Pyrimidyl cyclopentanes as akt-protein kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I, enantiomers and pharmaceutically acceptable salts thereof which have selective inhibitory action on AKT protein kinase, in particular protein kinase B. In formula I: A represents R¹ and R^1a are independently specified in H, Me, Et. vinyl, CF₃, CHF₂ or CH₂F:R₂ represents H, OH, OMe or F; R^2a represents H, Me or F; R³ represents H. Me. Et or CF₃; G represents phenyl optionally substituted by one to four groups R^c, or 5-6-member heteroaryl containing one heteroatom specified in sulphur optionally substituted by halogen; R⁵ and R⁶ independently represent H, OCH₃, C₃-C₆-cycloalkyl independently substituted by F, OH, C₁-C₃alkyl or O(C₁-C₃alkyl), 4-6-member heterocyclyl containing one heteroatom specified in nitrogen optionally substituted by F, OH, C₁-C₃alkyl, cyclopropylmethyl or -C(=O)(C₁-C₃alkyl), or C₁-C₆-alkyl optionally substituted by one or more groups independently specified in OH, oxo O(C₁-C₆-alkyl), CN, F, NH₂. NH(C₁-C₆-alkyl), O(C₁-C₆-alkyl)₂. cyclopropyl. phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanil or tetrahydropyranyl. The other radical values are specified in the patent claim.

EFFECT: compounds may be used treating the conditions selected from inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynaecological and dermatological diseases and disorders, preferentially in treating cancer.

15 cl, 2 tbl, 8 dwg, 14 ex

The technical field to which the invention relates.

The present invention relates to new inhibitors of serine/threonine-protein kinases (e.g., AKT and related kinases), pharmaceutical compositions containing such inhibitors, and methods for producing these inhibitors. These inhibitors are applicable, for example, for the treatment of hyperproliferative diseases such as cancer and inflammation, in mammals.

The level of technology

Protein kinase (RK) are enzymes that catalyze the phosphorylation of hydroxy groups tyrosine, serine and treoninove residues of proteins by transferring terminal (gamma) phosphate of ATP. Through the path of the signal transduction of these enzymes modulate the growth, differentiation and proliferation of cells, i.e. almost all aspects of cell life of one way or another dependent on the activity of PK (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I u II, Academic Press, San Diego, CA). In addition, the abnormal activity of the Republic of Kazakhstan connected with the family of diseases, ranging from the relatively safe, non-life threatening, such as psoriasis, to extremely virulent, such as glioblastoma (brain cancer). Protein kinases are an important class of targets for therapeutic modulation (Cohen, P. (2002) Nature Rev. Drug Discovery 1:309).

Atypical protein phosphorylation and/or expression, as often reported, to a large extent and represent one of the effects, causes of abnormal cell proliferation, metastasis, and survival in cancer cells. Abnormal regulation and/or expression of various kinases, including Akt, VEGF, ILK, ROCK, p70S6K, Bcl, PKA, PKC, Raf, Src, PDK1, ErbB2, MEK, IKK, Cdk, EGFR, BAD, CHK1, CHK2 and GSK3 among many others, is definitely organically linked with cancer.

Protein kinases include two classes: protein-tyrosine-kinase (RTK) and the serine-threonine kinase (STK). B/Akt-proteinkinase enzymes are a group of serine/threonine kinases that overproduction in many human cancers. One of the best characterized targets of PI3K lipid products is a 57-KD-serine/threonine-protein kinase Akt, below the site of PI3K in the path of signal transduction (Hemmings, B.A. (1997) Science 275:628; Hay N. (2005) Cancer Cell 8:179-183). Akt is a human homolog of the v-akt-proto-oncogene in dramatically transforming the retrovirus ACT. Because of the high degree of sequence Akt and protein kinases a and C, Akt, also called protein kinase B (RKV) and related a and C (RAC). It is known that there are three isoforms of Akt, a namely Akt1, Akt2 and Akt3, which have 80%overall homology [(Staal, S.P. (1987) Proc. Natl. Acad. Sci. 84:5034; Nakatani, K. (1999) Biochem. Biophys. Res. Commun. 257:906; Li et al. (2002) Current Topics in Med. Chem. 2:939-971; WO 2005/113762)]. The Akt isoforms participate in the common domain organization, which consists of a PH domain (pleckstrin homology domain) at the N-terminal, catalytic domain of kinases, and to odoi regulatory region at the C-end. In addition, as Akt2 and Akt3 are splicing variants. When recruitment to the cell membrane under the action of PtdInd(3,4,5)P₃, Akt fosfauriliruetsa (activated) PDK1 when T, T and T for isoforms Akt1 (PKBα), Akt2 (PKBβ and Akt3 (PKBγ), respectively, and at S473, S474 and S472 for isoforms Akt1, Akt2 and Akt3, respectively. This phosphorylation occurs under the action of an as yet unknown kinase (presumably named PDK2), although PDK1 [(Balendran, A., (1999) Curr. Biol. 9:393)], autophosphorylation [(Toker, A. (2000) J. Biol. Chem. 275:8271)] and integrin-linked kinase (ILK) (Delcommenne, M. (1998) Proc. Natl. Acad. Sci. USA, 95:11211) involved in this process. Activation of Akt requires its phosphorylation on residue Ser 473 in the C-terminal hydrophobic motif. (Brodbeck et al. (1999) J. Biol. Chem. 274:9133-9136; Coffer et al. (1991) Eur. J. Biochem. 201:475-481; Alessi et al. (1997) Curr. Biol. 7:261-269). Although monophosphorylation activates Akt kinase, for the maximum activity of the kinase is required bis(phosphorylation).

I believe that Akt affects cancer, inhibiting apoptosis and enhancing as angiogenesis and proliferation [(Toker et al. (2006) Cancer Res. 66(8):3963-3966)]. Akt overproduction in many forms of human cancer, including (but not limited to the following) colon cancer [(Zinda et al. (2001) Clin. Cancer Res. 7:2475)], ovarian [(Cheng et al. (1992) Proc. Natl. Acad. Sci. USA 89:9267)], brain [(Haas Kogan et al. (1998) Curr. Biol. 8:1195)], lung [(Brognard et al. (2001) Cancer Res. 61:3986)], pancreas [(Bellacosa et al. (1995) Int. J. Cancer 64:280-285; Cheng et al. (1996) Proc.Natl. Acad. Sci. 93:3636-3641)], prostate [(Graff et al. (2000) J. Biol. Chem. 275:24500)] and gastric cancer [(Staal et al. (1987) Proc. Natl. Acad. Sci. USA 84:5034-5037)].

For targeted therapy with small molecule inhibitor investigated the transport of rapamycin (mTOR) to target PI3K/Akt/mammalian [(Georgakis, G. and Younes, A. (2006) Expert Rev. Anticancer Ther. 6(1): 131-140; Granville et al. (2006) Clin. Cancer Res. 12(3):b-689)]. Inhibition of PI3K/Akt signal induces apoptosis and inhibits growth of tumor cells, which increase the levels of Akt [(Kim et al. (2005) Current Opinion in Investig. Drugs 6(12): 1250-1258; Luo et al. (2005) Molecular Cancer Ther. 4(6):977-986)].

Development of inhibitors of kinases, which focuses on the way with abnormal regulation, leading eventually to disease, represent a huge ethical and commercial interest for medical and pharmaceutical community. A compound that inhibits (1) the recruitment of Akt to the cell membrane, (2) activation by the action of PDK1 or PDK2, (3) phosphorylation of the substrate or (4) one of the lower targets Akt could be a valuable anti-cancer, current or as individual therapeutic techniques, or in combination with other approved methods.

Publication of an application for U.S. patent No. 2005/0130954 describes among others a number of compounds that act as inhibitors of the ACT. I believe that these compounds applicable in the treatment of hyperproliferative diseases such as cancer.

In the paper the purpose of application for U.S. patent No. 2008/0058327 and publish applications for U.S. patent No. 2008/0051399 describes among others a number of compounds that act as inhibitors of AKT.

Disclosure of inventions

The present invention relates to new compounds that inhibit AKT-protein kinase. Compounds of the present invention are useful as therapeutic agents for the treatment of diseases and conditions that can be treated by inhibiting AKT-protein kinases.

The present invention includes compounds of General formula I

and their enantiomers and salts, in which A, R¹, R^1a, R², R^2aand R³such as defined below.

The invention also relates to pharmaceutical compositions containing a compound of formula I, or its enantiomer, or its pharmaceutically acceptable salt.

An additional object of the present invention is a method of treating a mammal diseases or medical conditions mediated AKT-protein kinases, including the introduction of specified mammal one or more compounds of the formula I, or their enantiomers, or their pharmaceutically acceptable salts in an amount effective for treatment or prevention of a specified disease. State-mediated AKT-protein kinase, which can be treated by the methods of the present izobreteny is, include (but are not limited to, inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological and dermatological diseases and disorders.

An additional object of the present invention relates to a method of inhibiting the production of AKT-protein kinases in mammals, which includes the introduction of the specified mammal the compounds of formula I, or its enantiomer, or its pharmaceutically acceptable salt in an amount effective for inhibiting the production of AKT-protein kinase.

An additional object of the present invention relates to methods of inhibiting the activity of AKT-protein kinases, including the contacting of these kinases with a compound of formula I.

Compounds according to the invention can be successfully used in combination with other known therapeutic agents. Accordingly, the present invention also relates to pharmaceutical compositions containing a compound of formula I, or its enantiomer, or its pharmaceutically acceptable salt in combination with a second therapeutic agent.

The present invention also relates to compounds of formula I and their enantiomers and pharmaceutically acceptable salts for use as pharmaceuticals in the treatment of conditions mediated AKT-protein kinases.

Additional is the second object of the invention is the use of compounds of formula I, or its enantiomer, or pharmaceutically acceptable salts in the treatment. In one embodiment of the invention, therapy involves the treatment of a condition mediated AKT-protein kinase.

The present invention also relates to a kit for the treatment of diseases or disorders mediated AKT-protein kinase, which contains a compound of formula I or its enantiomer, or pharmaceutically acceptable salt, container and optional leaflet or the label indications for treatment. The kits can further comprise a second compound or a composition comprising a second pharmaceutical agent, applicable for the treatment of specified diseases or disorders.

The present invention additionally includes methods of preparation, methods of separation and purification methods of the compounds of the present invention.

Additional advantages and new features of the present invention will be described in the following part of the description and in part, will be obvious to experts in the examination of the following description, or which may be learned from practice of the invention. Advantages of the invention may be realized and attained by means of the combinations, compositions and methods specified in the attached claims.

The implementation of the invention

So is elany detailed references to specific embodiments of the invention, examples of which are illustrated with accompanying structures and formulas. Although the invention will be described in combination with variants of its implementation, it should be clear that not meant to limit the invention to these options for implementation. On the contrary, it is understood that the invention covers all alternatives, modifications and equivalents that may be included in the scope of the present invention according to the claims. Specialist in the art should know the many ways and substances similar to or equivalent to the one described here, which could be used in the practice of the present invention. The present invention is in no way limited to the described methods and substances. If one or more of the incorporated references to the literature and similar materials differ from this application or contradict it, including defined terms, use of terms, described techniques, or anything similar (but not limited to, this application takes precedence.

DEFINITION

The term "alkyl"used herein refers to saturated linear or branched monovalent hydrocarbon radical containing one to twelve carbon atoms, and the alkyl radical may be neoba is consequently independently substituted by one or more substituents, described below. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH₃), ethyl ("Et", -CH₂CH₃), 1-propyl (n-Pr, n-propyl, -CH₂CH₂CH₃), 2-propyl (i-Pr, isopropyl, -CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, -CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu", isobutyl, -CH₂CH(CH₃)₂), 2-butyl (s-Bu, sec-butyl, -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH₃)₃), 2,2-dimethylpropyl (CH₂C(CH₃)₃), 1 pentyl (n-pentyl, -CH₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH(CH₃)CH₂CH₂CH₃), 3-pentyl (-CH(CH₂CH₃)₂), 2-methyl-2-butyl (-C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (-CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (-CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (-C(CH 3)(CH₂CH₃)₂), 2-methyl-3-pentyl (-CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (-C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃))₃, 1-heptyl, 1-octyl and the like.

Used here, the terms "cycloalkyl", "carbocycle", "carbocyclic" and "carbocyclic ring" are used interchangeably, and they refer to a saturated or partially unsaturated cyclic hydrocarbon radicals containing from three to twelve carbon atoms. The term "cycloalkyl" includes monocyclic and polycyclic (e.g. bicyclic or tricyclic) structure, where the polycyclic structure include optional saturated or partially unsaturated cycloalkyl ring condensed with a saturated, partially unsaturated or aromatic cycloalkyl or heterocyclic ring. Cycloalkyl may be optionally independently substituted by one or more substituents described herein.

Examples cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl, cyclododecyl,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonan.

Used herein, the terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used interchangeably and refer to a saturated or partially unsaturated carbocyclic to radical containing 3-8 ring atoms, where at least one atom of the ring is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms are carbon atoms, and one or more atoms in the ring may be optionally independently substituted by one or more substituents described below. The radical may be a carbon-centered or heteroatom-centered. The term "heterocycle" includes heterocyclics. The term "heterocyclyl" also includes radicals where heterocyclic radicals are fused with a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring. The heterocycle may be substituted or N-substituted, in cases where this is possible. For example, a group derived from pyrrole, can be a pyrrol-1-yl (N-substitution) or pyrrol-3-yl (C-substitution). Further, a group derived from imidazole can be an imidazol-1-yl (N-substitution) or imidazol-3-yl (C-substitution). Examples of the heterocyclic group in which 2 carbon atoms of the ring substituted on the (=O) groups, represent isoindoline-1,3-dionyl and 1,1-dioxothiazolidine. Heterocyclic groups are optionally substituted independently by one or more substituents described in this application.

Typical heterocyclyl groups include (but are not limited to) oxiranyl, aziridinyl, thiiranes, azetidine, oxetane, titanyl, 1,2-dithietane, 1,3-digaetani, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, dioxane, piperazinil, homopiperazine, homopiperazine, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, dehydration, dihydropyran, dihydrofuran, tetrahydrofuranyl, tetrahydrothieno, tetrahydropyranyl, tetrahydropyranyl, 1-pyrrolidyl, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, pyrazolidine, dithienyl, dithiolane, pyrazolidine, imidazoline, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes and azabicyclo[2.2.2]hexanal.

Used herein, the term "heteroaryl" refers to a monovalent aromatic radical with 5-, 6 - or 7-membered ring and includes a condensed cyclic ring systems (at least one of which is aromatic) of 5 to 10 atoms, containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur. Heteroaryl can b the e s-substituted or N-substituted in cases where it is possible. Heteroaryl groups may be optionally independently substituted by one or more substituents described herein.

Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridines, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, indolyl, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, oxadiazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properidine.

Used herein, the term "halogen" denotes fluorine, chlorine, bromine or iodine.

The term "enantiomer" refers to two stereogram compounds that are analagies mirror images of each other.

The term "diastereoisomer" refers to a pair of optical isomers that are not mirror images of each other.

The term "tautomer or tautomeric form" refers to the structural isomers with different energies, which vzaimoprevrascheny via a low energy barrier.

The phrase "pharmaceutically acceptable" indicates that the substance or composition helices and or toxicologically compatible with other ingredients contained in the formulation, and/or mammals, which are subjected to treatment with this substance or composition.

The phrase "effective amount" denotes an amount of a compound that when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent specific diseases, conditions or disorders mediated by the activity of one or more AKT-protein kinases, tyrosinekinase, additional serine/trainingin and/or kinases with dual specificity, (ii) improve the condition, reduce or eliminate one or more symptoms of the particular disease, condition or violation, or (iii) prevent or delay the appearance of one or more symptoms of the particular disease, condition or violation that is described here.

It is implied that the term "treatment" means at least relieved the state of the disease in a mammal, such as man, which is influenced, at least partially, one or more AKT-protein kinases, tyrosinekinase, additional serine/trainingin and/or kinases with dual specificity. The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, the aim of which is to prevent or slow down (lessen) Eulalie physiological changes or disturbances. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to relieving symptoms, reducing the extent of injury, stabilized (i.e. not worsening) state of disease, delay or slowing of disease progression, improving or alleviating the disease state, and remission (partial or complete), defined or undefined. The term "treatment" can also mean prolonging survival time compared with the expected survival time without treatment. Those in need of treatment include those already affected by disease or morbid condition, as well as those that were found, are predisposed to the condition of the disease, but who have not been diagnosed. The terms "treatment", "treat" or "treatment" include both preventive, i.e. preventive and palliative treatment.

Used herein, the term "mammal" refers to a warm-blooded animal that suffers from a disease described herein, or in which there is a risk of developing such disease, and includes Guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans, but not limited to those listed below animals.

The term "insert" is used to refer to the instructions about what a rule is included in the sets of therapeutic products, held for sale, which contain information about the indications, usage, dosage, introduction, contraindications and/or warnings concerning the use of such therapeutic products.

Used herein, the terms "connection according to this invention", "compounds of the present invention" and "compounds of formula I include compounds of formula I and their tautomers, the enantiomers, the diastereomers, racemic mixture, solvate, metabolites, salts (including pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs.

It should be understood that the examples where two or more radicals used sequentially to determine the substituent attached to the structure, radical, called the first, is considered terminal, and the radical is called the last, is attached to the structure. For example, arylalkyl radical attached to the structure of the alkyl group.

The INHIBITORS ACT

Compounds according to the invention of the formula I apply for inhibition of AKT-protein kinases. In addition to the ACT, the compounds of formula I can also be used as inhibitors tyrosinekinase, and serine - and trainingin. Such compounds find use as therapeutic agents against diseases that can be treated in what euromania signaling pathway AKT-protein kinases and ways receptor tyrosine - and serine/trainingin.

In General, the invention includes compounds of formula I

and they separated the enantiomers, the diastereomers and pharmaceutically acceptable salts, where:

R¹and R^1aindependently selected from H, Me, Et, vinyl, CF₃, CHF₂or CH₂F;

R²represents H, HE, OMe or F;

R^2arepresents H, Me or F;

R³represents H, Me, Et or CF₃;

And is a;

G represents a phenyl, optionally substituted by one to four groups R^eor 5-6-membered heteroaryl, optionally substituted with halogen;

R⁵and R⁶independently represent H, och₃With₃-C₆-cycloalkyl, optionally substituted by F, HE, C₁-C₃the alkyl or O(C₁-C₃by alkyl), 4-6-membered heterocycle, optionally substituted by F, HE, C₁-C₃the alkyl, cyclopropylmethyl or C(=O)(C₁-C₃by alkyl), or C₁-C₆-alkyl, optionally substituted by one or more groups independently selected from HE, oxo, (C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or Tetra is itapiranga,

or R⁵and R⁶together with the nitrogen atom to which they are attached, form a 4-7-membered heterocyclic ring, optionally substituted by one or more groups independently selected from HE, halogen, oxo, CF₃CH₂CF₃CH₂CH₂OH, O(C₁-C₃alkyl), C(=O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃the alkyl, or R^crepresents hydrogen, a R^dand R⁶together with the atoms to which they are attached, form a 4-6-membered heterocyclic ring containing one nitrogen atom;

R^aand R^brepresent N

or R^arepresents N, and R^band R⁶together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring containing one or two nitrogen atom;

R^cand R^drepresent H or Me

or R^cand R^dtogether with the atom to which they are attached, form cyclopropyl ring;

each R^erepresents independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, O-(C₁-C₆-alkyl), CF₃, OCF₃S(C₁-C₆-alkyl), CN, och₂-phenyl, NH₂, NO₂, NH-(C₁-C₆-alkyl), N-(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂OCH ₂F, OCHF₃HE SO₂(C₁-C₆-alkyl), C(O)NH₂C(O)NH(C₁-C₆-alkyl) and C(O)N(C₁-C₆-alkyl)₂;

m and n are independently 0, 1, 2 or 3, provided that (m+n) must be equal to 2, 3 or 4; and

p is 0 or 1.

In General, the invention includes compounds of formula I

and they separated the enantiomers, the diastereomers and pharmaceutically acceptable salts, where:

R¹and R^1aindependently selected from H, Me, Et, vinyl, CF₃, CHF₂or CH₂F;

R²represents H, HE, OMe or F;

R^2arepresents H, Me or F;

R³represents H, Me, Et or CF₃;

And is a;

G represents a phenyl, optionally substituted by one to four groups R^eor 5-6-membered heteroaryl, optionally substituted with halogen;

R⁵and R⁶independently represent H, och₃With₃-C₆-cycloalkyl, optionally substituted by F, HE, C₁-C₃the alkyl or O-(C₁-C₃by alkyl), 4-6-membered heterocycle, optionally substituted by F, HE, C₁-C₃the alkyl, cyclopropylmethyl or C(=O)(C₁-C₃by alkyl), or C₁-C₆-alkyl, optionally substituted by one or more groups independently chosen is C HE oxo, O-(C₁-C₆the alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl,

or R⁵and R⁶together with the nitrogen atom to which they are attached, form a 4-7-membered heterocyclic ring, optionally substituted by one or more groups independently selected from HE, halogen, oxo, CF₃CH₂CF₃CH₂CH₂OH, O(C₁-C₃the alkyl), C(=O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃of alkyl;

R^aand R^brepresent N

or R^arepresents H, a R^band R⁶together with the atoms to which they are attached, form a 5-6-membered heterocyclic ring containing one or two nitrogen atom in the ring;

R^cand R^drepresent H or Me

or R^cand R^dtogether with the atom to which they are attached, form cyclopropyl ring;

each R^eindependently represents halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, O-(C₁-C₆-alkyl), CF₃, OCF₃S(C₁-C₆-alkyl), CN, och₂-phenyl, NH₂, NO₂, NH-(C₁-C₆-alkyl), N-(Csub> 1-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂HE SO₂(C₁-C₆-alkyl), C(O)NH₂C(O)NH(C₁-C₆-alkyl) and C(O)N(C₁-C₆-alkyl)₂;

m and n are independently 0, 1 or 2, provided that (m+n) must be equal to 2, 3 or 4; and

p is 0 or 1.

Examples belonging to the group G of the formula I, include phenyl (Ph), optionally substituted by one or more groups R^eindependently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, CN, CF₃, OMe, OEt, OCF₃, NO₂, SMe and OCH₂Ph. Typical embodiments of G include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-forfinal, 4-bromophenyl, 4-were, 4-ethylphenyl, 4-isopropylphenyl, 4-triptoreline, 4-cyanophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-dimethylphenyl, 4-trifloromethyl, 4-cyclopropylmethyl, 4-chloro-3-forfinal, 3,4-differenl, 4-bromo-3-forfinal, 3-fluoro-4-were, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-triptoreline, 4-cyano-3-forfinal, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-differenl, 2-chloro-4-forfinal, 2-fluoro-4-chlorophenyl, 3,5-dichlorophenyl, 3,5-differenl, 3-chloro-5-forfinal, 3-chloro-4-forfinal, 3-bromo-4-forfinal, 3,5-debtor-4-chlorophenyl, 2,3-debtor-4-chlorophenyl, 2,5-debtor-4-chlorophenyl, 3,5-debtor-4-bromophenyl, 2,3-debtor-4-bromophenyl, 2.5-debtor-4-bromophenyl, 4-(OCH₂Ph)-phenyl, chlorphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-3-forfinal, 3-chloro-4-forfinal, 3-fluoro-4-bromophenyl, 4-forfinal, 3,4-differenl, 2,4-differenl 4-bromophenyl, 4-chloro-2-forfinal, 4-methoxyphenyl, 4-were, 4-cyanophenyl, 4-triptoreline, 4-iopener, 4-nitrophenyl, 4-tert-butylphenyl, 2-forfinal, 3-triptoreline, 2-fluoro-4-triptoreline, 3-fluoro-4-trifloromethyl, 3-fluoro-4-triptoreline and 4-trifloromethyl.

The phrase "5-6-membered heteroaryl, optionally substituted by halogen, belonging to the group G of the formula I, includes tifany and pyridine, optionally substituted by halogen atoms. Specific examples include the structure:

,

but not limited to.

In one embodiment of formula I, R³represents N.

In another embodiment, formula I R³represents methyl, and methyl specified is not necessarily in the (S) configuration.

In another embodiment, formula I R³represents ethyl. In one embodiment of formula I, R¹represents methyl, and methyl specified is not necessarily in the (R) configuration. In some embodiments, the implementation of the formula I R^1arepresents N. In some embodiments, about what westline formula I R ¹and R^1aboth represent methyl.

In another embodiment, formula I R¹represents N. In some embodiments, the implementation of the formula I R^1arepresents N.

In another embodiment, formula I R¹represents ethyl. In some embodiments, the implementation of the formula I R^1arepresents N.

In another embodiment, formula I R¹represents CH=CH₂(vinyl). In some embodiments, the implementation of the formula I R^1arepresents N.

In another embodiment, formula I R¹represents CH₂HE. In some embodiments, the implementation of the formula I R^1arepresents N.

In one embodiment of formula I, R^1arepresents N.

In one embodiment of formula I, R²and R^2arepresent N.

In another embodiment, formula I R²and R^2arepresent F.

In another embodiment, formula I R²represents F and R^2arepresents N.

In another embodiment, formula I R²is a HE. In some embodiments, the implementation of the formula I R^2arepresents N.

In another embodiment, formula I R²represents OMe

In one embodiment, formula I G is a phenyl, optionally substituted by one to four groups R^e.

In one embodiment, formula I G is a phenyl, optionally substituted by one to four groups independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, CN, CF₃, OMe, OEt, OCF₃, NO₂, SMe and OCH₂Ph. Typical embodiments of G include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-forfinal, 4-bromophenyl, 4-were, 4-ethylphenyl, 4-isopropylphenyl, 4-triptoreline, 4-cyanophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-dimethylphenyl, 4-trifloromethyl, 4-cyclopropylmethyl, 4-chloro-3-forfinal, 3,4-differenl, 4-bromo-3-forfinal, 3-fluoro-4-were, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-triptoreline, 4-cyano-3-forfinal, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-differenl, 2-chloro-4-forfinal, 2-fluoro-4-chlorophenyl, 3,5-dichlorophenyl, 3,5-differenl, 3-chloro-5-forfinal, 3-chloro-4-forfinal, 3-bromo-4-forfinal, 3,5-debtor-4-chlorophenyl, 2,3-debtor-4-chlorophenyl, 2,5-debtor-4-chlorophenyl, 3,5-debtor-4-bromophenyl, 2,3-debtor-4-bromophenyl, 2.5-debtor-4-bromophenyl, 4-(OCH₂Ph)-phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-3-forfinal, 3-chloro-4-forfinal, 3-fluoro-4-bromophenyl, 4-forfinal, 3,4-differenl, 2,4-differenl 4-bromophenyl, 4-chloro-2-forfinal, 4-methoxyphenyl, 4-IU is ylphenyl, 4-cyanophenyl, 4-triptoreline, 4-iopener, 4-nitrophenyl, 4-tert-butylphenyl, 2-forfinal, 3-triptoreline, 2-fluoro-4-triptoreline, 3-fluoro-4-trifloromethyl, 3-fluoro-4-triptoreline and 4-trifloromethyl.

In one embodiment, formula I G is a 4-chlorophenyl, 4-forfinal, 4-bromophenyl, 4-iopener, 4-triptoreline, 4-trifloromethyl, 4-dimethylphenyl, 3-fluoro-4-chlorophenyl, 2,4-dichlorophenyl or 3,4-dichlorophenyl.

In one embodiment, formulas I, G can be a 5-6-membered monocyclic heteroaryl, optionally substituted by one or more halogen atoms. In some embodiments, the implementation of G can be a thiophene or pyridine, optionally substituted by one or more halogen atoms. In some embodiments, the implementation of G is substituted by one halogen atom. Specific options for implementation include:

.

In one embodiment of formula I, R⁵represents H or ethyl.

In one embodiment of formula I, R⁶represents H or ethyl.

In one embodiment of formula I, R⁶represents hydrogen, ethyl or isopropyl.

In one embodiment, the shape of the s I R ^aand R^brepresent N.

In one embodiment of formula I, R^cand R^drepresent N.

In one embodiment, R^crepresents hydrogen, and R^dand R⁶together with the atoms to which they are attached, form a 4-6-membered heterocyclic ring containing one nitrogen atom. In some embodiments, the implementation of m is 0, R^crepresents hydrogen, and R^dand R⁶together with the atoms to which they are attached, form a 4-6-membered heterocyclic ring containing one nitrogen atom, so that a has the formula:

,

where q is 1 or 2 and n is 1 or 2. In some embodiments, the implementation of n is 1 and q is 1, n is 1 and q is 2 or n is 2 and q is 2.

In one embodiment of formula I, m and n are independently 0, 1 or 2, provided that (m+n) must be equal to 2, 3 or 4. In specific embodiments, the implementation of m is 0 and n is 2, m is 1 and n is 2, m is 2 and n is 2, m is 1 and n is 1, m is 2 and n is 1 or m is 2 and n is 0.

In one embodiment of formula I, m and n are both equal to 1.

In another embodiment, formula I, m is 2 and n is 0. In another embodiment, formula I, n is 2 and m is 0.

In one embodiment of formula I, m is 1, n is 1, R is 0, so And fo is mulai 1

,

where G, R⁵, R⁶, R^cand R^dsuch as defined here.

In some embodiments, the implementation of formula 1, R^cand R^drepresent N.

In some embodiments, the implementation of formula 1, R⁵represents H or ethyl.

In some embodiments, the implementation of formula 1, R⁶represents H or ethyl.

In some embodiments, the implementation of formula I, m is 1, n is 1 and p is 1, so a is represented by formula 2

where G, R⁶, R⁷and R⁸such as here defined.

In some embodiments, the implementation of the formula 2 R^aand R^brepresent N.

In some embodiments, the implementation of the formula 2 R^cand R^drepresent N.

In some embodiments, the implementation of the formula 2 R⁵represents H or ethyl.

In some embodiments, the implementation of the formula 2 R⁶represents H or ethyl.

In specific embodiments, implementation And represents

.

In additional embodiments, implementation And selected from the structures:

In additional embodiments, implementation And represents

.

In specific embodiments, implementation And selected from:

.

In specific embodiments, implementation And represents

.

In some embodiments, the implementation of the salt is a "pharmaceutically acceptable salt", which, unless otherwise indicated, includes salts which retain the biological effectiveness of the free acid or free base of a specific connection and do not have undesirable biological or other effects.

The compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be used as intermediates for obtaining and/or purifying compounds of formula I and/or for separating enantiomers of compounds of formula I.

The SYNTHESIS of COMPOUNDS of FORMULA I

Connections this is the invention it is possible to synthesize such ways, that include processes analogous to well-known in chemistry, especially in light of the descriptions given here. Source materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, PCs Missouri), Alfa Aesar (ward hill, iminnesota), or TCI (Portland, PCs Oregon), or easily determined by methods well known to specialists in this field (for example, they are obtained by methods generally described in [Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, N.Y. (1967-1999 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including the application (also available from the online database Beilstein)].

For illustrative purposes in schemes 1-8 shows a General method of obtaining the compounds of the present invention, as well as key intermediates. For a more detailed description of the individual stages of the reactions, see examples below. Specialists in this field understand that for the synthesis of compounds according to the invention it is possible to use other synthetic way. Although the specific source materials and reagents shown in the diagram and described below, you can easily replace the original substances and reagents to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds obtained by the methods described below can be further mo is inficirovanyh in the light of the present description using traditional methods of chemistry, well-known specialists in this field.

Scheme 1

where: Reducing agent is a reducing agent,

Deprotection - unprotect,

Deprotection and optional functionalization - removing protection and optional functionalization.

Scheme 1 shows a method of obtaining a compound 9 of formula I, where p is 1; R^aand R^brepresent H; R², R^2a, R¹, R^1a, R³, R⁵, R⁶, R^c, R^d, m, and n are defined herein; a Pg and Pg' are aminosidine groups with mutually exclusive conditions removal (e.g., Pg=Boc and Pg'=Cbz - see, for example, "Protective Groups in Organic Synthesis ' by Greene and Wuts, Wiley-Interscience, third edition, Chapter 7). Reductive amination involving amine 2 and aldehyde 1 in standard conditions, such as NaBH(SLA₃)/Asón at a temperature of from 0 to 50°C gives a substituted amine 3. The acylation obtained substituted amine substituted 3-arylpiperazines 4 in the presence of a base (such as base Chunga) at a temperature of from -20 to 100°C gives a protected piperazine 5. The removal of this protective group (Cbz group, for example, by hydrogenolysis, etc.) gives the piperazine 6. Processing piperazine 6 halogenated pyrimidine 7 at a temperature of from 25 to 250°C. and/or at high pressure and/or under the action of microwave radiation provides an intermediate compound 8. Removing the protection of the amino group (In the group, for example, by the action of HCl in dioxane at a temperature from 0°C to 50°C) and final optional functionalization of amine (e.g., alkylation, reductive amination or acylation under standard conditions for the introduction of new substituents) gives the final compound (9). If required, their respective analogs can then be subjected to separation and to receive individual enantiomers.

Scheme 2

where: Deprotection - unprotect,

Optional functionalization is an optional functionalization,

Base - base

Oxidative - oxidative cleavage

Reduction recovery

Activation - activation.

Figure 2 shows the method of obtaining connection 20 of the formula I, where R¹, R²and R^2arepresent hydrogen; R^1arepresents Me, a R³, R⁵, R⁶, R^a, R^b, R^c, R^d, m, n and p are such as defined here. According to scheme 2, bromination of (+)-pulegone 10 bromine gives dibromide 11. Processing dibromide 11 base, such as ethoxide sodium, gives poligrat 12. Oxidative cleavage of polygenta 12, for example, by ozonolysis at low temperature, followed by treatment with a reducing agent (e.g., Zn) or by using NaIO₄/OsO₄at temperatures from 5°C to 50°C), gives ketoester 13. Processing keeeper 13 thiourea in the presence of the evidence, such as KOH in ethanol, with subsequent restoration of mercaptopropyl under standard conditions (for example, Raney Nickel as a catalyst in ammonia) gives hydroxypyrimidine 16. Activation of compound 16 (for example, halogenoalkane) action, for example, POCl₃or SOCl₂at a temperature of from -20 to 100°C with getting chloropyrimidine network ready functionalization pyrimidine-cyclopentane unit 17. Substitution of the leaving group by the action of a suitable protected/substituted piperidine 18 at a temperature of from 0 to 150°C gives the piperidine 19. Removing the protection of the amino group (BOC group, for example, by the action of HCl in dioxane at a temperature from 0 to 50°C) and final optional functionalization of amine (e.g., alkylation, reductive amination or acylation to introduce new substituents) gives final connection 20. If required, their respective analogs can then be subjected to separation and to receive individual enantiomers.

Scheme 3

where: Deprotection - unprotect,

Optional functionalization is an optional functionalization,

Oxidative - oxidative cleavage

Reduction recovery

Activation - activation

Hydrolysis - hydrolysis.

Figure 3 illustrates the method of obtaining connection 29 of the formula I, where R²HE is a, R^2arepresents N, the R ¹, R^1a, R³, R⁵, R⁶, R⁷, R^a, R^b, R^c, R^d, m, n and p are defined here. According to the scheme 3 processing keeeper 21 thiourea in the presence of a base such as KOH in ethanol, with subsequent restoration of mercaptopropyl under standard conditions (for example, Raney Nickel as a catalyst in ammonia) gives hydroxypyrimidine 23. Activation (e.g., halogenoalkane) hydroxypyrimidine 23 under standard conditions (for example, by the action of POCl₃) gives 4-halogenopyrimidines 24. Oxidation of 4-chloropyrimidine 24 oxidant, such as m-SRV or hydrogen peroxide, gives N-oxide 25. Rearrangement of N-oxide 25 acetic anhydride gives the intermediate connection 26. The connection 26 is then hydrolized (for example, by the action of LiOH or NaOH at a temperature of from 0 to 50°C) and get the alcohol 27. The connection 27 is then subjected to interaction with the desired substituted piperazine 18 in accordance with the methodology described in scheme 1, and get a connection 28. If the connection 29 should be optional functionalization, at this stage, the alcohol 28 can be protected (for example, TBS group), in order to prevent possible complications. The removal of the protective group (Pg) connection 28, for example, using an acid (for example, TFU at a temperature of from -20 to 50°C) in the case of the BOC group, and the subsequent optional functionalization of the freedoms of the CSOs amine (for example, alkylation, acylation, reductive amination, and the like) under standard conditions to give a fully functionalized compound 29. The obtained compound 29 can also be split to get individual diastereoisomers using either chiral separation, the standard organization of the achiral separation (for example, column chromatography, HPLC, SCGH etc.), recrystallization, or derivatization.

Scheme 4

where: Deprotection - unprotect,

Optional functionalization is an optional functionalization,

Activation - activation.

Scheme 4 shows an alternative method of obtaining connection 32 of the formula I, where R²and R^2arepresent H, a R¹, R^1a, R³, R⁵, R⁶, R⁷, R^a, R^b, R^c, R^d, m, n and p are defined here. According to the scheme 3 amination of keeeper 21 using ammonium Sinton network 30. The formation of pyrimidine, for example, using ammonium formate in the presence of formamide at a temperature from 0°C to 250°C, and/or at high pressure, and/or the action of microwave radiation gives the bicyclic product 23. Activation of compound 23 using, for example, POCl₃or SOCl₂gives activated pyrimidine, and the substitution of the leaving group by the action of a suitable protected/substituted piperidine 18 in temp is the temperature from 0 to 150°C gives the piperidine 31. Removing protection from amine group (BOC group, for example, by the action of HCl in dioxane at a temperature from 0 to 50°C) and final optional functionalization of amine (e.g., alkylation, reductive amination or acylation to introduce new substituents) gives the final connection 32. If required, their respective analogs can then be subjected to separation and to receive individual enantiomers.

Scheme 5

where: Deprotection - unprotect,

Optional functionalization is an optional functionalization.

Scheme 5 shows a method of obtaining a connection 35 of the formula I, where R²represents fluorine, R^2arepresents hydrogen, a R¹, R^1a, R³, R⁵, R⁶, R⁷, R^a, R^b, R^c, R^d, m, n and p are defined here. According to scheme 5, the processing of the alcohol 33 fluorinating agent such as DAST, at a temperature of from -78 to 100°C, gives ftoroproizvodnykh 34. Removing the protection of the amino group (BOC group, for example, by the action of HCl in dioxane at a temperature from 0 to 50°C) and final optional functionalization of amine (e.g., alkylation, reductive amination or acylation to introduce new substituents) gives final connection 35. If required, their respective analogs can then be subjected to separation and to obtain the individual enantiomers.

Scheme 6

where: Deprotection - unprotect.

Scheme 6 shows a method of obtaining a connection 39 of the formula I, where p is 0; NR⁵R⁶is a group that Amin could not be further allerban compound 4; and R², R^2a, R¹, R^1a, R³, R⁵, R⁶, R⁷, R^a, R^b, R^c, R^d, m, and n are defined here. The acylation of substituted amine 36 substituted by arylpiperazines 4 in the presence of a base (such as base Chunga) at a temperature of from -20 to 100°C gives a protected piperazine 37 (Pg = protective group). The removal of this protective group (BOC group, for example, by the action of HCl in dioxane for Cbz groups by hydrogenolysis, etc.) gives the piperazine 38. Processing of the received piperazine 38 halogenated pyrimidine 7 at a temperature of from 50 to 250°C. and/or at high pressure and/or under the action of microwave radiation gives the product 39. If you want, its corresponding analogs can then be subjected to separation and to receive individual enantiomers.

Scheme 7

where: Deprotection - unprotect,

Optional functionalization is an optional functionalization.

Scheme 7 shows an alternative education connection (44) of the formula I, where R², R^2a, R¹, R^1a, R³, R⁵, R 6, R⁷, R^a, R^b, R^c, R^d, m, p and n are defined here, and Pg and Pg¹represent protective groups with mutually exclusive conditions removal (for example, groups BOC and Cbz). The acylation of substituted amine 40 substituted by arylpiperazines 4 in the presence of a base (such as base Chunga) at a temperature from -20°C to 100°C gives a protected piperazine 41 (Pg = protective group). The removal of this protective group (for example, the BOC group by the action of HCl in dioxane or Cbz group by hydrogenolysis) gives the piperazine 42. Processing of the received piperazine 42 halogenated pyrimidine 7 at a temperature of from 50°C to 250°C and/or at high pressure or under the influence of microwave radiation provides an intermediate connection 43. Remove aminosidine group (for example, the BOC group by the action of HCl in dioxane at a temperature from 0 to 50°C) and subsequent optional functionalization (e.g., alkylation, reductive amination or acylation to introduce new substituents) gives end connection 44. If required, these corresponding analogs can then be subjected to separation to obtain an individual enantiomers.

Scheme 8

where: Deprotection - unprotect,

Optional functionalization is an optional functionalization,

Protection,

Triphosgene - triphosgene.

Figure 8 on the azan alternative way to obtain a connection 29 of the formula I, where R²is a HE; R²⁸represents H; R¹, R^1a, R³, R⁵, R⁶, R⁷, R^a, R^b, R^c, R^d, m, p and n are defined herein; a Pg and Pg' are protective groups with mutually exclusive conditions of their removal (e.g., groups Boc and TBS, see, for example, 'Protective Groups in Organic Synthesis' by Greene and Wuts, Wiley-Interscience). According to scheme 8 connection 45 is subjected to interaction with the desired substituted piperazine 46 according to the method described in scheme 1, for connection 47. Protection of the resulting alcohol 47 (for example, a group of TBS using TBSOTf in the presence of an amine base, such as base Chunga) gives compound 48. Remove aminosidine group [for example, using an acid (for example, TFU at temperatures from -20°C to 50°C) in the case of the BOC group] gives the free amine 49. The process of joining 49 equivalent of phosgene (such as triphosgene) gives the activated intermediate connection 50, and subsequent treatment with the amine 51 in the presence of a base (for example, the base Hunga at temperatures from -50°C to 100°C) gives the urea 52. Remove reintroduced to the connection 52 aminosidine group (Pg) in conditions that are known not to affect hydroxyamino group (Pg') (for example, TFU at temperatures from -50°C to 30°C for a group Vos), and subsequent optional functionalization free the aqueous amine (for example, alkylation, acylation, reductive amination, and the like) under standard conditions to give a fully functionalized compound 53. Finally, remove hydroxyamino group (for example, in the case of TBS group action of a source of fluoride ion, such as TBAF, at temperatures from -50°C to +50°C) gives the target compound 54. The compound obtained 54 can also be split to get the individual diastereomers by either chiral separation, the standard organization of the achiral separation (for example, column chromatography, HPLC, SCGH etc.), recrystallization or by derivatization method.

Similar methods can also be provided (without stages of protection of alcohol/unprotect) for compounds where R²represents H or F instead of IT.

Accordingly, another object of the invention relates to a method for producing compounds of formula I, including:

(a) interactions of the compounds of formula

,

where R¹, R^1a, R²and R^2asuch as defined here, a Hal represents halogen,

with the compound of the formula

,

where G, R³, R^c, R^dn, m and p are, as defined here, and Pg represents a protective group, such as defined here, the subsequent removal of the protection and optional the second functionalization with obtaining the compounds of formula I;

(b) activation of the compounds of formula

,

where R¹and R^1asuch as defined here,

action POCl₃or SOCl₂followed by a substitution reaction with the compound of the formula

,

where G, R³, R^c, R^dn and m are such as defined here, and Pg represents a protective group, such as defined here,

with the subsequent removal of the protection and optional functionalization that gives compound of formula I; or

(C) the interaction of the compounds of formula

,

where R¹, R^1aand R³such as defined here, and Pg' is a protective group as defined here,

with the compound of the formula

,

where G, R^a, R^b, R^c, R^dn, m and p are, as defined here, and Pg represents a protective group as defined here, with the subsequent removal of the protection and optional functionalization, which gives the compound of formula I.

Upon receipt of the compounds of formula I may be required to protect remote functional groups (e.g., primary or secondary amines and the like) of the intermediate compounds. The need for such protection may vary depending on the nature of remote functional groups and ways of gaining the. Suitable aminosidine group (NH-Pg) include acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl (VOS), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc). The need for such protection is easily determined by the person skilled in the art. General description of the protective groups and their applications, see .W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

SEPARATION METHODS

Compounds of the present invention can have one or more asymmetric centers; therefore, such compounds can be obtained in the form of individual (R)- or (S)-stereoisomers or as mixtures thereof. If not specified, it is understood that the description or title of a specific connection in the description and claims includes both individual enantiomers and diastereomers and their mixtures, racemic or other. Accordingly, the present invention also includes all such isomers, including diastereomeric mixture, pure diastereomers and pure enantiomers of the compounds of the present invention. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity.

It may be advantageous to separate reaction products from one another and/or from starting materials. Target products of each stage or series of stages separated and/or purified (hereafter R is sdelat) to the desired degree of homogeneity methods conventional in the art. Typically, these methods of separation include multiple extraction, crystallization from a solvent or mixtures of solvents, distillation, sublimation or chromatography. Chromatography may include any species, including, for example, chromatography with reversed phase and normal phase; exclusion chromatography; ion exchange chromatography; methods and apparatus for liquid chromatography high, medium and low pressure; small-scale analytical chromatography; chromatography with pseudoviruses layer (MPD) and preparative thin-layer chromatography, thick-layer chromatography, and methods small-scale thin-layer chromatography, flash chromatography. The person skilled in the art will apply the same methods that likely will help to achieve the desired separation.

Diastereomer mixture can be divided into individual diastereomers on the basis of differences in their physico-chemical properties of methods that are well known. specialists in this field, such as chromatography and/or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomer mixture interaction with an appropriate optically active compound (e.g., chiral auxiliary reagent, such as a chiral alcohol or chlorine is the acid anhydride of Mosera), separation of the diastereomers and converting (e.g., hydrolysis) of individual diastereoisomers in the corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC column.

Individual stereoisomer, for example enantiomer is essentially not containing its stereoisomer, can be obtained by separation of the racemic mixture using a method such as formation of diastereomers using optically active disintegrating agents [Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302]. Racemic mixtures of chiral compounds according to the invention can be divided and highlight any suitable method, including: (1) formation of ion diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivateservlet reagents, separation of the diastereomers and converting into pure stereoisomers, and (3) separating essentially pure or enriched stereoisomers directly in the chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

According to the method (1) diastereomeric salt can be obtained by interaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetric compounds containing acidic functional groups such as carboxylic acid and sulfonic acid. Separation of the diastereomeric salts can be induced by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds accession of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can lead to the formation of diastereomeric salts.

According to an alternative method (2) substrate, which should be divided, is subjected to the interaction with one enantiomer of chiral compounds, to form diastereomer pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p.322). Diastereomers connection can be formed by the interaction of asymmetric connections with enantiomerically pure derivateservlet reagents such as mental derivatives; subsequent separation of the diastereomers and hydrolysis results in pure or enriched enantiomer. The method of determining optical purity involves obtaining chiral esters, such as metalowy ether, for example, (-) methylchloroform, in the presence of a base, or an ester of Mosera, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47:4165), racemi eskay mixture and analysis ¹H-NMR spectrum in the presence of two atropisomers enantiomers or diastereomers. Stable diastereomers atropisomers compounds can be divided to allocate chromatography with normal or reversed phase, acting in accordance with the methods of separation atropisomers naphthyl-isoquinolines (WO 96/15111).

According to the method (3) racemic mixture of two enantiomers can be divided chromatography using chiral stationary phases Chiral Liquid Chromatography" (1989) W.J.Lough, Ed., Chapman and Hall, New York; Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods such as optical rotation and circular dichroism, which are used to distinguish between other chiral molecules with asymmetric carbon atoms.

Compounds of the present invention may also exist in different tautomeric forms, and all such forms are covered by the scope of the present invention. For example, proton tautomers (also known as prototroph the tautomers) include interconversion via migration of a proton, such as keto-enol and Imin-Tamina isomerization. Valence tautomers include interconversion by reorganizing some of the bonding electrons.

In the structures shown here, in cases where not specified stereochemistry of any specifically what about the chiral atom, considered and included as the compounds according to the invention are all stereoisomers. When the stereochemistry shown a solid wedge or a dashed line representing a particular configuration, then stereoisomer is thus specified and defined.

INTRODUCTION AND PHARMACEUTICAL COMPOSITIONS

Compounds according to the invention can be entered in any convenient way, the relevant condition being treated. Suitable routes of administration include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, local (including literal and sublingual), vaginal, intraperitoneally, intra-lungs and intranasal.

Connections can be entered at any time convenient to introduce the form, for example in the form of tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain commonly used for pharmaceutical components, such as diluents, carriers, pH modifiers, sweeteners, fillers and additional active agents. If you want parenteral administration, the composition must be sterile and prepared in the form of a solution or WM is enzie, suitable for injection or infusion.

A typical composition is prepared by mixing the compounds of the present invention and the substrate or excipient. Suitable carriers and excipients are well known to experts in the art and are described, for example, in [Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (8^thEd. 2004); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy (20^thEd. 2000); and Raymond C. Rowe, Handbook of Pharmaceutical Excipients (5^thEd. 2005)]. The compositions may also include one or more buffers, stabilizers, surfactants, moisturizers, lubricants, emulsifiers, suspendresume agents, preservatives, antioxidants, substances which impart opacity, substances imparting flowability, processing AIDS, colorants, sweeteners, flavoring agents, substances imparting taste and aroma, thinners and other additives, providing attractive form of the medicinal product (i.e. compounds of the present invention or pharmaceutical composition) or to facilitate the manufacture of the pharmaceutical product (i.e. medication).

One variant of implementation of the present invention includes a pharmaceutical composition comprising a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt. In an additional embodiment, assests the deposits present invention relates to pharmaceutical compositions, containing the compound of formula I, or a stereoisomer or pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or excipient.

The treatment of COMPOUNDS of FORMULA I

Compounds of the present invention can be used as a preventive or therapeutic agent for the treatment of diseases or disorders mediated by modulation or regulation of AKT-protein kinases, tyrosine kinases, additional serine/trainingin and/or kinases with dual specificity. State-mediated AKT-protein kinase, which can be treated by the methods of the present invention include inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological and dermatological diseases and disorders, but are not limited to.

In one embodiment, the specified pharmaceutical composition intended for the treatment of hyperproliferative disorders, including cancers of the following categories: (1) cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2) related to the lung: bronchus cancer (squamous cell, undifferentiated small cell, undifferentiated both, adenocarcinoma), alveolar (bronchiolar) carcinoma, adenoma of the bronchus, Sark is mA lymphoma, chondromalacia hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer; (3) related to gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insuloma, glucagonoma, ulcerogenic adenoma of the pancreas, carcinoid tumors, Vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, sarcoma Galoshes, leiomyomata, hemangioma, lipoma, neurofibroma, fibroma), the colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); (4) (relating to the genitourinary tract: kidney adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), the bladder and the urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate gland (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal cancer, teratocarcinoma, horiokartsinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); (5) related to liver hepatoma (hepato hepatocellular carcinoma), the cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepato hepatocellular adenoma, hemangioma; (6) related to the bones: osteoplastica sarcoma (osteomark the mA), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulation sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteo-cartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxoid, osteoid osteoma and giant cell tumors; (7) related to the nervous system: the skull (osteoma, hemangioma, granulomas, xanthoma, distortive ostit), to the soft meninges (meningioma, meningococcemia, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], multiform glioblastoma, oligodendroglioma, Sanoma, retinoblastoma, congenital tumors), spinal cord (neurofibroma, meningioma, glioma, sarcoma); (8) gynecological related to the uterus (endometrial carcinoma), cervix (cervical cancer, precancerous cervical dysplasia), ovaries (carcinoma of the ovary [serous cystadenocarcinoma, the mucinous cystadenocarcinoma, unspecified carcinoma localization], granulicatella tumors, tumors of Sertoli-madigosky cell seminoma of the ovary, malignant teratoma), to the vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), the vagina (clear carcin the mA squamous cell carcinoma, botryoidal sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (9) hematologic: related to blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-jackinsky lymphoma [malignant lymphoma]; (10) related to the skin: running melanoma, malignant melanoma, basal cell cancer, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, angioma, dermatofibroma, keloids, psoriasis; (11) related to the adrenal glands: neuroblastoma; (12) related to the breast: metastatic breast cancer; adenocarcinoma of the breast; (13) related to the colon; (14) related to the oral cavity; (15) leukemia, hairy cell; (16) related to head and neck; (17) and others, including refractory metastatic tumor; Kaposi's sarcoma; syndrome Banana-the time zone; and disease Caudina or disease, Lhermitte-Duclos, among other types of hyperproliferative diseases.

Compounds and methods of the present invention can also be used to treat diseases and conditions, such as rheumatoid arthritis, osteoarthritis, Crohn's disease, angiofibroma, g is asnie disease (for example, vascularization of the retina, diabetic retinopathy, age-related degeneration yellow spots dystrophy yellow spots and the like), multiple sclerosis, obesity, restenosis, autoimmune diseases, allergies, asthma, endometriosis, atherosclerosis, stenosis of the venous graft, peri-anastomosis stenosis prosthetic graft, prostatic hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, the formation of scar tissue (and may promote wound healing), multiple sclerosis, inflammatory bowel disease, infections, particularly bacterial, viral, retroviral or parasitic infection (by increasing apoptosis), lung disease, cancer, Parkinson's disease, graft rejection (as immunosuppressor), septic shock, etc.

Accordingly, another object of the present invention relates to a method of treatment of diseases or conditions in mammals mediated AKT-protein kinases, including the introduction of specified mammal one or more compounds of the formula I or its pharmaceutically acceptable salt or prodrug in amounts effective for the treatment or prevention of the specified diseases.

In the case of cancer, an effective amount is cartonnage tools can reduce the number of cancer cells, to reduce the size of the tumor, inhibit (i.e. somewhat slow and preferably stop) infiltration of cancer cells in the peripheral organs, to inhibit (i.e. somewhat slow and preferably stop) metastasis of tumors, to inhibit, to some extent, tumor growth and/or relieve to some extent one or more symptoms associated with cancer. On the extent to which the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. The effectiveness of cancer therapy can be measured by evaluating, for example, the time to disease progression (TTP) and/or determining the response rates (RR).

The amount of the compounds of formula I, which will correspond to such an amount will vary depending on such factors as the particular compound, disease stage and severity, characteristics (e.g., weight) of the mammal that needs treatment, but nevertheless it can usually be determined by a person skilled in the technical field.

The present invention also relates to compounds of formula I for use in the treatment of conditions mediated AKT-protein kinase.

An additional object of the invention is the use of compounds of formula I for proceduretesting drug therapy, such as the treatment or prevention of conditions mediated AKT-protein kinase.

COMBINATION THERAPY

Compounds of the present invention, their stereoisomers and pharmaceutically acceptable salts can be used alone or in combination with other therapeutic means for the treatment. Compounds of the present invention can be used in combination with one or more additional drugs, for example anti-inflammatory agent, which has a different mechanism of action. Preferably, when the second connection pharmaceutically combined composition or scheme, the introduction has a complementary activity, complement activity of the compounds of the present invention, so that connections do not have negative effects on each other. Accordingly, such compounds are included in combination in amounts that are effective for the intended purposes. Connections can be entered together in a single pharmaceutical composition or separately, with the introduction of individually may occur simultaneously or sequentially in any order. This gradual introduction can occur over short or long periods of time.

Examples of chemotherapeutic agents include erlotinib (Tarceva^®, Genentech,Inc./OSI Pharm.), trastuzumab (Herceptin^®, Genentech, Inc.); bevacizumab (Avastin^®, Genentech, Inc.); rituximab (Rituxan^®, Genentech, Inc./Biogen Idee, Inc.), bortezomib (Velcade^®Millennium Pharm.), fulvestrant (Faslodex^®, AstraZeneca), sutent (SU11248, Pfizer), letrozole (femara^®, Novartis), imatinib mesilate (Gleevec^®, Novartis), PTK787/ZK 222584 (Novartis), oxaliplatin (Eloxatin^®, Sanofi), 5-FU (5-fu), leucovorin, rapamycin (Sirolimus, Rapamune^®, Wyeth), lapatinib (GSK572016, Glaxo Smith Kline), lapatinib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib (IRESSA^®, AstraZeneca), AG1478 effect, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and Cytoxan^®cyclophosphamide, Adriamycin^®(doxorubicin), Taxol^®(paclitaxel; Bristol-Myers Squibb, Princeton, PCs, new Jersey, Abraxas^®(does not contain cremophor) and Takata^®(docetaxel; Rhône-Poulenc Rorer, Antony, France).

The FINISHED PRODUCT

Another variant embodiment of the invention relates to a finished product or "set"containing substances, applicable to the treatment of the diseases described above. In one embodiment, the kit includes a container comprising a compound of the present invention. Suitable containers include, for example, bottles, vials, syringes, blister packs and the like, the Container can be made of many materials such as glass or plastic. Container m which may contain the compound of the present invention or its composition, which is effective for the treatment of this condition, and may have a sterile entrance access (for example, the container may be a bag of solution for intravenous injection or bottle stopper, which can be pierced by a needle for subcutaneous injection).

In addition, the kit may contain a label or leaflet on the container or package. In one embodiment of the invention on the label or package insert indicates that the composition comprising the compound according to this invention, can be used for the treatment of diseases mediated, for example, AKT-kinase. On the label or the liner may also be mentioned that the composition can be used for treating other diseases.

In some embodiments, the implementation sets suitable for the delivery of solid oral forms of the compounds of the present invention, such as tablets or capsules. Such a kit preferably includes a number of standard dosage forms. Such kits can include a map containing a dosage in the order of their intended use. An example of such a set is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packing standard pharmaceutical dosage forms. If you set provide a "reminder", such as the er, in the form of numbers, letters, or other marks or calendar-liner, which marked the days of the regimen when you can enter the dose.

According to another variant of the invention, the kit may contain (a) a first container which contains a compound of the present invention; and (b) a second container containing a second pharmaceutical composition that contains a second connection applicable for the treatment of diseases mediated by AKT kinase. As an alternative or Supplement the kit may include a third container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution and dextrose. The kit can optionally include other substances and materials that are necessary from a commercial point of view and from the point of view of the user, including other buffers, diluents, filters, needles and syringes.

In addition, the kit may contain instructions for administering the compounds of the present invention and the second pharmaceutical composition, if available. For example, if the set contains a first composition comprising a compound of formula I, and the second pharmaceutical composition, the kit can further comprise instructions for simultaneous, sequential or separate introduction of the first and vtoro the pharmaceutical compositions to a patient, who need it.

In some other embodiments of the invention, where the set contains the composition of the compounds of formula I and a second therapeutic agent, the kit may include a container for the separate storage of compositions such as a divided bottle or a divided package of foil, however, the separate compositions may also be located inside United, not divided into parts of the container. In some embodiments, the implementation of the kit contains instructions for the implementation of separate components. Especially preferred is a form of set, in which the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) and with different time intervals, or such a form that requires titration of the individual components of the combination of the treating physician.

Thus, an additional object of the present invention is a kit for the treatment of disorders or diseases mediated Akt kinase, and the specified set contains a) a first pharmaceutical composition comprising a compound according to the invention or its pharmaceutically acceptable salt; and b) instructions for use.

In some embodiments of the invention the kit further comprises (C) a second pharmaceutical composition, which contains the which connection, suitable for treating disorders or diseases mediated by AKT kinase. In a particular embodiment of the invention, containing a second pharmaceutical composition, the kit further comprises instructions for simultaneous, sequential and separate introduction of these first and second pharmaceutical compositions to a patient in need. In some embodiments of the invention are specified first and second pharmaceutical compositions are in separate containers. In other embodiments, the implementation of these first and second pharmaceutical compositions are in the same container.

Although the compounds of formula I are primarily valuable as therapeutic agents for use in mammals, they are also applicable in all cases when you need to regulate AKT-protein kinases, tyrosinekinase, additional serine/threonine kinases and/or protein kinases with dual specificity". Thus, they are useful as pharmacological standards for use in the development of new biological tests and the search for new pharmacological agents.

The activity of the compounds of the present invention in relation to the ACT of kinases, tyrosinekinase, additional serine/threonine kinases and/or protein kinases with dual specificity" can be evaluated in vitro, in vivo or in kletochnykh. The in vitro tests include assays that determine inhibition of kinase activity. Alternating in vitro assays to quantitatively determine the ability of the inhibitor to bind to the kinase/e, which can be measured or by introducing a radioactive label in the inhibitor prior to binding, secretion of complex inhibitor/kinase and measuring the amount of bound radioactive label, or conducting competitive analysis, where new inhibitors are incubated with a known radio. These and other tests applicable in vitro and in cell cultures are well known to specialists in this field of technology.

Although the invention is described and illustrated with a certain degree of specificity, it is understood that this description is made only by way of examples, and numerous changes in the combination and organization of parts may be made by specialists in this field, without going beyond the nature and scope of the invention as claimed below.

BIOLOGICAL EXAMPLES

Analysis of AKT-1 kinase

The activity of compounds described in this invention, it is possible to define the following analysis of kinases, which uses fluorescence polarization measures the phosphorylation of a peptide (containing the fluorescent label) primary human recombinant active AKT-1 using a commercially available set of IMAP.

Labeled with fluorescein AKT-substrate (Crosstide) has the sequence (F1)-GRPRTSSFAEG. The working solution (20 μm) was prepared in 1× IMAP buffer for the reaction.

Used tablets include tablet Costar 3657 (382-hole, made of polypropylene and has a white v-shaped bottom), which is used for cultivation of connections and obtain a mixture of compound-APR. Analysis tablet is a Packard ProxyPlate™-384 F.

Used AKT-1 prepared from primary human recombinant AKT-1, which activate PDK1 and MAP kinase 2.

For analysis prepare working solutions of the compounds (10 μm) in DMSO. Working solutions and the control solution compounds are serially diluted 1:2 nine times in DMSO (10 μl compound + 10 μl DMSO) and receive a 50× serial dilution to the desired interval for the Les doses. Then 2,1-ál aliquots of the compounds in DMSO are transferred to the tablet Costar 3657 containing 50 µl of 10.4 μm solution of ATP in 1× IMAP buffer for the reaction containing 1 mm DTT. After thorough mixing a 2.5-μl aliquots transferred to the tablet ProxyPlate™-384 F.

The analysis initiated by addition of 2.5-µl aliquot of a solution containing 200 nm of the peptide substrate with a fluorescent label and 4 nm AKT-1. Tablet centrifuged for 1 min at 1000g and incubated for 60 minutes at ambient temperature. Then the reaction quenched by addition of 15 μl of a solution to bind, again centrifuged and incubated for 30 minutes at ambient temperature before reading the counter Victor 1420 Multilabel HTS configuration for measuring the polarization of the fluorescence.

Compounds of examples 1-20 were tested using the above analysis, it was shown that their IC₅₀is less than 1 micron.

PREPARATIVE EXAMPLES

To illustrate the present invention in the application included the following examples. However, it should be borne in mind that these examples do not limit the invention, but only to illustrate the proposed method of carrying out the invention. Specialists in the art will understand that the described chemical reaction can be easily adapted to obtain a number of other compounds according to the invention, and alternative methods according to the teachings of the compounds of the present invention are considered covered by the scope of the present invention. For example, the synthesis of compounds of the present invention, not shown in the examples, can be successfully performed by modifications of the synthesis, obvious to a person skilled in the art, for example, by appropriate protection of interfering groups, use other suitable reagents known in the art, different from those described here, and/or by customary modifications of reaction conditions. Alternatively, other reactions described herein or known in the art, will be considered as applicable for other compounds according to the invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise noted. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise stated. Tetrahydrofuran ("THF"), dichloromethane (DCM), toluene, and dioxane were purchased from Aldrich company in sealed bottles and used in the state of delivery.

The reactions described below, is usually carried out under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise noted) in anhydrous solvents, and the reaction flask is usually fitted with a rubber septum for the introduction of substrates and reagents via syringe. Glassware is dried in an oven and/or when heat is assured.

¹H-NMR spectra were recorded on the instrument Varian, with an operating frequency of 400 MHz.¹H-NMR spectra were recorded for solutions of compounds in CDCl₂CD₃OD, D₂O or d₆-DMSO (given in ppm), using as a standard tetramethylsilane was (is 0.00 ppm) or residual solvent (CDCl₃: to 7.25 ppm; CD₃OD: and 3.31 ppm; D₂O: 4,79 ppm; d₆-DMSO: 2,50 ppm). When describing the multiplicity of peaks using the following abbreviations: s (singlet), d (doublet), t (triplet), q (Quartet), m (multiplet), ush. (broadened), DD (doublet of doublets), dt (doublet of triplets). Constants of spin-spin interaction are given in Hertz (Hz), when they are listed.

Example 1

(R)-N-(2-amino-ethyl)-N-(4-Chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamide

Stage 1. Triacetoxyborohydride sodium (3.3 grams, to 15.4 mmol, 1.1 EQ.) added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl-2-aminoethylamino (4,5 ml, 28.5 mmol, 1.2 EQ.) and acetic acid (2.5 ml) in dichloroethane (20 ml). The reaction mixture was allowed to mix overnight and quenched with 0.5 M HCl solution (30 ml). The mixture is then once extracted with dichloromethane and added a saturated aqueous solution of sodium chloride. The precipitate is filtered off and dried, obtaining tert-butyl-2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%),MS (ESI) m/e (M+H ⁺) 285.

Stage 2. Benzyl-4-(chlorocarbonyl)piperazine-1-carboxylate (233 mg, 0.83 mmol) was added at room temperature to a solution of tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (235 mg, 0.83 mmol) and substrate Hunya (0.2 ml, 1.2 mmol, 1.5 EQ.) in dichloromethane (1.6 ml). The reaction mixture was allowed to mix overnight. Then the reaction mixture was concentrated, obtaining the crude product, which was purified column flash chromatography, giving benzyl-4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorbenzyl)carbarnoyl)piperazine-1-carboxylate as a foam (167 mg, 38%). MS (ESI) m/e (M+H⁺) 531.

Stage 3. A mixture of benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorbenzyl)carbarnoyl)piperazine-1-carboxylate (200 mg, 0.38 mmol) in a solution of KOH/Meon/N₂About (10 ml; prepared as the initial solution of 10 g of KOH, 50 ml Meon and 25 ml of H₂O) is stirred for 2 hours at 80°C. the Reaction mixture was extracted with EtOAc, dried over Na₂SO₄and concentrate under reduced pressure, obtaining tert-butyl-2-(N-(4-Chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate (132 mg, 89%). MS (ESI) m/e (M+H⁺) 397.

Stage 4. (R)-(+)-Pulegone (76,12 g, 0.5 mmol), anhydrous NaHCO₃(12.5 g) and anhydrous ether (500 ml) was placed in a round bottom flask with a volume of 1 L. the Reaction mixture was cooled in an ice bath under nitrogen atmosphere. Dropwise within 30 minutes pribavlyaetsya (25,62 ml, 0.5 mmol). The mixture is filtered and carefully add to NaOEt (21%, 412 ml, 1.11 mmol) under cooling in an ice bath. The mixture is stirred at room temperature overnight and then added 5% HCl (1 l) and ether (300 ml). The aqueous phase is extracted with ether (2×300 ml). The combined organic phase washed with water, dried and concentrated. The remainder is added to the heated solution of the hydrochloride semicarbazide (37.5 g) and NaOAc (37.5 g) in water (300 ml). Then add boiling ethanol (300 ml) and obtain a clear solution. The mixture is refluxed for 2.5 hours and then stirred at room temperature overnight. The mixture is treated with water (1 l) and ether (300 ml). The aqueous phase is extracted with ether (2×300 ml). The combined organic phase washed with water, dried and concentrated. The residue is purified by distillation in vacuum (73-76°C at 0.8 mm Hg)to give (2R)-ethyl-2-methyl-5-(propane-2-ilidene)cyclopentanecarboxylate (63 g, 64%).¹H NMR (CDCl₃, 400 MHz) δ of 4.13 (m, 2H), 3,38 (d, J=16 Hz, 0,5H), of 2.93 (m, 0,5H), 2,50-2,17 (m, 2H), up to 1.98 (m, 1H), 1,76 (m, 1H), 1,23 (m, 6N), of 1.05 (m, 6N).

Stage 5. (2R)-Ethyl-2-methyl-5-(propane-2-ilidene)cyclopentanecarboxylate (24 g, 0,122 mol) in ethyl acetate (100 ml) is cooled to -68°C with a mixture of dry ice/isopropanol. After the solution is passed ozonized oxygen (5-7 ft³/h O₂) for 3.5 hours. The reaction mixture is blown with nitrogen at room t is mperature to the disappearance of staining. The ethyl acetate is removed in vacuo, the residue is dissolved in acetic acid (150 ml) and cooled with ice water. Then add the powdered zinc (45 g). The solution is stirred for 30 minutes and then filtered. The filtrate is neutralized 2N NaOH solution (1.3 l) and NaHCO₃. The aqueous phase is extracted with ether (3×200 ml). The combined organic phases are washed with water, dried and concentrated, obtaining (2R)-ethyl-2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%).¹H NMR (CDCl₃, 400 MHz) δ is 4.21 (m, 2H), 2,77 (d, J=11.2 Hz, 1H), 2,60 (m, 1H), 2,50 is 2.10 (m, 3H), of 1.42 (m, 1H), 1,33 (m, 3H), of 1.23 (m, 3H).

Stage 6. KOHN (8,3 g, 147,9 mmol) in water (60 ml) was added to a solution mixture of (2R)-ethyl-2-methyl-5-oxocyclopentanecarboxylate (20 g, 117,5 mmol) and thiourea (9.2 grams, 120,9 mmol) in ethanol (100 ml). The mixture is refluxed for 10 hours. After cooling, the solvent is removed, and the residue is neutralized with concentrated HCl (12 ml) at 0°C. the mixture is Then extracted with DCM (3×150 ml). The solvent is removed, the residue is purified by chromatography on silica gel by elution with hexane/ethyl acetate (2:1) and receive (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (12 g, 56%). MS (APCI+) [M+H]⁺183.

Stage 7. The Raney Nickel (15 g) and NH₄OH (20 ml) was added to a suspension of (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (12 g, 65,8 mmol) in distilled water (100 ml). The mixture is of ipatt under reflux for 3 hours and then filtered. The filtrate is concentrated and receive (R)-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (9,89 g, 99%). MS (APCI+) [M+H]⁺151.

Stage 8. A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (5.8 g, 38,62 mmol) in POCl₃(20 ml) is refluxed for 5 minutes. Excess POCl₃removed in vacuo, and the residue is dissolved in DCM (50 ml). The mixture is then added to a saturated solution of NaHCO₃(200 ml). The aqueous phase is extracted with DCM (3×100 ml)and the combined organic phases are dried and concentrated. The residue is purified by chromatography on silica gel by elution with ethyl acetate, and receive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine (3,18 g, 49%).¹H NMR (CDCl₃, 400 MHz) δ 8,81 (s, 1H), 3,47 (m, 1H), 3,20 (m, 1H), 3,05 (m, 1H), 2,41 (m, 1H), 1,86 (m, 3H), 1,47 (m, 3H).

Stage 9. (R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine (46 mg, 0.27 mmol, 1.1 EQ.) added to a solution of tert-butyl 2-(N-(4-Chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate (100 mg, 0.25 mmol) and substrate Hunya (0.1 ml, 0.75 mmol, 3 EQ.) in acetonitrile (3 ml). The resulting mixture is heated at 80°C during the night. The reaction mixture was diluted with water and extracted with DCM, dried and concentrated, obtaining (R)-tert-butyl-2-(N-(4-Chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamido)ethylcarbamate (40 mg, 30%). MS (ESI) m/e (M+N⁺) 529.

Stage 10. Rast is the PR HCl in dioxane at 0°C was added to (R)-treat-butyl-2-(N-(4-Chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamido)ethylcarbamate (40 mg, of 0.075 mmol) in Meon (1 ml). The reaction mixture was stirred at 25°C for 1 hour. After removal of solvent the crude product is purified preparative HPLC and receive (R)-N-(2-amino-ethyl)-N-(4-Chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamide (32 mg, 90%). MS (ESI) m/e (M+N⁺) 429,2.¹H NMR δ=8,56 (s, 1H), δ=7.23 percent-7,56 (DD, 4H), δ=4,51 (s, 2H), δ=3,97-4,19 (m, 4H), δ=3,70 (m, 1H), δ=3,61 (m, 4H), δ=3,40-of 3.43 (t, 2H), δ=2,96 is 3.15 (m, 4H), δ=2,42 (m, 1H), δ=1,89 (m, 1H), δ=1,21-1,22 (d, 3H).

Example 2

(R)-N-(4-Chlorophenyl)-N-(2-(diethylamino)ethyl)-4-(5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamide

Stage 1. Acylpolyamines (130 g, 662 mmol) in EtOAc (900 ml) is cooled to -78°C in a bath of dry ice-isopropanol. The resulting mixture was subjected to ozonolysis to until the reaction mixture becomes purple. At this stage, stop the generation of ozone and the reaction mixture is removed from the bath with dry ice. After the reaction mixture was bubbled with oxygen until then, until it will become yellow in color. The reaction mixture was concentrated in vacuo and the resulting residue is dissolved in glacial acetic acid (400 ml). The solution is cooled to 0°C and gradually for 30 minutes was added Zn dust (65 g, 993 mmol), the mixture is then stirred for 2 hours and filtered through a layer of celite removal of Zn-dust. Acetic acid is the neutralized aqueous NaOH and NaHCO ₃to pH 7 and extracted with ether (3×800 ml). The combined organic layers washed with saturated aqueous sodium chloride, dried over MgSO₄concentrate and get (2R)-ethyl-2-methyl-5-oxocyclopentanecarboxylate liquid (107 g, 95%).

Stage 2. Ammonium acetate (240,03 g, 3113,9 mmol) was added to a solution of (R)-ethyl-2-methyl-5-oxocyclopentanecarboxylate (to 106.0 g, 622,78 mmol) in Meon (1.2 l). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 20 hours, after which the reaction is finished (according to TLC and HPLC). The reaction mixture was concentrated to remove the Meon. The resulting residue is dissolved in DCM, washed twice H₂O, once with a saturated aqueous solution of sodium chloride, dried (Na₂SO₄), filtered, concentrated and receive (R)-ethyl-2-amino-5-Methylcyclopentane-1-enecarboxylate (102 g, yield 97%) as oil. LC/MS (APCI+) m/z 170 [M+H]⁺.

Stage 3. A solution containing (R)-ethyl-2-amino-5-Methylcyclopentane-1-enecarboxylate (161,61 g, 955,024 mmol) and ammonium formate (90,3298 g, 1432,54 mmol) in formamide (303,456 ml, 7640,19 mmol) is heated to an internal temperature of 150°C and stirred for 17 hours. The reaction mixture is cooled and transferred to odnogolosy flask with a volume of 2 L. Then remove the excess of formamidine by distillation in high vacuum. As soon as formamidine stops Athanasia remaining peregonom Cuba oil was dissolved in DCM and washed with saturated aqueous sodium chloride (3×200 ml). United water, the washing water is extracted with DCM. The combined organic extracts dried (Na₂SO₄), filtered and concentrated. The obtained brown oil was dissolved in a minimum amount of DSM and the resulting solution was added using a separating funnel to a stirred solution of ether (about 5 volumes of ether to 1 volume of solution in DCM), which causes the formation of a brown precipitate. The precipitation is filtered off through a glass filter with an average pore size, washed with ether and removed. The filtrate is concentrated and rubbing with ether repeat two more times, then dried in high vacuum and receive (R)-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (93,225 g, yield 65,00%) as a paste-like substance. LC/MS (APCI-) m/z 149,2.

Stage 4. Clean POCl₃(463,9 ml, 5067 mmol) is slowly added through an addition funnel to a cooled to 0°C. a solution of (R)-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (152,2 g, 1013 mmol) in DCE (1.2 l). After completion of addition, the reaction mixture is heated to room temperature, then heated to boiling and stirred for 70 minutes. The reaction is complete (according to HPLC). The reaction mixture is cooled to room temperature and excess POCl₃extinguish 4 portions as follows: the reaction mixture was transferred into a separating funnel and poured dropwise into a beaker containing ice and a saturated solution of NaHCO ₃cooled in an ice bath. As soon as the addition of each portion of the reaction mixture is completed, the hydrated mixture is stirred for 30 minutes to ensure complete destruction of POCl₃before being transferred into a separating funnel. The mixture is transferred into a separating funnel and extracted twice with DCM. The combined extracts are dried (Na₂SO₄), filtered and concentrated. The crude product is purified on silica gel as follows: silica gel (1 kg) suspended in a mixture of hexane:ethyl acetate (9:1) on a glass filter with a volume of 3 l, silica gel precipitated in a vacuum, with sand on top. The crude product is loaded into a mixture of DCM/hexane, and carry out elution connection using flask with tap 1 liter in a vacuum. By-products with high Rf washed first, then eluted (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine (104,4 g, yield 61,09%) as oil.

Stage 5. 4-Chloroaniline (0.5 g, 3.9 mmol) was added to a solution of the hydrobromide of 2-bromo-N,N-diethylethanamine (1.12 g, 4.3 mmol) and N,N-diisopropylethylamine (2 ml, 11.7 mmol) in toluene (7.8 ml). The mixture is stirred at room temperature for 5 hours. The mixture is then diluted with EtOAc (30 ml) and a saturated solution of NaHCO₃(20 ml). The organic layer was washed with H₂About (1×20 ml), dried (Na₂SO₄), filtered, concentrated and receive 4-chloro-N-(2-(diethylamino)ethyl)be salamin in the form of oil, which is used without purification. MS (APCI+) [M+H]⁺227,3.

Stage 6. tert-Butyl-4-chlororespiration-1-carboxylate (0.97 g, 3.9 mmol) was added to a solution of 4-chloro-N-(2-(diethylamino)ethyl)benzenamine (884 mg, 3.9 mmol) and N,N-diisopropylethylamine (1.9 ml, 11.7 mmol) in DCM (8 ml). The reaction mixture is heated and refluxed for 20 hours. The mixture is cooled to room temperature, quenched with saturated solution of NH₄Cl (10 ml) and extracted with DCM (2×20 ml). The combined organic extracts dried (Na₂SO₄), filtered and concentrated. The crude product is purified by chromatography on silica gel and receive tert-butyl-4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbarnoyl)piperazine-1-carboxylate (311 mg, 18%). MS (APCI+) [M+H]⁺439,4.¹H NMR (CDCl₃, 400 MHz) δ 7.29 trend (d, J=8,8 Hz, 2H), to 7.09 (d, J=8,8 Hz, 2H), 3,70-3, 66 (m, 2H), 3.45 points-of 3.42 (m, 2H), 3,24-is 3.21 (m, 4H), 3,15-of 3.12 (m, 2H), 2,61-to 2.57 (m, 2H), 2,52 (kV, J=7.2 Hz, 4H), of 1.42 (s, N), 0,99 (t, J=7,2 Hz, 6N).

Stage 7. Triperoxonane acid (1 ml) was added to a solution of tert-butyl 4-(N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)carbarnoyl)piperazine-1-carboxylate (311 mg, 0.7 mmol) in DCM (5 ml). The mixture is stirred at room temperature for 3 hours and then concentrated in vacuo. The residue is dissolved in n-butanol (2 ml). Add N,N-diisopropylethylamine (0.5 ml, 3.6 mmol), then (R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopent[d]pyrimidine 113 mg, 0.84 mmol). The reaction mixture is heated at 80°C for 16 hours. The mixture is then diluted with H₂Oh and extracted with DCM (2×20 ml). The combined organic extracts dried (Na₂SO₄), filtered and concentrated. The crude product is purified preparative HPLC and get N-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-4-((R)-6,7-dihydro-5-methyl-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamide (39.9 mg, 12%). MS (APCI+) [M+H]⁺471,3.¹H NMR (CDCl₃, 400 MHz) δ 8,49 (s, 1H), 7,40-7,35 (m, 2H), 7,17-7,13 (m, 2H), 4,06-3,95 (m, 4H), of 3.77-3,70 (m, 2H), 3,51-3,44 (m, 1H), 3,39-to 3.02 (m, 11N), 2,42 of-2.32 (m, 1H). 1,88-to 1.82 (m, 1H), 1,33 (t, J=7.2 Hz, 6N)and 1.15 (d, J=6.8 Hz, 3H).

Example 3

N-(4-Chlorbenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamide

Stage 1. (R)-(+)-Pulegone (76,12 g, 0.5 mmol), anhydrous NaHCO₃(12.5 g) and anhydrous ether (500 ml) was placed in a round bottom flask with a volume of 1 L. the Reaction mixture was cooled in an ice bath under nitrogen atmosphere. Added dropwise bromine (25,62 ml, 0.5 mmol) over 30 minutes. The mixture is filtered and carefully add to NaOEt (21%, 412 ml, 1.11 mmol) in the bath, cooled by ice. The mixture is stirred at room temperature overnight and then added 5% aqueous HCl (1 l) and ether (300 ml). The aqueous phase is extracted with ether (2×300 ml). The combined organic phases are washed with water, with the shat and concentrate. The remainder is added to the heated solution of the hydrochloride semicarbazide (37.5 g) and NaOAc (37.5 g) in water (300 ml), then added boiling ethanol (300 ml) and obtain a clear solution. The mixture is refluxed for 2.5 hours and then stirred at room temperature overnight. The mixture is treated with water (1 l) and ether (300 ml). The aqueous phase is extracted with ether (2×300 ml). The combined organic phases are washed with water, dried and concentrated. The residue is purified by vacuum distillation (73-76°C at 0.8 mm Hg) and receive (2R)-ethyl-2-methyl-5-(propane-2-ilidene)cyclopentanecarboxylate (63 g, 64%).¹H NMR (CDCl₃, 400 MHz) δ of 4.13 (m, 2H), 3,38 (d, J=16 Hz, 0,5H), of 2.93 (m, 0,5H), 2,50-2,17 (m, 2H), up to 1.98 (m, 1H), 1,76 (m, 1H), 1,23 (m, 6N), of 1.05 (m, 6N).

Stage 2. (2R)-Ethyl-2-methyl-5-(propane-2-ilidene)cyclopentanecarboxylate (24 g, 0,122 mol) in ethyl acetate (100 ml) is cooled to -68°C with a mixture of dry ice/isopropanol. Ozonized oxygen (5-7 ft³/h O₂) bubbled through the solution for 3.5 hours. The reaction mixture is blown with nitrogen at room temperature until disappearance of the color. The ethyl acetate is removed in vacuo, the residue is dissolved in acetic acid (150 ml) and cooled with ice water. Then added zinc dust (45 g). The solution is stirred for 30 minutes and then filtered. The filtrate is neutralized 2N NaOH solution (1.3 l) and NaHCO₃. The aqueous phase extragere the ether (3×200 ml). The combined organic phases are washed with water, dried, concentrated and receive (2R)-ethyl-2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%).¹H NMR (CDCl₃, 400 MHz) δ is 4.21 (m, 2H), 2,77 (d, J=11.2 Hz, 1H), 2,60 (m, 1H), 2,50 is 2.10 (m, 3H), of 1.42 (m, 1H), 1,33 (m, 3H), of 1.23 (m, 3H).

Stage 3. To a solution of a mixture of (2R)-ethyl-2-methyl-5-oxocyclopentanecarboxylate (20 g, 117,5 mmol) and thiourea (9.2 grams, 120,9 mmol) in ethanol (100 ml) was added KOH (8,3 g, 147,9 mmol) in water (60 ml). The mixture is refluxed for 10 hours. After cooling remove the solvent, and the residue is neutralized with concentrated HCl (12 ml) at 0°C and then extracted with DCM (3×150 ml). The solvent is removed, the residue is purified by chromatography on silica gel by elution with hexane/ethyl acetate (2:1) and receive (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (12 g, 56%). MS (APCI+) [M+H]⁺183.

Stage 4. The Raney Nickel (15 g) and NH₄OH (20 ml) was added to a suspension of (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (12 g, 65,8 mmol) in distilled water (100 ml). The mixture is refluxed for 3 hours and then filtered. The filtrate is concentrated and receive (R)-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (9,89 g, 99%). MS (APCI+) [M+H]⁺151.

Stage 5. A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-4-ol (5.8 g, 38,62 mmol) in POCl₃(20 ml) cipated reflux for 5 minutes. Excess POCl₃removed in vacuo, and the residue is dissolved in DCM (50 ml). The mixture is then added to a saturated solution of NaHCO₃(200 ml). The aqueous phase is extracted with DCM (3×100 ml)and the combined organic phases are dried and concentrated. The residue is purified by chromatography on silica gel, carry out elution with ethyl acetate and receive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine (3,18 g, 49%).¹H NMR (CDCl₃, 400 MHz) δ 8,81 (s, 1H), 3,47 (m, 1H), 3,20 (m, 1H), 3,05 (m, 1H), 2,41 (m, 1H), 1,86 (m, 3H), 1,47 (m, 3H).

Stage 6. m-SRV (8,30 g, 37,0 mmol) was added in three portions to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine (2.5 g, of 14.8 mmol) in CHCl₃(60 ml). The mixture is stirred at room temperature for 2 days. The mixture is cooled to 0°C and added dropwise Na₂S₂O₃(10 g) in water (60 ml). Then add Na₂CO₃(6 g) in water (20 ml). The reaction mixture is stirred for 20 minutes. The aqueous phase is extracted with CHCl₃(2×200 ml) and the combined organic phases are concentrated at low temperature (<25°C). The residue is purified by chromatography on silica gel by elution with a mixture of ethyl acetate-DCM/MeOH (20:1) and receive oxide (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine (1.45 g, 53%).¹H NMR (CDCl₃, 400 MHz) δ 8,66 (s, 1H), 3,50 (m, 1H), 3,20 (m, 2H), 2,44 (m, 1H), 1,90 (m, 1H), 1,37 (d, 1=7.2 Hz, 3H).

Stage 7. The solution of the sid (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine (1.45 g, 7.85 mmol) in acetic anhydride (20 ml) is heated at 110°C for 2 hours. After cooling, remove excess solvent in vacuo. The residue is purified by chromatography on silica gel by elution with hexane/ethyl acetate (3:1) and receive (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-7-ylacetic (1,25 g, 70%).¹H NMR (CDCl₃, 400 MHz) δ of 8.92 (m, 1H), 6.30-in-6,03 (m, 1H), 3,60-3,30 (m, 1H), 2,84 (m, 1H), 2,40-of 2.20 (m, 1H), 2,15 (d, J=6 Hz, 2H), of 1.75 (m, 2H), 1,47 (d, J=6,8, 2H), 1,38 (d, J=7,2, 1H). MS (APCI+) [M+H]⁺227.

Stage 8. (5R)-4-Chloro-5-methyl-6,7-dihydro-5H-cyclopent[d]pyrimidine-7-ylacetic turn in (5R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopent[d]pyrimidine-7-ol treatment LiOH in N₂O/THF followed by treatment with an acid (2N HCl solution in water) to remove acetate groups.

Stage 9. 4-Chlorobenzylamino (1.0 ml, 8.2 mmol) was added to a solution of the hydrobromide of 2-bromo-N,N-diethylethanamine (2.4 g, 9.0 mmol) and triethylamine (3.4 ml, 25 mmol) in dichloromethane (16 ml). The mixture is stirred at room temperature for 5 hours. The mixture is then concentrated and receive N1-(4-chlorbenzyl)-N2,N2-diethylether-1,2-diamine in the form of oil, which is used directly without purification.

Stage 10. tert-Butyl-4-chlororespiration-1-carboxylate (245 mg, 0,99 mmol) was added to a solution of N1-(4-chlorbenzyl)-N2,N2-diethylether-1,2-diamine (235 mg, 0.98 mmol) and N,N-diisopropylethylamine (0.54 ml, to 2.94 mmol) in DC (2 ml). The reaction mixture was allowed to mix at room temperature for 1 hour. The mixture was quenched with saturated solution of NH₄Cl (2 ml) and extracted with DCM (2×5 ml). The combined organic extracts dried (Na₂SO₄), filtered and concentrated. The crude product is purified by chromatography on silica gel and receive tert-butyl-4-(N-(4-chlorbenzyl)-N-(2-(diethylamino)ethyl)carbarnoyl)piperazine-1-carboxylate (200 mg, 45%).¹H NMR (CDCl₃, 400 MHz) δ to 7.32 (d, J=8,4 Hz, 2H), 7,19 (d, J=8,4 Hz, 2H), 4,42 (s, 2H), 3.45 points is 3.40 (m, 4H), 3.25 to 3,20 (m, 4H), 3,18 (t, J=6,8 Hz, 2 Hz), of 2.56 (t, J=6,8 Hz, 2H), 2.49 USD (kV, J=7.2 Hz, 4H), of 1.46 (s, N), 0,99 (t, J=7.2 Hz, 6N).

Stage 11. Triperoxonane acid (1 ml) was added to a solution of tert-butyl 4-(N-(4-chlorbenzyl)-N-(2-(diethylamino)ethyl)carbarnoyl)piperazine-1-carboxylate (88 mg, 0,19 mmol) in DCM (1 ml). The mixture is stirred at room temperature for 3 hours and then concentrated in vacuo. The residue is dissolved in n-butanol (1 ml). To the solution was added N,N-diisopropylethylamine (of 0.11 ml, 0.6 mmol). Then to the solution was added (5R)-4-chloro-6,7-dihydro-5-methyl-5H-cyclopent[d]pyrimidine-7-ol (37 mg, 0.20 mmol). The reaction mixture is heated at 80°C for 16 hours. The mixture is then diluted with H₂O (1 ml) and extracted with DCM (2×5 ml). The combined organic extracts dried (Na₂SO₄), filtered and concentrated. The crude product is purified preparative HPLC the receive N-(4-chlorbenzyl)-N-(2-(diethylamino)ethyl)-4-((5R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopent[d]pyrimidine-4-yl)piperazine-1-carboxamide (19.9 mg, 21%). MS (APCI+) [M+H]⁺501,3.¹H NMR (CDCl₃, 400 MHz) δ 8,46 (s, 1H), 7,34 (d, J=8,4 Hz, 4H), 7,13 (d, J=8,4 Hz, 4H), of 5.50 (t, J=8 Hz, 1H), 5,28 (DD, J=3,6, and 8.4 Hz, 1H), 4,45 (s, 4H), 4,14-Android 4.04 (m, 4H), 3,94-3,81 (m, 4H), 3,51-of 3.42 (m, 8H), 3,20-3,00 (m, N), 2,73-of 2.64 (m, 2H), 2,40-of 2.20 (m, 4H), 2.05 is-to 1.98 (m, 1H), 1,86-of 1.78 (m, 1H), 1,33 (d, J=7.2 Hz, 3 Hz)of 1.28 (t, J=7.2 Hz, N), to 1.21 (d, J=6,8 Hz, 3 Hz).

Examples 4-14 shown in table 1, can also be obtained by the above-described method.

Although the invention is described in combination with variants of implementation, it is clear that the invention is not limited to these options for implementation. On the contrary, it is understood that the invention covers all alternatives, modifications and equivalents that may be included in the scope of the present invention, as defined in the claims. Thus, it is believed that the foregoing description is illustrative only of the principles of the present invention.

Used in the above description and the following claims, the terms "include", "includes", "include", "including" and "includes" are intended to indicate the presence of installed features, integers, components, or stages, but they do not preclude the presence or addition of one or more of the space of a few signs, integers, components, stages or groups.

Table 2
ADDITIONAL EXPERIMENTAL DATA
Structure	Example No.	AKT1 Enz IMAP Average IC50 value	PKA Enz IMAP Average IC50 value	Selectivity
Structure 8	Example 1	21.08	797.38	37.83
	Example 1
Structure 9	Party 2	13.57	721.7	53.18
Structure 3	Example 2	2053	1110.6	0.54
Structure 5	Example 3	645.25	10000.00001	15.50
Structure 13	Example 4	368.1	2973.65	8.08

ADDITIONAL EXPERIMENTAL DATA
Structure 14	Example 5	64.2	2913.5	45.38
Structure 15	Example 6	13.57	517.1	38.11
Structure 11	Example 7	458.2	4607.4	10.49
Structure 10	Example 8	584.2	4316.4	7.39
Structure 16	Example 9	26.47	559.3	21.13
Structure 12	Example 10	33.33	2096.3	62.90

ADDITIONAL EXPERIMENTAL DATA
Structure 17	Example 11	20.05	171.6	8.56
Structure 18	Example 12	35.1	515.25	At 14.68
Structure 2	Example 13	103.05	2245.35	At 21.79
Structure 19	Example 14	66.4	378.4	5.70
Structure 23	Example 15	146.73	10000.00001	68.15

ADDITIONAL EXPERIMENTAL DATA
Structure 24	Example 16	50.2	9103.3	181.34
Structure 25	Example 17	420.05	10000.00001	At 23.81
Structure 26	Example 18	2008.3	10000.00001	4.98
Structure 20	Example 19	60.1	10000.00001	166.39

ADDITIONAL EXPERIMENTAL DATA
Structure 22	Example 20	31.15	10000.00001	321.03

1. The compound of the formula I

and enantiomers and pharmaceutically acceptable salts, where:
R¹and R^1aindependently selected from H, Me, Et, vinyl, CF₃, CHF₂or CH₂F;
R²represents H, HE, OMe or F;
R^2arepresents H, Me or F;
R³represents H, Me, Et or CF₃;
And is a;
G represents a phenyl, optionally substituted by one to four groups R^eor 5-6-membered heteroaryl containing one heteroatom selected from sulfur, optionally substituted with halogen;
R⁵and R⁶independently represent H, och₃With₃-C₆-cycloalkyl, optionally substituted by F, HE, C₁-C₃the alkyl or O(C₁-C₃by alkyl), 4-6-membered heterocycle containing one g is teracom, selected from nitrogen, optionally substituted by F, HE, C₁-C₃the alkyl, cyclopropylmethyl or-C(=O)(C₁-C₃by alkyl), or C₁-C₆-alkyl, optionally substituted by one or more groups independently selected from HE, oxo, O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), O(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl,
or R⁵and R⁶together with the nitrogen atom to which they are attached, form a 4-7-membered heterocyclic ring containing one heteroatom selected from nitrogen, optionally substituted by one or more groups independently selected from HE, halogen, oxo, CF₃CH₂CF₃CH₂CH₂OH, O(C₁-C₃the alkyl), C(=O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃the alkyl, or
R^crepresents hydrogen, and R^dand R⁶together with the atoms to which they are attached, form a 4-6-membered heterocyclic ring containing one nitrogen atom;
R^aand R^brepresent H,
or R^arepresents H, a R^band R⁶together with the atoms to which they are attached, form a 5-6-membered heterocycle which ical ring, containing one or two nitrogen atom;
R^cand R^drepresent H or Me,
or R^cand R^dtogether with the atom to which they are attached, form cyclopropyl ring;
each R^erepresents independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, O-(C₁-C₆-alkyl), CF₃, OCF₃S(C₁-C₆-alkyl), CN, och₂-phenyl, NH₂, NO₂, NH-(C₁-C₆-alkyl), N-(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂HE SO₂(C₁-C₆-alkyl), C(O)NH₂C(O)NH(C₁-C₆-alkyl) and C(O)N(C₁-C₆-alkyl)₂;
m and n are independently 0, 1, 2 or 3, provided that (m+n) must be equal to 2, 3 or 4; and
p is 0 or 1.

2. The compound according to claim 1, where R³represents H, methyl, which is not necessarily in the (S)-configuration, or ethyl.

3. The compound according to claim 1, where R¹represents hydrogen or methyl, which is not necessarily in the (R)-configuration.

4. The compound according to claim 1, where R^1arepresents hydrogen or methyl.

5. The compound according to claim 1, where R²represents H, F or IT.

6. The compound according to claim 1, where R^2arepresents H or F.

7. The compound according to claim 1, where G is a 4-chlorophenyl, 4-forfinal, 4-bromophenyl, 4-iopener, 4-t is iformatter, 4-trifloromethyl, 4-dimethylphenyl, 3-fluoro-4-chlorophenyl, 2,4-dichlorophenyl or 3,4-dichlorophenyl, or
.

8. The compound according to claim 1, where R^arepresents H, R^brepresents H, R^crepresents H, R^drepresents N.

9. The compound according to claim 1, where R⁵represents H or ethyl and R⁶represents H or ethyl.

10. The compound according to claim 1, where m is 1, n is 1 and p is 0.

11. The compound according to claim 1, where a is a




or.

12. The compound according to claim 1, which is a




or.

13. Pharmaceutical composition having the properties of the inhibitor ACT-protein kinases containing an effective amount of a compound according to any one of claims 1 to 12.

14. The compound according to any one of claims 1 to 12 for use as a drug in the treatment of indirect ACT-protein kinase conditions selected from the group consisting of inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological or dermatological diseases and disorders.

15. The compound according to any one of claims 1 to 12 for use in the treatment of cancer.