Chemical compounds-759

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyarazol-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or pharmaceutically acceptable salt thereof, having inhibiting activity with respect to Trk (tropomyosin-related kinase). The compounds can be used as a medicinal agent for treating cancer. The invention also relates to use of said compound of pharmaceutically acceptable salt thereof to produce a medicinal agent for treating cancer in a warm-blooded animal and a pharmaceutical composition containing said compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, a solvent or an inert filler.

EFFECT: high efficiency of using the compound.

4 cl, 26 ex

 

The technical field of the invention

The present invention relates to a new compound, its pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of this compound in the manufacture of medicines for use in the treatment and prevention of myeloproliferative disorders and cancer.

The prior art inventions

Receptor tyrosine kinase (RTK) are a subfamily of protein kinases, which play a critical role in the signaling cells, and is involved in various cancer-related processes, including cell proliferation, survival, angiogenesis and metastasis. At the present time have been identified up to 100 different RTK, including tropomyosin kinase (Trk).

Trk are high-affinity receptors, activated by a group of soluble growth factors called neurotrophins (NT). The family of Trk receptor consists of three members - TrkA, TrkB and TrkC. Among the NT is (i) a growth factor nerve (NGF), which activates TrkA, (ii) Mospromstroy growth factor (BDNF) and NT-4/5, which activate TrkB, and (iii) NT3, which activates TrkC. Each Trk receptor contains an extracellular region (binding ligand), a transmembrane region and the intracellular region (including the region of the kinase). PEFC is binding ligand kinase catalyzes autophosphorylation and initiates located downstream transcription ways of signal transduction.

Trk is widely expressed in neural tissue during development, where Trk is crucial for the protection and survival of these cells. The post-embryonic role for Trk/neurotrophin axis (or path), however, remains controversial. There are reports showing that Trk play an important role in the development and functioning of the nervous system (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).

In the past decade has published a large number of literary documentation linking the Trk signaling with cancer. For example, while the Trk is expressed at low levels outside the nervous system in the adult, expression of Trk increases in the last stages of prostate cancer. And normal tissue of the prostate, androgen-dependent prostate tumors Express low levels of Trk a and undetectable levels of TRK b and C. However, all isomorphy Trk receptors as well as their cognate ligands, buck regulated at the last stage androgenization prostate cancer. There is additional evidence that these cells are the last stage of prostate cancer for their survival become dependent on TGC/neurotrophin axis. Thus, inhibitors of Trk may lead to class apoptosisinducing agents specific for androgenization prostate cancer (Weeraratna, A.T. et al., The Prostate, 2000, 45, I40-I48).

In addition, literaturtage shows what overexpression, activation, amplification and/or mutation Trk associated with secretory breast carcinoma (Cancer Cell, 2002, 2, 367-376), cancer of the colon and rectum (Bardelli et al. Science, 2003, 300, 949-949) and ovarian cancer (Davidson, C. et al. Clinical Cancer Research, 2003, 9, 2248-2259).

There are several reports of selective Trk tyrosine kinase inhibitors. Cephalon described CEP-751, CEP-701 (George, D. et al., Cancer Research, 1999, 59, 2395-2341) and other indolocarbazole analogues (WO 0114380) as inhibitors of Trk. It was shown that CEP-701 and/or SER, when combined with surgical or chemically caused by the removal of androgen, have the best effect in comparison with exclusively monotherapy. GlaxoSmithKline revealed some oxindole compounds as inhibitors of Trk WO 0220479 and WO 0220513. Recently Japan Tobacco announced pyrazolecontaining cyclic compounds as inhibitors of Trk (JP 2003231687 A). Pfizer has also recently released some isothiazoline Trk And inhibitors (Bioorg. Med. Chem. Lett. 2006, 16, 3444-3448).

In addition to the above Vertex Pharmaceuticals described pyrazol compounds as inhibitors of GSK3, Aurora, etc. in WO 0250065, WO 0262789, WO 03027111 and WO 200437814; and AstraZeneca reported pyrazol compounds as inhibitors against IGF-1 receptor kinase (WO 0348133). AstraZeneca also reported Trk inhibitors in International patent applications WO 2005/049033, WO 2005/103010, WO 2006/082392, WO 2006/087530 and WO 2006/087538.

D. whim this family of RTK is the JAK family. JAK (Janus-associated kinase - anusvara kinase)/STAT (signal transducers and activators or reduced - signal transducers and activators or transcription) signaling pathway is involved in various hyperproliferative and cancer-related processes, including development, cell cycle, apoptosis, angiogenesis, invasion, metastasis, and evasion of the immune system (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).

The JAK family consists of four preceptory tyrosinekinase Tyk2, JAK1, JAK2 and JAK3, which play a critical role in cytokine - and growth factor-mediated signal transduction. Binding of the cytokine and/or growth factor with its receptor(s) of the cell surface causes dimerization of the receptor and facilitates the activation receptorsare JAK-autophosphorylation. Activated JAK phosphorylates the receptor, creating sites merge SH2 region containing signaling proteins, in particular the STAT family (STAT1, 2, 3, 4, 5A, 5b and 6) proteins. Receptorsare STAT themselves phosphorylated JAK, promoting their dissociation from the receptor and subsequent dimerization and move to the nucleus. If only in the nucleus, STAT bind DNA and interact with other transcription factors to regulate the expression of many genes including, but not limited to, genes encoding inhibitors of apoptosis (for example, Bcl-XL, Mcl 1) and cell cycle regulation (e.g. the, Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).

Over the past decade has published a large amount of scientific literature linking constitutive JAK and/or STAT alarms with hyperproliferative disorders and cancer. Constitutive activation of STAT family, particularly STAT3 and STAT5 was detected in a wide range of cancers and hyperproliferative disorders (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324). In addition, Abbasanta activation pathway JAK/STAT provides significant proliferative and/or anti-apoptotic stimulation during transcription of many kinases (e.g., Flt3, EGFR), constitutive activation of which has been implicated as a key factor in various cancers and hyperproliferative disorders (Tibes et al., Annu Rev Pharmacol Toxicol 2550, 45, 357-384; Choudhary et al., International Journal of Hematology 2005, 82(2), 93-99; Sordella et al., Science 2004, 305, 1163-1167). In addition, the damage of negative regulatory proteins, such as suppressor of cytokine signaling proteins (SOCS), may also affect the activation status of JAK/STAT signaling pathway in disease (JC Tan and Rabkin R, Pediatric Nephrology 2005, 20, 567-575).

Several notirovannyh forms of JAK2 have been identified in different parameters of the disease. For example, translocation resulting in the fusion region of the JAK2 kinase with the oligomeric region, TEL-JAK2, Bcr-JAK2 and PCM1-JAK2, was is involved in the pathogenesis of various hematological malignancies (SD Turner and Alesander DR, Leukemia, 2006, 20, 572-582). Later acquired unique mutation encoding a substitution of valine for phenylalanine (V617F) JAK2 was detected in a significant number of patients exclude polycythemia Vera, essential trombozitemia and idiopathic myelofibrosis and to a lesser extent in several other diseases. Mutated JAK2 protein is capable of activating signaling during transcription in the absence of stimulation of cytokines, leading to Autonomous growth and/or hypersensitivity to cytokines, and, as expected, plays a critical role in the initiation of these diseases (MJ Percy and McMullin MF, Hematological Oncology 2005, 23(3-4), 91-93).

JAK (particularly JAK3) play an important biological role in the immunosuppressive region, and there are reports of inhibitors of JAK kinase as tools to prevent rejection of transplanted organs (Changelian, P.S. et al, Science, 2003, 302, 875-878). Merck (Thompson, J.E. et al Bioorg. Med. Chem. Lett. 2002, 12, 1219-1223) and Incyte (WO 2005/105814) reported that based on the imidazole inhibitors of JAK2/3 with an active content of the enzyme on a single nm levels. Recent publications Vertex PCT described azaindole as JAK inhibitors (WO 2005/95400). AstraZeneca announced quinoline-3-carboxamide as JAK3 inhibitors (WO 2002/92571).

In addition to the above Vertex Pharmaceutical described pyrazol compounds as inhibitors of GSK3, Aurora, etc. in WO 2002/50065, WO2002/62789, WO 2003/027111 and WO 2004/37814; and AstraZeneca reported pyrazol compounds as inhibitors against receptor kinase IGF-1 - WO 2003/48133 - and Trk WO 2005/049033, WO 2005/103010, WO 2006/082392.

Summary of the invention

In accordance with the present invention, the applicants, therefore, have discovered new compounds of Formula (I):

or their pharmaceutically acceptable salts.

It is believed that the compounds of Formula (I)or their pharmaceutically acceptable salts, have the best effective, metabolic and/or pharmacodynamic properties.

It is believed that the compounds of Formula (I)or their pharmaceutically acceptable salts, possess inhibitory activity of Trk kinases and therefore is applicable for their antiproliferative and/or proapoptotic (such as anti-cancer) activity and in the treatment of the body of humans or animals. The invention also relates to methods for producing the aforementioned compounds, or their pharmaceutically acceptable salts, to pharmaceutical compositions containing them and to their use in the manufacture of medicines for use in the production of anti-proliferative and/or proapoptotic effect in a warm-blooded animal such as man.

Also, in accordance with the present invention, applicants provide methods of using such compounds or their pharmaceutically acceptable salts, in the treatment of cancer.

The properties of the compounds of Formula (I)or their pharmaceutically acceptable salts are expected to be important in the treatment of painful conditions associated with cell proliferation such as cancers (solid tumors and leukemia), fibroproliferative and differentiating disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone disease and eye disease with proliferation of the retinal vessel.

In addition, the compounds of Formula (I)or their pharmaceutically acceptable salts are expected to be significant in the treatment or prevention of cancers selected from congenital fibrosarcoma, adenosarcoma kidney, mesothelioma, acute myeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma, melanoma, oesophageal cancer, myeloma, hepatocellular, pancreatic and cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, cancer of the colon and rectum, prostate cancer, including hormonesparanoika prostate cancer, bladder cancer, melanoma, lung cancer - non-small cell lung cancer (NCLR), and small cell lung cancer (the HRC), gastric cancer, head and neck cancer, kidney cancer, lymphoma, thyroid cancer, including papillary thyroid cancer, mesothelioma and leukemia, especially ovarian cancer, breast cancer, cancer of the colon and rectum, prostate cancer and lung cancer - MCLR and MCLR; more prostate cancer; and still more gormonzawisimogo prostate cancer.

The compounds of Formula (I)or their pharmaceutically acceptable salts as additionally assume significance in the treatment or prevention of inflammatory disorders, including conditions such as: allergies, including allergic rhinitis/sinusitis, skin allergies (urticaria/urticarnae rash, angioedema, atopic dermatitis), food allergies, drug allergies, allergies to insects, and rare allergic disorders such as mastocytosis, asthma; arthritis, including osteoarthritis, rheumatoid arthritis, and spondylarthrosis; autoimmune conditions, including systemic lupus erythematosus, dermatomyositis, polymyositis, inflammatory neuropathies (Guillain-Barre, inflammatory polyneuropathy), Crohn's disease, ulcerative colitis, vasculitis (Wegener's granulomatosis, Nowotny polyarteritis), and rare disorders such as polymyalgia rheumatica, temporal arteritis diagnostics, Sjogren syndrome, Bechet disease, syndrome Charge-Strauss and Takayasu's arteritis; cardiovascular inflammation; gastrointe tinline inflammation, infectious and immunitetni; leukocyte and immunological, neuroforaminal violations; and transplantation. Additionally, the compounds of Formula (I)or their pharmaceutically acceptable salts are expected to be significant in the treatment or prevention of persistent pain States, including neuropathic pain and pain associated with inflammation.

The compounds of Formula (I)or their pharmaceutically acceptable salts, as are also supposed to possess inhibitory activity of JAK kinases and therefore is applicable for their antiproliferative and/or proapoptotic activity, and methods of treatment of a human body or animal. The invention also relates to methods for making the compounds, or pharmaceutically acceptable salts, to pharmaceutical compositions containing it and to its use in the manufacture of medicines for use in the production of anti-proliferative and/or proapoptotic effect in a warm-blooded animal such as man. Also in accordance with the present invention, applicants provide methods of using the compounds, or pharmaceutically acceptable salts in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer.

The properties of the compounds of Formula (I)or their pharmaceutically acceptable salts, as expected, b is to be significant in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer, inhibition of tyrosine kinases, particularly the JAK family and more JAK2. Treatment is focused on the activity of tyrosine kinases, particularly on the activity of the JAK family and more on the activity of JAK2, which is involved in various myeloproliferative disorders, myelodysplastic syndrome and processes associated with cancer. Thus, inhibitors tyrosinekinase, particularly the JAK family, and more JAK2 is expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia Vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemia, myeloma and lymphoma, tumors of the Central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Inhibitors of tyrosine kinase, particularly inhibitors of the JAK family and more inhibitors of JAK2 are also expected to be useful for the treatment of other proliferative diseases including, but not limited to, autoimmune, inflammatory, neurologists the definition and cardiovascular disease.

In addition, the compounds of Formula (I)or their pharmaceutically acceptable salts are expected to be significant in the treatment or prophylaxis against myeloproliferative disorders selected from chronic myeloid leukemia, true polycythemia, essential of thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, cancer of the colon and rectum, prostate cancer, cancer bladder, melanoma. lung cancer - non-small cell lung cancer (NCLR) and small-cell lung cancer (MCLR), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukemia, particularly myeloma, leukemia, ovarian cancer, breast cancer and prostate cancer.

Detailed description

The present invention provides compounds of formula (I):

or their pharmaceutically acceptable salts, where

Q may be selected from N and C(R3);

D can be selected from N and CH;

R1can be selected from H, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, 3-clanlogo carbocycle, 5-membered heterocyclyl, -OR1a, -SR1a, -N(R1a)2, -N(R1a)C(O)R1b, -N(R1a)N(R1a)2, -NO2, -C(O)H, -C(O)R1b, -C(O)2R1a, -C(O)N(R1a)2, -OC(O)N(R1a)2, -N(R1a)C(O)2R1a, -N(R1a)C(O)N(R1a)2, -OC(O)R1b, -S(O)R1b, -S(O)2R1b, -S(O)2N(R1a)2, -N(R1a)S(O)2R1b, -C(R1a)=N(R1aand-C(R1a)=N(OR1a), where the mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, 3-5-membered carbocyclic and 5-membered heterocyclyl may be optionally substituted by one or more R10;

R1ain each instance can be independently selected from H and C1-6of alkyl, 3-to 5-membered carbocyclic and 5-membered heterocyclyl where the above-mentioned C1-6alkyl, 3-to 5-membered carbocyclic and 5-membered heterocyclyl in each case can be optionally and independently substituted by one or more R10;

R1bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, 3-5-membered carbocycle and 5-membered heterocyclyl where the above-mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, 3-5-membered carbocyclic and 5-membered heterocyclyl in each case can be optionally and independently substituted by one or more R10;

R2can be selected is C N, halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -N(R2a)S(O)2R2b, -C(R2a)=N(R2aand-C(R2a)=N(OR2a), where the mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, carbocyclic and heterocyclyl may be optionally substituted by one or more R20;

R2ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle where the above-mentioned C1-6alkyl, carbocyclic and heterocyclyl in each case can be optionally and independently substituted by one or more R20;

R2bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle where the above-mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, carbocyclic and heterocyclyl in each case can be optionally and independently substituted by one or more R20;

R3can be selected from H, halogen, -CN, C1-6Alki is a, With2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -N(R3a)N(R3a)2, -NO2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -OC(O)N(R3a)2, -N(R3a)C(O)2R3a, -N(R3a)C(O)N(R3a)2, -OC(O)R3b, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, -N(R3a)S(O)2R3b, -C(R3a)=N(R3aand-C(R3a)=N(OR3a), where the mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, carbocyclic and heterocyclyl may be optionally substituted by one or more R30;

R3ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle where the above-mentioned C1-6alkyl, carbocyclic and heterocyclyl in each case can be optionally and independently substituted by one or more R30;

R3bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle where the above-mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, carbocyclic and heterocyclyl in each case can be optionally and independently substituted by one or more R30;

R4can be selected from H, -CN, C1-6of alkyl, C2-6alkenyl,2-6alkyne is a, carbocycle, heterocyclyl, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2-C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4aand-C(R4a)=N(OR4a), where the mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, carbocyclic and heterocyclyl may be optionally substituted by one or more R40;

R4ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle where the above-mentioned C1-6alkyl, carbocyclic and heterocyclyl in each case can be optionally and independently substituted by one or more R40;

R4bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle where the above-mentioned C1-6alkyl, C2-6alkenyl,2-6quinil, carbocyclic and heterocyclyl in each case can be optionally and independently substituted by one or more R40;

R5can be independently selected from halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR5a, -SR5a, -N(R5 )2, -N(R5a)C(O)R5b, -N(R5a)N(R5a)2, -NO2, -C(O)H, -C(O)R5b, -C(O)2R5a, -C(O)N(R5a)2, -OC(O)N(R5a)2, -N(R5a)C(O)2R5a, -N(R6a)C(O)N(R5a)2, -OC(O)R5b, -S(O)R5b, -S(O)2R5b, -S(O)2N(R5a)2, -N(R5a)S(O)2R5b, -C(R5a)=N(R5aand-C(R5a)=N(OR5a);

R5ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle;

R5bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle;

R10in each instance can be independently selected from halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR10a, -SR10a, -N(R10a)2, -N(R10a)C(O)R10b, -N(R10a)N(R10a)2, -NO2, -C(O)H, -C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -OC(O)N(R10a)2, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2, -OC(O)R10b, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C(R10a)=N(R10aand-C(R10a)=N(OR10a);

R10ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heteros is Lila;

R10bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle;

R20in each instance can be independently selected from halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20aand-C(R20a)=N(OR20a);

R20ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle;

R20bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle;

R30in each instance can be independently selected from halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR30a, -SR30a, -N(R30a)2, -N(R30a)C(O)R30b, -N(R30a)N(R30a)2, -NO2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a) , -OC(O)N(R30a)2, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2, -OC(O)R30b, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, -C(R30a)=N(R30aand-C(R30a)=N(OR30a);

R30ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle;

R30bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle;

R40in each instance can be independently selected from halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40aand-C(R40a)=N(OR40a);

R40ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle; and

R40bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6Ala the Nile, carbocycle and heterocycle.

In this description, the prefix Cx-yas used terms such as Cx-yalkyl and the like (where x and y are integers), specifies the scope of the numeric values of the carbon atoms present in the group; for example, With1-4alkyl includes With1alkyl (methyl), C2alkyl (ethyl), C3alkyl (propyl and isopropyl) and (C4alkyl (butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl).

Alkyl As used here, the term "alkyl" refers to both unbranched and branched saturated hydrocarbon radicals, having the specified number of carbon atoms. References to individual alkyl groups such as "propyl"are specific only for option unbranched chain, and references to individual branched alkyl groups, such as "isopropyl", are specific only for option branched chain.

Alkenyl - As used here, the term "alkenyl" refers to both unbranched and branched hydrocarbon radical having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, "C2-6alkenyl" includes, but is not limited to, groups such as2-6alkenyl,2-4alkenyl, ethynyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl and 5-hexenyl.

Quinil - As used here, the term "quinil" refers to both unbranched and branched hydrocarbon radical having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, "C2-6quinil" includes, but is not limited to, groups such as2-6quinil,2-4quinil, ethinyl, 2-PROPYNYL, 2-methyl-2-PROPYNYL, 3-butynyl, 4-pentenyl and 5-hexenyl.

Halogen As used here, the term "halogen" refers to fluorine, chlorine, bromine and iodine. In one embodiment, "halogen" means fluorine, chlorine and bromine. In another embodiment, "halogen" means fluorine and chlorine.

Carbocyclic - As used here, the term "carbocyclic" refers to saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 cyclic atoms, of which one or more-CH2groups can be optionally substituted by a corresponding number of-C(O)- groups. Illustrative examples "carbocyclic" include, but are not limited to, substituted, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopent, 1-oxoindole, phenyl and tetralinyl. In one embodiment, "carbocyclic" may mean cyclopropyl.

3-5-membered carbocycles In one variant, "carbocyclic" maybe oz is acute "3-5-membered carbocycles." The term "3-to 5-membered carbocyclic" refers to saturated or partially saturated monocyclic carbon ring, containing 3-5 cyclic atoms, of which one or more-CH2groups can be optionally substituted by a corresponding number of-C(O)- groups. Illustrative examples of the "3-to 5-membered carbocyclic include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopent and cyclopentenyl. In one embodiment, "3-5-membered carbocyclic" may mean cyclopropyl.

Heterocyclyl - As used here, the term "heterocyclyl" refers to saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 cyclic atoms, of which at least one cyclic atom selected from nitrogen, sulfur and oxygen, and which may, if not specified otherwise, to be bound through a carbon atom or nitrogen, and of which-CH2- group can optionally be replaced by-C(O)-. Cyclic sulfur atoms can be optionally oxidized with the formation of the S-oxides. Cyclic nitrogen atoms can be optionally oxidized with the formation of N-oxides. Illustrative examples of the term "heterocyclyl" include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperazinyl, furanyl, imidazolyl, indolyl, ethenolysis, isothiazolin, isoxazolyl, morpholino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidin, 2-oxo-1,3-thiazolidine, piperazinil, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, Pirro is idini, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridinyl, hinely, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, diazolidinyl, thiomorpholine, thiophenyl, pyridinyl-N-oxides and chinoline-N-oxides.

5 - or 6-membered heterocyclyl In another embodiment, "heterocyclyl" can mean "5 - or 6-membered heterocyclyl", which refers to a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 cyclic atoms, of which at least one cyclic atom selected from nitrogen, sulfur and oxygen, and of which-CH2group can be optionally substituted-C(O)- group. Unless otherwise specified, "5 - or 6-membered heterocyclyl" can be linked via a carbon atom or nitrogen. Cyclic nitrogen atoms can be optionally oxidized with the formation of N-oxide. Cyclic sulfur atoms can be optionally oxidized with the formation of the S-oxides. Illustrative examples of the "5 - or 6-membered heterocyclyl" include, but are not limited to, 3,5-dioxopiperazinyl, furanyl, imidazolyl, isothiazolin, isoxazolyl, morpholino, oxazolyl, 2-oxopyrrolidin, 2-oxo-1,3-thiazolidine, piperazinil, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridinyl, tetrahydrofuranyl, tetrahed opyanil, thiazolyl, thiadiazolyl, diazolidinyl, thiomorpholine, thiophenyl, pyridine-N-oxides.

6-membered heterocyclyl In still another embodiment, "heterocyclyl" and "5-or 6-membered heterocyclyl" can mean "6-membered heterocyclyl," which refers to a saturated, partially saturated or unsaturated, monocyclic ring containing 6 cyclic atoms, of which at least one cyclic atom selected from nitrogen, sulfur and oxygen, and of which-CH2group can be optionally substituted-C(O)- group. Unless stated otherwise, the "6-membered heterocyclyl" can be linked via a carbon atom or nitrogen. Cyclic nitrogen atoms can be optionally oxidized with the formation of N-oxide. Cyclic sulfur atoms can be optionally oxidized with the formation of the S-oxides. Illustrative examples of the "6-membered heterocyclyl" include, but are not limited to, 3,5-dioxopiperazinyl, morpholino, piperazinil, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl and pyrimidinyl.

5-membered heterocyclyl In an additional variant, "heterocyclyl" and "5-or 6-membered heterocyclyl" can mean "5-membered heterocyclyl," which refers to a saturated, partially saturated or unsaturated, monocyclic ring containing 5 cyclic atoms, of which at least one cyclic atom selected the C nitrogen, sulfur and oxygen, and of which-CH2group can be optionally substituted-C(O)- group. Unless otherwise specified, the "5-membered heterocyclyl" can be linked via a carbon atom or nitrogen. Cyclic nitrogen atoms can be optionally oxidized with the formation of N-oxide. Cyclic sulfur atoms can be optionally oxidized with the formation of the S-oxides. Illustrative examples of the "5-membered heterocyclyl" include, but are not limited to, furanyl, imidazolyl, isothiazolin, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyrrolidinyl, tetrahydrofuranyl, thiazolyl and thiophenyl.

When a particular group of R (for example, R1a, R10and so on) is present in the compound of formula (I) more than once, meaning that each choice of the group of R is independent in each case from any selection in any other case. For example, -N(R)2the group expects to include: (1) such N(R)2group in which both of the substituent R are the same, such as those in which both of the substituent R are, for example, C1-6by alkyl; and 2) such-N(R)2group, in which each substituent R is different, such as those in which one substituent R denotes, for example, N, and the other substituent R denotes, for example, carbocyclic.

Unless specifically stated, linking atom group may be any suitably the atom of this group; for example, propyl includes prop-1-yl and prop-2-yl.

An effective amount As used here, the phrase "effective amount" means an amount of compound or composition that is sufficient to significantly and positively modify the symptoms and/or conditions that will be treated (for example, to provide a positive clinical response). An effective amount of the active ingredient for use in pharmaceutical compositions will vary depending on the individual state, which will be treated, the severity of the condition, the duration of treatment, type of joint therapy, specific active ingredient(s), which will take specific used pharmaceutically acceptable inert filler(s)/carrier(s) and the like factors within the knowledge and expertise of the treating physician.

In particular, an effective amount of the compounds of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically to reduce the warm-blooded animal, such as man, signs of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with signs of cancer and myeloproliferative diseases the risk of deterioration.

This group - As used here, the phrase "the walking group assumes toward groups, easily replaced by a nucleophile such as an amine nucleophile, alcoholic nucleophile or tylny nucleophile. Examples of suitable leaving groups include halogen, such as chlorine and bromine; and sulfonyloxy, such as methanesulfonamido and toluene-4-sulfonyloxy.

Optionally substituted As used here, the phrase "optionally substituted," indicates that substitution is optional and therefore it is possible for the specified group to be either substituted or unsubstituted. If desired substitution replaced can be any number of hydrogen atoms in the indicated group with the choice of the mentioned substituents, provided that not disturbed the normal valency of the atoms of certain zamestitel R, and such substitution results in a stable connection.

One or more, In one embodiment, when a separate group designated as optionally substituted by one or more substituents, in particular, may be unsubstituted. In another embodiment, the specific group may carry one substituent. In another embodiment, a single substituent R can carry two Deputy. In still another embodiment, a separate group can carry three Deputy. In yet another variant, a separate group can carry four Deputy. In an additional embodiment, separate the group can carry one or two Deputy. In another additional embodiment, a separate group may be unsubstituted or may bear one or two Deputy.

Pharmaceutically acceptable - As used here, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the medical voiced opinion, suitable for use in contact with the tissues of humans and animals without increased toxicity, irritation, allergic response, or other problem or difficulty, in accordance with an acceptable ratio of benefit/risk.

Protective group As used here, the term "protective group" assumes toward groups used to protect selected reactive groups (such as carboxy, amino, hydroxy and mercapto groups) from undergoing undesired reactions.

Illustrative examples of suitable protective groups for the hydroxy-group include, but are not limited to, alkyl group; alcoholnye groups, such as acetyl; aroline group such as benzoyl; silyl groups such as trimethylsilyl; and arylmethyl groups such as benzyl. Conditions unprotect for the above-mentioned protected hydroxy group will certainly vary from the choice of protective groups. So, for example, alkyl group, such as alcoolica or arolina group, Monothelite, for example, by hydrolysis with a suitable base, such as hydroxide of alkali metal such as lithium hydroxide or sodium. Alternative silyl group, such as trimethylsilyl, can be removed, for example, using fluoride or aqueous acid; or arylmethyl group such as benzyl group can be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-charcoal grill.

Illustrative examples of suitable protective groups for amino groups include, but are not limited to, acyl groups; alcoholnye groups, such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl; arylethoxysilanes groups, such as benzyloxycarbonyl; and aroline group as benzoyl. Conditions unprotect for the above protected amino certainly vary from choice of protective groups. So, for example, alkyl group, such as alcoolica, or alkoxycarbonyl, group, or arolina group, can be removed for example, by hydrolysis with a suitable base, such as hydroxide of alkali metal such as lithium hydroxide or sodium. Alternative alkyl group, such as tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid as hydrochloric, black, phosphoric acid or triperoxonane the acid, and arylethoxysilanes group, such as benzyloxycarbonyl group can be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal, or by treatment with a Lewis acid, such as trichloride boron. A suitable alternative protecting group for a primary amino group, for example, is colorina group which can be removed by treatment with alkylamines, such as dimethylaminopropylamine or 2-hydroxyethylamino, or hydrazine. Other suitable protecting group for an amine, for example, a cyclic ether, such as tetrahydrofuran, which can be removed by treatment with a suitable acid, such as triperoxonane acid.

The protective group can be removed at any suitable stage of the synthesis using conventional techniques, well known in chemistry, or they can be removed during a subsequent reaction stage or process.

As for the substituent R1as an illustration, the following definitions of the substituents have the values:

Disclosed here are the links, in many cases, were identified and/or verified using ACD/Name from ACD/Labs®.

The compounds of formula (I) can form pharmaceutically acceptable acid or basic salts, and in such cases, it may be intended application connection in the form of salts. Examples of acid salts of joining include acetate, adipate, ascorbate, benzoate, bansilalpet, bicarbonate, bisulfate, butyrate, comfort, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, aconsultant, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulphonic, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymet, lactate, salt, malic acid, maleate, methanesulfonate, meglumin, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenyl acetate, phosphate, diphosphate, picrate, pivalate, propionate, salt Hinn acid, salicylate, stearate, succinate, sulpham, sulfanilate, sulfate, tartrate, tosylate (p-toluensulfonate), triptorelin, undecanoate. Examples of basic salts include ammonium salts; alkali metal salts such as sodium salt, l is tiy and potassium; salts of alkaline-earth metals, such as aluminium salts, calcium and magnesium; salts with organic bases, such as salts dicyclohexylamine and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, etc. also, the basic nitrogen-containing groups can be quaternion using such reagents as: low alkylhalogenide, such as methyl, ethyl, propyl, and butylaldehyde; diallylsulfide, such as dimethyl, diethyl, dibutil; dimycolate; long chain halides such as decyl, lauryl myristyl and stearylamine; arylalkylamine, such as benzylbromide and other Preferred non-toxic physiologically acceptable salts, although other salts may be useful, such as in the separation and purification of products.

Salts can be obtained by conventional means, such as the interaction of the free base of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as water which is removed in vacuo or by lyophilization or replacement of the anion in an existing salt for another anion on a suitable ion-exchange resin.

Some compounds of formula (I) may have chiral centres and/or geometric isomeric centres (E - and Z - isomers), and it should be understood that the invention about vative all such optical, diastereoisomeric and geometric isomers. The invention further relates to any and all tautomeric forms of the compounds of formula (I).

Also should be understood that certain compounds of formula (I) can exist in solvated, and resolutional forms, such as, for example, hydrated forms. Should be understood that the invention encompasses all such solvated forms.

An additional variant embodiment of the invention are the following. These additional options embodiments relate to compounds of formula (I) and their pharmaceutically acceptable salts. When appropriate, can be applied to such specific substituents, any of the definitions, requirements or variations of the embodiments identified above or in the future.

Q

In one embodiment, Q may be selected from N and C(R3); and

R3can be selected from H and halogen.

In another embodiment, Q may mean N.

In still another embodiment, Q may be C(R3); and

R3can be selected from H and halogen.

In still another embodiment, Q may be C(R3); and

R3can mean halogen.

In still another embodiment, Q may be C(R3); and

R3can be selected from H, fluorine, and chlorine.

In still another embodiment, Q may be C(R3); and

R3can the mean N.

In still another embodiment, Q may be C(R3); and

R3can mean fluoride.

In another embodiment, Q may be C(R3); and

R3can mean chlorine.

D

In one embodiment, D may be selected from N.

In another embodiment, D may be selected from CH.

R1

R1can be selected from H, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, 3-5-membered carbocycle, 5-membered heterocyclyl, -OR1a, -SR1a, -N(R1a)2, -N(R1a)C(O)R1b, -N(R1a)N(R1a)2, -NO2, -C(O)H, -C(O)R1b, -C(O)2R1a, -C(O)N(R1a)2, -OC(O)N(R1a)2, -N(R1a)C(O)2R1a, -N(R1a)C(O)N(R1a)2, -OC(O)R1b, -S(O)R1b, -S(O)2R1b, -S(O)2N(R1a)2, -N(R1a)S(O)2R1b, -C(R1a)=N(R1aand-C(R1a)=N(OR1a);

R1ain each instance can be independently selected from H, C1-6of alkyl, 3-to 5-membered carbocyclic and 5-membered heterocyclyl;

R1bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, 3-5-membered carbocycle and 5-membered heterocyclyl.

In one embodiment, R1can be selected from C1-6of alkyl, 3-to 5-membered carbocycle and-OR1a; and

R1acan be C1-6alkyl.

In dragomiresti, R1can be C1-6alkyl.

In still another embodiment, R1can mean 3-5-membered carbocycles.

In yet another variant, R1may mean-OR1a; and

R1acan be C1-6alkyl.

In an additional embodiment, R1may be selected from methyl, cyclopropyl, isopropoxy and ethoxypropan.

In another additional embodiment, R1can mean methyl.

In another additional embodiment, R1may mean cyclopropyl.

In one embodiment, R1can mean isopropoxy.

In another embodiment, R1can mean ethoxy.

R2

In one embodiment, R2can be selected from H, halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -N(R2a)S(O)2R2b, -C(R2a)=N(R2aand-C(R2a)=N(OR2a),

R2ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle; and

R2bin each case the can is to be independently selected from C 1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle.

In one embodiment, R2can be selected from H, heterocyclyl, -OR2a, -N(R2a)2, -C(O)R2b;

R2ain each instance can be independently selected from H, C1-6the alkyl and heterocyclyl; and

R2bcan mean heterocyclyl.

In one embodiment, R2may mean N.

In another embodiment, R2can mean heterocyclyl.

In yet another variant, R2may mean-OR2a; and

R2acan be selected from C1-6the alkyl.

In yet another variant, R2may mean-N(R2a)2; and

R2ain each instance can be independently selected from H and heterocyclyl.

In still another embodiment, R2could mean a-C(O)R2b; and

R2bcan mean heterocyclyl.

In yet another variant, R2can be selected from H, metoxygroup, morpholine-4-yl, 2-morpholine-4-yl-2-oxoethyl and tetrahydro-2H-Piran-4-laminography.

In an additional embodiment, R2can mean methoxy.

In another additional embodiment, R2can mean morpholine-4-yl.

In another additional embodiment, R2can mean 2-morpholine-4-yl-2-oxoethyl.

In one embodiment, R2can mean tetrahydro-2H-Piran-4-luminograph.

R4

In one Varian is e, R4can be selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil where the above-mentioned C1-6alkyl, C2-6alkenyl,2-6quinil may be optionally substituted by one or more R40;

R40in each instance can be independently selected from halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40aand-C(R40a)=N(OR40a);

R40ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle; and

R40bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle.

In one embodiment, R4can be selected from C1-6the alkyl where the above-mentioned C1-6the alkyl may be optionally substituted by one or more R40;

R40may mean-OR40a; and

R40amay mean N.

In another embodiment, R4/sup> may be selected from methyl, ethyl and hydroxymethyl.

In still another embodiment, R4can mean methyl.

In yet another variant, R4can mean ethyl.

In one embodiment, R4can mean hydroxymethyl.

R5

In one embodiment, R5can mean halogen.

In another embodiment, R5can mean fluoride.

Q, D, R1, R2, R4and R5

In one embodiment, Q may be selected from N and C(R3);

D can be selected from N and CH;

R2can be selected from H, halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -N(R2a)S(O)2R2b, -C(R2a)=N(R2aand-C(R2a)=N(OR2a),

R2ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle;

R2bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle;

R3can be SEL is an from H and halogen;

R4can be selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil where the above-mentioned C1-6alkyl, C2-6alkenyl,2-6quinil may be optionally substituted by one or more R40;

R40in each instance can be independently selected from halogen, -CN, C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40aand-C(R40a)=N(OR40a);

R40ain each instance can be independently selected from H, C1-6of alkyl, carbocycle and heterocycle;

R40bin each instance can be independently selected from C1-6of alkyl, C2-6alkenyl,2-6the quinil, carbocycle and heterocycle; and

R5can mean halogen.

In another embodiment, Q may be selected from N and C(R3);

D can be selected from N and CH;

R1can be selected from C1-6of alkyl, 3-to 5-membered carbocycle and-OR1a;

R1acan be C1-6alkyl;

R2can be selected from H, heterocyclyl, -OR2a, -N(R2a)2, -C(O)R2b;

R2ain each instance can be independently selected from H, C1-6the alkyl and heterocyclyl;

R2bcan mean heterocyclyl;

R3can be selected from H and halogen;

R4can be C1-6alkyl, where the mentioned C1-6the alkyl may be optionally substituted by one or more R40;

R5can mean halogen;

R40may mean-OR40a; and

R40amay mean N.

In still another embodiment, Q may be selected from N and C(R3);

D can be selected from N and CH;

R1may be selected from methyl, cyclopropyl, isopropoxy and ethoxypropan;

R2can be selected from H, metoxygroup, morpholine-4-yl, 2-morpholine-4-yl-2-oxoethyl and tetrahydro-2H-Piran-4-laminography;

R3can be selected from H, fluorine and chlorine;

R4may be selected from methyl, ethyl and hydroxymethyl; and

R5can mean fluoride.

In yet another embodiment, the compound of formula (I) may mean that the compound of formula (Ia):

or its pharmaceutically acceptable salt, where Q, D, R1, R2, R4and R5means, as defined above.

In one embodiment, the present invention provides the connection f is rmula (I) or its pharmaceutically acceptable salt, as illustrated by means of Examples, each of which provides additional independent variant of the invention.

Utility

JAK2

The compounds of Formula (I) are suitable for the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting tyrosine kinase, particularly the JAK family and more JAK2. Treatments aimed at tyrosine kinase activity, particularly the activity of the JAK family and more activity of JAK2, which is involved in various myeloproliferative disorders, myelodysplastic syndrome and processes associated with cancer. Thus, tyrosine kinase inhibitors, particularly the JAK family, and more JAK2 is expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia Vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, or other tissues, as well as leukemia, myeloma and lymphoma, tumors of the Central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Inhibitors tyrosine the basics, especially inhibitors of the JAK family and more inhibitors of JAK2 are also expected to be useful for the treatment of other proliferative diseases including, but not limited to, autoimmune, inflammatory, neurological and cardiovascular diseases.

The compounds of Formula (I), has been shown to inhibit tyrosine kinase, particularly the JAK family and more JAK2, as determined by Analysis of JAK2 described here.

The compounds of Formula (I) should also be suitable as standards and reagents in determining the ability of a potential pharmaceutical products to inhibit tyrosine kinase, particularly the JAK family and more JAK2. They can offer industrial sets containing compounds of this invention.

The activity of JAK2 kinase was determined by measuring the ability of the kinase for the phosphorylation of synthetic tyrosine residues in a typical polypeptide based technology, using Amplified Luminescent Proximity Assay (Enhanced Luminescence Relatives Homogeneous Assays) (Alphascreen) (PerkinElmer, 549 Albany Street, Boston, MA).

To measure the activity of JAK2 kinase, can be used industrially available purified enzyme. The enzyme can be His6-tagged C-terminal, recombinant, human JAK2, 808 terminal amino acids (Genbank Accession number NM 004972), expressed by baculovirus in Sf21 cells (Upstate Biotechnology MA). P is after incubation of the kinase with the biotinylated substrate and adenosine triphosphate (ATP) for 60 minutes at room temperature, the kinase reaction can be stopped by adding 30 mm atendimentoonline acid (EDTA). The reaction can be carried out in 384-cell titration the microplate, and the reaction products can be detected by adding donor granules, coated with streptavidin, and the acceptor pellets coated phosphotyrosine-specific antibodies using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature.

Protein substrateTYK2 (Tyr 1054/1055 biotinylated peptide) Technology cell signaling #2200 Century 402 μm stock.
ATP Km15-mm
Conditions analysis150 pmol JAK2 enzyme, 15 μm ATP, 80 nm Tyk2, 10 mm MgCl2, 50 mm Hepes (N-2-hydroxyethylpiperazine-N-2-econsultancy acid) buffer, pH 7.5, 1 mm DTT (dithiothreitol), 0.025% DTT.
Incubation60 minutes, room temperature
Finish/Condition definitions6.3 mm HEPES, 30 mm EDTA, 525 mg/ml BSA (bis-trimethylsilylacetamide), 40 mm NaCl, 0.007% Triton® X-100, 12 ng/ml donor pellet 12 ng/ml acceptor pellets
Detection of incubationOvernight, room temperature
Set the key of fluorimetry Excitation=680 nm Absorption=570 nm While the Excitation=180 MS, the Total measurement time=550 MS

Although the pharmacological properties of the compounds of Formula (I) vary with structural change, it is considered that, in General, activity possessed by compounds of the Formula (I)may be demonstrated at concentrations of IC50 (the concentration to achieve 50%inhibition) or doses below 10 microns.

After the test in the above in-vitro analysis of JAK inhibitory activity of the next sample was measured in the following IC50.

PRIC50(µm)
170.003

TRK

The compounds of Formula (I) are useful for the treatment of cancer by inhibiting tyrosine kinase, especially Trk and more Trk a and B. Methods of treatment of the target tyrosine kinase activity, particularly the activity of Trk and more Trk a and activity B, which is involved in various processes associated with cancer. Thus, tyrosine kinase inhibitors, especially Trks and more Trk a and b are expected to be active against the disease-related tumors, such as carcinoma of the breast, ovary, lung, colon, prostate or others who Cana, as well as leukemia and lymphomas, tumors of the Central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. The tyrosine kinase inhibitors, especially inhibitors of Trk and more Trk a and inhibitors, as well as expected, will be useful for the treatment of other proliferative diseases including, but not limited to, autoimmune, inflammatory, neurological and cardiovascular diseases.

In addition, the compounds of the invention are expected to be significant in the treatment or prevention of cancers selected from the above regulated significantly activated by Trk kinases, including, but not limited to, cancer reconstruction, leading to mergers ETV6-TrkC, proteins merge TRP-TrkA, AML-ETO (t8; 21), autocrine or paracrine to signaling, leading to the rise of serum levels of NGF, BDNF, neurotrophins or tumors with constitutive active Trk associated with aggressiveness of the disease, tumor growth and proliferation or emergency signaling.

Compounds of the present invention, as shown to inhibit tyrosine kinase, especially Trk and more Trk a and b, as defined Trk And Analysis described here.

The connection represented by this invention should also be useful as standards and reagents in determining the ability potentialiimitations products to inhibit tyrosine kinase, especially Trk and more Trk a and B. They will be provided in commercial kits comprising the compounds of this invention.

The activity of the Trk kinase was determined by measuring the ability of the kinase for the phosphorylation of synthetic tyrosine residues in a typical polypeptide based technology, using Amplified Luminescent Proximity Assay (Alphascreen) (PerkinElmer, 549 Albany Street, Boston, MA).

To measure the activity of Trk And kinases, intracellular region HIS-labeled Trk And kinase person (amino acids 442-796 Trk A, Swiss-Prot Primary Accession Number P04629) can be expressed in SF9 cells and purified using standard Nickel chromatographic column. After incubation of the kinase with the biotinylated substrate and adenosine triphosphate (ATP) for 20 minutes at room temperature, the kinase reaction can be stopped by adding 30 mm ethylenediaminetetraacetic acid (EDTA). The reaction can be carried out in 384-cell titration the microplate, and the reaction products can be detected by adding donor granules, coated with streptavidin, and the acceptor pellets, coated phosphotyrosine-specific antibodies using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature.

Peptide substratePoly-EY-Biotin (PGT-bio)
ATP Km70 µm
Conditions analysis0.838 ng/ml Trk A, 9 mm HEPES, 45 μg/ml BSA, 10 mm MnCl25 nm PGT-bio, 0.01% Triton® X-100, 70 μm ATP
Incubation20 minutes, room temperature
Finish/Condition definitions6.3 mm HEPES (N-2-hydroxyethylpiperazine-N-2-econsultancy acid), 30 mm EDTA, 525 mg/ml BSA, 40 mm NaCl, 0.007% Triton® X-100, 12 ng/ml donor granules, 12 ng/ml acceptor pellets
Detection of incubationOvernight, room temperature
Install flourimeterExcitation=680 nm Absorption=570 nm While the Excitation=180 MS, the Total measurement time=550 MS

Although the pharmacological properties of the compounds of Formula (I) vary with structural change, it is considered that, as a rule, activity possessed by compounds of the Formula (I)or their pharmaceutically acceptable salts, can be demonstrated at concentrations of IC50 (the concentration to achieve 50%inhibition) or the dose level below 10 microns.

After researching throughout the analysis, based on in-vivo analysis, described in the above, Trk inhibiting the activity of the following examples was measured in the following IC50.

PRIC50(µm)
10.003
20.003
30.003
40.012
50.005
60.003
70.003
80.003
90.003
100.003
110.003
120.003
130.006
140.004
153.809
160.061
170.014
180.311
197.250
200.475
210.096
220.773
230.003

Thus, in one object, provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use as pharmaceuticals.

Another object provides for the use of compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of a medicinal product for the treatment or prevention of myeloproliferative disorders, myelodysplastic syndrome, and cancer in a warm-blooded animal such as man.

In still another object, is provided by the use of the compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of a medicinal product for the treatment or prevention of myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fibroproliferative and differenzierung disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic the institutions nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases and ocular diseases with the proliferation of retinal vessel in a warm-blooded animal such as man.

Another object provides for the use of compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of medicines to treat chronic myeloid leukemia, true polycythemia, essential trombozitemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, cancer of the colon and rectum, prostate cancer, bladder cancer, melanoma, lung cancer - non-small cell lung cancer (NCLR) and small-cell lung cancer (MCLR), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukemia in a warm-blooded animal such as man.

In an additional object is provided by the use of the compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of Lekarstvo the th tools for the treatment of inflammatory disorders, including conditions such as: allergies, including allergic rhinitis/sinusitis, skin allergies (urticaria/urticarnae rash, angioedema, atopic dermatitis, food Allergy, drug allergies, allergies to insect and rare allergic disorders such as mastocytosis; asthma; arthritis, including osteoarthritis, rheumatoid arthritis, and spondylarthrosis; Autoimmune conditions, including systemic lupus erythematosus, dermatomyositis, polymyositis, inflammatory neuropathies (Guillain-Barre, inflammatory polyneuropathy), Crohn's disease, ulcerative colitis, vasculitis (Wegener's granulomatosis, Nowotny polyarteritis)and rare disorders such as polymyalgia rheumatica, temporal arteritis diagnostics, Sjogren syndrome, Bechet disease, syndrome Charge-Strauss and Takayasu's arteritis; cardiovascular inflammation; gastrointestinale inflammation, infectious and immunitetni; leukocyte and immunological, provocatively violations; and transplantation.

In an additional object is provided by the use of the compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of medicinal products for the treatment of persistent pain States, including neuropathic pain and pain associated with inflammation.

In an additional object is provided by the use of the compounds of Formula (I)or its pharmaceutically praml is my salt in the manufacture of a medicinal product for producing anti-proliferative effect in a warm-blooded animal such as man.

In still further object provides for the use of compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of a medicinal product for producing the effect of inhibition of JAK.

In a still additional object is provided by the use of the compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of a medicinal product for producing the effect of inhibition of TRK.

In one object, provided by the use of the compounds of Formula (I)or its pharmaceutically acceptable salt, in the manufacture of a medicinal product for the treatment of cancer.

Another object provides a method of treating myeloproliferative disorders, myelodysplastic syndrome, and cancer in a warm-blooded animal, such as man, the foregoing method includes the introduction of the above animal an effective amount of the compounds of Formula (I)or its pharmaceutically acceptable salt.

Still another object provides a method of treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fibroproliferative and differentiating disorders, psoriasis, raumati the definition of arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone disease and eye disease with proliferation of retinal vessel in a warm-blooded animal, such as man, the foregoing method includes the introduction of the above animal an effective amount of the compounds of Formula (I)or its pharmaceutically acceptable salt.

In a still another object provides a method of treating chronic myeloid leukemia, true polycythemia, essential of thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, cancer of the colon and rectum, prostate cancer, bladder cancer, melanoma, lung cancer - non-small cell lung cancer (NCLR) and small-cell lung cancer (MCLR), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukemia in a warm-blooded animal, such as man, the aforesaid method comprising introducing to enter the said animal an effective amount of the compounds of Formula (I), or its pharmaceutically acceptable salt.

Additional object, a method for treating inflammatory disorders, including conditions such as: allergies, including allergic rhinitis/sinusitis, skin allergies (urticaria/urticarnae rash, angioedema, atopic dermatitis, food Allergy, drug allergies, allergies to insect and rare allergic disorders such as mastocytosis; asthma; arthritis, including osteoarthritis, rheumatoid arthritis and spondylarthrosis; autoimmune conditions, including systemic lupus erythematosus, dermatomyositis, polymyositis, inflammatory neuropathies (Guillain-Barre, inflammatory polyneuropathy), Crohn's disease, ulcerative colitis, vasculitis (Wegener's granulomatosis, Nowotny polyarteritis), and rare disorders such as polymyalgia rheumatica, temporal arteritis diagnostics, Sjogren syndrome, Bechet disease, syndrome Charge-Strauss and Takayasu's arteritis; cardiovascular inflammation; gastrointestinale inflammation, infectious and immunitetni; leukocyte and immunological, neuroforaminal violations; and transplantation of warm-blooded animal, such as man, the foregoing method includes the introduction of the above animal an effective amount of the compounds of Formula (I)or its pharmaceutically acceptable salt.

In a still additional object OEM home button Flex cable is TREN a method for the treatment of persistent pain States, including neuropathic pain, and pain associated with inflammation, the foregoing method includes the introduction of the above animal an effective amount of the compounds of Formula (I)or its pharmaceutically acceptable salt.

In still further object provides a method for producing anti-proliferative effect in a warm-blooded animal, such as man, the foregoing method includes the introduction of the above animal an effective amount of the compounds of Formula (I)or its pharmaceutically acceptable salt.

In one site, it is provided a method for producing the effect of JAK inhibition in a warm-blooded animal, such as man, the foregoing method includes the introduction of the above animal an effective amount of the compounds of Formula (I)or its pharmaceutically acceptable salt.

Another object provides a method for producing the effect of inhibition of TRK warm-blooded animal, such as man, the foregoing method includes the introduction of the above animal an effective amount of the compounds of Formula (I)or its pharmaceutically acceptable salt.

In a still another object provides a method for treating cancer in a warm-blooded animal, such as man, the foregoing method includes the introduction of the above animal an effective quantities of the compounds of Formula (I), or its pharmaceutically acceptable salt.

In yet another object, provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer in a warm-blooded animal such as man.

Additional object, provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use in the treatment of myeloproliferative disorders, myelodyplastic syndrome and cancers (solid and hematologic tumors), fibroproliferative and differentiating disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone disease and eye disease with proliferation of retinal vessel in a warm-blooded animal such as man.

In a still additional object is provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use in the treatment of chronic myeloid leukemia, true polycythemia, essential of thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, mielo is isplastic syndromes and cancers, selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, cancer of the colon and rectum, prostate cancer, bladder cancer, melanoma, lung cancer - non-small cell lung cancer (NCLR) and small-cell lung cancer (MCLR), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukemia in a warm-blooded animal such as man.

In still further object is provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use in the production of anti-proliferative effect in a warm-blooded animal such as man.

In one object, provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use in producing the effect of JAK inhibition in a warm-blooded animal such as man.

In another object, provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use in producing the effect of inhibition of TRK warm-blooded animal such as man.

In a still other object, provided by the compound of Formula (I)or its pharmaceutically acceptable salt, for use in the treatment of cancer in a warm-blooded animal such as man.

Another volume is regarding subsection, where reference is made to the effect of the inhibition of Trk, this may apply particularly to the effect of inhibition of Trk A.

Additional object, where reference is made to the effect of the inhibition of Trk, this may apply particularly to the effect of inhibition of Trk Century

In a still additional object where the reference is made to the treatment (or prevention) cancer, this may apply particularly to the treatment (or prevention) of adenosarcoma kidney, mesothelioma, acute myeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma, esophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, cancer of the colon and rectum, prostate cancer, including hormonesparanoika prostate cancer, bladder cancer, melanoma, lung cancer - non-small cell lung cancer lung (NCLR) and small-cell lung cancer (MCLR), gastric cancer, head and neck cancer, kidney cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma, leukemia, tumors of the Central and peripheral nervous system, melanoma, fibrosarcoma, including congenital fibrosarcoma and osteosarcoma. In more detail, it relates to prostate cancer. In addition, in more detail, it relates to MCLR, NCLR, cancer about the colonic and rectal cancer ovarian and/or breast cancer. In an additional object of this can relate to hormonespamelor prostate cancer.

In still further object provides a pharmaceutical composition comprising a compound of Formula (I)or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier, solvent or excipient.

Compositions of the invention can be in a form suitable for oral administration (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a fine powder or a liquid aerosol), for administration by insufflating (for example, as a fine powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a candle for rectal dosing).

Compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Thus, compositions intended for ErrorLog application, may contain, for example, one or more colorant, a sweetener, a flavouring agent and/or preservative.

Suitable pharmaceutically acceptable excipients to form tablets include, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl - or propyl-p-hydroxybenzoate; and antioxidants, such as ascorbic acid. Tableted drugs can be uncovered or covered, to change their dissolution and subsequent absorption of the active ingredient in the gastrointestinal tract or to improve their stability and/or appearance, in any case, using the usual covering substances and procedures that are known in the field of engineering.

Compositions for oral administration can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions generally contain the active ingredient in finely ground form or in the form of nano - or microtrenching particles together with one or more suspendresume substances, such as sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidine, tragacanth gum and Arabic gum; dispersing or wetting agents such as lecithin or condensation products of accelerated with fatty acids (for example, polyethylene oxide stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (for example, heptadecafluorooctyl), or condensation products of ethylene oxide with partial esters derived from fatty acids and exit such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols (for example, heptadecafluorooctyl), or condensation products of ethylene oxide with partial esters derived from fatty acids and exit such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit (for example, polyethylene, sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives such as ethyl - or propyl-p-g is toxibase; antioxidants, such as ascorbic acid); colorants; fragrances; and/or sweeteners such as sucrose, saccharin or aspartame.

Oil suspensions can be formed by suspendirovanie active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as set forth above, and flavoring agents can be added to provide a pleasant oral drug. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of aqueous suspension by the addition of water, usually contain the active ingredient together with a dispersing or wetting agent, suspenders agent and one or more preservative. Suitable dispersing or wetting agents and suspendresume agents are examples already mentioned above. There may be additional fillers, such as sweeteners, flavorings and colorings.

The pharmaceutical compositions of the invention may also be in the form of emulsions of oil in water. MA is Lana phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, such as, for example, liquid paraffin, or a mixture of any of them. Suitable emulsifying agents may be, for example, natural gums, such as Arabian gum or tragacanth gum, natural phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and anhydrides of exit (for example, sorbitan monooleate), and the condensation products mentioned partial ester with ethylene oxide, such as polyethylene oxide, sorbitan monooleate. The emulsion may also contain sweeteners, flavors and preservatives.

Syrups and elixirs can be prepared with a sweetener, such as glycerin, propylene glycol, sorbitol, aspartame or sucrose and can also contain a softener, a preservative, flavouring and/or colouring agents.

Pharmaceutical compositions may also be in the form of a sterile aqueous or oily suspension for injection, which can be prepared according to known procedures using one or more appropriate dispersing or wetting agents and suspendida agents which have been mentioned above. Sterile suspension for injection may also be a sterile solution for injection or suspension in a nontoxic parenterally acceptable diluent or solvent (EmOC is emer, solution in 1,3-butanediol).

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol adapted to the distribution of the active component in the form of an aerosol containing fine solid or liquid droplets. Can be used with conventional aerosol propellants such as volatile pteridomania hydrocarbons or hydrocarbons, and the aerosol device is suitably arranged to dispense a measured amount of the active component.

For more information about making drugs is recommended that the reader refer to Chapter 25.2 in volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The number of the active component, which is connected with one or more fillers to obtain a unit dosage form, necessarily varies depending on the organism, which is treated and the particular route of administration. For example, a drug intended for oral administration to humans, should, as a rule, contain, for example, from 0.5 mg to 4 g of the active substance prepared from the corresponding and appropriate number of fillers that can vary from about 5 to about 98 percent, calculated on the total weight of the composition. Unit dosage forms should, as a rule, contain about 1 mg to when listello 500 mg of the active component. For further information on routes of administration and Dosage Regimes is recommended that the reader refer to Chapter 25.3 in volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

As mentioned above, the size of the dose required for therapeutic or prophylactic treatment of specific painful conditions, necessarily will vary depending on the organism being treated, the route of administration and the severity of the disease that is being treated. Preferably it is applied daily dose in the range of 1-50 mg/kg, Respectively, the optimal dosage can be determined by a medical practitioner who treats any particular patient.

Cancer treatment described herein can be used as a standalone therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-cancer agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical Oncology, such as alkylating agents (for example CIS-Platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosamine); antimetabolites (for example antifolates such as ftorpirimidinu type 5-fluorouracil is tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines type adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubitsin, mitomycin-C, dactinomycin and mithramycin); antimitoticescoe agents (for example Vinca alkaloids type vincristine, vinblastine, vindesine and vinorelbine and taxaide type Taxol and Taxotere); and topoisomerase inhibitors (for example, epidophyllotoxin type etoposide and teniposide, amsacrine, topotecan and camptothecin); and inhibitors of calpaine (e.g., bortezomib [Velcade®Velcade®]); and the substance of anagrelide [Agrylin®Agrylin®]; and the substance alpha-interferon;

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), regulators reduction of estrogen receptor (for example fulvestrant), antiandrogens (for example, bicalutamide, flutamide, nilutamide and ciproteron acetate), LHRH antagonists (growth hormone-releasing factor, luteinizing hormone or LHRH agonists (for example goserelin, leiprorelina and buserelin), POCs (for example, megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorozole and exemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit the invasion of a cancer cell (e.g., inhibitors of metalloproteinases type mark the stat and inhibitors of receptor function plasminogen activator urokinase);

(iv) inhibitors of the function of growth factor such inhibitors include antibodies, growth factor, antibody growth factor receptor (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbb1 antibody cetuximab [S]), inhibitors farnesyltransferase, tyrosine kinase inhibitors and inhibitors of the kinase serine/threonine, for example, inhibitors of the family of epidermal growth factor (e.g., inhibitors of protein tyrosine kinase EGFR, such as N-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-Amin (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) and 6-acrylamide-N-(3-chloro-4-forfinal)-7-(3-morpholinopropan)hinzelin-4-amine (CL 1033)), for example, inhibitors of the family of platelet growth factor and, for example, inhibitors of the family factor restoreposition, for example inhibitors or phosphatidylinositol 3-kinase (PI3K) and for example inhibitors mitogen-activated protein kinase (MEK/2) and, for example, inhibitors of protein kinase B (PKB/Akt), for example inhibitors of the family of tyrosine kinase Src and/or family of tyrosine kinase Abelson (Abl), such as AZD0530 and dasatinib (BMS-354825) and imatinib mesilate (Gleevec™); and any substances that alter the STAT signaling;

(v) antiangiogenic agents such which inhibit the effects of growth factor vascular endothelial (e.g., antibody growth factor kitakatsushika endothelial bevacizumab [Avastin™], compounds such as disclosed in International patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)and compounds that work by other mechanisms (for example, linomide, inhibitors of the function of integrin αvβ3 and angiostatin);

(vi) substances that Deplete the blood vessels, such as Combretastatin A4 and compounds disclosed in International patent applications WO 99/02166, WO 00/40529. WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to the above-mentioned objectives, such as ISIS 2503, an anti-Ras antisense;

(viii) gene therapy approaches, including for example approaches to replace the abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy - annaprashana enzyme proletarienne therapy) approaches such that use of the cytosine deaminase, thymidine kinase or a bacterial enzyme nitroreductase and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multilatina resistant gene therapy;

(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of tumor cells of the patient, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage-colony stimulating factor, approaches to decrease anergia T cells, approaches, IP is alzouma transfetsirovannyh immunocytes, such as cytokine transfetsirovannyh dendritic cells, approaches using cytokine transfetsirovannyh cell line tumors, and approaches that use antiidiotypic antibodies, and approaches using immunomodulatory drugs thalidomide and lenalidomide [Revlimid®]; and

(x) other modes of treatment, including: dexamethasone, proteasome inhibitors (including bortezomib), isotretinoin (13-CIS retinoic acid), thalidomide, revimid, Rituximab, KOLYA, inhibitors of kinases Cephalon CEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal antibodies intended for radiation therapy with 131I-metaiodobenzylguanidine (131I-MIBG), anti-C(D2) monoclonal antibody therapy with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) after chemotherapy.

This combined treatment can be achieved by simultaneous, sequential or separate dosing of the individual components of treatment. Such combination products employ the compounds of this invention, or their pharmaceutically acceptable salts, within the dosage range described above, and the other pharmaceutically active agent within its approved dosage range.

In addition to their use in therapeutic medicine, the compounds of Formula (I) and their pharmaceutically acceptable salts, tangipahoa as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of JAK2 inhibitors in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In any of the above signs of a pharmaceutical composition, process, method, applications, pharmaceuticals and manufacturing of the present invention is also applicable to any of alternative embodiments of the compounds of the invention described here.

One object of the inhibition of JAK activity is particularly relevant to inhibition of JAK2 activity.

Way

If they are not commercially available, the necessary starting materials for methods such as those described herein may be produced using methods which are selected from standard methods of organic chemistry, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the Examples, the Methods and Circuits described herein.

It is noted that many of the raw materials for synthetic methods as described herein are commercially available and/or widely described in the scientific literature or can be obtained from commercially available compounds using modifications of the methods described in the scientific literature. The reader then refer to Advanced Organic Chemistry, 5thEdition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, the total is about leadership in terms of reactions and reagents.

Will also be appreciated that some of the reactions mentioned herein, it may be necessary/desirable to protect any sensitive groups in the compounds. Examples where protection is necessary or desirable, well-known specialist in the art as suitable methods for such protection. Can be used conventional protective groups in accordance with normal practice (for illustration see T.W.Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991).

The compounds of formula (I) can be obtained in various ways. Circuits and Methods, shown below, illustrate some of the methods of synthesis of compounds of formula (I) and intermediates that can be used for the synthesis of compounds of formula (I) (where Q, D, R1, R2, R4and R5unless otherwise specified, shall mean, as defined above). When a specific solvent or reagent is shown in Scheme or Method or referred to in the accompanying text, is to be understood that the usual chemist in the art is able to vary such solvent or reagent, if necessary. Circuits and Methods are not intended to represent an exhaustive list of methods of synthesis of compounds of formula (I); rather, additional ways that a qualified chemist knows and can also be used for synthesis of compounds. The form is and the invention is not intended, to be limited by the structures shown in the Methods and Schemes.

Skilled chemist in the state to use and to modify the information contained and referenced in the links above and accompanying examples here, as well as Examples, Methods, and Schemes here, to obtain the necessary raw materials and products.

In one embodiment, the compounds of formula (I) can be obtained using:

1) Method And the interaction of the compounds of formula (A)

with the compound of the formula (I):

2) How In the interaction of the compounds of formula (C):

with the compound of the formula (D):

and then, if necessary:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups; and/or

iii) forming a pharmaceutically acceptable salt,

where

L in each case may be identical or different and denotes a leaving group as described above; and

PG in each case may be identical or different and denotes a protective group, as described above.

Method And Examples of compounds of the formula (V) include formamidine acetate. Other compounds that can be similarly used instead of compounds of the formula (V)include orthoepy is, such as triethylorthoformate and triethylorthoformate.

Method - the compounds of Formula (C) and Formula (D) can interact together in a standard reaction conditions nucleophilic attachment. For example, such reactions can be carried out in the presence of a suitable base such as potassium carbonate and a suitable solvent, such as DMF, in a temperature range from about 25°to about 100°C.

In another embodiment, the compounds of formula (a) and the compounds of formula (I) can interact together in a standard reaction conditions Buchwald (for example, see J. Am. Chem. Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62, 1568 and 6066) with a suitable base. Examples of suitable bases include inorganic bases such as cesium carbonate, and an organic base, such as tert-piperonyl potassium. Such reactions can be mostly carried out in the presence of palladium acetate. Solvents suitable for this reaction include aromatic solvents such as toluene, benzene or xylene.

The compounds of formula (C) can be obtained according to

Figure 1:

The compounds of formula (A) can be obtained according to Scheme 2:

The invention now will be further described with reference to the following illustrative examples in which, if the do not set otherwise:

(i) temperatures are given in degrees Celsius (°C); the processes were carried out at room temperature or at ambient temperature, which are in a temperature range of 18-25°C.;

(ii) organic solvents were dried over anhydrous sulfate, unless otherwise indicated; evaporation of the organic solvent was carried out using a rotary evaporator under reduced pressure (4.5-30 mm Hg) with temperature in the bath to 60°C;

(iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was performed on plates with silica gel;

(iv) as a rule, the course of reactions was followed by TLC or liquid chromatography/mass spectrometry (LCMS), and reaction times are given for illustration only;

(v) final products meets these spectra the proton magnetic resonance (PMR) and/or data, mass spectrometry;

(vi) the outputs are given as examples only and not necessarily what can be obtained with careful improvement of the process; if you wanted more substance, its getting repeated;

(vii) when given, NMR data is presented in the form of Delta values for major distinctive protons, given in ppm (ppm) relative to tetramethylsilane (TMS) as internal standard, measured at 300 MHz, unless otherwise specified;

(vii) chemical symbols have the usual meanings;

(ix) the ratio of solvents are given as volume:volume (vol./vol.).

(x) "ISCO" refers to normal phase flash column chromatography using pre-cooked cartridge with silica gel (12 g, 40 g and so on), used according to manufacturer's instructions, obtained from ISCO, Inc, 4700 Superior Street Lincoln, NE, USA.

(xi) "Biotage" refers to normal phase flash column chromatography using pre-cooked cartridge with silica gel (12 g, 40 g, 80 g and so on), used according to manufacturer's instructions, obtained from Biotage inc. 1725 Discovery Drive Charlotteville, Virginia 22911, USA.

(xii) "Gilson" refers to YMC-AQC18 obetovannoi Columns for HPLC with dimensions of 20 mm/100 and 50 mm/250 in a mixture of H2O/MeCN with 0.1% TFA as the mobile phase, unless otherwise stated, and applied according to manufacturer's instructions, obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, USA

(xiii) Hydrogenator pair or hydrogenator Parr shaker type are systems for processing of chemical substances in the presence of a catalyst at pressures up to 5 atmospheres (60 psi) and temperatures up to 80°C.

(xiv) used the following abbreviations:

DCM dichloromethane;

HPLC high-performance liquid chromatography and

DIPEA N,N-diisopropylethylamine.

DMF N,N-dimethylformamide;

THF tetrahydrofuran;

DMAP 4-dimethylaminopyridine;

DMSO dimethyl sulfoxide;

EtOA acid ethyl ester;

Et2O diethyl ether;

Boc2O tert-butyloxycarbonyl anhydride;

GC, gas chromatography;

MTBE methyl tert-butyl ether;

DMAC (N,N-dimethylacetamide;

Pd2(dba)3tcis(dibenzylideneacetone)dipalladium(0);

NMP N-organic;

dppf 1,1'-bis(diphenylphosphino)ferrocene;

t-BuLi t-utility;

Meon methanol;

EtOH ethanol;

n-BuOH n-butanol;

Oxone® peroxomonosulfate potassium;

HATU O-(7-asobancaria-1-yl)-N,N,N, N'-tetramethyluronium hexaflurophosphate

Intermediate 1

5-Herperidin-2-carbonitril

2-Bromo-5-herperidin (93.0 g, 528 mmol), Zn powder (8.29 g, 127 mmol), cyanide zinc (40.3 g, 343 mmol), 1,1'-bis(diphenylphosphino)ferrocene (11.7 g, 21.1 mmol) and Pd2dba3(9.68 g, 10.6 mmol) in anhydrous DMAc (300 ml) was heated at 95°C for 3 hours After cooling to room temperature was added brine (100 ml) and ether (500 ml). Formed precipitate was separated by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml), dried over sodium sulfate and concentrated. After removal of solvent, the resulting residue was purified using column chromatography (hexane-DCM=1:1) to give the titled compound as a white powder (49 g, 72%).1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=2.8 Hz, 1H), 8.21 (dd, J=4.4 and 8.8 Hz, 1H), 8.05 (dd, J=2.8 and 8.8 Hz, 1H).

Intermediate 2

N-(1-(5-Herperidin-2-yl)vinyl)are the amide

A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0°C. was added dropwise 5-herperidin-2-carbonitrile (Intermediate 1, 53.6 g, 425.82 mmol) in THF (170 ml). The reaction was stirred at 0°C for 30 min, then was diluted with dichloromethane (170 ml). Dropwise at 0°C was added acetic anhydride (48.3 ml, 510.98 mmol) in dichloromethane (100 ml). After the addition the reaction was heated to room temperature and was stirred at room temperature for 8 hours was Added a saturated solution of sodium bicarbonate (50 ml) and was extracted with EtOAc (2×200 ml). The combined organic layers were dried over sodium sulfate. After removal of solvent, the obtained residue was purified using column chromatography (hexane:EtOAc=2.5:1) to give the titled compound as a white powder (26.6 g, 35%).1H NMR (400 MHz) δ 9.37 (s, 1H), 8.57 (d, J=2.8 Hz, 1H), 7.81 (m, 2H), 6.01 (s, 1H), 5.52 (s, 1H), 2.08 (s, 3H). MS: Calculation: 180; Found: [M+H]+181.

Intermediate 3

(S)-N-(1-(5-Herperidin-2-yl)ethyl)ndimethylacetamide

To a solution of N-(1-(5-herperidin-2-yl)vinyl)ndimethylacetamide (Intermediate 2, 11.0 g, 61.1 mmol) in Meon (120 ml) under N2added (+)-1,2-bis((2S,5S)-2,5-diethylphosphino)benzene(cyclooctadiene)rhodium(I)triftorbyenzola (0.441 g, 0.611 mmol). The solution was transferred into a high pressure autoclave was loaded with 150 psi H2. The reaction was stirred at room temperature and maintain rivali internal pressure between 120-150 psi for 7 hours The solvent was removed and the resulting residue was purified using column chromatography (EtOAc) to give the titled compound as a white powder (9.8 g, 88%).1H NMR (400 MHz) δ 8.49 (d, J=2.4 Hz, 1H), 8.32 (d, J=7.6 Hz, 1H), 7.66 (m, 1H), 7.39 (dd, J=4.4 and 8.8 Hz, 1H), 4.95 (m, 1H), 1.85 (s, 3H), 1.34 (d, J=7.2 Hz, 3H). MS: Calculate: 182; Found: [M+H]+183. The enantiomeric excess was determined by using HPLC (Chiralpak IA; 70:30 CO2/MeOH), 95.3% of it.

Intermediate 4

tert-Butyl [(1S)-1-(5-herperidin-2-yl)ethyl]carbamate

A solution of (S)-N-(1-(5-herperidin-2-yl)ethyl)ndimethylacetamide (Intermediate 3, 11.0 g, 60.37 mmol), DMAP (1.48 g, 12.07 mmol) and Boc2O (26.35 g, 120.7 mmol) in THF (100 ml) was stirred at 50°C for 20 h After cooling to room temperature was added monohydrate of lithium hydroxide (5.19 g, 123.8 mmol) and water (100 ml). The reaction was stirred at room temperature for 5 h and was diluted with ether (200 ml). The organic layer was separated, washed with brine (100 ml) and dried over sodium sulfate. After removal of solvent, the obtained residue was purified using column chromatography (hexane-EtOAc=5:1) to give the titled compound as a bright yellow oil (13.6 g, 94%).1H NMR (400 MHz) δ 8.46 (d. J=2.8 Hz, 1H), 7.69 (m, 1H), 7.35-7.41 (m, 2H), 4.67 (m, 1H), 1.37 (s, 9H), 1.32 (d, J=7.2 Hz, 3H). MS: Calculated: 240; Found: [M+H]+241.

Intermediate 5

hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine

To a solution of tert-butyl [(1S)-1-(5-f is herperidin-2-yl)ethyl]carbamate (Intermediate 4, 12.8 g, 53.3 mmol) in dichloromethane (100 ml) was added a solution of Hcl/dioxane (107 ml, 4 N, 428 mmol). The reaction was stirred at room temperature for 3 hours the Solvent was removed and added to 50 ml saturated sodium bicarbonate. The resulting aqueous solution was extracted with ether (6×400 ml), dried over sodium sulfate and concentrated to obtain the above compound (7.30 g, 98%) as a bright yellow oil.1H NMR (400 MHz) δ 8.44 (d, J=2.8 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 4.01 (q, J=6.8 Hz, 1H), 1.94 (b, 2H), 1.26 (d, J=6.8 Hz, 3H). MS: Calcd.: 140; Found: [M+H]+141.

Intermediate 6

5-Isopropoxy-1H-pyrazole-3-amine

A named connection can be obtained by using the following method. To a suspension of 3-amino-5-hydroxypyrazol (0.50 mol) in CH2Cl2was added triphenylphosphine (0.59 mol) and the resulting mixture was cooled to 0°C. was added dropwise aminobutiramida azodicarboxylate (0.59 mol) over a period of 35 min (the temperature of the reaction mixture was kept below 2°C) to obtain a suspension. The reaction mixture is then kept at 0°C for 1 hour. After 30 min the reaction can observe the formation of sludge. Then dropwise added isopropyl alcohol (1.25 mol) over a period of 30 min at 0°C, while the thick paste was significantly radigales with getting the suspension. The reaction mixture is then kept at 0°C for 1 hour. The reaction mixture medl the NGO was heated to room temperature and then kept at room temperature overnight. The reaction mixture was filtered to remove insoluble precipitate. The filtrate was dried (MgSO4) and concentrated under reduced pressure to obtain oil. Purification using column chromatography (5%→10% Meon in CH2Cl2provides a named connection. (400 MHz, DMSO-d6) δ ppm 10.3 (br s, 1H), 4.84 (br s, 2H), 4.65 (s, 1H), 4.52 (m, 1H), 1.20 (m, 6H).

Intermediate 7

6-Chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine

A mixture of 2,6-dichloro-3-nitropyridine (0.5 g) and 5-isopropoxy-1H-pyrazole-3-amine (Intermediate 6, 0.35 g) in acetonitrile (10 ml) with triethylamine (2 ml) was stirred at room temperature for 24 h the mixture was concentrated and the obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.45 g of the desired product. MS (elektrorazpredelenie): 298 (M+1) for C11H12ClN5O3.

Intermediate 8

N6-(1S)-1-(5-Herperidin-2-yl)ethyl]-N2-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine

A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 7, 0.8 g) and hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5, 0.4 g) in n-BuOH (10 ml) with diisopropylethylamine (2 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. Received mod is to separated using a column of silica gel (hexane/ethyl acetate), giving 0.6 g of the desired product. MS (elektrorazpredelenie): 402 (M+1) for C18H20FN7O3.1H NMR (300 MHz, DMSO-d6) δ ppm 12.3 (s, 1H), 11.0 (s, 1H), 8.80 (m, 1H), 8.50 (m, 1H), 8.15 (m, 1H), 7.80 (m, 1H), 7.30 (m, 1H), 6.20 (d, 1H), 5.80 (m, 1H), 5.35 (m, 1H), 4.60 (m, 1H), 1.50 (d, 3H), 1.20 (d, 6H).

Intermediate 9

6-Chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine

A mixture of 2,6-dichloro-3-nitropyridine (5 g) and 5-cyclopropyl-1H-pyrazole-3-amine (5 g) in acetonitrile (40 ml) with diisopropylethylamine (6 ml) was stirred at room temperature for 24 h the mixture was concentrated and the obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 5 g of the desired product. MS (elektrorazpredelenie): 280 (M+1) for C11H10ClN5O2.1H NMR (300 MHz, CD3OD) δ ppm 8.5 (d, 1H), 6.9 (d, 1H), 6.5 (s, 1H), 1.9 (m, 1H), 1.0 (m, 2H), 0.70 (m, 2H).

Intermediate 10

N2-(5-Cyclopropyl-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-herperidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine

A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 9, 0.5 g) and hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5, 0.35 g) in n-BuOH (10 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The resulting residue was separated using column is silica gel (hexane/ethyl acetate), giving 0.45 g of the desired product. MS (elektrorazpredelenie): 384 (M+1) for C18H18FN7O2.1H NMR (300 MHz, CD3OD) δ ppm 8.60 (s, 1H), 8.20 (m, 1H), 8.15 (m, 1H), 7.60 (m, 1H), 7.40 (s, 1H), 6.30 (d, 1H), 6.20 (s, 1H), 5.35 (m, 1H), 1.90 (m, 1H), 1.60 (d, 3H), 1.00 (m, 2H), 0.80 (m, 2H).

Intermediate 11

5-Ftorpirimidinu-2-carbonitril

10 ml microwave vial supplied 2-chloro-5-torpedinidae (2.0 g, 15.09 mmol), Pd2(dba)3(0.549 g, 0.6 mmol), dppf (0.67 g, 1.21 mmol), cyanide zinc (1.15 g, 9.81 mmol) and zinc powder (0.237 mg, 3.62 mmol). The vessel was evacuated and filled the N2and anhydrous DMAc. The ampoule was placed in a microwave reactor of Personal Chemistry microwave reactor and heated at 100°C for 10 h, the Reaction mixture was diluted with EtOAc and then washed with brine three times. The organic layer obtained was evaporated to dryness. The residue was purified using chromatography on silica gel using ISCO Combiflash with gradient EtOAc and hexane), giving a named connection in the form of a cream powder (1.50 g, 80%). GC-MS: 123 (M);1H NMR (CDCl3) δ 8.80 (s, 2H).

Intermediate 12

N-(1-(5-Ftorpirimidinu-2-yl)vinyl)ndimethylacetamide

To 5-ftorpirimidinu-2-carbonitrile (Intermediate 11, 1.0 g, 8.1 mmol) in THF (10 ml) was added dropwise a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether at 0°C. After addition the reaction was heated to room temperature, stirred at room temperature for 1 hour and then DCM (10 ml). To one portion was added acetic anhydride (1.23 ml, 13.0 mmol). The reaction was stirred at room temperature for 1 hour and 40°C for 1 hour. Was added a saturated solution of sodium bicarbonate (10 ml) and was extracted with EtOAc (2×20 ml). The combined organic layers were dried over sodium sulfate. After removal of solvent, the obtained residue was purified using column chromatography (hexane:EtOAc=2.5:1) to give the titled compound as a white powder (0.38 g, 26%).1H NMR (400 MHz) 9.34 (s, 1H), 8.95 (s, 2H), 6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H). MS: Calculated: 181; Found: [M+H]+182.

Intermediate 13

(S)-N-(1-(5-Ftorpirimidinu-2-yl)ethyl)ndimethylacetamide

To N-(1-(5-ftorpirimidinu-2-yl)vinyl)ndimethylacetamide (Intermediate 12, 0.10 g, 0.55 mmol) in Meon (5 ml) under N2added (+)-1,2-bis((2S, 5S)-2,5-diethylphosphino)benzene(cyclooctadiene)rhodium(I)triftorbyenzola (0.04 g, 0.0055 mmol). The solution was transferred into the reactor pressure vessels and were loaded with 150 psi H2. The reaction was stirred at room temperature for 4 hours the Solvent was removed and the resulting residue was purified using column chromatography (EtOAc) to give the titled compound as a white powder (0.096 g, 95%).1H NMR (400 MHz), 8.84 (d, J=0.8 Hz, 2H), 8.34 (d, J=7.6 Hz, 1H), 5.00 (m, 1H), 1.84 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). MS: Calculated: 183; Found: [M+H]+184. The enantiomeric excess was determined by using HPLC (Chiralpak IA; 95:5 COsub> 2/Meon), >99% EE.

Intermediate 14

tert-Butyl [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]carbamate

(S)-N-(1-(5-Ftorpirimidinu-2-yl)ethyl)ndimethylacetamide (Intermediate 13, 0.20 g, 1.09 mmol), DMAP (0.027 g, 0.22 mmol) and di-tert-butyl-dicarbonate (0.60 g, 2.73 mmol) in THF (10 ml) was stirred at 50°C for 40 h, After cooling to room temperature was added monohydrate of lithium hydroxide (0.094 g, 2.24 mmol) and water (10 ml). The reaction was stirred at room temperature for 9 hours was Added ether (30 ml), the organic layer was separated, washed with brine (20 ml) and dried over sodium sulfate. After removal of solvent, the obtained residue was purified using column chromatography (Hex-EtOAc=5:1) to give the titled compound as a bright yellow oil (0.21 g, 80%). NMR (400 MHz), 8.84 (s, 2H), 7.24 (d, J=7.6 Hz, 1H), 4.74 (m, 1H), 1.35 (s, 12H). MS: Calculated: 241; Found: [M+H]+242.

Intermediate 15

Hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine

To a solution of tert-butyl [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]carbamate (Intermediate 14, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours the Solvent was removed, giving a named connection in the form of a white powder (quantitatively). MS: Calculated: 141; Found: [M+H]+142.

Intermediate 16

N2-(5-Cyclopropyl-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-ftorpirimidinu-2-the l)ethyl]-3-nitropyridine-2,6-diamine

A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 9, 0.5 g) and hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (Intermediate 15, 0.35 g) in n-BuOH (10 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.5 g of the desired product. MS (elektrorazpredelenie): 385 (M+1) for C17H18FN8O2.1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2 H), 8.20 (d, 1H), 6.40 (m. 1H), 6.20 (d. 1H), 5.45 (m, 1H), 1.90 (m, 1H), 1.70 (d, 3H), 1.05 (m, 2H), 0.90 (m, 2H).

Intermediate 17

2-Chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine

A mixture of 2,4-dichloro-5-nitropyrimidine (2 g) and 5-cyclopropyl-1H-pyrazole-3-amine (2 g) in acetonitrile (20 ml) with diisopropylethylamine (2 ml) was stirred at room temperature for 24 h the mixture was concentrated and the obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 2.1 g of the desired product. MS (elektrorazpredelenie): 281 (M+1) for C10H9ClN6O2.

Intermediate 18

N4-(5-Cyclopropyl-1H-pyrazole-3-yl)-N2-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-5-nitropyrimidine-2,4-diamine

A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitro rimidine-4-amine (Intermediate 17, 0.35 g) and hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (Intermediate 15, 0.25 g) in n-BuOH (10 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.3 g of the desired product. MS (elektrorazpredelenie): 386 (M+1) for C16H16FN9O2.1H NMR (300 MHz, DMSO-d6) δ ppm 12.4 (s, 1H), 11.30 (s, 1H), 9.15 (s, 1H), 9.00 (s, 1H), 8.80 (s, 2H), 6.10 (d, 1H), 5.25 (m, 1H), 1.90 (m, 1H), 1.60 (d, 3H), 1.00 (m, 2H), 0.80 (m, 2H).

Intermediate 19

N4-(5-Cyclopropyl-1H-pyrazole-3-yl)-N2-(1S)-1-(5-herperidin-2-yl)ethyl]-5-nitropyrimidine-2,4-diamine

A mixture of 2-chloro-N-(5-temporaril-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine (Intermediate 17, 0.35 g) and hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5, 0.25 g) in n-BuOH (10 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.3 g of the desired product. MS (elektrorazpredelenie): 385 (M+1) for C17H16FN8O2.

Intermediate 20

N6-[(1S)-1-(5-Ftorpirimidinu-2-yl)ethyl]-N2-(5-what isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine

A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 7, 0.4 g) and hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (Intermediate 15, 0.25 g) in n-BuOH (5 ml) with diisopropylethylamine (1.5 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.55 g of the desired product. MS (elektrorazpredelenie): 403 (M+1) for C17H19FN8O3.1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 2H), 8.10 (d, 1H), 6.15 (d, 1H), 5.60 (s, 1H), 5.35 (m, 1H), 4.60 (m, 1H), 1.50 (d, 3H), 1.20 (d, 6 H).

Intermediate 21

(R)-N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropan-2-sulfinamide

To a solution of (R)-2-methylpropan-2-sulfinamide (2.5 g, 20.6 mmol) and {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (4.32 ml, 22.7 mmol) in CH2Cl2(30 ml) was added CuSO4(7.23 g, 45.32 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was filtered through Celite®, washed with CH2Cl2and concentrated in vacuum.

Column chromatography (0-30% EtOAc in hexane) to give the desired product (R)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropan-2-sulfinamide (Tepahedron Lett. 2001, 42, 2051-54).1H NMR (300 MHz, CDCl3) δ 7.86-8.24 (m, 1H), 4.53 (d, J=3.01 Hz, 2H), 1.15-1.2 (m, 9H), 0.90 (s, 9H), 0.08 (s, 6H).

Intermediate 22

(RS)-N-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-(5-herperidin-2-yl)etyl-2-methylpropan-2-sulfinamide*

To a cold solution of 2-bromo-5-herperidin (1.3 g, 7.2 mmol) in Et2O (8 ml) at -68°C. was carefully added a solution of tert-BuLi (1.7 M in pentane, 8.5 ml, 14.4 mmol). The temperature of the mixture was kept below -65°C. and the mixture was stirred for 15 min at -70°C. a Solution of (R)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropan-2-sulfinamide (Intermediate 21, 1.0g, 3.6 mmol) in Et2O (24 ml) was cooled to -75°C. thereto by means canula was added the above solution of lithium compounds for 15 minutes More Et2O (2 ml) was used for rinsing the solution of lithium compounds. The mixture was stirred at -78°C for 3 hours To it was added a saturated solution of NH4Cl. EtOAc was added and the organic layer was washed with brine and concentrated. Column chromatography (20-40% EtOAc in hexane) to give the desired product (Rs)-N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-herperidin-2-yl)ethyl]-2-methylpropan-2-sulfinamide* in powder form (significant Rf on TCX, 1.19 g) together with diastereoisomers (small Rf on TCX, 166 mg).1H NMR (300 MHz, CDCl3) δ ppm 8.41 (s, 1H), 7.35 (d, J=6.78 Hz, 2H), 4.59 (t, J=5.65 Hz, 1H), 4.43 (d, J=5.28 Hz, 1H), 3.82-4.02 (m, 2H), 1.23 (s, 9H), 0.81 (s, 9H), -0.06 (d, J=12.06 Hz, 6H).

* "Rs" is intended to indicate that the sulfur atom has the R is konfigurazio.

Intermediate 23

Hydrochloride (2R)-2-amino-2-(5-herperidin-2-yl)ethanol

To a solution of (Rs)-N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-herperidin-2-yl)ethyl]-2-methylpropan-2-sulfinamide (Intermediate 22, 1.13 g, 3.02 mmol) in Meon (15 ml) was added hydrochloric acid (4 M in dioxane, 3.02 ml, 12.08 mol) at 0°C and the mixture was stirred for 15 min and concentrated. The mixture was erased from hexane to obtain the named salt (575 mg). The product is highly hygroscopic.1H NMR (300 MHz, DMSO-d6) δ ppm at 8.62 (s, 1H), 8.55 (s, 2H), 7.76-7.93 (m, 1H), 7.65 (dd, J=8.29, 4.52 Hz, 1H), 4.43 (d, J=4.52 Hz, 1H), 3.77 (s, 2H).

Intermediate 24

(2R)-2-(5-Herperidin-2-yl)-2-({6-[(5-isopropoxy-1H-pyrazole-3-yl)amino]-5-nitropyridine-2-yl}amino)ethanol

A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 7, 0.5 g) and hydrochloride (2R)-2-amino-2-(5-herperidin-2-yl)ethanol (Intermediate 23, 0.45 g) in n-BuOH (10 ml) with diisopropylethylamine (3 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.45 g of the desired product. MS (elektrorazpredelenie): 418 (M+1) for C18H20FN7O4.1H NMR (300 MHz, CD3OD) δ ppm 8.50 (s, 1H), 8.20 (d, 1H), 7.60 (s, 1H), 7.45 (s. 1H), 6.30 (s, 1H), 5.70 (s, 1H), 5.45 (m. 1H), 4.60 (m, 1H), 3.90 (m, 2H), 1.30 (d, 6H).

Intermediate 25

5-Ethoxy-1H-pyrazole-3-amine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 6, using 3-amino-5-hydroxypyrazol as the starting material. (400 MHz, CD3OD) δ ppm 4.85 (br s, 3H), 4.02 (m. 2H), 1.30 (t, J=8 Hz, 3H).

Intermediate 26

6-Chloro-N-(5-ethoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 7, using Intermediate 25 as the starting material. MS (elektrorazpredelenie): 284 (M+1) for C10H10ClN5O.

Intermediate 27

(2R)-2-({6-[(5-Ethoxy-1H-pyrazole-3-yl)amino]-5-nitropyridine-2-yl}amino)-2-(5-herperidin-2-yl)ethanol

A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 26, 0.2 g) and hydrochloride (2R)-2-amino-2-(5-herperidin-2-yl)ethanol (Intermediate 23, 0.15 g) in n-BuOH (5 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.2 g of the named compound. MS (elektrorazpredelenie): 404 (M+1) for C17H18FN7O4.

Intermediate 28

N2-(5-Ethoxy-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-ftorpirimidinu-2-the l)ethyl]-3-nitropyridine-2,6-diamine

A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 26, 0.35 g) and hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (Intermediate 15, 0.20 g) in n-BuOH (5 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), which give 0.37 g of the named compound. MS (elektrorazpredelenie): 389 (M+1) for C16H17FN8O3.

Intermediate 29

N2-(5-Ethoxy-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-herperidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine

A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 26, 0.35 g) and hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5, 0.20 g) in n-BuOH (5 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), which give 0.37 g of the named compound. MS (elektrorazpredelenie): 388 (M+1) for C17H17FN7O3.

Intermediate 30

2-Chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine

A mixture of 2,4-dichloro-5-nitropyrimidine (2 is) and 5-isopropoxy-1H-pyrazole-3-amine (Intermediate 6, 1.5 g) in acetonitrile (50 ml) with triethylamine (5 ml) was stirred at room temperature for 24 h the mixture was concentrated and the obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 1 g of the named compound. MS (elektrorazpredelenie): 299 (M+1) for C10H12ClN6O3.

Intermediate 31

N2-[(1S)-1-(5-Herperidin-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine

A mixture of 2-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine (Intermediate 30, 1.0 g) and hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5, 0.8 g) in n-BuOH (5 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 1.0 g of the named compound. MS (elektrorazpredelenie): 403 (M+1) for C17H19FN8O3.1H NMR (300 MHz, CD3OD) δ ppm 9.10 (s, 1H), 8.50 (s, 1H), 7.60 (m, 1H), 7.40 (m, 1H), 5.80 (s, 1H), 5.20 (m, 1H), 4.70 (m, 2H), 1.60 (d, 3H), 1.40 (d, 6H).

Intermediate 32

N2-[(1S)-1-(5-Ftorpirimidinu-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine

A mixture of 2-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine (Intermediate 30, 0.2 g) of the hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (Intermediate 15, 0.15 g) in n-BuOH (5 ml) with diisopropylethylamine (1 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.2 g of the named compound. MS (elektrorazpredelenie): 404 (M+1) for C16H18FN9O3.

Intermediate 33

(S)-N-[(5-Herperidin-2-yl)methylene]-2-methylpropan-2-sulfinamide

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 21, using 5-herperidin-2-carbaldehyde and (S)-2-methylpropan-2-sulfinamide as source materials.1H NMR (300 MHz, CDCl3) δ ppm 8.67 (s, 1H), 8.58 (s, 1H), 8.06 (dd, J=8.29, 4.52 Hz, 1H), 7.51 (t, J=7.91 Hz, 1H), 1.20-1.33 (m, 9 H). The product was used without purification.

Intermediate 34

(Ss)-N-[(1S)-1-(5-Herperidin-2-yl)propyl]-2-methylpropan-2-sulfinamide*

To a solution of (S)-N-[(5-herperidin-2-yl)methylene]-2-methylpropan-2-sulfinamide (Intermediate 33, 1.5 g, 6.58 mmol) in CH2Cl2(10 ml) at -45°C. was added dropwise ethylmagnesium (1.0 M in MTBE, 6.6 ml, 6.6 mmol). The reaction mixture was stirred at -40°C for 30 minutes and thereto was added water. The layers were separated and the organic layer was concentrated. Column chromatography on silica gel (30-50% EtOAc in CH2Cl2gives named with the unity (significant Rf on TLC) in powder form (485 mg, 29%).1H NMR (300 MHz, CDCl3) δ ppm 8.39 (d, J=3.01 Hz, 1H), 7.29-7.41 (m, 1H), 7.21-7.24 (m, 1H), 4.60 (d, J=7.54 Hz, 1H), 4.31 (q, J=6.78 Hz, 2H), 1.22-1.27 (s, 9H), 0.86 (t, J=7.54 Hz, 3H).

* "Ss" is intended to indicate that the sulfur atom has the S configuration.

Intermediate 35

[(1S)-1-(5-Herperidin-2-yl)propyl]amine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 21, using (Ss)-N-[(1S)-1-(5-herperidin-2-yl)propyl]-2-methylpropan-2-sulfinamide (Intermediate 34) as the starting material.1H NMR (300 MHz, DMSO-d6) δ ppm 8.64 (s, 1H), 8.59 (s, 2H), 7.77-7.92 (m, 1H), 7.64 (dd, J=8.29, 4.52 Hz, 1H), 4.33 (d, J=7.54 Hz, 1H), 1.72-1.97 (m, 2H), 0.75 (t, J=7.54 Hz, 3H).

Intermediate 36

N6-(1S)-1-(5-Herperidin-2-yl)propyl]-N2-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine

A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 7, 0.5 g) and [(1S)-1-(5-herperidin-2-yl)propyl]amine (Intermediate 35, 0.45 g) in n-BuOH (10 ml) with diisopropylethylamine (3 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 0.45 g of the desired product. MS (elektrorazpredelenie): 416 (M+1) for C19H22FN7O3.

Intermediate 37

2,4,6-Trichloro-5-nitro-pyrimidine

A solution of 5-nitropyrimidin-2,4,6-triol (5 g) in POCl 3(30 ml) and 2,6-lutidine (15 ml) was heated to 90°C for 3 hours the Reaction mixture was left to cool to room temperature and the volatile components evaporated. Purification via column chromatography (ISCO, EtOAc/hexane 1:10) gives the titled compound (1.03 g) together with 2,4,5,6-tetrachloro-pyrimidine. LCMS: 228 [M+1].

Intermediate 38

5,6-Dichloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 7, using Intermediate 6 and Intermediate 7 as starting materials. MS (elektrorazpredelenie): 333 (M+1) for C11H11Cl2N5O3.

Intermediate 39

3-Chloro-N2-[(1S)-1-(5-Herperidin-2-yl)ethyl]-N6-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyridine-2,6-diamine

A mixture of 5,6-dichloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 38, 0.75 g) and hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5, 0.50 g) in n-BuOH (20 ml) with diisopropylethylamine (3 ml) was stirred at 70°C for 4 h the mixture was diluted with ethyl acetate (20 ml) and washed with brine (10 ml ×3). The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (hexane/ethyl acetate), giving 1.0 g of the desired product. MS (elektrorazpredelenie): 436 (M+1) for C18H19ClFN7O3. H NMR (300 MHz, DMSO-d6) δ ppm 12.0 (br, 1H), 10.8 (br, 1H), 8.60 (s. 1H), 8.30 (s, 3H), 7.80 (m, 1H), 7.40 (m, 1H), 6.00 (s, 1H), 5.50 (m, 1H), 4.50 (m, 1H), 1.60 (d, 3H), 1.30 (d, 6H).

Intermediate 40

2,3,6-Cryptor-5-nitropyridine

A 3-necked round bottom flask was added 2,3,6-triptorelin (25 g, 0.19 mol)was then added red fuming nitric acid (210 ml, 4.7 mol). To this mixture slowly from the dropping funnel was added sulfuric acid (150 ml, 2.8 mol), maintaining the internal temperature below 40°C. the resulting solution was heated to 60°C for 30 min and after heating was left to cool to room temperature. This solution is then further cooled in an ice bath and poured into a 2-l Erlenmeyer flask containing a mixture of ice and water (700 ml, 1:1 ratio). The cooled solution is then transferred into a 2 l separating funnel and separated hexane (600 ml). The aqueous layer was then washed with hexane (600 ml) and methylene chloride (600 ml). The combined organic layers were then dried over Na2SO4, was filtered and was concentrated with the formation of these compounds in the form of a light yellow liquid (19.2 g, 57% yield).1H NMR (CDCl3) δ 8.74 (s, 1H).

Intermediate 41

5,6-Debtor-N-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine

To a solution of 2,3,6-Cryptor-5-nitropyridine (Intermediate 40, 1.0 g) in EtOH (20 ml) at 0°C was added 5-methyl-1H-pyrazole-3-amine (550 mg) and DIPEA (2 ml). The resulting mixture premesis is whether at this temperature overnight. The named compound was separated by filtration (780 mg). LCMS: 377 [M+1].

Intermediate 42

3-Fluoro-N2-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N6-(5-methyl-1H-pyrazole-3-yl)-5-nitropyridine-2,6-diamine

To a solution of 5,6-debtor-N-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 41, 778 mg, 3.06 mmol) in n-BuOH (10 ml) was added cleaners containing hydrochloride salt of hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (554 mg, 3.06 mmol) and DIPEA (~1.1 ml). The resulting mixture was heated to 110°C overnight. The resulting mixture was cooled to room temperature and the solvent was removed under reduced pressure to obtain colored residue. Purification using column chromatography (Biotage, 50%→70% EtOAc/hexane) provides a named connection. LCMS: 378 [M+1].

Intermediate 43

6-Chloro-N-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 9 using 2,6-dichloro-3-nitropyridine and 5-methyl-1H-pyrazole-3-amine as starting materials. LCMS: 254 [M+1].

Intermediate 44

N6-[(1S)-1-(5-Ftorpirimidinu-2-yl)ethyl]-N2-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 8, using hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (Intermediate 15) and 6-chloro-N-(5-methyl-1H-pyrazole-3-yl)--nitropyridine-2-amine (Intermediate 43) as source materials. LCMS: 359 [M+1].

Intermediate 45

N6-[(1S)-1-(5-Herperidin-2-yl)ethyl]-N2-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 8, using hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5) and 6-chloro-N-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 43) as source materials. LCMS: 358 [M+1].

Intermediate 46

2-Chloro-N-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 30, using 2,6-dichloro-3-nitropyrimidin and 5-methyl-1H-pyrazole-3-amine as starting materials. LCMS: 255 [M+1].

Intermediate 47

(S)-N2-(1-(5-herperidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 18 using hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5) and 2-chloro-N-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine (Intermediate 46) as source materials. LCMS: 359 [M+1].

Intermediate 48

Ethyl 2-chloro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylate

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 30, WLL is I ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate and 5-methyl-1H-pyrazole-3-amine as starting materials. LCMS: 327 [M+1].

Intermediate 49

Ethyl 2-{[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylate

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 18 using hydrochloride [(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amine (Intermediate 15) and ethyl 2-chloro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylate (Intermediate 48) as source materials. LCMS: 432 [M+1].

Intermediate 50

2-{[(1S)-1-(5-Ftorpirimidinu-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylic acid

To a solution of ethyl 2-{[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylate (Intermediate 49, 2 mmol) in THF/MeOH (1:1 v/v, 10 ml) was added LiOH (0.42 g) in H2O (1 ml) and the resulting mixture was stirred at room temperature overnight. Volatile components are evaporated under reduced pressure and the solid residue was diluted with H2O. the Aqueous layer was acidified using 1N HCl (aq.) the solution was extracted with EtOAc (3×). The combined organic layers were dried and evaporated, giving the named compound (406 mg), which was used in the next stage without additional purification. LCMS: 402 [M-1].

Intermediate 51

N2-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N4-(5-methyl-1H-pyrazole-3-yl)-6-(morpholine-4-ylcarbonyl)-5-nitropyrimidine-2,4-diami the

To a solution of 2-{[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylic acid (Intermediate 50, 406 mg, ~1 mmol)in DMF (5 ml) was added DIPEA (~0.3 ml), HATU (456 mg) and morpholine (0.130 ml) at room temperature. The resulting mixture was stirred overnight. The mixture was diluted with H2O and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, saturated solution of NaHCO3(aq.), was dried and evaporated volatile components under reduced pressure, which gave colored residue. Purification via column chromatography (ISCO, 50%→70% EtOAc/hexane) gives a named connection. LCMS: 473 [M+1].

Intermediate 52

2-Chloro-N-(5-methyl-1H-pyrazole-3-yl)-5-nitro-N'-(tetrahydro-2H-Piran-4-yl)pyrimidine-4,6-diamine

To a solution of 2,4,6-trichloro-5-nitropyrimidine (Intermediate 37, 1g, 4.4 mmol) in EtOH at -50°C was added dropwise 5-methyl-1H-pyrazole-3-amine (255 mg) and DIPEA (1.6 ml). The resulting mixture was stirred at this temperature for 5 minutes and then were added 4-aminopyrene (300 mg). The resulting mixture was left to warm to room temperature over 4 h the Mixture was diluted with H2O and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, saturated solution of NaHCO3(aq.), was dried and evaporated volatile components under reduced pressure, which gave painted the STATCOM. A purified using Gilson (MeCN/H2O, 5%→95%, 15 min) to give the named compound (120 mg). LCMS: 354 [M+1].

Intermediate 53

N2-[(1S)-1-(5-Herperidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazole-3-yl)-5-nitro-N6-(tetrahydro-2H-Piran-4-yl)pyrimidine-2,4,6-triamine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 18 using hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5) and 2-chloro-N-(5-methyl-1H-pyrazole-3-yl)-5-nitro-N'-(tetrahydro-2H-Piran-4-yl)pyrimidine-4,6-diamine (Intermediate 52) as source materials. LCMS: 458 [M+1].

Intermediate 54

2-Chloro-6-methoxy-N-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 18 using 2,4,6-trichloro-5-nitropyrimidine (Intermediate 37), 5-methyl-1H-pyrazole-3-amine and sodium methoxide as the source materials. LCMS: 285 [M+1].

Intermediate 55

N2-[(1S)-1-(5-Herperidin-2-yl)ethyl]-6-methoxy-N4-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 18 using hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5) and 2-chloro-6-methoxy-N-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidin-4-amine (Intermediate 54) as source materials. LCMS: 389 [M+1].

Intermediate 56

4,6-Dichloro-2-(methylthio)-5-nitropyrimidin

To 50 ml of absolute tO added metal Na (1g) in small portions and the resulting mixture was stirred for 10 min after addition of Na. Added the thiourea (1.6 g) and diethylnitrosamine (2.0 g), resulting in the observed yellow suspension. This suspension was heated to boiling for 3 h and then left to cool to room temperature. The mixture was carefully acidified to pH~2 using 5N HCl (aq.), resulting in the observed sediment. The precipitate was separated by filtration, washed with EtOH, N2O and dried overnight in a vacuum heating Cabinet. Powder (2.15 g) was dissolved in a solution of 2.5N NaOH (16 ml) and the resulting mixture was stirred for 20 min at room temperature. Dropwise added methyl iodide (1.6 g) using a syringe, and upon completion of addition was observed colored suspension. The mixture was acidified ice Asón and the precipitate was separated by filtration, washed with H2O and dried in a vacuum heating Cabinet all night (1.2 g). Powder (1.2 g) was added slowly to the mixture POCl3(30 ml) and 2,6-lutidine (15 ml) and the resulting mixture was heated up to 80°C for 1 hour. The reaction mixture was left to cool to room temperature and the volatile components evaporated. Purification using column chromatography (EtOAc/hexane 1:10) ensures that n is called the compound (1.0 g). LCMS: 240 [M+1].

Intermediate 57

N-(5-Methyl-1H-pyrazole-3-yl)-2-(methylthio)-6-morpholine-4-yl-5-nitropyrimidin-4-amine

To a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (Intermediate 56, 820 mg) in THF at 0°C was added dropwise 5-methyl-1H-pyrazole-3-amine (350 mg) and DIPEA (1.6 ml). The resulting mixture was stirred at this temperature for 3 h, then was added morpholine (1 ml). The resulting mixture was left to warm to room temperature for 10 hours the Mixture was diluted with H2O and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, saturated solution of NaHCO3(aq.), was dried and evaporated volatile components under reduced pressure, which gives a colored residue. Purification using column chromatography (50% EtOAc/hexane) gives the titled compound (820 mg). LCMS: 352 [M+1].

Intermediate 58

N2-(1S)-1-(5-Herperidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazole-3-yl)-6-morpholine-4-yl-5-nitropyrimidine-2,4-diamine

To a solution of N-(5-methyl-1H-pyrazole-3-yl)-2-(methylthio)-6-morpholine-4-yl-5-nitropyrimidin-4-amine (Intermediate 57, 118 mg) in Meon (2 ml) and DCM (2 ml) was added Oxone® (302 mg) and NaHCO3(56 mg) and the resulting mixture was stirred at room temperature for 16 hours was Added [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 8, 250 mg) and DIPEA (3 ml) and the resulting mixture was stirred at room temperature for 3 hours CME is ü diluted H 2O and EtOAc and the aqueous layer was extracted with EtOAc (4×). The combined organic layers were washed with brine, saturated solution of NaHCO3(aq.), was dried and evaporated volatile components under reduced pressure, which gives a colored residue. Purification using column chromatography (60% EtOAc/hexane) gives the titled compound (220 mg). LCMS: 444 [M+1].

Intermediate 59

N2-(5-Ethoxy-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-herperidin-2-yl)propyl]-3-nitropyridine-2,6-diamine

The named compound is obtained by using a method similar to that described for the synthesis of Intermediate 28, using 6-chloro-N-(5-ethoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (Intermediate 26) and [(1S)-1-(5-herperidin-2-yl)propyl]amine (Intermediate 35) as source materials. LCMS: 402 [M+1].1H NMR (400MHz, DMSO-d6) δ 12.00 (s, 1H), 11.00 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.10 (d, 1H), 7.60 (m, 1H), 7.20 (m, 1H), 6.30 (m, 1H), 5.80 (s, 1H), 5.00 (m, 1H), 4.10 (q, 2H), 2.00 (m, 2H), 1.40 (d, 3H), 1.10 (t, 3H).

Intermediate 60

Ethyl 2-{[(1S)-1-(5-herperidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylate

The named compound is obtained using a method similar to that described for Intermediate 29, using hydrochloride [(1S)-1-(5-herperidin-2-yl)ethyl]amine (Intermediate 5) and ethyl 2-chloro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-5-nitropyrimidin-4-carboxylate (Intermediate 48) as source materials. LCMS: 431 [M+1].

Example 1

N-[(1S)-1-(5-CFT is pyridin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine

N6-[(1S)-1-(5-herperidin-2-yl)ethyl]-N2-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 8, 0.5 g) was dissolved in ethanol (20 ml) with Pd-C (60 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.29 g of the named compound. MS (elektrorazpredelenie): 382 (M+1) for C19H20FN7O.1H NMR (300 MHz, CD3OD) δ ppm 8.45 (s, 1H), 8.35 (s, 1H), 7.75 (d, 1H), 7.50 (s, 1H), 6.70 (d, 1H), 6.00 (s, 1H), 5.10 (m, 1H), 4.50 (m, 1H), 1.55 (d, 3H), 1.35 (d, 6H).

Example 2

3-(5-Cyclopropyl-1H-pyrazole-3-yl)-N-[(1S)-1-(5-herperidin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-5-amine

N2-(5-cyclopropyl-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-herperidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 10, 0.4 g) was dissolved in ethanol (20 ml) with Pd-C (60 mg) and inlet hydrogen. The mixture was stirred at room temperature until such time as there has been no the e source material when TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 95°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml × 3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.16 g of the named compound. MS (elektrorazpredelenie): 364 (M+1) for C19H18FN7.1H NMR (300 MHz, CD3OD) δ ppm 8.45 (s, 1H), 8.30 (s, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 6.70 (d, 1H), 6.20 (s, 1H), 5.10 (dd, 1H), 2.00 (m, 1H), 1.55 (d, 3H), 1.00 (m, 2H), 0.80 (m, 2H).

Example 3

3-(5-Cyclopropyl-1H-pyrazole-3-yl)-N-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-5-amine

N2-(5-cyclopropyl-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 16, 0.45 g) was dissolved in ethanol (20 ml) with Pd-C (60 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formylamino acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 95°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and conc the Wali. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.08 g of the named compound. MS (elektrorazpredelenie): 365 (M+1) for C18H14FN8.1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H), 8.30 (s, 1H), 7.70 (d, 1H), 6.70 (d,1H), 6.50 (s, 1H), 5.30 (dd, 1H), 2.00 (m, 1H), 1.60 (d, 3H), 1.10 (m, 2H), 0.90 (m, 2H).

Example 4

9-(5-Cyclopropyl-1H-pyrazole-3-yl)-N-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-9H-purine-2-amine

N4-(5-cyclopropyl-1H-pyrazole-3-yl)-N2-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-5-nitropyrimidine-2,4-diamine (Intermediate 18, 0.25 g) was dissolved in ethanol (20 ml) with Pd-C (40 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 95°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.013 g of the named compound. MS (elektrorazpredelenie): 366 (M+1) for C17H17FN9.1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H), 8.65 (s, 1H), 8.40 (s, 1H), 6.40 (d, 1H), 5.30 (dd, 1H), 2.00 (m, 1H), 1.65 (d, 3H), 1.10 (m, 2H), 0.90 (m, 2H).

Example 5

9-(-Cyclopropyl-1H-pyrazole-3-yl)-N-[(1S)-1-(5-herperidin-2-yl)ethyl]-N-purine-2-amine

N4-(5-cyclopropyl-1H-pyrazole-3-yl)-N2-[(1S)-1-(5-herperidin-2-yl)ethyl]-5-nitropyrimidine-2,4-diamine (Intermediate 19, 0.25 g) was dissolved in ethanol (20 ml) with Pd-C (40 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 95°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.03 g of the named compound. MS (elektrorazpredelenie): 365 (M+1) for C18H17FN8.1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H), 8.55 (s, 1H), 8.50 (s, 1H), 7.50 (d, 2H), 6.30 (br, 1H), 5.20 (dd, 1H), 2.00 (m, 1H), 1.65 (d, 3H), 1.10 (m, 2H), 0.90 (m, 2H).

Example 6

N-[(1S)-1-(5-Ftorpirimidinu-2-yl)ethyl]-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine

N6-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N2-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 20, 0.5 g) was dissolved in ethanol (20 ml) with Pd-C (60 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until he observed otsutstvie source material when TLC or LCM8. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.29 g of the named compound. MS (elektrorazpredelenie): 383 (M+1) for C18H19FN8O.1H NMR (300 MHz, CD3OD) δ ppm 8.75 (s, 2H), 8.35 (s, 1H), 7.80 (d, 1H), 6.80 (d, 1H), 6.30 (s, 1H), 5.30 (m, 1H), 4.70 (m, 1H), 1.55 (d, 3H), 1.35 (d, 6H).

Example 7

(2R)-2-(5-Herperidin-2-yl)-2-[(3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-yl]amino}ethanol

(2R)-2-(5-herperidin-2-yl)-2-({6-[(5-isopropoxy-1H-pyrazole-3-yl)amino]-5-nitropyridine-2-yl}amino)ethanol (Intermediate 24, 0.45 g) was dissolved in ethanol (20 ml) with Pd-C (90 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. Obtained OST the current shared through column with silica gel (ethyl acetate/Meon), that gives 0.075 g of the named compound. MS (elektrorazpredelenie): 398 (M+1) for C19H20FN7O2.1H NMR (300 MHz, CD3OD) δ ppm 8.50 (d, 1H), 8.30 (s, 1H), 7.80 (d, 1H), 7.50 (dd, 1H), 6.70 (d, 1H), 6.05 (s, 1H), 5.20 (m, 1H), 4.65 (m, 1H), 4.00 (m, 2H), 1.55-1.35 (m, 6H).

Example 8

(2R)-2-{[3-(5-Ethoxy-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-yl]amino}-2-(5-herperidin-2-yl)ethanol

(2R)-2-({6-[(5-ethoxy-1H-pyrazole-3-yl)amino]-5-nitropyridine-2-yl}amino)-2-(5-herperidin-2-yl)ethanol (Intermediate 27, 0.2 g) was dissolved in ethanol (20 ml) with Pd-C (50 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formylamino acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/ Meon)that give 0.06 g of the named compound MS (elektrorazpredelenie): 384 (M+1) for C18H18FN7O2.1H NMR (300 MHz, CD3OD) δ ppm 8.20 (d, 1 H), 8.15 (s, 1H), 7.50 (d, 1H), 7.30 (dd, 1H), 6.40 (d, 1H), 5.85 (s, 1H), 5.00 (m, 1H), 4.00 (d, 2H), 3.80 (m, 2H), 1.00 (t, 3H).

Example 9

3-(5-Ethoxy-1H-pyrazole-3-yl)-N-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N-imidazo[4,5-b]pyridine-5-amine

N2-(5-Ethoxy-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 28, 0.3 g) was dissolved in ethanol (20 ml) with Pd-C (90 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formylamino acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.034 g of the named compound. MS (elektrorazpredelenie): 369 (M+1) for C17H17FN8O.1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H), 8.30 (s, 1H), 7.80 (d, 1H), 6.80 (d, 1H), 6.30 (s, 1H), 5.40 (m, 1H), 4.30 (q, 2H), 1.70 (d, 3H), 1.55 (t, 3H).

Example 10

3-(5-Ethoxy-1H-pyrazole-3-yl)-N-[(1S)-1-(5-herperidin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-5-amine

N2-(5-Ethoxy-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-herperidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 29, 0.3 g) was dissolved in ethanol (20 ml) with Pd-C (90 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of original mater the Ala at TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.034 g of the desired product. MS (elektrorazpredelenie): 368 (M+1) for C18H18FN7O.1H NMR (300 MHz, CD3OD) δ ppm 8.30 (s, 1H), 8.20 (s, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 6.60 (d, 1H), 5.90 (s, 1H), 5.10 (m, 1H), 4.10 (q, 2H), 1.50 (d, 3H), 1.40 (t, 3H).

Example 11

N-[(1S)-1-(5-Herperidin-2-yl)ethyl]-9-(5-isopropoxy-1H-pyrazole-3-yl)-N-purine-2-amine

N2-[(1S)-1-(5-herperidin-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine (Intermediate 31, 1.0 g) was dissolved in ethanol (20 ml) with Pd-C (150 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formamidine acetate (1.0 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The remainder is abdelali through column with silica gel (ethyl acetate/Meon), giving 0.7 g of the desired product. MS (elektrorazpredelenie): 383 (M+1) for C18H19FN8O.1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.40 (m, 2H), 7.50 (dd, 2H), 6.00 (s, 1H), 5.20 (m, 1H), 4.20 (m, 1H), 1.50 (d, 3H), 1.40 (d, 6H).

Example 12

N-[(1S)-1-(5-Ftorpirimidinu-2-yl)ethyl]-9-(5-isopropoxy-1H-pyrazole-3-yl)-9H-purine-2-amine

N2-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N4-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine (Intermediate 32, 0.2 g) was dissolved in ethanol (20 ml) with Pd-C (40 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/ Meon)that give 0.08 g of the desired product. MS (elektrorazpredelenie): 384 (M+1) for C17H18FN9O.1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H), 8.60 (s, 1H), 8.40 (s, 1H), 6.20 (s, 1H), 5.30 (m, 1H), 4.60 (m, 1H), 1.60 (d, 3H), 1.50 (d, 6H).

Example 13

N-[(1S)-1-(5-Herperidin-2-yl)propyl]-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine

N6-[(1S)-1-(5-herperidin-2-yl)propyl]-N2-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 36, 0.45 g) was dissolved in ethanol (20 ml) with Pd-C (150 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of source material by TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.12 g of the desired product. MS (elektrorazpredelenie): 396 (M+1) for C20H22FN7O.1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 1H), 8.30 (s, 1H), 7.70 (d, 1H), 7.50 (m, 2H), 6.70 (d, 1H), 6.10 (s, 1H), 5.00 (m, 1H), 4.40 (m, 1H), 2.00 (m, 2H), 1.40 (d, 6H).

Example 14

6-Chloro-N-[(1S)-1-(5-herperidin-2-yl)ethyl]-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine

3-Chloro-N2-[(1S)-1-(5-herperidin-2-yl)ethyl]-N6-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 39, 0.5 g) was dissolved in ethanol (20 ml) with Pd-C (150 mg) and inlet hydrogen. The mixture was stirred at room temperature until, until there was a lack of original Mat is the Rial at TLC or LCMS. Formylamino acetate (0.5 g) was added to the filtrate after filtration of the resulting mixture. The mixture was stirred at 85°C for 4 h in ethyl Acetate (40 ml) was added to the obtained mixture, and brine (10 ml ×3) was used for washing of the organic layer. The organic layer was dried and concentrated. The obtained residue was separated through column with silica gel (ethyl acetate/Meon)that give 0.12 g of the desired product. MS (elektrorazpredelenie): 416 (M+1) for C19H19ClFN7O.1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 1H), 8.30 (s, 1H), 7.90 (d, 1H), 7.50 (m, 2H), 6.70 (d, 1H), 6.00 (s, 1H), 5.40 (m, 1H), 4.60 (m, 1H), 1.60 (d, 3H), 1.40 (d, 6H).

Example 15

6-Fluoro-N-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-3-(5-methyl-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine

To a solution of 3-fluoro-N2-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N6-(5-methyl-1H-pyrazole-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 42, 3.05 mmol) in EtOH (5 ml) was added SnCl2·2H2O (1.74g, 9.18 mmol) and triethylorthoformate (0.652 ml). The resulting solution was heated to 70°C. overnight. The mixture was left to cool to room temperature and filtered through Celite® and washed with EtOAc. Evaporation of volatile components under reduced pressure gives a colored residue, which was purified using Gilson (5%→95% MeCN/H2O) to obtain the titled compound. LC-MS: 357 [M+1].1H NMR δ 2.01 (d, 3H), 2.34 (s, 3H), 6.46-6.55 (m, 1H), 8.20 (s, 1H), 8.72 (s, H), 8.87 (s, 2H), 9.72 (s, 1H), 9.86 (s, 1H).

Example 16

N-[(1S)-1-(5-Ftorpirimidinu-2-yl)ethyl]-3-(5-methyl-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 15, using the N6-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N2-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 44) as the starting material. LCMS: 339 [M+1].1H NMR δ 1.46 (d, 3H), 2.28 (s, 3H), 5.08 (s, 1H), 6.33 (s, 1H), 6.65 (s, 1H), 7.71 (s, 1H), 8.77 (s, 2H).

Example 17

N-[(1S)-1-(5-Herperidin-2-yl)ethyl]-3-(5-methyl-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 15, using the N6-[(1S)-1-(5-herperidin-2-yl)ethyl]-N2-(5-methyl-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 45) as the starting material. LCMS: 338 [M+1].1H NMR (500 MHz, CDCl3) δ 1.58 (d, 3H), 2.40 (s, 3H), 5.05-5.17 (m, 1H), 5.45 (s, 1H), 6.43 (d, 1H), 6.53 (1H, s), 7.35 (m, 2H), 7.81 (1H, d), 8.41 (s, 1H), 8.6 (brs, 1H).

Example 18

N-[(1S)-1-(5-Herperidin-2-yl)etil-9-(5-methyl-1H-pyrazole-3-yl)-9H-purine-2-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 15, using (S)-N2-(1-(5-herperidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine

(Intermediate 47) as the starting material. LCMS: 339 [M+1].1H NMR (500 MHz, CDCl3) δ 1.62 (d, 3H), 2.41 (s, 3H), 5.23-5.26 (m, 1H), 6.094 (s, 1H), 6.52 (s, 1H), 7.41-7.32 (m, 2H), 8.26 (d, 1H), 8.34 (s, 1H), 8.45 (d, 1H), 8,73 (s, 1H).

Example 19

N-[(1S)-1-(5-Ftorpirimidinu-2-yl)etil-9-(5-methyl-1H-pyrazole-3-yl)-6-(morpholine-4-ylcarbonyl)-9H-purine-2-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 4, using N2-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N5-(5-methyl-1H-pyrazole-3-yl)-6-(morpholine-4-ylcarbonyl)-5-nitropyrimidine-2,4-diamine (Intermediate 51) as the starting material. LCMS: 453 [M+1].1H NMR δ 1.54 (d, 3H), 2.09 (s, 3H), 3.18-3.70 (m, 8H), 4.97-5.29 (m, 1H), 6.25 (s, 1H), 8.45 (s, 1H), 8.84 (s, 2H), 12.69 (s, 1H).

Example 20

N2-[(1S)-1-(5-Herperidin-2-yl)ethyl]-9-(5-methyl-1H-pyrazole-3-yl)-N6-(tetrahydro-2H-Piran-4-yl)-N-purine-2,6-diamine

The named compound is obtained by using a method similar to that described for the synthesis of Example 4, using N2-[(1S)-1-(5-herperidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazole-3-yl)-5-nitro-N6-(tetrahydro-2H-Piran-4-yl)pyrimidine-2,4,6-triamine (Intermediate 53) as the starting material. LCMS: 438 [M+1].1H NMR (MeOD) δ 1.74-2.02 (m, 7H), 2.31 (s, 3H), 3.60 (s, 5H), 5.05-5.41 (m, 1H), 6.34 (s, 1H), 7.47-7.99 (m, 2H), 8.20 (s, 1H), 8.49 (s, 1H).

Example 21

N-[(1S)-1-(5-Herperidin-2-yl)ethyl]-6-methoxy-9-(5-methyl-1H-pyrazole-3-yl)-9H-purine-2-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 4, using N2-[(1S)-1-(5-herperidin-2-yl)ethyl]-6-methoxy-N4-(5-methyl-1H-pyrazole-3-yl)-5-nitropyrimidine-2,4-diamine (Intermediate 55) as the starting material. LCMS: 369 [M+1].1H NMR (MeOD) δ 1.67 (d, 3H), 2.44 (s, 3H), 3.63 (s, 3H), 5.08-5.49 (m, 1H), 6.44 (s, 1H), 7.91-8.10 (m, 1H), 8.13-8.36 (m, 1H), 8.77 (s, 1H), 9.33 (s, 1H).

Example 22

N-[(1S)-1-(5-Herperidin-2-yl)ethyl]-9-(5-methyl-1H-pyrazole-3-yl)-6-morpholine-4-yl-N-purine-2-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 15, using the N2-[(1S)-1-(5-herperidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazole-3-yl)-6-morpholine-4-yl-5-nitropyrimidine-2,4-diamine (Intermediate 58) as the starting material. LCMS: 424 [M+1].1H NMR (500 MHz, CDCl3) δ 1.54 (d, 3H), 2.31 (s, 3H), 3.72-3.74 (m, 4H), 4.15-4.20 (m, 4H), 5.12-5.17 (m, 1H), 6.44 (s, 1H), 7.24-7.36 (m, 2H), 7.95 (s, 1H), 8.38 (d, 1H).

Example 23

3-(5-Ethoxy-1H-pyrazole-3-yl)-N-[(1S)-1-(5-herperidin-2-yl)propyl]-3H-imidazol[4,5-b]pyridine-5-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 9, using N2-(5-ethoxy-1H-pyrazole-3-yl)-N6-[(1S)-1-(5-herperidin-2-yl)propyl]-3-nitropyridine-2,6-diamine (Intermediate 59) as the starting material. LCMS: 382 [M+1].1H NMR (400 MHz, CD3OD) δ 8.4 (s, 1H), 8.30 (s, 1H), 7.70 (d, 1H), 7.40 (d, 2H), 6.60 (d, 1H), 6.10 (br. 1H), 5.90 (s, 1H), 4.20 (q, 2H), 2.00 (m, 2H), 1.40 (d, 3H), 1.10 (t, 3H).

Example 24

3-(5-Isopropoxy-1H-pyrazole-3-yl)-N-[(1S)-1-pyrimidine-2-ileti]-3H-imidazo[4,5-b]pyridine-5-amine

The named compound is obtained by using a method similar to that described for the synthesis of Example 6, using the N6-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-N2-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2,6-diamine (Intermediate 20) as the starting material. Source material (1.7 g) was dissolved in ethanol (10 ml). To the solution was added Pd-C (0.3 g, 10%). The inlet hydrogen was introduced into the reaction flask. The resulting mixture was stirred for 5 h Formamidine acetate (2 g) was added to the mixture. The mixture was stirred at 85°C for 4 h the mixture was filtered and the filtrate was concentrated. The obtained residue was separated through column with silica gel. The named compound was obtained (0.14 g) as a byproduct. LCMS: 365 [M+1].1H NMR (400 MHz, CD3OD) δ 8.60 (s, 2H), 8.20 (s, 1H), 7.60 (d, 1H), 7.20 (s, 2H), 6.50 (d, 1H), 6.10 (br, 1H), 5.10 (s, 1H), 4.70 (m, 1H), 1.40 (d, 3H), 1.30 (d, 6H).

Example 25

(S)-Ethyl 2-(1-(5-herperidin-2-yl)ethylamino)-9-(5-methyl-1H-pyrazole-3-yl)-N-purine-6-carboxylate

The named compound is obtained according to the method described for Example 4, using ethyl 2-{[(1S)-1-(5-herperidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-feast of the evils-3-yl)amino]-5-nitropyrimidin-4-carboxylate (Intermediate 60) as the starting material. The named compound is low decomposition after its synthesis. LCMS: 411 [M+1]+.

Example 26

To a solution of the compound obtained in example 6 (5.2 mmole)in DCM (5 ml) solution was added HCl (4.0 n, 1.3 ml, 5.2 mmole) in dioxane. The reaction mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure to obtain cleaners containing hydrochloride salt of the compound from example 6 with almost quantitative yield.

1. N-[(1S)-1-(5-ftorpirimidinu-2-yl)ethyl]-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo[4,5-b]pyridine-5-amine or its pharmaceutically acceptable salt.

2. The compound according to claim 1 or its pharmaceutically acceptable salt for use as a medicine.

3. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for a medicinal product for the treatment of cancer in a warm-blooded animal.

4. Pharmaceutical composition having inhibitory activity against Trk, comprising the compound according to claim 1 or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier, solvent or excipient.



 

Same patents:

The invention relates to new derivatives of 2-aryl-8-oxopiperidine formula (I) having a selective affinity towards BZw3receptor, the method thereof, pharmaceutical composition and means containing it, and also to the intermediate compound of formula (II) to obtain the derivatives of 2-aryl-8-oxopiperidine

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to an improved method for producing a purine compounds of General formula A, where X is hydrogen, hydroxy, chlorine, Ra and Rb denote hydrogen, acyl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel purinyl derivatives of formula or , a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, where n equals 0, 1, 2 or 3; X is O, S or NR', where R' is hydrogen or methyl; Y is cycloalkyl, phenyl, benzo[1,3]dioxolyl or pyridyl, where the cycloalkyl, phenyl, benzo[1,3]dioxolyl and pyridyl are possibly substituted with one substitute selected from a group consisting of halogen, trifluoromethyl, cyano, nitro and amine; R1 is hydrogen, alkyl or alkoxy-alkyl; and Het is a pyrazolyl group which is substituted twice or more with substitutes selected from a group consisting of alkyl, hydroxy-alkyl, halogen, trifluoromethyl, alkoxy-carbonyl and phenyl. The invention also relates to pharmaceutical compositions which are useful for treating or relieving symptoms of diseases and disorders associated with activity of potassium channels.

EFFECT: novel compounds which can be used as potassium channel modulators are obtained and described.

12 cl, 16 ex

Compounds // 2461559

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives possessing the properties of an inhibitor of the enzyme CDK specified in CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9. In formula (I): R1 and R2 each independently represents H, C1-6alkyl or C1-6halogenalkyl; R3 and R4 each independently represents H, C1-6-alkyl or C1-6-halogenalkyl; R5 represents C1-6-alkyl or C3-12-cycloalkyl, or C3-12-cycloalkyl-C1-6-alkyl each of which may be optionally substituted by one or more OH groups; R6 represents wherein Y represents N, X and Z represents CR9; R7, R8 and R9 optionally represent H, alkyl or C1-6-halogenalkyl; wherein at least one of R7 , R8 and R9 is other than H. The invention also refers to a pharmaceutical composition containing said compounds, using the compounds for treating alopecia, stroke, a proliferative disease, such as cancer, leukaemia, glomerulonephritis, rheumatoid arthritis, psoriasis, viral diseases, such as a disease caused by human cytomegalovirus, type 1 herpex simplex virus, type 1 human immunodeficiency virus, a neurodegenerative disease, a CNS disease, such as Alzheimer's disease.

EFFECT: preparing new purine derivatives possessing the properties of the inhibitor of the enzyme CDK.

30 cl, 8 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives of formula (I) and to their pharmaceutically acceptable salts exhibiting the properties of adenosine receptor A2A agonists. The compounds can find application for preparing a drug for treating an inflammatory or obstructive respiratory disease. In formula

,

R1, R2 and R3 are those as specified in the patent claim.

EFFECT: preparing new purine derivatives of formula (I) or their pharmaceutically acceptable salts showing the properties of adenosine receptor A2A agonists.

8 cl, 2 tbl, 264 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or salts or solvates thereof. Abacavir has strong HIV-1 and HIV-2 selective inhibitor activity and can be used in treating patients infected with HIV. The method involves i) closing the ring in a compound of formula (IV) by first reacting said compound (IV) with an anhydrous hydrochloric acid solution in (C1-C6)-alcohol, preferably isopropanol, and then with tri(C1-C4)-alkylorthoformate in anhydrous conditions to obtain a compound of formula (III), ii) reaction of the compound of formula (III) with cyclopropylamine to obtain a compound of formula (II) and iii) hydrolysis of the compound of formula (II) to obtain abacavir (I) or salt thereof. R1 denotes a (C1-C4)-alkyl radical, preferably isopropyl.

EFFECT: obtaining an end product with higher output and higher quality.

12 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.

EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.

15 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing abacavir of formula (I) or pharmaceutically acceptable salt thereof, involving reaction of a compound of formula (II), (I) (II), where R denotes H or (C1-C4)-alkyl radical with an inorganic base such as an alkali metal hydroxide in a mixture of (C1-C6)-alcohol and water; and extraction of abacavir of formula (I) in form of a free base or in form of a pharmaceutically acceptable salt by treating said free base with a corresponding acid.

EFFECT: method ensures high degree of conversion without racemation, enables to minimise formation of impurities and considerably shortens reaction time.

19 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I in free form or in form of pharmaceutically acceptable salt, which possess properties of adenosine receptor A2A agonists. In formula I , R1 represents (C1-C8)alkylcarbonyl, (C3-C8)cycloalkylcarbonyl, -SO2(C1-C8)alkyl, phenyl(C1-C4)alkylcarbonyl or -(C=O)-C(=O)-NH(C1-C8)alkyl, optionally substituted with R4; R2 represents H or (C1-C8)alkyl, optionally substituted with (C6-C10)aryl; R3 represents halogen or(C2-C8)alkinyl, or R3 stands for aminogroup, optionally substituted with (C3-C8)cycloalkyl, optionally substituted with amino, or R3 represents (C1-C8)alkylaminogroup, optionally substituted with hydroxy, phenyl or R5, or R3 stands for R6, optionally substituted with amino or -NH-C(=O)-NH-R7, or R3 stands for -NH-R6, optionally substituted with -NH-C(=O)-NH-R7, or R3 stands for (C1-C8)alkylaminocarbonyl, optionally substituted with. -NH-C(=O)-NH-R8; R4, R5 and R6 represent independently 5- or 6-member heterocyclic ring, which contains one-two N ring heteroatoms, optionally substituted with amino or (C1-C8)alkyl; and R7 and R8 represent independently 5- or 6-member heterocyclic ring, which contains one-two ring heteroatoms selected from N and S, and is optionally substitutedf with halogen, (C1-C8)alkylsulfonyl or 5- or 6-member aromatic heterocyclic ring, which contains one N ring heteroatom. Invention also relates to pharmaceutical composition and to application of said compounds for treatment of states, mediated by activation of adenosine receptor A2A.

EFFECT: obtaining composition, which possesses properties of adenosine receptor A2A agonists.

10 cl, 3 tbl, 80 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel purine derivatives of general formula I in free form or in form of a pharmaceutically acceptable salt which have A2A agonist properties. In formula I , R1 denotes a N-bonded 5-6-member heterocyclic group containing 1-4 nitrogen atoms in the ring, which can be optionally substituted with oxo, phenyl or C1-8-alkyl, optionally substituted with hydroxy; R2 is hydrogen or C1-C8-alkyl, optionally substituted with hydroxy or 1-2 phenyls possibly substituted with hydroxy or C1-C8-alkoxy; R3 is C2-C8-alkynyl or C1-C8-alkoxycarbonyl, or R3 is amino substituted with C3-C8-cycloalkyl, optionally substituted with amino, hydroxy, benzyloxy or NH-C(=O)-NH-R6, or R3 is amino substituted with R4, -R4-benzyl or C5-C10-mono- or bicarbocyclic group, optionally substituted with hydroxy or C1-C8-alkoxycarbonyl, or R3 is aminocarbonyl optionally substituted with R5, or R3 is C1-C8-alkylamino optionally substituted with hydroxy, R5, NH-C(=O)-C1-C8-alkyl, -MH-SO2-C1-C8-alkyl, -NH-C(=O)-NH-R6 or phenyl, optionally substituted with phenyloxy, or R3 is a N-bonded 5-member heterocyclic group containing 1 nitrogen atom in the ring which may optionally be substituted with amino, C1-C8-alkylamino, di(C1-C8-alkyl)amino and other groups.

EFFECT: compounds can be useful in treating conditions mediated by activation of the adenosine A2A receptor, especially inflammatory or obstructive respiratory tract diseases.

9 cl, 5 tbl, 161 ex

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula I, wherein W and Z represent CH; Y represents CH2; wherein R1 and R2 independently represent H, halogen, CH2F, CHF2, CF3, CF2CF3, or C1-C6alkyl; R' represents H; R3 and R4 independently represent H, or C1-C3alkyl, all mentioned C1-C3alkyl groups and mentioned C1-C6alkyl groups are independently substituted by one or two groups independently substituted by one or two groups independently specified in OH, halogen, C1-C3alkyl, OC1-C3alkyl or trifluoromethyl; q=1 or 0; R5 represents C1-C6alkyl; and to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a composition, a tablet and pharmaceutical syrup having potassium channel modulation activity and containing the compound of formula I, to a method of preventing and treating diseases that are affected by the activation of potentially opened potassium channels.

EFFECT: there are prepared and described the new biologically active compounds which may be effective in the prevention or treatment of diseases or disorders that are affected by potassium channel activity.

21 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline modification of para-methoxyanilide of 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid of formula: (I) , which is obtained by crystallisation from ethyl acetate, where values of interplanar distance (d) and relative reflection intensities (Irel) are given in claim 1.

EFFECT: novel crystalline modification exhibits a high diuretic effect.

2 dwg, 9 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to complexes of lanthanides and organic ligands which are luminescent in the visible spectrum and are used in electroluminescent devices, means of protecting security paper and documents from falsification etc. Disclosed are novel luminescent coordination compounds of lanthanides of formula: where Ln is Eu3+, Tb3+, Dy3+, Sm3+, Gd3+.

EFFECT: said compounds have high luminescence intensity and considerable thermal tolerance of up to 400°C, which enables use thereof in modern production of light-emitting diodes.

4 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

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