Title of Invention

SUBSTITUTED ALKYLAMINE DERIVATIVES

Abstract

Selected heterocyclic compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceuticatly acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Full Text

This is a divisional application of parent application number 1070/DELNF/2003 filed on July II, 2003 based on PCT Application PCT/US02/00743 dt: 11/1/2002, claiming priority from U.S. Provisional Application Nos, 60/261.339, /lied January 12, 2001, and 60/323.764 filed September 19, 2001 which are hereby incorporated by reference. FIELD OF THE INVENTION This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cancer and angiogenesis-related disorders. BACKGROUND OF THE INVENTION Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes abl, Atk, bcr-abl, BIk, Brk, Btk, c-kit, c-met, c-src, CDKI, CDK2, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDKIO, cRafl, CSFIR, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-l, Fps, Frk, Fyn, Hck, IGF-IR, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PK.C, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become an important therapeutic target. Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration. psoriasis, hemangioblastoma. hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or posl-transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemia). At the center of the network regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth, and in a wide number of pathological anomalies and diseases, lies the angiogenic factor known as Vascular Endothelial Growth Factor"(VEGF; originally termed 'Vascular Permeability Factor", VPF), along with its cellular receptors (see G. Breierelal., Trends in Cell Biology, 6, 454-6 {J996)). VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to "Platelet-Derived Growth Factor" (PDGF); it is produced by nonnal cell lines and tumor cell lines; is an endothelial cell-specific mitogen; shows angiogenic activity in in vivo test systems (e.g. rabbit cornea); is chemotaclic for endothelial cells and monocytes; and induces plasminogen activators in endothelial cells, which are involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of i so forms of VEGF are known, which show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as "Placenta Growth Factor"(PIGF) and VEGF-C. VEGF receptors (VEGFR) are transmembranous receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-I (also known as flt-l). VEGFR-2 (also known as KDR), and VEGFR-3. A large number of human tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF released by tumor cells stimulates the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner and through the improved blood supply, accelerate tumor grovrth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo is shown in studies in which VEGF expression or VEGF activity was inhibited. This was achieved with anti-VEGF antibodies, with dominant-negative VEGFR-2 mutants which inhibited signal transduction, and with antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumor cell lines in vivo as a result of inhibited tumor angiogenesis. Angiogenesis is regarded as an absolute prerequisite for tumors which grow beyond a diameter of about 1-2 mm; up to this limit, oxygen and nutrients may be supplied to the tumor cells by diffusion. Every tumor, regardless of its origin and its cause, is thus dependent on angiogenesis for its growth after it has reached a certain size. Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: I) Inhibition of the growth of vessels, especially capillaries, into avascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between cell death and proliferation; 2) Prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and 3) Inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11, 77-114 (2001). VEGF's are unique In that they are the only angiogenic growth factors known to contribute to vascular hyper permeability and the formation of edema. Indeed, vascular hyper permeability and edema that is associated with the expression or administration of many other growth factors appears to be mediated via VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous tissues; hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke VEGF/VPF-mediated responses. Vascular hyper permeability, associated edema, altered Tran endothelial exchange and macromolecular extravasation, which is often accompanied by diapedesis, can result in excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability can significantly contribute to disorders with these eliologic features. As such, regulators of angiogenesis have become an important therapeutic target. Schipper US patent 3,226,394, issued Dec. 28, 1965, describes anthranilamides as CNS depressants. Japanese patent JP2000256358 describes pyrazole derivatives that block the calcium release-activated calcium channel. EP application 9475000, published 6 October 1999, describes compounds as PGE2 antagonists. PCT publication W096/41795, published 27 December 1996, describes benzamides as vasopressin antagonists. WOOJ/29009 describes aminopyridines as KDR inhibitors, WOOl/30745 describes anthranilic acids as CGMP phosphodiesterase inhibitors. WOOO/02851, published 20 Jan 2000 describes arylsulfonylamnoaryl amides as guanylate cyclase activators. W098/45268 describes nicotinamide derivatives as PDE4 inhibitors. W098/24771 describes benzamides as vasopressin antagonists. US Patent No. 5,532,358, issued July 2, 1996, describes the preparation of 2-(cyclopropylamino)-N-(2-methoxy-4-methyl-3- pyridinyI)-3-pyridinecarboxamide as an intermediate for HIV inhibitors. Triazine-substituted amines are described for their aggregating ability (J, Amer. Chem. Soc, 115,905-16(1993). Substituted imidazolines were tested for their antidepressant activity in Ind. J. Het. Chem., 2, 129-32 (1992). N-(4-Pyridyl) anthranilic amides were described in Chem Abstr. 97:109837 (1981). PCT publication W099/32477, published 1 July 1999, describes anthranilamides as anti- coagulants. US patent 6,140,351 describes anthrani lam ides as anti-coagulants. PCT publication W099/62885, published 9 December 1999, describes l-{4-aminophenyl) pyrazoles as antiinflammatories. PCT publication WOOO/39111, published 6 July 2000, describes amides as factor Xa inhibitors. PCT publication WOOO/39117, published 6 July 2000, describes heteroaromatic amides as factor Xa inhibitors. PCT publication WOOO/27819, published 18 May 2000, describes anthranilic acid amides as VEGF inhibitors. PCT publication WOOO/27820 published 18 May 2000, describes N-aryl anthranilic acid amides as VEGF inhibitors. 7-Chloroquinolinylamines are described in FR216822? as antiinflammatories. WOOl/55114. published 2 Aug. 2001, describes nicotinamides for the treatment of cancer. WOOl/55115, published 2 Aug. 2001, describes nicotinamides as inducers of apoptosis. WOOl/85715, published 15 November 2001, describes substituted pyridines and pyrimidines as anti-angiogenesis agents. PCT publication WOOl/85691 published 15 November 200], describes anthranilic amides as VEGF inhibitors, PCT publication WOOl/85671 published 15 November 2001, describes anthranyl amides as VEGF inhibitors. PCT publication WOOl/81311 published 1 November 2001, describes anthranilic amides as VEGF inhibitors. However, compounds of the current invention have not been described as inhibitors of angiogenesis such as for the treatment of cancer. DESCRIPTION OF THE INVENTION A class of compounds useful in treating cancer and angiogenesis is defined by Formula I wherein each of A' and A^ is independently C, CH or N; wherein ring A is selected from a) 5- or 6-membered partially saturated heterocyclyl. even more preferably Y is -NH-CH2-; wherein R^ and R' are independently selected from H, halo, cyano and CM-alkyI substituted with R2, or wherein Ra and Rb together form C3-C4 cycloalkyl, preferably H, halo, cyano and C!-2-alkyl substituted with R2, or wherein Ra and Rfa together form C3-C4 cycloalkyl, more preferably H, halo and Cl-C2-alkyl, even more preferably H; wherein Rz is selected from C1-C4 alkylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an -NH-, preferably C1-C2 alkylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an -NH-more preferably C1-C2 alkylenyl; wherein R'd is cycloalkyl, preferably C3-C6 cycloalkyl; wherein R is selected from a) substituted or unsubslituled 5-6 membered heterocyclyl, preferably substituted or unsubstituted 5-6 membered heteroaryl comprising one or more nitrogen atoms, more preferably 4-pyrazolyl, triazolyl, 4-pyridyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 4-pyridazinyl, or 6-pyridazinyl, even more preferably 4-pyridyl, 4-pyrimidinyl and 4-pyridazinyl, even more preferably 4-pyridyl, and b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl, preferably substituted or unsubstituted 9-10 membered fused heteroaryl comprising one or more nitrogen atoms, more preferably indazolyl, quinolinyl, isoquinolinyl, or quinazolinyl. even more preferably indazoiyi, 4-quinoIyI, 5-quinolyl, 6-quinolyl, 4-isoquinolyl, 5-isoqumolyl, and 6-isoquinolyl, wherein substituted R is substituted with one or more substituents independently selected from halo, -0R^ -SR\ -S03R^-C02R^ -C0NR^R\ -COR^ -NR^R\ -S02NR^R^ -NR'C(0)OR^ -NR^C(0)R^ cycloalkyi, optionally substituted 5-6 membered heterocyclyl, optionally subsliluled phenyl, lower alky] substituted with R^ cyano, nitro, lower alkenyl and lower alkynyl; preferably haio, -0R3, -SR3, -C02R3, -CONR3R3, -C0R3, -NR3R3, -S02NR3R3, -NR3C(0)OR3, -NR3C(0)R3, -NR3C(0)NR3R3, cycloalkyi, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, Cl-2-alkyl, cyano, Cl-2-hydroxyalkyl, nitro and Cl-2-haloalkyl; wherein R' is selected from a) substituted or unsubstituted 6-10 membered aryl, preferably phenyl, naphthyl, indenyl, or tetrahydronaphthyl, more preferably phenyl, b) substituted or unsubstituted 5-6 membered heterocyclyl, preferably 5-6 membered heteroaryl, more preferably thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, ftiryl, or pyrrolyl, c) substituted or unsubstituted 9-10 membered fused heterocyclyl, preferably 9-10 membered fused heteroaryl, more preferably indazolyt, indolyl, 2,1,3-benzolhfadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl, benzodioxanyl, or quinazolinyl, d) cycloalkyi, and e) cycloalkenyl wherein substituted R' is substituted with one or more substituents independently selected from halo. -0R\ -SR\ -C02RI -C0NR^R\ -C0R\ -NR'R', -NH(C,-C4 alkylenylR'"}. -SOJR', -SO^NR^R', -NR'C(0)0R\ -NR^C(0)R\ optionally substituted cycloalkyi. optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R^, cyano, nitro, lower alkenyl and lower alkynyl, preferably R' is unsubstituted or substituted with one or more substituents independently selected from halo, -0R3, -SR3, -S02R3, -C02R3, -CONR3R3, -C0R3, -NR3R3, -NH(C1-C2 alkylenylR3), -(CI-C2 alkylenyl)NR3R3, -S02NR3R3, -NR3C(0)OR3, -NR3C(0)R3, optionally substituted cydoalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, optionally substituted phenyl-Cl-2-alkylenyl, optionally substituted 5-6 membered heterocyclyl-Cl-C2-alkylenyl, Cl-2- alkyl, cyano, C]-2-hydroxya]ky], nifroand Cl-2-haloalkyl, more preferably Rl is unsubstituted or substituted with one or more substituents selected from chloro, fluoro, bromo, methoxy, phenyloxy, benzyl, methylthio, methyl, ethyl, trifluoromethyi, difluoromethyl, pentafluoroethyl, hydroxymethyl, cyano, carboxy, aminocarbonyl, methylcarbonyl, amino, methylamino, cyclopropyl, cyclohexyl, piperidinyl, morpholinyl, N-melhylpiperazinyl, N-ethylpiperazinyl, morpholinylmethyl, methylpiperdinyimethyl, methylpiperazinyfmethyi, methylaminothiocarbonyl, N-methylamino-methylenyl, optionally substituted phenyl, N,N-dieihylamino, or N,N-dimethylamino; wherein R^ is one or more substituents independently selected from H, halo, -OR^, oxo, -SR\ -CO^R', -C0R\ -C0NR^R\ -NR^R^ -S02NR^R^ -NR^C(0)0R\ - NR^C(0)R^ cydoalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heleroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyi, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl, preferably R^ is one or more substituents independently selected from H, halo, -0R3, 0X0, -SR3, -C02R3, -CONR3R3, -C0R3, -NR3R3, -S02NR3R3, -NR3C{0)0R3, -NR3C{0)R3, cydoalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, Cl-2-alkyl, cyano, Cl-2-hydroxyalkyl, Cl-3-carboxyalkyl, nitro, C2-3-alkenyl, C2-3-alkynyl and Cl-2-haloalkyl; wherein R^ is selected from H, lower alkyl, phenyl. 5-6 membered heterocyclyl, d-C^, cydoalkyl, and lower haloalkyl, preferably H, C|-2-aikyl, phenyl, Ci-Ce cydoalkyl, and C|.2-haloalkyl, more preferably H, methyl, phenyl, cyclopropyl, cyclohexyl, and trifluoromethyi; wherein R' is independently selected from C2^-alkylenyl, C^^-alkenylenyl and C:^-alkynylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an -NH-, preferably C2_3-alkylenyl where one of the CHz groups may be substituted with an oxygen atom or an -NH-, more preferably Cj-d alkylenyl; wherein R^ is selected from H, lower alkyl, phenyl and lower aralkyl, preferably H, methyl or ethyl; wherein R^ is selected from H or C(-6-alkyl, preferably H orCi.3 alkyl; and wherein R' is selected from H, methyl and optionally substituted phenyl; wherein R'' is selected from H, phenyl, 5-6 membered heterocyclyl and C3-C6 cycloalkyi; wherein p is 0 to 2, preferably p is 2; and pharmaceutical ly acceptable salts thereof; provided A is not naphthyl when X is -C{0)NH- and when R' is phenyl when Y is -NHCH2- and when R is 4-pyridyl; further provided A is not pyridyl when X is -C(0)NH- and when R' is 4-[3,5-bis(trinuoromethyl)-lH-pyrazol-l-y!]phenyi when Y is -N(CH3)- and when R is 4-methylpiperidinyl; further provided A is not pyridyl when X is -C(0)NH- and when Y is -NHCH2 - and when R is 4-pyridylpiperidin-4-yl, 1-tertbutylpiperidin-4-y!, l-isopropylpiperidin-4-yl or l-cycloalkylpiperidin-4-yl; further provided A is not pyridyl when X is -C(0)NH- and when R' is 4-[3-(3-pyridyl)-5-(trifluoromethyl)-lH-pyra2ol-l-yl]phenyl when Y is -NHCH2- and when R is 4-pyridyl; and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl. The invention also relates to compounds of Formula 11 wherein R^ and R^ are independently selected from H, halo, CM-alkyI and -NCR"^);, preferably H; wherein n is 0-2; preferably 1-2; wherein R is selected from a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and b) unsubstituted or substituted 9- or lO-membered fused nitrogen-containing heteroaryl. preferably 4-p>'rid>'!, pyrimiamyi, ina^uiyt, pyi,uaz.uiy,, ,.,ui..ji, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl, where R is substituted with one or more substituents selected from halo, amino, hydroxy, C,-6-a]ky], C,-6-haloa)ky] and C,^-alkoxy, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted aryl, 5-6-membered heleroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl. pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, telrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, wherein Rl is substituted with one or more substituents selected from halo, CI-6-alkyl, optionally substituted C3-6-cycloaIkyi, optionally substituted phenyl, CI-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered Vieterocyclyl-C l-C2-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, Cl-6-haloalkyl, and Cl-6-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyi, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; wherein R^ is one or more substituents independently selected from H, halo, Ci-6-alkyl, Ci.6-haloalkyl, C|-6-alkoxy, Ci-6-haloalkoxy, C|^-carboxyalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5-6 membered heteroaryl; preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and wherein R*' is H or Ci-2-alky!; and pharmaceutically acceptable isomers and salts thereof. The invention also relates to compounds of Formula 111 wherein R* and R'^ are independently seiecled from H, halo, CM-alky( and -N(R^)2, preferably H; wherein n is 0-2; preferably 1-2; wherein R is selected from a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl, preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinoiyi, naphthyridinyl or quinozalinyl, ivhere R is substituted with one or more substittients selected from halo, amino, hydroxy, Ci^-alkyl, C|^-haloalkyl and Ci^-alkoxy, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted aryl, S-6-membered heteroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinoiyi, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothlenyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, wherein R' is substituted with one or more substituents selected from halo, Ci^-^lkyl, optionally substituted Cs-s-cycloalkyl, optionally substituted phenyl, C|^-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyc!y]-C,.C2-a!ky]en}'!, optionally substituted heteroaryi, optionally substituted heteroaryloxy, C|.6-haloalky!, and Ci^-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morphoiinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trjfluoromethyl, phenyloxy, metboxy and etboxy; wherein R^ is one or more substituents independently selected from H, halo, C,-6-alkyl, Ci^-haloalkyl, C|-6-alkoxy, Ci^-ha(oaikoxy, Cj^-carboxyalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5-6 membered heteroaryi; preferably one or more substituents independently selected from H, chioro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryi selected from ihienyl, furanyl, pyridyl, imidazolyl, and pyrazoiyi; and wherein R^ is H orCj.^-alkyl; and pharmaceutically acceptable isomers and salts thereof. The invention also relates to compounds of Formula IV wherein R is selected from a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and b) unsubstituted or substituted 9- or lO-membered fused nitrogen-containing iieteroaryl, preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, n^hthyridlnyl or quinozaliny], where R is substituted with one or more substituents selected from halo, amino, hydroxy, C|.6-aikyi, Ci^-ha(oaIkyI and C|^-a(koxy, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, telrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, wherein R' is substituted with one or more substituents selected from halo, C|-6-alkyl, optionally substituted Cs-b-cycloalkyl, optionally substituted phenyl, C|-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyctyl-C|.C:-alkylenyI, optionally substituted heteroary), optionally substituted heteroaryloxy, C|.6-haloalkyl, and Ci^-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; wherein R-^ is one or more substituents independently selected from H. halo, C,-6-alkyl, Ci-6-haloalkyl, C|^-a(koxy, Ci-6-haloalkoxy, Ci-6-carboxyalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5-6 membered heteroaryl; preferably one or more substiluents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethy), melboxy, ethoxy, trifluoromethoxy, carboxy methyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazoly); and wherein R6 is H or C|.2-alkyl; and pharmaceutically acceptable isomers and salts thereof. The invention also relates to compounds of Formula V wherein A^ is selected from S, O and NR^; wherein Ra and Rb' are independently selected from H, halo, C1-C6-alkyl and -N(R^)2, preferably H; wherein n is 0-2; preferably 1-2; wherein R is selected from a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and b) unsubstituted or substituted 9- or lO-membered fused nitrogen-containing heteroaryl, preferably 4-pyridy!, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinoly), isoquinolyl, naphtbyridinyl orquinozalinyl, where R is substituted with one or more substituents selected from halo, amino, hydroxy, C1-6-alkyl, 1-6-haloalkyl and C1-6alkoxy, preferably substituted with one or more substituents selected from chloro, fluoro. amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, telrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridiny!, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzolhienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, wherein R'1is substituted with one or more subslituents selected from halo, C16-alky), optionally substituted C3-6-cycloalkyl, optionally substituted phenyl, C1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-C1.C6-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryioxy, C1-6-haioaIkyi, and C1--6-aikoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methyl piperdiny I methyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromeihyl, phenyloxy, methoxy and ethoxy; wherein R2 is one or more substituents independently selected from H, halo, C1-6-alkyl, C1-6-haloalkyl, C1-6alkoxy, C1-6-haloalkoxy, C1-6-carboxyalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5-6 membered heteroaryl; preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, tritltioromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and wherein R* is H or Ci.2-alkyl; and pharmaceutical ly acceptable isomers and salts thereof. The invention also relates to compounds of Formula VI wherein R* and R" are independently selected from H, halo, CM-alkyl and -N(RV preferably H; wherein n is 0-2; preferably )-2; wherein R is selected from a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and b) unsubstituted or substituted 9- or 10-membered fiised nitrogen-containing heteroaryl, preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinoiyi, isoquinotyl, naphthyridinyt or quinozalinyl, where R is substituted with one or more substituents selected from halo, amino, hydroxy, C|-6-alkyl, Ci-6-haloalk.yl and C|^-alkoxy, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromelhyl, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, letrahydronaphthyl, naphthyl, isoquinoly], quinoiyi, pyridyl, pyrimidinyl, pyridaziny), indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, wherein R' is substituted with one or more substituents selected from halo, C|^-atkyl, optionally substituted Cs-e-cycloalkyl, optionally substituted phenyl, C|^-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-CuC2-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, Ci- preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylm ethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; wherein R^ is one or more substituents independently selected from H, halo, C|.6-a!kyl, Ci^-haloalkyl, Ci^-alkoxy, Ci-e-haioalkoxy, C|^-carboxyalkyl, unsubstituted or substituted aryl and unsubstituled or substituted 5-6 membered heteroaryl; preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, melhoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituled or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and wherein R^ is H orCi.2-alkyl; and pharmaceutical ly acceptable isomers and salts thereof. The invention also relates to compounds of Formula VU wherein R' is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinoly!, pyridyl, pyrimidinyl, pyridazinyt, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofury], benzjmidaioly), benzoxazoly), or benzthiazolyl, wherein R' is substituted with one or more subslituents selected from halo, Ci-6-a!kyl, optionally substituted C3-6-cycloa!(cyI, optionally substituted phenyl, C|^-haIoalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-C|-C2-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C|^-haloalkyl, and Ci-6-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethy], melhylpiperdinylmelhyl. methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; wherein R^ is one or more subslituents independently selected from H, halo, C|.6-alkyl, Ci.6-haloalkyl, Ci-6-a)koxy, Ci.6-haloalkoxy, Ci^-carboxyalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5-6 membered heteroaryl; preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, irifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and wherein R^ isH orC|.2-alkyl; and pharmaceutical I y acceptable isomers and salts thereof. The invention also relates to compounds of Formula Vlll wherein A^ is selected from S, O and NR^; wherein R' and R^are independently selected from H, halo, CM-alkyI and -N(R*)2, preferably H; wherein n is 0-2; preferably 1-2; wherein R is selected from a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl, preferably ^-pyridyl, pyrimidinyl, pyridazinyl, indolyl, tsoindojyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl, where R is substituted with one or more substituents selected from halo, amino, hydroxy, C|.6-alkyl, Ci-e-haloalkyl and C|^-alkoxy, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted aryl, 5-6-mem6ered heteroaryl and 9-!0 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofury!, benzimidazolyl, benzoxazolyl, or benzthiazolyl, wherein R' is substituted with one or more substituents selected from halo, C|-6-alkyl, optionally substituted C3-6-cycloalkyl, optionally substituted phenyl, Ci-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-Ci.Cj-alkylenyl, optionally substituted heteroaryl, optionally substituted heieroaryloxy, Ci-6-haloalkyl, and Ci-^-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmelhyl, morphoiinylmethyl, methyipiperdinylmethyl. methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; wherein R^ is one or more substituents independently selected from H, halo, C|.6-alkyl, C(.6-ha]oalkyl, Ci-6-alkoxy, C|-6-haloalkoxy, C(^-carboxyalkyl, unsubstituted or substituted aryl and unsubstiluted or substituted 5-6 membered heteroaryl; preferably one or more substituents independently selected from H, chloro, fluoro. bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, irifluoromethoxy, carboxy methyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and wherein R^ is H or Ci.2-alky!; and pharmaceutically acceptable isomers and salts thereof The invention also relates to compounds of Formula IX b) unsubslituted or substituted 9- or lO-membered fused nitrogen-containing heteroaryl, preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl, where R is substituted with one or more substituents selected from halo, amino, hydroxy, Ci-6-alkyl, C|^-haloalkyI and C]^-alkoxy, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trrfluoromethyl, melhoxy and elhoxy; wherein R' is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl, wherein R' is substituted with one or more substituents selected from halo, Ci^-alkyl, optionally substituted Cs^-cycloaikyl, optionally substituted phenyl, C]^-ha(oa(koxy, optionally substituted phenyloxy, benzyl, optionally substituted S-6 membered helerocyclyl-Cr-C2-alkylenyl, optionally subsliluled heteroaryl, optionally substituted heleroaryloxy, Ci^-haloalkyl, and Cj^-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylm ethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy; wherein R^ is one or more substituents independently selected from H, halo, Ci.6-alkyl, C,_6-haloa!kyl, Ci.6-alkoxy, C,.6-baloalkoxy, Cj^-carboxyalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5-6 membered heteroaryl; preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymeihyl, unsubstituted or substituted phenyl and unsubstituled or substituted heteroaryl selected from thienyl, furany!, pyridyl, imidazolyl, and pyrazolyl; and wherein R' is H or C|_2-alkyl; and pharmaceutically acceptable isomers and salts thereof. The invention also relates to compounds of Formula X wherein A^ is selected from S, O and NR*; wherein A^ is selected from N and CRwherein R^ and R** are independently selected from H, halo, Ci^-a)kyl and -N{R^)2, preferably H; wherein n is 0-2; preferably 1-2; wherein R is selected from a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and bj unsubstituted or substituted 9- or 10-membered ftjsed nitrogen-containing heteroaryl, preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl, where R is substituted with one or more substituents selected from halo, amino, hydroxy, Ci^-alkyl, Cu-haloalkyI and Ci^-alkoxy, preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted aryl, 5-6-men)bered heteroaryl and 9-10 membered fused heteroaryl, preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl. naphthyridinyl, quinozalinyl, telrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, orbenzthiazolyl, wherein R' is substituted with one or more substituents selected from halo, Cue-alkyl, optionally substituted Ca^-cycloalkyl, optionally substituted phenyl, C|^-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-Ci.C2-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, Ci-6-haloalkyl, and C]^-alkoxy, preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morphoiinylmethyi, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, metboxy and elhoxy; wherein R^ is one or more substituents independently selected from H, halo, C[^-alky!, C|-6-haloalkyl, C|-6-alkoxy, C|.6-haloalkoxy, Ci^-carboxyalkyl, unsubstituted or substituted aryl and unsubstituted or substituted 5-6 membered heteroaryl; preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, Irifiuoromethyl, methoxy, ethoxy, trifluoromelhoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; wherein preferably indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, benzotriazolyl, 2,3-dihydrobenzofuryl, 2-oxo-l,2-dihydroquinol-7-yI, naphthyridinyl and quinozalinyl, where substituted R is substituted with one or more substituents selected from halo, amino, hydroxy, oxo, Ci^-allcyl, C|^-ha!oalkyl, C,^-alkoxy, optionally substituted heterocyclyl-Ci-6-alkoxy, optionally substituted heterocyclyl-C|-6-alkylamino, optionally substituted heterocyclyl-Ci-s-alkyl, Ci-e-alkylamino-Ci^-alkynyl, Ci^-alkylamino-Ci.6-alkoxy, Ci.6-alkylamino-Ci^-alkoxy-Ci^-alkoxy, and optionally substituted heterocyclyl-C24-aiicynyl, preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromelhy), dimethylaminopropynyl, l-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and elhoxy; wherein R' is selected from unsubstituted or substituted aryl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, and naphthyl, cycloalkyi, preferably cyclohexyl, 5-6 inembered heteroaryl, preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimJdinyl, and pyridazinyl, and 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl, preferably 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-IH-indolyI, naphthyridinyl, quinozalinyl, betizo(d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-!H-3-aza-fluorenyl, 5,6,7-lrihydro-l,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, dihydro-benzimidazolyl, benzimidazolyl, benzoxazolyl and benzthiazolyl; wherein substituted R' is substituted with one or more substituents selected from halo, Ci^-alkyi, optionally substituted C3.6-cycloaIkyl, optionally substituted phenyl. optionally substituted phenyl-C,.Cj-alkylenyl, Ci.2-ha)oalkoxy, optionally substituted 4-6 membered helerocyclyl-Ci.C^-alkylenyl, optionally substituted 4-6 membered heterocyclyl-C2.C4-alkenylenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocycIyl-Ci-,-alkyloxy, optionally substituted 4-6 membetied heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 4-6 membered heterocyclyl-CM-alkylcarbonyl, C|.2-haloalkyl, C^-aminoalkyl, nitro, amino, -NHC(0)NH2, alkyIcarbonylamino, hydroxy, oxo, cyano, aminosulfonyl, C|.2-alkylsulfonyl, preferably bromo, chioro, fiuoro, iodo, nitro, amino, cyano, aminoethyl, Boc- aminoethyl, hydroxy, oxo, aminosulfonyl, 4-methylpiperazinylsu)fony], cyclohexy), phenyl, phenylmethyl, morpholinylmethyl, l-methylpipera2iii-4-ylmethyl, I- methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-l-ylmethyl, I- niethyIpiperidin-4-y (methyl, 2-methy!-2-(l-methyIpiperidin-4-yl)ethyl, mojphoJinylethy), l-(4-mDrphD]inyI)-2,2-dimethyIpropy), piperidin-4-ylethy], 1- Boc-piperidin-4-ylethyl, piperidin-1-ylethyl, l-Boc-piperidin-4-ylethyl, piperidin-4- ylmethyl, l-Boc-piperidin-4-ylmethyl, piperidin-4-y!propyl, l-Boc-piperidin-4- ylpropyl, piperidin-l-ylpropyl, pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl, 1-Boc- pyrrolidin-2-y I propyl, pyrrolidin-l-ylmethyl, pyrrolidin-2-ylniethyl, l-Boc- pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, melhylsulfonyl, methyl carbony I, Boc, piperidin-1-ylmethylcarbonyl, 4- methylpiperazin-l-ylcarbonylethyl, methoxycarbonyl, aminomethylcarbonyl, dimethyiaminomethylcarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yl, 4- methylpiperazin-1-yl. 4-methyl-l-piperidyl, 1-Boc-4-piperidyl. piperidin-4-yl, 1- methylpiperidin-4-yl, l-methyl-(l,2,3,6-tetrahydropyridyl), imidazolyl, morpholinyl, 4-trifluoromethyl-l-piperidinyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-bulyl, sec-bulyl, trifluoromethyi, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, l,l-di(trifluoromethyl)-l-hydroxyniethyi, l,l-di(trifluoromethyl)-l-(piperidinylethoxy)methyl, l,l-di(trifluoroniethyl)-l- (methoxyethoxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1 -aminoethyl, 2-aminoethyl, 1 -(N-isopropy(ami'no)ethyl, 2-(N- isoprop)']amino>ethyl, dimelhylaminoethoxy, 4-cblDrophenoxy, pbenyJoxy, azelidin-3-ylmethoxy, NBoc-azetidin-3-y!methoxy, pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy, pyrrol-l-y!methoxy, l-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-ylmethoxy, 1 -Boc-piperdin-4-ylmethoxy, piperdin-4-ylmethoxy, l-methy)piperdin-4-yloxy, isopropoxy, melboxy and ethoxy; wherein R~ is one or more substituents independently selected from H, halo. wherein R' is selected from H, C|.3-aikyt, optionally substituted phenyl, optionally substituted phenyl-Cj.j-alkyl, optionally substituted 4-6 membered heterocycly), optionally substituted 4-6 membered heterocyclyi-Ci-Cs-alkyl, Ci-j-alkylamino-Ci.3-alkyl, Ci-3-alkoxy-Ci-2-alkyl and C|-3-alkoxy-C|.3-alkoxy-C|.3-alkyl; provided R^ is not H, or provided R' is not heteroaryl or aryl or provided R is substituted with optionally substituted heterocyclyt-Cua-alkoxy, optionally substituted heterocyclyl-C|.6-alkylamino, oplionally substituted heterocyclyl-C]. 6-alkyl, Ci-6-alkylamino-C34-alkynyl, Ci^-alkylamino-Ci-6-alkoxy, C|-6> alkylamino-C|,6-alkoxy-C|-6-alkoxy, or optionally substituted heterocyclyl-Cz^-alkynyl, or R' is substituted with optionally substituted phenyloxy, optionally substituted 5-6 membered belerocyclyloxy, optionalJy substituted 5-6 membered heterocyclylsulfonyl, optionally substituted 5-6 membered heterocyclylamino, optionally substituted 5-6 membered heterocyclylcarbonyl, optionally substituted 5-6 membered heterocycIyl-CM-alkylcarbonyl, C1-5-alkyiamino-C|-3-alkoxy, or C|_3-alkylamino-C|.3-alkoxy-Ci.3-alkoxy; further provided R is not 3-pyridyl when R*" is CH2; and pharmaceutical ly acceptable isomers and derivatives thereof. The invention also relates to compounds of Formula XI wherein R is selected from a) ufisubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, preferably 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidinyl, triazolyl, and pyridazinyl, more preferably 4-pyridyl, and b) unsubstituted or substituted 9- or lO-membered fused heteroaryl preferably indolyl, isoindolyi, indazolyl, quinolyl. isoquinoiyi, benzotriazolyl, napbthyrJdinyl and quinozalinyl. where substituted R is substituted with one or more substituents se)ecled from halo, amino, hydroxy, C^-alkyl, Ci^-haloalkyl, C|_6-alkoxy, optionally substituted heterocyclyl-C|^-alkoxy, optionally substituted heterocyclyl-Ci-6-alkylammo, optionally substituted heterocyclyl-Cu-alkyl, Ci^-alkylamino-Ci^-alkynyl, C|_6-alkylamino-Ci^-alkoxy, C|.6-alkylamino-Ci-6-alkoxy-Ci-6-alkoxy, and optionally substituted heterocyclyl-C2-4-alkynyl, preferably chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, l-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy; wherein R' is selected from unsubstituted or substituted ary-l, cycloalky), 5-6 membered heteroaryl and 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl, preferably phenyl, tetrahydronaphthyl, indanyl, indenyl, naphthyl, cyclohexyl, isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-IH-indolyl, naphthyridinyl, quinozalinyl, ben2o[d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, letrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, dihydro-benzimidazoiyi, benzimidazoiyi, benzoxazoiyi and benzthiazoiyt, specifically 4-6 membered saturated or partially un-saturated monocyclic heterocyclyl, 9-]0 membered saturated or partially un-saturated bicyclic heterocyclyl, and 13-14 membered saturated or partially un-saturated tricyclic heterocyclyl, more specifically 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 2,3-dihydro-IH-indolyl, benzo[d]isothiazolyl, dihydro-benzimidazolyl, 2,3,4,4a,9,9a-hexahydro-1 H-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, and tetrahydroquinol iny 1, wherein substituted R' is substituted with one or more substituents selected from halo, Ci.6-alkyl, optionally substituted Cs-e-cycloalkyI, optionally substituted phenyl, optionally substituted phenyl-Ci_C4-alkylenyl, C|.2-haloalkoxy, optionally substituted 4-6 membered heterocycIyl-Ci.C4-aIkyl, optionally substituted 4-6 membered heterocyclyl-C2-C4-alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyU C,-Q-a)koxy, optionally substituted 4-6 membered helerocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 5-6 membered heterocyclyl-CM-alkylcarbonyl, C|.2-haloalkyl, C|.4-aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, Ci.j-alkylsulfonyl, halosulfonyl, CM- alkylcarbonyl, Cuj-alkylamino-Cis-alkyl, C|-3-alkylamino-C],3-a(koxy, Cio- alkylammo-C)o-alkoxy-C;o-alkoxy, CM-alkoxycarbonyl, Ci-4- alkoxycarbonylamino-CM-alkyl, C^-hydroxyalkyl, O and CM- alkoxy, preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoethyl, Boc- aminoethyl, hydroxy, oxo, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenyimethyt, morpfiolinyimethyl, i-methylpiperazin-4-ylmethyi, 1- methylpiperazin-4-y]propyl, morpholinylpropyl, piperidin-1-ylmetbyl, 1- methylpiperidin-4-ylmethyl, 2-methyl-2-{l-methylpiperidin-4-yl)ethyl, morpholinylethyl, 1 -(4-morpholinyl)-2,2-dimethylpropyl, piperidin-4-ylethyl, I - Boc-piperidin-4-ylethyl, piperidin-l-ylethyl, l-Boc-piperidin-4-ylethyl, piperidin-4- ylmethyl, 1 -Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl, 1 -Boc-piperidin-4- ylpropyl, prperrdin-l-ylpropyl, pyrrolidin-l-ylpropyl, pyfTol(din-2-ylpropyl, 1-Boc- pyrrolidin-2-ylpropyl, pyrrolidin-l-ylmethyl, pyrrol id in-2-ylmethyl, 1-Boc- pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl, 4- melhylpiperazin-l-ylcarbonylethyl, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyi, 3-ethoxycarbony 1-2-methyl-fur-5-yi, 4- methylpiperazin-l-yl, 4-methyl-l-piperidy!, I-Boc-4-piperidy!, piperJdin-4-y!, 1- methylpiperidin-4-yl, l-methyl-(l,2,3,6-tetrahydrop>Tidyl), imidazolyl, morpholinyl, 4-trifluoromelhyM-piperidinyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, l,l-di(trifluoromethyl)-l-hydroxymethyl, l,I-di(trifluorometfiyi)-I-(piperidinyiethoxy)methyi. I,l-di(trifluoromethyl)-l- (methoxyelboxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aniinoethyl, l-(N-isopropylamino)ethyl, 2-(N- isopropylamino)ethyl, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy. azetidin-3-ylmethoxy, I -Boc-azetidin.3-ylmethoxy, pyrrol-2-ylmeihoxy, 1 -Boc-pyrrol-2-ylinethoxy, pyrrol-1-ylmelhoxy, l-methyl-pyrrol-2-ylmethoxy, 1-isopropyl-pyrrol-2-yimelhoxy, 1 -Boc-piperdin-4-ylmethoxy, piperdin-4-yImethoxy, l-melhylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R is one or more substituents independently selected from H, halo, hydroxy, amino, C|-6-alkyl, C,^-haloalkyl, C|.(,-alkoxy, Ci-3-alkylamino, aminosulfonyl, Cj-e-cycloalkyl, cyano, C|.2-hydroxyalkyl, nitro, C2-3-a]kenyl, C2-3-alkynyl, Ci^-haloalkoxy, Ci,6-carboxyalkyl, 5-6-memberedheterocyclyl-C|-6-alkylaniino, unsubstituted or substituted phenyl and unsubslituted or substituted 5-6 membered heterocyclyl, preferably H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano, hydro xym ethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl, specifically chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyclopropyl, cyano, hydroxym ethyl, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluorom ethoxy, carboxymethyl. wherein R' is selected from unsubstituted or substituted aryl, preferably phenyl, telrahydronaphthyl, indanyl, indenyl, and naphthyl, cycloalkyi, preferably cyclohexyl, 5-6 membered heteroaryl, preferably isoxazolyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, pyridyl, pyrimidinyl, and pyridazinyl, and 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl, preferably 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinoly!, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1 H-indolyl, naphthyridinyl, quinozalinyl, benzo[d]isothiazolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-betizothiadiazoiyl, benzodioxanyl, benzothienyl, benzoftiryi, benzimidazoiyi, benzoxazolyl and benzthiazoiyl; wherein substituted R' is substituted with one or more substituents selected from halo, Ci^-alkyl, optionally substituted Cs^-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C|.C4-alkylenyl, C|.2-haloalkoxy, optionally substituted 4-6 membered heterocyclyl-C|.C4-alkyl, optionally substituted 4-6 membered heterocyc(yl-C2.C4-a(keny(, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy. optionally substituted 4-6 membered heterocyclyl-C|.C4-alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 5-6 membered heterocyc(yI-Cm-aIkyIcarbony(, C|-2-ha(oalkyl, CM-aminoalkyI, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, C(-2-alkyIsulfonyl, halosulfonyl, Ci^- alkylcarbonyl, C|.3-alkylamino-C|.3-alkyl, C|.3-alkylamino-Ci_3-a!koxy, Ci.j- alkylamino-C,,3-alkoxy-C|-3-alkoxy, CM-alkoxycarbonyl, CM- alkoxycarbonylaraitio-CM-aikyI, CM-hydroxya(ky(, ^ O and CM- alkoxy, preferably bromo, chloro, fluoro, iodo, nitro, amino, cyano, aminoelhyl, Boc- aminoethyl, hydroxy, oxo, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenyJmethyl, morphoJJnyJmethy), ]-methy)piperazin-4-ylmeIhyl, I- meIhylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-l-ylmethyl, 1- methylpiperidin-4-ylmelhyl, 2-methyl-2-(l-methylpiperidin-4-yl)ethyl, morpholinylethyl, l-(4-morphoImyl)-2,2-dimethylpropyl, piperidin-4-ytethyl, I- Boc-piperidin-4-ylethyl, piperidin-1-ylethyl, l-Boc-piperidin-4-ylethyl, piperidin-4- ylmethyl, l-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl, l-Boc-piperidin-4- ylpropyl, piperidin-1-yIpropyl, pyrroIidin-1-yIpropyl, pyrrolidin-2-ylprDpyI, 1-Boc- pyrrolidin-2-ylpropyl, pyrrolidin-1-ylmethyl, pyrrol idin-2-ylniethy I, 1-Boc- pyrrolidin-2-ylmethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, fluorosulfonyl, methylsulfonyl, methylcarbonyl, Boc, piperidin-l -yimethylcarbonyl, 4- methylpiperazin-) -ylcarbonylethy), meihoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, 3-ethoxycarbonyl-2-methyl-fur-5-yI, 4- methylpiperazin-l-yl, 4-methyl-l-piperidy!, l-Boc-4-piperidyl, piperidin-4-yl, 1- methylpiperidin-4-y(, I -melhyl-( i ,2,3,6-letrahydropyridyl), imidazolyl, morpholinyl, 4-trinuoromelhyl-l-piperidinyl, hydroxy butyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, l,l-di(trifluoromethyl)-l-hydroxymethyl, ], ] -di(trif]uoromelhy))-1 -(piperidiny]elhoxy)methyl, 1,1 -di(trifluoroniethyl)-1 - (methoxyethoxyethoxy)methyl, l-hydroxyethyl, 2-hydroxyethyl, triftuoromelhoxy, 1 -aminoethyl, 2-aminoethyl, 1 -(N-isopropylamino)ethyl, 2-(N- (sopropylamino)ethyl, dimethylaminoethoxy, 4-chIorophenoxy, phenyloxy, azetidin-3-ylmethoxy, l-Boc-azetidin-3-ylmethoxy, pyrrol-2-ylmethoxy, 1-Boc-pyrrol-2-ylmethoxy, pyrrol-1-ylmethoxy, 1-methyl-pyrrol-2-ylmethoxy, I-isopropyl-pyrrol-2-ylniethoxy, I-Boc-piperdin-4-yImethoxy, piperdin-4-ylmethoxy, 1 -niethylpiperdin-4-yloxy, isopropoxy, methoxy and ethoxy; wherein R^ is one or more substituents independently selected from H, halo. hydroxy, amino, Ci.6-alky(, Ci_6-haloalkyl, Ci^-alkoxy, C|.2-alkylamino, aminosuJfony], Cj^-cycloalkyl, cyano, C].2-hydroxyalkyl, nitro, C3.3-alkenyl, C2.3-alkynyl, Cj^-haloalkoxy, C|_6-carboxyalkyl, 5-6-membered heterocycly!-Ci_6-alkylamino, unsubstituted or substituted phenyl and unsubstituted or substituted 5-6 membered heterocyclyl, preferably H, chloro, fluoro, bromo. amino, hydroxy, methyl, ethyl, propyl, oxo, dimethylamino, aminosulfonyl, cyciopropyl, cyano, hydroxymethyi, nitro, propenyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, morpholinylethylamino, propynyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, ftiry, pyridyl, imidazolyl, and pyrazoly); wherein R^ and R'^are independently selected from H and C|.2-haloalkyl, preferably trifluoromethyl; wherein R^ is selected from H, C|.3-aikyl, optionally substituted phenyl, optionally substituted phenyl-C|.3-alkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-Ci.Cj-alkyl, C|.j-alkoxy-Ci.2-alkyl and Ci_3-alkoxy-C|.3-alkoxy-Ci.ralkyl; and wherein R^" is one or more substituents selected from halo, amino, hydroxy, C)_6-alkyl, Ci^-haloalkyl, Ci^-alkoxy, optionally substituted heterocyclyl-C|^-alkoxy, optionally substituted heterocyclyl-Ci-6-alkylamino, optionally substituted heterocyclyl-Cr-6-alkyl, Ci-6-alkylamino-C2-(-alkynyl, C|-e-a}kylamino-C(^-alkoxy, Ci^-alkylamino-Ci.6-alkoxy-Ci^-alkoxy, and optionally substituted heterocyclyl-C2-(-alkynyl, preferabjy chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, dimethylaminopropynyl, 1-methylpiperdinylmethoxy, dimethylaminoethoxyethoxy, methoxy and ethoxy; and pharmaceuticaily acceptable isomers and derivatives thereof. A family of specific compounds of particular interest within Formula I consist of compounds and pharmaceuticaliy-acceptable derivatives thereof as follows: ■N-(4-Isopropylphenyl) {2-[(4-pyridylmethyl)amino](3-pyridyl))carboxamide; N-[3-(lsopropy!)phenyl]{2-[(4-pyridylmethyl)aniino](3-pyridyl)}carboxamide; N-(3-lsoquinolyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-[4-lsopropylphenyl]{2-[{2-(3-pyridyl)ethyl)amino]{3-pyridyl)}carboxamide; N-[4-(tert-Butyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide; N-[4-(Methylpropyl)phenyl]{2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide; {2-[(2-(3-Pyridyl)ethy])amino](3-pyridy))}-N-{3-(trifluorometbyl)pbeny)]carboxamjde; {2-[(4-Pyridylraethyl)aminol(3-pyridyl)}-N-{4-[2,2,2-trifluoro-l-hydroxy-l- (trifluoromelhy l)ethy l]pheny I} carboxam ide; N-[5-(tert-Butyl>isoxazol-3-yl](2-[(4-pyndylmethyl)amino](3-pyndy!)}carboxamide; N-[5-(tert-Butyl)-l-methylpyrazol-3-yl]{2-[(4-pyridylmethyl)amino](3- pyridyl)}carboxamide; N-[4-(tert-Butyl)(t,3-Chiazol-2-yl)I{2-[(4-pyridylmethyl)am(noJ(3- pyridyl)}carboxamide; N-[5-(ten-Buty!)(l,3,4-thiadiazol-2-yl)]{2-[(4-pyridylmethyl)amino](3- pyridy()}carboxamide; lsj.[4,{4.Hydroxybutyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N .[2 -(4-C h loropheny l)ethy l]-2 - [(py rid in-4-y Imethy l)am ino](3 -pyridy Ocarboxam ide; 5-Bromo-N-|;2-(4-chIorophenyl)elhyll-2-[(pyridin-4-yimethyI)aminoI(3- pyridyl)carboxamide; N-[2-(4-Phenoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino](3-pyridyl)carboxamide; N -[2-(4-Methoxy pheny l)ethy 1] -2-[(pyrid in-4-y Imethy l)am ino] (3-pyridy l)carboxam ide; N-[2-{3,4-Dimethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] {3- py ridy l)carboxamide; N-[2-(4-Hydroxy-3-ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] (3- py ridy l)carboxam ide; N-f2-(4-Fiuorophenyl)ethyll-2-i;(pyridin-4-y(methyl)aniino]{3-pyridyi)carboxamide; N-[2-(4-(tert-Bulyl)phenyl)ethyl)-2-[(pyridin-4-y]melhy))amino] (3- py ri dy l)carboxani ide; N-[2-(3-Fluorophenyl}ethyl]-2-[(pyridm-4-ylmethyl)amino] (3-pyridyl)carboxamide; N-[2-(3-Chlorophenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] (3-pyridyl)carboxamide; N-[2-(3-{Tnfluoromethyl)phenyl)ethyI]-2-[(pyridin-4-ylmethyl)aniino] (3- pyridyl)carboxainide; N-[2-(3-Ethoxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] (3-pyridyl)carboxamide; N-|;2-(3,4-Dimethylphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] (3- pyridyl)carboxamide; N-[2-(l,3-Benzodioxol-5-y])ethyl]-2-[(pyridin-4-ylmethyl}amino] (3- pyridyl)carboxamide; N-[2-{4-Methy!phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] (3-pyridyl)carboxamide; >J-[2-(4-Hydroxyphenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] (3-pyridyl)carboxamide; N-[2-(3,4-Dimelhoxyphenyt)ethylj-2-[(pyridin-4-ylmethyi)amino] (3- pyridyl)carboxamide; N-[2-(4-Bromophenyl)ethyl]-2-[(pyridin-4-y!methy!)aniino] (3-pyridyl)carboxamide; N-[2-(3,4-Dichlorophenyl)elhyl]-2-[(pyridin-4-ylmelhyl)amino] (3- pyridyl)carboxamide; N-[2-(4-(Fluorosulfofiy0phenyI)ethyll-2-[(pyridin-4-ylmethyl)amino] (3- py ridy l)carboxam ide; N42-(3,5-(Dimethoxy)phenyl)ethyl]-2-[(pyridin-4-ylmethyl)amino] (3- pyridyl)carboxamide; N-[2-(2,4-DichlorophenyI)ethyI]-2-[(pyridin-4-y(methy()amino] (3- pyr(dy])carboxaniide; N-[2-(2-Fluorophenyl)ethyl]-2-[(pyridin-4-ylmelhyl)amino] (3-pyridyl)carboxamide; N-[2-(2-Chlorophenyl)ethyl]-2-[{pyridin-4-ylmethyl)amino] (3-pyridyl)carboxatnide; N-[2-(4-{Aminosulphonyl)phenyl)ethyl]-2-l(pyridin-4-ylmethyl)amino] (3- py ridy i)carboxain ide; N-[2-(2-Thienyl)ethyl]-2-((pyrid!n-4-ylmethyl)amino] (3-pyridyl)carboxamide; N-[2-(Pyridin-2-y!)ethyl]-24(pyridin-4-ylmethyl)amino]{3-pyridy!)}carboxamide; N-[2-(Pyridin-3-yl)ethyl]-2-[{pyridin-4-ylmethyl)amino](3-pyridyl)carbo>;amide; N-[2-(Pyridin-4-yl)ethy!]-2-[(pyridin-4-yImethyI)amino](3-pyridyl)carboxamide; N-{4-Phenylbulyl)-2-[(pyridin-4-ylmethy!)amino](3-pyr!dyl)carboxamide; N-(2-Hydroxy-3-phenoxypropyl)-2-[(pyridin-4-ylmethyl)amino] (3- pyridyl)carboxainide; {6-Chloro-5-fluoro-2-[(4-pyridylmethyl)amino]{3-pyridyl)}-N-[4- (isopropy l)pheny IJcarboxamide; {5-FIuoro-2-[(4-pyridyimethyi)amino](3-pyridyl)}-N-[4- (isopropy])phenyl]carboxaniide; 2-[(Pyridm-4-ylmethyl)amino]-A'-[4-/er/-buryl-3-(),2,3,6-telrabydropyridin-4- yl)phenyl](3-pyridyl)carboxamide; N-(3,4-Dichlorophenyl){6-[(2-morpholin-4-ylethyl)aniino]-2-[(4- pyridylmethyl)amino](3-pyridyl))carboxamide; N-[4-(Morpholin-4-ylmethyl)phenyl]{2-[(4-pyridylmethyl)amino](3- py ridy I)} carboxamide; N-{4-{2-[(iert-Buloxy)carbonylamino]ethyl}phenyl){2-[(4-pyridyImethyi)amino](3- pyridyl)}carboxaniide; N-[4-(2-Aminoerhyl)phenyl]{2-[(4-pyridylmethyl)amino]{3-pyr!dyl)}carbo.\am!de; N-[4-(tert-Butyl)-3-nitrophenyl]{2-[(2-pyridyImethyl)amino](3-pyridyl)}carboxamide; N-[3-Amino-4-(tert-butyl)phenyll{2-[(2-pyridylnieihyl)amino](3- pyridyl)} carboxamide; N-[4-(I sopropyl)pheny I] {2-[{2-py ridy Imethy l)am mo](3-py ridy!)} carboxamide; ■N-{3-Atninosulfonyl-4-chlorophenyl){2-[(4-pyridylmethyl)amino]{3- pyridyl)} carboxamide; N-{3-[(4-MethyIpiperazinyt)suifonyl]phenyt}(2-[(4-pyridylmethyl)amino](3- pyridyl) | carboxamide; N-[4-(],l,2,2,2-PeiitafluoroeIhyl)phenyl]{2-((4-pyridylmethyl)amino]{3- pyridyl)}carboxamide; N-l4-(l,l,2,2,3,3,4,4,4-Nonafluorobutyl)phenyl]{2-[(4-pyridylmethyl)amino](3- pyridyl)} carboxamide; N-[4-(Isopropyl)pheny!]{2-[(2-(l,2,4-triazolyl)ethyl)aminoX3-pyridyl)}carboxamide; (2-{[2-{2-Pyridylainino)ethyl]amino}(3-pyridyl))-N-[3- (tri fl uoromethy I )pheny I Jcarboxam ide; {2-[(i-(2-Pyndyl)pym)lfdin-3-yl)amino]{3-pyridyO)-N-p- (trifl uoromethy l)pheny IJcarboxamide; 2-[(Pyridin-4-y Imethy l)-amino]-N-( 3-trifluoromethyl-phenyl)-nicotinamide {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(8-quinolyl)carboxamide hydrochloride; N-[4-(4-Chlorophefioxy)phenyl]{2-[(4-pyridy)methyl)aminoI{3-pyridyt)}carboxamide hydrochloride; {2-[(4-Pyridylmethyl)amino](3-pyridyl)|-N-(2,3,4-lrifluorophenyl)carboxamide hydrochloride; N-(2-Naphthyl){2-[(4-pyridylmethyl)amino](3-pyridyi)}carboxamide hydrochloride; N-(2-Phenoxyphenyl)j2-I(4-pyridylmethyl)amino](3-pyridyl)}carboxamide hydrochloride; {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-(5,6,7,8-tetrahydronaphthyl) carboxamide hydrochloride; N-(2H-Benzo[3,4-d]l,3-dioxolen-5-yl){2-[(4-pyridylmethy))am)no](3- pyridyI)} carboxamide hydrochloride; N-Naphthyl{2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide hydrochloride; N-[3-BenzyIphenyl]{2-[(4-pyridylmethyl)ainino](3-pyridyl)} carboxamide hydrochloride; N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide hydrochloride; N-(Cyclohexylethyl){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide hydrochloride; N-lndan-2-yl{2-[{4-pyridylmethyl)amino](3-pyridyl)} carboxamide hydrochloride; N-[4-(tert-Butyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-(4-sec-Butyl-phenyl)-2-[(pyridin-4-ylmethyl)-ammo]-nicotinamide; N-(4-Methy!phenyt){2-[(4-pyridytmethyl)amftio](3-pyridyI)} carboxamide; {2-[(4-Pyridylmelhyl)amino](3-pyridyl)}-N-I4-trifluoromethoxy)phenyl] carboxamide; N-(4-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide; N-(4-Bulylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide; N-(4-[odophenyi){2-K4-pyridyimethyi)amino](3-pyridyl)} carboxamide; N-[3-(Hydroxyethy])phenyJ]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-(3-Ethylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide; Ethyl 2-methyl-5-[3-({2-[(4-pyridylmethyl)amino](3- pyridyl)}carbonyIamino)phenyl]furan-3-carboxylate; N-(3-PhenyJphenyl){2-[(4-pyridy)melhyl)amJno)(3-pyridyl)}carboxamide; N-[4-Benzylphenyl]{2-((4-pyridylmethyl)amino]{3-pyridyl)} carboxamide; N-(6-Ethyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide; N-(6-Propyl(2-pyridyl)){2-[(4-pyridylmethyl)amino](3-pyridy!)} carboxamide; N-[4-(ter(-BwiylX2-pyridy!»{2-((4-pyndylmethyl)amino](3-pyridyl))carboxamide; N-(3-Hydroxyphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide; N-[4-(Methylethyl)(2.pyridyl)]{2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxamide; N-[3,5-bts(Trrf!uorometliyl)phenyl]{2-[{4-pyridylmethy!)arnino](3- pyridy]))carboxaniide hydrochloride; N-[4-Chloro-3-(trifluoromelhyl)phenyll{2-[(4-pyridy!methyl)amino](3-pyridyl)} carboxamide hydrochloride; N-(3-Chlorophenyl){2-[(2-(4-pyridyl}ethyl}amino](3-pyridyl)}carboxamide hydrochloride; N-(4-Phenoxypheny!){2-[(2-(2-pyridyl)ethyl)amino](3-pyridyi)}carboxamide; 2-[(Benzo[b}thiophen-3-ylmeIhyl)amino]{3-pyndyl)}-N-(4- phenoxypheny Ocarboxam ide; N-(4-Phenoxyphenyl){2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}carboxamide; N-[4-(Methylsulfony!)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridy!)}carboxamide; N-(l-Acetylindolin-6-y!){2-[(4-pyridylmethyl)amino]{3-pyridyl)}carboxamide; N-lndolin-6-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-Indol-6-yI{2-[(4-pyridylmelhy0afn(no](3-pyridyl))carboxamide; N-]i]dol-5-y]{2-[(4-pyridylmethyl)ainino](3-pyridyl)}carboxamide; N-Indol-7-yl{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-[3-(tert-Butyl)pyrazol-5-yl](2-[{4-pyridylmethyl)ainino](3-pyridyl)}carboxamide; N-(3-Pheny lpyrazol-5 -y I) {2 -[{4-pyridy Imethy l)amino](3 -pyridy 1)} carboxamide; N-{2-[2-(dimethylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3- pyridyl)}carboxamide; N-[4-(tert-Buryl)-3-(4-methy)piperazinyl)phenyl]{2-[(4-pyridylmethyl)amino]{3- pyridy I)} carboxam i de; N-[3-(4-Methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3- pyridy I)} carboxamide; M.[4.(4-Methylpiperazinyl)phenyl]{2-t(4-pyridylmethy!)amino](3- pyridy[)}formamide; N-[l-(l-Methyl-{4-piperidyl))indolm-6-y!]{2-[(4-pyndylmethy!)am!no](3- pyridyl)}carboxamide; N-[I-(l-Methyl-(4-piperidyl))indolin-6-yl]{2-[(2-(3-pyridyl)ethyl)amino](3- pyridyl)} carboxamide; N-[l-(2-Piperidylethyl)indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-pyridy 1)} carboxam ide; N-[l-(2-Piperidy!acetyl)indolin-6-yl]{2-[(4-pyridy[methyl)amino](3-pyridyl)}carboxamide; N-[3,3-Dimethyl-l-(l-methyl(4-piperidyI))indolin-6-yl]{2-[(4-pyridylmethyl)amino](3-py ridy I)} carboxam ide; N-(3,3-Dimethy!indolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-[3-{t-Methyl-(4-piperidyl))iadol-5-yl]{2-[(4-pyridylmethyl)amino](3- pyridy!)} carboxam ide; N-[4-(l, 1 -Diinethyl-3-morpholin-4-ylpropyl)phenyl] {2-[(4-pyridylniethyl)amino]{3- pyridyl)} carboxam ide; N-[4-(ter1-Butyl)phenyl]{2-[({2-[(l-methyl{4-piperidyl))-methoxy](4- pyridyl)}methyl)amino](3-pyridyl)}carboxamide; N-(4-Bromo-2-fluorophenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-[4-(tert-Butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]aniino}(3- pyridyl))carboxamide; {2-[({2-[3-(Dimethylamino)prop-l-ynyl](4-pyridyl)}methyI)amino](3-pyridyl)}-N-[4- (tert-butyl)phenyl]carboxamide; (2-{[(2-Methoxy(4-pyridyl))methyl]amino}(3-pyridyl))-N-[4- (methyiethyl)phenyl]carboxamide; N.{3.[3.(Dimethylamino)propyl]-5-(trifluoromethyl)phenyl}-{2-[(4- py rid y Imethy l)am ino] (3 -py ridy ])} carboxam ide; N-[4-{tert-Butyl)-3-(3-piperid-l-ylpropyl)phenyl]{2-[(4-pyridylmethyl)amino](3- pyrid y 1)} carboxam ide; N-[4-(tert-Butyl)-3-(3-pyrro]idin-l-ylpropyl)phenyl]{2-[{4-pyridylmethyl)amino](3- pyridyl)}carboxaniide; N-[3-((lE)-4-Pyrrolidin-l-ylbuI-l-enyl)-4-(tert-butyl)phenyl]{2-[{4- pyridylmelhyl)amino](3-pyridyl)}carboxamide; N-[4-{lert-Butyl)-3-(3-morpholin-4-ylpropyl)phenyl]{2-[(4-pyridylmethyl)aminol(3- pyridyl)}carboxamide; N-[l-{2-Morpholin-4-ytethyl)indol-6-yl]{2-[(4-pyridylmethyl)amino](3- pyridyl)}carboxamide; N-[4-{tert-Butyl)phenyl]{2-[(pyrimidin-4-ylmelhyl)amino](3-pyridyl)}carboxamide; N-(4-Chlorophenyl){2-[(pyrimidin-4-ylmethyl)amino](3-pyridyl)}carboxamide; {2-[(Pyrimidin-4-ylmethyl)amino](3-pyridyl)}-N-[3- (trifluoromelhyl)phenyl]carboxamide; >i.[4-(lsopropyl)phenylH4-ti4-DvridvlmelhvhaminolDvrimidin-5-yl}carboxamide; (2-{[(2-{2-[2-{Diniethylatnino)ethoxy]ethoxy}(4-pyridyl))melhyl]amino}{3-pyridyl))-N-[4-(tert-butyl)phenyl]carboxamide; {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-{4-[2,2,2-trifluoro-l-(2-piperidylethoxy)- l-(trifluoromethyl)ethyl]phenyl}carboxamide; (2-{[(2-{2-[2-(Dimethylamino)ethoxy]ethoxy}{4-pyridyl))methyl]amino}-6-f]uoro(3- py ridy 1))-N- [3 -{tri fluoromethy l)pheny l]carboxamide; N-[4-(reM-Butyl)pheiiyl]{6-fluoro-2-[{4-pyridylmelhyl)amino](3- pyridyl)}carboxamide; {6-Fluoro-2-[(4-pyridylmethyl)atiiino](3-pyridyl)}-N-[4- (isopropyl)phenyl]carboxamide; {6-Fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-[3- (trif!uoromethyl)phenyl]carboxamide; N-(l-Bromo(3-isoquinoIyl)){6-fluoro-2-[(4-pyridylmethyl)amino](3-pyridyl)}- carboxamide; N-(4-Phenoxyphenyl){2-[{4-pyridylmethyl}amino](3-pyridyl)}carboxaniide hydrochloride; N-(4-Phenylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide hydrochloride; N-(3-Phenoxypheny 1) {2- [(4-pyridy Imethy l)ani ino] (3-py ridy I)} carboxam ide hydrochloride; N-(4-Cyclohexylphenyl){2-[{4-pyridylmethyl)am ino] (3-pyridyl)} carboxam ide hydrochloride; N-(4-lmidazol-l-ylphenyl){2-[{4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)} carboxam ide hydrochloride; N-(4-Cyanonaphthyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide hydrochloride; {2-l(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(lrinuoromethyl)phenyl]carboxamide hydrochloride; Methyl-4-({2-[{4-pyridylmethyl)amino]-3-pyridyl}carbonylamino)benzoate hydrochloride; N-[4-(Isopropyl)phenyl]{2-[(4-quinolylmethyl)amino](3-pyridyl)}carboxamide; N-[4-(tert-Buty])phenyl]{2-[(6-quinolylmethyl)amino](3-pyridyl)}carboxamide; {2-[(6-Quinoly Imethy l)am ino](3 -pyridyl)} -N -[3-(trifluoromethyl)phenyl] carboxam ide; N-(4-chlorophenyl){3-[{4-pyridylmethyl)amino]{2-thienyl)}carboxamide; N-phenyl{3-[(4-pyridy!methyl)amino](2-lhienyi)}carboxamide; ■N-{4-chlorophenyl)-3-[(4-pyridinylmethylene)amino]-4-pyridmecarboxamide; N-(4-chlorophenyi){2-[(4-pyridyImeihyI)amino](3-pyridyl)}carboxaniide; N-(3,4-dichlorophenyl){2-I{4-pyrid>'lmethyl)aminoJ(3-pyridyl)}-carboxamide; ■N-(3-chlorophenyl){2-[(4-pyridylniethyl)amino](3-pyridyl)}carboxamide; N-(4-chlorophenyl){3-[(4-pyridylmethyl)amino|(2-pyridyl)}carboxamide; N-(4-chlorophenyl}{3-((6-quinolylmethyl)amino](2-pyridyl)}carboxamide; N-(3,4-dichlorophenyl){2-[(6-quinolylmethyl)amino](3-pyridyl)}-carboxamide; N-(4-chlorophenyl){6-niethyl-2-[{4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-(3,4-dichlorophenyi}{6-inethyi-2-[(4-pyridyimethyi)amino](3- pyridy I)} carboxamide; M -(3-fl uoro-4-niethy Ipheny 1) {6-methy 1-2 -[(4-pyridy Imethy l)amitio](3 - pyridy 1)} carboxam ide; N-(3,4-dich)orophenyl)(6-chlDro-2-[{4-pyridylmethy))amino](3-pyridyl))carboxamide; N-(4-chlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; {6-chloro-2-[(4-pyridylmethyl)amino](3-pyridyl)}-N-(3-fluorophenyl)carboxamide; N-(3-chlorophenyI){6-chloro-2-((4-pyridylmethyl)amino](3-pyridyl)}carboxamide; ■N-(4-chlorophenyl){ 3-[(4-pyridy lmethy!)aniino](4-pyridyl)} carboxamide; N-(3-nuoro-4-methylphenyl){2-((4-pyridylmethyl)amino](3-pyridyl)}carboxamide; N-(4-chlorophenyl){2-[(4-quinoIylmelhyl)amino](3-pyridyI)}carboxamide; N-(4-ch)oropbeny!){2-[(5-c)uinolylmethyl)amino]{3-pyridy!))carboxatnide: N-(4-chlorophenyl){2-[(4-pyridylethyl)aniino]-5-(3-thienyl)-(3-pyridyl)}carboxamide; N-(4-chlorophenyl){5-{4-methoxyphenyl)-2-[(4-pyridylniethyl)aniino]-(3- pyr(dyl)}carboxamide; and N-(4-chlorQphenyl){5-bromo-2-[{4-pyridylmethyl)amino]-(3-pyridyl)}carboxamide. A family of specific compounds of particular interest within Formula 11' consists of compounds and pharmaceutically-acceptable derivatives thereof as follov^s: 2-{{2-(l-Isopropyl-azetidin-3-y!methoxy)-pyridin-4-y]methyl]-amino}-N-(4- trifluoromethyl-pheny[)-nicotinamide; M.(4-tert-Butyl-phenyl)-2-{t2-(l-isopropyl-azetidin-3-ylmethoxy)-pyridin-4-ylmethyl]- amino}-nicotinamide; 2-[(2.3-Dihydro-benzofuran-5-y!methyl)-amino]-N-{4-[l-methyl-l-(l-methyl- piperidin-4-yl)-ethyl]-phenyl}-nicotinamide; N-{l-Acelj'l-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-[(2,3-clihydro-benzofuran-5-ylniethyl)-amino]-nicotinamide; 2-((2,3-Dihydro-benzofuran-5-yimethyl)-aminoI-N-[3,3-dimethyl-I-(I-Boc-piperidin- 4-y]metbyl)-2,3-dihydro-]H-indoI-6-yl]-nicotinamide; 2-[{2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-l-(l- raethylpiperidin-4-ylmethyl)-2,3-dihydro-lH-indol-6-yl]-nicotinamide; N-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-({2-[2-(l-methyl-piperidin-4- y l)-ethoxy] -py ridin-4-y Imethyl} -am ino)-nicotinam ide; 2-({2-[2-(i-MethyI-piperidin-4-yI)-ethoxy]-pyridin-4-ylmethyl}-ammo)-N-(3- tri fl uorotnethyl-pheny l)-n (coti nam ide; N-(4-tert-Butyl-pheny])-2-{[2-ethylpyridin-4-y]methyl]-amino}-nicotinamide; N ylmethyl}-amino)-nicotmatnide; 2-({2-[2-(l-Methyl-pyrrolidin-2-yl)-ethoxy]-pyridin-4-ylmethyl}-amino)-N-(4- penlafluoroethyl-phenyl)-nicotinamide; N-(4-PentafluoroethyI-phenyO-2-{[2-(2-pyrrolidiii-I-yi-ethoxy)-pyridin-4-yimelhyt]. am Jno}-n icotinamide; N-(4-tert-Butyl-phenyl)-2-{{2-(2-pyrrolidin-l-yl-ethoxy)-pyridin-4-ylmethyl]-amino}- nicotinamide; N-[3-(4-Boc-piperazm-l-ylmethyl)-5-trifluoromethyl-phenyl]-2-i;(pyridin-4-ylmethy!)- am ino]-n icotinamide; N-[3-(4-Boc-piperazine-I-caTbonyl)-5-trifluoromethy(-phenyi]-2-[(pyridm-4- ylmethyl)-am'mo]-nicotinamide; N-[3-(4-Boc-piperazine-l-carbonyl)-5-trifluoromethyl-phenyl]-2-(2-pyridin-4-yl- ethylamino)-nicolinamide; N-[3-(4-Methyl-piperazin-l-ylmethyl)-4-pemafluoroethyl-phenyl]-2-[(pyridin-4- ylmelhyl)-amino]-nicotinamide; N-[3-(4-Boc-piperazin-l-ylmethyl)-4-pentafluoroethy(-phenyIl-2-[(pyridin-4- ylmethyi)-amino]-n icotinamide; 2-}[2-(l-Methyl-piperJdin-4-y]nielhoxy)-pyridin-4-ylmethyl]-amino}-N-(4- trifluoromethyl-phenyl)-nicotinamide; N-{4-tert-Butyl-phenyl)-2-{i;2-(l-methyl-piperidin-4-ylmethoxy)-pyridin-4-ylmethyl]- aminoI-nicotinamide; 2-({2-p-(l-Methyl-piperidiii-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4- pemafiuoroethy!-phenyi)-nicotiiiamide; N-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-[(2-methoxy-pyr!din-4- ylmelhyl)-amino]-nicotinamide; N-[3,3-Dimethyl-l-{i-methyi-piperidin-4-yi)-2,3-dihydro-IH-mdoI-6-yi]-2-((2- methoxy-pyridin-4-ylmethyl)-amino]-nicotJnamide; N-(l-Boc-3,3-dimethyl-2,3-dihydro-IH-indol-6-yl)-2-I(2-methoxy-pyridin-4- ylmethyl)-amino]-nicolinamide; N-[3,3-Dimethyl-l-(l-Boc-piperidin-4-ylmethyl)-2,3-dihydro-lH-indol.6-yl]-2-[(2- methoxy-pyridin-4-ylmeihyl)-amino]-nicotinamide; N-[3,3-DimethyI-l-(I-methyI-piperidin-4-yI)-2,3-dihydro-lH-indol-6-yI]-2-[(2- methoxy-pyridin-4-ylmethyl)-amino]-nicotinamide; N-[l-(2-Dimethylamino-acetyl)-3,3-dimeihyl-2,3-dihydro-lH-indo!-6-yl]-2-[{2- methoxy-py rid in-4-y Imethy l)-amino]-n icotinamide; N-[l-{2-Dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl]-2-[(pyridm- 4-ylmethyl)-amino]-iiicolinamide; 2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(l-Boc-piperidin-4-ylmethoxy)-5- iriftuoromethy l-pheny !]-nicot inam ide; N-[3,3-Dimelhyl-1 -(1 -Boc-pyrTolidin-2-ylmethoxy)-2,3-dibydro-) H-indol-6-y]J-2-[(2-melhoxy-pyridin-4-ylmethyl)-amino]-nicotinamide; N-[3,3-Dimethyl-l-{2-Boc-amino-acetyl)-2,3-dihydro-lH-indol-6-yl]-2-[(2-methoxy- pyridin-4-ylmelhyl)-amino]>nicotinamide; N-[3,3-Dimethy!-l-(2-Boc-amino-acetyl)-2,3-dihydro-lH-indol-6-yl]-2-[(pyridin-4- yImethyI)-amino]-nicotinamide; 2-[{2-Methoxy-pyridin-4-ylmelhyl)-amino]-N-[3-(l-methyl-pyrro)id!n-2-y]inelho.\y)-5- mfluoromethyl-pheny!]-nicolinamide; 2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-M-[3-(l-Boc-piperidin-4-ylmethyl)-5- lrifluoromethyl-phenyl]-n icotinamide; 2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(4-Boc-piperazin-I-ylmethyl)-5- trifluoromethyl-phenyl]-nicotinamide; 2-{[2-(3-MorphoItn-4-yI-propoxy)-pyndrn-4-ylniethyl]-amino}-N-(4-pentafluoroethyl- pheny])-nicotinamJde; (S) 2-{[2-(l-Methyl-pyrrolidin-2-ylmethoxy)-pyndin-4-ylniethyl]-amino}-N-(4- pentafluoroethyl-phenyl)-nicotinamide; N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridin-4-ylmethyll- amino}-nicQtinamide; N-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol.6-yl)-2-{[2-{3-morpholin-4-yl- propylamino)-pyridin-4-y(methyi]-amino}-nicotinamide; N-(4-tert-Butyl-phenyl)-2-{[2-(3-morpholin-4-yl-propoxy)-pyridm-4-ylmethyl]- aminoj-nicotinamide; N-(4-tert-Butyl-phenyl)-2-{[2-(2-morphoiin-4-yI-ethoxy)-pyridin-4-yimethy(]-amino}- nicotinamide; 2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino)-N-(4-trifluoromelhyl- pbenylj-nicotinamidc; 2-{[2-(2-Morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]-amino}-N-{3-lrifluoromelhyl- phenyl)-nicotinamide; 2-{[2-(2-Morpholin-4-y]-e!ho.\y)-pyridin-4-y)methy!l-amino}-N-(4-pentafluoroethy]- phenyl)-nicotinamide; N-(3-ten-Butyl-isoxa2ol-5-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-ylmethyl]- amino} -nicotinam ide; N.(l-Acelyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-{[2-(2-morpholin-4-yl- ethoxy)-pyridin-4-ylmethyl]-aniino}-nicotinamide; N-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-{[2-(l-methyl-piperidin-4- yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide; 2-{[2-(l-MethyI-piperidin-4-yloxy)-pyridin-4-yImethyI]-amino}-N-(4-trifluoromethyi- pheny!)-nicotinainide; 2-{[2-{l-Methyl-piperidin-4-yloxy)-pyridin-4>y!methyl]-amino}-N-(4- pentafluoroethyi-phenyl)-nicotinamide; 2-{[2-(l-Methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl- phenyl)-nicotinamide; (R) N-(4-tert-Butyl-phenyI)-2-{{2-{l-methyl-pyrrolidin-2-ylmethoxy)-pyriditi-4- ylmethyl]-amino}-nicolinamide; (R) N-[3-(l-Boc-pyrrolidin-2-ylmethoxy)-5-lrifluoromelhyl-phenyl]-2-[(pyridin-4- ylmethyl)-amino]-nicotinam ide; (R) N-[3-(l-Methyl-pyrro!idin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4- ylmelhyl)-amino]-nicotinamide; N-[3-(l-Methyl-piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)- aminol-nicotinamide; N-[3-(I-Methyl-piperid!n-4-ylmethyl)-5-trifluoromethy!-phenyl]-2-[(pyridin-4- y Imethy l}-am i no] -n icotinam ide; N-[3-tert-Butyl-4-(l-Boc-pyrrolidin-2-ylmethoxy)-phenyl]-2.[{pyridin-4-ylmethyl)- amino]-nicotinamide; N-(3,3-Dimethyl-2,3-dihydro-ben2ofliran-6-yl)-2-{[2-{l-melhyl-piperidin-4- ylmeihox>')-pyridin-4-y)meIhyl]-amino}-nicotinaniide; 2-({2-[3-(l-Melhyl-piperidin-4-yl)-propoxy]-pyridin-4-ylmethyl}-amino)-N-(4- trifluoromethyl-phenyi}-nicotinamide; 2-({2-[3-(l-Melhyl-piperidin-4-yl)-propoxy]-pyridin-4-y!inethyl}-amino)-N-(3- trifluoromethyl-phenyl)-nicotinamide; 2-({2-[3-(l-Melhyl-piperidin-4->'l)-propoxy]-pyridin-4-ylmethyI}-amino)-N-(4-tert- butyl-phenyl)-nicotinamide; 2-({2-[3-(l-Methyi-pipendin-4-yl}-propoxy]-pyridin-4-ytmethyl}-amino)-N-(3-terl- buty l-isoxazol-5 -y l)-n icot inam ide; N- propoxy]-pyridin-4-ylmethyl}-ainino)-nicotinamide; 2-[(Pyridin-4-ylmethyl)-amino]-N-{3,9,9-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-3-aza- fluoren-6-yl)-nicotinamide; N-[3,3-Dimethyl-l-{l-Boc-piperidin-4-ylmethyl)-2,3-dihydro-lH-mdol-6-yl]-2- [(pyridin-4-ylmethyl)-amino]-nicotinamide; N-(4-lmidazol-l-ylphenyl){2-[(4-pyridylmethyl)amitio](3-pyridyl)}carboxamide hydrochloride; N-[3,3-Dimelhyl-l-()-melhyl-piperidin-4-y)methy))-2,3-dihydro-lH-indo]-6-y!]-2- [(pyridin-4-ylmethyl)-amino]-nicotinamide; 2-{[2-(l-Melhyl-piperidin-4-yImethoxy)-pyridin-4-yImethyI]-ammo}-N-(4- pentafluoroethyl-phenyl)-nicotinamide; N-(3-lert-Butyl-isoxazol-5-yl}-2-{[2-(l-methyl-piperidin-4-ylmethoxy)-pyridin-4- ylmethyl]-amino}-nicotinamide; N-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-{[2-(l-methyl-piperidin-4- yIniethoxy)-pyridin-4-yimethyiJ-amino}-nicotinamide; N-{4-tert-Buty!-phenyI)-2-{[2-(3-morpholin-4-yl-propylamino)-pyrimidin-4-ylmethyl]- amino}-nicotmamide; 2-{[2-{3-Morpholin-4-yl-propylamino)-pyrimid!n-4-ylmethyl]-amino}-N-(4- pentafluoroethyl-phenyl)-nicolinamide; 2-{[2-(3-Morpholm-4-yl-propylamino)-pyrim(din-4-ylmethyl]-aminoJ--N-{3-trifluoromethyl-pheny I)-nicotinamide; N-(4-tert-Butyl-pheny0-2-({2.[2-(l-meth>'l-pyrrolidin-2->'l)-ethy]amino]-pyr)niidJn-4- y!methy!}-amino)-nicotinainide; N-()-Acely]-3,3-dimelhyl-2,3-dihydrD-]H-indo]-6-y]}-2-({2-[3-(l-meihyl-pyrrolidin-2- yl)-ethylamino]-pyrimidin-4-ylmethyl}-amino)-nicotinamide; N-(4-Phenoxyphenyl){2-[(4-pyrfdylmethy))amtno](3-pyridyl)}carboxamide hydrochloride; 2-{[2-((-Methy(-piperidm-4-yimethoxy)-pyridin-4-yimethy(]-amino}-N-[3-(I-methyl- piperidin-4-yl)-5-trifluoromethyl-phenyl]-nicotinamide; N-(3-tert-ButyI-isoxazol-5-yl)-2-{[2-(l-methyl-piperidin-4-ylmethoxy)-pyridm-4- ylmethyl]-amino}-nicoiinamide; N-[3-(l-Boc-azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylniethyl)- am ino]-nicotinamide; 2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(l-Boc-azelidin-3-ylmethoxy)-5- trifluoromethyl-phenyl]-nicotinamide; N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridyimethy!)amino](3-pyridyl)}carboxamide phosphate salt; N-(4-Morpholin-4-ylphenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide hydrochloride; N-(4-Cyanonaphthy!){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide, hydrochloride; {2-[(4-Pyridylmethyl)amino](3-pyridyl)}-N-[4-(trifluoromethyl)phenyI]carboxaniide hydrochloride; Methy[-({2-[(4-pyridylmethyl)amino]-3-pyridyl}carbonylamino)ben2oate, hydrochloride; 2-[(Pyridin-4-ylmethyl)-amino]-N-(2,2,4-trimethyl-3,4-dihydro-2H-benzo[l,4]oxazin- 6-yl)-nicotinamide; N.(4.Acetyl-2,2-dimethyl-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl)-2-[(pyridin-4- ylmethyl)-amino]-nicotinamide; N-(2,2-Dimethyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl)-2-[(pyridin-4- ylmelhyl)-amino]-nicotinamide; 2-{[2-(l-Benzhydryl-azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl- phenyl)-nicotinamide; N.(4,4.Dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquino!in-7-yl)-2-[(pyridin-4-ylmelhyl)- amino]-nicotinamide; N-{4-tert-Butyl-phenyl)-2-({2-[2-(l-methyl-piperidin-4-yl)-ethoxy]-pyridiii-4-ylmethyl}-amino)-nicotinaniide; N-(3-tert-Butyl-isoxazol-5-yl)-2-{{2-[2-(l-methyl-piperidin-4-yl)-ethoxy]-pyridin-4- yimethyi}-amino)-nicotinamide; N-(3-trifluoromethylphenyl)-2-{{2-[2-(l-methyl-piperidin-4-yl)-ethoxy]-pyridin-4- ylmethyl}-amino)-nicotinamide; 2-[{2,3-Dihydro-benzofuran-6-yl]T)elby])-am)no]-N-[3-(]-Boc-pyrro)!din-2- ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide; N-[3-(l-Methyl-piperidin-4-yimelhoxy)-4-penlanuoroethyl-phenyl]-2-[(pyridin-4- ylmethyl)-amino]-nicotinamide hydrochloride; (R) N-[3-(2-Hydroxy-3-pyrrolidin-l-yl-propoxy)-4-pentafluoroethyl-phenyl]-2- [{pyridin-4-ylmetbyl}-amino]-nicotinamide; (S) N-[3-(2-Hydroxy-3-pyrrolidin-l-yl-propoxy)-4-pentafluoroethyl-phenyl]-2- [(pyridin-4-ylmethyl)-aminol-nicotinamide; N-H-tert-Butyl-3-{l-methyl-piperidin-4-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)- aminoj-nicotinamide; N-(3-(I-Methyl-piperidtn-4-ylmethoxyH-pentafluoroelhyI-phefiyl]-2-[{pyridin-4- ylmelhyl)-aniino]-nicotinaniide; N-[4-Pentafluoroethyl-3-(2-piperidin-l-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)- amino]-nicotinamide; 2-[(Pyridin-4-ylmethyl)-amino]-N-{3-tri{luoromethyl-phenyl)-nicotinamide hydrochloride; ■N-(4-Imidazol-l-ylphenyl){2-[{4-pyridylmethyl)ainino](3-pyridyl)}carboxamide hydrochloride; N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-y0-2-[(pyridiii-4-ylmethyl)-amino]- nicotinamide hydrochloride; 2-[(Pyridin-4-ylmethyl}-amino]-N-(4-terl-butyl-phenyl)-nicotinamide hydrochloride; N-[4-Trifluoromethyl-3-(2-piperidin-l-yl-ethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)- amino]-nicotinamide; (S) N-[3-{l-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[{pyndin-4- ylmethyl)-amino]-nicotinamide; (R) N-[3-(I-Boc-pyrroIidin-2-yImethoxy)-4-trifluoromelhyI-phenyl]-2-[(pyridin-4- ylmethyl)-amino]-nicotinamide; (R) N-[3-(l-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4- yImethy))-amino]-nicotinamide; N-(4-lert-Butyl-pheny!)-2-{l2-{l-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]-amino}-nicotinamide; N-(3-Trifluoromethyl-phenyl)-2-{[2-(l-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]- amino}-nicotinamide; N-(3-tert-Butyl-isoxazol-5-yl)-2-{[2-(l-methyl-piperidin-4-yloxy)-pyridin-4-ylmethyl]- aminoj-nicotinamide; N-[;3-(3-Piperidin-l-yl-propyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)- amino]-nicotinamide; N-[3-(3-Morpholin-4-yl-propyl)-5-trifluoromethy!-phenyl]-2-[{pyridin-4-ylmethyi)- am ino]-nicotinamide; 2-[(2-Methoxy-pyridin-4-ylmethyi)-amino]-N-[3-(i-Boc-piperidin-4-y(oxy)-5- trifluoromelhyl-phenyl]-nicotinamide; N-(3,3-Dimelhy)indo])n-6-y]){2-[(4-p>'ridylmethyl)amijio](3-pyridy))}carboxamide edisylate; N-{4-tert-Buryl-3-[2-(!-Boc-piperidin-4-yl)-ethyl]-phenyl}-2-[(pyridin-4-y!methyl)- amino]-nicotinamide; N-[4-tert-Butyl-3-(!-methyl-azetidin-3-ylmethoxy)-phenyl]-2-[(pyridin-4-ylmethyl)- amino]-nicotinamide; N-(3,3-Dimethyl-1,1 -dioxo-2,3-dihydro-1 H-R-benzo[d]isothiazol-6-yl)-2-l(pyridin-4- ylmethyl)-amino]-nicotinamide; N-[l,l,4,4-Tetramethyl-l,2,3,4-tetrahydro-naphlh-6-yl]-2-[(pyridin-4-ylmelhyl)- am ino]-nicotinamide; N-{4-[l-Methyl-l-('-methyl-piperidin-4-y!)-ethyl]-phenyl}-2-[(pyridin-4-ylraethyl)- aminoj-nicotinamide; 2-[(2-Methoxy-pyridin-4-ylmethyl)-amino]-N-{4-[l-methyl-l-(l-methyl-piperidin-4- yl)-ethyl]-phenyl}-nicotinamide; N-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-2-[(pyridin-4-ylniethyl)-amino]- nicotinamide; N-(3,3-Dimelhyl-2,3-dihydro-lH-indol-6-yl)-2-({2-[2-(l-methyl-piperidin-4-yl)- ethoxy]-pyridin-4-ylmethyl}-amino)-nicotinamide; 2-({Pyridin-4-yimethyI)-amino]-N-[3-(2-pyrrolidin-J-yl-ethoxy)-4-trifluoromethyl- phenyl]-nicotinamide hydrochloride; N-{2,2-Dimethyl-3,4-dihydro-2H-ben2o[],4]oxazin-6-yl)-2-[(pyridiii-4-ylniethyl)- amino]-nicotinamide; N-{4,4-Dimethyl-l,2,3,4-letrahydro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide; N-(3,3-Dimethy!-2,3-dihydro-lH-indol-6-yl)-2-{[2-{l-methyl-piperidin-t-ylmethoxy)- pyridin-4-y]methyl]-amino}-nicotinamide; N-(3,3-Dimethylindolin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyI)}carboJcamide hydrochloride; N-(3,3-Dimethy!-l-piperidin-4-yl-2,3-dihydro-IH-indol-6-yl)-2-[(pyridin-4-ylmethyl)- am ino] -n icot inam ide; N-(3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl)-2-( {2-[2-{ I -niethyl-pyrrolidin-2-yl)- ethylamino]-pyrimidin-4-ylmethyl|-amino)-nicotinamide; N-(3,3-dimethyl-2,3-dihydro-lH-indol-6-yI)-2-[(2-methoxy-pyridin-4-ylmethyl)- am mo]-nicotinamide; N-[3,3-Dimethyl-l-(piperidin-4-ylmethyl)-2,3-dihydro-lH-indol-6-yt]-2-[(2-melhoxy- pyridin-4-yImethyI)-aminoJ-nicotinamide; N-(3,3-Dimethyt-l-piperidin-4-yl-2,3-dihydro-lH-indol-6-yl)-2-[{2-methoxy-pyridin- 4-yimethyl)-amino]-nicotinamide; 2-[{2-Methoxy-pyridin-4-ylmethyl)-amino]-N-[3-(piperidin-4-ylmethoxy)-5- trifluoromethyi-phenylj-nicotinamide; N-[3,3-Dimethyl-l-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-lH-indo!-6-yl]-2-[(2- me£hoxy-pyridin-4-ylmethyl)-amino]-nicotinamide; 2-[{2-Methoxy-pyridin-4-y!methyl)-amino]-N-[3-(piperazin-l-ylmeihyl)-5- trifluoromethyl-phenyl]-nicotinamide; N-{3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-{[2-(2-morpholin-4-yl-ethoxy)-pyridin- 4-ylmetbyl]-amino}-nicolinamide; N-{3,3-diniethyl-2,3-dihydro-lH-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propylaniino)- pyridin-4-ylmethyl]-amino}-nicotinamide hydrochloride; N-{3,3-dimethyl-2,3-dihydro-lH-indol-6-yl)-2-{[2-(l-methyl-piperidin-4-yloxy)- pyrid!n-4-ylmelhyl]-amino}-nicotinamide; N-(3.3-diniethyl-2,3-dihydro-lH-indol-6-yl)-2-{[2-(2-morpholin-4-yl-propoxy)- pyr)din-4-ylmethyl]-amino)-nicotinamide; N-(4-Penlafluoroethyl-phenyl)-2-[(pyrimidin-4-ylinethyl)-amino]-nicotinamide; 2-{[2-{Azetidin-3-yloxy)-pyridin-4-ylmethyl]-amino}-N-(4-tert-butyl- phenyl)nicotinamide; N-(2,3.3-Trimethyl-l.l-dioxo-2,3-dihydro-lH-U-benzo[d]isothiazol-6-yl)-2-[(pyridin- 4-ylmethyl)-amino]-benzamide; N-(4,4-Diinethyl-l-0X0-1,2,3,4-tetrah>'dro-isoquinolin-7-yl)-2-[(pyridin-4-ylmethy|)-aminoj-njcotinamjde hydrochloride; N-[3,3-Dimethyl-l,l-dioxo-2-(2-piperidin-l-yl-ethyl)-2,3-dihydro-lH-a'- benzo[d]isothiazol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide;and N-[2-{2-Dimethylamino-etliyl)-3,3-dimethyl-],l-dioxo-2,3-dihydro-lH-lV-benzo[d]isothia2ol-6-yl]-2-[(pyridin-4-ylmethyl)-amino]-nicotinamide. IndicatioDs Compounds of the present invention would be useful for, but not limited to, the prevention or treatment of angiogenesis related diseases. The compounds of the invention have kinase inhibitory activity, such as VEGFR/K.DR inhibitory activity. The compounds of the invention are useful in therapy as antineopiasJa agents or to minimize deleterious effects of VEGF. Compounds of the invention would be useful for the treatment of neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including smalt cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-ce(l-iymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma). Preferably, the compounds are useful for the treatment of neoplasia selected from lung cancer, colon cancer and breast cancer. The compounds also would be useft;! for treatment of ophlhalmologica] conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including infantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis. The compounds are also useful for the treatment of edema, and conditions of vascular hyperpermeability. The compounds of the invention are useful in therapy of proliferative diseases. These compounds can be used for the treatment of an inflammatory rheumatoid or rheumatic disease, especially of manifestations at the locomotor apparatus, such as various inflammatory rheumatoid diseases, especially chronic polyarthritis including rheumatoid arthritis, juvenile arthritis or psoriasis arthropathy; paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid effusions, collagenosis, such as systemic Lupus erythematosus, poly-myositis, dermato-myositis, systemic sclerodermia or mixed collagenosis; postinfectious arthritis (where no living pathogenic organism can be found at or in the affected part of the body), seronegative spondylarthritis, such as spondylitis ankylosans; vasculitis, sarcoidosis, or arthrosis; or further any combinations thereof An example of an inflammation related disorder is (a) synovial inflammation, for example, synovitis, including any of the particular forms of synovitis, in particular bursal synovitis and purulent synovitis, as far as it is not crjstal-induced. Such synovial inflammation may for example, be consequential to or associated with disease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis deformans. The present invention is further applicable to the systemic treatment of inflammation, e.g. inflammatory diseases or conditions, of the joints or locomotor apparatus in the region of the tendon insertions and tendon sheaths. Such inflammation may be, for example, consequential to or associated with disease or further (in a broader sense of the invention) with surgical intervention, including, in particular conditions such as insertion endopathy, myofasciale syndrome and tendomyosis. The present invention is further especially applicable to the treatment of inflammation, e.g. inflammatory disease or condition, of connective tissues including dermatomyositis and myositis. These compounds can be used as active agents against such disease states as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, fractures, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy or macular degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease). and cysts (such as hypervascuiarity of ovarian stroma, characteristic of polycystic ovarian syndrome {Stein- Leventhal syndrome)} since such diseases require a proHferation of blood vessel cells for growth and/or metastasis. Further, some of these compounds can be used as active agents against bums, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, brain tumor-associated cerebral edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, and other diseases where vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease. The compounds will also be useful in treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g. fibrosis, cirrhosis and carpal tunnel syndrome). The compounds of the present invention are also useful in the treatment of ulcers including bacterial, fungal, Mooren ulcers and ulcerative colitis. The compounds of the present invention are also useful in the treatment of conditions wherein undesired angiogenesis, edema, or stromal deposition occurs in viral infections such as Herpes simplex. Herpes Zoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis, following trauma, radiation, stroke, endometriosis, ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis, synovitis, Crohn's disease, sickle cell anaemia, Lyme disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic infiammation, chronic occlusive pulmonary disease, asthma, and inflammatory rheumatoid or rheumatic disease. The compounds are also useful in the reduction of sub-cutaneous fat and for the treatment of obesity. The compounds of the present invention are also useful in the treatment of ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, glaucoma, conjunctivitis, Stargardt's disease and Eales disease in addition to retinopathy and macular degeneration. The compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, arteriosclerosis, vascular occlusion and carotid obstructive disease. The compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Swing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma. hematopoietic malignancies, including leukemia and lymphoma, tumor- induced pleural or pericardial effusions, and malignant ascites. The compounds of the present invention are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy. The compounds of this invention may also act as inhibitors of other protein kinases, e.g. p38, EGFR, CDK-2. CDK-5, IKK, JNK3, and thus be effective in the treatment of diseases associated with other protein icinases. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. As used herein, the compounds of the present invention include the pharmaceutically acceptable derivatives thereof. Definitions The term "treatment" includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a preclinically evident stage of disorders in individuals). The term "prevention" includes either preventing the onset of disorders altogether or delaying the onset of a preclinically evident stage of disorders in individuals. This includes prophylactic treatment of those at risk of developing a disease, such as a cancer, for example. "Prophylaxis" is another term for prevention. A "pharmaceutically-acceptable derivative " denotes any salt, ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to inhibit angiogenesis. The phrase "therapeutically-effective" is intended to qualify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. For example, effective neoplastic therapeutic agents prolong the survivability of the patient, inhibit the rapidly-proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm. The term "H" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxy) radical. Where the term "alkyl" is used, either alone or within other terms such as "haloaHtyl" and "aikylamino", it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyi radicals are "lower aikyi" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, rert-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term "alkylenyl" embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl. The term "lower alkyl substituted with R^" does not include an acetaJ moiety. The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkeny) radicals include elhenyl, propeny), alJyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "alkynyl" denotes linear or branched radicals having at least one carbon-carbon triple bond and having two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, butynyl, and the like. The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more of the alkyi carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyi, dihaloalkyi and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fiuoromethyl, drfiuoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethy! and dichloropropyl. "PerfluoroalkyI" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl. The term "hydroxyalky 1" embraces iinear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxy! radicals. More preferred hydroxyaikyi radicals are "iower hydroxyaikyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyaikyl radicals having one to three carbon atoms. The term "alkoxy" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and lert-huloxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chJoro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, telrahydronaphthyl, and indanyl. More preferred aryl is phenyl. Said "aryl" group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyi, nitro, cyano, alkoxy and lower alkylamino. Phenyl substituted with -O-CH2-O- forms the aryl benzodioxolyl substituent. The term " heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -0-0-,-0-S- or -S-S-portions. Said "heterocyclyl" group may have I to 3 substituents such as hydroxyl, Boc, halo, haloalkyi, cyano, lower alkyl, lower aralkyi, 0x0, lower alkoxy, amino and lower alkylamino. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and I to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazoty). Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing ] to 4 nitrogen atoms, for example, pyrrolyl, iniidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-1,2,3-triazotyl, 2H-l,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyt, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and I to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, l,3,4-oxadia2olyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 lo 2 sulfur atoms and J to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. The term also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing I to 5 nitrogen atoms, for example, indolyl, isoindolyl, indoliziny!, benzimidazolyl, quinolyl, isoquinoly!, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolylj; unsaturated condensed heterocyclic group containing I to 2 suifm atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzoftiryl, benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dlhydrobenzofuryl]. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl, Panicular examples of non-nilrogen conlaining heteroaryl include pyranyl. 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, benzothienyl, and the like. Particular examples of partially saturated and saturated heterocyciyl include pyrrolidinyi, imidazolidinyl, piperidinyl, pyrroiinyl, pyrazoiidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-b€nzoll,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinoly!, 1,2,3,4-teirahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1 H-3-aza-fluorenyl, 5,6,7-trihydra- i ,2,4-lriazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3-dihydro-lH-lV-benzo[d]isothiazo]-6-yl, dibydropyranyl, dibydrofuryl and dihydrothiazolyl, and the like. The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-. The terms "sulfamyl," "aminosulfonyl" and "sulfonamidyl," denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2NH2). The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" where sulfamyl radicals are independently substituted with one or two alkyl radical(s). More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl. The terras "carboxy" or "carboxyl", whether used alone or with other terras, such as "carboxy alky I", denotes -CO2H. The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -(C'O)-. The term "aminocarbonyl" denotes an amide group of the formula -C(=0)NH2. The terms "N-aJkylaminocarbonyl" and "N.N-dialkylaminocarbonyl" denote aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are "lower alkylaminocarbonyl" having lower alkyl radicals as described above attached to an aminocarbonyl radical, The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. The term "heterocyclylalkylenyl" embraces heterocyclic-substituled alkyl radicals. More preferred heterocyclylalkylenyl radicals are "5- or 6-membered heteroarylalkylenyl" radicals having alkyl portions of one to six carbon atoms and a 5-or 6-membered beleroaryl radical. Even more preferred are lower heteroarylalkylenyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyi radicals are "lower aralkyV radicals having aryt radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are "phenylalkylenyl" attached to alkyl portions having one lo three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalky] and haloalkojiy. The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one lo three carbon atoms. An example of "alkylthio" is methylthio, (CH3S-). The term "haloalkylthio" embraces radicals containing a haloalkyi radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of "haloalkylthio" is trifluoromethylthio. The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino" where amino groups are substituted with one alkyl radical and with two independent alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-elhylamino, N,N-dimethy]amiiio, N,N-diethy]amino and the like. The term "arylamino" denotes amino groups which have been substituted with one OT two aryl radicals, such as N-phenylamino. The arylamino radicals may be further substituted on the aryl ring portion of the radical. The terra "heteroarylamino" denotes amino groups which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals may be further substituted on the heteroaryl ring portion of the radical. The term "aralkylamino" denotes amino groups which have been substituted with one or two aralkyl radicals. More preferred are phenyl-CpCs-alkylamino radicals, such as N-benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion. The terms "N-alkyl-N-arylamino" and "N-aralky(-N-a(kyIamino" denote amino groups which have been substituted with one aralkyi and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group. The term "aminoalkyi" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of v^-hich may be substituted with one or more amino radicals. More preferred aminoalkyi radicals are "lower aminoalkyi" radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyi, aminobutyi and aminohexyl. Even more preferred are lower aminoalkyi radicals having one to three carbon atoms. The term "alkylaminoalkyl" embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyi substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl, K,N-dtethylaminomethyl and the like. The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyi substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like. The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyi substituted, such as N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyelhoxy, N,N-diethylaminomethoxymelhoxy and the like. The term "carboxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH2 groups. The term "halosulfonyl" embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl. The term "arylthio" embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of "arylthio" is phenylthio, The term "aralkylthio" embraces aralkyl radicals as described above, attached to a divalent sulfur atom. More preferred are phenyl-CrCj-alkyllhio radicals. An example of "aralkylthio" is benzylthio. The term "aryloxy" embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having optionally substituted phenyl radicals attached to lower alkoxy radical as described above, The term "heteroaryloxy" embraces optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom. The term "heteroarylalkoxy" embraces oxy-containing heteroarylalkyl radicals attached through an oxygen atom to other radicals. More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy" radicals having optionally substituted heteroaryl radicals attached to lower alkoxy radical as described above. The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloatkyi groups include C3-C6 rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl. The term "cycloalkenyl" includes carbocyclic groups having one or more carbon-carbon double bonds including "cycloalkyldienyl" compounds. Preferred cycloalkenyl groups include C3-C6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopenladienyl, cyctohexenyl and cycloheptadienyl. The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements. The phrase "Formula I-XII" includes sub formulas such as 11'. The compounds of the invention are endowed with kinase inhibitory activity, such as KDR inhibitory activity. The present invention also comprises the use of a compound of the invention, or pharmaceutical!y acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of an angiogenesis mediated disease state. including those described previously. The compounds of the present invention are useful in the manufacture of an anti-cancer medicament. The compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of KDR. The present invention comprises a pharmaceutical composition comprising a therapeutical ly-effective amount of a compound of Formulas I-XII in association with a least one pharmaceutically-acceptable carrier, adjuvant or diluent. The present invention also comprises a method of treating angiogenesis related disorders in a subject having or susceptible to such disorder, the method comprising treating the subject with a therapeutically-effective amount of a compound of Formula I wherein p is 0 to 2, wherein R^ and R^ are independently selected from H, halo, cyano, -NHR^ and CM- alkyl substituted with R^ or wherein R^ and R** together form Cs-Q cycloalkyl; wherein R^ is selected from C2-C6-alkylenyl, where one of the CH^ groups may be replaced with an oxygen atom or an -NH-; wherein one of the CH2 groups may be substituted with one or two radicals selected from halo, cyano, -NHR^ and CM-alkyl substituted with R^; wherein R' is cycloalkyl; wherein R is selected from a) substituted or unsubstituted 5-6 membered heterocyclyl, b) substituted aryl, and c) substituted or unsubstituted fused 9-14-membered bicyclic or tricyclic heterocyclyl; wherein substituted R is substituted with one or more substituents independently selected from halo, -OR^ -SR', -S02RVC02R^ -CONR^R^ -COR^ -NR^R^ -S02NR^R\ -NR^C(0)0R\ -NR^C(0)R^ cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, nitro, alky lam inoalkoxyalkoxy, cyano, alky lam inoalkoxy, lower alkyi substituted with R^, lower alkenyl substituted with R^ and lower alkynyl substituted with R^; wherein R' is selected from a) substituted or unsubstituted 6-10 membered aryl, b) substituted or unsubstituted 5-6 membered heterocyclyl, c) substituted or unsubstituted 9-14 membered bicyclic or tricyclic heterocyclyl, d) cycloalkyi, and e) cycloalkenyl, wherein substituted R' is substituted with one or more subslituenls independently selected from halo, -0R\ -SR^ -C02R\ -C0NR^R\ -C0R-NR^R\ -NH(C|-C4 alkylenylR'"), -S02R\ -S02NR^R^ -NR^C(0)OR^ -NR^C(0)R', optionally substituted cycloalkyi, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, halosulfonyl, cyano, alkylaminoalkoxy, alky lam inoalkoxyalkoxy, nitro, lower alkyl substituted with R^, lower alkenyl substituted with R^, and lower alkynyl substituted with R^ wherein R^ is one or more substituents independently selected from H, halo, -OR^, oxo, -SR\ -COIR^ -C0R\ -CONR^R^ -NR^R^ -S02NR^R\ -NR^C(0)0R\ - NR"'C(0)R^, cycloalkyi, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkyienyl, optionally substituted phenyl, tower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyi, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyi; wherein R^ is selected from H, loiver alkyl, phenyl, heterocyclyl, C3-C6-cycloalkyi, phenylalkyl, heterocyclylalkyl, Cj-Cs cycloalkylalkyl, and lower haloalkyi; wherein R"" is selected from a direct bond, Q-j-alkylenyl, C2-4-alkenylenyl and C2-4-alkynylenyl, where one of the CH2 groups may be substituted with an oxygen atom or an -NH-, wherein R^ is optionally substituted with hydroxy; wherein R^ is selected from H, lower alkyl, phenyl and lower aralkyi; wherein R^^ is selected from H, lower alkyl, phenyl and lower aralkyi; wherein R* is selected from H or Ci^-alkyl; and wherein R'"* is selected from H, phenyl, 5-6 membered heterocyclyl and C3-C6 cycloalkyi; and pharmaceulically acceptable derivatives thereof; provided A is not naphthyl when X is -C(0)NH- and when R' is phenyl when Y is -NCH2- and when R is 4-pyridyl; and further provided R is not unsubslituted 2-thienyl, 2-pyridyl or 3-pyridyl when Y is -NHCH2-. COMBIIVATIOiVS While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds or the invention or other agents, when administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. The phrase "co-therapy" (or "combination-therapy"), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. 2,2-Dimethyl-6-nitro-4H-benzo[i,4]oxazin-3-one was added to BH3-THF complex (Aidrich) in THF with ice cooling. The mixture was healed to reflux for 2 h then carefully diluted with 12 mL of MeOH and heated to reflux for an additional 1 h. Concentrated HCI (12 mL) was added and heated to reflux for 1 h. The mixture was concentrated and the resulting solid was suspended in a dilute aqueous solution of NaOH (1 M) and extracted with EtOAc (100 mL x 4). The organic layers were washed with H2O and dried over MgS04. Evaporation of solvent gave a yellow solid. Preparation LXXVII - 2,2,4-Trimethyl-6-nitro-4H-benzo[l,4]oxazin-3-onc 2,2-Dimethyl-6-nitro-4H-benzotl,4]oxazin-3-one (1.1 g) was mixed with Mel (850 mg, Aidrich), K2COJ (1.38 g, Aidrich) and DMF (30 ml, Aidrich) at 40°C for 48 h. The DMF was removed in vacuo and the residue was diluted with EtOAc (80 ml). The organic phase was washed with H2O (50 ml), aqueous Na^SOj (50 ml) and brine (50 ml). The resuhing solution was dried (MgSO^) and concentrated to provide the compound which was used as is. Preparation LXXVIII - 2-Bronio-N-(2-hydroxy-5-nitro-pheiiyl)-2-methyl-propionamide 2-Amijio-4-nJtro-pheno) (3.08 g, Aldrich) was stirred with THF (30 ml, Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47 ml, Aldrich) and EtjN (2.0 g, Aldrich) was slowly added via syringe. The mixture was stirred for 45 min then poured into ice. The aqueous phase was extracted by EtOAc (50 mL x 4). The organic layer was dried and concentrated. The desired product was crystallized from EtOAc. {Chem. Pharm.BuU\996,44i\) 103-114). Preparation LXXIX - 2,2'Dimethyl-6-nitro-4H-benzo[I,4Ioxazin-3-one 2-Bromo-N-(2-hydroxy-5-nilro-phenyl)-2-methyl-propionamide was mixed with K2C03 in 20 mL of DMF and stirred overnight at 50°C. The reaction mixture was poured into ice water. The precipitate was collected by filtration and washed with H2O. The crude compound was recrystallized from EtOH. Preparation LXXX-4-ll-(2-Bromo-4-nitro-phenyl)-l-methyl-ethyl|-l-methyl-pyridinium iodide l-Methyl-4-[l-methyl-l-(4-nitro-phenyl)-ethyl]-pyridinium (8 g) was dissolved in glacial HOAc (10 ml) then diluted with H2SO4 (50 ml), then NBS (3.8 g) was added. After I h, additional NBS (1-2 g) was added, 30 min later another 0.5 g of NBS, then 15 min later 200 mg more NBS. After 1 h, the mixture was neutralized with NH4OH (cone.) with ice bath cooling. The neutralized mixture was then concentrated and used as is. Preparation LXXXl - 4-[]-(2-Bromo-4-nitro-phenyl)-l-melhyl-ethyl]-l-methyl-1,2,3,6-telrahydro-pyridine 4-[l-(2-Bromo-4-nitro-phenyi)-I-methyi-ethyI]-i-methyl-pyridinrumiodide was mixed with MeOH (400 ml) and CHiCb (200 ml), then treated with NaBHj (2.5 g) in portions. After stirring at RT for 2 h, the mixture was extracted with CH2CI2 (300 mL X 3). The CH2CI2 layer was washed with brine, dried over Na2S04 and concentrated in vacuo, to provide the desired product. Preparation LXXXII - l-Methyl-4-tl-methyl-l-(4-nitro-phenyl)-ethyI]-pyridinium iodide 4-{4-nitrobenzyl)pyridine (64 g, 300 ramol) and BU4NI (6 g, 16.2 mmol) were dissolved in CH2CI2 (500 ntiL) and the solution was suspended with NaOH (aq. 5N, 450 mL). With vigorous stirring, Mel (213 g, 1500 mmol) was added. The resulting solution was placed under N2 and stirred vigorously at RT for 60 h until blue color disappears, (MS: M"*=257). The reaction mixture was used in the next step without any further purification. Preparation LXXXIII - l-Methyl-4-(4-nitrobenzyl)-l^^,6-tetrahydro-pyridine l-Meth>'l-4-[l-meth>'l-l-(4-nitro-pheny])-ethyl]-pyridinium was treated with DEA (100 mL) in MeOH (300 mL) for 2 h. NaBH4 (19 g, 500 mmole) was added in small portions. The resulting mixture was stirred for 30 min at RT, then partitioned between CHjCb/HjO (500 mL/500 mL). The lower layer (organic) was collected and the upper layer was washed with CH2CI2 (300 mL x 3). The combined organic layer was washed with brine then concentrated in vacuo. The residue was purified on a silica washed-column (7% TEA in EtOAc). The desired fractions were combined and concentrated under vacuum to give the desired compound as a dark gray solid. (MS; M+l=261). Preparation LXXXIV - l-Boc-4-formylpiperidiiic 4A Molecular sieves were heated to 100°C and a vacuum was applied. They were cooled to RT and purged with N2. CH2CI2 (420 ml) and CH3CN (40 ml), NMO (40 g) and !-Boc-4-hydroxymethylpiperidine (50 g) were added and the mix was stirred for 5 min then cooled to 15°C. TPAP (4.1 g) is added and an exotherm was observed. The reaction was maintained at RT with external cooling. The reaction was stirred at RT for 3 h, filtered, concentrated, diluted with 50% ElOAc/hexanes and purified on a silica gel plug (50%EtOAc/hexanes). The eluant fractions were concentrated to afford a yellow oil. Preparation LXXXV 2-Cbloro-4-cyanopyridine 2-Chloro-4-cyanopyridine was prepared similar to the method described by Daves et al., J. Het. Chem., 1, 130-32(1964). Preparation LXXXVI 4-(2-tert-Butyi-5-nitro-phenyl)-but-3-en-l-ol A m'w of l-(rerl-bulyl)-2-bromo-4-nitrobenzene (3.652 g), TEA (5.92 ml), 3-buten-l-ol (5.48 ml), Pd(0Ac)2 (32 mg), Pd(PPh3)4 (327 mg) and toluene (40 ml) was degassed with nitrogen and heated in a sealed vessel for 16 h at 120°C. The next day, the reaction mixture was cooled to RT, filtered, and concentrated in vacuo. The crude was eiuted on a silica gel column with (5% to 22% EtOAc/hexanes gradient system to yield yellow-brown oil. Preparation LXXXVII 4-(2-tert-ButyI-5-nitro-phenyl)-but-3-enal 4-(2-rert-Buty]-5-iiitro-pheny]}-biit-3-en-l-ol (J.024 g) was dissolved in 10 ml of CH2CI2 and added dropwise over 5 min to a -78°C mix of oxalyl chloride (0.645 ml), DMSO (0.583 ml), and 10 ml CHaCb, The reaction was stirred at -78°C for 1 b, then treated with a solution of TEA (1.52 ml) in 7 ml CH2Cb and stirred at -78°C for an additional 25 min, then warmed to -30°C for 35 min. The reaction was treated with 50 ml of saturated aqueous NH4CI, diluted with H2O and extracted with ElOAc. The organic layer was brine-washed, dried over Na2S04, filtered, and concentrated in vacuo to yield yellow oil. Preparation LXXXVIII l-|4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine 4-(2-lert-Butyl-5-nitro-phenyl)-but-3-enal (895 mg) was dissolved in 40 ml THF, and to the solution was added pyrrolidine (0,317 ml). To the deep orange solution was added NaBH(0Ac)3 (1.151 g) and glacial AcOH (0,207 ml). The reaction was stirred at RT overnight, then treated with saturated aqueous NaHCOj and diluted with Et20 and some IN NaOH. The layers were separated, and the organic layer was extracted with aqueous 2N HCI. The acidic aqueous layer was basified to pH>I2 with 6 N NaOH, extracted with EtjO, brine-washed, dried over Na2S04, filtered, and concentrated in vacuo to provide !-[4-{2-tert-biJtyI-5-nitro-phenyl)-but-3-enyl]-pyrrolidine as a orange-brown oil. Preparation LXXXVIX N-Boc-(2'Chloropyrimidin-4-yl)-methylainine To 2-chloropyrimidine-4-carbonitrile [2.5 g, prepared by the procedure of Daves et. al. [J. Hel. Chem. 1964, /. 130-132)] in EtOH (250 ml) under N2 was added B0C2O (7.3 g). After the mixture was briefly placed under high vacuum and flushed with N2, 10% Pd/C (219 mg) was added. H2 was bubbled though the mixture (using balloon pressure with a needle outlet) as it stirred 4.2 h at RT. After filtration through Celite®, addition of 1.0 g additional B0C2O, and concentration, the residue was purified by silica gel chromatography (5:1 -> 4:1 hexanes/EtOAc) to obtain N-Boc-(2-chloropyrimidin-4-yl)-methylamine. Preparation XC Metbanesulfonic acid l-Boc-azetidin-3-yImeth>'] ester To a solution of (l-Boc-azetidin-3-yl)-methanol (1.06 g, 5.7 mmol), TEA (1.18 mL, 8.52mmoi) in CHjCh at 0°C was added MeSOjCi (0.53 mL, 6.82 mmol) via a syringe. The reaction was warmed to RT over 2 h and stirring was continued at RT for 2 h. The white solid formed was removed by filtration and the filtrate was washed with 25 mL of H2O. The organic phase was dried over Na2S04, and concentrated in vacuo to afford yellow oil. Preparation XCI3,9,9-Trimethyl-6-nitro-4,9-dihydro-3H-3-aza-nuoreDe 4-[ 1 -(2-Bromo-4-nitro-pheny|)-1 -methyl-ethyl]-1 -methyl-1,2,3,6-tetrahydro-pyridine (9 g), Pd(0Ac)2 (900 mg), and DIEA (15 mL) was dissolved in DMF (300 mL), and heated to SOX overnight. Solvents were removed in vacuo. The residue was partitioned between CH2Cl2/NaHC03(sat, aq.). The CH2CI2 layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified via flash chromatography on silica to give the desired compound. (MS: M+H=257) LCII 3,9,9-TrimethyI-2,3,4,4a,9,9a-hexahydro-l H-3-aza-fluoren-6-ylain ine(l 56) 3,9,9-Trimethy)-6-nilro-4,9-dihydro-3H-3-aza-fluorene (700 mg) was dissolved in EtOH (20 mL) with aqueous HCI (IN, 5 mL) and suspended with Pd/C (10%, 100 mg). The flask was capped with a baJloon filled with H2. The reaction was completed in 6 h at RT. The reaction mixture was filtered through a layer of Celite® with MeOH. The combined filtrate was concentrated to give desired compound. (MS; M+H=23!). Step A - Preparation of 3-r("tert-butoxvkarbonvlamino]thiophene-2-carboxvlic acid To a mixture of methyl 3-amino-2-thiophenecarboxy!ate (8 g, 5! mmol) and BOC2O (11 g, 50 mmol) in CH2CI2 (400 ml) was added 4-(dimethylamino)pyridine (I g, 8.1 mmoi). The reaction was stirred at RT overnight and washed with 1NHC1(I00 ml), followed by water and brine. The organic layer was dried over Na2S04 and evaporated under reduced pressure and used for the next step without further purification. To the residue (2 g, ~7 mmol) in EtOH (50 ml) was added IN NaOH (25 ml), the reaction was stirred at RT for 1 h and the solvent was evaporated under reduced pressure. Water (5 ml) was added and the solution was acidified with HOAc. The precipitate was filtered and used in the next step without further purification. MS (ES-): 242 (M-H)", Step B - Preparation of i3-|(tert-butoxy)carbonylamino](2-thienvl))-N-(4-chlorophenvHcarboxamide To a mixture of the thienyl carboxylic acid from Step A (300 mg, 1.23 mmol) and 4-chloroaniline (160 mg, 1.25 mmol) and DIEA (300 jil, 1.6 mmol) was added EDC (300 mg, 1.6 mmol) and HOBt (170 mg, 1.25 mmol) in CH^Cl^, the reaction was stirred at RT overnight. The solution was washed with IN HCl and saturated NaHCOa, followed by H2O and brine. The organic layer was dried over Na2S04 and evaporated under reduced pressure and purified with preparative TLC to give the amide. MS (ES+): 353 (M+H)^; (ES-): 351 (M-H)Step C - Preparation of N-(4-chlorophenvni3-rf4-pvridvlmethvl)aminQl(2-thienvDicarboxamide The amide from Step B was mixed with 25% TFA/CH2Cb and stirred at RT for 1 h (monitored by HPLC). The solvent was evaporated under reduced pressure and the residue was mixed with 4-pyridine carboxaldehyde (260 mg, 2.5 mmol) and NaCNBHs (160 mg, 2.5 mmol) in MeOH (40 ml). The reaction was stirred at RT overnight and evaporated under reduced pressure. The final product was purified by prep-HPLC as TFA salt. MS (ES+>: 344 (M+H)^; {ES-): 342 (M-H)". Calc'd. for C,7H,4C1N30S -343.84, Example 2 N-(4-ChIoropheny I) {2- [(4-py ridy Imethy ()amino J(3-py ridy l)}ca rboxa mide Step A - Preparation of (2-amino(3-pvridyn')-N-(4-chlorophenvncarboxamide To a mixture of 2-aminonicotinic acid (5.3 g, 38 mmol) and 4-chloroaniline (4.9 g, 38 mmoi) and DIEA (9 ml, 48 mmol) at 0°C in CHiCI; was added EDC (9.5 g, 48 mmol) and HOBt (5.1 g, 38 mmol). the reaction was warmed to RT and stirred overnight. The solvent was evaporated under reduced pressure and quenched with 2N NaOH solution (60 ml) and stirred for 20 min. The precipitate was filtered to give the titled compound. MS (ES+): 248 (M+H)^ (ES-): 246 (M-H)". Step B - Preparation of N-(4-chlorophenvl)(2-[(4-pyridvlmethyl)amino](3-pyridylltcarboxamide N-(4-Chlorophenyl){2-|(4-pyridylethyl)amino]-5-(3-thienylH3-py ridyl)}ca rboxamide Step A - Preparation of 5-bromo-2-hvdroxvnicotinic acid A solution of sodium hypobromide was made by adding Br2 (1.01 ml, 39.5 mrnol, 1.1 eq) slowly over a period of 5 min to NaOH (5N, 40 ml) that was previously cooled to 0'C in an ice bath. The solution was stirred for 10 min before adding 2-hydroxynicotinic acid (5.0 g, 35.9 mmol) and placed in a 50°C oil bath and stirred. Concurrently, a second pot of sodium hypobromide solution was made by slowly adding Br2 (1,01 ml, 39.5 mmol, 1.1 eq) to a NaOH solution (5N, 40 ml) in an ice bath. The second poi of sodium hypobromide was added to the solution of 2-hydroxynicotinic acid after 24 h of heating then was stirred for an additional 24 h. The solution was cooled to RT, placed in an ice bath and acidified with concentrated HCI while stirring. The precipitate which formed was filtered, washed and dried to afford the desired compound as an off-white solid. Step B - Preparation of 5-bromo-2-chloronicotinic acid A solution of 5-bromo-2-hydroxynicolinic acid, from Step A (8.3 g, 38.1 mmol) and SOCI2 (40 ml) in a 150 ml round bottom flask was placed in an SO^C oil bath and stirred while adding 10 ml of DMF. The solution was heated at reflux for 4 h at 80°C before cooling to RT. Excess SOCI2 was stripped off under reduced pressure forming a yellow-brown residue. The yellow-brown residue was placed in an ice bath and cooled to 0°C. Residual SOCI2 was neutralized and the chloro compound was precipitated by the dropwise addition of water. Precipitate was filtered, washed and dried to afford the desired chloro compound as a light yellow solid. Step C - Preparation of 5-bromo-2-chloro-A^-(4-chlorophenvniiicotinainide To a mixture of 4-chloroanaline (594 mg, 4.7 mniol, 1. eq.), EDC (1.62 g, 8.5 mmol, 2 eq.), HOBT (572 mg, 4.2 mmol, 1 eq.), and DIEA (I.I ml, 6.3 mmol, 1.5 eq.) in CH2CI2 (50 ml) was added 5-bromo-2-chloronicotinic acid from Step B (1.0 g, 4.2 mmol). The reaction was stirred at RT overnight. The solution was quenched with water and the organic layer was purified by chromatography (50% EtOAc in hexane) to afford a light-yellow compound. MS (ES+): 347.0, 349.0 (M+H)^; (ES-): 345.0, 347,0 (M-H)". Step D - Preparation of 5-(3-thiophene)-2-chloro-A'-(4-chlorophenvl)nicotinamide 3-Thiophene boronic acid (204 mg, 1.6 mmol, 1.1 eq), Pd(0Ac)2 (33 mg, 0.2 mmol, 0.2 eq.), and K2CO3 (505 mg, 4.3 mmol, 3 eq.) were added to a solution of 5- bromo-2-chloro-N-(4-chlorophenyl)nicotinamide from Step C (500 mg, 1.4 mmol) in DMF (20 ml). The reaction was placed in a 50°C oil bath and stirred overnight. The reaction was filtered and purified by medium pressure chromatography (30% EtOAc in hexane) to afford the desired thienyl compound as an off white solid. Step £ - Preparation of N-(4-chlorophenyl){2-[(4-pvridylethyl)amino]-5-(3-thienvh-(3-pyridyDtcarboxamide. 4-(Aminoethyl)pyridine (10 ml) was added to a 25 ml round-bottom flask containing 5-(3-thiophene)-2-chioro-A'-(4-chlorophenyl)nicotinamide from Step D (200 mg, 0.6 mmol). The solution was placed in an 80°C oil bath and stirred overnight. The reaction was cooled to RT, and after an aqueous work-up, was purified by medium-pressure chromatography (80% ElOAc in hexane) to afford the title compound as a light yellow solid.. MS: (ES+) 435.1 (M+H); (ES-) 432.8 (M-H). Calc'd. for C23H19CIN4OS-434.95. N-(4-Isopropylphenyl) {2-|(4-pyridylmethyl)amino](3-pyridyl)}carboxamide Step A: Preparation of |'2-ch]oro-3-pvridvl)-N-(4-isopropvlphenv])carboxajnide To a mixture of 2-chloronicotinic acid (6.3 g) and 4-isopropylaniline (5.26 ml) and DIEA (10 ml) in CH2CI2 (200 ml) was added EDC (10 g) and HOBt (5.4 g). The reaction was stirred at RT overnight and washed with 2 N NaOH (100 ml), H20 (250 ml) and brine (100 ml). The organic layer was dried over Na2S04 and evaporated to give (2-chloro-3-pyridyl)-N-(4-isopropylphenyl)-carboxamide. Step B: Preparation of N-[4-(isopropvl)phenvl1i2-|"(4-pvridylmethvl)amino](3-pyridyUlcarboxamide hydrochloride A mixture of (2-chloro(3-pyridyl))-N-(4-isopropylphenyl)carboxamide (1.5 g, from Step A) and 4-aminomethylpyridine (0.71 ml) was heated at 130°C neat for 3 h. The reaction was cooled and diluted with CH2CI2 and washed with H2O twice followed by brine. The organic layer was dried with Na2S04 and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc and further mixed with MeOH and 1 N HCI/Et20 (2 ml). The solution was evaporated to furnish the titled compound. MS (ES+): 347 (M+H)*; (ES-): 345 (M-H). Calc'd. for C31H22N4O -346.18. The following compounds (Examples 26-8 () were synthesized by the method described in Example 25 unless specifically described. Detailed intermediate preparations are included, Step A Preparation of 2-bromo-l-i'gfj'-btityl-4-nitrobenzene NBS {125.0 g, 697.5 mmol) was slowly added to a solution of TFA:H2S04 (5:1. 750 mL) and /e/-(-butyl-4-nitrobenzene (100.0 g, 558.0 mmol) at RT. The solution was stirred for 24 h then poured over 5 kg of ice. The resulting suspension was filtered and washed with a l:\ MeOH:H20 solution (200 mLJ and dried in a vacuum oven. MS (ES+): 258.1, 260,1 (M+H)". Calc'd for CioHisBrNOj: 257.01. Step B Preparation of 4-(2-/ert-butvl-5-nitrophenvnpvridine To a solution of 2-bromo-I-/erf-buty!-4-nitrobenzene (8.6 g, 33.3 mmoi) and toluene (70 mL) in a 150 mL round bottom flask, 4-pyridylboronic acid (4.5 g, 36.6 mmol), Pd(PPh3)4 (3.8 g, 3.3 mmol) and K2CO3 (13.8 g, 99.9 mmol) were added. The ' solution was stirred for 24 h at 80°C before cooling to RT. The solution was filtered through a pad of Celite® and purified by silica flash chromatography (30% EtOAc/Hexanes). This afforded the desired compound as a yellow solid. MS (ES+): 257,2 (M+H)^ (ES-): 255.2 (M-H)". Calc'd for C15H16N2O2: 256.12. Step C Preparation of 4-(2-fgrf-butv[-5-nitrophenyl)-1 -methvlpyridinium 4-(2-/f^r/-Buty)-5-nilrophenyl)pyridine (2.0 g, 7,8 mmol. Step B) was added to a round-bottom flask and dissolved in EtOH (10 mL). Mel (30 mL) was added and the flask was placed in an 80'C sand bath and healed to reflux. After 6 h the solution was cooled to RT and the excess Mel and EtOH was concentrated in vacuo resulting in the desired compound as a light brown solid. MS (ES+).- 271.2 (M+H)*; (ES-): 269.2 (M-H)-. Calc'd for Ci6Hi9N202^: 271.14. Step D Preparation of 4-tert-butyl-3-(l-methyl-1.2,3.6-tetrahvdropvridin-4-vhaniline 4-(2-/ert-Butyl-5-nitrophenyl>-l-methylpyridin!um (2.1 g, 7.8 mmol, Step C) was added to a 100 mL round-bottom flask and dissolved in a 10% H20/EtOH mixture. To the flask iron dust (1.31 g, 23.4 mmol) and NH4CI (460 mg, 8.6 mmol) were added. The flask was placed in a 100°C sand bath and heated to reflux. Alter 2 h the solution was cooled to RT and filtered through a pad of Celite®. The resulting solution was concentrated in vacuo to a yellow solid and re-dissolved in MeOH (20 mL, anhydrous). The solution was cooled to 0°C by placing it in an ice bath and slowly adding NaBH4 (450 mg, 11.7 mmol). After addition of the NaBH4, the solution was cooled to RT and stirred for 30 min. TTie solvent was concentrated w vacuo and the solid was re-dissolved in CH2CI2 and filtered. The solution was again concentrated in vacuo to afford an amorphous clear yellow solid. MS (ES+>: 245.2 (M+H)"", Calc'd for C16H34N2: 244.19. Step E Preparation of 2-[("pvridin-4-vlmethvl)amino1-A^-[4-ierf-butyl-3-(l,2.3.6-tetrahvdropvridin-4-vnphenvl]f3-pvridvl)carboxamide The titled compound was prepared from 4-tert-butyl-3-(l-methyl-I,2,3,6-tetrahydropyridin-4-yl)aniline {Step D) by the method described in Example 25. MS: (ES+) 456.3 (M+H); (ES-) 454.4 (M-H). Calc'd for CsgHsiNsO - 455.59. N-(3,4-I)ichlorophenyl){6-[(2-morpholin-4-yIethyl)ammo]-2-[{4-pyridylmethyl)ainino](3-pyridyl)}carboxamide A mixture of N-(3,4-dichlorophenyl){6-chloro-2-[(4-pyridylmethyl)amino]{3-pyridyOjcarboxamide {18 mg, 0.044 mmol, made from 2,6-dichloronicotinic acid) and 2-morpho)in-4-y!elhy)amine {300 pE) was stirred at 80°C for 20 h. The reaction mixture was purified on silica gel chromatography to yield N-(3,4-dichlorophenyl){6-[{2-morpholin-4-ylethy0ammo]-2-[(4-pyrfdylmethyl)-amino](3-pyridyl)}carboxamJde. MS {ES+): 501 (M+H)^; (ES-): 499 (M-Hy. Calc'd for C24H26CI2N6O2 - 500.15. N-|4-(Morpholin-4-ylmethyl)phenyl|{2'|(4-pyridylmetbyl)ainiDol(3- py r idyl) (car boxamide Step A Preparation of 4-[(4-TiJtrophenvl)ineihv)1mQrpholine A mixture of nitrobenzyl bromide (648 mg, 3.0 mmol) and morpholine (522 mg, 6.0 mmol) in CH2Cl2was stirred for 5 h at RT. Filtration to remove the white solid, and the filtrate was concentrated to give 4-[(4-nitrophenyI)-methyI]morpholine as a solid, which was used in next step without further purification. Step B Preparation of 4-(morpholin-4-ylmethyl)Dhenvlamine A mixture of 4-[(4-nitropheny!)methylImorpholine (220 mg, I.O mmol, Step A), iron powder (279 mg, 5.0 mmol) and NH4CI (39 mg, 0.7 mmol) in EtOH (3 mL) and H2O (3 mL) was stirred for 4 h at 80°C. Filtration and concentration gave the crude 4-(morpholin-4-ylmethyl)-phenylamine, which was used in next step without further purification. Step C Preparation of N-[4-(morpholin-4-vlmethyl)phenvll{2-[(4-pyridylmethvl)amino](3-pvridyl>tcarboxamide The titled compound was prepared from 4-(morpholin-4-ylmethyOphenylamine (Step B) by the method described in Example 25. MS (ES+): 404 (M+H); (ES-): 402 (M-H). Calc'd. for C22H24N4O2 - 403.20. Step A Preparation of (tert-butoxv)-N-r2-f4-nitrophenvnethvl1carboxamide A mixture of 2-(4-nitrophenyl)cthylam'me (}.0i g, 5.0 mmol), and di-tert-butyl dicarbonate (1,09 g, 5.0 mmol) in CH2CI2 (20 mL) and IN NaOH (20 mL) was stirred for 20 h at RT. The mixture was extracted with CH2CI2, washed with brine, and dried with MgS04. Filtration and concentration yielded (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]carboxamide, which was used in next step without further purification. Step B Preparation of N-[2-(4-aminophenvlkthvl|(tert-butoxv)carboxamide A mixture of (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]-carboxamide (570 mg, 2.15 mmol, Step A), iron powder (602 mg, 10.75 mmol) and NH4CI (S2 mg, 1.5 mmol) in EtOH (6 mL) and H2O (6 ml) was stirred for 4 h at 80°C. Filtration and concentration gave the crude compound, which was used in next step without further purification. Step C Preparation of N-|^4-(mo^pholi^-4-vlme^hv^phenvl]t2-^(4-pvrid vlmethvl)amino1(3 -pvridy 1) karboxamide The titled compound was prepared from N-[2-(4-aminophenyl)ethyl](lert-butoxy)carboxamide (Step B) by the method described in Example 25. MS (ES+): 448 (M+H); (ES-): 446 (M-H). Calc'd. for C2SH29NSO3 - 447.23. N-(4-(2-Aminoethyl)pf»enyll{2-{(4-pyridylmethyl)amiDoI(3-pyridyl)}carboxaiDide To the solution of N-(4-{2-[(tert-butoxy)carbonylamino]-ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (96 mg, 0.22 mmol. Example 71) in CH2CI2 (3 mL) was added TFA (3 mL). The mixture was stirred for 3 h at RT. The reaction mixture was concentrated and dried in vacuo to yield N-[4-(2-aminoethyI)phenyl]{2-[(4-pyridy(melhy!)-amino](3-pyridyl)}carboxamide. MS {ES+): 348 (M+H); (ES-): 346 (M-H). Calc'd. for C2UH21N5O - 347.17. The following compounds (Example a-m) were synthesized by the method described above, unless specifically described. a) N-[3-(azetidin-3->'lmethoxy)-5-tr(fJuoromethyl-phenyl]-2-[(pyridin-4-ylinethyl)- amino]-nicotinamide. b) 24(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-N-[3,3-dimethyl-l-{piperidin-4- y)methyl)-2,3-d!hydro-lH-indo]-6-yl]-n!cotinamide. M+H 512.3; Calc'd 511.7. c) N-[3-(piperazine-l-carbonyl)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmeihyl)- amino]-nicotinamide. M+H 485.3. d) N-[3-(pipera2Jne-l-meth)'l)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4-ylmethy])- amino]-nicotinamide. M+H 521,4. c) N-[3-(piperazine-l-methyl)-5-trifluoromethyl-phenyl]-2-[{pyridin-4-ylmethyl)- aminoj-nicotinamide. M+H 471.2; Calc'd 470, d) N-[l-{2-Amino-acetyl)-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl]-2-[(2-methoxy- pyridin-4-yImelhyl)-amino]nicotinamide. M+H 461.1. e) N-[l-(2-Amino-acetyl)-3,3-dimethyl-2,3-dihydro-lH-indol-6-yl]-2-[(pyridin-4- ylmethyl)-amino]nicotinamide. M+H 431.4. f) (S) N-[3-(pyrrol idin-2-y l-methoxy)-4-peniafluoroethyl-phenyl]-2-[(pyridin-4- ylraethyl)-amino]-nicotinamide. M+H 522.6; Calc'd 521.5. g) (R) N-[3-(pyrrolidin-2-yl-methoxy)-4-trifluoromethyl-phenyl]-2-[(pyridin-4- ylmethyO-amino]-nicotinamtde. M+H 472.6; Calc'd 471.5. h) (R) N-[3-(pyrrolidin-2-yl-meihoxy)-4-pentafluoroethyl-phenyl]-2-[(pyridin-4- ylmethyO-amino]-nicotinamide. M+H 522.3; Calc'd 521.5. i) (S) N-[3-(pyrro!idin-2-y)-melhoxy}-5-trifluoromethyl-phenyl]-2-[(pyridin-4-yl- methyl)-amino]-nicotinamide. M+H 472; Calc'd 471.5. j) (S) N-[3-{4-piperdinyloxy)-5-trifluoromethyl-phenyl]-2-[(pyridin-4-ylmethyl)- aminoj-nicolinamide. M+H 472; Calc'd 471,5. k) 2-[(2-Methoxy-pyridin-4-yl-methyl)-amino]-N-[3-(piperidin-4-yloxy)-5- trifluoromethyl-phenyl]-nicotinamide. I) N-|4-tert-Butyl-3-[2-(piperidin-4-yl)-methoxy]-phenyl}-2-[(pyridin-4-ylmethyl)- amino]-nicotinamide. M+H 474. N-{3-|(4-Methylpiperazinyl)sulfonyl]phcnyl}{2-|(4-pyridylmcthyl)amino](3- pyridyl)}carboxamide Step A Preparation of 3-[(4-methvlpiperazinvn sulfonvl]-l-nitrobenzene A mixture of 3-nitrobezenesulfonyl chloride (664 mg, 3.0 mmol) and methylpiperazine (600 mg, 6.0 mmoj) in EtOH was stirred for 2 h at RT. The reaction was concentrated and triturated in Et20 to yield a yellowisli solid, 3-[{4-methylpiperazinyl) suIfonyl]-l-nitrobenzene, and was used in next step without further purification. Step B Preparation of S-fM-methylpiperazinvOsulfonyllphenylamine 3-[(4-Methylpiperazinyl)sulfonyl]phenylamine was analogously synthesized from 3-[(4-methylpiperaziny|) sulfonyl]-l-nitrobenzene (Step A) by the method described in Example 74, which was used in next step without further purification. MS (ES+): 256 (M+H). Calc'd, for CnHnNjOaS - 255.10. Step C Preparation of N-[4-(morpholin-4-vlmethvnphenvl"[{2-|(4-PYridvlmethvnamino](3-pvridyl)}carboxamide The titled compound was prepared from 3-[(4- methylpiperazinyl)sulfonyl]phenylamine (Step B) by the method described in Example 25. MS (ES+): 467 (M+H); (ES-): 465 (M-H). Caic'd. for C23H26N6O3S - 466.i 8. Example 78 2-[(Pyri(]in-4-ylniethyl)-amino|-N-(3-trifluoromethyl-phenyl)-nicotinainide Step A: Preparation of (2-chloro(3-pvridvm-N-(3-trif1uoromethvlphenvncarboxamide 2-Chloropyridine-3-carbonyl chloride (18.02 g, 0.102 mol) in CH2CI2 (100 ml) was added dropwise (via an addition funnel) to a stirred solution of 3-(trifluorometiiyl)-aniline (15.00 g, 0.093 mol) and DIEA (24.39 ml, 0.14 mol) in CH2CI2 (500 ml) at 0°C. The mixture gradually was warmed to RT. The reaction continued for 18 h before washing several times with saturated NaHCOs aqueous solution and brine, respectively. The organic layer was dried over Na2S04 and evaporated. The resulting oil was purified over silica gel with EtOAc/hexane (2:1) as eluant to leave the amide as a white solid {26.08 g). MS: (ES+) 301 (M + 1)^; (ES-): 299 (M - l)", Calc'd for CuHsCIF^N.O: 300.03, Step B: Preparation of N-f3-trinuoromethvlphenyl phenvt}{2-f(4-pyridvlmethyl)amino)(3-pyridvl)tcarboxamide hydrochloride The amide (10.0 g 0.033 mol. Step A) and 4-aminomeIhylpyridine (lO.Si g, 0.10 mol) were combined and heated at 120°C for4h. After cooling to RT, the residue was dissolved in EtOAc and washed several times with saturated NaHCOs aqueous solution and brine, respectively. The organic layer was dried over Na2S04 and evaporated. The crude yellow oil was purified over silica gel with EtOAc as eluant to leave an amber oil (10.9 g). The free base was dissolved in MeOH (20 ml) and treated with a HCl ethereal solution (I.Oeq.). The solvent was evaporated lo leave the salt as a white solid. The HCl salt was dried in vacuo at 30°C for 24 h. MS: (ES+) 373 (M + 1 )^■ (ES-): 371 (M - 1)". Calc'd. for C,9H,sF3N40 - 372.12. The following compounds (E.\amp)es 83-138) were analogously synthesized by the method described in Example 82 unless specifically described. Detailed intermediate preparations are included. N.{2-|2-(Dimcthylamino)ethoxy]-5-(tert-butyl)phenyl}{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide Step A - Preparation of l2-f4-(tert-butvl)-2-nitrophenoxv]-ethvlMimethvlamine To a mixture of2-nitro-4-tert-butylphenol (2 g) and N,N-dimethylethanolamine (1.3 g) and PPhj (4 g) in THF (50 ml) was added DEAD (2.6 ml). The reaction was stirred at RT for ! h, diluted with EtOAc (50 ml) and washed with I N HCl twice. The aqueous layer was basified with NaHCOj, extracted with EtOAc twice and washed with H2O and brine. The organic layer was dried over Na2S04 and evaporated to give {2-[4-(terl-butyl)-2-nitrophenoxy]-ethyI}dimethylamine, was used in next step without further purification. Step B - Preparation of {2-[4-(tert-butvn-2-aminophenoxvt-ethvlVdimethvlamine {2-[4-(tert-Butyl)-2-nitrophenoxy]-ethyl} dimethylamine (Step A) was hydrogenated under H2 atmosphere to give {2-[4-(tert-butyl)-2-aminophenoxy]-ethyljdimelhylamine, and used in next step without further purification. Step C - Preparation of N-{2-[2-(dimethvlaminokthoxv]-5-(tert-butvl)phenvl}{2-f(4-pyridylmethyl)amino1f3-PYridvl)tcarboxamide The titled compound was prepared from {2-[4-(ten-butyl)-2-aminophenoxy]-ethy!} dimethylamine (Step B) by the method described in Example 82. MS (ES+): 448 (M+H); (ES-): 446 (M-H). Calc'd, for C26H33N5O2 - 447.26. Example 125 N-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmcthyl>amino](3-pyridyl)}carboxamide Step A - Preparation of l-[2-(tert-butvlphenvl1-4-methylpipera2ine A mixture of 2-tert-butylaniline (5.4 g) and N-methylbis{2-chlorocthyl)amme hydrochloride (7 g) and K2CO3 (5 g) in Nal (2 g) in diglyme (150 ml) was heated at I70'C for 8 h. The reaction was filtered and the filtrate was evaporated under high vacuum. The residue was mixed with EtOAc (200 ml) and H2O (200 ml) and extracted with EtOAc twice. The combined organic layer was washed with brine, dried over Na2S04 and evaporated to give crude t-[2-(tert-bulyiphenyl]-4-methyl-piperazine, which was used in next step without further purification. Step B - Preparation of l-[2-(tert-butvl)-5-aminophenv!1-4-methvlpiperazine The crude l-[2-(tert-butylphenyl]-4-methylpiperazine (260 mg. Step A) was stirred with H2SO4 (3 mi) at O^C and HNO3 (1.2 mi) was slowly added to the reaction. The reaction was warmed to RT, stirred for 30 min. and poured on ice and basified with K2CO3 slowly. The solution was extracted with EtOAc three times, washed with H2O, followed by brine, dried over Na2S04, and evaporated under reduced pressure. The residue was purified by column chromatography to give I-[2-(tert-buty[)-5-nitrophenyl]-4-methylpiperazine (260 mg), which was hydrogenated under H2 atmosphere to give l-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine. Step C - Preparation of N-H-(tert-Butvl)-3-(4-methvlpiperazinyl)phenyl){2-[(4- pvridvlmethvl)amino1(3-pvridvh}carboxamide N-|4-(4-Methylpiperazinyl)phenyll{2-|(4-pyridylmethyl)aminoj(3-py ridyl)} formam ide Step A - Preparation of 4-methvl-[-f4-nitrophenvI)piperazine l-Fluoro-4-nitrobenzene (3,0 g, 0.021 mol) and 1-methylpiperazine (6.98 ml, 0.63 mol) were combined and heated neat at 90°C for 48 h. Upon cooling to RT, the resulting brown oil solidified. The crude material was purified by re-crystallization from EtOAc/Hexane mixtures to leave the title compound as an orange solid (3.59 g>. MS: (ES+) 222 (M + 1)*; (ES-): 220 (M - l)". Calc'd for C11H15N3O2: 221.12. Step B - Preparation of 4-inethvl-l-{4-aminophenvnpiperazine 4-Methyl-l-(4-nitrophenyl)piperazine (2.0 g, 9 mmol. Step A) and 10% Pd/C (200 mg) were added to EtOH/MeOH (1:1) (50 ml) at RT. The reaction stirred under a H2 atmosphere (via balloon) overnight. The mixture was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to leave the desired material as light yellow oil. The material was used in subsequent reaction without purification. MS: (ES+) 192 (M + 1)^ (ES-): 190 (M - l)'. Calc'd for CuHnNs: 191.14. Step C Preparation of N-[4-f4-methylpiperazinvl)phenvl1{2-K4-pyridvlmethynamino1(3-pyridvl)}formamide The thled compound was prepared from 4-methyl-l-(4-aminophenyl)piperazine (Step B) by the method described in Example 82. MS (ES+): 403 (M+H); (ES-): 401 (M-H). Calc'd. for C23H26N6O - 402.22. Example 128 Step A - Preparation of l-(l-methyl(4-piperidvl'i)-6-nitroindoline 6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane, N-melhyl-4-piperidone (5 g) was added to the mixture, followed by 12 g NaBH(0Ac)3 and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. Saturated NaHCOa solution (200 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the oi^antc layer was extracted once with saturated NaHCOs solution and once with brine. The resulting organic layer was dried over MgSOj, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford an orange oil. MS: 262 (M+1). CalcU forC,4H)9N303-26l.32. Step B - Preparation of l-(l-methYl-4-piperidvnindoline-6-vlamine l-(l-Methyl(4-piperidyl))-6-nitroindoline (3 g, Step A) was dissolved in 100 mL MeOH, and the mixture was bubbled with N2 for !0 min. 10% Pd/C (200 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford a light yellow oil. MS: 232 (M+1). Calc'd.forCi4H2iN3-23L34. Step C - Preparation of N-[l-d-methYl(4-piperidvh)indolin-6-vl1{2-[(4- pyridvlmethvl1amino1(3-pyridvn)carboxamide The titled compound was prepared from l-(l-methyl-4-piperidyl)indoline-6-ylamine (Step B) by the method described in Example 82. MS: 443 (M+1). Calc'd. for C26H30N6O-442.56, MS: 457 (M+1). Calc'd. forC27H32N60-456.58. Example 130 N-[l-(2-Piperidylethyl)indolin-6-yl|{2-l(4-pyridylmethyl)amino](3-py ridyl)} car boxamide Step A - Preparation of 1 -f6-nitrQindolinvl)-2-piperidylethan-1 -one 6-Nitroindoline (2.5 g) was dissolved in 200 mL of CH2CI2, followed by DIEA (2.5 g). The mixture was cooled down to 0°C in ice bath. Chloroacety! chloride (1.7 g) in 20 mL CH2CI2 was added dropwise to the mixture over 10 min and the mixture was stirred at RT overnight. The mixture was extracted once with saturated NaHCOj solution and once with brine, the resulting organic layer was dried over MgSO^, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 3:2 HexaneiEtOAc to afford a yellow oil (1.4 g) which was added to piperidine (5 mL), followed by Nal (100 mg). The mixture was heated at 70°C overnight then concentrated in vacuo and extracted between EtOAc and saturated NaHCOa solution, the organic layer was washed with brine, the resulting organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 EtOAc:MeOH to afford a yellow oil. MS: 290 (M+1). Calc'd. for C,sHi9N303-289.33. Step B - Preparation of l-(2-piperidvlethvnindoline-6-vlamine l-(6-Nitroindolinyl)-2-piperidyleihan-l-one (1.6 g. Step A) was dissolved in 100 mL MeOH. the mixture was bubbled with Nj for 10 min. 10% Pd/C (200 mg) was added and the mixture was stirred under Hi overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford a yellow solid. 400 mg was dissolved in 20 mL anhydrous THF, 5 mL borane-THF (1 M) solution was added dropwise and ihe mixture was stirred al RT overnight. The mixture was quenched with MeOH, 100 mg NaOH added and heated at 70°C for 30 min. The resulting mixture was concentrated in vacuo and extracted between EtOAc and saturated NaHCOj solution, the organic layer was washed with brine, the resulting organic layer was dried over MgS04, filtered and concentrated in vacuo to afford a yellow oil. MS: 246 (M+1). Calc'd.forCi5H23N3-246.36. Step C - Preparation of N-[l-(2-piperidvlethvhindolin-6-vl1l2-[f4-pvridylmethvnamino1(3-pvridvnicarbQxamide The titled compound was prepared from l-(2-piperidylethyl)indoline-6-ylamine (Step B) by the method described in Example 82. MS: 457 (M+l). Calc'd. for C27H32N6O-456.58. Example 131 \-(33-Dimethyl-I-(I-methyI(piperid-4-yI)indo(in-6-ylI{2-[(4-pyridylinethyl)aiiiiDo|(3-pyridyl)}carboxamide Step A - Preparation of N-(2-broinn-5-nitrophenyl)acetamide 2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH2CI2, DIEA (6.6 g) was added to the mixture, followed by DMAP (100 mg). The mixture was cooled to 0°C in ice bath. Acetyl chloride (4 g in 50 mL CH2CI2) was added dropwise to the reaction mixture. After the mixture was stirred at RT over 3 h, extracted once with saturated NaHCO] solution and once with brine, the resuhing organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:! EtOAc:Hexane to 100% EtOAc to afford N-(2-bromo-5-nitrophenyl)acetamide as a while solid. MS: 258 (M-l). Calc'd. for C8H7BrN2O3-259.06. Step B - Preparation of N-f2-bromo-5-nitrophenv]i-N-(2-methv]prop-2-enyl)acelamide A suspension of 2 g NaH (95% powder) in anhydrous DMF (100 mL) was cooled to '78°C, N-(2-bromo-5-nitrophenyt)acetamide (7 g, Step A) in dry DMF (50 mL) was added to the mixture under N2 atmosphere. After the mixture was warmed to 0°C, 3-bromo-2-methylpropene (7.3 g in 20 dry DMF) was added to the mixture. The mixture was stirred at RT overnight. Next morning, the mixture was poured into a container of ice and extracted between saturated NaHCOs solution and EtOAc. The resulting organic layer was dried over MgSO^, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 7:2 hexane:EtOAc to afford the title compound as a yellow gum. MS: 314 (M+1). Calc'd. forCi2H,3BrN203-313.15. Step C - Preparation of l-(3.3-dimethvl-6-nitro-2.3-dihydro-indol-l-vl)ethanone N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide (4.5 g. Step B) was dissolved in anhydrous DMF (50 mL), tetraethyl-ammonium chloride (2.5 g), sodium formate (1.2 g), NaOAc (3 g) were added, and the resulting mixture was bubbled with N3 gas for 10 min. Pd(OAc)2 (350 mg) was added and the mixture was heated at 80°C under N2 atmosphere overnight. After the mixture was concentrated in vacuo, it was partitioned between saturated NaHCOj soiat'ion and EtOAc, the resulting organic layer was dried over MgS04, flhered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 Hexane:EtOAc to afford the title compound as a yellow gum. MS: 235 (M+l). Calc'd, for Ci:H|4N203-234.25. Step D - Preparation of 3.3-dimethvl-6-nitroindQlme l-(3,3-Dimethy!-6-nitro-2,3-dihydro-indol-l-yl)ethanone (1.8 g. Step C) was dissolved in EtOH (50 mL), 12N HCI (50 mL) was added and the resulting mixture was heated at 70°C overnight. After the mixture was concentrated in vacuo, it was partitioned between saturated NaHCOj solution and EtOAc, the resulting organic layer was dried over MgS04, filtered and concentrated in vacuo to afford a yellow solid. MS: 193 (M+l). Calc'd. forCioHi2N302-l92.21. Step E - Preparation of 3.3-dimethvl-l-(l-methvl-piperidin-4-vlV6-nitro-2.3-dihvdro-IH-indole 3,3-Dimethy!-6-nitroindo(ine (0.8 g) was dissolved in CHjCli (50 mL), N-meIhyl-4-piperidone (1 g) was added to the mixture, followed by 2.5 g NaBH(0Ac)3 and glacial AcOH (1 mL). The mixture was stirred at RT overnight. Saturated NaHCOs solution (50 ml) was added to the reaction mixture and stirred for i h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCOs solution and once with brine, the resulting organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 EtOAc:MeOH to afford the title compound as an orange oil. MS: 290 (M+l). Calc'd. for C16H23N3O2-289.37. Step F - Preparation of 3.3-dimethvl-l-(l-methvl(4-piperidvn)indoline-6-ylamine 3,3-Dimethyl-l-(l-melhyl-piperidin-4-yl)-6-nitro-2,3-dihydro-lH-indole (600 mg. Step E) was dissolved in MeOH (20 mL), the mixture was bubbled with Hi for 10 min. 10% Pd/C (100 mg) was added and the mixture was stirred under H2 overnight, The mixture was filtered through Celite® and concentrated in vacuo to afford the title compound as an oil. MS: 260 (M+I). Calc'd. for C16H25N3-259.39. Step G - Preparation of N-[33-dimethvl-l-(l-methyl(4-piperidvl))indolin-6-vlK2-f(4-pvrid vimeth vDaminolO'pyrid vl) f carboxamide The titled compound was prepared from 3,3-dimethyl-l-(l-methyl(4-piperidyl))indoline-6-ylamine (Step E) by the method described in Example 82. MS: 471 (M+l). Calc'd. forC2gHj.,N6O-470.61. N-(3,3-DimethylindoliD-6-yl){2-i(4-'pyridylmethyl)amino}(3-pyridyl)}carboxamide Step A - Preparation of l-acetvl-6-amino-3,3-dimethylindoliiie l-Acetyl-3,3-diinethyl-6-iiitromdoline (250 mg) was dissolved in MeOH (20 mL), the mixture was bubbled with H2 for 10 min. 10% Pd/C (50 mg) was added and the mixture was stirred under Hj overnight. The mixture was filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:CH2CI: to afford the title compound as a white crystalline material, MS: 205 (M+l). Calc'd, for C,2H(6N2O-204,27. Step B - Preparation ofN-(l-acetvl- 3.3-dimethvlindolin-6-vl){2-[(4-pyridv)methv))amino1(3-pvridv])}carboxamide The titled compound was prepared from l-acetyl-6-amino-3,3-dimethylindoline (Step A) by the method described in Example 82. Step C - Preparation of N-(3.3-dimethyli^dolin-6-vU{2-[(4-py^idvlmethvllamino1(3-pv^idv^lcarboxamide The titled compound was prepared from N-(l-acetyl- 3,3-dime(hylindoIin-6-yl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (Step B) by the deacylation method described in Example 993. MS: 374 (M+l). Calc'd. for C22H23N5O-373.45. N-I3-(l-Methyl-(4-pipcridyI))indol-5-yl|{2-l(4-pyridylmethyl)amino|(3-pyridyl)}carboxainide Step A - Preparation of 3-(l-methyl-l.2,3.6-tetrahydro-pyridin-4-vn-5-nitro-IH-indole 5-Nitroindole {2.6 g) was dissolved in anhydrous MeOH {100 ml), followed by N-methyl-4-piperidone {5 g) and NaOMe powder {5 g). The mixture was heated to reflux under N: overnight. The mixture was concentrated in vacuo. The crude was partitioned between saturated NaHCOs solution and EtOAc, the resulting organic layer was dried over MgS04, filtered and concentrated in vacuo to afford a yellow solid. This solid was washed with EtOAc (5 mL) and MeOH (2 ml) to afford the title compound as a bright yellow solid. MS: 258 {M+I). Calc'd. for Ci4H|sNj02-257.29. Step B - Preparation of 3-(l-methvl-4-piperidyl)indole-5-ylamine 3-(I-Methyl-I,2,3,6-telrahydro-pyridin-4-y()-5-nitro-!H-indole (2.7 g, Step A) was dissolved in MeOH (50 mL), the mixture was bubbled with H; for 10 min, 10% Pd/C (150 mg) was added and the mixture was stiired under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford 3-(i-methyl-4' piperidy])indole-5-ylamine as a yellow oil. MS: 230 (M+1). Calc'd. for C14H19N3-229.32. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabili2er(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations, Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl paJmilate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. AltemativeJy, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0,5 to 10% and particularly about 1.5% w/w. We claim: 1. A process for the preparation of Compound of formula 719

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