HK1122558A - Benzimidazoles useful as inhibitors of protein kinases - Google Patents

Description

Benzimidazoles useful as inhibitors of protein kinases

Technical Field

The present invention relates to protein kinase inhibitor compounds, compositions containing such compounds, methods of making such compounds, and methods of use. More particularly, these compounds are inhibitors of FLT-3, PDK1 and Aurora kinases and are useful in the treatment of disease states, such as cancer, that are alleviated by these kinase inhibitors.

Background

Aurora proteins are a family of three highly related serine/threonine kinases (termed Aurora-a, -B and-C) that are required for mitotic phase progression through the cell cycle. In particular, Aurora-a plays a crucial role in centrosome maturation and separation, mitotic spindle formation and reliable chromosome segregation. Aurora-B is a chromosomal messenger protein that plays a central role in regulating chromosome alignment on metaphase plates, spindle assembly checkpoints, and the correct completion of cytokinesis.

Overexpression of Aurora-A, Aurora-B or Aurora-C has been observed in some human cancers, including colorectal, ovarian, gastric, and invasive ductal adenocarcinomas.

Several studies have now demonstrated that Aurora-a or-B in human cancer cell lines is reduced or inhibited by siRNA, dominant negative or neutralizing antibodies by the progression of disruption through mitosis, with accumulation of 4NDNA cells. In some cases, this is followed by internal doubling 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-. FLT-3 is a receptor tyrosine kinase that regulates the maintenance of stem cells/early progenitor pools and the development of mature lymphoid and myeloid cells [ Lyman, S, Jacobsen, S, Blood, 1998, 91, 1101-1134 ].

FLT-3 has been shown to play a role in a variety of hematopoietic and non-hematopoietic malignancies. Mutations that induce ligand-independent FLT-3 activation have been implicated in Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), mastocytosis, and gastrointestinal stromal tumors (GIST). In addition to activating mutations, ligand-dependent (autocrine or paracrine) stimulation of overexpressed wild-type FLT-3 can also have an effect on the malignant phenotype [ Scheijen, B, Griffin JD, Oncogene, 2002, 21, 3314-3333 ].

PDK1 (3-phosphoinositide-dependent protein kinase-1) plays a key role in mediating many different cellular events, phosphorylating key regulatory proteins that play important roles, such as cell survival, growth, proliferation and glucose regulation [ (Lawlor, m.a. et al, j.cellsci., 114, pp.2903-2910, 2001), (Lawlor, m.a. et al, EMBO j., 21, pp.3728-3738, 2002) ]. Many human cancers, including prostate and NSCL, have elevated PDK1 signaling pathway functions, resulting from a number of different genetic events, such as PTEN mutations or overexpression of certain key regulatory proteins [ (Graff, j.r., expetpain. ther. targets, 6, pp.103-113, 2002), (brocard, j., et al, Cancer res., 61, pp.3986-3997, 2001) ]. Transfection of a PTEN negative human cancer cell line (U87MG) with an antisense oligonucleotide directed to PDK1 demonstrated PDK1 inhibition as a mechanism for treating cancer. The resulting reduction in PDK1 protein levels results in a reduction in cell proliferation and survival (Flynn, p., et al, curr. biol., 10, pp.1439-1442, 2000).

Protein kinases are attractive and well established targets for new therapeutic agents to treat a wide range of human diseases, examples of which include Gleevec and Tarceva. Aurora, FLT-3 and PDK1 kinases are particularly attractive because they are associated with a large number of human cancers and they play a role in the proliferation of these cancer cells. Thus, there is a need for compounds that inhibit protein kinases.

Disclosure of Invention

The present 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, R¹And R²As 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 the invention are also useful in kinase studies in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and comparative evaluation of novel kinase inhibitors.

The invention also provides methods of making the compounds of the invention.

Detailed description of the invention

The present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt thereof,

wherein

Q is selected from the group consisting of:

R¹is H, C_1-6Aliphatic radicals or C_3-8Cycloaliphatic radical, optionally substituted by 0 to 4J^RSubstitution;

each R²Independently is Z^R、M^R、(L^R)-Z^ROr (X)^R)-M^R；

Each J^QIndependently is Z^Q、M^Q、(L^Q)-Z^QOr (X)^Q)-M^Q；

Each L^R、L^Q、X^RAnd X^QIndependently is C_1-6Alkyl, optionally substituted up to 2 occurrences of-NR-, -O-, -S-, -CO₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NR-、-C(＝N-CN)、-C(＝N-OH)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-、-NRC(O)NR-、-OC(O)NR-、-NRSO₂NR-, -SO-or-SO₂-an interrupt;

wherein

Each L^RIndependently and selectively substituted by 0-2J^LRSubstitution;

each L^QIndependently and selectively substituted by 0-2J^LQSubstitution;

each X^RIndependently and selectively substituted by 0-2J^XRSubstitution;

each X^QIndependently and selectively substituted by 0-2J^XQSubstitution;

each Z^RAnd Z^QIndependently is H; c_1-6An aliphatic group; a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein

Each Z^RIndependently and selectively covered with 0-4J^ZRSubstitution;

each Z^QIndependently and selectively covered with 0-4J^ZQSubstitution;

each M^RAnd M^QIndependently is halo, CN, CF₃、NO₂OR, SR OR N (R)₂；

Each J^RIndependently is C_1-6Aliphatic radical, C_1-6Haloalkyl, halo, OH, C_1-3Alkoxy group, NO₂Or CN;

each J^LR、J^LQ、J^XR、J^XQ、J^ZRAnd J^ZQIndependently V, M, (L)^V)-V、(L^M)-M、C_1-6Haloalkyl, halo, OH, C_1-3Alkoxy group, NO₂Or CN;

each R is independently H, C_1-6Aliphatic radical, C_6-10Aryl, - (C)_1-6Aliphatic radical) - (C_6-10Aryl group), C_3-8Cycloaliphatic radical, -C (═ O) (C)_1-6Aliphatic group), -C (═ O) (C)_3-8Cycloaliphatic radical) or-C (═ O) O (C)_1-6Aliphatic groups); wherein each R is independently and optionally substituted with 0-2J;

each L^VAnd L^MIndependently is C_1-6Alkyl, optionally substituted up to 2 occurrences of-NR-, -O-, -S-, -CO₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NR-、-C(＝N-CN)、-C(＝N-OH)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-、-NRC(O)NR-、-OC(O)NR-、-NRSO₂NR-, -SO-or-SO₂-an interrupt;

wherein

Each L^VIndependently and selectively substituted by 0-2J^LVSubstitution;

each L^MIndependently and selectively substituted by 0-2J^LMSubstitution;

each V is independently H; c_1-6An aliphatic group; a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each V is independently and selectively substituted by 0-2J^VSubstitution;

each J, J^LV、J^LMAnd J^VIndependently is R', C_3-6Cycloalkyl radical, C_1-6Haloalkyl, halo, NO₂、CN、OH、OR′、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、SO₂NH₂、SO₂NHR′、SO₂N(R′)₂、NHSO₂R 'or NR' SO₂R′；

R' is unsubstituted C_1-6An aliphatic group; or two R' groups together with the atoms to which they are bonded form an unsubstituted 3-8 membered saturated or partially saturated monocyclic ring having 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each M is independently halo, CN, CF₃、NO₂、OH、O(C_1-6Alkyl), SH, S (C)_1-6Alkyl), NH₂、NH(C_1-6Alkyl) or N (C)_1-6Alkyl radical)₂。

One embodiment provides

When Q is，R²Not in position 5 or 6 of the benzimidazole ring

When Q isOrAnd R is²Is H, F, Cl, CH at position 5 or 6 of the benzimidazole ring₃、CF₃、OCH₃Or OCH₂CH₃When, J^QIs not-O- (C)_1-3Aliphatic groups);

when Q isOrWhen, J^QNot being optionally substituted by methyl

When R is¹And R²When is H, Q is notOr

When Q isWhen, J^QNot Cl, NH₂、Or NR "-Ar, wherein Ar is an optionally substituted group selected from phenyl, piperonyl or pyridyl; and R' is H or optionally substituted C_1-6An aliphatic group.

The compounds of the present invention include those generally described above, further illustrated as major classes, minor classes, and species disclosed herein. Unless otherwise stated, the following definitions will apply. For the purposes of the present invention, the chemical elements will be according to the CAS version of Handbook of chemistry and Physics, 75^thAnd Ed is identified. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, university science Books, Sausaltito: 1999, and "March's Advanced organic chemistry", 5^th Ed.，Ed.：Smith，M.B.and March，J.，John Wiley&Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, the designated range of atomic numbers includes any integer therein. For example, a group having 1-4 atoms can have 1, 2, 3, or 4 atoms.

As described herein, the numbering of the benzimidazole ring is as follows.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those described generally above, or as illustrated by the general classes, subclasses, and species disclosed herein. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted. In general, the term "substituted," with or without the preceding term "optionally," means that a hydrogen radical in a given structure is replaced with a radical of a particular substituent. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Substituent combinations contemplated by the present invention are preferably those that form stable or chemically feasible compounds.

The term "stable" as used herein means compounds that are substantially unchanged when subjected to the conditions used for their preparation, detection, preferably their recovery, purification, and for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that remains substantially unchanged in the absence of moisture or other chemically reactive conditions at a temperature of 40 ℃ or less for at least one week.

The term "aliphatic group" or "aliphatic group" as used herein means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation, having a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, 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 radical" (alternatively "carbocycle" or "cycloalkyl") denotes a monocyclic C₃-C₈Hydrocarbons or bicyclic radicals C₈-C₁₂A hydrocarbon, which is fully saturated or contains one or more units of unsaturation, but is not aromatic, which has a single point of attachment to the rest of the molecule, wherein any single ring in said bicyclic ring system is a 3-7 membered ring. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl. In some embodiments, the cycloaliphatic group may be "bridged".

A "bridged" ring consists of a ring containing an additional alkyl chain, wherein each end of the chain is bonded to a ring member of the ring, with the proviso that the two ends of the chain are not bonded to the same ring member. The alkyl chain may optionally be interrupted by a heteroatom selected from O, N and S. Examples of bridged cycloaliphatic radicals include, but are not limited to, bicyclo [3.3.2] decane, bicyclo [3.1.1] heptane, and bicyclo [3.2.2] octane.

The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein, refers to a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is 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, the rings are 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] octane.

Suitable heterocycles include, but are not limited to, 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyrazinyl, 2-tetrahydropyrazinyl, 3-tetrahydropyrazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 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, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiepino, benzodithiane (benzodithiane), and 1, 3-dihydro-imidazol-2-one.

The term "heteroatom" means one or more oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized forms of any basic nitrogen or heterocyclic ring substitutable nitrogen, e.g. 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 the moiety has one or more units of unsaturation.

The term "alkoxy" or "thioalkyl" as used herein means an alkyl group, as defined above, attached to the bulk carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote alkyl, alkenyl or alkoxy groups, as the case may be, substituted with one or more halogen atoms. The term "halogen" denotes F, Cl, Br or I.

The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", denotes 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, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring".

The term "heteroaryl", used alone or as part of a larger portion of "heteroaralkyl" or "heteroarylalkoxy", denotes 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 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Suitable heteroaryl rings include, but are not limited to, 2-furyl, 3-furyl, 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 (e.g., 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, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, purinyl, pyrazinyl, 1, 3, 5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

Aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroaralkoxy, and the like) may contain one or more substituents and thus may be "optionally substituted". Unless the context defines otherwise, suitable substituents on the unsaturated carbon atoms of an aryl or heteroaryl group are generally selected from halogen; -R^o；-OR^o；-SR^o(ii) a Is optionally substituted by R^oSubstituted phenyl (Ph); is optionally substituted by R^oSubstituted-o (ph); - (CH)₂)_1-2(Ph), optionally substituted by R^oSubstitution; -CH ═ CH (ph), optionally with R^oSubstitution; is optionally substituted by R^oSubstituted 5-6 membered heteroaryl or heterocycle; -NO₂；-CN；-N(R^o)₂；-NR^oC(O)R^o；-NR^oC(S)R^o；-NR^oC(O)N(R^o)₂；-NR^oC(S)N(R^o)₂；-NR^oCO₂R^o；-NR^oNR^oC(O)R^o；-NR^oNR^oC(O)N(R^o)₂；-NR^oNR^oCO₂R^o；-C(O)C(O)R^o；-C(O)CH₂C(O)R^o；-CO₂R^o；-C(O)R^o；-C(S)R^o；-C(O)N(R^o)₂；-C(S)N(R^o)₂；-OC(O)N(R^o)₂；-OC(O)R^o；-C(O)N(OR^o)R^o；-C(NOR^o)R^o；-S(O)₂R^o；-S(O)₃R^o；-SO₂N(R^o)₂；-S(O)R^o；-NR^oSO₂N(R^o)₂；-NR^oSO₂R^o；-N(OR^o)R^o；-C(＝NH)-N(R^o)₂；-P(O)₂R^o；-PO(R^o)₂；-OPO(R^o)₂(ii) a Or- (CH)₂)_0-2NHC(O)R^o(ii) a Wherein each independently occurring R^oSelected from hydrogen, optionally substituted C_1-6Aliphatic, unsubstituted 5-6 membered heteroaryl or heterocycle, phenyl, -O (Ph) or-CH₂(Ph), or R independently occurs twice on the same substituent or on different substituents, although as defined above^oAnd each R^oThe atoms to which the groups are bonded together form an optionally substituted 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

R^oIs selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1-4Aliphatic group) or halogeno C_1-4An aliphatic radical, in which R^oEach of the above C_1-4Aliphatic groups are unsubstituted.

An aliphatic group or a non-aromatic heterocycle may contain one or more substituents and thus may be "optionally substituted". Unless the context defines otherwise, suitable substituents on saturated carbon atoms of aliphatic or heteroaliphatic groups or non-aromatic heterocycles are selected from those listed above for aryl or heteroaryl unsaturated carbons, and additionally include the following groups: o, S, NNHR^*、＝NN(R^*)₂、＝NNHC(O)R^*、＝NNHCO₂(alkyl) ═ NNHSO₂(alkyl), or ═ NR^*Wherein each R is^*Independently selected from hydrogen or optionally substituted C_1-6An aliphatic group.

Unless the context defines otherwise, optional substituents on non-aromatic heterocyclic nitrogen are generally selected from-R⁺、-N(R⁺)₂、-C(O)R⁺、-CO₂R⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-SO₂R⁺、-SO₂N(R⁺)₂、-C(＝S)N(R⁺¹)₂、-C(＝NH)-N(R⁺)₂or-NR⁺SO₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C₁-C₆An aliphatic group, an optionally substituted phenyl group, an optionally substituted-O (Ph), an optionally substituted-CH₂(Ph), optionally substituted- (CH)₂)_1-2(Ph), optionally substituted-CH ═ CH (Ph), or unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen or sulfur, or R independently occurring twice on the same substituent or on different substituents, although as defined above⁺And each R⁺The atoms to which the groups are bonded together form an optionally substituted 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

R⁺Is selected from-NH or an optional substituent on the phenyl ring₂、-NH(C_1-4Aliphatic radical), -N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, -OH, -O (C)_1-4Aliphatic radical), -NO₂、-CN、-CO₂H、-CO₂(C_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group) and halogeno C_1-4Aliphatic radical, wherein R⁺Each of the above C_1-4Aliphatic groups are unsubstituted.

The term "alkylene chain" denotes a straight or branched carbon chain, which may be fully saturated or have one or more units of unsaturation, and has two points of attachment to the rest of the molecule.

The term "protecting group" as used herein means an ingredient that is used to temporarily block one or more desired reactive sites in a multifunctional compound. In certain embodiments, the protecting group has one or more, or preferably all, of the following characteristics: a) selective reaction in good yield to give a protected substrate which is stable to reactions occurring at one or more other reactive sites; and b) selectively removed in good yield by a reagent that does not attack the regenerated functional group. Exemplary protecting Groups are found in Greene, T.W., Wuts, P.G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference. The term "nitrogen protecting group" as used herein means an ingredient used to temporarily block one or more desired nitrogen reactive sites in a polyfunctional compound. Preferred nitrogen protecting Groups also have the above characteristics, and certain exemplary nitrogen protecting Groups are also described in Chapter 7 in Greene, T.W., Wuts, P.G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference.

As noted above, in some embodiments, two independent occurrences of R^o(or R)⁺R, R' or any other variable similarly defined herein) together with the atoms to which they are bonded form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Two independently occurring R^o(or R)⁺R, R', or any other variable similarly defined herein) along with the atoms to which each variable is bonded include, but are not limited to, the following: a) two independently occurring R^o(or R)⁺R, R' or any other variable similarly defined herein) to the same atom and together with that atom form a ring, e.g. N (R)^o)₂In which two R are present^oTogether with the nitrogen atom, form piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl; and b) two independent occurrences of R^o(or R)⁺R, R' or any other of the herein describedIn which similarly defined variables) are bonded to different atoms and together with these atoms form a ring, e.g.OR in which the phenyl radical is present twice^oSubstitution, R of both occurrences^oTogether with the oxygen atoms to which they are bonded form a fused 6-membered oxygen containing ring:it will be appreciated that two independent occurrences of R^o(or R)⁺R, R', or any other variable similarly defined herein) may form a variety of other rings along with the atom to which each variable is bonded, and the above detailed examples are not intended to be limiting.

In some embodiments, the alkyl or aliphatic chain may be optionally interrupted by another atom or group. This means that the methylene units of the alkyl or aliphatic chain are optionally replaced by said other atoms or groups. Examples of such atoms or groups include, but are not limited to, -NR-, -O-, -S-, -CO₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NR-、-C(＝N-CN)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-、-NRC(O)NR-、-OC(O)NR-、-NRSO₂NR-, -SO-or-SO₂-, wherein R is as defined herein. Unless otherwise indicated, the selective substitution results in a chemically stable compound. The selective interruption may occur within the chain and at one of the two ends of the chain; i.e., the point and/or end of attachment. Two alternative substitutions may also be adjacent to each other within the chain, as long as they result in a chemically stable compound. Unless otherwise indicated, if a substitution or interruption occurs at a terminus, the substituting atom is bonded to the H at the terminus. For example, if-CH₂CH₂CH₃Optionally interrupted by-O-, so that the compound may be-OCH₂CH₃、-CH₂OCH₃or-CH₂CH₂OH。

Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of these compounds are within the scope of the invention.

Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Unless otherwise specified, a substituent may rotate freely about any rotatable valence. For example, is painted asThe substituents also represent

In addition, unless otherwise specified, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium or carbon is replaced by¹³C-or¹⁴C-enriched carbon instead of compounds having the structure of the present invention 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

DCM is dichloromethane

DIPEA is diisopropylethylamine

DMSO is dimethyl sulfoxide

DMF being dimethylformamide

EtOAc is ethyl acetate

HPLC is high performance liquid chromatography

i-PrOH is isopropanol

MeCN is acetonitrile

TEA is triethylamine

TFA is trifluoroacetic acid

TMP is 2, 2, 6, 6-tetramethylpiperidine

Rt is retention time

LCMS is liquid chromatography-mass spectrometry

¹H NMR is nuclear magnetic resonance

According to one embodiment of the invention, R¹Is H.

In another embodiment, Q is

In some embodiments, Q is

In some embodiments, Q is

In other embodiments, Q is

In other embodiments, Q is

In some embodiments, J^QIs (L)^Q)-Z^QOr (X)^Q)-M^Q。

In some embodiments of the invention, Q is J^QMonosubstitution, as shown in formula II

In some embodiments, J^QIs (L)^Q)-Z^Q。

In certain embodiments, L^QIs C_1-6Alkyl, optionally substituted up to 2 times by-NR-, -O-, -S-, -C (O) NR-, -NRCO-, -SO₂NR-or-NRSO₂-an interrupt.

In other embodiments, L^QIs C_1-6Alkyl, optionally interrupted by up to 2 occurrences of-NR-, -O-or-S-.

In some embodiments, L^QIs C_1-6Alkyl, optionally interrupted by up to 1 occurrence of-NR-. In certain embodiments, 1 occurrence of-NR-is directly attached to ring Q.

In some embodiments, L^Qis-NH-, -NR-, -NH (C)_1-5Alkyl) -or-NR (C)_1-5Alkyl) -; wherein R is C_1-6An alkyl group.

In some embodiments of the invention, each J is^LQIndependently is halo, C_1-6Aliphatic radicals or C_1-6A haloalkyl group.

In another embodiment of the present invention, Z^QSelected from H or an optionally substituted group selected from: c_1-6Aliphatic radical, C_3-10Cycloaliphatic, phenyl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl.

In some embodiments, Z^QIs H or optionally substituted C_1-6An aliphatic group.

In other embodiments, Z^QIs an optionally substituted phenyl group.

In other embodiments, Z^QIs a 5-8 membered heterocyclic group containing up to 2 heteroatoms selected from O, N and S. In some embodiments, Z^QIs a 5-8 membered heterocyclic group containing up to 2 nitrogen atoms. In some embodiments, the heterocyclyl is piperidine, piperazine, homopiperidine, or homopiperazine. In some embodiments, the heterocyclyl is piperidine or piperazine.

In another embodiment of the present invention, J^QIs (X)^Q)-M^Q。

In some embodiments, X^QIs C_1-6Alkyl, optionally substituted up to 2 times by-NR-, -O-, -S-, -C (O) NR-, -NRCO-, -SO₂NR-or-NRSO₂-an interrupt. In some embodiments, X^QIs C_1-6Alkyl, optionally interrupted by up to 2 occurrences of-NR-, -O-or-S-. In other embodiments, X^QIs C_1-6Alkyl, optionally interrupted by up to 1 occurrence of-NR-. In other embodiments, 1 occurrence of-NR-is directly bonded to ring Q.

In some embodiments of the invention, each J is^XQIndependently is halo, C_1-6Aliphatic radicals or C_1-6A haloalkyl group.

In certain embodiments, M^QIs OR ORN(R)₂. In other embodiments, M^QIs NH₂。

In some embodiments, J^QIs Z^QOr M^Q. In some embodiments, J^QIs Z^Q. In other embodiments, J^QIs M^Q。

In some embodiments, J^QIs an optionally substituted group selected from N (R)₂、-NR-(C_1-3Alkyl) -N (R)₂or-NR- (5-8 membered heterocyclyl).

In one embodiment of the invention, J^QIs NH₂、-NHCH₂CH₂NH₂、-NHCH(J^XQ)CH₂NH₂Or

In some embodiments, J^Qis-NHCH (J)^XQ)CH₂NH₂。

In some embodiments, J^XQIs H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

In another embodiment, R²Is selected from Z^ROr M^R。

In certain embodiments, Z^RIs H or an optionally substituted group selected from: c_1-6Aliphatic radical, C_3-6Cycloaliphatic radical and C_3-6A heterocyclic group. In some embodiments, Z^RIs H or optionally substituted C_1-6An aliphatic group. In some embodiments, Z^RIs an optionally substituted group selected from C_1-6Aliphatic radical, C_3-6Cycloaliphatic radical and C_3-6A heterocyclic group.

In some embodiments, M^RIs halo, CN, CF₃、NO₂OR OR N (R)₂Wherein R is H or C_1-3An alkyl group.

One embodiment of the present invention may be represented by formula II-a:

another embodiment of the invention may be represented by formula III:

another embodiment of the present invention may be represented by formula III-a:

III-a。

in some embodiments of the invention, at least one R is²Is not H. In some embodiments, two R are²Are not H. In some embodiments, each R is²Independently is Z^ROr M^R. In some embodiments, two R are²The radicals are all Z^ROr M^R. In some embodiments, two R are²The radicals are all Z^R. In other embodiments, R²Is C_1-3An alkyl group. In some embodiments, R²Is methyl.

In some embodiments, Z^RIs C_1-6An aliphatic group; a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or having 0-5 heteroatoms independently selected from nitrogen, oxygen and sulfurA bicyclic ring system of 8-12 membered saturated, partially unsaturated or fully unsaturated. In some embodiments, Z^RIs C_1-6An aliphatic group.

In some embodiments, the variables are as depicted for the compounds of table 1.

Representative compounds of the invention are listed in table 1 below.

Table 1: examples of Compounds of formula I

The compounds of the invention can generally be prepared by methods known to those skilled in the art for analogous compounds, as illustrated in the following schemes.

Scheme I

Scheme I depicts a method of preparing compounds wherein Q is 2, 4-pyrimidine.NHR' represents J^QGroup, wherein J^QAttached to the pyrimidine via a nitrogen atom.

Process I'

Scheme I' depicts a method of preparing compounds wherein Q is 2, 4-pyrimidine. NH-JJ for J^QGroup, wherein J^QAttached to the pyrimidine via a nitrogen atom.

Scheme I-a

Scheme I-a depicts the preparation wherein Q is

OrA method of using the compound of (1); r¹、R²And J^QAs defined herein.

Examples of bases suitable for use in scheme I-a include, but are not limited to, DIPEA, TEA, DBU, and TMP.

Examples of solvents suitable for use in scheme I-a include, but are not limited to, DMF, I-PrOH, n-butanol, t-butanol, acetonitrile, THF, and dioxane.

Scheme I-b

Scheme I-b depicts the preparation wherein Q isOrA method of using the compound of (1); r¹、R²And J^QAs defined herein; -B (OR)^X)₂Represents boronates or acids known to those skilled in the art.

As will be appreciated by those skilled in the art, boronic acids and esters can be coupled to the nitrogen atom of the benzimidazole via a variety of known conditions. Typically, these 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 (OAc)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-OMe.

Scheme II

Scheme II depicts the preparation of wherein R²A method of making a compound that is an aryl or heteroaryl group.

One embodiment provides a process for preparing a compound of formula I:

wherein R is¹、R²And J^QAs defined herein;

ring Q isOr

Comprising reacting a compound of formula a:

wherein R is¹And R²As defined herein;

with a compound of formula b:

wherein ring Q isOr

J^QAs defined herein;

under suitable boronic acid/ester coupling conditions.

Another embodiment provides a process for preparing a compound of formula I:

wherein R is¹、R²And J^QAs defined herein;

ring Q is

Comprising reacting a compound of formula a:

wherein R is¹And R²As defined herein;

with a compound of formula c:

wherein J^QAs defined herein; while

Ring Q is

Under suitable displacement conditions.

In some embodiments, the halo group in formula c is chloro.

Another embodiment provides a process for preparing a compound of formula I:

wherein R is²、R²Ring Q and J^QAs defined herein;

comprising reacting a compound of formula 7:

wherein R is²And ring Q is as defined herein;

cyclizing with CN-Br under suitable cyclization conditions. Examples of cyclization conditions include, but are not limited to, stirring in MeOH at room temperature for 30 h.

Another embodiment provides a method of preparing a compound of formula 7, comprising reducing a compound of formula 6:

wherein R is²And ring Q is as defined herein;

under reducing conditions known to those skilled in the art, a compound of formula 7 is produced. Examples of reducing conditions include, but are not limited to, SnCl₂EtOH, Fe/AcOH, In/HCl and Pd/C.

Another embodiment provides a method of preparing a compound of formula 6, comprising reacting a compound of formula 5:

wherein R is²As defined herein;

anda reaction wherein ring Q is as defined herein;

under suitable displacement conditions, the compound of formula 6 is produced. Suitable displacement conditions include, but are not limited to, bases and solvents. Examples of suitable bases include, but are not limited to, Cs₂CO₃And 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, the compound of formula 5 is formed. Examples of suitable deprotection conditions include, but are not limited to, the use of an acid (e.g., HCl or H) in a suitable solvent (e.g., MeOH, EtOH)₂SO₄)。

Another embodiment provides a method of preparing a compound of formula 4, comprising reacting a compound of formula 3:

and H₂N-C(CH₃)₃Under suitable displacement conditions to produce the compound of formula 4. Suitable displacement conditions include, but are not limited to, a suitable base, such as DIPEA, TEA, DBU or TMP, and in a suitable solvent, such as DMF, dioxane or THF.

Another embodiment provides a method of preparing a compound of formula 3, comprising couplingAnd R²-B(OR^X)₂Wherein R is²As defined herein, -B (OR)^X)₂Represents boronates or acids known to those skilled in the art; under suitable Suzuki (boronic acid/ester) coupling conditions known to those skilled in the art, the compound of formula 3 is formed. Suitable Suzuki coupling conditions generally involve the use of a catalyst, a base and a boronic acid or ester, and in a suitable solvent. Examples of suitable catalysts include, but are not limited to, Pd (PPh)₃)₂Cl₂、Pd(PPh₃)₄And PdCl₂(dppf). Suitable bases include, but are not limited to, K₂CO₃And Na₂CO₃. Suitable solvents include, but are not limited to, tetrahydrofuran, dioxane, toluene, and ethanol.

Another embodiment provides a method of preparing a compound of formula 1:

comprising reacting a compound of formula a:

wherein R is¹And R²As defined herein;

andunder suitable displacement conditions to produce the compound of formula 1. Suitable displacement conditions 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 THF.

Another embodiment provides a method of preparing a compound of formula 2:

comprising heating a compound of formula 1 with NH₂JJ (reactive amino group-containing J)^QGroup) under suitable displacement conditions to yield the compound of formula 2. Suitable displacement conditions include, but are not limited to, heating a suitable base, such as DIPEA, TEA, DBU or TMP, and in a suitable solvent, such as DMF, isopropanol, dioxane or THF.

One aspect of the present invention pertains to methods of treating a disease state that is alleviated by treatment with a protein kinase inhibitor in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

The method is particularly useful for treating disease states that are alleviated by the use of Aurora kinases (Aurora a, Aurora B, Aurora C), FLT-3 or PDK 1.

The activity of a compound as a protein kinase inhibitor can be determined in vitro, in vivo or in a cell line. In vitro assays include measuring inhibition of kinase activity or ATPase activity that activates kinases. Alternatively, in vitro assays quantify the ability of an inhibitor to bind to a protein kinase and can be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/kinase complex and determining the amount of radiolabel bound, or by performing competition experiments in which the new inhibitor is incubated with a kinase bound to a known radioligand.

Another aspect of the present invention relates to a method of treating cancer in a recipient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, sequentially or concurrently with an anti-cancer agent. In some embodiments, the anti-cancer agent is selected from camptothecin, doxorubicin, idarubicin, cisplatin, paclitaxel, taxotere (taxotere), vincristine, tarceva, a MEK inhibitor, U0126, a KSP inhibitor, or vorinostat.

The protein kinase inhibitor or a pharmaceutical salt thereof may be formulated into a pharmaceutical composition for administration to an animal or human. These pharmaceutical compositions comprise a protein kinase inhibitor in an amount effective to treat or prevent Aurora, FLT-3 or PDK1 mediated disorders 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, allergies and asthma.

The term "cancer" includes, but is not limited to, the following cancers:of mouthEpidermoid tumors: oral cavity, lip, tongue, mouth, pharynx;heart with heart-shaped: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;lung (lung): bronchial carcinomas (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcomas, lymphomas, hamartoma, mesothelioma;gastrointestinal tract: 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 tumor)Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon-rectum, colorectal, rectal;genitourinary tract: kidney (adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);liver disease: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract;bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrosoma (osteochondral exostosis), benign chondroma, chondroblastoma, osteoid osteoma, and giant cell tumor;nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningosarcoma, glioma disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);gynaecology department: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (severe cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, 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;blood, blood-enriching agent and method for producing the same: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, boneMyeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma); hair cells; lymphoid disorders;skin(s): malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; andkidney (Kidney) Upper gland: neuroblastoma. Thus, the term "cancer cell" as provided herein includes cells afflicted by any one of the above conditions. In some embodiments, the cancer is selected from colorectal, thyroid, or breast cancer.

The term "Aurora-mediated disorder" or "Aurora-mediated disease" as used herein denotes any disease or other deleterious disorder in which Aurora (Aurora a, Aurora B and Aurora C) is known to play a role. Such conditions include, without limitation, cancers such as colorectal, thyroid, and breast cancers; and myeloproliferative diseases such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, Chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia, eosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis.

The term "FLT-3-mediated disease" or "FLT-3-mediated disorder" as used herein denotes any disease or other deleterious condition in which a kinase of the FLT-3 family is known to play a role. Such conditions include, without limitation, hematopoietic diseases, particularly Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Acute Promyelocytic Leukemia (APL), and Acute Lymphocytic Leukemia (ALL).

In addition to the compounds of the present invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of the present invention may also be employed in compositions for the treatment or prevention of the above-mentioned conditions.

By "pharmaceutically acceptable derivative or prodrug" is meant any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a metabolite or residue of the compound of the invention or its inhibitory activity. Particularly desirable derivatives and prodrugs are those which increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood), or which enhance delivery of the parent compound to a biological cavity (e.g., the liver, brain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of the present invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts, and sulfonate esters.

The invention also includes pharmaceutically acceptable salts of the compounds of the invention.

Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Other acids, such as oxalic, while not per se pharmaceutically acceptable, may be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from suitable bases include, but are not limited to, alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., magnesium), ammonium, and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also encompasses the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Such quaternization can result in water or oil soluble or dispersible products.

Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

Such pharmaceutical compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally or intravenously.

Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable excipients and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, for example, carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. For formulation purposes, other commonly used surfactants such as tweens, spans, and other emulsifying agents or bioavailability enhancers, which are commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule dosage forms, useful diluents include 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 may also be added.

Alternatively, the pharmaceutical compositions of the present invention may be administered rectally in the form of suppositories. They may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible for topical application, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical administration to the lower intestinal tract may be carried out as a rectal suppository (see above) or as a suitable enema. Topical transdermal patches may also be used.

For topical administration, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved 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 may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic purposes, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably as solutions in isotonic, pH adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

The pharmaceutical compositions of the present invention may also be administered by means of nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The amount of kinase inhibitor that may be combined with the carrier material to form a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 and 100mg/kg body weight/day of inhibitor can be administered to a patient receiving these compositions.

It will also be understood that the specific dose and regimen of treatment for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the attending physician, and the severity of the particular disease being treated. The amount of inhibitor will also depend on the particular compound in the composition.

One embodiment of the present invention provides a method of treating or preventing an Aurora-mediated disorder 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 of treating or preventing a FLT-3-mediated disorder comprising the step of administering to a patient a compound of formula I, or a composition comprising the compound.

Another embodiment provides a method of 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 a method of inhibiting Aurora or FLT-3 activity in a patient, comprising administering to the patient a compound of formula I, or a composition comprising said compound.

One embodiment provides a method of inhibiting Aurora protein kinase activity in a patient comprising administering to the patient a compound of formula I or a composition comprising the compound.

Another embodiment provides a method of inhibiting FLT-3 protein kinase activity in a patient comprising administering to the patient a compound of formula I or a composition comprising the compound.

Another embodiment provides a method of inhibiting PDK1 protein kinase activity in a patient comprising administering to the patient a compound of formula I or a composition comprising the compound.

In some embodiments, the methods are used to treat or prevent a disorder selected from the group consisting of cancers, such as cancers 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, cardiac hypertrophy, alzheimer's disease, cystic fibrosis, and viral disease, or any particular disease or condition described herein.

According to another embodiment, the present invention provides a method of 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 present invention provides a method of treating or preventing cancer comprising the step of administering to a patient one of the compounds or pharmaceutical compositions described herein. In some embodiments, the cancer is selected from brain (glioma), breast, colon, head and neck, kidney, lung, liver, melanoma, ovary, pancreas, prostate, sarcoma, or thyroid. In other embodiments, the cancer is selected from melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from: colon, breast, stomach, ovary, cervix, lung, Central Nervous System (CNS), kidney, prostate, bladder or pancreatic cancer. In other embodiments, the cancer is selected from pancreatic, prostate, or ovarian cancer.

According to another embodiment, the present invention provides a method of treating or preventing a FLT-3-mediated disorder comprising the step of administering to a patient a compound of formula I, or a composition comprising said compound.

Preferably, the method is for the treatment or prevention of a condition selected from hematopoietic disorders, in particular Acute Myeloid Leukemia (AML), Acute Promyelocytic Leukemia (APL), Chronic Myeloid Leukemia (CML) and Acute Lymphocytic Leukemia (ALL).

Another aspect of the invention relates to inhibiting Aurora, FLT-3, or PDK1 activity in a patient, comprising administering to the patient a compound of formula I or a composition comprising said compound.

Another aspect of the invention relates to inhibiting Aurora, FLT-3 or PDK1 activity in a biological sample or patient, comprising contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample" as used herein meansIn vitroOr fromBody Inner partIncluding, without limitation, cell cultures and extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of Aurora, FLT-3 or PDK1 activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and bioassay.

Another embodiment provides a method of treating cancer in a patient in need thereof, comprising the step of disrupting cancer cell mitosis by inhibiting Aurora with a compound of formula I or a composition comprising the compound.

Another embodiment provides a method of treating cancer in a patient in need thereof comprising the step of disrupting cancer cell mitosis by inhibiting FLT-3 with a compound of formula I or a composition comprising the compound.

Depending on the particular disease or condition to be treated or prevented, additional drugs that normally treat or prevent the condition may be administered with the inhibitors of the invention. For example, chemotherapeutic agents or other antiproliferative agents may be combined with Aurora, FLT-3, or PDK1 inhibitors of the invention to treat proliferative diseases.

These additional ingredients may be administered separately from the compounds or compositions containing the Aurora, FLT-3 or PDK1 inhibitors as part of a multiple dosage regimen. Alternatively, these ingredients may be part of a single dosage form, mixed together in a single composition with the Aurora, FLT-3 or PDK1 inhibitor.

Detailed Description

In order that the invention may be more fully understood, the following preparation and test examples are set forth. These examples are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way.

Example 1

1- (6-Chloropyrimidin-4-yl) -5, 6-dimethyl-1H-benzo [ d]Imidazol-2-amine (1): a round-bottom flask was charged with 4, 6-dichloropyrimidine (1.69g, 11.3mmol), 2-amino-5, 6-dimethylbenzimidazole (1.83g, 11.3mmol), D I PEA (1.92ml, 11.3mmol) and DMF (50 ml). The reaction mixture was stirred vigorously at 80 ℃ for 6 days, then cooled to room temperature. The volatile components of the reaction mixture were then removed in vacuo and the residue was adsorbed on silica and then purified by column chromatography using hexane (40-60)/EtOAc 0% to 100% as eluent to give a yellow solid (1.09g, 35%). 1H NMR (CDCl)₃)：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/MS 374.30[M+H] 372.50[M-H]。

1- (6- ((S) -1-1-amino-3-methylbutan-2-ylamino) pyrimidin-4-yl) -5, 6-dimethyl-1H-benzo [ d]Imidazol-2-amine, bis-TFA salt (compound 2): the test tubes were filled with 1- (6-chloropyrimidin-4-yl) -5, 6-dimethyl-1H-benzo [ d ]]Imidazol-2-amine (1) (0.27g, 1.0mmol), tert-butyl (S) -2-amino-3-methylbutylcarbamate (0.20g, 1.0mmol), DIPEA (0.34ml, 2.0mmol) and isopropanol (5ml), then sealed and heated to 120 ℃ for 2 days. After the mixture is cooled to the room temperature,the volatile components were removed in vacuo and the residue was purified by column chromatography using hexane (40-60)/EtOAc 0% to 100% as eluent to give a waxy white solid. This product was dissolved in DCM (5ml) and TFA (2ml) and stirred at room temperature for 2 h. The volatile components were then removed in vacuo and the residue was purified by preparative HPLC on a C-18 reverse phase column using a gradient of 0% to 100% MeCN and water/0.05% w/v TFA as eluent. The product containing fractions were then freeze dried to give the desired product as a white solid (0.13g, 29.6%). 1H NMR (DMSO-d)₆)：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[M+H]338.63[M-H]。

Compounds 1-15 and 19-44 were prepared in a similar manner to example 1. Compounds 45-58 can also be prepared in a similar manner to example 1.

Example 2

3- (4-fluoro-3-nitrophenyl) pyridine 2.0g of 3-pyridineboronic acid, 3.22g of 4-bromo-1-fluoro-2-nitrobenzene and 285mg of Pd (PPh)₃)₂Cl₂Then 50mL of degassed 1, 4-dioxane were added and the mixture was stirred at room temperature for 20 min. 50mL of degassed aqueous sodium carbonate (1M) were added and the reaction mixture was heated at reflux for 1.5h under argon. The solvent was removed in vacuo, ethyl acetate was added and the solution was filtered through celite. The filtrate was washed with brine, over MgSO₄Drying and concentration gave 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/CHCl₃As eluent, a yellow solid was obtained (1.58g, 80%). m.p.87-88 ℃;

to a stirred solution of 1.58g of 3- (4-fluoro-3-nitrophenyl) pyridine in 5.0mL of DMF under a nitrogen atmosphere was added 1.124g of N-ethyldiisopropylamine followed by 2.116g of tert-butylamine. The reaction mixture was maintained at 50 ℃ 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 brine solution. The organic layer was dried over sodium sulfate and evaporated to give an orange solid (1.57g, 85%). m.p.67-69 ℃;

2-Nitro-4- (pyridin-3-yl) aniline to a stirred solution of 1.5g N-tert-butyl-2-nitro-4- (pyridin-3-yl) aniline in 15mL of methanol was added 9mL of 6N HCl. The solution was refluxed for 3 h. The reaction was then diluted with chloroform and saturated NaHCO₃The solution was adjusted to pH 7. The organic layer was separated, washed with water followed by brine, dried over sodium sulfate and evaporated to give an orange solid (1.06g, 90%).

2- (2-Nitro-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonitrile to a stirred solution of 0.5g 2-nitro-4- (pyridin-3-yl) aniline in 3mL DMF was added 2.267g CS₂CO₃Followed by 0.386g of 2-chloro-3-cyano-pyridine. The reaction mixture was heated to 130 ℃ for 5h under nitrogen atmosphere. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated, washed with water followed by brine, dried over sodium sulfate and evaporated to give a yellow solid (0.440g, 60%). mp: 91-92 ℃.

2- (2-amino-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonitrile to a stirred solution of 0.3g 2- (2-nitro-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonitrile in 15mL ethanol at room temperature was added 0.471g stannous chloride. The reaction mixture was refluxed for 2.5 h. The reaction was diluted with 20mL ethyl acetate, 15mL water and then adjusted to basic pH 8-9 with saturated sodium bicarbonate solution. The organic layer was separated, washed with water followed by brine solution, dried over sodium sulfate and evaporated to give a yellow solid (0.217g, 80%). mp: 67-68 ℃;

2- (2-amino-5- (pyridin-3-yl) -1H-benzo [ d]Imidazol-1-yl) pyridine-3-carbonitrile (compound 18) to a stirred solution of 170mg 2- (2-amino-4- (pyridin-3-yl) phenylamino) pyridine-3-carbonitrile in 5mL methanol and 5mL water at 0 deg.C was added 65mg of cyanogen bromide. The reaction mixture was brought to room temperature and stirred at this temperature under nitrogen for 3 h. The reaction was diluted with 20mL ethyl acetate, 15mL water and then adjusted to basic pH8 with saturated sodium bicarbonate solution. The organic layer was separated, washed with water followed by brine solution, dried over sodium sulfate and evaporated to give a crude solid. The crude compound was purified by preparative TLC using 5% MeOH/CHCl₃As eluent, light yellow solid (25mg, 10.6%) was obtained. LC/MS 313.2[ M + H ]]¹HNMR(300MHz、CDCl₃)：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 prepared in a similar manner to example 2.

Table 2 below depicts data for certain exemplary compounds. The compound numbers correspond to those depicted in table 1.

The following analytical methods were used.

Method A

Mass spectral samples were analyzed on a MicroMass Quattro Micro mass spectrometer using single MS mode and electrospray ionization. The sample was introduced to the mass spectrometer using a chromatographic method. The mobile phase for all mass analyses consisted of 10mM ammonium acetate pH 7 and a 1: 1 acetonitrile-methanol mixture, column gradient conditions 5% to 100% acetonitrile-methanol over a 4.5min gradient time and 6.2min run time, column ACE C83.0 x 75 mM. The flow rate was 1.0 ml/min.

Method B

Mass spectral samples were analyzed on MicroMass ZQ, ZMD or Quattro II mass spectrometers using single MS mode and electrospray ionization. The sample is introduced to the mass spectrometer using Flow Injection (FIA) or chromatographic methods. The mobile phase for all mass spectrometry consists of an acetonitrile-water mixture containing 0.2% formic acid or 0.1% TFA as modifier. Column gradient conditions 10% -90% acetonitrile over a 3min gradient time and 5min run time, column Waters YMC Pro-C184.6 x50 mm. The flow rate was 1.5 ml/min.

Method C

Same as procedure C, but with column gradient conditions of 5% -45% acetonitrile over a 5min gradient time and 7min run time, the column was Waters YMC Pro-C182 x50 mm. The flow rate was 1.0 ml/min.

TABLE 2

No	M+1(obs)	1H NMR	Rt(mins)	Mass spectrometry method
					1	312.5	1H NMR (DMSO-d6)：0.94(6H，s)，1.95(1H，m)，2.86(1H，br s)，3.13(1H，br s)，4.34(1H，m)，6.92(1H，s)，7.28(1H，t)，7.32(1H，t)，7.45(1H，d)，7.55(1H，d)，7.93(4H，m)，8.56(1H，s)，8.83(2H，br s)	6.796	A
2	340.45	1H NMR (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)	7.939	A
					3	310.49	1H 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，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)	5.874	A

4	338.43	1H NMR (DMSO-d6)：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)，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)	7.134	A
					5	297	1H NMR (CD3SOCD3，400MHz)：d 0.91(d，6H)，2.03-2.14(m，1H)，3.02-3.67(m，5H)，6.84-7.11(m，1H)，7.25-7.39(m，2H)，7.47(d，1H)，7.52-7.66(m，1H)，8.61(s，1H)，8.91(s，br.，2H)	2.00	B
6	410.5	1H NMR (DMSO-d6)：1.48(9H，s)，1.76(5H，m)，2.01(1H，m)，3.60(3H，m)，5.36(1H，br s)，6.37(2H，s)，6.66(1H，s)，7.13(1H，t)，7.22(1H，t)，7.44(2H，d)，8.58(1H，s)	9.263	A
					7	412.58	1H 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，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)	9.295	A
8	352.1	1H NMR (CD3SOCD3，400MHz)：d 1.75-1.81(m，1H)，1.83-1.89(m，1H)，1.97(s，3H)，3.40-3.56(m，2H)，3.62-3.80(m，4H)，3.87-4.08(m，2H)，7.05-7.18(m，1H)，7.27-7.32(m，1H)，7.33-7.38(m，1H)，7.46-7.59(m，2H)，8.65(d，1H)，8.96(s，br.，2H)	2.10	C
					9	294.9	1H NMR (CD3SOCD3，400MHz)：d 1.14-1.29(m，3H)，1.70-1.79(m，1H)，1.94-2.17(m，4H)，3.27-3.74(m，2H)，6.72-6.90(m，1H)，7.26-7.63(m，4H)，8.61(s，1H)，8.92(s，br.，2H)	1.80	B
10	309	1H NMR (CD3SOCD3，400MHz)：d 1.48-1.58(m，4H)，1.71-1.79(m，4H)，3.53-3.61(m，2H)，3.84-3.90(m，2H)，6.96(s，1H)，7.26-7.37(m，2H)，7.46(d，1H)，7.50(d，1H)，8.61(s，1H)，8.85(s，b r.，2H)	2.00	B

11	335	1H NMR (CD3SOCD3，400MHz)：d 1.61-1.68(m，8H)，2.12-2.19(m，2H)，3.52-4.41(m，4H)，7.17(s，1H)，7.27-7.38(m，2H)，7.44-7.52(m，2H)，8.61(s，1H)，8.85(s，br.，2H)	2.30	B
					12	346.9	1H NMR (CD3SOCD3，400MHz)：d 3.67-3.76(m，2H)，5.22-5.30(m，1H)，6.99-7.61(m，10H)，8.38-8.68(m，2H)，9.00(s，br.，2H)	1.80	B
13	324.9	1H NMR (CD3SOCD3，400MHz)：d 1.56-2.02(m，8H)，3.69(s，2H)，6.91(s，1H)，7.28-7.74(m，5H)，8.52(s，1H)，8.99(s，br.，2H)	1.80	B
					14	320.9	1H NMR (CD3SOCD3，400MHz)：d 7.16-7.64(m，8H)，7.95-8.02(m，1H)，8.72(s，1H)，8.85(s，br.，2H)，9.89(s，1H)	2.00	B
15	366.1	1H NMR (CD3SOCD3，400MHz)：d 1.08-1.27(m，6H)，2.07(s，3H)，3.17-3.32(m，2H)，4.00-4.75(m，4H)，7.23-7.49(m，5H)，8.65(s，1H)，8.85(s，br.，2H)	1.60	B
					16	-	1H NMR (CDCl3)：d 8.92(d，1H)，8.83(s，1H)，8.81(s，1H)，8.57(dd，1H)，8.51(d，1H)，7.92(dt，1H)，7.6(s，1H)，7.32-7.38(m，2H)，7.21(m，2H)，7.10(b s，1H).	-	-
17	-	1H NMR (CDCl3，300MHz)：8.9(s，1H)，8.6(br.t、J＝7.5Hz，2H)，7.9(m，2H)，7.72(d、J＝8.4Hz，1H)，7.66(s，1H)，7.52(d、J＝8.4Hz，1H)，7.28(m，3H)，6.4(b s，2H).	-	-
					18	-	1H NMR (CDCl3，300MHz)：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(b r.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).	-	-
19	246.26	1H NMR (DMSO-d6)：7.01(1H，t)，7.14(1H，t)，7.18(2H，s)，7.27(1H，d)，7.63(1H，d)，7.97(1H，s)，9.08(1H，s)；1H NMR (CD3SOCD3，400MHz)：d 7.23-7.28(m，1H)，7.32-7.36(m，1H)，7.45(d，1H)，7.66(d，1H)，8.13(s，1H)，8.81(s，br.，2H)，9.22(s，1H)	7.778	A

20	294.90	1H NMR (CD3SOCD3，400MHz)：d 1.14-1.29(m，3H)，1.70-1.79(m，1H)，1.94-2.17(m，4H)，3.27-3.74(m，2H)，6.72-6.90(m，1H)，7.26-7.63(m，4H)，8.61(s，1H)，8.92(s，br.，2H)	1.80	B
					21	366.10	1H NMR (CD3SOCD3，400MHz)：d 1.08-1.27(m，6H)，2.07(s，3H)，3.17-3.32(m，2H)，4.00-4.75(m，4H)，7.23-7.49(m，5H)，8.65(s，1H)，8.85(s，br.，2H)	1.60	B
22	283.29	1H NMR (DMSO-d6)：2.28(6H，d)，3.16(6H，s)，6.71(1H，s)，6.95(2H，s)，7.03(1H，s)，7.31(1H，s)，8.53(1H，s)	8.862	A
					23	269.31	1H NMR (DMSO-d6)：2.24(6H，d)，2.90(3H，s)，6.57(1H，s)，7.02(3H，s)，7.20(1H，s)，7.72(1H，m)，8.48(1H，s)	8.862	A
24	311.32	1H NMR (DMSO)：0.95(6H，d)，1.88(1H，m)，2.24(6H，d)，3.23(2H，m)，6.78(1H，s)，7.03(1H，s)，7.08(2H，s)，7.25(1H，s)，7.80(1H，t)，8.44(1H，s)	9.69	A
					25	352.36	1H NMR (DMSO)：1.26(2H，m)，1.53(1H，m)，1.84(2H，m)，2.29(1H，m)，2.31(6H，d)，2.67(3H，m)，3.27(2H，t)，6.84(1H，s)，7.26(1H，s)，7.36(1H，s)，8.21(1H，t)，8.56(1H，s)，8.75(1H，d)，8.97(2H，s)	7.235	A
26	338.37	1H NMR (DMSO)：1.81(1H，m)，2.08(1H，m)，2.31(6H，d)，2.59(1H，m)，2.98(1H，m)，3.37(4H，m)，3.50(1H，t)，6.83(1H，s)，7.35(1H，s)，8.02(1H，s)，8.24(1H，t)，8.57(1H，s)，8.81(2H，br s)，8.95(1H，s)	9.984	A
					27	365.44	1H NMR (CDCl3)：1.19(3H，m)，1.23(6H，m)，1.55(1H，br s)，1.80(6H，m)，2.34(5H，m)，5.70(1H，br s)，6.58(1H，s)，6.60(1H，br s)，7.22(2H，s)，7.73(1H，s)，8.46(1H，s)，8.92(1H，s)	10.888	A
28	389.42	1H NMR (CDCl3)：2.14(3H，m)，2.21(6H，m)，3.83(2H，m)，6.77(1H，br s)，7.08(1H，s)，7.38(3H，m)，7.43(4H，m)，8.43(1H，s)	9.016	A
					29	341.38	1H NMR (CDCl3)：1.07(6H，d)，2.06(2H，m)，2.20(6H，d)，3.85(1H，m)，3.92(1H，m)，6.00(1H，d)，6.37(1H，s)，6.70(1H，br s)，7.01(1H，s)，7.16(1H，s)，8.35(1H，s)	8.801	A

30	359.35	1H NMR (CDCl3)：1.65(3H，d)，2.12(3H，s)，2.28(3H，s)，4.72(1H，br s)，6.39(2H，br s)，6.94(2H，br s)，7.14(1H，s)，7.40(5H，m)，8.49(1H，s)	9.872	A
					31	324.32	1H NMR (DMSO-d6)：2.15(1H，br s)，2.31(6H，d)，2.38(1H，br s)，3.75(5H，br m)，6.86(1H，s)，7.26(1H，s)，7.35(1H，s)，8.25(3H，d)，8.66(1H，s)，8.91(2H，s)	7.189	A
32	324.32	1H NMR (DMSO-d6)：2.18(1H，br s)，2.31(6H，d)，2.46(1H，s)，3.84(5H，br m)，6.86(1H，s)，7.27(1H，s)，7.35(1H，s)，8.27(2H，d)，8.66(1H，s)，8.94(2H，s)	7.200	A
					33	338.37	1H NMR (DMSO-d6)：1.64(4H，m)，1.85(1H，m)，2.08(1H，m)，2.31(6H，d)，3.23(3H，m)，7.16(1H，s)，7.26(1H，s)，7.31(1H，s)，8.08(3H，s)，8.67(1H，s)，8.89(2H，s)	7.572	A
34	338.37	1H NMR (DMSO-d6)：1.67(4H，m)，1.85(1H，m)，2.07(1H，m)，2.31(6H，d)，3.23(3H，m)，7.16(1H，s)，7.26(1H，s)，7.31(1H，s)，8.10(3H，s)，8.67(1H，s)，8.90(2H，s)	7.550	A
					35	331.32	1H NMR (CDCl3)：2.35(6H，d)，7.27(4H，m)，7.44(2H，t)，7.64(1H，d)，7.76(1H，s)，8.95(1H，s)	9.768	A
36	298.31	1H NMR(DMSO-d6)：2.33(6H，d)，3.04(2H，d)，3.66(2H，d)，6.86(1H，s)，7.25(1H，s)，7.33(1H，s)，7.92(3H，br s)，8.22(1H，s)，8.60(1H，s)，8.87(2H，s)	6.640	A
					37	352.43	1H NMR (DMSO-d6)：1.24(4H，m)，1.91(4H，m)，2.29(6H，d)，2.51(1H，br s)，3.89(1H，br s)，6.73(1H，s)，7.12(1H，s)，7.30(1H，s)，8.02(3H，br s)，8.16(1H，d)，8.55(1H，d)，8.83(2H，s)	7.514	A
38	374.39	1H NMR (DMSO-d6)：2.33(6H，d)，4.05(2H，d)，4.69(2H，d)，6.92(1H，s)，7.13(1H，s)，7.40(5H，m)，8.19(3H，br s)，8.56(2H，m)，8.89(2H，s)	7.799	A
					39	312.29	1H NMR (MeOD)：2.04(2H，m)，2.35(6H，d)，3.07(2H，t)，3.66(2H，m)，6.88(1H，s)，7.19(1H，s)，7.37(1H，s)，8.56(1H，s)	6.816	A

40	361.38	1H NMR (DMSO-d6)：2.31(6H，d)，3.87(3H，s)，7.02(1H，m)，7.18(3H，m)，7.37(1H，s)，7.44(1H，s)，7.84(1H，s)，8.67(1H，s)，8.88(2H，s)，9.50(1H，s)	9.739	A
					41	361.31	1H NMR (DMSO-d6)：2.31(6H，d)，3.78(3H，s)，6.71(1H，d)，7.23(2H，s)，7.28(1H，m)，7.42(2H，s)，8.78(3H，m)，10.14(1H，s)13.06(1H，brs)	9.770	A
42	361.31	1H NMR (DMSO-d6)：2.31(6H，d)，3.76(3H，s)，6.99(3H，m)，7.23(1H，s)，7.39(1H，s)，7.59(2H，s)，8.81(1H，s)，8.97(2H，s)，9.98(1H，s)	9.557	A
					43	365.30	1H NMR (DMSO-d6)：2.33(6H，d)，7.15(2H，m)，7.26(1H，s)，7.42(2H，m)，7.58(1H，d)，8.06(1H，s)，8.81(3H，m)，10.32(1H，s)	10.366	A
44	365.30	1H NMR (DMSO-d6)：2.47(6H，d)，7.24(1H，s)，7.37(1H，s)，7.60(3H，m)，7.94(2H，d)，8.92(3H，m)，10.58(1H，s)	10.238	A

Biological method

Example 1: aurora B inhibition assay(radiation analysis)

Assay buffer solutions were prepared from 25mM HEPES (pH 7.5), 10mM MgCl₂0.1% BSA and 10% glycerol. A22 nM Aurora-B solution was prepared in assay buffer, also containing 1.7mM DTT and 1.5mM Kemptide (LRRASLG). In 96-well plates, 22. mu.L of Aurora-B solution was added with 2. mu.l of DMSO stock solution of the compound and the mixture was allowed to equilibrate for 10 minutes at 25 ℃. The enzyme reaction was initiated by adding 16. mu.l of stock [ gamma-³³P]ATP solution (. about.20 nCi/. mu.L) at a final assay concentration of 800. mu.M. After 3 hours, the reaction was terminated by adding 16. mu.L of 500mM phosphoric acid, and binding to the peptide substrate was determined by the following method³³The level of P.

Phosphocellulose 96-well plates (Millipore, Cat No. maphnob50) were pre-treated with 100 μ L of 100mM phosphoric acid, followed by addition of the enzyme reaction mixture (40 μ L). The phosphocellulose membrane was soaked with the solution for 30 minutes and the plate was then washed four times with 200 μ L of 100mM phosphoric acid. To each well of the dry plate was added 30 μ L Optiphase 'Supermix' liquid scintillation cocktail reagent (Perkin Elmer) followed by scintillation counting (1450 Microbeta Liquid science Counter, Wallac). The background radioactivity level without enzyme catalysis was determined by adding 16. mu.L of 500mM phosphoric acid containing all assay components (which act to denature the enzyme) to the control wells followed by [ gamma-³³P]-an ATP solution. Calculating enzyme catalyzed by subtracting the average background counts from the counts measured at each inhibitor concentration³³P binding level. For each Ki assay, 8 data points were obtained in duplicate, typically covering a compound concentration range of 0-10 μ M (DMSO stocks prepared from initial 10mM compound stocks followed by 1: 2.5 serial dilutions). Ki values were calculated from the initial rate data by means of non-linear regression analysis using the Prism Software package (Prism 3.0, Graphpad Software, San Diego, CA).

The following compounds inhibited Aurora-B with Ki values < 1 uM: compounds 1-4, 14 and 28.

Example 2: inhibition of FLT-3By means of assays

Compounds were screened for their ability to inhibit FLT-3 activity using a radioactive filter-binding assay. Assay monitoring³³Binding of P to the substrate poly (Glu, Tyr) 4: 1(pE 4Y). The reaction was carried out in the presence of 100mM HEPES (pH 7.5), 10mM MgCl₂25mM NaCl, 1mM DTT, 0.01% BSA and 2.5% DMSO. The final substrate concentration in the assay was 90. mu.M ATP and 0.5mg/mL pE4Y (both from Sigma Chemicals, St Louis, Mo.). The final concentration of the compounds of the invention is generally between 0.01 and 5. mu.M. Typically, serial dilutions are prepared from a 10mM stock solution of test compound in DMSO and a 12-point titration is performed. The reaction is carried out at room temperature.

Two assay solutions were prepared. Solution 1 contained 100mM HEPES (pH 7.5), 10mM MgCl₂25mM NaCl, 1mg/mL pE4Y and 180mM ATP (each reaction containing 0.3mCi [ gamma-³³P]ATP). Solution 2 contained 100mM HEPES (pH 7.5), 10mM MgCl₂25mM NaCl, 2mM DTT, 0.02% BSA and 3nM FLT-3. Mix 50 μ L of solution 1 and 2.5mL of the compound of the invention in a 96 well plate. The reaction was initiated with solution 2. After 20min incubation at room temperature, the reaction was stopped with 50 μ L of 20% TCA containing 0.4mM ATP. The total reaction volume was then transferred to filter plates with the aid of Harvester 9600 from TOMTEC (Hamden, CT) and washed with 5% TCA. Binding to pE4Y was analyzed by means of a Packard Top countMicroplate scintillation counter (Meriden, CT)³³The amount of P. Data were analyzed using Prism software to obtain IC₅₀Or Ki.

The following compounds inhibited FLT-3 with Ki values < 1. mu.M: compounds 1-5, 8-17, 20-42 and 44.

Example 3: PDK-1 inhibition assay

Compounds were screened for their ability to inhibit PDK-1 using a radioactive phosphate binding assay (Pitt and Lee, j.biomol.screen., (1996)1, 47). The assay was at 100mM HEPES (pH 7.5), 10mM MgCl₂25mM NaCl, 2mM DTT. The final substrate concentrations in the assay were 40. mu.M ATP (Sigma Chemicals) and 65. mu.M peptide (PDKtide, Upstate, Lake plasmid, NY). At 27.5 nCi/mu L [ gamma-³²P]The assay was performed in the presence of ATP (Amersham Pharmacia Biotech, Amersham, UK) at 30 ℃ and 25nM PDK-1. Assay stock buffer solutions were prepared containing all the reagents listed above, except ATP, and the relevant test compounds. Mu.l of the stock solution was placed in a 96-well plate, followed by the addition of 1. mu.l of a 0.5mM DMSO stock solution containing the test compound (final compound concentration 25. mu.M, final DMSO concentration 5%). The plate was preincubated at 30 ℃ for about 10 minutes and the reaction was initiated by adding 4. mu.l ATP (final concentration 40. mu.M).

After 10 minutes, 100. mu.L of 100mM phosphoric acid, 0.01% Tween-20 was added to terminate the reaction. Phosphocellulose 96-well plates (Millipore, Cat No. MAPHHNOB50) were pretreated with 100. mu.L of 100mM phosphoric acid, 0.01% Tween-20, and then the reaction mixture (100. mu.L) was added. The spots were soaked for at least 5 minutes and then washed (4X 200. mu.L of 100mM phosphoric acid, 0.01% Tween-20). After drying, 20 μ L of Optiphase 'Supermix' Liquid Scintillation cocktail reagent (Perkin Elmer) was added to the wells, followed by Scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

Titration of compounds exhibiting greater than 50% inhibition relative to a standard well containing assay mixture and DMSO without test compound, determination of IC₅₀The value is obtained.

While we have described a number of embodiments of this invention, it is apparent that our basic examples can be altered to provide other embodiments that utilize the compounds, methods and processes of this invention. It is therefore to be appreciated that the scope of the invention is limited by the claims and not by the specific embodiments represented by the above examples.

Claims (36)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof;

wherein

Q is selected from the group consisting of:

R¹is H, C_1-6Aliphatic radicals or C_3-8Cycloaliphatic radical, optionally substituted by 0 to 4J^R；

Each R²Independently is Z^R、M^R、(L^R)-Z^ROr (X)^R)-M^R；

Each J^QIndependently is Z^Q、M^Q、(L^Q)-Z^QOr (X)^Q)-M^Q；

Each L^R、L^Q、X^RAnd X^QIndependently is C_1-6Alkyl, optionally substituted up to 2 occurrences of-NR-, -O-, -S-, -CO₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NR-、-C(＝N-CN)、-C(＝N-OH)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-、-NRC(O)NR-、-OC(O)NR-、-NRSO₂NR-, -SO-or-SO₂-an interrupt;

wherein

Each L^RIndependently and selectively substituted by 0-2J^LRSubstitution;

each L^QIndependently and selectively substituted by 0-2J^LQSubstitution;

each X^RIndependently and selectively substituted by 0-2J^XRSubstitution;

each X^QIndependently and selectively substituted by 0-2J^XQSubstitution;

each Z^RAnd Z^QIndependently is H; c_1-6An aliphatic group; a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein

Each Z^RIndependently and selectively covered with 0-4J^ZRSubstitution;

each Z^QIndependently and selectively covered with 0-4J^ZQSubstitution;

each M^RAnd M^QIndependently is halo, CN, CF₃、NO₂OR, SR OR N (R)₂；

Each J^RIndependently is C_1-6Aliphatic radical, C_1-6Haloalkyl, halo, OH, C_1-3Alkoxy group, NO₂Or CN;

each J^LR、J^LQ、J^XR、J^XQ、J^ZRAnd J^ZQIndependently V, M, (L)^V)-V、(L^M)-M、C_1-6Haloalkyl, halo, OH, C_1-3Alkoxy group, NO₂Or CN;

each R is independently H, C_1-6Aliphatic radical, C_6-10Aryl, - (C)_1-6Aliphatic radical) - (C_6-10Aryl group), C_3-8Cycloaliphatic radical, -C (═ O) (C)_1-6Aliphatic group), -C (═ O) (C)_3-8Cycloaliphatic radical) or-C (═ O) O (C)_1-6Aliphatic groups); wherein each R is independently and optionally substituted with 0-2J;

each L^VAnd L^MIndependently is C_1-6Alkyl, optionally substituted up to 2 occurrences of-NR-, -O-, -S-, -CO₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NR-、-C(＝N-CN)、-C(＝N-OH)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-、-NRC(O)NR-、-OC(O)NR-、-NRSO₂NR-, -SO-or-SO₂-an interrupt;

wherein

Each L^VIndependently and selectively substituted by 0-2J^LVSubstitution;

each L^MIndependently and selectively substituted by 0-2J^LMSubstitution;

each V is independently H; c_1-6An aliphatic group; a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each V is independently and selectively substituted by 0-2J^VSubstitution;

each J, J^LV、J^LMAnd J^VIndependently is R', C_3-6Cycloalkyl radical, C_1-6Haloalkyl, halo, NO₂、CN、OH、OR′、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、SO₂NH₂、SO₂NHR′、SO₂N(R′)₂、NHSO₂R 'or NR' SO₂R′；

R' is unsubstituted C_1-6An aliphatic group; or two R' groups together with the atoms to which they are bonded form an unsubstituted 3-8 membered saturated or partially saturated monocyclic ring having 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each M is independently halo, CN, CF₃、NO₂、OH、O(C_1-6Alkyl), SH, S (C)_1-6Alkyl), NH₂、NH(C_1-6Alkyl) or N (C)_1-6Alkyl radical)₂；

Provided that it is

When Q isWhen R is²Not in position 5 or 6 of the benzimidazole ring

When Q isOrAnd R is²Is H, F, Cl, CH at position 5 or 6 of the benzimidazole ring₃、CF₃、OCH₃Or OCH₂CH₃When, J^QIs not-O- (C)_1-3Aliphatic groups);

when Q isOrWhen, J^QNot being optionally substituted by methyl

When R is¹And R²When is H, Q is not

When Q isWhen, J^QNot 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 C_1-6An aliphatic group.

2. The compound of claim 1, wherein R¹Is 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 of any one of claims 1-4, wherein J^QIs (L)^Q)-Z^QOr (X)^Q)-M^Q。

7. The compound of claim 6, wherein L^QIs C_1-6Alkyl, optionally substituted up to 2 times by-NR-, -O-, -S-, -C (O) NR-, -NRCO-, -SO₂NR-or-NRSO₂-an interrupt.

8. The compound of claim 7, wherein L^QIs C_1-6Alkyl, optionally interrupted by up to 1 occurrence of-NR-.

9. The compound of claim 8, wherein 1 occurrence of-NR-is directly attached to ring Q.

10. The compound of any one of claims 1-4, wherein J^QIs Z^QOr M^Q。

11. The compound of any one of claims 6-10, wherein Z is^QIs H or an optionally substituted group selected from: c_1-6Aliphatic radical, C_3-8Cycloaliphatic, phenyl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl.

12. The compound of any one of claims 6-11, wherein X^QIs C_1-6Alkyl, optionally substituted up to 2 times by-NR-, -O-, -S-, -C (O) NR-, -NRCO-, -SO₂NR-or-NRSO₂-an interrupt.

13. The compound of claim 12, wherein X^QIs C_1-6Alkyl, optionally interrupted by up to 1 occurrence of-NR-.

14. The compound of any one of claims 6-13, wherein J, wherein ring Q is 2 occurrences^QSubstituted, one of which is J^QIs (L)^Q)-Z^QOr (X)^Q)-M^QAnother J^QIs Z^QOr M^Q。

15. The compound of any one of claims 1-14, wherein each R²Is selected from Z^ROr M^R。

16. The compound of any one of claims 1-15, substituted as shown in formula III:

formula III.

17. The compound of claim 16, wherein at least one R²Is not H.

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

19. the compound of claim 1 selected from the following:

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

21. A method of inhibiting Aurora protein kinase activity in a patient comprising administering to said patient

a) The composition of claim 20; or

b) A compound according to any one of claims 1 to 19.

22. A method of inhibiting Aurora protein kinase activity in a biological sample comprising contacting said biological sample with:

a) the composition of claim 20; or

b) Contacting a compound of any one of claims 1-19.

23. A method of inhibiting FLT-3 protein kinase activity in a patient comprising administering to said patient

a) The composition of claim 20; or

b) A compound according to any one of claims 1 to 19.

24. A method of inhibiting FLT-3 protein kinase activity in a biological sample comprising contacting said biological sample with:

a) the composition of claim 20; or

b) Contacting a compound of any one of claims 1-19.

25. A method of inhibiting PDK1 protein kinase activity in a patient comprising administering to said patient

a) The composition of claim 20; or

b) A compound according to any one of claims 1 to 19.

26. A method of inhibiting PDK1 protein kinase activity in a biological sample comprising contacting said biological sample with:

a) the composition of claim 20; or

b) Contacting a compound of any one of claims 1-19.

27. A method of treating a proliferative disorder in a patient comprising administering to said patient

a) The composition of claim 20; or

b) A compound according to any one of claims 1 to 19.

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

29. A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from: colon, breast, stomach, ovary, cervix, lung, Central Nervous System (CNS), kidney, prostate, bladder, pancreas, brain (glioma), head and neck, kidney, liver, melanoma, sarcoma, or thyroid cancer, wherein the method comprises administering to the patient

a) The composition of claim 20; or

b) A compound according to any one of claims 1 to 19.

30. A method of treating cancer in a patient in need thereof, comprising treating the cancer by administering to the patient:

a) the composition of claim 20; or

b) Compounds according to any of claims 1 to 19

Step of inhibiting Aurora to destroy cancer cell mitosis.

31. A method of treating cancer in a patient in need thereof, comprising treating the cancer by administering to the patient:

a) the composition of claim 20; or

b) Compounds according to any of claims 1 to 19

A step of inhibiting FLT-3 to disrupt cancer cell mitosis.

32. A process for preparing a compound of formula I:

wherein R is¹、R²And J^QAs defined herein;

ring Q isOr

Comprising reacting a compound of formula a:

wherein R is¹And R²Is as defined in any one of claims 1 to 19;

with a compound of formula b:

wherein ring Q isOr

And J^QIs as defined in any one of claims 1 to 19;

under the coupling condition of proper boric acid or boric acid ester.

33. A process for preparing a compound of formula I:

wherein R is¹、R²And J^QIs as defined in any one of claims 1 to 19;

ring Q is

Comprising reacting a compound of formula a:

wherein R is¹And R²Is as defined in any one of claims 1 to 19;

with a compound of formula c:

wherein J^QIs as defined in any one of claims 1 to 19;

ring Q is

Under suitable displacement conditions.

34. A process for preparing a compound of formula I:

wherein R is²、R²Ring Q and J^QIs as defined in any one of claims 1 to 19;

comprising reacting a compound of formula 7:

wherein R is²And ring Q is as defined in any one of claims 1 to 19;

cyclizing with CN-Br under suitable cyclization conditions.

35. A process for preparing a compound of formula 2:

comprising heating a compound of formula 1 with NH under suitable displacement conditions₂-JJ to produce the compound of formula 2.

36. The method of claim 35, comprising reacting a compound of formula a:

wherein R is¹And R²Is as defined in any one of claims 1 to 19;

andunder suitable displacement conditions to produce a compound of formula 1: