# Patent

## Title
Substituted triazole diamine derivatives as kinase inhibitors

## Abstract

The present invention provides substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.

## Background
This present application is a divisional of U.S. application Ser. No. 10/029,750, filed on Dec. 21, 2001, now U.S. Pat. No. 6,924,302, and claims priority of 60/257,703 filed on Dec. 22, 2000.


FIELD OF THE INVENTION
The present invention provides substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use thereof. More particularly, the present invention provides substituted 1,2,4-triazole-3,5-diamine derivatives as selective kinase or dual-kinase inhibitors and a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.
BACKGROUND OF THE INVENTION
This Application claims priority from U.S. provisional patent application 60/257,703 entitled “1,2,4-triazole-3,5-diamine derivatives” filed Dec. 22, 2000 the contents of which are hereby incorporated by reference.
Patent application WO 99/21845 describes 4-aminothiazole derivatives as inhibitors of cyclin dependent kinases of the formula:




wherein

    R1 is a substituted or unsubstituted group selected from: C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl); C1-6-alkenyl; C1-6-alkynyl; C1-6-alkoxyl; C1-6-alcohol; carbocyclic or heterocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, morpholinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); carbonyl (e.g., carboxyl, ester, aldehyde, or ketone); ether; (C1-6 alkyl)-carbonyl; (C1-6 alkyl)-aryl; (C1-6 alkyl)-cycloalkyl; (C1-6 alkyl)-(C1-6-alkoxyl); aryl-(C1-6-alkoxyl); thioether (e.g., aryl-S-aryl, cycloalkyl-S-aryl, cycloalkyl-S-cycloalkyl, or dialkyl sulfide); thiol; and sulfonyl; and R2 is a substituted or unsubstituted: carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure; where each optional substituent for R1 and R2 is independently a halogen (e.g., chloro, iodo, bromo, or fluoro); oxygen (═O); haloalkyl (e.g., trifluoromethyl); C1-6 alkyl; C1-6-alkenyl; C1-6-alkynyl; hydroxyl; C1-6-alkoxyl; carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester; (ii) pharmaceutically acceptable salts of compounds of the Formula; and (iii) prodrugs and pharmaceutically active metabolites of compounds of the Formula or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier.


Patent application WO 01/09106 describes diamino-1,2,4-triazole-carboxylic and derivatives as GSK-3 (glycogen synthase kinase) inhibitors of formula (I):




wherein

    the R3CZ-moiety may be attached to the nitrogen atom at position I or the nitrogen atom at position 2; R1 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic; R2 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R1 and R2 together with the nitrogen atom to which they are attached may form a heterocyclic ring which ring may be unsubstituted or substituted; R3 is alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q is O or S, aralkenyl, alicyclic, heteroaryl, heteroaralkyl, arylcarbonylalkyl, alicyclylalkyl, diarylalkyl, or NR6R7; R4 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic; R5 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R4 and R5 together with the nitrogen atom to which they are attached may form a heterocyclic ring which ring may be unsubstituted or substituted; R6 is hydrogen, aryl or alicyclic; R7 is hydrogen, aryl or alicyclic, and; Z is oxygen or sulphur. Suitably, R1 is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6)alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro. Favourably, R1 is phenyl either unsubstituted or substituted with up to three of methyl, methoxy, or chloro. Suitably, R2 is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy(C1-C6)alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro. Favourably, R2 is hydrogen. Suitably, R3 is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted benzyl, unsubstituted or substituted thienylmethyl, unsubstituted or substituted phenylthiomethyl, unsubstituted or substituted naphthylmethyl, unsubstituted or substituted furylethenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted pyridyl, unsubstituted or substituted indolylmethyl, unsubstituted or substituted phenylcarbonylethyl, unsubstituted or substituted cyclopentenylmethyl, unsubstituted or substituted phenylpropyl, unsubstituted or substituted diphenylethyl, wherein the substituents for the R3 aryl groups are selected from —O(CH2)nO—, where n is 1 to 3, or up to three of halo, aryl, perfluoro(C1-C6)alkyl, nitro, arylcarbonyl, aryloxy, C1-C6acyl; or R3 is NR6R7 where R6 and R7 are each independently hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C1-C6alicyclic, wherein the substituents for the R6 and R7 groups are independently selected from up to three of halo, aryl, aryloxy, alkyl, nitro, and alkoxy. Favourably, R3 is phenyl either unsubstituted or substituted with up to three of chloro, bromo, phenyl, trifluoromethyl, nitro, benzoyl, phenoxy, acetyl, or 3,4-OCH2O—; naphthyl; benzyl either unsubstituted or substituted with up to three of phenyl or fluoro; 2-thienylmethyl; phenylthiomethyl 2-naphthylmethyl; cyclohexyl; 3-pyridyl; 3-indolylmethyl; phenylcarbonylethyl; cyclopent-2-enylmethyl; phenylpropyl; 2,2-diphenylethyl; or 2-furylethenyl; or NR6R7 where R6 and R7 are each independently hydrogen, phenyl either unsubstituted or substituted with up to three of chloro, phenyl, phenoxy, methyl, bromo, nitro, or methoxy; cyclohexyl; or 1-naphthyl. Suitably, R4 is hydrogen. Suitably, R5 is hydrogen. Suitably, R6 is unsubstituted or substituted aryl or unsubstituted or substituted alicyclic. Favourably R6 is cyclohexyl, naphthyl or phenyl which phenyl group may be either unsubstituted or substituted with up to three of chloro, bromo, phenyl, methyl, phenoxy, nitro or methoxy. Suitably, R7 is hydrogen.


U.S. Pat. No. 5,750,545 describes triazole derivatives, as agents for the prophylaxis and treatment of immune-related diseases, of formula (I) and formula (III):




wherein

    X is an oxygen atom or a sulfur atom; W is —NR4R5 or —SR6; R1 is a hydrogen atom, a lower alkyl, —NR10R11, —N═R13 or a group of the formula (II)






wherein

    Y is a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen, a cyano, a nitro, a lower alkyl substituted by halogen, —NR14R15, a tetrazolyl, an optionally substituted phenyl, a hydroxy or a carboxyl, L is a direct bond, an oxygen atom, a sulfur atom, an alkylene, a vinylene or an ethynylene, and n is an integer of 1 to 3, provided that when n is 2 or 3, Y may be the same or different; and R2 and R3 are the same or different and each is a hydrogen atom or a lower alkyl; wherein R4 and R5 are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, cycloalkyl, a phenyl or —(CH2)mCOOR16, R16 is a hydrogen atom or a lower alkyl, m is an integer of 1 to 6, R6 is a lower alkyl, R10 and R11 are the same or different and each is a hydrogen atom, an optionally substituted benzoyl, an optionally substituted phenyl, a lower alkylcarbonyl or —COCOOR17, R17 is a lower alkyl, R13 is an optionally substituted methylene, R14 and R15 are the same or different and each is a hydrogen atom, a lower alkyl, —COCOOR17 or —CSNHR18, and R18 is a lower alkyl, or a pharmaceutically acceptable salt thereof.


Accordingly, it is an object of the present invention to provide substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use thereof. It is an object of the present invention to provide substituted 1,2,4-triazole-3,5-diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use for treating or ameliorating a selective kinase or dual-kinase mediated disorder.
SUMMARY OF THE INVENTION
The present invention provides a compound of Formula (I):




wherein

    R1 is selected from the group consisting of C1-8alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of:
    
        C1-8alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —SO2—(C1-8)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl) and heteroaryl)},
        cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C1-8alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-8alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl)}};
    
    
    R2 is selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl and hydroxy(C1-8)alkyl;
    X is selected from the group consisting of —C(O)—, —C(S)— and —SO2—; and,
    R3 is selected from the group consisting of:
    
        C1-8alkyl, C2-8alkenyl, C2-8alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},
        cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
        
            C1-8alkyl, C2-8alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
            —CH(OH)—(C1-8)alkyl,
            C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
            —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
            amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C(O)(C1-8)alkyl),
            —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
            —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl))},
            —NH—SO2—(C1-8)alkyl,
            cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and
        
        
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};
    and pharmaceutically acceptable salts thereof.


An embodiment of the present invention is a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.
An embodiment of the present invention includes a method for producing the instant compounds and pharmaceutical compositions and medicaments thereof.


DETAILED DESCRIPTION OF THE INVENTION


    Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R1 is selected from the group consisting of: C1-4alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of:
    
        C1-4alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-4)alkyl, —CO2H, —CO2(C1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        C1-4alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-4)alkyl, —CO2H, —CO2(C1-4)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and —SO2—(C1-4)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl) and heteroaryl)},
        cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C1-4alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-4alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl)}}.
    
    
    More preferably, R1 is selected from the group consisting of C1-4alkyl and aryl {wherein aryl is substituted with a substituent selected from the group consisting of:
    
        C1-4alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy and nitro),
        C1-4alkoxy,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and —SO2—(C1-4)alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl) and heteroaryl)},
        heterocyclyl (wherein heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C1-4alkyl and oxo) and heteroaryl}.
    
    


Most preferably, R1 is selected from the group consisting of C1-4alkyl and phenyl {wherein phenyl is substituted with a substituent selected from the group consisting of:

    amino (substituted with two substituents independently selected from the group consisting of:
    
        hydrogen, C1-4alkyl and —SO2—(C1-4)alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of piperidinyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl) and pyridinyl)}, and
        piperazinyl (wherein piperazinyl is optionally substituted with 1 to 2 C1-4alkyl substituents), imidazolidinyl, isothiazolidinyl (wherein imidazolidinyl and isothiazolidinyl are optionally substituted with 1 to 2 oxo substituents), imidazolyl and triazolyl}.
    
    


Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R2 is selected from the group consisting of hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl and hydroxy(C1-4)alkyl.
More preferably, R2 is selected from the group consisting of hydrogen and C1-4alkyl.
Most preferably, R2 is hydrogen.
Embodiments of the present invention include compounds of Formula (I) wherein, preferably, X is selected from the group consisting of —C(O)—, —C(S)— and —SO2—.
Embodiments of the present invention include compounds of Formula I wherein, preferably, R3 is selected from the group consisting of:

    C1-4alkyl, C2-4alkenyl, C2-4alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-4)alkyl, —CO2H, —CO2(C1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, cyano, halo, (halo)1-3(C1-4)alkyl, (halo)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)},
    cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-4alkyl, C2-4alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-4)alkyl, —CO2H, —CO2(C1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        —CH(OH)—(C1-4)alkyl,
        C1-4alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-4)alkyl, —CO2H, —CO2(C1-4)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and —C(O)(C1-4)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and —C1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl))},
        —NH—SO2—(C1-4)alkyl,
        cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, cyano, halo, (halo)1-3(C1-4)alkyl, (halo)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)}.


More preferably, R3 is selected from the group consisting of:

    C1-4alkyl, C2-4alkenyl, C2-4alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, cyano, halo, (halo)1-3(C1-4)alkyl, (halo)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)},
    cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-4alkyl, C2-4alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —CO2H, —CO2(C1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        —CH(OH)—(C1-4)alkyl,
        C1-4alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-4)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and —C(O)(C1-4)alkyl),
        aryl and heteroaryl} and
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and aryl (wherein aryl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, cyano, halo, (halo)1-3(C1-4)alkyl, (halo)1-3(C1-4)alkoxy, hydroxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy and nitro)}.


Most preferably, R3 is selected from the group consisting of:

    C1-4alkyl, C2-4alkenyl, C2-4alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy, nitro, phenyl and thienyl (wherein phenyl and thienyl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of C1-4alkyl, cyano, halo, hydroxy and nitro)},
    cyclopentyl, cyclohexyl, cycloheptyl, benzo[b]thienyl, phenyl, furyl, thienyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridinyl {wherein cyclohexyl and phenyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cyclohexyl and phenyl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-4alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy and nitro),
        —CH(OH)—(C1-4)alkyl,
        C1-4alkoxy,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl),
    
    
    and wherein thienyl and thiazolyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein thienyl and thiazolyl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-4alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of —CO2H, —CO2(C1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy and nitro),
        C1-4alkoxy,
        —C(O)(C1-4)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of: hydrogen, C1-4alkyl and —C(O)(C1-4)alkyl),
        pyrrolyl and pyridinyl;
    
    
    and, wherein thiadiazolyl is optionally substituted with one substituent selected from the group consisting of C1-4alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of:
    
        amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-4alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl),
        cyano, halo, hydroxy and nitro} and
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and phenyl (wherein phenyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-4alkyl, cyano, halo, hydroxy and nitro)}.


Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ia):




wherein

    R4 is selected from the group consisting of:
    C1-8alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl},
    C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
    —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
    amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —SO2—(C1-8)alkyl),
    —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
    —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl) and heteroaryl)},
    cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents};
    R2 is selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl and hydroxy(C1-8)alkyl;
    X is selected from the group consisting of —C(O)—, —C(S)— and —SO2—; and,
    R3 is selected from the group consisting of:
    C1-8alkyl, C2-8alkenyl, C2-8alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},
    cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-8alkyl, C2-8alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        —CH(OH)—(C1-8)alkyl,
        C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C(O)(C1-8)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl))},
        —NH—SO2—(C1-8)alkyl,
    
    
    cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};
    and pharmaceutically acceptable salts thereof.


Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ib):




wherein

    R4 is selected from the group consisting of:
    C1-8alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl},
    C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
    —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
    amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —SO2—(C1-8)alkyl),
    —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
    —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl) and heteroaryl)},
    cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents};
    R2 is selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl and hydroxy(C1-8)alkyl;
    X is selected from the group consisting of —C(O)—, —C(S)— and —SO2—; and,
    R3 is selected from the group consisting of:
    C1-8alkyl, C2-8alkenyl, C2-8alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},
    cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-8alkyl, C2-8alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and
        C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        —CH(OH)—(C1-8)alkyl,
        C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C(O)(C1-8)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl))},
        —NH—SO2—(C1-8)alkyl,
        cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};
    and pharmaceutically acceptable salts thereof.


Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ic):




wherein

    R4 is selected from the group consisting of:
    C1-8alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl},
    C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
    —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
    amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —SO2—(C1-8)alkyl),
    —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
    —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl) and heteroaryl)},
    cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents};
    R2 is selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl and hydroxy(C1-8)alkyl;
    X is selected from the group consisting of —C(O)—, —C(S)— and —SO2—; and,
    R3 is selected from the group consisting of:
    C1-8alkyl, C2-8alkenyl, C2-8alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},
    cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-8alkyl, C2-8alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and
        C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        —CH(OH)—(C1-8)alkyl,
        C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C(O)(C1-8)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl))},
        —NH—SO2—(C1-8)alkyl,
        cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};
    and pharmaceutically acceptable salts thereof.


Embodiments of the present invention include compounds of Formula (Ic) wherein, preferably, R4 is selected from the group consisting of:

    amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl and —SO2—(C1-4)alkyl),
    —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-4alkyl, —C1-4alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-4alkyl) and heteroaryl)},
    heterocyclyl (wherein heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C1-4alkyl and oxo) and heteroaryl.


Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Id):




wherein

    R4 is selected from the group consisting of:
    C1-8alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl},
    C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
    —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
    amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —SO2—(C1-8)alkyl),
    —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
    —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl) and heteroaryl)},
    cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-8alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents};
    R2 is selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl and hydroxy(C1-8)alkyl;
    X is selected from the group consisting of —C(O)—, —C(S)— and —SO2—; and,
    R3 is selected from the group consisting of:
    C1-8alkyl, C2-8alkenyl, C2-8alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},
    cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-8alkyl, C2-8alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        —CH(OH)—(C1-8)alkyl,
        C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C(O)(C1-8)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl))},
        —NH—SO2—(C1-8)alkyl,
        cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};
    and pharmaceutically acceptable salts thereof.


Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ie):




wherein

    R1 is selected from the group consisting of C1-8alkyl,
    cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of:
    
        C1-8alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —SO2—(C1-8)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl) and heteroaryl)},
        cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C1-8alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy and nitro), C1-8alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl)}}; and,
    
    
    R3 is selected from the group consisting of:
    C1-8alkyl, C2-8alkenyl, C2-8alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)},
    cycloalkyl, heterocyclyl, aryl, heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxy and nitro; and, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of:
    
        C1-8alkyl, C2-8alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl), cyano, (halo)1-3, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl),
        —CH(OH)—(C1-8)alkyl,
        C1-8alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)1-3 and hydroxy),
        —C(O)H, —C(O)(C1-8)alkyl, —CO2H, —CO2(C1-8)alkyl,
        amino (substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C(O)(C1-8)alkyl),
        —C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl),
        —SO2— {substituted with one substituent selected from the group consisting of heterocyclyl and amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl and —C1-8alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl))},
        —NH—SO2—(C1-8)alkyl,
        cycloalkyl, heterocyclyl (optionally substituted with 1 to 2 oxo substituents), aryl and heteroaryl} and
    
    
    amino {substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-8alkyl, cyano, halo, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl, hydroxy(C1-8)alkoxy and nitro)};
    and pharmaceutically acceptable salts thereof.


Exemplified compounds of the present invention include a compound of Formula (I) selected from a compound of Formula (Ic):




wherein X, R2, R3 and R4 are dependently selected from:















Cpd
X
R2
R3
R4



















1
C(O)
H
(2,6-F2)Ph
4-SO2—NH2


2
C(O)
H
(2,6-F2-3-CH3)Ph
4-SO2—NH2


3
C(O)
H
(2,4,6-F3)Ph
4-SO2—NH2


4
C(O)
H
(2-F)Ph
4-SO2—NH2


5
C(O)
H
(2,4-F2)Ph
4-SO2—NH2


6
C(O)
H
(2-F-6-CF3)Ph
4-SO2—NH2


7
C(O)
H
(2,6-Cl2)Ph
4-SO2—NH2


8
C(O)
H
(2,4,6-Cl3)Ph
4-SO2—NH2


9
C(O)
H
(2-NO2)Ph
4-SO2—NH2


10
C(O)
H
[2,6-(OCH3)2]Ph
4-SO2—NH2


11
C(O)
H
[2,4,6-(CH3)3]Ph
4-SO2—NH2


12
C(O)
H
Ph
4-SO2—NH2


13
C(O)
H
(2,6-F2)Ph
4-SO2-1-H-piperidin-1-yl


14
C(O)
H
2-thienyl
4-SO2—NH2


15
C(O)
H
(3-CH3)2-thienyl
4-SO2—NH2


16
C(O)
H
(3-F)2-thienyl
4-SO2—NH2


17
C(O)
H
(3-Cl)2-thienyl
4-SO2—NH2


18
C(O)
H
(3-OCH2CH3)2-thienyl
4-SO2—NH2


19
C(O)
H
(3-NHCOCH3)2-thienyl
4-SO2—NH2


20
C(O)
H
(5-CH3)2-thienyl
4-SO2—NH2


21
C(O)
H
(5-Br)2-thienyl
4-SO2—NH2


22
C(O)
H
(5-COCH3)2-thienyl
4-SO2—NH2


23
C(O)
H
2-thienyl
4-SO2-1-H-piperidin-1-yl


24
C(O)
H
(3-CH3)2-thienyl
4-SO2-1-H-piperidin-1-yl


25
C(O)
H
2-furyl
4-SO2—NH2


26
C(O)
H
5-isoxazolyl
4-SO2—NH2


27
C(O)
H
2-pyridinyl
4-SO2—NH2


28
C(O)
H
3-pyridinyl
4-SO2—NH2


29
C(O)
H
4-pyridinyl
4-SO2—NH2


30
C(O)
H
3-thienyl
4-SO2—NH2


31
C(O)
H
3a,7a-dihydrobenzo[b]thien-2-yl
4-SO2—NH2


32
C(O)
H
(5-CH2CH3)2-thienyl
4-SO2—NH2


33
C(O)
H
[3,5-(CH3)2]2-thienyl
4-SO2—NH2


34
C(O)
H
[2,4-(CH3)2]5-thiazolyl
4-SO2—NH2


35
C(O)
H
(3-Br)2-thienyl
4-SO2—NH2


36
C(O)
H
4-(CH3)-1,2,3-thiadiazol-5-yl
4-SO2—NH2


37
C(O)
H
1,2,3-thiadiazol-4-yl
4-SO2—NH2


38
C(O)
H
cyclopentyl
4-SO2—NH2


39
C(O)
H
cyclohexyl
4-SO2—NH2


40
C(O)
H
2-thienyl-CH2
4-SO2—NH2


42
C(O)
H
2-thienyl-(CH)2
4-SO2—NH2


43
C(O)
H
(2,6-F2)—Ph—CH2
4-SO2—NH2


44
C(O)
H
(2,6-F2)Ph(CH)2
4-SO2—NH2


45
C(O)
H
cycloheptyl
4-SO2—NH2


46
C(O)
H
4-CH3-cyclohexyl
4-SO2—NH2


47
C(O)
H
4-CH3-cyclohexyl
4-SO2—NH2


48
C(O)
H
4-(CH2)3CH3-cyclohexyl
4-SO2—NH2


49
C(O)
H
5-(2-pyridinyl)2-thienyl
4-SO2—NH2


50
C(O)
H
3-(1H-pyrrol-1-yl)2-thienyl
4-SO2—NH2


51
C(O)
H
5-[C(CH3)3]2-thienyl
4-SO2—NH2


52
C(O)
H
5-[(CH)2C(O)OC(CH3)3]2-thienyl
4-SO2—NH2


53
C(O)
H
Ph(C)2
4-SO2—NH2


54
C(O)
H
(2,6-F2-3-NO2)Ph
4-SO2—NH2


55
C(O)
H
(2,6-F2-3-NH2)Ph
4-SO2—NH2


56
C(O)
H
[2,6-(CH3)2]Ph
4-SO2—NH2


57
C(O)
H
(2-CH3)Ph
4-SO2—NH2


58
C(O)
H
[2,6-F2-3-CH(OH)CH3]Ph
4-SO2—NH2


59
C(O)
H
(2,6-F2)Ph
4-SO2—NH2


60
C(O)
H
(2,6-F2-3-CH3)Ph
4-SO2—NH2


61
C(O)
H
(2,6-F2)Ph
H


62
C(O)
H
Ph
H


63
C(O)
H
(2,6-F2)Ph
3-Cl


64
C(O)
H
Ph
3-Cl


65
C(O)
H
—NH(Ph)
H


66
C(S)
H
—NH[(2,6-F2)Ph]
4-SO2—NH2


67
C(O)
H
—NH[(2,6-F2)Ph]
4-SO2—NH2


68
SO2
H
(2,6-F2)Ph
4-SO2—NH2


69
C(O)
H
(2-Cl-3-CH3-6-F)Ph
4-SO2—NH2


70
C(O)
H
(2-Cl-6-F)Ph
4-SO2—NH2


71
C(O)
H
(2,6-F2)Ph
4-(4-CH3-1,4-H-piperazin-1-yl)


72
C(O)
H
(2,6-F2-3-CH3)Ph
4-(4-CH3-1,4-H-piperazin-1-yl)


73
C(O)
H
(3-CH3)2-thienyl
4-(4-CH3-1,4-H-piperazin-1-yl)


74
C(O)
H
[3,5-(CH3)2]2-thienyl
4-(4-CH3-1,4-H-piperazin-1-yl)


75
C(O)
H
(5-CH2CH3)2-thienyl
4-(4-CH3-1,4-H-piperazin-1-yl)


76
C(O)
H
(2,6-F2)Ph
4-SO2—NH(CH2CH3)


78
C(O)
H
(2,6-F2-5-Cl)Ph
4-SO2—NH2


80
C(O)
H
(2,6-F2)Ph
4-SO2—NH(CH3)


81
C(O)
H
(2,6-F2-3-CH3)Ph
4-SO2—NH(CH3)


82
C(O)
H
(3-CH3)2-thienyl
4-SO2—NH(CH3)


83
C(O)
H
[3,5-(CH3)2]2-thienyl
4-SO2—NH(CH3)


84
C(O)
H
(5-CH2CH3)2-thienyl
4-SO2—NH(CH3)


85
C(O)
H
[3,5-(CH3)2]2-thienyl
4-SO2—N(CH3)2


86
C(O)
H
(5-CH2CH3)2-thienyl
4-SO2—N(CH3)2


87
C(O)
H
(3-CH3)2-thienyl
4-SO2—N(CH3)2


88
C(O)
H
(2,6-F2-3-CH3)Ph
4-SO2—N(CH3)2


89
C(O)
H
(2,6-F2)Ph
4-SO2—N(CH3)2


90
C(O)
H
(5-CH2CH3)2-thienyl
4-(1-H-imidazol-1-yl)


91
C(O)
H
(3-CH3)2-thienyl
4-(1-H-imidazol-1-yl)


92
C(O)
H
[3,5-(CH3)2]2-thienyl
4-(1-H-imidazol-1-yl)


93
C(O)
H
(2,6-F2)Ph
4-(1-H-imidazol-1-yl)


94
C(O)
H
(2,6-F2-3-CH3)Ph
4-(1-H-imidazol-1-yl)


95
C(O)
H
(2,6-F2-3-CH3)Ph
4-(1-H-1,2,4-triazol-1-yl)


96
C(O)
H
(2,6-F2)Ph
4-(1-H-1,2,4-triazol-1-yl)


97
C(O)
H
(5-CH2CH3)2-thienyl
4-(1-H-1,2,4-triazol-1-yl)


98
C(O)
H
[3,5-(CH3)2]2-thienyl
4-(1-H-1,2,4-triazol-1-yl)


99
C(O)
H
(3-CH3)2-thienyl
4-(1-H-1,2,4-triazol-1-yl)


100
C(O)
H
(2,6-F2)Ph
4-(1-H-1,2,4-triazol-1-yl)


101
C(O)
H
(2,6-F2-3-CH3)Ph
4-(1-H-1,2,4-triazol-1-yl)


102
C(O)
H
(3-CH3)2-thienyl
4-(1-H-1,2,4-triazol-1-yl)


103
C(O)
H
(5-CH2CH3)2-thienyl
4-SO2—NH[(CH2)2N(CH3)2]


104
C(O)
H
(3-CH3)2-thienyl
4-SO2—NH[(CH2)2N(CH3)2]


105
C(O)
H
(2,6-F2-3-CH3)Ph
4-SO2—NH[(CH2)2N(CH3)2]


106
C(O)
H
(2,6-F2)Ph
4-SO2—NH[(CH2)2N(CH3)2]


107
C(O)
H
[3,5-(CH3)2]2-thienyl
4-SO2—NH[(CH2)2N(CH3)2]


108
C(O)
H
[3,5-(CH3)2]2-thienyl
4-NH—SO2—CH3


109
C(O)
H
(3-CH3)2-thienyl
4-NH—SO2—CH3


110
C(O)
H
(5-CH2CH3)2-thienyl
4-NH—SO2—CH3


111
C(O)
H
(2,6-F2)Ph
4-NH—SO2—CH3


112
C(O)
H
(2,6-F2-3-CH3)Ph
4-NH—SO2—CH3


113
C(O)
H
(3-CH3)2-thienyl
4-(2-imidazolidinone)


114
C(O)
H
(2,6-F2-3-CH3)Ph
4-(2-imidazolidinone)


115
C(O)
H
(2,6-F2)Ph
4-(2-imidazolidinone)


116
C(O)
H
(3-CH3)2-thienyl
4-(1,1-dioxido-2-isothiazolidinyl)


117
C(O)
H
(2,6-F2)Ph
4-(1,1-dioxido-2-isothiazolidinyl)


118
C(O)
H
(2,6-F2)Ph
4-SO2—NH-2-pyridinyl


119
C(O)
H
(5-CH2CH3)2-thienyl
4-SO2—NH-2-pyridinyl


120
C(O)
H
[3,5-(CH3)2]2-thienyl
4-SO2—NH-2-pyridinyl



and,


121
C(O)
H
(3-CH3)2-thienyl
4-SO2—NH-2-pyridinyl









and pharmaceutically acceptable salts thereof.

Exemplified compounds of the present invention include a compound of Formula (I) selected from a compound of Formula (Id):




wherein X, R3 and R4 are dependently selected from:














Cpd
X
R3
R4







122
C(O)
(2,6-F2)Ph
4-SO2—NH2


123
C(O)
(2,6-F2-3-CH3)Ph
4-SO2—NH2


124
C(O)
(2,6-F2)Ph
H


125
C(O)
Ph
H


126
C(O)
(2,6-F2)Ph
3-Cl


127
C(O)
Ph
3-Cl



and,


128
C(S)
—NH[(2,6-F2)Ph]
4-SO2—NH2









and pharmaceutically acceptable salts thereof.

Exemplified compounds of the present invention include a compound of Formula (I) selected from a compound of Formula (Ie):




wherein R1 and R3 are dependently selected from:













Cpd
R1
R3







79
CH3
(3-CH3)2-thienyl









and pharmaceutically acceptable salts thereof.

The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997 (January), 66, 1, 1). Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds, which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention and moreover that the term “a compound of Formula x” will encompass a compound's enantiomers, diastereomers, and the like.
Unless specified otherwise, the term “alkyl” refers to a saturated straight or branched chain consisting solely of 1-8 hydrogen substituted carbon atoms; preferably, 1-6 hydrogen substituted carbon atoms; and, most preferably, 1-4 hydrogen substituted carbon atoms. The term “alkenyl” refers to a partially unsaturated straight or branched alkyl chain that contains at least one double bond. The term “alkynyl” refers to a partially unsaturated straight or branched alkyl chain that contains at least one triple bond. The term “alkoxy” refers to —O-alkyl, where alkyl is as defined supra.
The term “cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl ring consisting of 3-8 hydrogen substituted carbon atoms. Examples include, and are not limited to, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term “heterocyclyl” refers to a saturated or partially unsaturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having six members of which one, two or three members are a N atom; a saturated or partially unsaturated bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms; and, a saturated or partially unsaturated bicyclic ring having ten members of which one, two or three members are a N atom. Examples include, and are not limited to, pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl or piperazinyl.
The term “aryl” refers to an aromatic monocyclic ring system containing 6 hydrogen substituted carbon atoms, an aromatic bicyclic ring system containing 10 hydrogen substituted carbon atoms or an aromatic tricyclic ring system containing 14 hydrogen substituted carbon atoms. Examples include, and are not limited to, phenyl, naphthalenyl or anthracenyl.
The term “heteroaryl” refers to an aromatic monocyclic ring system containing five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms and an aromatic bicyclic ring having ten members of which one, two or three members are a N atom. Examples include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, quinolinyl or isoquinolinyl.
The term “halo” or “halogen” refers to a fluoro, chloro, bromo or iodo atom.
“Independently” means that when a group is substituted with more than one substituent that the substituents may be the same or different. “Dependently” means that the substituents are specified in an indicated combination of structure variables.
An embodiment of the invention is a pharmaceutical composition or medicament comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrative of the invention is a pharmaceutical composition or medicament made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition or medicament comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier. Further illustrative of the present invention are pharmaceutical compositions or medicaments comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The compounds of the present invention are selective kinase or dual-kinase inhibitors useful in a method for treating or ameliorating a kinase or dual-kinase mediated disorder. In particular, the kinase is selected from a cyclin dependent kinase and a tyrosine kinase. More particularly, the kinase is selected from cyclin dependent kinase-1, cyclin dependent kinase-2, cyclin dependent kinase-4, vascular endothelial growth factor receptor-2, endothelial growth factor receptor or human epidermal growth factor receptor-2.
Cyclin-dependent kinase inhibitors play a critical role in regulating progression of the eukaryotic cell through the cell cycle by associating with protein complexes composed of cyclins and cyclin-dependent kinases and thus down-regulating the activity of the cyclin-dependent kinases. Pathways involving cyclin-dependent kinase inhibitors are frequently disrupted in tumor cells leading to abnormal regulation of the cell cycle. Overexpression of cyclin-dependent kinase inhibitors leads to arrest of cells at one of the check points in the cell cycle. Therefore, using cyclin-dependent kinase inhibitors for tumor therapy is intuitively attractive because it has the potential for tumour growth. Inhibition or for the inhibition or control of uncontrolled cell proliferation such as occurs in some angiopathies, benign tumor growth, leukemias, and the like. A particularly good CDK inhibitor target for the design of anti-tumor agents is the CDK-1 receptor. This protein controls the last checkpoint in the cell cycle between the G2 and M phase.
A second protein target that can facilitate elimination of a tumor is the tyrosine kinase vascular endothelial growth factor (VEGF) receptor. This protein is associated with both normal and pathological angiogenesis. The VEGF receptors are tripartite, consisting of an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. Presently there are two known VEGF receptors: (1) VEGF-R2 (KDR/Flk1/VEGF-R2), a receptor that mediates the biological activities of mitogenesis and proliferation of endothelial cells; and (2) VEGF-R1 (Flt1/VEGF-R1), a receptor that mediates functions such as endothelial cell adhesion. Inhibition of VEGF-R2 signalling has been shown to inhibit the process of angiogenesis. Inhibitors of this receptor are likely useful in controlling or limiting angiogenesis.
Many conventional cytotoxic cancer therapies destroy the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin dependent kinases may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia by arresting the cell cycle and reducing the sensitivity of epithelial cells to antitumor agents (Davis S. T., et al., Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors, Science, 2001, (Jan. 5), 291, 5501, 25-6). Topical application of non-apoptotic CDK inhibitors represents a potentially useful approach for the prevention of chemotherapy-induced alopecia in cancer patients.
Although coronary angioplasty is a highly effective procedure used to reduce the severity of coronary occlusion, its long-term success is limited by a high rate of restenosis. Vascular smooth muscle cell activation, migration, and proliferation is largely responsible for restenosis following angioplasty (Ross, R., Nature, 1993, 362, 801-809). Recent studies have shown that CDK2 is activated very early after endothelial denudation in a rat carotid artery model of restenosis (Wei, G. L., et al., Circ. Res., 1997, 80, 418-426). Therefore, antiproliferative therapies targeted to cyclin dependent kinases or other components of the cell cycle machinery may be a suitable approach to treat these disorders.
Embodiments of the method of the present invention include a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an instant compound or pharmaceutical composition thereof. The therapeutically effective amount of the compounds of Formula (I) exemplified in such a method is from about 0.001 mg/kg/day to about 300 mg/kg/day.
Embodiments of the present invention include the use of a compound of Formula (I) for the preparation of a medicament for treating or ameliorating a kinase or dual-kinase mediated disorder in a subject in need thereof.
In accordance with the methods of the present invention, an individual compound of the present invention or a pharmaceutical composition thereof can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly.
Embodiments of the present method include a compound or pharmaceutical composition thereof advantageously co-administered in combination with other agents for treating or ameliorating a kinase or dual-kinase mediated disorder. The combination product comprises co-administration of a compound of Formula (I) or pharmaceutical composition thereof and an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder, the sequential administration of a compound of Formula (I) or pharmaceutical composition thereof and an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder, administration of a pharmaceutical composition containing a compound of Formula (I) or pharmaceutical composition thereof and an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder or the essentially simultaneous administration of a separate pharmaceutical composition containing a compound of Formula (I) or pharmaceutical composition thereof and a separate pharmaceutical composition containing an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder.
The term “other agents” includes, and is not limited to, anti-angiogenic agents, anti-tumor agents, cytotoxic agents, inhibitors of cell proliferation, and the like. The term “treating or ameliorating” includes, and is not limited to, facilitating the eradication of, inhibiting the progression of or promoting stasis of a malignancy. For example, a dual CDK1-VEGF-R inhibitor compound of the present invention, acting as an anti-angiogenic agent can be administered in a dosing regimen with at least one other cytotoxic compound, such as a DNA alkylating agent. Preferred anti-tumor agents are selected from the group consisting of cladribine (2-chloro-2′-deoxy-(beta)-D-adenosine), Chlorambucil (4-[bis(2-chlorethyl)amino]benzenebutanoic acid), DTIC-Dome (5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide), platinum chemotherapeutics and nonplatinum chemotherapeutics. Platinum containing anti-tumor agents include, but are not limited to, cisplatin (cis-dichlorodiamineplatinum). Non-platinum containing anti-tumor agents include, but are not limited to, cyclophosphamide, fluorouracil, epirubicin, methotrexate, vincristine, doxorubicin, bleomycin, and etoposide. Each anti-tumor agent is administered in a therapeutically effective amount, which varies based on the agent used, the type of malignancy to be treated or ameliorated and other conditions, according to methods well known in the art.
The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
The ubiquitous nature of the kinase isoforms and their important roles in physiology provide incentive to produce highly selective kinase inhibitors. Given the evidence demonstrating linkage of certain isoforms to disease states, it is reasonable to assume that inhibitory compounds that are selective to one or two isoforms (those compounds selective to at least two cyclin dependent kinase or tyrosine kinase isoforms are referred to as dual kinase inhibitors) or to a single isoform relative to other isoforms and other kinases are superior therapeutic agents. Such compounds should demonstrate greater efficacy and lower toxicity by virtue of their specificity. Accordingly, it will be appreciated by one skilled in the art that a compound of Formula (I) is therapeutically effective for certain kinase or dual-kinase mediated disorders based on the modulation of the disorder by selective kinase or dual-kinase inhibition. The activity of the instant compounds as selective kinase or dual-kinase inhibitors is derived from the novel combination of the structural elements X, R3 and R4 optimally substituted on the triazole scaffold. The usefulness of a compound of Formula (I) as a selective kinase or dual-kinase inhibitor can be determined according to the methods disclosed herein and the scope of such usefulness includes use in one or more kinase or dual-kinase mediated disorders.
Therefore, the term “kinase or dual-kinase mediated disorders” as used herein, includes, and is not limited to compounds capable of inhibiting one or more kinases where knase inhibition is also associated with cancers, abnormal cell proliferation, tumor growth, tumor vascularization, as well as angiopathy, angiogenesis, chemotherapy-induced alopecia and restenosis.
The compounds of this invention are useful as an adjunct to a variety of chemotherapeutic agents that are recommended for specific cancer therapy regimes. For example, the compounds of this invention have been demonstrated to be useful in combination therapies with at least one other chemotherapeutic agent for the treatment of a number of different cancers and advantageously appears to facilitate the use of a reduced dose of the chemotherapeutic agent that is recommended for a particular cancer or cell proliferation disorder. Therefore, it is contemplated that the compounds of this invention can be used in a treatment regime before the administration of a particular chemotherapeutic agent recommended for the treatment of a particular cancer, during adminstration of the chemotherapeutic agent or after treatment with a particular chemotherapeutic agent.
Pharmaceutical compositions contemplated within this invention can be prepared according to conventional pharmaceutical techniques. A pharmaceutically acceptable carrier may be used in the composition of the invention. The composition may take a wide variety of forms depending on the form of preparation desired for administration including, but not limited to, intravenous (both bolus and infusion), oral, nasal, transdermal, topical with or without occlusion, intraperitoneal, subcutaneous, intramuscular or parenteral, all using forms well known to those of ordinary skill in the pharmaceutical arts. In preparing the compositions in oral dosage form, one or more of the usual pharmaceutical carriers may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, syrup and the like in the case of oral liquid preparations (for example, suspensions, elixirs and solutions), or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (for example, powders, capsules and tablets).
As is also known in the art, the compounds may alternatively be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. The injectable formulation can include the active ingredient mixed with an appropriate inert liquid carrier. Acceptable liquid carriers include vegetable oils such as peanut oil, cotton seed oil, sesame oil, and the like, as well as organic solvents such as solketal, glycerol, formal, and the like. As an alternative, aqueous parenteral formulations may also be used. For example, acceptable aqueous solvents include water, Ringer's solution and an isotonic aqueous saline solution. Further, a sterile non-volatile oil can usually be employed as solvent or suspending agent in the aqueous formulation. The formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.005 to 10% by weight of the active ingredient. Other additives including a preservative, an isotonizer, a solubilizer, a stabilizer and a pain-soothing agent may adequately be employed.
Furthermore, compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
Because of their ease of administration, tablets and capsules represent an advantageous oral dosage unit form, wherein solid pharmaceutical carriers are employed. If desired, tablets may be sugarcoated or enteric-coated by standard techniques.
For liquid forms the active drug component can be combined in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, including for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents that may be employed include glycerin and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes containing delivery systems as well known in the art are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The instant pharmaceutical composition will generally contain a per dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful and the like) from about 0.001 to about 100 mg/kg. In one embodiment, the instant pharmaceutical composition contains a per dosage unit of from about 0.01 to about 50 mg/kg of compound, and preferably from about 0.05 to about 20 mg/kg. Methods are known in the art for determining therapeutically effective doses for the instant pharmaceutical composition. The therapeutically effective amount for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.
Abbreviations


    “Cpd” Compound
    “CSCl2” thiophosgene
    “DIC” diisopropyl carbodiimide
    “DMF” N,N-dimethylformamide
    “EDCI” ethyl dimethylaminopropyl carbodiimide
    “HOBT” hydroxybenzyl triazole
    “NH2NH2” hydrazine
    “Pd” palladium(II)
    “Ph” phenyl
    “rt” room temperature
    “TBAF” tetrabutylammonium fluoride
    “TFA” trifluoroacetic acid
    “THF” tetrahydrofuran


Nomenclature
Compounds are named according to nomenclature well known in the art, as exemplified using ring numbering as follows:




4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide
Names can be generated using a nomenclature system based on this example, or may be generated using commercial chemical naming software such as ACD/Index Name (Advanced Chemistry Development, Inc., Toronto, Ontario).
General Synthetic Methods
Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes that follow. Since the schemes are illustrations, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
Scheme A
To prepare a Compound A3 (as described in Jenardanan, G. C., Francis, M., Deepa, S., and Rajaskekharan, N. R., Synthetic Communications, 1997, 27, 19, 3457-3462), the isocyanate Compound A1 (prepared according to R. L. McKee and R. W. Bost, J. Am. Chem. Soc., 1946, 68, 2506-2507) (wherein R1 is as previously defined) was dissolved in a suitable solvent and combined with a suspension of Compound A2 and potassium hydroxide in solvent. The mixture was warmed and stirred and the product Compound A3 was isolated by precipitation in cold water.
To prepare a Compound A5 (Reiter, J., Pongo, L. and Dvortsak, P, J. Heterocyclic Chemistry, 1987, 24, 127-142), Compound A3 was dissolved in a suitable solvent and reacted with hydrazine. The solvent was then evaporated and the residue of Compound A3 was refluxed in an alcohol solvent to produce a solid Compound A4. Compound A4 was dissolved in a suitable solvent and reacted with R3CO2H or R3COCl (wherein R3 is as previously defined) and a coupling reagent such as DIC (diisopropyl carbodiimide) or EDCI (ethyl dimethylaminopropyl carbodiimide) to yield the target Compound A5.




Scheme B
Alternatively, Compound B3 was prepared according to published procedure (as described in Webb, R. L., Eggleston, D. S. and Labaw, C. S., J. Heterocyclic Chemistry, 1987, 24, 275-278). Following the procedure of Scheme A, Compound B3 was reacted with hydrazine to produce the target intermediate Compound A4.




Scheme C
Compound C1 (CAS # 1455-77-2) was dissolved in a suitable solvent and reacted with R3CO2H or R3COCl (wherein R3 is as previously defined) and a coupling reagent such as DIC or EDCI to yield the Compound C2. Compound C2 was purified, dissolved in a suitable solvent and reacted in an inert atmosphere with R1-halo (wherein R1 and halo are as previously defined; in addition to halo, R1 may be coupled with another suitable leaving group) in the presence of a base, such as potassium carbonate, and a catalyst, such as a palladium complex. The product Compound A5 was isolated using conventional means.




Scheme D
Alternatively, Compound D1 (CAS# 24807-56-5) was dissolved in a suitable solvent and reacted with R1NH2 in the presence of a base such as potassium carbonate, and a catalyst such as a palladium complex to yield the Compound D2. Compound D2 was purified, dissolved in a suitable solvent and subjected to catalytic hydrogenation to give Compound A4. Compound A4 may then be used to produce other target compounds of the invention as described in Scheme A.




Scheme E
Compound A3 was dissolved in a solvent and reacted with a protecting group such as a substituted benzyl halide (for example, 4-methoxybenzyl bromide) in the presence of a base (such as potassium carbonate) to yield a Compound E1. Compound E1 was purified, dissolved in a suitable solvent and then reacted with R2-halo (wherein R2 and halo are as previously defined; in addition to halo, R2 may be coupled with another suitable leaving group) in the presence of a base (such as potassium carbonate) to give a Compound E2. Compound E2 was treated with a suitable reagent, such as trifluoroacetic acid, which upon heating produced Compound E3. Compound E3 was dissolved in a suitable solvent and reacted with R3CO2H or R3COCl (wherein R3 is as previously defined) and a coupling reagent such as DIC or EDCI to yield a target Compound E4. The product Compound E4 was purified using conventional means.







Alternatively, to prepare a Compound E4, Compound A5 was dissolved in a suitable solvent and reacted with R2-halo (wherein R2 and halo are as previously defined; in addition to halo, R2 may be coupled with another suitable leaving group) in the presence of a base (such as potassium carbonate).
SPECIFIC SYNTHETIC EXAMPLES
Specific compounds which are representative of this invention were prepared as per the following examples and reaction sequences; the examples and the diagrams depicting the reaction sequences are offered by way of illustration, to aid in the understanding of the invention and should not be construed to limit in any way the invention set forth in the claims which follow thereafter. The depicted intermediates may also be used in subsequent examples to produce additional compounds of the present invention. No attempt has been made to optimize the yields obtained in any of the reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.
1H and 13C NMR spectra were measured on a Bruker AC-300 (300 MHz) spectrometer using tetramethylsilane and DMSO respectively as internal standards. Elemental analyses were obtained by Quantitative Technologies Inc. (Whitehouse, N.J.), and the results were within 0.4% of the calculated values unless otherwise mentioned. Melting points were determined in open capillary tubes with a Mel-Temp II apparatus (Laboratory Devices Inc.) and were uncorrected. Electrospray mass spectra (MS-ES) were recorded on a Hewlett Packard 59987A spectrometer.
Example 1
4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide (Cpd 1)
A suspension of 1-amidino-3,5-dimethylpyrazole nitrate Compound 1C (2.012 g, 10 mmol) and potassium hydroxide powder (0.561 g, 10 mmol) in DMF (8 mL) at 0° C. was added to a DMF solution (3 mL) of isocyanate Compound 1B (prepared from sulfanilamide Compound 1A and thiophosgene according to R. L. McKee and R. W. Bost, J. Am. Chem. Soc., 1946, 68, 2506-2507). The reaction mixture was warmed up to 50-60° C., stirred for 1 h, and then poured into 250 ml of icy water. The resultant yellow solid was filtered, rinsed with water and dried in vacuo to give an intermediate Compound 1D as yellow powder (2.5513 g); m.p. 69-80° C. (decomposed); 1H NMR (300 MHz, CD3OD) δ 7.90 (m, 4H), 6.05 (s, 1H), 2.22 (s, 3H), 2.20 (s, 3H); (CDCl3) δ 10.75 (s, br, 1H), 8.35 (s, br, 1H), 7.90 (q, 4H), 7.65 (s, br, 2H), 5.95 (s, 1H), 5.00 (s, br, 2H); MS (ESI) m/z: 353 (M+H+).
Hydrazine (1.845 g, 57.58 mmol) was added to a solution of the intermediate Compound 1D (1.88 g, 5.33 mmol) in THF (60 mL). The reaction mixture was stirred vigorously at 50-60° C. for 2-3 hours, and then evaporated in vacuo. The residue was then refluxed in methanol (60 mL) and cooled down to rt. The resultant solid was collected by filtration and rinsed with methanol to produce intermediate Compound 1E as a gray solid (0.8722 g, 64%). m.p. 291-296° C. (decomposed); 1H NMR (300 MHz, (CD3)2SO) δ 9.20 (s, 1H), 7.60 (m, 4H), 7.00 (s, 2H), 5.90 (s, 2H); MS (ESI) m/z: 255 (M+H+), 277 (M+Na+).
2,6-difluorobenzoyl chloride Compound 1F (41.4 uL, 0.33 mmol) was added to a solution of the intermediate Compound 1E (63.6 mg, 0.25 mmol) dissolved in anhydrous pyridine (2.5 mL) in an ice-water bath. The resulting reaction mixture was stirred at rt for 6 hours, and then evaporated in vacuo to dryness. Chromatography purification of the residue with 10% methanol/methylene chloride and recrystallization from THF/methylene chloride gave Compound 1 (50.2 mg, 51%) as a white powder. m.p. 149-155° C. (decomposed); 1H NMR (300 MHz, CD3OD) δ 7.65 (m, 3H), 7.55 (d, 2H), 7.18 (t, 2H); ((CD3)2SO) δ 9.86 (s, 1H), 8.03 (s, 2H), 7.72 (m, 1H), 7.58 (d, J=8.9 Hz, 2H), 7.46 (d, J=8.9 Hz, 2H), 7.35 (t, J=8.3 Hz, 2H), 7.11 (s, 2H); 13C NMR (300 MHz, (CD3)2SO) δ 160.4, 159.7, 158.9, 157.9, 157.1, 157.0, 156.6, 144.0, 135.6, 133.9, 127.0, 116.3, 112.9, 112.5, 112.3; MS (ESI) m/z: 395 (M+H+), 417 (M+Na+). Anal. Calcd. For C15H12F2N6O3S: C, 45.69; H, 3.07; N, 21.31. Found: C, 45.29; H, 3.04; N, 20.89.







Using the procedure for Example 1, the following compounds were prepared by acylation of the intermediate Compound 1E using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l

















2
4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-1,2,4-
2,6-difluoro-3-



triazol-3-yl]amino]-benzenesulfonamide
methylbenzoyl



1H NMR(300MHz, (CD3)2CO) δ 8.80(s, 1H), 7.78-7.55
chloride in



(m, 5H), 7.52(s, 2H), 7.12(t, 2H), 6.38(s, 2H), 2.22(s,
anhydrous pyridine



3H); MS(ESI)m/z: 409(M+H+), 431(M+Na+)


3
4-[[5-amino-1-(2,3,6-trifluorobenzoyl)-1H-1,2,4-triazol-
2,3,6-



3-yl]amino]-benzenesulfonamide
trifluorobenzoyl



1H NMR(300MHz, (CD3)2CO) δ 8.85(s, 1H), 7.78-7.50
chloride in



(m, 7H), 7.32(m, 1H), 6.38(s, 2H); MS(ESI)m/z: 413
anhydrous pyridine



(M+H+), 435(M+Na+)


4
4-[[5-amino-1-(2-fluorobenzoyl)-1H-1,2,4-triazol-3-
2-fluorobenzoyl



yl]amino]-benzenesulfonamide
chloride in



1H NMR(300MHz, (CD3)2CO) δ 8.90(s, br, 1H), 8.00
anhydrous pyridine



(s, br, 2H), 7.82(t, 1H), 7.78-7.20(m, 7H), 6.35(s, br,



2H); MS(ESI)m/z: 377(M+H+), 399(M+Na+)


5
4-[[5-amino-1-(2,4-difluorobenzoyl)-1H-1,2,4-triazol-3-
2,4-difluoromethyl-



yl]amino]-benzenesulfonamide
benzoyl chloride in



1H NMR(300MHz, (CD3)2CO) δ 8.88(s, 1H), 7.95(s,
anhydrous pyridine



2H), 7.78-7.58(m, 4H), 7.48(s, 2H), 7.35-7.77(m, 2H),



6.38(s, 2H); MS(ESI)m/z: 395(M+H+), 417(M+Na+)


6
4-[[5-amino-1-[2-fluoro-6-(trifluoromethyl)benzoyl]-1H-
2-fluoro-6-



1,2,4-triazol-3-yl]amino]-benzenesulfonamide
(trifluoromethyl)-



1H NMR(300MHz, (CD3)2SO) δ 9.86(s, 1H), 8.06(s,
benzoyl chloride in



2H), 7.85(m, 3H), 7.54(d, J=8.9Hz, 2H), 7.40(d, J=8.9
THF



Hz, 2H), 7.09(s, 2H); MS(ESI)m/z: 445(M+H+), 467



(M+Na+)


7
4-[[5-amino-1-(2,6-dichlorobenzoyl)-1H-1,2,4-triazol-3-
2,6-dichlorobenzoyl



yl]amino]-benzenesulfonamide
chloride in



1H NMR(300MHz, (CD3)2CO) δ 8.82(s, 1H), 7.68-7.45
anhydrous pyridine



(m, 9H), 6.35(s, 2H); (CD3OD) δ 7.60(d, 2H), 7.55(m,



3H), 7.38(d, 2H); MS(ESI)m/z: 428(M+H+), 450(M+Na+)


8
4-[[5-amino-1-(2,4,6-trichlorobenzoyl)-1H-1,2,4-triazol-
2,4,6-



3-yl]amino]-benzenesulfonamide
trichlorobenzoyl



1H NMR(300MHz, (CD3)2CO) δ 8.88(s, 1H), 7.78(s,
chloride in



2H), 7.75-7.48(m, 6H), 6.38(s, 2H); MS(ESI)m/z: 462
anhydrous pyridine



(M+H+), 484(M+Na+)


9
4-[[5-amino-1-(2-nitrobenzoyl)-1H-1,2,4-triazol-3-
2-nitrobenzoyl



yl]amino]-benzenesulfonamide
chloride in



1H NMR(300MHz, CD3OD) δ 8.28(d, 2H), 8.95-7.85
anhydrous pyridine



(m, 3H), 7.62(d, 2H), 7.35(d, 2H); MS(ESI)m/z: 404



(M+H+), 426(M+Na+)


10
4-[[5-amino-1-(2,6-dimethoxybenzoyl)-1H-1,2,4-triazol-
2,6-



3-yl]amino]-benzenesulfonamide
dimethoxybenzoyl



1H NMR(300MHz, (CD3)2CO) δ 8.65(s, br, 1H), 7.68
chloride in



(m, 4H), 7.50(d, 1H), 7.30(s, br, 2H), 6.72(d, 1H), 6.68
anhydrous pyridine



(dd, 1H), 6.35(s, br, 2H), 3.92(s, 3H), 3.85(s, 3H); MS



(ESI)m/z: 419(M+H+), 441(M+Na+)


11
4-[[5-amino-1-(2,4,6-trimethylbenzoyl)-1H-1,2,4-triazol-
2,4,6-



3-yl]amino]-benzenesulfonamide
trimethylbenzoyl



1H NMR(300MHz, (CD3)2CO) δ 8.78(s, 1H), 7.78(s,
chloride in



2H), 7.72-7.43(m, 5H), 7.75-6.78(m, 3H), 6.35(s, 2H),
anhydrous pyridine



2.38-2.16(m, 9H); MS(ESI)m/z: 401(M+H+), 423(M+Na+)


12
4-[(5-amino-1-benzoyl-1H-1,2,4-triazol-3-yl)amino]-
Benzoyl chloride in



benzenesulfonamide
anhydrous pyridine



1H NMR(300MHz, (CD3)2CO) δ 8.80(s, 1H), 8.28(d,



2H), 7.80-7.58(m, 7H), 7.52(s, 2H), 6.38(s, 2H); MS



(ESI)m/z: 359(M+H+), 381(M+Na+)


14
4-[[5-amino-1-(2-thienylcarbonyl)-1H-1,2,4-triazol-3-
Thiophene-2-



yl]amino]-benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2CO) δ 8.92(s, 1H), 8.40(dd,
mediated by



1H), 8.12(dd, 1H), 7.88(q, 4H), 7.50(s, 2H), 7.32(t,
DIC/HOBt (1-



1H), 6.45(s, 2H); MS(ESI)m/z: 365(M+H+), 387(M+Na+)
hydroxybenzo




triazole) in




anhydrous DMF


15
4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-
3-methyl-



triazol-3-yl]amino]-benzenesulfonamide
thiophene-2-



m.p. 280-284° C.; 1H NMR(300MHz, (CD3)2SO) δ
carboxylic acid



9.88(s, 1H), 8.05(d, 1H), 7.88(s, 2H), 7.78(q, 4H), 7.15
mediated by



(m, 3H), 2.62(s, 3H);
DIC/HOBt in



(CD3)2CO δ 8.92(s, 1H), 7.98(d, 1H), 7.90(q, 4H), 7.45
anhydrous DMF



(s, 2H), 7.15(d, 1H), 6.42(s, 2H), 2.68(s, 3H);



13C NMR(300MHz, (CD3)2SO) δ 160.6, 157.9, 157.4,



157.2, 150.9, 143.9, 136.0, 135.5, 131.8, 127.3, 124.3,



116.3, 18.1; MS(ESI)m/z: 379(M+H+), 401(M+Na+)


16
4-[[5-amino-1-[(3-fluoro-2-thienyl)carbonyl]-1H-1,2,4-
3-fluorothiophene-



triazol-3-yl]amino]-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.92(s, br, 1H), 8.18
(prepared according



(t, 1H), 7.92(s, br, 2H), 7.78(q, 4H), 7.25(d, 1H), 7.18
to E. C. Taylor and



(s, br, 2H); MS(ESI)m/z: 383(M+H+), 405(M+Na+)
P. Zhou, Org. Prep.




Proced. Int., 1997,




29, 221) mediated




by DIC/HOBt in




anhydrous DMF


17
4-[[5-amino-1-[(3-chloro-2-thienyl)carbonyl]-1H-1,2,4-
3-chlorothiophene-



triazol-3-yl]amino]-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.92(s, br, 1H), 8.25
mediated by



(d, 1H), 7.95(s, br, 2H), 7.78(q, 4H), 7.32(d, 1H), 7.18
EDCI/HOBt in



(s, br, 2H); MS(ESI)m/z: 399(M+H+), 421(M+Na+)
anhydrous DMF


18
4-[[5-amino-1-[(3-ethoxy-2-thienyl)carbonyl]-1H-1,2,4-
3-ethoxythiophene-



triazol-3-yl]amino]-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.85(s, br, 1H), 8.08
mediated by



(d, 1H), 7.85-7.75(m, 6H), 7.28(d, 1H), 7.15(s, br, 2H);
DIC/HOBt in



MS(ESI)m/z: 409(M+H+), 431(M+Na+)
anhydrous DMF


19
N-[2-[[5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-1H-
3-(acetylamino)-



1,2,4-triazol-1-yl]carbonyl]-3-thienyl]-acetamide
thiophene-2-



1H NMR(300MHz, (CD3)2SO) δ 11.0(s, br, 1H), 9.92
carboxylic acid



(s, br, 1H), 8.18(q, 2H), 7.85(s, br, 2H), 7.78(q, 4H),
mediated by



7.15(s, br, 2H), 2.20(s, 3H); MS(ESI)m/z: 421
DIC/HOBt in



(M+H+), 444(M+Na+)
anhydrous DMF


20
4-[[5-amino-1-[(5-methyl-2-thienyl)carbonyl]-1H-1,2,4-
5-methyl-



triazol-3-yl]amino]-benzenesulfonamide
thiophene-2-



1H NMR(300MHz, (CD3)2SO) δ 9.92(s, br, 1H), 8.15
carboxylic acid



(d, 1H), 7.85(s, br, 2H), 7.78(q, 4H), 7.20(s, br, 2H),
mediated by



7.08(d, 1H), 2.62(s, 3H); MS(ESI)m/z: 379(M+H+)
DIC/HOBt in




anhydrous DMF


21
4-[[5-amino-1-[(5-bromo-2-thienyl)carbonyl]-1H-1,2,4-
5-bromothiophene-



triazol-3-yl]amino]-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.98(s, br, 1H), 8.05
mediated by



(d, 1H), 7.95(s, br, 2H), 7.78(q, 4H), 7.48(d, 1H), 7.20
DIC/HOBt in



(s, br, 2H); MS(ESI)m/z: 444(M+H+)
anhydrous DMF


22
4-[[1-[(5-acetyl-2-thienyl)carbonyl]-5-amino-1H-1,2,4-
5-acetylthiophene-



triazol-3-yl]amino]-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 10.02(s, br, 1H), 8.28
mediated by



(d, 1H), 8.02(d, 1H), 7.95(s, br, 2H), 7.75(q, 4H), 7.20
DIC/HOBt in



(s, br, 2H), 2.65(s, 3H); MS(ESI)m/z: 407(M+H+), 429
anhydrous DMF



(M+Na+)


25
4-[[5-amino-1-(2-furanylcarbonyl)-1H-1,2,4-triazol-3-
2-furoyl chloride in



yl]amino]-benzenesulfonamide
anhydrous pyridine



1H NMR(300MHz, (CD3)2CO) δ 8.87(s, 1H), 8.20(d,



1H), 8.02(dd, 1H), 7.85(q, 4H), 7.48(s, 2H), 6.88(dd,



1H), 6.42(s, 2H); MS(ESI)m/z: 349(M+H+), 371



(M+Na+)


26
4-[[5-amino-1-(5-isoxazolylcarbonyl)-1H-1,2,4-triazol-3-
isoxazole-5-



yl]amino]-benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.95(s, br, 1H), 8.92
mediated by



(d, 1H), 8.00(s, br, 2H), 7.78(d, 2H), 7.68(m, 3H), 7.15
DIC/HOBt in



(s, br, 2H); MS(ESI)m/z: 350(M+H+), 372(M+Na+)
anhydrous DMF


27
4-[[5-amino-1-(2-pyridinylcarbonyl)-1H-1,2,4-triazol-3-
picolic acid



yl]amino]-benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.75(s, 1H), 8.72(d,
DIC/HOBt in



1H), 8.00(m, 2H), 7.90(s, br, 2H), 7.68-7.48(m, 5H),
anhydrous DMF



7.10(s, br, 2H); MS(ESI)m/z: 360(M+H+), 382,



(M+Na+)


28
4-[[5-amino-1-(3-pyridinylcarbonyl)-1H-1,2,4-triazol-3-
nicotinic acid



yl]amino]-benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.82(s, 1H), 9.22(d,
DIC/HOBt in



1H), 8.78(dd, 1H), 8.45(dd, 1H), 7.92(s, br, 2H), 77.62
anhydrous DMF



(q, 4H), 7.15(s, br, 2H); MS(ESI)m/z: 360(M+H+),



382, (M+Na+)


29
4-[[5-amino-1-(4-pyridinylcarbonyl)-1H-1,2,4-triazol-3-
isonicotinic acid



yl]amino]-benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.80(s, 1H), 8.82(d,
DIC/HOBt in



2H), 8.00-7.90(m, 4H), 7.60(q, 4H), 7.12(s, br, 2H);
anhydrous DMF



MS(ESI)m/z: 360(M+H+), 382, (M+Na+)


30
4-[[5-amino-1-(3-thienylcarbonyl)-1H-1,2,4-triazol-3-
thiophene-3-



yl]amino]-benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2CO) δ 9.08(d, 1H), 8.85(s,
mediated by



br, 1H), 7.98(dd, 1H), 7.82(q, 4H), 7.62(dd, 1H), 7.48
DIC/HOBt in



(s, br, 1H), 6.45(s, br, 2H); MS(ESI)m/z: 365(M+H+),
anhydrous DMF



387(M+Na+)


31
4-[[5-amino-1-(benzo[b]thien-2-ylcarbonyl)-1H-1,2,4-
benzo[b]thiophene-



triazol-3-yl]amino]-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.95(s, br, 1H), 8.85
mediated by



(s, 1H), 8.15(dd, 2H), 8.02(s, br, 2H), 7.85(q, 4H), 7.55
DIC/HOBt in



(m, 2H), 7.18(s, br, 2H); MS(ESI)m/z: 415(M+H+)
anhydrous DMF


34
4-[[5-amino-1-[(2,4-dimethyl-5-thiazolyl)carbonyl]-1H-
2,4-dimethylthiazole-5-



1,2,4-triazol-3-yl]amino]-benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.88(s, br, 1H), 7.90
mediated by



(s, br, 2H), 7.78(q, 4H), 7.15(s, br, 2H), 2.78(s, 6H);
DIC/HOBt in



MS(ESI)m/z: 394(M+H+), 416(M+Na+)
anhydrous DMF


35
4-[[5-amino-1-[(3-bromo-2-thienyl)carbonyl]-1H-1,2,4-
3-bromothiophene-



triazol-3-yl]amino]-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.95(s, 1H), 8.23(d,
mediated by



J=5.3, 1H), 7.95(s, 2H), 7.77(s, 4H), 7.39(d, J=5.3, 1H),
DIC/HOBt in



7.16(s, 2H); MS(ESI)m/z: 444.9(M+H), 466.9(M+Na+)
anhydrous DMF


36
4-[[5-amino-1-[(4-methyl-1,2,3-thiadiazol-5-
4-methyl-1,2,3-



yl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]-
thiadiazol-5-



benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 10.07(s, 1H), 8.09(s,
mediated by



2H), 7.86(d, J=8.8, 2H), 7.72(d, J=8.9, 2H), 7.21(s, 2H),
DIC/HOBt in



3.02(s, 3H); MS(ESI)m/z: 381.0(M+H), 403.0(M+Na+)
anhydrous DMF


37
4-[[5-amino-1-(1,2,3-thiadiazol-4-ylcarbonyl)-1H-1,2,4-
1,2,3-thiadiazole-4-



triazol-3-yl]amino]-benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 10.18(s, 1H), 9.93(s,
mediated by



1H), 8.05(s, 2H), 7.76(d, J=8.8, 2H), 7.63(d, J=8.8, 2H),
DIC/HOBt in



7.16(s, 2H); MS(ESI)m/z: 367.0(M+H), 389.0
anhydrous DMF



(M+Na+)


38
4-[[5-amino-1-(cyclopentylcarbonyl)-1H-1,2,4-triazol-3-
cyclopetanecar-



yl]amino]-benzenesulfonamide
boxylic acid mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.73(s, 1H), 7.69(s,
DIC/HOBt in



4H), 7.65(s, 2H), 7.13(s, 2H), 1.78(m, 3H), 1.65(m,
anhydrous DMF



6H); MS(ESI)m/z: 351.0(M+H), 373.0(M+Na+)


39
4-[[5-amino-1-(cyclohexylcarbonyl)-1H-1,2,4-triazol-3-
cyclohexanecar-



yl]amino]-benzenesulfonamide
boxylic acid mediated



1H NMR(300MHz, (CD3)2SO) δ 9.76(s, 1H), 7.69(s,
by DIC/HOBt in



4H), 7.66(s, 2H), 7.13(s, 2H), 1.98(s, 2H), 1.80(s, 2H),
anhydrous DMF



1.69(d, 1H), 1.36(m, 6H); MS(ESI)m/z: 365.0(M+H),



387.1(M+Na+)


40
4-[[5-amino-1-(2-thienylacetyl)-1H-1,2,4-triazol-3-
2-thiopheneacetic



yl]amino]-benzenesulfonamide
acid mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.80(s, 1H), 7.73(d,
DIC/HOBt in



J=1.2, 4H), 7.69(s, 2H), 7.45(dd, J=1.5, 1H), 7.16(s,
anhydrous DMF



2H), 7.08(d, J=2.7, 1H), 7.01(t, J=5.1, 1H), 4.52(s, 2H);



MS(ESI)m/z: 379.0(M+H), 400.9(M+Na+)


42
4-[[5-amino-1-[(2E)-1-oxo-3-(2-thienyl)-2-propenyl]-1H-
3-(2-thienyl)acrylic



1,2,4-triazol-3-yl]amino]-benzenesulfonamide
acid mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.82(s, 1H), 7.92(d,
DIC/HOBt in



J=8.3, 1H), 7.72(s, 4H), 7.35(d, J=15.8, 2H), 7.26(d,
anhydrous DMF



J=19.5, 3H), 7.15(s, 2H), 6.26(s, 1H); MS(ESI)m/z:



391.0(M+H), 412.9(M+Na+)


43
4-[[5-amino-1-[(2,6-difluorophenyl)acetyl]-1H-1,2,4-
2,6-difluorophenyl



triazol-3-yl]amino]-benzenesulfonamide
acetic acid mediated



1H NMR(300MHz, (CD3)2SO) δ
by DIC/HOBt in



9.81(s, 1H), 7.69(s, 6H), 7.44(t, J=16.6, 1H), 7.16(s,
anhydrous DMF



3H), 4.37(s, 2H); MS(ESI)m/z: 409.0(M+H), 431.0(M+Na+)


44
4-[[5-amino-1-[(2E)-3-(2,6-difluorophenyl)-1-oxo-2-
2,6-difluoro



propenyl]-1H-1,2,4-triazol-3-yl]amino]-
cinnamic acid



benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.86(s, 1H), 7.85(d,
DIC/HOBt in



J=4.7, 2H), 7.71(s, 4H), 7.31(m, 4H), 7.16(s, 2H), 6.31
anhydrous DMF



(s, 1H); MS(ESI)m/z: 421.0(M+H), 442.9(M+Na+)


45
4-[[5-amino-1-(cycloheptylcarbonyl)-1H-1,2,4-triazol-3-
cycloheptanecar-



yl]amino]-benzenesulfonamide
boxylic acid mediated



1H NMR(300MHz, (CD3)2SO) δ 9.75(s, 1H), 7.69(s,
by DIC/HOBt in



4H), 7.66(s, 2H), 7.12(s, 2H), 2.00(d, J=11.7, 2H), 1.77
anhydrous DMF



(d, J=10.5, 2H), 1.40(m, 3H), 1.07(m, 2H), 0.91(d,



J=6.4, 4H); MS(ESI)m/z: 254, 379.0(M+H), 401.0(M+Na+)


46
4-[[5-amino-1-[(4-methylcyclohexyl)carbonyl]-1H-1,2,4-
trans-4-methyl-1-



triazol-3-yl]amino]-benzenesulfonamide
cyclohexanecar-



1H NMR(300MHz, (CD3)2SO) δ 9.75(s, 1H), 7.69(s,
boxylic acid mediated



4H), 7.66(s, 2H), 7.12(s, 2H), 2.00(d, J=11.7, 2H), 1.77
by DIC/HOBt in



(d, J=10.5, 2H), 1.40(m, 3H), 1.07(m, 2H), 0.91(d,
anhydrous DMF



J=6.4, 4H); MS(ESI)m/z: 254, 379.0(M+H), 401.0(M+Na+)


47
4-[[5-amino-1-[(2-methylcyclohexyl)carbonyl]-1H-1,2,4-
2-methyl-1-



triazol-3-yl]amino]-benzenesulfonamide
cyclohexanecar-



1H NMR(300MHz, (CD3)2SO) δ 9.75(s, 1H), 7.68(s,
boxylic acid mediated



4H), 7.66(s, 2H), 7.13(s, 2H), 1.55(m, 9H), 0.85(d,
by DIC/HOBt in



J=6.0, 4H); MS(ESI)m/z: 254, 379.0(M+H), 401.0(M+Na+)
anhydrous DMF


48
4-[[5-amino-1-[(4-butylcyclohexyl)carbonyl]-1H-1,2,4-
trans-4-butyl-1-



triazol-3-yl]amino]-benzenesulfonamide
cyclohexanecar-



1H NMR(300 MHZ, (CD3)2SO) δ 9.75(S, 1H), 7.68(S,
boxylic acid mediated



4H), 7.66(S, 2H), 7.12(S, 2H), 2.02(D, J=11.3, 2H),
by DIC/HOBt in



1.82(D, J=9.9, 2H), 1.40(D, J=11.3, 2H), 1.25(S, 7H),
anhydrous DMF



1.02(M, 4H), 0.87(S, 4H). MS(ESI)M/Z: 254, 435.1



(M+H), 457.1(M+NA+)


49
4-[[5-amino-1-[[5-(2-pyridinyl)-2-thienyl]carbonyl]-1H-
5-(2-pyridyl)-



1,2,4-triazol-3-yl]amino]-benzenesulfonamide
thiophene-2-



1H NMR(300MHz, (CD3)2SO) δ 9.98(s, 1H), 8.65(d,
carboxylic acid



1H), 8.25(d, 1H), 8.08(d, 1H), 8.02-7.75(m, 8H), 7.42
mediated by



(dd, 1H), 7.20(s, 2H). MS(ESI)m/z: 442(M+H+), 464(M+Na+)
DIC/HOBt in




anhydrous DMF


50
4-[[5-amino-1-[[3-(1H-pyrrol-1-yl)-2-thienyl]carbonyl]-
3-(1H-pyrrol-1-yl)-



1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide
thiophene-2-



1H NMR(300MHz, (CD3)2SO) δ 9.85(s, 1H), 8.18(d,
carboxylic acid



1H), 7.85-7.70(m, 6H), 7.32(d, 1H), 7.18(s, 2H), 7.12
mediated by



(t, 2H), 6.20(t, 2H). MS(ESI)m/z: 430(M+H+)
DIC/HOBt in




anhydrous DMF


51
4-[[5-amino-1-[[5-(1,1-dimethylethyl)-2-
5-tert-



thienyl]carbonyl]-1H-1,2,4-triazol-3-yl]amino]-
butylthiophene-2-



benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2CO) δ 8.95(s, 1H), 8.25(d,
mediated by



1H), 7.95(d, 2H), 7.85(d, 2H), 7.50(s, 2H), 7.18(d,
DIC/HOBt in



1H), 6.48(s, 2H), 1.55(s, 9H). MS(ESI)m/z: 421
anhydrous DMF



(M+H+), 443(M+Na+)


52
3-[5-[[5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-1H-
5-(2-tert-



1,2,4-triazol-1-yl]carbonyl]-2-thienyl]-(2E)-2-propenoic
butoxycarbonyl-



acid-1,1-dimethylethyl ester
vinyl)-thiophene-2-



1H NMR(300MHz, (CD3)2SO) δ 9.95(s, 1H), 8.22(d,
carboxylic acid



1H), 7.95(s, 2H), 7.82-7.68(m, 6H), 7.15(s, 2H), 6.52
(prepared by Heck



(d, 1H), 1.52(s, 9H). MS(ESI)m/z: 491(M+H+), 513
reaction of 5-



(M+Na+)
bromothiophene-2-



5-(2-tert-butoxycarbonyl-vinyl)-thiophene-2-carboxylic
carboxylic acid and



acid(intermediate) 1H NMR(300MHz, (CD3)2CO) δ
t-butyl acrylate)



7.80-70(m, 2H), 7.48(d, 1H), 7.32(d, 1H), 1.50(s, 9H);
mediated by



MS(ESI)m/z: 253(M−H+), 209(M−H+-CO2)
DIC/HOBt in




anhydrous DMF


53
4-[[5-amino-1-[[5-(phenylethynyl)-2-thienyl]carbonyl]-
5-phenylethynyl-



1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide
thiophene-2-



1H NMR(300MHz, (CD3)2SO) δ 9.98(s, 1H), 8.20(d,
carboxylic acid



1H), 7.95(s, 2H), 7.78(m, 4H), 7.62(m, 2H), 7.60(d,
(intermediate



1H), 7.45(m, 3H), 7.18(s, 2H). MS(ESI)m/z: 465
prepared by



(M+H+), 487(M+Na+)
oxidation of 5-



5-phenylethynyl-thiophene-2-carboxylic acid
phenylethynyl-



(intermediate) 1H NMR(300MHz, (CD3)2CO) δ 7.98
thiophene-2-



(d, 1H), 7.58(m, 2H), 7.45(m, 3H), 7.35(d, 1H); MS
carboxaldehyde),



(ESI)m/z: 229(M+H+)
mediated by




DIC/HOBt in




anhydrous DMF


54
4-[[5-amino-1-(2,6-difluoro-3-nitrobenzoyl)-1H-1,2,4-
2,6-difluoro-3-



triazol-3-yl]amino]-benzenesulfonamide
nitro-benzoic acid



1H NMR(300MHz, (CD3)2CO) δ 8.90(s, 1H), 8.55(m,
mediated by



1H), 7.75-7.50(m, 7H), 6.25(s, 2H); MS(ESI)m/z: 440
DIC/HOBt in



(M+H+), 462(M+Na+)
anhydrous DMF


55
4-[[5-amino-1-(3-amino-2,6-difluorobenzoyl)-1H-1,2,4-
catalytic



triazol-3-yl]amino]-benzenesulfonamide
hydrogenation of



1H NMR(300MHz, (CD3OD) δ 7.68(d, 2H), 7.45(d,
compound 54 in



2H), 6.95(m, 1H), 6.85(m, 1H); MS(ESI)m/z: 410
methanol by



(M+H+), 432(M+Na+)
catalysis of 10%




palladium on




charcoal


56
4-[[5-amino-1-(2,6-dimethylbenzoyl)-1H-1,2,4-triazol-3-
2,6-dimethylbenzoic



yl]amino]-benzenesulfonamide
acid mediated by



1H NMR(300MHz, (CD3)2CO) δ 8.75(s, 1H), 7.65-7.28
DIC/HOBt in



(m, 7H), 7.15(d, 2H), 6.32(s, 2H), 2.25(s, 6H); MS
anhydrous DMF



(ESI)m/z: 387(M+H+), 409(M+Na+)


57
4-[[5-amino-1-(2-methylbenzoyl)-1H-1,2,4-triazol-3-
2-methylbenzoyl



yl]amino]-benzenesulfonamide
chloride in



1H NMR(300MHz, (CD3)2CO) δ 8.75(s, 1H), 7.72-7.25
anhydrous pyridine



(m, 10H), 6.35(s, 2H), 2.45(s, 3H); MS(ESI)m/z: 373



(M+H+), 395(M+Na+)


66
5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-
2,6-difluorophenyl



difluorophenyl)-1H-1,2,4-triazole-1-carbothioamide
isothiocyanate in



1H NMR(300MHz, (CD3)2CO) δ 10.40(s, 1H), 8.90(s,
anhydrous pyridine



1H), 8.15(s, 2H), 7.85(d, 2H), 7.75(d, 2H), 7.40(m,



1H), 7.15(m, 2H), 6.35(s, 2H), 5.75(s, 2H); MS(ESI)



m/z: 426(M+H+), 448(M+Na+)


67
5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-
2,6-difluorophenyl



difluorophenyl)-1H-1,2,4-triazole-1-carboxamide
isocyanate in



1H NMR(300MHz, (CD3)2CO) δ 9.15(s, 1H), 8.80(s,
anhydrous DMF



1H), 7.80(d, 2H), 7.70(d, 2H), 7.42(m, 1H), 7.15(m,



2H), 7.00(s, 2H), 6.35(s, 2H); MS(ESI)m/z: 410



(M+H+), 432(M+Na+)


68
4-[[5-amino-1-[(2,6-difluorophenyl)sulfonyl]-1H-1,2,4-
2,6-difluorobenzenesul-



triazol-3-yl]amino]-benzenesulfonamide
fonyl chloride in



1H NMR(300MHz, (CD3)2CO) δ 8.80(s, 1H), 7.85(m,
anhydrous pyridine



1H), 7.75(d, 2H), 7.65(d, 2H), 7.30(t, 2H), 6.95(s,



2H), 6.35(s, 2H); MS(ESI)m/z: 431(M+H+), 453



(M+Na+)


69
4-[[5-amino-1-(2-chloro-6-fluoro-3-methylbenzoyl)-1H-
2-chloro-6-fluoro-3-



1,2,4-triazol-3-yl]amino]-benzenesulfonamide
methylbenzoyl



1H NMR(300MHz, (CD3)2SO) δ 9.85(s, 1H), 8.05(s,
chloride in



2H), 7.64-7.55(m, 3H), 7.45-7.35(m, 3H), 7.10(s, 2H),
anhydrous pyridine



2.38(s, 3H); MS(ESI)m/z: 425(M+H+), 447(M+Na+)


70
4-[[5-amino-1-(2-chloro-6-fluorobenzoyl)-1H-1,2,4-
2-chloro-6-fluoro



triazol-3-yl]amino]-benzenesulfonamide
benzoyl chloride in



1H NMR(300MHz, (CD3)2SO) δ 9.87(s, 1H), 8.05
anhydrous pyridine



(s, 2H), 7.68-7.63(m, 1H), 7.57-7.50(m, 3H), 7.48-7.42



(m, 3H), 7.09(s, 2H); MS(ESI)m/z: 411(M+H+), 433(M+Na+)


78
4-[[5-amino-1-(3-chloro-2,6-difluorobenzoyl)-1H-1,2,4-
3-chloro-2,6-



triazol-3-yl]amino]-benzenesulfonamide
difluorobenzoic



1H NMR(300MHz, (CD3)2SO) δ 9.89(s, 1H), 8.07(s,
acid, mediated by



2H), 8.00-7.92(m, 1H), 7.59(d, 2H), 7.49-7.44(m, 3H),
DIC/HOBt in



7.12(s, 2H); MS(ESI)m/z: 429(M+H+)
anhydrous DMF


122
4-[[3-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-5-
2,6-difiuorobenzoyl



yl]amino]-benzenesulfonamide(minor regioisomer of Cpd 1)
chloride in



1H NMR(300MHz, CD3CN) δ 9.90(s, 1H), 7.90(q, 4H), 7.60(m, 1H),
anhydrous pyridine



7.15(t, 2H), 5.62(s, 2H), 4.85(s, 2H); MS(ESI)m/z: 395



(M+H+), 417(M+Na+)


123
4-[[3-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-1,2,4-
2,6-difluorobenzoyl



triazol-5-yl]amino]-benzenesulfonamide
chloride in



(minor regioisomer of Cpd 2) 1H NMR(300MHz,
anhydrous pyridine



((CD3)2SO) δ 10.0(s, 1H), 8.00(d, 2H), 7.78(d, 2H),



7.50(m, 1H), 7.20(s, 2H), 7.15(t, 2H), 6.25(s, 2H),



2.28(s, 3H); MS(ESI)m/z: 409(M+H+), 431(M+Na+)


128
3-amino-5-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-
—



difluorophenyl)-1H-1,2,4-triazole-1-carbothioamide



(minor regioisomer of Cpd 66) 1H NMR(300MHz,



(CD3)2CO) δ 12.10(s, 1H), 10.28(s, 1H), 7.85(m, 4H),



7.45(m, 1H), 7.20(m, 2H), 6.45(s, 2H), 5.75(s, 2H);



MS(ESI)m/z: 426(M+H+), 448(M+Na+)









Example 2
1-(2,6-difluorobenzoyl)-N3-[4-(1-piperidinylsulfonyl)phenyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 13)
Using the procedure for Example 1, 1-amidino-3,5-dimethylpyrazole nitrate Compound 1C was reacted with 1-(4-isothiocyanatophenylsulfonyl)piperidine Compound 2B to produce Compound 2C. 1H NMR (300 MHz, CD3CN) δ 10.75 (s, br, 1H), 8.40 (s, br, 1H), 7.95 (s, br, 1H), 7.55 (q, 4H), 5.95 (s, 1H), 3.00 (m, 4H), 2.25 (s, 6H), 1.68 (m, 4H), 1.45 (m, 2H); MS (ESI) m/z: 421 (M+H+). Compound 2C was then reacted with hydrazine to produce Compound 2D. 1H NMR (300 MHz, CD3CN) δ 10.75 (s, br, 1H), 7.65 (s, br, 1H), 7.55 (q, 4H), 5.85 (s, br, 2H), 2.82 (m, 4H), 1.55 (m, 4H), 1.32 (m, 2H); MS (ESI) m/z: 323 (M+H+). Compound 2D was acylated with 2,6-difluoro-3-methylbenzoyl chloride Compound 1F in anhydrous pyridine to produce Compound 13 (85% yield). 1H NMR (300 MHz, CDCl3) δ 7.60-7.50 (m, 3H), 7.42 (d, 2H), 7.18 (t, 2H), 6.98 (s, br, 1H), 6.55 (s, br, 2H), 2.98 (m, 4H), 1.65 (m, 4H), 1.42 (m, 2H); MS (ESI) m/z: 363 (M+H+), 485 (M+Na+).







Using the procedure for Example 3, the following compounds were prepared by acylation of the intermediate Compound 2D using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l







23
N3-[4-(1-piperidinylsulfonyl)phenyl]-1-(2-
thiophene-2-



thienylcarbonyl)-1H-1,2,4-triazole-3,5-diamine
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 10.02(s, br, 1H), 8.40
mediated by



(dd, 1H), 8.18(dd, 1H), 7.92(s, br, 2H), 7.88(d, 2H),
DIC/HOBt in DMF



7.58(d, 2H), 7.32(t, 1H), 2.88(m, 4H), 1.55(m, 4H),



1.35(m, 2H); MS(ESI)m/z: 433(M+H+), 455(M+Na+)


24
1-[(3-methyl-2-thienyl)carbonyl]-N3-[4-(1-
3-methylthiophene-



piperidinylsulfonyl)phenyl]-1H-1,2,4-triazole-3,5-
2-carboxylic acid



diamine
mediated by



1H NMR(300MHz, (CD3)2SO) δ 10.02(s, br, 1H), 8.02
DIC/HOBt in DMF



(d, 1H), 7.95-7.80(m, 4H), 7.68(d, 2H), 7.18(d, 1H),



2.88(m, 4H), 2.68(s, 3H), 1.55(m, 4H), 1.35(m, 2H);



MS(ESI)m/z: 447(M+H+), 469(M+Na+)









Example 3
4-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide  (Cpd 32)
Hydrazine monohydrate (0.97 mL, 1.019 mol) and potassium hydroxide (1.12 g, 20 mmol) were added to a solution of 5-acetyl-thiophene-2-carboxylic acid (1.70 g, 10 mmol) in diethylene glycol (20 mL) and water (1 mL). The reaction mixture was stirred in an oil bath at 110° C. for 16 hrs, cooled to rt, acidified with 2N HCl and then extracted with methylene chloride (4×50 mL). Organic layers were combined, dried, concentrated and subjected to chromatography separation on silica gel (eluted with 10% methanol/methylene chloride) to produce 3-ethylthiophene-2-carboxylic acid Compound 3A as a pale yellow solid (1.161 g, 74%). 1H NMR (300 MHz, CD3OD) δ 7.59 (d, J 3.7, 1H), 6.87 (d, J 3.7, 1H), 2.88 (q, J 7.5, 1H), 1.32 (t, J 7.5, 3H); MS (ESI) m/z: 155 (M−H+). Using the procedure of Example 1, Compound 1E was acylated with Compound 3A mediated by DIC/HOBt in anhydrous DMF to produce Compound 32 (59% yield). 1H NMR (300 MHz, (CD3)2CO) δ 8.90 (s, br, 1H), 8.25 (d, 1H), 7.88 (q, 4H), 7.45 (s, br, 2H), 7.10 (d, 1H) 6.45 (s, br, 2H), 3.05 (q, 2H), 1.42 (t, 3H); MS (ESI) m/z: 393 (M+H+), 415 (M+Na+).




Example 4
4-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide (Cpd 33)
2.2 equivalents of 2.0 M LDA solution in heptane/THF/ethylbenzene (0.97 mL, 1.019 mol) was added to a solution of 3-methylthiophene-2-carboxylic acid (1.42 g, 10 mmol) in anhydrous THF (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hr; and then methyl iodide (1.4 mL, 22 mmol) was added. The resulting mixture was stirred at 0° C. for an additional 2 hr, acidified with 2N HCl and extracted with methylene chloride (4×50 mL). The organic layers were then combined, concentrated and separated via HPLC to give 3,5-dimethylthiophene-2-carboxylic acid Compound 4A as a white powder. 1H NMR (300 MHz, CD3OD) δ 6.72 (s, 1H), 2.43 (s, 3H), 2.46 (s, 3H); MS (ESI) m/z: 155 (M−H+). Using the procedure of Example 1, Compound 1E was acylated with Compound 4A mediated by DIC/HOBt in anhydrous DMF to produce Compound 33 (73% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.88 (s, br, 1H), 7.85 (s, br, 2H), 7.78 (q, 4H), 7.18 (s, br, 2H), 6.92 (s, 1H), 2.58 (s, 3H), 2.55 (s, 3H); MS (ESI) m/z: 393 (M+H+), 415 (M+Na+).




Example 5
4-[[5-amino-1-[2,6-difluoro-3-(1-hydroxyethyl)benzoyl]-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide (Cpd 58)
2′,4′-difluoroacetophenone (5 g, 32 mmol) was reacted with sodium borohydride (1.21 g) in THF (20 mL) and methanol (10 mL) for 1 hr. The resultant mixture was evaporated to dryness and partitioned between methylene chloride and water. The organic layer was separated, dried, and evaporated to give 1-(2′,4′-difluorophenyl)-ethanol as a colorless oil (4.86 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.48 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 5.15 (q, 1H), 2.0 (s, 1H), 1.5 (d, 3H). 1-(2′,4′-difluorophenyl)-ethanol (5.384 g, 34 mmol), t-butyltrimethylsilyl chloride (6.148 g, 40.8 mmol) and imidazole (5.567 g, 81.8 mmol) in DMF (60 mL) were combined and stirred at rt overnight. The resultant mixture was evaporated to dryness in vacuo, and then the residue was partitioned between methylene chloride and water. The organic layer was separated, dried and evaporated to give 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether as a white solid (6.88 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.45 (q, 1H), 6.75 (m, 1H), 6.62 (m, 1H), 5.05 (q, 1H), 1.32 (d, 3H), 0.88 (s, 9H), 0.05 and 0.01 (each s, each 3H). A 1.6 M solution of n-butyl lithium in hexane (3.75 mL, 6 mmol) was added dropwise to a solution of 1-(2′,4′-difluorophenyl)-ethyl t-butyltrimethylsilyl ether (1.362 g, 5 mmol) in THF (60 mL) at −50° C. and was stirred at the same temperature for 3 h. The reaction mixture was poured to dry ice; and then was evaporated to dryness. The residue was partitioned between methylene chloride and water, acidified with acetic acid. The organic layer was separated, dried, and evaporated to give 2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoic acid Compound 5A as white solid (1.57 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.70 (q, 1H), 7.00 (t, 1H), 6.00 (br, 1H), 5.15 (q, 1H), 1.40 (d, 3H), 0.90 (s, 9H), 0.12 and 0.05 (each s, each 3H).
Using the procedure of Example 1, Compound 1E was acylated with Compound 5A mediated by DIC/HOBt in anhydrous DMF to provide 4-[[5-amino-1-(2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide Compound 5B (46% yield). 1H NMR (300 MHz, CDCl3) δ 7.72 (m, 3H), 7.38 (d, 2H), 7.02 (t, 1H), 6.80 (s, 1H), 6.45 (s, 2H), 5.15 (q, 1H), 4.68 (s, 2H), 1.15 (d, 3H), 0.92 (s, 9H), 0.10 (s, 3H), 0.02 (s, 3H); MS (ESI) m/z: 553 (M+H+), 575 (M+Na+). 4-[[5-amino-2-(2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoyl)-2H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide (a minor regioisomer) was also isolated from the reaction mixture (192 mg, 34%). 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (d, 2H), 7.82 (d, 2H), 7.70 (q, 1H), 7.02 (t, 1H), 5.18 (q, 1H), 4.82 (s, 2H), 4.32 (s, 2H), 1.42 (d, 3H), 0.92 (s, 9H), 0.10 (s, 3H), 0.02 (s, 3H); MS (ESI) m/z: 553 (M+H+), 575 (M+Na+).
0.7 mL of 1.0 M TBAF solution in THF was added to a solution of 4-[[5-amino-1-(2,6-difluoro-3-(1-t-butyltrimethylsilyloxyethyl)-benzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonamide Compound 5B (193 mg, 0.35 mol) in THF (10 mL). The reaction solution was stirred at rt for 1 hr and evaporated to dryness. The resultant residue was then subjected to column chromatography on silica gel with 20% methanol/methylene chloride to give the product Compound 58 as a white foam (90 mg, 59%). 1H NMR (300 MHz, (CD3)2SO) δ 9.85 (s, 1H), 8.00 (s, 2H), 7.75 (m, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.30 (t, 1H), 7.10 (s, 2H), 6.80 (s, 1H), 5.55 (d, 1H), 5.00 (m, 1H), 1.38 (d, 3H); MS (ESI) m/z: 421 (M+H+−H2O), 439 (M+H+), 461 (M+Na+).







Example 6
4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-benzenesulfonic acid (Cpd 59)
The sodium salt of 4-sulfophenyl isothiocyanate Compound 6B, (prepared using the procedure of Example 1) was reacted with 1-amidino-3,5-dimethylpyrazole nitrate Compound 1C to produce Compound 6C which was reacted with hydrazine to produce Compound 6D. 1H NMR (300 MHz, (CD3)2SO) δ 11.1 (s, 1H), 8.75 (s, 1H), 7.3 (m, 4H), 5.85 (s, 2H); MS (ESI) m/z: 256 (M+H+). Using the procedure of Example 1, Compound 6D was acylated with 2,6-difluorobenzoyl chloride Compound 1F in anhydrous pyridine to produce compound 59 (4% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.35 (s, 1H), 7.95 (s, 2H), 7.82 (m, 2H), 7.45-7.25 (m, 5H); MS (ESI) m/z 396 (M+H+).







Using the procedure for Example 6, the following compounds were prepared by acylation of the intermediate Compound 6D using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l







60
4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-1,2,4-
2,6-difluoro-3-



triazol-3-yl]amino]-benzenesulfonic acid
methylbenzoyl



1H NMR(300MHz, CD3OD) δ 7.62(d, 2H), 7.50(m,
chloride in



1H), 7.38(d, 2H), 7.05(m, 1H), 2.30(s, 3H); MS(ESI)
anhydrous pyridine



m/z: 410(M+H+)









Example 7
1-(2,6-Difluorobenzoyl)-N3-phenyl-1H-1,2,4-triazole-3,5-diamine (Cpd 61)
3-Anilino-5-amino-1,2,4-triazole Compound 7A (prepared using the procedure of Example 1) was acylated with 2,6-difluorolbenzoyl chloride Compound 1F in anhydrous pyridine to produce Compound 61 as a white solid (61% yield). 1H NMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 7.45 (m, 1H), 7.30-7.15 (m, 4H), 7.05-6.85 (m, 5H), 6.70 (s, 2H); MS (ESI) m/z: 316 (M+H+), 338 (M+Na+).




Using the procedure for Example 7, the following compounds were prepared by acylation of Compound 7A using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l

















62
1-benzoyl-N3-phenyl-1H-1,2,4-triazole-3,5-diamine
benzoyl chloride in



1H NMR(300MHz, CDCl3) δ 8.30(s, 2H), 7.65-7.40
anhydrous pyridine



(m, 5H), 7.28(d, 2H), 7.00(t, 1H), 6.80(s, 1H), 6.70(s,



2H); MS(ESI)m/z: 280(M+H+), 302(M+Na+)


65
5-amino-N-phenyl-3-(phenylamino)-1H-1,2,4-
phenyl isocyanate



triazole-1-carboxamide
in anhydrous DMF



1H NMR(300MHz, (CD3)2CO) δ 9.20(s, 1H), 8.20(s,



1H), 7.70(m, 4H), 7.35(t, 2H), 7.25(t, 2H), 7.15(t,



1H), 7.98(s, 2H), 6.88(t, 1H); MS(ESI)m/z: 295



(M+H+), 317(M+Na+)


124
1-(2,6-difluorobenzoyl)-N5-phenyl-1H-1,2,4-
—



triazole-3,5-diamine



(minor regioisomer of Cpd 61) 1H NMR(300MHz,



CDCl3) δ 9.80(s, 1H), 7.65(d, 2H), 7.60-7.32(m, 3H),



7.25-7.00(m, 3H), 4.40(s, 2H); MS(ESI)m/z: 316



(M+H+), 338(M+Na+)


125
1-benzoyl-N5-phenyl-1H-1,2,4-triazole-3,5-diamine
—



(minor regioisomer of Cpd 62) 1H NMR(300MHz,



CDCl3) δ 10.20(s, 1H), 8.18(d, 2H), 7.72-7.30(m, 7H),



7.15(t, 1H), 4.30(s, 2H); MS(ESI)m/z: 280(M+H+),



302(M+Na+)









Example 8
N3-(3-chlorophenyl)-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazole-3,5-diamine (Cpd 63)
3-(3-Chloroanilino)-5-amino-1,2,4-triazole Compound 8A (prepared using the procedure of Example 1) was acylated with 2,6-difluorobenzoyl chloride Compound 1F in anhydrous pyridine to produce Compound 63 as a pale yellow solid (66% yield). 1H NMR (300 MHz, CDCl3) δ 7.6-7.50 (m, 2H), 7.15-6.80 (m, 6H), 6.60 (s, 2H); MS (ESI) m/z: 350 (M+H+), 372 (M+Na+).




Using the procedure for Example 8, the following compounds were prepared by acylation of the intermediate Compound 8A using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l

















64
1-benzoyl-N3-(3-chlorophenyl)-1H-1,2,4-triazole-3,5-
benzoyl chloride in



diamine
anhydrous pyridine



1H NMR(300MHz, (CD3)2CO) δ 8.58(s, 1H), 8.30(d,



2H), 8.00(m, 1H), 7.75-7.25(m, 6H), 6.90(d, 1H);



MS(ESI)m/z: 314(M+H+), 336(M+Na+)


126
N5-(3-chlorophenyl)-1-(2,6-difluorobenzoyl)-1H-1,2,4-



triazole-3,5-diamine(minor regioisomer of Cpd 63)



1H NMR(300MHz, CDCl3) δ 9.90(s, 1H), 7.90(s, 1H),



7.58-6.95(m, 7H), 4.35(s, 2H); MS(ESI)m/z:



350(M+H+), 472(M+Na+)


127
1-benzoyl-N5-(3-chlorophenyl)-1H-1,2,4-triazole-3,5-



diamine (minor regioisomer of Cpd 64)



1H NMR(300MHz, (CD3)2CO) δ 10.30(s, 1H),



8.20(d, 2H), 8.15(m, 1H), 7.70-7.60(m, 2H),



7.55(t, 2H), 7.35(t, 1H), 7.10(d, 1H), 5.60(s, 2H);



MS(ESI)m/z: 314(M+H+), 336(M+Na+)









Example 9
1-(2,6-difluorobenzoyl)-N3-[4-(4-methyl-1-piperazinyl)phenyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 71)
4-(4-Methylpiperazino)-phenyl isothiocyanate was reacted with 1 equivalent of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 1.1 equivalents of potassium t-butoxide in DMSO at 55° C. for 4 hours. 10 equivalents of hydrazine were added and stirred at 55° C. for 4 hrs. Subsequent concentration, dissolution in methanol, filtering of impurities and concentration gave 3-(4-methylpiperazino)-anilino-5-amino-1,2,4-triazole Compound 9A (87% yield). 1H NMR (400 MHz, (CD3)2SO) δ 9.05 (s, 1H), 8.60 (s, 1H), 7.35 (d, 2H), 6.77 (d, 2H), 5.70 (s, 2H), 2.97 (m, 4H), 2.48 (m, 4H), 2.23 (s, 3H); MS (ESI) m/z: 274 (M+H+). 3-(4-methylpiperazino)-anilino-5-amino-1,2,4-triazole Compound 9A was acylated with 2,6-difluoro benzoyl chloride Compound 1F in anhydrous pyridine to produce compound 71 (30% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.07 (s, 1H), 7.88 (s, 1H), 7.72-7.66 (m, 1H), 7.32 (t, 1H), 7.25-7.17 (m, 2H), 6.97-6.92 (m, 1H), 6.71 (d, 1H), 3.39-3.35 (m, 2H), 3.17 (s, 3H), 3.00-2.97 (m, 4H), 2.51-2.46 (m, 4H); MS (ESI) m/z: 414 (M+H+).




Using the procedure for Example 9, the following compounds were prepared by acylation of the intermediate Compound 9A using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l







72
1-(2,6-difluoro-3-methylbenzoyl)-N3-[4-(4-methyl-
2,6-difluoro-3-methyl



1-piperazinyl)phenyl]-1H-1,2,4-triazole-3,5-diamine
benzoyl chloride in



1H NMR(300MHz, (CD3)2SO) δ 9.05(s, 1H), 7.87
anhydrous pyridine



(s, 1H), 7.59-7.51(m, 1H), 7.24-7.18(m, 2H), 6.72



(d, 2H), 3.35(s, 2H), 2.99-2.96(m, 4H), 2.45-2.42



(m, 4H), 2.28(s, 3H); MS(ESI)m/z: 428(M+H+)


73
N3-[4-(4-methyl-1-piperazinyl)phenyl]-1-[(3-methyl-
3-methyl-2-thiophene



2-thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine
carboxylic acid,



1H NMR(300MHz, (CD3)2SO) δ 9.13(s, m), 7.77
mediated by DIC/HOBt



(s, 1H), 7.58-7.55(m, 2H), 7.38-7.26(m, 1H), 6.92
in anhydrous DMF



(d, 2H), 3.17(s, 3H), 3.09-3.07(m, 4H), 2.62(s,



4H), 2.35(s, 3H); MS(ESI)m/z: 398(M+H+)


74
1-[(3,5-dimethyl-2-thienyl)carbonyl]-N3-[4-(4-
3,5-dimethyl-2-



methyl-1-piperazinyl)phenyl]-1H-1,2,4-triazole-3,5-
thiophene carboxylic



diamine
acid, mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.11(s, 1H), 7.73
DIC/HOBt in



(s, 2H), 7.59-7.54(m, 2H), 7.38-7.26(m, 1H), 6.94
anhydrous DMF



(d, 2H), 3.16-3.13(m, 4H), 2.80-2.78(m, 4H), 2.56



(s, 3H), 2.53(s, 3H), 2.46(s, 3H); MS(ESI)m/z:



412(M+H+)


75
1-[(5-ethyl-2-thienyl)carbonyl]-N3-[4-(4-methyl-1-
5-ethyl-2-thiophene



piperazinyl)phenyl]-1H-1,2,4-triazole-3,5-diamine
carboxylic acid,



1H NMR(300MHz, (CD3)2SO) δ 9.17(s, 1H), 7.78
mediated by DIC/HOBt



(s, 1H), 7.51(d, 2H), 7.35-7.24(m, 3H), 7.08(d,
in anhydrous DMF



2H), 3.14-3.12(m, 4H), 2.96(q, 2H), 2.76-2.73(m,



4H), 2.43(s, 3H), 1.34(t, 3H); MS(ESI)m/z: 412



(M+H+)









Example 10
4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-N-ethyl-benzenesulfonamide (Cpd 76)
Compound 1 (100 mg, 0.254 mmol) was reacted with 1.2 equivalents of ethyl trifluoromethanesulfonate (Et-TFMS) (40 μL, 0.305 mmol), and 1.5 equivalents of potassium t-butoxide (K-t-BO) (0.38 mmol, 381 μL of a 1.0 M THF solution) in THF (5 mL) at 50° C., stirring for 16 hours. Purification of the reaction mixture by column chromatography in 10% methanol/methylene chloride gave the product Compound 76 (27.1 mg, 25% yield). 1H NMR (400 MHz, (CD3)2SO) δ 9.87 (s, 1H), 8.00 (s, 2H), 7.76-7.68 (m, 1H), 7.55-7.48 (m, 4H), 7.34 (t, 2H), 7.22 (t, 1H), 2.73-2.67 (m, 2H), 0.94 (t, 3H); MS (ESI) m/z: 423 (M+H+)




Example 12
N3-methyl-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 79)
Using the procedure of Example 1,3,5-diamino-1,2,4-triazole Compound 12A was acylated with 3-methylthiophene-2-carboxylic acid Compound 12B mediated by DIC/HOBt in anhydrous DMF to produce Compound 41 (72% yield). 1H NMR (300 MHz, (CD3)2SO) δ 7.88 (d, J=4.5, 1H), 7.59 (s, 2H), 7.05 (d, J=4.8, 1H), 5.78 (s, 2H), 2.55 (s, 3H); MS (ESI) m/z: 224.1 (M+H+), 245.9 (M+Na+). Compound 41 (0.45 mmol, 100 mg) was reacted with 3 equivalents of iodomethane (1.34 mmol, 84 uL) and 1.1 equivalents of potassium t-butoxide (0.49 mmol, 493 uL of 1.0 M THF solution) in THF (5 mL), stirring 16 hours at 25° C. Purification by column chromatography (eluting with 10% methanol/dichloromethane) gave the product Compound 79 (7.7 mg, 7% yield). 1H NMR (400 MHz, (CD3)2SO) δ 9.80 (s, 1H), 7.60 (d, 1H), 6.96 (d, 1H), 6.17 (s, 2H), 3.47 (s, 3H), 2.40 (s, 3H); MS (ESI) m/z: 238 (M+H+), 260 (M+Na+).




Example 13
4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-N-methyl-benzenesulfonamide (Cpd 80)
t-BuOK (23.1 mL, 1.0 M solution in t-BuOH, 23.1 mmol) was added dropwise to a solution of 4-isothiocyanato-N-methylbenzenesulfonamide Compound 13B (prepared using the procedure of Example 1) (4.8 g, 21.0 mmol) and 2,5-dimethylpyrazole-1-carboximidine nitrate Compound 1C (4.2 g, 21.0 mmol) in DMF (20 mL). The mixture was heated to 60° C. for 2 h, then poured into ice. The precipitate was collected by filtration and washed with water, then air dried to afford 4-[3-(3,5-dimethylpyrazol-1-yliminomethyl)thioureido]-N-methylbenzenesulfonamide Compound 13C as a yellow solid (7.3 g, 95% yield). 1H NMR (300 MHz, (CD3)2SO) δ 8.01 (s, 1H), 7.71 (m, 4H), 6.15 (s, 1H), 2.40 (s, 3H), 2.22 (s, 6H); MS (ESI) m/z: 367 (M+H+). Hydrazine (3.3 g, 110.0 mmol) at 0° C. was added to a suspension of 4-[3-(3,5-dimethylpyrazol-1-yliminomethyl)thioureido]-N-methylbenzenesulfonamide Compound 13C (2.0 g, 5.5 mmol) in THF (20 mL). The mixture was heated to 60° C. for 2 hrs, then poured into ice. The precipitate was collected by filtration, washed with water and CH2Cl2, then air dried to produce Compound 13D as a white solid (1.3 g, 87% yield). 1H NMR (300 MHz, (CD3)2SO) δ 11.36 (s, 1H), 9.31 (s, 1H), 7.63 (q, 4H), 7.09 (q, 1H), 6.05 (s, 2H), 2.39 (d, 3H); MS (ESI) m/z: 269 (M+H+). Using the procedure of Example 1, Compound 13D was acylated with 2,6-difluorobenzoyl chloride Compound 1F in anhydrous pyridine to produce Compound 80 (80% yield). 1H NMR (300 MHz, CD3OD) δ 7.64 (m, 1H), 7.63 (d, 2H), 7.53 (d, 2H), 7.15 (t, 2H), 2.43 (s, 3H); MS (ESI) m/z: 409 (M+H+).







Using the procedure for Example 13, the following compounds were prepared by acylation of the intermediate Compound 13D using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l







81
4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-
2,6-difluoro-3-



1,2,4-triazol-3-yl]amino]-N-methyl-
methylbenzoyl



benzenesulfonamide
chloride in



1H NMR(300MHz, CD3OD) δ 7.55(d, 2H), 7.48-
anhydrous



7.44(m, 1H), 7.46(d, 2H), 2.42(s, 3H), 2.25(s, 3H);
pyridine



MS(ESI)m/z: 423(M+H+)


82
4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-
3-methylthiophene-2-



1,2,4-triazol-3-yl]amino]-N-methyl-
carboxylic acid



benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.92(s, 1H), 8.03
DIC/HOBt in DMF



(d, 1H), 7.81(d, 2H), 7.69(d, 2H), 7.14(m, 2H), 2.62



(s, 3H), 2.55(s, 3H); MS(ESI)m/z: 393(M+H+)


83
4-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-
3,5-



1H-1,2,4-triazol-3-yl]amino]-N-methyl-
dimethylthiophene-2-



benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.89(s, 1H), 8.09
mediated by



(d, 1H), 7.74(d, 2H), 7.63(d, 2H), 7.02(d, 1H), 2.94
DIC/HOBt in DMF



(q, 2H), 2.32(s, 3H), 1.33(t, 3H); MS(ESI)m/z: 407



(M+H+)


84
4-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-
5-ethylthiophene-2-



1,2,4-triazol-3-yl]amino]-N-methyl-
carboxylic acid



benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.65(s, 1H), 7.64
DIC/HOBt in DMF



(d, 1H), 7.50(d, 2H), 7.69(d, 2H), 6.66(s, 1H), 2.36



(s, 3H), 2.34(s, 3H), 2.12(s, 3H); MS(ESI)m/z: 407



(M+H+)









Example 14
1-[(3,5-dimethyl-2-thienyl)carbonyl]-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 85)
4-Isothiocyanato-N,N-dimethylbenzenesulfonamide Compound 14B (prepared using the procedure of Example 1) (1.8 g, 7.4 mmol) was reacted with 2,5-dimethylpyrazole-1-carboximidine nitrate Compound 1C (1.5 g, 7.4 mmol) and t-BuOK (7.4 mL, 1.0 M solu in t-BuOH, 7.4 mmol) to produce 4-[3-(3,5-dimethylpyrazol-1-yliminomethyl)thioureido]-N,N-dimethylbenzenesulfonamide Compound 14C as a yellow solid (2.5 g, 89% yield). 1H NMR (300 MHz, (CD3)2SO) δ 10.05 (s, 1H), 8.91 (s, 1H), 7.67 (m, 4H), 6.15 (s, 1H), 2.57 (s, 6H), 2.18 (s, 6H); MS(ESI) m/z: 381 (M+H+). Compound 14C (2.5 g, 6.6 mmol) was reacted with hydrazine (4.2 g, 132.0 mmol) to produce 1.7 g (90%) of Compound 14D as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 9.47 (s, 1H), 7.81 (d, 2H), 7.75 (d, 2H), 6.10 (s, 1H), 2.67 (s, 6H); MS (ESI) m/z: 283 (M+H+). Compound 14D was acylated with 3,5-dimethylthiophene-2-carboxylic acid Compound 1F mediated by DIC/HOBt in DMF to produce Compound 85 (52% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.93 (s, 1H), 7.88 (d, 2H), 7.85 (s, 1H), 7.65 (d, 2H), 6.90 (s, 1H), 2.60 (s, 6H), 2.56 (s, 3H), 2.54 (s, 3H); MS (ESI) m/z: 421 (M+H+).







Using the procedure for Example 14, the following compounds were prepared by acylation of the intermediate Compound 14D using the indicated starting material in place of Compound 14E and reagent(s):












Cpd
Name/Data
Starting Mat'l







86
4-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-
5-ethylthiophene-2-



triazol-3-yl]amino]-N,N-dimethyl-benzenesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 10.03(s, 1H), 8.13(d,
mediated by



1H), 7.91(s, 1H), 7.86(d, 2H), 7.66(d, 2H), 7.10(d,
DIC/HOBt in DMF



2H), 2.95(q, 2H), 2.56(s, 6H), 1.32(t, 3H); MS(ESI)



m/z: 421(M+H+)


87
4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-
3-methylthiophene-



triazol-3-yl]amino]-N,N-dimethyl-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 10.01(s, 1H), 8.05(d,
mediated by



1H), 7.86(d, 3H), 7.69(d, 2H), 7.13(d, 1H), 2.63(s,
DIC/HOBt in DMF



3H), 2.55(s, 6H); MS(ESI)m/z: 407(M+H+)


88
4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-1,2,4-
2,6-difluoro-3-



triazol-3-yl]amino]-N,N-dimethyl-benzenesulfonamide
methylbenzoyl



1H NMR(300MHz, CDCl3) δ 7.79(s, 1H), 7.55(d,
chloride in



2H), 7.40(d, 2H), 7.35(m, 1H), 6.95(s, 2H), 6.92(m,
anhydrous pyridine



1H), 2.65(s, 6H), 2.27(s, 3H); MS(ESI)m/z: 437



(M+H+)


89
4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-
2,6-difluorobenzoyl



yl]amino]-N,N-dimethyl-benzenesulfonamide
chloride in



1H NMR(300MHz, (CD3)2SO) δ 9.74(s, 1H), 7.77(s,
anhydrous pyridine



2H), 7.50-7.40(m, 1H), 7.30-7.20(m, 4H), 7.10(m,



2H), 2.25(s, 6H); MS(ESI)m/z: 423(M+H+)









Example 15
1-[(5-ethyl-2-thienyl)carbonyl]-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 90)
Using the published procedure (Webb et al., J. Heterocyclic Chem., 1987, 24, 275-278), 4-imidazol-1-yl-aniline (0.50 g, 3.14 mmol), diphenyl cyanocarbonimidate (0.75 g, 3.14 mmol) and THF (30 mL) were combined in a nitrogen purged flask. The mixture was refluxed for 2 hrs, then cooled down to ice temperature and hydrazine (31.4 mL, 1.0 M solution in THF, 31.4 mmol) was added dropwise. The mixture was then refluxed for 2 hrs. The precipitate was filtered and collected, washed with ethyl acetate and air dried to produce the intermediate Compound 15A (0.60 g, 79%). 1H NMR (300 MHz, (CD3)2SO) δ 11.15 (s, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.57 (s, 1H), 7.48 (d, 2H), 7.35 (d, 2H), 7.04 (s, 1H), 5.85 (s, 2H); MS (ESI) m/z: 242 (M+H+). Using the procedure of Example 1, Compound 15A was acylated with 5-ethylthiophene-2-carboxylic acid Compound 15B mediated by DIC/HOBt in DMF to provide Compound 90 (59% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.63 (s, 1H), 8.14 (d, 1H), 7.85-7.70 (m, 7H), 7.56-7.53 (m, 2H), 7.07 (d, 2H), 2.95 (q, 2H), 1.33 (t, 3H); MS (ESI) m/z: 380 (M+H+).




Using the procedure for Example 15, the following compounds were prepared by acylation of the intermediate Compound 15A using the indicated starting material in place of Compound 15B and reagent(s):












Cpd
Name/Data
Starting Mat'l







91
N3-[4-(1H-imidazol-1-yl)phenyl]-1-[(3-methyl-2-
3-methylthiophene-



thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.62(s, 1H), 7.97(d,
mediated by



1H), 7.92(s, 1H), 7.82-7.72(m, 5H), 7.56-7.53(m, 2H),
DIC/HOBt in DMF



7.11(d, 1H), 2.61(s, 3H); MS(ESI)m/z: 366(M+H+)


92
1-[(3,5-dimemyl-2-thienyl)carbonyl]-N3-[4-(1H-
3,5-dimethylthiophene-



imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.51(s, 1H), 8.15(s,
mediated by



1H), 7.75(m, 4H), 7.61(s, 1H), 7.53(d, 2H), 7.05(s,
DIC/HOBt in DMF



1H), 6.85(s, 1H), 2.53(s, 3H), 2.52(s, 3H); MS(ESI)



m/z: 380(M+H+)


93
1-(2,6-difluorobenzoyl)-N3-[4-(1H-imidazol-1-
2,6-difluorobenzoyl



yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
chloride in



1H NMR(300MHz, (CD3)2SO) δ 9.52(s, 1H), 8.06(s,
anhydrous pyridine



1H), 7.93(s, 1H), 7.70(p, 1H), 7.57(s, 1H), 7.45(d,



2H), 7.36(d, 2H), 7.30(t, 2H), 7.01(s, 1H); MS(ESI)



m/z: 382(M+H+)


94
1-(2,6-difluoro-3-methylbenzoyl)-N3-[4-(1H-imidazol-1-
2,6-difluoro-3-



yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
methylbenzoyl



1H NMR(300MHz, (CD3)2SO) δ 9.52(s, 1H), 8.08(s,
chloride in



1H), 7.93(s, 1H), 7.57(s, 1H), 7.53(m, 1H), 7.42(d,
anhydrous pyridine



2H), 7.35(d, 2H), 7.18(t, 1H), 7.02(s, 1H), 2.25(s,



3H); MS(ESI)m/z: 396(M+H+)









Example 16
1-(2,6-difluoro-3-methylbenzoyl)-N3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 95)
Using the procedure of Example 15, 4-(1,2,4-triazol-1-yl)-aniline (0.35 g, 2.18 mmol), diphenyl cyanocarbonimidate (0.52 g, 2.18 mmol) and hydrazine (21.8 mL, 1.0 M solution in THF, 21.8 mmol) were reacted to produce Compound 16D (0.40 g, 78% yield) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 11.21 (s, 1H), 9.06 (s, 1H), 8.92 (s, 1H), 8.13 (s, 1H), 7.61 (m 4H), 5.87 (s, 2H); MS (ESI) m/z: 243 (M+H+). Using the procedure of Example 1, Compound 16D was acylated with 2,6-difluoro-3-methylbenzoyl chloride Compound 16B in anhydrous pyridine to produce Compound 95 (51% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.62 (s, 1H), 9.11 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.56 (d, 2H), 7.60-7.50 (q, 1H), 7.45 (d, 2H), 7.16 (t, 1H), 2.25 (s, 3H); MS (ESI) m/z: 397 (M+H+).




Using the procedure for Example 16, the following compounds were prepared by acylation of the intermediate Compound 16A using the indicated starting material in place of Compound 16B and reagent(s):












Cpd
Name/Data
Starting Mat'l







96
1-(2,6-difluorobenzoyl)-N3-[4-(1H-1,2,4-triazol-1-
2,6-difluorobenzoyl



yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
chloride in



1H NMR(300MHz, (CD3)2SO) δ 9.61(s, 1H), 9.05(s,
anhydrous pyridine



1H), 8.07(s, 1H), 7.85(s, 2H), 7.63(p, 1H), 7.53(d,



2H), 7.41(d, 2H), 7.30(t, 2H), 7.29(t, 2H); MS(ESI)



m/z: 383(M+H+)


97
1-[(5-ethyl-2-thienyl)carbonyl]-N3-[4-(1H-1,2,4-triazol-
5-ethylthiophene-2-



1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.72(s, 1H), 9.15(s,
mediated by



1H), 8.17(s, 1H), 8.16(d, 1H), 7.78(s, 2H), 7.77(d,
DIC/HOBt in DMF



2H), 7.72(d, 2H), 7.04(d, 1H), 2.96(q, 2H), 1.33(t,



3H); MS(ESI)m/z: 381(M+H+)


98
1-[(3,5-dimethyl-2-thienyl)carbonyl]-N3-[4-(1H-1,2,4-
3,5-dimethylthiophene-



triazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.67(s, 1H), 9.15(s,
mediated by



1H), 8.18(s, 1H), 7.75(m, 6H), 6.89(s, 1H), 2.52(s,
DIC/HOBt in DMF



3H), 2.51(s, 3H); MS(ESI)m/z: 381(M+H+)


99
1-[(3-methyl-2-thienyl)carbonyl]-N3-[4-(1H-1,2,4-
3-methylthiophene-



triazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.68(s, 1H), 9.13(s,
mediated by



1H), 8.16(s, 1H), 7.99(d, 1H), 7.77(m, 6H), 7.12(d,
DIC/HOBt in DMF



1H); MS(ESI)m/z: 367(M+H+)









Example 17
1-(2,6-difluorobenzoyl)-N3-[4-(4H-1,2,4-triazol-4-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 100)
Using the procedure of Example 15, 4-(1,3,4-triazol-1-yl)-aniline (1.35 g, 8.43 mmol), diphenyl cyanocarbonimidate (2.00 g, 8.43 mmol) and hydrazine (84.3 mL, 1.0 M solution in THF, 84.3 mmol) were reacted to provide Compound 17A (1.10 g, 77% yield) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 8.90 (s, 2H), 7.62 (d, 2H), 7.36 (d, 2H), 5.82 (s, 2H); MS (ESI) m/z: 243 (M+H+). Using the procedure of Example 1, Compound 17A was acylated with 2,6-difluorobenzoyl chloride Compound 1F in anhydrous pyridine to provide Compound 100 (36% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.61 (s, 1H), 8.98 (s, 2H), 7.96 (s, 2H), 7.67 (p, 1H), 7.47 (d, 2H), 7.42 (d, 2H), 7.32 (t, 2H); MS (ESI) m/z: 383 (M+H+).




Using the procedure for Example 17, the following compounds were prepared by acylation of the intermediate Compound 17D using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l







101
1-(2,6-difluoro-3-methylbenzoyl)-N3-[4-(4H-1,2,4-
2,6-difluoro-3-



triazol-4-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
methylbenzoyl



1H NMR(300MHz, (CD3)2SO) δ 9.61(s, 1H), 8.94(s,
chloride in



2H), 7.91(s, 2H), 7.55(q, 1H), 7.43(q, 4H), 7.18(t,
anhydrous pyridine



1H); MS(ESI)m/z: 397(M+H+)


102
1-[(3-methyl-2-thienyl)carbonyl]-N3-[4-(4H-1,2,4-
3-methylthiophene-



triazol-4-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 10.22(s, 1H), 9.04(s,
mediated by



2H), 7.95(m, 3H), 7.67(d, 2H), 7.07(d, 1H), 6.13(s,
DIC/HOBt in DMF



2H); MS(ESI)m/z: 367(M+H+)









Example 18
4-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]-N-[2-(dimethylamino)ethyl]-benzenesulfonamide (Cpd 103)
Using the procedure of Example 15, 4-amino-N-(2-dimethylaminoethyl)-benzenesulfonamide (2.00 g, 8.22 mmol), diphenyl cyanocarbonimidate (2.00 g, 8.22 mmol) and hydrazine (82.3 mL, 1.0 M solution in THF, 82.3 mmol) were reacted to produce Compound 18A (1.35 g, 50% yield) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 9.22 (s, 1H), 8.43 (s, 1H), 7.55 (m, 4H), 7.02 (s, 1H), 5.91 (s, 2H), 2.71 (t, 2H), 2.15 (t, 2H), 2.05 (s, 6H); MS (ESI) m/z: 326 (M+H+). Using the procedure of Example 1, Compound 18A was acylated with 5-ethylthiophene-2-carboxylic acid Compound 15B mediated by DIC/HOBt in DMF to produce Compound 103 (40% yield). 1H NMR (300 MHz, (CD3)2SO) δ 10.02 (s, 1H), 8.13 (d, 1H), 7.88 (s, 1H), 7.75 (d, 2H), 7.71 (d, 2H), 7.07 (d, 1H), 7.01 (s, 2H), 2.95 (q, 2H), 2.75 (t, 2H), 2.20 (t, 2H), 2.04 (s, 6H), 1.35 (t, 3H); MS (ESI) m/z: 464 (M+H+).




Using the procedure for Example 18, the following compounds were prepared by acylation of the intermediate Compound 18A using the indicated starting material in place of Compound 15B and reagent(s):












Cpd
Name/Data
Starting Mat'l







104
4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-
3-methylthiophene-



triazol-3-yl]amino]-N-[2-(dimethylamino)ethyl]-
2-carboxylic acid



benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.89(s, 1H), 8.04(d,
DIC/HOBt in DMF



1H), 7.83(s, 1H), 7.79(d, 2H), 7.71(d, 2H), 7.15(s,



2H), 7.08(d, 1H), 2.76(t, 2H), 2.61(s, 3H), 2.21(t,



2H), 2.07(s, 6H); MS(ESI)m/z: 450(M+H+)


105
4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-1,2,4-
2,6-difluoro-3-



triazol-3-yl]amino]-N-[2-(dimethylamino)ethyl]-
methylbenzoyl



benzenesulfonamide
chloride in



1H NMR(300MHz, CD3OD) δ 7.57(d, 2H), 7.45(m,
anhydrous pyridine



3H), 7.00(t, 1H), 2.86(t, 2H), 2.32(t, 2H), 2.25(s, 3H),



2.11(s, 6H); MS(ESI)m/z: 480(M+H+)


106
4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-
2,6-difluorobenzoyl



yl]amino]-N-[2-(dimethylamino)ethyl]-
chloride in



benzenesulfonamide
anhydrous pyridine



1H NMR(300MHz, CD3OD) δ 7.60(m, 1H), 7.55(d,



2H), 7.45(d, 2H), 7.11(t, 1H), 2.87(t, 2H), 2.32(t, 2H),



2.12(s, 6H); MS(ESI)m/z: 466(M+H+)


107
4-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-
3,5-dimethylthiophene-



1,2,4-triazol-3-yl]amino]-N-[2-(dimethylamino)ethyl]-
2-carboxylic acid



benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.89(s, 1H), 7.81(m,
DIC/HOBt in DMF



4H), 7.71(d, 2H), 7.22(s, 1H), 6.86(s, 1H), 2.79(t,



2H), 2.63(s, 3H), 2.61(s, 3H), 2.21(t, 6H), 2.06(s,



6H); MS(ESI)m/z: 464(M+H+)









Example 19
N-[4-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]phenyl]-methanesulfonamide (Cpd 108)
Using the procedure of Example 15, N-(4-aminophenyl)methanesulfonamide (2.00 g, 10.70 mmol), diphenyl cyanocarbonimidate (2.60 g, 10.70 mmol), and hydrazine (107.0 mL, 1.0 M solution in THF, 107.0 mmol) were reacted to produce Compound 19A (1.30 g, 45% yield) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 8.80 (s, 1H), 8.55 (s, 1H), 7.43 (d, 2H), 6.96 (d, 2H), 5.75 (s, 2H), 2.82 (s, 3H); MS (ESI) m/z: 269 (M+H+). Using the procedure of Example 1, Compound 19A was acylated with 3,5-dimethylthiophene-2-carboxylic acid Compound 19B mediated by DIC/HOBt in DMF to provide Compound 108 (11% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.30 (s, 1H), 9.25 (s, 1H), 7.70 (s, 1H), 7.61 (d, 2H), 7.12 (d, 2H), 6.83 (s, 1H), 2.87 (s, 3H), 2.50 (s, 3H); MS (ESI) m/z: 407 (M+H+).




Using the procedure for Example 19, the following compounds were prepared by acylation of the intermediate Compound 19A using the indicated starting material in place of Compound 14E and reagent(s):












Cpd
Name/Data
Starting Mat'l







109
N-[4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-
3-methylthiophene-



1,2,4-triazol-3-yl]amino]phenyl]-methanesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.35(s, 1H), 9.30(s,
mediated by



1H), 8.01(d, 1H), 7.75(s, 1H), 7.62(d, 2H), 7.12(m,
DIC/HOBt in DMF



3H), 6.83(s, 1H), 2.89(s, 3H), 2.59(s, 3H); MS(ESI)



m/z: 393(M+H+)


110
N-[4-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-
5-ethylthiophene-2-



1,2,4-triazol-3-yl]amino]phenyl]-methanesulfonamide
carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.37(s, 1H), 9.30(s,
mediated by



1H), 8.12(d, 1H), 7.74(s, 1H), 7.62(d, 2H), 7.12(d,
DIC/HOBt in DMF



2H), 7.03(d, 1H), 2.95(q, 2H), 2.89(s, 3H), 1.35(t,



3H); MS(ESI)m/z: 407(M+H+)


111
N-[4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-
2,6-difluorobenzoyl



triazol-3-yl]amino]phenyl]-methanesulfonamide
chloride in



1H NMR(300MHz, (CD3)2SO) δ 9.32(s, 1H), 9.21(s,
anhydrous pyridine



1H), 7.88(s, 2H), 7.64(p, 1H), 7.25(m, 4H), 6.92(d,



2H), 2.82(s, 3H); MS(ESI)m/z: 409(M+H+)


112
N-[4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-
2,6-difluoro-3-



1,2,4-triazol-3-yl]amino]phenyl]-methanesulfonamide
methylbenzoyl



1H NMR(300MHz, (CD3)2SO) δ 9.33(s, 1H), 7.88(s,
chloride in



2H), 7.54(q, 1H), 7.25(d, 2H), 7.16(t, 1H), 6.92(d,
anhydrous pyridine



2H), 2.82(s, 3H), 2.25(s, 3H); MS(ESI)m/z: 423



(M+H+)









Example 20
1-[4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazol-3-yl]amino]phenyl]-2-imidazolidinone (Cpd 113)
Using the procedure of Example 15, 1-(4-aminophenyl)imidazolidin-2-one (0.24 g, 1.35 mmol), diphenyl cyanocarbonimidate (0.32 g, 1.35 mmol) and hydrazine (13.5 mL, 1.0 M solution in THF, 13.5 mmol) were reacted to produce Compound 20A (0.28 g, 80%) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 11.05 (s, 1H), 8.42 (s, 1H), 7.35 (d, 2H), 7.24 (d, 2H), 6.65 (s, 1H), 5.78 (s, 2H), 3.74 (t, 2H), 3.32 (t, 2H); MS (ESI) m/z: 260 (M+H+). Using the procedure of Example 1, Compound 20A was acylated with 3-methylthiophene-2-carboxylic acid Compound 20B mediated by DIC/HOBt in DMF to provide Compound 113 (41% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.21 (s, 1H), 8.01 (d, 1H), 7.68 (s, 1H), 7.55 (d, 2H), 7.43 (d, 2H), 7.11 (d, 1H), 6.71 (s, 1H), 3.83 (q, 2H), 3.37 (q, 2H), 2.63 (s, 3H); MS (ESI) m/z: 384 (M+H+).




Using the procedure for Example 20, the following compounds were prepared by acylation of the intermediate Compound 20A using the indicated starting material in place of Compound 20B and reagent(s):












Cpd
Name/Data
Starting Mat'l







114
1-[4-[[5-amino-1-(2,6-difluoro-3-methylbenzoyl)-1H-
2,6-difluoro-3-



1,2,4-triazol-3-yl]amino]phenyl]-2-imidazolidinone
methylbenzoyl



1H NMR(300MHz, (CD3)2SO) δ 9.12(s, 1H), 7.82(s,
chloride in



2H), 7.50(m, 1H), 7.21(m, 4H), 7.20(m, 1H), 6.70(s,
anhydrous pyridine



1H), 3.72(t, 2H), 3.28(t, 3H), 2.21(s, 3H); MS(ESI)



m/z: 414(M+H+)


115
1-[4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-
2,6-difluorobenzoyl



triazol-3-yl]amino]phenyl]-2-imidazolidinone
chloride in



1H NMR(300 MHz, (CD3)2SO) δ 9.16(s, 1H), 7.87(s,
anhydrous pyridine



2H), 7.63(m, 1H), 7.19(m, 6H), 6.74(s, 1H), 3.72(t,



2H), 3.28(t, 3H); MS(ESI)m/z: 400(M+H+)









Example 21
N3-[4-(1,1-dioxido-2-isothiazolidinyl)phenyl]-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 116)
Using the procedure of Example 15, 4-(1,1-dioxoisothiazolidin-2-yl)phenylamine (0.92 g, 4.36 mmol), diphenyl cyanocarbonimidate (1.10 g, 4.36 mmol) and hydrazine (43.6 mL, 1.0 M solution in THF, 43.6 mmol) were reacted to produce Compound 21A (1.2 g, 95%) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 11.05 (s, 1H), 8.58 (s, 1H), 7.47 (d, 2H), 7.05 (d, 2H), 5.78 (s, 1H), 3.55 (t, 2H), 3.32 (t, 2H), 2.30 (p, 2H); MS (ESI) m/z: 295 (M+H+). Using the procedure of Example 1, Compound 21A was acylated with 3-methylthiophene-2-carboxylic acid Compound 20B mediated by DIC/HOBt in DMF to produce Compound 116 (48% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.38 (s, 1H), 8.01 (d, 1H), 7.73 (s, 2H), 7.62 (d, 2H), 7.15 (d, 2H), 7.08 (d, 1H), 3.67 (t, 2H), 3.42 (t, 2H), 2.58 (s, 3H), 2.35 (p, 2H); MS (ESI) m/z: 419 (M+H+).




Using the procedure for Example 21, the following compounds were prepared by acylation of the intermediate Compound 21A using the indicated starting material in place of Compound 20B and reagent(s):












Cpd
Name/Data
Starting Mat'l

















117
1-(2,6-difluorobenzoyl)-N3-[4-(1,1-dioxido-
2,6-difluorobenzoyl



2-isothiazolidinyl)phenyl]-1H-1,2,4-triazole-
chloride in



3,5-diamine
anhydrous pyridine



1H NMR (300 MHz, (CD3)2SO) δ 9.31 (s,



1H), 7.80 (s, 2H), 7.62 (t, 2H), 7.28 (m,



3H), 7.01 (d, 2H), 3.63 (t, 2H), 3.35 (t,



2H), 2.32 (p, 2H); MS (ESI) m/z: 435



(M + H+)









Example 22
4-[[5-amino-1-(2,6-difluorobenzoyl)-1H-1,2,4-triazol-3-yl]amino]-N-(2-pyridinyl)-benzenesulfonamide (Cpd 118)
Using the procedure of Example 15, 4-amino-N-pyridin-2-yl-benzenesulfonamide (1.48 g, 5.96 mmol), diphenyl cyanocarbonimidate (1.42 g, 5.96 mmol), and hydrazine (59.6 mL, 1.0 M solution in THF, 59.6 mmol) were reacted to provide Compound 22A (0.98 g, 50%) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ 9.22 (s, 1H), 8.05 (s, 1H), 7.73 (m, 3H), 7.53 (d, 2H), 7.04 (d, 1H), 6.85 (m, 2H), 5.85 (s, 2H); MS (ESI) m/z: 332 (M+H+). Using the procedure of Example 1, Compound 22A was acylated with 2,6-difluorobenzoyl chloride Compound 1F in anhydrous pyridine to provide Compound 118 (61% yield). 1H NMR (300 MHz, (CD3)2SO) δ 9.85 (s, 1H), 8.00-7.90 (m, 2H), 7.65 (m, 1H), 7.59 (d, 2H), 7.35 (d, 2H), 7.25 (t, 2H), 7.04 (d, 1H), 6.81 (t, 1H), 3.31 (s, 2H); MS (ESI) m/z: 472 (M+H+).




Using the procedure for Example 22, the following compounds were prepared by acylation of the intermediate Compound 22A using the indicated starting material in place of Compound 1F and reagent(s):












Cpd
Name/Data
Starting Mat'l







119
4-[[5-amino-1-[(5-ethyl-2-thienyl)carbonyl]-1H-1,2,4-
5-ethylthiophene-



triazol-3-yl]amino]-N-(2-pyridinyl)-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.87(s, 1H), 8.11(d,
mediated by



1H), 8.01(s, 1H), 7.90(s, 1H), 7.75(m, 4H), 7.68(d,
DIC/HOBt in DMF



2H), 7.63(t, 1H), 7.07(m, 2H), 6.85(m, 1H), 2.95(q,



2H), 1.32(t, 3H); MS(ESI)m/z: 470(M+H+)


120
4-[[5-amino-1-[(3,5-dimethyl-2-thienyl)carbonyl]-1H-
3,5-dithylthiophene-



1,2,4-triazol-3-yl]amino]-N-(2-pyridinyl)-
2-carboxylic acid



benzenesulfonamide
mediated by



1H NMR(300MHz, (CD3)2SO) δ 9.84(s, 1H), 7.98(s,
DIC/HOBt in DMF



1H), 7.91(s, 1H), 7.74(m, 4H), 7.71(d, 2H), 7.63(t,



1H), 7.07(m 1H), 6.85(m, 2H), 2.53(s, 3H), 2.52(s,



3H); MS(ESI)m/z: 470(M+H+)


121
4-[[5-amino-1-[(3-methyl-2-thienyl)carbonyl]-1H-1,2,4-
3-methylthiophene-



triazol-3-yl]amino]-N-(2-pyridinyl)-benzenesulfonamide
2-carboxylic acid



1H NMR(300MHz, (CD3)2SO) δ 9.85(s, 1H), 8.02(m,
mediated by



2H), 7.79(m, 4H), 7.73(d, 2H), 7.63(t, 1H), 7.13(d,
DIC/HOBt in DMF



1H), 7.07(m 1H), 6.81(m, 1H), 2.61(s, 3H); MS(ESI)



m/z: 456(M+H+)









BIOLOGICAL EXAMPLES
The utility of the compounds to treat or ameliorate a cyclin dependent kinase and tyrosine kinase mediated disorders was determined using the following procedures.
Example 1
CDK1 Screening Assay
A kinase reaction mixture was prepared containing 50 mM Tris-HCl pH=8, 10 mM MgCl2, 0.1 mM Na3PO4, 1 mM DTT, 10 μM ATP, 0.025 μM biotinylated histone-H1 peptide substrate and 0.2 μCuries per well 33P-γ-ATP [2000-3000 Ci/mmol]. 70 μL of the kinase reaction mixture was dispensed into the well of a streptavidin coated FlashPlateTM (Cat. # SMP103, NEN, Boston, Mass.). Then 1 μL of test compound stock in 100% DMSO was added to the wells resulting in a final concentration of 1% DMSO in the reaction with a 100 μl final reaction volume. Next, CDK1:Cyclin-B protein was diluted in 50 mM Tris-HCl pH=8.0, 0.1% BSA at a concentration of 1 ng per μL and 30 μl (30 ng enzyme per test well) was added to each well to initiate the reaction. The reaction was incubated for one hour at 30° C. At the end of the 1-hour incubation, the reaction was terminated by aspirating the reaction mixture from the plate and washing the wells twice with PBS containing 100 mM EDTA. The histone-H1 biotinylated peptide substrate became immobilized on the FlashplateTM and the incorporation of 33P-γ-ATP was measured by reading the plate on a scintillation counter. Inhibition of the enzymatic activity of CDK1 was measured by observing a reduced amount of 33P-γ-ATP incorporated into the immobilized peptide.
VEGF-R Screening Assay
A kinase reaction mixture was prepared containing 50 mM Tris-HCl pH=8, 10 mM MgCl2, 0.1 mM Na3PO4, 1 mM DTT, 10 μM ATP, 0.025 μM biotinylated peptide substrate and 0.8 μCuries per well 33P-γ-ATP [2000-3000 Ci/mmol]. 70 μL of the kinase reaction mixture was dispensed into the well of a streptavidin coated FlashPlateTM (Cat. # SMP103, NEN, Boston, Mass.). Then 1 μL of test compound stock in 100% DMSO was added to the wells resulting in a final concentration of 1% DMSO in the reaction with a 100 μL final reaction volume. Next, soluble rat tyrosine kinase containing an N-terminal 6×HIS tag was diluted in 50 mM Tris-HCl pH=8.0, 0.1% BSA at a concentration of 5 ng per μL and 30 μL (150 ng enzyme per test well) was added to each well to initiate the reaction. The reaction was incubated for one hour at 30° C. At the end of the 1-hour incubation, the reaction was terminated by aspirating the reaction mixture from the plate and washing the wells twice with PBS containing 100 mM EDTA. The PLC1 biotinylated peptide substrate became immobilized on the FlashplateTM and the incorporation of 33P-γ-ATP was measured by reading the plate on a scintillation counter. Inhibition of the enzymatic activity of the VEGF-R was measured by observing a reduced amount of 33P-γ-ATP incorporated into the immobilized peptide.
IC50 data for VEGF-R and CDK are shown in Table 1. IC50 values listed as >10 or >100 indicate no observed 50% inhibition at the highest dose tested, nor was an inhibition maxima observed. ND means not tested.










TABLE 1









IC50 (uM)












Cpd
CDK1
VEGF-R
HER2
CDK2














1
0.0064
0.1062
ND
ND


2
0.0032
0.3659
ND
ND


3
0.0080
0.3324
ND
ND


4
0.02232
0.3866
ND
ND


5
0.1436
0.5209
ND
ND


6
0.0394
8.144
ND
ND


7
0.057
>10
ND
ND


8
0.136
>100
ND
ND


9
0.039
1.597
ND
ND


10
0.252
0.4907
ND
ND


11
0.3046
>100
ND
ND


12
0.0454
0.08406
ND
ND


13
0.5353
0.5318
ND
ND


14
0.0045
0.0267
ND
ND


15
0.0048
0.0511
ND
ND


16
0.0021
0.0137
ND
ND


17
0.0025
0.027
ND
ND


18
0.067
0.058
ND
ND


19
0.0339
0.2907
ND
ND


20
0.0044
0.031
ND
ND


21
0.0088
0.023
ND
ND


22
0.0318
0.2334
ND
ND


23
0.0889
0.0353
ND
ND


24
0.2823
0.0674
ND
ND


25
0.01953
0.064
ND
ND


26
18.4
~100
ND
ND


27
~100
>100
ND
ND


28
0.9816
13.25
ND
ND


29
70.39
~100
ND
ND


30
0.017
0.0406
ND
ND


31
0.030
0.044
ND
ND


32
0.0031
0.0219
ND
ND


33
0.0032
0.0234
ND
ND


34
0.0016
0.0681
ND
ND


35
0.0011
0.0463
ND
ND


36
1.561
18.61
ND
ND


37
10.5
54.98
ND
ND


38
0.0299
0.8795
ND
ND


39
0.0122
0.3336
ND
ND


40
0.1949
11.06
ND
ND


42
0.1342
0.4433
ND
ND


43
0.0873
0.6279
ND
ND


44
0.5223
2.677
ND
ND


45
0.0137
0.3553
ND
ND


46
0.0358
0.4527
ND
ND


47
0.0586
2.523
ND
ND


48
2.603
~100
ND
ND


49
>1
>1
>1
ND


50
0.12
0.19
0.20
ND


51
0.007
0.019
0.031
ND


52
0.035
0.11
1.47
ND


53
>1
>1
>1
ND


54
0.55
14.0
6.1
ND


55
0.022
0.58
2.19
ND


56
0.49
20.0
4.17
ND


57
0.067
0.19
1.32
ND


58
0.014
0.42
0.65
ND


59
1.54
0.92
7.83
ND


60
1.37
0.89
7.46
ND


66
0.0006
0.032
0.060
0.0005


67
0.0037
0.038
0.052
0.0014


68
0.66
5.14
ND
ND


69
0.023
0.69
0.14
ND


70
0.035
0.91
1.23
ND


71
3.71
0.43
1.30
ND


72
1.43
0.38
1.49
ND


73
2.20
0.029
0.176
ND


74
0.46
0.021
0.062
ND


75
0.52
0.033
0.060
ND


76
0.012
0.53
~1
0.0044


78
0.0066
0.42
0.78
0.0017


79
>100
>100
>100
>100


80
0.0452
0.9346
1.1200
ND


81
0.0178
0.4822
1.6990
0.001


82
0.0090
0.0217
0.1183
ND


83
0.0084
0.0404
0.0130
ND


84
0.0038
0.0432
0.0516
ND


85
0.4126
0.1943
>1
ND


86
0.1087
0.0869
0.4128
ND


87
0.2171
0.0168
0.4357
ND


88
0.3134
0.9647
~1
ND


89
0.7096
0.5979
~10
ND


90
~1
~0.1
~0.1
ND


91
0.3349
0.0736
0.2233
ND


92
0.3493
0.1336
0.0558
ND


93
0.4525
0.7267
~1
ND


94
0.2716
0.4089
0.1469
ND


95
0.1387
0.2598
0.9138
ND


96
0.3726
0.8171
1.4080
ND


97
~0.1
~0.1
~0.01
ND


98
>0.1
~0.1
~0.1
ND


99
0.3656
0.098
0.0945
ND


100
0.3404
1.1000
1.2870
ND


101
0.1426
0.6498
0.8195
ND


102
2.3530
1.1010
2.2600
ND


103
0.0074
0.0449
0.2284
0.001


104
0.0156
0.0156
0.2033
0.001


105
0.0461
0.2756
0.8448
0.002


106
0.1250
0.5591
37.230
0.001


107
0.0138
0.0324
0.0297
0.002


108
0.0657
0.0307
0.0417
0.0120


109
0.1465
0.0252
0.1705
0.0210


110
0.0219
0.0136
0.0055
0.0050


111
0.1499
0.7019
16.830
ND


112
0.0870
0.7039
16.350
ND


113
0.2545
0.0302
0.0680
ND


114
0.2275
0.3125
1.3870
ND


115
0.3134
0.4666
1.4420
ND


116
0.0208
0.0261
0.1313
0.0010


117
0.0352
0.9080
5.4350
0.0070


118
0.33
0.397
>10
0.021


119
0.0672
0.0571
~1
0.0030


120
0.277
0.082
1.0
0.0090


121
0.0997
0.0272
0.7169
0.0030


122
2.21
>10
ND
ND


123
2.05
5.53
~100
0.031


128
0.0032
0.118
0.111
0.0033









Example 2
Kinase Selectivity Assays
Assays to test compound inhibition of other kinases were preformed using methods that measure the amount of phosphorylation of a biotinylated peptide substrate. Biotinylated peptide substrates were selected from the literature as appropriate for the enzyme being evaluated. The general procedure used to assay for kinase activity is as follows: A kinase reaction mix was prepared in 50 mM Tris-HCl pH=8, 10 mM MgCl2, 0.1 mM Na3VO4, 1 mM DTT, 10 μM ATP, 0.25-1 μM biotinylated peptide substrate, 0.2-0.8 μCuries per well 33P-γ-ATP [2000-3000 Ci/mmol]. Assay conditions vary slightly for each protein kinase, for example, insulin receptor kinase requires 10 mM MnCl2 for activity and Calmodulin-dependent protein kinase requires calmodulin and 10 mM CaCl2. These assay conditions are known in the art. The reaction mixture was dispensed into the wells of a streptavidin coated Flashplate and 1 μl drug stock in 100% DMSO was added to a 100 μl reaction volume resulting in a final concentration of 1% DMSO in the reaction. Enzyme was diluted in 50 mM Tris-HCl pH=8.0, 0.1% BSA and added to each well. The reaction was incubated for one hour at 30° C. in the presence of compound. After one hour the reaction mix was aspirated from the plate and the plate was washed with PBS containing 100 mM EDTA. The plate was read on a scintillation counter to determine 33P-γ-ATP incorporated into the immobilized peptide. Test compounds were assayed in duplicate at 8 concentrations [100 uM, 10 uM, 1 uM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM]. A maximum and minimum signal for the assay was determined on each plate. The IC50 was calculated from the dose response curve of the percent inhibition of the maximum signal in the assay according to the formula [max signal−background/test compound signal−background (100)=% inhibition] by graphing the percent inhibition against the log concentration of test compound. Known inhibitor compounds appropriate for the kinase being assayed were also included on each plate.
Definition and Source of Kinase Enzymes
VEGF-R (vascular endothelial growth factor receptor-2) is a fusion protein containing a polyhistidine tag at the N-terminus followed by amino acids 786-1343 of the rat VEGF-R2 kinase domain (GenBank Accession #U93306). CDK1 (cyclin dependent kinase 1) was isolated from insect cells expressing both the human CDK1 catalytic subunit and its positive regulatory subunit cyclin B (New England Biolabs, Beverly, Mass., Cat. #6020). CDK2 in complex with cyclin A is commercially available (Upstate Biotech, Lake Placid, N.Y.). The CDK4 complex was composed of a mouse CDK4 protein and a mouse Cyclin D1 protein (The mouse CDK4 protein was genetically fused to an N-terminal Flag-epitope tag and the mouse Cyclin D1 protein was fused with an N-terminal AU-1 epitope tag. The genes encoding these proteins were transferred to commercially available baculoviral vectors. The recombinant CDK4/D1 complex was then made by co-infecting commercially available insect cells with viruses carrying these two constructs). Insulin Receptor Kinase consists of residues 941-1313 of the cytoplasmic domain of the beta-subunit of the human insulin receptor (BIOMOL, Plymouth Meeting, Pa., Cat. #SE-195). Protein Kinase A is the catalytic subunit of cAMP dependent protein kinase-A purified from bovine heart (Upstate Biotech, Lake Placid, N.Y., Cat#14-114). PKC (protein kinase-C) is the gamma or beta isoform of the human protein produced in insect cells (BIOMOL, Plymouth Meeting, Pa., Cat. #SE-143). Casein Kinase 1 is a truncation at amino acid 318 of the C-terminal portion of the rat CK1 delta isoform produced in E. coli (New England Biolabs, Beverly, Mass., Cat. #6030). Casein Kinase 2 includes the alpha and beta subunits of the human CK2 protein produced in E. coli (New England Biolabs, Beverly, Mass., Cat. #6010). Calmodulin Kinase (calmodulin-dependent protein kinase 2) is a truncated version of the alpha subunit of the rat protein produced in insect cells (New England Biolabs, Beverly, Mass., Cat. #6060). Glycogen Synthase Kinase-3 is the beta isoform of the rabbit enzyme produced in E. coli (New England Biolabs, Beverly, Mass., Cat. #6040). MAP Kinase is the rat ERK-2 isoform containing a polyhistidine tag at the N-terminus produced in E. coli. and activated by phosphorylation with MEK1 prior to purification (BIOMOL, Plymouth Meeting, Pa., Cat. #SE-137). ERK-1 protein (Discontinued from Calbiochem). EGFR (epidermal growth factor receptor) is purified from human A431 cell membranes (Sigma, St. Louis, Mo., Cat.# E3641). PDGF-R (platelet derived growth factor receptor) is a fusion protein containing a polyhistidine tag at the N-terminus followed by nucleotides 1874-3507 of the human PDGF-R beta subunit kinase domain (Accession #M21616). The HER2 (human epidermal growth factor receptor-2) construct contains a polyhistidine tag at the N-terminus followed by 24 additional amino acids and begins at amino acid 676 followed by the remainder of the HER2 cytoplasmic domain.
The IC50 data for various kinases are shown in Table 2a through Table 2k. IC50 values listed as >10 or >100 indicate no observed 50% inhibition at the highest dose tested for the indicated assay, nor was an inhibition maxima observed. Values shown as  ̃10 indicate an approximate value based on an observed 50% inhibition. ND means not tested.







TABLE 2a







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 1
Cpd 2
Cpd 14
Cpd 15
Cpd 16















CDK1
0.006
0.003
0.0045
0.0048
0.021


PKA
>100
>100
5.43
4.26
ND


Caseine Kinase 1
11.16
>100
0.348
0.547
0.214


Caseine Kinase 2
>100
>100
8.05
>100
>100


PKC
ND
>100
ND
ND
ND


ERK 1
ND
ND
>100
ND
ND


ERK 2
19.35
9.48
2.14
5.95
0.39


Calmodulin Kinase 2
>100
>100
60.44
10.53
>100


EGF-R
>100
45.8
1.92
8.44
>100


VEGF-R
0.131
0.366
0.026
0.051
0.0137


Insulin R Kinase
>100
9.8
1.2
2.42
>100


GSK-3
0.041
0.031
0.003
0.0018
0.004


PDGF-R kinase
11.76
10.7
0.189
0.079
0.1


FGF-R2 Kinase
ND
0.269
0.027
ND
ND
















TABLE 2b







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 17
Cpd 23
Cpd 30
Cpd 32
Cpd 33















CDK1
0.0025
0.089
0.017
0.003
0.003


PKA
ND
>100
ND
>100
>100


Caseine Kinase 1
0.643
0.113
1.54
0.181
0.104


Caseine Kinase 2
2.65
>100
7.6
0.527
>10


ERK 2
1.87
1.62
5.93
0.563
>10


Calmodulin Kinase 2
2.8
10.5
88.3
>100
>10


EGF-R
4.13
>100
9.6
>100
>100


VEGF-R
0.027
0.035
0.0406
0.022
0.023


Insulin R Kinase
2.02
>100
4.96
0.123
0.316


GSK-3
0.009
0.016
0.014
0.003
0.004


PDGF-R kinase
0.081
0.629
0.392
0.074
0.039


HER2 Kinase
ND
ND
ND
0.009
0.005
















TABLE 2c







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 34
Cpd 38
Cpd 39
Cpd 51
Cpd 55















CDK1
0.002
0.029
0.012
0.007
0.020


PKA
>100
>100
>100
0.911
>100


Caseine Kinase 1
0.182
6.1
4.1
0.223
9.6


Caseine Kinase 2
>100
>100
>100
1.78
>100


ERK 2
>10
24.2
13.2
0.928
12.9


Calmodulin Kinase 2
>100
>100
>100
0.813
>100


EGF-R
>100
>100
>100
1.1
16.12


VEGF-R
0.068
0.880
0.334
0.019
0.577


Insulin R Kinase
>10
>100
19.4
0.077
>100


GSK-3
0.015
0.122
0.127
0.020
0.040


PDGF-R kinase
0.292
6.37
3.98
0.199
16.18


FGF-R2 Kinase
ND
ND
ND
ND
0.478


HER2 Kinase
ND
ND
ND
0.031
2.19
















TABLE 2d







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 57
Cpd 58
Cpd 61
Cpd 62
Cpd 63















CDK1
0.067
0.014
0.18
0.53
0.079


CDK2
ND
ND
0.049
0.29
0.056


PKA
>100
>100
ND
ND
ND


Caseine Kinase 1
14.0
11.24
ND
ND
ND


Caseine Kinase 2
>100
>100
ND
ND
ND


ERK 2
>100
10.7
ND
ND
ND


Calmodulin Kinase 2
>100
>100
ND
ND
ND


EGF-R
>100
>10
ND
ND
ND


VEGF-R
0.191
0.419
0.072
0.064
0.32


Insulin R Kinase
>100
>100
ND
ND
ND


GSK-3
0.098
0.015
0.055
0.073
0.073


PDGF-R kinase
4.19
8.53
ND
ND
ND


FGF-R2 Kinase
ND
0.096
ND
ND
ND


HER2 Kinase
1.32
0.654
0.82
0.41
0.15
















TABLE 2e







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 64
Cpd 65
Cpd 66
Cpd 69
Cpd 70















CDK1
0.21
0.67
0.0006
0.023
0.035


CDK2
0.20
0.41
ND
ND
ND


CDK4
ND
ND
ND
0.187
0.167


PKA
ND
ND
5.19
46.6
34.2


Caseine Kinase 1
ND
ND
2.75
16.6
35.7


Caseine Kinase 2
ND
ND
>100
>100
>100


ERK 2
ND
ND
1.0
12.5
19.4


Calmodulin Kinase 2
ND
ND
8.99
>100
>100


EGF-R
ND
ND
>10
>100
>100


VEGF-R
0.051
0.18
0.032
0.685
0.911


Insulin R Kinase
ND
ND
>10
45.1
>100


GSK-3
0.021
0.10
0.137
0.147
0.22


PDGF-R kinase
ND
ND
1.58
0.1
16.2


FGF-R2 Kinase
ND
ND
ND
0.365
0.273


HER2 Kinase
0.076
0.79
0.060
0.139
1.23
















TABLE 2f







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 71
Cpd 81
Cpd 82
Cpd 83
Cpd 84















CDK1
3.71
0.018
0.009
0.008
0.004


CDK4
0.129
ND
ND
ND
ND


PKA
>100
>100
>100
>100
2.2


Caseine Kinase 1
>100
6.96
0.354
0.275
0.188


Caseine Kinase 2
>100
>100
>100
>100
1.67


ERK 2
>100
11.68
1.95
>100
1.22


Calmodulin Kinase 2
60.9
>100
>100
>100
>100


EGF-R
>10
>100
>100
>100
>10


VEGF-R
0.43
0.482
0.022
0.040
0.043


Insulin R Kinase
35.3
29.6
1.1
>10
0.172


GSK-3
1.72
0.049
0.025
0.007
0.019


PDGF-R kinase
27
7.76
0.042
0.113
0.280


FGF-R2 Kinase
0.441
0.268
0.089
0.022
0.300


HER2 Kinase
1.30
1.7
0.118
0.013
0.052
















TABLE 2g







Kinase Selectivity











Kinase Assay (IC50 uM)
Cpd 92
Cpd 99
Cpd 103
Cpd 104














CDK1
0.349
0.366
0.007
0.0016


PKA
>100
ND
>100
>100


Caseine Kinase 1
>10
>1
0.322
0.624


Caseine Kinase 2
>100
>100
5.3
>100


PKC
ND
>100
ND
ND


ERK 2
>100
>100
0.845
>100


Calmodulin Kinase 2
19.7
>100
>100
>10


EGF-R
>100
>100
>10
>10


VEGF-R
0.134
0.098
0.045
0.016


Insulin R Kinase
3.08
>100
0.123
2.09


GSK-3
0.021
0.030
0.013
0.020


PDGF-R kinase
0.282
0.385
0.702
0.192


FGF-R2 Kinase
0.242
ND
0.170
0.200


HER2 Kinase
0.056
0.095
0.228
0.202
















TABLE 2h







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 105
Cpd 107
Cpd 108
Cpd 109
Cpd 110















CDK1
0.046
0.014
0.066
0.147
0.022


PKA
>100
>100
>100
>100
>100


Caseine Kinase 1
4.49
0.412
0.816
1.18
0.192


Caseine Kinase 2
>100
>10
>10
>10
>5


ERK 2
18.19
>10
2.39
>10
8.75


Calmodulin Kinase 2
>100
3.43
>10
>100
>100


EGF-R
9.60
0.936
>100
>100
>10


VEGF-R
0.276
0.032
0.030
0.025
0.014


Insulin R Kinase
9.85
0.311
0.811
2.76
0.053


GSK-3
0.082
0.015
0.023
0.039
0.008


PDGF-R kinase
2.20
0.143
0.217
0.413
0.285


FGF-R2 Kinase
0.142
0.235
0.307
0.244
0.153


HER2 Kinase
0.845
0.030
0.042
0.170
0.006
















TABLE 2i







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 113
Cpd 114
Cpd 115
Cpd 116
Cpd 117















CDK1
0.254
0.228
0.313
0.021
0.035


PKA
>100
>100
>100
>100
>100


Caseine Kinase 1
0.318
2.0
9.98
>1
13.46


Caseine Kinase 2
>100
>100
>100
>100
>100


PKC
>100
ND
ND
ND
ND


ERK 2
>100
15.8
>10
>100
>100


Calmodulin Kinase 2
>10
>100
>100
>100
>100


EGF-R
>10
>100
>10
>100
>100


VEGF-R
0.030
0.313
0.467
0.026
0.908


Insulin R Kinase
>10
>100
>10
>100
>100


GSK-3
0.071
0.431
0.391
0.062
1.04


PDGF-R kinase
0.370
13.8
>10
0.302
>100


HER2 Kinase
0.068
1.39
1.44
0.131
5.44
















TABLE 2j







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 118
Cpd 119
Cpd 120
Cpd 121
Cpd 123















CDK1
0.330
0.067
0.277
0.099
2.05


PKA
>100
>100
>100
>100
>100


Caseine Kinase 1
>100
0.757
>10
>10
>100


Caseine Kinase 2
>100
>100
>100
>100
>100


PKC
ND
>100
ND
ND
ND


ERK 2
>100
>100
>100
>100
>100


Calmodulin Kinase 2
>100
>100
>100
>100
>100


EGF-R
>100
0.159
>10
>10
>100


VEGF-R
0.397
0.057
0.082
0.027
5.52


Insulin R Kinase
>100
0.159
>100
>100
>100


GSK-3
0.159
0.006
0.018
0.029
3.01


PDGF-R kinase
>100
>10
0.822
0.394
>100


HER2 Kinase
>10
1.0
1.0
0.717
>100
















TABLE 2k







Kinase Selectivity












Kinase Assay (IC50 uM)
Cpd 124
Cpd 125
Cpd 126
Cpd 127
Cpd 128















CDK1
2.2
>100
>100
>100
0.003


CDK2
1.7
7.3
>100
>100
ND


PKA
ND
ND
ND
ND
>100


Caseine Kinase 1
ND
ND
ND
ND
8.97


Caseine Kinase 2
ND
ND
ND
ND
>100


ERK 2
ND
ND
ND
ND
2.07


Calmodulin Kinase 2
ND
ND
ND
ND
13.2


EGF-R
ND
ND
ND
ND
>100


VEGF-R
4.8
>100
>100
>100
0.118


Insulin R Kinase
ND
ND
ND
ND
2.65


GSK-3
3.0
>100
>100
>100
0.094


PDGF-R kinase
ND
ND
ND
ND
1.91


HER2 Kinase
0.82
>100
~100
>100
0.11









Example 3
Assay to Measure Inhibition of Cell Proliferation
The ability of a test compound to inhibit the proliferation of cell growth was determined by measuring incorporation of 14C-labelled thymidine into newly synthesized DNA within the cells. This method was used on cell lines derived from carcinomas originating from several tissues such as HeLa cervical adenocarcinoma (American Type Culture Collection (ATCC), Virginia, Cat. #CCL-2), A375 malignant melanoma (ATCC CRL-1619), SK-OV-3 ovarian adenocarcinoma (ATCC HTB-77) HCT-116 colon carcinoma (CCL-247), PC-3 prostate adenocarcinoma (ATCC CRL-1435), and MDA-MB-231 (Xenogen Corp.) In this way the effect of a compound on cell growth of cells with many different phenotypes can be determined. Cells were trypsinized and counted and 3000-8000 cells were added to each well of a 96-well CytoStar tissue culture treated scintillating microplate (Amersham #RPNQ0160) in complete medium in a volume of 100 μl. Cells were incubated for 24 hours in complete medium at 37° C. in an atmosphere containing 5% CO2.
Next, 1 μl of test compound in 100% DMSO was added to the wells of the plate. DMSO only was added to control wells. Cells were incubated for 24 more hours in complete medium at 37° C. in an atmosphere containing 5% CO2. Methyl 14C-thymidine 56 mCi/mmol (NEN #NEC568 or Amersham #CFA532) was diluted in complete medium and 0.2 uCi/well was added to each well of the CytoStar plate in a volume of 20 ul. The plate was incubated for 24 hours at 37° C. plus 5% CO2 in drug plus 14C-thymidine. The contents of the plate were discarded into a 14C radioactive waste container by inverting the plate and the plate was washed twice with 200 μl PBS. 200 μl of PBS is added to each well. The top of the plate was sealed with a transparent plate sealer and a white plate backing sealer (Packard #6005199) was applied to the bottom of the plate. The degree of methyl 14C-thymidine incorporation was quantified on a Packard Top Count.







TABLE 3







Inhibition of Cell Proliferation (IC50 nM)









Cell Line

















MDA-MB-




Cpd
HeLa
HCT-116
SK-OV-3
231
PC-3
A375
















1
284
254
750
587
119
447


14
550
1940
727
756
157
26460


15
91
127
242
550
107
247


16
263
213
2110
ND
368
942


17
215
309
3900
ND
294
4970


23
1180
376
1420
868
859
424


30
215
1930
5750
ND
951
8240


32
71
26
ND
131
30
ND


33
72
27
ND
171
37
ND


34
707
996
ND
898
626
ND


35
663
172
ND
1140
231
ND


38
4560
2270
ND
6760
2750
ND


39
270
1410
ND
2910
625
ND


51
220
ND
ND
ND
57
333


57
339
95
ND
ND
ND
113


58
186
1,270
ND
ND
362
981


66
35
20
ND
ND
ND
92


69
218
1,720
ND
ND
8
441


70
196
1,580
ND
ND
11
1,100


71
1,920
ND
ND
ND
25
ND


80
880
ND
16,300
ND
272
ND


81
189
778
348
ND
25
1,770


82
245
ND
921
ND
15
ND


83
122
192
ND
ND
12
556


84
142
ND
461
ND
23
ND


92
269
ND
ND
ND
1,120
ND


99
3,350
ND
ND
ND
1,690
ND


103
62
75
ND
ND
ND
115


104
186
41
ND
ND
ND
108


105
626
320
ND
ND
ND
652


107
177
95
ND
ND
ND
113


108
221
76
ND
ND
ND
259


109
479
51
ND
ND
307
ND


110
237
187
ND
ND
ND
239


113
242
281
281
ND
ND
ND


114
2,530
1,380
ND
ND
ND
1,690


115
676
486
ND
ND
ND
529


116
380
349
ND
ND
ND
639


117
2,060
1,120
ND
ND
ND
2,190


118
1,940
1,170
ND
ND
ND
1,620


119
146
117
ND
ND
ND
199


120
978
334
ND
ND
ND
259


121
310
608
ND
ND
ND
215


123
28,500
4,140
ND
ND
ND
>10,000


128
128
910
ND
ND
ND
968









Example 4
In Vivo Models—Inhibition of Tumor Growth
The in vivo effect of a compound on the growth of human tumor cells can be evaluated by implanting human tumor cells into the hindflank of athymic mice and administering test compound to the mice. Human tumor cells originating from a variety of different tumor types, such as A375 human melanoma cells, are implanted subcutaneously into the hindflank of male athymic mice (Charles River) and allowed to establish a sizeable tumor for 6-10 days as determined by caliper measurements. Test compound is then administered by injecting the compound formulated in an appropriate vehicle intraperitoneally into the mice once a day for 30 days. The test compound can also be administered by other routes such as orally, sub cutaneously or by intravenous infusion. The size of the tumor in this study is measured every four days and the degree of inhibition is determined by comparing drug-treated animals to animals that are injected with vehicle only
The synergistic action or enhancement of conventional chemotherapeutic agent by a test compound can also be determined with this model by comparing animals treated with the standard therapy alone to animals treated with test compound plus the same standard therapy. An additive effect on the delay of tumor growth will be observed if synergistic action due to test compound is occurring.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and modifications as come within the scope of the following claims and their equivalents.
Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

## Claims

1. A method for treating a kinase mediated disorder selected from the group consisting of cervical adenocarcinoma, melanoma, ovarian adenocarcinoma, colon carcinoma, prostate adenocarcinoma, and breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the following formula:




wherein
R4 is selected from the group consisting of:
—SO2—, substituted with one substituent selected from the group consisting of thienyl, imidazolinyl, triazolyl and amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl, thienyl, imidazolinyl, and triazolyl;
or triazolyl;
X is selected from the group consisting of —C(O)—, —C(S)— and —SO2—; and,
R3 is selected from the group consisting of:
cycloalkyl, thienyl, imidazolinyl, triazolyl, and phenyl, wherein cycloalkyl, thienyl, imidazolinyl, triazolyl, and phenyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halo, hydroxyl, nitro, C1-8alkyl, C2-8alkenyl, or C1-8alkoxy;
and pharmaceutically acceptable salts thereof.

2. The method of claim 1 wherein the therapeutically effective amount is from about 0.001 mg/kg/day to about 300 mg/kg/day.

3. The method of claim 1 which is an adjunct to chemotherapy and radiation therapy.

4. The method of claim 3 in which a therapeutically effective amount of a chemotherapeutic agent to treat cancer is also administered.

5. The method of claim 1 in which the compound has the following formula:




wherein
R4 is selected from the group consisting of:
—SO2—, substituted with one substituent selected from the group consisting of thienyl, imidazolinyl, triazolyl and amino, wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C1-8alkyl, —C1-8alkylamino, wherein —C1-8alkylamino is substituted with two substituents independently selected from the group consisting of hydrogen and C1-8alkyl, thienyl, imidazolinyt, and triazolyl; and
R3 is selected from the group consisting of:
thienyl, imidazolinyl, triazolyl, and phenyl;
wherein the thienyl, imidazolinyl, triazolyl, and phenyl substituents are optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-8alkyl, C1-8alkyl(mono-, di- or tri-halo), C1-8alkoxy, cyano, halo, hydroxy and nitro —C(O)(C1-8)alkyl and —CH(OH)(C1-8)alkyl;
and pharmaceutically acceptable salts thereof.

6. The method of claim 1 in which X, R3 and R4 are dependently selected from the group consisting of:















X
R3
R4









C(O)
(2,6-F2)Ph
4-SO2—NH2;



C(O)
(2,6-F2-3-CH3)Ph
4-SO2—NH2;



C(O)
(2,4,6-F3)Ph
4-SO2—NH2;



C(O)
(2-F)Ph
4-SO2—NH2;



C(O)
(2,4-F2)Ph
4-SO2—NH2;



C(O)
(2-F-6-CF3)Ph
4-SO2—NH2;



C(O)
(2,6-Cl2)Ph
4-SO2—NH2;



C(O)
(2,4,6-Cl3)Ph
4-SO2—NH2;



C(O)
(2-NO2)Ph
4-SO2—NH2;



C(O)
[2,6(OCH3)2]Ph
4-SO2—NH2;



C(O)
[2,4,6-(CH3)3]Ph
4-SO2—NH2;



C(O)
Ph
4-SO2—NH2;



C(O)
2-thienyl
4-SO2—NH2;



C(O)
(3-CH3)2-thienyl
4-SO2—NH2;



C(O)
(3-F)2-thienyl
4-SO2—NH2;



C(O)
(3-Cl)2-thienyl
4-SO2—NH2;



C(O)
(3-OCH2CH3)2-thienyl
4-SO2—NH2;



C(O)
(3-NHCOCH3)2-thienyl
4-SO2—NH2;



C(O)
(5-CH3)2-thienyl
4-SO2—NH2;



C(O)
(5-Br)2-thienyl
4-SO2—NH2;



C(O)
3-thienyl
4-SO2—NH2;



C(O)
(5-CH2CH3)2-thienyl
4-SO2—NH2;



C(O)
[3,5-(CH3)2]2-thienyl
4-SO2—NH2;



C(O)
(3-Br)2-thienyl
4-SO2—NH2;



C(O)
Cyclopentyl
4-SO2—NH2;



C(O)
Cyclohexyl
4-SO2—NH2;



C(O)
2-thienyl-CH2
4-SO2—NH2;



C(O)
2-thienyl-(CH)2
4-SO2—NH2;



C(O)
(2,6-F2)-Ph—CH2
4-SO2—NH2;



C(O)
(2,6-F2)Ph(CH)2
4-SO2—NH2;



C(O)
Cycloheptyl
4-SO2—NH2;



C(O)
4-CH3-cyclohexyl
4-SO2—NH2;



C(O)
4-CH3-cyclohexyl
4-SO2—NH2;



C(O)
4-(CH2)3CH3-cyclohexyl
4-SO2—NH2;



C(O)
5-[C(CH3)3]2-thienyl
4-SO2—NH2;



C(O)
(2,6-F2-3-NO2)Ph
4-SO2—NH2;



C(O)
(2,6-F2-3-NH2)Ph
4-SO2—NH2;



C(O)
[2,6-(CH3)2]Ph
4-SO2—NH2;



C(O)
(2-CH3)Ph
4-SO2—NH2;



C(O)
[2,6-F2-3-CH(OH)CH3]Ph
4-SO2—NH2;



C(O)
(2,6-F2)Ph
4-SO2—NH2;



C(O)
(2,6-F2-3-CH3)Ph
4-SO2—NH2;



SO2
(2,6-F2)Ph
4-SO2—NH2;



C(O)
(2-Cl-3-CH3-6-F)Ph
4-SO2—NH2;



C(O)
(2-Cl-6-F)Ph
4-SO2—NH2; and



C(O)
(2,6-F2-5-Cl)Ph
4-SO2—NH2.

7. The method of claim 1 in which X, R3 and R4 are dependently selected from the group consisting of:















X
R3
R4









C(O)
(2,6-F2)Ph
4-SO2—NH2; and



C(O)
(2,6-F2-3-CH3)Ph
4-SO2—NH2.

8. The method of claim 1 in which X, R3 and R4 are dependently selected from the group consisting of:















X
R3
R4









C(O)
(2,6-F2)Ph
4-SO2—NH(CH2CH3);



C(O)
(2,6-F2)Ph
4-SO2—NH(CH3);



C(O)
(2,6-F2-3-CH3)Ph
4-SO2—NH(CH3);



C(O)
(3-CH3)2-thienyl
4-SO2—NH(CH3);



C(O)
[3,5-(CH3)2]2-thienyl
4-SO2—NH(CH3);



C(O)
(5-CH2CH3)2-thienyl
4-SO2—NH(CH3);



C(O)
[3,5-(CH3)2]2-thienyl
4-SO2—N(CH3)2;



C(O)
(5-CH2CH3)2-thienyl
4-SO2—N(CH3)2;



C(O)
(3-CH3)2-thienyl
4-SO2—N(CH3)2;



C(O)
(2,6-F2-3-CH3)Ph
4-SO2—N(CH3)2; and



C(O)
(2,6-F2)Ph
4-SO2—N(CH3)2.

9. The method of claim 1 in which X, R3 and R4 are dependently selected from the group consisting of:















X
R3
R4









C(O)
(2,6-F2-3-CH3)Ph
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(2,6-F2)Ph
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(5-CH2CH3)2-thienyl
4-(1-H-1,2,4-triazol-1-yl);



C(O)
[3,5-(CH3)2]2-thienyl
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(3-CH3)2-thienyl
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(2,6-F2)Ph
4-(1-H-1,3,4-trlazol-1-yl);



C(O)
(2,6-F2-3-CH3)Ph
4-(1-H-1,3,4-triazol-1-yl); and



C(O)
(3-CH3)2-thienyl
4-(1-H-1,3,4-triazol-1-yl).

10. The method of claim 1 in which the X, R3 and R4 are dependently selected from the group consisting of:















X
R3
R4









C(O)
(2,6-F2-3-CH3)Ph
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(2,6-F2)Ph
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(5-CH2CH3)2-thienyl
4-(1-H-1,2,4-triazol-1-yl);



C(O)
[3,5-(CH3)2]2-thienyl
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(3-CH3)2-thienyl
4-(1-H-1,2,4-triazol-1-yl);



C(O)
(2,6-F2)Ph
4-(1-H-1,3,4-tziazol-l-yl);



C(O)
(2,6-F2-3-CH3)PH
4-(1-H-1,3,4-triazol-1-yl); and



C(O)
(3-CH3)2-thienyl
4-(1-H-1,3,4-trlazol-1-yl).

11. The method of claim 1 in which X, R3 and R4 are dependently selected from the group consisting of:












X
R3
R4







C(O)
(5-CH2CH3)2-thienyl
4-SO2—NH[(CH2)2N(CH3)2];


C(O)
(3-CH3)2-thienyl
4-SO2—NH[(CH2)2N(CH3)2];


C(O)
(2,6-F2-3-CH3)Ph
4-SO2—NH[(CH2)2N(CH3)2];


C(O)
(2,6-F2)Ph
4-SO2—NH[(CH2)2N(CH3)2]; and


C(O)
[3,5-(CH3)2]2-thienyl
4-SO2—NH[(CH2)2N(CH3)2].