Potent and selective novel compounds as serotonin 1B receptor modulators

Abstract

The present invention relates to the 5-hydroxytryptamine receptor 1B (5-HT 1B Serotonin receptor 1B (5-HTR), also known as 1B ) as a modulator of the compound of formula (I): [Formula 1] This compound is a novel compound of TIFF2023547346000082.tif53161. This compound binds to serotonin receptor type 1B (5-HTR 1B ), such as cancer, including hematological cancers and solid tumors, respiratory diseases, and liver disorders.

Description

Technical Field

[0001] The present invention relates to novel, potent and selective compounds as modulators of serotonin receptor 1B (5-HTR 1B ), also known as 5-hydroxytryptamine receptor 1B (5-HT 1B , 1B , 1B ). The compounds are potentially useful in the treatment of diseases and conditions mediated by serotonin receptor type 1B (5-HTR 1B ), such as cancers including blood cancers and solid tumors, as well as respiratory diseases and liver disorders. The present invention also relates to the use of such compounds as medicaments, pharmaceutical compositions containing them, and synthetic routes for their manufacture.

Background Art

[0002] Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system (CNS), a local mediator in the gut, and a vasoactive agent in the blood. It is synthesized from the essential amino acid tryptophan by a two-step pathway. Most of the body's serotonin is located peripherally (Sarrouilhe D. et al., Serotonin and Cancer: What Is the Link?, Current Molecular Medicine 2015, 15, 62-77).

[0003] ​​​​​​Serotonin is associated with various CNS functions, such as brain development, circadian rhythm, body temperature regulation, cognition, pain, appetite, sexual drive, fear, mood, violent behavior, motor function, and neuroendocrine. Also, serotonin is involved in many CNS and mental disorders: Parkinson's disease, depression, hallucinations, schizophrenia, bulimia, anxiety, addiction, and chronic stress. Therefore, the serotonergic system is a target for numerous psychoactive compounds, including antidepressants, antipsychotics, and hallucinogens (Marin P. et al., 5-HT Receptor-Associated Protein Networks: New Targets for Drug Discovery in Psychiatric Disorders?, Current Drug Targets, 2012, 13, 28-52).

[0004] Mammals use 5-HT as a neurotransmitter within the central and peripheral nervous systems, as well as a local hormone in many other tissues, including the gastrointestinal tract, cardiovascular system, and immune cells. This functional diversity involves 5-HT in numerous physiological and pathological processes. Therefore, this plethora of roles has promoted the development of many compounds with therapeutic value, including various antidepressants, antipsychotics, and antiemetics (Barnes N.M. et al., Neuronal 5-HT Receptors and SERT, Tocris Scientific Review Series, https: / / www.tocris.com / literature / scientific-reviews / 5-ht-receptors).

[0005] Part of the ability of 5-HT to mediate a wide range of actions results from an impressive number of 5-HT receptors, which are divided into seven families, all of which except one are members of the G protein-coupled receptor (GPCR) superfamily. The exception is the 5-HT 3 receptor, which is a Cys-loop ligand-gated ion channel.

[0006] In particular, 5-HT 1The receptor family consists of five separate gene products: 5-HT 1A 、5-HT 1B 、5-HT 1D 、5-HT 1E 、and 5-HT 1F receptors. Each is encoded by an open reading frame lacking a single intron, and they share significant sequence homology. All of these receptors couple to Gi / o to inhibit adenylyl cyclase and reduce cAMP levels, although additional signaling mechanisms have also been described. Some of these receptors are well known as autoreceptors that regulate the firing of serotonin neurons and the release of serotonin, but they are also expressed in non-serotonergic neurons where they may have similar effects on other neurotransmitters.

[0007] In the case of the 5-HT 1B receptor, this is widely distributed in the CNS in both serotonergic and non-serotonergic neurons. This autoreceptor has been found to reduce the synthesis and release of serotonin and enhance reuptake via the serotonin transporter. Also, depending on the type of neuron expressing it, this receptor inhibits the release of a range of different neurotransmitters. Systemic administration of 5-HT 1B receptor agonists has several behavioral effects including increased locomotor activity, changes in the brain's reward mechanisms, and decreased aggression, while selective antagonists may have some potential for cognitive enhancement. The expression of this receptor in a diverse set of potentially competing neurons can affect its usefulness as a clinical target, although some 5-HT 1B / D receptor agonists are effective as anti-migraine treatments. 5-HT 1BReceptor knockout mice have been extensively tested and have distinct phenotypes characterized by increased aggression and, in most cases, a predisposition to addictive-like behaviors (Barnes N.M. et al., Neuronal 5-HT Receptors and SERT, Tocris Scientific Review Series, https: / / www.tocris.com / literature / scientific-reviews / 5-ht-receptors).

[0008] On the other hand, there have been studies focusing on the role of 5-HT 1B receptors in uterine leiomyomas (ULs) that cause various complaints, such as abnormal uterine bleeding and fertility problems. This research demonstrated the relationship between the expression of 5-HT 1B receptors and cell proliferation / death in UL cases. Overall, 5-HT 1B receptors are involved in the proliferation and survival of UL cells. The effectiveness of 5-HT 1B receptor antagonists needs to be tested in vivo in preclinical studies to better understand their role in tumor growth and potential therapeutic targets for the development of drug therapies in the management of ULs (Gurbuz, N et al., A selective Serotonin 5-HT1B receptor inhibition suppresses cells proliferation and clonocenicty, and induces of apoptosis in human uterine leiomyoma, Eur J Obstet Gynecol Reprod Biol. November 2016; 206:114 - 119).

[0009] Other studies have shown that serotonin is involved in the pathogenesis of pulmonary arterial hypertension (PAH) and is recognized as a potent naturally occurring pulmonary vasoconstrictor and smooth muscle cell mitogen. Serotonin is 5-HT 1BIt promotes pulmonary artery (PA) remodeling and the proliferation of human PA smooth muscle cells (hPASMCs) via receptors and the serotonin transporter (SERT). Serotonin can induce cell Src-related kinase-regulated Nox1-derived ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidation modification of proteins and the activation of the redox-sensitive signaling pathway in hPASMCs associated with mitogenic responses. 5-HT 1B Receptors contribute to experimental pulmonary hypertension by inducing pulmonary ROS production. These results suggest that the 5-HT 1B receptor-dependent cell Src-related kinase Nox1 pathway contributes to vascular remodeling in PAH (Hood, K Y. et al., Serotonin Signaling Through the 5-HT1B Receptor and NADPH Oxidase 1 in Pulmonary Arterial Hypertension, Arterioscler Thromb Vasc Biol. 2017;37:1361-1370).

[0010] In addition, recent studies have demonstrated that serotonin exhibits a growth-stimulatory effect on several types of carcinomas, carcinoids, and other tumor cells. In contrast, there is little available data on the involvement of serotonin in the processes of cancer cell migration and metastasis. Serum serotonin levels have been found to be suitable for the prognostic evaluation of urothelial carcinoma in the bladder, adenocarcinoma of the prostate, and renal cell carcinoma (Sarrouilhe D. et al., Serotonin and Cancer: What Is the Link?, Current Molecular Medicine 2015, 15, 62-77).

[0011] Other studies have demonstrated that serotonin receptors 1B and 2B are expressed in patients with hepatocellular carcinoma. Both receptors are associated with an increase in the proliferation index, and receptor 1B correlates with tumor size. Serotonin antagonists of receptors 1B and 2B consistently decreased survival and proliferation in Huh7 and HepG2 cell lines (Soll C. et al., Expression of Serotonin Receptors in Human Hepatocellular Cancer, Clin Cancer Res;18(21), November 1, 2012).

[0012] In addition, selective antagonists of 5-HTR 1B have been demonstrated to reduce serotonin-mediated cellular steatosis in HepG2 cells. It has also been demonstrated that serotonin positively modulates cell proliferation / survival and cellular steatosis in liver cancer cells by inducing autophagy and activating Notch signaling (Niture S. et al., Serotonin induced hepatic steatosis is associated with modulation of autophagy and notch signaling pathway, Cell Communication and Signaling(2018)16:78).

[0013] 5-HT is involved in the autocrine loop of growth factors that contribute to cell proliferation in invasive tumors, but several studies have shown that serotonin can also exert an anti-neoplastic effect through the inhibition of angiogenesis. In silico screening was performed to search for small molecules that induce terminal differentiation, and apomorphine, an HTR1 / 2 antagonist, was identified. The study was conducted in immunodeficient mice, which were transplanted with human acute myeloid leukemia (AML) cells and left untreated for 7 days to establish leukemia. Thereafter, the mice were treated with apomorphine (5 mg / kg body weight) or methiothepine (0.1 mg / kg body weight) every 2 days for 14 days. Both HTR1 antagonists resulted in a significant reduction in the amount of AML in the bone marrow (BM) compared to vehicle-treated mice. Similarly, the clonogenicity of the transplanted AML cells was impaired in both treated mice, highlighting the effect of HTR inhibition on the self-renewal ability of AML cells. The results indicate that AML cells 1A and HTR 1B are expressed and that their inhibition induces terminal differentiation and cell death. Interestingly, leukemia stem cells (LSCs) are more sensitive to HTR1 antagonists than more mature AML blasts. Thus, HTR 1A and HTR 1B may constitute interesting targets for AML treatment. This study demonstrated the association of HTR1 in cancer stem cells, and the results highlighted the biological role of HTR1 in the maintenance of leukemia, suggesting that HTR1 signaling is involved in the survival of AML blasts and the functionality of LSCs (Etxabe, A. et al., Inhibition of serotonin receptor type 1 in acute myeloid leukemia impairs leukemia stem-cell functionality: A promising novel therapeutic target, Leukemia, 2017, 1-15).

[0014] Other studies have identified serotonin as a well-known mitogen that mediates diverse physiological effects through multiple receptors, among which the receptor subtype 1B (5-HT 1B ) has been identified in prostate cancer (PC) cell lines. Recently, 5-HT has been found to exhibit growth-promoting activity and to be functional in relation to oncogenes (Dizeyi N. et al., Expression of Serotonin Receptors and Role of Serotonin in Human Prostate Cancer Tissue and Cell Lines, The Prostate, 59:328-336, 2004).

[0015] On the other hand, 5-HT 2A receptor subtypes have been identified in both the central nervous system (CNS) and peripherally. 5-HT 2A receptors have been found in many parts of the CNS, including the cerebral cortex, basal ganglia, hippocampus, thalamus, cerebellum and hypothalamus. Peripherally, 5-HT 2A receptors are located on platelets, vascular smooth muscle and uterine smooth muscle. 5-HT 2A receptors are involved in various processes, such as vascular smooth muscle contraction, extravascular smooth muscle contraction (including uterine contraction) and platelet aggregation (Nagatomo T et al., Functions of 5-HT 2A receptor and its antagonists in the cardiovascular system, Pharmacology & Therapeutics 104(2004)59-81).

[0016] Regarding patent literature, several patent applications disclose compounds as modulators, agonists or antagonists of 5-HT 1B receptors, which are addressing CNS disorders such as migraine, depression, anxiety, schizophrenia, stress and pain, among others. See, for example, WO2007 / 057742A2.

[0017] Patent application WO2018 / 130685A1 discloses a combination therapy for treating cancer, particularly acute myeloid leukemia (AML), comprising an anti-neoplastic agent and a type 1 serotonin receptor (HTR1 / 5-HT 1 ) modulator, for example, an HTR1 antagonist, and specifically describes apomorphine, metitepine, and SB-224289 (SB9) as serotonin receptor antagonists. All of them can easily cross the blood-brain barrier and act in the central nervous system (CNS). In the case of apomorphine and metitepine, they are non-selective 5-HT 1B receptor modulators.

[0018] Patent application WO95 / 15954A1 discloses biphenylylamide compounds as 5-HT 1D antagonists for use in the treatment of various CNS disorders, endocrine disorders, and gastrointestinal disorders.

[0019] Therefore, there is a great need for new treatment options for treating peripheral diseases related to said receptor, particularly for 5-HT 1 receptors, especially 5-HT 1B receptors. Such diseases are selected from cancers including blood cancers and solid tumors, as well as respiratory diseases. In order to minimize side effects on the CNS, it is desirable to develop new compounds with low penetration of the brain barrier and good selectivity for other 5-HT receptors, particularly good selectivity for 5-HT 2A receptors.

[0020] The problem solved by the present invention is to provide a novel, more selective and safer 5-HT 1B receptor modulator with improved polarity and less brain penetration compared to the compounds of the prior art. SUMMARY OF THE INVENTION

[0021] In one aspect (Aspect 1) thereof, the present invention provides a compound of formula (I): [Chemical formula] [wherein, - G represents a) -C(O)NH, b) -NHC(O) a group selected therefrom, - X 1 , X 2 , X 3 and X 4 each represents an N atom or a C-R 5 group, - R 1 and R 2 are each independently a) a hydrogen atom, b) -N(R 6 )R 7 and -OR 6 , a halogen atom, and a linear or branched C 3 -C 6 alkyl optionally substituted by 1, 2 or 3 substituents selected from cycloalkyl, 1 -C 6 alkyl, c) C 3 -C 6 cycloalkyl selected from the group consisting of, - or alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic group further containing a second heteroatom selected from N and O, - R 3 is a) a cyano group, and b) a halogen atom selected from the group consisting of, - R 4 is a) a halogen atom, b) a C 3 -C 4 cycloalkyl group, c) a C 1 -C 3 alkoxy group, d) a C 1 -C 3 haloalkyl group, e) a cyano group represents a group selected from -R 5 is a) a hydrogen atom b) C 1 -C 3 alkyl c) a halogen atom represents a group selected from -R 6 and R 7 are, independently, a) C 1 -C 3 alkyl b) a hydrogen atom represents a group selected from provided that at least one of X 1 , X 2 , X 3 and X 4 represents an N atom] relates to novel compounds of and pharmaceutically acceptable salts thereof.

[0022] Other aspects of the invention are described below.

[0023] In a second aspect, the invention relates to a method for preparing a compound as defined in the first aspect.

[0024] In a third aspect, the invention relates to a pharmaceutical composition comprising an effective amount of a compound as defined in the first aspect.

[0025] In a fourth aspect, the invention relates to a combination comprising a compound as defined in the first aspect and another therapeutic agent selected from agents for treating cancer, respiratory diseases and liver disorders. The cancer is selected from blood cancers such as acute myeloid leukemia (AML) and solid tumors, the respiratory disease may be, inter alia, pulmonary arterial hypertension, and the liver disorder may be, inter alia, non-alcoholic steatohepatitis.

[0026] In a fifth aspect, the present invention relates to the use of a compound of the first aspect for the manufacture of a medicament for treating a disease that can be alleviated by antagonism of a serotonin receptor type 1 (HTR1), in particular by antagonism of 5-HTR 1B wherein the disease or condition that can be improved by antagonism of the serotonin receptor 5-HTR 1B may be selected from cancer, respiratory diseases and liver disorders. The cancer may be selected from blood cancers such as acute myeloid leukemia (AML) and solid tumors, the respiratory disease may in particular be pulmonary arterial hypertension, and the liver disorder may in particular be non-alcoholic steatohepatitis.

[0027] In a sixth aspect, the present invention relates to a method for treating a disease that can be alleviated by antagonism of a serotonin receptor 5-HTR by administration to a subject in need of said treatment of a compound defined in the first aspect, or a pharmaceutical composition of the third aspect, or a combination of the fourth aspect. 1B

[0028] In a seventh aspect, the present invention relates to a compound defined in the first aspect, a pharmaceutical composition defined in the third aspect, or a combination defined in the fourth aspect for use as a medicament.

[0029] In an eighth aspect, the present invention relates to a compound defined in the first aspect, a pharmaceutical composition defined in the third aspect, or a combination defined in the fourth aspect for use in the treatment of a disease or condition selected from the group consisting of cancer, respiratory diseases and liver disorders. The cancer may be selected from blood cancers such as acute myeloid leukemia (AML) and solid tumors, the respiratory disease may in particular be pulmonary arterial hypertension, and the liver disorder may in particular be non-alcoholic steatohepatitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0030]

Figure 1

Mode for Carrying Out the Invention

[0031] Detailed Description of the Invention As described above, the compounds of the present invention are useful in the treatment or prevention of diseases known to be readily remitted by treatment with modulators / antagonists of serotonin receptor type 1 (HTR1), particularly modulators / antagonists of the 5-HTR 1B receptor. Such diseases are, for example, cancer, respiratory diseases, and liver disorders. The cancer is selected from blood cancers such as acute myeloid leukemia (AML) and solid tumors, the respiratory disease may be, in particular, pulmonary arterial hypertension, and the liver disorder may be, in particular, non-alcoholic steatohepatitis.

[0032] Accordingly, the derivatives of the present invention, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and / or their salts can be used in a method for treating a pathological condition or disease of the human body, which comprises administering an effective amount of the compound of the present invention or its pharmaceutically acceptable salt to a subject in need of such treatment.

[0033] As used herein, the term halogen atom is used to designate an atom selected from the group consisting of a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, preferably a bromine atom, a fluorine atom, or a chlorine atom.

[0034] As used herein, the term alkyl refers to a straight-chain or branched hydrocarbon radical (C n H 2n+1) is used to specify. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl and 3-methylpentyl. Therefore, C n -C m The term "alkyl" should be understood to specify an alkyl containing from n to m carbon atoms.

[0035] As used herein, C n -C m The term "alkoxy" is used to specify a radical containing a linear or branched C n -C m alkyl group linked to an oxygen atom. Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy and tert-butoxy.

[0036] As used herein, C n -C m The term "cycloalkyl" is used to specify a hydrocarbon cyclic group (C n H 2n-1 ) having from n to m carbon atoms. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0037] As used herein, the term haloalkyl is used to designate an alkyl group in which one or more of its hydrogen atoms are replaced by halogen atoms. Preferred haloalkyl radicals include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0038] As used herein, the term 4- to 6-membered heterocyclyl is used to designate a 4- to 6-membered saturated ring containing carbon and a second heteroatom selected from N and O as part of the ring. Examples of heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.

[0039] As used herein, an atom, radical, chain or part of a ring present in the general structure of the present invention may be "optionally substituted". This means that these atoms, radicals, chains or rings can be unsubstituted or can be substituted at any position by one or more, for example, 1, 2 or 3 substituents, whereby a hydrogen atom bonded to an unsubstituted atom, radical, chain or ring is replaced by a chemically acceptable atom, radical, chain or ring. When two or more substituents are present, each substituent may be the same or different.

[0040] As used herein, the term pharmaceutically acceptable salt is used to designate salts with pharmaceutically acceptable acids or bases. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid and nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Pharmaceutically acceptable bases include hydroxides of alkali metals (e.g., sodium or potassium), alkaline earth metals (e.g., calcium or magnesium), and organic bases such as alkylamines, phenylalkylamines and heterocyclic amines.

[0041] Another preferred salt according to the present invention is a quaternary ammonium compound, wherein an equivalent of the anion (X -n ) (wherein “-n” represents the negative charge of the anion and is typically -1, -2 or -3) is associated with the positive charge of the N atom. X -n can be, for example, an anion of various mineral acids such as chloride ion, bromide ion, iodide ion, sulfate, nitrate, phosphate, or an anion of organic acids such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, maleate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulfonate. X -n is preferably an anion selected from chloride ion, bromide ion, iodide ion, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X - is chloride ion, bromide ion, trifluoroacetate or methanesulfonate.

[0042] According to one embodiment of the present invention, in the compound of formula (I), R 1 and R 2 are linear or branched C1 -C 3 is alkyl. In a preferred embodiment, R 1 and R 2 are methyl groups.

[0043] According to one embodiment of the present invention, in the compound of formula (I), G represents -C(O)NH-, and the carbonyl group is linked to the ring containing X 3 and X 4 , and the amine group is linked to the ring containing X 1 and X 2 .

[0044] According to one embodiment of the present invention, in the compound of formula (I), R 3 is a cyano group.

[0045] According to one embodiment of the present invention, in the compound of formula (I), R 4 is selected from a halogen atom and a C 3 -C 4 cycloalkyl group. In a preferred embodiment, R 4 is selected from a chlorine atom, a fluorine atom, and a cyclopropyl group.

[0046] According to one embodiment of the present invention, in the compound of formula (I), core:

Chemical formula

Chemical formula

[0047] In a preferred embodiment, core:

Chemical formula

Chemical formula

[0048] In another preferred embodiment, the core: [Chemical formula] is [Chemical formula] as follows.

[0049] In another preferred embodiment, the core: [Chemical formula] is [Chemical formula] as follows.

[0050] According to one embodiment of the present invention, the compound of formula (I) is represented by the following formulas (Ia), (Ib) and (Ic): [Chemical formula] TIFF0007687636000011.tif53160TIFF0007687636000012.tif48160[wherein, R 4 represents a group selected from a halogen atom and a cyclopropyl group] has one of

[0051] As individual compounds of the present invention, N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-cyclopropyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-fluoro-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-chloro-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-2’-(trifluoromethyl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-methoxy-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-cyano-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Cyano-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-chloro-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-cyclopropyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-fluoro-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide 2’-Chloro-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2’-cyclopropyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2’-fluoro-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2’-chloro-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2’-cyclopropyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 4-Bromo-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Bromo-N-(6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 4-Bromo-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Cyano-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide N-(6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-4-cyano-3-(2-(dimethylamino)ethoxy)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 4-Cyano-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide include

[0052] According to one embodiment of the present invention, preferred compounds are N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)nicotinamide 4-Cyano-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide selected from the following.

[0053] In a more preferred embodiment of the present invention, the compound is N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide selected from the following.

[0054] When the compound of the present invention is combined with other therapeutic agents, the other therapeutic agents are selected from the group consisting of chemotherapeutic agents selected from vincristine, daunorubicin, cytarabine, 6-mercaptopurine, methotrexate, cyclophosphamide, prednisone, dexamethasone, nelarabine, and immunotherapeutic agents selected from the group consisting of anti-PD1 antibodies, anti-PDL1 antibodies, and anti-CTLA4 antibodies. Specifically, the immunotherapeutic agents are selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, MPDL3280A, MEDI4736, and MDX-1105.

[0055] The compounds of the present invention can be prepared by using the procedures described in the following schemes and examples, or by methods known in the art. Starting materials and intermediates may be obtained from commercial sources, prepared from commercially available compounds, or prepared using well-known synthetic methods. Specific examples are used to facilitate the description of the procedures, but they do not limit the scope of the present invention in any way.

[0056]

Chem.

[0057] Scheme 1 shows one of the synthetic routes leading to the compound of formula (VI) which is an intermediate in the synthesis of the compound of formula (I). Starting from a derivative of 2-aminoethan-1-ol (II), the reaction with methanesulfonyl chloride results in the formation of 2-aminoethyl methanesulfonate (III), which reacts with a heteroaryl alcohol or phenol (IV) to form the ether of compound (V). For example, after hydrogenation with zinc powder and ammonium chloride, the intermediate of formula (VI) is obtained.

[0058]

Chem.

[0059] X 2 In the specific case of intermediate (IV) where X represents a nitrogen atom, the synthesis starts with the halogenation of 6-fluoropyridin-2-amine with N-halosuccinimide in acetic acid at room temperature, providing the intermediate of formula (VIIa).

[0060] R 3For the synthesis of the compounds of the invention where R is a cyano group, the compound 6-fluoro-5-iodopyridin-2-amine is reacted with Zn(CN) 2 by means of a palladium complex to obtain an intermediate of formula (VIIb). According to Scheme 2, finally, the intermediate (VIIa) or (VIIb) is reacted with a disubstituted aminoethanol at room temperature in the presence of a base, for example potassium bis(trimethylsilyl)amide in THF, to form the amino ether (VIa).

[0061]

Chemical formula

[0062] On the other hand, the intermediate of formula (VIb) is obtained by applying a reaction similar to that described in Scheme 2. In this case, 4-chloropyrimidin-2-amine is halogenated with N-halosuccinimide in DMF at room temperature to obtain an intermediate of formula (VIIa). R 3 For the synthesis of the compounds of the invention where R is a cyano group, the introduction of said group is catalyzed by a palladium complex to provide an intermediate (VIIIb), which is converted to the intermediate (VIb) by reaction with a disubstituted aminoethanol at room temperature in the presence of a base, for example potassium bis(trimethylsilyl)amide in THF, as described in Scheme 3.

[0063]

Chemical formula

[0064] In acetic acid, halogenation of 4-fluoropyridin-2-amine with N-halosuccinimide at room temperature gives the intermediate of formula (VIIc). The amino group is protected by the formation of the intermediate of formula (VIId). Introduction of cyano to the previously described R 3 group gives the precursor (XII). According to Scheme 4, in the presence of a base, such as sodium hydride in DMF, HO-CH 2 -CH 2 -NR 1 R 2 reacts to give the intermediate (XIII), which, after deprotection with trifluoroacetic acid in DCM, gives the intermediate (VId).

[0065]

Chemical Structure

[0066] In Scheme 5, when the group G of the compound of general formula (I) represents an amide (-C(O)NH), two routes for synthesizing the carboxylic acid of formula (XVII) are shown. The phenyl or heteroaryl bromide precursor (XIV) can be reacted with bis(pinacolato)diboron in the presence of a palladium catalyst to obtain the intermediate (XV). Applying the Suzuki reaction, these intermediates can be converted to the acid of formula (XVIII) by reaction with the bromide precursor (XVI). An alternative route is possible by the coupling reaction of the precursor (XVIII) with the boronic acid (XIX) under palladium catalyst conditions.

[0067]

Chem.

[0068] The synthesis of the amide of formula (Id) is carried out by reaction of the corresponding carboxylic acid (XVII) of the amine of formula (VI) at room temperature in the presence of a coupling agent, for example, HATU and a base, as described in Scheme 6.

[0069] Alternatively, the carboxylic acid of formula (XVII) can be converted to the corresponding acid chloride using standard procedures. The corresponding acid chloride of the precursor (XVII) is reacted with the amine precursor of formula (VI) in the presence of a base, for example, triethylamine, to also obtain the derivative of formula (Id).

[0070]

Chem.

[0071]

Chem.

[0072] In Scheme 7, a route for obtaining the inverse amide (-NHC(O)) (Ie) in the G moiety of the compound of general formula (I), which is also the object of this patent, is described. Ether formation of the 2-aminoethyl methanesulfonate (III) with the precursor (XX) gives the precursor (XXI), and then hydrolysis yields the acid of formula (XXII). On the other hand, the amine precursor (XXV) can be synthesized by a Suzuki-type coupling reaction of the boronic acid or boronate derivative (XXIII) with the precursor (XXIV) using a palladium catalyst. This is also possible by changing the functionality of the intermediate in a similar reaction depending on whether the product is commercially available or not, as shown in the reaction of the boronic acid or boronate derivative (XXVII) with the precursor (XXVI) under palladium catalyst conditions. The synthesis of the inverse amide of formula (Ie) is carried out by reaction of the amine precursor of formula (XXV) with the corresponding carboxylic acid (XXII) at room temperature in the presence of a coupling agent, for example, HATU and a base.

[0073] The synthesis of the compounds of the present invention is illustrated by the following examples, including the preparation of intermediates, which in no way limit the scope of the present invention.

[0074] Abbreviations In this application, the following abbreviations with corresponding definitions are used. ACN: Acetonitrile CN: Cyano group RT: Room temperature Halo: Halogen atom HATU: N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide EDTA: Ethylenediaminetetraacetic acid DIPEA: N,N-Diisopropylethylamine DME: Dimethoxyethanol DMF: Dimethylformamide DCM: Dichloromethane NBS: N-Bromosuccinimide TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide

[0075] Pharmacological activity Determination of binding at human serotonin receptors Human 5-HT 1B Competitive binding at receptors: Serotonin 5-HT 1B Receptor competitive binding experiments were performed in polypropylene 96-well plates. In each well, 5 μg of Hela-5-HT cell line-derived membranes prepared in the laboratory were incubated (lot: A001 / 14-11-2011, protein concentration = 3179 μg / ml), and 1.5 nM of 1B [3H]-GR125743 (77.3 Ci / mmol, 0.1 mCi / ml, Perkin Elmer NET1172100UC) and the compound were studied and standardized. Nonspecific binding was determined in the presence of 10 μM GR55562 (TOCRIS 1054). The reaction mixture (V 3 : 250 μl / well) was incubated at 25 °C for 90 minutes, and 200 μL was transferred to a GF / C 96-well plate (Millipore, Madrid, Spain) pretreated with 0.5% PEI, and the binding buffer (50 mM Tris-HCl, 1 mM EDTA, 10 mM MgCl t : 250 μl / well) was incubated at 25 °C for 90 minutes, and 200 μL was transferred to a GF / C 96-well plate (Millipore, Madrid, Spain) pretreated with 0.5% PEI, and the binding buffer (50 mM Tris-HCl, 1 mM EDTA, 10 mM MgCl2 treated at pH = 7.4, then filtered, washed four times with 250 μl of wash buffer (50 mM Tris-HCl, pH = 7.4), and then measured in a Microbeta Trilux microplate beta scintillation counter (PerkinElmer, Madrid, Spain). The raw radioactivity data was adapted to a four-parameter logistic regression using GraphPad Prism software, and from specific binding, the IC 50 value was obtained. From the IC 50 , the Ki was calculated according to the following formula:

Equation

[0076] Human 5-HT 2A Competitive binding at receptors : Serotonin 5-HT 2A receptor competitive binding experiments were performed in polypropylene 96-well plates. In each well, 80 μg of membranes derived from the CHO-5-HT 2A cell line prepared in the laboratory was incubated (protein concentration = 4337 μg / ml), and 1 nM 3[[H]]-Ketanserin (47.3 Ci / mmol, 1 mCi / ml, Perkin Elmer NET791250UC) and the compound were studied and standardized. Nonspecific binding was determined in the presence of 1 μM methysergide (Sigma M137). The reaction mixture (Vt: 250 μl / well) was incubated at 37 °C for 30 min, and 200 μL was transferred to GF / B 96-well plates (Millipore, Madrid, Spain) pretreated with 0.5% PEI, treated with binding buffer (50 mM Tris-HCl, pH = 7.4), then filtered and washed 6 times with 250 μl of wash buffer (50 mM Tris-HCl, pH = 6.6), and then measured in a microplate beta scintillation counter (Microbeta Trilux, PerkinElmer, Madrid, Spain).

[0077] The raw radioligand data were fitted to a four-parameter logistic regression using GraphPad Prism software to obtain the IC 50 values from specific binding. The Ki was calculated from the IC 50 using the following equation:

Equation

[0078] Cell viability assay 0.15 × 10 6 AML cell lines (HL-60 or MonoMac-1) per mL were cultured in complete RPMI medium supplemented with 10% fetal bovine serum (FBS). The compound was added to the medium at the indicated concentrations (0.1, 1, and 10 μM), while the control was treated with an equal concentration of vehicle (DMSO). The primary validation screening was analyzed 72 h after treatment to obtain the EC 50was determined in 48 hours of treatment. Cells were stained with the viability - death discrimination dyes 7 - aminoactinomycin D (7 - AAD) and Hoechst 33342 and acquired on a flow cytometer using volume counting. Viable cells were discriminated based on distinct FSC - SSC profiles that were 7 - AAD negative and dim positive for Hoechst 33342. EC 50 was calculated using Prism GraphPad software.

[0079] Selectivity study against leukemia cells Primary AML patient samples derived from peripheral blood at diagnosis were Ficoll - purified for mononuclear cells (MNC). The isolated MNC were cultured in IMDM medium supplemented with 3% heat - inactivated fetal bovine serum, 1×BIT (StemCell Technologies), 5 ng / mL human IL3, 2 mM NaPyr and 5×10−5 M β - mercaptoethanol. Cells were treated with vehicle control (DMSO), and 10 μM of the selected compound (example compound or reference compound) at 37 °C and 5% CO 2 for 72 hours. After treatment, cells were stained for the pan - hematopoietic marker CD45 and the viability - death discriminator 7 - AAD and acquired by flow cytometry. Analysis was performed within the live gate (FSC - SSC profile, discriminating the 7 - AAD dim population). Histograms show the intensity of CD45 staining (X - axis) and SSC (Y - axis) within the live cell gate. The blast gate (upper right) and lymphocyte gate (lower left) are shown in their respective histograms. Selectivity against AML blasts was represented by the reduction in the relative frequency of AML blasts to lymphocytes.

[0080] Healthy blood cell - viability assay 0.5×10 per mL 6Individual peripheral blood mononuclear blood cells were cultured in complete RPMI medium supplemented with 10% FBS. Compounds were added to the medium at 0.5 / 1 / 5 / 10 / 50 μM, while the control was treated with an equal concentration of vehicle (DMSO). After 48 hours of treatment, the cells were stained with the live-dead discrimination dyes 7-AAD and Hoechst 33342 and the pan-hematopoietic surface marker CD45, and acquisition was performed on a flow cytometer using volumetric counting. Live cells were discriminated based on distinct FSC-SSC profiles that were negative for 7-AAD and dim positive and CD45 positive for Hoechst 33342. EC 50 was calculated using Prism GraphPad software.

[0081] Estimation of brain penetration The tPSA values of several compounds were determined theoretically using the ChemDraw Professional program version 17.0.0.206(121) by Perkin Elmer Informatics, Inc. PSA was used as a predictor for blood-brain barrier (BBB) penetration (see, for example, Lenz GR. Technical problems in getting results. In: From data to drugs: strategies for benefiting from the new drug discovery technologies (Feng MR, Assessment of blood-brain barrier penetration: in silico, in vitro and in vivo; Curr Drug Metab. December 2002; 3(6):647-57)).

[0082] Results Human serotonin receptor h5-HT 1B And h5-HT 2A Determination of binding Table 1 shows the binding of some of the compounds of the present invention to serotonin receptors.

[0083]

Table 1

[0084] Results of cell viability assay Table 2 shows the cytotoxic ability of some of the compounds of the present invention against AML cell lines.

[0085]

Table 2

[0086] Selectivity study against leukemia cells As shown in Figure 1, some compounds were highly selective against AML blasts based on the elimination of the blast population and the survival of the non-tumorigenic lymphocyte population. However, the conventional HTR 1BAfter treatment with the antagonist SB-224289, the frequency of each population is similar to that of the vehicle control DMSO.

[0087] Healthy blood cell - viability assay Table 3 shows the cytotoxic ability of some of the compounds of the present invention against healthy cell lines.

[0088]

Table 3

[0089] tPSA value The following Table 4 shows the estimated values of tPSA for some exemplary compounds.

[0090]

Table 4

[0091] As can be seen from the results described above, the compounds of the present invention are potent 5-HT receptor modulators with good selectivity for other serotonin receptors, more specifically for the 5-HT 2A receptor. 1B receptor.

[0092] In addition, the compounds of the present invention show enhanced cytotoxic activity against AML cells, significantly lower cytotoxicity against healthy cell lines, and a lower potential for brain penetration compared to the reported 5-HT 1B receptor modulators.

[0093] The derivatives of the present invention are 5-HT 1BIt is useful in the treatment or prevention of diseases known to be readily improved by treatment with modulators of serotonin receptors. Such diseases are, for example, cancers selected from blood cancers such as acute myeloid leukemia (AML) and solid tumors, and respiratory diseases such as pulmonary arterial hypertension.

[0094] Accordingly, the derivatives of the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds and / or salts thereof can be used in a method for treating disorders of the human body, which includes administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0095] As mentioned above, the present invention also provides a pharmaceutical composition which, in combination with other therapeutic agents, contains at least a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient such as a carrier or a diluent. The active ingredient can constitute from 0.001% to 99% by weight, preferably from 0.01% to 90% by weight of the composition, depending on the nature of the formulation and whether further dilution is carried out before application. Preferably, the composition is prepared in a form suitable for oral, topical, nasal, rectal, transdermal or injectable application.

[0096] Pharmaceutically acceptable excipients mixed with the active compound or a salt of such a compound to form the composition of the present invention are well known per se, and the actual excipients used depend, inter alia, on the method by which the composition is intended to be administered.

[0097] The compositions of the present invention are preferably adapted for injectable and per os administration. In this case, the compositions for oral administration may take the form of tablets, sustained release tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalants, or liquid preparations such as mixtures, elixirs, syrups or suspensions, all of which contain the compound of the present invention, and such preparations may be made by methods well known in the art.

[0098] Diluents that can be used in the preparation of the composition include liquid and solid diluents, which are compatible with the active ingredient, optionally together with a colorant or flavorant. Tablets or capsules may conveniently contain from 2 to 500 mg of the active ingredient or an equivalent amount of its salt.

[0099] Liquid compositions suitable for oral use may be in the form of solutions or suspensions. The solution may be, for example, an aqueous solution of a soluble salt or other derivative of the active compound that associates with sucrose to form a syrup. The suspension may contain the insoluble active compound of the present invention or a pharmaceutically acceptable salt thereof that associates with water, together with a suspending agent or flavorant.

[0100] Compositions for parenteral injection may be prepared from soluble salts, which may or may not be lyophilized, and dissolved in a pyrogen-free aqueous medium or other suitable parenteral injection liquid.

[0101] The effective dose is usually in the range of 2 to 2000 mg of the active ingredient per day. The daily dosage may be administered in one or more treatments per day, preferably 1 to 4 treatments per day.

[0102] The present invention will be further illustrated by the following examples. The following are shown by way of illustration and in no way limit the scope of the present invention. The synthesis of the compounds of the present invention is described by the following examples, including the preparation of intermediates, which in no way limit the scope of the present invention.

Examples

[0103] General The reagents, solvents, and starting products were obtained from commercial sources. The term "concentrated" refers to vacuum evaporation using a Buechi rotary evaporator. When indicated, the reaction products were purified by "flash" chromatography on silica gel (40 - 63 μm) with the indicated solvent system. Spectral analysis data were measured on a Varian Mercury 400 spectrometer. Melting points were measured on a Buechi 535 instrument. HPLC - MS was performed on a Gilson instrument 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.

[0104] Preparation of intermediates General procedure Intermediate 1 : 2 - (Dimethylamino)ethyl methanesulfonate

Chem.

[0105] Intermediate 2 : 2 - (2 - Bromo - 5 - nitrophenoxy)-N,N - dimethylethan - 1 - amine

Chem.

[0106] The following intermediates were synthesized using the procedure described for Intermediate 2.

[0107] Intermediate 3 : 2-(2-chloro-5-nitrophenoxy)-N,N-dimethylethane-1-amine The procedure described for Intermediate 2 was used, except that 2-chloro-5-nitrophenol was used. 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 7.93 (d, 1H), 7.83 (dd, 1H), 7.74 (d, 1H), 4.30 (t, 2H), 2.70 (t, 2H), 2.24 (s, 6H). HPLC-MS: Rt 2.54 m / z: 245.1 (MH + ).

[0108] Intermediate 4 : 2-(2-(dimethylamino)ethoxy)-4-nitrobenzonitrile [Chemical formula] To a solution of 2-hydroxy-4-nitrobenzonitrile (500 mg, 3.05 mmol) and cesium carbonate (1489 mg, 4.57 mmol) in 15 mL of dry 1,4-dioxane was added 2-(dimethylamino)ethyl methanesulfonate (1019 mg, 6.09 mmol). The suspension was stirred at 60 °C for 16 h in a sealed tube. The reaction mixture was evaporated, and the residue was partitioned between dichloromethane and saturated NaHCO 3 and. The organic phase was dried over Na 2 SO 4 and evaporated to dryness. The residue was purified by normal-phase chromatography to give 2-(2-(dimethylamino)ethoxy)-4-nitrobenzonitrile as a yellow solid (452 mg, 63%). 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 8.07 (d, 1H), 8.02 (d, 1H), 7.90 (dd, 1H), 4.39 (t, 2H), 2.73 (s, 2H), 2.27 (s, 6H). HPLC-MS: Rt 1.64 m / z 206.1 (MH + ).

[0109] Intermediate 5 : 4-Bromo-3-(2-(dimethylamino)ethoxy)aniline [Chemical formula] A solution of 2-(2-bromo-5-nitrophenoxy)-N,N-dimethylethane-1-amine (405 mg, 1.40 mmol) and zinc powder (412.1 mg, 6.30 mmol) in 16.2 mL of methanol and 4 mL of saturated ammonium chloride aqueous solution was stirred at room temperature for 30 min. The reaction mixture was filtered and concentrated under vacuum. The residue was partitioned between dichloromethane and saturated NaHCO 3 and, and the organic layer was dried over Na 2 SO 4 and concentrated under vacuum to give the amine intermediate (317.7 mg, 87.6%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.09 (d, 1H), 6.31 (d, 1H), 6.09 (dd, 1H), 5.26 (s, 2H), 3.98 (t, 2H), 2.63 (t, 2H), 2.24 (s, 6H). HPLC-MS: Rt 2.06 m / z 259.0 (MH + ).

[0110] Intermediate 6 : 4-Chloro-3-(2-(dimethylamino)ethoxy)aniline The procedure described in Intermediate 5 was used, except that Intermediate 3 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 6.96 (d, 1H), 6.32 (d, 1H), 6.12 (dd, 1H), 5.22 (s, 2H), 3.98 (t, 2H), 2.63 (t, 2H), 2.23 (s, 3H). HPLC-MS: Rt 1.96 m / z 215.1 (MH + ).

[0111] Intermediate 7 : 4-Amino-2-(2-(dimethylamino)ethoxy)benzonitrile The procedure described in Intermediate 6 was used, except that Intermediate 4 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.23 (d, 1H), 6.24 (d, 1H), 6.17 (dd, 1H), 6.15 (s, 2H), 4.04 (t, 2H), 2.65 (t, 2H), 2.23 (s, 6H). HPLC-MS: Rt 1.64 m / z 206.1 (MH + ).

[0112] Intermediate 8 : 6-Fluoro-5-iodopyridin-2-amine

Chemical Structure

[0113] Intermediate 9 : 4-Fluoro-5-iodopyridin-2-amine

Chemical Structure

[0114] Intermediate 10 : 4-Chloro-5-iodopyrimidin-2-amine

Chem.

[0115] The above procedure was used, except that N-bromosuccinimide was used, to synthesize Intermediate 11. Intermediate 11 : 5-Bromo-4-chloropyrimidin-2-amine 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 8.41 (s, 1H), 7.34 (s, 2H). HPLC-MS: Rt 1.87 m / z 209.8 (MH + ).

[0116] Intermediate 12 : 2-Amino-4-chloropyrimidine-5-carbonitrile

Chem.

[0117] Intermediate 13 : 2-Amino-4-(2-(dimethylamino)ethoxy)pyrimidine-5-carbonitrile

Chemical formula

[0118] Intermediate 14 : tert-Butyl N-(tert-butoxycarbonyl)-N-(4-fluoro-5-iodopyridin-2-yl)carbamate

Chem.

[0119] Intermediate 15 : 6-Amino-4-fluoronicotinonitrile

Chem.

[0120] Using the above procedure, but using 5-bromo-6-fluoropyridin-2-amine, Intermediate 16 was synthesized. Intermediate 16 : 6-Amino-2-fluoronicotinonitrile 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 7.82 (t, 1H), 7.54 (s, 2H), 6.38 (dd, 1H). HPLC-MS: Rt 1.51 m / z 138.0 (MH + +).

[0121] Intermediate 17 : 6-Amino-4-(2-(dimethylamino)ethoxy)nicotinonitrile

Chemical Structure

[0122] Using the above procedure, but using 6-amino-2-fluoronicotinonitrile, Intermediate 18 was synthesized. Intermediate 18 : 6-Amino-2-(2-(dimethylamino)ethoxy)nicotinonitrile 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 7.59 (d, 1H), 7.04 (s, 2H), 6.05 (d, 1H), 4.35 (t, 2H), 2.59 (t, 2H), 2.20 (s, 6H). HPLC-MS: Rt 1.58 m / z 207.1 (MH + ).

[0123] Intermediate 19: 5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-amine

Chem.

[0124] Intermediate 20 : Methyl 4-bromo-3-(2-(dimethylamino)ethoxy)benzoate

Chem.

[0125] Intermediate 21 : 4-bromo-3-(2-(dimethylamino)ethoxy)benzoic acid

Chemical formula

[0126] Intermediate 22 : Methyl 4-cyano-3-hydroxybenzoate [Chemistry] Methyl 4-bromo-3-hydroxybenzoate (200 mg, 0.87 mmol), zinc cyanide (112 mg, 0.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42 mg, 0.05 mmol) were suspended in anhydrous dimethylformamide (2 mL) in a sealed tube. The reaction mixture was degassed using nitrogen and stirred at 120 °C for 16 hours. The reaction was filtered through Celite and eluted with ethyl acetate, and the filtrate was washed with H 2 O and brine. The organic phase was dried over Na 2 SO 4 and evaporated to dryness. The resulting solid was purified by normal-phase chromatography to obtain methyl 4-cyano-3-hydroxybenzoate as a pale brown solid (120 mg, 78%). 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 11.58 (s, 1H), 7.77 (d, 1H), 7.56 (s, 1H), 7.45 (d, 1H), 3.86 (s, 3H). HPLC-MS: Rt 1.26 m / z 178.0 (MH + ).

[0127] Intermediate 23 : Methyl 4-cyano-3-(2-(dimethylamino)ethoxy)benzoate [Chemistry] To a solution of methyl 4-cyano-3-hydroxybenzoate (200 mg, 1.13 mmol) and cesium carbonate (551 mg, 1.69 mmol) in 7 mL of dry 1,4-dioxane, 2-(dimethylamino)ethyl methanesulfonate (377 mg, 2.26 mmol) was added. The suspension was stirred at 100 °C for 5 hours in a sealed tube. The reaction mixture was evaporated, and the residue was partitioned between dichloromethane and saturated NaHCO 3 and. The organic phase was dried over Na 2 SO 4It was dried and evaporated to dryness. The residue was purified by normal-phase chromatography to obtain methyl 4-cyano-3-(2-(dimethylamino)ethoxy)benzoate as a pale yellow solid (260 mg, 93%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.89 (d, 1H), 7.68 (d, 1H), 7.62 (dd, 1H), 4.30 (t, 2H), 3.89 (s, 3H), 2.69 (t, 2H), 2.24 (s, 6H). HPLC-MS: Rt 2.19 m / z 249.2 (MH + ).

[0128] Intermediate 24 : 4-Cyano-3-(2-(dimethylamino)ethoxy)benzoic acid

Chemical formula

[0129] Intermediate 25 : 4-Amino-3-bromobenzonitrile [Chemistry] To a solution of 4-aminobenzonitrile (1500 mg, 12.70 mmol) in DMF (15 mL) was added NBS (2757 mg, 15.49 mmol). The reaction mixture was stirred at room temperature for 30 minutes and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the residue by normal phase chromatography gave 4-amino-3-bromobenzonitrile (1726 mg, 69%). 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 7.82 (d, 1H), 7.45 (dd, 1H), 6.81 (d, 1H), 6.36 (s, 2H). HPLC-MS: Rt 2.08 m / z: 198.94 (MH + +).

[0130] Intermediate 26 : 4-Amino-3-chlorobenzonitrile The procedure described in Intermediate 25 was used, except that N-chlorosuccinimide in ACN was used at 90 °C for 3 hours. 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 7.69 (d, 1H), 7.41 (dd, 1H), 6.82 (d, 1H), 6.42 (s, 2H). HPLC-MS: 2.01 m / z 152.9 Rt (MH + +).

[0131] Intermediate 27 : 4-Amino-3-cyclopropylbenzonitrile [Chemistry] A solution of 600 mg (3.05 mmol) of 4-amino-3-bromobenzonitrile, cyclopropylboronic acid (523 mg, 6.09 mmol), palladium(II) acetate (68.4 mg, 0.3 mmol), tricyclohexylphosphine (170.8 mg, 0.61 mmol) and potassium phosphate (1939 mg, 9.14 mmol) in 17 mL of toluene and 1.7 mL of H2O was degassed with N2 and stirred at 90 °C for 16 h. The reaction mixture was filtered through celite, eluted with EtOAc, and the filtrate was washed with 1 M NaOH, saturated NaHCO 3 and brine. The organic layer was collected, dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by a normal-phase chromatography column (hexane / ethyl acetate) to give 4-amino-3-cyclopropylbenzonitrile (350 mg, 72%). 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 7.27 (dd, 1H), 7.14 (d, 1H), 6.65 (d, 1H), 6.04 (s, 2H), 1.62 (m, 1H), 0.86 (m, 2H), 0.52 (m, 2H). HPLC-MS: Rt 2.19 m / z: 159.06 (MH + +).

[0132] Intermediate 28 : 4-Bromo-3-cyclopropylbenzonitrile

Chemical Structure

[0133] Intermediate 29 : 4-Bromo-3-chlorobenzonitrile

Chemical Structure

[0134] Intermediate 30 : 4-Bromo-3-cyclopropyl-N-hydroxybenzamidine

Chemical formula

[0135] Intermediate 31 : (Z)-4-Bromo-3-fluoro-N'-hydroxybenzamidine The procedure described in Intermediate 30 was used, except that 4-bromo-3-fluorobenzonitrile was used as the starting compound to obtain it. 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 9.89 (s, 1H), 7.71 (t, 1H), 7.61 (dd, 1H), 7.49 (dd, 1H), 5.97 (s, 2H). HPLC-MS: Rt 1.88 m / z 232.9 (MH + +).

[0136] Intermediate 32 : 4-Bromo-3-chloro-N-hydroxybenzamidine The procedure described in Intermediate 30 was used, except that 4-bromo-3-chlorobenzonitrile was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.90 (s, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.57 (dd, 1H), 5.98 (s, 3H). HPLC-MS: Rt 2.08 m / z 250.9 (MH + ).

[0137] Intermediate 33 : 4-bromo-N-hydroxy-3-(trifluoromethyl)benzimidamide The procedure described in Intermediate 30 was used, except that 4-bromo-3-(trifluoromethyl)benzonitrile was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.97 (s, 1H), 8.09 (d, 1H), 7.91 (d, 1H), 7.86 (dd, 1H), 6.08 (s, 2H). HPLC-MS: Rt 2.24 m / z 282.9 (MH + ).

[0138] Intermediate 34 : (Z)-4-bromo-N'-hydroxy-3-methoxybenzimidamide The procedure described in Intermediate 30 was used, except that 4-bromo-3-methoxybenzonitrile was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.75 (s, 1H), 7.56 (d, 1H), 7.36 (d, 1H), 7.21 (dd, 1H), 5.95 (s, 2H), 3.87 (s, 3H). HPLC-MS: Rt 1.83 m / z 246.9 (MH + ).

[0139] Intermediate 35 : 4-amino-3-bromo-N-hydroxybenzimidamide [Chemical formula] 4-Amino-3-bromobenzonitrile (1000 mg, 5.08 mmol) and sodium carbonate (349 mg, 3.3 mmol) in ethanol / water (4.5 mL / 1.6 mL) were heated to 60 °C. Then, hydroxylamine hydrochloride (423 mg, 6.09 mmol) dissolved in 1.6 mL of water was slowly added dropwise at 60 °C. The reaction mixture was stirred at 60 °C for 16 h. The mixture was cooled and concentrated to dryness. The crude reaction product was partitioned between EtOAc / H 2 O, the organic layer was collected, dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was triturated in cold Et 2 O to give 4-amino-3-bromo-N-hydroxybenzamide (500 mg, 43%). 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 9.36 (s, 1H), 7.64 (d, 1H), 7.38 (dd, 1H), 6.74 (d, 1H), 5.66 (s, 2H), 5.51 (s, 2H). HPLC-MS: Rt 1.23 m / z: 229.9 (MH + +).

[0140] Intermediate 36 : 3-(4-Bromo-3-cyclopropylphenyl)-5-methyl-1,2,4-oxadiazole [Chemical formula] A solution of 500 mg (2 mmol) of 4-bromo-3-cyclopropyl-N-hydroxybenzamide in 1.4 mL of acetic anhydride was stirred at 80 °C for 16 h. The reaction mixture was poured into cold water and filtered. The crude product was purified by CombiFlash chromatography column (hexane / ethyl acetate) to give the desired intermediate (336.5 mg, 61.5%). 1 1H-NMR (400 MHz, DMSO-d 6): δ = 7.78 (d, 1H), 7.70 (dd, 1H), 7.53 (m, 1H), 2.66 (s, 3H), 2.16 (m, 1H), 1.08 (m, 2H), 0.74 (m, 2H). HPLC-MS: Rt 3.24 m / z: 279.03 (MH + )。

[0141] Intermediate 37 : 3-(4-Bromo-3-fluorophenyl)-5-methyl-1,2,4-oxadiazole The procedure described in Intermediate 36 was used, except that 4-bromo-3-fluoro-N-hydroxybenzimidamide was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.92 (m, 1H), 7.86 (dd, 1H), 7.76 (dd, 1H), 2.68 (s, 3H). HPLC-MS: Rt 2.89 m / z 256.9 (MH + )。

[0142] Intermediate 38 : 3-(4-Bromo-3-chlorophenyl)-5-methyl-1,2,4-oxadiazole The procedure described in Intermediate 36 was used, except that 4-bromo-3-chloro-N-hydroxybenzimidamide was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.11 (d, 1H), 7.98 (d, 1H), 7.85 (dd, 1H), 2.68 (s, 3H). HPLC-MS: Rt 3.13 m / z 274.9 (MH + )。

[0143] Intermediate 39 : 3-(4-Bromo-3-(trifluoromethyl)phenyl)-5-methyl-1,2,4-oxadiazole The procedure described in Intermediate 36 was used, except that 4-bromo-N-hydroxy-3-(trifluoromethyl)benzimidamide was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.27 (d, 1H), 8.16 (dd, 1H), 8.11 (d, 1H), 2.70 (s, 3H). HPLC-MS: Rt 3.14 m / z 306.9 (MH + ).

[0144] Intermediate 40 : 3-(4-Bromo-3-methoxyphenyl)-5-methyl-1,2,4-oxadiazole The procedure described in Intermediate 36 was used, except that 4-bromo-N-hydroxy-3-methoxybenzamidine was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.78 (d, 1H), 7.59 (d, 1H), 7.51 (dd, 1H), 3.94 (s, 3H), 2.68 (s, 3H). HPLC-MS: Rt 2.76 m / z 269.0 (MH + ).

[0145] Intermediate 41 : 2-Bromo-4-(5-methyl-1,2,4-oxadiazol-3-yl)aniline

Chemical Structure

[0146] Intermediate 42 : 2-Amino-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzonitrile

Chemical Structure

[0147] Intermediate 43 : 2-Bromo-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzonitrile

Chemical Structure

[0148] Intermediate 44 : 3-(3-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1,2,4-oxadiazole

Chemical Structure

[0149] Intermediate 45 : 3-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1,2,4-oxadiazole The procedure described in Intermediate 44 was used, except that precursor 37 was used as the starting compound. 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 7.84 (m, 2H), 7.67 (d, 1H), 2.68 (s, 3H), 1.32 (s, 12H). HPLC-MS: Rt 1.13 m / z 223.1 (MH + +).

[0150] Intermediate 46 : 3-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1,2,4-oxadiazole The procedure described in Intermediate 44 was used, except that precursor 38 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.96 (d, 1H), 7.94 (s, 1H), 7.82 (d, 1H), 2.68 (s, 3H), 1.33 (s, 12H). HPLC-MS: Rt 3.19 m / z 321.1 (MH + ).

[0151] Intermediate 47 : 5-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole The procedure described in Intermediate 44 was used, except that precursor 39 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.27 (d, 1H), 8.24 (s, 1H), 7.93 (d, 1H), 2.70 (s, 3H), 1.33 (s, 12H). HPLC-MS: Rt 3.41 m / z 355.0 (MH + ).

[0152] Intermediate 48 : 3-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1,2,4-oxadiazole The procedure described in Intermediate 44 was used, except that precursor 40 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6): δ = 7.69 (s, 1H), 7.57 (d, 1H), 7.49 (s, 1H), 3.83 (s, 3H), 2.67 (s, 3H), 1.29 (s, 12H). HPLC-MS: Rt 1.83 m / z 235.0 (MH + ).

[0153] Intermediate 49 : 5-(5-Methyl-1,2,4-oxadiazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile The procedure described in Intermediate 44 was used, except that precursor 43 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.32 (s, 1H), 8.28 (dd, 1H), 8.01 (d, 1H), 2.70 (s, 3H), 1.34 (s, 12H).

[0154] Intermediate 50 : 2'-Cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxylic acid

Chemical Structure

[0155] Intermediate 51 : 2'-Fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxylic acid The procedure described in Intermediate 50 was used, except that precursor 37 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.12 (s, 1H), 8.06 (d, 2H), 7.94 (dd, 1H), 7.86 (dd, 1H), 7.79 (t, 1H), 7.74 (d, 2H), 2.69 (s, 3H). HPLC-MS: Rt 1.68 m / z 299.0 (MH + ).

[0156] Intermediate 52 : 2'-Chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxylic acid The procedure described in Intermediate 50 was used, except that precursor 38 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.13 (s, 1H), 8.12 (d, 1H), 8.05 (m, 3H), 7.64 (m, 3H), 2.70 (s, 3H). HPLC-MS: Rt 1.76 m / z 315.0 (MH + )。

[0157] Intermediate 53 : 4'-(5-Methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxylic acid The procedure described in Intermediate 50 was used, except that precursor 39 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.15 (s, 1H), 8.35 (s, 1H), 8.33 (d, 1H), 8.04 (d, 2H), 7.66 (d, 1H), 7.51 (d, 2H), 2.72 (s, 3H). HPLC-MS: Rt 1.86 m / z 349.0 (MH + )。

[0158] Intermediate 54 : 2'-Methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxylic acid The procedure described in Intermediate 50 was used, except that precursor 40 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 12.91 (s, 1H), 8.00 (d, 2H), 7.70 (dd, 1H), 7.66 (m, 3H), 7.53 (d, 1H), 3.88 (s, 3H), 2.69 (s, 3H). HPLC-MS: Rt 1.63 m / z 311.0 (MH + )。

[0159] Intermediate 55 : 2'-Cyano-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxylic acid The procedure described in Intermediate 50 was used, except that precursor 43 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d6 ): δ = 13.22 (s, 1H), 8.48 (s, 1H), 8.37 (dd, 1H), 8.11 (d, 2H), 7.88 (d, 1H), 7.79 (d, 2H), 2.72 (s, 3H). HPLC-MS: Rt 1.61 m / z 306.0 (MH + ).

[0160] Intermediate 56 : Methyl 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinate

Chemical formula

[0161] Intermediate 57 : Methyl 6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinate The procedure described in Intermediate 56 was used, except that precursor 45 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.24 (d, 1H), 8.45 (dd, 1H), 8.24 (t, 1H), 8.06 (d, 1H), 8.01 (dd, 1H), 7.92 (d, 1H), 3.93 (s, 3H), 2.70 (s, 3H). HPLC-MS: Rt 2.81 m / z 314.0 (MH + ).

[0162] Intermediate 58 : Methyl 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinate The procedure described in Intermediate 56 was used, except that precursor 46 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.22 (s, 1H), 8.44 (d, 1H), 8.14 (s, 1H), 8.10 (d, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 3.94 (s, 3H), 2.71 (s, 3H). HPLC-MS: Rt 2.81 m / z 330.0 (MH + ).

[0163] Intermediate 59 : Methyl 6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinate The procedure described in Intermediate 56 was used, except that precursor 47 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d6 ): δ = 9.17 (d, 1H), 8.44 (dd, 1H), 8.39 (m, 2H), 7.82 (d, 1H), 7.78 (d, 1H), 3.93 (s, 3H), 2.72 (s, 3H). HPLC-MS: Rt 2.88 m / z 364.0 (MH + )

[0164] Intermediate 60 : Methyl 6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinate The procedure described in Intermediate 56 was used, except that precursor 48 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.18 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 8.02 (d, 1H), 7.74 (m, 1H), 7.71 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 2.70 (s, 3H). HPLC-MS: Rt 2.66 m / z 326.0 (MH + )

[0165] Intermediate 61 : Methyl 6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinate The procedure described in Intermediate 56 was used, except that precursor 49 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.25 (dd, 1H), 8.53 (d, 1H), 8.50 (dd, 1H), 8.42 (dd, 1H), 8.18 (d, 1H), 8.14 (dd, 1H), 3.94 (s, 3H), 2.72 (s, 3H). HPLC-MS: Rt 2.53 m / z 321.0 (MH + )

[0166] Intermediate 62: Ethyl 2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxylate

Chemical Structure

[0167] Intermediate 63 : 6-(2-Cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid [Chemistry] To a solution of methyl 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinate (325.3 mg, 0.97 mmol), the intermediate 56 in THF (4 mL), 1 M NaOH (4.8 mL, 4.80 mmol) was added and the mixture was stirred at room temperature for 3 h. The solvent was evaporated and the pH value was adjusted to 2.0 by the addition of 1 M HCl. The solid was filtered and washed with water and pentane (284.6 mg, 91.3%). 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.49 (s, 1H), 9.19 (s, 1H), 8.37 (dd, 1H), 7.90 (d, 1H), 7.83 (d, 1H), 7.66 - 7.58 (m, 2H), 2.68 (s, 3H), 2.14 (ddd, 1H), 0.95 - 0.87 (m, 2H), 0.67 (q, 2H). HPLC-MS: Rt 1.63 m / z 322.1 (MH + ).

[0168] Intermediate 64 : 2-(2-Cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxylic acid [Chemistry] To a solution of ethyl 2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxylate (276.8 mg, 0.79 mmol) in 6 mL of THF and 2 mL of MeOH, 4 mL (3.99 mmol) of 1 M NaOH was added. The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The aqueous phase was neutralized with 4 M HCl and acidified to pH = 2 with 1 M HCl. The resulting solid was filtered and washed with water and pentane (218 mg, 85.6%). 1 H-NMR (400 MHz, DMSO-d 6): δ = 13.88 (s, 1H), 9.36 (s, 2H), 7.93 (d, 1H), 7.89 (d, 1H), 7.66 (s, 1H), 2.69 (s, 3H), 2.60 (ddd, 1H), 0.95 - 0.87 (m, 2H), 0.64 (q, 2H). HPLC-MS: Rt 1.54 m / z: 323.0 (MH + ).

[0169] Intermediate 65 : 6-(2-Fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid The procedure described in Intermediate 63 was used, except that precursor 57 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.56 (s, 1H), 9.20 (d, 1H), 8.40 (dd, 1H), 8.21 (t, 1H), 7.99 (m, 2H), 7.88 (d, 1H), 2.70 (s, 3H). HPLC-MS: Rt 1.53 m / z 300.0 (MH + ).

[0170] Intermediate 66 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid The procedure described in Intermediate 63 was used, except that precursor 58 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.59 (s, 1H), 9.19 (d, 1H), 8.40 (dd, 1H), 8.13 (d, 1H), 8.09 (dd, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 2.70 (s, 3H). HPLC-MS: Rt 1.56 m / z 316.0 (MH + ).

[0171] Intermediate 67 : 6-(4-(5-Methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinic acid The procedure described in Intermediate 63 was used, except that precursor 59 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.60 (s, 1H), 9.15 (d, 1H), 8.40 (m, 3H), 7.81 (d, 1H), 7.74 (d, 1H), 2.72 (s, 3H). HPLC-MS: Rt 1.68 m / z 350.0 (MH + ).

[0172] Intermediate 68 : 6-(2-Methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid The procedure described in Intermediate 63 was used, except that precursor 60 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 13.43 (s, 1H), 9.16 (d, 1H), 8.31 (dd, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.73 (d, 1H), 7.71 (s, 1H), 3.96 (s, 3H), 2.70 (s, 3H). HPLC-MS: Rt 1.48 m / z 312.0 (MH + ).

[0173] Intermediate 69 : 6-(2-Cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid The procedure described in Intermediate 63 was used, except that precursor 61 was used as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.21 (dd, 1H), 8.48 (m, 2H), 8.41 (dd, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 2.72 (s, 3H). HPLC-MS: Rt 1.46 m / z 307.0 (MH + ).

[0174] Intermediate 70 : 6-(2-Cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride

Chemical formula

[0175] Intermediate 71 : 2-(2-Cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carbonyl chloride The starting compound was Precursor 64, which was obtained using the procedure described in Intermediate 70. The solid was used in the next reaction step without further purification.

[0176] Intermediate 72 : 2'-Fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carbonyl chloride The starting compound was Precursor 51, which was obtained using the procedure described in Intermediate 70. The solid was used in the next reaction step without further purification.

[0177] Intermediate 73 : 2'-Chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carbonyl chloride The starting compound was Precursor 52, which was obtained using the procedure described in Intermediate 70. The solid was used in the next reaction step without further purification.

[0178] Intermediate 74: 4'-(5-Methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbonyl chloride The starting compound was precursor 53, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0179] Intermediate 75 : 2'-Methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carbonyl chloride The starting compound was precursor 54, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0180] Intermediate 76 : 2'-Cyano-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carbonyl chloride The starting compound was precursor 55, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0181] Intermediate 77 : 6-(2-Fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride The starting compound was precursor 65, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0182] Intermediate 78 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride The starting compound was precursor 66, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0183] Intermediate 79: 6-(4-(5-Methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinoyl chloride The starting compound was precursor 67, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0184] Intermediate 80 : 6-(2-Methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride The starting compound was precursor 68, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0185] Intermediate 81 : 6-(2-Cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride The starting compound was precursor 69, which was obtained using the procedure described for intermediate 70. The solid was used in the next reaction step without further purification.

[0186] Intermediate 82 : 6-(2-Cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine

Chemical Structure

[0187] Intermediate 83 : 6-(2-Fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine It was obtained using the procedure described for Intermediate 82 with Precursor 45 as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.11 (dd, 2H), 7.87 (dd, 1H), 7.76 (dd, 1H), 7.60 (m, 1H), 7.01 (dd, 1H), 5.73 (s, 2H), 2.68 (s, 3H). HPLC-MS: Rt 2.81 m / z 499.1 (MH + ).

[0188] Intermediate 84 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine It was obtained using the procedure described for Intermediate 82 with Precursor 46 as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6): δ = 8.06 (d, 1H), 8.03 (d, 1H), 7.98 (dd, 1H), 7.76 (d, 1H), 7.48 (d, 1H), 7.01 (dd, 1H), 5.65 (s, 2H), 2.68 (s, 3H). HPLC-MS: Rt 2.23 m / z 287.0 (MH + ).

[0189] Intermediate 85 : 6-(4-(5-Methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-amine It is precursor 47 as the starting compound and was obtained using the procedure described in Intermediate 82. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.30 (s, 1H), 8.27 (d, 1H), 8.01 (d, 1H), 7.72 (d, 1H), 7.25 (d, 1H), 7.01 (dd, 1H), 5.62 (s, 2H), 2.70 (s, 3H). HPLC-MS: Rt 2.38 m / z 321.1 (MH + ).

[0190] Intermediate 86 : 6-(2-Methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine It is precursor 48 as the starting compound and was obtained using the procedure described in Intermediate 82. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.05 (d, 1H), 7.93 (d, 1H), 7.70 (d, 1H), 7.64 (d, 1H), 7.61 (s, 1H), 6.96 (dd, 1H), 5.56 (s, 2H), 3.91 (s, 3H), 2.68 (s, 3H). HPLC-MS: Rt 2.04 m / z 283.0 (MH + ).

[0191] Intermediate 87: 2-(5-Aminopyridin-2-yl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzonitrile It was obtained using the procedure described for Intermediate 82, with Precursor 49 as the starting compound. 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.32 (d, 1H), 8.26 (dd, 1H), 8.10 (d, 1H), 8.01 (d, 1H), 7.68 (d, 1H), 7.06 (dd, 1H), 5.87 (s, 2H), 2.70 (s, 3H). HPLC-MS: Rt 2.06 m / z 278.0 (MH + ).

[0192] Examples Example 1 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide (Example of General Procedure A described in Scheme 6)

Chemical Structure

[0193] General procedure B described in Scheme 6

Chem.

[0194] The following Examples 2 - 6 were synthesized according to the general procedure A described in Example 1 using the corresponding carboxylic acid chlorides and aromatic amides.

[0195] Example 2 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.62 (s, 1H), 9.26 (d, 1H), 8.44 (dd, 1H), 8.23 (t, 1H), 8.03 (dd, 2H), 7.91 (d, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.38 (dd, 1H), 4.12 (t, 2H), 2.72 (d, 2H), 2.70 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.96 m / z 541.9 (MH + ).

[0196] Example 3 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.65 (s, 1H), 9.23 (s, 1H), 8.43 (d, 1H), 8.15 (s, 1H), 8.11 (d, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.39 (d, 1H), 4.14 (t, 2H), 2.75 (t, 2H), 2.71 (s, 3H), 2.30 (s, 6H). HPLC-MS: Rt 2.98 m / z 557.9 (MH + ).

[0197] Example 4 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 10.65 (s, 1H), 9.20 (d, 1H), 8.44 (dd, 1H), 8.39 (m, 2H), 7.84 (d, 1H), 7.80 (d, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.40 (dd, 1H), 4.13 (t, 2H), 2.72 (m, 5H), 2.27 (s, 6H). HPLC-MS: Rt 3.04 m / z 591.9 (MH + )。

[0198] Example 5 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.58 (s, 1H), 9.20 (d, 1H), 8.35 (dd, 1H), 8.10 (d, 1H), 8.02 (d, 1H), 7.76 (m, 1H), 7.72 (s, 1H), 7.69 (d, 1H), 7.56 (d, 1H), 7.38 (dd, 1H), 4.14 (t, 2H), 3.97 (s, 3H), 2.76 (t, 2H), 2.70 (s, 3H), 2.30 (s, 6H). HPLC-MS: Rt 2.86 m / z 554.0 (MH + )。

[0199] Example 6 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.67 (s, 1H), 9.29 (dd, 1H), 8.52 (dd, 1H), 8.49 (d, 1H), 8.42 (dd, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 7.68 (d, 1H), 7.57 (d, 1H), 7.40 (dd, 1H), 4.14 (t, 2H), 2.75 (t, 2H), 2.72 (s, 3H), 2.29 (s, 6H). HPLC-MS: Rt 2.81 m / z 549.0 (MH + ).

[0200] Examples 7 to 64 below were synthesized according to General Procedure B described in Example 1 using the corresponding carboxylic acid chlorides and aromatic amides.

[0201] Example 7 : N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 1H-NMR (400 MHz, DMSO-d 6 6): δ = 10.86 (s, 1H), 9.24 (s, 1H), 8.43 (d, 1H), 7.96 - 7.85 (m, 2H), 7.80 (s, 1H), 7.73 (d, 1H), 7.68 - 7.60 (m, 2H), 7.55 (d, 1H), 4.21 (t, 2H), 2.74 (t, 2H), 2.69 (s, 3H), 2.28 (s, 6H), 2.17 (dd, 1H), 0.92 (d, 2H), 0.69 (d, 2H). HPLC-MS: Rt 2.76 m / z 509.1 (MH + ).

[0202] Example 8 : N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 1H-NMR (400 MHz, DMSO-d 6 6): δ = 10.85 (s, 1H), 9.25 (d, 1H), 8.44 (dd, 1H), 8.22 (t, 1H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.91 (d, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.52 (dd, 1H), 4.20 (t, 2H), 2.73 (d, 2H), 2.70 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt m / z 2.73 m / z 487.0 (MH + ).

[0203] Example 9 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.93 (s, 1H), 9.24 (d, 1H), 8.45 (dd, 1H), 8.15 (s, 1H), 8.11 (d, 1H), 7.96 (d, 1H), 7.86 (d, 1H), 7.83 (s, 1H), 7.74 (d, 1H), 7.54 (d, 1H), 4.27 (t, 2H), 2.91 (t, 2H), 2.71 (s, 3H), 2.40 (s, 6H). HPLC-MS: Rt 2.74 m / z 503.0 (MH + )

[0204] Example 10 : N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.93 (s, 1H), 9.20 (d, 1H), 8.44 (dd, 1H), 8.35 (m, 2H), 7.85 (d, 1H), 7.82 (d, 1H), 7.80 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 4.20 (t, 2H), 2.75 (t, 2H), 2.71 (s, 3H), 2.30 (s, 6H). HPLC-MS: Rt 2.83 m / z 537.0 (MH + )

[0205] Example 11 : N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d6 ): δ = 10.81 (s, 1H), 9.21 (s, 1H), 8.36 (dd, 1H), 8.06 (m, 2H), 7.80 (d, 1H), 7.72 (d, 3H), 7.53 (dd, 1H), 4.21 (t, 2H), 3.97 (s, 3H), 2.72 (m, 5H), 2.27 (s, 6H). HPLC-MS: Rt 2.61 m / z 499.0 (MH + ).

[0206] Example 12 : N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.90 (s, 1H), 9.29 (d, 1H), 8.52 (dd, 1H), 8.49 (d, 1H), 8.42 (dd, 1H), 8.20 (d, 1H), 8.17 (d, 1H), 7.80 (s, 1H), 7.73 (d, 1H), 7.54 (dd, 1H), 4.22 (t, 2H), 2.75 (t, 2H), 2.73 (s, 3H), 2.28 (s, 6H). HPLC-MS: Rt 2.51 m / z 494.1 (MH + ).

[0207] Example 13 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 2.84 (d, 2H), 2.69 (s, 3H), 2.65 - 2.59 (m, 1H), 2.35 (s, 6H), 0.98 - 0.89 (m, 2H), 0.67 (q, 2H). 10.74 (s, 1H), 9.42 (s, 2H), 7.95 (dd, 1H), 7.91 (d, 1H), 7.70 - 7.65 (m, 2H), 7.59 (d, 1H), 7.37 (dd, 1H), 4.16 (t, 2H), 2.82 (t, 2H), 2.69 (s, 3H), 2.65 - 2.60 (m, 1H), 2.35 (s, 6H), 0.95 - 0.91 (m, 2H), 0.67 (q, 2H). HPLC - MS: Rt 2.89 m / z 564.0 (MH + ).

[0208] Example 14 : N-(4 - Cyano - 3-(2-(dimethylamino)ethoxy)phenyl)-2-(2 - cyclopropyl - 4-(5 - methyl - 1,2,4 - oxadiazol - 3 - yl)phenyl)pyrimidine - 5 - carboxamide 1 1H - NMR (400 MHz, DMSO - d 6 ): δ = 11.00 (s, 1H), 9.43 (s, 2H), 7.93 (dd, 2H), 7.79 (s, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.52 (d, 1H), 4.25 (t, 2H), 2.84 (t, 2H), 2.69 (s, 3H), 2.65 - 2.59 (m, 1H), 2.35 (s, 6H), 0.98 - 0.89 (m, 2H), 0.67 (q, 2H). HPLC - MS: Rt 2.74 m / z 510.0 (MH + ).

[0209] Example 15 : N-(5 - Bromo - 4-(2-(dimethylamino)ethoxy)pyridin - 2 - yl)-2’ - cyclopropyl - 4’-(5 - methyl - 1,2,4 - oxadiazol - 3 - yl)-[1,1’ - biphenyl]-4 - carboxamide 1 1H - NMR (400 MHz, DMSO - d 6): δ = 11.02 (s, 1H), 8.39 (s, 1H), 8.14 (m, 2H), 8.08 (s, 1H), 7.87 (dd, 1H), 7.61 (m, 3H), 7.43 (d, 1H), 4.27 (t, 2H), 2.74 (t, 2H), 2.68 (s, 3H), 2.27 (s, 6H), 1.91 (td, 1H), 0.87 (m, 2H), 0.73 (m, 2H). HPLC-MS: Rt 3.29 m / z 564.0 (MH + )。

[0210] Example 16 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.06 (s, 1H), 8.39 (s, 1H), 8.15 (d, 2H), 8.07 (d, 1H), 7.95 (d, 1H), 7.88 (d, 1H), 7.83 (d, 1H), 7.77 (d, 2H), 4.28 (t, 2H), 2.76 (t, 2H), 2.70 (s, 3H), 2.29 (s, 6H). HPLC-MS: Rt 3.11 m / z 540.0 (MH + )。

[0211] Example 17 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.06 (s, 1H), 8.39 (s, 1H), 8.14 (d, 2H), 8.06 (m, 2H), 7.66 (m, 3H), 4.28 (t, 2H), 2.76 (t, 2H), 2.70 (s, 3H), 2.29 (s, 6H). HPLC-MS: Rt 3.24 m / z 557.9 (MH + )。

[0212] Example 18 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.07 (s, 1H), 8.37 (d, 2H), 8.34 (d, 1H), 8.13 (d, 2H), 8.07 (s, 1H), 7.67 (d, 1H), 7.53 (d, 2H), 4.27 (t, 2H), 2.73 (m, 5H), 2.27 (s, 6H). HPLC-MS: Rt 3.28 m / z 592.0 (MH + )

[0213] Example 19 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.99 (s, 1H), 8.39 (s, 1H), 8.09 (m, 3H), 7.70 (dd, 4H), 7.55 (d, 1H), 4.28 (t, 2H), 3.89 (s, 3H), 2.77 (t, 2H), 2.70 (s, 3H), 2.29 (s, 6H). HPLC-MS: Rt 3.04 m / z 554.0 (MH + )

[0214] Example 20 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyano-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 11.12 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.38 (d, 1H), 8.19 (d, 2H), 8.08 (s, 1H), 7.90 (d, 1H), 7.81 (d, 2H), 4.27 (t, 2H), 2.75 (t, 2H), 2.72 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.93 m / z 549.0 (MH + )。

[0215] Example 21 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-cyclopropyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.34 (s, 1H), 8.67 (s, 1H), 8.14 (m, 3H), 7.87 (d, 1H), 7.64 (d, 2H), 7.59 (s, 1H), 7.43 (d, 1H), 4.35 (s, 2H), 2.79 (s, 2H), 2.68 (s, 3H), 2.30 (s, 6H), 1.91 (m, 1H), 0.92 (m, 2H), 0.73 (m, 2H). HPLC-MS: Rt 3.04 m / z 509.3 (MH + )。

[0216] Example 22 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2’-fluoro-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.37 (s, 1H), 8.67 (s, 1H), 8.15 (d, 3H), 7.91 (dd, 2H), 7.81 (t, 1H), 7.77 (d, 2H), 4.33 (t, 2H), 2.74 (t, 2H), 2.70 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.88 m / z 487.1 (MH + )。

[0217] Example 23 : 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.38 (s, 1H), 8.67 (s, 1H), 8.14 (d, 4H), 8.05 (d, 1H), 7.66 (m, 3H), 4.34 (t, 2H), 2.75 (t, 2H), 2.70 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.99 m / z 503.0 (MH + )。

[0218] Example 24 : N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.41 (s, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.34 (d, 1H), 8.14 (s, 1H), 8.13 (d, 2H), 7.67 (d, 1H), 7.54 (d, 2H), 4.39 (t, 2H), 2.88 (t, 2H), 2.72 (s, 3H), 2.36 (s, 6H). HPLC-MS: Rt 3.04 m / z 537.1 (MH + )。

[0219] Example 25 : N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 11.31 (s, 1H), 8.66 (s, 1H), 8.15 (s, 1H), 8.09 (d, 2H), 7.69 (dd, 4H), 7.55 (d, 1H), 4.33 (t, 2H), 3.89 (s, 3H), 2.74 (t, 2H), 2.70 (s, 3H), 2.26 (s, 6H). HPLC-MS: Rt 2.81 m / z 499.1 (MH + )。

[0220] Example 26 : 2'-Cyano-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.45 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 8.38 (d, 1H), 8.18 (m, 3H), 7.90 (d, 1H), 7.83 (d, 2H), 4.35 (t, 2H), 2.76 (t, 2H), 2.72 (s, 3H), 2.28 (s, 6H). HPLC-MS: Rt 2.71 m / z 494.0 (MH + )。

[0221] Example 27 : N-(5-bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.72 (s, 1H), 8.09 (d, 2H), 8.02 (d, 1H), 7.88 (dd, 1H), 7.75 (d, 1H), 7.64 (d, 2H), 7.60 (s, 1H), 7.44 (d, 1H), 4.47 (t, 2H), 2.68 (s, 3H), 2.67 (m, 2H), 2.24 (s, 6H), 1.92 (ddd, 1H), 0.93 (m, 2H), 0.73 (q, 2H). HPLC-MS: Rt 3.51 m / z 563.9 (MH+ )。

[0222] Example 28 : N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR(400 MHz, DMSO-d 6 ): δ = 10.75 (s, 1H), 8.11 (d, 2H), 8.02 (d, 1H), 7.96 (d, 1H), 7.89 (d, 1H), 7.82 (t, 1H), 7.78 (d, 2H), 7.75 (d, 1H), 4.47 (t, 2H), 2.70 (s, 3H), 2.66 (t, 2H), 2.24 (s, 6H). HPLC-MS: Rt 3.31 m / z 541.9 (MH + )。

[0223] Example 29 : N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR(400 MHz, DMSO-d 6 ): δ = 10.77 (s, 1H), 8.10 (m, 3H), 8.03 (m, 2H), 7.75 (d, 1H), 7.67 (m, 3H), 4.47 (t, 2H), 2.71 (s, 3H), 2.68 (t, 2H), 2.25 (s, 6H). HPLC-MS: Rt 3.44 m / z 557.8 (MH + )。

[0224] Example 30 : N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR(400 MHz, DMSO-d 6): δ = 11.10 (s, 1H), 8.25 (d, 1H), 8.10 (d, 2H), 7.93 (d, 1H), 7.88 (dd, 1H), 7.66 (d, 2H), 7.60 (s, 1H), 7.44 (d, 1H), 4.61 (t, 2H), 2.92 (s, 2H), 2.68 (s, 3H), 2.41 (s, 6H), 1.91 (ddd, 1H), 0.92 (m, 2H), 0.74 (q, 2H). HPLC-MS: Rt 3.21 m / z 509.0 (MH + ).

[0225] Example 31 : N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.09 (s, 1H), 8.23 (d, 1H), 8.11 (d, 2H), 7.96 (d, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 7.80 (t, 3H), 4.54 (t, 2H), 2.70 (s, 3H), 2.67 (d, 2H), 2.24 (s, 6H). HPLC-MS: Rt 3.03 m / z 487.0 (MH + ).

[0226] Example 32 : 2'-Chloro-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.12 (s, 1H), 8.23 (d, 1H), 8.09 (m, 4H), 7.92 (d, 1H), 7.67 (d, 3H), 4.54 (t, 2H), 2.70 (s, 3H), 2.69 (t, 2H), 2.24 (s, 6H). HPLC-MS: Rt 3.14 m / z 503.0 (MH + ).

[0227] Example 33 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.12 (s, 1H), 8.64 (s, 1H), 8.04 (d, 2H), 7.88 (dd, 1H), 7.61 (m, 3H), 7.44 (d, 1H), 4.51 (t, 2H), 2.68 (s, 3H), 2.66 (t, 2H), 2.21 (s, 6H), 1.91 (td, 1H), 0.92 (m, 2H), 0.73 (m, 2H). HPLC-MS: Rt 2.99 m / z 565.0 (MH + )

[0228] Example 34 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.15 (s, 1H), 8.64 (s, 1H), 8.05 (m, 2H), 7.96 (dd, 1H), 7.88 (dd, 1H), 7.82 (t, 1H), 7.76 (m, 2H), 4.48 (t, 2H), 2.70 (s, 3H), 2.66 (t, 2H), 2.21 (s, 6H). HPLC-MS: Rt 2.81 m / z 542.9 (MH + )

[0229] Example 35 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4- 1 H-NMR (400 MHz, DMSO-d 6): δ = 11.18 (s, 1H), 8.65 (s, 1H), 8.13 (s, 1H), 8.04 (m, 3H), 7.66 (m, 3H), 4.51 (t, 2H), 2.74 (t, 2H), 2.71 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.94 m / z 558.8 (MH + )。

[0230] Example 36 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.56 (s, 1H), 8.99 (s, 1H), 8.06 (d, 2H), 7.88 (d, 1H), 7.64 (d, 2H), 7.60 (s, 1H), 7.43 (d, 1H), 4.72 (s, 2H), 3.19 (s, 2H), 2.68 (s, 3H), 2.58 (s, 3H), 1.91 (m, 1H), 0.92 (m, 2H), 0.74 (m, 2H). HPLC-MS: Rt 2.83 m / z 510.3 (MH + )。

[0231] Example 37 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.56 (s, 1H), 8.91 (s, 1H), 8.05 (d, 2H), 7.96 (dd, 1H), 7.88 (dd, 1H), 7.82 (t, 1H), 7.75 (m, 2H), 4.52 (t, 2H), 2.70 (s, 3H), 2.65 (t, 2H), 2.20 (s, 6H). HPLC-MS: Rt 2.68 m / z 488.0 (MH + )。

[0232] Example 38 : 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.97 (s, 1H), 8.19 (d, 1H), 8.13 (s, 1H), 8.05 (m, 3H), 7.67 (m, 3H), 4.61 (t, 2H), 2.88 (t, 2H), 2.71 (s, 3H), 2.37 (s, 6H). HPLC-MS: Rt 2.78 m / z 504.0 (MH + )。

[0233] Example 39 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.29 (s, 1H), 9.27 (d, 1H), 8.47 (dd, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.91 (dd, 1H), 7.85 (d, 1H), 7.67 - 7.61 (m, 2H), 4.28 (t, 2H), 2.75 (t, 2H), 2.69 (s, 3H), 2.27 (s, 6H), 2.18 (td, 1H), 0.96 - 0.89 (m, 2H), 0.68 (q, 2H). HPLC-MS: Rt 2.91 m / z 564.1 (MH + )。

[0234] Example 40 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 11.31 (s, 1H), 9.28 (s, 1H), 8.49 (d, 1H), 8.40 (s, 1H), 8.23 (t, 1H), 8.07 (s, 1H), 8.00 (t, 2H), 7.90 (d, 1H), 4.27 (t, 2H), 2.75 (t, 2H), 2.70 (s, 3H), 2.28 (s, 6H). HPLC-MS: Rt 2.88 m / z 542.8 (MH + )。

[0235] Example 41 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.33 (s, 1H), 9.27 (s, 1H), 8.49 (dd, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 8.09 (m, 2H), 7.93 (d, 1H), 7.86 (d, 1H), 4.28 (t, 2H), 2.76 (t, 2H), 2.71 (s, 3H), 2.29 (s, 6H). HPLC-MS: Rt 2.89 m / z 558.9 (MH + )。

[0236] Example 42 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.34 (s, 1H), 9.23 (d, 1H), 8.50 (dd, 1H), 8.39 (m, 3H), 8.07 (s, 1H), 7.83 (d, 1H), 7.76 (d, 1H), 4.28 (t, 2H), 2.76 (t, 2H), 2.73 (s, 3H), 2.28 (s, 6H). HPLC-MS: Rt 2.98 m / z 593.0 (MH + )。

[0237] Example 43 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR(400MHz, DMSO-d 6 ): δ = 11.25(s, 1H), 9.24(d, 1H), 8.40(m, 2H), 8.09(d, 2H), 8.03(d, 1H), 7.74(d, 1H), 7.71(s, 1H), 4.28(t, 2H), 3.97(s, 3H), 2.77(t, 2H), 2.70(s, 3H), 2.29(s, 6H). HPLC-MS: Rt 2.76 m / z 554.9(MH + )

[0238] Example 44 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR(400MHz, DMSO-d 6 ): δ = 11.41(s, 1H), 9.30(d, 1H), 8.57(dd, 1H), 8.49(s, 1H), 8.45(s, 1H), 8.42(dd, 1H), 8.19(d, 1H), 8.13(d, 1H), 8.09(s, 1H), 4.46(t, 2H), 3.21(t, 2H), 2.73(s, 3H), 2.62(s, 6H). HPLC-MS: Rt 2.71 m / z 549.9(MH + )

[0239] Example 45 : N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR(400MHz, DMSO-d 6): δ = 11.60 (s, 1H), 9.26 (d, 1H), 8.69 (s, 1H), 8.47 (dd, 1H), 8.14 (s, 1H), 7.91 (d, 1H), 7.86 (d, 1H), 7.67 - 7.61 (m, 2H), 4.35 (t, 2H), 2.76 (t, 2H), 2.69 (s, 3H), 2.28 (s, 6H), 2.18 (ddd, 1H), 0.97 - 0.88 (m, 2H), 0.69 (q, 2H). HPLC-MS: Rt 2.70 m / z 510.1 (MH + ).

[0240] Example 46 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.62 (s, 1H), 9.28 (d, 1H), 8.68 (s, 1H), 8.49 (dd, 1H), 8.22 (d, 1H), 8.13 (s, 2H), 8.00 (m, 2H), 7.90 (d, 1H), 4.34 (t, 2H), 2.75 (t, 2H), 2.70 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.64 m / z 488.0 (MH + ).

[0241] Example 47 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.64 (s, 1H), 9.27 (d, 1H), 8.69 (s, 1H), 8.49 (dd, 1H), 8.14 (s, 2H), 8.10 (dd, 1H), 7.94 (d, 1H), 7.86 (d, 1H), 4.35 (t, 2H), 2.75 (t, 2H), 2.71 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.69 m / z 504.0 (MH + )。

[0242] Example 48 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 11.65 (s, 1H), 9.22 (d, 1H), 8.69 (s, 1H), 8.50 (dd, 1H), 8.39 (m, 2H), 8.13 (s, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 4.34 (t, 2H), 2.75 (t, 2H), 2.73 (s, 3H), 2.26 (s, 6H). HPLC-MS: Rt 2.74 m / z 538.1 (MH + )。

[0243] Example 49 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 1H-NMR (400 MHz, DMSO-d 6 ): δ = 11.55 (s, 1H), 9.23 (d, 1H), 8.68 (s, 1H), 8.40 (dd, 1H), 8.14 (s, 1H), 8.09 (d, 1H), 8.03 (d, 1H), 7.74 (d, 1H), 7.71 (s, 1H), 4.34 (t, 2H), 3.97 (s, 3H), 2.75 (t, 2H), 2.70 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.56 m / z 500.0 (MH + )。

[0244] Example 50 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.70 (s, 1H), 9.30 (s, 1H), 8.71 (s, 1H), 8.57 (d, 1H), 8.49 (s, 1H), 8.42 (d, 1H), 8.19 (d, 1H), 8.14 (d, 2H), 4.46 (t, 2H), 3.05 (t, 2H), 2.73 (s, 3H), 2.45 (s, 6H). HPLC-MS: Rt 2.49 m / z 495.0 (MH + ).

[0245] Example 51 : N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.99 (s, 1H), 9.22 (s, 1H), 8.42 (dd, 1H), 8.05 (d, 1H), 7.92 (d, 1H), 7.85 (d, 1H), 7.76 (d, 1H), 7.63 (m, 2H), 4.50 (t, 2H), 2.79 (s, 2H), 2.69 (s, 3H), 2.33 (s, 6H), 2.18 (m, 1H), 0.92 (d, 2H), 0.69 (d, 2H). HPLC-MS: Rt 3.18 m / z 564.9 (MH + ).

[0246] Example 52 : N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 11.00 (s, 1H), 9.24 (d, 1H), 8.46 (dd, 1H), 8.23 (t, 1H), 8.03 (dd, 3H), 7.92 (d, 1H), 7.75 (d, 1H), 4.47 (t, 2H), 2.71 (s, 3H), 2.68 (d, 2H), 2.25 (s, 6H). HPLC-MS: Rt 3.13 m / z 542.9 (MH + )。

[0247] Example 53 : N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.03 (s, 1H), 9.21 (d, 1H), 8.44 (dd, 1H), 8.14 (s, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.92 (d, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 4.46 (t, 2H), 2.71 (s, 3H), 2.66 (t, 2H), 2.24 (s, 6H). HPLC-MS: Rt 3.16 m / z 558.8 (MH + )。

[0248] Example 54 : N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.31 (s, 1H), 9.22 (s, 1H), 8.43 (d, 1H), 8.26 (d, 1H), 7.92 (d, 2H), 7.86 (d, 1H), 7.63 (m, 2H), 4.55 (s, 2H), 2.69 (s, 5H), 2.26 (s, 6H), 2.18 (s, 1H), 0.92 (d, 2H), 0.69 (d, 2H). HPLC-MS: Rt 2.88 m / z 510.0 (MH + )。

[0249] Example 55 : N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.32 (s, 1H), 9.24 (d, 1H), 8.45 (dd, 1H), 8.23 (dd, 2H), 8.02 (dd, 2H), 7.91 (d, 2H), 4.54 (t, 2H), 2.71 (s, 3H), 2.68 (d, 2H), 2.24 (s, 6H). HPLC-MS: Rt 2.83 m / z 488.0 (MH + )

[0250] Example 56 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.36 (s, 2H), 9.21 (d, 1H), 8.44 (dd, 1H), 8.26 (d, 1H), 8.14 (d, 1H), 8.10 (dd, 1H), 7.92 (t, 2H), 7.85 (d, 1H), 4.54 (t, 2H), 2.71 (s, 3H), 2.70 (t, 2H), 2.25 (s, 6H). HPLC-MS: Rt 2.84 m / z 504.0 (MH + )

[0251] Example 57 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 11.36 (s, 1H), 9.18 (s, 1H), 8.66 (s, 1H), 8.38 (d, 1H), 7.92 (d, 1H), 7.84 (d, 1H), 7.67 - 7.61 (m, 2H), 4.51 (t, 2H), 2.75 - 2.64 (m, [5H(2H + 3H)]), 2.24 (s, 1H), 2.17 (dd, 1H), 0.92 (d, 2H), 0.69 (d, 2H). HPLC-MS: Rt 2.66 m / z 565.9 (MH + )。

[0252] Example 58 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.38 (s, 1H), 9.19 (d, 1H), 8.65 (s, 1H), 8.40 (dd, 1H), 8.23 (t, 1H), 8.01 (ddd, 2H), 7.91 (dd, 1H), 4.47 (t, 2H), 2.70 (s, 3H), 2.66 (t, 2H), 2.20 (s, 6H). HPLC-MS: Rt 2.61 m / z 543.9 (MH + )。

[0253] Example 59 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.38 (s, 1H), 9.17 (d, 1H), 8.65 (s, 1H), 8.39 (dd, 1H), 8.14 (d, 1H), 8.10 (dd, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 4.48 (t, 2H), 2.71 (s, 3H), 2.67 (t, 2H), 2.22 (s, 6H). HPLC-MS: Rt 2.64 m / z 559.8 (MH +)。

[0254] Example 60 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.74 (s, 1H), 9.17 (d, 1H), 8.95 (s, 1H), 8.38 (dd, 1H), 7.92 (dd, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.63 (d, 1H), 4.55 (t, 2H), 2.71 - 2.65 (m, 5H (2H + 3H)), 2.22 (s, 6H), 2.17 (ddd, 1H), 0.96 - 0.89 (m, 2H), 0.72 - 0.66 (m, 2H). HPLC-MS: Rt 2.46 m / z 511.1 (MH + )。

[0255] Example 61 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.67 (s, 1H), 9.20 (d, 1H), 8.97 (s, 1H), 8.41 (dd, 1H), 8.23 (t, 1H), 8.02 (td, 2H), 7.92 (m, 1H), 4.55 (t, 2H), 2.75 (t, 2H), 2.71 (s, 3H), 2.27 (s, 6H). HPLC-MS: Rt 2.39 m / z 489.0 (MH + )。

[0256] Example 62 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)nicotinamide 1H-NMR (400 MHz, DMSO-d 6 ): δ = 11.73 (s, 1H), 9.18 (d, 1H), 8.96 (s, 1H), 8.40 (dd, 1H), 8.15 (d, 1H), 8.13 - 8.07 (m, 1H), 7.92 (d, 1H), 7.86 (d, 1H), 4.53 (t, 2H), 2.71 (s, 3H), 2.67 (t, 2H), 2.22 (s, 6H). HPLC-MS: Rt 2.43 m / z 505.0 (MH + ).

[0257] Example 63 : N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.49 (s, 1H), 9.43 (s, 2H), 8.43 (s, 1H), 8.07 (s, 1H), 7.92 (q, 2H), 7.67 (s, 1H), 4.28 (t, 2H), 2.75 (t, 2H), 2.69 (s, 3H), 2.63 (td, 1H), 2.28 (s, 6H), 0.98 - 0.88 (m, 2H), 0.66 (q, 2H). HPLC-MS: Rt 2.89 m / z 565.0 (MH + ).

[0258] Example 64 : N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 11.78 (s, 1H), 9.44 (s, 2H), 8.71 (s, 1H), 8.13 (s, 1H), 7.92 (q, 2H), 7.67 (s, 1H), 4.35 (t, 2H), 2.75 (t, 2H), 2.69 (s, 3H), 2.63 (td, 1H), 2.27 (s, 6H), 0.98 - 0.89 (m, 2H), 0.66 (q, 2H). HPLC-MS: Rt 2.67 m / z 511.0 (MH + ).

[0259] Example 65 : 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide (Example of the general procedure described in Scheme 7b)

Chemical Structure

[0260] Examples 66 - 76 were obtained as shown in Example 65 starting from the corresponding carboxylic acids and amines.

[0261] Example 66 : 4 - Bromo - N-(6-(2 - cyclopropyl - 4-(5 - methyl - 1,2,4 - oxadiazol - 3 - yl)phenyl)pyridin - 3 - yl)-3-(2-(dimethylamino)ethoxy)benzamide 1 H - NMR (400 MHz, DMSO - d 6 ): δ = 10.62 (s, 1H), 9.06 (s, 1H), 8.31 (d, 1H), 7.88 (d, 1H), 7.83 (d, 1H), 7.73 (d, 1H), 7.68 (s, 1H), 7.64 - 7.57 (m, 3H), 4.45 - 4.39 (m, 2H), 2.68 (s, 5H), 2.65 (s, 6H), 2.24 - 2.15 (m, 1H), 0.92 (d, 2H), 0.67 (d, 2H). HPLC - MS: Rt 2.99 m / z 564.0 (MH + )

[0262] Example 67 : 4 - Bromo - N-(6-(2 - chloro - 4-(5 - methyl - 1,2,4 - oxadiazol - 3 - yl)phenyl)pyridin - 3 - yl)-3-(2-(dimethylamino)ethoxy)benzamide 1 H - NMR (400 MHz, DMSO - d 6): δ = 10.72 (s, 1H), 9.09 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 8.07 (dd, 1H), 7.87 (d, 1H), 7.83 (d, 2H), 7.71 (s, 1H), 7.65 (dd, 1H), 4.55 (t, 2H), 3.63 (t, 2H), 2.96 (s, 6H), 2.71 (s, 3H). HPLC-MS: Rt 3.01 m / z: 557.9 (MH + ).

[0263] Example 68 : 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.76 (s, 1H), 9.06 (s, 1H), 8.36 (m, 3H), 7.84 (d, 1H), 7.81 (d, 1H), 7.74 (s, 1H), 7.63 (t, 2H), 4.52 (t, 2H), 3.44 (t, 2H), 2.81 (s, 6H), 2.72 (s, 3H). HPLC-MS: Rt 3.06 m / z: 592.0 (MH + ).

[0264] Example 69 : 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.62 (s, 1H), 9.05 (m, 1H), 8.25 (dd, 1H), 8.00 (dd, 2H), 7.84 (d, 1H), 7.71 (m, 3H), 7.62 (dd, 1H), 4.49 (s, 2H), 3.96 (s, 3H), 2.83 (s, 5H), 2.70 (s, 3H). HPLC-MS: Rt 2.84 m / z 553.9 (MH + ).

[0265] Example 70 : 4-Bromo-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.75 (s, 1H), 9.12 (d, 1H), 8.45 (d, 1H), 8.42 (dd, 1H), 8.38 (dd, 1H), 8.13 (d, 1H), 8.03 (d, 1H), 7.86 (d, 1H), 7.70 (d, 1H), 7.63 (dd, 1H), 4.48 (t, 2H), 3.54 (t, 2H), 2.79 (s, 6H), 2.72 (s, 3H). HPLC-MS: Rt 2.84 m / z: 548.9 (MH + ).

[0266] Example 71 : 4-Cyano-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.75 (s, 1H), 9.05 (d, 1H), 8.31 (dd, 1H), 7.96 (d, 1H), 7.88 (d, 1H), 7.79 - 7.72 (m, 2H), 7.68 (d, 1H), 7.64 - 7.57 (m, 2H), 4.38 (t, 2H), 2.84 (s, 2H), 2.68 (s, 3H), 2.35 (s, 6H), 2.25 - 2.16 (m, 1H), 0.92 (q, 2H), 0.72 - 0.63 (m, 2H). HPLC-MS: Rt 2.74 m / z 509.1 (MH + ).

[0267] Example 72 : 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.15 (s, 1H), 9.21 (d, 1H), 8.43 (dd, 1H), 8.19 (t, 1H), 8.00 (d, 1H), 7.96 (t, 3H), 7.87 (d, 1H), 7.78 (d, 1H), 4.73 (m, 2H), 3.64 (d, 2H), 2.92 (d, 6H), 2.70 (s, 3H). HPLC-MS: Rt 2.71 m / z 487.1 (MH + ).

[0268] Example 73 : N-(6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-4-cyano-3-(2-(dimethylamino)ethoxy)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.11 (s, 1H), 9.17 (d, 1H), 8.42 (dd, 1H), 8.12 (d, 1H), 8.07 (dd, 1H), 8.02 (d, 1H), 7.94 (s, 1H), 7.85 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 4.72 (t, 2H), 3.65 (t, 2H), 2.93 (d, 6H), 2.70 (s, 3H). HPLC-MS: Rt 2.74 m / z: 503.1 (MH + ).

[0269] Example 74 : 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide 1 H-NMR (400 MHz, DMSO-d 6): δ = 10.82 (s, 1H), 9.02 (d, 1H), 8.36 (m, 2H), 8.33 (d, 1H), 7.99 (d, 2H), 7.81 (d, 1H), 7.78 (s, 1H), 7.71 (d, 1H), 7.65 (d, 1H), 4.46 (t, 2H), 3.09 (t, 2H), 2.72 (s, 3H), 2.53 (s, 6H). HPLC-MS: Rt 2.81 m / z: 537.1 (MH + )。

[0270] Example 75 : 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.73 (s, 1H), 9.04 (d, 1H), 8.25 (dd, 1H), 7.99 (m, 3H), 7.77 (d, 1H), 7.72 (dd, 1H), 7.69 (m, 2H), 4.41 (t, 2H), 3.96 (m, 3H), 2.91 (s, 2H), 2.70 (s, 3H), 2.40 (s, 6H). HPLC-MS: Rt 2.59 m / z 499.0 (MH + )。

[0271] Example 76 : 4-Cyano-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.89 (s, 1H), 9.12 (d, 1H), 8.45 (d, 1H), 8.42 (dd, 1H), 8.38 (dd, 1H), 8.13 (d, 1H), 8.03 (t, 2H), 7.79 (d, 1H), 7.75 (dd, 1H), 4.56 (t, 2H), 3.39 (t, 2H), 2.76 (s, 6H), 2.72 (s, 3H). HPLC-MS: Rt 2.56 m / z 494.0 (MH + )。

Claims

1. Formula (I): 【Chemical 1】 [wherein, -G is, a) -C(O)NH-, b) -NHC(O)- represents a group selected from, -X １ , X ２ , X ３ and X ４ represent an N atom or a C-R ５ group, -R １ and R ２ are, independently, a) a hydrogen atom, b) -N(R ６ )R ７ , -OR ６ , a halogen atom and C ３ -C ６ optionally substituted by one, two or three substituents selected from cycloalkyl, a linear or branched C １ -C ６ alkyl c) C ３ -C ６ Cycloalkyl is selected from the group consisting of, - Or, R １ and R ２ together with the nitrogen atom to which they are attached further form a 4- to 6-membered heterocyclic group containing a second heteroatom selected from N and O -R ３ is a) a cyano group, and b) a halogen atom represents a group selected from, -R ４ is a) a halogen atom, b) C ３ -C ４ cycloalkyl group, c) C １ -C ３ an alkoxy group, d) C １ -C ３ haloalkyl group, e) a cyano group represents a group selected from, -R ５ is a) a hydrogen atom, b) C １ -C ３ alkyl, c) a halogen atom represents a group selected from, -R ６ and R ７ are each, independently, a) C １ -C ３ alkyl, b) a hydrogen atom represents a group selected from, However, the above X １ , X ２ , X ３ and X ４ at least one of which represents an N atom]] a compound of or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ is a methyl group, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. G represents -C(O)NH, and the carbonyl group is linked to a ring containing X ３ and X ４ and the amine group is linked to a ring containing X １ and X ２ The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein the carbonyl group is linked to a ring containing X and X, and the amine group is linked to a ring containing X and X.

4. R ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is a cyano group.

5. R ４ is selected from a halogen atom and C ３ -C ４ -cycloalkyl group, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R ４ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R is selected from a chlorine atom, a fluorine atom and a cyclopropyl group.

7. Core: 【Chemical 2】 is, 【Chemical 3】 [wherein, X ３ is N, and X １ , X ２ , X ４ and G are as defined in any one of claims 1 and 3], [Chemical Formula 4] [wherein, X １ is N, X ２ , X ３ , X ４ and G are as defined in any one of claims 1 and 3], and 【Chemical Formula 5】 [wherein, X １ and X ３ are N, X ２ , X ４ and G are as defined in any one of claims 1 and 3] selected from, The compound according to any one of Claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. The said core: 【Chemical Formula 6】 is, 【Chemical Formula 7】 [wherein, G is as defined in any one of Claims 1 and 3] is, The compound according to Claim 7 or a pharmaceutically acceptable salt thereof.

9. The said core: [Chemical Formula 8] is, 【Chemical Formula 9】 [wherein, G is as defined in any one of Claims 1 and 3] is, The compound according to Claim 7 or a pharmaceutically acceptable salt thereof.

10. Having one of the following formulas (Ia), (Ib) and (Ic): 【Chemical 10】 【Chem.】 【Chem.】 [wherein, R ４ represents a group selected from a halogen atom and a cyclopropyl group] The compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

11. The group consisting of: N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyano-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Cyano-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide 2'-Chloro-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)nicotinamide N-(5-Bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide N-(5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 4-Bromo-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Bromo-N-(6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 4-Bromo-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Cyano-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide N-(6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-4-cyano-3-(2-(dimethylamino)ethoxy)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-yl)benzamide 4-Cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)benzamide 4-Cyano-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

13. A combination comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a therapeutic agent, wherein the therapeutic agent is - a chemotherapeutic agent selected from vincristine, daunorubicin, cytarabine, 6-mercaptopurine, methotrexate, cyclophosphamide, prednisone, dexamethasone, nelarabine, and - one or more immunotherapeutic agents selected from the group consisting of anti-PD1 antibodies, anti-PDL1 antibodies, and anti-CTLA4 antibodies, such as ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, MPDL3280A, MEDI4736, and MDX-1105 selected from the combination.

14. A disease or condition that can be improved by antagonism of 5-HT １Ｂ The pharmaceutical composition according to claim 12, or the combination according to claim 13, for treating a disease or condition that can be improved by antagonism of a receptor selected from cancer, respiratory diseases, and liver disorders.

15. said 5-HT １Ｂ The pharmaceutical composition or combination according to claim 14, wherein the disease or condition that can be improved by antagonism of the receptor is selected from blood cancer and solid tumors.

16. The pharmaceutical composition or combination according to claim 15, wherein the blood cancer is acute myeloid leukemia.

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