Title - TRPC6 INHIBITORS

Abstract

The present refers to compounds of formula (1), or pharmaceutically acceptable salts thereof, in which R 1 to R 7 A, Y, and L are as defined herein. This also refers to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, procedures for preparing these compounds, and intermediate products useful in these procedures.

Description

09-0675^-3 TRPC6 INHIBITORS FIELD OF INVENTION The present invention relates to compositions, pharmaceutical compounds and methods for the treatment of cardiac and respiratory conditions, kidney disease, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia or ischemia* reperfusion injury, and cancer, as well as inhibiting the transient receptor potential C6 ion channel (TRPC6). BACKGROUND A variety of ion channel proteins exist to mediate the flow of ions across cell membranes. Proper expression and function of ion channel proteins is essential for the maintenance of cellular function, intracellular communication, and the like. An important aspect of achieving cellular homeostasis is the maintenance of adequate ionic concentrations in various cell types during development and in response to numerous stimuli. Large amounts of various types of ion channels act to maintain cellular homeostasis by moving ions into and out of cells across the plasma membrane, and into cells by moving ions across membranes of intracellular organelles including, e.g. , the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria and endocytic organelles including endosomes and lysosomes. Numerous diseases are the result of misregulation of membrane potential or aberrant calcium handling. Given the central importance of ion channels in the modulation of membrane potential and ion flux in cells, the identification of agents that can promote or inhibit particular ion channels is of great interest as research tools and as possible therapeutic agents. One such channel is the transient receptor potential C6 channel (TRPC6). TRPC6 belongs to the largest family of TRP ion channels (see, Desai et ai, 2005 Eur J Physiol 451:11-18; Clapham et a / ., 2001 Nat Neurosci 2:387-396; Clapham, 2003 Nature 426: 517 -524; Clapham et al.t2002IUPHAR Compendium). TRPC6 is a calcium-permeable channel, specifically a non-selective calcium-permeable cation channel. In addition to calcium ions, TRPC6 channels are permeable to other cations, for example sodium. Therefore, TRPC6 channels modulate not only the intracellular calcium concentration, but also the membrane potential by modulating the flux of cations including calcium and sodium ions. Although nonselective cation channels such as TRPC6 modulate, among other things, calcium ion flux, they are mechanistically distinct from voltage-gated calcium channels. Generally, voltage-gated calcium channels IF-2018-67688982-APN-ANP#INPI Page 1 of 161 09-0675-W-3 respond to depolarization of the potential difference across the membrane and can open to allow an influx of calcium from the extracellular medium and a rapid increase in intracellular calcium concentrations or levels. In contrast, nonselective cation channels such as TRPC6 are generally signal transduction-dependent, long-lived, and produce fewer rapid changes in ion concentration. They show increased activity in response to the production of the second messenger, diacylglycerol (Hofmann et al., 1999). Additionally, TRPC6 can respond to changes in pressure. These mechanical differences are accompanied by structural differences between voltage-gated and cation-permeable channels. Therefore, although many diverse channels act to regulate ion flux and membrane potential in diverse cell types and in response to numerous stimuli, it is important to recognize significant structural, functional, and mechanical differences between different classes of ion channels. The function of TRPC6 has been implicated in, among other things, the modulation of myogenic tone. TRPC6 is highly expressed in smooth muscle cells, vascular smooth muscle cells, cardiomyocytes, pulmonary arteries, aorta, heart, liver, brain and kidney. The expression of TRPC6, together with experiments carried out in knockout mice and cells in culture, suggests that TRPC6 may provide a useful target for the treatment of hypertension and other cardiac and vascular conditions, preeclampsia. Mutation in the human TRPC6 channel can cause focal segmental glomerulosclerosis (FSGS) (Winn etal., 2005, Reiser etal., 2005). These mutations, which are reported to be gain of function (Reiser et al., 2005), are sufficient to induce disease. Furthermore, elevated TRPC6 expression has been associated with nephrotic syndrome, minimal change disease, and diabetic nephropathy ( Moller et al., 2006 , llatovskaya et al., 2013 , Thilo et al., 2011 ), or other renal states. Based on its expression and work implicating it in TGF-B signaling, TRPC6 is also thought to be important in respiratory states, restenosis, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia and ischemia-reperfusion injury, and certain forms of cancer. Yue et al. studied TRPC6 channels to determine the role in mediating pulmonary artery smooth muscle cell proliferation that can lead to idtopathic pulmonary arterial hypertension (IPAH). Hypertrophy of the pulmonary vascular media caused by excessive proliferation of pulmonary artery smooth muscle cells (PASMO) is a major cause of resistance. Page 2 of 161 09-0675-W-3 patients with IPAH. The authors found that TRPC6 was highly expressed and TRPC3 was minimally expressed in PASMC from healthy lung tissue. However, in lung tissue from patients with IPAH, the mRNA and protein expression of TRPC3 and TRPC6 were significantly elevated compared with those from normotensive patients. Furthermore, the proliferation of PASMC cells derived from IPAH patients was markedly reduced after incubation with TRPC6 siRNA. Based on these results, the authors concluded that TRPC6 may be important in measuring proper PASMC proliferation, and that misregulation of TRPC6 may lead to increased PASMC proliferation and pulmonary vascular media hypertrophy observed in patients with IPAH (Yu et al. al., 2004 Proc Natl Acad Sci 101(38):13861-6). Additional support is provided by the observation that in patients with IPAH, the frequency of a single nucleotide polymorphism in the TRPC6 promoter that increases expression was significantly higher when compared with that in normal subjects (Yue, et al. , 2009 Circulation 119: 2313-22). Additional evidence implicating misregulation of TRPC6 in IPAH comes from studies of bosentan, a dual endothelin receptor blocker, which has been used clinically to treat IPAH. This inhibitor decreases PASMC proliferation, but the mechanism by which this occurs is unclear. Interestingly, bosentan decreases both PASMC proliferation and also decreases TRPC6 expression in lung tissue from IPAH patients (Kunichika et a / ., 2004 Am J Respir Crit Care Med 170(10):1101-7). Chronic cigarette smoke (CS) exposure to rats resulted in an increase in TRPC6 mRNA and protein expression in distal pulmonary arteries and similar effects were observed using PASMC in vitro. Nicotine treatment of cultured rat PASMCs upregulated TRPC6 expression and increased intracellular calcium levels, both of which were reduced by TRPC6 siRNA silencing (Wang et al., 2014 Am J Physiol Cell Physiol 306: C364-73). These results suggest a role for TRPC6 in CS-induced lung injury. Evidence supports a role for TRPC6 in additional lung disorders. In alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD), TRPC6 expression was found to be elevated compared to controls (Finney-Hayward et al., 2010 Am J Respir Cell Mol Biol 43:296-304). In human cystic fibrosis epithelial cells, TRPC6-mediated calcium influx is abnormally increased and may contribute to mucus hypersecretion. siRNA-TRPC6 was able to reduce this aberrant calcium influx (Antigny et al. 2011 Am J Resp Cell Mol Biol, 44:83 IF-2018-67688982-APN-ANP#INPI Page 3 of 161 09-0675-W-3 90). In mouse lung fibroblasts, the profibrotic activity of PDGF depends on the activation of TRPC6, suggesting that inhibition of TRPC6 would reduce lung fibrosis (Leí et al., 2014 Biomaterials 35:2868-77). The role of TRPC6 in pulmonary endothelial cell function was demonstrated in mouse lung models of ischemia-reperfusion-induced edema and lipopolysaccharide-induced inflammation in which TRPC6 deficiency was able to reduce acute lung injury while preserving endothelial cell function. endothelial barrier (Weissmann et al., 2011 Nat Comm, 3:649-58 and Tauseef et al., 2012 J Exp Med 209:1953-68). Recent studies also implicate a role for TRPC6 in other cardiac states, including cardiac hypertrophy. Hearts from patients with dilated cardiomyopathy have elevated TRPC6 mRNA expression compared to normal hearts (Kuwahara et al., 2006 J Clin Invest 116:3114-26). In mouse models of cardiac hypertrophy, cardiac TRPC6 mRNA levels are elevated by pressure overload (Kuwahara et al., 2006 J Clin Invest 116:3114-26), chronic isoproterenol treatment (Xie et al., 2012 Nat Commun 3:1238), and partial nephrectomy-induced uremic cardiomyopathy (Xie et al., 2015 J Am Soc Nephrol 26:1150-60). Furthermore, cardiac-specific TRPC6 overexpression in the cardiomyocytes of transgenic mice induced cardiac hypertrophy and premature death (Kuwahara etal., 2006 J Clin Invest 116:3114-26). Wu et al found that transgenic mice expressing dominant negative TRPC6 in a cardiac-specific manner had an attenuated cardiac hypertrophic response either after neuroendocrine agonist infusion or after simulated pressure overload, indicating that TRPC6 is a component of channel complexes. which are essential mediators of hypertrophy (Wu etal., 2010 Proc Natl Acad Sci. 107:7000-05). Recently, small molecule drugs that target TRPC6 have also begun to show promise in the treatment of cardiac conditions. For example, Seo and colleagues demonstrated that TRPC6 and TRPC3 antagonists (GSK2332255B and GSK833503A) exhibited dose-dependent inhibition of cellular hypertrophy signaling in neonatal and adult cardiac myocytes (Seo et al., 2014 Proc Nati Acad Sci 111:1551 -1556). Similarly, TRPC6-deficient mice were protected from isoproterenol-induced cardiac hypertrophy (Xie et al., 2012 Nat Commun 3:1238). Reducing TRPC6 activity may be beneficial for the treatment of cardiovascular disease. In vitro, atheroesderosis-prone shear stress induces increased TRPC6 mRNA levels in human vascular endothelial cells (ECs). IF-2018-67688982- APN-ANP#INPI Page 4 of 161 09-0675-W-3 compared to flow conditions for protection against atherosclerosis (Thilo, et al., 2012 Hypertension 59:1232-40). EC migration is important for healing after arterial injury, and lysophosphatidylcholine-mediated inhibition of EC migration was prevented in vitro in cells from TRPC6-deficient mice. Furthermore, a high-cholesterol diet combined with carotid injury did not affect healing in TRPC6-deficient mice compared to wild-type controls (Rosembaum et al., 2015 J Vasc Surg 62:1040-47 and Chaudhuri et al. ., 2008 Mol Biol Cell 19: 3203-11). Similarly, a balloon dilation-induced injury of human internal mammary arteries ex vivo resulted in increased TRPC6 mRNA levels compared to non-dilated arteries (Bergdahl et al., 2005 Am J Physiol Cell Physiol 288:C872-80 ). Endothelial cell apoptosis is involved in the initiation and progression of atherosclerotic lesions, and oxidized low-density lipoprotein-induced apoptosis of human aortic ECs was shown to be TRPC6-dependent (Zhang et al., 2015 Sci Rep 5:9401- 10). In a rat model of forebrain ischemia, TRPC6 mRNA levels were increased in vascular SMCs and correlated with reduced cerebral blood flow (Johannson et al., 2015 Acta Physiol 214:376-89). Studies by Reiser, Winn and Schlóndorff identified mutations in TRPC6 in patients as causing FSGS (Reiser et al., 2005 Nature Genet 37:739-744; Winn et al., 2005 Science 308:1801-1804; Schlóndorff et al., 2009 Am J Physiol Cell Physiol 296:C558-69). Subsequent studies identified additional TRPC6 mutations associated with spheroid-resistant nephrotic syndrome (C. Sadowski et al., 2014 J Am Soc Nephrol 26:1279-89). Additional studies demonstrated that TRPC6 is important in normal podocyte function by controlling the entry of calcium and nuclear factor activation of activated T cells as an elevated current through the channel is associated with kidney injury and the induction of proteinuria (Moller et al. al., 2007 J Am Soc Nephrol 18:29-36 and Schlóndorff et al., 2009 Am J Physiol Cell Physiol 296:C558-69). In addition to gain-of-function mutations, TRPC6 expression has been shown to be elevated in human chronic kidney diseases including FSGS, minimal change disease, membranous glomerulonephritis, and diabetic nephropathy (Moller et al., 2007 J Am Soc Nephrol 18:29 -36 and Thilo etal., 2011 Nephrol. Dial. Transplant 27:921-9) as well as in mouse models of podocyte injury (Moller et al., 2007 J Am Soc Nephrol 18:29-36). TRPC6-deficient mice have been shown to have reduced angiotensin II (Ang II)-induced albuminuria (Eckel et al., 2011 J Am Soc Nephrol 22:526-35) while transgenic podocyte-specific expression of human gain-of-function mutations in mice induces albuminuria and glomerular lesions (Krall et al., 2010 PLoS ONE e12859 and Channels et al., 2015 Br'rt J Medicine Med Res 5:1198-1212). Therefore, inhibition of TRPC6 may be useful in the treatment^pii^ 5 Page 5 of 161 09-0675W-3 chronic kidney disease. These findings not only suggest that TRPC6 functions normally to maintain adequate kidney function, but also implicate TRPC6 as a specific cause of at least certain cases of FSGS. Based on the likely role of TRPC6 in kidney function, TRPC6 inhibitory compounds may be used in the treatment or improvement of chronic kidney diseases or conditions caused (in whole or in part) by TRPC6 dysfunction. Furthermore, TRPC6 inhibitory compounds can be used in the treatment or improvement of symptoms of kidney diseases (eg, hypertension, proteinuria, etc.), regardless of the cause of the disease. TRPC6 is expressed in the myometrium and placenta during pregnancy (Ku et al., 2006 J Soc Gynecol Investig 13:217-225; Clarson etal., 2003 J Physiol 550:515-528). As such, TRPC6 may contribute to maintaining adequate myogenic tone in the placenta and / or maintaining adequate fetal and maternal blood pressure during pregnancy. Recent evidence has emerged implicating TRPC6 in certain forms of cancer. Several groups have established that TRPC6 expression is elevated in cells taken from patients with gliobastoma multiforme, the most common and incurable type of brain cancer (Chígurupati, et al., 2010 Cancer Res, 70:418-427; Ding et al. , 2010 J Natl Cancer Inst. 102:1052-1068). Similarly, Ding et al. found elevated levels of TRPC6 in human glioma cells, and inhibition of TRPC6 pharmacologically or with a dominant negative mutant suppressed cell growth in vitro. In two xenograft models of human gliomas, lentivirus-mediated expression of dominant negative TRPC6 in tumor cells before subcutaneous or intracranial implantation reduced tumor volume compared to controls (Ding et al., J. Natl. Cancer Inst. 2010, 102,1052-1068). Increased levels of TRPC6 were also found to be associated with cervical cancer (Wan et al, 2012 Onco Targets Ther 5:171-176), breast cancer (Dhennin-Duthille etal., 2011 Cell Physiol Biochem 28:813-822 ), renal cell carcinoma (Song et al, 2013 Mol Biol Rep 40:5115-5122), head and neck squamous cell carcinoma (de Quíros, et al. 2013 BMC Cancer 13:116-127), and esophageal squamous cells (Zhang et al., 2013 Med Oncol 30:607), among others. In hepatocellular carcinoma cells, it was shown that doxorubicin, hypoxia, and ionizing radiation increased TRPC6 mRNA expression, and that TRPC6 is found at higher levels in tumor tissues than in uninvolved tissues. Elevated TRPC6 was associated with drug resistance that was decreased by TRPC6 RNA silencing in vitro. Lentiviral delivery of TRPC6-specific short hairpin RNA into Huh7 tumor cells prior to implantation in a mouse subcutaneous xenograft model reduced tumor growth and sensitized tumors to doxorubicin. IF-2018-67688982- APN-ANP#INgI Page 6 of 161 09-0675-W-3 (Wen et al.t2016 Sci Rep 6:23269). These findings suggest that TRPC6 may be a promising therapeutic target for e! cancer treatment. Liver diseases including nonalcoholic steatohepatitis can be treated by reducing TRPC6 activity. Hypoxia increased TRPC6 expression in a human hepatic stellate cell line compared to normoxic conditions. Using these cells, RNA silencing of TRPC6 downregulated transcripts for alpha smooth muscle actin and collagen 1A1, both of which were associated with fibrosis, in response to hypoxia (lyer et al, 2015 Exp Cell Res 336:66-75). TRPC6 inhibition may be beneficial for patients with Duchenne muscular dystrophy (DMD). In the mdx / utm+ / * model of DMD using isolated cardiomyocytes, TRPC6 deficiency restored stress-stimulated contractility force and transient calcium response to normal compared with mice possessing the wild-type TRPC6 gene, suggesting that TRPC6 inhibition will preserve cardiac function in DMD patients (Seo et al.t2014 Circ Res 114:823-32). Fibrotic disorders can be treated with TRPC6 inhibitors. Overexpression of TRPC6 induced myofibroblast activation while deletion of TRPC6 reduced transforming growth factor beta-induced myofibroblast transformation. Furthermore, TRPC6-deficient mice demonstrated reduced dermal and cardiac healing (Davis et al., 2012 Dev Cell 23:705-15). TRPC6 inhibitors may be useful for the treatment of pain. Spinal administration of TRPC6 antisense oligonucleotides reduced hyperalgesia induced by mechanical, hypotonic and thermal stimuli in preclinical pain models (AlessandriHaber et af., 2009 J Neurosci 29:6217-28). Modulating a function of TRPC6 provides a means to modulate calcium homeostasis, sodium homeostasis, intracellular calcium levels, membrane polarization (resting membrane potential), and / or cationic levels in a cell. Compounds that can modulate one or more functions of TRPC6 are useful in many aspects including, but not limited to, maintaining calcium homeostasis; maintain sodium homeostasis; modulate intracellular calcium levels; modulate membrane polarization (membrane potential); modulate cationic levels; and / or treat or prevent diseases, disorders or conditions associated with calcium homeostasis, sodium homeostasis, calcium or sodium dyshomeostasis, or membrane polarization / hyperpolarization (including hypo- and hyperexcitability), and / or treat or prevent diseases, disorders or states associated with regulation or misregulation of TRPC6 expression or function. IF-2018-67688982-APN-ANP#INPI Page 7 of 161 09-0675-W-3 There is a need for highly selective TRPC6 antagonists to treat diseases or disorders that can be alleviated by modulation of TRPC6. Brief summary of the invention The present invention provides novel compounds that modulate TRPC6 and are therefore useful for treating a variety of diseases and disorders that can be alleviated by modulation of TRPC6 including hypertension, preeclampsia, restenosis, a cardiac or respiratory condition, kidney disease, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia or ischemia-reperfusion injury, and cancer. This invention also relates to pharmaceutical compositions comprising these compounds, to methods of using these compounds in the treatment of various diseases and disorders, to methods for preparing these compounds and intermediates useful in these methods. In one embodiment (embodiment one), the invention relates to a compound of formula (1), (0 in which L is absent or is methylene or ethylene; Yes CHoN; A is CHoN; R1 is selected from the group consisting of: Ci-e alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, C^e cycloalkyl and OCm cycloalkyl; phenyl optionally substituted with 1 to 3 groups selected independently of the group consisting of CFS, -ANP#INPI Page 8 of 161 090675-^-3 OCm cycloalkyl, OCm alkyl optionally substituted with one to three halo; and cycloalkyl Cm optionally substituted with 1 to 3 groups selected independently of! group consisting of halo and Cm alkyl optionally substituted with 1 to 3 halo; R2 is selected from the group consisting of H, Cm alkyl, OCF3icycloalkyl Cm, alkyl OCm, cycloalkyl OCm; R3is selected from! group consisting of H, Cm alkyl, Cm cycloalkyl, OC3 cycloalkyl. and; in which each of! Cm alkyl, Cm cycloalkyl, OCm cycloalkyl of the group R3 may optionally be substituted with one to three groups each independently selected from the group consisting of halo, OH, OCm alkyl, SCm alkyl, N(Cm alkyl)j; and wherein one to three carbon atoms of the Cm alkyl of the R3 group can be optionally replaced by one or two residues selected from! group consisting of NH, N(Cm alkyl), O and S; R4 and R5 are each selected independently of the group consisting of H or alkyl CmJ R3 and R4 may, together with the atom to which they are incorporated, join to form a 3 to 9 membered carbocyclyl ring which may optionally contain one to three heteroatoms selected from the group consisting of N, O and S; either R3 and R5 may together form a 3- to 9-membered bicyclic ring that may optionally contain one to three heteroatoms selected from the group consisting of N, O and S; R® is selected from the group consisting of H, Cm alkyl, CN, CF3, OCF3, Cm cycloalkyl, OCm alkyl, and OCm cycloalkyl; R7 is selected from the group consisting of H and OCm alkyl; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment two), the invention relates to a compound according to the first embodiment above, wherein R1 is selected from the group consisting of: Cm alkyl optionally substituted with 1 to 3 selected groups IF-2018-67688982-APN-ANP#INPI Page 9 of 161 09-0675-W-3 regardless of the group consisting of halo, cycloalkyl C«; phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF3, halo, cycloalkyl OCm and alkyl Ocm optionally substituted with one to three halo; and Cm cycloalkyl optionally substituted with 1 to 3 halo groups; R2is alkyl OCm! R3 is selected from the group consisting of H, Cm alkyl optionally substituted with OH or OCm alkyl, R4is H; R5is H; R3 and R4 may, together with the atom to which they are incorporated, join to form a 3 to 9 membered carbocyclyl ring which may optionally contain one to three heteroatoms selected from the group consisting of N and O; either R3 and R5 may together form a 3- to 9-membered bicyclic that may optionally contain one to three heteroatoms selected from the group consisting of N and O; R® is selected from the group consisting of H, Cm alkyl, OCm alkyl, and OCm cycloalkyl, R7 is selected from the group consisting of H and OCm alkyl; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment three), the invention relates to a compound according to embodiment one or two above, wherein A is CH and Y is N; either A is CH and Y is CH; either AesNeYes CH; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment four), the invention relates to a compound according to any one of embodiments one to three above, in which Page 10 of 161 09-0675-0^3 R1 is selected from the group consisting of phenyl optionally substituted with a group selected from the group consisting of CF3, OCF3, halo, cycloalkyl OCm and alkyl OCm optionally substituted with one to three halo; and, R2 is OCm alkyl; R3 is selected from the group consisting of H, Cm alkyl optionally substituted with OH or OCm alkyl; R4is H; R5is H; R3 and R4 may, together with the atom to which they are incorporated, join to form a 3 to 9 membered carbocyclyl ring which may optionally contain one to three heteroatoms selected from the group consisting of N, O; either R3 and R5 may together form a 3- to 9-membered bicyclic that may optionally contain one to three heteroatoms selected from the group consisting of N and O; R0 is selected from the group consisting of H, Cm alkyl, OCm alkyl, and OCm cycloalkyl; R7 is selected from the group consisting of H and OCm alkyl; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment five), the invention relates to a compound according to any one of embodiments one to four above, wherein R1 is selected from the group consisting of phenyl optionally substituted with a group selected from the group consisting of CF3, OCF3tF, and methoxy; R2 is selected from the group consisting of methoxyl or ethoxyl; R3 is selected from the group consisting of H, 2-hydroxymethyl, methoxymethyl, 1-hydroxyethyl; R4is H; R5is H; either R3 is ethyl, and R3 and R4 join to form a spirocyclic ring; IF-2018-67688982-APN-ANP#INPI Page 11 of 161 09-0675-la EITHER R3 is ethyl or methoxymethyl, and R3 and R5 join together to form a bicyclic ring; R® is selected from the group consisting of H, methyl, methoxy, ethoxy, propoxy and cyclylpropyloxy; R7 is selected from the group consisting of H and methoxy; or a pharmaceutically acceptable salt of! same. In another embodiment (embodiment six), the invention relates to a compound according to any one of embodiments one to five above, wherein R1 together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl 4-cyclopropyloxyphenyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 2fluorobenzyl, and phenylethyl; R2 is methoxyl or ethoxyl; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment seven), the invention relates to a compound according to any one of embodiments one to six above, wherein Yes CHyAes N; R1 together with L represent a selected group of! group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 4-cyclopropyloxyphenyl, benzyl, 2-fluorobenzyl, and phenylethyl; R2 is methoxyl or ethoxyl; R3, R4, and R5 are each H; R® is H, methyl, methoxy or ethoxy; R7is H; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment eight), the invention relates to a compound according to a IF-2018-67688982-APN-ANP#INPI Page 12 of 161 09-0675-W-3 any of embodiments one to six above, wherein Yes CHyAes CH; R1 together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, cyclopentyl, cyclohexyl, benzyl, 2-fluorobenzyl, phenylethyl; R2 is methoxyl or ethoxyl; R3, R4, and R5 are each H; R® is H, methyl, methoxy, or ethoxy; R7is H; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment nine), the invention relates to a compound according to any one of embodiments one to five above, wherein YesNyAes CH; R1 together with L represent a group selected from the group consisting of phenyl, and 4fluorophenyl; R2 is methoxyl; R3 is selected from the group consisting of H, 2-hydroxymethyl and hydroxyethyl, R4is H; R5is H; R3 and R4 can join to form a spirocyclic ring; R3 and R5 can join to form a btcyclic ring; R® is selected from the group consisting of H and methoxyl; R7is H; or a pharmaceutically acceptable salt thereof. IF-2018-67688982- APN-ANP#INPI Page 13 of 161 09-0675 In another embodiment (embodiment ten), the invention relates to a compound according to any one of embodiments one to four above, wherein R1 is C« alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo and cycloalkyl R2 is alkyl OCi-e; R3, R4, and R5 are each H; R® is selected from the group consisting of H, Cm alkyl and OCm alkyl; R7is H; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment eleven), the invention relates to a compound according to any one of embodiments one to four and ten above, wherein R1 together with L represent a group selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclohexyl, 2, 2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl and 3,3,3-trifluoro-2-methyl-propyl; R2 is methoxyl; R3, R4, and R5 are each H; R® is selected from the group consisting of H, methyl and methoxyl; R7is H; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment twelve), the invention relates to a compound according to any one of embodiments one to four, ten and eleven above, wherein Yes CHyAes N; R1 together with L represent a group selected from the group consisting of propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-cyclopropylethyl, 2-cyclopropylethyl, and cyclohexyl; IF-2018-67688982- APN-ANP#INPI Page 14 of 161 09-0675-0^-3 R2 is methoxyl; R3, R4, and R5 are each H; R® is selected from the group consisting of H, methyl and methoxyl; R7is H; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment thirteen), the invention relates to a compound according to any one of embodiments one to four, ten and eleven above, wherein Y is CH and A is CH; R1 together with L represent a group selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2t2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cidopropylethyl, cyclopentyl, cyclohexyl, 2, 2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl and 3,3,3-trifluoro-2-methyl-propyl; R2 is methoxyl; R3, R4, and R5 are each H; R6is selected from! group consisting of H, methyl and methoxyl; R7is H; or a pharmaceutically acceptable salt of! same. In another embodiment (embodiment fourteen), the invention relates to a compound according to embodiment one above, wherein R3 and R4, together with the atom to which they are incorporated, join to form a 3-membered carbocyclyl ring; or a pharmaceutically acceptable salt of! same. In another embodiment (embodiment fifteen), the invention relates to a compound according to embodiment one above, wherein IF-2018-67688982-APN-ANP#INPI Page 15 of 161 09-0675-ÍW3 R3 and R5 together form a 3- to 9-membered bicyclic ring that may optionally contain one to two heteroatoms independently selected from the group consisting of N and O, and or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment sixteen), the invention relates to a compound according to embodiment one above, wherein Yes c; A is N; R2is OCH3;y R3, R4, R5, and R7 are each H; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment seventeen), the invention relates to a compound according to embodiment one or sixteen above, wherein L is absent; R1 is phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF3, halo, Cm cycloalkyl, OC^e cycloalkyl, OCi^ alkyl optionally substituted with one to three halo; and R® is H; or OCH3; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment eighteen, the invention relates to a compound according to any one of embodiments one or sixteen above, wherein R1 is selected from the group consisting of phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF3, halo, cycloalkyl OCm and alkyl OCm optionally substituted with one to three halo; R2is OCH3or OCH2CH3; R3, R4, R5- Re, and R7 are each H; and IF-2018-67688982-APN-ANP#INPI Page 16 of 161 09-0675-^3 or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment nineteen), the invention relates to a compound according to any one of embodiments one or sixteen above, wherein R1 is selected from the group consisting of phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF3, halo, OCy« cycloalkyl and OC1-8 alkyl optionally substituted with one to three halo; R2is OCH3of OCH2CH3; R3, R4, R5, and R7 are each H; Rees CH3o OCH3; And it is CH; and A is N; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment twenty), the invention relates to any one of embodiments one or sixteen to nineteen, wherein L is absent; or a pharmaceutically acceptable salt thereof. In another embodiment (embodiment twenty-one), the invention relates to a compound according to embodiment one above, wherein the compound is selected from the group consisting of any one of compounds 1-95 in Table 1, or to a pharmaceutical salt acceptable of it. In another embodiment (embodiment twenty-two), the invention relates to a pharmaceutical composition comprising any one of the compounds according to embodiments one to twenty-one above, or to a pharmaceutically acceptable salt thereof, and optionally to a pharmaceutically acceptable excipient. In another embodiment (embodiment twenty-three), the invention relates to a method of treating a disease or disorder that can be alleviated by TRPC6 inhibition comprising administering a therapeutically effective amount of any one of the compounds according to any one of embodiments one to twenty-one. above, or a pharmaceutically acceptable salt thereof, to a patient in need. IF-2018-67688982-APN-ANP#INPI Page 17 of 161 09-0675-W-3 In another embodiment (embodiment twenty-four), the invention relates to a method according to embodiment twenty-three, wherein the disease or disorder is selected from the group consisting of cardiac hypertrophy, ischemia, ischemia-reperfusion injury, hypertension, pulmonary arterial hypertension , idiopathic pulmonary arterial hypertension, restenosis, chronic obstructive pulmonary disease, cystic fibrosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), trauma-induced brain disorders, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis , osteoarthritis, inflammatory bowel disease, multiple sclerosis, muscular dystrophy, Duchenne muscular dystrophy, preeclampsia and pregnancy-induced hypertension, non-alcoholic steatohepatitis, minimal change disease, focal segmental glomerulosclerosis (FSGS), nephrotic syndrome, diabetic nephropathy or kidney disease diabetes (DKD), kidney failure, end-stage renal disease, ischemia or ischemia-reperfusion injury, cancer, IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratory disease syndrome), emphysema, and diabetes. Detailed description of the invention Table 1 shows the compounds of the invention that can be made by the synthesis schemes and examples shown in the Synthesis Examples section below, and the methods known in the art. Table 1. comp no. Structure Name of compound 1 ΥΊ í 7 O CHj CH, [4-(6-Amino-4-methoxyÍ-pyridin-3-yl)piperazin-1-yl]-[5-(4-fluoro-phenoxy)-4methoxy- pyridin-2-yl]-methanone 2 ΛΑ CHj (6-Amino-4-methyl-3',4',5*,6'-tetrahydro- 2'H-[3,4']bipyridinÍl-1'-yl )¿5-(4-fluoro-phenoxy)-4-methoxy-pyridin-2-yl]-methanone IF-2018-67688982- APN-ANP#INPI Page 18 of 161 09-0675 3 3 (6-Amino-3\4\5\6'-tetrahydro-2'H[3(4']bipyridinyl-r-yl)-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 4 or ^)-O z=Z / ° J—z o—o )--' *x \__( P z (e-Amino-^-methoxy-S'X'.S'.e'-tetrahydro- 2'H -[3(41bipyridÍn¡l-T-yl)¿5-(4-fluoro- phenoxy)-4-methoxy-pyridin-2-yl]-methanone 5 z δ 0-0 z—L ' o ·£ / P~ [ 4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 6 NHj [4-(6-Amino-pyridazin -3-yl)-piperidin-1yl]-[5-(4-isopropoxy-phenoxy)-4-niethoxypyridin-2-yl]-methanone 7 •i z Q : o z—< o <? / y.„ / V— 2 *o f=\ o >0 [(R)-4-(6-Amino-4-methi!-pyridin-3-yl)-2hydroxymetn-piperazin-1-yl]-[5-(4-fluorophenoxy)- 4-methoxy-pyridin-2-yl]-methanone 8 CH3 0 Ok£rW >^nh2 [7-(6-Amino-4-methoxy-pyridin-3-yl)-4,7diaza-spiro[2.5]oct- 4-yl]-(4-methoxy-5phenoxy-pyridin-2-yl)-methanone 9 N )-4t7diaza-spiro[2.5]oct-4-yl]-[5-(4-fluorophenoxy)-4-methoxy-pyridin-2-yl]-methanone IF-2018-67688982-APN-ANP#INPI Page 19 of 161 09-06753 10? P o / ° 4} / z z—< ( / £* \( o z—\ z X* (e-Amino^-methyl-S'.A'.S'.e'-tetrahydro2'H-[3,4 ']bipyridtnyl-T-yl)-(4-methoxy-5phenoxy-pyridin-2-yl)-methanone 11 0 O 0-0 Y-Z -x z=\ / —z jr / —' X M [4-(6-Amino -5-methoxy-pyridazin-3-yl)piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4methoxy-pyridin-2-ylJ-methanone 12 CH, CH, O ^^νη2 [4- (6-Amino-pyridin-3-yl)-piperazin-1-yl][4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2yl]-methanone 13 [4-(6-Amino-pyridin- 3-yl)-piperazin-1-yl][5-(4-fluoro-phenoxy)-4-methoxy-pyridtn-2yl]-methanone 14 <rH, or (6-Amino-3',4',5* ,6'-tetrahydro-2'H- [3,4']bipyrid¡nil-T-¡!)¿5-(4-fluoro-phenoxy)- 4-methoxy-pyridin-2-JI]-methanone 15 r , pyridin-2-yl)methanone 16 ?H3 9 Cl^O^ N NHj [4-(6-Amino-pyridazin-3-yl)-piperidin-1iI]-(4-methoxy-5-phenoxy-pyridin-2- il)methanone IF-2018-67688982-APN-ANP#INPI Page 20 of 161 09-0675 17 'oSAiq, [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[5¿4-fluoro-phenoxy)-4-methoxy-pyridin2-yl]-methanone 18 2 9—O \ / \ )=7 O=\ -i!]-(4-methoxy-5phenoxy-pyridin-2-yl)-methanone 19 0 / --\ Z=N nJ^nvV~WNHi Q < z-O H,C (e-Amino^-methoxy-y. ^S'.e'-tetrahydro2'H-[3,4']bipyridinyl-T-yl)-[5-(2-fluorobenzyloxy)-4-methoxy-pyridin-2-yl]methanone 20 x&AiL [(R) -4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-[5-(4-fIuorophenoxy)-4-methoxy-pyridin-2-yl]-methanone 21 0 i V rY CH3 «A Ύ or h3c [4-(6-Amino-5-methoxy-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 22 ?Η· ?H> fl (6-Amino-3*,4',5*,6'-tetrahydro-2'H-[3,4']bipyridinyl-T-yl)-[4-methoxy-5-(4- methoxy-phenoxy)-pyridin-2-yl]-methanone IF-2018-67688982-APN-ANP#INPI Page 21 of 161 09-0675-0-3 23 ch3 (6-Amino-4-methoxy-3\4\5\6Metrahydro2'H-[3,4]bipyridinyl-T-Íl)-(4-methoxy-5phenoxy-pyridín-2-ÍI)- methanone 24 (6-Amino-4-methoxy-3',4',5\6'-tetrahydro2'H-[3,4']bipyridÍnÍI-r-yl)-[4-methoxyÍ-5-(4trifluoromethyl-phenoxy )-pyridin-2-yl]methanone 25 O / —\ N=H Nyvn-T· r- / ~° -° I—J H'c [4-(6-Amino-pyridazin-3-ÍI)-piperidÍn -1¡l]-(5-cyclobirtylmethoxy-4-methoxyÍ-pyridin2-yl)-methanone 26 0 / --\ / =N O °' H.C CH, <J h3c (e-Amino^-methoxy-S'^' .S'.e'-tetrahydro2'H-[3,4']bipyridinyl-1 '-yl)-[4-methoxy-5-(1 methyl-cyclopropylmethoxy)-pyridin-2-yl]methanone 27 X M z β O—O Z“—\ 0—0 ζ- / ''7 * )- 2-methoxymethyl-piperazin-1-yl]-(4-methoxy- 5-phenoxy-pyridin-2-yl)-methanone 28 ?Η, ^H, O “αχΑο^ CHj (e-Amino^-methoxy- S'^'^'.e'-tetrahydro2'H-[3l4,]bipyridinyl-1'-yl)-[4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl]-methanone IF-2018-67688982-APN -ANP#I^£I Page 22 of 161 09-0675-^-3 29 / 0 o o p o==\ Z--L \ / I* '—( o p $ [4-(6-Amino-4-methi!-pyridazin-3-yl)piperidin-1-yl]-[5-( 4-fluoro-phenoxy)-4methoxy-pyridin-2-yl]-methanone 30 0 / —\ / =N Ζ-Λ Q ( VX\ CH, V / 0 0 h3c (6-Amino-4-methoxy-3\ 4\5\6Metrahydro2*H-[3,4']bipyridinyl-1'-yl)-(5-cyc!ohexyloxy4-methoxy-pyridin-2-yl)-methanone 31 X K> z z o O )-- JE / \ '—Z \=O Z— / / / A V V-O o \= / O T G» [4-(6-Amino-4-methyl-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5- phenoxypyridin-2-yl)-methanone 32 z z—ά / Vo-Ü z—' o $ (e-AmincM-methoxy-S^'.S^e-tetrahydro2'H-[3,4,]bipyridinyl-r- il)-[5-(4-fIuorobenzyloxy)-4-methoxy-pyridin-2-yl]methanone 33 έ^νη2 [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[4- methoxy-5-(4-trifluoromethyl-phenoxy)pyridin-2-yl]-methanone 34 ?Η' fl [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl]-[5-(4- chloro-phenoxy)-4-methoxy-pyridin2-yl]-methanone 35 0 / --\ / =N z“K )—a ^~nh, NX \_ / rA W °' O-°P h3c (e- AmincM-methoxy-S'Z'.S'.e'-tetrahydro2'H-[3,4*]bipyridini!-1 *-yl)-(5cyclopentyloxy-4-methoxy-pyridin-2-yl)methanone IF-2018-67688982-APN-ANP#INPI Page 23 of 161 09-0675-^-3 36 0 / --\ N=N ^-N )--λ— NH2 w H,C- / ~° A Ah, h'c [4-(6-Amino-pyridazin-3-yl)-piperidin-1yl ]-(5-isobutoxy-4-methoxy-pyridin-2-yl)methanone 37 0 / \ z=N z—N >—X-NH, n= / \ / o °„ z-oQo <J h3c (6 -Amino-4-methoxy-3')4,t5',6'-tetrahydro- 2'H-[3,4*lbipyridinH-1 *-yl)-(5- cyclopropylmethoxy-4-methoxy-pyridin-2- il)methanone 38 [3.2.1]oct-8-yl]-[5-(4-fluorophenoxy)-4-methoxy-pyridin-2-yl]-methanone 39 x z II 1 x o ° rV°' o Γ i· (6-Amino -4-methoxy-3',4',5',6'-tetrahydro2^[3,43bipyridinH-T-yl)-(5-isobutoxy-4methoxy-pyridin-2-yl)-methanone 40 [4-(6 -Amino-pyridazin-3-yl)-piperidin-1-yl][5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone 41 ΛΤ·Α>ΰ,. HjC' [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl][5-(4-fluoro-benzyloxy)-4-methoxy-pyridin2-yl]-methanone 42 0 o o t \__i o x —< JT \ y—ZZ O \ -ft z(S~°p z X M [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]- [5-(4-fluorophenoxy)-4-methoxy-pyridin-2-yl]-methanone IF-2018-67688982-APN-ANP#INPI Page 24 of 161 09-0675-^-3 43 q *b '°Λ_ / .—z y—z z M (e-Amino-^-methoxy-S'^'.S'.e'-tetrahydro2'H-[3,41bipyridinyl-T-yl)-(5 -benzyloxy-4methoxy-pyridin-2-yl)-methanone 44 VH> JH, 0 'txVo^ [4-(6-Amino-pyridazin-3-yl)-piperid¡n-1-ÍI][4-methoxy- 5-(4-methoxy-phenoxy)-pyridin-2yl]-methanone 45 TI Λ o o-o \___ / JC 0 0O / —z Z (e-AmincM-methoxy-S'X^S'.e'-tetrahydroZH- IS^Ibipyridinyl-T-iO-IS-CS.S-difluorocyclobutylmethoxy)-4-methoxy-pyridin-2-yl]methanone 46 X* z II 1 II I °» x o $ (e-Amino^-methoxy-S' " .CL i V Tth CHa joc^ “A 0 [4-(6-AmÍno-4-methoxy-pyridazÍn-3-yl)piperidin-1-¡l]-(4-methoxy-5-phenoxy-pyrídin2- ¡l)-methanone 48 0 / —\ / =N ^-N >—< / )—NH, \_ / \_ΰ S~) ° ,~r / \ CH. P H3C (e-AmincM-methoxy-S'^'.S'.e-tetrahydro2,H-

[314] bipyridinyl-T-yl)-[5-(2-cyclopropylethoxy)-4-methoxy-pyridin-2- il]-methanone 49 I*' z ti / —\ ' Z— / °=¿ >=z £* / —\ 0-0 o 0 [4-(6-AmÍno-4-methoxy-pyridazin-3-yl )piperidin-1-yl]-[5-(4-fluoro-phenoxy)-4methoxy-pyridin-2-n]-methanone 14-2018-6 / 688982-ΑΡΝ-ΑΝΡ#1ΝΡΙ Page 25 of 161 09-0675-W-3 50 P o \=o / 1-(5-phenoxypyridine-2-carbonyl)piper azÍn-2-yl]ethan-1-ol 51 αχΑχχ %^nh2 [3-(6-Amino-4-methoxy-pyridin-3-yl)-3,8diaza -bicyclo[3.2.1 ]oct-8-yl]-(4-methoxy-5phenoxy-pyridin-2-¡l)-methanone 52 JOp-”· A^0 CH' \=Z h3c' (e-Amino^ -methoxy-S' / '.S'.e'-tetrahydro2,H-[3(4t]bipyridinyl-r-¡l)-(4-methoxy-5phenethyloxy-pyridin-2-yl)-methanone 53 0 / —< / =N Z-N )—Λ— nh2 N- / \__f O °v __ / —( CH, r-Λ '° |_J H3C (e-AmincM-methoxW / '.S'.e'-tetrahydro2 'H-[3t41bipyridinyl-1'-yl)-(5- cyclobutylmethoxy-4-methoxy-pyridin-2-yl)methanone 54 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-ylJ[ 5-(4-difluoromethoxy-phenoxy)-4-methoxypyridin-2-yl]-methanone 55 z 0-0 Z—\ 0-0 -x -1 *b / =^=° '°-W o 0 *n [(R)-4-(6-Amino-4-methoxy-pyridin-3-yl)-2methoxymethyl-piperazin-1-yl]-[5-(4-fIuorophenoxy)-4-methoxy-pyridin-2-yl ]-methanone 56 □r _7 \ / / z z— o=¿ / =z 1Γ 0-0 o [4-(6-Amino-4-methoxy-pyridazin-3-yl)piperidin-1 -ÍI]-[4 -methoxy-5-(4trifluoromethyl-phenoxy)-pyridin-2-yl]methanone -------IF 2018 67688982 ΛΡΝ AW / dWt Page 26 of 161 09-0675f-3 57 0 ¡--k N=N y— N )--k >-NH2 ​​nV \_ / O O~f H>c [4-(6-Amino-pyridazin-3-yl)-piperidin-1- il][5-(2-fluoro-benzyloxy)-4-methoxy-pyridin2-yl]-methanone 58 / X J (1S)-1-[(2R)-4-(6-amino-4-niethoxypyrid¡n3- íl)-1-(5-phenoxypyridine-2-carbonyl)piper azin-2-yl]ethan-1-ol 59 0 / --< / =N / —N ) ¿ i— NH. nV \_ / W °' \ CH, '0 h3c ch3HaC (6-AmÍno-4-methoxy-3',4',5',6'-tetrahydro2'H-[3.4,]bipyridinyl-1'-yl) -[5-(2,2-dimethi!propoxy)-4-methoxy-pyridin-2-iI]-methanone 60 ?«» ?H« s HjC0 [4-(6-Amino-5-methoxy-pyridazin-3 -yl)piperidin-1-yl]-[4-methoxy-5-(4-methoxyphenoxy)-pyridÍn-2-yl]-methanone 61 b ​​Π-O 2—V Q 4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-(5-cyclopropylmethoxy-4methoxy-pyridin-2-yl)-methanone 62 \ / X z=\ / ° / — z d'* / —z 2 [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl](5-cyclohexyloxy¡-4-methoxy-pyridín-2-yl)methanone IF-2018-67688982-APN-ANP#INPI Page 27 of 161 09-0675-W-3 63 χ0Η Cl lj OC -4-methoxy-pyridin-2-yl]-methanone 64 O / --s. z=N NXV / V NH¡ Q << F (6-Amino^-methoxyX3',4',5',6'-tetrahydro- ZH-IS^lbipyridinyl-r-ylHS-CIfluoromethyl-cyclopropylmethoxy)-4-methoxypyridine -2-H]-methanone 65 0 / --< / =N / —N )--G Λ— NH, N^Z \__ / h3c g h3c (e-Amino^-methoxy-S'^'.S '.e'-tetrahydro2'H-[3(43bipyridinyl-T-yl)-(5-ethoxMmethoxy-pyridin-2-yl)-methanone 66 CM, CH, 0 °·Ο.ΧΓΌ.Τ% CH, [4 -(6-Amino-4-methoxy-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4-methoxyphenoxy)-pyridin-2-yl]-niethanone 67 0 i—\ N =N ^0-0.. h3c [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl](5-(2-cyclopropyl-ethoxy)-4-methoxy-pyridin2-yl]- methanone 68 7H3 0 αχό&χ [7-(6-Amino-4-methoxy-pyridin-3-yl)-3-oxa9-aza-bicyclo[3.3.1 ]non-9-yl]-(4-methoxy5-phenoxy- pyridin-2-yl)-methanone IF-2018-67688982-APN-ANP#INPI Page 28 of 161 09-0675-W-3 69 O—^~^z o' (4-methoxy-5phenoxy-pyridin-2-i!)-methanone 70 0 / —\ / =N ^-N )--d i— NHL Ní= / \__f H3C, V / °x p 3 < / H>c ' (6-Amino-4-methoxy-3*,4*,5',6'-tetrahydro2'H-[3(4']bipyridinyl-1,-yl)-[5-((S)- 1cyclopropyl-ethoxy)-4-methoxy-pyridin-2-yl]methanone 71 4-(6-Amino-4-methoxy-pyridin-3-II)-2hydroxymethyl-piperazin-1-yl]-(4-methoxy-5phenoxy-pyridin-2-yl)-methanone 72 0 / —\ / =N N )--ά zH NH, N^ / \__ / \_J / h3c y__ / ° \ CH. ¡droZH-p^Jbipyridinyl-T-ilHS-isopropoxy^methoxy-pyridin-2-iI)-methanone 73 0 / —< N=N Z-N )--C λ— NH. N=s / \__f O / ~ν-ζ~οθ \^=Z HjC [4-(6-Amino-pyridazin-3-yl)-piperidin-1-Íl](4-methoxy-5-phenethyloxyÍ-pyridin -2-i1)methanone 74 O / --\ N=N ηΛη. h'c [4-(6-Amino-pyridazÍn-3-ÍI)-pÍperidin-1-yl][5-(2(2-dimethyl-propoxy)-4-methoxy-pyridin2-¡l]-methanone IF-2018-67688982-ΑΡΝ-ΑΝΡ#Ι1ΦΙ Page 29 of 161 09-0675-^-3 75 O / --< N=N 7-N )—A— NHaH3V~° O <J H,C [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl][4-methoxy- 5-(1-methyl-cyclopropylmethoxy)pyridin-2-yl]-methanone 76 0 / --V N=N NHs H-C- / *0 / ° 3 H3C [4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl](4-methoxy-5-propoxy-pyridin-2-yl)methanone 77 0 / --\ / =N N )--¿ X— NH- N- / \__f H,C °s \ _y\ ch. y-o '0 <j hjcz (6-amino-4-metoxi-3’,4’,5’,6’-tetrahidro2’h-[3,41bipiridini!-r-il)-[5-((r)-1ciclopropil-etoxi)-4-metoxi-piridin-2-il]metanona 78 0-0 \="°" je z—\>—z z— / ¿ Y-o \__ / wz z [4-(6-Amino-4-methyl-pyridazin-3-yl)piperidin-1-yl]-(5-cyclopropylmethoxy-4methoxy-pyridin-2-yl)- methanone 79 0 / —\ Λ=Ν N )—¿ y~ NHa \__f h3c Vy Λ~° o <j h3c [4-(6-amino-piridazin-3-il)-piperidin-1-il][5-((s)-1-cidopropil-etoxi)-4-metoxi- piridin-2-il]-metanona 80 •n ή© 0 o="C" (>z [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl][4-methoxy-5-(4-trifluoromethoxy-phenoxy)pyridin-2-yl]-methanone IF-2018-67688982-APN-ANP#INPI Page 30 of 161 09-0675-1 81 θΡ . \ / methoxy-5phenoxy-pyridin-2-yl)-methanone 82 ch3 ch3 or <0H Wiu [(R)-4-(6-Aniino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-[4- methoxy-5(4-methoxy-phenoxy)-pyridin-2-yl]-methanone 83 / CH3 λ «Αχ., [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]- [5-{phenoxy)-4-ethoxy-pyridin-2-yl]-methanone 84 coXco* (e-Amino^-cyclopropoxy-S'^'.S'.etetrahydro-2'H-[3,4'] bipyridini!-r-yl)-[5(phenoxy)-4-methoxy-pyridin-2-yl]-methanone 85 VH, j coXoy?· N NHj (4-(6-Amino-4-ethoxy-pyridazin-3 -yl)piperidin-1-i!H4-methoxy-5-(phenoxy)pyridin-2-yl]-methanone 86 (fH3 0 ccoXr ^n^nh2 (e-AmincM-propoxy-S'^'.S'. e'-tetrahydro- ZH-n^lbipyridinyl-T-ylHS-iphenoxy)^methoxy-pyridin-2-yl]-methanone 87 F c CH, 0 'War (e-AmincM-ethoxy-S' / ', 5* ,6-tetrahyd ro2'H-[3,43bipyridinyl-T-yl)-[5-(4trifluoromethyl-phenoxy)-4-methoxy-pyridin-2yl]-methanone IF-2018-67688982-APN-ANP#INPI Page 31 of 161 09-0675-1 88 > 0 'ΌΧή^ [3-(6-Amino-pyridazin-3-yl)-8-azabicyclo[3.2.1 ]oct-8-yl]-[4-ethoxy-5-(4fluoro-phenoxy)-pyridin- 2-yl]-methanone 90 X* z z—' >=z «w X* / \ 0-0 o o U.- / u. or. 6-(1¿4-Methoxy-5-[4-(trifluoromethyl)phenoxy ]pyridine-2-carbonyl}piperidin-4-yl)-5-methyl pyridazin-3-amine 91 ... ch3 5-Methoxy¡- 6-(1¿5-[4-(trifluoromethyl)phenoxy]-pyridine-2-carbonn}piperidin-4-H)pyridazin-3-amine 92 F^T «¡Τ'^ΝΗ, F CH, 4-Methoxy -5-[1-(4-methoxy-5-{[trans- 3-(trifluoromethyl)cyclobutyl]methoxy}pyridine-2-carbonyl)piperidin-4-yl]pyridin-2-amine 93 πΓ z c5 / —\ °-* Z—' \=z V? if λ"λ u-o o 4-Methoxy-5-[1-(4-methoxy-5-{[(cis-3-(triflu oromethyl)-cyclobutyl]methoxy}-pyridine-2-carbontl)piperidin-4-iI ]pyridin-2 -amine 94 aT z / \ X / —( o-o z—< °=¿ >=z n y — t -methoxy-5-[(2)-3,3,3-trifluoro-2-methylpropoxy]-pyridine-2-carbonyl}piperidin-4-yl)pyridin-2-amine IF-2018-67688982-APN-ANP#INPI Page 32 of 161 09-0675-W-3 95 0-0 c / — y) 5-(1 ¿5-1(2,2-Difluorocyclobutyl)methoxy]-4-methoxypyridine-2-carbonyl}-piperidin-4-yl)-4-methoxypyridine-2-amine In one embodiment, the invention relates to any of the compounds 1 to 95 represented in Table 1 above, and to pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to any one of the compounds 6,16,17, 33, 34,40, 41,44, 54, 57, 80, 83 and 88 represented in Table 1; and the pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to any one of the compounds 29, 31, 49, 56, 66, 85, 87 and 90 represented in Table 1; and the pharmaceutically acceptable salts thereof. GENERAL DEFINITIONS Terms not specifically defined herein will be given the meanings that would be given to them by one skilled in the art taking into account the disclosure and context. As used in the specification, however, unless otherwise specified, the following terms have the meanings indicated and the following conventions are observed. In the groups, radicals or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, alkyl Ci^ means an alkyl group or radical having 1 to 6 carbon atoms. In general, in groups such as HO, HaN, (O)S, (OJjS, NC (cyano), HOOC, F3C or the like, the person skilled in the art can see the point(s) of attachment of the radical to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last subgroup named is the point of attachment of the radical, for example, the aryl-C1-3 alkyl substituent means an aryl group that It is linked to a Ci-3 alkyl group, the latter of which is attached to the nucleus or the group to which the substituent is attached. IF-2018-67688982- APN-ANP#INPI Page 33 of 161 09-0675W-3 In the event that a compound of the present invention is represented in the form of a chemical name and as a formula, in the event of any discrepancy, the formula will prevail. An asterisk may be used in the subformulae to indicate the bond that connects to the core molecule as defined. X,3 CH, ' ' 23H,C CH, The term substituted as used herein means that any one or more hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded, and the substitution ends in a stable compound. Unless specifically stated throughout the specification and appended claims, a given chemical name or formula should include tautomers and all stereoisomers, optical isomers, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers). etc.) and racemates thereof as well as mixtures in different proportions of the separated enantiomers, mixtures of diastereomers or mixtures of any of the above forms in which such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts of the same and solvates thereof, such as, for example, hydrates that include solvates of the free compounds or solvates of a salt of the compound. The enantiomerically pure compounds of this invention or intermediates can be prepared by means of asymmetric synthesis, for example by the preparation and subsequent separation of appropriate diastereomeric compounds or intermediates that can be separated by known methods (for example, by chromatographic separation or crystallization). and / or using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries. Furthermore, one skilled in the art knows how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; or by resolution of a racemate using an appropriate resolving agent, for example by formation of the diastereomeric salt of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt; or by derivatization delló^^bhípbré^d^rádérnibb^IXPI 34 Page 34 of 161 09-0675-1 corresponding with chiral optically active auxiliary reagents, subsequent diastereomeric separation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (for example by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphic crystals under suitable conditions; or by (fractional) crystallization using a suitable solvent in the presence of an optically active chiral auxiliary. The phrase pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical criteria, suitable for use in contact with the tissues of human beings. and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and consistent with a reasonable benefit / risk ratio. As used herein, pharmaceutically acceptable salt refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; organic or alkaline salts of acid residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gentisic acid, bromhydric acid, hydrochloric acid, maleic acid, melic acid, malonic acid, mandelic acid, acid methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, tartaric acid and trifluoroacetic acid. In addition, pharmaceutically acceptable salts can be formed with ammonia cations, L-arginine, calcium, 2,2'-iminobisethanol, L-üsin, magnesium, N-mettl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic residue by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate acid or base in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture of the same. Salts of other acids of those mentioned above that, for example, are useful for the purification or isolation of the compounds of the present invention (for example, trifluoroacetate salts, formates) also comprise a part of the invention. IF-2018-67688982-APN-ANP#INPI Page 35 of 161 09-0675-W-3 The term halogen generally indicates fluorine, chlorine, bromine and iodine. The term alkyl Cm, where n is an integer selected from the group consisting of 2,3,4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical! indicates an acyclic, saturated, branched or linear hydrocarbon radical! with 1 to n C atoms. For example, the term Cm alkyl encompasses the radicals H3C-, H3C-CH2-, HsC-CHz-CHz-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C -CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-. H3C-CH2-CH2-CH2-CH2-, H3C-CHrCH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C (CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. The term cycloalkyl Cm, where n is an integer from 4 to n, either alone or in combination with another radical, indicates a saturated, unbranched, cyclic hydrocarbon radical with 3 to n C atoms. For example, The term C3-7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term halo added to an alkyl, alkylene or cycloalkyl group (saturated or unsaturated) is an alkyl or cycloalkyl group in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H2FC-, HF2C-, F3C-, Equivalently, the term halo added to an aryl group (e.g., phenyl) means that one or more hydrogen atoms are replaced by a halogen atom selected from fluorine , chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. The term carbocyclyl, used either alone or in combination with another radical, means a mono-, bi- or tricyclic ring structure consisting of 3 to 9 carbon atoms and optionally a heteroatom which is selected from the group consisting of N, O and S. The term carbocyclyl refers to fully saturated ring systems and encompasses fused, bridged and spirocyclic systems. Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of each other. The present application provides compounds that can modulate the function of TRPC6. Methods employing these compounds are also provided. Certain embodiments provide a method of modulating a function of TRPC6 in a cell or animal comprising administering an effective amount of a compound that inhibits a IF-2018-67688982-APN-ANP#INPI Page 36 of 161 09-0675-W-3 function of TRPC6, in which the compound inhibits a TRPC6-mediated ion flux. Certain embodiments provide a method of modulating a function of TRPC6 in a cell or animal comprising administering an effective amount of a compound that inhibits a function of TRPC6, wherein the compound inhibits a TRPC6-mediated calcium flux. Certain embodiments provide a method of modulating a function of TRPC6 in a cell or animal comprising administering an effective amount of a compound that inhibits a function of TRPC6, wherein the compound inhibits a TRPC6-mediated reorganization or alteration in cytoskeletal cell morphology. . Certain embodiments provide a method of modulating a function of TRPC6 in a cell comprising administering to the cell an effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits an outward current mediated by TRPC6. Certain embodiments provide a method of modulating a function of TRPC6 in a cell comprising administering to the cell an effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits TRPC6-mediated inward current. Certain embodiments provide a method of modulating a function of TRPC6 in a cell comprising administering to the cell an effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits both outward and inward mediated reactions. by TRPC6. Certain embodiments provide a method of modulating a function of TRPC6 in a cell comprising administering to the cell an effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits TRPC6-mediated increases in intracellular calcium concentration. Certain embodiments provide a method of modulating a function of TRPC6 in a cell comprising administering to the cell an effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits alterations in cell morphology. Certain embodiments also provide a method of preventing or treating a disease or condition related to the function of TRPC6 in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits the current inwardly mediated by TRPC6. Certain embodiments provide a method of preventing or treating a disease or condition related to the function of TRPC6 in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits the current the exterior mediated by TRPC6. Certain embodiments also provide a method of preventing or treating a disease or condition related to the function of TRPC6 in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits the function of TRPC6, wherein the compound inhibits both the comment outwards like IF-2018-67688982-APN-ANP#INPI 37 Page 37 of 161 09-0675-H-3 inwardly mediated by TRPC6. Certain embodiments provide a method of preventing or treating a disease or condition related to TRPC6 function in a subject comprising administering to the subject a therapeutically effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits ionic flux. mediated by TRPC6. Note that inhibition of a particular current refers to the ability of a compound to inhibit this current (e.g., inwardly and / or outwardly) in either an in vitro assay or an in vivo assay. Inhibition of a particular reaction in either an in vivo assay or an in vitro assay serves as an approximation to the particular functional activity of the particular compound. The present invention provides methods for treating a TRPC6-mediated disorder in a subject, the method comprising administering an effective amount of a compound of the invention wherein each of the above variables is described herein, for example, in following detailed description. The present invention further provides a method of treating a TRPC6-mediated disorder in a subject, wherein the method comprises administering a composition comprising a compound of the invention and a pharmaceutically acceptable excipient, diluent or carrier. The present invention further provides a method of treating a TRPC6-mediated disorder in a subject, wherein the method comprises administering a composition comprising a compound of the invention and a pharmaceutically acceptable excipient, diluent or carrier, and the mediated disorder is selected. byTRPC6 of! group consisting of cardiac hypertrophy, ischemia, ischemia-reperfusion injury, hypertension, arterial hypertension! pulmonary, idiopathic pulmonary arterial hypertension, restenosis, chronic obstructive pulmonary disease, cystic fibrosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), trauma-induced brain disorders, asthma, chronic obstructive pulmonary disease, arthritis rheumatoid, osteoarthritis, inflammatory bowel disease, multiple sclerosis, muscular dystrophy, preeclampsia and pregnancy-induced hypertension, non-alcoholic steatohepatitis, glomerulosclerosis seal! and segmental, nephrotic syndrome, diabetic nephropathy or diabetic kidney disease, kidney failure, end-stage renal disease, ischemia-reperfusion injury or ischemia, cancer, FP1 (idiopathic pulmonary fibrosis), ARDS (acute respiratory disease syndrome), emphysema and diabetes. Unless specifically stated throughout the accompanying specification and claims, a given chemical name or formula shall include tautomers and all stereoisomers, optical isomers, and anp#INPI isomers. Page 38 of 161 09-0675-IB-3 enantiomers, diastereomers, E / Z isomers etc.) and racemates thereof as well as mixtures in different proportions of the separated enantiomers, mixtures of diastereomers, or mixtures of any of the above forms in which such isomers and enantiomers exist, as well as salts, which include pharmaceutically acceptable salts thereof and solvates thereof such as for example hydrates including solvates of the free compounds or solvates of a salt of the compound. Some of the compounds in Table 1 may exist in more than one tautomeric form. The invention includes methods for the use of such tautomers. The invention includes pharmaceutically acceptable derivatives of compounds of the invention. A pharmaceutically acceptable derivative refers to any pharmaceutically acceptable salt or ester, or any other compound that, when administered to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active metabolite or residue. pharmacologically active thereof. A pharmacologically active metabolite will be understood as any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the invention. As used herein, pharmaceutically acceptable salts refers to derivatives of the disclosed compounds in which the compound originates! It is modified by producing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; organic or alkaline salts of acid residues such as carboxylic acids; and the like. For example, such salts include ethane acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides / hydrobromides, edetates, camsylates, carbonates, chlorides / hydrochlorides, c'rtrates, edisylates, disuthonates. estolates, esylates, formates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycolylarsanilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methylbromides, methylnitrates, methyl sulfates, mucates, napsilates, nitrates, oxalates, pamoates, pantothenates, phenylacetates, phosphates / diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfonamides, sulfates, tannates, tartrates, theoclates, toluenesulfonates, triethiodes, trifluoroacetates, ammoniums, benzathines, chloropro cainas, cholines, diethanolamines, ethylenediamines, meglumines and procaines. In addition, pharmaceutical salts can be formed. Page 39 of 161 09-0675-1 metates such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (See also Pharmaceutical salts, BirgetS.M. et al., J. Pharm. Sci.t(1977), 66,1-19). The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic residue by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate acid or base in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture of them. Salts of other acids of those mentioned above which, for example, are useful for the purification or isolation of the compounds of the present invention (for example trifluoroacetate salts, formates) also comprise a part of the invention. Furthermore, within the scope of the invention is the use of prodrugs of compounds of the invention. Prodrugs include those compounds that, through simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug can be transformed into a compound disclosed herein above, thereby giving the desired pharmacological effect. The compounds of the invention also include their isotopically labeled forms. An isotopically labeled form of an active agent of a combination of the present invention is identical to said active agent except for the fact that one or more atoms of said active agent have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom that can usually be found in nature. Examples of isotopes that are readily commercially accessible and that can be incorporated into an active agent of a combination of the present invention according to well-defined procedures include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2H ,3H,13C,14C,15N,18O,170,31P, ^P,35S,18F and "Cl, respectively. An active agent of a combination of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt containing one or more of the aforementioned isotopes and / or other isotopes of other atoms are considered to be within the scope of the present invention. The compounds of the invention are only those that are considered to be "chemically stable* as those skilled in the art will appreciate. For example, a compound that IF-2018-67688982-APN-ANP#INPI Page 40 of 161 09-0675-W-3 would have a free valency* or a carbanion* are not considered compounds by the inventive methods disclosed herein. For all compounds disclosed hereinbefore in this application, in the event that the nomenclature conflicts with the structure, the compound will be understood to be defined by the structure. List of abbreviations AA ACN / MeCN ac. BEH BOC ’C CDI CPhos-3Gpalladacycle methanesulfonate DCM DIPEA DMF DMA DMSO DTAD EE eq. ESI-EM EtOH EtOAc / EE h h2 h3po4 HATU Acetic acid Acetonitrite Aqueous Ethylene-bridged hybrid column Tert-butyloxycarbonyl Degrees Celsius Di(imidazol-1 -yl)methanone (2-Dicyclohexylphosphino-2,>6,-bis(dimethylamino) -11T-brfeniI)(2'-amino1t1*-bifeniI-2-iI)palladium(ll)methanesulfonate Dichloromethane N. / V-diisopropylethylamine N, N-dimethylformamide NtN-dimethylacetamide Dimethylsulfoxide Di-tenc-butyl azodicarboxylate Diethyl ether Equivalent Electrospray ionization mass spectrometry Ethanol Ethyl acetate Hour Hydrogen Phosphoric acid N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1yl)uronium hexafluorophosphate HCl HPLC MeOH min Met ml MS NaH NaOH NMP Pd2 (dba)3 Hydrochloric acid High performance liquid chromatography Methanol Minute Iodomethane Milliliter Mass spectrometry Sodium hydride Sodium hydroxide N-methyl-2-pyrrolidinone Tris(dibenzylideneacetone)dipalladium(0) IF-2018-67688982- APN-ANP#INPI Page 41 of 161 09-0675-1^3 Pd / C PdCl2(dppf)CH2CI2 Palladium on carbon [1,1*-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane Pd(OH)2 EP Fl taoTA CFS TBTU TFA THF TLC Xantphos Xphos 2' gen . Palladium hydroxide Petroleum ether Reverse phase Room temperature (approximately 25®C) Supercritical fluid chromatography Benzotriazolyltetramethyluronium tetrafluoroborate Trifluoroacetic acid Tetrahydrofuran Thin layer chromatography on SiO2 4,5-Bis(diphenylphosphine)-9,9-dimethylxanthene Chlorine(2- dicyclohexylphosphino-2,,4',6'-triisopropyl-1,T-biphenyl)[2-(2'amino-1,1-biphenyl)]pa ladi 0 (I I) TPP Triphenylphosphine General Methods: Unless otherwise specified, all reactions are carried out at room temperature (approximately 25°C), under inert atmosphere (e.g., argon, N2), and under anhydrous conditions. All compounds are characterized by at least one of the following methods: Ή NMR, HPLC, MS, HPLC-ΕΜ or melting point. Typically, reaction progression is monitored by thin layer chromatography (TLC) or HPLC-ΕΜ. Intermediates and products are purified using at least one of the following methods: Flash silica gel chromatography, recrystallization, chiral supercritical fluid HPLC (FSC) using a RegisPack 3.0 x 25.0 cm column, eluting with a Socratic mixture of MeOH, isopropylamine (IPA), and supercritical carbon dioxide at 125 bar; 80 ml / min and / or reverse phase HPLC using a semipreparative C18 column eluting with a gradient of: • MeCN + 0.1% TFA and H2O + 0.1% TFA, • MeCN + 0.1% formic acid and H2O + 0.1% formic acid, or • MeCN and H2O containing NH4HCO3 2, 5 mM • MeCN and H2O + 0.1% TFA, • MeCN and H2O + 0.1% NH3, • MeCN and H2O and 0.1% TFA • MeCN and H2O and 0.1% NH3 IF-2018-67688982-APN-ANP#INPI Page 42 of 161 09-0675-0^3 ANALYTICAL DATA Data collected from mass spectrometry (MS) are for an observed mass (e.g., [M+H]*). The HPLC method used to characterize the compounds of the invention is described in Table 2. Table 2. HPLC methods Method Mobile phase A Mobile phase B Gradient Flow rate (ml / min.) Column A 0.1% formic acid in water 0.1% formic acid in MeCN Time (min) % of A % of B 0.8 BEH 2, 5x50mm C18, particle diameter 1.7 gm 0 95.0 5.0 1.0 5.0 95.0 1.3 5.0 95.0 1.4 95.0 5.0 1.7 95.0 5.0 This method is used for all remaining tables in this section for the ESI-EM and retention time data. If a different HPLC-ΕΜ is used, it is indicated in the text. Method 1 ESI+ / - ion mode. Column: CSH C18 2.1x50mm, particle diameter 1.7gm. Gradient: from 90% A to 100% B in 1.19 minutes maintained at 100% B for 1.70 minutes. Flow rate 0.8 ml / min. A= (95% water + 5% acetonitrile + 0.05% formic acid) B= (acetonitrile + 0.05% formic acid). Method 2 ES1+ / - ion mode. Column: BEH 2.1x50mm C18, particle diameter 1.7gm. Gradient: from 90% A to 100% B in 4.45 minutes maintained at 100% B for 4.58 minutes. Flow rate 0.8 ml / min. A= (95% water + 5% acetonitrile + 2.5 mM ammonium bicarbonate) B= (acetonitrile). Method 3 ESI+ / - ion mode. Column: BEH 2.1x50mm C18, particle diameter 1.7gm. Gradient: from 90% of A to 95% of B in 1.19 minutes maintained at 95% of B for 1.70 minutes. IF-2018-67688982-APN-ANP#INPI Page 43 of 161 09-0675-”-3 Flow rate 0.8 ml / min. A= (95% water + 5% acetonitrile + 2.5 mM ammonium bicarbonate) B= (acetonitrile). Method 4 ESI+ / - ion mode. Column: HSS T3 2.1x1 OOmm, particle diameter 1.8gm. Gradient: from 100% of A maintained for 1.00 minutes, from 100% of A to 95% of B in 4.50 minutes maintained at 100% of B for 4.91 minutes. Flow rate 0.6 ml / min. A= (95% water + 5% acetonitrile + 0.05% formic acid) B= (acetonitrile + 0.05% formic acid). Method 5 ESI+ / - ion mode. Column: CSH C18 2.1x50mm, particle diameter 1.7μτη: Gradient: from 90% A to 100% B in 4.45 minutes maintained at 100% B for 4.58 minutes. Flow rate 0.8mL / min. A= (95% water + 5% acetonitrile + 0.05% formic acid) B= (acetonitrile + 0.05% formic acid). Method 6 ESI+ / - ion mode. Column: HSS T3 2.1x100mm, particle diameter 1.8μτη. Gradient: from 95% A to 100% B in 3.65 minutes, held at 100% B for 4.95 minutes. Flow rate 0.6 ml / min. Column temperature 60°C. A= (95% water + 5% acetonitrile + 0.05% formic acid) B= (acetonitrile + 0.05% formic acid). Method 7 (column temperature 60°C) Mobile phase A Mobile phase B Gradient Flow rate (ml / min.) Column TFAal 0.1% in water ACN Time (min) % of A % of B Sun fire C18_3,Ox 30 mm, particle diameter 2.5 μηη 0 97 .0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.4 0.0 100.0 3.0 Method 8 (column temperature 40°C) Mobile phase Phase Gradient Flow Column IF-2018-67688982-APN-ANP#INPI Page 44 of 161 09-0675-1 A mobile B (ml / min.) Supercritical carbon dioxide 20 mM EtOH in NH3 Time (min) % of A % of B 4.0 CHIRAL ART® Cellulose SC_4.6 x 250 mm_ particle diameter 5pm 0 60 40 10 60 40 Method 9 Mobile phase A Mobile phase B Gradient Flow (ml / min.) Column TFAal 0.1% in water ACNal 0.08% in TFA Time (min) % of A % of B 1.5 Sun fire C18_3.0x 30 mm, diameter particle 2.5 gm 0 95.0 5.0 1.3 0.0 100.0 1.5 0.0 100.0 1.6 95.0 5.0 Method 10 (column temperature 60°C) Mobile phase A Mobile phase B Gradient Flow (ml / min.) Column TFAal 0.1% in Water ACN Time (min) % of A % of B Zorbax Stable Bond C18_3.0 x 30 mm, particle diameter 1.8pm 0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 IF-2018-67688982- APN-ANP#INPI Page 45 of 161 09-0675-1 1.4 0.0 100.0 3.0 Method 11 Mobile phase A Mobile phase B Gradient Flow rate (ml / min) Column r 0.1% NH3 in water ACN Time (min) % of A % of B XBridge C18_3.0x30 mm, particle diameter 2.5 μιτι 60°C 0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.4 0.0 100, 0 3.0 Method 12 Mobile phase A Mobile phase B Gradient Flow rate (ml / min) Column T° TFAal 0.1% in water ACN Time (min) % of A % of B Sun fire C18-2.1 x 30 mm, particle diameter 2, 5 pm 60°C 0 99.0 1.0 1.5 0.02 99.0 1.0 1.5 1.00 0.0 100.0 1.5 1.10 0.0 100.0 1.5 Method 13 Mobile phase A Mobile phase B Gradient Flow (ml / min) Column r NH3 to ACN Time % of % of XBridge IF-2018-67688982- APN A\PI\p Page 46 of 161 09-0675· W-3 0.1% in water (min) A B C18-3.0 x 30 mm, particle diameter 2.5 gm 60°C 0 95.0 5.0 1.5 1.3 0.0 100.0 1.5 1.5 0.0 100.0 1.5 1.6 95 5.0 1.5 Method 14 Mobile phase A Mobile phase B Gradient Flow rate (ml / min) Column ψθ 0.5% H3PO4 in water 0.5% H3PO4 in ACN Time (min) % of A % of B Halo C18_4.6 mmx 15 cm, diameter particle size 2.7 gm 15°C 0 95.0 5.0 1.2 1 95.0 5.0 1.2 4 70.0 30.0 1.2 5 62.5 37.5 1.2 7.5 61 39 1.2 10 2 98 1.2 12 2 98 1.2 EXAMPLES OF SYNTHESIS The following examples are illustrative and, as recognized by one skilled in the art, particular reagents or conditions can be modified as necessary for individual compounds without undue experimentation. The compounds of the invention can be prepared by the general methods and examples presented below and methods known to those of ordinary skill in the art. Optimal reaction conditions and reaction times may vary depending on the reagents used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthesis Examples section. The intermediate products IF-2018-67688982-APN-ANP#INPI Page 47 of 161 09-0675-W-3 used in the following syntheses are either readily available commercially or can be readily prepared by methods known to those skilled in the art. The progression of the reaction can be monitored by conventional methods such as thin layer chromatography (TLC) or high performance liquid chromatography mass spectrometry (HPLC-MS). Intermediates and products can be purified by methods known in the art, including column chromatography, HPLC, preparative TLC or recrystallization. General synthesis procedure The compounds of the invention are generally prepared by reaction of a carboxylic acid intermediate of formula INT-1 with an amine intermediate of formula INT-2 under appropriate conditions depicted below in Scheme 1. Scheme 1 (YO) Intermediates INT-1 and INT-2 are known in the art or can be prepared by the methods described below. The group terms R1 to R7(A, Y and L are as defined above for the compound of formula (I). Synthesis of intermediate products IF-2018-67688982- APN-ANP#INPI Page 48 of 161 09-0675W-3 44642.5-Dimethyl-pyrTol-1-¡l)-4-methoxyl-pyridin-3-inplperazlna-1-carboxylic acid tert-butyl ester A tert-butyl ester of piperazine-1-carboxylic acid (1.0 g, 5.37 mmol) and 5-bromo-2-(2,5dimethyl-pyrrol-1-yl)-4-methoxypyridine (1, 5 g, 5.37 mmol) in 1,4-dioxane (15 ml), CPhos-G3-palladacyclo methanesulfonate and sodium tert-butoxide (216 mg, 16.1 mmol) are added and degassed with nitrogen for 5 min. . The resulting mixture is stirred at 100°C for 10 h. The reaction mixture is filtered through a silica pad eluting with EtOAc and concentrated. The crude product is purified by silica gel column chromatography to provide the title compound. Yield: 2.1 g (88%) Rt(HPLC): 1.15 min (Method 1) 4-(6-Amlno-4-methoxyl-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester A 4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-piperazine-1carboxylic acid tert-butyl ester (2.1 g, 4.73 mmol ) in EtOH (10 ml) and water (5 ml), hydroxylamine hydrochloride (1.64 g, 23.6 mmol) and trimethylamine (659 μΙ_, 4.73 mmol) are added and stirred at 80eC for 18 h. The reaction mixture is concentrated under reduced pressure. The residue is suspended in DCM and filtered to remove the salts. The filtrate is purified by silica gel column chromatography to provide the title compound. IF-2018-67688982-APN-ANP#INPI 49 Page 49 of 161 09-0675-1 Yield: 1.07 g (73%) 4-methoxy-5-plperazin-1-ll-pyridin-2-llamine dihydrochloride To 4-(6-amino-4-methoxy-pyridin-3-II)-piperazine-1-carboxylic acid tert-butyl ester (1.07 g, 3.47 mmol) in DCM (12 ml) is added M HCI4 in 1,4-dioxane (4.34 ml, 17.35 mmol) and stirred at ΤΑ for 2 h. The reaction mixture is concentrated under reduced pressure. Yield: 976 mg (quantitative) 6-Amino-4-methyl-3’,6’-dihldro-2’H-r3,4’1blplrldinll-rcarboxylic acid tert-butyl ester 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboroIan-2-yl)-3,6-dihydro-2Hpyridine-1-carboxylic acid tert-butyl ester (1, 24 g, 4.01 mmol) and 5-bromo-4-methyl-pyridin-2-ylamine (750 mg, 4.01 mmol) in 1,4-dioxane are added 2 M NajCOs solution (4, 01 mi, 8.02 mmol) and PdCh(dppf) (328 mg, 0.40 mmol). The reaction mixture is degassed with nitrogen for 5 min and stirred in the microwave at 150°C for 30 min. The reaction is diluted with EtOAc and water and the phases are separated. The ac phase is extracted. again with EtOAc. The combined organic phases are washed with brine, dried over MgSO< and concentrated in vacuo. The residue is purified by silica gel chromatography to give the title compound. Yield: 1.1 g (95%) ESI-EM: m / z = 290 (M+H)* Rt(HPLC): 1.82 min (Method 2) IF-2018-67688982-APN-ANP#I^gI Page 50 of 161 09-0675-W-3 6-Amlno-4-methyl-3t,4,.5,.6,-tetrahydro-2,K-f3.4Tblp¡rÍdinyl-rcarboxylic acid tert-butyl ester 6-Amino-4-methyl-3',6*-dihydro-2'H-[3,4']bipyridinyl-T-carboxylic acid tert-butyl ester (1.10 g, 3.80 mmol) in MeOH (10 ml) is added to Pd / C (405 mg, 0.38 mmol) under nitrogen. The reaction mixture is degassed and subjected to a Hz flask. The reaction is filtered and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography to give the title compound. Yield: 511 mg (46%) ESI-MS: m / z = 292 (M+H)* Rt(HPLC): 1.80 min (Method 2) 4-Methíl-1,,2,l3Í,4,l5,t6,-hexahydro-r3.4nblplridinyl-6-ílamina dihydrochloride The title compound is synthesized from 6-amino-4-methylS'^'.S'.e'-tetrahydro-ZH-IS^'jbipyridinyl-r-carboxylic acid tert-butyl ester (511 mg, 1, 75 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy¡-5piperazin-1-yl-pyridin-2-ylamine dihydrochloride. Yield: 347 mg (75%) ESI-MS: m / z = 192 (M+H)* Rt(HPLC): 0.36 min (Method 2) 6-Amlno-3*,6,-dihydro-2lH-r3,41bÍpyridinyl-r-carboxylic acid tert-butyl ester IF-2018-67688982- APN-ANP#INPI Page 51 of 161 09-0675a A 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2Hpyridine-1-carboxylic acid tert-butyl ester (1.70 g , 5.50 mmol) and 5-bromo-pyridin-2-ylamlna (1.00 mg, 5.78 mmol) in 1,4-dioxane are added 2 M NazCOa solution (2 ml, 4.00 mmol) and PdCl2(dppf)CH2Cl2(449 mg, 0.55 mmol). The reaction mixture is degassed with nitrogen for 5 mln and stirred at 120°C for 16 h. All volatiles are evaporated under reduced pressure. The matter is purified! crude by standard phase chromatography! to provide the title compound. Yield: 1.2 g (79%) 6-AmIno-3*.4',5',6'-tetrahydro-2'H-r3,41blplridÍnll-rcarboxylic acid tert-butyl ester A 6-amino-3',6'-dihtdiO-2'H-[3,4']bipyridín¡l-T-carboxylic acid tert-butyl ester (45.0 g, 163.4 mmol) in EtOH ( 1000 mi) Pd(OH)2 on carbon (4.5 g, 32.4 mmol) is added under nitrogen. The reaction mixture is stirred at 30 PSI on a Parr shaker for 16h. The reaction is filtered through Celite®. The filtrate is evaporated under reduced pressure and the residue is purified by silica gel column chromatography to obtain the title compound. Yield: 23.7 g (79%) 1*<2*,3,l4,,5\6,-hexahydro-r3,41bipyridinyl-6-llamlna dichlorhydride IF-2018-67688982- APN-ANP#INPI Page 52 of 161 09-0675-1 The title compound is synthesized from 6-amino-3',4't5*f6'tetrahydro-2'H-[3,4']bipyridinII-r-carboxylic acid tert-butyl ester (800 mg, 2.88 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-piperazin-1-ylpyridin-2-ylamine dihydrochloride. Yield: 694 mg (96%) 6-amlno-4-methoxy-3,.6>-dihldro-2'H-r3.4'1biplridinyl-rcarboxylic acid tert-butyl ester A 4-(4,4t5,5-tetramethyl-[1,312]dioxaborolan-2-yl)-3,6-dihydro-2Hpyridine-1-carboxylic acid tert-butyl ester (10.0 g, 49.3 mmol) and 5-bromo-4-methoxy-pyridin-2-ylamine (15.2 g, 49.3 mmol) in 1,4-dioxane (100 ml) 2 M Na2CO3 solution (2 ml, 148 mmol) is added. and PdChfdppOCHjCh (3.93 g, 4.93 mmol). The reaction mixture is degassed with nitrogen for 5 min and stirred at 120*C for 16 h. All volatiles are evaporated under reduced pressure. The residue is diluted with water and extracted three times with EtOAc. The combined organic phases are washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material is purified by normal phase chromatography to provide the title compound. Yield: 2.50 g (55%) G-amino^-methoxy-S’^’.S’.e’-tetrahldro^’H-nMTblpIrldinyl1'-carboxylic acid tert-butyl ester IF-2018-67688982-APN-ANP#INPI Page 53 of 161 09-06751®3 The title compound is synthesized from 6-amino-4-methoxy3',6*-dihydro-2'H-[3,4*]bipyridiníl-r-carboxylic acid tert-butyl ester (750 mg, 2, 46 mmol) according to the procedure described for the synthesis of the intermediate product 6-amino-4-methyl3*,4',5',6*-tetrahydro-2'H-[3,4']bipyridinyl acid tert-butyl ester -r-carboxylic acid Yield: 715 mg (95%) ESI-MS: m / z = 308 (M+H)* Rt(HPLC): 0.88 min (Method 5) 4-Methox dihydrochlorideMl.2,t3,t4><5,<6,-hexahldro-r3,41blplridinll-6-llamlna The title compound is synthesized from 6-amino-4-methoxy3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-T-carboxyl acid tert-butyl ester ic (715 mg, 2.33 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5piperazin-1 -yl-pyridin-2-ylamine dihydrochloride. Yield: 745 mg (quantitative) ESI-EM: m / z = 208 (M+H)* Rt(HPLC): 0.56 min (Method 6) 446-amlno-pyridazin-3-yl)-3,6-dihydro-2H-pyrldine-1 carboxylic acid tert-butyl ester IF-2018-67688982-APN-ANP#INPI Page 54 of 161 09-0675W3 The title compound is synthesized from 4-(4,4,5,5tetramethyl-[1,3,2]dÍoxaborolan-2-yl)-3,6-dihydro-2H-pyride acid tert-butyl ester. na-1-carboxylic acid (977 mg, 3.16 mmol) and 6-cioro-pyridazine-3-ylamine (500 mg, 2.87 mmol) according to the procedure described for the synthesis of the intermediate product e acid tert-butyl ester -amino^-methoxy-S'.e'-dihydro2'H-[3,4']bipyridinyl-1'-carboxylic acid. Yield: 590 mg (74.3%) ESI-MS: m / z = 276 (M+H)* Rt(HPLC): 0.44 min (Method 1) 4-(6-amino-pyridazine-3-ll)-piperidine-1-carboxylic acid tert-butyl ester The title compound is synthesized from 4-(6-aminopyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.40 g, 19.5 mmol ) according to the procedure described for the synthesis of the intermediate product tert-butyl ester of 6amino^-methyl-S' / '.S'.e'-tetrahydro-ZH-IS^'lbipyridinyl-r-carboxylic acid. Yield: 3.93 g (72%) ESI-EM: m / z = 279 (M+H)* Rt(HPLC): 0.38 min (Method 1) 6-plperidin-4-ll-pyridazin-3-llamlna dihydrochloride IF-2018-67688982-APN-ANP#INPI Page 55 of 161 09-0675-W-3 The title compound is synthesized from 4-(6-aminopyridazin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.60 g, 12.9 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-piperazín-1-yl-pyridin-2ylamine dihydrochloride. Yield: 2.30 g (quantitative) ESI-EM: m / z =179 (M+H)* Rt(HPLC): 0.32 min (Method 1) (R)-2-ftert-butyl-dimetll-sHanÍloxymetll)-plperazlna-1carboxylic acid tert-butyl ester To (R)-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 4.62 mmol) in DMA (10 ml) is added tert-butyl-chloro-dimethyl-silane ( 1.05 g, 6.94 mmol) and imidazole (944 mg, 13.9 mmol) and the reaction mixture was stirred for 14 h at rt. The reaction mixture is diluted with EtOAc and washed with water and brine, dried over NajSOx, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound. Yield: 1.45 g (95%) S-Bromo^-foS-dimethyl-pyrroM-IIM-metlI-plridine A 5-bromo-4-methyl-pyridin-2-ylamÍne (2.00 g, 10.7 mmol) and hexane-2,5-dione (1.47 g, 12.8 mmol) in toluene (50 ml) Paratoluenesulfonic acid (61.0 mg, 0.32 mmol) is added, and the reaction mixture is stirred for 18h at 140°C. Pour the reaction mixture into water and IF-2018-67688982-APN-ANP#INPI Page 56 of 161 09-0675-1 is diluted in EtOAc. The separated organic phase is washed with brine and dried over MgSOx, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the compound! qualification. Yield: 2.68 g (95%) (R)-2-(tert-but¡l-dimethyl-silani!oxymethyl)-4-r6-(2,5-dimethylpyrrol-1-yl)-4-methyl-pyridin-3-tert-butyl ester in-piperazine-1-carboxylic acid A 5-bromo-2-(2,5-dimethyl-pyrrole-1-II)'4-methyl-pyridine (1.00 g, 3.77 mmol) and (R)-2- tert-butyl ester (tert-butII-dimethi!-sflanyloxymethyl)-piperazine-1-carboxylic acid (1.25 g, 3.77 mmol) in 1,4-dioxane (13 ml) sodium tert-butoxide (1.09 g) is added , 11.3 mmol) and CPhos-G3palladacyclo methanesulfonate (152 mg, 0.19 mmol). The mixture is degassed with nitrogen for 5 min, and stirred for 18 h at 100°C. The reaction mixture is filtered through a silica gel pad and elute with EtOAc. Concentrate the filtrate under reduced pressure to give the title compound. Yield: 1.67 g (86%) ESI-EM: m / z = 515 (M+H)+Rt(HPLC): 1.56 min (Method 1) (R)-4- tert-butyl ester (6-amino-4-methyl-pyridin-3-II)-2-hydroxymethylpiperazine-1-carboxylic IF-2018-67688982-APN -A\PI\yi Page 57 of 161 09-0675-1 A mixture of tert-butyl ester of (R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5dimethyl-pyrrol-1-yl)-4-methyl-pyridín-3- II]-pÍperazÍne-1-carboxylic acid (1.67 g, 3.24 mmol), hydroxylamine hydrochloride (1.13 g, 16.2 mmol) and trimethylamine (452 ​​μΙ, 3.24 mmol) in ethanol (10 ml ) and water (5 ml) is stirred for 18 h at 80eC. The reaction mixture is concentrated under reduced pressure and the residue is purified by reverse phase chromatography to provide the title compound. Yield: 1.67 g (86%) Rt(HPLC): 0.66 min (Method 3) f(ff)-4-(6-Amlno-4-methyl-plridin-3-in-pÍperazln-2-in-methanol dihydrochloride The title compound is synthesized from (R)-4-(6-amino-4methyl-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.40 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5piperazin-1-yl-pyridin-2-ylamine dihydrochloride. Yield: 412 mg (quantitative) 5-Bromo-2-(2t5-dimethyl-plrrol-1-ll)-4-methoxyplridine The title compound is synthesized from 5-bromo-4-methoxy-pyridin-2-ylamine (2.00 g, 9.85 mmol) according to the procedure described for the synthesis of the intermediate product 5bromo-2-(2, 5-dÍmethyl-pyrrol-1-yl)-4-methyl-pyridine. Yield: 2.48 g, (90%) ESI-EM: m / z = 283 (M+H)* Rt(HPLC): 2.13 min (Method 5) 7-r642,5-dimethyl-pyrrole-1-ll)-4-methoxyl-pyridin-3-in-4t7-diazasplrof2.51octane-4-carboxylic acid tert-butyl ester IF-2018-67688982-APN-ANP#INPI Page 58 of 161 09-0675-Wl A 5-bromo-2-(2,5-dimethyl-pyrroI-1-yl)-4-methoxypyridine (1.25 g, 4.45 mmol) and 4,7-diaza-spiro[ tert-butyl ester 2.5]octane-4-carboxylic acid (1.13 g, 5.34 mmol) in 1,4-dioxane (13 ml) add CS2CO3 (4.35 g, 13.3 mmol) and CPhos-G3-palladacyclo methanesulfonate (359 mg, 0.45 mmol. The mixture is degassed with nitrogen for 5 min, and stirred for 18h at 100®C. The reaction mixture is extracted with EtOAc, washed with brine, dried over MgSO«, Filter and concentrate under reduced pressure. Purify the residue by silica gel column chromatography to give the title compound. Yield: 1.51 g (82%) ESI-MS: m / z = 413 (M+H). )* Rt(HPLC): 2.69 min (Method 5) 746-amlno-4-methoxl-plrldin-3-ll)-4t7-diazaspiro f2.51octane-4-carboxylic acid tert-butyl ester The title compound is synthesized from 7-(6-(2,5-dimethyl!1pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-4,7 tert-butyl ester. -diaza-spiro[2.5]octane-4-carboxylic acid (1.51 g, 3.66 mmol) according to the procedure described for the synthesis of the intermediate product (R)-4-(6-amino-) tert-butyl ester 4-methyl-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylic Yield: 1.07 g (87%) ESI-MS: m / z = 335 (M+H)* Rt(HPLC): 0.74 min (Method 5) 544,7-dÍaza-esplror2.51oct-7-ÍD-4-methoxl-plridÍn-2-llamÍn dihydrochloride IF-2018-67688982- APN- ANP#INPI Page 59 of 161 09-0675-1 The title compound is synthesized from 7-(6-amino-4methoxy-pyridin-3-yl)-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.07 g , 3.19 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5piperazin-1 -II-pyridin-2-ylamine dihydrochloride. Yield: 1.10 g (quantitative) ESI-EM: m / z = 235 (M+H)+Rt(HPLC): 0.17 min (Method 5) 4-16-Amlno-5-methoxy-pyridazine-3-1)-3,6-dihydrO'2H-pyridine-1-carboxateTere-butyl hate The title compound is synthesized from 4-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-tert-butyl ester. carboxylic acid (1.74 g, 5.64 mmol) and 6-chloro-4-methoxy-pyridazIn-3-ylamine (900 mg, 5.64 mmol) according to the procedure described for the synthesis of the intermediate product tert-butyl ester of 6-amino-4-methoxy-3',6 *dihydro-2'H-[3,4']bipyridinyl-T-carboxylic acid Yield: 787 mg (46%) ESI-MS: m / z = 307 (M+H)+Rt(HPLC): 0.59 min (Method 5) 446-Tere-butyl amino-5-methoxy-pyridazín-3-yl)-plperidine-1-carboxylate Tere-butyl A4-(6-amino-5-methoxy-pyridazIn-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (785 mg, 2.56 mmol) in MeOH (10 mi) and acetic acid (1mL) Pd / C (273 mg, 0.26 mmol) is added under nitrogen. The reaction mixture is degassed and subjected to a balloon of H2. IF-2018-67688982-APN-ANP#INPI 60 Page 60 of 161 09-0675-O-3 The reaction is filtered and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography to give the title compound. Yield: 513 mg (65%) ESl-MS: m / z = 309 (M+H)* Rt(HPLC): 0.54 min (Method 5) 4-Methoxl-6-plperidin-4-II-plrÍdazln-3-llamlna dihydrochloride The title compound is synthesized from tere-butyl 4-(6-amino-5-methoxy-pyridazIn-3-II)-piperidine1-carboxylate (510 mg, 1.65 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-piperazÍn-1-ÍI-pyridin-2-ylamine dihydrochloride. Yield: 514 mg (quantitative) ESI-EM: m / z = 209 (M+H)* Rt(HPLC): 0.14 min (Method 5) Tere-butyl 4-(6-{r(tert-butoxl)carboninamlnoM-methoxlplridazÍn-3-ll)-1,2,3,6-tetrahldroplridlna-1-ca rboxylate The title compound is synthesized from Tere-butyl 4-(4t4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.76 g, 20 mmol) and N-(6-chloro-5-methoxypyridazin-3-yl)tere-butyl carbamate (4.00 g, 20 mmol) according to the procedure described for the synthesis of the intermediate product 6-amino-acid tert-butyl ester. 4-methoxy-3',6*-dihydro-2'H-[3,4']bÍpyridinyl-T-carboxylic acid. Yield: 4.56 g (59%) 4-f6-fr(tert-butoxl)carboninamÍnoM-methoxlplridazln-3-ll|plperldin-1-carboxylate tere-butyl IF-2018-67688982-APN-ANP#INPI Page 61 of 161 09-0675W3 TO tert-butyl 4'(6'(tert-butoxy)carbonyl]amine}-4-methoxypyridazin-3-l)-1,2,3t6-tetrahydropyridine-1-carboxylate (1.50 g, 3.69 mmol) in MeOH (15 ml) Pd / C (1.18 g, 1.11 mmol) is added under a nitrogen atmosphere. The reaction mixture is degassed and subjected to a balloon of H2 at 30eC overnight. The mixture is treated with Pd / C (0.3 g) and stirred at 30eC for 3h. The reaction is filtered and concentrated under reduced pressure. Yield: 1.42 g (94%) 5-Methoxl-6-(plperÍdin-4-IDplridazin-3-amlna) dihydrochloride The title compound is synthesized from tere-butyl 4-(6¿[(tert-butoxy)carbonyl]amino}-4·methoxypyridazin-3-yl)piperidine-1-carboxylate (1.42 g, 3. 48 mmol) according to the procedure described for the synthesis of 4-methoxy-5-piperazin-1-yl-pyridin-2ylamine dihydrochloride. Yield: 0.99 g (quantitative) 446-nItro-pyridine-3-ll)-piperazine-1-carboxylic acid tert-butyl ester IF-2018-67688982- APN-ANP#INPI Page 62 of 161 09-0675-1 5-Bromo-2-nitro-pyridine (5.00 g, 24.63 mmol) and piperazine-1carboxylic acid tert-butyl ester (13.7 g, 73.9 mmol) in NMP (50 ml) are stirred for 3 h at 120eC. The reaction mixture is poured into water. The precipitate is filtered, washed with water and dried to give the title compound. Yield: 6.80 g (90%) 4-(6-Amino-pyridine-3-ID-plperazine-1-carboxylic acid tert-butyl ester 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.00 g, 65.9 mmol) and Pd / C (200 mg) in ethanol is stirred with a H2 balloon for 3 h. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Yield: 1.90 g (quantitative) 5-pÍperazin-1-ll-plrÍdin-2-llamlna dihydrochloride 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.50 g, 8.98 mmol) in DCM (30 mL) and 1,4-M HCl Dioxane (11.2 ml, 44.9 mmol) is stirred for 16 h at rt. The reaction mixture is filtered and washed with ether to give the title compound. Yield: 2.23 g (99%) (R)-2-(fert-butyl-dimethyl-silanyloxymethyl)-4-(6-nitro-pyridine-3ÍD-piperazine-1-carboxylic acid tert-butyl ester IF-2018-67688982-APN-ANP#INPI Page 63 of 161 09-0675-W-3 A (R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.50 g, 4.54 mmol) and 5-bromo-2-nitropyridine (1, 00 g, 4.93 mmol) in 1,4-dioxane (12 ml) are added CS2CO3 (4.44 g, 13.6 mmol), Pd2(dba)3 (208 mg, 0.23 mmol) and Xantphos (263 mg, 0.45 mmol). The reaction mixture is stirred at 100°C for 24 h, filtered through Celite®, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to provide the title compound. Yield: 1.35 g (66%) ESI-EM: m / z = 453 (M+H)*Rt(HPLC): 1.31 min (Method 1) (R)-4-(6-amino-pyridÍn-3-in-2-(tenc-butyl-dimethyl-dimethyl) tert-butyl ester (R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4-(6-nitro-pyridin-3-Il)piperazine-1-carboxylic acid tert-butyl ester (1.35 g, 2.98 mmol ) and Pd / C (317 mg, 0.15 mmol) in methanol (20 ml) is stirred with a balloon of H2 for 24 h. The reaction mixture is filtered through Celite®, washed with methanol, and the filtrate is concentrated under reduced pressure. Yield: 1.26 g (quantitative) f(R)-4-(6-AmÍno-pyridin-3-ÍD-piperazÍn-2-in-methanol dihydrochloride IF-2018-67688982-APN -ANPtfEgJI Page 64 of 161 09-0675-#3 (R)-4-(6-amino-pyridin-3-yl)-2-(tert^butyl-dimethyl-silanyloxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.26 g, 2.98 mmol ) in DCM (10 m!) and HCl4 M in 1,4-dioxane (7.5 m!, 30.0 mmol) is stirred for 1 h at rt. The reaction mixture is concentrated under reduced pressure, suspended in ether, filtered and washed with ether to give the title compound. Yield: 838 mg (quantitative) (R)-4-f6-(2t5-dimethyl-plrrol-1-ll)-4-methyl-pyridin-3-yn-2hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester h3c A (R)-2-(tert-butyl-dimethyl-silanyloxymethiI)-4-[6-(2,5-dimethyl-pyrrol-1yl)-4-methyl-pyridin-3-yl] acid tert-butyl ester -piperazine-1-carboxylic acid (8.56 g, 16.1 mmol) in THF (100 ml), tetrabutylammonium fluoride (16.1 ml, 16.1 mmol) is added, and the reaction mixture is stirred at RT for 1.5 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel column chromatography to provide the title compound. Yield: 6.10 g (91%) ESI-EM: mfe = 417 (M+H)+Rt(HPLC): 0.98 min (Method 1) -f6-(2.5-dimethyl-4-pyrrole-1-ll)-4-methyl-plrídin-3-in-2 methoxymethyl-plperazine-1-carboxylic acid tert-butyl ester IF-2018-67688982-APN-ANP#INPI Page 65 of 161 09-0675-1 A (R)-4-[6-(2,5-dimethyl-pyrrol-1-yl)-4-methyl-pyridin-3-yl]-2hydroxymethyl-piperazine-l-carboxylic acid tert-butyl ester (2 .00 g, 4.80 mmol) and methyl iodide (915 mg, 7.20 mmol) in DMA (15 ml) 60% NaH (230 mg, 5.76 mmol) is added. The reaction mixture is stirred for 2 h at RT and cooled with water. Extract the mixture three times with EtOAc, wash the combined organic phases with brine, dry over MgSOx, filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound. Yield: 1.80 g (87%) ESI-EM: m / z = 431 (M+H)*Rt(HPLC): 1.12 min (Method 1) (R)-4-(6-amino-4-methyl-pyridin-3-yl)-2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester The title compound is synthesized from (R)-4-[6-(2,5dimethyl-pyrrole-1-II)-4-methylpyridin-3-yl]-2-methoxymethyl-piperazine tert-butyl ester. -1-carboxylic acid (1.80 g, 4.18 mmol) according to the procedure described for the synthesis of the intermediate product (R)-4-(6-amino-4-methyl-pyridin-3-yl) tert-butyl ester -2-hydroxymethyl-piperazine-1-carboxylic Yield: 1.07 g (87%) ESI-MS: m / z = 353 (M+H)+Rt(HPLC): 0.44 min (Method 1) 5-((R)-3-methoxymethyl-pÍperazin-1-yl)-4-methyl-pyridin-2-ylamine hydrochloride IF-2018-67688982- AP\-A\PI\yi Page 66 of 161 09-0675-0^3 It synthesizes e! title compound from (R)-4-(6-amino-4-methyl-pyridin-3-yl)-2methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester (440 mg, 1.25 mmol) according to the procedure described for the synthesis of! intermediate product 4-methoxy5-piperazin-1 -yl-pyridin-2-ylamine dihydrochloride. Yield: 406 mg (quantitative) 4-F6-amino-4-methyl-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1carboxylic acid tert-butyl ester The title compound is synthesized from 4-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 acid tert-butyl ester. -carboxylic acid (538 mg, 1.74 mmol) and 6-chloro-5-methyl-pyridazIn-3-ylamine (250 mg, 1.74 mmol) according to the procedure described for the synthesis of the intermediate product tert-butyl acid ester 6-amino-4-methyl-3',6'dihydro-ZH-p^'lbipyridinyl-T-carboxylic acid. Yield: 326 mg (65%) ESI-MS: m / z = 292 (M+H)* Rt(HPLC): 0.51 min (Method 5) 4-(6-amino-4-methyl-p!rldazin-3-ID-piperidine-1-carboxylic acid tert-butyl ester The compound is synthesized! titer from 4-(6-amino-4methyl-pyridazín-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (326 mg, 1.12 mmol ) according to him IF-2018-67688982-APN -ANP#Hg£I Page 67 of 161 09-0675-17^3 procedure described for the synthesis of the intermediate product tert-butyl ester of 6amino-4-methyl-3',4*,5',6'-tetrahydro-2'H-[3,4* ]bipyridinyl-r-carboxylic. Yield: 289 mg (88%) ESI-MS: m / z = 293 (M+H)* Rt(HPLC): 0.60 min (Method 5) 5-methyl-6-plperidin-4-ll-plridazin-3-llamlna dihydrochloride The title compound is synthesized from 4-(6-amino-4methyl-pyridazin-3-yl)-piperidtna-1-carboxylic acid tert-butyl ester (175 mg, 0.60 mmol) according to the procedure described for the synthesis of the intermediate product 5-piperazin-1-II-pyridín-2ylamine dihydrochloride. Yield: 154 mg (97%) ESI-MS: m / z = 193 (M+H)* Rt(HPLC): 0.46 min (Method 2) 5-Bromo-2-(2,5-dimethyl-pyrrole-1-ll)-4-methoxyplridine The title compound is synthesized from 5-bromo-4-methoxy-pyridin-2-ylamine (10.6 g, 52.1 mmol) according to the procedure described for the synthesis of the intermediate product 5bromo-2-(2, 5-dimethyl-pyrrol-1-yl)-4-metll-pyridine. Yield: 14.0 g (96%) ESI-EM: m / z = 283 (M+H)* Rt(HPLC): 0.93 min (Method 3) (R)-2-ftert-butyl-dimethyl-silanyloxymethyl)-4-r6-(2.5-dimethyl·pyrro1-1-yl)-4-methoxyl-pyridin-3-yn-piperazine-1 tert-butyl ester -carboxylic IF-2018-67688982-APN-ANP#INPI Page 68 of 161 09-0675-0^3 A 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4-methoxypyridine (1.24 g, 4.41 mmol) and tert-butyl ester of! (R)-2-(tert-butyl-dimethi!-si!anyloxymethyl)-piperazine-1-carboxylic acid (1.46 g, 4.41 mmol) in 1,4-dioxane (13 ml) tert is added -sodium butoxide (1.27 g, 13.2 mmol) and CPhos-G3palladacyclo methanesulfonate (178 mg, 0.22 mmol). The mixture is degassed with nitrogen for 5 min, and stirred for 4 h at 100eC. Filter the reaction mixture through a pad of silica gel and elute with EtOAc. The filtrate is concentrated under reduced pressure and the residue is purified by reverse phase column chromatography to give the title compound. Yield: 1.68 g (72%) ESI-EM: m / z - 531 (M+H)* Rt(HPLC): 1.43 min (R)-4-(6-amino-4-methoxy-plridin-3-yl)-2-hydroxylmethylplperazlna-1-carboxylic acid tert-butyl ester tert-butyl ester of! (R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1yl)-4-methoxy-pyridin-3-yl]-piperazine-1-carboxylic acid co (1.68 g, 3.17 mmol), hydroxylamine hydrochloride (1.10 g, 15.8 mmol) and trimethylamine (320 μ!, 3.24 mmol) in ethanol (6 m!) and water ( 3 mi) is stirred for 18 h at 80eC. Hydroxylamine hydrochloride (440 mg, 6.33 mmol) is added again and stirred at 80eC. The reaction mixture is concentrated under reduced pressure and IF-2018-67688982-APN-ANP#INPI Page 69 of 161 09-0675-0^3 the residue is purified by reverse phase column chromatography (to provide the title compound. Yield: 620 mg (58%) FiR)-4-(6-amlno-4-methoxy-pyridin-3-in-piperazÍn-2-in-methanol hydrochloride The title compound is synthesized from (R)-4-(6-amino-4methoxy-pyridin-3-yl)-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (620 mg, 1, 83 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5piperazin-1-yl-pyridin-2-ylamine dihydrochloride. Yield: 503 mg (quantitative) 3-r6-f2,5-dimethyl-pyrroM-ll)-4-methoxl-pyridin-3-ll1-3,8-diazabicyclof3.2.1loctane-8-carboxylic acid tert-butyl ester A 5-bromo-2-(2,5-dÍmethyl-pyrrole-1-ÍI)-4-methoxypyridine (1.00 g, 3.56 mmol) and 3,8-diaza-bicyclo[ tert-butyl ester 3.2.1]octane-8-carboxylic acid (830 mg, 3.91 mmol) in 1,4-dioxane (13 ml), sodium tert-butoxide (3.48 g, 10.7 mmol) and CPhos- G3-palladacyclo methanesulfonate (287 mg, 0.36 mmol). The mixture is degassed with nitrogen for 5 min, and stirred for 18h at 80eC. The reaction mixture is extracted with EtOAc, washed with brine, dried over MgSO«, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound. Yield: 760 mg (52%) ESI-MS: m / z = 412 (M+H)* Rt(HPLC): 1.23 min (Method 1) IF-2018-67688982-APN-ANP#INPI 70 Page 70 of 161 09-067541^3 346-Amino-4-methoxy-pyridin-3-ll)-3,8-diazabicyclor3.2.11octane-8-carboxylic acid tert-butyl ester The title compound is synthesized from 3-[6-(2,5-dimethylpyrrol-1-yl)-4-methoxy-pyridin-3-yl]-3,8-diaza-bicyclo acid tert-butyl ester. [3.2.1]octane-8-carboxylic acid (760 mg, 1.84 mmol) according to the procedure described for the synthesis of the intermediate product tert-butyl ester of acid 4-(6-amino-4-methoxy-pyridin-3-i! )-piperazine-1-carboxylic acid. Yield: 330 mg (54%) ESl-MS: m / z = 335 (M+H)* Rt(HPLC): 1.75 min (Method 6) 543,8-diaza-bicyclochlor3.2.11oct-3-yl)-4-methoxy-plridin-24lamine dihydrochloride The title compound is synthesized from 3-(6-amino-4methoxy-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (330 mg , 0.99 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5piperazin-1-íl-pyridin-2-ylamine dihydrochloride. Yield: 330 mg (quantitative) ESl-MS: m / z = 235 (M+H)* Rt(HPLC): 0.15 min (Method 5) (2R)-2-rMethoxy(methyl)carbamoinpiperazine-1 4-benzyl and 1-tere-butyl ,4-dicarboxylate IF-2018-67688982- AP\-A\PI\PI Page 71 of 161 09-0675-^3 (2R)-4-[(benzyloxy)carbonII]-1-[(tert-butoxy)carbonyl]perazine-2-carboxylic acid (4.00 g, 11.0 mmol), DIPEA (5.1 ml, 27, 4 mmol), HATU (5.01 g, 13.2 mmol) and N,Odimethylhydroxylamine hydrochloride (1.29 g, 13.2 mmol) in DMA (40 ml) are stirred at RT for 3 days. Dilute the reaction mixture with EtOAc, wash with water and brine. The organic phase is dried over MgSO<, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound. Yield: 4.44 g (99%) ESI-MS: m / z = 408 (M+H)* (2R)-2-Acetylperazine-1,4-dicarboxylate 4-benchyl and 1-ether -butyl To a mixture cooled to -20®C of (2R)-2-[methoxy(methyl)carbamoyl]piperazine-1,4-dicarboxylate of 4-benzyl and 1-tere-butyl (4.40 g, 10.80 mmol ) in THF (25 ml), methylmagnesium bromide (5.40 ml, 16.20 mmol) is added dropwise and stirred at 20°C for 30 min. The reaction mixture is cooled with saturated aqueous NH4Cl solution, diluted with EtOAc, and washed with HCl + 1 N water and brine. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified by chromatography to give the desired product. Further purification is done by separation with chiral chromatography to give the pure R-enantiomer. Yield: 2.38 g (61%) IF-2018-67688982-APN -AXPINPI Page 72 of 161 09-0675-W-3 (2R)-2-(1-Hldroxletil)plperazine-1,4-dlcarboxylate 4-benzyl and 1-fert-butyl Sodium borohydride (0f36 g, 9.52 mmol) is added to 4-benzyl 1-tere-butyl (2R)-2-acetylpiperazine-1,4-dicarboxylate (2.30 g, 6.35 mmol) in methanol (100 ml). After stirring the reaction mixture for 30 mtn, the solvent is removed under reduced pressure. The residue is purified by silica chromatography. Yield: 2.10 g (91%) 4-benzyl and 1-tere-butyl IF-2018-67688982- APN-ANP#INPI Page 73 of 161 09-0675-W-3 Tert-butyl(chloro)dimethylsilane (1.30 g, 8.64 mmol) is added to 4-benzyl 1-tert-butyl (2R)-2-(1-hydroxyethyl)piperazine-1,4-dicarboxylate ( 2.10 g, 5.76 mmol) and imidazole (1.18 g, 17.29 mmol) in dichloromethane (15 ml). The reaction mixture is stirred overnight. After adding water (10 ml), the aqueous phase is extracted with dichloromethane (2 x 25 ml). The combined organic phases are washed with brine. The organic phase is dried, filtered and concentrated under reduced pressure. The residue is purified by silica chromatography. Yield: 2.75 g (99.7%) Tere-butyl (2R)-2-{1-r(tert-Butyldimethylsil¡Doxnetyl}piperazine-1-carboxylate IF-2018-67688982-APN-ANP#INPI Page 74 of 161 09-0675-ro-3 4-Benzyl (2R)-2¿1-[(tert-butyldimethylsilyl)-oxy]ethyl}pÍperazine-1,4-dicarboxylate and 1-Tere-butyl (2.75 g, 5.75 mmol) and Pd / C (0.20 g) are stirred at room temperature in ethanol (50 ml) for 2 h under a hydrogen atmosphere (balloon). After removing the catalyst by filtration through Celite®, the solvent is removed under reduced pressure. The residue is filtered through silica eluting with 10% MeOH / dichloromethane. Yield: 1.89 g (96%) (2Ρ)-2414(ίΕΓσ-Βυ1ίΙόίΓΤΊ6ίΠ3ΠΠ)οχηθ1ίΠ-4-Γ6-{2.5-όίηΊ61Π-1Η-ρΪΓΓθΙ-1- Π)-4-ΠΊ6ίοχϊρ1Γ1άίπ-3 tere-butyl -lipperazine-l-carboxylate IF-2018-67688982-APN-ANP#INPI Page 75 of 161 09-0675i®3 A (2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1-carboxylate tere-butyl (1.89 g, 5.49 mmol) and 5-bromo-2-(2, 5-dimethyl-pyrro1-1-yl)-4-methoxypyridine (1.54 g, 5.49 mmol) in 1,4dioxane (20 ml) are added CPhos-G3-palladacyclo methanesulfonate (0.22 g) and tert-butoxide of sodium (1.58 g, 16.5 mmol), and the reaction mixture is sprayed with nitrogen. The reaction mixture is stirred at 100°C for 10 h. The reaction mixture is filtered through a silica pad eluting with EtOAc and concentrated. The residue is purified twice by silica chromatography to give the title compounds. Performance: (2R)-2-[(fS)-1-[(tere-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1H-pyrro!-1-ÍI)-4- tere-butyl methoxypyridin-3-II] piperazine-1-carboxylate: 0.57 g (19%) and (2R)-2-[(ÍR)-1 -[(tert-butyldimethylsilyl)oxy]ethyl]-4 -[6-(2,5-d imethyl-1 H-pyrro I -1 -iI)-4-methoxypyridin-3-yl] tere-butyl piperazine-1-carboxylate: 0.78 g (26%) ( Tere-butyl 2 / ?)-4-(6-Amino-4-methoxypyridin-3-yl)-2-n 1RI-1-hydroxyethinepiperazine-1-carboxylate IF-2018-67688982-APN-ANP#INPI Page 76 of 161 09-0675-OT-3 (2R)-2-[( 1R)-1 -[(ferc-butyldim ethyls ¡HI)oxy]ethyl]-4 -(6-(2,5-dimethyl-1 H-pyrrol-1 -yl)- tert-butyl 4-methoxypyridin-3-yl]piperazine-1-carboxylate (0.87 g, 1.60 mmol), hydroxylamine hydrochloride (0.56 g, 7.99 mmol) and trimethylamine (0.22 ml , 1.60 mmol) in 8 ml of ethanol and 4 ml of water is heated at 80°C for 42 h. An additional amount of hydroxylamine hydrochloride (0.22 g, 3.19 mmol) is added and stirred. the reaction mixture at 80°C overnight. The reaction mixture is concentrated under reduced pressure, incorporated into dichloromethane and filtered. The desired compound is purified by silica chromatography. Yield: 0.20 g (36%), (<fRb1-fí2ff)-446-Amino-4-methoxypyridin-3-yl)piperazÍn-2-llletan-,1-ol dihydrochloride HCI4 N in dioxane (0.71 ml, 2.84 mmol) is added to (2R)-4-(6-amino-4-methoxypyridin-3-yl)-2-[(1R)-1-hydroxyethyl] Fe / nc-butyl piperazine-1-carboxylate (0.20 g, 0.57 mmol) in 5 ml of dichloromethane and stirred at RT for 2 h. An additional 1 ml of 4 N HCl in dioxane is added and stirred for 1 h at RT. The reaction mixture is concentrated under reduced pressure. The residue is used without further purification. Yield: 0.18 g (quantitative) IF-2018-67688982-APN-ANP#INPI Page 77 of 161 09-0675-OT-3 (2R)-4-(6-Amino-4'methoxyplridin-3-yl)-2-niS)-1'hydroxyethinepiperazine-1-carboxylate tere-butyl (2R)-2-[(1S)-1 -[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2l5-dimethyl-1 H-pyrrol-1-yl)-4-methoxypyridin-3- tere-butyl il]piperazine-1-carboxylate (0.57 g, 1.04 mmol), hydroxylamine hydrochloride (0.36 g, 5.21 mmol) and trimethylamine (0.15 ml, 1.04 mmol) in 4 ml of ethanol and 2 ml of water, it is heated at 80°C for 42 h. An additional amount of hydroxylamine hydrochloride (0.15 g, 2.09 mmol) is added and the reaction mixture is stirred at 80°C overnight. The reaction mixture is concentrated under reduced pressure, incorporated into dichloromethane and filtered. The desired compound is purified by silica chromatography and repurified by HPLC. Yield: 0.12 g (33%), (ÍS)-1-r<2R)-4-(6-amino-4-methoxylpliidin-3-ÍDpÍperazÍn-2-inethan-1-ol dichlorhydride HCI4 N in dioxane (0.50 ml, 2.00 mmol) is added to (2R)-4-(6-amino-4-methoxypyridin-3-yl)-2-[(1S)-1-hydroxyethyl] tere-butyl piperazine-1-carboxylate (0.12 g, 0.34 mmol) in 1 ml of dichloromethane and stirred at RT for 1 h. The reaction mixture is concentrated under reduced pressure. The residue is used without further purification. IF-2018-67688982-APN-ANP#INPI Page 78 of 161 09-0675-^5-3 Performance: quantitative 7-(6-Amino-4-methoxl-plridin-3-II)-3-oxa-9-azablclclol3.3.11non-6-ene-9-carboxylic acid tert-butyl ester The title compound is synthesized from 5-bromo-4-methoxy-pyridin-2-ylamÍne (202 mg, 1.00 mmol) and / -(ÁAS.S-tetramethyl-ÍI.S) tert-butyl ester ^jdioxaborolan^-ilj-S-oxa9-aza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid (350 mg, 1.00 mmol) according to the procedure described for the synthesis of the tert-butyl ester intermediate of 6-amino-4-methyl3',6'-dihydro-2'H¿3,4']bipyridínyl-T-carboxylic acid. Yield: 220 mg (64%) ESl-MS: m / z = 348 (M+H)* Rt(HPLC): 1.52 min (Method 2) 7-(6-amino-4-methoxl-plridin-3-yl)-3-oxa-9-azabiclchlor3.3.11nonan-9-carboxylic acid tert-butyl ester A 7-(6-amino-4-methoxy-pyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]non6-ene-9-carboxylic acid tert-butyl ester (220 mg, 0.63 mmol) in EtOAc (10 ml) Pd / C (67.0 mg, 0.06 mmol) is added under nitrogen. The reaction mixture is degassed, placed under a balloon of H2 and stirred for 18 h at 50*C. Filter the reaction through Celite®, concentrate under reduced pressure and purify by silica gel column chromatography to give the title compound. Yield: 145 mg (66%) ESl-MS: m / z = 350 (M+H)* Rt(HPLC): 1.60 min (Method 2) 4-Methoxl-5-(3-oxa-9-aza-bicychlor3.3.1lnon-7-yl)-plridin-2-ylamine dihydrochloride IF-2018-67688982-APN-ANP#IF^I Page 79 of 161 09-0675-W-3 The title compound is synthesized from tert-butyl ester of 7-(6-amino-4methoxy-pyridin-3-II)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid (145 mg, 0.41 mmol) according to the procedure described for the synthesis of the intermediate product 4methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride. Yield: 133 mg (quantitative) ESI-EM: m / z = 250 (M+H)* Rt(HPLC): 0.15 min (Method 5) (S)-2-(fert-butyl-dimethyl-slanyloxymethyl)-piperazine-1carboxylic acid tert-butyl ester Fert-butyl-chloro-dimethyl-silane ( 2.09 g, 13.9 mmol) and imidazole (1.89 g, 27.7 mmol), and the reaction mixture was stirred for 24 h at rt. The reaction mixture is diluted with NH4CI solution and extracted with EtOAc. The organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound. Yield: 2.80 g (92%) (S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4-r6-(2,5-dimethylpyrrol-1-yl)-4-methoxy-pyridin-3-iri-plperazine-tert-butyl ester 1-carboxylic IF-2018-67688982-APN-ANP#Il^gI Page 80 of 161 09-0675la The title compound is synthesized from 5-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-4methoxypyridine (3.25 g, 11.6 mmol) and tert-butyl acid ester (S )-2-(tert-butyl-dÍmethylsilanyloxymethyl)-piperazine-1-carboxylic acid (3.82 g, 11.6 mmol) according to the procedure described for the synthesis of the intermediate product tert-butyl acid ester 3-[6-( 2,5-dimethyl-pyrrol-1yl)-4-methoxy-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid. Yield: 4.94 g (73%) ESI-EM: m / z = 531 (M+H)* Rt(HPLC): 1.49 min (Method 3) (S)-4-(6-amino-4-methoxy-pyridin-3-n)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (S)-2-(tert-buty!-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl] tert-butyl ester is stirred. -piperazine-1-carboxylic acid (11.9 g, 22.4 mmol), hydroxylamine hydrochloride (3.89 g, 56.0 mmol) and trimethylamine (7.8 ml, 56.0 mmol) in ethanol (30 ml ) and water (15 mi) for 18 h at 80eC. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography to give the compound of! qualification. Yield: 2.57 g (68%) (S)-4-(6-amino-4-methoxl-pyridin-3-ll)-piperazine-2-in-methanol hydrochloride IF-2018-67688982-APN-ANP#INPI Page 81 of 161 09-0675W-3 The title compound is synthesized from (S)-4-(6-amino-4methoxy-pyridín-3-yl)-2-hydroxymethyl-pÍperazine-1-carboxylic acid tert-butyl ester (264 mg, 0. 58 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5piperazin-1-yl-pyridin-2-ylamine dihydrochloride. Yield: 160 mg (quantitative) Fl?)-4-r6-(2.5-dimethyl-pyrroM-ÍÍ)-4-methoxl-pÍrldln-3-in-2- tert-butyl ester A tert-butyl ester of (R)-2-(tem-butyl-dimethyl-silanyloxymethyl)-4-[6-(2,5-dimethyl-pyrrol-1yl)-4-methoxy-pyridine- 3-yl]-piperazine-1-carboxylic acid (8.56 g, 16.1 mmol) in THF (100 ml) TBAF (1 M in THF, 16.1 ml, 16.1 mmol) is added. The reaction mixture was stirred for 2.5 h at rt. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography to obtain the title product. Yield: 180 mg (87%) (R)-4-r6-(2,5-dimethyl-pyrrole-1-II)-4-methoxl-plridln-3-ÍI1-2methoxlmetll-plperazlna-1-carboxylic acid tert-butyl ester IF-2018-67688982-APN -ANPtfUjgl Page 82 of 161 09-0675-W-3 NaH (60%, 230 mg, 9.58 mmol) is added to fR>-4-[6-(2t5dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-ylJ tert-butyl ester -2-hydroxymethyl-piperazine-1-carboxylic acid (2.0 gt4.80 mmol) and Mel (401 μΐ, 7.20 mmol) in DMA (20 ml). The reaction mixture was stirred for 2 h at rt. Water is added and the reaction mixture is extracted with EtOAc (3 times). The combined organic phases are washed with brine, dried over MgSOj, filtered and concentrated under reduced pressure. The residue is purified by normal phase chromatography. Yield: 1.8 g (87%) ESI-EM: m / z - 431 (M+H)* Rt(HPLC): 1.11 min (Method 1) ff?)-4-(6-amlno-4-niethoxyÍ-pyrldin-3-lí)-2-methoxlmethylpiperazine-1-carboxylic acid tert-butyl ester (RM¿6¿2,5-Dimethyl-pyrrol-1-yl)-4-methoxy-pyridin-3-yl]-2methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester (1.8 g, 4.18 mmol ), hydroxylamine hydrochloride (1.45 g, 20.9 mmol) and trimethylamine (0.58 ml, 4.18 mmol) in ethanol (10 ml) and water (5 ml) are stirred at 80eC for 18 h. The reaction mixture is concentrated under reduced pressure, suspended in DCM, filtered to remove salts, and concentrated again under reduced pressure. The residue is purified by normal phase column chromatography to give the title product. Yield: 440 mg (30%) ESI-EM: m / z = 353 (M+H)* Rt(HPLC): 0.44 min (Method 1) 4-Methoxl-5-(fR)-3-methoxymethyl-pIperazin-1-yl)-pyridin-2-ylamine dihydrochloride IF-2018-67688982- APN- ANPINl^I Page 83 of 161 09-0675W-3 It synthesizes e! title compound from (R)-4-(6-amino-4-methoxy-pyridin-3-I)-2methoxymethyl-tert-butyl ester of piperazine-1-carboxylic acid (440 mg, 1.25 mmol ) according to the procedure described for the synthesis of the intermediate product hydrochloride of [(R)-4-(6amino-4-methoxy-pyridin-3-yl)-piperazin-2-yl]-methanol. Yield: 406 mg (quantitative) 5*Fluoro-4-methoxylpyrldlna-2-carbonitril 2-Chloro-5-fluoro-4-methoxypyridine (1.00 g. 6.19 mmol) is taken in a closed tube. Zinc cyanide (799 mg, 6.81 mmol) and zinc (40.5 mg, 0.31 mmol) are added and purged with argon. PdCl2(dppf)CH2Cl2(253 mg, 0.62 mmol) and NMP are then added and the mixture is heated for 45 min. at 150'C in the microwave. Water and EtOAc are added to the reaction mixture and filtered through Celite®. The organic phase is washed with sodium bicarbonate solution, water, brine and dried over MgSO", filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to provide the title compound. Yield: 689 mg (73%) ESI-MS: m / z = 153 (M+H)* Rt(HPLC): 0.61 min (Method 1) 5-(4-Fluoro-phenoxyM-methoxypyridine-2-carbonltrile 5-Fluoro-4-methoxypyridine-2-carbontrile (6.00 g, 39.4 mmol), 4-fluorophene are heated! (5.31 g, 47.3 mmol) and K2CO3 (12.0 g, 86.8 mmol) in NMP (12 ml) at 100eC for 3 h in a closed tube. Dilute the reaction mixture with water and extract with EtOAc. The phase is washed IF-2018-67688982-APN-ANP#INPI Page 84 of 161 09-0675organic with brine and dried over MgSO<, filtered and concentrated under reduced pressure. Triturate the residue with ether and heptane to give the title compound. Yield: 8.99 g (93%) ESI-EM: m / z = 245 (M+H)* Rt(HPLC): 0.91 min (Method 1) 5-(4-fluoro-fenoxD-4-methoxyplridine-2-carboxylic acid 5-(4-fluoro-phenoxy)-4-methoxypyridine-2-carbonitrile (8.50 g, 34.8 mmol) in 2 N aqueous NaOH solution (90 ml) is stirred at 100°C for 6 h. The reaction mixture is cooled to rt and the pH of the solution is adjusted to pH 4.5 with 4 N HCl. The precipitate is collected and dried in a drying oven to give the title compound. Yield: 8.80 g (96%) ESI-EM: m / z = 264 (M+H)* Rt(HPLC): 1.58 min (Method 4) 4-Methoxy-5-phenoxyplridine-2-carbonitrile Heat 5-fluoro-4-methoxypyridine-2-carbonitrile (8.00 g, 52.6 mmol), phenol (5.94 g, 63.1 mmol), and K2CO3 (16.0 g, 115 mmol) in NMP. (3 ml) at 100°C for 3 h in a closed tube. Dilute the reaction mixture with water and extract with EtOAc. The organic phase is washed with brine and dried over MgSOx, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give the title compound. Yield: 11.5 g (93%) ESI-EM: m / z = 227 (M+H)* Rt(HPLC): 0.92 min (Method 1) 4-Methoxyl-5-phenoxylplrldlna-2-carboxylic acid IF-2018-67688982-APN-ANP#INPI Page 85 of 161 09-0675-0^3 The title compound is synthesized from 4-methoxy-5-phenoxypyridine-2-carbonitrile (11.5 g, 50.8 mmol) according to the procedure described for the synthesis of the acidic intermediate 5-(4-fluoro-phenoxy )-4-methoxypyridine-2-carboxylic acid, Yield: 9t57 g (77%) ESI-MS: m / z = 246 (M+H)*Rt(HPLC): 2.64 min (Method 4) 544-lsopropoxy-phenoxyÍM-methoxypyridine-2-carbonltrile The title compound is synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (500 mg, 3.29 mmol) and 4-Isopropoxyphenol (600 mg, 3.94 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-phenoxypyridine-2-carbonitrile. Yield: 850 mg (91%) ESI-MS: m / z = 285 (M+H)* Rt(HPLC): 1.02 min (Method 1) 544-isopropoxy-fenoxQ-4-methoxypyridine-2-carboxylic acid The title compound is synthesized from 5-(4-isopropoxy-phenoxy)-4-methoxypyridine-2carbonitrile (200 mg, 0.70 mmol) according to the procedure described for the synthesis of the acidic intermediate 5-(4* fluoro-phenoxy¡)-4-methoxypyridine-2-carboxylic acid. Yield: 190 mg (77%) Rt(HPLC): 0.73 min (Method 1) 4-Methoxy-5-(4-methoxy-phenoxy)-polydine-2-carbonitrile The title compound is synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (500 mg, 3.29 mmol) and 4-methoxyphenol (490 mg, 3.94 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-phenoxypyridine-2-carbonitrile. Yield: 740 mg (88%) 4-methoxy-5-(4-methoxy-phenoxy)-pyridine-2-carboxylic acid IF-2018-67688982- APN- ANP#INPI Page 86 of 161 09-0675®3 It synthesizes e! title compound from 4-methoxy-5-(4-methoxy-phenoxy)-pyridine-2carbonitrile (740 mg, 2.89 mmol) according to the procedure described for the synthesis of! 5-(4-fluoro-phenoxy)-4-methoxypyridine-2-carboxylic acid intermediate product. Yield: 610 mg (77%) 4-Methoxy-5-(4-trifluoromethyl-phenoxy)-plridine-2-carbonitri!o The title compound is synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (500 mg, 3.29 mmol) and 4-trifluoromethyl-phenol (639 mg, 3.94 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-phenoxypyridine-2-carbonitrile. Yield: 320 mg (33%) ESI-EM: m / z ~ 294 (M+H)*Rt(HPLC): 1.06 min (Method 1) 4-Methoxl-5-(4-trifluoromethyl-phenoxy)-pyridine-2-carboxylic acid The title compound is synthesized from 4-methoxy-5-(4-trifluoromethyl-phenoxy)-pyridine-2carbonitrile (151 mg, 0.51 mmol) according to the procedure described for the synthesis of the acidic intermediate 5-(4 -fluoro-phenoxy)-4-methoxypyridine-2-carboxylic. Yield: 150 mg (93%) 5-(4-Chloro-phenoxy)-4-methoxyplridine-2-carbonltrile IF-2018-67688982- APN-ANP#INPI Page 87 of 161 09-0675-W-3 The title compound is synthesized from 5-fluoro-4-methoxypyridina-2-carbonítrio (500 mg, 3.29 mmol) and 4-chlorophenol (507 mg, 3.94 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-phenoxypyridine-2-carbonitriIo. Yield: 695 mg (81%) 5-(4-chloro-phenoxy)-4-methoxylipidine-2-carboxylic acid The title compound is synthesized from 5-(4-chloro-phenoxy)-4-methoxypyridine-2carbonitrile (645 mg, 2.47 mmol) according to the procedure described for the synthesis of the acidic intermediate 5-(4-fluoro -phenoxy)-4-methoxypyridine-2-carboxylic. Yield: 622 mg (90%) ESI-EM: m / z = 280 (M+H)* 544-Difluoromethoxy-phenoxy)-4-methoxyplridine-2-carbonitrile The title compound is synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (75.0 mg, 0.49 mmol) and 4-difluoromethoxy-phenol (101 mg, 0.63 mmol) according to the described procedure for the synthesis of the intermediate product 4-methoxy-5-phenoxypyridine-2-carbonitrile. Yield: 98.0 mg (68%) Rt(HPLC): 0.93 min (Method 1) 544-Difluoromethoxy-phenoxy)-4-methoxypyridine-2-carboxylic acid The title compound is synthesized from 5-(4-difluoromethoxy-phenoxy)-4-methoxypyridine-2carbonitrile (98.0 mg, 0.34 mmol) according to the procedure described for the synthesis of the acidic intermediate 5¿4- fluoro-phenoxy)-4-methoxypyridine-2-carboxylic acid. Yield: 94.0 mg (90%) Rt(HPLC): 0.60 min (Method 1) IF-2018-67688982-APN-ANP#INPI Page 88 of 161 09-06754-Clclopropoxy-phenol 2-(4-cyclopropoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (800 mg, 3.08 mmol) and 4-methyl-morpholine-4-oxide ( 1.03 g, 8.83 mmol) in THF (100 ml) at 75°C for 1.5 h and then for 18 h at rt. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel chromatography to provide the title compound. Yield: 389 mg (84%) 5-(4-Clclopropoxy-phenoxy)-4-methoxylpyridine-2-carbonitrillo The title compound is synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (350 mg, 2.30 mmol) and 4-cyclopropoxyphenol (389 mg, 2.59 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-phenoxypyridine-2-carbonitrile. Yield: 342 mg (53%) Rt(HPLC): 1.00 min (Method 1) 544-Cyclopropoxl-phenoxy)-4-methoxylpyridine-2-carboxylic acid The title compound is synthesized from 5-(4-cyclopropoxy-phenoxy)-4-methoxypyridine-2carborytrile (100 mg, 0.35 mmol) according to the procedure described for the synthesis of the acidic intermediate 5-(4-fluorine -phenoxy)-4-methoxypyridine-2-carboxylic. Yield: 622 mg (90%) Rt(HPLC): 0.63 min (Method 1) 4-Methoxl-5-(4-trifluoromethoxy-phenoxy)-pyridine-2-carbonitrile IF-2018-67688982- APN-ANP#INPI Page 89 of 161 09-0675- The title compound is synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (115 mg, 0.76 mmol) and 4-trifluoromethoxy-phenoI (162 mg, 0.91 mmol) according to the procedure described for the synthesis of the intermediate product 4-methoxy-5-phenoxypyridine-2-carbonitrile. Yield: 140 mg (60%) 4-Methoxl-5-(4-trifluoromethoxy-phenoxD-pyridine-2-carboxylic acid The title compound is synthesized from 4-methoxy-5-(4-trifluoromethoxy-phenoxy)-pyridine-2carbonitrile (150 mg, 0.48 mmol) according to the procedure described for the synthesis of the acidic intermediate 5-(4 -fluoro-phenoxy)-4-methoxypyridine-2-carboxylic. Yield: 120 mg (75%) 542-Fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester A 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol), triphenylphosphine (372 mg, 1.42 mmol) and 2-fluorophenol (114 μί, 1.065 mmol) in THF ( 2 mi) diethyl azodicarboxylate (646 μ!, 1.42 mmol) is added at 0°C. The reaction mixture is allowed to warm to RT and stirred for 16 h. The resulting mixture is concentrated in vacuo and the residue is purified by silica gel chromatography to give the title compound. Yield: 66.0 mg (32%) Rt(HPLC): 0.77 min (Method 1) 542-fluoro-benzyloxyM-methoxylplrldín-2-carboxyHco acid IF-2018-67688982-APN-ANP#INPI Page 90 of 161 09-0675-uft 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester (66.0 mg, 0.23 mmol) in THF / water / MeOH (3 ml / 1 ml / 1 mi) was LiOH (38.0 mg, 0.91 mmol) is added, and the reaction mixture is stirred at rt. The reaction mixture is acidified to pH 4.5 with 4N HCI and concentrated in vacuo. The residue is dissolved in DCM and toluene and concentrated again under reduced pressure. The product was used without further purification. Yield: 62.0 mg (99%) Rt(HPLC): 0.48 min (Method 1) 5-Clclobutylmethoxy-4-methoxylridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and cyclobutylmethanol (91.7 mg, 1.07 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5-{2-fluoro-benzyloxy)-4-methoxypyridíne-2-carboxylic acid. Yield: 132 mg (74%) Rt(HPLC): 0.80 min (Method 1) 5-cyc!butylmethoxyl-4-methoxylridine-2-carboxylic acid The title compound is synthesized from 5-cyclobutylmethoxy-4methoxypyridine-2-carboxylic acid methyl ester (132 mg, 0.53 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzylox ¡)-4-methoxypyridine-2-carboxylic acid. Yield: 124 mg (quantitative) Rt(HPLC): 0.53 min (Method 1) 4-methoxyl acid methyl ester 1-5-(1-methyl l-clc lo prop i Imethoxyl-plrid in a-2-carboxyl ico IF-2018-67688982-APN-ANP#INPI Page 91 of 161 09-0675-^3 The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and (l-methyl-cyclopropyl)methanol (103 mg, 1.07 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 115 mg (65%) Rt(HPLC): 0.81 min (Method 1) 4-Methoxl-541-methyl-cyclopropylmethoxy)-pyridine-2-carboxylic acid The title compound is synthesized from 5-cyclobutylmethoxy-4methoxypyridine-2-carboxylic acid methyl ester (115 mg, 0.46 mmol) according to the procedure described for the synthesis of the acid intermediate 5-{2-fluoro-benzyloxy )-4-methoxypyridine-2-carboxylic acid. Yield: 108 mg (quantitative) Rt(HPLC): 0.52 min (Method 1) 5-Clclohexyloxl-4-methoxypyrldine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxyl-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and cyclohexanol (111 μι, 1.07 mmol) according to the procedure described for the synthesis of intermediate product 5(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester. Yield: 171 mg (91%) Rt(HPLC): 0.87 min (Method 1) 5-Cyclohexyloxl-4-methoxypyridine-2-carboxylic acid ----------------------------- --- ---------------- IF-2018-67688982-APN-ANP#INPI Page 92 of 161 09-0675W3 The title compound is synthesized from 5-cyclohexyloxy-4methoxypyridine-2-carboxylic acid methyl ester (131 mg, 0.49 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzyloxy )-4-methoxypyridine-2-carboxylic acid. Yield: 124 mg (quantitative) Rt(HPLC): 0.57 min (Method 1) 5-(4-Fluoro-benzyloxy)-4-methoxylpyridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and (4-fluoro-phenyl)methanol (115 μΙ_, 1.07 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy¡)-4-methoxypyridine-2-carboxylic acid. Yield: 150 mg (62%) Rt(HPLC): 0.82 min (Method 1) 5-(4-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid The title compound is synthesized from 5-(4-fluoro-benzyloxy)4-methoxypyridine-2-carboxylic acid methyl ester (150 mg, 0.44 mmol) according to the procedure described for the synthesis of the intermediate product 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 177 mg (quantitative) Rt(HPLC): 0.82 min (Method 1) S-clopentyloxl-4-methoxypyridine-2-carboxylic acid methyl ester IF-2018-67688982-APN-ANP#I^I Page 93 of 161 09-0675-1^3 The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and cyclopentanol (96.7 μ!_, 1.07 mmol) according to the described procedure for the synthesis of the intermediate product 5(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester. Yield: 170 mg (95%) Rt(HPLC): 0.87 min (Method 1) 5-cyclopentyloxy-4-methoxypyridine-2-carboxylic acid The title compound is synthesized from 5-cyclopentyloxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.52 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzyloxy )-4-methoxypyridine-2-carboxylic. Yield: 122 mg (99%) Rt(HPLC): 0.49 min (Method 1) 5-Lsobutoxl-4-methoxylridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and isobutyl alcohol (71.6 mg, 0.97 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 141 mg (92%) Rt(HPLC): 0.78 min (Method 1) IF-2018-67688982-APN-ANP#INPI Page 94 of 161 09-0675-1 5-lsobutoxl-4-methoxylridine-2-carboxylic acid The title compound is synthesized from 5-isobutoxy-4methoxypyridine-2-carboxylic acid methyl ester (141 mg, 0.59 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzyloxy )-4-methoxypyridine-2-carboxylic acid. Yield: 133 mg (quantitative) Rt(HPLC): 0.51 min (Method 1) 5-Clclopropylmethoxy-4-methoxylpyrldine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and cyclopropylmethanol (84.2 pl_, 1.07 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 146 mg (87%) Rt(HPLC): 0.74 min (Method 1) 5-Cyclopropylmethoxy-4-methoxypyrindine-2-carboxylic acid The title compound is synthesized from 5-cyclopropylmethoxy-4methoxypyridine-2-carboxylic acid methyl ester (325 mg, 1.37 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzylox ¡)-4-methoxypyridine-2-carboxylic acid. Yield: 358 mg (quantitative) ESl-MS: m / z = 224 (M+H)* Rt(HPLC): 0.40 min (Method 5) IF-2018-67688982-APN-ANP#INPI Page 95 of 161 09-0675-1 5-bencloxyÍ-4-methoxypyridine-2-carboxylic acid methyl ester It synthesizes e! title compound from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and benzyl alcohol (100 μΙ_, 0.97 mmol) according to the procedure described for the synthesis of the ester intermediate 5(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxnic acid methyl. Yield: 140 mg (80%) Rt(HPLC): 0.79 min (Method 1) 5-bencloxM-methoxypyridine-2-carboxylic acid The title compound is synthesized from 5-benzyloxyÍ-4methoxypyridine-2-carboxylic acid methyl ester (140 mg, 0.51 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzyloxy )-4-methoxypyridine-2-carboxylic. Yield: 358 mg (99%) Rt(HPLC): 0.54 min (Method 1) 543,3-Difluoro-cyclobutylmethoxl)-4-methoxypyridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and (3,3-difluoro-cyclobutyl)-methanol (150 mg, 0.82 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 111 mg (47%) ESl-MS: m / z = 288 (M+H)* Rt(HPLC): 1.20 min (Method 5) 543,3-drfluoro-cyclobutylmethoxy)-4-methoxypyridine-2-carboxylic acid --------- --------ll· -2U18-6 / 688982-AP\-A\ PEE Page 96 of 161 09-0675-W-3 The title compound is synthesized from methyl ester of! 5-(3,3-difluorocyclobutylmethoxy)-4-methoxypyridine-2-carboxylic acid (110 mg, 0.38 mmol) according to e! procedure described for the synthesis of the 5-(2-fluoro-benzyloxy)-4-methoxypyridine2-carboxylic acid intermediate product. Yield: 73.4 mg (70%) ESI-MS: m / z = 274 (M+H)* Rt(HPLC): 0.56 min (Method 5) 4-Methoxy-5-propoxylipridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 1-propanol (80.0 μΙ_, 1.07 mmol) according to the described procedure for the synthesis of the intermediate product methyl ester of 5-(2fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 114 mg (71%) Rt(HPLC): 0.69 min (Method 1) 4-Methoxl-5-propoxylridine-2-carboxylic acid The title compound is synthesized from 4-methoxy-5propoxypyridine-2-carboxylic acid methyl ester (114 mg, 0.51 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzyloxy )-4-methoxypyridine-2-carboxylic. Yield: 106 mg (99%) Rt(HPLC): 0.41 min (Method 1) IF-2018-67688982-APN-ANP#INPI Page 97 of 161 09-0675W3 5-(2-cyclopropyl-ethoxyM-methoxypyridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 2-cyclopropylethanol (91.7 mg, 1.07 mmol) according to the described procedure. for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 130 mg (73%) Rt(HPLC): 0.82 min (Method 1) 5-f2-clclopropyl-ethoxy)-4-methoxyplridine-2-carboxyHco acid The title compound is synthesized from 5-(2-cyclopropyl-ethoxy)4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.52 mmol) according to the procedure described for the synthesis of the intermediate product 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 122 mg (99%) Rt(HPLC): 0.53 min (Method 1) 4-Methoxy-5-phenethyloxypyridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 2-phenylethanol (128 μ!_, 1.07 mmol) according to the described procedure for the synthesis of the intermediate product 5(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester. Yield: 177 mg (87%) Rt(HPLC): 0.90 min (Method 1) IF-2018-67688982-APN-ANP#P^gI Page 98 of 161 09-0675-W-3 4-methoxy-5-phenethyloxypyridine-2-carboxylic acid The title compound is synthesized from 4-methoxy-5phenethyloxypyridine-2-carboxylic acid methyl ester (177 mg, 0.62 mmol) according to the procedure described for the synthesis of the 5-(2-fluoro-benzyloxy acid intermediate). )-4-methoxypyridine-2-carboxylic acid. Yield: 168 mg (quantitative) Rt(HPLC): 0.63 min (Method 1) 542t2-dimethyl-propox0-4-methoxypyridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 2,2-dÍmethylpropan-1-ol (93.8 mg, 1.07 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5¿2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 160 mg (89%) Rt(HPLC): 0.92 min (Method 1) 5-I2,2-dimethyl-propoxy)-4-methoxylpyridine-2-carboxylic acid The title compound is synthesized from 5-(2,2-dimethyl-propoxy)4-methoxypyridine-2-carboxylic acid methyl ester (160 mg, 0.63 mmol) according to the procedure described for the synthesis of the intermediate product 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 150 mg (99%) Rt(HPLC): 0.61 min (Method 1) IF-2018-67688982-APN-ANP#I^[ Page 99 of 161 09-0675-W-3 5-(1-fluoromethyl-cyclopropylmethoxl)-4-methoxylridine-2carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and (l-fluoromethylcyclopropyl)-methanol (101 mg, 0.97 mmol) according to procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 159 mg (92%) Rt(HPLC): 0.69 min (Method 1) 541-fluoromethyl-cyclopropylmethoxyM-methoxylridine-2-carboxylic acid The title compound is synthesized from 5-(1-fluoromethylcyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester (159 mg, 0.59 mmol) according to the procedure described for the synthesis of the acid intermediate. 5-{2-fluoro-benzyloxy)-4methoxypyridine-2-carboxylic acid. Yield: 150 mg (quantitative) Rt(HPLC): 0.43 min (Method 1) 5-EthoxyÍ-4-methoxyplrídine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and ethanol (62.1 μΐ, 1.07 mmol) according to the IF-2018-67688982-APN-ANP#INPI 100 Page 100 of 161 09-0675-1 procedure described for the synthesis of the intermediate product methyl ester of 5-(2fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 151 mg (100%) Rt(HPLC): 0.92 min (Method 1) 5-Ethoxy-4-methoxypyridine-2-carboxylic acid The title compound is synthesized from 5-ethoxy-4methoxypyridine-2-carboxylic acid methyl ester (151 mg, 0.71 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzyloxy )-4-methoxypyridine-2-carboxylic. Yield: 140 mg (99%) Rt(HPLC): 0.83 min (Method 1) 5-((SM-clc!ooropi!-ethoxylM-methoxypyridlna-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and (R)-l-cyclopropylethanol (83.2 mg, 0.97 mmol). according to the procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 102 mg (63%) 54(S)-1-cyclopropyl-ethoxD-4-methoxyiridine-2-carboxylic acid The title compound is synthesized from 5-((S)-1-cidopropylethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester (102 mg, 0.41 mmol) according to the described procedure. IF-2018-67688982- APN- ANPtf^gl Page 101 of 161 09-0675-H-3 for the synthesis of the intermediate product 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2carboxylic acid. Yield: 96.0 mg (100%) Rt(HPLC): 0.51 min (Method 1) 5-lsopropoxyl-4-methoxyplridlna-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxy-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and propan-2-ol (81.5 μ!_, 0.97 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 154 mg (96%) Rt(HPLC): 0.62 min (Method 1) 5-Isopropoxy-4-methoxypyridine-2-carboxylic acid The title compound is synthesized from 5-isopropoxy-4methoxypyridine-2-carboxylic acid methyl ester (154 mg, 0.68 mmol) according to the procedure described for the synthesis of the acid intermediate 5-(2-fluoro-benzene). loxy)-4-methoxypyridine-2-carboxylic acid. Yield: 144 mg (quantitative) 5-((R)-1-cyclopropyl-ethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester The title compound is synthesized from 5-hydroxyl-4methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and (S)-1-cyclopropylethanol (83.2 mg, 0.97 IF-2018-67688982-APN -ANP#Il·^ Page 102 of 161 09-0675^-3 mmol) according to the procedure described for the synthesis of the intermediate product methyl ester of 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 101 mg (63%) 5-((Rl-1-ci cl or prop i l-ethoxy)-4-methoxy pyridine-2-carboxylic acid The title compound is synthesized from 5-((R)-1-cyclopropylethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester (101 mg, 0.40 mmol) according to the procedure described for the synthesis of the product. 5-(2-fluoro-benzyloxy)-4-methoxypyridine-2carboxylic acid intermediate. Yield: 94.0 mg (99%) Rt(HPLC): 0.51 min (Method 1) 3-(Trifluoromethyl)cyclobutyrimethanol F ^-F F To 3-(trifluoromethyl)cyclobutane-1-carboxylic acid (50 mg, 0.29 mmol) in THF (2 ml) is added CD1 (57 mg, 0.36 mmol) and stirred at RT for 2h. Sodium borohydride (12 mg, 0.31 mmol) in water (0.5 ml) is added and the reaction mixture is stirred at RT for 30 min. The reaction mixture is acidified with 11 M HC and extracted with DCM. The combined organic phases are separated and dried over Na2SO4, filtered and concentrated. Yield: 45 mg (quantitative) Methyl 4-Methoxy-5-phy3-(trifluoromethyl)cyclobutynmethoxnpyridine-2-carboxylate The title compound is synthesized from methyl 5-hydroxy-4-methoxypyridine-2-carboxylate (53 mg, 0.29 mmol) and [3-(trifluoromethyl)cyclobutyl]methanol (45 mg, 0.29 mmol). according to him IF-2018-67688982- APN-ANP#I>^ Page 103 of 161 09-0675-TO-3 procedure described for the synthesis of the intermediate product methyl ester of 5-(2fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid. Yield: 90 mg (97%) 4-methoxy-5fr3-(trifluoromethyl)clclobutinmethoxnpIridlna-2-carboxylic acid An aqueous solution of 4 M NaOH (0.55 ml, 2.2 mmol) is added to methyl 4-methoxy-5-{[3*(tnfluoromethyl)-cycIobutn]methoxy}-pyridine-2-carboxylate (350 mg, 1.10 mmol) in 5 ml of methanol. The reaction mixture is stirred overnight at RT. An aqueous solution of 4 M HCl (0.5 ml) is added and the reaction mixture is stirred for 30 min. The reaction mixture is evaporated under reduced pressure. DMF is added to the residue and the desired compound is purified by HPLC. Yield: 150 mg (45%) Methyl 4-Methoxl-5-(3,3.3-trifluoro-2-methylpropoxy)pyridine-2-carboxylate To methyl 5-hydroxyl-4-methoxypyridine-2-carboxylate (100 mg, 0.55 mmol) in THF is added 3,3,3-trifluoro-2-methylpropan-1-ol (105 mg, 0.82 mmol) and triphenylphosphine (286 mg, 1.10 mmol) and followed by diisopropylazodicarboxylate (221 mg, 1.10 mmol). The reaction mixture was stirred at RT for 3h, the reaction mixture was evaporated under reduced pressure and the residue was purified by HPLC. The product contains fractions that are combined and freeze-dried. Yield: 160 mg (quantitative) 4-Methoxy-5-(3t3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylic acid IF-2018-67688982-APN-ANP#INPI 104 Page 104 of 161 09-0675-W-3 An aqueous solution of 4 M NaOH (0.52 ml, 2.08 mmol) is added to methyl 4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylate. (160 mg, 0.55 mmol) in methanol. The reaction mixture is stirred for 2h at RT. The reaction mixture is neutralized with aqueous HCl4 M solution and evaporated under reduced pressure. The residue is used without further purification. Yield: 150 mg (98%) General procedure: The procedures for preparing compounds of the invention 1-80 are summarized in Table 3A. Analyzes of compounds of the invention 1-80 are summarized in Table 3B. I: HATU (1.2 eq.) is added to carboxylic acid (1 eq.) in DMA and stirred. Amine (1 eq.) and DIPEA (4.0 eq.) are added and stirred for 18 h at rt. Purification by Fl column (ACN / water, acidic or basic conditions) or by silica gel chromatography. II: Carboxylic acid (1 eq.) and CDI (1.5 eq.) are stirred in DMA for 30 min at rt. Amine (1 eq.) and DIPEA (2.0 eq.) are added and stirred for 3 h at rt. Purification by Fl column (ACN / water, acidic or basic conditions) or by silica gel chromatography. Ill: Amine (1.0 eq.), carboxylic acid (0.9 eq.), TBTU (1.0 eq.) and DIPEA (4.0 eq.) are stirred in NMP for 18 h at rt. The filtered reaction mixture is purified by Fl column (ACN / water, acidic or basic conditions) or by silica gel chromatography. Table 3A. General procedures for preparing the compounds of the invention 1-80. Page 105 of 161 09-0675-^-3 2 HC! H nh2 H0X^° ¿L II 82 3 b hci C J HCI i'll ksz-N NHj P ip o' III 15 4 Ha L J HQ ΑζΟγΗ fl η NHj Xa OH III 13 5 £o \_y \=z a a X X V-O~ v zb H,C 1 80 6 B Ha LJ > OH 1 33 IF-2018-67688982-APN -ΑΝΡ#η$Ι Page 106 of 161 09-0675-^-3 9 o § o nh2 ch3 O'CH= OH III 72 12 a NHj o'CH· vom, OH CHS III 63 13 Ó Φ” NHj O'CH> OH III 74 14 A AA ho A. ho NHj o'CH> OH III 72 IF-2018-67688982-APN -ANP#INg^ Page 107 of 161 09-0675-W-3 15 A HCI Φ” nh2 ^CH3 X°O OH II! 11 16 C J hci X hci II NHj a;no ch3 oh II 52 17 N LJ HCI 75 20 Λ JL H0 Ω HCI "Φ NH, v¿ra OH III 24 21 χ Γ ΊHCI JT HCI V 11 n^A0'ch> NH, ^CH, 0 3 Χ°Ό OH 11 6.9 IF-2018-67688982-APN-ANP#INBL Page 108 of 161 09-0675 22 ο σ CHj OH II 41 25 I HO 9 NH, O-\ / P / = / OH Οχ ch3 III 44 26 HCI X^X Ηί'Ό HCI T NH, ch3 / = / OH °x ch3 III 58 27 p-o-. NH, nX-°yx T^p OH H,C 1 58 28 U HCI Ohc, and CH· NH, q'CH3 ojj U OH CH3 III 76 IF-2018-67688982- APN-ANP#HJjg Page 109 of 161 09-0675-W-3 29 Μ Ha LJ HCI a ¡T NHj AH, O 3 OH II 48 30 HCI A HCI Η.Ο'θ'Α] NH, 0 \ / —\ OH CH, III 39 31 JJ na xJ Ha xX^CH, nZT NH, O'CH3 0 3 o / XO OH II 62 32 ho h Ha [] rii \zN NH, F—< z-N 0 )=7 OH °' CH, III 24 33 A Γ J Ha NH, ίΤν°ν^ Ν F CH3 OH II 56 34 0 0 X OH ch3 111 42 IF-2018-67688982-APN -ANP#EgJ Page 110 of 161 09-0675-1 36 A Γ Ί HCI '° \ / —c )= / OH °x ch3 III 37 38 A HCI y nh, 9xCH1 ΟγΧΧ XX OH 1 31 39 hci HCt kA pi NHj HX / Λ / P HjC 0—C V- )= / OH CH, III 51 40 A Γ JHCI J-N na <> NH, 0j- w )= / OH V III 13 41 A r J Ha A na NH, fhGKhTnw° )= / OH R CH, III 29 42 A Xr Il 1 NHj rA ΊΟ CHaOH ​​1 42 IF-2018-67688982-APN-ANP#^gPI Page 111 of 161 09-0675-1 43 HCI M HCI U Η>ε'ο'τίη nh3 —\ Z-N 0 0= / '□—p— OH °x CHj III 49 44 [J HQ JL HQ A NHj OH CHj III 61 45 ó: í / '· ' ΝΗ, ^0^ HO CH, v3rF 1 50 46 HCI R » o w'°p nh2 HjC S / w )=^ OH CHj III 60 47 H HCt L J HCI JL Λ I1 if CHj NHj P-CHj Α-^ Ν-ο H0 Ν χ) II 61 48 HCI HCI I J Η>°'°Ύη NHj '—x ¿"Λ / P o—p— OH °x CHj III 48 49 Ü HCI LJ HQ n'0<O'Xh . N.J ΝΗ, νόΑλ OH III 54 IF-2018-67688982-APN-ANP#ggI Page 112 of 161 09-0675-1 50 ¢3 y» vO°O OH 1 51 51 H HCI HCI Sr nh2 O-CH, Q ?—( —^7"O HO 0 1 36 52 HC' A Ha kJ ^'θΎη NHj w )=^ OH % » III 66 53 HCl M Ha [] Η3ο'°Ύη χ^·Ν NHj y= / oh °x CH, 111 54 54 A H« p η nd Ha ίί^Ν II yw NHj F 3~°\ 0 \ 7\ )= / OH °x CH, 111 39 55 Jy^0'CH· N f'u i V”· Ο Ha T Ha nh2 H,C \=( F 1 64 56 H HCI ^yJ Ha A. y if CH > Ny / NHj F CH, OH II 35 IF-2018 -67688982-APN-ANP#^gI Page 113 of 161 09-0675-1 57 A OHa T HCf Φ NHj R CH, III 67 58 oí» Ar° NHj γΓΟ OH I 56 59 HCI ti ™ o Ύ NH, HX / Ά Z"\ / 9 h3c o—e 2—\ )= / OH ° x ch3 III 42 60 HCI HCI II νύ^? NHj CHj X* O-Q 0 °\ θ λ=χ \ / \ °~X»x \ W Vo ΗΟ H3C I 26 62 A HCI J-n HCI II NH2 V-rw 0 \ / CHj OH I -------tf! 29 '2018-6768* Page 114 of 161 64 HCt HCI LJ η·ο'°Ύί NHj CH3 III 34 66 HCI LJ HCI ^0x N CH, i* NH2 rrCH> yy OH CH, III 51 67 A _ p I HCI γ hci i NHj / P θ \ / 2= / OH °x CH, III 60 68 HCI NHj HCI 1 H o-ch3 wy, "O 1 62 69 OH y 1 A / O ll I HCI NH2 ί^ΊΓθϊ^Ι Μ ο^Αγ0 i 1 ch3 oh 1 17 70 HQ tí Ha [ 1 ^θΎη NHj *CH ' [>--< / T~N o XO- / W 2= / oh °x ch3 III 47 1Ρ-2018-67688982-ΑΡΝ-ΑΝΡ#ΙΝΡΙ 115 Page 115 of 161 09-0675-1 71 HCI Ha II NHj 4_) A / V )= / OH Οχ CH, III 60 74 A Γ j ho ho ii NHj h3c 79 h3c o—c p—\ )= / OH °' ch3 III 35 75 A L J HCI hci iX^n II NH2 )= / OH °x ch3 III 57 76 A Γ J Ha JL hci x 11 NHj H3C )= / OH °x ch3 111 62 77 Ha χ. HO kJ ^Ίιί ΙΧ>Ν NHj *CH3 x° \ / —C )= / OH οχ ch3 III 38 IF-2018-67688982-APN-ANP#INPI Page 116 of 161 09-0675-US-3 Table 3B. Analytical data for compounds of the invention 1-80. IF-2018-67688982-APN-ANP#INH7 Page 117 of 161 09-0675-1^3 com no. P- ESI-EM m / z( M+H* HPLC Rt (min.) HPLC Method 1 454 0.47 1 2 437 1.07 5 3 405 0.83 1 4 453 0.86 1 5 436 0.44 1 6 464 0.80 3 7 468 0.44 1 8 462 1.02 5 9 480 1.08 5 10 419 1.02 5 11 454 0.79 1 12 436 0.78 1 13 424 0.80 1 14 423 0.87 1 15 406 0.79 1 16 406 1.52 6 17 424 1.38 2 18 450 0.43 1 19 467 0.90 3 20 454 0.77 1 21 436 0. 78 1 22 435 0.83 1 23 435 0.83 1 24 503 1.93 6 25 398 0.75 3 26 427 0.80 3 27 480 0.50 1 28 465 1.02 1 29 438 1.58 2 30 441 0.86 3 31 420 1.48 2 32 467 0.91 3 33 474 1.91 6 Com# P- ESI-EM m / z, M+H* HPLC Rt (mln.) HPLC Method 34 440 0.83 1 35 427 0.80 3 36 386 0.73 3 37 413 0. 71 3 38 480 0.94 5 39 415 0.79 3 40 462 0.80 1 41 438 0.78 3 42 484 0.68 3 43 449 0.81 3 44 436 0.76 1 45 463 0.73 5 46 401 0.73 3 47 436 1.36 2 48 427 0.80 3 49 454 0.84 1 50 450 0.46 1 51 462 0.89 5 52 463 0.85 3 53 427 0.81 3 54 472 0.77 1 55 498 0.51 1 56 504 1.84 6 57 438 0.77 3 58 450 0.49 1 59 429 0.87 3 60 466 0.77 1 61 414 0.70 3 62 412 0. 76 1 63 484 0.70 3 64 445 0.74 3 65 387 0.65 3 66 466 0.82 1 IF-2018-67688982-APN-ANP#INPI 118 Page 118 of 161 09-0675-W-3 comp no. ESI-EM m / z, M+H* HPLC Rt (min.) HPLC method 67 398 0.74 3 68 477 0.73 5 69 466 0.67 3 70 427 0.78 3 71 466 0.68 1 72 401 0.69 3 73 434 0.79 3 Com# Ρ· ESI-EM m / z, M+H* HPLC Rt (min.) HPLC Method 74,400 0.81 3 75,398 0.75 3 76,372 0.66 3 77,427 0.77 3 78 398 1.24 2 79 398 0.71 3 80 490 2.60 Synthesis of nitro intermediates r(R)-4-(6-nitro-plridin-3-ll)-plperazin-2-¡n-methanol hydrochloride (R)-2-{ten>butyl-dimethyl-silaniIoxymethyl)- 4-(6-nitro-pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (1.73 g, 3.82 mmol ) in DCM (10 ml) and 4 M HCl (9.55 ml, 38.2 mmol) is stirred at RT for 2 h. The reaction mixture is concentrated under reduced pressure. Yield: 950 mg (91%) r(R)-2-HydroxÍmethyl-4-(6-nltro-pyridÍn-3-ÍI)-plperazin-1-yn-(4-methoxyl-5-phenoxyÍ-pyridin-2- ll)methanone [(R)-4-(6-nitro-pyridin-3-yl)-pÍperazin-2-yl]-methanol hydrochloride (60.0 mg, 0.21 mmol) and 4-methoxy-5-phenoxypyridine acid 2-carboxylic acid (42.8 mg, 0.18 mmol) in NMP (500 gL) with TBTU IF-2018-67688982-APN-ANP#INPI 119 Page 119 of 161 09-0675W3 (70.1 mg, 0.22 mmol) and DI PEA (151 μ!_, 0.87 mmol) are stirred for 18 h at rt. The reaction mixture is purified by Fl column chromatography (ACN / water / NH4HCO3). The residue is purified again by normal phase column chromatography (MeOH / DCM) to give the title compound. Yield: 95 mg (93%) f(R)-2-Hydroxymethyl-4-(6-nitro-plridin-3-ii)-piperazin-1-in-r4-methoxl-5-(4-methoxy-phenoxy) - The title compound is synthesized from [(R)-4-(6-nitro-pyridin-3-yl)piperazin-2-ylj-methanol hydrochloride (60.0 mg, 0.22 mmol) and 4-methoxy-5-(4-methoxy-phenoxy)-pyridine-2carboxylic acid (48.1 mg, 0.18 mmol) according to the procedure described for the synthesis of the intermediate product [(R)-2-hydroxymethyl-4- (6-nitro-pyridin-3-yl)-piperazin-1 -yl]-(4-methoxy-5phenoxy-pyridin-2-yl)-methanone. Yield: 102 mg (quantitative) ESI-EM: m / z = 496 (M+H)* Rt(HPLC): 0.78 min (Method 1) Procedure: IV: A nitro intermediate (1 eq.) and Pd / C (10%) in MeOH are stirred for 20 h at RT under a hydrogen atmosphere. The reaction mixture is concentrated in vacuo and purged with argon. The residue is filtered through Celite® and washed with MeOH. The filtrate is concentrated under reduced pressure and the crude product is purified by Fl column chromatography (ACN / water, acidic or basic condition). Table 4. Procedures for preparing the compounds of the invention 81 and 82. comp no. Nitro intermediate product Proc. gen. Yield % ESI-EM m / z M+H* HPLC Rt (min.) HPLC Method IF-2018-67688982-APN-ANP#INPI 120 Page 120 of 161 09-0675- 81 II i or* IV 47 436 0.75 1 82 II i ¿' IV 36 466 0.74 1 Compounds of the invention 83-89 are generally prepared by reaction of a carboxylic acid intermediate with an amine intermediate under conditions similar to those described for general procedure (I) in Table 3A. Analyzes of inventive compounds 83-89 are summarized in Table 5B. Synthesis of intermediate products 4-Ethoxy-5-phenoxyplco1ynonitrile Add solution with stirring of 5-fluoro-4-isopropoxypicolÍnonitrile (500 mg, 3.01 mmol) in DMF (10 ml) at RT under a N2 atmosphere, add phenol (339.85 mg, 3.61 mmol) and K2CO3 (1.25 g, 9.03 mmol), the resulting mixture is heated to 100 °C for 3 h. The reaction mixture is then diluted with ethyl acetate (50 ml), washed with water and brine, dried over anhydrous NaaSO4, filtered and concentrated. The residue is purified by column chromatography on silica gel. Yield: 530 mg (73%) m / z = 241 (M+H)*. 4-ethoxy-5-phenoxypicholinic acid IF-2018-67688982-APN-ANP#INPI Page 121 of 161 09-0675-0^3 A mixture of 4-ethoxy-5-phenoxypicolinonitrile (530 mg, 2.21 mmol) in 2 N sodium hydroxide solution (10 ml) is stirred at 100°C overnight. The reaction mixture is then acidified with 11 N HC to adjust the pH = 4 and extracted with DCM (2 x 20 ml). The combined organic phases are separated and dried over Na2SO4, filtered and concentrated to give the desired product which can be used without further purification. Yield: 420 mg (73%) m / z = 260 (M+H)* e-Amino^-clclopronoxy-r.Z'.S'.G'-tetrahydro-n^-bipyridinal-l'-tere carboxylate -butyl To a stirred mixture of 5-bromo-4-cyclopropoxypyridin-2-amine (2.1 g, 9.17 mmol), 4-(4,4,5,5-tetramethyl-[1, 3,2ldioxaborolane-2-yl)-3,6-dihydro-2H-pyridine1-carboxylic acid (4.25 g, 13.75 mmol) and Cs2CO3 (9.0 g, 27.50 mmol) in dioxane (60 mi) and water (12 ml) at rt under a nitrogen atmosphere, Pd(dppf)CI2 (200 mg, 0.27 mmol) is added. The resulting mixture is stirred at 90 °C for 4 h. The reaction mixture was then poured into ice water and extracted with DCM (3 x 50 ml). The combined organic phases are washed with brine, dried over anhydrous Na2SOx, filtered and concentrated. The residue is purified by silica gel column chromatography to give the desired product. Yield: 3 g (98%) m / z = 332 (M+H)*. IF-2018-67688982-APN-ANP#INPI 122 Page 122 of 161 09-0675®3 Tere-butyl 4-(6'Amino-4-cyclopropoxypyridin-3-ll)plperidine-1-carboxylate To a solution of e-amino^-cyclopropoxy-r.^.S^e'-tetrahydro-IS.^-bipyridinej-r-carboxylate tere-butyl (3 g, 9.05 mmol) in EtOH (40 ml) Pd(OH)2 / C (2 g) are added. The resulting reaction mixture was stirred at 25°C under a hydrogen atmosphere for 16 h. The catalyst is filtered through Celite®, and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product. Yield: 1.8 g (60%) m / z = 334 (M+H)*. 4-Clclopropoxl-5-(plperÍdin-4-iDpyridln-2-amine dihydrochloride Tere-butyl 4-(6-amino-4-cyclopropoxypyridIn-3-yl)piperidine-1-carboxylate (1.6 g, 4.8 mmol) is dissolved in a solution of HCl(g) in EtOH ( 10 mi). The reaction mixture was stirred at RT for 2 h. After completion of the reaction, the solvent is removed under reduced pressure. The crude product is then triturated with EfeO to give the desired product which can be used without further purification. Yield: 1g (90%) m / z = 234 (M+H)*. IF-2018-67688982-APN-ANP#INPI 123 Page 123 of 161 09-0675-W3 (4-Propoxyplridin-2-ll)tere-butyl carbamate To a stirred solution of 2-aminopyridin-4-ol (1.25 g, 11.4 mmol) in N,Ndimethylacetamide (15 ml), cesium carbonate (7.42 g, 22.8 mmol) is added. 1bromopropane (1.24 mi, 13.6 mmol) and cesium iodide (2.95 g, 11.4 mmol). The resulting mixture is stirred at 100°C for 1 day. Di-tere-butyl dicarbonate (2.74 g, 12.6 mmol) is added to the reaction mixture and stirred at 100°C for 16 h. Dilute the reaction mixture with water (20 ml) and extract with EtOAc (50 ml). The phases are separated and the organic phase is concentrated. The crude mixture is purified by silica gel column chromatography to provide the desired product. Yield: 787 mg (27%) m / z = 253 (M+H)*. Tere-butyl (5-Bromo-4-propoxlpyridin-2-i1)carbamate To a stirred solution of tert-butyl (4-propoxypyridin-2-yl)carbamate (0.79 g, 3.11 mmol) in acetic acid (5 ml) is added bromine (0.40 g, 2, 49 mmol, in 1 ml of acetic acid) drop by drop at 0°C. After 0.5 h, an additional amount of acetic acid (8 ml) is added and the reaction mixture is allowed to warm to room temperature. After 1 h, the mixture is concentrated and purified by silica gel column chromatography to the desired product. Yield: 255 mg (31%) m / z = 331 (M+H)*. Tere-butyl 6-fritert-Butoxy)carboninamine1-T-carboxylate IF-2018-67688982- APN- A\PI\TI Page 124 of 161 09-0675IW3 To a solution of tert-butyl (5-bromo-4-propoxypyridin-2-yl)carbamate (254 mg, 0.77 mmol) in dioxane (4 ml), 4-(4) tert-butyl ester is added. ,4,5,5-tetramethyl[1,3,2]dioxaboroIan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (596 mg, 1.93 mmol), sodium carbonate (solution 2 M aqueous, 0.77 ml) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (56 mg, 0.077 mmol). The reaction mixture is stirred at 100eC for 24h. Dilute the reaction mixture with EtOAc (10 mL) and filter through a pad of SuperCell filter agent. The filtrate is concentrated and purified by silica gel column chromatography to provide the desired product. Yield:333 mg (quantitative) m / z = 434 (M+H)*. Tere·butyl 4-(6-((te / ,c-Butoxlcarbonyl)amino)-4-propoxypyridine-3-inpiperidine-1-carboxylate It is added to 6¿[(tero-butoxy)carbonÍI]am¡no}-4-propoxy-r,2',3',6'-tetrahydro-[3,4'-bipyridine]-r-carboxylate tertero-butyl (333 mg, 0.77 mmol) in EtOH (18 ml) and EtOAc (3 ml) palladium hydroxide on carbon (20% humidity, 27 mg). The reaction mixture is stirred under a hydrogen atmosphere (43 psi) for 3 days and filtered through SuperCell filter agent. The filtrate is concentrated under reduced pressure to provide the desired product. Yield: 330 mg (98%) m / z = 436 (M+H)*. IF-2018-67688982-APN-ANP# iA)[ Page 125 of 161 09-0675-OT-3 5-(plperldin-4-iD-4-propoxyÍplridin-2-amlna dihydrochloride Add to tere-butyl 4-(6-((tert-butoxycarbon¡l)amino)-4-propoxypyridin-3-yl)piperidine-1-carboxylate (330 mg, 0.76 mmol) in dichloromethane (2 ml) a solution of HCl in dioxane (2.00 ml, 4 M, 8.0 mmol). The reaction mixture was stirred for 16 h and concentrated. The residue is ground with DCM and dried under vacuum to provide the desired product. Yield: 233 mg quantitative. 4-Ethoxy-5-(piperidln-4-ll)pyridin-2-amlna dihydrochloride 4-Ethoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride can be synthesized in a manner analogous to the protocol for the synthesis of 5-(piperidin-4-yl)-4-propoxypyridin-2 dihydrochloride. -amine. Alkylation of 2-aminopyridin-4-ol with ethyl bromide and subsequent protection of Boc leads to the formation of tere-butyl N-(4-ethoxypyridin-2-yl)carbamate. The bromination of N-(4-ethoxypyridin-2-yl)tere-butylcarbamate leads to the synthesis of (5-bromo-4ethoxypyridin-2-yl)tere-butylcarbamate. The subsequent reaction with 4-(4,4,5,5-tetramethiI-[1,3,2]dioxaboroIan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester leads to the formation of tere 6-{[(tere-butoxy)carbonyl]amino}-4-ethoxy-T,2',3',6'-tetrahydro-[3,4'-bipyridine]-r-carboxylate -butyl. In the next step, tere-butyl 4-(6-((tera-butoxycarbonyl)amino)-4-ethoxypyridin-3yl)piperidine-1-carboxylate is obtained by hydrogenac^n2^e^^^^p{uqy.p ixl)I126 Page 126 of 161 09-0675-W-3 Boc protector leads to the synthesis of 4-ethoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride. 3-(6-Amlnoplrldazin-3-ll)-8-azabicyclor3.2.1loct-2-ene-8-carboxylate efe tere-butyl A3-(4,4,5,5-tetramethiM,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]-oct-2-ene-8-carboxylate tere-butyl (1 .93 g, 5.75 mmol) and 6-bromopyridazin-3-amine (1.00 g, 5.75 mmol) in 1,4dioxane (25 ml) aq. solution is added. of Na2CO32 M (11.5 mi, 23.0 mmol) and 2nd generation Xphos catalyst (136 mg, 0.17 mmol). The reaction mixture is degassed with argon and stirred at 100°C for 2 h. All volatiles evaporate under reduced pressure. The crude material is purified by normal phase chromatography to obtain the title compound. Yield: 0.80 g (46%) ESI-MS: m / z = 303 (M+H)* ferc-Butyl-3-(6-amlnoplridazln-3-ll)-8-azablclchlor3.2.11octane-8- carboxylate Tere-butyl A3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (0.80 g, 2.65 mmol) in MeOH (30 ml) Pd / C (250 mg) is added under nitrogen. The reaction mixture is degassed and hydrogenated under a hydrogen atmosphere at 3 bar at RT overnight. The reaction mixture is filtered and concentrated under reduced pressure. Yield: 800 mg (quantitative) ESI-EM: m / z = 305 (M+H)* 6-{8-azablclchlor3.2.11octan-3-ll)plridazln-3-amlna dihydrochloride IF-2018-67688982-APN-ANP#INPI 127 Page 127 of 161 09-0675W3 To tert-butyl 3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg, 2.63 mmol) in an appropriate volume of DCM is added HCl 4 M in 1,4 dioxane and stirred at RT until the reaction is complete. All volatiles evaporate under reduced pressure. Yield: 700 mg (96%) ESI-EM: m / z = 205 (M+H)* 2-Chloro-5-fluoro-4-methoxyplridlna OH Iodomethane (1.15 g, 8.13 mmol) at room temperature. The resulting reaction mixture was stirred at RT for 2 h. Dilute the reaction mixture with water (20 ml) and extract with EtOAc (2 x 30 ml). The combined organic phases are washed with water and brine, dried over anhydrous Na2SÜ4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product. Yield: 1 g (91%) m / z =162 (M+H)* 5-Fluoro-4-methoxylplcholinonitrile A 2-chloro-5-fluoro-4-methoxypyridine (1.0 g, 6.2 mmol), zinc cyanide (800 mg, 6.8 mmol) and dppf (34 mg, 0.62 mmol) in DMF ( 10 ml) stirred at RT under a nitrogen atmosphere, Pd2(dba)s (56 mg, 0.62 mmol) is added. The reaction mixture is stirred at 150'C under a nitrogen atmosphere for 3 h. The reaction mixture is then diluted with water (30 ml) and extracted with EtOAc (2 x 30 ml). The combined organic phases are washed with water and IF-2018-67688982-APN-ANP#INPI 128 Page 128 of 161 09-0675-^-3 brine, dried over anhydrous NasSQi, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product. Yield: 700 mg (74%) m / z = 153 (M+H)*. 4-Methoxy-5-(4-(trifluoromethyl)phenoxy)p¡cholinonitrile To 5-fluoro-4-methoxypÍcolinonItrile (700 mg, 4.6 mmol) in DMF (10 ml) are added 4(trifluoromethyl)phenol (746 mg, 4.6 mmol) and K2CO3 (636 mg, 4.6 mmol ). The reaction mixture is stirred at 100 °C for 16 h. Dilute the reaction mixture with water (20 ml) and extract with EtOAc (2 x 20 ml). The combined organic phases are combined, washed with water and brine, dried over anhydrous NaZSO1, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product. Yield: 1 g (80%) m / z = 295 (M+H)*. 4-Methoxy-5-(4-(trifluoromethyl)phenoxy)pico1inlic acid 4-methoxy-5-(4(trifluoromethyl)phenoxy)picolinonitrile (700 mg, 2.4 mmol) is added to a solution of NaOH (1.6 g, 40 mmol) in water (20 ml). The reaction mixture is stirred at 100°C overnight. The reaction mixture is acidified with 6 M HCl to adjust pH = 2, extracted with EtOAc (2 x 30 ml). The combined organic phases are washed with water and brine, dried over anhydrous NazSO^, filtered and concentrated under reduced pressure to give the crude product which can be used directly without further purification; Yield: 700 mg (94%) m / z = 314 (M+H)*. 2-Chloro-5-fluoropridin-4-ol IF-2018-67688982-APN-ANP#INPI 129 Page 129 of 161 09-0675W3 OH Under a nitrogen atmosphere at -78°C, a solution with stirring of 2-chloro-5-fluoropyridine (5.0 g, 38 mmol) in tetrahydrofuran (50 ml), lithium diisopropylamide (24 .7 ml, 49.4 mmol, 2 M in tetrahydrofuran) over 30 min. The reaction mixture was stirred at -78°C for 2 h. A solution of trimethyl borate (7.9 g, 76.03 mmol) in tetrahydrofuran (10 ml) is then added dropwise over 20 min. After addition, the reaction mixture is stirred at RT for another 2 h. The reaction mixture is cooled to 0 °C and acetic acid (6.5 ml) is added. The reaction mixture is stirred at 0°C for 30 min. Hydrogen peroxide (11.5 ml, 30% solution) is added drop by drop at 0°C. The reaction mixture was stirred at RT overnight. The reaction mixture is cooled with saturated aqueous NaS2O<. 5 N HCl is added to the reaction mixture. After extraction with EtOAc (3 x 50 ml), the combined organic phases are washed with water and brine, dried over anhydrous Na2SO<, filtered and concentrated under pressure reduced. The residue is purified by silica gel chromatography to give the desired product. Yield: 3.8 g (68%). m / z = 149 (M+H)*. 2-Chloro-4-ethoxy¡-5-fluoropyridine OH To 2-cyoro-5-fluoropyridin-4-ol (2, 3.0 g, 20.33 mmol) and silver carbonate (I) (8.4 g, 30.50 mmol) in DMF (50 ml) were Adds iodoethane (9.51 g, 61.00 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture is then diluted with ethyl acetate (100 m!) and washed with water and brine, dried over anhydrous Na2SO<, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product. Yield: 3.0 g (84%) m / z = 177 (M+H)*. 4-Ethoxl-5-fluoropicolinonitrile IF-2018-67688982- APN-ANP#INPI 130 Page 130 of 161 09-0675#3 A2-chloro-4-ethoxy-5-fluoropyridine (300 mg, 1.71 mmol) in DMF (10 ml) are added dicyanozinc (141 mg, 1.2 mmol), zinc (22.3 mg, 0.34 mmol) and Pd(dppf)Cl2 (50 mg) under a nitrogen atmosphere. The reaction mixture is stirred at 150 °C for 3 h. Dilute the reaction mixture with ethyl acetate (50 ml), wash with water and brine, dry over anhydrous NazSOx, filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product. Yield: 220 mg (78%) LC-MS: m / z 167 [M+Hj*. 4-Ethoxy-5-(4-fluorophenoxy) picol i non-nitrile A4-fluorophenoI (202 mg, 1.81 mmol) and K2CO3 (249 mg, 1.81 mmol) in DMF (5 ml) are added to 4-ethoxy-5-fluoropicolinonitrile (200 mg, 1.2 mmol) in a portion. The reaction mixture is stirred at 100 °C for 3 h. After cooling, the reaction mixture is diluted with ethyl acetate (20 ml), washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the desired product. Yield: 220 mg (71%) m / z = 259 (M+H)*. 4-ethoxy-5-(4-fluorophenoxy)polycholinic acid F or ch3 A mixture of 4-ethoxy-5-(4-fluorophenoxy)picolinonitrile (500 mg, 1.94 mmol) in a 2 N aqueous sodium hydroxide solution (10 mL) is stirred at 100 °C overnight. After cooling, the reaction mixture is acidified with 1 N aqueous HCl to adjust to pH = 4 and extracted with DCM (2 x 20 ml). The combined organic phases are washed with water and brine, dried over anhydrous NazSO4, filtered and concentrated under reduced pressure to give the desired crude product. IF-2018-67688982- APN-ANP#INPI Page 131 of 161 09-0675-W-3 Yield: 490 mg (91%) m / z = 278 (M+H)*. Table 5A. Procedures for preparing the compounds of the invention 83-89. com no. Ρ· Amine intermediate Carboxylic acid intermediate Proc, gen. Efficiency % 83 η° Ti hq H3(X 0 CCCA 1 32 84 A HCI Ha IL X N NHj )-O V- / z = / 2=0 O Ha T Jl HCI N^NHj fl 1 20 87 hn^A o^ch3 HCI Ν ΝΗ, 'X¿x / " 1 18 88 HN^A Ha T Ϊ Ha O-NHj ΧΗ' 0 Fn;xA" 1 21 89 ΗΝ'Ύ'ί hq Ti HQ 0 χ..;χΧ 1 15 IF-2018-67688982-APN-ANP#INPI 132 Page 132 of 161 09-0675-W-3 Table 5B. Analytical data for the compounds of the invention 83-89. comp no. ESI-EM m / z, M+H* HPLC Rt (min) 83 420 0.79 84 461 0.84 85 450 0.83 86 463 0.84 87 518 0.97 88 438 0.80 89 465 0 .82 General procedures: The procedures for preparing inventive compounds 90 and 91 are summarized in Table 6A. The analyzes of inventive compounds 90 and 91 are summarized in Table 6B. V: To carboxylic acid (1.0 eq.) (intermediate product 2 in Table 6A below) in DMF, DIPEA (3.0 eq.) and HATU (1.0 eq.) are added and the mixture is stirred. reaction for 30 min at rt. Amine (1.0 eq.) (intermediate 1 in Table 6A below) is added and the reaction mixture is stirred overnight. The filtered reaction mixture is purified by Fl column chromatography (ACN / water + TFA or basic conditions). Table 6A. General procedures for preparing the compounds of the invention 90 and 91. com no. Ρ· amine (Intermediol product) carboxylic acid (Intermediate 2 product) Proc. gen. Performance % IF-2018-67688982-APN -ANP#P^I Page 133 of 161 09-0675-O-3 90 «HCI HCI NAxCH> « NH, p f <¡«, <¡>H O- A. Ami ΊΑϊι V 55 91 H HCI LJ HCI N |< CH, NH, 'Vlox / °” V 31 Table 6B. Analytical data for compounds of the invention 90 and 91. n.® of comp p. ESI-EM m / z, M+H* HPLC Rt (min.) 90,488 0.86 (Method 7) 91,474 0.87 (Method 7) Compounds 92 and 93: 4-Methoxy-5-f1-(4-methoxyl-5-{r3-(trifluoromethyl)-cyclobutinmethoxy>pyridine-2-carbonyl)piperidin-4-ir|pyridin-2-amlna TFA salt 4-Methoxy-5-(3-trifluoromethyl-cyclobutylmethoxy)-pyridine-2-carboxylic acid (40 mg, 0.13 mmol), DIPEA (113 pL, 0.66 mmol), HATU (54 mg, 0.144 mmol) are stirred. ) and 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (37 mg, 0.13 mmol) Page 134 of 161 to ta. The reaction mixture is purified by Fl column chromatography (ACN / water + TFA) to obtain monostereoisomers. Yield: compound 92 (trans isomer): 5 mg (6%) HPLC Rt: 0.50 min (method 12) and compound 93 (cis isomer): 8 mg (10%) HPLC Rt: 0.48 min (method 12) ), ESI-EM: m / z = 495 (M+H)* Compound 94: 4'methoxyÍ-541'r4-methoxy-5-(3t3,34rifluoro-2-methylpropoxy)oiridine-2-carboninpiperidin-4'i l)plridin-2-amlna N NH2 4-Methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylic acid (110 mg, 0.39 mmol), DIPEA (271 pL, 1.58 mmol), HATU ( 150 mg, 0.39 mmol) and 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (121 mg, 0.43 mmol) in DMF (2 ml), 2 h at RT. The reaction mixture is purified by Fl column chromatography. Yield: 110 mg (60%) ESI-EM: m / z = 469 (M+H)* HPLCRt: 0.71 min (method 13) Enantlomers of 4-Methoxl-5-(1-(4-methoxy-5-r3.3,3-trifluoro-2-methylpropoxnplridin-2-carboninplperidin-4-l D-pyrldin-2-amlna (94): 4-Methoxl-5-(1-{4-methoxl-5-r(2S)-3,3.3-trifluoro-2-methylpropoxnpyridine-2-carbonir)plperidi n-4-ll)-plrldln-2-amlna and 4’Μ6ΐοχΙ’5-(1- / 4’ηΊ61οχΙ·5-ίϊ2 / ?)-3,3,34ΓίίΙυοΓθ-2-ΓηθϋΙρΓθροχΠρΐΓΐόίη3’2-€8ΓΡο ηίΠρΙρ6Γίό in-4-yl)pyridin-2-amine IF-2018-67688982-APN-ANP#INPI 135 Page 135 of 161 09-0675- It also separates 4-methoxy-5-{1-[4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carbonyl]piperidin-4-yl}pyridine n-2-amine (292 mg , 0.62 mmol) by chiral supercritical fluid chromatography (CFS, supercritical carbon dioxide / NHa 20 mM in EtOH, Chiral ART,® Amilose-SC 20x250 mm. μΜ) to obtain both enantiomers 94a (first eluted fraction) and 94b (second eluted fraction). Stereochemistry is assigned randomly. Yield: 70 mg (48%, compound 94a; Rt: 5.69 min) and 74 mg (50%, compound 94b; Rt: 6.23 min) 5-Hydroxy-4-methoxypyridine-2-carboxylic acid Potassium hydroxide (6.28 g, 111.98 mmol) in 50 ml of water is added to methyl 5-bromo-4-methoxypyridine-2-carboxylate (5.00 g, 20.32 mmol) in 1, 4-dioxane (50 ml). d'- / era-butyl-(2,,4',6'-triisopropyl-3,4,5,6-tetramethi!-biphenyl-2-II)-phosphane (1.57 g, 3, 27 mmol) and tris(dibenzylideneacetone)dipalladium(0) (949 mg, 1.04 mmol) under argon. The reaction mixture is stirred at 100°C for 2h. The reaction mixture is filtered and concentrated under reduced pressure. The residue is acidified with 4 M HCl and the solid is filtered. The liquid phase is concentrated and the precipitate is collected, washed and dried. Yield: 2.61g (76%) ESI-EM: m / z = 170 (M+H)* 6-f4-(6-Amino-4-methoxyplridin-3-IDplperldin-1-carbonin-4-methoxyplridin-3-ol IF-2018-67688982- APN-ANP#IJ^ Page 136 of 161 09-0675W-3 DIPEA (407 μί, 2.36 mmol) and 4-methoxy-5-dihydrochloride are added to 5-hydroxypyridine-2-carboxylic acid (100 mg, 0.59 mmol) in DMF (5 ml). (piperidin-4-yl)pyridin-2-amine (331 mg, 1.18 mmol). HATU (225 mg, 0.59 mmol) is then added. The reaction mixture was stirred overnight at RT and purified by reverse phase column chromatography to provide the title compound. Yield: 140 mg (66%) ESl-MS: m / z = 359 (M+H)* Rt(HPLC): 0.61 min (method 10) General procedures: A procedure for preparing compound 95 of the invention is summarized in Table 7A. The analysis of compound 95 of the invention is summarized in Table 7B. VI: A 6-[4-(6-amino-4-methoxypyridin-3-yl)piperidine-1-carbonyl]-4-methoxypyridin-3-ol (1.0 eq.) (intermediate 2 in the following table 7A) in dioxane, alcohol (2.4 eq.) (intermediate product 1 in the following table 7A), TPP (2.7 eq.) and DTAD (2.5 eq.) are added. The reaction mixture is stirred at 60°C for 1 h. If the reaction shows complete conversion, the reaction mixture is purified by Fl column chromatography (ACN / water + TFA). If the reaction does not show completion, additional TPP (2.7 eq.) and DTAD (2.5 eq.) are added until conversion occurs. The reaction mixture is stirred after each addition at 60eC for 1h. The reaction mixture is purified by Fl column chromatography (ACN / water + TFA). Table 7A. General procedures for preparing the compound of the invention 95. comp no. alcohol (intermediate product 1) nucleus (intermediate product 2) Proc. gen. Yield % 95 ΓΊ^ΟΗ / ^F F W. CHj VI quant. IF-2018-67688982-APN-ANP#INPI 137 Page 137 of 161 09-0675-W-3 Table 7B. Analytical data for the compound of the invention 95. Com# P- ESI-EM m / z, M+H* HPLC Rt (min.) 95,463 0.65 (Method 13) Alternative preparation of compound 1 544-f5-(4-FluorophenoxlM-methoxypyridln-2-carboninplperazln-1-ÍIM-methoxypyridín-2amine 5-Bromo-2-(2,5-dimethiM H-pyrrole-1 -ylM-methoxypyridine 5-Bromo-4-methoxy-pyridin-2-ylamine (9.50 g, 46.79 mmoi), hexane-2,5-dione (7.08 ml, 60.83 mmol) and p-toluenesulfonic acid are stirred. (0.81 g, 4.68 mmol) in toluene (80 ml) overnight at 120°C using a Dean-Stark apparatus. The reaction mixture is concentrated under reduced pressure, incorporated into DCM and purified by silica gel chromatography (DCM). Yield: 7.60 g (58%) ESI-EM: m / z = 281 [M+H]* Rt(HPLC): 1.13 min (method 7) 146-(2,5-Dimethyl-1H-plrrol-1-ll)-4-methoxyÍplrÍdin-3-inplperazlna (trifluoroacetic acid) TFA TFA IF-2018-67688982-APN-ANP#INPI 138 Page 138 of 161 09-0675-W-3 The reaction is carried out under an argon atmosphere. Stir 5-bromo-2-(2,5-dimethyl-1Hpyrrol-1-yl)-4-methoxypyridine (1.00 g, 3.56 mmol), tere-butyl piperazine-1-carboxylate (0 .73 g, 3.92 mmol), CPhos-3G-methanesulfonate (0.30 g, 0.36 mmol) and cesium carbonate (3.48 g, 10.67 mmol) in 1,4-dioxane (15 ml ) overnight at 80eC. The reaction mixture is filtered and concentrated under reduced pressure. The residue is incorporated into DCM (20 ml) and TFA (1.37 ml; 17.76 mmol) is added. The reaction mixture is stirred for 3 days at RT and after addition of the same amount of TFA the reaction mixture is stirred overnight at 40°C. The reaction mixture was evaporated to dryness and used without further purification. Yield: 1.80 g (98%) ESI-EM: m / z = 287 [M+H]* Rt(HPLC): 0.67 min (method 7) 4-Methoxy-5-(piperazin-1-yl)pyridin-2-aniine Stir 1-[6-(2,5-dimethiI-1H-pinol-1-yl)-4-methoxypyridin-3-yl]piperazine bis(trifluoroacetic acid) (1.20 g, 2.33 mmol), hydrochloride of hydroxylamine (0.70 g, 10.03 mmol) and triethylamine (1.00 ml, 7.11 mmol) in EtOH / water (1 / 1; 16 ml) overnight at 80*C. The organic solvent is removed under reduced pressure. The residue is purified by HPLC-Fl (ACN / water + NH3). Yield: 290 mg (60%) ESI-EM: m / z = 209 [M+H]* Rt(HPLC): 0.35 min (method 11) 5-(4-FluorophenoxlM-methoxylplridlna-2-carbonltrile 5-fluoro-4-methoxypyridin-2-carbonitril (1.00 g; 6.57 mmol), 4-fluorophenol (0.88 g; 7.89 mmol) and potassium carbonate (2.00 g; 14 mmol) are stirred. .46 mmol) in NMP at 105eC for 1.5 hours. The reaction mixture is allowed to cool to RT and extracted with EtOAc. The organic phase is washed with water and brine, separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is levigated with EP, filtered and dried in a drying oven at 60eC. Yield: 1.54 g (96%) ESI-EM: m / z = 245 [M+H]* Rt(HPLC): 1.03 min (method 7) IF-2018-67688982- APN- ANP#INPI 139 Page 139 of 161 09-0675-O-3 5-(4-fluorophenoxylM-methoxlipridine-2-carboxylic acid 5-(4-fluorophenoxy)-4-methoxypyridine-2-carbonitrile (1.54 g; 6.31 mmol) and NaOH (2 mol / l, aq. solution; 15.40 ml, 30.80 mmol) are stirred. at 105eC for 10 hours. The reaction mixture is allowed to cool to RT and left for 3 days. The resulting precipitate is filtered and levigated in water. Heat the reaction mixture to 50°C and adjust the pH to pH7 using HC1 (4 mol / L, aq. solution). The resulting precipitate is filtered, washed with EE and dried in a drying oven at 60°C. Yield: 0.84 g (51%) ESI-MS: m / z = 264 [M+H]* Rt( HPLC): 0.77 min (method 7) 544-[544-Fluorophenoxy)-4-methoxyylridine-2-carbonyl1piperazin-1-ID-4-methoxyoiridin-2amine 5-(4-fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (0.40 g; 1.92 mmol), HATU (0.75 g; 1.97 mmol) and DIPEA (1.16 ml; 6.72 mmol) in DMF (10 ml) for 30 minutes at RT. 4-Methoxy-5-(piperazin-1-yl)pyridin-2-amine (0.52 g; 1.98 mmol) is added and the reaction mixture is allowed to stir at RT overnight. The mixture is purified by HPLC-FI (ACN / water + NH3). Yield: 0.31 g (36%) ESI-EM: m / z = 454 [M+H]* RrfHPLC): 0.88 min (method 11) Alternative preparation of compound 39 4-Methoxl-5-(1-r4-methoxl-5-(2-methylpropoxl)plrldine-2carboninplperld¡n-4-ll}-pyridin-2-amine trifluoroacetic acid Methyl-4-methoxyl-5-(2-methylpropoxy)pyridine-2-carboxylate IF-2018-67688982-APN-ANP#INPI 140 Page 140 of 161 09-0675 Methyl 5-hydroxy-4-methoxypyridine-2-carboxylate (0.40 g, 2.18 mmol), 2-methylpropan-1-ol (0.40 ml, 4.37 mmol) and TPP (1.72 g) are stirred. , 6.55 mmol) in THF for 10 minutes at RT. The reaction mixture is cooled in an ice bath and DTAD (1.51 g; 6.55 mmol) is added. After 30 minutes, the reaction mixture is purified by HPLC-FI (ACN / water+TFA). Yield: 0.30 g (57%) ESI-EM: m / z = 240 [M+H]* Rt(HPLC): 0.85 min (method 7) 4-methoxy-542-methylpropoxy)pyridine-2-carboxylic acid Methyl 4-methoxy-5-(2-methylpropoxy)pyridine-2-carboxylate (0.30 g; 1.25 mmol) and NaOH (4 mol / l, aq. solution; 0.47 ml; 1. 88 mmol) in MeOH (8 ml) at RT for 3 days. The pH of the reaction mixture is neutralized using HCl (4 mol / l; aq. solution) and the solvents are removed under reduced pressure. DCM and a small amount of MeOH are added to the residue. The insoluble material is filtered and the mother liquid is removed under reduced pressure. The residue is used without further purification. Yield: 0.20 g (71%) ESI-EM: m / z = 226 [M+H]* Rt(HPLC): 0.76 min (method 7) 6-amino-4-methoxl-rt2,<3\6,-tetrahldro-f3<4,-bipyrldinal-1,-fert-butyl carboxylate The reaction is carried out under an argon atmosphere. 5-Bromo-4-methoxypyridin-2amine (7.40 g; 32.80 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-II)-1 are purged tert-butyl 2,3,6-tetrahydropyridine-l-carboxylate (11.16 g; 36.08 mmol) and sodium carbonate (2 mol / l, aq. solution; 65.60 ml; 131.21 mmol ) in 1,4-dioxane (300 ml) with argon. After 5 minutes, 2' gen Xphos is added. (0.77 g; 0.98 mmol) and stir the reaction mixture overnight in a vial IF-2018-67688982- APN- ANKJgl Page 141 of 161 09-0675-0T-3 closed at 100°C. The reaction mixture is concentrated under reduced pressure. The residue is incorporated into water and extracted several times with EtOAc. The combined organic phases are dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (DCM / MeOH). Yield: 9.69 g (97%) ESl-MS: m / z = 306 [M+H]* Rt(HPLC): 0.83 min (method 10) Tere-butyl 4-(6-amino-4-methoxypyridine-3-iD-pyridine-1-carboxylate Fenc-butyl e-amino^-methoxy-T.Z.S'.e'-tetrahydro-IS^'-bipyridtnaJ-T-carboxylate (5.11 g; 16 psi) is stirred under a hydrogen atmosphere (Pair apparatus; 50 psi). .73 mmol) and Pd / C (10%; 0.60 g) in MeOH (100 ml) at RT for 41.5 hours. Additional catalyst is added twice and the reaction mixture is also hydrogenated. After removing the catalyst by filtration, the mother liquid is concentrated under reduced pressure. The product is used without additional purification! Yield: 4.71 g (92%) ESl-MS: m / z = 308 [M+H]*Rt(HPLC): 0.82 min (method 10) 4-methoxy-5-(plperidin-4-ll)plrldin-2-amine dihydrochloride Tert-butyl 4-(6-amino-4-methoxypyridin-3-yl)-piperidine-1-carboxylate (6.90 g; 22.45 mmol) and HCl (4 mot / l; solution in 1, 4-dioxane; 69.00 ml; 224.47 mmol) in DCM (89.70 ml) at RT overnight. The reaction mixture is concentrated under reduced pressure. The residue is levigated in EE and filtered. The product is used without additional purification. Yield: 5.30 g (84%) ESl-MS: m / z = 208 [M+H]* Rt(HPLC): 0.66 min (method 11) 4-Methoxy-5-{1-[4-methoxy-5-(2-methylpropoxy)pyridine-2carboninplperidin-4-íD-pyridin-2-amine trifluoroacetyl acid IF-2018-67688982- APN-ANP#INPI 142 Page 142 of 161 09-0675-O-3 TFA 4-Methoxy-5-(2-methylpropoxy)pyridine-2-carboxylic acid (80 mg; 0.36 mmol), 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride ( 96 mg; 0.36 mmol), DIPEA (0.24 ml; 1.42 mmol) and HATU (149 mg; 0.39 mmol) in DMF (3 ml) at RT overnight. The reaction mixture is purified by HPLC-FI (ACN / water + TFA). Yield: 0.11 g (72%) ESI-EM: m / z = 415 [M+H]* Rt(HPLC): 0.80 min (method 7) Alternative preparation of compound 17 6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboninpiperidin-4-¡l}pyrádazÍn-3-amlna 446-Amlnopyridazin-3-II)-1,2,3,6-tetrahydropyridanine-1-carboxylate tere-butyl The reaction is carried out under an argon atmosphere. 6-chloropyridazin-3-amine (5.20 g; 40.14 mmol) is purged, tero-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (13.65 g; 44 .15 mmol) and sodium carbonate (2 mol / l, aq. solution; 80.28 ml; 160.56 mmol) in 1,4-dioxane (350 ml) with argon. After 5 minutes, 2' gen Xphos is added. (0.95 g; 1.20 mmol) and the mixture is stirred overnight in a closed vial at 100°C. The reaction mixture is filtered and concentrated under reduced pressure. The residue is incorporated into MeOH, precipitated with water and filtered. The resulting precipitate is dried in a drying oven at 50°C. The product is used without additional purification. Performance: Quantitative ESI-EM: m / z = 277 [M+H]*Rt(HPLC): 0.78 min (method 10) 446-Tere-butyl aminopyridazin-3-yl)-piperididine-1-carboxylate IF-2018-67688982-APN-ANP#INPI 143 Page 143 of 161 09-0675-W-3 Tere-butyl 4-(6-aminopyridazin-3-yl)1,2,3,6-tetrahydropyridine-1-carboxylate (4.85 g; 17.85 g) is stirred under a hydrogen atmosphere (Parr apparatus, 4 bar). 55 mmol) and Pd / C (10%; 0.50 g) in MeOH (100 ml) at RT for 3 hours. After removing the catalyst by filtration, the mother liquid is concentrated under reduced pressure. The product is used without additional purification. Performance: Quantitative ESI-EM: m / z = 279 [M+H]+Rt(HPLC): 0.86 (method 11) 6-(PÍperÍdln-4-inplridazin-3-amine Tere-butyl 4-(6-amÍnopyridazin-3-yl)-piperidine-1-carboxylate (4.89 g; 17.55 mmol) is stirred for 1 hour in TFA (20 ml; 259.25 mmol). The solvent is evaporated and the residue is purified by silica gel chromatography (DCM / MeOH + NH3). Performance: quantitative ESI-EM: m / z = 179 [M+H]* Rt(HPLC): pico injection (method 11) Amine used alternatively: 64Piperidin-4-ll)plridazln-3-amine dihydrochloride The reaction is carried out using a nitrogen atmosphere. Tere-butyl 4-(6-aminopyridazIn-3yl)-piperidine-1-carboxylate (1.00 g; 3.59 mmol) and HCl (4 mol / l, solution in 1,4dioxane; 2.96 ml) are stirred. ; 11.84 mmol) in ACN (6 ml) at 35°-40°C for 2 hours. The reaction mixture is cooled to RT and diluted with isopropylacetate. After 10 minutes of stirring, the resulting precipitate is filtered and dried in a drying oven at 45'C. Performance: Quantitative ESI-EM: m / z = 179 [M+H]* Rt(HPLC): 0.94 min (method 14) 6-{1-r5-(4-Fluorophenoxl)-4-methoxypyridine-2-carboninplperidin-44l)pyridazln-3-amine IF-2018-67688982-APN-ANP#INPI 144 Page 144 of 161 09-0675-W-3 5-(4-fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (0.70 g; 2.66 mmol), HATU (1.52 g; 3.99 mmol) and DIPEA (1.83 ml; 10.64 mmol) in DMF (20 ml) for 30 minutes. 6-(Piperidin-4-Il)pyridazine-3-amine (0.71 g; 3.98 mmol) is added and the reaction mixture is allowed to stir at RT overnight. The mixture is purified by HPLC-Fl (ACN / water + TFA). To remove the trifluoroacetate salt, the product is incorporated into water / EtOH (1.5 / 1) and levitated with polymer-bound bicarbonate. After 30 minutes of stirring, the mixture is filtered and concentrated under reduced pressure. Yield: 180 mg (16%) ESI-MS: m / z = 424 [M+H]* Rt(HPLC): 0.77 min (method 7) Alternatively, the title compound can be obtained as follows: 6-f1-r544-Fluorophenoxy)-4-methoxylpyridine-2-carboninoiperidin-4-yl)pyridazin-3-amlna 5-(4-fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (0.50 g; 1.90 mmol) and CDl (0.46 g; 2.85 mmol) in NMP (1 mL) are stirred at RT. for 1 hour. 6(piperidin-4-yl)pyridazine-3-amine dihydrochloride (0.52 g; 2.09 mmol) and DIPEA (0.99 ml; 5.70 mmol) are added. After stirring for 3 hours, the reaction mixture is diluted with water and extracted with EtOAc. The organic phase is separated, washed with water and brine, dried over MgSO< and filtered. The mother liquid is concentrated under reduced pressure and purified by silica gel chromatography (DCM / MeOH). The desired fractions are concentrated under reduced pressure and treated with ACN / diethyl ether to provide the title product in solid form. Yield: 0.27 g (34%) ESI-EM: m / z = 424 [M+H]* Rt(HPLC): 0.49 min (method 1) Alternative preparation of compound 37 541-f5-(Cyclopropylmethoxy)-4-methoxypyridin-2-carboninpiperidin-4-in-4-methoxyplridin-2amlna Methyl 54Clclopropylmethoxy)-4-methoxylpr¡dina-2-carboxate IF-2018-67688982- APN-ANP#INPI 145 Page 145 of 161 09-0675-08-3 5-Hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (0.20 g; 1.09 mmol) and cyclopropylmethanol (88 μΙ; 1.09 mmol) in THF (3 ml) are cooled in a water bath. ice. TPP (0.32 g; 1.20 mmol) and DTAD (0.28 g; 1.20 mmol) are added. The reaction mixture is allowed to warm to RT overnight. The reaction mixture is concentrated under reduced pressure and purified by HPLC-FI (ACN / water + TFA). Yield: 0.18 g (70%) ESI-EM: m / z = 238 [M+H]* Rt(HPLC): 0.41 min (method 12) 5-(cycopropylmethoxy)-4-methoxypyridine-2-carboxylic acid Methyl 5-(cyclopropylmethoxy)-4-methoxypyridine-2-carboxylate (0.18 g; 0.76 mmol) and NaOH (4 mol / l, aq. solution; 0.50 ml; 2.00 mmol) are stirred. in MeOH (3 ml) at RT for 1 hour. The reaction mixture is concentrated under reduced pressure. The residue is incorporated into water and washed with EtOAc. HCl (4 mol / l, aq. solution; 0.5 ml) is added to the aqueous phase and concentrated under reduced pressure. The product is used without additional purification. Yield: 0.13 g (74%) ESI-EM: m / z = 224 [M+H]* Rt(HPLC): 0.30 min (method 12) 541-[5-(Cyclopropylmethoxy)-4-methoxypyridine-2-carboninpiperidin-4-ylM-methoxypyridin-2amine 5-(cyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid (50 mg; 0.22 mmol), 4-methoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (63) are stirred. mg; 0.22 mmol), DI PEA (193 μΙ; 1.12 mmol) and HATU (94 mg; 0.25 mmol) in DMF (2 ml) at RT overnight. The resulting mixture is purified by HPLC-FI (ACN / water + NH3). Yield: 45 mg (49%) ESI-MS: m / z = 413 [M+H]* Rt(HPLC): 0.87 min (method 11) Alternative preparation of compound 90 IF-2018-67688982- APN-ANP#INH 146 Page 146 of 161 09-0675-W-3 trifluoroacetic acid 6-d44-methoxy-5-[4-(trifluoromethyl)phenoxynpyridine-2-carbonyl)piperidin-4-in-5-methypyride zln-3-amlna 4-Methoxl-5-r4-(trifluoromethyl)phenoxynpyridine-2-carbonitrile 5-fluoro-4-methoxypyridine-2-carbonitrile (4.69 g; 30.84 mmol), 4-trifluoromethylphenol (5.00 g; 30.84 mmol) and potassium carbonate (6.39 g; 46 mmol) are stirred. .27 mmol) in DMSO at 110eC for 1 hour. The reaction mixture is allowed to cool to RT and diluted with water. The resulting precipitate is filtered, washed with water and dried in a drying oven at 50'C. Yield: 7.40 g (82%) ESI-EM: m / z » 295 [M+H]* Rt(HPLC): 1.08 min (method 10) 4-Ethoxy-5-r4-(trifluoromethyl)phenoxyflpyridine-2-carboxnic acid 4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonitrile (7.40 g; 25.51 mmol) and NaOH (4 mol / L, aq. solution; 31.44 ml, 125 mmol) are stirred. .75 mmol) in MeOH (100 ml) at 70'C overnight. The reaction mixture is allowed to cool to RT and the organic solvent is evaporated. The remaining solvent is diluted with water and adjusted to pH 3 using HCl (4 mol / L, aq. solution). The resulting precipitate is filtered and dried in a drying oven at 50°C. Yield: 6.80 g (51%) ESI-EM: m / z = 314 [M+H]* Rt(HPLC): 0.87 min (method 10) Fert-butyl 4-(6-Amlno-4-methylplridazin-3-II)-1,2,3,6-tetrahydropyridine-1-carboxylate IF-2018-67688982-APN-ANP#INPI 147 Page 147 of 161 09-0675-W-3 The reaction is carried out under an argon atmosphere. 6-Chloro-5-methylpyridazin-3amine (3.00 g; 20.90 mmol), 4-(4,4,5,5-tetramethyl-1(3,2-dioxaborolan-2-yl)-1 are purged tero-butyl ,2,3,6-tetrahydropyridine-1-carboxylate (7.11 g; 22.98 mmol) and sodium carbonate (2 mol / l, aq. solution; 41.79 ml; 83.58 mmol ) in 1,4-dioxane (150 ml) with argon. After 5 minutes, Xphos 2' gen (0.49 g; 0.63 mmol) is added and the mixture is stirred overnight in a closed vial. 100eC. The reaction mixture is concentrated under reduced pressure. The residue is incorporated into water and extracted several times with EtOAc. The combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. purify the residue by silica gel chromatography (DCM / MeOH). Yield: 5.20 g (86%) ESl-MS: m / z = 291 [M+H]* Rt(HPLC): 0.79 min (method 10) Tere-butyl 4-(6-Amlno-4-methylplrÍdazln-3-ll)plperidine-1-carboxylate Tere-butyl 4-(6-amino-4-methylpyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (5, 20 g; 17.91 mmol) and Pd / C (10%; 0.75 g) in MeOH (100 ml) at RT for 17 hours. After removing the catalyst by filtration, the mother liquid is concentrated under reduced pressure. Yield: 5.00 g (96%) ESI-EM: m / z = 293 [M+H]* Rt(HPLC): 0.79 min (method 10) 5-Methyl-6-piperldln-4-ll)pyridazin-3-amine dihydrochloride HCI Tere-butyl 4-(6-amino-4-methylpyridazin-3-yl)piperidine-1-carboxylate (4.91 g; 16.79 mmol) and HCl (4 mol / l; solution in 1 ,4-dioxane; 73.65 ml; 251.90 mmol) in 1,4dioxane (34.37 ml) at RT overnight. The reaction mixture is concentrated under reduced pressure. The residue is levigated in EtOAc and filtered. The product is used without additional purification. IF-2018-67688982-APN-ANP#I^g[ Page 148 of 161 09-0675-O-3 Performance: Quantitative ESI-EM: m / z = 193 [M+H]+Rt(HPLC): 0.59 min (method 11) trifluoroacetic acid 6-(144-Methoxl-5-r4-(trifluorometll)phenoxnplridine-2-carboninpiperidin-4-ll)-5-methylplrlda zln-3-amlna 4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carboxylic acid (0.12 g; 0.37 mmol), HATU (0.15 g; 0.39 mmol) and DIPEA (0.39 mmol) are stirred. .19 ml; 1.11 mmol) in DMF (3 ml) for 30 minutes. 5-Methyl-6-(piperidin-4-yl)pyridazín-3-amine dihydrochloride (0.10 g; 0.38 mmol) is added and the reaction mixture is allowed to stir at TA overnight. The reaction mixture is purified by HPLC-FI (ACN / water + TFA). Yield: 0.12 g (55%) ESI-EM: m / z = 488 [M+H]* Rt(HPLC): 0.86 min (method 7) Alternative preparation of compound 47 5-Methoxy-6-n-(4-methoxy-5-phenoxylridin-2-carbonll)piperidin-4-inpÍridazin-3-amlna 5-Fluoro-4-methoxypyridine-2-carbonitrile (0.40 g; 2.63 mmol), phenol (0.25 g; 2.66 mmol) and potassium carbonate (0.54 g; 3.91 mmol) are stirred. mmol) in DMSO (10 ml) at 110eC for 2 hours. The reaction mixture is allowed to cool to RT and diluted with water. The aqueous phase is extracted several times with EtOAc. The combined organic phases are dried over Na2SO4, filtered and concentrated under reduced pressure. Yield: 0.55 g (92%) %) ESI-EM: m / z = 227 [M+H]* Rt(HPLC): 1.01 min (method 7) 4-Methoxyl-5-phenoxyplridlna-2-carboxylic acid IF-2018-67688982-APN-ANP#INPI 149 Page 149 of 161 09-0675W-3 4-Methoxy-5-phenoxypyridine-2-carbonitrile (0.54 g; 2.39 mmol) and NaOH (4 mol / L, aq. solution; 3.00 ml, 12.00 mmol) are stirred in MeOH (10 ml) at 70eC overnight. The reaction mixture is allowed to cool to RT and the organic solvent is evaporated. The remaining solvent is diluted with water and acidified to pH 3 using HCl (4 mol / l, aq. solution). The resulting precipitate is filtered and dried in a desiccator. Yield: 0.30 g (51%) ESI-EM: m / z = 246 [M+H]* Rt(HPLC): 0.72 min (method 10) Tere-butyl 4-(6-{r(tert-ButoxDcarboninamino}-4-methoxyplridazÍn-3-ÍIMt2,3,6-tetrahydroplridine-1-c arboxylate The reaction is carried out under an argon atmosphere. Tert-butyl (6-chloro-5-methoxy-pyridazin-3yl)-carbamate (4.00 g; 15.40 mmol), 4-(4,4,5,5-tetramethyl-1,3, tere-butyl 2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.76 g; 15.40 mmol) and sodium carbonate (2 mol / l, aq. solution) ; 15.40 ml; 30.81 mmol) in 1,4-dioxane (80 ml) with argon. After 5 minutes, 2' gen Xphos is added. (1.26 g; 1.54 mmol) and the mixture is stirred overnight in a closed vial at 90eC. The reaction mixture is concentrated under reduced pressure. The residue is incorporated into EtOAc and washed with water and brine. The organic phase is separated and concentrated under reduced pressure. The residue is purified by silica gel chromatography (DCM / MeOH). Yield: 4.56 g (59%) 4-(6-phy(tert-Butoxl)carboninaminol-4-methoxyplridazin-3-II)piperÍdine-1-carboxylate tere-butyl IF-2018-67688982-APN-ANP#INPI 150 Page 150 of 161 09-0675W-3 4-(6¿[(fefc-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1 is stirred under a hydrogen atmosphere (Parr apparatus; 50 psi). -carboxylate of tere-butyl (4.55 g; 11.19 mmol) and Pd / C (10%; 3.57 g) in MeOH (45.5 ml) at 30eC overnight. After removing the catalyst by filtration, the mother liquid is concentrated under reduced pressure. Yield: 3.67 g (80%) S-methoxl-G-fpiperidin dihydrochloride^-IDpyridazln-S-amine ch3H,C—|—CH,μN-N y—< o ch3O p h3c hci Tere-butyl 4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)piperidine-1-carboxylate (3.67 g; 8.98 mmol) and HCl ( 4 mol / l; solution in 1,4-dioxane; 55.05 ml; 134.76 mmol) in 1,4-dioxane (26.69 ml) at RT overnight. The reaction mixture is concentrated under reduced pressure. The residue is levigated in EtOAc and filtered. The product is used without additional purification. Yield: 2.07 g (82%) ESI-EM: m / z = 209 [M+H]* Rt(HPLC): 0.60 min (method 11) 5-Methoxy-6-ri-(4-methoxy-5-phenoxylpyridine-2-carbonyl)piperidin-4-inpyridazin-3-amine 4-Methoxy-5-phenoxypyridine-2-carboxylic acid (0.10 g; 0.41 mmol), HATU (0.16 g; 0.419 mmol) and DIPEA (0.18 ml; 1.05 mmol) are stirred. ) in DMF (3 mi) for 30 minutes. 5-methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.12 g; 0.41 mmol) is added to it. IF-2018-67688982- APN-ANP#I£j£I Page 151 of 161 09-0675-W-3 and the reaction mixture is allowed to stir at RT overnight. The mixture is purified by HPLC-F1 (ACN / water + NH3). Yield: 0.09 g (53%) ESI-EM: m / z = 436 [M+H]* Rt(HPLC): 0.63 min (method 13) Alternative preparation of compound 29 trifluoroacetic acid 6-f1-r5-f4-fluorophenoxy)-4-methoxypyridina-2-carboninpiperidin-4-yl}-5-methylpyrldazln-3-aml na 5-(4-fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (60 mg; 0.23 mmol), 5-methyl-6-(piperidin-4-yl)pyridazIn-3-amine dihydrochloride (60 mg) are stirred. mg; 0.23 mmol) HATU (95 mg; 0.25 mmol) and DIPEA (0.12 ml; 0.68 mmol) in DMF (3 ml) at RT for 1 hour. The mixture is purified by HPLC-FI (ACN / water + TFA). Yield: 73 mg (59%) ESI-MS: m / z = 438 [M+H]* Rt(HPLC): 0.82 min (method 7) Alternative preparation of compound 91 trifluoroacetic acid 5-methoxy-6-(1-f5-r4-(trifluoromethyl)phenoxynpyridine-2-carboninplperidin-4-yl)pyridazin-3-a mine 5-r4-rrifluoromethyl)phenoxynpyridine-2-carbonltrile 2-cyano-5-fluoropyridine (3.54 g; 28.99 mmol), 4-trifluoromethylphenol (4.70 g; 28.99 mmol) and potassium carbonate (6.01 g; 43.49 mmol) are stirred. mmol) in DMSO (150 ml) at 110eC for 1 hour. Dilute the reaction mixture with water and extract with EtOAc. The organic phase is washed with water, separated, dried over NazSO^, filtered and concentrated under reduced pressure. IF-2018-67688982-APN-ANP#INPI 152 Page 152 of 161 09-0675-O-3 Performance: Quantitative ESI-EM: m / z = 265 [M+H]*Rt(HPLC): 1.03 min (method 10) 5-F4-(trifiuoromethyl)phenoxynplrÍdine-2-carboxylic acid 5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonitrile (3.87 g; 14.65 mmol) and NaOH (4 mol / l, aq. solution; 18.31 ml, 73.24 mmol) are stirred. in MeOH (50 ml) at 70'C overnight. The reaction mixture is concentrated under reduced pressure. The residue is incorporated into water and acidified to pH3 using HCl (4 mol / l, aq. solution). The organic solvent is completely evaporated and the resulting precipitate is filtered. The residue is incorporated into DCM, filtered and dried in a drying oven at 50'C. Performance: quantitative ESI-EM: m / z = 284 [M+H]* R¿HPLC): 0.68 min (method 11) δχτηβΙοίά Trifluoroacetic Acid ΜΊΙΙβΙπ^βζΙιν^ mine 5-[4-(trifluoromethyl)phenoxy]pyridine-2-carboxylic acid (0.10 g; 0.35 mmol), HATU (0.15 g; 0.39 mmol) and DIPEA (0.19 ml; 1.11 mmol) in DMF (3 ml) for 30 minutes at RT. 5-Methoxy-6-(piperidin-4-yl)pyridazine-3-amine dihydrochloride (0.11 g; 0.37 mmol) is added and the reaction mixture is allowed to stir at RT overnight. The mixture is purified by HPLC-FI (ACN / water + TFA). Yield: 0.06 g (31%) ESI-EM: m / z = 474 [M+H]* Rt(HPLC): 0.87 min (method 7) Alternative preparation of compound 31 Trifluoroacetic acid 6-ri-(4-methoxy-5-phenoxypyridine-2-carbonyl)pÍperÍdin-4-yn-5-methylpyridazin-3-amine IF-2018-67688982-APN-ANP#INPI 153 Page 153 of 161 09-0675-H-3 4-Methoxy-5-phenoxypyridine-2-carboxylic acid (60 mg; 0.23 mmol), 5-methyl-6-(piperidin-4-yl)pyridazine-3-amine dihydrochloride (55 mg; 0.23 mmol) are stirred. mmol), HATU (95 mg; 0.25 mmol) and DIPEA (0.12 ml; 0.68 mmol) in DMF (3 ml) for 1 hour at RT. The mixture is purified by HPLC-FI (ACN / water + TFA). Yield: 69 mg (57%) ESI-MS: m / z = 420 [M+H]* Rt(HPLC): 0.81 min (method 7) EVALUATION OF BIOLOGICAL ACTIVITY Ultrarapid analytical screening assay This screening assay measures activation of the TRPC6 (transient receptor potential ion channel, subfamily C, member 6) ion channel by the addition of either the commercially available DAG ligand analogue OAG (1-oleoyl-2-acetyl- sn-glycero1) or the TRPC6 agonist 1 -[ 1-(4,5,6,7,8-pentahydrocyclohepta[2,1-d]thiophen-2-ylcarbonyl)-4-pÍperidÍIJ3-hydrobenzimidazole-2 -one (GSK1702934A). The assay uses a FLIPR fluorescent calcium sensor, tetrakis(acetoxymethyl) acid ester 4-(6-acetoxymethoxy-2,7-difluoro-3-oxo-9xanthenII)-4'-methyl-2(2'-( ethylenedioxy)dianylÍn-N,N,N'lN'-tetraacetic acid (Fluo4 / AM), membrane potential (FMP) dye from Molecular Devices, which is a voltage-sensitive indicator with a fluorescent quencher Changes (increases) in. The intracellular membrane calcium concentration potential as measured by the increase in fluorescent signal during membrane depolarization provides a measure of channel activity. The commercially available HEK293 / TREx line (Invitrogen) was stably transfected with a TRPC6 construct and examined by conventional calcium imaging for clones with TRPC6 expression upon stimulation with 1 pg / ml tetracycline. These cells were maintained in the manufacturer's recommended growth medium supplemented with 100 pg / ml hygromycin to promote retention of the TRPC6 construct. After growing to near confluence, cells were plated at a density of 35,000 cells / well in 384-well CellBind plates (Corning) in the presence of pg / ml tetracyclinal, and allowed to grow for 20-30 h. As a result, an almost confluent monophase was obtained. The growth media was removed from the wells, and the cells were then loaded with 25 ml of Fluo4 / AM diluted in solution of IF-2018-67688982-APN-ANP#INPI 154 Page 154 of 161 09-0675-W-3 Ringer (6.5g NaCl, 0.42g KCl, 0.25g CaCl2 and 0.2g sodium bicarbonate; pH 7.4) supplemented with 1% Pluronic F-127 to a final concentration of 0. 5 μΜ and incubated for 60 min at room temperature. The dye solution was then removed from the cells by inverting the plates with an abrupt movement, and replaced with 25 μl of Ringer's solution. After 0.5 hour for charge recovery, cells were assayed using the Hamamatsu FDSS 6000 system, which allowed illumination at 485 nm. Frames were obtained at a speed of 0.2 Hz. During the assay, the plates were continuously shaken with vortex, mixing the wells with a pipette after the addition of each reagent. For the screening assay, 26 μΙ of a diluted compound stock (at 50 μΜ) was added to each well for 2 minutes after collection of a short reference (4 frames). Then 13 μΙ of agonist solution consisting of 125 nM GSK1702934A diluted in high-Ca2+ Ringer's solution (containing 90 m m Ca2+) was added to each well, achieving a final concentration of 20 m m Ca2+ and 10 μΜ test compound. Data were collected for 3 minutes after the addition of high-Ca2+ Ringer's solution. The fluorescent ratio for each well was divided by the initial fluorescent intensity for that well and the global response was determined by averaging the fluorescent ratio of the last 4 frames acquired during the experiment except for the final frame. Negative and positive controls were included on each plate. Negative control plates consisted of HEK293 / TREx TRPC6 cells exposed to assay buffer and agonist solution, but without test compound. Positive control wells consisted of HEK293 / TREx TRPC6 cells exposed to 3-[(2chlorophenoxy)methyl]phenyl piperidyl ketone 25 μΜ (Chembridge) diluted in Ringer's solution and agonist solution. These controls defined the zero percent and 100 percent block respectively, and the intensity of each well was normalized to these values. Clso were determined using the fluorescence method above with the exception that instead of testing the compounds at 10 μΜ, the compounds were tested at final concentrations of 20 μΜ, 6.667 μΜ, 2.222 μΜ, 0.741 μΜ, 0.247 μΜ, 0.082 μΜ and 0.027 μΜ. Compounds were tested in triplicate at all concentrations. Conventional software was used to fit the ICm curves. Table 8. Antagonistic effects of the compounds of the invention against TRPC6 (CIm) Compound No. MIC of TRPC6 (nM) 1 <27 2 <27 compound no. CIm ofTRPC6 (nM) PI 3 <27 4 -----------fF-2018-67' <27 ^8982-ΑΡΝ-ΑΑΓΡ#ΙΝ 155 Page 155 of 161 09-0675-W-3 Compound No. Cl» of TRPC6 (nM) 5 27 6 27 7 27 8 27 9 27 10 27 11 27 12 27 13 27 14 27 15 27 16 27 17 29 18 31 19 32 20 42 21 43 22 46 23 54 24 67 25 70 26 71 27 75 28 100 29 110 30 110 31 120 32 130 33 82 34 85 35 94 36 97 Compound No. TRPC6 IC50 (nM) 37 160 38 170 39 170 40 170 41 180 42 140 43 140 44 140 45 150 46 160 47 220 48 250 49 250 50 47 51 290 5 2 190 53 210 54 220 55 220 56 290 57,300 58,100 59,340 60,440 61,500 62,550 63,670 64,820 65,830 66,840 67,560 68,630 IF-2018-67688982-APN-ANP#INPI 156 Page 156 of 161 09-0675-11-3 compound no. Cl» deTRPC6 (nM) 69 630 70 640 71 850 72 910 73 1300 74 1400 75 1500 76 1800 77 2200 78 2800 79 3700 80 <27 81 71 82 180 98 84 300 85 320 86 350 87 620 88 750 89 2100 90 364 91 414 92 635 93 595 94a 343 94b 351 95 445 IF-2018-67688982-APN-ANP#INPI 157 Page 157 of 161 09-0675-O-3 The biological activity of the claimed compounds can also be shown using a TRPC6 patch clamp assay. METHODS OF THERAPEUTIC USE Inhibition of TRPC6 is an attractive means to prevent and treat a variety of diseases or conditions that are exacerbated by TRPC6 activity. The compounds disclosed herein effectively inhibit TRPC6 activity. In particular, the compounds of the invention are inhibitors of selective ion channels and have good metabolic stability in human microsomes. More particularly, the compounds of the invention have very good potency and selectivity over TRPC6 channels compared to other TRP channels including TRPC3, TRPC5 and TRPC7. Therefore, the compounds of the invention are useful for the treatment of diseases and conditions as described in the Background and Detailed Description section, including the following conditions and diseases: cardiac conditions (e.g., cardiac hypertrophy), hypertension (e.g., primary or secondary), pulmonary arterial hypertension (e.g., IPAH), a neurodegenerative disease or disorder (e.g., Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and other brain disorders caused by trauma or other injuries including aging), inflammatory diseases (for example, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, multiple sclerosis, and immune system disorders), preeclampsia and pregnancy-induced hypertension, kidney diseases (focal segmental glomerulosclerosis, nephrotic syndrome, diabetic nephropathy, kidney failure, end-stage renal disease, minimal change disease), ischemia or ischemia-reperfusion injury , cancer, IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratory disease syndrome) and metabolic disorders such as diabetes. Methods of preventing or treating any of the above or following diseases and conditions include treating any of the symptoms associated with these diseases or conditions. For example, methods of treating kidney disease contemplate treating symptoms including, but not limited to, secondary hypertension, proteinuria, Itpiduria, hypercholesterolemia, hyperipidemia, and coagulation abnormalities. Due to the important role that calcium regulation plays in many cellular processes including cell activation, cytoskeletal rearrangement, gene expression, IF-2018-67688982- APN-ANP#INPI 158 Page 158 of 161 09-0675-W-3 cell trafficking and apoptotic cell death, calcium dyshomeostasis is implicated in many diseases and disorders. These diseases and disorders include neurological and neurodegenerative diseases and disorders; inflammatory diseases and disorders such as inflammatory bowel disease and Crohn's disease; kidney disease such as hypercalcemia, kidney stones and polycystic kidney disease; metabolic diseases and disorders including obesity and diabetes; liver and kidney diseases and disorders; chronic kidney disease, cardiovascular diseases and disorders including hypertension; respiratory diseases including COPD, IPAH, asthma and emphysema; and cancers, including cancers of the brain, breast, kidney, cervix, prostate, gastrointestinal tract, (for example, gastric cancer or stomach cancer), skin and epithelium. These disorders have been well characterized in man, but a similar etiology also exists in other mammals, and can be treated by pharmaceutical compositions of the present invention. Accordingly, a compound of the invention, as described herein, or a pharmaceutically acceptable salt thereof can be used for the preparation of a medicament for treating a TRPC6-mediated disease or disorder, including those mentioned above and in the Background and Detailed Description sections. For therapeutic use, the compounds of the invention can be administered by means of a pharmaceutical composition in any conventional pharmaceutical dosage form in any conventional manner. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable for the particular dosage form selected. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred modes of administration are oral and intravenous mode. The compounds of this invention can be administered alone or in combination with adjuvants that enhance the stability of the inhibitors, facilitate the administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide complementary therapy, and similar, including other active ingredients. In one embodiment, for example, multiple compounds of the present invention may be administered. Advantageously, such combination therapies use lower dosages of IF-2018-67688982- APN-ANP#INPI 159 Page 159 of 161 09-0675-W-3 conventional therapeutic products, thus avoiding the possible toxicity and adverse side effects incurred when the agents are used as monotherapies. The compounds of the invention can be physically combined with conventional therapeutics or other adjuvants to give a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of the invention (w / w) or a combination thereof. The optimal percentage (w / w) of a compound of the invention can vary and is within the scope of those skilled in the art. Alternatively, the compounds of the present invention and conventional therapeutics or other adjuvants may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regimen. As mentioned above, dosage forms of the compounds of this invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable for the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). The dosage requirements and levels for the compounds of the present invention can be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 11,000 mg / dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be provided. For oral doses, up to 2000 mg / day may be required. As will be appreciated by those skilled in the art, lower or higher doses may be required depending on particular factors. For example, specific treatment and dosing regimens will depend on factors such as your overall health profile! patient, severity and course of! disorder of the patient or the disposition to it, and the judgment of the responsible physician. IF-2018-67688982-APN-ANP#IF£gI Page 160 of 161 09-0675-W-3 The compounds of the invention can be used alone or in combination with one or more additional therapeutic agents. Non-limiting examples of additional therapeutic agents may include. angiotensin II receptor antagonists (angiotensin receptor blockers (ARBs)) such as candesartan, eprosartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, azilsartan and medoxomil; angiotensin-converting enzyme inhibitors (for example, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril and perindopril); antidiabetics such as alpha-glucosidase inhibitors (e.g. miglitol and acarbose), amylin analogues (e.g. pramlintide), dipeptidyl peptidase 4 inhibitors (e.g. alogliptin, sitagliptin, saxagliptin and linagliptin), incretin mimetics (e.g. for example, liraglutide, exenatide, liraglutide, exenatide, dulaglutide, albiglutide and lixisenatide), insulin, meglitinides (for example, repaglinide and nateglinide), biguanides (for example, metformin); SGLT-2 inhibitors (e.g., canagliflozin, empagliflozin, and dapagliflozin), sulfonylureas (e.g., chlorpropamide, glimepiride, glyburide, glipizide, glyburide, tolazamide, and tolbutamide), and thiazolidinediones (e.g., rosiglitazone and pioglitazone); bronchodilators including short-acting and long-acting beta-agonists (e.g., albuterol, levalbuterol, salmeterol, formoterol, and arformoterol) and short- and long-acting anticholinergics (ipratropium, tiotropium, umeclidinium, glycopyrrolate) and aclidinium). steroids such as fluticasone and budesonide; When used as a combination treatment of a pharmaceutical combination, the compounds of the invention and the one or more additional agents may be administered in the same dosage form or different dosage forms. The compounds of the invention and the one or more additional agents may be administered simultaneously or separately, as part of a regimen. IF-2018-67688982- APN-ANP#^£I Page 161 of 161 Argentine Republic - National Executive Branch 2018 - Year of the Centennial of the University Reform Additional Signature Sheet Graphic report Number: IF-2018-67688982-APN-ANP#INPI BUENOS AIRES CITY Thursday December 27, 2018 Reference: 20180103108 The document was imported by the GEDO system with a total of 161 page / s. Digitally signed by GESTION DOCUMENTAL ELECTRONICA - GDE DN: cn=ELECTRONIC DOCUMENTARY MANAGEMENT - GDE, c=AR, o=MINISTRY OF MODERNIZATION, ou=SECRETARY OF ADMINISTRATIVE MODERNIZATION, serialNumber=CUIT 30715117564 Date: 2018.12.27 09:06:44 -03'00' Mariela Flavia Gonnet Administrative Advisor National Patent Administration National Institute of Industrial Property Digitally signed by GESTION DOCUMENTAL ELECTRONICA GDE DN: cn=GEST10N ELECTRONIC DOCUMENTARY - GDE, c=AR, o=MINISTRY OF MODERNIZATION, ou=SECRETARY OF ADMINISTRATIVE MODERNIZATION, serialNumber=CUIT 30715117564 Date: 2018.12.27 09:06:45 -03'00'< / j> < / j>

Claims

1. A compound, characterized in that it is selected from the group consisting of any one of compounds 1 to 95 in the table below (FORMULAS: 1 TO 95) or a pharmaceutically acceptable salt thereof. Two claims follow.