EA041069B1 - BENZAMIDE DERIVATIVES AS PPAR-GAMMA MODULATORS - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to novel optionally substituted benzamide derivatives as PPARgamma receptor modulators.

Other objects of the present invention are a method for obtaining these compounds; pharmaceutical compositions containing an effective amount of these compounds; the use of these compounds for the manufacture of a medicament for the treatment or prevention of pathological conditions or diseases that can be alleviated by modulation of the PPAR-gamma receptor, such as cancer, metabolic disorders, disorders of glucose metabolism, inflammatory diseases, autoimmune disease, neurodegenerative disease, cardiovascular diseases, neoplastic diseases and kidney disease; said compounds for use in the treatment or prevention of said diseases; and methods of treating or preventing said diseases.

State of the art

Peroxisome proliferator-activated receptor PPARs are transcription factors belonging to the nuclear receptor superfamily (CHAWLA, Ajay, et al. Nuclear receptors and lipid physiology: opening the X-files. Science, 2001, vol. 294, no 5548, pp. 1866-1870). They are predominantly expressed in adipose tissue and in many cells of the immune system, including monocytes, macrophages, B and T lymphocytes, natural killer cells, dendritic cells, neutrophils, eosinophils, and mast cells (CHAWLA, Ajay, et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation (Endocrinology, 1994, vol. 135, no 2, pp. 798-800).

PPARs are activated by small molecule ligands, including endogenous saturated and unsaturated fatty acids, their metabolites, and synthetic ligands. PPARs act as obligate heterodimers with retinoid X receptors (RXR), which bind to peroxisome proliferator response element (PPRE) located in the regulatory domains of genes that regulate transcription of target genes in a ligand-dependent manner. Ligand binding to PPARs stabilizes their conformation and subsequently modulates cofactor recruitment, leading to transcriptional activation. To date, three PPAR subtypes have been identified with distinct distributions and specific roles: PPARa (PPAR alpha), PPAR β/δ (PPAR beta/delta), and PPARy (PPAR gamma). The three PPARs differ in their structure, function, and tissue distribution (BERGER, Joel; MOLLER, David E. The mechanisms of action of PPARs. Annual review of medicine, 2002, vol. 53, no 1, p. 409-435).

The cardinal biological activity of PPAR-gamma is the induction of differentiation of adipocytes, cells that express the highest levels of PPAR-gamma in normal tissues. However, lower levels of PPAR-gamma are found in other normal tissues and cell types such as skeletal muscle, liver, breast, prostate, colon, type 2 alveolar pneumocytes, some endothelial cells, and monocytes and B lymphocytes ( BURTON, Jack D.; GOLDENBERG, David M.; BLUMENTHAL, Rosalyn D. Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types (PPAR research, 2008, vol. 2008).

PPAR-gamma and cancer

PPAR-gamma has become a putative therapeutic target for cancer treatment in various epithelial cell tumors. It is known that PPAR-gamma activation can inhibit tumor processes by suppressing tumor cell replication and reducing tumor cell survival (PANIGRAHY, Dipak, et al. Therapeutic potential of thiazolidinediones as anticancer agents. Expert opinion on investigational drugs, 2003, vol. 12, no 12, pp. 1925-1937).

PPAR-gamma ligands have been shown to promote differentiation and apoptosis in various cancer cells, including colon cancer, breast cancer, prostate cancer, gastric cancer, bladder cancer, and pancreatic cancer (YOUSEFI, Bahman, et al. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies Chemical biology & drug design, 2016, vol. 88, no 1, pp. 17-25, and its references). (ELSTNER, Elena, et al. Ligands for peroxisome proliferator-activated receptory and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proceedings of the National Academy of Sciences, 1998, vol. 95, no 15, pp. 8806-8811). In addition, PPAR ligands are known to exhibit a synergistic effect when used in combination with a tyrosine kinase inhibitor such as imatinib, which is used in patients with chronic myeloid leukemia (CML).

Several studies have identified the potential and efficacy of PPAR-gamma agonists as a novel lung cancer monotherapy (CHANG, Tsg-Hui; SZABO, Eva. Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor in non-small cell lung cancer. Cancer research, 2000, vol. 60, no 4, pp. 1129-1138), as well as in combination with standard cytotoxic chemotherapy. PPAR-gamma agonists show a synergistic effect in combination with traditional chemothera

- 1 041069 peutic agents, enhancing their cytotoxic effect on cancer cells (REDDY, Aravind T.; LAKSHMI, SowmyaP.; REDDY, Raju C. PPAR-gammaasanovel therapeutic target in lung cancer. PPAR research, 2016, vol. 2016).

Similarly, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been found in some human leukemic cells. Recent studies have shown that PPARgamma ligands inhibit cell proliferation and induce apoptosis in both normal and malignant B cell lines (TAKENOKUCHI, M., et al. Troglitazone inhibits cell growth and induces apoptosis of B-cell acute lymphoblastic leukemia cells with t (14; 18) Acta Haematologica, 2006, vol. 116, no 1, pp. 30-40).

However, although in some cases PPAR-gamma activation is associated with tumor cell death, some observations suggest that inhibition of PPAR-gamma function may also be useful in the treatment of certain cancers.

PPAR-gamma is overexpressed in many epithelial tumor cells, including stomach, breast, and lung cells, and may be a tumor survival factor (MUELLER, Elisabetta, et al. Terminal differentiation of human breast cancer through PPAR-gamma. Molecular cell, 1998, vol. 1, no 3, pp. 465-470).

Other studies have shown that PPAR-gamma or RXRA activating alterations result in a specific gene expression signature in bladder cancer. Decrease in PPAR-gamma activity through pharmacological inhibition or genetic ablation inhibited the proliferation of PPAR-gamma activated bladder cancer cells (GOLDSTEIN, Jonathan T., et al. Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer. Cancer Research, 2017, p. canres. 1701.2017).

Another study evaluated the effect of the PPAR-gamma antagonists BADGE, GW9662 and T0070907, on four squamous cell carcinoma cell lines derived from oral tumors. An antiproliferative effect was shown for the three antagonists but not for the pioglitazone agonist, indicating that compounds of various chemical structures that are PPAR-gamma antagonists have several significant anticancer effects in vitro and in vivo in epithelial cancer model systems, including breast cancer. gland, colon cancer, squamous cell carcinoma of the gastrointestinal tract and hepatocellular carcinoma (MASUDA, Tomotake, et al. Critical role of peroxisome proliferator-activated receptor in on anoikis and invasion of squamous cell carcinoma. Clinical Cancer Research, 2005, vol. 11 , no 11, pp. 4012-4021).

In hematoblastosis model systems, initial screening showed that some myeloma (MM) cell lines as non-Hodgkin's lymphoma (NHL) cell lines were most sensitive to the antiproliferative effects of GW9662 and T0070907 antagonists (BURTON, Jack D., et al. Peroxisome proliferator-activated receptor -y antagonists exhibit potent antiproliferative effects versus many hematopoietic and epithelial cancer cell lines (Anti-cancer drugs, 2007, vol. 18, no 5, pp. 525-534).

Another study shows that silencing of PPAR-gamma expression by RNAi in human Burkitt type B lymphosarcoma cells increases basal and mitogen-induced proliferation and survival. These cells also had increased survival when exposed to PPAR-gamma ligands and showed a less differentiated phenotype (GARCIA-BATES, Tatiana M., et al. Peroxisome proliferator-activated receptor gamma overexpression and knockdown: impact on human B cell lymphoma proliferation and survival. Cancer immunology, immunotherapy, 2009, vol.58, no 7, pp. 1071-1083).

Another study suggests that combination treatment with PPARy Ligand and its inhibitor, GW9662, may be a potential therapeutic strategy targeting glioblastoma stem cells (IM, Chang-Nim. Combination Treatment with PPARy Ligand and Its Specific Inhibitor GW9662 Downregulates BIS and 14-3-3 Gamma, Inhibiting Stem-Like Properties in Glioblastoma Cells BioMed Research International, 2017, vol. 2017).

PPAR-gamma and metabolic diseases

Significant in vitro studies have shown that this receptor is necessary and sufficient for adipocyte differentiation and that it promotes lipid accumulation by adipocytes. The anti-diabetic thiazolidinedione (TZD) family, which are PPAR-gamma agonists, is known to suppress insulin resistance in adipose tissue as well as in skeletal muscle and liver, which contain low concentrations of PPAR-gamma. In line with this, they have been shown to alter the expression of genes that are involved in lipid uptake, lipid metabolism, and insulin action in adipocytes. Data from patients with type 2 diabetes mellitus (DM2) and its preclinical species also indicate that PPAR-gamma function agonists function as adipose tissue remodeling factors that redistribute lipids from insulin-resistant, lipolytic visceral fat depots to subcutaneous fat, which contains small, newly differentiated, insulin-responsive adipocytes (BERGER, Joel P.; AKIYAMA, Taro E.; MEINKE, Peter T. PPARs: therapeutic targets for metabolic disease. Trends in pharmacological sciences, 2005, vol. 26, no 5, pp. 244-251, and its references).

- 2 041069

Atherosclerosis

PPAR-gamma is also expressed at relatively high expression levels in various vascular cells, including endothelial cells, smooth muscle cells, and monocytes/macrophages. PPAR-gamma agonists have been reported to attenuate atherosclerosis in genetically predisposed atherosclerosis mouse models: LDLR ^- / ^- and ApoE ^- / ^- or intima to a medial ratio in human patients. In another study, troglitazone treatment of male LDLR ^- / ^- mice previously fed a high fat (HFD) or high fructose diet significantly reduced atherosclerotic lesions (HAN, Lu, et al. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease Part II: PPAR-β/δ and PPAR-γ Future cardiology, 2017). Another study showed that administration of PPAR-gamma activators reduces the size of atherosclerotic lesions in low-density lipoprotein receptor (LDLRK/K) knockout (LI, Andrew C., et al. Peroxisome proliferator-activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor- deficient mice, The Journal of clinical investigation, 2000, vol.106, no 4, pp. 523-531). This anti-atherogenic activity appears to be independent of alleviation of dyslipidemia, insulin resistance, and hypertension, indicating direct vascular effects; as a result, PPAR-gamma agonists also exhibit a wide range of anti-atherogenic effects in vitro and in animal models of atherosclerosis (HSUEH, Willa A.; BRUEMMER, Dennis. Peroxisome proliferator-activated receptor γ: implications for cardiovascular disease. Hypertension, 2004, vol. 43, no 2, pp. 297-305).

PPAR-gamma regulation of metabolic functions in the liver, skeletal muscle and heart

Unlike adipose tissue, the liver, skeletal muscle, and heart only express PPAR-gamma at low to moderate levels. However, under certain pathophysiological conditions, PPAR-gamma protein expression is significantly increased in these tissues. Several studies have provided evidence that hepatic PPAR-gamma expression is markedly elevated in many models of obesity (lipoatrophy and hyperphagic obesity), insulin resistance, and diabetes with varying degrees of steatosis (NEUSCHWANDER-TETRI, Brent A., et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-γ ligand rosiglitazone Hepatology, 2003, vol.38, no 4, pp. 1008-1017).

Similarly, increased expression of hypoxia-inducible factor HIF-1a and PPAR-gamma has been described in human and mouse ventricular biopsies with hypertrophic cardiomyopathy (KRISHNAN, Jaya, et al. Activation of a HIF1a-PPAR/ axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy (Cell metabolism, 2009, vol. 9, no 6, pp. 512-524). Further investigation of mouse biopsy specimens showed that HIF-1a causes upregulation of PPAR-gamma gene expression and subsequently leads to cardiac steatosis, apoptosis, and heart failure (KINTSCHER, Ulrich; LAW, Ronald E. PPARγ-mediated insulin sensitization: the importance of fat versus fat muscle American Journal of Physiology-Endocrinology And Metabolism, 2005, vol.288, no 2, pp. E287-E291).

In addition, PPAR-γ gene expression is elevated in skeletal muscle of obese and type II diabetic subjects. Diabetes, 1997 , vol. 46, no 7, pp. 1230-1234).

Inflammation, hypertension and the vasculature

PPAR-gamma ligands have also been shown to inhibit the production of many inflammatory mediators and cytokines in various cell types, including monocytes/macrophages, epithelial cells, smooth muscle cells, endothelial cells, dendritic cells, and lymphocytes (see DAYNES, Raymond A.; JONES, Dallas C, Emerging roles of PPARs in inflammation and immunity Nature reviews Immunology, 2002, vol 2, no 10, p 748 mechanisms of inflammation Current medicinal chemistry, 2005, vol 12, no 25, p 29953009). In addition, PPAR-gamma ligands have been shown to exert anti-inflammatory effects in several disease models, including atherosclerosis, obesity-induced insulin resistance, allergic encephalomyelitis, Parkinson's disease, Alzheimer's disease, psoriasis, inflammatory bowel disease, and arthritis (RICOTE, Mercedes; GLASS, Christopher K. PPARs and molecular mechanisms of transrepression Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 2007, vol.1771, no 8, pp. 926-935, cited in the publication).

Regarding the effects of PPAR-gamma on hypertension, genetic analysis shows that 2 dominant negative mutations in PPAR-gamma are associated with severe hypertension in humans, indicating an important role for PPAR-gamma in blood pressure regulation. PPARy agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. Hypertension, 2004, vol. 43, no 3, p. 661 -666).

PPAR-gamma agonists exhibit strong anti-inflammatory effects and have direct neuroprotective effects. PPARy agonists have been shown to be effective in animal models of Alzheimer's disease, stroke, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis (SUNDARARAJAN, Sophia, et al. PPARy as a therapeutic target in cen).

- 3 041069 tral nervous system diseases. Neurochemistry international, 2006, vol. 49, no 2, p. 136-144 and references cited in the publication).

Cardiovascular diseases

PPAR-gamma agonists are known to be beneficial in diabetes and atherosclerosis, which are known risk factors associated with cardiovascular disease. Preclinical studies have shown that pharmacological modulation of PPAR can enhance the expression of fatty acid oxidation genes in cardiomyocytes. Moreover, PPAR agonists have been shown to be able to improve ventricular contractility and reduce cardiac remodeling in animal models through their anti-inflammatory, antioxidant, anti-fibrotic, and anti-apoptotic activities (ABUSHOUK, Abdelrahman Ibrahim, et al. Peroxisome proliferator-activated receptors as therapeutic targets for heart failure). Biomedicine & Pharmacotherapy, 2017, vol. 95, pp. 692-700).

Immunotherapy

PPAR-gamma antagonists are known to act as negative regulators of T cells in addition to inhibiting bone marrow adipogenesis (BM). This leads to the possibility of using PPAR-gamma antagonists in immune-mediated pathophysiology in both laboratory and clinical settings (SATO, Kazuya, et al. PPARy antagonist attenuates mouse immunemediated bone marrow failure by inhibition of T cell function, haematologica, 2016, vol. 101, no 1, pp. 57-67).

It is known from another study that PPAR-gamma-deficient T cells are hyperreactive to TCR stimulation. Various cytokines, including IFN-c, IL-4, IL-17, and IL-2, were elevated in PPARgamma-deficient T cells compared to control littermate T cells, suggesting that these cells are hyperreactive to TCR stimulation. In addition, PPAR-gamma-deficient T cells proliferated significantly more than control CD4+ T cells, suggesting that PPAR-gamma plays a negative regulator of T cell activation and proliferation (PARK, Hong-Jai, et al. PPARy negatively regulates Tcell activation to prevent follicular helper T cells and germinal center formation (PloS one, 2014, vol. 9, no 6, p. e99127).

On the other hand, reduction of PPAR-gamma activity by treatment with a PPAR-gamma antagonist or deletion of one allele of the PPAR-gamma gene has been reported to reduce high-fat diet-induced adipocyte hypertrophy and insulin resistance. Treatment with a PPAR-gamma antagonist also significantly improved insulin sensitivity in diabetic mice. Thus, both antiobesity and antidiabetic activity have been shown (EUSSET, Jennifer, et al. A new selective peroxisome proliferator-activated receptor y antagonist with antiobesity and antidiabetic activity. Molecular Endocrinology, 2002, vol. 16, no 11, p 2628-2644).

Evidence from genetic studies in humans and PPAR-gamma heterozygous knockout mice indicates that a reduction in PPAR-gamma activity can paradoxically improve insulin sensitivity. These data suggest that modulation of PPAR-gamma activity by partial agonists or compounds that affect cofactor recruitment may be promising for the treatment of insulin resistance.

On the other hand, there is genetic evidence that decreased peroxisome proliferation receptor-y antagonists have clinical potential as combined antiobesity and antidiabetic drugs? Expert opinion on investigational drugs, 2003, vol. 12, no 4, pp. 713-716).

It has been shown that a PPAR-gamma antagonist is involved in bone formation and is effective, for example, as a therapeutic agent for osteoporosis and the like. (DUQUE, Gustavo, et al. Pharmacological inhibition of PPARy increases osteoblastogenesis and bone mass in male C57BL/6 mice. Journal of Bone and Mineral Research, 2013, vol. 28, no 3, p. 639-648).

Therefore, the problem to be solved by the present invention is to develop a compound as a PPARgamma receptor modulator and more specifically as a PPARgamma receptor antagonist.

The present inventors have developed novel benzamide derivatives, conveniently substituted, as a potent PPARgamma receptor modulator.

The essence of the invention

In the first aspect (aspect 1) the present invention relates to new benzamide derivatives of formula (I)

^R4

- 4 041069 where

R ² is selected from Cl and F atoms;

R ¹ is cyano;

G ¹ and G ² are independently a group selected from N and -CR ⁹ where G ¹ and G ² are not CR ⁹ at the same time;

R ⁹ is independently selected from the group consisting of

a) a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group;

b) pyridinyl ring;

c) morpholinyl and piperazinyl groups unsubstituted or substituted with a group selected from a C ₁ -C ₃ alkyl group; And

d) -C ₃ -C ₆ -cycloalkyl group;

R ³ , R ⁴ and R ⁵ are hydrogen atoms; and its pharmaceutically acceptable salts.

Other aspects of the present invention are the following aspects.

Aspect 2: The use of compounds according to aspect 1 for the treatment or prevention of a disease or condition that can be alleviated by modulation of the PPARgamma receptor, wherein said disease or condition is selected from the group consisting of cancer, selected from breast cancer, pancreatic cancer gland, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer or hematopoietic cancer selected from lymphoma, multiple myeloma and leukemia; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; lung diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; a neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cardiovascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in tumor diseases and kidney diseases.

Aspect 3: pharmaceutical compositions containing from 0.001% to 99% by weight of the compound of aspect 1, a pharmaceutically acceptable diluent or carrier.

Aspect 4: The use of compounds according to aspect 1 for the manufacture of a medicament for the treatment or prevention of a disease or condition that can be facilitated by modulation of the PPARgamma receptor, wherein said disease or condition is selected from the group consisting of cancer, selected from breast cancer cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer, or hematopoietic cancer selected from lymphoma, multiple myeloma, and leukemia ; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; lung diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; a neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cardiovascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in tumor diseases and kidney diseases.

Aspect 5: methods of treating or preventing a disease or condition that can be alleviated by modulating the PPARgamma receptor by administering the compounds of aspect 1 to a patient in need of said treatment, wherein said disease or condition is selected from the group consisting of a cancer selected from breast cancer cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer, or hematopoietic cancer selected from lymphoma, multiple myeloma, and leukemia ; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; lung diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; a neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cordially

- 5 041069 vascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in tumor diseases and kidney diseases.

Accordingly, the derivatives of the present invention and their pharmaceutically acceptable salts and pharmaceutical compositions containing said compounds and/or salts thereof can be used in a method for treating pathological conditions or diseases of the human body, which comprises administering to a patient in need of said treatment an effective amount of benzamide derivatives according to of the present invention or their pharmaceutically acceptable salts.

As mentioned above, the benzamide derivatives of the present invention are useful in the treatment or prevention of diseases known as diseases that are susceptible to relief by treatment with a PPARgamma receptor modulator. Such diseases are selected from cancer selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer or hematopoietic cancer selected from lymphoma, multiple myeloma and leukemia; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia, osteoporosis, rickets, arthrosis; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; lung diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; a neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cardiovascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in tumor diseases and kidney diseases.

The term halogen atom, as used herein, includes a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom, a chlorine atom, or a bromine atom. The term halogen, when used as a prefix, has the same meaning.

The term C ₁ -C ₃ -haloalkyl, when used in the present description, means C ₁ -C ₃ -alkyl substituted with one or more halogen atoms, preferably one, two or three halogen atoms. Preferably the halogen atoms are selected from the group consisting of fluorine atoms or chlorine atoms. In a preferred embodiment, the haloalkyl group is Ci-alkyl substituted with three fluorine atoms (trifluoromethyl group).

The term C ₁ -C ₃ -alkyl, when used in the present description, means linear or branched hydrocarbon radicals (C _n -H _2n+1 ) containing from 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl radicals.

The term Cn-Cm-cycloalkyl, as used herein, means monocyclic hydrocarbon groups containing n to m carbon atoms, for example 3 to 6 or 3 to 4 carbon atoms. Such cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term C ₁ -C ₃ -alkoxy, when used in the present description, means radicals that contain a linear or branched C ₁ -C ₃ -alkyl group connected to an oxygen atom (C _n H _2n+1 -O-). The preferred alkoxy radical is methoxy.

The term C ₃ -C ₄ -cycloalkoxy, when used in the present description, means radicals consisting of C ₃ -C ₄ -cycloalkyl groups connected to an oxygen atom.

The term five- to six-membered heteroaryl ring, when used in the present specification, means a heteroaromatic ring containing carbon, hydrogen, and one or more heteroatoms selected from N, O, and S atoms as ring-forming atoms such as furan, pyridine, pyrazine, pyrrole, imidazole, pyrazole, oxazole, thiazole and thiophene. These radicals may be optionally substituted with one or more substituents as defined in each instance. Preferred radicals are optionally substituted pyridyl, pyrimidinyl. When the heteroaryl radical bears two or more substituents, the substituents may be the same or different.

The term five- or six-membered saturated heterocyclic ring, when used in the present specification, means a saturated heterocyclic ring containing carbon, hydrogen, and one or more heteroatoms selected from N and O atoms as ring-forming atoms such as pyrrolidinyl, tetrahydrofuranyl , dioxolanil, pyrazolidinyl, imidazolinil, piperazinil, piperidinyl and morpholinyl. These radicals may be optionally substituted with one or more substituents as defined in each instance. Preferred radicals are optionally substituted piperidinyl, piperazinyl and morpholinyl. When a heterocyclic radical bears 2 or more substituents, the substituents may be the same or different.

In the present description, some of the atoms, radicals, chains or cycles present in the general structures of the invention are optionally substituted. This means that these atoms

- 6 041069 radicals, chains or cycles may be unsubstituted or substituted at any position with one or more substituents, for example, 1, 2, 3 or 4 substituents, where the hydrogen atoms associated with unsubstituted atoms, radicals, chains or cycles are replaced by chemically acceptable atoms, radicals, chains or cycles. When two or more substituents are present, the substituents may be the same or different.

The term pharmaceutically acceptable salt, when used herein, means salts with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. Pharmaceutically acceptable acids include both inorganic acids, such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic, and nitric acids, as well as organic acids, such as citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal hydroxides (eg sodium or potassium), alkaline earth metal hydroxides (eg calcium or magnesium), and organic bases such as alkylamines, arylalkylamines and heterocyclic amines.

Other preferred salts of the present invention are quaternary ammonium compounds in which the equivalent of the anion (X ^-n ) is associated with the positive charge of the N atom. X ^-n can be an anion of various mineral acids, such as, for example, chloride, bromide, iodide, sulfate , nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, maleate, mandelate, trifluoroacetate, methanesulfonate and toluenesulfonate. X ^-n is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X ⁿ is chloride, bromide, trifluoroacetate or methanesulfonate.

The term modulator refers to a molecule, such as a compound, drug, enzyme, or hormone, that blocks or otherwise interferes with a particular biological activity.

The term IC ₅₀ when used in the present description, refers to the concentration that causes inhibition equal to half the maximum inhibition of control specific binding. IC ₅₀ values can be determined from the corresponding dose-response curve, more precisely IC ₅₀ values can be determined using non-linear regression analysis.

In accordance with one embodiment of the present invention G ¹ represents a nitrogen atom; G ² is a -CR ⁹ group, where R ⁹ is selected from

a) a phenyl group optionally substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group,

b) pyridinyl ring,

c) a morpholinyl and piperazinyl group optionally substituted with a group selected from a C ₁ -C ₃ alkyl group.

In accordance with another embodiment of the present invention, G ² represents a nitrogen atom; G ¹ is a -CR ⁹ group, where R ⁹ is selected from

a) a phenyl group optionally substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group;

b) pyridinyl ring;

c) morpholinyl and piperazinyl groups optionally substituted with a group selected from a C ₁ -C ₃ alkyl group.

In another embodiment of the present invention, R ¹ is cyano; R ³ , R ⁴ and R ⁵ are hydrogen atoms; G ¹ is an N atom; and G ² is a -CR ⁹ group, where R ⁹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group.

In another preferred embodiment of the present invention, R ¹ is cyano; R ³ , R ⁴ and R ⁵ independently represent a hydrogen atom; G ¹ is an N atom; G ² is a -CR ⁹ group, where R ⁹ is a pyridinyl ring.

In another preferred embodiment of the present invention, R ¹ is cyano; R ³ , R ⁴ and R ⁵ independently represent hydrogen atoms; G ² is an N atom; and G ¹ is a -CR ⁹ group, where R ⁹ is selected from

a) a phenyl group optionally substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group;

b) pyridinyl ring.

Specific individual compounds of the present invention include the following compounds:

- 7 041069

2-chloro-5-cyano-X-(2-phenylpyridin-4-yl)benzamide, 2-chloro-5-cyano-M-(6-phenylpyridin-3-yl)benzamide, 2-chloro-5-cyano- M-(2-(4-fluorophenyl)pyridin-4-yl)benzamide, 2-chloro-5-cyano-X-(6-(4-fluorophenyl)pyridin-3-yl)benzamide, N-([2, 3'-bipyridine in]-5-yl)-2-chloro-5-cyanobenzamide, M-([2,3'-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide, 7U-([ 2,4'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide, M-([2,4'-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide, N-([ 2,3'-bipyridin]-5-yl)-5-cyano-2-φτopbenzamide, 5-cyano-2-fluoro-M-(6-(4-fluorophenyl)pyridin-3-yl)benzamide, 5-cyano -2-fluoro-M-(2-(4-fluorophenyl)pyridin-4-yl)benzamide, N-([2,3'-bipyridin]-4-yl)-5-cyano-2-φτopbenzamide, M- ([2,2'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide,

2-chloro-5-cyano-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide, 2-chloro-5-cyano-N-(2-(4-methylpiperazin-1 -yl)pyridin-4-yl)benzamide, 2-chloro-5-cyano-M-(2-morpholinopyridin-4-yl)benzamide, 2-chloro-5-cyano-M-(6-morpholinopyridin-3-yl )benzamide, 7U-([2,4'-bipyridin]-4-yl)-5-cyano-2-fluorobenzamide, N-([2,4'-bipyridin]-5-yl)-5-cyano-2 -φτopbenzamide, 2-chloro-5-cyano-M-(pyridazin-4-yl)benzamide, 5-cyano-2-fluoro-M-(pyridazin-4-yl)benzamide, 2-chloro-5-cyano-M -(6-cyclopropylpyridin-3-yl)benzamide, 3-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoic acid, 4-(5-(2-chloro-5-cyanobenzamido)pyridine -2-yl)benzoic acid.

Compounds of the present invention can be obtained using the methods described below. Specific examples have been used to facilitate the description of the techniques, but they do not limit the scope of the present invention in any way.

The synthesis of the compound of formula (I) is shown in the following schemes.

Scheme 1.

Scheme 1 describes the synthesis of intermediates of formula (III) and compounds of formula (I).

(IV) (V) (I)

Reagents and conditions: a) SOCl ₂ ; b) Y=Cl or OH; (Y=Cl), TEA, DMAP, acetonitrile, 40°C; (Y=OH), HATU, DIPEA, DCM, KT/EDC, pyridine, 60°C.

Amines of formula (V) may be acylated using a carboxylic acid of formula (II) or an acyl chloride derivative of formula (III) where R ¹ is as defined above to give amide derivatives of formula (I) which are specific examples of compounds of the present invention. invention. Commercially available acids of formula (II) are reacted with thionyl chloride to give an acyl chloride of formula (III). To prepare amides of formula (I) using a carboxylic acid of formula (II), the acid is activated with a typical coupling reagent such as HATU, EDC in the presence of a base such as triethylamine or DIPEA to give the corresponding heteroarylamine of formula (IV) at room temperature.

- 8 041069

Scheme 2.

Scheme 2 describes the synthesis of intermediates of formula (IX) and (X).

Reagents and conditions: c) [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II), Cs ₂ CO ₃ , 1,4dioxane/H ₂ O, 100°C, 12 h.

The synthesis of amines of formula (IX) and (X), which are specific examples of amines of formula (V), is carried out by the Suzuki coupling reaction of a heteroarylamine of formula (VI) or (VII) with boronic acid or boronate derivatives R ⁹ using a palladium catalyst such as complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane, in dioxane in the presence of an aqueous solution of a base such as cesium carbonate at a temperature in the range from 25 to 110°C.

Scheme 3.

Scheme 3 describes the synthesis of intermediates of formula (IX) and (X).

Reagents and conditions: d) molecular sieves, p-toluenesulfonic acid, toluene, reflux for 4 hours; f) tetrakis(triphenylphosphine)palladium, toluene, N2, 130°C overnight; f) Hydroxylamine hydrochloride, triethylamine, ethanol/H ₂ O, 80°C, 20 hours.

In some cases, tributylstannyl derivatives are used to introduce the R ⁹ substituent. The reaction is carried out under N2 atmosphere using tetrakis(triphenylphosphine)palladium as a catalyst in dry toluene at 130°C overnight. The amino group is protected before reacting with hexane-2,5-dione (XI) to give a 2,5-dimethyl-1H-pyrrole derivative (XII) or (XIII). The amino group is released again with hydroxylamine in the presence of triethylamine in aqueous ethanol at 80° C. for 20 hours to give intermediates of formula (IX) or (X).

Scheme 4.

Scheme 4 describes the synthesis of intermediates of formula (IX) and (X).

- 9 041069 (VI) (IX)

Reagents and conditions: g) tetrakis(triphenylphosphine)palladium, toluene, N2, 130°C, 48 h.

The reaction can also be carried out without an amino protecting group. In this case, the heteroarylamines of formula (VI) or (VII) are reacted with tributylstannyl derivatives under N2 using tetrakis(triphenylphosphine)palladium as a catalyst in dry toluene at 130° C. for 48 hours, in particular in good yield.

Abbreviations.

In this application, abbreviations are used, the meanings of which are presented below:

CT: room temperature

Pd2(dBA) ₃ : tris(dibenzylideneacetone)dipalladium

SPhos: dicyclohexyl(2',6'-dimethoxy-[1,G-biphenyl]-2-yl)phosphine

TEA: triethylamine

NaHMDS: sodium bis(trimethylsilyl)amide

THF: tetrahydrofuran

DMSO: dimethyl sulfoxide

pharmacological activity.

Results.

The compounds of the present invention are tested in a human PPARgamma (h) binding assay (an agonist radioligand) at several concentrations to determine the IC50.

Compound binding is calculated as % inhibition of radiolabeled ligand binding specific to each target as described in the literature (FERRY, Gilles, et al. Binding of prostaglandins to human PPARy: tool assessment and new natural ligands. European journal of pharmacology, 2001, vol. 417, no 1, pp. 77-89).

IC ₅₀ values (concentration causing inhibition equal to half the maximum inhibition of control specific binding) are determined by non-linear regression analysis of competition curves obtained with replicate means using Hill's equation approximation.

IA-D

Υ=0*(---------] ¹ where Y=specific binding, A=left curve asymptote, O=right curve asymptote, C=compound concentration, C _{5 O} =IC _5O and nH=slope factor. This analysis is performed using software developed by EUROFINS Cerep (Hill software) and confirmed by comparison with data generated by the commercial software SigmaPlot® 4.0 for windows® (© SPSS Inc., 1997).

Inhibition constants (Ki) are calculated using the Cheng Prusoff equation (1+L/K _D ) where L=radioligand concentration used in the assay, KD=radioligand receptor affinity. The Scatchard plot is used to determine KD.

Table 1 shows the IC ₅₀ values of some of the compounds of the present invention.

IC ₅₀ value ranges: A <0.2 μM; 0.2 μM <= B < 1 μM; 1 µM <= C<50 µM, D>=50 µM.

- 10 041069

Table 1

Example UPAC name IC50 (nM) 1 2-chloro-5-cyano-M-(2-phenylpyridin-4-yl)benzamide A 2 2-chloro-5-cyano-M-(6-phenylpyridin-3-yl)benzamide A 3 2-chloro-5-cyano-X-(2-(4-fluorophenyl)pyridin-4yl)benzamide IN 4 2-chloro-5-cyano-M-(6-(4-fluorophenyl)pyridin-3yl)benzamide A 5 X-([2,3'-bipyridine]-5-yl)-2-chloro-5-cyanobenzamide A 6 X-([2,3'-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide WITH 7 X-([2,4'-bipyridine]-5-yl)-2-chloro-5-cyanobenzamide WITH 9 X-([2,3'-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide A 10 5-cyano-2-fluoro-M-(6-(4-fluorophenyl)pyridin-3yl)benzamide A 13 X-([2,2'-bipyridine]-5-yl)-2-chloro-5-cyanobenzamide A 14 2-chloro-5-cyano-M-(6-(4-methylpiperazin-1yl)pyridin-3-yl)benzamide WITH 15 2-chloro-5-cyano-M-(2-(4-methylpiperazin-1yl)pyridin-4-yl)benzamide D 16 2-chloro-5-cyano-N-(2-morpholinopyridin-4yl)benzamide WITH 17 2-chloro-5-cyano-M-(6-morpholinopyridin-3yl)benzamide WITH

The results presented in Table 1 show that the compounds of the present invention are PPARgamma receptor modulators.

The compounds of the present invention are useful in the treatment or prevention of diseases known as diseases that can be ameliorated by modulation of the PPARgamma receptor. Such diseases are selected from cancer selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer or hematopoietic cancer selected from lymphoma, multiple myeloma and leukemia; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; pulmonary diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; neurodegenerative disease

- 11 041069 selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cardiovascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in tumor diseases and kidney diseases.

Accordingly, the derivatives of the present invention and their pharmaceutically acceptable salts and pharmaceutical compositions containing such compounds and/or their salts can be used in a method of treating disorders of the human body, which comprises administering to a patient in need of such treatment, an effective amount of the benzamide derivatives of the invention or their pharmaceutically acceptable salts.

One therapeutic use for the compounds of the present invention is in the treatment of proliferative diseases or disorders such as cancer. Cancer selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer, or hematopoietic cancer selected from lymphoma , multiple myeloma and leukemia.

One more preferred therapeutic use for the compounds of the present invention is in the treatment of bladder cancer.

The present invention also relates to pharmaceutical compositions which comprise as active ingredient at least the benzamide derivatives of formula (I) or a pharmaceutically acceptable salt thereof in combination with other therapeutic agents, as well as a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise from 0.001 to 99% by weight of the composition, preferably from 0.01 to 90% by weight, depending on the nature of the composition and whether the composition is to be further diluted prior to use. Preferably the compositions are in a form suitable for oral, topical, nasal, rectal, transdermal or injection administration.

Pharmaceutically acceptable excipients which are mixed with the active compound or salts of such a compound to obtain the compositions of the present invention are well known per se, and essentially the excipients used depend inter alia on the intended mode of administration of the compositions.

The compositions of the present invention are preferably adapted for administration by injection and for oral administration. Compositions for oral administration may be in the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, inhalable dry powders or liquid preparations such as mixtures, elixirs, syrups or suspensions which contain a compound of the present invention. invention; such formulations may be prepared by methods well known in the art.

Diluents that can be used to prepare the compositions include liquid and solid diluents that are compatible with the active ingredient, as well as coloring or flavoring agents, if desired. Tablets or capsules may contain from 2 to 500 mg of the active ingredient, or an equivalent amount of its salt.

The liquid composition intended for oral administration may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in combination with, for example, sucrose to form a syrup. Suspensions may contain the insoluble active compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with water and a suspending agent or flavoring agent.

Compositions for parenteral administration may be prepared from soluble salts, which may be lyophilized or non-lyophilized, and which may be dissolved in a pyrogen-free aqueous medium or other suitable parenteral liquid.

Effective doses are usually in the range of 2-2000 mg of the active ingredient per day. The daily dose may be administered as a single dose or in multiple doses, preferably 1-4 doses per day.

The present invention will be further illustrated by the following examples. The following examples are given by way of illustration and in no way limit the scope of the present invention. The synthesis of the compounds of the invention is illustrated by the following examples, including the preparation of intermediates, which in no way limit the scope of the invention.

Examples

General provisions.

Reagents, solvents and starting materials are purchased from commercial sources. The term concentration refers to evaporation under vacuum using a Buchi rotary evaporator. When indicated, the reaction products are purified by flash chromatography on silica gel (40-63 μm) using the indicated solvent system. Spectroscopy data were obtained on a Varian Mercury 400 spectrometer. Melting points were measured on a Buchi 535 instrument. HPLC-MS was performed on a Gilson apparatus equipped with a Gilson 321 piston pump, Gilson 864 vacuum degasser, Gilson 189 injection module, 1/1000 Gilson splitter , Gilson 307 pump, Gilson 170 detector and Thermoquest Fennigan aQa detector.

Intermediate 1: 2-chloro-5-cyanobenzoyl chloride.

oh he

SOCI ₂

ABOUT

CI

2-Chloro-5-cyanobenzoic acid (100 mg, 0.55 mmol) is suspended in 1 ml of thionyl chloride and the reaction mixture is refluxed with stirring overnight. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The solid product was used in the next reaction step without further purification.

The intermediate below was prepared according to the procedure for preparing Intermediate 1 starting from 5-cyano-2-fluorobenzoic acid.

Intermediate 2: 5-cyano-2-fluorobenzoyl chloride.

The resulting carboxylic acid chloride is also used in the next step without further purification.

Intermediate 3: 2-phenylpyridine-4-amine.

Bromopyridine-4-amine (150 mg, 0.86 mmol), phenylboronic acid (21.14 mg, 1.73 mmol) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (42.46 mg, 0.054 mmol) is suspended in a mixture of 2M CS ₂ CO ₃ in water (1.3 ml, 2.60 mmol) and 6.5 ml of 1,4-dioxane. The reaction mixture is degassed, the vessel is closed, heated to 110°C and maintained at the same temperature overnight. The reaction mixture was quenched with 1 M NaOH and extracted twice with ethyl acetate. The organic layer was washed (saturated NaHCO ₃ solution and brine), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (CombiFlash, cyclohexane:ethyl acetate) to give the amine derivative (91.2 mg, 61.8%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.08 (d, 1H), 7.90 (d, 2H), 7.44 (t, 2H), 7.37 (t, 1H ), 6.99 (d, 1H), 6.45 (dd, 1H), 6.07 (s, 2H).

HPLC-MS: Rt 3.014; m/z 170.9 (MH ⁺ ).

The intermediates below were prepared according to the procedure for the preparation of Intermediate 3 starting from the corresponding pyridinyl halide derivatives and boronic acid derivatives.

Intermediate 4: 2-(4-fluorophenyl)pyridine-4-amine.

¹ H-NMR (400 MHz, DMSOCH): δ=8.07 (d, 1H), 7.95 (dd, 2H), 7.25 (t, 2H), 6.96 (d, 1H), 2H ), 644 (dd, 1H), 6.06 (s, 2H).

HPLC-MS: Rt 3.328; m/z 189.1 (MH ⁺ ).

Intermediate 5: 6-phenylpyridine-3-amine.

¹ H-NMR (400 MHz, DMSOCH): δ=8.02 (d, 1H), 7.91 (d, 2H), 7.62 (d, 1H), 7.38 (t, 2H), 7.26 (t, 1H), 6.99 (dd, 1H), 5.45 (s, 2H).

HPLC-MS: Rt 3.442; m/z 170.9 (MH ⁺ ).

Intermediate 6: 6-(4-fluorophenyl)pyridine-3-amine.

1H-NMR (400 MHz, DMSOCH): δ=8.01 (d, 1H), 7.93 (dd, 2H), 7.60 (d, 1H), 7.20 (t, 2H), 6, 99 (dd, 1H),

- 13 041069

5.45 (s, 2H).

HPLC-MS: Rt 3.670; m/z 188.9 (MH ⁺ ).

Intermediate 7: [2,4'-bipyridine]-4-amine.

¹ H-NMR (400 MHz, DMSOCH): δ=8.64 (d, 2H), 8.13 (d, 1H), 7.86 (d, 2H), 7.11 (d, 1H), 6 .54 (dd, 1H), 6.21 (s, 2H).

HPLC-MS: Rt 2.326; m/z 172.0 (MH ⁺ ).

Intermediate 8: [2,4'-bipyridine]-5-amine.

r^N to II ¹ H-NMR (400 MHz, DMSOCH): δ=8.54 (d, 2H), 8.07 (d, 1H), 7.87 (d, 2H), 7.79 (d , 1H), 7.01 (dd, 1H), 5.76 (s, 2H).

HPLC-MS: Rt 2.479; m/z 171.9 (MH ⁺ ).

Intermediate 9: [2,3'-bipyridine]-4-amine.

h ₂ n-^Q ¹ H-NMR (400 MHz, DMSO-b ₆ ): δ=9.02 (d, 1H), 8.69 (dd, 1H), 8.23 (d, 1H), 8 .15 (d, 1H), 7.57 (dd, 2H), 7.28 (s, 1H), 7.08 (d, 1H), 6.70 (dd, 1H).

HPLC-MS: Rt 2.303; m/z 172.0 (MH ⁺ ).

Intermediate 10: [2,3'-bipyridine]-5-amine.

1H-NMR (400 MHz, DMSO-dg): δ=9.10 (d, 1H), 8.46 (dd, 1H), 8.24 (m, 1H), 8.05 (d, 1H), 7.71 (d, 1H), 7.40 (dd, 1H), 7.01 (dd, 1H), 5.58 (s, 2H).

HPLC-MS: Rt 2.471; m/z 172.0 (MH ⁺ ).

Intermediate 11: tert-butyl 3-(5-aminopyridin-2-yl)benzoate.

1H-NMR (400 MHz, DMSO-a ₆ ): δ=8.45 (s, 1H), 8.12 (d, 1H), 8.05 (d, 1H), 7.79 (d, 1H) , 7.67 (d, 1H), 7.50 (t, 1H), 7.02 (dd, 1H), 5.55 (s, 2H), 1.57 (s, 9H).

HPLC-MS: Rt 4.808; m/z 271.1 (MH ⁺ ).

Intermediate 12: methyl 3-(5-aminopyridin-2-yl)benzoate.

1H-NMR (400 MHz, DMSO-b ₆ ): δ=8.55 (s, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.85 (d, 1H) , 7.70 (d, 1H), 7.54 (t, 1H), 7.01 (dd, 1H), 5.56 (s, 2H), 3.88 (s, 3H).

HPLC-MS: Rt 3.731; m/z 229.1 (MH ⁺ ).

Intermediate 13: tert-butyl 4-(5-aminopyridin-2-yl)benzoate.

¹ H-NMR (400 MHz, DMSO-dg): δ=8.04 (d, 3H), 7.90 (d, 2H), 7.73 (d, 1H), 7.00 (dd, 1H) , 5.66 (s, 2H), 1.55 (s, 9H).

HPLC-MS: Rt 4.589; m/z 271.1 (MH ⁺ ).

- 14 041069

Intermediate 14: methyl 4-(5-aminopyridin-2-yl)benzoate.

1H-NMR (400 MHz, DMSO-d6): δ=8.07 (d, 3H), 7.97 (d, 2H), 7.74 (d, 1H), 7.01 (dd, 1H), 5.66 (s, 2H), 3.85 (s, 3H).

HPLC-MS: Rt 3.724; m/z 229.1 (MH ⁺ ).

Intermediate 15: 2-morpholinopyridine-4-amine.

In a sealed flask, 2-bromopyridine-4-amine (100 mg, 0.58 mmol) and morpholine (0.25 ml, 2.9 mmol) are dissolved in 0.8 ml of dry DMSO. Potassium carbonate (239.6 mg, 1.73 mmol) was added to the mixture and the reaction mixture was stirred at 190° C. for 16 hours. The mixture was quenched with saturated NaHCO ₃ solution and extracted with ethyl acetate. The organic layer is dried and concentrated. The crude product was purified by column chromatography (CombiFlash, DCM/MeOH) to give the desired product (25 mg, 24.1%).

¹ H-NMR (400 MHz, DMSO-d6): δ=7.63 (d, 1H), 5.98 (dd, 1H), 5.85 (s, 3H), 3.66 (m, 4H) , 3.27 (m, 4H).

HPLC-MS: Rt 1.661; m/z 180.0 (MH ⁺ ).

The following intermediate is synthesized according to the procedure for preparing Intermediate 15, starting from the corresponding pyridinyl halide and amine.

Intermediate 16: 6-morpholinopyridine-3-amine.

¹ H-NMR (400 MHz, DMSO-d6): δ=7.61 (s, 1H), 6.93 (d, 1H), 6.62 (d, 1H), 4.66 (s, 2H) , 3.68 (s.4H), 3.17 (s.4H).

HPLC-MS: Rt 1.730; m/z 179.9 (MH ⁺ ).

Intermediate 17: 2-(4-methylpiperazin-1-yl)pyridine-4-amine.

2-Bromopyridine-4-amine (100 mg, 0.58 mmol) in 1-methylpiperazine (0.64 ml, 5.8 mmol) is heated in a sealed container to 135°C and kept at this temperature for 16 hours. the mixture is dissolved in a mixture of diethyl ether and methanol and then concentrated. The solid product was purified by column chromatography (CombiFlash, DCM/MeOH) to give 2-(4-methylpiperazin-1yl)pyridine-4-amine (84.2 mg, 75.7%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.61 (d, 1H), 5.95 (dd, 1H), 5.86 (s, 1H), 5.82 (s, 2H ), 3.33 (m, 4H), 3.04 (m, 4H), 2.23 (s, 3H).

HPLC-MS: Rt 1.995; m/z 193.0 (MH ⁺ ).

The following intermediate was synthesized according to the procedure for preparing Intermediate 17, starting from the corresponding pyridinyl halide and amine.

Intermediate 18: 6-(4-methylpiperazin-1-yl)pyridine-3-amine.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=7.59 (s, 1H), 6.90 (d, 1H), 6.62 (d, 1H), 4.61 (s, 2H ), 3.23 (s, 4H), 2.46 (s, 4H), 2.25 (s, 3H).

HPLC-MS: Rt 1.903; m/z 192.9 (MH ⁺ ).

- 15 041069

Intermediate 19: 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine.

Add 6-bromopyridine-3-amine (100 mg, 0.58 mmol), hexane-2,5-dione (0.075 mL, 0.64 mmol) and p-toluenesulfonic acid (1.5 mg, 0.008 mmol) in 2 ml of anhydrous toluene. The mixture is refluxed with stirring for 4 hours. The reaction mixture is quenched with saturated NaHCO ₃ solution and extracted with toluene (x2). The organic layer was dried, concentrated in vacuo and purified by column chromatography (CombiFlash, cyclohexane/ethyl acetate) to give the title intermediate (83.2 mg, 57.3%).

¹ H-NMR (400 MHz, DMSO-d6): δ=8.39 (d, 1H), 7.79 (m, 2H), 5.85 (s, 2H), 1.99 (s, 6H) .

HPLC-MS: Rt 4.988; m/z 251.8 (MH ⁺ ).

The following intermediate was synthesized according to the procedure for preparing Intermediate 19 starting from the appropriate amine.

Intermediate 20: 2-bromo-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine.

Ή-NMR (400 MHz, DMSO<): δ=8.51 (d, 1H), 7.72 (s, 1H), 7.45 (d, 1H), 5.88 (s, 2H), 2 .06 (s, 6H).

HPLC-MS: Rt 4.892; m/z 251.8 (MH ⁺ ).

Intermediate 21: 5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,2'-bipyridine.

To a solution of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (73.2 mg, 0.29 mmol) in 1.5 ml of dry toluene at room temperature dropwise under N2 2-(tributylstannyl)pyridine (0.02 ml, 0.44 mmol) was added followed by tetrakis(triphenylphosphine)palladium (10.1 mg, 0.009 mmol). The reaction mixture is degassed with nitrogen and stirred at 130° C. overnight. The reaction mixture is cooled to room temperature. The mixture is then treated with 2 M NaOH and separated with ethyl acetate (x2). The organic layer was washed with brine, dried over Na ₂ SO ₄ and the solvent was removed in vacuo. The crude product was purified by column chromatography (CombiFlash, cyclohexane/ethyl acetate) to give the title compound (60.2 mg, 82.9%).

¹ H-NMR (400 MHz, DMSOCH): δ=8.77 (d, 1 H), 8.68 (d, 1 H), 8.55 (d, 1H), 8.51 (d, 1 H ), 8.12 (t, 1H), 7.98 (dd, 1H), 7.60 (m, 1H), 5.89 (s, 2H), 2.04 (s, 6H).

HPLC-MS: Rt 5.044; m/z 249.9 (MH ⁺ ).

The following intermediate was synthesized according to the procedure for preparing Intermediate 21 starting from the corresponding (2,5-dimethyl-1H-pyrrol-1yl)pyridine derivative.

Intermediate 22: 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2,2'-bipyridine.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.82 (d, 1H), 8.70 (d, 1H), 8.45 (d, 1H), 8.19 (d, 1H ), 8.00 (t, 1H), 7.48 (m, 2H), 5.91 (s, 2H), 2.08 (s, 6H).

HPLC-MS: Rt 5.056; m/z 249.9 (MH ⁺ ).

- 16 041069

Intermediate 23: [2,2'-bipyridine]-5-amine.

Method A A mixture of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,2'-bipyridine (75.6 mg, 0.3 mmol), hydroxylamine hydrochloride (210.7 mg, 3 0 mmol) and triethylamine (0.084 ml, 0.6 mmol) in 1.4 ml of ethanol and 0.6 ml of H2O, stirred at 80°C for 20 h. The mixture was poured into 1 M HCl and washed with diethyl ether. The aqueous layer was neutralized and basified with 5M NaOH and 2M NaOH until pH=9-10 was reached and then extracted with dichloromethane (x3). The various organic layers are collected and dried. The crude product was purified by column chromatography (CombiFlash, dichloromethane/dichloromethane: methanol 20%) to give the amine derivative (19.6 mg, 37.8%).

Method B. To a solution of 6-bromopyridin-3-amine (50 mg, 0.29 mmol) in 1.5 ml of dry toluene at room temperature under N2 was added 2-(tributylstannyl)pyridine (0.013 ml, 0.35 mmol) followed by the addition of tetrakis(triphenylphosphine)palladium (40.2 mg, 0.03 mmol). The reaction mixture is degassed with nitrogen and stirred at 130° C. for two days. The reaction mixture is cooled to room temperature. The mixture is then treated with 2M NaOH and separated with ethyl acetate (x2). The organic layer was washed with brine, dried with Na ₂ SO ₄ and the solvent was removed in vacuo. The crude product was purified by column chromatography (CombiFlash, DCM/DCM:MeOH 20%) to give the title compound (21.6 mg, 43.5%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=8.54 (d, 1H), 8.17 (d, 1H), 8.08 (d, 1H), 8.01 (d, 1H ), 7.80 (td, 1H), 7.25 (m, 1H), 7.01 (dd, 1H), 5.65 (s, 2H).

HPLC-MS: Rt 2.746; m/z 172.0 (MH ⁺ ).

The following intermediate was synthesized according to the procedure for preparing Intermediate 23 starting from the appropriate derivatives.

Intermediate 24: [2,2'-bipyridine]-4-amine.

¹ H-NMR (400 MHz, DMSO-H6): δ = 8.62 (d, 1H), 8.29 (d, 1H), 8.09 (d, 1H), 7.88 (td, 1H) , 7.61 (d, 1H), 7.39 (dd, 1H), 6.53 (dd, 1H), 6.27 (s, 2H).

HPLC-MS: Rt 2.851; m/z 171.9 (MH ⁺ ).

Intermediate 25: 6-cyclopropylpyridin-3-amine.

300 mg (1.73 mmol) of 6-bromopyridine-3-amine, 297.9 mg (3.47 mmol) of cyclopropylboronic acid, 97.25 mg (0.35 mmol) of tricyclohexylphosphine, 38.92 mg ( 0.17 mmol) palladium acetate and 1104 mg (5.20 mmol) potassium phosphate in 12 ml toluene and 0.6 ml H2O. The reaction mixture is degassed with N2 and stirred at 100° C. for two days. The mixture is taken up in ethyl acetate and extracted with 1M NaOH (x2). The organic layer was dried in vacuo and the resulting crude product was purified by column chromatography (Combi-Flash, hexane:ethyl acetate) to give 28 mg (0.21 mmol, 12.03%) of 6-cyclopropylpyridine-3-amine.

1H-NMR (400 MHz, DMSO-H6): δ=7.77 (d, 1H), 6.89 (d, 1H), 6.81 (dd, 1H), 4.96 (s, 2H), 1.85 (m, 1H), 0.75 (m, 2H), 0.70 (m, 2H).

HPLC-MS: Rt 2.589; m/z 135.1 (MH ⁺ ).

Intermediate 26: N-(2-bromopyridin-4-yl)-2-chloro-5-cyanobenzamide.

- 17 041069

A mixture of 2-chloro-5-cyanobenzoic acid (50 mg, 0.27 mmol), 2-bromopyridine-4-amine (47.6 mg, 0.27 mmol) and EDC (116.2 mg, 0.60 mmol ) in 0.5 ml of pyridine was stirred at 60°C for 48 hours. The pyridine was removed in vacuo and the resulting crude product was purified by column chromatography (CombiFlash, hexane/ethyl acetate) to obtain the desired product (6.2 mg, 6.7%) .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.23 (s, 1H), 8.33 (d, 1H), 8.27 (d, 1H), 8.05 (dd, 1H ), 7.98 (s, 1H), 7.86 (d, 1H), 7.60 (dd, 1H).

HPLC-MS: Rt 4.289; m/z 337.9 (MH ⁺ ).

The following intermediates were synthesized according to the procedure for preparing Intermediate 26 starting from the appropriate derivatives.

Intermediate 27: N-(6-bromopyridin-3-yl)-2-chloro-5-cyanobenzamide.

1H-NMR (400 MHz, DMSO-d ₆ ): δ=11.01 (s, 1H), 8.68 (s, 1H), 8.25 (d, 1H), 8.09 (dd, 1H) , 8.03 (dd, 1H), 7.85 (d, 1H), 7.68 (d, 1H).

HPLC-MS: Rt 4.243; m/z 337.9 (MH ⁺ ).

Intermediate 28: tert-butyl 3-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoate.

¹ H-NMR (400 MHz, DMSO-06): δ=11.01 (s, 1H), 8.94 (d, 1H), 8.59 (s, 1H), 8.30 (m, 3H) , 8.08 (d, 1H), 8.04 (dd, 1H), 7.94 (d, 1H), 7.86 (d, 1H), 7.62 (t, 1H), 1.59 ( s, 9H).

HPLC-MS: Rt 5.584; m/z 434.1 (MH ⁺ ).

Intermediate 29: tert-Butyl 4-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoate.

¹ H-NMR (400 MHz, DMSO-06): δ=11.05 (s, 1H), 8.95 (d, 1H), 8.30 (m, 2H), 8.20 (d, 2H) , 8.11 (d, 1H), 8.04 (dd, 1H), 8.00 (d, 2H), 7.86 (d, 1H), 1.57 (s, 9H).

HPLC-MS: Rt 5.610; m/z 434.1 (MH ⁺ ).

Intermediate 30: pyridazin-4-ylamine.

This product is commercially available and can also be prepared according to the procedure described in Hara, H. and Van Der Plas, H. C. (1982), On amination azaheterocycles. A new procedure for the introduction of an amino group. Journal of Heterocyclic Chemistry, 19: 1285-1287. doi:10.1002/jhet.5570190605.

end products

Example 1: 2-chloro-5-cyano-N-(2-phenylpyridin-4-yl)benzamide.

2-Chloro-5-cyanobenzoyl chloride (Intermediate 1) (55.1 mg, 0.27 mmol) in dry DCM was added dropwise to the cooling mixture of 2-phenylpyridine-4-amine (Intermediate 3) (42.5 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.37 mmol) in 1 ml dry DCM. The reaction mixture is stirred at 40° C. overnight. The mixture is extracted with DCM and saturated NaHCO ₃ solution. The organic layer is dried (Na ₂ SO ₄ ) and concentrated. The crude product is purified by column chromatography (CombiFlash, cyclohexane/ethyl acetate) to give the amide derivative (54.2, 59.1%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.11 (s, 1H), 8.61 (d, 1H), 8.29 (d, 1H), 8.20 (s, 1H ), 8.05 (dd, 1H), 7.99 (d, 2H), 7.86 (d, 1H), 7.64 (d, 1H), 7.52 (t, 2H), 7.46 (t, 1H).

- 18 041069

HPLC-MS: Rt 4.737; m/z 333.8 (MH ⁺ ).

The compounds of the examples below were prepared according to the procedure of Example 1, starting from the corresponding substituted acid chlorides and amines of benzoic acid.

Example 2: 2-chloro-5-cyano-N-(6-phenylpyridin-3-yl)benzamide (using intermediates 1 and 5).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.96 (s, 1H), 8.91 (d, 1H), 8.27 (t, 1H), 8.24 (d, 1H ), 8.04 (m, 4H), 7.85 (d, 1H), 7.49 (t, 2H), 7.42 (t, 1H).

HPLC-MS: Rt 4.785; m/z 333.8 (MH ⁺ ).

Example 3: 2-chloro-5-cyano-X-(2-(4-fluorophenyl)pyridin-4-yl)benzamide.

¹ H-NMR (400 MHz, DMSO-66): δ=11.11 (s, 1H), 8.60 (d, 1H), 8.28 (s, 1H), 8.19 (s, 1H) , 8.04 (t, 3H), 7.86 (d, 1H), 7.62 (d, 1H), 7.35 (t, 2H).

HPLC-MS: Rt 4.838; m/z 351.8 (MH ⁺ ).

Example 4: 2-chloro-5-cyano-X-(6-(4-fluorophenyl)pyridin-3-yl)benzamide (using intermediates 1 and 6).

¹ H-NMR (400 MHz, DMSO-66): δ=10.96 (s, 1H), 8.90 (s, 1H), 8.25 (d, 2H), 8.12 (m, 2H) , 8.02 (t, 2H), 7.85 (d, 1H), 7.31 (t, 2H).

HPLC-MS: Rt 4.870; m/z 351.8 (MH ⁺ ).

Example 5 N-([2,3'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide (using intermediates 1 and 10).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.02 (s, 1H), 9.25 (d, 1H), 8.95 (d, 1H), 8.62 (dd, 1H ), 8.42 (d, 1H), 8.29 (dd, 2H), 8.11 (d, 1H), 8.04 (dd, 1H), 7.86 (d, 1H), 7.52 (dd, 1H).

HPLC-MS: Rt 3.897; m/z 334.8 (MH ⁺ ).

Example 6: X-([2,3'-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide (using intermediates 1 and 9).

¹ H-NMR (400 MHz, DMSO-66): δ=11.17 (s, 1H), 9.16 (d, 1H), 8.66 (d, 2H), 8.33 (d, 1H) , 8.28 (d, 1H), 8.22 (s, 1H), 8.05 (dd, 1H), 7.87 (d, 1H), 7.71 (d, 1H), 7.55 ( dd, 1H).

HPLC-MS: Rt 3.908; m/z 334.8 (MH ⁺ ).

Example 7: N-([2,4'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide.

- 19 041069

2-Chloro-5-cyanobenzoyl chloride (Intermediate 1) (64.3 mg, 0.32 mmol) in dry acetonitrile was added dropwise to a solution of [2,4'-bipyridine]-5-amine (Intermediate 8) (50 mg, 0.29 mmol), triethylamine (0.05 ml, 0.37 mmol) and 4-DMAP (0.36 mg, 0.0029 mmol) in 3 ml dry acetonitrile. The reaction mixture is stirred at 50° C. overnight. The mixture is quenched with water and extracted three times with ethyl acetate. The organic layer is dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by column chromatography (CombiFlash, DCM/methanol) to give the amide derivative (21.7, 22.2%).

¹ H-NMR (400 MHz, DMSO-b ₆ ): δ=11.09 (s, 1H), 8.97 (d, 1H), 8.69 (d, 2H), 8.33 (dd, 1H ), 8.29 (d, 1H), 8.19 (d, 1H), 8.05 (dd, 3H), 7.86 (d, 1H).

HPLC-MS: Rt 3.874; m/z 334.8 (MH ⁺ ).

The compounds of the examples below were prepared according to the procedure of Example 7, starting from the corresponding substituted acid chlorides and amines of benzoic acid.

Example 8: N-([2,4'-bipyridin]-4-yl)-2-chloro-5-cyanobenzαmide (using intermediates 1 and 7).

1H-NMR (400 MHz, DMSO-66): δ=11.21 (s, 1H), 8.70 (m, 3H), 8.30 (d, 2H), 8.06 (d, 1H), 7.94 (s, 2H), 7.87 (d, 1H), 7.75 (s, 1H).

HPLC-MS: Rt 3.902; m/z 334.8 (MH ⁺ ).

Example 9: N-([2,3'-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide (using intermediates 2 and 10).

¹ H-NMR (400 MHz, DMSO-d6): δ=10.96 (s, 1H), 9.25 (d, 1H), 8.97 (d, 1H), 8.61 (d, 1H) , 8.42 (d, 1H), 8.30 (m, 2H), 8.13 (dd, 2H), 7.66 (t, 1H), 7.52 (dd, 1H).

HPLC-MS: Rt 3.759; m/z 318.8 (MH ⁺ ).

Example 10 5-cyano-2-fluoro-N-(6-(4-fluorophenyl)pyridin-3-yl)benzamide (using intermediates 2 and 6)

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.90 (s, 1H), 8.92 (d, 1H), 8.31 (dd, 1H), 8.24 (dd, 1H ), 8.14 (td, 3H), 8.01 (d, 1H), 7.66 (t, 1H), 7.31 (t, 2H).

HPLC-MS: Rt 4.816; m/z 335.8 (MH ⁺ ).

Example 11 5-cyano-2-fluoro-N-(2-(4-fluorophenyl)pyridin-4-yl)benzamide (using intermediates 2 and 4)

1H-NMR (400 MHz, DMSO- _d6 ): δ=11.04(s, 1H), 8.60(d, 1H), 8.31(dd, 1H), 8.19(d, 1H) , 8.16 (dd, 1H), 8.04 (dd, 2H), 7.68 (d, 1H), 7.64 (m, 1H), 7.35 (t, 2H).

HPLC-MS: Rt 4.724; m/z 335.8 (MH ⁺ ).

Example 12 N-([2,3'-bipyridin]-4-yl)-5-cyano-2-fluorobenzamide (using intermediates 2 and 9)

¹ H-NMR (400 MHz, DMSO-b ₆ ): δ=11.10 (s, 1H), 9.16 (d, 1H), 8.66 (d, 2H), 8.32 (t, 2H ), 8.24 (d, 1H), 8.16 (m, 1H), 7.72 (dd, 1H), 7.67 (t, 1H), 7.55 (dd, 1H).

HPLC-MS: Rt 3.756; m/z 318.9 (MH ⁺ ).

- 20 041069

Example 13: N-([2,2'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide (using intermediates 1 and 23).

¹ H-NMR (400 MHz, DMSO-b ₆ ): δ=11.04 (s, 1H), 8.93 (d, 1H), 8.67 (d, 1H), 8.43 (d, 1H ), 8.35 (d, 2H), 8.30 (dd, 1H), 8.04 (dd, 1H), 7.94 (td, 1H), 7.86 (d, 1H), 7.43 (dd, 1H).

HPLC-MS: Rt 4.229; m/z 334.8 (MH ⁺ ).

Example 14 2-chloro-5-cyano-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide (using intermediates 1 and 18).

¹ H-NMR (400 MHz, DMSO-66): δ=10.47 (s, 1H), 8.38 (d, 1H), 8.18 (d, 1H), 7.99 (dd, 1H) , 7.86 (dd, 1H), 7.81 (d, 1H), 6.87 (d, 1H), 3.44 (m, 4H), 2.40 (m, 4H), 2.21 ( s, 3H).

HPLC-MS: Rt 3.618; m/z 355.9 (MH ⁺ ).

Example 15 2-chloro-5-cyano-N-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)benzamide (using intermediates 1 and 17)

1H-NMR (400 MHz, DMSO-b ₆ ): δ=10.74 (s, 1H), 8.20 (d, 1H), 8.04 (d, 1H), 8.01 (dd, 1H) , 7.83 (d, 1H), 7.19 (s, 1H), 6.90 (d, 1H), 3.44 (d, 4H), 2.40 (m, 4H), 2.22 ( s, 3H).

HPLC-MS: Rt 3.776; m/z 355.8 (MH ⁺ ).

Example 16 2-chloro-5-cyano-N-(2-morpholinopyridin-4-yl)benzamide (using intermediates 1 and 15).

1H-NMR (400 MHz, DMSO-66): δ=10.93 (s, 1H), 8.22 (d, 1H), 8.07 (d, 1H), 8.03 (dd, 1H), 7.84 (d, 1H), 7.28 (s, 1H), 6.98 (d, 1H), 3.72 (s, 4H), 3.43 (s, 4H).

HPLC-MS: Rt 3.938; m/z 342.8 (MH ⁺ ).

Example 17 2-chloro-5-cyano-N-(6-morpholinopyridin-3-yl)benzamide (using intermediates 1 and 16)

1H-NMR (400 MHz, DMSOL): δ=10.50 (s, 1H), 8.41 (d, 1H), 8.19 (d, 1H), 7.99 (dd, 1H), 7, 90 (dd, 1H), 7.81 (d, 1H), 6.88 (d, 1H), 3.70 (m, 4H), 3.40 (m, 4H).

HPLC-MS: Rt 3.774; m/z 342.8 (MH ⁺ ).

Example 18: N-([2,4'-bipyridin]-4-yl)-5-cyano-2-fluorobenzamide (using intermediates 2 and 7).

1H-NMR (400 MHz, DMSO-b ₆ ): δ 11.14 (s, 1H), 8.71 (dd, 3H), 8.33 (s, 2H), 8.18 (d, 1H), 7.95 (d, 2H), 7.76 (d, 1H), 7.67 (t, 1H).

HPLC-MS: 3.811; m/z 319.0 (MH ⁺ ).

Example 19 N-([2,4'-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide (using intermediates

- 21 041069 connections 2 and 8).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.02 (s, 1H), 8.99 (s, 1H), 8.69 (d, 2H), 8.33 (dd, 2H ), 8.19 (d, 1H), 8.15 (m, 1H), 8.04 (d, 2H), 7.66 (t, 1H).

HPLC-MS: Rt 3.829; m/z 319.0 (MH ⁺ ).

Example 20: 2-chloro-5-cyano-N-(pyridazin-4-yl)benzamide (using intermediates 1 and 30).

Ή-NMR (400 MHz, DMSO-d ₆ ): δ=11.31 (s, 1H), 9.36 (d, 1H), 9.13 (d, 1H), 8.30 (d, 1H) , 8.06 (dd, 1H), 8.03 (dd, 1H), 7.87 (d, 1H).

HPLC-MS: Rt 3.149; m/z 259.0 (MH ⁺ ).

Example 21 5-cyano-2-fluoro-N-(pyridazin-4-yl)benzamide (using intermediates 2 and 30)

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=11.23 (s, 1H), 9.39 (m, 1H), 9.13 (d, 1H), 8.32 (dd, 1H ), 8.18 (m, 1H), 8.03 (dd, 1H), 7.67 (m, 1H).

HPLC-MS: Rt 2.958; m/z 243.0 (MH ⁺ ).

Example 22: 2-chloro-5-cyano-X-(6-cyclopropylpyridin-3-yl)benzamide (using intermediates 1 and 25).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ=10.73 (s, 1H), 8.63 (d, 1H), 8.21 (d, 1H), 8.00 (m, 2H ), 7.82 (d, 1H), 7.30 (d, 1H), 2.08 (m, 1H), 0.92 (m, 2H), 0.88 (m, 2H).

HPLC-MS: Rt 4.239; m/z 296.1 (MH ⁺ ).

Example 23: 3-(5-(2-Chloro-5-cyanobenzamido)pyridin-2-yl)benzoic acid.

0.3 ml (3 .5 mmol) trifluoroacetic acid. The reaction mixture was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure. The resulting solid is washed with THF and methanol and filtered. The filtrate was purified by column chromatography (CombiFlash, DCM/MeOH) to give the desired carboxylic acid derivative (22.3 mg, 33.7%).

¹ H-NMR (400 MHz, DMSO-d6): δ=13.11 (s, 1H), 11.01 (s, 1H), 8.94 (d, 1H), 8.66 (s, 1H) , 8.30 (m, 3H), 8.09 (d, 1H), 8.04 (dd, 1H), 7.98 (d, 1H), 7.86 (d, 1H), 7.62 ( t, 1H).

HPLC-MS: Rt 2.991; m/z 378.0 (MH ⁺ ).

The compound of the following example was synthesized according to the procedure of Example 23, starting from the corresponding substituted acid chlorides and amines of benzoic acid.

Example 24 4-(5-(2-Chloro-5-cyanobenzamido)pyridin-2-yl)benzoic acid (using Intermediate 29)

-

Claims (11)

1H-NMR 400 MHz, DMSO-d ₆ ): δ=13.05 (s, 1H), 11.05 (s, 1H), 8.95 (d, 1H), 8.30 (dd, 2H), 8.20 (d, 2H), 8.12 (d, 1H), 8.05 (d, 3H), 7.86 (d, 1H). HPLC-MS: Rt 2.899; m/z 378.0 (MH ⁺ ). CLAIM 1. Compound of formula (I) Where R ² is selected from Cl and F atoms; R ¹ is cyano; G ¹ and G ² are independently a group selected from N and -CR ⁹ where G ¹ and G ² are not CR ⁹ at the same time; R ⁹ is independently selected from the group consisting of a) a phenyl group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group, b) pyridinyl ring, c) morpholinyl and piperazinyl groups unsubstituted or substituted with a group selected from a C ₁ -C ₃ alkyl group, and d) C ₃ -C ₆ -cycloalkyl group; R ³ , R ⁴ and R ⁵ are hydrogen atoms; and its pharmaceutically acceptable salts. 2. The compound according to claim 1, in which G ¹ represents an N atom; and G ² is a -CR ⁹ group, where R ⁹ is selected from a) a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group; b) pyridyl ring; c) a morpholinyl and piperazinyl group, unsubstituted or substituted by a group selected from a C ₁ -C ₃ alkyl group. 3. The compound according to claim 1, in which G ² represents an N atom; and G ¹ is a -CR ⁹ group, where R ⁹ is selected from a) a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group; b) pyridinyl ring; c) morpholinyl and piperazinyl groups, unsubstituted or substituted with a group selected from a C ₁ -C ₃ alkyl group. 4. The compound according to claim 1, in which R ¹ represents a cyano group; R ³ , R ⁴ and R ⁵ are hydrogen atoms; G ¹ is an N atom; and G ² is a -CR ⁹ group, where R ⁹ is a phenyl group, unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group. 5. The compound according to claim 1, in which R ¹ represents a cyano group; R ³ , R ⁴ and R ⁵ independently represent a hydrogen atom; G ¹ is an N atom; and G ² is a -CR ⁹ group, where R ⁹ is a pyridyl ring. 6. The compound according to claim 1, in which R ¹ represents a cyano group; R ³ , R ⁴ and R ⁵ independently represent a hydrogen atom; G ² is an N atom; and G ¹ is a -CR ⁹ group, where R ⁹ is selected from a) a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom and a -COOH group; b) pyridyl ring. - 23 041069 7. The compound according to claim 1, which is one of: 2-chloro-5-cyano-N-(2-phenylpyridin-4-yl)benzamide, 2-chloro-5-cyano-N-(6-phenylpyridin- 3-yl)benzamide, 2-chloro-5-cyano-N-(2-(4-fluorophenyl)pyridin-4-yl)benzamide, 2-chloro-5-cyano-N-(6-(4-fluorophenyl) pyridin-3-yl)benzamide, K-([2,3'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide, K-([2,3'-bipyridin]-4-yl)- 2-chloro-5-cyanobenzamide, K-([2,4'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide, K-([2,4'-bipyridin]-4-yl)- 2-chloro-5-cyanobenzamide, K-([2,3'-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide, 5-cyano-2-fluoro-K-(6-(4-fluorophenyl )pyridin-3-yl)benzamide, 5-cyano-2-fluoro-N-(2-(4-fluorophenyl)pyridin-4-yl)benzamide, N-([2,3'-bipyridin]-4-yl )-5-cyano-2-fluorobenzamide, K-([2,2'-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide, 2-chloro-5-cyano-K-(6-(4 -methylpiperazin-1-yl)pyridin-3-yl)benzamide, 2-chloro-5-cyano-N-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)benzamide, 2-chloro-5 -cyano-N-(2-morpholinopyridin-4-yl)benzamide, 2-chloro-5-cyano-N-(6-morpholinopyridin-3-yl)benzamide, N-([2,4'-bipyridine] -4-yl)-5-cyano-2-fluorobenzamide, K-([2,4'-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide, 2-chloro-5-cyano-K-( pyridazin-4-yl)benzamide, 5-cyano-2-fluoro-N-(pyridazin-4-yl)benzamide, 2-chloro-5-cyano-N-(6-cyclopropylpyridin-3-yl)benzamide, 3- (5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoic acid, 4-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoic acid, and their pharmaceutically acceptable salts. 8. The use of a compound according to any one of claims 1 to 7 for the treatment or prevention of a disease or condition that can be alleviated by modulation of the PPARgamma receptor, wherein said disease or condition is selected from the group consisting of cancer, selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer or hematopoietic cancer selected from lymphoma, multiple myeloma and leukemia; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; lung diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; a neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cardiovascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in tumor diseases and kidney diseases. 9. A pharmaceutical composition containing from 0.001 to 99% by weight of a compound according to any one of claims 1 to 7, a pharmaceutically acceptable diluent or carrier. 10. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment or prevention of a disease or condition that can be facilitated by modulation of the PPARgamma receptor, wherein said disease or condition is selected from the group consisting of a cancer selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer, or hematopoietic cancer selected from lymphoma, multiple myeloma and leukemia; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; lung diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; a neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cardiovascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in neoplastic diseases and kidney diseases. 11. A method of treating or preventing a disease or condition that can be alleviated by modulating the PPARgamma receptor, comprising administering to a patient in need - 24 041069 in this, compounds according to any one of claims 1 to 7, wherein said disease or pathological condition is selected from the group consisting of cancer selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, bladder cancer, testicular cancer, urothelial cancer, skin cancer, melanoma, colon cancer, brain cancer or hematopoietic cancer selected from lymphoma, multiple myeloma and leukemia; metabolic diseases selected from osteoporosis, rickets, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorders, pancreatitis, glucose metabolism disorders, diabetic neuropathy, diabetic complications, hyperuricemia; inflammatory skin diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitis and pruritus; pulmonary diseases selected from asthma and chronic obstructive pulmonary disease; autoimmune disease; a neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease; cardiovascular diseases selected from atherosclerosis, occlusive diseases of veins and arteries, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in tumor diseases and kidney diseases. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2