RU2548363C2 - SELECTIVE INHIBITORS OF Haspin kinase - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula

or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X₁, X₂, X₃, X₄, X₅, X₆ is selected from N, and the remaining ones represent C, X₇ is selected from N or CH; each of X₈, X₉, X₁₀ and X₁₁ is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R₁, R₂, R₃ and R₄ are selected from H, 6-membered aryl, CF₃, halogen; R₅, R₆, R₇ represent C₁-alkyl on condition that X₉, X₁₀ or X₁₁ in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon):

,

where R₉ is selected from CH₂OH, CON(R₁₅, R₁₆), where R₁₅, R₁₆ can independently represent H, C₁-alkyl, Het represents N, n=1, n₁=3; R₈ is selected from H, C_1-6-alkyl, C₁-alkylcarbonyl, derivetives of arylacetic acid of general structure:

, where

methylheteroaryls of general structure:

, where

derivatives of alkylsulphonyls of general structure

where R₁₄=Alk, with Alk representing C₁-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

Description

Field of Invention

The present invention describes derivatives of annelated bicyclic aromatic [6 + 5] heterocycles containing at least one nitrogen atom in a five-membered ring. These compounds are selective inhibitors of the serine-threonine Haspin protein kinase, including compounds that can block mitosis (simple division) in proliferating (dividing) cells, including tumor cells, and can be used in the treatment of diseases including cancer.

State of the art

Protein kinases (kinases) are a large class of cellular enzymes that perform key cellular functions such as the regulation of cell division, its proliferation, metabolism and, obviously, play a key role in many painful conditions, such as diseases characterized by uncontrolled cell proliferation and differentiation. These diseases involve a variety of cell types and include diseases such as cancer, atherosclerosis, and restenosis.

Kinase drugs, and especially drugs based on low molecular weight chemicals that inhibit kinase activity, are important drugs that can significantly improve health, extend life expectancy, or improve the quality of life for people around the world, including patients suffering from such debilitating diseases like cancer. Indeed, imatinib (GLEEVEC / GLIVEC; Novartis) is a kinase inhibitor and is used to successfully treat certain types of cancer, including but not limited to leukemia (chronic myeloid leukemia, CML) and certain types of cancer of the gastrointestinal tract (stromal tumors of the gastrointestinal tract). High efficacy of this drug is noted in comparison with previously used standard CML treatment, as well as its significantly better tolerance, which is manifested in less pronounced side effects.

At the same time, drugs that interrupt the process of simple division (mitosis) of cancer cells are effective anti-cancer drugs. Well-known examples of such drugs affecting the apparatus of the spindle division, for example, taxa vinca alkaloids, epothilones. Despite the fact that the above drugs are effective for the treatment of a number of cancers, they are not without a number of serious drawbacks. In particular, this class of drugs has serious side effects, such as neutropenia (a decrease in the number of white blood cells in the blood), fatigue, and infectious processes. They also cause excessive skin irritation upon administration, which may complicate their use. To solve this problem, a search was made for compounds with a new mechanism of action that could block the mitosis process and trigger the apoptosis (programmed death) of cancer cells, but which did not have a toxic effect on resting cells. More recently, new classes of compounds have been discovered that act on unique molecular targets during mitosis, including a number of serine-threonine protein kinases. Protein kinases that play a key role in mitosis include, for example, the Aurora kinase family (includes three representatives of Aurora A, Aurora B and Aurora C), a large family of CDK kinases, SNK. 1,2 kinase, Nek2 kinase, Pik kinase [ Susanne M. A. Lens, Emile E. Voest and Rene H. Medema, Nature Reviews Cancer, volume 10, 2010, p. 825], as well as Haspin kinase.

Haspin kinase is a serine-threonine protein kinase that phosphorylates the Thr-3 threonine residue on the amino-containing terminal fragment of histone NS during mitosis [Dai J, Sultan S, Taylor SS, Higgins JMG, Genes Dev 2005; 19: 472-488; Dai J, Higgins JMG, Cell Cycle 2005; 4: 665-668; Dai J, Sullivan BA, Higgins JMG; Dev Cell 2006.11: 741-750]. Many factors indicate that specific (selective) Haspin kinase inhibitors can be an interesting and promising class of compounds for the study and treatment of cancer. First, most important factor: Haspin kinase plays an important role in the regulation of mitosis (simple cell division). As experiments with Haspin RNAi in vitro have shown, blocking Haspin kinase function disrupts chromosome alignment in the early stages of mitosis. This leads to the impossibility of the normal completion of mitosis, which indicates that Haspin kinase inhibitors may be new antimitotic agents that can prevent the excessive proliferation of cancer cells.

Second, Haspin kinase is expressed only in proliferating, but not in resting cells [Higgins, Gene 2001; 267: 55-69]. This fact suggests that selective Haspin kinase inhibitors may act as a less toxic alternative to traditional antimitotic drugs. And third, based on the unique primary structure of Haspin kinase, it can be expected that the creation of selective inhibitors of this target is a completely solvable task [Eswaran J, Patnaik D, Filippakopoulos P, Wang F, Stein RL, Murray JW, Higgins JM, Knapp S .Proc Nati Acad Sci USA. (2009) 106 (48): 20198-20203].

Recently, several publications have appeared in the scientific literature reporting on the identification of the first Haspin kinase inhibitors [Debasis Patnaik, J Biomol Screen 2008; 13; 1025; Gregory D. Cuny, Bioorganic & Medicinal Chemistry Letters, 20, 491], as well as on the method of binding some small molecules to the Haspin kinase active (ATP-binding) site based on x-ray structural analysis. However, an analysis of modern scientific and patent literature shows that to date there are no data on truly active and selective Haspin kinase inhibitors.

In accordance with the foregoing, despite some progress, the search continues for compounds with low molecular weight, which are kinase inhibitors, especially compounds that inhibit Haspin kinase, which can be used in the treatment of a variety of diseases, including cancer, and other proliferative diseases or disorders, including restenosis, angiogenesis, diabetic retinopathy, psoriasis, surgical adhesions, macular degeneration and atherosclerosis, or other diseases and disorders mentioned above. Thus, there is an urgent need to create compositions, pharmaceutical and / or medicinal, with kinase inhibitory activity, in particular, inhibitory activity against Haspin kinase and antiproliferative activity against cells such as tumor cells. Such compositions, pharmaceutical and / or medicamentous, can possess not only the indicated activity, but also cause acceptable, acceptable or limited side effects compared to other antiproliferative substances. Moreover, the range of tumors or other diseases susceptible to treatment with such compounds can be wide. The active ingredients in such compositions, drugs and medications can be used for the above indications as monotherapy and / or in combination therapy with other therapeutic agents, with radiation, with surgical / surgical procedures, with heat treatment or with any other treatment known to treat mentioned testimony.

It is known that certain classes of bicyclic annelated aromatic [6 + 5] heterocyclic compounds, for example, imidazopyridines that are substituted in a certain way, have useful pharmacological properties, such as antiproliferative or anti-inflammatory activity. However, at the moment, the compounds described in the scientific and patent literature are structurally different from the compounds of this invention.

A UCB article [Bioorganic & Medicinal Chemistry Letters 18, 3291] describes substituted imidazo [1,2-a] pyridines, which have been shown to inhibit IRAK 1,4 kinases and inhibit the formation of the known TNF-α cytokine inflammatory mediator in vitro .

A recent article [Yoshiyuki Sato, Bioorganic & Medicinal Chemistry Letters, Volume 19, 4673] described a new class of selective Plk1 kinase inhibitors based on substituted imidazopyridines exhibiting in vivo antitumor activity in xenograft models.

It is also necessary to mention the compound SGI-1776, which is a non-selective inhibitor of PIM-1,2,3 kinases, developed by the American company SuperGene for the treatment of hematological proliferative diseases (in particular, resistant to the treatment of acute myeloid leukemia) and a number of solid tumors. Compound SGI-1776 is an imidazo [1,2-b] pyridazine derivative. It should be noted that along with the inhibition of PIM kinases, SGI-1776 also exhibits inhibitory activity against Haspin kinase.

SUMMARY OF THE INVENTION

We have discovered a class of specifically substituted annelated bicyclic [6 + 5] heteroaromatic compounds, which are selective inhibitors of Haspin serine-threonine protein kinase, and are also able to block the process of mitosis of cancer cells, thereby causing their death. The proposed compounds make it possible to develop new and effective methods of treating diseases that are associated with uncontrolled proliferation.

The compounds of the present invention are specifically substituted annelated bicyclic [6 + 5] heteroaromatic compounds, as described in detail below, and can be used for further preclinical or clinical research and development to treat various diseases and disorders, including oncological, proliferative, degenerative, inflammatory and other diseases and disorders.

In one aspect, the present invention describes, in a specific way, substituted annelated bicyclic [6 + 5] heteroaromatic compounds having a structure that is described by general formula (I) below, or its tautomeric or stereoisomeric forms, which can be used as Haspin kinase inhibitors and therefore, they can be used to treat the diseases and disorders referred to herein, including proliferative diseases and disorders such as cancer, inflammatory diseases or frustration.

In another aspect, the present invention relates to pharmaceutical compositions that include pharmaceutically acceptable diluents, excipients or carriers, and the Haspin kinase inhibitors of the invention in an amount comprising a therapeutically effective dose, for example, a dose that is expected to alleviate the symptoms of a disease or disorder, mentioned in the application, including proliferative diseases and disorders, such as cancer and inflammatory diseases or disorders.

In another aspect, the present invention relates to a pharmaceutical package, which includes the pharmaceutical composition and instructions stating that the pharmaceutical composition can be used to treat a patient suffering from a disease or disorder mentioned in the application, including proliferative diseases and disorders, such as cancer and inflammatory diseases or disorders.

On the other hand, the invention relates to methods by which a therapeutically effective amount of a compound or a pharmaceutical composition described in an application is used by a subject or brought into contact with a subject, cell, tissue, organ or organism. These methods include, but are not limited to, the prophylaxis and / or treatment of the disease or disorder mentioned in the application, including, but not limited to, proliferative diseases and disorders, such as cancer and inflammatory diseases or disorders.

On the other hand, the present invention relates to the use of the compounds of the present invention for the preparation of medicaments for the treatment of a disease or disorder mentioned in the application, including proliferative diseases and disorders such as cancer.

On the other hand, the invention relates to the use of the compounds of the present invention for the preparation of drugs used to treat an inflammatory disease or disorder.

On the other hand, the invention relates to methods for the synthesis of both the final compounds of the present invention and intermediates for the preparation of said compounds.

Thus, the present invention provides compounds having a structure represented by general formula (I)

or any tautomeric forms thereof, or their pharmaceutically acceptable salts, where

each of X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X _{6 is} selected from N or C;

X _{7 is} selected from N or CH;

each of X ₈ , X ₉ , X ₁₀ and X _{11 is} independently selected from N or CH, provided that the fragment can simultaneously contain one or two nitrogen atoms;

R ₁ , R ₂ , R ₃ and R ₄ are selected from H, C _1-12 alkyl, 6-14 membered aryl, OC _1-12 alkyl, CF ₃ , halogen, COOH, COOC _1-12 alkyl, CONH ₂ , CON (C _1-12 alkyl) ₂ , CN, N (C _1-12 alkyl) ₂ , 4-14 membered heteroaryl containing at least one heteroatom selected from nitrogen and oxygen;

R ₅ , R ₆ , R ₇ selected from C _{1-12 of} alkyl, halogen, CN, provided that X ₉ , X ₁₀ or X ₁₁ in this case, respectively, is equal to C;

“A” may be a single bond or a bridged ethine moiety;

Y may be a single bond, or independently selected from methylene or ethylene bridging fragments;

Fragment Z is independently selected from unsubstituted or substituted at the nitrogen atom of heterocycloalkyl, or is unsubstituted or substituted by cycloalkyl, provided that N (nitrogen) is equal to C (carbon):

where R _{9 is} selected from OH, F, OC _1-12 alkyl, NH ₂ , NH (C _1-12 alkyl), N (C _1-12 alkyl) ₂ , CH ₂ OH, CON (R ₁₅ R ₁₆ ), where R ₁₅ , R ₁₆ may independently be H, C _1-12 alkyl, C _3-12 cycloalkyl, 6-14 membered aryl, 4-14 membered heteroaryl containing at least one heteroatom selected from nitrogen and oxygen , or

R ₉ may be the following heterocyclic substituents:

where Y ₁ , Y ₂ = H or C ₁ -C ₅ alkyl.

R _{8 is} selected from H, C _1-12 alkyl,

cycloalkyl and heterocycloalkyl of the general structure:

,

,

C _1-12 alkylcarbonyl, C _3-12 cycloalkylcarbonyl,

heterocycloalkylcarbonyl of the general structure:

arylcarbonyls of the general structure:

heteroarylcarbonyls of the general structure:

derivatives of alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl acetic acids of the general structure:

derivatives of methylcycloalkyls, methylheterocycloalkyls, methylaryls (benzyls), methylheteroaryls of the general structure:

,

,

derivatives of alkylsulfonyls, arylsulfonyls and dialkylaminosulfonyls of the general structure:

,

,

,

,

where in all cases where Het, Het ₁ are heteroatoms and can be independently selected from N or O.

Other aspects and advantages of the invention will be apparent from the following detailed description and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

General terms

The term “H” means hydrogen.

The term “alkyl” or “Alk” refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups containing from 1 to 12 carbon atoms. In certain embodiments, the alkyl substituents may be lower alkyl substituents. The term "lower alkyl" refers to alkyl groups containing from 1 to 6 carbon atoms. Examples of lower alkyls include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, and n-hexyl.

When referred to in the application, the term "cycloalkyl" should be understood as a hydrocarbon cycle, which is part of any stable monocyclic or polycyclic system in which this cycle contains from 3 to 12 carbon atoms, but does not contain heteroatoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes, such as [2.2.2] bicyclooctane, bicyclononanes, such as [4.3.0] bicyclononane, and bicyclodecans, ] bicyclodecane (decalin) or spiro compounds, but are not limited to.

The term “heterocycloalkyl” means a cycle that is a stable monocyclic or polycyclic system, or is part of a polycyclic system in which this cycle contains from 3 to 8 atoms, and in which this cycle consists of carbon atoms and at least one heteroatom, independently selected from the group consisting of N, O and S, wherein heterocycloalkyl denotes a system where this cycle is fully saturated. For clarity, if the substituent is a polycyclic system in which one cycle contains at least one heteroatom as described in the application, then such a substituent will be referred to as “heterocycloalkyl”. Heterocycloalkyl groups can be bonded to other groups via a cyclic carbon atom (“heterocycloalkyl linked via a C atom”), or through a cyclic nitrogen atom (“heterocycloalkyl linked through an N atom”). In certain embodiments, the nitrogen in the heterocycle may be quaternized.

Examples of heterocycloalkyls include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl and decahydroquinolinyl (linked via a piperidinyl moiety). Also encompassed are fused ring systems and spiro compounds containing, for example, any of the above heterocycles, when they are attached via a ring containing a heteroatom.

The term “aryl” means a cycle or cyclic system that is part of any stable monocyclic or polycyclic system in which said cycle or cyclic system contains from 6 to about 14 carbon atoms but does not contain any heteroatoms, and in which the cycle or cyclic system represents aromatic fragment, which is determined by the rule "(4n + 2)" π-electrons ". For clarity, if the substituent is a polycyclic system in which one cycle or a cyclic system comprising an aromatic moiety is included in said polycyclic system, as defined in the application, then the substituent will be defined as “aryl” if substitution occurs through said aromatic moiety. Such systems include phenyl and cyclic condensed benzene systems, for example, naphthalene, anthracene or phenanthrene cyclic systems, or, for example, a benzene core condensed with one or more cycloalkyl moieties to form, for example, indanyl, fluorenyl or tetrahydronaphthyl, or condensed with one or more heterocycloalkyl fragment, as, for example, in indolinyl, however, provided that in all these cases this condensed system is attached as a substituent via aroma cal fragment, but are not limited to.

When referred to in the application, the term “heteroaryl” means a cycle or cyclic system that is part of any stable mono- or polycyclic system, where this cycle or cyclic system contains from 4 to about 14 atoms, and where this cycle or cyclic system is an aromatic fragment, which is determined by the "(4n + 2)" π-electrons rule, and consists of carbon atoms and one or more heteroatoms that are selected from nitrogen or oxygen. For clarity, if the substituent is a polycyclic system, which includes a cycle or a cyclic system representing an aromatic fragment containing a heteroatom, as defined in the application, then such a substituent will be defined as “heteroaryl” if the substitution occurs through an aromatic fragment containing a heteroatom . In certain embodiments, the nitrogen in the heterocycle may be quaternized or oxidized to an N-oxide. Examples of heteroaryl include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, furanyl, benzofuranyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, and quinazolinyl.

The term heteroaryl also includes fused heteroaryls containing, for example, the aforementioned heteroaryl fused to cycloalkyls or heterocycloalkyls (provided that in all cases the condensed system is attached as a substituent via an aromatic moiety containing at least one heteroatom).

The —C (O) - fragment denotes a carbonyl group. Examples of carbonyl-containing fragments, without limiting the scope of this invention, are alkylcarbonyls, cycloalkylcarbonyls, arylcarbonyls, etc.

The terms “alkylsulfonyl” and “arylsulfonyl” mean respectively “alkyl” or “aryl” as defined above, attached to the corresponding moiety of the molecule through a sulfonyl group —SO ₂ . Examples of alkylsulfonyls, without limiting the scope of the present invention, are methylsulfonyl, ethylsulfonyl, etc. Examples of arylsulfonyls, without limiting the scope of the present invention, are phenylsulfonyl, p-methylphenylsulfonyl, etc.

Throughout the application, the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups, as well as any other substructures containing at least one hydrogen atom, can be replaced by one or more substituents.

Substituents may be independently selected from the following list:

- "heteroatoms": O, N, S, P, (as well as CO, SO ₂ , SO included in the cycle of the heterocycloalkyl structure),

- "halogens": F, Cl, Br, I,

- “functional groups”: CHO, CN, COOH, NO ₂ , NAlkz, SO ₂ Alk, SO ₂ aryl SO ₂ NH ₂ , SO ₂ NHAlk, SO ₂ NAlk ₂ , CONH ₂ , CONHAlk, CONAlk ₂ , P (O) (OAlk) ₂ , PO (OH) ₂ ,

- “aryl”,

- "alkyl"

- “heteroaryl”

- "heterocycloalkyl"

Example: any hydrogen atom can be substituted by a heterocycloalkyl substituent (N-morpholinyl), an aryl or carboxyl group, if the chemical structure of the compounds formed by such substitution does not contradict the general principles of the theory of the structure of organic compounds

The term “substituted” indicates that one or more hydrogen atoms on an atom or group referred to as “substituted” is replaced by any of the listed groups, provided that the atom has a normal valency or that the valency of the substituted corresponding atom of the group is not is redundant, and that substitution leads to a stable connection.

The terms “stereoisomer” and “tautomer”, as mentioned in the application, include all possible stereoisomeric and tautomeric forms of the compounds of the present invention. Where the compounds of the present invention contain one or more chiral centers, all possible enantiomeric and diastereomeric forms are included, unless otherwise indicated.

The present invention is intended to include all isotopes of atoms contained in the compounds of the invention. Isotopes are atoms having the same atomic number but different mass numbers. As a general example, and not limited to, isotopes of hydrogen include tritium and deuterium.

Carbon isotopes include ¹² C, ¹³ C and ¹⁴ C.

The term "metabolite", as used herein, refers to any substance resulting from a metabolism or metabolic process in vitro and in vivo. Metabolism, as mentioned in the application, refers to various physical / chemical / biochemical / pharmacological reactions involved in the transformation of molecules or chemical compounds that occur in a cell, tissue, system, body, animal, individual, patient or person.

The term "IC ₅₀ ", as mentioned in the application, refers to concentrations at which the measured activity, phenotype or response, for example, the growth or proliferation of cells, such as tumor cells, is inhibited by 50%. Values of 1050 can be estimated from appropriate dose response curves, for example, by eye, or using suitable curve processing programs or statistical programs. More precisely, IC ₅₀ values can be determined using non-linear regression analysis.

When referring to the application, the terms “proliferative disease” or “proliferative disorder” are understood to mean diseases or disorders that are affected by the processes of cell growth, differentiation or proliferation.

When referred to in the application as “oncogenic diseases and disorders”, it is understood diseases and disorders that are characterized by impaired regulation of cell growth, proliferation, differentiation, fusion or migration, which may lead to the appearance of tumors or to the development of a tendency to tumor. When referred to in the application, “tumor” refers to benign or malignant proliferation of tissue. Examples of cell growth or proliferation diseases include, but are not limited to, tumors, cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative diseases, and cardiovascular diseases.

When referring to the terms “anti-cancer drug” or “anti-proliferative drug” in the application, they are referred to compounds with anti-cancer or anti-proliferative properties, respectively. Such compounds include alteramine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, phloxuridine, gemcitabine, thioguanine, pentostatin, methotrexin, carptoprintoprintopinlapin, cytroptinpincylpincinoprin, cytaprindoprintoprintlapin, cytaprintoprintopinlapin, cytroptinpin, cytaprindoprintoprintinpin, cytaprintoprintoprintopinlapinoprilatin, carcinoptin, cytaprintoprintinpin, cytaprintoprintopinlapin, , picoplatin, LA-12, iproplatin, tetraplatin, lobaplatin, JM216, JM335, satraplatin, fludarabine, aminoglutetimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastlazetetl diaztetlaztametlaztetazolit bestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, topotecan, irinotecan, 9-aminocamptocan, 9-nitrocamptocopidene, vinone 118, J-ten, J-shadow, GS, GS , vincristine, vinorelbine, procarbazine, asparaginase, pegasparagas, octreotide, estramustine and hydroxyurea, SAHA, erlotinib, sunitinib, lapatinib, sorafenib, vemurafenib, azacitadine, decitabine. These terms also include high molecular weight preparations, such as antibodies, for example, 1D09C3 and other anti-HLA-DR antibodies, as described in patents WO 01/87337 and WO 01/97338, rituxan. as described in US patents 5,736,137, 5,776,456, 5,843,437, 4D5, Mab225, C225, daclizumab (Zenapax), Antegren, CDP 870, CMB-401, MDX-33, MDX-220, MDX-477, CEA-CIDE, AHM, vitaxin , 3622W94, Therex, 5G1.1, IDEC-131, HU-901, Mylotarg, Zarnyl (SMART M195), MDX-210, Humicade, EymphoCIDE, ABX-EGF, 17-1 A, trastuzumab (Herceptin®, rhuMAb), Epratuzumab, Cetuximab (Erbitux®), Pertuzumab (Omnitarg®, 2C4), R3, CDP860, Bevacizumab (Avastin®), tositumomab (Bexxar®), Ibritumomab tiuxetan (Zevalin®), M195, 1D10olumab1 , Danton / DN1924, an “HD” antibody, such as HD4 or HD8, CAMATH-1 and CAMATH-1H or their other variants, fragments, conjugates, derivatives and other modifications, or other equivalent compositions with improved or optimized properties Twi, and proteins or peptides, for example, as those described in, but not limited to, Trends in Biotechnology (2003), 21 (12), p. 566-562.

As mentioned in the application, the terms “inflammatory diseases” or “inflammatory diseases” include diseases or diseases that are caused or accompanied by inflammatory processes. They include diseases or diseases such as arthritis, including rheumatoid arthritis, spondylarthropathy, gouty arthritis, ostearthritis, systemic lupus erythematosus and chronic polyarthritis in children, osteoarthritis, gouty arthritis and other arthritis diseases; pulmonary diseases and pneumonia, including adult respiratory distress syndrome, pulmonary sarcodiosis, asthma, silicosis, and chronic inflammatory lung diseases; viral and bacterial infections, including sepsis, septic shock, gram-negative sepsis, malaria, meningitis, cachexia caused by infection or malignant disease, cachexia caused by acquired immunodeficiency syndrome (AIDS), AIDS, AIDS-associated complex, pneumonia and herpes simplex virus; bone resorption diseases such as osteoarthritis, endotoxic bacterial toxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease, including the transplant versus host disease and allograft rejection, cardiovascular diseases, including atherosclerosis, thrombosis, congestive heart failure renal reperfusion injury, liver disease and nephritis, and myalgia due to infection; Alzheimer's disease, influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), skin-related diseases such as psoriasis, eczema, burning sensation, dermatitis, keloid formations and scar tissue formation; gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis; ophthalmic diseases such as retinitis, retinopathy, uveitis, photophobia and acute injuries of eye tissue; angiogenesis, including neoplasia; metastasis; ophthalmic diseases such as corneal tissue rejection, ophthalmic neovascularization, retinal neovascularization, including neovascularization after trauma or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; peptic ulcers, such as a stomach ulcer; pathological but not malignant diseases such as hemangiomas, including infantile hemangiomas, nasopharyngeal angiofibromas and avascular necrosis of bones; diabetic nephropathy and cardiomyopathy; and diseases of the female reproductive system, such as endometriosis.

When referred to in the application, the term "pharmaceutically acceptable salts" refers to derivatives of the described compounds in which the starting compound is modified to produce their acidic or basic salts. Examples of pharmaceutically acceptable salts include salts of inorganic or organic acids at basic residues such as amines; salts of alkalis or organic bases on acid residues such as carboxylic acids and the like, but are not limited to. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, which are formed, for example, with non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts formed by inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and salts obtained with organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilibenzoic, 2- fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isatinic, etc.

Pharmaceutically acceptable salts of the present invention can be synthesized from starting compounds that contain a basic or acidic moiety using conventional chemical methods. Typically, such salts can be prepared by reacting these compounds in the form of free acids or bases with a stoichiometric amount of the corresponding base or acid in water or an organic solvent, or a mixture of both; a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is usually preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the contents of which are incorporated herein by reference.

Any salt that retains the desired biological activity of the compounds contained in the application, and exhibiting minor or not showing undesirable toxic effects, is considered to be included in the application. Pharmaceutically acceptable salts include salts prepared with pharmaceutically acceptable organic and inorganic acids and bases. Pharmaceutically unacceptable salts and bases also find use in the application, for example, in the synthesis and / or purification of compounds of interest. Thus, all “salts” are also encompassed by the scope of the present invention.

Non-limiting examples of suitable salts include salts prepared with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid; and salts obtained with organic acids, such as, for example, formic acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, malonic acid, ascorbic acid, citric acid, benzoic acid, tannic acid, alginic acid, polyglutamic acid, toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, alpha-ketoglutaric acid, 3-glycerophosphoric acid and polygalacturonic acid. Suitable salts include salts prepared with alkali metals such as lithium, potassium and sodium, with alkaline earth metals such as calcium and magnesium, as well as other acids well known to those skilled in the art of pharmacy. Other suitable salts include salts obtained with metal cations, such as zinc, bismuth, barium or aluminum, or with cations derived from amines, such as ammonium, N, N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium or ethylenediamine. In addition, suitable salts include salts prepared with a combination of acids and bases, such as, for example, zinc tannate salt.

The phrase "pharmaceutically acceptable" is used in the application to refer to those compounds, materials, compositions and / or dosage forms that, in terms of a thorough medical assessment, are suitable for use in contact with the tissues of the human body and animal, without causing excessive toxicity, inflammation, allergic reactions or other problems or difficulties comparable to a reasonable balance of benefits and risks.

The term "prodrug", as referred to in the application, refers to a substance that is converted into a pharmacologically active parent drug in vivo, such as the compounds described in the application. The term “prodrug” includes any covalently bound carrier that releases the active parent drug of the present invention in vivo upon administration of the prodrug to animals. Since prodrugs are known to improve many of the desired qualities of the drugs (e.g., solubility, bioavailability, production, transportation, pharmacodynamics, etc.), the compounds of the present invention can be delivered in prodrug form. Prodrugs, for example, may have oral bioavailability, even if the parent drug does not possess it. Thus, the present invention encompasses prodrugs of the claimed compounds, methods for the delivery of compounds and compositions containing them. The prodrugs of the present invention are obtained by modifying the functional groups represented in the compound so that the modifying groups are cleaved either by normal handling or in vivo, releasing the parent compound. Prodrugs include compounds of the present invention in which a hydroxy, amino or sulfhydryl group is linked to any group that, when a prodrug of the present invention is administered to mammalian subjects, cleaves to give a free hydroxyl, free amino or free sulfhydryl group, respectively. Examples of prodrugs include acetate, formate and benzoate derivatives of the compounds of the present invention on alcohol and amine functional groups.

Generally speaking, prodrugs are derivatives of drugs per se that, after use, undergo transformation or metabolism into physiologically active compounds. The conversion may be spontaneous, such as hydrolysis in a physiological environment, or catalyzed by enzymes. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, esterified, alkylated, dealkylated, phosphorylated and / or dephosphorylated to form the active compound.

From the multivolume scientific literature devoted generally to prodrugs, references are made to the following sources: Gang-war et al., "Prodrug, molecular structure and percutaneous delivery", Des. Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21. (1977); Nathwani and Wood, "Penicillins: a current review of their clinical pharmacology and therapeutic use", Drags 45 (6): 866-94 (1993); Sinhababu and Thakker, "Prodrugs of anticancer agents", Adv. Drag Delivery Rev. 19 (2): 241-273 (1996); Stella et al., "Prodrugs. Do they have advantages in clinical practice? ” Drugs 29 (5): 455-73 (1985); Tan et al. "Development and optimization of anti-HIV nucleoside analogs and prodrugs: A review of their cellular pharmacology, structure-activity relationships and pharmacokinetics," Adv. Drag Delivery Rev. 39 (1-3): 117-151 (1999); Design of Prodrugs (Bundgaard H. ed.) 1985 Elsevier Science Publishers B.V. (Biomedical Division), Chapter 1; Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities (Hans Bundgaard); Bundgaard et al. Int. J. of Pharmaceutics 22 (1984) 45-56 (Elsevier); Bundgaard et al. Int. J. of Pharmaceutics 29 (1986) 19-28 (Elsevier); Bundgaard et al. J. Med. Chem. 32 (1989) 2503-2507 Chem. Abstracts 93, 137935y (Bundgaard et al.); Chem. Abstracts 95, 13 8493 f (Bundgaard et al.); Chem. Abstracts 95, 138592n (Bundgaard et al.); Chem. Abstracts 110, 57664p (Alminger et al.); Chem. Abstracts 115, 64029s (Buur et al.); Chem. Abstracts 115, 189582y (Hansen et al.); Chem. Abstracts 117, 14347q (Bundgaard et al.); Chem. Abstracts 117, 55790x (Jensen et al.); and Chem. Abstracts 123, 17593b (Thomsen et al.).

The term “used”, “application”, “administration” of a compound should be understood as providing any compound of the invention to an individual, including an animal having indications for treatment, by bringing such an individual into contact with, or using the individual in any other way.

The term "in vitro" refers to a biological object, biological process or biological reaction outside the body, in artificial conditions. For example, in vitro cell growth should be understood as cell growth in a medium outside the body, for example, in a test tube, culture dish or microplate.

The term “therapeutically effective amount” means the amount of a compound that will elicit that biological, physiological, pharmacological, therapeutic or medical response in a cell, tissue, system, organism, animal, individual, patient, or person that is intended by a researcher, scientist, pharmacologist, pharmacist , veterinarian, doctor or other clinician, for example, attenuating the effects / symptoms of a disease or disease, such as cancer or a tumor, or stopping or inhibiting the growth of proliferating adhesives ok, such as cancerous cells. A therapeutically effective amount may be determined in accordance with standard procedures, including those described below in the Dosage section.

The term "additional treatment", "additional use" or "additionally applied" means that various medicinal substances or compounds can be used together, alternately or periodically. Such additional application can be divided in time or space, for example, at different times, on different days, or by various methods or routes of application.

Some compounds of the present invention

In one embodiment of the present invention, the compounds of the invention have a molecular weight of from 250 to 1000, in particular from 400 to 800, more specifically from 400 to 600 and even more specifically from 280 to 500. In certain embodiments, the compounds of the invention have one or more of the following characteristics: (i) no more than 5 hydrogen bond donors, (11) no more than 10 hydrogen bond acceptors, and (111) no more than 10 freely rotatable bonds (excluding bonds with terminal atoms). In certain embodiments, the compounds of formula (I) are in accordance with Lipinsky's “rule of five” (Lipinski, Adv. Drug Del. Rev. 1997; 23: 3), since they have a molecular weight of less than 500, not more than 5 donors of hydrogen bonds, not more than 10 acceptors of hydrogen bonds and cLogP value from -2 to 5.

In one embodiment of the present invention, the compounds of the invention are inhibitors of Haspin kinase activity. In certain embodiments of the invention, the compounds inhibit Haspin kinase activity, with IC ₅₀ values of less than 1 μM, these IC ₅₀ values are determined according to the inhibition assay using the HTRF method described in the examples below. In certain embodiments, the Haspin kinase IC ₅₀ is less than 0.5 µM, less than 0.2 µM, less than 0.1 µM, or less than 0.01 µM. In certain embodiments, the compounds inhibit not only Haspin, but also a number of other Haspin kinases: cKIT, FLT3, FLT3 ITD (and other mutant forms of FLT kinases), IRAK-4, Lyn (and other kinases of the Src kinase family) , MEK1.2 kinases, PDGFR-alfa, PDGFR-beta, VEGFR1,2,3, as well as the LRRK2 kinase and its mutant form LRRK2 (G19S20) with IC ₅₀ values less than 10 μM.

The compound of the present invention may exist in one or more crystalline forms, and may exist as an anhydrous solid or as solvates comprising certain amounts of solvents, including hydrates including certain amounts of water.

In another embodiment, the compounds of the invention are planned and deliberate products of a synthetic chemical scheme, i.e. obtained as a result of certain and planned chemical processes carried out in reaction vessels, and not by degradation, metabolism or fermentation, or obtained as impurities or by-products in the synthesis of other compounds. In certain embodiments of the present invention, the compounds are purified or isolated, for example, to a degree of purity of at least 80%, in particular at least 90%, more specifically at least 95%, even more specifically at least 97%, at least 98% or even at least 99%. Purity, when mentioned in the application, can be defined either as absolute or as relative purity. Absolute purity is defined as the amount of a compound of the invention obtained as a product of a synthetic chemical scheme, either before or after one or more purification steps. Relative purity refers to the amount of a compound of the invention with respect to one or more impurities, such as by-products, decomposition products (e.g. metabolites, products of oxidation or hydrolysis, etc.) and / or compounds that decompose to form a compound of the invention (e.g. precursors and prodrugs), for example, which may relate to a product of a synthetic chemical scheme. Thus, absolute purity refers to the amount of compound relative to everything else, while relative purity generally does not depend on the presence of unrelated compounds, such as excipients, stabilizers, and other medications for joint use. Purity can be estimated by weight, volume or molar ratios of the compound with respect to other compounds. Purity can be determined by various analytical methods including elemental analysis, visible UV spectroscopy, HPLC, GC-MS, NMR, mass spectrometry and thin layer chromatography, preferably HPLC, GC-MS or NMR.

Dosage Forms, Dosages and Applications

The present invention further provides a pharmaceutical composition comprising a compound described above, or a prodrug thereof, and a pharmaceutically acceptable excipient, diluent or carrier, comprising a therapeutically effective amount of such a compound or prodrug.

Dosage Forms

The compositions of the present invention can be included in the dosage form and used to treat an individual in need of treatment in any way that provides contact of the active ingredient with the site of action of the substance, such as a cell, in the body of the individual. They can be used by any conventional method available for use in conjunction with pharmaceuticals, either as an individual therapeutically active ingredient, or in combination with other therapeutically active ingredients. They can be used individually, but are usually used in conjunction with pharmaceutically acceptable diluents, excipients or carriers selected based on the chosen route of administration and standard pharmaceutical practice.

A pharmaceutical composition may also be used comprising less than a therapeutically effective amount of a compound described above or a prodrug thereof, for example, when used in combination with another pharmaceutical composition, such as an anticancer agent, such that the combination is therapeutically effective, or may be used for preventive treatment.

A pharmaceutical composition for use in accordance with the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable diluents, excipients or carriers. The pharmaceutical compositions of the invention may be formulated for various routes of administration, including systemic, local or local administration. General preparation methods and dosage forms can be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA. As described in detail below, the pharmaceutical compositions of the present invention may be formulated for use in solid or liquid form, including dosage forms adapted for: (1) oral administration, for example, in the form of medicines (aqueous or non-aqueous solutions or suspensions) tablets, capsules, boluses, powders, granules, pastes for use on the tongue; (2) parenteral administration, for example, in the form of subcutaneous, intramuscular or intravenous injections, such as, for example, sterile solutions or suspensions; (3) topical application, for example, in the form of a cream, ointment or spray for application to the skin; or (4) intravaginally or intrarectally, for example, in the form of suppositories, cream or foam. In certain embodiments, the pharmaceutical preparations may be pyrogen-free, i.e. Do not cause an increase in body temperature in the patient.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and perfumes, preservatives and antioxidants, may also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (E320, BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminotetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Dosage forms of the present invention include dosage forms suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. Dosage forms can be conventionally presented in the form of dosage forms and can be prepared by any means well known in the art of pharmacy. The amount of active ingredient that can be combined with the material of the carrier to form a single dosage form may vary depending on the organism to be treated, as well as on the specific route of administration. The amount of active ingredient that can combine with the material of the carrier to form a single dosage form is usually such an amount of an inhibitor that causes a therapeutic effect. Typically, this amount is one hundred percent from about 1 to about 95 percent of the active ingredient, preferably from about 5 to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods for preparing these dosage forms or compositions include the step of combining a compound of the present invention with a carrier and, optionally, one or more accessory ingredients. In general, dosage forms are prepared by uniformly and thoroughly mixing a compound of the present invention with a liquid filler, or a finely divided solid filler, or both, and then, if necessary, formulating the product.

For systemic administration, injections are preferred, including intramuscular, intravenous, intraperitoneal and subcutaneous (i.m., i.v., i.p. and s.c. respectively). The phrases “systemic administration”, “systemically applied” and “peripherally applied” when referred to in the application means the use of a compound, drug or other material in a manner other than directly into the central nervous system, so that it enters the patient’s circulatory system and, thus, undergoes metabolism and similar processes, for example, subcutaneous administration.

The pharmaceutical compositions of the invention in an injectable dosage form can be liquid solutions, preferably in a physiologically compatible buffer system, such as Hanks's solution or Ringer's solution. In addition, the pharmaceutical compositions may be in solid dosage form and dissolved or suspended immediately before use. Lyophilized dosage forms are also included.

The pharmaceutical compositions of the invention may be in a dosage form suitable for oral administration in the form of capsules, sachets, pills, tablets, dragees (using flavored bases, usually sucrose or Arabian or tragacanth gum), powders, granules, or in the form of a solution or suspension in an aqueous or non-aqueous medium, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose or gum) and / or polo mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compound of the present invention may also be used as a bolus, electuary or paste.

In the prescription of the pharmaceutical compositions of the invention in solid dosage forms for oral (po) administration (capsules, tablets, pills, dragees, powders, granules, etc.), the compound of the invention as an active ingredient is mixed with one or more pharmaceutically acceptable an excipient such as sodium citrate or or dicalcium phosphate and / or one of the following ingredients: (1) fillers or additives such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants, such as glycerin; (4) substances for improving the disintegration of tablets, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) a retarder of the setting of a solution, such as paraffin; (6) a suction accelerator such as a quaternary ammonium compound; (7) wetting agents, such as, for example, cetyl alcohol or glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) dyes. In the case of capsules, tablets and pills, the pharmaceutical composition may also include buffering agents. Solid compositions of a similar type can also be used in soft and hard gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols, and the like.

Gelatin capsules contain a compound of the present invention as an active ingredient and powdered excipients such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar excipients can be used to make compressed tablets. Both tablets and capsules can be formulated as sustained release dosage forms in order to provide continuous release of the drug over an extended period. Compressed tablets may be coated with a sugar or film coating to mask an unpleasant taste and to protect the tablet from the atmosphere, or with an enteric coating for selective digestion in the gastrointestinal tract. Solid compositions of this type are also used as fillers in soft and hard gelatin capsules; preferred materials also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. A preferred dosage form is a solution or suspension in an oil, for example olive oil, Miglyol or Capmul, in a soft gelatin capsule. If necessary, antioxidants can be added to prevent decomposition over time.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. A compressed tablet may be made using a binder (e.g. gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, preservative, disintegrant (e.g. sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactants or dispersants. A molded tablet may be made by molding a powdered inhibitor moistened with an inert liquid diluent in a suitable apparatus.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, optionally, may be labeled or coated, such as enteric or other coatings, as is well known in the art of dosage forms. They can also be in such a dosage form that provides a slow or controlled release of the active ingredient contained therein, using, for example, hydroxypropyl methylcellulose in various ratios, to provide the desired release profile, as well as other polymer matrices, liposomes and / or microspheres. They can also be sterilized, for example, by filtering through a bacteria-retaining filter, or by introducing a sterilizing agent into the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain radiopaque substances and may be a composition that releases the active ingredient (s) only, or preferably, in certain sections of the gastro-intestinal tract, optionally, in a delayed manner. Examples of included compositions that may be used include polymeric materials and resins.

Liquid dosage forms for oral administration of the pharmaceutical compositions of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents known 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, oils (in particular cottonseed, peanut, corn, wheat germ oil, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and fatty ethers GOVERNMENTAL acids of sorbitan, and mixtures thereof.

In addition to inert diluents, pharmaceutical compositions for oral use may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors, colorants, perfumes and preservatives.

Suspensions, in addition to the pharmaceutical composition of the present invention, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and gum tragacanth, and mixtures thereof.

For buccal administration, the pharmaceutical compositions may take the traditional form of lozenges or lozenges.

For use by inhalation, the pharmaceutical compositions of the present invention can be provided in the form of a sprayable aerosol in pressurized packages or in the form of a nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, a single dose may be determined by using a suitable valve to deliver a metered amount of the substance. Capsules and cartridges of, for example, gelatin for use in an inhaler or blower may contain a powder of a mixture of therapeutic agents and a suitable powder base, such as lactose and starch.

The pharmaceutical compositions may be formulated for parenteral administration by injection, for example, a bolus injection or continuous infusion. Dosage forms for injection can be presented in the form of a single dose, for example, in ampoules or reusable containers containing an additional preservative. The pharmaceutical compositions may also be in the form of suspensions, solutions or emulsions in an oil or aqueous medium and may contain additional substances, such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder that is reconstituted with a suitable medium, for example sterile pyrogen-free water, before use.

The phrase "parenteral administration" and "applied parenterally" when referred to in the application means a route of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracalsular, intraocular, intracardiac, intradermal , intraperitoneal, transtracheal, subcutaneous, subcultural, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions.

Pharmaceutical compositions of the present invention useful for parenteral administration include one or more Haspin kinase inhibitors in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or are sterile powders that can be reconstituted in sterile injectable solutions or dispersions immediately prior to administration, these compositions may contain antioxidants, buffers, bacteriostats, solutions that maintain the isotonic composition with the patient’s blood, or suspending agents or thickeners.

Examples of suitable aqueous and non-aqueous excipients that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyalcohols (such as glycerin, propylene glycol, polyethylene glycol and the like) and their acceptable mixtures, vegetable oils such as olive oil, and suitable for injection, organic esters such as ethyl oleate. The desired consistency can be maintained, for example, by using shell materials such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants.

The claimed pharmaceutical compositions may also contain auxiliary substances, such as preservatives, wetting agents, emulsifiers and dispersing agents. Protection against microorganisms can be achieved by the inclusion of various antibacterial and antifungal substances, for example, paraben, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic substances such as sugars, sodium chloride, and the like in the pharmaceutical composition. In addition, by incorporating absorption delaying agents such as aluminum monostearate and / or gelatin, sustained absorption of the injectable dosage form can be achieved.

In addition to the dosage forms already described, the pharmaceutical compositions may be presented in delayed absorption dosage form. Such long-acting dosage forms can be used by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, pharmaceutical compositions can be formulated together with suitable polymeric or hydrophobic materials (for example, as an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

Systemic administration can also be carried out by transmucosal or transdermal methods. For transmucosal or transdermal use, appropriate suitable penetrants are used in the prescription to overcome the tissue barrier. Such penetrants are known in pharmacology and include, for example, bile salts and fusidic acid derivatives for transmucosal use. Transmucosal administration may be via a nasal spray or using suppositories. The pharmaceutical compositions of the invention for topical administration are included in ointments, rubbing, gels or creams, which is generally known in the pharmaceutical field. Wash solutions can be applied topically to treat wounds or places of inflammation to accelerate healing.

In some cases, to prolong the therapeutic effect of the inhibitor when administered by subcutaneous or intramuscular injection, it is desirable to slow the absorption of the inhibitor. This can be achieved by using a liquid suspension of crystalline or amorphous material having a low solubility in water. In this case, the absorption rate of the inhibitor depends on the dissolution rate, which, in turn, may depend on the size and shape of the cystals. Alternatively, delayed absorption of a parenterally administered inhibitor can be achieved by dissolving or suspending the inhibitor in a fatty medium.

The pharmaceutical compositions of the invention can be formulated for rectal or vaginal administration in the form of suppositories, which can be prepared by mixing one or more compounds of the invention with one or more suitable excipients or carriers that do not cause irritation, including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, which remains solid at room temperature but becomes liquid at body temperature, and therefore will melt in the anus or vaginal cavity and release an active inhibitor.

Dosage forms of the pharmaceutical compositions of the present invention suitable for vaginal use also include uterine rings, tampons, creams, gels, pastes, foams or spray containing excipients suitable for this.

Dosage forms for topical or transdermal use of the compounds of the present invention include powders, spray, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalation dosage forms. Such a compound may be mixed under sterile conditions with a pharmaceutically acceptable excipient and any necessary preservative, buffer or propellant.

Ointments, pastes, creams and gels, in addition to the compounds of the invention, may contain fillers such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays of a compound of the invention may contain fillers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures thereof. The spray may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the added benefit of controlled delivery to the body of a compound of the present invention. Such a dosage form can be made by dissolving or dispersing the inhibitor of the present invention in a suitable medium. Absorption enhancers can also be used to increase the permeability of the drug through the skin. The absorption rate in this case can be controlled either by the presence of a special membrane that controls the speed, or by dispersing the compounds of the invention in a polymer matrix or gel.

Ophthalmic dosage forms, ophthalmic ointments, powders, solutions, etc. are also within the scope of the present invention.

The pharmaceutical compositions may, if desired, be in a package or in a dispensing device, which may contain one or more single dosage units containing the active ingredient. The package may, for example, include metal or plastic foil, such as in a blister pack. Instructions for use may be included with the packaging or dosing device. In other embodiments, the package or dispenser may further be packaged in a cardboard box.

The pharmaceutical compositions of the present invention may also be formulated as sustained and / or sustained release formulations. Such sustained and / or sustained release dosage forms may be carried out using sustained release delivery methods and devices well known to any person skilled in the art, for example, as described in US Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 4,710,384 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, the contents of which are incorporated into the application by reference. The pharmaceutical compositions of the present invention can be used to provide slow or sustained release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, etc. p., or combinations thereof in various ratios to provide the desired release profile. Suitable sustained release dosage forms known to any person skilled in the art of pharmacology, including those described in the application, can be easily applied for use with the pharmaceutical compositions of the invention. Thus, unit dosage forms suitable for oral administration, such as tablets, capsules, gelatin capsules, capsule tablets, powders and the like, but not only those adapted for sustained release use, are considered to be encompassed by the present invention.

Sustained-release injection dosage forms are prepared by forming microencapsulated particles of said inhibitor in biodegradable polymers such as polyactide-polyglycolide. The rate of drug release can be controlled by the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Sustained-release injection dosage forms are prepared by incorporating the drug into liposomes or microemulsions compatible with body tissues.

When using the compounds of the present invention as medicaments for individuals, such as humans and animals, they can be used alone or in a pharmaceutical composition comprising, for example, from 0.1 to 99.5% (in certain embodiments, from 0, 5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable excipient.

The present invention provides new methods of treating proliferative, degenerative and other diseases and disorders, including cancer, by using a therapeutically effective amount of at least one of the compounds described in the application, or its prodrug, tautomer, pharmaceutically acceptable salt, N-oxide or stereoisomeric form. The present invention further provides methods for treating proliferative, degenerative and other diseases and disorders, including cancer, by using a therapeutic combination of at least one of these compounds and another anticancer or antiproliferative drug.

The compound may be used in the form of a salt or prodrug thereof, which, when used by an individual, is capable of directly or indirectly releasing a parent compound, such as the compound described herein, or exhibiting activity as such. Non-limiting examples include a pharmaceutically acceptable salt, alternatively referred to as a “physiologically acceptable salt”. In addition, such modifications of the compound may affect its biological activity, in some cases increasing it compared to the starting compound. This activity can be assessed by preparing the compound in the form of a salt or prodrug and determining its activity using the methods described in the application or other methods known to the skilled person.

It will be apparent to one skilled in the art that when a prodrug of a particular compound is used by an individual, such as an animal using or receiving such a prodrug, he will also be exposed and therefore indirectly use the parent compound. Such a procedure may expose cells associated with a disease, such as a proliferative disease or a disorder including cancer, to the parent compound.

The compounds of the present invention may contain an asymmetrically substituted carbon atom and may be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as resolving racemic forms or synthesizing from optically active starting materials, are well known to those skilled in the art. The invention encompasses all chiral, diastereomeric, racemic forms, unless a specific stereochemical or isomeric form is specifically designated. All processes used to prepare the compounds of the present invention and intermediates for their preparation are part of the present invention.

Dosage

The dosage used, which is a therapeutically effective amount, sufficient or powerful, in the opinion of medical professionals such as a doctor, nurse or pharmacist, to alleviate symptoms, such as cancer, will obviously vary depending on known factors such as pharmacodynamic the characteristics of the particular active ingredient and its method and route of administration; age, gender, state of health and weight of the recipient; the nature and severity of the symptoms; type of parallel treatment, the frequency of treatment and the desired effect.

Selected compounds may also be used for prophylactic treatment. If the compound is applied before the clinical manifestation of undesirable symptoms (e.g., illness or other undesirable animal conditions), then such treatment is prophylactic (i.e., it protects the individual from the onset, development or further development of undesirable symptoms). The claimed compounds can also be used to prevent symptoms, diseases or disorders, such as cancer, or a complex of symptoms, such as heart failure, or other medical diseases. Such treatment includes the use of a compound in order to reduce the frequency or delay the onset of symptoms of a medical illness in an individual compared to an individual who does not receive the compound. Thus, cancer prevention includes, for example, a reduction in the number of detectable cancers, tumors or malignancies in a population of patients receiving prophylactic treatment in relation to a control population not receiving such treatment, later occurrence of detectable cancers, formations or malignancies in a population patients receiving treatment relative to the untreated control population and / or slowing the progression of the disease I and / or an improvement in the quality of life of the patient, for example, statistically significant or clinically significant.

The toxicity and therapeutic efficacy of the pharmaceutical compositions of the present invention can be determined by standard pharmaceutical methods on cell cultures or experimental animals, for example, by determining LD ₅₀ (dose lethal for 50% of the population) and ED ₅₀ (dose therapeutically effective for 50% of the population). The ratio of toxic and therapeutic dose is a therapeutic index and is expressed by the ratio of LD ₅₀ / ED ₅₀ .

Therapeutic agents exhibiting high therapeutic indices are useful in many cases. In certain circumstances, therapeutic compositions exhibiting a minor therapeutic effect or having toxic effects may also be used, including when treatment is undertaken in order to develop a delivery system to areas of damaged tissue in order to minimize the potential for damage to intact cells, and thus , reduce or localize side effects.

Data from experiments on tissue cells and animal models can be used to formulate dosages for use in humans. Preferably, the dosage lies in a range of circulating concentrations that include ED ₅₀ and do not cause or cause minor toxicity. Dosage

may vary in this range depending on the dosage form used and the route of administration used. For any drugs used in the method of the invention, the therapeutically effective dose can initially be estimated based on cell experiments. Dosage can be adjusted in animal models until a circulating plasma concentration of IC _{50 is} reached (i.e., the concentration of the studied therapeutic agent that provides half of the maximum inhibition of symptoms or inhibition of biochemical activity) as determined by cell cultures. This information can be used to more accurately determine the dosage in humans. The plasma level can be determined, for example, by high performance liquid chromatography.

It should be understood that the appropriate dosage of therapeutic substances depends on a number of factors known to the specialist, for example, doctors. The dosage (s) of specific compounds will vary, for example, depending on the individuality, size and condition of the subject or sample being treated, in addition, on the route of administration of the composition, and the effect of the drug that the physician wishes to receive on the therapeutic target or targets, such like cells, nucleic acids or polypeptides that cause a disease or mediate a disease or symptoms.

Exemplary dosages include milligram or microgram amounts of the compounds of the present invention per kilogram of the weight of a subject or sample, for example, from about 1 microgram per kilogram to about 500 milligrams per kilogram, from about 100 micrograms per kilogram to about 50 milligrams per kilogram, or from about 1 milligram per kilogram to about 5 milligrams per kilogram.

One skilled in the art will recognize that dosage can also be calculated based on body surface. A person weighing 70 kg has a body surface of about 1.8 square meters. meters, and dosages can be expressed as milligram or microgram amounts of the compound per surface area of the body of the subject or sample, for example, from about 50 micrograms per square meter. meter to about 15 grams per square meter. meter, from about 5 milligrams per square meter. meter to about 1.5 grams per square meter. meter, or from about 50 milligrams per square meter. meter to about 150 milligrams per square meter. meter.

Applications

The present invention further provides compounds described above for treatment. In other aspects, the invention provides compounds of the present invention for prophylactic use.

In certain embodiments, said treatment or prophylactic use is the treatment or prophylaxis of proliferative diseases or disorders, such as a tumor or cancer. In certain embodiments, said treatment is a cancer treatment that can be treated by inhibiting the activity of a protein kinase or its mutant form.

Thus, the present invention further provides a method of treating an individual, such as a mammal, suffering from a disease condition selected from the group of proliferative diseases and disorders, or inflammatory diseases and disorders, comprising the use of the indicated individual a therapeutically effective amount of a compound, prodrug or pharmaceutical composition as described above . In certain embodiments, said individual is a human. In certain embodiments, said proliferative disease or disorder is cancer. In certain embodiments, said treatment is a cancer treatment that can be treated by inhibiting the activity of a protein kinase or its mutant form.

The present invention also provides a method of prophylactically treating an individual, such as an animal, including a mammal, in particular a human, in order to reduce the frequency or delay the onset of symptoms of a medical disease, such as cancer, in a subject compared to a subject not receiving the composition.

In an additional aspect, the invention provides methods for treating or preventing individuals suffering from a disease such as mammals, including domestic mammals, cats, dogs, horses, sheep, cows, rodents and humans, comprising the step of exposing the individual to a certain amount, including a therapeutically effective amount claimed compound. In certain embodiments, the disease is a proliferative disease or disorder, such as a cancer or tumor. In yet another embodiment, cells associated with said proliferative disease or disorder, including cancer cells, are exposed to the claimed compound. In certain embodiments, said compound, or prodrug thereof, is administered to said individual. In certain embodiments, said treatment is a cancer treatment that inhibits the activity of a protein kinase or its mutant form. In certain embodiments, said compound, or prodrug thereof, is administered to said individual.

In an additional aspect, the invention provides a method of inhibiting or inhibiting cell proliferation or growth, comprising contacting the cell with a compound of the invention. In one embodiment, the cells are grown in vitro, while in an alternative embodiment, the cell is in the individual. In a specific embodiment, the cell is a cancer cell, for example, cancer cell line cells or cells included in a tumor, including tumor cancer cells, which can be treated by inhibiting the activity of a protein kinase or its mutant (mutant form).

Another aspect of the invention relates to the use of the above compound, or prodrug thereof, for the manufacture of a medicament for the treatment or prophylaxis of a proliferative disease or disorder including cancer, including those cancers that can be treated by inhibiting the activity of a protein kinase or its mutant. The invention further relates to a pharmaceutical composition comprising the compound described above, or a prodrug thereof, and a pharmaceutically acceptable diluent, excipient or carrier, for treating or preventing a proliferative disease or disorder including cancer, including those cancers that can be treated by inhibiting activity protein kinase or its mutant.

The claimed compounds may be useful in the treatment of various diseases and disorders, including proliferative diseases and disorders and inflammatory diseases and disorders. The term "proliferative diseases and disorders" is also recognized by specialists and includes diseases and disorders affecting individuals, such as animals, in a manner that is characterized by impaired, or otherwise undesirable, proliferation of a group of individual cells. Cancer and tumors are proliferative diseases or disorders. Cells isolated or derived from a tumor are generally considered proliferating cells, typically hyperproliferating cells, and, in other circumstances, the tumor cell may be dysplastic or proliferating. In certain embodiments, said treatment is a cancer treatment that can be treated by inhibiting the activity of a protein kinase or its mutant.

When reading the description of the present invention, it will be apparent to one skilled in the art that methods, pharmaceutical compositions and packaged pharmaceutical preparations comprising the claimed compounds may be useful for treating other proliferative diseases or disorders, or for inhibiting or inhibiting cell proliferation, including tumor cells.

The compounds of the present invention can be used in the treatment of disease processes that are characterized by impaired cell proliferation, such as hyperproliferative diseases including cancer, benign prostatic hyperplasia, familial colon adenomatosis, neurofibromatosis, psoriasis, fungal infections, endotoxic shock, hypertrophic scar formation, inflammatory bowel diseases transplant rejection, vascular smooth muscle cell proliferation associated with atherosclerosis, psoriasis, ibroz lung, arthritis, glomerunefrity, restenosis following angioplasty or vascular surgery, and other post-surgical stenosis and restenosis. See for example. US Patents 6,114,365; and 6,107,305.

It is expected that the compounds described in the application can be used in the treatment of proliferative or hyperproliferative diseases or disorders, such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular diseases.

In certain embodiments, the tumor may be a solid tumor, which is a cancer of body tissues other than blood, bone marrow, or the lymphatic system. In certain embodiments, the tumors may be hematologic tumors, such as leukemia and lymphoma. Leukemia is a collective term for malignant diseases characterized by proliferation of malignantly altered white blood cells. Diseases that occur in the lymphatic tissue are called lymphomas.

Solid tumors can be selected from: liver cancer, stomach cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, skin cancer, kidney cancer, bone cancer, thyroid cancer, skin cancer, including epidermoid cancer, esophageal cancer , kidney cancer, bladder cancer, gall bladder cancer, cervical cancer, ovarian cancer, lung cancer, bronchial cancer, small cell and non-small cell lung cancer, stomach cancer, head and neck cancer.

Hematologic tumors can be leukemia, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, acute leukemia, acute promyelocytic leukemia, chronic granulocytic leukemia (CHL), chronic leukemia, leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, common acute lymphoblastic leukemia, eosinophilic leukemia, erythroleukemia, extranodal lymphoma, follicular lymphoma, hairy skin intramural leukemia, monocytic leukemia, prolymphocytic leukemia.

Hematologic tumors can also be lymphomas, such as B-cell lymphomas, Burkitt’s lymphoma, cutaneous T-cell lymphoma, high malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, low malignant lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, lymphoma edge of the lymph nodes, lymphoma of the lymphoid tissues of the mucous membranes (MALT), T-cell lymphomas, peripheral T-cell lymphoma, multiple myeloma, essential thrombocytosis, hairy cell lymphoma, e stramedullyarnaya myeloma, granulocytic sarcoma.

Hematologic tumors can also be tumors of myelocytic origin, including acute and chronic myelocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia.

Tumors can also be of mesenchymal nature, such as fibrosarcoma and rhabdomyosarcoma. Moreover, tumors can be tumors in the central and peripheral nervous system, such as astrocytoma, glioblastoma, meduloblastoma, neuroblastoma, glioma and schwannoma; the tumors can be other tumors, such as melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, caratacanthoma, follicular thyroid cancer, and Kaloshi sarcoma.

Tumors that are resistant or poorly treated with other anti-cancer or antiproliferative drugs can also benefit from treatment with the methods and pharmaceutical compositions of the present invention.

The compounds described herein may also be useful in cancer chemoprophylaxis. Chemoprophylaxis is defined as inhibiting the development of invasive cancer, either by blocking the initial mutagenic processes or by blocking the development of pre-cancerous cells, for example, by blocking the growth of a tumor that the patient is already suffering from or by inhibiting metastasis.

The compounds described herein may also be useful in inhibiting tumor angiogenesis and metastasis.

The compounds of the present invention can also be used in combination (administered concurrently or sequentially) with a known anti-cancer treatment, such as radiation therapy, or with anti-cancer, antiproliferative, cytostatic or cytotoxic drugs. Other anticancer and antiproliferative drugs that can be used in combination with the compounds of the present invention include the preparations described in the application. In the combination treatment, the compounds of the present invention can be used additionally with any other anticancer and antiproliferative drug described in the application.

When used in a single dosage form, such a combination of products includes the compounds of the present invention in the dosage range described in the application, and another pharmaceutically active drug or medicament in the dosage range approved for it. For example, it was found that the cdc2 inhibitor olomucine acts synergistically with known cytotoxic drugs, inducing apoptosis (J. Cell Sci., 108, 2897 (1995)). The compounds described in the application can also be used sequentially with known anticancer or antiproliferative drugs, if their single dosage form is unacceptable. The invention does not limit the sequence of use; the compounds described in the application can be used before or after taking known anti-cancer or antiproliferative drugs. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopindol (flavopindol) depends on the sequence of its use with anticancer drugs (Cancer Research, 57, 3375 (1997)).

Additional aspects of the invention

Another aspect of the invention provides a pharmaceutical package in which said package comprises a compound of any of the claims of the present invention. In certain embodiments, the package includes instructions that indicate that the composition can be used in the treatment of an individual in need of such treatment, including a human. In certain embodiments, the package includes a dosage form containing one or more compounds of the present invention together with another pharmaceutical ingredient, such as an anti-cancer or anti-proliferative substance. In this case, the compound (s) of the present invention and another pharmaceutical ingredient may be presented in separate dosage forms in an individual dosage.

Other pharmaceutical ingredients that may be included in the dosage form, together or separately with the compounds of the present invention, include other anti-cancer and antiproliferative drugs, such as those described above, but not limited to. In certain further embodiments, the pharmaceutical package includes instructions for treating a patient in need of such treatment. In yet another aspect, the invention provides a pharmaceutical package for treating an individual suffering from proliferative diseases and disorders such as a tumor or cancer, wherein said package includes at least one compound of the present invention. In certain further embodiments, the pharmaceutical package includes instructions for treating a disease .

When referred to in the application, the term “pharmaceutical packaging” or “pharmaceutical packaging” refers to any packaging system for storing and packaging individual dosages of a drug. Preferably, the pharmaceutical package contains a number of dosage units sufficient for the treatment period, or an amount convenient for the patient's regimen. In certain embodiments, the pharmaceutical package comprises one or more containers comprising an active ingredient, for example, a compound of the present invention. Such a container may be a container, such as a bottle, vessel, syringe or capsule, or may be in unit dosage form, such as a pill. The active ingredient may be provided in a container in its pharmaceutically acceptable form or may be provided, for example, as a lyophilized powder. In further embodiments, the pharmaceutical package may further include a solvent for preparing the active ingredient for administration. In certain embodiments, the active ingredient may already be contained in a delivery system, such as a syringe, or a suitable delivery device may be included in the package. Pharmaceutical packaging may include pills, liquids, gels, tablets, dragees, or pharmaceutical preparations in any other suitable form. A package may contain any number of daily pharmaceutical dosage units. The package may be of any shape, and unit dosage forms may be arranged in any manner, such as a circular, triangular, trapezoidal hexagonal or other configuration. One or more dosage or subunit can be allocated, for example, to help a doctor, pharmacist or patient, for example, by applying staining, labels, prints, relief, drawing lines or compositions. The pharmaceutical packaging may also include instructions for the patient, doctor, pharmacist, or any other treatment related person.

Some embodiments include the use of more than one active ingredient, including the compounds described in the application. Such an application may be carried out simultaneously or sequentially. Active ingredients may be included in a single dosage form, so that a single administration delivers both components. Alternatively, the active ingredients may come in different dosage forms. A pharmaceutical package may include a compound of the present invention and another pharmaceutical ingredient in a single prescription, i.e. they are part of one dosage form, or a compound of the present invention and another pharmaceutical ingredient may be part of different dosage forms. Each dosage form may include a compound of the present invention and another pharmaceutical ingredient in the amount of individual dosages (in approximately equal or unequal amounts). The use of a compound of the present invention and another pharmaceutical ingredient creates a concentration that provides a therapeutically effective amount in combination.

When referred to in the application, the term “instruction” means a product label and / or documents or other information describing relevant materials and methodologies related to the packaging, preparation or use of a kit or packaging of a preparation. These materials may include any combination of the following: reference information, steps or rules of use, list of components, suitable dosages, warnings regarding possible side effects, instructions for use of the medicine, reference materials, or any other related documents. Instructions may be in printed form, such as a label on the package or package insert. Instructions for the packaged preparation or pharmaceutical composition may be included in a cardboard box or in a final package, for example, as a package insert, and the insert text must be approved by a competent regulatory authority such as the Food and Drug Administration (FDA) USA. Alternatively or additionally, the instruction may also be stored in electronic form, for example, on a computer-readable medium, such as a computer memory device, a centralized database, a magnetic medium, such as a hard disk, diskette and magnetic tape; optical media such as a CD, CD-ROM, and holographic devices; magneto-optical media such as a floppy disk; and hardware that is specifically configured for storing and processing program code, such as application integrated circuit (ASICs), programmable logic device (PLDs) and ROM (read-only memory) and RAM (random access memory) devices. The instructions may include the web address of the corresponding web site on the Internet from which you can download more detailed instructions, or a recorded presentation. The instructions may contain one or more documents for future updates.

Thus, in one aspect, the invention relates to a pharmaceutical package comprising the pharmaceutical composition of the present invention and instructions that indicate that said pharmaceutical composition can be used to treat an individual in need thereof.

In certain embodiments of such a pharmaceutical package, said instruction indicates that the pharmaceutical composition can be used to treat a person.

In certain embodiments of such a pharmaceutical package, said instruction indicates that the pharmaceutical composition can be used to treat an individual suffering from a disease or disorder.

In certain embodiments of such a pharmaceutical package, said instruction indicates that the pharmaceutical composition can be used to treat a person suffering from a disease or disorder.

In another aspect, the invention relates to a method for treating a disease or disorder in an individual, comprising exposing the cells of the disease or disorder to a compound of the present invention.

In certain embodiments of this method, said compound, or prodrug thereof, is administered to said individual.

In certain embodiments of this method, said individual is a mammal selected from: a domestic mammal, dog, cat, horse, sheep, cow, rodent, and human.

In certain embodiments of this method, said mammal is a human.

In another aspect, the invention relates to methods for inhibiting cell proliferation, comprising contacting a cell with a compound of the present invention.

In another aspect, the present invention relates to the use of a compound of the present invention for the manufacture of a medicament for the treatment of a disease or disorder.

In another aspect, the present invention relates to the use of a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent or carrier, for treating a disease or disorder.

In certain embodiments of such a pharmaceutical composition, pharmaceutical package, method or use of the present invention, the disease or disorder is a proliferative disease or disorder.

In certain embodiments, said proliferative disease or disorder is cancer.

In certain embodiments, said disease or disorder is an inflammatory disease or disorder.

To obtain compounds of the general formula (1) according to this invention, several synthetic schemes have been developed.

The synthesis of the necessary derivatives of imidazoazines (4), as well as their aza analogs, is carried out by a number of methods (Scheme I):

When reacting 2-aminoazine derivatives (and a number of other aminoazines, such as 2-aminopyrimidine, 2-aminopyrazine) of the general formula (2) with dialkyl acetals of chloro (bromo) acetic aldehyde, imidazoazines derivatives are obtained in good yield (3). These compounds are suitable as a substrate for the palladium-catalyzed Heck cross coupling reaction. The resulting imidazoazines (3) are easily brominated (iodinated) into the imidazole ring by the action of various halogenating reagents. Thus, the synthesized halogen-containing imidazoazines are converted to trialkyltin derivatives as a result of the interaction of the corresponding halogen-containing imidazoazines with hexaalkyldiol (or trialkyl halide) in the presence of various palladium-based catalysts (usually (tetrakis) triphenylphosphine palladium (0), etc.). As a result, compounds of the general formula (4) are obtained, which are a suitable substrate for the Style cross-coupling reaction.

Synthesis of mono-halogen derivatives of pyridines and pyrazines (Scheme 2):

By the interaction of the hexamethyldisilazane sodium salt (1.1 equiv.) With the corresponding carboxylic acid esters (1 equiv.) (Compounds of general structure 5), which contain an acidic hydrogen atom in the α-position to the carbonyl group CH, a sodium salt is obtained, which further reacts with dihalogenated pyridines (as well as other dynamogenazines containing an activated halogen atom). The reaction is carried out with moderate cooling (-50-0 ° C) in dry tetrahydrofuran for 1-4 hours.

The resulting product (7) is isolated by diluting the reaction mass with water, followed by extraction with dichloromethane and concentration under reduced pressure. Further, the ester group is saponified to a carboxylic acid by the action of a 10% aqueous potassium hydroxide solution with moderate heating (60-70 ° C). The resulting acid (9) is isolated by acidifying the reaction mixture with aqueous hydrochloric acid to pH = 4 and extracting with dichloromethane. The organic acid extract (9) is concentrated under reduced pressure and used in further transformations without further purification. Halogen derivatives (10) are obtained by decarboxylation of the corresponding acids (9) in dimethyl sulfoxide at 100 ° C or in a mixture at 120-130 ° C (Scheme 3):

The preparation of mono-halogen derivatives of pyrimidines was carried out according to scheme 4:

Ketoesters (11) are synthesized based on carboxylic acids of the general formula (9a). The latter are obtained in dry acetonitrile by the action of malonic acid methyl ester of monosodium salt on the corresponding imidazolid (the intermediate product is formed by the interaction of acid (9a) and carbonyldiimidazole) in the presence of magnesium chloride. The isolated ketoesters (11) easily react with amidines (guanidines) in the presence of sodium methylate in various solvents (alcohol, dioxane, etc.) and form hydroxypyrimidine derivatives (13).

On the basis of carboxylic acids (9a), amidines (12) are synthesized by the action of triethyloxonium tetrafluoroborate on the primary amide of acid (9a) in dry dichloromethane, followed by treatment of the imidoester with a saturated solution of ammonia in alcohol (methanol, ethanol) for 12-24 hours at room temperature. After removal of the solvent under reduced pressure, the corresponding amidines (12) are isolated from the reaction mixture, which are used in further transformations without further purification. The isolated amidines (12) easily react with ketoesters (derivatives of acetoacetic ester) in the presence of bases (potassium carbonates (cesium), potassium phosphates, diazobicycloundecene, etc.) in various solvents (alcohol, dioxane, etc.), forming pyrimidine derivatives (14) .

Pyrimidine derivatives (13-14) reacting with phosphorus (V) oxychloride in the presence of N, N-dimethylaniline (4-5 equiv.) In benzene (toluene) at room temperature form chloropyrimidines in high yield (15), which are used in further cross-coupling reactions to obtain the final target compounds.

The synthesis of a mono-halogen derivative of pyridines (pyrazines, pyrimidines) connected by a methylene (ethylene) "bridge":

The synthesis of these derivatives is carried out by the interaction of dihalogenated pyridines (pyrazines, pyrimidines) and exocyclic alkenes.

For the synthesis of alkenes, 2 approaches are used (Scheme 5):

The first approach is based on the use of the Wittig reaction (reaction of carbonyl compounds with phosphorus ylides).

The reaction is usually carried out in tetrahydrofuran, dioxane or dimethyl sulfoxide. For this, the phosphonium salt is suspended in an appropriate solvent. Then, a base (usually sodium (or lithium) hexametidisilazide or sodium hydride (1.1-1.2 equivalents) is added. After holding for 1-2 hours (generation of phosphonium ylide), a solution of the corresponding ketone is added in portions (or dropwise) Next, the reaction mixture is gradually brought to room temperature and incubated for several hours (from 3 to 24 hours). Standard reaction product is isolated (the reaction mixture is treated with water, then the target product is extracted with dichloromethane, the extract is washed with water, then a saturated solution ohm brine, dried over sodium sulfate and concentrated in vacuo) Substances isolated by chromatography on silica gel (Flash-chromatography) using as solvent mixtures of hexane and ethyl acetate yields the desired products are in the range -.. 60-85%.

The second approach is based on the intramolecular reaction of a “double” nucleophilic addition by cyclization of derivatives of 1,2-amino alcohols (or 1,2-diamines) with dichloropropene. During the reaction, the corresponding seven-membered carboheterocycles are obtained (Scheme 6).

Reaction of ethanolamine with tert-butyloxycarbonyl pyrocarbonate in dichloromethane at room temperature gives the N-tert-butyloxycarbonyl derivative. In the case of ethylenediamine, a mono-Boc derivative is first obtained (use a 5-6 fold excess of ethylene diamine to reduce the likelihood of a di-Boc derivative). Next, the synthesized mono-Boc derivative is converted to Boc, a Cbz derivative of ethylenediamine by an acylation reaction with Cbz-Cl.

The intermediates (18a, b) thus obtained react with dichloropropene to form a seven-membered ring in the presence of a suitable base according to the principle of a double nucleophilic substitution reaction. A similar reaction is carried out either in anhydrous dimethylformamide (1,4-dioxane) in the presence of potash, or under reaction conditions in a two-phase system (water-dichloromethane) in the presence of an interphase transfer catalyst (less commonly used).

The obtained alkenes (17) and (19a, b) upon reaction with 9-BBN (9-borabicyclononan, (20) (according to the principle of hydroboration reaction) form alkyl-9-BBN derivatives, which is used in subsequent transformations without intermediate isolation in the form of a solution in THF (~ 0.2-0.4 M solution). The indicated conversion is carried out at room temperature in tetrahydrofuran medium for 24 hours. The reaction can be accelerated (reaction time 3-4 hours) if carried out at a higher temperature (for example, by boiling in THF) .

The most important step in the synthesis of key intermediates is the cross-coupling reaction of alkyl-9-BBN derivatives, as shown above, and aromatic heterocyclic halides (or their synthetic equivalents) (compound (4), Scheme 1) in the presence of palladium (nickel) catalysts and bases (usually potash, alkali, etc.) in water-dioxane (tetrahydrofuran, diglyme, etc.) media.

As a source of palladium is usually used:

- palladium acetate (trifluoroacetate);

- a complex of palladium (0) with dibenzylideneacetone;

- complexes of palladium (II) chloride with various alkenes (propene, 1,5-cyclooctadiene, etc.);

As ligands are usually used:

- phosphines (less often phosphites);

- carbenes based on imidazole (and its reduced forms);

- dicarbonyl compounds (e.g. acetylacetone);

Sometimes apply the method of obtaining in-situ catalysts. So use the pre-prepared form of the catalyst (tetrakis) triphenylphosphine palladium.

Purification and subsequent isolation of the reaction products is usually carried out by column chromatography on silica gel using typical organic solvents (n-hexane, petroleum ether, ethyl acetate, dichloromethane, etc.).

Cross-coupling reactions of previously obtained halogen derivatives of pyridines (pyrimidine, pyrazine) such as (10), (15), (21), (22) with derivatives of imidazoazines and their analogues (4) lead to key intermediates of the general formula (24) (diagram 8):

The indicated conversion is carried out under the conditions of the Heck reaction (LG = H) or the Stille reaction (LG = SnAlk3) during catalysis with palladium complex compounds in the presence or absence of a base.

As a source of palladium is usually used:

- palladium (II) acetate (trifluoroacetate);

- a complex of palladium (0) with dibenzylideneacetone;

- complexes of palladium (II) chloride with various alkenes (propene, 1,5-cyclooctadiene, etc.).

As the ligands that make up the palladium complexes are usually used:

- phosphines (less often phosphites);

- carbenes based on imidazole (and its reduced forms);

- dicarbonyl compounds (acetylacetone for example).

To obtain the target compounds, it is necessary to remove the “protective” groups (for example, Boc, Cbz) in the derivatives obtained previously (24).

In the case of Boc derivatives, the procedure reduces to processing (24) with a solution of hydrogen chloride in anhydrous 1,4-dioxane or with a mixture of trifluoroacetic acid - dichloromethane. The temperature can vary from room temperature to 100 ° C (in the case of 1,4-dioxane). The removal of the Cbz group is usually carried out by the action of a 30% solution of hydrogen bromide in glacial acetic acid, or by catalytic hydrogenolysis (in the presence of palladium metal on activated carbon). The yields in such reactions are usually high (more than 80%) or almost quantitative.

The secondary (or primary) amines thus obtained are then converted into amides (sulfamides), carbamates, tertiary amines, carbamates and other derivatives using well-developed methods of organic synthesis.

Amides are synthesized by the interaction between amines and acids (or their activated derivatives) in the presence of a condensing agent (the entire spectrum of agents known today in peptide chemistry, for example TBTU, CDI) and, as a rule, an organic base (for example, triethylamine) in an inert a solvent (inert under the conditions of an acylation reaction, for example, acetonitrile).

Obtaining tertiary amines is carried out by the reaction between the corresponding amines and carbonyl compounds (aldehydes and ketones) in the presence of a reducing agent (complex boron or metal hydrides, molecular hydrogen, organic reducing agents).

The N-arylation reaction is carried out by the interaction between amines and aromatic (heteroaromatic) halides (Buchwald-Hartwig reaction variant) or boronic acids in the presence of copper (II) salts (Chan reaction variant).

Purification and subsequent isolation of reaction products is usually carried out by column chromatography on silica gel using typical organic solvents (n-hexane, petroleum ether, ethyl acetate, dichloromethane, carbon tetrachloride, methanol) or by preparative HPLC on a reversed-phase column using as a mobile phase mixture of water with methanol (acetonitrile).

In a number of specific cases, as will be demonstrated in the Examples section, a part of the compounds was obtained using synthetic schemes that did not fall under the above formal description of the general synthesis methodology.

Examples

A selection of compounds within the scope of the present invention is presented in Table 1. The compounds of Table 1 were synthesized in accordance with examples 1-35 below, and the Haspin kinase inhibitory activity of these compounds in biochemical experiments is presented in Table 5. The selectivity profile of the selected compound on the serine panel -threonine and tyrosine kinases are presented in Table 6.

Materials and methods

All starting materials, reagents and solvents were chemically pure and were used without further purification. Chromatographic solvents were HPLC purity and used without further purification. The reactions were monitored by thin layer chromatography (TLC) using thin layer chromatography plates Merck Silica Gel 60 F-254. Flash column chromatography was performed on Merck silica gel 60 silica gel (0.015-0.040 mm).

LC / MS analysis of the compounds was performed on a Surveyor MSQ (Thermo Fisher Scientific) using atmospheric pressure chemical ionization.

1. Type of HPLC column: ZORBAX Eclipse XDB-C18 2.1 × 15 mm, 1.8 μm; Part No: 921700-902

2. Solvent: 50% DMSO, 50% acetonitrile

3. Flow rate: 750 μl / min; column temperature 25 ° C.

4. Mobile phase: A = 0.1% solution of formic acid in water, B = acetonitrile

5. Gradient:

Time min BUT, % AT, % 0.0 one hundred 0 0.2 one hundred 0 1.0 one 99 2.7 one 99 2.8 one hundred 0 3.0 one hundred 0

6. Detection: diode array (PDA), 200-800 nm; photodiode array detector. Detection was carried out over the entire range of ultraviolet and visible regions from 200 to 800 nm.

APCI (+ and / or - ions) - chemical ionization at atmospheric pressure ELSD (evaporative light scattering detector) (PL-ELS 2100)

7. Total travel time: 3 minutes

8. Injection volume: 2.5 μl.

1 H NMR spectra were recorded on a MERCURY plus 400 MHz spectrometer (Varian). The values of chemical shifts in ppm are given relative to tetramethylsilane (TMS) using the resonance of solvent residues as an internal standard.

Preparative HPLC purification was performed on an Agilent 1100 Series chromatograph using a Luna C18 (2) column (Phenomenex, USA), 250 × 21.2 mm, μm.

Reactions in the CEM Discovery Unit microwave reactor were carried out at a radiation power of 200 W with continuous mixing and temperature control.

The method for determining the inhibition of kinase activity of Haspin kinase

Recombinant human Haspin kinase has been obtained from commercial sources.

The interaction of the tested compounds with Haspin kinase was determined by sandwich immunoassay (ELISA - enzyme-linked immunosorbent assay).

A brief description of the experiment:

The reaction for the determination of kinase activity was carried out in polypropylene plates (Costar, 3363) in the reaction buffer (20 mm HEPES, pH 7.5, 15 mm MgCl ₂ , 2 mm DTT, 0.2 mm Na3VO4, 0.005% Triton X-100) for 60 minutes at 30 ° C and vigorous shaking on a horizontal shaker for tablets. The final concentrations of the reaction components were: 0.05 μg / ml Haspin kinase, 5 nM Histon H3 substrate (1-21) biotinylated (Anaspec, 61702), 150 μM ATP (Sigma, A6419), the studied compounds (from 10 μM with a hemogarithmic step) and 5% DMSO.

The enzymatic reaction was stopped with a buffer containing 20 mM HEPES (Sigma, H4034), pH 7.5, and 150 mM EDTA (Sigma, E5513).

To detect a phosphorylated substrate, the reaction mixture was transferred to pre-prepared plates (Nunc, 468667) coated with neutravidin (Pierce, 31000) 1 ng / well and treated with bovine serum albumin to block non-specific binding sites and incubated for one hour at room temperature. After washing the plates three times with Tween-20 phosphate-buffered saline, incubation with anti-phospho-Histon NZ antibodies (Millipore, 04-746) 0.3 ng / μl and incubation with specific antibodies conjugated with the anti-rabbit IgG enzyme label were performed sequentially. HRP-lmked Antibody (Cell Signaling, 7074) titer 1/5000. At the end of each incubation step (60 minutes at room temperature with constant stirring), the boards were washed three times from unbound antibody molecules.

Before measuring the optical density, the color reaction was stopped using 0.5 M sulfuric acid.

The optical density of the solution of the colored product was measured at λ = 450 nm using a tablet spectrophotometer (TECAN Safire).

Haspin kinase activity inhibition IC50 values were calculated using GraphPad Prism 5.0 software.

To calculate the IC50 values, data from at least two independent experiments were used, and the standard deviation did not exceed 20%.

Defining a selectivity profile for a selected compound

The selectivity profile for the selected compound was determined by radioligand analysis at ProQinase (Germany)

Table 1 EXAMPLE STRUCTURE 1. 3- (6- (Piperidin-4-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

2. 3- (6- (Azepan-4-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

3. 3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5] decane dihydrochloride

4.3 - ((6- (6- (Trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5] decane dihydrochloride

5.3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1,4-oxazepane dihydrochloride

6.4 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -N-methyl-cyclohexanamine dihydrochloride

7. 3- (6 - (((3aS, 6aR) octahydro-cyclopenta [c] pyrrol-4-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

8.3- (6 - (((5aS, 7aR) -Octahydro-1H-isoindol-4-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

9.3- (6 - ((1,4-diazepan-6-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrobromide

10. 3- (6- (Azepan-4-ylmethyl) -2-methylpyrimidin-4-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

11. 3- (6 - ((1R, 5S) -8-azabicyclo [3.2.1] octan-3-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

12. 3 - ((6- (Imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -8- (pyridin-3-ylmethyl) -1-oxa-8-azaspiro [ 4.5] Dean

13. 2-Methylamino-1- (3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5 ] decan-8-yl) ethanone dihydrochloride

14. 3- (6- (pyrrolidin-2-yl) pyrazin-2-yl) imidazo [1,2-a] pyrimidine dihydrochloride

15. 3- (6- (1-Isopropylpiperidin-3-yl) -2-methylpyrimidin-4-yl) imidazo [1,2-a] pyrimidine

16.1- (4 - ((6- (Imidazo [1,2-a] pyrimidin-3-yl) pyridin-2-yl) methyl) piperidin-1-yl) ethanone

17. 1- (2- (2- (6- (Imidazo [1,2-a] pyrimidin-3-yl) pyrimidin-4-yl) ethyl) pyrrolidin-1-yl) ethanone

18. 3- (6 - ((1- (Methylsulfonyl) pyrrolidin-3-yl) methyl) pyridin-2-yl) imidazo [1,2-a] pyrimidine

19. 3- (6- (Piperidin-3-yl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

20. 3- (6- (Piperidin-3-yl) pyrazin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

21.3- (6- (Piperidin-3-yl) pyridin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a] pyridine dihydrochloride

22. 2- (6- (6- (Trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) morpholine dihydrochloride

23. 1- (2- (6- (6- (Trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) morpholino) -2-phenyl ethanone

24. 3- (6- (Piperidin-3-yl) pyridin-2-yl) -6-chlorimidazo [1,2-6] pyridazine dihydrochloride

25. 3- (6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) piperidine-3-carboxylic acid dihydrochloride

26.3 - (6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) -N, N-dimethylpiperidin-3-carboxamide dihydrochloride

27. 3- (6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) methanol dihydrochloride

28. 3- (6- (Piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyridine dihydrochloride

29. 3- (6- (Piperidin-3-yl) pyridin-2-yl) -6- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] pyridine dihydrochloride

30. 3- (6- (Piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyrimidine dihydrochloride

31. 3- (6- (Piperidin-3-yl) pyridin-2-yl) ethynyl) -6-phenylpyrazolo [1,5-a] pyrimidine

32. 3- (6- (Piperidin-3-yl) pyridin-2-yl) -6-chloropyrazolo [1,5-a] pyridine dihydrochloride

33. 3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -2-oxa-8-azaspiro [4.5] decane dihydrochloride

34. 3 - ((6- (6-Chlorimidazo [1,2-d] pyridin-3-yl) pyridin-2-yl) methyl) -2-oxa-9-azaspiro [5.5] undecane dihydrochloride

35. 2 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) octahydrofuro [3,2-c] pyridine dihydrobromide

Synthesis of Key Intermediates

Intermediates 4a-k were prepared using commercially available dihalo-azines (3) and alkenes of the general formula (2) according to the following scheme in three steps (scheme 1):

Scheme 1

General procedure for the synthesis of substituted alkenes (2), stage (a), scheme 1:

Commercially available carbonyl compounds were used for alkenes syntheses. Some carbonyl compounds were synthesized according to the methods described in the literature.

To a suspension of methyltriphenylphosphonium iodide (50 mmol) in anhydrous THF (100 ml), sodium hydride (75 mmol) was gradually added under an inert atmosphere at 5 ° C. The reaction mixture was stirred for 1 h at 10 ° C. Thereafter, a solution of the corresponding carbonyl compound (1) (45 mmol) in anhydrous THF (20 ml) was added to the reaction mixture at 5 ° C. The resulting reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into water (150 ml) and extracted with dichloromethane (2 × 70 ml). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated in vacuo on a rotary evaporator. The residue was purified by silica gel column chromatography. The yields of the resulting substituted alkenes are shown in Table 2.

table 2 Synthesis of Alkenes 2a-i Carbonyl compounds (1) Alken (2) Exit, %

61

78

56

34

67

53

45

70

67

Synthesis of Intermediates (4a-k). Stage (b), scheme 1

Alkenes 2a-i were synthesized as described above. Alkenes (2j) and (2k) (Table 3) were synthesized according to the procedure described in the patent literature (WO 2004/74291 A1, pp. 67-68).

To a solution of the corresponding alkene (2) (0.1 mol) in 80 ml of anhydrous THF under an argon atmosphere, 9-borabicyclo [3.3.1] nonane (0.1 mol, 200 ml, 0.5 M solution in THF) was added. The resulting solution was stirred at room temperature for 24 hours. After this, the corresponding halide (3) (0.12 mol), potassium carbonate (110.4 g, 0.8 mol), water (80 ml) and Pd (PPh ₃ ) ₄ (5.5 g, 0.0067 mol) were added. ) The resulting reaction mixture was boiled for 3 hours, then cooled to room temperature and poured into ice water. The reaction mixture was extracted several times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate in vacuo. The residue was purified by silica gel column chromatography and the corresponding key intermediate was obtained (4). The outputs are shown in Table 3.

Table 3 Synthesis of Intermediates (4) Alken (2) Halide (3) Intermediate (4) Exit, %

57

57

56

87

71

34

47

35

52

45

40

45

Intermediates 8a-d were prepared using commercially available cyclic amino acid methyl esters (5) and dihalo azines (3) in Scheme 2 in three steps:

Scheme 2

Stage (a), synthesis of intermediates (6)

To a solution of ester (5) (1.5 mol) in anhydrous THF (800 ml), a solution of sodium bis (trimethylsilyl) amide (1 M in THF, 1950 ml) was added dropwise and with vigorous stirring at 0 ° C. The mixture was stirred for 1.5 hours at 0 ° C, and then a solution of the corresponding halide (3) (1.6 mol) in anhydrous THF (700 ml) was added dropwise. After that, the reaction mixture was stirred for 3 hours at 0 ° C. Then a solution of ammonium chloride (67 g, 1.1 mol) in water was carefully added. The organic layer was separated and concentrated in vacuo. Product (6) was used in the next step without further purification.

Stage (b), synthesis of intermediates (7)

To a solution of ester (6) in ethanol (300 ml) was added a 10% solution of sodium hydroxide in water (2000 ml). The mixture was boiled for 5 h (TLC control). The reaction mixture was cooled, concentrated in vacuo to half the original volume, and extracted with MTBE (methyl tert-butyl ether) (2 × 150 ml). The aqueous layer was acidified with 3M hydrochloric acid to pH = 4 and extracted with dichloromethane (3 × 150 ml). The combined organic fractions were dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give product (7). Acids (7) were used in the next step without further purification.

Intermediates 8a-d, Stage C

A solution of acid (7) in DMSO (400 ml) was stirred at 120 ° C for 5 h (TLC control). The reaction mixture was cooled to room temperature, diluted with water (700 ml) and extracted with ethyl acetate (3 × 400 ml). The combined organic extracts were dried over sodium sulfate. The solvent was evaporated in vacuo to give the crude product (8), which was purified by silica gel column chromatography. Table 4 shows the outputs of intermediates 6, 7 and 8

Table 4 Ester (5) Halide (3) Intermediate (6) Exit Intermediate (7) Exit Intermediate (8) Exit

45

81

56

71

89

69

49

92

83

34

68

87

The intermediate (11) was obtained according to Scheme 3

Scheme 3

3-Carbamimidoyl-piperidine-1-carboxylic acid tert-butyl ether (9)

To a solution of 3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (296 g, 1.3 mol) in dichloromethane, triethyloxonium tetrafluoroborate (270 g, 1.365 mol) was added with constant stirring; the resulting reaction mixture was stirred for 4 hours at room temperature. After this, the reaction mixture was concentrated at ~ 45 ° C. The residue was treated with a solution of NH3 / CH3OH (pH = 10) and left overnight. The reaction mixture was concentrated in vacuo. The residue was used in the next step without further purification.

3- (4-Hydroxy-6-methyl-pyrimidin-2-yl) -piperidin-1-carboxylic acid tert-butyl ether (10)

Compound (9) (94 g, 0.3 mol) was added to a solution of sodium ethylate (0.3 mol) in anhydrous ethanol (200 ml). The mixture was stirred at room temperature for 10 minutes, and then methyl 3-oxobutyrate (23.2 g, 0.2 mol) was added in small portions. The resulting mixture was boiled for 2 hours (TLC control). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, acidified with 1N HCl to pH 5.0 and the product was extracted with ethyl acetate (2 × 200 ml). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: n-hexane / ethyl acetate 1: 1) to give compound (10) (39 g, 74%).

3- (6-Methyl-4-chloro-pyrimidin-2-yl) piperidin-1-carboxylic acid tert-butyl ether (11)

Intermediate (10) (50 g, 0.170 mol) and N, N-dimethylaniline (166 g, 1.365 mol) were dissolved in anhydrous toluene (1000 ml) and POCl3 (52 g, 0.34 mol) was added dropwise. The reaction mixture was boiled for 3 hours; then cooled to room temperature and left overnight. After this, the mixture was poured into water, the organic layer was separated and washed sequentially with 1N HCl and water. The crude product was concentrated in vacuo and purified by flash chromatography on silica gel (eluent: n-hexane / ethyl acetate 4: 1) to give the product (11) (34.3 g, 65%).

SYNTHESIS OF FINITE COMPOUNDS

Example 1

3- (6- (piperidin-4-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

6-chlorimidazo [1,2a] pyridine (12)

A suspension of 5-chloro-2-aminopyridine (0.195 mol), chloroacetaldehyde (50% aqueous solution) (0.234 mol) and sodium hydrogen carbonate (0.195 mol) in 150 ml of water was stirred for 8 hours at room temperature. Then the reaction mixture was acidified with concentrated hydrochloric acid to pH = 1, the reaction mixture was stirred at room temperature for one hour, and then it was made alkaline with an aqueous NaOH solution to pH = 9 and extracted with dichloromethane (2 times 50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, then evaporated in vacuo on a rotary evaporator. The crude product was purified by flash chromatography on silica gel. A solvent gradient of n-hexane / ethyl acetate from 100% n-hexane to 20% ethyl acetate was used as an eluent. Yield: 85%.

3-Bromo-6-chlorimidazo [1,2-a] pyridine (13)

To a solution of compound (12) (45 mmol) in 120 ml of anhydrous dichloromethane with vigorous stirring and room temperature was added N-bromosuccinimide (50 mmol) in small portions. The reaction mixture was stirred for four hours at room temperature. Then about a third of the volume of solvent was evaporated on a rotary evaporator. The precipitate was filtered off, washed with a small amount of methyl tert-butyl ether. The combined filtrates were washed with water (twice 50 ml each), dried over anhydrous sodium sulfate and evaporated in vacuo on a rotary evaporator. The target product was isolated by flash chromatography on silica gel. A solvent gradient of ethyl n-hexane / ethyl acetate from 100% n-hexane to 10% ethyl acetate was used as an eluent. Yield: 70%.

4- [6 - ((6-chlorimidazo11,2-a] pyridin-3-yl) pyridin-2yl) methyl] piperidin-1-carboxylic acid tert-butyl ether (14)

To a solution of compound (13) (20 mmol) in anhydrous THF (100 ml) in an inert atmosphere at -78 ° C was added via a dropping funnel 13 ml (25 mmol) of a 2M solution of isopropyl magnesium chloride in THF. The reaction mixture was stirred an hour and a half at -78 °, then a solution of three (n-butyl) tin chloride (25 mmol) in 30 ml of THF was added through a dropping funnel. After which the reaction mixture was allowed to warm to room temperature for one hour. With vigorous stirring, a solution of compound 4b (Table 3) (20 mmol) in 30 ml of THF and 1.5 mmol of Pd (PPh ₃ ) _{4 was} added. The reaction mixture was boiled with stirring for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into a 5% aqueous potassium fluoride solution (500 ml), after which it was stirred for 12 hours and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The target product was isolated by flash chromatography on silica gel. A mixture of n-hexane / ethyl acetate 3: 2 was used as an eluent. Yield: 66%

3 - ((6-piperidin-4-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

To a solution of compound (14) (1 mmol) in methanol (5 ml) was added a solution of 16% hydrogen chloride in anhydrous 1,4-dioxane (1 ml), stirred for 24 hours at room temperature. Then the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate / methanol. Yield: 95%.

Mass spectrum (APCI), m / z (Irel,%): 327.18 [M + H] ⁺ (100), 329.20 [M + H] ⁺ (35).

EXAMPLE 2

3- (6- (Azepan-4-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compounds (13) and a key intermediate (4 s) (Table 3). The output in stage c) 51%, in stage d) 90%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.32-1.48 (m, 1H), 1.61-1.97 (m, 5H), 2.16-2.27 (m, 1H), 2.81-3.27 (m, 6H), 7.29-7.38 (m, 1H), 7.82-8.04 (m, 4H), 8.85 (s, 1H), 8.98-9.22 (m, 2H), 10.25 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 341.28 [M + H] ⁺ (100), 343.45 [M + H] ⁺ (35).

EXAMPLE 3

3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5] decane dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from the compounds (13) and the key intermediate (4i) (Table 3). The output in stage a) 45%, in stage b) 88%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.48-1.62 (m, 1H), 1.65-1.96 (m, 4H), 1.97-2.09 (m, 1H), 2.76-3.10 (m, 7H), 3.50-3.62 (m, 1H), 3.91-4.05 (m, 1H), 7.35-7.39 (m, 1H), 7.90-8.12 (m, 4n0, 8.91-9.25 (m, 3H), 10.29 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 383.25 [M + H] ⁺ (100), 385.22 [M + H] ⁺ (35).

EXAMPLE 4

3 - ((6- (6- (Trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5] decane dihydrochloride

The above compound was obtained in four stages by a method similar to that described previously in Example 1, starting from commercially available 5-trifluoromethyl-2-aminopyridine. The output in stage a) 71%, in stage b) 88%, in stage c) 61%, in stage d) 90%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.51-1.56 (m, 1H), 1.71-1.89 (m, 4H), 1.98-2.03 (m, 1H), 2.80-2.88 (m, 1H), 2.95-2.03 (m, 6H), 3.54 (t, 1H), 3.94 (t, 1H), 7.31 (d, 1H), 7.85-7.96 (m, 3H), 8.07 (d, 1H) ), 8.78 (s, 1H), 8.93 (br.s, 2H), 10.61 (s, 1H)

Mass spectrum (APCI), m / z (Irel,%): 417.19 [M + H] ⁺ (100).

EXAMPLE 5

3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1,4-oxazepane dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compound (13) and key intermediate (4j) (Table 3). The output in stage a) 65%, in stage b) 98%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 2.68-2.71 (m, 1H), 2.87-2.97 (m, 2H), 3.09-3.33 (m, 4H), 3.51-3.62 (m, 1H), 3.78-3.92 (m, 3H), 7.43 (m, 1H), 7.97-8.10 (m, 2H), 8.08 (q, 2H), 8.82-9.09 (m, 3H), 10.22 (s , 1H).

Mass spectrum (APCI), m / z (Irel,%): 343.11 [M + H] ⁺ (100), 345.14 [M + H] ⁺ (35).

EXAMPLE 6

{4- [6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -pyridin-2-ylmethyl] cyclohexyl} methylamine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compound (13) and key intermediate (4k) (Table 3). The output in stage a) 70%, in stage b) 78%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.11 (q, 2H), 1.39 (q, 2H), 1.48-1.68 (m, 2H), 1.72-1.93 (m, 3H ), 2.02-2.13 (m, 2H), 2.72-2.91 (m, 3H), 3.01-3.12 (m, 1H), 7.34 (d, 1H), 7.91-7.98 (m, 2H), 8.01-8.06 (m , 1H), 8.08-8.12 (m, 1H), 9.00 (s, 1H), 9.12-9.20 (m, 2H), 10.27-10.33 (m, 1H).

Mass spectrum (APCI), m / z (Irel,%): 355.28 [M + H] ⁺ (100), 357.25 [M + H] ⁺ (35).

EXAMPLE 7

3- (6 - (((3aS, 6aR) -Octahydro-cyclopenta [c] pyrrol-4-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride (mixture of diastereomers)

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compound (13) and key intermediate (4g) (Table 3). The output in stage a) 46%, in stage b) 97%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.48-1.79 (m, 4H), 2.66-2.82 (m, 3H), 2.90-3.08 (m, 3H), 3.12 -3.22 (m, 2H), 3.32-3.46 (m, 1H), 7.38-7.41 (m, 1H), 7.92-8.11 (m, 4H), 8.98-9.51 (m, 2H), 10.29 (s, 1H) .

Mass spectrum (APCI), m / z (Irel,%): 353.22 [M + H] ⁺ (100), 355.23 [M + H] ⁺ (35).

EXAMPLE 8

3- (6 - (((3aS, 7aR) -Octahydro-1H-isoindol-4-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride (mixture of diastereomers)

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compound (13) and key intermediate (4h) (Table 3). The output in stage a) 69%, in stage b) 93%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.17-1.29 (m, 2H), 1.42-1.72 (m, 3H), 1.99-2.43 (m, 3H), 2.74-2.92 (m, 2H), 2.94-3.25 (m, 5H), 7.32-7.51 (m, 1H), 7.94-8.12 (m, 4H), 8.99 (s, 1H), 9.41-9.78 (m, 2H), 10.29 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 367.24 [M + H] ⁺ (100), 369.24 [M + H] ⁺ (35).

EXAMPLE 9

3- (6 - ((1,4-diazepan-6-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrobromide

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compound (13) and key intermediate (4l) (Table 3). The output in stage a) is 29%. Stage b) was carried out as follows: compound (24) (1 mmol) was heated at 60 ° C in a 30% solution of HBr in acetic acid for 30 minutes. After that, the reaction mixture was evaporated in a vacuum of a rotary evaporator. The residue was treated with diethyl ether, filtered off, washed on the filter several times with ether and dried in air. Yield: 83%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 2.86-3.03 (m, 3H), 3.18-3.57 (m, 8H), 7.42-7.51 (m, 1n), 7.92-8.11 (m, 3H), 8.92 (s, 1H), 9.02-9.30 (m, 3H), 10.12 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 342.25 [M + H] ⁺ (100), 344.16 [M + H] ⁺ (35).

EXAMPLE 10

3- (6- (Azepan-4-ylmethyl) -2-methylpyrimidin-4-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compound (13) and key intermediate (4d) (Table 3). The output in stage a) 90%, in stage b) 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.32-1.43 (m, 1H), 1.58-1.92 (m, 5H), 2.22-2.33 (m, 1H) , 2.71-2.86 (m, 5H), 2.92-3.22 (m, 4H), 7.81-7.86 (m, 1H), 7.96-8.01 (m, 1H), 8.07 (s, 1H), 9.04 (s, 1H) 9.11-9.13 (m, 2H); 10.12 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 356.25 [M + H] ⁺ (100), 358.25 [M + H] ⁺ (35).

EXAMPLE 11

3- (6 - ((1R, 5S) -8-Azabicyclo [3.2.1] oct-3-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compound (13) and key intermediate (4e) (Table 3). The output in stage a) 79%, in stage b) 87%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.60-1.78 (m, 3Н), 1.91-2.01 (m, 1Н), 2.21-2.43 (m, 3Н), 2.76-2.84 (m, 1H), 3.06-3.19 (m, 3H), 4.85-4.96 (m, 2H), 7.35-7.45 (m, 1H), 7.93-8.03 (m, 3H), 8.07-8.12 (m, 1H) 8.93-9.11 (m, 2H), 9.28-9.43 (m, 1H), 10.29 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 353.23 [M + H] ⁺ (100), 355.21 [M + H] ⁺ (35).

EXAMPLE 12

3 - ((6- (Imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -8- (pyridin-3-ylmethyl) -1-oxa-8-azaspiro [4.5] dean

The above compound was obtained in four stages by a method similar to that described previously in Example 1, based on commercially available 2-aminopyridine. The yield in step a) is 90%, in step b) 89%, in step c) 51%. Stage d) was carried out as follows: a mixture of compound (29) (0.5 mmol), 3-pyridinecarbaldehyde (0.55 mmol), sodium triacetoxyborohydride (1 mmol) in acetonitrile (5 ml) was stirred for 24 hours at room temperature. After the reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The target product was isolated by flash chromatography on silica gel. Yield: 79%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.20-1.31 (m, 1H), 1.32-1.66 (m, 5H), 1.85-1.98 (m, 1H), 2.21-2.40 (m, 3H), 2.72-2.98 (m, 3H), 3.35-3.52 (m, 3H), 3.86-3.92 (m, 1H), 7.07 (t, 1H), 7.14 (d, 1H), 7.31 (m , 1H), 7.38 (t, 1H), 7.63-7.72 (m, 1H), 7.74-7.83 (m, 1H), 8.34 (s, 1H), 8.40-8.46 (m, 2H), 9.95 (d, 1H )

Mass spectrum (APCI), m / z (Irel,%): 440.27 [M + H] ⁺ (100).

EXAMPLE 13

2-Methylamino-1- {3- [6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-ylmethyl] -1-oxa-8-azaspiro [4.5] decan-8- silt} -ethanone dihydrochloride

(2- {3- [6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -pyrvdin-2-ylmethyl] -1-oxa-8-azaspiro [4.5] decan-8-yl} -2-oxoethyl) methylcarbamic acid tert-butyl ether (30)

A mixture of 3 - ((6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5] decane (EXAMPLE 3) (0 5 mmol), N-Boc-sarcosine (0.55 mmol), TBTU and triethylamine (2 mmol) in acetonitrile (4 ml) was stirred for 24 hours at room temperature. After completion of the reaction, the reaction mixture was poured into water and extracted with DCM. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The target product was isolated by flash chromatography on silica gel. Yield: 90%

2-Methylamino-1- {3- [6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-ylmethyl] -1-oxa-8-azaspiro [4.5] decan-8- silt} -ethanone dihydrochloride (EXAMPLE 13)

The above compound was obtained in two stages by a method similar to that described previously in Example 1 (step d) starting from compound (30). Yield: 98%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.51-1.72 (m, 4H), 1.97-2.05 (m, 1H), 2.82-2.87 (m, 1H), 2.97-3.02 (m, 2H), 3.23-3.37 (m, 3H), 3.55-3.58 (m, 2H), 3.73-3.78 (m, 1H), 3.97-3.98 (m, 3H), 7.34 (d, 1H), 7.90 -7.96 (m, 3H), 8.01-8.05 (m, 1H), 8.9 (m, 3H), 10.28 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 454.21 [M + H] ⁺ (100), 456.20 [M + H] ⁺ (35)

EXAMPLE 14

3- (6- (pyrrolidin-2-yl) pyrazin-2-yl) imidazo [1,2-a] pyrimidine dihydrochloride

Imidazo [1,2-a] pyrimidine (31) was synthesized according to the literature method [Loeber, Stefan; Huebner, Harald; Gmeiner, Peter Bioorganic & Medicinal Chemistry Letters, 1999, vol.9, # 1 p.97-102]

2- (6-Imidazo [1,2-a] pyrimidin-3-ylpyrazin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ether (32)

Imidazo [1,2-a] pyrimidine (1 mmol), compound (8a) (Table 4) (1 mmol), potassium carbonate (3 mmol), palladium (II) acetate, (5% molar), tris- (cyclohexyl ) phosphine (10% molar) was dissolved in anhydrous DMF (4 ml). The reaction mixture was purged with argon and heated in a microwave at 150 ° C for 30 minutes (radiation power 150 W). The reaction mixture was cooled, poured into water, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The target product was isolated by flash chromatography on silica gel. A chloroform / methanol 20: 1 mixture was used as an eluent. Yield: 34%

3- (6- (Pyrrolidin-2-yl) pyrazin-2-yl) imidazo [1,2-a] pyrimidine dihydrochloride (EXAMPLE 14)

To a solution of compound (32) (0.34 mmol) in methanol (1 ml) was added 16% HCl in dioxane (1 ml), stirred for 24 hours at room temperature, then the solvent was removed in vacuo. Yield 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 2.07-2.24 (m, 4H), 2.57-2.59 (m, 1H), 3.41-3.44 (m, 2H), 4.92 (m , 1H), 7.38 (s, 1H), 8.71 (s, 1H), 8.81 (s, 1H), 8.87 (s, 1H), 9.34 (s, 1H), 9.40-9.52 (m, 1H), 9.23- 9.25 (m, 1H), 10.66-10.77 (m, 1H)

Mass spectrum (APCI), m / z (Irel,%): 267.30 [M + H] ⁺ (100).

EXAMPLE 15

3- (6- (1-Isopropylpiperidin-3-yl) -2-methylpyrimidin-4-yl) imidazo [1,2-a] pyrimidine

3- (2-Methyl-6-piperidin-3-yl-pyrimidin-4-yl) -imidazo [1,2-a] pyrimidine dihydrochloride (34)

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 14, starting from compounds (31) (4 mmol) and (11) Yield: stage a) 25%, stage b) 99%

3- (6- (1-Isopropylpiperidin-3-yl) -2-methylpyrimidin-4-yl) imidazo [1,2-a] pyrimidine (EXAMPLE 15)

The above compound was obtained in one step by a method similar to that described previously in EXAMPLE 13 (step d), starting from compound (34) (1 mmol) and acetone. Yield: 51%

Mass spectrum (APCI), m / z (Irel,%): 337.40 [M + H] ⁺ (100).

EXAMPLE 16

1- (4 - ((6- (Imidazo [1,2-a] pyrimidin-3-yl) pyridin-2-yl) methyl) piperidin-1-yl) ethanone

3- (6-Piperidin-4-ylmethylpyridin-2-yl) -imidazo [1,2-a] pyrimidine dihydrochloride (36)

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 14, starting from compounds (31) (2 mmol) and (4b) (Table 3). Yield: stage a) 49%, stage b) 99%

1- (4 - ((6- (Imidazo [1,2-a] pyrimidin-3-yl) pyridin-2-yl) methyl) piperidin-1-yl) ethanone (EXAMPLE 16)

The above compound was obtained in one step by a method similar to that described previously in EXAMPLE 13 (step a), starting from compound (36) (1 mmol) and acetic acid. Yield: 93%

Mass spectrum (APCI), m / z (Irel,%): 336.40 [M + H] ⁺ (100).

EXAMPLE 17

1- (2- (2- (6- (Imidazo [1,2-a] pyrimidin-3-yl) pyrimidin-4-yl) ethyl) pyrrolidin-1-yl) ethanone

3- [6- (2-Pyrrolidin-2-yl-ethyl) -pyrimidin-4-yl] -imidazo [1,2-a] pyrimidine dihydrochloride (38)

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 14, starting from compounds (31) (4 mmol) and (4f) (Table 3). Yield: stage a) 23%, stage b) 99%, stage c) 88%

1- (2- (2- (6- (Imidazo [1,2-a] pyrimidin-3-yl) pyrimidin-4-yl) ethyl) pyrrolidin-1-aftanone (EXAMPLE 17)

The above compound was obtained in one step by a method similar to that described previously in EXAMPLE 13 (step a), starting from compound (36) (1 mmol) and acetic acid. Yield: 93%

Mass spectrum (APCI), m / z (Irel,%): 337.39 [M + H] ⁺ (100).

EXAMPLE 18

3- (6-Pyrrolidin-3-ylmethylpyridin-2-yl) -imidazo [1,2-a] pyrimidine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 14, starting from compounds (31) (4 mmol) and (4a) (Table 3). Yield: step a) 39%, step b) 99%

3- (6 - ((1- (Methylsulfonyl) pyrrolidin-3-yl) methyl) pyridin-2-yl) imidazo [1,2-a] pyrimidine (EXAMPLE 18)

A mixture of compound (40) (0. 5 mmol), methanesulfonyl chloride (0.52 mmol), and triethylamine (2 mmol) in acetonitrile (4 ml) was stirred for 24 hours at room temperature. After completion of the reaction, the reaction mixture was poured into water and extracted with DCM. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The target product was isolated by flash chromatography on silica gel. Yield: 76%

Mass spectrum (APCI), m / z (Irel,%): 358.40 [M + H] ⁺ (100).

EXAMPLE 19

3- (6- (piperidin-3-yl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 2, starting from compounds (13) (2 mmol) and (8b) (Table 4). Yield: stage a) 59%, stage b) 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.72-1.98 (m, 1Н), 2.12-2.30 (m, 1Н), 2.80-2.92 (m, 1Н), 3.09-3.21 (m, 1H), 3.30-3.43 (m, 2H), 3.55-3.63 (m, 1H), 7.35-7.42 (m, 1H), 7.70-7.81 (m, 1H), 7.86-8.00 (m, 3H) 8.71 (s, 1H), 9.26-9.51 (m, 2H), 10.09 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 313.19 [M + H] ⁺ (100), 315.18 [M + H] ⁺ (35)

EXAMPLE 20

3- (6- (piperidin-3-yl) pyrazin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 2, starting from compounds (13) (2 mmol) and (8d) (Table 4). Yield: step a) 69%, step b) 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.71-1.98 (m, 3Н), 2.10-2.18 (m, 1Н), 2.80-2.98 (m, 1Н), 3.12-3.22 (m, 2H), 3.28-3.40 (m, 2H), 7.65-7.72 (m, 1H), 7.88-7.95 (m, 1H), 8.60 (m, 1H), 8.75 (m, 1H), 9.12-9.41 (m, 3H), 9.72 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 314.20 [M + H] ⁺ (100), 316.22 [M + H] ⁺ (35)

EXAMPLE 21

3- (6- (piperidin-3-yl) pyridin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a] pyridine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 2, starting from compounds (18) (1 mmol) and (8b) (Table 4). Yield: step a) 70%, step b) 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.75-1.96 (m, 3Н), 2.10-2.21 (m, 1Н), 2.71-2.87 (m, 1Н), 3.03-3.12 (m, 1H), 3.30-3.50 (m), 7.38-7.42 (m, 1H), 7.88-8.10 (m, 4H), 8.75 (s, 1H), 9.11-9.32 (m, 1H), 10.52 (s , 1H).

Mass spectrum (APCI), m / z (Irel,%): 347.20 [M + H] ⁺ (100).

EXAMPLE 22

2- (6- (6- (Trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) morpholine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in EXAMPLE 2, starting from compounds (18) (4 mmol) and (8 s) (Table 4). Yield: stage a) 45%, stage b) 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 3.05-3.28 (m, 2H), 3.54-3.68 (m, 2H), 4.01-4.22 (m, 2H), 5.07 (d , 1H), 7.52 (d, 1H), 7.88 (d, 1H), 8.01-8.15 (m, 3H), 8.78 (s, 1H), 9.66 (br.s, 1H), 9.82 (br.s, 1H ), 10.49 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 349.33 [M + H] ⁺ (100).

EXAMPLE 23

1- (2- (6- (6- (Trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) morpholino) -2-phenyl ethanone

The above compound was obtained in one step by a method similar to that described previously in EXAMPLE 13 (step a), starting from the compound (EXAMPLE 22) (0.5 mmol) and phenylacetic acid. Yield: 67%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 2.28-3.00 (m, 1H), 3.52-3.68 (m, 1H), 3.78 (s, 2H), 3.95-4.04 (m , 2H), 4.25-4.41 (m, 1H), 4.54-4.58 (m, 1H), 4.61-4.77 (m, 1H), 7.12-7.45 (m, 6H), 7.58-7.66 (m, 1H), 7.89 -8.06 (m, 3H), 8.57 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 467.19 [M + H] ⁺ (100).

EXAMPLE 24

3- (6- (piperidin-3-yl) pyridin-2-yl) -6-chlorimidazo [1,2-b] pyridazine dihydrochloride

The above compound was obtained in four stages by a method similar to that described previously in Example 1, based on commercially available 3-amino-6-chloropyridazine. The output in stage a) 41%, in stage b) 48%, in stage c) 29%, in stage d) 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.72-1.82 (m, 1H), 1.84-1.89 (m, 2H), 2.06-2.12 (m, 1H), 2.94-2.96 (m, 1H), 3.26-3.34 (m, 3H), 3.48-3.51 (m, 1H). 7.40 (d, 1H), 7.55 (d. 1H), 7.99 (t, 1H), 8.29 (d, 1H), 8.38 (d, 1H), 8.57 (s, 1H), 9.30-9.33 (m, 2H) .

Mass spectrum (APCI), m / z (Irel,%): 314.18 [M + H] ⁺ (100), 316.16 [M + H] ⁺ (100).

EXAMPLE 25

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -1 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl-3'-carbon acid dihydrochloride

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -5 ', 6'-dihydro-4'H- [2,3'] bipyridinyl-1 ', 3'-dicarboxylic acid 1' tert-butyl ether 3'-methyl ether (49)

The above compound was obtained in one step by a method similar to that described previously in EXAMPLE 2, starting from compounds (13) (15 mmol) and (6b) (Table 4). Yield: 65%

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -5 ', 6'-dihydro-4'H- [2,3'] bipyridinyl-1 ', 3'-dicarboxylic acid 1' tert-butyl ether (50)

Compound (49) (5 mmol) was heated at 50 ° C with potassium hydroxide (10 mmol) in a water-methanol mixture (4: 1) with stirring for 8 hours. After the reaction, half the volume of the solution was evaporated on a rotary evaporator. The remaining reaction mixture was filtered through a glass filter and acidified to pH = 4 with dilute hydrochloric acid. The precipitate was filtered off, washed on the filter with a small amount of ice water and dried in vacuum for 48 hours. Yield: 87%

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -1 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl-3'-carbon acid dihydrochloride (EXAMPLE 25)

The above compound was obtained in one step by a method similar to that described previously in Example 1, (step d). Yield: 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.65-1.79 (m, 1H), 1.89-1.97 (m, 1H), 2.34 (t, 1H), 2.88-3.011 (m , 1H), 3.12-3.19 (m, 1H), 3.35-3.46 (m, 1H), 3.78-4.12 (m), 7.53-7.56 (m, 1H), 7.71 (d, 1H), 7.91 (d, 1H ), 8.03-8.04 (m, 2H), 8.39-8.52 (m, 1H), 8.72 (s, 1H), 9.41-9.52 (m, 1H), 10.04 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 313.11 [M + H-CO2] ⁺ (100), 315.12 [M + H-CO2] ⁺ (35).

EXAMPLE 26

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -1 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl-3'-carbon dimethylamine acid dihydrochloride

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -3'-dimethylcarbamoyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl -1'-carboxylic acid tert-butyl ether (51)

The above compound was obtained in one step by a method similar to that described previously in EXAMPLE 13 (step a), starting from compound (50) (1 mmol) and dimethylamine hydrochloride (2 mmol). Yield: 43%

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -1 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl-3'-carbon dimethylamine acid dihydrochloride (EXAMPLE 26)

The above compound was obtained in one step by a method similar to that described previously in Example 1, (step d). Yield: 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.57 (q, 1H), 2.00 (d, 1H), 2.81 (t, 2H), 2.95 (q, 2H), 3.22 ( d, 1H), 3.65 (d, 1H), 7.50 (d, 1H), 7.76 (d, 1H), 7.95 (d, 2H), 8.05-8.11 (m, 2H), 8.83 (s, 1H), 9.83 -9.85 (m, 1H), 9.99 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 384.10 [M + H] ⁺ (100), 386.12 [M + H] ⁺ (35).

EXAMPLE 27

3- (6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) methanol dihydrochloride

6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) -3'-hydroxymethyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl -1'-carboxylic acid tert-butyl ether (52)

To a solution of compound (49) (3 mmol) in anhydrous THF (30 ml) at 0 ° С with vigorous stirring, lithium aluminum hydride (3 mmol) was added in several portions. The reaction mixture was stirred at 10 ° C for 10 hours. After this, the mixture was cooled to 0 ° C and 20% KOH solution (1 ml) was added. Carefully decanted the clear solution from the solid precipitate that had formed and evaporated in a vacuum of a rotary evaporator. The target product was isolated by flash chromatography on silica gel. Yield: 66%

3- (6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) methanol dihydrochloride (EXAMPLE 27)

The above compound was obtained in one step by a method similar to that described previously in Example 1, (step d). Yield: 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.48-1.62 (m, 1H), 1.80-1.83 (m, 1H), 1.94-2.03 (m, 1H), 2.22-2.25 (m, 1H), 2.98 (br.s, 2H), 3.32 (t, 1H), 3.64-3.71 (m, 2H), 3.76-3.82 (m, 1H), 6.78 (br.s), 7.63 (d , 1H), 7.92-7.97 (m, 2H), 8.00-8.06 (m, 2H), 8.43 (br.s, 1H), 8.85 (s, 1H), 9.49-9.52 (m, 1H), 10.02 (s , 1H).

Mass spectrum (APCI), m / z (Irel,%): 343.11 [M + H] ⁺ (100), 345.10 [M + H] ⁺ (35).

EXAMPLE 28

3- (6- (piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyridine dihydrochloride

6-Ethinyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl-1'-carboxylic acid tert-butyl ether (53)

Copper (I) iodide (0.19 g, 1 mmol), PdCl2 (PPh3) 2 (0.35 g, 0.5 mmol), triethylamine (4 ml) were added to a solution of compound (8b) (3.5 g, 10 mol) in anhydrous THF (20 ml) in an argon atmosphere at room temperature and was stirred for 5 minutes. Then trimethylsilylacetylene (1.5 g, 15 mmol) was added dropwise to the solution. The reaction mass was stirred for 2 hours at room temperature (monitoring the reaction by TLC and LCMS), diluted with water (50 ml) and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel and evaporated on a rotary evaporator. The resulting brown residue was dissolved in THF (20 ml), cooled to 5 ° C, and a 1 M solution of tetrabutylammonium fluoride in THF (0.5 ml) was added. The reaction mass was stirred for 1 hour at 5 ° C (TLC control), diluted with water (50 ml) and extracted with dichloromethane. The extract was dried over sodium sulfate, the solvent was removed in vacuo. The target compound was isolated by silica gel column chromatography. Yield: 59%

6-Pyrazolo [1,5-a] pyridin-3-yl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl-1'-carboxylic acid tert-butyl ether (55)

Potassium carbonate (2.8 mmol) was added to a solution of commercially available compound (54) (2 mmol) in anhydrous DMF (5 ml), the reaction mixture was stirred for 30 minutes at room temperature, and the solution changed color from colorless to dark blue.

Then acetylene (53) (1.5 mmol) was added and stirring was continued at 90 ° C for 2 hours (TLC control). The reaction mass was diluted with water (50 ml), extracted with dichloromethane. The extract was dried over sodium sulfate, the solvent was removed in vacuo. The target compound was isolated by silica gel column chromatography. Yield: 39%

3- (6- (piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyridine dihydrochloride (EXAMPLE 28)

To a solution of compound (55) (0.6 mmol) in methanol (5 ml) was added a 16% solution of HCl in 1,4-dioxane (1 ml), stirred for 3 hours at room temperature, then the solvent was removed in vacuo. The target material was crystallized from ethyl acetate. Yield: 97%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.76-1.86 (m, 1H), 1.88-1.93 (m, 2H), 2.11-2.14 (m, 1H), 2.93-3.03 (m, 1H), 3.19-3.41 (m, 3H), 3.54-3.61 (m, 1H), 7.04 (t, 1H), 7.17 (d, 1H), 7.45 (t, 1H), 7.77-7.74 (m , 2H). 8.52 (d, 1H), 8.69 (s, 1H), 8.77 (d, 1H), 9.37 (br s, 2H).

Mass spectrum (APCI), m / z (Irel,%): 279.17 [M + H] ⁺ (100).

EXAMPLE 29

3- (6- (piperidin-3-yl) pyridin-2-yl) -6- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] pyridine dihydrochloride (5).

1'-tert-butyloxycarbonyl-6-cyano-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] - bipyridinyl (56)

Zinc (II) cyanide (7.5 mmol), zinc dust (1.9 mmol), Pd2dba3 (0.26 mmol) and DPPF (0.37 mmol) were added to a solution of compound (8b) (12 mmol) in dimethylacetamide (18 ml) at room temperature. The reaction mixture was heated at 130-140 ° C under argon for 3 hours, then cooled to room temperature, poured into 100 ml of water and extracted with ethyl acetate. The extract was dried over sodium sulfate, the solvent was removed in vacuo. The target compound was isolated by silica gel column chromatography. Yield: 70%

1'-tert-butyloxycarbonyl-6-formyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] - bipyridinyl (57)

To a solution of compound (56) (8.2 mmol) in dry dichloromethane (100 ml) at -78 ° С in an argon atmosphere (14 mmol) of a 1M DIBAL-H solution was added through a dropping funnel at a temperature not higher than -78 ° С. After completion of the addition, the resulting reaction mass was stirred at -78 ° C for 3-4 hours. Then the reaction mass was heated to -40 ° C, a 1M hydrochloric acid solution was added to it and left to mix until it reached room temperature. After that, the organic layer was separated, dried over sodium sulfate. The solvent was evaporated under reduced pressure. From the obtained residue, the target product is isolated by chromatography on silica gel (eluent hexane-ethyl acetate). Yield: 60%

1'-tert-Butyloxycarbonyl-6- (6-trifluoromethyl- [1,2,4] triazolo [4,3a] pyridin-3-yl) -3 ', 4', 5 ', 6'-tetrahydro-2' H- [2,3 '] bipyridinyl (58)

(5-Trifluoromethyl-pyridin-2-yl) -hydrazine (2 mmol) was added to a solution of compound (57) (2 mmol) in THF (5 ml) at room temperature. The resulting solution was heated at 60-70 ° C for 2 hours. The presence of an intermediate hydrazone in the reaction mixture was monitored by TLC. After completion of the hydrazone formation process, the reaction mixture was cooled in a water bath to room temperature and 0.55 g (2.4 mmol) of chloramine-T was added. The resulting suspension was heated at 80 ° C for about 1 hour. Then the reaction mass was cooled to room temperature, the pH was adjusted to 9-10 with a diluted potassium hydroxide solution, and extracted with ethyl acetate. The extract was dried over sodium sulfate, evaporated in a vacuum rotary evaporator. The target compound was isolated by flash chromatography on silica gel (eluent hexane - ethyl acetate). Yield: 60%

3- (6- (piperidin-3-yl) pyridin-2-yl) -6- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] pyridine dihydrochloride (EXAMPLE 29).

The above compound was obtained in one step by a method similar to that described previously in Example 1, (step d). Yield: 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.78-1.89 (m, 1H), 1.93-1.97 (m, 2H), 2.17-2.21 (m, 1H), 2.75-2.87 (m, 1H), 3.07-3.16 (m, 1H), 3.34-3.45 (m, 2H), 7.58 (d, 1H), 7.76 (d, 1H), 8.07 (t, 1H), 8.03 (d, 1H) ), 9.42 (br s, 2H), 10.16 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 348.17 [M + H] ⁺ (100).

EXAMPLE 30

3- (6- (piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyrimidine dihydrochloride

4-iodo-2H-pyrazol-3-ylamine (59)

Iodine (0.1 mol) and potassium carbonate (0.1 mol) were added to a solution of 3-aminopyrazole (0.1 mol) in 100 ml of methanol. The reaction mass was stirred at room temperature for 3 hours, then diluted with saturated sodium sulfite solution, extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated under reduced pressure. The target compound was purified by flash chromatography on silica gel. Yield: 57%

3-iodo-pyrazolo [1,5-a] pyrimidine (60)

To a solution of compound (59) (10 mmol) in 20 ml of glacial acetic acid was added malondialdehyde (12 mmol). The reaction mixture was stirred at 70 ° C for 3 h (TLC control), then cooled and diluted with water. The precipitate formed was filtered off and washed with water. The target compound was purified by flash chromatography on silica gel, then crystallized from dichloromethane / n-hexane (1:10). Yield: 79%

3- (6- (piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyrimidine dihydrochloride (EXAMPLE 30)

The above compound was obtained in two stages by a method similar to that described previously in Example 1, starting from compounds (60) and (8b). The output in stage c) 31%, in stage d) 98%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.76-1.83 (m, 3H), 2.07-2.12 (m, 1H), 3.07-3.09 (m, 1H), 3.18-3.24 (m, 1H), 3.33-3.38 (m, 2H), 3.42-3.47 (m, 1H), 7.17-7.23 (m, 2H), 7.87 (t, 1H), 8.22 (d, 1H), 8.77 (d , 1H), 8.91 (s, 1H), 9.22 (d, 1H), 9.28 (br.s, 1H), 9.42 (br.s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 280.15 [M + H] ⁺ (100).

EXAMPLE 31

3- (6- (piperidin-3-yl) pyridin-2-yl) ethynyl) -6-phenylpyrazolo [1,5-a] pyrimidine

3-iodo-6-phenyl-pyrazolo [1,5-a] pyrimidine (62)

To a solution of compound (59) (10 mmol) in 20 ml of glacial acetic acid was added 2-phenylmalonic aldehyde (12 mmol) via a dropping funnel. The mixture was stirred at 70 ° C for 3 h (TLC control), then cooled to room temperature and diluted with water (50 ml). The precipitate formed was filtered off and washed with water. The target compound was purified by flash chromatography on silica gel (eluent dichloromethane) and crystallized from a mixture of dichloromethane - n-hexane (1:10). Yield: 69%

6-Phenyl-3-ethynyl-pyrazolo [1,5-a] pyrimidine (63)

Copper (I) iodide (0.4 mmol), PdCl2 (PPh3) 2 (0.2 mmol), triethylamine (8 mmol) were added to a solution of compound (62) (4 mmol) in 10 ml of THF in an argon atmosphere. The resulting mixture was stirred for 10 minutes at room temperature, and then trimethylsilylacetylene (8 mmol) was added. The reaction mass was stirred for 4 hours at 60 ° C (TLC control), then diluted with water (50 ml) and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel, the solvent was distilled off under reduced pressure. The residue was dissolved in THF (20 ml), cooled to 5 ° C and a 1 M solution of tetrabutylammonium fluoride in THF (1.5 ml) was added. The reaction mass was stirred for 1 hour at + 5 ° C (TLC control), diluted with water and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel, the solvent was distilled off under reduced pressure. The target compound was isolated by silica gel column chromatography (eluent, ethyl acetate / n-hexane, 1: 4). Yield: 61%

6- (6-Phenylpyrazolo [1,5-a] pyrimidin-3-ylethynyl) -3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,3'] bipyridinyl-1'-carboxylic tert-butyl ether acids (64)

A mixture of palladium (II) acetate (0.025 mmol) and triphenylphosphine (0.05 mmol) in anhydrous THF under argon was stirred for 10 minutes, then compound (8b) (0.8 mmol), compound (63) (0.8 mmol) and cesium carbonate were added. (1 mmol). The resulting mixture was boiled for 6 h (TLC control), diluted with water, extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel, the solvent was distilled off under reduced pressure. The target compound was isolated by silica gel column chromatography. Yield: 40%

3- (6- (piperidin-3-yl) pyridin-2-yl) ethynyl) -6-phenylpyrazolo [1,5-a] pyrimidine (EXAMPLE 31)

To a solution of compound (64) (0.2 mmol) in 3 ml of 1,4-dioxane was added 10% aqueous sulfuric acid (4 ml). It was stirred at room temperature for 8 h (TLC control), then poured into water, neutralized with potassium carbonate, the precipitate formed was filtered off, washed with water on a filter and dried in air. Yield: 93%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.29-1.79 (m, 3Н), 1.83-1.98 (m, 1Н), 2.58-2.63 (m, 2Н), 2.71-311 (m, 2H), 3.97-4.29 (m, 1H), 7.24 (d, 1H), 7.36-7.56 (m, 5H), 7.72 (t, 1H), 7.85-7.92 (m, 2H), 8.58 (s , 1H), 9.07 (s, 1H), 9.52 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 380.24 [M + H] ⁺ (100).

EXAMPLE 32

3- (6- (piperidin-3-yl) pyridin-2-yl) -6-chloropyrazolo [1,5-a] pyridine dihydrochloride

The above compound was obtained in two stages by a method similar to that described previously in Example 28 from compounds (53) and (65). The synthesis of compound (65) was carried out according to the literature method [Johnston, Karen A .; Allcock, Robert W .; Jiang, Zhong; Collier, Ian D .; Blakli, Haakon; Rosair, Georgina M .; Bailey, Patrick D .; Morgan, Keith M .; Kohno, Yasushi; Adams, David R. Organic and Biomolecular Chemistry, 2008, vol.6, # 1 pp. 175-186] Yield: stage a) 9%, stage b) 99%

Mass spectrum (APCI), m / z (Irel,%): 313.15 [M + H] ⁺ (100), 315.13 [M + H] ⁺ (35).

EXAMPLE 33

3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -2-oxa-8-azaspiro [4.5] decane dihydrochloride

4-Allylpiperidin-1,4-dicarboxylic acid 1-tert-butyl ether 4-methyl ether (67)

94 To a solution of N-Boc-4-piperidinecarboxylic acid methyl ester (0.2 mol) in anhydrous THF (200 ml) in an argon atmosphere was added a 2M solution of NaHMDS in THF (0.22 mol) at a temperature of 0 ° С. The reaction mixture was stirred for 1 hour at 0 ° C, then the temperature was lowered to -30 ° C and allyl bromide (0.22 mol) was added through a dropping funnel with vigorous stirring. After that, the cooling of the reaction mixture was removed and the temperature of the reaction mixture was brought to room temperature. After completion of the reaction, the reaction mixture was poured into a saturated solution of ammonium chloride, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel, the solvent was distilled off under reduced pressure. The target compound was isolated by flash chromatography on silica gel. Yield: 91%

4-Allyl-4-hydroxymethylpiperidin-1-carboxylic acid tert-butyl ether (68)

Lithium aluminum hydride (30 mmol) was added in several stages to a solution of compound (67) (50 mmol) in anhydrous THF (100 ml) at 0 ° С with vigorous stirring. The reaction mixture was stirred at 10 ° C for 10 hours. After this, the mixture was cooled to 0 ° C and 20% KOH solution (3 ml) was added. The transparent solution was carefully decanted from the solid precipitate that had formed and the solvent was distilled off in a vacuum of a rotary evaporator. The target product was isolated by flash chromatography on silica gel. Yield: 76%

3- [6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-ylmethyl] -2-oxa-8-azaspiro [4.5] decan-8-carboxylic acid tert-butyl ether (70)

A mixture of compounds (67) (3 mmol), (69) [George M. Buckley et al. Bioorganic & Medicinal Chemistry Letters 18 (2008), pp.3656-3660] (3 mmol), cesium carbonate (9 mmol), Pd2dba3 (1% molar), DPEphos (2% molar) in anhydrous THF was boiled under argon for 15 hours with vigorous stirring. After completion of the reaction, the reaction mixture was poured into a saturated solution of ammonium chloride, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel, the solvent was distilled off under reduced pressure. The target compound was isolated by flash chromatography on silica gel. Yield: 21%

3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -2-oxa-8-azaspiro [4.5] decane dihydrochloride (EXAMPLE 33)

The above compound was obtained in one step by a method similar to that described previously in Example 1, (step d). Yield: 99%

Mass spectrum (APCI), m / z (Irel,%): 383.22 [M + H] ⁺ (100), 385.24 [M + H] ⁺ (35).

EXAMPLE 34

3 - ((6- (6-Chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -2-oxa-9-azaspiro [5.5] undecane dihydrochloride

The above compound was obtained in four stages by a method similar to that described previously in Example 33, from commercially available methyl ester of N-Boc-4-piperidinecarboxylic acid (0.2 mol) and 4-bromo-but-1-ene. Yield: stage a) 78%, stage b) 65%, stage c) 34%, stage d) 99%

Mass spectrum (APCI), m / z (Irel,%): 397.28 [M + H] ⁺ (100), 399.28 [M + H] ⁺ (35).

EXAMPLE 35

2 - ((6- (6-Chlorimidazo [1,2-d] pyridin-3-yl) pyridin-2-yl) methyl) octahydrofuro [3,2-c] pyridine dihydrobromide

3-Allyl-4-oxopiperidin-1-carboxylic acid benzyl ester (74)

To a solution of N-benzyloxycarbonyl-4-piperidone (100 mmol) and allyl alcohol (110 mmol) in DMSO (100 ml) in an argon atmosphere was added allyl palladium dimer (1% mole percent), BINAP (2% mole), racemic proline (30 mmol). The reaction mixture was heated at 70 ° C for 10 hours (TLC control).

After completion of the reaction, the reaction mixture was cooled, poured into water, extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel, the solvent was distilled off under reduced pressure. The target compound was isolated by flash chromatography on silica gel. Yield: 69%

trans-3-allyl-4-hydroxypiperidin-1-carboxylic acid benzyl ether (75) Compound (74) (100 mmol) was dissolved in anhydrous THF (100 ml).

The reaction mixture was cooled to 0 ° C. and a solution of lithium t-(sec-butyl (hydrido) lithium borate (L-selectride) (150 mmol) was added through a dropping funnel with vigorous stirring.The reaction mixture was stirred for 12 hours at room temperature.

After completion of the reaction, a concentrated potassium carbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, passed through a layer of silica gel, the solvent was distilled off under reduced pressure. The target compound was isolated by flash chromatography on silica gel. Yield: 72%

2- [6- (6-Chlorimidazo [1,2-a] pyrvdin-3-yl) -pyridin-2-ylmethyl] hexahydro-furo [3,2-c] pyridin-5-carboxylic acid benzyl ether (76 )

The above compound was obtained in one step by a method similar to that described previously in Example 33, from compounds (75) (10 mmol) and (69). Yield: 13%

2 - ((6- (6-Chlorimidazo [1,2-yl] pyridin-3-yl) pyridin-2-yl) methyl) octahydrofuro [3,2-c] pyridine dihydrobromide (EXAMPLE 35)

The above compound was obtained in one step by a method similar to that described previously in Example 9, from compound (76) (1 mmol). Yield: 99%

¹ H NMR spectrum (400 MHz, D6-DMSO), δ, ppm: 1.88-2.00 (m, 4H), 2.56-2.69 (m, 1H), 2.79-2.90 (m, 1H), 3.06-3.24 (m, 4H), 4.08 (m), 4.66-4.73 (m, 1H), 7.40 (t, 1H), 7.90-8.08 (m, 4H), 8.35-8.43 (m, 1H), 8.64-8.67 (m, 1H), 8.94 (s, 1H), 10.31 (s, 1H).

Mass spectrum (APCI), m / z (Irel,%): 369.07 [M + H] ⁺ (100), 371.06 [M + H] ⁺ (35).

Table 5 Inhibition of Haspin Kinase Activity for Selected Examples EXAMPLE IC50, μM / L 10 > 1 34 <1 13 0.5 33 0.5 09 0.5 one 0.5 6 0.5 twenty 0.5 2 0.5 5 0.05 3 0.05 22 0.05 8 0.05 19 0.05 eleven 0.05 21 0.05 7 <0.05 four 0.05

Table 6 The selectivity profile of the compound EXAMPLE 5 Kinase IC50, μM / L Aurora a > 20 Axl 5 VTK > 20 CDC7α / Dbf4 10 SNK1 > 20 cKIT > 20 Csk > 20 Egfr > 20 Epha2 > 20 Lck > 20 Lyn > 20 p38α > 20 PDGFRα 3.5 PDGFRβ 8 PIM1 > 20 PLK1 > 20 RON > 20 Trka > 2 VEGFR2 > 20

One skilled in the art will appreciate that the present invention is adapted to bring objects to an end and to obtain the mentioned and implied advantages.

The methods and reagents described in the application are typical in preferred embodiments, but are taken as an example and should not limit the scope of the invention. Their possible modifications and other applications are known to those skilled in the art. These modifications are embraced by the spirit of the invention and are included in the claims.

Many equivalents to the specific embodiments of the invention described in the application are known to the skilled person or can be ascertained by routine experimentation. These equivalents are considered to be covered by the following claims. Those skilled in the art will also appreciate that all combinations of embodiments, combinations of aspects, or features of the claims described in the application are within the scope of the invention.

All of the above references and publications are incorporated into the application by reference.

Claims (5)

1. The compound of General formula (I)

or any tautomeric form thereof, or a pharmaceutically acceptable salt thereof,
Where
1-2 of X ₁ , X ₂ , X ₃ , X ₄ X ₅ , X ₆ selected from N, and others represent C;
Χ _{7 is} selected from N or CH;
each of X ₈ , X ₉ , X ₁₀ and X _{11 is} independently selected from N or CH, provided that the fragment can simultaneously contain one or two nitrogen atoms;
R ₁ , R ₂ , R ₃ and R ₄ are selected from H, 6-membered aryl, CF ₃ , halogen;
R ₅ , R ₆ R ₇ are C ₁ -alkyl provided that X ₉ , X ₁₀ or X ₁₁ in this case is respectively equal to C;
″ A ″ may be a single bond or a bridged ethylene moiety;
Y may be a single bond or independently selected from methylene or ethylene bridging fragments;
fragment Z is independently selected from unsubstituted or substituted at the nitrogen atom of heterocycloalkyl or is unsubstituted or substituted by cycloalkyl, provided that N (nitrogen) is equal to C (carbon):

where R _{9 is} selected from CH ₂ OH, CON (R ₁₅ R ₁₆ ), where R ₁₅ , R ₁₆ may independently be H, C ₁ -alkyl,
Het represents N,
n = 1, n ₁ = 3;
R _{8 is} selected from H, C _1-6 alkyl, C ₁ alkylcarbonyl,
Derivatives of aryl acetic acid of the general structure:

methyl heteroaryl general structure:

derivatives of alkylsulfonyls of the general structure:

where R ₁₄ = Alk, and Alk represents a C ₁ -alkyl,
or the compound 2-methylamino-1- {3- [6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-ylmethyl] -1-oxa-8-azaspiro [4.5] decan- 8-yl} ethanone dihydrochloride,
or the compound 6- (6-chlorimidazo [1,2-a] pyridin-3-yl) -1 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,3 ′] bipyridinyl-3 ′ β-carboxylic acid dihydrochloride,
or the compound 6- (6-chlorimidazo [1,2-a] pyridin-3-yl) -1 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,3 ′] bipyridinyl-3 ′ β-carboxylic acid dimethylamine dihydrochloride,
or any pharmaceutically acceptable salt of said compounds. 2. The compound according to claim 1, selected from:
3- (6-piperidin-4-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride,
3- (6- (azepan-4-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride,
3 - ((6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5] decane dihydrochloride,
3 - ((6- (6- (trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1-oxa-8-azaspiro [4.5] decane dihydrochloride,
3 - ((6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -1,4-oxazepane dihydrochloride,
{4- [6- (6-chlorimidazo [1,2-a] pyridin-3-yl) -pyridin-2-ylmethyl] cyclohexyl} methylamine dihydrochloride,
3- (6 - (((3aS, 6aR) octahydro-cyclopenta [c] pyrrol-4-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride (mixture of diastereomers) ,
3- (6 - (((3aS, 7aR) -octahydro-1H-isoindol-4-yl) methyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride (mixture of diastereomers),
3- (6 - ((1,4-diazepan-6-yl) methyl) pyridin-2-yl) -6-chloro-imidazo [1,2-a] pyridine dihydrobromide,
3- (6- (azepan-4-ylmethyl) -2-methylpyrimidin-4-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride,
3- (6 - ((1R, 5S) -8-azabicyclo [3.2.1] oct-3-ylmethyl) pyridin-2-yl) -6-chlorimidazo [1,2-a] pyridine dihydrochloride,
3 - ((6- (imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -8- (pyridin-3-ylmethyl) -1-oxa-8-azaspiro [4.5] Dean
2-methylamino-1- {3- [6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-ylmethyl] -1-oxa-8-azaspiro [4.5] decan-8- silt} -ethanone dihydrochloride,
3- (6- (pyrrolidin-2-yl) pyrazin-2-yl) imidazo [1,2-a] pyrimidine dihydrochloride,
3- (6- (1-isopropylpiperidin-3-yl) -2-methylpyrimidin-4-yl) imidazo [1,2-a] pyrimidine,
1- (4 - ((6- (imidazo [1,2-a] pyrimidin-3-yl) pyridin-2-yl) methyl) piperidin-1-yl) ethanone,
1- (2- (2- (6- (imidazo [1,2-a] pyrimidin-3-yl) pyrimidin-4-yl) ethyl) pyrrolidin-1-yl) ethanone,
3- (6 - ((1- (methylsulfonyl) -pyrrolidin-3-yl) methyl) pyridin-2-yl) imidazo [1,2-a] pyrimidine,
3- (6- (piperidin-3-yl) pyridin-2-yl) -6-chloro-imidazo [1,2-a] pyridine dihydrochloride,
3- (6- (piperidin-3-yl) pyrazin-2-yl) -6-chloro-imidazo [1,2-a] pyridine dihydrochloride,
3- (6- (piperidin-3-yl) pyridin-2-yl) -6- (trifluoromethyl) imidazo [1,2-a] pyridine dihydrochloride,
2- (6- (6- (trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) morpholine dihydrochloride,
1- (2- (6- (6- (trifluoromethyl) imidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) morpholino) -2-phenyl ethanone,
3- (6- (piperidin-3-yl) pyridin-2-yl) -6-chlorimidazo [1,2-b] pyridazine dihydrochloride,
6- (6-chlorimidazo [1,2-a] pyridin-3-yl) -1 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,3 ′] bipyridinyl-3′-carbon dihydrochloride acids
6- (6-chlorimidazo [1,2-a] pyridin-3-yl) -1 ′, 4 ′, 5 ′, 6′-tetrahydro-2′H- [2,3 ′] bipyridinyl-3′-carbon dimethylamine dihydrochloride acid,
3- (6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) piperidin-3-yl) methanol dihydrochloride,
3- (6- (piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyridine dihydrochloride,
3- (6- (piperidin-3-yl) pyridin-2-yl) -6- (trifluoromethyl) - [1,2,4] triazolo [4,3-a] pyridine dihydrochloride,
3- (6- (piperidin-3-yl) pyridin-2-yl) pyrazolo [1,5-a] pyrimidine dihydrochloride,
3- (6- (piperidin-3-yl) pyridin-2-yl) ethynyl) -6-phenylpyrazolo [1,5-a] pyrimidine,
3- (6- (piperidin-3-yl) pyridin-2-yl) -6-chloropyrazolo [1,5-a] pyridine dihydrochloride,
3 - ((6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -2-oxa-8-azaspiro [4.5] decane dihydrochloride,
3 - ((6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) -2-oxa-9-
azaspiro [5.5] undecane dihydrochloride,
2 - ((6- (6-chlorimidazo [1,2-a] pyridin-3-yl) pyridin-2-yl) methyl) octahydrofuro [3,2-c] pyridine dihydrobromide. 3. The compound according to any one of claims 1 or 2, as a medicine having the ability to inhibit Haspin kinase. 4. A pharmaceutical composition having the ability to inhibit Haspin kinase, containing a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient, diluent or carrier. 5. A method of inhibiting Haspin kinase, comprising administering a therapeutically effective amount of a compound according to claim 1.