2 H), 1.90-2.01 (m, 2 H), 2.26-2.37 (m, 2 H), 5.04-5.19 (m, 1 H), 7.06 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (br dd, J = 8.62, 5.07 Hz, 2 H), 8.52 (br s, 1 H), 8.66 (br s, 1 H), 8.76 (s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.12 min MS (ESIpos): m/z = 487.4 [M + H].sup.+ 16% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- methylcyclobutyl)isoxazole-3-carboxamide 30.1 and (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- 30.2 ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- methylcyclobutyl)isoxazole-3-carboxamide and (S)- 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- methylcyclobutyl)isoxazole-3-carboxamide 30.1 [00213] Example 30 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.60 Hz, 3 H), 1.43 (s, 3 H), 1.73-1.84 (m, 2 H), 1.90-2.01 (m, 2 H), 2.26-2.37 (m, 2 H), 5.04-5.19 (m, 1 H), 7.06 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (br dd, J = 8.62, 5.07 Hz, 2 H), 8.52 (br s, 1 H), 8.66 (br s, 1 H), 8.76 (s, 1 H) LC-MS (method 2) Rt = 1.12 min MS (ESIpos): m/z = 487.4 [M + H].sup.+ 41% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methyl- cyclobutyl)isoxazole-3-carboxamide (enantiomer 1) Chiral HPLC Example 30.1 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole- 5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide (180 mg, 0.37 mmol, Example 30) on a chiral column gave 77 mg (41% yield) of 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Cellulose SC 5μ, 250 × 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 50 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.56 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3μ, 100 × 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 254 nm 30.2 [00214] Example 30 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.60 Hz, 3 H), 1.43 (s, 3 H), 1.73-1.84 (m, 2 H), 1.90-2.01 (m, 2 H), 2.26-2.37 (m, 2 H), 5.04-5.19 (m, 1 H), 7.06 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (br dd, J = 8.62, 5.07 Hz, 2 H), 8.52 (br s, 1 H), 8.66 (br s, 1 H), 8.76 (s, 1 H) LC-MS (method 2) Rt = 1.12 min MS (ESIpos): m/z = 487.4 [M + H].sup.+ 43% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- methylcyclobutyl)isoxazole-3-carboxamide (enantiomer 2) Chiral HPLC Example 30.2 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole- 5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide (180 mg, 0.37 mmol, Example 30) on a chiral column gave 81 mg (43% yield) of 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Cellulose SC 5μ, 250 × 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 50 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 5.02 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3μ, 100 × 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 254 nm 31 [00215] Intermediate 14, bicyclo[1.1.1]pentan- 1-amine .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 2.06 (s, 6 H), 2.45 (s, 1H), 5.03- 5.18 (m, 1 H), 7.04 (s, 1 H), 7.30 (br s, 1 H), 7.39 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (br dd, J = 8.62, 5.07 Hz, 2 H), 8.53 (br s, 1 H), 8.68 (br s, 1 H), 9.34 (s, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.10 min MS (ESIpos): m/z = 485.4 [M + H].sup.+ 16% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- bicyclo[1.1.1]pentanyl)isoxazole- 3-carboxamide 32 [00216] Intermediate 14, 3,3- difluorocyclobutanamine hydrochloride (1:1) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 2.71-2.83 (m, 2 H), 2.86-3.00 (m, 2 H), 4.15-4.29 (m, 1 H), 5.04-5.18 (m, 1 H), 7.08 (s, 1 H), 7.30 (br s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.62, 5.07 Hz, 2 H), 8.55 (br s, 1 H), 8.66 (br s, 1 H), 9.29 (d, J = 6.59 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.03 min MS (ESIpos): m/z = 509.4 [M + H].sup.+ 8% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide 32.1 and (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- 32.2 ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide and (S)- 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide 32.1 [00217] Example 32 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 2.71-2.83 (m, 2 H), 2.86-3.00 (m, 2 H), 4.15-4.29 (m, 1 H), 5.04-5.18 (m, 1 H), 7.08 (s, 1 H), 7.30 (br s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.62, 5.07 Hz, 2 H), 8.55 (br s, 1 H), 8.66 (br s, 1 H), 9.29 (d, J = 6.59 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.03 min MS (ESIpos): m/z = 509.4 [M + H].sup.+ 47% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide (enantiomer 1) Chiral HPLC Example 32.1 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole- 5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide (200 mg, 0.39 mmol, Example 32) on a chiral column gave 95 mg (47% yield) of 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 5μ, 250 × 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 90% A + 10% B; flow: 40 mL/min; temperature: 25° C.; UV: 280 nm Analytical chiral HPLC: Rt = 2.08 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 280 nm 32.2 [00218] Example 32 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 2.71-2.83 (m, 2 H), 2.86-3.00 (m, 2 H), 4.15-4.29 (m, 1 H), 5.04-5.18 (m, 1 H), 7.08 (s, 1 H), 7.30 (br s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.62, 5.07 Hz, 2 H), 8.55 (br s, 1 H), 8.66 (br s, 1 H), 9.29 (d, J = 6.59 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.03 min MS (ESIpos): m/z = 509.4 [M + H].sup.+ 42% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide (enantiomer 2) Chiral HPLC Example 32.1 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole- 5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide (200 mg, 0.39 mmol, Example 32) on a chira column gave 85 mg (42% yield) of 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4- fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 5μ, 250 × 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 90% A + 10% B; flow: 40 mL/min; temperature: 25° C.; UV: 280 nm Analytical chiral HPLC: Rt = 3.03 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 280 nm

[1486] The following examples were prepared from the starting materials stated in Table 5, below, using the procedure as for Example 1.

[1487] The crude product was either purified by RP-HPLC (methods A-D depending on polarity) or by preparative flash chromatography (methods X, Y or Z depending on polarity) after precipitation, extraction or filtration of the reaction mixture if necessary.

[1488] Enantiomers were separated from their racemate by chiral HPLC using the column and solvent conditions stated.

TABLE-US-00005 TABLE 5 Examples 33-50 Example Chemical structure number Compound name Starting materials Analytics/purification/yield 33 [00219] Intermediate 18, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 1.74-1.86 (m, 1 H), 2.04-2.30 (m, 4 H), 2.39-2.46 (m, 1 H), 4.31-4.43 (m, 1 H), 5.04-5.19 (m, 1 H), 7.08 (s, 1 H), 7.30 (br s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.62, 5.07 Hz, 2 H), 8.53 (br s, 1 H), 8.68 (br s, 1 H), 9.02 (d, J = 7.35 Hz, 1 H) Biotage (method X) LC-MS (method 1) Rt = 1.08 min MS (ESIpos): m/z = 523.4 [M + H].sup.+ 100% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers) 34 [00220] Intermediate 19, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.13 (d, J = 6.59 Hz, 6 H), 1.20 (d, J = 7.35 Hz, 3 H), 3.98- 4.10 (m, 1 H), 5.04-5.17 (m, 1 H), 7.07 (s, 1 H), 7.30 (s, 1 H), 7.36-7.43 (m, 2 H), 7.63 (br s, 1 H), 7.68-7.74 (m, 2 H), 8.45- 8.57 (m, 1 H), 8.61-8.64 (m, 1 H), 8.64-8.71 (m, 1 H) RP-HPLC (method C) LC-MS (method 1) Rt = 1.03 min MS (ESIpos): m/z = 461.4 [M + H].sup.+ 74% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5- carbonyl]-N-isopropyl-isoxazole-3-carboxamide 35 [00221] Intermediate 22, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.60 Hz, 3 H), 4.32 (d, J = 5.58 Hz, 2 H), 4.99- 5.19 (m, 1 H), 7.13 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.87, 5.07 Hz, 2 H), 8.58 (br s, 1 H), 8.69 (br s, 1 H), 9.56 (t, J = 5.58 Hz, 1 H) RP-HPLC (method C) LC-MS (method 2) Rt = 0.88 min MS (ESIpos): m/z = 458.3 [M + H].sup.+ 23% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- (cyanomethyl)isoxazole-3-carboxamide 36 [00222] Intermediate 20, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.10 (d, J = 6.84 Hz, 3 H), 1.20 (d, J = 7.35 Hz, 3 H), 3.24 (s, 3 H), 3.25-3.29 (m, 1 H), 3.35- 3.39 (m, 1 H), 4.08-4.20 (m, 1 H), 5.05-5.18 (m, 1 H), 7.07 (s, 1 H), 7.30 (s, 1 H), 7.40 (dd, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.87, 5.07 Hz, 2 H), 8.54 (br s, 1 H), 8.60 (d, J = 8.36 Hz, 1 H), 8.68 (br s, 1 H) RP-HPLC (method C) LC-MS (method 1) Rt = 1.00 min MS (ESIpos): m/z = 491.4 [M + H].sup.+ 39% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(2- methoxy-1-methyl-ethyl)isoxazole-3-carboxamide (mixture of stereoisomers) 37 [00223] Intermediate 17, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 0.83 (s, 3 H), 0.96 (s, 3 H), 1.20 (d, J = 7.35 Hz, 3 H), 1.38- 1.59 (m, 3 H), 1.61-1.73 (m, 2 H), 1.83-1.97 (m, 1 H), 4.00 (q, J = 8.28 Hz, 1 H), 5.04-5.18 (m, 1 H), 7.10 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.87 Hz, 2 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.74, 5.20 Hz, 2 H), 8.37 (d, J = 9.12 Hz, 1 H), 8.53 (br s, 1 H), 8.67 (br s, 1 H) Biotage (method X) LC-MS (method 1) Rt = 1.21 min MS (ESIpos): m/z = 515.4 [M + H].sup.+ 65% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2- dimethylcyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers) 38 [00224] Intermediate 24, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm = 0.72-0.88 (m, 2H), 1.20 (d, J = 7.35 Hz, 3 H), 2.22-2.31 (m, 1 H), 2.68-2.73 (m, 1 H), 3.87-4.00 (m, 1 H), 4.72-4.95 (m, 1 H), 5.05-5.19 (m, 1 H), 7.07 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.74, 5.20 Hz, 2 H), 8.54 (br s, 1 H), 8.67 (br s, 1 H), 9.13 (d, J = 7.60 Hz, 1 H) RP-HPLC (method C) LC-MS (method 1) Rt = 1.00 min MS (ESIpos): m/z = 491.4 [M + H].sup.+ 13% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(cis-3- fluorocyclobutyl)isoxazole-3-carboxamide (mixture of stereoisomers) 39 [00225] Intermediate 15, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19 (d, J = 7.35 Hz, 3 H), 1.38 (s, 3H), 1.50-1.69 (m, 6 H), 2.03-2.12 (m, 2 H), 5.05-5.17 (m, 1 H), 7.06 (s, 1 H), 7.30 (br s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.62, 5.07 Hz, 2 H), 8.23 (s, 1 H), 8.52 (br s, 1 H), 8.68 (br s, 1 H) Biotage (method X) LC-MS (method 1) Rt = 1.16 min MS (ESIpos): m/z = 501.4 [M + H].sup.+ 28% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1- methylcyclopentyl)isoxazole-3-carboxamide 40 [00226] Intermediate 21, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 4.40-4.57 (m, 3 H), 4.59-4.65 (m, 2 H), 5.05-5.18 (m, 1 H), 7.12 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.87, 5.07 Hz, 2 H), 8.55 (br s, 1 H), 8.65 (br s, 1 H), 9.11 (d, J = 7.86 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 0.95 min MS (ESIpos): m/z = 497.4 [M + H].sup.+ 36% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N- [2-fluoro-1-(fluoromethyl)ethyl]isoxazole-3- carboxamide 41 [00227] Intermediate 23, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (m, J = 7.22, 1.39 Hz, 6 H), 4.26-4.41 (m, 1 H), 5.05- 5.18 (m, 1 H), 5.96 (td, J = 1.00 Hz, 1 H),7.12(s, 1 H), 7.28-7.32 (m, 1 H), 7.36-7.43 (m, 2 H), 7.63 (br s, 1 H), 7.71 (dd, J = 8.87, 5.07 Hz, 2 H), 8.55 (br s, 1 H), 8.67 (br s, 1 H), 9.00-9.06 (m, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.00 min MS (ESIpos): m/z = 497.4 [M + H].sup.+ 74% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2- difluoro-1-methyl-ethyl)isoxazole-3-carboxamide (mixture of stereoisomers) 42 [00228] Intermediate 25, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.20 (d, J = 7.35 Hz, 3 H), 2.39-2.47 (m, 2 H), 4.45-4.55 (m, 1 H), 5.04-5.14 (m, 1 H), 5.15-5.36 (m, 1 H), 7.06 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.87 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.74, 5.20 Hz, 2 H), 8.53 (br s, 1 H), 8.67 (br s, 1 H), 9.16 (d, J = 7.10 Hz, 1 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.01 min MS (ESIpos): m/z = 491.4 [M + H].sup.+ 13% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(trans-3- fluorocyclobutyl)isoxazole-3-carboxamide (mixture of stereoisomers) 43 [00229] Intermediate 16, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 0.96 (s, 3 H), 1.04 (s, 3 H), 1.20 (d, J = 7.60 Hz, 3 H), 1.31- 1.44 (m, 2 H), 1.47-1.56 (m, 1 H), 1.58-1.69 (m, 1 H), 1.70- 1.78 (m, 1 H), 1.94-2.05 (m, 1 H), 4.23-4.36 (m, 1 H), 5.04- 5.19 (m, 1 H), 7.07 (s, 1 H), 7.30 (s, 1 H), 7.40 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.70 (dd, J = 8.62, 5.07 Hz, 2 H), 8.54 (br s, 1 H), 8.66 (br s, 1 H), 8.74 (d, J = 7.60 Hz, 1 H) Biotage (method X) LC-MS (method 2) Rt = 1.01 min MS (ESIpos): m/z = 515.4 [M + H].sup.+ 100% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3- dimethylcyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers) 44 [00230] Intermediate 29, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.22 (d, J = 7.35 Hz, 3 H), 1.44 (s, 3 H), 1.73-1.85 (m, 2 H), 1.90-2.01 (m, 2 H), 2.27-2.38 (m, 2 H), 5.02-5.11 (m, 1 H), 7.09 (s, 1 H), 7.34 (s, 1 H), 7.51- 7.71 (m, 3 H), 7.81-7.88 (m, 1 H), 8.57 (br s, 1 H), 8.64 (br s, 1 H), 8.77 (s, 1 H) Biotage (method X) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 505.4 [M + H].sup.+ 31% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]- N-(1-methylcyclobutyl)isoxazole-3-carboxamide 44.1 (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- and ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]- 44.2 N-(1-methylcyclobutyl)isoxazole-3-carboxamide and (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2- oxo-ethyl)-3,4-difluoro-anilino)thiazole-5- carbonyl]-N-(1-methylcyclobutyl)isoxazole-3- carboxamide 44.1 [00231] Example 44 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.22 (d, J = 7.35 Hz, 3 H), 1.44 (s, 3 H), 1.73-1.85 (m, 2 H), 1.90-2.01 (m, 2 H), 2.27-2.38 (m, 2 H), 5.02-5.11 (m, 1 H), 7.09 (s, 1 H), 7.34 (s, 1 H), 7.51- 7.71 (m, 3 H), 7.81-7.88 (m, 1 H), 8.57 (br s, 1 H), 8.64 (br s, 1 H), 8.77 (s, 1 H) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 505.4 [M + H].sup.+ 34% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1- methylcyclobutyl)isoxazole-3-carboxamide (enantiomer 1) Chiral HPLC Example 44.1 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl) isoxazole-3-carboxamide (200 mg, 0.39 mmol, Example 44) on a chiral column gave 98 mg (34% yield) of 5-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Cellulose SC 5μ, 250 × 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 50 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.81 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3μ, 100 × 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25° C. ; UV: 254 nm 44.2 [00232] Example 44 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.22 (d, J = 7.35 Hz, 3 H), 1.44 (s, 3 H), 1.73-1.85 (m, 2 H), 1.90-2.01 (m, 2 H), 2.27-2.38 (m, 2 H), 5.02-5.11 (m, 1 H), 7.09 (s, 1 H), 7.34 (s, 1 H), 7.51- 7.71 (m, 3 H), 7.81-7.88 (m, 1 H), 8.57 (br s, 1 H), 8.64 (br s, 1 H), 8.77 (s, 1 H) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 505.4 [M + H].sup.+ 33% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1- methylcyclobutyl)isoxazole-3-carboxamide (enantiomer 2) Chiral HPLC Example 44.2 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl) isoxazole-3-carboxamide (200 mg, 0.39 mmol, Example 44) on a chiral column gave 98 mg (33% yield) of 5-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Cellulose SC 5μ, 250 × 30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 60% A + 40% B; flow: 50 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.81 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SC 3μ, 100 × 4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 60% A + 40% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 254 nm 45 [00233] Intermediate 30, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.22 (d, J = 7.35 Hz, 3 H), 2.70-2.83 (m, 2 H), 2.87-3.00 (m, 2 H), 4.17-4.28 (m, 1 H), 5.01-5.14 (m, 1 H), 7.11 (s, 1 H), 7.34 (s, 1 H), 7.54-7.60 (m, 1 H), 7.61-7.70 (m, 2 H), 7.80-7.89 (m, 1 H), 8.57 (br s, 1 H), 8.66 (br s, 1 H), 9.30 (d, J = 6.84 Hz, 1 H) Biotage (method X) LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 527.3 [M + H].sup.+ 52% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N- (3,3-difluorocyclobutyl)isoxazole-3-carboxamide 45.1 (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- and ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N- 45.2 (3,3-difluorocyclobutyl)isoxazole-3-carboxamide and (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide 45.1 [00234] Example 45 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.22 (d, J = 7.35 Hz, 3 H), 2.70-2.83 (m, 2 H), 2.87-3.00 (m, 2 H), 4.17-4.28 (m, 1 H), 5.01-5.14 (m, 1 H), 7.11 (s, 1 H), 7.34 (s, 1 H), 7.54-7.60 (m, 1 H), 7.61-7.70 (m, 2 H), 7.80-7.89 (m, 1 H), 8.57 (br s, 1 H), 8.66 (br s, 1 H), 9.30 (d, J = 6.84 Hz, 1 H) LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 527.3 [M + H].sup.+ 42% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide (enantiomer 1) Chiral HPLC Example 45.1 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide (137 mg, 0.26 mmol, Example 45) on a chiral column gave 59 mg (42% yield) of 5-[4-amino- 2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 5μ, 250 × 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 95% A + 5% B; flow: 50 mL/min; temperature: 25° C.; UV: 280 nm Analytical chiral HPLC: Rt = 3.17 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 280 nm 45.2 [00235] Example 45 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.22 (d, J = 7.35 Hz, 3 H), 2.70-2.83 (m, 2 H), 2.87-3.00 (m, 2 H), 4.17-4.28 (m, 1 H), 5.01-5.14 (m, 1 H), 7.11 (s, 1 H), 7.34 (s, 1 H), 7.54-7.60 (m, 1 H), 7.61-7.70 (m, 2 H), 7.80-7.89 (m, 1 H), 8.57 (br s, 1 H), 8.66 (br s, 1 H), 9.30 (d, J = 6.84 Hz, 1 H) LC-MS (method 2) Rt = 1.05 min MS (ESIpos): m/z = 527.3 [M + H].sup.+ 52% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide (enantiomer 2) Chiral HPLC Example 45.2 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3- difluorocyclobutyl)isoxazole-3-carboxamide (137 mg, 0.26 mmol, Example 45) on a chiral column gave 63 mg (46 % yield) of 5-[4-amino- 2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-3; Column: YMC Amylose SA 5μ 250 × 30; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol + 0.1 vol % diethylamine; isocratic: 95% A + 5% B; flow: 50 mL/min; temperature: 25° C.; UV: 280 nm Analytical chiral HPLC: Rt = 4.60 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3μ 100 × 4.6;eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 95% A + 5% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 280 nm 46 [00236] Intermediate 28, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19-1.24 (m, 3 H), 1.46- 1.57 (m, 4H), 1.62-1.70 (m, 2 H), 1.80-1.92 (m, 2 H), 4.12- 4.23 (m, 1 H), 5.00-5.13 (m, 1 H), 7.11 (s, 1 H), 7.30-7.38 (m, 1 H), 7.54-7.60 (m, 1 H), 7.62- 7.71 (m, 2 H), 7.79-7.88 (m, 1 H), 8.56 (br s, 1 H), 8.64 (br s, 1 H), 8.71 (d, J = 7.35 Hz, 1 H) Biotage (method X) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 505.4 [M + H].sup.+ 36% yield rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-3,4-difluoro-anilino)thiazole-5- carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide 46.1 (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- and ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]- 46.2 N-cyclopentyl-isoxazole-3-carboxamide and (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo- ethyl)-3,4-difluoro-anilino)thiazole-5- carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide 46.1 [00237] Example 46 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19-1.24 (m, 3 H), 1.46- 1.57 (m, 4H), 1.62-1.70 (m, 2 H), 1.80-1.92 (m, 2 H), 4.12- 4.23 (m, 1 H), 5.00-5.13 (m, 1 H), 7.11 (s, 1 H), 7.30-7.38 (m, 1 H), 7.54- 7.60 (m, 1 H), 7.62- 7.71 (m, 2 H), 7.79-7.88 (m, 1 H), 8.56 (br s, 1 H), 8.64 (br s, 1 H), 8.71 (d, J = 7.35 Hz, 1 H) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 505.4 [M + H].sup.+ 45% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 3,4-difluoro-anilino)thiazole-5-carbonyl]-N- cyclopentyl-isoxazole-3-carboxamide (enantiomer 1) Chiral HPLC Example 46.1 HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl- isoxazole-3-carboxamide (48 mg, 0.10 mmol, Example 46) on a chiral column gave 22 mg (45% yield) of 5-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide, enantiomer 1. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Amylose SA 10μ, 250 × 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 100 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 2.61 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25° C.; UV: 254 nm 46.2 [00238] Example 46 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.19-1.24 (m, 3 H), 1.46- 1.57 (m, 4H), 1.62-1.70 (m, 2 H), 1.80-1.92 (m, 2 H), 4.12- 4.23 (m, 1 H), 5.00-5.13 (m, 1 H), 7.11 (s, 1 H), 7.30-7.38 (m, 1 H), 7.54-7.60 (m, 1 H), 7.62- 7.71 (m, 2 H), 7.79-7.88 (m, 1 H), 8.56 (br s, 1 H), 8.64 (br s, 1 H), 8.71 (d, J = 7.35 Hz, 1 H) LC-MS (method 2) Rt = 1.13 min MS (ESIpos): m/z = 505.4 [M + H].sup.+ 45% yield 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)- 3,4-difluoro-anilino)thiazole-5-carbonyl]-N- cyclopentyl-isoxazole-3-carboxamide (enantiomer 2) HPLC separation of rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl- isoxazole-3-carboxamide (48 mg, 0.1 mmol, Example 46) on a chiral column gave 22 mg (45% yield) of 5-[4-amino-2-(N-(2-amino-1- methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide, enantiomer 2. Preparative chiral HPLC Instrument: PrepCon Labomatic HPLC-4; Column: YMC Amylose SA 10μ, 250 × 50; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 100 mL/min; temperature: 25° C.; UV: 254 nm Analytical chiral HPLC: Rt = 3.49 min Instrument: Thermo Fisher UltiMate 3000; Column: YMC Amylose SA 3μ, 100 × 4.6; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine; eluent B: acetonitrile; isocratic: 90% A + 10% B; flow: 1.4 mL/min; temperature: 25° C.;UV: 254 nm 47 [00239] Intermediate 45, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 8.76-8.39 (m, 2H), 7.73- 7.68 (m, 2H), 7.46 (s, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.28 (s, 1 H), 6.85 (s, 1H), 5.15-5.05 (m, 1H), 3.12-3.07 (m, 1H), 2.00-1.91 (m, 2H), 1.70-1.55 (m, 6H), 1.19 (d, J = 7.6 Hz, 3H) RP-HPLC [Instrument: ACSWH- GX-k; Column: Phenomenex Gemini-NX C18 75 * 30 mm * 3 μm); eluent A: water (0.225% formic acid v/v), eluent B: acetonitrile; gradient: rac-2-(N-[4-amino-5-(3-cyclopentylisoxazole-5- 0-10 minutes 52-62% B; flow 25 carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide mL/minute; temperature: RT; Detector: UV 220/254 nm LC-MS (method 4): Rt = 0.936 min MS (ESIpos): m/z = 444.1 [M + H].sup.+. 67% yield 48 [00240] Intermediate 39, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 8.71-8.50 (m, 2H), 7.73-7.46 (m, 4H), 7.41-7.32 (m, 2H), 7.29 (s, 1H), 6.98 (s, 1H), 5.15-5.05 (m, 1H), 1.19 (d, J = 7.6 Hz, 3H) LC-MS (method 4): Rt = 0.865 min; MS (ESIpos): m/z = 441.8 [M + H].sup.+ RP-HPLC (Instrument: ACSWH- GX-G; Column: Unisil 3-100 C18 Ultra 150 * 50 mm * 3 μm; eluent A: water (0.225% formic acid in water), eluent B: acetonitrile; gradient: 0-10 minutes 30-60% B; flow 25 mL/minute; temperature: RT; rac-2-(N-[4-amino-5-[3-(difluoromethoxy)isoxazole-5- Detector: UV 220/254 nm 48% yield carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 49 [00241] Intermediate 32, rac- 2- bromopropanamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 1.13-1.25 (m, 9 H), 2.96- 3.10 (m, 1 H), 5.01-5.21 (m, 1 H), 7.27-7.32 (m, 1 H), 7.39 (t, J = 8.74 Hz, 2 H), 7.63 (br s, 1 H), 7.69 (br dd, J = 8.49, 4.94 Hz, 2 H), 8.68-8.79 (m, 2 H) RP-HPLC (method C basic) LC-MS (method 2) Rt = 1.08 min MS (ESIpos): m/z = 419.4 [M + H].sup.+ 55% yield rac-2-(N-[4-amino-5-(3-isopropyl-1,2,4-oxadiazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide 50 [00242] Intermediate 82, rac- 2- bromopropanamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm = 8.57 (br s, 1 H) 8.42 (br s, 1 H) 7.90-7.99 (m, 3 H) 7.69 (dd, J = 8.67, 5.20 Hz, 2 H) 7.64 (br s, 1 H) 7.43-7.52 (m, 3 H) 7.37 (t, J = 8.67 Hz, 2 H) 7.31 (br s, 1 H) 5.07-5.11 (br s, 1 H) 1.19 (d, J = 7.25 Hz, 3 H). Biotage (method Y) LC-MS (method 2): Rt = 1.27 min; MS(ESIpos) m/z = 468.5 [M + H].sup.+ 19% yield rac-2-(N-[4-amino-5-(3-phenylisothiazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

EXAMPLE 51

rac-2-(N-[4-amino-5-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino) propanamide

[1489] ##STR00243##

[1490] To a mixture of ammonia in methanol (1.0 mL, ammonia gas was bubbled into methanol at −78° C. for 10 minutes) was added ethyl 2-(N-[4-chloro-5-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanoate (Intermediate 51, 80.0 mg, 0.160 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC [Instrument: GX-c; Column: Phenomenex luna C18 150*25 mm*10 μm); eluent A: water (0.225% formic acid vv), eluent B: acetonitrile; gradient: 0-10 minutes 38˜68% B; flow 25 mL/minute; temperature: RT; Detector: UV 220254 nm] and preparative thin layer chromatography (dichloromethane: methanol=20:1) to give the title compound (3.70 mg, 5% yield) as a yellow solid.

[1491] LC-MS (method 4): Rt=0.823 min; MS (ESlpos): m/z=453.2 [M+H].sup.+.

[1492] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.81 (s, 2H), 7.92-7,82 (m, 2H), 7.75-7.69 (m, 2H), 7.63-7.58 (m, 1H), 7.56-7.52 (m, 2H), 7.42 (t, J=8.0 Hz, 2H), 7.31 (s, 1H), 5.21-5.04 (m, 1H), 1.21 (d, J=7.6 Hz, 3H).

EXAMPLE 52

rac-2-(N-[4-amino-5-(3-methyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

[1493] ##STR00244##

[1494] To a mixture of ammonia in methanol (2.0 mL, ammonia gas bubbled into methanol at −78° C. for 10 minutes) was added ethyl 2-(N-[4-chloro-5-(3-methyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanoate (Intermediate 53, 70.0 mg, 0.160 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hours. The mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC [Instrument: ACS-WH-GX-L; Column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm); eluent A: water (0.225% formic acid vv), eluent B: acetonitrile; gradient: 0-10 minutes 24˜54% B; flow 25 mL/minute; temperature: RT; Detector: UV 220254 nm] to give the title compound (16.0 mg, 25% yield) as a yellow solid.

[1495] LC-MS (method 4): R.sub.t=0.837 min; MS (ESlpos): m/z=391.0 [M+H].sup.+.

[1496] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm=8.85-8.72 (m, 2H), 7.71-7.65 (m, 2H), 7.61 (s, 1H), 7.40 (t, J=8.8 Hz, 2H), 7.28 (s, 1H), 5.14-5.11 (m, 1H), 2.07 (s, 3H), 1.17 (d, J=7.6 Hz, 3H). The following examples were prepared from the starting materials stated in Table 6, below, using the procedure as for Example 52.

TABLE-US-00006 TABLE 6 Examples 53-59 Example Chemical structure Starting Analytics/purification/yield number Compound name materials 53 [00245] Intermediate 55, ammonia in methanol .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm = 8.71 (s, 2H), 7.75-7.55 (m, 3H), 7.40 (t, J = 8.4 Hz, 2H), 7.29 (s, 1H), 5.21-5.05 (m, 1H), 1.39- 1.15 (m, 12H). LC-MS (method 4): Rt = 0.823 min; MS (ESIpos): m/z = 433.2 [M + H].sup.+ 25% yield rac-2-(N-[4-amino-5-(3-tert-butyl-1,2,4-oxadiazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide 54 [00246] Intermediate 57, ammonia in methanol .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm = 8.88-8.65 (m, 3H), 8.05- 7.95 (m, 1H), 7.93-7.86 (m, 1H), 7.75-7.59 (m, 4H), 7.41 (t, J = 8.4 Hz, 2H), 7.31 (s, 1H), 5.21-5.08 (m, 1H), 1.19 (d, J = 7.2 Hz, 3H). LC-MS (method 4): Rt = 0.843 min; MS (ESIpos): m/z = 453.9 [M + H].sup.+ 3% yield rac-2-(N-[4-amino-5-[3-(2-pyridyl)-1,2,4-oxadiazole-5- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 55 [00247] Intermediate 59, ammonia in methanol .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm = 8.80 (s, 2H), 7.78-7.71 (m, 3H), 7.70-7.45 (m, 4H), 7.43 (t, J = 8.0 Hz, 2H), 7.32 (s, 1H), 5.19- 5.10 (m, 1H), 1.22 (d, J = 7.2 Hz, 3H). LC-MS (method 4): R = 0.844 min; MS (ESIpos): m/z = 471.1 [M + H].sup.+ 4% yield rac-2-(N-[4-amino-5-[3-(3-fluorophenyl)-1,2,4-oxadiazole-5- carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 56 [00248] Intermediate 61, ammonia in methanol .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm = 8.78-8.71 (m, 2H), 7.71- 7.59 (m, 3H), 7.51-7.47 (m, 1H), 7.45-7.35 (m, 3H) 7.27-7.23 (m, 1H), 7.21 (t, J = 7.6 Hz, 1H), 5.23- 5.04 (m, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 1.21 (d, J = 7.2 Hz, 3H) LC-MS (method 4): R = 0.873 min; MS (ESIpos): m/z = 481.2 [M + H].sup.+ 3% yield rac-2-(N-[4-amino-5-[3-(2,3-dimethylphenyl)-1,2,4-oxadiazole- 5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 57 [00249] Intermediate 63, ammonia in methanol .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm = 8.68-8.65 (m, 2H), 7.71- 7.66 (m, 2H), 7.59 (s, 1H), 7.39 (t, J = 8.4 Hz, 2H), 7.24 (s, 1H), 5.11 (s, 1H), 2.13-2.05 (m, 1H), 1.19 (d, J = 7.6 Hz, 3H), 1.07-1.03 (m, 2H), 0.77-0.65 (m, 2H). LC-MS (method 4): R = 0.679 min; MS (ESIpos): m/z = 416.9 [M + H].sup.+. 9% yield rac-2-(N-[4-amino-5-(3-cyclopropyl-1,2,4-oxadiazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide 58 [00250] Intermediate 66, ammonia in methanol .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm = 8.80-8.71 (m, 2H), 8.27 (s, 1H), 7.79-7,62 (m, 4H), 7.41 (t, J = 8.4 Hz, 2H), 7.30 (s, 1H), 5.20- 5.08 (m, 1H), 3.91 (s, 3H), 1.20 (d, J = 7.2 Hz, 3H). LC-MS (method 4): R = 0.736 min; MS (ESIpos): m/z = 457.2 [M + H].sup.+ 6% yield rac-2-(N-[4-amino-5-[3-(1-methylpyrazol-4-yl)-1,2,4- oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide 59 [00251] Intermediate 69, ammonia in methanol .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm = 8.70 (s, 2H), 7.75-7.65 (m, 2H), 7.62 (s, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.28 (s, 1H), 5.20-5.05 (m, 1H), 3.26-3.20 (m, 1H), 1.95- 1.85 (m, 2H), 1.65-1.57 (m, 6H), 1.20 (d, J = 7.2 Hz, 3H). LC-MS (method 4): R= 0.918 min; MS (ESIpos): m/z = 444.9 [M + H].sup.+. 28% yield rac-2-(N-[4-amino-5-(3-cyclopentyl-1,2,4-oxadiazole-5- carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

EXAMPLE 60

rac-2-(N-[4-amino-5-[3-[[cyclopentyl(methyl)amino]methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1497] ##STR00252##

[1498] rac-2-(N-[4-amino-5-(3-formylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Intermediate 78, 97 mg, 0.24 mmol) was dissolved in a mixture of MeOH (2.5 mL), THF (0.4 mL) and DMF (0.4 mL). Cyclopentyl-methyl-amine (57 μL, 0.48 mmol) was added followed by the addition of acetic acid (14 μL, 0.24 mmol).The reaction mixture was stirred for 15 minutes at room temperature followed by the addition of sodium cyanoborohydride (23 mg, 0.36 mmol).The reaction was stirred overnight and then diluted with ethyl acetate and a saturated aqueous solution of sodium carbonate and brine. The organic phase was dried over sodium sulfate, filtered off and the solvent was evaporated in vacuo The residue obtained was purified by automated flash column chromatography (method Z, methanol+2 Vol-% aqueous ammonia (33%)) to give 14 mg (0.029 mmol, 12%) of the title compound as a yellow solid.

[1499] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=8.67 (br s, 1H), 8.42 (br s, 1H, J=1.5 Hz), 7.72-7.62 (m, 2H), 7.62 (br s, 1H), 7.39 (t, 2H, J=8.9 Hz), 7.29 (s, 1H), 6.75 (s, 1H), 5.11 (br s, 1H, J=2.5, 5.6 Hz), 3.60 (s, 2H), 2.6-2.7 (m, 1H), 2.09 (s, 3H), 1.7-1.8 (m, 2H), 1.5-1.7 (m, 2H), 1.4-1.5 (m, 2H), 1.3-1.4 (m, 2H), 1.19 (d, 3H, J=7.4 Hz).

[1500] LC-MS (method 2): Rt=1.17 min; MS(ESlpos) m/z=487.4 [m+H].sup.+.

EXAMPLE 61

rac-2-(Np[4-amino-5-[3-[[(1-methylcyclopentyl)amino]methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1501] ##STR00253##

[1502] rac-2-(N-[4-amino-5-(3-formylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Intermediate 78, 20 mg, 50 μmol) was dissolved in a mixture of MeOH (0.5 mL), THF (0.1 mL) and DMF (0.1 mL). 1-methyl-cyclopentanamine (12 μL, 99 μmol) was added followed by the addition of acetic acid (3 μL, 50 μmol) and the reaction mixture was stirred for 15 minutes at room temperature followed by the addition of sodium cyanoborohydride (5 mg, 74 μmol). The reaction mixture was stirred overnight at room temperature and 5 h at 50° C. The reaction mixture was diluted with DMSO and acetonitrile and purified by preparative RP-HPLC (method C, basic) to obtain 4.4 mg (9 μmol, 18%) of the title compound .

[1503] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=8.65 (br s, 1H), 8.40 (br s, 1H), 7.69 (dd, 2H, J=5.1, 8.9 Hz), 7.62 (br s, 1H), 7.39 (t, 2H, J=8.9 Hz), 7.28 (br s, 1H), 6.82 (s, 1H), 5.10 (br s, 1H), 3.66 (d, 2H, J=7.6 Hz), 1.6-1.7 (m, 2H), 1.5-1.6 (m, 4H), 1.3-1.4 (m, 2H), 1.18 (d, 3H, J=7.4 Hz), 1.09 (s, 3H).

[1504] LC-MS (method 2): Rt=1.14 min; MS(ESlneg) m/z=485.4 [M−H].sup.−.

EXAMPLE 62

rac-2-(N-[4-amino-5-[3-[(cyclopentylamino)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1505] ##STR00254##

[1506] rac-2-(N-[4-amino-5-(3-formylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Intermediate 78, 17 mg, 43 μmol) was dissolved in a mixture of MeOH (0.5 mL) and DMF (0.1 mL). Cyclopentanamine (10 μL, 85 μmol) was added followed by the addition of acetic acid (2.4 μL, 43 μmol). The reaction mixture was stirred for 15 minutes at room temperature and then sodium cyanoborohydride (4 mg, 64 μmol) was added. The reaction mixture was stirred for 4 h at room temperature and then was heated to 50° C. overnight. The solvent was partially reduced with a stream of nitrogen and the residue was diluted with DMSO and purified by preparative RP-HPLC (method C, basic) to obtain 6.0 mg (13 μmol, 30%) of the title compound.

[1507] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) δ ppm=8.67 (brs, 1H, J=1.9 Hz), 8.40 (brs, 1H), 7.70 (dd, 2H, J=5.2, 8.7 Hz), 7.62 (br s, 1H), 7.39 (t, 2H, J=8.8 Hz), 7.28 (br s, 1H), 6.86 (s, 1H), 5.0-5.2 (m, 1H), 3.67 (d, 2H, J=6.0 Hz), 2.91-2.85 (m, 1H), 2.30-2.20 (m, 1H), 1.5-1.7 (m, 4H), 1.3-1.5 (m, 2H), 1.2-1.3 (m, 2H), 1.18 (d, 3H, J=7.6 Hz).

[1508] LC-MS (method 2): Rt=1.10 min; MS(ESlpos) m/z=473.6 [M+H].sup.+.

EXAMPLE 63

rac-2-(N-[4-amino-5-[3-(1-piperidylmethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1509] ##STR00255##

[1510] rac-2-(N-[4-amino-5-(3-formylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Intermediate 78, 14 mg, 35 μmol) was dissolved in MeOH (0.5 mL), piperidine (5 μL, 52 μmol) was added followed by the addition of acetic acid (2.0 μL, 35 μmol). The reaction mixture was stirred for 15 minutes at room temperature followed by the addition of sodium cyanoborohydride (2.6 mg, 42 μmol). The reaction mixture was stirred for two days at room temperature. The reaction mixture was diluted with DMSO and purified by preparative RP-HPLC (method C, basic) to obtain 3.2 mg (7 μmol, 20%) of the title compound.

[1511] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=8.66 (brs, 1H, J=1.5 Hz), 8.43 (brs, 1H), 7.70 (dd, 2H, J=5.1, 8.9 Hz), 7.62 (br s, 1H), 7.39 (t, 2H, J=8.9 Hz), 7.29 (br s, 1H), 6.74 (s, 1H), 5.11 (br s, 1H, J=3.3 Hz), 3.50 (s, 2H), 2.31 (m, 4H), 1.45 (m, 4H), 1.34 (m, 2H), 1.19 (d, 3H, J=7.4 Hz).

[1512] LC-MS (method 2): Rt=1.12 min; MS(ESlneg) m/z=471.5 [M−H].sup.−.

EXAMPLE 64

rac-2-(N-[4-amino-5-[3-[(4-cyanophenoxy)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1513] ##STR00256##

[1514] rac-2-(N-[4-amino-5-[3-(hydroxymethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (Example 65, 50 mg, 0.123 mmol), triphenylphosphine (65 mg, 0.247 mmol) and 4-cyanophenol (29 mg, 0.247 mmol) were dissolved in THF (1 mL) and DMF (0.5 mL). To this solution diisopropyl azodicarboxylate (46 μL, 0.234 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of ammonium chloride. The phases were separated and the organic phase was washed with a saturated aqueous solution of sodium carbonate and brine, dried over sodium sulfate, filtered off and evaporated in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, methanol+2 Vol-% aqueous ammonia (33%)) to give 30 mg (0.058 mmol, 47%) of the title compound.

[1515] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=8.69 (br s, 1H), 8.49 (br s, 1H), 7.8-7.8 (m, 2H), 7.70 (dd, 2H, J=4.9, 8.7 Hz), 7.62 (br s, 1H), 7.39 (t, 2H, J=8.7 Hz), 7.29 (br s, 1H), 7.2-7.2 (m, 2H), 6.98 (s, 1H), 5.33 (s, 2H), 5.1-5.2 (m, 1H), 1.18 (d, 3H, J=7.4 Hz).

[1516] LC-MS (method 2): Rt=1.09 min; MS(ESlneg) m/z=505.4 [M−H].sup.−.

EXAMPLE 65

rac-2-(N-[4-amino-5-[3-(hydroxymethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1517] ##STR00257##

[1518] [4-amino-2-(4-fluoroanilino)thiazol-5-yl]-[3-(hydroxymethyl)isoxazol-5-yl]methanone (700 mg, 2.09 mmol, Intermediate 77) and potassium carbonate (868 mg, 6.28 mmol) were mixed together in DMF (14 mL), then rac-2-bromopropanamide (382 mg, 2.51 mmol) was added portion wise and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of ammonium chloride. The phases were separated and the organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under vacuo distillation, the residue thus obtained was purified by automated flash column chromatography (method Z, methanol+2 Vol-% aqueous ammonia (33%)) to give 535 mg (1.32 mmol, 63%) of the title compound.

[1519] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.67 (br s, 1H) 8.43 (br s, 1H) 7.70 (dd, J=8.87, 5.07 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (br s, 1H) 6.79 (s, 1H) 5.53 (t, J=6.08 Hz, 1H) 5.11 (m, 1H) 4.49 (d, J=6.08 Hz, 2H), 1.18 (d, J=7.60 Hz, 3H).

[1520] LC-MS (method 1): Rt=0.82 min; MS(ESlpos) m/z=406.0 [M+H].sup.+.

EXAMPLE 66

rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl N-phenylcarbamate

[1521] ##STR00258##

[1522] rac-2-(N-[4-amino-5-[3-(hydroxymethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (Example 65, 25 mg, 62 μmol) was dissolved in DMF (0.3 mL), diisopropylethylamine (32 μL, 0.185 mmol) was added followed by the addition of 4-nitrophenyl-chloroformiate (15 mg, 0.074 mmol) as solution in THF (0.3 mL). The reaction mixture was stirred for three hours then further diisopropylethylamine (32 μL, 0.185 mmol) followed by aniline (11 μL, 0.123 mmol) were added. The reaction was stirred for two days then it was diluted with ethyl acetate and a saturated aqueous solution of ammonium chloride. The phases were separated and the organic phase was washed with a saturated aqueous solution of sodium carbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative RP-HPLC (method B, basic) to obtain 2.4 mg (5 μmol, 7%) of the title compound.

[1523] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=9.88 (s, 1H), 8.68 (br s, 1H, J=0.8 Hz), 8.4-8.5 (m, 1H), 7.69 (dd, 2H, J=5.1, 8.6 Hz), 7.62 (br s, 1H), 7.3-7.5 (m, 4H), 7.2-7.3 (m, 3H), 7.0-7.1 (m, 1H), 6.92 (s, 1H), 5.21 (s, 2H), 5.0-5.2 (m, 1H), 1.18 (d, 3H, J=7.4 Hz).

[1524] LC-MS (method 2): Rt=1.11 min; MS(ESlpos) m/z=525.4 [M+H].sup.+.

EXAMPLE 67

rac-2-(N-[4-amino-5-[3-(2-fluorophenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1525] ##STR00259##

[1526] rac-2-(N-(4-amino-5-prop-2-ynoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (Intermediate 71, 18.5 mg, 56 μmol) was dissolved in DMSO (0.5 mL) and water (0.1 mL). 2-fluoro-N-hydroxy-benzimidoyl chloride (15 mg, 83 μmol, Intermediate 72) was added as a solution in t-BuOH (0.25 mL) directly followed by the addition of premixed copper(II) sulfate pentahydrate (2.8 mg, 11 μmol) and L-(+)-ascorbic acid (2.5 mg, 14 μmol) in water (0.15 mL) and finally potassium hydrogen carbonate (25 mg, 250 μmol) was added at once. The reaction mixture was stirred for 3 h and then it was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was purified by preparative RP-HPLC (method D, basic) to obtain 3.9 mg (8 μmol, 15%) of the title compound.

[1527] .sup.1H NMR (acetone-d.sub.6, 400 MHz) δ ppm=8.8-8.9 (br s, 1H), 7.95 (dt, 1H, J=1.9, 7.7 Hz), 7.7-7.8 (m, 2H), 7.5-7.6 (m, 1H), 7.50 (br s, 1H), 7.3-7.4 (m, 4H), 7.21 (d, 1H, J=3.3 Hz), 7.1-7.2 (m, 1H), 6.64 (br s, 1H), 5.32 (q, 1H, J=7.4 Hz), 1.31 (d, 3H, J=7.4 Hz).

[1528] LC-MS (method 2): Rt=1.19 min; MS(ESlpos) m/z=470.3 [M+H].sup.+.

EXAMPLE 68

rac-2-(N-[4-amino-5-[3-(2-pyridypisoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1529] ##STR00260##

[1530] rac-2-(N-(4-amino-5-prop-2-ynoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (Intermediate 71, 20 mg, 60 μmol) was dissolved in DMSO (0.5 mL) and t-BuOH (0.25 mL), then N-hydroxypyridine-2-carboximidoyl chloride (12 mg, 75 μmol, Intermediate 74) was added as a solution in THF (0.1 mL) directly followed by the addition of premixed copper(II) sulfate pentahydrate (3 mg, 12 μmol) and L-(+)-ascorbic acid (2.7 mg, 15 μmol) in water (0.15 mL) and finally potassium hydrogen carbonate (27 mg, 271 μmol) as a solution in water (0.1 mL). The reaction mixture was stirred for three hours and then diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was purified by preparative RP-HPLC (method C, basic) to obtain 2.5 mg (5 μmol, 18%) of the title compound.

[1531] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=8.7-8.8 (m, 2H), 8.51 (br s, 1H), 7.9-8.0 (m, 2H), 7.72 (dd, 2H, J=5.1, 8.6 Hz), 7.64 (br s, 1H), 7.54 (ddd, 1H, J=1.5, 4.9, 7.3 Hz), 7.41 (t, 2H, J=8.7 Hz), 7.30 (br s, 1H), 7.28 (s, 1H), 5.13 (br s, 1H), 1.20 (d, 3H, J=7.4 Hz).

[1532] LC-MS (method 2): Rt=1.03 min; MS(ESlpos) m/z=453.4 [M+H].sup.+.

EXAMPLE 69

rac-2-(N-[4-amino-5-[3-[4-(trifluoromethoxy)phenyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1533] ##STR00261##

[1534] rac-2-(N-(4-amino-5-prop-2-ynoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (Intermediate 71, 15 mg, 45 μmol) was dissolved in DMSO (0.3 mL) and t-BuOH (0.1 mL), then N-hydroxy-4-(trifluoromethoxy)benzimidoyl chloride (Intermediate 75, 29 mg, 122 μmol) was added as a solution in THF (0.1 mL) directly followed by premixed copper(II) sulfate pentahydrate (1.4 mg, 9 μmol) and L-(+)-ascorbic acid (2.0 mg, 11 μmol) in water (0.15 mL) and finally potassium hydrogen carbonate (23 mg, 226 μmol). The reaction mixture was stirred at 38° C. overnight and then diluted with ethyl acetate and water. The phases were separated, and the organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by preparative RP-HPLC (method E, basic) to obtain 7.5 mg (14 μmol, 31%) of the title compound.

[1535] .sup.1H NMR (400 MHz, methanol-d.sub.4) δ ppm=7.92-7.98 (m, 2H) 7.62-7.69 (m, 2H) 7.36-7.43 (m, 2H) 7.29 (t, J=8.74 Hz, 2H) 7.25 (s, 1H) 5.28 (q, J=7.35 Hz, 1H) 1.29 (d, J=7.35 Hz, 3H).

[1536] LC-MS (method 2): Rt=1.33 min; MS(ESlpos) m/z=436.3 [M+H].sup.+.

EXAMPLE 70

rac-2-(N-[4-amino-5-[3-(2-methoxyphenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1537] ##STR00262##

[1538] rac-2-(N-(4-amino-5-prop-2-ynoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (9.5 mg, 29 μmol, Intermediate 71) was dissolved in DMSO (0.3 mL) and t-BuOH (0.1 mL), then N-hydroxy-2-methoxy-benzimidoyl chloride (11 mg, 60 μmol, Intermediate 73) was added as a solution in THF (0.1 mL) directly followed by premixed copper(II) sulfate (0.9 mg, 6 μmol) and L-(+)-ascorbic acid (1.3 mg, 7 μmol) in water (0.15 mL) and finally potassium hydrogen carbonate (13 mg, 129 μmol) was added at once. The reaction mixture was stirred at 37° C. for 2 h and at room temperature for two days. After dilution with ethyl acetate and water, the phases were separated and the organic phase was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was purified by preparative RP-HPLC (method D, basic) to obtain 2.5 mg (5 μmol, 18%) of the title compound.

[1539] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=8.69 (br s, 1H), 8.47 (br s, 1H), 7.7-7.8 (m, 3H), 7.64 (br s, 1H), 7.50 (ddd, 1H, J=1.8, 7.2, 8.6 Hz), 7.41 (t, 2H, J=8.7 Hz), 7.30 (br s, 1H), 7.2-7.2 (m, 2H), 7.06 (dt, 1H, J=0.9, 7.5 Hz), 5.0-5.2 (m, 1H), 3.85 (s, 3H), 1.20 (d, 3H, J=7.6 Hz)

EXAMPLE 71

rac-2-(N-[4-amino-5-[3-(6-methoxy-3-pyridyl))isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1540] ##STR00263##

[1541] rac-2-(N-(4-Amino-5-prop-2-ynoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (19 mg, 57 μmol, Intermediate 71) was dissolved in THF (0.3 mL) then N-hydroxy-6-methoxy-pyridine-3-carboximidoyl chloride (17 mg, 91 μmol, Intermediate 76) as a solution in THF (0.3 mL) was added to it followed by triethylamine (32 μL, 229 mmol). The reaction mixture was heated to 37° C. overnight. The solvent was then removed with a stream of nitrogen and the residue thus obtained was purified by preparative RP-HPLC (method D, basic) to obtain 4.5 mg (9 μmol, 16%) of the title compound.

[1542] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=8.74 (d, 2H, J=1.8 Hz), 8.49 (br s, 1H), 8.18 (dd, 1H, J=2.4, 8.7 Hz), 7.71 (dd, 2H, J=5.2, 8.7 Hz), 7.64 (br s, 1H), 7.57 (s, 1H), 7.41 (t, 2H, J=8.7 Hz), 7.30 (s, 1H), 6.9-7.0 (m, 1H), 5.0-5.2 (m, 1H), 3.91 (s, 3H), 1.20 (d, 3H, J=7.4 Hz).

[1543] LC-MS (method 2): Rt=1.15 min; MS(ESlpos) m/z=483.6 [M+H].sup.+.

EXAMPLE 72

rac-2-(N-[4-amino-5-(1-phenyltriazole-4-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

[1544] ##STR00264##

[1545] rac-2-(N-(4-amino-5-prop-2-ynoyl-thiazol-2-yl)-4-fluoro-anilino)propanamide (Intermediate 71, 27 mg, 81 μmol) and a 0.5 M solution of phenyl azide in 2-methyltetrahydrofuran (0.24 mL, 122 μmol) were dissolved in a mixture of DMSO (0.5 mL), t-BuOH (0.25 mL) and water (0.1 mL). To this solution a premixed solution of copper(II) sulfate (2.59 mg, 16 μmol) and L-(+)-ascorbic acid (3.58 mg, 20 μmol) in water (0.15 mL) were added and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and brine, the organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was purified by preparative RP-HPLC (method C, basic) to obtain 7.5 mg (17 μmol, 37%) of the title compound.

[1546] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ ppm=9.24 (s, 1H), 8.65 (br s, 1H), 8.05 (br s, 1H), 7.9-8.0 (m, 2H), 7.6-7.7 (m, 2H), 7.6-7.6 (m, 3H), 7.5-7.5 (m, 1H), 7.40 (t, 2H, J=8.7 Hz), 7.26 (br s, 1H), 5.0-5.2 (m, 1H), 1.19 (d, 3H, J=7.4 Hz).

[1547] LC-MS (method 2): Rt=1.07 min; MS(ESlpos) m/z=452.3 [M+H].sup.+.

EXAMPLE 73

rac-2-(N-[4-amino-5-[3-[(3-fluoroazetidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1548] ##STR00265##

[1549] rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl methanesulfonate (Intermediate 79, 200 mg, 0.41 mmol) was dissolved in THF (4 mL). Diisopropyl ethyl amine (0.36 mL, 2.1 mmol) and 3-fluoroazetidine hydrochloride (92 mg, 0.83 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and brine, the phases separated, and the organic phase was dried over sodium sulfate and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) to give 11 mg (0.02 mmol, 6%) of the title compound as yellow solid.

[1550] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.68 (br s, 1H) 8.44 (br s, 1H) 7.70 (dd, J=8.87, 5.07 Hz, 2H) 7.62 (s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (s, 1H) 6.77 (s, 1H) 5.16-5.26 (m, 1H) 5.00-5.15 (m, 2H) 3.68 (s, 2H) 3.48-3.63 (m, 2H) 3.12-3.26 (m, 2H) 1.18 (d, J=7.35 Hz, 3H).

[1551] LC-MS (method 2): Rt=0.97 min; MS(ESlpos) m/z=463.6 [M+H].sup.+.

EXAMPL 74

rac-2-(N-[4-amino-5-[3-[(3,3-difluoroazetidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1552] ##STR00266##

[1553] rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl methanesulfonate (Intermediate 79, 200 mg, 0.41 mmol) was dissolved in THF (4 mL). Diisopropyl ethyl amine (0.36 mL, 2.1 mmol) and 3,3-difluoroazetidine hydrochloride (107 mg, 0.83 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and brine, the phases were separated, and the organic phase was dried over sodium sulfate and reduced in vacuo The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) to give 52 mg (0.11 mmol, 26%) of the title compound as yellow solid.

[1554] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.68 (br s, 1H) 8.45 (br s, 1H) 7.70 (dd, J=8.74, 5.20 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (s, 1H) 6.82 (s, 1H) 5.10 (br s, 1H) 3.80 (s, 2H) 3.66 (t, J=12.55 Hz, 4H) 1.18 (d, J=7.35 Hz, 3H).

[1555] LC-MS (method 2): Rt=1.03 min; MS(ESlpos) m/z=481.5 [M+H].sup.+.

EXAMPLE 75

rac-2-(N-[4-amino-5-[3-[(4,4-difluoro-1-piperidyl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1556] ##STR00267##

[1557] rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl methanesulfonate (Intermediate 79, 200 mg, 0.41 mmol) was dissolved in THF (4 mL). Diisopropyl ethyl amine (0.36 mL, 2.1 mmol) and 4,4-difluoropiperidine (100 mg, 0.83 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and brine, the phases were separated, and the organic phase was dried over sodium sulfate and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) to give 61 mg (0.12 mmol, 29%) of the title compound as yellow solid.

[1558] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.67 (br s, 1H) 8.44 (br s, 1H) 7.70 (dd, J=8.74, 5.20 Hz, 2H) 7.62 (s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (s, 1H) 6.81 (s, 1H) 5.10 (br s, 1H) 3.65 (s, 2H) 1.82-2.07 (m, 4H) 1.19 (d, J=7.35 Hz, 3H).

[1559] LC-MS (method 2): Rt=1.11 min; MS(ESlpos) m/z=509.4 [M+H].sup.+.

EXAMPLE 76

2-(N-[4-amino-5-[3-[(4,4-difluoro-3-methyl-1-piperidyl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers)

[1560] ##STR00268##

[1561] rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl methanesulfonate (Intermediate 79, 190 mg, 0.39 mmol) was dissolved in THF (4 mL). Diisopropyl ethyl amine (0.21 mL, 1.18 mmol) and rac-4,4-difluoro-3-methylpiperidine (106 mg, 0.79 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and brine, the phases were separated, and the organic phase was dried over sodium sulfate and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) to give 52 mg (0.1 mmol, 25%) of the title compound as yellow solid.

[1562] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.67 (br s, 1H) 8.44 (br s, 1H) 7.70 (dd, J=8.74, 5.20 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (s, 1H) 6.80 (s, 1H) 5.10 (br s 1H) 3.63 (s, 2H) 2.65-2.78 (m, 2H) 2.22-2.31 (m, 1H) 1.83-2.13 (m, 4H) 1.19 (d, J=7.35 Hz, 3H) 0.89 (d, J=6.59 Hz, 3H).

[1563] LC-MS (method 2): Rt=1.18 min; MS(ESlpos) m/z=523.4 [M+H].sup.+.

EXAMPLE 77

2-(N-[4-amino-5-[3-[(3-fluoropyrrolidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers)

[1564] ##STR00269##

[1565] rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl methanesulfonate (Intermediate 79, 190 mg, 0.39 mmol) was dissolved in THF (4 mL). Diisopropyl ethyl amine (0.21 mL, 1.18 mmol) and rac-3-fluoropyrrolidine (70 mg, 0.79 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and brine, the phases were separated, and the organic phase was dried over sodium sulfate and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) to give 48 mg (0.1 mmol, 25%) of the title compound as yellow solid.

[1566] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.68 (br s, 1H) 8.44 (br s, 1H) 7.70 (dd, J=8.87, 5.07 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (br s, 1H) 6.79 (s, 1H) 5.03-5.28 (m, 2H) 3.69 (s, 2H) 2.56-2.89 (m, 3H) 2.29-2.41 (m, 1H) 2.00-2.24 (m, 1H) 1.73-1.95 (m, 1H) 1.19 (d, J=7.35 Hz, 3H).

[1567] LC-MS (method 2): Rt=0.99 min; MS(ESlpos) m/z=477.4 [M+H].sup.+.

EXAMPLE 78

rac-2-(N-[4-Amino-5-(3-hydroxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

[1568] ##STR00270##

[1569] rac-2-(N-[5-(3-allyloxyisoxazole-5-carbonyl)-4-amino-thiazol-2-yl]-4-fluoro-anilino)propanamide (Intermediate 85, 1.95 g, 4.52 mmol) was dissolved in MeOH (135 mL) and THF (55 mL). Tetrakis(triphenylphosphine)palladium(0) (521 mg, 0.45 mmol) was added and the reaction was stirred for 10 minutes followed by the addition of potassium carbonate (1.25 g, 9.03 mmol) and stirring was prolonged for one hour. Few drops of acetic acid were added and the solvent was evaporated under vacuum. The residue was purified by automated flash column chromatography (method Z, acidic, 1 vol % AcOH) to give 1.64 g (4.09 mmol, 91%) of the title compound as yellow solid.

[1570] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=11.78 (br s, 1H) 8.66 (br s, 1H) 8.38 (br s, 1H) 7.69 (dd, J=8.74, 4.94 Hz, 2H) 7.61 (br s, 1H) 7.39 (t, J=8.87 Hz, 2H) 7.28 (br s, 1H) 6.34 (s, 1H) 5.10 (br s, 1H) 1.18 (d, J=7.35 Hz, 3H).

[1571] LC-MS (method 2): Rt=0.47 min; MS(ESlneg) m/z=390.3 [M−H].sup.−.

EXAMPLE 79

rac-2-(N-[4-amino-5-[3-(cyclobutoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1572] ##STR00271##

[1573] rac-2-(N-[4-Amino-5-(3-hydroxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Example 78, 162 mg, 0.41 mmol) was dissolved in DMF (1 mL) and potassium carbonate (200 mg, 1.45 mmol) followed by cyclobutyl bromide (52 μL, 0.50 mmol) were added. The reaction mixture was heated to 70° C. overnight then diluted with ethyl acetate and water. The phases were separated, and the organic phase was washed with brine, dried over sodium sulfate, and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) to give 68 mg (0.15 mmol, 37%) of the title compound.

[1574] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.66 (br s, 1H) 8.39-8.45 (br s, 1H) 7.69 (dd, J=8.74, 4.94 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.28 (br s, 1H) 6.60 (s, 1H) 5.10 (br s, 1 H) 4.83 (quin, J=7.22 Hz, 1H) 2.28-2.41 (m, 2H) 1.98-2.16 (m, 2H) 1.68-1.85 (m, 1H) 1.49-1.65 (m, 1H) 1.18 (d, J=7.35 Hz, 3H).

[1575] LC-MS (method 1): Rt=1.21 min; MS(ESlpos) m/z=446.4 [M+H].sup.+.

EXAMPLE 80

rac-2-(N-[4-amino-5-[3-(cyclobutylmethoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1576] ##STR00272##

[1577] 2-(N-[4-amino-5-(3-hydroxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Example 78, 104 mg, 0.27 mmol) was dissolved in DMF (2 mL) and potassium carbonate (147 mg, 1.06 mmol) was added. The reaction mixture was heated to 70° C. for one hour and cooled to room temperature followed by the addition of bromomethyl cyclobutane (36 μL, 0.32 mmol). The reaction mixture was heated to 70° C. overnight. The reaction was then diluted with ethyl acetate and water, the organic phase was washed with brine and dried over sodium sulfate and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) and again by preparative RP-HPLC (method E, basic) to obtain 39 mg (84 μmol, 32%) of the title compound.

[1578] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.66 (br s, 1H) 8.45 (br s, 1H) 7.69 (dd, J=8.74, 5.20 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.87 Hz, 2H) 7.29 (br s, 1H) 6.63 (s, 1H) 5.10 (br s, 1H) 4.14 (d, J=6.84 Hz, 2H) 2.61-2.81 (m, 1H) 1.95-2.10 (m, 2H) 1.68-1.97 (m, 4H) 1.18 (d, J=7.60 Hz, 3H).

[1579] LC-MS (method 2): Rt=1.28 min; MS(ESlpos) m/z=460.3 [M+H].sup.+.

EXAMPLE 81

rac-2-(N-[4-Amino-5-[3-(4,4-difluorocyclohexoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide

[1580] ##STR00273##

[1581] rac-2-(N-[4-Am ino-5-(3-hydroxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Example 78, 112 mg, 0.29 mmol) was dissolved in DMF (2 mL) and potassium carbonate (159 mg, 1.15 mmol) was added. The reaction mixture was heated to 70° C. for one hour and cooled to room temperature followed by the addition of 4-bromo-1,1-difluorocyclohexane (69 mg, 0.34 mmol). The reaction mixture was heated to 70° C. for 72 hours, then cooled to room temperature and further 4-bromo-1,1-difluorocyclohexane (69 mg, 0.34 mmol) was added and the reaction mixture was heated to 70° C. for additional two hours. The reaction mixture was then diluted with ethyl acetate and water, the organic phase was washed with brine and dried over sodium sulfate and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) followed by suspension of the residue in DMSO and a mixture of acetonitrilewater (1:1) causing a dense precipitate. The solid was collected by vacuum filtration and dried at high vacuum to afford 19 mg (38 μmol, 13%) of the title compound.

[1582] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.65 (br s, 1H) 8.46 (br s, 1H) 7.69 (dd, J=8.74, 5.20 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (br s, 1H) 6.67 (s, 1H) 5.10 (br s, 1H) 4.74 (br m, 1H) 1.77-2.05 (m, 8H) 1.18 (d, J=7.35 Hz, 3H).

[1583] LC-MS (method 2): Rt=1.24 min; MS(ESlpos) m/z=510.3 [M+H].sup.+.

EXAMPLE 82

rac-2-(N-[4-amino-5-(3-isopropoxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

[1584] ##STR00274##

[1585] rac-2-(N-[4-amino-5-(3-hydroxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (Example 78, 100 mg, 0.26 mmol) was dissolved in DMF (2 mL) and potassium carbonate (142 mg, 1.03 mmol) followed by 2-bromopropane (29 μL, 0.31 mmol) were added to the reaction mixture and the reaction was heated to 70° C. overnight. The reaction mixture was then diluted with ethyl acetate and water, the organic phase was washed with brine and dried over sodium sulfate and reduced in vacuo. The residue obtained was purified by automated flash column chromatography (method Z, basic, 2 vol % aqueous ammonia in MeOH) and again by preparative RP-HPLC (method E, basic) to yield 44 mg (102 μmol, 40%) of the title compound.

[1586] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm=8.66 (br s, J=4.31 Hz, 1H) 8.44 (br s, J=2.28 Hz, 1H) 7.69 (dd, J=8.74, 4.94 Hz, 2H) 7.62 (br s, 1H) 7.39 (t, J=8.74 Hz, 2H) 7.29 (br 5, 1H) 6.60 (s, 1H) 5.10 (br s, 1H) 4.76 (quin, J=6.08 Hz, 1H) 1.30 (d, J=6.08 Hz, 6H) 1.18 (d, J=7.35 Hz, 3H).

Experimental Section—Determination of Absolute Stereochemistry by Means of X-Ray -Analysis

Determination of the Absolute Configuration of Example 3.1

(R)-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide

[1587] The crystallographic data of Example 3.1 as well as a figure depicting the thermal ellipsoids and numbering of the structure, are shown in Table 7 and FIG. 6. Colorless crystals of Example 3.1 were obtained by slow evaporation from a propanol solution. A single crystal was mounted on a cryoloop using a protective oil. Single-crystal X-ray diffraction data were collected at 100 K on a Rigaku XtaLAB Synergy S system with a kappa goniometer and a HyPix-6000HE hybrid photon detector using Cu X-ray radiation (CuKα,=1.54178 Å). Data were integrated using the program CrysAlis.sup.PRO. SHELXM was used for structure solution and SHELXL was used for full-matrix least-squares refinement on F.sup.2. In the asymmetric unit one molecule of Example 3.1 is present. In addition, a propanol molecule (half occupied) and one water molecule are present. The two solvent molecules are highly disordered and could not be refined properly, so the only a best model was included. These atoms were not refined anisotropically, hydrogens atoms were not added. All non-hydrogen atoms of example 3.1 were refined anisotropically and all hydrogen atoms were added in calculated positions and refined riding on their resident atoms. The isotropic temperature factors of the hydrogen atoms were refined as 1.2 and 1.5 times the size of the temperature factors of the corresponding heavy atoms, respectively. The absolute stereochemistry (R-configuration) could be assigned unambiguously with a Flack Parameter of −0.03(9). The program XP was used for molecular representations.

TABLE-US-00007 TABLE 7 Crystal data and structure refinement for Example 3.1 Identification code 3.1 Empirical formula C22 H23 F N5 O3 S + 0.5 C2 H6 O + H2 O Formula weight 456.51 + 20.01 + 18.02 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Hexagonal Space group P61 Unit cell dimensions a = 26.728(4) Å a = 90°. b = 26.728(4) Å b = 90°. c = 6.876(3) Å g = 120°. Volume 4254(2) Å.sup.3 Z 6 Density (calculated) 1.154 Mg/m.sup.3 Absorption coefficient 1.380 mm.sup.−1 F(000) 1542 Crystal size 0.100 × 0.050 × 0.050 mm.sup.3 Theta range for data collection 3.307 to 54.283°. Reflections collected 2749 Independent reflections 18122 [R(int) = 11.96] Completeness to theta = 54.283° 97.7% Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 2749/3/305 Goodness-of-fit on F2 0.997 Final R indices [I>2sigma(I)] R1 = 0.0931, wR2 = 0.2238 R indices (all data) R1 = 0.1765, wR2 = 0.2702 Absolute structure parameter −0.03(9) Extinction coefficient n/a Largest diff. peak and hole 0.662 and −0.322 e.A.sup.−3

Experimental Sextion —Biological Assays and Biological Data

[1588] Table 8, below, lists the abbreviations used in this paragraph and in the Assays section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.

TABLE-US-00008 TABLE 8 Abbreviations nL nanoliter μL microliter mL milliliter nM nanomolar μM micromolar mM millimolar min minute(s) s second(s) kDa kilodalton MW molecular weight cAMP cyclic adenosine monophosphat ADP adenosine diphosphate ATP adenosine triphosphate FCS fetal calf serum FBS fetal bovine serum PBS phosphate buffered saline RPMI Roswell Park Memorial Institute ACK lysing buffer ammonium-chloride-potassium lysis buffer DMEM Dulbecco's Modified Eagle's Medium HEPES 2-[4-(2-hydroxyethyl)piperazin-1- yl]ethanesulfonic acid MOPS 3-(N-morpholino) propanesulfonic acid Pen/Strep penicillin and streptomycin HBS-P+ buffer containing 0.1 M HEPES, 1.5 M NaCl and 0.5% v/v Surfactant P20 DTT DL-Dithiothreitol BGG bovine gamma globulin PBMC peripheral blood mononuclear cells APC antigen presenting cells CD cluster of differentiation IgG immunoglobulin G OKT3 CD3 monoclonal antibody FLAG-Tag amino acid sequence DYKDDDDK DNA deoxyribonucleic acid CFSE carboxyfluorescein succinimidyl ester OVA ovalbumin antigen FACS fluorescence-activated cell sorting s.c. subcutaneous i.v. intravenous i.p. intraperitoneal

[1589] Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein [1590] the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and [1591] the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

[1592] Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

[1593] The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:

Human DGKζ Kinase Activity Inhibition Assay.

[1594] Human diacylglycerol kinase zeta (DGKζ) inhibitory activity of compounds of the present invention was quantified employing the human DGKζ kinase activity assay as described in the following paragraphs. In essence, the enzyme activity was measured by quantification of the adenosine-di-phosphate (ADP) generated as a co-product of the enzyme reaction via the “ADP-Glo™ Kinase Assay” kit from the company Promega. This detection system works as follows: In a first step the adenosine-tri-phosphate (ATP) not consumed in the kinase reaction is quantitatively converted to cyclic adenosine-mono-phosphate (cAMP) employing an adenylate cyclase (“ADP-Glo-reagent”), then the adenylate cyclase is stopped and the ADP generated in the kinase reaction is converted to ATP, which subsequently generates in a luciferase-based reaction a glow-luminescence signal (“Kinase Detection Reagent”).

[1595] C-terminally FLAG-tagged, recombinant full-length human DGKζ (inhouse expressed in baculovirus infected insect cells, purified using anti-Flag pulldown and size exclusion chromatography) was used as enzyme. As an alternative, commercially available enzyme by Carnabio can be used. As substrate for the kinase, 1,2-dioleoyl-sn-glycerol, reconstituted in octyl-β-D-glucopyranoside micelles, was used. For the preparation of the micelles, 1 volume of a 16.1 mM solution of 1,2-dioleoyl-sn-glycerol (Avanti, Cat. #08001-25G) in chloroform was slowly evaporated using a nitrogen stream. Subsequently, 22.55 volumes of a 510 mM solution of octyl-β-D-glucopyranoside (Sigma-Aldrich, Cat. #O8001-10G) in 50 mM MOPS buffer (pH 7.4) were added, and the mixture was sonicated in an ultrasonic bath for 20 s. Then 35 volumes of 50 mM MOPS buffer (pH 7.4) were added to yield a solution of 0.28 mM 1,2 dioleoyl-sn-glycerol and 200 mM octyl-β-D-glucopyranoside, which was aliquoted, flash-frozen in liquid nitrogen, and stored at −20° C. until use. For each experiment, a fresh aliquot was quickly thawed and diluted 24-fold with aqueous assay buffer (described below) containing 95.7 μM adenosine triphosphate (Promega) to yield a 1.67-fold concentrated substrate solution.

[1596] For the assay 50 nl of a 100-fold concentrated solution of the test compound in dimethyl sulfoxide (DMSO, Sigma) was pipetted into either a white 1536-well or a white low-volume 384-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany). Subsequently, 2 μl of a solution of human DGKζ in aqueous assay buffer [50 mM (3-(N-morpholino)propanesulfonic acid (MOPS, pH 7.4, Sigma-Aldrich), 1 mM dithiothreitol (DTT, Sigma-Aldrich), 100 mM NaCl (Sigma-Aldrich), 10 mM MgCl.sub.2 (Sigma-Aldrich), 0.1% (w/v) bovine gamma globulin (BGG, Sigma-Aldrich), 1 μM CaCl.sub.2 (Sigma-Aldrich)] were added to the wells, and the mixture was incubated for 15 min at 22° C. to allow pre-binding of the test compounds to the enzyme. The reaction was initiated by the addition of 3 μL of substrate solution [preparation described above; 11.7 μM 1,2-dioleoyl-sn-glycerol (.Math.final conc. in the 5 μL assay volume is 7 μM), 8.33 mM octyl-β-D-glucopyranoside (.Math.final conc. in 5 μL assay volume is 5 mM), and 91.67 μM adenosine triphosphate (.Math.final conc. in 5 μL assay volume is 55 μM) in assay buffer] and the resulting mixture was incubated for a reaction time of 20 min at 22° C. The concentration of DGKζ was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range, a typical concentration is about 0.1 nM. The reaction was stopped by the addition of 2.5 μL of “ADP-Glo-reagent” (1 to 1.5 diluted with water) and the resulting mixture was incubated at 22° C. for 1 h to convert the ATP not consumed in the kinase reaction completely to cAMP. Subsequently 2.5 μl of the “kinase detection reagent” (1.2 fold more concentrated than recommended by the producer) were added, the resulting mixture was incubated at 22° C. for 1 h and then the luminescence measured with a suitable measurement instrument (e.g. Viewlux™ from Perkin-Elmer). The amount of emitted light was taken as a measure for the amount of ADP generated and thereby for the activity of the DGKζ.

[1597] The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition). Usually the test compounds were tested on the same microtiterplate in 11 different concentrations in the range of 20 μM to 0.07 nM (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the 100 fold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC.sub.50 values were calculated using Genedata Screener™ software.

TABLE-US-00009 TABLE 9 IC.sub.50 values of examples in in vitro human DGKζ kinase activity inhibition assays Example number IC.sub.50 [nM] 1 9 2 27 3 104 3.1 61 3.2 1752 4 37 5 67 6 123 6.1 64 6.2 3486 7 407 8 728 9 189 10 23 11 2358 12 938 13 977 14 999 15 565 16 420 17 699 18 492 19 315 20 300 21 293 22 182 23 212 24 120 25 134 26 138 27 148 28 90 29 97 30 88 30.1 29 30.2 13437 31 193 32 93 32.1 31 32.2 897 33 48 34 223 35 566 36 446 37 43 38 344 39 53 40 204 41 134 42 146 43 94 44 59 44.1 19 44.2 4511 45 53 45.1 20 45.2 1275 46 77 46.1 27 46.2 2279 47 42 48 73 49 28 50 409 51 17 52 412 53 25 54 306 55 17 56 14 57 32 58 325 59 12 60 58 61 98 62 194 63 88 64 32 65 751 66 29 67 109 68 402 69 117 70 27 71 96 72 999 73 325 74 113 75 26 76 10 77 242 78 n.d. 79 88 80 31 81 17 82 49

TABLE-US-00010 TABLE 10 IC.sub.50 values of intermediates in in vitro human DGKζ kinase activity inhibition assays. Intermediate number IC.sub.50 [nM] 3 >5710 5 >5710 19 >20000 24 >20000 28 19450 30 11950

Transactivation Assay in Jurkat IL2-Reporter Cell Line

[1598] Transactivation assays were carried out in Jurkat cells purchased from Promega (Promega, #CS187001) stably transfected with a firefly luciferase reporter gene construct under the control of the IL2-promoter. Cells were cultured as specified by the manufacturer. Bulk cells were harvested at a culture density of approx. 1E+06 cells/mL, suspended in cryo-storage medium (70% RPMI/20%FCS/10% DMSO), frozen at controlled rate of −1° min in 1.8 mL cryo-vials with cell densities of 1E+07 to 1E+08 cells per vial, and stored at −150° C. or below until further use. Frozen cells were thawed and cultured in medium at a starting density of 3.5E+05 cells/mL for 6 days. On day 6 cells were centrifuged for 5 min at 300×g, medium was decanted and cell concentration was adjusted to 5.0E+06 cells/mL with fresh assay medium (500 mL RPMI (Gibco, #22400)+5 mL L-Glutamin (Sigma, #G7513)+5 mL Penicillin Streptomycin (Sigma #P0781)+5 mL Non-essential amino acids (Invitrogen, #11140)+5 mL sodium-pyruvate (Gibco #1136088), 5 mL FBS (Biochrom, #S0615)). Cell working stock was split in two parts: neutral control and compounds with EC30 stimulation, high control with EC100 stimulation. An antibody premix was prepared by diluting anti-CD3 (BD Pharmingen, #555329), anti-CD28 (BD Pharmingen, #555725) and goat anti mouse anti-IgG (ThermoFisher, #31160) antibodies at 1/14 ratio in assay medium at 2-fold of final concentration (final concentrations depend on cell batch, typically for neutral control 0.0550.0550.22 μg/mL, for high control 0.50.52 mg/mL). The premix solutions were added to the cells in 1+1 volume prior use.

[1599] Fifty nL of a 100-fold concentrated solution of the test compounds in DMSO were transferred into a white microtiter test plate (384, Greiner Bio-One, Germany). For this, either a Hummingbird liquid handler (Digilab, USA) or an Echo acoustic system (Labcyte, USA) was used. Five μL of the freshly prepared cell suspension was added to the wells of a test plate and incubated at 37° C. in a 5% CO.sub.2 atmosphere. After completion of the incubation for 4 hours, 3 μl of Bio-Glo Luciferase assay reagent (Promega, #G7941, prepared as recommended by the supplier) were added to all wells. The test plate was incubated at 20° C. for 10 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Data were normalized (neutral control=0% effect, high control=100% effect). Compounds were tested in duplicates at up to 11 concentrations (typically 20 μM, 5,7 μM, 1,6 μM, 0,47 μM, 0,13 μM, 38 nM, 11 nM, 3,1 nM, 0,89 nM, 0,25 nM and 0,073 nM). Dilution series were made prior to the assay in a 100-fold concentrated form by serial dilution. EC.sub.50 values were calculated by 4-Parameter fitting using a commercial software package (Genedata Analyzer, Switzerland).

Polyclonal Activation of Hhuman PBMCs

[1600] To test the effect of DGKζ inhibitors of the present invention on IL-2 and IFN-γ secretion of human Peripheral Blood Mononuclear Cells (PBMCs) a 24 h human PBMC assay was performed as screening assay. For this, a 96 well flat bottom plate was coated with a suboptimal stimulation condition (EC 10-30) of human aCD3 (Invitrogen, clone OKT3) antibody in 50 μL PBS/well at 4° C. overnight. PBMCs isolated and frozen at liquid N.sub.2 from leucapherese samples was thawed and resuspended in culture medium (X-Vivo-20). 4×10.sup.5 cells/well were plated. Wells were treated with the DGKζ inhibitors of the present invention at the respective concentrations (5-fold dilution steps from 10 μM to 3 nM) and the final DMSO concentration per well is 0.1%. Medium+DMSO (0.1%) was used as baseline value. As positive controls 1000 ng/mL aCD3+aCD28 (1 μg/mL) and a DGKζ reference inhibitor was used. After 24 h the medium was collected and hIL-2 or hIFN-γ ELISA were performed. The following parameters were calculated: EC50 value, concentration at 50% increase; max increase in % and respective concentration and maximum effect normalized to max concentration (10 μM) of a selected DGKζ reference inhibitor.

In Vitro Activation of Mouse OT-I Antigen-Specific T-Cells

[1601] To test the effect of DGKζ inhibitors of the present invention in murine antigen-specific T-cells, spleens and lymph nodes of OT-l mice were collected and mashed through a 40 μm cell strainer and incubated for 1 min in 1 mL ACK lysing buffer (Gibco)/spleen. 4×106 cells/mL were incubated in medium containing 0.05 ng/mL SIINFEKL (FIG. 2) in a 50 mL falcon at 37° C. for 30 min. Afterwards cells were centrifuged and 4×106 cells/mL were resuspended in fresh medium (DMEM; 10% FCS, 1% Pen/Strep, 0.1% β-mercaptoethanol, 1% HEPES). 4×105 cells were plated per well in a 96-well round bottom plate. Wells were treated with DGKζ inhibitors of the present invention at the respective concentrations (5-fold dilution steps from 10 μM to 3 nM) in a final DMSO concentration of 0.1%. Medium+DMSO (0.1%) was used as baseline value. As positive controls cells incubated with the 4× SIINFEKL concentration (0.2 ng/ml) and a DGKζ reference inhibitor were used. The plates were centrifuged to reduce the distance between T-cells and APCs before incubation. After 24 h the medium was collected and mIL-2 or mIFN-γ ELISAs were performed. The following parameters were calculated: EC.sub.50 value, concentration at 50% increase; max increase in % and respective concentration and maximum effect normalized to max concentration (10 μM) of a selected DGKζ reference inhibitor.

DGKζ Surface Plasmon Resonance Interaction Assay

[1602] The ability of the compounds described in this invention to bind to DGKζ were determined using surface plasmon resonance (SPR). This allows for the quantification of binding in terms of the equilibrium dissociation constant (K[M]), as well as association and dissociation rate constants (k.sub.on [1/Ms] and k.sub.of [1/s], respectively). The measurements were performed using Biacore® T200 , Biacore® S200 or Biacore® 8K (GE Healthcare).

[1603] All buffers described in this section were prepared with 10×HBS-P+ Buffer (GE Healthcare, #BR.sup.100671) supplemented with additional buffer components as indicated below, dithiothreitol (DTT from Sigma, #D0632-25G), Adenosine 5′-triphosphate (ATP from Sigma, #A26209-10G), MgCl.sub.2 (Sigma, #M1028-100ML), dimethyl sulfoxide (DMSO from Biomol, #54686.500).

[1604] For SPR measurements, recombinant and biotinylated human DGKζ (obtained from Carna Biosciences, Product number: 12-410-20N) was immobilized via the streptavidin-biotin interaction onto a Series S Sensor Chip SA (GE Healthcare, #BR-1005-31). Briefly, DGKζ was diluted to a concentration of 10 μg/mL in Immobilization Buffer (10 mM HEPES, 150 mM NaCl, 0.05% vv Surfactant P20, 2 mM MgCl.sub.2, 1 mM DTT, pH 7.4) and captured on the SA Chip surface using a flow rate of 10 μL/min for 500 seconds at a temperature of 10° C. Immobilization levels of approximately 6000 RU were typically achieved. The reference surface consisted of a streptavidin surface without immobilized protein. Compounds were diluted from 10 mM DMSO stock solution into Running Buffer (10 mM HEPES, 150 mM NaCl, 0.05% vv Surfactant P20, 2 mM MgCl.sub.2, 1 mM DTT, 0.2 mM ATP and 1% vv DMSO, pH 7.4). For SPR-binding measurements serial dilutions (typically 1:3 dilutions resulting in 8 concentrations up to 2 μM or 20 μM) were injected over immobilized protein. Binding affinity and kinetics were measured at 18° C. and at a flow rate of 100 μL/min.

[1605] A variation of the assay with an additional regeneration step was performed by injection of Regeneration Buffer without ATP (10 mM HEPES, 150 mM NaCl, 0.05% vv Surfactant P20, 1 mM DTT and 1% vv DMSO, pH 7.4) for 200 s at a flow rate of 30 μL/min

[1606] The double-referenced sensorgrams were fit to a simple reversible Langmuir 1:1 reaction mechanism as implemented in the Biacore® T200, S200 and 8K evaluation software (Biacore T200 Evaluation Software version 2.0, Biacore S200 Evaluation Software version 1.0, Biacore 8K Evaluation Software, GE Healthcare).

Expression of DGKζ in Insect Cells using the Baculovirus System

Expression Constructs:

[1607] The cDNA encoding the full length sequence of human DGKζ (Uniprot Q13574-2) was optimized for expression in eukaryotic cells and synthesized by the GeneArt Technology at Life Technologies.

[1608] The DNA sequence encoded the following sequence:

[1609] Construct DGKζ_hu amino acid M1 to V928

[1610] Additionally the expression construct encoded: a Kozak DNA sequence for translation initiation (GCCACC), a translational start codon for methionine followed by amino acid glycine, a Flag (DYKDDDDK) sequence at the N-terminus of DGKζ, and at the C-terminus of DGKζ two stop codons and moreover 5′ and 3′ att-DNA sequences for Gateway Cloning. The DGKζ c construct was subcloned using the Gateway Technology into the Destination vector pD-INS. The vector pD-INS is a Baculovirus transfer vector (based on vector pVL1393, Pharmingen) which enables the expression of the Flag-DGKζ protein. The respective protein was named DGKz_hu_1.

[1611] Generation of recombinant Baculovirus

[1612] The DGkζ transfer vector was co-transfected in Sf9 cells with Baculovirus DNA (Flashbac Gold DNA, Oxford Expression Technologies) using Fugene HD (Roche). After 5 days the supernatant of the transfected cells containing the recombinant Baculovirus encoding the various DGK proteins was used for further infection of Sf9 cells for virus amplification whereby the virus titer was monitored using qPCR.

[1613] DGKζ expression in Sf9 cells using bioreactor

[1614] Sf9 cells cultured (Insect-xpress medium, Lonza, 27° C.) in a Wave-bioreactor with a disposable culture bag were infected at a cell density of 10.sup.6 cellsmL with one of the recombinant baculovirus stocks at a multiplicity of infection of 1 and incubated for 72. Subsequently, the cells were harvested by centrifugation (800×g) and the cell pellet frozen at −80° C.

[1615] Purification of the DGKz_hu_1 protein:

[1616] Purification of the DGKz_hu_1 protein was achieved by a two-step chromatography procedure as follows.

[1617] The pelleted cells (from 8 L cell culture) were resuspended in Lysis-Buffer (25 mM Tris HCl 8.0; 500 mM NaCl; 250 mM Sucrose, 1 mM DTT; 0.1% Triton X-100; Complete Protease Inhibitor Cocktail-(Roche)) and lysed by a freeze-thaw cycle followed by an incubation on ice for 60 min in the presence of Benzonase (25 U/mL). The lysate was centrifuged at 63.000×g for 30 min at 4° C. The soluble supernatant was than incubated with 40 mL anti-Flag M2 Agarose (Sigma) in a plastic flask rotating for 16 h at 4° C. for binding of the tagged DGKζ proteins, subsequently rinsed with 5×50 mL Wash-Buffer (25 mM Tris HCl 8.0; 500 mM NaCl; 250 mM Sucrose; 1 mM DTT) and finally the bound protein was eluted using Elution-Buffer (Wash-Buffer with 250 μg/mL FLAG-Peptide, incubated 30 min. at 4° C. with 3×25 mL).

[1618] The elution fractions from the affinity chromatography were concentrated (using Amicon Ultra 15, Centrifugal Filters, 30 kDa MW cut-off; Millipore #UFC903024) to 25 mL and applied to a size exclusion chromatography column (S200 prep grade 2660, GE Healthcare) and the resulting monomeric peak fraction was collected, pooled and again concentrated. Wash-buffer with 300 mM NaCl was used for size exclusion chromatography and the final concentrated sample. The final protein sample concentration was 5 to 10 mg/mL and the yield was 5 mg final protein per L cell culture.

[1619] The in vivo activity of the compounds of the present invention can be demonstrated in the following assays:

[1620] In vivo activation of murine antigen specific OT-I T cells

[1621] Oral Administration of compounds enhances antigen-specific T cell activation in vivo.

[1622] Direct detection of antigen-specific T cell proliferation in vivo is technically challenging, since it requires the presence of T cells specific for a cognate antigen and also a specific measurement procedure for cell proliferation. Both these requirements are fulfilled in the OT-I transfer model, which utilizes the direct transfer of CD8 T cells transgenic for a T cell receptor recognizing an Ovalbumin-derived peptide as antigen.

[1623] Before transfer, the OT-I T cells were labeled with the fluorescent dye CFSE, which was diluted by every cell division and therefore allowed detection of cell proliferation. After transfer of the CFSE-labeled T cells, mice were vaccinated with the Ovalbumin antigen OVA-30 (FIG. 3). Only transferred OT-I cells were able to recognize the OVA-antigen presented by APC and only these transferred T cells then got activated. Flow cytometric analysis of CFSE-levels in the OT-I cells can be combined with measurement of multiple activation markers like CD69, CD25 and PD1. In particular, Wild type C57B16 mice received 2×10×6 CFSE-labeled OT-I T cells and were vaccinated one day later by intravenous application of 2.5 μg OVA-30. Mice were then divided into groups which received vehicle only, DGKζ inhibitors of the present invention alone or in combination with other immune modulating agents. Mice were treated for 2 to 20 days and T cell composition (incl. transferred OT-1 cells) of spleen, blood and lymph nodes were analysed by FACS.

In Vivo Syngeneic Tumor Models

[1624] Mice were assigned to a study at the age of 6-8 weeks. Animal husbandry, feeding and health conditions were according to animal welfare guidelines. Syngeneic tumor cell lines were cultivated with appropriate medium and split at least 3 times before inoculation. Female mice were inoculated with appropriate amount of tumor cells in medium or a medium matrigel mixture s.c, i.v., or i.p, depending on the model. After 4-10 days the mice were randomized and therapeutic treatment started when tumors had reached a size of approx. 40-70mm.sup.2. Tumor size was measured using calipers determining length (a) and width (b). Tumor volume was calculated according to:

v=(a×b{circumflex over ( )}2)/2

[1625] Significance of monotherapies and combination treatment was calculated versus control group as determined by 2-Way ANOVA analysis.