EA040737B1 - PYRIDINECARBONYL DERIVATIVES AND THEIR THERAPEUTIC APPLICATIONS AS TRPC6 INHIBITORS - Google Patents

Description

The field to which the invention relates

The invention relates to pharmaceutical compounds, compositions and methods for the treatment of cardiac and respiratory conditions, kidney disease, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia or ischemic reperfusion injury and cancer, as well as inhibition of the C6 transient receptor potential ion channel (TRPC6).

Prerequisites for the creation of the invention

Various ion channel proteins exist to mediate the flow of ions across cell membranes. Appropriate expression and function of ion channel proteins is essential for maintaining cellular function, intracellular communication, and the like. An important aspect of achieving cellular homeostasis is the maintenance of appropriate concentrations of ions in various cell types during development and in response to various stimuli. A large number of different types of ion channels act to maintain cellular homeostasis by moving ions in and out of cells across the plasma membrane and in cells by moving ions across the membranes of intracellular organelles including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria, and endocytic organelles, including endosomes and lysosomes. A number of diseases are the result of membrane potential dysregulation or aberrant calcium transport. Given the fundamental importance of ion channels in modulating membrane potential and ion flux in cells, the identification of agents that can promote or inhibit specific ion channels is of great interest as research tools and as possible therapeutic agents.

One such channel is the C6 transient receptor potential channel (TRPC6). TRPC6 belongs to the larger TRP family of ion channels (see Desai et al., 2005 Eur. J. Physiol. 451:1118; Clapham et al., 2001 NatNeurosci. 2:387-396; Clapham, 2003 Nature 426:517- 524; Clapham et al., 2002 IUPHAR Compendium). TRPC6 is a calcium permeable channel, in particular a non-selective calcium permeable cation channel. In addition to calcium ions, TRPC6 channels are permeable to other cations, such as sodium. Thus, TRPC6 channels modulate not only intracellular calcium concentration, but also membrane potential by modulating the flux of cations, including calcium and sodium ions. Although non-selective cation channels such as TRPC6 modulate calcium ion flux, among other things, they are mechanistically distinct from voltage-gated calcium channels. Typically, voltage-gated calcium channels respond to depolarization of a potential difference across the membrane and can open to allow calcium influx from the extracellular environment and a rapid increase in intracellular calcium levels or concentrations. In contrast, non-selective cation channels such as TRPC6 tend to be signal transduction dependent, long lasting, and result in slower changes in ion concentration. They show increased activity in response to the production of the second messenger, diacylglycerol (Hofmann et al., 1999). In addition, TRPC6 can respond to pressure changes. These mechanistic differences are accompanied by structural differences between voltage-dependent and cation-permeable channels. Thus, although many different channels have ion flux and membrane potential regulating activities in different cell types and in response to different stimuli, it is important to understand the significant structural, functional, and mechanistic differences between different classes of ion channels.

The function of TRPC6 is associated, among other things, with the modulation of muscle tone. TRPC6 is highly expressed in smooth muscle cells, vascular smooth muscle cells, cardiomyocytes, pulmonary arteries, aorta, heart, liver, brain, and kidneys. The expression of TRPC6, along with experiments performed in knockout mice and cells in culture, suggest that TRPC6 may serve as a useful target for the treatment of hypertension and other cardiac and vascular conditions, preeclampsia.

A mutation in the human TRPC6 channel can cause focal segmental glomerulosclerosis (FSGS) (Winn et al., 2005, Reiser et al., 2005). These mutations, reported to be gain-of-function mutations (Reiser et al., 2005), are sufficient to induce disease. In addition, overexpression of TRPC6 is associated with nephrotic syndrome, lipoid nephrosis, and diabetic nephropathy (Moller et al., 2006, Ilatovskaya et al., 2013, Thilo et al., 2011) or other kidney diseases.

Given its expression and its involvement in TGF-B signaling, TRPC6 is also believed to be important in respiratory disease, restenosis, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia and ischemic reperfusion injury, and some forms of cancer. .

Yue et al. studied the role of TRPC6 channels in mediating proliferation of pulmonary artery smooth muscle cells, which can lead to idiopathic pulmonary arterial hypertension (IPAH). Hypertrophy of the medial pulmonary vascular layer caused by excessive proliferation of pulmonary artery smooth muscle cells (PASMC) is the main cause of increased pulmonary vascular resistance in patients with IPAH. The authors found that TRPC6 was highly expressed and TRPC3 was

- 1 040737 minimally expressed in PASMC from healthy lung tissue. However, in the lung tissue of IPAH patients, TRPC3 and TRPC6 mRNA and protein expression was significantly increased compared to their expression in normotensive patients. In addition, 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 play an important role in mediating proper PASMC proliferation and that dysregulation of TRPC6 may lead to increased PASMC proliferation and medial pulmonary vascular hypertrophy observed in patients with IPAH (Yu et al., 2004 Proc Natl Acad Sci 101 (38): 13861-6). Additional support comes from the observation that in patients with IPAH, the frequency of a single nucleotide polymorphism in the TRPC6 promoter that increases expression was significantly higher than in healthy subjects (Yue et al., 2009 Circulation 119: 2313-22).

Additional evidence suggesting TRPC6 dysregulation in IPAH comes from a study of bosentan, a dual endothelin receptor blocker that has been clinically used to treat IPAH. This inhibitor reduces PASMC proliferation, but the mechanism by which this occurs is unclear. Interestingly, bosentan reduces PASMC proliferation and also reduces TRPC6 expression in the lung tissue of IPAH patients (Kunichika et al., 2004 Am. J. Respir. Crit. Care Med. 170(10): 1101-7).

Chronic exposure to cigarette smoke (CS) in rats resulted in an increase in TRPC6 mRNA and protein expression in the distal pulmonary arteries, and similar effects were observed with PASMC in vitro. Nicotine treatment of cultured rat PASMCs increased TRPC6 expression and increased intracellular calcium levels, both of which were reduced by TRPC6 siRNA silencing (Wang et al., 2014 Am. Physiol. Cell Physiol. 306:C364-73). These results point to a role for TRPC6 in CS-induced lung injury.

Evidence supports a role for TRPC6 in additional pulmonary disorders. TRPC6 expression was found to be elevated in alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) 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. muPHK-TRPC6 can reduce this abnormal calcium influx (Antigny et al. 2011 Am. J. Resp. Cell Mol. Biol., 44:83-90). In mouse lung fibroblasts, the profibrotic activity of PDGF is dependent on TRPC6 activation, suggesting that TRPC6 inhibition might reduce pulmonary fibrosis (Lei et al., 2014 Biomaterials 35:2868-77). The role of TRPC6 in pulmonary endothelial cell function has been demonstrated in mouse lung models with ischemia/reperfusion-induced edema and lipopolysaccharide-induced inflammation, in which TRPC6 deficiency was able to reduce acute lung injury by maintaining endothelial barrier function (Weissmann et al., 2011 Nat. Comm. ., 3:649-58 and Tauseef et al., 2012, J. Exp. Med. 209:1953-68).

Recent studies also point to a role for TRPC6 in other heart diseases, including cardiac hypertrophy. The hearts of patients with dilated cardiomyopathy have increased TRPC6 mRNA expression compared to normal hearts (Kuwahara et al., 2006 J. Clin. Invest. 116:3114-26). In mouse models of cardiac hypertrophy, TRPC6 mRNA levels in the heart are elevated following pressure overload (Kuwahara et al., 2006 J. Clin. Invest. 116:3114-26), long-term isoproterenol treatment (Xie et al., 2012 Nat. Commun. 3: 1238) and uremic cardiomyopathy induced by partial nephrectomy (Xie et al., 2015 J. Am. Soc. Nephrol. 26:1150-60). In addition, heart-specific TRPC6 overexpression in transgenic mouse cardiomyocytes induced cardiac hypertrophy and premature death (Kuwahara et al., 2006 J. Clin. Invest. 116:3114-26).

Wu et al. found that transgenic mice expressing dominant-negative TRPC6 in a cardiospecific manner had an attenuated hypertrophic cardiac response after neuroendocrine agonist infusion or pressure overload simulation, indicating that TRPC6 is a component of channel complexes that are important mediators of hypertrophy (Wu et al. , 2010 Proc Natl Acad Sci 107:7000-05). Small molecule drugs targeting TRPC6 have also recently begun to show promise in the treatment of heart disease. For example, Seo et al. demonstrated that TRPC6 and TRPC3 antagonists (GSK2332255B and GSK833503A) exhibit dose-dependent inhibition of cellular hypertrophy signaling in neonatal and adult cardiac myocytes (Seo et al., 2014 Proc. Natl. Acad. Sci. 111:1551-1556). Similarly, TRPC6-deficient mice were protected from isoproterenol-induced cardiac hypertrophy (Xie et al., 2012 Nat. Commun. 3:1238).

Decreased TRPC6 activity may be beneficial in the treatment of cardiovascular disease. In vitro, atheroprotective shear stress induces an increase in TRPC6 mRNA levels in human vascular endothelial cells (EC) compared to atheroprotective flow conditions (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. In addition, a high-cholesterol diet combined with carotid injury did not impair healing in TRPC6-deficient mice compared with

- 2040737 wild-type control animals (Rosembaum et al., 2015 J Vasc Surg 62:1040-47 and Chaudhuri et al., 2008 Mol. Biol. Cell 19: 3203-11). Similarly, balloon dilatation-induced injury to human internal mammary arteries ex vivo resulted in elevated levels of TRPC6 mRNA compared to non-dilated arteries (Bergdahl et al., 2005, Am. J. Physiol. Cell Physiol. 288:C87280). Endothelial cell apoptosis is involved in the initiation and progression of atherosclerotic lesions, and oxidized low density lipoprotein-induced apoptosis of human aortic EC has been 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 elevated in vascular SMCs and correlated with decreased cerebral blood flow (Johannson et al., 2015 Acta Physiol. 214: 376-89).

Studies by Reiser, Winn and Schlondorff have identified mutations in TRPC6 in patients as the cause of FSGS (Reiser et al., 2005 Nature Genet. 37: 739-744; Winn et al., 2005 Science 308:1801-1804; Schlondorff et al., 2009 Am J Physiol Cell Physiol 296:C558-69). Subsequent studies have identified additional TRPC6 mutations associated with steroid-resistant nephrotic syndrome (C. Sadowski et al., 2014 J. Am. Soc. Nephrol. 26:1279-89). Further studies have shown that TRPC6 is important for normal podocyte function by controlling calcium influx and nuclear activating factor of activated T cells, where increased channel current is associated with kidney damage and proteinuria induction (Moller et al., 2007 J. Am. Soc. Nephrol 18:29-36 and Schlondorff 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 upregulated in human chronic kidney diseases, including FSGS, lipoid nephrosis, membranous glomerulonephritis, and diabetic nephropathy (Moller et al., 2007 J. Am. Soc. Nephrol. 18:29-36 and Thilo et al., 2011, Nephrol. Dial. Transplant 27:921-9), as well as in a mouse model 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), whereas transgenic podocyte-specific expression human GoF mutations in mice cause albuminuria and glomerular lesions (Krall et al., 2010 PLoS ONE e12859 and Canales et al., 2015 Brit. J. Medicine. Med. Res. 5:1198-1212). Therefore, inhibition of TRPC6 may be useful in the treatment of chronic kidney disease. These data not only suggest that TRPC6 normally functions to maintain normal kidney function, but also indicate that TRPC6 is a specific cause in at least some cases of FSGS. Based on the likely role of TRPC6 in kidney function, TRPC6 inhibitory compounds can be used to treat or alleviate chronic kidney diseases or conditions caused (in whole or in part) by TRPC6 dysfunction. In addition, TRPC6 inhibitor compounds can be used to treat or alleviate symptoms of kidney disease (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 et al., 2003 J. Physiol. 550: 515-528). As such, TRPC6 may help maintain proper myogenic tone in the placenta and/or maintain appropriate intrauterine and maternal blood pressure during pregnancy.

Recently, evidence has emerged that implicates TRPC6 in certain forms of cancer. Several groups have found that TRPC6 expression is upregulated in cells taken from patients with gliobastoma multiforme, the most common and incurable type of brain cancer (Chigurupati 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 by a dominant negative mutant suppressed cell growth in vitro. In two human glioma xenograft models, lentivirus-mediated expression of dominant-negative TRPC6 in tumor cells prior to subcutaneous or intracranial implantation reduced tumor volume compared to controls (Ding et al., J. Natl. Cancer Inst. 2010, 102, 10521068). Elevated TRPC6 levels have also been found to be associated with cervical cancer (Wan et al., 2012 Onco Targets Ther 5:171-176), breast cancer (Dhennin-Duthille et al., 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 Quiros et al. 2013 BMC Cancer 13:116-127) and squamous cell carcinoma esophageal carcinoma (Zhang et al., 2013, Med. Oncol. 30:607), among others. In hepatocellular carcinoma cells, it has been demonstrated that doxorubicin, hypoxia, and ionizing radiation increase TRPC6 mRNA expression, and that TRPC6 is found at higher levels in tumor tissues than in uninvolved tissues. Elevated TRPC6 levels have been associated with drug resistance, which has been reduced by in vitro TRPC6 RNA silencing. Lentiviral delivery of TRPC6 specific short hairpin RNA into Huh7 tumor cells prior to implantation in a subcutaneous xenograft mouse model reduced tumor growth and sensitized tumors to doxorubicin (Wen et al., 2016 Sci. Rep. 6:23269). These results indicate that TRPC6 may be a promising therapeutic target for cancer treatment.

Liver diseases, including non-alcoholic steatohepatitis, can be treated by reducing TRPC6 activity. Hypoxia increased TRPC6 expression in the human liver stellate cell line

- 3 040737 compared with normoxic conditions. Using these cells, TRPC6 RNA silencing resulted in down-regulation of transcripts for α-smooth muscle actin and collagen 1A1, both of which are associated with fibrosis, in response to hypoxia (Iyer et al., 2015 Exp Cell Res 336:66-75).

TRPC6 inhibition may benefit patients with Duchenne muscular dystrophy (DMD). In the mdx/utrn ^+/- model of DMD using isolated cardiomyocytes, TRPC6 deficiency restored stress-stimulated contractility and transient calcium response to normal levels compared to wild-type TRPC6 mice, suggesting that TRPC6 inhibition would preserve cardiac function. in patients with DMD (Seo et al., 2014 Circ. Res. 114:823-32).

Fibrotic disorders can be treated with TRPC6 inhibitors. TRPC6 overexpression induced myofibroblast activation, while TRPC6 deletion reduced myofibroblast transformation induced by transforming growth factor beta. In addition, TRPC6-deficient mice showed decreased skin and cardiac wound healing (Davis et al., 2012 Dev Cell 23:705-15).

TRPC6 inhibitors may be useful for pain management. Spinal delivery of TRPC6 antisense oligonucleotides reduced hyperalgesia induced by mechanical, hypotonic and thermal stimuli in preclinical pain models (Alessandri-Haber et al., 2009 J. Neurosci. 29:6217-28).

Modulation of TRPC6 function provides a means to modulate calcium homeostasis, sodium homeostasis, intracellular calcium levels, membrane polarization (resting membrane potential), and/or cation levels in the cell. Compounds that can modulate one or more of TRPC6 functions are useful in many ways including, but not limited to, maintaining calcium homeostasis; maintenance of sodium homeostasis; modulation of intracellular calcium levels; modulation of membrane polarization (membrane potential); modulation of cation levels; and/or treatment or prevention of diseases, disorders or conditions associated with calcium homeostasis, sodium homeostasis, calcium or sodium dyshomeostasis or membrane polarization/hyperpolarization (including hypo- and hyper-excitability), and/or treatment or prevention of diseases, disorders or conditions associated with regulation or dysregulation of TRPC6 expression or function.

There is a need for highly selective TRPC6 antagonists for the treatment of diseases or disorders that can be alleviated by modulating TRPC6.

The essence of the invention

The invention provides novel compounds that modulate TRPC6 and thus are useful in the treatment of a number of diseases and disorders that can be alleviated by TRPC6 modulation, including hypertension, preeclampsia, restenosis, cardiac or respiratory conditions, kidney disease, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia or ischemic reperfusion injury, and cancer. The present 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 to intermediates useful in these methods.

In one embodiment (embodiment 1), the invention relates to a compound of formula (I)

(I) where L is absent or is methylene or ethylene;

Y is CH or N;

A is CH or N;

R ¹ is selected from the group consisting of

_C1-6 alkyl optionally substituted with 1-3 groups independently selected from _the group consisting of halo and _C3-6 cycloalkyl;

phenyl optionally substituted with 1-3 groups independently selected from the group consisting of CF ₃ , halogen, C ₃ - ₆ cycloalkyl, OC ₃ - ₆ cycloalkyl, OC 1 - ₆ alkyl optionally substituted with one to three halogen atoms; And

C ₃ - ₆ cycloalkyl optionally substituted with 1-3 groups independently selected from the group consisting of halogen and C 1_ ₆ alkyl optionally substituted with 1-3 halogen atoms;

R ² is selected from the group consisting of H and _OC1-6 alkyl;

R ³ is selected from the group consisting of H and _C1-6 alkyl, where each _C1-6 alkyl is substituted with a group selected from OH and _OC1-6 alkyl;

- 4 040737 each of R ⁴ and R ⁵ represents H;

R ³ and R ⁴ may, together with the atom to which they are attached, combine to form a 3-9 membered carbocyclyl ring; or

R ³ and R ⁵ may together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O;

R ⁶ is selected from the group consisting of H _, C _1-6 alkyl, OC _1-6 alkyl, and OC _{3_6} cycloalkyl;

R ⁷ is selected from the group consisting of H and OS _1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment 2), the invention relates to a compound according to the first embodiment described above, wherein

R ¹ is selected from the group consisting of

C _1-6 alkyl optionally substituted with 1-3 groups independently selected from the group consisting of halo and C ₃ - ₆ cycloalkyl;

phenyl optionally substituted with 1-3 groups independently selected from the group consisting of CF ₃ , halogen, OC ₃ _ ₆ cycloalkyl and OC _1-6 alkyl optionally substituted with one to three halogen atoms, and

C ₃ _ ₆ cycloalkyl optionally substituted with 1-3 halogen groups;

R ² is OS _1-6 alkyl;

R ³ is selected from the group consisting of H and C _1-6 alkyl substituted with OH or OC ₁ . ₆ αkyl;

R ⁴ is H;

R ⁵ is H;

R ³ and R ⁴ may, together with the atom to which they are attached, combine to form a 3-9 membered carbocyclyl ring; or

R ³ and R ⁵ may together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O;

R ⁶ is selected from the group consisting of H _, C _1-6 alkyl, OC _1-6 alkyl, and OC _{3_6} cycloalkyl; And

R ⁷ is selected from the group consisting of H and OS _1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment 3), the invention relates to a compound according to embodiment 1 or 2 described above, wherein

A is CH and Y is N; or

A is CH and Y is CH; or

A is N and Y is CH;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 4), the invention relates to a compound according to any of Embodiments 1-3 described above, wherein

R ¹ is selected from the group consisting of phenyl optionally substituted with a group selected from the group consisting of CF ₃ , halogen, OC ₃ _ ₆ cycloalkyl and OC _1-6 alkyl optionally substituted with one to three halogen atoms;

R ² is OS _1-6 alkyl;

R ³ is selected from the group consisting of H and C _1-6 alkyl substituted with OH or OS _1-6 alkyl;

R ⁴ is H;

R ⁵ is H;

R ³ and R ⁴ may, together with the atom to which they are attached, combine to form a 3-9 membered carbocyclyl ring; or

R ³ and R ⁵ may together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O;

R ⁶ is selected from the group consisting of H, C _1-6 alkyl, OS _1-6 alkyl and OS _3-6 cycloalkyl;

R ⁷ is selected from the group consisting of H and OS _1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 5), the invention relates to a compound according to any of Embodiments 1-4 described above, wherein

R ¹ is selected from the group consisting of phenyl optionally substituted with a group selected from the group consisting of CF ₃ , OCF ₃ , F and methoxy;

R ² is selected from the group consisting of methoxy or ethoxy;

R ³ is selected from the group consisting of H, 2-hydroxymethyl, methoxymethyl, 1-hydroxyethyl;

R ⁴ is H;

R ⁵ is H;

or

R ³ is ethyl, and R ³ and R ⁴ combine to form a spirocyclic ring; or

R ³ is ethyl or methoxymethyl and R ³ and R ⁵ combine to form a bicyclic ring;

R ⁶ is selected from the group consisting of H, methyl, methoxy, ethoxy, propoxy and cyclylpropyloxy; And

R ⁷ is selected from the group consisting of H and methoxy;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 6), the invention relates to a compound according to any of Embodiments 1-5 described above, wherein

R ¹ together with L are 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, 2-fluorobenzyl, phenylethyl; And

R ² is methoxy or ethoxy;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 7), the invention relates to a compound according to any of Embodiments 1-6 described above, wherein

Y is CH and A is N;

R ¹ together with L are a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 4-cyclopropoxyphenyl, benzyl, 2-fluorobenzyl , phenylethyl;

R ² is methoxy or ethoxy;

R ³ , R ⁴ and R ⁵ each represents H;

R ⁶ is H, methyl, methoxy or ethoxy; And

R ⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 8), the invention relates to a compound according to any of Embodiments 1-6 described above, wherein

Y is CH and A is CH;

R ¹ together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, cyclopentyl, cyclohexyl, benzyl, 2fluorobenzyl, phenylethyl;

R ² is methoxy or ethoxy;

R ³ , R ⁴ and R ⁵ each represents H;

R ⁶ is H, methyl, methoxy or ethoxy; And

R ⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 9), the invention relates to a compound according to any of Embodiments 1-5 described above, wherein

Y is N and A is CH;

R ¹ together with L represent a group selected from the group consisting of phenyl and 4-fluorophenyl;

R ² is methoxy;

R ³ is selected from the group consisting of H, 2-hydroxymethyl and hydroxyethyl;

R ⁴ is H;

R ⁵ is H;

R ³ and R ⁴ can combine to form a spirocyclic ring; or

R ³ and R ⁵ can combine to form a bicyclic ring;

R ⁶ is selected from the group consisting of H and methoxy; And

R ⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 10), the invention relates to a compound according to any of Embodiments 1-4 described above, wherein

R ¹ is _{C1_6} alkyl optionally substituted with 1-3 groups _{independently} selected from the group consisting of halo and _{C3_6} cycloalkyl;

R ² is _{OC1_6} alkyl;

R ³ , R ⁴ and R ⁵ each represents H;

R ⁶ is selected from the group consisting of H, _C1-6 alkyl and _{OC1_6} alkyl; And

R ⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 11), the invention relates to a compound according to any of Embodiments 1-4 and 10 described above, wherein

R ¹ together with L are 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 ,

- 6 040737 cyclohexyl, 2,2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl and 3,3,3-trifluoro-2-methylpropyl;

R ² is methoxy;

R ³ , R ⁴ and R ⁵ each represents H;

R ⁶ is selected from the group consisting of H, methyl and methoxy; And

R ⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (embodiment 12), the invention relates to a compound according to any of embodiments 1-4, 10 and 11 described above, wherein

Y is CH and A is N;

R ¹ together with L represent a group selected from the group consisting of propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-cyclopropylethyl and 2cyclopropylethyl;

R ² is methoxy;

R ³ , R ⁴ and R ⁵ each represents H;

R ⁶ is selected from the group consisting of H, methyl and methoxy; And

R ⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 13), the invention relates to a compound according to any of Embodiments 1-4, 10 and 11 described above, wherein

Y is CH and A is CH;

R ¹ together with L are 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-difluoro-cyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl and 3,3,3-trifluoro-2-methylpropyl;

R ² is methoxy;

R ³ , R ⁴ and R ⁵ each represents H;

R ⁶ is selected from the group consisting of H, methyl and methoxy; And

R ⁷ is H;

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 14), the invention relates to a compound according to Embodiment 1 described above, wherein

R ³ and R ⁴ together with the atom to which they are attached combine to form a 3-membered carbocyclyl ring, or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 15), the invention relates to a compound according to Embodiment 1 described above, wherein

R ³ and R ⁵ together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O, or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 16), the invention relates to a compound according to Embodiment 1 described above, consisting of any of Compounds 1-95 selected from the table below.

- 7 040737

Comm. No. Structure Connection name 1 Ov. Ab ch ₃ O 'Z nh ₂ CH ₃ [4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-[5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 2 o%" O 0 LL (6-Amino-4-methyl-3',4',5',6'-tetrahydro2'H-[3,4'-bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxypyridine -2-yl]methanone 3 x'z 0-0 about d (6-Amino-3',4',5',6'-tetrahydro-2'Н[3,4']bipyridinyl-1-yl)-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 4 x ⁴ z θ /—\ θ-θ λ 0-0 0 0 LL (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4]bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxypyridine- 2-yl]methanone 5 JE b 0-0 z—v 'a I>° “o /=0 y_/ [4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 6 “o ⁰⁵ _o 0 0-0 . z ΣΕ _ [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-isopropoxyphenoxy)-4-methoxy-pyridin-2-yl] methanone

- 8 040737

7 Llo Z^O / I oTs ^x /......sz * O -Z o 'X ZZ [(K)-4-(6-Amino-4-methyl-pyridin-3-yl)2-hydroxymethyl-piperazin-1-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridin-2-yl] methanone 8 θ ^Η 3 0 <K Ζ ^-°Η ₃ A ηρ Ϊ k 1 Α^ν \/χζ ^Ν -.. A ν— γη P νη ₂ [7-(6-Amino-4-methoxy-pyride in-3-yl)4,7-d iaza-spiro[2.5] οκτ-4-yl]-(4methoxy-5-phenoxy-pyridin-2-yl )- methanone 9 0 O 0-0 I # 0% ζ ^ω ΖΓ [7-(6-Amino-4-methoxypyride in-3-yl)4,7-diaza-spiro[2.5]oct-4-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridin-2 -yl] methanone 10 about ρ ό ^! (6-Amino-4-methyl-3',4',5',6'-tetrahydro2'H-[3,4]bipyridinyl-G-yl)-(4-methoxy5-phenoxy-pyride in-2- yl)-methanone eleven π / ο-ο ο LL [4-(6-Amino-5-methoxy-pyride azin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 12 ύ'2 0-0 ο ,Ρ 0-0 [4-(6-Amino-pyridin-3-yl)-piperazin-1 yl]-[4-methoxy-5-(4-methoxy-phenoxy)pyridin-2-yl]-methanone 13 6 ο °ζ Μ Ο-ο ο LL [4-(6-Amino-pyridin-3-yl)-piperazin-1 yl]-[5-(4-fluorophenoxy)-4-methoxypyridin-2-yl]-methanone

-9040737

14 OH ₃ O F. O. Jk OXTCu -''<h (6-Amino-3',4',5',6'-tetrahydro-2'H[3,4']bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxy-pyridin-2- silt] methanone 15 _CH3 ? Π°γΑί '^''NH. [4-(6-Amino-pyridin-3-yl)-piperazin-1 yl]-(4-methoxy-5-phenox n-pyridine in-2yl)-methanone 16 CH3 0 O -. rEr Ek ,----. lO N NH ₂ [4-(6-Amino-pyr idazin-3 -yl)- piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 17 SNz o ΎΥ rr ^N i /% ,N < A, .Nx - 0 - γ N [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 18 Q O o) \u003d ⁷ ° 7 O. O ⁴ -Z O α τ' [(K)-4-(6-Amino-4-methyl-pyridin-3-yl)2-hydroxymethyl-piperazin-1-yl]-(4methoxy-5-phenoxy-pyridin-2-yl)- methanone 19 ο. _Λ <α °- Αχ ^ι 1 ο'ΡΡΡ^.ο ζ >3^ 2 Υύ “ Υ/ ² ζ X (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(2-fluorobenzyloxy)-4-methoxy -pyridin-2-yl]methanone 20 π 0 Ο 0-0 k /—ζ Ο Q ζ w ^X [(K)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridin-2-yl] methanone

- 10 040737

21 o /=\ o °—y, // To 2—V ° to τ' [4-(6-Amino-5-methoxy-pyride azin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 22 CH ₃ CH ₃ O ³ ₁ ³ II (6-Amino-3',4',5',6'-tetrahydro-2'Н- [3,4']bipyridinyl-G-yl)-[4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] - methanone 23 9 About 0-0 A y-z 0-0 \' 9 Z 7L KZ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-1'-yl)-(4-methoxy5-phenoxy-pyride in- 2-yl)-methanone 24 and ⁷ O 0-0 s 9 Z * Ζ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[4-methoxy5-(4-trifluoromethylphenoxy) -pyridin-2yl]-methanone 25 o y - H N \u003d N i / -0 ^x ₀ □ H ₃ C [4-(6-Amino-pyr idazin-3 -yl)- piperide in-1 -yl] -(5-cyclobutylmethoxy- 4-methoxy-pyridin-2-yl)-methanone 26 o / - y / = C 0 ° A μ g / \ CH, ^Η 3\Α~ ^Ο 0 Α ^Η 3° ^Ζ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[4-methoxy5-(1-methyl-cyclopropylmethoxy) pyridin-2-yl]-methanone

- 11 040737

27 CH, 1 ³ o _s 0 h ₂ n o n ₃ s CH ₃ [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-methoxymethyl-piperazin-1-yl]-(4methoxy-5-phenoxy-pyridin-2-yl)- methanone 28 CH, CH, o ά' Al ΎΑ yya Ά\./α _ν oAA _N h ₂ ch ₃ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[4-methoxy5-(4-methoxyphenoxy) -pyridin-2-yl]methanone 29 LL i o o o '—( o M [4-(6-Amino-4-methyl-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone thirty ° /--k / \u003d N ^ ^Ν θν ^NHz /-L W 4 H ₃ C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5cyclohexyloxy-4-methoxy-pyridin-2yl)- methanone 31 %□% z t [4-(6-Amino-4-methyl-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 32 FM HjC'° 0^ CH ₃ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(4-fluorobenzyloxy)-4-methoxy -pyridin-2-yl]methanone

- 12040737

33 F g CH, O Ν,. Ν ΝΗ ₂ [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl]-[4-methoxy-5-(4grifluoromethyl-phenoxy)-pyridin-2-yl]methanone 34 Ο d Ο 0-0 with /—ζ ¢/ and [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-chloro-phenoxy)-4methoxy-pyridin-2-yl]-methanone 35 Γ CH, <Ζ~° 0 ³ Η ₃ 0 (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5cyclopentyloxy-4-methoxy-pyridin-2yl)- methanone 36 0 /--4 Ν=Ν Η ₃ ο^° Ρ CH ₃ ^{n c} [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl]-(5-isobutoxy-4methoxy-pyridin-2-yl)-methanone 37 ⁰ /—\ /~ ^N Hj^vAdM^ ² g <τ /+< ^{CH1 H} c ^C ' (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5cyclopropylmethoxy-4-methoxypyridin-2-yl)- methanone 38 “Π d O 0-0 < '^=7 o JE [3-(6-Amino-4-methoxy-pyride in-3-yl)3,8-diaza-bicyclo[3.2.1]oct-8-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridine -2-yl]methanone 39 ⁰ 7 - \ / \u003d ^N 0 ° %'Z' ° ^/> C) ° ^Hz n, s ^ / R C ⁿ ' ^s (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5isobutoxy-4-methoxy-pyridin-2-yl ) methanone

- 13 040737

40 A α-ο about R [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-cyclopropoxyphenoxy)-4-methoxy-pyridin-2-yl] methanone 41 O A-A АА°Аг ν A Λ J o -/nh, ¥ Η,Ο [4-(6-Amino-pyr idazin-3 -yl)- piperid in-1 -yl] - [5 - (4-fluoro-benzyloxy) - 4-methoxy-pyridin-2-yl]-methanone 42 CM Τ o°AA ² ° _v Hell d° o O Ll [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1-yl]-[5(4-fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 43 o _ο Χθγχ Ο, Ο H ₃ C ο sn ₃ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5benzyloxy-4-methoxy-pyridin-2-yl ) methanone 44 CH, CH ₃ O 1 1 II O. Οχ X VA /A Χ^Ν to X. -D -Ν [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl]-[4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] methanone 45 D ο °\^chAk χΧΧ η X ν η ³ ο Α ν ΑΑΑ _F -G / Xfl Ν ΝΗ ₂ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(3,3cyfluoro-cyclobutylmethoxy)-4 -methoxypyridin-2-yl]-methanone 46 ⁰ /—\ /^ ^N nJ^ ⁿ vJy^ ^NH2 W °χ ^{CH3 H} ' ^s n ₃ s (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(4-methoxy5-propoxy-pyridin-2-yl )-methanone

- 14 040737

47 τ th ^0-0 /—\ Α o \=/ o JE [4-(6-Amino-4-methoxy-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 48 ⁰ /--\ /= ^Ν ν/ ^Ν %Η/ ^ΝΗ2 to /-O ' ^CH s /4_/ ° 0 n ₃ s (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(2cyclopropylethoxy)-4-methoxypyr id in-2-yl]-methanone 49 sn ₃ O O. ,^χ A. ^-χ ΊΟ ΥϊΟ A _z n L Nx x ^x _o Ύ N c<He ₂ ch ₃ [4-(6-Amino-4-methoxy-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 50 id ......{) ' O rt (1K)-1-[(2K)-4-(6-amino-4- methoxypyridin-3 -yl) -1 - (5- phenoxypyridine-2-carbonyl)piperazin2-yl]ethan-1-ol 51 o О 0-0 s rt rt~l· / ΣΕ Z ^w ΣΕ [3-(6-Amino-4-methoxy-pyride in-3-yl)3,8-diaza-bicyclo[3.2.1]oct-8-yl]-(4methoxy-5-phenoxy-pyridin-2-yl ) methanone 52 O /--\ z \u003d N nJ ^ v_oLO ^nh 0 ° fx <~ ^o ° ^CH3 H ₃ C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(4-methoxy5-phenethyloxy-pyridin-2-yl )-methanone 53 ° /---h /=N nA'vMU^ ² W ° ^ ^a ° ^0Hs □ n ₃ s (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5- cyclobutylmethoxy-4-methoxy-pyridin2-yl)-methanone

- 15 040737

54 Τ about P O 0-0 With Si [4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl] - [5-(4-d ifluoromethoxyphenoxy)-4-methoxy-pyridin-2-yl] methanone 55 'ti 0-0 0-0 “ / )..... ^/ “ Μ” 0 Р “Π [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-methoxymethyl-piperazin-1-yl]-[5(4-fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 56 F _with CH, O IF 1 1 /K cf xn, ^F ΪΙΊ Til O ? Ν ΝΗ, [4-(6-Amino-4-methoxy-pyridazin-3-yl)piperide in-1-yl]-[4-methoxy-5-(4grifluoromethyl-phenoxy)-pyridin-2-yl]methanone 57 Ο /--\ Ν = Ν /~° b / \ hx' L/~ ^f [4-(6-Amino-pyr idazin-3 -yl)- piperid in-1 -yl] - [5 - (2-fluoro-benzyloxy) - 4-methoxy-pyridin-2-yl]-methanone 58 o ^HC Y α,ί/άζι XI Ν ΝΗ _: (1S)-1-[(2K)-4-(6-amino-4methoxypyridin-3-yl)-1-(5phenoxypyridin-2-carbonyl)piperazin2-yl]ethan-1-ol 59 ⁰ /--\ / ^=Ν nJKJHX^ i »β-τΓ '° Khon, ^n,s (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(2,2cymethylpropoxy)-4 -methoxy-pyridin2-yl]-methanone

- 16 040737

60 CH, CH, o I 1 II O, /,. O, /G/ X /-,, ΥΊ /%/NO\/N/ ' Q ./- '--/-- --4/- / _N γ^ΝΗ;, „o H ₃ C [4-(6-Amino-5-methoxy-pyride azin-3-yl)piperide in-1-yl] - [4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] methanone 61 I a 0-0 2-. ' Q I )^O b---( '°yf [4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1 -yl] -(5- cyclopropylmethoxy-4-methoxy- pyridin-2-yl)-methanone 62 θ ^Η 3 0 n°rrn kA, /%/N 0 A, o ^N [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl]-(5-cyclohexyloxy-4methoxy-pyridin-2-yl)-methanone 63 ΠΊ P O o— ό ^ω /—o o...... ri ⁸ γ/ ζ JT [(8)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1-yl]-[5(4-fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 64 ⁰ /—\ /= ^Ν i % γν F (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(1fluoromethyl-cyclopropylmethoxy)-4methoxypyride in-2-yl]-methanone 65 ° /--\ /= ^Ν Νγν3γ> ^ΝΗι n ₃ s ί/ °\ ³ Vq^ ^sn z ⁰ 0 n ₃ s (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2Ή-[3,4']inyl-1'-yl bipyride)-(5-ethoxy-4methoxy-pyridin-2-yl )-methanone

- 17 040737

66 0-0 0' Oh oh s — m and JE [4-(6-Amino-4-methoxy-pyridazin-3-yl)piperide in-1-yl] - [4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] - methanone 67 0 )--< Ν=Ν Κν UCH 4νη ₂ R [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(2-cyclopropylethoxy)-4-methoxy-pyridin-2-yl]methanone 68 h 0-0 o 0 [7-(6-Amino-4-methoxy-pyride in-3 -yl)-3 oxa-9-aza-bicyclo[3.3.1 ]non-9-yl]-(4methoxy-5-phenoxy-pyridin-2 -il)- methanone 69 BUT. 0 A Ek ALS,. Ο,ί ή k Jk CH ₃ u Un ₂ [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl]-(4methoxy-5-phenoxy-pyridin-2-yl)- methanone 70 ⁰ /—\ /= ^N ν4 ^Ν \444 ^{Ν !} % I \ <7 H ₃ C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2Ή-[3,4']bipyridinyl-1'-yl)-[5-((8)-1 cyclopropylethoxy) -4-methoxypyridin-2-yl]-methanone 71 . /0%' O O [(8)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl]-(4methoxy-5-phenoxy-pyridin-2-yl)- methanone 72 ⁰ / - \ / \u003d ¹⁴ Vn) - C /% ^NH 2 N ~ 4 \ _ / Ya Ya n ₃ s V / / ° Ya / \ ^sn z L-o 8 ^{3 H} s ^C H ₃ C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5isopropoxy-4-methoxy-pyridin-2-yl ) methanone

- 18 040737

73 O /---\ N=N 'L'CHL W n ₃ s [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenethyloxy-pyridin-2-yl)-methanone 74 0 /--y N \u003d N _Ν Ο ^Ν νΛΛΛ ^ΝΗ2 H ₃ C-^ ° P n Ln ^N s ^S n ₃ s sn ₃ [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(2,2-dimethylpropoxy)-4-methoxy-pyridin-2-yl]- methanone 75 0 y--y N = N Vn >—<l zHnh ₂ N-/ \__/ 0_A O ^H 'V-° 0 < ^H . ^WITH [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl]-[4-methoxy-5-(1-methylcyclopropylmethoxy)-pyridin-2-yl]methanone 76 0 Y y N \u003d N LOO n ₃ s - / ° P n ₃ s [4-(6-Amino-pyr idazin-3 -yl)- piperide in-1-yl]-(4-methoxy-5-propoxypyridin-2-yl)-methanone 77 About y--y / ^\u003d M ^na _o m ° h <f ^{n s} ' (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2Ή-[3,4']bipyridinyl-1'-yl)-[5-((K)-1 cyclopropylethoxy) -4-methoxypyridin-2-yl]-methanone 78 sn ₃ 0 0 - /O. A ΥΎ Ϊ ] ? ^Nz V7 ⁰ G 1 VN, /k 'N NH ₂ [4-(6-Amino-4-methyl-pyridazin-3-yl)piperide in-1-yl] -(5 - cyclopropylmethoxy-4-methoxy- pyridin-2-yl)-methanone 79 O y--\ N=N n ₃ with LO <! p [4-(6-Amino-pyr idazin-3 -yl)- piperide in-1 -yl] - [5-((S)-l -cyclopropylethoxy)-4-methoxy-pyridin-2-yl]- methanone

- 19 040737

80 LT .NH ^F fY°i0 ^M ΓγΖ sn ₃ o [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl]-[4-methoxy-5-(4grifluoromethoxy-phenoxy)-pyridin-2yl]-methanone 81 R About 0-0 ,—-Z. z—/ o 0' and jr [(K)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-(4methoxy-5-phenoxy-pyridin-2-yl) methanone 82 0-0 0' Oh oh s /--Z Z—/ o 0 Z ξε [(K)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-[4methoxy-5-(4-methoxy-phenoxy)-pyridin2-yl]-methanone 83 / '- o o O [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(phenoxy)-4-ethoxypyridin-2-yl]-methanone 84 0 O 0-0 With — JL (6-Amino-4-cyclopropoxy-3',4',5',6'hetrahydro-2'Н-[3,4']bipyridinyl-1'-yl)[5-(phenoxy)-4-methoxy- pyridin-2-yl]methanone 85 sn ₃ 0 s l Ν NH ₂ [4-(6-Amino-4-ethoxy-pyridazin-3-yl)piperide in-1-yl]-[4-methoxy-5-(phenoxy)pyridin-2-yl]-methanone 86 sn ₃ 0 CXP0T..'........'...... Ν MN„ (6-Amino-4-propoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-G-yl)[5-(phenoxy)-4-methoxypyridine -2-yl]methanone

- 20 040737

87 A % fl Α xfv Ov x^v xb ,.--- χ-ν ^F 11 1 r II 'll O CH ₃ LA-V CD m -A N NH ₂ 5-Ethoxy-6-(1-{4-methoxy-5-[4(trifluoromethyl)phenoxy]pyridine-2carbonyl }piperidin-4-yl)pyridazin-3amine 88 b O -' z JL [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4ethoxy-pyridin-2-yl]-methanone 89 “P 0 O Ο -, z [3-(6-Amino-pyridazin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-[4-ethoxy-5-(4fluorophenoxy)-pyridin-2-yl]-methanone 90 fl? ^H = fl A. x>v CL .00 x\ ^F 1ΓΊ Air A ί AA,n LA vN- 'vx _-o -v_x -v^x -VX v _N 6-( 1 - { 4-Methoxy-5 - [4- (trifluoromethyl)phenoxy]pyridine-2carbonyl } piper idin-4-yl)-5 - methylpyridazine-3-amine 91 AOaa A. 5 -Methoxy-6-( 1 - { 5 - [4-(trifluoromethyl)phenoxy]-pyridine-2- carbonyl } piper idin-4-yl)-pyr id azine-3 amine 92 A o-o o b 4-Methoxy-5 - [ 1 - (4-methoxy-5 - {[trans-3 (trifluoromethyl) cyclobutyl] methoxy} pyridine-2-carbonyl) piperidine in-4-yl] pyride in-2-amine 93 o-o c y-Z 0-0 \--/ p 4-Methoxy-5 - [ 1 - (4-methoxy-5 - {[(cis-3 (trifluoromethyl)-cyclobutyl] methoxy } pyridine-2-carbonyl) piperidine-4yl] pyridine-2-amine 94 b / \ °—u ooo A_ \ £ k 4-Methoxy-5 -(1 - {4-methoxy-5 - [(2)-3,3,3 gryfluoro-2-methylpropoxy]-pyridine-2carbonyl }piperidin-4-yl)pyridine-2amine 95 q ^C .. Q^x-S. r Ii 1 cf^ 7 << Ά, g 1 sn. 5 - (1 - { 5 - [(2,2-Difluorocyclobutyl) methoxy] -4-methoxy-pyridine-2carbonyl } -piperid in-4-yl) -4 methoxypyridin-2-amine

or a pharmaceutically acceptable salt thereof.

In another embodiment (Embodiment 17), the invention relates to a compound according to Embodiment 1 described above, wherein the compound is selected from the group consisting of

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[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-isopropoxy-phenoxy)-4-methoxy-pyridine in-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2yl)-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluorophenoxy)-4-methoxypyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl]-[4-metho xy-5-(4-trifluoromethylphenoxy)-pyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl]-[5-(4-chlorophenoxy)-4-methoxypyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-cyclopropoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl]-[5-(4-fluoro-benzyloxy)-4-methoxypyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)pyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-difluoromethoxy-phenoxy)-4-methoxy-pyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl]-[5-(2-fluoro-benzyloxy)-4-methoxypyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-trifluoromethoxyphenoxy)-pyridin-2-yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl]-[5-(phenoxy)-4-ethoxy-pyridin-2yl]-methanone;

[4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluorophenoxy)-4-ethoxypyride in-2-yl]-methanone;

[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone,

[4-(6-Amino-4-methyl-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenox ipyridin-2-yl)-methanone,

[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone,

[4-(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4trifluoromethyl-phenoxy)-pyridin-2-yl]-methanone, [4 -(6-Amino-4-methoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxyphenoxy)-pyridin-2-yl]-methanone,

[4-(6-Amino-4-ethoxy-pyridazin-3-yl)-piperidin-1-yl]-[4-methoxy-5-(phenoxy)pyridin-2-yl]-methanone,

5-Ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2carbonyl}piperidin-4-yl)pyridazin-3-amine and

6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyride in-2-carbonyl}piperidin-4yl)-5-methylpyridazine-3-amine.

In another embodiment (Embodiment 18), the invention relates to a pharmaceutically acceptable salt of the compound according to Embodiment 17 described above.

In another embodiment (embodiment 19), the invention relates to a compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl]-[5-(4-isopropoxyphenoxy)4-methoxypyridin-2-yl ]Methanone.

In another embodiment (embodiment 20), the invention relates to a compound that is [4-(6-aminopyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)methanone.

In another embodiment (embodiment 21), the invention relates to a compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-fluorophenoxy)-4-methoxypyridin-2-yl ]Methanone.

In another embodiment (embodiment 22), the invention relates to a compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-difluoromethoxyphenoxy)-4-methoxypyridin-2-yl ]Methanone.

In another embodiment (embodiment 23), the invention relates to a compound that is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][4-methoxy-5-(4-trifluorome-22 040737 toxiphenoxy) pyridin-2-yl]methanone.

In another embodiment (embodiment 24), the invention relates to a compound that is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(phenoxy)-4-ethoxypyridin-2-yl]methanone .

In another embodiment (embodiment 25), the invention relates to a compound which is 5-ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2carbonyl}piperidin-4-yl) pyridazine-3-amine.

In another embodiment (Embodiment 26), the invention relates to a compound which is 6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5 -methylpyridazine-3-amine.

In another embodiment (Embodiment 27), the invention relates to a pharmaceutical composition comprising any of the compounds according to Embodiments 1 to 26 described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment (Embodiment 28), the invention relates to the use of a compound according to any of Embodiments 1-26 described above, or a pharmaceutically acceptable compound thereof, in the treatment of a disease or disorder that can be ameliorated by inhibition of the C6 transient receptor potential ion channel ( TRPC6), wherein the disease or disorder is selected from the group consisting of cardiac hypertrophy, ischemia, ischemic reperfusion injury, hypertension, restenosis, chronic obstructive pulmonary disease, cystic fibrosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), trauma-induced brain damage, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, multiple sclerosis, muscular dystrophy, preeclampsia, non-alcoholic steatohepatitis, lipoid nephrosis, focal segmental glottis merulosclerosis (FSGS), nephrotic syndrome, diabetic nephropathy or diabetic kidney disease (DKD), chronic kidney disease, renal failure, ischemia or ischemic reperfusion injury, cancer, IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratory distress syndrome), emphysema and diabetes.

In another embodiment (embodiment 29), the invention relates to the use according to embodiment 28, wherein hypertension is selected from pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, and pregnancy-induced hypertension.

In another embodiment (embodiment 30), the invention relates to the use according to embodiment 28, wherein the muscular dystrophy is Duchenne muscular dystrophy.

In another embodiment (embodiment 31), the invention relates to the use according to embodiment 28, wherein the renal failure is end-stage chronic renal failure.

Detailed description of the invention

Tab. 1 shows compounds of the invention that can be prepared according to the synthesis schemes and examples shown in the Synthesis Examples section below and by methods known in the art.

- 23 040737

Table 1

Comm. No. Structure Connection name 1 o CH ₃ O NH, SN ₃ [4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-[5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 2 Oh \ co about 0 LL (6-Amino-4-methyl-3',4',5',6'-tetrahydro2H-[3,4']bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxy-pyridin-2yl ]-methanone 3 R About 0-0 With y--Z r to? (6-Amino-3',4',5',6'-tetrahydro-2'H[3,4']bipyridinyl-G-yl)-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 4 SNz O OXPCv O Il SN ₃ (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H- [3,4' ] bipyridinyl-1 yl)- [5-(4-fluorophenox u)-4 -methoxypyridin-2-yl]-methanone 5 O^ C - o \=/ o, pp ¹ o . ⁴ —Z 0-0 0 Zj τ' ¹ [4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone

- 24 040737

6 b O ABOUT About 0-0 Z g? [4-(6-Amino-pyridazin-3 -yl) piperidin-1 -yl] - [5 - (4-isopropoxyphenoxy) -4-methoxy-pyridin-2-yl] - methanone 7 t i . O g - O - ¹ O ......' I 0 ° “o g \u003d (o P [(A)-4-(6-Amino-4-methyl-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl] [5-(4-fluorophenoxy)-4-methoxypyride in-2-yl] - methanone 8 p O 0-0 \___/ o 0 h 0^0 o_ \—/ o / t z ^{w t} [7-(6-Amino-4-methoxy-pyridin-3-yl)4,7-diaza-spiro[2.5]oct-4-yl]-(4methoxy-5-phenoxy-pyridin-2-yl) methanone 9 sn ₃ ? °\ wn, V Π Ti N p O ³ 0X _o 00Ed [7-(6-Amino-4-methoxy-pyr idin-3-yl)4,7-diaza-spiro[2.5] οκτ-4-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridin-2yl ]-methanone 10 jr ζ h O /-\ Oh oh ABOUT ' (6-Amino-4-methyl-3',4',5',6'-tetrahydro2Ή- [3,4'] bipyridinyl-1'-yl)-(4methoxy-5-phenoxy-pyridin-2-yl ) methanone eleven -P o o o-o C /—-Z. I / °I/ -Z. JE [4-(6-Amino-5-methoxy-pyridazin-3 yl)-piperidin-1-yl]-[5-(4- fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 12 CH ₃ CHz and I । Т if । 1 4 0- , Λ>,Ν to Lk |j ^N 'U [4-(6-Amino-pyridin-3-yl)-piperazin1-yl]-[4-methoxy-5-(4-methoxyphenoxy)-pyridin-2-yl]-methanone

- 25 040737

13 ΰ o Υ 0-0 ο P Ll [4-(6-Amino-pyridin-3-yl)-piperazin1-yl]-[5-(4-fluorophenoxy)-4-methoxypyride in-2-yl]-methanone 14 rt O 0-0 ζ (6-Amino-3',4',5',6'-tetrahydro-2'H[3,4']bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxy-pyridin-2yl] -methanone 15 SNz □ ί| Ν''Χ'νη ₂ [4-(6-Amino-pyridin-3-yl)-piperazin1-yl]-(4-methoxy-5-phenoxy-pyridin-2yl)-methanone 16 sn ₃ 0 k^k kL/X ' ^{s Nχ} N^ΝΗ ₂ [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 17 : ooo R LL [4-(6-Amino-pyr idazin-3 -yl)- piperidin-1-yl]-[5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 18 yu ¹ d . about Z—. o = Q, 7-X b [(7?)-4-(6-Amino-4-methyl-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl] (4-methoxy-5-phenoxy-pyridin-2-yl) methanone 19 O /--ξ /=N nJ^ ⁿ vVVJ^ ^NH2 O °χ o ^CH3 T\ ^Η 3θ VX~ ^F (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)- [5-(2-fluoro-benzyloxy)-4- methoxypyridin-2-yl]-methanone

- 26 040737

20 . d U o-o o 0 LL [(7?)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 21 0 z .. K N fY ^SN C DO Ί Nx Jk. N O ⁿ O ό n ₃ s [4-(6-Amino-5-methoxy-pyridazin-3 yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 22 _CH3 ? ^H = ft θγ4 ^Ο -χ^χΑ _Ν ^ Τ ] Τ η ι 1 dxdx. ΑχχΝ 1 Jx χ ' ^/ 0 ^/ '-' || 4 ^'Ύ^ΝΗ., (6-Amino-3',4',5',6'-tetrahydro-2'H[3,4']bipyridinyl-G-yl)-[4-methoxy-5(4-methoxy-phenoxy)-pyridine -2-yl]methanone 23 0 Ο ο-ο C ,—г ο-ο )—/ JE \___/ W ζ Μ ¹ (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-1'yl)-(4-methoxy-5-phenoxy-pyridine- 2yl)-methanone 24 F g CH, Ο 00 SH ° ο! Ν ΝΗ ₂ (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-1'yl)-[4-methoxy-5-(4-trifluoromethylphenoxy )-pyridin-2-yl]-methanone 25 Ο ,---, Ν=Ν /~ ⁰ /J 1 1 n ₃ s' [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-(5-cyclobutylmethoxy-4-methoxypyridin-2-yl)-methanone 26 Ο ΥΎξ >νη ₂ ν^/ \__/ НзС/^θΌ ^CH s <7 H ₃ c ^z (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-1'yl)-[4-methoxy-5-(1-methyl - cyclopropylmethoxy)-pyridin-2-yl]methanone

- 27 040737

27 J 0-0 0-0 oF / \....../ t I° “o /=/ o O [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-methoxymethyl-piperazin-1 -yl] (4-methoxy-5-phenoxy-pyridin-2-yl) methanone 28 0 oh oh .0 oh-oh (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-1'yl)-[4-methoxy-5-(4-methoxy -phenoxy)pyride in-2-yl]-methanone 29 o // /k // „o, Г ν r t sn ₃ С to N Г - —' 11 1 h ₂ n ^-^ci-l R/ 2 3 χζ/γ [4-(6-Amino-4-methyl-pyridazin-3-yl)piperidin-1-yl]-[5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone thirty O /---4 /=N m0H_/Hk^ ^Sh! Oz ^sn H ₃ C ^Z (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-cyclohexyloxy-4-methoxypyridin-2-yl) -methanone 31 τ th γ O ) --- to W / \ ₍ o CO / I o [4-(6-Amino-4-methyl-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 32 oh oh <woo -( O b x b And_ (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)- [5-(4-φτop-benzyloκci)-4- methoκsipiride in-2-yl]-methanone

- 28 040737

33 to to u-i ZnF [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4grifluoromethyl-phenoxy)-pyridin-2yl]-methanone 34 O W oh oh oh y--Z 0 Z I [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-chloro-phenoxy)4-methoxy-pyridin-2-yl]-methanone 35 ⁰ /—\ /~ ^N n=k Acc/k™ ² ch kz ° OA ^CHs n ₃ s (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-cyclopentyloxy-4-methoxypyridin-2-yl) -methanone 36 O y--\ Ν=Ν nJ^vJ^Vj^ ² I ^Η ₃ Ο^/~~ ^Ο , ⁰ sn ₃ ^NzS [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-(5-isobutoxy-4methoxy-pyridin-2-yl)-methanone 37 ⁰ /—\ /= ^Ν "ANk ^{1 2} O °' ^CHs Υ ^H s ^C (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-cyclopropylmethoxy-4-methoxypyridin-2-yl) -methanone 38 CHs 0 A. /l-ο. .ζχ Jk ,sn„ π ΥΥιΟ ϊ XX [3-(6-Amino-4-methoxy-pyr idin-3-yl)3,8-diaza-bicyclo[3.2.1]oct-8-yl]-[5-(4fluorophenoxy)-4-methoxypyridine -2yl]-methanone 39 ⁰ / ^— \ /= ^N ν= _ΛΟΛ > ^ΝΗ2 О °x h ₃ ^cY ~ ^O (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-isobutoxy-4-methoxy-pyridin2-yl) -methanone

- 29 040737

40 sn ₃ ίι χθ. Λ. Οχ l. A L. FX π ΐΊ kA Α,ν L Α f _ο 'x/ γ χ _Ν Α _Ν η ₂ [4-(6-Amino-pyridazin-3 -yl)piperidin-1-yl]-[5-(4-cyclopropoxyphenoxy)-4-methoxy-pyridin-2-yl]- methanone 41 Α b LL [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-fluorobenzyloxy)-4-methoxy-pyridin-2-yl]methanone 42 zf Ζ ο°Α Α Yj ο θ υ_ [(7?)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl] [5-(4-fluorophenoxy)-4-methoxypyride in-2-yl] -methanone 43 ΑΧ . ^x Β J to ΑχΧν ΓΑ° τ 1 Α Ο ,ο /-α-νη, H ₃ C ο ΟΗ ₃ (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-benzyloxy-4-methoxy-pyridin2-yl) -methanone 44 0-0 ο' Ο 0-0 y ζ χ [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl]methanone 45 . - 0-0 ί Lu (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)- [5-(3,3-difluorocyclobutylmethoxy)-4- methoxypyride in-2-yl]-methanone 46 ⁰ /—\ Χ ^Ν UCH /4 ^ΝΗ = AA ^NzS n ₃ s (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(4-methoxy-5-propoxy-pyridin-2yl) -methanone

- 30 040737

47 τ' o χ=\ θ O-L /) A < o * ⁴ --< 0-0 [4-(6-Amino-4-methoxy-pyridazin-3yl)-piperidin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl)-methanone 48 i /"L / \u003d \ PrPrP ² U ° CH, p_U' ° o nU (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-1'yl)- [5-(2-cyclopropyl-ethoxy)- 4methoxy-pyridin-2-yl]-methanone 49 A <□ · i ooo 0 LL. [4-(6-Amino-4-methoxy-pyridazin-3yl)-piperidin-1-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 50 BUT. o A OL _o A/ ^ ^N v\ (17?)-1 -[(27?)-4-(6-amino-4methoxypyride in-3 -yl)-1 -(5- phenoxypyridine-2- carbonyl)piperazin-2-yl]ethan- Rol 51 sn ₃ O CHGOA ⁰ 11 Ρ'''ΉΗ ₂ [3-(6-Amino-4-methoxy-pyridin-3-yl)3,8-diaza-bicyclo[3.2.1]oct-8-yl]-(4methoxy-5-phenoxy-pyridin-2-yl ) methanone 52 A XV n3 ^{n vVP NH2} _O (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-1'yl)-(4-methoxy-5-phenethyloxypyridin-2- yl)-methanone

- 31 040737

53 O y - \ y \u003d N »\u003e νΜ / ^ΝΗ · sn ₃ / ^ ° o □ n ₃ s (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-cyclobutylmethoxy-4-methoxypyridin-2-yl) -methanone 54 “POR O 0-0 A - ₂ 0 m ¹ [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-difluoromethoxyphenoxy)-4-methoxy-pyridin-2-yl]methanone 55 X 0 0-0 2—. 0-0 'θ....../ ~ x 0° O /=( °Λ~7 about 0 “P [(A)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-methoxymethyl-piperazin-1 -yl][5-(4-fluorophenoxy)-4-methoxypyride in-2-yl] - methanone 56 F CH ₃ O / K o. TC ,,SN, ^F |P ΟιΛ ? /k'.. 0ΖζΝ 0 0Ч0Х o Ν ΝΗ ₂ [4-(6-Amino-4-methoxy-pyridazin-3yl)-piperidin-1-yl]-[4-methoxy-5-(4grifluoromethyl-phenoxy)-pyridin-2yl]-methanone 57 0 y - y N \u003d N nO ⁿ vOO ^NH2 o / \ H ₃ c ^x [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-(2-fluorobenzyloxy)-4-methoxy-pyridin-2-yl]methanone 58 short circuit % O O (IS)-1 -[(27?)-4-(6-amino-4methoxypyride in-3 -yl)-1 -(5phenoxypyridine-2- carbonyl)piperazin-2-yl]ethan-1-ol

- 32 040737

59 ⁰ /—\ / ^-N W )-\\ P ^NH 2 N,--/ \__/ A# g h /-°% ^CH ' ND-/ U n ₃ s sn ₃ ^NzS (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-[5-(2,2-dimethyl-propoxy)- 4methoxy-pyridin-2-yl]-methanone 60 CH, CH, o 1 ³ 1 ³ II o. O. /- A, /-- VX ΎΥτ С /% to /% /N- -0- % N d^inz ,,Ο n ₃ s' [4-(6-Amino-5-methoxy-pyridazin-3 yl)-piperidin-1-yl]-[4-methoxy-5-(4-methoxy-phenoxy)-pyridin-2-yl] methanone 61 o - Z^ /> - O od ¹ D . % g Y [4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-(5-cyclopropylmethoxy-4-methoxypyridin-2-yl)-methanone 62 CH ₃ O O-oXY ¹ ' Ογ% [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-(5-cyclohexyloxy4-methoxy-pyridin-2-yl)-methanone 63 ΌΗ 0 C XXX CH ₃ ΝΗ ₂ [(5)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl][5-(4-fluorophenoxy)-4-methoxypyride in-2-yl] - methanone 64 ⁰ / \ /^ ^Ν Κν Vg /Ρνη ₂ Ν% \ / 0% g < cn ₃ i\g ^o ο Η ₃ ο' F (6-Amino-4-methoxy-3',4',5',6'tetrahydro-2'H-[3,4']bipyridinyl-Gyl)-[5-(1-fluoromethyl- cyclopropylmethoxy)-4-methoxypyride in-2-yl]-methanone

- 33 040737

65 O /--\ z \u003d N _{n \} u003d\u003e ⁿ v\u003e ^NH2 H ₃ CV / 4 H ₃ C (6-Amino-4-methoxy-3',4',5',6'tetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-ethoxy-4-methoxy-pyridin-2yl) -methanone 66 0-0 U O 0-0 y ,—ζ 0—0 )--/ I G? [4-(6-Amino-4-methoxy-pyridazin-3yl)-piperidin-1-yl]-[4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl]- methanone 67 0 , --- y Ν-Ν Ν0 n ₃ s [4-(6-Amino-pyridazin-3 -yl)piperidin-1-yl]-[5-(2-cyclopropylethoxy)-4-methoxy-pyridin-2-yl]- methanone 68 ρ O 0-0 U r I Ζ ^ω JC [7-(6-Amino-4-methoxy-pyr idin-3-yl)3-oxa-9-aza-bicyclo[3.3.1 ]non-9-yl](4-methoxy-5-phenoxy-pyridine -2-yl) methanone 69 C S-E O ⁴ /=/ I \ ω \-O ° I Ζ 0= [(7?)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1-yl] (4-methoxy-5-phenoxy-pyridin-2-yl) methanone 70 ⁰ / - \ / \u003d ^Ν n ₃ with O H > οΉ _ο -z I ^N 3 ^C (6-Amino-4-methoxy-3',4',5',6'tetrahydro-2'H-[3,4']bipyridinyl-Gyl)-[5-((5)-1-cyclopropyl-ethoxy )-4methoxy-pyridin-2-yl]-methanone

- 34 040737

71 - A H/ oA \ I /=\ O O O [(5)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl] (4-methoxy-5-phenoxy-pyridin-2-yl) methanone 72 O /--y ζ \u003d Ν nAAU ^ΝΗ2 / \ / H ₃ C Ay ° AO ^CH s ^H 3 ^C H, C (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-(5-isopropoxy-4-methoxypyridin-2-yl) -methanone 73 About y - y N \u003d N pPtA ² A / n ₃ s [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenethyloxy-pyride in-2-yl)-methanone 74 O y - y N \u003d N pPLA ² r ⁿ s ^s -A ° '° n Ln ^Nz ° P ₃ O bN ₃ [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-(2,2-dimethylpropoxy)-4-methoxy-pyridin-2-yl]methanone 75 O y--y Ν=N _N p ^N vPPP ^{NH2 N} A~o C></ n ₃ s [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(1-methyl-cyclopropylmethoxy)-pyridin2-yl]-methanone 76 About y - y N \u003d N n / ⁿ P4 / ^NH2 n ₃ c ^ O n ₃ s [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-propoxy-pyridin-2-yl)-methanone 77 ⁰ /—\ /“ AND A ) — C _z Vnh ₂ ΝΑ \_/%' n ₃ with P / °\ <J AP (6-Amino-4-methoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-[5-((7?)-1-cyclopropyl- ethoxy)-4methoxy-pyridin-2-yl]-methanone

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78 sn ₃ 0 Οχ A /X X ? ^Hc Aχ>ν AAA \ V ° g 1 V Nx X Ν NH ₂ [4-(6-Amino-4-methyl-pyridazin-3-yl)piperidin-1-yl]-(5cyclopropylmethoxy-4-methoxypyridin-2-yl)-methanone 79 O /--y N \u003d N n ₃ s A ⁰ O A A [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-((A)-1 cyclopropyl-ethoxy)-4-methoxypyride in-2-yl]-methanone 80 X ⁴ Z ζ - with about 0-0 Q About LL [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5-(4grifluoromethoxy-phenoxy)-pyridin-2yl]-methanone 81 0-0 ok [(7?)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-(4methoxy-5-phenoxy-pyridin-2-yl) methanone 82 oh-oh 0 O 0-0 With U--2 Z^O To ' Z NF [(7?)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1 -yl]- [4methoxy-5 -(4-methox and-phenoxy)pyridin-2-yl] - methanone 83 0 o o , X >—Z y/ Z.L- [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-(phenoxy)-4ethoxy-pyride in-2-yl]-methanone 84 D' o-o o -b (6-Amino-4-cyclopropoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-Gyl)-[5-(phenox and)-4-methoxypyr id in-2yl]-methanone

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85 mid ₃ 0 sco TlG ^Nx n^nh ₂ [4-(6-Amino-4-ethoxy-pyridazin-3-yl)piperidin-1-yl]-[4-methoxy-5(phenoxy)-pyridin-2-yl]-methanone 86 9 ^N s o Q XTO V ⁰ Ν NH ₂ (6-Amino-4-propoxy-3',4',5',6'hetrahydro-2'Н-[3,4']bipyridinyl-1'yl)-[5-(phenox and)-4-methoxy -pyr id in-2yl]-methanone 87 X O 0-0 C t z o oF 5-Ethoxy-6-(1-{4-methoxy-5-[4(trifluoromethyl)phenoxy]pyridine-2carbonyl}piperidin-4-yl)pyridazine3-amine 88 / X ⁴ -o OR [4-(6-Amino-pyridazin-3-yl)piperidin-1-yl]-[5-(4-fluorophenoxy)-4ethoxypyridin-2-yl]-methanone 89 X Oh Oh Oh and_ [3-(6-Amino-pyridazin-3-yl)-8-azabicyclo[3.2.1 ]oct-8-yl]-[4-ethoxy-5-(4fluorophenoxy)-pyridin-2-yl]-methanone 90 k O 0-0 k / - ² b \ - y / Z 6-(1-{4-Methoxy-5-[4- (trifluoromethyl)phenoxy]pyridine-2carbonyl}piperidin-4-yl)-5- methyl pyride azine-3-amine 91 m ⁴ Z and / - X to LL LL 5 -Methox and-6-( 1 - {5-[4-(trifluoromethyl)phenoxy] -pyridine-2- carbonyl}piperidin-4-yl)-pyridazine3-amine

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- (1 - { 5 - [(2,2-Difluorocyclobutyl) methoxy] -4-methoxy-pyridine-2carbonyl } -piperide in-4-yl) -4 methoxypyridin-2-amine

4-Methox and-5 - [ 1 - (4-methoxy-5 - {[trans-3 (trifluoromethyl) cyclobutyl] -methoxy} pyridine-2-carbonyl)-piperidine-4yl] pyridine-2-amine

4-Methox and-5 - [ 1 - (4-methoxy-5 - {[(cis-3 (trifluoromethyl) -cyclobutyl] methoxy} pyridine-2-carbonyl) piperidine-4yl] pyridine-2-amine

4-Methox u-5 -(1 - {4-methox u-5 - [(2)-3,3,3trifluoro-2-methylpropoxy]-pyridine-2carbonyl}piperidin-4-yl)pyridine-2amine

In one embodiment, the invention relates to any of the compounds 1-95 presented in table. 1 above, and their pharmaceutically acceptable salts.

In another embodiment, the invention relates to any of the compounds 6, 16, 17, 33, 34, 40, 41, 44, 54, 57, 80, 83 and 88, presented in table. 1; and their pharmaceutically acceptable salts.

In another embodiment, the invention relates to any of the compounds 29, 31, 49, 56, 66, 85, 87 and 90 presented in table. 1; and their pharmaceutically acceptable salts.

General definitions.

Terms that are not specifically defined in this application should have the meanings that would be given to them by those skilled in the art in light of the present disclosure and context. In the context of the present description, however, unless otherwise specified, the following terms have the indicated meaning, and the following conventions apply to them.

In the groups, radicals or fragments defined below, the number of carbon atoms is often indicated before the group, for example C1. ₆ alkyl means an alkyl group or radical containing 1-6 carbon atoms. As a rule, in groups such as HO, H2N, (O)S, (O) ₂ S, NC (cyano), HOOC, F ₃ C or the like, the specialist can see the point (s) of attachment of the radical to the molecule from the free valences of this group itself. With respect to combined groups comprising two or more subgroups, the last subgroup named is the point of attachment of a radical, for example an aryl-C1 substituent. ₃ alkyl means an aryl group that is linked to C ₁ . ₃ alkyl group, the last of which is linked to the core or to the group to which this substituent is attached.

When a compound of the present invention is presented as a chemical name and as a formula, in case of any inconsistency, the formula takes precedence.

An asterisk can be used in subformulas to indicate a bond that is attached to the nucleus of a molecule, as defined

The term "substituted" in the context of this application means that any one or more hydrogen atoms on the specified atom is replaced by a choice from the specified group, provided that the normal valency of the specified atom is not exceeded and that the substitution results in a stable compound.

Unless otherwise stated, in all sections of the specification and in the appended claims, a given chemical formula or name shall cover tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and their racemates. , as well as mixtures in various proportions of individual enantiomers, mixtures of diastereomers, or mixtures of any of the above forms, where such isomers and enantiomers exist, as well as salts, including their pharmaceutically acceptable salts, and their solvates, such as, for example, hydrates, including solvates of free - 38 040737 compounds or solvates of the salt of the compound.

Enantiomerically pure compounds of the present invention or intermediates can be obtained by asymmetric synthesis, for example by preparing and then separating suitable diastereomeric compounds or intermediates, which can be separated by known methods (for example, chromatographic separation or crystallization) and/or using chiral reagents such as chiral starting materials, chiral catalysts, or chiral auxiliaries.

In addition, those skilled in the art are aware of how enantiomerically pure compounds can be obtained from appropriate racemic mixtures, for example by chromatographic separation of the appropriate racemic mixtures on chiral stationary phases; or by separating the racemic mixture using a suitable resolving agent, for example by forming a diastereomeric salt of the racemic compound with optically active acids or bases, followed by separating the salts and isolating the desired compound from the salt; or by derivatization of the corresponding racemic compounds using optically active chiral auxiliary reagents, followed by separation of the diastereomers and removal of the chiral auxiliary group; or by kinetic resolution of the racemate (eg enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphic crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

The phrase pharmaceutically acceptable is used in this application to refer to those compounds, substances, compositions and/or dosage forms which, within the framework of a considered medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problems or complications. commensurate with a reasonable benefit/risk ratio. In the context of the present application, the term pharmaceutically acceptable salt refers to derivatives of the disclosed compounds, where the parent compound is modified by the formation of its acid or alkali salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of alkali residues such as amines formed with mineral or organic acids; alkali or organic salts of acid residues such as carboxylic acids; and so on.

For example, such salts include salts of benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4- methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, tartaric acid, and trifluoroacetic acid.

Other pharmaceutically acceptable salts may be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, K-methyl-O-glucamine, potassium, sodium, and tris(hydroxymethyl)aminomethane.

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains an alkaline or acidic group by conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof.

Salts of acids other than those mentioned above which are, for example, useful for purifying or isolating the compounds of the present invention (eg trifluoroacetate salts, formates) also form part of the invention. The term halogen generally means fluorine, chlorine, bromine and iodine.

The term _{C1_p} alkyl, 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, means an acyclic saturated branched or linear hydrocarbon radical with 1-p number of C atoms. For example, the term C1_ ₅ alkyl covers the radicals H ₃ C-, H ₃ C-CH ₂ -, H ₃ C-CH ₂ -CH ₂ -, H ₃ C-CH (CH ₃ )-, H ₃ C-CH ₂ -CH ₂ -CH ₂ -, H3C-CH2-SNCHCH3) -, H3C-CH (CH3) -CH2-, SC-C (CH3) 2-, H3C-CH2-CH2-CH2-CH2-, H3CCH2-CH2-CH ( CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2CH2-, H3C- CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

The term C ₃ _ _p cycloalkyl, where n is an integer from 4 to n, either alone or in combination with another radical, means a cyclic saturated straight hydrocarbon radical with 3 to n C atoms. For example, the term C ₃ _ ₇ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term halogen added to an alkyl, alkylene or cycloalkyl group (whether saturated or unsaturated) means that alkyl or cycloalkyl group wherein one or more hydrogen atoms has been replaced by a halogen atom selected from fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H2FC-, HF2C-,

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F3C-. Similarly, the term halogen added to an aryl group (eg phenyl) means that one or more hydrogen atoms have been replaced by a halogen atom selected from fluorine, chlorine or bromine, preferably fluorine and chlorine, fluorine being particularly preferred.

The term carbocyclyl, used either alone or in combination with another radical, means a mono-bi- or tricyclic ring structure consisting of 3-9 carbon atoms and optionally a heteroatom selected from the group consisting of N, O and S. The term carbocyclyl refers to to fully saturated ring systems and encompasses fused, bridged, and spirocyclic systems.

Many of the terms above can 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.

This application provides compounds that can modulate TRPC6 function. Methods for using these compounds are also provided. Some embodiments provide a method for modulating TRPC6 function in a cell or animal, comprising administering an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits TRPC6-mediated ion flux. Some embodiments provide a method for modulating TRPC6 function in a cell or animal, comprising administering an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits TRPC6-mediated calcium influx. Some embodiments provide a method for modulating TRPC6 function in a cell or animal, comprising administering an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits TRPC6-mediated cytoskeletal reorganization or alteration in cell morphology. Some embodiments provide a method for modulating TRPC6 function in a cell, comprising administering to the cell an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits TRPC6 mediated outward current. Some embodiments provide a method for modulating TRPC6 function in a cell, comprising administering to the cell an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits TRPC6 mediated inward current. Some embodiments provide a method for modulating TRPC6 function in a cell, comprising administering to the cell an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits both inward and outward currents mediated by TRPC6. Some embodiments provide a method for modulating TRPC6 function in a cell, comprising administering to the cell an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits TRPC6-mediated increases in intracellular calcium concentration. Some embodiments provide a method for modulating TRPC6 function in a cell, comprising administering to the cell an effective amount of a compound that inhibits TRPC6 function, wherein the compound inhibits changes in cell morphology. Some embodiments also provide a method for preventing or treating a disease or condition associated with 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 TRPC6 mediated inward current. Some embodiments provide a method for preventing or treating a disease or condition associated with 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 TRPC6 mediated outward current. Some embodiments also provide a method of preventing or treating a disease or condition associated with 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 both inward and outward current mediated by TRPC6. Some embodiments provide a method for preventing or treating a disease or condition associated with 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 TRPC6 mediated ion flux. It should be noted that inhibition of a particular current refers to the ability of a compound to inhibit that current (eg, in and/or out) in an in vitro or in vivo assay. The inhibition of a particular current in an in vivo or in vitro assay serves as a proxy for the particular functional activity of a particular compound.

The present invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder that can be ameliorated by inhibition of a transient C6 receptor potential (TRPC6) ion channel, wherein the disease or disorder is selected from the group consisting of cardiac hypertrophy, ischemia, ischemic reperfusion injury, hypertension, restenosis, chronic obstructive pulmonary disease, cystic fibrosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), trauma-induced brain damage, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory disease bowel disease, multiple sclerosis, muscular dystrophy, preeclampsia, non-alcoholic steatohepatitis, lipoid nephrosis, focal segmental glomerulosclerosis (FSGS), nephrotic syndrome, diabetic nephropathy, or diabetic th kidney disease (DKD), chronic kidney disease, kidney failure, ischemia or ischemic reperfusion injury, cancer, IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratory distress syndrome), emphysema, and diabetes.

Unless otherwise indicated, throughout the specification and the appended claims, a given chemical formula or name shall cover tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and their racemates. , as well as mixtures in various proportions of individual enantiomers, a mixture of diastereomers, or a mixture of any of the above forms, where such isomers and enantiomers exist, as well as salts, including their pharmaceutically acceptable salts, and their solvates, such as, for example, hydrates, including solvates of free compounds or solvates of the salt of the compound.

Some of the compounds in Table. 1 may exist in more than one tautomeric form. The invention includes methods for using all such tautomers.

In the context of this application, the term pharmaceutically acceptable salts refers to derivatives of the disclosed compounds, where the parent compound is modified by the formation of its acid or alkali salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of alkali residues such as amines formed with mineral or organic acids; alkali or organic salts of acid residues such as carboxylic acids; and so on. For example, such salts include acetates, ascorbates, benzenesulfonates, benzoates, besilates, bicarbonates, bitartrates, bromides/hydrobromides, edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates, esylates, formates, fumarates, gluceptates, gluconates. , glutamates, glycolates, glycolylarsenylates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucinates, nitrates, oxalates, pamoates, pantothenates, phenylacetates /diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, theoclates, toluenesulfonates, triethiodides, trifluoroacetates, ammonium salts, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Other pharmaceutically acceptable salts may be formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. (See also Pharmaceutical salts, Birge S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains an alkaline or acidic group by conventional chemical methods. Typically, such salts can be prepared by reacting these compounds in the free acid or base form with a sufficient amount of the corresponding base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which are, for example, useful for purifying or isolating the compounds of the present invention (eg trifluoroacetate salts) also form part of the invention.

Also within the scope of the invention is the use of prodrugs of the compounds of the invention. Prodrugs include those compounds which, by simple chemical transformation, are modified to form the compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. In particular, when a prodrug is administered to a patient, the prodrug can be converted to the compound disclosed above, thus conferring the desired pharmacological effect.

The compounds of the invention also include their isotopically labeled forms. The isotopically labeled form of the active substance of the combination of the present invention is identical to said active substance, except that one or more atoms of said active substance are replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom, which commonly found in nature. Examples of isotopes that are readily available commercially and which can be incorporated into the active substance of the combination of the present invention according to well known procedures include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively.

The active substance of the combination of the present invention, its prodrug or a pharmaceutically acceptable salt of such a compound which contains one or more of the above isotopes and/or other isotopes of other atoms is intended to be within the scope of the present invention.

The compounds of the invention are only those compounds which are considered to be chemically stable, as will be appreciated by those skilled in the art. For example, a compound that may have a free valence or a carbanion are not compounds contemplated by the methods of the invention disclosed in this application.

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For all compounds described above in this application, in case the nomenclature is in conflict with the structure, it should be understood that the connection is determined by the structure.

List of abbreviations

AA Acetic acid ACN/MeCN Acetonitrile aq. Water VEN Ethylene bridged hybrid particle column WOS tert-butyloxycarbonyl °C Degrees Celsius CDI Di(imidazol-1 -yl) methanone CPhos-3G- Methanesulfonato(2-dicyclohexylphosphino-2',6'- palladacycle bis(dimethylamino)-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2 - methanesulfonate yl)palladium(P) DCM dichloromethane DTPEA N, Y-diisopropylethylamine DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DMSO Dimethyl sulfoxide DTAD Di-ot/?eo-butylazodicarboxylate HER diethyl ether equiv. Equivalent ESI-MC Mass spectrometry with electrospray ionization EtOH ethanol EtOAc/EE ethyl acetate h Hour n ₂ Hydrogen

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H ₃ RO ₄ Phosphoric acid HATU N, X, X', X'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HC1 Hydrochloric acid HPLC High Performance Liquid Chromatography Meon methanol min Minute Me! Swept ml Milliliter MS mass spectrum NaH sodium hydride NaOH Sodium hydroxide NMP X-methyl-2-pyrrolidinone Pd ₂ (dba) ₃ Pd/C Tris(dibeysilideneacetone)dipalladium(0) Palladium on carbon PdCl ₂ (dppf) CH ₂ Cl ₂ [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane Pd(OH) _2PE Palladium hydroxide Petroleum ether RP reversed phase rt or RT Room temperature (about 25°C) SFH Supercritical Fluid Chromatography TBTU Benzotriazolyl tetramethyluronium tetrafluoroborate TFA Trifluoroacetic acid THF Tetrahydrofuran those Thin layer chromatography on SiO ₂ Xantphos Xphos ^2'r0 generation 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(II) TPP Triphenylphosphine

General Methods: Unless otherwise noted, all reactions are carried out at room temperature (about 25°C), under an inert atmosphere (eg Argon, N2) and under anhydrous conditions. All compounds were characterized by at least one of the following methods: 1 H NMR, HPLC, MS, HPLC-MS, or melting point.

Typically, the progress of the reaction is monitored by thin layer chromatography (TLC) or HPLC-MS. Intermediates and products are purified using at least one of the following methods: silica gel flash chromatography, recrystallization, supercritical fluid (SCF), chiral HPLC using a RegisPack 3.0 x 25.0 cm column, elution using isocratic MeOH, isopropylamine ( IPA) and supercritical carbon dioxide at 125 bar; 80 ml/min, and/or reverse-phase HPLC using a C18 semi-preparative column, elution with a gradient:

MeCN + 0.1% TFA and H ₂ O + 0.1% TFA,

MeCN + 0.1% formic acid and H ₂ O + 0.1% formic acid, or

MeCN and H ₂ O containing 2.5 mM NH4HCO3

MeCN and H2O + 0.1% TFA,

MeCN and H2O + 0.1% NH3,

MeCN and H ₂ O and 0.1% TFA,

MeCN and H ₂ O and 0.1% NH ₃

Analytical data.

Mass spectrometric analysis (MS) data are presented for the observed mass (eg, [M+H] ⁺ ). The HPLC method used to characterize the compounds of the invention is described in Table 1. 2.

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Table 2. HPLC Methods

Method Mobile phase A Mobile phase B Gradient Flow (ml/min.) Column A 0.1% formic acid in water 0.1% formic acids in MeCN Time (min) %A %IN 0.8 VEN 2.5 * 50mm C18, particle diameter 1.7 microns 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 in the remaining tables in this section for ESI-MC data and retention times.

If another HPLC-MS method is used, this is indicated in the text.

Method 1

ESI+/- ionization mode. Column: CSH C18 2.1x50 mm, particle diameter 1.7 µm. Gradient: 90%A to 100%B in 1.19 min, hold at 100%B to 1.70 min. Flow rate 0.8 ml/min. A=(95% water+5% acetonitrile+0.05% formic acid) B=(acetonitrile+0.05% formic acid).

Method 2

ESI+/- ionization mode. Column: BEN 2.1x50 mm C18, particle diameter 1.7 µm. Gradient: 90%A to 100%B in 4.45 min hold at 100%B to 4.58 min. Flow rate 0.8 ml/min. A=(95% water+5% acetonitrile+2.5mM ammonium bicarbonate) B=(acetonitrile).

Method 3

ESI+/- ionization mode. Column: BEN 2.1x50 mm C18, particle diameter 1.7 µm. Gradient: 90%A to 95%B over 1.19 min hold at 95%B to 1.70 min. Flow rate 0.8 ml/min. A=(95% water+5% acetonitrile+2.5 mM ammonium bicarbonate) B=(acetonitrile).

Method 4

ESI+/- ionization mode. Column HSS T3 2.1 x 100 mm, particle diameter 1.8 µm. Gradient: 100%A hold for 1.00 min, 100%A to 95%B for 4.50 min hold at 100%B to 4.91 min. Flow rate 0.6 ml/min. A=(95% water+5% acetonitrile+0.05% formic acid) B=(acetonitrile+0.05% formic acid).

Method 5

ESI+/- ionization mode. Column: CSH C18 2D x 50 mm, particle diameter 1.7 µm. Gradient: 90%A to 100%B in 4.45 min hold at 100%B to 4.58 min. Flow rate 0.8ml/min. A=(95% water+5% acetonitrile+0.05% formic acid) B=(acetonitrile+0.05% formic acid).

Method 6

ESI+/- ionization mode. Column: HSS T3 2.1 x 100 mm, particle diameter 1.8 µm. Gradient: 95%A to 100%B over 3.65 min hold at 100%B to 4.95 min. 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 (ml/min.) Column 0.1% TFA in water ACN Time (min) %A %IN sun fire С18_3.0*30 mm, particle diameter 2.5 µm, 0 97.0 h, o 2.2 0.2 97.0 h, o 2.2 1.2 oh oh 100.0 2.2 1.25 oh oh 100.0 h, o 1.4 oh oh 100.0 3.0

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Method 8 (column temperature 40°C)

Mobile phase A Mobile phase B Gradient Flow (ml/min.) Column Supercritical carbon dioxide EtOH 20 mM NH ₃ Time (min) %A %IN 4.0 CHIRALART® Cellulose SC_4.6χ250 mm, particle diameter 5 µm 0 60 40 10 60 40

Method 9

Mobile phase A Mobile phase B Gradient Flow (ml/min.) Column 0.1% TFA in water ACN 0.08% TFA Time (min) %A %IN 1.5 sun fire C18_3.0x30 mm, particle diameter 2.5 µm 0 95.0 5.0 1.3 0.0 100.0 1.5 oh oh 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 0.1% TFA in water ACN Time (min) %A %IN Zorbax Stable Bond C18_3.0x30 mm, particle diameter 1.8 µm 0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 oh oh 100.0 2.2 1.25 oh oh 100.0 h, o 1.4 oh oh 100.0 3.0

Method 11

Mobile phase A Mobile phase B Gradient Flow (ml/min) Column wow 0.1% NH ₃ in ACN Time %A %IN XB ridge 60°C water (min) C18_3.0x30 mm, particle diameter 2.5 µm 0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 oh oh 100.0 2.2 1.25 oh oh 100.0 h, o 1.4 oh oh 100.0 3.0

- 45 040737

Method 12

Mobile phase A Mobile phase B Gradient Flow (ml/min) Column wow 0.1% TFA in water ACN Time (min) %A %IN sun fire С18_2ДхЗО mm, particle diameter 2.5 micron 60°С 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 oh oh 100.0 1.5

Method 13

Mobile phase A Mobile phase B Gradient Flow (ml/min) Column T° 0.1% NH ₃ in water ACN Time (min) %A %IN XBridge C18_3.0x30 mm, particle diameter 2.5 µm 60°С 0 95.0 5.0 1.5 1.3 oh oh 100.0 1.5 1.5 oh oh 100.0 1.5 1.6 95 5.0 1.5

Method 14

Mobile phase A Mobile phase B Gradient Flow (ml/min) Column wow 0.5% H ₃ RO ₄ in water 0.5% H3PO4 in ACN Time (min) %A %IN Halo C18 4.6 mm x 15 cm, particle diameter 2.7 µm 15°С 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

Synthesis examples

The following examples are illustrative and, as will be appreciated by those skilled in the art, specific reagents or conditions can be changed as needed for individual compounds without undue experimentation.

Compounds of the invention can be prepared using the general methods and examples below and methods known to those skilled in the art. Optimum reaction conditions and reaction times may vary depending on the particular reagents used. Unless otherwise indicated, solvents, temperatures, pressures, and other reaction conditions can be easily selected by one skilled in the art. Specific procedures are presented in the Synthesis Examples section. The intermediates used in the synthetic methods below are either commercially available or can be readily prepared by methods known to those skilled in the art. The progress of the reaction can be monitored by conventional methods such as thin layer chromatography (TLC) or high performance liquid chromatography with 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.

Compounds of the invention are generally prepared by reacting a carboxylic acid intermediate of formula INT-1 with an amine intermediate of formula INT-2 under appropriate conditions as shown in Scheme 1 below.

- 46 040737

Scheme 1

Intermediates INT-1 and INT-2 are known in the art or can be obtained by the methods described below. The groups/terms R1-R ⁷ , A, Y and L have the same meaning as defined above for the compound of formula (I).

Synthesis of intermediates

To piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.37 mmol) and 5-bromo-2-(2,5dimethylpyrrol-1-yl)-4-methoxypyridine (1.5 g, 5.37 mmol) 37 mmol) in 1,4-dioxane (15 mL) add CPhosG3-palladacyl methanesulfonate and sodium tert-butoxide (216 mg, 16.1 mmol) and degas with nitrogen for 5 min. The resulting mixture was stirred at 100°C for 10 hours. The reaction mixture is filtered through a pad of silica eluting with EtOAc and concentrated. The crude product was purified by silica gel column chromatography to give the title compound.

Yield: 2.1 g (88%) R _t (HPLC): 1.15 min (Method 1) 4-(6-Amino-4-methoxypyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

To 4-[6-(2,5-Dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 4.73 mmol) in EtOH (10 ml ) and water (5 ml) are added hydroxylamine hydrochloride (1.64 g, 23.6 mmol) and trimethylamine (659 μl, 4.73 mmol) and stirred at 80° C. for 18 hours. The reaction mixture is concentrated under reduced pressure. The residue is suspended in DCM and filtered to remove salts. The filtrate was purified by silica gel column chromatography to give the title compound.

Yield: 1.07 g (73%).

4-Methoxy-5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride

- 47 040737

To 4-(6-amino-4-methoxypyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (1.07 g, 3.47 mmol) in DCM (12 mL) was added 4 M HCl in 1.4 -dioxane (4.34 ml, 17.35 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure.

Yield: 976 mg (quantitative).

6-Amino-4-methyl-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester

To 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-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, a solution of 2M Na ₂ CO ₃ (4.01 ml, 8.02 mmol) and PdCl ₂ (dppf) (328 mg, 0.40 mmol). The reaction mixture was degassed with nitrogen for 5 minutes and stirred in a microwave oven at 150° C. for 30 minutes. The reaction mixture is diluted with EtOAc and water and the layers are separated. The aqueous layer is extracted again with EtOAc. The combined organic layers are washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound.

Yield: 1.1 g (95%) ESI-MS: m/z=290 (M+H) ⁺ Rt (HPLC): 1.82 min (Method 2).

6-Amino-4-methyl-3',4',5',6'-tetrahydro-2H-[3,4']bipyridinyl-G-carboxylic acid tert-butyl ester

To 6-amino-4-methyl-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (1.10 g, 3.80 mmol) in MeOH (10 ml) was added with Pd/C (405 mg, 0.38 mmol) under nitrogen. The reaction mixture is degassed and exposed to H ₂ (balloon). The reaction mixture is filtered and concentrated under reduced pressure. The crude product was 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-Methyl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamine dihydrochloride

The title compound was synthesized from 6-amino-4-methyl3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (511 mg , 1.75 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1-yl-pyridin2-ylamine dihydrochloride.

Yield: 347 mg (75%) ESI-MS: m/z=192 (M+H) ⁺ Rt (HPLC): 0.36 min (Method 2).

6-Amino-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester

- 48 040737

To 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.70 g, 5.50 mmol) and 5-bromopyridin-2-ylamine (1.00 mg, 5.78 mmol) in 1,4dioxane are added a solution of 2M Na ₂ CO ₃ (2 ml, 4.00 mmol) and PdCl ₂ ( dppf)CH ₂ Cl ₂ (449 mg, 0.55 mmol). The reaction mixture is degassed with nitrogen for 5 minutes and stirred at 120° C. for 16 hours. All volatiles are evaporated under reduced pressure. The crude material is purified by normal phase chromatography to give the title compound.

Yield: 1.2 g (79%).

6-Amino-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester

To 6-amino-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (45.0 g, 163.4 mmol) in EtOH (1000 ml ) add Pd(OH) ₂ on carbon (4.5 g, 32.4 mmol) under nitrogen atmosphere. ^{The reaction mixture was stirred at 30 psi (2.109 kg/cm 2 )} in a Parr shaker for 16 hours. The reaction mixture is filtered through Celite®. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound.

Yield: 23.7 g (79%).

1',2',3',4',5',6'-Hexahydro-[3,4']bipyridinyl-6-ylamine dihydrochloride

The title compound was synthesized from 6-amino-3',4',5',6'tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (800 mg, 2. 88 mmol) according to the procedure described for the synthesis of intermediate 4-methoxy-5-piperazin-1-yl-pyridin-2 ylamine dihydrochloride.

Yield: 694 mg (96%).

6-Amino-4-methoxy-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester

To 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (10.0 g, 49.3 mmol) and 5-bromo-4-methoxypyridin-2-ylamine (15.2 g, 49.3 mmol) in 1,4-dioxane (100 ml) was added a solution of 2M Na ₂ CO ₃ (2 ml , 148 mmol) and PdCl ₂ (dppf)CH ₂ Cl ₂ (3.93 g, 4.93 mmol). The reaction mixture is degassed with nitrogen for 5 minutes and stirred at 120° C. for 16 hours. All volatiles are evaporated under reduced pressure. The residue was diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material is purified by normal phase chromatography to give the title compound.

- 49 040737

Yield: 2.50 g (55%).

6-Amino-4-methoxy-3',4',5',6'-tetrahydro-2H-[3,4']bipyridinyl-G-carboxylic acid tert-butyl ester

The title compound was synthesized from 6-amino-4-methoxy-3',6'dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (750 mg, 2.46 mmol ) according to the procedure described for the synthesis of the tert-butyl ester intermediate 6-amino-4-methyl3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'- carboxylic acid.

Yield: 715 mg (95%) ESI-MS: m/z=308 (M+H) ⁺ R _t (HPLC): 0.88 min (Method 5).

4-Methoxy-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamine dihydrochloride

The title compound was synthesized from 6-amino-4-methoxy3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester (715 mg , 2.33 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1-yl-pyridin2-ylamine dihydrochloride.

Yield: 745 mg (quantitative) ESI-MS: m/z=208 (M+H) + R _t (HPLC): 0.56 min (Method 6).

4-(6-Aminopyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

The title compound is synthesized from 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (977 mg, 3.16 mmol) and 6-chloro-pyridazin-3-ylamine (500 mg, 2.87 mmol) according to the procedure described for the synthesis of the tert-butyl ester intermediate 6-amino-4-methoxy-3' ,6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid.

Yield: 590 mg (74.3%) ESI-MS: m/z=276 (M+H) + R _t (HPLC): 0.44 min (Method 1).

4-(6-Aminopyridazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized from 4-(6-aminopyridazin-3yl)-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 6-amino-4-methyl-3',4',5',6'tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ester intermediate.

Yield: 3.93 g (72%) ESI-MS: m/z=279 (M+H)+K, (HPLC): 0.38 min (Method 1).

6-Piperidin-4-yl-pyridazin-3-ylamine dihydrochloride

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The title compound was synthesized from 4-(6-aminopyridazin-3yl)-piperidine-1-carboxylic acid tert-butyl ester (3.60 g, 12.9 mmol) according to the procedure described for the synthesis of intermediate 4-methoxy- 5-piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 2.30 g (quantitative) ESI-MS: m/z=179 (M+H) + R _t (HPLC): 0.32 min (Method 1).

(R)-2-(tert-Butyldimethylsilanyloxymethyl)piperazine-1-carboxylic acid tert-Butyl ester

To (R)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (1.00 g, 4.62 mmol) in DMA (10 ml) was added tert-butylchlorodimethylsilane (1.05 g, 6.94 mmol) and imidazole (944 mg, 13.9 mmol) and the reaction mixture was stirred for 14 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Yield: 1.45 g (95%).

5-Bromo-2-(2,5-dimethylpyrrol-1-yl)-4-methylpyridine

Vg

Para -toluenesulfonic acid (61.0 mg, 0.32 mmol) and the reaction mixture was stirred for 18 hours at 140°C. The reaction mixture was poured into water and diluted in EtOAc. The separated organic layer was washed with brine and dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Yield: 2.68 g (95%).

(R)-2-(tert-Butyldimethylsilaneuloxymethyl)-4-[6-(2,5-dimethylpyrrol-1-yl)4-methylpyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester

To 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-4-methylpyridine (1.00 g, 3.77 mmol) and tert-butyl ether (R)-2-(tert-butyldimethylsilanyloxymethyl)piperαzine -1-carboxylic acid (1.25 g, 3.77 mmol) in 1,4-dioxane (13 mL) sodium tert-butoxide (1.09 g, 11.3 mmol) and GPhos-G3-palladacyl 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 plug of silica gel and eluted with EtOAc The filtrate is concentrated under reduced pressure to give the title compound.

Yield: 1.67 g (86%) ESI-MS: m/z=515 (M+H) ⁺ R _t (HPLC): 1.56 min (Method 1).

- 51 040737 (R)-4-(6-amino-4-methylpyridin-3-yl)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester

(R)-2-(tert-Butyldimethylsilanyloxymethyl)-4-[6-(2,5-dimethylpyrrol-1-yl)-4-methylpyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester mixture (1 .67 g, 3.24 mmol), hydroxylamine hydrochloride (1.13 g, 16.2 mmol) and trimethylamine (452 μl, 3.24 mmol) in ethanol (10 ml) and water (5 ml) were stirred for 18 h at 80°C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography to give the title compound.

Yield: 1.67 g (86%) R _t (HPLC): 0.66 min (Method 3).

[(R)-4-(6-Amino-4-methylpyridin-3-yl)piperazin-2-yl]methanol dihydrochloride

The title compound was synthesized from (R)-4-(6-Amino-4methylpyridin-3-yl)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (450 mg, 1.40 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1-ylpyridin-2-ylamine dihydrochloride.

Yield: 412 mg (quantitative).

-Bromo-2-(2,5-dimethylpyrrol-1 -yl)-4-methoxypyridine

The title compound was synthesized from 5-bromo-4-methoxypyridin-2-ylamine (2.00 g, 9.85 mmol) according to the procedure described for the synthesis of intermediate 5-bromo-2(2,5-dimethylpyrrole- 1-yl)-4-methylpyridine.

Yield: 2.48 g, (90%) ESI-MS: m/z=283 (M+H) ⁺ R _t (HPLC): 2.13 min (Method 5).

7-[6-(2,5-Dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl]-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester

To 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-4-methoxypyridine (1.25 g, 4.45 mmol) and 4,7-diazaspiro[2.5]octane-4- tert-butyl ester carboxylic acid (1.13 g, 5.34 mmol) in 1,4-dioxane (13 ml) add CS ₂ CO ₃ (4.35 g, 13.3 mmol) and CPhos-G3-palladacyl methanesulfonate (359 mg, 0.45 mmol The mixture is degassed with nitrogen for 5 min and stirred for 18 h at 100° C. The reaction mixture is extracted with EtOAc, washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure The residue was purified by silica gel column chromatography to give the title compound.

Yield: 1.51 g (82%) ESI-MS: m/z=413 (M+H) ⁺ R _t (HPLC): 2.69 min (Method 5).

7-(6-Amino-4-methoxypyridin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester

The title compound was synthesized from 7-[6-(2,5-dimethylpyrrol1-yl)-4-methoxypyridin-3-yl]-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (1 .51 g, 3.66 mmol) according to the procedure described for the synthesis of the tert-butyl ester intermediate (R)-4-(6-amino-4-methylpyridin-3-yl)-2-hydroxymethylpiperazine-1-carboxylic acids.

Yield: 1.07 g (87%) ESI-MS: m/z=335 (M+H)^(HPLC): 0.74 min (Method 5).

-(4,7-Diazaspiro[2.5]oct-7-yl)-4-methoxypyridin-2-ylamine dihydrochloride

The title compound was synthesized from 7-(6-amino-4-methoxypyridin-3-yl)-4,7-diazaspiro[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 4-methoxy-5-piperazin-1-yl-pyridin2-ylamine dihydrochloride intermediate.

Yield: 1.10 g (quantitative) ESI-MS: m/z=235 (M+H) + R _t (HPLC): 0.17 min (Method 5).

4-(6-Amino-5-methoxypyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

The title compound is synthesized from 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.74 g, 5.64 mmol) and 6-chloro4-methoxypyridazin-3-ylamine (900 mg, 5.64 mmol) according to the procedure described for the synthesis of 6-amino-4-tert-butyl ester intermediate. methoxy-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid.

Yield: 787 mg (46%) ESI-MS: m/z=307 (M+H) + R _t (HPLC): 0.59 min (Method 5).

4-(6-Amino-5-methoxypyridazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

4-(6-amino-5-methoxypyridazin-3-yl)-3,6-dihydro-2H-pyridine-1 ester K tert-butyl carboxylic acid (785 mg, 2.56 mmol) in MeOH (10 ml) and acetic acid (1 ml) was added with Pd/C (273 mg, 0.26 mmol) under nitrogen. The reaction mixture is degassed and exposed to H ₂ (balloon). The reaction mixture is filtered and concentrated under reduced pressure. crude pro

- 53 040737 The product was purified by silica gel column chromatography to give the title compound.

Yield: 513 mg (65%) ESI-MS: m/z=309 (M+H) ⁺ R _t (HPLC): 0.54 min (Method 5).

4-Methoxy-6-piperidin-4-yl-pyridazin-3-ylamine dihydrochloride

The title compound was synthesized from 4-(6-amino-5-methoxy-pyridazin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (510 mg, 1.65 mmol) according to the procedure described for the synthesis of Intermediate 4- methoxy-5-piperazin-1-yl-pyridin-2 ylamine dihydrochloride.

Yield: 514 mg (quantitative) ESI-MS: m/z=209 (M+H) ⁺ R _t (HPLC): 0.14 min (Method 5).

tert-Butyl 4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

The title compound was synthesized from tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4 .76 g, 20 mmol) and tert-butyl Ν-(6-χλορ-5methoxypyridazin-3-yl)carbamate (4.00 g, 20 mmol) according to the procedure described for the synthesis of the tert-butyl ester intermediate 6- amino-4-methoxy-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid.

Yield: 4.56 g (59%).

tert-Butyl 4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)piperidine-1-carboxylate

To tert-butyl 4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (1.50 g, 3 .69 mmol) in MeOH (15 mL) was added with Pd/C (1.18 g, 1.11 mmol) under nitrogen. The reaction mixture is degassed and exposed to H ₂ (balloon) at 30° C. overnight. The mixture was treated with Pd/C (0.3 g) and stirred at 30° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure.

Yield: 1.42 g (94%).

5-Methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride

The title compound was synthesized from t-butyl 4-(6-{[(t-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-2-ylamine dihydrochloride.

Yield: 0.99 g (quantitative).

4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester

- 54 040737

5-Bromo-2-nitropyridine (5.00 g, 24.63 mmol) and piperazine-1-carboxylic acid tert-butyl ester (13.7 g, 73.9 mmol) in NMP (50 ml) were stirred for 3 h at 120°C. 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-Aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester

4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.00 g, 65.9 mmol) and Pd/C (200 mg) in ethanol was stirred using an H ₂ balloon for 3 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure.

Yield: 1.90 g (quantitative).

5-Piperazin-1-yl-pyridin-2-ylamine dihydrochloride

4-(6-Aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.50 g, 8.98 mmol) in DCM (30 mL) and 4M HCl in 1,4-dioxane (11, 2 ml, 44.9 mmol) was stirred for 16 hours at room temperature. The reaction mixture is filtered and washed with ether to give the title compound.

Yield: 2.23 g (99%).

(R)-2-(tert-Butyldimethylsilαnyloxymethyl)-4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester

To (I)-2-(tert-butyldimethylsilanyloxymethyl)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) add Cs ₂ CO ₃ (4.44 g, 13.6 mmol), Pd ₂ (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 was purified by silica gel column chromatography to give the title compound.

Yield: 1.35 g (66%) ESI-MS: m/z=453 (M+H)X(HPLC): 1.31 min (Method 1).

(R)-4-(6-aminopyridin-3-yl)-2-(tert-butyldimethylsilanyloxymethyl)piperazine-1-carboxylic acid tert-butyl ester

- 55 040737

(R)-2-(tert-Butyldimethylsilanyloxymethyl)-4-(6-nitropyridin-3-yl)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) was stirred using an H ₂ balloon for 24 hours. The reaction mixture was filtered through Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure.

Yield: 1.26 g (quantitative).

[(R)-4-(6-Aminopyridin-3-yl)piperazin-2-yl]methanol dihydrochloride

(R)-4-(6-aminopyridin-3-yl)-2-(tert-butyldimethylsilanyloxymethyl)piperazine-1-carboxylic acid tert-Butyl ester (1.26 g, 2.98 mmol) in DCM (10 ml) and 4M HCl in 1,4-dioxane (7.5 ml, 30.0 mmol) was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure, suspended in ether, filtered and washed with ether to give the title compound.

Yield: 838 mg (quantitative).

(K)-4-[6-(2,5-dimethylpyrrol-1-yl)-4-methylpyridin-3-yl]-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester

To (R)-2-(tert-Butyldimethylsilanyloxymethyl)-4-[6-(2,5-dimethylnpyrrol-1yl)-4-methylpyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester (8.56 g, 16.1 mmol) in THF (100 ml) was added tetrabutylammonium fluoride (16.1 ml, 16.1 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column silica gel chromatography to give the title compound.

Yield: 6.10 g (91%) ESI-MS: m/z=417 (M+H) ⁺ R _t (HPLC): 0.98 min (Method 1).

(R)-4-[6-(2,5-Dimethyl-4-pyrrol-1-yl)-4-methylpyridin-3-yl]-2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester

To (R)-4-[6-(2,5-dimethylpyrrol-1-yl)-4-methylpyridin-3-yl]-2-hydroxymethyl-56 040737 tylpiperazin-1-carboxylic acid tert-butyl ester (2, 00 g, 4.80 mmol) and methyl iodide (915 mg, 7.20 mmol) in DMA (15 ml) are added 60% NaH (230 mg, 5.76 mmol). The reaction mixture is stirred for 2 hours at room temperature and quenched with water. The mixture is extracted three times with EtOAc, the combined organic layers are washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Yield: 1.80 g (87%) ESI-MS: m/z=431 (M+H)0 (HPLC): 1.12 min (Method 1).

(R)-4-(6-Amino-4-methylpyridin-3-yl)-2-methoxymethylpiperazine-1-carboxylic acid tert-Butyl ester

The title compound was synthesized from (R)-4-[6-(2,5dimethylpyrrol-1-yl)-4-methylpyridin-3-yl]-2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester (1.80 g, 4.18 mmol) according to the procedure described for the synthesis of the tert-butyl ester intermediate (R)-4-(6-amino-4-methylpyridin-3-yl)-2-hydroxymethylpiperazine-1-carboxylic acid.

Yield: 1.07 g (87%) ESI-MS: m/z=353 (M+H)0 (HPLC): 0.44 min (Method 1).

5-((R)-3-Methoxymethylpiperazin-1-yl)-4-methylpyridin-2-ylamine dihydrochloride

The title compound was synthesized from (R)-4-(6-amino-4methylpyridin-3-yl)-2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester (440 mg, 1.25 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1-ylpyridin-2-ylamine dihydrochloride.

Yield: 406 mg (quantitative).

4-(6-Amino-4-methylpyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

The title compound is synthesized from 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (538 mg, 1.74 mmol) and 6chloro-5-methylpyridazin-3-ylamine (250 mg, 1.74 mmol) according to the procedure described for the synthesis of 6-amino-4-methyl-tert-butyl ester intermediate. 3',6'-dihydro-2'H[3,4']bipyridinyl-1'-carboxylic acid.

Yield: 326 mg (65%) ESI-MS: m/z=292 (M+Hy^HPLC): 0.51 min (Method 5).

4-(6-Amino-4-methylpyridazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was synthesized from 4-(6-amino-4-methylpyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (326 mg, 1.12 mmol) in According to

- 57 040737 the procedure described for the synthesis of the tert-butyl ester intermediate 6-amino-4methyl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acids.

Yield: 289 mg (88%) ESI-MS: m/z=293 (M+H) + R _t (HPLC): 0.60 min (Method 5).

5-Methyl-6-piperidin-4-yl-pyridazin-3-ylamine dihydrochloride

The title compound was synthesized from 4-(6-amino-4methylpyridazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (175 mg, 0.60 mmol) according to the procedure described for the synthesis of Intermediate 5- piperazin-1-yl-pyridin-2-ylamine dihydrochloride.

Yield: 154 mg (97%) ESI-MS: m/z=193 (M+H) + R _t (HPLC): 0.46 min (Method 2).

5-Bromo-2-(2,5-dimethylpyrrol-1-yl)-4-methoxypyridine

The title compound was synthesized from 5-bromo-4-methoxypyridin-2-ylamine (10.6 g, 52.1 mmol) according to the procedure described for the synthesis of intermediate 5-bromo-2(2,5-dimethylpyrrole- 1-yl)-4-methylpyridine.

Yield: 14.0 g (96%) ESI-MS: m/z=283 (M+H) + I-HPLC): 0.93 min (Method 3).

(R)-2-(tert-Butyldimethylsilanyloxymethyl)-4-[6-(2,5-dimethylpyrrol-1-yl)4-methoxypyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester

To 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-4-methoxypyridine (1.24 g, 4.41 mmol) and tert-butyl ether (R)-2-(tert-butyldimethylsilanyloxymethyl)piperazine -1-carboxylic acid (1.46 g, 4.41 mmol) in 1,4-dioxane (13 mL) sodium tert-butoxide (1.27 g, 13.2 mmol) and CPhos-G3-palladacyl methanesulfonate ( 178 mg, 0.22 mmol). The mixture is degassed with nitrogen for 5 minutes and stirred for 4 hours at 100°C. The reaction mixture is filtered through a pad of silica gel and eluted with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography to give the title compound.

Yield: 1.68 g (72%) ESI-MS: m/z=531 (M+H) ⁺ R _t (HPLC): 1.43 min.

(R)-4-(6-Amino-4-methoxypyridin-3-yl)-2-hydroxymethylpiperazine-1-carboxylic acid tert-Butyl ester

(R)-2-(tert-Butyldimethylsilanyloxymethyl)-4-[6-(2,5-dimethylpyrrol-1-yl)4-methoxypyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester (1.68 g, 3.17 mmol), hydroxylamine hydrochloride (1.10 g, 15.8 mmol) and trimethylamine (320 μl, 3.24 mmol) in ethanol (6 ml) and water (3 ml) were stirred in for 18 hours at 80°C. Hydroxylamine hydrochloride (440 mg, 6.33 mmol) is added again and stirred at 80°C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (to give the title compound.

Yield: 620 mg (58%).

[(R)-4-(6-Amino-4-methoxypyridin-3-yl)piperazin-2-yl]methanol hydrochloride

The title compound was synthesized from (R)-4-(6-Amino-4methoxypyridin-3-yl)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (620 mg, 1.83 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1-ylpyridin-2-ylamine dihydrochloride.

Yield: 503 mg (quantitative).

3-[6-(2,5-Dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

To 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-4-methoxypyridine (1.00 g, 3.56 mmol) and 3,8-diaza-bicyclo[3.2.1] tert-butyl ether 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-palladαcycle methanesulfonate (287 mg, 0.36 mmol). The mixture is degassed with nitrogen for 5 minutes and stirred for 18 hours at 80°C. The reaction mixture is extracted with EtOAc, washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Yield: 760 mg (52%) ESI-MS: m/z=412 (M+H) ⁺ R _t (HPLC): 1.23 min (Method 1).

3-(6-Amino-4-methoxypyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

The title compound is synthesized from 3-[6-(2,5-dimethylpyrrol1-yl)-4-methoxypyridin-3-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (760 mg, 1.84 mmol) according to the procedure described for the synthesis of 4-(6-amino-4-methoxypyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester intermediate.

Yield: 330 mg (54%) ESI-MS: m/z=335 (M+H) ⁺ R _t (HPLC): 1.75 min (Method 6).

5-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-4-methoxypyridin-2-ylamine dihydrochloride

- 59 040737

The title compound was synthesized from 3-(6-Amino-4methoxypyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (330 mg, 0.99 mmol) in according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1yl-pyridin-2-ylamine dihydrochloride.

Yield: 330 mg (quantitative) ESI-MS: m/z=235 (M+H) ⁺ R _t (HPLC): 0.15 min (Method 5).

4-Benzyl 1-tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]ninerazine-1,4-dicarboxylate

(2R)-4-[(Benzyloxy)carbonyl]-1-[(tert-butoxy)carbonyl]n-piperazine-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,O-dimethylhydroxylamine hydrochloride (1.29 g, 13.2 mmol) in DMA (40 ml) were stirred at room temperature for 3 days. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Yield: 4.44 g (99%) ESI-MS: m/z=408 (M+H)+.

4-Benzyl 1-tert-butyl (2R)-2-acetylpiperazine-1,4-dicarboxylate

To a mixture of 4-benzyl 1-tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pinerazine 1,4-dicarboxylate (4.40 g, 10.80 mmol) in THF (25 ml) cooled to -20°C ) was added dropwise with methylmagnesium bromide (5.40 ml, 16.20 mmol) and stirred at -20°C for 30 min. The reaction mixture was quenched with saturated aqueous NH ₄ Cl, diluted with EtOAc and washed with water+IN HCl and brine. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified by chromatography to give the desired product. Further purification is carried out by separation by chiral chromatography to give the pure R enantiomer.

Yield: 2.38 g (61%).

4-Benzyl 1-tert-butyl (2R)-2-(1-hydroxyethyl)piperazine-1,4-dicarboxylate

- 60 040737

Sodium borohydride (0.36 g, 9.52 mmol) is added to (4-benzyl 1-tert-butyl (2R)-2-acetylpiperαzine-1,4-dicarboxylate (2.30 g, 6.35 mmol) in methanol (100 ml) After the reaction mixture was stirred for 30 minutes, the solvent was removed under reduced pressure The residue was purified by chromatography on silica.

Yield: 2.10 g (91%).

4-Benzyl 1-tert-butyl (2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1,4-dicarboxylate

tert-Butyl(chloro)dimethylsilane (1.30 g, 8.64 mmol) is added to 4-benzyl 1-tert-butyl (2R)-2-(1hydroxyethyl)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 water (10 ml) was added, the aqueous layer was extracted with dichloromethane (2x25 ml). The combined organic layers are washed with brine. The organic layer is dried, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica.

Yield: 2.75 g (99.7%).

tert-Butyl(2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1-carboxylate

Under hydrogen atmosphere (balloon) 4-benzyl 1-tert-butyl (2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1,4-dicarboxylate (2.75 g, 5.75 mmol ) and Pd/C (0.20 g) was stirred at room temperature in ethanol (50 ml) for 2 hours. After removal of the catalyst by filtration through Celite®, the solvent was removed under reduced pressure. The residue is filtered through silica, eluting with 10% MeOH/dichloromethane.

Yield: 1.89 g (96%).

- 61 040737 (tert-Butyl (2R)-2-{1 -[(tert-butyldimethylsilyl)oxy]ethyl}-4-[6-(2,5-dimethyl-1 H-pyrrol-1 -yl)-4methoxypyridine -3 -yl]piperazine-1-carboxylate

To tert-butyl (2R)-2-{1-[(tert-butyldimethylsilyl)oxy]ethyl}piperazine-1-carboxylate (1.89 g, 5.49 mmol) and 5-bromo-2-(2.5 -dimethylpyrrol-1-yl)-4-methoxypyridine (1.54 g, 5.49 mmol) in 1,4-dioxane (20 ml) was added CPhos-G3-palladacyl methanesulfonate (0.22 g) and sodium tert-butoxide (1.58 g, 16.5 mmol) and the reaction mixture was purged with nitrogen. The reaction mixture is stirred at 100° C. for 10 hours. The reaction mixture is filtered through a pad of silica, eluting with EtOAc, and concentrated. The residue was purified twice by silica chromatography to give the title compounds.

Exit:

tert-Butyl (2R)-2-[(1S)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)4-methoxypyridine -3-yl]piperazin-1-carboxylate: 0.57 g (19%) and tert-butyl (2R)-2-[(1R)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6- (2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazin-1carboxylate: 0.78 g (26%) tert-butyl (2R)-4-(6-amino- 4-methoxypyridin-3-yl)-2-[(1R)-1-hydroxyethyl]piperazine-1-carboxylate

tert-Butyl (2R)-2-[( 1R)- 1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1 H-pyrrol-1 yl)-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 are heated at 80° C. for 42 hours. Additional hydroxylamine hydrochloride (0.22 g, 3.19 mmol) is added and the reaction mixture is stirred at 80° C. overnight. The reaction mixture is concentrated under reduced pressure, taken up in dichloromethane and filtered. The desired compound is purified by chromatography on silica.

Yield: 0.20 g (36%).

(1R)-1-[(2R)-4-(6-Amino-4-methoxypyridin-3-yl)piperazin-2-yl]ethan-1-ol dihydrochloride

A solution of 4N HCl in dioxane (0.71 ml, 2.84 mmol) is added to tert-butyl (2R)-4-(6-amino-4-62 040737 methoxypyridin-3-yl)-2-[(1R)- 1-hydroxyethyl]piperazine-1-carboxylate (0.20 g, 0.57 mmol) in 5 ml dichloromethane and stirred at room temperature for 2 h. Add an additional 1 ml of 4N HCl solution in dioxane and stirred for 1 h at room temperature. The reaction mixture is concentrated under reduced pressure. The residue is used without further purification.

Yield: 0.18 g (quantitative).

tert-Butyl (2R)-4-(6-amino-4-methoxypyridin-3-yl)-2-[( 1S)-1-hydroxyethyl]piperazine-1-carboxylate

tert-Butyl (2R)-2-[(1S)-1-[(tert-butyldimethylsilyl)oxy]ethyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1yl)-4-methoxypyridin- 3-yl]piperazin-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 ethanol and 2 ml of water are heated at 80°C for 42 hours Add more hydroxylamine hydrochloride (0.15 g, 2.09 mmol) and the reaction mixture is stirred at 80°C overnight. The reaction mixture is concentrated under reduced pressure, taken up in dichloromethane and filtered. The desired compound is purified by silica chromatography and purified again by HPLC.

Yield: 0.12 g (33%).

(1S)-1-[(2R)-4-(6-Amino-4-methoxypyridin-3-yl)piperazin-2-yl]ethan-1-ol dihydrochloride

A solution of 4N HCl in dioxane (0.50 ml, 2.00 mmol) is added to tert-butyl (2R)-4-(6-amino-4methoxypyridin-3-yl)-2-[(1S)-1-hydroxyethyl] piperazine-1-carboxylate (0.12 g, 0.34 mmol) in 1 ml dichloromethane and stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure. The residue is used without further purification.

Output: quantitative.

7-(6-Amino-4-methoxypyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-6-en-9carboxylic acid tert-butyl ester

The title compound was synthesized from 5-bromo-4-methoxypyridin-2-ylamine (202 mg, 1.00 mmol) and 7-(4,4,5,5-tetramethyl-[1,3,2 ]dioxaborolan-2-yl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxylic acid (350 mg, 1.00 mmol) according to the procedure described for the synthesis of intermediate tert -butyl ester of 6-amino-4-methyl-3',6'-dihydro2'H-[3,4']bipyridinyl-1'-carboxylic acid.

Yield: 220 mg (64%) ESI-MS: m/z=348 (M+H) + R _t (HPLC): 1.52 min (Method 2).

7-(6-Amino-4-methoxypyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester

- 63 040737

To 7-(6-amino-4-methoxypyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]non-6-ene9-carboxylic acid tert-butyl ester (220 mg, 0.63 mmol) in EtOAc (10 mL) was added with Pd/C (67.0 mg, 0.06 mmol) under nitrogen. The reaction mixture is degassed, placed under an H ₂ balloon and stirred for 18 hours at 50°C. The reaction mixture is filtered through Celite®, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound.

Yield: 145 mg (66%) ESI-MS: m/z=350 (M+H) + Rt(HPLC): 1.60 min (Method 2).

4-Methoxy-5-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)pyridin-2-ylamine dihydrochloride

The title compound was synthesized from 7-(6-amino-4-methoxypyridin-3-yl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (145 mg, 0.41 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1-ylpyridin-2-ylamine dihydrochloride.

Yield: 133 mg (quantitative) ESI-MS: m/z=250 (M+H) + Jp-HPLC): 0.15 min (Method 5).

(S)-2-(tert-Butyldimethylsilanyloxymethyl)piperazine-1-carboxylic acid tert-butyl ester

To (S)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (2.00 g, 9.25 mmol) in DMA (10 ml) was added tert-butylchlorodimethylsilane (2.09 g, 13.9 mmol) and imidazole (1.89 g, 27.7 mmol) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with NH ₄ Cl solution and extracted with EtOAc. The organic layer is washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Yield: 2.80 g (92%).

(S)-2-(tert-Butyldimethylsilanyloxymethyl)-4-[6-(2,5-dimethylpyrrol-1-yl)4-methoxypyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester

The title compound was synthesized from 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-4methoxypyridine (3.25 g, 11.6 mmol) and (S)-2-(tert- butyldimethylsilanyloxymethyl)piperazine-1-carboxylic acid (3.82 g, 11.6 mmol) according to the procedure described for the synthesis of the tert-butyl ester intermediate 3-[6-(2,5-dimethylpyrrol-1yl)-4- methoxypyridin-3 -yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid.

Yield: 4.94 g (73%) ESI-MS: m/z=531 (M+H) ⁺ R _t (HPLC): 1.49 min (Method 3).

(S)-4-(6-Amino-4-methoxypyridin-3-yl)-2-hydroxymethylpiperazine-1-carbo tert-Butyl ether

- 64 040737 new acid

(S)-2-(tert-Butyldimethylsilanyloxymethyl)-4-[6-(2,5-dimethylpyrrol-1-yl)4-methoxypyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester (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 ml) were stirred for 18 h at 80°C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound.

Yield: 2.57 g (68%).

(S)-4-(6-Amino-4-methoxypyridin-3-yl)piperazin-2-yl]methanol hydrochloride

The title compound was synthesized from (S)-4-(6-Amino-4methoxypyridin-3-yl)-2-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester (264 mg, 0.58 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-piperazin-1-ylpyridin-2-ylamine dihydrochloride.

Yield: 160 mg (quantitative).

(R)-4-[6-(2,5-Dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl]-2-hydroxymethylpiperazin-1-carboxylic acid tert-butyl ester

To (R)-2-(tert-Butyldimethylsilanyloxymethyl)-4-[6-(2,5-dimethylpyrrol-1yl)-4-methoxypyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester (8.56 g, 16.1 mmol) in THF (100 ml) was added TBAF (1M in THF, 16.1 ml, 16.1 mmol). The reaction mixture is stirred for 2.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography to give the title product.

Yield: 180 mg (87%).

(R)-4-[6-(2,5-Dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl]-2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester

NaH (60%, 230 mg, 9.58 mmol) is added to the tert-butyl ester N)-4-[6-(2,5-dimethylpyrrol-1-65 040737 yl)-4-methoxypyridin-3-yl]- 2-hydroxymethylpiperazine-1-carboxylic acid (2.0 g, 4.80 mmol) and Mel (401 μl, 7.20 mmol) in DMA (20 ml). The reaction mixture is stirred for 2 hours at room temperature. Water is added and the reaction mixture is extracted with EtOAc (3 times). The combined organic layers are washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue is purified by normal phase chromatography.

Yield: 1.8 g (87%) ESI-MS: m/z=431 (M+H) ⁺ Rt (HPLC): 1.11 min (Method 1).

(R)-4-(6-Amino-4-methoxypyridin-3-yl)-2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester

(R)-4-[6-(2,5-Dimethylpyrrol-1-yl)-4-methoxypyridin-3-yl]-2-methoxymethylpiperazine-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) were stirred at 80°C 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 was purified by normal phase column chromatography to give the title product.

Yield: 440 mg (30%) ESI-MS: m/z=353 (M+H) + R _t (HPLC): 0.44 min (Method 1).

4-Methoxy-5-((R)-3-methoxymethylpiperazin-1-yl)pyridin-2-ylamine dihydrochloride

The title compound was synthesized from (R)-4-(6-Amino-4methoxypyridin-3-yl)-2-methoxymethylpiperazine-1-carboxylic acid tert-butyl ester (440 mg, 1.25 mmol) according to the procedure described for the synthesis of the intermediate [(R)-4-(6-amino-4-methoxypyridin-3-yl)piperazin-2-yl]-methanol hydrochloride.

Yield: 406 mg (quantitative).

5-Fluoro-4-methoxypyridine-2-carbonitrile

2-Chloro-5-fluoro-4-methoxypyridine (1.00 g, 6.19 mmol) is placed in a sealed tube. Zinc cyanide (799 mg, 6.81 mmol) and zinc (40.5 mg, 0.31 mmol) are added and purged with argon. Then add PdCl ₂ (dppf)CH ₂ Cl ₂ (253 mg, 0.62 mmol) and NMP and the mixture is heated for 45 min at 150°C in a microwave oven. Water and EtOAc are added to the reaction mixture and filtered through Celite®. The organic layer is washed with sodium bicarbonate solution, water, brine and dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound.

Yield: 689 mg (73%) ESI-MS: m/z=153 (M+H) ⁺ Rt (HPLC): 0.61 min (Method 1).

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonitrile

5-Fluoro-4-methoxypyridine-2-carbonitrile (6.00 g, 39.4 mmol), 4-fluorophenol (5.31 g, 47.3 mmol) and K2CO3 (12.0 g, 86.8 mmol) in NMP (12 ml) heated at 100°C for 3 h in a sealed tube. The reaction mixture was diluted with water and extracted with EtOAc. organic layer

- 66 040737 washed with brine and dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue is triturated with ether and heptane to give the title compound.

Yield: 8.99 g (93%) ESI-MS: m/z=245 (M+H) ⁺ R _t (HPLC): 0.91 min (Method 1).

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonitrile (8.50 g, 34.8 mmol) in aqueous 2N NaOH solution (90 ml) was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature. temperature and pH of the solution is adjusted to pH 4.5 with a solution of 4 N HCl. The precipitate is collected and dried in a drying oven to give the title compound.

Yield: 8.80 g (96%) ESI-MS: m/z=264 (M+H) ⁺ R _t (HPLC): 1.58 min (Method 4).

4-Methoxy-5-phenoxypyridine-2-carbonitrile

5-Fluoro-4-methoxypyridine-2-carbonitrile (8.00 g, 52.6 mmol), phenol (5.94 g, 63.1 mmol) and K ₂ CO ₃ (16.0 g, 115 mmol) in NMP (3 ml) is heated at 100° C. for 3 hours in a sealed tube. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer is washed with brine and dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound.

Yield: 11.5 g (93%) ESI-MS: m/z=227 (M+H) ⁺ R _t (HPLC): 0.92 min (Method 1).

4-Methoxy-5-phenoxypyridine-2-carboxylic acid

The title compound was synthesized from 4-methoxy-5-phenoxypyridine-2-carbonitrile (11.5 g, 50.8 mmol) according to the procedure described for the synthesis of intermediate 5(4-fluorophenoxy)-4-methoxypyridine-2 -carboxylic acid.

Yield: 9.57 g (77%) ESI-MS: m/z=246 (M+H) ⁺ Rt (HPLC): 2.64 min (Method 4).

5-(4-Isopropoxyphenoxy)-4-methoxypyridine-2-carbonitrile

The title compound was 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 Intermediate 4 -methoxy-5-phenoxypyridine-2-carbonitrile.

Yield: 850 mg (91%) ESI-MS: m/z=285 (M+H) ⁺ R _t (HPLC): 1.02 min (Method 1).

5-(4-Isopropoxyphenoxy)-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-(4-isopropoxyphenoxy)-4-methoxypyridine-2carbonitrile (200 mg, 0.70 mmol) according to the procedure described for the synthesis of intermediate 5-(4-fluorophenoxy)-4-methoxypyridine- 2-carboxylic acid.

Yield: 190 mg (77%) Rt (HPLC): 0.73 min (Method 1).

4-Methoxy-5-(4-methoxyphenoxy)pyridine-2-carbonitrile

The title compound was 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

- 67 040737 synthesis of intermediate compound 4-methoxy-5-phenoxypyridine-2-carbonitrile.

Yield: 740 mg (88%).

4-Methoxy-5-(4-methoxyphenoxy)pyridine-2-carboxylic acid

The title compound was synthesized from 4-methoxy-5-(4-methoxyphenoxy)pyridine-2carbonitrile (740 mg, 2.89 mmol) according to the procedure described for the synthesis of intermediate 5-(4-fluorophenoxy)-4-methoxypyridine -2-carboxylic acid.

Yield: 610 mg (77%).

4-Methoxy-5-(4-trifluoromethylphenoxy)pyridine-2-carbonitrile

The title compound was synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (500 mg, 3.29 mmol) and 4-trifluoromethylphenol (639 mg, 3.94 mmol) according to the procedure described for the synthesis of Intermediate 4 -methoxy-5-phenoxypyridine-2-carbonitrile.

Yield: 320 mg (33%) ESI-MS: m/z=294 (M+H) ⁺ R _t (HPLC): 1.06 min (Method 1).

4-Methoxy-5-(4-trifluoromethylphenoxy)pyridine-2-carboxylic acid

The title compound was synthesized from 4-methoxy-5-(4-trifluoromethylphenoxy)pyridine2-carbonitrile (151 mg, 0.51 mmol) according to the procedure described for the synthesis of intermediate 5-(4-fluorophenoxy)-4 -methoxypyridine-2-carboxylic acid.

Yield: 150 mg (93%).

5-(4-Chlorophenoxy)-4-methoxypyridine-2-carbonitrile

The title compound was synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (500 mg, 3.29 mmol) and 4-chlorophenol (507 mg, 3.94 mmol) according to the procedure described for the synthesis of Intermediate 4 -methoxy-5-phenoxypyridine-2-carbonitrile.

Yield: 695 mg (81%).

5-(4-Chloro-phenoxy)-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-(4-chlorophenoxy)-4-methoxypyridine-2-carbonitrile (645 mg, 2.47 mmol) according to the procedure described for the synthesis of intermediate 5-(4-fluorophenoxy)-4- methoxypyridine-2-carboxylic acid.

Yield: 622 mg (90%) ESI-MS: m/z=280 (M+H) ⁺ .

5-(4-Difluoromethoxyphenoxy)-4-methoxypyridine-2-carbonitrile

The title compound was synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (75.0 mg, 0.49 mmol) and 4-difluoromethoxyphenol (101 mg, 0.63 mmol) according to the procedure described for the synthesis of the intermediate 4-methoxy-5-phenoxypyridine-2-carbonitrile compounds.

Yield: 98.0 mg (68%) Rt (HPLC): 0.93 min (Method 1).

5-(4-Difluoromethoxyphenoxy)-4-methoxypyridine-2-carboxylic acid

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The title compound was synthesized from 5-(4-difluoromethoxyphenoxy)-4-methoxypyridine-2-carbonitrile (98.0 mg, 0.34 mmol) according to the procedure described for the synthesis of intermediate 5-(4-fluorophenoxy)- 4-methoxypyridine-2-carboxylic acid.

Yield: 94.0 mg (90%) R _t (HPLC): 0.60 min (Method 1).

4-Cyclopropoxyphenol

2-(4-Cyclopropoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (800 mg, 3.08 mmol) and 4-methylmorpholine 4-oxide (1.03 g, 8, 83 mmol) in THF (100 ml) was stirred at 75°C for 1.5 h and then for 18 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give the title compound.

Yield: 389 mg (84%).

5-(4-Cyclopropoxyphenoxy)-4-methoxypyridine-2-carbonitrile

The title compound was 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 Intermediate 4 -methoxy-5-phenoxypyridine-2-carbonitrile.

Yield: 342 mg (53%) R _t (HPLC): 1.00 min (Method 1).

5-(4-Cyclopropoxyphenoxy)-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-(4-cyclopropoxyphenoxy)-4-methoxypyridine-2-carbonitrile (100 mg, 0.35 mmol) according to the procedure described for the synthesis of intermediate 5-(4-fluorophenoxy)-4- methoxypyridine-2-carboxylic acid.

Yield: 622 mg (90%) R _t (HPLC): 0.63 min (Method 1).

4-Methoxy-5-(4-trifluoromethoxyphenoxy)pyridine-2-carbonitrile

The title compound was synthesized from 5-fluoro-4-methoxypyridine-2-carbonitrile (115 mg, 0.76 mmol) and 4-trifluoromethoxyphenol (162 mg, 0.91 mmol) according to the procedure described for the synthesis of Intermediate 4 -methoxy-5-phenoxypyridine-2-carbonitrile.

Yield: 140 mg (60%).

4-Methoxy-5-(4-trifluoromethoxyphenoxy)pyridine-2-carboxylic acid

The title compound was synthesized from 4-methoxy-5-(4-trifluoromethoxyphenoxy)pyridine-2-carbonitrile (150 mg, 0.48 mmol) according to the procedure described for the synthesis of intermediate 5-(4-Fluorophenoxy)-4 -methoxypyridine-2-carboxylic acid.

Yield: 120 mg (75%).

5-(2-Fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester

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To 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol), triphenylphosphine (372 mg, 1.42 mmol) and 2-fluorobenzyl alcohol (114 µl, 1.065 mmol) in THF ( 2 ml) add diethyl azodicarboxylate (646 μl, 1.42 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give the title compound.

Yield: 66.0 mg (32%) R _t (HPLC): 0.77 min (Method 1).

5-(2-Fluorobeuyloxy)-4-methoxypyridine-2-carboxylic acid

To 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester (66.0 mg, 0.23 mmol) in THF/water/MeOH (3 mL/1 mL/1 mL) was added LiOH (38 0 mg, 0.91 mmol) and the reaction mixture was stirred at room temperature. The reaction mixture is acidified to pH 4.5 with 4N HCl solution and concentrated in vacuo.

The residue is taken up in DCM and toluene and concentrated again under reduced pressure. The product was used without further purification.

Yield: 62.0 mg (99%) R _t (HPLC): 0.48 min (Method 1).

5-Cyclobutylmethoxy-4-methoxypyridine-2-carboxylic acid methyl ester

compound synthesized from methyl ester

Titled

5-Hydroxy-4-methoxypyridine-2-carboxylic acid (130 mg, 0.71 mmol) and cyclobutylmethanol (91.7 mg, 1.07 mmol) according to the procedure described for the synthesis of the methyl ester intermediate 5-( 2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid.

Yield: 132 mg (74%) R _t (HPLC): 0.80 min (Method 1).

5-Cyclobutylmethoxy-4-methoxypyridine-2-carboxylic acid

synthesized from 5-cyclobutylmethoxy-4 methyl ester. -carboxylic acid.

Yield: 124 mg (quantitative) R _t (HPLC): 0.53 min (Method 1).

4-Methoxy-5-(1-methylcyclopropylmethoxy)pyridine-2-carboxylic acid methyl ester

The title compound is synthesized from methyl ester

5-Hydroxy-4-methoxypyridine-2-carboxylic acid (130 mg, 0.71 mmol) and (1-methylcyclopropyl)methanol (103 mg, 1.07 mmol) according to the procedure described for the synthesis of the methyl ester intermediate 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid.

Yield: 115 mg (65%) R _t (HPLC): 0.81 min (Method 1).

4-Methoxy-5-(1-methylcyclopropylmethoxy)pyridine-2-carboxylic acid

- 70 040737

synthesized from methyl

The title compound of 5-cyclobutylmethoxy-4methoxypyridine-2-carboxylic acid ester (115 mg, 0.46 mmol) according to the procedure described for the synthesis of 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid intermediate .

Yield: 108 mg (quantitative) R _t (HPLC): 0.52 min (Method 1).

5-Cyclohexyloxy-4-methoxypyridine-2-carboxylic acid methyl ester

compound synthesized from methyl ester

Titled

-hydroxy-4-methoxypyridine-2-carboxylic acid (130 mg, 0.71 mmol) and cyclohexanol (111 μl, 1.07 mmol) according to the procedure described for the synthesis of the methyl ester intermediate 5-(2fluorobenzyloxy)- 4-methoxypyridine-2-carboxylic acid.

Yield: 171 mg (91%) R _t (HPLC): 0.87 min (Method 1).

5-Cyclohexyloxy-4-methoxypyridine-2-carboxylic acid

synthesized from methyl

The title compound of 5-cyclohexyloxy-4-methoxy-pyridine-2-carboxylic acid ester (131 mg, 0.49 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid .

Yield: 124 mg (quantitative) R _t (HPLC): 0.57 min (Method 1).

5-(4-Fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and (4-fluorophenyl)methanol (115 µl, 1.07 mmol) according to the procedure described for the synthesis of the 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 150 mg (62%) I-HPLC: 0.82 min (Method 1).

5-(4-Fluoro-benzyloxy)-4-methoxypyridine-2-carboxylic acid

The title methyl ester compound is synthesized from

-(4-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid (150 mg, 0.44 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid.

Yield: 177 mg (quantitative) R _t (HPLC): 0.82 min (Method 1).

5-Cyclopentyloxy-4-methoxypyridine-2-carboxylic acid methyl ester

- 71 040737

the compound is synthesized from 5-hydroxy-4-methoxy methyl ester of the title pyridine-2-carboxylic acid (130 mg, 0.71 mmol) and cyclopentanol (96.7 μl, 1.07 mmol) according to the procedure described for the synthesis 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 170 mg (95%) R _t (HPLC): 0.87 min (Method 1).

5-Cyclopentyloxy-4-methoxypyridine-2-carboxylic acid

synthesized from methyl

The title compound of 5-cyclopentyloxy-4-methoxy-pyridine-2-carboxylic acid ester (130 mg, 0.52 mmol) according to the procedure described for the synthesis of 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid intermediate .

Yield: 122 mg (99%) R _t (HPLC): 0.49 min (Method 1).

5-Isobutoxy-4-methoxypyridine-2-carboxylic acid methyl ester

compound synthesize

Titled from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and isobutyl alcohol (71.6 mg, 0.97 mmol) following the procedure described for the synthesis of the methyl intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid ester.

Yield: 141 mg (92%) R _t (HPLC): 0.78 min (Method 1).

5-Isobutoxy-4-methoxypyridine-2-carboxylic acid

compound synthesize

Titled from 5-isobutoxy-4-methoxypyridine-2-carboxylic acid methyl ester (141 mg, 0.59 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid acids.

Yield: 133 mg (quantitative) R _t (HPLC): 0.51 min (Method 1).

5-Cyclopropylmethoxy-4-methoxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and cyclopropylmethanol (84.2 μl, 1.07 mmol) according to the procedure described for the synthesis 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 146 mg (87%) R _t (HPLC): 0.74 min (Method 1).

5-Cyclopropylmethoxy-4-methoxypyridine-2-carboxylic acid

- 72 040737

The title compound was synthesized from 5-cyclopropylmethoxy-4methoxypyridine-2-carboxylic acid methyl ester (325 mg, 1.37 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine-2 -carboxylic acid.

Yield: 358 mg (quantitative) ESI-MS: m/z=224 (M+H) + R _t (HPLC): 0.40 min (Method 5).

5-Benzyloxy-4-methoxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and benzyl alcohol (100 μl, 0.97 mmol) according to the procedure described for the synthesis of the intermediate 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester compounds.

Yield: 140 mg (80%) R _t (HPLC): 0.79 min (Method 1).

5-Benzyloxy-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-benzyloxy-4-methoxypyridine-2-carboxylic acid methyl ester (140 mg, 0.51 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine -2-carboxylic acid.

Yield: 358 mg (99%) A (HPLC): 0.54 min (Method 1).

5-(3,3-Difluorocyclobutylmethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and (3,3-difluorocyclobutyl)methanol (150 mg, 0.82 mmol) according to the procedure described for the synthesis of 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 111 mg (47%) ESI-MS: m/z=288 (M+H) ⁺ R _t (HPLC): 1.20 min.

(Method 5) 5-(3,3-Difluorocyclobutylmethoxy)-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-(3,3-difluorocyclobutylmethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester (110 mg, 0.38 mmol) according to the procedure described for the synthesis of intermediate 5-(2- fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid.

Yield: 73.4 mg (70%) ESI-MS: m/z=274 (M+H) ⁺ AQ(HPLC): 0.56 min (Method 5).

4-Methoxy-5-propoxypyridine-2-carboxylic acid methyl ester

- 73 040737

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 1-propanol (80.0 μl, 1.07 mmol) according to the procedure described for the synthesis of 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 114 mg (71%) R _t (HPLC): 0.69 min (Method 1).

4-Methoxy-5-propoxypyridine-2-carboxylic acid

The title compound was synthesized from 4-methoxy-5-propoxypyridine-2-carboxylic acid methyl ester (114 mg, 0.51 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine -2-carboxylic acid.

Yield: 106 mg (99%) R _t (HPLC): 0.41 min (Method 1).

5-(2-Cyclopropylethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 2-cyclopropylethanol (91.7 mg, 1.07 mmol) according to the procedure described for the synthesis of 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 130 mg (73%) R _t (HPLC): 0.82 min (Method 1).

5-(2-Cyclopropylethoxy)-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-(2-cyclopropylethoxy)-4methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.52 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4 -methoxypyridine-2-carboxylic acid.

Yield: 122 mg (99%) A (HPLC): 0.53 min (Method 1).

4-Methoxy-5-phenethyloxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 2-phenylethanol (128 μl, 1.07 mmol) according to the procedure described for the synthesis 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 177 mg (87%) R _t (HPLC): 0.90 min (Method 1).

4-Methoxy-5-phenethyloxypyridine-2-carboxylic acid

- 74 040737

The title compound was synthesized from 4-methoxy-5-phenethyloxypyridine-2-carboxylic acid methyl ester (177 mg, 0.62 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine -2-carboxylic acid.

Yield: 168 mg (quantitative) R _t (HPLC): 0.63 min (Method 1).

5-(2,2-Dimethylpropoxy)-4-methoxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (130 mg, 0.71 mmol) and 2,2-dimethylpropan-1-ol (93.8 mg, 1.07 mmol) according to the procedure described for the synthesis of 5-(2-fluoro-benzyloxy)-4-methoxy-pyridine-2-carboxylic acid methyl ester intermediate.

Yield: 160 mg (89%) R _t (HPLC): 0.92 min (Method 1).

5-(2,2-Dimethylpropoxy)-4-methoxypyridine-2-carboxylic acid

synthesized from 5-(2,2-dimethylpropoxy)-4 methyl ester. -4-methoxypyridine-2-carboxylic acid.

Yield: 150 mg (99%) R _t (HPLC): 0.61 min (Method 1).

5-(1-Fluoromethylcyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester

The title compound was synthesized from 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and (1-fluoromethylcyclopropyl)methanol (101 mg, 0.97 mmol) according to the procedure described for the synthesis of 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 159 mg (92%) ^(HPLC): 0.69 min (Method 1).

5-(1-Fluoromethylcyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid

synthesized from methyl

The title compound of 5-(1-fluoromethylcyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid ester (159 mg, 0.59 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4- methoxypyridine-2 carboxylic acid.

Yield: 150 mg (quantitative) R _t (HPLC): 0.43 min (Method 1).

5-ethoxy-4-methoxypyridine-2-carboxylic acid methyl ester

- 75 040737

synthesized from methyl ester 5-hydroxy-4-methoxy compound

Titled pyridine-2-carboxylic acid (130 mg, 0.71 mmol) and ethanol (62.1 µl, 1.07 mmol) according to the procedure described for the synthesis of the methyl ester intermediate 5-(2-fluorobenzyloxy) -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 was synthesized from 5-ethoxy-4-methoxypyridine2-carboxylic acid methyl ester (151 mg, 0.71 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine-2 -carboxylic acid.

Yield: 140 mg (99%) Rt (HPLC): 0.83 min (Method 1).

5-((S)-1-cyclopropylethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester

compound synthesized from 5-hydroxy-4-methoxy title pyridine-2-carboxylic acid methyl ester (118 mg, 0.64 mmol) and (R)-1-cyclopropylethanol (83.2 mg, 0.97 mmol) according to with the procedure described for the synthesis of the 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 102 mg (63%).

5-((S)-1-Cyclopropylethoxy)-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-((S)-l-cyclopropylethoxy)-4methoxypyridine-2-carboxylic acid methyl ester (102 mg, 0.41 mmol) according to the procedure described for the synthesis of intermediate 5-(2- fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid.

Yield: 96.0 mg (100%) Rt (HPLC): 0.51 min (Method 1).

5-Isopropoxy-4-methoxypyridine-2-carboxylic acid methyl ester

compound synthesized from methyl ester

Titled

5-hydroxy-4-methoxypyridine-2-carboxylic acid (130 mg, 0.71 mmol) and propan-2-ol (81.5 µl, 0.97 mmol) according to the procedure described for the synthesis of the methyl intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid ester. Yield: 154 mg (96%) R _t (HPLC): 0.62 min (Method 1).

5-Isopropoxy-4-methoxypyridine-2-carboxylic acid

- 76 040737

The title compound was synthesized from 5-isopropoxy-4-methoxypyridine-2-carboxylic acid methyl ester (154 mg, 0.68 mmol) according to the procedure described for the synthesis of intermediate 5-(2-fluorobenzyloxy)-4-methoxypyridine-2 -carboxylic acid.

Yield: 144 mg (quantitative).

5-((R)-1-cyclopropylethoxy)-4-methoxypyridine-2-carboxylic acid methyl ester

compound synthesized from methyl ester

Titled

5-hydroxy-4-methoxypyridine-2-carboxylic acid (118 mg, 0.64 mmol) and (S)-1-cyclopropylethanol (83.2 mg, 0.97 mmol) according to the procedure described for the synthesis of the intermediate 5-(2fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester compounds.

Yield: 101 mg (63%).

5-((R)-1-Cyclopropylethoxy)-4-methoxypyridine-2-carboxylic acid

The title compound was synthesized from 5-((R)-l-cyclopropylethoxy)-4methoxypyridine-2-carboxylic acid methyl ester (101 mg, 0.40 mmol) according to the procedure described for the synthesis of intermediate 5-(2- fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid.

Yield: 94.0 mg (99%) I-HPLC: 0.51 min (Method 1).

-(Trifluoromethyl)cyclobutyl]methanol

To 3-(trifluoromethyl)cyclobutane-1-carboxylic acid (50 mg, 0.29 mmol) in THF (2 mL) was added CDI (57 mg, 0.36 mmol) and stirred at room temperature for 2 h. Borohydride was added sodium (12 mg, 0.31 mmol) in water (0.5 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture is acidified with a 1M HCl solution and extracted with DCM. The combined organic phases are separated and dried over Na ₂ SO ₄ , filtered and concentrated.

Yield: 45 mg (quantitative).

Methyl 4-methoxy-5-{[3-(trifluoromethyl)cyclobutyl]methoxy}pyridine-2-carboxylate

The title compound was 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 the procedure described for the synthesis of 5-(2-fluorobenzyloxy)-4-methoxypyridine-2-carboxylic acid methyl ester intermediate.

Yield: 90 mg (97%).

4-Methoxy-5-{[3-(trifluoromethyl)cyclobutyl]methoxy}pyridine-2-carboxylic acid

An aqueous solution of 4M NaOH (0.55 ml, 2.2 mmol) is added to methyl 4-methoxy-5-{[3-(trifluoromethyl)cyclobutyl]methoxy}-pyridine-2-carboxylate (350 mg, 1.10 mmol) in 5 ml of methanol. The reaction mixture is stirred overnight at room temperature. An aqueous solution of 4M HCl (0.5 ml) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was evaporated at reduced

- 77 040737 pressure. DMF is added to the residue and the desired compound is purified by HPLC.

Yield: 150 mg (45%).

Methyl 4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylate

To methyl 5-hydroxy-4-methoxypyridine-2-carboxylate (100 mg, 0.55 mmol) in THF was added 3,3,3-trifluoro-2-methylpropan-1-ol (105 mg, 0.82 mmol) and triphenylphosphine ( 286 mg, 1.10 mmol) followed by diisopropyl azodicarboxylate (221 mg, 1.10 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture is evaporated under reduced pressure and the residue is purified by HPLC. Fractions containing product are pooled and lyophilized.

Yield: 160 mg (quantitative).

4-Methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylic acid

An aqueous solution of 4M NaOH (0.52 ml, 2.08 mmol) was added to methyl 4-methoxy-5-(3,3,3-trifluoro-2methylpropoxy)pyridine-2-carboxylate (160 mg, 0.55 mmol) in methanol. The reaction mixture is stirred for 2 hours at room temperature. The reaction mixture was neutralized with an aqueous solution of 4M HCl and evaporated under reduced pressure. The residue is used without further purification.

Yield: 150 mg (98%).

General procedure.

Procedures for obtaining compounds according to the invention 1-80 are summarized in table. 3A. Analysis of compounds according to the invention 1-80 summarized in table. 3B.

I. To carboxylic acid (1 eq.) in DMA add HATU (1.2 eq.) and mix. Add amine (1 eq.) and DIPEA (4.0 eq.) and stir for 18 hours at room temperature. Purification by RP column (ACN/water, acidic or basic conditions) or silica gel chromatography.

II. The carboxylic acid (1 eq.) and CDI (1.5 eq.) are stirred in DMA for 30 minutes at room temperature. Add amine (1 eq.) and DIPEA (2.0 eq.) and stir for 3 hours at room temperature. Purification by RP column (ACN/water, acidic or basic conditions) or silica gel chromatography.

III. Amine (1.0 eq.), carboxylic acid (0.9 eq.), TBTU (1.0 eq.) and DIPEA (4.0 eq.) in NMP were stirred for 18 hours at room temperature. The filtered reaction mixture is purified on an RP column (ACN/water, acid or basic conditions) or silica gel chromatography.

- 78 040737

Table 3A. General Procedures for the Preparation of Compounds of the Invention 1-80

Comm. No. Amine intermediate carboxylic acid intermediate connection General procedure Exit % 1 .N “Oh on ? ? ^Nz ΥχχΟ il I pl. b0 _; AN -ζ O I 72 2 ^NS| e Μ hci νη ₂ ^but O y ^CH 3 Λ J II 82 3 Η on [ J on Vx T Η nh ₂ R NI \I Λ—O ABOUT III 15 4 JA hci D J ^HCI M-..D nh ₂ C< ³ d'C. He III 13 5 6-0 0 ϋ Ζ τ O Ν—X H _s I 80 6 Η χ ^Ν χ on LJ ^HCI An n Xx- ^N νη ₂ n, with to ° \ / - X he O SN ₃ III 49

- 79 040737

7 A 4 ^chi nh _{2 OHCH3} I 69 8 A ^HCI U ^kci Lg ⁰ ^ τ nh ₂ _CH ₃ Ao OH I 33 9 P ^cih HCl 1 A nh ₂ d n 0 A o o I eleven 10 IS Q on aa ^SNz ¥ nh ₂ xCH, O ³ c' o he II 82 eleven H LJ HCl _N -bv HCl l Nx, o o 1 nh ₂ ch ₃ „SN ₃ .,ζΟΟ, he III 72 12 C 3 ^hci ξτ nh ₂ „sn _e - ύ ' oh, he sn ₃ III 63 13 0 ™ i NH ₂ xCH ₃ A'o, he III 74

- 80 040737

14 Η ζ-Ν 0Ζ HCI ΚΚ ^HCI Γ ιΐ NHL, book ₃ νόκ, he III 72 15 Η ξτ νη ₂ KN, 0 ³ K'K he III eleven 16 Η 1 J ^HCI X ^ns| >> νη ₂ o ⁰ ^ cn ₃ he II 52 17 Η XX ^ns| ιι %X- ^N νη ₂ KN, %'C, OH III 74 18 " HCI V ₄ k; o he ch ₃ I 69 19 ύ 0 nh ₂ V Y \ /^N P o - (( F ) ' OH O SN ₃ III 75 20 Z :, Q ^ns 'f kn _z •7'o. He III 24

- 81 040737

21 Η U” [ HCI Α kDDsn, νη ₂ „SN, He II 6, 9 22 Η DD G J HCl Αχ HCI Γ ii nh ₂ „SN, 0 ³ ., Us, he SN ₃ III 67 23 N HCI X А°' ^SN з ГД Nl-Lj „SN, ,σ o he 44 24 N ^HCI Y A nh ₂ 'o 0-0 o I \___/ o d O II 41 25 N ^HCI 1 HCI An nh ₂ \ / T-N about OD beat he 0 sn ₃ III 44 26 H HCI x ^N x D HCI 1 nh ₂ sn ₃ / - N O A ) \u003d/ he 0 \ sn ₃ III 58 27 Ao^ VCH. Ax Il T hci nJ 1 hci nh ₂ aa he H ₃ C I 58 28 ii ^HCI O° d nh ₂ dn ₃ ...x, he ch ₃ III 76

- 82 040737

29 N HCl LJ HCl A xCH, i ¹ |f nh ₂ .CH, 0 ³ _v σ'Ό, OH II 48 thirty /--\ /=z /\/\X 0 LLC X X dG Q rV) \u003d ² OH 0 CH ₃ III 39 31 ύ ^Ηα A xn, u nh. ,,SN _{3 ν} δ'€ OH II 62 32 b Q o \ o X \ /--\ ^M Z=/ \' F—to V--ch Λ ^- Ν 0 \=/ w; / \u003d OH o ch ₃ III 24 33 H a ⁿ a LJ ^HCI nA ^hci M nh ₂ X o-o o “UCH o —Z ¹ o II 56 34 H ^N G 1 ^HC6 1 HCI XN I nh ₂ xn, 0 ³ •P'O... OH III thirty 35 “Ξ x i 0 0 0 0 Z—C-/zz “z=/ '—' χ^Ν O oA W p \u003d/ he ο _χ cn ₃ III 42

- 83 040737

36 Η Γ J HCI Α^ ^hci νη ₂ ΗΧ /—\ Ζ^ ^Ν /° n ₃ s ο—y --U /=^ he o SS 53 37 HCI U hci LJ .0 „А ⁿ , ^с г II %^ ^Ν NH, L>---\ /?—Ν o ^x ₀ / \\^ )=/ he O _ch sn ₃ III 37 38 Η HCI ύ» _α Ν O ^Asn ' νη ₂ ^sn ₃ ..PT, he I 31 39 Η HCI < ^Ν Χ HCI LJ ^.Ο. 9χ ^H - ^C Al Ί ΝΗ- H ₃ C)--ξ Ν O ⁿ _s s ) \u003d/ he O c ₃ III 51 40 Η .Νχ Γ J HCI An HCI II Αχ/Ν νη ₂ x ^;> ° zTW ° \ /—\ Y \u003d I he o sn _e III 13 41 Η Ν r J ^NS| Λ HCI to Ν and νη ₂ F - C Y - \ g - N O% \u003d/ W) \u003d/ he O _h sn ₃ III 29 42 ΟΗ cY ^αΗ Ν CH, ό νη ₂ A 0-0 ok I 42

- 84 040737

43 HCl ,N. HCl ^{n s} Υη nh ₂ V 7--\ Z ^ N O) \u003d 2 OH o CH ₃ III 49 44 Η ^N [J HCl 1 HCl 0 N II k-,N nh ₂ 0H. , ΰ' Ό, OH ch ₃ III 61 45 N ^HCI 11 HCl A. 0., fl 0 ^{x CH} 3 o N^Jk 0 ^'XV ¹⁷ F I 50 46 HCl R per G J ^ O, D, n ₃ s -uch% N nh ₂ H, C 4 / GUU he o ^z CH ₃ III 60 47 H HCl 0 “ 0°'“ nh ₂ O-CH ₃ urU ^{HO N} K II 61 48 HCl D HCl 1 J 0, As, ^H X HI nh ₂ 2—\ l N o OD W 7=2 he CHj III 48 49 N ^HCI LJ HCl mur ^ CH, II ^{3 N} -,<y nh ₂ ,CH ₃ A'P, OH III 54

- 85 040737

50 Oh oh X I δ-f δ-ο ΑΤΌ ΟΗ I 51 51 Ν HCI Ο HCI νη ₂ o-sn ₃ 0, ,----( y—ν° NO Ν=/ )—, Ο I 36 52 /---X /7-^ Ν Ζ^ΑΑ Vi ο ϋ ο ο * * χ ν) \ K /—Ν Ο 0Υ he Ο _ξ sn _; III 66 53 HCI Η - ο • ^c φ νη ₂ Τ / \ Λ—ν Ο w /= ⁷ ο Η 0^ cn ₃ III 54 54 Η ΌΌ HCI Γ Ί nul HCI Όή 1 nh ₂ ^Α ' O _l , ⁰ \ / X )= ⁷ ΟΗ Ο sn ₃ III 39 55 C o O o „ ^{1 X} / I ί υ-ο / \ χ ⁴ ιζ ζ:—( ⁷ τ—ζ ο Ν—> w Υ° but 4=7 \— ° Ο n ₃ with F I 64 56 Ν HCI ΥΤ HCI k-,Ο. 7 |G ^SN \u003d ^ν Α νη ₂ Ο Ό ο ο-ω Τ II 35

- 86 040737

57 Η Ν/ LJ ^HCI X ^ns| II νη ₂ Y 7--\ /7- N 0 \=< \W F )=/ OH o ^z CH, 67 58 ο ο Τ X ο—ς δ-ο \--/ \=2 γτο OH I 56 59 ^HCI Α by [ J γ γ νη ₂ H ₃ C H.cA-- ₄ III 42 60 Η γ ^Ν γ HCI \ HCI N% ι \ ° νη ₂ ch ₃ / CH _? ,/'o, OH cn ₃ III 76 61 η ^NS| Q ^HCI Y nh ₂ ⁰ 7 -/- ⁰ but \=) \-<) o Η ₃ 0 ^Ζ I 26 62 Η .Ν, kk HCI Dy HCI C/ ⁿ nh ₂ X JF^ ° \ /—λ )=/ he o cn ₃ III 19 63 HQ A-° HCI nh ₂ to O 0-0 h I 29

- 87 040737

64 HCl N HCl kJ nh ₂ _^-F -X r-N 0 oU w Y ⁷ he O CH ₃ III 37 65 H HCl Hd LJ ^c nh ₂ H, C^ /—n o ° -\ UCH ) \u003d/ OH 0 CH ₃ III 34 66 H HCl LJ HCl N U CH. II ³ N-^Y nh ₂ ^CH ₃ νά°4 OH CH ₃ III 51 67 H ( J ^HCI y on ll yN nh ₂ '—\ z^N 0 )=/ OH 0 CH ₃ III 60 68 HCl nh ₂ hci 1 HC XJ ³ Loy IT H O-CHj Shch-O n ° b I 62 69 OH :U N CH, Λτ ^{ό n} Y but nh, o\\/° C-/O 0-0 0 I 17 70 hci J HCI 1 J "O. P ^NZS To Ui NH ₂ SN ₃ ---( ό ^N θ )=/ OH o CH ₃ III 47

- 88 040737

71 Η ,ν - .. C' γ on νη ₂ σχχθ sn ₃ he I 27 72 ^NS| Η but. 0 ° φ νη ₂ sn ₃ H.C^ G- Ν O ⁴¹ // W // °\ /—\ \=^ he O sn ₃ III 38 73 Η,Ν. / 0 ^HCI HCI ιι %/Ν νη ₂ Vy he o sn ₃ III 60 74 Η ,Ν Г 1 ^HCI HCI νη ₂ n ₃ s N, sD --- U, -, Ν O ks 0-0 XX Y \u003d / OH 0 CH ₃ III 35 75 Η /Ν Γ J ^HCI XX HCI and %/Ν νη ₂ sn _h Г>^-l O °l W he o SN ₃ III 57 76 Η Γ J HCI I ^HCI and Χ,ν νη ₂ H ₃ S --- H O UCH ON about sleep ₃ III 62 77 η HCI /Ν HCI kY n ₃ s >px νη ₂ SN ₃ G>--C L-N O cd W X^o ⁷ he o SN ₃ III 38

- 89 040737

78 ъ ^m \—/ Ω o o-sn ₃ HO Ν=/ \--<3 I 17 79 n .ha, G J per 1 ^ns| an II ^; v ^N nh ₂ SN ₃ Г>--(' ζ^Ν ,0 0-0 b- 7= ⁷ OH o _to SN ₃ III 43 80 Η Γ Ί HCI on An II ΑχΝ νη ₂ A o co a C and_ I 20

Table 3B. Analytical data for compounds according to the invention 1-80

Comm. No. ESI-MC m/z, M+H ⁺ HPLC R _t (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 h 7 468 0.44 1 8 462 1.02 5 9 480 1.08 5 10 419 1.02 5 eleven 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 h 27 480 0.50 1 28 465 1.02 1 29 438 1.58 2 thirty 441 0.86 3

- 90 040737

31 420 1.48 2 32 467 0.91 3 33 474 1.91 6 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

- 91 040737

65 387 0.65 3 66 466 0.82 1 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 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 intermediate nitro compounds.

[(R)-4-(6-Nitropyridin-3-yl)piperazin-2-yl]methanol hydrochloride

(R)-2-(tert-Butyldimethylsilanyloxymethyl)-4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (1.73 g, 3.82 mmol) in DCM (10 ml) and 4M HCl (9.55 ml, 38.2 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure.

Yield: 950 mg (91%).

[(R)-2-Hydroxymethyl-4-(6-nitropyridin-3-yl)piperazin-1-yl]-(4-methoxy-5-phenoxypyridin-2yl)methanone

[(R)-4-(6-Nitropyridin-3-yl)piperazin-2-yl]methanol hydrochloride (60.0 mg, 0.21 mmol) and 4-methoxy-5-phenoxypyridine-2-carboxylic acid (42 .8 mg, 0.18 mmol) in NMP (500 μl) with TBTU (70.1 mg, 0.22 mmol) and DIPEA (151 μl, 0.87 mmol) was stirred for 18 hours at room temperature. The reaction mixture was purified by reverse phase column chromatography (ACN/water/NH ₄ HCO ₃ ). The residue was purified again by normal phase column chromatography (MeOH/DCM) to give the title compound.

Yield: 95 mg (93%).

[(R)-2-Hydroxymethyl-4-(6-nitropyridin-3-yl)piperazin-1-yl][4-methoxy-5-(4-methoxyphenoxy)pyridin-2-yl]methanone

The title compound was synthesized from [(R)-4-(6-nitropyridin-3-yl)piperazin-2-92 040737yl]methanol hydrochloride (60.0 mg, 0.22 mmol) and 4-methoxy-5- (4-methoxyphenoxy)pyridine-2-carboxylic acid (48.1 mg, 0.18 mmol) according to the procedure described for the synthesis of intermediate [(R)-2-hydroxymethyl-4-(6-nitropyridine-3- yl)piperazin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)methanone.

Yield: 102 mg (quantitative) ESI-MS: m/z=496 (M+H) + R _t (HPLC): 0.78 min (Method 1).

Procedure.

IV. The nitro intermediate (1 eq.) and Pd/C (10%) in MeOH are stirred for 20 hours at room temperature under a hydrogen atmosphere. The reaction mixture was 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 reverse phase column chromatography (ACN/water, herringbone or acidic conditions).

Table 4 Procedures for the Preparation of Compounds of the Invention 81 and 82

Comm. No. intermediate nitro compound General procedure Exit d % ESI-MC m/z M+H ⁺ HPLC Rt (min.) Method HPLC 81 sn ₃ o _G ^he ί * ο IV 47 436 0.75 1 82 .on si ₃ CH ₃ o Z • 1%.. IV 36 466 0.74 1

Compounds of the invention 83-89 are typically prepared by reacting a carboxylic acid intermediate with an amine intermediate under conditions similar to those described for General Procedure (I) in Table 1. 3A. Analysis of compounds according to the invention 83-89 summarized in table. 5V.

Synthesis of intermediate compounds.

4-Ethoxy-5-phenoxypicolinonitrile

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 hours. The reaction mixture was then diluted with ethyl acetate (50 ml), washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography.

Yield: 530 mg (73%) m/z=241 (M+H)+.

4-Ethoxy-5-phenoxypicolinic acid

A mixture of 4-ethoxy-5-phenoxypicolinonitrile (530 mg, 2.21 mmol) in 2N sodium hydroxide solution (10 ml) was stirred at 100° C. overnight. The reaction mixture was then acidified with 1N HCl to adjust to pH 4 and extracted with DCM (20 ml x2). The combined organic phases are separated and dried over Na ₂ SO ₄ , filtered and concentrated to give the desired product which can be used without further purification.

Yield: 420 mg (73%) m/z=260 (M+H)+.

tert-Butyl 6-amino-4-cyclopropoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-1'-carboxylate

- 93 040737

To a stirred mixture of 5-bromo-4-cyclopropoxypyridine-2-amine (2.1 g, 9.17 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan- 2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (4.25 g, 13.75 mmol) and CS ₂ CO ₃ (9.0 g, 27.50 mmol) in dioxane (60 ml) and water (12 ml) at room temperature under nitrogen atmosphere, Pd(dppf)Cl ₂ (200 mg, 0.27 mmol) is added. The resulting mixture was stirred at 90° C. for 4 hours. The reaction mixture was then poured into ice water and extracted with DCM (50 ml x3). The combined organic phases are washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to obtain the desired product.

Yield: 3 g (98%) m/z=332 (M+H) ⁺ .

tert-Butyl 4-(6-amino-4-cyclopropoxypyridin-3-yl)piperidine-1-carboxylate

To a solution of tert-butyl 6-amino-4-cyclopropoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-1'-carboxylate (3 g, 9.05 mmol) in EtOH (40 ml) was added with Pd(OH) ₂ /C (2 g). The resulting reaction mixture was stirred at 25° C. under hydrogen atmosphere for 16 hours. The catalyst was filtered off through Celite® and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

Yield: 1.8 g (60%) m/z=334 (M+H)+.

4-Cyclopropoxy-5-(piperidin-4-yl)pyridine-2-amine dihydrochloride

tert-Butyl 4-(6-amino-4-cyclopropoxypyridin-3-yl)piperidine-1-carboxylate (1.6 g, 4.8 mmol) was dissolved in a solution of HCl(g) in EtOH (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure. The crude product is then triturated with Et2O to give the desired product which can be used without further purification.

Yield: 1 g (90%) m/z=234 (M+H) ⁺ .

tert-Butyl (4-propoxypyridin-2-yl) carbamate

To a stirred solution of 2-aminopyridin-4-ol (1.25 g, 11.4 mmol) in N,N-dimethylacetamide (15 ml) was added cesium carbonate (7.42 g, 22.8 mmol), propyl bromide (1. 24 ml, 13.6 mmol) and cesium iodide (2.95 g, 11.4 mmol). The resulting mixture was stirred at 100° C. for 1 day. To the reactionary

- 94 040737 di-tert-butyl dicarbonate (2.74 g, 12.6 mmol) is added to the mixture and stirred at 100° C. for 16

h. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (50 ml). The phases are separated and the organic layer is concentrated. The crude mixture was purified by silica gel column chromatography to give the desired product.

Yield: 787 mg (27%) m/z=253 (M+H)+.

tert-Butyl (5-bromo-4-propoxypyridin-2-yl) carbamate

Bromine (0.40 g, 2.49 mmol, in 1 ml acetic acid) dropwise at 0°C. After 0.5 h, additional acetic acid (8 ml) was added and the reaction mixture was allowed to warm to room temperature. After 1 hour, the mixture was concentrated and purified by silica gel column chromatography to give the desired product.

Yield: 255 mg (31%) m/z=331 (M+H)+.

tert-Butyl 1'-carboxylate

6-{[(tert-butoxy)carbonyl]amino}-4-propoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-

To a solution of tert-butyl (5-bromo-4-propoxypyridin-2-yl)carbamate (254 mg, 0.77 mmol) in dioxane (4 ml) was added tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2Hpyridine-1-carboxylic acid (596 mg, 1.93 mmol), sodium carbonate (2M aqueous solution, 0.77 ml) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56 mg, 0.077 mmol). The reaction mixture was stirred at 100° C. for 24 hours. The reaction mixture was diluted with EtOAc (10 ml) and filtered through a pad of SuperCell filter agent. The filtrate is concentrated and purified by silica gel column chromatography to obtain the desired product.

Yield: 333 mg (quantitative) m/z=434 (M+H)+.

tert-Butyl 4-(6-((tert-butoxycarbonyl)amino)-4-propoxypyridin-3-yl)piperidine-1-carboxylate

To tert-butyl 6-{[(tert-butoxy)carbonyl]amino}-4-propoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]1'-carboxylate (333 mg, 0.77 mmol) in EtOH (18 ml) and EtOAc (3 ml) add palladium hydroxide on carbon (20% moisture, 27 mg). The reaction mixture is stirred under a hydrogen atmosphere (43 psi ² (3.023 kg/cm ² )) for 3 days and filtered through SuperCell filter agent. The filtrate is concentrated under reduced pressure to give the desired product.

Yield: 330 mg (98%) m/z=436 (M+H)+.

-(Piperidin-4-yl)-4-propoxypyridin-2-amine dihydrochloride

A solution of HCl in dioxane (2.00 ml, 4M, 8.0 mmol). The reaction mixture is stirred for 16 hours and concentrated. The residue is triturated with DCM and dried in vacuo to give the desired product.

Yield: 233 mg quantitative.

- 95 040737

4-Ethoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride can be synthesized similarly

4-Ethoxy-5-(piperidin-4-yl)pyridin-2-amine dihydrochloride protocol for the synthesis of 5-(piperidin-4-yl)-4-propoxypyridin-2-amine dihydrochloride. Alkylation of 2-aminopyridin-4-ol with ethyl bromide and subsequent Boc protection leads to the formation of tert-butyl N-(4-ethoxypyridin-2-yl)carbamate. Bromination of tert-butyl N-(4-ethoxypyridin-2-yl)carbamate leads to the synthesis of tert-butyl (5-bromo-4-ethoxypyridin-2-yl)carbamate. Subsequent reaction with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2Hpyridine-1-carboxylic acid tert-butyl ester leads to the formation of tert -butyl 6-{[(tert-butoxy)carbonyl]amino}4-ethoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-1'-carboxylate. In the next step, tert-butyl 4-(6((tert-butoxycarbonyl)amino)-4-ethoxypyridin-3-yl)piperidine-1-carboxylate is obtained by hydrogenation. Cleavage of the Boc protecting group leads to the synthesis of 4-ethoxy-5-(piperidin-4-yl)pyridin-2amine dihydrochloride.

tert-Butyl 3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

To tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]-oct-2-en-8-carboxylate (1 .93 g, 5.75 mmol) and 6-bromopyridazin-3-amine (1.00 g, 5.75 mmol) in 1,4-dioxane (25 ml) was added an aqueous solution of 2M Na ₂ CO ₃ (11.5 ml, 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 hours. All volatiles are evaporated off under reduced pressure. The crude material is purified by normal phase chromatography to give the title compound.

Yield: 0.80 g (46%) ESI-MS: m/z=303 (M+H)+.

tert-Butyl-3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

To tert-butyl 3-(6-aminopyridazin-3-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (0.80 g, 2.65 mmol) in MeOH (30 ml) add Pd/C (250 mg) under nitrogen atmosphere. The reaction mixture is degassed and hydrogenated under a hydrogen atmosphere at 3 bar at room temperature overnight. The reaction mixture is filtered and concentrated under reduced pressure.

Yield: 800 mg (quantitative) ESI-MS: m/z=305 (M+H)+.

6-{8-Azabicyclo[3.2.1]octan-3-yl}pyridazin-3-amine dihydrochloride

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 was added 4 M HCl in 1,4 dioxane and stirred at room temperature until the reaction is complete. All volatiles are evaporated off under reduced pressure.

Yield: 700 mg (96%) ESI-MS: m/z=205 (M+H)+.

2-Chloro-5-fluoro-4-methoxypyridine

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_Iodomethane (1.15 _g , 8.13 mmol) at room temperature. The resulting reaction mixture was

stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (30 ml x2). The combined organic phases are washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

Yield: 1 g (91%) m/z=162 (M+H)+.

-Fluoro-4-methoxypicolinonitrile

To 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 room temperature under nitrogen atmosphere, Pd ₂ (dba) ₃ (56 mg, 0.62 mmol) is added. The reaction mixture was stirred at 150° C. under nitrogen atmosphere for 3 hours. The reaction mixture was then diluted with water (30 ml)) and extracted with EtOAc (30 ml x 2). The combined organic phases are washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

Yield: 700 mg (74%) m/z=153 (M+H) ⁺ .

4-Methoxy-5-(4-(trifluoromethyl)phenoxy)picolinonitrile

To 5-fluoro-4-methoxypicolinonitrile (700 mg, 4.6 mmol) in DMF (10 mL) was added 4-(trifluoromethyl)phenol (746 mg, 4.6 mmol) and K ₂ CO ₃ (636 mg, 4.6 mmol) 6 mmol). The reaction mixture was stirred at

100° C. for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (20 ml x 2). The combined organic phases are combined, washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

Yield: 1 g (80%) m/z=295 (M+H)+.

4-Methoxy-5-(4-(trifluoromethyl)phenoxy)picolinic acid

To a solution of NaOH (1.6 g, 40 mmol) in water (20 ml) was added 4-methoxy-5-(4-(trifluoromethyl)phenoxy)picolinonitrile (700 mg, 2.4 mmol). The reaction mixture is stirred at 100° C. overnight. The reaction mixture was acidified with a 6M HCl solution to bring to pH 2, extracted with

EtOAc (30 ml x 2). The combined organic phases are washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product which can be used directly without further purification. Yield: 700 mg (94%) m/z=314 (M+H)+.

2-Chloro-5-fluoropyridin-4-ol

Lithium diisopropylamide (24.7 ml, 49.4 mmol, 2M in tetrahydro furan) drop by drop over 30 minutes. The reaction mixture was stirred at -78°C for 2 hours. Then

- 97 040737 a solution of trimethyl borate (7.9 g, 76.03 mmol) in tetrahydrofuran (10 ml) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was cooled to 0° C. and acetic acid (6.5 ml) was added. The reaction mixture was stirred at 0° C. for 30 minutes. Added dropwise hydrogen peroxide (11.5 ml, 30% solution) at 0°C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaS ₂ O ₄ . A 5N HCl solution was added to the reaction mixture. After extraction with EtOAc (50 ml x 3), the combined organic phases are washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography to obtain the desired product.

Yield: 3.8 g (68%) . m/z=149 (M+H)+.

2-Chloro-4-ethoxy-5-fluoropyridine

To 2-chloro-5-fluoropyridin-4-ol (2, 3.0 g, 20.33 mmol) and silver(I) carbonate (8.4 g, 30.50 mmol) in

DMF (50 ml) iodoethane (9.51 g, 61.00 mmol) is added at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate (100 ml) and washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product. Yield: 3.0 g (84%) m/z=177 (M+H)+.

4-Ethoxy-5-fluoropicolinonitrile

To 2-chloro-4-ethoxy-5-fluoropyridine (300 mg, 1.71 mmol) in DMF (10 ml) was added dicyanozinc (141 mg, 1.2 mmol), zinc (22.3 mg, 0.34 mmol ) and Pd(dppf)Cl ₂ (50 mg) under nitrogen atmosphere. The reaction mixture was stirred at 150° C. for 3 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

Yield: 220 mg (78%) LC-MS: m/z 167 [M+H]+.

4-Ethoxy-5-(4-fluorophenoxy)picolinonitrile

To 4-fluorophenol (202 mg, 1.81 mmol) and K2CO3 (249 mg, 1.81 mmol) in DMF (5 mL) was added 4-ethoxy-5-fluoropycolinonitrile (200 mg, 1.2 mmol) in one portion. The reaction mixture was stirred at 100° C. for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate (20 ml), washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired product.

Yield: 220 mg (71%) m/z=259 (M+H)+.

4-Ethoxy-5-(4-fluorophenoxy)picolinic acid

A mixture of 4-ethoxy-5-(4-fluorophenoxy)picolinonitrile (500 mg, 1.94 mmol) in aqueous 2N sodium hydroxide solution (10 ml) was stirred at 100° C. overnight. After cooling, the reaction mixture was acidified with 1N aqueous HCl to adjust to pH 4 and extracted with DCM (20 ml x 2). The combined organic phases are washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude desired product.

Yield: 490 mg (91%) m/z=278 (M+H)+.

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Table 5A. Procedures for the Preparation of Compounds of the Invention 83-89

Comm. No. Amino intermediate connection Carboxy acid intermediate General Procedure Exit % 83 hn^A hci ]| H HCI ν.Α,Η ₂ O j o O— ⁷ o t I 32 84 ΗνΆ cA^ AAA ^HCI on ί A N NH. O About 0-0 X about I 33 85 hn'A o%h ₃ HCI hci Anh, θ ^Η 3 O o .. A oA I 66 86 HN'A O— naCA! HCI νΆη, / Ooo R I 20 87 hn'A cAh, -aa HCI N NH ₂ sn ₃ o ΆΐΡ I 18 88 HlA L A. a- HCl^|f I ¹ HCI AA _N h ₃ D O O—h A ABOUT I 21 89 HCI d o o— C! ABOUT I I 15

Table 5B. Analytical data for compounds of the invention 83-89

Comm. No. ESI-MC m/z, M+H ⁺ HPLC R _t (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.

Procedures for obtaining compounds according to the invention 90 and 91 are summarized in table. 6A. The analysis of compounds according to the invention 90 and 91 are summarized in table. 6B.

V. DIPEA (3.0 eq) and HATU (1.0 eq) were added to carboxylic acid (1.0 eq) (intermediate 2 in the following Table 6A) in DMF and the reaction was stirred for 30 min. at room temperature. An amine (1.0 eq.) (intermediate 1 in the following Table 6A) was added and the reaction mixture was stirred overnight. The filtered reaction mixture was purified by reverse phase column chromatography (ACN/water+TFA or basic conditions).

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Table 6A. General Procedures for the Preparation of Compounds of the Invention 90 and 91

Comm. No. amine (intermediate connection 1) carboxylic acid (intermediate 2) General procedure Exit % 90 n HCI 0™ mHk ^SNz 0 nh ₂ O A 0-0 o .0 Ll Ll. V 55 91 A BUT, LJ HCI L ^sn nh ₂ Ar OK About I V 31

Table 6B. Analytical Data for Compounds of the Invention 90 and 91

Comm. No. ESI-MC m/z, M+H ⁺ HPLC R _t (min.) 90 488 0.86 (Method 7) 91 474 0.87 (Method 7)

Compounds 92 and 93.

TFA salt of 4-methoxy-5-[1-(4-methoxy-5-{[3-(trifluoromethyl)cyclobutyl]methoxy}pyridine-2-carbonyl)piperidin-4-yl]pyridine-2-amine

4-Methoxy-5-(3-trifluoromethylcyclobutylmethoxy)pyridine-2-carboxylic acid (40 mg, 0.13 mmol), DIPEA (113 µl, 0.66 mmol), HATU (54 mg, 0.144 mmol) and 4-methoxy -5-(piperidin-4yl)pyridine-2-amine dihydrochloride (37 mg, 0.13 mmol) in DMF (2 ml) was stirred overnight at room temperature. The reaction mixture was purified by reverse phase column chromatography (ACN/water+TFA) to give both stereoisomers.

Yield: compound 92 (trans-isomer): 5 mg (6%) HPLC R _t : 0.50 min (Method 12) and compound 93 (cis-isomer): 8 mg (10%) HPLC R _t : 0.48 min (Method 12), ESI-MS: m/z=495 (M+H) ⁺ .

Compound 94.

4-Methoxy-5-{1-[4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carbonyl]piperidine-4 yl}pyridine-2-amine

4-Methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carboxylic acid (110 mg, 0.39 mmol), DIPEA (271 µl, 1.58 mmol), HATU (150 mg , 0.39 mmol) and 4-methoxy-5-(piperidin-4-yl)pyridine-2amine dihydrochloride (121 mg, 0.43 mmol) in DMF (2 ml) were stirred for 2 hours at room temperature. The reaction mixture was purified by reverse phase column chromatography.

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Yield: 110 mg (60%) ESI-MS: m/z=469 (M+H) + HPLC Rt: 0.71 min (Method 13).

Enantiomers of 4-methoxy-5-(1-{4-methoxy-5-[3,3,3-trifluoro-2-methylpropoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridine-2-amine (94) :

4-methoxy-5-(1-{4-methoxy-5-[(2S)-3,3,3-trifluoro-2-methylpropoxy]pyridine-2-arbonyl}pineridin4-yl)pyridine-2-amine and 4 -methoxy-5-(1-{4-methoxy-5-[(2R)-3,3,3-trifluoro-2-methylpropoxy]niridine-2carbonyl}piperidin-4-yl)pyridine-2-amine

4-Methoxy-5-{1-[4-methoxy-5-(3,3,3-trifluoro-2-methylpropoxy)pyridine-2-carbonyl]piperidin-4yl}pyridine-2-amine (292 mg, 0. 62 mmol) was then separated by chiral supercritical fluid chromatography (SFC, supercritical carbon dioxide/20 mM NH3 in EtOH, Chiral ART,® Amylose-SC

20x250 mm, 5 μM) to give both enantiomers 94a (first eluting fraction) and 94b (second eluting fraction). Stereochemistry assigned randomly.

Yield: 70 mg (48%, compound 94a; R _t : 5.69 min) and 74 mg (50%, compound 94b; R _t : 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). Add di-tert-butyl-(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-biphenyl-2-yl)-phosphane (1.57 g, 3.27 mmol) and tris (dibenzylideneacetone)dipalladium(0) (949 mg, 1.04 mmol) under argon. The reaction mixture was stirred at

100° C. for 2 hours. The reaction mixture is filtered and concentrated under reduced pressure. The residue is acidified with a 4M HCl solution and the solid is filtered. The liquid phase is concentrated and the precipitate is collected, washed and dried.

Yield: 2.61 g (76%) ESI-MS: m/z=170 (M+H) ⁺ .

6-[4-(6-Amino-4-methoxypyridin-3-yl)piperidine-1-carbonyl]-4-methoxypyridin-3-ol

DIPEA (407 µl, 2.36 mmol) and 4-methoxy-5-(piperidine-4 -yl)pyridine-2-amine dihydrochloride (331 mg, 1.18 mmol). HATU (225 mg, 0.59 mmol) is then added. The reaction mixture was stirred overnight at room temperature and purified by reverse phase column chromatography to give the title compound.

Yield: 140 mg (66%) ESI-MS: m/z=359 (M+H) ⁺ R _t (HPLC): 0.61 min (Method 10).

General procedures.

The procedure for obtaining compounds 95 according to the invention is summarized in table. 7A. Analysis of compound 95 according to the invention is summarized in table. 7B.

VI.

To 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 1 in the following Table 7A), TPP (2.7 eq) and DTAD (2.5 eq) are added. The reaction mixture was stirred at 60° C. for 1 hour. If the reaction shows complete conversion, the reaction mixture is purified by reverse phase column chromatography (ACN/water+TFA).

If the reaction does not show completion, add more TPP (2.7 eq) and

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DTAD (2.5 eq) until conversion occurs. After each addition, the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was purified by reverse phase column chromatography (ACN/water+TFA).

Table 7A. General Procedures for the Preparation of a Compound of the Invention 95

Comm. No. alcohol (intermediate connection 1) core (intermediate connection 2) I am a fool Exit % 95 /F F ooo VI quantity

Table 7B. Analytical data for the compound of the invention 95

Comm. No. ESI-MC m/z, M+H ⁺ HPLC R _t (min.) 95 463 0.65 (Method 13)

Alternative preparation of compound 1.

5-{4-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperazin-1-yl}-4-methoxypyridine-2amine 5-bromo-2-(2,5-dimethyl-1H-pyrrole -1-yl)-4-methoxypyridine

5-Bromo-4-methoxypyridin-2-ylamine (9.50 g, 46.79 mmol), hexane-2,5-dione (7.08 ml, 60.83 mmol) and p-toluenesulfonic acid (0.81 g, 4.68 mmol) in toluene (80 ml) was stirred overnight at 120° C. using a Dean-Stark apparatus. The reaction mixture is concentrated under reduced pressure, taken up in DCM and purified by silica gel chromatography (DCM).

Yield: 7.60 g (58%) ESI-MS: m/z=281 [M+H]+ ^(HPLC): 1.13 min (Method 7).

1-[6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine bis(trifluoroacetic acid).

The reaction is carried out in an argon atmosphere. 5-bromo-2-(2,5-dimethyl-1H-n-pyrrol-1-yl)-4methoxypyridine (1.00 g, 3.56 mmol), tert-butylpiperazine-1-carboxylate (0.73 g, 3.56 mmol) 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) were stirred overnight at 80°C . The reaction mixture is filtered and concentrated under reduced pressure. The residue is taken up in DCM (20 ml) and TFA (1.37 ml; 17.76 mmol) is added. The reaction mixture is stirred for 3 days at room temperature and after adding 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-MS: m/z=287 [M+H] ⁺ Rt (HPLC): 0.67 min (Method 7).

4-Methoxy-5-(piperazin-1-yl)pyridine-2-amine

1-[6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl]piperazine bis(trifluoroacetic acid) (1.20 g, 2.33 mmol), hydroxylamine hydrochloride ( 0.70 g, 10.03 mmol) and triethylamine (1.00 ml, 7.11 mmol) in EtOH/water (1/1; 16 ml) were stirred overnight at 80°C. The organic solvent is removed under reduced pressure. The residue was purified by RP-HPLC (ACN/water+NH ₃ ).

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Yield: 290 mg (60%) ESI-MS: m/z=209 [M+H] ⁺ R _t (HPLC): 0.35 min (Method 11).

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonitrile

5-Fluoro-4-methoxypyridine-2-carbonitrile (1.00 g; 6.57 mmol), 4-fluorophenol (0.88 g; 7.89 mmol) and potassium carbonate (2.00 g; 14.46 mmol ) was stirred in NMP at 105° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and extracted with EtOAc. The organic layer is washed with water and brine, separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is triturated with PE, filtered, and dried in a drying oven at 60°C.

Yield: 1.54 g (96%) ESI-MS: m/z=245 [M+H]+R _t (HPLC): 1.03 min (Method 7).

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonitrile (1.54 g; 6.31 mmol) and NaOH (2 mol/l, aqueous solution; 15.40 ml, 30.80 mmol) were stirred at 105°C for 10 hours the Reaction mixture is allowed to cool to room temperature and left to stand for 3 days. The precipitate obtained is filtered and triturated with water. The reaction mixture is heated to 50°C and the pH is adjusted to pH 7 using HCl (4 mol/l, aqueous solution). The precipitate obtained 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).

5-{4-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperazin-1-yl}-4-methoxypyridine-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) was stirred for 30 min at room temperature. 4-Methoxy-5-(piperazin-1-yl)pyridine-2-amine (0.52 g; 1.98 mmol) is added and the reaction mixture is left to stir at room temperature overnight. The mixture was purified by RP-HPLC (ACN/aq+NH ₃ ).

Yield: 0.31 g (36%) ESI-MS: m/z=454 [M+H] ⁺ R _t HPLC): 0.88 min (Method 11).

Alternative preparation of compound 39.

4-Methoxy-5-{1-[4-methoxy-5-(2-methylpropoxy)pyridine-2-carbonyl]piperidin-4-yl}pyridine-2amine trifluoroacetic acid.

Methyl 4-methoxy-5-(2-methylpropoxy)pyridine-2-carboxylate

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 , 6.55 mmol) in THF was stirred for 10 minutes at room temperature. 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 was purified by RP-HPLC (ACN/water+TFA).

Yield: 0.30 g (57%) ESI-MS: m/z=240 [M+H] ⁺ R _t (HPLC): 0.85 min (Method 7).

4-Methoxy-5-(2-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) was stirred at room temperature in

- 103 040737 within 3 days. The pH of the reaction mixture was neutralized using HCl (4 mol/l; aq. solution) and the solvents were removed under reduced pressure. To the residue is added DCM and a small amount

Meon. The insoluble matter is filtered off and the mother liquor is removed under reduced pressure. The residue is used without further purification.

Yield: 0.20 g (71%) ESI-MS: m/z=226 [M+H]+ R _t (HPLC): 0.76 min (Method 7).

tert-Butyl 6-amino-4-methoxy-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-1'-carboxylate

The reaction is carried out in an argon atmosphere. 5-Bromo-4-methoxypyridin-2-amine (7.40 g; 32.80 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1,2,3,6-tetrahydropyridine-1-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) was flushed with argon. After 5 minutes Xphos 2nd generation (0.77 g; 0.98 mmol) is added and the reaction mixture is stirred overnight in a sealed vessel at 100°C. The reaction mixture is concentrated under reduced pressure. The residue is taken up in water and extracted several times with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (DCM/MeOH).

Yield: 9.69 g (97%) ESI-MS: m/z=306 [M+H]+ R _t (HPLC): 0.83 min (Method 10).

tert-Butyl 4-(6-amino-4-methoxypyridin-3-yl)piperidine-1-carboxylate

In a hydrogen atmosphere (Parr apparatus; 50 psi (3.515 kg/cm ² )) tert-butyl 6-amino-4-methoxy 1', ² ',3',6'-tetrahydro-[3,4'-bipyridine ]-1'-carboxylate (5.11 g; 16.73 mmol) and Pd/C (10%; 0.60 g) in MeOH (100 ml) were stirred at room temperature for 41.5 h. Added twice additional catalyst and the reaction mixture is hydrogenated again. After removing the catalyst by filtration, the mother liquor is concentrated under reduced pressure. The product was used without further purification.

Yield: 4.71 g (92%) ESI-MS: m/z=308 [M+H] ⁺ R _t (HPLC): 0.82 min (Method 10).

4-Methoxy-5-(piperidin-4-yl)pyridine-2-amine dihydrochloride

tert-Butyl 4-(6-amino-4-methoxypyridin-3-yl)piperidine-1-carboxylate (6.90 g; 22.45 mmol) and HCl (4 mol/l; solution in 1,4-dioxane); 69.00 ml; 224.47 mmol) in DCM (89.70 ml) was stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue is triturated with EE and filtered. The product was used without further purification.

Yield: 5.30 g (84%) ESI-MS: m/z=208 [M+H] + R _t (HPLC): 0.66 min (Method 11) 4-methoxy-5-{1-[4trifluoroacetic methoxy-5-(2-methylpropoxy)pyridine-2-carbonyl]piperidin-4-yl}-pyridine-2-amino acid

4-Methoxy-5-(2-methylpropoxy)pyridine-2-carboxylic acid (80mg; 0.36mmol), 4-methoxy-5(piperidin-4-yl)pyridine-2-amine dihydrochloride (96mg; 0 .36 mmol), DIPEA (0.24 ml; 1.42 mmol) and HATU (149 mg; 0.39 mmol) in DMF (3 ml) were stirred at room temperature overnight. The reaction mixture was purified by RP-HPLC (ACN/water+TFA).

Yield: 0.11 g (72%) ESI-MS: m/z=415 [M+H] ⁺ R _t (HPLC): 0.80 min (Method 7).

Alternative preparation of compound 17.

6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridin-2-carbonyl]piperidin-4-yl}pyridazin-3-amine tert-butyl 4-(6-aminopyridazin-3-yl)-1,2, 3,6-tetrahydropyridine-1-carboxylate

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The reaction is carried out in an argon atmosphere. 6-Chloropyridazin-3-amine (5.20 g; 40.14 mmol), tert-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) purged with argon. After 5 minutes Xphos 2nd generation (0.95 g; 1.20 mmol) is added and the mixture is stirred overnight in a sealed vessel at 100°C. The reaction mixture is filtered and concentrated under reduced pressure. The residue is taken up in MeOH, precipitated with water and filtered. The resulting precipitate is dried in a drying oven at 50°C. The product was used without further purification.

Yield: quantitative ESI-MS: m/z=277 [M+H] ⁺ R _t (HPLC): 0.78 min (Method 10).

tert-Butyl 4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate

In a hydrogen atmosphere (Parr apparatus; 4 bar) tert-butyl 4-(6-aminopyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.85 g; 17.55 mmol) and Pd/ C (10%; 0.50 g) in MeOH (100 ml) was stirred at room temperature for 3 hours. After removal of the catalyst by filtration, the mother liquor was concentrated under reduced pressure. The product was used without further purification.

Yield: quantitative ESI-MS: m/z=279 [M+H] ⁺ R _t (HPLC): 0.86 (method 11).

6-(Piperidin-4-yl)pyridazin-3-amine

tert-Butyl 4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate (4.89 g, 17.55 mmol) was stirred for 1 h in TFA (20 mL, 259.25 mmol). The solvent is evaporated off and the residue is purified by silica gel chromatography (DCM/MeOH+NH ₃ ).

Yield: Quantitative ESI-MS: m/z=179 [M+H] ⁺ R _t (HPLC): injection peak (Method 11).

An alternative amine used.

6-(Piperidin-4-yl)pyridazin-3-amine dihydrochloride

The reaction is carried out under a nitrogen atmosphere. tert-Butyl 4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate (1.00 g; 3.59 mmol) and HCl (4 mol/l, solution in 1,4-dioxane; 2.96 ml; 11 .84 mmol) in ACN (6 ml) was stirred at 35-40°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with isopropyl acetate. After stirring for 10 min, the resulting precipitate was filtered off and dried in a drying oven at 45°C.

Yield: quantitative ESI-MS: m/z=179 [M+H] ⁺ R _t (HPLC): 0.94 min (Method 14).

6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}pyridazin-3-amine

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) was stirred for 30 min. Add 6-(piperidin-4-yl)pyridazin-3-amine (0.71 g; 3.98 mmol) and the reaction mixture is left to stir at room temperature overnight. The mixture was purified by RP-HPLC (ACN/water+TFA). To remove the trifluoroacetate salt, the product is taken up in water/EtOH (1.5/1) and triturated with polymer-bound bicarbonate. After stirring for 30 minutes, the mixture is filtered and concentrated under reduced pressure.

Yield: 180 mg (16%) ESI-MS: m/z=424 [M+H] ⁺ R _t (HPLC): 0.77 min (Method 7).

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Alternatively, the header connection can be obtained as follows:

6-{1-[5-(4-fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}pyridazin-3-amine

5-(4-Fluorophenoxy)-4-methoxypyridine-2-carboxylic acid (0.50 g; 1.90 mmol) and CDI (0.46 g; 2.85 mmol) in NMP (1 ml) stirred at room temperature over 1 hour. Add 6(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.52 g; 2.09 mmol) and DIPEA (0.99 ml; 5.70 mmol). After stirring for 3 hours, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer is separated, washed with water and brine, dried over MgSO ₄ and filtered. The mother liquor 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/ethyl ether to give the title product in solid form.

Yield: 0.27 g (34%) ESI-MS: m/z=424 [M+H] ⁺ R _t HPLC): 0.49 min (Method 1).

Alternative preparation of compound 37.

5-{1-[5-(Cyclopropylmethoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}-4-methoxypyridine-2-amine.

Methyl 5-(cyclopropylmethoxy)-4-methoxypyridine-2-carboxylate

Methyl 5-hydroxy-4-methoxypyridine-2-carboxylate (0.20 g; 1.09 mmol) and cyclopropylmethanol (88 μl; 1.09 mmol) in THF (3 ml) are cooled in an ice bath. 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 room temperature overnight. The reaction mixture is concentrated under reduced pressure and purified by RP-HPLC (ACN/aq+TFA).

Yield: 0.18 g (70%) ESI-MS: m/z=238 [M+H] ⁺ R _t (HPLC): 0.41 min (Method 12).

5-(Cyclopropylmethoxy)-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) in MeOH ( 3 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue is taken up in water and washed with EtOAc. HCl (4 mol/l, aq. solution; 0.5 ml) was added to the aqueous layer and concentrated under reduced pressure. The product was used without further purification.

Yield: 0.13 g (74%) ESI-MS: m/z=224 [M+H] ⁺ R _t (HPLC): 0.30 min (Method 12) 5-{1-[5-(cyclopropylmethoxy) -4-methoxypyridine-2-carbonyl]piperidin-4-yl}-4-methoxypyridine-2-amine

5-(Cyclopropylmethoxy)-4-methoxypyridine-2-carboxylic acid (50 mg; 0.22 mmol), 4-methoxy5-(piperidin-4-yl)pyridin-2-amine dihydrochloride (63 mg; 0.22 mmol) , DIPEA (193 μl; 1.12 mmol) and HATU (94 mg; 0.25 mmol) in DMF (2 ml) were stirred at room temperature overnight. The resulting mixture was purified by RP-HPLC (ACN/ _water +NH ₃ ).

Yield: 45 mg (49%) ESI-MS: m/z=413 [M+H] ⁺ R _t (HPLC): 0.87 min (Method 11).

Alternative preparation of compound 90.

6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine trifluoroacetic acid 4-methoxy-5-[4 -(trifluoromethyl)phenoxy]pyridine-2-carbonitrile

- 106 040737

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; 46.27 mmol ) was stirred in DMSO at 110° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and diluted with water. The precipitate obtained is filtered, washed with water, and dried in a drying oven at 50°C.

Yield: 7.40 g (82%) ESI-MS: m/z=295 [M+H] + Rt (HPLC): 1.08 min (Method 10).

4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carboxylic 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, 125.75 mmol) in MeOH (100 ml) was stirred at 70° C. overnight. The reaction mixture is allowed to cool to room temperature 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 precipitate obtained is filtered and dried in a drying oven at 50°C.

Yield: 6.80 g (51%) ESI-MS: m/z=314 [M+H] ⁺ R _t (HPLC): 0.87 min (Method 10).

tert-Butyl 4-(6-amino-4-methylpyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

The reaction is carried out in an argon atmosphere. 6-Chloro-5-methylpyridazin-3-amine (3.00 g; 20.90 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1,2,3,6-tetrahydropyridine-1-carboxylate (7.11 g; 22.98 mmol) and sodium carbonate (2 mol/l, aq. solution; 41.79 ml; 83.58 mmol) in 1,4dioxane (150 ml) was flushed with argon. After 5 minutes Xphos 2nd generation (0.49 g; 0.63 mmol) is added and the mixture is stirred overnight in a sealed vessel at 100°C. The reaction mixture is concentrated under reduced pressure. The residue is taken up in water and extracted several times with EtOAc. The combined organic layers are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure.

The residue is purified by silica gel chromatography (DCM/MeOH).

Yield: 5.20 g (86%) ESI-MS: m/z=291 [M+H]+ R _t (HPLC): 0.79 min (Method 10).

tert-Butyl 4-(6-amino-4-methylpyridazin-3-yl)piperidine-1-carboxylate

In a hydrogen atmosphere (Parr apparatus; 50 psi (3.515 kg/cm ² )) tert-butyl 4-(6-amino-4methylpyridazin-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) were stirred at room temperature for 17 hours. After removal of the catalyst by filtration, the mother liquor was concentrated under reduced pressure.

Yield: 5.00 g (96%) ESI-MS: m/z=293 [M+H] + Rt (HPLC): 0.79 min (Method 10).

5-Methyl-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride

tert-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 1,4-dioxane (34.37 ml) was stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue is triturated with EtOAc and filtered. The product was used without further purification.

Yield: quantitative ESI-MS: m/z=193 [M+H] ⁺ R _t (HPLC): 0.59 min (Method 11).

6-(1-{4-Methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5methylpyridazin-3-amine trifluoroacetic acid

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 (0.19 ml; 1.11 mmol) in DMF (3 ml) was stirred for 30 minutes. Add 5-methyl-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.10 g; 0.38 mmol) and the reaction mixture is left to stir at room temperature overnight. The reaction mixture was purified by RP-HPLC (ACN/water+TFA).

Yield: 0.12 g (55%) ESI-MS: m/z=488 [M+H]+ AQ(HPLC): 0.86 min (Method 7).

Alternative preparation of compound 47.

5-Methoxy-6-[1-(4-methoxy-5-phenoxypyridine-2-carbonyl)piperidin-4-yl]pyridazin-3-amine 4methoxy-5-phenoxypyridine-2-carbonitrile

5-Fluoro-4-methoxypyridine-2-carbonitrile (0.40 g; 2.63 mmol), phenol (0.25 g; 2.66 mmol mmol) and potassium carbonate (0.54 g; 3.91 mmol) stirred in DMSO (10 ml) at 110° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and diluted with water. The aqueous layer is extracted several times with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure.

Yield: 0.55 g (92%) ESI-MS: m/z=227 [M+H]+ R _t (HPLC): 1.01 min (Method 7).

4-Methoxy-5-phenoxypyridine-2-carboxylic acid

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) in MeOH (10 ml) stirred at 70° C. overnight. The reaction mixture is allowed to cool to room temperature 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 precipitate obtained is filtered and dried in a desiccator.

Yield: 0.30 g (51%) ESI-MS: m/z=246 [M+H] ⁺ R _t (HPLC): 0.72 min (Method 10).

tert-Butyl 4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

The reaction is carried out in an argon atmosphere. (6-Chloro-5-methoxypyridazin-3yl)-carbamic acid tert-butyl ester (4.00 g; 15.40 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-tert-butyl) -dioxaborolan-2yl)-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) was flushed with argon. After 5 minutes Xphos 2nd generation (1.26 g; 1.54 mmol) is added and the mixture is stirred overnight in a sealed vessel at 90°C. The reaction mixture is concentrated under reduced pressure. The residue is taken up in EtOAc and washed with water and brine. The organic layer is separated and concentrated under reduced pressure. The residue is purified by silica gel chromatography (DCM/MeOH).

Yield: 4.56 g (59%).

tert-Butyl 4-(6-{[(tert-butoxy)carbonyl]amino}-4-methoxypyridazin-3-yl)piperidine-1-carboxylate

- 108 040737 tert-butyl 4-(6-{[(tert-

^In a hydrogen atmosphere (Parr apparatus; 50 psi (3.515 kg/cm ² )) butoxy)carbonyl] amino}-4-methoxypyridazin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate ( 4.55 g; 11.19 mmol) and Pd/C (10%; 3.57 g) in MeOH (45.5 ml) was stirred at 30° C. overnight. After removing the catalyst by filtration, the mother liquor is concentrated under reduced pressure.

Yield: 3.67 g (80%).

5-Methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride

tert-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) was stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue is triturated with EtOAc and filtered. The product was used without further purification.

Yield: 2.07 g (82%) ESI-MS: m/z=209 [M+H] + R _t (HPLC): 0.60 min (Method 11).

5-Methoxy-6-[1-(4-methoxy-5-phenoxypyridine-2-carbonyl)piperidin-4-yl]pyridazin-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) in DMF ( 3 ml) stirred for 30 min. 5-Methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.12 g; 0.41 mmol) was added and the reaction mixture was left to stir at room temperature overnight. The mixture was purified by RP-HPLC (ACN/water+NH3).

Yield: 0.09 g (53%) ESI-MS: m/z=436 [M+H]+ R _t (HPLC): 0.63 min (Method 13).

Alternative preparation of compound 29.

6-{1-[5-(4-Fluorophenoxy)-4-methoxypyridine-2-carbonyl]piperidin-4-yl}-5-methylpyridazin-3amine trifluoroacetic acid

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; 0.23 mmol) 23 mmol) HATU (95 mg; 0.25 mmol) and DIPEA (0.12 ml; 0.68 mmol) in DMF (3 ml) were stirred at room temperature for 1 h. The mixture was purified using RP-HPLC (ACN /water+TFA).

Yield: 73 mg (59%) ESI-MS: m/z=438 [M+H]+ R _t (HPLC): 0.82 min (Method 7).

Alternative preparation of compound 91.

5-Methoxy-6-(1-{5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3amine trifluoroacetic acid,

- [4-(trifluoromethyl)phenoxy]pyridine-2-carbonitrile

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 in DMSO (150 ml) at 110°C for 1 hour.

- 109 040737 the mixture is diluted with water and extracted with EtOAc. The organic layer is washed with water, separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure.

Yield: quantitative ESI-MS: m/z=265 [M+H] ⁺ R _t (HPLC): 1.03 min (Method 10).

5-[4-(Trifluoromethyl)phenoxy]pyridine-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) in MeOH (50 ml) was stirred at 70° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue is taken up in water and acidified to pH 3 using HCl (4 mol/l, aq. solution). The organic solvent is completely evaporated and the resulting precipitate is filtered. The residue is taken up in DCM, filtered and dried in an oven at 50°C.

Yield: quantitative ESI-MS: m/z=284 [M+H] ⁺ R _t (HPLC): 0.68 min (Method 11).

5-Methoxy-6-(1-{5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3amine trifluoroacetic acid

HCI

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) was stirred for 30 min at room temperature. Add 5-methoxy-6-(piperidin-4-yl)pyridazin-3-amine dihydrochloride (0.11 g; 0.37 mmol) and the reaction mixture is left to stir at room temperature overnight. The mixture was purified by RP-HPLC (ACN/water+TFA).

Yield: 0.06 g (31%) ESI-MS: m/z=474 [M+H] ⁺ R _t HPLC): 0.87 min (Method 7).

Alternative preparation of compound 31.

6-[1-(4-Methoxy-5-phenoxypyridine-2-carbonyl)piperidin-4-yl]-5-methylpyridazin-3-amine trifluoroacetic acid

4-Methoxy-5-phenoxypyridine-2-carboxylic acid (60 mg; 0.23 mmol), 5-methyl-6-(piperidin-4yl)pyridazin-3-amine dihydrochloride (55 mg; 0.23 mmol), HATU (95 mg; 0.25 mmol) and DIPEA (0.12 ml; 0.68 mmol) in DMF (3 ml) were stirred for 1 hour at room temperature. The mixture was purified by RP-HPLC (ACN/water+TFA).

Yield: 69 mg (57%) ESI-MS: m/z=420 [M+H] ⁺ R _t (HPLC): 0.81 min (Method 7).

Assessment of biological activity.

High throughput screening assay.

This screening assay measures the activation of the TRPC6 (transient receptor potential cation channel, subfamily C, member 6) ion channel by the addition of either a commercially available DAG analogue of OAG ligand (1-oleoyl-2-acetyl-sn-glycerol) or a TRPC6 agonist 1-[ 1-(4,5,6,7,8pentahydrocyclohepta[2,1-d]thiophen-2-ylcarbonyl)-4-piperidyl]-3-hydrobenzimidazol-2-one (GSK1702934A). The assay uses a FLIPR fluorescent calcium sensor, dye tetrakis(acetoxymethyl)ether 4-(6-acetoxymethoxy-2,7-difluoro-3-oxo-9-xanthenyl)-4'-methyl-2,2'-(ethylenedioxy)dianiline -N,N,N',N'-Tetraacetic Acid (Fluo4/AM), for Membrane Potential Change (FMP) from Molecular Devices, which is a voltage sensitive indicator with fluorescence quencher. Changes (increases) in the calcium concentration potential in the intracellular membrane, measured by an increase in the fluorescent signal during membrane depolarization, provide a measure of channel activity.

A commercially available HEK293/TREx line (Invitrogen) was stably transfected with a TRPC6 construct and screened with conventional calcium imaging to detect clones expressing TRPC6 after stimulation with 1 μg/ml tetracycline. These cells were maintained in the manufacturer's recommended growth medium supplemented with 100 μg/ml hygromycin to promote the retention of the TRPC6 construct. After growing to near confluency, cells were plated at ~35,000 cells/well in 384-well CellBind plates (Corning) in the presence of

- 110 040737 1 μg/ml tetracycline and let them grow for 20-30 hours. Almost a confluent monolayer was obtained. The growth medium was removed from the wells and the cells were then loaded with 25 ml Fluo4/AM diluted in Ringer's solution (6.5 g NaCl, 0.42 g KCl, 0.25 g CaCl ₂ and 0.2 g sodium bicarbonate; pH 7.4 ) supplemented with 1% Pluronic F-127 to a final concentration of 0.5 μM and incubated for 60 min at room temperature. The dye solution was then removed from the cells by inverting the plates, tapping them sharply, and replaced with 25 μl of Ringer's solution. After ˜0.5 h to recover from loading, cells were analyzed using a Hamamatsu FDSS 6000 system that allowed illumination at 485 nm. Frames were acquired at a rate of 0.2 Hz. During the assay, the plates were shaken continuously, with agitation of the wells with a pipette after the addition of each reagent. For the screening assay, 26 μl of a diluted compound stock solution (at 50 μM) was added to each well within 2 min after a short (4 frame) baseline was obtained. 13 µl of an agonist solution consisting of 125 nM GSK1702934A diluted in high Ca2+ Ringer's solution (containing 90 mM Ca2+) was then added to each well to achieve a final concentration of 20 mM Ca2+ and 10 µM of test compound. Data was collected within ~3 min after the addition of Ringer's high Ca2+ solution. The fluorescence level for each well was divided by the initial fluorescence intensity for that well, and the overall response was determined by averaging the fluorescence level of the last 4 frames obtained during the experiment, excluding the final frame. Each plate contained negative and positive controls. Negative control wells consisted of HEK293/TREx TRPC6 cells exposed to assay buffer and agonist solution, but not to test compound. The positive control consisted of wells containing HEK293/TREx TRPC6 cells exposed to 25 μM 3-[(2-chlorophenoxy)methyl]phenylpiperidylketone (Chembridge) diluted in Ringer's solution and agonist solution. These controls were defined as zero percent and 100%, respectively, and the intensity of each well was normalized to these values.

IC ₅₀ values were determined using the fluorescent method described above, except that instead of testing compounds at 10 μM, compounds were tested at final concentrations of 20, 6.667, 2.222, 0.741, 0.247, 0.082, and 0.027 μM. Compounds were tested in triplicate at all concentrations. Used a standard program for fitting IC ₅₀ curves.

- 111 040737

Table 8. Antagonistic effects of the compounds of the invention against TRPC6 (IC50)

Connection No. TRPC6 1C ₅₀ (nM) 1 <27 2 <27 3 <27 4 <27 5 27 6 27 7 27 8 27 9 27 10 27 AND 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

- 112040737

thirty 110 31 120 32 130 33 82 34 85 35 94 36 97 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 52 190 53 210 54 220 55 220 56 290 57 300 58 100 59 340 60 440 61 500

- 113 040737

The biological activity of the claimed compounds can also be shown using the TRPC6 patch clamp assay.

Methods of therapeutic use.

Inhibition of TRPC6 is an attractive tool for the prevention and treatment of various diseases or conditions that are exacerbated by TRPC6 activity. The compounds disclosed in this application effectively inhibit the activity of TRPC6. In particular, the compounds of the invention are selective ion channel inhibitors and have good metabolic stability in human microsomes. More specifically, the compounds of the invention have very good activity and selectivity for the TRPC6 channel over other TRP channels, including TRPC3, TRPC5 and TRPC7. Thus, the compounds of the invention are useful in the treatment of the diseases and conditions described in the Background of the Invention and the Detailed Description of the Invention, including the following conditions and diseases:

cardiac conditions (eg, cardiac hypertrophy), hypertension (eg, primary or secondary), pulmonary arterial hypertension (eg, IPAH), neurodegenerative disease, or

- 114 040737 disorder (eg, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) and other brain disorders caused by trauma or other damaging factors, including aging), inflammatory diseases (eg, asthma, chronic obstructive lung disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, multiple sclerosis, and immune system disorders), preeclampsia and pregnancy-induced hypertension, kidney disease (focal segmental glomerulosclerosis, nephrotic syndrome, diabetic nephropathy, renal failure, terminal chronic renal failure, lipoid nephrosis ), ischemia or ischemic reperfusion injury, cancer, IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratory distress syndrome), and diabetic metabolic disorders such as diabetes. Methods for preventing or treating any of the diseases and conditions listed above or below include treating any of the symptoms associated with those diseases or conditions. For example, methods of treating kidney disease include treating symptoms including, but not limited to, secondary hypertension, proteinuria, lipiduria, hypercholesterolemia, hyperlipidemia, and bleeding disorders.

Because of the important role that calcium regulation plays in many cellular processes, including cellular activation, cytoskeletal remodeling, gene expression, cellular traffic, and apoptotic cell death, calcium dyshomeostasis has been 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; diseases and disorders of the liver and kidneys; 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 (eg, gastric or stomach cancer), skin, and epithelium.

These disorders are well understood in humans, but also exist with a similar etiology in other mammals and can be treated with the pharmaceutical compositions of the present invention.

Accordingly, the compound of the invention described herein, or a pharmaceutically acceptable salt thereof, can be used in the manufacture of a medicament for the treatment of a disease or disorder mediated by TRPC6, including the diseases and disorders as set forth above and in the Background and Detailed Description of the Invention.

For therapeutic use, the compounds of the invention may be administered as a pharmaceutical composition in any conventional pharmaceutical dosage form by any conventional route. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable for the particular dosage form chosen. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, topical, or inhalation administration. Preferred routes of administration are oral and intravenous.

The compounds of the present invention may be administered alone or in combination with adjuvants that enhance the stability of inhibitors, facilitate administration of pharmaceutical compositions containing them in some embodiments, provide enhanced dissolution or dispersion, enhance inhibitory activity, provide adjuvant therapy, and the like, including other active ingredients. In one embodiment, for example, multiple compounds of the present invention may be administered. Advantageously, such combination therapies use lower doses of conventional therapeutic agents, thus avoiding the potential toxicity and side effects that occur when these agents are used as monotherapy. The compounds of the invention may be physically combined with conventional therapeutic agents or other adjuvants into one pharmaceutical composition. Preferably, the compounds can then be administered together in the same 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 may vary and is within the skill of the art to determine. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants may be administered separately (either sequentially or in parallel). Separate introduction provides greater flexibility in the introduction scheme.

As indicated above, dosage forms of the compounds of the present invention may include pharmaceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, buffers, water, salts.

- 115 -

Claims (31)

or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, emulsion, troche, syrup, reconstituted 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)). Levels and need for administration of doses of the compounds of the present invention can be selected by a person skilled in the art from the available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from 1 to 1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be administered. For oral doses, up to 2000 mg/day may be required. As will be appreciated by one of skill in the art, lower or higher doses may be required depending on specific factors. For example, specific administration and treatment regimens will depend on such factors as the general health profile of the patient, the severity and course of the disorder or the patient's susceptibility to it, and the judgment of the attending physician. The compounds of the invention may be used alone or in combination with one or more additional therapeutic agents. Non-limiting examples of additional therapeutic agents may include the following: 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 (eg, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril and perindopril); antidiabetic agents such as α-glucosidase inhibitors (eg miglitol and acarbose), amylin analogs (eg pramlintide), dipeptidyl peptidase 4 inhibitors (eg alogliptin, sitagliptin, saxagliptin and linagliptin), incretin mimetics (eg liraglutide, exenatide, dulaglutide , albiglutide and lixisenatide), insulin, meglitinides (eg repaglinide and nateglinide), biguanides (eg metformin); SGLT-2 inhibitors (eg canagliflozin, empagliflozin and dapagliflozin), sulfonylureas (eg chlorpropamide, glimepiride, glyburide, glipizide, glyburide, tolazamide and tolbutamide) and thiazolidinediones (eg rosiglitazone and pioglitazone); bronchodilators, including short and long acting β-agonists (eg 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 combination therapy as a pharmaceutical combination, the compounds of the invention and one or more additional agents may be administered in the same dosage form or in different dosage forms. The compounds of the invention and one or more additional agents may be administered simultaneously or separately as part of a treatment regimen. CLAIM 1. Compound of formula (I) (O where L is absent or is methylene or ethylene; Y is CH or N; A is CH or N; R ¹ is selected from the group consisting of C _1-6 alkyl optionally substituted with 1-3 groups independently selected from the group consisting of halo and C _3-6 cycloalkyl; phenyl optionally substituted with 1-3 groups independently selected from the group consisting of CF ₃ , halogen, C _3-6 cycloalkyl, OC _3-6 cycloalkyl, OC _1-6 alkyl optionally substituted with one to three halogen atoms; And C _3-6 cycloalkyl optionally substituted with 1-3 groups independently selected from the group consisting of halogen and C _1-6 alkyl optionally substituted with 1-3 halogen atoms; R ² is selected from the group consisting of H and OS _1-6 alkyl; R ³ is selected from the group consisting of H and C _1-6 alkyl, where each C _1-6 alkyl is substituted with a group selected from OH and OS _1-6 alkyl; - 116 040737 each of R ⁴ and R ⁵ represents H; R ³ and R ⁴ may, together with the atom to which they are attached, combine to form a 3-9 membered carbocyclyl ring; or R ³ and R ⁵ may together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O; R ⁶ is selected from the group consisting of H _, C _1-6 alkyl, OC _1-6 alkyl, and OC _{3_6} cycloalkyl; R ⁷ is selected from the group consisting of H and OS _1-6 alkyl; or a pharmaceutically acceptable salt thereof. 2. Connection according to claim 1, where R ¹ is selected from the group consisting of C _1-6 alkyl optionally substituted with 1-3 groups independently selected from the group consisting of halo and C ₃ _ ₆ cycloalkyl; phenyl optionally substituted with 1-3 groups independently selected from the group consisting of CF ₃ , halogen, OC _3-6 cycloalkyl and OC _1-6 alkyl optionally substituted with one to three halogen atoms, and C ₃ _ ₆ cycloalkyl optionally substituted with 1-3 halogen groups; R ² is OS _1-6 alkyl; R ³ is selected from the group consisting of H and C _1-6 alkyl substituted with OH or OC ₁ . ₆ αkyl; R ⁴ is H; R ⁵ is H; R ³ and R ⁴ may, together with the atom to which they are attached, combine to form a 3-9 membered carbocyclyl ring; or R ³ and R ⁵ may together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O; R ⁶ is selected from the group consisting of H, C _1-6 alkyl, OS _1-6 alkyl and OS _3-6 cycloalkyl; And R ⁷ is selected from the group consisting of H and OS ₁ - ₆ alkyl; or a pharmaceutically acceptable salt thereof. 3. Connection according to claim 1 or 2, where A is CH and Y is N; or A is CH and Y is CH; or A is N and Y is CH; or a pharmaceutically acceptable salt thereof. 4. The compound according to any one of claims 1-3, where R ¹ is selected from the group consisting of phenyl, optionally substituted by a group selected from the group consisting of CF ₃ , halogen, OC ₃ _ ₆ cycloalkyl and OC _1-6 alkyl, optionally substituted with one to three halogen atoms; R ² is OS _1-6 alkyl; R ³ is selected from the group consisting of H and C _1-6 alkyl substituted with OH or OS _1-6 alkyl; R ⁴ is H; R ⁵ is H; R ³ and R ⁴ may, together with the atom to which they are attached, combine to form a 3-9 membered carbocyclyl ring; or R ³ and R ⁵ may together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O; R ⁶ is selected from the group consisting of H, C _1-6 alkyl, OS _1-6 alkyl and OS _3-6 cycloalkyl; R ⁷ is selected from the group consisting of H and OS _1-6 alkyl; or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of paragraphs.1-4, where R ¹ is selected from the group consisting of phenyl, optionally substituted by a group selected from the group consisting of CF3, OCF3, F and methoxy; R ² is selected from the group consisting of methoxy or ethoxy; R ³ is selected from the group consisting of H, 2-hydroxymethyl, methoxymethyl, 1-hydroxyethyl; R ⁴ is H; R ⁵ is H; or R ³ is ethyl, and R ³ and R ⁴ combine to form a spirocyclic ring; or R ³ is ethyl or methoxymethyl, and R ³ and R ⁵ combine to form a bicyclic ring; R ⁶ is selected from the group consisting of H, methyl, methoxy, ethoxy, propoxy and cyclylpropyloxy; And R ⁷ is selected from the group consisting of H and methoxy; or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1 to 5, wherein R ¹ together with L is 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 - 117 040737 la, cyclohexyl, benzyl, 2-fluorobenzyl, phenylethyl; And R ² is methoxy or ethoxy; or a pharmaceutically acceptable salt thereof. 7. Connection according to any one of claims 1-6, where Y is CH and A is N; R ¹ together with L are a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 4-cyclopropoxyphenyl, benzyl, 2-fluorobenzyl , phenylethyl; R ² is methoxy or ethoxy; R ³ , R ⁴ and R ⁵ each represents H; R ⁶ is H, methyl, methoxy or ethoxy; And R ⁷ is H; or a pharmaceutically acceptable salt thereof. 8. Connection according to any one of claims 1-6, where Y is CH and A is CH; R ¹ 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; R ² is methoxy or ethoxy; R ³ , R ⁴ and R ⁵ each represents H; R ⁶ is H, methyl, methoxy or ethoxy; And R ⁷ is H; or a pharmaceutically acceptable salt thereof. 9. Connection according to any one of claims 1-5, where Y is N and A is CH; R ¹ together with L represent a group selected from the group consisting of phenyl and 4-fluorophenyl; R ² is methoxy; R ³ is selected from the group consisting of H, 2-hydroxymethyl and hydroxyethyl; R ⁴ is H; R ⁵ is H; R ³ and R ⁴ can combine to form a spirocyclic ring; or R ³ and R ⁵ can combine to form a bicyclic ring; R ⁶ is selected from the group consisting of H and methoxy; And R ⁷ is H; or a pharmaceutically acceptable salt thereof. 10. Connection according to any one of claims 1-4, where R ¹ is _{C1_6} alkyl optionally substituted with 1-3 groups _{independently} selected from the group consisting of halo and _{C3_6} cycloalkyl; R ² is _{OC1_6} alkyl; R ³ , R ⁴ and R ⁵ each represents H; R ⁶ is selected from the group consisting of H, C1_ ₆ alkyl and OC1_ ₆ alkyl; and R ⁷ is H; or a pharmaceutically acceptable salt thereof. 11. The compound according to any one of claims 1-4 and 10, where R ¹ 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-methylpropyl; R ² is methoxy; R ³ , R ⁴ and R ⁵ each represents H; R ⁶ is selected from the group consisting of H, methyl and methoxy; And R ⁷ is H; or a pharmaceutically acceptable salt thereof. 12. The connection according to any one of claims 1-4, 10 and 11, where Y is CH and A is N; R ¹ together with L represent a group selected from the group consisting of propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-cyclopropylethyl and 2cyclopropylethyl; R ² is methoxy; R ³ , R ⁴ and R ⁵ each represents H; R ⁶ is selected from the group consisting of H, methyl and methoxy; And R ⁷ is H; - 118 040737 or a pharmaceutically acceptable salt thereof. 13. Connection according to any one of claims 1-4, 10 and 11, where Y is CH and A is CH; R ¹ together with L are 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-methylpropyl; R ² is methoxy; R ³ , R ⁴ and R ⁵ each represents H; R ⁶ is selected from the group consisting of H, methyl and methoxy; And R ⁷ is H; or a pharmaceutically acceptable salt thereof. 14. The compound of claim 1 wherein R ³ and R ⁴ together with the atom to which they are attached combine to form a 3-membered carbocyclyl ring, or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1 wherein R ³ and R ⁵ together form an 8-9 membered bicyclic ring which contains one or two heteroatoms selected from the group consisting of N and O, or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 1, selected from the group consisting of any of compounds 1-95 in the table below Comm. No. Structure Connection name 1 o Aud CH, O NH, ³ 1 ² CH ₃ in-2-yl]-methanone - 119 040737 2 O--\rt X O R LL (6-Amino-4-methyl-3',4',5',6'-tetrahydro2'H-[3,4'-bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxypyridine -2-yl]methanone 3 D 0 oX-x X o XX X X (6-Amino-3',4',5',6'-tetrahydro-2'Н[3,4']bipyridinyl-1-yl)-(4-methoxy-5- phenoxy-pyridin-2-yl)-methanone 4 R oh oh 0 LL (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4]bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxypyridine- 2-yl]methanone 5 ΞΓ 'and th 0-0 -Z.—Ch 'Q o /=0 _'°r [4-(6-Amino-4-methoxy-pyridin-3-yl)piperazin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 6 D o ' ^Η3 Α°ΎΑ °Α7ι ^N A sn ₃ YES _o Ah AA% || | ' NH [4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl] - [5-(4-isopropoxyphenoxy)-4-methoxy-pyridin-2-yl] methanone 7 LL o /=/ o °x ^x ” /..... o. o \u003d 2 o 'n Z x * [(K) -4- (6-Amino-4-methyl-pyridin-3-yl) 2-hydroxymethyl-piperazin-1-yl] - [5- (4fluorophenoxy) -4 -methoxy-pyridin-2-yl] methanone 8 SCH ft X ΥΧτΆ ? YES Ax vA^- ⁿ A^ xx-o-x/ A Y1 yl]-(4methoxy-5-phenoxy-pyridin-2-yl) methanone - 120 040737 9 one, O ^^ΝΗ ₂ )-4-methoxy-pyridin-2-yl] methanone 10 O jOA O h ₂ n - CH ₃ (6-Amino-4-methyl-3',4',5',6'-tetrahydro2'H-[3,4]bipyridinyl-G-yl)-(4 -methoxy5-phenoxy-pyride in-2-yl)-methanone eleven “P with O 0-0 With ,--Z b =< Z JE [4-(6-Amino-5-methoxy-pyridine azin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyride in-2-yl]-methanone 12 CH, CH, oh [4-(6-Amino-pyridin-3 -yl)-piperazin-1 yl]-[4-methoxy-5-(4-methoxy-phenox and) pyridin-2-yl]-methanone 13 O o L 0-0 o X LL [4-(6-Amino-pyridin-3-yl)-piperazin-1 yl]-[5-(4-fluorophenoxy)-4-methoxypyridin-2-yl]-methanone 14 O O 0-0 With y-z m ZJE (6-Amino-3',4',5',6'-tetrahydro-2'H[3,4']bipyridinyl-G-yl)-[5-(4fluorophenoxy)-4-methoxy-pyridin-2- silt] methanone 15 d 0-0 o ύ [4-(6-Amino-pyridin-3-yl)-piperazin-1 yl]-(4-methoxy-5-phenox n-pyridine in-2yl)-methanone - 121 040737 16 θH ₃ o GA T' ¹ C .Α>/N < Jx/x Ν,. Ν ΝΗ ₂ [4-(6-Amino-pyridazin-3-yl)-piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 17 CH, Ο 1 II ϊί Α' ΐΆ Q χζ x-^ X/ ^ _Ν ^ Τ-ΙΗ. [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 18 kF Ί . ο ο 'Q'' I Η ^{Ο ω} ο /=<°D> ο b ]-(4methoxy-5-phenoxy-pyridin-2-yl) methanone 19 Ο /--4 /=Ν n^A ⁿ vVYaA ^NH2 Ο 4 /=/~° l ^sn 'O~X' ^C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(2-fluorobenzyloxy)-4-methoxy-pyridin-2-yl]methanone 20 . 0 ° X 0-0 ο 0 LL [(K)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridin-2-yl] methanone 21 7- 7- Ί “ο \—ζ ο— X 0—ο ο \=/ ο JE [4-(6-Amino-5-methoxy-pyride azin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)-methanone 22 ο-ο 0' Ο 0-0 C y-Ζ ζ kF (6-Amino-3',4',5',6'-tetrahydro-2'Н- [3,4']bipyridinyl-G-yl)-[4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] - methanone - 122 040737 23 P O 0-0 With Y-z 0-0 )--/ JE \___/ M z nF (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(4-methoxy5-phenoxy-pyride in-2 -yl)-methanone 24 1 ^F AH A ΖΪ4 Ά A AH, AkXAXX, ° AC N _{NH 2} G-yl)-[4-methoxy5-(4-trifluoromethyl-phenoxy)-pyridin-2yl]-methanone 25 О /--\ N=N n> ^N cJ4/ ^NH2 Z' ⁰ 0 □ A 4-methoxy-pyridin-2-yl)-methanone 26 Oh, ---. z=N AvK/ ² O ° ^CH3 AA -methoxy5-(1-methyl-cyclopropylmethoxy)pyridin-2-yl]-methanone 27 CH, 1 ³ Ao AA s H ₂ N 0 H ₃ C CH ₃ [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-methoxymethyl-piperazin-1-yl]-( 4methoxy-5-phenoxy-pyridin-2-yl) methanone 28 CH ₃ CH ₃ O 0. /V. 0. A X- A SHA οΆ _Ν η ₂ CH ₃ (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl) -[4-methoxy5-(4-methoxy-phenox and)-pyridin-2-yl] methanone - 123 040737 29 ΞΕ ζ S-z About >---\ Q ao ύ oh oh o= Π [4-(6-Amino-4-methyl-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone 30 ⁰ /—\ /= ¹⁴ _n U h ^On < cH3 R yl)-(5cyclohexyloxy-4-methoxy-pyridin-2yl)-methanone 31 O I / / O ^. \ 7 ch ^sn _e /N. A.) N -/ '^ O [4- (6-Amino-4-methyl-pyridazin-3-yl) piperidin-1-yl] - (4-methoxy-5-phenoxypyridin-2-yl) - methanone 32 0 I o b \=h z ^{νγ i} rH (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl) [5-(4-Fluoro-benzyloxy)-4-methoxy-pyridin-2-yl] methanone 33 to O 0-0 to , - Έ. ζ=/ ζ [4-(6-Amino-pyridazin-3 -yl)piperide in-1-yl] - [4-methoxy-5 -(4grifluoromethyl-phenoxy)-pyridin-2-yl]- methanone 34 sn, oh rfrA'l [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-chloro-phenoxy)-4methoxy-pyridin-2-yl]-methanone 35 SH°H ° ^SN 'N ₃ s 5-cyclopentyloxy-4-methoxy-pyridin-2yl)-methanone - 124 040737 36 O /--\ N = N _Ν Χ ^Ν νΧΧΧ ^ΝΗ2 '° U -yl)-methanone 37 O /--\ /=N O °, /PS <J ^H 3 ^C '(6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4' ]bipyridinyl-G-yl)-(5-cyclopropylmethoxy-4-methoxypyridin-2-yl)-methanone 38 t η Ζ O /=( o-o o 0LL [3-(6-Amino-4-methoxy-pyride in-3-yl)3,8-diaza-bicyclo[3.2.1]oct-8-yl]-[5-(4fluorophenoxy)-4-methoxy-pyridine -2-yl]methanone 39 ⁰ /—\ /= ^Ν UL /Pn dd A/ ^sn X ⁿ > ^s (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4' ]bipyridinyl-G-yl)-(5isobutoxy-4-methoxy-pyridin-2-yl) methanone 40 0 0 0 About 0-0 2 X Yu [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-cyclopropoxyphenoxy)-4-methoxy-pyridin-2-yl] methanone 41 V o ^х Ll yl]-methanone 42 nH /d d Hu νχ° о 0 Ll [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1-yl]-[5(4-fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone - 125 040737 43 Υ o =( ο 0=<Ο Ο*b (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5benzyloxy-4-methoxy-pyridin-2-yl ) methanone 44 CH, CH, 0 ΊιΛ ΤΛ|Λ [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] - methanone 45 υ-ο Ο X LL (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-[5-(3,3cyfluoro-cyclobutylmethoxy)-4 -methoxypyridin-2-yl]-methanone 46 ⁰ /—\ /^ ^N νΛαΛυΛ^ Ο ° ^{CH3 H3C} n ₃ s G-yl)-(4-methoxy5-propoxy-pyridin-2-yl)-methanone ^I -yl)-methanone 48 ⁰ /—\ / ^=N νΛΛη ^NHa R A A—/^° p H ₃ C ]bipyridinyl-G-yl)-[5-(2-cyclopropyl-ethoxy)-4-methoxypyridin-2-yl]-methanone 49 0 / X /—ς o-o z—/=^ - 0-0 o o LL [4-(6-Amino-4-methoxy-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4methoxy-pyridin-2-yl]-methanone - 126 040737 50 But. ,... OU Ρ,ϋ 0 At (1K)-1-[(2K)-4-(6-amino-4- methoxypyride in-3 -yl) -1 - (5 - phenoxypyride in-2-carbonyl)piperazine- 2-yl]ethan-1-ol 51 03 _O o _. [3.2.1]oct-8-yl]-(4methoxy-5-phenoxy-pyridin-2-yl)methanone 52 o /—\ /= ^Ν O < G AyR ^CH3 0 / H ₃ C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H-[3,4']bipyridinyl -G-yl)-(4-methoxy5-phenethyloxy-pyridin-2-yl)-methanone 53 O /--h /=N 0 ^ν 040 ^Ηι O 5 oU □ A -G-yl)-(5-cyclobutylmethoxy-4-methoxy-pyridin2-yl)-methanone 54 0 about R O 0-0 % [4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl] - [5-(4-d ifluoromethoxyphenoxy)-4-methoxy-pyridin-2-yl] methanone 55 0-0 Z—.. 0-0 ' o.....’ 0 0 h P [(R)-4-(6-Amino-4-methoκci-pyridin-3yl)-2-methoxymethyl-piperazin-1-yl]-[5(4-fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 56 P O 0-0 $x z ^w kJE -pyridin-2-yl]methanone - 127 040737 57 O /--y N \u003d N A \ nA W \u003d ^F 4-methoxy-pyridin-2-yl]-methanone 58 o ^HC Y obfe Ta Ν NH ₂ (1S) -1 - [(2K) -4- (6-amino-4methoxypyride in-3 -yl) -1 - (5 phenoxypyride in-2-carbonyl) piperazin2-yl ]ethan-1-ol 59 ⁰ /—\ A ^N JTKA A ^{0 n} » ^c A - ^CH> n ₃ s ch ₃ ^H ' ^C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2'H -[3,4']bipyridinyl-G-yl)-[5-(2,2cimethyl-propoxy)-4-methoxy-pyridin2-yl]-methanone 60 CH, CH, o 1 ³ 1 ³ II o, l, ά ϊ | Τ ϊ ΐ | LA A-l to ,ν- Q ·χ· ^χ'-'νχ-- χ _Ν 'γ W [4-(6-Amino-5-methoxy-pyride azin-3-yl)piperide in-1 - yl] - [4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] methanone 61 f Τ* ^- ° )=/ ο ots ^Χ ο . -ζ 0-0 ζ CM 62 θ ^Η 3 0 η°Γ^η kA kA/Nv Q χΖ -/ \Χ-[4-(6-Amino-pyridazin-3-yl)piperide in-1-yl]-(5-cyclohexyloxy-4methoxy -pyridin-2-yl)-methanone - 128 040737 63 k Ο - o ^{z ω} / - o C ...... X g / ⁸ % and 1-yl]-[5(4-fluorophenoxy)-4-methoxy-pyridin-2yl]-methanone 64 ⁰ /—\ /= ^N nJ4jv ^nHz R % F -[5-(1fluoromethyl-cyclopropylmethoxy)-4methoxy-pyridin-2-yl]-methanone 65 ⁰ /--\ n/ ⁿ vJP ^NH2 n ₃ s V/ 4 ³ v/% CH ₃ ⁰ P H ₃ C (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2Ή- [3,4'] inyl-1'-yl)-(5-ethoxy-4methoxy-pyridin-2-yl)-methanone bipyride 66 CH ₃ CH ₃ 0 °%\A% [ j \ Il 'i ] eg Pa/N 0Aa O -^ γ N X^%H ₂ CH ₃ [4-(6-Amino-4-methoxy-pyridazine- 3-yl)piperide in-1-yl] - [4-methoxy-5-(4methoxy-phenoxy)-pyridin-2-yl] - methanone 67 0 /--y N~N Kn YX /Xnh ₂ ji ^P H ₃ C -4-methoxy-pyridin-2-yl]- methanone 68 P O 0-0 c Λ— ^z /L° \ °s \—/ b / I Z “ nF [7-(6-Amino-4-methoxypyride in-3-yl)-3 oxa-9-aza -bicyclo[3.3.1 ]non-9-yl]-(4methoxy-5-phenoxy-pyridin-2-yl)methanone 69 C o p^^ X o ^z % \u003d/ T \ ω ) \u003d 0 y-2 O .g and nF [(K)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl -piperazin-1-yl]-(4methoxy-5-phenoxy-pyridin-2-yl)- methanone - 129 040737 70 O /--\ /=N ADA n ₃ s C U ° Ao^A A / ° O % A (6-Amino-4-methoxy-3',4',5',6'-tetrahydro2Ή-[3 ,4']bipyridinyl-1 '-yl)-[5-((8)-1 cyclopropyl-ethoxy)-4-methoxypyridin-2-yl]-methanone 71 O O o— o \=/ “ /=o Db 0g Z [(8)-4-(6-Amino-4-methoxy-pyridin-3yl)-2-hydroxymethyl-piperazin-1 -yl]-(4methoxy-5-phenoxy-pyridin-2-yl)- methanone 72 О /--у /=N _An )—( _h ^Anh ₂ nA \ / ^{DA n} ₃ s f J ',6'-tetrahydro2'H-[3,4']bipyridinyl-G-yl)-(5isopropoxy-4-methoxy-pyridin-2-yl)methanone 73 O /--\ N=N νΑ^ΑΑ^^^ Aa° o Da _H3 and pyridin-2-yl)-methanone 74 nJ^vA^J^ ² /—Q o and ₃ cA,° n with gn ⁿ s ^with gDi Gn^ [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [ 5-(2,2-dimethylpropoxy)-4-methoxy-pyridin-2-yl] methanone 75 o/---h N = N nJ^vA^aH” ² A ^Η 3° ^Ζ -5 -(1-methylcyclopropylmethoxy)-pyridin-2-yl]- methanone 76 О /---ν Ν=Ν nA ^Ν Α^ ^ΝΗ2 A n ₃ s—A r n ₃ s [4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl] -( 4-methoxy-5-propoxypyridin-2-yl)-methanone - 130 040737 77 O y--yy=N > n )—( /Vnh ₂ nV \_/ h ₃ c V ² / θ CH _a </ n>c (6-Amino-4-methoxy-3',4',5 ',6'-tetrahydro2Ή-[3,4']bipyridinyl-1'-yl)-[5-((K)-1 cyclopropyl-ethoxy)-4-methoxypyridin-2-yl]-methanone 78 CH ₃ 0 Οχ /X. sn ₃ ⁰ % L1 -Ν ΝΗ ₂ [4-(6-Amino-4-methyl-pyridazin-3-yl)piperide in-1-yl] -(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl) -methanone 79 O y--y Ν = Ν n ₃ s <Ο 9° b < J d^ [4-(6-Amino-pyridazin-3-yl)-piperide in-1-yl] - [5-(( S)-l -cyclopropylethoxy)-4-methoxy-pyridin-2-yl]- methanone 80 ^N. ,ΝΗ . ν, ......,ο ΟΗ ₃ ° -2yl]-methanone 81 . X Ο y^Z 0—0 o d [(K)-4-(6-Amino-pyridin-3-yl)-2hydroxymethyl-piperazin-1-yl]-(4methoxy-5-phenoxy-pyridin-2-yl) methanone 82 0-0 o ⁷ o oo "/—ζ o 0 ' Ζ _W T -(4-methoxy-phenoxy)-pyridin2-yl]-methanone 83 . ' —o o c> [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(phenoxy)-4-ethoxypyridin-2-yl]-methanone - 131 040737 84 υ-ο about ABOUT (6-Amino-4-cyclopropoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-G-yl)[5-(phenoxy)-4-methoxypyridine -2-yl]methanone 85 SN ₃ 0 OXVy N ₄ L Ν ΝΗ ₂ 2-yl]-methanone 86 CH ₃ θ GU °ΥΎΓΊ °^ ^CH3 m η y l λ j. ⁰ XI Ν ΝΗ ₂ (6-Amino-4-propoxy-3',4',5',6'hetrahydro-2'H-[3,4']bipyridinyl-G-yl)[5-(phenoxy)- 4-methoxy-pyridin-2-yl] methanone 87 F ρ CH, Ο ΛχΓατ'· N . a. ν μη ₂ 5 -Ethoxy-6-( 1 - {4-methoxy-5 -[4(trifluoromethyl)phenoxy]pyridine-2carbonyl}piperidin-4-yl)pyridazin-3amine 88 Y / -Ο ο 0 [4-(6-Amino-pyridazin-3-yl)piperide in-1-yl] - [5-(4-fluorophenoxy)-4ethoxy-pyridin-2-yl]-methanone 89 Y' ο ο 0 LL [3-(6-Amino-pyridazin-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-[4-ethoxy-5-(4fluorophenoxy)-pyridin-2-yl]-methanone 90 U P ίΐ ^F r γνηη kA E-lx k Ο ' y Ν H ₃ C'^0^'IN ₂ 6-( 1 - {4-Methoxy-5 - [4-(trifluoromethyl)phenoxy]pyridine-2carbonyl} piper idin-4-yl)-5 - methylpyr idazin-3-amine - 132 040737 5-Methoxy-6-( 1 - { 5 - [4-(trifluoromethyl)phenoxy]-pyridine-2carbonyl } piperidin-4-yl)-pyride azine-3 amine sn ₃ amine 4-Methoxy-5 -(1 - { 4-methoxy-5 - [(2)-3,3,3 gryfluoro-2-methylpropoxy]-pyridine-2carbonyl } piper idin-4-yl)pyridine-25 -( 1 - { 5 - [(2,2-Difluorocyclobutyl) methoxy] -4-methoxy-pyridine-2carbonyl } -piperid in-4-yl) -4 methoxypyridin-2-amine 4-Methoxy-5 - [ 1 - (4-methoxy-5 - {[(cis-3 (trifluoromethyl)-cyclobutyl] methoxy } pyridine-2-carbonyl) piperidine-4yl] pyridine-2-amine 4-Methoxy-5 - [ 1 - (4-methoxy-5 - {[trans-3 (trifluoromethyl) cyclobutyl] methoxy} pyridine-2-carbonyl) piperide in-4-yl] pyride in-2-amine or pharmaceutically thereof acceptable salt. 17. The compound according to claim 1, selected from the group consisting of [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-isopropoxyphenoxy)-4-methoxypyridin-2yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-fluorophenoxy)-4-methoxypyridin-2-yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][4-methoxy-5-(4-trifluoromethylphenoxy)pyridin-2yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-chlorophenoxy)-4-methoxypyridin-2-yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-cyclopropoxyphenoxy)-4-methoxypyridin-2yl] methanone; [4-(6-Aminopyridazin-3-yl)piperidin-1-yl][5-(4-fluorobenzyloxy)-4-methoxypyridin-2-yl]methanona; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][4-methoxy-5-(4-methoxyphenoxy)pyridin-2-yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-difluoromethoxyphenoxy)-4-methoxypyridin-2yl] methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(2-fluorobenzyloxy)-4-methoxypyridin-2-yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][4-methoxy-5-(4-trifluoromethoxyphenoxy)pyridin-2yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(phenoxy)-4-ethoxypyridin-2-yl]methanone; [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-fluorophenoxy)-4-ethoxypyridin-2-yl]methanone; [4-(6-amino-4-methylpyridazin-3-yl)piperidin-1-yl][5-(4-fluorophenoxy)-4-methoxypyridin-2yl] methanone; [4-(6-amino-4-m ethylpyridase in-3-yl)piper idin-1-yl]-(4-metho xy-5-phenoxypyridin-2-yl)methanone; [4-(6-amino-4-methoxypyridazin-3-yl)piperidin-1-yl][5-(4-fluorophenoxy)-4-methoxypyridin-2yl] methanone; [4-(6-amino-4-methoxypyridazin-3-yl)piperidin-1-yl][4-methoxy-5-(4-trifluoromethylphenoxy)pyridin-2-yl] methanone; -133040737 [4-(6-amino-4-methoxypyridazin-3-yl)piperidin-1-yl][4-methoxy-5-(4-methoxyphenoxy)pyridin2-yl]methanone; [4-(6-Amino-4-is xypyr idazin-3-yl)piperidin-1-yl] [4-m eto xy-5-(phenoxy)pyridin-2-yl]methone, 5-ethoxy-6 -(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-amine and 6-(1-{4-methoxy-5-[ 4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)5-methylpyridazin-3-amine. 18. A pharmaceutically acceptable salt of a compound according to claim 17. 19. A compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4isopropoxyphenoxy)-4-methoxypyridin-2-yl]methanone. 20. A compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl]-(4-methoxy-5-phenoxypyridin-2-yl)methanone. 21. A compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4fluorophenoxy)-4-methoxypyridin-2-yl]methanone. 22. A compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4difluoromethoxyphenoxy)-4-methoxypyridin-2-yl]methanone. 23. A compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][4-methoxy-5-(4-trifluoromethoxyphenoxy)pyridin-2-yl]methanone. 24. A compound which is [4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(phenoxy)-4-ethoxypyridin-2-yl]methanone. 25. A compound which is 5-ethoxy-6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)pyridazin-3-amine. 26. A compound which is 6-(1-{4-methoxy-5-[4-(trifluoromethyl)phenoxy]pyridine-2-carbonyl}piperidin-4-yl)-5-methylpyridazin-3-amine. 27. A pharmaceutical composition comprising any of the compounds of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 28. The use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder that can be ameliorated by inhibition of a transient C6 receptor potential ion channel (TRPC6), wherein the disease or disorder is selected from the group consisting of cardiac hypertrophy , ischemia, ischemic reperfusion injury, 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, preeclampsia, non-alcoholic steatohepatitis, lipoid nephrosis, focal segmental glomerulosclerosis (FSGS), nephrotic syndrome, diabetic nephropathy or diabetic kidney disease (DKD), chronic ical kidney disease, renal failure, ischemia or ischemic reperfusion injury, cancer, IPF (idiopathic pulmonary fibrosis), ARDS (acute respiratory distress syndrome), emphysema and diabetes. 29. Use according to claim 28, wherein the hypertension is selected from pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, and pregnancy-induced hypertension. 30. Use according to claim 28, wherein the muscular dystrophy is Duchenne muscular dystrophy. 31. Use according to claim 28, wherein the renal failure is end-stage chronic renal failure. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 134 -