Potent and selective compounds as serotonin 1b receptor modulators

Abstract

The present invention relates to novel compounds of formula (I): which are modulators of the serotonin receptor 1B (5-HTR1B), also known as 5-hydroxytryptamine receptor 1B (5-HT1B). The compounds are useful in the treatment of diseases and conditions mediated by the 1B type serotonin receptor (5-HTR1B), such as cancer, including hematological cancers and solid tumors, respiratory diseases and liver diseases.

Description

TECHNICAL FIELD

[0001] The present invention relates to new potent and selective compounds as modulators of the serotonin receptor 1B (5-HTR 1B ) also known as 5-hydroxytryptamine receptor 1B (5-HT 1B ). Said compounds are useful in the treatment of diseases and conditions mediated by the serotonin receptor type 1B (5-HTR 1B ), such as cancer, including hematological cancers and solid tumors, and respiratory and liver diseases. The present invention also relates to the use of such compounds as a medicament, to pharmaceutical compositions containing said compounds and to synthetic routes for the production of said compounds. BACKGROUND

[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 in a two-step pathway. Most of the body’s serotonin is located in the periphery (Sarrouilhe D. et al., Serotonin and Cancer: What Is the Link?, Current Molecular Medicine 2015, 15, 62-77).

[0003] Serotonin is associated with a variety of CNS functions, such as brain development, circadian rhythm, temperature regulation, cognition, pain, appetite, sexual drive, fear, mood, aggression, motor function and secretion of neuroendocrine. In addition, serotonin is implicated in many CNS and psychiatric disorders: Parkinson’s disease, depression, hallucinations, schizophrenia, bulimia, anxiety, addiction, chronic stress. Therefore, the serotonergic system is the target of a large number of psychoactive compounds including antidepressants, antipsychotics and psychedelics (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] Mammalians utilize 5-HT as a neurotransmitter in both the central and peripheral nervous systems, and also as a local hormone in many other tissues, including the gastrointestinal tract, cardiovascular system, and immune cells. This diversity of functions involves 5-HT in a wide range of physiological and pathological processes. Consequently, these numerous roles have spurred the development of a variety of compounds with therapeutic value, including various antidepressants, antipsychotics, and antiemetics (Barnes NM et al., "Neuronal 5-HT Receptors and SERT", Tocris Scientific Review Series, https: / / www.tocris.com / literature / scientific-reviews / 5-ht-receptors).

[0005] The ability of 5-HT to mediate various functions is partly due to the large number of 5-HT receptors, which are divided into seven families, all but one of which are members of the G-protein coupled receptor (GPCR) superfamily. The exception is the 5-HT3 receptor, a Cysloop ligand-gated ion channel.

[0006] Specifically, the 5-HT1 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 a single intronless reading frame and exhibits considerable sequence homology. All of these receptors are coupled to Gi / o to inhibit adenylate cyclase and reduce cAMP levels, but additional signal transduction mechanisms are also described. Several of these receptors are known as autoreceptors regulating the excitability of serotonergic neurons and serotonin release, and they are also expressed in non-serotonergic neurons where they may have similar effects on other neurotransmitters.

[0007] In 5-HT 1B In the case of the receptor, it is widely distributed in serotonergic and non-serotonergic neurons in the CNS. This autoreceptor has been found to reduce serotonin synthesis and release and enhance reuptake via serotonin transporters. Furthermore, it inhibits the release of a range of different neurotransmitters, depending on the type of neuron expressing it. 5-HT 1BSystemic administration of agonists of the receptor has several behavioral effects, including increased locomotion, altered brain reward mechanisms, and decreased aggression, while selective antagonists can have some potential to promote cognition. The expression of this receptor in different and possibly competing neuronal populations can influence its utility as a clinical target, but several 5-HT 1B / D Receptor agonists can be effective as anti-migraine treatments. 5-HT 1B Receptor knockout mice, which have a unique phenotype characterized by increased aggression and, in most cases, addictive-like behaviors (Barnes N.M. et al., Neuronal 5-HT Receptors and SERT, Tocris Scientific Reviews Series, https: / / www.tocris.com / literature / scientific-reviews / 5-ht-receptors).

[0008] On the other hand, there is a study that focuses on the role of 5-HT 1B Receptors in uterine leiomyomas (UL), which cause a variety of diseases such as abnormal uterine bleeding and fertility problems. This study demonstrated the relationship between the expression of 5-HT 1B Receptors and cell proliferation / death in the context of UL. Overall, 5-HT 1B Receptors are involved in the proliferation and survival of UL cells. It is necessary to test the efficacy of 5-HT 1B Receptor antagonists in vivo in preclinical studies to better understand their role in tumor growth and potential therapeutic targets for the development of medical therapies to manage UL. (Gurbuz, N et al., A selective Serotonin 5-HT1B receptor inhibition suppresses cell proliferation and clonocenicty, and induces of apoptosis in human uterine leiomyoma, Eur J Obstet Gynecol Reprod Biol. 2016 Nov;206:114-119).

[0009] Other studies have shown that serotonin is involved in the pathogenesis of pulmonary arterial hypertension (PAH) and has been considered an effective naturally occurring pulmonary vasoconstrictor and smooth muscle cell mitogen. Serotonin induces cell Src-related kinase-regulated Noxl-induced ROS and Nrf-2 dysregulation, promoting post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, leading to mitogenic responses. 5-HT 1B receptors and serotonin transporters (SERTs) contribute to pulmonary artery (PA) remodeling and proliferation of human PA smooth muscle cells (hPAMCs). Serotonin can induce cell Src-related kinase-regulated Noxl-induced ROS and Nrf-2 dysregulation, promoting post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, leading to mitogenic responses. 5-HT 1B receptors contribute to experimental pulmonary hypertension by inducing lung ROS production. This result suggests that 5-HT 1B receptor-dependent cell Src-related kinase-Noxl-pathway contributes to vascular remodeling in PAH. (Hood, KY. 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 growth-stimulating effects on several types of carcinomas, carcinoids, and other tumor cells. In contrast, there is little data on the involvement of serotonin in the migration and metastasis processes of cancer cells. Serum serotonin levels were found to be suitable for 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?, Curr Mol Med. 2015, 15, 62-77).

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

[0012] In addition, 5-HTR 1B Selective antagonists reduce serotonin-mediated cellular steatosis in HepG2 cells. In addition, it has been demonstrated that serotonin positively regulates cell proliferation / survival and cellular steatosis in hepatocarcinoma 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 autocrine loops of growth factors, promoting cell proliferation in invasive tumors, but several studies show that serotonin can also exert an anti-tumor effect via inhibition of angiogenesis. A computer simulation screen was performed to search for small molecules that induce terminal differentiation, and apomorphine, a HTR1 / 2 antagonist, was identified. A study was performed in immunodeficient mice that were transplanted with human acute myeloid leukemia (AML) cells and left for 7 days to establish leukemia. Then, mice were treated with apomorphine (5 mg / kg body weight) or methiothepin (0.1 mg / kg body weight) every 2 days for 14 days. Both HTR1 antagonists significantly reduced AML load in bone marrow (BM) compared to vehicle-treated mice. Similarly, the clonogenic capacity of transplanted AML cells was attenuated in both treated mice, highlighting the effect of HTR inhibition on the self-renewal capacity of AML cells. The results indicate that AML cells express HTR 1A and HTR1B and inhibits terminal differentiation and cell death. Interestingly, leukemia stem cells (LSCs) are more sensitive to HTR1 antagonists than more mature AML blast cells. Thus, HTR1 1A and HTR 1B can constitute a target of interest for AML therapy. This study demonstrates that HTR1 is implicated in cancer stem cells and the results highlight the biological role of HTR1 on leukemia maintenance, suggesting that HTR1 signaling is involved in the survival of AML blast cells 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 various physiological effects via 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 a pro-growth activity and to be functionally associated with 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, the 5-HT 2A receptor subtype has been identified in both the central nervous system (CNS) and the periphery. The 5-HT 2A receptor has been found in many parts of the CNS, including the cerebral cortex, basal ganglia, hippocampus, thalamus, cerebellum, and hypothalamus. In the periphery, the 5-HT 2A receptor is located in platelets, vascular smooth muscle, and uterine smooth muscle. The 5-HT 2AReceptors are involved in various processes, such as vascular smooth muscle contraction, extravascular smooth muscle contraction (including uterine contractions), and platelet aggregation (Nagatomo T et al., "5-HT 2A Functions of 5-HT 2A receptor and its antagonists in the cardiovascular system)", Pharmacology & Therapeutics 104 (2004) 59-81).

[0016] With respect to patent literature, several patent applications disclosing compounds as 5-HT 1B modulators, agonists or antagonists of the 5-HT

[0017] The patent application WO 2018 / 130685 Al discloses a combination therapy for the treatment of cancer, especially acute myeloid leukemia (AML), comprising an antineoplastic agent and a modulator of the serotonin receptor type 1 (HTR1 / 5-HT1), for example an HTR1 antagonist, describing in particular apomorphine, metitepine and SB-224289 (SB9) as serotonin receptor antagonists. All of these readily cross the blood-brain barrier, act on the central nervous system (CNS), and in the case of apomorphine and metitepine, they are non-selective 5-HT 1B modulators.

[0018] The patent application WO 95 / 15954 Al discloses biphenyl amide compounds as 5-HT 1D antagonists for the treatment of various CNS, endocrine and gastrointestinal disorders.

[0019] There is therefore a great need for novel therapeutic options with respect to the 5-HT1 receptor, especially the 5-HT 1B receptor, which can be used for the treatment of peripheral diseases related to said receptor. Such diseases are selected from the group consisting of cancer, including hematological cancers and solid tumors, and respiratory diseases. In order to have minimal side effects on the CNS, it is desirable to develop novel compounds which are less permeable to the brain barrier and which have a good selectivity over other 5-HT receptors, especially over the 5-HT 2A receptor.

[0020] The problem to be solved by the present invention is to provide novel, more selective and safe 5-HT 1BReceptor modulators with improved polarity and less brain penetration compared to the compounds of the prior art. SUMMARY

[0021] In one of its aspects (aspect 1), the present application relates to novel compounds of formula (I):

[0022]

[0023] wherein:

[0024] - G represents a group selected from:

[0025] a) -C(O)NH,

[0026] b) -NHC(O),

[0027] - X 1 , X 2 , X 3 and X 4 represents a N atom or a C-R 5 group,

[0028] - R 1 and R 2 are independently selected from the group consisting of:

[0029] a) a hydrogen atom,

[0030] b) a linear or branched C1-C6 alkyl group optionally substituted with 1, 2 or 3 substituents selected from -N(R 6 )R 7 and -OR 6 , a halogen atom and a C3-C6 cycloalkyl group,

[0031] c) a C3-C6 cycloalkyl group,

[0032] - or R 1 and R 2 together with the nitrogen atom to which they are attached form a four- to six-membered heterocyclyl group, said four- to six-membered heterocyclyl group additionally comprising a second heteroatom selected from N and O;

[0033] - R 3 represents a group selected from:

[0034] a) a cyano group, and

[0035] b) a halogen atom,

[0036] - R 4 represents a group selected from:

[0037] a) a halogen atom,

[0038] b) a C3-C4cycloalkyl group,

[0039] c) a C1-C3alkoxy group,

[0040] d) a C1-C3haloalkyl group,

[0041] e) a cyano group,

[0042] -R 5 represents a group selected from:

[0043] a) a hydrogen atom,

[0044] b) a C1-C3alkyl group,

[0045] c) a halogen atom,

[0046] -R 6 and R 7 independently represent a group selected from:

[0047] a) a C1-C3alkyl group,

[0048] b) a hydrogen atom,

[0049] with the proviso that at least one of said X 1 , X 2 , X 3 and X 4 represents a N atom,

[0050] and pharmaceutically acceptable salts thereof.

[0051] Other aspects of the application are described hereafter.

[0052] In a second aspect, the present application relates to a process for preparing a compound as defined in the first aspect.

[0053] In a third aspect, the present application relates to a pharmaceutical composition comprising an effective amount of a compound as defined in the first aspect.

[0054] In a fourth aspect, the present application relates to a combination product comprising a compound as defined in the first aspect and another therapeutic agent selected from agents for the treatment of cancer, respiratory diseases and liver diseases. The cancer is selected from blood cancers, such as acute myeloid leukemia (AML) and solid tumors, the respiratory disease can be in particular pulmonary arterial hypertension, and the liver disease can be in particular non-alcoholic steatohepatitis.

[0055] In a fifth aspect, the present application relates to the use of a compound of the first aspect for the manufacture of a medicament, in particular for the treatment of a disease which can be treated by antagonism of type 1 serotonin receptors (HTR1), in particular by 5-HTR 1Bmedicament for the treatment of a disease ameliorated by antagonism of the serotonin receptor 5-HTR 1B The disease or pathological condition ameliorated by antagonism of the serotonin receptor 5-HTR

[0056] In a sixth aspect, the present application relates to a method for the treatment of a disease ameliorated by antagonism of the serotonin receptor 5-HTR 1B by administering to a subject in need of said treatment a compound as defined in the first aspect or a pharmaceutical composition of the third aspect or a combination product of the fourth aspect.

[0057] In a seventh aspect, the present application relates to a compound as defined in the first aspect, a pharmaceutical composition as defined in the third aspect or a combination product as defined in the fourth aspect for use as a medicament.

[0058] In an eighth aspect, the present application relates to a compound as defined in the first aspect, a pharmaceutical composition as defined in the third aspect or a combination product as defined in the fourth aspect for use in the treatment of a disease or pathological condition selected from the group consisting of cancer, respiratory diseases and liver diseases. Cancer is selected from hematological cancers, such as acute myeloid leukemia (AML) and solid tumors, respiratory diseases can be in particular pulmonary arterial hypertension, and liver diseases can be in particular non-alcoholic steatohepatitis. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 shows flow cytometry histograms representing selectivity of several compounds on leukemia cells. DETAILED DESCRIPTION

[0060] As mentioned previously, the compounds of the present application are suitable for the treatment or prevention of diseases known to be ameliorated by treatment with a modulator / antagonist of the serotonin receptor type 1 (HTR1), in particular the 5-HTR 1B receptor. Such diseases are for example cancer, respiratory diseases and liver diseases. Cancer is selected from hematological cancers, such as acute myeloid leukemia (AML) and solid tumors, respiratory diseases can be in particular pulmonary arterial hypertension, and liver diseases can be in particular non-alcoholic steatohepatitis.

[0061] The derivatives of the present application and their pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising such compounds and / or their salts, are therefore useful in a method of treating a pathological condition or a disease of the human body, which method comprises administering to a subject in need of said treatment an effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof.

[0062] As used herein, the term halogen atom is used to denote an atom selected from the group consisting of a chlorine, fluorine, bromine or iodine atom, preferably a bromine, fluorine or chlorine atom.

[0063] As used herein, the term alkyl is used to denote a straight-chain or branched hydrocarbon group (C n H 2n+1 ). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-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. Thus, the term C n -C m alkyl is understood to denote an alkyl group comprising n to m carbon atoms.

[0064] As used herein, the term C n -C m alkoxy is used to denote a group containing a straight-chain or branched C n -C m alkyl group attached to an oxygen atom. Preferred alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and t-butoxy.

[0065] As used herein, the term C n -C m cycloalkyl is used to denote a hydrocarbon cyclic group (C n H 2n-1 ) having n to m carbon atoms. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0066] As used herein, the term haloalkyl is used to denote an alkyl group in which one or more hydrogen atoms has been replaced by a halogen atom. Preferred haloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0067] As used herein, the term four- to six-membered heterocyclyl is used to denote a saturated ring having four to six members comprising carbon and a second heteroatom selected from N and O as part of the ring. Heterocyclyl groups include, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.

[0068] As used herein, some atoms, groups, chains or rings present in the general structure of the application are "optionally substituted". This means that these atoms, groups, chains or rings can be unsubstituted, or substituted at any position with one or more, for example 1, 2 or 3, substituents, whereby a hydrogen atom bound to an unsubstituted atom, group, chain or ring is replaced by a chemically acceptable atom, group, chain or ring. When two or more substituents are present, each substituent can be the same or different.

[0069] As used herein, the term pharmaceutically acceptable salt is used to denote a salt that is formed with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid, and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (for example sodium or potassium), alkaline earth metal (for example calcium or magnesium) hydroxides and organic bases, for example alkyl amines, phenylalkyl amines and heterocyclic amines.

[0070] Other preferred salts according to the application are quaternary ammonium compounds wherein an equivalent amount of an anion (X -n ) is associated with the positive charge of the N atom, wherein "-n" indicates the negative charge of the anion and is typically -1, -2 or -3. X -n may be an anion of various mineral acids, for example chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid, for example acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. X -n is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably, X - is chloride, bromide, trifluoroacetate or methanesulphonate.

[0071] According to one embodiment of the application, in the compound of formula (I), R 1 and R 2 are linear or branched C1-C3 alkyl groups. In a preferred embodiment, R 1 and R 2 are methyl groups.

[0072] According to one embodiment of the application, in the compound of formula (I), G represents -C(O)NH-, wherein the carbonyl group is attached to the ring comprising X 3 and X 4 and the amino group is attached to the ring comprising X 1 and X2 The ring.

[0073] According to an embodiment of the present invention, in the compound of formula (I), R 3 It is a cyano group.

[0074] According to an embodiment of the present invention, in the compound of formula (I), R 4 Selected from halogen atoms and C3-C4 cycloalkyl groups. In a preferred embodiment, R 4 It is selected from chlorine atoms, fluorine atoms and cyclopropyl groups.

[0075] According to one embodiment of the present invention, in the compound of formula (I), the core is:

[0076]

[0077] Selected from:

[0078]

[0079] In a preferred embodiment, the core is:

[0080]

[0081] yes:

[0082]

[0083] In another preferred embodiment, the core is:

[0084]

[0085] yes:

[0086]

[0087] In another preferred embodiment, the core is:

[0088]

[0089] yes:

[0090]

[0091] According to one embodiment of the present invention, the compound of formula (I) has one of the following formulas (Ia), (Ib) and (Ic):

[0092]

[0093] Where R 4 This indicates a group selected from halogen atoms and cyclopropyl groups.

[0094] The various compounds of the invention include:

[0095] N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0096] N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0097] N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-chloro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0098] N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl- 1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide

[0099] N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0100] N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0101] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0102] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0103] 6-(2-chloro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)-N-(4-cyano-3-(2- (dimethylamino)ethoxy)phenyl)nicotinamide

[0104] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl- 1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide

[0105] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0106] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0107] N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide

[0108] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide

[0109] 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

[0110] 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

[0111] 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

[0112] 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

[0113] 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

[0114] 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

[0115] 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

[0116] 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

[0117] 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

[0118] 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

[0119] 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

[0120] 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

[0121] 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

[0122] 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

[0123] 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

[0124] 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

[0125] 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

[0126] 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

[0127] 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

[0128] 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

[0129] 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

[0130] 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

[0131] 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

[0132] 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

[0133] 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

[0134] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0135] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0136] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl-1,2,4- oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide

[0137] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0138] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0139] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5- methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0140] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0141] 6-(2-chloro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2- (dimethylamino)ethoxy)pyridin-2-yl)nicotinamide

[0142] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(4-(5-methyl- 1,2,4- oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide

[0143] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0144] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyano-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0145] N-(5-bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0146] N-(5-bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0147] N-(5-bromo-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-chloro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0148] N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0149] N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0150] 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-6-(2- (dimethylamino)ethoxy)pyridin-2-yl)nicotinamide

[0151] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0152] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0153] N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-chloro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0154] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-cyclopropyl-4-(5- methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0155] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0156] 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2- (dimethylamino)ethoxy)pyrimidin-2-yl)nicotinamide

[0157] 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

[0158] 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

[0159] 4-bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol- 3-yl)phenyl)pyridin-3-yl)benzamide

[0160] 4-bromo-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3- yl)-3-(2-(dimethylamino)ethoxy)benzamide

[0161] 4-bromo-N-(6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3- (2-(dimethylamino)ethoxy)benzamide

[0162] 4-bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2- (trifluoromethyl)phenyl)pyridin-3-yl)benzamide

[0163] 4-bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol- 3-yl)phenyl)pyridin-3-yl)benzamide

[0164] 4-bromo-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3- (2-(dimethylamino)ethoxy)benzamide

[0165] 4-cyano-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2-(dimethylamino)ethoxy)benzamide

[0166] 4-cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)benzamide

[0167] N-(6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-4-cyano-3-(2- (dimethylamino)ethoxy)benzamide

[0168] 4-cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2- (trifluoromethyl)phenyl)pyridin-3-yl)benzamide

[0169] 4-cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)benzamide

[0170] 4-cyano-N-(6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3-(2- (dimethylamino)ethoxy)benzamide.

[0171] According to one embodiment of the present application, preferred compounds are selected from:

[0172] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl)nicotinamide

[0173] 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(4-cyano-3-(2- (dimethylamino)ethoxy)phenyl)nicotinamide

[0174] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl)pyrimidine-5-carboxamide

[0175] 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

[0176] 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

[0177] 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

[0178] 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

[0179] 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

[0180] 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

[0181] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0182] 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2( dimethylamino)ethoxy)pyridin-2-yl)nicotinamide

[0183] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0184] N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0185] N-(5-cyano-6-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0186] 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-6-(2- (dimethylamino)ethoxy)pyridin-2-yl)nicotinamide

[0187] 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2- (dimethylamino)ethoxy)pyrimidin-2-yl)nicotinamide

[0188] 4-cyano-N-(6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3- yl)-3-(2-(dimethylamino)ethoxy)benzamide

[0189] 4-cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)benzamide

[0190] 4-cyano-3-(2-(dimethylamino)ethoxy)-N-(6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)benzamide.

[0191] In a more preferred embodiment of the application, the compound is selected from:

[0192] N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl)nicotinamide

[0193] 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

[0194] 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

[0195] 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

[0196] N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-cyclopropyl-4-(5-methyl-1,2,4- oxadiazol-3-yl)phenyl)nicotinamide

[0197] 6-(2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-N-(5-cyano-4-(2- dimethylamino)ethoxy)pyridin-2-yl)nicotinamide.

[0198] When the compounds of the application are combined with other therapeutic agents, the other therapeutic agents are selected from the group consisting of chemotherapeutic drugs 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. In particular, the immunotherapeutic agents are selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, MPDL3280A, MEDI4736 and MDX-1105.

[0199] The compounds of the application can be prepared by using the procedures described hereinafter in the Schemes and Examples or by methods known in the art. Starting materials and intermediates can be obtained from commercial sources, prepared from commercially available compounds or prepared using well-known synthetic methods. To facilitate the description of these procedures, specific examples have been used, but these examples do not limit the scope of the application in any way.

[0200] Scheme 1

[0201]

[0202] Reagents and conditions: a) DCM, 0°C, 3h; b) Cs2C03, dioxane, reflux, 16h; c) Zn; NH4CI, EtOH, 80°C, 16h.

[0203] Scheme 1 shows one route to produce compounds of formula (VI), which are intermediates in the synthesis of compounds of formula (I). Starting from a derivative of 2-aminoethan-1-ol (II), reaction with methane sulfonyl chloride forms 2-aminoethyl methanesulfonate (III), which reacts with a heteroaryl alcohol or phenol (IV) to form the ether of compound (V). After hydrogenation, for example with zinc dust and ammonium chloride, the intermediate of formula (VI) is obtained.

[0204] Option 2

[0205]

[0206] Reagents and conditions: d) N-halosuccinimide, AcOH, room temperature; e) Zn(CN)2, tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3), 1,1'-ferrocene di-bis(diphenylphosphine)(dppf), DMF, 120℃, 12 hours; f) 1M bis(trimethylsilyl)amino potassium in THF solution, room temperature, 12 hours.

[0207] In X 2 In the specific case of intermediate (VI) representing a nitrogen atom, the synthesis begins with the halogenation of 6-fluoropyridine-2-amine in acetic acid at room temperature with N-halosuccinimide to give intermediate (VIIa).

[0208] In order to synthesize R 3 The compound of the present invention, which is a cyano group, is reacted with Zn(CN)2 via a palladium complex to give the intermediate of formula (VIIb). Finally, according to scheme 2, the intermediate (VIIa) or (VIIb) is reacted with a disubstituted aminoethanol in THF at room temperature in the presence of a base, for example, bis(trimethylsilyl)aminopotassium, to form an amino ether (VIa).

[0209] Option 3

[0210]

[0211] Reagents and conditions: g) N-halosuccinimide, DMF, room temperature; h) Zn(CN)2, (Pd2(dba)3), (dppf), DMF, 120℃, 12 hours; i) 1M bis(trimethylsilyl)amino potassium in THF solution, room temperature, 12 hours.

[0212] On the other hand, an intermediate of formula (VIb) is obtained by applying a reaction similar to that described in scheme 2. In this case, 4-chloropyrimidine-2-amine is halogenated with N-halosuccinimide in DMF at room temperature to obtain the intermediate of formula (VIIa). To synthesize R... 3 The compound of the present invention having a cyano group, by introducing the group via a palladium complex catalyst, yields intermediate (VIIIb), which is then converted to intermediate (VIb) by reacting with a disubstituted aminoethanol in THF at room temperature in the presence of, for example, a base of bis(trimethylsilyl)aminopotassium, as described in Scheme 3.

[0213] Option 4

[0214]

[0215] Reagents and conditions: j) N-halosuccinimide, acetonitrile, room temperature; k) di-tert-butyl dicarbonate, TEA, DMAP, THF, 40°C, 3 hours; 1) Zn(CN)2, (Pd2(dba)3), (dppf), DMF, 120°C, 12 hours; m) HO-CH2-CH2-NR 1 2 , NaH, DMF, 80°C, 6 hours; n) trifluoroacetic acid, DCM, room temperature.

[0216] In acetic acid at room temperature, 4-fluoropyridin-2-amine is halogenated with N-halosuccinimide to yield the intermediate of formula (VIIc). The amino group is protected by formation of the intermediate of formula (VIId). The cyano group is introduced into the R 3 group as previously described to yield the precursor (XII). According to scheme 4, the reaction with HO-CH2-CH2-NR 1 2 in the presence of a base such as sodium hydride in DMF forms the intermediate (XIII) which, after deprotection of the protecting group with trifluoroacetic acid in DCM, yields the intermediate (VId).

[0217] Scheme 5

[0218]

[0219]

[0220] Reagents and conditions: o) [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (Pd(dppf)Cl2-DCM), KOAc, dioxane / H20, 100°C, 8 hours; p) or q) Pd(dppf)Cl2-DCM, Cs2C03, dioxane / H20, 100°C, 12 hours.

[0221] In scheme 5, when the group G of the compounds of general formula (I) represents an amide (-C(O)NH), two routes for the synthesis of carboxylic acids of formula (XVII) are depicted. Phenyl or heteroaryl bromide precursors (XIV) can react with bis(pinacolato)diboron in the presence of a palladium catalyst to give intermediates (XV). Applying the Suzuki reaction, these intermediates can be converted into acids of formula (XVIII) by reaction with bromide precursors (XVI). An alternative route can be performed by coupling reaction of precursors (XVIII) with boronic acids (XIX) under palladium catalysis.

[0222] Scheme 6

[0223] ​​

[0224] Reagents and conditions:

[0225] r) General procedure A: HATU, DIPEA, DCM, room temperature, overnight;

[0226] r) General procedure B: conversion of carboxylic acid (XVII) into an acyl chloride, then reaction with amine (VI) using TEA, DCM, room temperature, overnight.

[0227] The synthesis of amides of formula (Id) is performed by reaction of an amine of formula (VI) with the corresponding carboxylic acid (XVII) in the presence of a coupling agent such as HATU and a base at room temperature, as described in scheme 6.

[0228] Alternatively, carboxylic acids of formula (XVII) can be converted into the corresponding acyl chloride using standard procedures. Reaction of the corresponding acyl chloride of precursor (XVII) with an amine precursor of formula (VI) in the presence of a base such as triethylamine also affords derivatives of formula (Id).

[0229] Scheme 7a

[0230]

[0231] Scheme 7b

[0232]

[0233] Reagents and conditions: s) Cs2C03, dioxane, reflux, 12 hours; t) NaOH, MeOH, room temperature, 3 hours; u) or; v) Pd(dppf)Cl2.DCM, Cs2C03, dioxane / H20, 100 °C, 12 hours; w) HATU, DIPEA, DCM, room temperature, overnight.

[0234] A route to the reverse amide (-NHC(O)) (Ie) in moiety G of the compounds of general formula (I), which are also the object of the present patent, is described in Scheme 7. The ether formation of the precursor (XX) with 2-aminoethyl methanesulfonate (III) gives the precursor (XXI), which upon hydrolysis gives the acid of formula (XXII). On the other hand, the amine precursor (XXV) can be synthesized by Suzuki-type coupling of boronic acid or boronate ester derivative (XXIII) with the precursor (XXIV) using a palladium catalyst. It is also possible to change the functionality of the intermediates in analogous reactions under palladium catalyzed conditions depending on whether the product is commercially available or not by this way, as shown in the reaction of the precursor (XXVI) with boronic acid or boronate ester derivative (XXVII). The synthesis of the reverse amide of formula (Ie) is carried out by reaction of the amine precursor of formula (XXV) with the corresponding carboxylic acid (XXII) in the presence of a coupling agent such as HATU and a base at room temperature.

[0235] The following examples illustrate the synthesis of the compounds of the present application, including the preparation of intermediates, which examples do not limit the scope of the present application in any way.

[0236] Abbreviations

[0237] The following abbreviations are used in the present application with the corresponding definitions:

[0238] ACN: acetonitrile

[0239] CN: cyano group

[0240] RT: room temperature

[0241] halo: halogen atom

[0242] HATU: N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylidene]-N- methylmethanaminium N-oxide hexafluorophosphate

[0243] EDTA: ethylenediaminetetraacetic acid

[0244] DIPEA: N,N-diisopropylethylamine

[0245] DME: dimethoxyethanol

[0246] DMF: dimethylformamide

[0247] DCM: dichloromethane

[0248] NBS: N-bromosuccinimide

[0249] TEA: triethylamine

[0250] TFA: trifluoroacetic acid

[0251] THF: Tetrahydrofuran

[0252] DMSO: Dimethyl sulfoxide

[0253] Pharmacological activity

[0254] Determination of binding at human serotonin receptors

[0255] Human 5-HT 1B Competitive binding in the human 5-HT

[0256] Serum 5-HT was analyzed in a polypropylene 96-well plate. 1B Receptor competition binding assay. Hela-5-HT prepared in the laboratory was cultured in each well. 1B 5 μg membrane of cell line (batch number: A001 / 14-11-2011, protein concentration = 3179 μg / ml), 1.5 nM [ 3 H]-GR125743 (77.3 Ci / mmol, 0.1 mCi / ml, Perkin Elmer NET1172100UC) and the investigated compound and standards. Non-specific binding was determined in the presence of 10 μM GR55562 (TOCRIS 1054). The reaction mixture (V t 250 μL / well was incubated at 25 °C for 90 min. 200 μL was transferred to a GF / C 96-well plate (Millipore, Madrid, Spain) pretreated with 0.5% PEI and treated with binding buffer (Tris-HCl 50 mM, EDTA 1 mM, MgCl2 10 mM, pH 7.4). The plate was then filtered and washed four times with 250 μL of washing buffer (Tris-HCl 50 mM, pH 7.4). Measurements were then taken using a microplate β-scintillation counter (Microbeta Trilux, PerkinElmer, Madrid, Spain). The raw radioactivity data were adjusted to a 4-parameter logistic regression using GraphPad Prism software to obtain IC50 values ​​from specific binding sites. 50 Value. According to the following formula, from IC 50 Calculate Ki:

[0257]

[0258] in:

[0259] -IC 50 Inhibitory concentration,

[0260] -D: The actual concentration of the radioactive ligand, and

[0261] -Kd: dissociation constant (affinity of a radioligand to its receptor).

[0262] Human 5-HT 2A Competitive binding in the human 5-HT

[0263] Serum 5-HT was analyzed in a polypropylene 96-well plate. 2A Receptor competition binding assay. In each well, CHO-5-HT prepared in the laboratory was cultured. 2A 80 μg membrane of cell line (protein concentration = 4337 μg / ml), 1 nM [ 3 H]-ketoserin (47.3 Ci / mmol, 1 mCi / ml, Perkin Elmer NET791250UC) and the studied compound and standards. Nonspecific binding was determined in the presence of 1 μM dimethylergonovine (Sigma M137). The reaction mixture (V t Incubate at 37°C for 30 minutes (250 μL / well), then transfer 200 μL to a GF / B96-well plate (Millipore, Madrid, Spain) pretreated with 0.5% PEI and treat with binding buffer (Tris-HCl 50 mM, pH 7.4). After filtration, wash six times with 250 μL of washing buffer (Tris-HCl 50 mM, pH 6.6) and then measure using a microplate β-scintillation counter (Microbeta Trilux, PerkinElmer, Madrid, Spain).

[0264] Using GraphPad Prism software, the raw radioactivity data were adjusted to a 4-parameter logistic regression to obtain IC from specific junctions. 50 Value. According to the following formula, from IC 50 Calculate Ki:

[0265]

[0266] in:

[0267] -IC 50 Inhibitory concentration,

[0268] -D: The actual concentration of the radioactive ligand, and

[0269] -Kd: dissociation constant (affinity of a radioligand to its receptor).

[0270] Cell viability assay

[0271] Cultured in complete RPMI medium supplemented with 10% fetal bovine serum (FBS) at a density of 0.15 × 10⁶ ppm. 6AML cell line (HL-60 or MonoMac-1). Compounds were added to the culture medium at the indicated concentrations (0.1, 1 and 10 μΜ) while controls were treated with equivalent concentrations of vehicle (DMSO). Primary validation screening was analyzed after 72 hours of treatment, EC 50 Cells were stained with the live-dead discrimination dyes 7-Aminoactinomycin D (7-AAD) and Hoechst 33342 and acquired in a flow cytometer, counting by volume. Live cells were discriminated based on discrete FSC-SSC profile, 7-AAD negative and weak positive to Hoechst 33342. Prism GraphPad software was used to calculate EC 50 .

[0272] Selectivity studies against leukemia cells

[0273] Primary AML patient samples from peripheral blood at diagnosis were ficolled to obtain mononuclear cells (MNC). Isolated MNC were cultured in IMDM medium supplemented with 3% heat inactivated fetal bovine serum, 1x BIT (StemCell Technologies), 5 ng / mL human IL3, 2 mM NaPyr and 5x10-5M beta-mercaptoethanol. Cells were treated with vehicle control (DMSO) and 10 μΜ of selected compounds (example compounds or reference compounds) for 72 hours at 37°C and 5% CO2. After treatment, cells were stained against pan-hematopoietic marker CD45 and the live-dead discriminator 7-AAD and acquired in flow cytometry. Analysis was performed within the live gate (discrete FSC-SSC profile, 7-AAD weak population). Histograms show the intensity of CD45 staining (X axis) and SSC (Y axis) within the live cell gate. In each histogram, the blast gate (upper right) and the lymphocyte gate (lower left) are indicated. Selectivity for AML blasts is represented by the decrease in the relative frequency of AML blasts over lymphocytes.

[0274] Healthy blood cell-viability assay

[0275] Cells were cultured at 0.5x10 6Peripheral blood-mononuclear cells. Compounds were added to the culture medium at 0.5 / 1 / 5 / 10 / 50 mM, while controls were treated with vehicle (DMSO) at equivalent concentrations. After 48 hours of treatment, cells were stained with the live-dead discrimination dye 7-AAD and Hoechst 33342, for the pan-hematopoietic surface marker CD45, and acquired in a flow cytometer, counted by volume. Live cells were discriminated based on discrete FSC-SSC profile, 7-AAD negative, weakly positive for Hoechst 33342 and CD45 positive. EC 50 .

[0276] Estimation of brain penetration

[0277] tPSA values for several compounds were determined theoretically by Perkin Elmer Informatics using ChemDraw Professional program 17.0.0.206 (121) version. PSA has been used as a predictor of blood brain barrier (BBB) penetration (see for example Lenz GR. Technical problems in the results obtained. 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. 2002 Dec;3(6):647-57).

[0278] Results

[0279] determining the binding of a compound to the human serotonin receptor h5-HT 1B and h5-HT 2A Place Determination of binding at human serotonin receptors

[0280] Table 1 shows the binding of some compounds of the present application at serotonin receptors.

[0281] Table 1

[0282]

[0283] SB41 = SB-216641 (CAS No. 193611-67-5) N-[3-[3-(dimethylamino)ethoxy]-4- methoxyphenyl]-2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-[l,l'-biphenyl]-4- carboxamide hydrochloride.

[0284] SB9 = SB-224289-HCl (CAS No. 180084-26-8) l'-methyl-5-[[2'-methyl-4'-(5-methyl- 1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- f]indol-3,4'-piperidine hydrochloride.

[0285] Cell viability assay results

[0286] Table 2 demonstrates the cytotoxic ability of some compounds of the present application on AML cell lines.

[0287] Table 2

[0288]

[0289]

[0290] SB41 = SB-216641 (CAS No. 193611-67-5) N-[3-[3-(dimethylamino)ethoxy]-4- methoxyphenyl]-2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-[l,l'-biphenyl]-4- carboxamide hydrochloride.

[0291] SB9 = SB-224289-HCl (CAS No. 180084-26-8) l'-methyl-5-[[2'-methyl-4'-(5-methyl- 1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3- f]indol-3,4'-piperidine hydrochloride.

[0292] Selectivity studies against leukemia cells

[0293] As shown in Figure 1, several compounds were highly selective for AML blast cells based on the elimination of blast cell populations and the survival of non-oncogenic lymphocyte populations. However, in the conventional HTR 1B After treatment with the antagonist SB-224289, the frequency of each population was similar to the vehicle control, DMSO.

[0294] Healthy blood cell-viability assay

[0295] Table 3 demonstrates the cytotoxic potential of some compounds of the application on healthy cell lines.

[0296] Table 3

[0297] Examples EC 50 (uM) 7 50 21 >50 23 >50 36 25 38 50 39 50 45 >50 47 25 SB41 12.5

[0298] SB41 = SB-216641 (CAS No. 193611-67-5) N-[3-[3-(dimethylamino)ethoxy]-4- methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1 '-biphenyl]-4- carboxamide hydrochloride.

[0299] tPSA values

[0300] The following Table 4 demonstrates the estimated tPSA values for some exemplary compounds.

[0301] Table 4

[0302]

[0303] From the results described above, it can be seen that the compounds of the application are potent 5-HT 1B receptor modulators, with respect to other serotonin receptors, and more specifically, with respect to the 5-HT 2A receptor, with good selectivity.

[0304] In addition, in comparison to reported 5-HT 1B receptor modulators, the compounds of the application demonstrate enhanced cytotoxic activity against AML cells, significantly lower cytotoxicity against healthy cell lines, and lower potential for brain penetration.

[0305] The derivatives of the application are suitable for use in the treatment or prevention of diseases known to be susceptible to amelioration by treatment with 5-HT 1B serotonin receptor modulators. 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.

[0306] The derivatives of the application and their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and / or their salts, are therefore useful in methods of treating a disorder of the human body, the methods comprising administering to a subject in need of such treatment an effective amount of a compound of the application or a pharmaceutically acceptable salt thereof.

[0307] The present application also provides pharmaceutical compositions comprising, as an active ingredient, at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with other therapeutic agents as mentioned above, and a pharmaceutically acceptable excipient, such as a carrier or diluent. Depending on the nature of the formulation and whether or not further dilution prior to administration is to be performed, the active ingredient can represent from 0.001 to 99% by weight, preferably from 0.01 to 90% by weight, of the composition. Preferably, the composition is prepared in a form suitable for oral, topical, nasal, rectal, transdermal or injectable administration.

[0308] Pharmaceutically acceptable excipients with which the active compounds or salts of such compounds are combined to form the compositions of the present application are themselves well known in the art and the actual excipient used will depend, inter alia, on the method of administration of the composition desired.

[0309] The compositions of the present application are preferably suitable for injectable and oral (peroral) administration. In this case, the compositions for oral administration can be in the form of tablets, sustained release tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalers or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compounds of the present application; such preparations can be prepared by methods well known in the art.

[0310] Diluents, which can be used to prepare the compositions, include those liquid and solid diluents that are compatible with the active ingredient and the colorants or flavoring agents, if desired. Tablets or capsules conveniently contain from 2 mg to 500 mg of the active ingredient or an equivalent amount of a salt thereof.

[0311] Liquid compositions suitable for oral use can be in the form of solutions or suspensions. The solutions can be aqueous solutions of soluble salts or other derivatives of the active compounds in combination with, for example, sucrose to form a syrup. The suspensions can comprise insoluble active compounds of the present application or pharmaceutically acceptable salts thereof in combination with water and a suspending agent or flavoring agent.

[0312] Compositions for parenteral injection can be prepared from soluble salts which can be lyophilized and which can be dissolved in pyrogen-free water or other appropriate parentally administrable fluids.

[0313] Effective doses are generally in the range from 2-2000 mg of active ingredient per day. The daily dose can be administered in one or more treatments, preferably 1 to 4 treatments.

[0314] The present application will be further illustrated by the following examples. The following examples are given by way of illustration and not by way of limitation of the scope of the present application. The following examples illustrate the synthesis of the compounds of the present application, including the preparation of intermediates, which examples do not limit the scope of the present application in any way.

[0315] Examples

[0316] General

[0317] Reagents, solvents and starting materials were obtained from commercial sources. The term "concentration" refers to vacuum evaporation using a Bϋchi rotary evaporator. When indicated, reaction products were purified by "flash" chromatography on silica gel (40-63 μιη) using the indicated solvent system. Spectroscopic data were measured in a Varian Mercury 400 spectrometer. Melting points were measured in a Bϋchi 535 instrument. HPLC-MS were performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1 / 1000 Gilson splitter, a Gilson 307 pump, a Gilson 170 detector and a Thermoquest Fennigan aQa detector.

[0318] Preparation of intermediates

[0319] General procedures

[0320] Intermediate 1 : 2-(dimethylamino)ethyl methanesulfonate

[0321]

[0322] To a solution of 2-(dimethylamino)ethan-1-ol (2000 mg, 22.44 mmol) in 40 mL of dry DCM was added dropwise at 0 °C methanesulfonyl chloride (2.083 mL, 26.92 mmol). The reaction mixture was stirred at 0 °C for 4 hours and the solvent was removed under vacuum to dryness, obtaining a white solid (3600 mg, 96%) which was used in the next step without further purification.

[0323] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 4.59 (t, 2H), 3.48 (t, 2H), 3.32 (s, 3H), 2.80 (s, 3H), 2.78 (s, 3H).

[0324] Intermediate 2 : 2-(2-bromo-5-nitrophenoxy)-N,N-dimethylethan-1-amine

[0325]

[0326] To a solution of 2-bromo-5-nitrophenol (500 mg, 2.29 mmol) and cesium carbonate (1120.9 mg, 3.44 mmol) in 10.0 mL of anhydrous 1,4-dioxane was added 2-(dimethylamino)ethyl methanesulfonate (767.1 mg, 4.59 mmol). The reaction mixture was stirred at room temperature for 16 hours. The dioxane was removed under vacuum and saturated NaHC03 was added. The mixture was extracted with dichloromethane and the organic layer was dried, concentrated and purified by CombiFlash chromatography column (DCM:MeOH) to give 306.1 mg (46.2%) of 2-(2-bromo-5-nitrophenoxy)-N,N-dimethylethan-1-amine.

[0327] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.90 (d, 1H), 7.87 (d, 1H), 7.75 (dd, 1H), 4.29 (t, 2H), 2.70 (t, 2H), 2.25 (s, 6H).

[0328] HPLC-MS: Rt 2.580 m / z 289.0 (MH + ).

[0329] The following intermediate was synthesized using the procedure described for Intermediate 2.

[0330] Intermediate 3 : 2-(2-chloro-5-nitrophenoxy)-N,N-dimethylethan-1-amine

[0331] Obtained as described using the procedure described in Intermediate 2 but using 2-chloro-5-nitrophenol.

[0332] 1 H-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).

[0333] HPLC-MS: Rt 2.54 m / z: 245.1 (MH + ).

[0334] Intermediate 4 : 2-(2-(dimethylamino)ethoxy)-4-nitrobenzonitrile

[0335]

[0336] 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 anhydrous 1,4-dioxane was added 2-(dimethylamino)ethyl methanesulfonate (1019 mg, 6.09 mmol). The suspension was stirred at 60 °C in a sealed tube for 16 hours. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and saturated NaHC03. The organic phase was dried over Na2S04and 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%).

[0337] 1 H-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).

[0338] HPLC-MS: Rt 1.64 m / z 206.1 (MH + ).

[0339] Intermediate 5 : 4-bromo-3-(2-(dimethylamino)ethoxy)aniline

[0340]

[0341] A solution of 2-(2-bromo-5-nitrophenoxy)-N,N-dimethylethan-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 aqueous ammonium chloride was stirred at room temperature for 30 minutes. The reaction mixture was filtered and concentrated in vacuo. The residue was partitioned between dichloromethane and saturated NaHC03and the organic layer was dried over Na2S04and concentrated in vacuo to give the amine intermediate (317.7 mg, 87.6%).

[0342] 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).

[0343] HPLC-MS: Rt 2.06 m / z 259.0 (MH + ).

[0344] Intermediate 6 : 4-chloro-3-(2-(dimethylamino)ethoxy)aniline

[0345] Obtained as described in the procedure used for intermediate 5 but using intermediate 3 as starting compound.

[0346] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 6.96 (d, 1 H), 6.32 (d, 1 H), 6.12 (dd, 1 H), 5.22 (s, 2 H), 3.98 (t, 2 H), 2.63 (t, 2 H), 2.23 (s, 3 H).

[0347] HPLC-MS: Rt 1.96 m / z 215.1 (MH + ).

[0348] Intermediate 7: 4-amino-2-(2-(dimethylamino)ethoxy)benzonitrile

[0349] Obtained as described in the procedure used for intermediate 5 but using intermediate 4 as starting compound.

[0350] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.23 (d, 1 H), 6.24 (d, 1 H), 6.17 (dd, 1 H), 6.15 (s, 2 H), 4.04 (t, 2 H), 2.65 (t, 2 H), 2.23 (s, 6 H).

[0351] HPLC-MS: Rt 1.64 m / z 206.1 (MH + ).

[0352] Intermediate 8 : 6-fluoro-5-iodopyridin-2-amine

[0353]

[0354] To a solution of 6-fluoropyridin-2-amine (500 mg, 4.46 mmol) in 6 mL of acetic acid was added N-iodosuccinimide (1003.4 mg, 4.46 mmol) gradually at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction was dried under vacuum and neutralized with a saturated NaHC03solution. The aqueous phase was extracted twice with ethyl acetate. The organic layer was dried over Na2S04and concentrated to dryness. The crude material was purified by CombiFlash chromatographic column (hexane / ethyl acetate) to obtain the desired intermediate (698.9 mg, 65.8%).

[0355] 1H-NMR (400 MHz, DMSO-d6): δ = 7.74 (t, 1 H), 6.54 (s, 2H), 6.19 (dd, 1 H). 6 ).

[0356] HPLC-MS: Rt 2.09 m / z 438.9 (MH + ).

[0357] Intermediate 9 : 4-Fluoro-5-iodopyridin-2-amine

[0358]

[0359] A solution of 4-fluoropyridin-2-amine (1000 mg, 8.92 mmol) was dissolved in 10 mL of dry acetonitrile. N-Iodosuccinimide (2207.5 mg, 9.81 mmol) and 0.34 mL of trifluoroacetic acid were added slowly at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2S04and concentrated to dryness. The residue was purified by CombiFlash chromatography (hexane / ethyl acetate). The solid was washed with diethyl ether to give the desired intermediate (1550 mg, 73%).

[0360] 1 H-NMR (400 MHz, DMSO-d6): δ = 8.18 (d, 1 H), 6.71 (bs, 2H), 6.40 (d, 1 H). 6 .

[0361] HPLC-MS: Rt 1.94 m / z 238.9 (MH + ).

[0362] Intermediate 10 : 4-Chloro-5-iodopyrimidin-2-amine

[0363]

[0364] To a solution of 4-chloropyrimidin-2-amine (1000 mg, 7.72 mmol) in 10 mL of dry DMF was added N-iodosuccinimide (3473 mg, 15.44 mmol) gradually at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was poured onto cold water (50 mL) and the obtained precipitate was filtered, washed with water, pentane and dried under vacuum. The solid was purified by normal phase chromatography to give the desired intermediate (1235 mg, 62%).

[0365] 1 H-NMR (400 MHz, DMSO-d6): δ = 8.18 (d, 1 H), 6.71 (bs, 2H), 6.40 (d, 1 H). 6): δ = 8.46 (s, 1H), 7.26 (s, 2H).

[0366] HPLC-MS: Rt 1.93 m / z 256.0 (MH + ).

[0367] Intermediate 11 was synthesized using the procedure described above but using N-bromosuccinimide.

[0368] Intermediate 11 : 5-bromo-4-chloropyrimidin-2-amine

[0369] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.41 (s, 1H), 7.34 (s, 2H).

[0370] HPLC-MS: Rt 1.87 m / z 209.8 (MH + ).

[0371] Intermediate 12 : 2-amino-4-chloropyrimidine-5-carbonitrile

[0372]

[0373] To a solution of 2,4-dichloropyrimidine-5-carbonitrile (500 mg, 2.87 mmol) in 5 mL of ethanol was added 2M ammonia in ethanol (5 mL, 10.06 mmol). The reaction was stirred at room temperature for 30 minutes. The precipitate formed was filtered and washed with ethanol to obtain 320 mg 360 mg (72%) of 2-amino-4-chloropyrimidine-5-carbonitrile as a white solid.

[0374] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.68 (s, 1H), 8.24 (s, 2H).

[0375] HPLC-MS: Rt 1.41 m / z: 154.9 (MH + ).

[0376] Intermediate 13 : 2-amino-4-(2-(dimethylamino)ethoxy)pyrimidine-5-carbonitrile

[0377]

[0378] To a solution of 2-(dimethylamino)ethan-1-ol (0.486 mL, 4.85 mmol) in 8 mL of dry THF was added 1 M potassium bis(trimethylsilyl)amide in THF (6.47 mL, 6.47 mmol) and 2-amino-4-chloropyrimidine-5-carbonitrile (500 mg, 3.23 mmol) dissolved in dry THF (5 mL). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water and washed with brine. The organic layer was dried over sodium sulfate and concentrated to dryness to give 360 mg (53%) of 2-amino-4-(2-(dimethylamino)ethoxy)pyrimidine-5-carbonitrile as a yellow solid.

[0379] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.44 (s, 1H), 7.68 (d, 2H), 4.43 (t, 2H), 2.61 (t, 2H), 2.20 (s, 6H).

[0380] HPLC-MS: Rt 1.43 m / z: 208.1 (MH + ).

[0381] Intermediate 14 : N-(tert-Butoxycarbonyl)-N-(4-fluoro-5-iodopyridin-2-yl)carbamic acid tert-butyl ester

[0382]

[0383] In a round bottom flask with 15 mL THF containing 4-fluoro-5-iodopyridin-2-amine (1500 mg, 6.30 mmol), was added triethylamine (2.6 mL, 18.91 mmol), DMAP (84.7 mg, 0.69 mmol) and di-tert-butyl dicarbonate (3438.8 mg, 15.76 mmol). The mixture was stirred at 40 °C for three hours. The mixture was partitioned between ethyl acetate and saturated NaHC03solution. The organic phase was dried over Na2S04and concentrated to dryness. The residue was purified by CombiFlash chromatography column (hexanes / ethyl acetate). The solid was washed with diethyl ether to give the desired intermediate (1400 mg, 50%).

[0384] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.79 (d, 1H), 7.57 (d, 1H), 1.40 (s, 18H).

[0385] HPLC-MS: Rt 3.39 m / z 439.1 (MH + ).

[0386] Intermediate 15 6-amino-4-fluoronicotinonitrile

[0387]

[0388] A mixture of 5-bromo-4-fluoropyridin-2-amine (400 mg, 2.10 mmol), zinc cyanide (257 mg, 2.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (96 mg, 0.105 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (116 mg, 0.21 mmol) in anhydrous DMF (8 mL) was degassed. The mixture was stirred at 120 °C overnight. The reaction mixture was diluted with saturated aqueous NaHCO3solution, extracted with EtOAc (4 times), the combined EtOAc layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using hexane / EtOAc (3 / 1) as eluent to give 6-amino-4-fluoronicotinonitrile (192 mg, 67% yield).

[0389] 1 H-NMR (400 MHz, DMSO-d6): δ = 8.39 (d, 1H), 7.40 (s, 2H), 6.31 (d, 1H). 6

[0390] HPLC-MS: Rt 1.39 m / z 138.0 (MH + ).

[0391] Intermediate 16 was synthesized using the procedure described above but using 5-bromo-6-fluoropyridin-2-amine.

[0392] Intermediate 16 6-amino-2-fluoronicotinonitrile

[0393] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.82 (t, 1H), 7.54 (s, 2H), 6.38 (dd, 1H). 6

[0394] HPLC-MS: Rt 1.51 m / z 138.0 (MH + ).

[0395] Intermediate 17 6-amino-4-(2-(dimethylamino)ethoxy)nicotinonitrile

[0396]

[0397] ​​A 1 M solution of potassium bis(trimethylsilyl)amide in THF (4.00 ml, 4.00 mmol) was added to a solution of 2-(dimethylamino)ethan-1-ol (0.20 ml, 2.00 mmol) in dry THF (5 mL) at room temperature. After 2 minutes, 6-amino-4-fluoronicotinonitrile (250 mg, 1.82 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated aqueous NH4CI and EtOAc, the combined EtOAc layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using DCM / MeOH (93 / 7) as eluent to give 6-amino-4-(2-(dimethylamino)ethoxy)nicotinonitrile (211.3 mg, 56.3% yield).

[0398] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.13 (s, 1 H), 6.90 (s, 2H), 6.04 (s, 1 H), 4.11 (t, 2H), 2.65 (t, 2H), 2.22 (s, 6H).

[0399] HPLC-MS: Rt 1.48 m / z 207.1 (MH + ).

[0400] Intermediate 18 was synthesized using the procedure described above but using 6-amino-2-fluoronicotinonitrile.

[0401] Intermediate 18 : 6-amino-2-(2-(dimethylamino)ethoxy)nicotinonitrile

[0402] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.59 (d, 1 H), 7.04 (s, 2H), 6.05 (d, 1 H), 4.35 (t, 2H), 2.59 (t, 2H), 2.20 (s, 6H).

[0403] HPLC-MS: Rt 1.58 m / z 207.1 (MH + ).

[0404] Intermediate 19 : 5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-amine

[0405]

[0406] A 1 M solution of potassium bis(trimethylsilyl)amide in THF (6.33 ml, 6.33 mmol) was added to a solution of 2-(dimethylamino)ethan-1-ol (0.32 ml, 3.15 mmol) in dry THF (12 mL) at room temperature. After 2 minutes, 5-bromo-4-chloropyrimidin-2-amine (600 mg, 2.87 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated aqueous NH4C1 and EtOAc, the combined EtOAc layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography using DCM / MeOH (93 / 7) as eluent to give 5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-amine (533 mg, 71 % yield).

[0407] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.09 (s, 1 H), 6.79 (s, 2H), 4.36 (t, 2H), 2.60 (t, 2H), 2.21 (s, 6H).

[0408] HPLC-MS: Rt 1.78 m / z 262.9 (MH + ).

[0409] Intermediate 20 : 4-Bromo-3-(2-(dimethylamino)ethoxy)benzoic acid methyl ester

[0410]

[0411] A solution of 2-bromophenol-5-carboxylic acid methyl ester (1000 mg, 4.33 mmol), cesium carbonate (2115.2 mg, 6.49 mmol) and 2-(dimethylamino)ethyl methanesulfonate (1457.4 mg, 4.33 mmol) in 30 mL of dry 1,4-dioxane was stirred at 90 °C overnight. The dioxane was removed under vacuum and saturated NaHC03was added. The mixture was extracted with dichloromethane and the organic phase was dried, concentrated and purified by CombiFlash chromatography column (DCM / MeOH) to give 958.5 mg (73.3%) of 4-bromo-3-(2-(dimethylamino)ethoxy)benzoic acid methyl ester.

[0412] 1 H-NMR (400 MHz, DMSO-d 6): δ = 7.74 (d, 1H), 7.55 (d, 1H), 7.46 (dd, 1H), 4.20 (t, 2H), 3.86 (s, 3H), 2.69 (t, 2H), 2.25 (s, 6H).

[0413] HPLC-MS: Rt 2.63 m / z 304.1 (MH + ).

[0414] Intermediate 21 : 4-bromo-3-(2-(dimethylamino)ethoxy)benzoic acid methyl ester

[0415]

[0416] Methyl 4-bromo-3-(2-(dimethylamino)ethoxy)benzoate (405 mg, 1.34 mmol) was dissolved in 10 mL of THF and added 8 mL of methanol and 6.7 mL (6.7 mmol) of 1 M NaOH. The reaction was stirred at room temperature for three hours. The solvent was removed under reduced pressure and the aqueous phase was acidified with 1 M HC1 to pH = 4. The aqueous layer was concentrated to dryness. The residue was suspended in DCM / MeOH 20% and filtered. The filtrate was concentrated under vacuum to obtain the acid derivative (366.9 mg, 95.02%).

[0417] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.71 (d, 1H), 7.57 (d, 1H), 7.47 (dd, 1H), 4.38 (t, 2H), 3.15 (t, 2H), 2.59 (s, 6H).

[0418] HPLC-MS: Rt 1.39 m / z 288.1 (MH + ).

[0419] Intermediate 22 : methyl 4-cyano-3-hydroxybenzoate

[0420]

[0421] Methyl 4-cyano-3-hydroxybenzoate (200 mg, 0.87 mmol), zinc cyanide (112 mg, 0.95 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (42 mg, 0.05 mmol) were suspended in anhydrous dimethylformamide (2 mL) in a sealed tube. The reaction mixture was degassed with nitrogen and stirred at 120 °C for 16 h. The reaction was filtered over celite, eluted with ethyl acetate and the filtrate was washed with H2O and brine. The organic phase was dried over Na2S04and evaporated to dryness. The obtained solid was purified by normal phase chromatography to give methyl 4-cyano-3-hydroxybenzoate as a light brown solid (120 mg, 78%).

[0422] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.58 (s, 1 H), 7.77 (d, 1 H), 7.56 (s, 1 H), 7.45 (d, 1 H), 3.86 (s, 3H).

[0423] HPLC-MS: Rt 1.26 m / z 178.0 (MH + ).

[0424] Intermediate 23 Methyl 4-cyano-3-(2-(dimethylamino)ethoxy)benzoate

[0425]

[0426] 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 anhydrous 1,4-dioxane was added 2-(dimethylamino)ethyl methanesulfonate (377 mg, 2.26 mmol). The suspension was stirred at 100 °C for 5 h in a sealed tube. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and saturated NaHC03. The organic phase was dried over Na2S04and evaporated to dryness. The residue was purified by normal phase chromatography to give methyl 4-cyano-3-(2-(dimethylamino)ethoxy)benzoate as a light yellow solid (260 mg, 93%).

[0427] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.89 (d, 1 H), 7.68 (d, 1 H), 7.62 (dd, 1 H), 4.30 (t, 2H), 3.89 (s, 3H), 2.69 (t, 2H), 2.24 (s, 6H).

[0428] HPLC-MS: Rt 2.19 m / z 249.2 (MH + ).

[0429] Intermediate 24 : 4-cyano-3-(2-(dimethylamino)ethoxy)benzoic acid

[0430]

[0431] To a solution of methyl 4-cyano-3-(2-(dimethylamino)ethoxy)benzoate (1020 mg, 4.11 mmol) in tetrahydrofuran (20 mL) was added 1 M aqueous NaOH (12.32 mL, 12.32 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with 0.1 M aqueous NaOH (5 mL) and the tetrahydrofuran evaporated. The pH of the aqueous phase was adjusted to 3 and evaporated to dryness. The residue was suspended in dichloromethane-MeOH (8:2) and filtered. The filtrate was evaporated to dryness and the obtained solid was washed with diethyl ether-methanol (4:1) to give 4-cyano-3-(2-(dimethylamino)ethoxy)benzoic acid as a white solid (860 mg, 88%).

[0432] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.86 (d, 1 H), 7.68 (s, 1 H), 7.63 (d, 1 H), 4.52 (t, 2 H), 3.28 (t, 2 H), 2.67 (s, 6 H).

[0433] HPLC-MS: Rt 1.16 m / z 235.1 (MH + ).

[0434] Intermediate 25 : 4-amino-3-bromobenzonitrile

[0435]

[0436] 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. The residue was purified by normal phase chromatography to give 4-amino-3-bromobenzonitrile (1726 mg, 69%).

[0437] 1 H-NMR (400 MHz, DMSO-d 6): δ = 7.82 (d, 1 H), 7.45 (dd, 1 H), 6.81 (d, 1 H), 6.36 (s, 2H).

[0438] HPLC-MS: Rt 2.08 m / z: 198.94 (MH + ).

[0439] Intermediate 26 : 4-Amino-3-cyclopropylbenzonitrile

[0440] Obtained as described in the procedure used for intermediate 25 but using N- chlorosuccinimide in ACN at 90°C for 3 hours.

[0441] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.69 (d, 1 H), 7.41 (dd, 1 H), 6.82 (d, 1 H), 6.42 (s, 2H).

[0442] HPLC-MS: 2.01 m / z 152.9 Rt (MH + ).

[0443] Intermediate 27 : 4-Amino-3-cyclopropylbenzonitrile

[0444]

[0445] 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 N2and stirred at 90°C for 16 hours. The reaction mixture was filtered through celite, eluted with EtOAc and the filtrate washed with 1 M NaOH, saturated NaHCO3and brine. The organic layer was collected, dried over sodium sulfate and the solvent removed under reduced pressure. The crude material was purified by normal phase chromatography column (hexane / ethyl acetate) to obtain 4-amino-3-cyclopropylbenzonitrile (350 mg, 72%).

[0446] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.27 (dd, 1 H), 7.14 (d, 1 H), 6.65 (d, 1 H), 6.04 (s, 2H), 1.62 (m, 1 H), 0.86 (m, 2H), 0.52 (m, 2H).

[0447] HPLC-MS: Rt 2.19 m / z: 159.06 (MH + ).

[0448] Intermediate 28 : 4-Bromo-3-cyclopropylbenzonitrile

[0449]

[0450] To a solution of 4-amino-3-cyclopropylbenzonitrile (350 mg, 2.21 mmol) in dry acetonitrile (10 mL) was added dropwise isoamyl nitrite (0.414 mL, 3.10 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes and copper (II) bromide (622 mg, 2.79 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and HCI (1 M). The organic layer was collected, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by normal phase chromatography (hexane / EtOAc) to yield 4-bromo-3-cyclopropylbenzonitrile (410 mg, 82%).

[0451] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.81 (d, 1 H), 7.55 (m, 1 H), 7.49 (d, 1 H), 2.13 (m, 1 H), 1.04 (m, 2H), 0.82 (m, 2H).

[0452] HPLC-MS: Rt 3.01 m / z: 222.10 (MH + ).

[0453] Intermediate 29 : 4-Bromo-3-chlorobenzonitrile

[0454]

[0455] To a solution of 4-amino-3-chlorobenzonitrile (750 mg, 4.92 mmol) in dry acetonitrile (25 mL) was added dropwise isoamyl nitrite (0.92 mL, 6.88 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes and copper (II) bromide (1383 mg, 6.19 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and HCI (1 M). The organic layer was collected, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by normal phase chromatography (hexane / EtOAc) to yield 4-bromo-3-chlorobenzonitrile (800 mg, 75%).

[0456] 1 H-NMR (400 MHz, DMSO-d6 ): δ = 8.26 (d, 1H), 8.01 (d, 1H), 7.77 (dd, 1H).

[0457] Intermediate 30 : 4-bromo-3-cyclopropyl-N-hydroxybenzamidine

[0458]

[0459] To a sealed tube with 15 mL of ethanol containing 4-bromo-3-cyclopropylbenzonitrile (850.6 mg, 3.83 mmol), hydroxylamine hydrochloride (478 mg, 6.89 mmol) was added triethylamine (0.959 mL, 6.89 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was trituration in water for 30 minutes. The obtained solid was filtered and dried to obtain a white solid (764.6 mg, 92%).

[0460] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.69 (s, 1H), 7.56 (d, 1H), 7.40 (dd, 1H), 7.24 (d, 1H), 5.88 (s, 1H), 2.11 (m, 1H), 1.01 (m, 2H), 0.74 (m, 2H).

[0461] HPLC-MS: Rt 2.26 m / z: 255.02 (MH + ).

[0462] Intermediate 31 : (Z)-4-bromo-3-fluoro-N'-hydroxybenzamidine

[0463] Obtained as described in the procedure used in intermediate 30 but using 4-bromo-3-fluorobenzonitrile as starting compound.

[0464] 1 H-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).

[0465] HPLC-MS: Rt 1.88 m / z 232.9 (MH + ).

[0466] Intermediate 32 : 4-bromo-3-chloro-N-hydroxybenzamidine

[0467] Obtained as described in the procedure used for intermediate 30 but using 4-bromo-3- chlorobenzonitrile as starting compound.

[0468] 1 H-NMR (400 MHz, DMSO-d6): δ = 9.90 (s, 1 H), 7.87 (d, 1 H), 7.77 (d, 1 H), 7.57 (dd, 1 H), 5.98 (s, 3H). 6

[0469] HPLC-MS: Rt 2.08 m / z 250.9 (MH +

[0470] Intermediate 33 : 4-Bromo-N-hydroxy-3-(trifluoromethyl)benzimidamide

[0471] Obtained as described in the procedure used for intermediate 30 but using 4-bromo-3- (trifluoromethyl)benzonitrile as starting compound.

[0472] 1 H-NMR (400 MHz, DMSO-d6): δ = 9.97 (s, 1 H), 8.09 (d, 1 H), 7.91 (d, 1 H), 7.86 (dd, 1 H), 6.08 (s, 2H). 6

[0473] HPLC-MS: Rt 2.24 m / z 282.9 (MH +

[0474] Intermediate 34 : (Z)-4-Bromo-N'-hydroxy-3-methoxybenzimidamide

[0475] Obtained as described in the procedure used for intermediate 30 but using 4-bromo-3- methoxybenzonitrile as starting compound.

[0476] 1 H-NMR (400 MHz, DMSO-d6): δ = 9.75 (s, 1 H), 7.56 (d, 1 H), 7.36 (d, 1 H), 7.21 (dd, 1 H), 5.95 (s, 2H), 3.87 (s, 3H). 6

[0477] HPLC-MS: Rt 1.83 m / z 246.9 (MH +

[0478] Intermediate 35 : 4-Amino-3-bromo-N-hydroxybenzimidamide

[0479] ​​​​​​

[0480] A solution of 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) was heated to 60°C. Then, hydroxylamine hydrochloride (423 mg, 6.09 mmol) dissolved in 1.6 mL of water was added slowly dropwise at 60°C. The reaction mixture was stirred at 60°C for 16 hours. The mixture was allowed to cool and concentrated to dryness. The crude material was partitioned between EtOAc / H2O and the organic layer was collected, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was triturated in cold Et2O to obtain 4-amino-3-bromo-N-hydroxybenzimidamide (500 mg, 43%).

[0481] 1 H-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).

[0482] HPLC-MS: Rt 1.23 m / z: 229.9 (MH + ).

[0483] Intermediate 36 : 3-(4-Bromo-3-cyclopropylphenyl)-5-methyl-1,2,4-oxadiazole

[0484]

[0485] A solution of 500 mg (2 mmol) of 4-bromo-3-cyclopropyl-N-hydroxybenzimidamide in 1.4 mL of acetic anhydride was stirred at 80°C for 16 hours. The reaction mixture was poured on cold water and filtered. The crude material was purified by CombiFlash chromatography column (hexane / ethyl acetate) to obtain the desired intermediate (336.5 mg, 61.5%).

[0486] 1 H-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).

[0487] HPLC-MS: Rt 3.24 m / z: 279.03 (MH + ).

[0488] Intermediate 37: 3-(4-bromo-3-fluorophenyl)-5-methyl-1,2,4-oxadiazole

[0489] Obtained as described in the procedure using intermediate 36 but using 4-bromo-3-fluoro-N-hydroxybenzimidamide as starting compound.

[0490] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.92 (m, 1 H), 7.86 (dd, 1 H), 7.76 (dd, 1 H), 2.68 (s, 3H). 6

[0491] HPLC-MS: Rt 2.89 m / z 256.9 (MH + ).

[0492] Intermediate 38 : 3-(4-bromo-3-chlorophenyl)-5-methyl-1,2,4-oxadiazole

[0493] Obtained as described in the procedure using intermediate 36 but using 4-bromo-3-chloro-N-hydroxybenzimidamide as starting compound.

[0494] 1 H-NMR (400 MHz, DMSO-d6): δ = 8.11 (d, 1 H), 7.98 (d, 1 H), 7.85 (dd, 1 H), 2.68 (s, 3H). 6

[0495] HPLC-MS: Rt 3.13 m / z 274.9 (MH + ).

[0496] Intermediate 39 : 3-(4-bromo-3-(trifluoromethyl)phenyl)-5-methyl-1,2,4-oxadiazole

[0497] Obtained as described in the procedure using intermediate 36 but using 4-bromo-N-hydroxy-3-(trifluoromethyl)benzimidamide as starting compound.

[0498] 1 H-NMR (400 MHz, DMSO-d6): δ = 8.27 (d, 1 H), 8.16 (dd, 1 H), 8.11 (d, 1 H), 2.70 (s, 3H). 6

[0499] HPLC-MS: Rt 3.14 m / z 306.9 (MH + ).

[0500] Intermediate 40 ​​​: 3-(4-bromo-3-methoxyphenyl)-5-methyl-1,2,4-oxadiazole

[0501] Obtained as described in the procedure used for intermediate 36 but using 4-bromo-N-hydroxy-3-methoxybenzimidamide as starting compound.

[0502] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.78 (d, 1 H), 7.59 (d, 1 H), 7.51 (dd, 1 H), 3.94 (s, 3H), 2.68 (s, 3H). 6 ): δ = 7.78 (d, 1 H), 7.59 (d, 1 H), 7.51 (dd, 1 H), 3.94 (s, 3H), 2.68 (s, 3H).

[0503] HPLC-MS: Rt 2.76 m / z 269.0 (MH + ).

[0504] Intermediate 41 : 2-bromo-4-(5-methyl-1,2,4-oxadiazol-3-yl)aniline

[0505]

[0506] To a solution of 4-amino-3-bromo-N-hydroxybenzimidamide (490 mg, 2.13 mmol) in anhydrous dimethylsulfoxide (3 mL) were added ethyl acetate (0.312 mL, 3.19 mmol) and powdered NaOH (127 mg, 3.19 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was added to cold water (30 mL) and the resulting precipitate was filtered off, washed with water and dried. The crude material was purified by normal phase chromatography (hexane / EtOAc) to obtain 2-bromo-4-(5-methyl-1,2,4-oxadiazol-3-yl)aniline (362 mg, 67%).

[0507] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.90 (d, 1 H), 7.67 (dd, 1 H), 6.88 (d, 1 H), 5.99 (s, 2H), 2.60 (s, 3H). 6 ): δ = 7.90 (d, 1 H), 7.67 (dd, 1 H), 6.88 (d, 1 H), 5.99 (s, 2H), 2.60 (s, 3H).

[0508] HPLC-MS: Rt 2.31 m / z 255.9 (MH + ).

[0509] Intermediate 42 : 2-amino-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzonitrile

[0510]

[0511] A mixture of 2-bromo-4-(5-methyl-l,2,4-oxadiazol-3-yl)aniline (950 mg, 3.74 mmol), zinc cyanide (307 mg, 2.62 mmol), Pd2(dba)3(171 mg, 0.19 mmol), zinc powder (171 mg, 3.74 mmol), dppf (207 mg, 0.37 mmol) was suspended in anhydrous acetonitrile (15 mL) in a sealed tube. The reaction mixture was degassed with nitrogen and stirred at 85 °C for 24 h. The reaction was filtered through celite, eluted with EtOAc and the filtrate washed with NH4OH (aq) / NH4CI (sat.) (1 : 1) and brine. The organic phase was dried over anhydrous Na2S04and evaporated to dryness. The obtained solid was purified by normal phase chromatography to give 2-amino-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzonitrile (320 mg, 42%) as a light brown solid.

[0512] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.92 (d, 1H), 7.86 (dd, 1H), 6.90 (d, 1H), 6.73 (s, 2H), 2.61 (s, 3H).

[0513] HPLC-MS: Rt 1.93 m / z 201.0 (MH + ).

[0514] Intermediate 43 : 2-bromo-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzonitrile

[0515]

[0516] To a solution of 2-amino-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzonitrile (936 mg, 4.68 mmol) in anhydrous acetonitrile (30 mL) was added dropwise isopentyl nitrite (0.875 mL, 6.55 mmol) at 0 °C. The reaction mixture was stirred for 10 min and copper(II) bromide (1315 mg, 5.89 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and HCI (1 M). The organic layer was collected, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by normal phase chromatography (hexane / EtOAc) to give 2-bromo-5-(5-methyl-l,2,4-oxadiazol-3-yl)benzonitrile (710 mg, 57%).

[0517] Obtained as described in the procedure used for intermediate 36 but using 4-bromo-3-cyano-N-hydroxybenzamidine as starting compound.

[0518] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.42 (d, 1 H), 8.17 (dd, 1 H), 8.08 (d, 1 H), 2.69 (s, 3H).

[0519] HPLC-MS: Rt 2.59 m / z 265.9 (MH + ).

[0520] Intermediate 44 : 3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5- methyl-1,2,4-oxadiazole

[0521]

[0522] A solution of 3-(4-bromo-3-cyclopropylphenyl)-5-methyl-1,2,4-oxadiazole (553 mg, 1.98 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (602.0 mg, 2.37 mmol), [1,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium(ll) (80.7 mg, 0.10 mmol) and potassium acetate (581.6 mg, 5.93 mmol) in dioxane (7 mL) was degassed with N2. After the reaction mixture was stirred at 90 °C for 8 h, it was filtered over celite and extracted with ethyl acetate. The organic phase was washed twice with H2O. It was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by flash chromatography (hexane: ethyl acetate) and evaporated to give the product as a yellow solid (540.2 mg, 83.6%).

[0523] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.75 (s, 2H), 7.39 (s, 1 H), 2.65 (s, 3H), 1.33 (s, 12H), 1.16 (d, 1 H), 1.02 (q, 2H), 0.69 (q, 2H).

[0524] HPLC-MS: Rt 3.46 m / z 327.1 (MH + ).

[0525] Intermediate 45 : 3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5- methyl-1,2,4-oxadiazole

[0526] Obtained as described in the procedure used for intermediate 44 but using precursor 37 as starting compound.

[0527] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.84 (m, 2H), 7.67 (d, 1H), 2.68 (s, 3H), 1.32 (s, 12H). 6

[0528] HPLC-MS: Rt 1.13 m / z 223.1 (MH + ).

[0529] Intermediate 46 : 3-(3-Chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-l,2,4- oxadiazole

[0530] Obtained as described in the procedure used for intermediate 44 but using precursor 38 as starting compound.

[0531] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.96 (d, 1H), 7.94 (s, 1H), 7.82 (d, 1H), 2.68 (s, 3H), 1.33 (s, 12H). 6

[0532] HPLC-MS: Rt 3.19 m / z 321.1 (MH + ).

[0533] Intermediate 47 : 5-Methyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)- 1,2,4-oxadiazole

[0534] Obtained as described in the procedure used for intermediate 44 but using precursor 39 as starting compound.

[0535] 1 H-NMR (400 MHz, DMSO-d6): δ = 8.27 (d, 1H), 8.24 (s, 1H), 7.93 (d, 1H), 2.70 (s, 3H), 1.33 (s, 12H). 6

[0536] HPLC-MS: Rt 3.41 m / z 355.0 (MH + ).

[0537] Intermediate 48 ​​​: 3-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5- methyl-1,2,4-oxadiazole

[0538] Obtained as described in the procedure using intermediate 44 but using precursor 40 as starting compound.

[0539] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.69 (s, 1 H), 7.57 (d, 1 H), 7.49 (s, 1 H), 3.83 (s, 3H), 2.67 (s, 3H), 1.29 (s, 12H). 6

[0540] HPLC-MS: Rt 1.83 m / z 235.0 (MH + ).

[0541] Intermediate 49 : 5-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile

[0542] Obtained as described in the procedure using intermediate 44 but using precursor 43 as starting compound.

[0543] 1 H-NMR (400 MHz, DMSO-d6): δ = 8.32 (s, 1 H), 8.28 (dd, 1 H), 8.01 (d, 1 H), 2.70 (s, 3H), 1.34 (s, 12H). 6

[0544] Intermediate 50 : 2'-cyclopropyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1 '-biphenyl]-4-carboxylic acid

[0545]

[0546] ​​In a sealed tube, 3-(4-bromo-3-cyclopropylphenyl)-5-methyl-1,2,4-oxadiazole (441 mg, 1.58 mmol), 4-dihydroxyborylbenzoic acid (262.2 mg, 1.58 mmol), sodium carbonate (703.4 mg, 6.63 mmol) and [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (27.4 mg, 0.02 mmol) were mixed in 6 mL of DME and 1 mL of H2O. The reaction mixture was degassed with nitrogen and stirred at 100°C for 8 hours. The mixture was quenched with HCI 1 M to pH=2-3. The solution was extracted twice with ethyl acetate. The organic layer was collected, dried over Na2S04and the ethyl acetate was removed under vacuum. The obtained solid was purified by CombiFlash chromatographic column (DCM / MeOH) to give the desired compound (315.8 mg, 62.4%).

[0547] 1 H-NMR (400 MHz, DMSO-d6): δ = 13.05 (s, 1 H), 8.04 (d, 2H), 7.87 (dd, 1 H), 7.61 (d, 2H), 7.58 (d, 1 H), 7.42 (d, 1 H), 2.68 (s, 3H), 1.88 (m, 1 H), 0.91 (m, 2H), 0.71 (m, 2H). 6

[0548] HPLC-MS: Rt 1.83 m / z 321.17 (MH + ).

[0549] Intermediate 51 2'-fluoro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1 '-biphenyl]-4-carboxylic acid

[0550] Obtained as described in the procedure used in intermediate 50 but using precursor 37 as starting compound.

[0551] 1 H-NMR (400 MHz, DMSO-d6): δ = 13.12 (s, 1 H), 8.06 (d, 2H), 7.94 (dd, 1 H), 7.86 (dd, 1 H), 7.79 (t, 1 H), 7.74 (d, 2H), 2.69 (s, 3H). 6

[0552] HPLC-MS: Rt 1.68 m / z 299.0 (MH + ).

[0553] Intermediate 52 ​​: 2'-chloro-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1 '-biphenyl]-4-carboxylic acid

[0554] Obtained as described in the procedure using intermediate 50 but using precursor 38 as starting compound.

[0555] 1 H-NMR (400 MHz, DMSO-d6): δ = 13.13 (s, 1 H), 8.12 (d, 1 H), 8.05 (m, 3H), 7.64 (m, 3H), 2.70 (s, 3H). 6

[0556] HPLC-MS: Rt 1.76 m / z 315.0 (MH + ).

[0557] Intermediate 53 : 4'-(5-methyl-1,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[1,1 '-biphenyl]-4-carboxylic acid

[0558] Obtained as described in the procedure using intermediate 50 but using precursor 39 as starting compound.

[0559] 1 H-NMR (400 MHz, DMSO-d6): δ = 13.15 (s, 1 H), 8.35 (s, 1 H), 8.33 (d, 1 H), 8.04 (d, 2H), 7.66 (d, 1 H), 7.51 (d, 2H), 2.72 (s, 3H). 6

[0560] HPLC-MS: Rt 1.86 m / z 349.0 (MH + ).

[0561] Intermediate 54 : 2'-methoxy-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1 '-biphenyl]-4-carboxylic acid

[0562] Obtained as described in the procedure using intermediate 50 but using precursor 40 as starting compound.

[0563] 1 H-NMR (400 MHz, DMSO-d6): δ = 12.91 (s, 1 H), 8.00 (d, 2H), 7.70 (dd, 1 H), 7.66 (m, 3H), 7.53 (d, 1 H), 3.88 (s, 3H), 2.69 (s, 3H). 6

[0564] ​​​HPLC-MS: Rt 1.63 m / z 311.0 (MH + ).

[0565] Intermediate 55 : 2'-cyano-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxylic acid

[0566] Obtained as described in the procedure used for intermediate 50 but using precursor 43 as starting compound.

[0567] 1 H-NMR (400 MHz, DMSO-d 6 ): 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).

[0568] HPLC-MS: Rt 1.61 m / z 306.0 (MH + ).

[0569] Intermediate 56 : 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid methyl ester

[0570]

[0571] To a solution of 3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-5-methyl-1,2,4-oxadiazole (544.7 mg, 1.67 mmol), 6-bromonicotinic acid methyl ester (431.8 mg, 2.00 mmol) and [1,1'-bis(diphenylphosphino)- ferrocene]dichloropalladium(ll) (81.6 mg, 0.10 mmol) in 12.5 mL of dioxane was added 2M Cs2CO3(2.5 mL, 5.00 mmol). The mixture was degassed with N2and stirred at 90 °C overnight. After the reaction was finished, it was extracted with ethyl acetate and washed with saturated NaHCO3and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by flash chromatography (hexane: ethyl acetate) and evaporated to give the desired product as a white solid (407.2 mg, 72.7%).

[0572] 1 H-NMR (400 MHz, DMSO-d 6): δ = 9.21 (d, 1H), 8.40 (dd, 1H), 7.91 (dd, 1H), 7.86 (d, 1H), 7.67 - 7.59 (m, 2H), 3.93 (s, 3H), 2.68 (s, 3H), 2.19 - 2.09 (m, 1H), 0.94 - 0.87 (m, 2H), 0.66 (q, 2H).

[0573] HPLC-MS: Rt 2.81 m / z 330.0 (MH + ).

[0574] Intermediate 57 : 6-(2-fluoro-4-(5-methyl-1, 2, 4-oxadiazol-3-yl) phenyl) nicotinic acid methyl ester

[0575] Obtained as described in the procedure using intermediate 56 but using precursor 45 as starting compound.

[0576] 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).

[0577] HPLC-MS: Rt 2.81 m / z 330.0 (MH + ).

[0578] Intermediate 58 : 6-(2-fluoro-4-(5-methyl-1, 2, 4-oxadiazol-3-yl) phenyl) nicotinic acid methyl ester

[0579] Obtained as described in the procedure using intermediate 56 but using precursor 45 as starting compound.

[0580] 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).

[0581] HPLC-MS: Rt 2.81 m / z 330.0 (MH + ).

[0582] Intermediate 596-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl) nicotinic acid methyl ester

[0583] Obtained using the procedure described in intermediate 56, but with precursor 47 as the starting compound.

[0584] 1 H-NMR (400MHz, DMSO-d) 6 ): 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).

[0585] HPLC-MS: Rt 2.88 m / z 364.0 (MH) + ).

[0586] Intermediate 60 6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl) nicotinic acid methyl ester

[0587] Obtained using the procedure described in intermediate 56, but with precursor 48 as the starting compound.

[0588] 1 H-NMR (400MHz, 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).

[0589] HPLC-MS: Rt 2.66 m / z 326.0 (MH) + ).

[0590] Intermediate 61 6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl) nicotinic acid methyl ester

[0591] Obtained using the procedure described in intermediate 56, but using precursor 49 as the starting compound.

[0592] 1 H-NMR (400MHz, 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).

[0593] HPLC-MS: Rt 2.53 m / z 321.0 (MH + ).

[0594] Intermediate 62 : 2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxylic acid ethyl ester

[0595]

[0596] In a sealed tube, 541.5 mg (1.66 mmol) of 3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1,2,4-oxadiazole, 2-chloropyrimidine-5-carboxylic acid ethyl ester (404.1 mg, 2.16 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (81.6 mg, 0.09 mmol), potassium phosphate (1060.7 mg, 4.99 mmol) were mixed in 15 mL of anhydrous DME and 3 mL of H2O. The mixture was stirred at 90°C overnight. The reaction mixture was filtered over celite, eluted with EtOAc and the filtrate washed with saturated NaHCO3. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography column (hexane / ethyl acetate) to obtain 2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxylic acid ethyl ester (278.6 mg, 47.9%).

[0597] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 9.38 (s, 1H), 7.94 (dd, 1H), 7.89 (d, 1H), 7.66 (s, 1H), 4.41 (q, 2H), 2.69 (s, 3H), 2.60 (ddd, 1H), 1.37 (t, 3H), 0.96 - 0.87 (m, 2H), 0.64 (q, 2H).

[0598] HPLC-MS: Rt 3.01 m / z 351.1 (MH + ).

[0599] Intermediate 636-(2-Cyclopropyl-4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid

[0600]

[0601] To a solution of intermediate 56 methyl 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid (325.3 mg, 0.97 mmol) 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 hours. The solvent was evaporated and the pH was adjusted to 2.0 by adding 1 M HCl. The solid was filtered and washed with water and pentane (284.6 mg, 91.3%).

[0602] 1 H-NMR (400MHz, DMSO-d) 6 ): δ=13.49(s,1H),9.19(s,1H),8.37(dd,1H),7.90(d,1H),7.83(d,1H),7.6 6–7.58(m,2H),2.68(s,3H),2.14(ddd,1H),0.95–0.87(m,2H),0.67(q,2H).

[0603] HPLC-MS: Rt 1.63 m / z 322.1 (MH) + ).

[0604] Intermediate 64 2-(2-Cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5-carboxylic acid

[0605]

[0606] Add 4 mL (3.99 mmol) of 1 M NaOH to a solution of ethyl 2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidin-5-carboxylate (276.8 mg, 0.79 mmol) in 6 mL THF and 2 mL MeOH. Stir the mixture overnight at room temperature. Remove the solvent under vacuum. Neutralize the aqueous phase with 4 M HCl and acidify to pH 2 with 1 M HCl. Filter the obtained solid and wash with water and pentane (218 mg, 85.6%).

[0607] 1 H-NMR (400MHz, 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).

[0608] HPLC-MS: Rt 1.54 m / z: 323.0 (MH + ).

[0609] Intermediate 65 : 6-(2-Fluoro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid

[0610] Obtained as described in the procedure using intermediate 63 but using precursor 57 as starting compound.

[0611] 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).

[0612] HPLC-MS: Rt 1.53 m / z 300.0 (MH + ).

[0613] Intermediate 66 : 6-(2-Chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid

[0614] Obtained as described in the procedure using intermediate 63 but using precursor 58 as starting compound.

[0615] 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).

[0616] HPLC-MS: Rt 1.56 m / z 316.0 (MH + ).

[0617] Intermediate 67 : 6-(4-(5-Methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinic acid

[0618] Obtained using the procedure described in intermediate 63, but using precursor 59 as the starting compound.

[0619] 1 H-NMR (400MHz, 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).

[0620] HPLC-MS: Rt 1.68 m / z 350.0 (MH) + ).

[0621] Intermediate 68 6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid

[0622] Obtained using the procedure described in intermediate 63, but using precursor 60 as the starting compound.

[0623] 1 H-NMR (400MHz, 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).

[0624] HPLC-MS: Rt 1.48 m / z 312.0 (MH) + ).

[0625] Intermediate 69 6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinic acid

[0626] Obtained using the procedure described in intermediate 63, but using precursor 61 as the starting compound.

[0627] 1 H-NMR (400MHz, 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).

[0628] HPLC-MS: Rt 1.46 m / z 307.0 (MH) + ).

[0629] Intermediate 70 : 6-(2-cyclopropyl-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)nicotinic acid

[0630]

[0631] Intermediate 63, 6-(2-cyclopropyl-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)nicotinic acid (385.6 mg, 1.12 mmol) was suspended in 2.6 mL (35.64 mmol) of thionyl chloride and the reaction mixture was stirred at reflux for three hours. The reaction was allowed to cool to room temperature and the solvent was removed under vacuum. The solid was used in the next reaction step without further purification.

[0632] Intermediate 71 : 2-(2-cyclopropyl-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)pyrimidine-5- carbonyl chloride

[0633] Obtained as described in the procedure using Intermediate 70 but precursor 64 as starting compound. The solid was used in the next reaction step without further purification.

[0634] Intermediate 72 : 2'-fluoro-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-[l,l'-biphenyl]-4-carbonyl chloride

[0635] Obtained as described in the procedure using Intermediate 70 but precursor 51 as starting compound. The solid was used in the next reaction step without further purification.

[0636] Intermediate 73 : 2'-chloro-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-[l,l'-biphenyl]-4-carbonyl chloride

[0637] Obtained as described in the procedure using Intermediate 70 but precursor 52 as starting compound. The solid was used in the next reaction step without further purification.

[0638] Intermediate 74 : 4'-(5-methyl-l,2,4-oxadiazol-3-yl)-2'-(trifluoromethyl)-[l,l'-biphenyl]-4- carbonyl chloride

[0639] Obtained as described in the procedure using Intermediate 70 but precursor 53 as starting compound. The solid was used in the next reaction step without further purification.

[0640] Intermediate 75 : 2'-methoxy-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-[l,l'-biphenyl]-4-carbonyl chloride

[0641] Obtained as described in the procedure using Intermediate 70 but with precursor 54 as the starting compound. The solid was used in the next reaction step without further purification.

[0642] Intermediate 76 : 2'-cyano-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-[l,l'-biphenyl]-4-carbonyl chloride

[0643] Obtained as described in the procedure using Intermediate 70 but with precursor 55 as the starting compound. The solid was used in the next reaction step without further purification.

[0644] Intermediate 77 : 6-(2-fluoro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride

[0645] Obtained as described in the procedure using Intermediate 70 but with precursor 65 as the starting compound. The solid was used in the next reaction step without further purification.

[0646] Intermediate 78 : 6-(2-chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride

[0647] Obtained as described in the procedure using Intermediate 70 but with precursor 66 as the starting compound. The solid was used in the next reaction step without further purification.

[0648] Intermediate 79 : 6-(4-(5-methyl-l,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinoyl chloride

[0649] Obtained as described in the procedure using Intermediate 70 but with precursor 67 as the starting compound. The solid was used in the next reaction step without further purification.

[0650] Intermediate 80 : 6-(2-methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride

[0651] Obtained as described in the procedure using Intermediate 70 but with precursor 68 as the starting compound. The solid was used in the next reaction step without further purification.

[0652] Intermediate 81 : 6-(2-cyano-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride

[0653] Obtained as described in the procedure using Intermediate 70 but with precursor 69 as the starting compound. The solid was used in the next reaction step without further purification.

[0654] Intermediate 82 : 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine

[0655]

[0656] A solution of 541.49 mg (1.66 mmol) of 3-(3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-1,2,4-oxadiazole, 6-bromo-pyridin-3-amine (288.2 mg, 1.66 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (81.6 mg, 0.09 mmol) and potassium phosphate (707.2, 3.33 mmol) in 15 mL of DME and 2.5 mL of H2O was stirred at 90°C for 16 hours. The reaction mixture was filtered over celite and the filtrate was washed twice with saturated NaHCO3. The organic layer was collected, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography column (hexane / ethyl acetate) to obtain the amine intermediate (279.5 mg, 57.6%).

[0657] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.05 (d, 1H), 7.80 (dd, 1H), 7.53 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 7.01 (dd, 1H), 5.48 (s, 2H), 2.66 (s, 3H), 2.22 (tt, 1H), 0.95 - 0.87 (m, 2H), 0.68 - 0.61 (m, 2H).

[0658] HPLC-MS: Rt 2.24 m / z 293.1 (MH + ).

[0659] Intermediate 83 : 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine

[0660] Obtained as described in the procedure using intermediate 82 but precursor 45 as starting compound.

[0661] 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).

[0662] HPLC-MS: Rt 2.81 m / z 499.1 (MH + ).

[0663] Intermediate 84 : 6-(2-Chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine

[0664] Obtained as described in the procedure using intermediate 82 but precursor 46 as starting compound.

[0665] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.06 (d, 1 H), 8.03 (d, 1 H), 7.98 (dd, 1 H), 7.76 (d, 1 H), 7.48 (d, 1 H), 7.01 (dd, 1 H), 5.65 (s, 2 H), 2.68 (s, 3 H).

[0666] HPLC-MS: Rt 2.23 m / z 287.0 (MH + ).

[0667] Intermediate 85 : 6-(4-(5-Methyl-l,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)pyridin-3-amine

[0668] Obtained as described in the procedure using intermediate 82 but precursor 47 as starting compound.

[0669] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.30 (s, 1 H), 8.27 (d, 1 H), 8.01 (d, 1 H), 7.72 (d, 1 H), 7.25 (d, 1 H), 7.01 (dd, 1 H), 5.62 (s, 2 H), 2.70 (s, 3 H).

[0670] HPLC-MS: Rt 2.38 m / z 321.1 (MH + ).

[0671] Intermediate 86 : 6-(2-Methoxy-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)pyridin-3-amine

[0672] Obtained as described in the procedure using intermediate 82 but precursor 48 as starting compound.

[0673] 1 H-NMR (400 MHz, DMSO-d6 ): δ = 8.05 (d, 1 H), 7.93 (d, 1 H), 7.70 (d, 1 H), 7.64 (d, 1 H), 7.61 (s, 1 H), 6.96 (dd, 1 H), 5.56 (s, 2H), 3.91 (s, 3H), 2.68 (s, 3H).

[0674] HPLC-MS: Rt 2.06 m / z 278.0 (MH + ).

[0675] Intermediate 87 : 2-(5-Aminopyridin-2-yl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzonitrile

[0676] Obtained as described in the procedure using intermediate 82 but precursor 49 as starting compound.

[0677] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 8.32 (d, 1 H), 8.26 (dd, 1 H), 8.10 (d, 1 H), 8.01 (d, 1 H), 7.68 (d, 1 H), 7.06 (dd, 1 H), 5.87 (s, 2H), 2.70 (s, 3H).

[0678] HPLC-MS: Rt 2.06 m / z 278.0 (MH + ).

[0679] Examples

[0680] Example 1 : N-(4-Bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0681] (Example of general procedure A according to scheme 6)

[0682]

[0683] To a solution of intermediate 63 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)nicotinic acid (109.3 mg, 0.34 mmol) in dry DMF (1.7 mL) was added HATU (141.6 mg, 0.37 mmol) and DIPEA (0.13 mL, 0.75 mmol). After stirring the reaction at room temperature under N2for 15 min, 4-bromo-3-(2-(dimethylamino)ethoxy)aniline (105.3 mg, 0.41 mmol) was added and the reaction was stirred overnight at room temperature. The mixture was extracted twice with saturated NaHCO3and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue which was purified by flash chromatography (dichloromethane:methanol 10%) to give the product as a white solid (95.4 mg, 49.9%).

[0684] General procedure B according to scheme 6

[0685]

[0686] To a solution of 4-bromo-3-(2-(dimethylamino)ethoxy)aniline (64.8 mg, 0.25 mmol) and N,N-dimethylpyridin-4-amine (1.5 mg, 0.01 mmol) in dry CH3CN was added triethylamine (104.1 μL, 0.75 mmol). After stirring the reaction at room temperature under N2for 15 min, 6-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinoyl chloride (84.6 mg, 0.25 mmol) was added dropwise at 0°C and the reaction was stirred overnight at room temperature. The mixture was extracted twice with saturated NaHCO3and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue which was purified by flash chromatography (dichloromethane:methanol 10%) to give the product as a white solid (84.5 mg, 60.3%).

[0687] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.61 (s, 1H), 9.23 (d, 1H), 8.42 (dd, 1H), 7.94 - 7.90 (m, 1H), 7.87 (d, 1H), 7.68 (d, 1H), 7.67 - 7.61 (m, 2H), 7.56 (d, 1H), 7.40 (dd, 1H), 4.14 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.31 (s, 6H), 2.18 (ddd, 1H), 0.97 - 0.87 (m, 2H), 0.69 (q, 2H).

[0688] HPLC-MS: Rt 2.99 m / z 563.1 (MH + ).

[0689] Examples 2-6 below were synthesized according to the general procedure A described for example 1 using the corresponding carboxylic acid and arylamide.

[0690] Example 2 : N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0691] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.62 (s, 1 H), 9.26 (d, 1 H), 8.44 (dd, 1 H), 8.23 (t, 1 H), 8.03 (dd, 2H), 7.91 (d, 1 H), 7.67 (d, 1 H), 7.56 (d, 1 H), 7.38 (dd, 1 H), 4.12 (t, 2H), 2.72 (d, 2H), 2.70 (s, 3H), 2.27 (s, 6H).

[0692] HPLC-MS: Rt 2.96 m / z 541.9 (MH + ).

[0693] Example 3 : N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-fluoro-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0694] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.65 (s, 1 H), 9.23 (s, 1 H), 8.43 (d, 1 H), 8.15 (s, 1 H), 8.11 (d, 1 H), 7.95 (d, 1 H), 7.86 (d, 1 H), 7.68 (s, 1 H), 7.57 (d, 1 H), 7.39 (d, 1 H), 4.14 (t, 2H), 2.75 (t, 2H), 2.71 (s, 3H), 2.30 (s, 6H).

[0695] HPLC-MS: Rt 2.98 m / z 557.9 (MH + ).

[0696] Example 4N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenyl)nicotinamide

[0697] 1 H-NMR (400MHz, 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,1 H),7.67(d,1H),7.56(d,1H),7.40(dd,1H),4.13(t,2H),2.72(m,5H),2.27(s,6H).

[0698] HPLC-MS: Rt 3.04 m / z 591.9 (MH) + ).

[0699] Example 5 N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0700] 1 H-NMR (400MHz, 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),7.6 9(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).

[0701] HPLC-MS: Rt 2.86 m / z 554.0 (MH) + ).

[0702] Example 6 N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyano-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0703] 1 H-NMR (400MHz, 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).

[0704] HPLC-MS: Rt 2.76 m / z 509.1 (MH + ).

[0705] Examples 7-64 below were synthesized according to the general procedure B described for example 1 using the corresponding carboxylic acid chloride and aryl amide.

[0706] Example 7 : N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0707] 1 H-NMR (400 MHz, DMSO-d 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).

[0708] HPLC-MS: Rt 2.76 m / z 509.1 (MH + ).

[0709] Example 8 : N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-cyclopropyl-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0710] 1 H-NMR (400 MHz, DMSO-d 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).

[0711] HPLC-MS: Rt 2.73 m / z 487.0 (MH + ).

[0712] Example 9 : 6-(2-Chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)-N-(4-cyano-3-(2- (dimethylamino)ethoxy)phenyl)nicotinamide

[0713] 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).

[0714] HPLC-MS: Rt 2.74 m / z 503.0 (MH + ).

[0715] Example 10 : N-(4-Cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(4-(5-methyl-l,2,4-oxadiazol-3- yl)-2-(trifluoromethyl)phenyl)nicotinamide

[0716] 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).

[0717] HPLC-MS: Rt 2.83 m / z 537.0 (MH + ).

[0718] Example 11 : N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0719] 1 H-NMR (400 MHz, DMSO-d 6 6): δ = 10.81 (s, 1 H), 9.21 (s, 1 H), 8.36 (dd, 1 H), 8.06 (m, 2H), 7.80 (d, 1 H), 7.72 (d, 3H), 7.53 (dd, 1 H), 4.21 (t, 2H), 3.97 (s, 3H), 2.72 (m, 5H), 2.27 (s, 6H).

[0720] HPLC-MS: Rt 2.61 m / z 499.0 (MH + ).

[0721] Example 12 : N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0722] 1 H-NMR (400 MHz, DMSO-d 6 6): δ = 10.90 (s, 1 H), 9.29 (d, 1 H), 8.52 (dd, 1 H), 8.49 (d, 1 H), 8.42 (dd, 1 H), 8.20 (d, 1 H), 8.17 (d, 1 H), 7.80 (s, 1 H), 7.73 (d, 1 H), 7.54 (dd, 1 H), 4.22 (t, 2H), 2.75 (t, 2H), 2.73 (s, 3H), 2.28 (s, 6H).

[0723] HPLC-MS: Rt 2.51 m / z 494.1 (MH + ).

[0724] Example 13 : N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0725] 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).

[0726] HPLC-MS: Rt 2.89 m / z 564.0 (MH + ).

[0727] 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

[0728] 1 H-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).

[0729] HPLC-MS: Rt 2.74 m / z 510.0 (MH + ).

[0730] 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

[0731] 1 H-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).

[0732] HPLC-MS: Rt 3.29 m / z 564.0 (MH + ).

[0733] 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

[0734] 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).

[0735] HPLC-MS: Rt 3.24 m / z 557.9 (MH + ).

[0736] Example 17 : 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

[0737] 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).

[0738] HPLC-MS: Rt 3.24 m / z 557.9 (MH + ).

[0739] 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

[0740] 1 H-NMR (400 MHz, DMSO-d6): δ = 11.07 (s, 1 H), 8.37 (d, 2H), 8.34 (d, 1 H), 8.13 (d, 2H), 8.07 (s, 1 H), 7.67 (d, 1 H), 7.53 (d, 2H), 4.27 (t, 2H), 2.73 (m, 5H), 2.27 (s, 6H). 6

[0741] HPLC-MS: Rt 3.28 m / z 592.0 (MH + ).

[0742] Example 19 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

[0743] 1 H-NMR (400 MHz, DMSO-d6): δ = 10.99 (s, 1 H), 8.39 (s, 1 H), 8.09 (m, 3H), 7.70 (dd, 4H), 7.55 (d, 1 H), 4.28 (t, 2H), 3.89 (s, 3H), 2.77 (t, 2H), 2.70 (s, 3H), 2.29 (s, 6H). 6

[0744] HPLC-MS: Rt 3.04 m / z 554.0 (MH + ).

[0745] 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

[0746] 1 H-NMR (400 MHz, DMSO-d6): δ = 10.99 (s, 1 H), 8.39 (s, 1 H), 8.09 (m, 3H), 7.70 (dd, 4H), 7.55 (d, 1 H), 4.28 (t, 2H), 3.89 (s, 3H), 2.77 (t, 2H), 2.70 (s, 3H), 2.29 (s, 6H). 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).

[0747] HPLC-MS: Rt 2.93 m / z 549.0 (MH + ).

[0748] Example 21 : 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

[0749] 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).

[0750] HPLC-MS: Rt 2.93 m / z 549.0 (MH + ).

[0751] 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

[0752] 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).

[0753] HPLC-MS: Rt 2.93 m / z 549.0 (MH + ).

[0754] 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

[0755] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.38 (s, 1 H), 8.67 (s, 1 H), 8.14 (d, 4H), 8.05 (d, 1 H), 7.66 (m, 3H), 4.34 (t, 2H), 2.75 (t, 2H), 2.70 (s, 3H), 2.27 (s, 6H).

[0756] HPLC-MS: Rt 2.99 m / z 503.0 (MH + ).

[0757] 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

[0758] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.41 (s, 1 H), 8.68 (s, 1 H), 8.36 (s, 1 H), 8.34 (d, 1 H), 8.14 (s, 1 H), 8.13 (d, 2H), 7.67 (d, 1 H), 7.54 (d, 2H), 4.39 (t, 2H), 2.88 (t, 2H), 2.72 (s, 3H), 2.36 (s, 6H).

[0759] HPLC-MS: Rt 3.04 m / z 537.1 (MH + ).

[0760] 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

[0761] 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).

[0762] HPLC-MS: Rt 2.71 m / z 494.0 (MH + ).

[0763] 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

[0764] 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).

[0765] HPLC-MS: Rt 2.71 m / z 494.0 (MH + ).

[0766] 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

[0767] 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).

[0768] HPLC-MS: Rt 3.51 m / z 563.9 (MH+ ).

[0769] 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

[0770] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.75 (s, 1 H), 8.11 (d, 2H), 8.02 (d, 1 H), 7.96 (d, 1 H), 7.89 (d, 1 H), 7.82 (t, 1 H), 7.78 (d, 2H), 7.75 (d, 1 H), 4.47 (t, 2H), 2.70 (s, 3H), 2.66 (t, 2H), 2.24 (s, 6H).

[0771] HPLC-MS: Rt 3.31 m / z 541.9 (MH + ).

[0772] Example 29 : 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

[0773] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.77 (s, 1 H), 8.10 (m, 3H), 8.03 (m, 2H), 7.75 (d, 1 H), 7.67 (m, 3H), 4.47 (t, 2H), 2.71 (s, 3H), 2.68 (t, 2H), 2.25 (s, 6H).

[0774] HPLC-MS: Rt 3.44 m / z 557.8 (MH + ).

[0775] Example 30 : 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

[0776] 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).

[0777] HPLC-MS: Rt 3.21 m / z 509.0 (MH + ).

[0778] 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

[0779] 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).

[0780] HPLC-MS: Rt 3.03 m / z 487.0 (MH + ).

[0781] 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

[0782] 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).

[0783] HPLC-MS: Rt 3.14 m / z 503.0 (MH + ).

[0784] 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

[0785] 1 H-NMR (400MHz, 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),4.5 1(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).

[0786] HPLC-MS: Rt 2.99 m / z 565.0 (MH) + ).

[0787] 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

[0788] 1 H-NMR (400MHz, 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).

[0789] HPLC-MS: Rt 2.81 m / z 542.9 (MH) + ).

[0790] 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-

[0791] 1 H-NMR (400MHz, 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).

[0792] HPLC-MS: Rt 2.94 m / z 558.8 (MH + ).

[0793] Example 36 : 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

[0794] 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).

[0795] HPLC-MS: Rt 2.83 m / z 510.3 (MH + ).

[0796] 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

[0797] 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).

[0798] HPLC-MS: Rt 2.68 m / z 488.0 (MH + ).

[0799] 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

[0800] 1 H-NMR (400MHz, 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).

[0801] HPLC-MS: Rt 2.78 m / z 504.0 (MH) + ).

[0802] 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

[0803] 1 H-NMR (400MHz, 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).

[0804] HPLC-MS: Rt 2.91 m / z 564.1 (MH) + ).

[0805] 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

[0806] 1 H-NMR (400MHz, 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).

[0807] HPLC-MS: Rt 2.88 m / z 542.8 (MH + ).

[0808] 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

[0809] 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).

[0810] HPLC-MS: Rt 2.89 m / z 558.9 (MH + ).

[0811] 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

[0812] 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).

[0813] HPLC-MS: Rt 2.98 m / z 593.0 (MH + ).

[0814] 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

[0815] 1 H-NMR (400 MHz, DMSO-d 6 6): δ = 11.25 (s, 1 H), 9.24 (d, 1 H), 8.40 (m, 2H), 8.09 (d, 2H), 8.03 (d, 1 H), 7.74 (d, 1 H), 7.71 (s, 1 H), 4.28 (t, 2H), 3.97 (s, 3H), 2.77 (t, 2H), 2.70 (s, 3H), 2.29 (s, 6H).

[0816] HPLC-MS: Rt 2.76 m / z 554.9 (MH + ).

[0817] Example 44 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0818] 1 H-NMR (400 MHz, DMSO-d 6 6): δ = 11.41 (s, 1 H), 9.30 (d, 1 H), 8.57 (dd, 1 H), 8.49 (s, 1 H), 8.45 (s, 1 H), 8.42 (dd, 1 H), 8.19 (d, 1 H), 8.13 (d, 1 H), 8.09 (s, 1 H), 4.46 (t, 2H), 3.21 (t, 2H), 2.73 (s, 3H), 2.62 (s, 6H).

[0819] HPLC-MS: Rt 2.71 m / z 549.9 (MH + ).

[0820] Example 45 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(2-methoxy-4-(5-methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0821] 1 H-NMR (400 MHz, 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).

[0822] HPLC-MS: Rt 2.70 m / z 510.1 (MH + ).

[0823] 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

[0824] 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).

[0825] HPLC-MS: Rt 2.64 m / z 488.0 (MH + ).

[0826] 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

[0827] 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).

[0828] HPLC-MS: Rt 2.69 m / z 504.0 (MH + ).

[0829] 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

[0830] 1 H-NMR (400 MHz, DMSO-d 6 6): δ = 11.65 (s, 1 H), 9.22 (d, 1 H), 8.69 (s, 1 H), 8.50 (dd, 1 H), 8.39 (m, 2H), 8.13 (s, 1 H), 7.83 (d, 1 H), 7.77 (d, 1 H), 4.34 (t, 2H), 2.75 (t, 2H), 2.73 (s, 3H), 2.26 (s, 6H).

[0831] HPLC-MS: Rt 2.74 m / z 538.1 (MH + ).

[0832] 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

[0833] 1 H-NMR (400 MHz, DMSO-d 6 6): δ = 11.55 (s, 1 H), 9.23 (d, 1 H), 8.68 (s, 1 H), 8.40 (dd, 1 H), 8.14 (s, 1 H), 8.09 (d, 1 H), 8.03 (d, 1 H), 7.74 (d, 1 H), 7.71 (s, 1 H), 4.34 (t, 2H), 3.97 (s, 3H), 2.75 (t, 2H), 2.70 (s, 3H), 2.27 (s, 6H).

[0834] HPLC-MS: Rt 2.56 m / z 500.0 (MH + ).

[0835] 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

[0836] 1H-NMR (400MHz, 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,1 H),8.19(d,1H),8.14(d,2H),4.46(t,2H),3.05(t,2H),2.73(s,3H),2.45(s,6H).

[0837] HPLC-MS: Rt 2.49 m / z 495.0 (MH) + ).

[0838] 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

[0839] 1 H-NMR (400MHz, 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).

[0840] HPLC-MS: Rt 3.18 m / z 564.9 (MH) + ).

[0841] 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

[0842] 1 H-NMR (400MHz, 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).

[0843] HPLC-MS: Rt 3.13 m / z 542.9 (MH + ).

[0844] 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

[0845] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.03 (s, 1 H), 9.21 (d, 1 H), 8.44 (dd, 1 H), 8.14 (s, 1 H), 8.10 (d, 1 H), 8.04 (d, 1 H), 7.92 (d, 1 H), 7.85 (d, 1 H), 7.75 (d, 1 H), 4.46 (t, 2 H), 2.71 (s, 3 H), 2.66 (t, 2 H), 2.24 (s, 6 H).

[0846] HPLC-MS: Rt 3.16 m / z 558.8 (MH + ).

[0847] 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

[0848] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.31 (s, 1 H), 9.22 (s, 1 H), 8.43 (d, 1 H), 8.26 (d, 1 H), 7.92 (d, 2 H), 7.86 (d, 1 H), 7.63 (m, 2 H), 4.55 (s, 2 H), 2.69 (s, 5 H), 2.26 (s, 6 H), 2.18 (s, 1 H), 0.92 (d, 2 H), 0.69 (d, 2 H).

[0849] HPLC-MS: Rt 2.88 m / z 510.0 (MH + ).

[0850] 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

[0851] 1 H-NMR (400 MHz, DMSO-d6 ): 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).

[0852] HPLC-MS: Rt 2.83 m / z 488.0 (MH + ).

[0853] 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

[0854] 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).

[0855] HPLC-MS: Rt 2.84 m / z 504.0 (MH + ).

[0856] 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

[0857] 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).

[0858] HPLC-MS: Rt 2.66 m / z 565.9 (MH + ).

[0859] 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

[0860] 1 H-NMR (400 MHz, DMSO-d 6 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).

[0861] HPLC-MS: Rt 2.61 m / z 543.9 (MH + ).

[0862] Example 59 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5- methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0863] 1 H-NMR (400 MHz, DMSO-d 6 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).

[0864] HPLC-MS: Rt 2.64 m / z 559.8 (MH + ).

[0865] Example 60 : N-(5-bromo-4-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-6-(2-fluoro-4-(5- methyl- 1,2,4-oxadiazol-3-yl)phenyl)nicotinamide

[0866] 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).

[0867] HPLC-MS: Rt 2.46 m / z 511.1 (MH + ).

[0868] 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

[0869] 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).

[0870] HPLC-MS: Rt 2.39 m / z 489.0 (MH + ).

[0871] 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

[0872] 1 H-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).

[0873] HPLC-MS: Rt 2.43 m / z 505.0 (MH+ ).

[0874] 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

[0875] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.49 (s, 1 H), 9.43 (s, 2H), 8.43 (s, 1 H), 8.07 (s, 1 H), 7.92 (q, 2H), 7.67 (s, 1 H), 4.28 (t, 2H), 2.75 (t, 2H), 2.69 (s, 3H), 2.63 (td, 1 H), 2.28 (s, 6H), 0.98 - 0.88 (m, 2H), 0.66 (q, 2H).

[0876] HPLC-MS: Rt 2.89 m / z 565.0 (MH + ).

[0877] Example 64 : 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

[0878] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 11.78 (s, 1 H), 9.44 (s, 2H), 8.71 (s, 1 H), 8.13 (s, 1 H), 7.92 (q, 2H), 7.67 (s, 1 H), 4.35 (t, 2H), 2.75 (t, 2H), 2.69 (s, 3H), 2.63 (td, 1 H), 2.27 (s, 6H), 0.98 - 0.89 (m, 2H), 0.66 (q, 2H).

[0879] HPLC-MS: Rt 2.67 m / z 511.0 (MH + ).

[0880] 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

[0881] (Example of a general procedure according to Scheme 7b)

[0882]

[0883] To a solution of 4-bromo-3-(2-(dimethylamino)ethoxy)benzoic acid (80 mg, 0.29 mmol), HATU (124.1 mg, 0.32 mmol) and DIPEA (0.11 mL, 0.65 mmol) in 0.5 mL dry DMF was added dropwise 6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-amine (85.3 mg, 0.29 mmol) in 1.0 mL dry DMF. The mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed twice with saturated NaHC03. The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by CombiFlash chromatography column (DCM / MeOH) to give 4-bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(2-fluoro-4-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl)pyridin-3-yl)benzamide (91.4 mg, 57.1 %).

[0884] 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 10.82 (s, 1 H), 9.15 (d, 1 H), 8.38 (dd, 1 H), 8.20 (t, 1 H), 7.96 (t, 2H), 7.86 (dd, 2H), 7.77 (d, 1 H), 7.64 (dd, 1 H), 4.59 (m, 2H), 3.63 (d, 2H), 2.95 (d, 6H), 2.70 (s, 3H).

[0885] HPLC-MS: Rt 2.98 m / z 542.0 (MH + ).

[0886] Examples 66 to 76 were obtained as shown in Example 65, starting from the corresponding carboxylic acid and amine.

[0887] 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

[0888] 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).

[0889] HPLC-MS: Rt 2.99 m / z 564.0 (MH + ).

[0890] Example 67 : 4-Bromo-N-(6-(2-chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl)pyridin-3-yl)-3- (2-(dimethylamino)ethoxy)benzamide

[0891] 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).

[0892] HPLC-MS: Rt 3.01 m / z: 557.9 (MH + ).

[0893] Example 68 : 4-Bromo-3-(2-(dimethylamino)ethoxy)-N-(6-(4-(5-methyl-l,2,4-oxadiazol-3-yl)-2- (trifluoromethyl)phenyl)pyridin-3-yl)benzamide

[0894] 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).

[0895] HPLC-MS: Rt 3.06 m / z: 592.0 (MH+ )..

[0896] 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

[0897] 1 H-NMR (400 MHz, DMSO-d 6 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).

[0898] HPLC-MS: Rt 2.84 m / z 553.9 (MH + )..

[0899] 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

[0900] 1 H-NMR (400 MHz, DMSO-d 6 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).

[0901] HPLC-MS: Rt 2.84 m / z: 548.9 (MH + )..

[0902] 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

[0903] 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).

[0904] HPLC-MS: Rt 2.74 m / z 509.1 (MH + ).

[0905] 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

[0906] 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).

[0907] HPLC-MS: Rt 2.71 m / z 487.1 (MH + ).

[0908] 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

[0909] 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).

[0910] HPLC-MS: Rt 2.74 m / z: 503.1 (MH + ).

[0911] 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

[0912] 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).

[0913] HPLC-MS: Rt 2.81 m / z: 537.1 (MH + ).

[0914] 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

[0915] 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).

[0916] HPLC-MS: Rt 2.59 m / z 499.0 (MH + ).

[0917] 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

[0918] 1H-NMR (400 MHz, DMSO-d 6 ): δ = 10.89 (s, 1 H), 9.12 (d, 1 H), 8.45 (d, 1 H), 8.42 (dd, 1 H), 8.38 (dd, 1 H), 8.13 (d, 1 H), 8.03 (t, 2H), 7.79 (d, 1 H), 7.75 (dd, 1 H), 4.56 (t, 2H), 3.39 (t, 2H), 2.76 (s, 6H), 2.72 (s, 3H).

[0919] HPLC-MS: Rt 2.56 m / z 494.0 (MH + ).

Claims

1. A compound of formula (I): in: -G indicates that the following groups are selected: a)-C(O)NH-, b)--NHC(O)-, -X 1 X 2 X 3 and X 4 Represents N atom or CR 5 Group, -R 1 and R 2 It is methyl; -R 3 It indicates that the group is selected from the following: a) cyano group, and b) Halogen atoms, -R 4 It indicates that the group is selected from the following: a) Halogen atom, b) C3-C4 cycloalkyl groups, c) C1-C3 alkoxy groups, d) C1-C3 haloalkyl groups, e) Cyano group -R 5 It indicates that the group is selected from the following: a) Hydrogen atom, b) C1-C3 alkyl groups, c) Halogen atoms, The limiting condition is the X 1 X 2 X 3 and X 4 At least one of them represents the N atom and its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein G represents -C(O)NH, and wherein the carbonyl group is attached to the compound containing X. 3 and X 4 The ring and amino group are connected to the X-containing ring. 1 and X 2 The ring.

3. The compound according to claim 1 or 2, wherein R 3 It is a cyano group.

4. The compound according to claim 1 or 2, wherein R 4 Selected from halogen atoms and C3-C4 cycloalkyl groups.

5. The compound according to claim 4, wherein R 4 It is selected from chlorine atoms, fluorine atoms and cyclopropyl groups.

6. The compound according to claim 1 or 2, wherein the core: Selected from: Where X 3 It is N and X 1 X 2 X 4 And G as defined in any of claims 1 and 2, Where X 1 It is N and X 2 X 3 X 4 and G as defined in any of claims 1 and 2; and Where X 1 and X 3 It is N and X 2 X 4 And G as defined in any of claims 1 and 2.

7. The compound according to claim 6, wherein the core: yes: Wherein G is as defined in any of claims 1 and 2.

8. The compound according to claim 6, wherein the core: yes: Wherein G is as defined in any of claims 1 and 2.

9. The compound according to claim 1, having one of the following formulas (Ia), (Ib) and (Ic): Where R 4 This indicates a group selected from halogen atoms and cyclopropyl groups.

10. The compound according to claim 1, wherein the compound is selected from 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)pyrimidin-5-carboxamide N-(4-cyano-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-cyclopropyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)pyrimidin-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)pyrimidin-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)pyrimidin-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.

11. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 10 and a pharmaceutically acceptable diluent or carrier.

12. A combination product comprising the compound as claimed in any one of claims 1 to 10 and a therapeutic agent selected from: chemotherapeutic agents selected from vincristine, daunorubicin, cytarabine, 6-mercaptopurine, methotrexate, cyclophosphamide, prednisone, dexamethasone, and nelarabine, and one or more immunotherapeutic agents selected from the group consisting of anti-PD1 antibodies, anti-PDL1 antibodies, and anti-CTLA4 antibodies.

13. The combination product of claim 12, wherein the immunotherapeutic agent is selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, MPDL3280A, MEDI4736, and MDX-1105.

14. Use of the compound according to any one of claims 1 to 10, the pharmaceutical composition according to claim 11, or the combination product according to claim 12 or 13 for the manufacture of a medicament for the treatment of acute myeloid leukemia.

Images