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.

Description: SUBSTITUTED TRIAZOLE DIAMINE DE INATINES AS KINASE INHIBITORS 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 l,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 Patent application WO 99/21845 describes 4-aminothiazole derivatives as inhibitors of cyclin dependent kinases of the formula: wherein R, is a substituted or unsubstituted group selected from: C__ 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl); C L g-alkenyl; C^-alkynyl; C_. 6 -alkoxyl; C^-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; (C__ 6 alkyl)-carbonyl; (C 6 alkyl)-aryl; (Cj. 6 alkyl)- cycloalkyl; (C^ alkyl)-(C 1 . 6 -alkoxyl); aryl-(C 1.6 -alkoxyl); thioether (e.g., aryl- S-aryl, cycloalkyl-S-aryl, cycloalkyl-S-cycloalkyl, or dialkyl sulfide); thiol; and sulfonyl; and R 2 is a substituted or unsubstituted: carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure; where each optional substituent for Rj and R 2 is independently a halogen (e.g., chloro, iodo, bromo, or fluoro); oxygen (=O); haloalkyl (e.g., trifluoromethyl); C^ alkyl; C L g-alkenyl; C__ 6 - alkynyl; hydroxyl; C__ 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-l,2,4-triazole-carboxylic and derivatives as GSK-3 (glycogen synthase kinase) inhibitors of formula (I): (I) wherein the R 3 CZ- moiety may be attached to the nitrogen atom at position I or the nitrogen atom at position 2; R 1 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic; R 2 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R 1 and R 2 together with the nitrogen atom to which they are attached may form a heterocyclic ring which ring may be unsubstituted or substituted; R 3 is alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q is O or S, aralkenyl, alicyclic, heteroaryl, heteroaralkyl, arylcarbonylalkyl, alicyclylalkyl, diarylalkyl, or NR 6 R 7 ; R 4 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic; R 5 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R 4 and R 5 together with the nitrogen atom to which they are attached may form a heterocyclic ring which ring may be unsubstituted or substituted; R 6 is hydrogen, aryl or alicyclic; R 7 is hydrogen, aryl or alicyclic, and; Z is oxygen or sulphur. Suitably, R 1 is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of Cj-Cgalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy(C 1 -C 6 )allcyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro. Favourably, R 1 is phenyl either unsubstituted or substituted with up to three of methyl, methoxy, or chloro. Suitably, R 2 is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C r C 6 alkyl, - alkoxy, C 1 -C 6 alkoxy(C 1 -Cg)alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro. Favourably, R 2 is hydrogen. Suitably, R 3 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 R 3 aryl groups are selected from -O(CH 2 ) n O-, where n is 1 to 3, or up to three of halo, aryl, perfluoro^^C^alkyl, nitro, arylcarbonyl, aryloxy, C t -C 6 acyl; or R 3 is NR 6 R 7 where R 6 and R 7 are each independently hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C r C 6 alicyclic, wherein the substituents for the R 6 and R 7 groups are independently selected from up to three of halo, aryl, aryloxy, alkyl, nitro, and alkoxy. Favourably, R 3 is phenyl either unsubstituted or substituted with up to three of chloro, bromo, phenyl, trifluoromethyl, nitro, benzoyl, phenoxy, acetyl, or 3,4-OCH 2 O-; naphthyl; benzyl either unsubstituted or substituted with up to three of phenyl or fiuoro; 2-thienylmethyl; phenylthiomethyl 2- naphthylmethyl; cyclohexyl; 3-pyridyl; 3 -indolylmethyl; phenylcarbonylethyl; cyclopent-2- enyhnethyl; phenylpropyl; 2,2-diphenylethyl; or 2-furylethenyl; or NR 6 R 7 where R 6 and R 7 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, R 4 is hydrogen. Suitably, R 5 is hydrogen. Suitably, R 6 is unsubstituted or substituted aryl or unsubstituted or substituted alicyclic. Favourably R 6 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, R 7 is hydrogen. United States Patent 5,750,545 describes triazole derivatives, as agents for the prophylaxis and treatment of immune-related diseases, of formula (I) and formula (III): (I) (HI) wherein X is an oxygen atom or a sulfur atom; W is -NR 4 R 5 or -SR 6 ; R 1 is a hydrogen atom, a lower alkyl, -NR 10 R π , -N=R 13 or a group of the formula (II) (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, -NR 14 R 15 , 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 R 2 and R 3 are the same or different and each is a hydrogen atom or a lower alkyl; wherein R 4 and R 5 are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, cycloalkyl, a phenyl or -(CH 2 ) m COOR 16 , R 16 is a hydrogen atom or a lower alkyl, m is an integer of 1 to 6 , R 6 is a lower alkyl, R 10 and R u are the same or different and each is a hydrogen atom, an optionally substituted benzoyl, an optionally substituted phenyl, a lower alkylcarbonyl or -COCOOR 17 , R 17 is a lower alkyl, R 13 is an optionally substituted methylene, R 14 and R 15 are the same or different and each is a hydrogen atom, a lower alkyl, -COCOOR 17 or -CSNHR 18 , and R 18 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): Formula (I) wherein Rj is selected from the 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: C^alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1.8 )all yl, -CO 2 H, -CO 2 (C 1 . s )all yl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), Cj.galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C μ8 alkyl and -SO 2 -(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C^alkyl), -SO 2 - {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, C 8 alkyl,-C 8 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 (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 C h alky!), cyano, hydroxy and nitro), C^alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C^alkyl)}}; R 2 is selected from the group consisting of hydrogen, C^alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C 1 . 8 )alkyl; X is selected from the group consisting of -C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: C^alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C^alkyl), cyano, (halo)^ hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C^alkyl, cyano, halo, (halo) 1 . 3 (C 1 . s )alkyl, (halo)ι. 3 (C 1.8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 . 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: C^alkyl, C 2 . 8 alkenyl (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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo^. j and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C^alkyl and -C(O)(C 1.8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C^alkyl and - .galkylammo (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, - H-SO 2 -(C w )aJkyl, 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, C^alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C h alky!, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1.8 )alkoxy, hydroxy, hydroxy(C 1.8 )alkyl, hydroxy(Cι. 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, R x is selected from the group consisting of : C^alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of: C M alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 4 )alkyl, -CO 2 H, -CO^C^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C alkyl), cyano, (halo)^, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), C M alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) j . 3 and hydroxy), -C(O)H, -C(O)(C M )alkyl, -CO 2 H, -CO 2 (C 1 . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, Cι_ 4 alkyl and -SO 2 -(C )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C M alkyl, -C 1 . 4 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C M alkyl (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 C M alkyl), cyano, (halo) ! . 3 , hydroxy and nitro), C w alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M al yl)}}. More preferably, R_ is selected from the group consisting of C M alkyl and aryl {wherein aryl is substituted with a substituent selected from the group consisting of: C M alkyl (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 C h alky!), cyano, (halo)^, hydroxy and nitro), C^alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C M )alky ), -SO 2 - {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, C M alkyl, -C^alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C, .4 alkyl) and heteroaryl)}, heterocyclyl (wherein heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C M alkyl and oxo) and heteroaryl}. Most preferably, R_ is selected from the group consisting of C M alkyl 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, C M alkyl and -SO 2 -(C M )alkyl), -SO 2 - {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, C M alkyl, -C M alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl) and pyridinyl)}, and piperazinyl (wherein piperazinyl is optionally substituted with 1 to 2 C M alkyl 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, R 2 is selected from the group consisting of hydrogen, C 1 . 4 alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl and hydroxy^^alkyl. More preferably, R 2 is selected from the group consisting of hydrogen and C M alkyl. Most preferably, R 2 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 -SO 2 -. Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R 3 is selected from the group consisting of: C M alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, - OX ^alkyl, -CO 2 H, -CO 2 (C M )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyι), cyano, (h&ϊό)^, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 4 )alkyl, (halo) 1 _ 3 (C 1 _ 4 )alkoxy, hydroxy, hydroxy(C 1 . 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: C M alkyl, C 2 . 4 alkenyl (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)(C 1 . 4 )alkyl, -CO 2 H, -CO 2 (C 1 . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and ^alkyl), cyano, (halo)^ hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH^HMC^alkyl, ^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -C(O)(C 1 . 4 )alkyl, -CO 2 H, -CO 2 (C M )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . 4 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C M alkyl and -C w alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl))}, -NH-SO 2 -(C lJt )al yl, 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, ^alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 4 )alkyl, (halo)ι_ 3 (C 1 . 4 )alkoxy, hydroxy, hydroxy(C 1 . 4 )alkyl, hydroxy(C M )alkoxy and nitro)}. More preferably, R 3 is selected from the group consisting of: C M alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl {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 C M alkyl), cyano, (halo)^;,, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1.3 (C 1 . 4 )alkyl, (halo^.^C L alkoxy, hydroxy, hydroxy(C 1.4 )alkyl, hydroxy(C 1 _ 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: C M alkyl, C^alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -CO 2 H, -CO^C L ^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo . 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 a]kyl, C M alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -C(O)(C 1 . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C j ^alkyl and -C(O)(C ! . 4 )alkyl), aryl and heteroaryl} and amino {substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and aryl (wherein aryl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1.3 (C 1 . 4 )alkyl, (halo) 1 . 3 (C 1 . 4 )alkoxy, hydroxy, hydroxy(Cι. 4 )alkyl, hydroxy(C 1.4 )alkoxy and nitro)} . Most preferably, R 3 is selected from the group consisting of: C 2 . 4 alkenyl, C 2 . 4 alkynyl {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 C h alky!), cyano, (halo)^ hydroxy, nitro, phenyl and thienyl (wherein phenyl, and thienyl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of C M alkyl, 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: C j . 4 alkyl (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 C j ^alkyl), cyano, (halo) !.3 , hydroxy and nitro), -CH(OH)-(C 1 . 4 )alkyl, C^alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), 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: C 1 . 4 alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of -CO 2 H, -CO 2 (C t . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and hydroxy and nitro), C 1 . 4 alkoxy, -C(O)(C 1.4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of: hydrogen, C M alkyl and -C(O)(C !.4 )alkyl), pyrrolyl and pyridinyl; and, wherein thiadiazolyl is optionally substituted with one substituent selected from the group consisting of C 1 . 4 alkyl (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 C M alkyl), cyano, (halo)ι_ 3 , hydroxy and nitro), C alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, halo, hydroxy and nitro} and amino {substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and phenyl (wherein phenyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C t . 4 alkyl, cyano, halo, hydroxy and nitro)} . Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (la): Formula (la) wherein R 4 is selected from the group consisting of: C M alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^ hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl}, C M alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) ^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(Cι. 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C M alkyl, -C 8 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C M alkyl (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 C h alky!), cyano, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, C M alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C 1 .g)alkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: C^aUcyl, C 2 .galkenyl, C 2 . 8 alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and Cj.galkyl), cyano, (halo)^, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C^aUcyl, cyano, halo, (halo) 1.3 (C 1 . 8 )alkyl, (halo) 1.3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1.8 )alkyl, hydroxy(C,.g)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: C h alky!, C 2.8 alkenyl (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)(C ! . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C j. galkyl), cyano, ( alo)__ 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) ! . 3 and hydroxy), -C(O)H, -CCOXC, Jalkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl and -Cι_ g alkylarnino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO 2 -(C 1 . 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, C^ancyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of .galkyl, cyano, halo, (halo) 1 . 3 (Cι_ 8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 . 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 (lb): Formula (lb) wherein R 4 is selected from the group consisting of: C M alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^ hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl}, C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) ! .;, and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, Cj. g alkyl, -Q.galkylam.ino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C j .galkyl (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 C h alky!), cyano, (halo^.;,, hydroxy and nitro), .galkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, C h alky!, C 2 . s alkenyl, C 2 . 8 alkynyl and hydroxy(C 1 . 8 )alkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: Cj.galkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and Cι_ 8 alkyl), cyano, (halo)ι .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 C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 _ 3 (Cι_ 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 . 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: .galkyl, C 2 . 8 alkenyl (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)(C,. 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo) ! . 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C,. 8 )alkyl, C 1 . 8 alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) j . 3 and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl and - .galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO 2 -(C 1 . s )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, C M alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C^an yl, cyano, halo, (halo) 1 . 3 (C 1 .g)alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 .g)alkyl, hydroxy(C 1 .g)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): Formula (Ic) wherein R 4 is selected from the group consisting of: Cι. 8 alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo) ! . 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl}, C L galko y (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C^aUcyl and -SO 2 -(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, Cι_ 8 alkyl, (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C^aUcyl (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 C M alkyl), cyano, (halo),_ 3 , hydroxy and nitro), . C^alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, C^aUcyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C 1 . 8 )alkyl; X is selected from the group consisting of -C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: Cι. 8 alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (Cι_ 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and Cj.galkyl), cyano, (halo . .,, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C,. 8 alkyl, cyano, halo, (halo) 1 . 3 (C I . 8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1.8 )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: C M alkyl, C 2 . s alkenyl (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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . s )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^ hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, C galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . g )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . s )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl and (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO^C^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, .galkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C h alky! cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 .g)alkyl, hydroxy(C 1 . 8 )alkoxy and nitro)}; and pharmaceutically acceptable salts thereof. Embodiments of the present invention include compounds of Formula (Ic) wherein, preferably, R 4 is selected from the group consisting of: amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C ! . 4 )alkyl), -SO 2 - {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, C 1 . 4 alkyl, (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C 1 . 4 alkyl) and heteroaryl)}, heterocyclyl (wherein heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C 1.4 alkyl and oxo) and heteroaryl. Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Id): wherein R 4 is selected from the group consisting of: C^an yl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C I . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^ ; ,, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl}, Cι_ 8 alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo .., and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C h alky! and -SO 2 -(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C^aH yl, -Cj.galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C M alkyl (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 C h alky!), cyano, (halo j, hydroxy and nitro), Cι. 8 alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, C 1 . 8 alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C 1.8 )alkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: C h alky!, C 2 . 8 alkenyl, C 2. galkynyl {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)(C 1 . s )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)ι .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 C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1.3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 .g)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: C h alky., C 2 . 8 alkenyl (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)(C 1.8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )all yl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo . ; ,, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) ! .-, and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO^ ^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . s )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, Cι. 8 alkyl and -C j. galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO 2 -(C 1 . 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, C^aUcyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of .galkyl, cyano, halo, (halo) 1 . 3 (C 1 . g )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 .g)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): Formula (Ie) wherein R_ is selected from the group consisting of C j. galkyl, 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: C j. galkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^ hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo ^ and hydroxy), -C(O)H, -C(O)(C 1 .g)alkyl, -CO 2 H, -CO^C^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, .galkyl, - .galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C M alkyl (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 C h alky!), cyano, (halo)^, hydroxy and nitro), C L galkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl)}}; and, R 3 is selected from the group consisting of: C M alkyl, C 2.8 alkenyl, C 2 . 8 alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 _ 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and cyano, (halo)ι_ 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 C 1 . g alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . g )alkyl, hydroxy(C 1 . 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: C j _ g alkyl, C 2 _ 8 alkenyl (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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo) ! ..,, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, .galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -QOX ^alkyl, -CO 2 H, -CO 2 (C ] . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C^ancyl and -C(O)(C 1 .g)alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl and -C^alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO 2 -(C 1 . 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, C M alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C^an yl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . s )alkyl, hydroxy(C 1 . g )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): > N> N> N> © so 00 l o o ° P . n n n n o p p p p p o n opp oppppppp > o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o X e C(0) H 3a,7a- 4-SO 2 -NH 2 dihydrobenzo [b]thien-2-yl C(0) H (5-CH 2 CH 3 )2-tlιienyl 4-SO 2 -NH 2 C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-SO 2 -NH 2 C(0) H [2,4-(CH 3 ) 2 ]5-thiazolyl 4-SO 2 -NH 2 C(O) H (3-Br)2-thienyl 4-SO 2 -NH 2 C(O) H 4-(CH 3 )- 1 ,2,3-thiadiazol-5- 4-SO 2 -NH 2 C(O) H l,2,3-thiadiazol-4-yl 4-SO 2 -NH 2 C(O) H cyclopentyl 4-SO 2 -NH 2 C(O) H cyclohexyl 4-SO 2 -NH 2 C(O) H 2-thienyl-CH 2 4-SO 2 -NH 2 C(O) H 2-thienyl-(CH) 2 4-SO 2 -NH 2 C(O) H (2,6-F 2 )-Ph-CH 2 4-SO 2 -NH 2 C(O) H (2,6-F 2 )Ph(CH) 2 4-SO 2 -NH 2 C(O) H cycloheptyl 4-SO 2 -NH 2 C(O) H 4-CH 3 -cyclohexyl 4-SO 2 -NH 2 C(O) H 4-CH 3 -cyclohexyl 4-SO 2 -NH 2 C(O) H 4-(CH 2 ) 3 CH 3 -cyclohexyl 4-SO 2 -NH 2 C(O) H 5-(2-pyridinyl)2-thienyl 4-SO 2 -NH 2 C(O) H 3-(lH-pyrrol-l-yl)2-thieny 4-SO 2 -NH 2 1 C(O) H 5-[C(CΗ 3 ) 3 ]2-thienyl 4-SO 2 -NH 2 C(O) H 5-[(CH) 2 C(O)OC(CH 3 ) 3 ]2-t 4-SO 2 -NH 2 hienyl C(O) H Ph(C) 2 4-SO 2 -NH 2 C(O) H (2,6-F 2 -3-NO 2 )Ph 4-SO 2 -NH 2 C(O) H (2,6-F 2 -3-NH 2 )Ph 4-SO 2 -NH 2 C(O) H [2,6-(CH 3 ) 2 ]Ph 4-SO 2 -NH 2 C(O) H (2-CH 3 )Ph 4-SO 2 -NH 2 C(O) H [2,6-F 2 -3-CH(OH)CH 3 ]Ph 4-SO 2 -NH 2 C(O) H (2,6-F 2 )Ph 4-SO 2 -NH 2 C(O) H (2,6-F 2 -3-CH 3 )Ph 4-SO 2 -NH 2 C(O) H (2,6-F 2 )Ph H C(O) H Ph H SO SO SO SO SO SO 00 00 00 00 00 00 00 00 00 00 -4 -4 μ-ι © 00 0> ≤ ON (Λ 4i. W I>> l-' © S0 00 l ©> ( Λ *>. U ) I ι-* © so oo -j s » *. o n n n n n o n o n n a n n a n o p n o p O O O O O O O O o o o o o o o o o o o o o o o o o o o o " o o O O O O o S o O O ffi HI 96 C(O) H (2,6-F 2 )Ph 4-(l-H-l,2,4-triazol-l-yl) 97 C(O) H (5-CH 2 CH 3 )2-thienyl 4-(l-H-l,2,4-triazol-l-yl) 98 C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-(l-H-l,2,4-triazol-l-yl) 99 C(O) H (3-CH 3 )2-thienyl 4-(l-H-l,2,4-triazol-l-yl) 100 C(0) H (2,6-F 2 )Ph 4-(l-H-l,3,4-triazol-l-yl) 101 C(O) H (2,6-F 2 -3-CH 3 )Ph 4-(l-H-l,3,4-triazol-l-yl) 102 C(0) H (3-CH 3 )2-thienyl 4-(l-H-l,3,4-triazol-l-yl) 103 C(O) H (5-CH 2 CH 3 )2-thienyl 4-SO 2 - NΗ[(CΗ 2 ) 2 N(CΗ 3 ) 2 ] 104 C(O) H (3-CH 3 )2-thienyl 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ] 105 C(O) H (2,6-F 2 -3-CH 3 )Ph 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ] 106 C(O) H (2,6-F 2 )Ph 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ] 107 C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ] 108 C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-NH-SO 2 -CH 3 109 C(O) H (3-CH 3 )2-thienyl 4-NH-SO 2 -CH 3 110 C(O) H (5-CH 2 CH 3 )2-thienyl 4-NH-SO 2 -CH 3 111 C(O) H (2,6-F 2 )Ph 4-NH-SO 2 -CH 3 112 C(O) H (2,6-F 2 -3-CH 3 )Ph 4-NH-SO 2 -CH 3 113 C(O) H (3-CH 3 )2-thienyl 4-(2-imidazolidinone) 114 C(O) H (2,6-F 2 -3-CH 3 )Ph 4-(2-imidazolidinone) 115 C(O) H (2,6-F 2 )Ph 4-(2-imidazolidinone) 116 C(O) H (3-CH 3 )2-thienyl 4-(l,l-dioxido-2- isothiazolidinyl) 117 C(O) H (2,6-F 2 )Ph 4-(l,l-dioxido-2- isothiazolidinyi) 118 C(O) H (2,6-F 2 )Ph 4-SO 2 -NH-2-pyridinyl 119 C(O) H (5-CH 2 CH 3 )2-thienyl 4-SO 2 -NH-2-pyridinyl 120 C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-SO 2 -NH-2-ρyridinyl and, 121 C(O) H (3-CH 3 )2-thienyl 4-SO 2 -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): Formula (Id) wherein X, R 3 an R 4 i are dependently selected from: Cpd X R 3 R 4 122 C(0) (2,6-F 2 )Ph 4-SO 2 -NH 123 C(0) (2,6-F 2 -3-CH 3 )Ph 4-SO 2 -NH : 124 C(0) (2,6-F 2 )Ph H 125 C(O) Ph H 126 C(O) (2,6-F 2 )Ph 3-Cl 127 C(O) Ph 3-Cl and, 128 C(S) -NH[(2,6-F 2 )Ph] 4-SO, -NH. and pharmaceutically ; acceptable salts thereof. Exemplified compounds of the present invention include a compound of Formula (I) selected from a compound of Formula (Ie): Formula (Ie) wherein R x and R 3 are dependently selected from: Cpd R, R 3 79 CH 3 (3-CH 3 )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" (Ret? International J. Pharm., 1986, 33, 201-217; J Pharm.Scl, 1997 (Jan), 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, aleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, j?-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 aN 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 aN 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 (NEGF) receptor. This protein is associated with both normal and pathological angiogenesis. The NEGF receptors are tripartite, consisting of an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. Presently there are two known NEGF receptors: (1) NEGF-R2 (KDR/Flkl/NEGF-R2), a receptor that mediates the biological activities of mitogenesis and proliferation of endothelial cells; and (2) NEGF-R1 (Fltl/NEGF- Rl), a receptor that mediates functions such as endothelial cell adhesion, inhibition of NEGF-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., etal., 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 Fonnula (I) or pharmaceutical composition thereof and an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder or the essentially simultaneous admimstration 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-NEGF-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-l-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 refened 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, R 3 and R 4 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 fonn 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 "CSC1 2 " thiophosgene "DIC" diisopropyl carbodiimide "DMF" N,N-dimethylformamide "EDCI" ethyl dimethylaminopropyl carbodiimide "HOBT" hydroxybenzyl triazole "NH 2 NH 2 " 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-l-[(3-methyl-2-thienyl)carbonyl]-lH-l,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 Al (prepared according to R. L. McKee and R. W. Bost, J Am. Chem. Soc, 1946, 68, 2506-2507) (wherein R_ 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 stireed 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 R 3 CO 2 H or R 3 COCl (wherein R 3 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. NCN PhcΛoPh R i N R1 - N H 2 B2 Ph NH 2 NH 2 1 ^ *- H A4 B1 B3 Scheme C Compound Cl (CAS # 1455-77-2) was dissolved in a suitable solvent and reacted with R 3 CO 2 H or R 3 COCl (wherein R 3 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 R r halo (wherein R_ and halo are as previously defined; in addition to halo, R_ 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. N IN-N I HΠ R rv 3 β--COuT 2 πH _ H 2 N- NH 2 ° r R3CbCI C1 C2 Scheme D Alternatively, Compound Dl (CAS# 24807-56-5) was dissolved in a suitable solvent and reacted with R ! NH 2 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. N Br- A4 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 El. Compound El was purified, dissolved in a suitable solvent and then reacted with R 2 -halo (wherein R 2 and halo are as previously defined; in addition to halo, R 2 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 R 3 CO 2 H or R 3 COCl (wherein R 3 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 R 2 -halo (wherein R 2 and halo are as previously defined; in addition to halo, R 2 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. ! H and 13 C 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, New Jersey), 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 unconected. Electrospray mass spectra (MS-ES) were recorded on a Hewlett Packard 59987A spectrometer. Example 1 4-[[5-amino-l-(2,6-difluorobenzoyl)-lH-l,2,4-triazol-3-yl]amino]-benzenesulfonamide (Cpd 1) A suspension of l-amidino-3,5-dimethylpyrazole nitrate Compound IC (2.012 g, 10 mmol) and potassium hydroxide powder (0.561g, 10 mmol) in DMF (8 mL) at 0 °C was added to a DMF solution (3 mL) of isocyanate Compound IB (prepared from sulfanilamide Compound 1 A 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, stnred 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 ID as yellow powder (2.5513 g); m.p. 69-80 °C (decomposed); Η NMR (300 MHz, CD 3 OD) δ 7.90 (m, 4H), 6.05 (s, IH), 2.22 (s, 3H), 2.20 (s, 3H); (CDC1 3 ) δ 10.75 (s, br, IH), 8.35 (s, br, IH), 7.90 (q, 4H), 7.65 (s, br, 2H), 5.95 (s, IH), 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 ID (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 IE as a gray solid (0.8722 g, 64%). m.p. 291 - 296 °C (decomposed); Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.20 (s, IH), 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 IF (41.4 uL, 0.33 mmol) was added to a solution of the intermediate Compound IE (63.6 mg, 0.25 mmol) dissolved in anhydrous pyridine (2.5 mL) in an ice-water bath. The resulting reaction mixture was stined 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); Η NMR (300 MHz, CD 3 OD) δ 7.65 (m, 3H), 7.55 (d, 2H), 7.18 (t, 2H); ((CD 3 ) 2 SO) δ 9.86 (s, IH), 8.03 (s, 2H), 7.72 (m, IH), 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); 13 C NMR (300 MHz, (CD 3 ) 2 SO) 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 C 15 H 12 F 2 N 6 O 3 S: C, 45.69; H, 3.07; N, 21.31. Found: C, 45.29; H, 3.04; N, 20.89. 1 E Compound 1 Using the procedure for Example 1, the following compounds were prepared by acylation of the intermediate Compound IE using the indicated starting material in place of Compound IF and reagent(s): Cpd Name/Data Starting Mat'l 2 4-[[5-amino- 1 -(2,6-difluoro-3-methylbenzoyl)- IH- 1 ,2,4- 2,6-difluoro-3- triazol-3-yl]amino]-benzenesulfonamide methylbenzoyl chloride in Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.80 (s, IH), 7.78-7.55 anhydrous pyridine (m, 5H), 7.52 (s, 2H), 7.12 (t, 2H), 6.38 (s, 2H), 2.22 (s, 3H); MS (ESI) m/z: 409 (M+H + ), 431 (M+Na + ) 3 4-[[5-amino-l-(2,3,6-trifluorobenzoyl)-lH-l,2,4-triazol- 2,3,6- 3-yl]amino]-benzenesulfonamide trifluorobenzoyl chloride in ] Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.85 (s, IH), 7.78-7.50 anhydrous pyridine (m, 7H), 7.32 (m, IH), 6.38 (s, 2H); MS (ESI) m/z: 413 (M+H + ), 435 (M+Na + ) 4-[[5-amino-l-(2-fluorobenzoyl)-lH-l,2,4-triazol-3- 2-fluorobenzoyl yl] amino] -benzenesulfonamide chloride in anhydrous pyridine Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.90 (s, br, IH), 8.00 (s, br, 2H), 7.82 (t, IH), 7.78-7.20 (m, 7H), 6.35 (s, br, 2H); MS (ESI) m/z: 377 (M+H + ), 399 (M+Na + ) 4-[[5-amino-l-(2,4-difluorobenzoyl)-lH-l,2,4-triazol-3- 2,4- y 1] amino] -b enzenesulfonamide difluoromethylbenz oyl chloride in Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.88 (s, IH), 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 + ) 4-[[5-amino-l-[2-fluoro-6-(trifluoromethyl)benzoyl]-lH- 2-fluoro-6- 1 ,2,4-triazol-3 -yl] amino] -benzenesulfonamide (trifluoromethyl)- benzoyl chloride hi Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.86 (s, IH), 8.06 (s, THF 2H), 7.85 (m, 3H), 7.54 (d, J=8.9 Hz, 2H), 7.40 (d, J= 8.9 Hz, 2H), 7.09 (s, 2H); MS (ESI) m/z: 445 (M+ H + ), 467 (M+Na + ) 4-[[5-amino-l-(2,6-dichlorobenzoyl)-lH-l,2,4-triazol-3- 2,6-dichlorobenzoyl yl] amino] -benzenesulfonamide chloride in anhydrous pyridine Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.82 (s, IH), 7.68-7.45 (m, 9H), 6.35 (s, 2H); (CD 3 OD) δ 7.60 (d, 2H), 7.55 (m, 3H), 7.38 (d, 2H); MS (ESI) m/z: 428 (M+H + ), 450 (M+Na + ) 4-[[5-amino-l-(2,4,6-trichlorobenzoyl)-lH-l,2,4-triazol- 2,4,6- 3 -yl] amino] -benzenesulfonamide trichlorobenzoyl chloride in Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.88 (s, IH), 7.78 (s, anhydrous pyridine 2H), 7.75-7.48 (m, 6H), 6.38 (s, 2H); MS (ESI) m/z: 462 (M+H + ), 484 (M+Na + ) 4-[[5-amino-l-(2-nitrobenzoyl)-lH-l,2,4-triazol-3- 2-nitrobenzoyl yl] amino]-benzenesulfonamide chloride in anhydrous pyridine Η NMR (300 MHz, CD 3 OD) δ 8.28 (d, 2H), 8.95-7.85 (m, 3H), 7.62 (d, 2H), 7.35 (d, 2H); MS (ESI) m/z: 404 (M+H + ), 426 (M+Na + ) 4-[[5-amino- 1 -(2,6-dimethoxybenzoyl)- IH- 1 ,2,4-triazol- 2,6- 3 -yl] amino] -benzenesulfonamide dimethoxybenzoyl chloride in Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.65 (s, br, IH), 7.68 anhydrous pyridine (m, 4H), 7.50 (d, IH), 7.30 (s, br, 2H), 6.72 (d, IH), 6.68 (dd, IH), 6.35 (s, br, 2H), 3.92 (s, 3H), 3.85 (s, 3H); MS (ESI) m/z: 419 (M+H + ), 441 (M+Na + ) 4-[[5-amino-l-(2,4,6-trimethylbenzoyl)-lH-l,2,4-triazol- 2,4,6- 3 -yl] amino] -benzenesulfonamide trimethylbenzoyl chloride in Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.78 (s, IH), 7.78 (s, anhydrous pyridine 2H), 7.72-7.43 (m, 5H), 7.75-6.78 (m, 3H), 6.35 (s, 2H), 2.38-2.16 (m, 9H); MS (ESI) m/z: 401 (M+lf), 423 (M+Na + ) 4-[(5 -amino- 1 -benzoyl- IH- 1 ,2,4-triazol-3-yl)amino]- Benzoyl chloride in benzenesulfonamide anhydrous pyridine Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.80 (s, IH), 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 + ) 4-[[5-amino- 1 -(2-thienylcarbonyl)- 1H-1 ,2,4-triazol-3- Thiophene-2- yl] amino] -b enzenesulfonamide carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.92 (s, IH), 8.40 (dd, DIC/HOBt (1- IH), 8.12 (dd, IH), 7.88 (q, 4H), 7.50 (s, 2H), 7.32 (t, hydroxybenzo IH), 6.45 (s, 2H); MS (ESI) m/z: 365 (M+H÷), 387 triazole) in (M+Na + ) anhydrous DMF 4- [[5-amino- 1 - [(3 -methyl-2-thienyl)carbonyl]- IH- 1 ,2,4- 3-methyl- triazol-3-yl]amino]-benzenesulfonamide thiophene-2- m.p. 280 - 284 °C; Η NMR (300 MHz, (CD 3 ) 2 SO) δ carboxylic acid 9.88 (s, IH), 8.05 (d, IH), 7.88 (s, 2H), 7.78 (q, 4H), 7.15 mediated by (m, 3H), 2.62 (s, 3H); DIC HOBt in anhydrous DMF (CD 3 ),CO δ 8.92 (s, IH), 7.98 (d, IH), 7.90 (q, 4H), 7.45 (s, 2H), 7.15 (d, IH), 6.42 (s, 2H), 2.68 (s, 3H); 13 C NMR (300 MHz, (CD 3 ) 2 SO) 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 + ) 4-[[5-amino- l-[(3-fluoro-2-thienyl)carbonyl]- IH- 1 ,2,4- 3-fluorothiophene- triazol-3-yl]amino]-benzenesulfonamide 2-carboxylic acid (prepared according Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.92 (s, br, IH), 8.18 to E. C. Taylor and (t, IH), 7.92 (s, br, 2H), 7.78 (q, 4H), 7.25 (d, IH), 7.18 P. Zhou, Org. Prep. (s, br, 2H); MS (ESI) m z: 383 (M+H 4 ), 405 (M+Na + ) Proced. Int., 1997, 29, 221) mediated by DIC/HOBt in anhydrous DMF 4-[[5-amino-l-[(3-chloro-2-thienyl)carbonyl]-lH-l,2,4- 3 -chlorothiophene- triazol-3 -yl] amino] -benzenesulfonamide 2-carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.92 (s, br, IH), 8.25 EDCI/HOBt in (d, IH), 7.95 (s, br, 2H), 7.78 (q, 4H), 7.32 (d, IH), 7.18 anhydrous DMF (s, br, 2H); MS (ESI) m/z: 399 (M+lF), 421 (M+Na + ) 4-[[5-amino-l-[(3-ethoxy-2-thienyl)carbonyl]-lH-l,2,4- 3 -ethoxythiophene- triazol-3-yl]amino]-benzenesulfonamide 2-carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.85 (s, br, IH), 8.08 DIC HOBt in (d, IH), 7.85-7.75 (m, 6H), 7.28 (d, IH), 7.15 (s, br, 2H); anhydrous DMF MS (ESI) m/z: 409 (M+H + ), 431 (M+Na + ) N-[2-[[5-amino-3-[[4-(aminosulfonyl)phenyl]amiιιo]-lH- 3-(acetylamino)- 1 ,2,4-triazol- 1 -yl]carbonyl]-3-thienyl]-acetamide thioρhene-2- carboxylic acid Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 11.0 (s, br, IH), 9.92 mediated by (s, br, IH), 8.18 (q, 2H), 7.85 (s, br, 2H), 7.78 (q, 4H), DIC/HOBt in 7.15 (s, br, 2H), 2.20 (s, 3H); MS (ESI) m/z: 421 anhydrous DMF (M+H + ), 444 (M+Νa + ) 4-[[5-amino-l-[(5-methyl-2-thienyl)carbonyl]-lH-l,2,4- 5-methyl- triazol-3-yl]amino]-benzenesulfonamide thiophene-2- carboxylic acid Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.92 (s, br, IH), 8.15 mediated by (d, IH), 7.85 (s, br, 2H), 7.78 (q, 4H), 7.20 (s, br, 2H), DIC/HOBt in 7.08 (d, IH), 2.62 (s, 3H); MS (ESI) m/z: 379 (M+H + ) anhydrous DMF 4-[[5-amino- 1 -[(5-bromo-2-thienyl)carbonyl]- IH- 1 ,2,4- 5-bromofhiophene- triazol-3 -yl] amino] -benzenesulfonamide 2-carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.98 (s, br, IH), 8.05 DIC HOBt in (d, IH), 7.95 (s, br, 2H), 7.78 (q, 4H), 7.48 (d, IH), 7.20 anhydrous DMF (s, br, 2H); MS (ESI) m z: 444 (M+H + ) 4-[[l-[(5-acetyl-2-thienyl)carbonyl]-5-amino-lH-l,2,4- 5 -acetylthiophene- triazol-3-yl]amino]-benzenesulfonamide 2-carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 10.02 (s, br, IH), 8.28 DIC HOBt in (d, IH), 8.02 (d, IH), 7.95 (s, br, 2H), 7.75 (q, 4H), 7.20 anhydrous DMF (s, br, 2H), 2.65 (s, 3H); MS (ESI) m/z: 407 (M+H + ), 429 (M+Na + ) 4-[[5-amino-l-(2-furanylcarbonyl)-lH-l,2,4-triazol-3- 2-furoyl chloride in yl] amino] -b enzenesulfonamide anhydrous pyridine Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.87 (s, IH), 8.20 (d, IH), 8.02 (dd, IH), 7.85 (q, 4H), 7.48 (s, 2H), 6.88 (dd, IH), 6.42 (s, 2H); MS (ESI) m/z: 349 (M+H + ), 371 (M+Na + ) 4-[[5-amino- 1 -(5-isoxazolylcarbonyl)- IH- 1 ,2,4-triazol-3 - isoxazole-5- yl]amino]-benzenesulfonamide carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.95 (s, br, IH), 8.92 DIC/HOBt in (d, IH), 8.00 (s, br, 2H), 7.78 (d, 2H), 7.68 (m, 3H), 7.15 anhydrous DMF (s, br, 2H); MS (ESI) m/z: 350 (M+lT), 372 (M+Na + ) 4-[[5-amino-l-(2-pyridinylcarbonyl)-lH-l,2,4-triazol-3- picolic acid yl]amino]-benzenesulfonamide mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.75 (s, IH), 8.72 (d, anhydrous DMF IH), 8.00 (m, 2H), 7.90 (s, br, 2H), 7.68-7.48 (m, 5H), 7.10 (s, br, 2H); MS (ESI) m/z: 360 (M+H÷), 382, (M+Na + ) 4-[[5-amino- 1 -(3-pyridinylcarbonyl)- IH- 1 ,2,4-triazol-3- nicotinic acid yl]amino]-benzenesulfonamide mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.82 (s, IH), 9.22 (d, anhydrous DMF IH), 8.78 (dd, IH), 8.45 (dd, IH), 7.92 (s, br, 2H), 77.62 (q, 4H), 7.15 (s, br, 2H); MS (ESI) m/z: 360 (M+H÷), 382, (M+Na + ) 4-[[5-amino-l-(4-pyridinylcarbonyl)-lH-l,2,4-triazol-3- isonicotinic acid yl] amino] -benzenesulfonamide mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.80 (s, IH), 8.82 (d, anhydrous DMF 2H), 8.00-7.90 (m, 4H), 7.60 (q, 4H), 7.12 (s, br, 2H); MS (ESI) m/z: 360 (M+Ε ), 382, (M+Na + ) 4-[[5-amino-l-(3-thienylcarbonyl)-lH-l,2,4-triazol-3- thiophene-3 - yl] amino] -benzenesulfonamide carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 CO) δ 9.08 (d, IH), 8.85 (s, DIC/HOBt in br, IH), 7.98 (dd, IH), 7.82 (q, 4H), 7.62 (dd, IH), 7.48 anhydrous DMF (s, br, IH), 6.45 (s, br, 2H); MS (ESI) m/z: 365 (M+Efj, 387 (M+Na + ) 4-[[5-amino-l-(benzo[b]thien-2-ylcarbonyl)-lH-l,2,4- benzo[b]thiophene- triazol-3 -yl] amino] -benzenesulfonamide 2-carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.95 (s, br, IH), 8.85 DIC/HOBt in (s, IH), 8.15 (dd, 2H), 8.02 (s, br, 2H), 7.85 (q, 4H), 7.55 anhydrous DMF (m, 2H), 7.18 (s, br, 2H); MS (ESI) m/z: 415 (M+H + ) 4-[[5-amino-l-[(2,4-dimethyl-5-thiazolyl)carbonyl]-lH- 2,4- 1 ,2,4-triazol-3 -yl] amino] -benzenesulfonamide dimethylfhiazole-5- carboxylic acid Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.88 (s, br, IH), 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 4-[[5-amino-l-[(3-bromo-2-thienyl)carbonyl]-lH-l,2,4- 3 -bromothiophene- triazol-3-yl]amino]-benzenesulfonamide 2-carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.95 (s, IH), 8.23 (d, DIC HOBt in J=5.3,1H), 7.95 (s, 2H), 7.77 (s, 4H), 7.39 (d, J=5.3, IH), anhydrous DMF 7.16 (s, 2H); MS (ESI) m/z: 444.9 (M+H), 466.9 (M+Na + ) 4-[[5-amino-l-[(4-methyl-l,2,3-thiadiazol-5- 4-methyl- 1,2,3 - yl)carbonyl] - IH- 1 ,2,4-triazol-3 -yl] amino] - thiadiazol-5- benzenesulfonamide carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 10.07 (s, IH), 8.09 (s, DIC HOBt in 2H), 7.86 (d, J=8.8, 2H), 7.72 (d, J=8.9, 2H), 7.21(s, 2H), anhydrous DMF 3.02 (s, 3H); MS (ESI) m/z: 381.0 (M+H), 403.0 (M+Na + ) 4-[[5-amino-l-(l,2,3-thiadiazol-4-ylcarbonyl)-lH-l,2,4- 1 ,2,3-thiadiazole-4- triazol-3 -yl] amino] -benzenesulfonamide carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 SO) δ 10.18 (s, IH), 9.93 (s, DIC/HOBt in IH), 8.05 (s, 2H), 7.76 (d, J=8.8, 2H), 7.63(d, J=8.8, 2H), anhydrous DMF 7.16 (s, 2H); MS(ESI) m/z: 367.0 (M+H), 389.0 (M+Na + ) 4-[[5-amino-l-(cyclopentylcarbonyl)-lH-l,2,4-triazol-3- cyclopetanecarboxy yl] amino] -benzenesulfonamide lie acid mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.73 (s, IH), 7.69 (s, anhydrous DMF 4H), 7.65 (s, 2H), 7.13 (s, 2H), 1.78 (m, 3H), 1.65 (m, 6H); MS (ESI) m/z: 351.0 (M+H), 373.0 (M+Na + ) 4-[[5-amino- 1 -(cyclohexylcarbonyl)- 1H-1 ,2,4-triazol-3- cyclohexanecarbox yl]amino]-benzenesulfonamide ylic acid mediated by DIC HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.76 (s, IH), 7.69 (s, anhydrous DMF 4H), 7.66 (s, 2H), 7.13 (s, 2H), 1.98 (s, 2H), 1.80 (s, 2H), 1.69 (d, IH), 1.36 (m, 6H); MS (ESI) m/z: 365.0 (M+H), 387.1 (M+Na + ) 4-[[5-amino-l-(2-thienylacetyl)-lH-l,2,4-triazol-3- 2-thiopheneacetic yl] amino] -benzenesulfonamide acid mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.80 (s, IH), 7.73 (d, anhydrous DMF J=1.2, 4H), 7.69 (s, 2H), 7.45 (dd, J=1.5, IH), 7.16 (s, 2H), 7.08 (d, J=2.7, IH), 7.01 (t, J=5.1, IH), 4.52 (s, 2H); MS (ESI) m/z: 379.0 (M+H), 400.9 (M+Na + ) 4-[[5-amino- 1 -[(2E)-1 -oxo-3-(2-thienyl)-2-propenyl]- 1H- 3-(2-thienyl)acrylic l,2,4-triazol-3-yl]amino]-benzenesulfonamide acid mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.82 (s, IH), 7.92 (d, anhydrous DMF J=8.3, IH), 7.72 (s, 4H), 7.35 (d, J=15.8, 2H), 7.26 (d, J=19.5, 3H), 7.15 (s, 2H), 6.26 (s, IH); MS (ΕSI) m/z: 391.0 (M+H), 412.9 (M+Na + ) 4-[[5-amino-l -[(2,6-difluoroρhenyl)acetyl]- IH- 1 ,2,4- 2,6-difluorophenyl triazol-3-yl]amino]-benzenesulfonamide acetic acid mediated Η NMR (300 MHz, (CD 3 ) 2 SO) δ by DIC/HOBt in 9.81 (s, IH), 7.69 (s, 6H), 7.44 (t, J=16.6, IH), 7.16 (s, anhydrous DMF 3H), 4.37 (s, 2H); MS (ΕSI) m z: 409.0 (M+H), 431.0 (M+Na + ) 4-[[5-amino-l-[(2E)-3-(2,6-difluorophenyl)-l-oxo-2- 2,6-difluoro propenyl]-lH-l,2,4-triazol-3-yl]amino]- cinnamic acid benzenesulfonamide mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.86 (s, IH), 7.85 (d, anhydrous DMF J=4.7, 2H), 7.71 (s, 4H), 7.31 (m, 4H), 7.16 (s, 2H), 6.31 (s, IH); MS (ΕSI) m z: 421.0 (M+H), 442.9 (M+Na + ) 4-[[5-ammo-l-(cycloheptylcarbonyl)-lH-l,2,4-triazol-3- cycloheptanecarbox yl]amino]-benzenesulfonamide ylic acid mediated by DIC/HOBt in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.75 (s, IH), 7.69 (s, anhydrous DMF 4H), 7.66 (s, 2H), 7.12 (s, 2H), 2.00 (d, J=11.7, 2H), 1.77 (d, J=10.5, 2H), 1.40 (m, 3H), 1.07 (m, 2H), 0.91 (d, J=6.4, 4H); MS (ΕSI) m/z: 254, 379.0 (M+H), 401.0 (M+Na + ) 4-[[5-amino-l -[(4-methylcyclohexyl)carbonyl]- IH- 1 ,2,4- trans-4-methy 1- 1 - triazol-3-yl]amino]-benzenesulfonamide cyclohexanecarbox ylic acid mediated Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.75 (s, IH), 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 (ΕSI) m/z: 254, 379.0 (M+H), 401.0 (M+Na + ) 4-[[5-amino- 1 -[(2-methylcyclohexyl)carbonyl]-lH- 1 ,2,4- 2-mefhyl-l- triazol-3-yl]amino]-benzenesulfonamide cyclohexanecarbox ylic acid mediated Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.75 (s, IH), 7.68 (s, by DIC/HOBt in 4H), 7.66 (s, 2H), 7.13 (s, 2H), 1.55 (m, 9H), 0.85 (d, anhydrous DMF J=6.0, 4H); MS (ΕSI) m/z: 254, 379.0 (M+H), 401.0 (M+Na + ) 4-[[5-amino-l-[(4-butylcyclohexyl)carbonyl]- IH- 1 ,2,4- trans-4-butyl-l- triazol-3-yl]amino]-benzenesulfonamide cyclohexanecarbox ylic acid mediated Η NMR (300 MHZ, (CD 3 ) 2 SO) δ 9.75 (S, IH), 7.68 (S, by DIC/HOBt in 4H), 7.66 (S, 2H), 7.12 (S, 2H), 2.02 (D, J=11.3, 2H), anhydrous DMF 1.82 (D, J=9.9, 2H), 1.40 (D, J=11.3, 2H), 1.25 (S, 7H), 1.02 (M, 4H), 0.87 (S, 4H). MS (ΕSI) M/Z: 254, 435.1 (M+H), 457.1 (M+NA + ) 4-[[5-amino-l-[[5-(2-pyridinyl)-2-thienyl]carbonyl]-lH- 5-(2-pyridyl)- 1 ,2,4-triazol-3-yl]amino]-benzenesulfonamide thiophene-2- carboxylic acid Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.98 (s, IH), 8.65 (d, mediated by IH), 8.25 (d, IH), 8.08 (d,lH), 8.02 - 7.75 (m, 8H), 7.42 DIC/HOBt in (dd, IH), 7.20 (s, 2H). MS (ΕSI) m/z: 442 (M+H + ), 464 anhydrous DMF (M+Na + ) 4-[[5-amino-l-[[3-(lH-pynol-l-yl)-2-thienyl]carbonyl]- 3-(lH-ρynol-l-yl)- 1H- 1 ,2,4-triazol-3 -yl] amino] -benzenesulfonamide thiophene-2- carboxylic acid Η NMR (300 MHz, (CD 3 ),SO) δ 9.85 (s, IH), 8.18 (d, mediated by IH), 7.85 - 7.70 (m, 6H), 7.32 (d, IH), 7.18 (s, 2H), 7.12 DIC HOBt in (t, 2H), 6.20 (t, 2H). MS (ESI) m/z: 430 (M+H + ) anhydrous DMF 4-[[5-amino- 1 -[[5-(l , 1 -dimethylethyl)-2- 5-tert- thienyl] carbonyl] - IH- 1 ,2,4-triazol-3 -yl] amino] - butylthiophene-2- benzenesulfonamide carboxylic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.95 (s, IH), 8.25 (d, DIC/HOBt in IH), 7.95 (d, 2H), 7.85 (d, 2H), 7.50 (s, 2H), 7.18 (d, anhydrous DMF IH), 6.48 (s, 2H), 1.55 (s, 9H). MS (ESI) m/z: 421 (M+PT), 443 (M+Na + ) 3-[5-[[5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-lH- 5-(2-tert- l,2,4-triazol-l-yl]carbonyl]-2-thienyl]-(2E)-2-propenoic buioxycarbonyl- acid-l,l-dimethylethyl ester vinyl)-thiophene-2- carboxylic acid Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.95 (s, IH), 8.22 (d, (prepared by Heck IH), 7.95 (s, 2H), 7.82-7.68 (m, 6H), 7.15 (s, 2H), 6.52 reaction of 5- (d, IH), 1.52 (s, 9H). MS (ESI) m/z: 491 (M+H + ), 513 bromothiophene-2- (M+Na + ) carboxylic acid and 5-(2-tert-butoxycarbonyl-vinyl)-thiophene-2-carboxylic t-butyl acrylate) acid (intermediate) Η NMR (300 MHz, (CD 3 ) 2 CO) δ mediated by 7.80-70 (m, 2H), 7.48 (d, IH), 7.32 (d, IH), 1.50 (s, 9H); DIC/HOBt in MS (ESI) m/z: 253 (M-H + ), 209 (M-H÷-CO,) anhydrous DMF 4-[[5-amino- 1 -[[5-(phenylethynyl)-2-thienyl]carbonyl]- 5-phenylethynyl- 1 H- 1 ,2,4-triazol-3 -yl] amino] -benzenesulfonamide thiophene-2- carboxylic acid Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.98 (s, IH), 8.20 (d, (intermediate IH), 7.95 (s, 2H), 7.78 (m, 4H), 7.62 (m, 2H), 7.60 (d, prepared by IH), 7.45 (m, 3H), 7.18 (s, 2H). MS (ESI) m/z: 465 oxidation of 5- (M+H + ), 487 (M+Na + ) phenylethynyl- 5 -phenylethynyl-thiophene-2-carboxylic acid thiophene-2- (intermediate) Η NMR (300 MHz, (CD 3 ),CO) δ 7.98 (d, carboxaldehyde), IH), 7.58 (m, 2H), 7.45 (m, 3H), 7.35 (d, IH); MS (ESI) mediated by m/z: 229 (M+H + ) DIC/HOBt in anhydrous DMF 4-[[5-amino-l-(2,6-difluoro-3-nitrobenzoyl)-lH-l,2,4- 2,6-difluoro-3- triazol-3 -yl] amino] -benzenesulfonamide nitro-benzoic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.90 (s, IH), 8.55 (m, DIC/HOBt in IH), 7.75-7.50 (m, 7H), 6.25 (s, 2H); MS (ESI) m/z: 440 anhydrous DMF (M+H + ), 462 (M+Na + ) 4-[[5-ammo-l-(3-amino-2,6-difluorobenzoyl)-lH-l,2,4- catalytic triazol-3 -yl] amino] -benzenesulfonamide hydrogenation of compound 54 in Η NMR (300 MHz, (CD 3 OD) δ 7.68 (d, 2H), 7.45 (d, methanol by 2H), 6.95 (m, IH), 6.85 (m, IH); MS (ESI) m/z: 410 catalysis of 10% (M+H*), 432 (M+Na + ) palladium on charcoal 4-[[5-amino-l-(2,6-dimethylbenzoyl)-lH-l,2,4-triazol-3- 2,6- y 1] amino] -b enzenesulfonamide dimethylbenzoic acid mediated by Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.75 (s, IH), 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 + ) 4-[[5-amino- 1 -(2-methylbenzoyl)- 1 H- 1 ,2,4-triazol-3 - 2-methylbenzoyl yl]amino]-benzenesulfonamide chloride in anhydrous pyridine Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.75 (s, IH), 7.72-7.25 (m, 10H), 6.35 (s, 2H), 2.45 (s, 3H); MS (ESI) m/z: 373 (M+H + ), 395 (M+Na + ) 5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6- 2,6-difmorophenyl difluorophenyl)- IH- 1 ,2,4-triazole-l -carbothioamide isothiocyanate in anhydrous pyridine Η NMR (300 MHz, (CD 3 ) 2 CO) δ 10.40 (s, IH), 8.90 (s, IH), 8.15 (s, 2H), 7.85 (d, 2H), 7.75 (d, 2H), 7.40 (m, IH), 7.15 (m, 2H), 6.35 (s, 2H), 5.75 (s, 2H); MS (ESI) m/z: 426 (M+H + ), 448 (M+Na + ) 5-amino-3 - [ [4-(aminosulfonyl)phenyl] amino] -N-(2,6- 2,6-difmorophenyl difluorophenyl)- IH- 1 ,2,4-triazole- 1 -carboxamide isocyanate in anhydrous DMF Η NMR (300 MHz, (CD 3 ) 2 CO) δ 9.15 (s, IH), 8.80 (s, IH), 7.80 (d, 2H), 7.70 (d, 2H), 7.42 (m, IH), 7.15 (m, 2H), 7.00 (s, 2H), 6.35 (s, 2H); MS (ESI) m/z: 410 (M+H + ), 432 (M+Na + ) 4-[[5-amino-l-[(2,6-difluorophenyl)sulfonyl]-lH-l,2,4- 2,6- triazol-3 -yl] amino] -benzenesulfonamide difluorobenzenesulf onyl chloride in Η NMR (300 MHz, (CD 3 ) 2 CO) δ 8.80 (s, IH), 7.85 ( , anhydrous pyridine IH), 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 1" ), 453 (M+Na + ) 4-[[5-amino- 1 -(2-chloro-6-fluoro-3-methylbenzoyl)- 1H- 2-chloro-6-fluoro-3- l,2,4-triazol-3-yl]amino]-benzenesulfonamide methylbenzoyl chloride in Η NMR (300MHz, (CD 3 ) 2 SO) δ 9.85 (s, IH), 8.05 (s, anhydrous pyridine 2H), 7.64-7.55 (m, 3H), 7.45-7.35 (m, 3H), 7.10 (s, 2H), 2.38 (s, 3H); MS (ESI) m z: 425 (M+H÷), 447 (M+Na + ) 70 4-[[5-amino-l-(2-chloro-6-fluorobenzoyl)-lH-l,2,4- 2-chloro-6-fluoro triazol-3-yl]amino]-benzenesulfonamide benzoyl chloride in anhydrous pyridine Η NMR (300MHz, (CD 3 ) 2 SO) δ 9.87 (s, IH), 8.05 (s,2H), 7.68-7.63 (m, IH), 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)- IH- 1 ,2,4- 3-chloro-2,6- triazol-3-yl]amino]-benzenesulfonamide difluorobenzoic acid, mediated by Η NMR (300MHz, (CD 3 ) 2 SO) δ 9.89 (s, IH), 8.07 (s, DIC/HOBt in 2H), 8.00-7.92 (m,lH), 7.59 (d, 2H), 7.49-7.44 (m, 3H), anhydrous DMF 7.12 (s, 2H); MS (ESI) m/z: 429 (M+H + ) 122 4-[[3-amino-l-(2,6-difluorobenzoyl)-lH-l,2,4-triazol-5- 2,6-difluorobenzoyl yl] amino] -benzenesulfonamide chloride in (minor regioisomer of Cpd 1) *Η NMR (300 MHz, anhydrous pyridine CD 3 CN) δ 9.90 (s, IH), 7.90 (q, 4H), 7.60 (m, IH), 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-l-(2,6-difluoro-3-methylbenzoyl)-lH-l,2,4- 2,6-difluorobenzoyl triazol-5-yl]amino]-benzenesulfonamide chloride in (minor regioisomer of Cpd 2) *Η NMR (300 MHz, anhydrous pyridine ((CD 3 ) 2 SO) δ 10.0 (s, IH), 8.00 (d, 2H), 7.78 (d, 2H), 7.50 (m, IH), 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)- IH- 1 ,2,4-triazole-l -carbothioamide (minor regioisomer of Cpd 66) X Η ΝMR (300 MHz, (CD 3 ) 2 CO) δ 12.10 (s, IH), 10.28 (s, IH), 7.85 (m, 4H), 7.45 (m, IH), 7.20 (m, 2H), 6.45 (s, 2H), 5.75 (s, 2H); MS (ESI) m/z: 426 (M+H + ), 448 (M+Νa + ) Example 2 1 -(2,6-difluorobenzoyl)-N 3 -[4-(l -piperidinylsulfonyl)phenyl]- IH- 1 ,2,4-triazole-3,5- diamine (Cpd 13) Using the procedure for Example 1, l-amidino-3,5-dimethylpyrazole nitrate Compound IC was reacted with l-(4-isothiocyanatophenylsulfonyl)piperidine Compound 2B to produce Compound 2C. Η ΝMR (300 MHz, CD 3 CΝ) δ 10.75 (s, br, IH), 8.40 (s, br, IH), 7.95 (s, br, IH), 7.55 (q, 4H), 5.95 (s, IH), 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. Η NMR (300 MHz, CD 3 CN) δ 10.75 (s, br, IH), 7.65 (s, br, IH), 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 IF in anhydrous pyridine to produce Compound 13 (85% yield). Η NMR (300 MHz, CDC1 3 ) δ 7.60-7.50 (m, 3H), 7.42 (d, 2H), 7.18 (t, 2H), 6.98 (s, br, IH), 6.55 (s, br, 2H), 2.98 (m, 4H), 1.65 (m, 4H), 1.42 (m, 2H); MS (ESI) m z: 363 (M+PT), 485 (M+Na + ). NH NHs 2C Compound 13 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 IF and reagent(s): Cpd Name/Data Starting Mat'l 23 N 3 -[4-(l-piperidinylsulfonyl)ρhenyl]-l-(2- thiophene-2- thienylcarbonyl)-lH-l,2,4-triazole-3,5-diamine carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 10.02 (s, br, IH), 8.40 DIC/HOBt in DMF (dd, IH), 8.18 (dd, IH), 7.92 (s, br, 2H), 7.88 (d, 2H), 7.58 (d, 2H), 7.32 (t, IH), 2.88 (m, 4H), 1.55 (m,4H), 1.35 (m, 2H); MS (ESI) m/z: 433 (M+H + ), 455 (M+Νa + ) 24 1 -[(3-methyl-2-thienyl)carbonyl]-N 3 -[4-(l - 3 -methy lthiophene- piperidinylsulfonyl)phenyl] - IH- 1 ,2,4-triazole-3 , 5 - 2-carboxylic acid diamine mediated by DIC/HOBt in DMF Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 10.02 (s, br, IH), 8.02 (d, IH), 7.95-7.80 (m, 4H), 7.68 (d, 2H), 7.18 (d, IH), 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+Νa + ) ' Example 3 4-[[5-amino-l-[(5-ethyl-2-thienyl)carbonyl]-lH-l,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 stined in an oil bath at 110 °C for 16 hrs, cooled to rt, acidified with 2N HC1 and then extracted with methylene chloride (4 x 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%). Η NMR (300 MHz, CD 3 OD) δ 7.59 (d, J3.7, IH), 6.87 (d, J3.7, IH), 2.88 (q, J7.5, IH), 1.32 (t, J7.5, 3H); MS (ESI) m/z: 155 (M-H + ). Using the procedure of Example 1, Compound IE was acylated with Compound 3 A mediated by DIC/HOBt in anhydrous DMF to produce Compound 32 (59% yield). IH NMR (300 MHz, (CD 3 ) 2 CO) δ 8.90 (s, br, IH), 8.25 (d, IH), 7.88 (q, 4H), 7.45 (s, br, 2H), 7.10 (d, IH) 6.45 (s, br, 2H), 3.05 (q, 2H), 1.42 (t, 3H); MS (ESI) m/z: 393 (M+H÷), 415 (M+Na + ). Compound 32 Example 4 4-[[5-amino-l-[(3,5-dimethyl-2-thienyl)carbonyl]-lH-l,2,4-triazol-3-yl]amino]- benzenesulfonamide (Cpd 33) 2.2 equivalents of 2.0 M LDA solution in heptane/TΗF/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 TΗF (20 mL) at 0 °C. The reaction mixture was stined at 0 °C for 1.5 hr; and then methyl iodide (1.4 mL, 22 mmol) was added. The resulting mixture was stined at 0 °C for an additional 2 hr, acidified with 2N ΗC1 and extracted with methylene chloride (4 x 50 mL). The organic layers were then combined, concentrated and separated via ΗPLC to give 3,5-dimethylthiophene-2-carboxylic acid Compound 4A as a white powder. Η NMR (300 MHz, CD 3 OD) δ 6.72 (s, IH), 2.43 (s, 3H), 2.46 (s, 3H); MS (ESI) m/z: 155 (M-H*). Using the procedure of Example 1, Compound IE was acylated with Compound 4A mediated by DIC/HOBt in anhydrous DMF to produce Compound 33 (73% yield). Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.88 (s, br, IH), 7.85 (s, br, 2H), 7.78 (q, 4H), 7.18 (s, br, 2H), 6.92 (s, IH), 2.58 (s, 3H), 2.55 (s, 3H); MS (ESI) m/z: 393 (M+H 1" ), 415 (M+Na + ). Compound 33 ] Example 5 4-[[5-amino-l-[2,6-difluoro-3-(l-hydroxyethyl)berιzoyl]-lH-l,2,4-triazol-3-yl]amino]- benzenesulfonamide (Cpd 58) 2',4'-difluoroacetophenone (5g, 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 l-(2',4'-difluorophenyl)- ethanol as a colorless oil (4.86 g, 96%). Η NMR (300 MHz, CDC1 3 ) δ 7.48 (m, IH), 6.85 (m, IH), 6.75 (m, IH), 5.15 (q, IH), 2.0 (s, IH), 1.5 (d, 3H). l-(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 stined 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 l-(2',4'-difluorophenyl)-ethyl t- butyltrimethylsilyl ether as a white solid (6.88 g, 74%). Η NMR (300 MHz, CDC1 3 ) δ 7.45 (q, IH), 6.75 (m, IH), 6.62 ( , IH), 5.05 (q, IH), 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 l-(2',4'-difluorophenyl)-ethyl t- butyltrimethylsilyl ether (1.362 g, 5 mmol) in THF (60 mL) at -50 °C and was stined 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-(l-t-butyltrimethylsilyloxyethyl)-benzoic acid Compound 5 as white solid (1.57 g, 99%). Η NMR (300 MHz, CDC1 3 ) δ 7.70 (q, IH), 7.00 (t, IH), 6.00 (br, IH), 5.15 (q, IH), 1.40 (d, 3H), 0.90 (s, 9H), 0.12 and 0.05 (each s, each 3H). Using the procedure of Example 1, Compound IE was acylated with Compound 5A mediated by DIC/HOBt in anhydrous DMF to provide 4-[[5-amino-l-(2,6-difluoro-3- ( 1 -t-butyltrimethylsilyloxyethyl)-benzoyl)- IH- 1 ,2,4-triazol-3 -yl] amino] - benzenesulfonamide Compound 5B (46% yield). Η NMR (300 MHz, CDC1 3 ) δ 7.72 (m, 3H), 7.38 (d, 2H), 7.02 (t, IH), 6.80 (s, IH), 6.45 (s, 2H), 5.15 (q, IH), 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-(l-t-butyltrimethylsilyloxyethyl)-benzoyl)- 2H-l,2,4-triazol-3-yl]amino]-benzenesulfonamide (a minor regioisomer) was also isolated from the reaction mixture (192 mg, 34%). Η NMR (300 MHz, CDC1 3 ) δ 10.00 (s, IH), 7.92 (d, 2H), 7.82 (d, 2H), 7.70 (q, IH), 7.02 (t, IH), 5.18 (q, IH), 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+BT), 575 (M+Na + ). 0.7 mL of 1.0 M TBAF solution in THF was added to a solution of 4-[[5-amino-l-(2,6- difluoro-3 -( 1 -t-butyltrimethylsilyloxy ethy l)-benzoy 1)- IH- 1 ,2,4-triazol-3 -yl] amino] - benzenesulfonamide Compound 5B (193 mg, 0.35 mol) in TΗF (10 mL). The reaction solution was stined 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%). Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.85 (s, IH), 8.00 (s, 2H), 7.75 (m, IH), 7.55 (m, 2H), 7.45 (m, 2H), 7.30 (t, IH), 7.10 (s, 2H), 6.80 (s, IH), 5.55 (d, IH), 5.00 (m, IH), 1.38 (d, 3H); MS (ESI) m/z: 421 (M+H + -H 2 O), 439 (M+H + ), 461 (M+Na + ). Compound 58 Example 6 4-[[5-amino-l-(2,6-difluoroberιzoyl)-lH-l,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 l-amidino-3,5-dimethylpyrazole nitrate Compound IC to produce Compound 6C which was reacted with hydrazine to produce Compound 6D. Η NMR (300 MHz, (CD 3 ) 2 SO) δ 11.1 (s, IH), 8.75 (s, IH), 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 IF in anhydrous pyridine to produce compound 59 (4% yield). *H NMR (300 MHz, (CD 3 ) 2 SO) δ 9.35 (s, IH), 7.95 (s, 2H), 7.82 (m, 2H), 7.45-7.25 (m, 5H); MS (ESI) m/z: 396 (M+H ). CSCI 6A 6B NH NH 6C *■ 6D *- Compound 59 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 IF and reagent(s): Cpd Name/Data Starting Mat'l 60 4-[[5-amino-l-(2,6-difluoro-3-methylbenzoyl)-lH- 2,6-difluoro-3- 1 ,2,4-triazol-3-yl]amino]-benzenesulfonic acid methyibenzoyl chloride in Η NMR (300 MHz, CD 3 OD) δ 7.62 (d, 2H), 7.50 (m, anhydrous pyridine IH), 7.38 (d, 2H), 7.05 (m, IH), 2.30 (s, 3H); MS (ESI) m z: 410 (M+H" " ) Example 7 1 -(2,6-Difluorobenzoyl)-N 3 -phenyl- IH- 1 ,2,4-triazole-3 ,5-diamine (Cpd 61) 3-Anilino-5-amino-l,2,4-triazole Compound 7A (prepared using the procedure of Example 1) was acylated with 2,6-difluorolbenzoyl chloride Compound IF in anhydrous pyridine to produce Compound 61 as a white solid (61% yield). l H ΝMR (300 MHz, CDC1 3 ) δ 7.80 (s, IH), 7.45 (m, IH), 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+Νa + ). 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 lF and reagent(s): Cpd Name/Data Starting Mat'l 62 l-benzoyl-Λ^-phenyl-lH-l^^-triazole-SjS-diamine benzoyl chloride in anhydrous pyridine Η NMR (300 MHz, CDC1 3 ) δ 8.30 (s, 2H), 7.65-7.40 (m, 5H), 7.28 (d, 2H), 7.00 (t, IH), 6.80 (s, IH), 6.70 (s, 2H); MS (ESI) m/z: 280 (M+tF), 302 (M+Na + ) 65 5-amino-N-phenyl-3-(phenylamino)-lH-l,2,4-triazole- phenyl isocyanate 1-carboxamide in anhydrous DMF Η ΝMR (300 MHz, (CD 3 ) 2 CO) δ 9.20 (s, IH), 8.20 (s, IH), 7.70 (m, 4H), 7.35 (t, 2H), 7.25 (t, 2H), 7.15 (t, IH), 7.98 (s, 2H), 6.88 (t, IH); MS (ESI) m/z: 295 (M+H + ), 317 (M+Νa + ) 124 l-(2,6-difluorobenzoyl)-N 5 -phenyl-lH-l,2,4-triazole- 3,5-diamine (minor regioisomer of Cpd 61) Η ΝMR (300 MHz, CDC1 3 ) δ 9.80 (s, IH), 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 1 ), 338 (M+Νa + ) 125 l-benzoyl-N^phenyl-lH-l^^-triazole-S^-diamine (minor regioisomer of Cpd 62) ! Η NMR (300 MHz, CDC1 3 ) δ 10.20 (s, IH), 8.18 (d, 2H), 7.72-7.30 (m, 7H), 7.15 (t, IH), 4.30 (s, 2H); MS (ESI) m/z: 280 (M+H*), 302 (M+Na + ) Example 8 N 3 -(3-chlorophenyl)-l-(2,6-difluorobenzoyl)-lH-l,2,4-triazole-3,5-diamine (Cpd 63) 3-(3-Chloroanilino)-5-amino-l,2,4-triazole Compound 8A (prepared using the procedure of Example 1) was acylated with 2,6-difluorobenzoyl chloride Compound IF in anhydrous pyridine to produce Compound 63 as a pale yellow solid (66% yield). Η ΝMR (300 MHz, CDC1 3 ) δ 7.6-7.50 (m, 2H), 7.15-6.80 (m, 6H), 6.60 (s, 2H); MS (ESI) m/z: 350 (M+H 1 ), 372 (M+Νa + ). 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 IF and reagent(s): Cpd Name/Data Starting Mat'l 64 l-benzoyl-N 3 -(3-chlorophenyl)-lH-l,2,4-triazole-3,5- benzoyl chloride in diamine anhydrous pyridine Η ΝMR (300 MHz, (CD 3 ) 2 CO) δ 8.58 (s, IH), 8.30 (d, 2H), 8.00 (m, IH), 7.75-7.25 (m, 6H), 6.90 (d, IH); MS (ESI) m/z: 314 (M+H + ), 336 (M+Νa + ) 126 N 5 -(3-chlorophenyl)-l-(2,6-difluorobenzoyl)-lH-l,2,4- triazole-3,5-diamine (minor regioisomer of Cpd 63) Η ΝMR (300 MHz, CDC1 3 ) δ 9.90 (s, IH), 7.90 (s, IH), 7.58-6.95 (m, 7H), 4.35 (s, 2H); MS (ESI) m/z: 350 (M+H 4 ), 472 (M+Νa + ) 127 l-benzoyl-N s -(3-chlorophenyl)-lH-l,2,4-triazole-3,5- diamine (minor regioisomer of Cpd 64) Η ΝMR (300 MHz, (CD 3 ) 2 CO) δ 10.30 (s, IH), 8.20 (d, 2H), 8.15 (m, IH), 7.70-7.60 (m, 2H), 7.55 (t, 2H), 7.35 (t, IH), 7.10 (d, IH), 5.60 (s, 2H); MS (ESI) m/z: 314 (M+H"), 336 (M+Νa + ) Example 9 1 -(2,6-difluorobenzoyl)-N 3 -[4-(4-methyl- 1 -piperazinyl)phenyl]- IH- 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 stined at 55 °C for 4 hrs. Subsequent concentration, dissolution in methanol, filtering of impurities and concentration gave 3-(4-methylpiperazino)-anilino-5-amino-l,2,4-triazole Compound 9A (87% yield). Η ΝMR (400MΗz, (CD 3 ) 2 SO) δ 9.05 (s,lH), 8.60 (s, IH), 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-l,2,4-triazole Compound 9A was acylated with 2,6-difluoro benzoyl chloride Compound IF in anhydrous pyridine to produce compound 71 (30% yield). *H ΝMR (300MHz, (CD 3 ) 2 SO) δ 9.07 (s, IH), 7.88 (s, IH), 7.72-7.66 (m, IH), 7.32 (t, IH), 7.25-7.17 (m, 2H), 6.97-6.92 (m, IH), 6.71 (d, IH), 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 4 ). 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 IF and reagent(s): Cpd Name/Data Starting Mat'l 72 1 -(2,6-difluoro-3-methylbenzoyl)-N 3 -[4-(4-methyl- 2, 6-difluoro-3 -methyl 1 -piperazinyl)phenyl]- IH- 1 ,2,4-triazole-3 ,5-diamine benzoyl chloride in anhydrous pyridine Η ΝMR (300MHz, (CD 3 ) 2 SO) δ 9.05(s, IH), 7.87 (s, IH), 7.59-7.51 (m, IH), 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 4 ) 73 N 3 - [4-(4-methyl- 1 -piperazinyl)phenyl] - 1 - [(3 -methyl- 3 -methyl-2-thiophene 2-thienyl)carbonyl]-lH-l,2,4-triazole-3,5-diamine carboxylic acid, mediated by DIC/HOBt Η ΝMR (300MHz, (CD 3 ) 2 SO) δ 9.13 (s, IH), 7.77 in anhydrous DMF (s,lH), 7.58-7.55 (m, 2H), 7.38-7.26 (m, IH), 6.92 (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 4 ) 74 l-[(3,5-dimethyl-2-thienyl)carbonyl]-N 3 -[4-(4- 3,5-dimethyl-2- methyl- 1 -piperazinyl)phenyl]- IH- 1 ,2,4-triazole-3 ,5- thiophene carboxylic diamine acid, mediated by DIC/HOBt in Η ΝMR (300MHz, (CD 3 ) 2 SO) δ 9.11 (s, IH), 7.73 anhydrous DMF (s, 2H), 7.59-7.54 (m, 2H), 7.38-7.26 (m, IH), 6.94 (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 4 ) 75 l-[(5-ethyl-2-thienyl)carbonyl]-N 3 -[4-(4-methyl-l- 5 -ethyl-2-thiophene piperazinyl)phenyl]-lH-l,2,4-triazole-3,5-diamine carboxylic acid, mediated by DIC/HOBt Η ΝMR (300MHz, (CD 3 ) 2 SO) δ 9.17 (s, IH), 7.78 in anhydrous DMF (s, IH), 7.51 (d, 2H), 7.35-7.24 (m, 3H), 7.08 (d, 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 4 ) Example 10 4-[[5-amino-l-(2,6-difluorobenzoyl)-lH-l,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 TΗF solution) in TΗF (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). Η NMR (400MHz, (CD 3 ) 2 SO) δ 9.87 (s,lH), 8.00 (s, 2H), 7.76- 7.68 (m, IH), 7.55-7.48 (m, 4H), 7.34 (t, 2H), 7.22 (t, IH), 2.73-2.67 (m, 2H), 0.94 (t, 3H); MS (ESI) m/z: 423 (M+H 4 ) Compound 1 Compound 76 Example 12 N 3 -methyl-l-[(3-methyl-2-thienyl)carbonyl]-lH-l,2,4-triazole-3,5-diamine (Cρd 79) Using the procedure of Example 1, 3,5-diamino-l,2,4-triazole Compound 12A was acylated with 3-methylthiophene-2-carboxylic acid Compound 12B mediated by DIC/ΗOBt in anhydrous DMF to produce Compound 41 (72% yield). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 7.88 (d, J=4.5, IH), 7.59 (s, 2H), 7.05 (d, J=4.8, IH), 5.78 (s, 2H), 2.55 (s, 3H); MS (ESI) m/z: 224.1 (M+H 4 ), 245.9 (M+Νa 4 ). 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). Η ΝMR (400MHz, (CD 3 ) 2 SO) δ 9.80 (s, IH), 7.60 (d,lH), 6.96 (d, IH), 6.17 (s, 2H), 3.47 (s, 3H), 2.40 (s, 3H); MS (ESI) m/z: 238 (M+H 4 ), 260 (M+Νa 4 ). Compound 41 Compound 79 Example 13 4-[[5-amino-l-(2,6-difluorobenzoyl)-lH-l,2,4-triazol-3-yl]amino]-N-methyl- benzenesulfonamide (Cpd 80) t-BuOK (23.1 mL, 1.0 M solution in t-BuOΗ, 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-l- carboximidine nitrate Compound IC (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-l- yliminomethyl)thioureido]-N-methylbenzenesulfonamide Compound 13C as a yellow solid (7.3 g, 95% yield). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 8.01 (s, IH), 7.71 (m, 4H), 6.15 (s, IH), 2.40 (s, 3H), 2.22 (s, 6H); MS (ESI) m/z: 367 (M+H 4 ). Hydrazine (3.3 g, 110.0 mmol) at 0 °C was added to a suspension of 4-[3-(3,5-dimethylpyrazol-l- 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 CH 2 C1 2 , then air dried to produce Compound 13D as a white solid (1.3 g, 87% yield). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 11.36 (s, IH), 9.31 (s, IH), 7.63 (q, 4H), 7.09 (q, IH), 6.05 (s, 2H), 2.39 (d,3H); MS (ESI) m/z: 269 (M+H 4 ). Using the procedure of Example 1, Compound 13D was acylated with 2,6-difluorobenzoyl chloride Compound IF in anhydrous pyridine to produce Compound 80 (80% yield). H ΝMR (300 MHz, CD 3 OD) δ 7.64 (m, IH), 7.63 (d, 2H), 7.53 (d, 2H), 7.15 (t, 2H), 2.43 (s, 3H); MS (ESI) m/z: 409 (M+H 4 ). Compound 80 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 IF and reagent(s): Cpd NameData Starting Mat'I 81 4-[[5-amino-l-(2,6-difluoro-3-methylbenzoyl)-lH- 2,6-difluoro-3- 1 ,2,4-triazol-3 -yl] amino] -N-methyl- methylbenzoyl benzenesulfonamide chloride in anhydrous Η ΝMR (300 MHz, CD 3 OD) δ 7.55 (d, 2H), 7.48- P^ne 7.44 (m, IH), 7.46 (d, 2H), 2.42 (s, 3H), 2.25 (s, 3H); MS (ESI) m/z: 423 (M+H 4 ) 82 4-[[5-amino-l-[(3-methyl-2-thienyl)carbonyl]-lH- 3 -methylthiophene-2- 1 ,2,4-triazol-3 -yl] amino] -N-methyl- carboxylic acid benzenesulfonamide mediated by DIC/HOBt in DMF Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.92 (s, IH), 8.03 (d, IH), 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 4 ) 83 4-[[5-amino- 1 -[(3,5-dimethyl-2-thienyl)carbonyl]- 3,5- lH-l,2,4-triazol-3-yl]amino]-N-methyl- dimethylthiophene-2- benzenesulfonamide carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.89 (s, IH), 8.09 DIC/HOBt in DMF (d, IH), 7.74 (d, 2H), 7.63 (d, 2H), 7.02 (d, IH), 2.94 (q, 2H), 2.32 (s, 3H), 1.33 (t, 3H); MS (ESI) m/z: 407 (M+H 4 ) 84 4-[[5-amino-l-[(5-ethyl-2-thienyl)carbonyl]-lH- 5-ethylthiophene-2- l,2,4-triazol-3-yl]amino]-N-methyl- carboxylic acid benzenesulfonamide mediated by DIC/HOBt in DMF Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.65 (s, IH), 7.64 (d, IH), 7.50 (d, 2H), 7.69 (d, 2H), 6.66 (s, IH), 2.36 (s, 3H), 2.34 (s, 3H), 2.12 (s, 3H); MS (ESI) m/z: 407 (M+H 4 ) Example 14 1 -[(3,5-dimethyl-2-thienyl)carbonyl]-N 3 -[4-(lH-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 IC (1.5 g, 7.4 mmol) and t-BuOK (7.4 mL, 1.0 M solu in t-BuOΗ, 7.4 mmol) to produce 4-[3-(3,5-dimethylpyrazol-l- yliminomethyl)thioureido]-N,N-dimethylbenzenesulfonamide Compound 14C as a yellow solid (2.5 g, 89% yield). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 10.05 (s, IH), 8.91 (s, IH), 7.67 (m, 4H), 6.15 (s, IH), 2.57 (s, 6H), 2.18 (s, 6H); MS (ESI) m/z: 381 (M+H 4 ). 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. Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.47 (s, IH), 7.81 (d, 2H), 7.75 (d, 2H), 6.10 (s IH), 2.67 (s, 6H); MS (ESI) m/z: 283 (M+H 4 ). Compound 14D was acylated with 3,5- dimethylthiophene-2-carboxylic acid Compound IF mediated by DIC/HOBt in DMF to produce Compound 85 (52% yield). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.93 (s, IH), 7.88 (d, 2H), 7.85 (s, IH), 7.65 (d, 2H), 6.90 (s, IH), 2.60 (s, 6H), 2.56 (s, 3H), 2.54 (s, 3H); MS (ESI) m/z: 421 (M+H 4 ). 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'I 86 4-[[5-amino-l -[(5-ethyl-2-thienyl)carbonyl]- IH- 1 ,2,4- 5 -ethylthiophene-2- triazol-3-yl]amino]-N,N-dimethyl-benzenesulfonamide carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 10.03 (s, IH), 8.13 (d, DIC/HOBt in DMF IH), 7.91 (s, IH), 7.86 (d, 2H), 7.66 (d, 2H), 7.10 (d, 2H), 2.95 (q, 2H), 2.56 (s, 6H), 1.32 (t, 3H); MS (ESI) m/z: 421 (M+H 4 ) 87 4-[[5-amino-l-[(3-methyl-2-thienyl)carbonyl]-lH-l,2,4- 3 -methylthiophene- triazol-3 -yl] amino] -N,N-dimethyl-benzenesulfonamide 2-carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 10.01 (s, IH), 8.05 (d, DIC/HOBt in DMF IH), 7.86 (d, 3H), 7.69 (d, 2H), 7.13 (d, IH), 2.63 (s, 3H), 2.55 (s, 6H); MS (ESI) m/z: 407 (M+H 4 ) 88 4-[[5-amino- 1 -(2,6-difluoro-3-methylbenzoyl)- 1H- 2,6-difluoro-3- l,2,4-triazol-3-yl]amino]-N,N-dimethyl- methylbenzoyl benzenesulfonamide chloride in anhydrous pyridine Η ΝMR (300 MHz, CDC1 3 ) δ 7.79 (s, IH), 7.55 (d, 2H), 7.40 (d, 2H), 7.35 (m, IH), 6.95 (s, 2H), 6.92 (m, IH), 2.65 (s, 6H), 2.27 (s, 3H); MS (ESI) m/z: 437 (M+H 4 ) 89 4-[[5-amino-l -(2,6-difluorobenzoyl)- IH- 1 ,2,4-triazol-3- 2,6-difluorobenzoyl yl]amino]-N,N-dimethyl-benzenesulfonamide chloride in anhydrous pyridine Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.74 (s, IH), 7.77 (s, 2H), 7.50-7.40 (m, IH), 7.30-7.20 (m, 4H), 7.10 (m, 2H), 2.25 (s, 6H); MS (ESI) m z: 423 (M+H 4 ) Example 15 1 -[(5-ethyl-2-thienyl)carbonyl]-N 3 -[4-(lH-imidazol- 1 -yl)phenyl]- IH- 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-l-yl-aniline (0.50 g, 3.14 mmol), diphenyl cyanocarbonimidate (0.75 g, 3.14 mmol) and TΗF (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 TΗF, 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 %). ! Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 11.15 (s, IH), 8.85 (s, IH), 8.05 (s, IH), 7.57 (s, IH), 7.48 (d, 2H), 7.35 (d, 2H), 7.04 (s, IH), 5.85 (s, 2H); MS (ESI) m/z: 242 (M+H 4 ). 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). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.63 (s, IH), 8.14 (d, IH), 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 4 ). 15A Compound 90 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 N 3 -[4-(lH-imidazol-l-yl)phenyl]-l-[(3-methyl-2- 3 -methy lthiophene- thienyl)carbonyl] - IH- 1 ,2,4-triazole-3 , 5-diamine 2-carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.62 (s, IH), 7.97 (d, DIC/HOBt in DMF IH), 7.92 (s, IH), 7.82-7.72 (m, 5H), 7.56-7.53 (m, 2H), 7.11 (d, IH), 2.61 (s, 3H); MS (ESI) m/z: 366 (M+H 4 ) 92 l-[(3,5-dimethyl-2-thienyl)carbonyl]-N 3 -[4-(lH- 3,5- imidazol- 1 -yl)phenyl] - IH- 1 ,2,4-triazole-3 , 5 -diamine dimethylthiophene- 2-carboxylic acid Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.51 (s, IH), 8.15 (s, mediated by IH), 7.75 (m, 4H), 7.61 (s, IH), 7.53 (d, 2H), 7.05 (s, DIC/HOBt in DMF IH), 6.85 (s, IH), 2.53 (s, 3H), 2.52 (s, 3H); MS (ESI) m z: 380 (M+H 4 ) 93 l-(2,6-difluorobenzoyl)-N 3 -[4-(lH-imidazol-l- 2,6-difluorobenzoyl yl)phenyl] - IH- 1 ,2,4-triazole-3 , 5 -diamine chloride in anhydrous pyridine Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.52 (s, IH), 8.06 (s, IH), 7.93 (s, IH), 7.70 (p, IH), 7.57 (s, IH), 7.45 (d, 2H), 7.36 (d, 2H), 7.30 (t, 2H), 7.01 (s, IH); MS (ESI) m/z: 382 (M+H 4 ) 94 l-(2,6-difluoro-3-methylbenzoyl)-N 3 -[4-(lH-imidazol-l- 2,6-difluoro-3- yl)phenyl]-lH-l,2,4-triazole-3, 5-diamine methylbenzoyl chloride in Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.52 (s, IH), 8.08 (s, anhydrous pyridine IH), 7.93 (s, IH), 7.57 (s, IH), 7.53 (m, IH), 7.42 (d, 2H), 7.35 (d, 2H), 7.18 (t, IH), 7.02 (s, IH), 2.25 (s, 3H); MS (ESI) m/z: 396 (M+H 4 ) Example 16 1 -(2,6-difluoro-3-methylbenzoyl)-N 3 -[4-(lH- 1 ,2,4-triazol-l -yl)ρhenyl]- 1H-1 ,2,4- triazole-3,5-diamine (Cpd 95) Using the procedure of Example 15, 4-(l,2,4-triazol-l-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. Η NMR (300 MHz, (CD 3 ) 2 SO) δ 11.21 (s, IH), 9.06 (s, IH), 8.92 (s, IH), 8.13 (s, IH), 7.61 (m 4H), 5.87 (s, 2H); MS (ESI) m/z: 243 (M+H 4 ). 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). Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.62 (s, IH), 9.11 (s, IH), 8.12 (s, IH), 7.91 (s, IH), 7.56 (d, 2H), 7.60-7.50 (q, IH), 7.45 (d, 2H), 7.16 (t, IH), 2.25 (s, 3H); MS (ESI) m/z: 397 (M+H 4 ). 16A Compound 95 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)-N 3 -[4-(lH-l ,2,4-triazol-l - 2,6-difluorobenzoyl yl)phenyl]-lH-l,2,4-triazole-3,5-diamine chloride in anhydrous pyridine Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.61 (s, IH), 9.05 (s, IH), 8.07 (s, IH), 7.85 (s, 2H), 7.63 (p, IH), 7.53 (d, 2H), 7.41 (d, 2H), 7.30 (t, 2H), 7.29 (t, 2H); MS (ESI) m/z: 383 (M+H 4 ) 97 l-[(5-ethyl-2-thienyl)carbonyl]-N 3 -[4-(lH-l,2,4-triazol- 5 -ethylthiophene-2- 1 -yl)phenyl]- IH- 1 ,2,4-triazole-3,5-diamine carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.72 (s, IH), 9.15 (s, DIC/HOBt in DMF IH), 8.17 (s, IH), 8.16 (d, IH), 7.78 (s, 2H), 7.77 (d, 2H), 7.72 (d, 2H), 7.04 (d, IH), 2.96 (q, 2H), 1.33 (t, 3H); MS (ESI) m/z: 381 (M+H 4 ) 98 l-[(3,5-dimethyl-2-thienyl)carbonyl]-N 3 -[4-(lH-l,2,4- 3,5- triazol- 1 -yl)phenyl] - IH- 1 ,2,4-triazole-3 , 5-diamine dimethylthiophene- 2-carboxylic acid Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.67 (s, IH), 9.15 (s, mediated by IH), 8.18 (s, IH), 7.75 (m, 6H), 6.89 (s, IH), 2.52 (s, DIC/HOBt in DMF 3H), 2.51 (s, 3H); MS (ESI) m/z: 381 (M+H 4 ) 99 1 -[(3-methyl-2-thienyl)carbonyl]-N 3 -[4-(lH- 1 ,2,4- 3 -methylthiophene- triazol- 1 -yl)phenyl] - IH- 1 ,2,4-triazole-3 ,5 -diamine 2-carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.68 (s, IH), 9.13 (s, DIC/HOBt in DMF IH), 8.16 (s, IH), 7.99 (d, IH), 7.77 (m, 6H), 7.12 (d, IH); MS (ESI) m/z: 367 (M+H 4 ) Example 17 1 -(2,6-difluorobenzoyl)-N 3 -[4-(4H- 1 ,2,4-triazol-4-yl)phenyl]-lH- 1 ,2,4-triazole-3,5- diamine (Cpd 100) Using the procedure of Example 15, 4-(l,3,4-triazol-l-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 TΗF, 84.3 mmol) were reacted to provide Compound 17A (1.10 g, 77% yield) as a white solid. Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 8.90 (s, 2H), 7.62 (d, 2H), 7.36 (d, 2H), 5.82 (s, 2H); MS (ESI) m/z: 243 (M+H 4 ). Using the procedure of Example 1, Compound 17A was acylated with 2,6-difluorobenzoyl chloride Compound IF in anhydrous pyridine to provide Compound 100 (36% yield). *H ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.61 (s, IH), 8.98 (s, 2H), 7.96 (s, 2H), 7.67 (p, IH), 7.47 (d, 2H), 7.42 (d, 2H), 7.32 (t, 2H); MS (ESI) m/z: 383 (M+H 4 ). 17A Compound 100 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 IF andreagent(s): Cpd Name Data Starting Mat'l 101 1 -(2,6-difluoro-3-methylbenzoyl)-N 3 -[4-(4H- 1 ,2,4- 2,6-difluoro-3- triazol-4-yl)phenyl]- IH- 1 ,2,4-triazole-3,5-diamine methylbenzoyl chloride in Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.61 (s, IH), 8.94 (s, anhydrous pyridine 2H), 7.91 (s, 2H), 7.55 (q, IH), 7.43 (q, 4H), 7.18 (t, ■ IH); MS (ESI) m/z: 397 (M+H 4 ) 102 l-[(3-methyl-2-thienyl)carbonyl]-N 3 -[4-(4H-l ,2,4- 3 -methylthiophene- triazol-4-yl)phenyl]-lH-l,2,4-triazole-3, 5-diamine 2-carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 10.22 (s, IH), 9.04 (s, DIC/HOBt in DMF 2H), 7.95 (m, 3H), 7.67 (d, 2H), 7.07 (d, IH), 6.13 (s, 2H); MS (ESI) m/z: 367 (M+H 4 ) 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 TΗF, 82.3 mmol) were reacted to produce Compound 18A (1.35 g, 50% yield) as a white solid. Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.22 (s, IH), 8.43 (s, IH), 7.55 (m, 4H), 7.02 (s, IH), 5.91 (s, 2H), 2.71 (t, 2H), 2.15 (t, 2H), 2.05 (s, 6H); MS (ESI) m/z: 326 (M+H 4 ). 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). 'H ΝMR (300 MHz, (CD 3 ) 2 SO) δ 10.02 (s, IH), 8.13 (d, IH), 7.88 (s, IH), 7.75 (d, 2H), 7.71 (d, 2H), 7.07 (d, IH), 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 4 ). 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-l-[(3-methyl-2-thienyl)carbonyl]-lH-l,2,4- 3 -methy lthiophene- triazol-3 -yl] amino] -N- [2-(dimethylamino)ethyl] - 2-carboxylic acid benzenesulfonamide mediated by DIC/HOBt in DMF Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.89 (s, IH), 8.04 (d, IH), 7.83 (s, IH), 7.79 (d, 2H), 7.71 (d, 2H), 7.15 (s, 2H), 7.08 (d, IH), 2.76 (t, 2H), 2.61 (s, 3H), 2.21 (t, 2H), 2.07 (s, 6H); MS (ESI) m/z: 450 (M+H 4 ) 105 4-[[5-amino- 1 -(2,6-difluoro-3-methylbenzoyl)-lH- 2,6-difluoro-3- l,2,4-triazol-3-yl]amino]-N-[2-(dimethylamino)ethyl]- methylbenzoyl benzenesulfonamide chloride in anhydrous pyridine Η ΝMR (300 MHz, CD 3 OD) δ 7.57 (d, 2H), 7.45 (m, 3H), 7.00 (t, IH), 2.86 (t, 2H), 2.32 (t, 2H), 2.25 (s, 3H), 2.11 (s, 6H); MS (ESI) m/z: 480 (M+H 4 ) 106 4-[[5-amino-l-(2,6-difluorobenzoyl)-lH-l,2,4-triazol-3- 2,6-difluorobenzoyl yl]amino]-N-[2-(dimethylamino)ethyl]- chloride in benzenesulfonamide anhydrous pyridine Η ΝMR (300 MHz, CD 3 OD) δ 7.60 (m, IH), 7.55 (d, 2H), 7.45 (d, 2H), 7.11 (t, IH), 2.87 (t, 2H), 2.32 (t, 2H), 2.12 (s, 6H); MS (ESI) m/z: 466 (M+H 4 ) 107 4-[[5-amino- 1 -[(3 ,5-dimethyl-2-thienyl)carbonyl]- 1H- 3,5- l,2,4-triazol-3-yl]amino]-N-[2-(dimethylamino)ethyl]- dimethyltliiophene- benzenesulfonamide 2-carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.89 (s, IH), 7.81 (m, DIC/HOBt in DMF 4H), 7.71 (d, 2H), 7.22 (s, IH), 6.86 (s, IH), 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 4 ) Example 19 N-[4-[[5-amino-l-[(3,5-dimethyl-2-thienyl)carbonyl]-lH-l,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 TΗF, 107.0 mmol) were reacted to produce Compound 19A (1.30 g, 45% yield) as a white solid. Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 8.80 (s, IH), 8.55 (s, IH), 7.43 (d, 2H), 6.96 (d, 2H), 5.75 (s, 2H), 2.82 (s, 3H); MS (ESI) m/z: 269 (M+H 4 ). 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). Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.30 (s, IH), 9.25 (s, IH), 7.70 (s, IH), 7.61 (d, 2H), 7.12 (d, 2H), 6.83 (s, IH), 2.87 (s, 3H), 2.50 (s, 3H); MS (ESI) m/z: 407 (M+H 4 ). 19A Compound 108 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'I 109 N-[4-[[5-amino-l-[(3-methyl-2-thienyl)carbonyl]-lH- 3 -methy lthiophene- 1 ,2,4-triazol-3 -yl] aminojphenyi] -methanesulfonamide 2-carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.35 (s, IH), 9.30 (s, DIC/HOBt in DMF IH), 8.01 (d, IH), 7.75 (s, IH), 7.62 (d, 2H), 7.12 (m, 3H), 6.83 (s, IH), 2.89 (s, 3H), 2.59 (s, 3H); MS (ESI) m/z: 393 (M+H 4 ) 110 N-[4-[[5-amino-l-[(5-ethyl-2-thienyl)carbonyl]-lH- 5-ethylthiophene-2- 1 ,2,4-triazol-3 -yl] amino]phenyl] -methanesulfonamide carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.37 (s, IH), 9.30 (s, DIC/HOBt in DMF IH), 8.12 (d, IH), 7.74 (s, IH), 7.62(d, 2H), 7.12 (d, 2H), 7.03 (d, IH), 2.95 (q, 2H), 2.89 (s, 3H), 1.35 (t, 3H); MS (ESI) m/z: 407 (M+H 4 ) 111 N-[4-[[5-amino- 1 -(2,6-difluorobenzoyl)- 1H-1 ,2,4- 2,6-difluorobenzoyl triazol-3-yl]amino]phenyl]-methanesulfonamide chloride in anhydrous pyridine Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.32 (s, IH), 9.21 (s, IH), 7.88 (s, 2H), 7.64 (p, IH), 7.25 (m, 4H), 6.92 (d, 2H), 2.82 (s, 3H); MS (ESI) m/z: 409 (M+H 4 ) 112 N-[4-[[5-amino-l-(2,6-difluoro-3-methylbenzoyl)-lH- 2,6-difluoro-3- 1 ,2,4-triazol-3 -yl] aminojphenyl] -methanesulfonamide methylbenzoyl chloride in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.33 (s, IH), 7.88 (s, anhydrous pyridine 2H), 7.54 (q, IH), 7.25 (d, 2H), 7.16 (t, IH), 6.92 (d, 2H), 2.82 (s, 3H), 2.25 (s, 3H); MS (ESI) m/z: 423 (M+H 4 ) Example 20 l-[4-[[5-amino-l-[(3-methyl-2-thienyl)carbonyl]-lH-l,2,4-triazol-3-yl]amino]phenyl]- 2-imidazolidinone (Cpd 113) Using the procedure of Example 15, l-(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 TΗF, 13.5 mmol) were reacted to produce Compound 20A (0.28 g, 80%) as a white solid. Η NMR (300 MHz, (CD 3 ) 2 SO) δ 11.05 (s, IH), 8.42 (s, IH), 7.35 (d, 2H), 7.24 (d, 2H), 6.65 (s, IH), 5.78 (s, 2H), 3.74 (t, 2H), 3.32 (t, 2H); MS (ESI) m/z: 260 (M+H 4 ). 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). Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.21 (s, IH), 8.01 (d, IH), 7.68 (s, IH), 7.55 (d, 2H), 7.43 (d, 2H), 7.11 (d, IH), 6.71 (s, IH), 3.83 (q, 2H), 3.37 (q, 2H), 2.63 (s, 3H); MS (ESI) m/z: 384 (M+H 4 ). 20A Compound 113 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- l-(2,6-difluoro-3-methylbenzoyl)- 1H- 2,6-difluoro-3- l,2,4-triazol-3-yl]amino]phenyl]-2-imidazolidinone methylbenzoyl chloride in Η NMR (300 MHz, (CD 3 ) 2 SO) δ 9.12 (s, IH), 7.82 (s, anhydrous pyridine 2H), 7.50 (m, IH), 7.21 (m, 4H), 7.20 (m, IH), 6.70 (s, IH), 3.72 (t, 2H), 3.28 (t, 3H), 2.21 (s, 3H); MS (ESI) m/z: 414 (M+H 4 ) 115 l-[4-[[5-amino-l-(2,6-difluorobenzoyl)-lH-l,2,4- 2,6-difluorobenzoyl triazol-3 -yl] amino]phenyl] -2-imidazolidinone chloride in anhydrous pyridine Η NMR (300 MΗ Z ; (CD 3 ) 2 SO) δ 9.16 (s, IH), 7.87 (s, 2H), 7.63 (m, IH), 7.19 (m, 6H), 6.74 (s, IH), 3.72 (t, 2H), 3.28 (t, 3H); MS (ESI) m z: 400 (M+H 4 ) Example 21 N 3 - [4-( 1 , 1 -dioxido-2-isothiazolidinyl)phenyl] - 1 - [(3 -methyl-2-thienyl)carbonyl] - 1H- l,2,4-triazole-3, 5-diamine (Cpd 116) Using the procedure of Example 15, 4-(l,l-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 TΗF, 43.6 mmol) were reacted to produce Compound 21 A (1.2 g, 95%) as a white solid. Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 11.05 (s, IH), 8.58 (s, IH), 7.47 (d, 2H), 7.05 (d, 2H), 5.78 (s, IH), 3.55 (t, 2H), 3.32 (t, 2H), 2.30 (p, 2H); MS (ESI) m/z: 295 (M+H 4 ). Using the procedure of Example 1, Compound 21 A was acylated with 3-methylthiophene-2-carboxylic acid Compound 20B mediated by DIC/HOBt in DMF to produce Compound 116 (48% yield). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.38 (s, IH), 8.01 (d, IH), 7.73 (s, 2H), 7.62 (d, 2H), 7.15 (d, 2H), 7.08 (d, IH), 3.67 (t, 2H), 3.42 (t, 2H), 2.58 (s, 3H), 2.35 (p, 2H); MS (ESI) m/z: 419 (M+H 4 ). Using the procedure for Example 21, the following compounds were prepared by acylation of the intermediate Compound 21 A using the indicated starting material in place of Compound 20B and reagent(s): Cpd Name/Data Starting Mat'l 117 1 -(2,6-difluorobenzoyl)-N 3 -[4-(l , 1 -dioxido-2- 2,6-difluorobenzoyl isothiazolidinyl)phenyl] - IH- 1 ,2,4-triazole-3 , 5 -diamine chloride in anhydrous pyridine Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.31 (s, IH), 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 4 ) Example 22 4-[[5-amino-l-(2,6-difluorobenzoyl)-lH-l,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 TΗF, 59.6 mmol) were reacted to provide Compound 22A (0.98 g, 50%) as a white solid. Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.22 (s, IH), 8.05 (s, IH), 7.73 (m, 3H), 7.53 (d, 2H), 7.04 (d, IH), 6.85 (m, 2H), 5.85 (s, 2H); MS (ESI) m/z: 332 (M+H 4 ). Using the procedure of Example 1, Compound 22A was acylated with 2,6- difluorobenzoyl chloride Compound IF in anhydrous pyridine to provide Compound 118 (61% yield). Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.85 (s, IH), 8.00-7.90 (m, 2H), 7.65 (m, IH), 7.59 (d, 2H), 7.35 (d, 2H), 7.25 (t, 2H), 7.04 (d, IH), 6.81 (t, IH), 3.31 (s, 2H); MS (ESI) m/z: 472 (M+H 4 ). Using the procedure for Example 22, the following compounds were prepared by acylation of the intermediate Compound 22 A using the indicated starting material in place of Compound IF and reagent(s): Cpd Name/Data Starting Mat'l 119 4-[[5-amino-l-[(5-ethyl-2-thienyl)carbonyl]-lH-l,2,4- 5-ethylthiophene-2- triazol-3 -yl] amino] -N-(2-pyridinyl)-benzenesulfonamide carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.87 (s, IH), 8.11 (d, DIC/HOBt in DMF IH), 8.01 (s, IH), 7.90 (s, IH), 7.75 (m, 4H), 7.68 (d, 2H), 7.63 (t, IH), 7.07 (m, 2H), 6.85 (m, IH), 2.95 (q, 2H), 1.32 (t, 3H); MS (ESI) m/z: 470 (M+H 4 ) 120 4-[[5-amino-l-[(3,5-dimethyl-2-thienyl)carbonyl]-lH- 3,5- 1 ,2,4-triazol-3 -yl] amino] -N-(2-pyridinyl)- dithylthiophene-2- benzenesulfonamide carboxylic acid mediated by ! Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.84 (s, IH), 7.98 (s, DIC/HOBt in DMF IH), 7.91 (s, IH), 7.74 (m, 4H), 7.71 (d, 2H), 7.63 (t, IH), 7.07 (m IH), 6.85 (m, 2H), 2.53 (s, 3H), 2.52 (s, 3H); MS (ESI) m/z: 470 (M+H 4 ) 121 4-[[5-amino- 1 -[(3-methyl-2-thienyl)carbonyl]-lH- 1 ,2,4- 3 -methylthiophene- triazol-3-yl]amino]-N-(2-pyridinyl)-benzenesulfonamide 2-carboxylic acid mediated by Η ΝMR (300 MHz, (CD 3 ) 2 SO) δ 9.85 (s, IH), 8.02 (m, DIC/HOBt in DMF 2H), 7.79 (m, 4H), 7.73 (d, 2H), 7.63 (t, IH), 7.13 (d, IH), 7.07 (m IH), 6.81 (m, IH), 2.61 (s, 3H); MS (ESI) m/z: 456 (M+H 4 ) . 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 MgCl 2 , 0.1 mM a 3 PO 4 , 1 mM DTT, 10 μM ATP, 0.025 μM biotinylated histone-Hl 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 FlashPlate™ (Cat. # SMP103, NEN, Boston, MA). 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 (30ng 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-Hl biotinylated peptide substrate became immobilized on the Flashplate ™ and the incorporation of 33 P-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 33 P-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 MgCl 2 , 0.1 mM Na^O 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 FlashPlate™ (Cat. # SMP103, NEN, Boston, MA). 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 6XHIS 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 Flashplate ™ and the incorporation of 33 P-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 33 P-γ-ATP incorporated into the immobilized peptide. IC 50 data for NEGF-R and CDK are shown in Table 1. IC 50 values listed as >10 or >100 indicate no observed 50% inhibition at the highest dose tested, nor was an inhibition maxima observed. ΝD means not tested. Table 1 IC S0 (uM) Cpd CDK1 VEGF-R HER2 CDK2 0.0064 0.1062 ND ND 0.0032 0.3659 ND ND 0.0080 0.3324 ND ND 0.02232 0.3866 ND ND 0.1436 0.5209 ND ND 0.0394 8.144 ND ND 0.057 >10 ND ND 0.136 >100 ND ND 0.039 1.597 ND ND 0 0.252 0.4907 ND ND 1 0.3046 >100 ND ND 2 0.0454 0.08406 ND ND 3 0.5353 0.5318 ND ND 4 0.0045 0.0267 ND ND 5 0.0048 0.0511 ND ND 6 0.0021 0.0137 ND ND 7 0.0025 0.027 ND ND 8 0.067 0.058 ND ND 9 0.0339 0.2907 ND ND 0 0.0044 0.031 ND ND 1 0.0088 0.023 ND ND 2 0.0318 0.2334 ND ND 3 0.0889 0.0353 ND ND 4 0.2823 0.0674 ND ND 5 0.01953 0.064 ND ND 6 18.4 -100 ND ND 7 -100 >100 ND ND 8 0.9816 13.25 ND ND 9 70.39 -100 ND ND 0 0.017 0.0406 ND ND 1 0.030 0.044 ND ND 2 0.0031 0.0219 ND ND 3 0.0032 0.0234 ND ND 4-. *- *- Oi Oi Oi Oi Oi > to v© 00 -4 *- vo p H—* o o -j o >—* 4^ to σs v o V 4^ J to J δ 4^ bs OJ 4^ O to o Oh δ bo σs OJ Oh 1 OJ σs t o 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 Exarr. Lple 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 MgCl 2 , 0.1 mM NaaVC 1 mM DTT, 10 μM ATP, 0.25-1 μM biotinylated peptide substrate, 0.2-0.8 μCuries per well 33 P-γ-ATP [2000-3000 Ci/mmol]. Assay conditions vary slightly for each protein kinase, for example, insulin receptor kinase requires 10 mM MnCl 2 for activity and Calmodulin-dependent protein kinase requires calmodulin and 10 mM CaCl 2 . 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 33 P-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 IC 50 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 NEGF-R (vascular endothelial growth factor receptor-2) is a fusion protein containing a polyhistidine tag at the Ν-terminus followed by amino acids 786-1343 of the rat NEGF- 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, MA, Cat. # 6020). CDK2 in complex with cyclin A is commercially available (Upstate Biotech, Lake Placid, NY). The CDK4 complex was composed of a mouse CDK4 protein and a mouse Cyclin Dl protein (The mouse CDK4 protein was genetically fused to an N- terminal Flag-epitope tag and the mouse Cyclin Dl protein was fused with an N- tenninal AU-1 epitope tag. The genes encoding these proteins were transfened to commercially available baculo viral 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, NY, 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, MA, Cat. #6030). Casein Kinase 2 includes the alpha and beta subunits of the human CK2 protein produced in E.coli (New England Biolabs, Beverly, MA, 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, MA, Cat. #6060). Glycogen Synthase Kinase-3 is the beta isoform of the rabbit enzyme produced in E.coli (New England Biolabs, Beverly, MA, Cat. #6040). MAP Kinase is the rat ERK-2 isofonn 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. Peptide Substrates VEGF-R (Biotin)KHKKLAEGSAYEEV-Amide CDK1 (Biotin)KTPKKAKKPKTPKKAKKL-Amide CDK2 (Biotin)KTPKKAKKPKTPKKAKKL- Amide CDK4 (GST)Amino Acids 769-921 of retinoblastoma EGF-R (Biotin)Poly(GT) 4:l Protein Kinase A (Biotin)GRTGRRNSI-Amide PKC (Biotin)RFARKGSLRQKNV-NH2 Casein Kinase 1 (Biotin)KRRRALS(phospho)VASLPGL-Amide Casein Kinase 2 (Biotin)RREEETEEE-Amide Calmodulin Kinase Biotin)KKALRRQETVDAL-Amide GSK-3 Biotin)KRREILSRRP(phospho)SYR-Amide MAP Kinase ERK-1 (Biotin)APRTPGGRR-Amide MAP Kinase ERK-2 (Biotin)APRTPGGRR-Amide Insulin Kinase (Biotin)TRDIYETDYYRK-Amide FGF-R2 (Biotin)Poly(GT) 4:l PDGF-R (Biotin)KHKKLAEGSAYEEV-Amide HER2 (Biotin)KHKKLAEGSAYEEV-Amide The IC 50 data for various kinases are shown in Table 2a through Table 2k. IC 50 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 (IC 50 uM) Cpd l 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 (IC 50 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 (IC 50 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 (IC S0 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 (IC 50 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 (IC 50 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 (ICso 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 (IC 50 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 (IC S0 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 (IC 50 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 (IC S0 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 ΝD PKA ΝD ΝD ΝD ΝD >100 Caseine Kinase 1 ΝD ΝD ΝD ΝD 8.97 Caseine Kinase 2 ΝD ΝD ΝD ΝD >100 ERK 2 ΝD ΝD ΝD ΝD 2.07 Calmodulin Kinase 2 ΝD ΝD ΝD ΝD 13.2 EGF-R ΝD ΝD ΝD ΝD >100 NEGF-R 4.8 >100 >100 >100 0.118 Insulin R Kinase ΝD ΝD ΝD ΝD 2.65 GSK-3 3.0 >100 >100 >100 0.094 PDGF-R kinase ΝD ΝD ΝD ΝD 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 14 C-labelled thymidine into newly synthesized DΝA 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 #RPΝQ0160) 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% CO 2 . 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% CO 2 . Methyl 14 C-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% CO 2 in drug plus 14 C- thymidine. The contents of the plate were discarded into a 14 C 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 14 C-thymidine incorporation was quantified on a Packard Top Count. Table 3 Inhibition of Cell Proliferation (IC 50 nM) Cell Line Cpd HeLa HCT-116 SK-OV : 3 MDA-MB-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 16 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 Exam pie 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.

Claims: WHAT IS CLAIMED IS: 1. A compound of Formula (I) : Formula (I) wherein Rj is selected from the group consisting of C M alkyl, 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: C h alky! (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1.8 )alkyl, -CO 2 H 5 -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo) j.3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ ; , and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 I )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C h alky! and -SO 2 -(C 1.8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C M alkyl, -C^alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C^ancyl (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 C h alky!), cyano, (halo) ! .;,, hydroxy and nitro), and amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!)}}; R 2 is selected from the group consisting of hydrogen, C j .galkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(Cι_ 8 )alkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: C M alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo) ! .;,, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C h alky!, cyano, halo, (halo) 1 . 3 (C 1 . g )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 . 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: C M alkyl, C 2 . s alkenyl (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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo) ! ^, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, Cj.galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl and -C^alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO 2 -(C 1 . 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, Cι. 8 alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (haro) 1 . 3 (C 1 .g)alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . s )alkyl, hydroxy(C 1 . 8 )alkoxy and nitro)}; and pharmaceutically acceptable salts thereof. 2. The compound of claim 1 wherein R λ is selected from the group consisting of C M alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl {wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of: C M alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 4 )alkyl, -CO 2 H, -CO 2 (C 1 . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)j_ 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), Cj. 4 alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)j_ 3 and hydroxy), -C(O)H, -C(O)(C 1 . 4 )alkyl, -CO 2 H, -CO 2 (C 1 . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C 1 . 4 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C M alkyl, -C^alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl) 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 C M alkyl (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 C M alkyl), cyano, (halo .-j, hydroxy and nitro), C j ^alkoxy and amino (substituted with two substituents independently selected from the group consisting of hydrogen and The compound of claim 1 wherein R t is selected from the group consisting of C M alkyl and aryl {wherein aryl is substituted with a substituent selected from the group consisting of: C 1 . 4 alkyl (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 C M alkyl), cyano, (halo) j _ 3 , hydroxy and nitro), C^alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C 1 . 4 )alkyl), -SO 2 - {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, C M alkyl, -C 1.4 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl) and heteroaryl)}, heterocyclyl (wherein heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C M alkyl and oxo) and heteroaryl} . 4. The compound of claim 1 wherein R λ is selected from the group consisting of Ci. 4 alkyl 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, C M alkyl and -SO 2 -(C 1 . 4 )alkyl), -SO 2 - {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, C M alkyl, -Cj. 4 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) and pyridinyl)}, piperazinyl (wherein piperazinyl is optionally substituted with 1 to 2 C M alkyl substituents), imidazolidinyl, isothiazolidinyl (wherein imidazolidinyl and isothiazolidinyl are optionally substituted with 1 to 2 oxo substituents), imidazolyl and triazolyl}. 5. The compound of claim 1 wherein R 2 is selected from the group consisting of hydrogen, C M alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl and hydroxy(C 1 . 4 )alkyl. 6. The compound of claim 1 wherein R 2 is selected from the group consisting of hydrogen and C M alkyl.. 7. The compound of claim 1 wherein R 2 is hydrogen. 8. The compound of claim 1 wherein X is selected from the group consisting of- C(O)-, -C(S)- and -SO 2 -. 9. The compound of claim 1 wherein R 3 is selected from the group consisting of: C M alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl {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)(C M )alkyl, -CO 2 H, -CO 2 (C 1 . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and Cι_ 4 alkyl), cyano, (halo) ] . 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 C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 4 )alkyl, (halo) 1 . 3 (C 1 . 4 )alkoxy, hydroxy, hydroxy(C 1 . 4 )alkyl, hydroxy(C 1 . 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: C M alkyl, C 2 . 4 alkenyl (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)(C 1.4 )alkyl, -CO 2 H, -CO^C^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)^, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 4 )alkyl, C M alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)j. 3 and hydroxy), -C(O)H, -C(O)(C 1 . 4 )alkyl, -CO 2 H, -CO 2 (C M )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C M )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C M alkyl and -C 1 . 4 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl))}, -NH-SO 2 -(C 1 . 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, C M alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 4 )alkyl, (halo) 1 . 3 (C 1 . 4 )alkoxy, hydroxy, hydroxy(C j.4 )alkyl, hydroxy^^alkoxy and nitro)}. 10. The compound of claim 1 wherein R 3 is selected from the group consisting of: C M alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl {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 C 1 . 4 alkyl), cyano, (halo) ].; ,, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally, substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1.3 (C 1.4 )alkyl, (halo) 1.3 (C 1 . 4 )alkoxy, hydroxy, hydroxy(C M )alkyl, hydroxy(C 1 . 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: C M alkyl, C 2 . 4 alkenyl (wherein alkyl and alkenyl are optionally substituted on a terminal carbon with a substituent selected from the group consisting of -CO 2 H, -CO 2 (C 1 _ 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo .;,, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1.4 )all yl, C M alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)__ 3 and hydroxy), -C(O)H, -C(O)(C M )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . 4 )alkyl), aryl and heteroaryl} and amino {substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and aryl (wherein aryl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 4 )alkyl, (halo) 1 . 3 (C 1 . 4 )alkoxy, hydroxy, hydroxy(C 1 . 4 )alkyl, hydroxy(C M )alkoxy and nitro)}. 11. The compound of claim 1 wherein R 3 is selected from the group consisting of: C M alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl {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 C M alkyl), cyano, (halo . 3 , hydroxy, nitro, phenyl and thienyl (wherein phenyl and thienyl are optionally substituted with 1 to 2 substituents independently selected from 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: C M alkyl (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 C M alkyl), cyano, (halo)^ hydroxy and nitro), -CH(OH)-(C M )al yl, C 1 . 4 alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), 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: C M alkyl (wherein alkyl is optionally substituted on a terminal carbon with a substituent selected from the group consisting of -CO 2 H, -CO 2 (C M )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)^ hydroxy and nitro), C 1.4 alkoxy, -C(O)(C 1 . 4 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . 4 )alkyl), pynolyl and pyridinyl; and, wherein thiadiazolyl is optionally substituted with one substituent selected from the group consisting of C M alkyl (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 C M alkyl), cyano, (halo .; ,, hydroxy and nitro), C^alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, halo, hydroxy and nitro} and amino {substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and phenyl (wherein phenyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, hydroxy and nitro)}. 12. A compound of Formula (la): Formula (la) wherein R 4 is selected from the group consisting of: .galkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C ! . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)j_ 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl} , C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, and -SO 2 -(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl, -C j .galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C, .8 alkyl) 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 C M alkyl (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 amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, C M alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C 1 . 8 )alkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: Cj_ g alkyL C 2 . 8 alkenyl, C 2 . g alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)^, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected cyano, halo, (halo) ] . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (Cι_ 8 )alkoxy, hydroxy, hydroxy(C 1.8 )alkyl, hydroxy(C 1.8 )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: Cj. 8 alkyl, C 2 . 8 alkenyl (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)(C ! . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo) ι _ 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C M )alky C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) ! _ 3 and hydroxy), -C(O)H, -CCOX alkyl, -CO 2 H, -CO^C^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C ι _ s )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and -SO 2 - {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, C M alkyl and -C j . 8 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO^C^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, C M alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Cj_ 8 alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy^.^alkyl, hydroxy(C ι _ 8 )alkoxy and nitro)}; and pharmaceutically acceptable salts thereof. 13. A compound of Formula (lb) : Formula (lb) wherein R 4 is selected from the group consisting of: C M alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (Cj Jal yl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C j . 8 alkyl), cyano, (halo) j . 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl}, (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo) !.3 and hydroxy), -C(O)H, -C(O)(C,.g)alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, and -SO 2 -(C j . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C h alky!, -Cj.galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C^aUcyl) 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 C M alkyl (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 C h alky!), cyano, (halo) !.3 , hydroxy and nitro), .galkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, C M alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C j . 8 )aιkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: C M alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl {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)(C 1.8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and Cι. 8 alkyl), cyano, (halo^. ; ,, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1.3 (C 1 . s )alkoxy, hydroxy, hydroxy(C 1.8 )alkyl, hydroxy(C 1.8 )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: C^aUcyl, C 2 . s alkenyl (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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C^aUcyl), cyano, (halo) ! . ; ,, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, Cj. 8 alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C^aUcyl and -C(O)(C 1.8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C^aU yl and -C h alky lamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C 1 . 8 alkyl))}, -NH-SO 2 -(C 1 . 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, C^aUcyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1 . s )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C j . 8 )alkoxy and nitro)}; and pharmaceutically acceptable salts thereof. 14. A compound of Formula (Ic): Formula (Ic) wherein R 4 is selected from the group consisting of: C h alky! {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)^ hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl}, C^alkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of ( alo)__ 3 and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C^aUcyl and -SO 2 -(Cι_ 8 )alkyι), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, -C h alky lamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C M alkyl (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 C h alky!), cyano, (halo)^;,, hydroxy and nitro), C j ^alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, .galkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C 1 . 8 )alkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: C 2 .galkenyl, C 2 . 8 alkynyl {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)(C 1.8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo^ .; ,, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1.3 (C 1.8 )alkoxy, hydroxy, hydroxy(C 1.8 )alkyl, hydroxy(C 1 . 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: Ci . galkyl, C 2.8 alkenyl (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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and Cι .8 alkyl), cyano, (halo . ; ,, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, C j .galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^;, and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl and (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and Cj. g alkyl))}, -NH-SO 2 -(C 1 . 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, C M alkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Cj.galkyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1.8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 .g)alkoxy and nitro)}; and pharmaceutically acceptable salts thereof. 15. The compound of claim 14 wherein R 4 is selected from the group consisting of: amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C M )alkyl), -SO 2 - {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, C M alkyl, -C j . 4 alkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl) and heteroaryl)}, heterocyclyl (wherein heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C M alkyl and oxo) and heteroaryl. 16. A compound of Formula (Id): wherein R 4 is selected from the group consisting of: C M alkyl {optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C 1.8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo) ! . 3 , hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl}, .galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)ι_ 3 and hydroxy), -C(O)H, -C(O)(C 1.8 )alkyl, -CO 2 H, -CO^ ^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C^aUcyl and -SO 2 -(C 1 . 8 )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, .galkyl, -C^aUcylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C^aUcyl (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 C M alkyl), cyano, (halo . ; ,, hydroxy and nitro), C^alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, halo, hydroxy and nitro; and, wherein heterocyclyl is optionally substituted with 1 to 2 oxo substituents}; R 2 is selected from the group consisting of hydrogen, C^aUcyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl and hydroxy(C 1.8 )alkyl; X is selected from the group consisting of-C(O)-, -C(S)- and -SO 2 -; and, R 3 is selected from the group consisting of: C M alkyl, C 2 _ 8 alkenyl, C 2 . 8 alkynyl {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)(C 1.8 )alkyl, -CO 2 H, -CO^C^alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)^ ; ,, hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C^aUcyl, cyano, halo, (halo) 1 . 3 (C 1 . 8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1 . 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: C M alkyl, C 2 . 8 alkenyl (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)(C 1.8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo^ .; ,, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, Cj.galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo^. ; , and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -C(O)(C 1 _ 8 )alkyι), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C M alkyl and -C^alkyla ino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO 2 -(C 1 . 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, C j .galkyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1.3 (C 1 .g)alkyl, (halo) 1 . 3 (C 1 . 8 )aιkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1.8 )alkoxy and nitro)}; and pharmaceutically acceptable salts thereof. 17. A compound of Formula (Ie): Formula (Ie) wherein R_ is selected from the group consisting of C M alkyl, 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: C M alkyl (optionally substituted on a terminal carbon with a substituent selected from the group consisting of -C(O)H, -C(O)(C ! . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^ hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo .- j and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C M alkyl and -SO 2 -(C 1.s )alkyl), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), -SO 2 - {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, C^an yl, -C j .galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!) 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 C M alkyl (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 C h alky!), cyano, (halo)ι_ 3 , hydroxy and nitro), C^alkoxy and amino (substituted with two substituents. independently selected from the group consisting of hydrogen and C h alky!)}}; and, R 3 is selected from the group consisting of: C M alkyl, C 2 . s alkenyl, C 2 . s alkynyl {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)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), cyano, (halo)^ hydroxy, nitro, aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (C 1.8 )alkyl, (halo) 1 . 3 (C 1 . 8 )alkoxy, hydroxy, hydroxy(C 1 . 8 )alkyl, hydroxy(C 1.8 )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: C,. 8 alkyl, C 2 . 8 alkenyl (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)(C 1.8 )alkyl, -CO 2 H, -CO 2 (C 1.8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!), cyano, (halo)^, hydroxy, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl), -CH(OH)-(C 1 . 8 )alkyl, C galkoxy (optionally substituted on a terminal carbon with a substituent selected from the group consisting of (halo)^ and hydroxy), -C(O)H, -C(O)(C 1 . 8 )alkyl, -CO 2 H, -CO 2 (C 1 . 8 )alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C j ^alkyl and -C(O)(C 1 „ 8 )alkyι), -C(O)amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C M alkyl), -SO 2 - {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, C M alkyl and -Cj.galkylamino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C h alky!))}, -NH-SO^C^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, C^aUcyl, cycloalkyl, aryl and heteroaryl (wherein cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C M alkyl, cyano, halo, (halo) 1 . 3 (Cι_ 8 )alkyl, (halo) ! . 3 (C,. 8 )alkoxy, hydroxy, hydroxy(C 1 . g )alkyl, hydroxy(Cι_g)alkoxy and nitro)}; and pharmaceutically acceptable salts thereof. 18. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected o o o o o o op n n o op o o n npp ppp o o o o o o o o o o o o o o o o o o o o o o oo o o o o o o o x & a 1 •§ C(0) H (3-Br)2-thienyl 4-SO 2 -NH 2 ; C(0) H 4-(CH 3 )-l,2,3-thiadiazol-5- 4-SO 2 -NH 2 ; yi C(O) H 1 ,2,3-thiadiazol-4-yl 4-SO 2 -NH 2 ; C(0) H Cyclopentyl 4-SO 2 -NH 2 ; C(0) H Cyclohexyl 4-SO 2 -NH 2 ; C(O) H 2-thienyl-CH 2 4-SO 2 -NH 2 ; C(O) H 2-thienyl-(CH) 2 4-SO 2 -NH 2 ; C(O) H (2,6-F 2 )-Ph-CH 2 4-SO 2 -NH 2 ; C(O) H (2,6-F 2 )Ph(CH) 2 4-SO 2 -NH 2 ; C(O) H Cycloheptyl 4-SO 2 -NH 2 ; C(O) H 4-CH 3 -cyclohexyl 4-SO 2 -NH 2 ; C(O) H 4-CH 3 -cyclohexyl 4-SO 2 -NH 2 ; C(O) H 4-(CH 2 ) 3 CH 3 -cyclohexyl 4-SO 2 -NH 2 ; C(O) H 5-(2-pyridinyl)2-thienyl 4-SO 2 -NH 2 ; C(O) H 3 -( lH-pynol- 1 -yl)2-thieny 4-SO 2 -NH 2 ; 1 C(O) H 5-[C(CΗ 3 ) 3 ]2-thienyl 4-SO 2 -NH 2 ; C(O) H 5-[(CH) 2 C(O)OC(CH 3 ) 3 ]2-t 4-SO 2 -NH 2 ; hienyl C(O) H Ph(C) 2 4-SO 2 -NH 2 ; C(O) H (2,6-F 2 -3-NO 2 )Ph 4-SO 2 -NH 2 ; C(O) H (2,6-F 2 -3-NH 2 )Ph 4-SO 2 -NH 2 ; C(O) H [2,6-(CH 3 ) 2 ]Ph 4-SO 2 -NH 2 ; C(O) H (2-CH 3 )Ph 4-SO 2 -NH 2 ; C(O) H [2,6-F 2 -3-CH(OH)CH 3 ]Ph 4-SO 2 -NH 2 ; C(O) H (2,6-F 2 )Ph 4-SO 2 -NH 2 ; C(O) H (2,6-F 2 -3-CH 3 )Ph 4-SO 2 -NH 2 ; C(S) H -NH[(2,6-F 2 )Ph] 4-SO 2 -NH 2 ; C(O) H -NH[(2,6-F 2 )Ph] 4-SO 2 -NH 2 ; SO 2 H (2,6-F 2 )Ph 4-SO 2 -NH 2 ; C(O) H (2-Cl-3-CH 3 -6-F)Ph 4-SO 2 -NH 2 ; C(O) H (2-Cl-6-F)Ph 4-SO 2 -NH 2 ; and C(O) H (2,6-F 2 -5-Cl)Ph 4-SO 2 -NH 2 . 19. The compound of claim 16 wherein X, R 3 and R 4 are dependently selected from the group consisting of: X R 3 R 4 C(O) (2,6-F 2 )Ph 4-SO 2 -NH 2 ; C(O) (2,6-F 2 -3-CH 3 )Ph 4-SO 2 -NH 2 ; and, C(S) -NH[(2,6-F 2 )Ph] 4-SO 2 -NH 2 . 20. The compound of claim 17 wherein R t and R 3 are dependently selected from: R, R 3 CH 3 3-CH 3 -2-thienyl. 21. The compound of claim 1 wherein the compound of Formula (I) is selected from the group consisting of: 5 -amino-3 - [ [4-(aminosulfonyl)phenyl] amino] -N-(2,6-difluorophenyl)- 1 H- 1 ,2,4-triazole- 1 -carbothioamide; 5-amino-3-[[4-(aminosulfonyl)phenyl]amino]-N-(2,6-difluorophenyl)-lH- 1 ,2,4-triazole- 1 -carboxamide; 4-[[5-amino-l-(2-chloro-6-fluoro-3-methylbenzoyl)-lH-l,2,4-triazol-3- yl]amino]-benzenesulfonamide; 4-[[5-amino-l-(2-chloro-6-fluorobenzoyl)-lH-l,2,4-triazol-3-yl]amino]- benzenesulfonamide; 4-[[5-amino- 1 -(2,6-difluoro-3-methylbenzoyl)- IH- 1 ,2,4-triazol-3-yl] amino] -N- methyl-benzenesulfonamide; 4- [[5 -amino- 1 - [(3 -methyl-2-thienyl)carbonyl] - IH- 1 ,2,4-triazol-3 -yl] amino] -N- methyl-benzenesulfonamide; 4- [ [5-amino- 1 - [(3 -methyl-2-thienyl)carbonyl] - IH- 1 ,2,4-triazol-3 -yl] amino] -N- [2-(dimethylamino)ethyl]-benzenesulfonamide; l-[4-[[5-amino-l-[(3-methyl-2-thienyl)carbonyl]-lH-l,2,4-triazol-3- yl] amino]phenyl] -2-imidazolidinone; N 3 -[4-(l,l-dioxido-2-isothiazolidinyl)phenyl]-l-[(3-methyl-2- thienyl)carbonyl]-lH-l ,2,4-triazole-3,5-diamine; and, 4- [[5 -amino- 1 - [(3 -methyl-2-thienyl)carbonyl] - IH- 1 ,2,4-triazol-3 -yl] amino] -N- (2-pyridinyl)-benzenesulfonamide. 22. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 23. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier. 24. A method for preparing a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier. 25. Use of a compound of any of claims 1-21 and claims 36-44 in the treatment of a a kinase mediated disorder. 26. The use of claim 25 wherein the disorder is mediated by selective inhibition of a kinase selected from the group consisting of a cyclin dependent kinase and a tyrosine kinase. 27. The use of claim 26 wherein the kinase is selected from the group consisting of cyclin dependent kinase- 1, cyclin dependent kinase-2, cyclin dependent kinase-4, vascular endothelial growth factor receptor-2, endothelial growth factor receptor and human epidennal growth factor receptor-2. 28. The use of claim 25 wherein the disorder is mediated by dual inhibition of at least two kinases selected from the group consisting of a cyclin dependent kinase and a tyrosine kinase. 29. The use of claim 28 wherein at least two kinases are selected from the group consisting of cyclin dependent kinase- 1, cyclin dependent kinase-2, cyclin dependent kinase-4, vascular endothelial growth factor receptor-2, endothelial growth factor receptor and human epidermal growth factor receptor-2. 30. The use of claim 25 wherein the therapeutically effective amount of the compound of claim 1 is from about 0.001 mg/kg/day to about 300 mg/kg/day. 31. The use of claim 25 wherein the kinase mediated disorder is selected from the group consisting of cancer and tumor growth, tumor vascularization, angiopathy, angiogenesis, chemotherapy-induced alopecia and restenosis. 32. The use of claim 25 further comprising using the compound as an adjunct to chemotherapy and radiation therapy. 33. The use of claim 25 further comprising use of a therapeutically effective amount of a pharmaceutical composition of claim 22. 34. The method of claim 33 wherein the therapeutically effective amount of a pharmaceutical composition of claim 22 is from about 0.001 mg/kg/day to about 300 mg/kg/day. 35. The use of claim 25 further comprising using the compound in combination with a therapeutically effective amount of at least one other agent. 36. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: R, R, R 4 C(O) H (2,6-F 2 )Ph 4-SO 2 - 1 -H-piperidin- 1 - yi; C(O) H 2-thienyl 4-S O 2 - 1 -H-piperidin- 1 - yi; C(O) H (3-CH 3 )2-thienyl 4-S O 2 - 1 -H-piperidin- 1 - yi; C(O) H (2,6-F 2 )Ph 4-(4-CΗ 3 -l,4-H- piperazin-1-yl); C(O) H (2,6-F 2 -3-CH 3 )Ph 4-(4-CΗ 3 -l,4-H- ρiperazin-1-yl); C(O) H (3-CH 3 )2-thienyl 4-(4-CΗ 3 -l,4-H- piperazin-1-yl); C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-(4-CΗ 3 -l,4-H- piperazin-1-yl); and C(O) H (5-CH 2 CH 3 )2-thienyl 4-(4-CΗ 3 -l,4-H- piperazin-1-yl). 37. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R, R, R 4 C(O) H (2,6-F 2 )Ph 4-SO 2 -NH(CH 2 CH 3 ); C(O) H (2,6-F 2 )Ph 4-SO 2 -NH(CH 3 ); C(O) H (2,6-F 2 -3-CH 3 )Ph 4-SO 2 -NH(CH 3 ); C(O) H (3-CH 3 )2-thienyl 4-SO 2 -NH(CH 3 ); C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-SO 2 -NH(CH 3 ); C(O) H (5-CH 2 CH 3 )2-thienyl 4-SO 2 -NH(CH 3 ); C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-SO 2 -N(CH 3 ) 2 ; C(O) H (5-CH 2 CH 3 )2-thienyl 4-SO 2 -N(CH 3 ) 2 ; C(O) H (3-CH 3 )2-thienyl 4-SO 2 -N(CH 3 ) 2 ; C(O) H (2,6-F 2 -3-CH 3 )Ph 4-SO 2 -N(CH 3 ) 2 ; and C(O) H (2,6-F 2 )Ph 4-SO 2 -N(CH 3 ) 2 . 38. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R 2 R 3 R 4 C(O) H (5-CH 2 CH 3 )2-thienyl 4-(l-H-imidazol- 1 -yl); C(O) H (3-CH 3 )2-thienyl 4-(l-H-imidazol-l-yl); C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-(l -H-imidazol-1 -yl); C(O) H (2,6-F 2 )Ph 4-( 1 -H-imidazol- 1 -yl) ; and C(O) H (2,6-F 2 -3-CH 3 )Ph 4-( 1 -H-imidazol- 1 -yl) . 39. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R, R, R 4 C(O) Η (2,6-F 2 -3-CΗ 3 )Ph 4-(l-H-l,2,4-triazol-l- yi); C(O) H (2,6-F 2 )Ph 4-(l-H-l,2,4-triazol-l- yi); C(O) H (5-CH 2 CH 3 )2-thienyl 4-(l-H-l,2,4-triazol-l- yi); C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-(l-H-l,2,4-triazol-l- yi); C(O) H (3-CH 3 )2-thienyl 4-(l-H-l,2,4-triazol-l- yi); C(O) H (2,6-F 2 )Ph 4-(l-H-l,3,4-triazol-l- yi); C(O) H (2,6-F 2 -3-CH 3 )Ph 4-(l-H-l,3,4-triazol-l- yl); and C(O) H (3-CH 3 )2-thienyl 4-(l-H-l,3,4-triazol-l- yi)- 40. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R 2 R 3 R 4 C(O) Η (2,6-F 2 -3-CΗ 3 )Ph 4-(l-H-l,2,4-triazol-l- yi); C(O) Η (2,6-F 2 )Ph 4-(l-H-l,2,4-triazol-l- yi); C(O) Η (5-CH 2 CH 3 )2-thi( 4-(l-H-l,2,4-triazol-l- yi); C(O) Η [3,5-(CH 3 ) 2 ]2-thi< 4-(l-H-l,2,4-triazol-l- yi); C(O) Η (3-CH 3 )2-thienyl 4-(l-H-l,2,4-triazol-l- yi); C(O) Η (2,6-F 2 )Ph 4-(l-H-l,3,4-triazol-l- yi); C(O) Η (2,6-F 2 -3-CH 3 )Ph 4-(l-H-l,3,4-triazol-l- yi); C(O) Η (3-CH 3 )2-thienyl 4-(l-H-l,3,4-triazol-l- yi); 41. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R 2 R 3 R 4 C(O) Η (5-CΗ 2 CΗ 3 )2-thi< 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ]; C(O) Η (3-CH 3 )2-thienyl 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ]; C(O) Η (2,6-F 2 -3-CH 3 )Ph 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ]; C(O) H (2,6-F 2 )Ph 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ]; C(0) H [3,5-(CH 3 ) 2 ]2-thienyl 4-SO 2 - NH[(CH 2 ) 2 N(CH 3 ) 2 ]; C(0) H [3,5-(CH 3 ) 2 ]2-thienyl 4-NH-SO 2 -CH 3 ; C(O) H (3-CH 3 )2-thienyl 4-NH-SO 2 -CH 3 ; C(0) H (5-CH 2 CH 3 )2-thienyl 4-NH-SO 2 -CH 3 ; C(O) H (2,6-F 2 )Ph 4-NH-SO 2 -CH 3 ; and C(O) H (2,6-F 2 -3-CH 3 )Ph 4-NH-SO 2 -CH 3 . 42. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R 2 R 3 R 4 C(O) H (3-CH 3 )2-thienyl 4-(2-imidazolidinone) ; C(O) H (2,6-F 2 -3-CH 3 )Ph 4-(2-imidazolidinone); and C(O) H (2,6-F 2 )Ph 4-(2-imidazolidinone) . 43. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R 2 R 3 R 4 C(O) H (3-CH 3 )2-thienyl 4-(l,l-dioxido-2- isothiazolidinyl); and C(O) H (2,6-F 2 )Ph 4-(l,l-dioxido-2- isothiazolidinyl). 44. The compound of claim 14 wherein X, R 2 , R 3 and R 4 are dependently selected from the group consisting of: X R 2 R 3 R 4 C(O) H (2,6-F 2 )Ph 4-SO 2 -NH-2-pyridinyl; C(O) H (5-CH 2 CH 3 )2-thienyl 4-SO 2 -NH-2-pyridinyl; C(O) H [3,5-(CH 3 ) 2 ]2-thienyl 4-SO 2 -NH-2-ρyridinyl; and C(O) H (3-CH 3 )2-thienyl 4-SO 2 -NH-2-pyridinyl. 45. The use of claim 35 wherein the at least one other agent is a chemotherapeutic agent to treat cancer. 46. The use of claim 45 wherein the dose of the chemotherapeutic agent is reduced relative to the dose that would be given in the absence of the therapeutically effective amount of the compound of claim 1. 47. The use of claim 45 wherein the therapeutically effective amount of a compound of claim 1 is given to the subject before, during or after the chemotherapeutic agent.

Inventors: CONNOLLY PETER J, EMANUAL STUART, GUNINGER ROBERT, HUANG SHENLIN, LIN RONGHUI, MIDDLETON STEVE, WETTER STEVEN, CONNOLLY, PETER, J., EMANUAL, STUART, GUNINGER, ROBERT, HUANG, SHENLIN, LIN, RONGHUI, MIDDLETON, STEVE, WETTER, STEVEN
Applicants: ORTHO MC NEIL PHARMACEUTICAL I, ORTHO MC NEIL PHARMACEUTICAL, INC.
Application year: 2001
Main classification: C07D249
IPC codes: A61K31, C07D249, C07D401, C07D405, C07D409, C07D413, C07D417