NOVEL HETEROARYL-TRIAZOLE COMPOUNDS AS PESTICIDES

Abstract

The present invention relates to novel heteroaryl-triazole compounds of the general formula (I), in which the structural elements X, Y, R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4 and R.sup.5 have the meaning given in the description, to formulations and compositions comprising such compounds and for their use in the control of animal pests including arthropods and insects in plant protection and to their use for control of ectoparasites on animals.

##STR00001##

Claims

1. A compound of formula (I) ##STR00290## in which X is O or S; Y is a direct bond or optionally substituted CH.sub.2; R.sup.1 is hydrogen; C.sub.1-C.sub.6alkyl optionally substituted with one substituent selected from —CN, —CONH.sub.2, —COOH, —NO.sub.2 and —Si(CH.sub.3).sub.3; C.sub.1-C.sub.6haloalkyl; C.sub.2-C.sub.6alkenyl; C.sub.2-C.sub.6haloalkenyl; C.sub.2-C.sub.6alkynyl; C.sub.2-C.sub.6haloalkynyl; C.sub.3-C.sub.4cycloalkyl-C.sub.1-C.sub.2alkyl-wherein the C.sub.3-C.sub.4cycloalkyl is optionally substituted with one or two halogen atoms; oxetan-3-yl-CH.sub.2— or benzyl optionally substituted with halogen atoms or C.sub.1-C.sub.3haloalkyl; R.sup.2 is phenyl, pyridine, pyrimidine, pyrazine or pyridazine, wherein the phenyl, pyridine, pyrimidine, pyrazine or pyridazine is substituted with a total of one to three substituents, provided the substituent(s) are not on either carbon adjacent to the carbon bonded to the C═X-group and at least one and up to two substituent(s) are independently selected from a group consisting of C.sub.3-C.sub.6cycloalkoxy, optionally substituted with one to two substituents selected from the group consisting of halogen, ═O (oxo), —CN, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or C.sub.1-C.sub.6alkyl substituted with one to two substituents selected from the group consisting of —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or C.sub.1-C.sub.6alkylcarbonyl and C.sub.3-C.sub.6cycloalkylcarbonyl, wherein C.sub.1-C.sub.6alkylcarbonyl and C.sub.3-C.sub.6cycloalkylcarbonyl are optionally substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or C.sub.1-C.sub.6alkoxy substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or C.sub.1-C.sub.6haloalkyl substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or C.sub.1-C.sub.6haloalkoxy substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or C.sub.2-C.sub.6alkenyloxy substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or C.sub.1-C.sub.6alkylSO.sub.2O— substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or phenyl-C.sub.1-C.sub.3haloalkyl and phenyl-C.sub.1-C.sub.3alkoxy, wherein the phenyl is optionally substituted by one to three substituents independently selected from the group consisting of halogen, —CN, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, or heterocyclyloxy and heterocyclyl-C.sub.1-C.sub.3alkoxy, wherein the heterocyclyl is selected from the group consisting of saturated and partially unsaturated 4- to 6-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, each of which optionally substituted by one to three substituents independently selected from the group consisting of halogen, —CN, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, C.sub.3-C.sub.6cycloalkylkylthio, C.sub.3-C.sub.6cycloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfonyl, and the other optional substituent is selected from a group consisting of hydrogen, halogen, hydroxy, —NH.sub.2, —CN, —NO.sub.2, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, C.sub.1-C.sub.3haloalkylthio, C.sub.1-C.sub.3haloalkylsulfinyl and C.sub.1-C.sub.3haloalkylsulfonyl; R.sup.3a, R.sup.3b are independently selected from the group consisting of hydrogen, halogen and —CN; and C.sub.1-C.sub.6alkyl optionally substituted by one to three substituents independently selected from the group consisting of halogen, hydroxy, —CN, —COOH, —CONH.sub.2, —NO.sub.2, —NH.sub.2, in each case optionally substituted C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, —NH(C.sub.1-C.sub.6alkyl), —N(C.sub.1-C.sub.6alkyl).sub.2, —NHCO—C.sub.1-C.sub.6alkyl, —N(C.sub.1-C.sub.6alkyl)CO—C.sub.1-C.sub.6alkyl, —CO.sub.2C.sub.1-C.sub.6alkyl, —CONH(C.sub.1-C.sub.6alkyl), and —CON(C.sub.1-C.sub.6alkyl).sub.2; and in each case optionally substituted C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl; and benzyl wherein the phenyl substituent is optionally substituted with one to five substituents, each independently selected from the group consisting of halogen, hydroxy, —CN, —COOH, —CONH.sub.2, —NO.sub.2, —NH.sub.2, —SF.sub.5 and in each case optionally substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, and C.sub.1-C.sub.6alkylsulfonyl; and heterocyclyl-C.sub.1-C.sub.6alkyl wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered saturated and partially unsaturated heterocyclyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted by one to three substituents independently selected from the group consisting of halogen, ═O (oxo), hydroxy, —CN, —COOH, —CONH.sub.2, —NO.sub.2, —NH.sub.2 and in each case optionally substituted C.sub.1-C.sub.6alkyl, and C.sub.1-C.sub.6alkoxy; or R.sup.3a, R.sup.3b form together with the carbon to which they are connected a C.sub.3-C.sub.6-carbocyclic or 3- to 6-membered heterocyclic ring system, optionally substituted with one to two substituents, each independently selected from the group consisting of halogen, —CN, in each case optionally substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy and C.sub.1-C.sub.6haloalkoxy; R.sup.4 is selected from one of the following substructures T1 to T6, in which the bond to the triazole is marked with a #: ##STR00291## wherein X.sup.1 is the following substructure S4-a, in which the bond to the pyridine, pyrimidine, pyrazine or thiazole is marked with a # ##STR00292## R.sup.41 is hydrogen or in each case optionally substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6cycloalkyl, —C.sub.1-C.sub.6alkyl-C.sub.3-C.sub.6cycloalkyl and phenyl, R.sup.42 is hydrogen or in each case optionally substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl and C.sub.3-C.sub.6cycloalkyl; X.sup.2 is —CN or X.sup.1; R.sup.5 is selected from the group of hydrogen, halogen; and in each case optionally substituted C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, (C.sub.1-C.sub.6alkoxy).sub.2CH—, —CO.sub.2C.sub.1-C.sub.6alkyl, —C(═NOC.sub.1-C.sub.6alkyl)H, —C(═NOC.sub.1-C.sub.6alkyl)-C.sub.1-C.sub.6alkyl.

2. The compound according to claim 1, in which X is O or S; Y is a direct bond or CH.sub.2; R.sup.1 is hydrogen; C.sub.1-C.sub.3alkyl optionally substituted with one substituent selected from —CN, —CONH.sub.2, —COOH, —NO.sub.2 and —Si(CH.sub.3).sub.3; C.sub.1-C.sub.3haloalkyl; C.sub.2-C.sub.4alkenyl; C.sub.2-C.sub.4haloalkenyl; C.sub.2-C.sub.4alkynyl; C.sub.2-C.sub.4haloalkynyl; C.sub.3-C.sub.4cycloalkyl-C.sub.1-C.sub.2alkyl-wherein the C.sub.3-C.sub.4cycloalkyl is optionally substituted with one or two halogen atoms; oxetan-3-yl-CH.sub.2—; or benzyl optionally substituted with halogen atoms or C.sub.1-C.sub.3haloalkyl; R.sup.2 is phenyl, pyridine, pyrimidine, pyrazine or pyridazine, wherein the phenyl, pyridine, pyrimidine, pyrazine or pyridazine is substituted with a total of one to three substituents, provided the substituent(s) are not on either carbon adjacent to the carbon bonded to the C═X-group and at least one and up to two substituent(s) are independently selected from a group consisting of C.sub.3-C.sub.6cycloalkoxy, optionally substituted with one to two substituents selected from the group consisting of halogen, ═O (oxo), —CN, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3alkyl substituted with one to two substituents selected from the group consisting of —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3alkylcarbonyl and C.sub.3-C.sub.6cycloalkylcarbonyl, wherein C.sub.1-C.sub.3alkylcarbonyl and C.sub.3-C.sub.6cycloalkylcarbonyl are optionally substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3alkoxy substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3 haloalkyl substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3haloalkoxy substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.2-C.sub.4alkenyloxy substituted with one to two substituents selected from the group consisting of halogen, —CN, and C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3alkylSO.sub.2O— substituted with one to two substituents selected from the group consisting of halogen, —CN, and C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or phenyl-C.sub.1-C.sub.3haloalkyl and phenyl-C.sub.1-C.sub.3alkoxy, wherein the phenyl is optionally substituted by one to three substituents independently selected from the group consisting of halogen, —CN, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or heterocyclyloxy and heterocyclyl-C.sub.1-C.sub.3alkoxy, wherein the heterocyclyl is selected from the group consisting of saturated and partially unsaturated 4- to 6-membered heterocyclyl, 5-membered heteroaryl, 6-membered heteroaryl, each of which optionally substituted by one to three substituents independently selected from the group consisting of halogen, —CN, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, and the other optional substituent is selected from a group consisting of hydrogen, halogen, hydroxy, —NH.sub.2, —CN, —NO.sub.2, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, C.sub.1-C.sub.3haloalkylthio, C.sub.1-C.sub.3haloalkylsulfinyl and C.sub.1-C.sub.3haloalkylsulfonyl; R.sup.3a, R.sup.3b are independently selected from the group consisting of hydrogen, halogen, and —CN; and C.sub.1-C.sub.4alkyl optionally substituted by one to three substituents independently selected from the group consisting of hydroxy, halogen —CN, —COOH, —CONH.sub.2, —NO.sub.2, —NH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, C.sub.1-C.sub.4alkylthio, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, C.sub.1-C.sub.4haloalkylthio, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl; and C.sub.3-C.sub.6cycloalkyl optionally substituted with one to two substituents selected from the group consisting of halogen, —CN, —COOH, —CONH.sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy; and C.sub.1-C.sub.4haloalkyl optionally substituted with one to two substituents selected from the group consisting of hydroxy, —CN, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy; R.sup.4 is selected from one of the following substructures T1 to T6, in which the bond to the triazole is marked with a #: ##STR00293## wherein X.sup.1 is the following substructure S4-a, in which the bond to the pyridine, pyrimidine, pyrazine or thiazole is marked with a # ##STR00294## R.sup.41 is hydrogen or in each case optionally substituted C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkyl-C.sub.3-C.sub.6cycloalkyl and phenyl; R.sup.42 is hydrogen and in each case optionally substituted C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl and C.sub.3-C.sub.6cycloalkyl; X.sup.2 is —CN or X.sup.1; R.sup.5 is selected from the group of hydrogen, halogen; and C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkoxy, (C.sub.1-C.sub.4alkoxy).sub.2CH—, —CO.sub.2C.sub.1-C.sub.4alkyl, —C(═NOC.sub.1-C.sub.4alkyl)H, —C(═NOC.sub.1-C.sub.4alkyl)-C.sub.1-C.sub.4alkyl.

3. The compound according to claim 1, in which X is O or S; Y is a direct bond; R.sup.1 is hydrogen; C.sub.1-C.sub.3alkyl optionally substituted with one substituent selected from —CN, —NO.sub.2 and —Si(CH.sub.3).sub.3; C.sub.3-C.sub.4cycloalkyl-C.sub.1-C.sub.2alkyl-wherein the C.sub.3-C.sub.4cycloalkyl is optionally substituted with one or two halogen atoms; or benzyl optionally substituted with halogen atoms or C.sub.1-C.sub.3haloalkyl; R.sup.2 is phenyl or pyridine, substituted with one to two substituents, provided the substituent(s) are not on either carbon adjacent to the carbon bonded to the C═X group and at least one and up to two substituent(s) are independently selected from a group consisting of C.sub.3-C.sub.6cycloalkoxy, optionally substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkyl substituted with one to two substituents selected from the group consisting of —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3alkylcarbonyl and C.sub.3-C.sub.4cycloalkylcarbonyl, optionally substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, or C.sub.1-C.sub.3alkoxy substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3haloalkyl substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3haloalkoxy substituted with one to two substituents selected from the group consisting of ═O (oxo), —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.2-C.sub.4alkenyloxy substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or C.sub.1-C.sub.3alkylSO.sub.2O— substituted with one to two substituents selected from the group consisting of halogen, —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.3-C.sub.4halocycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, or phenyl-C.sub.1-C.sub.3haloalkyl and phenyl-C.sub.1-C.sub.3alkoxy, wherein the phenyl is optionally substituted by one to three substituents independently selected from the group consisting of halogen, —CN, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, or heterocyclyloxy and heterocyclyl-C.sub.1-C.sub.3alkoxy, wherein the heterocyclyl is selected from the group consisting of a saturated 4- to 6-membered heterocyclyl containing one oxygen atom, and the heterocyclyl phenyl is optionally substituted by one to three substituents independently selected from the group consisting of halogen, —CN, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, and the other optional substituent is selected from a group consisting of hydrogen, halogen, hydroxy, —NH.sub.2, —CN, —NO.sub.2, C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkylthio, C.sub.1-C.sub.3alkylsulfinyl, C.sub.1-C.sub.3alkylsulfonyl, C.sub.3-C.sub.4cycloalkylkylthio, C.sub.3-C.sub.4cycloalkylsulfinyl, C.sub.3-C.sub.4cycloalkylsulfonyl, C.sub.1-C.sub.3haloalkylthio, C.sub.1-C.sub.3haloalkylsulfinyl and C.sub.1-C.sub.3haloalkylsulfonyl; R.sup.3a, R.sup.3b are independently selected from the group consisting of hydrogen; C.sub.1-C.sub.3alkyl optionally substituted by one to three substituents independently selected from the group consisting of halogen, —CN, C.sub.3-C.sub.4cycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl; R.sup.4 is selected from one of the following substructures T1 to T6, in which the bond to the triazole is marked with a #: ##STR00295## wherein X.sup.1 is the following substructure S4-a, in which the bond to the pyridine, pyrimidine, pyrazine or thiazole is marked with a # ##STR00296## R.sup.41 is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3cyanoalkyl, C.sub.1-C.sub.3haloalkyl and C.sub.3-C.sub.4cycloalkyl; R.sup.42 is hydrogen, C.sub.1-C.sub.3alkyl and C.sub.1-C.sub.3haloalkyl; X.sup.2 is —CN or X.sup.1; R.sup.5 is hydrogen, halogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.3-C.sub.4cycloalkyl, or C.sub.1-C.sub.3alkoxy.

4. The compound according to claim 1, in which X is O; Y is a direct bond; R.sup.1 is hydrogen; R.sup.2 is selected from the following substructure(s) Q1 and Q2, wherein the bond to the C═X-group is marked with a #: ##STR00297## wherein R.sup.21 is cyclopropyloxy, (2,2-dichlorocyclopropyl)oxy, cyanomethyl, 2-cyanopropan-2-yl, cyclopropyl(difluoromethyl), cyclopropylcarbonyl, 2-cyanopropan-2-yloxy, cyclopropylmethoxy, (2,2-difluorocyclopropyl)methoxy, (2,2-dichlorocyclopropyl)methoxy, (3,3-dichloroprop-2-en-1-yl)oxy, (2,3,3-trichloroprop-2-en-1-yl)oxy, difluoro-(4-fluorophenyl)methyl, R.sup.22 is hydrogen, fluorine, chlorine, bromine, iodine, cyclopropyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, difluoromethylsulfonyl or trifluoromethylsulfonyl; R.sup.3a is hydrogen; R.sup.3b is hydrogen or methyl; R.sup.4 is selected from one of the following substructures T1 to T6, in which the bond to the triazole is marked with a #: ##STR00298## wherein X.sup.1 is the following substructure S4-a, in which the bond to the pyridine, pyrimidine, pyrazine or thiazole is marked with a # ##STR00299## R.sup.41 is hydrogen, methyl, ethyl or cyclopropyl; R.sup.42 is hydrogen, methyl or ethyl X.sup.2 is —CN or X.sup.1; R.sup.5 is hydrogen, methyl, ethyl or cyclopropyl.

5. The Compound according to claim 1, wherein X is O; Y is a direct bond; R.sup.1 is hydrogen; R.sup.2 is 3-bromo-5-(cyclopropoxy)phenyl, 3-cyclopropyloxy-5-(trifluoromethoxy)phenyl, 3-bromo-5-(2,2-dichlorocyclopropyl)oxyphenyl, 3-chloro-5-(cyanomethyl)phenyl, 3-(cyanomethyl)-5-(trifluoromethoxy)phenyl, 3-chloro-5-(2-cyanopropan-2-yl)phenyl, 3-(2-cyanopropan-2-yl)-5-(trifluoromethyl)phenyl, 3-(2-cyanopropan-2-yl)-5-(trifluoromethoxy)phenyl, 3-(2-cyanopropan-2-yl)-5-methylsulfonylphenyl, 3-chloro-5-(cyclopropylcarbonyl)phenyl, 3-chloro-5-(2-cyanopropan-2-yloxy)phenyl, 3-bromo-5-(2-cyanopropan-2-yloxy)phenyl, 3-bromo-5-[cyclopropyl(difluoro)methyl]phenyl, 3-(2-cyanopropan-2-yloxy)-5-cyclopropylphenyl, 3-bromo-5-[(2,2-difluorocyclopropyl)methoxy]phenyl, 3-bromo-5-[(2,2-dichlorocyclopropyl)methoxy]phenyl, 3-[(2,2-dichlorocyclopropyl)methoxy]-5-(trifluoromethyl)phenyl, 3-[(2,3,3-trichloroprop-2-en-1-yl)oxy]-5-(trifluoromethyl)phenyl, 3-bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]phenyl, 3-bromo-5-[difluoro-(4-fluorophenyl)methyl]phenyl, or 2-chloro-6-(2-cyanopropan-2-yl)pyridin-4-yl; R.sup.3a is hydrogen; R.sup.3b is methyl; R.sup.4 is 5-[[ethyl(methyl)amino]carbonyl]pyridin-2-yl, 5-cyanopyrazin-2-yl, 6-cyanopyrimidin-4-yl, 6-(aminocarbonyl)pyrimidin-4-yl, 6-(methylaminocarbonyl)pyrimidin-4-yl, 5-cyano-1,3-thiazol-2-yl, 5-(methylcarbamoyl)-1,3-thiazol-2-yl, or 5-(dimethylaminocarbonyl)-1,3-thiazol-2-yl; R.sup.5 is hydrogen, methyl, or cyclopropyl.

6. The compound according to claim 1 comprising, a structure according to formula (I″) ##STR00300## in which R.sup.3b is C.sub.1-C.sub.3alkyl, optionally Me, and R.sup.3a is H, and in which the structural elements R.sup.1, R.sup.2, R.sup.4, R.sup.5 and Y have the meanings given in Configuration (1-3) or the meanings given in Configuration (2-3) or the meanings given in Configuration (3-3) or the meanings given in Configuration (4-3) or the meanings given in Configuration (5-3).

7. The compound according to claim 1, comprising, a structure according to formula (I′″) ##STR00301## in which R.sup.3b is C.sub.1-C.sub.3alkyl, optionally Me, and R.sup.3a is H, and in which the structural elements R.sup.1, R.sup.2, R.sup.4, R.sup.5 and Y have the meanings given in Configuration (1-3) or the meanings given in Configuration (2-3) or the meanings given in Configuration (3-3) or the meanings given in Configuration (4-3) or the meanings given in Configuration (5-3).

8. A compound comprising 3-chloro-5-(2-cyanopropan-2-yl)benzoic acid, 3-chloro-5-(cyclopropylcarbonyl)benzoic acid, 3-[(methylsulfinyl)methoxy]-5-(trifluoromethyl)benzoic acid, 3-(cyanomethyl)-5-(trifluoromethoxy)benzoic acid, sodium, 3-(2-cyanopropan-2-yl)-5-(trifluoromethoxy)benzoic acid, 3-bromo-5-(2,2-dichlorovinyl)benzoic acid, 3-bromo-5-[difluoro(4-fluorophenyl)methyl]benzoic acid, 3-chloro-5-[(methylsulfonyl)methyl]benzoic acid, 3-(cyclopropoxy)-5-(trifluoromethoxy)benzoic acid, 3-bromo-5-(1-cyano-1-methyl-ethoxy)benzoic acid, 3-chloro-5-(1-cyano-1-methyl-ethoxy)benzoic acid, 5-[5-[(1S)-1-aminoethyl]-1,2,4-triazol-1-yl]pyrazine-2-carbonitrile hydrochloride, 6-[5-[(1S)-1-aminoethyl]-3-cyclopropyl-1,2,4-triazol-1-yl]pyrimidine-4-carbonitrile hydrochloride, 6-[5-[(1S)-1-aminoethyl]-3-cyclopropyl-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide hydrochloride, 3-chloro-6-(1-cyano-1-methyl-ethyl)pyridine-4-carboxylic acid, 6-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N-ethyl-N-methylnicotinamide hydrochloride, 3-(cyanomethyl)-5-(methylsulfonyl)benzoic acid, 3-(2-cyanopropan-2-yl)-5-(methylsulfonyl)benzoic acid, and/or 3-(1-cyano-1-methyl-ethoxy)-5-cyclopropyl-benzoic acid and/or a salt thereof.

9. A formulation, optionally an agrochemical formulation, comprising at least one compound of the formula (I) according to claim 1.

10. The formulation according to claim 9 further comprising at least one extender and/or at least one surface-active substance.

11. The formulation according to claim 9, wherein, the compound of the formula (I) is in a mixture with at least one further active compound.

12. A method for controlling one or more pests, optionally animal pests, said method comprising allowing a compound of the formula (I) according to claim 1 or a formulation thereof to act on the pests and/or a habitat thereof.

13. The method according to claim 12, wherein the pest is an animal pest and comprises an insect or an arachnid, or the pest is an insect or an arachnid.

14. A product comprising a compound of the formula (I) according to claim 1 or of a formulation thereof for controlling one or more animal pests.

15. The product according to claim 14, wherein the animal pest comprises an insect or an arachnid, or the animal pest is an insect or an arachnid.

16. The product according to claim 14 adapted for crop protection.

17. The product according to claim 14 adapted for a field of animal health.

18. A method for protecting seed or a germinating plant from one or more pests, optionally animal pests, comprising contacting the seed with a compound of formula (I) according to claim 1 or a formulation thereof.

19. A seed obtained by a method according to claim 18.

Description

DESCRIPTION OF THE PROCESSES AND INTERMEDIATES

[0971] Compounds of formula I′ may be prepared as illustrated in the following scheme 1 where R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5 and Y are as previously defined and X.sup.1 stands for OH or Cl.

##STR00034##

[0972] X.sup.1═OH: A triazole compound of formula (1) is reacted with a carboxylic acid of formula (2a) (X.sup.1═OH) to form compounds of formula (I′). For example, a mixture of a triazole of formula (1), a carboxylic acid of formula (2a) (X.sup.1═OH), a suitable coupling reagent, such as T3P®, HATU or DCC/HOBt, a suitable base such as triethylamine or DIPEA, in a suitable solvent, such as ethyl acetate or DMF are mixed at temperatures ranging from around 0 to 100° C. to provide compounds of formula (I′) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[0973] X.sup.1═Cl: A triazole compound of formula (1) is reacted with a carboxylic acid chloride of formula (2b) (X.sup.1═Cl) to form compounds of formula (I′). For example, a mixture of a triazole of formula (1), a carboxylic acid chloride of formula (2b) (X.sup.1═Cl), a suitable base such as triethylamine or DIPEA, in a suitable solvent, such as dichloromethane or THF are mixed at temperatures ranging from around 0 to 100° C. to provide compounds of formula (I′) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[0974] Carboxylic acids of formula (2a) (X.sup.1═OH) and carboxylic acid chlorides of formula (2b) (X.sup.1═Cl) are commercially available or may be synthesized by or in analogy to literature reported syntheses (see, e.g. WO2020/002563) or by methods known to a person skilled in the state of the art.

[0975] For example

[0976] 3-Chloro-5-[(methylsulfonyl)methyl]benzoic acid: Prepareded by saponification of methyl 3-chloro-5-[(methylsulfonyl)methyl]benzoate, the latter is yielded from methyl 3-(bromomethyl)-5-chlorobenzoate (see U.S. Pat. No. 5,254,584 or by NBS-bromination of methyl 3-chloro-5-methylbenzoate in analogy to CN104387332) by reaction with sodium methylsulfinate in analogy to US2012/10205.

[0977] The preparation of methyl 3-chloro-5-methylbenzoate is described in U.S. Pat. No. 5,254,584.

[0978] 3-[(2,3,3-Trichloroprop-2-en-1-yl)oxy]-5-(trifluoromethyl)benzoic acid: From commercially available 3-hydroxy-5-(trifluoromethyl)benzoic acid and 1,1,1,2,3-pentachloropropane. The reaction (potassium carbonate, DMSO, 45° C.) yields 2,3,3-trichloroprop-2-en-1-yl 3-[(2,3,3-trichloroprop-2-en-1-yl)oxy]-5-(trifluoromethyl)benzoate which is then saponified to the acid.

[0979] 3-Bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzoic acid is prepared analogously starting from commercially available 3-bromo-5-hydroxybenzoic acid.

[0980] 3-[(3,3-Dichloroprop-2-en-1-yl)oxy]-5-(trifluoromethyl)benzoic acid is prepared analogously starting from 3-hydroxy-5-(trifluoromethyl)benzoic acid and 1,1,1,3-tetrachloropropane.

[0981] 3-[(2,2-Dichlorocyclopropyl)methoxy]-5-(trifluoromethyl)benzoic acid: Prepared analogously starting from commercially available 3-hydroxy-5-(trifluoromethyl)benzoic acid and 2-(bromomethyl)-1,1-dichlorocyclopropane, the latter is known e.g. from DE2804739.

[0982] 3-Bromo-5-[(2,2-difluorocyclopropyl)methoxy]benzoic acid: Prepared analogously starting from commercially available 3-bromo-5-hydroxybenzoic acid and commercially available 2-(bromomethyl)-1,1-difluorocyclopropane.

[0983] 3-Bromo-5[(2,2-dichlorocyclopropyl)methoxy]benzoic acid: Prepared starting from allyl 3-(allyloxy)-5-bromobenzoate (synthesis described in Angewandte Chemie-International Edition, 2012, vol. 51, #52, p. 13036-13040) followed by dichlorocarbene addition, e.g. in analogy to a procedure described in Russian Journal of General Chemistry, 2001, vol. 71, #4, p. 542-545, followed by hydrolysis of the remaining ester.

[0984] 3-Bromo-5[(2,2-dichlorocyclopropyl)oxy]benzoic acid: Prepared starting from methyl 3-bromo-5-hydroxybenzoate (synthesis described in WO2015/66515, 2015, A1). Conversion to methyl 3-bromo-5-(2-hydroxyethoxy)benzoate is performed in analogy to the procedure described in US2016/244460 A1. The following chlorination with thionyl chloride in the presence of DMF is performed in analogy to the procedure described WO2004/16611, A1. Elimination to yield the vinyloxy ether is performed in analogy to the procedure described in WO2006/77364 A1, the conditions of the conversion simultaneously lead to hydrolysis of the ester function. The following addition of dichlorocarbene is performed in analogy to to a procedure described in Russian Journal of General Chemistry, 2001, vol. 71, #4, p. 542-545 and succeeds in the presence of an alcohol as EtOH. The conditions of the conversion simultaneously lead to esterification of the carboxylic acid function. To yield the acid, the ester function is hydrolysed.

[0985] 3-[(Methylsulfinyl)methoxy]-5-(trifluoromethyl)benzoic acid: Prepared (potassium carbonate, DMSO, a similar conversion is described in CN106083539) from commercially available 3-hydroxy-5-(trifluoromethyl)benzoic acid and chloro(methylsulfinyl)methane, the latter is known from CN106083539.

[0986] The requisite triazole compounds of formula (1) may be prepared as illustrated in the following scheme 2, where R.sup.1, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5 and Y are as previously described and LG is a suitable leaving group such as bromine, chlorine or —OSO.sub.2Me (see also WO 2017192385).

##STR00035##

[0987] An amine of formula (4) is reacted with a substituted azole of formula (3) to form compounds of formula (1b). For example, a mixture of an azole of formula (3), an amine of formula (4), a suitable base, such as K.sub.2CO.sub.3, NaH or DIPEA in a suitable solvent, such as acetonitrile or DMF are mixed at temperatures ranging from around 20 to 120° C. to provide compounds of formula (1b) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[0988] Alternatively, a substituted azole of formula (3) is reacted with ammonia (5) to form compounds of formula (1a). For example, a solution of ammonia (5) in a suitable solvent, such as methanol, and a substituted azole of formula (3) are mixed in a sealed tube at temperatures ranging from around 0 to 25° C. to provide compounds of formula (1a) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as trituration.

[0989] A substituted azole of formula (1a), a compound of formula (6), a suitable base, such as K.sub.2CO.sub.3 or DIPEA in a suitable solvent, such as acetonitrile or DMF are then mixed at temperatures ranging from around 20 to 120° C. to provide compounds of formula (1b) which may then be isolated and, if necessary and desired, purified using techniques well known in the art such as chromatography.

[0990] Amines of formula (4) and compounds of formula (6) are commercially available or may be synthesized by methods known to a person skilled in the state of the art.

[0991] The requisite triazole compounds of formula (3) may be prepared as illustrated in the following scheme 3, where R.sup.3a, R.sup.3b, R.sup.4, and Y are as previously described, LG is a suitable leaving group such as bromine, chlorine or —OSO.sub.2Me and R.sup.5 is hydrogen or C.sub.1-C.sub.3alkyl (see also WO 2017192385).

##STR00036##

[0992] An amide of formula (7) is reacted with an N,N-dimethylamide dimethyl acetal (8) to form compounds of formula (9) which are subsequently reacted with hydrazines (10) or their corresponding salts, e.g. hydrochloride salts, under acidic conditions to form compounds of formula (3). For example, a compound of formula (7) and an N,N-dimethylamide dimethyl acetal of formula (8) are reacted in a suitable solvent, such as CH.sub.2Cl.sub.2 at reflux to provide compounds of formula (9). Upon removal of the solvent, compounds of formula (9) are reacted with a substituted hydrazine (10) in a suitable solvent such as 1,4-dioxane, acetic acid or a mixture of such solvents at temperatures ranging from around 20 to 100° C. to provide compounds of formula (3) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[0993] N,N-dimethylamide acetals of formula (8), amides of formula (7) and hydrazines of formula (10) or their corresponding salts, e.g. hydrochloride salts, are commercially available or may be synthesized by methods known to a person skilled in the state of the art.

[0994] For example

[0995] 6-hydrazinonicotinonitrile is described in US2010/305085.

[0996] Compounds of formula (I′) may be prepared as illustrated in the following scheme 4 where R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4 and Y are as previously defined and R.sup.5 is hydrogen or C.sub.1-C.sub.3alkyl.

##STR00037##

[0997] An amide of formula (11) is reacted with an N,N-dimethylamide dimethyl acetal of formula (8) to form compounds of formula (12) which are subsequently reacted with substituted hydrazines of formula (10) or their corresponding salts, e.g. hydrochloride salts, under acidic conditions to form compounds of formula (I′). For example, a compound of formula (11) and an N,N-dimethylamide dimethyl acetal of formula (8) are reacted in a suitable solvent, such as CH.sub.2Cl.sub.2 at reflux to provide compounds of formula (12). Upon removal of the solvent, compounds of formula (12) are reacted with a substituted hydrazine of formula (10) in a suitable solvent such as 1,4-dioxane, acetic acid or a mixture of such solvents at temperatures ranging from around 20 to 100° C. The resulting compounds of formula (I′) may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[0998] The requisite amides of formula (11) may be prepared as illustrated in the following scheme 5, where R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, and Y are as previously described (see also WO 2017192385).

##STR00038##

[0999] An amino amide of formula (13) is reacted with a carboxylic acid of formula (2a) to form compounds of formula (11). For example, a mixture of an amino amide of formula (13), a carboxylic acid (2a), a suitable coupling reagent, such as T3P®, HATU or DCC/HOBt, a suitable base such as triethylamine or DIPEA, in a suitable solvent such as ethyl acetate or DMF are mixed at temperatures ranging from around 0 to 100° C. to provide compounds of formula (11) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1000] Alternatively, an amino acid of formula (14) is reacted with thionyl chloride in a suitable solvent, such as MeOH, at r.t. to provide amino esters of formula (15). The resulting amino esters (15) may then be alkylated through reaction with an aldehyde or a ketone in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, a dehydrating agent such as Na.sub.2SO.sub.4, in a suitable solvent such as acetic acid, at r.t. to provide compounds of formula (16).

[1001] Amino esters of formula (15) and (16) are reacted with a carboxylic acid of formula (2a), a suitable coupling reagent, such as T3P®, a suitable base such as DIPEA, in a suitable solvent, such as ethyl acetate at about 90° C. to provide amido esters of formula (17) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography. The resulting amido esters of formula (17) are reacted with magnesium nitride in a suitable solvent, such as MeOH at about 80° C. in a sealed tube to provide compounds of formula (11) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography or extraction. Compounds of formula (2a) and (14) are commercially available or accessible by methods known to the skilled artist.

[1002] The requisite amino amide compounds of formula (13) are commercially available or may be prepared as illustrated in the following scheme 6, where R.sup.1, R.sup.3a, R.sup.3b, and Y are as previously described and LG is a suitable leaving group (see also WO 2017192385).

##STR00039##

[1003] An amine of formula (4) is reacted with an amide of formula (7) to form compounds of formula (13). For example, a mixture of an amine of formula (4), an amide of formula (7), a suitable base, such as K.sub.2CO.sub.3 or DIPEA in a suitable solvent, such as acetonitrile or DMF are mixed at 25-80° C. to provide compounds of formula (13) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1004] Compounds of formula (4) and (7) are commercially available, or may be synthesized by methods known to a person skilled in the state of the art.

[1005] In an alternative approach compounds of formula (I′) may be prepared as illustrated in the following scheme 7 where R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4 and Y are as previously defined and R.sup.5 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl or C.sub.3-C.sub.6cycloalkyl.

##STR00040##

[1006] An amidine or its suitable corresponding salt, e.g. hydrochloride salt, of formula (8) is reacted with an acid of formula (19). For example, an amidine hydrochloride of formula (18), a carboxylic acid (19), a suitable coupling reagent, such as HATU or DCC/HOBt, a suitable base such as triethylamine or DIPEA, in a suitable solvent such as acetonitrile or DMF are mixed at temperatures ranging from around 0 to 100° C., to form compounds of formula (20) which are subsequently reacted with substituted hydrazines of formula (10) or their corresponding salts, e.g. hydrochloride salts, under acidic conditions to form compounds of formula (I′) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1007] Amidine hydrochlorides of formula (18), carboxylic acid derivatives of formula (19) and hydrazines of formula (10) are commercially available or may be synthesized by methods known to the skilled artisan.

[1008] In an alternative approach compounds of formula (1) may be prepared as illustrated in the following scheme 8 where R.sup.1, R.sup.3a, R.sup.3b, R.sup.4 and Y are as previously defined and R.sup.5 is hydrogen or C.sub.1-C.sub.3alkyl.

##STR00041##

[1009] An amide of formula (21) is reacted with an N,N-dimethylamide dimethyl acetal of formula (8) to form compounds of formula (22) which are subsequently reacted with substituted hydrazines of formula (10) or their corresponding salts, e.g. hydrochloride salts, under acidic conditions to form compounds of formula (23). For example, a compound of formula (21) and a N,N-dimethylamide dimethyl acetal of formula (8) are reacted in a suitable solvent, such as CH.sub.2Cl.sub.2 at reflux to provide compounds of formula (22). After removal of the solvent, compounds of formula (22) are reacted with a substituted hydrazine of formula (10) in a suitable solvent such as 1,4-dioxane, acetic acid or a mixture of such solvents at temperatures ranging from around 20 to 80° C. The resulting compounds of formula (23) may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1010] A carbamate of formula (23) is treated with an acid to form amines of formula (1). For example, a carbamate of formula (23) and a suitable acid, such as hydrogen chloride or trifluoracetic acid, are reacted in a suitable solvent, such as dioxane or in the case of trifluoroacetic acid without an additional solvent at temperatures ranging from around 0 to 80° C. The resulting amines of formula (1) may then be isolated as their acid salts or after base treatment as free amines and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1011] The requisite amides of formula (21) and hydrazines of formula (10) or their corresponding salts, e.g. hydrochloride salts, are commercially available or may be synthesized by methods described in this application or methods known to the skilled artisan (e.g. amides of formula (21) may be synthesized by reacting amino amides for formula (13) with bis(1,1-dimethylethyl) dicarbonate).

[1012] Scheme 9 illustrates the preparation of 3-haloalkyl triazoles containing amines (1c) where R.sup.4 is as previously defined, R.sup.5 is C.sub.1-C.sub.6haloalkyl and alkyl is C.sub.1-C.sub.6alkyl.

##STR00042##

[1013] In a first step, a hydrazone amide (25) is formed as described in EP 1099695. In a second step, 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (26), prepared from 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid and oxalyl chloride according to Tetrahedron: Asymmetry, 21(8), 936-942, 2010, reacts with the hydrazone amide (25) in the presence of a base, like pyridine, as described in EP 1099695 to form a triazole of formula (27). In a third step, the phthalimide protecting group is removed by reaction with hydrazine hydrate in a suitable solvent, like ethanol, as described in WO 2018086605. In a final step, the obtained amine (1c) is reacted with a carboxylic acid as described in scheme 1 to form the example compounds.

[1014] Scheme 10 illustrates the preparation of alkoxytriazole containing amines (1d) where R.sup.4 is as previously defined and alkyl is optionally substituted C.sub.1-C.sub.6alkyl.

##STR00043##

[1015] The synthesis starts with the reaction of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (26) with potassium thiocyanate (KSCN) in acetone to yield the corresponding isothiocyanate intermediate (28) which is treated in the next step with the corresponding alcohol to afford the O-alkyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]carbamothioates (29). The reaction between intermediate (29) and a hydrazine of formula (10) in ethanol affords cyclized products of formula (30) as described in Bioorganic & Medicinal Chemistry 26 (2018) 3321-3344. The deprotection of the amino group with hydrazine hydrate yields primary amines of formula (1d). In a final step, the obtained amine (1d) is reacted with a carboxylic acid as described in scheme 1 to form the example compounds.

[1016] Scheme 11 illustrates the preparation of alkyltriazole containing amines (1e) where R.sup.5 is optionally substituted C.sub.3-C.sub.6cyloalkyl and C.sub.1-C.sub.6alkyl, wherein the C.sub.1-C.sub.6alkyl is substituted as previously described. Z is NH.sub.2 or OC.sub.1-C.sub.6alkyl. R.sup.4 is as previously defined.

##STR00044##

[1017] N-(tert-butoxycarbonyl)-alanine (31) is reacted with a alkylamidine (18a, Z═NH.sub.2) or an alkylimidate (24a, Z═OC.sub.1-C.sub.6alkyl) to form intermediates of formula (32) which are subsequently reacted with substituted hydrazines of formula (10) to form alkyltriazoles of formula (23a). For example in the case of (18a, Z═NH.sub.2) (compare J. Org. Chem. 2011, 76, 1177-1179) N-(tert-butoxycarbonyl)-alanine and an alkylamidine of formula (18a) are reacted in the presence of a suitable coupling reagent, such as HATU, a suitable base such as triethylamine or DIPEA, in a suitable solvent, such as DMF, at temperatures ranging from 0 to 50° C. to form acylamidine intermediate of formula (32). After removal of the solvent, the intermediates of formula (32) are reacted with a substituted hydrazine of formula (10) in a suitable solvent such as acetic acid at temperatures ranging from around 20 to 80° C. The resulting alkyltriazoles of formula (23a) may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1018] In the case of Z═OC.sub.1-C.sub.6alkyl N-(tert-butoxycarbonyl)-alanine and an alkylimidate of formula (24a) or a suitable salt thereof are reacted in the presence of a suitable coupling reagent, such as HATU, a suitable base such as triethylamine or DIPEA, in a suitable solvent, such as THF at temperatures ranging from around 0 to 25° C. to form acyl imidate intermediates of formula (32). Upon addition of a substituted hydrazine of formula (10) the intermediate of formula (32) reacts at temperatures ranging from around 20 to 80° C. to give alkyltriazoles of formula (23) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1019] Carbamates of formula (23a) are treated with an acid to form amines of formula (1e) as shown in scheme 8.

[1020] The requisite alkylamidines (18a) and alkylimidates (24a) or their suitable salts and hydrazines of formula (10) are commercially available or may be synthesized by methods described in this application or methods known to the skilled artisan (see for example WO 2011/133447 for the synthesis of methyl cyclopropanecarboximidate hydrochloride).

[1021] Compounds of formula (I′c) may be prepared as illustrated in the following scheme 12, where R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.5, R.sup.41 and R.sup.42 are as previously defined. T is pyridine, pyrimidine, pyrazine, pyridazine or thiazole substituted with one —CO.sub.2—C.sub.1-C.sub.6-alkyl group, —COOH, or —CON(R.sup.41)R.sup.42 group respectively. Alk is C.sub.1-C.sub.6alkyl.

##STR00045##

[1022] An ester compound of formula (I′a) is saponified to obtain the respective carboxylic acid compound of formula (I′b) followed by an amide coupling step with amines of formula (33) to obtain amides of formula (I′c) by methods known to a person skilled in the state of the art.

[1023] For example, an ester of formula (I′a) and a suitable base such as LiOH, NaOH or KOH, in a suitable solvent such as dioxane, methanol, water or THF or mixtures thereof, are mixed at temperatures ranging from around 0 to 100° C. to provide acids of formula (I′b) which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1024] For example, a mixture of an amine of formula (33), a carboxylic acid (I′b), a suitable coupling reagent, such as T3P HATU or DCC/HOBt, a suitable base such as triethylamine or DIPEA, in a suitable solvent such as ethyl acetate or DMF are mixed at temperatures ranging from around 0 to 100° C. to provide compounds of formula Ic which may then be isolated and, if necessary and desired, purified using techniques well known in the art, such as chromatography.

[1025] Amines of formula (33) are commercially available or may be synthesized by methods known to the skilled artisan. Compounds of formula (I′ a) and (I′b) may be prepared a described for example in scheme 4 using hydrazines of the general formula (10) in which R.sup.4 is pyridine, pyrimidine, pyrazine, pyridazine or thiazole substituted with one —CO.sub.2—C.sub.1-C.sub.6-alkyl or —COOH group respectively.

[1026] The preparation and use examples which follow illustrate the invention without limiting it.

General Procedure 1: O-Alkylation of Phenols

[1027] To a solution of phenol (1 eq) in an appropriate solvent was added potassium carbonate (1-3 eq) freshly crushed and the corresponding alkylating reagent (1-3 eq) and the mixture was stirred till the reaction was complete. The mixture was diluted with water, extracted several times with ethyl acetate and then the combined organic layer was washed with brine and dried over Na.sub.2SO.sub.4. After evaporation of the solvent under vacuo the crude product was purified by reserved-phase chromatography (water/acetonitrile) or flash chromatography.

[1028] When acetonitrile was used as the solvent, the reaction was stirred at room temperature. When using DMF as the solvent, the mixture was stirred between 60-100° C.

STARTING COMPOUNDS AND INTERMEDIATES

Intermediate 1A

Methyl 3-chloro-5-(hydroxymethyl)benzoate

[1029] ##STR00046##

[1030] Dimethyl 5-chloroisophthalate (90.0 g, 394 mmol, 1.00 eq) was dissolved in MeOH (900 mL) and DCM (900 mL) and the solution was cooled to 0° C. NaBH.sub.4 (59.6 g, 1.57 mol, 4.00 eq) was added in portions to the mixture. The reaction mixture was stirred at 25° C. for 16 hrs. TLC (petroleum ether/ethyl acetate=3:1, R.sub.f=0.17) indicated ca. 30% of the starting compound remained, and one new spot was formed. The reaction mixture was poured into aqueous saturated solution of NH.sub.4C.sub.1 (500 mL) and extracted with DCM (2×200 mL). The combined organic phases were washed with brine (500 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=50/1 to 3/1). Methyl 3-chloro-5-(hydroxymethyl)benzoate (52.8 g, 263 mmol, 66.9% yield) was obtained as colorless oil.

Intermediate 2A

Methyl 3-chloro-5-(chloromethyl)benzoate

[1031] ##STR00047##

[1032] Methyl 3-chloro-5-(hydroxymethyl)benzoate (52.0 g, 259 mmol, 1.00 eq) was dissolved in DCE (360 mL) and cooled to 0° C. and kept under inert atmosphere (N.sub.2). SOCl.sub.2 (123 g, 1.04 mol, 75.2 mL, 4.00 eq) was added dropwise to the mixture. The reaction mixture was stirred at 50° C. for 16 hrs. TLC (petroleum ether/ethyl acetate=5:1, R.sub.f=0.75) indicated the starting material was consumed completely and one new spot was formed. The reaction mixture was diluted with H.sub.2O (200 mL) and extracted with DCM (2×200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Methyl 3-chloro-5-(chloromethyl)benzoate (54.5 g, crude) was obtained as off-white oil.

Intermediate 3A

Methyl 3-chloro-5-(cyanomethyl)benzoate

[1033] ##STR00048##

[1034] Methyl 3-chloro-5-(chloromethyl)benzoate (54.0 g, 246 mmol, 1.00 eq) and trimethylsilylcyanide (97.8 g, 986 mmol, 123 mL, 4.00 eq) were dissolved in DMF (380 mL). Cesium fluoride (74.9 g, 493 mmol, 18.2 mL, 2.00 eq) was added to the mixture at room temperature. The reaction mixture was stirred at 25° C. for 16 hrs. The reaction mixture was poured into a saturated aqueous solution of NH.sub.4Cl (500 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine (200 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=50/1 to 3/1). Methyl 3-chloro (cyanomethyl)benzoate (42.0 g, 200 mmol, 81.3% yield) was obtained as off-white solid.

Intermediate 4A

Methyl 3-chloro-5-(2-cyanopropan-2-yl)benzoate

[1035] ##STR00049##

[1036] Methyl 3-chloro-5-(cyanomethyl)benzoate (20.0 g, 95.4 mmol, 1.00 eq) and methyl iodide (67.7 g, 477 mmol, 29.7 mL, 5.00 eq) were dissolved in THF (140 mL) and cooled to −65° C. under inert atmosphere (N.sub.2). LDA (2.00 M, 143 mL, 3.00 eq) was added dropwise to the mixture. The reaction mixture was stirred at −65° C. for 2 hrs. TLC (petroleum ether/ethyl acetate=3:1, R.sub.f=0.43) indicated the starting material was consumed completely and many new spots formed. The mixture was allowed to warm to room temperature and was poured into ice water (200 mL) and then extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether/ethyl acetate=50/1 to 3/1). The isolated major product was triturated with MTBE (40.0 mL) at 25° C. for 16 hrs. Methyl 3-chloro-5-(2-cyanopropan-2-yl)benzoate (10.0 g, 41.1 mmol, 43.1% yield, 97.7% purity) was obtained as colorless solid.

Intermediate 5A

3-Chloro-5-(2-cyanopropan-2-yl)benzoic acid

[1037] ##STR00050##

[1038] Methyl 3-chloro-5-(2-cyanopropan-2-yl)benzoate (9.50 g, 40.0 mmol, 1.00 eq) was dissolved in MeOH (40.0 mL) and H.sub.2O (30 mL) at 0° C. Lithium hydroxide (1.91 g, 79.9 mmol, 2.00 eq) was added portion wise to the mixture. The reaction mixture was stirred at 25° C. for 3 hrs. TLC (petroleum ether/ethyl acetate=1:1, R.sub.f=0.04) indicated the starting material was consumed completely and one new spot was formed. The reaction mixture was concentrated under vacuum. The remaining residue was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL). The aqueous phase was adjusted to pH 4 with 3N HCl. The aqueous phase was then extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with brine (30 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The crude product was triturated with MTBE (30 mL) at 25° C. for 16 hrs. The title compound, 3-chloro-5-(2-cyanopropan-2-yl)benzoic acid (5.00 g, 22.3 mmol, 55.7% yield, 99.6% purity), was obtained as colorless solid.

[1039] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=1.79 (s, 6H) 7.76-7.77 (m, 1H), 8.06-8.07 (m, 1H), 8.09-8.10 (m, 1H). Measured using a Bruker 400 MHz spectrometer.

Intermediate 6A

3-Chloro-5-(methoxycarbonyl)benzoic acid

[1040] ##STR00051##

[1041] To a mixture of dimethyl 5-chloroisophthalate (5.00 g, 21.8 mmol) in MeOH/THF (250 mL/250 mL) was added 1 M NaOH (21.8 mL, 21.8 mmol) in portions, then the reaction was stirred at 25° C. for 16 hrs.

[1042] HPLC-UV indicated complete conversion of the starting material. The reaction was concentrated to remove the solvents, the residue was adjusted to pH=2 with 4 N HCl to give a precipitate. The solid was collected by filtration, washed with water, dried in vacuo to yield the desired product as colorless solid (3.75 g, 80% yield).

[1043] .sup.1H NMR (600 MHz, CDCl.sub.3): δ=8.64 (s, 1H), 8.27 (s, 2H), 3.98 (s, 3H). Measured using a Bruker Biospin GmbH 600 NMR spectrometer.

Intermediate 7A

Methyl 3-chloro-5-[methoxy(methyl)carbamoyl]benzoate

[1044] ##STR00052##

[1045] To a solution of N, O-dimethylhydroxylamine hydrochloride (2.73 g, 27.6 mmol) in DCM (200 mL) was added triethylamine (11.3 mL, 80.6 mmol) and the solution was stirred for 30 min at 25° C. Then, 3-chloro-5-(methoxycarbonyl)benzoic acid (5.00 g, 23.3 mmol) was added followed by EDCI (8.82 g, 45.9 mmol) and HOBt (5.99 g, 46.6 mmol) at 0° C. The reaction mixture was allowed to warm to 25° C. and stirred for another 4 hrs. The mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel column (EtOAc/petroleum ether=1/10 to 1/5) to give the pure desired product (4.33 g, 72%).

[1046] .sup.1H NMR (600 MHz, CDCl.sub.3): δ=8.24 (s, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 3.95 (s, 3H), 3.56 (s, 3H), 3.38 (s, 3H). Measured using a Bruker Biospin GmbH 600 NMR spectrometer.

Intermediate 8A

Methyl 3-chloro-5-(cyclopropylcarbonyl)benzoate

[1047] ##STR00053##

[1048] A solution of methyl 3-chloro-5-[methoxy(methyl)carbamoyl]benzoate (5.00 g, 19.4 mmol) in dry THF (200 mL) was added dropwise cyclopropylmagnesium bromide (38.8 mL, 19.4 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 hrs, followed by quenching at 0° C. with aqueous NH.sub.4Cl and extraction with EtOAc (3×50.0 mL). The organic layers were combined and washed with brine twice, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column (EtOAc/petroleum ether=1/30) to give the pure desired product (1 g, 21%).

[1049] .sup.1H NMR (600 MHz, CDCl.sub.3): δ=8.55 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 3.96 (s, 3H), 2.69-2.65 (m, 1H), 1.31-1.25 (m, 2H), 1.14-1.11 (m, 2H). Measured using a Bruker Biospin GmbH 600 NMR spectrometer.

Intermediate 9A

3-Chloro-5-(cyclopropylcarbonyl)benzoic acid

[1050] ##STR00054##

[1051] To a mixture of methyl 3-chloro-5-(cyclopropylcarbonyl)benzoate (3.80 g, 15.9 mmol) in MeOH/THF (15.0 mL/15.0 mL) was added 1 M NaOH (31.8 mL, 31.8 mmol) in portions, then the reaction was stirred at 25° C. for 16 hrs. The reaction mixture was concentrated to remove the solvents and the residue was adjusted to pH=2 with 3 N HCl to give a precipitate. The solid was collected by filtration, washed with water, dried over vacuo to give pure target compound as colorless solid (3.1 g, 87%).

[1052] .sup.1H NMR (600 MHz, CDCl.sub.3): δ=13.56 (bs, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 2.99-2.95 (m, 1H), 1.14-1.07 (m, 4H). Measured using a Bruker Biospin GmbH 600 NMR spectrometer.

Intermediate 10A

3-[(Methylsulfinyl)methoxy]-5-(trifluoromethyl)benzoic acid

[1053] ##STR00055##

[1054] 4.85 g (23.5 mmol) 3-hydroxy-5-(trifluoromethyl)benzoic acid, 7.5 g (66.2 mmol) chloro(methylsulfinyl)methane and 19 g (137.5 mmol) K.sub.2CO.sub.3 were stirred in DMSO. After evaporation of the volatiles under reduced pressure the residue was dissolved in EtOAc, aq. citric acid, aq. NaCl. The aquous layer was extracted three times with EtOAc, the combined organic phases were dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. Chromatography of the residue (RP-18, Water-Acetone, 0.1% HCOOH) yielded 2.3 g (68%, yield corrected by purity).

[1055] ESI mass [m/z]: 280.9 [M−H].sup.−

Intermediate 11A

N-[(2S)-1-Amino-1-oxopropan-2-yl]-3-[(methylsulfinyl)methoxy]-5-(trifluoromethyl)benzamide

[1056] ##STR00056##

[1057] 1.8 g (6.4 mmol) 3-[(methylsulfinyl)methoxy]-5-(trifluoromethyl)benzoic acid and 1.2 g (9.6 mmol) L-alaninamide-HCl were dispersed in 100 mL DMF with 10 mL Et.sub.3N. At ice-water cooling, 7 mL (10.2 mmol) T3P (Propylphosphonic anhydride) 50% in acetonitrile were added during 0.5 h. The mixture was stirred at RT over night. After addition of excess aquous citric acid, the mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc/THF, aq. citric acid, aq. NaCl. The aquous phase was extracted three times with EtOAc, the combined organic phases were washed two times with aq. K.sub.2CO.sub.3, dried with aq. NaCl, then Na.sub.2SO.sub.4 and evaporated under reduced pressure to yield 2.25 g (75%, yield corrected by purity).

[1058] ESI mass [m/z]: 353.1 [M+H].sup.+

Intermediate 12A

N-[(2S)-1-{(E)-[(Dimethylamino)methylene]amino}-1-oxopropan-2-yl]-3-[(methylsulfinyl)methoxy](trifluoromethyl)benzamide

[1059] ##STR00057##

[1060] A mixture of 0.7 g (2 mmol) N-[(2S)-1-amino-1-oxopropan-2-yl]-3-[(methylsulfinyl)methoxy]-5-(trifluoromethyl)benzamide and dimethylformamide dimethyl acetal (5 ml) in 80 mL THF was heated to reflux for 15 min. The mixture was evaporated under reduced pressure and directly used in the subsequent step.

Intermediate 13A

2,3,3-Trichloroprop-2-en-1-yl 3-bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzoate

[1061] ##STR00058##

[1062] 5.07 g (23.4 mmol) 3-bromo-5-hydroxybenzoic acid, 9.5 g (43.9 mmol) 1,1,1,2,3-pentachloropropane and 11.05 g (80 mmol) K.sub.2CO.sub.3 were stirred in 200 mL DMSO at 45° C. for 1 d. After evaporation of the volatiles under reduced pressure the residue was dissolved in EtOAc, aq, citric acid, aq. NaCl. The aquous phase was extracted three times with EtOAc and the combined organic phases were dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure to yield 11 g (84%, yield corrected by purity).

[1063] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.8 (m, 1H), 7.55 (m, 1H), 7.3 (m, 1H), 5.2 (s, 2H), 4.9 (s, 2H)

Intermediate 14A

3-Bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzoic acid

[1064] ##STR00059##

[1065] 11 g (21.8 mmol) 2,3,3-trichloroprop-2-en-1-yl 3-bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzoate were stirred in water-THF with aq. NaOH. After completion of the reaction aq. citric acid was added and the organic solvent was evaporated under reduced pressure. The precipitate was filtered off, washed with water an dried to yield 10.7 g crude product.

[1066] ESI mass [m/z]: 358.9 [M−H].sup.−

Intermediate 15A

N-[(2S)-1-Amino-1-oxopropan-2-yl]-3-bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzamide

[1067] ##STR00060##

[1068] 5.3 g (14.7 mmol) 3-bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzoic acid and 2.7 g (21.7 mmol) L-alaninamide-HCl were dispersed in 100 mL DMF with 10 mL Et.sub.3N. At ice-water cooling, 7 mL (10.2 mmol) T3P (Propylphosphonic anhydride) 50% in acetonitrile were added during 0.5 h. The mixture was stirred at RT over night. A further lot of 6 mL T3P was added, now totalling 13 mL (19 mmol). The mixture was stirred at RT over night. After addition of excess aqueous citric acid, the mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc/THF, aq. citric acid, aq. NaCl. The aquous phase was extracted three times with EtOAc, the combined organic phases were washed two times with aq. K.sub.2CO.sub.3, dried with aq. NaCl, than Na.sub.2SO.sub.4 and evaporated under reduced pressure to yield 4.8 g (44%, yield corrected by purity).

[1069] ESI mass [m/z]: 431.0 [M+H].sup.+

Intermediate 16A

3-Bromo-N-[(2S)-1-{(E)-[(dimethylamino)methylene]amino}-1-oxopropan-2-yl]-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzamide

[1070] ##STR00061##

[1071] 4.75 g (11 mmol) N-[(2 S)-1-amino-1-oxopropan-2-yl]-3-bromo-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzamide were refluxed with 10 mL (75 mmol) dimethylformamide dimethyl acetal in THF for 0.5 h. The mixture was evaporated under reduced pressure and directly used in the next step.

Intermediate 17A

2-Hydrazino-1,3-thiazole-5-carbonitrile

[1072] ##STR00062##

[1073] A mixture of 9.00 g (62.2 mmol) 2-chloro-1,3-thiazole-5-carbonitrile and 124.5 mL (124.5 mmol) of a 1 M solution of hydrazine in THF was refluxed for 2 h. After cooling to room temperature, the mixture was evaporated and then the residue was suspended in 50 mL of hot water. The resulting precipitate was filtered, washed with water and dried under vacuo to yield the title compound (9.00 g). Further drying by co-evaporation with absolute toluene resulted in a decrease in mass and this material was used in the next step.

[1074] .sup.1H NMR peak list (DMSO-d.sub.6, 400 MHz): δ=9.7694 (1.7); 7.8727 (13.8); 5.3331 (16.0); 3.3330 (6.9); 2.5083 (12.7); 2.5040 (16.5); 2.4997 (12.5)

[1075] ESI mass [m/z]: 141.0 [M+H].sup.+

Intermediate 18A

tert-Butyl {(1S)-1-[1-(5-cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate

[1076] ##STR00063##

[1077] To a solution of 2.00 g (10.6 mmol) N.sup.2-(tert-butoxycarbonyl)-L-alaninamide in 40 mL dichloromethane was added 2.1 mL (16 mmol) N,N-dimethylformamide dimethylacetal. The solution was heated at reflux for 2 h after which the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 20 mL 1,4-dioxane and 20 mL glacial acetic acid. 1.7 g (13 mmol) 6-hydrazinonicotinonitrile was added and the mixture stirred at 50° C. for 60 min. The solvents were removed under reduced pressure, a saturated aqueous solution of NaHCO.sub.3 was added and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. The residue was purified by reversed phase chromatography (H.sub.2O/acetonitrile) to provide 3.0 g of tert-butyl {(1S)-1-[1-(5-cyanopyridin-2-yl)-1H-1,2,4-triazol yl]ethyl}carbamate.

[1078] [α].sub.D.sup.20=+89 (c=1.0; ethanol)

[1079] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 9.10 (s, 1H), 8.57 (dd, 1H), 8.21 (s, 1H), 8.05 (d, 1H), 7.52 (d, 1H), 5.63 (m, 1H), 1.43 (d, 3H), 1.31 (s, 9H).

[1080] ESI mass [m/z]: 259.2 [M-C.sub.4H.sub.8+H].sup.+

Intermediate 19A

6-{5-[(1S)-1-Aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride

[1081] ##STR00064##

[1082] To a solution of 2.9 g (9.2 mmol) tert-butyl {(1S)-1-[1-(5-cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}carbamate in 40 mL 1,4-dioxane were added 23 mL of a 4 M solution of HCl in 1,4-dioxane. The mixture was stirred for 4 h at 50° C. and overnight at room temperature. The solvent was removed under reduced pressure to provide 2.81 g of a residue containing 6-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride. This was used without further purification.

[1083] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 9.11 (d, 1H), 8.80 (br d, 3H), 8.61 (dd, 1H), 8.45 (s, 1H), 8.13 (d, 1H), 5.39 (m, 1H), 1.63 (d, 3H).

[1084] ESI mass [m/z]: 215.2 [amine+H].sup.+

Intermediate 20A

O-Methyl [(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]carbamothioate

[1085] ##STR00065##

[1086] To a solution of 1.0 g (4.6 mmol) (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propanoic acid in toluene (15 ml) was added 0.80 mL (9.12 mmol) oxalyl chloride and one drop of N,N-dimethylformamide. The reaction mixture was stirred 3 h at room temperature and then hexane (15 ml) was added and the stirring was continued over night. After this time additional oxalyl chloride (0.5 ml) was added again and the reaction mixture was stirred 3 h and finally was evaporated. The crude residue was dissolved in acetone (15 ml) and then 0.44 g (4.56 mmol) KSCN were added as a solution in acetone (5 ml) and the mixture was stirred at 60° C. for 2 h. Then 0.46 mL (11.4 mmol) of methanol were added and the mixture was stirred at 60° C. over night, cooled to room temperature and evaporated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with water and brine respectively and finally the organic layer was dried over anhydrous Na.sub.2SO.sub.4, and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to yield the tittle compound (0.82 g, 59%).

[1087] ESI mass [m/z]: 293.1 [M+H].sup.+

Intermediate 21A

6-{5-[(1S)-1-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-methoxy-1H-1,2,4-triazol-1-yl}nicotinonitrile

[1088] ##STR00066##

[1089] To a solution of 1.5 g (5.1 mmol) O-methyl [(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]carbamothioate in ethanol (30 ml) were added 0.69 g (5.1 mmol) 6-hydrazinonicotinonitrile and the reaction mixture was stirred at 90° C. over night. The mixture was cooled to room temperature, evaporated under reduced pressure and the resulting residue was dissolved in EtOAc, washed with water and brine respectively. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography to yield the tittle compound (1.23 g, 58%).

[1090] ESI mass [m/z]: 375.1 [M+H].sup.+

Intermediate 22A

6-{5-[(1S)-1-Aminoethyl]-3-methoxy-1H-1,2,4-triazol-1-yl}nicotinonitrile

[1091] ##STR00067##

[1092] To a solution of 1.20 g (3.20 mmol) 6-{5-[(1S)-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-methoxy-1H-1,2,4-triazol-1-yl}nicotinonitrile in ethanol (30 ml) were added 0.39 mL (8.01 mmol) hydrazin hydrate and the reaction was heated to reflux temperature over night. After cooling the mixture to room temperature, acetone (10 ml) was added and it was heated again to reflux temperature for 3 h. The resulting precipitate was filtered and the filtrate evaporated under reduced pressure to yield a residue which was used in the next step without further purification (1.05 g, 44% purity, 59% yield).

[1093] ESI mass [m/z]: 245.1 [M+H].sup.+

Intermediate 23A

tert-Butyl {(1S)-1-[1-(5-cyanopyridin-2-yl)-3-cyclopropyl-1H-1,2,4-triazol-5-yl]ethyl}carbamate

[1094] ##STR00068##

[1095] To a solution of 2.0 g (10.5 mmol) N-(tert-butoxycarbonyl)-L-alanine in N,N-dimethylformamide (37.5 ml) was added 1.91 g (15.9 mml) cyclopropylamidin followed by 4.42 g (11.63 mmol) of HATU and 5.52 mL (31.7 mmol) of N,N-diisopropylethylamin and the reaction mixture was stirred at room temperature for 3 h. Afterwards 6.05 mL (105.7 mmol) of acetic acid and 2.13 g (15.8 mmol) of 6-hydrazinonicotinonitrile were added and the reaction mixture was stirred 5 h at 80° C. and then at room temperature overnight. The reaction mixture was cooled to room temperature, a saturated aqueous solution of Na.sub.2CO.sub.3 was added and then the mixture was extracted with EtOAc. The combined organic layers were washed with water, an aqueous solution of 5% NaH.sub.2PO.sub.4, brine and finally dried over Na.sub.2SO.sub.4. After filtration and evaporation of the solvent under vacuo the crude was purified by preparative HPLC (water/acetonitrile). The combined product fractions were evaporated to yield the title compound (0.77 g, 21%).

[1096] ESI mass [m/z]: 355.3 [M+H].sup.+

[1097] .sup.1H-NMR peaklist (400.2 MHz, CD3CN):

[1098] δ=8.8116 (6.3); 8.8100 (6.6); 8.8062 (6.7); 8.8046 (5.9); 8.2628 (4.8); 8.2573 (4.6); 8.2412 (5.5); 8.2357 (5.4); 7.9980 (7.0); 7.9964 (6.6); 7.9764 (5.9); 7.9747 (5.6); 5.8766 (0.8); 5.7388 (0.5); 5.7213 (1.4); 5.7031 (1.9); 5.6849 (1.3); 5.6682 (0.4); 2.1614 (41.0); 2.0585 (1.0); 2.0462 (2.0); 2.0378 (2.2); 2.0344 (1.4); 2.0255 (3.5); 2.0194 (1.3); 2.0132 (2.1); 2.0049 (2.2); 1.9926 (1.1); 1.9648 (4.6); 1.9528 (18.4); 1.9467 (34.9); 1.9405 (49.0); 1.9343 (33.6); 1.9281 (17.1); 1.4498 (14.5); 1.4328 (14.5); 1.3608 (16.0); 1.2685 (1.1); 1.2388 (0.7); 1.1974 (0.7); 1.0334 (0.4); 1.0281 (0.4); 1.0173 (1.7); 1.0106 (5.0); 1.0083 (4.1); 1.0049 (6.3); 0.9990 (1.5); 0.9901 (6.0); 0.9848 (6.4); 0.9754 (1.5); 0.9669 (2.7); 0.9546 (1.2); 0.9464 (3.2); 0.9446 (3.1); 0.9403 (2.8); 0.9385 (2.8); 0.9342 (3.2); 0.9324 (3.0); 0.9274 (4.6); 0.9204 (2.9); 0.9154 (3.3); 0.9084 (2.6); 0.9047 (1.3); 0.9014 (1.4); 0.8974 (1.0); 0.8927 (0.8); 0.8872 (0.7); 0.8837 (0.6); 0.1459 (0.8); 0.0080 (6.7); −0.0002 (166.9); −0.0086 (6.2); −0.0171 (0.6); −0.1495 (0.8)

Intermediate 24A

6-{5-[(1S)-1-Aminoethyl]-3-cyclopropyl-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride (1:1)

[1099] ##STR00069##

[1100] A solution of 830 mg (2.34 mmol) tert-butyl {(1S)-1-[1-(5-cyanopyridin-2-yl)-3-cyclopropyl-1H-1,2,4-triazol-5-yl]ethyl}carbamate in dioxane (22 ml) was treated with HCl 4N in dioxane (10.9 ml). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was separated by filtration and dried under air to yield the title compound (0.71, 100%).

[1101] ESI mass [m/z]: 255.1 [amine+H].sup.+

Intermediate 25A

3-(Cyanomethyl)-5-(trifluoromethoxy)benzoic acid

[1102] ##STR00070##

[1103] A vial was charged with 3-bromo-5-(trifluoromethoxy)benzoic acid (500 mg, 1.75 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (418 mg, 2.10 mmol) and DMSO (17.5 mL). Then, potassium fluoride (306 mg, 5.26 mmol) and water (5.0 mL) were added and the mixture was degassed. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (128 mg, 0.17 mmol) was added and the vial was sealed and heated to 130° C. for 16 h. After cooling to RT, the mixture was filtered over a plug of Celite and the filter cake was washed with ethyl acetate. Aqueous sodium hydroxide solution (1.0 M) was added and the layers were separated. The aqueous layer was acidified with hydrochloric acid (0.1 M) until pH 5 and extracted with ethyl acetate. All organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound. Yield: 217 mg (50% of theory).

[1104] ESI mass [m/z]: 246.0 [M+H].sup.+

[1105] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=13.63 (br s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 4.23 (s, 2H).

Intermediate 26A

Sodium 3-(1-cyano-1-methyl-ethyl)-5-(trifluoromethoxy)benzoate

[1106] ##STR00071##

[1107] A flask was charged with a mixture of iodomethane (173 μL, 2.77 mmol) and sodium hydride (159 mg, 4.16 mmol, 63% dispersion in mineral oil) in DMF (1.0 ml). The mixture was cooled to 0° C. and a solution of 3-(cyanomethyl)-5-(trifluoromethoxy)benzoic acid (170 mg, 0.69 mmol) in DMF (2.0 ml) was added dropwise at this temperature. After complete addition, the mixture was allowed to warm to r.t. and stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to leave the crude title compound which was used in the next steps without further purification. Yield: 95.2 mg (47% of theory).

[1108] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=8.07 (s, 1H), 7.77-7.73 (m, 1H), 7.57 (s, 1H), 1.72 (s, 6H).

Intermediate 27A

3-Bromo-5-(2,2-dichlorovinyl)benzonitrile

[1109] ##STR00072##

[1110] To a solution of 1.0 g (4.8 mmol) 3-bromo-5-formylbenzonitrile in 5 mL acetonitrile were added 1.89 g (9.52 mmol) bromo(trichloro)methane and 3.75 g (14.2 mmol) triphenylphosphine. The mixture was stirred overnight at ambient temperature after which the crude reaction mixture was purified by reversed phase chromatography (MeCN/H.sub.2O) to provide 1.06 g 3-bromo-5-(2,2-dichlorovinyl)benzonitrile.

[1111] EI mass [m/z]: 277 [M.sup.+](EI=electron ionization)

Intermediate 28A

3-Bromo-5-(2,2-dichlorovinyl)benzoic acid

[1112] ##STR00073##

[1113] A mixture of 300 mg (1.1 mmol) 3-bromo-5-(2,2-dichlorovinyl)benzonitrile and 2.5 mL a 50% sulfuric acid was stirred for 6 h at 100° C. and overnight at room temperature. Water and ethyl acetate were then added and the reaction mixture repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to provide 277 mg of 3-bromo-5-(2,2-dichlorovinyl)benzoic acid.

[1114] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ=13.5 (brs, 1H), 8.20 (s, 1H), 8.01-8.02 (m, 2H), 7.38 (s, 1H).

[1115] ESI mass [m/z]: 294.8 [M−H].sup.−

Intermediate 29A

3-Chloro-5-[(methylsulfonyl)oxy]benzoic acid

[1116] ##STR00074##

[1117] To a suspension of 250 mg (1.4 mmol) 3-chloro-5-hydroxybenzoic acid in 5.9 mL THF were added at 0° C. 0.22 mL (2.89 mmol) methanesulfonyl chloride and 0.81 mL (5.8 mmoL) triethylamine. The reaction mixture was stirred for 15 min and then diluted with ethyl acetate and washed with 1 M hydrochloric acid. The organic layer was dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to provide 365 mg of a residue containing 3-chloro-5-[(methylsulfonyl)oxy]benzoic acid. This was used without further purification.

[1118] ESI mass [m/z]: 249.0 [M−H].sup.−

Intermediate 30A

3-Acetoxy-5-chlorobenzoic acid

[1119] ##STR00075##

[1120] 250 mg (1.4 mmol) 3-chloro-5-hydroxybenzoic acid was dissolved in a mixture of 0.8 mL water and 64 mg (1.59 mmol) sodium hydroxide. 1 g of ice was added to this solution, followed of the addition of 0.18 mL (1.9 mmol) acetic acid anhydride. The reaction mixture was stirred overnight at room temperature. It was then acidified using 1 M hydrochloric acid and repeatedly extracted with ethyl acetate. The combined organic layers were dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure to provide 233 mg of 3-acetoxy-5-chlorobenzoic acid. This was used without further purification.

[1121] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ=13.5 (brs, 1H), 7.80 (m, 1H), 7.65 (m, 1H), 7.61 (m, 1H), 2.29 (s, 3H).

[1122] ESI mass [m/z]: 213.0 [M−H].sup.−

Intermediate 31A

3,5-Dibromo-N-methoxy-N-methylbenzamide

[1123] ##STR00076##

[1124] To a mixture of 3,5-dibromobenzoic acid (40.0 g, 143 mmol, 1.00 eq) and N,O-dimethylhydroxylamine hydrochloride (18.1 g, 186 mmol, 1.30 eq) and N-ethyl-N-isopropylpropan-2-amine (55.4 g, 429 mmol, 74.7 mL, 3.00 eq) in acetonitrile (250 mL) was added HATU (81.5 g, 214 mmol, 1.50 eq). The mixture was stirred at 25° C. for 16 hrs. The mixture was then diluted with water (500 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether/EtOAc) to obtain 3,5-dibromo-N-methoxy-N-methylbenzamide (43.7 g, 135 mmol, 94.7% yield) as a yellow oil.

Intermediate 32A

(3,5-Dibromophenyl)(4-fluorophenyl)methanone

[1125] ##STR00077##

[1126] To a solution of 3,5-dibromo-N-methoxy-N-methylbenzamide (8.50 g, 26.3 mmol, 1.00 eq) in THF (60.0 mL) was added bromo(4-fluorophenyl)magnesium (1.00 M, 39.5 mL, 1.50 eq) at −10 to 0° C. The mixture was stirred at 25° C. for 12 hrs. The mixture was added into an aqueous solution of NH.sub.4Cl (50.0 mL). The mixture was extracted with ethyl acetate (2×30.0 mL). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate) to obtain (3,5-dibromophenyl)(4-fluorophenyl)methanone (7.14 g, 19.9 mmol, 75.8% yield) as a white solid.

Intermediate 33A

1,3-Dibromo-5-[difluoro(4-fluorophenyl)methyl]benzene

[1127] ##STR00078##

[1128] Under a nitrogen atmosphere (3,5-dibromophenyl)(4-fluorophenyl)methanone (6.80 g, 19.0 mmol, 1.00 eq) was dissolved in Bis(2-methoxyethyl)aminosulfur trifluoride (45.0 mL). The mixture was stirred at 60° C. for 16 hrs. The mixture was then diluted with the CH.sub.2Cl.sub.2 (30.0 mL) and added dropwise into water (50.0 mL). After phase separation the aqueous phase was extracted with CH.sub.2Cl.sub.2 (2×20.0 mL). The combined organic phase was dried with anhydrous Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate) to obtain compound 1,3-dibromo-5-[difluoro(4-fluorophenyl)methyl]benzene (6.90 g, 18.2 mmol, 95.6% yield) as a white solid.

Intermediate 34A

1-Bromo-3-[difluoro(4-fluorophenyl)methyl]-5-vinylbenzene

[1129] ##STR00079##

[1130] To a mixture of 1,3-dibromo-5-[difluoro(4-fluorophenyl)methyl]benzene (6.10 g, 16.1 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.23 g, 14.5 mmol, 2.45 mL, 0.90 eq), Na.sub.2CO.sub.3 (3.40 g, 32.1 mmol, 2.00 eq), dioxane (50.0 mL) and H.sub.2O (10.0 mL) was added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl.sub.2dppf) (940 mg, 1.28 mmol, 0.08 eq) under a nitrogen atmosphere. The mixture was stirred at 80° C. for 16 h. Water (50.0 mL) was then added and the aqueous phase extracted with ethyl acetate (2×30.0 mL). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate) to obtain 1-bromo-3-[difluoro(4-fluorophenyl)methyl]vinylbenzene (4.70 g, 14.4 mmol, 89.5% yield) as a white solid.

Intermediate 35A

3-Bromo-5-[difluoro(4-fluorophenyl)methyl]benzoic acid

[1131] ##STR00080##

[1132] KMnO.sub.4 (1.16 g, 7.34 mmol, 0.50 eq) was added to a mixture of 1-bromo-3-[difluoro(4-fluorophenyl)methyl]-5-vinylbenzene (4.80, 14.7 mmol, 1.00 eq) and NaIO.sub.4 (12.6 g, 58.7 mmol, 3.25 mL, 4.00 eq) in acetone (40 mL) and H.sub.2O (20 mL) at 30° C. The mixture was stirred at 30° C. for 0.5 hrs and then acidified by the addition of 2 N HCl until pH=3. The mixture was filtered and extracted with CH.sub.2Cl.sub.2 (3×20 ml). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (water/acetonitrile/0.1% TFA) to 3-bromo-5-[difluoro(4-fluorophenyl)methyl]benzoic acid (1.10 g, 3.03 mmol, 20.6% yield, 95.2% purity) as a white solid.

[1133] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ=8.14 (s, 1H), 8.03-7.99 (m, 1H), 7.94 (s, 1H), 7.69-7.61 (m, 2H), 7.39-7.27 (m, 2H).

[1134] ESI mass [m/z]: 344.9 [M−H].sup.−

Intermediate 36A

tert-Butyl (1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl carbamate

[1135] ##STR00081##

[1136] To a solution of 0.500 g (2.65 mmol) N.sup.2-(tert-butoxycarbonyl)-L-alaninamide in 17 mL CH.sub.2Cl.sub.2 were added 0.53 mL (4.0 mmol) N,N-dimethylformamide dimethylacetal. The solution was heated at reflux for 2 h after which the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 10 mL glacial acetic acid and 10 mL 1,4-dioxane. 0.596 g (4.25 mmol) 2-hydrazino-1,3-thiazole carbonitrile were added and the mixture was stirred for 1 h at 50° C. The solvent was then removed under reduced pressure, a saturated aq. NaHCO.sub.3 solution was added and the mixture repeatedly extracted with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica (ethyl acetate/cyclohexane) to provide 356 mg of tert-butyl {(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol yl]ethyl}carbamate.

[1137] .sup.1H NMR peak list (DMSO-d.sub.6, 400 MHz): δ=8.6600 (4.0); 8.2923 (2.2); 7.6953 (0.8); 7.6777 (0.8); 5.5940 (0.6); 5.5771 (0.8); 5.5591 (0.6); 3.3345 (44.8); 2.8917 (0.5); 2.7322 (0.4); 2.6766 (0.4); 2.6721 (0.5); 2.6676 (0.4); 2.5253 (1.7); 2.5119 (31.6); 2.5076 (60.4); 2.5031 (78.1); 2.4986 (58.0); 2.4944 (28.8); 2.3345 (0.4); 2.3300 (0.5); 2.3255 (0.4); 1.9897 (0.7); 1.9092 (0.5); 1.4244 (7.1); 1.4069 (7.1); 1.3706 (0.6); 1.3363 (16.0); 1.1752 (0.5); 1.0697 (1.0); 0.0078 (2.3); −0.0002 (50.8); −0.0085 (2.0)

[1138] ESI mass [m/z]: 265.0 [M-C.sub.4H.sub.8+H].sup.+

Intermediate 37A

Methyl 3-(cyclobutyloxy)-5-methylbenzoate

[1139] ##STR00082##

[1140] Intermediate 37A was synthesized under reaction conditions described in the general procedure 1 from 100 mg (0.60 mmol) methyl 3-hydroxy-5-methylbenzoate, 89 mg (0.66 mmol) bromocyclobutane and 166 mg (1.20 mmol) K.sub.2CO.sub.3 in DMF at 85° C. to yield the title compound (75 mg, 57%).

[1141] ESI mass [m/z]: 221.3 [M+H].sup.+

Intermediate 38A

3-(Cyclobutyloxy)-5-methylbenzoic acid

[1142] ##STR00083##

[1143] To a solution of 71 mg (0.32 mmol) methyl 3-(cyclobutyloxy)-5-methylbenzoate in 1 mL dioxane and 1 mL water was added 18 mg (0.80 mmol) LiOH and the mixture was stirred at room temperature overnight. After removing the dioxane under vacuo, water was added, and the solution was acidified with aq. 10% HCl till pH 3. Water was evaporated under vacuo and codestillated with toluene to give the title compound (66 mg, 95%) which was used in the next without further purification.

[1144] ESI mass [m/z]: 207.2 [M+H].sup.+

Intermediate 39A

Methyl 3-(cyclopropylmethoxy)-5-methylbenzoate

[1145] ##STR00084##

[1146] Intermediate 39A was synthesized under reaction conditions described in the general procedure 1 from 300 mg (1.80 mmol) methyl 3-hydroxy-5-methylbenzoate, 268 mg (1.98 mmol) (bromomethyl)cyclopropane and 499 mg (3.61 mmol) K.sub.2CO.sub.3 in DMF at room temperature to yield the title compound (329 mg, 82%).

[1147] ESI mass [m/z]: 221.1 [M+H].sup.+

Intermediate 40A

3-(Cyclopropylmethoxy)-5-methylbenzoic acid

[1148] ##STR00085##

[1149] To a solution of 285 mg (1.29 mmol) methyl 3-(cyclopropylmethoxy)-5-methylbenzoate in 7 mL dioxane and 2.3 mL water was added 74 mg (3.23 mmol) LiOH and the mixture was stirred at room temperature overnight. After removing the dioxane under vacuo, water was added and the solution was acidified with aq. 10% HCl till pH 1. Water was evaporated under vacuo and codestillated with toluene to give the title compound (520 mg, 93%) which was used in the next without further purification.

[1150] ESI mass [m/z]: 207.2 [M+H].sup.+

Intermediate 41A

Methyl 3-(cyclopentyloxy)-5-methylbenzoate

[1151] ##STR00086##

[1152] This intermediate was synthesized under reaction conditions described in the general procedure 1 from 100 mg (0.60 mmol) methyl 3-hydroxy-5-methylbenzoate, 99 mg (0.66 mmol) bromocyclopentane and 166 mg (1.20 mmol) K.sub.2CO.sub.3 in DMF at 60° C. to yield the title compound (74 mg, 38%).

[1153] ESI mass [m/z]: 235.2 [M+H].sup.+

Intermediate 42A

3-(Cyclopentyloxy)-5-methylbenzoic acid

[1154] ##STR00087##

[1155] To a solution of 79 mg (0.33 mmol) methyl 3-(cyclopentyloxy)-5-methylbenzoate 1.8 mL dioxane and 0.6 mL water was added 19 mg (0.84 mmol) LiOH and the mixture was stirred at room temperature overnight. After removing the dioxane under vacuo, water was added, and the solution was acidified with aq. 10% HCl till pH 1. Water was evaporated under vacuo and codestillated with toluene to give the title compound (73 mg, 97%) which was used in the next without further purification.

[1156] ESI mass [m/z]: 221.2 [M+H].sup.+

Intermediate 43A

Methyl 3-methyl-5-(oxetan-3-yloxy)benzoate

[1157] ##STR00088##

[1158] Intermediate 43A was synthesized under reaction conditions described in the general procedure 1 from 100 mg (0.60 mmol) methyl 3-hydroxy-5-methylbenzoate, 91 mg (0.66 mmol) 3-bromooxetane and 166 mg (1.20 mmol) K.sub.2CO.sub.3 in DMF at 85° C. to yield the title compound (85 mg, 60%).

[1159] ESI mass [m/z]: 223.1 [M+H].sup.+

Intermediate 44A

3-Methyl-5-(oxetan-3-yloxy)benzoic acid

[1160] ##STR00089##

[1161] To a solution of 86 mg (0.38 mmol) methyl 3-methyl-5-(oxetan-3-yloxy)benzoate 2 mL dioxane and 0.7 mL water was added 22 mg (0.96 mmol) LiOH and the mixture was stirred at room temperature overnight. After removing the dioxane under vacuo, water was added, and the solution was acidified was acidified with aq. 10% HCl till pH 1. Water was evaporated under vacuo and codestillated with toluene to give the title compound (79 mg) which was used in the next without further purification.

[1162] ESI mass [m/z]: 209.1 [M+H].sup.+

Intermediate 45A

Methyl 3-chloro-5-methylbenzoate

[1163] ##STR00090##

[1164] To 25.5 g (145 mmol) 3-chloro-5-methylbenzoic acid in 100 ml DCM containing 5 drops DMF were added 16 ml (0.22 mmol) thionyl chloride at reflux. The mixture was heated under reflux overnight and the volatiles were then removed under reduced pressure. The residue was dissolved in 100 ml DCM and at 0-5° C. a mixture of MeOH and Et.sub.3N was added. The mixture was stirred overnight. Aq. HCl was added and the organic layer was washed with water, dried and evaporated under reduced pressure to yield 24.4 g (72%, yield corrected by purity).

[1165] ESI mass [m/z]: 185.2 [M+H].sup.+

[1166] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=2.4 (s, 3H), 3.85 (s, 3H), 7.6 (s, 1H), 7.7 (m, 2H).

Intermediate 46A

Methyl 3-(bromomethyl)-5-chlorobenzoate

[1167] ##STR00091##

[1168] 51.7 g (280 mmol) Methyl 3-chloro-5-methylbenzoate and 0.55 g AIBN were heated under reflux in 160 ml ACN. NBS was added in portions, the mixture was heated under reflux for 1 day, stirred at room temperature for 3 days and the volatiles were then removed under reduced pressure. The residue was dissolved in EtOAc and washed with aq. sodium bisulfite, dried and evaporated to yield 75.9 g (77%, yield corrected by purity).

[1169] ESI mass [m/z]: 262.9 [M+H].sup.+

Intermediate 47A

Methyl 3-chloro-5-[(methylsulfonyl)methyl]benzoate

[1170] ##STR00092##

[1171] 12.2 g (44 mmol) Methyl 3-(bromomethyl)-5-chlorobenzoate and 13.4 g (132 mmol) sodium sulfinate were stirred in 90 ml DMF at 80° C. for 1.5 d. 13 g sodium sulfinate were added and stirring at 80° C. was continued for 5 h. The volatiles were then removed under reduced pressure and the residue was taken up in DCM. Washing the DCM phase twice with water, drying and evaporation under reduced pressure yielded 12.6 g crude product. Reversed phase chromatography (acetonitrile/water, 0.1% HCOOH) gave 7.94 g (69%).

[1172] ESI mass [m/z]: 261.1 [M−H].sup.−

[1173] .sup.1H NMR (400 MHz, D6-DMSO): δ=2.95 (s, 3H), 3.9 (s, 3H), 4.15 (s, 2H), 7.75 (m, 1H), 7.95 (m, 1H), 8.0 (m, 1H).

Intermediate 48A

3-[(Methylsulfinyl)methoxy]-5-(trifluoromethyl)benzoic acid

[1174] ##STR00093##

[1175] 4.67 g (26.8 mmol) Methyl 3-chloro-5-[(methylsulfonyl)methyl]benzoate was dissolved in 50 ml EtOH. 2.9 g (32 mmol) NaOH in 25 ml water were added. The mixture was stirred overnight and the volatiles were removed under reduced pressure. The residue was taken up in water and the pH was adjusted to pH=2 using aq. HCl. The mixture was stirred for 1 h, the precipitate filtered off, washed with water and dried. This yielded 4.45 g (quantitative yield corrected by purity) of the title compound.

[1176] ESI mass [m/z]: 247.1 [M−H].sup.−

[1177] .sup.1H NMR (400 MHz, D6-DMSO): δ=2.95 (s, 3H), 4.65 (m, 2H), 7.75 (m, 1H), 7.9 (m, 1H), 7.95 (m, 1H), 13.5 (br, 1H).

Intermediate 49A

3-Chloro-5-[(methylsulfonyl)methyl]benzoyl chloride

[1178] ##STR00094##

[1179] To 0.3 g (1.1 mmol) 3-[(methylsulfinyl)methoxy]-5-(trifluoromethyl)benzoic acid in 7.5 ml DCM were added two drops of DMF and 0.33 g (206 mmol) oxaxlyl chloride. The mixture was heated under reflux for 2 h and the volatiles were removed under reduced pressure. The crude product was directly used in the following step to synthesize the example compounds.

Intermediate 50A

3-(Cyclopropoxy)-5-(trifluoromethoxy)benzoic acid

Step 1: 1-Bromo-3-(cyclopropoxy)-5-(trifluoromethoxy)benzene

[1180] ##STR00095##

[1181] To a solution of 3-bromo-5-(trifluoromethoxy)phenol (1) (10 g, 38.9 mmol) in DMF (200 mL) cesium carbonate (25.35 g, 77.8 mmol) and bromocyclopropane (23.59 g, 195 mmol) were added. The mixture was stirred at 130° C. in sealed reactor for 48 hours, poured in water (300 mL) and extracted with EtOAc (5×100 mL). The organic phase was washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and purified by flash chromatography affording 1-bromo-3-(cyclopropoxy)-5-(trifluoromethoxy)benzene (2) (3.5 g, 11.78 mmol, 30.3% yield).

Step 2: 1-Methyl 3-(cyclopropoxy)-5-(trifluoromethoxy)benzoate

[1182] ##STR00096##

[1183] To a solution of 1-bromo-3-(cyclopropoxy)-5-(trifluoromethoxy)benzene (2) (3.5 g, 11.78 mmol) in MeOH (50 mL), triethylamine (2.38 g, 23.6 mmol) and Pd(dppf)Cl.sub.2 (0.861 g, 1.178 mmol) were added. The mixture was stirred at 130° C. under pressure of CO (10 Torr) for 48 h, diluted with EtOAc (200 mL), filtered through a pad of celite and concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford methyl 3-(cyclopropoxy)-5-(trifluoromethoxy)benzoate (3) (3.1 g, 11.2 mmol, 95% yield, ˜90% purity).

Step 3: 3-(Cyclopropoxy)-5-(trifluoromethoxy)benzoic acid (50A)

[1184] ##STR00097##

[1185] To a solution of methyl 3-(cyclopropoxy)-5-(trifluoromethoxy)benzoate (3) (3.1 g, 11.2 mmol) in a mixture of THF and H.sub.2O (1:3, 50 mL) LiOH.H.sub.2O (0.6367 g, 15.17 mmol) was added at 0° C. The mixture was stirred for 8 h at r.t. THF was removed under reduced pressure, water phase was acidified to pH˜5 and extracted with EtOAc (2×50 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by HPLC gave 3-(cyclopropoxy)-5-(trifluoromethoxy)benzoic acid (1.17 g, 4.47 mmol, 40% yield).

[1186] ESI mass [m/z]: 261.0 [M−H].sup.−

[1187] .sup.1H NMR (400 MHz, D6-DMSO): δ=0.65 (m, 2H), 0.83 (d, 2H), 3.99 (m, 1H), 7.27 (s, 1H), 7.41 (s, 1H), 7.58 (m, 1H), 13.51 (s, 1H). Measured with Bruker AVANCE III 400 MHz.

Intermediate 51A

3-Bromo-5-(1-cyano-1-methyl-ethoxy)benzoic acid

Step 1: Methyl 3-(2-amino-1,1-dimethyl-2-oxo-ethoxy)-5-bromo-benzoate

[1188] ##STR00098##

[1189] To a solution of methyl 3-bromo-5-hydroxy-benzoate (9.74 g, 42.2 mmol) in dry dioxane (100 mL) was added NaH (2.12 g, 88.62 mmol). The reaction mixture was stirred for 1 h and 2-bromo-2-methylpropanamide (14 g, 84.4 mmol) was added. The resulting mixture was stirred under reflux for 4 h. The mixture was filtrated, the filtrate was concentrated in vacuo to obtain 6 (8 g, 60% yield).

[1190] Step 2: Methyl 3-bromo-5-(1-cyano-1-methyl-ethoxy)benzoate

##STR00099##

[1191] To a solution of methyl 3-(2-amino-1,1-dimethyl-2-oxo-ethoxy)-5-bromo-benzoate (8 g, 25.3 mmol) and triethylamine (10.22 g, 101 mmol) in dry dichloromethane (80 mL), cooled to 0° C., was added dropwise a solution of trifluoroacetic anhydride (15.9 g, 75.9 mmol) in dichloromethane. The reaction mixture was stirred overnight at r.t. and diluted with an aqueous NaHCO.sub.3 solution. The water phase was extracted with dichloromethane three times and the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain 5.67 g of compound 7 (75% yield).

Step 3: 3-Bromo-5-(1-cyano-1-methyl-ethoxy)benzoic acid (51A)

[1192] ##STR00100##

[1193] To a solution of methyl 3-bromo-5-(1-cyano-1-methyl-ethoxy)benzoate (5.67 g, 19 mmol) in a mixture of THF/H.sub.2O (15/1.3) was added in portions LiOH.H.sub.2O (2.4 g, 57 mmol) and the mixture was stirred overnight at r.t. The reaction mixture was acidified with 2 N solution of HCl to pH=2-3. The water phase was extracted with dichloromethane three times and the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain 1.56 g of the title compound (28.9% yield).

[1194] ESI mass [m/z]: 283.9 [M−H].sup.−

[1195] .sup.1H NMR (400 MHz, D6-DMSO): δ=13.55 (bs, 1H, COOH), 7.88 (m, 1H), 7.73 (m, 1H), 7.64 (m, 1H), 1.72 (s, 6H).

Intermediate 52A

3-Chloro-5-(1-cyano-1-methyl-ethoxy)benzoic acid

[1196] ##STR00101##

[1197] 3-Chloro-5-(1-cyano-1-methyl-ethoxy)benzoic acid was synthesized analoguously to intermediate 51A.

[1198] ESI mass [m/z]: 238.0 [M−H].sup.−

[1199] .sup.1H NMR (400 MHz, D6-DMSO): δ=13.55 (bs, 1H, COOH), 7.75 (m, 1H), 7.70 (m, 1H), 7.51 (m, 1H), 1.73 (s, 6H).

Intermediate 53A

tert-Butyl N-[(1S)-1-[2-(5-cyanopyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate

[1200] ##STR00102##

[1201] tert-Butyl N-[(1S)-1-[2-(5-cyanopyrazin-2-yl)-1,2,4-triazol-3-yl]ethyl]carbamate was synthesized analoguously to intermediate 18A.

[1202] Chiral purity: 100%—measured by SFC. Column. Chiralpak AD-3, 100×4.6 mm, I.D., 3 μm, mobile phase: A: CO.sub.2/B: isopropylamine (0.05% diethanolamine); gradient: from 5% to 40% in 2 min and hold 40% for 1 min, then from 40% to 5% of B for 1 min; Flow rate: 3.4 mL/min; column temp.: 35° C.; pressure 1800 psi.

[1203] ESI mass [m/z]: 260.1 [M-C.sub.4H.sub.8+H].sup.+

[1204] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=1.41 (s, 9H), 1.57 (d, J=6.8 Hz, 3H), 5.49 (d, J=7.2 Hz, 1H), 5.83-5.95 (m, 1H), 8.05 (s, 1H), 8.80 (d, J=1.2 Hz, 1H), 9.43 (d, J=0.8 Hz, 1H). Measured with Bruker AVANCE III 400 MHz.

Intermediate 54A

5-[5-[(1S)-1-Aminoethyl]-1,2,4-triazol-1-yl]pyrazine-2-carbonitrile hydrochloride

[1205] ##STR00103##

[1206] 5-[5-[(1S)-1-Aminoethyl]-1,2,4-triazol-1-yl]pyrazine-2-carbonitrile hydrochloride was synthesized analoguously to intermediate 19A.

[1207] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 9.40 (s, 1H), 9.29 (s, 1H), 8.55 (s, 1H), 6.55 (br s, 2H, NH.sub.2), 5.34-5.28 (m, 1H), 1.66 (d, 3H).

[1208] ESI mass [m/z]: 216.1 [amine+H].sup.+

Intermediate 55A

tert-Butyl N-[(1S)-1-[2-(6-cyanopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate

[1209] ##STR00104##

[1210] tert-Butyl N-[(1S)-1-[2-(6-cyanopyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate was synthesized analoguously to intermediate 18A.

[1211] Chiral purity: 100%—measured by chiral HPLC. Method OD_RH (0.1% H.sub.3PO.sub.4/ACN).

[1212] ESI mass [m/z]: 260.0 [M-C.sub.4H.sub.8+H].sup.+

[1213] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=1.43 (s, 9H), 1.58 (d, J=6.8 Hz, 3H), 5.45-5.58 (m, 1H), 5.97-6.10 (m, 1H), 8.02 (s, 1H), 8.32 (d, J=0.8 Hz, 1H), 9.24 (d, J=1.2 Hz, 1H). Measured with Bruker AVANCE III 400 MHz.

Intermediate 56A

6-[5-[(1S)-1-Aminoethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carbonitrile 2,2,2-trifluoroacetic acid salt

[1214] ##STR00105##

[1215] 6-[5-[(1S)-1-Aminoethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carbonitrile 2,2,2-trifluoroacetic acid salt was synthesized analoguously to intermediate 19A using trifluoroacetic acid in dichloromethane.

[1216] ESI mass [m/z]: 216.1 [amine+H].sup.+

Intermediate 57A

tert-Butyl N-[(1S)-1-[2-(6-cyanopyrimidin-4-yl)-5-cyclopropyl-1,2,4-triazol-3-yl]ethyl]carbamate

[1217] ##STR00106##

[1218] tert-Butyl N-[(1S)-1-[2-(6-cyanopyrimidin-4-yl)-5-cyclopropyl-1,2,4-triazol-3-yl]ethyl]carbamate was synthesized analoguously to intermediate 23A.

[1219] Chiral purity: 96.2%—measured by chiral HPLC. Method OD_RH (0.1% H.sub.3PO.sub.4/ACN).

[1220] ESI mass [m/z]: 356.0 [M+H].sup.+

[1221] .sup.1H NMR (400 MHz, MeOD): δ=9.21 (s, 1H), 8.36 (s, 1H), 5.82 (q, J=6.8 Hz, 1H), 2.15-2.04 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.40 (br s, 9H), 1.09-0.98 (m, 4H). Measured with Bruker AVANCE III 400 MHz.

Intermediate 58A

6-[5-[(1S)-1-Aminoethyl]-3-cyclopropyl-1,2,4-triazol-1-yl]pyrimidine-4-carbonitrile hydrochloride

[1222] ##STR00107##

[1223] 6-[5-[(1S)-1-Aminoethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carbonitrile hydrochloride was synthesized analoguously to intermediate 24A.

[1224] ESI mass [m/z]: 256.2 [amine+H].sup.+

Intermediate 59A

6-[5-[(1S)-1-Aminoethyl]-3-cyclopropyl-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide hydrochloride

[1225] ##STR00108##

[1226] 6-[5-[(1S)-1-Aminoethyl]-3-cyclopropyl-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide hydrochloride was obtained as side hydrolysis product with intermediate 58A.

[1227] ESI mass [m/z]: 274.2 [amine+H].sup.+

Intermediate 60A

3-Chloro-6-(1-cyano-1-methyl-ethyl)pyridine-4-carboxylic acid

Step 1: 2-Chloro-6-(cyanomethyl)pyridine-4-carboxylic acid

[1228] ##STR00109##

[1229] n-BuLi (91.14 mL, 2M, 183.3 mmol)) was diluted in anhydrous THF (150 mL) and cooled to −78° C. under argon. A solution of anhydrous acetonitrile (11.4 mL, 218.8 mmol) in anhydrous THF (30 mL) was added dropwise and the reaction mixture was maintained at −78° C. for 30 min. A solution of 2,6-dichloropyridine-4-carboxylic acid (7 g, 36.5 mmol) in THF (200 mL) was added dropwise over one hour and the reaction mixture was stirred at −78° C. for 45 min and then 1 h at room temperature. Then the reaction mixture was quenched with saturated aqueous citric acid solution (200 mL) and extracted with EtOAc (3×250 mL). The organic layer was washed with water (3×300 mL) followed by brine solution (200 mL) and dried over anhydrous Na.sub.2SO.sub.4, solvents were removed under reduced pressure. The residue was purified by flash silica gel chromatography using a gradient of 0% to 10% acetone in DCM. The obtained solid was triturated with 50% diethyl ether in n-pentane to obtained 4.2 g (58% yield) of 2-chloro-6-(cyanomethyl)pyridine-4-carboxylic acid as an off-white solid.

[1230] ESI mass [m/z]: 195.0 [M−H].sup.−

[1231] .sup.1H NMR (400 MHz, D6-DMSO): δ=7.87 (s, 1H), 7.82 (s, 1H), 4.27 (s, 2H). COOH not detected.

Step 2: 3-Chloro-6-(1-cyano-1-methyl-ethyl)pyridine-4-carboxylic acid

[1232] ##STR00110##

[1233] To a stirred solution of 2-chloro-6-(cyanomethyl)pyridine-4-carboxylic acid (4 g, 20.3 mmol) in acetonitrile (60 mL) under nitrogen, tetrabutylammonium bromide (6.56 g, 20.3 mmol) was added. Then methyl iodide (2.78 mL, 44.8 mmol) was added dropwise at room temperature, and then the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., 8 mL of an aqueous NaOH solution (50%) was slowly added dropwise over 20 min. Then the reaction mixture was allowed to warm to room temperature and stirred for further 48 h. The reaction mixture was concentrated under vacuum at room temperature. The remaining residue was diluted with water and acidified with citric acid (pH˜5) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with water (3×100 mL) and sodium thiosulfate solution (100 mL) followed by brine solution (150 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, solvents were removed under vacuum. The crude material was purified by by flash silica gel chromatography using a gradient 0% to 10% acetone in DCM. The resulting solid was washed with n-pentane to obtain 2.1 g (45% yield) of the title compounds as off-white solid.

[1234] ESI mass [m/z]: 223.1 [M−H].sup.−

[1235] .sup.1H NMR (400 MHz, D6-DMSO): δ=14.20 (bs, 1H, COOH), 7.96 (s, 1H), 7.85 (s, 1H), 1.74 (s, 6H).

Intermediate 61A

Step 1: 6-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)nicotinic acid

[1236] ##STR00111##

[1237] To solution of 2.5 g (13.2 mmol) of N-(tert-butoxycarbonyl)-L-alaninamide in 15.7 ml dry dichloromethane was added 2.65 g (19.9 mmol) 1,1-dimethoxy-N,N-dimethylethanamine and the mixture was refluxed for 60 minutes. After cooling to room temperature, the mixture was evaporated under vacuo and the residue was dissolved in 30 ml acetic acid. Then 2.48 g (16.2 mmol) methyl 6-hydrazinonicotinate was added to the solution and the reaction mixture was stirred at 80° C. overnight. After cooling to room temperature the reaction mixture was poured into water and the corresponding precipitate was filtered and dried under vacuo to provide the title compound (1.99 g).

[1238] ESI mass [m/z]: 348.2 [M+H].sup.+

Step 2: tert-Butyl [(1S)-1-(1-{5-[ethyl(methyl)carbamoyl]pyridin-2-yl}-3-methyl-1H-1,2,4-triazol-5-yl)ethyl]carbamate

[1239] ##STR00112##

[1240] To a solution of 1.85 g (5.32 mmol) 6-(5-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)nicotinic acid in 45 ml of dry dichloromethane were added 2.43 g (6.39 mmol) HATU and 1.86 ml (10.6 mmol) N,N-diisopropylethylamine After stirring for 60 minutes at room temperature a solution of 0.69 mg (7.99 mmol) ethylmethylamine in 7.0 ml dry dichloromethane was added slowly and the reaction mixture was stirred 16 h at room temperature. The mixture was then diluted with a 5% aq. solution of NaH.sub.2PO.sub.4 and extracted with dichloromethane. Finally, the combine organic layers were concentrated and the residue was purified by preparative chromatography to yield the title compound (1.42 g).

[1241] ESI mass [m/z]: 389.3 [M+H].sup.+

[1242] .sup.1H NMR (400 MHz, D6-DMSO, peaklist): δ=8.5766 (0.6); 8.5465 (0.5); 8.3152 (0.4); 8.0715 (0.6); 8.0482 (0.4); 7.8590 (2.0); 7.8380 (1.7); 7.4108 (0.7); 7.3909 (0.7); 5.6124 (0.8); 5.5940 (1.2); 5.5760 (0.8); 3.5054 (0.6); 3.4891 (0.6); 3.3250 (138.0); 3.2915 (0.4); 3.2749 (0.5); 3.2710 (0.5); 2.9851 (2.4); 2.9738 (1.9); 2.9608 (1.9); 2.6899 (6.4); 2.6803 (0.4); 2.6757 (0.7); 2.6711 (0.9); 2.6666 (0.7); 2.6619 (0.3); 2.5245 (3.0); 2.5196 (5.1); 2.5112 (55.1); 2.5067 (110.6); 2.5022 (144.3); 2.4976 (102.2); 2.4930 (48.4); 2.3274 (16.0); 2.0862 (9.0); 1.9533 (0.4); 1.4300 (3.6); 1.4128 (3.3); 1.3811 (0.6); 1.3519 (0.3); 1.3096 (14.5); 1.2731 (0.6); 1.2565 (0.5); 1.1749 (0.9); 1.1577 (1.4); 1.1386 (1.3); 1.1348 (1.3); 1.1187 (1.7); 1.1077 (1.4); 1.0405 (0.9); 0.1459 (0.4); 0.0080 (4.1); −0.0002 (107.0); −0.0085 (3.7); −0.1497 (0.4).

Step 3: 6-{5-[(1S)-1-Aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N-ethyl-N-methylnicotinamide hydrochloride (61A)

[1243] ##STR00113##

[1244] To 1.42 g (3.65 mmol) of tert-butyl [(1S)-1-(1-{5-[ethyl(methyl)carbamoyl]pyridin-2-yl}-3-methyl-1H-1,2,4-triazol-5-yl)ethyl]carbamate were added 17.1 mL of a 4 M solution of HCl in 1,4-dioxane. The mixture was stirred at room temperature until starting material disappeared. The solvent was removed under reduced pressure and the residue was used without further purification to yield 1.41 g of the title compound which was used without further purification (82% purity).

[1245] ESI mass [m/z]: 289.2 [amine+H].sup.+

[1246] .sup.1H NMR (400 MHz, D6-DMSO, peaklist): δ=8.7292 (0.9); 7.9513 (1.1); 7.9302 (0.9); 5.3597 (0.4); 3.7138 (1.1); 3.7099 (1.1); 3.6997 (1.2); 3.6788 (1.3); 3.6667 (1.3); 3.6227 (1.6); 3.5686 (16.0); 3.4928 (0.4); 2.9946 (1.0); 2.9600 (1.0); 2.6904 (1.6); 2.5264 (0.5); 2.5088 (19.3); 2.5045 (24.0); 2.5000 (17.4); 2.4177 (6.5); 1.6326 (2.7); 1.6158 (2.6); 1.1647 (0.6); 1.1475 (0.4); 1.1358 (0.4); 1.1212 (0.5); 1.1081 (0.6); −0.0002 (0.9).

Intermediate 62A

Step 1: (2,2-Difluorocyclopropyl)methyl 3-bromo-5[(2,2-difluorocyclopropyl)methoxy]benzoate

[1247] ##STR00114##

[1248] A mixture of 3-bromo-5-hydroxybenzoic acid (1.841 g, 6.49 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (2.99 mg, 17.5 mmol) and potassium carbonate (2.42, 17.5 mmol) in acetonitrile (16 ml) was stirred at 60° C. over night and concentrated under reduced pressure. After addition of aq. HCl and ethyl acetate, the organic layer was washed with water, dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. Chromatography (silica, cyclohexane/ethyl acetate) yielded 0.657 g (25% of theory, 98% purity).

[1249] ESI mass [m/z]: 399.1 [M+H].sup.+

[1250] .sup.1H-NMR (400 MHz, D6-DMSO): δ=1.5 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 4.1 (m, 1H), 4.3 (m, 2H), 4.4 (m, 1H), 7.45 (s, 1H), 7.55 (s, 1H), 7.65 (s, 1H).

Step 2: 3-Bromo-5-[(2,2-difluorocyclopropyl)methoxy]benzoic acid

[1251] ##STR00115##

[1252] A mixture of (2,2-difluorocyclopropyl)methyl 3-bromo-5[(2,2-difluorocyclopropyl)methoxy]benzoate (0.657 g, 1.63 mmol) and sodium hydroxide (0.290 g, 3.26 mmol) in a mixture of ethanol (12 mL) and water (12 mL) was stirred at 40° C. for 2 hours and concentrated under reduced pressure. The residue was dissolved in aq. HCl/EtOAc, the organic layer was washed with water, dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to yield 469 mg (97% of theory, 100% purity).

[1253] ESI mass [m/z]: 309.0 [M+H].sup.+

[1254] .sup.1H-NMR (400 MHz, D6-DMSO): δ=1.5 (m, 1H), 1.7 (m, 1H), 2.3 (m, 1H), 4.1 (m, 1H), 4.3 (m, 1H), 7.45 (s, 1H), 7.5 (s, 1H), 7.65 (s, 1H), 13.4 (br, 1H).

Intermediate 63A

Step 1: Allyl 3-bromo-5-[(2,2-dichlorocyclopropyl)methoxy]benzoate

[1255] ##STR00116##

[1256] A mixture of 17 g (55.4 mmol) allyl 3-(allyloxy)-5-bromobenzoate (synthesis described in Angewandte Chemie-International Edition, 2012, vol. 51, #52, p. 13036-13040), 205 mL CHCl.sub.3, 2.74 g (12 mmol) triethylbenzylammonium chloride, 0.5 g (5.7 mmol) lithium bromide and 0.6 mL EtOH was heated under reflux with vigorous stirring. 88.6 g (996 mmol) aq. NaOH (45%) were added dropwise. After 4.5 h, stirring was continued at RT for 3 days. The mixture was acidified with aq. HCl, the aqueous layer extracted with DCM, the combined organic layers were washed with water, dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure to yield a crude product of 18 g (85% of theory). Chromatography (silica, cyclohexane-EtOAc, then RP (ACN, water, 0.1% HCOOH) yielded 10.6 g of an enriched mixture, that was directly used in the subsequent step.

[1257] ESI mass [m/z]: 380.9 [M+H].sup.+

Step 2: 3-Bromo-5-[(2,2-dichlorocyclopropyl)methoxy]benzoic acid

[1258] ##STR00117##

[1259] 10.67 g of the material from the previous step and 4.5 g (56 mmol) aq. NaOH (45%) were stirred in EtOH 0.5 days at 40° C., 0.5 days at reflux and 5 days at RT. The organic solvent was removed under reduced pressure. The residue was dissolved in aq. HCl and EtOAc, the organic layer was washed with water, dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. Repeated RP-chromatography (RP-18, ACN-water, 0.1% HCOOH, 0.05% HCOOH) yielded 0.6 g.

[1260] ESI mass [m/z]: 340.9 [M+H].sup.+

[1261] .sup.1H-NMR (400 MHz, D6-DMSO): δ=1.6 (m, 1H), 1.9 (m, 1H), 2.3 (m, 1H), 4 (m, 1H), 4.4 (m, 1H), 7.45 (s, 1H), 7.5 (s, 1H), 7.65 (s, 1H), 13.4 (br, 1H).

Intermediate 64A

Step 1: Methyl 3-bromo-5-(2-hydroxyethoxy)benzoate

[1262] ##STR00118##

[1263] To a stirred mixture of 14.8 g (64.4 mmol) methyl 3-bromo-5-hydroxybenzoate (synthesis described in WO2015/66515, 2015, A1) and 10.7 g (77.3 mmol) potassium carbonate in 200 mL ACN were added after 1 h 40.2 g (322 mmol) 2-bromoethanol. Stirring was continued at 60° C. for 0.5 days and the volatiles were removed under reduced pressure. EtOAc and water were added to the residue, the organic layer was washed with water, dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. Chromatography of the crude product (silica, cyclohexane/EtOAc) yielded 9.7 g (53% of theory, corrected by purity).

[1264] ESI mass [m/z]: 275.1 [M+H].sup.+

Step 2: Methyl 3-bromo-5-(2-chloroethoxy)benzoate

[1265] ##STR00119##

[1266] To a stirred mixture of 9.7 g (34.6 mmol) methyl 3-bromo-5-(2-hydroxyethoxy)benzoate in DCM with five drops of DMF were added 100 ml (1370 mmol) thionyl chloride. The mixture was heated under reflux for 0.5 days and the volatiles evaporated under reduced pressure. DCM was added, the insolubles removed by filtration and the remaining solution concentrated under reduced pressure. Chromatography of the crude product (silica, cyclohexane/EtOAc) yielded 7.3 g (70% of theory, yield corrected by purity).

[1267] ESI mass [m/z]: 295.0 [M+H].sup.+

[1268] .sup.1H-NMR (400 MHz, D6-DMSO): δ=3.9 (s, 3H), 4 (m, 2H), 4.4 (m, 2H), 7.45 (s, 1H), 7.5 (s, 1H), 7.7 (s, 1H).

Step 3: 3-Bromo-5-(vinyloxy)benzoic acid

[1269] ##STR00120##

[1270] To 6.45 g (21.4 mmol) methyl 3-bromo-5-(2-chloroethoxy)benzoate in 100 mL THF were added at 0-5° C. 6 g (53 mmol) potassium t.-butanolate. The mixture was stirred at RT for 0.5 days. The volatiles were removed under reduced pressure and the residue was dissolved in water/EtOAc. The mixture was acidified with aq. HCl, the organic layer was washed with water, dried with Na.sub.2SO.sub.4 and evaporated to yield 5 g (88% of theory, corrected by purity).

[1271] ESI mass [m/z]: 245.0 [M+H].sup.+

[1272] .sup.1H-NMR (400 MHz, D6-DMSO): δ=4.65 (m, 1H), 4.85 (m, 1H), 7 (m, 1H), 7.55 (s, 1H), 7.6 (m, 1H), 7.75 (s, 1H), 13.5 (br, 1H).

Step 4: Ethyl 3-bromo-5-[(2,2-dichlorocyclopropyl)oxy]benzoate

[1273] ##STR00121##

[1274] 5 g (18.8 mmol) 3-bromo-5-(vinyloxy)benzoic acid, 200 mL CHCl (ABCR, Art.-Nr. AB139647, Lot-Nr. 1362314, contains EtOH according to declaration) and 0.8 g (2.9 mmol) tetrabutylammonium chloride were stirred and 30 g (340 mmol) aq. NaOH 45% were added slowly. After 1 day, the addition of NaOH was repeated. The mixture was stirred for 2 days, water and DCM were added and the mixture was acidified with aq. HCl., the organic layer was washed with water, dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure to yield 6.8 g crude product. Repeated RP-chromatography (RP-18, ACN-water, 0.1% HCOOH, 0.05% HCOOH) yielded 2.21 g (33% of theory).

[1275] ESI mass [m/z]: 355.0 [M+H].sup.+

[1276] .sup.1H-NMR (400 MHz, D6-DMSO): δ=1.3 (m, 3H), 2 (m, 1H), 2.2 (m, 1H), 4.3 (m, 2H), 4.7 (m, 1H), 7.55 (s, 1H), 7.6 (s, 1H), 7.75 (s, 1H).

Step 5: 3-Bromo-5[(2,2-dichlorocyclopropyl)oxy]benzoic acid

[1277] ##STR00122##

[1278] 0.97 g (2.7 mmol) ethyl 3-bromo-5[(2,2-dichlorocyclopropyl)oxy]benzoate and 0.5 g (5.5 mmol) aq. NaOH (45%) were stirred in 40 mL of a 1:1 mixture of EtOH and water for 4 h at 40° C. The organic solvent was removed under reduced pressure. Aq. HCl and DCM were added, the organic layer was washed with aq. NaCl, dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure to yield 0.78 g.

[1279] ESI mass [m/z]: 327.0 [M+H].sup.+

[1280] .sup.1H-NMR (400 MHz, D6-DMSO): δ=2 (m, 1H), 2.2 (m, 1H), 4.65 (m, 1H), 7.5 (s, 1H), 7.6 (s, 1H), 7.75 (s, 1H), 13.5 (br, 1H).

Intermediate 65A

Dimethyl 5-(methylsulfonyl)isophthalate

[1281] ##STR00123##

[1282] Dimethyl 5-bromoisophthalate (230 g, 842 mmol), potassium carbonate (233 g, 1.68 mol), L-proline (48.5 g, 421 mmol), sodium methanesulfinate (172 g, 1.68 mol) and CuI (160 g, 842 mmol) were added into DMSO (1.15 L). The reaction mixture was stirred at 80° C. for 16 h. After cooling to RT, the reaction mixture was partitioned between ethyl acetate (2.50 L) and water (800 mL). The organic phase was separated, washed with water (2×500 mL) and brine (2×500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=50/1 to 5/1) to afford the title compound. Yield: 80.0 g (294 mmol, 35% of theory).

Intermediate 66A

Methyl 3-(hydroxymethyl)-5-(methylsulfonyl)benzoate

[1283] ##STR00124##

[1284] Dimethyl 5-(methylsulfonyl)isophthalate (50.0 g, 184 mmol) was dissolved in THF (500 mL). Lithium borohydride (10.0 g, 459 mmol) was added in portions slowly at 0° C. The mixture was stirred at 0° C. for 4 h. The mixture was slowly added into ice water (500 mL) and stirred thoroughly. Then, the mixture was extracted with ethyl acetate (2×1.50 L). The combined organic layers were washed with water (2×500 mL) and brine (2×500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=50/1 to 5/1) to afford the title compound. Yield: 26.0 g (106 mmol, 58% of theory).

Intermediate 67A

Methyl 3-(chloromethyl)-5-(methylsulfonyl)benzoate

[1285] ##STR00125##

[1286] Methyl 3-(hydroxymethyl)-5-(methylsulfonyl)benzoate (77.0 g, 315 mmol) was dissolved in 1,2-dichloroethane (540 mL) at 0° C. under a nitrogen atmosphere. Thionyl chloride (150 g, 1.26 mol) was dropped into the mixture at 0° C. After complete addition, the reaction mixture was stirred at 50° C. for 16 h. Then, the reaction mixture was quenched by addition of water (100 mL) at 0° C., and then extracted with DCM (2×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=50/1 to 1/1) to afford the title compound. Yield: 55.0 g (210 mmol, 67% of theory).

Intermediate 68A

Methyl 3-(cyanomethyl)-5-(methylsulfonyl)benzoate

[1287] ##STR00126##

[1288] Methyl 3-(chloromethyl)-5-(methylsulfonyl)benzoate (50.0 g, 190 mmol) and trimethylsilyl cyanide (28.3 g, 285 mmol, 35.7 mL) were dissolved in DMF (400 mL). Caesium fluoride (57.8 g, 381 mmol) was added into the mixture. The reaction mixture was stirred at 25° C. for 8 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (300 mL) and extracted with ethyl acetate (2×400 mL). The combined organic phases were washed with brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 1/1) to afford the title compound. Yield: 20.0 g (79.0 mmol, 42% of theory).

Intermediate 69A

3-(Cyanomethyl)-5-(methylsulfonyl)benzoic acid

[1289] ##STR00127##

[1290] Methyl 3-(cyanomethyl)-5-(methylsulfonyl)benzoate (10.0 g, 39.5 mmol) and lithium hydroxide monohydrate (1.99 g, 47.4 mmol) were dissolved in THF (50.0 mL) and water (10.0 mL). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove the THF. Then, 1.0 M aqueous hydrochloric acid was added dropwise to the reaction mixture slowly at 0° C. until pH=4. After 5 min, a solid precipitated which was collected by filtration an dried to afford the crude title compound. The crude product was purified by reversed-phase HPLC (0.1% TFA condition) to afford the title compound. Yield: 5.20 g (21.7 mmol, 55% of theory).

[1291] ESI mass [m/z]: 238.0 [M−H].sup.−.

[1292] .sup.1H-NMR (400 MHz, MeOD): δ [ppm]=68.51 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 4.17 (s, 2H), 3.21 (s, 3H).

Intermediate 70A

3-(2-Cyanopropan-2-yl)-5-(methylsulfonyl)benzoic acid

[1293] ##STR00128##

[1294] Under an argon atmosphere, a solution of 3-(cyanomethyl)-5-(methylsulfonyl)benzoic acid (250 mg, 1.04 mmol) in dry DMF (2.50 mL) was treated with sodium hydride (238 mg, 6.27 mmol, 63% dispersion in mineral oil) followed by iodomethane (593 mg, 260 μL, 4.18 mmol) and the resulting mixture was stirred at RT overnight. After careful addition of water, the mixture was extacted with ethyl acetate. The combined organic layers were discarded. The aqeous layer was acidified by addition of hydrochloric acid follwoed by extraction with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was dried to afford the title compound along with some remaining DMF. The product was used in the next step without further purififcation.

[1295] ESI mass [m/z]: 268.1 [M+H].sup.+

[1296] .sup.1H NMR (DMSO-d.sub.6) δ [ppm]=8.38-8.40 (m, 1H), 8.36-8.38 (m, 1H), 8.26-8.28 (m, 1H), 1.91 (s, 3H), 1.79 (s, 6H).

Intermediate 71A

Step 1: tert-Butyl N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]carbamate

[1297] ##STR00129##

[1298] tert-Butyl N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]carbamate (150 g, 797 mmol, 1.00 eq) was dissolved in dioxane (1.50 L). N,N-Dimetyhlformamide dimethylacetal (142 g, 1.20 mol, 159 mL, 1.50 eq) was added into the mixture. The reaction mixture was stirred at 25° C. for 3 hrs. TLC (dichloromethane:methanol=10:1, Rf=0.67) indicated the starting material was consumed. The crude product (193 g, calculated) in dioxane was used in the next step without further purification.

Step 2: tert-Butyl N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate

[1299] ##STR00130##

[1300] The reaction mixture of tert-Butyl N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]carbamate (193 g, 793 mmol, 1.00 eq) was added dropwise to a mixture of (6-chloropyrimidin-4-yl)hydrazine (126 g, 873 mmol, 1.10 eq) dissolved in AcOH (1900 mL). The reaction mixture was stirred at 25° C. for 16 hrs. TLC (petroleum ether:ethyl acetate=3:1, Rf=0.22) indicated the starting material was consumed completely. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=50/1 to 3/1). tert-Butyl N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (160 g, 493 mmol, 62.1% yield) was obtained as a white solid.

Step 3: Methyl 6-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylate

[1301] ##STR00131##

[1302] To a solution of tert-butyl N-[(1S)-1-[2-(6-chloropyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (80.0 g, 246 mmol, 1.00 eq) in MeOH (1.50 L) was added triethylamine (49.9 g, 493 mmol, 68.6 mL, 2.00 eq) and Pd(dppf)Cl.sub.2 (18.0 g, 24.6 mmol, 0.100 eq) under nitrogen. The suspension was degassed under vacuum and purged with CO (carbon monoxide) several times. The mixture was stirred under CO (246 mmol, 1.00 eq) (50.0 psi) at 40° C. for 16 hrs. TLC (petroleum ether:ethyl acetate=1:1, Rf=0.27) indicated the starting material was consumed. The reaction mixture was filtered and the filter liquor was concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=50/1 to 1/1). Methyl 6-[5-[(1S)-1-(tert-butoxy carbonylamino)ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylate (80.0 g, 230 mmol, 46.6% yield) was obtained as a white solid.

[1303] .sup.1H NMR (DMSO-d.sub.6) δ [ppm]=9.29 (s, 1H), 8.63 (s, 1H), 8.02 (s, 1H), 7.27 (s, 1H), 6.09-6.06 (m. 1H), 5.58-5.56 (d, 1H), 1.60-1.58 (d, 3H), 1.42 (s, 9H).

Step 4: tert-Butyl N-[(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate

[1304] ##STR00132##

[1305] Methyl 6-[5-[(1S)-1-(tert-butoxycarbonylamino)ethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxylate (40.0 g, 115 mmol, 1.00 eq) was dissolved in THF (240 mL) and MeOH (80.0 mL). NH.sub.4OH (96.6 g, 689 mmol, 106 mL, 25.0% purity, 6.00 eq) was added into the mixture. The reaction mixture was stirred at 25° C. for 6 hrs. TLC (petroleum ether:ethyl acetate=3:1, Rf=0.1) indicated the starting material was consumed completely. The reaction mixture was concentrated. The crude product was triturated with MTBE (300 mL) at 25° C. for 30 minutes. tert-Butyl N-[(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol yl]ethyl]carbamate (64.0 g, 189 mmol, 82.1% yield, 98.2% purity) was obtained as a white solid.

[1306] .sup.1H NMR (DMSO-d.sub.6) δ [ppm]=9.30 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 5.80-5.76 (m. 1H), 1.46-1.44 (d, 3H), 1.32 (s, 9H).

Step 5: 6-[5-[(1S)-1-Aminoethyl]-1,2,4-triazol-1-yl]pyrimidine-4-carboxamide; hydrochloride

[1307] ##STR00133##

[1308] tert-Butyl N-[(1S)-1-[2-(6-carbamoylpyrimidin-4-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (1 g, 3 mmol) was dissolved in 30 mL dioxane, then 4 M HCl/dioxane (7.5 mL) was added and the mixture was stirred at 50° C. for 7 hrs and additional 4 days at r.t. The mixture was evaporated under reduced pressure to obtain 1.02 g of the crude product.

[1309] ESI mass [m/z]: 234.2 [amine+H].sup.+

[1310] .sup.1H NMR (DMSO-d.sub.6) δ [ppm]=9.36 (s, 1H), 8.78 (s, 2H, NH.sub.2), 8.52 (s, 1H), 8.50 (bs, 1H), 8.39 (s, 1H), 8.17 (bs, 1H), 5.07-5.45 (m, 1H), 1.67-1.65 (d, 3H).

Intermediate 72A

3-(1-Cyano-1-methyl-ethoxy)-5-cyclopropyl-benzoic acid

[1311] ##STR00134##

[1312] 3-Bromo-5-(1-cyano-1-methyl-ethoxy)benzoic acid (1 g, 4 mmol) and cyclopropylboronic acid (0.6 g, 7 mmol) were dissolved in a mixture of 12 mL dioxane and 5 mL water under nitrogen, then subsequently K.sub.2CO.sub.3 (1.7 g, 12 mmol) and Pd(dppf)Cl.sub.2 (129 mg, 0.176 mmol) were added and the mixture was stirred under nitrogen at 100° C. for 2 hrs. The reaction mixture was evaporated under vacuum, the residue was quenched with water and acidified with 1M HCl to pH 4-5 and extracted with ethyl acetate three times. The combined organic layers were washed with brine and evaporated under vacuum. The residue was taken up with dichlormethane, the organic phase was extracted with a saturated aqueous solution of NaHCO.sub.3, the aqueous phase was separated and acidified with 2M HCl until pH 2, and again extracted with dichloromethane. The organic layers were collected and dried over Na.sub.sSO.sub.4, filtered, and evaporated in vacuum to obtain 3-(1-cyano-1-methyl-ethoxy)-5-cyclopropyl-benzoic acid as colorless solid (554 mg, yield 62.9%).

[1313] .sup.1H NMR (DMSO-d.sub.6) δ [ppm]=13.20 (bs, 1H, COOH), 7.49 (s, 2H), 7.06 (s, 1H), 2.05-2.01 (m, 1H), 1.69 (s, 6H), 1.03-0.99 (m, 2H), 0.73-0.69 (m, 2H).

EXAMPLES

Example I-3

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(cyclopropylmethoxy)-5-methylbenzamide

[1314] ##STR00135##

[1315] To a solution of 100 mg (0.39 mmol) 6-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride (1:1) in 2 mL DCM was added 0.14 mL (0.79 mmol) DIPEA and the solution was stirred 30 minutes at room temperature. Then 173 mg (0.41 mmol, 50% pure) 3-(cyclopropylmethoxy)-5-methylbenzoic acid, 182 mg (0.47 mmol) HATU and 0.10 mL DIPEA (0.55 mmol) were added into the mixture and further stirred for 16 h. The reaction mixture was quenched with an aqueous solution of 5% NaH.sub.2PO.sub.4 and then was extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, filtered and after evaporation of the solvent under vacuo the crude was purified by flash chromatography. The combined product fractions were evaporated to yield the title compound (120 mg, 75%).

[1316] ESI mass [m/z]: 403.3 [M+H].sup.+

[1317] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.0615 (3.4); 9.0597 (3.7); 9.0560 (3.8); 9.0542 (3.6); 8.9222 (2.0); 8.9047 (2.0); 8.5765 (3.2); 8.5709 (3.0); 8.5550 (3.4); 8.5494 (3.3); 8.3142 (0.9); 8.2169 (9.6); 8.0658 (3.8); 8.0640 (3.8); 8.0443 (3.6); 8.0425 (3.6); 7.1671 (3.7); 7.1090 (2.9); 6.8856 (3.0); 6.0463 (1.4); 6.0289 (2.2); 6.0114 (1.4); 5.7545 (6.8); 4.0380 (0.6); 4.0203 (0.6); 3.8173 (6.1); 3.7999 (6.2); 3.3213 (139.9); 2.6800 (0.3); 2.6753 (0.7); 2.6708 (0.9); 2.6661 (0.7); 2.6620 (0.3); 2.5243 (3.0); 2.5195 (4.4); 2.5109 (52.5); 2.5064 (106.2); 2.5018 (140.5); 2.4972 (101.8); 2.4927 (48.7); 2.3332 (0.6); 2.3286 (0.9); 2.3241 (0.6); 2.2819 (16.0); 1.9886 (2.8); 1.6176 (8.6); 1.6002 (8.5); 1.2394 (0.4); 1.2341 (0.5); 1.2200 (0.7); 1.2140 (0.7); 1.2103 (0.6); 1.2022 (1.2); 1.1929 (1.3); 1.1821 (0.8); 1.1751 (1.8); 1.1573 (0.8); 0.5856 (1.0); 0.5747 (3.1); 0.5704 (3.2); 0.5658 (1.5); 0.5600 (1.5); 0.5546 (3.2); 0.5502 (3.0); 0.5400 (1.1); 0.3300 (1.2); 0.3195 (3.5); 0.3160 (3.5); 0.3078 (3.1); 0.3040 (3.7); 0.2929 (0.9); 0.1460 (0.4); 0.0080 (2.8); −0.0002 (88.0); −0.0085 (2.7); −0.1495 (0.3)

Example I-4

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(cyclopentyloxy)-5-methylbenzamide

[1318] ##STR00136##

[1319] To a solution of 85 mg (0.33 mmol) 6-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride (1:1) in 2 mL DCM was added 0.12 mL (0.67 mmol) DIPEA and the solution was stirred 30 minutes at room temperature. Then 78 mg (0.35 mmol) 3-(cyclopentyloxy)-5-methylbenzoic acid, 155 mg (0.40 mmol) HATU and 0.08 mL DIPEA (0.47 mmol) were added into the mixture and further stirred for 16 h. The reaction mixture was quenched with an aqueous solution of 5% NaH.sub.2PO.sub.4 and then was extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, filtered and after evaporation of the solvent under vacuo the crude was purified by flash chromatography. The combined product fractions were evaporated to yield the title compound (84 mg, 60%).

[1320] ESI mass [m/z]: 417.3 [M+H].sup.+

[1321] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.0598 (3.4); 9.0581 (3.6); 9.0543 (3.7); 9.0525 (3.4); 8.9215 (1.9); 8.9039 (2.0); 8.5770 (3.0); 8.5715 (2.9); 8.5556 (3.2); 8.5500 (3.2); 8.2184 (9.4); 8.0683 (3.8); 8.0666 (3.8); 8.0468 (3.5); 8.0451 (3.6); 7.1565 (3.6); 7.1553 (3.6); 7.0677 (2.9); 6.8560 (2.9); 6.0436 (1.4); 6.0261 (2.2); 6.0086 (1.4); 5.7552 (5.9); 4.8379 (0.4); 4.8318 (0.9); 4.8230 (1.0); 4.8173 (1.6); 4.8028 (0.8); 4.0384 (0.6); 4.0206 (0.6); 3.3251 (74.8); 2.6762 (0.3); 2.6717 (0.5); 2.6670 (0.3); 2.5252 (1.4); 2.5205 (2.1); 2.5118 (27.3); 2.5073 (55.7); 2.5027 (73.5); 2.4981 (52.6); 2.4935 (25.0); 2.3342 (0.3); 2.3295 (0.5); 2.3248 (0.3); 2.2836 (16.0); 1.9892 (2.6); 1.8961 (1.4); 1.8822 (1.2); 1.8699 (0.9); 1.8641 (0.9); 1.7247 (0.4); 1.6904 (4.7); 1.6817 (2.5); 1.6758 (2.1); 1.6705 (2.0); 1.6609 (1.7); 1.6504 (1.1); 1.6445 (1.2); 1.6163 (9.1); 1.5988 (9.6); 1.5817 (1.9); 1.5726 (1.5); 1.1932 (0.8); 1.1754 (1.5); 1.1576 (0.7); 0.0080 (1.4); −0.0002 (46.5); −0.0086 (1.3)

Example I-5

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-(cyclobutyloxy)-5-methylbenzamide

[1322] ##STR00137##

[1323] To a solution of 85 mg (0.33 mmol) 6-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride (1:1) in 2 mL DCM was added 0.12 mL (0.67 mmol) DIPEA and the solution was stirred 30 minutes at room temperature. Then 73 mg (0.35 mmol) 3-(cyclobutyloxy)-5-methylbenzoic acid, 155 mg (0.40 mmol) HATU and 0.08 mL DIPEA (0.47 mmol) were added into the mixture and further stirred for 16 h. The reaction mixture was quenched with an aqueous solution of 5% NaH.sub.2PO.sub.4 and then was extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, filtered and after evaporation of the solvent under vacuo the crude was purified by flash chromatography. The combined product fractions were evaporated to yield the title compound (74 mg, 53%).

[1324] ESI mass [m/z]: 403.3 [M+H].sup.+

[1325] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.0612 (3.2); 9.0597 (3.6); 9.0559 (3.5); 9.0542 (3.4); 8.9249 (1.9); 8.9073 (2.0); 8.5793 (2.6); 8.5738 (2.5); 8.5579 (2.8); 8.5523 (2.8); 8.3149 (0.8); 8.2184 (8.6); 8.0688 (3.4); 8.0673 (3.6); 8.0473 (3.2); 8.0458 (3.3); 7.1772 (3.6); 7.0035 (3.0); 6.7972 (3.0); 6.0434 (1.4); 6.0257 (2.2); 6.0082 (1.4); 4.7176 (0.3); 4.6993 (1.2); 4.6816 (1.9); 4.6637 (1.3); 4.6462 (0.3); 3.3192 (84.0); 2.6749 (1.5); 2.6704 (2.1); 2.6660 (1.6); 2.5239 (6.5); 2.5190 (9.8); 2.5103 (127.4); 2.5060 (254.4); 2.5015 (332.3); 2.4969 (241.0); 2.4925 (117.1); 2.4392 (0.8); 2.4326 (0.8); 2.4100 (1.5); 2.4022 (1.5); 2.3938 (1.5); 2.3718 (0.8); 2.3653 (0.6); 2.3329 (1.5); 2.3283 (2.1); 2.3238 (1.5); 2.2835 (16.0); 2.0738 (0.4); 2.0516 (0.4); 2.0263 (1.4); 2.0212 (0.9); 2.0070 (1.4); 2.0017 (1.7); 1.9965 (1.4); 1.9826 (1.1); 1.9773 (1.4); 1.9527 (0.4); 1.8114 (0.4); 1.7855 (1.0); 1.7607 (1.0); 1.7354 (0.4); 1.6714 (0.6); 1.6674 (0.7); 1.6463 (1.3); 1.6143 (8.5); 1.5969 (8.5); 0.1458 (0.6); 0.0080 (4.9); −0.0001 (151.7); −0.0084 (5.3); −0.1497 (0.6)

Example I-6

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-methyl-5-(oxetan-3-yloxy)benzamide

[1326] ##STR00138##

[1327] To a solution of 85 mg (0.33 mmol) 6-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride (1:1) in 2 mL DCM was added 0.12 mL (0.67 mmol) DIPEA and the solution was stirred 30 minutes at room temperature. Then 74 mg (0.35 mmol) 3-methyl-5-(oxetan-3-yloxy)benzoic acid, 155 mg (0.40 mmol) HATU and 0.08 mL DIPEA (0.47 mmol) were added into the mixture and further stirred for 16 h. The reaction mixture was quenched with an aqueous solution of 5% NaH.sub.2PO.sub.4 and then was extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4, filtered and after evaporation of the solvent under vacuo the crude was purified by flash chromatography. The combined product fractions were evaporated to yield the title compound (73 mg, 53%).

[1328] ESI mass [m/z]: 405.3 [M+H].sup.+

[1329] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.0613 (0.5); 9.0594 (0.5); 9.0558 (0.5); 9.0539 (0.5); 8.5807 (0.4); 8.5752 (0.4); 8.5593 (0.4); 8.5537 (0.4); 8.2218 (1.3); 8.0713 (0.5); 8.0694 (0.5); 8.0498 (0.5); 8.0479 (0.5); 7.2397 (0.5); 6.9486 (0.4); 6.7691 (0.4); 4.9083 (0.4); 4.5298 (0.4); 4.5165 (0.4); 4.5119 (0.4); 4.4984 (0.4); 3.3214 (26.8); 2.6897 (16.0); 2.5242 (0.8); 2.5195 (1.2); 2.5108 (15.5); 2.5063 (31.8); 2.5017 (42.0); 2.4970 (30.0); 2.4924 (14.2); 2.2950 (2.1); 1.6174 (1.2); 1.6000 (1.2); 0.0080 (0.8); 0.0057 (0.4); −0.0002 (25.2); −0.0086 (0.7)

Example I-12

3-[1-(3-Chlorophenyl)ethoxy]-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethyl)benzamide

[1330] ##STR00139##

[1331] Example I-12 was synthesized under the same reaction conditions described in the general procedure 1 from 150 mg (0.36 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 50 mg (0.36 mmol) potassium carbonate and 79 mg (0.36 mmol) 1-(1-bromoethyl)-3-chlorobenzene in acetonitrile at room temperature to yield the title compound (36 mg, 18%).

[1332] ESI mass [m/z]: 555.3 [M+H].sup.+

[1333] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.2736 (1.4); 9.2612 (1.8); 9.2561 (1.8); 9.2441 (1.5); 9.0145 (4.4); 9.0095 (4.4); 8.5374 (1.9); 8.5345 (2.2); 8.5320 (2.2); 8.5291 (2.0); 8.5159 (2.1); 8.5130 (2.4); 8.5105 (2.4); 8.5076 (2.1); 8.3167 (0.4); 8.0179 (4.6); 7.9964 (4.2); 7.7298 (2.4); 7.6923 (2.4); 7.6515 (1.9); 7.6320 (1.9); 7.5205 (2.3); 7.4997 (2.3); 7.4066 (6.9); 7.3958 (4.6); 7.3933 (4.0); 7.3904 (3.8); 7.3835 (2.4); 7.3806 (3.0); 7.3717 (0.8); 7.3620 (0.7); 7.3576 (0.6); 7.3521 (1.5); 7.3468 (2.6); 7.3416 (1.6); 7.3390 (1.8); 7.3321 (1.8); 7.3290 (1.3); 7.3240 (1.1); 7.3187 (0.6); 6.0867 (0.3); 6.0693 (1.4); 6.0521 (2.1); 6.0355 (1.4); 6.0182 (0.3); 5.7569 (5.1); 5.7476 (1.6); 5.7369 (1.6); 5.7317 (1.6); 5.7214 (0.5); 5.7162 (0.5); 3.3261 (124.6); 2.6760 (1.0); 2.6716 (1.4); 2.6671 (1.1); 2.5250 (4.7); 2.5115 (86.5); 2.5072 (171.5); 2.5027 (225.8); 2.4981 (168.0); 2.4938 (84.8); 2.3374 (15.2); 2.3300 (16.0); 2.2436 (0.5); 1.6057 (8.5); 1.5884 (9.0); 1.5793 (6.7); 1.5716 (6.6); 1.5635 (6.3); 1.5558 (5.7); 0.1460 (0.3); 0.0079 (3.0); −0.0002 (77.7); −0.0085 (3.1); −0.1495 (0.3)

Example I-13

3-[(3-Chlorobenzyl)oxy]-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethyl)benzamide

[1334] ##STR00140##

[1335] Example I-13 was synthesized under the same reaction conditions described in general procedure 1 from 150 mg (0.36 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 50 mg (0.36 mmol) potassium carbonate and 0.05 mL (0.36 mmol) 1-(bromomethyl)-3-chlorobenzene in acetonitrile at room temperature to yield the title compound (27 mg, 14%).

[1336] ESI mass [m/z]: 541.1 [M+H].sup.+

[1337] .sup.1H-NMR peaklist (400.2 MHz, d6-DMSO): δ=9.3095 (1.4); 9.2919 (1.4); 9.0299 (2.5); 9.0251 (2.5); 8.5402 (1.8); 8.5347 (1.7); 8.5188 (1.9); 8.5132 (1.9); 8.0226 (2.6); 8.0010 (2.4); 7.7723 (3.7); 7.7661 (2.4); 7.5618 (2.6); 7.5316 (2.2); 7.4513 (1.4); 7.4469 (1.0); 7.4376 (6.3); 7.4303 (2.5); 7.4255 (1.8); 7.4188 (0.8); 7.4156 (0.8); 6.1051 (1.0); 6.0876 (1.6); 6.0700 (1.1); 5.7564 (3.7); 5.2517 (7.1); 3.3287 (70.6); 2.6764 (0.4); 2.6720 (0.5); 2.6675 (0.4); 2.5252 (1.4); 2.5118 (28.1); 2.5075 (56.8); 2.5030 (75.4); 2.4984 (55.8); 2.4940 (27.7); 2.3406 (16.0); 1.6272 (5.7); 1.6098 (5.7); 0.0079 (0.9); −0.0002 (32.0); −0.0084 (1.3)

Example I-14

3-[1-(2-Chlorophenyl)ethoxy]-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethyl)benzamide

[1338] ##STR00141##

[1339] Example I-14 was synthesized under the same reaction conditions described in the general procedure 1 from 150 mg (0.36 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 50 mg (0.36 mmol) potassium carbonate and 79 mg (0.36 mmol) 1-(1-bromoethyl)-2-chlorobenzene in acetonitrile at room temperature to yield the title compound (21 mg, 10%).

[1340] ESI mass [m/z]: 555.4 [M+H].sup.+

[1341] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.2743 (1.4); 9.2639 (1.6); 9.2568 (1.7); 9.2463 (1.5); 8.9982 (2.3); 8.9924 (4.3); 8.9868 (2.5); 8.5358 (3.2); 8.5303 (3.1); 8.5143 (3.4); 8.5087 (3.4); 8.3164 (0.4); 8.0178 (2.9); 8.0158 (2.9); 7.9963 (2.7); 7.9943 (2.7); 7.7510 (2.4); 7.7232 (2.4); 7.5822 (2.0); 7.5601 (2.0); 7.5110 (1.3); 7.5049 (1.4); 7.4958 (2.5); 7.4921 (3.6); 7.4878 (2.4); 7.4840 (2.5); 7.4791 (3.4); 7.4751 (3.1); 7.4667 (1.5); 7.4608 (1.9); 7.3638 (0.4); 7.3591 (0.6); 7.3550 (0.4); 7.3498 (0.7); 7.3452 (1.6); 7.3407 (1.7); 7.3353 (2.7); 7.3284 (4.5); 7.3208 (3.8); 7.3160 (2.0); 7.3106 (2.8); 7.3048 (1.4); 7.2977 (0.6); 7.2920 (0.8); 7.2768 (3.5); 6.0788 (0.3); 6.0620 (1.5); 6.0447 (2.3); 6.0279 (1.5); 6.0102 (0.4); 5.8845 (0.4); 5.8691 (1.6); 5.8592 (1.7); 5.8534 (1.7); 5.8435 (1.6); 5.8276 (0.4); 5.7565 (3.5); 3.3250 (93.1); 2.6804 (0.5); 2.6761 (1.1); 2.6715 (1.5); 2.6671 (1.1); 2.6629 (0.6); 2.5250 (4.6); 2.5202 (6.9); 2.5115 (87.7); 2.5071 (177.9); 2.5026 (235.7); 2.4981 (174.8); 2.4937 (87.7); 2.3391 (15.5); 2.3264 (16.0); 2.2423 (0.5); 1.6155 (6.7); 1.6097 (7.2); 1.5938 (13.4); 1.5791 (7.2); 1.5760 (7.1); 0.1461 (0.4); 0.0080 (2.8); −0.0002 (87.9); −0.0084 (3.4); −0.1494 (0.4)

Example I-15

3-[1-(4-Chlorophenyl)ethoxy]-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethyl)benzamide

[1342] ##STR00142##

[1343] Example I-15 was synthesized under the same reaction conditions described in general procedure 1 from 150 mg (0.36 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 50 mg (0.36 mmol) potassium carbonate and 79 mg (0.36 mmol) 1-(1-bromoethyl)-4-chlorobenzene in acetonitrile at room temperature to yield the title compound (21 mg, 11%).

[1344] ESI mass [m/z]: 555.4 [M+H].sup.+

[1345] .sup.1H-NMR peaklist (400.2 MHz, d6-DMSO): δ=9.2635 (1.6); 9.2548 (1.8); 9.2458 (1.8); 9.2370 (1.7); 9.0172 (2.7); 9.0127 (4.7); 9.0077 (2.7); 8.5405 (1.9); 8.5362 (2.7); 8.5314 (1.8); 8.5190 (2.0); 8.5147 (2.9); 8.5098 (1.9); 8.3168 (0.3); 8.0200 (4.8); 7.9985 (4.4); 7.7236 (2.6); 7.6839 (2.6); 7.6315 (2.2); 7.6143 (2.2); 7.4732 (2.2); 7.4580 (3.1); 7.4517 (6.2); 7.4373 (6.2); 7.4264 (6.3); 7.4202 (2.8); 7.4153 (6.5); 7.4100 (2.5); 7.4052 (2.6); 7.3988 (1.3); 7.3936 (2.4); 7.3818 (4.1); 6.0823 (0.3); 6.0647 (1.3); 6.0500 (2.0); 6.0472 (2.0); 6.0323 (1.3); 6.0152 (0.3); 5.7570 (5.0); 5.7510 (1.6); 5.7403 (1.7); 5.7353 (1.7); 5.7248 (1.5); 5.7101 (0.4); 3.3257 (111.7); 2.6762 (1.1); 2.6718 (1.5); 2.6674 (1.1); 2.5072 (184.3); 2.5028 (236.4); 2.4984 (175.3); 2.3378 (15.4); 2.3298 (16.0); 1.6034 (10.5); 1.5860 (10.6); 1.5663 (6.6); 1.5607 (6.9); 1.5506 (6.8); 1.5450 (6.4); 1.4358 (0.4); 0.1463 (0.4); 0.0080 (4.2); 0.0000 (92.0); −0.0082 (3.9); −0.1493 (0.4)

Example I-16

3-[(2-Chlorobenzyl)oxy]-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}(trifluoromethyl)benzamide

[1346] ##STR00143##

[1347] Example I-16 was synthesized under the same reaction conditions described in general procedure 1 from 150 mg (0.36 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 50 mg (0.36 mmol) potassium carbonate and 74 mg (0.36 mmol) 1-(bromomethyl)-2-chlorobenzene in acetonitrile at room temperature to yield the title compound (12 mg, 6%).

[1348] ESI mass [m/z]: 541.4 [M+H].sup.+

[1349] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.3220 (1.4); 9.3043 (1.4); 9.0308 (2.2); 9.0290 (2.5); 9.0253 (2.4); 9.0235 (2.4); 8.5406 (2.0); 8.5350 (1.9); 8.5191 (2.2); 8.5135 (2.2); 8.0251 (2.5); 8.0234 (2.6); 8.0036 (2.3); 8.0018 (2.4); 7.7878 (2.5); 7.7701 (1.9); 7.6549 (1.2); 7.6496 (0.8); 7.6458 (0.7); 7.6395 (1.1); 7.6317 (1.4); 7.5538 (2.1); 7.5489 (2.6); 7.5434 (1.2); 7.5337 (0.8); 7.5298 (1.1); 7.5256 (1.9); 7.4490 (0.3); 7.4432 (0.6); 7.4305 (1.8); 7.4230 (2.3); 7.4150 (3.6); 7.4057 (2.4); 7.4005 (1.5); 7.3867 (0.4); 6.1064 (1.0); 6.0890 (1.6); 6.0714 (1.0); 5.7565 (3.2); 5.2883 (6.9); 3.3529 (0.3); 3.3276 (153.2); 2.6760 (0.6); 2.6714 (0.9); 2.6669 (0.6); 2.5250 (2.4); 2.5203 (3.6); 2.5116 (49.6); 2.5071 (102.6); 2.5025 (137.2); 2.4979 (100.6); 2.4934 (48.8); 2.3405 (16.0); 2.3295 (1.2); 2.3248 (0.8); 2.3206 (0.4); 1.6270 (5.4); 1.6096 (5.4); 0.0080 (2.1); −0.0002 (69.5); −0.0085 (2.3)

Example I-17

3-chloro-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-5-[(methylsulfonyl)methyl]benzamide

[1350] ##STR00144##

[1351] To 0.23 g (0.9 mmol) 6-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride (WO2019206799) and 0.37 ml Et.sub.3N in 10 ml DCM were added 0.27 g (0.9 mmol) 3-chloro[(methylsulfonyl)methyl]benzoyl chloride in 5 ml DCM at ice-water cooling. The mixture was stirred overnight at room temperature. Water was added, the organic layer was dried and evaporated under reduced pressure. Reversed phase chromatography of the residue (acetonitrile/water) yielded 6 mg (1.5%) of the title compound.

[1352] ESI mass [m/z]: 445.2 [M+H].sup.+

[1353] .sup.1H NMR (400 MHz, D6-DMSO): δ=1.6 (d, 3H), 2.9 (s, 3H), 4.55 (s, 2H), 6.1 (m, 1H), 7.65 (s, 1H), 7.8 (s, 1H), 7.9 (s, 1H), 8.1 (d, 1H), 8.3 (s, 1H), 8.55 (m, 1H), 9.05 (m, 1H), 9.25 (m, 1H).

Example I-18

3-(Benzyloxy)-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethyl)benzamide

[1354] ##STR00145##

[1355] Example I-18 was synthesized under the same reaction conditions described in general procedure 1 from 300 mg (0.19 mmol, 27% purity) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 27 mg (0.19 mmol) potassium carbonate and 32 mg (0.19 mmol) benzyl bromide in acetonitrile at room temperature to yield the title compound (23 mg, 23%).

[1356] ESI mass [m/z]: 507.5 [M+H].sup.+

[1357] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.3008 (1.4); 9.2832 (1.5); 9.0287 (2.4); 9.0270 (2.6); 9.0232 (2.6); 9.0215 (2.4); 8.5397 (1.9); 8.5341 (1.9); 8.5182 (2.1); 8.5126 (2.1); 8.3161 (0.5); 8.0225 (2.6); 8.0209 (2.6); 8.0009 (2.4); 7.9993 (2.4); 7.7597 (4.7); 7.7558 (5.0); 7.5074 (2.3); 7.4865 (1.6); 7.4828 (2.2); 7.4653 (3.6); 7.4290 (1.4); 7.4261 (1.9); 7.4214 (0.7); 7.4085 (3.8); 7.4046 (1.7); 7.3899 (2.0); 7.3670 (1.5); 7.3556 (0.5); 7.3492 (1.6); 7.3423 (0.3); 7.3313 (0.4); 6.1004 (1.0); 6.0828 (1.6); 6.0654 (1.0); 5.2354 (7.0); 3.3261 (212.6); 2.6756 (1.2); 2.6710 (1.6); 2.6666 (1.2); 2.5245 (5.4); 2.5110 (98.2); 2.5066 (194.8); 2.5021 (255.0); 2.4976 (188.2); 2.4932 (93.4); 2.3397 (16.0); 2.3291 (2.0); 2.3246 (1.4); 2.2461 (0.4); 1.6238 (5.6); 1.6064 (5.6); 0.1459 (0.4); 0.0080 (3.0); −0.0001 (87.3); −0.0084 (3.3); −0.1496 (0.4).

Example I-19

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(trifluoromethyl)benzamide

[1358] ##STR00146##

[1359] Example I-19 was synthesized under the same reaction conditions described in general procedure 1 from 200 mg (0.48 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 66 mg (0.48 mmol) potassium carbonate and 86 mg (0.48 mmol) 1 4-(bromomethyl)tetrahydro-2H-pyran in acetonitrile at room temperature to yield the title compound (43 mg, 17%).

[1360] ESI mass [m/z]: 515.2 [M+H].sup.+

[1361] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.2934 (1.4); 9.2756 (1.4); 9.0304 (2.4); 9.0289 (2.5); 9.0250 (2.6); 8.5400 (1.8); 8.5345 (1.8); 8.5185 (2.0); 8.5129 (2.0); 8.3160 (0.4); 8.0198 (2.6); 8.0184 (2.5); 7.9983 (2.4); 7.9968 (2.3); 7.7255 (2.6); 7.6509 (2.1); 7.4017 (2.2); 6.0962 (1.0); 6.0786 (1.6); 6.0611 (1.0); 3.9646 (3.4); 3.9486 (3.5); 3.9003 (1.2); 3.8927 (1.3); 3.8723 (1.4); 3.8648 (1.4); 3.3648 (1.4); 3.3260 (132.6); 2.6756 (0.9); 2.6711 (1.2); 2.6666 (0.9); 2.5246 (3.6); 2.5198 (5.4); 2.5111 (74.7); 2.5067 (152.9); 2.5022 (202.5); 2.4977 (150.1); 2.4933 (75.5); 2.3399 (16.0); 2.3292 (1.7); 2.3246 (1.1); 2.0267 (0.4); 2.0178 (0.6); 2.0090 (0.4); 1.9901 (0.4); 1.6993 (1.2); 1.6711 (1.5); 1.6667 (1.5); 1.6256 (5.7); 1.6082 (5.6); 1.4028 (0.4); 1.3916 (0.5); 1.3725 (1.0); 1.3613 (1.2); 1.3401 (1.1); 1.3297 (1.0); 1.3102 (0.4); 1.2995 (0.4); 0.1460 (0.4); 0.0079 (2.9); −0.0002 (94.9); −0.0084 (4.0); −0.1497 (0.4)

Example I-20

3-[(4-Chlorobenzyl)oxy]-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-5-(trifluoromethyl)benzamide

[1362] ##STR00147##

[1363] Example I-20 was synthesized under the same reaction conditions described in general procedure 1 from 200 mg (0.48 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide, 66 mg (0.48 mmol) potassium carbonate and 99 mg (0.48 mmol) 1-(bromomethyl)-4-chlorobenzene in acetonitrile at room temperature to yield the title compound (48 mg, 19%).

[1364] ESI mass [m/z]: 541.4 [M+1-1].sup.+

[1365] .sup.1H-NMR peaklist (400.2 MHz, d6-DMSO): δ=9.3032 (1.4); 9.2855 (1.5); 9.0278 (2.6); 9.0236 (2.5); 8.5404 (1.8); 8.5348 (1.7); 8.5189 (1.9); 8.5133 (1.8); 8.3153 (1.0); 8.0214 (2.6); 8.0000 (2.4); 7.7672 (2.7); 7.7471 (2.2); 7.5156 (2.8); 7.5103 (2.9); 7.4952 (6.6); 7.4806 (7.3); 7.4646 (0.8); 7.4589 (1.8); 6.0994 (1.0); 6.0821 (1.6); 6.0646 (1.0); 5.2365 (7.0); 3.3983 (0.4); 3.3287 (761.0); 2.6756 (2.4); 2.6711 (3.3); 2.6667 (2.5); 2.5244 (11.0); 2.5066 (406.8); 2.5022 (531.9); 2.4977 (395.5); 2.3389 (16.0); 2.3292 (3.9); 2.3245 (2.7); 2.0743 (0.6); 1.6231 (5.6); 1.6058 (5.6); 0.1459 (1.2); 0.0079 (9.9); −0.0001 (267.9); −0.0084 (11.5); −0.1498 (1.2)

Example I-21

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-(tetrahydro-2H-pyran-4-yloxy)-5-(trifluoromethyl)benzamide

[1366] ##STR00148##

[1367] To a solution of 252 mg (0.961 mmol) triphenylphosphine in 4 mL THF under argon was added 221 mg (0.961 mmol) di-tert-butyl azodicarboxylate and the mixture was stirred for 15 minutes. Then 245 mg (2.40 mmol) tetrahydro-4-pyranol were added and after 15 minutes finally a solution of 200 mg (0.48 mmol) N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide in 2 mL THF was added and the reaction mixture was stirred at room temperature for 16 h. After evaporation of the solvent under vacuo the crude was purified by flash chromatography to yield the title compound (32 mg, 13%).

[1368] ESI mass [m/z]: 501.4 [M+H].sup.+

[1369] .sup.1H-NMR peaklist (400.2 MHz, d.sub.6-DMSO): δ=9.2882 (1.4); 9.2705 (1.5); 9.0292 (2.4); 9.0277 (2.4); 9.0238 (2.6); 8.5415 (1.8); 8.5360 (1.8); 8.5200 (2.0); 8.5144 (2.0); 8.0222 (2.6); 8.0208 (2.5); 8.0007 (2.4); 7.9992 (2.3); 7.7254 (2.6); 7.6610 (2.1); 7.4683 (2.2); 6.0904 (1.0); 6.0730 (1.6); 6.0554 (1.0); 4.7990 (0.5); 4.7879 (0.7); 4.7778 (1.0); 4.7674 (0.7); 4.7565 (0.5); 3.8734 (0.8); 3.8628 (1.5); 3.8501 (1.0); 3.8449 (1.1); 3.8331 (1.8); 3.8220 (0.9); 3.5337 (1.0); 3.5269 (1.2); 3.5105 (1.3); 3.5041 (2.0); 3.4817 (1.1); 3.4751 (1.0); 3.3354 (257.8); 2.6765 (0.7); 2.6722 (1.0); 2.6676 (0.7); 2.5255 (3.2); 2.5206 (5.1); 2.5120 (58.5); 2.5076 (116.8); 2.5031 (153.3); 2.4986 (114.2); 2.4942 (57.7); 2.3403 (16.0); 2.3304 (1.5); 2.3255 (0.9); 1.9860 (0.9); 1.9765 (1.0); 1.9645 (0.8); 1.9530 (1.2); 1.9442 (1.1); 1.6236 (6.2); 1.6061 (6.4); 1.5915 (1.1); 1.5801 (1.4); 1.5701 (0.9); 1.5577 (0.5); 1.5478 (0.4); 0.1460 (0.8); 0.0080 (6.3); −0.0002 (171.7); −0.0083 (7.6); −0.1496 (0.8)

Example I-27

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-3-[(methylsulfinyl)methoxy]-5-(trifluoromethyl)benzamide

[1370] ##STR00149##

[1371] 0.82 g (2.0 mmol) N-[(2S)-1-{(E)-[(dimethylamino)methylene]amino}-1-oxopropan-2-yl]-3-[(methylsulfinyl)methoxy]-5-(trifluoromethyl)benzamide and 0.3 g (2.2 mmol) 6-hydrazono-1,6-dihydropyridine-3-carbonitrile were stirred in AcOH at 75° C. for 20 min. The mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc aq. K.sub.2CO.sub.3, aq. NaCl. The aquous phase was extracted two times with EtOAc, the combined organic phases were dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. Chromatography of the residue (silica, i-hexane-acetone) yielded 0.41 g (40%, yield corrected by purity).

[1372] .sup.1H NMR: see peak list in table 1

[1373] ESI mass [m/z]: 479.2 [M+H].sup.+

Example I-31

3-Bromo-N-{(1S)-1-[1-(5-cyano-1,3-thiazol-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzamide

[1374] ##STR00150##

[1375] 0.7 g (1.4 mmol) 3-bromo-N-[(2S)-1-{(E)-[(dimethylamino)methylene]amino}-1-oxopropan-2-yl]-5-[(2,3,3-trichloroprop-2-en-1-yl)oxy]benzamide and 0.3 g (2.14 mmol) (2E)-2-hydrazono-2,3-dihydro-1,3-thiazole-5-carbonitrile were stirred in AcOH at 85° C. for 20 min. The mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc, aq. K.sub.2CO.sub.3, aq. NaCl. The aquous phase was extracted two times with EtOAc, the combined organic phases were dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. Chromatography of the residue (silica, petrol ether-acetone), trituration of the material with MTBE and drying yielded 0.35 g (40%, yield corrected by purity).

[1376] .sup.1H NMR: see peak list in table 1

[1377] ESI mass [m/z]: 562.9 [M+H].sup.+

Example I-33

3-Chloro-5-(2-cyanopropan-2-yl)-N-{(1S)-1-[1-(5-cyanopyridin-2-yl)-1H-1,2,4-triazol-5-yl]ethyl}benzamide

[1378] ##STR00151##

[1379] A mixture of 98 mg (0.43 mmol) 3-chloro-5-(2-cyanopropan-2-yl)benzoic acid, 303 mg (0.79 mmol) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 0.24 mL (1.4 mmol) N-ethyldiisopropylamine and 3 mL DMF was stirred for 60 min at room temperature. 100 mg of 6-{5-[(1S)-1-aminoethyl]-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride were added and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with DCM, the DCM phase was separated, washed with brine, concentrated under reduced pressure and purified by preparative HPLC chromatography to provide 65 mg of the title compound.

[1380] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ [ppm]=9.30-9.29 (d, 1H), 9.06 (dd, 1H), 8.59-8.56 (dd, 1H), 8.25 (s, 1H), 8.07-8.06 (d, 1H), 7.81-7.87 (m, 2H), 7.75-7.74 (m, 1H), 6.09-6.06 (quint, 1H), 1.71 (s, 6H), 1.65-1.62 (d, 3H).

[1381] ESI mass [m/z]: 420.2 [M+H].sup.+

Example I-40

2-(5-{(1S)-1-[3-Chloro-5-(1,1,1-trichloro-2-cyanopropan-2-yl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide

[1382] ##STR00152##

[1383] To a solution of 109 mg (0.34 mmol) 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N,N-dimethyl-1,3-thiazole-5-carboxamide hydrochloride (1:1) in 2 mL DCM was added 0.08 mL (0.4 mmol) DIPEA and the solution was stirred 30 minutes at room temperature. Then a solution of 73 mg (0.32 mmol) 3-chloro-5-(2-cyanopropan-2-yl)benzoic acid, 149 mg (0.39 mmol) HATU and 0.08 mL DIPEA (0.4 mmol) was added into the mixture and further stirred for 16 h. The reaction mixture was quenched with an aqueous solution of 5% NaH.sub.2PO.sub.4 and then was extracted with dichloromethane. The organic phase was washed sodium bicarbonate, brine, dried over Na.sub.2SO.sub.4 and after evaporation of the solvent under vacuo the crude was purified by reserved-phase chromatography. The combined product fractions were evaporated to yield the title compound (139 mg, 87%).

[1384] .sup.1H-NMR peaklist (600.1 MHz, CD3CN 260 K): δ=8.0493 (0.5); 8.0375 (0.5); 7.9051 (4.0); 7.8297 (1.1); 7.8271 (1.8); 7.8244 (1.2); 7.7982 (1.2); 7.7954 (1.8); 7.7927 (1.0); 7.6978 (1.1); 7.6947 (1.9); 7.6917 (1.0); 6.1026 (0.6); 6.0907 (1.0); 6.0789 (0.6); 4.0563 (0.5); 4.0443 (0.5); 3.2669 (8.0); 3.0484 (7.3); 2.3379 (10.5); 2.3336 (1.0); 2.3078 (17.9); 2.2774 (0.5); 1.9846 (2.2); 1.9778 (0.6); 1.9700 (14.6); 1.9659 (28.1); 1.9617 (40.8); 1.9576 (28.1); 1.9535 (14.3); 1.7297 (1.3); 1.7244 (16.0); 1.6456 (3.6); 1.6339 (3.6); 1.2179 (0.5); 1.2059 (1.1); 1.1940 (0.5); 0.0054 (0.8); −0.0001 (21.6); −0.0057 (0.7)

[1385] ESI mass [m/z]: 486.1 [M+H].sup.+

Example I-41

2-(5-{(1S)-1-[3-Chloro-5-(cyanomethyl)benzamido]ethyl}-3-methyl-1H-1,2,4-triazol-1-yl)-N,N-dimethyl-1,3-thiazole-5-carboxamide

[1386] ##STR00153##

[1387] To a solution of 109 mg (0.34 mmol) 2-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N,N-dimethyl-1,3-thiazole-5-carboxamide hydrochloride (1:1) in 2 mL DCM was added 0.08 mL (0.4 mmol) DIPEA and the solution was stirred 30 minutes at room temperature. Then a solution of 64 mg (0.32 mmol) 3-chloro-5-(cyanomethyl)benzoic acid, 149 mg (0.39 mmol) HATU and 0.08 mL DIPEA (0.4 mmol) was added into the mixture and further stirred for 16 h. The reaction mixture was quenched with an aqueous solution of 5% NaH.sub.2PO.sub.4 and then was extracted with dichloromethane. The organic phase was washed sodium bicarbonate, brine, dried over Na.sub.2SO.sub.4 and after evaporation of the solvent under vacuo the crude was purified by reserved-phase chromatography. The combined product fractions were evaporated to yield the title compound (112 mg, 75%).

[1388] .sup.1H-NMR peaklist (600.1 MHz, CD3CN 260 K): δ=7.9965 (1.0); 7.9846 (1.1); 7.9095 (8.5); 7.7882 (1.7); 7.7855 (2.9); 7.7827 (1.8); 7.7237 (3.0); 7.5548 (2.6); 6.0924 (1.2); 6.0806 (1.9); 6.0687 (1.3); 4.0561 (0.4); 4.0443 (0.4); 3.9086 (9.2); 3.2720 (16.0); 3.0501 (14.6); 2.3358 (21.9); 2.3214 (0.5); 2.3040 (276.6); 2.2711 (5.2); 2.0806 (0.4); 2.0765 (0.7); 2.0724 (1.0); 2.0682 (0.8); 2.0639 (0.5); 2.0026 (0.4); 1.9928 (0.4); 1.9845 (2.3); 1.9776 (2.2); 1.9732 (3.9); 1.9697 (59.5); 1.9656 (115.0); 1.9615 (167.7); 1.9574 (115.1); 1.9533 (58.2); 1.9446 (0.7); 1.8546 (0.3); 1.8505 (0.6); 1.8464 (1.0); 1.8423 (0.6); 1.6314 (7.2); 1.6197 (7.2); 1.2178 (0.5); 1.2059 (1.0); 1.1940 (0.5); 0.9167 (0.4); 0.9055 (0.4); 0.0968 (0.4); 0.0054 (3.4); −0.0001 (98.0); −0.0057 (2.7); −0.1001 (0.4)

[1389] ESI mass [m/z]: 458.1 [M+H].sup.+

Example I-42

3-(1-Cyano-1-methyl-ethyl)-N-[(1S)-1-[2-(5-cyano-2-pyridyl)-1,2,4-triazol-3-yl]ethyl](trifluoromethyl)benzamide

[1390] ##STR00154##

[1391] A solution of 3-(1-cyano-1-methyl-ethyl)-5-(trifluoromethyl)benzoic acid (102 mg, 0.39 mmol) in DMF (1.0 mL) was treated with HATU (265 mg, 0.69 mmol) and a solution of 6-[5-[(1S)-1-aminoethyl]-1,2,4-triazol-1-yl]pyridine-3-carbonitrile hydrochloride (100 mg, 0.39 mmol) in DMF (1.0 mL) was treated with DIPEA (125 μL, 1.03 mmol). After stirring at RT for 1 h, the two solutions were combined and the mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound. Yield: 108 mg (56% of theory).

[1392] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.45 (d, 1H), 9.07 (d, 1H), 8.57 (dd, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.08 (d, 1H), 7.99 (s, 1H), 6.15-6.07 (m, 1H), 1.75 (s, 6H), 1.67 (d, 3H).

[1393] ESI mass [m/z]: 454.2 [M+H].sup.+

Example I-43

3-(1-Cyano-1-methyl-ethyl)-N-[(1S)-1-[2-(5-cyanothiazol-2-yl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethoxy)benzamide

[1394] ##STR00155##

[1395] A solution of sodium 3-(1-cyano-1-methyl-ethyl)-5-(trifluoromethoxy)benzoate (79.8 mg, 0.27 mmol) in DMF (1.0 mL) was treated with HATU (194 mg, 0.51 mmol) and a solution of 2-[5-[(1S)-1-aminoethyl]-1,2,4-triazol-1-yl]thiazole-5-carbonitrile hydrochloride (75.0 mg, 0.29 mmol) in DMF (1.0 mL) was treated with DIPEA (75 μL, 0.43 mmol). After stirring at RT for 1 h, the two solutions were combined and the mixture was stirred at RT overnight. The reaction mixture was directly purified by preparative HPLC to afford the title compound. Yield: 39.2 mg (28% of theory).

[1396] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.44 (d, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 8.04-8.02 (m, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 6.08-6.01 (m, 1H), 1.74 (s, 6H), 1.64 (d, 3H).

[1397] ESI mass [m/z]: 476.1 [M+H].sup.+

Example I-44

3-(1-Cyano-1-methyl-ethyl)-N-[(1S)-1-[2-(5-cyanothiazol-2-yl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide

[1398] ##STR00156##

[1399] A solution of 3-(1-cyano-1-methyl-ethyl)-5-(trifluoromethyl)benzoic acid (100 mg, 0.39 mmol) in DMF (1.0 mL) was treated with HATU (258 mg, 0.69 mmol) and a solution of 2-[5-[(1S)-1-aminoethyl]-1,2,4-triazol-1-yl]thiazole-5-carbonitrile hydrochloride (100 mg, 0.39 mmol) in DMF (1.0 mL) was treated with DIPEA (125 μL, 1.01 mmol). After stirring at RT for 1 h, the two solutions were combined and the mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound. Yield: 109 mg (57% of theory).

[1400] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.54 (d, 1H), 8.68 (s, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 6.11-6.03 (m, 1H), 1.77 (s, 6H), 1.65 (d, 3H).

[1401] ESI mass [m/z]: 460.1 [M+H].sup.+

Example I-45

3-(1-Cyano-1-methyl-ethyl)-N-[(1S)-1-[2-(5-cyano-2-pyridyl)-1,2,4-triazol-3-yl]ethyl](trifluoromethoxy)benzamide

[1402] ##STR00157##

[1403] A solution of sodium 3-(1-cyano-1-methyl-ethyl)-5-(trifluoromethoxy)benzoate (81.7 mg, 0.28 mmol) in DMF (1.0 mL) was treated with HATU (199 mg, 0.52 mmol) and a solution of 6-[5-[(1S)-1-aminoethyl]-1,2,4-triazol-1-yl]pyridine-3-carbonitrile hydrochloride (75.0 mg, 0.29 mmol) in DMF (1.0 mL) was treated with DIPEA (76 μL, 0.44 mmol). After stirring at RT for 1 h, the two solutions were combined and the mixture was stirred at RT overnight. The reaction mixture was directly purified by preparative HPLC to afford the title compound. Yield: 55.8 mg (40% of theory).

[1404] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]=9.36 (d, 1H), 9.07-9.04 (m, 1H), 8.57 (dd, 1H), 8.25 (s, 1H), 8.07 (d, 1H), 7.99-7.96 (m, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 6.12-6.05 (m, 1H), 1.73 (s, 6H), 1.66 (d, 3H).

[1405] ESI mass [m/z]: 470.2 [M+H].sup.+

Example I-47

N-{(1S)-1-[1-(5-Cyanopyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl]ethyl}-3-hydroxy-5-(trifluoromethyl)benzamide

[1406] ##STR00158##

[1407] A solution of 82 mg (0.39 mmol) 3-hydroxy-5-(trifluoromethyl)benzoic acid, 172 mg (0.45 mmol) HATU and 0.09 mL DIPEA (0.52 mmol) was stirred for 30 minutes at room temperature. A second solution of 100 mg (0.37 mmol) 6-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}nicotinonitrile hydrochloride (1:1) and 0.13 mL (0.75 mmol) DIPEA in 3 mL DCM previously stirred for 30 minutes was added into the mixture and further stirred for 16 h. The reaction mixture was quenched with an aqueous solution of 5% NaH.sub.2PO.sub.4 and was extracted with dichloromethane. The organic phase was washed sodium bicarbonate, brine, dried over Na.sub.2SO.sub.4 and finally, after evaporation of the solvent under vacuo, the crude was purified by flash chromatography. The combined product fractions were evaporated to yield the title compound (29 mg, 19%).

[1408] ESI mass [m/z]: 417.4 [M+H].sup.+

[1409] .sup.1H-NMR peaklist (400.2 MHz, d6-DMSO): δ=10.3838 (0.4); 9.2349 (1.5); 9.2172 (1.5); 9.0264 (2.5); 9.0213 (2.5); 8.5412 (1.8); 8.5357 (1.7); 8.5197 (1.9); 8.5141 (1.9); 8.0221 (2.7); 8.0005 (2.5); 7.6049 (2.6); 7.4725 (2.3); 7.1749 (2.4); 6.0744 (1.1); 6.0570 (1.7); 6.0394 (1.1); 5.7565 (0.8); 3.3280 (41.9); 2.6763 (0.4); 2.6718 (0.5); 2.6672 (0.4); 2.5251 (1.4); 2.5115 (30.1); 2.5072 (60.2); 2.5027 (79.8); 2.4983 (59.5); 2.4940 (29.9); 2.3395 (16.0); 2.3300 (1.0); 1.6054 (5.9); 1.5880 (5.9); 0.0079 (1.7); −0.0002 (47.4); −0.0085 (1.7)

Example I-52

6-[5-[(1S)-1-[[3-chloro-5-(1-cyano-1-methyl-ethyl)benzoyl]amino]ethyl]-3-methyl-1,2,4-triazol-1-yl]-N-ethyl-N-methyl-pyridine-3-carboxamide

[1410] ##STR00159##

[1411] To a solution of 69 mg (0.30 mmol) 3-chloro-5-(2-cyanopropan-2-yl)benzoic acid in 3.0 ml of dry dichloromethane were added 140 mg (0.36 mmol) HATU and 0.075 ml (0.43 mmol) N,N-diisopropylethylamine. After stirring 60 minutes at room temperature a solution of 100 mg (0.30 mmol) 6-{5-[(1S)-1-aminoethyl]-3-methyl-1H-1,2,4-triazol-1-yl}-N-ethyl-N-methylnicotin-amide hydrochloride (1:1) in 2.0 ml dry and dichloromethane together with 0.11 ml (0.61 mmol) N,N-diisopropylethylamine were added and the mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with a 5% aq. sol. of NaH.sub.2PO.sub.4 and extracted several times with dichloromethane. Finally, the combine organic layers were concentrated and the residue was purified by preparative chromatography to provide the title compound (78 mg).

[1412] ESI mass [m/z]: 494.3 [M+H].sup.+

[1413] .sup.1H NMR (DMSO-d6, 400 MHz): see NMR peak list in table 1

Analytical Data of the Compounds

[1414] The determination of [M+H].sup.+ or [M−H].sup.− by LC-MS under acidic chromatographic conditions was done with 1 mL formic acid per liter acetonitrile and 0.9 mL formic acid per liter Millipore water as eluents. The column Zorbax Eclipse Plus C18 50 mm*2.1 mm was used. The temperature of the column oven was 55° C.

[1415] The determination of the .sup.1H NMR data was effected with a Bruker Avance III 400 MHz equipped with a 1.7 mm TCI cryo probe, a Bruker Avance III 600 MHz equipped with a 5 mm multi-nuclear cryo probe or a Bruker Avance NEO 600 MHz equipped with a 5 mm TCI cryo probe with tetramethylsilane as reference (0.0) and the solvents CD.sub.3CN, CDCl.sub.3 or D.sub.6-DMSO.

[1416] The NMR data of selected examples are listed either in conventional form (8 values, multiplet splitting, number of hydrogen atoms) or as NMR peak lists.

NMR Peak List Method

[1417] The .sup.1H NMR data of selected examples are stated in the form of .sup.1H NMR peak lists. For each signal peak, first the δ value in ppm and then the signal intensity in round brackets are listed. The pairs of δ value-signal intensity numbers for different signal peaks are listed with separation from one another by semicolons.

[1418] The peak list for one example therefore takes the form of:

δ.sub.1 (intensity.sub.1); δ.sub.2 (intensity.sub.2); . . . ; δ.sub.i (intensity.sub.i); . . . ; δ.sub.n (intensity.sub.n)

[1419] The intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities. In the case of broad signals, several peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum.

[1420] For calibration of the chemical shift of .sup.1H NMR spectra, we use tetramethylsilane and/or the chemical shift of the solvent, particularly in the case of spectra which are measured in DMSO. Therefore, the tetramethylsilane peak may but need not occur in NMR peak lists.

[1421] The lists of the .sup.1H NMR peaks are similar to the conventional .sup.1H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation.

[1422] In addition, like conventional .sup.1H NMR printouts, they may show solvent signals, signals of stereoisomers of the target compounds which are likewise provided by the invention, and/or peaks of impurities.

[1423] In the reporting of compound signals within the delta range of solvents and/or water, our lists of .sup.1H NMR peaks show the standard solvent peaks, for example peaks of DMSO in DMSO-D.sub.6 and the peak of water, which usually have a high intensity on average.

[1424] The peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of >90%).

[1425] Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of our preparation process with reference to “by-product fingerprints”.

[1426] A person skilled in the art calculating the peaks of the target compounds by known methods (MestreC, ACD simulation, but also with empirically evaluated expected values) can, if required, isolate the peaks of the target compounds, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional .sup.1H NMR interpretation.

[1427] Further details of .sup.1H NMR peak lists can be found in the Research Disclosure Database Number 564025.

[1428] The compounds according to the invention described in table 1 below are likewise preferred compounds of the formula (I), wherein R.sup.1 is hydrogen, R.sup.3b is methyl, R.sup.3a is hydrogen, X is oxygen and Y is a direct bond which are obtained according to or analogously to the preparation examples described above.

##STR00160##

TABLE-US-00001 TABLE 1 ESI Mass Example Structure.sup.1) NMR Peak List.sup.2) (m/z).sup.3) 1-1  [00161] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.1398 (1.3); 9.1223 (1.3); 9.0698 (2.4); 9.0680 (2.8); 9.0643 (2.8); 9.0624 (2.7); 8.5848 (1.2); 8.5817 (1.4); 8.5793 (1.4); 8.5762 (1.3); 8.5633 (1.3); 8.5603 (1.5); 8.5578 (1.5); 8.5547 (1.4); 8.2355 (3.7); 8.2318 (3.8); 8.0825 (2.6); 8.0610 (2.4); 7.8235 (1.6); 7.8195 (1.7); 7.8158 (1.6); 7.7839 (1.4); 7.7646 (1.6); 7.5683 (1.0); 7.5521 (1.5); 7.5491 (1.5); 7.5012 (1.6); 7.4820 (2.3); 7.4629 (0.9); 6.0937 (0.8); 6.0766 (1.3); 6.0590 (0.8); 4.3771 (0.5); 4.3591 (1.7); 4.3411 (1.7); 4.3231 (0.5); 4.0559 (1.1); 4.0381 (3.5); 4.0203 (3.6); 4.0026 (1.2); 3.3270 (22.5); 2.5252 (0.9); 2.5118 (17.4); 2.5074 (35.5); 2.5028 (46.8); 2.4982 (33.8); 2.4937 (16.3); 2.0866 (1.8); 2.0753 (1.8); 1.9894 (16.0); 1.6427 (5.8); 1.6253 (5.8); 1.5664 (8.2); 1.5483 (8.1); 1.3973 (0.4); 1.1931 (4.3); 1.1753 (8.5); 1.1575 (4.2); −0.0002 (8.6) 372.3 1-2  [00162] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.1350 (1.6); 9.1176 (1.6); 9.0703 (2.8); 9.0687 (3.2); 9.0649 (3.1); 9.0631 (3.1); 8.5845 (2.5); 8.5790 (2.5); 8.5631 (2.7); 8.5575 (2.7); 8.2282 (8.2); 8.0850 (3.2); 8.0832 (3.4); 8.0635 (3.0); 8.0617 (3.2); 7.7752 (4.2); 7.7714 (5.0); 7.7587 (1.3); 7.7548 (1.9); 7.5118 (0.8); 7.5076 (0.6); 7.4926 (2.9); 7.4859 (2.8); 7.4824 (1.6); 7.4659 (2.2); 7.4465 (0.7); 6.0883 (1.3); 6.0708 (2.0); 6.0533 (1.3); 4.0825 (10.4); 4.0555 (0.6); 4.0377 (1.9); 4.0199 (1.9); 4.0022 (0.6); 3.3245 (39.3); 2.6895 (16.0); 2.6800 (0.4); 2.6756 (0.6); 2.6710 (0.9); 2.6665 (0.6); 2.5245 (2.8); 2.5197 (4.5); 2.5111 (51.6); 2.5066 (104.7); 2.5020 (137.0); 2.4974 (97.6); 2.4929 (46.1); 2.3333 (0.6); 2.3289 (0.8); 2.3242 (0.6); 2.0747 (0.8); 1.9889 (8.4); 1.6313 (7.9); 1.6139 (7.8); 1.1927 (2.3); 1.1749 (4.7); 1.1571 (2.3); 0.1458 (0.7); 0.0165 (0.3); 0.0079 (6.4); −0.0002 (174.1); −0.0086 358.3 (5.8); −0.1498 (0.7) 1-3  [00163] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.0615 (3.4); 9.0597 (3.7); 9.0560 (3.8); 9.0542 (3.6); 8.9222 (2.0); 8.9047 (2.0); 8.5765 (3.2); 8.5709 (3.0); 8.5550 (3.4); 8.5494 (3.3); 8.3142 (0.9); 8.2169 (9.6); 8.0658 (3.8); 8.0640 (3.8); 8.0443 (3.6); 8.0425 (3.6); 7.1671 (3.7); 7.1090 (2.9); 6.8856 (3.0); 6.0463 (1.4); 6.0289 (2.2); 6.0114 (1.4); 5.7545 (6.8); 4.0380 (0.6); 4.0203 (0.6); 3.8173 (6.1); 3.7999 (6.2); 3.3213 (139.9); 2.6800 (0.3); 2.6753 (0.7); 2.6708 (0.9); 2.6661 (0.7); 2.6620 (0.3); 2.5243 (3.0); 2.5195 (4.4); 2.5109 (52.5); 2.5064 (106.2); 2.5018 (140.5); 2.4972 (101.8); 2.4927 (48.7); 2.3332 (0.6); 2.3286 (0.9); 2.3241 (0.6); 2.2819 (16.0); 1.9886 (2.8); 1.6176 (8.6); 1.6002 (8.5); 1.2394 (0.4); 1.2341 (0.5); 1.2200 (0.7); 1.2140 (0.7); 1.2103 (0.6); 1.2022 (1.2); 1.1929 (1.3); 1.1821 (0.8); 1.1751 (1.8); 1.1573 (0.8); 0.5856 (1.0); 0.5747 (3.1); 0.5704 (3.2); 0.5658 (1.5); 0.5600 (1.5); 0.5546 (3.2); 0.5502 (3.0); 0.5400 (1.1); 0.3300 (1.2); 0.3195 (3.5); 0.3160 (3.5); 0.3078 403.3 (3.1); 0.3040 (3.7); 0.2929 (0.9); 0.1460 (0.4); 0.0080 (2.8); −0.0002 (88.0); −0.0085 (2.7); −0.1495 (0.3) 1-4  [00164] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.0598 (3.4); 9.0581 (3.6); 9.0543 (3.7); 9.0525 (3.4); 8.9215 (1.9); 8.9039 (2.0); 8.5770 (3.0); 8.5715 (2.9); 8.5556 (3.2); 8.5500 (3.2); 8.2184 (9.4); 8.0683 (3.8); 8.0666 (3.8); 8.0468 (3.5); 8.0451 (3.6); 7.1565 (3.6); 7.1553 (3.6); 7.0677 (2.9); 6.8560 (2.9); 6.0436 (1.4); 6.0261 (2.2); 6.0086 (1.4); 5.7552 (5.9); 4.8379 (0.4); 4.8318 (0.9); 4.8230 (1.0); 4.8173 (1.6); 4.8028 (0.8); 4.0384 (0.6); 4.0206 (0.6); 3.3251 (74.8); 2.6762 (0.3); 2.6717 (0.5); 2.6670 (0.3); 2.5252 (1.4); 2.5205 (2.1); 2.5118 (27.3); 2.5073 (55.7); 2.5027 (73.5); 2.4981 (52.6); 2.4935 (25.0); 2.3342 (0.3); 2.3295 (0.5); 2.3248 (0.3); 2.2836 (16.0); 1.9892 (2.6); 1.8961 (1.4); 1.8822 (1.2); 1.8699 (0.9); 1.8641 (0.9); 1.7247 (0.4); 1.6904 (4.7); 1.6817 (2.5); 1.6758 (2.1); 1.6705 (2.0); 1.6609 (1.7); 1.6504 (1.1); 1.6445 (1.2); 1.6163 (9.1); 1.5988 (9.6); 1.5817 (1.9); 1.5726 (1.5); 1.1932 (0.8); 1.1754 (1.5); 1.1576 (0.7); 0.0080 (1.4); 417.3 −0.0002 (46.5); −0.0086 (1.3) 1-5  [00165] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.0612 (3.2); 9.0597 (3.6); 9.0559 (3.5); 9.0542 (3.4); 8.9249 (1.9); 8.9073 (2.0); 8.5793 (2.6); 8.5738 (2.5); 8.5579 (2.8); 8.5523 (2.8); 8.3149 (0.8); 8.2184 (8.6); 8.0688 (3.4); 8.0673 (3.6); 8.0473 (3.2); 8.0458 (3.3); 7.1772 (3.6); 7.0035 (3.0); 6.7972 (3.0); 6.0434 (1.4); 6.0257 (2.2); 6.0082 (1.4); 4.7176 (0.3); 4.6993 (1.2); 4.6816 (1.9); 4.6637 (1.3); 4.6462 (0.3); 3.3192 (84.0); 2.6749 (1.5); 2.6704 (2.1); 2.6660 (1.6); 2.5239 (6.5); 2.5190 (9.8); 2.5103 (127.4); 2.5060 (254.4); 2.5015 (332.3); 2.4969 (241.0); 2.4925 (117.1); 2.4392 (0.8); 2.4326 (0.8); 2.4100 (1.5); 2.4022 (1.5); 2.3938 (1.5); 2.3718 (0.8); 2.3653 (0.6); 2.3329 (1.5); 2.3283 (2.1); 2.3238 (1.5); 2.2835 (16.0); 2.0738 (0.4); 2.0516 (0.4); 2.0263 (1.4); 2.0212 (0.9); 2.0070 (1.4); 2.0017 (1.7); 1.9965 (1.4); 1.9826 (1.1); 1.9773 (1.4); 1.9527 (0.4); 1.8114 (0.4); 1.7855 (1.0); 1.7607 (1.0); 403.3 1.7354 (0.4); 1.6714 (0.6); 1.6674 (0.7); 1.6463 (1.3); 1.6143 (8.5); 1.5969 (8.5); 0.1458 (0.6); 0.0080 (4.9); −0.0001 (151.7); −0.0084 (5.3); −0.1497 (0.6) 1-6  [00166] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.0613 (0.5); 9.0594 (0.5); 9.0558 (0.5); 9.0539 (0.5); 8.5807 (0.4); 8.5752 (0.4); 8.5593 (0.4); 8.5537 (0.4); 8.2218 (1.3); 8.0713 (0.5); 8.0694 (0.5); 8.0498 (0.5); 8.0479 (0.5); 7.2397 (0.5); 6.9486 (0.4); 6.7691 (0.4); 4.9083 (0.4); 4.5298 (0.4); 4.5165 (0.4); 4.5119 (0.4); 4.4984 (0.4); 3.3214 (26.8); 2.6897 (16.0); 2.5242 (0.8); 2.5195 (1.2); 2.5108 (15.5); 2.5063 (31.8); 2.5017 (42.0); 2.4970 (30.0); 2.4924 (14.2); 2.2950 (2.1); 1.6174 (1.2); 1.6000 (1.2); 0.0080 (0.8); 0.0057 (0.4); −0.0002 (25.2); −0.0086 (0.7) 405.3 1-7  [00167] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2257 (3.2); 9.2084 (3.3); 9.0393 (5.6); 9.0374 (6.3); 9.0338 (6.3); 9.0319 (6.0); 8.5700 (5.2); 8.5645 (5.0); 8.5486 (5.6); 8.5430 (5.6); 8.3142 (0.4); 8.2223 (16.0); 8.0629 (6.2); 8.0611 (6.4); 8.0415 (5.8); 8.0396 (6.0); 7.6660 (4.9); 7.6618 (7.6); 7.6579 (5.3); 7.4668 (0.7); 7.4610 (4.9); 7.4558 (2.0); 7.4486 (1.0); 7.4424 (7.6); 7.4397 (7.4); 7.4340 (1.2); 7.4260 (2.4); 7.4210 (6.8); 7.4151 (0.9); 7.3307 (4.5); 7.3271 (5.2); 7.3251 (6.0); 7.3215 (5.2); 7.2514 (5.4); 7.2460 (8.0); 7.2412 (7.2); 7.2231 (5.2); 7.2073 (1.3); 7.2046 (2.3); 7.2020 (1.4); 7.0932 (6.8); 7.0904 (9.0); 7.0852 (2.4); 7.0740 (4.1); 7.0714 (7.6); 7.0690 (6.7); 7.0625 (0.8); 6.0584 (0.5); 445.1 6.0411 (2.4); 6.0238 (3.7); 6.0064 (2.4); 5.9891 (0.5); 5.7545 (2.2); 3.3182 (75.3); 2.6803 (0.4); 2.6756 (0.8); 2.6711 (1.1); 2.6665 (0.8); 2.6618 (0.4); 2.5246 (3.4); 2.5199 (5.0); 2.5112 (64.7); 2.5067 (133.6); 2.5021 (177.4); 2.4975 (126.9); 2.4929 (60.6); 2.3380 (0.4); 2.3335 (0.8); 2.3289 (1.1); 2.3244 (0.8); 2.3197 (0.4); 1.6071 (14.3); 1.5896 (14.2); 1.2342 (0.4); 0.0080 (2.7); −0.0001 (84.2); −0.0085 (2.6); −0.1496 (0.3) 1-8  [00168] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2346 (3.4); 9.2172 (3.4); 9.0463 (5.5); 9.0449 (6.1); 9.0411 (6.0); 9.0394 (5.8); 8.5743 (4.8); 8.5687 (4.6); 8.5528 (5.2); 8.5473 (5.1); 8.2250 (16.0); 8.0677 (6.2); 8.0661 (6.3); 8.0462 (5.7); 8.0446 (5.8); 7.6957 (5.0); 7.6917 (7.8); 7.6877 (5.1); 7.4962 (1.1); 7.4875 (12.2); 7.4819 (3.9); 7.4707 (4.0); 7.4651 (14.2); 7.4565 (1.3); 7.3623 (4.4); 7.3586 (5.4); 7.3567 (6.3); 7.3531 (5.4); 7.3171 (5.2); 7.3119 (7.6); 7.3068 (4.0); 7.1329 (1.3); 7.1242 (13.8); 7.1187 (4.1); 7.1074 (3.8); 7.1019 (12.4); 7.0932 (1.1); 6.0673 (0.5); 6.0500 (2.4); 6.0327 (3.8); 6.0153 (2.4); 5.9978 (0.5); 5.7548 (4.0); 3.3197 (56.3); 2.6764 (0.6); 2.6718 (0.8); 2.6670 (0.6); 2.5253 (2.5); 479.1 2.5205 (3.9); 2.5118 (49.0); 2.5074 (98.3); 2.5028 (128.0); 2.4982 (91.0); 2.4937 (43.0); 2.3342 (0.5); 2.3296 (0.7); 2.3252 (0.5); 1.6103 (14.5); 1.5929 (14.4); 1.2346 (0.4); 0.0081 (2.1); −0.0001 (61.7); −0.0084 (1.9) 1-9  [00169] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2320 (3.8); 9.2148 (3.9); 9.0442 (6.8); 9.0392 (7.0); 8.5758 (4.2); 8.5704 (4.1); 8.5543 (4.5); 8.5489 (4.5); 8.2251 (14.9); 8.0669 (6.9); 8.0454 (6.4); 7.6600 (8.3); 7.3035 (5.6); 7.2952 (10.1); 7.2732 (10.0); 7.2572 (2.4); 7.2516 (7.0); 7.2399 (5.5); 7.2350 (7.8); 7.2300 (4.2); 7.1777 (0.8); 7.1684 (7.1); 7.1572 (7.4); 7.1513 (3.9); 7.1458 (5.1); 7.1401 (2.4); 7.1346 (4.8); 6.0609 (0.6); 6.0439 (2.7); 6.0266 (4.2); 6.0093 (2.7); 5.9919 (0.6); 3.3237 (39.1); 2.6719 (1.0); 2.6681 (0.7); 2.5073 (127.9); 2.5032 (156.3); 2.4989 (114.1); 2.3343 (0.7); 2.3299 (0.9); 1.6090 (16.0); 1.5916 (15.9); 1.2338 (0.6); 0.1461 (0.6); 0.0074 (6.1); −0.0002 (118.4); −0.0077 (7.4); 463.1 −0.1495 (0.6) 1-10 [00170] .sup.1H-NMR (600.1 MHz, d.sub.6-DMSO): δ = 9.2234 (3.5); 9.2118 (3.6); 9.0549 (5.0); 9.0539 (5.2); 9.0514 (5.3); 9.0503 (4.8); 8.5773 (4.2); 8.5736 (4.1); 8.5630 (4.4); 8.5593 (4.4); 8.5484 (7.4); 8.2250 (12.3); 8.0770 (5.6); 8.0761 (5.4); 8.0628 (5.2); 8.0617 (5.1); 7.9286 (7.9); 7.8529 (3.9); 7.8502 (6.3); 7.8475 (4.0); 7.6758 (6.6); 7.5263 (6.0); 6.0721 (0.5); 6.0605 (2.3); 6.0489 (3.6); 6.0373 (2.4); 6.0256 (0.5); 5.7537 (10.0); 5.4264 (16.0); 4.0244 (0.3); 3.3226 (128.4); 2.6183 (0.5); 2.6154 (0.7); 2.6124 (0.5); 2.5242 (1.6); 2.5212 (2.0); 2.5181 (2.0); 2.5091 (34.8); 2.5063 (73.6); 2.5033 (100.9); 2.5003 (74.1); 2.4974 (35.4); 2.3901 (0.5); 2.3872 (0.6); 2.3841 (0.4); 1.9893 (1.4); 1.6181 (13.8); 1.6065 (13.9); 1.1879 (0.4); 1.1761 (0.8); 1.1641 (0.4); 0.0053 (2.8); −0.0001 (77.5); −0.0056 501.4 (3.1); −0.1002 (0.3) 1-11 [00171] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2572 (1.2); 9.2399 (1.3); 9.0649 (2.0); 9.0636 (2.1); 9.0596 (2.2); 9.0582 (2.0); 8.5825 (1.7); 8.5769 (1.6); 8.5610 (1.8); 8.5554 (1.8); 8.2322 (5.5); 8.0819 (2.2); 8.0804 (2.2); 8.0604 (2.0); 8.0589 (2.1); 7.7859 (1.7); 7.7817 (2.8); 7.7776 (1.8); 7.5480 (1.6); 7.5431 (2.6); 7.5393 (2.0); 7.5134 (1.9); 7.5084 (3.0); 7.5034 (1.4); 6.0744 (0.9); 6.0570 (1.4); 6.0396 (0.9); 3.3289 (70.6); 2.6719 (0.4); 2.5253 (1.4); 2.5204 (2.1); 2.5119 (22.7); 2.5075 (44.8); 2.5029 (59.1); 2.4983 (44.2); 2.4939 (22.1); 411.3 2.3298 (0.4); 2.2853 (16.0); 2.0748 (2.7); 1.6240 (5.2); 1.6066 (5.2); 0.0080 (0.7); −0.0002 (21.9); −0.0084 (0.8) 1-12 [00172] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2736 (1.4); 9.2612 (1.8); 9.2561 (1.8); 9.2441 (1.5); 9.0145 (4.4); 9.0095 (4.4); 8.5374 (1.9); 8.5345 (2.2); 8.5320 (2.2); 8.5291 (2.0); 8.5159 (2.1); 8.5130 (2.4); 8.5105 (2.4); 8.5076 (2.1); 8.3167 (0.4); 8.0179 (4.6); 7.9964 (4.2); 7.7298 (2.4); 7.6923 (2.4); 7.6515 (1.9); 7.6320 (1.9); 7.5205 (2.3); 7.4997 (2.3); 7.4066 (6.9); 7.3958 (4.6); 7.3933 (4.0); 7.3904 (3.8); 7.3835 (2.4); 7.3806 (3.0); 7.3717 (0.8); 7.3620 (0.7); 7.3576 (0.6); 7.3521 (1.5); 7.3468 (2.6); 7.3416 (1.6); 7.3390 (1.8); 7.3321 (1.8); 7.3290 (1.3); 7.3240 (1.1); 7.3187 (0.6); 6.0867 (0.3); 6.0693 (1.4); 6.0521 (2.1); 6.0355 (1.4); 6.0182 (0.3); 5.7569 (5.1); 5.7476 (1.6); 5.7369 (1.6); 5.7317 (1.6); 5.7214 (0.5); 5.7162 (0.5); 3.3261 (124.6); 2.6760 (1.0); 2.6716 (1.4); 2.6671 (1.1); 2.5250 (4.7); 2.5115 (86.5); 2.5072 (171.5); 2.5027 (225.8); 2.4981 (168.0); 2.4938 (84.8); 2.3374 (15.2); 555.3 2.3300 (16.0); 2.2436 (0.5); 1.6057 (8.5); 1.5884 (9.0); 1.5793 (6.7); 1.5716 (6.6); 1.5635 (6.3); 1.5558 (5.7); 0.1460 (0.3); 0.0079 (3.0); −0.0002 (77.7); −0.0085 (3.1); −0.1495 (0.3) 1-13 [00173] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3095 (1.4); 9.2919 (1.4); 9.0299 (2.5); 9.0251 (2.5); 8.5402 (1.8); 8.5347 (1.7); 8.5188 (1.9); 8.5132 (1.9); 8.0226 (2.6); 8.0010 (2.4); 7.7723 (3.7); 7.7661 (2.4); 7.5618 (2.6); 7.5316 (2.2); 7.4513 (1.4); 7.4469 (1.0); 7.4376 (6.3); 7.4303 (2.5); 7.4255 (1.8); 7.4188 (0.8); 7.4156 (0.8); 6.1051 (1.0); 6.0876 (1.6); 6.0700 (1.1); 5.7564 (3.7); 5.2517 (7.1); 3.3287 (70.6); 2.6764 (0.4); 2.6720 (0.5); 2.6675 (0.4); 2.5252 (1.4); 2.5118 (28.1); 2.5075 (56.8); 2.5030 (75.4); 2.4984 (55.8); 2.4940 (27.7); 2.3406 (16.0); 1.6272 (5.7); 1.6098 (5.7); 0.0079 (0.9); −0.0002 (32.0); −0.0084 (1.3) 541.1 1-14 [00174] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2743 (1.4); 9.2639 (1.6); 9.2568 (1.7); 9.2463 (1.5); 8.9982 (2.3); 8.9924 (4.3); 8.9868 (2.5); 8.5358 (3.2); 8.5303 (3.1); 8.5143 (3.4); 8.5087 (3.4); 8.3164 (0.4); 8.0178 (2.9); 8.0158 (2.9); 7.9963 (2.7); 7.9943 (2.7); 7.7510 (2.4); 7.7232 (2.4); 7.5822 (2.0); 7.5601 (2.0); 7.5110 (1.3); 7.5049 (1.4); 7.4958 (2.5); 7.4921 (3.6); 7.4878 (2.4); 7.4840 (2.5); 7.4791 (3.4); 7.4751 (3.1); 7.4667 (1.5); 7.4608 (1.9); 7.3638 (0.4); 7.3591 (0.6); 7.3550 (0.4); 7.3498 (0.7); 7.3452 (1.6); 7.3407 (1.7); 7.3353 (2.7); 7.3284 (4.5); 7.3208 (3.8); 7.3160 (2.0); 7.3106 (2.8); 7.3048 (1.4); 7.2977 (0.6); 7.2920 (0.8); 7.2768 (3.5); 6.0788 (0.3); 6.0620 (1.5); 6.0447 (2.3); 6.0279 (1.5); 6.0102 (0.4); 5.8845 (0.4); 5.8691 (1.6); 5.8592 (1.7); 5.8534 (1.7); 5.8435 (1.6); 5.8276 (0.4); 5.7565 (3.5); 555.4 3.3250 (93.1); 2.6804 (0.5); 2.6761 (1.1); 2.6715 (1.5); 2.6671 (1.1); 2.6629 (0.6); 2.5250 (4.6); 2.5202 (6.9); 2.5115 (87.7); 2.5071 (177.9); 2.5026 (235.7); 2.4981 (174.8); 2.4937 (87.7); 2.3391 (15.5); 2.3264 (16.0); 2.2423 (0.5); 1.6155 (6.7); 1.6097 (7.2); 1.5938 (13.4); 1.5791 (7.2); 1.5760 (7.1); 0.1461 (0.4); 0.0080 (2.8); −0.0002 (87.9); −0.0084 (3.4); −0.1494 (0.4) 1-15 [00175] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2635 (1.6); 9.2548 (1.8); 9.2458 (1.8); 9.2370 (1.7); 9.0172 (2.7); 9.0127 (4.7); 9.0077 (2.7); 8.5405 (1.9); 8.5362 (2.7); 8.5314 (1.8); 8.5190 (2.0); 8.5147 (2.9); 8.5098 (1.9); 8.3168 (0.3); 8.0200 (4.8); 7.9985 (4.4); 7.7236 (2.6); 7.6839 (2.6); 7.6315 (2.2); 7.6143 (2.2); 7.4732 (2.2); 7.4580 (3.1); 7.4517 (6.2); 7.4373 (6.2); 7.4264 (6.3); 7.4202 (2.8); 7.4153 (6.5); 7.4100 (2.5); 7.4052 (2.6); 7.3988 (1.3); 7.3936 (2.4); 7.3818 (4.1); 6.0823 (0.3); 6.0647 (1.3); 6.0500 (2.0); 6.0472 (2.0); 6.0323 (1.3); 6.0152 (0.3); 5.7570 (5.0); 5.7510 (1.6); 5.7403 (1.7); 5.7353 (1.7); 5.7248 (1.5); 5.7101 (0.4); 3.3257 (111.7); 2.6762 (1.1); 2.6718 (1.5); 2.6674 (1.1); 2.5072 (184.3); 2.5028 (236.4); 2.4984 (175.3); 2.3378 (15.4); 2.3298 (16.0); 1.6034 (10.5); 1.5860 (10.6); 1.5663 (6.6); 1.5607 (6.9); 1.5506 (6.8); 1.5450 (6.4); 1.4358 (0.4); 0.1463 (0.4); 0.0080 (4.2); 555.4 0.0000 (92.0); −0.0082 (3.9); −0.1493 (0.4) 1-16 [00176] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3220 (1.4); 9.3043 (1.4); 9.0308 (2.2); 9.0290 (2.5); 9.0253 (2.4); 9.0235 (2.4); 8.5406 (2.0); 8.5350 (1.9); 8.5191 (2.2); 8.5135 (2.2); 8.0251 (2.5); 8.0234 (2.6); 8.0036 (2.3); 8.0018 (2.4); 7.7878 (2.5); 7.7701 (1.9); 7.6549 (1.2); 7.6496 (0.8); 7.6458 (0.7); 7.6395 (1.1); 7.6317 (1.4); 7.5538 (2.1); 7.5489 (2.6); 7.5434 (1.2); 7.5337 (0.8); 7.5298 (1.1); 7.5256 (1.9); 7.4490 (0.3); 7.4432 (0.6); 7.4305 (1.8); 7.4230 (2.3); 7.4150 (3.6); 7.4057 (2.4); 7.4005 (1.5); 7.3867 (0.4); 6.1064 (1.0); 6.0890 (1.6); 6.0714 (1.0); 5.7565 (3.2); 5.2883 (6.9); 3.3529 (0.3); 3.3276 (153.2); 2.6760 (0.6); 2.6714 (0.9); 2.6669 (0.6); 2.5250 (2.4); 2.5203 (3.6); 2.5116 (49.6); 2.5071 (102.6); 2.5025 (137.2); 2.4979 (100.6); 2.4934 (48.8); 2.3405 (16.0); 2.3295 (1.2); 2.3248 (0.8); 2.3206 (0.4); 541.4 1.6270 (5.4); 1.6096 (5.4); 0.0080 (2.1); −0.0002 (69.5); −0.0085 (2.3) 1-17 [00177] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2516 (1.7); 9.2341 (1.8); 9.0658 (3.1); 9.0605 (3.2); 8.5855 (2.0); 8.5801 (1.9); 8.5641 (2.2); 8.5586 (2.1); 8.2368 (7.0); 8.0845 (3.3); 8.0630 (3.0); 7.9201 (3.4); 7.7869 (3.6); 7.6325 (3.4); 6.0822 (1.2); 6.0648 (1.8); 6.0473 (1.2); 4.5643 (6.8); 3.3230 (77.5); 2.9410 (16.0); 2.6752 (1.0); 2.6709 (1.4); 2.5241 (4.4); 2.5063 (180.2); 2.5020 (225.5); 2.4977 (161.9); 2.3330 (1.0); 2.3286 (1.3); 2.3244 (1.0); 1.6346 (7.0); 1.6172 (6.9); 0.0078 (2.2); −0.0002 (58.2) 445.2 1-18 [00178] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3008 (1.4); 9.2832 (1.5); 9.0287 (2.4); 9.0270 (2.6); 9.0232 (2.6); 9.0215 (2.4); 8.5397 (1.9); 8.5341 (1.9); 8.5182 (2.1); 8.5126 (2.1); 8.3161 (0.5); 8.0225 (2.6); 8.0209 (2.6); 8.0009 (2.4); 7.9993 (2.4); 7.7597 (4.7); 7.7558 (5.0); 7.5074 (2.3); 7.4865 (1.6); 7.4828 (2.2); 7.4653 (3.6); 7.4290 (1.4); 7.4261 (1.9); 7.4214 (0.7); 7.4085 (3.8); 7.4046 (1.7); 7.3899 (2.0); 7.3670 (1.5); 7.3556 (0.5); 7.3492 (1.6); 7.3423 (0.3); 7.3313 (0.4); 6.1004 (1.0); 6.0828 (1.6); 6.0654 (1.0); 5.2354 (7.0); 3.3261 (212.6); 2.6756 (1.2); 2.6710 (1.6); 2.6666 (1.2); 2.5245 (5.4); 2.5110 (98.2); 2.5066 (194.8); 2.5021 (255.0); 2.4976 (188.2); 2.4932 (93.4); 2.3397 (16.0); 2.3291 (2.0); 2.3246 (1.4); 2.2461 (0.4); 1.6238 (5.6); 1.6064 (5.6); 0.1459 (0.4); 0.0080 (3.0); −0.0001 (87.3); −0.0084 (3.3); 507.5 −0.1496 (0.4) 1-19 [00179] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2934 (1.4); 9.2756 (1.4); 9.0304 (2.4); 9.0289 (2.5); 9.0250 (2.6); 8.5400 (1.8); 8.5345 (1.8); 8.5185 (2.0); 8.5129 (2.0); 8.3160 (0.4); 8.0198 (2.6); 8.0184 (2.5); 7.9983 (2.4); 7.9968 (2.3); 7.7255 (2.6); 7.6509 (2.1); 7.4017 (2.2); 6.0962 (1.0); 6.0786 (1.6); 6.0611 (1.0); 3.9646 (3.4); 3.9486 (3.5); 3.9003 (1.2); 3.8927 (1.3); 3.8723 (1.4); 3.8648 (1.4); 3.3648 (1.4); 3.3260 (132.6); 2.6756 (0.9); 2.6711 (1.2); 2.6666 (0.9); 2.5246 (3.6); 2.5198 (5.4); 2.5111 (74.7); 2.5067 (152.9); 2.5022 (202.5); 2.4977 (150.1); 2.4933 (75.5); 2.3399 (16.0); 2.3292 (1.7); 2.3246 (1.1); 2.0267 (0.4); 2.0178 (0.6); 2.0090 (0.4); 1.9901 (0.4); 1.6993 (1.2); 1.6711 (1.5); 1.6667 (1.5); 1.6256 (5.7); 1.6082 (5.6); 1.4028 (0.4); 1.3916 (0.5); 1.3725 (1.0); 1.3613 (1.2); 1.3401 (1.1); 1.3297 (1.0); 515.2 1.3102 (0.4); 1.2995 (0.4); 0.1460 (0.4); 0.0079 (2.9); −0.0002 (94.9); −0.0084 (4.0); −0.1497 (0.4) 1-20 [00180] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3032 (1.4); 9.2855 (1.5); 9.0278 (2.6); 9.0236 (2.5); 8.5404 (1.8); 8.5348 (1.7); 8.5189 (1.9); 8.5133 (1.8); 8.3153 (1.0); 8.0214 (2.6); 8.0000 (2.4); 7.7672 (2.7); 7.7471 (2.2); 7.5156 (2.8); 7.5103 (2.9); 7.4952 (6.6); 7.4806 (7.3); 7.4646 (0.8); 7.4589 (1.8); 6.0994 (1.0); 6.0821 (1.6); 6.0646 (1.0); 5.2365 (7.0); 3.3983 (0.4); 3.3287 (761.0); 2.6756 (2.4); 2.6711 (3.3); 2.6667 (2.5); 2.5244 (11.0); 2.5066 (406.8); 2.5022 (531.9); 2.4977 (395.5); 2.3389 (16.0); 2.3292 (3.9); 2.3245 (2.7); 2.0743 (0.6); 1.6231 (5.6); 1.6058 (5.6); 0.1459 (1.2); 0.0079 (9.9); −0.0001 (267.9); −0.0084 (11.5); −0.1498 (1.2) 541.4 1-21 [00181] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2882 (1.4); 9.2705 (1.5); 9.0292 (2.4); 9.0277 (2.4); 9.0238 (2.6); 8.5415 (1.8); 8.5360 (1.8); 8.5200 (2.0); 8.5144 (2.0); 8.0222 (2.6); 8.0208 (2.5); 8.0007 (2.4); 7.9992 (2.3); 7.7254 (2.6); 7.6610 (2.1); 7.4683 (2.2); 6.0904 (1.0); 6.0730 (1.6); 6.0554 (1.0); 4.7990 (0.5); 4.7879 (0.7); 4.7778 (1.0); 4.7674 (0.7); 4.7565 (0.5); 3.8734 (0.8); 3.8628 (1.5); 3.8501 (1.0); 3.8449 (1.1); 3.8331 (1.8); 3.8220 (0.9); 3.5337 (1.0); 3.5269 (1.2); 3.5105 (1.3); 3.5041 (2.0); 3.4817 (1.1); 3.4751 (1.0); 3.3354 (257.8); 2.6765 (0.7); 2.6722 (1.0); 2.6676 (0.7); 2.5255 (3.2); 2.5206 (5.1); 2.5120 (58.5); 2.5076 (116.8); 2.5031 (153.3); 2.4986 (114.2); 2.4942 (57.7); 2.3403 (16.0); 2.3304 (1.5); 2.3255 (0.9); 501.4 1.9860 (0.9); 1.9765 (1.0); 1.9645 (0.8); 1.9530 (1.2); 1.9442 (1.1); 1.6236 (6.2); 1.6061 (6.4); 1.5915 (1.1); 1.5801 (1.4); 1.5701 (0.9); 1.5577 (0.5); 1.5478 (0.4); 0.1460 (0.8); 0.0080 (6.3); −0.0002 (171.7); −0.0083 (7.6); −0.1496 (0.8) 1-22 [00182] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2407 (1.1); 9.2235 (1.1); 9.0652 (2.0); 9.0635 (2.0); 9.0598 (2.1); 9.0580 (1.8); 8.5877 (1.6); 8.5822 (1.5); 8.5662 (1.7); 8.5607 (1.7); 8.2277 (5.1); 8.0840 (2.1); 8.0823 (1.9); 8.0625 (2.0); 8.0607 (1.8); 7.8072 (1.3); 7.8030 (2.1); 7.7988 (1.3); 7.6263 (2.2); 7.4603 (1.3); 7.4564 (2.0); 6.0601 (0.8); 6.0428 (1.2); 6.0254 (0.7); 4.8564 (5.4); 3.3301 (74.4); 3.1268 (16.0); 2.6762 (0.5); 2.6715 (0.6); 2.6669 (0.4); 2.5250 (2.1); 2.5202 (3.4); 2.5116 (38.3); 2.5071 (76.2); 2.5026 (98.8); 2.4980 (70.7); 2.4935 (33.7); 2.3340 (0.4); 2.3294 (0.6); 2.3247 (0.4); 2.1435 (15.3); 1.6191 (4.5); 1.6017 (4.4); 0.1461 (0.4); 0.0080 (3.6); −0.0002 (89.6); −0.0085 (3.0); −0.1495 (0.4) 478.0 1-23 [00183] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2526 (3.9); 9.2352 (4.0); 9.0590 (7.2); 9.0551 (6.8); 8.5846 (4.8); 8.5791 (4.5); 8.5632 (5.2); 8.5576 (4.9); 8.3160 (0.5); 8.2379 (16.0); 8.0824 (7.0); 8.0609 (6.5); 8.0080 (8.8); 8.0040 (7.5); 7.9952 (8.5); 7.9099 (8.0); 7.3086 (13.0); 6.0947 (0.6); 6.0775 (2.7); 6.0602 (4.2); 6.0428 (2.7); 6.0256 (0.6); 3.3253 (52.7); 2.6762 (1.2); 2.6715 (1.6); 2.6671 (1.2); 2.5071 (205.0); 2.5027 (255.2); 2.4983 (184.1); 2.3340 (1.2); 2.3296 (1.5); 2.3251 (1.1); 2.0751 (0.5); 1.6271 (16.0); 1.6097 (15.8); 0.1458 (0.9); −0.0002 (191.9); −0.0084 (7.8); −0.1497 (0.9) 492.9 1-24 [00184] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 10.6331 (0.4); 9.3436 (2.4); 9.3261 (2.5); 9.0659 (4.1); 9.0645 (4.6); 9.0607 (4.5); 9.0590 (4.3); 8.5849 (3.2); 8.5794 (3.1); 8.5634 (3.5); 8.5579 (3.5); 8.2456 (10.9); 8.0886 (4.5); 8.0870 (4.6); 8.0671 (4.2); 8.0655 (4.3); 7.7992 (4.7); 7.7172 (3.7); 7.5258 (3.8); 6.1272 (0.4); 6.1100 (1.7); 6.0927 (2.7); 6.0752 (1.8); 6.0579 (0.4); 5.7576 (0.7); 5.1451 (16.0); 3.3345 (42.8); 2.5281 (1.0); 2.5147 (19.9); 2.5104 (40.1); 2.5058 (52.0); 2.5013 (37.6); 2.4970 (18.3); 1.6500 (10.2); 1.6326 (10.2); 1.0886 (2.9); 1.0389 (1.9); 1.0104 (0.4); 0.8839 (0.4); 0.8656 (0.7); 0.8478 (0.3); 0.8401 (0.9); 0.8228 (0.9); 0.7989 (0.4); 0.0080 (0.5); −0.0002 (13.7); −0.0085 (0.5) 547.0 1-25 [00185] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3913 (3.6); 9.3739 (3.7); 9.0551 (5.9); 9.0536 (6.6); 9.0498 (6.6); 9.0481 (6.2); 8.5784 (4.8); 8.5729 (4.6); 8.5569 (5.1); 8.5514 (5.1); 8.3171 (0.4); 8.2382 (16.0); 8.1623 (7.0); 8.0794 (6.4); 8.0778 (6.4); 8.0580 (6.0); 8.0563 (6.0); 7.9356 (7.1); 7.9077 (7.0); 7.6504 (4.2); 7.6372 (4.8); 7.6283 (5.3); 7.6153 (4.9); 7.3723 (4.7); 7.3502 (8.6); 7.3281 (4.0); 6.0980 (0.5); 6.0808 (2.5); 6.0635 (3.9); 6.0461 (2.5); 6.0287 (0.5); 3.3292 (113.3); 2.6772 (1.0); 2.6727 (1.3); 2.6682 (1.0); 2.5260 (3.9); 2.5125 (84.0); 2.5082 (167.5); 2.5037 (216.5); 2.4991 (155.8); 2.4948 (75.7); 2.3349 (1.0); 2.3305 (1.3); 2.3260 (0.9); 543.1 2.0763 (1.2); 1.6339 (14.8); 1.6165 (14.8); −0.0002 (3.8) 1-26 [00186] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3321 (3.7); 9.3147 (3.8); 9.0652 (6.3); 9.0634 (6.9); 9.0597 (7.0); 9.0579 (6.4); 8.5839 (5.0); 8.5784 (4.9); 8.5625 (5.4); 8.5569 (5.4); 8.3167 (0.5); 8.2433 (16.0); 8.0845 (6.8); 8.0828 (6.7); 8.0630 (6.3); 8.0613 (6.2); 7.7592 (7.0); 7.6586 (5.6); 7.4603 (5.7); 6.5245 (3.7); 6.5080 (8.9); 6.4916 (3.8); 6.1204 (0.6); 6.1031 (2.6); 6.0857 (4.0); 6.0683 (2.6); 6.0512 (0.5); 4.8457 (0.3); 4.8288 (0.5); 4.8139 (12.5); 4.7974 (12.3); 4.0380 (0.4); 4.0200 (0.4); 3.3270 (125.3); 2.6762 (1.2); 2.6716 (1.6); 2.6671 (1.3); 2.5251 (5.2); 2.5115 (100.2); 2.5072 (195.9); 2.5027 (254.1); 2.4981 (187.8); 2.4938 (93.5); 2.3341 (1.1); 2.3295 (1.5); 2.3249 (1.1); 1.9894 (1.8); 1.9086 (1.1); 1.6482 (15.1); 1.6308 (15.1); 1.4261 (0.4); 1.3976 (7.3); 1.1931 (0.5); 1.1754 511.2 (1.0); 1.1575 (0.5); 0.8886 (0.4); 0.8716 (0.3); 0.0079 (2.0); −0.0002 (49.1); −0.0084 (2.0) 1-27 [00187] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 10.6313 (1.3); 10.5673 (0.7); 9.3581 (1.7); 9.3410 (1.7); 9.0683 (3.1); 9.0644 (3.1); 8.5856 (2.2); 8.5800 (2.0); 8.5641 (2.3); 8.5585 (2.3); 8.2442 (7.3); 8.0871 (3.1); 8.0856 (3.1); 8.0656 (2.9); 8.0640 (2.9); 7.8231 (2.2); 7.8094 (3.1); 7.6919 (2.6); 6.1059 (1.2); 6.0885 (1.8); 6.0712 (1.2); 5.4597 (1.6); 5.4548 (1.5); 5.4328 (1.9); 5.4279 (1.9); 5.2171 (2.7); 5.1903 (2.2); 5.1887 (2.2); 3.3312 (32.5); 2.6776 (0.3); 2.6726 (0.5); 2.6560 (16.0); 2.5261 (0.9); 2.5128 (19.6); 2.5085 (38.5); 2.5040 (49.9); 2.4994 (36.3); 2.4950 (17.7); 2.4816 (0.7); 2.1189 (0.6); 2.0873 (1.2); 1.6533 (7.0); 1.6359 (7.0); 1.4383 (0.3); 1.4250 (0.6); 1.4199 (0.4); 1.4152 (0.4); 1.4053 (0.4); 1.3958 (0.8); 1.3074 (0.4); 1.2896 (0.5); 1.2615 (0.3); 1.2321 (0.4); 1.1414 479.2 (1.3); 1.0876 (9.2); 1.0378 (6.0); 1.0094 (1.1); 0.8833 (1.1); 0.8651 (2.3); 0.8582 (0.3); 0.8471 (1.1); 0.8394 (3.0); 0.8221 (2.8); 0.8169 (0.8); 0.7980 (1.2); 0.7792 (0.5); −0.0002 (1.6) 1-28 [00188] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 11.6398 (0.5); 10.6341 (1.1); 10.5702 (0.6); 9.4255 (2.7); 9.4091 (2.8); 8.6725 (11.8); 8.3188 (10.5); 8.0742 (3.2); 7.8705 (5.1); 7.7638 (4.2); 7.5497 (4.3); 6.0724 (0.4); 6.0553 (1.8); 6.0382 (2.7); 6.0211 (1.8); 6.0040 (0.4); 5.7581 (0.7); 5.1559 (16.0); 3.3317 (43.0); 2.6770 (0.6); 2.6725 (0.7); 2.6680 (0.5); 2.5079 (97.0); 2.5035 (122.3); 2.4991 (92.3); 2.3348 (0.6); 2.3304 (0.8); 2.3259 (0.6); 2.0872 (7.2); 1.9757 (11.6); 1.9587 (12.1); 1.6348 (10.4); 1.6174 (10.3); 1.4469 (0.4); 1.4377 (0.4); 1.4244 (0.6); 1.4199 (0.4); 1.4148 (0.4); 1.4053 (0.4); 1.3954 (0.7); 1.3069 (0.5); 1.2969 (0.4); 1.2889 (0.7); 1.2792 (0.6); 1.2683 (0.6); 1.2608 (0.7); 1.2371 (2.9); 1.1722 (0.6); 1.1568 (0.6); 1.1461 (1.0); 1.1406 (0.7); 1.1352 (0.8); 1.1047 (0.4); 1.0870 553.0 (7.0); 1.0523 (0.4); 1.0373 (4.4); 1.0089 (0.9); 0.8832 (1.1); 0.8649 (2.3); 0.8541 (1.7); 0.8471 (1.6); 0.8391 (3.0); 0.8218 (2.5); 0.8166 (1.1); 0.7976 (1.0); 0.7789 (0.5); 0.1459 (0.4); 0.0075 (5.3); −0.0002 (97.4); −0.0083 (5.1); −0.1496 (0.4) 1-29 [00189] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 10.6351 (0.5); 9.3402 (2.4); 9.3340 (2.5); 9.3232 (2.6); 9.3169 (2.4); 9.0677 (6.9); 9.0627 (6.9); 8.5839 (4.7); 8.5784 (4.5); 8.5625 (5.0); 8.5570 (5.0); 8.2427 (15.8); 8.0848 (7.1); 8.0633 (6.6); 7.7353 (7.7); 7.7219 (3.4); 7.7074 (3.2); 7.4842 (6.2); 6.1221 (0.6); 6.1048 (2.6); 6.0874 (4.0); 6.0701 (2.6); 6.0528 (0.6); 5.7582 (0.7); 4.4671 (2.8); 4.4547 (2.9); 4.4402 (3.2); 4.4276 (3.1); 4.0518 (3.2); 4.0285 (4.0); 4.0251 (3.8); 4.0017 (3.0); 3.3342 (35.6); 2.6785 (0.4); 2.6739 (0.6); 2.6697 (0.4); 2.5136 (35.9); 2.5095 (69.7); 2.5051 (90.6); 2.5006 (67.5); 2.3363 (0.4); 2.3318 (0.6); 2.3275 (0.4); 2.3053 (0.7); 2.2928 (0.8); 2.2830 (1.3); 2.2787 (1.2); 2.2731 (1.4); 2.2643 (1.6); 2.2560 (1.5); 2.2458 (1.4); 2.2363 (0.9); 2.2233 (0.8); 2.0882 525.2 (3.0); 1.9099 (3.6); 1.8913 (4.4); 1.8827 (3.5); 1.8642 (3.4); 1.6512 (15.9); 1.6338 (16.0); 1.6241 (4.6); 1.6048 (6.4); 1.5858 (3.0); 1.4282 (0.6); 1.4098 (0.6); 1.3957 (0.4); 1.2358 (0.6); 1.0879 (3.6); 1.0381 (2.5); 1.0096 (0.5); 0.8836 (0.5); 0.8654 (1.0); 0.8537 (0.5); 0.8474 (0.6); 0.8396 (1.4); 0.8224 (1.3); 0.8171 (0.4); 0.7984 (0.5); 0.0078 (1.4); −0.0002 (35.1); −0.0084 (1.4) 1-30 [00190] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4193 (2.6); 9.4144 (2.7); 9.4033 (2.8); 9.3980 (2.6); 8.6730 (14.5); 8.3162 (15.3); 7.8065 (7.4); 7.7684 (4.2); 7.5082 (6.2); 6.0736 (0.6); 6.0562 (2.5); 6.0392 (3.9); 6.0221 (2.5); 6.0049 (0.6); 4.4806 (2.9); 4.4681 (3.1); 4.4535 (3.4); 4.4410 (3.2); 4.0629 (3.1); 4.0396 (4.0); 4.0363 (3.7); 4.0128 (2.9); 3.3326 (45.5); 2.6773 (0.6); 2.6728 (0.8); 2.6685 (0.6); 2.5261 (2.8); 2.5083 (101.3); 2.5039 (129.9); 2.4994 (95.6); 2.4954 (47.3); 2.3350 (0.6); 2.3308 (0.8); 2.3263 (0.6); 2.3112 (0.6); 2.2982 (0.7); 2.2896 (1.2); 2.2780 (1.4); 2.2701 (1.6); 2.2625 (1.5); 2.2509 (1.4); 2.2422 (0.9); 2.2293 (0.7); 2.0875 (1.0); 1.9118 (3.6); 1.8933 (4.5); 1.8847 (3.6); 1.8749 (0.5); 1.8662 (3.5); 1.6372 (15.8); 1.6197 (16.0); 1.6072 (6.5); 1.5881 (2.8); 1.4245 (0.5); 1.4198 (0.3); 1.4051 (0.4); 1.3953 531.1 (0.6); 1.3071 (0.4); 1.2890 (0.5); 1.2798 (0.3); 1.2609 (0.4); 1.2367 (1.0); 1.1406 (0.3); 1.1047 (0.4); 1.0872 (6.4); 1.0375 (4.0); 1.0091 (0.8); 0.8832 (0.9); 0.8651 (1.8); 0.8545 (0.7); 0.8472 (1.0); 0.8392 (2.3); 0.8219 (2.0); 0.8167 (0.7); 0.7978 (0.9); 0.7789 (0.4); 0.0079 (2.2); −0.0001 (50.5); −0.0084 (1.9) 1-31 [00191] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2703 (2.7); 9.2538 (2.7); 8.6676 (11.8); 8.3089 (10.2); 7.7123 (6.0); 7.4681 (4.8); 7.4651 (4.0); 7.4465 (4.1); 7.4424 (4.9); 7.4369 (2.7); 6.0346 (0.4); 6.0172 (1.8); 6.0002 (2.7); 5.9831 (1.8); 5.9662 (0.4); 5.7563 (1.6); 5.0966 (0.4); 5.0700 (16.0); 3.3276 (33.4); 2.6767 (0.4); 2.6723 (0.5); 2.6682 (0.4); 2.5077 (60.6); 2.5034 (76.2); 2.4990 (56.3); 2.3303 (0.5); 2.3256 (0.3); 1.9758 (0.4); 1.9590 (0.4); 1.6123 (10.2); 1.5949 (10.1); 0.0078 (2.5); −0.0002 (58.4); −0.0082 (2.8) 562.9 1-32 [00192] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.1884 (2.4); 9.1706 (2.4); 9.0621 (4.2); 9.0568 (4.3); 8.5841 (3.3); 8.5787 (2.9); 8.5627 (3.3); 8.5571 (3.3); 8.3155 (2.5); 8.2340 (10.5); 8.0830 (4.4); 8.0615 (4.1); 7.6436 (5.8); 7.4198 (12.3); 7.4161 (11.6); 6.0887 (0.4); 6.0718 (1.7); 6.0543 (2.6); 6.0369 (1.7); 6.0186 (0.4); 5.0880 (0.5); 5.0571 (16.0); 3.4182 (0.4); 3.3258 (732.1); 2.6756 (5.2); 2.6710 (6.9); 2.6665 (5.0); 2.6359 (0.4); 2.6132 (0.5); 2.5243 (24.0); 2.5108 (433.4); 2.5065 (840.8); 2.5021 (1085.4); 2.4975 (782.6); 2.4933 (379.2); 2.3332 (4.8); 2.3289 (6.6); 2.3245 (4.8); 1.6217 (10.0); 1.6043 (9.9); 1.3851 (0.3); 1.2374 (0.6); 1.0866 (1.8); 1.0369 (1.4); 0.8653 (0.4); 0.8389 (0.8); 0.8219 (0.6); 0.1460 (3.5); 0.0402 (0.4); 0.0079 (32.4); −0.0002 (798.8); −0.0085 (29.5); −0.0358 (0.6); −0.1496 (3.6) 557.0 I-33 [00193] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3030 (0.9); 9.2858 (0.9); 9.0686 (1.6); 9.0644 (1.6); 8.5869 (1.0); 8.5814 (1.0); 8.5654 (1.1); 8.5599 (1.1); 8.2470 (3.7); 8.1981 (0.5); 8.0857 (1.6); 8.0643 (1.4); 8.0632 (1.4); 7.8709 (3.7); 7.8665 (4.0); 7.7466 (1.2); 7.7421 (2.0); 7.7377 (1.1); 6.0944 (0.6); 6.0771 (1.0); 6.0597 (0.6); 5.7574 (1.8); 2.5099 (11.1); 2.5054 (14.3); 2.5010 (10.6); 1.7103 (16.0); 1.6513 (3.6); 1.6339 (3.6); 0.0078 (0.5); −0.0002 (10.8); −0.0084 (0.4) 419.9 1-34 [00194] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4555 (2.5); 9.4392 (2.6); 8.8822 (10.7); 8.3571 (10.3); 7.8892 (4.8); 7.7813 (3.8); 7.5532 (3.8); 6.0839 (0.4); 6.0667 (1.7); 6.0498 (2.7); 6.0326 (1.7); 6.0154 (0.4); 5.7561 (5.7); 5.1591 (16.0); 3.3319 (13.3); 2.5265 (0.9); 2.5130 (19.7); 2.5088 (38.2); 2.5043 (49.3); 2.4998 (35.7); 2.4955 (17.2); 1.6472 (10.2); 1.6297 (10.2); 1.2361 (1.5); 1.1738 (0.5); 1.1584 (0.5); 1.1479 (0.8); 1.1370 (0.7); 1.0879 (3.0); 1.0382 (2.0); 1.0098 (0.4); 0.8837 (0.5); 0.8655 (1.0); 0.8535 (0.8); 0.8478 (0.7); 0.8397 (1.3); 0.8225 (1.1); 0.8171 (0.4); 0.7984 (0.5); 0.0079 (1.3); −0.0002 (32.4); −0.0085 (1.1) 573.0 1-35 [00195] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.4243 (3.6); 9.4072 (3.6); 9.0703 (7.0); 9.0664 (6.7); 9.0649 (6.6); 8.5856 (4.8); 8.5800 (4.6); 8.5641 (5.1); 8.5586 (5.0); 8.3626 (8.6); 8.3592 (5.2); 8.3158 (0.7); 8.2472 (16.0); 8.2386 (0.7); 8.1851 (4.9); 8.1805 (7.7); 8.1766 (5.2); 8.1068 (5.4); 8.1026 (7.8); 8.0983 (4.8); 8.0872 (6.7); 8.0859 (6.9); 8.0657 (6.1); 8.0643 (6.4); 6.1301 (0.6); 6.1129 (2.6); 6.0955 (4.2); 6.0782 (2.8); 6.0603 (0.6); 3.4488 (0.4); 3.3280 (263.7); 2.9852 (0.7); 2.9732 (1.6); 2.9665 (1.8); 2.9543 (3.0); 2.9428 (1.8); 2.9358 (1.6); 2.9239 (0.8); 2.6761 (1.7); 2.6715 (2.3); 2.6670 (1.7); 2.5247 (8.2); 2.5112 (148.0); 2.5070 (293.5); 2.5025 (381.9); 2.4980 (275.6); 2.4937 (133.9); 2.3338 (1.6); 2.3293 (2.2); 2.3248 (1.6); 2.0749 (3.5); 1.6530 (15.8); 1.6356 (15.8); 1.2310 (0.5); 1.2153 (0.8); 1.1999 (0.5); 1.1390 (0.9); 1.1265 (2.8); 1.1184 (7.0); 1.1132 (4.1); 1.1068 (3.0); 1.0991 (8.1); 421.1 1.0946 (7.0); 1.0896 (7.3); 1.0780 (8.2); 1.0695 (3.1); 1.0570 (0.8); 0.0080 (1.6); −0.0001 (46.1); −0.0084 (1.7) I-36 [00196] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2381 (3.0); 9.2207 (3.1); 9.0700 (4.9); 9.0685 (5.1); 9.0647 (5.3); 9.0631 (4.8); 8.5867 (4.0); 8.5811 (3.9); 8.5652 (4.3); 8.5596 (4.3); 8.2389 (12.5); 8.0896 (5.3); 8.0880 (5.2); 8.0681 (5.0); 8.0665 (4.9); 7.6696 (6.0); 7.6359 (1.8); 7.6306 (2.2); 7.6119 (1.8); 7.6080 (2.2); 7.4066 (2.2); 7.3837 (2.3); 6.1124 (0.5); 6.0952 (2.1); 6.0778 (3.3); 6.0604 (2.1); 6.0430 (0.5); 4.1239 (16.0); 3.3466 (1.8); 2.5304 (0.4); 2.5168 (7.2); 2.5124 (14.5); 2.5078 (19.7); 2.5033 (14.9); 2.4990 (7.4); 2.0796 (0.8); 1.6401 (11.9); 1.6227 (12.0); −0.0002 (0.9) 376.1 1-37 [00197] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3788 (0.9); 9.3625 (0.9); 8.6717 (3.7); 8.3184 (3.4); 7.9355 (1.9); 7.9315 (1.4); 7.9219 (1.4); 7.9181 (1.9); 7.7686 (1.2); 7.7642 (2.0); 7.7597 (1.1); 6.0468 (0.6); 6.0299 (0.9); 6.0128 (0.6); 5.7560 (7.9); 3.3242 (16.1); 2.5072 (32.1); 2.5029 (41.0); 2.4985 (30.4); 1.7190 (16.0); 1.6354 (3.5); 1.6180 (3.5) 426.1 1-38 [00198] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2467 (1.0); 9.2289 (1.0); 9.0117 (1.7); 9.0069 (1.6); 8.5319 (1.1); 8.5264 (1.0); 8.5104 (1.2); 8.5049 (1.2); 8.0079 (1.7); 7.9862 (1.5); 7.8506 (3.9); 7.8463 (4.1); 7.7422 (1.3); 7.7379 (2.1); 7.7335 (1.1); 6.0478 (0.7); 6.0303 (1.0); 6.0130 (0.7); 5.7557 (5.0); 3.3236 (32.2); 2.6713 (0.4); 2.5068 (50.4); 2.5025 (63.2); 2.4981 (46.1); 2.3292 (0.4); 2.0746 (0.5); 2.0658 (0.5); 2.0536 (0.8); 2.0416 (0.5); 2.0331 (0.4); 1.7299 (2.4); 1.7086 (16.0); 1.6092 (3.7); 1.5918 (3.7); 1.2317 (0.8); 1.2213 (0.9); 1.2161 (0.9); 1.2055 (0.8); 1.0006 (1.3); 0.9952 (1.7); 0.9798 (1.2); 0.9743 (1.6); 0.9037 (0.3); 0.8925 (1.0); 0.8867 (0.6); 0.8801 (1.0); 0.8749 (0.9); 0.8683 (0.8); 0.8562 (0.7); −0.0002 (8.2); −0.0083 (0.4) 460.3 1-39 [00199] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2959 (0.9); 9.2789 (0.9); 9.0192 (1.5); 9.0139 (1.6); 8.5447 (1.0); 8.5392 (1.0); 8.5231 (1.1); 8.5176 (1.1); 7.9820 (1.6); 7.9603 (1.5); 7.9010 (2.0); 7.8968 (1.7); 7.8920 (1.6); 7.8880 (2.0); 7.7538 (1.2); 7.7494 (2.0); 7.7451 (1.1); 6.0706 (0.6); 6.0534 (1.0); 6.0359 (0.6); 5.7558 (1.2); 3.9641 (9.6); 3.3242 (23.5); 2.5072 (33.9); 2.5028 (42.8); 2.4984 (31.3); 1.7124 (16.0); 1.6256 (3.5); 1.6082 (3.5); −0.0002 (4.9) 450.2 1-40 [00200] .sup.1H-NMR (600.1 MHz, CD3CN lowT): δ = 8.0493 (0.5); 8.0375 (0.5); 7.9051 (4.0); 7.8297 (1.1); 7.8271 (1.8); 7.8244 (1.2); 7.7982 (1.2); 7.7954 (1.8); 7.7927 (1.0); 7.6978 (1.1); 7.6947 (1.9); 7.6917 (1.0); 6.1026 (0.6); 6.0907 (1.0); 6.0789 (0.6); 4.0563 (0.5); 4.0443 (0.5); 3.2669 (8.0); 3.0484 (7.3); 2.3379 (10.5); 2.3336 (1.0); 2.3078 (17.9); 2.2774 (0.5); 1.9846 (2.2); 1.9778 (0.6); 1.9700 (14.6); 1.9659 (28.1); 1.9617 (40.8); 1.9576 (28.1); 1.9535 (14.3); 1.7297 (1.3); 1.7244 (16.0); 1.6456 (3.6); 1.6339 (3.6); 1.2179 (0.5); 1.2059 (1.1); 1.1940 (0.5); 0.0054 (0.8); −0.0001 (21.6); −0.0057 (0.7) 486.1 1-41 [00201] .sup.1H-NMR (600.1 MHz, CD3CN lowT): δ = 7.9965 (1.0); 7.9846 (1.1); 7.9095 (8.5); 7.7882 (1.7); 7.7855 (2.9); 7.7827 (1.8); 7.7237 (3.0); 7.5548 (2.6); 6.0924 (1.2); 6.0806 (1.9); 6.0687 (1.3); 4.0561 (0.4); 4.0443 (0.4); 3.9086 (9.2); 3.2720 (16.0); 3.0501 (14.6); 2.3358 (21.9); 2.3214 (0.5); 2.3040 (276.6); 2.2711 (5.2); 2.0806 (0.4); 2.0765 (0.7); 2.0724 (1.0); 2.0682 (0.8); 2.0639 (0.5); 2.0026 (0.4); 1.9928 (0.4); 1.9845 (2.3); 1.9776 (2.2); 1.9732 (3.9); 1.9697 (59.5); 1.9656 (115.0); 1.9615 (167.7); 1.9574 (115.1); 1.9533 (58.2); 1.9446 (0.7); 1.8546 (0.3); 1.8505 (0.6); 1.8464 (1.0); 1.8423 (0.6); 1.6314 (7.2); 458.1 1.6197 (7.2); 1.2178 (0.5); 1.2059 (1.0); 1.1940 (0.5); 0.9167 (0.4); 0.9055 (0.4); 0.0968 (0.4); 0.0054 (3.4); −0.0001 (98.0); −0.0057 (2.7); −0.1001 (0.4) 1-42 [00202] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 9.45 (d, 1H), 9.07 (d, 1H), 8.57 (dd, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.08 (d, 1H), 7.99 (s, 1H), 6.15-6.07 (m, 1H), 1.75 (s, 6H), 1.67 (d, 3H). 454.2 1-43 [00203] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 9.44 (d, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 8.04− 8.02 (m, 1H), 7.83 (s, 1H), 7.69 (s, 1H), 6.08−6.01 (m, 1H), 1.74 (s, 6H), 1.64 (d, 3H). 476.1 1-44 [00204] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 9.54 (d, 1H), 8.68 (s, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 6.11-6.03 (m, 1H), 1.77 (s, 6H), 1.65 (d, 3H). 460.1 1-45 [00205] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm] = 9.36 (d, 1H), 9.07-9.04 (m, 1H), 8.57 (dd, 1H), 8.25 (s, 1H), 8.07 (d, 1H), 7.99-7.96 (m, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 6.12-6.05 (m, 1H), 1.73 (s, 6H), 1.66 (d, 3H). 470.2 1-46 [00206] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.3539 (3.5); 9.3366 (3.6); 9.0684 (5.8); 9.0667 (6.3); 9.0630 (6.2); 9.0612 (6.0); 8.5866 (5.0); 8.5811 (4.8); 8.5652 (5.4); 8.5596 (5.4); 8.2450 (16.0); 8.0905 (6.3); 8.0888 (6.4); 8.0691 (6.0); 8.0673 (6.1); 7.9300 (5.1); 7.9258 (8.0); 7.9218 (5.4); 7.7401 (4.3); 7.7347 (7.1); 7.7311 (6.0); 7.7139 (6.1); 7.7089 (8.4); 7.7037 (3.9); 6.1140 (0.5); 6.0969 (2.5); 6.0795 (3.9); 6.0622 (2.5); 6.0449 (0.5); 3.4768 (46.5); 3.4684 (3.1); 3.3336 (21.8); 2.5289 (0.8); 2.5241 (1.3); 2.5154 (15.6); 2.5110 (31.0); 2.5064 (40.7); 2.5018 (30.1); 2.4974 (14.8); 2.0782 (7.0); 1.6427 (14.2); 1.6253 (14.2); 0.9036 (0.4); 0.0080 (0.5); −0.0002 (16.7); −0.0085 (0.5) 447.3 1-47 [00207] .sup.1H-NMR (400.2 MHz, d6-DMSO): δ = 10.3838 (0.4); 9.2349 (1.5); 9.2172 (1.5); 9.0264 (2.5); 9.0213 (2.5); 8.5412 (1.8); 8.5357 (1.7); 8.5197 (1.9); 8.5141 (1.9); 8.0221 (2.7); 8.0005 (2.5); 7.6049 (2.6); 7.4725 (2.3); 7.1749 (2.4); 6.0744 (1.1); 6.0570 (1.7); 6.0394 (1.1); 5.7565 (0.8); 3.3280 (41.9); 2.6763 (0.4); 2.6718 (0.5); 2.6672 (0.4); 2.5251 (1.4); 2.5115 (30.1); 2.5072 (60.2); 2.5027 (79.8); 2.4983 (59.5); 2.4940 (29.9); 2.3395 (16.0); 2.3300 (1.0); 1.6054 (5.9); 1.5880 (5.9); 0.0079 (1.7); −0.0002 (47.4); −0.0085 (1.7) 417.4 1-48 [00208] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.1127 (0.9); 9.0950 (0.9); 9.0605 (1.6); 9.0555 (1.5); 8.5805 (1.1); 8.5749 (1.0); 8.5591 (1.2); 8.5536 (1.1); 8.2387 (3.6); 8.0741 (1.6); 8.0526 (1.5); 7.8931 (0.4); 7.7893 (0.4); 7.6946 (1.8); 7.6279 (2.0); 7.5063 (1.8); 6.0818 (0.6); 6.0644 (1.0); 6.0469 (0.6); 5.7549 (0.9); 3.3235 (46.6); 2.9760 (0.6); 2.9588 (0.8); 2.9416 (0.6); 2.6756 (0.4); 2.6713 (0.5); 2.6664 (0.4); 2.5065 (57.0); 2.5021 (73.2); 2.4977 (53.1); 2.3333 (0.3); 2.3290 (0.4); 2.3246 (0.3); 2.0112 (0.4); 1.9887 (0.4); 1.9087 (0.4); 1.7141 (4.3); 1.6896 (16.0); 1.6610 (3.8); 1.6436 (3.7); 1.2583 (0.4); 1.2471 (2.6); 1.2329 (10.4); 1.2157 (9.1); 0.8886 (0.5); 0.8718 (0.5); 0.1457 (0.5); 0.0078 (4.9); 0.0069 (4.9); −0.0002 (110.4); −0.0085 (4.8); −0.1498 (0.5) 428.3 1-49 [00209] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO): δ = 9.2535 (2.7); 9.2370 (2.7); 8.6671 (16.0); 8.3156 (0.5); 8.3043 (11.5); 7.6842 (3.8); 7.6803 (6.4); 7.6765 (4.0); 7.4836 (3.4); 7.4799 (4.1); 7.4779 (4.8); 7.4743 (4.0); 7.4315 (4.2); 7.4269 (5.2); 7.4214 (3.2); 6.0253 (0.4); 6.0081 (1.8); 5.9911 (2.8); 5.9741 (1.8); 5.9568 (0.4); 5.7556 (6.5); 3.9728 (0.6); 3.9656 (1.3); 3.9580 (1.9); 3.9505 (2.6); 3.9432 (1.9); 3.9355 (1.3); 3.9282 (0.6); 3.3244 (113.0); 2.6801 (0.4); 2.6756 (0.8); 2.6711 (1.1); 2.6665 (0.8); 2.6620 (0.4); 2.5245 (3.5); 2.5111 (69.0); 2.5067 (136.6); 2.5022 (176.3); 461.0 2.4976 (125.5); 2.4930 (59.9); 2.3336 (0.8); 2.3290 (1.1); 2.3244 (0.8); 2.3199 (0.4); 1.6067 (11.0); 1.5892 (11.0); 0.8293 (0.8); 0.8135 (3.4); 0.8104 (3.3); 0.7958 (4.1); 0.7814 (1.2); 0.6833 (1.5); 0.6706 (3.5); 0.6652 (5.0); 0.6529 (1.3); 0.6453 (1.0); 0.1457 (1.2); 0.0079 (12.8); −0.0002 (290.0); −0.0086 (11.1); −0.0216 (0.6); −0.0268 (0.4); −0.1497 (1.2) 1-50 [00210] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3595 (2.9); 9.3430 (2.9); 8.6679 (12.8); 8.3149 (2.0); 8.3102 (11.6); 7.9117 (5.4); 7.7920 (5.4); 7.6200 (5.0); 6.0421 (0.4); 6.0253 (2.0); 6.0084 (2.9); 5.9912 (1.9); 5.9739 (0.4); 4.1290 (16.0); 3.3233 (310.9); 2.6755 (3.4); 2.6711 (4.7); 2.6667 (3.5); 2.5796 (0.5); 2.5242 (16.1); 2.5108 (298.6); 2.5066 (581.1); 2.5022 (747.3); 2.4977 (543.5); 2.4935 (272.8); 2.3333 (3.4); 2.3289 (4.6); 2.3245 (3.4); 2.0741 (2.1); 1.6204 (11.4); 1.6029 (11.5); 0.1460 (1.7); 0.0237 (0.4); 0.0076 (16.2); −0.0001 (349.4); −0.0076 (15.5); −0.1495 (1.7) 398.1 1-51 [00211] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.2466 (1.4); 9.2298 (1.4); 8.6315 (8.0); 7.7492 (2.0); 7.7455 (3.3); 7.7419 (2.0); 7.5529 (1.4); 7.5469 (2.4); 7.5436 (2.2); 7.5295 (2.3); 7.5253 (2.5); 7.5195 (1.3); 6.0042 (1.0); 5.9872 (1.5); 5.9700 (1.0); 4.9073 (0.8); 4.8854 (2.8); 4.8634 (2.9); 4.8412 (1.0); 3.3257 (82.0); 2.6758 (0.5); 2.6713 (0.7); 2.6668 (0.5); 2.5247 (2.4); 2.5199 (3.8); 2.5113 (43.6); 2.5069 (86.2); 2.5024 (110.3); 2.4978 (77.2); 2.4932 (36.3); 2.3405 (16.0); 2.3294 (1.0); 2.3247 (0.6); 2.0746 (3.0); 1.5949 (5.4); 1.5774 (5.4); 0.0079 (0.4); −0.0002 (12.1); −0.0085 (0.4) 490.2 1-52 [00212] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.2133 (0.6); 9.1962 (0.6); 8.5516 (0.3); 8.5079 (0.4); 8.0656 (0.4); 8.0223 (0.3); 7.8824 (0.4); 7.8789 (0.3); 7.8653 (1.9); 7.8509 (2.5); 7.8462 (2.5); 7.7286 (1.2); 7.7240 (2.1); 7.7195 (1.1); 6.0676 (0.6); 6.0499 (0.9); 6.0322 (0.6); 5.7559 (0.7); 3.4837 (0.3); 3.4690 (0.3); 3.3266 (29.1); 3.1512 (0.3); 3.1367 (0.3); 2.9648 (1.1); 2.8544 (1.0); 2.6717 (0.4); 2.5250 (1.1); 2.5113 (22.7); 2.5072 (43.6); 2.5028 (55.2); 2.4982 (39.6); 2.4940 (19.3); 2.3418 (8.9); 1.7299 (3.0); 1.6986 (16.0); 1.6276 (3.3); 1.6102 (3.3); 1.1612 (0.4); 1.1447 (0.7); 1.0235 (0.7); −0.0002 (0.8) 494.3 1-53 [00213] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4556 (2.8); 9.4393 (2.8); 8.6727 (12.2); 8.3200 (10.7); 8.2017 (5.3); 8.1432 (0.9); 8.0174 (5.3); 7.9233 (5.1); 6.0642 (0.4); 6.0473 (1.9); 6.0302 (2.9); 6.0131 (1.9); 5.9957 (0.4); 3.3322 (240.9); 2.6762 (1.4); 2.6717 (1.9); 2.6672 (1.5); 2.6628 (0.8); 2.5250 (8.3); 2.5116 (112.4); 2.5072 (216.8); 2.5027 (282.2); 2.4982 (214.1); 2.4938 (112.2); 2.3386 (0.7); 2.3340 (1.4); 2.3295 (1.9); 2.3250 (1.4); 2.0752 (12.7); 1.8036 (0.7); 1.7880 (0.9); 1.7780 (0.6); 1.7718 (1.3); 1.7655 (0.6); 1.7559 (0.9); 1.7390 (0.7); 1.7235 (0.4); 1.6312 (11.2); 1.6137 (11.1); 0.7129 (6.0); 0.7071 (6.7); 495.1 495.1 0.6934 (16.0); 0.1458 (1.0); 0.0078 (10.9); −0.0003 (232.1); −0.0084 (11.4); −0.1497 (1.0) 1-54 [00214] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4279 (2.9); 9.4115 (2.9); 8.6682 (15.9); 8.3171 (13.3); 7.9017 (5.7); 7.8107 (4.0); 7.5736 (3.8); 6.0574 (0.4); 6.0402 (1.9); 6.0232 (3.0); 6.0062 (2.0); 5.9889 (0.4); 4.1890 (16.0); 3.3718 (0.4); 3.3331 (418.8); 2.8913 (0.7); 2.7317 (0.6); 2.6807 (0.8); 2.6762 (1.6); 2.6717 (2.2); 2.6672 (1.6); 2.6628 (0.8); 2.5252 (7.3); 2.5204 (11.5); 2.5118 (129.3); 2.5073 (254.7); 2.5027 (330.6); 2.4982 (242.2); 2.4936 (118.9); 2.3386 (0.7); 2.3341 (1.5); 2.3296 (2.1); 2.3250 (1.6); 2.3205 (0.7); 2.0751 (0.9); 1.6322 (11.7); 1.6148 (11.7); 0.1460 (1.0); 0.0080 (9.1); −0.0002 (247.0); −0.0085 (8.6); −0.0234 (0.3); −0.1495 (1.1) 448.2 I-55 [00215] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.5944 (0.9); 9.5780 (1.0); 8.6803 (4.8); 8.4158 (1.2); 8.4122 (2.1); 8.4086 (1.3); 8.3340 (4.1); 8.2863 (1.2); 8.2822 (1.9); 8.2782 (1.2); 8.1796 (1.3); 8.1754 (2.1); 8.1711 (1.1); 6.1034 (0.6); 6.0863 (0.9); 6.0693 (0.6); 3.3330 (29.6); 3.3207 (9.8); 2.5257 (1.0); 2.5123 (15.2); 2.5079 (29.1); 2.5034 (36.7); 2.4989 (26.4); 2.4945 (12.8); 2.0759 (4.5); 1.7746 (16.0); 1.6646 (3.6); 1.6472 (3.6); 0.0079 (0.9); −0.0002 (20.5); −0.0085 (0.7) 470.2 1-56 [00216] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3967 (0.9); 9.3792 (1.0); 9.3742 (2.9); 9.3707 (2.9); 9.2515 (2.8); 9.2481 (2.6); 8.3678 (4.1); 8.0014 (1.2); 7.9976 (2.0); 7.9937 (1.2); 7.7857 (1.3); 7.6814 (1.3); 6.0657 (0.6); 6.0484 (1.0); 6.0310 (0.6); 3.3279 (18.6); 2.5263 (0.5); 2.5215 (0.8); 2.5129 (11.3); 2.5084 (22.9); 2.5039 (29.6); 2.4993 (20.5); 2.4948 (9.4); 2.0757 (1.5); 1.7322 (16.0); 1.6563 (3.7); 1.6389 (3.7); 0.0079 (1.1); −0.0002 (32.6); −0.0086 (1.0) 471.3 1-57 [00217] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3735 (11.0); 9.3702 (11.1); 9.3550 (2.9); 9.2487 (8.8); 9.2452 (8.3); 8.3575 (13.3); 7.8794 (5.6); 7.7714 (4.0); 7.5605 (3.9); 6.0698 (0.4); 6.0524 (2.0); 6.0351 (3.2); 6.0178 (2.1); 6.0003 (0.5); 5.7551 (10.4); 4.1903 (0.8); 4.1787 (16.0); 3.3407 (16.0); 2.6766 (0.6); 2.6721 (0.8); 2.6676 (0.6); 2.5256 (2.3); 2.5209 (3.4); 2.5122 (48.8); 2.5077 (101.4); 2.5032 (132.8); 2.4986 (92.8); 2.4940 (43.0); 2.3345 (0.6); 2.3300 (0.8); 2.3254 (0.6); 1.6377 (12.4); 1.6203 (12.3); 0.1459 (0.7); 0.0079 (5.9); −0.0002 (178.7); −0.0086 (5.9); −0.0166 (0.4); −0.1496 (0.7) 443.2 1-58 [00218] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4907 (0.8); 9.4735 (0.8); 9.3775 (2.5); 9.3741 (2.6); 9.2596 (2.6); 9.2561 (2.4); 8.3697 (4.0); 8.2318 (1.5); 8.1859 (1.4); 7.9970 (1.4); 6.0884 (0.6); 6.0711 (0.9); 6.0538 (0.6); 3.3279 (18.4); 2.5262 (0.6); 2.5214 (0.8); 2.5129 (10.6); 2.5084 (21.8); 2.5039 (28.5); 2.4993 (20.0); 2.4947 (9.3); 2.0758 (2.0); 1.7579 (16.0); 1.6638 (3.5); 1.6464 (3.5); 0.0079 (1.3); −0.0002 (37.2); −0.0086 (1.3) 455.2 1-59 [00219] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4006 (4.4); 9.3833 (4.6); 9.3737 (9.1); 9.3705 (11.4); 9.2538 (7.9); 9.2504 (9.2); 8.7856 (1.0); 8.4239 (0.4); 8.4143 (0.4); 8.4115 (0.4); 8.3647 (12.1); 8.3618 (7.3); 8.1624 (7.3); 8.0955 (0.7); 8.0518 (0.6); 7.9950 (0.8); 7.9783 (7.4); 7.9137 (7.4); 6.0721 (0.6); 6.0555 (2.3); 6.0382 (3.6); 6.0209 (2.4); 6.0039 (0.6); 3.3646 (358.8); 3.3467 (270.7); 3.0337 (1.0); 2.7149 (0.7); 2.6790 (1.2); 2.6750 (1.6); 2.6706 (1.2); 2.5487 (53.3); 2.5454 (161.0); 2.5283 (10.9); 2.5101 (206.6); 2.5059 (254.4); 2.5015 (195.9); 2.3713 (0.8); 2.3371 (1.3); 2.3328 (1.6); 2.3284 (1.3); 2.0778 (0.6); 1.9037 (0.8); 1.8889 (0.9); 1.8799 (0.7); 1.8129 (0.8); 1.7981 (1.3); 1.7821 (1.6); 490.3 490.3 1.7672 (1.8); 1.7489 (1.5); 1.7356 (1.0); 1.7172 (0.6); 1.6375 (14.5); 1.6202 (14.6); 1.5168 (1.1); 1.4994 (1.1); 0.7145 (9.1); 0.6915 (16.0) 1-60 [00220] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3432 (0.6); 9.3269 (0.6); 8.6610 (4.0); 8.3123 (3.0); 7.9606 (0.9); 7.9567 (1.6); 7.9528 (0.9); 7.6269 (0.9); 7.6233 (1.0); 7.6213 (1.2); 7.6178 (1.0); 7.5673 (1.0); 7.5628 (1.3); 7.5574 (0.8); 6.0248 (0.4); 6.0078 (0.6); 5.9907 (0.4); 3.3264 (25.1); 2.5254 (0.4); 2.5207 (0.6); 2.5120 (9.2); 2.5075 (19.1); 2.5029 (25.2); 2.4983 (17.8); 2.4937 (8.2); 2.0749 (2.7); 1.7172 (16.0); 1.6183 (2.6); 1.6008 (2.6); −0.0002 (1.7) 488.1 1-61 [00221] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3399 (0.7); 9.3235 (0.7); 8.6615 (3.9); 8.3127 (3.0); 7.8260 (1.0); 7.8219 (1.5); 7.8180 (1.0); 7.5954 (0.9); 7.5917 (1.1); 7.5898 (1.2); 7.5862 (1.0); 7.4465 (1.0); 7.4413 (1.5); 7.4362 (0.9); 6.0259 (0.4); 6.0089 (0.7); 5.9919 (0.4); 3.3269 (20.8); 2.5256 (0.4); 2.5208 (0.5); 2.5121 (8.1); 2.5077 (16.5); 2.5031 (21.7); 2.4985 (15.4); 2.4940 (7.3); 2.0752 (1.1); 1.7234 (16.0); 1.7057 (0.4); 1.6201 (2.7); 1.6027 (2.7); −0.0002 (1.3) 442.2 1-62 [00222] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.2637 (2.1); 9.2583 (2.2); 9.2474 (2.2); 9.2420 (2.1); 8.6670 (15.0); 8.3147 (0.6); 8.3054 (14.6); 7.6461 (6.4); 7.4800 (2.1); 7.4742 (3.0); 7.4707 (4.1); 7.4669 (2.7); 7.4647 (3.0); 7.4612 (2.5); 7.4120 (4.6); 7.4075 (6.2); 7.4020 (3.7); 6.0338 (0.5); 6.0167 (2.1); 5.9997 (3.2); 5.9827 (2.1); 5.9649 (0.5); 5.7552 (7.8); 4.3983 (2.6); 4.3856 (2.7); 4.3711 (3.0); 4.3585 (2.9); 3.9933 (2.4); 3.9700 (2.9); 3.9667 (2.8); 3.9432 (2.2); 3.3285 (190.5); 2.6765 (0.6); 2.6721 (0.9); 2.6675 (0.6); 2.5255 (2.5); 2.5208 (3.7); 2.5121 (52.7); 2.5076 (108.7); 2.5031 (142.7); 2.4984 (101.2); 2.4939 (47.6); 2.3345 (0.6); 2.3299 (0.9); 2.3253 (0.6); 2.2833 (0.6); 2.2703 (0.6); 2.2623 (1.0); 2.2504 (1.1); 2.2426 (1.3); 2.2351 (1.2); 2.2228 (1.1); 2.2148 (0.8); 2.2021 (0.6); 1.8950 (3.3); 1.8765 (4.0); 1.8678 (3.3); 1.8494 (3.2); 1.6137 (13.3); 1.5964 (16.0); 1.5782 (5.6); 1.5593 (2.5); 1.2343 (1.9); 0.8540 (0.4); −0.0001 (3.7) 543.0 1-63 [00223] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.2492 (2.3); 9.2355 (2.3); 8.6669 (16.0); 8.3147 (0.4); 8.3051 (13.6); 7.6402 (6.2); 7.4375 (4.0); 7.4349 (4.4); 7.4320 (4.7); 7.3853 (4.3); 7.3805 (5.8); 7.3754 (3.5); 6.0338 (0.5); 6.0166 (2.1); 5.9996 (3.2); 5.9825 (2.1); 5.9655 (0.5); 5.7556 (2.7); 4.2604 (0.9); 4.2531 (0.9); 4.2439 (1.0); 4.2350 (1.7); 4.2268 (1.2); 4.2173 (1.3); 4.2106 (1.1); 4.0620 (1.5); 4.0368 (2.4); 4.0141 (1.2); 3.3300 (97.8); 2.6771 (0.4); 2.6727 (0.5); 2.6679 (0.4); 2.5259 (1.6); 2.5211 (2.5); 2.5125 (30.6); 2.5081 (62.3); 2.5036 (81.8); 2.4990 (58.5); 2.4945 (28.0); 2.3350 (0.4); 2.3304 (0.5); 2.3258 (0.4); 2.2704 (0.6); 2.2539 (0.7); 2.2389 (1.1); 2.2210 (1.1); 2.2059 (0.7); 2.1894 (0.6); 1.7840 (0.5); 1.7719 (0.6); 1.7640 (0.7); 1.7529 (1.5); 1.7417 (1.1); 1.7340 (1.2); 1.7231 (1.4); 1.7121 (0.6); 1.7044 (0.6); 1.6925 (0.6); 1.6122 (12.5); 1.5947 (12.4); 1.5300 (0.6); 1.5198 (0.7); 1.5109 (1.0); 1.5004 (1.2); 1.4853 (1.0); 1.4773 511.1 (1.2); 1.4666 (1.1); 1.4579 (0.6); 1.4475 (0.6); 1.2341 (0.6); −0.0002 (2.6) 1-64 [00224] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3085 (2.4); 9.2923 (2.4); 8.7046 (0.6); 8.6663 (16.0); 8.4149 (0.5); 8.3154 (1.2); 8.3099 (11.6); 7.8071 (0.4); 7.5762 (3.2); 7.5726 (3.9); 7.5706 (3.9); 7.5671 (3.4); 7.5540 (0.5); 7.5507 (0.5); 7.4441 (3.5); 7.4416 (3.2); 7.4277 (0.4); 7.2193 (3.3); 7.2174 (3.3); 7.1462 (0.4); 6.0404 (0.4); 6.0227 (1.8); 6.0057 (2.5); 5.9888 (1.7); 5.9713 (0.4); 5.8824 (0.3); 3.9995 (0.7); 3.9926 (1.3); 3.9850 (1.9); 3.9776 (2.6); 3.9703 (1.9); 3.9627 (1.3); 3.9554 (0.7); 3.3278 (498.0); 2.9760 (0.3); 2.8903 (0.3); 2.6805 (1.0); 2.6758 (2.1); 2.6712 (2.8); 2.6666 (2.0); 2.6620 (1.0); 2.5248 (9.1); 2.5201 (13.2); 2.5114 (164.9); 2.5069 (339.2); 2.5023 (443.4); 2.4977 (309.5); 465.2 2.4931 (142.5); 2.3383 (0.9); 2.3337 (2.0); 2.3291 (2.7); 2.3245 (1.9); 2.3201 (0.8); 2.1355 (0.9); 1.9889 (0.4); 1.6442 (0.5); 1.6206 (10.2); 1.6031 (10.1); 1.2981 (0.3); 1.2589 (0.6); 1.2347 (1.2); 1.2253 (1.8); 1.2088 (2.6); 1.1927 (1.5); 1.1751 (0.3); 1.0484 (0.3); 1.0331 (0.3); 0.8732 (0.4); 0.8540 (0.4); 0.8470 (1.0); 0.8303 (3.5); 0.8272 (3.4); 0.8128 (4.0); 0.7984 (1.2); 0.7145 (0.4); 0.7044 (1.8); 0.6962 (3.1); 0.6919 (3.4); 0.6861 (4.5); 0.6740 (1.2); 0.6663 (0.8); −0.0002 (2.0) 1-65 [00225] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.2577 (3.1); 9.2413 (3.1); 8.6122 (16.0); 8.3158 (0.8); 7.5555 (4.0); 7.5518 (5.1); 7.5468 (4.1); 7.4169 (4.7); 7.2145 (4.5); 5.9777 (0.5); 5.9601 (2.3); 5.9429 (3.4); 5.9258 (2.2); 5.9084 (0.5); 3.9983 (0.7); 3.9910 (1.5); 3.9834 (2.2); 3.9760 (3.0); 3.9686 (2.2); 3.9611 (1.4); 3.9536 (0.7); 3.3255 (226.0); 2.6798 (1.0); 2.6758 (1.9); 2.6712 (2.5); 2.6668 (1.9); 2.5245 (9.8); 2.5111 (160.4); 2.5068 (314.7); 2.5023 (405.2); 2.4978 (287.0); 2.4934 (136.3); 2.3336 (1.7); 2.3291 (2.4); 2.3247 (1.8); 2.1074 (0.6); 2.0950 (1.4); 2.0862 (1.6); 2.0744 (2.9); 2.0624 (1.7); 2.0537 (1.5); 2.0414 (0.7); 1.5797 (12.4); 1.5622 (12.3); 1.3978 (0.7); 1.2352 (0.7); 1.0347 505.3 (3.8); 1.0293 (4.8); 1.0140 (3.6); 1.0084 (5.1); 0.9876 (0.4); 0.9814 (0.4); 0.9040 (0.8); 0.8961 (0.9); 0.8918 (0.9); 0.8791 (2.6); 0.8674 (2.6); 0.8506 (2.8); 0.8337 (4.7); 0.8293 (4.4); 0.8143 (5.3); 0.8006 (1.5); 0.7079 (1.8); 0.6898 (5.9); 0.6778 (1.6); 0.6699 (1.1); −0.0001 (1.4) 1-66 [00226] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4311 (0.8); 9.4139 (0.8); 9.3891 (2.7); 9.3861 (2.7); 8.6143 (2.7); 8.6112 (2.6); 8.3658 (4.0); 8.0200 (1.1); 8.0162 (1.8); 8.0123 (1.1); 7.8109 (1.3); 7.8085 (1.2); 7.6853 (1.2); 6.2181 (0.6); 6.2007 (0.9); 6.1834 (0.6); 3.8924 (0.5); 3.3326 (21.3); 3.2418 (0.5); 3.2247 (0.5); 2.5266 (0.7); 2.5219 (1.1); 2.5132 (11.5); 2.5087 (22.7); 2.5041 (29.5); 2.4995 (21.4); 2.4950 (10.2); 2.0762 (0.7); 1.7455 (2.2); 1.7343 (16.0); 1.6683 (3.4); 1.6509 (3.4); 0.0080 (0.4); −0.0002 (10.2) 471.4 1-67 [00227] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4000 (1.2); 9.3835 (1.2); 8.6148 (6.8); 8.0054 (1.6); 8.0016 (2.6); 7.9979 (1.6); 7.7968 (1.7); 7.6926 (1.8); 5.9978 (0.8); 5.9807 (1.3); 5.9635 (0.9); 3.3322 (129.8); 2.6766 (0.5); 2.6721 (0.6); 2.6675 (0.5); 2.6535 (0.5); 2.5255 (2.2); 2.5207 (3.4); 2.5121 (39.9); 2.5077 (79.3); 2.5031 (103.1); 2.4985 (74.4); 2.4940 (35.9); 2.3345 (0.5); 2.3299 (0.6); 2.3253 (0.4); 2.1003 (0.5); 2.0916 (0.6); 2.0796 (1.1); 2.0675 (0.6); 2.0589 (0.6); 1.7387 (16.0); 1.6066 (4.6); 1.5891 (4.6); 1.3977 (3.0); 1.2003 (0.4); 1.1896 (0.3); 1.1837 (0.4); 1.0364 (1.5); 1.0319 (1.9); 1.0156 (1.5); 1.0110 (1.9); 0.8869 (1.0); 0.8801 (0.7); 0.8744 (1.2); 0.8678 (1.0); 0.8629 (1.0); 0.8510 (0.8); 0.0079 (2.1); −0.0002 (57.3); 516.2 −0.0086 (1.7) 1-68 [00228] .sup.1H NMR (DMSO-d.sub.6) δ: 9.36 (d, 1H), 9.24 (d, 1H), 8.44 (s, 1H), 8.32 (d, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 6.17-6.25 (m, 1H), 2.06-2.14 (m, 1H), 1.73 (s, 6H), 1.63 (d, 3H), 0.97-1.06 (m, 2H), 0.85-0.96 (m, 2H) ppm. 529.4 1-69 [00229] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.5669 (1.3); 9.5503 (1.4); 8.6146 (9.2); 7.8882 (15.3); 5.9937 (1.0); 5.9766 (1.5); 5.9596 (1.0); 3.3331 (12.8); 2.5262 (0.8); 2.5214 (1.1); 2.5128 (15.8); 2.5083 (32.2); 2.5037 (42.4); 2.4991 (30.3); 2.4945 (14.4); 2.1064 (0.6); 2.0977 (0.6); 2.0947 (0.5); 2.0858 (1.3); 2.0768 (0.7); 2.0737 (0.7); 2.0650 (0.7); 2.0529 (0.3); 1.7249 (16.0); 1.7220 (15.9); 1.6012 (5.1); 1.5837 (5.2); 1.0595 (0.3); 1.0458 (1.5); 1.0402 (2.1); 1.0283 (1.2); 1.0251 (1.4); 1.0195 (2.1); 1.0081 (0.4); 0.8994 (0.6); 0.8904 (1.4); 0.8874 (1.5); 0.8833 (1.4); 0.8788 (1.8); 0.8727 (1.5); 0.8607 (0.4); −0.0002 (6.0) 467.1 1-70 [00230] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.6064 (1.1); 9.5896 (1.1); 8.6349 (7.3); 7.9533 (0.6); 7.9187 (12.8); 6.0356 (0.8); 6.0186 (1.3); 6.0014 (0.8); 5.7588 (4.4); 3.3453 (0.6); 3.3325 (68.4); 2.8915 (5.1); 2.7323 (4.2); 2.7311 (4.1); 2.5256 (1.0); 2.5209 (1.5); 2.5122 (19.2); 2.5077 (39.0); 2.5031 (50.9); 2.4985 (36.3); 2.4940 (17.0); 2.3539 (13.4); 2.3300 (0.4); 1.7246 (16.0); 1.6217 (4.5); 1.6043 (4.5); −0.0002 (6.3) 441.1 1-71 [00231] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.6274 (1.0); 9.6111 (1.0); 8.6713 (6.5); 8.3411 (4.6); 7.9041 (11.4); 6.0539 (0.7); 6.0369 (1.0); 6.0199 (0.7); 3.3307 (38.4); 2.5256 (0.8); 2.5208 (1.2); 2.5122 (15.4); 2.5077 (30.9); 2.5031 (40.2); 2.4984 (28.4); 2.4939 (13.2); 2.0763 (0.7); 1.7224 (16.0); 1.6425 (4.1); 1.6250 (4.0); −0.0002 (7.9) 427.1 1-72 [00232] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3225 (1.6); 9.3188 (1.6); 9.3059 (1.8); 9.3027 (1.6); 8.6682 (16.0); 8.3127 (8.9); 7.8354 (1.8); 7.8317 (3.0); 7.8280 (1.8); 7.8129 (1.9); 7.8091 (3.1); 7.8054 (1.9); 7.5358 (1.8); 7.5323 (2.1); 7.5298 (2.4); 7.5265 (3.5); 7.5231 (2.0); 7.5206 (2.2); 7.5171 (1.8); 7.4477 (3.3); 7.4429 (4.4); 7.4378 (2.7); 6.0256 (1.0); 6.0215 (1.0); 6.0085 (1.6); 6.0045 (1.5); 5.9914 (1.1); 5.9875 (1.0); 5.7586 (15.7); 4.6451 (1.3); 4.6372 (1.4); 4.6326 (1.6); 4.6245 (2.8); 4.6164 (1.5); 4.6117 (1.4); 4.6038 (1.2); 3.3326 (76.1); 2.6724 (0.4); 2.5258 (1.4); 2.5211 (2.2); 2.5124 (24.9); 2.5080 (49.5); 2.5034 (64.1); 2.4988 (45.5); 2.4942 (21.3); 2.3301 (0.4); 2.2075 (1.2); 2.2025 (1.1); 2.1863 (1.9); 2.1842 (2.1); 2.1816 (2.0); 2.1794 (1.8); 2.1633 (1.4); 2.1584 (1.3); 429.1 1.9683 (1.6); 1.9642 (1.5); 1.9557 (1.6); 1.9515 (1.5); 1.9451 (1.4); 1.9409 (1.3); 1.9325 (1.3); 1.9283 (1.2); 1.6166 (6.8); 1.6144 (6.8); 1.5991 (6.7); 1.5969 (6.6); −0.0002 (9.2) 1-73 [00233] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4499 (0.8); 9.4333 (0.8); 8.2576 (3.9); 8.1614 (4.4); 8.0450 (1.1); 8.0411 (1.8); 8.0373 (1.1); 7.8420 (1.2); 7.8395 (1.0); 7.6949 (1.2); 6.0932 (0.5); 6.0760 (0.9); 6.0588 (0.6); 5.7586 (1.8); 4.0381 (0.8); 4.0203 (0.8); 3.7938 (0.4); 3.7771 (0.4); 3.3338 (56.0); 3.2403 (0.7); 3.0256 (0.7); 2.6897 (1.1); 2.5256 (0.9); 2.5209 (1.2); 2.5121 (17.1); 2.5076 (34.9); 2.5030 (45.8); 2.4984 (32.7); 2.4939 (15.5); 2.0123 (1.3); 2.0008 (0.5); 1.9897 (3.6); 1.7375 (16.0); 1.6570 (3.2); 1.6395 (3.2); 1.1928 (1.0); 1.1750 (2.0); 1.1572 (1.0); 0.8881 (1.4); 0.8714 (1.3); −0.0002 (6.2) 522.2 1-74 [00234] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.4386 (0.8); 9.4219 (0.8); 8.7805 (0.6); 8.7690 (0.6); 8.2560 (3.9); 8.2452 (4.8); 8.0285 (1.1); 8.0246 (1.8); 8.0208 (1.1); 7.8286 (1.0); 7.8261 (1.2); 7.8235 (1.1); 7.6923 (1.2); 6.0770 (0.5); 6.0600 (0.8); 6.0428 (0.5); 3.3310 (67.1); 3.3170 (0.4); 2.8060 (4.1); 2.7945 (4.0); 2.6717 (0.4); 2.5252 (1.3); 2.5204 (2.0); 2.5118 (24.7); 2.5073 (49.6); 2.5027 (64.1); 2.4981 (45.3); 2.4935 (21.0); 2.3296 (0.4); 2.0760 (2.5); 1.7349 (16.0); 1.6468 (3.1); 1.6293 (3.1); −0.0002 (5.5) 508.3 1-75 [00235] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.6072 (0.9); 9.5899 (1.0); 9.3902 (3.5); 9.3871 (3.4); 8.6136 (3.4); 8.6106 (3.4); 8.3807 (4.8); 7.8963 (10.3); 6.2127 (0.7); 6.1954 (1.1); 6.1781 (0.7); 3.3623 (0.4); 3.3403 (111.1); 3.3217 (0.4); 2.6898 (0.7); 2.5260 (0.8); 2.5213 (1.1); 2.5127 (15.0); 2.5082 (31.3); 2.5036 (41.5); 2.4989 (29.7); 2.4944 (13.9); 2.0759 (2.0); 1.7191 (16.0); 1.6580 (4.1); 1.6406 (4.0); 1.4332 (0.8); −0.0002 (0.5) 422.0 1-76 [00236] .sup.1H-NMR (400.2 MHz, d.sub.6-DMSO) δ = 9.3833 (1.1); 9.3658 (1.1); 9.3224 (2.9); 9.3195 (2.8); 8.5090 (3.0); 8.5061 (2.9); 7.9870 (2.2); 7.9836 (1.4); 7.7819 (1.6); 7.6883 (1.6); 6.1569 (0.7); 6.1395 (1.1); 6.1221 (0.7); 5.7607 (0.4); 3.3335 (17.6); 2.5266 (0.6); 2.5129 (10.7); 2.5087 (20.9); 2.5043 (27.1); 2.4998 (20.0); 2.4958 (10.1); 2.0984 (0.4); 2.0896 (0.5); 2.0777 (0.9); 2.0656 (0.5); 2.0570 (0.5); 1.9906 (1.3); 1.7349 (16.0); 1.6272 (3.9); 1.6098 (3.9); 1.1934 (0.3); 1.1756 (0.7); 1.1578 (0.3); 1.0385 (1.2); 1.0324 (1.7); 1.0178 (1.1); 1.0117 (1.8); 0.9302 (0.8); 0.9183 (0.8); 0.9125 (0.6); 0.9091 (0.6); 0.9034 (0.8); 0.8967 (0.6); 0.8915 (0.7); −0.0002 (3.6) 511.4 1-77 [00237] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.4185 (4.1); 9.4012 (4.2); 9.3659 (10.3); 9.3628 (10.7); 9.2422 (10.8); 9.2390 (10.3); 8.3558 (16.0); 8.1854 (7.8); 7.9647 (7.9); 7.9197 (7.8); 7.6560 (4.8); 7.6428 (5.4); 7.6341 (5.9); 7.6210 (5.2); 7.3743 (5.2); 7.3523 (9.4); 7.3302 (4.4); 6.0559 (0.6); 6.0392 (2.7); 6.0219 (4.1); 6.0046 (2.7); 5.9873 (0.6); 3.3306 (141.6); 2.6761 (1.6); 2.6718 (2.1); 2.5072 (279.4); 2.5028 (348.8); 2.4986 (259.9); 2.3337 (1.6); 2.3297 (2.1); 2.3253 (1.6); 2.0765 (3.4); 1.6230 (15.6); 1.6057 (15.3); −0.0002 (2.0) 544.0 1-78 [00238] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.4718 (2.7); 9.4554 (2.8); 8.6624 (16.0); 8.3148 (12.6); 8.2254 (5.1); 7.9972 (5.2); 7.9387 (5.1); 7.6661 (3.2); 7.6530 (3.5); 7.6440 (3.8); 7.6309 (3.6); 7.3786 (3.5); 7.3566 (6.4); 7.3345 (3.0); 6.0497 (0.4); 6.0324 (1.8); 6.0155 (2.7); 5.9984 (1.8); 5.9811 (0.4); 3.3793 (0.4); 3.3436 (297.1); 2.6796 (0.7); 2.6750 (0.9); 2.6705 (0.7); 2.5286 (3.0); 2.5238 (4.6); 2.5151 (58.9); 2.5107 (118.2); 2.5061 (152.7); 2.5016 (109.2); 2.4971 (52.1); 2.3375 (0.7); 2.3329 (0.9); 2.3283 (0.6); 2.0789 (1.0); 1.6228 (10.7); 1.6053 (10.6) 549.0 1-79 [00239] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.4450 (1.4); 9.4285 (1.4); 8.6254 (8.6); 8.2411 (2.6); 8.0117 (2.6); 7.9390 (2.6); 7.6666 (1.6); 7.6534 (1.8); 7.6444 (2.0); 7.6313 (1.8); 7.3777 (1.8); 7.3557 (3.3); 7.3335 (1.5); 6.0124 (1.0); 5.9954 (1.5); 5.9782 (1.0); 3.3318 (81.7); 2.6764 (0.6); 2.6718 (0.8); 2.6674 (0.6); 2.5254 (2.6); 2.5207 (3.9); 2.5119 (48.7); 2.5075 (97.2); 2.5030 (125.0); 2.4984 (88.8); 2.4939 (42.0); 2.3371 (16.0); 2.0766 (0.8); 1.5994 (5.3); 1.5820 (5.3); −0.0002 (0.7) 563.0 1-80 [00240] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.4494 (3.5); 9.4323 (3.6); 9.3800 (10.6); 9.3770 (9.9); 8.6075 (10.5); 8.6046 (9.8); 8.3525 (16.0); 8.2111 (6.6); 7.9865 (6.7); 7.9245 (6.5); 7.6596 (4.1); 7.6464 (4.6); 7.6376 (4.9); 7.6245 (4.5); 7.3756 (4.5); 7.3535 (8.2); 7.3315 (3.9); 6.2071 (0.5); 6.1899 (2.4); 6.1726 (3.7); 6.1553 (2.4); 6.1380 (0.5); 5.7603 (7.2); 3.3345 (156.7); 2.6770 (0.9); 2.6726 (1.2); 2.6681 (0.8); 2.5260 (4.1); 2.5125 (81.8); 2.5081 (156.3); 2.5036 (195.3); 2.4991 (136.9); 2.4947 (64.0); 2.3349 (0.9); 2.3304 (1.2); 2.3259 (0.8); 1.6375 (14.0); 1.6201 (13.9); 1.6004 (0.4); −0.0003 (0.4) 544.0 1-81 [00241] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.4842 (3.6); 9.4669 (3.9); 9.3929 (10.3); 9.3900 (10.3); 8.6174 (10.5); 8.6145 (10.7); 8.4036 (8.4); 8.3640 (16.0); 8.3196 (0.4); 8.2076 (4.6); 8.2033 (7.6); 8.1991 (5.4); 8.1553 (5.4); 8.1511 (7.6); 8.1467 (4.4); 6.2371 (0.6); 6.2203 (2.5); 6.2030 (4.0); 6.1857 (2.5); 6.1685 (0.6); 3.4584 (0.3); 3.4230 (0.4); 3.4130 (0.4); 3.4019 (0.5); 3.3311 (1076.8); 2.9969 (0.7); 2.9852 (1.6); 2.9779 (1.8); 2.9662 (3.0); 2.9544 (1.8); 2.9476 (1.7); 2.9356 (0.8); 2.7836 (0.3); 2.6902 (0.7); 2.6758 (8.1); 2.6713 (10.8); 2.6669 (8.3); 2.5246 (38.1); 2.5109 (685.9); 2.5068 (1334.6); 2.5023 (1732.0); 422.2 2.4978 (1295.8); 2.3929 (0.3); 2.3474 (0.5); 2.3336 (7.8); 2.3291 (10.6); 2.3247 (8.0); 1.6563 (14.5); 1.6389 (14.4); 1.6144 (0.6); 1.4328 (2.2); 1.2335 (0.3); 1.1412 (0.8); 1.1290 (2.5); 1.1205 (6.5); 1.1095 (2.9); 1.1014 (7.4); 1.0967 (6.3); 1.0913 (6.8); 1.0795 (7.8); 1.0709 (3.1); 0.0080 (1.4); 0.0001 (41.3) 1-82 [00242] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.4872 (1.6); 9.4704 (1.6); 8.6401 (7.6); 8.6343 (0.5); 8.4394 (2.1); 8.4359 (3.6); 8.4324 (2.1); 8.2146 (1.8); 8.2103 (3.1); 8.2063 (2.1); 8.1823 (2.4); 8.1782 (3.1); 8.1738 (1.6); 6.0434 (1.1); 6.0263 (1.6); 6.0091 (1.1); 3.3309 (103.9); 2.9917 (0.6); 2.9847 (0.7); 2.9728 (1.2); 2.9614 (0.7); 2.9542 (0.7); 2.9421 (0.3); 2.6761 (0.8); 2.6717 (1.0); 2.6671 (0.7); 2.5249 (3.2); 2.5113 (65.5); 2.5071 (127.0); 2.5027 (161.3); 2.4982 (114.9); 2.4938 (54.6); 2.3461 (16.0); 2.3382 (1.7); 2.3295 (1.1); 2.3249 (0.8); 1.6206 (5.8); 1.6031 (5.9); 441.3 1.5819 (0.4); 1.1438 (0.3); 1.1312 (1.1); 1.1231 (2.7); 1.1177 (1.6); 1.1118 (1.2); 1.1038 (3.2); 1.0995 (2.8); 1.0948 (3.1); 1.0832 (3.3); 1.0747 (1.2); 0.0079 (1.5); −0.0001 (40.1); −0.0084 (1.3) 1-83 [00243] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.5078 (2.6); 9.4914 (2.6); 8.6747 (16.0); 8.6675 (0.6); 8.4325 (0.5); 8.4222 (3.5); 8.4186 (6.3); 8.4149 (3.6); 8.3228 (12.5); 8.3181 (1.1); 8.3138 (0.5); 8.3082 (0.5); 8.2128 (3.4); 8.2081 (5.5); 8.2041 (3.9); 8.1651 (4.1); 8.1608 (5.4); 8.1563 (3.2); 8.1495 (0.5); 8.1447 (0.4); 6.0788 (0.4); 6.0614 (1.8); 6.0444 (2.7); 6.0273 (1.8); 6.0098 (0.4); 5.7587 (0.7); 3.3328 (106.9); 2.9989 (0.5); 2.9868 (1.1); 2.9801 (1.3); 2.9681 (2.2); 2.9624 (1.0); 2.9563 (1.3); 2.9495 (1.2); 2.9374 (0.6); 2.8910 (0.9); 2.7310 (0.8); 2.6804 (0.6); 2.6761 427.1 (1.2); 2.6715 (1.6); 2.6670 (1.2); 2.6625 (0.6); 2.5251 (5.6); 2.5203 (8.4); 2.5116 (102.5); 2.5072 (205.6); 2.5026 (265.8); 2.4980 (188.6); 2.4935 (89.0); 2.3385 (0.5); 2.3340 (1.2); 2.3294 (1.6); 2.3248 (1.1); 2.3204 (0.5); 2.0759 (2.8); 1.6407 (10.7); 1.6232 (10.8); 1.6099 (0.6); 1.6012 (0.5); 1.1427 (0.7); 1.1300 (1.9); 1.1218 (5.0); 1.1166 (2.7); 1.1104 (1.9); 1.1026 (5.8); 1.0983 (5.0); 1.0936 (5.0); 1.0856 (4.8); 1.0819 (5.6); 1.0734 (2.1); 1.0609 (0.5); −0.0002 (1.8) 1-84 [00244] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.3685 (1.9); 9.3652 (2.0); 9.2962 (0.7); 9.2790 (0.7); 9.2373 (2.0); 9.2339 (1.9); 8.3586 (3.1); 7.9187 (1.0); 7.9150 (1.6); 7.9114 (1.0); 7.5991 (0.9); 7.5937 (1.3); 7.5902 (1.1); 7.5576 (1.1); 7.5529 (1.5); 7.5477 (0.8); 6.0321 (0.5); 6.0147 (0.8); 5.9974 (0.5); 3.3326 (23.3); 2.5254 (0.7); 2.5119 (13.0); 2.5075 (25.5); 2.5029 (33.2); 2.4984 (24.6); 2.4941 (12.2); 2.0765 (0.7); 1.7112 (16.0); 1.6215 (2.8); 1.6042 (2.8) 483.0 I-85 [00245] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.3791 (2.7); 9.3761 (2.0); 9.3288 (1.2); 9.3124 (1.1); 8.6100 (2.7); 8.6071 (2.0); 8.3606 (3.0); 7.9493 (2.1); 7.9459 (2.1); 7.6179 (2.0); 7.6147 (2.0); 7.5640 (2.0); 7.5596 (1.9); 6.1850 (0.8); 6.1675 (1.0); 6.1506 (0.6); 5.7637 (3.3); 3.3379 (44.6); 2.6795 (0.5); 2.6759 (0.5); 2.5111 (71.9); 2.5068 (70.1); 2.3378 (0.5); 1.7163 (16.0); 1.6385 (4.0); 1.6214 (3.6) 483.2 1-86 [00246] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.3747 (10.3); 9.3714 (10.1); 9.2592 (4.1); 9.2511 (11.5); 9.2477 (10.9); 9.2425 (4.1); 8.3607 (16.0); 7.5392 (5.0); 7.5355 (6.3); 7.5306 (4.9); 7.4006 (5.8); 7.2155 (5.6); 6.0495 (0.6); 6.0323 (2.6); 6.0150 (4.1); 5.9977 (2.6); 5.9801 (0.5); 5.7650 (2.1); 3.9979 (0.9); 3.9907 (1.8); 3.9832 (2.6); 3.9757 (3.6); 3.9685 (2.6); 3.9608 (1.8); 3.9537 (0.9); 3.3388 (148.8); 2.9813 (0.5); 2.8953 (0.5); 2.6818 (0.8); 2.6774 (1.1); 2.6729 (0.8); 2.5306 (4.1); 2.5171 (72.7); 2.5129 (135.6); 2.5084 (171.7); 2.5039 (125.6); 2.4996 (61.4); 2.3397 (0.8); 2.3353 (1.1); 2.3310 (0.8); 1.6306 (15.2); 1.6132 (15.2); 1.3606 (0.5); 0.8495 (1.1); 0.8304 (5.0); 0.8153 (5.8); 0.8011 (1.6); 0.7736 (0.3); 0.7591 (0.3); 0.7045 (2.4); 0.6863 (7.3); 0.6736 (1.8); 0.6660 (1.4) 460.4 1-87 [00247] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.3862 (10.4); 9.3833 (10.5); 9.2921 (3.8); 9.2749 (3.8); 8.6176 (10.4); 8.6147 (10.4); 8.3573 (16.0); 7.5634 (4.6); 7.5598 (6.1); 7.5547 (5.0); 7.4276 (5.7); 7.2195 (5.4); 6.1988 (0.6); 6.1820 (2.5); 6.1647 (3.9); 6.1474 (2.5); 6.1305 (0.5); 4.0000 (0.8); 3.9929 (1.7); 3.9854 (2.5); 3.9779 (3.4); 3.9706 (2.5); 3.9630 (1.7); 3.9560 (0.9); 3.3862 (0.4); 3.3378 (547.8); 2.6804 (2.4); 2.6760 (3.3); 2.6716 (2.4); 2.5293 (11.9); 2.5157 (201.9); 2.5115 (392.7); 2.5070 (510.4); 2.5025 (383.5); 2.3383 (2.3); 2.3338 (3.2); 2.3293 (2.3); 1.6414 (14.6); 1.6240 (14.6); 0.8488 (1.1); 0.8323 (4.7); 0.8297 (4.6); 0.8148 (5.6); 0.8007 (1.6); 0.7583 (0.3); 0.7044 (2.0); 0.6862 460.3 (6.9); 0.6661 (1.3); 0.0044 (0.5) 1-88 [00248] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.2972 (1.5); 9.2807 (1.5); 8.6395 (6.8); 7.5993 (2.0); 7.5955 (2.6); 7.5912 (2.0); 7.4682 (2.4); 7.2296 (2.3); 6.0074 (1.1); 5.9904 (1.6); 5.9734 (1.1); 4.0081 (0.4); 4.0011 (0.7); 3.9934 (1.1); 3.9861 (1.4); 3.9790 (1.1); 3.9715 (0.8); 3.9644 (0.4); 3.3413 (224.8); 2.6811 (1.1); 2.6767 (1.5); 2.6725 (1.1); 2.5299 (5.6); 2.5121 (185.8); 2.5077 (237.0); 2.5033 (176.3); 2.3458 (16.0); 2.3348 (1.8); 2.3303 (1.3); 1.6057 (5.9); 1.5883 (5.9); 0.8537 (0.6); 0.8384 (2.0); 0.8201 (2.4); 0.8062 (0.8); 0.7112 (0.9); 0.6928 (2.9); 0.6733 (0.6) 479.3 1-89 [00249] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.1693 (0.8); 9.1529 (0.8); 8.6719 (3.9); 8.3127 (3.3); 7.4031 (1.6); 7.3760 (1.1); 7.3706 (1.3); 7.3670 (0.9); 7.0471 (1.0); 7.0427 (1.3); 7.0381 (0.9); 6.0281 (0.5); 6.0111 (0.8); 5.9941 (0.5); 5.7637 (4.0); 3.3408 (22.8); 2.8955 (1.6); 2.7366 (1.4); 2.5302 (0.5); 2.5167 (8.5); 2.5124 (16.5); 2.5079 (21.5); 2.5033 (16.1); 2.4990 (8.0); 2.0034 (0.4); 1.9909 (0.6); 1.9785 (0.4); 1.9700 (0.3); 1.6895 (16.0); 1.6226 (3.0); 1.6051 (3.0); 1.0361 (0.4); 1.0251 (1.1); 1.0196 (1.2); 1.0092 (0.6); 1.0042 (1.1); 0.9988 (1.1); 0.9885 (0.4); 0.7672 (0.4); 0.7564 (1.3); 0.7515 (1.3); 0.7442 (1.2); 0.7392 (1.3); 0.7279 (0.4) 448.1 1-90 [00250] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.1393 (0.8); 9.1225 (0.8); 8.6321 (3.9); 7.4145 (1.7); 7.3876 (1.2); 7.3824 (1.4); 7.3787 (1.0); 7.0438 (1.0); 7.0396 (1.4); 7.0350 (1.0); 6.0025 (0.6); 5.9853 (0.9); 5.9681 (0.6); 3.3352 (24.6); 2.5255 (0.6); 2.5119 (10.8); 2.5078 (20.3); 2.5034 (25.6); 2.4989 (18.8); 2.3401 (8.4); 2.0766 (1.7); 2.0090 (0.3); 2.0004 (0.4); 1.9881 (0.7); 1.9755 (0.4); 1.9671 (0.4); 1.6877 (16.0); 1.5986 (3.1); 1.5812 (3.1); 1.0327 (0.4); 1.0218 (1.2); 1.0164 (1.3); 1.0059 (0.6); 1.0009 (1.2); 0.9956 (1.2); 0.9855 (0.4); 0.7653 (0.5); 0.7548 (1.3); 0.7500 (1.3); 0.7426 (1.3); 0.7378 (1.3); 0.7266 (0.4); −0.0002 (3.9) 462.1 1-91 [00251] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.3604 (2.1); 9.3571 (2.0); 9.2346 (2.1); 9.2313 (1.9); 9.0946 (0.8); 9.0775 (0.8); 8.3508 (3.2); 7.3375 (1.8); 7.3325 (1.9); 7.3261 (1.5); 7.0275 (1.0); 7.0232 (1.4); 7.0187 (0.9); 6.0183 (0.5); 6.0011 (0.8); 5.9837 (0.5); 3.3330 (28.8); 2.5249 (0.9); 2.5071 (28.2); 2.5027 (35.5); 2.4983 (26.0); 1.9922 (0.3); 1.9837 (0.4); 1.9714 (0.6); 1.9587 (0.4); 1.9505 (0.3); 1.7528 (0.4); 1.6770 (16.0); 1.6253 (3.1); 1.6079 (3.1); 1.0237 (0.4); 1.0129 (1.1); 1.0074 (1.2); 0.9969 (0.6); 0.9921 (1.1); 0.9865 (1.1); 0.9765 (0.4); 0.7475 (0.5); 0.7368 (1.3); 0.7321 (1.2); 0.7248 (1.2); 0.7199 (1.3); 0.7085 (0.4); −0.0002 (3.3) 443.2 1-92 [00252] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.3739 (2.4); 9.3709 (2.3); 9.1280 (0.7); 9.1107 (0.8); 8.6036 (2.4); 8.6006 (2.2); 8.3484 (3.4); 7.3707 (1.6); 7.3672 (1.0); 7.3494 (1.1); 7.3439 (1.3); 7.3402 (0.9); 7.0287 (0.9); 7.0239 (1.2); 7.0194 (0.8); 6.1714 (0.5); 6.1541 (0.8); 6.1368 (0.5); 3.3289 (26.4); 2.6754 (0.4); 2.6709 (0.5); 2.6666 (0.4); 2.5245 (1.7); 2.5196 (2.6); 2.5110 (31.3); 2.5066 (60.8); 2.5020 (78.4); 2.4975 (56.8); 2.4930 (27.2); 2.3335 (0.4); 2.3288 (0.5); 2.3244 (0.3); 1.9892 (0.4); 1.9769 (0.6); 1.9640 (0.4); 1.6923 (2.5); 1.6777 (16.0); 1.6360 (3.0); 1.6186 (3.0); 1.0260 (0.4); 1.0152 (1.2); 1.0096 (1.1); 1.0053 (0.6); 0.9994 (0.7); 0.9942 (1.2); 443.2 0.9887 (1.1); 0.9784 (0.4); 0.7520 (0.5); 0.7413 (1.2); 0.7362 (1.2); 0.7292 (1.2); 0.7239 (1.3); 0.7128 (0.4); −0.0002 (2.9) 1-93 [00253] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.5332 (1.0); 9.5166 (1.0); 8.6247 (6.7); 8.6216 (1.2); 8.3914 (1.3); 8.3876 (2.4); 8.3838 (1.4); 8.3368 (0.3); 8.2640 (1.3); 8.2597 (2.0); 8.2556 (1.3); 8.1770 (1.4); 8.1727 (2.3); 8.1683 (1.2); 6.0419 (0.7); 6.0248 (1.1); 6.0076 (0.7); 3.3963 (0.3); 3.3300 (73.1); 3.3216 (11.3); 2.6758 (0.5); 2.6713 (0.7); 2.6667 (0.5); 2.5249 (2.4); 2.5201 (3.4); 2.5114 (41.6); 2.5069 (83.8); 2.5023 (109.6); 2.4976 (78.7); 2.4931 (37.2); 2.3337 (0.5); 2.3291 (0.7); 2.3245 (0.5); 2.1038 (0.5); 2.0950 (0.5); 2.0831 (1.0); 2.0758 (2.3); 2.0711 (0.6); 2.0625 (0.5); 1.7734 (16.0); 1.6217 (4.0); 1.6043 (4.0); 1.1552 (0.3); 1.1369 (0.8); 1.1185 510.1 (0.3); 1.0375 (1.4); 1.0336 (1.6); 1.0169 (1.4); 1.0127 (1.5); 0.8941 (0.6); 0.8874 (0.8); 0.8819 (1.1); 0.8761 (1.3); 0.8709 (1.1); 0.0080 (0.8); −0.0002 (29.1); −0.0086 (0.8) 1-94 [00254] 1H-NMR (400.2 MHz, d6-DMSO) δ = 9.4179 (0.8); 9.4002 (0.9); 9.3134 (2.4); 9.3106 (2.5); 8.4684 (0.9); 8.3811 (2.6); 8.3782 (2.8); 8.3278 (3.6); 8.1304 (0.8); 8.0133 (1.0); 8.0094 (1.8); 8.0057 (1.1); 7.8063 (1.2); 7.8040 (1.1); 7.6790 (1.2); 6.2783 (0.6); 6.2610 (0.9); 6.2436 (0.6); 3.3303 (29.9); 2.6719 (0.4); 2.5253 (1.0); 2.5119 (23.2); 2.5075 (48.2); 2.5030 (63.8); 2.4984 (45.4); 2.4939 (21.2); 2.3299 (0.4); 2.0761 (2.4); 1.7271 (16.0); 1.6806 (3.2); 1.6632 (3.2); 0.1459 (0.4); 0.0079 (3.3); −0.0002 (91.5); −0.0086 (2.9); −0.1497 (0.4) 489.1 1-95 [00255] .sup.1H-NMR (600.1 MHz, d.sub.6-DMSO): δ = 10.6231 (0.2); 10.5596 (0.1); 9.4016 (0.2); 9.3900 (0.2); 9.3123 (0.4); 9.3105 (0.3); 9.1405 (0.1); 9.1325 (0.1); 8.3717 (0.4); 8.3699 (0.4); 8.3277 (0.5); 8.0054 (0.2); 8.0031 (0.3); 8.0008 (0.2); 7.8009 (0.2); 7.6765 (0.2); 6.2709 (0.1); 6.2594 (0.2); 6.2478 (0.1); 3.3203 (16.0); 3.0766 (0.3); 2.8694 (0.7); 2.8613 (0.7); 2.7988 (0.1); 2.7908 (0.1); 2.6139 (0.1); 2.5227 (0.4); 2.5197 (0.5); 2.5165 (0.6); 2.5075 (7.5); 2.5048 (14.0); 2.5018 (18.1); 2.4988 (13.2); 2.3857 (0.1); 2.0086 (0.2); 1.9676 (0.2); 1.7248 (2.6); 1.6765 (0.6); 1.6649 (0.6); 1.4014 (0.1); 1.1062 (1.0); 1.0871 (1.5); 1.0375 (1.0); 1.0091 (0.2); 0.8773 (0.2); 0.8651 (0.4); 0.8530 (0.2); 0.8365 503.2 (0.5); 0.8249 (0.5); 0.7979 (0.2); −0.0001 (0.2 .sup.1)‘abs’ denotes that the compound was obtained in an enantiomerically enriched or pure form with the major stereoisomer having the absolute configuration depicted in the drawing. .sup.2)‘lowT’ denotes that the measurement was conducted at a temperature of 260 Kelvin. .sup.3)The stated mass corresponds to the peak from the isotope pattern of the [M + H].sup.+ ion with the highest 5 intensity. # denotes that the [M − H].sup.− ion was recorded.

TABLE-US-00002 TABLE 2 (Intermediates) ESI Mass Intermediate Structure.sup.1) NMRPeak List.sup.2) (m/z).sup.3) Intermediate 5A [00256] .sup.1H NMR (400 MHz, CDCl.sub.3): δ = 1.79 (s, 6 H) 7.76-7.77 (m, 1 H), 8.06-8.07 (m, 1 H), 8.09-8.10 (m, 1 H). Intermediate 9A [00257] .sup.1H NMR (600 MHz, CDCl.sub.3): δ = 13.56 (bs, 1H), 8.43 (s, 1 H), 8.31 (s, 1 H), 8.14 (s, 1H), 2.99-2.95 (m, 1H), 1.14-1.07 (m, 4H). Intermediate 10A [00258] 280.9.sup.# Intermediate 14A [00259] 358.9.sup.# Intermediate 17A [00260] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO) δ = 9.7694 (1.7); 7.8727 (13.8); 5.3331 (16.0); 3.3330 (6.9); 2.5083 (12.7); 2.5040 (16.5); 2.4997 (12.5) 141.0 Intermediate 19A [00261] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 9.11 (d, 1H), 8.80 (br d, 3H), 8.61 (dd, 1H), 8.45 (s, 1H), 8.13 (d, 1H), 5.39 (m, 1H), 1.63 (d, 3H). 215.2 Intermediate 22A [00262] 245.1 Intermediate 24A [00263] 255.1 [amine + H].sup.+ Intermediate 25A [00264] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]= 13.63 (br s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 4.23 (s, 2H). 246.0 Intermediate 26A [00265] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ [ppm]= 8.07 (s, 1H), 7.77-7.73 (m, 1H), 7.57 (s, 1H), 1.72 (s, 6H). Intermediate 28A [00266] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ = 13.5 (brs, 1 H), 8.20 (s, 1 H), 8.01-8.02 (m, 2 H), 7.38 (s, 1 H). 294.8 Intermediate 29A [00267] 249.0.sup.# Intermediate 30A [00268] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ = 13.5 (brs, 1 H), 7.80 (m, 1 H), 7.65 (m, 1 H), 7.61 (m, 1 H), 2.29 (s, 3 H). 213.0 Intermediate 35A [00269] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): δ = 8.14 (s, 1H), 8.03-7.99 (m, 1H), 7.94 (s, 1H), 7.69-7.61 (m, 2H), 7.39-7.27 (m, 2H). 344.9.sup.# Intermediate 38A [00270] 207.2 Intermediate 40A [00271] 207.2 Intermediate 42A [00272] 221.2 Intermediate 44A [00273] 209.1 Intemediate 48A [00274] .sup.1H NMR (400 MHz, D6-DMSO): δ = 2.95 (s, 3H), 4.65 (m, 2H), 7.75 (m, 1H), 7.9 (m, 1H), 7.95 (m, 1H), 13.5 (br, 1H). 247.1.sup.# Intermediate 50A [00275] .sup.1H NMR (400 MHz, D6-DMSO): δ = 0.65 (m, 2H), 0.83 (d, 2H), 3.99 (m, 1H), 7.27 (s, 1H), 7.41 (s, 1H), 7.58 (m, 1H), 13.51 (s, 1H). 261.0.sup.# Intermediate 51A [00276] .sup.1H NMR (400 MHz, D6-DMSO): δ = 13.55 (bs, 1H, COOH), 7.88 (m, 1H), 7.73 (m, 1H), 7.64 (m, 1H), 1.72 (s, 6H). 283.9.sup.# Intermediate 52A [00277] .sup.1H NMR (400 MHz, D6-DMSO): δ = 13.55 (bs, 1H, COOH), 7.75 (m, 1H), 7.70 (m, 1H), 7.51 (m, 1H), 1.73 (s, 6H). 238.0.sup.# Intermediate 54A [00278] .sup.1H NMR (DMSO-d.sub.6, 400 MHz): 9.40 (s, 1H), 9.29 (s, 1H), 8.55 (s, 1H), 6.55 (br s, 2H, NH.sub.2), 5.34-5.28 (m, 1H), 1.66 (d, 3H). 216.1 [amine + H].sup.+ Intermediate 56A [00279] 216.1 [amine + H].sup.+ Intermediate 58A [00280] 256.2 [amine + H].sup.+ Intermediate 59A [00281] 274.2 [amine + H].sup.+ Intermediate 60A [00282] .sup.1H NMR (400 MHz, D6-DMSO): δ = 14.20 (bs, 1H, COOH), 7.96 (s, 1H), 7.85 (s, 1H), 1.74 (s, 6H). 223.1.sup.# Intermediate 61A [00283] .sup.1H-NMR(400.2 MHz, d.sub.6-DMSO): δ = 8.7292 (0.9); 7.9513 (1.1); 7.9302 (0.9); 5.3597 (0.4); 3.7138 (1.1); 3.7099 (1.1); 3.6997 (1.2); 3.6788 (1.3); 3.6667 (1.3); 3.6227 (1.6); 3.5686 (16.0); 3.4928 (0.4); 2.9946 (1.0); 2.9600 (1.0); 2.6904 (1.6); 2.5264 (0.5); 2.5088 (19.3); 2.5045 (24.0); 2.5000 (17.4); 2.4177 (6.5); 1.6326 (2.7); 1.6158 (2.6); 1.1647 (0.6); 1.1475 (0.4); 1.1358 (0.4); 1.1212 (0.5); 1.1081 (0.6); −0.0002 (0.9) 289.2 [amine + H].sup.+ Intermediate 62A [00284] for analytical data, see description of preparation Intermediate 63A [00285] for analytical data, see description of preparation Intermediate 64A [00286] for analytical data, see description of preparation Intermediate 70A [00287] .sup.1H NMR (DMSO-d.sub.6) δ = 8.38-8.40 (m, 1H), 8.36-8.38 (m, 1H), 8.26-8.28 (m, 1H), 1.91 (s, 3H), 1.79 (s, 6H). 268.1 Intermediate 71A [00288] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ = 9.36 (s, 1H), 8.78 (s, 2H, NH.sub.2), 8.52 (s, 1H), 8.50 (bs, 1H), 8.39 (s, 1H), 8.17 (bs, 1H), 5.07-5.45 (m, 1H), 1.67-1.65 (d, 3H). 234.2 [amine + H].sup.+ Intermediate 72A [00289] .sup.1H NMR (400 MHz, D6-DMSO): δ = 13.20 (bs, 1H, COOH), 7.49 (s, 2H), 7.06 (s, 1H), 2.05-2.01 (m, 1H), 1.69 (s, 6H), 1.03-0.99 (m, 2H), 0.73-0.69 (m, 2H). 244.1.sup.# .sup.1)′abs′ denotes that the compound was obtained in an enantiomerically enriched or pure form with the major stereoisomer having the absolute configuration depicted in the drawing. .sup.2)′lowT′ denotes that the measurement was conducted at a temperature of 260 Kelvin. .sup.3)The stated mass corresponds to the peak from the isotope pattern of the [M + H].sup.+ ion with the highest 5 intensity. .sup.#denotes that the [M − H].sup.− ion was recorded.

BIOLOGICAL EXAMPLES

[1429] Rhipicephalus (Boophilus) microplus—In-Vitro Contact Tests Larval Cattle Tick (Strain Parkhurst, Resistant Against Synthetic Pyrethroids)

[1430] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[1431] After the solvent has evaporated, each test tube is filled with 20-50 cattle tick larvae (Rhipicephalus microplus), closed with a perforated lid and incubated in a horizontal position at 85% relative humidity and 27° C. in an incubator. After 48 hours efficacy is determined. The larvae are patted on the ground of the tubes and negative geotactic behavior is recorded. Larvae that climb back to the top of the vial in a manner comparable to untreated control larvae are marked as alive, larvae not climbing back up comparable to untreated control larvae but are moving uncoordinatedly or only twitching their legs are marked as moribund, tick larvae remaining on the bottom and not moving at all are counted as dead.

[1432] A compound shows a good efficacy against Rhipicephalus microplus, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all larvae are dead or moribund; 0% means no larvae are dead or moribund.

[1433] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-7, I-19, I-21, I-25, I-26, I-27, I-28, I-33, I-35, I-42, I-44, I-45, I-46, I-48, I-58, I-59, I-60, I-65.

[1434] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-1, I-6, I-9, I-52, I-54.

[1435] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-2.

Rhipicephalus (Boophilus) microplus—Iniectiontest [1436] Solvent: dimethyl sulfoxide

[1437] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 mL solvent, and the concentrate is diluted with solvent to the desired concentration.

[1438] Five adult engorged female ticks (Rhipicephalus microplus) are injected with 1 μL compound solution into the abdomen. The ticks are transferred into replica plates and incubated in a climate chamber.

[1439] After 7 days egg deposition of fertile eggs is monitored. Eggs where fertility is not visible are stored in a climate chamber till hatching after about 42 days. An efficacy of 100% means all eggs are infertile; 0% means all eggs are fertile.

[1440] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 μg/rick: I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-12, I-13, I-14, I-15, I-16, I-46, I-47.

[1441] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 20 μg/tick: I-11.

[1442] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 4 μg/tick: I-2, I-3, I-4, I-6, I-7, I-9, I-10, I-12, I-14, I-15, I-16, I-18, I-19, I-20, I-23, I-25, I-28, I-46, I-47.

[1443] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 4 μg/tick: I-8, I-11, I-13.

Ctenocephalides felis—In-Vitro Contact Tests Adult Cat Flea

[1444] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[1445] After the solvent has evaporated, each test tube is filled with 5-10 adult cat fleas (Ctenocephalides felis), closed with a perforated lid and incubated in a lying position at room temperature and relative humidity. After 48 hours efficacy is determined. The fleas are patted on the ground of the tubes and are incubated on a heating plate at 45-50° C. for at most 5 minutes Immotile or uncoordinated moving fleas, which are not able to escape the heat by climbing upwards, are marked as dead or moribund.

[1446] A compound shows a good efficacy against Ctenocephalides felis, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all fleas are dead or moribund; 0% means no fleas are dead or moribund.

[1447] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-6, I-35, I-44, I-46, I-58.

[1448] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-30, I-33, I-42, I-59, I-60.

[1449] Ctenocephalides felis—Oral Test [1450] Solvent: dimethyl sulfoxide

[1451] To produce a suitable preparation of active compound, 10 mg of active compound are dissolved in 0.5 mL solvent, and the concentrate is diluted with cattle blood to the desired concentration.

[1452] Approximately 20 adult unfed cat fleas (Ctenocephalides felts) are placed in flea chambers. The blood chamber, sealed with parafilm on the bottom, are filled with cattle blood supplied with compound solution and placed on the gauze covered top of the flea chamber, so that the fleas are able to suck the blood. The blood chamber is heated to 37° C. whereas the flea chamber is kept at room temperature.

[1453] After 2 days mortality in % is determined. 100% means all the fleas have been killed; 0% means none of the fleas have been killed.

[1454] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 ppm: I-1, I-2, I-3, I-5, I-6, I-10, I-23, I-46.

[1455] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 ppm: I-8, I-25.

[1456] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 100 ppm: I-19.

Rhipicephalus sanguineus—In-Vitro Contact Tests with Adult Brown Dog Ticks

[1457] 9 mg compound is solved in 1 mL acetone and diluted with acetone to the desired concentration. 250 μL of the test solution is filled in 25 mL glass test tubes and homogeneously distributed on the inner walls by rotation and tilting on a shaking device (2 h at 30 rpm). With a compound concentration of 900 ppm, an inner surface of 44.7 cm.sup.2 and a homogeneous distribution, a dose of 5 μg/cm.sup.2 is achieved.

[1458] After the solvent has evaporated, each test tube is filled with 5-10 adult brown dog ticks (Rhipicephalus sanguineus), closed with a perforated lid and incubated in a lying position at room temperature and relative humidity. After 48 hours efficacy is determined. The ticks are patted on the ground of the tubes and are incubated on a heating plate at 45-50° C. for at most 5 minutes Immotile or uncoordinated moving ticks, which are not able to escape the heat by climbing upwards, are marked as dead or moribund.

[1459] A compound shows a good efficacy against Rhipicephalus sanguineus, if at a compound concentration of 5 μg/cm.sup.2 an efficacy of at least 80% is monitored. An efficacy of 100% means all ticks are dead or moribund; 0% means no ticks are dead or moribund.

[1460] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-33, I-46, I-59.

[1461] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 5 μg/cm.sup.2 (=500 g/ha): I-15, I-21, I-35, I-42, I-44, I-58.

Diabrotica balteata—Spray Test [1462] Solvent: 78.0 parts by weight of acetone [1463] 1.5 parts by weight of dimethylformamide [1464] Emulsifier: alkylarylpolyglycol ether

[1465] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1466] Soaked wheat seeds (Triticum aestivum) are placed in a multiple well plate filled with agar and some water and are incubated for 1 day to germinate (5 seeds per well). The germinated wheat seeds are sprayed with a test solution containing the desired concentration of the active ingredient. Afterwards each unit is infected with 10-20 larvae of the banded cucumber beetle (Diabrotica balteata).

[1467] After 7 days efficacy in % is determined. 100% means all the seedlings have grown up like in the untreated, uninfected control; 0% means none of the seedlings have grown.

[1468] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 500 g/ha (=160 μg/well): I-4, I-5, I-6, I-24, I-27.

[1469] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha (=32 μg/well): I-13, I-15, I-18, I-24, I-26, I-27, I-28, I-29, I-30, I-33, I-35, I-37, I-38, I-39, I-42, I-43, I-45, I-48, I-49, I-50, I-51, I-53, I-56, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-66, I-67, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-86, I-88, I-89, I-90.

[1470] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 100 g/ha (=32 μg/well): I-40, I-87, I-93.

Meloidogyne incognita—Test [1471] Solvent: 125.0 parts by weight of acetone

[1472] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water to the desired concentration. Vessels are filled with sand, a solution of the active ingredient, a suspension containing eggs and larvae of the southern root-knot nematode (Meloidogyne incognita) and salad seeds. The salad seeds germinate and the seedlings grow. Galls develop in the roots.

[1473] After 14 days the nematicidal activity is determined on the basis of the percentage of gall formation. 100% means no galls were found and 0% means the number of galls found on the roots of the treated plants was equal to that in untreated control plants.

[1474] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 ppm: I-39, I-52.

[1475] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 20 ppm: I-9, I-24, I-25, I-61.

Myzus persicae—Oral Test [1476] Solvent: 100 parts by weight acetone

[1477] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water to the desired concentration.

[1478] 50 μL compound solution is filled in microtiter plates and 150 μL IPL41 insect medium (33%+15% sugar) is added to obtain a total volume of 200 μL per well. Afterwards the plates are sealed with parafilm through which a mixed population of the green peach aphid (Myzus persicae) can suck on the compound preparation.

[1479] After 5 days mortality in % is determined. 100% means all aphids have been killed and 0% means none of the aphids have been killed.

[1480] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 ppm: I-27.

[1481] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 4 ppm: I-27, I-33, I-35, I-46.

[1482] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 4 ppm: I-29, I-30, I-34.

Myzus persicae—Spray Test [1483] Solvent: 78.0 parts by weight acetone [1484] 1.5 parts by weight dimethylformamide [1485] Emulsifier: alkylarylpolyglycol ether

[1486] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1487] Chinese cabbage (Brassica pekinensis) leaf disks infected with all instars of the green peach aphid (Myzus persicae), are sprayed with a preparation of the active ingredient of the desired concentration.

[1488] After 5 days mortality in % is determined. 100% means all aphids have been killed and 0% means none of the aphids have been killed.

[1489] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-42, I-43, I-44, I-46, I-66, I-73, I-74.

[1490] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 g/ha: I-27, I-37, I-40, I-45, I-56, I-58, I-59.

Nezara viridula—Spray Test [1491] Solvent: 78.0 parts by weight of acetone [1492] 1.5 parts by weight of dimethylformamide [1493] Emulsifier: alkylarylpolyglycol ether

[1494] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1495] Barley plants (Hordeum vulgare) are sprayed with a test solution containing the desired concentration of the active ingredient and are infested with larvae of the southern green stink bug (Nezara viridula).

[1496] After 4 days mortality in % is determined. 100% means all the stink bugs have been killed; 0% means none of the stink bugs have been killed.

[1497] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 500 g/ha: I-27, I-37, I-38, I-42, I-43, I-44, I-45, I-51, I-52, I-56, I-58, I-59, I-64, I-66, I-70, I-71, I-73, I-74, I-75.

[1498] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 500 g/ha: I-55.

[1499] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-4, I-6, I-27, I-35, I-42, I-43, I-44, I-45, I-46, I-58, I-59, I-74.

[1500] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 100 g/ha: I-38, I-55, I-56.

[1501] Nilaparvata lugens—Spray Test [1502] Solvent: 78.0 parts by weight of acetone [1503] 1.5 parts by weight of dimethylformamide [1504] Emulsifier: alkylarylpolyglycol ether

[1505] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1506] Rice plants (Oryza sativa) are sprayed with a preparation of the active ingredient of the desired concentration and the plants are infested with the brown planthopper (Nilaparvata lugens).

[1507] After 4 days mortality in % is determined. 100% means all planthoppers have been killed and 0% means none of the planthoppers have been killed.

[1508] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 500 g/ha: I-38, I-51, I-66.

[1509] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-4, I-6.

Spodoptera frugiperda—Spray Test [1510] Solvent: 78.0 parts by weight acetone [1511] 1.5 parts by weight dimethylformamide [1512] Emulsifier: alkylarylpolyglycol ether

[1513] To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amount of solvents and is diluted with water, containing an emulsifier concentration of 1000 ppm, to the desired concentration. Further test concentrations are prepared by dilution with emulsifier containing water.

[1514] Maize (Zea mays) leaf sections are sprayed with a preparation of the active ingredient of the desired concentration. Once dry, the leaf sections are infested with fall armyworm larvae (Spodoptera frugiperda). After 7 days mortality in % is determined. 100% means all caterpillars have been killed and 0% means none of the caterpillars have been killed.

[1515] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 500 g/ha: I-3, I-6, I-24, I-27.

[1516] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 100 g/ha: I-24, I-25, I-27, I-28, I-33, I-35, I-37, I-38, I-39, I-40, I-42, I-43, I-44, I-46, I-49, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-64, I-66, I-67, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-92, I-93.

[1517] In this test, for example, the following compounds from the preparation examples showed good activity of 83% at an application rate of 100 g/ha: I-21, I-48.

Aedes aegypti Test (AEDSAE Surface Treatment & Contact Assay) [1518] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[1519] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult mosquitoes of the species Aedes aegypti strain MONHEIM are placed onto the dried surface. The exposure time is 30 minutes.

[1520] Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[1521] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-27, I-33, I-35, I-42, I-43, I-44, I-45, I-46, I-53, I-56.

[1522] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-27, I-33, I-35, I-42, I-43, I-44, I-45, I-46, I-56.

Culex quinquefasciatus Test (CULXFA Surface Treatment & Contact Assay) [1523] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[1524] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2 000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult mosquitoes of the species Culex Quinquefasciatus strain P00 are placed onto the dried surface. The exposure time is 30 minutes. Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[1525] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-33, I-35, I-37, I-42, I-43, I-44, I-45, I-46.

[1526] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-42, I-43, I-44, I-45.

Musca domestica Test (MUSCDO Surface Treatment & Contact Assay) [1527] Solvent: Aceton+2000 ppm rapeseed oil methyl ester (RME)

[1528] In order to produce a sufficient, active ingredient containing solution it is necessary to solve the test compound in the solvent-mix (acetone at 2 mg/ml/RME 2000 ppm). This solution is pipetted onto a glazed tile and after evaporation of the acetone, adult flies of the species Musca domestica strain WHO-N are placed onto the dried surface. The exposure time is 30 minutes.

[1529] Mortality in percent (%) is determined 24 hours after contact of the insects to the treated surface. 100% mortality means that all tested insects are dead, whereas 0% means that no insect died.

[1530] The following examples showed in this test efficacy of 80-100% at a surface concentration of 20 mg/m.sup.2: I-33, I-35, I-38, I-42, I-43, I-44, I-45.

[1531] The following examples showed in this test efficacy of 80-100% at a surface concentration of 4 mg/m.sup.2: I-33, I-35, I-42, I-43, I-44, I-45, I-46.