MX2008001172A - Benzimidazoles useful as inhibitors of protein kinases - Google Patents

Abstract

The present invention relates to compounds useful as inhibitors of Aurora, FLT-3, or PDKl protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the invention.

Description

BENZIMIDAZOLES USEFUL AS PROTEIN KINASE INHIBITORS TECHNICAL FIELD OF THE INVENTION This invention relates to compounds that are inhibitors of protein kinases, compositions containing such compounds, processes for obtaining such compounds, and methods of use. More particularly, the compounds are inhibitors of FLT-3, PDK1, and Aurora kinases and are useful for the treatment of diseases, such as cancer, that are alleviated by these kinase inhibitors.

BACKGROUND OF THE INVENTION Aurora proteins are a family of three highly related serine / threonine kinases (termed Aurora-A, -B and -C) that are essential for progression through the mitotic phase of the cell cycle. Specifically, Aurora-A plays a crucial role in the maturation and segregation of the centrosome, the formation of mitotic spindles and the faithful segregation of chromosomes. Aurora-B is a transient chromosomal protein that plays a central role in the regulation of the alignment of the chromosomes in the meta-phase plate, the spindle assembly checkpoint control points and for the correct completion of the cytokinesis Overexpression of Aurora-A, -B or -C have been observed in a range of human cancers including colorectal, ovarian, gastric and invasive duct adenocarcinomas. Currently a number of studies have shown that the depletion or inhibition of Aurora-A or -B in human cancer cell lines by siANR, neutralizing or dominant negative antibodies interrupts the progression through mitosis with accumulation of cells with 4N DNA, and in some cases this is followed by endoreduplication and cell death. FLT-3 plays an important role in the maintenance, growth, and development of hematopoietic and non-hematopoietic cells. [Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333 and Reilly, JT, British Journal of Hematology, 2002, 116, 744-757]. FLT-3 is a tyrosine kinase receptor which regulates the maintenance of early progenitor / stem cell collections as well as the development of mature myeloid and lymphoid cells [Lyman, S, Jacobsen, S, Blood, 1998, 91, 1101-1134 ] It has been shown that FLT-3 plays a role in a variety of malignant diseases of hematopoietic and non-hematopoietic cells. Mutations that induce ligand-independent activation of FLT-3 have been implicated in acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis, and stromal tumor. gastrointestinal (or its English term 'GIST'). In addition to activation mutations, the stimulation of ligand-dependent (autocrine or paracrine) wild-type FLT-3 can contribute to malignant phenotypes [Scheijen, B, Griffin JD, Oncogen, 2002, 21, 3314- 3333]. PDK1 (the 3-phosphoinositide-dependent kinase-1 protein) plays a key role in mediating several diverse cellular events by phosphorylation of key regulatory proteins such as cell survival, growth, proliferation and glucose regulation [(Lawlor, .A., and other, J. Cell Sci. 114, pages 2903-2910, 2001), (Lawlor, MA and other, EMBO J., 21, pages 3728-3738, 2002)]. Many human cancers including NSCL and prostate have elevated the function of PDK1 signaling pathway resulting from a number of different genetic events such as PTEN mutations or overexpression of certain key regulatory proteins [(Graff, JR, Expert Opin., Ter. Targets , 6, pages 103-113, 2002), (Brognard, J., et al., Cancer Res., 61, pages 3986-3997, 2001)]. Inhibition of PDK1 was demonstrated as a mechanism to treat cancer by transfection of a human cancer cell line negative PTEN (U87 G) with antisense oligonucleotides directed against PDK1. The resulting decrease in PDK1 protein levels leads to reduction in cell proliferation and survival (Flynn, P., and another, Curr. Biol., 10, pages 1439-1442, 2000). Protein kinases are proven and attractive targets for novel therapeutic agents to treat a range of human diseases, including the Gleevec and Tarceva examples. The Aurora, FLT-3, and PDK1 kinases are especially attractive because of their association with numerous human cancers and the roles they play in the proliferation of these cancer cells. Therefore, there is a need for compounds that inhibit protein kinases.

SUMMARY OF THE INVENTION This invention provides compounds and pharmaceutically acceptable compositions thereof which are useful as inhibitors of protein kinases, such as Aurora protein kinases (Aurora A, Aurora B, Aurora C), FLT-3 kinase, and PDK1 kinase. These compounds have the formula I: or a pharmaceutically acceptable salt thereof, wherein Q, R1, and R2 are as defined below. These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders or conditions, including, but not limited to, cancer and other proliferative disorders. The compounds provided by this invention are also useful for the study of kinases in pathological and biological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new inhibitors kinases. This invention also provides processes to obtain the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula I: I or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of R is H, aliphatic C_6, or C3-8 cycloaliphatic optionally substituted with 0-4 JR; each R2 is independently ZR, MR, (LR) -ZR or (XR) -MR; each JQ is independently ZQ, MQ, (LQ) -ZQ, or (XQ) -MQ; each LR, LQ, XR, and XQ is independently C1-6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -O-, -S-, -CO2-, -OC (O) -, -C (0) CO-, -C (O) -, -C (0) NR-, -C (= N-CN), -C (= N-OH), -NRCO-, -NRC (0) 0-, -S02NR-, -NRSO2-, -NRC (0 ) NR-, -OC (0) NR-, -NRS02NR-, -SO-, or -S02- wherein each LR is independently and optionally substituted with 0-2 JLR; each LQ is independently and optionally substituted with 0-2 JLQ; each XR is independently and optionally substituted with 0-2 JXR; each X is independently and optionally substituted with 0-2 JXQ; each ZR and ZQ is independently H; Ci_6alifático; a completely unsaturated, partially unsaturated, or saturated 3 to 8 membered monocyclic ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a completely unsaturated, or partially unsaturated, or saturated 8 to 12 member bicyclic ring system having from 0 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ZR is independently and optionally substituted with 0-4 JZR; each ZQ is independently and optionally substituted with 0-4 J2Q; each MR and MQ is independently halo, CN, CF3, NO2, O, SR, or N (R) 2; each JR is independently C1-6 aliphatic, Ci-6 haloalkyl, halo, OH, Ci-3alkoxy, N02, or CN; each J, J, J, J, J, and J is independently V, M, (Lv) -V, (LM) -M, haloalkyl C_6, halo, OH, Ci_3alkoxy, N02, or CN; each R is independently H, Ci-6 aliphatic, C6-i0f ~ (Ci_6 aliphatic) - (C6-10 aryl) C3-8 cycloaliphatic, -C (= 0) (Ci-6 aliphatic) -C (= 0) (C3_8 cycloaliphatic), or -C (= 0) 0 (Ci-e aliphatic); wherein each R is independently and optionally substituted with 0-2 J; each Lv and LM is independently Ci-6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -0-, -S-, -C02-, -0C (0) -, -C (0) C0-, -C (O) -, -C (0) NR-, -C (= N-CN), -C (= N-0H), -NRC0-, -NRC (0) 0-, -S02NR-, -NRS02- , -NRC (0) NR-, -0C (0) NR-, -NRS02NR-, -SO-, or -S02-; wherein each Lv is independently and optionally substituted with 0-2 JLV; each LM is independently and optionally substituted with 0-2 JLM; each V is independently H; aliphatic Ci-β; a fully unsaturated, or partially unsaturated or saturated, 3 to 8 membered monocyclic ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a fully unsaturated, or partially unsaturated or saturated bicyclic ring system of 8 to 12 members having from 0 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each V is independently and optionally substituted with 0-2 Jv; each J, JLV, J1", and Jv is independently R ', C3-6 cycloalkyl, Ci-6 haloalkyl, halo, N02, CN, OH, 0', SH, SR ', NH2, NHR', N (R ') ) 2, COH, COR ', CONH2, CONHR', CON (R ') 2, NHCOR', NR'COR ', NHCONH2 (NHCONHR', NHCON (R ') 2, NR' CONH2, NR 'CONHR', NR 'CON (R') 2, S02NH2, S02NHR ', S02N (R') 2, NHS02R ', or NR' S02R ', R' is unsubstituted C1-6 aliphatic, or two R 'groups, together with the which are bound, form a partially unsaturated or saturated monocyclic ring of 3 to 8 unsubstituted members having from 0 to 1 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each M is independently halo, CN, CF3, N02, OH , O (Ci-6alkyl), SH, S (Ci_6alkyl), NH2, NH (Ci_6alkyl), or N (Ci-6alkyl) 2. An embodiment provides that when Q is in the position or 6 of the benzimidazole ring; when Q is and R 2 is H, F, Cl, CH3, CF3, OCH3, or OCH2CH3 at the 5 or 6 position of the benzimidazole ring, then JQ is not -O- (Ci-3aliphatic); when Q is then / \ -N O optionally substituted with methyl; when R1 and R2 are H, then Q is not when Q is H N jQ, then JQ is not Cl, NH2,, or NR "-Ar where Ar is an optionally substituted group selected from phenyl, piperonyl, or pyridyl, and R" is H or optionally substituted Ci-6aliphatic. The compounds of this invention include those described in general form herein, and are further illustrated by the classes, sub-classes and species described herein. As used herein, the following definitions will apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Manual of Chemistry and Physics, 75th Edition. Additionally, the general principles of organic chemistry are described in "Organic Chemistry", Tomas Sorrell, University Science Books, Sausalito: 1999, and "March 's Advanced Organic Chemistry", 5th. Edition, Ed .: Smit, MB and March, J., John Wiley & Sons, New York: 2001, the complete contents of which are incorporated herein by reference. As described herein, a range of specified atom numbers includes any integer included therein. For example, a group that has 1-4 atoms might have 1, 2, 3, or 4 atoms. As described herein, the numbering for the benzimidazole ring is as shown below. 4 3 As described herein, the compounds of the invention could optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, sub-classes and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, an optionally substituted group could present a substituent at each substitutable position in the group, and when more than one position in any given structure could be substituted with more than one substituent selected from a specified group, the substituent could be either the same or different in each position. The combinations of substituents encompassed by this invention are preferably those that result in the formation of chemically viable or stable compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow their production, detection, and preferably their recovery, purification, and use for one or more purposes. described here. In some embodiments, a stable compound or a chemically viable compound is one that is not substantially altered when kept at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least a week. The term "aliphatic" or "aliphatic group", as used herein, means a branched or straight chain (ie, unbranched) substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more unsaturation units that presents a single point of fixation to the rest of the molecule. Unless otherwise specified, aliphatic groups contain from 1 to 20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain from 1 to 8 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contain from 1 to 6 aliphatic carbon atoms, and in still other embodiments the aliphatic groups contain from 1 to 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched alkyl groups, substituted or unsubstituted, alkenyl or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl. The term "cycloaliphatic" (or "carbocycle" or "carbocyclyl" or "cycloalkyl") refers to a C3-C8 monocyclic hydrocarbon or a C8-C12 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, having a single point of attachment to the rest of the molecule, wherein any individual ring in said bicyclic ring system has from 3 to 7 members. Suitable aliphatic cyclogroups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl. In some embodiments, said cycloaliphatic group can be "bridged". A "bridged" ring consists of a ring containing an additional alkyl chain, wherein each terminal of said chain is linked to a ring member of the ring, providing that both terminals of the chain are not linked to the same ring member. Said alkyl chain may be optionally interrupted by a heteroatom selected from 0, N, and S. Examples of bridged aliphatic cyclogroups include, but are not limited to, bicyclo [3.3.2] decane, bicyclo [3.1.1] heptane, and bicyclo [3.2.2] nonane. The term "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the group "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic" have three to fourteen ring members in which one or more ring members are a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members. In some embodiments, said ring is bridged. Examples of bridged heterocycles include, but are not limited to, 7-aza-bicyclo [2.2.1] heptane and 3-aza-bicyclo [3.2.2] nonane. Suitable heterocycles include, but are not limited to, 3-lH-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, -imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzoditiano, and 1,3-dihydro-imidazol-2-one. The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon); the quaternized form of any basic nitrogen or; to substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)). The term "unsaturated," as used herein, means that a portion has one or more units of unsaturation. The term "alkoxy", or "thioalkyl", as used herein, refers to an alkyl group, as previously defined, attached to the carbon backbone through an oxygen atom ("alkoxy") or sulfur. "Ptioalkyl") The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.The term "halogen" means F, Cl , Br, or I. The term "aryl" used alone or as part of a larger portion as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems that exhibit a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains from 3 to 7 ring members.The term "aryl" could be used interchangeably with the term "aryl ring." The term "heteroaryl", used alone or co or part of a larger portion as in "heteroaralkyl" or "heteroaryloalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains from 3 to 7 ring members. The term "heteroaryl" could be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Suitable heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2 -oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl ( example, 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (for example, 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1,2-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (for example, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl ( example, 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). An aryl group (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroaryl alkoxy and the like) could contain one or more substituents and thus could be "optionally substituted". Unless otherwise defined above and here, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are generally selected from halogen; -R °; -0o; -MR; phenyl (Ph) optionally substituted with R °; -O (Ph) optionally substituted with R °; - (CH2) 1-2 (Ph), optionally substituted with R °; -CH = CH (Ph), optionally substituted with R °; a 5-6 membered heterocyclic or heterocyclic ring optionally substituted with R °; -N02; -CN; -N (R °) 2; -NR ° C (0) R °; -NR ° C (S) R °; -NR ° C (0) N (R °) 2; -NR ° C (S) N (R °) 2; -NR ° C02R °; -NR ° NR ° C (O) R °; -NR ° NR0C (0) N (R0) 2; -NR ° NRoC02Ro; -C (0) C (0) °; -C (O) CH2C (O) R °; -C02R °; -C (0) R °; -C (S) R °; -C (0) N (R °) 2; -C (S) N (R °) 2; -0C (O) N (R °) 2; -OC (0) R °; -C (0) N (0 °) R °; -C (N0R °) R °; -S (0) 2R °; -S (0) 3R °; -S02N (R °) 2; -S (0) R °; -NR ° S02N (R °) 2; -NR ° S02R °; -N (0 °) R °; -C (= NH) -N (R °) 2; -P (0) 2R °; -FOR 2; -OPO (R °) 2; or - (CH2) 0-2NHC (0) R °; wherein each independent occurrence of R ° is selected from hydrogen, optionally substituted Ci_6 aliphatic, a 5-6 membered unsaturated heteroaryl or heterocyclic ring, phenyl, -O (Ph), or -CH2 (Ph), or, in spite of the definition given above, two independent occurrences of R °, on the same substituent or on different substituents, taken together with the atom (s) to which each R ° group is bound, to form an optionally substituted monocyclic or bicyclic ring of 3 -12 members saturated, partially unsaturated, or completely unsaturated having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents in the aliphatic group of R ° are selected from NH2, NH (aliphatic Ci_4), N (aliphatic Ci-4) 2, halogen, aliphatic Ci-4, OH, O (aliphatic Ci-4), N02, CN, C02H, C02 (aliphatic Ci_4), 0 (aliphatic halo Ci-4), or aliphatic halo Ci-4, wherein each of the following aliphatic groups Ci-4 of R ° is unsubstituted. An aliphatic group or a non-aromatic heterocyclic ring could contain one or more substituents and thus could be "optionally substituted". Unless defined otherwise hereinbefore, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: = 0, = S, = NNHR *, = NN (R *) 2, = NNHC02 (alkyl), = NNHS02 (alkyl), or = NR *, where each R * is independently selected from hydrogen or an optionally substituted Ci_6 aliphatic group. Unless defined otherwise herein above, optional substituents on the nitrogen of a non-aromatic heterocyclic ring are generally selected from -R +, -N (R +) 2, -C (0) R +, -C02R +, -C (0) C (0) R +, -C (0) CH2C (0) R +, -S02R +, -S02N (R +) 2, -C (= S) N (R + 1) 2, -C (= NH) -N (R +) 2, or -NR + S02R +; wherein R + is hydrogen, an optionally substituted Ci-6 aliphatic, an optionally substituted phenyl, -0 (Ph) optionally substituted, -CH2 (Ph) optionally substituted, - (CH2) i-2 (Ph) optionally substituted; CH = CH (Ph) optionally substituted; or an unsubstituted heterocyclic or heterocyclic ring of 5 to 6 members having from one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, despite the definition given above, two independent occurrences of R +, in the same substituent or in different substituents, taken together with the atom (s) to which each R + group is bound, form a monocyclic or bicyclic optionally substituted 3 to 12 membered saturated, partially unsaturated or fully unsaturated ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R + are selected from -NH2, NH (aliphatic C1-4), -N (aliphatic Ci-.4) 2, halogen, aliphatic Ci_4, -OH, -0 (aliphatic Ci_4), -N02, -CN, -C02H, -C02 (aliphatic Ci-4), -0 (aliphatic halo C1-4), or halo (C1-4 aliphatic), wherein each of the following aliphatic groups C1 -4 of R + are unsubstituted. The term "alkyloid chain" refers to a straight or branched carbon chain that could be completely saturated or have one or more units of unsaturation and has two attachment points to the rest of the molecule. The term "protecting group", as used herein, refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In certain embodiments, a protecting group has one or more, preferably all, of the following characteristics: a) it reacts selectively in good yields to provide a protected substrate that is stable to the reactions that occur in one or more of the other reactive sites; and b) is selectively removable in good yields by reagents that do not attack the regenerated functional group. Exemplary protective groups are detailed in Greeno, T.W., uts, P. G in "Protective Groups in Organic Synthesis" (Protective Groups in Organic Synthesis), Third Edition, John iley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference. The term "nitrogen protecting group", as used herein, refers to an agent used to temporarily block one or more of the desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protective groups are also detailed in Chapter 7 of the work of Greeno, TW, Wuts, P. G called "Protective Groups in Organic Synthesis" (Protective Groups). in Organic Synthesis), Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference. As detailed above, in some embodiments, two independent occurrences of R ° (or R +, R, R 'or any other variable defined similarly here), are taken in conjunction with the atom (s) to which they are ligated to form a completely unsaturated or partially unsaturated or saturated monocyclic or bicyclic ring optionally substituted from 3 to 12 members, having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Exemplary rings that are formed when two independent occurrences of R ° (or R +, R, R 'or any other variable similarly defined here), are taken in conjunction with the atom (s) to which each variable is linked include, but are not limited to the following: a) two independent occurrences of R ° (or R +, R, R 'or any other variable defined similarly here) that are linked to the same atom and are taken together with this atom to form a ring, for example, N (R °) 2, where both occurrences of R ° are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R ° (or R +, R, R 'or any other variable defined similarly here) that are linked to different atoms and are taken together with both of said atoms to form a ring, for example where the phenyl group is substituted with two occurrences of OR ° , these two occurrences of R ° are taken in conjunction with the oxygen atoms to which they are bound to form a fused 6-membered ring containing: It is appreciated that a variety of other rings can be formed when two independent occurrences of R ° (or R +, R, R 'or any other variable similarly defined here) are taken in conjunction with the atom (s) to which each variable it is linked and that the examples detailed above can not be interpreted as limiting the scope of the invention. In some embodiments, an alkyl or aliphatic chain may be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain is optionally replaced with said other atom or group. Examples of such atoms or groups include, but are not limited to, -NR-, -O-, -S-, -CO2-, -OC (O) -, -C (0) CO-, -C (O) -, -C (0) NR-, -C (= N-CN), -NRCO-, -NRC (0) 0-, -SO2NR-, -NRSO2-, -NRC (0) NR-, -OC ( 0) NR-, -NRS02NR-, -SO-, or -SO2-, where R is defined herein. Unless otherwise specified, optional replacements form a chemically stable compound. Optional interruptions can occur both within the chain at either end of the chain; that is, both at the fixation point and / or at the terminal end. Two optional replacements may also be adjacent to each other within a chain as they result in a chemically stable compound. Unless otherwise specified, if the interruption or replacement occurs at the terminal end, the replacement atom is linked to an H at the terminal end. For example, if -CH2CH2CH3 was optionally interrupted with -0-, the resulting compound could be -OCH2CH3, -CH2OCH3, or -CH2CH2OH. Unless otherwise specified, the structures described herein are understood to also include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers (Z) and (E), and conformational isomers (Z) and (E). Therefore, mixtures of the unique stereochemical, as well as enantiomeric, diastereomeric, and geometric (or conformational) isomers of the present compounds are also within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the present invention. Unless otherwise specified, a substituent may freely rotate around any rotatable bond. For example, a substituent drawn as it also represents Additionally, unless otherwise specified, the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the compounds present in the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon with a carbon enriched 13C- or 14C- are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. The following abbreviations are used: DBU is diazabicycloundecane DC is dichloromethane DIPEA is diisopropylmethylamine DMSO is dimethyl sulfoxide DMF is dimethylformamide EtOAc is ethyl acetate HPLC is high performance liquid chromatography i-PrOH is isopropyl alcohol MeCN is acetonitrile TEA is Triethyloamine TFA is trifluoroacetic acid TP is 2, 2, 6, 6, tetramethylpiperidine Rt is retention time LCMS is liquid chromatography mass spectrometry XH NMR is nuclear magnetic resonance According to one embodiment of the invention, R1 is H. In another embodiment, Q is In some embodiments, Q is In some embodiments, Q is In other embodiments, Q is And in yet other realizations, Q is In some embodiments, JQ is (LQ) -ZQ or (XQ) -MQ. In some embodiments of this invention, Q is mono-substituted with JQ as illustrated in formula II I In some embodiments, JQ is (LQ) -ZQ. In certain embodiments, LQ alkyl Ci-6 optionally interrupted with up to 2 occurrences of -NR-, -O-, -S-, -C (O) -, -C (0) NR-, -NRCO-, -S02NR- , or -NRS02-. In other embodiments, LQ is Ci-6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -O-, or -S-. In some embodiments, LQ is Ci-6 alkyl optionally interrupted with up to an occurrence of -NR-. In certain embodiments, the occurrence of -NR- is directly linked to the Q ring.

In some embodiments, LQ is -NH-, -NR-, -NH (Ci_5 alkyl) -, or -NR (C 1-5 alkyl) -; where R is alkyl C1-6. In some embodiments of this invention, each JLQ is independently halo, C 1-6 aliphatic, or C 1-6 haloalkyl. In another embodiment of this invention, ZQ is selected from H or an optionally substituted group selected from C 1-6 aliphatic, C 3-10 cycloaliphatic phenyl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl. In some embodiments, ZQ is H or optionally substituted Ci_6 aliphatic. In other embodiments, ZQ is optionally substituted phenyl. And in still other embodiments, ZQ is a heterocyclyl having from 5 to 8 members containing up to 2 heteroatoms selected from the group consisting of 0, N, and S. In some embodiments, ZQ is a heterocyclyl having from 5 to 8 members containing up to 2 nitrogen atoms. In some embodiments, said heterocyclyl is piperidine, piperazine, homopiperidine, or homopiperazine. In some embodiments, said heterocyclyl is piperidine or piperazine. In another embodiment of this invention, JQ is (XQ) -MQ.

In some embodiments, XQ is Ci_6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -0-, -S-, -C (0) -, -C (0) NR-, -NRCO-, -S02NR-, or -NRS02-. In some embodiments, XQ is Ci-6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -0-, or -S-. In other embodiments, XQ is Ci-6 alkyl optionally interrupted with up to 1 occurrence of -NR-. And in yet other embodiments, the occurrence of -NR- is directly linked to the Q-ring. In some embodiments of this invention, each JXQ is independently halo, Ci-6 aliphatic, or Ci-6 haloalkyl. In certain embodiments, MQ is 0 or N (R) 2. In other embodiments, Q is NH2. In some embodiments, JQ is ZQ or MQ. In some embodiments, JQ is ZQ. In other embodiments, JQ is MQ. In some embodiments, JQ is an optionally substituted group selected from N (R) 2, -NR- (Ci-3alkyl) -N (R) 2, or -NR- (having from 5 to 8 heterocyclyl members). In one embodiment of this invention, JQ is NH2, -NHCH2CH2NH2, -NHCH (JXQ) CH2NH2, In some embodiments, JQ is -NHCH (JXQ) CH2NH2.

In some embodiments, J Q is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In another embodiment, R2 is selected from ZR or MR. In certain embodiments, ZR is H or an optionally substituted group selected from Ci-6 aliphatic, C3-6 cycloaliphatic, and C3.6 heterocyclyl. In some embodiments, ZR is H or optionally substituted C1-6 aliphatic. In some embodiments, ZR is an optionally substituted group selected from C 1-6 aliphatic, C 3-6 cycloaliphatic, and C 3-6 heterocyclyl. In some embodiments, MR is halo, CN, CF3, N02, 0, or N (R) 2 wherein R is H or C1-3 alkyl. An embodiment of this invention can be represented by Formula Il-a: IL-a Another embodiment of this invention can be represented by Formula III: III. Another embodiment of this invention can be represented by the Formula Ill-a: Ill-a. In some embodiments of this invention, at least one R2 is not H. In some embodiments, neither R2 is H. In some embodiments, each R2 is independently ZR or R. In some embodiments, both R2 groups are ZR or MR. In some embodiments, both groups R2 are ZR. In other embodiments, R2 is Ci_3 alkyl. In some embodiments, R2 is methyl. In some embodiments, ZR is Ci-6 aliphatic; a fully unsaturated, or partially unsaturated or saturated, 3 to 8 membered monocyclic ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a fully unsaturated, or partially unsaturated or saturated bicyclic ring system of 8 to 12 members having from 0 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ZR is aliphatic Cl-6.

In some embodiments, the variables are as described and illustrated in the compounds of Table 1. The representative compounds of this invention are expressed below in Table 1.

Table 1: Examples of Compounds of Formula I - 3. 4 - - 36 - 58 The compounds of this invention could be prepared in general by methods known to those skilled in the art for analogous compounds and as illustrated by the schemes added below.

Scheme I 1 2 Scheme I represents a method for obtaining the compounds wherein Q is 2,4-pyrimidine. NHR 'represents groups JQ where JQ is linked to pyrimidine via a nitrogen atom.

Scheme I ' 1 2 Scheme I 'represents a method for obtaining compounds where Q is 2, -pyrimidine. NH-JJ represents JQ groups in which JQ is linked to pyrimidine via a nitrogen atom.

Scheme I-a I The I-a scheme represents a method for obtaining compounds where R1, R2, and JQ are as defined here. Examples of suitable bases that may be used in Scheme I-a include, but are not limited to, DIPEA, TEA, DBU, and TMP. Examples of suitable solvents that may be used in Scheme I-a include, but are not limited to, DMF, i-PrOH, n-butanol, t-butanol, acetonitrile, TF, and dioxane.

Scheme I-b 1 Scheme I-b represents a method for obtaining compounds wherein R1 / R2 and JQ are as defined herein; and -B (0RX) 2 represents boronic esters or acids known to those skilled in the art. As would be known to those skilled in the art, boronic acids and esters can be coupled to a nitrogen atom of a benzimidazole via a variety of known conditions. Typically, conditions include, but are not limited to, a catalyst, a base, and a ligand in a suitable solvent. Examples of suitable catalysts include, but are not limited to, Pd (0Ac) 2and Pd2 (dba) 3. Examples of suitable solvents include, but are not limited to, toluene, xylene, and dioxane. Examples of suitable bases include, but are not limited to, sodium tert-butoxide, potassium tert-butoxide, and CS2CO3. Examples of suitable ligands include, but are not limited to, BINAP, DPPF, (o-tol) 3P, and (±) PPF-O e.

Scheme II Reduction conditions Scheme II represents a method for obtaining compounds wherein R2 is aryl or heteroaryl. One embodiment provides a process for preparing a compound of formula I: NH (R2) < My wherein R1, R2, and JQ are as defined herein; and the ring Q is that it comprises causing the reaction of a compound of formula wherein R1 and R2 are as defined herein; with a compound of formula b: b; where in ring Q is and JQ is as defined here; under suitable coupling conditions of boronic acid. Another embodiment provides a process for preparing a compound of formula I: 1 wherein R1, R2, and JQ are as defined herein; and in Q ring is which comprises causing the reaction of a compound of formul wherein R1 and R2 are as defined herein with a compound of formula c: c; where JQ is as defined here; and the Q ring is Under suitable conditions of displacement.

In some embodiments, halo in the formula c is chloro. Another embodiment provides a process for preparing a compound of formula I: I where R2, R2, ring Q, and JQ are as defined herein; comprising the formation of a ring in compound of formula 7: wherein R2 and the Q ring are as defined herein; with CN-Br under suitable ring formation conditions. Examples of ring-forming conditions include, but are not limited to, stirring in MeOH at RT for 30h.

Another embodiment provides a process for preparing a compound of formula 7 comprising reducing a compound of formula 6; wherein R2 and the Q ring are as defined herein; under reducing conditions known to those skilled in the art to form a compound of formula 7. Examples of reducing conditions include, but are not limited to, SnCl 2 / EtOH, Fe / AcOH, En / HCl, and Pd / C. Another embodiment provides a process for preparing a compound of formula 6 which comprises causing the reaction of a compound of formula 5; where R2 is as defined here; with, where the Q ring is as defined here; under suitable displacement conditions to form a compound of formula 6. Suitable displacement conditions include, but are not limited to, a base and a solvent. Examples of suitable bases include, but are not limited to, CS2CO3 and K2CO3. Suitable solvents include, but are not limited to, DMF and EtOH. Another embodiment provides a process for preparing a compound of formula 5 comprising deprotecting a compound of formula 4; Under suitable deprotection conditions known to those skilled in the art, to form a compound of formula 5. Examples of suitable deprotection conditions include, but are not limited to, the use of an acid (such as HC1 or H2SO4) in a solvent suitable (such as MeOH, EtOH). Another embodiment provides a process for preparing a compound of formula 4 which comprises causing the reaction of a compound of formula 3: 3 with H2 -C (CH3) 3 under suitable displacement conditions to form a compound of formula 4. Suitable conditions of displacement include, but are not limited to, a suitable base, such as DIPEA, TEA, DBU, or TP, in a suitable solvent, such as DMF, dioxane, or TF. Another embodiment provides a process for preparing a compound of formula 3 comprising coupling Br N02 with R2-B (ORx) 2, wherein R2 is as defined herein and -B (OR) 2 represents acids or boronic esters known to those skilled in the art; suffers suitable Suzuki coupling conditions (acid / boronic ester) known to those skilled in the art, to form a compound of formula 3. Suitable Suzuki coupling conditions typically involve the use of a catalyst, a base, and a boronic acid or ester in a suitable solvent. Examples of suitable catalysts include, but are not limited to, Pd (PPh3) 2C12, Pd (PPh3) 4, and PdCl2 (dppf). Suitable bases include, but are not limited to, K2C03 and Na2C03. Suitable solvents include, but are not limited to, tetrahydrofuran, dioxane, toluene, and ethanol. Another embodiment provides a process for preparing a compound of formula 1: which comprises causing the reaction of a compound of formula wherein R1 and R2 are as defined herein; N ^ N with Cl Cl under suitable conditions of displacement to form a compound of formula 1. Suitable conditions of displacement include, but are not limited to, a suitable base, such as DIPEA, TEA, DBU, or TMP, in a suitable solvent , such as DMF, dioxane, or TF. Another embodiment provides a process for preparing a compound of formula 2: 2 comprising heating the compound of formula 1 with N¾-JJ (a group JQ containing a reactive amino group), under suitable conditions of displacement, to form the compound of formula 2. Suitable conditions of displacement include, but are not limited to , heating a suitable base, such as DIPEA, TEA, DBU, or TMP, in a suitable solvent, such as DMF, isopropanol, dioxane, or TF. One aspect of this invention relates to a method for the treatment of a disease state in patients that is alleviated by treatment with a protein kinase inhibitor, this method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The method is particularly useful for the treatment of a disease state that is alleviated by the use of an inhibitor of an Aurora kinase (Aurora A, Aurora B, Aurora C), FLT-3, or PDKl. The activity of the compounds as inhibitors of protein kinases could be tested in vitro, in vivo or in a cell line. In vitro assays include assays to determine the inhibition of either the kinase activity or the ATPase activity of the kinase activity. Alternative in vitro assays quantify the ability of the inhibitor to bind to the protein kinase and could be measured either by radiolabel of the pre-binding inhibitor, by isolating the inhibitor / kinase complex and determining the radiolabel bound amount, or by means of carrying performed a competition experiment in which the new inhibitors are incubated with the kinase bound to the known radioligands. Another aspect of this invention is directed to a method for the treatment of cancer to a subject in need thereof, comprising the sequential administration or co-administration of a compound of this invention or a pharmaceutically acceptable salt thereof, and an anti-cancer agent. In some embodiments, said anti-cancer agent is selected from camptothecin, doxorubicin, idarubicin, Cisplatin, taxol, taxotera, vincristine, tarceva, the MEK inhibitor, U0126, a KSP inhibitor, or vorinostat. Inhibitors of protein kinases or pharmaceutical salts thereof could be formulated in pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an effective amount of the protein inhibitor effective to treat or prevent a condition mediated by Aurora, FLT-3, or PDK1 and a pharmaceutically acceptable carrier, are another embodiment of the present invention. The term "protein kinase mediated condition", as used herein, means any disease or other deleterious condition in which a protein kinase is known to play a role. Such conditions include, without limitation, autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergy and asthma. The term "cancer" includes, but is not limited to, the following cancers: Oral epidermal: oral cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous or squamous cell, undifferentiated small cells, undifferentiated large cells, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatoma hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors) , Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, colon adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinary tract: kidney (adenocarcinoma, Wilm tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma) , embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages Bones: osteogenic sarcoma (osteosarcoma), fibrosarcoma, fibrous malignant histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, cervical pre-tumor dysplasia), ovaries (ovarian carcinoma [serum cystadenocarcinoma, mucosal cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli cell tumors -Leydig, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma) ), breast, hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell; lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, s Karposi's arcoma, keratoacanthoma, atypical moles, lipoma, angioma, dermatofibroma, keloids, psoriasis, thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B , medullary familial thyroid cancer, pheochromocytoma, paraganglioma; and Adrenal glands: neuroblastoma. Thus, the term "cancer cell" as provided or used herein, includes a cell afflicted by any one of the conditions identified above. In some embodiments, the cancer is selected from colorectal, thyroid, or breast cancer. The term "Aurora-mediated condition" or "Aurora-mediated disease" as used herein means any disease or other deleterious condition in which Aurora (Aurora A, Aurora B, and Aurora C) is known to play a role. Conditions of this type include, without limitation, cancers such as colorectal, thyroid, and breast cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia (or its acronym in English 1 CML 1), chronic myelomonocytic leukemia, hypereosinophilic syndrome, chronic myelomonocytic leukemia, and systemic mast cell disease. The term "FLT-3 mediated disease" or "FLT-3 mediated condition," as used herein, means any disease or other deleterious condition in which a FLT-3 family kinase is known to play a role. Conditions of this type include, without limitation, haematopoietic disorders, in particular, acute myelogenous leukemia (or its acronym in English 'A L'), chronic myelogenous leukemia (or its acronym in English 'CML'), acute promyelocytic leukemia (or its acronym in English APL), and acute lymphocytic leukemia (or its acronym in English 'ALL'). In addition to the compounds of this invention, the pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may be employed in compositions for treating or preventing the disorders identified above. A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, once administered to the container, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite in its inhibitory activity or a residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, by allowing a compound that can be administered orally to be more rapidly absorbed into the blood) or which it improves the release of the original compound into a biological compartment (for example, the brain or the lymphatic system) related to the original or mother species.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters. This invention also includes pharmaceutically acceptable salts of the compounds of this invention. The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable organic and inorganic acids and bases. Examples of suitable acid salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camforate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate , glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate , pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, although not in themselves pharmaceutically acceptable, could be used in the preparation of the salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include, but are not limited to, alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium, and N + (alkyl 1-4) salts 4. This invention also comprises the quaternization of any basic nitrogen-containing group of the compounds described herein. Water or oil soluble or dispersible products could be obtained by such quaternization. Pharmaceutically acceptable carriers could be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable oil acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, trisilicate of magnesium, polyvinyl pyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, polyethylene glycol and wool grease. The compositions of the present invention could be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted receptacle. The term "parenteral" as used herein includes subcutaneous injection, infusion, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial techniques.

Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable forms of the compositions of this invention could be aqueous or oleaginous suspensions. These suspensions could be formulated according to techniques known in the art using suitable dispersing or humifying agents and suspending agents. The sterile injectable preparation could also be a sterile injectable solution or suspension in an acceptable parenteral non-toxic diluent or solvent, for example as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that could be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil mixture could be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, such as pharmaceutically acceptable natural oils, such as olive or castor oil, especially in their polyoxyethylated versions. These solutions or oily solutions may also contain a long chain alcohol dispersant or diluent, such as carboxymethyl cellulose dispersing agents or the like which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as T eens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of solid, liquid, pharmaceutically acceptable dosage forms, may also be used for the purposes of the present invention. of another type. The pharmaceutical compositions of this invention could be administered orally, in a dosage form that is orally acceptable including, but not limited to, capsules, tablets, solutions and aqueous suspensions. In the case of tablets for oral use, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnesium stearate, are likewise typically added. For oral administration in capsule form, useful diluents include, but are not limited to, lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents could also be added. Alternatively, the pharmaceutical compositions of this invention could be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore melt in the patient's rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol. The pharmaceutical compositions of this invention could also be administered topically, especially when the subject of the treatment includes areas or organs that are readily accessible for topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be done in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches could also be used. For topical applications, the pharmaceutical compositions could be formulated into a suitable ointment containing the active compound dissolved or suspended in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

Alternatively, the pharmaceutical compositions can be formulated in a suitable cream or lotion containing the active compounds suspended or dissolved in one or more pharmaceutically acceptable carriers. Acceptable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octylododecanol, benzoyl alcohol, and water. For ophthalmic use, the pharmaceutical compositions could be formulated as micronized suspensions in isotonic solutions, sterile pH-adjusted salines, or, preferably, as isotonic saline solutions, pH-adjusted sterile salines, either with or without preservatives such as lauryl dimethyl chloride. benzyl ammonium Alternatively, for ophthalmic uses, the pharmaceutical compositions could be formulated as an ointment such as petrolatum. The pharmaceutical compositions of this invention could also be administered by means of an aerosol or nasal inhalation. Such compositions are prepared according to techniques that are well known in the art of pharmaceutical formulations and could be prepared as saline solutions, employing benzoyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional dispersing or solubilizing agents. The amount of kinase inhibitor that could be combined with the carrier materials to produce a single dose form will vary depending on the host to be treated, and the particular mode of administration. Preferably, the compositions should be formulated such that the dose that can be administered to a patient receiving these compositions is in a range of 0.01-100 mg / kg body weight / day of inhibitor. It should further be understood that the specific dose and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, range of excretion, combination of drugs, and the judgment of the doctor treating the patient, and the severity of the particular disease to be treated. The amount of inhibitor will also depend on the particular compound in the composition. An embodiment of this invention provides a method for treating or preventing an Aurora-mediated condition comprising the step of administering to a patient one of the compounds or pharmaceutical compositions described herein. The term "patient", as used herein, means an animal, preferably a human. Another embodiment provides a method for treating or preventing a condition mediated by an FLT-3 comprising the step of administering to a patient a compound of formula I or a composition comprising said compound. Yet another embodiment provides a method for treating or preventing a proliferative disorder or cancer comprising the step of administering to a patient a compound of formula I or a composition comprising said compound. Another aspect of the invention relates to the inhibition of Aurora or FLT-3 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound. One embodiment provides a method for inhibiting Aurora protein kinase activity in a patient comprising administering to a patient a compound of formula I or a composition comprising said compound. Another embodiment provides a method for inhibiting FLT-3 protein kinase activity in a patient comprising administering to a patient a compound of formula I or a composition comprising said compound. Yet another embodiment provides a method for inhibiting PDK1 protein kinase activity in a patient comprising administering to a patient a compound of formula I or a composition comprising said compound.

In some embodiments, these methods are used to treat or prevent a selected condition of cancers such as cancer of the breast, colon, prostate, skin, pancreas, brain, genitourinary tract, lymphatic system, stomach, larynx, and lung, including lung adenocarcinoma. and small cell lung cancer; stroke, diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease or disorder described here. According to another embodiment, the invention provides methods for treating or preventing a condition selected from a proliferative disorder or cancer comprising the step of administering to a patient one of the compounds or pharmaceutical compositions described herein. In some embodiments, the invention provides methods for treating or preventing cancer comprising the step of administering to a patient one of the compounds or pharmaceutical compositions described herein. In some embodiments, said cancer is selected from brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid. In other embodiments, said cancer is selected from melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or selected cancer of colon, breast, gastric, ovarian, cervical, lung, central nervous system (or its acronym in English CNS), renal, prostate, bladder, or pancreatic cancer. And in still other embodiments, said cancer is selected from pancreatic, prostate, or ovarian cancer. According to another embodiment, the invention provides methods for treating or preventing a condition mediated by FLT-3 comprising the step of administering to a patient a compound of formula I or a composition comprising said compound. Preferably, this method is used to treat or prevent a condition selected from hematopoietic disorders, in particular, acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic myelogenous leukemia (CML), and acute lymphocytic leukemia (ALL). Another aspect of the invention relates to inhibiting the activity of Aurora, FLT-3, or PDK1 in a patient, this method comprising administering to the patient a compound of formula I or a composition comprising said compound. Another aspect of the invention relates to the inhibition of the activity of Aurora, FLT-3, or PDK1 in a biological sample or a patient, this method comprising contacting said biological sample with a compound of formula I or a composition comprising said compound . The term "biological sample", as used herein, means an in vitro sample or an ex vivo sample, and includes, without limitation, the extracts or cell cultures thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts from it. The inhibition of the activity of Aurora, FLT-3, or PDK1 in a biological sample is useful for a variety of purposes that are known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays. Another embodiment provides a method for the treatment of cancer in a patient in need thereof comprising the step of interrupting mitosis of cancer cells for the inhibition of Aurora with a compound of formula I or a composition comprising said compound. Another embodiment provides a method for the treatment of cancer in a patient in need thereof comprising the step of interrupting mitosis of cancer cells for the inhibition of FLT-3 with a compound of formula I or a composition comprising said compound Depending on the particular diseases, or conditions to be treated or prevented, additional drugs, which are normally administered to treat or prevent this condition, could be administered in conjunction with the inhibitors of this invention. For example, chemotherapeutic agents or other anti-proliferative agents could be combined with the inhibitors of Aurora, FLT-3, or PDK1 of this invention to treat proliferative diseases. Those additional agents could be administered separately, as part of a multiple dose regimen, of the inhibitory compound or composition of Aurora, FLT-3, or PDK1. Alternatively, those agents could be part of a single dose form, mixed in conjunction with the Aurora inhibitor, FLT-3, or PDK1 in a single composition. In order that this invention be more fully understood, the following preparatory and test examples are described. These examples are for the purpose of illustrating the invention only, and in no way can be understood as a limitation of the invention.

Example 1 (1) 1- (6-chloropyrimidin-4-yl) -5,6-dimethyl-lH-benzo [d] imidazol-2-amine (1): A rounded bottom flask was charged with 4,6-dichloropyrimide (1.69g) , 11.3mmol), 2-amino-5,6-dimethylbenzimidazole (1.83g, 11.3mmol), DIPEA (1.92ml, 11.3mmol) and D F (50ml). The reaction mixture was vigorously stirred at 80 ° C for 6 days and then allowed to cool to room temperature. The volatile components of the reaction mixture were then removed in vacuo and the residue absorbed on silica and then purified by column chromatography using hexanes (40-60) / 0% to 100% EtOAc as eluent to obtain a yellow solid ( 1.09g, 35%). 1H NMR (CDC13): 2.35 (3H, s), 2.39 (3H, s), 6.43 (2H, brs), 7.25 (2H, m), 7.75 (1H, s), 8.93 (1H, s). LC / S 374.30 [M + H] 372.50 [M-H]. (2) Sal diTFA 1- (6- l (S) -l-amino-3-methyl-butan-2-ylamino) pyrimidin-4-yl) -5,6-dimethyl-lH-benzo [d] imidazole-2- amine, (Compound 2): A tube was loaded with l- (6-chloropyrimidin-4-yl) -5,6-dimethyl-l / 1-benzo [d] imidazol-2-amine (1) (0.27 g, l.Ommol), tert-butyl (S) -2-amino-3-methylbutylcarbamate (0.20g, l.Ommol), DIPEA (0.34ml, 2.0mmol) and isopropyl alcohol (5ml) and then sealed and heated to 120 ° C for 2 days. After cooling to room temperature, the volatile components were removed in vacuo and the residue purified by column chromatography using as eluent hexanes (0-60) / 0% to 100% EtOAc, to obtain a white waxy solid, this material was dissolved in DC (5ml) and TFA (2ml) and stirred at room temperature for 2h. The volatile components were then removed in vacuo and the residue purified by preparative HPLC on a C-18 reverse phase column, using as eluent a gradient from 0% to 100% MeCN and water / 0.05% w / v TFA. The fractions containing the product were then dried by freezing, obtaining the desired product as a soft solid (0.13g, 29.6%) 1H NR (DMSO-d6): 0.94 (6H, m), 1.95 (1H, m), 2.31 ( 6H, s), 2.87 (1H, m), 3.11 (1H, m), 4.34 (1H, s), 6.90 (1H, s), 7.25 (1H, s), 7.36 (1H, s), 7.94 (4H , m), 8.55 (1H, s), 8.84 (2H, s); LC / MS 340.45 [+ H] 338.63 [M-H]. Compounds 1-15 and 19-44 were made in a manner similar to Example 1. Compounds 45-58 can also be made in a similar manner to Example 1. 3- (4-fluoro-3-nitrophenyl) pyridine 2.0 g of 3-pyridine boronic acid, 3.22 g of 4-Bromo-l-fluoro-2-nitrobenzene, and 285 mg of Pd (PPh3) 2Cl2 were sequentially added to 50 mL of degassed 1,4-dioxane and the mixture was stirred at rt for 20 min. 50 mL of a 1M solution of degassed aqueous sodium carbonate was added and the reaction mixture was heated under argon under reflux for 1.5 h. The solvent was removed in vacuo, ethyl acetate was added, and the solution was filtered through celite. The filtrate was washed with saline, dried over MgSO 4 and concentrated to obtain the crude compound 3 as a dark brown solid. The crude mixture was purified by column chromatography on a 60-120 mesh silica gel column using 2% MeOH / CHCl3 as eluent to form a yellow solid (1.58 g, 80%). m.p. 87-88 ° C; (4) N-tert-Butyl-2-nitro-4- (pyridin-3-yl) benzenamine To the stirred solution of 1.58 g of 3- (4-fluoro-3-nitrophenyl) pyridine in 5.0 mL DMF was added 1.124 g of N-ethyl diisopropylamino followed by 2.116 g of tert-butyl amine under a nitrogen atmosphere. The reaction mixture was maintained at 50 ° C for 5.0 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water followed by saline. The organic layer was dried over sodium sulphate and evaporated to obtain an orange solid (1.57 g, 85%) m.p. 67-69 ° C; (5) 2-Nitro-4- (pyridin-3-yl) benzenamine To a stirred solution of 1.5 g of N-tert-butyl-2-nitro-4- (pyridin-3-yl) benzenamine in 15 mL of methanol were added. mL of 6 N HC1. The solution was treated by reflux for 3 h. The reaction mass was then diluted with chloroform and the pH was adjusted to 7 using a saturated solution of NaHCC > 3. The organic layer was separated, washed with water followed by saline, dried over sodium sulfate, and evaporated to obtain an orange solid (1.06 g, 90%). 2- (2-nitro-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonitrile To the stirred solution of 0.5 g of 2-nitro-4 (pyridin-3-yl) benzenamine in 3 mL of DF was 2.267 aggregate of CS2CO3 followed by 0.386 g of 2-chloro-3-cyano-pyridine. The reaction mixture was heated at 130 ° C for 5 h under a nitrogen atmosphere. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated, washed with water followed by saline, dried over sodium sulfate, and evaporated to obtain a yellow solid (0.440 g, 60%). mp: 91-92 ° C. 2- (2-amino-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonyl group To the stirred solution of 0.3 g of 2- (2-nitro-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonitrile in 15 mL of ethanol was added 0.471 of tin chloride to rt. The reaction mixture was treated by reflux for 2.5 h. The reaction mass was diluted with 20 mL of ethyl acetate, 15 mL of water and then made alkaline at a pH of 8-9 using a solution of saturated sodium bicarbonate. The organic layer was separated and washed with water followed by saline, dried over sodium sulfate and evaporated to obtain a yellow solid (0.217 g, 80%). mp: 67-68 ° C; 2- (2-amino-5- (pyridin-3-yl) -β-benzo [d] imidazol-1-yl) pyridine-3-carbonitrile (Compound 18) To the stirred solution of 170 mg of 2- ( 2-amino-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonitrile in 5 mL of methanol and 5 ral of water was added 65 mg of cyanogen bromide at 0 ° C. The reaction mixture was allowed to stand to obtain rt and stirred at this temperature for 3 h under a nitrogen atmosphere. The reaction mass was diluted with 20 mL of ethyl acetate, 15 mL of water, then made alkaline to a pH of 8 using a solution of saturated sodium bicarbonate. The organic layer was separated and washed with water followed by saline, dried over sodium sulfate, and evaporated to obtain a crude solid. The crude compound was purified on preparative TLC using 5% MeOH / CHCl 3 as eluent to form a pale yellow solid (25mg, 10.6%). LC / MS 313.2 [M + H] 1HNMR (300MHz, CDCI3): 8.99 (br.d, J = 3.0Hz, 1H), 8.83 (dd, J = 8.1Hz, 1H), 8.73 (d, J = 8.4Hz , 1H), 8.57 (dd, J = 3.3Hz, 1H), 8.24 (br.s, 1H), 8.18 (dt, J = 2.1Hz, 1H), 7.96 (d, 1H, J = 1.5Hz), 7.65 (m, 3H), 7.51 (q, 2H, J = 4.8Hz). Compounds 16-18 were made in a similar manner to Example 2. Table 2 below represents the data for certain exemplary compounds. The compound numbers correspond to the compounds described in Table 1. The following analytical methods were used.

Method? The samples of spec. of mass were analyzed in a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrode ionization. The samples were introduced into the mass spectrometer using chromatography. The mobile phase for all mass spectrography analyzes consisted of lOmM ammonium acetate pH 7 and a 1: 1 mixture of acetonitrile-methanol, gradient column conditions are 5% -100% acetonitrile-methanol for a gradient time of 4.5 mins and a run time of 6.2 mins on an ACE C8 3.0 x 75mm column. Flow range is 1.0 ml / min.

Method B Samples of the spec. of mass were analyzed on a MicroMass ZQ, ZMD or Quattro II mass spectrometer operated in single MS mode with electroroated ionization. The samples were introduced into the mass spectrometer using chromatography or flow injection (or FIA). The mobile phase for all spec analysis. Dough consisted of acetonitrile-water mixtures with either 0.2% formic acid or 0.1% TFA as a modifier. Column gradient conditions are 10% -90% acetonitrile over a 3-minute time gradient and a 5-minute run time over a YMC Pro-C18 4.6x50mm column. The flow range is 1.5 ml / min.

Method C Same as in Method C except that the column gradient conditions are acetonitrile 5% -45% over a time gradient of 5 mins and an execution time of 7 mins over a YMC Pro-C18 2x50mm column. The flow range is 1.0 ml / min.

Table 2 1H NMR Method M + l Rt No Spec (obs) (mins) mass XH NMR (DMSO-de): 0.94 (6H, s), 1.95 (1H, m), 2.8 6 (1H, br s), 3.13 (1H, br s ), 4.34 (1H, m), 1 312.5 6.92 (1H, s), 7.28 (1H, t), 7.32 6.796 A (1H, t), 7.45 (1H, d), 7.55 (1H, d), 7.93 (4H, m), 8.56 (1H, s), 8.83 (2H, br s AH NMR (DMSO-de): 0.94 (6H, m), 1.95 (1H, m), 2.31 (6H, s), 2.87 (1H, m), 3.11 (1H, m), 4.34 (1H, 340 .45 7.939 A s), 6.90 (1H, s), 7.25 (1H, s), 7.36 (1H, s), 7.94 (4H, m), 8.55 (1H, s), 8.84 (2H, s) ?? NMR (DMSO-d6): 1.58 (1H, m), 1.75 (1H, m), 1.92 (2H, m), 2.88 (2H, m), 3.16 (1H, m), 3.38 (1H, m), 4.33. (1H, br s), 6.93 (1H, 310 .49 5 .874 A s), 7.27 (1H, t), 7.31 (1H, t), 7.49 (1H, d), 7.54 (1H, d), 8.46 (1H, m), 8.61 (1H, s), 9.11 (2H, s), 9.24 (1H, s), 9 .35 (1H, s) XH NMR (DMSO-de): 1.62 (1H, m), 1.74 (1H, m), 1.94 (1H, d), 2.03 (1H, d), 2.30 (6H, d), 2.84 (2H, m), 3.22 (1H, d), 3.42 (1H, d), 338 .43 7,134 A 4. 27 (1H, br s), 6.85 (1H, s), 7.25 (1H, s), 7.34 (1H, s), 8.22 (1H, d), 8.60 (1H, s), 8.85 (1H, m), 8.97 (3H, m) Biological Methods Example 1: Aurora B Inhibition Assay (radiometric) A test buffer was prepared which consisted of 25 mM HEPES (pH 7.5), 10 mM MgCl 2, 0.1% BSA and 10 glycerol. %. A 22 nM solution of Aurora-B solution, also containing 1.7 mM DTT and 1.5 mM Kemptide (LRRASLG), was prepared in a test buffer. It was added to 22 μ] 1. of the Aurora-B solution, in a 96-well plate, 2 μ? of a stock solution compound in DMSO and the mixture was allowed to equilibrate for 10 minutes at 25 ° C. The enzyme reaction was initiated by the addition of 16 μ? of stock solution of [D-33P] -ATP (~ 20 nCi / L) prepared in a test buffer, up to a final assay concentration of 800 μ ?. The reaction was then stopped for 3 hours by the addition of 16 μL of 500 mM phosphoric acid and the 33P incorporation levels in the peptide substrate were determined by the following methods. A 96-well plate of phosphocellulose (Millipore, Cat No. MAPHNOB50) was pre-treated with 100 μL of a 100 mM phosphoric acid prior to the addition of the enzyme reaction mixture (40 μL). The solution was then allowed to float on the phosphocellulose membrane for 30 minutes and the plate was subsequently washed four times with 200 pL of a 100 mM phosphoric acid. To each receptacle of the dry plate were added 30 L of a liquid flash cocktail Optiphase xSuperMix '(Perkin Elmer) prior to the flash count (1450 icrobeta Liquid Scintillation Counter, Wallac). The non-enzymatic catalyzed base radioactivity levels were determined by the addition of 16 L of 500 mM phosphoric acid to the control receptacles, containing all the test components (which act to denature the enzyme), prior to the addition of the solution of [D-33P] -ATP. The levels of enzyme-catalyzed 33P incorporation were calculated by subtracting the average base count from those measured at each inhibitor concentration. For each of the Ki determination data points 8, typically covering the compound concentration range from 0 to 10 μ ?, were obtained in duplicate (DMSO stocks were prepared from an initial compound stock of 10 mM with dilutions). Subsequent serials of 1: 2.5). The Ki values were calculated from the initial range data for non-linear regressions using the Prism software package (Prism 3.0, Graphpad Software, San Diego, CA). The following compounds inhibited Aurora-B with a Ki value of < 1 uM: Compounds 1-4, 14, and 28.

Example 2: Inhibition assay of FLT-3 The compounds were selected for their ability to inhibit FLT-3 activity using a radiometric filter binding assay. This assay monitors the incorporation of 33P into a poly substrate (Glu, Tyr) 4: 1 (pE4Y). The reactions were carried out in a solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl 2, 25 mM NaCl, 1 mM DTT, 0.01% BSA and 2.5% DMSO. The final substrate concentrations in the assay were ATP 90 μ? and pE4Y 0.5mg / ml (both from Sigma Chemicals, St Louis, MO). The final concentration of a compound of the present invention is generally between 0.01 and 5 μ ?. Typically, a 12-point titration was carried out by preparing serial dilutions of 10 mM DMSO of the test compound. The reactions were carried out at room temperature. Two test solutions were prepared. Solution 1 containing 100 mM HEPES (pH 7.5), MgCl210 mM, 25 mM NaCl, 1 mg / ml pE4Y and 180 mM ATP (containing 0.3 mCi of ATP [D-33p] for each reaction). Solution 2 containing 100 mM HEPES (pH 7.5), MgCl210 mM, 25 mM NaCl, 2 mM DTT, 0.02% BSA and 3 nM FLT-3. The assay was performed on a 96-well plate by mixing 50 μ? each of Solution 1 and 2.5 ml of the compounds of the present invention. The reaction was started with Solution 2. After 20 minutes of incubation at room temperature, the reaction was stopped with 50μl of 20% TCA containing 0.4mM of ATP. The entire reaction volume was then transferred to a filter plate and washed with 5% TCA by a Harvester 9600 from TOMTEC (Hamden, CT). The amount of incorporation of 33P into pE4 and were analyzed by a Packard microplate flash counter (Meriden, CT). The data were adjusted using the Prism software to achieve an IC50 or Ki. The following compounds inhibited FLT-3 with a Ki value of <; 1 uM: Compounds 1-5, 8-17, 20-42, and 44.

Example 3: PDK-1 Inhibition Assay Compounds are selected for their ability to inhibit PDK-1 using a radioactive phosphate incorporation assay (Pitt and Lee, J. Biomol. Screen., (1996) 1, 47). The assays were carried out in a mixture of 100 m HEPES (pH 7.5), 10 mM MgCl 2, 25 mM NaCl, 2 mM DTT. The final substrate concentrations in this assay are ATP 40 μ? (Sigma Chemicals) and peptide 65 μ? (PDKtide, Upstato, Lake Placid, NY). The assays are carried out at 30 ° C and 25 nM PDK-1 in the presence of -27.5 nCi / pL of [D-32P] ATP (Amersham Pharmacia Biotech, Amersham, UK). A buffer solution of test stock is prepared containing all the reagents listed above, with the exception of ATP, and the test compound of interest. They were placed 15 μ? of the stock solution in a 96-well plate followed by the addition of 1 μ? of DMSO 0.5 mM stock containing the test compound (final concentration of compound 25 μ, final concentration of DMSO 5%). The plate is pre-incubated for approximately 10 minutes at 30 ° C and the reaction initiated by the addition of 4 μ? of ATP (final concentration 40 μ?). The reaction is stopped after 10 minutes by the addition of 100μL of 100mM phosphoric acid, 0.01% Tween-20. A plate of 96 receptacles of phosphocellulose (Millipore, Cat No. MAPHNOB50) is pretreated with ??? μ? of lOOmM phosphoric acid, 0.01% Tween-20 prior to the addition of the reaction mixture (100 L). The spots were left to soak for 5 minutes, prior to the washing steps (4 x 200μL lOOmM phosphoric acid, 0.01% Tween-20). After drying, 20μL of an Optiphase 'SuperMix' liquid flash cocktail (Perkin Elmer) was added to the receptacle prior to flash counting (1450 Microbeta Liquid Scintillation Counter, Wallac). Compounds greater than 50% inhibition versus standard receptacles containing the assay mixture and DMSO without test compound are titrated to determine the IC 50 values.

While a number of embodiments of this invention have been described, it is obvious that our basic examples could be altered to provide other embodiments utilizing the compounds, methods, and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example herein.

Claims (36)

What is claimed:

1. A compound of formula (I): i; or a pharmaceutically acceptable salt thereof wherein Q is selected from the group consisting of R is H, aliphatic Ci-6 / or cycloaliphatic C3_e optionally substituted with 0-4 JR; each R2 is independently ZR, MR, (LR) -ZR or (XR) -MR; each JQ is independently ZQ, MQ, (LQ) -ZQ, or (XQ) -Q; each LR, LQ, XR, and XQ is independently Ci_6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -O-, -S-, -C02-, -OC (0) -, -C (0) CO- , -C (O) -, -C (0) NR-, -C (= N-CN), -C (= N-OH), -NRCO-, -NRC (0) 0-, -S02NR-, -NRS02-, -NRC (0) NR-, -0C (0) NR-, -NRS02NR-, -SO-, or -S02-; wherein each LR is independently and optionally substituted with 0-2 JLR; each LQ is independently and optionally substituted with 0-2 JLQ; each XR is independently and optionally substituted with 0-2 JXR; each XQ is independently and optionally substituted with 0-2 JXQ; each ZR and ZQ is independently H; Ci-6 aliphatic, * a fully unsaturated, or partially unsaturated or saturated 3 to 8 membered monocyclic ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a fully unsaturated, or partially unsaturated or saturated bicyclic ring system of 8 to 12 members having from 0 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ZR is independently and optionally substituted with 0-4 JZR; each ZQ is independently and optionally substituted with 0-4 JZQ; each MR and MQ is independently halo, CN, CF3, NO2, O, SR, or N (R) 2; each JR is independently aliphatic Ci-6, haloalkyl Ci-6 halo, OH, alkoxy Ci_3, N02, or CN; each JLR, JLQ, JXR, JXQ, JZR, and JZQ is independently V, M, (Lv) -V, (LM) -M, Ci-6 haloalkyl, halo, OH, C1-3 alkoxy, N02, or CN; each R is independently H, aliphatic Ci-6, aryl C6-10 - (aliphatic Ci-6) - (aryl C6-10) / cycloaliphatic C3-e, -C (= 0) (aliphatic Ci-6), -C (= 0) (C3_8 cycloaliphatic), or -C (= 0) 0 (C1-6 aliphatic); wherein each R is independently and optionally substituted with 0-2 J; each Lv and LM is independently C -6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -0-, -S-, -CO2-, -0C (0) -, -C (0) C0-, -C (0) -, -C (0) NR-, -C (= N-CN), -C (= N-0H), -NRCO-, -NRC (0) 0-, -S02NR-, -NRS02- , -NRC (0) NR-, -0C (0) NR-, -NRS02NR-, -SO-, or -S02-; wherein each Lv is independently and optionally substituted with 0-2 JLV; each LM is independently and optionally substituted with 0-2 JLM; each V is independently H; aliphatic Ci_6; a fully unsaturated, or partially unsaturated or saturated, 3 to 8 membered monocyclic ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a fully unsaturated, or partially unsaturated or saturated bicyclic ring system of 8 to 12 members having from 0 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each V is independently and optionally substituted with 0-2 Jv; each J, JLV, J1", and Jv is independently R ', C3-6 cycloalkyl, Ci-6 haloalkyl, halo, N02, CN, OH, O', SH, SR ', NH2, NHR', N (R ') ) 2, COH, COR ', CONH2, CONHR', CON (R ') 2, NHCOR', NR'COR ', NHCONH2 / NHCONHR', NHCON (R ') 2, NR'CONH2, NR' CONHR ', NR 'CON (R') 2, S02NH2, S02NHR ', S02N (R') 2, NHS02R ', O NR' S02R ', R' is unsubstituted aliphatic Ci_6, or two R 'groups, together with the atom to which the they are bound, form a partially unsaturated or saturated monocyclic ring of 3 to 8 unsubstituted members having from 0 to 1 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each M is independently halo, CN, CF3, N02, OH, O (Ci-6 alkyl), SH, S (Ci-6 alkyl), NH 2, NH (Ci-6 alkyl), or N (Ci-6 alkyl) 2; when Q is, FT is not in position 5 or 6 of the benzimidazole ring; when Q is and R is H, F, Cl, CH3, CF3, OCH3, or OCH2CH3 at the 5 or 6 position of the benzimidazole ring, then JQ is not -0- (C1-3 aliphatic); when Q is then JQ is not optionally substituted with methyl; when R1 and R2 are H, then Q is not when Q is H N JQ, then JQ is not Cl, NH2,, or NR "-Ar wherein Ar is an optionally substituted group selected from phenyl, piperonyl, and pyridyl, and R" is H or optionally substituted Ci_6 aliphatic.

2. The compound of claim 1 wherein R1 is H.

3. The compound of claim 1 or claim 2 wherein Q is

4. The compound of claim 3 wherein Q is

5. The compound of claim 4 wherein Q is

6. The compound according to any one of claims 1-4, wherein JQ is (LQ) -ZQ or (XQ) -MQ.

7. The compound of claim 6, wherein LQ is Ci-6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -0-, -S-, -C (0) -, -C (0) NR-, - NRCO-, -S02NR-, or -NRS02-

8. The compound of claim 7, wherein LQ is Ci_6 alkyl optionally interrupted with up to an occurrence of -NR-.

9. The compound of claim 8, wherein the occurrence of -NR- is directly linked to the Q ring.

10. The compound according to any one of claims 1-4, wherein JQ is ZQ or MQ.

11. The compound according to any one of claims 6-10, wherein ZQ is H or an optionally substituted group selected from aliphatic Ci-6, C3-8 cycloaliphatic, phenyl, having from 5 to 8 heteroaryl members, and having from 5 to 8 heterocyclyl members.

12. The compound according to any one of claims 6-11, wherein XQ is C1-6 alkyl optionally interrupted with up to 2 occurrences of -NR-, -O-, -S-, -C (O) -, -C (0) NR-, -NRCO-, -SO2NR-, or -NRSO2-.

13. The compound of claim 12, wherein XQ is Ci-6 alkyl optionally interrupted with up to an occurrence of -NR-.

14. The compound according to any one of claims 6-13, wherein the Q ring is substituted with 2 occurrences of JQ where one JQ is (LQ) -ZQ or (XQ) -Q and the other JQ is ZQ or Q .

15. The compound according to any one of claims 1-14, wherein each R2 is selected from ZR or R.

16. The compound according to any one of claims 1-15, substituted as illustrated in Formula III: Formula III

The compound of claim 16, wherein at least one of R2 is not H.

18. The compound of claim 1, selected from the following:

19. The compound of claim 1, selected from the following: 16 17 18 31 32 33 34 35 36 37 38 39 43 44 45 - 107 -

20. A composition comprising a compound according to any one of claims 1-19 and a pharmaceutically acceptable carrier, adjuvant or carrier.

21. A method for inhibiting Aurora protein kinase activity in a patient comprising administering to said patient: a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

22. A method for inhibiting the activity of the Aurora protein kinase in a biological sample comprising contacting said biological sample with: a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

23. A method for inhibiting the activity of the FLT-3 protein kinase in a patient comprising administering to said patient: a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

24. A method for inhibiting the activity of the protein kinase FLT-3 in a biological sample comprising contacting said biological sample with: a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

25. A method for inhibiting PDK1 protein kinase activity in a patient comprising administering to said patient: a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

26. A method for inhibiting the protein kinase PDK1 activity in a biological sample comprising contacting said biological sample with: a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

27. A method for the treatment of a proliferative disorder in a patient comprising the step of administering said patient: a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

28. The method according to claim 27, which comprises administering to said patient an additional therapeutic agent with said composition as a single dose form or separately from said composition as part of a multiple dose form.

29. A method for the treatment of melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or cancer selected from colon, breast, gastric, ovarian, cervical, lung cancer, central nervous system (CNS), renal, prostate, bladder, pancreatic, brain (gliomas), head and neck, kidney, liver, melanoma, sarcoma, or thyroid in a patient in need thereof wherein said method comprises administering to said patient a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

30. A method for treating cancer in a patient in need thereof comprising the step of interrupting mitosis of cancer cells by means of Aurora inhibition with: a) a composition of claim 20; or b) a compound according to any one of claims 1-19. 31. A method for the treatment of cancer in a patient in need thereof comprising the step of interrupting mitosis of cancer cells by inhibiting FLT-3 with a) a composition of claim 20; or b) a compound according to any one of claims 1-19.

A process for preparing a compound of formula

I where R1, R2, and JQ are as defined here; which comprises causing the reaction of a compound of formula a: a wherein R1 and R2 are as defined according to any one of claims 1-19; with a compound of formula b: b; wherein ring Q is and Ju is as defined according to any one of claims 1-19; under suitable conditions of boronic acid or boronic ester.

33. A process for preparing a compound of formula I wherein R1, R2, and JQ are as defined according to any one of claims 1-19; and the Q ring is which comprises causing the reaction of a compound of formula wherein R1 and R2 are as defined according to any one of claims 1-19; with a compound of formula c: c; wherein JQ is as defined according to any one of claims 1-19; and the Q ring is under proper conditions of displacement.

34. A process for preparing a compound of formula I: I wherein R2, R2, ring Q, and JQ are as defined according to any one of claims 1-19; comprising the formation of a ring of a compound formula 7: 7 wherein R2 and the Q ring are as defined according to any one of claims 1-19; with CN-Br under suitable ring formation conditions.

35. A process for preparing a compound of formula 2: which comprises heating the compound of formula 1 with NH2-JJ under suitable conditions of displacement to form the compound of formula 2.

36. The process of claim 35, which comprises causing the reaction of a compound of formula a to: a wherein R1 and R2 are as defined according to any one of claims 1-19; N ^ N with Cl under suitable conditions of displacement to form a compound of formu 1