RU2486178C2 - Pyrimidyl cyclopentanes as akt-protein kinase inhibitors - Google Patents

Abstract

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

Description

FIELD OF THE INVENTION

The present invention relates to novel serine / threonine protein kinase inhibitors (e.g., AKT and related kinases), pharmaceutical compositions containing such inhibitors, and methods for preparing said inhibitors. These inhibitors are useful, for example, in the treatment of hyperproliferative diseases such as cancer and inflammation in mammals.

State of the art

Protein kinases (PK) are enzymes that catalyze the phosphorylation of hydroxy groups of tyrosine, serine and threonine protein residues by transferring terminal (gamma) phosphate from ATP. Through signal transduction pathways, these enzymes modulate cell growth, differentiation, and proliferation, i.e. almost all aspects of cell life in one way or another depend on PK activity (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 PK is associated with a family of diseases, ranging from relatively safe, non-life-threatening, such as psoriasis, to extremely virulent, such as glioblastoma (brain cancer). Protein kinases represent an important class of targets for therapeutic modulation (Cohen, P. (2002) Nature Rev. Drug Discovery 1: 309).

Atypical protein phosphorylation and / or expression is often reported to be largely one of the effects of abnormal cell proliferation, metastasis and cell survival in cancer. 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 are definitely organically linked specifically to cancer.

Protein kinases include two classes: protein tyrosine kinase (PTK) and serine threonine kinase (STK). B / Akt protein kinase enzymes are a group of serine / threonine kinases that are overproduced in many human tumors. One of the best characterized targets for PI3K lipid products is 57-KD-serine / threonine protein kinase Akt, below the PI3K site in the signal transduction pathway (Hemmings, BA (1997) Science 275: 628; Hay N. (2005) Cancer Cell 8 : 179-183). Akt is the human homologue of v-akt-proto-oncogen in the dramatically transforming AK8 retrovirus. Due to the high degree of affinity of the Akt sequences and protein kinases A and C, Akt is also called protein kinase B (RKB) and related A and C (RAC). It is known that there are three Akt isoforms, namely Akt1, Akt2, and Akt3, which have 80% total homology [(Staal, SP (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)]. Akt isoforms participate in a common domain organization, which consists of a PH domain (pleckstrin homology domain) at the N-terminus, a catalytic domain of kinases, and a short regulatory region at the C-terminus. In addition, both Akt2 and Akt3 have splicing options. When recruiting to the cell membrane under the action of PtdInd (3,4,5) P ₃ , Akt phosphorylates (activates) PDK1 at T308, T309 and T305 for the isoforms Akt1 (PKBα), Akt2 (PKBβ) and Akt3 (PKBγ), respectively, and at S473 , S474 and S472 for the isoforms Akt1, Akt2 and Akt3, respectively. Such phosphorylation occurs under the action of a still unknown kinase (supposedly called PDK2), although PDK1 [(Balendran, A., (1999) Curr. Biol. 9: 393)], autophosphorylation [(Toker, A. (2000) J. Biol. Chem. 275: 8271)] and integrin-bound kinase (ILK) (Delcommenne, M. (1998) Proc. Natl. Acad. Sci. USA, 95: 11211) are involved in this process. Activation of Akt requires its phosphorylation at the Ser 473 residue 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 of Akt activates kinase, bis (phosphorylation) is required for maximum kinase activity.

It is believed that Akt acts on cancer by inhibiting apoptosis and enhancing both angiogenesis and proliferation [(Toker et al. (2006) Cancer Res. 66 (8): 3963-3966)]. Akt is overproduced in many forms of human cancer, including (but not limited to) colon cancer [(Zinda et al. (2001) Clin. Cancer Res. 7: 2475)], ovaries [(Cheng et al. (1992) Proc . Natl. Acad. Sci. USA 89: 9267)], brain [(Haas Kogan et al. (1998) Curr. Biol. 8: 1195)], lungs ((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 glands [(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 inhibitor molecules, the transport of rapamycin (mTOR) to the PI3K / Akt / mammalian target [Georgakis, G. and Younes, A. (2006) Expert Rev. Anticancer Ther. 6 (1): 131-140; Granville et al. (2006) Clin. Cancer Res. 12 (3): b79-689)]. Inhibition of PI3K / Akt signal transduction induces apoptosis and inhibits the growth of tumor cells that increase Akt levels [(Kim et al. (2005) Current Opinion in Investig. Drugs 6 (12): 1250-1258; Luo et al. (2005) Molecular Cancer Ther. 4 (6): 977-986)].

The development of kinase inhibitors that target pathways with abnormal regulation, ultimately leading to disease, is of great ethical and commercial interest to the medical and pharmaceutical community. A compound that inhibits (1) Akt recruitment to the cell membrane, (2) activation by PDK1 or PDK2, (3) phosphorylation of the substrate, or (4) one of Akt's lower targets could be a valuable anti-cancer agent, acting or as a separate therapeutic methods, or in combination with other accepted methods.

U.S. Patent Application Publication No. 2005/0130954 describes, among others, a variety of compounds that act as ACT inhibitors. These compounds are believed to be useful in the treatment of hyperproliferative diseases such as cancer.

U.S. Patent Application Publication No. 2008/0058327 and US Patent Application Publication No. 2008/0051399 describes among others a number of compounds that act as AKT inhibitors.

Disclosure of invention

The present invention relates to new compounds that inhibit AKT protein kinases. The compounds of the present invention are useful as therapeutic agents for treating 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, R ¹ , R ^1a , R ² , R ^2a and R ³ are as defined below.

The invention also relates to pharmaceutical compositions comprising a compound of formula I, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

An additional object of the present invention is a method of treating diseases or medical conditions mediated by AKT protein kinases in mammals, comprising administering to said mammals one or more compounds of formula I, or their enantiomers, or their pharmaceutically acceptable salts, in an amount effective to treat or prevent said disease. AKT protein kinase-mediated conditions that can be treated by the methods of the present invention 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 for inhibiting the production of AKT protein kinases in mammals, which comprises administering to said mammals a compound of formula I, or its enantiomer, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the production of AKT protein kinase.

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

The compounds of the invention can be successfully used in combination with other known therapeutic agents. Accordingly, the present invention also relates to pharmaceutical compositions comprising a compound of formula I, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, 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 medicaments in the treatment of conditions mediated by AKT protein kinases.

An additional object of the invention is the use of a compound of formula I, or an enantiomer thereof, or a pharmaceutically acceptable salt in therapy. In one embodiment, the therapy includes treating a condition mediated by AKT protein kinase.

The present invention also relates to a kit for treating diseases or disorders mediated by AKT protein kinase, which contains a compound of formula I or its enantiomer, or a pharmaceutically acceptable salt, container, and optionally a package leaflet or label for treatment indications. The kits may further comprise a second compound or composition comprising a second pharmaceutical agent useful for treating said disease or disorder.

The present invention further includes preparation methods, separation methods 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 the part that will be obvious to experts in this field when examining the following description or which can be learned from the practice of the invention. The advantages of the invention can be realized and achieved using combinations, compositions and methods specifically indicated in the attached claims.

The implementation of the invention

Detailed references will now be made to certain embodiments of the invention, examples of which are illustrated by the accompanying structures and formulas. Although the invention will be described in combination with numbered embodiments, it should be understood that the invention is not meant to be limited to these embodiments. On the contrary, it is intended that the invention covers all alternatives, modifications, and equivalents that may be included in the scope of the present invention according to the claims. A person skilled in the art should know a variety of methods and substances similar or equivalent to those described herein that could be used in the practice of the present invention. The present invention is in no way limited to the described methods and substances. In the event that one or more of the included references to literature and similar materials differs from or contradicts this application, including certain terms, the use of terms, the described methods, or something similar (but not limited to), this application takes precedence.

DEFINITIONS

The term “alkyl” as used herein refers to a saturated linear or branched monovalent hydrocarbon radical containing one to twelve carbon atoms, wherein the alkyl radical may optionally be independently substituted with one or more substituents described below. Examples of alkyl groups include, but are not limited to, methyl ("Me", -CH ₃ ), ethyl ("Et", -CH ₂ CH ₃ ), 1-propyl ("n-Pr", n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl ("i-Pr", isopropyl, -CH (CH ₃ ) ₂ ), 1-butyl ("n-Bu", n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl ("i-Bu", isobutyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl ("s-Bu", sec-butyl, -CH (CH ₃ ) CH ₂ CH ₃ ), 2-methyl-2-propyl ("t-Bu", tert-butyl, -C (CH ₃ ) ₃ ), 2,2-dimethylpropyl (CH ₂ C (CH ₃ ) ₃ ), 1 -pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl- 1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ ) CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (CH ₃ ) (CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C (CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH (CH ₃ ) C (CH ₃ )) ₃ , 1-heptyl, 1-octyl and the like.

The terms “cycloalkyl”, “carbocycle”, “carbocyclyl” and “carbocyclic ring” as used herein are used interchangeably and refer to saturated or partially unsaturated cyclic hydrocarbon radicals containing from three to twelve carbon atoms. The term “cycloalkyl” includes monocyclic and polycyclic (eg, bicyclic and tricyclic) structures, where the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl ring fused to a saturated, partially unsaturated or aromatic cycloalkyl or heterocyclic ring. Cycloalkyl may optionally be independently substituted with one or more of the substituents described herein.

Examples of 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, cyclononyl, cyclodecyl, cyclodecyl, cyclododecyl, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2. 2] nonane.

As used herein, the terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” are used interchangeably and refer to a saturated or partially unsaturated carbocyclic radical containing 3-8 atoms in the ring, 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, moreover, one or more atoms in the ring may optionally be independently substituted with one or more substituents described below. The radical may be carbon-centered or heteroatom-centered. The term “heterocycle” includes heterocycloalkoxy. The term “heterocyclyl” also includes radicals in which heterocyclic radicals are fused to a saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic ring. The heterocycle may be C-substituted or N-substituted, where possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-substitution) or pyrrole-3-yl (C-substitution). Further, the group derived from imidazole may be imidazol-1-yl (N-substitution) or imidazol-3-yl (C-substitution). Examples of heterocyclic groups in which 2 ring carbon atoms are substituted with oxo (= O) groups are isoindolin-1,3-dionyl and 1,1-dioxothiomorpholinyl. Heterocyclic groups are optionally substituted independently with one or more of the substituents described herein.

Typical heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-didiethanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazine, piperazine, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrroinyl, 2-pyrrolinyl, 2-pyrroinyl, 2-pyrroinyl, 2-pyrroinyl, 2-pyrroinyl, 2-pyrroinyl, 2-pyrroinyl, 2-pyrroinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl, 2-pyrro-vinyl,-2-pyrro-vinyl,--2-pyrro-vinyl, -l-2-pyrro-vinyl, , 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl and azabicyclo [2.2.2].

The term “heteroaryl” as used herein refers to a monovalent aromatic radical with a 5-, 6- or 7-membered ring and includes fused cyclic (ring) systems (at least one of which is aromatic) of 5-10 atoms containing at least one heteroatom independently selected from nitrogen, oxygen and sulfur. Heteroaryl may be C-substituted or N-substituted where possible. Heteroaryl groups may optionally be independently substituted with one or more of the substituents described herein.

Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, benzinolinyl, quinolinyl, quinolinyl, indolinolinyl cinnolinyl, indazolyl, indolisinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolinyl, quinidinyl and furopyridinyl.

The term “halogen” as used herein means fluoro, chloro, bromo or iodo.

The term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

The term “diastereomer” refers to a pair of optical isomers that are not mirror images of each other.

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that interconvert through a low energy barrier.

The phrase "pharmaceutically acceptable" indicates that the substance or composition is chemically or toxicologically compatible with other ingredients contained in the formulation and / or with a mammal that is being treated with this substance or composition.

The phrase "effective amount" means an amount of a compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition or disorder mediated by the activity of one or more AKT protein kinases, tyrosine kinases, additional serine / threonine kinases and / or kinases with "double" specificity, (ii) improving the condition, alleviating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing increasing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term "treatment" is intended to mean at least alleviating a disease condition in a mammal, such as a human, which is affected at least in part by one or more AKT protein kinases, tyrosine kinases, additional serine / threonine kinases and / or kinases with "double" specificity. The terms “treat” and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, the purpose of which is to prevent or slow down (reduce) unwanted physiological changes or disorders. For the purposes of the present invention, favorable or desirable clinical results include, but are not limited to, amelioration of symptoms, a decrease in the degree of damage, a stabilized (i.e., not worsening) condition of the disease, a delay or slowdown in the development of the disease, improvement or alleviation of the disease, and remission (partial or full), defined or undefined. The term "treatment" may also mean an extension of the survival time compared to the expected survival time without receiving treatment. Those in need of treatment include those who are already suffering from a disease or condition, as well as those who have been found to be predisposed to the condition of the disease, but who have not yet been diagnosed. The terms “treating”, “treating” or “treating” include as preventative, i.e. preventive and palliative treatment.

As used herein, the term “mammal” refers to a warm-blooded animal that suffers from the disease described herein, or at risk of developing such a disease, and includes guinea pigs, dogs, cats, rats, mice, hamsters and primates, including humans, but not limited to listed animals.

The term “package leaflet” is used to refer to instructions usually included in therapeutic product kits intended for sale that contain information about the indications, use, dosage, administration, contraindications and / or warnings regarding the use of such therapeutic products .

The terms “compound of this invention”, “compounds of the present invention” and “compounds of formula I” as used herein include compounds of formula I and their tautomers, resolved enantiomers, resolved diastereomers, racemic mixtures, solvates, metabolites, salts (including pharmaceutically acceptable salts) and pharmaceutically acceptable prodrugs.

It should be understood that examples where two or more radicals are used sequentially to determine the substituent attached to the structure, the radical called the first is considered terminal, and the radical called the last is considered attached to the structure under consideration. Thus, for example, an arylalkyl radical is attached to the structure under consideration by an alkyl group.

ACT INHIBITORS

The compounds of the invention of formula I are useful for inhibiting AKT protein kinases. In addition to ACT, the compounds of formula I may also be useful as inhibitors of tyrosine kinases, as well as serine and threonine kinases. Such compounds find use as therapeutic agents against diseases that can be treated by inhibiting the signaling pathway of AKT protein kinases and tyrosine and serine / threonine kinase receptor pathways.

In general, the invention includes compounds of formula I

and their separated enantiomers, separated diastereomers and pharmaceutically acceptable salts, where:

R ¹ and R ^{1a are} independently selected from H, Me, Et, vinyl, CF ₃ , CHF ₂ or CH ₂ F;

R ² represents H, OH, OMe or F;

R ^2a represents H, Me or F;

R ³ represents H, Me, Et or CF ₃ ;

;A represents

;

G is phenyl optionally substituted with one to four R ^e groups, or 5-6 membered heteroaryl optionally substituted with halogen;

R ⁵ and R ⁶ independently represent H, OCH ₃ , C ₃ -C ₆ cycloalkyl optionally substituted with F, OH, C ₁ -C ₃ alkyl or O (C ₁ -C ₃ alkyl), 4-6 membered heterocycle optionally substituted with F, OH, C ₁ -C ₃ alkyl, cyclopropylmethyl or C (= O) (C ₁ -C ₃ alkyl), or C ₁ -C ₆ alkyl optionally substituted with one or more groups independently selected from OH , oxo, O (C ₁ -C ₆ alkyl), CN, F, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl,

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ OH, O (C ₁ -C ₃ alkyl), C (= O) CH ₃ , NH ₂ , NHMe, N (Me) ₂ , S (O) ₂ CH ₃ , cyclopropylmethyl and C ₁ -C ₃ alkyl or R ^c represents hydrogen, and R ^d and R ^6, together with the atoms to which they are attached, form a 4-6 membered heterocyclic ring containing one nitrogen atom;

R ^a and R ^b represent H

or R ^a represents H, and R ^b and R ⁶ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring containing one or two nitrogen atoms;

R ^c and R ^d represent H or Me

or R ^c and R ^d together with the atom to which they are attached form a cyclopropyl ring;

each R ^e is independently halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, O- (C ₁ -C ₆ alkyl), CF ₃ , OCF ₃ , S (C ₁ -C ₆ - alkyl), CN, OCH ₂ -phenyl, NH ₂ , NO ₂ , NH- (C ₁ -C ₆ -alkyl), N- (C ₁ -C ₆ -alkyl) ₂ , piperidine, pyrrolidine, CH ₂ F, CHF ₂ , OCH ₂ F, OCHF ₃ , OH, SO ₂ (C ₁ -C ₆ alkyl), C (O) NH ₂ , C (O) NH (C ₁ -C ₆ alkyl) and C (O) N (C ₁ -C ₆ alkyl) ₂ ;

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

p is 0 or 1.

In general, the invention includes compounds of formula I

and their separated enantiomers, separated diastereomers and pharmaceutically acceptable salts, where:

R ¹ and R ^{1a are} independently selected from H, Me, Et, vinyl, CF ₃ , CHF ₂ or CH ₂ F;

R ² represents H, OH, OMe or F;

R ^2a represents H, Me or F;

R ³ represents H, Me, Et or CF ₃ ;

;A represents

;

G is phenyl optionally substituted with one to four R ^e groups, or 5-6 membered heteroaryl optionally substituted with halogen;

R ⁵ and R ⁶ independently represent H, OCH ₃ , C ₃ -C ₆ cycloalkyl optionally substituted with F, OH, C ₁ -C ₃ alkyl or O- (C ₁ -C ₃ alkyl), 4-6 membered a heterocycle optionally substituted with F, OH, C ₁ -C ₃ alkyl, cyclopropylmethyl or C (= O) (C ₁ -C ₃ alkyl), or C ₁ -C ₆ alkyl optionally substituted with one or more groups independently selected from OH, oxo, O- (C ₁ -C ₆ alkyl), CN, F, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , cyclopropyl, phenyl, imidazolyl , piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl,

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ OH, O (C ₁ -C ₃ alkyl), C (= O) CH ₃ , NH ₂ , NHMe, N (Me) ₂ , S (O) ₂ CH ₃ , cyclopropylmethyl and C ₁ -C ₃ alkyl ;

R ^a and R ^b represent H

or R ^a represents H, a R ^b and R ⁶ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring containing one or two nitrogen atoms in the ring;

R ^c and R ^d represent H or Me

or R ^c and R ^d together with the atom to which they are attached form a cyclopropyl ring;

each R ^e independently represents halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, O- (C ₁ -C ₆ alkyl), CF ₃ , OCF ₃ , S (C ₁ -C ₆ - alkyl), CN, OCH ₂ -phenyl, NH ₂ , NO ₂ , NH- (C ₁ -C ₆ -alkyl), N- (C ₁ -C ₆ -alkyl) ₂ , piperidine, pyrrolidine, CH ₂ F, CHF ₂ , OCH ₂ F, OCHF ₂ , OH, SO ₂ (C ₁ -C ₆ alkyl), C (O) NH ₂ , C (O) NH (C ₁ -C ₆ alkyl) and C (O) N (C ₁ -C ₆ alkyl) ₂ ;

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

p is 0 or 1.

Examples relating to group G of formula I include phenyl (“Ph”) optionally substituted with one or more R ^e groups independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, CN , CF ₃ , OMe, OEt, OCF ₃ , NO ₂ , SMe and OCH ₂ Ph. Typical embodiments of G include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl , 4-ethoxyphenyl, 4-thiomethylphenyl, 4-trifluoromethoxyphenyl, 4-cyclopropylphenyl, 4-chloro-3-fluorophenyl, 3,4-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro -4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-cyano-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro -4-chlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 3-chloro-5-fluorophenyl, 3 or-4-fluorophenyl, 3-bromo-4-fluorophenyl, 3,5-difluoro-4-chlorophenyl, 2,3-difluoro-4-chlorophenyl, 2,5-difluoro-4-chlorophenyl, 3,5-difluoro- 4-bromophenyl, 2,3-difluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 4- (OCH ₂ Ph) phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-bromophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl 4-bromophenyl, 4-chloro-2-fluorophenyl , 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-iodophenyl, 4-nitrophenyl, 4-tert-butylphenyl, 2-fluorophenyl, 3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro -4-trifluoromethoxyphenyl, 3-fluoro-4-tr trifluoromethylphenyl and 4-trifluoromethoxyphenyl.

The phrase “5-6 membered heteroaryl optionally substituted with halogen” referring to group G of formula I includes thiophenes and pyridines optionally substituted with halogen atoms. Specific examples include structures:

,

,

but not limited to them.

In one embodiment of the formula, IR ³ is H.

In yet another embodiment of formula I, IR ³ is methyl, said methyl optionally being in the (S) configuration.

In yet another embodiment of the formula, IR ³ is ethyl. In one embodiment of formula I, IR ¹ is methyl, said methyl optionally being in the (R) configuration. In some embodiments, the implementation of formula IR ^1a is H. In some embodiments, the implementation of formula IR ¹ and R ^{1a are} both methyl.

In yet another embodiment of formula I, IR ¹ is H. In some embodiments of formula I, IR ^1a is H.

In yet another embodiment of formula I, IR ¹ is ethyl. In some embodiments, the implementation of formula IR ^1a represents N.

In yet another embodiment of the formula, IR ¹ is CH = CH ₂ (vinyl). In some embodiments, the implementation of formula IR ^1a represents N.

In yet another embodiment of the formula, IR ¹ is CH ₂ OH. In some embodiments, the implementation of formula IR ^1a represents N.

In one embodiment of formula I, IR ^1a is H.

In one embodiment, formulas IR ² and R ^2a are H.

In yet another embodiment, formulas IR ² and R ^2a are F.

In yet another embodiment of the formula, IR ² is F and R ^2a is H.

In yet another embodiment of the formula, IR ² is OH. In some embodiments, the implementation of formula IR ^2a represents N.

In yet another embodiment of the formula, IR ² is OMe.

In one embodiment of the formula IG is phenyl optionally substituted with one to four R ^e groups.

In one embodiment of the formula, IG is phenyl optionally substituted with one to four groups independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, CN, CF ₃ , OMe, OEt, OCF ₃ , NO ₂ , SMe and OCH ₂ Ph. Typical embodiments of G include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl , 4-ethoxyphenyl, 4-thiomethylphenyl, 4-trifluoromethoxyphenyl, 4-cyclopropylphenyl, 4-chloro-3-fluorophenyl, 3,4-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro -4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-cyano-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro -4-chlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 3-chloro-5-fluorophenyl, 3 or-4-fluorophenyl, 3-bromo-4-fluorophenyl, 3,5-difluoro-4-chlorophenyl, 2,3-difluoro-4-chlorophenyl, 2,5-difluoro-4-chlorophenyl, 3,5-difluoro- 4-bromophenyl, 2,3-difluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 4- (OCH ₂ Ph) phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-bromophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl 4-bromophenyl, 4-chloro-2-fluorophenyl , 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-iodophenyl, 4-nitrophenyl, 4-tert-butylphenyl, 2-fluorophenyl, 3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro -4-trifluoromethoxyphenyl, 3-fluoro-4-tr trifluoromethylphenyl and 4-trifluoromethoxyphenyl.

In one embodiment of formula I, IG is 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-thiomethylphenyl, 3-fluoro-4-chlorophenyl, 2,4-dichlorophenyl or 3,4-dichlorophenyl.

In one embodiment of Formula I, G may be a 5-6 membered monocyclic heteroaryl optionally substituted with one or more halogen atoms. In some embodiments, G may be thiophene or pyridine optionally substituted with one or more halogen atoms. In some embodiments, G is substituted with one halogen atom. Specific embodiments include:

.

.

In one embodiment of the formula, IR ⁵ is H or ethyl.

In one embodiment of the formula, IR ⁶ is H or ethyl.

In one embodiment of the formula, IR ⁶ is hydrogen, ethyl or isopropyl.

In one embodiment, formulas IR ^a and R ^b are H.

In one embodiment, formulas IR ^c and R ^d are H.

In one embodiment, R ^c represents hydrogen, and R ^d and R ^6, together with the atoms to which they are attached, form a 4-6 membered heterocyclic ring containing one nitrogen atom. In some embodiments, m is 0, R ^c is hydrogen, and R ^d and R ^6, together 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, 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 2, 3, or 4. In specific embodiments, 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 1.

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

In one embodiment of formula I, m is 1, n is 1, p is 0, so A is represented by formula 1

,

,

where G, R ⁵ , R ⁶ , R ^c and R ^d are as defined herein.

In some embodiments of Formula 1, R ^c and R ^d are H.

In some embodiments of Formula 1, R ⁵ is H or ethyl.

In some embodiments of Formula 1, R ⁶ is H or ethyl.

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

where G, R ⁶ , R ⁷ and R ⁸ are as defined herein.

In some embodiments of Formula 2, R ^a and R ^b are H.

In some embodiments of Formula 2, R ^c and R ^d are H.

In some embodiments of Formula 2, R ⁵ is H or ethyl.

In some embodiments of Formula 2, R ⁶ is H or ethyl.

In specific embodiments, A is

.

.

In further embodiments, A is selected from the structures:

In further embodiments, A is

.

.

In specific embodiments, A is selected from:

.

.

In specific embodiments, A is

.

.

In some embodiments, the salt is a “pharmaceutically acceptable salt,” which, unless otherwise indicated, includes salts that retain the biological effectiveness of the corresponding free acid or free base of the particular compound and do not have undesirable biological or other effects.

Compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and which may be useful as intermediates for the preparation and / or purification of compounds of formula I and / or for the separation of enantiomers of compounds of formula I.

SYNTHESIS OF COMPOUNDS OF FORMULA I

The compounds of the present invention can be synthesized in such ways that include methods similar to those well known in chemistry, especially in light of the description herein. Starting materials are usually available from commercial sources such as Sigma-Aldrich (St. Louis, Missouri), Alfa Aesar (Ward Hill, Minnesota), or TCI (Portland, Oregon), or are readily prepared by methods well-known specialists in this field (for example, they are obtained by the methods usually described in [Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, NY (1967-1999 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin, including applications (which are also available from the Beilstein online database)].

For illustrative purposes, Schemes 1-8 show general methods for preparing the compounds of the present invention, as well as key intermediates. For a more detailed description of the individual reaction steps, see the examples section below. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds of the invention. Although the specific starting materials and reagents are shown in the schemes and are discussed below, they can be easily replaced with other starting materials and reagents to provide a variety of derivatives and / or reaction conditions. In addition, many compounds obtained by the methods described below can be further modified in the light of the present description using methods of traditional chemistry, well known to specialists in this field.

Scheme 1

where: Reducing agent - reducing agent,

Deprotection - removal of protection,

Deprotection and optional functionalization - deprotection and optional functionalization.

Scheme 1 shows a process for preparing compound 9 of formula I, wherein p is 1; R ^a and R ^b represent H; R ² , R ^2a , R ¹ , R ^1a , R ³ , R ⁵ , R ⁶ , R ^c , R ^d , m and n are defined herein; a Pg and Pg 'are amino protecting groups with mutually exclusive removal conditions (for example, 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 with amine 2 and aldehyde 1 under standard conditions such as NaBH (OAc ₃ ) / AcOH at a temperature of 0 to 50 ° C gives a substituted amine 3. Acylation of the resulting substituted amine 3 with substituted acyl piperazine 4 in the presence of a base (such as Hyunig base) at a temperature of -20 to 100 ° C gives protected piperazine 5. Removal of this protective group (for the Cbz group, for example, by hydrogenolysis, etc.) gives piperazine 6. Treatment of piperazine 6 with halogenated pyrimidine 7 at a temperature from 25 to 250 ° C, and / or at high pressure yielding, and / or under the influence of microwave radiation gives intermediate compound 8. Deprotection of the amino group (for the Boc group, for example, by the action of HCl in dioxane at a temperature from 0 ° C to 50 ° C) and the final optional functionalization of the amine (for example, alkylation, reductive amination or acylation under standard conditions for introducing new substituents) gives the final compounds 9. If required, their corresponding analogs can then be separated and individual enantiomers can be obtained.

Scheme 2

where: Deprotection - deprotection,

Optional functionalization - optional functionalization,

Base - base

Oxidative - oxidative cleavage,

Reduction - recovery,

Activation - activation.

Scheme 2 shows a process for preparing a compound 20 of formula I, wherein R ¹ , R ^2, and R ^2a are hydrogen; R ^1a represents Me, a R ³ , R ⁵ , R ⁶ , R ^a , R ^b , R ^c , R ^d , m, n and p are as defined herein. According to Scheme 2, bromination of the (+) - bulletin 10 with bromine gives dibromide 11. Treatment of the dibromide 11 with a base, such as sodium ethoxide, gives bulletin 12. Oxidative cleavage of the bulletin 12, for example, by ozonolysis at low temperature, followed by treatment with a reducing agent (for example, Zn) or using NaIO ₄ / OsO ₄ at a temperature of from 5 ° C to 50 ° C) gives the ketoester 13. Treatment of the ketoester 13 with thiourea in the presence of a base such as KOH in ethanol, followed by reduction of the mercapto group under standard conditions (for example, Raney nickel like the catalyst in ammonia) gives hydroxypyrimidine 16. Activation of compound 16 (for example, halogenation) by the action of, for example, POCl ₃ or SOCl ₂ at a temperature of -20 to 100 ° C to produce chloropyrimidine gives a pyrimidine-cyclopentane unit 17 ready for functionalization. Substitution of the leaving group the action of a suitable protected / substituted piperidine 18 at a temperature of from 0 to 150 ° C gives piperidine 19. Deprotection of the amino group (for the Boc group, for example, the action of HCl in dioxane at a temperature of from 0 to 50 ° C) and the final optional functionalization of ami a (e.g., alkylation, reductive amination or acylation to introduce new substituents) gives the final compound 20. If desired, their corresponding analogs can be subjected to separation and then receive the individual enantiomers.

Scheme 3

where: Deprotection - deprotection,

Optional functionalization - optional functionalization,

Oxidative - oxidative cleavage,

Reduction - recovery,

Activation - activation,

Hydrolysis - hydrolysis.

Scheme 3 shows a process for preparing a compound 29 of formula I, wherein R ² is OH, R ^2a is H, and R ¹ , R ^1a , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^a , R ^b , R ^c , R ^d , m, n and p are defined herein. According to Scheme 3, treatment of the ketoester 21 with thiourea in the presence of a base such as KOH in ethanol, followed by reduction of the mercapto group under standard conditions (for example, Raney nickel as a catalyst in ammonia) gives hydroxypyrimidine 23. Activation (e.g., halogenation) of hydroxypyrimidine 23 under standard conditions ( for example, the action of POCl ₃₎ provides the 4-halopyrimidine 24. The oxidation of the 4-chloropyrimidine 24 oxidizing agent such as m-CPBA or hydrogen peroxide gives the N-oxide 25. rearrangement of N-oxide 25 with acetic anhydride yields the intermediate compound 26. Compound 26 is then hydrolyzed (for example, by LiOH or NaOH at a temperature of 0 to 50 ° C.) to give alcohol 27. Compound 27 is then reacted with the desired substituted piperazine 18 according to the procedure described in Scheme 1, and obtained compound 28. If compound 29 is to undergo optional functionalization, at this stage the alcohol 28 may be protected (for example, with a TBS group) to prevent possible complications. Removal of the protective group (Pg) of compound 28, for example, with an acid (e.g., TFA at a temperature of -20 to 50 ° C) in the case of a Boc group, and subsequent optional functionalization of the free amine (e.g., alkylation, acylation, reductive amination, etc.) .p.) under standard conditions give a fully functionalized compound 29. The obtained compound 29 can also be separated to obtain individual diastereoisomers using either chiral resolution, standard non-chiral resolution (for example, column chromatography, HPLC, SLC, etc.), recrystallization, or derivatization.

Scheme 4

where: Deprotection - deprotection,

Optional functionalization - optional functionalization,

Activation - activation.

Scheme 4 shows an alternative method for preparing compound 32 of formula I, wherein R ² and R ^2a are H, a R ¹ , R ^1a , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^a , R ^b , R ^c , R ^d , m, n and p are defined here. According to Scheme 3, amination of the ketoester 21 with an ammonium synthon gives 30. The formation of pyrimidine, for example, with 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 bicyclic product 23. Activation of compound 23 with, for example, POCl ₃ or SOCl ₂ gives activated pyrimidine, and substitution of the leaving group with the action of a suitable protected / substituted piperidine 18 at temperatures from 0 to 150 ° C gives piperidine 31. Deprotection of the amine group py (for the Boc group, for example, by the action of HCl in dioxane at a temperature from 0 to 50 ° C) and the final optional functionalization of the amine (for example, alkylation, reductive amination or acylation for the introduction of new substituents) gives the final compounds 32. If necessary, their corresponding analogues can then be subjected to separation and to obtain individual enantiomers.

Scheme 5

where: Deprotection - deprotection,

Optional functionalization - optional functionalization.

Scheme 5 shows a process for preparing compound 35 of formula I, wherein R ² is fluoro, R ^2a is hydrogen, and R ¹ , R ^1a , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^a , R ^b , R ^c , R ^d , m, n and p are defined herein. According to Scheme 5, treating alcohol 33 with a fluorinating agent, such as DAST, at a temperature of -78 to 100 ° C, gives a fluorine derivative 34. Deprotection of the amino group (for the Boc group, for example, by the action of HCl in dioxane at a temperature of from 0 to 50 ° C) and the final optional functionalization of the amine (for example, alkylation, reductive amination or acylation to introduce new substituents) give the final compounds 35. If desired, their corresponding analogs can then be separated and individual enantiomers can be obtained.

Scheme 6

where: Deprotection - deprotection.

Scheme 6 shows a process for preparing a compound 39 of formula I, wherein p is 0; NR ⁵ R ⁶ is such a group that the amine cannot be further acylated with compound 4; and R ² , R ^2a , R ¹ , R ^1a , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^a , R ^b , R ^c , R ^d , m and n are defined herein. Acylation of the substituted amine 36 with substituted acyl piperazine 4 in the presence of a base (such as a Hunig base) at a temperature of from -20 to 100 ° C gives protected piperazine 37 (Pg = protecting group). Removal of this protective group (for the Boc group, for example, by the action of HCl in dioxane, for Cbz groups by hydrogenolysis, etc.) gives piperazine 38. Treatment of the obtained piperazine 38 with halogenated pyrimidine 7 at a temperature of from 50 to 250 ° C, and / or at high pressure, and / or under the influence of microwave radiation gives the product 39. If required, its corresponding analogs can then be subjected to separation and obtain individual enantiomers.

Scheme 7

where: Deprotection - deprotection,

Optional functionalization - optional functionalization.

Scheme 7 shows an alternative way of forming a compound (44) of formula I, where R ² , R ^2a , R ¹ , R ^1a , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^a , R ^b , R ^c , R ^d , m, p and n are defined here, and Pg and Pg ¹ are protecting groups with mutually exclusive deletion conditions (for example, Boc and Cbz groups). Acylation of the substituted amine 40 with substituted acyl piperazine 4 in the presence of a base (such as a Hunig base) at a temperature of from -20 ° C to 100 ° C gives protected piperazine 41 (Pg = protecting group). Removal of this protective group (for example, the Boc group by the action of HCl in dioxane or the Cbz group by hydrogenolysis) gives piperazine 42. Treatment of the obtained piperazine 42 with halogenated pyrimidine 7 at a temperature of from 50 ° C to 250 ° C and / or at high pressure or under microwave action radiation is provided by intermediate 43. The removal of the amino protecting group (for example, the Boc group by the action of HCl in dioxane at a temperature from 0 to 50 ° C) and the subsequent optional functionalization (for example, alkylation, reductive amination or acylations of to introduce new substituents) gives the final compound 44. If desired, the appropriate analogs can then be subjected to separation to obtain the individual enantiomers.

Scheme 8

where: Deprotection - deprotection,

Optional functionalization - optional functionalization,

Protection

Triphosgene - Triphosgene.

Scheme 8 shows an alternative route to the preparation of compound 29 of formula I, wherein R ² is OH; R ²⁸ represents H; R ¹ , R ^1a , R ³ , R ⁵ , R ⁶ , R ⁷ , 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 for their removal (for example, Boc and TBS groups, see, for example,' Protective Groups in Organic Synthesis' by Greene and Wuts, Wiley-Interscience). According to Scheme 8, compound 45 is reacted with the desired substituted piperazine 46 according to the procedure described in scheme 1 to obtain compound 47. Protection of the resulting alcohol 47 (for example, with a TBS group using TBSOTf in the presence of an amine base such as Hyunig base) gives compound 48 Removal of the amino protecting group [for example, using acid (for example, TFA at a temperature of −20 ° C. to 50 ° C.) in the case of the Boc group] gives free amine 49. Treatment of compound 49 with an equivalent phosgene (such as triphosgene) gives activated daily compound 50, and subsequent treatment with amine 51 in the presence of a base (for example, Hunig base at a temperature of from -50 ° C to 100 ° C) gives urea 52. Removal of the newly introduced amino protecting group (Pg) in compound 52 under conditions that are known as not affecting the hydroxy protecting group (Pg ') (for example, TFA at a temperature of from -50 ° C to 30 ° C for the Boc group), and subsequent optional functionalization of the free amine (for example, alkylation, acylation, reductive amination, etc.) under standard conditions give a fully functional ionized compound 53. Finally, removal of the hydroxy protecting group (for example, in the case of the TBS group by the action of a fluoride ion source such as TBAF at a temperature of from -50 ° C to + 50 ° C) gives the final compound 54. The resulting compound 54 can also be subjected separation to obtain individual diastereomers by either chiral resolution, standard non-chiral resolution (e.g., column chromatography, HPLC, SLC, etc.), recrystallization or derivatization.

Similar techniques may also be provided (without alcohol protection / deprotection steps) for compounds where R ² is H or F instead of OH.

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

(a) the interaction of the compounds of formula

,

,

where R ¹ , R ^1a , R ² and R ^2a are as defined herein, a Hal is halogen,

with a compound of the formula

,

,

where G, R ³ , R ^c , R ^d , n, m, and p are as defined herein, and Pg is a protecting group, as defined herein, subsequent deprotection and optional functionalization to give a compound of formula I;

(b) activation of the compounds of formula

,

,

where R ¹ and R ^1a are as defined here,

the action of POCl ₃ or SOCl ₂ , followed by a substitution reaction with a compound of the formula

,

,

where G, R ³ , R ^c , R ^d , n and m are as defined herein, and Pg is a protecting group, as defined herein,

followed by deprotection and optional functionalization, which gives a compound of formula I; or

(c) reacting a compound of the formula

,

,

where R ¹ , R ^1a and R ³ are as defined here, and Pg 'represents a protective group, as defined here,

with a compound of the formula

,

,

where G, R ^a , R ^b , R ^c , R ^d , n, m and p are as defined herein, and Pg is a protecting group as defined herein, followed by deprotection and optional functionalization to give a compound of formula I .

In the preparation of compounds of formula I, protection of distant functional groups (e.g., primary or secondary amines, etc.) of intermediate compounds may be necessary. The need for such protection may vary depending on the nature of the remote functional group and the conditions of the preparation methods. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is easily determined by a person skilled in the art. For a general description of protective groups and their uses, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

SEPARATION METHODS

The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds can be obtained as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, it is understood that the description or name of a particular compound in the description and claims includes both individual enantiomers and diastereomers, and mixtures thereof, racemic or others. Accordingly, the present invention also encompasses all such isomers, including diastereomeric mixtures, pure diastereomers and pure enantiomers of the compounds of the present invention. Diastereomers have different physical properties, for example, melting points, boiling points, spectral properties and reactivity.

It may be advantageous to separate the reaction products from each other and / or from the starting materials. The target products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired degree of uniformity by methods conventional in the art. Typically, such separation methods include multiple extraction, crystallization from a solvent or solvent mixtures, distillation, sublimation or chromatography. Chromatography may include any of its varieties, including, for example, chromatography with reverse phase and normal phase; size exclusion chromatography; ion exchange chromatography; methods and equipment for high, medium and low pressure liquid chromatography; small-scale analytical chromatography; fluid-bed chromatography (PDS) and preparative thin-layer and thick-layer chromatography, as well as methods of small-scale thin-layer and flash chromatography. A person skilled in the art will apply those methods that are most likely to achieve the desired separation.

Diastereomeric mixtures can be divided into individual diastereomers, based on differences in their physicochemical properties by methods well known. those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary reagent, such as chiral alcohol or Mosher acid chloride), resolution of the diastereomers, and conversion (e.g., hydrolysis) of the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be resolved using a chiral HPLC column.

An individual stereoisomer, for example an enantiomer substantially free of its stereoisomer, can be obtained by resolving the racemic mixture using a method such as the formation of diastereomers using optically active cleavage 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]. The racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of diastereomers and conversion to pure stereoisomers; and (3) separating substantially pure or enriched stereoisomers directly under chiral conditions. See: "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

According to method (1), diastereomeric salts can be obtained by reacting enantiomerically pure chiral bases, such as brucin, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like, with asymmetric compounds containing acidic functional groups, such as carboxylic acids and sulfonic acids. Separation of diastereomeric salts may be induced by fractional crystallization or ion chromatography. To separate the optical isomers of amino compounds, the addition 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 alternative method (2), the substrate to be separated is reacted with a single enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p .322). Diastereomeric compounds can be formed by reacting an asymmetric compound with enantiomerically pure derivatizing reagents, such as mental derivatives; subsequent separation of the diastereomers and hydrolysis give a pure or enriched enantiomer. A method for determining optical purity involves the preparation of chiral esters, such as menthyl ester, for example (-) menthyl chloroformate, in the presence of a base, or Mosher ester, α-methoxy-α- (trifluoromethyl) phenylacetate (Jacob III. J. Org. Chem ., (1982) 47: 4165), a racemic mixture and analysis of ¹ H-NMR spectrum for the presence of two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal or reverse phase chromatography, operating in accordance with separation techniques of atropisomeric naphthyl-isoquinolines (WO 96/15111).

According to method (3), a racemic mixture of two enantiomers can be separated chromatographically using a chiral stationary phase (Chiral Liquid Chromatography (1989) WJLough, 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 other chiral molecules with asymmetric carbon atoms.

The compounds of the present invention may also exist in various tautomeric forms, and all such forms are encompassed by the scope of the present invention. For example, proton tautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the binding electrons.

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

INTRODUCTION AND PHARMACEUTICAL COMPOSITIONS

The compounds of the invention may be administered by any convenient route appropriate to the 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, intraperitoneal, intrapulmonary and intranasal.

The compounds can be administered in any convenient form for administration, for example, in the form of tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, plasters, and the like. Such compositions may contain components commonly used in pharmaceutical preparations, for example, diluents, carriers, pH modifiers, sweeteners, excipients and additional active agents. If parenteral administration is required, the compositions should be sterile and prepared in the form of a solution or suspension suitable for injection or infusion.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in [Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (8 ^th Ed. 2004); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy (20 ^th Ed. 2000); and Raymond C. Rowe, Handbook of Pharmaceutical Excipients (5 ^th Ed. 2005)]. The compositions may also include one or more buffers, stabilizers, surfactants, humectants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, friability agents, processing aids, colorants, sweeteners, flavors, flavoring agents, diluents and other additives providing an attractive form of the drug (i.e., the compounds of the present invention or its pharmaceutically th composition) or facilitating the manufacture of a pharmaceutical product (i.e., drug).

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

METHODS FOR TREATING COMPOUNDS OF FORMULA I

The compounds of the present invention can be used as prophylactic or therapeutic agents for the treatment of diseases or disorders mediated by the modulation or regulation of AKT protein kinases, tyrosine kinases, additional serine / threonine kinases and / or kinases with "double" specificity. AKT protein kinase-mediated conditions that can be treated by the methods of the present invention include, but are not limited to, inflammatory diseases, hyperproliferative, cardiovascular, neurodegenerative, gynecological and dermatological diseases.

In one embodiment, said pharmaceutical composition is 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) lung related: bronchial cancer (squamous, undifferentiated small-cell, undifferentiated large-cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous lung carcinoma, small cell lung carcinoma, lung-cell carcinoma; (3) related to the gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insuloma, glucagonoma, carcinoma, carcinoma ), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaloshi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); (4) (related to the genitourinary tract): kidneys (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate gland (adenocarcinoma, c) (seminoma, teratoma, embryonic cancer, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); (5) related to the liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) related to bones: osteoblastic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocellular sarcoma), multiple myeloma, malignant glandular tumor cell, chondroblastoma, chondromixofibroma, osteoid osteoma and giant cell tumors; (7) related to the nervous system: to the skull (osteoma, hemangioma, granuloma, xanthoma, deforming osteitis), to the soft membranes of the brain (meningioma, meningiosarcoma, gliomatosis), to the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma] [ multiforme glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), to the spinal cord (neurofibroma, meningioma, glioma, sarcoma); (8) gynecological related to the uterus: (endometrial carcinoma), cervix (cervical cancer, precancerous dysplasia of the cervix uteri), to the ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unspecified granulomas cell carcinoma, unspecified tumor cell carcinoma,] -Leydig cells, ovarian seminoma, malignant teratoma), to the vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), to the vagina (clear cell carcinoma, squamous Naya carcinoma, acinar sarcoma (embryonal rhabdomyosarcoma), to the 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-Hodgkin’s lymphoma [malignant lymphoma]; (10) related to the skin: advanced melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, sarcoma Sarcoma, dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; (11) related to the adrenal gland: neuroblastoma; (12) related to the mammary gland: metastatic breast cancer; breast adenocarcinoma; (13) related to the colon; (14) related to the oral cavity; (15) nappy cell leukemia; (16) related to the head and neck; (17) and others, including a refractory metastatic tumor; Kaposi's sarcoma; Bannyan-Zonan syndrome; and Cowden's disease or Lermitt-Duclos disease, among other types of hyperproliferative diseases.

The 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, eye diseases (e.g. retinal vascularization, diabetic retinopathy, age-related macular degeneration, macular degeneration, etc. p.), multiple sclerosis, obesity, restenosis, autoimmune diseases, allergies, asthma, endometriosis, atherosclerosis, venous transplant stenosis, peri-anastomotic prosthetic stenosis, hyperplasia p prostate gland, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, scar tissue formation (and can contribute to wound healing), multiple sclerosis, inflammatory bowel disease, infections, specifically bacterial, viral, retroviral or parasitic infections (by increasing apoptosis), lung disease, neoplasm, Parkinson's disease, transplant rejection (as an immunosuppressor), septic shock, etc.

Accordingly, another object of the present invention relates to a method for treating diseases or conditions in mammals mediated by AKT protein kinases, comprising administering to said mammals one or more compounds of formula I or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat or prevent said disease.

In the case of cancer, an effective amount of the drug can reduce the number of cancer cells, reduce the size of the tumor, inhibit (i.e., slow to some extent and preferably stop) the cancer cell infiltration into peripheral organs, inhibit (i.e., slow down to some extent, and preferably stop) tumor metastasis, inhibit to some extent tumor growth and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that the drug can prevent the growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. The effectiveness of cancer therapy can be measured by evaluating, for example, the time of disease progression (TTR) and / or determining the response rate (RR).

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

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

An additional object of the invention is the use of a compound of formula I for the preparation of a medicament for therapy, such as the treatment or prophylaxis of conditions mediated by AKT protein kinase.

COMBINED THERAPY

The compounds of the present invention, their stereoisomers and pharmaceutically acceptable salts thereof can be used individually or in combination with other therapeutic agents for treatment. The compounds of the present invention can be used in combination with one or more additional drugs, for example with an anti-inflammatory agent that has a different mechanism of action. Preferably, when the second compound in a pharmaceutically combined composition or in the administration scheme has complementary activities that complement the activity of the compounds of the present invention, so that the compounds do not adversely affect each other. Accordingly, such compounds are included in the combination in amounts that are effective for the intended purpose. The compounds can be administered together in a single pharmaceutical composition or separately, and the administration separately can occur simultaneously or sequentially in any order. Such sequential administration may occur at short or long intervals.

Examples of chemotherapeutic agents include erlotinib (Tarseva ^{®, Genentech, Inc./OSI Pharm.)} , Trastuzumab (Gerseptin ^®, Genentech, Inc.); bevacizumab (Avastin ^® , Genentech, Inc.); rituximab (Rituxan ^® , Genentech, Inc./Biogen Idee, Inc.), bortezomab (Velcade ^® , Millennium Pharm.), fulvestrant (Faslodex ^® , AstraZeneca), sutent (SU11248, Pfizer), letrozole (Femara ^® , Novartis), imatinib mesylate (Glivec ^® , Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin (Eloxatin ^® , Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Rapamun ^® , Wyeth), lapatinib (GS Glaxo Smith Kline), lopafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs), and gefitinib (IRESSA ^® , AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and Cytoxan ^® cyclophosphamide , Adriamycin ^® (doksorrubitsin) Taxol ^® (paclitaxel; Bristol-Myers Squibb, rinston, NJ), Abraxane ^® (not containing Cremophor) and Taksotep ^® (doxetaxel;. Rhône-Poulenc Rorer, Antony , France).

FINISHED GOODS

Another embodiment of the invention relates to a finished product or “kit” containing substances useful for treating the diseases described above. In one embodiment, the kit comprises a container comprising a compound of the present invention. Suitable containers include, for example, vials, vials, syringes, blister packs, and the like. The container may be made of a variety of materials, such as glass or plastic. The container may contain a compound of the present invention or its composition, which are effective for treating this condition, and may have a sterile access entrance (for example, the container may be an intravenous injection solution bag or a vial with a stopper that can be pierced with a hypodermic needle).

In addition, the kit may contain a label or package insert on the container or in a set with it. In one embodiment of the invention, the label or package insert indicates that the composition containing the compound of this invention can be used to treat diseases mediated, for example, by AKT kinase. The label or package insert may also indicate that the composition can also be used to treat other diseases.

In some embodiments, the kits are suitable for delivering solid oral forms of a compound of the present invention, such as tablets or capsules. Such a kit preferably includes a number of unit dosage forms. Such kits may include a map containing dosages in the order of their intended use. An example of such a kit is “blister packs”. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If required, the kit is provided with a “reminder”, for example, in the form of numbers, letters or other marks, or an insert calendar that indicates the days in the treatment regimen when doses can be entered.

According to another embodiment of the invention, the kit may comprise (a) a first container that contains a compound of the present invention; and (b) a second container containing a second pharmaceutical composition which contains a second compound useful for treating a disease mediated by AKT kinase. As an alternative or addition, 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 solution. The kit may further 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 a compound of the present invention and a second pharmaceutical composition, if any. For example, if the kit contains a first composition containing a compound of formula I and a second pharmaceutical composition, the kit may further contain instructions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need.

In some other embodiments, where the kit contains a composition of a compound of formula I and a second therapeutic agent, the kit may contain a container for separately storing the compositions, such as a split bottle or a split foil bag, however, the separate compositions may also be contained within a single not divided into parts of the container. In some embodiments, the kit contains instructions for administering the separate components. Particularly preferred is a kit form in which the individual components are preferably administered in different dosage forms (for example, orally and parenterally) and at different intervals, or in a form in which the individual physician requires titration of the individual components of the combination.

Thus, an additional object of the present invention is a kit for treating a disorder or disease mediated by Akt kinase, said kit comprising a) a first pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof; and b) instructions for use.

In some embodiments, the kit further comprises (c) a second pharmaceutical composition that comprises a second compound suitable for treating a disorder or disease mediated by AKT kinase. In a particular embodiment of the invention comprising a second pharmaceutical composition, the kit further comprises instructions for the simultaneous, sequential and separate administration of said first and second pharmaceutical compositions to a patient in need thereof. In some embodiments, said first and second pharmaceutical compositions are in separate containers. In other embodiments, said 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 where regulation of AKT protein kinases, tyrosine kinases, additional serine / threonine kinases and / or “double specificity” kinases is required. 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 AKT protein kinases, tyrosine kinases, additional serine / threonine kinases and / or kinases with "double specificity" can be evaluated in vitro, in vivo or on cell lines. In vitro assays include assays that determine inhibition of kinase activity. In vitro alternating assays quantitatively determine the ability of an inhibitor to bind kinase / e, which can be measured either by introducing a radioactive label into the inhibitor before binding, isolating the inhibitor / kinase complex and determining the amount of bound radioactive label, or by conducting a competitive assay, where new inhibitors are incubated with known radioligands . These and other assays applicable in vitro and on cell cultures are well known to those skilled in the art.

Although the invention has been described and illustrated with some degree of specificity, it is understood that the present description is made only by way of examples, and numerous changes in the combination and organization of parts can be made by those skilled in the art without departing from the spirit and scope of the invention as stated below.

BIOLOGICAL EXAMPLES

Analysis of AKT-1 kinase

The activity of the compounds described in the present invention can be determined by the following kinase assay, which, using fluorescence polarization, measures the phosphorylation of a peptide (containing a fluorescent label) of the primary human recombinant active AKT-1 using a commercially available IMAP kit.

Substances for analysis are obtained from the IMAP ACT Assay Bulk Kit, product # R8059, from Molecular Devices (Sunnyvale, Calif.). Substances from the kit include an IMAP reaction buffer (5 ×). Diluted 1 × IMAP reaction buffer contains 10 mM Tris-HCl, pH 7.2, 10 mM MgCl ₂ , 0.1% BSA, 0.05% NaN ₃ . Usually, immediately before use, DTT is added to a final concentration of 1 mM. The kit also includes an IMAP binding buffer (5 ×) and an IMAP binding reagent. The binding solution is prepared 1: 400 by diluting the IMAP reagent for binding with 1 × IMAP binding buffer.

Fluorescein-labeled AKT substrate (from Crosstide) has the sequence (F1) -GRPRTSSFAEG. A working solution (20 μM) was prepared in 1 × IMAP reaction buffer.

Used plates include a Costar 3657 plate (382-well, made of polypropylene and having a white v-shaped bottom), which is used to dilute the compounds and obtain the compound-ATP mixture. The assay plate is a Packard ProxyPlate ™ -384 F.

The AKT-1 used is prepared from primary human recombinant AKT-1, which is activated by PDK1 and MAP kinase 2.

For analysis, working solutions of the compounds (10 μM) in DMSO are prepared. The working solutions and the control compound solution are serially diluted 1: 2 nine times in DMSO (10 μl of compound + 10 μl of DMSO) and 50 × serial dilutions are obtained in the desired dose range. Then, 2.1 μl aliquots of the compounds in DMSO were transferred to a Costar 3657 plate containing 50 μl of a 10.4 μM ATP solution in 1 × IMAP reaction buffer containing 1 mM DTT. After thorough mixing, 2.5 μl aliquots are transferred onto a ProxyPlate ™ -384 F plate.

The analysis is initiated by adding 2.5 μl aliquots of a solution containing 200 nM peptide substrate with a fluorescent label and 4 nM AKT-1. The tablet is centrifuged for 1 minute at 1000g and incubated for 60 minutes at ambient temperature. The reaction was then quenched by adding 15 μl of binding solution, centrifuged again and incubated for another 30 minutes at ambient temperature until the Victor 1420 Multilabel HTS counter was read with a configuration for measuring fluorescence polarization.

The compounds of examples 1-20 were tested using the above analysis, and it was shown that their IC ₅₀ is less than 1 μm.

PREPARATORY EXAMPLES

To illustrate the present invention, the following examples are included in the application. However, it must be borne in mind that these examples do not limit the invention, but only illustrate the proposed method for carrying out the invention. Those skilled in the art will recognize that the described chemical reactions can be readily adapted to produce a number of other compounds of the invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of compounds of the present invention, not shown as examples, can be successfully carried out using modifications of the syntheses that are obvious to specialists in this field of technology, for example, by appropriate protection of interfering groups, the use of other suitable reagents known in the art different from those described herein and / or by conventional changes in the reaction conditions. Alternatively, other reactions described herein or known in the art will be considered as applicable to the preparation of other compounds of the invention.

In the examples described below, all temperatures are given in degrees Celsius, unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and used without further purification unless otherwise indicated. Tetrahydrofuran (“THF”), dichloromethane (“DCM”), toluene and dioxane were purchased from Aldrich in sealed bottles and used as delivered.

The reactions described below are usually carried out at a positive pressure of nitrogen or argon or with a drying tube (unless otherwise specified) in anhydrous solvents, and the reaction flasks are usually equipped with a rubber septum for introducing substrates and reagents using a syringe. Glassware is dried in an oven and / or heated.

¹ H-NMR spectra were recorded on a Varian instrument with an operating frequency of 400 MHz. ¹ H-NMR spectra were recorded for solutions of the compounds in CDCl ₂ , CD ₃ OD, D ₂ O or d ₆ -DMSO (given in ppm) using tetramethylsilane (0.00 ppm) or residual as standard solvent (CDCl ₃ : 7.25 ppm; CD ₃ OD: 3.31 ppm; D ₂ O: 4.79 ppm; d ₆ -DMSO: 2.50 ppm) . When describing the multiplicity of the peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), sq (quartet), m (multiplet), ear. (expanded), dd (doublet of doublets), dt (doublet of triplets). The spin-spin interaction constants are given in hertz (Hz) when they are given.

Example 1

(R) -N- (2-aminoethyl) -N- (4-chlorobenzyl) -4- (5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-yl) piperazine-1-carboxamide

Stage 1 Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) Is added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl-2-aminoethylcarbamate (4.5 ml, 28 5 mmol, 1.2 equiv.) And acetic acid (2.5 ml) in dichloroethane (20 ml). The reaction mixture was allowed to stir overnight and quenched with a 0.5 M HCl solution (30 ml). The mixture was then extracted once with dichloromethane and a saturated aqueous solution of sodium chloride was added. The precipitate was filtered off and dried, yielding tert-butyl-2- (4-chlorobenzylamino) ethyl carbamate (3.58 g, 90%), MS (ESI) m / e (M + H ⁺ ) 285.

Stage 2 Benzyl 4- (chlorocarbonyl) piperazine-1-carboxylate (233 mg, 0.83 mmol) is added at room temperature to a solution of tert-butyl 2- (4-chlorobenzylamino) ethyl carbamate (235 mg, 0.83 mmol) and base Hyuniga (0.2 ml, 1.2 mmol, 1.5 equiv.) In dichloromethane (1.6 ml). The reaction mixture was allowed to stir overnight. The reaction mixture was then concentrated to give a crude product which was purified by flash column chromatography to give benzyl 4 - ((2- (tert-butoxycarbonylamino) ethyl) (4-chlorobenzyl) carbamoyl) 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-chlorobenzyl) carbamoyl) piperazine-1-carboxylate (200 mg, 0.38 mmol) in a solution of KOH / MeOH / H ₂ O (10 ml; prepared as a stock solution of 10 g of KOH, 50 ml of MeOH and 25 ml of H ₂ O) is stirred for 2 hours at 80 ° C. The reaction mixture was extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain tert-butyl 2- (N- (4-chlorobenzyl) piperazine-1-carboxamido) ethyl carbamate (132 mg, 89%). MS (ESI) m / e (M + H ⁺ ) 397.

Stage 4 . (R) - (+) - Pulegon (76.12 g, 0.5 mmol), anhydrous NaHCO ₃ (12.5 g) and anhydrous ether (500 ml) were placed in a 1 L round-bottom flask. The reaction mixture is cooled in an ice bath under nitrogen. Bromine (25.62 ml, 0.5 mmol) was added dropwise over 30 minutes. The mixture was filtered and carefully added to NaOEt (21%, 412 ml, 1.11 mmol) while cooling in an ice bath. The mixture was stirred at room temperature overnight and then 5% HCl (1 L) and ether (300 ml) were added. The aqueous phase is extracted with ether (2 × 300 ml). The combined organic phase is washed with water, dried and concentrated. The residue was added to a heated solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5 g) in water (300 ml). Then boiling ethanol (300 ml) was added and a clear solution was obtained. The mixture was 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 is washed with water, dried and concentrated. The residue was purified by vacuum distillation (73-76 ° C at 0.8 mmHg) to give (2R) ethyl-2-methyl-5- (propan-2-ylidene) cyclopentanecarboxylate (63 g, 64%) . ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J = 16 Hz, 0.5 H), 2.93 (m, 0.5 H), 2.50 -2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05 (m, 6H).

Stage 5 . (2R) -ethyl-2-methyl-5- (propan-2-ylidene) cyclopentanecarboxylate (24 g, 0.122 mol) in ethyl acetate (100 ml) was cooled to -68 ° C with a dry ice / isopropanol mixture. Ozonated oxygen (5-7 ft ³ / h O ₂ ) was passed through the solution for 3.5 hours. The reaction mixture was purged with nitrogen at room temperature until the color disappeared. Ethyl acetate was removed in vacuo, the residue was dissolved in acetic acid (150 ml) and cooled with ice water. Then zinc powder (45 g) is added. The solution was stirred for 30 minutes and then filtered. The filtrate was neutralized with a 2N solution of NaOH (1.3 L) and NaHCO ₃ . The aqueous phase is extracted with ether (3 × 200 ml). The organic phases are combined, washed with water, dried and concentrated to give (2R) -ethyl-2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.21 (m, 2H), 2.77 (d, J = 11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2 10 (m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).

Stage 6 . KOH (8.3 g, 147.9 mmol) in water (60 ml) was added to a solution of a mixture of (2R) -ethyl-2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5 mmol) and thiourea (9.2 g, 120.9 mmol) in ethanol (100 ml). The mixture was refluxed for 10 hours. After cooling, the solvent was removed and the residue was neutralized with concentrated HCl (12 ml) at 0 ° C. The mixture was then extracted with DCM (3 × 150 ml). The solvent was removed, the residue was purified by silica gel chromatography, eluting with hexane / ethyl acetate (2: 1), and (R) -2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4- was obtained ol (12 g, 56%). MS (APCI +) [M + H] ⁺ 183.

Stage 7 . Raney Nickel (15 g) and NH ₄ OH (20 ml) are added to a suspension of (R) -2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (12 g, 65.8 mmol) in distilled water (100 ml). The mixture was refluxed for 3 hours and then filtered. The filtrate was concentrated to give (R) -5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (9.89 g, 99%). MS (APCI +) [M + H] ⁺ 151.

Stage 8 . A mixture of (R) -5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (5.8 g, 38.62 mmol) in POCl ₃ (20 ml) was refluxed 5 minutes. Excess POCl _{3 was} removed in vacuo and the residue was dissolved in DCM (50 ml). The mixture was then added to a saturated solution of NaHCO ₃ (200 ml). The aqueous phase was extracted with DCM (3 × 100 ml), and the combined organic phases were dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate, and (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine (3.18 g, 49%) was obtained. ¹ H NMR (CDCl ₃ , 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-cyclopenta [d] pyrimidine (46 mg, 0.27 mmol, 1.1 eq.) Are added to the solution of tert-butyl-2- ( N- (4-chlorobenzyl) piperazine-1-carboxamido) ethyl carbamate (100 mg, 0.25 mmol) and Hunig base (0.1 ml, 0.75 mmol, 3 equiv.) In acetonitrile (3 ml). The resulting mixture was heated at 80 ° C. overnight. The reaction mixture was diluted with water and extracted with DCM, dried and concentrated to give (R) -tert-butyl-2- (N- (4-chlorobenzyl) -4- (5-methyl-6,7-dihydro-5H-cyclopenta [d ] pyrimidin-4-yl) piperazin-1-carboxamido) ethyl carbamate (40 mg, 30%). MS (ESI) m / e (M + H ⁺ ) 529.

Stage 10 . A solution of HCl in dioxane at 0 ° C is added to (R) -treot-butyl-2- (N- (4-chlorobenzyl) -4- (5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine- 4-yl) piperazin-1-carboxamido) ethyl carbamate (40 mg, 0.075 mmol) in MeOH (1 ml). The reaction mixture was stirred at 25 ° C for 1 hour. After removing the solvent, the crude product was purified by preparative HPLC to give (R) -N- (2-aminoethyl) -N- (4-chlorobenzyl) -4- (5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine -4-yl) piperazin-1-carboxamide (32 mg, 90%). MS (ESI) m / e (M + H ⁺ ) 429.2. ¹ H NMR δ = 8.56 (s, 1H), δ = 7.23-7.56 (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 = 3.40-3.43 (t, 2H), δ = 2.96-3, 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-cyclopenta [d] pyrimidin-4-yl) piperazine- 1-carboxamide

Stage 1 Ethylpulegenate (130 g, 662 mmol) in EtOAc (900 ml) was cooled to -78 ° C in a dry ice-isopropanol bath. The resulting mixture was ozonolized until the reaction mixture turned purple. At this stage, ozone generation is stopped and the reaction mixture is removed from the dry ice bath. Oxygen is bubbled through the reaction mixture until it turns yellow. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in glacial acetic acid (400 ml). The solution was cooled to 0 ° C and Zn dust (65 g, 993 mmol) was added gradually over 30 minutes, then the mixture was stirred for 2 hours and filtered through a pad of celite to remove Zn dust. Acetic acid was neutralized with aqueous NaOH and NaHCO ₃ to pH 7 and extracted with ether (3 × 800 ml). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over MgSO ₄ , concentrated, and (2R) ethyl-2-methyl-5-oxo cyclopentanecarboxylate was obtained as a 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-oxocyclo-pentanecarboxylate (106.0 g, 622.78 mmol) in MeOH (1.2 L). The reaction mixture was stirred at room temperature in a nitrogen atmosphere for 20 hours, after which the reaction was completed (according to TLC and HPLC). The reaction mixture was concentrated to remove MeOH. The resulting residue was dissolved in DCM, washed twice with H ₂ O, once with a saturated aqueous solution of sodium chloride, dried (Na ₂ SO ₄ ), filtered, concentrated to give (R) -ethyl-2-amino-5-methylcyclopent-1 -carboxylate (102 g, 97% yield) as an oil. LC / MS (APCI +) m / z 170 [M + H] ⁺ .

Stage 3 . A solution containing (R) -ethyl-2-amino-5-methylcyclopent-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) are heated to an internal temperature of 150 ° C and stirred for 17 hours. The reaction mixture was cooled and transferred to a 2 L single neck flask. The excess formamidine is then removed by distillation in high vacuum. As soon as formamidine ceases to distill off, the oil remaining in the still is dissolved in DCM and washed with a saturated aqueous solution of sodium chloride (3 × 200 ml). The combined aqueous washings were extracted with DCM. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting brown oil is dissolved in a minimal amount of DSM and the resulting solution is added via a separatory funnel to the stirred ether solution (about 5 volumes of ether per 1 volume of solution in DCM), which causes the formation of a brown precipitate. The precipitate formed is filtered through a glass filter with an average pore size, washed with ether and removed. The filtrate was concentrated, trituration with ether was repeated two or more times, then dried in high vacuum to obtain (R) -5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (93.225 g, yield 65 , 00%) as a pasty substance. LC / MS (APCI-) m / z 149.2.

Stage 4 . Pure POCl ₃ (463.9 ml, 5067 mmol) is slowly added via a dropping funnel to a solution of (R) -5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (cooled to 0 ° C) ( 152.2 g, 1013 mmol) in DCE (1.2 L). After completion of the addition, the reaction mixture was warmed to room temperature, then heated to boiling and stirred for 70 minutes. The reaction is complete (according to HPLC). The reaction mixture was cooled to room temperature and the excess POCl _{3 was} quenched in 4 portions as follows: the reaction mixture was transferred to a separatory funnel and poured dropwise into a glass containing ice and a saturated solution of NaHCO ₃ cooled in an ice bath. As soon as the addition of each portion of the reaction mixture is complete, the quenched mixture is stirred for 30 minutes to ensure complete destruction of POCl ₃ before being transferred to a separatory funnel. The mixture was transferred to a separatory funnel and extracted twice with DCM. The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified on silica gel as follows: silica gel (1 kg) is suspended in a mixture of hexane: ethyl acetate (9: 1) on a 3 L glass filter, silica gel is precipitated in vacuum, with sand on top. The crude product was charged into a DCM / hexane mixture, and the compound was eluted using 1 liter flasks in a vacuum. High Rf by-products are washed first, then (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine (104.4 g, 61.09% yield) is eluted as an oil .

Stage 5 . 4-Chloraniline (0.5 g, 3.9 mmol) was added to a solution of 2-bromo-N, N-diethylethylamine hydrobromide (1.12 g, 4.3 mmol) and N, N-diisopropylethylamine (2 ml, 11, 7 mmol) in toluene (7.8 ml). The mixture was stirred at room temperature for 5 hours. The mixture was then diluted with EtOAc (30 ml) and saturated NaHCO ₃ solution (20 ml). The organic layer was washed with H ₂ O (1 × 20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated to give 4-chloro-N- (2- (diethylamino) ethyl) benzeneamine as an oil, which was used without purification. MS (APCI +) [M + H] ⁺ 227.3.

Stage 6 . tert-Butyl-4-chlorocarbonylpiperazine-1-carboxylate (0.97 g, 3.9 mmol) is added to a solution of 4-chloro-N- (2- (diethylamino) ethyl) benzeneamine (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 was cooled to room temperature, quenched with saturated NH ₄ Cl solution (10 ml) and extracted with DCM (2 × 20 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4- (N- (4-chlorophenyl) -N- (2- (diethylamino) ethyl) carbamoyl) piperazine-1-carboxylate (311 mg, 18%). MS (APCI +) [M + H] ⁺ 439.4. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.29 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 3.70-3, 66 (m, 2H), 3.45-3.42 (m, 2H), 3.24-3.21 (m, 4H), 3.15-3.12 (m, 2H), 2.61-2 57 (m, 2H), 2.52 (q, J = 7.2 Hz, 4H), 1.42 (s, 9H), 0.99 (t, J = 7.2 Hz, 6H).

Stage 7 . Trifluoroacetic acid (1 ml) was added to a solution of tert-butyl 4- (N- (4-chlorophenyl) -N- (2- (diethylamino) ethyl) carbamoyl) piperazine-1-carboxylate (311 mg, 0.7 mmol) in DCM (5 ml). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in n-butanol (2 ml). N, N-diisopropylethylamine (0.5 ml, 3.6 mmol) was added, followed by (R) -4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta [d] pyrimidine (113 mg, 0, 84 mmol). The reaction mixture is heated at 80 ° C. for 16 hours. The mixture was then diluted with H ₂ O and extracted with DCM (2 × 20 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified by preparative HPLC to give N- (4-chlorophenyl) -N- (2- (diethylamino) ethyl) -4 - ((R) -6,7-dihydro-5-methyl-5H-cyclopenta [d] pyrimidine -4-yl) piperazin-1-carboxamide (39.9 mg, 12%). MS (APCI +) [M + H] ⁺ 471.3. ¹ H NMR (CDCl ₃ , 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), 3.77-3.70 (m, 2H), 3.51-3.44 (m, 1H), 3.39-3.02 (m, 11H), 2, 42-2.32 (m, 1H). 1.88-1.82 (m, 1H), 1.33 (t, J = 7.2 Hz, 6H), 1.15 (d, J = 6.8 Hz, 3H).

Example 3

N- (4-Chlorobenzyl) -N- (2- (diethylamino) ethyl) -4 - ((5R) -7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4- il) piperazine-1-carboxamide

Stage 1 (R) - (+) - Pulegon (76.12 g, 0.5 mmol), anhydrous NaHCO ₃ (12.5 g) and anhydrous ether (500 ml) were placed in a 1 L round-bottom flask. The reaction mixture is cooled in an ice bath under nitrogen. Bromine (25.62 ml, 0.5 mmol) was added dropwise over more than 30 minutes. The mixture was filtered and carefully added to NaOEt (21%, 412 ml, 1.11 mmol) in an ice-cooled bath. The mixture was stirred at room temperature overnight and then 5% HCl solution (1 L) and ether (300 ml) were added. The aqueous phase is extracted with ether (2 × 300 ml). The combined organic phases are washed with water, dried and concentrated. The residue was added to a heated solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5 g) in water (300 ml), then boiling ethanol (300 ml) was added to obtain a clear solution. The mixture was 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 was purified by vacuum distillation (73-76 ° C at 0.8 mm Hg) to give (2R) ethyl-2-methyl-5- (propan-2-ylidene) cyclopentanecarboxylate (63 g, 64%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J = 16 Hz, 0.5 H), 2.93 (m, 0.5 H), 2.50 -2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05 (m, 6H).

Stage 2 (2R) -ethyl-2-methyl-5- (propan-2-ylidene) cyclopentanecarboxylate (24 g, 0.122 mol) in ethyl acetate (100 ml) was cooled to -68 ° C with a dry ice / isopropanol mixture. Ozonated oxygen (5-7 ft ³ / h O ₂ ) is bubbled through the solution for 3.5 hours. The reaction mixture was purged with nitrogen at room temperature until the color faded. Ethyl acetate was removed in vacuo, the residue was dissolved in acetic acid (150 ml) and cooled with ice water. Then zinc dust (45 g) is added. The solution was stirred for 30 minutes and then filtered. The filtrate was neutralized with a 2N solution of NaOH (1.3 L) and NaHCO ₃ . The aqueous phase is extracted with ether (3 × 200 ml). The organic phases are combined, washed with water, dried, concentrated and (2R) -ethyl-2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%) is obtained. ¹ H NMR (CDCl ₃ , 400 MHz) δ 4.21 (m, 2H), 2.77 (d, J = 11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2 10 (m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 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 g, 120.9 mmol) in ethanol (100 ml) was added KOH (8.3 g, 147.9 mmol) in water (60 ml). The mixture was refluxed for 10 hours. After cooling, the solvent was removed and the residue was neutralized with concentrated HCl (12 ml) at 0 ° C and then extracted with DCM (3 × 150 ml). The solvent was removed, the residue was purified by silica gel chromatography, eluting with hexane / ethyl acetate (2: 1), and (R) -2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4- was obtained ol (12 g, 56%). MS (APCI +) [M + H] ⁺ 183.

Stage 4 . Raney Nickel (15 g) and NH ₄ OH (20 ml) are added to a suspension of (R) -2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (12 g, 65.8 mmol) in distilled water (100 ml). The mixture was refluxed for 3 hours and then filtered. The filtrate was concentrated to give (R) -5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (9.89 g, 99%). MS (APCI +) [M + H] ⁺ 151.

Stage 5 . A mixture of (R) -5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-4-ol (5.8 g, 38.62 mmol) in POCl ₃ (20 ml) was refluxed 5 minutes. Excess POCl _{3 was} removed in vacuo and the residue was dissolved in DCM (50 ml). The mixture was then added to a saturated solution of NaHCO ₃ (200 ml). The aqueous phase was extracted with DCM (3 × 100 ml), and the combined organic phases were dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate, and (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine (3.18 g, 49%) was obtained. ¹ H NMR (CDCl ₃ , 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-CPBA (8.30 g, 37.0 mmol) is added in three portions to a solution of (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine (2.5 g, 14.8 mmol) in CHCl ₃ (60 ml). The mixture was stirred at room temperature for 2 days. The mixture was cooled to 0 ° C. and Na ₂ S ₂ O ₃ (10 g) in water (60 ml) was added dropwise. Then, Na ₂ CO ₃ (6 g) in water (20 ml) was added. The reaction mixture was stirred for 20 minutes. The aqueous phase was extracted with CHCl ₃ (2 × 200 ml) and the combined organic phases were concentrated at low temperature (<25 ° C). The residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM / MeOH (20: 1), and (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine oxide was obtained (1, 45 g, 53%). ¹ H NMR (CDCl ₃ , 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 . A solution of (R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidine oxide (1.45 g, 7.85 mmol) in acetic anhydride (20 ml) is heated at 110 ° C within 2 hours. After cooling, excess solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with hexane / ethyl acetate (3: 1), to give (5R) -4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d] pyrimidin-7-yl acetate (1 , 25 g, 70%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.92 (m, 1H), 6.30-6.03 (m, 1H), 3.60-3.30 (m, 1H), 2.84 ( m, 1H), 2.40-2.20 (m, 1H), 2.15 (d, J = 6 Hz, 2H), 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-cyclopenta [d] pyrimidin-7-yl acetate is converted to (5R) -4-chloro-6,7-dihydro-5-methyl-5H -cyclopenta [d] pyrimidin-7-ol by treatment of LiOH in H ₂ O / THF followed by treatment with acid (2N HCl in water) to remove acetate groups.

Stage 9 . 4-Chlorobenzylamine (1.0 ml, 8.2 mmol) is added to a solution of 2-bromo-N, N-diethylethylamine hydrobromide (2.4 g, 9.0 mmol) and triethylamine (3.4 ml, 25 mmol) in dichloromethane (16 ml). The mixture was stirred at room temperature for 5 hours. The mixture was then concentrated to give N1- (4-chlorobenzyl) -N2, N2-diethylethan-1,2-diamine as an oil, which was used directly without purification.

Step 10. Tert-Butyl-4-chlorocarbonylpiperazine-1-carboxylate (245 mg, 0.99 mmol) is added to a solution of N1- (4-chlorobenzyl) -N2, N2-diethylethane-1,2-diamine (235 mg, 0 98 mmol) and N, N-diisopropylethylamine (0.54 ml, 2.94 mmol) in DCM (2 ml). The reaction mixture was allowed to stir at room temperature for 1 hour. The mixture was quenched with saturated NH ₄ Cl solution (2 ml) and extracted with DCM (2 × 5 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 4- (N- (4-chlorobenzyl) -N- (2- (diethylamino) ethyl) carbamoyl) piperazine-1-carboxylate (200 mg, 45%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.32 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 4.42 (s, 2H ), 3.45-3.40 (m, 4H), 3.25-3.20 (m, 4H), 3.18 (t, J = 6.8 Hz, 2 Hz), 2.56 (t , J = 6.8 Hz, 2H), 2.49 (q, J = 7.2 Hz, 4H), 1.46 (s, 9H), 0.99 (t, J = 7.2 Hz, 6H )

Stage 11 . Trifluoroacetic acid (1 ml) was added to a solution of tert-butyl 4- (N- (4-chlorobenzyl) -N- (2- (diethylamino) ethyl) carbamoyl) piperazine-1-carboxylate (88 mg, 0.19 mmol) in DCM (1 ml). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in n-butanol (1 ml). N, N-diisopropylethylamine (0.11 ml, 0.6 mmol) was added to the solution. Then, (5R) -4-chloro-6,7-dihydro-5-methyl-5H-cyclopenta [d] pyrimidin-7-ol (37 mg, 0.20 mmol) was added to the solution. The reaction mixture is heated at 80 ° C. for 16 hours. The mixture was then diluted with H ₂ O (1 ml) and extracted with DCM (2 × 5 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product is purified by preparative HPLC to give N- (4-chlorobenzyl) -N- (2- (diethylamino) ethyl) -4 - ((5R) -6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta [d] pyrimidin-4-yl) piperazin-1-carboxamide (19.9 mg, 21%). MS (APCI +) [M + H] ⁺ 501.3. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.46 (s, 1H), 7.34 (d, J = 8.4 Hz, 4H), 7.13 (d, J = 8.4 Hz, 4H ), 5.50 (t, J = 8 Hz, 1H), 5.28 (dd, J = 3.6, 8.4 Hz, 1H), 4.45 (s, 4H), 4.14-4 04 (m, 4H), 3.94-3.81 (m, 4H), 3.51-3.42 (m, 8H), 3.20-3.00 (m, 16H), 2.73 -2.64 (m, 2H), 2.40-2.20 (m, 4H), 2.05-1.98 (m, 1H), 1.86-1.78 (m, 1H), 1 33 (d, J = 7.2 Hz, 3 Hz), 1.28 (t, J = 7.2 Hz, 12H), 1.21 (d, J = 6.8 Hz, 3 Hz).

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

Although the invention has been described in conjunction with numbered embodiments, it is understood that the invention is not limited to these embodiments. 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 an illustration only of the principles of the present invention.

Used in the above description and in the following claims, the words “comprise”, “comprising”, “include”, “include” and “include” are intended to indicate the presence of established signs; integers, components or stages, but they do not exclude the presence or addition of one or more features, integers, components, stages or their groups.

table 2 ADDITIONAL EXPERIMENTAL DATA Structure Example No. AKT1 Enz IMAP Average IC50 PKA Enz IMAP Average IC50 Selectivity

Structure 8 Example 1 08.21 797.38 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 14.68

Structure 2 Example 13 103.05 2245.35 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 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

Claims (15)

1. The compound of formula I

and its enantiomers and pharmaceutically acceptable salts, where:
R ¹ and R ^{1a are} independently selected from H, Me, Et, vinyl, CF ₃ , CHF ₂ or CH ₂ F;
R ² represents H, OH, OMe or F;
R ^2a represents H, Me or F;
R ³ represents H, Me, Et or CF ₃ ;
A represents

;
G is phenyl optionally substituted with one to four R ^e groups, or a 5-6 membered heteroaryl containing one heteroatom selected from sulfur, optionally substituted with halogen;
R ⁵ and R ⁶ independently represent H, OCH ₃ , C ₃ -C ₆ cycloalkyl optionally substituted with F, OH, C ₁ -C ₃ alkyl or O (C ₁ -C ₃ alkyl), 4-6 membered heterocycle containing one heteroatom selected from nitrogen, optionally substituted with F, OH, C ₁ -C ₃ alkyl, cyclopropylmethyl or -C (= O) (C ₁ -C ₃ alkyl), or C ₁ -C ₆ alkyl optionally substituted one or more groups independently selected from OH, oxo, O (C ₁ -C ₆ alkyl), CN, F, NH ₂ , NH (C ₁ -C ₆ alkyl), O (C ₁ -C ₆ alkyl ) ₂ , cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofur anil, oxetanyl or tetrahydropyranyl,
or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring containing one heteroatom selected from nitrogen, optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ OH, O (C ₁ -C ₃ alkyl), C (= O) CH ₃ , NH ₂ , NHMe, N (Me) ₂ , S (O) ₂ CH ₃ , cyclopropylmethyl and C ₁ -C ₃ alkyl, or
R ^c represents hydrogen, and R ^d and R ⁶ together with the atoms to which they are attached form a 4-6 membered heterocyclic ring containing one nitrogen atom;
R ^a and R ^b represent H,
or R ^a represents H, a R ^b and R ⁶ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring containing one or two nitrogen atoms;
R ^c and R ^d represent H or Me,
or R ^c and R ^d together with the atom to which they are attached form a cyclopropyl ring;
each R ^e is independently halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, O- (C ₁ -C ₆ -alkyl), CF ₃ , OCF ₃ , S (C ₁ -C ₆ - alkyl), CN, OCH ₂ -phenyl, NH ₂ , NO ₂ , NH- (C ₁ -C ₆ -alkyl), N- (C ₁ -C ₆ -alkyl) ₂ , piperidine, pyrrolidine, CH ₂ F, CHF ₂ , OCH ₂ F, OCHF ₂ , OH, SO ₂ (C ₁ -C ₆ alkyl), C (O) NH ₂ , C (O) NH (C ₁ -C ₆ alkyl) and C (O) N (C ₁ -C ₆ alkyl) ₂ ;
m and n are independently 0, 1, 2, or 3, provided that (m + n) must be 2, 3, or 4; and
p is 0 or 1. 2. The compound according to claim 1, where R ³ represents H, methyl, which is optionally in the (S) configuration, or ethyl. 3. The compound according to claim 1, where R ¹ represents hydrogen or methyl, which is optionally in the (R) configuration. 4. The compound according to claim 1, where R ^1a represents hydrogen or methyl. 5. The compound according to claim 1, where R ² represents H, F or OH. 6. The compound according to claim 1, where R ^2a represents H or F. 7. The compound according to claim 1, where G is 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-thiomethylphenyl, 3-fluoro-4-chlorophenyl, 2, 4-dichlorophenyl or 3,4-dichlorophenyl or

. 8. The compound according to claim 1, where R ^a represents H, R ^b represents H, R ^c represents H, R ^d represents N. 9. The compound according to claim 1, where R ⁵ represents H or ethyl and R ⁶ represents 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 represents a

or

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

or

. 13. A pharmaceutical composition having the properties of an inhibitor of AKT 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 medicine in the treatment of AKT protein kinase-mediated 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.