EA043088B1 - (PYRIDIN-2-YL)AMINE DERIVATIVES AS TGF-BETA R1 (ALK5) INHIBITORS FOR THE TREATMENT OF MALIGNANT NEOPLASMS - Google Patents

Description

The present invention relates to the field of compounds, pharmaceutical compositions and methods, in particular compositions and methods for the treatment of cell proliferation disorders such as fibrosis or malignancy, in particular in tissues and organs, where the compounds of the invention tend to accumulate in relatively high concentrations due to their pharmacokinetic properties.

State of the art

The present invention relates to novel aryloxypyridinyl compounds containing an acidic moiety that inhibit the activity of transforming growth factor receptor 1 beta (TGFeR1) due to the acidic moiety tending to limited systemic distribution and thus limiting the effect of the inhibitor on non-target tissues. The compounds can be used to treat conditions such as malignancies and fibrosis occurring in the digestive system and first pass metabolism tissues (liver, kidneys). The invention relates to pharmaceutical compositions containing compounds and methods of using the compounds for the treatment of malignant neoplasm, preferably colon cancer, hepatocellular carcinoma (HCC), kidney cancer, pancreatic cancer, myelodysplastic syndrome (MDS) and gastric cancer, and/or fibrosis , preferably, liver fibrosis and chronic renal failure.

Transforming growth factor beta (TGF-beta or TGFe) is a multifunctional cytokine that binds to the heteromeric TGFbeta type I and type II serine/threonine kinase receptor complexes and activates the TGF-beta receptor complex, phosphorylates and activates SMAD2 and SMAD3, which then bind to SMAD4 and migrate to the nucleus and regulate the expression of various target genes. Key factors in the TGF-beta receptor signaling pathway include TGFp1, TGFe2, TGFe3, TGFpR1, TGFeR2, SMAD, SnoN, SARA, SKI, DAB, TRAP, TAKI, SMIF, E2F4, E2F5, RBL1, RBL2, RBI, TFDP1, TFDP2, SMURF1, SMURF2, P300, SVR, and JUN. The SMAD-mediated TGF-beta receptor pathway regulates various cellular processes, and signaling through the TGF pathway has been associated with malignancy and tumor progression in several indications (Elliott et. al. (2005) J Clin Oncol 23:2078; Levy et. al. (2006 ) Cytokine & Growth factor Rev 17:41-58). There are several types of cancers in which TGF ligands produced by the tumor or stroma in the tumor microenvironment may be involved in tumor progression.

TGF-e1 is associated with angiogenesis, metastasis and poor prognosis in advanced human prostate cancer and advanced gastric cancer (Wikstrom, P., et al. (1998) Prostate 37: 19-29; Saito, H. et al. (1999 ) Cancer 86: 1455-1462). In breast cancer, poor prognosis is associated with elevated TGF-β (Dickson, et al. (1987) Proc. Natl. Acad. Sci. USA84:837-841; Kasid, et al. (1987) Cancer Res. 47:5733- 5738; Daly, et al. (1990) J. Cell Biochem. 43:199-211; Barrett-Lee, et al. (1990) Br. J Cancer 61:612-617; King, et al. (1989) J Steroid Biochem 34:133-138 Welch, et al (1990) Proc Natl Acad Sci USA 87:7678-7682 Walker et al (1992) Eur J Cancer 238:641- 644), and induction of TGF-e1 by tamoxifen treatment (Butta, et al. (1992) Cancer Res. 52:4261-4264) is associated with tamoxifen treatment failure in breast cancer (Thompson, et al. (1991) Br. J Cancer 63:609-614). Anti-TGF-β 1 antibodies inhibit the growth of MDA-231 human breast cancer cells in nude mice (Arteaga, et al. (1993) J. Clin. Invest. 92:2569-2576), this treatment correlates with increased spleen natural killer activity . CHO cells transfected with latent TGF-e1 also showed reduced NK cell activity and increased tumor growth in nude mice (Wallick, et al. (1990) J. Exp. Med. 172:1777-1784). Thus, TGF-β secreted by breast cancer can cause endocrine immune suppression. High plasma concentrations of TGF-β 1 have been shown to be associated with poor prognosis in advanced breast cancer patients (Anscher, et al. (1993) N. Engl. J. Med. 328:1592-1598). Patients with high circulating TGF before high-dose chemotherapy and autologous bone marrow transplantation are at high risk of veno-occlusive liver disease (15-50% of all patients with a mortality rate of up to 50%) and idiopathic interstitial pneumonitis (40-60% of all patients). The significance of these results is that:

1) elevated plasma levels of TGFe can be used to identify patients at risk of developing disease, and

2) that reduced TGFe signaling may reduce morbidity and mortality in this common treatment for breast cancer patients.

Recent publications have also suggested that TGFe signaling may be important for the development of tumor resistance to standard therapies, including chemotherapy and receptor tyrosine kinases (WO 2012138783). In particular, in colon cancer, it has been shown that a specific gene expression signature can identify a group of patients who are resistant to common first line treatments. These tumor cells reacquire

- 1 043088 therapy sensitivity when blocking the TGFe pathway using a TGFeRI-specific small molecule inhibitor (Huang, et al. (2012) Cell 151:937-950; Sadanandam et al. (2013) Nat Med

19:619-625; Vermeulen et al. (2013) NatNed 19:614-618; Roepmanet et al. (2014) 134:552-562).

Myelodysplastic syndromes (MDS) are disorders of the hematopoietic system in the myeloid compartment and are characterized by inefficient production of myeloid cells. MDS is associated with TGFe pathway changes represented by reduced levels of SMAD7. SMAD7 is an inhibitory SMAD that inhibits TGFe-mediated SMAD signaling and is downstream of ligand-activated signaling via TGFeRI and TGFeRII. Thus, overexpression of SMAD7 is believed to lead to hyperactivation of TGFe signaling in MDS, and this phenotype can be reversed by administration of a small molecule inhibitor of TGFeRI (Zhou et al. (2011) Cancer Res. 71:955-963). Similarly, in glioblastoma (GBM), TGFe ligand levels are elevated and are associated with disease progression. The antisense oligonucleotide therapeutic, AP1002, has been shown to be potentially active in a subset of GBM patients (Bogdahn et al. (2011). Curr Phann Biotechnol). In melanoma, activation of the TGFe signaling pathway is also associated with resistance to BRAF and MEK inhibitors (Sun et al. (2014) Nature. 508:118-122).

Many cancer cells secrete transforming growth factor-e (TGF-e), a potent immunosuppressant, suggesting that TGFe production may represent an important mechanism for tumor evasion of host immune surveillance (Flavell et al. (2010) Nat Rev Immunol 10: 554-567 Kast et al (1999) Leukemia 13:1188-1199). Generation of a leukocyte subpopulation with impaired TGFe signaling in a tumor-bearing host is a potential tool for cancer immunotherapy alone or in combination with one or more other immunotherapeutic agents, e.g., in combination with one or more PD-1 inhibitors, such as nivolumab, pembrolizumab, PD-L1 inhibitors, cancer vaccines, and immune cell-attracting bispecific molecules such as IMCgp100. Lymphocyte-produced TGFe ligand has been shown preclinically to antagonize immune surveillance (Donkor et al. (2012) Development. Oncoimmunology 1:162-171, Donkor et al. (2011) Cytokine Immunity 35:123-134); disruption of this axis has been shown preclinically to provide antitumor benefit in mouse and in vitro models (Zhong et al. (2010) Cancer Res 16:1191-1205; Petrausch et al. (2009) J Immunol 183:3682-3689); Wakefield et al. (2013) Nat. Rev Cancer 13:328-341). The bispecific fusion protein binding to TGFe and PD-L1 also showed synergistic antitumor activity compared to separate binding agents. Lan, et al., Sci. Transl. Med. Vol. 10, 17 January 2018. In a transgenic animal model with impaired TGFe signaling in T cells, normally lethal TGFe-overexpressing EL4 lymphoma can be abolished (Gorelik and Flavell, (2001) Nature Medicine 7(10): 1118-1122). Downregulation of TGF secretion in tumor cells results in restoration of immunogenicity in the host, while insensitivity of T cells to TGFe leads to accelerated differentiation and autoimmunity, elements of which may be required to combat autoantigen-expressing tumors in a tolerized host. The immunosuppressive effects of TGFe are also associated with a subset of HIV patients with lower than predicted immune responses based on their CD4/CD8 T cell counts (Garba, et al. J. Immunology (2002) 168: 2247-2254). A TGFe neutralizing antibody can reverse the effect in culture, suggesting that inhibitors of TGFe signaling can be used to reverse the immunosuppression that occurs in a subset of HIV patients.

In the earliest stages of oncogenesis, TGF-e 1 can act as a potent tumor suppressor and mediate the action of some chemopreventive agents. However, at some point during the development and progression of malignant neoplasia, tumor cells appear to escape TGFe-dependent growth inhibition in parallel with the emergence of bioactive TGFe in the microenvironment. The dual role of TGFe in tumor suppression/promotion is most clearly seen in a transgenic system overexpressing TGFe in keratinocytes. Although transgenic models were more resistant to benign skin lesions, the rate of metastatic transformation was significantly increased in transgenic models (Cui, et al. (1996) Cell 86(4):531-42).

The production of TGFe by malignant cells in primary tumors appears to increase with tumor staging. Studies of many extensive epithelial malignancies suggest that increased TGFe production by human malignancies occurs as a relatively late event in the course of tumor progression. In addition, this tumor-associated TGFe provides tumor cells with a selective advantage and promotes tumor progression. The effects of TGFe on cell/cell and cell/stroma interactions result in a higher propensity for invasion and metastasis. Tumor-associated TGF may allow tumor cells to evade immune surveillance by it is a potent inhibitor of the clonal expansion of activated lymphocytes. It has been shown that TGFe inhibits the production of angiostatin.

Cancer therapies, such as radiation therapy and chemotherapy, induce the production of activated TGF3 in the tumor, thereby leading to the outgrowth of cancer cells that are resistant to the growth-inhibiting effects of TGFe. Thus, these antitumor therapies increase the risk and accelerate the development of overgrowth and invasive tumors. In this case, agents targeting TGFβ-mediated signaling may represent a very effective therapeutic strategy. It has been shown that resistance of tumor cells to TGFe neutralizes a significant part of the cytotoxic effects of radiation therapy and chemotherapy, and treatment-dependent activation of TGFe in the stroma can even be harmful, because it can make the microenvironment more conducive to tumor progression and contribute to tissue damage leading to fibrosis. The development of inhibitors of TGFe signaling is likely to be useful for the treatment of advanced malignancies when used alone or in combination with other therapies.

In addition, TGFe signaling is known in the art to contribute to fibrotic disorders such as liver fibrosis and chronic renal failure. See, for example, Ueha S, et al., 2012. Front Immunol. 3:71. Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis; Bottinger et al., 2002. J Amer Soc Nephrol. 13:2600. TGFe Signaling in Renal Disease; Trachtman H., et al., 2011. Kidney International 79:1236. A phase 1, single-dose study of fresolimumab, an anti-TGFp antibody, in treatment-resistant primary focal segmental glomerulosclerosis; and Rosenbloom J, et al., 2010. Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med 152: 159-166.

Small molecule inhibitors of TGFeR1 are known in the art for the treatment of cancer and/or fibrosis. See, for example, WO 2012/002680, WO 2009/022171, WO 2004/048382, WO 2002/094833 and WO 2016/057278. Unfortunately, there are no drugs in the known classes of inhibitors that have achieved regulatory approval (although at least one of them, galunisertib, remains under investigation), probably due to the diverse biological activities of TGFeR1, which can lead to toxic effects. responses in vivo at concentrations similar to those required for therapeutic efficacy.

galunisertib

There remains a need for new small molecule inhibitors of TGFeR1 that can be used to treat disorders of cell proliferation like malignancy and fibrosis, and in particular for inhibitors having pharmacokinetic properties that can provide higher concentrations in organs or tissues to be treated, and lower effective concentrations in other tissues, thereby reducing toxic effects in non-target tissues. For example, small molecule inhibitors can be administered orally for the treatment of malignancies of the digestive system, where they can interact directly with target tissues without the need for systemic distribution. Similarly, these compounds may have pharmacokinetic properties that cause them to preferentially concentrate in target organs such as the liver or kidneys, allowing them to be used to treat malignancies in these organs, while the compounds can still be excreted relatively quickly before being completely absorbed into the systemic circulation. and thus do not result in high systemic concentrations of drugs that tend to cause toxicity elsewhere, such as in cardiac tissues.

The invention relates to compounds that inhibit TGFeR1, also known as Alk5, and contain an acidic residue in the region of the structure where it does not interfere with binding to the target site. The compounds of the invention may be effective even if present only intermittently; thus, long retention times (long in vivo half-life) and maintenance of drug levels above the minimum inhibitory concentration (MIC) are not necessarily necessary to achieve therapeutic efficacy, in particular when the compounds of the invention are used in combination with an additional anticancer therapeutic agent, including inhibitor of PD-1 or PD-L1. Thus, these compounds can be used to treat cancer and fibrotic disorders in target tissues such as the liver, kidney and gastrointestinal tract while achieving reduced toxicity in non-target organs or tissues.

Without wishing to be bound by any theory, it is believed that the acidic moiety in the compounds of formula (I) and formula (II) tends to reduce drug concentration in many tissues or promote relatively rapid excretion while leading to locally effective concentrations, for example, in the large intestine, small intestine, liver and/or kidneys, such

- 3 043088 thus increasing the therapeutic index of relatively non-acidic TGFeRl inhibitors for use in these organs. An increase in the therapeutic index in these tissues is particularly preferred in the case of oral administration. It is also believed that acidic compounds are actively transported by transport polypeptides (eg, OATP1, OATP2) to the tissues of the liver and kidneys, thus resulting in localized concentrations in these organs, even if the compounds enter the systemic circulation. In addition, because Since colon cancer often metastasizes to the liver, the compounds of the invention are also expected to inhibit metastasis, causing locally high concentrations in both colon and liver tissues. Thus, the compounds of the invention can be used to treat colon cancer, hepatocellular carcinoma (HCC), kidney cancer, liver cancer and gastric cancer, as well as fibrosis in the digestive system and first pass metabolism systems, in particular liver fibrosis and fibrotic disorders of the kidneys.

The essence of the invention

In one aspect, the present invention relates to a heterocyclic compound having the structure of formula (I)

where ring A is a 5- or 6-membered heteroaromatic ring, optionally containing an additional nitrogen atom as a ring member and optionally fused to a phenyl or pyridinyl ring, and ring A is optionally substituted with one or two groups independently selected from halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy groups, C 1 -C 4 haloalkoxy groups, phenyl, pyridinyl and C ₃ -C ₆ cycloalkyl;

R ¹ is selected from H, halogen, CN, C1-C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₃ -C ₆ cycloalkyl, 5- 6-membered heterocyclyl containing N, O or S as a ring member, phenyl and 5-6-membered heteroaryl containing one or two nitrogen atoms as ring members, where each of the specified C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy groups, C 1 -C 4 haloalkoxy groups, C ₃ -C ₆ cycloalkyl, phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or two groups selected from ^R2 ;

where R ² at each occurrence is independently selected from halo, CN, -OH, C1- _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, C1- _C4 haloalkoxy, and _C3 - _C6- cycloalkyl;

Cy is a ring selected from C ₃ -C ₆ -cycloalkyl, phenyl and 5-6 membered heteroaryl containing one or two nitrogen atoms as ring members, and is optionally further substituted with one or two groups selected from halogen, C1-C ₄ alkyl, C ₁ -C ₄ haloalkyl, C 1 -C 4 alkoxy and C ₁ -C ₄ haloalkoxy groups;

L is a bivalent linker selected from the bond, -CR2-, -(CR ₂ ) _2-4 - and -O-(CR ₂ ) _1-3 -, where R is in each case independently selected from H, F and C1-C ₄ -alkyl; or two R groups on the same carbon atom can be taken into account together with the carbon atom to which they are attached, giving a 3-6 membered cycloalkyl ring or a 3-6 membered cyclic ether; or a pharmaceutically acceptable salt thereof.

Other aspects of the invention relate to pharmaceutical compositions containing a compound of formula (I). In other aspects, the invention relates to methods of using the compounds and compositions of the invention for the treatment of conditions such as cancer, as further described in the present description. Additional aspects of the invention are presented in the present description.

Although they are depicted as a specific tautomer, it should be understood that the compounds of formula (I) include other tautomers, in particular, in the balance of the tetrazole ring of the compounds of formula (I).

The compounds provided herein can be used for a variety of purposes. In some embodiments, the above-described compound can be used in therapy, in particular therapy for the treatment of disorders of cell proliferation, such as malignancies and fibrotic disorders, in particular disorders of the gastrointestinal tract or first pass metabolism, including those described herein.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or any of the subformulas provided herein, admixed with at least one pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention relates to a method for treating and/or preventing a cell proliferation disorder such as cancer or fibrosis, comprising

administering to an individual in need thereof an effective amount of a compound of formula (I) or any of the subformulas provided herein, or a pharmaceutical composition containing at least one compound of formula (I) or any of the subformulas presented herein. Although they are suitable for the treatment of many disorders of cell proliferation, the compounds are specifically indicated for use in the treatment of malignancies associated with excessive activity of TGFeR1, also known as Alk5, in particular malignancies of the liver, kidney and gastrointestinal tract, where their physicochemical properties contribute to the formation of higher localized concentrations in these organs with reduced exposure to other tissues, where there is a tendency to develop toxic effects.

In yet another aspect, the present invention relates to the use of a compound of formula (I), or any of the subformulas provided herein, for the manufacture of a medicament. The acidic compounds of the invention are particularly suitable for the manufacture of a medicament for use in the treatment of cancers associated with excessive activity of TGFeR1, also known as Alk5, in particular cancers of the liver, kidneys and gastrointestinal tract.

In yet another aspect, the present invention provides a combination for the treatment and/or prevention of a cell proliferation disorder in an individual, wherein the combination comprises an effective amount of a compound of formula (I) or any of the subformulas provided herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and/or preventing a cell proliferation disorder such as cancer or fibrosis in an individual, preferably an individual who has been diagnosed as in need of treatment for such a disorder. Suitable second therapeutic agents for use in combination with the compounds of the invention include a small molecule compound and antibody-based therapeutic agents that can be used to treat the same compounds to be treated with compounds of formula (I) and its subformulas. Chemotherapeutic agents for use in such combinations include 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, irinotecan, regorafenib, trifluridine, tipiracil, a drug that targets VEGF such as bevacizumab, ziv-aflibercept, or ramucirumab, or a drug that targets on EGFR, such as cetuximab or panitumumab.

In one aspect, the combination of the invention comprises a compound of formula (I), or any subformula thereof, in combination with an immuno-oncological therapeutic agent, such as a PD-1 or PD-L1 inhibitor, or other known checkpoint inhibitors that assist the body's own immune system to recognize malignant cells and fight them. Checkpoint inhibitors help the individual's immune system to recognize and attack abnormal cells, such as cancer cells, and can greatly enhance the effectiveness of chemotherapeutic agents, such as the compounds described herein. Suitable checkpoint inhibitors include biological agents as well as small molecule therapeutic agents; examples thereof include ipilimumab, nivolumab, atezolizumab, avelumab, pembrolizumab, tiselizumab and durvalumab.

In yet another aspect, the present invention relates to a method of treating and/or preventing a proliferation disorder, malignancy, or fibrosis in an individual, comprising administering to an individual in need thereof an effective amount of a combination described above, containing a compound of formula (I) or any of the subformulas presented herein. description. The acidic compounds of the invention are particularly suitable for the treatment of cancers associated with excessive activity of TGFeR1, also known as Alk5, in particular liver, kidney and gastrointestinal cancers.

In yet another aspect, the present invention provides a method for inhibiting TGFeR1 activity, comprising administering to an individual in need thereof, or bringing a cell having such activity into contact with an effective amount of a compound of formula (I) or any of the subformulas provided herein, or a pharmaceutical composition or a combination containing such a compound.

Other aspects and embodiments of the invention are presented in the detailed description and examples below, or will be apparent from them.

Detailed description of the invention

Unless otherwise indicated, all technical and scientific terms used in the present description have the meaning generally understood by a person skilled in the art to which the present invention belongs. All patents, patent applications, published applications, and other publications referred to in the present specification are incorporated herein by reference in their entirety. If a definition in this section differs from or otherwise conflicts with a definition in a patent, patent application, or other publication incorporated herein by reference, the definition in this section takes precedence over

- 5 043088 definition included in the present description by reference.

In the context of the invention, the term in the singular means at least one or one or more.

Within the scope of the invention, the term individual refers to an animal. In certain aspects, the animal is a mammal. The term individual also refers to, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In some embodiments, the individual is a human. For the purposes of the invention, the term patient refers to a human.

As used herein, the terms inhibit, inhibiting, or inhibitory refer to the reduction or suppression of a specified condition, symptom, disorder, or disease, or a significant reduction in the underlying activity of a biological activity or process.

As used herein, the term treat or treat any disease or disorder, in one embodiment, refers to amelioration of the disease or disorder (i.e., slowing down or stopping or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, the term treatment refers to alleviating or improving at least one physical parameter, including parameters that may not be apparent to the patient. In yet another embodiment, the term treatment refers to modulating a disease or disorder physically (eg, stabilizing an apparent symptom), physiologically (eg, stabilizing a physical parameter), or both.

In yet another embodiment, the term treatment refers to preventing or delaying the onset or development or progression of a disease or disorder.

Within the scope of the invention, terms in the singular used in the context of the present invention (especially in relation to the claims) should be construed as covering both the singular and the plural, unless otherwise indicated in the present description or clearly contrary to the context.

The term "optionally substituted" means a group which may be unsubstituted or substituted at one or more positions with any one radical or any combination of radicals suitable for substitution on that group or the indicated radicals. The number, arrangement and choice of substituents should be such as to include only those substituents that the chemist would expect to be sufficiently stable; thus an oxo group will not be a substituent on an aryl or heteroaryl ring, for example, and one carbon atom will not have three hydroxy or amino substituents.

Within the scope of the invention, the halogen may be fluorine, chlorine, bromine or iodine.

Within the scope of the invention, the term C1-C ₆ -alkyl or C ₁ . ₆ -alkyl means straight or branched alkyl containing 1-6 carbon atoms. If a different number of carbon atoms is indicated, such as C ₄ or C ₃ , then the definition should be changed accordingly, for example, C 1 -C 4 alkyl will be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

Within the scope of the invention, the term C1- _C6 alkoxy or _C1-6 alkoxy means a straight or branched alkoxy group containing 1-6 carbon atoms. If a different number of carbon atoms is indicated, such as C ₄ or C ₃ , then the definition should be changed accordingly, for example C 1 -C ₄ -alkoxy group will be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, a sec-butoxy; and a tert-butoxy group.

Within the scope of the invention, the term C1- _C4 haloalkyl or _C1-4 haloalkyl means straight or branched alkyl containing 1-4 carbon atoms, where at least one hydrogen atom is replaced by a halogen atom. The number of halogen substituents may be from one to the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms is indicated, such as C ₆ or C ₃ , then the definition should be modified accordingly. Thus C1- _C4 haloalkyl will be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl containing at least one hydrogen atom substituted by a halogen atom, for example, if the halogen is fluorine: CF3CF2-, (CF ₃ )2CH-, CH3-CF2-, CF3CF2-, CF ₃ , CF2H-, CF3CF2CHCF3 or CF3CF2CF2CF2-.

Within the scope of the invention, the term C ₃ -C ₈ -cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If a different number of carbon atoms is indicated, such as C3C6, then the definition should be modified accordingly.

In the context of the invention, the term 3-6 membered cyclic ether refers to a 3-6 membered saturated heterocyclic ring containing one oxygen atom as a ring member, including oxirane, oxitane, tetrahydrofuran and tetrahydropyran. These 3-6 membered cyclic ethers may be substituted with groups suitable as substituents on other heterocyclic ring moieties.

Terms 4-8 membered heterocyclyl, 5-6 membered heterocyclyl, 3-10 membered heterocyclyl,

- 6 043088

3-14-membered heterocyclyl, 4-14-membered heterocyclyl and 5-14-membered heterocyclyl refer respectively to 4-8-membered, 5-6-membered, 3-10-membered, 3-14-membered, 4 -14-membered and 5-14-membered heterocyclic rings; unless otherwise indicated, such rings contain 1 to 7, 1 to 5, or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur as ring members, and the rings may be saturated or partially saturated, but not aromatic. The heterocyclic group can be attached via a heteroatom or a carbon atom. The term heterocyclyl includes single ring groups, fused ring groups and bridge groups. Non-limiting examples of such a heterocyclyl include pyrrolidine, piperidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxatian, 8-aza-bicyclo[3.2.1]octane, 3 ,8-diazabicyclo[3.2.1]octane, 3oxa-8-aza-bicyclo[3.2.1]octane, 8-oxa-3-aza-bicyclo[3.2.1]octane, 2-oxa-5-aza-bicyclo [2.2.1]heptane, 2,5diaza-bicyclo[2.2.1]heptane, azetidine, ethylenedioxo, oxitane or thiazole. Preferred heterocycles or heterocyclic groups are 5-membered saturated rings containing one heteroatom selected from N, O and S and 6-membered saturated rings containing one or two non-contiguous heteroatoms selected from N, O and S.

Within the scope of the invention, the term cyclic ether refers to a heterocyclic ring containing at least one oxygen atom as a ring member. Generally, the term refers to a heterocyclic ring containing only one oxygen atom as a ring member. Specific examples of cyclic ethers include oxitane or oxytanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. Cyclic ethers may be substituted with one or more groups suitable as substituents on heterocyclic rings.

Heteroaryl is a fully unsaturated (aromatic) ring. The term heteroaryl refers to a 5-14 membered monocyclic or bicyclic or tricyclic aromatic ring system containing 1 to 8 heteroatoms selected from N, O, or S. Typically, a heteroaryl is a 5-10 membered ring or ring system (e.g. , 5-7-membered monocyclic group or 8-10-membered bicyclic group), often - 5-6-membered ring. Typical heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3 -, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4 - or 5-pyrazinyl, 2-pyrazinyl and 2-, 4- or 5-pyrimidinyl.

The term hydroxy group or hydroxyl refers to the -OH group.

Within the scope of the invention, the term alkyl refers to saturated hydrocarbon groups in a straight, branched or cyclic configuration, or any combination thereof, and in particular, envisaged alkyl groups include groups containing ten or fewer carbon atoms, in particular 1-6 carbon atoms, and lower alkyl groups containing 1-4 carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, etc.

Alkyl groups may be unsubstituted, or they may be substituted to the extent that such a substitution makes sense from a chemical point of view. Representative substituents include, but are not limited to, halogen, ═O, ═N-CN, ═N-OR ^a , ═NR ^a , -OR ^a , -NR ^a 2 , -SR ^a , -SO2R ^a , -SO2NR ^a 2 , -NR ^a SO2R ^a , -NR ^a CONR ^a 2, -NR ^a COOR ^a , -NR ^a COR ^a , -CN, -COOR ^a , -CONR\ -OOCR ^a , -COR ^a and -NO2, where each R ^a is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4C10 heterocycloalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8- heteroalkenyl, C2-C8-alkynyl, C2-C8-heteroalkynyl, C6-C10-aryl or C5-C10-heteroaryl, and each R ^a is optionally substituted with halogen, =O, =N-CN, =N-OR ^b , =NR ^b , OR ^b , NR ^b 2, SR ^b , SO2R ^b , SO2NR ^b 2, NR ^b SO2R ^b , NR ^b CONR ^b 2, NR ^b COOR ^b , NR ^b COR ^b , CN, COOR ^b , CONR ^b 2, OOCR ^b , COR ^b and NO2, where each R ^b independently represents H, C1C8-alkyl, C ₂ -C ₈ -heteroalkyl, C ₃ -C ₈ -heterocyclyl, C4-C ₁₀ -heterocycloalkyl, C ₁ -C ₈ -acyl , C ₂ -C ₈ heteroacyl, C ₂ -C ₈ -alkenyl, C ₆ -C ₁₀ -aryl or C ₅ -C ₁₀ -heteroaryl. Alkyl, alkenyl and alkynyl groups may also be substituted with C ₁ -C ₈ acyl, C ₂ -C ₈ heteroacyl, C ₆ -C ₁₀ aryl, or C ₅ -C ₁₀ heteroaryl, each of which may be substituted with suitable substituents. for a specific group. If the substituent group contains two R ^a or R ^b groups on the same or adjacent atoms (for example, -NR ^b ₂ , or -NR ^b -C(O)R ^b ), the two R ^a or R ^b groups may optionally be considered together with the substituent group to which they are attached, giving a ring containing 5-8 members which may be substituted as permitted for R ^a or R ^b themselves and may contain an additional heteroatom (N, O or S) as a ring member .

As used herein, the term alkenyl refers to an alkyl as defined above containing at least two carbon atoms and at least one carbon-carbon double bond. Thus, in particular, envisaged alkenyl groups include linear, branched or cyclic alkenyl groups containing from two to ten carbon atoms (for example, ethenyl, propenyl, butenyl, pentenyl, etc.) or 5-10 atoms in the case of cyclic alkenyl groups. Alkenyl groups are optionally substituted with groups suitable for alkyl groups as specified in

- 7 043088 present description.

Similarly, within the scope of the invention, the term alkynyl refers to an alkyl or alkenyl, as defined above, containing at least two (preferably three) carbon atoms and at least one carbon-carbon triple bond. In particular, contemplated alkynyls include straight, branched or cyclic alkynes having only two to ten carbon atoms (eg ethynyl, propynyl, butynyl, cyclopropylethynyl, etc.). Alkynyl groups are optionally substituted with groups suitable for alkyl groups as defined herein.

Within the scope of the invention, the term cycloalkyl refers to a cyclic alkane (ie, in which the chain of carbon atoms of the hydrocarbon forms a ring), preferably containing from three to eight carbon atoms. Thus, examples of cycloalkanes include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cycloalkyls also include one or two double bonds forming cycloalkenyl groups. Cycloalkyl groups are optionally substituted with groups suitable for alkyl groups as described herein.

Within the scope of the invention, the term aryl or aromatic residue refers to an aromatic ring system, which may additionally include one or more non-carbon atoms. They are typically 5-6 membered isolated rings or 8-10 membered bicyclic groups and may be substituted. Thus contemplated aryl groups include (eg phenyl, naphthyl, etc.) and pyridyl. Additional provided aryl groups can be fused (i.e. covalently attached to 2 atoms on the first aromatic ring) with one or two 5- or 6-membered aryl or heterocyclic groups and are thus referred to as a fused aryl or fused aromatic group .

Aromatic groups containing one or more heteroatoms (typically N, O or S) as ring members may be referred to as heteroaryl or heteroaromatic groups. Typical heteroaromatic groups include monocyclic 5-6 membered aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and imidazolyl and fused bicyclic residues formed by the condensation of one of these monocyclic groups with a phenyl ring or any of the heteroaromatic monocyclic groups to form an 8-10 membered bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopyrimidyl, quinazolyl, quinoxalinyl, cinnolinyl, etc. P. This definition includes any monocyclic or fused ring bicyclic system that has aromaticity characteristics in terms of electron distribution throughout the ring system. It also includes bicyclic groups where at least the ring directly attached to the rest of the molecule has aromatic characteristics. As a rule, ring systems contain 5-12 ring members. Preferred heteroaryl groups are 5-6 membered rings.

For the purposes of the invention, the terms heterocycle, cycloheteroalkyl, and heterocyclic residues are used interchangeably herein and refer to any compound in which a plurality of atoms form a ring via a plurality of covalent bonds, where the ring includes at least one atom other than a carbon atom, in as a member of the ring. In particular, envisaged heterocyclic rings include 5- and 6-membered rings with nitrogen, sulfur or oxygen as non-carbon atoms (eg imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, thiazole, tetrazole, etc.). Typically, these rings contain 0-1 oxygen or sulfur atoms, at least one, and typically 2-3 carbon atoms, and up to four nitrogen atoms as ring members. Within the scope of the invention, the additional provided heterocycles may be fused (i.e. covalently bonded to two atoms on the first heterocyclic ring) to one or two carbocyclic rings or heterocycles and are thus referred to as a fused heterocycle, or a fused heterocyclic ring, or fused heterocyclic residues. If the ring is aromatic, it may be referred to herein as heteroaryl or heteroaromatic groups.

Heterocyclic groups that are not aromatic may be substituted with groups suitable for substituents on alkyl groups as described above.

Aryl and heteroaryl groups may be substituted if possible. Suitable substituents include, but are not limited to, halogen, -OR ^a , -NR ^a 2 , -SR ^a , -SO2R ^a , -SO2NR ^a 2 , -NR ^a SO2R ^a , -NR ^a CONR ^a 2 , -NR ^a COOR ^a , -NR ^a COR ^a , -CN, -COOR ^a , -CONR ^a 2 , -OOCR ^a , -COR ^a and -NO2, where each R ^a is independently H, C1-C8-alkyl, C2-C8- heteroalkyl, C3-C8heterocyclyl, C4-C10-heterocycloalkyl, C1-C8-acyl, C2-C8-heteroacyl, C2-C8-alkenyl, C2-C8heteroalkenyl, C2-C8-alkynyl, C2-C8-heteroalkynyl, C6-C10- aryl or C5-C10-heteroaryl and each R ^a is optionally substituted with halogen, =O, =N-CN, =N-OR ^b , =NR ^b , OR ^b , NR ^b 2, SR ^b , SO2R ^b , SO2NR ^b 2 , NR ^b SO2R ^b , NR ^b CONR ^b 2 , NR ^b COOR ^b , NR ^b COR ^b , CN, COOR ^b , CONR ^b 2 , OOCR ^b , COR ^b and NO2, where each R ^b is independently H, C1- C ₈ -alkyl, C ₂ -C ₈ -heteroalkyl, C ₃ -C ₈ -heterocyclyl, C ₄ -C ₁₀ heterocycloalkyl, C ₁ -C ₈ -acyl, C ₂ -C ₈ -heteroacyl, C ₂ -C ₈ - alkenyl, C ₆ -C ₁₀ -aryl or C ₅ -C ₁₀ -heteroaryl. Alkyl, alkenyl and alkynyl groups can also be substituted with C ₁ -C ₈ -acyl, C ₂ -C ₈

- 8 043088 heteroacyl, C6-C1o-aryl or C ₅ -C ₁₀ -heteroaryl, each of which may be substituted by substituents suitable for a particular group. If the substituent group contains two R ^a or R ^b groups on the same or adjacent atoms (for example, -NR ^b 2 or -NR ^b -C(O)R ^b ), the two R ^a or R ^b groups may optionally be counted together with the group substituent to which they are attached, giving a ring containing 5-8 members which may be substituted as permitted for R ^a or R ^b themselves and may contain an additional heteroatom (N, O or S) as a ring member.

Within the scope of the invention, the term alkoxy group refers to a hydrocarbon group connected through an oxygen atom, for example, -O-Hc, where the Hc hydrocarbon moiety may contain any number of carbon atoms, typically 1-10 carbon atoms, may additionally include a double or triple bond, and may include one or two oxygen, sulfur or nitrogen atoms in the alkyl chains and may be substituted with aryl, heteroaryl, cycloalkyl and/or heterocyclyl groups. For example, suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like. Similarly, the term alkylthio refers to alkyl sulfides of the general formula -S-Hc, where the Hc hydrocarbon moiety is as described for alkoxy groups. For example, contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.

Within the scope of the invention, the term amino refers to the -NH2 group. The term alkylamino refers to amino groups in which one or both of the hydrogen atoms are replaced by an Hc hydrocarbon group as described above, where the nitrogen of the amino N group may be replaced by one or two Hc groups, as described above for alkoxy groups. Examples of alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, etc. In addition, the term substituted amino group refers to amino groups in which one or both of the hydrogen atoms are replaced by an Hc hydrocarbon group as described above, where the nitrogen of the amino group N can be replaced by one or two Hc groups, as described above for alkoxy groups.

Within the scope of the invention, the term acyl refers to a group of the formula -C(=O)-D, where D is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocycle as described above. Typical examples are groups where D is C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or -alkynyl or phenyl, each of which is optionally substituted. In some embodiments, D may be H, Me, Et, isopropyl, propyl, butyl, C1- _C4 alkyl, substituted-OH, -OMe, or NH2, phenyl, halophenyl, alkylphenyl, and the like.

Within the scope of the invention, the term aryloxy refers to an aryl group attached to an oxygen atom, where the aryl group may be further substituted. For example, suitable aryloxy groups include phenyloxy, and so on. Similarly, within the scope of the invention, the term arylthio refers to an aryl group attached to a sulfur atom, where the aryl group may be further substituted. For example, suitable arylthio groups include phenylthio, and so on.

The hydrocarbon portion of each alkoxy group, alkylthio group, alkylamino group, and aryloxy group, etc. may be substituted, if necessary, with an appropriate hydrocarbon residue.

The following numbered embodiments are representative of some aspects of the invention:

1. Compound of formula (I):

where ring A is a 5- or 6-membered heteroaromatic ring optionally containing an additional nitrogen atom as a ring member and optionally fused to a phenyl or pyridinyl ring, and ring A is optionally substituted with one or two groups independently selected from halo, C1- _C4 alkyl, C1- _C4 haloalkyl, C1- _C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridinyl and _C3 - _C6 cycloalkyl;

R ¹ is selected from H, halogen, CN, C ₁ -C ₄ alkyl, C 1 -C ₄ haloalkyl, C 1 -C 4 alkoxy, C 1 -C ₄ haloalkoxy, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl , containing N, O or S as a ring member, phenyl and 5-6-membered heteroaryl containing one or two nitrogen atoms as ring members, where each of the specified C 1 -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl , C ₁ -C ₄ alkoxy, C 1 -C 4 haloalkoxy, C ₃ -C ₆ cycloalkyl, phenyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or two groups selected from R ² ;

where R ² at each occurrence is independently selected from halo, CN, -OH, C1- _C4 alkyl, C1-C4 haloalkyl, _C1 - _C4 alkoxy, C1- _C4 haloalkoxy, and _C3 - _C6 cycloalkyl;

Cy is a ring selected from C3-C6 cycloalkyl, phenyl and a 5-6 membered heteroaryl containing one or two nitrogen atoms as ring members, and is optionally further substituted with one or two groups selected from halo, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C1-C4

- 9 043088 alkoxy groups and C ₁ -C ₄ haloalkoxy groups;

L is a bivalent linker selected from the bond, -CR ₂ -, -(CR ₂ ) ₂ - ₄ - and -O-(CR ₂ ) ₁ . ₃ -, where R in each case is independently selected from H, F and C ₁ -C ₄ -alkyl; or two R groups on the same carbon atom can be taken into account together with the carbon atom to which they are attached, giving a 3-6 membered cycloalkyl ring or a 3-6 membered cyclic ether; or a pharmaceutically acceptable salt thereof.

2. The compound of Embodiment 1 wherein R ¹ is selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₃ -C ₆ -cycloalkyl, 5-6 membered heterocyclyl containing N, O or S as a ring member, phenyl and 5-6 membered heteroaryl containing one or two nitrogen atoms as ring members, where each of the specified C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C _{4 -alkoxy groups, C 1 -C 4} haloalkoxy groups, C ₃ -C ₆ -cycloalkyl, 5-6-membered heterocyclyl containing N, O or S as a ring member, phenyl and 5-6 membered heteroaryl is optionally substituted with one or two groups selected from R ² ;

or a pharmaceutically acceptable salt thereof.

3. The compound according to embodiment 1 or 2, where R ¹ is methyl, phenyl or pyridin2-yl; or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of embodiments 1 or 2, wherein Cy is a ring selected from phenyl and pyridinyl and is optionally further substituted with a group selected from halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C1- C ₄ alkoxy groups and C 1 -C ₄ haloalkoxy groups;

or a pharmaceutically acceptable salt thereof.

5. The compound of Embodiment 4 having the formula

where Z represents CH or N, and Q is selected from H, Me, CF ₃ , OMe and halogen; or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of embodiments 1, 2 and 5, wherein L is a bivalent linker selected from -CR ₂ -, -(CR ₂ ) ₂ . ₄ - and -O-(CR ₂ )1. ₃ -; where R is at each occurrence independently selected from H, F and Me;

or a pharmaceutically acceptable salt thereof.

7. The compound of Embodiment 6 wherein L is selected from -CH ₂ -, -CH ₂ CH ₂ -, -C(Me) ₂ -, -CHMe-, -OCH2-, -CH2CF2-, -CF2CH2-, -CMe2CH2 - and -CH2CMe2-;

or a pharmaceutically acceptable salt thereof.

8. The compound according to any of embodiments 1, 2 and 4, which is a compound of formula (Ia):

where Q is at each occurrence independently selected from halo, C1- _C4 alkyl, C1- _C4 haloalkyl, and C1-C4 alkoxy; And

Z is CH, CQ or N;

or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of any of embodiments 1, 2 and 4, which is a compound of formula (Ib):

n νΆ

II , NN (Ib) where R ⁴ and R ⁵ are independently selected from H, halogen, C1-C ₄ alkyl, C ₁ -C ₄ haloalkyl, C1-C4 alkoxy, C1-C ₄ haloalkoxy, phenyl and pyridinyl; or R ⁴ and R ⁵ can be taken into account together with the carbon atoms to which they are attached, giving a phenyl ring fused to the pyridinyl ring to which R ⁴ and R ⁵ are attached;

or a pharmaceutically acceptable salt thereof.

10. The compound of embodiment 1, wherein the compound is selected from the following compounds:

- 10 043088

- 11 043088

- 12 043088

- 13 043088

- 14 043088

- 15 043088

- 16 043088

- 17 043088

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to any one of embodiments 1, 2, 5 and 10 mixed with at least one pharmaceutically acceptable carrier or excipient.

12. The use of a compound according to any of embodiments 1, 2, 5 and 10, or a pharmaceutically acceptable salt thereof, for the treatment of cancer or fibrosis.

13. The use of Embodiment 12 for the treatment of colon cancer, hepatocellular carcinoma (HCC), kidney cancer, liver cancer, gastric cancer, or liver or kidney fibrosis.

14. The use of a compound according to any of embodiments 1 or 2 in therapy.

15. A pharmaceutical combination containing an effective amount of a compound according to any one of embodiments 1 or 2 and an additional therapeutic agent.

It should be understood that in all substituted groups defined above, compounds obtained by defining substituents with additional substituents on them (for example, a substituted aryl containing a substituted aryl group as a substituent that is itself substituted with a substituted aryl group further substituted with a substituted aryl groups, etc.) are not intended to be included in this description. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.

With respect to any of the groups provided herein containing one or more substituents, of course, it should be understood that such groups do not contain any substitution or substitution patterns that are sterically impractical and/or synthetically unrealizable. Besides,

- 18 043088 compounds according to the invention include all stereochemical isomers obtained by replacing these compounds.

The term optical isomer or stereoisomer refers to any of the various stereoisomeric configurations that may exist for said compound of the present invention and includes geometric isomers. It should be understood that a substituent may be attached to the chiral center of a carbon atom. The term chiral refers to molecules that have the mismatch property when superimposed on a mirror image, while the term achiral refers to molecules that can be superimposed on a mirror image. Thus, the invention includes the enantiomers, diastereoisomers or racemates of the compound. Enantiomers are a pair of stereoisomers that are mismatched when superimposed with mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. The term is used to refer to a racemic mixture, if necessary. Diastereoisomers are stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is determined by the Kahn-Ingold-Prelog R-S system. If the compound is the pure enantiomer, the stereochemistry at each chiral carbon atom can be defined as R or S. Allowed compounds whose absolute configuration is unknown can be denoted as (+) or (-) depending on the direction (right or left hand) in which they rotate the plane of polarized light at the sodium D-line wavelength. Some of the compounds provided herein contain one or more asymmetric centers or axes and thus can give rise to enantiomers, diastereoisomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-.

Depending on the choice of starting materials and methods, the compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as pure optical isomers or mixtures of isomers such as racemates and mixtures of diastereoisomers, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms, unless otherwise indicated. Optically active (R)- and (S)-isomers can be obtained using chiral synthons or chiral reagents or resolved by conventional methods. If the compound contains a di- or tri-substituted double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may be in the cis or trans configuration. All tautomeric forms are also intended to be included.

Any resulting mixtures of isomers can be separated, taking into account the physico-chemical differences of the components, into pure or essentially pure geometric or optical isomers or diastereoisomers, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of end products or intermediates can be resolved to optical antipodes by known methods, for example by separating their diastereomeric salts prepared using an optically active acid or base and releasing the optically active acidic or basic compound. In particular, the basic residue can thus be used to resolve the compounds of the present invention to their optical antipodes, for example by fractional crystallization of the salt formed by using an optically active acid, for example tartaric acid, dibenzoyl-tartaric acid, diacetyltartaric acid, di- O, O'-p-toluoyl-tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, eg high performance liquid chromatography (HPLC), eg using a chiral stationary phase.

In addition, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or they include other solvents used for their crystallization. The compounds of the present invention may, by nature or by design, form solvates with pharmaceutically acceptable solvents (including water); thus, the invention is to be understood to include solvated and unsolvated forms. The term solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more acids, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable basic addition salts can be prepared using inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I-XII of the periodic table. In some embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; especially suitable

- 19 043088 salts include ammonium, potassium, sodium, calcium and magnesium salts.

Molecules of organic solvents. Such solvent molecules are solvents commonly used in the pharmaceutical field which are known to be harmless to the recipient, eg water, ethanol and the like. The term hydrate refers to a complex where the solvent molecule is water.

The compounds of the present invention, including their salts, hydrates, and solvates, may, by nature or by design, form polymorphic forms.

As used herein, the terms salt or salts refer to the acidic or basic addition salt of a compound of the present invention. The term salts includes, in particular, pharmaceutically acceptable salts. The term pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of the present invention, and which, as a rule, are not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acidic and/or basic salts due to the presence of amino groups and/or carboxyl groups, or groups similar to them.

Pharmaceutically acceptable acid addition salts can be prepared using inorganic acids and organic acids, e.g. acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfates/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophyllonate, citrate, ethane disulfonate, fumarate , gluceptate, gluconate, glucuronate, hippurate, iodohydrate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsilate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate , phosphate/hydrophosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and etc. Some organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic residue by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate or the like) or by reacting the free basic forms of these compounds with a stoichiometric amount of suitable acid. Such reactions are generally carried out in water or an organic solvent, or mixtures thereof. Generally, it is desirable to use non-aqueous agents like ether, ethyl acetate, ethanol, isopropanol or acetonitrile, if possible. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, ^20th ed., Mack Publishing Company, Easton, Pa., (1985); and Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCT, Weinheim, Germany, 2002).

The compounds and compositions provided herein may be administered to an individual in need of treatment for a cell proliferation disorder such as cancer or fibrosis, in particular cancers occurring in the gastrointestinal tract and organs and tissues of the first pass metabolism.

The subject for treatment with the compounds and pharmaceutical compositions of the invention is typically a mammal that has been diagnosed as in need of treatment for one or more of these proliferative disorders, and often the subject is a human. Typically, the subject is a patient diagnosed with a malignancy associated with excessive activity of TGFeR1, also known as Alk5, in particular malignancies of the liver, kidneys and gastrointestinal tract. The methods include administering an effective amount of at least one compound of the invention; optionally, the compound may be administered in combination with one or more additional therapeutic agents, in particular therapeutic agents known to be useful in the treatment of a cancer or proliferative disorder suffered by a particular individual.

The compounds of the invention may be used in the treatment of conditions, disorders, or diseases as described herein, or in the manufacture of pharmaceutical compositions for use in the treatment of these diseases. The invention relates to methods of using the compounds of the present invention in the treatment of these diseases or the preparation of pharmaceutical compositions containing the compounds of the present invention for the treatment of these diseases.

The term pharmaceutical composition includes preparations suitable for administration to mammals, eg humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, such as humans, they may be administered as they are or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0 .5 to

- 20 043088

90%) of a compound of formula (I), or formula (II), or any subformula thereof, provided herein as an active ingredient in combination with a pharmaceutically acceptable excipient and optionally two or more pharmaceutically acceptable excipients.

The phrase pharmaceutically acceptable excipient is understood by those skilled in the art and includes a pharmaceutically acceptable material, composition, or carrier suitable for administering the compounds of the present invention to mammals. Excipients include a liquid or solid excipient, diluent, carrier, solvent, or encapsulating material involved in the transport of the agent of the invention from one organ or body part to another organ or body part, or which can be used to make the drug product easier to formulate. , tableting, storage, use or administration. Each excipient must be acceptable in the sense that it must be compatible with the other ingredients of the formulation and not harm the patient. Some examples of materials that can serve as pharmaceutically acceptable excipients include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions and other non-toxic compatible substances used in pharmaceutical formulations. Typically, pharmaceutically acceptable excipients are sterilized and/or are substantially free of pyrogens.

Moisturizers, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring and flavoring agents, preservatives, and antioxidants may also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The compositions of the present invention include formulations suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may suitably be provided in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to form a single dose dosage form will generally be the amount of the compound resulting in a therapeutic effect. Typically, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods for preparing these formulations or compositions include the step of bringing into association a compound of the present invention with a carrier or excipient and, optionally, one or more accessory ingredients. In general, formulations are prepared by uniformly, directly combining a compound of the present invention with a liquid excipient, or a finely divided solid excipient, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, typically sucrose, and gum arabic or gum tragacanth), powders, granules, or in as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and gum arabic), and/or mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compound of the present invention can also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or calcium diphosphate, and/or any from the following: fillers such as starches, lactose, sucrose, glucose, mannitol and/or silicic

- 21 043088 acid; binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; humectants such as glycerin; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; dissolution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; humectants such as, for example, cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and dyes. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose as well as high molecular weight polyethylene glycols and the like.

The tablet can be obtained by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (for example, gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrating agent (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be obtained by molding in a suitable device a mixture of a powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be risk-adjusted or may be prepared with coatings and shells such as enteric coatings and other coatings well known in the art. pharmaceutical formulations. They can also be formulated to provide sustained or controlled release of the active ingredient using, for example, hydroxypropyl methylcellulose in varying proportions to achieve the desired release profile, other polymeric matrices, liposomes and/or microspheres. They can be sterilized by, for example, filtration through a bacterial filter, or by including sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may optionally also contain opacifying agents and may be of a composition that releases the active ingredients only or predominantly in some part of the gastrointestinal tract, optionally in a delayed manner. Examples of sealing compositions that can be used include polymeric materials and waxes. The active ingredient may also be in microencapsulated form, optionally with one or more of the excipients described above.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain an inert diluent commonly used in the art such as, for example, water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, wheat germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and their mixtures.

In addition to inert diluents, oral compositions may also include adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavors, colors, flavors and preservatives.

Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth and mixtures thereof.

Formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art.

Dosage forms for topical or transdermal administration of a compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable excipient and with any preservatives, buffers or propellants that may be required.

Powders and sprays may contain, in addition to the compound of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

- 22 043088

Ophthalmic formulations, eye ointments, powders, solutions and the like. are also within the scope of the present invention.

Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable carriers such as sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted. in sterile injectable solutions or dispersions immediately prior to use, which may contain antioxidants, buffers, bacteriostatic agents, solutes to render the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions and by using surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of an injectable pharmaceutical form can be achieved by the inclusion of absorption delaying agents such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done using a liquid slurry of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug depends on the rate of dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of a parenterally administered drug is achieved by dissolving or suspending the drug in an oil vehicle.

The formulations of the present invention may be administered orally, parenterally, topically or rectally. Of course, they can be administered in forms suitable for each route of administration. For example, they are administered in tablets or capsules, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion or inhalation; topically with a lotion or ointment; and rectally with suppositories.

In the context of the invention, the phrases parenteral administration and parenterally administered means methods of administration other than enteral and topical administration, typically by injection, and include, as non-limiting examples, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal , intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Sometimes intravenous infusion is the preferred route of administration for the compounds of the invention. The infusion can be used to administer a single daily dose or multiple doses. In some embodiments, a compound of the invention is administered by infusion over a period of 15 minutes to 4 hours, typically 0.5 to 3 hours. Such an infusion can be used once a day, twice a day, or up to three times a day.

These compounds can be administered to humans and other animals for therapy by any suitable route of administration, including oral, nasal administration, for example by spray, rectal, vaginal, parenteral, intracisternal and topical administration, for example, by powders, ointments or drops, buccal and sublingual administration.

Regardless of the route of administration chosen, compounds of the present invention which may be used in a suitable hydrated form and/or pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

Precise dosage levels of active ingredients in the pharmaceutical compositions of the present invention can be varied so as to achieve an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and route of administration, without toxicity to the patient.

The selected dose level will depend on a variety of factors, including the activity of the particular compound of the present invention used or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion of the particular compound used, the duration

- 23 043088 treatment, other drugs, compounds and/or materials used in combination with the specific compound used, age, sex, body weight, condition, general health and medical history of the patient being treated, and similar factors well known in the art. the field of medicine.

The attending physician or veterinarian can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian may begin administering doses of the compounds of the invention used in a pharmaceutical composition at levels lower than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to achieve a therapeutic effect. Such an effective dose will generally depend on the factors described above. In general, intravenous and subcutaneous doses of the compounds of the present invention to a patient when used for the effects shown will be in the range of from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg. per kg per day, and even more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is the amount by which the desired or observable therapeutic effect is achieved.

If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. Compounds administered orally or by inhalation are typically administered in an amount of one to four doses per day. Compounds administered by injection are typically administered once a day or once every other day. Compounds administered by infusion are typically administered in 1-3 doses per day.

While it is possible to administer the compound of the present invention alone, it is preferable to administer the compound as a pharmaceutical composition, such as those described herein.

Pharmaceutical compositions, combinations and other related uses

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or formula (II), or any of their subformulas presented in the present description, mixed with at least one pharmaceutically acceptable carrier or excipient.

The compounds described above can be used for any suitable purpose. For example, the compounds of the invention may be used in therapy and/or testing.

In yet another aspect, the present invention relates to a method for treating and/or preventing a proliferation disorder such as a cancer or tumor. The compounds, compositions and methods are particularly useful in cancers with excessive activity of TGFeR1, also known as Alk5, in particular in cancers of the liver, kidneys and gastrointestinal tract.

In yet another aspect, the present invention relates to the use of a compound as described above for the manufacture of a medicament.

In yet another aspect, the present invention relates to a combination for the treatment and/or prevention of a proliferation disorder, wherein the combination comprises an effective amount of a compound of formula (I), or formula (II), or any of their subformulas as provided herein, or a pharmaceutically acceptable compound thereof. salt, and an effective amount of a second prophylactic or therapeutic agent for the treatment and/or prevention of a proliferation disorder, malignancy, tumor or fibrosis, in particular for the treatment of colon cancer, hepatocellular carcinoma (HCC), kidney cancer, liver cancer and gastric cancer, as well as fibrosis in the digestive system and the system of first-pass metabolism, in particular, fibrosis of the liver and fibrosis of the kidneys.

Lineups

You can get any suitable composition of the compounds presented in the present description. In general, see Remington's Pharmaceutical Sciences, (2000) Hoover, JE editor, ^20th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. The formulation is chosen to be suitable for the respective route of administration. In cases where the compounds are acidic enough to form stable, non-toxic base salts, it may be appropriate to introduce the compounds as salts. Examples of pharmaceutically acceptable salts are organic acid addition salts prepared with acids forming a physiologically acceptable anion such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. You can also get suitable inorganic salts, including hydrochloride, sulfate, nitrate, bicarbonate and carbonate. Pharmaceutically acceptable salts are prepared by standard methods well known in the art, for example by using a sufficiently basic compound such as an amine with an appropriate acid to give a physiologically acceptable anion.

Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts are also prepared, as well as amine salts of carboxylic acids and tetrazoles.

If the intended compounds are administered in a pharmacological composition, it is envisaged that the compounds may be formulated in admixture with a pharmaceutically acceptable excipient and/or carrier. For example, the provided compounds can be administered orally as neutral compounds or pharmaceutically acceptable salts, or intravenously in saline. For this purpose, conventional buffers such as phosphates, bicarbonates or citrates can be used. Of course, a person skilled in the art can modify the formulations, taking into account the ideas set forth in the present description, to obtain numerous formulations for a particular route of administration. In particular, the compounds provided can be modified to make them more soluble in water or other carrier, which, for example, can easily be done with minor modifications (salt composition, esterification, etc.) well known in the art. One skilled in the art will know how to select or modify the route of administration and dosage regimen for a particular compound to adjust the pharmacokinetics of the compounds of the invention for maximum patient benefit.

Compounds having formula I-II as described herein are generally soluble in organic solvents such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N-dimethylformamide, N,N- dimethylacetamide, dimethyl sulfoxide, etc. In one embodiment, the present invention relates to compositions obtained by mixing a compound having formula I-II with a pharmaceutically acceptable excipient. In one aspect, the composition can be obtained by a method including:

a) dissolving the described compounds in a water-soluble organic solvent, a non-ionic solvent, a water-soluble lipid, a vitamin such as tocopherol, a fatty acid, a fatty acid ester, or a combination thereof to obtain a solution; And

b) adding saline or buffer containing 1-10% carbohydrate solution. In one example, the carbohydrate includes dextrose.

Solution pharmaceutical compositions prepared by the methods of the invention are stable and can be used in animals and in clinical settings.

Illustrative non-limiting examples of water-soluble organic solvents for use in the methods of the invention include polyethylene glycol (PEG), alcohols, acetonitrile, Nmethyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or a combination thereof. Non-limiting examples of alcohols include methanol, ethanol, isopropanol, glycerin or propylene glycol.

Illustrative non-limiting examples of water-soluble non-ionic surfactants for use in the methods of the invention include CREMOPHOR® EL, polyethylene glycol-modified CREMOPHOR® (polyoxyethylene glycerol triricinoleate 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, PEG-succinate, polysorbate 20, polysorbate 80 , SOLUTOL® HS (polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, LABRAFIL® (ethoxylated peach oil), LABRASOL® (capryl-caproyl macrogol-8-glyceride), GELUCIRE® (glycerol ester), SOFTIGEN® (PEG 6- caprylic glyceride), glycerin, glycol polysorbate, or a combination thereof.

Illustrative non-limiting examples of water-soluble lipids for use in the methods of the invention include vegetable oils, triglycerides, vegetable oils, or a combination thereof. Non-limiting examples of oils include castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil triglyceride, palm kernel oil and their hydrogenated forms, or a combination thereof.

Illustrative non-limiting examples of fatty acids and fatty acid esters for use in the methods of the invention include oleic acid, monoglycerides, diglycerides, PEG fatty acid mono- or di-esters, or a combination thereof.

The person skilled in the art can modify the formulations using the ideas set forth in the present description, to obtain numerous formulations for a particular route of administration. In particular, the compounds can be modified to make them more soluble in water or other carrier. One skilled in the art will also know how to modify the route of administration and dosing regimen of a particular compound to adjust the pharmacokinetics of the compounds of the invention for maximum patient benefit.

Combinations of medicines

The methods of the embodiments include administering an effective amount of at least one example of a compound of the invention; optionally, the compound may be administered in combination with one or more additional therapeutic agents, in particular therapeutic agents that are known to be useful in the treatment of a condition or disease from which an individual suffers.

Additional active ingredients may be administered in a pharmaceutical composition separate from at least one example of a compound of the invention, or may be included with at least one example of a compound of the invention in a single pharmaceutical composition. Additional active ingredients may be administered simultaneously, before or after administration of at least one example of a compound of the invention.

Methods for using exemplary compounds and their pharmaceutical compositions

The present invention also relates to pharmaceutical compositions for the treatment and/or prevention of a proliferation disorder or malignancy, such as those described herein, containing any compound having Formula I.

For the practice of the method of the present invention, the compounds having the formula and their pharmaceutical compositions can be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, or other methods of drug administration. Within the scope of the invention, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion routes.

A sterile injectable composition, such as a sterile injectable aqueous or oleaginous suspension, can be formulated by methods known in the art using suitable dispersants or humectants and suspending agents. The sterile injectable may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Suitable carriers and other pharmaceutical excipients are generally sterile.

In addition, sterile fatty oils are commonly used as a solvent or suspending medium (for example, synthetic mono- or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, as can pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose, or similar dispersants. Various emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation.

The composition for oral administration can be any orally acceptable dosage form, including, as non-limiting examples, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate may also be added. For oral administration in capsule form, diluents that may be used include lactose and dried cornstarch. If aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in the oil phase in combination with emulsifiers or suspending agents. If necessary, you can add some sweeteners, flavors or colors. Nasal aerosol or inhalation compositions may be prepared by methods well known in the art of pharmaceutical formulations and may be prepared as solutions, e.g., in saline, using suitable preservatives (e.g., benzyl alcohol), absorption promoters to obtain bioavailability, and/or other solubilizers. or dispersants known in the art.

In addition, compounds having formula (I), or formula (II), or any subformula thereof, can be administered alone or in combination with other therapeutic agents, such as antitumor agents, to treat an individual in need of treatment. The combination treatments of the present invention include administering at least one example of a compound of formula (I), or formula (II), or any subformula thereof, as described herein, and at least one additional pharmaceutically active ingredient. The compound of the invention and additional pharmaceutically active agents may be administered separately or together. The amounts of the compound of the invention and additional pharmaceutically active agents and the relative timing of administration will be chosen to achieve the desired combined therapeutic effect.

The compounds provided herein can be synthesized by the general synthetic methods below, specific examples of which are described in more detail in the examples.

Within the scope of this specification, only an easily removable group that is not a component of a particular desired end product of the compounds of the present invention is referred to as a protecting group, unless the context indicates otherwise. The protection of functional groups with such protecting groups, the protecting groups themselves and their cleavage reactions are described, for example, in commonly used reference books such as, for example, Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627pp. (URL: http://www.science-ofsynthesis.com (Electronic Version, 48 Volumes)); JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York 1973, in T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, Third edition, Wiley, New York 1999, in Peptides; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in Methoden der organischen Chemie (Methods of Organic Chemistry), Houben Weyl, 4 ^th edition, Volume 15/1, Georg Thieme Verlag , Stuttgart 1974, in H.-D. Jakubkeand H. Jeschkeit, Aminosauren, Peptide, Proteine (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide und Derivate (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be easily removed (i.e. without undergoing unwanted secondary reactions), for example, by solvolysis, reduction, photolysis, or alternatively under physiological conditions ( for example, by enzymatic digestion).

Salts of the compounds of the present invention having at least one salt-forming group can be prepared in a manner known in the art. For example, salts of compounds of the present invention having acidic groups can be obtained, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example, the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds. , such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with the appropriate calcium compounds, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of salt-forming agent. Acid addition salts of the compounds of the present invention are prepared in a conventional manner, for example by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of the compounds of the present invention containing acidic and basic salt-forming groups, for example a free carboxy group and a free amino group, can be obtained, for example, by neutralizing salts, such as acid addition salts, to the isoelectric point, for example, with free bases, or by ion exchangers.

Salts can be converted in a conventional manner to the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.

Mixtures of isomers that can be obtained according to the invention can be separated by a method known in this field into individual isomers; diastereoisomers can be separated, for example, by separation of mixtures of polyphasic solvents, recrystallization and/or chromatographic separation, for example on silica gel, or by, for example, medium pressure liquid chromatography using a reverse phase column, and racemates can be separated, for example, by formation of salts with optically pure salt-forming reagents and separating the mixture of diastereoisomers thus obtained, for example by fractional crystallization or chromatography on optically active column materials.

Intermediates and end products can be isolated and/or purified by standard methods, eg chromatographic methods, partition methods, (recrystallization) and the like.

The process steps for synthesizing the compounds of the invention may be carried out under reaction conditions known in the art, including those specifically mentioned, in the absence or, as usual, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert with respect to the reagents used. and dissolving them, in the absence or presence of catalysts, condensing or neutralizing agents, e.g. ion exchange agents, such as ^cation exchange agents, e.g. , in the temperature range from about -100°C to about 190°C, including, for example, from about -80°C to about 150°C, for example from -80 to -60°C, at room temperature, at a temperature of - 20 to 40°C or at boiling point, at atmospheric pressure or in a closed vessel, optionally under pressure and/or in an inert atmosphere, such as argon or nitrogen.

At all stages of the reaction mixtures of resulting isomers can be separated into individual isomers, e.g. diastereoisomers or enantiomers, or into any desired mixtures of isomers, e.g. racemates or mixtures of diastereoisomers, for example, in a manner analogous to the methods described in Science of Synthesis: Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag, Stuttgart, Germany, 2005.

Solvents from which solvents suitable for any particular reaction can be selected

- 27 043088 include specifically mentioned solvents or, for example, water, esters, such as lower alkyl-lower alkanoates, such as ethyl acetate, ethers, such as aliphatic ethers, such as diethyl ether, or cyclic ethers, such as , tetrahydrofuran or dioxane, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride or chloroform, acid amides such as dimethylformamide or dimethylacetamide, bases such as heterocyclic nitrogen bases such as pyridine or Nmethylpyrrolidin-2-one, carboxylic acid anhydrides such as lower alkanoic anhydrides such as acetic anhydride, cyclic, linear or branched hydrocarbons such as cyclohexane, hexane or isopentane, or mixtures of these solvents, for example, aqueous solutions, unless otherwise indicated in the description of the methods. Such solvent mixtures can also be used in isolation, for example by chromatography or separation.

The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include a solvent used for crystallization. Various crystalline forms may be present.

The present invention also relates to forms of the method in which a compound that can be obtained as an intermediate in any step of the method is used as a starting material and the remaining steps of the method are carried out, or in which the starting material is obtained under the reaction conditions or used in the form of a derivative, for example, in a protected form or in the form of a salt, or a compound that can be obtained by the process of the invention is prepared under appropriate conditions and further processed in situ.

In accordance with the above, in another additional aspect, the present invention relates to:

Pharmaceutical combination containing:

a) a first agent which is a compound of the invention, for example a compound of formula (I) or any of its subformulas, and

b) an additional agent, for example, an additional pharmaceutically active agent, as defined above.

A method as defined above, comprising co-administering, for example, simultaneously or sequentially, a therapeutically effective amount of a compound of the invention, for example, a compound of formula I or any subformula thereof, and an additional agent, for example, an additional therapeutic agent, as defined above.

Within the scope of the invention, the terms co-administration or combined administration or the like. are intended to include the administration of selected therapeutic agents to a single patient and to include treatment regimens in which the agents may not be administered by the same route of administration or at the same time. Fixed combinations are also within the scope of the present invention. The administration of the pharmaceutical combination of the invention results in a beneficial effect, eg a synergistic therapeutic effect, as compared to a monotherapy using only one of the pharmaceutically active ingredients.

Each component of the combination of the present invention can be administered separately, together, or in any combination thereof.

The compound of the invention and any additional agent may be formulated into separate dosage forms. Alternatively, to reduce the number of dosage forms administered to a patient, the compound of the invention and any additional agent may be formulated together in any combination. For example, an inhibitor compound of the invention may be formulated in one dosage form and an additional agent may be formulated together in another dosage form. Any separate dosage forms can be administered simultaneously or at different times.

Alternatively, the composition of the present invention contains an additional tool, as presented in the present description. Each component may be in individual compositions, combined compositions, or a single composition.

Abbreviations

Ac - Acetyl.

ACN - Acetonitrile.

AcOEt/EtOAc - Ethyl acetate.

AcOH - Acetic acid.

Water - Water.

Ar - Aryl.

Bn - Benzyl.

Bu - Butyl (nBu=n-butyl, tBu=tert-butyl).

CDI - Carbonyldiimidazole.

CH ₃ CN - Acetonitrile.

DBU - 1,8-diazabicyclo[5,4.0]-indec-7-ene.

- 28 043088

Boc2O - Di-tert-butyl dicarbonate.

DCE - 1,2-diclopentane.

DCM - Dichloromethane.

DiBAl-H - Diisobutylaluminum hydride.

DIPEA - N-ethyldiisopropylamine.

DMA - N,N-dimethylacetamide.

DMAP - Dimethylaminopyridine.

DMF - N,N'-dimethylformamide.

DMSO - Dimethyl Sulfoxide.

EI - Electrospray ionization.

Et ₂ O - Diethyl ether.

Et ₃ N - Triethylamine.

Ether - Diethyl ether.

EtOAc or EA - Ethyl acetate.

EtOH - Ethanol.

FC - Flash Chromatography.

hours - hours.

HATU - O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

HBTU - O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

HCl - Hydrochloric acid.

HMPA - Hexamethylphosphamide.

HOBt - 1-hydroxybenzotriazole.

HPLC - High Performance Liquid Chromatography.

H2O - Water.

l - liters.

LC-MS - Liquid Chromatography Mass Spectrometry.

LiHMDS - Lithium bis(trimethylsilyl)amide.

wCPBA - Meta-chloroperoxybenzoic acid.

MgSO ₄ - Magnesium sulfate.

Me - Methyl.

MeI - Iodomethane.

MeOH - Methanol.

mg - Milligram.

min - Minutes.

ml - Milliliter.

MS - Mass spectrometry.

NaHCO ₃ - Sodium bicarbonate.

Na ₂ SO ₄ - Sodium sulfate.

NH ₂ OH - Hydroxylamine.

Pd/C - Palladium black.

Pd (OH) ₂ - Palladium hydroxide.

PE - Petroleum ether.

PG - Protecting group.

Ph - Phenyl.

Ph ₃ P - Triphenylphosphine.

Rev. - Preparative.

Rf - Ratio of fronts.

RP - Reversed phase.

Rt - Hold time.

RT - Room temperature.

SiO ₂ - Silica gel.

SOCl ₂ - Thionyl chloride.

TBAF - Tetrabutylammonium fluoride.

TBDMS - Tert-butyldimethylsilyl.

TEA - Triethylamine.

TFA - Trifluoroacetic acid.

THF - Tetrahydrofuran.

TLC - Thin Layer Chromatography.

TsCl - Toluenesulfonyl chloride.

The compounds of the invention can be prepared by organic synthetic methods known to the person skilled in the art, with reference to the following reaction schemes and examples. General methods for the synthesis of compounds of formula (I) and formula (II) are shown in schemes 1-3 below.

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General methods of synthesis.

Compounds of the present invention are obtained from public compounds by methods known to specialists in this field, taking into account the examples and schemes given in the present description.

Scheme 1

In scheme 1, ring A, substituted with an amino group and associated with an ester, is subjected to conjugation with chloropyridine. The ester can be hydrolyzed to give the free carboxylic acid. Depending on the choice of R, the product may be a compound of formula (I) or a precursor to such compounds. Ring A corresponds, for example, to the Cy group in the compounds of formula (I).

Scheme 2

In Scheme 2, ring A has an amino group and is linked to a nitrile; after conjugation with chloropyridine, the nitrile can be converted into a carboxylate group by hydrolysis, or can be converted with trimethylsilyl azide into an acidic tetrazole group. Again, depending on the choice of R, the product may be a compound of formula (I) or a precursor to such compounds.

Scheme 3

alkylated with tert-butyl bromoacetate to give

In Scheme 3, the tetrazole product from the scheme of two isomeric carboxymethyltetrazole products. Again, depending on the choice of R, the product may be a compound of formula (I) or a precursor to such compounds.

Using these and known alternative starting materials, one skilled in the art can prepare a wide variety of compounds of formula (I) having a carboxylate or a tetrazole as the acid group.

Intermediates:

Intermediate A1: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine

The compound was obtained by the method described in WO 2005080377.

Step 1: (4,5-dimethylfuran-2-yl)(pyridin-2-yl)methanone.

In an argon atmosphere, to a solution of 2,3-dimethylfuran (1.0 eq.) in Et ₂ O (0.65 M) was added dropwise nBuLi (1.6 M, 1.3 eq.) at 0°C. The mixture was stirred at 40° C. for 1.5 h and then cooled to -78 C. A solution of picolinonitrile (1.0 eq.) in Et ₂ O (2 M) was added dropwise to it. The resulting mixture was stirred at RT for 1.5 hours before quenching on ice. The pH of the mixture was adjusted to approximately 5 with 2N HCl. The mixture was extracted with DCM. The combined DCM layer was washed with water and dried over Na ₂ SO ₄ . The organic solvent was removed and the residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 10:1) to give the title product as a yellow solid. LC-MS (m/z): [M+1]+=202;

¹ H NMR (400 MHz, CDCl3) δ 8.70 (d, J=5.2 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 7.86 (t, J= 7.6Hz, 1H), 7.82

- 30 043088 (s, 1H), 7.46 (dd, J=7.6, 5.2 Hz, 1H), 2.38 (s, 3H), 2.04 (s, 3H).

Step 2: 5,6-dimethyl-[2,2'-bipyridine]-3-ol.

A mixture of the above product (1.0 eq.) in MeOH (0.033 M) and 28% NH 3 H ₂ O (10 ml) was sealed in a tube and stirred at 170°C for 8 h. The mixture was cooled to RT, concentrated and purified by flash chromatography on silica gel (eluent: petroleum ether/EtOAc 20:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+1]+=201;

1H NMR (400 MHz, CDCl3) δ 13.86 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.47 (d, J=4.4 Hz, 1H), 7.86 (td, J=8.0, 1.6 Hz, 1H), 7.28-7.25 (m, 1H), 7.08 (s, 1H), 2.47 (s, 3H) , 2.28 (s, 3H).

Step 3: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine.

A mixture of the above product (1.0 eq.), 2,4-dichloropyridine (2.0 eq.), Cs ₂ CO ₃ (2.0 eq.) in DMSO (0.09 M) was stirred at 180°C in for 5 h. The mixture was cooled to RT. The mixture was quenched with water and extracted with EtOAc. The solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 2:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+1] ⁺ =312;

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (ddd, J=4.8, 2.0, 1.2 Hz, 1H), 8.13 (d, J=6.0 Hz, 1H) , 7.84 (dt, J=7.6, 1.2 Hz, 1H), 7.70 (td, J=7.6, 1.6 Hz, 1H), 7.27 (d, J=6 .0 Hz, 1H), 7.20 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.70 (dd, J=6.0, 2.0 Hz, 1H), 2.63 (s, 3H), 2.38 (s, 3H).

Intermediate A2: 3-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine Ύ V

The compound was obtained by the method described in WO 2009022171.

A mixture of 2,6-dimethylpyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.5 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMSO (0.5 M) was stirred at 150° C. for 3 hours. The reaction was monitored by TLC. the solution was cooled to RT and extracted with EA/H ₂ O, washed with brine, dried over Na ₂ SO ₄ . The organic phase was concentrated. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 9:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=235.3;

1H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J=5.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.09 (d, J= 8.0 Hz, 1H), 6.746.71 (m, 2H), 2.58 (s, 3H), 2.38 (s, 3H).

Intermediate A3: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2,2'-bipyridine

The compound was obtained by the method described in WO 2009022171.

Step 1: 3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine.

A mixture of 2-iodo-6-methylpyridin-3-ol (1.05 eq.), 2,4-dichloropyridine (1.0 eq.), Cs ₂ CO ₃ (2.0 eq.) in DMF (0.22 M) stirred at 100° C. for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was cooled to RT, filtered, washed with EtOAc. The filtrate was washed with brine and then dried over Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 8:1) to give the product as a white solid. LC-MS (m/z): [M+H]+=347;

1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J=5.6 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.6, 2.4 Hz, 1H), 2.54 (s, 3H).

Step 2: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2,2'-bipyridine.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine (1.0 eq.), pyridin-2ylzinc (II) bromide (0.5 m in THF, 1.2 eq. ), Pd(PPh ₃ ) ₄ (0.1 equiv.) in DmA (0.43 m) was stirred at 120°C for 16 h in an argon atmosphere. The reaction was monitored by LC-MS. The mixture solution was cooled to RT and diluted with EtOAc. The mixture was washed with brine and then dried over Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (100% EtOAc) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=298.

The following compounds were prepared as described for Intermediate A3.

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The compound was obtained by the method described in WO 2009022171.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine (1.0 eq.), Phenylboronic acid (1.2 eq.), Pd(dppf)Cl ₂ (0, 1 eq.) HNa ₂ CO ₃ (2.0 eq.) in dioxane/H ₂ O (5:1, 0.25 M) was stirred at 100° C. for 3 hours. The reaction was monitored by LC-MS. The mixture solution was cooled to RT and diluted with EtOAc. The mixture was washed with brine and then dried over Na ₂ SO ₄ . The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (100% EtOAc) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=297;

¹ H NMR (400 MHz, CDCl3) δ 8.06 (d, J=6.0 Hz, 1H), 7.68 (dd, J=8.0, 1.6 Hz, 2H), 7.31- 7.24 (m, 4H), 7.13 (d, J=8.0 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 6.59 (dd, J=6 .0, 2.4 Hz, 1H), 2.59 (s, 3H).

The following compounds were prepared as described for Intermediate A6.

intermediate connection Structure LC-MS [M+1] ⁺ and/or Ή NMR A7 From ² about LC-MS (m/z): [M+1] ⁺ =298 A8 o — g LC-MS (m/z): [M+1] ⁺ =298 A9 Q LC-MS (m/z): [M+1] ⁺ =331.3 AYu O LC-MS (m/z): [M+1] ⁺ =331 AN /=\ o LC-MS (m/z): [M+1] ⁺ =331

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Intermediate A12: 2-chloro-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1Hpyrazol-4-yl)oxy)pyridine

The compound was obtained by the method described in WO 2016057278.

Step 1: 2-((2-chloropyridin-4-yl)oxy)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one.

A mixture of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one (1.0 eq.), 2-chloropyridin-4-ol (1.0 eq.) and K2CO3 (1.0 eq.) 5 eq.) in acetone (0.12 M) was stirred for 16 h at RT. The reaction was monitored by TLC. The solid was then filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil.

Step 2: 2-chloro-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridine.

A solution of 2-((2-chloropyridin-4-yl)oxy)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one (1.0 eq.) in DMFDMA (0.37 M) was stirred at 100° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (50 ml) at 0°C, treated with NH2NH2H2O (80 wt.%, 3.0 eq.). The resulting mixture was stirred at RT for 16 hours. The reaction was monitored by LC-MS. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure to give the title compound as a brown oil. LC-MS (m/z): [M+H]+=280.

Step 3: 2-chloro-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridine.

A mixture of pyridine (1.1 eq.) and Cu(OAc) ₂ (1.1 eq.) in DCE (0.37 M) was stirred at 75°C for 0.5 h. The mixture was cooled to RT and a solution of the indicated above product (1.0 eq.) in DCE (0.1 M) followed by cyclopropylboronic acid (2.0 eq.) and Na ₂ CO ₃ (2.0 eq.). The resulting mixture was stirred at 75° C. for 16 hours under an oxygen atmosphere. The reaction was monitored by LCMS. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 10:1 to 2:1) to give the title compound as a brown oil. LC-MS (m/z): [M+H] ⁺ =320.

Intermediate A13: 3-((2-chloropyridin-4-yl)oxy)-6-methylpicolinonitrile

Stage 1: 5-hydroxy-2-methylpyridine-1-oxide.

To a solution of 6-methylpyridin-3-ol (1.0 eq.) in DCM (0.5 M) was added m-CPBA (1.2 eq.). The mixture was stirred at RT for 16 hours. The reaction was monitored by LC-MS. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in hot EtOH, then cooled to RT and treated with Et2O. The precipitated solid was collected by filtration, dried to give the title compound as a yellow solid. LC-MS (m/z): [M+H] ⁺ =126.

Stage 2: 3-hydroxy-6-methylpicolinonitrile.

A mixture of the above product (1.0 eq.), TMSCN (3.5 eq.) and TEA (2.5 eq.) in MeCN (3.0 ml) was sealed in a tubular reactor. The mixture was stirred at 150°C for 2.5 hours in a microwave oven. The reaction was monitored by LC-MS. The mixture was concentrated under reduced pressure to give the title compound as a black oil, which was used directly in the next step without further purification. LC-MS (m/z): [M+H] ⁺ =135;

¹ H NMR (400 MHz, DMSO) δ11.34 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 2.33 (s, 3H).

Step 3: 3-((2-chloropyridin-4-yl)oxy)-6-methylpicolinonitrile.

A mixture of the above product (1.0 eq.), 2,4-dichloropyridine (1.5 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMSO (0.37 M) was stirred at 120°C in for 16 hours. The reaction was monitored by LC-MS. The mixture was then diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 10:1 to 3:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H] ⁺ =246.

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Intermediate A14: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(trifluoromethyl)pyridine

Step 1: 6-methyl-2-(trifluoromethyl)pyridin-3-ol.

A mixture of 2-iodo-6-methylpyridin-3-ol (1.0 eq.), methyl-2-chloro-2,2-difluoroacetate (3.0 eq.), CuI (1.5 eq.), KF (2 equiv.), KBr (2.0 equiv.) in DMF (0.2 M) was stirred at 110°C for 16 h in an argon atmosphere. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 1:0 to 50:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H] ⁺ =178.4.

Step 2: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(trifluoromethyl)pyridine.

A mixture of 6-methyl-2-(trifluoromethyl)pyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (2.0 eq.), Cs ₂ CO ₃ (2.0 eq.) in DMSO ( 0.1 M) was stirred at 140° C. for 3 hours. The reaction mixture was cooled to RT, treated with water and extracted with EtOAc. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 2:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+1] ⁺ =289.

Intermediate A15: 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-methylpyridine

A mixture of 2-ethyl-6-methylpyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.0 eq.), Cs ₂ CO ₃ (2.0 eq.) in DMF (1.5 M) stirred at 110° C. for 16 hours. The reaction was monitored by LC-MS. The mixture was filtered and washed with water, extracted with EtOAc. The organic layer was washed with brine and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc 20:1) to give the title compound as a colorless oil. LC-MS (m/z): [M+H]+=249;

1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=5.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.23 (d, J =8.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.91 (dd, J=5.6, 2.4 Hz, 1H), 2.60 (k , J=7.6 Hz, 2H), 2.50 (s, 3H), 1.13 (t, J=7.6 Hz, 3H).

Intermediate A16: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine

Stage 1: 6-iodo-2-methylpyridin-3-ol.

A mixture of 2-methylpyridin-3-ol (1.0 eq.), I ₂ (1.0 eq.), Na ₂ CO ₃ (2.2 eq.) in H ₂ O (0.46 M) was stirred at RT for 1 h in an argon atmosphere. The reaction was monitored by LC-MS. The pH of the solution was adjusted to 6 with HCl (2 N). The precipitated solid was filtered, washed with water (10 ml, 2 times) and dried to give a yellow solid. The solid was dissolved in EtOAc at 80° C. and petroleum ether (70 ml) was added. The mixture was cooled to room temperature. The crystallized solid was filtered and dried to give the title compound as a yellow solid.

Stage 2: 2-methyl-6-vinylpyridin-3-ol.

A mixture of 6-iodo-2-methylpyridin-3-ol (1.0 eq.), Potassium trifluoro(vinyl)borate (1.0 eq.), Pd(dppf)Cl ₂ (0.1 eq.), K ₂ CO ₃ (3.0 eq.) in 1,4-dioxane/water (20:1, 0.85 M) was stirred at 100° C. for 16 hours under argon. The reaction was monitored by LC-MS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give the title compound as a yellow oil.

Stage 3: 6-ethyl-2-methylpyridin-3-ol.

To a solution of 2-methyl-6-vinylpyridin-3-ol (1.0 eq.) in MeOH (0.35 M) was added Pd/C (10 wt.%, 0.02 eq.). The reaction mixture was stirred at RT for 16 h under H ₂ atmosphere. The reaction was monitored by LC-MS. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow oil.

Step 4: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine.

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A mixture of 6-ethyl-2-methylpyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.0 eq.), Cs ₂ CO ₃ (2.0 eq.) in DMF (0.58 M) stirred at 100° C. for 16 hours. The reaction was monitored by LC-MS. The mixture was filtered and washed with water (15 ml), extracted with EtOAc (15 ml, 3 times). The organic layer was washed with brine (10 ml, 2 times) and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc 20:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=249.1;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.24 (d , J=8.4 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 6.90 (dd, J=5.6, 2.4 Hz, 1H), 2.76 (k, J=7.6 Hz, 2H), 2.29 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).

Alternative way to obtain 6-ethyl-2-methylpyridin-3-ol

Step 1: 2-methyl-6-vinylpyridin-3-amine.

A mixture of 6-bromo-2-methylpyridine-3-amine (1.0 eq.), C2H3BF3K (1.2 eq.), K2CO3 (3.0 eq.) and Pd(dppf)Cl ₂ (0.05 eq. ) in 1,4-dioxane:H ₂ O (4:1, 0.27 M) was stirred under argon at 100° C. for 16 h. The reaction mixture was cooled to RT and diluted with water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=10:1-1:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=135.

Stage 2: 6-ethyl-2-methylpyridine-3-amine.

A mixture of 2-methyl-6-vinylpyridin-3-amine (1.0 eq.) and Pd/C (10%, 0.01 eq.) in MeOH (2.1 M) was stirred under H ₂ atmosphere at RT for 2 h. The solid was filtered off and the filtrate was concentrated to give the title compound as a white solid.

Stage 3: 6-ethyl-2-methylpyridin-3-ol.

At 0°C to a solution of 6-ethyl-2-methylpyridine-3-amine (1.0 eq.) in aq. HCl (1.0 N, 5 eq.) was added dropwise with a solution of NaNO ₂ (1.5 eq.) in H ₂ O (3.1 M). The reaction mixture was stirred at 0° C. for 1 h and then heated at 70° C. for 16 h. The reaction mixture was cooled to RT, washed twice with EtOAc. The aqueous layer was concentrated and the pH was adjusted to ~7 with 3.0 M aq. NaOH solution. The solvent was completely evaporated under reduced pressure and the residue was dissolved in DCM/MeOH (v/v=8:1). The solid was filtered off and the filtrate was concentrated to give the title compound as a brown solid. LC-MS (m/z): [M+H]+=138.

Intermediate A17: 3-((2-chloropyridin-4-yl)oxy)-2-methylquinoline

CI

Stage 1: 3-methoxy-2-methylquinoline.

A mixture of 2-aminobenzaldehyde (1.0 eq.), 1-methoxypropan-2-one (1.4 eq.), KOH (1 eq.) in EtOH-water (5:1, 0.34 M) was heated at 85 °C for 1 h. The mixture was cooled to RT and isolated. The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc 15:1) to give the title compound as a yellow oil.

Stage 2: 2-methylquinolin-3-ol

A solution of 3-methoxy-2-methylquinoline (5.7 g, 32.95 mmol, 1.0 eq.) in DCM (0.33 M) was cooled to 20°C. BBr ₃ (3.0 eq) was added slowly under argon and the resulting mixture was stirred at RT overnight. The reaction was monitored by LC-MS and TLC. Upon completion, the reaction mixture was cooled to below 0° C., quenched with saturated aqueous NaHCO ₃ and extracted with DCM/MeOH. The organic layer was concentrated under reduced pressure to give the title compound as a yellow solid.

Step 3: 3-((2-chloropyridin-4-yl)oxy)-2-methylquinoline.

A mixture of 2-methylquinolin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.2 eq.), Cs ₂ CO ₃ (3.0 eq.) in DMSO (0.16 M) was stirred at 150°C for 3 h in an atmosphere of N ₂ . The reaction was monitored by TLC. The mixture was cooled to RT, treated with water, extracted with EtOAc and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc 4:1) to give the title compound as a yellow oil.

1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=5.6 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.75-7.71 (m , 1H), 7.56 (t, J=7.2 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.82 (dd, J=5.6, 2, 0 Hz, 1H), 2.61 (s, 3H).

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Intermediate A18: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-6-methyl-2,2'-bipyridine

Stage 1: 2-methyl-5-nitro-3-vinylpyridine.

In an argon atmosphere, a mixture of 3-bromo-2-methyl-5-nitropyridine (1.0 eq.), Potassium trifluoro(vinyl)borate (1.0 eq.), K ₂ CO ₃ (2.0 eq.) and Pd (dppf)Cl ₂ (0.1 eq.) in dioxane/H ₂ O (v/v=4:1, 0.5 M) was stirred at 100° C. for 16 h. The mixture was filtered through a celite pad. The filtrate was diluted with EtOAc, washed with water, brine and the organic layer was dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography to give the title compound. LCMS (m/z): [M+H]+=165.3.

Stage 2: 5-ethyl-6-methylpyridine-3-amine.

A mixture of 2-methyl-5-nitro-3-vinylpyridine (1.0 eq.) and Pd/C (10%, 0.01 eq.) in MeOH (0.3 M) was stirred under H ₂ atmosphere at RT for 16 hours The solid was filtered off and the filtrate was concentrated under reduced pressure to obtain the title compound. LC-MS (m/z): [M+H]+=137.2.

Stage 3: 5-ethyl-6-methylpyridin-3-ol.

At 0° C. to a stirred solution of 5-ethyl-6-methylpyridine-3-amine (1.0 eq.) in 1.0 N of water. HCl (0.7 M) was added dropwise with a solution of NaNO ₂ (1.0 eq.) in H ₂ O (7 M). The reaction mixture was stirred at 0°C for 0.5 h and then heated at 70°C for another 2 h. The resulting mixture was stirred at RT for 16 h and neutralized with NaHCO ₃ to pH ~8, and then extracted with EtOAc. The organic layer was washed with brine and then dried over Na ₂ SO ₄ . The title compound was obtained after removal of the solvent. LC-MS (m/z): [M+H]+=138.2.

Step 4: 5-ethyl-2-iodo-6-methylpyridin-3-ol.

A mixture of 5-ethyl-6-methylpyridin-3-ol (1.9 g, 13.8 mmol, 1.0 eq.), I2 (3.52 g, 13.8 mmol, 1.0 eq.) and Na ₂ CO ₃ (3.23 g, 30.5 mmol, 2.2 eq.) in H ₂ O (50 ml) was stirred at RT for 2 h. The reaction mixture was extracted with EtOAc and the combined organic layer was concentrated under reduced pressure . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=10:1 to 5:1) to give the title compound. LCMS (m/z): [M+H]+=264.2.

Step 5: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-2-iodo-6-methylpyridine.

A mixture of 5-ethyl-2-iodo-6-methylpyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.05 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMF (0.2 M) was stirred for 16 h at 100°C in an argon atmosphere. The mixture was diluted with EtOAc, washed with brine 10 times and then dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=50:1 to 10:1) to give the title compound. LC-MS (m/z): [M+H]+=375.0.

Step 6: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-6-methyl-2,2'-bipyridine.

To a mixture of 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-2-iodo-6-methylpyridine (1.0 eq.) and Pd(dppf)Cl ₂ (0.1 eq.) in DMA (0.4 M) pyridin-2-ylzinc(II) bromide (0.5 M in THF, 1.2 eq.) was added. The reaction mixture was stirred at 120° C. for 16 h under argon. The mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was diluted with EtOAc, washed with brine and then dried over Na2SO4. The crude product was purified by silica gel flash chromatography to give the title compound. LC-MS (m/z): [M+H]+=326.2.

The following intermediate was prepared as described for Intermediate A18.

intermediate connection Structure LC-MS [M+1] ⁺ and/or Ή NMR A19 XX ζΧα LC-MS (m/z/[M+l] ⁺ =338.2

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Bipyridine intermediate

3-((2-chloropyridin-4-yl)oxy)-5-isopropyl-6-methyl-2,2'A20:

Stage 1: methyl 5-(hydroxy(pyridin-2-yl)methyl)-2-methylfuran-3-carboxylate.

At 0°C, to a suspension of AlBr ₃ (1.0 eq.) in dry DCM (0.2 M) was added picolinaldehyde (1.0 eq.) and the resulting mixture was stirred at 0°C for 30 min in an argon atmosphere before adding dropwise solution of methyl-2-methylfuran-3-carboxylate (1.0 eq.) in DCM (0.1 M). The resulting suspension was stirred at RT for 16 h and then quenched with sat. aqueous solution of NaHCO ₃ . The mixture was partitioned between DCM/water, the organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent petroleum ether/EtOAc 100:1 to 2:1) to give the title compound. LC-MS (m/z): [M+H]+=248.1.

Step 2: 2-(5-(hydroxy(pyridin-2-yl)methyl)-2-methylfuran-3-yl)propan-2-ol.

To a solution of methyl 5-(hydroxy(pyridin-2-yl)methyl)-2-methylfuran-3-carboxylate (1.0 eq.) in THF (0.12 M) was added CH ₃ MgBr (4.0 eq. ). The resulting mixture was stirred at RT for 2 h under argon before quenching with sat. _NaHC03 . The mixture was partitioned between EtOAc/water. The organic layer was separated and dried over Na ₂ SO ₄ After removal of the solvent, the title compound was obtained and used in the next step without further purification. LC-MS (m/z): [M+H] ⁺ =248.1.

Step 3: (4-(2-hydroxypropan-2-yl)-5-methylfuran-2-yl)(pyridin-2-yl)methanone.

MnO ₂ (3.0 eq.) and the resulting mixture was stirred overnight at RT. The mixture was filtered through a Celite pad, the filtrate was concentrated and purified by silica gel flash chromatography (eluent petroleum ether/EtOAc 100:1 to 2:1) to give the title compound as a light yellow solid. LC-MS (m/z): [M+H] ⁺ =246.1.

Step 4: 5-(2-hydroxypropan-2-yl)-6-methyl-[2,2'-bipyridin]-3-ol.

A solution of (4-(2-hydroxypropan-2-yl)-5-methylfuran-2-yl)(pyridin-2-yl)methanone (1.0 eq.) in NH ₃ H ₂ O/MeOH (1:1, 0.15 M) in a sealed tube was stirred for 8 hours at 170°C. The solvents were removed and the residue was lyophilized to give the title compound as a light yellow solid. LC-MS (m/z): [M+H] ⁺ =245.2.

Step 5: 6-methyl-5-(prop-1-en-2-yl)-[2,2'-bipyridine]-3-ol.

A mixture of 5-(2-hydroxypropan-2-yl)-6-methyl-[2,2'-bipyridin]-3-ol (370 mg, 1.51 mmol, 1.0 eq.), pTsOH (317 mg, 1.67 mmol, 1.1 eq.) in toluene was refluxed at 135° C. for 16 h. After completion of the reaction, the mixture was concentrated to give the title compound. LC-MS (m/z): [M+H] ⁺ =227.3.

Step 6: 5-isopropyl-6-methyl-[2,2'-bipyridine]-3-ol.

A mixture of 6-methyl-5-(prop-1-en-2-yl)-[2,2'-bipyridin]-3-ol (343 mg, 1.52 mmol, 1.0 eq) and Pd/C (10%, 0.06 eq.) in THF/MeOH (5:1, 0.025 M) was stirred under H ₂ atmosphere at RT for 5 h. The solid was filtered off and the filtrate was concentrated to give the title compound. LC-MS (m/z): [M+H] ⁺ =229.1.

Step 7: 3-((2-chloropyridin-4-yl)oxy)-5-isopropyl-6-methyl-2,2'-bipyridine.

A mixture of 5-isopropyl-6-methyl-[2,2'-bipyridin]-3-ol (1.0 eq.), 2,4-dichloropyridine (2.0 eq.), Cs ₂ CO ₃ (2.0 eq.) in DMSO (0.1 M) was stirred at 150° C. for 6 h. The mixture was cooled to RT and quenched with water. The crude product was purified by silica gel flash chromatography (0 to 5% MeOH/DCM eluent) to give the title compound as a light yellow solid. LC-MS (m/z): [M+H] ⁺ =340.1.

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Intermediate A21: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,2'-bipyridine

GI

The compound was obtained by the method described for intermediate compound A1.

Step 1: (5-ethylfuran-2-yl)(pyridin-2-yl)methanone.

At 0°C, to a stirred solution of 2-ethylfuran (2.0 g, 20.8 mmol, 1.0 eq.) in Et ₂ O (80 ml) was added dropwise n-BuLi (2.5 M, 10.8 ml, 27.1 mmol, 1.3 eq.). The mixture was stirred at 40°C for 1.5 h, then cooled to -78°C. A solution of picolinonitrile (2.4 g, 22.9 mmol, 1.1 eq.) in Et ₂ O (20 ml) was added dropwise to the above mixture. The resulting mixture was stirred at RT for 1.5 hours. The reaction was monitored by LC-MS. The reaction mixture was quenched with ice water. The pH of the mixture was adjusted to ~5 with 2 N HCl. The aqueous layer was extracted with DCM. The organic layer was washed with water and dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by FCC (eluent: PE/EA=10:1) to give compound 3 (1.25 g, 30%) as a yellow solid. LC-MS (m/z): [M+1]+=202.2.

Step 2: 6-ethyl-[2,2'-bipyridine]-3-ol.

A mixture of (5-ethylfuran-2-yl)(pyridin-2-yl)methanone (1.25 g, 4.97 mmol, 1.0 eq.), MeOH (10 ml) and NH ₃ -H ₂ O (10 ml) placed in a sealed tube was heated at 170° C. for 8 h. The mixture was allowed to cool to RT and the solvents were removed to give the title compound as a yellow solid, which was used directly in the next step without further purification. LC-MS (m/z): [M+1] ⁺ =201.2

Step 3: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,2'-bipyridine.

A mixture of 6-ethyl-[2,2'-bipyridin]-3-ol (1.0 eq.), 2,4-dichloropyridine (1.05 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMF (0.4 M) was stirred at 100° C. for 16 hours under argon. The reaction was monitored by LC-MS. The mixture was quenched with water and extracted with EA. The organic layer was dried over Na ₂ SO ₄ , concentrated. The residue was purified by FCC (eluent: PE/EA=2:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+1] ⁺ =312.1.

The following intermediates were prepared as described for Intermediate A21.

intermediate connection Structure LC-MS [M+1] ⁺ and/or Ή NMR A22 o ⁴⁼⁷ LC-MS (m/z): [M+1] ⁺ =311.1 A45 G G -'O LC-MS (m/z): [M+1] ⁺ =311.1

Intermediate A23: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-5-methyl-2,2'-bipyridine

CI

Stage 1: 2-bromo-3-methylfuran.

A mixture of 3-methylfuran (1.0 equiv.), NBS (1.0 equiv.) and AIBN (0.08 equiv.) in Et ₂ O (0.5 M) was stirred at 50°C for 2 h in an atmosphere argon. The product was obtained after routine isolation and used in the next step without further purification.

Step 2: (5-bromo-4-methylfuran-2-yl)(pyridin-2-yl)methanol.

At 0 _° C, AlBr ₃ (1.0

- 38 043088 eq.). After stirring the mixture at 0° C. for 0.5 h, picolinaldehyde (1.0 eq.) was added. The resulting mixture was stirred at RT for 16 h under argon before quenching aq. NaOH. The mixture was extracted with EtOAc and the combined organic layer was washed with brine and then dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=20:1-5:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+: 268.

Step 3: (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanol.

At 0°C to a mixture of (5-bromo-4-methylfuran-2-yl)(pyridin-2-yl)methanol (1.0 eq.) and Pd(dppf)Cl ₂ (0.05 eq.) in THF (0.25 M) Et ₂ Zn (3.0 eq.) was added dropwise. The mixture was stirred at 70° C. for 16 h under argon. The mixture was poured into ice water and filtered through a Celite pad. The filtrate was extracted with EtOAc and the combined organic layer was dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=20:1-5:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+: 218.

Step 4: (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanone.

A mixture of (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanol (1.0 eq.) and MnO ₂ (5.0 eq.) in THF (0.2 M) was stirred at 50 °C for 16 hours. The mixture was filtered through a Celite pad and the filtrate was concentrated to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+: 216.

Step 5: 6-ethyl-5-methyl-[2,2'-bipyridine]-3-ol.

A mixture of (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanone (1.0 eq.) and NH ₃ -H ₂ O/MeOH (1:1, 0.2 M) in a sealed the tube was heated at 170° C. for 8 hours. The solvents were removed to give the title compound, which was used in the next step without further purification. LC-MS (m/z): [M+H]+: 215.

Step 6: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-5-methyl-2,2'-bipyridine.

A mixture of 6-ethyl-5-methyl-[2,2'-bipyridin]-3-ol (1.0 eq.), 2,4-dichloropyridine (1.5 eq.) and Cs ₂ CO ₃ (2.0 equiv.) in DMF (0.5 M) was stirred at 100° C. for 16 h under argon. The mixture was cooled to RT, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and then dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=10:1-1:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+: 326.

Alternative way to obtain (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanone:

Step 1: (4-(chloromethyl)-5-ethylfuran-2-yl)(pyridin-2-yl)methanone.

A mixture of (5-ethylfuran-2-yl)(pyridin-2-yl)methanone (1.0 eq.), (HCHO) _p (4.0 eq.), ZnCl ₂ (4.0 eq.) and HCl/ dioxane (10 eq.) in DCE (0.22 M) was stirred at 50° C. for 16 hours under argon. Most of the solvent was removed and the pH of the residue was adjusted to ~8 with 1.0 M aq. NaOH. The mixture was diluted with DCM. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layer was washed with brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=20:1-5:1) to give the title compound as a brown oil. LC-MS (m/z): [M+H]+=250.

Step 2: (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanone.

A mixture of (4-(chloromethyl)-5-ethylfuran-2-yl)(pyridin-2-yl)methanone (1.0 eq.), Pd/C (10%, 0.03 eq.) and TEA (2, 0 eq.) in EtOAc (0.2 M) was stirred under H ₂ atmosphere at RT for 2.5 h. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=10:1-5:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=216.

Intermediate A24: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2-(tetrahydro-2Hpyran-4-yl)pyridine

- 39 043088

Stage 1: 5,6-dimethylpyridin-3-ol.

At 0°C to a mixture of 5,6-dimethylpyridin-3-amine (1.0 eq.) in 2 M H ₂ SO ₄ (0.33 M) was added dropwise a solution of NaNO ₂ (1.0 eq.) in H ₂ O. The mixture was stirred for 30 min at RT, 2 h at 70°C, and then 16 h at RT. The mixture was diluted with EtOAc/H ₂ O. The organic layer was separated and dried over Na ₂ SO ₄ . The solvent was removed to give the title compound, which was used in the next step without further purification. LC-MS (m/z): [M+H]+=124.4.

Stage 2: 2-iodo-5,6-dimethylpyridin-3-ol.

_{I 2} ( ₁ 1 eq.) and the mixture was stirred at RT for 0.5 h. The mixture was diluted with DCM/H2O, the organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=2:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H] ⁺ =250.0.

Step 3: 2-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethylpyridin-3-ol.

A mixture of 2-iodo-5,6-dimethylpyridin-3-ol (1.0 eq.), 2-(3,6-dihydro-2P-pyran-4-yl)-4,4,5,5tetramethyl-1, 3,2-dioxaborolane (1.5 eq.), PdCl ₂ (dppf) (0.1 eq.) HNa ₂ CO ₃ (2.0 eq.) in dioxane/H ₂ O (10:1, 0.2 M) stirred at 100° C. for 16 hours under argon. The mixture was diluted with DCM/H2O, the organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=3:1) to give the title compound as a white solid. LC-MS (m/z): [M+H] ⁺ =206.4.

Step 4: 5,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol.

A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethylpyridin-3-ol (1.0 eq.), Pd/C (20 wt.%, 0.05 eq. ) in MeOH (0.1 M) was stirred under H ₂ atmosphere at RT for 2 h. The solid was filtered off and the filtrate was concentrated to give the title compound as a white solid. LC-MS (m/z): [M+H] ⁺ =208.4.

Step 5: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)pyridine.

A mixture of 6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.1 eq.), Cs ₂ CO ₃ (2 0 eq.) in DMSO (0.1 M) was stirred at 130° C. for 2 hours under argon. The mixture was cooled to RT and diluted with EtOA and water. The organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by preparative TLC (eluent: petroleum ether/EIAc=3:1) to give the title compound as a colorless oil. LC-MS (m/z): [M+H] ⁺ =319.3.

Intermediate A25: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(tetrahydro-2H-pyran-4yl)pyridine. D . J Ύ X ζΧα

This compound was prepared as described for Intermediate A24. LC-MS (m/z): [M+1] ⁺ =305.

Intermediate A26: 3-chloro-5-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine

Stage 1: 5-chloro-6-methylpyridine-3-amine.

_Zn powder (10 eq.) and NH ₄ Cl (10 eq.) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was filtered through a Celite pad and the solid was washed with EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=5:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H] ⁺ =143.1.

Stage 2: 5-chloro-6-methylpyridin-3-ol.

At 0°C, to a solution of 5-chloro-6-methylpyridine-3-amine (1.0 eq.) in 1 M HCl (0.56 M) was added dropwise a solution of NaNO ₂ (1.1 eq.) in water ( 3.0 M) and the reaction mixture was stirred at 0°C for 2 h,

- 40 043088 then heated at 70°C for 16 hours the Reaction was quenched with sat. aq. Na ₂ CO ₃ (20 ml) and the mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: DCM/MeOH=30:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=144.1.

Stage 3: 5-chloro-2-iodo-6-methylpyridin-3-ol.

At 0°C to a mixture of 5-chloro-6-methylpyridin-3-ol (1.0 eq.), Na ₂ CO ₃ (2.0 eq.) in water (1.0 M) was added I ₂ (1, 0 eq.) and the mixture was stirred at RT for 16 h. The mixture was extracted with EtOA and the combined organic layers were dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=5:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=270.0.

Step 4: 5-chloro-2,6-dimethylpyridin-3-ol.

A mixture of 5-chloro-2-iodo-6-methylpyridin-3-ol (1.0 eq.), trimethylboroxine (1.1 eq.), Pd(dppf)Cl ₂ (0.05 eq.) and K ₂ CO ₃ (2.5 eq.) in dioxane (0.2 M) was stirred at 100° C. for 16 hours under argon. The reaction was quenched with aq. NH ₄ Cl (10 ml) and the mixture was filtered through a celite pad. The filtrate was extracted with EtOAc and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=10:1) to give the title compound as a white solid. LCMS (m/z): [M+H]+=158.1.

Step 5: 3-chloro-5-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine.

To a solution of 5-chloro-2,6-dimethylpyridin-3-ol (1.0 eq.) in DMF (0.07 M) was added 2,4 dichloropyridine (1.1 eq.) and Cs ₂ CO ₃ (2.5 equiv.). After stirring under argon at 100° C. for 16 h, the reaction mixture was quenched with ice water (10 ml) and extracted with EtOAc. The combined organic layers were washed with brine and then dried over anhydrous Na ₂ SO ₄ . The crude product was purified by preparative TLC (eluent: petroleum ether/EtOAc=6:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=269.0.

Intermediate A27: 3-((2-chloropyridin-4-yl)oxy)-2,5,6-trimethylpyridine

This compound was prepared as described for Intermediate A26. LC-MS (m/z): [M+l]+=249.1.

The following intermediates were prepared as described for Intermediate A6.

intermediate connection Structure LC-MS [Μ+1] ⁺ and/or Ή NMR A28 o ⁴⁼⁷ LC-MS (m/z): [M+l] ⁺ =315 A29 g % P LC-MS (m/z): [M+l] ⁺ =315 AZO .NXl Ύ J Λ ΝζζΙ LC-MS (m/z): [M+l] ⁺ =315.3

- 41 043088

A31 V ⁿ yQ LA _o cn Λ N' GI LC-MS (m/z): [M+l] ⁺ =322 A32 pX o z LC-MS (m/z): [M+l] ⁺ =322 AZZ pX o g LC-MS (m/z): [M+l] ⁺ =322 A34 Oh oh \=/ LC-MS (m/z): [M+l] ⁺ =311 AZ 5 P Ύ V ζ \ α LC-MS (m/z): [M+l] ⁺ =311 AZ 6 ϊ ^'Ό O^ci LC-MS (m/z): [M+l] ⁺ =311 AZ 7 xx LC-MS (m/z): [M+l] ⁺ =327 AZ 8 '- Oh θοι LC-MS (m/z): [M+l] ⁺ =327.3 AZ 9 Huh o / LC-MS (m/z): [M+l] ⁺ =327.3 A40 - With LC-MS (m/z): [M+l] ⁺ =331.0

- 42 043088

Intermediate A41: 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine

Stage 1: 3-cyclopropyl-2-methyl-5-nitropyridine.

A solution of 3-bromo-2-methyl-5-nitropyridine (1.0 eq.), cyclopropylboronic acid (1.2 eq.), Na ₂ CO ₃ (2.0 eq.) and Pd(dppf)Cl ₂ (0 1 eq.) in dioxane/H ₂ O (10:1, 0.3 M) was stirred at 100° C. for 16 hours under argon. The mixture was filtered and the filtrate was diluted with EA, washed with water, brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography to give the title compound. LC-MS (m/z): [M+H]+=179.2.

Stage 2: 5-cyclopropyl-6-methylpyridine-3-amine.

A mixture of 3-cyclopropyl-2-methyl-5-nitropyridine (1.0 eq.), Pd/C (10 wt.%, 0.1 eq.) in MeOH (0.3 M) was stirred under H ₂ atmosphere at RT over 16 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound. LC-MS (m/z): [M+H]+=149.2.

Stage 3: 5-cyclopropyl-6-methylpyridin-3-ol.

At 0° C. to a stirred solution of 5-cyclopropyl-6-methylpyridin-3-amine (1.0 eq.) in 1 N aq. HCl (0.3 M) was added dropwise with a solution of NaNO ₂ (1.0 eq.) in H ₂ O (2.7 M). The mixture was stirred for 0.5 h at 0°C, 2 h. at 70°C and 16 h at RT. The pH of the mixture was adjusted to ~8 with NaHCO ₃ and then extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ . The title compound was obtained after removal of the solvent. LC-MS (m/z): [M+H]+= 150.4.

Stage 4: 5-cyclopropyl-2-iodo-6-methylpyridin-3-ol.

A mixture of 5-cyclopropyl-6-methylpyridin-3-ol (1.0 eq.), I ₂ (1.0 eq.), Na ₂ CO ₃ (2.2 eq.) in H ₂ O (0.25 M ) was stirred at RT for 2 h. The mixture was extracted with EA and the combined organic layer was dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=10:1 to 5:1) to give the title compound. LC-MS (m/z): [M+H]+=276.1.

Step 5: 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine.

A solution of 5-cyclopropyl-2-iodo-6-methylpyridin-3-ol (1.0 eq.), phenylboronic acid (1.2 eq.), Na ₂ CO ₃ (2.0 eq.) and Pd(dppf) Cl ₂ (0.1 eq.) in dioxane/H ₂ O (10:1, 0.1 M) was stirred at 100° C. for 16 hours under argon. The mixture was filtered, the filtrate was diluted with EA, washed with water, brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography to give the title compound. LC-MS (m/z): [M+H]+=226.3.

Step 6: 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine (1.0 eq.), 2,4dichloropyridine (1.05 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMF (0.1 M) was stirred at 100° C. for 16 hours under argon. The mixture was diluted with EA and brine. The organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=50:1 to 5:1) to give the title compound. LC-MS (m/z): [M+H] ⁺ =337.1.

Intermediate A42: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-6-methyl-2-phenylpyridine

L 1 'm 'S

This compound was prepared as described for Intermediate A41. LC-MS (m/z): [M+H]+=325.1.

- 43 043088

Intermediate A43: 3-((2-chloropyridin-4-yl)oxy)-5-isopropyl-6-methyl-2-phenylpyridine

This compound was prepared as described for Intermediate A20 with slight modification.

Stage 1: methyl 5-benzoyl-2-methylfuran-3-carboxylate.

To a suspension of FeCl ₃ (0.013 equiv.) in CCl ₄ (4.5 M) was added benzoyl chloride (1.05 equiv.) followed by methyl 2-methyl-furan-3-carboxylate (6.0 g, 42.8 mmol, 1, 0 equiv.). The mixture was stirred at 80° C. for 1 hour and then partitioned between DCM/water. The organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc=1:0 to 10:1) to give the title compound as a yellow oil.

Stage 2: methyl 5-(hydroxy(phenyl)methyl)-2-methylfuran-3-carboxylate.

At 0°C, to a solution of methyl 5-benzoyl-2-methylfuran-3-carboxylate (1.0 eq.) in MeOH (1.0 M), NaBH ₄ (2.0 eq.) was added in parts, and the mixture was stirred for 2 h at 0°C. The reaction was quenched with sat. NH ₄ Cl and the mixture was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc=1:0 to 5:1) to give the title compound as a yellow oil.

The remaining steps were carried out as described for intermediate A20 (steps 2-7). The crude product was purified by silica gel flash chromatography (eluent MeOH/DCM=0 to 5%) to give Intermediate A43 as a light yellow solid. LC-MS (m/z): [M+H]+=339.3.

Intermediate A44: 2-(5-((2-chloropyridin-4-yl)oxy)-2-methyl-6-phenylpyridin-3yl)propan-2-ol

- _Ύ Ν _γ Ο no^XD _o

Οόι

This compound was prepared as described for Intermediate A43. The crude product was purified by silica gel flash chromatography (eluent: McOH/DCM=ot 0 to 5%) to give the title compound as a light yellow solid. LC-MS (m/z): [M+H]+=355.

Intermediate A45: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-phenylpyridine

Stage 1: 2-phenylpyridin-3-ol.

A mixture of 2-iodopyridin-3-ol (1.0 eq.), phenylboronic acid (1.1 eq.), PdCl ₂ (dppf) (0.1 eq.) and Na ₂ CO ₃ (2.0 eq.) in dioxane/H ₂ O (10:1, 0.2 M) was stirred at 90°C for 16 h in an argon atmosphere. The mixture was diluted with DCM. The organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=3:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=172.2.

Stage 2: 6-iodo-2-phenylpyridin-3-ol.

I _{2 ( 1.1} eq.) and the mixture was stirred at RT for 0.5 h before dilution with DCM. The organic layer was separated, washed with brine and then dried over Na ₂ SO ₄ . The crude product was purified by flash chromatography on silica gel (eluent: petroleum

- 44 043088 ether/EtOAc=4:1) to obtain the title compound as a yellow solid. LC-MS (m/z):

[M+H]+=297.9.

Step 3: 2-phenyl-6-vinylpyridin-3-ol.

A mixture of 6-iodo-2-phenylpyridin-3-ol (1.0 eq.), CH ₂ CHBF ₃ K (1.5 eq.), K ₂ CO ₃ (2.0 eq.) and PdCl ₂ (dppf) (0.1 eq.) in dioxane/H ₂ O (4:1, 0.1 M) was stirred at 95°C for 16 h in an argon atmosphere. The mixture was diluted with DCM and the organic layer separated and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=3:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=198.0.

Step 4: 6-ethyl-2-phenylpyridin-3-ol.

A mixture of 2-phenyl-6-vinylpyridin-3-ol (1.0 eq.) and Pd/C (10 wt.%, 0.02 eq.) in MeOH (0.06 M) was stirred under H ₂ atmosphere at RT for 1 h. The solid was filtered off and the filtrate was concentrated to give the title compound as a white solid. LC-MS (m/z): [M+H]+=200.0.

Step 5: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-phenylpyridine.

A mixture of 6-ethyl-2-phenylpyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (2.0 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMSO (0.1 M) stirred at 130° C. for 2 hours under argon. The mixture was diluted with EtOAc and water. The organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by preparative TLC (eluent: petroleum ether/EIAc=4:1) to give the title compound as a colorless oil. LC-MS (m/z): [M+H]+=311.1.

The following intermediates were prepared as described for Intermediate A45.

intermediate connection Structure LC-MS (m/z) [M+1] ⁺ and/or Ή NMR A46 ι _Ν η %£ £ ' 0 OC1 LC-MS (m/z). [M+l] ⁺ =315 A47 O LC-MS (m/z). [M+l] ⁺ =315 A48 Ύί ⁰ Α-' Ό O. LC-MS (m/z). [M+l] ⁺ =315.3

Intermediate A49: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,5-dimethylpyridine ν vg (MebO) ₃ FtK ng over ^BFaK

Stage 1: 2,5-dimethyl-3-nitropyridine.

A mixture of 2,5-dibromo-3-nitropyridine (1.0 eq.), trimethylboroxine (3.0 eq.), Pd(dppf)Cl ₂ (0.04 eq.) and K2CO3 (6.0 eq.) in dioxane (0.25 M) was stirred at 100°C for 16 h in an argon atmosphere. The mixture was isolated and the crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=5:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=153.

Step 2: 2,5-dimethylpyridine-3-amine.

A mixture of 2,5-dimethyl-3-nitropyridine (1.0 eq.), 10% Pd/C (10 wt.%, 0.01 eq.) in MeOH (0.3 M) was stirred under H ₂ atmosphere for 16 h at RT. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=123.

Stage 3: 6-bromo-2,5-dimethylpyridine-3-amine

At 0° C., to a stirred solution of 2,5-dimethylpyridin-3-amine (1.0 eq.) in MeCN (0.4 M), NBS (1.0 eq.) was added in portions under argon. The mixture was stirred at 0°C for 1 hour and then

- 45 043088 extinguished with water. The acetonitrile was removed and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and then dried over Na2SO4. The title compound was obtained after removal of the solvent. LC-MS (m/z): [M+H]+=201.

Step 4: 2,5-dimethyl-6-vinylpyridin-3-amine.

A mixture of 6-bromo-2,5-dimethylpyridin-3-amine (1.0 eq.), potassium trifluoro(vinyl)borate (1.2 eq.), Pd(dppf)Cl ₂ (0.05 eq.) and K ₂ CO ₃ (3.0 eq.) in dioxane/water (14:1, 0.27 M) was stirred at 100° C. for 16 hours under argon. The mixture was isolated and the crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=5:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H] ⁺ =150.

Step 5: 6-ethyl-2,5-dimethylpyridin-3-amine.

A mixture of 2,5-dimethyl-6-vinylpyridin-3-amine (1.0 eq.), Pd/C (10 wt.%, 0.01 eq.) in MeOH (0.32 M) was stirred under H ₂ at RT for 16 h. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow solid. LC-MS (m/z): [M+H] ⁺ =151.

Step 6: 6-ethyl-2,5-dimethylpyridin-3-ol.

At 0°C, to a solution of 6-ethyl-2,5-dimethylpyridin-3-amine (1.0 equiv.) in 1 N HCl (0.16 M) was added dropwise a solution of NaNO2 (1.0 equiv.) in H2O (2.4 M). The mixture was stirred at 0° C. for 1 h, then heated to 70° C. for 16 h. After adjusting the pH to -8 with 1.0 M aq. NaOH, the mixture was concentrated and the residue was dissolved in DCM/MeOH (v/v=10/1). The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow solid. LC-MS (m/z): [M+H] ⁺ =152.

Step 7: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,5-dimethylpyridine.

A mixture of 6-ethyl-2,5-dimethylpyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.0 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMF (0 .25 M) was stirred at 100°C for 16 h in an argon atmosphere, and then the mixture was diluted with water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=2:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H] ⁺ =263.

Intermediate A50: 3-chloro-5-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-methylpyridine

Stage 1: 5-chloro-2-methylpyridine-3-amine.

To a solution of 5-chloro-2-methyl-3-nitropyridine (30.0 g, 0.17 mol, 1.0 eq.) in EtOH/sat. aq. NH4Cl (1:4, 0.7M) Zn powder (4.0 eq.) was added. The reaction mixture was stirred for 16 hours at RT before being filtered through a Celite pad. The filtrate was extracted with EtOAc and the combined organic layers were dried over anhydrous Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: DCM/MeOH=100:1) to give the title compound as a white solid. LC-MS (m/z): [M+H] ⁺ =142.0.

Stage 2: 6-bromo-5-chloro-2-methylpyridine-3-amine

At 0° C., NBS (1.0 eq.) was added in portions to a solution of 5-chloro-2-methylpyridin-3-amine (1.0 eq.) in acetonitrile (0.5 M). The reaction mixture was stirred at 0° C. for 2 h and then quenched with ice water (100 ml). Part of the solvent was removed under reduced pressure and the residue was extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=5:1) to give the title compound as a white solid. LC-MS (m/z): [M+H] ⁺ =221.0.

Step 3: 5-chloro-2-methyl-6-vinylpyridin-3-amine.

A mixture of 6-bromo-5-chloro-2-methylpyridin-3-amine (1.0 eq.), Potassium trifluoro(vinyl)borate (1.2 eq.), Pd(dppf)Cl ₂ (0.05 eq. ) and K ₂ CO ₃ (2.5 equiv.) in dioxane/water (5:1, 0.4 M) was stirred at 80°C for 2 h in the atmosphere. The mixture was filtered through a Celite pad and the filtrate was extracted with EtOAc. The combined organic layers were dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=8:1) to give the title compound as a colorless oil. LC-MS (m/z): [M+H] ⁺ =169.0.

Step 4: 5-chloro-6-ethyl-2-methylpyridine-3-amine.

- 46 043088

To a solution of 5-chloro-2-methyl-6-vinylpyridin-3-amine (1.0 eq.) and sat. aq. NH4Cl/EtOH (2:1, 0.5M) Zn powder (5.0 eq.) was added. The reaction mixture was stirred at 50° C. for 16 hours. The mixture was filtered through a Celite pad and the filtrate was extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: 100% DCM) to give the title compound as a colorless oil. LC-MS (m/z): [M+H]+=171.0.

Step 5: 5-chloro-6-ethyl-2-methyl-pyridin-3-ol.

At 0°C to a solution of 5-chloro-6-ethyl-2-methylpyridine-3-amine (1.0 eq.) in 1 N aq. HCl (0.25 M) was added dropwise a solution of NaNO ₂ (1.5 eq.) in water (3.0 M) and the mixture was stirred for 2 h at 0°and then 16 h at 70°C. Added saturated aq. NaHCO ₃ and the resulting mixture was extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: DCM/MeOH=100:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=172.0.

Step 6: 3-chloro-5-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-methylpyridine.

To a solution of 5-chloro-6-ethyl-2-methylpyridin-3-ol (1.0 eq.) in DMF (0.4 M) was added 2,4dichloropyridine (1.2 eq.) and Cs ₂ CO ₃ (2 .5 equiv.). The reaction mixture was stirred at 100° C. for 16 h under argon and cooled at RT. Ice water (100 ml) was added and the resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine and then dried over Na2SO4. The crude product was purified by preparative TLC (eluent: petroleum ether/EIAc=10:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=283.1;

1H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J=5.6 Hz, 1H), 7.34 (s, 1H), 6.77 (d, J=2.0 Hz, 1H) , 6.74 (dd, J=6.0, 2.4 Hz, 1H), 2.96 (c, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.32 ( t, J=7.2 Hz, 3H).

The following intermediates were prepared as described for Intermediate A12.

intermediate connection Structure LC-MS [M+l] ⁺ and/or SNMR A51 To LC-MS (m/z): [M+l] ⁺ =312.2; Ή NMR (400 MHz, CDC1 ₃ ) δ 8.20 (d, 7=6.0 Hz, 1H), 7.747.70 (m, 2H), 7.45 (s, 1H), 7.35-7, 24 (m, ZN), 6.92 (d, 7=2.0 Hz, 1H), 6.86 (dd, 7=5.6, 2.4 Hz, 1H), 3.69-3.64 (m, 1H), 1.26-1.20 (m, 2H), 1.12-1.07 (m, 2H). A52 O x, LC-MS (m/z): [M+1] ⁺ =318.2 A53 A LC-MS (m/z): [M+1] ⁺ =304 A54 A LC-MS (m/z): [M+1] ⁺ =290 A55 O O-\ Ύ O LC-MS (m/z): [M+1] ⁺ =313

- 47 043088

Intermediate A56: 2-chloro-4-((1-cyclobutyl-3-phenyl-1H-n-nirazol-4-yl)oxy)pyridine

A mixture of 2-chloro-4-((3-phenyl-1H-pyrazol-4-yl)oxy)pyridine (1.0 eq.), Bromocyclobutane (2.0 eq.) and K ₂ CO ₃ (2.0 eq. .) in dioxane (0.35 M) was stirred at 80° C. for 16 h. The reaction mixture was cooled to RT and diluted with EtOAc. The organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=5:1-1:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=326.

The following intermediates were prepared as described for Intermediate A56.

intermediate connection Structure LC-MS [M+1] ⁺ and/or Ή NMR A57 ABOUT -'ό A LC-MS (m/z): [M+1] ⁺ =286.1 A58 Oh\mm About 0C1 LC-MS (m/z): [M+1] ⁺ =300.1 A59 / O F—( md OS1 LC-MS (m/z): [M+1] ⁺ =336.1 A60 - δ M ° about ABOUT LC-MS (m/z): [M+1] ⁺ =314.2 A61 O 0 V N 1 ά. MM LC-MS (m/z): [M+1] ⁺ =328 A62 at Nd With. LC-MS (m/z): [M+1] ⁺ =322.1 A63 /Ό l <>O' 0 b. LC-MS (m/z): [M+1] ⁺ =334

- 48 043088

Intermediate yl)oxy)pyridine compound A64:

2-chloro-4-(( 1 -(difluoromethyl) -3 -phenyl-1 H-pyrazole-4-

A mixture of 2-chloro-4-((3-phenyl-1H-pyrazol-4-yl)oxy)pyridine (1.0 eq.), diethyl(bromodifluoromethyl)phosphonite (10 eq.), KF (2.0 eq. .) and NaI (1.0 equiv.) in MeCN (0.2 M) was stirred at 80° C. overnight under argon. The mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=5:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+1]+=322.1.

Intermediate A65: 3-((2-chloropyridin-4-yl)oxy)-2-methyl-6-phenylpyridine

Stage 1: 2-methyl-6-phenylpyridin-3-ol.

Mixture of 6-iodo-2-methylpyridin-3-ol (Step 1 for Intermediate A16, 1.0 eq.), Phenylboronic acid (1.05 eq.), Pd(dppf)Cl ₂ (0.1 eq.) and K ₂ CO ₃ (3.0 eq.) in dioxane/H ₂ O (8:1, 0.61 M) was stirred at 115° C. for 16 hours under argon. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (petroleum ether:EtOAc=10:1) to give the title compound as a white solid.

Step 2: 3-((2-chloropyridin-4-yl)oxy)-2-methyl-6-phenylpyridine.

A mixture of 2-methyl-6-phenylpyridin-3-ol (1.0 eq.), 2,4-dichloropyridine (1.0 eq.) and Cs ₂ CO ₃ (2.0 eq.) in DMF (0.36 M) stirred at 115° C. for 16 hours under argon. The mixture was filtered and the filtrate was treated with water, extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (petroleum ether:EtOAc=20:1) to give the title compound as a colorless oil.

Intermediate A66: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(1-methyl-1H-pyrazol-4yl)pyridine

-sN

Ύ ~- Ο ie,

3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine mixture (Step 1 for Intermediate A3, 500 mg, 1.45 mmol, 1.0 eq.), (1-methyl -1H-pyrazol-4-yl)boronic acid (1.2 eq.), Pd(dppf)Cl ₂ (0.1 eq.), Na ₂ CO ₃ (2.0 eq.) in dioxane/H ₂ O (10:1, 0.13 M) was stirred overnight at 100° C. under argon. The solid was filtered off and the filtrate was diluted with EtOAc, washed with water, brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography to give the title compound. LC-MS (m/z): [M+H] ⁺ =301.1.

Intermediate B1: methyl 3-(3-aminophenyl)propanoate °-X η soci ₂ .-'-'y. D Meon, 60 'C

XX ------- XX - he

O^'^^'clearly TEA,nsoon 2) Pdm ₂ h ₂ n - γ

DMF. 130 °C o o

Stage 1: 3-(3-nitrophenyl)propionic acid.

At RT, TEA (1.4 eq.) was added dropwise to stirred HCOOH (3.5 eq.). The resulting reagent was added to a solution of 3-nitrobenzaldehyde (1.0 eq.), 2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 eq.) in DMF (2.5 M). The reaction mixture was heated at 130° C. for 3 hours. The solution was cooled to RT, diluted with H ₂ O (200 ml), pH was adjusted to 9 sat. aq. NaHCO ₃ and washed with EtOAc (2 times, 50 ml). The aqueous phase was acidified to pH 2 with conc. HCl. The precipitated solid was collected by filtration, washed with H2O and dried under vacuum to give the title compound as a yellow solid. LC-MS (m/z): [2M-1] ^- =389.

Step 2: methyl 3-(3-nitrophenyl)propanoate.

To a solution of the above product (1.0 eq.) in MeOH (0.74 M) was added SOCl ₂ (2.0 eq.) at

- 49 043088

R.T. The resulting mixture was stirred at 60° C. for 2 hours. The mixture was then cooled to RT, concentrated under reduced pressure. The residue was diluted with H ₂ O (150 ml) and was extracted with EtOAc (2 times, 50 ml). The organic phase was washed with sat. aq. NaHCO ₃ (2 times, 20 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 10:1) to give the title compound as a white solid.

Step 3: methyl 3-(3-aminophenyl)propanoate.

To a stirred solution of the above product (1.0 eq.) in MeOH (0.5 M) was added Pd/C (10 wt.%) and the mixture was stirred under H ₂ atmosphere for 16 h at RT. The solid was filtered off and the filtrate was concentrated. The residue was dissolved in DCM (30 ml) and treated with 4.0 M HCl/dioxane (9 ml). The mixture was concentrated and the residue was triturated with Et ₂ O (30 ml). The solid was collected by filtration and then dissolved in H ₂ O (100 ml). The pH of the solution was adjusted to approximately 9 with sat. aq. NaHCO ₃ and extracted with DCM (2 times, 50 ml). The DCM layer was dried over Na2SO4, concentrated under reduced pressure to give the title compound as a slightly yellow oil. LC-MS (m/z): [M+1]+=180.

Intermediate B2: 3-(3-aminophenyl)propanenitrile

Step 1: 3-(3-nitrophenyl)propanamide.

To a solution of 3-(3-nitrophenyl)propionic acid (1.0 eq.) in DCM (0.25 M) was added HATU (1.2 eq.), the mixture was stirred at RT for 30 min, then NH ₄ Cl was added (1.5 eq.) and DIEA (3.0 eq.). The mixture was stirred at RT for 4 h and then quenched with H ₂ O (50 ml). The aqueous layer was extracted with DCM (3 times, 30 ml). The combined organic layer was dried over Na ₂ SO ₄ , concentrated to give the title compound as a yellow oil, which was used directly in the next step without further purification. LC-MS (m/z): [M+1]+=195.

Step 2: 3-(3-nitrophenyl)propanenitrile.

A mixture of 3-(3-nitrophenyl)propanamide (1.0 eq.) and (CNCl) ₃ (1.5 eq.) in DMF (0.25 mmol) was stirred at RT for 2 h. The reaction mixture was quenched with H ₂ O (200 ml) and extracted with EA (3 times, 50 ml). The combined organic layer was washed with brine (60 ml) and then dried over Na2SO4. The solvent was removed and the residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 4:1 to 2:1) to give the title compound as a white solid. LC-MS (m/z): [M+1]+=177;

1H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J=8.4 Hz, 1H), 8.12 (s, 1H), 7.62 (d, J=7.6 Hz, 1H) , 7.55 (t, J=8.0 Hz, 1H), 5.01 (s, 2H), 3.09 (t, J=7.2 Hz, 2H), 2.72 (t, J= 7.2 Hz, 2H).

Step 3: 3-(3-aminophenyl)propanenitrile.

A mixture of 3-(3-nitrophenyl)propanenitrile (1.0 eq.), Zn (5.0 eq.) in MeOH/NH ₄ Cl (1:1, 0.4 M) was stirred at 80°C for 16 h The reaction was monitored by TLC. The reaction mixture was cooled to RT and filtered. The filtrate was extracted with EA. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed to give the title product as a yellow oil. LC-MS (m/z): [M+1]+=147;

1H NMR (400 MHz, DMSO) δ 6.95 (dd, J=8.4, 7.2 Hz, 1H), 6.44 (d, J=0.8 Hz, 1H), 6.43-6 .39 (m, 2H), 5.01 (s, 2H), 2.73-2.68 (m, 4H).

Intermediate B3: methyl 3-(4-aminophenyl)propanoate

The compound was prepared as described for intermediate B1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.98 (d, J=8.4 Hz, 2H), 6.62 (d, J=8.4 Hz, 2H), 3.66 (s, 3H ), 2.84 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H).

Intermediate B4: 3-(4-aminophenyl)propanenitrile

Step 1: 3-(4-nitrophenyl)propanamide.

To a solution of 3-(4-nitrophenyl)propionic acid (1.0 eq.) in DCM (0.4 M) was added HATU (1.2 eq.) and stirred at RT for 30 min, then NH ₄ Cl ( 1.5 eq.) and DIEA (3.0 eq.). The mixture was stirred at RT for 4 h before quenching with H ₂ O (50 ml). The aqueous layer was extracted with DCM (3 times, 30 ml) and dried over Na ₂ SO ₄ . The solvent was removed to give the title compound as a yellow oil, which was used directly in the next step without further purification.

Step 2: 3-(4-nitrophenyl)propanenitrile.

- 50 043088

A mixture of 3-(4-nitrophenyl)propanamide (1.0 eq.) and (CNCl) ₃ (1.5 eq.) in DMF (0.25 mmol) was stirred at RT for 2 h. The solution was quenched with H ₂ O. The aqueous layer was extracted with EA (3 times, 50 ml). The combined organic layer was washed with brine (60 ml) and dried over

_{Na2SO4 .} The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 4:1 to 2:1) to give the title compound as a yellow solid.

1H NMR (400 MHz, DMSO) δ 8.21 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 3.05 (t, J=7 .2 Hz, 2H), 2.90 (t, J=7.2 Hz, 2H).

Step 3: 3-(4-aminophenyl)propanenitrile.

To a solution of 3-(4-nitrophenyl)propanenitrile (1.0 eq.) in MeOH (0.4 M) was added Pd/C (0.1 eq.). The mixture was stirred at RT for 3 h under H ₂ atmosphere. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow oil. LC-MS (m/z): [M+1]+=147, 1H NMR (400 MHz, DMSO) δ 6.92 (d, J=8.4 Hz, 2H), 6.51 (d, J = 8.4 Hz, 2H), 4.94 (s, 2H), 2.68 (s, 4H).

Intermediate B5: 2-(3-aminophenyl)-2-methylpropanenitrile

Step 1: 2-methyl-2-(3-nitrophenyl)propanenitrile.

To a solution of 2-(3-nitrophenyl)acetonitrile (1.0 eq.) in DMF (0.3 M), t-BuOK (3.0 eq.) was added in portions at 0°C. The mixture was stirred at 0° C. for 15 min and MeI (5.0 eq.) was added dropwise. The mixture was then stirred at RT for 2 hours. The reaction was monitored by TLC. The mixture solution was quenched with NH ₄ Cl (aq., 50 ml), extracted with EtOAc (100 ml). The organic phase was washed with saline, dried over Na ₂ SO ₄ . The organic phase was concentrated. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 8:1) to give the title compound as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.24 (t, J=2.0 Hz, 1H), 8.14 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.82 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 3.74 (s, 2H), 2 .83 (t, J=7.2 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H).

Stage 2: 2-(3-aminophenyl)-2-methylpropanenitrile.

A mixture of the above product (1.0 eq.), Zn (5.0 eq.), NH ₄ Cl (10.0 eq.) in MeOH-H ₂ O (2:1, 0.15 mmol) was stirred at 80 °C for 16 hours. The reaction was monitored by LC-MS. The mixture solution was filtered, washed with EtOAc (10 ml). The filtrate was extracted with EtOAc (50 ml) and the organic layer was washed with brine, dried over Na2SO4, concentrated to give a residue. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 5:1) to give the title product as a yellow oil. LC-MS (m/z): [M+H] ⁺ =161,

1H NMR (400 MHz, CDCl3) δ 7.08 (t, J=8.0 Hz, 1H), 6.76-6.72 (m, 2H), 6.57-6.53 (m, 1H) , 3.38 (s, 2H), 1.61 (s, 6H).

Intermediate B6: 3-(3-amino-4-fluorophenyl)propanenitrile

COgEt . F , ΐ-.- E k ..-.. F

MBS[| Ί CO ₂ Et ri T CO _E Et

JL D. .D Br ---------“ JI JL 1

BRO.SSC O _g m NaH, DMF O ₂ N ^ - CO _z Et

Stage 1: 2-(bromomethyl)-1-fluoro-4-nitrobenzene.

A mixture of 1-fluoro-2-methyl-4-nitrobenzene (1.0 eq.), NBS (1.1 eq.) and BPO (benzoyl peroxide, 0.1 eq.) in CCl4 (0.86 M) was stirred at 95 °C for 16 h in an argon atmosphere. The reaction was monitored by TLC. The mixture was then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 1:0 to 50:1) to give the title compound as a white solid.

Step 2: diethyl 2-(2-fluoro-5-nitrobenzyl)malonate.

At 0°C, to a stirred solution of NaH (60% in oil, 1.0 eq.) in DMF (0.22 M) was added a solution of diethyl malonate (2.0 eq.) in DMF (2 M). The mixture was stirred at 0°C for 0.5 h, and then 2-(bromomethyl)-1-fluoro-4-nitrobenzene (1.0 eq.) in DMF (0.34 M) was added dropwise to the above mixture. and stirred for another 0.5 h. The reaction was monitored by TLC. The resulting mixture was diluted with ice water and extracted with EtOAc. The organic layer was washed with brine and then dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound as an oil.

Step 3: 2-(2-fluoro-5-nitrophenyl)propionic acid.

A mixture of diethyl 2-(2-fluoro-5-nitrobenzyl)malonate (1.0 eq.) in 6 N aq. HCl (31 eq., 0.19 M) was heated at 120° C. for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was washed with brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 3:1) to give the title compound.

1H NMR (400 MHz, CDCl ₃ ) δ 8.20-8.12 (m, 2H), 7.26-7.16 (m, 1H), 3.07 (t, J=7.6 Hz, 2H ), 2.75 (t, J=7.6 Hz, 2H).

Step 4: 2-(2-fluoro-5-nitrophenyl)propanamide.

A mixture of 2-(2-fluoro-5-nitrophenyl)propionic acid (1.0 eq.), SOCl ₂ (2.0 eq.) and sat. DMF (1 drop) in toluene (0.42 M) was stirred at 85° C. for 1 hour. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure. The residue was taken back into Et2O (0.8 M) and added dropwise to a stirred solution of NH3H2O (30 ml) at 0°C. The resulting mixture was stirred at 0° C. for 0.5 h. The reaction was monitored by LC-MS until completion. The reaction mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure to give the title compound.

Step 5: 2-(2-fluoro-5-nitrophenyl)propanenitrile.

At 0°C, to a solution of 2-(2-fluoro-5-nitrophenyl)propanamide (1.0 eq.) and pyridine (2.5 eq.) in DCM (0.39 M), TFAA (2 5 eq.). The resulting mixture was stirred at 0° C. for 0.5 h. The completion of the reaction was determined by TLC. The mixture was washed with 1.0 M aq. HCl, brine and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the title compound.

Step 6: 2-(5-amino-2-fluorophenyl)propanenitrile.

A mixture of 2-(2-fluoro-5-nitrophenyl)propanenitrile (1.0 eq.), Zn (5.0 eq.) and NH ₄ Cl (10 eq.) in EJUN/H2O (v/v=5 :1, 0.5M) was stirred at 80°C for 0.5 h. The mixture was filtered. The filtrate was diluted with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give the title compound. LC-MS (m/z): [M+H]+=165;

1H NMR (400 MHz, CDCl ₃ ) δ 6.82-8.87 (m, 2H), 6.52-6.56 (m, 2H), 2.90 (t, J=7.6 Hz, 2H ), 2.62 (t, J=7.2 Hz, 2H).

The following compounds were prepared as described for Intermediate B6.

intermediate connection Structure LC-MS and/or Ή NMR AT 7 Ύχ Ή NMR (400 MHz, CDC1 ₃ ) δ 6.93 (dd, 7=10.8, 8.0 Hz, 1H), 6.64 (dd, 7=8.4, 2.4 Hz, 1H), 6.53 (ddd, 7=8.4, 4.4, 2.4 Hz, 1H), 3.74 (s, 2H), 2.83 (t, 7=7.2 Hz, 2H), 2 .57 (t, 7=7.2 Hz, 2H). AT 8 Γχ ο'γ·-^ F LC-MS (m/z): [M+H] ⁺ =165 Ή NMR (400 MHz, DMSO) δ 6.81 (t, 7=7.7 Hz, 1H), 6.66 (td, 7= 8.7 Hz, 1.6 Hz, 1H), 6.51-6.41 (m, 1H), 5.12 (s, 2H), 2.86-2.80 (m, 2H), 2, 79-2.74 (m, 2H). AT 9 1 X H ₂ N Ή NMR (400 MHz, CDC1 ₃ ) δ 8.137-8.143 (m, 1H), 8.05-8.08 (m, 1H), 7.52 (d, 7=8.0 Hz, 1H), 3, 14 (t, 7=7.2 Hz, 2H), 2.69 (t, 7=7.2 Hz, 2H).

Intermediate B10: methyl 3-(5-amino-2-fluorophenyl)propanoate

Step 1: methyl 3-(2-fluoro-5-nitrophenyl)propanoate.

To a solution of 3-(2-fluoro-5-nitrophenyl)propionic acid (1.0 eq.) in 2.5 M HCl/MeOH (6.7 eq., 0.37 M) was stirred at RT for 1 h. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to give the title compound.

- 52 043088

Step 2: methyl 3-(5-amino-2-fluorophenyl)propanoate.

To a solution of a mixture of methyl 3-(2-fluoro-5-nitrophenyl)propanoate (1.0 eq.) in MeOH (0.35 M) was added

Pd/C (10 wt.%, 0.02 eq.). The reaction mixture was stirred under a hydrogen atmosphere at RT for 3

h. The reaction was monitored by TLC. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil. LC-MS (m/z): [M+H]+=198.3;

¹ H NMR (400 MHz, CDCl3) δ 6.77 (t, J=7.6 Hz, 1H), 6.53-6.61 (m, 2H), 3.64 (s, 3H), 2, 83 (t, J=7.6 Hz,

2H), 2.58 (t, J=8.0 Hz, 2H).

The following compounds were prepared as described for Intermediate B10.

intermediate connection Structure LC-MS and/or Ή NMR IN AND ABOUT LC-MS (m/z). [M+H] ⁺ =198; Ή NMR (400 MHz, DMSO-J6) δ 6.85 (dd, 7=11.6, 8.4 Hz, 1H), 6.58 (dd, 7=8.8, 2.0 Hz, 1H) , 6.33 (ddd, 7=8.4, 4.4, 2.0 Hz, 1H), 5.02 (s, 2H), 3.58 (s, ZN), 2.68 (t, 7 \u003d 7.6 Hz, 2H), 2.54 (t, 7 \u003d 7.6 Hz, 2H) AT 12 A. ₀ h _£ n T F o LC-MS (m/zf. [M+H] ⁺ =198; Ή NMR (400 MHz, DMSO) δ 6.76 (t, 7=7.7 Hz, 1H), 6.62 (t, 7= 8.3 Hz, 1H), 6.39 (t, 7=6.5 Hz, 1H), 5.04 (s, 2H), 3.59 (s, ZN), 2.80 (t, 7= 7.6 Hz, 2H), 2.58 (t, 7=7.7 Hz, 2H). B13 X m O / LC-MS (m/z). [M+H] ⁺ =214.1

Intermediate B14: 3-(6-aminopyridin-2-yl)propanenitrile

Step 1: (E)-3-(6-aminopyridin-2-yl)acrylonitrile.

A mixture of 6-bromopyridine-2-amine (1.0 eq.), acrylonitrile (3.0 eq.), Pd ₂ (dba) ₃ (0.1 eq.), tri-otolylphosphine (0.3 eq.) DMF (0.57 M) was heated at 140° C. overnight. The mixture was cooled to RT. The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc 1:1) to give the title compound as a yellow solid.

Step 2: 3-(6-aminopyridin-2-yl)propanenitrile.

A mixture of (E)-3-(6-aminopyridin-2-yl)acrylonitrile (1.0 eq.) and Pd/C (10 wt.%, 0.02 eq.) in MeOH (0.41 M) was stirred at R.T. for 2 hours in an H2 atmosphere. The reaction was monitored by TLC. The solid was filtered off and the filtrate was concentrated to give the title compound as a white solid.

¹ H NMR (400 MHz, CDCl3) δ 7.38 (t, J=8.0 Hz, 1H), 6.56 (d, J=7.2 Hz, 1H), 6.38 (d, J= 8.0 Hz, 1H), 4.41 (s, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.6 Hz, 2H).

The following intermediates were prepared as described for Intermediate B14.

intermediate connection Structure LC-MS and/or Ή NMR B15 L A W NMR (400 MHz, CDC1 ₃ ) 7 8.02 (d, 7=5.2 Hz, 1H), 6.52 (d, 7=5.2 Hz, 1H), 6.37 (s, 1H) , 4.49 (s, 2H), 2.83 (t, 7=7.6 Hz, 2H), 2.61 (t, 7=7.6 Hz, 2H). B16 H S Μ Ή NMR (400 MHz, CDCI3) 7 8.01 (d, 7=2.8 Hz, 1H), 7.89 (d, 7=1.6 Hz, 1H), 6.87 (t, 7=2 .4 Hz, 1H), 3.79 (s, 2H), 2.87 (t, 7=7.6 Hz, 2H), 2.61 (t, 7=7.2 Hz, 2H).

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Intermediate B17: methyl 3-(6-aminopyridin-2-yl)propanoate

Step 1: methyl-(E)-3-(6-aminopyridin-2-yl)acrylate.

A mixture of 6-bromopyridine-2-amine (3.0 g, 17.34 mmol, 1.0 eq.), methyl acrylate (4.5 ml, 52.02 mmol, 3.0 eq.), Pd ₂ (dba) ₃ (0.1 eq.), tri-o-tolylphosphine (0.3 eq.) in DMF (0.58 M) was heated at 140° C. overnight. The mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 2:1) to give the title compound as a yellow solid.

Step 2: methyl 3-(6-aminopyridin-2-yl)propanoate.

Mixture of methyl-(E)-3-(6-aminopyridin-2-yl)acrylate (1.0 eq.) and Pd/C (10 wt.%, 0.02 eq.) in MeOH (0.36 M) stirred at RT. for 4 h in an H ₂ atmosphere. The reaction was monitored by TLC. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow oil.

¹ H NMR (400 MHz, CDCl3) δ 7.33 (t, J=7.6 Hz, 1H), 6.52 (d, J=7.2 Hz, 1H), 6.32 (d, J= 8.0 Hz, 1H), 4.36 (s, 2H), 3.67 (s, 3H), 2.93 (t, J=7.2 Hz, 2H), 2.73 (t, J= 7.2 Hz, 2H).

The following intermediates were prepared as described for Intermediate B17.

intermediate connection Structure LC-MS and/or Ή NMR B18 T / O / Ή NMR (400 MHz, CDCL) δ 7.97 (d, 7=5.2 Hz, 1H), 6.50 (d, 7=5.2 Hz, 1H), 6.34 (s, 1H), 4.38 (s, 2H), 3.68 (s, 3H), 2.83 (t, 7=7.2 Hz, 2H), 2.61 (t, 7=7.6 Hz, 2H). B19 - THAT Ή NMR (400 MHz, CDC1 ₃ ) δ 7.94 (d, 7=2.4 Hz, 1H), 7.88 (d, 7=2.0 Hz, 1H), 6.32 (t, 7= 2.4 Hz, 1H), 3.67 (s, 3H), 2.86 (t, 7=7.2 Hz, 2H), 2.61 (t, 7=7.6 Hz, 2H).

Intermediate B20: ethyl 3-(4-aminopyridin-2-yl)propanoate

Step 1: Ethyl-(E)-3-(4-aminopyridin-2-yl)acrylate.

2-bromopyridine-4-amine mixture (842 mg, 4.86 mmol, 1.0 eq.), ethyl-(E)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolane-2 -yl)acrylate (0.95 eq.), Pd(PPh ₃ ) ₂ Cl ₂ (0.1 eq.), K2CO3 (2.5 eq.) in dioxane/H ₂ O (5:1, 0.4 M) heated at 95° C. for 16 hours. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 1:4) to give the title compound as a yellow solid.

Step 2: Ethyl 3-(4-aminopyridin-2-yl)propanoate.

A mixture of ethyl (E)-3-(4-aminopyridin-2-yl)acrylate (1.0 eq.) and Pd/C (0.02 eq.) in MeOH (0.3 M) was stirred at RT. for 2 hours in an H2 atmosphere. The reaction was monitored by TLC. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil.

1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J=5.6 Hz, 1H), 6.43 (d, J=2.0 Hz, 1H), 6.38-6.36 ( m, 1H), 3.66 (s, 3H), 2.96 (t, J=7.6 Hz, 2H), 2.75 (t, J=7.6 Hz, 2H).

Intermediate B21: 3-(5-Amino-2-methylphenyl)propanenitrile Ργ Pd/C, H _{S r} iSf

O,N Br ^M 3- P(o-Tol) _{3 N} H AA,.--'' _CN

Step 1: (E)-3-(2-methyl-5-nitrophenyl)αcrylonitrile.

A mixture of 2-bromo-1-methyl-4-nitrobenzene (1.0 eq.), acrylonitrile (1.5 eq.), Pd ₂ (dba) ₃ (0.1 eq.), P(oTol) ₃ (0 ,2 eq.) and TEA (3.0 eq.) in DMF (2.3 M) were stirred at 120° C. for 16 hours under argon. The reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 20:1 to 5:1) to give the title compound as a brown solid.

Step 2: 3-(5-amino-2-methylphenyl)propanenitrile.

- 54 043088

To a solution of (E)-3-(2-methyl-5-nitrophenyl)acrylonitrile (1.0 eq.) in MeOH (0.15 M) was added Pd/C (10 wt.%, 0.02 eq.). The reaction mixture was stirred at RT for 16 h under H ₂ atmosphere. The reaction was monitored by LC-MS. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid. LC-MS (m/z): [M+H]+=161;

1H NMR (400 MHz, CDCl ₃ ) δ 6.96 (d, J=8.8 Hz, 1H), 6.55-6.52 (m, 2H), 3.57 (br s, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.55 (t, J=8.0 Hz, 2H), 2.20 (s, 3H).

The following intermediates were prepared as described for Intermediate B21.

intermediate connection Structure LC-MS and/or Ή NMR B22 TT Ή NMR (400 MHz, CDC1 ₃ ) δ 7.00 (d, 7=7.2 Hz, 1H), 6.55 (d, 7=8.8 Hz, 1H), 6.53(s, 1H) , 3.62 (s, 2H), 2.84 (t, 7=7.6 Hz, 7=7.2 Hz, 2H), 2.57 (t, 7=7.2 Hz, 7=7, 6 Hz, 2H), 2.14 (s, 3H). B23 LC-MS (m/z): [M+H] ⁺ =161; Ή NMR (400 MHz, CDC1 ₃ ) δ 6.42-6.35 (m, 3H), 3.63 (b.s., 2H), 2.82 (t, 7=7.6 Hz, 2H) , 2.57 (t, 7=7.6 Hz, 2H), 2.24(s, 3H). B24 χχ LC-MS (m/z): [M+H] ⁺ =161; ^X H NMR (400 MHz, CDC1 ₃ ) δ 6.99 (t, 7=8.0 Hz, 1H), 6.62 (d, 7=7.6 Hz, 2H), 3.64 (br.s ., 2H), 2.97 (t, 7=7.6 Hz, 2H), 2.54 (t, 7=7.6 Hz, 2H), 2.10(s, 3H). B25 GT LC-MS (m/z): [M+H] ⁺ =215.

Intermediate B26: methyl 1-(3-aminophenyl)cyclopropane-1-carboxylate

Stage 1: 1-(3-nitrophenyl)cyclopropane-1-carbonitrile.

To a mixture of 2-(3-nitrophenyl)acetonitrile (2.0 g, 12.33 mmol, 1.0 eq.), 1,2-dibromoethane (3.47 g, 18.50 mmol, 1.5 eq.) , Et ₃ NBnCl (562 mg, 2.47 mmol, 0.2 eq.) in toluene (1.2 M) was added water, NaOH solution (50 wt.%, 10 eq.). The reaction mixture was stirred at 35° C. for 16 hours. The reaction was monitored by TLC and 1H NMR. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1.0 M aq. HCl, brine and then dried over Na ₂ SO ₄ . After removal of the solvent, the title compound 3 (700 mg, 30%) was obtained as a brown solid. Step 2: 1-(3-nitrophenyl)cyclopropane-1-carboxylic acid To a solution of 1-(3nitrophenyl)cyclopropane (600 mg, 3.19 mmol, 1.0 eq.) in conc. HCl (10 ml) was stirred at 120° C. for 4 hours. The reaction was monitored by LC-MS. The mixture was diluted with water and extracted with DCM. The organic layer was washed with aq. NaHCO ₃ and then dried over Na ₂ SO ₄ . The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a black solid. LC-MS (m/z): [MH]-=206;

1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.8 Hz, 1H), 6.55-6.52 (m, 2H), 3.57 (br s, 2H), 2 .88 (t, J=7.6 Hz, 2H), 2.55 (t, J=8.0 Hz, 2H), 2.20 (s, 3H).

Stage 3: 1-(3-aminophenyl)cyclopropane-1-carboxylic acid.

To a solution of 1-(3-nitrophenyl)cyclopropane-1-carboxylic acid (1.0 eq.) in MeOH (0.24 M) was added Pd/C (20 wt.%, 0.1 eq.). The mixture was stirred at 35° C. for 3 hours under H ₂ atmosphere. The reaction was monitored by TLC. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid.

Stage 4: methyl-1-(3-aminophenyl)cyclopropane-1-carboxylate.

To a solution of 1-(3-aminophenyl)cyclopropane-1-carboxylic acid (428 mg, 2.41 mmol, 1.0 eq.) in 2.5 M HCl/MeOH (1.0 eq., 0.24 M) stirred at 50° C. for 3 hours. The reaction was monitored by TLC and LC-MS until completion. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM, washed with aq. NaHCO3. The organic layer was dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: DCM/MeOH from 1:0

- 55 043088 to 20:1) to obtain the title compound as a white solid. LC-MS (m/z):

[M+H]+=192.

Intermediate B27: methyl 2-(3-aminophenyl)-2-methylpropanoate

Step 1: methyl 2-methyl-2-(3-nitrophenyl)propanoate.

To a solution of methyl-2-(3-nitrophenyl)acetate (1.0 eq.) in DMF (0.14 M) was added t-BuOK (3.0 eq.) in portions at 0°C. The mixture was stirred for 10 minutes at the same temperature. MeI (5.0 eq.) was added to the mixture and the temperature was maintained below 5°C. The reaction mixture was quenched with water after stirring for 2 hours at room temperature. The resulting solution was extracted with Et ₂ O. The organic layers were combined and concentrated and the residue was purified by silica gel flash chromatography (petroleum ether/EtOAc 20:1-15:1) to give the title compound as a light yellow oil.

Stage 2: methyl 2-(3-aminophenyl)-2-methylpropanoate.

NH ₄ Cl ₍ 10 eq.) and Zn (5.0 eq.). The reaction mixture was heated at 80° C. for 2 hours. The reaction was monitored by TLC. The solid was filtered off and the filtrate was concentrated and extracted with DCM. The organic layers were combined, dried and purified by silica gel flash chromatography (petroleum ether/EtOAc 15:1-8:1) to give the title compound.

1H NMR (400 MHz, CDCl ₃ ) δ 7.11 (t, J=8.0 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.65 (t, J= 1.6 Hz, 1H), 6.57 (dd, J=8.0, 1.6 Hz, 1H), 3.65 (s, 3H), 1.48 (s, 6H).

Intermediate B28: 3-(3-Amino-5-methoxyphenyl)propanenitrile

Ό Λ Η - with Ν

Intermediate was prepared as described for Intermediate B2. LC-MS (m/z): [M+H]+=177;

1H NMR (400 MHz, CDCl ₃ ) δ 6.18-6.13 (m, 3H), 3.76 (s, 3H), 3.69 (s, 2H, NH ₂ ), 2.82 (t, J=7.6, 2H), 2.58 (t, J=7.6 Hz, 2H).

Intermediate B29: 3-(3-Amino-5-fluorophenyl)propanenitrile F

Λ

Intermediate was prepared as described for Intermediate B2. LC-MS (m/z): [M+1]+=165.2;

1H NMR (400 MHz, CDCl ₃ ) δ 6.32-6.26 (m, 3H), 3.80 (br s, 2H), 2.83 (t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H).

Intermediate B30: 3-(3-Amino-5-chlorophenyl)propanenitrile CI

Intermediate was prepared as described for Intermediate B6. LC-MS (m/z): [M+1]+=181.1.

Intermediate B31: 3-(3-aminophenyl)-2,2-dimethylpropanenitrile jOl

Stage 1: 1-(bromomethyl)-3-nitrobenzene.

A solution of 1-methyl-3-nitrobenzene (1 eq.), NBS (1.05 eq.) and AIBN (0.03 eq.) in CCl ₄ was heated at 95° C. for 16 h. The reaction was monitored by TLC until its completion. The solid was filtered off and the filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (petroleum ether as eluent) to give the title compound.

Step 2: 2,2-dimethyl-3-(3-nitrophenyl)propanenitrile.

At -78°C to a solution of LDA (1.1 eq.) in THF was added a solution of isobutyronitrile (1.0 eq.) in THF and the resulting solution was stirred for 30 min at -78°C. A solution of 1-(bromomethyl)3-nitrobenzene (1.0 eq.) in THF was then added and the reaction mixture was allowed to warm to RT over 3 h. After completion, the reaction was quenched with sat. NH4Cl solution and extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel flash chromatography (100% petroleum ether) to give the title compound.

Step 3: 3-(3-aminophenyl)-2,2-dimethylpropanenitrile.

A mixture of 2,2-dimethyl-3-(3-nitrophenyl)propanenitrile (1.0 eq.) and palladium black (0.03 eq.) in MeOH was stirred under H ₂ (from a balloon) at RT for 16 h. The solid was filtered off and the filtrate was concentrated to give the title compound. LC-MS (m/z): [M+H]+=175;

1H NMR (400 MHz, CDCl ₃ ) δ 7.11 (t, J=7.2 Hz, 1H), 6.65-6.61 (m, 3H), 3.67 (br s, 2H), 2.72 (s, 2H), 1.34 (s, 6H).

Intermediate B32: 3-(3-amino-5-methylphenyl)-2,2-dimethylpropanenitrile A

Intermediate was prepared as described for Intermediate B31. LC-MS (m/z): [M+1]+=189.3;

¹ H NMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 6.44 (s, 1H), 6.42 (s, 1H), 3.61 (br.s, 2H), 2, 68 (s, 2H), 2.25 (s, 3H), 1.34 (s, 6H).

Intermediate B33: 3-(3-aminobenzyl)oxitane-3-carbonitrile /V ⁰ jQ O cm

Intermediate was prepared as described for Intermediate B31. In the last step of the reduction of the nitro group to the amine, the Zn/NH ₄ Cl method was used instead of the Pd/C/H2 method. LC-MS (m/z): [M+1]+=189.2.

Intermediate B34: methyl 3-(3-aminophenyl)-3-methylbutanoate n X o

Step 1:3-(4-bromophenyl)-3-methylbutanoic acid.

A mixture of 3-methylbut-2-enoic acid (1 eq.), AlCl ₃ (2 eq.) in bromobenzene (4 eq.) was stirred at 65°C for 1 h. The mixture was quenched with water. NaOH and washed with EtOAc (3 times, 50 ml). The aqueous phase was neutralized with a solution of citric acid and was extracted with EtOAc (3 times, 50 ml). The organic layer was washed with brine, dried over NaSO4, and concentrated in vacuo to give the title compound as a yellow solid. LC-MS (m/z): [MH]-=255.

Stage 2: 3-(4-bromo-3-nitrophenyl)-3-methylbutanoic acid.

A mixture of 3-(4-bromophenyl)-3-methylbutanoic acid (1.6 eq.) and KNO3 (1.0 eq.) in concentrated H2SO4 (1.2 M) was stirred at -30°C for 5 min. The mixture was quenched with water and extracted with EtOAc (2x, 50 ml). The combined organic layers were washed with brine, concentrated. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=5/1 to 2/1) to give the title compound as a yellow solid. LC-MS (m/z): [MH] ^- =300.

Stage 3: 3-(3-aminophenyl)-3-methylbutanoic acid.

A mixture of 3-(4-bromo-3-nitrophenyl)-3-methylbutanoic acid (1 eq.) and Pd/C (10%, 0.03 eq.) in MeOH (0.3 M) was stirred at RT for 16 h. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow oil LC-MS (m/z): [M+H]+=194.

Step 4: methyl 3-(3-aminophenyl)-3-methylbutanoate.

A solution of 3-(3-aminophenyl)-3-methylbutanoic acid (1.55 mmol) in 1 M HCl/MeOH (0.16 M) was stirred at RT for 1 h and the solvent was removed under reduced pressure to give the title compound as yellow solid. LC-MS (m/z): [M+H]+=208.

Intermediate B35: 3-(3-aminophenyl)-3-methylbutanenitrile

1.0

H _Z N D CN

Stage 1: 3-(4-bromo-3-nitrophenyl)-3-methylbutanamide.

To a solution of 3-(4-bromo-3-nitrophenyl)-3-methylbutanoic acid (1.0 eq.) in THF (0.25 M) was added HATU (1.3 eq.), DIEA (2.0 eq. ) and NH ₄ Cl (2.0 eq.). The mixture was stirred at RT for 16 hours. The mixture was quenched with water, extracted with EA (2 times, 30 ml). The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=301.0.

Stage 2: 3-(4-bromo-3-nitrophenyl)-3-methylbutanenitrile.

To a solution of 3-(4-bromo-3-nitrophenyl)-3-methylbutanamide (1.0 eq.) in DMF (0.66 M) was added (CNCl) ₃ (1.2 eq.) and the resulting mixture was stirred at RT within 16 h. The mixture was quenched aq. NH ₄ Cl and

- 57 043088 was extracted with EA (3 times, 20 ml). The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EULs=5:1 to 1:1) to give the title compound as a yellow oil.

Step 3: 3-(3-aminophenyl)-3-methylbutanenitrile.

To a solution of 3-(4-bromo-3-nitrophenyl)-3-methylbutanenitrile (1.0 eq.) in MeOH (0.4 M) was added 10% Pd/C (10 wt.%, 0.03 eq.) . The mixture was stirred under H ₂ at RT for 16 hours. The solid was filtered off and the filtrate was concentrated in vacuo to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=175.1.

Intermediate B36: 2-(3-amino-5-methylphenyl)acetonitrile

Stage 1: 1-(bromomethyl)-3-methyl-5-nitrobenzene.

A mixture of 1,3-dimethyl-5-nitrobenzene (1.0 eq.), NBS (1.1 eq.) and BPO (0.015 eq.) in CCl ₄ (0.5 M) was stirred overnight at 95°C in argon atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether) to give the title compound as a yellow oil.

Step 2: 2-(3-methyl-5-nitrophenyl)acetonitrile.

A mixture of 1-(bromomethyl)-3-methyl-5-nitrobenzene (1.0 eq.), KCN (2.0 eq.) in DMSO (0.65 M) was stirred overnight at 40° C. under argon. Upon completion, the reaction mixture was diluted with EtOAc, washed with brine and dried over Na ₂ SO _4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether: EtOAc=5:1) to give the title compound as a yellow oil.

Step 3: 2-(3-amino-5-methylphenyl)acetonitrile.

A mixture of 2-(3-methyl-5-nitrophenyl)acetonitrile (1.0 eq.) and Pd/C (10%, 0.01 eq.) in MeOH (0.1 M) was stirred under H ₂ atmosphere (from a balloon ) at RT for 2 hours. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether:EULs=1:1) to give the title compound as a yellow oil. LCMS (m/z): [M+H]+=147.

Intermediate B37: 2-(3-amino-5-methylphenyl)-2-methylpropanenitrile

Step 1:2-methyl-2-(3-methyl-5-nitrophenyl)propanenitrile.

At 0°C, to a stirred solution of 2-(3-methyl-5-nitrophenyl)acetonitrile (1.0 eq.) in DMF (0.13 M), t-BuOK (3.0 eq.) was added in portions under argon and the resulting mixture was stirred at RT for 16 h. The mixture was quenched with ice water, extracted with EtOAc three times. The combined organic layer was washed with brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EULs=25:1 to 10:1) to give the title compound.

¹ H NMR (400 MHz, CDC13) δ 8.09 (s, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 2.51 (s, 3H), 1.78 ( s, 6H).

Stage 2: 2-(3-amino-5-methylphenyl)-2-methylpropanenitrile.

To a solution of 2-methyl-2-(3-methyl-5-nitrophenyl)propanenitrile (1.0 eq.) in MeOH (0.06 M) was added Pd/C (10 wt.%, 0.04 eq.) and the resulting mixture was stirred under H ₂ atmosphere at RT for 6 hours. The solid was filtered off and the filtrate was concentrated and purified by flash chromatography on silica gel (eluent: petroleum ether/EHLC=20:1 to 8:1) to give the title compound as oils. LC-MS (m/z): [M+H]+=175.0.

Intermediate B38: methyl 2-(5-amino-2-methylphenyl)acetate

Step 1: 2-(2-methyl-5-nitrophenyl)acetic acid.

At 0°C, to a mixture of 2-(o-tolyl)acetic acid (3.5 g, 23.6 mmol, 1.0 eq.) in DCM (20 ml) was added a pre-chilled mixture of conc. H ₂ SO ₄ (10 ml) and HNO ₃ (1.0 ml) and the reaction mixture was stirred at RT for 2 h before being poured into ice water. The white solid was collected by filtration, the solid was washed with water and dried under vacuum. The crude product was further purified by silica gel flash chromatography (DCM/MeOH=10:1) to give the title compound.

Step 2: methyl 2-(2-methyl-5-nitrophenyl)acetate.

To a solution of 2-(2-methyl-5-nitrophenyl)acetic acid (1.7 _g , 6.52 mmol, 1.0 eq.) in MeOH (8.0 ml) 0 eq.) and the reaction mixture was stirred under argon at 40°C for 16 hours. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4. The title compound was obtained as a yellow oil after removal of the solvent.

Step 3: methyl 2-(5-amino-2-methylphenyl)acetate.

A mixture of methyl 2-(2-methyl-5-nitrophenyl)acetate (200 mg, 0.96 mmol, 1.0 eq.) and Pd/C (10%, 20 mg) in MeOH (20 mL) was stirred under atmospheric H ₂ (from balloon) at RT for 2 h. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether: EtOAc=10:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=180.

Intermediate B39: 2-(5-amino-2-methylphenyl)-2-methylpropanenitrile

Stage 1: (2-methyl-5-nitrophenyl) methanol.

To a solution of methyl 2-methyl-5-nitrobenzoate (1.0 eq.) in EtOH (0.5 M) at 0°C was added CeCl ₃ 7 H ₂ O (0.2 eq.), and then added in parts NaBH4 (2.0 eq.). The resulting mixture was stirred at RT for 16 hours before quenching with ice water. The mixture was extracted with EtOAc and the combined organic layer was dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=10:1) to give the title compound as a white solid.

Stage 2: 2-(chloromethyl)-1-methyl-4-nitrobenzene.

SOCl2 (5.0 ml) was added dropwise to a solution of (2-methyl-5-nitrophenyl)methanol (1.0 eq.) in DCM (0.3 M) at 0°C. The resulting mixture was stirred at RT for 16 h before quenching with cold aq. _NaHC03 . The mixture was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the compound as a white solid.

Step 3: 2-(2-methyl-5-nitrophenyl)acetonitrile.

To a solution of 2-(chloromethyl)-1-methyl-4-nitrobenzene (1.0 eq.) in DMSO (0.27 M) was added KCN (2.0 eq.). The mixture was stirred at RT for 16 hours before quenching with ice water. The mixture was extracted with EtOAc and the combined organic layer was dried over Na ₂ SO ₄ The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=5:1-3:1) to give the title compound as a white solid .

Step 4: 2-methyl-2-(2-methyl-5-nitrophenyl)propanenitrile.

At 0°C, aq. NaOH (5.0 ml, 30 wt%) followed by MeI (10 eq.). The mixture was stirred at 0° C. for 5 min, quenched with aq. _NH4Cl . The mixture was isolated and the crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=20:1-8:1) to give the title compound as a yellow solid.

Step 5: 2-(5-amino-2-methylphenyl)-2-methylpropanenitrile.

A mixture of 2-methyl-2-(2-methyl-5-nitrophenyl)propanenitrile (1.0 eq.) and Pd/C (10 wt.%, 0.05 eq.) in MeOH (0.04 M) was stirred in atmosphere of H2 at RT for 1 h. The solid was filtered off and the filtrate was concentrated to give the title compound. LC-MS (m/z): [M+H]+=175.2.

Intermediate B40: methyl 2-(4-aminophenyl)-2-methylpropanoate

Step 1: methyl 2-methyl-2-(4-nitrophenyl)propanoate.

At -5°C, NaH (3.0 eq.) was added in portions to a solution of methyl 2-(4-nitrophenyl)acetate (1.0 eq.) in DMF (0.1 M). The cooling bath was removed and the reaction mixture was stirred at RT for 30 minutes. The mixture was again cooled to -5°C and MeI (6.0 eq.) was added dropwise. The resulting mixture was stirred at RT for 1 hour before quenching with ice water. The mixture was extracted with EtOAc and the combined organic layer was washed with brine and then dried over Na2SO4. The title compound was obtained as a yellow solid after removal of the solvent.

Stage 2: methyl 2-(4-aminophenyl)-2-methylpropanoate.

A mixture of methyl 2-methyl-2-(4-nitrophenyl)propanoate (1.0 eq.), Pd/C (10 wt.%, 0.03 eq.) in MeOH (0.1 M) was stirred under H2 atmosphere at RT for 3 hours. The solid was filtered off and the filtrate was concentrated to give the title compound as a colorless oil. LC-MS (m/z): [M+H]+=194.0.

Intermediate B41: methyl-2-(3-aminophenyl)-2,2-difluoroacetate iP]S

F F

Step 1: methyl 2,2-difluoro-2-(3-nitrophenyl)acetate.

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At -70° C., a solution of KHMDS (3.0 eq.) was added dropwise to a stirred solution of methyl 2-(3-nitrophenyl)acetate (1.0 eq.) in THF (0.13 M). The mixture was stirred at -70°C for 20 min, and then a solution of FN(SO ₂ Ph) ₂ (3.0 eq.) in THF (1.5 M) was slowly added. The resulting mixture was stirred at -70°C for 30 min and allowed to warm to -10°C. The reaction mixture was quenched with water and the mixture was extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EIAc=20:1 to 10:1) to give the title compound as an oil.

Stage 2: methyl-2-(3-aminophenyl)-2,2-difluoroacetate.

A mixture of methyl 2,2-difluoro-2-(3-nitrophenyl)acetate (1 eq.) and Pd/C (10%, 0.03 eq.) in MeOH (0.2 M) was stirred under H ₂ ( bottle) at RT for 16 h. The solid was filtered off, the filtrate was concentrated and the residue was purified by silica gel flash chromatography (eluent: petroleum ether/E1OAc = 10:1 to 5:1) to give the title compound as a brown oils. LC-MS (m/z): [M+H]+=202.

Intermediate B42: 2-(3-aminophenoxy)acetonitrile

ΙΓχ

A mixture of 3-nitrophenol (1.0 eq.), 2-bromoacetonitrile (1.2 eq.) and K2CO3 (2.0 eq.) in CH3CN (0.5 M) was stirred at RT for 16 h. The solid was filtered off and the filtrate was concentrated to give the crude product 2-(3-nitrophenoxy)acetonitrile, which was treated with Zn (1.0 eq.), sat. NH4Cl/MeOH (5 ml/5 ml) at 65°C for 3 h. The reaction mixture was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent petroleum ether:EIAc=50:1) to give the title compound as a brown oil. LC-MS (m/z): [M+1]+=149.0.

Intermediate B43: 3-(5-amino-2-methoxyphenyl)propanenitrile ίt

Step 1: (E)-3-(5-αmino-2-methoxyphenyl)acrylonitrile.

A mixture of 3-bromo-4-methoxyaniline (1 eq.), acrylonitrile (5 eq.), Pd ₂ (dba) ₃ (0.05 eq.) and triethylamine (1.25 eq.) in DMF was sparged with argon and heated at 100°C for 1 hour in a microwave reactor. The mixture was cooled to RT and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (petroleum ether/EIAc=6:1) to give the title compound as a brown solid.

Step 2: 3-(5-Amino-2-methoxyphenyl)propanenitrile.

A mixture of (E)-3-(5-amino-2-methoxyphenyl)acrylonitrile (1 eq.) and Pd/C (10 wt.%, 0.05 eq.) in MeOH (0.05 M) was stirred under H ₂ at RT for 16 hours. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography to give the title compound as a brown solid. LC-MS (m/z): [M+H]+=177.2;

1H NMR (400 MHz, CDCl3) δ 6.72-6.68 (m, 1H), 6.60-6.56 (m, 2H), 3.76 (s, 3H), 2.87 (t, J=7.4 Hz, 2H), 2.60 (t, J=7.4 Hz, 2H).

Intermediate B44: 3-(4-Amino-1H-pyrazol-1-yl)propαnnitrile

Step 1: 3-(4-nitro-1H-n-pyrazol-1-yl)propanenitrile.

A mixture of 4-nitro-1H-pyrazole (1.0 eq.), acrylonitrile (1.0 eq.) and Na ₂ CO ₃ (2.0 eq.) in H ₂ O (0.9 M) was stirred at 50° C for 12 h in an argon atmosphere. The reaction mixture was extracted with DCM/i-PrOH=5:1 (100 ml, 3 times) and H ₂ O (100 ml). The combined organic layer was washed with brine and then dried over Na2SO4. The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=4:1 to 1:1) to give the title compound as a white solid.

LC-MS (m/z): [M+H]+=167.3.

Step 2: 3-(4-Amino-1H-pyrazol-1-yl)propαnnitrile.

A mixture of 3-(4-nitro-1H-pyrazol-1-yl)propanenitrile (1.0 eq.) and Zn (10.0 eq.) in saturated aq. NH ₄ Cl/MeOH (1:2, 0.1 M) was stirred at 80° C. for 1 h. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: DCM/MeOH=10:1) to give the title compound as a brown oil. LC-MS (m/z): [M+H]+=137.4.

Intermediate B45: 3-(3-amino-1H-pyrazol-1-yl)propαnnitrile ^CN

G

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This intermediate was prepared as described for intermediate

B44, using 3-nitro-1H-pyrazole as starting material and 1:1 H2O/THF as solvent in the first step. LC-MS (m/z): [M+H]+=137.0.

Examples

Example 1: 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

Step 1: methyl 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanoate.

Mixture of 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine (Intermediate A1, 1.0 eq.), methyl 3-(3-aminophenyl)propanoate (intermediate B1, 1.0 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthos (0.1 eq.) HPd(OAc) ₂ (0.1 eq.) in dioxane (0.064 M) stirred at 120°C for 16 h in an argon atmosphere. The mixture was cooled to RT. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc5:1 to 0:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+1]+=455.

Step 2: 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid.

To a solution of methyl 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanoate (1, 0 eq.) in THF (0.022 M) was added 1 N aq. NaOH (45 equiv.). The reaction solution was heated to 70° C. and stirred for 2 hours. The completion of the reaction was determined by LC-MS. The reaction mixture was concentrated under reduced pressure and the residue was purified by HPLC (mobile phase: CH ₃ CN/H ₂ O/0.1% HCOOH). Fractions were collected and the solvent removed with a lyophilizer to give the title compound as a white solid (formic acid salt). LC-MS (m/z): [M+1]+=441.2;

¹ H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.50 (ddd, J=4.8, 1.6, 0.8 Hz, 1H), 8.23 (s, 0 .4H, HCOOH), 7.97 (d, J=5.6 Hz, 1H), 7.84 (ddd, J=7.2, 4.8, 1.2 Hz, 1H), 7.78 ( d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.46-7.44 (m, 1H), 7.36 (s, 1H), 7.34-7.31 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 6.71 (d, J=7.6 Hz, 1H), 6.34 (dd, J=.6, 2 .0 Hz, 1H), 6.09 (d, J=2.4 Hz, 1H), 2.74 (t, J=7.6 Hz, 2H), 2.53 (s, 3H), 2, 48 (t, J=7.6 Hz, 2H), 2.35 (s, 3H).

The following compounds were prepared in the manner described in Example 1 using the appropriate intermediates. Compounds without example numbers do not fall within the scope of formula (I) or (II).

Example Structure LC-MS (m/z) [M+1] ⁺ W NMR JT Ax A Ύ · ^Ϊ: ' Ο O Ν Ν'Ο Obtained from intermediates A1 and B3. 441.3 Ή NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 8.50 (d, 7=4.4 Hz, 1H), 8.16 (s, 1H, HCOOH), 7.94 (d , 7=5.6 Hz, 1H), 7.84 (td, 7=7.6, 2.0 Hz, 1H), 7.78 (d, 7=7.6 Hz, 1H), 7.57 (s, 1H), 7.47 (d, 7=8.4 Hz, 2H), 7.347.31 (m, 1H), 7.06 (d, 7=8.4 Hz, 2H), 6.32 (dd, 7=5.6, 2.0 Hz, 1H), 6.06 (d, 7=2.4 Hz, 1H), 2.73 (t, 7=7.6 Hz, 2H), 2 .52 (s, ZN), 2.47 (t, 7=7.6 Hz, 2H), 2.35 (s, ZN). About χτ ⁿ 0 Obtained from intermediates A1 and B19. 442.2 Ή NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.56 (d, 7=2.0 Hz, 1H), 8.49 (d, 7=4.4 Hz, 1H), 8.01 (d, 7=5.6 Hz, 1H), 7.96-7.90 (m, 2H), 7.87-7.78 (m, 2H), 7.59 (s, 1H) , 7.357.30 (m, 1H), 6.41 (d, 7=5.6, 2.0 Hz, 1H), 6.11 (d, 7=2.0 Hz, 1H), 2.76 ( t, 7=7.6 Hz, 2H), 2.53 (s, 3H), 2.47 (t, 7=7.6 Hz, 2H), 2.35 (s, 3H).

- 61 043088

4 PE ch.k..YES hake ' - 'ABOUT dHAHDu^ Retrieved from 459.2 Ή NMR (400 MHz, DMSO) δ 8.87(s, 1H), 8.50 (d, 7=4.0 Hz, 1H), 7.95 (d, 7=5.6 Hz, 1H), 7.84 (td, 7=7.6, 2.0 Hz, 1H), 7.78 (d, 7=7.6 Hz, 1H), 7.57 (s, 1H), 7.52-7 .48 (m, 1H), 7.40 (dd, 7=6.8, 2.4 Hz, 1H), 7.34-7.30 (m, 1H), 6.98 (t, 7=9 .6 Hz, 1H), 6.34-6.32 (m, 1H), 6.04 (d, 7=2.0 Hz, 1H), 2.76 (t, intermediate compounds A1 and B10. 7=7.6 Hz, 2H), 2.52 (s, 3H), 2.44 (t, 7=7.6 Hz, 2H), 2.35 (s, 3H). 5 xX AX- _G Obtained from intermediates A1 and B13. 475.3 Ή NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.49 (s, 1H), 7.98 (d, 7=5.6 Hz, 1H), 7.85-7.77 (m, 2H), 7.57 (m, 2H), 7.46 (s, 1H), 7.32 (m, 1H), 7.19 (d, 7=9.2 Hz, 1H), 6 .37 (d, 7=4.0 Hz, 1H), 6.08 (s, 1H), 2.77 (t, 7=7.6 Hz, 2H), one CH2 and methyl group captured by the solvent, 2, 34 (s, 3N). 6 XCX - '- 0 Retrieved from intermediate compounds A1 and VI. 459.2 W NMR (400 MHz, CD ₃ OD) δ 8.57 (d, 7=4.4 Hz, 1H), 7.87-7.83 (m, 2H), 7.73 (d, 7=8, 0 Hz, 1H), 7.56 (d, 7=7.2 Hz, 1H), 7.52 (s, 1H), 7.38 (t, 7=5.6 Hz, 1H), 7.01 -6.94 (m, 1H), 6.90-6.88 (m, 1H), 6.27 (d, 7=4.4 Hz, 1H), 6.11 (s, 1H), 2, 84 (t, 7=7.6 Hz, 2H), 2.58 (s, 3H), 2.47 (t, 7=7.6 Hz, 2H), 2.40 (s, 3H). 7 ^.,ιχ At. J Xx Retrieved from intermediate compounds of Al and B17. 442.4 Ή NMR (400 MHz, CD3OD) δ 8.51 (d, 7=4.4 Hz, 1H), 8.31 (s, 1H), 8.14 (d, 7=6.4 Hz, 2H), 7.86 (d, 7=3.6 Hz, 2H), 7.67-7.61 (m, 2H), 7.37-7.35 (m, 1H), 6.94-6.88 ( m, ZN), 6.68 (dd, 7=6.4, 2.4 Hz, 1H), 2.99 (t, 7=6.8 Hz, ZN), 2.62-2.57 (s , ZN), 2.59 (t, 7=6.8 Hz, 2H), 2.44 (s, ZN). |П Ύ -''' '0 Retrieved from intermediate compounds A1 and B18. 442.4 Ή NMR (400 MHz, CD3OD) δ 8.53 (d, 7=4.8 Hz, 1H), 8.06 (d, 7=5.2 Hz, 1H), 8.03 (d, 7=6 .4 Hz, 1H), 7.86-7.80 (m, 2H), 7.58 (s, 1H), 7.38-7.34 (m, 1H), 7.17 (s, 1H) , 6.92 (d, 7=5.2 Hz, 1H), 6.86 (s, 1H), 6.53 (dd, J=6.0, 2.0 Hz, 1H), 2.91 ( t, 7=7.2 Hz, 2H), 2.61 (s, 3H), 2.57 (t, 7=7.2 Hz, 2H), 2.43 (s, 3H).

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Ύ j 'Α'Ό ill ί -L X,Jk ..--......-one ΗΝ ³⁴ -Ύ ^H O Obtained from intermediates A1 and B20. 442.3 Ή NMR (400 MHz, DMSO) δ 9.36 (s, 1H), 8.48 (d, 7=4.0 Hz, 1H), 8.24 (s, 1.4 H, HCOOH), 8, 16 (d, 7=5.2 Hz, 1H), 8.08 (d, 7=6.0 Hz, 1H), 7.84-7.79 (m, 2H), 7.60 (s, 1H ), 7.46 (d, 7=5.2 Hz, 1H), 7.44 (s, 1H), 7.35-7.30 (m, 1H), 6.49 (d, 7=5, 6 Hz, 1H), 6.18 (s, 1H), 2.84 (t, 7=6.8 Hz, 2H), 2.60 (t, 7=6.8 Hz, 2H), 2.53 (s, ZN), 2.35 (s, ZN). 10 O Ύ T ^M F O Obtained from intermediates A1 and B12. 459.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.58 (d, 7=4.8 Hz, 1H), 7.89-7.82 (m, 2H), 7.74 (d, 7=8, 0 Hz, 1H), 7.58-7.52 (m, 2H), 7.38 (ddd, 7=7.6, 4.8, 1.2 Hz, 1H), 7.00-6.91 (m, 2H), 6.27 (dd, 7=5.6, 2.0 Hz, 1H), 6.13 (d, 7=2.0 Hz, 1H), 2.92 (t, 7= 7.2 Hz, 2H), 2.58 (s, 3H), 2.43 (t, 7=7.2 Hz, 2H), 2.41 (s, 3H). eleven κ,Ν^,ΟΝ XX -- o ⁿ S Obtained from intermediates A13 and B1. 375.2 Ή NMR (400 MHz, DMSO-76) δ 9.02 (d, 7=3.2 Hz, 1H), 8.13 (t, 7=5.6 Hz, 1H), 7.897.85 (m, 1H ), 7.75-7.72 (m, 1H), 7.50 (m, 1H), 7.39 (s, 1H), 7.15-7.12 (m, 1H), 6.75 ( m, 1H), 6.53 (m, 1H), 6.30 (s, 1H), 2.73 (t, 7=6.0 Hz, 2H), 2.54 (s, 3H), 2, 41 (t, 7=6.0 Hz, 2H).

Example 12: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((5,6-dimethyl-[2,2'-bipyridine!-3yl)oxy)pyridine -2-amine

Step 1: 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propane nitrile.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine (intermediate A1, 1.0 eq.), 3-(3-aminophenyl)propanenitrile (intermediate compounds B2, 1.0 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthphos (0.1 eq.) and Pd(OAc) ₂ (0.1 eq.) in dioxane (0.06 M ) was stirred at 120° C. for 16 hours. The mixture was cooled to RT. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: Petroleum ether/EtOAc 1:1 to 0:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+1]+=422.

Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((5,6-dimethyl-[2,2'-bipyridine]-3yl)oxy)pyridine- 2-amine

A mixture of the above product (1.0 equiv.), Bu ₂ SnO (2.0 equiv.) and TMSN3 (5.0 equiv.) in dioxane (0.08 M) was stirred at 120°C for 16 h in an atmosphere argon. The mixture was concentrated under reduced pressure. The residue was purified by HPLC (mobile phase: CH ₃ CN/H ₂ O/0.1% HCOOH). Fractions were collected and the solvent was removed with a lyophilizer to give the title compound as a yellow solid. LC-MS (m/z): [M+1]+=465.2;

¹ H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.51-8.49 (m, 1H), 8.15 (s, 1H), 7.97 (d, J=6 .0 Hz, 1H), 7.84 (td, J=7.6, 1.6 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.57 (s, 1H ), 7.43 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.32 (ddd, J=7.2, 4.8, 1.2 Hz, 1H) , 7.11 (t, J=8.0 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.35 (dd, J=6.0, 2.4 Hz, 1H), 6.09 (d, J=2.0 Hz, 1H), 3.13 (t, J=7.6 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H) , 2.52 (s, 3H), 2.35 (s, 3H).

The following compounds were prepared in the manner described in Example 12 using the appropriate intermediates.

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Example Structure LC-MS (m/z) [M+1] ⁺ W NMR 13 Ή X X Χχχ N-N Retrieved from intermediate compounds of Al and commercially available 3-aminobenzonitrile 437.3 Ή NMR (400 MHz, DMSO-J6) δ 9.18 (s, 1H), 8.51 (d, 7=2.4 Hz, 1H), 8.37 (s, 1H), 8.03 (d , 7=6.0 Hz, 1H), 7.86-7.73 (m, ZN), 7.60 (s, 1H), 7.47 (d, 7=7.6 Hz, 1H), 7 .41 (t, 7=7.6 Hz, 1H), 7.35-7.33 (m, 1H), 6.42 (d, 7=4.0 Hz, 1H), 6.15 (s, 1H), 2.53 (s, 3N), 2.35 (s, 3N). 14 ϊΠ AsA n Retrieved from intermediate compounds A1 and 437.3 Ή NMR (400 MHz, DMSO-76) δ 9.24 (s, 1H), 8.50 (d, 7=4.8 Hz, 1H), 8.04 (d, 7=5.6 Hz, 1H ), 7.88-7.78 (m, 7H), 7.59 (s, 1H), 7.34-7.31 (m, 1H), 6.45-6.43 (m, 1H), 6.16 (s, 1H), 2.54 (s, 3H), 2.36 (s, 3H). commercially available 4-aminobenzonitrile 15 ιΧ A. J XI -'I n Η Retrieved from intermediate compounds A1 and commercially available 2-(4aminophenyl)acetonitrile a 451.2 Ή NMR (400 MHz, DMSO-76) δ 8.85 (s, 1H), 8.50 (d, 7=4.4 Hz, 1H), 8.20 (s, 0.75H, HCOOH), 7 .95 (d, 7=5.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.56 (s, 1H), 7.50 (d, 7=8.4 Hz, 2H), 7.33-7.30 (m, 1H), 7.09 (d, 7=8.4 Hz, 2H), 6.33 (dd, 7=6.0, 2.0 Hz, 1H ), 6.07 (d, 7=2.0 Hz, 1H), 4.09 (s, 2H), 2.52 (s, 3H), 2.35 (s, 3H). 16 A Ύ X A Λ Ν'Ν II J A and ν A''ν Η η Retrieved from intermediate compounds of Al and commercially available 2-(3aminophenyl)acetonitrile a 451.3 Ή NMR (400 MHz, DMSO-76) δ 9.59 (br.s., 1H), 8.55 (d, 7=4.4 Hz, 1H), 7.987.96 (m, 3H), 7, 67 (s, 1H), 7.45-7.40 (m, 2H), 7.32 (s, 1H), 7.27 (t, 7=7.6 Hz, 1H), 6.94 (d , 7=5.2 Hz, 1H), 6.55 (d, 7=4.0 Hz, 1H), 6.25 (d, 7=1.6 Hz, 1H), 4.25 (s, 2H ), 2.55 (s, ZN), 2.36 (s, ZN).

- 64 043088

17 ϊΠ Χϊ ΑΑ _{Ο ν} -ν %. O~ ^V Η Obtained from intermediate compounds Al and B4. 465.2 Ή NMR (400 MHz, DMSOA6) δ 8.82 (s, 1H), 8.50 (ddd, J=4.8, 1.6, 0.8 Hz, 1H), 8.15 (s, 0, 4H, HCOOH), 7.94 (d, 7=6.0 Hz, 1H), 7.84 (td, 7=7.6, 2.0 Hz, 1H), 7.78 (d, 7=7 .6 Hz, 1H), 7.57 (s, 1H), 7.48 (d, 7=8.4 Hz, 2H), 7.32 (ddd, J=7.6,4.8, 1, 2 Hz, 1H), 7.03 (d, 7=8.4 Hz, 2H), 6.33 (dd, 7=5.6, 2.0 Hz, 1H), 6.05 (d, 7= 2.0 Hz, 1H), 3.13 (t, 7=8.0 Hz, 2H), 2.94 (t, 7=8.0 Hz, 2H), 2.52 (s, ZN), 2 .35 (s, ZN). 18 x Ah J Ύ T L Ull |l J Lil )[ n h Ah Retrieved from intermediate compounds Al and B5. 479.4 Ή NMR (400 MHz, CD ₃ OD) δ 8.56 (d, 7=4.0 Hz, 1H), 7.87-7.82 (m, 2H), 7.75 (d, 7=7, 6 Hz, 1H), 7.52 (s, 1H), 7.38-7.35 (m, 1H), 7.23-7.15 (m, ZN), 6.80 (d, 7=8 .4 Hz, 1H), 6.25 (dd, 7=6.0, 2.4 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 2.57 (s, ZN ), 2.40(s, 3H), 1.77(s, 6H). 19 ιΠ χχ-Sch-Ax J Ύ χ <' χ' Ό Ν~Ν Retrieved from intermediate compounds Al and B7. 483.3 Ή NMR (400 MHz, DMSO-76) δ 8.538.50 (m, 2H), 7.98 (d, 7=6.4 Hz, 1H), 7.95 (d, 7=5.6 Hz, 1H ), 7.84 (td, 7=8.0, 1.6 Hz, 1H), 7.79 (d, 7=8.0 Hz, 1H), 7.56 (s, 1H), 7.33 (t, 7=6.0 Hz, 1H), 7.05 (dd, J=11.2, 8.4 Hz, 1H), 6.77-6.76 (m, 1H), 6.36 ( e, 7=5.6 Hz, 1H), 6.33 (s, 1H), 3.12 (t, 7=7.2 Hz, 2H), 2.96 (t, 7=7.2 Hz, 2H), 2.53 (s, 3N), 2.35 (s, 3N). 20 ιΠ -x,hL Αχ J Ύ χ -^==^0 Αν. Ά Retrieved from intermediate compounds Al and B9. 499.4 Ή NMR (400 MHz, DMSO-J6) δ 9.02 (s, 1H), 8.50 (d, 7=4.4 Hz, 1H), 8.22 (s, 1H, HCOOH), 7.99 (d, 7=6.0 Hz, 1H), 7.857.78 (m, 2H), 7.61-7.58 (m, 2H), 7.49 (d, 7=2.4 Hz, 1H) , 7.33 (t, 7=5.6 Hz, 1H), 7.25 (d, 7=8.8 Hz, 1H), 6.39 (dd, 7=6.0, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 3.06-3.02 (m, 4H), 2.52 (s, 3H), 2.35 (s, 3H). 21 ιΠ x,N,AJ Ύ X -' Χ' Ό X^jOC-a N-n Retrieved from intermediate compounds A1 and Wb. 483.5 Ή NMR (400 MHz, DMSO-76) δ 8.86 (s, 1H), 8.51 (s, 1H), 7.95 (d, 7=5.2 Hz, 1H), 7.86-7 .80 (m, 2H), 7.58 (s, 1H), 7.47-7.33 (m, ZH), 7.01 (t, 7=9.6 Hz, 1H), 6.35 ( e, 7=4.0 Hz, 1H), 6.04 (s, 1H), 3.13 (t, 7=7.6 Hz, 2H), 3.00 (t, 7=7.6 Hz, 2H), 2.50 (s, 3N), 2.34 (s, 3N).

-65043088

22 A? Al. ^H #n Prepared from intermediates A1 and B25. 533.1 Ή NMR (400 MHz, CD ₃ OD) δ 8.76 (d, 7=5.2 Hz, 1H), 8.39 (d, 7=8.0 Hz, 1H), 8.36-8.31 (m, 1H), 8.08 (d, 7=6.4 Hz, 1H), 7.77 (t, 7=6.4 Hz, 1H), 7.68 (s, 1H), 7.61 (d, 7=8.8 Hz, 1H), 7.50 (s, 1H), 7.42 (d, 7=8.4 Hz, 1H), 6.67 (dd, 7=6.4, 2.4 Hz, 1H), 6.43 (d, 7=2.4 Hz, 1H), 3.25 (br.s., 4H), 2.66 (s, ZN), 2.45 (s , ZN). 23 A Ύ χ '=' 0 (Y _i AX ^ d, NN Obtained from intermediates A1 and B16. 466.2 Ή NMR (400 MHz, DMSO-76) δ 9.07 (s, 1H), 8.49-8.54 (m, 2H), 7.9-8.0 (m, 2H), 7.92 ( d, 7=2.0 Hz, 1H), 7.78-7.85 (m, 2H), 7.59 (s, 1H), 7.31-7.34 (m, 1H), 6.42 (dd, 7=5.6, 2.4 Hz, 1H), 6.10 (d, 7=2.0 Hz, 1H), 3.11 (t, 7=7.6 Hz, 2H), 2 .98 (t, 7=7.6 Hz, 2H), 2.52 (s, ZN), 2.35 (s, ZN). 24 •,,l .YES XX (XXX/^d N-N Retrieved from intermediate compounds A1 and B15. 466.3 Ή NMR (400 MHz, CD3OD) δ 8.50 (d, 7=4.8 Hz, 1H), 8.09 (d, 7=6.4 Hz, 2H), 7.86-7.84 (m , 2H), 7.58 (s, 1H), 7.35 (dd, 7=8.4, 4.8 Hz, 1H), 6.96 (d, 7=5.6 Hz, 1H), 6 .94 (s, 1H), 6.66 (dd, 7=6.4, 2.0 Hz, 1H), 6.58 (d, 7=2.0 Hz, 1H), 3.19 (t, 7=7.2 Hz, 2H), 3.11(t, 7=7.2 Hz, 2H), 2.61(s, 3H), 2.42(s, 3H). 25 ιΠ _x a.AJ XX ХХАА» F N-Ν Obtained from Al and B8 intermediates. 483.4 Ή NMR (400 MHz, DMSO-76) δ 8.57 (s, 1H), 8.50 (d, 7=4.0 Hz, 1H), 8.04 (dd, 7=8.0, 6, 8 Hz, 1H), 7.94 (d, 7=6.4 Hz, 1H), 7.84 (td, 7=7.6, 1.6 Hz, 1H), 7.78 (d, 7= 7.6 Hz, 1H), 7.56 (s, 1H), 7.35-7.31 (m, 1H), 6.97 (t, 7=7.6 Hz, 1H), 6.79 ( t, 7=7.2 Hz, 1H), 6.38-6.35 (m, 2H), 3.14 (t, 7=7.6 Hz, 2H), 3.03 (t, 7=7 .6 Hz, 2H), 2.54(s, ZN), 2.35(s, ZN).

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26 ΎJ '=' 0 ν-ν Retrieved from intermediate compounds of Al and B14. 466.3 Ή NMR (400 MHz, DMSO-J6) δ 11.28 (s, 1H), 8.44 (d, 7=4.0 Hz, 1H), 8.38 (d, 7=7.2 Hz, 1H ), 8.03 (d, 7=8.0 Hz, 1H), 7.94 (td, 7=7.6, 1.6 Hz, 1H), 7.79 (t, 7=8.0 Hz , 1H), 7.76 (s, 1H), 7.39 (dd, 7=6.0, 5.2 Hz, 1H), 7.06 (d, 7=7.2 Hz, 1H), 7 .04-7.01 (m, 1H), 6.92 (d, 7=8.0 Hz, 1H), 6.60 (s, 1H), 3.353.28 (m, 4H), 2.57 ( s, ZN), 2.34 (s, ZN). 27 ιΧ .. h. 4¾% ¹ Ύ Αχ NN Prepared from intermediates A1 and B24. 479.4 Ή NMR (400 MHz, CD ₃ OD) δ 8.56 (d, 7=3.6 Hz, 1H), 8.22 (s, 0.7H, HCOOH), 7.87 (td, 7=8, 0, 2.0 Hz, 1H), 7.79 (d, 7=8.0 Hz, 1H), 7.73 (d, 7=6.0 Hz, 1H), 7.53 (s, 1H) , 7.42-3.36 (m, 1H), 7.09 (t, 7=7.2 Hz, 1H), 7.03 (d, 7=7.2 Hz, 1H), 6.92 ( d, 7=7.2 Hz, 1H), 6.31 (dd, 7=6.0, 2.0 Hz, 1H), 5.86 (d, 7=2.0 Hz, 1H), 5, 34 (m, 1H), 3.17-3.11 (m, 4H), 2.56 (s, 3H), 2.40 (s, 3H), 2.06 (s, 3H). 28 ϊΧ Xh A Ύ T ν-ν Retrieved from intermediate compounds A1 and B21. 479.5 Ή NMR (400 MHz, CD3OD) δ 8.58 (d, 7=4.4 Hz, 1H), 8.26 (s, 0.6H, HCOOH), 7.90-7.78 (m, 3H) , 7.53 (s, 1H), 7.41-3.37 (m, 1H), 7.08-6.99 (m, ZN), 6.92 (d, 7=7.2 Hz, 1H ), 6.31 (dd, 7=6.4, 2.4 Hz, 1H), 6.06 (d, 7=2.4 Hz, 1H), 3.16 (t, 7=7.6 Hz , 2H), 3.01 (t, 7=7.6 Hz, 2H), 2.62 (s, 3H), 2.52 (s, 3H), 2.21 (s, 3H). 29 Ύ'Χ N U „Ν Ν-Ν Retrieved from intermediates A1 and B23 479.2 Ή NMR (400 MHz, CDCI3) δ 8.57 (d, 7=4.0 Hz, 1H), 7.90-7.75 (m, 3H), 7.53 (s, 1H), 7.41 -3.37 (m, 1H), 7.08-6.99 (m, 3H), 6.96 (s, 1H), 6.94 (s, 1H), 6.60 (s, 1H), 6.31 (dd, 7=5.6, 1.6 Hz, 1H), 6.09 (d, 7=1.6 Hz, 1H), 3.15 (t, 7=7.6 Hz, 2H ), 2.96 (t, 7=7.6 Hz, 2H), 2.55 (s, ZN), 2.39 (s, ZN), 2.22 (s, ZN).

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thirty A, JXj N-n' Retrieved from intermediate compounds Al and B22 479.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.56 (d, 7=3.6 Hz, 1H), 7.90-7.78 (m, 3H), 7.53 (s, 1H), 7 .41-3.37 (m, 1H), 7.11 (d, 7=7.6 Hz, 1H), 7.07 (s, 1H), 6.84 (d, 7=7.2 Hz, 1H), 6.28 (dd, 7=6.4, 2.4 Hz, 1H), 5.94 (d, 7=2.4 Hz, 1H), 3.12 (t, 7=6.8 Hz, 2H), 2.97 (t, 7=6.8 Hz, 2H), 2.54 (s, ZN), 2.38 (s, ZN), 2.10 (s, ZN). 31 O xX D Ν Ν Η Retrieved from intermediate compounds of Al and B44. 455.4 Ή NMR (400 MHz, CD ₃ OD) δ 8.56 (d, 7=4.4 Hz, 1H), 7.87 (td, 7=7.6, 1.6 Hz, 1H), 7.82 -87.77 (m, 2H), 7.64 (s, 1H), 7.52 (s, 1H), 7.41-7.36 (m, 2H), 6.26 (dd, 7=6 .4, 2.4 Hz, 1H), 5.97 (d, 7=2.4 Hz, 1H), 4.50 (t, 7=6.8 Hz, 2H), 3.42 (t, 7 = 6.8 Hz, 2H), 2.58 (s, ZN), 2.41 (s, ZN). 32 ιΌ A, J X p ' ^ν Ό D wX 11 JL n—' V ^m Prepared from Al and B45 intermediates. 455.4 SH NMR (400 MHz, CD ₃ OD) δ 8.55 (d, 7=3.6 Hz, 1H), 7.90-7.75 (m, 3H), 7.54 (s, 1H), 7 .39-7.32 (m, 2H), 6.74 (br.s., 1H), 6.33 (d, 7=4.8 Hz, 1H), 5.93 (s, 1H), 4 .35 (t, 7=6.8 Hz, 2H), 3.31 (2H, overlapped with MeOH), 2.52 (s, 3H), 2.39 (s, 3H). 33 IC I AXyrX n- _n Prepared from Al and B42 intermediates. 467.3 Ή NMR (400 MHz, CD ₃ OD) δ 8.57 (d, 7=4.8 Hz, 1H), 7.87 (d, 7=5.6 Hz, 1H), 7.85 (td, 7 =7.6, 1.6 Hz, 1H), 7.75 (d, 7=8.0 Hz, 1H), 7.53 (s, 1H), 7.39-7.35 (m, 1H) , 7.14 (t, 7=8.0 Hz, 1H), 7.10 (t, 7=2.0 Hz, 1H), 6.92 (dd, 7=8.0, 2.0 Hz, 1H), 6.66 (dd, 7=8.0, 2.0 Hz, 1H), 6.28 (dd, 7=6.0, 2.0 Hz, 1H), 6.13 (d, 7 =2.0 Hz, 1H), 5.24 (s, 2H), 2.57 (s, 3H), 2.39 (s, 3H).

Example 34 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)benzyl)-2Htetrazole -2-yl)acetic acid (34A) and 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2yl) amino)benzyl)-1H-tetrazol-1-yl)acetic acid (34B)

Step 1: tert-butyl 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2yl)amino)benzyl)- 2H-tetrazol-2-yl)acetate and tert-butyl 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3yl)oxy)pyridine-2- yl)amino)benzyl)-1 H-tetrazol-1 -yl)acetate.

To a stirred solution of N-(3-((1H-tetrazol-5-yl)methyl)phenyl)-4-((5,6-dimethyl-[2,2'bipyridin]-3-yl)oxy)pyridin-2 -amine (example 16, 1.0 eq.) in acetone (0.01 M) was added K ₂ CO ₃ (1.5 eq.) at 0°C in an argon atmosphere. The resulting mixture was stirred at 0° C. for 30 min and tert-butyl-2-bromoacetate (1.5 eq.) was added dropwise. The mixture was slowly warmed to RT and stirred for 5 hours. The mixture was quenched with sat. _NH4Cl . The mixture was partitioned between DCM/water. The organic phase was dried over Na ₂ SO ₄ , concentrated and purified by preparative HPLC (mobile phase: 0.1% TFA/MeCN/H ₂ O) to give the title compounds A and B as a yellow oil. LC-MS (m/z): [M+1]+=565.

Step 2 for isomer 34A: 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridine-2

- 68 043088 yl)amino)benzyl)-2H-tetrazol-2-yl)acetic acid.

To a stirred solution of the above mixture (1.0 eq.) in MeCN (0.2 M) was added 4N HCl/dioxane (80 eq.). The resulting mixture was stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by HPLC (mobile phase: MeCN/H ₂ O/0.1% HCOOH). Collected fractions and removed the solvent using a lyophilizer to obtain the title compound. LC-MS (m/z): [M+1]+=509.2;

¹ H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.48 (dd, J=4.8, 0.8 Hz, 1H), 7.95 (d, J=5 .6 Hz, 1H), 7.82 (td, J=7.6, 2.0 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.59 (dd, J =8.0, 1.2Hz, 1H), 7.55(s, 1H), 7.38(s, 1H), 7.31(ddd, J=7.6, 4.8, 1.6 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.34 (dd, J=6.0, 2 .4 Hz, 1H), 6.08 (d, J=2.4 Hz, 1H), 5.27 (s, 2H), 4.21 (s, 2H), 2.51 (s, 3H), 2.34 (s, 3H).

Step 2 for isomer 34B: 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2yl)amino)benzyl)- 1 H-tetrazol-1-yl)acetic acid.

To a stirred solution of the mixture from step 1 (1.0 eq.) in MeCN (0.2 M) was added 4N HCl/dioxane (80 eq.). The resulting mixture was stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by HPLC (mobile phase: MeCN/H2O/0.1% HCOOH). Collected fractions and removed the solvent using a lyophilizer to obtain the title compound. LC-MS (m/z): [M+1]+=509.2;

¹ H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.50 (dd, J=4.8, 0.4 Hz, 1H), 7.96 (d, J=6 .0 Hz, 1H), 7.84 (td, J=7.6, 2.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.57 (s, 1H ), 7.54 (dd, J=9.2, 0.8 Hz, 1H), 7.47 (s, 1H), 7.32 (dd, J=7.2, 4.8, 1.2 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.34 (dd, J=6.0, 2 .0 Hz, 1H), 6.09 (d, J=2.0 Hz, 1H), 5.59 (s, 2H), 4.16 (s, 2H), 2.52 (s, 3H), 2.35 (s, 3H).

The following compounds were obtained by the method described in example 34.

Example Structure LC-MS (m/z) [M+1] ⁺ W NMR (400 MHz, DMSO) 35A Γχ He Derived from example 15. 509.2 Ή NMR (400 MHz, DMSO-76) δ 8.90 (s, 1H), 8.50 (dd, 7=4.0.0.8 Hz, 1H), 8.30 (s, 2H, HCOOH) , 7.95 (d, 7=6.0 Hz, 1H), 7.84 (td, 7=7.6, 1.6 Hz, 1H), 7.78 (d, 7=7.6 Hz, 1H), 7.57 (s, 1H), 7.53 (d, 7=7.6 Hz, 2H), 7.34-7.30 (m, 1H), 7.09 (d, 7=8 .4 Hz, 2H), 6.34 (dd, 7=5.6, 2.4 Hz, 1H), 6.07 (d, 7=2.4 Hz, 1H), 4.62 (s, 2H ), 4.10 (s, 2H), 2.52 (s, 3H), 2.35 (s, 3H). 35V ιΠ dD' ^he od s,sp·· n Obtained from Example 15. 509.2 Ή NMR (400 MHz, DMSO-76) δ 8.86 (s, 1H), 8.50 (d, 7=4.4 Hz, 1H), 8.18 (s, 1H, HCOOH), 7.95 (d, 7=6.0 Hz, 1H), 7.84 (t, 7=6.8 Hz, 1H), 7.78 (d, 7=8.0 Hz, 1H), 7.57 (s , 1H), 7.51 (d, 7=8.0 Hz, 2H), 7.34-7.30 (m, 1H), 7.10 (d, 7=8.4 Hz, 2H), 6 .33 (dd, 7=5.6, 1.6 Hz, 1H), 6.06 (d, 7=1.6 Hz, 1H), 4.99 (s, 2H), 4.08 (s, 2H), 2.52 (s, 3N), 2.35 (s, 3N).

Example 36 3-(5-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2-fluorophenyl)propionic acid

Step 1: methyl 3-(5-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2fluorophenyl)propanoate.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine (intermediate A2, 1.0 eq.), methyl 3-(5-amino-2-fluorophenyl)propanoate (intermediate B10, 1.3 equiv.), Pd(OAc) ₂ (0.1 equiv.), xanthos (0.1 equiv.) and Cs ₂ CO ₃ (2.0 equiv.) in dioxane (0.29 M) stirred at 115° C. for 16 hours. The reaction was monitored by LC-MS. the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on

- 69 043088 silica gel (eluent petroleum ether/EtOAc 10:1 to 3:1) to give the title compound as a yellow oil. LC-MS: [M+H]+=396.2.

Step 2: 3-(5-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2-fluorophenyl)propionic acid.

A mixture of methyl 3-(5-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2-fluorophenyl)propanoate (1.0 eq.) and NaOH ( 5.0 eq.) in MeOH/H ₂ O (v/v 5:1, 0.08 M) was stirred at 50° C. for 2 h. The reaction was monitored by LC-MS. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (mobile phase: 0.1% NH ₃ -H ₂ O/MeCN/H ₂ O) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=382.2;

1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.04 (d, J=6.0 Hz, 1H), 7.55-7.51 (m, 1H), 7 .47 (d, J=8.0 Hz, 1H), 7.41 (dd, J=6.4, 2.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H) , 6.99 (t, J=9.2 Hz, 1H), 6.40 (dd, J=5.6, 2.0 Hz, 1H), 6.02 (d, J=2.0 Hz, 1H), 2.75 (t, J=7.6 Hz, 2H), 2.47 (s, 3H), 2.37 (t, J=7.6 Hz, 2H), 2.28 (s, 3H).

The following compounds were prepared by the method described in Example 36 using the appropriate intermediates.

Prime R Structure LC-MS (m/z) [M+1] ⁺ Ή NMR 37 if Retrieved from intermediate compounds A2 and B17. 365.1 Ή NMR (400 MHz, DMSO) δ 9.62 (s, 1H), 8.11 (d, 7=2.0 Hz, 1H), 7.53-7.45 (m, 3H), 7.28 (d, 7=8.0 Hz, 1H), 7.20 (d, 7=8.4 Hz, 1H), 6.69 (d, 7=7.2 Hz, 1H), 6.52 (dd , 7=5.6, 2.0 Hz, 1H), 2.66 (t, 7=7.6 Hz, 2H), 2.47 (s, ZN), 2.46 (t, 7=7, 6 Hz, 2H), 2.28 (s, 3H). Ύ G Retrieved from intermediate compounds A2 and B19. 365.2 Ή NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.59 (d, 7=2.0 Hz, 1H), 8.10 (d, 7=5.6 Hz, 1H), 7.97-7.95 (m, 2H), 7.50 (d, 7=8.4 Hz, 1H), 7.23 (d, 7=8.4 Hz, 1H), 6.48 (dd , 7=6.0, 2.4 Hz, 1H), 6.07 (d, 7=2.0 Hz, 1H), 2.76 (t, 7=7.6 Hz, 2H), 2.48 (s, ZN), 2.44 (t, 7=7.6 Hz, 2H), 2.29 (s, ZN).

- 70 043088

39 Ύ V ' J Retrieved from intermediate compounds A2 and B11. 382.2 Ή NMR (400 MHz, CD ₃ OD) δ 7.97 (d, 7=6.0 Hz, 1H), 7.60 (dd, 7=8.0, 1.6 Hz, 1H), 7.44 (d, 7=8.4 Hz, 1H), 7.22 (d, 7=8.4 Hz, 1H), 7.21 (d, 7=8.4 Hz, 1H), 7.00-6 .89 (m, 2H), 6.36 (dd, 7=6.0, 2.0 Hz, 1H), 6.13 (d, 7=2.0 Hz, 1H), 2.85 (t, 7=8.0 Hz, 2H), 2.52 (s, 3H), 2.46 (t, 7=8.0 Hz, 2H), 2.36 (s, 3H). 40 Ύί ^h F O Prepared from intermediates A2 and B12. 382.2 Ή NMR (400 MHz, DMSO-J6) δ 8.63 (s, 1H), 8.04 (t, 7=8.0 Hz, 1H), 8.02 (d, 7=5.6 Hz, 1H ), 7.47 (d, 7=8.0 Hz, 1H), 7.21 (d, 7=8.0 Hz, 1H), 7.21 (d, 7=8.4 Hz, 1H), 6.98 (t, 7=8.0 Hz, 1H), 6.84 (r.7=7.2 Hz, 1H), 6.43 (dd, 7=5.6, 2.0 Hz, 1H ), 6.30 (d, 7=2.0 Hz, 1H), 2.80 (t, 7=7.6 Hz, 2H), 2.47 (s, 3N), 2.45 (t, 7 = 7.6 Hz, 2H), 2.28 (s, 3H). 41 XV '-O 6,oc _r Prepared from intermediates A2 and B13. 398.1 Ή NMR (400 MHz, CD3OD) δ 8.01 (d, 7=5.6 Hz, 1H), 7.44 (d, 7=8.4 Hz, 1H), 7.41 (d, 7=2 .4 Hz, 1H), 7.35 (dd, 7=8.4, 2.4 Hz, 1H), 7.23 (d,7=6.8 Hz, 1H), 7.21 (d, 7 = 8.4 Hz, 1H), 6.37 (dd, 7=6.0, 2.0 Hz, 1H), 6.10 (d, 7=2.0 Hz, 1H), 2.96 (t , 7=8.0 Hz, 2H), 2.56 (t, 7=8.0 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H). x ν ^:? 'O 0γXX^ Obtained from intermediates A2 and B18. 365.3 Ή NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.10 (d, 7=5.6 Hz, 1H), 8.02 (d, 7=5.2 Hz, 1H), 7.50 (s, 1H), 7.47 (d, 7=8.4 Hz, 1H), 7.36 (d, 7=2.0 Hz, 1H), 7.20 (d, 7=8 .4 Hz, 1H), 6.75 (d, 7=4.8 Hz, 1H), 6.35 (dd, 7=5.6, 2.0 Hz, 1H), 2.76 (t, 7 = 7.6 Hz, 2H), 2.54 (t, 7=7.6 Hz, 2H), 2.48 (s, 3H), 2.29 (s, 3H). 43 .N CN XT 375.2 ^1H NMR (400 MHz, DMS0-76) δ 9.02 (d, 7=3.2 Hz, 1H), 8.13 (t, 7=5.6 Hz, 1H), 7.897.85 (m, 1H), 7.75-7.72(m, 1H), 7.51-7.49(m, 1H), 7.39(s, 1H), 7.15-7.12(m, 1H) , 6.76 (m, 1H), 6.53 (m, 1H), 6.30 (s, 1H), 2.73 (m, 2H), 2.54 (s, 3H), 2.41 ( m, 2H). Retrieved from intermediate compounds A13 and B1.

Example 44: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((2,6-dimethylpyridin-3-yl)oxy)pyridine-2amine

Step 1: 3-(3-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile.

Mixture of 3-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine (Intermediate A2, 1.0 eq.), 3-(3-aminophenyl)propanenitrile (Intermediate B2, 1.3 eq. .), Cs ₂ CO ₃ (2.0 equiv.), xanthos (0.1 equiv.), Pd(OAc) ₂ (0.1 equiv.) in dioxane (0.2 M) was stirred at 115°C in for 16 hours. The reaction was monitored by LC-MS. The solution was cooled to RT and diluted with EtOAc (50 ml). The mixture was washed with brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (petroleum ether/EtOAc 3:2) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=345.

Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((2,6-dimethylpyridin-3-yl)oxy)pyridine-2amine.

Mixture of 3-(3-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile (1.0 eq.), TMSN3 (5.0 eq. ) and Bu ₂ SnO (2.0 equiv.) in dioxane (0.06 M) were stirred at 120°C for 16 h. The reaction was monitored by LC-MS. The mixture solution was cooled. The organic phase was concentrated. The residue was purified by HPLC (mobile phase: 0.1% HCOOH/MeCN/H ₂ O). Fractions were collected and the solvent removed with a lyophilizer to give the title compound as a white solid (formic acid salt). LC-MS (m/z): [M+H]+=388.3;

1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.17 (s, 0.6H, HCOOH), 8.06 (d, J=5.6 Hz, 1H), 7.50 -7.43 (m, 3H), 7.22 (d, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.72 (d, J= 7.2 Hz, 1H), 6.43 (dd, J=5.6, 2.0 Hz, 1H), 6.04 (d, J=1.6 Hz, 1H), 3.15 (t, J=7.6Hz, 2H), 2.97(t, J=7.6Hz, 2H), 2.47(s, 3H), 2.29(s, 3H).

The following compounds were prepared by the method described in Example 44 using the appropriate intermediates.

Example Structure LC-MS (m/z) [M+1] ⁺ W NMR 45 γχ A'Hy Retrieved from intermediate compounds A2 and B7. 406.2 Ή NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.04-8.00 (m, 2H), 7.47 (d, 7=8.0 Hz, 1H), 7.21 (d, 7=8.0 Hz, 1H), 7.06 (dd, 7=11.6, 8.4 Hz, 1H), 6.80-6.76 (m, 1H), 6.44 ( dd, 7=5.6, 2.0 Hz, 1H), 6.29 (d, 7=2.0 Hz, 1H), 3.14 (t, 7=7.6 Hz, 2H), 2, 98 (t, 7=7.6 Hz, 2H), 2.47 (s, ZN), 2.28(s, ZN). 46 T I ' ^: - 0 F Ν=Ν Prepared from intermediates A2 and B8. 406.2 Ή NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.23 (s, 1H), 8.07 (t, 7=8.0 Hz, 1H), 8.03 (d, 7 =6.0 Hz, 1H), 7.48 (d, 7=8.0 Hz, 1H), 7.21 (d, 7=8.0 Hz, 1H), 6.98 (t, 7=8 .0 Hz, 1H), 6.82 (t, 7=6.4 Hz, 1H), 6.44 (dd, 7=5.6, 2.0 Hz, 1H), 6.32 (d, 7 \u003d 2.0 Hz, 1H), 3.11-2.95 (m, 4H), 2.47 (s, ZN), 2.29 (s, ZN). 47 t t -'o Retrieved from intermediate compounds A2 and B14. 389.2 Ή NMR (400 MHz, DMSO) δ 9.66(s, 1H), 8.11 (d, 7=5.6 Hz, 1H), 7.51-7.43 (m, 3H), 7.30 (d, 7=8.0 Hz, 1H), 7.16 (d, 7=8.4 Hz, 1H), 6.64 (d, 7=7.2 Hz, 1H), 6.50 (dd , 7=5.6, 2.0 Hz, 1H), 3.01 (t, 7=7.6 Hz, 2H), 2.85 (t, 7=7.6 Hz, 2H), 2.37 (s, ZN), 2.28 (s, ZN).

- 72 043088

48 .N... XX Xrcv ⁿ 1 Prepared from intermediates A2 and B15. 389.3 Ή NMR (400 MHz, DMSO) δ 9.62(s, 1H), 8.10 (d, 7=5.6 Hz, 1H), 8.02 (d, 7=4.4 Hz, 1H), 7.50 (s, 1H), 7.46 (d, 7=8.0 Hz, 1H), 7.33 (s, 1H), 7.20 (d, 7=8.0 Hz, 1H), 6.75-6.73 (m, 1H), 6.36 (dd, 7=5.6, 2.0 Hz, 1H), 3.22 (t, 7=7.6 Hz, 2H), 2 .95 (t, 7=7.6 Hz, 2H), 2.48 (s, ZN), 2.29 (s, ZN). 49 .r< XV + 'O Retrieved from intermediate 389.2 Ή NMR (400 MHz, DMSO-76) δ 9.13 (s, 1H), 8.56 (d, 7=2.4 Hz, 1H), 8.10 (d, 7=5.6 Hz, 1H ), 7.99 (s, 1H), 7.94 (s, 1H), 7.51 (d, 7=8.4 Hz, 1H), 7.24 (d, 7=8.4 Hz, 1H ), 6.50 (dd, 7=5.6, 2.0 Hz, 1H), 6.06 (d, 7=2.0 Hz, 1H), 3.10 (t, compounds A2 and B16. 7=7.6 Hz, 2H), 2.97 (t, 7=7.6 Hz, 2H), 2.48 (s, 3H), 2.28 (s, 3H). 50 XX ⁿ X Prepared from intermediates A2 and B9. 422.3 Ή NMR (400 MHz, CD ₃ OD) δ 8.25 (s, 1H), 8.00 (d, 7=2.0 Hz, 1H), 7.44 (d, 7=8.0 Hz, 1H ), 7.39 (d, 7=2.4 Hz, 1H), 7.33 (dd, 7=8.8, 2.4 Hz, 1H), 7.25-7.21 (m, 2H) , 6.39 (dd, 7=6.0, 2.0 Hz, 1H), 6.09 (d, 7=2.0 Hz, 1H), 3.23 (t, 7=7.6 Hz, 2H), 3.15 (t, 7=7.6 Hz, 2H), 2.52 (s, 3H), 2.37 (s, 3H). 51 XX Retrieved from intermediate compounds A2 and Wb. 406.4 Ή NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.95 (d, 7=2.0 Hz, 1H), 7.45 (d, 7=8.4 Hz, 1H), 7.30 (dd, 7=6.4, 2.4 Hz, 1H), 7.23 (d, 7=8.4 Hz, 2H), 6.97 (t, 7=9.2 Hz, 1H ), 6.38 (dd, 7=6.0, 2.0 Hz, 1H), 6.06 (d, 7=2.0 Hz, 1H), 3.183.06 (m, 4H), 2.52 (s, ZN), 2.37(s, ZN).

N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-methyl-2-phenylpyridine-352:

Example yl)oxy)pyridine-2-amine

Step 1: 3-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile.

Mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (Intermediate A6, 1.0 eq.), 3-(3-aminophenyl)propanenitrile (Intermediate B2, 1, 5 equiv.), Cs ₂ CO ₃ (2.0 equiv.), xanthos (0.1 equiv.) and Pd(OAc) ₂ (0.1 equiv.) in dioxane (0.25 M) were stirred at 120 ° C for 16 hours the reaction mixture was cooled to RT, diluted with EtOAc (50 ml), washed with saline, and then dried over Na ₂ SO ₄ . Concentrate the organic phase to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=407.

Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridine2-amine.

Mixture of 3-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile (1.0 eq.), TMSN3 (5.0 equiv.) and Bu ₂ SnO (2.0 equiv.) in dioxane (0.17 M) was stirred at 120°C for 16 hours the Reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 8:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=450.4;

¹ H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.00 (d, J=6.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H) , 6.66 (d, J=8.4 Hz, 1H), 7.44-7.36 (m, 7H), 7.11 (t, J=7.6 Hz, 1H), 6.71 ( d, J=7.6 Hz, 1H), 6.41-6.39 (m, 1H), 6.09 (s, 1H), 3.11

- 73043088 (t, J=7.6 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.58 (s, 3H).

The following compounds were prepared by the methods described for Example 52 using the appropriate intermediates._______________________________________________

Example Structure LC-MS (m/z) [M+1] ⁺ W NMR (400 MHz) 53 OK .....Υ,.Χ,Ι κ/χ Retrieved from intermediate compounds A7 and B2. 451.4 Ή NMR (400 MHz, DMSO) δ 8.95 (dd, 7=2.0, 0.8 Hz, 1H), 8.90 (s, 1H), 8.56 (dd, 7=4.8, 1.6 Hz, 1H), 8.16-8.13 (m, 1H), 8.01 (d, 7=6.0 Hz, 1H), 7.73 (d, 7=8.4 Hz, 1H), 7.47-7.39 (m, 4H), 7.12 (t, 7=7.6 Hz, 1H), 6.71 (d, 7=7.6 Hz, 1H), 6, 42 (dd, 7=6.0, 2.0 Hz, 1H), 6.11 (d, 7=2.0 Hz, 1H), 3.12 (t, 7=8.4 Hz, 2H), 2.95 (t, 7=8.4, 2H), 2.60 (s, 3H). 54 XX Retrieved from intermediate compounds A8 and B2. 451.4 Ή NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.63 (d, 7=6.0 Hz, 2H), 8.03 (d, 7=6.0 Hz, 1H), 7.77 (d, 7=6.0 Hz, 2H), 7.74 (d, 7=8.4 Hz, 1H), 7.49 (d, 7=8.4 Hz, 1H), 7. 43 (d, 7=8.0 Hz, 1H), 7.39 (s, 1H), 7.12 (t, 7=8.0 Hz, 1H), 6.71 (d, 7=7.2 Hz, 1H), 6.44 (dd, 7=6.0, 2.0 Hz, 1H), 6.11 (d, 7=2.0 Hz, 1H), 3.13 (t, J=8 .0 Hz, 2H), 2.96 (t, 7=8.4 Hz, 2H), 2.60 (s, 3H). 55 γΧ ν=ν Retrieved from intermediate compounds AZ and B2. 451.3 Ή NMR (400 MHz, CD ₃ OD) δ 8.60 (d, 7=4.0 Hz, 1H), 7.89-7.80 (m, 3H), 7.66 (d, 7=8, 4 Hz, 1H), 7.47 (d, 7=8.4 Hz, 1H), 7.45-7.40 (m, 1H), 7.20-7.13 (m, ZN), 6, 78-6.76 (m, 1H), 6.30 (br.s., 1H), 6.10 (d, 7=2.0 Hz, 1H), 3.15 (m, 2H), 3. 01 (t, 7=8.0 Hz, 2H), 2.60 (s, ZN).

- 74 043088

56 h.N. /A vp Ά Retrieved from intermediate compounds Al 5 and B2. 402.2 Ή NMR (400 MHz, DMSO-J6) δ 8.93 (s, 1H), 8.15 (s, HCOOH, 1H), 8.06 (d, 7=6.0 Hz, 1H), 749- 746 ( _m , 2H), 7.43 (s, 1H), 7.22 (d, 7=8.4 Hz, 1H), 7.13 (t, 7=7.6 Hz, 1H), 6 .72 (d, 7=7.2 Hz, 1H), 6.43 (dd, 7=5.6, 1.6 Hz, 1H), 6.07 (d, 7=1.6 Hz, 1H) , 3.15 (t, 7=7.6 Hz, 2H), 2.98 (t, 7=7.6 Hz, 2H), 2.62 (c, 7=7.6 Hz, 2H), 2 .49 (s, ZN), 1.14 (t, 7=7.6 Hz, ZN). 57 -Αχ t ^' Ό Retrieved from intermediate compounds A16 and B2. 402.2 Ή NMR (400 MHz, DMSO-76) δ 8.93 (s, 1H), 8.30 (s, HCOOH, 1.2H), 8.07 (d, 7=5.6 Hz, 1H), 7 .52 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.23 (d, 7=8, 4 Hz, 1H), 7.12 (t, 7=7.6 Hz, 1H), 6.74 (d, 7=7.6 Hz, 1H), 6.41 (dd, 7=5.6, 2.0 Hz, 1H), 6.07 (d, 7=2.0 Hz, 1H), 3.00-2.80 (m, 4H), 2.75 (k, 7=7.6 Hz, 2H), 2.31 (s, ZN), 1.25 (t, 7=7.6 Hz, ZN). 58 cf ₃ Ν=v' Obtained from intermediates A14 and B2. 442.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.02 (d, 7=6.0 Hz, 1H), 7.67 (d, 7=8.4 Hz, 1H), 7.59 (d, 7 = 8.4 Hz, 1H), 7.33 (s, 1H), 7.24-7.14 (m, ZN), 6.77 (d, 7=6.8 Hz, 1H), 6.41 (dd, 7=6.0, 2.0 Hz, 1H), 6.23 (d, 7=2.0 Hz, 1H), 3.24 (t, 7=7.6 Hz, 2H), 3 .05 (t, 7=7.6 Hz, 2H), 2.58 (s, 3H). 59 ay n 1, - ^Ν ν= _ν Obtained from intermediates A17 and B2. 424.4 Ή NMR (400 MHz, CD3OD) δ 8.17(s, 1H), 8.02-7.98(m, 3H), 7.88(d, 7=8.0Hz, 1H), 7.72 (t, 7=7.2 Hz, 1H), 7.56 (t, 7=7.2 Hz, 1H), 7.28 (s, 1H), 7.20-7.12 (m, 2H) , 6.75 (d, 7=7.2 Hz, 1H), 6.50 (dd, 7=6.0, 2.0 Hz, 1H), 6.23 (d, 7=2.0 Hz, 1H), 3.18 (t, 7=7.6 Hz, 2H), 2.99 (t, 7=7.6 Hz, 2H), 2.61 (s, 3H). 60 eh! K L 2 464.4 Ή NMR (400 MHz, CD3OD-A) δ 7.85 (d, 7=6.0 Hz, 1H), 7.68 (dd, 7=8.0, 1.6 Hz, 2H), 7.57 (d, 7=8.4 Hz, 1H), 7.40-7.34 (m, 4H), 7.22-7.19 (m, ZN), 6.89 (dt, 7=7.2 , 1.6 Hz,

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Retrieved from intermediate compounds Ab and B5. 1H), 6.28 (dd, 7=5.6, 2.0 Hz, 1H), 6.07 (d, 7=2.0 Hz, 1H), 2.60 (s, 3H), 1, 78 (s, 6H). 61 χX A jOliX Retrieved from intermediates A65 and B5. 464.3 Ή NMR (400 MHz, DMSO-76) δ 8.90 (s, 1H), 8.27 (s, 1H, HCOOH), 8.10 (d, 7=7.2 Hz, 2H), 8.05 (d, 7=6.0 Hz, 1H), 7.93 (d, 7=8.4 Hz, 1H), 7.68 (d, 7=8.4 Hz, 2H), 7.51 (t , 7=7.2 Hz, 2H), 7.44 (t, 7=7.2 Hz, 1H), 7.16 (s, 1H), 7.10 (t, 7=8.4 Hz, 1H ), 6.72 (d, 7=8.0 Hz, 1H), 6.46 (dd, 7=6.0, 1.6 Hz, 1H), 6.13 (d, 7=1.6 Hz , 1H), 2.42 (s, 3H), 1.66 (s, 6H). 62 / X g N=n' Retrieved from intermediates A66 and B2. 454.3 ^X H NMR (400 MHz, CD ₃ OD) δ 8.08 (s, 1H), 8.00-7.90 (m, 2H), 7.47 (d, 7=8.0 Hz, 1H), 7.26 (s, 1H), 7.20-7.10 (m, ZN), 6.76 (d, 7=6.4 Hz, 1H), 6.44 (dd, 7=6.0, 2.0 Hz, 1H), 6.17 (d, 7=2.0 Hz, 1H), 3.89 (s, ZN), 3.20 (t, 7=7.6 Hz, 2H), 3 .02 (t, 7=7.6 Hz, 2H), 2.55 (s, 3H). 63 % N=v' Retrieved from intermediate compounds A4 and B2. 465.3 Ή NMR (400 MHz, DMSO-76) δ 8.83 (s, 1H), 8.22 (s, 1H, HCOOH), 7.98 (d, 7=5.6 Hz, 1H), 7.73 (t, 7=7.6 Hz, 1H), 7.70 (d, 7=8.0 Hz, 1H), 7.60 (d, 7=8.0 Hz, 1H), 7.48-7 .40 (m, ZN), 7.19 (d, 7=7.6 Hz, 1H), 7.10 (t, 7=7.6 Hz, 1H), 6.72 (d, 7=7, 6 Hz, 1H), 6.33 (dd, 7=6.0, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 2.98 (t, 7= 8.0 Hz, 1H), 2.87 (t, 7=8.0 Hz, 2H), 2.57 (s, ZN), 2.32 (s, ZN). 64 ^73 Ύ Gm o x _N n I ^NH N=N Prepared from intermediates A5 and B2. 465.3 Ή NMR (400 MHz, CDCh) δ 8.32 (d, 7=4.0 Hz, 1H), 7.87 (d, 7=6.0 Hz, 1H), 7.59 (d, 7=8 .0 Hz, 1H), 7.51 (d, 7=8.4 Hz, 1H), 7.40 (s, 1H), 7.34 (d, 7=8.4 Hz, 1H), 7, 22-7.16 (m, 2H), 6.82 (d, 7=7.6 Hz, 1H), 6.75 (dd, 7=8.0, 1.2 Hz, 1H), 6.37 (dd, 7=6.0, 2.0 Hz, 1H), 6.11 (d, 7=2.0 Hz, 1H), 3.13-3.05 (m, 2H), 3.05-2.97 (m, 2H), 2.45 (s, ZN), 2.35 (s , ZN). 65 A Retrieved from intermediate compounds AZ and B25. 519.4 SH NMR (400 MHz, CD3OD) δ 8.59 (d, 7=4.4 Hz, 1H), 7.97 (d, 7=6.0 Hz, 1H), 7.88 (t, 7=7 .2 Hz, 1H), 7.79 (d, 7=7.6 Hz, 1H), 7.67 (d, 7=8.0 Hz, 1H), 7.51-7.38 (m, 5H ), 6.37 (d, 7=4.0 Hz, 1H), 6.14 (s, 1H), 3.20 (br.s., 4H), 2.63 (s, 3H).

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Example 66 3-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

A mixture of 3-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile (Example 52 step 1, 1.0 eq) and KOH (10.0 eq.) in dioxane/H ₂ O (5:1, 0.07 M) was stirred at 120° C. for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was cooled to RT and the dioxane was removed. The pH of the residue was adjusted to 6-7 with 1 N HCl (aq) and the solid was collected by filtration and washed with H ₂ O. The solid was purified by silica gel flash chromatography (DCM/MeOH 8:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=426.4;

1H NMR (400 MHz, CDCl ₃ ) δ 9.64 (br s, 1H), 7.76-7.72 (m, 3H), 7.41-7.35 (m, 4H), 7.23 -7.17 (m, 2H), 7.14 (s, 1H), 6.99 (dd, J=7.6, 1.6 Hz, 1H), 6.40 (d, J=2.0 Hz, 1H), 6.21 (dd, J=6.0, 2.0 Hz, 1H), 2.95 (t, J=6.8 Hz, 2H), 2.66 (t, J=6 .8 Hz, 2H), 2.65 (s, 3H).

Example 67: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4yl)-1H-pyrazol- 4-yl)oxy)pyridine-2-amine

Stage 1: 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin2-yl)amino)phenyl) propanenitrile.

To a solution of 2-chloro-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4yl)oxy)pyridine (Intermediate A12, 1.0 eq.), 3 -(3-aminophenyl)propanenitrile (intermediate B2, 1.3 eq.), Pd(OAc) ₂ (0.1 eq.), xanthos (0.1 eq.) and Cs ₂ CO ₃ (2.0 eq. .) in dioxane (0.21 M) was stirred at 115° C. for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc 10:1 to 2:1) to give the title compound as a yellow oil. LC-MS (m/z): [M+H]+=430.

Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)1H-pyrazol- 4-yl)oxy)pyridine-2-amine.

A mixture of 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-yl)oxy)pyridin-2yl)amino)phenyl)propanenitrile (1.0 eq.), TMSN3 (5.0 eq.) and Bu ₂ SnO (2.0 eq.) in dioxane (0.12 M) were stirred at 120° C. for 16 hours. The reaction was monitored by LC -MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: DCM/MeOH 10:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=473.5;

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.02 (d, J=5.6 Hz, 1H), 7.85 (s, 1H), 7.49 ( d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.13 (t, J=7.6 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.44 (dd, J=5.6, 2.0 Hz, 1H), 6.25 (d, J=2.0 Hz, 1H), 3.84-3.81 (m, 2H ), 3.68-3.63 (m, 1H), 3.34-3.30 (m, 2H), 3.15 (t, J=7.6 Hz, 2H), 2.98 (t, J=7.6 Hz, 2H), 2.742.69 (m, 1H), 1.67-1.62 (m, 4H), 1.03-0.91 (m, 4H).

Example 68: 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4yl)oxy)pyridin-2-yl)amino)phenyl) propionic acid

A mixture of 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2yl)amino)phenyl)propanenitrile ( step 1 of example 67, 1.0 eq.) and KOH (5.0 eq.) in DMSO/H ₂ O (v/v=1:1, 0.12 M) were stirred at 120°C for 16 hours The reaction was monitored by LC-MS. The reaction mixture was filtered and the pH of the filtrate was adjusted to 7 with 1.0 M aq. HCl. The precipitated solid was collected by filtration. The filter cake was washed with water and purified by HPLC (mobile phase: 0.1% NH ₃ -H ₂ O/MeCN/H ₂ O). Fractions were collected and the solvent removed with a lyophilizer to give the title compound as a white solid. LC-MS (m/z): [M+H]+=449.4;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.02 (d, J=6.0 Hz, 1H), 7.85 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.11 (t, J=7.6 Hz, 1H), 6.72 (d, J=7.6 Hz , 1H), 6.43 (dd, J=5.6, 2.0 Hz, 1H), 6.25 (d, J=2.0 Hz, 1H), 3.84-3.80 (m, 2H), 3.67-3.63 (m, 1H), 3.34-3.27 (m, 2H), 2.76-2.71 (m, 3H), 2.41 (t, J= 8.0 Hz, 2H), 1.67-1.62 (m, 4H), 1.03-0.93 (m, 4H).

The following compound was prepared in the manner described in Example 1 using the appropriate intermediates.

Example Structure LC-MS (m/z) [M+1] ⁺ Ή NMR (400 MHz) A J.·,™ „ _th --γ Obtained from intermediates A12 and B20. 450.4 Ή NMR (400 MHz, DMSO-76) δ 9.49 (s, 1H), 8.18 (d, 7=5.2 Hz, 1H), 8.14 (d, 7=5.2 Hz, 1H ), 7.87 (s, 1H), 7.52 (d, 7=4.4 Hz, 1H), 7.47 (s, 1H), 6.59 (d, 7=4.4 Hz, 1H ), 6.36 (s, 1H), 3.903.80 (m, 2H), 3.67-3.63 (m, 1H), 3.38-3.25 (m, 2H), 2.85 ( t, 7=7.2 Hz, 2H), 2.71 (m, 1H), 2.56 (t, 7=7.2 Hz, 2H), 1.67-1.62 (m, 4H), 1.03-0.93 (m, 4H).

Example 70: 2-methyl-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2yl)amino)phenyl)propionic acid

Step 1: 2-methyl-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2yl)amino)phenyl)propanenitrile

Solution of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (Intermediate A6, 1.0 eq.), 2-(3-Aminophenyl)-2-methylpropanenitrile (Intermediate B5 , 1.5 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthphos (0.1 eq.), Pd(OAc) ₂ (0.1 eq.) in dioxane (0.3 M) was stirred at 120° C. for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water, brine and then dried over Na ₂ SO ₄ . The crude product was purified by silica gel flash chromatography (eluent petroleum ether/EtOAc 100:1 to 10/1) to give the title compound. LC-MS (m/z): [M+H]+=421.4;

1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=6.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.61 (d, J=8.4 Hz , 2H), 7.427.27 (m, 6H), 7.10 (d, J=8.0 Hz, 1H), 6.34 (dd, J=6.0, 2.0 Hz, 1H), 6 .13 (d, J=2.0 Hz, 1H), 2.63 (s, 3H), 1.71 (s, 6H).

Step 2: 2-methyl-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid.

A solution of 2-methyl-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile (1.0 eq.) in concentrated an aqueous solution of HCl (0.06 M) was stirred at 110°C for 16 h in a sealed test tube. The reaction was monitored by LC-MS. The mixture was purified by HPLC (0.1% NH3-H2O/ACN/H2O) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=440.5;

1H NMR (400 MHz, CD3OD δ 7.86 (d, J=5.6 Hz, 1H), 7.67 (d, J=6.4 Hz, 2H), 7.55 (d, J=8, 4 Hz, 1H), 7.397.29 (m, 5H), 7.20-7.18 (m, 2H), 7.00-6.99 (m, 1H), 6.26-6.25 (m , 1H), 6.11 (s, 1H), 2.59 (s, 3H), 1.48 (s, 6H).

Example 71 2-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2methylpropionic acid

Stage 1: 2-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2- 78 043088 methylpropanenitrile.

Mixture of 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine (Intermediate A1, 1.0 eq.), 2-(3-aminophenyl)-2- methylpropanenitrile (intermediate B5, 1.1 eq.), Pd(OAc) ₂ (0.1 eq.) and xanthos (0.1 eq.) in dioxane (0.18 M) was stirred at 120°C for 16 hours The reaction was monitored by LC-MS. The mixture solution was cooled to RT and diluted with EtOAc (50 ml). The mixture was washed with brine and then dried over Na ₂ SO ₄ . The organic phase was concentrated and the residue was purified by preparative TLC to give the title compound as a light yellow solid. LC-MS (m/z): [M+H]+=436.3;

1H NMR (400 MHz, CDCl3) δ 8.58-8.56 (m, 1H), 7.90 (d, J=5.6 Hz, 1H), 7.71 (d, J=8.0 Hz , 1H), 7.64-7.60 (m, 1H), 7.29 (t, J=1.8 Hz, 1H), 7.25-7.21 (m, 2H), 7.18- 7.12 (m, 2H), 7.05-7.02 (m, 1H), 6.76 (s, 1H), 6.23 (dd, J=5.6, 2.0 Hz, 1H) , 6.15 (d, J=2.0 Hz, 1H), 2.54 (s, 3H), 2.28 (s, 3H), 1.62 (s, 6H).

Step 2: 2-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2methylpropionic acid.

A mixture of the above product (1.0 eq.) in HCl (aq. 12 N) (0.04 M) was stirred at 110° C. in a sealed tube for 16 hours. The reaction was monitored by LC-MS. The mixture solution was purified by HPLC (CH ₃ CN/H ₂ O/0.1% HCOOH) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=455.4;

¹ H NMR (400M Hz, CD3OD) δ 8.56 (d, J=4.8 Hz, 1H), 8.09 (s, 1H, HCOOH), (m, 1H), 7.92 (td, J =7.6, 1.2 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.82 (d, J=6.4 Hz, 1H), 7.57 (s , 1H), 7.42 (t, J=5.6 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.21-7 .17 (m, 2H), 6.49 (dd, J=6.4, 2.4 Hz, 1H), 6.19 (d, J=2.4 Hz, 1H), 2.60 (s, 3H), 2.41 (s, 3H), 1.51 (s, 6H).

Example 72 2-methyl-2-(3-((4-((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

Step 1: 2-methyl-2-(3-((4-((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2,2'-bipyridine (Intermediate A3, 1.0 eq.), 2-(3-aminophenyl)-2-methylpropanenitrile ( intermediate B5, 1.5 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthos (0.1 eq.), Pd(OAc) ₂ (0.1 eq.) in dioxane (0.033 M) stirred at 120° C. for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was cooled to RT and diluted with EtOAc, washed with brine and then dried over Na2SO4. The organic phase was concentrated under reduced pressure. The residue was purified by HPLC (0.1% NH ₃ -H ₂ O/ACN/H ₂ O) to give the product as a white solid.

LC-MS (m/z): [M+H]+=422.3;

1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7.91-7.75 (m, 5H), 7.48-7.25 (m, 4H), 7.08-7, 06 (m, 1H), 6.30 (s, 1H), 6.12 (s, 1H), 2.63 (s, 3H), 1.68 (s, 6H).

Step 2: 2-methyl-2-(3-((4-((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid.

A mixture of 2-methyl-2-(3-((4-((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile (1.0 eq.), KOH (20 eq.) in dioxane-H ₂ O (1:1, 0.015 M) was stirred at 120° C. for 36 h. The reaction was monitored by LC-MS. The mixture solution was cooled to RT and concentrated. The residue was purified by HPLC (0.1% NH ₃ -H ₂ O/ACN/H ₂ O) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=441.4;

1H NMR (400 MHz, DMSO) δ 12.25 (br s, 1H), 8.89 (s, 1H), 8.52 (d, J=2.8 Hz, 1H), 7.95 (d , J=5.2 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.69 (d, J =8.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.40-7.34 (m, 2H) , 7.15 (m, 1H), 6.86-6.81 (m, 1H), 6.33 (d, J=3.6 Hz, 1H), 6.09 (s, 1H), 2, 58 (s, 3H), 1.41 (s, 6H).

The following compounds were prepared by the method described in Example 72 using the appropriate intermediates.

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Example Structure LC-MS (m/z) [M+1] ⁺ W NMR (400 MHz) 73 χγ Ho 378.2 Ή NMR (400 MHz, DMSO-76) δ 8.96 (s, 1H), 8.05 (d, 7=5.6 Hz, 1H), 7.67 (d, 7=8.0 Hz, 1H ), 7.48 (d, 7=8.4 Hz, 1H), 7.41 (s, 1H), 7.23-7.16 (m, 2H), 6.85 (d, 7=7, 6 Hz, 1H), 6.41 (d, 7=3.6 Retrieved from intermediate compounds A2 and B5. Hz, 1H), 6.05 (s, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 1.42 (s, 6H). 74 Retrieved from intermediate compounds A12 and B5. 463.4 Ή NMR (400 MHz, CD ₃ OD) δ 8.25 (s, 0.5H, HCOOH), 7.94 (d, 7=5.6 Hz, 1H), 7.62 (s, 1H), 7 .38 (s, 1H), 7.29 (d, 7=7.2 Hz, 1H), 7.24 (t, 7=7.6 Hz, 1H), 7.04 (d, 7=7, 6 Hz, 1H), 6.45 (dd, 7=5.6, 2.0 Hz, 1H), 6.31 (d, 7=2.0 Hz, 1H), 3.90-3.80 ( m, 2H), 3.58 (sep, 3.6 Hz, 1H), 3.503.40 (m, 2H), 2.79 (tg, 7=11.6, 4.0 Hz, 1H), 1, 88-1.60 (m, 4H), 1.52 (s, 6H), 1.03-0.93 (m, 4H). 75 XI edd Retrieved from intermediates A65 and B5. 440.2 Ή NMR (400 MHz, DMSO-76) δ 9.65 (b.s., 1H), 8.10 (d, 7=7.2 Hz, 2H), 8.06 (d, 7=6.4 Hz, 1H), 7.97 (d, 7=8.4 Hz, 1H), 7.75 (d, 7=8.4 Hz, 1H), 7.52 (t, 7=7.2 Hz, 2H), 7.45 (t, 7=7.2 Hz, 1H), 7.46 (d, 7=7.6 Hz, 1H), 7.34 (s, 1H), 7.29 (t, 7=8.0 Hz, 1H), 7.02 (d, 7=7.6 Hz, 1H), 6.67 (d, 7=5.6 Hz, 1H), 6.20 (d, 7= 2.4 Hz, 1H), 2.44 (s, 3H), 1.42 (s, 6H). 76 η Ύ £ Χν -XX°-^ y ^it Obtained from intermediate compounds A1 and B42. 443.2 Ή NMR (400 MHz, CD3OD) δ 8.58 (d, 7=4.8 Hz, 1H), 7.89-7.84 (m, 2H), 7.75 (d, 7=8.0 Hz , 1H), 7.53 (s, 1H), 7.40-7.37 (m, 1H), 7.10 (t, 7=8.0 Hz, 1H), 6.98 (t, 7= 2.0 Hz, 1H), 6.92 (dd, 7=8.0, 2.0 Hz, 1H), 6.66 (dd, 7=8.0, 2.0 Hz, 1H), 6, 24 (dd, 7=6.0, 2.0 Hz, 1H), 6.13 (d, 7=2.0 Hz, 1H), 4.34 (s, 2H), 2.58 (s, ZN ), 2.41 (s, 3N).

Example 77: 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropane-1-carboxylic acid

Step 1: methyl 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropan-1-carboxylate.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (Intermediate A6, 1.0 eq.), methyl-1-(3-aminophenyl)cyclopropane-1-carboxylate ( intermediate B26, 1.0 eq.), xanthos (0.1 eq.), Cs ₂ CO ₃ (2.0 eq.) and Pd(OAc) ₂ (0.1 eq.) in dioxane (0.17 M) sealed in a tubular reactor. The resulting mixture was stirred at 115° C. for 16 hours under argon. The reaction was monitored by LC-MS. The mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: DCM/MeOH 20:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=452.3.

Step 2: 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropane

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1-carboxylic acid.

Methyl 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropane-1-carboxylate mixture (100 mg, 0.22 mmol, 1.0 equiv.), aq. NaOH (2.0 M, 5.0 eq.) in MeOH (0.05 M) was stirred at 50° C. for 2 hours. The reaction was monitored by LC-MS. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (mobile phase: 0.1% HCOOH/MeCN/H ₂ O). The solvent was removed with a lyophilizer to give the title compound as a white solid (formic acid salt). LC-MS (m/z): [M+H]+=438.2;

¹ H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.29 (s, 1H, HCOOH), 8.00 (d/=6.0 Hz, 1H), 7.78 (d, J=6.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.45-7 .35 (m, 5H), 7.11 (t, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.38 (dd, J=6, 0, 2.0 Hz, 1H), 6.09 (d, J=2.0 Hz, 1H), 2.58 (s, 3H), 1.39 (m, 2H), 1.03 (m, 2H).

The following compounds were prepared by the method described in Example 77 using the appropriate intermediates.

Example Structure LC-MS (m/z) [M+1] ⁺ W NMR (400 MHz) 78 3U ¹ Prepared from intermediates A9 and B27. 474.4 Ή NMR (400 MHz), CD ₃ OD δ 7.90 (d, 7=6.0 Hz, 1H), 7.75 (dd, 7=2.4, 2.0 Hz, 1H), 7.68 -7.65 (m, 1H), 7.59 (d, 7=8.4 Hz, 1H), 7.39-7.36 (m, ZN), 7.31 (s, 1H), 7.237, 17 (m, 2H), 7.00 (dt, 7=7.2, 1.6 Hz, 1H), 6.29 (dd, 7=6.0, 2.0 Hz, 1H), 6.12 (d, 7=2.0 Hz, 1H), 2.61 (s, 3H), 1.49 (s, 6H). 79 χ, ^ΧΧ xx Retrieved from intermediate compounds AIO and B27. 474.3 Ή NMR (400 MHz), CD3OD δ 7.90 (d, 7=6.0 Hz, 1H), 7.72 (dt, 7=8.8, 2.0 Hz, 2H), 7.58 (d , 7=8.4 Hz, 1H), 7.40 (dt, 7=8.8, 2.0 Hz, 2H), 7.36 (d, 7=8.4 Hz, 1H), 7.32 (t, 7=1.6 Hz, 1H), 7.24-7.17 (m, 2H), 7.00 (dt, 7=6.8, 1.6 Hz, 1H), 6.29 ( dd, 7=6.0, 2.0 Hz, 1H), 6.12 (d, 7=2.0 Hz, 1H), 2.60 (s, 3N), 1.49 (s, 6H). 80 Ci XA XX Retrieved from intermediate compounds Al 1 and B27. 474.3 Ή NMR (400 MHz), CD3OD δ 7.85 (d, 7=6.0 Hz, 1H), 7.63 (d, 7=8.4 Hz, 1H), 7.46-7.42 (m , 2H), 7.39-7.31 (m, 4H), 7.27-7.18 (m, 2H), 6.99 (d, 7=6.8 Hz, 1H), 6.22 ( dd, 7=6.0, 2.0 Hz, 1H), 6.15 (d, 7=2.0 Hz, 1H), 2.59 (s, 3N), 1.50 (s, 6H).

Example 81 2-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2methylpropionic acid

Step 1: methyl 2-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2methylpropanoate.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine (intermediate A16, 1.0 eq.), methyl-2-(3-aminophenyl)-2-methylpropanoate (intermediate compounds B27, 1.5 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthos (0.1 eq.) and Pd(OAc) ₂ (0.1 eq.) in dioxane (0.1 M ) was stirred at 115° C. for 16 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=10:1 to 1:1) to give the title compound. LC-MS (m/z): [M+H]+=406.2.

Step 2: 2-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionic acid.

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A mixture of methyl 2-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2methylpropanoate (1.0 eq.) and KOH ( 5.0 eq.) in MeOH/H ₂ O (4:1, 0.05 M) was stirred at 50°C for 16 h. MeOH was removed under reduced pressure and the pH of the aqueous residue was adjusted to ~7 with 1.0 M aq. HCl. The mixture was extracted with EtOAc and the combined organic layer was washed with brine and then dried over Na ₂ SO ₄ . The crude product was purified by preparative HPLC (mobile phase: 0.1% NH ₃ -H ₂ O/MeCN/H ₂ O) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=392.3;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.27 (br s, 1H), 8.98 (s, 1H), 8.06 (d, J=6.0 Hz, 1H), 7 .69 (dd, J=8.0, 1.2Hz, 1H), 7.50 (d, J=8.0Hz, 1H), 7.43 (t, J=1.6Hz, 1H) , 7.22 (d, J=8.4 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6 .42 (dd, J=6.0, 2.0 Hz, 1H), 6.07 (d, J=2.0 Hz, 1H), 2.76 (k, J=7.6 Hz, 2H) , 2.46 (s, 3H), 1.44 (s, 6H), 1.26 (t, J=7.6 Hz, 3H).

The following compounds were obtained by the method described in example 81, using the appropriate intermediates.

Example Structure LC-MS (m/z) [M+1] ⁺ W NMR (400 MHz) 82 % X X'-' O XXa Retrieved from intermediate compounds A49 and B27. 406.2 Ή NMR (400 MHz, CD ₃ OD) δ 7.96 (d, 7=6.4 Hz, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.31-7 .21 (m, 2H), 7.04 (d, 7=7.6 Hz, 1H), 6.41 (dd, 7=6.4, 2.0 Hz, 1H), 6.14 (d, 7=2.0 Hz, 1H), 2.82 (c, 7=7.6 Hz, 2H), 2.34 (s, 6H), 1.51 (s, 6H), 1.24 (t, 7=7.6 Hz, ZN). 83 XX Retrieved from intermediate compounds A50 and B27. 426.3 ^1H NMR (400 MHz, CD3OD) δ 8.01 (d, 7=6.0 Hz, 1H), 7.59(s, 1H), 7.41 (s, 1H), 7.32 (d, 7=8.4 Hz, 1H), 7.21 (t, 7=7.6 Hz, 1H), 7.00 (d, 7=7.6 Hz, 1H), 6.38 (dd, 7= 6.0, 2.0 Hz, 1H), 6.17 (d, 7=2.0 Hz, 1H), 2.94 (c, 7=7.6 Hz, 2H), 2.37 (s, ZN), 1.51 (s, 6H), 1.28 (t, 7=7.6 Hz, ZN). 84 ABOUT Λ A, / X^ ΧΧα Retrieved from intermediate compounds A21 and B27. 455.3 Ή NMR (400 MHz, DMSO-76) δ 8.90 (s, 1H), 8.52 (d, 7=4.8 Hz, 1H), 7.96 (d, 7=6.0 Hz, 1H ), 7.88-7.78 (m, 2H), 7.70 (d, 7=8.4 Hz, 1H), 7.64 (d, 7=8.4 Hz, 1H), 7.47 (d, 7=8.4 Hz, 1H), 7.41 (s, 1H), 7.36-7.33 (m, 1H), 7.15 (t, 7=8.0 Hz, 1H) , 6.83 (d, 7=8.0 Hz, 1H), 6.34-6.32 (m, 1H), 6.10 (d, 7=2.4 Hz, 1H), 2.86 ( k, 7=7.6 Hz, 2H), 1.31 (t, 7=7.6 Hz, ZN).

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85 L/ L i - ---0 AH/L Retrieved from intermediate compounds A23 and B27. 469.5 Ή NMR (400 MHz, CD ₃ OD) δ 8.55 (s, 1H), 7.87-7.81 (m, 2H), 7.77 (d, 7=7.6 Hz, 1H), 7 .49 (s, 1H), 7.38-7.31 (m, 2H), 7.20-7.17 (m, 2H), 7.00 (d, 7=4.8 Hz, 1H), 6.27 (d, 7=4.4 Hz, 1H), 6.10 (s, 1H), 2.92 (q, 7=7.2 Hz, 2H), 2.43 (s, 3H), 1.50 (s, 6H), 1.32 (t, 7=7.2 Hz, ZN). 86 L L .ol n /\ Retrieved from intermediate connections AZ 7 and B27. 470.2 Ή NMR (400 MHz, CDCI3) δ 8.24 (s, 1H), 7.83 (d, 7=6.0 Hz, 1H), 7.27-7.21 (m, 4H), 7.08 (d, 7=8.4 Hz, 1H), 7.00-6.90 (m, ZN), 6.77 (d, 7=8.0 Hz, 2H), 6.31 (s, 1H) , 6.18 (dd, 7=6.0, 1.6 Hz, 1H), 3.44 (s, 3H), 2.57 (s, 3H), 1.23 (s, 6H). 87 gg ³ - A OL H /\ Obtained from intermediate compounds AZ 8 and B27. 470.4 Ή NMR (400 MHz, CD3OD) δ 7.88 (d, 7=5.6 Hz, 1H), 7.57 (d, 7=8.4 Hz, 1H), 7.35-7.16 (m , 7H), 7.01-6.98 (m, 1H), 6.92 (ddd, 7=7.2, 2.4, 1.6 Hz, 1H), 6.28 (dd, 7=6 .0, 2.0 Hz, 1H), 6.12 (d, 7=2.0 Hz, 1H), 3.75 (s, ZN), 2.60 (s, ZN), 1.48 (s , 6H). 88 Ύ Retrieved from intermediate connections AZ 9 and B27. 470.4 SH NMR (400 MHz, CD3OD) δ 7.87 (d, 7=6.0 Hz, 1H), 7.68-7.64 (m, 2H), 7.53 (d, 7=8.0 Hz , 1H), 7.32-7.26 (m, 2H), 7.24-7.18 (m, 2H), 7.00-6.97 (m, 1H), 6.95-6.92 (m, 2H), 6.28 (dd, 7=6.0, 2.0 Hz, 1H), 6.11 (d, 7=2.0 Hz, 1H), 3.79 (s, 3H) , 2.58 (s, 3H), 1.49 (s, 6H).

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89 Ά 0.0,!.. Retrieved from intermediate compounds A28 and B27. 458.3 Ή NMR (400 MHz, DMSO-J6) δ 12.26 (s, 1H, CO ₂ H), 9.02 (s, 1H), 7.95 (d, 7=5.6 Hz, 1H), 7 .69 (d, 7=7.6 Hz, 1H), 7.65-7.60 (m, 1H), 7.49-7.439 (m, 4H), 7.27-7.15 (m, ZN ), 6.86 (d, 7=7.2 Hz, 1H), 6.32 (d, 7=4.8 Hz, 1H), 6.14 (d, 7=2.0 Hz, 1H), 2.57 (s, 3H), 1.43 (s, 6H). 90 ^a _F ^: 'O XI1 Prepared from intermediates A29 and B27. 458.3 Ή NMR (400 MHz, CD ₃ OD) δ 8.10 (d, 7=8.4 Hz, 1H), 7.82 (d, 7=7.2 Hz, 1H), 7.73 (d, 7 = 8.4 Hz, 1H), 7.63-7.41 (m, 5H), 7.33-7.26 (m, 2H), 7.19 (d, 7=7.2 Hz, 1H) , 6.77 (dd, 7=7.2, 2.8 Hz, 1H), 6.38 (d, 7=2.4 Hz, 1H), 2.77 (s, 3H). 91 _vV a ^F XX XXl- Obtained from intermediates AZO and B27. 458.4 Ή NMR (400 MHz, CD3OD) δ 7.87 (d, 7=6.0 Hz, 1H), 7.76-7.73 (m, 2H), 7.56 (d, 7=8.4 Hz , 1H), 7.33 (d, 7=8.4 Hz, 1H), 7.24 (s, 1H), 7.19-7.09 (m, 4H), 7.05-7.02 ( m, 1H), 6.26 (dd, 7=6.0, 2.4 Hz, 1H), 6.11 (d, 7=2.0 Hz, 1H), 2.59 (s, 3H), 1.45 (s, 6H). 92 P X Tm =' 0 Retrieved from intermediate connections AZ 4 and B27. 454.3 Ή NMR (400 MHz, CD3OD) δ 7.82 (d, 7=6.0 Hz, 1H), 7.63 (d, 7=8.0 Hz, 1H), 7.41 (d, 7=8 .4 Hz, 1H), 7.31 (s, 1H), 7.25-7.14 (m, 6H), 7.02-6.98 (m, 1H), 6.17 (dd, 7= 6.0, 2.0 Hz, 1H), 6.07 (d, 7=2.0 Hz, 1H), 2.58 (s, ZN), 2.15 (s, ZN), 1.50 ( s, 6H).

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93 Retrieved from intermediate connections AZ 5 and B27. 454.1 Ή NMR (400 MHz, CD ₃ OD) δ 7.78 (d, 7=6.0 Hz, 1H), 7.47 (d, 7=8.4 Hz, 1H), 7.40 (s, 1H ), 7.36 (d, 7=7.6 Hz, 1H), 7.25-7.21 (m, 2H), 7.16 (t, 7=7.6 Hz, 1H), 7.11 -7.07 (m, ZN), 6.92-6.90 (m, 1H), 6.17 (dd, 7=6.0, 2.0 Hz, 1H), 6.01 (d, 7 =2.0 Hz, 1H), 2.50 (s, 3H), 2.24 (s, 3H), 1.39 (s, 6H). 94 .. GT st ό. XXa % -YAy' _OH Prepared from intermediates AZ 6 and B27. 454.1 Ή NMR (400 MHz, CD ₃ OD) δ 7.78 (d, 7=6.0 Hz, 1H), 7.49 (d, 7=8.0 Hz, 2H), 7.45 (d, 7 = 8.4 Hz, 1H), 7.22 (d, 7=8.0 Hz, 1H), 7.21 (s, 1H), 7.12-7.08 (m, 4H), 6.93 -6.89 (m, 1H), 6.17 (dd, 7=6.0, 2.4 Hz, 1H), 6.01 (d, 7=2.0 Hz, 1H), 2.50 ( s, 3H), 2.24 (s, 3H), 1.39 (s, 6H). 95 όΑ Αχχ" Retrieved from intermediate connections AZ 1 and B27. 465.2 Ή NMR (400 MHz, CD ₃ OD) δ 7.78 (d, 7=6.0 Hz, 1H), 7.71 (dd, 7=8.0, 0.8 Hz, 1H), 7.59 (td, J=7.6, 1.2 Hz, 1H), 7.57 (d, 7=8.4 Hz, 1H), 7.51 (dd, 7=7.6, 0.8 Hz, 1H), 7.47 (td, J=7.6, 1.2 Hz, 1H), 7.38 (d, 7=8.4 Hz, 1H), 7.26 (t, 7=2.0 Hz, 1H), 7.18-7.15 (m, 1H), 7.11 (t, 7=7.6 Hz, 1H), 6.92-6.89 (m, 1H), 6.13 (dd, 7=6.0, 2.4 Hz, 1H), 6.07 (d, 7=2.4 Hz, 1H), 2.53 (s, 3N), 1.41 (s, 6H) . 96 ό 6 xx ι Retrieved from intermediate connections AZ 2 and B27. 465.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.02 (s, 1H), 8.00-7.96 (m, 1H), 7.82 (d, 7=6.0 Hz, 1H), 7 .64-7.61 (m, 1H), 7.52-7.46 (m, 2H), 7.31 (d, 7=8.4 Hz, 1H), 7.24 (s, 1H), 7.12-7.09 (m, 2H), 6.94-6.91 (m, 1H), 6.21 (dd, 7=6.0, 2.4 Hz, 1H), 6.03 ( e, 7=2.0 Hz, 1H), 2.53 (s, 3H), 1.39 (s, 6H).

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97 cn Ύjm Retrieved from intermediate connections A3 and B27. 465.1 Ή NMR (400 MHz, CD ₃ OD) ό 7.95 (d, 7=8.4 Hz, 2H), 7.92 (d, 7=6.0 Hz, 1H), 7.77 (d, 7 = 8.4 Hz, 2H), 7.61 (d, 7=8.4 Hz, 1H), 7.41 (d, 7=8.4 Hz, 1H), 7.34 (s, 1H), 7.24-7.20 (m, 2H), 7.03-7.00 (m, 1H), 6.31 (dd, 7=6.0, 2.4 Hz, 1H), 6.15 ( e, 7=2.0 Hz, 1H), 2.63 (s, 3H), 1.50 (s, 6H). 98 xd X-Od Retrieved from intermediate compounds A22 and B27. 454.2 S NMR (400 MHz, CD3OD) δ 7.85 (d, 7=6.0 Hz, 1H), 7.66 (d, 7=6.4 Hz, 2H), 7.44 (s, 1H), 7.38-7.32 (m, ZN), 7.18-7.13 (m, ZN), 7.077.04 (m, 1H), 6.24 (dd, 7=6.0, 2.0 Hz, 1H), 6.10 (d, 7=2.0 Hz, 1H), 2.54 (s, 3H), 2.36 (s, 3H), 1.43 (s, 6H). 99 Ύ Dod Retrieved from intermediate compounds A40 and B27. 474.1 Ή NMR (400 MHz, DMSO-76) δ 8.84(s, 1H), 8.02 (s, 1H), 7.98 (d,7=5.6 Hz, 1H), 7.79-7 .77 (m, 2H), 7.59 (d.7=7.2 Hz, 1H), 7.45-7.38 (m, ZN), 7.26 (s, 1H), 7.05 ( t, 7=8.0 Hz, 1H), 6.87 (d, 7=8.0 Hz, 1H), 6.37 (dd, 7=6.0, 2.0 Hz, 1.5 Hz, 1H), 6.14 (d, 7=2.0 Hz, 1H), 2.63 (s, 3H), 1.29 (s, 6H). 100 Dod Retrieved from intermediate compounds A42 and B27. 468.3 S NMR (400 MHz, CD3OD) δ 7.84 (d, 7=6.0 Hz, 1H), 7.67 (d, 7=6.8 Hz, 2H), 7.44 (s, 1H), 7.39-7.32 (m, ZN), 7.20-7.11 (m, ZN), 7.05 (d, 7=7.2 Hz, 1H), 6.24 (dd, 7= 6.0, 1.6 Hz, 1H), 6.10 (d, 7=1.6 Hz, 1H), 2.73 (c, 7=7.6 Hz, 2H), 2.58 (s, ZN), 1.43 (s, 6H), 1.26 (t, 7=7.6 Hz, ZN).

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101 γΧ Xx/y™ Retrieved from intermediate compounds A41 and B27. 480.1 Ή NMR (400 MHz, CD ₃ OD) δ 7.84 (d, 7=4.8 Hz, 1H), 7.65 (d, 7=6.8 Hz, 2H), 7.38-7.28 (m, 4H), 7.23-7.18 (m, 3H), 7.00 (d, 7=6.4 Hz, 1H), 6.27-6.24 (m, 1H), 6, 06 (s, 1H), 2.69 (s, 3H), 2.05-1.97 (m, 1H), 1.49 (s, 6H), 1.071.02 (m, 2H), 0.70 -0.66 (m, 2H). 102 χχχ XXZ Retrieved from intermediate compounds A43 and B27. 482.2 Ή NMR (400 MHz, CDCI3) δ 9.62 (s, 1H), 7.69 (d, 7=6.4 Hz, 1H), 7.66 (d, 7=7.2 Hz, 2H), 7.32-7.14 (m, 5H), 7.11 (t, 7=8.0 Hz, 1H), 7.02 (d, 7=8.0 Hz, 1H), 6.89 (d , 7=8.0 Hz, 1H), 6.36 (d, 7=2.0 Hz, 1H), 6.13 (dd, 7=6.0, 2.0 Hz, 1H), 3.06 (quin, 7=7.6 Hz, 1H), 2.56 (s, 3N), 1.54 (s, 6H), 1.17 (d, 7=6.8 Hz, 6H) 103 γΧ Retrieved from intermediate compounds A44 and B27. 498.2 Ή NMR (400 MHz, DMSO-76) δ 8.95 (s, 1H), 8.20 (s, 1H), 7.99 (d, 7=6.0 Hz, 1H), 7.81 (d , 7=7.2 Hz, 2H), 7.66-7.63 (m, 2H), 7.44-7.30 (m, 4H), 7.16 (t, 7=8.4 Hz, 1H), 6.84 (d, 7=8.0 Hz, 1H), 6.37 (dd, 7=5.6, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 2H), 2.77 (s, 3H), 1.56 (s, 6H), 1.42 (s, 6H). 104 X.X ^; -' O X-Tsu Prepared from intermediates A45 and B27. 454.1 ΉNMR (400 MHz, CD3OD) δ 7.85 (d, 7=6.0 Hz, 1H), 7.71 (dd, 7=8.0, 1.6 Hz, 2H), 7.58 (d, 7=8.4 Hz, 1H), 7.41-7.33 (m, 4H), 7.22-7.12 (m, ZN), 7.05 (d, 7=7.2 Hz, 1H ), 6.25 (dd, 7=6.0, 2.4 Hz, 1H), 6.11 (d, 7=2.4 Hz, 1H), 2.88 (c, 7=7.6 Hz , 2H), 1.44 (s, 6H), 1.35 (t, 7=7.6 Hz, 3H).

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105 Χχθ '--' O Retrieved from intermediate compounds A48 and B27. 466.3 ΉNMR (400 MHz, CD ₃ OD) δ 7.85 (d, 7=5.6 Hz, 1H), 7.75 (d, 7=6.8 Hz, 2H), 7.47 (d, 7= 8.4 Hz, 1H), 7.36-7.31 (m, ZN), 7.25-7.14 (m, 4H), 7.04 (d, 7=6.4 Hz, 1H), 6.26-6.24 (m, 1H), 6.09 (d, 7=1.6 Hz, 1H), 2.16-2.14 (m, 1H), 1.45 (s, 6H) , 1.04-1.01 (m, 4H). 106 Retrieved from intermediate compounds A47 and B27. 468.4 Ή NMR (400 MHz, CD3OD) δ 7.87 (d, 7=6.0 Hz, 1H), 7.71-7.69 (m, 2H), 7.57 (d, 7=8.0 Hz , 1H), 7.40-7.32 (m, 4H), 7.27 (s, 1H), 7.197.16 (m, 2H), 7.03-7.00 (m, 1H), 6, 26 (dd, 7=6.0, 2.0 Hz, 1H), 6.10 (d, 7=2.0 Hz, 1H), 2.84 (t, 7=7.6 Hz, 2H), 1.81 (sext, J=7.6 Hz, 2H), 1.47 (s, 6H), 1.01 (t, 7=7.6 Hz, ZN). 107 AAE ύ G ^; 'o Prepared from intermediates A46 and B27. 468.4 ^1H NMR (400 MHz, DMSO-76) δ 10.26 (br.s., 1H), 7.96 (d, 7=6.8 Hz, 1H), 7.79 (d, 7=8, 4 Hz, ZN), 7.46-7.41 (m, 4H), 7.38-7.34 (m, 1H), 7.26-7.16 (m, ZN), 6.72-6 .69 (m, 1H), 6.21 (d, 7=2.4 Hz, 1H), 3.15 (sep, 7=6.8 Hz, 1H), 1.43 (s, 6H), 1 .31 (d, 7=6.8 Hz, 6H). 108 Ao x A J DD Retrieved from intermediate compounds A25 and B27. 448.3 Ή NMR (400 MHz, CDCI3) δ 7.89 (d, 7=6.4 Hz, 1H), 7.37 (s, 1H), 7.21-7.11 (m, 4H), 7.03 (d, 7=8.0 Hz, 1H), 6.49 (d, 7=1.6 Hz, 1H), 6.19 (dd, 7=6.4, 2.4 Hz, 1H), 4 .07 (dd, 7=11.2, 3.6 Hz, 2H), 3.46 (t, 7=11.6 Hz, 2H), 3.10-3.02 (m, 1H), 2, 54 (s, 3H), 2.11-1.93 (m, 4H), 1.60 (s, 6H).

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109 Ύ ^τθχν ^ΟΗ Obtained from intermediate compounds Al and B34. 469.3 Ή NMR (400 MHz, DMSO-J6) δ 8.83 (s, 1H), 8.51-8.49 (m, 1H), 7.96 (d, 7=5.6 Hz, 1H), 7 .85-7.76 (m, 2H), 7.58-7.55 (m, 2H), 7.39-7.36 (m, 1H), 7.34-7.30 (m, 1H) , 7.12 (t, 7=8.0 Hz, 1H), 6.87 (d, 7=7.6 Hz, 1H), 6.33 (dd, 7=6.0, 2.0 Hz, 1H), 6.09 (d, 7=2.0 Hz, 1H), 2.52 (s, 3H), 2.51 (s, 2H), 2.35 (s, 3H), 1.32 ( s, 6H). BY ,. η Ύ , = ^: > Ό Obtained from intermediate compounds Ab and B34. 454.3 Ή NMR (400 MHz, DMSO-76) δ 8.87 (s, 1H), 8.31 (s, 1H), 7.99 (d, 7=5.6 Hz, 1H), 7.80-7 .77 (m, 2H), 7.65 (d, 7=8.0 Hz, 1H), 7.56 (dd, 7=8.0, 1.2 Hz, 1H), 7.41-7, 35 (m, 4H), 7.12 (t, 7=8.0 Hz, 1H), 6.88 (d, 7=8.4 Hz, 1H), 6.38 (dd, 7=6.0 , 2.4 Hz, 1H), 6.08 (d, 7=2.4 Hz, 1H), 2.58 (s, 3H), 1.33 (s, 6H), the missing CH2 overlapped with the solvent peak. on V-Xr ⁰ Prepared from intermediates A12 and commercially available methyl-3 aminobenzoate. 421.4 Ή NMR (400 MHz, CD ₃ OD) δ 7.95 (d, 7=6.0 Hz, 1H), 7.81 (s, 1H), 7.63-7.55 (m, 3H), 7 .25 (t, 7=8.0 Hz, 1H), 6.40 (dd, 7=6.0, 2.0 Hz, 1H), 6.28 (d, 7=2.0 Hz, 1H) , 3.95-3.91 (m, 2H), 3.61-3.58 (m, 1H), 3.43 (td, 7=11.6, 2.0 Hz, 2H), 2.84 -2.77 (m, 1H), 1.89-1.69 (m, 4H), 1.14-1.00 (m, 4H). ABOUT . Ο'Ν'ίΧχΠ ⁿ O Obtained from intermediates A12 and 435.2 Ή NMR (400 MHz, CD ₃ OD) δ 7.95 (d, 7=6.0 Hz, 1H), 7.63 (s, 1H), 7.62 (s, 1H), 7.43 (s , 1H), 7.42 (s, 1H), 6.40 (dd, 7=6.0, 2.4 Hz, 1H), 6.28 (d, 7=2.4 Hz, 1H), 3 .95-3.91 (m, 2H), 3.59-3.56 (m, 1H), 3.43 (td, 7=11.6, 2.0 Hz, 2H), 2.82-2 .78 (m, 1H), 2.33 (s, 3H),

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commercially available methyl-3 amino-5-methyl benzoate. 1.85-1.80 (m, 2H), 1.72-1.69 (m, 2H), 1.061.00 (m, 4H). Retrieved from intermediate compounds A12 and B40. 463.5 Ή NMR (400 MHz, DMSO-J6) δ 8.89 (s, 1H), 7.99 (d, 7=6.0 Hz, 1H), 7.84 (s, 1H), 7.47 (d , 7=8.8 Hz, 2H), 7.22 (d, 7=8.8 Hz, 2H), 6.40-6.38 (m, 1H), 6.23 (d, 7=2, 4 Hz, 1H), 3.83-3.80 (m, 2H), 3.66-3.63 (m, 1H), 3.33-3.28 (m, 2H), 2.73-2 .67 (m, 1H), 1.671.63 (m, 4H), 1.37 (s, 6H), 1.04-0.93 (m, 4H). 'Ό 0.0 _g Prepared from intermediates A12 and commercially available methyl 3 amino-6 methyl benzoate. 435.4 Ή NMR (400 MHz, DMSO-76) δ 8.90 (s, 1H), 8.00 (d, 7=6.0 Hz, 1H), 7.83 (s, 1H), 7.76 (s , 1H), 7.58 (d, 7=7.6 Hz, 1H), 6.98 (d, 7=8.4 Hz, 1H), 6.38 (dd, 7=6.0, 2, 0 Hz, 1H), 6.23 (d, 7=2.0 Hz, 1H), 3.83-3.80 (m, 2H), 3.67-3.63 (m, 1H), 3, 33-3.27 (m, 2H), 2.732.69 (m, 1H), 2.37 (s, ZN), 1.66-1.62 (m, 4H), 1.02-0.92 ( m, 4H). 115 X 7X1 H Retrieved from intermediate compounds A12 and B38. 449.3 Ή NMR (400 MHz, DMSO-76) δ 8.73 (s, 1H), 7.97 (d, 7=5.6 Hz, 1H), 7.84 (s, 1H), 7.36 (dd , 7=8.0, 2.0 Hz, 1H), 7.14 (d, 7=2.4 Hz, 1H), 6.87 (d, 7=8.0 Hz, 1H), 6.34 (dd, 7=5.6, 2.4 Hz, 1H), 6.23 (d, 7=2.4 Hz, 1H), 3.85-3.79 (m, 2H), 3.68- 3.62 (m, 1H), 3.313.21 (m, 2H), 3.07 (s, 2H), 2.71-2.70 (m, 1H), 2.14 (s, 3H), 1 .69-1.61 (m, 4H), 1.04-0.91 (m, 4H).

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'ό Ha ™ Retrieved from Al 2 intermediates; and commercially available methyl 4-aminopicolinate. 422.1 Ή NMR (400 MHz, CD ₃ OD) δ 8.24 (d, 7=6.4 Hz, 1H), 8.19 (d, 7=5.6 Hz, 1H), 8.06 (s, 2H ), 7.67 (s, 1H), 6.65 (dd, 7=6.0, 2.0 Hz, 1H), 6.45 (d, 7=1.6 Hz, 1H), 3.94 -3.91 (m, 2H), 3.62-3.58 (m, 1H), 3.43 (td, 7=12.0, 2.0 Hz, 2H), 2.84-2.78 (m, 1H), 1.89-1.78 (m, 2H), 1.74-1.70 (m, 2H), 1.11-1.00 (m, 4H). 118 oA XjOa Retrieved from intermediate compounds A63 and B27. 477.3 Ή NMR (400 MHz, CD ₃ OD) δ 7.95 (d, 7=5.6 Hz, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 7.30 (d , 7=8.0 Hz, 1H), 7.21 (t, 7=8.0 Hz, 1H), 7.00 (d, 7=7.6 Hz, 1H), 6.43 (dd, 7 =6.0, 2.4 Hz, 1H), 6.30 (d, 7=2.4 Hz, 1H), 4.73 (quin, J=8.4 Hz, 1H), 3.96-3 .92 (m, 2H), 3.44 (td, 7=12.0, 2.0 Hz, 2H), 2.83-2.81 (m, 1H), 2.532.42 (m, 4H), 1.90-1.80 (m, 4H), 1.74-1.69 (m, 2H), 1.51 (s, 6H). 119 mX XX A Retrieved from intermediate compounds A51 and B27. 455.2 Ή NMR (400 MHz, DMSO-76) δ 12.26 (b.s., 1H), 9.08 (br.s., 1H), 8.10 (s, 1H), 8.03 (d, 7=6.0 Hz, 1H), 7.70 (d, 7=7.2 Hz, 2H), 7.64 (d, 7=7.6 Hz, 1H), 7.42 (s, 1H) , 7.37 (t, 7=7.6 Hz, 2H), 7.28 (t, 7=7.6 Hz, 1H), 6.87 (d, 7=7.6 Hz, 1H), 6 .36 (dd, 7=6.0, 2.0 Hz, 1H), 6.23 (d, 7=2.0 Hz, 1H), 3.85-3.78 (m, 1H), 1, 48 (s, 6H), 1.18-1.13 (m, 2H), 1.081.00 (m, 2H). 120 ABOUT -ν Ί χιχ Retrieved from intermediate 429.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.21 (br.s., 1H, HCO2H), 7.92 (d, 7=6.0 Hz, 1H), 7.727.68 (m, 3H), 7.37-7.30 (m, ZN), 7.28-7.24 (m, 1H), 7.21 (t, 7=7.6 Hz, 1H), 7.16 (d, 7= 8.4 Hz, 1H), 7.01 (d, 7=7.6 Hz, 1H), 6.49 (dd,

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compounds A57 and B27. 7=6.0, 2.4 Hz, 1H), 6.36 (d, 7=2.0 Hz, 1H), 3.92 (s, 3H), 1.50 (s, 6H). 121 Oh F^'Oh Retrieved from intermediate compounds A64 and B27. 465.2 Ή NMR (400 MHz, DMSO-76) δ 8.92 (s, 1H), 8.84 (s, 1H), 8.23 (t, 7=59.2 Hz, 1H), 8.04 (d , 7=6.0 Hz, 1H), 7.77 (d, 7=7.2 Hz, 2H), 7.44 (t, 7=7.2 Hz, 2H), 7.40-7.32 (m, ZH), 7.04 (t, 7=7.6 Hz, 1H), 6.89 (d, 7=8.0 Hz, 1H), 6.52 (dd, 7=6.0, 2.0 Hz, 1H), 6.40 (d, 7=2.0 Hz, 1H), 1.29 (s, 6H). 122 O \ X _y -Oa-o " Obtained from intermediates A58 and B27. 443.2 Ή NMR (400 MHz, CD ₃ OD) δ 7.92 (s, 1H), 7.73 (s, 1H), 7.71 (dd, 7=7.2, 1.2 Hz, 2H), 7 .36-7.30 (m, ZN), 7.28 (t, 7=7.2 Hz, 1H), 7.20-7.18 (m, 2H), 7.02-6.99 (m , 1H), 6.47 (d, 7=4.0 Hz, 1H), 6.35 (s, 1H), 4.20 (q, 7=7.2 Hz, 2H), 1.57-1 .43 (m, 9H). 123 ABOUT Retrieved from intermediate compounds A59 and B27. 479.1 Ή NMR (400 MHz, CD3OD) δ 7.93 (b.s., 1H), 7.80 (s, 1H), 7.74 (d, 7=7.2 Hz, 2H), 7.35- 7.26 (m, 4H), 7.20-7.18 (m, 2H), 7.0Ιό.99 (m, 1H), 6.47-6.45 (m, 1H), 6.35 ( s, 1H), 6.25 (tt, 7=55.2, 4.0 Hz, 1H), 4.57 (dt, 7=14.0, 4.0 Hz, 2H), 1.50 (s , 6H). 124 Oh bd, Retrieved from intermediate compounds A60 and B27. 457.2 Ή NMR (400 MHz, DMSO-76) δ 8.97(s, 1H), 8.05(s, 1H), 8.02(d,7=5.6Hz, 1H), 7.71(d , 7=8.4 Hz, 2H), 7.65 (d, 7=8.0 Hz, 1H), 7.40 (s, 1H), 7.36 (t, 7=7.6 Hz, 2H ), 7.26 (t, 7=7.6 Hz, 1H), 7.14 (t, 7=7.6 Hz, 1H), 6.86 (d, 7=7.6 Hz, 1H), 6.50 (dd, 7=6.0, 2.0 Hz, 1H), 6.30 (d, 7=2.0 Hz, 1H), 4.52 (sep, 7=6.8 Hz, 1H ), 1.49 (d, 7=6.8 Hz, 6H), 1.42 (s, 6H).

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125 ΧΟγοΗ Retrieved from intermediate compounds A56 and B27. 469.3 Ή NMR (400 MHz, CD ₃ OD) δ 7.92 (d, 7=5.6 Hz, 1H), 7.82 (s, 1H), 7.72 (d, 7=7.2 Hz, 2H ), 7.35-7.26 (m, 4H), 7.19 (d, 7=4.8 Hz, 2H), 7.01-6.98 (m, 1H), 6.47 (dd, 7=6.0, 2.0 Hz, 1H), 6.33 (d, 7=2.4 Hz, 1H), 4.86-4.80 (m, 1H), 2.63-2.48 (m, 4H), 1.94-1.87 (m, 2H), 1.50 (s, 6H). 126 oA—hi Ύ XXa n /\ Retrieved from intermediate compounds A61 and B27. 471.2 Ή NMR (400 MHz, CD3OD) δ 7.94 (d, 7=6.0 Hz, 1H), 7.89 (s, 1H), 7.80-7.77 (m, 2H), 7.37 -7.25(m, 4H), 7.19-7.10(m, 2H), 7.006.97(m, 1H), 6.48(dd, 7=6.0, 2.4Hz, 1H ), 6.34 (d, 7=2.0 Hz, 1H), 5.57-5.51 (m, 1H), 5.12 (t, 7=6.4 Hz, 2H), 5.06 (t, 7=7.2 Hz, 2H), 1.49 (s, 6H). 127 ^ ^N X. o Xχχ Prepared from intermediates A52 and B27. 461.4 ^{X H} NMR (400 MHz, CD3OD) δ 7.94 (d, 7=5.2 Hz, 1H), 7.56 (s, 1H), 7.37 (s, 1H), 7.30-7, 19 (m, 2H), 7.02 (d, 7=8.0 Hz, 1H), 6.41 (d, 7=4.8 Hz, 1H), 6.28 (s, 1H), 3. 56-3.53 (m, 1H), 2.53-2.51 (m, 1H), 1.79-1.65 (m, 4H), 1.52-1.44 (m, 8H), 1.30-1.187 (m, 4H), 1.040.97 (m, 4H). 128 ^ ^N X _O XXL Prepared from intermediates A53 and B27. 447.6 Ή NMR (400 MHz, CD3OD) δ 7.85 (dd, 7=7.2, 2.8 Hz, 1H), 7.80 (s, 1H), 7.49 (t, 7=8.0 Hz , 1H), 7.45-7.42 (m, 1H), 7.32 (s, 1H), 7.23 (d, 7=7.6 Hz, 1H), 6.81 (dd, 7= 7.2, 2.4 Hz, 1H), 6.46 (d, 7=2.4 Hz, 1H), 3.65-3.60 (m, 1H), 2.96-2.91 (m , 1H), 1.97-1.93 (m, 2H), 1.75-1.56 (m, 6H), 1.56 (s, 6H), 1.14-1.00 (m, 4H ). 129 L A XX Ϊ VV^i CH n /\ Retrieved from intermediate compounds A54 and B27. 433.3 Ή NMR (400 MHz, CD3OD) δ 7.93 (d, 7=6.0 Hz, 1H), 7.58 (s, 1H), 7.39-7.36 (m, 1H), 7.29 -7.24 (m, 1H), 7.22 (t, 7=7.6 Hz, 1H), 7.02 (d, 7=7.6 Hz, 1H), 6.40 (dd, 7= 6.0.2.0 Hz, 1H), 6.26 (d, 7=2.0 Hz, 1H), 3.58-3.56 (m, 1H), 3.41-3.31 (m , 1H), 2.31-1.82 (m, 6H), 1.52 (s, 6H), 1.07-1.00 (m, 4H). 130 X Χχχ Retrieved from intermediate compounds A55 and B27. 456.1 Ή NMR (400 MHz, CD ₃ OD) δ 8.69-8.67 (m, 1H), 7.90-7.85 (m, 2H), 7.59 (d, 7=8.0 Hz, 1H), 7.48 (s, 1H), 7.39 (ddd, 7=7.6, 4.8, 1.2 Hz, 1H), 7.35 (s, 1H), 7.24-7 .21 (m, 2H), 7.01 (d, 7=7.2 Hz, 1H), 6.40 (dd, 7=6.0, 2.4 Hz, 1H), 6.31 (d, 7=2.0 Hz, 1H), 4.10-4.07 (m, 1H), 1.51 (s, 6H), 1.03-0.90 (m, 4H).

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Example 131:

yl)amino)phenyl)acetic acid

2,2-difluoro-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridine-2-

Mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (Intermediate A6, 1.0 eq.), methyl-2-(3-aminophenyl)-2,2-difluoroacetate (intermediate B41, 2.2 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthos (0.10 eq.), Pd(OAc) ₂ (0.10 eq.) in dioxane (0, 23 M) was stirred at 110°C for 16 h in an argon atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (mobile phase: 0.1% HCOOH/CH3CN//H2O to give the title compound as a solid. LC-MS (m/z): [M+H]+=448.2;

¹ H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.24 (s, 0.4H, HCO2H), 8.03 (d, J=5.6 Hz, 1H), 7.82-7.76 (m, 4H), 7.67 (d, J=8.4 Hz, 1H), 7.43-7.28 (m, 5H), 7.02 (d, J= 7.6 Hz, 1H), 6.44 (dd, J=6.0, 2.0 Hz, 1H), 6.11 (d, J=2.0 Hz, 1H), 2.59 (s, 3H).

Example 132 2-(3-((4-((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)phenyl)2,2-difluoroacetic acid

This compound was prepared by the method described in Example 131 using Intermediate A51 and Intermediate B41. LC-MS (m/z): [M+H]+=463.2;

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (s, 1H), 8.09 (s, 1H), 8.05 (d, J=5.6 Hz, 1H), 7.78 ( d, J=8.8 Hz, 1H), 7.71-7.68 (m, 3H), 7.36 (t, J=7.6 Hz, 2H), 7.29-7.23 (m , 2H), 6.99 (d, J=7.6 Hz, 1H), 6.53 (dd, J=5.6, 2.4 Hz, 1H), 6.32 (d, J=2, 4 Hz, 1H), 3.84-3.77 (m, 1H), 1.17-1.13 (m, 2H), 1.04-1.00 (m, 2H).

Example 133 3-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2dimethylpropionic acid

Step 1: 3-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2dimethylpropanenitrile.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine (intermediate A16, 1.0 eq.), 3-(3-aminophenyl)-2,2-dimethylpropanenitrile (intermediate compounds B31, 1.1 eq.), Pd(OAc) ₂ (0.1 eq.), xanthos (0.1 eq.) and Cs ₂ CO ₃ (2.0 eq.) in dioxane (0.1 M ) was stirred at 110°C for 16 h under argon. The mixture was cooled to RT and diluted with DCM/H2O. The organic layer was separated and dried over Na ₂ SO ₄ . The crude product was purified by preparative TLC (petroleum ether/EtOAc=2:1) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=387.4.

Step 2: 3-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2dimethylpropionic acid.

A mixture of 3-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2dimethylpropanenitrile (1.0 eq.) in conc. HCl (0.04 M) was stirred at 115° C. for 16 h. The mixture was concentrated and the residue was purified by preparative HPLC (mobile phase: 0.1% HCOOH/MeCN/H ₂ O) to give the title compound as a white solid . LC-MS (m/z): [M+H]+=406.3;

1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=6.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.26-7.22 (m , 2H), 7.177.13 (m, 2H), 6.81 (d, J=7.2 Hz, 1H), 6.36 (dd, J=6.0, 2.4 Hz, 1H), 6 .11 (d, J=2.0 Hz, 1H), 2.81 (s, 2H), 2.80 (c, J=7.6 Hz, 2H), 2.38 (s, 3H), 1 .29 (d, J=7.6 Hz, 3H), 1.14 (s, 6H).

The following compounds were obtained by the method described in example 133, using the appropriate intermediates.

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Example Structure LC-MS (m/z) [M+1] ⁺ W NMR (400 MHz) 134 A Yes Retrieved from intermediate compounds A1 and B37. 469.2 Ή NMR (400 MHz, DMSO-J6) δ 8.58 (d, 7=4.8 Hz, 1H), 7.87-7.83 (m, 2H), 7.75 (d, 7=8, 0 Hz, 1H), 7.51 (s, 1H), 7.38 (dd, 7=6.8, 5.6 Hz, 1H), 7.07 (s, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 6.27 (dd, 7=5.6, 1.6 Hz, 1H), 6.11 (s, 1H), 2.57 (s, 3N), 2.40 (s, 3N), 2.27 (s, 3N), 1.47 (s, 6H). 135 A, J XI' = 0 । XxXa ⁿ j Prepared from intermediates A1 and B32. 483.3 Ή NMR (400 MHz, DMSO-76) δ 8.58 (d, 7=4.4 Hz, 1H), 7.87-7.82 (m, 2H), 7.75 (d, 7=7, 6 Hz, 1H), 7.51 (s, 1H), 7.40-7.35 (m, 1H), 6.99 (s, 1H), 6.88 (s, 1H), 6.63 ( s, 1H), 6.25 (dd, 7=6.0, 2.4 Hz, 1H), 6.10 (d, 7=2.0 Hz, 1H), 2.75 (s, 2H), 2.58 (s, 3N), 2.40 (s, 3N), 2.24 (s, 3N), 1.12 (s, 6H). 136 | X a . A< J ¹ XX XXX Prepared from intermediates A1 and B39. 469.5 Ή NMR (400 MHz, MeOD-d4) δ 8.57 (d, 7=3.6 Hz, 1H), 7.87-7.81 (m, 2H), 7.76-7.74 (m, 1H), 7.52 (s, 1H), 7.39-7.36 (m, 1H), 7.28 (s, 1H), 7.10-7.02 (m, 2H), 6.28 (d, 7=6.0 Hz, 1H), 6.11 (s, 1H), 2.57 (s, ZN), 2.40 (s, ZN), 2.23 (s, ZN), 1 .48 (s, 6H). 137 ϊΧ ^ν,ΑΑΙ X Г сХхх>А ^it Obtained from intermediate compounds A1 and B31. 469.3 Ή NMR (400 MHz, DMSO-76) δ 8.82 (s, 1H), 8.50 (d, 7=4.0 Hz, 1H), 7.95 (d, 7=6.0 Hz, 1H ), 7.85 (td, 7=8.0, 1.2 Hz, 1H), 7.78 (d, 7=8.0 Hz, 1H), 7.56 (s, 1H), 7.51 (d, 7=8.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.28 (s, 1H), 7.09 (t, 7=7.6 Hz, 1H) , 6.64 (d, 7=7.2 Hz, 1H), 6.33 (dd, 7=5.6, 2.0 Hz, 1H), 6.09 (d, 7=2.4 Hz, 1H), 2.67 (s, 2H), 2.53 (s, 3H), 2.33 (s, 3H), 1.06 (s, 6H).

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138 -q Retrieved from intermediate compounds A21 and B2. 441.3 Ή NMR (400 MHz, CD ₃ OD) δ 8.58-8.57 (m, 1H), 7.90-7.84 (m, 2H), 7.79 (d, 7=7.6 Hz, 1H), 7.67 (d, 7=8.4 Hz, 1H), 7.48 (d, 7=8.4 Hz, 1H), 7.41-7.38 (m, 1H), 7, 18-7.14 (m, ZN), 6.86-6.83 (m, 1H), 6.29 (dd, 7=6.0, 2.0 Hz, 1H), 6.11 (d, 7=2.4 Hz, 1H), 2.93 (c, 7=7.6 Hz, 2H), 2.85 (t, 7=7.6 Hz, 2H), 2.56 (t, 7= 7.6 Hz, 2H), 1.36 (t, 7=7.6 Hz, ZN). 139 NX) Ut Retrieved from intermediate compounds A23 and B2. 455.4 Ή NMR (400 MHz, CD3OD) δ 8.56 (d, 7=4.0 Hz, 1H), 8.34 (s, 1H, HCO2H), 7.89-7.80 (m, 2H), 7 .79 (d, 7=8.0 Hz, 1H), 7.51 (s, 1H), 7.37 (ddd, 7=7.2, 4.8, 1.2 Hz, 1H), 7, 19-7.11 (m, ZN), 6.86-6.82 (m, 1H), 6.27 (dd, 7=6.0, 2.0 Hz, 1H), 6.09 (d, 7=2.0 Hz, 1H), 2.93 (c, 7=7.6 Hz, 2H), 2.84 (t, 7=7.6 Hz, 2H), 2.55 (t, 7= 7.6 Hz, 2H), 2.43 (s, ZN), 1.32 (t, 7=7.6 Hz, ZN). 140 η .1 - about Retrieved from intermediate connections Ab and VZ 1. 454.3 Ή NMR (400 MHz, CDCI3) δ 13.63 (br.s., 1H), 10.29 (s, 1H), 8.59 (s, 1H), 7.75-7.40 (m, 7H ), 7.09-7.00 (m, 2H), 6.92 (m, 1H), 6.47 (m, 1H), 6.17 (s, 1H), 3.07 (s, 3H) , 2.73 (s, 2H), 1.20 (s, 6H). 141 X"A) Ύ H ⁿ S Obtained from intermediates Ab and B32. 468.2 Ή NMR (400 MHz, DMSO-76) δ 7.85 (d, 7=6.0 Hz, 1H), 7.70-7.67 (m, 2H), 7.56 (d, 7=8, 0 Hz, 1H), 7.39-7.33 (m, 4H), 6.98 (s, 1H), 6.87 (s, 1H), 6.64 (s, 1H), 6.27 ( dd, J=6.0, 2.0 Hz, 1H), 6.08 (d,7=2.0 Hz, 1H), 2.75 (s, 2H), 2.60 (s, ZN), 2.24(s, 3H), 1.12(s, 6H).

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142 ύΆ Α Αχ Retrieved from intermediate compounds Ab and B37. 454.3 Ή NMR (400 MHz, DMSO-J6) δ 8.85(s, 1H), 7.99 (d, 7=5.6 Hz, 1H), 7.79-7.76 (m, 2H), 7 .65 (d, 7=8.4 Hz, 1H), 7.43-7.35 (m, 5H), 7.17 (s, 1H), 6.66 (s, 1H), 6.38 ( dd, 7=6.0, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 2.58 (s, ZN), 2.23 (s, ZN), 1.39 (s, 6H). 143 A ⁰ ' A Ad ⁴ _Ν -γ·^ Obtained from intermediates A24 and B37. 476.3 Ή NMR (400 MHz, DMSO-76) δ 8.90 (s, 1H), 8.06 (d, 7=5.6 Hz, 1H), 7.50 (s, 1H), 7.35 (s , 1H), 7.20 (s, 1H), 6.66 (s, 1H), 6.44 (dd, 7=6.0, 2.4 Hz, 1H), 6.06 (d, 7= 2.4 Hz, 1H), 3.69-3.66 (m, 2H), 3.34-3.28 (m, 2H), 3.002.98 (m, 1H), 2.45 (s, ZN ), 2.23 (s, 6H), 1.891.85 (m, 2H), 1.50-1.47 (m, 2H), 1.42 (s, 6H). 144 A AI Retrieved from intermediates A16 and B37. 406.3 Ή NMR (400 MHz, CD ₃ OD) δ 7.98 (d, 7=5.6 Hz, 1H), 7.46 (d, 7=8.4 Hz, 1H), 7.23 (d, 7 = 8.4 Hz, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 6.84 (s, 1H), 6.37 (dd, 7=6.0, 2, 4 Hz, 1H), 6.12 (d, 7=1.6 Hz, 1H), 2.80 (c, 7=7.6 Hz, 2H), 2.38 (s, ZN), 2.27 (s, ZN), 1.47 (s, 6H), 1.29 (d, 7=7.6 Hz, ZN). 145 A .. t X ^- 0 I Χ _ν ααα ^{η n} o Prepared from intermediates A16 and B32. 420.3 Ή NMR (400 MHz, CD3OD) δ 8.26 (d, 7=8.4 Hz, 1H), 7.93 (d, 7=7.2 Hz, 1H), 7.79 (d, 7=8 .8 Hz, 1H), 7.05 (s, 2H), 6.92 (s, 1H), 6.85 (dd, 7=7.2, 2.4 Hz, 1H), 6.47 (d , 7=2.4 Hz, 1H), 3.05 (c, 7=7.6 Hz, 2H), 2.85 (s, 2H), 2.65 (s, ZN), 2.36 (s , ZN), 1.42 (t, 7=7.6 Hz, ZN), 1.15 (s, 6H). 146 A X ——Ό 378.2 Ή NMR (400 MHz, CD3OD) δ 7.98 (d, 7=6.0 Hz, 1H), 7.47 (d, 7=8.0 Hz, 1H), 7.25-7.20 (m , ZN), 7.16 (t, 7=7.6 Hz, 1H), 6.85 (d, 7=7.2 Hz, 1H), 6.37 (dd, 7=5.6, 2, 4 Hz, 1H), 6.12 (d, 7=2.4 Hz, 1H), 2.86 (t, 7=7.6 Hz, 2H), 2.81

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Retrieved from intermediate compounds A16 and B2. (c, 7=7.6 Hz, 2H), 2.57 (t, 7=7.6 Hz, 2H), 2.38 (s, ZN), 1.29 (t, 7=7.6 Hz ,ZN). 147 l.-hk ΐ X ₀ ^H O Obtained from intermediates A16 and B23. 392.2 Ή NMR (400 MHz, DMSO-76) δ 8.85 (s, 1H), 8.06 (d, 7=6.0 Hz, 1H), 7.52 (d, 7=8.4 Hz, 1H ), 7.28 (s, 1H), 7.26 (d, 7=10.4 Hz, 1H), 7.17 (s, 1H), 6.55 (s, 1H), 6.41 (dd , 7=6.0, 1.6 Hz, 1H), 6.05 (d, 7=1.6 Hz, 1H), 2.79-2.68 (m, 4H), 2.45 (t, 7=7.6 Hz, 2H), 2.30 (s, ZN), 2.20 (s, ZN), 1.25 (t, 7=7.6 Hz, ZN). 148 'A Hell Retrieved from intermediates A49 and B37. 420.3 Ή NMR (400 MHz, CD ₃ OD) δ 7.95 (d, 7=6.0 Hz, 1H), 7.34 (s, 1H), 7.13 (s, 1H), 7.08 (s , 1H), 6.88 (s, 1H), 6.43 (dd, 7=6.0, 2.4 Hz, 1H), 6.13 (d, 7=2.4 Hz, 1H), 2 .82 (c, 7=7.6 Hz, 2H), 2.34 (s, 6H), 2.29 (s, 3H), 1.49 (s, 6H), 1.24 (t, 7= 7.6 Hz, ZN). 149 A A Retrieved from intermediates A49 and B2. 392.2 Ή NMR (400 MHz, CD3OD) δ 7.97 (d, 7=6.0 Hz, 1H), 7.32 (s, 1H), 7.25-7.20 (m, 2H), 7.16 (t, 7=7.6 Hz, 1H), 6.85 (d, 7=7.2 Hz, 1H), 6.37 (dd, 7=6.0, 2.0 Hz, 1H), 6 .10 (d, 7=2.0 Hz, 1H), 2.88-2.76 (m, 4H), 2.57 (t, 7=7.6 Hz, 2H), 2.34 (s, ZN), 2.33 (s, ZN), 1.24 (t, 7=7.6 Hz, ZN). 150 A A ΧΑ-γ® ⁿ O Prepared from intermediates A49 and B23. 406.2 Ή NMR (400 MHz, CD3OD) δ 7.96(d, 7=6.0 Hz, 1H), 7.32(s, 1H), 7.02(s, 1H), 7.01(s, 1H ), 6.68 (s, 1H), 6.37 (dd, 7=6.0, 2.0 Hz, 1H), 6.09 (d, 7=2.0 Hz, 1H), 2.85 -2.78 (m, 4H), 2.54 (t, 7=7.6 Hz, 2H), 2.34 (s, ZN), 2.33 (s, ZN), 2.25 (s, ZN), 1.24 (t, 7=7.6 Hz, ZN). 151 A. A O 420.3 Ή NMR (400 MHz, CD3OD) δ 7.97 (d, 7=4.8 Hz, 1H), 7.31 (s, 1H), 7.25 (d, 7=8.0 Hz, 1H), 7.17 (s, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.81 (d, 7=7.6 Hz, 1H), 6.35-6.33 (m , 1H), 6.10 (s,

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Retrieved from intermediate compounds A49 and B31. 1H), 2.85-2.78 (m, 4H), 2.34 (s, ZN), 2.33 (s, ZN), 1.24 (t, 7=7.6 Hz, ZN), 1.13 (s, 6H). 152 χ X ΧΧτχ Retrieved from intermediates A49 and B32. 434.2 Ή NMR (400 MHz, CD3OD) δ 7.95 (d, 7=6.0 Hz, 1H), 7.31 (s, 1H), 7.05 (s, 1H), 6.94 (s, 1H ), 6.63 (s, 1H), 6.34 (dd, 7=6.0, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 2.81 (c, 7=7.6 Hz, 2H), 2.76 (s, 2H), 2.34 (s, ZN), 2.33 (s, ZN), 2.24 (s, ZN), 1 .24 (t, 7=7.6 Hz, ZN), 1.13 (s, 6H). 153 t χ CI' +’ O । 0.sh Retrieved from intermediates A50 and B37. 440.1 Ή NMR (400 MHz, CD3OD) δ 7.95(d, 7=6.4 Hz, 1H), 7.65(s, 1H), 7.15(s, 1H), 7.10(s, 1H ), 6.96 (s, 1H), 6.52 (dd, J=6.4, 2.0 Hz, 1H), 6.18 (d, 7=2.4 Hz, 1H), 2.95 (c, 7=7.6 Hz, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 1.50 (s, 6H), 1.28 (t, 7=7, 6 Hz, ZN). 154 n - + .x XX Cl· '^ Xx _r ⁿ o Prepared from intermediates A50 and B2. 412.1 Ή NMR (400 MHz, CD3OD) δ 8.00 (d, 7=5.6 Hz, 1H), 7.60 (s, 1H), 7.28-7.23 (m, 2H), 7.17 (t, 7=7.6 Hz, 1H), 6.85 (d, 7=7.2 Hz, 1H), 6.38 (dd, 7=5.6, 2.0 Hz, 1H), 6 .15 (d, 7=2.0 Hz, 1H), 2.94 (c, 7=7.6 Hz, 2H), 2.86 (t, 7=8.0 Hz, 2H), 2.58 (t, 7=7.6 Hz, 2H), 2.37 (s, ZN), 1.28 (t, 7=7.6 Hz, ZN). 155 .l Ύ £ sg+ o Χπ£1χοΗ Retrieved from intermediate compounds A50 and VZ 1. 440.1 Ή NMR (400 MHz, CD3OD) δ 7.99 (d, 7=6.0 Hz, 1H), 7.59 (s, 1H), 7.27 (d, 7=8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (t, 7=8.0 Hz, 1H), 6.81 (d, 7=7.6 Hz, 1H), 6.37 (dd, 7=6 .0, 2.4 Hz, 1H), 6.14 (d, 7=2.0 Hz, 1H), 2.94 (c, 7=7.6 Hz, 2H), 2.81 (s, 2H ), 2.37 (s, 3H), 1.28 (t, 7=7.6 Hz, 3H), 1.14 (s, 6H). 156 t ... X £ Cl -- +---0 Χ-Οχ-ΟΗ ^H O 454.1 Ή NMR (400 MHz, CD3OD) δ 7.87 (d, 7=6.8 Hz, 1H), 7.74 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H ), 6.90 (s, 1H), 6.71 (dd, 7=6.8, 2.4 Hz, 1H), 6.19 (d, 7=2.4 Hz, 1H), 2.96 (k, 7=7.6

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Retrieved from intermediates A50 and B32. Hz, 2H), 2.84 (s, 2H), 2.39 (s, ZN), 2.33 (s, ZN), 1.29 (t, 7=7.6 Hz, ZN), 1, 15 (s, 6H). 157 X Г С|- ^; -a I 0. ώ I T ^L X''y%n Obtained from intermediates A26 and B37. 426.1 Ή NMR (400 MHz, CD ₃ OD) δ 7.89 (d, 7=6.8 Hz, 1H), 7.74 (s, 1H), 7.12-7.07 (m, 3H), 6 .68 (dd, 7=6.8, 2.4 Hz, 1H), 6.23 (d, 7=2.4 Hz, 1H), 2.60 (s, 3N), 2.37 (s, 3H), 2.35 (s, 3H), 1.51 (s, 6H). 158 XV CI - Α- 'Ό ⁿ o Prepared from intermediates A26 and B32. 440.2 Ή NMR (400 MHz, CD3OD) δ 8.14(s, 1H), 7.89 (d, 7=6.0 Hz, 1H), 7.06 (s, 2H), 6.91 (s, 1H ), 6.83-6.80 (m, 1H), 6.37 (s, 1H), 2.86 (s, 2H), 2.70 (s, 3H), 2.50 (s, 3H) , 2.36 (s, 3H), 1.15 (s, 6H). 116 G-.1, XXd Retrieved from intermediates A12 and B39. 477.3 Ή NMR (400 MHz, CD3OD) δ 7.92 (d, 7=5.6 Hz, 1H), 7.61 (s, 1H), 7.28 (d, 7=8.4 Hz, 1H), 7.17 (d, 7=8.4 Hz, 1H), 7.13 (s, 1H), 6.41 (d, 7=6.0 Hz, 1H), 6.28 (s, 1H), 3.94-3.91 (m, 2H), 3.59-3.55 (m, 1H), 3.47-3.37 (m, 2H), 2.82-2.78 (m, 1H ), 2.25 (s, 3H), 1.84-1.78 (m, 2H), 1.71-1.68 (m, 2H), 1.53 (s, 6H), 1.050.98 ( m, 4H). 159 X ό^XXγ ^0Η Η L 11 Prepared from intermediates A12 and B35. 477.3 Ή NMR (400 MHz, DMSO-76) δ 8.39 (br.s., 1H, HCO2H), 7.94 (d, 7=5.2 Hz, 1H), 7.61 (s, 1H), 7.36 (s, 1H), 7.32-7.30 (m, 1H), 7.227.20 (m, 2H), 7.07-7.04 (m, 1H), 6.42 (dd, 7=6.0, 2.0 Hz, 1H), 6.31 (d, 7=2.0 Hz, 1H), 3.95-3.91 (m, 2H), 3.60-3.56 (m, 1H), 3.43 (td, 7=12.0, 2.0 Hz, 2H), 2.83-2.75 (m, 1H), 2.59 (s, 2H), 1, 87-1.77 (m, 2H), 1.72-1.67 (m, 2H), 1.42 (s, 6H), 1.08-1.00 (m, 4H).

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160 JO O'mRAD'™ Retrieved from intermediate compounds A12 and B31. 477.4 Ή NMR (400 MHz, DMSO-J6) δ 7.93 (d, 7=6.0 Hz, 1H), 7.61 (s, 1H), 7.24 (d, 7=8.4 Hz, 1H ), 7.19-7.14 (m, 2H), 6.84 (d, 7=7.6 Hz, 1H), 6.42 (dd, 7=6.0, 2.0 Hz, 1H) , 6.27 (d, 7=1.6 Hz, 1H), 3.96-3.91 (m, 2H), 3.60-3.56 (m, 1H), 3.43 (td, 7 =11.6, 2.0 Hz, 2H), 2.82 (s, 2H), 2.82-2.80 (m, 1H), 1.84-1.80 (m, 2H), 1, 72-1.69(m, 2H), 1.05(s, 6H), 1.04-1.00(m, 4H). 161 ,,X L Retrieved from intermediates A12 and B37. 477.3 Ή NMR (400 MHz, CD ₃ OD) δ 7.94 (d, 7=6.0 Hz, 1H), 7.61 (s, 1H), 7.14 (s, 1H), 7.10 (s , 1H), 6.84 (s, 1H), 6.42 (dd, 7=6.0, 2.4 Hz, 1H), 6.29 (d, 7=2.0 Hz, 1H), 3 .95-3.90 (m, 2H), 3.59-3.56 (m, 1H), 3.42 (td, 7=11.6, 2.0 Hz, 2H), 2.82-2 .78(m, 1H), 2.29(s, 3H), 1.84-1.78(m, 2H), 1.72-1.68(m, 2H), 1.49(s, 6H ), 1.07-0.99 (m, 4H). 162 Χί/ A ⁿ O Obtained from intermediates A12 and B32. 491.2 Ή NMR (400 MHz, CD3OD) δ 7.92 (d, 7=1.6 Hz, 1H), 7.60 (s, 1H), 7.06 (s, 1H), 6.94 (s, 1H ), 6.66 (s, 1H), 6.40 (d, 7=4.0 Hz, 1H), 6.26 (s, 1H), 3.95-3.91 (m, 2H), 3 .60-3.56 (m, 1H), 3.43 (td, 7=11.6, 2.0 Hz, 2H), 2.83-2.77 (m, ZN), 2.26 (s , 3H), 1.85-1.68 (m, 4H), 1.28 (s, 6H), 1.14-0.98 (m, 4H). 163 Ο^Ν^θ^ΟΗ Η Retrieved from intermediates A12 and commercially available 2-(3- 435.4 Ή NMR (400 MHz, CD3OD) δ 7.94 (d, 7=5.6 Hz, 1H), 7.62 (s, 1H), 7.33-7.28 (m, 2H), 7.19 (t, 7=7.6 Hz, 1H), 6.92 (d, 7=7.6 Hz, 1H), 6.41 (dd, 7=6.0, 2.0 Hz, 1H), 6 .29 (d, 7=2.0 Hz, 1H), 3.95-3.91 (m, 2H), 3.59-3.55 (m, 1H), 3.51 (s, 2H), 3.43 (td, 7=12.0, 2.0 Hz, 2H), 2.84-2.77 (m, 1H), 1.89-1.69 (m, 4H), 1.091.00 ( m, 4H).

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aminophenyl)acetonitr silt 164 m DAx n Retrieved from intermediates A12 and B36. 449.2 Ή NMR (400 MHz, DMSO-76) δ 8.92 (s, 1H), 8.02 (d, 7=6.0 Hz, 1H), 7.85 (s, 1H), 7.37 (s , 1H), 7.26 (s, 1H), 6.59 (s, 1H), 6.42 (dd, 7=6.0, 2.4 Hz, 1H), 6.26 (d, 7= 2.0 Hz, 1H), 3.85-3.80 (m, 2H), 3.68-3.63 (m, 1H), 3.39 (s, 2H), 3.30-3.27 (m, 2H), 2.72-2.69 (m, 1H), 2.22 (s, ZN), 1.67-1.62 (m, 4H), 1.05-0.93 (m , 4H). 165 m 6.x1a Retrieved from intermediates A63 and B37. 491.4 Ή NMR (400 MHz, CD ₃ OD) δ 7.94 (d, 7=6.0 Hz, 1H), 7.68 (s, 1H), 7.15 (s, 1H), 7.10 (s , 1H), 6.83 (s, 1H), 6.43 (dd, 7=6.0, 2.0 Hz, 1H), 6.29 (d, 7=2.0 Hz, 1H), 4 .75-4.70 (m, 1H), 3.96-3.92 (m, 2H), 3.44 (td, 7=12.0, 2.0 Hz, 2H), 2.83-2 .81 (m, 1H), 2.52-2.42 (m, 4H), 1.90-1.80 (m, 4H), 1.74-1.69 (m, 2H), 1.49 (s, 6H). 166 (Χ-οχ Retrieved from intermediates A63 and B39. 491.3 Ή NMR (400 MHz, CD3OD) δ 8.38 (br.s., 1H, HCO2H), 7.92 (d, 7=5.6 Hz, 1H), 7.68 (s, 1H), 7, 35 (d, 7=2.0 Hz, 1H), 7.18-7.14 (m, 1H), 7.05 (d, 7=8.4 Hz, 1H), 6.42 (dd, 7 =6.0, 2.4 Hz, 1H), 6.29 (d, 7=2.0 Hz, 1H), 4.72 (quin, 7=8.4 Hz, 1H), 3.95-3 .91 (m, 2H), 3.44 (td, 7=12.0, 2.0 Hz, 2H), 2.85-2.78 (m, 1H), 2.52-2.40 (m , 4H), 2.24 (m, 3H), 1.90-1.78 (m, 4H), 1.74-1.69 (m, 2H), 1.50 (s, 6H). 167 /^0 at νΜΜ ά. Oh L-'M ^Du-'ON Retrieved from intermediates A62 and B37. 479.3 Ή NMR (400 MHz, CD3OD) δ 7.90(d, 7=6.4 Hz, 1H), 7.64(s, 1H), 7.13(s, 1H), 7.09(s, 1H ), 6.95 (s, 1H), 6.53 (dd, 7=6.0, 2.0 Hz, 1H), 6.31 (d, 7=2.0 Hz, 1H), 4.45 -4.39 (m, 1H), 3.96-3.92 (m, 2H), 3.45 (td, 7=12.0, 2.0 Hz, 2H), 2.85-2.79 (m, 1H), 2.31 (s, 3H), 1.88-1.78 (m, 2H), 1.73-1.69 (m, 2H), 1.51 (s, 6H), 1.46 (d, 7=6.8 Hz, 6H).

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168 O.^0^ O Retrieved from intermediate compounds A51 and B31. 469.3 Ή NMR (400 MHz, DMSO-J6) δ 12.16 (br.s., 1H), 8.91 (s, 1H), 8.07(s, 1H), 8.02(d, 7=5 .6 Hz, 1H), 7.70 (d, 7=7.2 Hz, 2H), 7.53 (d, 7=7.6 Hz, 1H), 7.36 (t, 7=7.6 Hz, 2H), 7.287.24 (m, 2H), 7.10 (t, 7=7.6 Hz, 1H), 6.66 (d, 7=8.0 Hz, 1H), 6.51 ( dd, 7=6.0, 2.4 Hz, 1H), 6.29 (d, 7=2.4 Hz, 1H), 3.82-3.78 (m, 1H), 2.70 (s , 2H), 1.17-1.13 (m, 2H), 1.06 (s, 6H), 1.03-1.01 (m, 2H). 169 ABOUT Khal Retrieved from intermediates A51 and B37. 469.2 Ή NMR (400 MHz, CD ₃ OD) δ 7.92 (d, 7=6.0 Hz, 1H), 7.77 (s, 1H), 7.70 (d, 7=7.2 Hz, 2H ), 7.34-7.25 (m, 3H), 7.11 (s, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 6.46 (dd, 7= 6.0, 2.0 Hz, 1H), 6.32 (d, 7=2.0 Hz, 1H), 3.73-3.67 (m, 1H), 2.27 (s, 3H), 1.48 (s, 6H), 1.19-1.14 (m, 2H), 1.10-1.05 (m, 2H). 170 0 about । DDa-on ^H O Obtained from intermediates A51 and B32 483.2 Ή NMR (400 MHz, CD3OD) δ 7.91 (d, 7=6.0 Hz, 1H), 7.76 (s, 1H), 7.72-7.69 (m, 2H), 7.33 (t, 7=7.6 Hz, 2H), 7.28-7.26 (m, 1H), 6.99 (s, 1H), 6.89 (s, 1H), 6.64 (s, 1H), 6.44 (dd, 7=6.0, 2.0 Hz, 1H), 6.29 (d, 7=2.0 Hz, 1H), 3.72-3.68 (m, 1H ), 2.75 (s, 2H), 2.24 (s, 3H), 1.12 (s, 6H), 1.18-1.05 (m, 4H). 171 0 Retrieved from intermediate compounds A51 and B2. 441.2 Ή NMR (400 MHz, CD3OD) δ 7.91 (d, 7=5.6 Hz, 1H), 7.79 (s, 1H), 7.71 (d, 7=8.0 Hz, 2H), 7.36-7.25 (m, ZN), 7.22-7.10 (m, ZN), 6.89 (d, 7=7.2 Hz, 1H), 6.51 (d, 7= 5.6 Hz, 1H), 6.31 (s, 1H), 3.73-3.69 (m, 1H), 2.85 (t, 7=7.6 Hz, 2H), 2.57 ( t, 7=7.6 Hz, 2H), 1.17-1.01 (m, 4H). 172 ABOUT L ^0^ DD/™ 483.3 Ή NMR (400 MHz, CD3OD) δ 7.89 (d, 7=6.0 Hz, 1H), 7.84 (s, 1H), 7.72 (d, 7=7.2 Hz, 2H), 7.34 (t, 7=7.6 Hz, 2H), 7.27 (t, 7=7.6 Hz, 1H), 7.09 (s, 1H), 7.02 (s, 1H), 6.90 (s, 1H), 6.54 Retrieved from intermediates A56 and B37. (dd, 7=6.0, 2.4 Hz, 1H), 6.34 (d, 7=2.4 Hz, 1H), 4.81-4.78 (m, 1H), 2.63- 2.46 (m, 4H), 2.28 (s, 3H), 1.94-1.87 (m, 2H), 1.49 (s, 6H). 173 (ϊΑ AC-uOn Retrieved from intermediates A56 and B2. 455.3 Ή NMR (400 MHz, DMSO-76) < 12.16 (b.s., 1H), 8.92 (s, 1H), 8.13 (s, 1H), 8.04 (d, 7=6 .0 Hz, 1H), 7.72 (d, 7=7.2 Hz, 2H), 7.46 (d, 7=8.8 Hz, 1H), 7.30-7.25 (m, ZN ), 7.27 (t, 7 = 7.6 Hz, 1H), 7.11 (t, 7 = 7.6 Hz, 1H), 6.72 (d, 7 = 7.2 Hz, 1H), 6.52-6.50 (m, 1H), 6.28 (s, 1H), 4.88-4.83 (m, 1H), 2.74 (t, 7=7.6 Hz, 2H) , 2.66-2.45 (m, 6H), 1.83-1.79 (m, 2H).

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Example 174 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)oxitane3-carboxylic acid

Step 1: 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)oxytan-3carbonitrile.

A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,5-dimethylpyridine (Intermediate A49, 1.0 eq.), 3-(3-aminobenzyl)oxytan-3-carbonitrile ( intermediate B33, 1.0 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthos (0.2 eq.) and Pd(OAc) ₂ (0.2 eq.) in dioxane (0.06 M) stirred at 110° C. for 16 hours under argon. The mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was redissolved in EtOAc, washed with water, brine and then dried over Na ₂ SO ₄ The crude product was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=10:1 to 2:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+H]+=415.2.

Step 2: 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)oxytan-3carboxylic acid.

Mixture of 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)oxytan-3carbonitrile (1.0 eq.) and KOH (5.0 eq.) in ethylene glycol/H2O (v/v=4:1, 0.02 M) was stirred at 130° C. for 2 h. The mixture was cooled to RT, washed with EtOAc. The pH of the aqueous layer was adjusted to ~7 with 1.0 M aq. HCl and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (mobile phase: 0.1% HCOOH/MeCN/H ₂ O) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=434.2;

¹ H NMR (400 MHz, CD3OD) δ 7.97 (d, J=6.0 Hz, 1H), 7.33 (s, 1H), 7.27-7.25 (m, 2H), 7, 17 (t, J=7.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.38 (dd, J=6.0, 2.0 Hz, 1H), 6.10 (d, J=1.6 Hz, 1H), 4.84 (d, J=6.4 Hz, 2H), 4.60 (d, J=6.0 Hz, 2H), 3. 27 (s, 2H), 2.82 (q, J=7.6 Hz, 2H), 2.34 (s, 6H), 1.24 (t, J=7.6 Hz, 3H).

Example 175: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-ethyl-[2,2'-bipyridine]-3yl)oxy)pyridine-2- amine

Step 1: 3-(3-((4-((6-ethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile.

Mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,2'-bipyridine (Intermediate A21, 1.0 eq.), 3-(3-aminophenyl)propanenitrile (Intermediate B2 , 1.0 eq.), Cs ₂ CO ₃ (2.0 eq.), xanthos (0.10 eq.), Pd(OAc) ₂ (0.1 eq.) in dioxane (0.1 M) was stirred at 110°C for 16 h in an argon atmosphere. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (eluent: petroleum ether/EtOAc=20:1) to give the title compound as a yellow solid. LC-MS (m/z): [M+1]+=422.3.

Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-ethyl-[2,2'-bipyridin]-3-yl)oxy)pyridine- 2 amine.

A mixture of 3-(3-((4-((6-ethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propanenitrile (1.0 eq.), TMSN3 (5.0 eq.) and Bu ₂ SnO (2.0 eq.) in dioxane (0.04 M) were stirred at 100° C. for 16 h under argon. The solvent was removed and the residue was purified by preparative HPLC (mobile phase: 0.1% HCOOH/MeCN/H2O) to give the title compound as a white solid. LC-MS (m/z): [M+H]+=465.2;

1H NMR (400 MHz, CD3OD) δ 8.58 (d, J=4.8 Hz, 1H), 7.89 (td, J=8.0, 1.6 Hz, 1H), 7.86 (d , J=6.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.43-7.38 (m, 1H), 7.22 (s, 1H), 7.17-7.10 (m, 2H), 6.76 (d, J=6.8 Hz, 1H), 6.32 (dd, J=6.0, 2.0 Hz, 1H), 6.09 (d, J=2.0 Hz, 1H), 3.18 ( t, J=7.6 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 2.90 (c, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H).

The following compounds were obtained by the method described in example 175, using intermediate compounds.

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Example Structure LC-MS (m/z) [M+1] ⁺ W NMR (400 MHz) 176 η Ύ Τ - '- O ΝΑ Retrieved from intermediate compounds Al and B31. 493.4 Ή NMR (400 MHz, CD ₃ OD) δ 8.49 (d, 7=4.0 Hz, 1H), 7.78-7.68 (m, 3H), 7.447.30 (m, 2H), 7 .04-6.93(m, 2H), 6.80(s, 1H), 6.30-6.18(m, 2H), 5.96(s, 1H), 2.86(s, 2H ), 2.49 (s, 3H), 2.32 (s, 3H), 1.35 (s, 6H). 177 Π '=' 0 ζΧΧΧΧ^ ^ν α Obtained from intermediate compounds Al and B43. 495.4 Ή NMR (400 MHz, DMSO-76) δ 8.62 (s, 1H), 8.51 (d, 7=4.0 Hz, 1H), 8.18 (s, 1H), 7.91 (d , 7=6.0 Hz, 1H), 7.83 (m, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.41-7 .38 (m, 1H), 7.34 -7.31 (m, 1H), 7.22 (s, 1H), 6.84 (d, 7=8.8 Hz, 1H), 6.27 ( dd, 7=6.0, 2.4 Hz, 1H), 6.00 (d, 7=2.4 Hz, 1H), 3.72 (s, ZN), 3.00-2.98 (m , 2H), 2.90-2.78 (m, 2H), 2.47 (s, 3H), 2.34 (s, 3H). 178 X 'Ax- ₀ A cIhZAv» ^N and D NH NA Prepared from intermediates A1 and B28. 495.3 Ή NMR (400 MHz, CD3OD) δ 8.57 (d, 7=4.8 Hz, 1H), 7.87-7.76 (m, 3H), 7.52 (s, 1H), 7.40 -7.36(m, 1H), 6.80(s, 1H), 6.70(s, 1H), 6.31(s, 2H), 6.10(s, 1H), 3.69( s, ZN), 3.16 (t, 7=7.6 Hz, 2H), 2.96 (t, 7=7.6 Hz, 2H), 2.55 (s, ZN), 2.39 ( s, ZN). 179 Ύ χ'^ΐχ'Α F NA- Retrieved from intermediate compounds A1 and B29. 483.4 Ή NMR (400 MHz, CD3OD) δ 8.57 (d, 7=4.0 Hz, 1H), 7.91 (d, 7=5.6 Hz, 1H), 7.85 (t, 7=7 .6 Hz, 1H), 7.77 (d, 7=8.0 Hz, 1H), 7.52 (s, 1H), 7.37 (t, 7=5.2 Hz, 1H), 7, 23 (d, 7=11.2 Hz, 1H), 6.92 (s, 1H), 6.46 (dd, 7=5.6, 4.0 Hz, 1H), 6.32 (d, 7 =4.0 Hz, 1H), 6.09 (s, 1H), 3.17 (t, 7=7.6 Hz, 2H), 3.00 (t, 7=7.6 Hz, 2H), 2.57 (s, 3N), 2.40 (s, 3N).

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180 ΐΠ x Ν ΑχJJ '=' 0 _C | ν=ν Obtained from Al and TSO intermediates. 499.3 Ή NMR (400 MHz, CD ₃ OD) δ 8.58 (d, 7=4.8 Hz, 1H), 7.92 (d, 7=5.6 Hz, 1H), 7.86 (td, 7 =7.6, 1.2 Hz, 1H), 7.78 (d, 7=7.2 Hz, 1H), 7.53 (s, 1H), 7.42-7.37 (m, 2H) , 7.10(s, 1H), 6.74(s, 1H), 6.33(dd, 7=6.0, 2.4 Hz, 1H), 6.07(d, 7=2.4 Hz, 1H), 3.18 (t, 7=8.0 Hz, 2H), 3.00 (d, 7=8.0 Hz, 2H), 2.58 (s, ZN), 2.41 ( s, ZN). 181 ν=ν Retrieved from intermediate compounds A18 and B2. 479.2 Ή NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 7.86-7.79 (m, 3H), 7.54 (s, 1H), 7.407.39 (m, 1H), 7 .18-7.10 (m, ZN), 6.77 (d, 7=6.8 Hz, 1H), 6.31 (m, 1H), 6.09 (m, 1H), 3.15- 3.12 (m, 2H), 3.02-2.98 (m, 2H), 2.782.73 (m, 2H), 2.58 (s, 3H), 1.27 (t, 7=6, 8 Hz, ZN). 182 X. P u x ⁿ Obtained from intermediates A19 and B2. 491.4 Ή NMR (400 MHz, CD3OD) δ 8.70 (d, 7=5.2 Hz, 1H), 8.25 (s, 2H), 7.85 (d, 7=7.2 Hz, 1H), 7.69-7.67 (m, 1H), 7.45 (s, 1H), 7.39 (t, 7=7.6 Hz, 1H), 7.18-7.11 (m, ZN) , 6.74 (dd, 7=7.2, 2.4 Hz, 1H), 6.31 (d, 7=2.4 Hz, 1H), 3.27 (t, 7=7.6 Hz, 2Н), 3.11 (t, 7=7.6 Hz, 2Н), 2.79 (s, ZN), 2.14-2.10 (m, 1Н), 1.19-1.14 (m , 2H), 0.81-0.77 (m, 2H). 183 At ...w AsA y X xmx, Retrieved from intermediate compounds A20 and B2. 493.2 Ή NMR (400 MHz, DMSO-76) δ 8.84 (s, 1H), 8.50 (d, 7=4.2 Hz, 1H), 8.29 (s, 2H, HCO2H), 7.96 (d, 7=6.0 Hz, 1H), 7.84 (td, 7=7.6, 1.6 Hz, 1H), 7.79 (d, 7=7.6 Hz, 1H), 7 .59 (s, 1H), 7.45 (d, 7=8.4 Hz, 1H), 7.39 (s, 1H), 7.35-7.27 (m, 1H), 7.10 ( t, 7=8.0 Hz, 1H), 6.72 (d, 7=7.6 Hz, 1H), 6.31 (dd, 7=6.0, 2.4 Hz, 1H), 6, 07 (d, 7=2.4 Hz, 1H), 3.17 (sep, 7=6.8 Hz, 1H), 3.00-2.95 (m, 2H), 2.90-2.85 (m, 2H), 2.61 (s, 3H), 1.25 (d, 7=6.8 Hz, 6H).

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184 .-JO Ύ ν= _ν Obtained from intermediates 3 and B43. 481.4 Ή NMR (400 MHz, DMSO-J6) 8.51 (d, 7=5.8 Hz, 1H), 7.95-7.92 (m, 2H), 7.84 (d, 7=6.8 Hz, 1H), 7.78-7.76 (m, 1H), 7.53 (d, 7=7.8 Hz, 1H), 7.44-7.41 (m, 1H), 7.217.19 (m, 1H), 7.10 (s, 1H), 7.02-6.99 (m, 1H), 6.60-6.58 (m, 1H), 6.12 (s, 1H), 3.78 (s, 3H), 3.12 (t, 7=7.6 Hz, 2H), 2.97 (t, 7=7.6 Hz, 2H), 2.59 (s, 3H). 185 xx - A' O Retrieved from intermediate compounds A23 and B2. 479.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.56 (d, 7=4.8 Hz, 1H), 7.88-7.81 (m, 3H), 7.52 (s, 1H), 7 .40-7.36 (m, 1H), 7.21 (s, 1H), 7.177.10 (m, 2H), 6.76 (d, 7=6.8 Hz, 1H), 6.33 ( dd, 7=6.0, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 3.19 (t, 7=7.6 Hz, 2H), 3, 02 (t, 7=7.6 Hz, 2H), 2.91 (c, 7=7.6 Hz, 2H), 2.44 (s, ZN), 1.30 (t, 7=7.6 Hz, ZN). 186 ί Cr^-'Ό Η 1, - ν= _ν Obtained from intermediates A50 and B23. 450.2 Ή NMR (400 MHz, CD3OD) δ 7.99 (d, 7=6.0 Hz, 1H), 7.61 (s, 1H), 7.07 (s, 1H), 7.03 (s, 1H ), 6.61 (s, 1H), 6.40 (dd, 7=6.0, 2.0 Hz, 1H), 6.12 (d, 7=2.4 Hz, 1H), 3.21 (t, 7=7.6 Hz, 2H), 2.99 (t, 7=7.6 Hz, 2H), 2.94 (c, 7=7.6 Hz, 2H), 2.37 (s , ZN), 2.24 (s, ZN), 1.28 (t, 7=7.6 Hz, ZN). 187 ΑΎ 0 | ^Ν ϋ G MN ⁿ ν CN- Obtained from intermediates A16 and B23 416.3 Ή NMR (400 MHz, CD3OD) δ 7.97 (d, 7=5.6 Hz, 1H), 7.48 (d, 7=8.4 Hz, 1H), 7.24 (d, 7=8 .4 Hz, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 6.62 (s, 1H), 6.41 (dd, 7=6.0, 1.6 Hz , 1H), 6.10 (d, 7=1.6 Hz, 1H), 3.21 (t, 7=7.6 Hz, 2H), 2.99 (t, 7=7.6 Hz, 2H ), 2.80 (c, 7=7.6 Hz, 2H), 2.39 (s, ZN), 2.23 (s, ZN), 1.29 (t, 7=7.6 Hz, ZN ). 188 -9 uh° ΤΖ Z 402.2 Ή NMR (400 MHz, DMSO-76) δ 9.30 (br.s., 1H), 8.06 (d, 7=6.0 Hz, 1H), 7.64 (s, 1H), 7, 43-7.39 (m, 2H), 7.19 (t, 7=8.0 Hz, 1H), 6.82 (d, 7=7.6 Hz, 1H), 6.52-6.50 (m,

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Retrieved from intermediates A27 and B2. 1H), 6.18 (s, 1H), 3.17 (t, 7=7.6 Hz, 2H), 3.01 (t, 7=7.6 Hz, 2H), 2.49 (s, ZN), 2.35 (s, ZN), 2.29 (s, ZN). 189 HA CI -'O | AA^ n= _n Prepared from intermediates A26 and B23. 436.1 Ή NMR (400 MHz, DMSO-J6) δ 8.85(s, 1H), 8.16 (s, 0.6H, HCO2H), 8.08 (d,7=6.0 Hz, 1H), 7 .85 (s, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 6.57 (s, 1H), 6.44 (dd, 7=6.0, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 3.07 (t, 7=7.6 Hz, 2H), 2.89 (t, 7=7.6 Hz, 2H), 2.54 (s, 3N), 2.28 (s, 3N), 2.20 (s, 3N). 190 .'AZH.AX ⁿ ν=ν Prepared from intermediates A49 and B23. 430.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.38 (s, 2H, HCO 2 H), 7.96 (d, 7=6.0 Hz, 1H), 7.33 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.62 (s, 1H), 6.39 (dd, 7=6.0, 2.0 Hz, 1H), 6.08 (d, 7=2.0 Hz, 1H), 3.18 (t, 7=7.6 Hz, 2H), 2.97 (t, 7=7.6 Hz, 2H), 2.81 (c, 7= 7.6 Hz, 2H), 2.34 (s, 6H), 2.23 (s, ZN), 1.23 (t, 7=7.6 Hz, ZN). 191 A° j< A 7 X X -' O Retrieved from intermediate compounds A25 and B2. 458.3 Ή NMR (400 MHz, CDCI3) δ 8.05 (d, 7=6.0 Hz, 1H), 7.58 (s, 1H), 7.26-7.19 (m, 2H), 7.08 (d, 7=8.0 Hz, 1H), 6.83 (d, 7=7.6 Hz, 1H), 6.78 (d, 7=7.6 Hz, 1H), 6.41 (dd , 7=6.0, 2.0 Hz, 1H), 6.12 (d, 7=2.4 Hz, 1H), 5.36-5.33 (m, 1H), 4.07 (dd, 7=11.2, 3.6 Hz, 2H), 3.53-3.46 (m, 2H), 3.38 (t, 7=7.2 Hz, 2H), 3.17-3.08 (m, 2H), 2.56 (s, 3H), 2.24-2.13 (m, 2H), 2.12-2.05 (m, 2H). 192 Ύ (XXXa^ _n M'N Obtained from intermediates Ab and B31. 478.4 Ή NMR (400 MHz, CDCI3) δ 7.88 (s, 1H), 7.78 (d, 7=6.8 Hz, 2H), 7.42-7.34 (m, 4H), 7.20 (d, 7=8.0 Hz, 1H), 7.07 (t, 7=7.6 Hz, 1H), 6.90 (d, 7=7.2 Hz, 1H), 6.77 (s , 1H), 6.51 (d, 7=7.6 Hz, 1H), 6.30 (d, 7=4.4 Hz, 1H), 6.09 (s, 1H), 2.91 (s , 2H), 2.65 (s, 3H), 1.51 (s, 6H).

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193 X _N= N iui nh LL ^: H Prepared from Al 2 intermediates and commercially available 2-(3-aminophenyl)acetonitrile. 459.3 Ή NMR (400 MHz, DMSOX) δ 9.03 (s, 1H), 8.16 (s, 0.6H, HCO2H), 8.01 (d, 7=6.0 Hz, 1H), 7.84 (s, 1H), 7.63 (d, 7=8.0 Hz, 1H), 7.40 (s, 1H), 7.17 (t, 7=7.6 Hz, 1H), 6.76 (d, 7=7.6 Hz, 1H), 6.44 (dd, 7=6.0, 2.4 Hz, 1H), 6.24 (d, 7=2.4 Hz, 1H), 4 .18 (s, 2H), 3.82 (dt, 7=11.2, 3.2 Hz, 2H), 3.69-3.63 (m, 1H), 3.34-3.27 (m , 2H), 2.722.69 (m, 1H), 1.69-1.62 (m, 4H), 1.05-0.93 (m, 4H). 194 hU./'X HchD 0 I L A Retrieved from intermediates A12 and B36. 473.4 ^1H NMR (400 MHz, DMSO-J6) δ 8.91 (s, 1H), 8.01 (d, 7=6.0 Hz, 1H), 7.84 (s, 1H), 7.42 ( s, 1H), 7.18 (s, 1H), 6.58 (s, 1H), 6.42 (dd, 7=6.0, 2.0 Hz, 1H), 6.24 (d, 7 =2.0 Hz, 1H), 4.08 (s, 2H), 3.84-3.79 (m, 2H), 3.67-3.63 (m, 1H), 3.33-3, 26 (m, 2H), 2.752.65 (m, 1H), 2.21 (s, 3H), 1.67-1.61 (m, 4H), 1.04-0.99 (m, 2H) , 0.97-0.92 (m, 2H). 195 Χοχ· Retrieved from intermediate compounds A12 and B5. 487.4 Ή NMR (400 MHz, DMSO-76) δ 9.06 (b.s., 1H), 8.14 (s, 0.6H, HCO2H), 7.98 (d, 7=6.0 Hz, 1H ), 7.85 (s, 1H), 7.72-7.70 (m, 1H), 7.23-7.17 (m, 2H), 6.78-6.73 (m, 1H), 6.47-6.44(m, 1H), 6.22(s, 1H), 3.843.83(m, 2H), 3.68-3.62(m, 2H), 2.73-2, 67 (m, 1H), 2.44-2.33 (m, 1H), 1.75 (s, 6H), 1.71-1.58 (m, 4H), 1.07-0.85 ( m, 4H). 196 X XX Retrieved from intermediates A12 and B37. 501.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.21 (s, 0.6H, HCO 2 H), 7.92 (d, 7=6.0 Hz, 1H), 7.63 (s, 1H), 7 .11 (s, 1H), 7.07 (s, 1H), 6.68 (s, 1H), 6.45 (dd, 7=6.0, 2.4 Hz, 1H), 6.26 ( d, 7=2.4 Hz, 1H), 3.96-3.91 (m, 2H), 3.61-3.56 (m, 1H), 3.43 (td, 7=7.6, 2.0 Hz, 2H), 2.84-2.76 (m, 1H), 2.27 (s, ZN), 1.80

- 109 043088

(s, 6H), 1.87-1.66 (m, 2H), 1.73-1.69 (m, 2H), 1.09-0.91 (m, 4H). 197 _Ν ίΧ >-“A Ca.ax^h^ Obtained from intermediates A51 and B2. 465.2 Ή NMR (400 MHz, CD ₃ OD) δ 8.14 (br.s., 0.4H, HCO2H), 7.93-7.90 (m, 1H), 7.807.78 (m, 1H), 7 .72-7.70 (m, 2H), 7.33-7.11 (m, 6H), 6.76 (s, 1H), 6.51-6.49 (m, 1H), 6.30 -6.29(m, 1H), 3.72-3.69(m, 1H), 3.213.19(m, 2H), 3.03-3.01(m, 2H), 1.18-1 .06 (m, 4H). 198 hh? ί A XX A L ⁿ n Prepared from intermediates A51 and commercially available 2-(3-aminophenyl)acetonitrile. 451.2 Ή NMR (400 MHz, DMSO-J6) δ 8.98 (s, 1H), 8.08 (s, 1H), 8.02 (d, 7=5.6 Hz, 1H), 7.70-7 .67 (m, 2H), 7.59-7.56 (m, 1H), 7.387.33 (m, ZN), 7.28-7.26 (m, 1H), 7.15 (t, 7 =8.0 Hz, 1H), 6.74 (d, 7=7.6 Hz, 1H), 6.52 (dd, 7=6.0, 2.4 Hz, 1H), 6.29 (d , 7=2.4 Hz, 1H), 4.16 (s, 2H), 3.83-3.78 (m, 1H), 1.161.12 (m, 2H), 1.04-1.00 ( m, 2H). 199 ABOUT 0l XXXAn Η Retrieved from intermediate compounds A51 and VZb. 465.2 Ή NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.80 (d, 7=7.2 Hz, 1H), 7.67 (d, 7=6.8 Hz, 2H), 7.38-7.31 (m, ZN), 7.14 (s, 1H), 7.02 (s, 2H), 6.85 (dd, 7=7.2, 2.4 Hz, 1H) , 6.45 (d, 7=2.4 Hz, 1H), 4.29 (s, 2H), 3.763.74 (m, 1H), 2.35 (s, 3H), 1.19-1, 16(m, 2H), 1.11-1.08(m, 2H). 200 O Y A ^ 0 Y _Ν , _ΝΗ ^Η Ν=Ν Obtained from intermediates A56 and B2. 479.5 Ή NMR (400 MHz, CD3OD) δ 7.92 (d, 7=6.0 Hz, 1H), 7.83 (s, 1H), 7.73 (d, 7=6.8 Hz, 2H), 7.35-7.30 (m, 2H), 7.30-7.22 (m, 2H), 7.16-7.09 (m, 2H), 6.76 (d, 7=6.0 Hz, 1H), 6.50-6.49 (m, 1H), 6.30 (s, 1H), 4.854.77 (m, 1H), 3.20 (t, 7=7.2 Hz, 2H ), 3.01 (t, 7=7.2 Hz, 2H), 2.62-2.57 (m, 2H), 2.552.50 (m, 2H), 1.91-1.88 (m, 2H).

- 110 043088

201 O χ/ ⁿ a Δ jOla > Prepared from intermediates A56 and commercially available 2-(3-aminophenyl)acetonitrile. 465.2 Ή NMR (400 MHz, CD ₃ OD) δ 7.91 (d, 7=6.0 Hz, 1H), 7.84 (s, 1H), 7.73 (d, 7=7.6 Hz, 2H ), 7.36-7.20 (m, 6H), 6.89-6.86 (m, 1H), 6.52 (dd, 7=6.0, 2.0 Hz, 1H), 6, 31 (d, 7=2.0 Hz, 1H), 4.81-4.79 (m, 1H), 4.23 (s, 2H), 2.64-2.54 (m, 2H), 2 .54-2.48 (m, 2H), 1.95-1.87 (m, 2H). 202 O A O\D _o Xόχ™ n Obtained from intermediates A56 and B36. 479.4 Ή NMR (400 MHz, CD3OD) δ 7.90 (d, 7=6.0 Hz, 1H), 7.84 (s, 1H), 7.73 (d, 7=7.2 Hz, 2H), 7.33 (t, 7=7.6 Hz, 2H), 7.26 (t, 7=7.2 Hz, 1H), 7.11 (s, 1H), 7.03 (s, 1H), 6.73 (s, 1H), 6.52 (dd, 7=6.0, 2.4 Hz, 1H), 6.31 (d, 7=2.4 Hz, 1H), 4.84-4 .79 (m, 1H), 4.18 (s, 2H), 2.63-2.46 (m, 4H), 2.24 (s, 3H), 1.94-1.87 (m, 2H ).

The following compounds can be obtained using the reaction schemes and methods presented in the present description.

Additional examples Structure 203 X N N . Η and ,Ν Ν^ν 204 mX ⁰¹ Α'Ό X jCX-b

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205 _nJU ΎT n-n 206 Ύ +' Ό X jOvu ^N -~ i7 207 χι _Ρ '-^ 0 ό. Hk^u 208 . _N j3^ Γ X ^oru1e XX-O if j£jl ν ^N T4 209 CVy- '-' 0 Xn££-x _n ^H nn 210 Un UJ ⁿ ^ JT X ΧΧχ. _ΝNN 211 and J Ϊ '<' 0 £υ<Ά ⁿ 'N

- 112 043088

In some embodiments, the implementation of the present invention relates to a compound selected from the group consisting of examples of compounds presented in the present description.

Analyzes.

Cellular analysis of the HEK-Blue TGFe reporter gene.

HEK-Blue TGFe cells were purchased from Invivogen. A suspension of 2.5x105 cells/ml was prepared using a test medium (DMEM containing 0.5% v/v thermally inactivated FBS). A working solution of TGF-β (6 ng/ml) was prepared by diluting a stock solution of TGF-β (10 μg/ml) with test medium before use. Eight different concentrations of all compounds were obtained by the 3-fold dilution gradient method using TGF-β working solution. 100 μl of test medium (carrier) or test article or TGF-β working solution was added per well of a flat-bottomed 96-well plate. 100 μl of HEK-Blue TGF-β cell suspension was added per well. The plate was incubated at 37°C in a CO ₂ incubator for 22-23 hours. 150 μl of resuspended QUANTI-Blue was added per well of a new flat-bottomed 96-well plate. Added 30 μl of the supernatant of induced HEK-Blue TGF-β cells. Avoid pipetting at the bottom of the well. The plate was incubated at 37°C in an incubator for 30-40 min. The levels of secreted embryonic alkaline phosphatase (SEAP) were determined using a spectrophotometer at 630 nm.

Inhibition was calculated using the following equation:

Coefficient ( ^TGF &' - (Compound - Carrier) of inhibition (%) = . _Carrier

- 113 043088

Activity data.

Cellular analysis of the HEK-Blue TGFe reporter gene:

Example 1C ₅₀ HEK-Blue TGFp reporter (µM) Prime R 1C ₅₀ HEK-Blue TGFp reporter (µM) Example 1C ₅₀ HEK-Blue TGFp reporter (µM) 1 0.18 2 0.23 3 >10 4 0.20 5 0.15 6 0.16 7 0.17 8 0.59 9 >10 10 0.22 eleven 3.81 12 0.13 13 1.08 14 >10 15 1.84 16 0.39 17 0.65 18 0.18 19 0.16 20 0.12 21 0.16 22 0.23 23 >10 24 4.53 25 0.64 26 0.35 27 0.25 28 0.05 29 0.038 thirty oh and 31 >10 32 3.71 33 7.31 34A 12.7 34V >10 35A >10 35V >10 36 0.18 37 0.20 38 >10 39 0.26 40 0.22 41 0.10 42 0.14 43 3.81 44 0.12 45 0.42 46 0.52 47 0.31 48 3.03 49 >10

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50 0.63 51 0.27 52 0.037 53 2.95 54 6.39 55 0.20 56 0.16 57 0.13 58 0.15 59 0.45 60 0.079 61 0.19 62 2.11 63 0.72 64 2.60 65 0.52 66 0.024 67 2.65 68 0.74 69 >10 70 0.007 71 0.14 72 0.18 73 0.14 74 0.23 75 8.12 76 >10 77 0.080 78 ο,ιι 79 0.18 80 ο,ιι 81 0.031 82 0.018 83 0.035 84 0.055 85 0.044 86 0.24 87 0.094 88 0.039 89 0.027 90 0.024 91 0.018 92 0.080 93 0.12 94 0.064 95 0.29 96 0.19 97 0.20 98 0.051 99 0.023 100 2.59 101 3.31 102 2.71 103 >10 104 0.022 105 0.13 106 0.12 107 0.18 108 0.90 109 0.051 110 0.030 111 6.20 112 1.67 FROM 0.51 114 2.54 115 ι, ιο 116 1.02 117 >10 118 0.31 119 0.013 120 0.050 121 0.078 122 0.029 123 0.18 124 0.19 125 0.066 126 0.20 127 0.012 128 0.022 129 0.029 130 >10 131 1.73 132 >10 133 0.028 134 0.078 135 0.043 136 0.10 137 0.071 138 0.049 139 0.042 140 0.035 141 0.012 142 0.007 143 0.13 144 0.075 145 0.033 146 0.021 147 0.025 148 0.034 149 0.021 150 0.027 151 0.030

- 115 043088

152 0.020 153 0.070 154 0.016 155 0.030 156 0.023 157 0.027 158 0.037 159 0.14 160 0.21 161 0.18 162 0.12 163 3.60 164 1D1 165 0.25 166 0.48 167 0.62 168 0.21 169 0.007 170 0.014 171 0.016 172 0.12 173 0.026 174 0.057 175 0.044 176 0.15 177 0.15 178 0.21 179 0.17 180 0.079 181 0.21 182 0.64 183 0.24 184 0.33 185 0.039 186 0.051 187 0.027 188 0.073 189 0.024 190 0.006 191 3.69 192 0.065 193 >10 194 4.14 195 2.23 196 0.27 197 0.035 198 0.11 199 0.060 200 0.086 201 0.089 202 0.12

_Liver A&C/ _cardiac A&C ratios of selected examples were compared with the clinical compounds galunisertib and LY3200882. Tissue exposure was measured in Balb/c mice treated with PO at a dose of 10 mg/kg. It should be noted that cardiac toxicity was identified as the most important in the case of LY3200882 and as a limiting factor in the case of galunisertib. See Stauber, et al., J. Clin. Pract, 2014, 4(3), 196.

General PK protocol.

Balb/c mice were kept on an empty stomach overnight with free access to drinking water before treatment. Compounds were in 0.5% CMC/0.5% Tween 80 with 1 eq. NaOH or without it and was administered intragastrically at a dose of 10 mg/kg. Mouse liver and heart tissues were harvested at 0.5, 1, 3, 5, 7, 24 hours (2 mice per time point) post-dose, first sacrificing the animal by CO2 inhalation. After washing with ice-cold saline and removing excess water on their surface, liver and heart tissues were weighed and homogenized in a 1:5 (w/v) volume of water with 20% methanol. Before analysis, tissue samples were stored at -40 - -20°C. Compound concentrations in the liver and heart were determined by the conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Tissue concentration-time data were processed by linear regression analysis. All pharmacokinetic parameters were calculated using the non-compartmental Pharsight Phoenix 8.0 model.

Galun Ise rtib ί¥3200ββ2

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Example AU _Liver C/ _{Heart AiS} G alunisertib 2.9 LY3200882 1.3 1 13.2 12 60.9 16 142 44 29.9 52 70.6 70 67.7 74 266 81 124 104 27.8 161 464 175 183

The data show that the compounds of the invention are much more likely to be concentrated in the liver than in cardiac tissue compared to galunisertib or LY3200882 and thus may better provide a favorable safety profile and therapeutic index than known compounds. Since cardiotoxicity is a major concern in new drug development, it has been shown that compounds of the invention exhibiting potent in vitro activity at the target site and significantly better pharmacokinetic properties for safety are superior to compounds known in the art.

The above detailed description is provided to assist those skilled in the art in the practice of the present invention. However, the present invention described and claimed in the present description is not limited in scope to the specific embodiments presented in the present description, since these embodiments are intended to illustrate several aspects of the invention. Any obvious alternative or additional embodiments are intended to be included within the scope of the present invention. In fact, various modifications of the invention, in addition to those presented in the present description, will be obvious to experts in this field from the above description and do not deviate from the essence or scope of the present invention. Such modifications are also intended to be included within the scope of the claims.

All publications, patents, patent applications and other sources cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other source were specifically and are individually listed as incorporated herein in their entirety by reference for all purposes. The citation of a reference in the present specification should not be construed as an acknowledgment of it as prior art with respect to the present invention.

Claims (15)

1. The compound of formula (I) l/ A _ 11'5 ν ^N th (I) where ring A is a 5- or 6-membered heteroaromatic ring, optionally containing an additional nitrogen atom as a ring member and optionally fused to a phenyl or pyridinyl ring, and ring A is optionally substituted with one or two groups, independently selected from halogen, C ₁ -C ₄ alkyl, C _g C ₄ haloalkyl, C 1 -C 4 alkoxy, C 1 -C ₄ haloalkoxy, phenyl, pyridinyl, and C ₃ -C ₆ cycloalkyl; R ¹ is selected from H, halogen, CN, C 1 -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C 1 -C ₄ alkoxy, C ₁ -C 4 haloalkoxy, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl containing N, O or S as a ring member, phenyl and 5-6-membered heteroaryl containing one or two nitrogen atoms as ring members, where each of the specified C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy groups, C ₁ -C ₄ haloalkoxy groups, C ₃ -C ₆ -cycloalkyl, phenyl, 5-6-membered heterocyclyl and 5-6-membered hetero-117 043088 ryl are optionally substituted with one or two groups selected from R ² ; where R ² at each occurrence is independently selected from halogen, CN, -OH, C ₁ -C ₄ alkyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ alkoxy, C 1 -C ₄ haloalkoxy, and C ₃ -C 6 cycloalkyl ; Cy is a ring selected from C ₃ -C 6 -cycloalkyl, phenyl and 5-6 membered heteroaryl containing one or two nitrogen atoms as ring members, and optionally further substituted with one or two groups selected from halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl, C1 -C ₄ alkoxy and C ₁ -C ₄ haloalkoxy groups; L is a bivalent linker selected from the bond, -CR2-, -(CR ₂ ) _2-4 - and -O-(CR ₂ ) _1-3 -, where R is in each case independently selected from H, F and C1-C ₄ -alkyl; or two R groups on the same carbon atom can be taken into account together with the carbon atom to which they are attached, giving a 3-6 membered cycloalkyl ring or a 3-6 membered cyclic ether; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where R ¹ is selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy groups, C ₁ -C ₄ -haloalkoxy groups, C ₃ -C ₆ -cycloalkyl, 5-6 membered heterocyclyl containing N, O or S as a ring member, phenyl and 5-6 membered heteroaryl containing one or two nitrogen atoms as ring members, where each of the specified C ₁ -C ₄ -αalkyl, C ₁ -C ₄ haloαalkyl, C ₁ -C ₄ alkoxy groups, C 1 -C ₄ haloalkoxy groups, C ₃ -C ₆ -cycloalkyl, 5-6-membered heterocyclyl containing N, O or S as a ring member , phenyl and 5-6 membered heteroaryl is optionally substituted with one or two groups selected from R ² ; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, where R ¹ is methyl, phenyl or pyridin-2-yl; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1 or 2, where Cy is a ring selected from phenyl and pyridinyl and is optionally further substituted with a group selected from halogen, C ₁ -C ₄ -alkylα, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ alkoxy groups and C ₁ -C ₄ haloalkoxy groups; or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4, having the formula where Z represents CH or N, and Q is selected from H, Me, CF ₃ , OMe and halogen; or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of claims 1, 2 and 5, where L is a bivalent linker selected from -CR ₂ -, -(CR ₂ ) _2-4 - and -O-(CR ₂ ) _1-3 -; where R is at each occurrence independently selected from H, F and Me; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 6 wherein L is selected from -CH-, -CH2CH2-, -C(Me)2-, -CHMe-, -OCH2-, -CH2CF2-, -CF2CH2-, -CMe2CH2- and -CH2CMe2 -; or a pharmaceutically acceptable salt thereof. 8. The compound according to any one of claims 1, 2 and 4, which is a compound of formula (Ia) where Q is at each occurrence independently selected from halo, C1- _C4 alkyl, C1- _C4 haloalkyl, and C1- _C4 alkoxy; And Z is CH, CQ or N; or a pharmaceutically acceptable salt thereof. 9. The compound according to any one of claims 1, 2 and 4, which is a compound of formula (Ib) where R ⁴ and R ⁵ are independently selected from H, halogen, C1-C ₄ alkyl, C ₁ -C ₄ haloalkyl, C1-C ₄ alkoxy, C1-C ₄ haloalkoxy, phenyl and pyridinyl; or R ⁴ and R ⁵ can be taken into account together with the carbon atoms to which they are attached, obtaining a phenyl ring fused with - 118 043088 pyridinyl ring to which R ⁴ and R ⁵ are attached; or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, where the compound is selected from the following compounds: - 119 043088 - 120 043088 - 121 043088 - 122 043088 - 123 043088 - 124 043088 or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition containing a compound according to any one of claims 1, 2, 5 and 10 mixed with at least one pharmaceutically acceptable carrier or excipient. 12. The use of a compound according to any one of claims 1, 2, 5 and 10, or a pharmaceutically acceptable salt thereof, for the treatment of cancer or fibrosis. 13. Use according to claim 12 for the treatment of colon cancer, hepatocellular carcinoma (HCC), kidney cancer, liver cancer, gastric cancer, or liver or kidney fibrosis. 14. The use of a compound according to any one of claims 1 or 2 in therapy. 15. A pharmaceutical combination containing an effective amount of a compound according to any one of claims 1 or 2 and an additional therapeutic agent.