Pyrrolopyrazines suitable as aurora a kinase inhibitors

The present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods for their use. In particular, the compounds are inhibitors of the Aurora kinases and are useful for the treatment of disease states such as cancer, which facilitate by Aurora kinase inhibitors.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the regulation of a number of signal transduction processes within cells (see. Hardie, G. and Hanks, S. The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995). Protein kinases are attractive and proven targets for new therapeutic agents to treat a variety of human diseases, examples of which include Gleevec and Tarceva.

Aurora kinases are especially attractive due to their association with numerous human cancers and the role they play in promoting proliferation of these cancer cells (Harrington et al., Nature Med., 2004, 10, 262).

Aurora proteins are a family of three with a high degree of kinship of serine / threonine kinases (referred Aurora-A, -B and -C) that are essential in advancing through the mitotic phase of the cell cycle. Particularly Aurora-A plays a key role in the maturation of the centrosome and segregation, formation of the mitotic spindle and proper chromosome segregation. Aurora-B is a chromosomal a protein "passenger", which plays a central role in regulating the alignment of chromosomes on the metaphase plate, the spindle assembly checkpoint and the correct completion of cytokinesis (cell division).

Overexpression of Aurora-A, -B or -C observed in a number of human cancers, including gastrointestinal, ovarian, gastric and invasive ductal adenocarcinoma. In addition, the amplification of the locus AURKA, which codes for Aurora-A correlates (correlated) with imperfect prognosis for breast cancer patients without lymph node involvement. Furthermore overexpression of Aurora-A has been shown to transform mammalian fibroblasts, giving rise to aneuploid cells containing multipolar spindles.

A number of studies currently demonstrated that a reduction or inhibition of Aurora-A or -B in human cancer cell lines by means of siRNA (short interfering RNA molecules), dominant negative or neutralizing antibodies is penalized for advancement through mitotic cell division with accumulation of cells with 4N DNA, and in some cases this is followed endoreduplication and cell death.

SUMMARY OF THE INVENTION

It has now been found that the compounds of this invention and pharmaceutically acceptable compositions thereof are effective as inhibitors of protein kinases. In certain embodiments, these compounds are effective as inhibitors of Aurora protein kinase and, in some embodiments - as inhibitors of Aurora-A kinase. These compounds have the general formula I:

<img file="00000001.tif" he="46" wi="132" img-format="tif" img-content="undefined" />

or represented in the form of pharmaceutically acceptable salts thereof, wherein X, R1, R2 and R3 are as defined below.

These compounds and pharmaceutical compositions thereof are useful for the treatment or prevention of many diseases, including heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorder, such as osteoporosis, proliferative or hyperproliferative disorders, infectious diseases, immunologically related diseases and viral diseases, but not limited thereto.

The compositions are also useful in methods for preventing cell death and hyperplasia and therefore may be used to treat or prevent reperfusion / ischemia in stroke, heart attacks, and organ hypoxia. The compositions are useful in methods for preventing thrombin-induced platelet aggregation. Particularly useful compositions are for treatment of disorders (disorders) such as chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, but not limited to, ovarian cancer, breast cancer and endometrial cancer), liver disease including hepatic ischemia, heart disease such as myocardial infarction and congestive heart failure, pathologic immune conditions involving T cell activation, and neurodegenerative disorders.

The compounds of the present invention are also useful for the study of kinases in biological and pathological phenomena; for the study of intracellular signal transduction pathways caused by such kinases; and the comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

1. General Description of Compounds of the invention

The present invention relates to a compound of formula I:

<img file="00000002.tif" he="43" wi="58" img-format="tif" img-content="undefined" />

or a pharmaceutically acceptable salt thereof,

wherein X is CH or N;

R1 is C6-10 aryl or 5-14 membered heteroaryl independently and optionally substituted with up to five J groups;

R2 and R3, each independently represents hydrogen, halogen, -CN, -NO2, -VR, -V-Ra or -V-Rb, optionally substituted with R7;

R4 is R5, -S1-4 aralkyl, -COR5, -CO2R5, -CON (R5) 2, SO2R5 or -SO2N (R5) 2; or two of R4, taken together with the atom (s) to which (ies) they are attached form an optionally substituted 3-10 membered cycloaliphatic, or 5-14 membered heterocyclic group;

R5 is optionally substituted by R, C6-10 aryl, C3-10 cycloaliphatic, 5-14-membered heteroaryl group or a 5-14 membered heterocyclic group;

or two R5 taken together with the atom (s) to which (ies) they are attached form an optionally substituted 3-7 membered monocyclic or 8-14 membered bicyclic ring;

R is H or an optionally substituted C1-6 aliphatic group;

Ra is an optionally substituted C6-10 aryl group, C3-10 cycloaliphatic, 5-14-membered heteroaryl group or a 5-14 membered heterocyclic group;

Rb is-OR5, -N (R5) 2, or -SR5;

V represents a bond, Q, or optionally substituted C1-6 aliphatic chain wherein up to two methylene units of the chain are optionally and independently replaced by Q in a chemically stable moiety;

Q is -NR5-, -S-, -O-, -CS-, -C (O) O-, -OC (O) -, -C (O) -, -C (O) C (O) -, -C (O) NR5-, -NR5C (O) -, -NR5C (O) O-, -SO2NR5-, -NR5SO2-, -C (O) NR5NR5-, -NR5C (O) NR5-, - OC (O) NR5-, -NR5NR5-, -NR5SO2NR5-, -SO-, -SO2-, -PO-, -PO2- or -PONR5-;

each J is independently halogen, optionally substituted C1-6 aliphatic, C1-6 alkoxy, -N (R5) 2, -C (O) R5, -NC (O) R5, -C (O) NR5, - C (O) OR5, -SOR5, -SO2R5 or -U- (R6) n,

wherein each R6 is independently H or an optionally substituted C1-12 aliphatic, C3-10 cycloaliphatic, C7-12 benzo cycloaliphatic, C6-10 aryl, 5-14 membered heterocyclic group, 5-14-membered heteroaryl group , -OR5, -N (R4) 2, or -SR5;

U is a bond or an optionally substituted C1-6 aliphatic wherein up to two methylene units are optionally and independently replaced by Y in a chemically stable moiety;

Y represents a group selected from -O-, -NR5-, -S-, -NR5C (O) -, -N (SO2) -, -NR5C (O) NR5-, -C (O) NR5-, - C (O) -, -OC (O) NR5-, -NR5C (O) O-, -C (O) O- or -OC (O) -;

n is 1 or 2;

R7 is = O, = NR, = S, -CN, -NO2 and -Z-Rc;

Z represents a bond or an optionally substituted C1-6 aliphatic wherein up to two methylene units of the chain are optionally and independently replaced by a group -NR5-, -S-, -O-, -CS-, -C (O) O-, - OC (O) -, -C (O) -, -C (O) C (O) -, -C (O) NR5-, -NR5C (O) -, -NR5C (O) O-, -SO2NR5- , -NR5SO2-, -C (O) NR5NR5-, -NR5C (O) NR5-, -OC (O) NR5-, -NR5NR5-, -NR5SO2NR5-, -SO-, -SO2-, -PO-, - PO2- or -POR5-;

Rc is an optionally substituted 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an optionally substituted 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, for compounds described directly above:

a) when R1 is unsubstituted phenyl, R2 and R3 are not each independently, H, CH3 group or unsubstituted phenyl;

b) in cases where R1 is unsubstituted phenyl, R2 is not CN and R3 is not NH2;

c) in cases where X is N, and R2 and R3 are H, R1 is not unsubstituted 2-naphthyl;

d) In cases where one of R2 or R3 is optionally substituted phenyl, one of R2 or R3 is not

<img file="00000003.tif" he="31" wi="88" img-format="tif" img-content="undefined" />

wherein Ring A is an optionally substituted heterocyclic group.

In other embodiments,

a) R1 is not

&lt;IMG&gt;

b) in cases where R1 is a five-membered heteroaryl, it is not substituted in the ortho-position with J, wherein J is 2,3-dihalo substituted phenyl.

2. Compounds and Definitions

Compounds of this invention include those broadly described above and are further illustrated by the classes, subclasses, chemical compounds and substances disclosed in this disclosure. Unless otherwise indicated, the following definitions are used to describe them. For the purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of Elements, a version of CAS (Chemical Abstracts Service = Chemistry Abstracts Service), Handbook of Chemistry and Physics, 75th Ed. Furthermore, the general laws of organic chemistry are described in «Organic Chemistry», Thomas Sorrell, University Science Books, Sausalito: 1999, and «March's Advanced Organic Chemistry», 5th Ed., Ed .: Smith, MB and March, J., John Wiley &amp; Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

Described herein compounds of the invention may be optionally substituted by one or more substituents as illustrated generally above, or as exemplified particular classes, subclasses, and chemical substances of the invention. Note that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted" preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with a specified substituent groups. Unless otherwise indicated, an optionally substituted group may have a substituent at each replacement position of the group, and in those cases where it may be substituted with more than one position in any given structure with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents contemplated by this invention are preferably combinations that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds which substantially do not change when subjected to conditions which allow their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed this patent application. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially changed, while maintaining a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive media for at least a week.

The term "aliphatic" or "aliphatic group", as used herein, means a substituted or unsubstituted hydrocarbon straight (i.e. unbranched) or branched chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon, or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which are not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has 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 still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, the term "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which are not They are aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl, but not limited thereto.

The term "heteroaliphatic", as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups.

The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to fourteen ring members, wherein 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. Suitable heterocycles include 3-1N-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetragidropiperazinil, tetragidropiperazinil-2, 3-tetragidropiperazinil, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzotiolan, benzoditian and 1,3-dihydro-imidazole-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; the quaternized form of any basic nitrogen or exchangeable nitrogen of a heterocyclic ring, for example N (as the 3 , 4-dihydro-2H-pyrrolyl), NH (in pyrrolidinyl) or NR + (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, refers to an alkyl group as defined earlier which is attached to the principal carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl").

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

The term "aryl" used alone or as part of a larger moiety as in the terms "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at at least one ring in the system is aromatic and wherein each ring in the system contains 3-7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems as defined in the description below. The term "heteroaryl", used alone or as part of a larger moiety as in the terms "heteroarylalkyl" "or" geteroarilalkoksigruppa ", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3-7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Suitable heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (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, benzofuryl, benzothiophenyl, indolyl (e.g., 2 indole), 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 arylalkyl, arylalkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroarylalkyl and geteroarilalkoksigruppu and the like) group may contain one or more substituents and thus may be "optionally substituted". Unless otherwise specified above in this specification, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are generally selected from halogen; -R °; -OR °; -SR °; phenyl (Ph), optionally substituted by R °; -O (Ph), optionally substituted by R °; - (CH2) 1-2 (Ph), optionally substituted by R °; -CH = CH (Ph), optionally substituted by R °; 5-6 membered heteroaryl or heterocyclic ring optionally substituted by R °; -NO2; -CN; -N (R °) 2; -NR ° C (O) R °; -NR ° C (S) R °; -NR ° C (O) N (R °) 2; -NR ° C (S) N (R °) 2; -NR ° CO2R °; -NR ° NR ° C (O) R °; -NR ° NR ° C (O) N (R °) 2; -NR ° NR ° CO2R °; -C (O) C (O) R °; -C (O) CH2C (O) R °; -CO2R °; -C (O) R °; -C (S) R °; -C (O) N (R °) 2; -C (S) N (R °) 2; -OC (O) N (R °) 2; -OC (O) R °; -C (O) N (OR °) R °; -C (NOR °) R °; -S (O) 2R °; -S (O) 3R °; -SO2N (R °) 2; -S (O) R °; -NR ° SO2N (R °) 2; -NR ° SO2R °; -N (OR °) R °; -C (= NH) -N (R °) 2; -P (O) 2R °; -PO (R °) 2; -OPO (R °) 2, or - (CH2) 0-2NHC (O) R °; wherein each R ° is independently selected from hydrogen, optionally substituted C1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O (Ph), or -CH2 (Ph), or, notwithstanding the definition above, two independent occurrences of R ° on the same substituent or different substituents, taken together with the atom (s) to which (i) each R ° is linked, 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.

Optional substituents on the aliphatic group, R °, is selected from NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, halogen, C1-4 aliphatic, OH, O (C1-4 aliphatic) , NO2, CN, CO2H, CO2 (C1-4 aliphatic), O (galogenS1-4 aliphatic) galogenS1-4 or aliphatic, wherein each of the foregoing C1-4aliphatic groups R ° is unsubstituted.

Aliphatic or heteroaliphatic group or non-aromatic heterocyclic ring may contain one or more substituents and thus may be "optionally substituted". Unless otherwise defined above and herein, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group or non-aromatic heterocyclic ring selected from the substituents listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: = O, = S, = NNHR * , = NN (R *) 2, = NNHC (O) R *, = NNHCO2 (alkyl), = NNHSO2 (alkyl), or = NR *, where each R * groups are independently selected from hydrogen or an optionally substituted C1-6 aliphatic group .

Unless otherwise defined above and herein, optional substituents on the nitrogen of a non-aromatic heterocyclic ring 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 + ) 2, or -NR + SO2R +; wherein R + is hydrogen, an optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted by a group -O (Ph), optionally substituted by a group -CH2 (Ph), optionally substituted by a group - (CH2) 1-2 (Ph); optionally substituted -CH = CH (Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen or sulfur, or, notwithstanding the definition above, two independent R +, on the same substituent or different substituents, taken together with the atom (s) to which (i) each R + group is bound, 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 .

Optional substituents on the aliphatic group or the phenyl ring, R +, selected from -NH2, -NH (C1-4 aliphatic), -N (C1-4 aliphatic) 2, halogen, C1-4 aliphatic, -OH, -O (C1-4 aliphatic), -NO2, -CN, -CO2H, -CO2 (C1-4 aliphatic), -O (galogenS1-4 aliphatic), or halo (C1-4 aliphatic), wherein each of the foregoing C1-4aliphatic groups of R + is unsubstituted.

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

The term "protecting group", as used herein, refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In some embodiments, a protecting group has one or more, or preferably all of the following characteristics: a) reacts selectively in good yield to give a protected substrate (molecule multifunctional compound), which is stable with respect to the reactions occurring at one or more other reactive centers ; and b) is selectively removable in good yield by reagents that do not affect the reducible functional group. Representative protecting groups are described in the publications: Greene, TW, Wuts, PG in «Protective Groups in Organic Synthesis», Third Edition, John Wiley &amp; Sons, New York: 1999, incorporated herein by reference. The term "nitrogen protecting group", as used herein, refers to agents used to temporarily block one or more desired nitrogen / nitrogen reactive sites in a multifunctional compound. Preferred protecting groups for nitrogen and have the properties shown as an example above, and some typical protecting group for nitrogen as described in detail in Chapter 7 publications: Greene, TW, Wuts, PG in «Protective Groups in Organic Synthesis», Third Edition, John Wiley &amp; Sons, New York: 1999, fully incorporated herein by reference.

As detailed above, in some embodiments, two independent R ° (or R +, R, R ', or any other variable similarly defined herein) are taken together with the atom (s) to which (i) they are attached, 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.

<img file="00000005.tif" he="24" wi="43" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

<img file="00000006.tif" he="24" wi="46" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

but not limited thereto. It will be understood that there may be formed many more rings when two independent R ° (or R +, R, R ', or any other variable similarly defined herein) are taken together with the atom (s) to which (s) for each variable is bound and that the examples described in detail above is not intended to be limiting.

Unless otherwise stated, structures reflected in this specification, is understood to also include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example R- and S-configurations for each asymmetric center, (Z) - and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures reflected in this specification are intended also to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon 13C- or 14C-enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes in biological assay.

3. A description of representative compounds

In some embodiments, X is a CH group.

In other embodiments, X is N.

In one embodiment, R1 is a 5-6 membered aryl or heteroaryl. Each ring R1 independently is either unsubstituted or substituted with up to five groups J.

In another embodiment, R1 is a 5-6 membered heteroaryl.

<img file="00000007.tif" he="49" wi="66" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

wherein R1 is a 6-membered monocyclic ring, wherein

each G (G2, G3, G4, G5 and G6) independently represents CH or N;

zero, one, two or three G are N;

m is 0-5.

In one embodiment, one, two or three G are N.

In another embodiment, G2 represents N.

In yet another embodiment, any two of G, selected from G2, G3, G4, G5 and G6, are N.

In yet another embodiment, only one G is N.

In another embodiment, R1 is phenyl optionally substituted with up to five groups J.

In some embodiments of this invention, J represents -U- (R6) n, where

each R6 is independently H or an optionally substituted C1-12 aliphatic, C3-10 cycloaliphatic, C7-12 benzo cycloaliphatic, C6-10 aryl, 5-14 membered heterocyclic group, 5-14-membered heteroaryl group, OR5, N (R4) 2 or SR5;

U is a bond or an optionally substituted C1-6 aliphatic wherein up to two methylene units are optionally replaced by Y in a chemically stable moiety;

Y represents a group selected from -O-, -NR5-, -S-, -NR5C (O) -, -N (SO2) -, -NR5C (O) NR5-, -C (O) NR5-, - C (O) -, -OC (O) NR5-, -NR5C (O) O-, -C (O) O- or -OC (O) -; and

n is 1 or 2.

In one embodiment of this invention, Y represents -O-, -S- or -NR5-.

In another embodiment, Y represents -NR5 (C = O) - or - (C = O) NR5-.

In another embodiment, Y represents -NR5-.

In yet another embodiment, one methylene unit is replaced by U Y.

In another embodiment, U is a group -Y- (S1-5alifaticheskaya group) -. In some embodiments, Y is bonded to R1, and S1-5alifaticheskaya group is attached to R6. In other embodiments, Y is bonded to R6, and S1-5alifaticheskaya group is attached to R1.

<img file="00000008.tif" he="49" wi="60" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Formula III

In some embodiments, J represents -U- (R6) n.

In one embodiment of the invention, R6 represents optionally substituted C3-10 cycloaliphatic or C7-12 benzo cycloaliphatic.

In another embodiment, R6 is an optionally substituted 5-6 membered aryl or heteroaryl. In some embodiments, R6 is an optionally substituted 5-6-membered aryl; in other embodiments, R6 is an optionally substituted 5-6-membered heteroaryl.

In another embodiment, R6 represents optionally substituted phenyl.

In yet another embodiment, R6 is an optionally substituted 5-6-membered heterocyclic group.

In certain embodiments, U represents a bond.

In other embodiments, U is a C1-3 aliphatic wherein zero methylene units are replaced.

In one embodiment, U is a group of -NRCH (CH3) -, where the methyl group is in the S-conformation. It will be understood that the atom in the group -NRCH (CH3) -, which is attached to the formula I, formula II or formula III, represents a «-N».

In another embodiment R6 is substituted by halogen, C1-6 aliphatic, C1-6, -CN, -N (R5) 2, -C (O) R5, -NC (O) R5, -C (O) NR5, -C (O) OR5, -SOR5 or -SO2R5.

In another embodiment of this invention, R2 and R3 are, each independently, VR.

In one embodiment, R2 and R3 are, each independently, V-Ra.

In another embodiment, R2 and R3 are, each independently, V-Rb.

In another embodiment, V is an aliphatic chain; one methylene unit of V is replaced by Q and Q is selected from the group -O-, -NR5-, -S-, -C (O) O- and -NR5C (O) -.

In another embodiment, V is an optionally substituted C1-6 aliphatic chain wherein one methylene unit of Q is replaced by a chemically stable arrangement, wherein Q represents a group -CONR5- or -O (CH2) -.

In yet another embodiment, V is Q, wherein Q is a group -C (O) - or -SO2-.

In some embodiments, R2 and R3 are each independently hydrogen, halogen, CN or VR, where V is -C (O) O-, -NH-, -N (CH3) -, -N (CH2CH3) - , -N (CH (CH3) 2) -, -O (CH2) 2O-, -C (O) NH-, -C (O) O-, -O-, -CH2O-, -NHC (O) - , -SO2NH- or -SO2N (CH3) -.

In other embodiments, VR represents -C (O) OH, -C (O) OR5, -O (CH2) 2OCH3, -C (O) OCH3, -OH, -CH2OH, -NHC (O) CH3, -SO2NH2 or -SO2N (Me) 2.

In other embodiments, VR represents -C (O) OH, -C (O) O (C1-6 alkyl), -O (CH2) 2O (C1-6alkyl), -C (O) O (C1-6 alkyl), -OH, -CH2OH, -C (O) NH2, -C (O) NH (C1-6 alkyl), -C (O) N (C1-6alkyl) 2, -SO2NH2, -SO2NH (C1-6alkyl), or - SO2N (C1-6alkyl) 2.

In some embodiments, V is a bond.

In some embodiments, R is H. In other embodiments, R represents H or methyl.

In some embodiments, Rb is N (R4) 2.

In certain other embodiments, Ra is a 5-6 membered aryl or heteroaryl.

In still other embodiments, R2 and R3 are, each independently, H, halogen, CN,

V-Rb, where V represents a bond, and Rb represents -N (R4) 2, or

Ra-V, wherein V is a bond and Ra is a 5-6 membered aryl or 5-6-membered heteroaryl.

In some embodiments, R2 and R3 are each independently halogen.

In other embodiments, R2 and R3 are each independently chloro.

In some embodiments, R2 and R3, each independently contain up to three radicals R7.

In other embodiments, at least one of R2 and R3 is H.

In some embodiments, R3 is H.

In some embodiments, n is 0-3; in other embodiments - 0-2 and in yet other embodiments - 0-1.

Illustrative examples of the compounds of this invention are set forth below in Table I.

<img file="00000009.tif" he="126" wi="143" img-format="tif" img-content="undefined" /><img file="00000010.tif" he="210" wi="140" img-format="tif" img-content="undefined" />

<img file="00000011.tif" he="211" wi="139" img-format="tif" img-content="undefined" /><img file="00000012.tif" he="121" wi="132" img-format="tif" img-content="undefined" /><img file="00000013.tif" he="60" wi="133" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

4. The general procedure for the synthesis

Compounds of this invention may be prepared by methods known to those skilled in the art for analogous compounds and illustrated in Scheme I below. These compounds may be analyzed by known methods including LC / MS (liquid chromatography coupled with mass spectrometry), HPLC (high performance liquid chromatography) and NMR (nuclear magnetic resonance), but not limited to.

It should be understood that the specific conditions shown below are only examples and are not intended to limit the scope of the conditions that can be used to prepare the compounds of this invention. Instead, this invention also includes conditions known to those skilled in the art for the preparation of compounds of this invention. Shown starting materials are either commercially available or can be readily achieved by methods known to those skilled in the art. Unless otherwise indicated, all variables in the following schemes are as defined herein.

<img file="00000014.tif" he="98" wi="137" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

5-Chloro-pyrazin-2-ylamine (1): In a 250 mL round bottom flask was charged with 2-aminopyrazine (10 g, 0.1 mol), N-chlorosuccinimide (14 g, 0.1 mol) and dichloromethane (100 mL) under nitrogen. The reaction mixture was refluxed for 5 hours, then allowed to cool to room temperature. The reaction mixture was filtered through a pad of Celite 1 cm thick, then thoroughly washed with dichloromethane. Organic matter is concentrated in vacuo and the compound purified by flash chromatography using as eluent pentane / EtOAc 0-50% to give the title compound (3 g, 22%).

<img file="00000015.tif" he="39" wi="90" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

3-Bromo-5-chloro-pyrazin-2-ylamine (2): In a 250 mL round bottom flask was charged with 5-chloro-pyrazin-2-ylamine (1) (3 g, 23 mmol), N-bromosuccinimide (4 g, 23 mmol) and dichloromethane (100 ml) under nitrogen. The reaction mixture was refluxed for 1 hour, then allowed to cool to room temperature and concentrated in vacuo. The compound was purified by flash chromatography using as eluent pentane / EtOAc 0-50% to give the title compound (3 g, 62%).

<img file="00000016.tif" he="44" wi="73" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

5-Chloro-3- (trietilsilaniletinil) pyrazin-2-ylamine (3) in a 250 mL round bottom flask was charged with 3-bromo-5-chloro-pyrazin-2-ylamine (2) (1 g, 4.8 mmol), THF (10 mL), copper iodide (9 mg, 0.05 mmol) and PdCl2 (PPh3) 2 (34 mg, 0.05 mmol) under nitrogen. To the reaction mixture was added triethylamine (2 mL, 14.4 mmol) and trietilsililatsetilen (1 mL, 5.76 mmol). The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo and the residue was purified by flash chromatography using as eluent pentane / EtOAc 10-30% to afford the title compound as an off-white solid and (1 , 2 g, 100%).

<img file="00000017.tif" he="35" wi="53" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

<img file="00000018.tif" he="37" wi="72" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

2-Chloro-7-iodo-5H-pyrrolo [2,3-b] pyrazine (5): A 1 M solution of iodine chloride in dichloromethane (4 ml, 4 mmol) was added dropwise to an ice-cold solution of 2-chloro-5H-pyrrolo [ 2,3-b] pyrazine (4) in N-methylpyrrolidone (the residue of the previous step) and pyridine (5 ml). The reaction mixture was stirred for 60 min at 0 ° C and then concentrated in vacuo. The residue was purified by flash chromatography using as eluent pentane / EtOAc 0-50% to give the title compound (820 mg, 75% over two steps).

<img file="00000019.tif" he="50" wi="69" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

2-Chloro-7-iodo-5- (toluene-4-sulfonyl) -5H-pyrrolo [2,3-b] pyrazine (6): Sodium hydride (140 mg, 3.5 mmol) was added to an ice cold solution of 2- chloro-7-iodo-5H-pyrrolo [2,3-b] pyrazine (5) (820 mg, 2.9 mmol) in dimethylformamide (7 ml) under nitrogen. After 30 min the reaction mixture was added tosyl chloride (570 mg, 3 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (~ 15 mL). The solid was off-white filtered off and dried in vacuo (950 mg, 75%).

<img file="00000020.tif" he="45" wi="54" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

7- (3-bromophenyl) -2-chloro-5H-pyrrolo [2,3-b] pyrazine (7) in a 50 ml round bottom flask under a stream of nitrogen 2-chloro-7-iodo-5- (toluene- 4-sulfonyl) -5H-pyrrolo [2,3-b] pyrazine (6) (950 mg, 2.2 mmol), 3-bromfenilboronovuyu acid (440 mg, 2.2 mmol), tetrakis-triphenylphosphine palladium (50 mg, 0.04 mmol), 2M aqueous potassium carbonate (2.2 mL, 4.4 mmol) in toluene / ethanol (15/3 ml) under nitrogen. The reaction mixture was refluxed for 18 h, then allowed to cool to room temperature. The solution was diluted with ethyl acetate (~ 70 ml). The organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in dichloromethane / methanol. Pale-yellow solid was removed by filtration (300 mg). The residue was taken up in a mixture of tetrahydrofuran / methanol / 1M NaOH (4/1/1 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in methanol. The solid was filtered as the title compound (10 mg, 1%).

1H NMR (DMSO-d6): 7.35-7.45 (2H, m), 8.10-8.15 (1H, d), 8.35 (1H, s), 8.4 (1H, s ), 8.6 (1H, s). MS (ES +): 310, 312.

<img file="00000021.tif" he="118" wi="170" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Reagents and conditions: (a) i) NCS, DCM, reflux; ii) NBS, DCM, reflux; (b) trietilsililatsetilen, copper iodide (I), PdCl2 (PPh3) 2, Et3N, THF; (c) t-BuOK, NMP, 80 ° C, 2 h; (d) I2 DCM; (e) NaH, TsCl, DMF; (f) Pd (PPh3) 4, toluene, EtOH, 90 ° C, 18 h; (g) 1M NaOH, MeOH, THF.

Scheme II, above, shows a general synthetic route that is used for preparing compounds 9 of this invention when R1 and R3 are as described herein.

Intermediate Compound 2, prepared by sequential chlorination and bromination derivative 1 is treated in trietilsililatsetilenom by Sonogashira conditions (Sonogashira), which are well known to those skilled in the art. The cyclization of intermediate 3 yields a compound of Structure 4. Intermediates 6 was prepared by iodination of compounds of structure 4, followed by protection of intermediate compounds 5 via the tosyl group. The formation of derivatives 8 is achieved by treating the iodide 6 with a boronic acid derivative 7 in the presence of palladium as a catalyst by using the Suzuki coupling methods that are well known in the art. This reaction may occur with a variety of boronic acid derivatives of 7. Finally, the tosyl protecting group is removed under basic conditions according to step (g) of Scheme II to give compounds of structure 9.

<img file="00000022.tif" he="53" wi="184" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Reagents and conditions: (a) PdCl2 (dppf) 2, dioxane, KOAc, bis (pinacol) diboron, 18 h; (b) Pd (PPh3) 4, Na2CO3, DME, EtOH / H2O, microwave irradiation, 120 ° C, 2 h; (c) 1 M NaOH, MeOH, THF.

Scheme III, above, shows a general synthetic route that is used for preparing compounds 9 of this invention when R1 and R3 are as described herein. Esters of boronic acid 10 produced in accordance with step (a) of Scheme III. The formation of derivatives 8 is achieved by treating the bromide 11 ester derivatives of boronic acid 10 in the presence of palladium as a catalyst by using the Suzuki coupling methods that are well known in the art. This reaction may occur with a variety of substituted aryl or geteroarilbromidami 11. Finally, the tosyl protecting group is removed under basic conditions according to step (c) of Scheme II to give compounds of structure 9.

<img file="00000023.tif" he="119" wi="193" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Reagents and conditions: (a) NBS, DCM, 0 ° C, then reflux, 4 h; (b) trietilsililatsetilen, copper iodide (I), PdCl2 (PPh3) 2, Et3N, THF; (c) t-BuOK, NMP, 80 ° C, 2 h; (d) AlCl3, CH2Cl2, room temperature, 16 h; (e) EtOH, microwave irradiation, 120 ° C, 10 min.

Scheme IV above shows a general synthetic route that is used for preparing compounds 18 of this invention where R3 is as described herein. J2 and J3 J correspond group, defined herein. Intermediate 12 obtained dibromirovaniem derivative 1 is treated under trietilsililatsetilenom by Sonogashira, which are well known to those skilled in the art. Cyclization of intermediate 13 affords compounds of structure 14. The intermediate 16 was prepared using the methods of acylation by Friedel-Crafts acylation well known in the art. This reaction may occur with a variety of 15-substituted chloroacetyl chloride to form compounds of formula 16. Finally the compound of formula 18 is prepared by cyclization of intermediates 16, in accordance with step (e) of Scheme IV.

<img file="00000024.tif" he="74" wi="189" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Reagents and conditions: (a) Pd (PPh3) 4, toluene, EtOH, 90 ° C, 18 h.

Scheme V, above, shows a general synthetic route that is used for preparing compounds 21 of this invention where R1, R2 and R3 are as described herein. Compounds of structure 19 is treated with boronic acid 20 in the presence of palladium as a catalyst by using the Suzuki coupling method which is well known in the art. The reaction may proceed with a variety of boronic acid 20.

<img file="00000025.tif" he="65" wi="152" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Reagents and conditions: (a) PdCl2 (dppf), NaO-t-Bu, THF, heating; or Cu, K2CO3, nitrobenzene, heating; or microwave radiation to 180 ° C, 4 hours.

Scheme VI, above, shows a general synthetic route that is used for preparing compounds 23 of this invention where R1, R3 and R5 are as described herein. The group -Y-R5, as described in Scheme V, corresponds to R2, as defined in the present specification. Compounds of formula 19 is treated with a nucleophilic compound 22 in the presence of palladium as a catalyst by using cross coupling reaction by-Hartwig Bushvaldu well known in the art. This cross-coupling reaction can also be carried out by treating the compounds 19 with a nucleophilic compound 22 in the presence of copper as catalyst using the Ullmann reaction is well known in the art. Finally, compounds of formula 23 can be formed by the replacement of the excess nucleophilic compound 22 by microwave irradiation at high temperature. These reactions can occur with many nucleophilic substituted compounds 22.

<img file="00000026.tif" he="138" wi="180" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Reagents and conditions: (a) CuCN, DMF, 80 ° C, 18 h; (b) KOH, EtOH, 30% H2O2, 55-60 ° C, 1 hour; (c) Lawesson's reagent, toluene, 110 ° C, O / N; (d) EtOH, reflux, O / N; (e) EtOH, 1N NaOH, 12 h; (f) EDC, HOBt, DMF, N (R5) 2H, room temperature, O / N.

Scheme VII, above, shows a general synthetic route that is used for preparing compounds 31 of this invention where R2, R3, R, R5 and J are as described herein. Intermediate 25, obtained by reaction of 24 with bromo analogues copper cyanide, partially hydrolyzed to the derivative 26 in the presence of alkaline peroxide. The derivatives 27 are formed by the reaction of compounds 26 with Lawesson's reagent. The cyclization of compounds 27 in the presence of β-keto esters 28 gives intermediates 29. This reaction may occur with a number of β-ketoesters 28. After saponification of the esters 29 are formed in step 31 derivatives coupling reactions well known to those skilled in the art.

<img file="00000027.tif" he="95" wi="186" img-format="tif" img-content="undefined" />

&lt;IMG&gt;

Reagents and conditions: (a) i) DMF, POCl3, 1 hour; ii) oxidation; (b) CDI, DMF; (c) P2S5, pyridine.

Scheme VIII, above, shows a general synthetic route that is used for preparing compounds 36 of this invention where R2 and R3 are as described herein. Group J4 corresponds to the group J, defined herein. Intermediate compound 33 was prepared by reacting a Vilsmeier-Haack derivative 32, followed by oxidation to acids 33. The intermediates 33 are reacted with the amines 34, following step (b) scheme VII. The reaction may occur with many amine 34. Cyclization of compound 35 in the presence of P2S5 provides the desired derivatives 36.

Table II below shows data for some representative compounds. Compound numbers correspond to the compounds outlined in Table 1. The 1 H NMR spectra were recorded at 400 MHz using a Bruker DPX instrument from 400. The term "retention time (min)", as used herein, refers to the HPLC retention time, in minutes, put in accordance with the connection. Unless otherwise indicated, the HPLC method used for the preparation represented by retention time is as follows:

Column: Column: ACE C8, 4,6 mm × 150

Gradient: 0-100% acetonitrile + methanol 60:40 (20mM Tris phosphate)

Flow rate: 1.5 ml / min

Detection: 225 nm

The samples for mass spectrometric analysis examined a mass spectrometer MicroMass Quattro Micro, functioning in simple mode MS ionization in a spark or glow discharge.

Table IISoedinenie №M + 1 (obs.) 1H YaMRVremya Retention (min) I-1 310 312 (DMSO-d6): 7.35-7.45 (2H, m), 8.10-8.15 (1H, d), 8.35 (1H, s), 8.4 (1H, s), 8.6 (1H, s) 10,3I-2360, 362 (MeOH-d4): 2,95-3,00 ( 6H, s), 3,50-3,55 (2H, m), 3.80-3.90 (2H, m), 7.30-7.40 (2H, m), 7,80-7, 85 (1H, s), 7.90-8.00 (2H, m), 8,40-8,50 (1H, s) 10,2I-28- (MeOH-d4): 1,70-1, 80 (3H, d), 5,75-5,85 (1H, qd), 7.05-7.15 (2H, m), 7.50-7.60 (2H, m), 8 40 (1H, d), 8.50 (1H, s), 8.80 (1H, s) 9,4I-81354,57,36-7,49 (2H, m), 8,11-8,20 (1H, m), 8,30-8,49 (2H, m), 8,61-8,69 (1H, m), 12.75 (1H, brs) 82359,73-10,39I, 48-3,60 (4H, m), 3,76-3,89 (4H, m), 7.30-7.38 (2H, m), 8.11 (1H, s), 8,17- 8.30 (2H, m), 8.48 (1H, brs), 12.01 (1H, brs) 9,83I-83274,67,21-7,30 (1H, m), 7 , 40-7,49 (2H, m), 8.10-8.15 (1H, m), 8.44 (1H, s), 8.53 (1H, s), 12.64 (1H, br .s) 9,67I-84252,67,10 (1H, brs), 7.26 (1H, brs), 7.75 (1H, brs), 7.83 (1H, br. s), 8.70 (1H, s), 12.10 (1H, brs), 9.04

5. Applications, preparation and administration

As discussed above, the present invention provides compounds which are inhibitors of protein kinases, and thus the present compounds are useful for treating diseases, disorders and conditions, including autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease, but not limited to . Accordingly, another aspect of the present invention are pharmaceutically acceptable compositions comprising any of the compounds described herein, and optionally comprise a pharmaceutically acceptable carrier, excipient or base. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

One feature of this invention relates to a method of treating a disease state in patients that is soften by a protein kinase inhibitor treatment, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

Another feature of this invention relates to a method for treating or lessening the severity of a disease or condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disease, an immunologically-mediated diseases, viral diseases or bone disease in patient, comprising the step of administering to said patient a compound or composition of this invention.

In one embodiment, the method is particularly useful for treating a disease condition which is alleviated by the use of an inhibitor of Aurora-A or Aurora.

In some embodiments, the "effective amount" of the compound or pharmaceutically acceptable composition is that amount which is effective against the disease caused by Aurora-A or Aurora. Compounds and compositions in accordance with the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease caused or Aurora Aurora-A. The exact amount required will vary from subject to subject, depending on the type, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, etc. Compounds of the invention are preferably made in a single dosage form for ease of administration and uniformity of dosage. In some embodiments, the compound used in an amount that allows for detection of inhibiting Aurora protein kinase activity.

The expression "drug dosage form" as used herein refers to a physically discrete unit of agent appropriate to the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the particular composition; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; duration of treatment; drugs used in combination or coincidentally at the same time with the specific compound employed, and like factors well known in medicine. The term "patient", as used herein, means an animal, preferably a mammal and most preferably a human.

Activity of compounds as inhibitors of protein kinases, such as inhibitors of Aurora-A, can be analyzed (quantified) in vitro, in vivo or in a cell line. In vitro tests include tests that determine inhibition of the kinase activity or ATPase activity, or (adenosinetriphosphatase) activated Aurora-A. Alternate in vitro assays quantitatively assess the ability of the inhibitor to bind Aurora-A and the measurement can be done either by introducing a radioactive label in the inhibitor prior to binding, isolating the inhibitor / Aurora-A and determining the amount of bound radiolabel, or by conducting an experiment regarding successful competition where new inhibitors are incubated with Aurora-A protein kinase bound to known radioligands.

In accordance with one embodiment such pharmaceutical compositions comprise a compound of this invention and a pharmaceutically acceptable carrier. In accordance with one embodiment such pharmaceutical compositions comprise an amount of the protein inhibitor effective to treat or prevent conditions caused or Aurora Aurora-A and a pharmaceutically acceptable carrier.

The term "condition caused by a protein kinase" as used herein means any disease or other dangerous condition in which it is known that protein kinase plays 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: breast cancer; ovarian cancer; cervical cancer; prostate cancer; testicular cancer, cancer of the urinary tract; esophageal carcinoma; laryngeal cancer, glioblastoma; neuroblastoma; stomach cancer; skin cancer, keratoacanthoma; lung cancer, squamous cell carcinoma, large cell carcinoma, small cell lung cancer, adenocarcinoma of the lung; bone cancer; bowel cancer, adenoma; cancer of the pancreas, adenocarcinoma; thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; carcinoma of the liver and cancer of the bile ducts; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's disease, cancer, hairy cell; cancer of the mouth and throat (oral), lip cancer, mouth, tongue, mouth, pharynx; cancer of the small intestine; cancer, colorectal cancer, colon cancer, rectal cancer; cancer of brain and central nervous system, and leukemia.

The term "condition caused Aurora", as used herein, means any disease or other dangerous condition in which it is known to play a role of Aurora, particularly Aurora-A. Such conditions include, without limitation, cancers such as colon and breast.

In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the above identified disorders.

A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to the recipient may provide, directly or indirectly, a compound of this invention or an active metabolite inhibitor, or residue thereof. Especially take advantage derivatives or prodrugs that enhance the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., enabling easier absorption of orally administered compound into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or in the lymphatic system) relative to the starting material.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and esters of sulfonic acids.

"Pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester compound of this invention which upon administration to the recipient may provide, directly or indirectly, a compound of this invention or an active metabolite inhibitor or residue thereof. As used herein, the term "inhibitor active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of Aurora kinase.

Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salt thereof in the publication: J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.

Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.

Additional examples of suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate , hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate (pivalate), propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Other acids such as oxalic, despite the fact that in themselves are not pharmaceutically acceptable may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. magnesium), ammonium and N + (C1-4alkyl) 4. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Through such quaternization may be prepared water- or oil-soluble or dispersible products. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions in such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include ion exchanger (anion exchange resin), alumina, aluminum stearate, lecithin, seroproteiny 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, but not limited thereto.

Additional examples include sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; an agent having a buffering action, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, at the discretion of the formulation composition.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intracisternally, intraperitoneally, or via an implanted reservoir. The term "parenteral" as used herein includes injections or infusion techniques: subcutaneous, intravenous, intramuscular, intraarticular, intrasternal, intrathecal, intrahepatic, intralesional / lesions and intracranial. Preferably, the compositions are administered orally, intraperitoneally or intravenously. In some embodiments, compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg body weight of the subject per day, one or more times a day, to obtain the desired therapeutic effect.

Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. Such 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 sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the suitable bases and solvents which may be employed 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 can be applied, any bland fixed oils, 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 oil solutions or suspezii may also contain alcohol diluent or long chain dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents and agents that increase bioavailability, are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used to draw up the formulation.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs but not limited thereto. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions and solutions, but is not limited to these. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Also added are typically lubricants such as magnesium stearate. For oral administration in capsule form, useful diluents include lactose and dried corn starch. In those cases where oral aqueous suspensions are required, the active ingredient is combined with emulsifying and suspending agents. If desired, it can also be added sweetening, flavoring or coloring agents.

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

The pharmaceutical compositions of this invention may also be administered topically, especially when the object of treatment includes areas or organs readily accessible for topical application, including diseases of eyes, skin, or the lower intestinal tract. Suitable formulations for topical use for each of these areas or organs readily prepared.

Topical administration in the zone of the lower intestinal tract can be effected by means of the composition for rectal suppository formulation (see. Above), or by a suitable enema formulation. It may also be used with topical patches for transdermal administration.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water, but not limited thereto. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, based wax cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water, but not limited thereto.

For ophthalmic use, the pharmaceutical compositions may be formulated as suspensions of finely divided particles in isotonic, sterile saline with pH adjusted or, preferably, as solutions in isotonic, sterile saline with pH adjusted, either the preservative or without a preservative such as chloride benzylalkonium. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as Vaseline ointment.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared sootvetviii to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, while applying benzyl alcohol or other suitable preservatives, promoters of absorption to enhance bioavailability, fluorocarbons, and / or other traditional solubilizing or dispersing agents.

The amount of protein kinase inhibitor of Aurora kinase that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a patient receiving these compositions, it was possible to introduce a dose of 0.01-100 mg inhibitor / kg body weight / day.

It should also be understood that a specific dosage and treatment regimen 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, and conclusion treating physician and the severity of the particular disease being treated. The amount of inhibitor will also depend upon the particular compound in the composition.

In accordance with yet another embodiment, the invention provides methods of treating or preventing a condition caused by Aurora comprising a step of administering to a patient one of the above pharmaceutical compositions.

In one embodiment, the method is used to treat or prevent a condition selected from 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, heart enlargement, Alzheimer's disease, cystic fibrosis, and viral disease, or any specific disease or disorder described above.

In some embodiments, methods in accordance with this invention comprise the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or antiproliferative agent, an antiinflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an antiviral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein 1) said additional therapeutic agent corresponding disease being treated; and 2) said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a formulation consisting of a plurality of particles.

Such additional agents may be administered separately from a composition containing an inhibitor of Aurora as part of a multiple dosage regimen. Alternatively, such agents may be part of a single dosage form, mixed together with the Aurora inhibitor in a single composition.

6. Biological methods

Example 1: Analysis of the inhibition of Aurora-A

Compounds are tested for their ability to inhibit Aurora A full-length (AA 1-403) using standard bienzyme system (Fox et al., Protein Sci., 7, pp.2249 (1998)). Reactions were carried out in a solution containing 100 mM HEPES (4- (2-hydroxyethyl) -1-piperazinetansulfokislota) (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 300 M NADH, 1 mM DTT and 3% DMSO. Final substrate concentrations in the sample for analysis is 200 uM ATP (Sigma Chemicals, St. Louis, MO) and 800 uM peptide (LRRASLG, American Peptide, Sunnyvale, CA). Reactions were carried out at 30 ° C and 35 nM Aurora-A. Final concentrations of the components bienzyme system were 2.5 mM phosphoenolpyruvate, 200 uM NADH, 60 ug / ml pyruvate kinase and 20 / ml lactate dehydrogenase.

The starting buffer for analysis, which was prepared to contain all of the reagents listed above, with the exception of ATP and the test compound of interest. Stock buffer solution for analysis (60 ul) incubated in 96-well plates with 2 .mu.l of the test compound of interest at final concentrations spanning the range from 0.002 uM to 30 uM at 30 ° C for 10 min. Typically, a 12-point titration is conducted by performing serial dilutions (from 1 mM stock solutions of compounds) by DMSO of the test compounds in daughter plates. The reaction was initiated by addition of 5 l of ATP (final concentration 200 pM). Rates of reaction were obtained using a spectrophotometer plate reader Molecular Devices Spectramax (Sunnyvale, CA) for 10 min at 30 ° C. Ki values ​​were determined from the rate data as a function of inhibitor concentration using computerized nonlinear regression (Prism 3.0, Graphpad Software, San Diego, CA). The compounds tested and found to inhibit Aurora-A. It has been found that the compounds I-1 and I-28 are tested to inhibit Aurora-A with a Ki of less than 200 nM.

Example 2: Analysis of the inhibition of Aurora-B (radiometric)

Prepare the buffer solution for assay consisting of 25 mM HEPES (pH 7.5), 10 mM MgCl2, 0.1% BSA and 10% glycerol. The assay buffer was prepared 22 nM Aurora-B solution, also containing 1.7 mM DTT and 1.5 mM Kemptide (LRRASLG). To 22 l of Aurora-B solution in a 96-well plate were added 2 l of a compound stock solution in DMSO and the mixture allowed to equilibrate for 10 minutes at 25 ° C. The enzyme reaction was initiated by addition of 16 l of feed solution [□ 33P] -ATP (~ 20 HCI / ml) prepared in the assay buffer to a final concentration in the sample for the analysis of 800 uM. The reaction was stopped after 3 hour by adding 16 .mu.l of 500 mM phosphoric acid and the levels of introducing 33 P into the peptide substrate is determined by the following method.