(Pyridin-2-yl)amine derivatives as TGF-beta R1 (ALK5) inhibitors for the treatment of cancer

Abstract

The present invention relates to pharmaceutical compounds, compositions, and methods, particularly as they relate to compositions and methods for treating and / or preventing proliferative disorders associated with TGFβR1 activity, such as cancer or fibrosis. The present invention provides compounds of Formula (I) and Formula (II) as further described herein, which have an acidic moiety that enhances tissue specificity to target tissues and organs. The present invention includes pharmaceutical compositions, pharmaceutical combinations, and methods of using these compounds to treat disorders including cancer or fibrosis.

Description

Invention Field

[0001] The field of this invention is compounds, pharmaceutical compositions and methods, particularly in relation to compositions and methods for treating proliferative disorders such as fibrosis or cancer, especially in tissues and organs where the compounds of this invention tend to accumulate at relatively high concentrations due to their pharmacokinetic properties. Background of the Invention

[0003] This invention relates to novel aryloxypyridyl compounds having an acidic moiety that inhibit the activity of transforming growth factor β receptor 1 (TGFβR1) and, due to the acidic moiety, tend to have limited systemic distribution and thus limit off-target tissue exposure to the inhibitor. The compounds must be used to treat conditions occurring in the digestive tract and first-pass metabolic tissues (liver, kidneys), such as cancer and fibrosis. This invention provides pharmaceutical compositions comprising the compounds, and methods for using the compounds to treat cancer, preferably colon cancer, hepatocellular carcinoma (HCC), renal cell carcinoma, pancreatic cancer, myelodysplastic syndrome (MDS), and gastric cancer, and / or fibrosis, preferably liver fibrosis and chronic kidney disease.

[0004] Transforming growth factor β (TGF-β or TGFβ) is a multifunctional cytokine that binds to the heteropolymeric complex of TGF-β type I and type II serine / threonine kinase receptors and activates the TGF-β receptor complex. This complex phosphorylates and activates SMAD2 and SMAD3, which then bind to SMAD4 and migrate to the nucleus to regulate the expression of various target genes. Key participants in the TGF-β receptor signaling pathway include TGFβ1, TGFβ2, TGFβ3, TGFβR1, TGFβR2, SMADs, SnON, SARA, SKI, DAB, TRAP, TAKI, SMIF, E2F4, E2F5, RBL1, RBL2, RBI, TFDP1, TFDP2, SMURF1, SMURF2, P300, CBP, and JUN. The SMAD-mediated TGF-β receptor pathway regulates various cellular and signaling pathways via the TGF pathway, which is already associated with cancer 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). Several types of cancer exist in which TGF ligands produced by the tumor or by the stroma within the tumor microenvironment are involved in tumor progression.

[0005] TGF-β1 is associated with angiogenesis, metastasis, and poor prognosis in 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 levels (Dickson et al. (1987) Proc. Natl. Acad. Sci. USA 84:837-841; 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). TGF-β1 was induced by tamoxifen treatment (Butta et al. (1992) Cancer Res. 52:4261-4264) and was associated with tamoxifen treatment failure in breast cancer (Thompson et al. (1991) Br. J. Cancer 63:609-614). Anti-TGF-β1 antibodies inhibited the growth of MDA-231 human breast cancer cells in athymic mice (Arteaga et al. (1993) J. Clin. Invest. 92:2569-2576), which was associated with increased splenic natural killer cell activity. CHO cells transfected with latent TGF-β1 also showed reduced NK activity and increased tumor growth in nude mice (Wallick et al. (1990) J. Exp. Med. 172:1777-1784). Therefore, TGF-β secreted by breast tumors can cause endocrine immunosuppression. High plasma concentrations of TGFβ1 have been shown to indicate a poor prognosis in patients with advanced breast cancer (Anscher et al. (1993) N. Engl. J. Med. 328: 1592-1598). Patients with high circulating TGF levels prior to high-dose chemotherapy and autologous bone marrow transplantation are at high risk for hepatic venous occlusive disease (15-50% of all patients, with a mortality rate as high as 50%) and idiopathic interstitial pneumonia (40-60% of all patients). These findings suggest that: 1) elevated plasma TGFβ levels can be used to identify patients at risk, and 2) reduced TGFβ signaling may decrease morbidity and mortality associated with these commonly used treatments for breast cancer.

[0006] Recent publications have also indicated that TGFβ signaling can be important in driving tumor resistance to standard care therapies, including chemotherapy and receptor tyrosine kinases (WO2012138783). In particular, in colorectal cancer, specific gene expression signatures have been shown to isolate a group of patients resistant to commonly used first-line treatments. When the TGFβ pathway is blocked by TGFβRI-specific small molecule inhibitors, these tumor cells regain sensitivity to treatment (Huang et al. (2012) Cell 151:937-950; Sadanandam et al. (2013) Nat Med 19:619-625; Vermeulen et al. (2013) Nat Ned 19:614-618; Roepman et al. (2014) 134:552-562).

[0007] Myelodysplastic syndromes (MDS) are hematopoietic disorders of the medullary tract characterized by ineffective bone marrow cell production. MDS is associated with alterations in the TGFβ pathway, represented by decreased SMAD7 levels. SMAD7 is an inhibitory SMAD that inhibits TGFβ-mediated SMAD signaling downstream of signaling activated by TGFβRI and TGFβRII ligands. Therefore, it is believed that overexpression of SMAD7 leads to overactivation of TGFβ signaling in MDS, and this phenotype can be reversed by treatment with small molecule inhibitors of TGFβRI (Zhou et al. (2011) Cancer Res. 71:955-963). Similarly, in glioblastoma (GBM), elevated TGFβ ligand levels are associated with disease progression. The antisense oligonucleotide therapeutic AP1002 has been shown to have potential activity in a subgroup of GBM patients (Bogdahn et al. (2011) Curr Phann Biotechnol). In melanoma, activation of the TGFβ pathway signaling is also associated with tolerance to BRAF and MEK inhibitors (Sun et al. (2014) Nature. 508: 118-122).

[0008] Many malignant cells secrete transforming growth factor-β (TGF-β), a potent immunosuppressant, suggesting that TGF-β production may represent an important mechanism by which tumors evade host immune surveillance (Flavell et al. (2010) Nat Rev Immunol 10:554-567; Kast et al. (1999) Leukemia 13:1188-1199). Establishing a subset of leukocytes with disrupted TGF-β signaling in tumor-bearing hosts provides a potential avenue for cancer immunotherapy, alone or in combination with one or more other immunotherapies, such as one or more PD-1 inhibitors (e.g., nivolumab, pembrolizumab), PD-L1 inhibitors, cancer vaccines, and bispecific immune-conjugating molecules (e.g., IMCgp100). TGFβ ligands produced by lymphocytes have been shown to antagonize tumor immune surveillance in preclinical studies (Donkor et al. (2012) Development. Oncoimmunology 1:162-171; Donkor et al. (2011) CytokineImmunity 35:123-134); disruption of this axis has been shown to provide antitumor benefits in mouse models and in vitro in preclinical studies (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). Bispecific fusion proteins binding both TGFβ and PD-L1 also exhibit synergistic antitumor activity compared to individual binders. (Lan et al., Sci. Transl. Med. Vol. 10, January 17, 2018). Transgenic animal models with disrupted TGFβ signaling in T cells were able to eradicate the typically lethal TGFβ-overexpressing lymphoma EL4 (Gorelik and Flavell, (2001) Nature Medicine 7(10):1118-1122). Downregulation of TGF secretion in tumor cells restores immunogenicity in the host, and T cell insensitivity to TGFβ leads to accelerated differentiation and autoimmunity, potentially requiring its components to combat tumors expressing autoantigens in the tolerant host. The immunosuppressive effects of TGFβ are also involved in a subgroup of HIV patients with a lower-than-predicted immune response based on CD4 / CD8 T cell counts (Garba et al. J. Immunology (2002) 168:2247-2254). TGFβ neutralizing antibodies were able to reverse this effect in cultures, suggesting that TGFβ signaling inhibitors could be used to reverse the immunosuppression present in this subgroup of HIV patients.

[0009] During the earliest stages of cancer development, TGFβ1 can act as a potent tumor inhibitor and mediate the effects of some chemopreventive agents. However, at certain points during the development and progression of malignancies, tumor cells appear to evade TGFβ-dependent growth inhibition in parallel with the presence of bioactive TGFβ in the microenvironment. The dual tumor-suppressive / tumor-promoting effects of TGFβ have been most clearly elucidated in transgenic systems that overexpress TGFβ in keratinocytes. Although transgenes are more resistant to the formation of benign skin lesions, the rate of metastatic transformation in transgenes is significantly increased (Cui et al. (1996) Cell 86(4):531-42).

[0010] TGFβ production in malignant cells of primary tumors appears to increase as the tumor progresses. Studies in numerous major epithelial carcinomas have shown that increased TGFβ production in human cancers occurs as a relatively late event during tumor progression. Furthermore, this tumor-associated TGFβ provides a selective advantage to tumor cells and promotes tumor progression. The effects of TGFβ on cell / cell and cell / matrix interactions lead to a greater tendency for invasion and metastasis. Tumor-associated TGFβ can allow tumor cells to evade immune surveillance because it is a potent inhibitor of clonal expansion of activated lymphocytes. TGFβ has also been shown to inhibit angiostatin production.

[0011] Cancer treatment modalities such as radiotherapy and chemotherapy induce the production of activated TGFβ in tumors, thereby promoting the overgrowth of malignant cells resistant to TGFβ growth inhibition. Therefore, these anticancer therapies increase the risk of tumors with enhanced growth and invasiveness and promote tumorigenesis. In this context, targeting agents that activate TGFβ-mediated signal transduction could be a highly effective therapeutic strategy. It has been shown that tumor cell tolerance to TGFβ counteracts many of the cytotoxic effects of radiotherapy and chemotherapy, and treatment-dependent activation of TGFβ in the matrix can even be detrimental, as it can make the microenvironment more conducive to tumor progression and promote tissue damage, leading to fibrosis. Developing TGFβ signal transduction inhibitors may be beneficial for treating progressive cancers, whether used alone or in combination with other therapies.

[0012] In addition, TGFβ signaling is known in the art to be involved in fibrotic diseases, such as liver fibrosis and chronic kidney disease. 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. TGFβ Signaling in Renal Disease; Trachtman H. et al. 2011. Kidney International 79:1236. A phase 1, single-dose study of fresolimumab, an anti-TGFβ 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.

[0013] Small molecule inhibitors of TGFβR1 known in the art are used to treat cancer and / or fibrosis. See, for example, WO2012 / 002680, WO2009 / 022171, WO2004 / 048382, WO2002 / 094833, and WO2016 / 057278. Unfortunately, no known class of inhibitors has yet produced a drug that has achieved regulatory approval (although at least one, Galunisertib, is still under investigation), likely due to the multiple biological activities of TGFβR1, which can produce toxic effects at in vivo concentrations similar to those required for therapeutic efficacy.

[0014]

[0015] There remains a need for novel small-molecule inhibitors of TGFβR1 suitable for treating proliferative disorders such as cancer and fibrosis, particularly inhibitors with pharmacokinetic properties that provide higher concentrations in the target organ or tissue and lower effective concentrations in other tissues, thereby reducing toxicity in non-target tissues. For example, small-molecule inhibitors can be administered orally to treat digestive system cancers, interacting directly with the target tissue within the digestive system without systemic distribution. Similarly, these compounds can have pharmacokinetic properties that preferentially accumulate in target organs such as the liver or kidneys, enabling their use in treating cancers in those organs, while still being relatively rapidly excreted before fully entering systemic circulation, thus avoiding high systemic drug concentrations that tend to produce toxicity elsewhere, such as in cardiac tissue.

[0016] This invention provides compounds that inhibit TGFβR1 (also known as Alk5) and contain an acidic moiety in a structural region that does not interfere with binding to the target site. The compounds of this invention are effective even when only intermittently present; therefore, long retention times (long in vivo half-lives) and maintaining drug levels above the minimum inhibitory concentration (MIC) are not necessarily required to achieve therapeutic efficacy, especially when the compounds of this invention are used in combination with other anticancer therapeutic agents, including PD-1 or PD-L1 inhibitors. These compounds are therefore used to treat cancers and fibrotic conditions in targeted tissues such as the liver, kidneys, and gastrointestinal system, while exhibiting reduced toxicity in non-target organs or tissues.

[0017] Without being bound by theory, the acidic portions of compounds of formulas (I) and (II) tend to reduce drug concentrations in many tissues or promote relatively rapid excretion, while producing locally effective concentrations in, for example, the colon, small intestine, liver, and / or kidneys, thus increasing the therapeutic index relative to non-acidic inhibitors of TGFβR1 used in these organs. This increased therapeutic index in these tissues is particularly advantageous for oral administration. It is also believed that the acidic compounds are actively transported to the liver and kidney tissues via transport peptides (e.g., OATP1, OATP2), thus producing local concentrations in those organs, even as the compounds enter systemic circulation. Furthermore, since colon cancer frequently metastasizes to the liver, the compounds of the present invention are also expected to inhibit cancer metastasis by presenting locally high concentrations in both the colon and liver tissues. The compounds of the present invention are therefore particularly useful for treating colon cancer, hepatocellular carcinoma (HCC), renal cell carcinoma, liver cancer, and gastric cancer, as well as fibrosis in the digestive and first-pass metabolic systems, particularly liver and kidney fibrosis.

[0018] Invention Summary

[0019] In one aspect, the present invention provides heterocyclic compounds having a structure according to Formula I:

[0020]

[0021] in:

[0022] Ring A is a 5-6 membered heteroaromatic ring, optionally containing other nitrogen atoms as ring members, and optionally further substituted by one or two independent groups selected from the following: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridyl and C3-C6 cycloalkyl, or fused with other phenyl or pyridyl rings;

[0023] R 1 It is selected from H, halogen, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 5-6 membered heterocyclic groups containing N, O or S as ring members, phenyl, and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0024] The C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, phenyl, and 5-6 heteroaryl groups are each optionally selected from one or two of R 2 Substitution of groups;

[0025] R 2 Each time it appears, it is independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl;

[0026] Cy is a ring selected from C3-C6 cycloalkyl, phenyl and 5-6 heteroaryl containing one or two nitrogen atoms as ring members, and optionally further substituted by one or two groups selected from the following: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy.

[0027] L is a divalent linker selected from the following: bond, CR2, -(CR2). 2-4 -、-O-(CR2) 1-3 - and -(CR2) m -X-(CR2) n -,

[0028] R is independently selected from H, F and C1-C4 alkyl groups each time it appears; or two R groups on the same carbon can form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloether together with the carbon they are attached to.

[0029] m is 0, 1, or 2;

[0030] n is 0, 1, or 2; and

[0031] X is a 5-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O and S as ring members;

[0032] Or its medicinal salt.

[0033] In another aspect, the present invention provides compounds of formula (II):

[0034]

[0035] in:

[0036] Ring A is a 5- or 6-membered heteroaromatic ring, optionally containing other nitrogen atoms as ring members and optionally fused with a phenyl or pyridyl ring, and ring A is optionally substituted by one or two independent groups selected from the following groups: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridyl and C3-C6 cycloalkyl;

[0037] R 1 It is selected from CN; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C1-C4 haloalkoxy; C3-C6 cycloalkyl; 5-6 membered heterocyclic groups containing N, O or S as ring members; phenyl; and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0038] The C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 5-6 heterocyclic, phenyl, and 5-6 heteroaryl groups are each optionally selected from Q. 1 Substitution of groups;

[0039] Q 1 Each time it appears, it is independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl;

[0040] L 1 It is a divalent linker selected from the following: -C(R) 9 )2-、-(C(R 10 )2) 2-4 -、-O-(C(R 10 )2) 1-3 - and -(C(R) 10 )2) m -XC(R 10 )2) n -;

[0041] R 9Each is independently a C1-C2 alkyl group, or two R groups. 9 It can form 3-6 membered cycloalkyl rings or 3-6 membered cycloethers together with the carbon atoms connected to both.

[0042] R 10 Each time it appears, it is independently selected from H, F, and C1-C4 alkyl groups; or two Rs on the same carbon. 10 The group can form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloether together with the carbon to which it is attached;

[0043] m is 0, 1, or 2;

[0044] n is 0, 1, or 2;

[0045] X is a pyrazolyl, triazolyl, or tetrazolyl ring;

[0046] Z 2 It is selected from CH and CQ 2 and N; and

[0047] q is 0 or 1;

[0048] Q 2 It is selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups;

[0049] Or its medicinal salt.

[0050] Other aspects of the invention relate to pharmaceutical compositions comprising compounds of formula (I) or formula (II). In other aspects, the invention provides methods of treating conditions such as cancer using the compounds and compositions of the invention, as further disclosed herein. Other aspects of the invention are disclosed herein.

[0051] Although described as specific tautomers, it should be understood that compounds of formula (I) and formula (II) include other tautomers, particularly in the tetrazolium ring moiety of compound (I).

[0052] The compounds described herein can be used for a variety of suitable purposes. In some embodiments, the compounds described above can be used therapeutically, particularly for the treatment of proliferative disorders such as cancer and fibrosis, especially disorders of the gastrointestinal or first-pass metabolic systems, including those described herein.

[0053] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) or any subform thereof as described herein, and at least one pharmaceutically acceptable carrier or excipient.

[0054] In another aspect, the present invention provides a method for treating and / or preventing proliferative disorders, such as cancer or fibrosis, comprising administering to an individual in need an effective amount of a compound of formula (I) or (II) or any subform thereof described herein, or a pharmaceutical composition containing at least one compound of formula (I) or (II) or any subform thereof described herein. While suitable for treating many proliferative disorders, the compound is specifically designated for treating cancers associated with excessive activity of TGFβR1 (also known as Alk5), particularly cancers of the liver, kidneys, and gastrointestinal system, wherein its physicochemical properties promote higher local concentrations in these organs and reduce exposure in other tissues prone to toxic effects.

[0055] In another aspect, the present invention provides the use of compounds of formula (I) or formula (II) or any subform thereof described herein for the preparation of medicaments. The acidic compounds of the present invention are particularly suitable for the preparation of medicaments for treating cancers associated with excessive activity of TGFβR1 (also known as Alk5), particularly cancers of the liver, kidneys, and gastrointestinal system.

[0056] In another aspect, the present invention provides a combination for treating and / or preventing a cellular proliferative condition in an individual, the combination comprising an effective amount of formula (I) or formula (II) or any subform thereof described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a second preventive or therapeutic agent for treating and / or preventing a cellular proliferative condition, such as cancer or fibrosis, in an individual, preferably an individual diagnosed with a condition requiring treatment. Suitable second therapeutic agents for use in combination with the compounds of the present invention include small molecule and antibody therapeutic agents suitable for treating the same condition as that treated with compounds of formula (I) or formula (II) and their subforms. Chemotherapy agents used in such combinations include 5-fluorouracil; leucovorin; oxaliplatin; capecitabine; irinotecan; regorafenib; trifluridine; tipiracil; drugs targeting VEGF, such as bevacizumab, aflibercept, or ramucirumab; or drugs targeting EGFR, such as cetuximab or panitumumab.

[0057] In one aspect, the combinations of the present invention comprise compounds of formula (I) or formula (II) or any subform thereof, combined with immuno-oncology therapeutic agents, such as PD-1 or PD-L1 inhibitors, or other known checkpoint inhibitors that help the body's own immune system recognize and fight cancer cells. Checkpoint inhibitors help an individual's immune system recognize and attack abnormal cells, such as cancer cells, and can significantly enhance the efficacy of chemotherapy, such as the compounds disclosed herein. Suitable checkpoint inhibitors include biologics and small molecule therapeutics; examples of these include ipilimumab, nivolumab, atezolizumab, avelumab, pembrolizumab, tislelizumab, and durvalumab.

[0058] In another aspect, the present invention provides a method for treating and / or preventing proliferative disorders, cancers, or fibrosis in an individual, the method comprising administering to the individual in need an effective amount of the combination described above, containing a compound of formula (I) or formula (II) or any subform thereof as described herein. The acidic compounds of the present invention are particularly suitable for treating cancers associated with excessive activity of TGFβR1 (also known as Alk5), especially cancers of the liver, kidneys, and gastrointestinal system.

[0059] In another aspect, the present invention provides a method for inhibiting TGFβR1 activity, the method comprising administering an effective amount of a pharmaceutical composition of formula (I) or formula (II) or any subform thereof or containing a combination of such compounds to an individual in need or contacting such cells with cells having such activity.

[0060] Other aspects and embodiments of the invention will be apparent from the following detailed description and examples, or from the following detailed description and examples.

[0061] Detailed description

[0062] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, patent applications, published patent applications, and other publications mentioned herein are incorporated herein by reference in their entirety. Where a definition set forth in this section contradicts or otherwise differs from a definition set forth in a patent, patent application, or other publication incorporated herein by reference, the definition set forth in this section shall prevail with respect to the definition incorporated herein by reference.

[0063] As used in this article, "a" or "an" means "at least one" or "one or more".

[0064] As used herein, the term "individual" refers to an animal. In some respects, an animal is a mammal. An individual also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some implementations, an individual is a human being. As used herein, "patient" refers to a human individual.

[0065] As used in this article, the term “inhibition” means reducing or suppressing a given condition, symptom, ailment, or disease, or significantly reducing the baseline activity of a biological activity or process.

[0066] As used herein, in one embodiment, the term "treatment" for any disease or condition means improving the disease or condition (i.e., slowing or halting or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" means alleviating or improving at least one physiological parameter, including physiological parameters that the patient may not be able to discern. In yet another embodiment, "treatment" means regulating the disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing bodily parameters), or both.

[0067] In another implementation plan, "treatment" means preventing or delaying the onset, development, or progression of a disease or symptom.

[0068] As used herein, unless otherwise indicated herein or clearly contradicted by the context, the terms “a,” “an,” “the,” and similar terms used in the context of this invention (particularly in the context of the claims) shall be construed as encompassing both the singular and plural forms.

[0069] "Optionally substituted" means that the mentioned group may be unsubstituted or may be substituted at one or more positions by a group suitable for replacing the group, or by any one or any combination of those specified groups. The number, position, and choice of substituents are understood to cover only those substitutions that a skilled chemist would expect to be fairly stable; therefore, 'oxo' will not be a substituent on, for example, an aryl or heteroaryl ring, and a single carbon atom will not have three hydroxyl or amino substituents.

[0070] As used in this article, "halogenated" or "halogen" can refer to fluorine, chlorine, bromine, or iodine.

[0071] As used in this article, “C1-C6 alkyl” or “C 1-6 "Alkyl" indicates a straight-chain or branched alkyl group having 1 to 6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, the definition is modified accordingly. For example, "C1-C4 alkyl" would represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0072] As used in this article, “C1-C6 alkoxy” or “C 1-6 "Alkoxy" indicates a straight-chain or branched alkoxy group having 1 to 6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, the definition is modified accordingly. For example, "C1-C4 alkoxy" would represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0073] As used in this article, “C1-C4 haloalkyl” or “C 1-4 "Halogenated alkyl" indicates a straight-chain or branched alkyl group having 1-4 carbon atoms, wherein at least one hydrogen atom has been replaced by a halogen. The number of halogen substitutions can be from one hydrogen atom to the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C6 or C3, the definition is modified accordingly. Thus, "C1-C4 halogenated alkyl" would represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl having at least one halogen-substituted hydrogen atom, for example, where the halogen is fluorine: CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CHCF3, or CF3CF2CF2CF2-.

[0074] As used herein, "C3-C8 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring having 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The definition is modified accordingly if a different number of carbon atoms is specified, such as C3-C6.

[0075] As used herein, "3-6 membered cyclic ethers" refers to 3-6 membered saturated heterocycles containing one oxygen atom as a ring member, including ethylene oxide, propylene oxide, tetrahydrofuran, and tetrahydropyran. These 3-6 membered cyclic ethers can be substituted with groups suitable for use as substituents on other heterocyclic moieties.

[0076] "4- to 8-membered heterocyclic group", "5- to 6-membered heterocyclic group", "3- to 10-membered heterocyclic group", "3- to 14-membered heterocyclic group", "4- to 14-membered heterocyclic group" and "5- to 14-membered heterocyclic group" refer to heterocycles of 4 to 8, 5 to 6, 3 to 10, 3 to 14, 4 to 14, and 5 to 14 members, respectively; unless otherwise specified, the ring contains 1 to 7, 1 to 5, or 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members, and the ring may be saturated or partially saturated but not aromatic. Heterocyclic groups may be attached at heteroatoms or carbon atoms. The term "heterocyclic group" includes monocyclic groups, fused-ring groups, and bridging groups. Examples of heterocyclic groups include (but are not limited to) pyrrolidine, piperidine, piperazine, pyrrolidine, pyrrolidone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiaran, tetrahydropyran, 1,4-dioxane, 1,4-oxathiacyclohexane, 8-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, azabicyclobutane, ethylenedioxy, oxacyclobutane, 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-adjacent heteroatoms selected from N, O, and S.

[0077] As used herein, "cyclic ether" refers to a heterocycle containing at least one oxygen atom as a ring member. More generally, the term refers to a heterocycle containing exactly one oxygen atom as a ring member. Specific examples of cyclic ethers include propylene oxide or propylene oxide alkyl, tetrahydrofuranyl, tetrahydropyranyl, etc. Cyclic ethers may be substituted with one or more groups suitable as substituents on the heterocycle.

[0078] "Heteroaryl" refers to a fully unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5-14 membered monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, or S. Typically, heteroaryl groups are 5-10 membered rings or ring systems (e.g., 5-7 membered monocyclic groups or 8-10 membered bicyclic groups), usually 5-6 membered rings. Typical heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2-thienyl or 3-thienyl, 2-furanyl or 3-furanyl, 2-pyrroleyl or 3-pyrroleyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl or 5-oxazolyl. 3-Isoxazolyl, 4-isoxazolyl or 5-isoxazolyl, 3-(1,2,4-triazolyl) or 5-(1,2,4-triazolyl), 4-(1,2,3-triazolyl) or 5-(1,2,3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-pyridyl, 3-pyridyl or 4-pyridyl, 3-pyrazinyl or 4-pyrazinyl, 3-pyrazinyl, 4-pyrazinyl or 5-pyrazinyl, 2-pyrazinyl, and 2-pyrimidine, 4-pyrimidine or 5-pyrimidine.

[0079] The term "hydroxyl group" refers to the -OH group.

[0080] As used herein, the term "alkyl" refers to a saturated hydrocarbon group in a straight-chain, branched, or cyclic configuration or any combination thereof, and particularly envisioned alkyl groups include those having ten or fewer carbon atoms, especially 1 to 6 carbon atoms, and lower alkyl groups having 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, etc.

[0081] Alkyl groups may be unsubstituted, or may be substituted to a chemically meaningful degree. Typical substituents include, but are not limited to, halogens, =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 a 2. -OOCR a -COR a and -NO2, where each R a Independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclic, C4-C 10 Heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 kynyl, C2-C8 heterokynyl, C6-C 10 Aryl or C5-C 10 heteroaryl, and R a Each of these groups may be optionally substituted with the following groups: 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, of which R b Each of the following groups is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclic, or C4-C 10 Heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C6-C 10 Aryl or C5-C 10 Heteroaryl groups. Alkyl, alkenyl, and alkynyl groups can also be replaced by C1-C8 acyl groups, C2-C8 heteroacyl groups, and C6-C... 10 Aryl or C5-C 10 Heteroaryl substitutions can each be replaced by substituents suitable for a specific group. When the substituents contain two R groups on the same or adjacent atoms... a Or R b Groups (e.g., -NR) b 2, or -NR b -C(O)R b When ), the two R a Or R bThe group may optionally form a ring with 5-8 ring members together with the atoms of the substituents to which it is attached, which can be used for R a Or R b It can be substituted where permitted, and may contain other heteroatoms (N, O, or S) as ring members.

[0082] As used herein, the term "alkenyl" refers to an alkyl group as defined above, having at least two carbon atoms and at least one carbon-carbon double bond. Therefore, alkenyl groups particularly contemplated include straight-chain, branched, or cyclic alkenyl groups having two to ten carbon atoms (e.g., vinyl, propenyl, butenyl, pentenyl, etc.) or five to ten atoms (for cyclic alkenyl groups). Alkenyl groups may optionally be substituted with groups suitable for use with the alkyl groups described herein.

[0083] Similarly, as used herein, the term "alkynyl" refers to an alkyl or alkenyl group as defined above and having at least two (preferably three) carbon atoms and at least one carbon-carbon triple bond. Particularly contemplated alkynyl groups include straight-chain, branched, or cyclic alkynes having two to ten total carbon atoms (e.g., ethynyl, propynyl, butynyl, cyclopropylethynyl, etc.). The alkynyl group may optionally be substituted with a group suitable for use with the alkyl group described herein.

[0084] As used herein, the term "cycloalkyl" refers to a cyclic alkane (i.e., in which the carbon atoms of the hydrocarbon are linked to form a ring), preferably comprising three to eight carbon atoms. Thus, exemplary cycloalkane include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group may also include one or two double bonds forming a "cycloalkenyl". The cycloalkyl group may optionally be substituted with groups suitable for use with the alkyl groups described herein.

[0085] As used herein, the term "aryl" or "aromatic moiety" refers to an aromatic ring system that may further include one or more non-carbon atoms. These are typically 5-6 membered single rings or 8-10 membered bicyclic groups and may be substituted. Thus, anticipated aryl groups include (e.g., phenyl, naphthyl, etc.) and pyridyl groups. Additionally, anticipated aryl groups may be fused with one or two 5- or 6-membered aryl or heterocyclic groups (i.e., covalently bonded to two atoms on the first aromatic ring), hence the term "fused aryl" or "fused aromatic ring."

[0086] Aromatic groups containing one or more heteroatoms (typically N, O, or S) as ring members are called heteroaryl groups or heteroaromatic groups. Typical heteroaryl groups include monocyclic 5-6 membered aromatic groups, such as pyridyl, pyrimidinyl, pyrazinyl, thiophene, furanyl, pyrroleyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and imidazoleyl, as well as fused bicyclic moieties formed by fusion of one of these monocyclic groups with a benzene ring or any of the heteroaromatic monocyclic groups to form 8-10 membered bicyclic groups, such as indolyl, benzimidazolyl, indazoleyl, benzotriazolyl, isoquinolinyl, quinolinyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopyrimidinyl, quinazolinyl, quinoxalinyl, cenolinyl, etc. Any monocyclic or fused bicyclic system with aromatic characteristics in terms of the electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups in which at least one ring directly connected to the rest of the molecule has aromatic characteristics. Typically, the ring system contains 5-12 ring atoms. Preferably, the heteroaryl group is a 5-6 membered ring.

[0087] As used herein, the terms “heterocycle,” “cycloheteroalkyl,” and “heterocyclic moiety” are used interchangeably to refer to any compound in which multiple atoms form a ring via multiple covalent bonds, wherein the ring includes at least one atom other than a carbon atom as a ring member. Particularly anticipated heterocycles include 5- and 6-membered rings having nitrogen, sulfur, or oxygen as non-carbon atoms (e.g., imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, thiazole, tetraazole, etc.). Typically, these rings contain 0-1 oxygen or sulfur atoms, at least one and typically 2-3 carbon atoms, and at most four nitrogen atoms as ring members. Additionally, anticipated heterocycles may be fused with one or two carbon rings or heterocycles (i.e., covalently bonded to two atoms on a first heterocycle), and are therefore referred to as “fused heterocycles” or “fused heterocyclic moiety” as used herein. When the ring is an aromatic ring, these may be referred to herein as ‘heteroaryl’ or heteroaryl.

[0088] Non-aromatic heterocyclic groups can be substituted by groups suitable for alkyl substituents as described above.

[0089] Aryl and heteroaryl groups may be substituted where permitted. Suitable substituents include, but are not limited to, halogens, -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 Independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclic, C4-C 10 Heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 kynyl, C2-C8 heterokynyl, C6-C 10 Aryl or C5-C 10 heteroaryl, and R a Each of these groups may be optionally substituted with the following groups: 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, of which R b Each of the following groups is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclic, or C4-C 10 Heterocyclic alkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C6-C 10 Aryl or C5-C 10 Heteroaryl groups. Alkyl, alkenyl, and alkynyl groups can also be replaced by C1-C8 acyl groups, C2-C8 heteroacyl groups, and C6-C... 10 Aryl or C5-C 10 Heteroaryl substitutions can each be replaced by substituents suitable for a specific group. When the substituents contain two R groups on the same or adjacent atoms... a Or R b Groups (e.g., -NR) b 2, or -NR b -C(O)R b When ), the two R a Or R bThe group may optionally form a ring with 5-8 ring members together with the atoms of the substituents to which it is attached, which can be used for R a Or R b It can be substituted where permitted, and may contain other heteroatoms (N, O, or S) as ring members.

[0090] As used herein, the term "alkoxy" refers to a hydrocarbon group linked via an oxygen atom, such as -O-Hc, wherein the hydrocarbon moiety Hc may have any number of carbon atoms, typically 1-10 carbon atoms, and may further include double or triple bonds and may include one or two oxygen, sulfur, or nitrogen atoms in the alkyl chain, and may be substituted with aryl, heteroaryl, cycloalkyl, and / or heterocyclic groups. Suitable alkoxy groups, for example, include methoxy, ethoxy, propoxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, etc. Similarly, the term "alkathioyl" refers to an alkyl sulfide of the general formula -S-Hc, wherein the hydrocarbon moiety Hc is as described with respect to alkoxy groups. Desired alkathioyl groups include, for example, methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, etc.

[0091] As used herein, the term 'amino' refers to the group -NH2. The term 'alkylamino' refers to an amino group in which one or both hydrogen atoms are replaced by a hydrocarbon group Hc as described above, wherein the amino nitrogen "N" may be replaced by one or two Hc groups as described with respect to the alkoxy group above. Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, etc. Additionally, the term 'substituted amino' refers to an amino group in which one or both hydrogen atoms are replaced by a hydrocarbon group Hc as described above, wherein the amino nitrogen "N" may be replaced by one or two Hc groups as described with respect to the alkoxy group above.

[0092] As used herein, the term 'acyl' refers to a group of the formula -C(=O)-D, where D represents an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group as described above. A typical example is a group where D is C1-C2. 10 Alkyl, C2-C 10 The group may be an alkenyl, alkynyl, or phenyl group, each of which may be optionally substituted. In some embodiments, D may be H; Me; Et; isopropyl; propyl; butyl; C1-C4 alkyl substituted with -OH, -OMe, or NH2; phenyl; halophenyl; alkylphenyl, etc.

[0093] As used herein, the term "aryloxy" refers to an aryl group attached to an oxygen atom, wherein the aryl group may be further substituted. Suitable aryloxy groups include, for example, phenoxy groups. Similarly, as used herein, the term "arylthio" refers to an aryl group attached to a sulfur atom, wherein the aryl group may be further substituted. Suitable arylthio groups include, for example, phenylthio groups.

[0094] Each hydrocarbon moiety, such as alkoxy, alkylthio, alkylamino, and aryloxy, may be substituted where appropriate for the relevant hydrocarbon moiety.

[0095] The following embodiments represent some aspects of the present invention:

[0096] 1. Compound of formula (I):

[0097]

[0098] in:

[0099] Ring A is a 5-6 membered heteroaromatic ring, optionally containing other nitrogen atoms as ring members, optionally fused with other phenyl or pyridyl rings, and optionally further substituted by one or two independent groups selected from the following: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridyl and C3-C6 cycloalkyl;

[0100] R 1 It is selected from H; halogen; CN; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C1-C4 haloalkoxy; C3-C6 cycloalkyl; 5-6 membered heterocyclic groups containing N, O or S as ring members; phenyl; and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0101] The C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, phenyl, and 5-6 heteroaryl groups are each optionally selected from one or two of R 2 Substitution of groups;

[0102] R 2 Each time it appears, it is independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl;

[0103] Cy is a ring selected from C3-C6 cycloalkyl, phenyl and 5-6 heteroaryl containing one or two nitrogen atoms as ring members, and optionally further substituted by one or two groups selected from the following: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy.

[0104] L is a divalent linker selected from the following: bond, CR2, -(CR2). 2-4 -、-O-(CR2) 1-3 -and-(CR2) m -X-(CR2) n -,

[0105] R is independently selected from H, F and C1-C4 alkyl groups each time it appears; or two R groups on the same carbon can form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloether together with the carbon they are attached to.

[0106] m is 0, 1, or 2;

[0107] n is 0, 1, or 2; and

[0108] X is a 5-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O and S as ring members;

[0109] Or its medicinal salt.

[0110] 2. The compound according to embodiment 1, wherein R 1 It is selected from C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C1-C4 haloalkoxy; C3-C6 cycloalkyl; 5-6 membered heterocyclic groups containing N, O or S as ring members; phenyl; and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0111] The C1-C4 alkyl group; C1-C4 haloalkyl group; C1-C4 alkoxy group; C1-C4 haloalkoxy group; C3-C6 cycloalkyl group; 5-6 membered heterocyclic group containing N, O or S as a ring member; phenyl group and 5-6 membered heteroaryl group are each optionally selected from one or two of R. 2 Substitution of groups;

[0112] Or its medicinal salt.

[0113] 3. The compound according to embodiment 1 or 2, wherein R 1 It is methyl, phenyl, or 2-pyridyl; or a pharmaceutically acceptable salt thereof.

[0114] 4. A compound according to any one of embodiments 1 to 3, wherein Cy is a ring selected from phenyl and pyridyl, and optionally further substituted by a group selected from: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy;

[0115] Or its medicinal salt.

[0116] 5. The compound according to embodiment 4 has the following formula:

[0117]

[0118] Where Z is CH or N, and Q is selected from H, Me, CF3, OMe and halogens;

[0119] Or its medicinal salt.

[0120] 6. The compound according to any of the foregoing embodiments, wherein L is a divalent linker selected from: CR2, -(CR2). 2-4 -、-O-(CR2) 1-3 -and-(CR2) m -X-(CR2) n -;

[0121] Or its medicinal salt.

[0122] 7. The compound according to embodiment 6, wherein R is independently selected from H, F and Me each time it appears;

[0123] Or its medicinal salt.

[0124] 8. The compound according to embodiment 6, wherein L is selected from CH2, -CH2CH2-, C(Me)2, -CHMe-, -OCH2-, -CH2CF2-, -CF2CH2-, -CMe2CH2- and -CH2CMe2-;

[0125] Or its medicinal salt.

[0126] 9. The compound according to any one of the foregoing embodiments is a compound of formula (Ia):

[0127]

[0128] Wherein Q is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy in each occurrence; and

[0129] Z represents CH, CQ, or N;

[0130] Or its medicinal salt.

[0131] 10. A compound according to any of the foregoing embodiments, wherein ring A is pyridinyl or pyrazolyl and optionally substituted by one or two groups independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl.

[0132] Or its medicinal salt.

[0133] 11. The compound according to embodiment 1, wherein R 1 It is pyridyl, phenyl, methyl, tetrahydrofuranyl, or tetrahydropyranyl, and optionally is selected from one or two of R. 2 Substitution of groups;

[0134] Or its medicinal salt. Preferably, R 1 In these embodiments, it is 2-pyridyl, methyl, or phenyl.

[0135] 12. A compound according to any one of embodiments 1 to 10, which is a compound of formula (Ib):

[0136]

[0137] Where R 4 and R 5 Independently selected from H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, and pyridyl; or R 4 and R 5 It can form a benzene ring together with the carbon atom it is attached to, and this benzene ring is related to R. 4 and R 5 The pyridinium rings are fused together;

[0138] Or its medicinal salt.

[0139] 13. A compound according to any one of embodiments 1 to 10, which is a compound of formula (Ic):

[0140]

[0141] Where R 6 It is selected from C1-C4 alkyl, C1-C4 haloalkyl and C3-C6 cycloalkyl;

[0142] Or its medicinal salt.

[0143] 14. The compound according to embodiment 13, wherein R 6 It is selected from methyl, ethyl, isopropyl and cyclopropyl; or their pharmaceutically acceptable salts.

[0144] 15. A compound according to any of the foregoing embodiments, wherein L is [Cy]-(CR2). m -X-(CR2) n - where [Cy] indicates the junction point between L and the group Cy;

[0145] m is 1 or 2;

[0146] n is 0, 1, or 2; and

[0147] X is a tetrazolium ring;

[0148] Or its medicinal salt.

[0149] 16. A compound according to any one of embodiments 1 to 15, wherein L is CH2, C(Me)2, -OCH2-[T], -CH2CH2-, -C(Me)2CH2-[T], -CH2C(Me)2-[T] or -CF2CH2-[T], wherein [T] indicates the terminal of L connected to the tetrazolium ring in formula (I); or a pharmaceutically acceptable salt thereof.

[0150] 17. The compound according to embodiment 1, wherein the compound is selected from the compounds of Examples 12-33, 44-65, 67 and 175-216; or pharmaceutically acceptable salts thereof.

[0151] 18. Compound of formula (II):

[0152]

[0153] in:

[0154] Ring A is a 5- or 6-membered heteroaromatic ring, optionally containing other nitrogen atoms as ring members and optionally fused with a phenyl or pyridyl ring, and ring A is optionally substituted by one or two independent groups selected from the following groups: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridyl and C3-C6 cycloalkyl;

[0155] R 1 It is selected from CN; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C1-C4 haloalkoxy; C3-C6 cycloalkyl; 5-6 membered heterocyclic groups containing N, O or S as ring members; phenyl; and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0156] The C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 5-6 heterocyclic, phenyl, and 5-6 heteroaryl groups are each optionally selected from Q. 1 Substitution of groups;

[0157] Q 1 Each time it appears, it is independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl;

[0158] L 1 It is a divalent linker selected from the following: -C(R) 9 )2-、-(C(R 10 )2) 2-4 -、-O-(C(R 10 )2) 1-3 - and -(C(R)10 )2) m -XC(R 10 )2) n -;

[0159] Each R 9 Independently C1-C2 alkyl, or two R 9 It can form 3-6 membered cycloalkyl rings or 3-6 membered cycloethers together with the carbon atoms connected to both.

[0160] R 10 Each time it appears, it is independently selected from H, F, and C1-C4 alkyl groups; or two Rs on the same carbon. 10 The group can form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloether together with the carbon to which it is attached;

[0161] m is 0, 1, or 2;

[0162] n is 0, 1, or 2;

[0163] X is a pyrazolyl, triazolyl, or tetrazolyl ring;

[0164] Z 2 It is selected from CH and CQ 2 and N; and

[0165] q is 0 or 1;

[0166] Q 2 It is selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups;

[0167] Or its medicinal salt.

[0168] 19. The compound according to embodiment 18, wherein the compound has formula (IIa):

[0169]

[0170] R 7 and R 8 Independently selected from H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, and pyridyl; or R 7 and R 8 It can form a benzene ring together with the carbon atom it is attached to, and this benzene ring is related to R. 7 and R 8 The pyridinium rings are fused together;

[0171] Or its medicinal salt.

[0172] 20. A compound according to embodiment 18 or 19, wherein the compound has formula (IIb):

[0173]

[0174] Z 1 It is selected from CH and N;

[0175] p is 0, 1, or 2; and

[0176] Q 1 Each is independently selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups;

[0177] Or its medicinal salt.

[0178] 21. A compound according to any one of embodiments 18 to 20, wherein L 1 The values ​​are C(Me)2, -OCH2-[C], -CH2CH2-, -C(Me)2CH2-[C], -CH2C(Me)2-[C] or -CF2CH2-[C], where [C] indicates the linking end of L with the carboxylic acid in formula (II) or (IIa) or (IIb);

[0179] Or its medicinal salt.

[0180] 22. A compound according to any one of embodiments 18 to 20, wherein L 1 -(CR) 10 2) m -X-(CR 10 2) n - where m is 1 and n is 1; or its medicinal salt.

[0181] 23. A compound according to any one of embodiments 19 to 22, wherein R 7 and R 8 Each is independently selected from H and Me; or their medicinal salts.

[0182] 24. A compound according to any one of embodiments 19 to 23, wherein Z 2 It is CH or N; or its medicinal salt.

[0183] 25. A compound according to any one of embodiments 18 to 24, wherein Z 2 CH; or its medicinal salt.

[0184] 26. The compound according to embodiment 18, selected from the compounds of Examples 1, 4-7, 10-11, 34-37, 39-41, 43, 66, 68, 70-110, 115-116, 118-174 and 217; or pharmaceutically acceptable salts thereof.

[0185] 27. A compound selected from the compounds of Examples 1-217;

[0186] Or its medicinal salt.

[0187] 28. A pharmaceutical composition comprising a compound according to any one of the foregoing embodiments and at least one pharmaceutically acceptable carrier or excipient.

[0188] 29. A method for treating cancer or fibrosis, comprising administering to an individual in need an effective amount of a compound according to any one of embodiments 1 to 27, or a pharmaceutical composition according to embodiment 28.

[0189] 30. The method according to implementation plan 29 is a method for treating colon cancer, hepatocellular carcinoma (HCC), renal cancer, liver cancer, gastric cancer, or fibrosis in the liver or kidney.

[0190] 31. A compound according to any one of embodiments 1 to 27, used for treatment.

[0191] 32. The use of a compound according to any one of embodiments 1 to 27, for the preparation of a medicine.

[0192] 33. A pharmaceutical combination comprising an effective amount of a compound according to any one of embodiments 1 to 27 and other therapeutic agents.

[0193] Another set of embodiments of the present invention includes the following:

[0194] 1A. Compound of formula (II):

[0195]

[0196] in:

[0197] Ring A is a 5- or 6-membered heteroaromatic ring, optionally containing other nitrogen atoms as ring members and optionally fused with a phenyl or pyridyl ring, and ring A is optionally substituted by one or two independent groups selected from the following groups: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridyl, 4-6 membered cyclic ether and C3-C6 cycloalkyl;

[0198] R 1 It is selected from CN; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C1-C4 haloalkoxy; C3-C6 cycloalkyl; 5-6 membered heterocyclic groups containing N, O or S as ring members; phenyl; and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0199] The C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 5-6 heterocyclic, phenyl, and 5-6 heteroaryl groups are each optionally selected from Q. 1 Substitution of groups;

[0200] Q 1 Each time it appears, it is independently selected from halogen, CN, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl;

[0201] L 1 It is a divalent linker selected from the following: -C(R) 9 )2-、-(C(R 10 )2) 2-4 -、-O-(C(R 10 )2) 1-3 - and -(C(R) 10 )2) m -XC(R 10 )2) n -;

[0202] R 9 Each is independently a C1-C2 alkyl or halogen, or two Rs 9 It can form 3-6 membered cycloalkyl rings or 3-6 membered cycloethers together with the carbon atoms connected to both.

[0203] R 10 Each time it appears, it is independently selected from H, F, and C1-C4 alkyl groups; or two Rs on the same carbon. 10 The group can form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloether together with the carbon to which it is attached;

[0204] m is 0, 1, or 2;

[0205] n is 0, 1, or 2;

[0206] X is a pyrazolyl, triazolyl, or tetrazolyl ring;

[0207] Z 2 It is selected from CH and CQ 2 and N; and

[0208] q is 0 or 1;

[0209] Q 2 It is selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups;

[0210] Or its medicinal salt.

[0211] In an example of implementation scheme 1A, ring A is pyridinyl or pyrazolyl.

[0212] 2A. The compound according to embodiment 1A, wherein the compound has formula (IIa):

[0213]

[0214] in:

[0215] R 7 and R 8 Independently selected from H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, and pyridyl; or R 7 and R 8 It can form a benzene ring together with the carbon atom it is attached to, and this benzene ring is related to R. 7 and R 8 The pyridinium rings are fused together;

[0216] Or its medicinal salt.

[0217] Preferably, in this embodiment 2A, R 7 and R 8 Each is independently selected from H, halogens, and C1-C4 alkyl groups. In one example of embodiment 2A, R 1 It is selected from methyl, phenyl, pyridyl and tetrahydropyranyl.

[0218] 3A. A compound according to embodiment 1A or 2A, wherein the compound has formula (IIb):

[0219]

[0220] Z 1 It is selected from CH and N;

[0221] p is 0, 1, or 2; and

[0222] Q 1 Each is independently selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups;

[0223] Or its medicinal salt.

[0224] Preferably, in embodiment 3A, R 7 and R 8 Each is independently selected from H, halogens, and C1-C4 alkyl groups.

[0225] 4A. The compound according to embodiment 1A or 2A, wherein R 1It is selected from CN, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl and 5-6 membered heterocyclic groups containing N, O or S as ring members; or pharmaceutically acceptable salts thereof.

[0226] 5A. The compound according to embodiment 1A, wherein the compound has the formula (IIc):

[0227]

[0228] Where R 6 It is selected from C1-C4 alkyl, C1-C4 haloalkyl and C3-C6 cycloalkyl;

[0229] Or its medicinal salt.

[0230] In one example of implementation scheme 5A, R 1 It is selected from methyl, phenyl, pyridyl and tetrahydropyranyl.

[0231] 6A. A compound according to any one of embodiments 1A-5A, wherein L 1 The values ​​are C(Me)2, -OCH2-[C], -CH2CH2-, -C(Me)2CH2-[C], -CH2C(Me)2-[C] or -CF2CH2-[C], where [C] indicates the connection end of L with the carboxylic acid in formula (II) or (IIa) or (IIb);

[0232] Or its medicinal salt.

[0233] 7A. A compound according to any one of embodiments 1A to 5A, wherein L 1 -(CR) 10 2) m -X-(CR 10 2) n - where m is 1 and n is 1; or its medicinal salt.

[0234] 8A. A compound according to any one of embodiments 1AA-4, wherein R 7 and R 8 Each is independently selected from H, Me and Et; or their medicinal salts.

[0235] 9A. A compound according to any one of embodiments 1A to 8A, wherein Z 2 It is CH or N; or its medicinal salt.

[0236] 10A. The compound according to embodiment 9A, wherein Z 2 CH; or its medicinal salt.

[0237] 11A. The compound according to embodiment 10A, wherein R 1For Me and L 1 It is -C(Me)2-, or its medicinal salt.

[0238] 12A. The compound according to embodiment 1A, selected from the compounds of Examples 1, 4-7, 10-11, 34-37, 39-41, 43, 66, 68, 70-110, 115-116, 118-174 and 217; or pharmaceutically acceptable salts thereof.

[0239] 13A. Compound of formula (I):

[0240]

[0241] in:

[0242] Ring A is a 5- or 6-membered heteroaromatic ring, optionally containing other nitrogen atoms as ring members and optionally fused with a phenyl or pyridyl ring, and ring A is optionally substituted by one or two independent groups selected from the following groups: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridyl, 4-6 membered cyclic ether and C3-C6 cycloalkyl;

[0243] R 1 It is selected from H; halogen; CN; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C1-C4 haloalkoxy; C3-C6 cycloalkyl; 5-6 membered heterocyclic groups containing N, O or S as ring members; phenyl; and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0244] The C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, phenyl, 5-6 membered heterocyclic and 5-6 membered heteroaryl groups are each optionally selected from one or two of R 2 Substitution of groups;

[0245] R 2 Each time it appears, it is independently selected from halogen, CN, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl;

[0246] Cy is a ring selected from C3-C6 cycloalkyl, phenyl and 5-6 heteroaryl containing one or two nitrogen atoms as ring members, and optionally further substituted by one or two groups selected from the following: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy.

[0247] L is a divalent linker selected from the following: bond, CR2, -(CR2). 2-4-、-O-(CR2) 1-3 -and-(CR2) m -X-(CR2) n -,

[0248] R is independently selected from H, F and C1-C4 alkyl groups each time it appears; or two R groups on the same carbon can form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloether together with the carbon they are attached to.

[0249] m is 0, 1, or 2;

[0250] n is 0, 1, or 2; and

[0251] X is a 5-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O and S as ring members;

[0252] Or its medicinal salt.

[0253] Typically, in implementation scheme 13A, R 1 It is methyl, phenyl, pyridyl, or tetrahydropyranyl. Preferably, ring A is pyridyl or pyrazolyl. Also preferably, Cy is a phenyl or pyridyl ring, and in some embodiments, the -NH and -L groups shown in formula (I) are meta-oriented (1,3-disubstituted).

[0254] 14A. The compound according to embodiment 13A, wherein R 1 It is selected from C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C1-C4 haloalkoxy; C3-C6 cycloalkyl; 5-6 membered heterocyclic groups containing N, O or S as ring members; phenyl; and 5-6 membered heteroaryl groups containing one or two nitrogen atoms as ring members.

[0255] The C1-C4 alkyl group; C1-C4 haloalkyl group; C1-C4 alkoxy group; C1-C4 haloalkoxy group; C3-C6 cycloalkyl group; 5-6 membered heterocyclic group containing N, O or S as a ring member; phenyl group and 5-6 membered heteroaryl group are each optionally selected from one or two of R. 2 Substitution of groups;

[0256] Or its medicinal salt.

[0257] 15A. The compound according to embodiment 13A or 14A, wherein R 1 It is methyl, phenyl, or 2-pyridyl; or a pharmaceutically acceptable salt thereof.

[0258] 16A. A compound according to any one of embodiments 13A to 15A, wherein Cy is a ring selected from phenyl and pyridyl, and optionally further substituted by a group selected from: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy;

[0259] Or its medicinal salt.

[0260] 17A. The compound according to embodiment 16A has the following formula:

[0261]

[0262] Where Z is CH or N, and Q is selected from H, Me, CF3, OMe and halogens;

[0263] Or its medicinal salt.

[0264] In a preferred embodiment of embodiment 17A, ring A is pyridinyl or pyrazolyl. In many examples of such compounds, R 1 It is selected from methyl, phenyl and 2-pyridyl.

[0265] 18A. A compound according to any one of embodiments 13A to 17A, wherein L is a divalent linker selected from: CR2, -(CR2). 2-4 -、-O-(CR2) 1-3 -and-(CR2) m -X-(CR2) n -;

[0266] Or its medicinal salt.

[0267] 19A. The compound according to embodiment 18A, wherein R is independently selected from H, F and Me each time it appears;

[0268] Or its medicinal salt.

[0269] 20A. The compound according to embodiment 19A, wherein L is selected from CH2, -CH2CH2-, C(Me)2, -CHMe-, -OCH2-, -CH2CF2-, -CF2CH2-, -CMe2CH2- and -CH2CMe2-;

[0270] Or its medicinal salt.

[0271] 21A. A compound according to any one of embodiments 13A to 20A, which is a compound of formula (Ia):

[0272]

[0273] Wherein Q is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy in each occurrence; and

[0274] Z represents CH, CQ, or N;

[0275] Or its medicinal salt.

[0276] In a preferred embodiment of the compound of embodiment 21A, ring A is a pyrazolyl or pyridinyl ring, and typically R 1 It is selected from methyl, phenyl and pyridyl.

[0277] 22A. A compound according to any one of embodiments 13A to 21A, wherein ring A is pyridinyl or pyrazolyl and optionally substituted by one or two groups independently selected from: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C3-C6 cycloalkyl;

[0278] Or its medicinal salt.

[0279] 23A. The compound according to embodiment 13A, wherein R 1 It is pyridyl, phenyl, tetrahydrofuranyl, or tetrahydropyranyl, and optionally is selected from one or two of R. 2 Substitution of groups;

[0280] Or its medicinal salt.

[0281] Preferably, when R 1 When it is pyridyl, it is an optionally substituted 2-pyridyl group, and the N atom of the pyridine ring is adjacent to (ortho) the A atom of the ring.

[0282] 24A. A compound according to any one of embodiments 13A to 23A, which is a compound of formula (Ib):

[0283]

[0284] Where R 4 and R 5 Independently selected from H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, and pyridyl; or R 4 and R 5 It can form a benzene ring together with the carbon atom it is attached to, and this benzene ring is related to R. 4 and R 5 The pyridinium rings are fused together;

[0285] Or its medicinal salt.

[0286] In a preferred embodiment of the compound of embodiment 24A, R 4and R 5 The radical is independently selected from H, halogen, methyl, ethyl, and cyclopropyl. In these embodiments, preferably, R... 4 Not H.

[0287] 25A. A compound according to any one of embodiments 13A to 23A, which is a compound of formula (Ic):

[0288]

[0289] Where R 6 It is selected from C1-C4 alkyl, C1-C4 haloalkyl and C3-C6 cycloalkyl;

[0290] Or its medicinal salt.

[0291] In the compound of embodiment 25A, R 1 Preferably, it is methyl, phenyl, or pyridyl.

[0292] 26A. The compound according to embodiment 25A, wherein R 6 It is selected from methyl, ethyl, isopropyl and cyclopropyl; or their pharmaceutically acceptable salts.

[0293] 27A. A compound according to any one of embodiments 13A to 26A, wherein L is [Cy]-(CR2). m -X-(CR2) n - where [Cy] indicates the junction point between L and the group Cy;

[0294] m is 1 or 2;

[0295] n is 0, 1, or 2; and

[0296] X is a tetrazolium ring;

[0297] Or its medicinal salt.

[0298] 28A. A compound according to any one of embodiments 13A to 27A, wherein L is CH2, C(Me)2, -OCH2-[T], -CH2CH2-, -C(Me)2CH2-[T], -CH2C(Me)2-[T] or -CF2CH2-[T], wherein [T] indicates the connection end of L with the tetrazolium ring in formula (I);

[0299] Or its medicinal salt.

[0300] 29A. The compound according to embodiment 13A, wherein the compound is selected from the compounds of Examples 12-33, 44-65, 67 and 175-216;

[0301] Or its medicinal salt.

[0302] 30A. A compound selected from the compounds numbered Examples 1-217;

[0303] Or its medicinal salt.

[0304] 31A. A pharmaceutical composition comprising a compound according to any one of embodiments 1A to 30A and at least one pharmaceutically acceptable carrier or excipient.

[0305] 32A. A method for treating cancer or fibrosis, comprising administering to an individual in need an effective amount of a compound according to any one of embodiments 1A to 30A, or a pharmaceutical composition according to embodiment 31A.

[0306] 33A. The method according to implementation plan 32A is a method for treating colon cancer, hepatocellular carcinoma (HCC), renal cancer, liver cancer, gastric cancer, or fibrosis in the liver or kidney.

[0307] 34A. A compound according to any one of embodiments 1A to 30A, used for treatment.

[0308] 35A. Use of a compound according to any one of embodiments 1A to 30A, for the preparation of a pharmaceutical product.

[0309] 36A. A pharmaceutical combination comprising an effective amount of a compound according to any one of embodiments 1A to 30A and other therapeutic agents.

[0310] 37A. A pharmaceutical composition comprising the pharmaceutical composition according to embodiment 36A and at least one pharmaceutically acceptable excipient.

[0311] 38A. A method for treating cancer or fibrosis in an individual in need, comprising administering an effective amount of a pharmaceutical composition according to embodiment 37A.

[0312] Unless otherwise indicated herein or otherwise obviously contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all instances or exemplary language (e.g., “for example”) provided herein is for the purpose of better illustrating the invention and does not limit the scope of the otherwise claimed invention.

[0313] It should be further recognized that all groups defined above may be further substituted by one or more substituents, which may be further substituted by hydroxyl, amino, cyano, C1-C4 alkyl, halogen, or C1-C4 haloalkyl. For example, the hydrogen atom in the alkyl or aryl group may be replaced by an amino, halogen, or C1-C4 haloalkyl or alkyl group.

[0314] It should be understood that, among all the substituted groups as defined above, this document does not intend to include compounds obtained by defining a substituent by another substituent of itself (e.g., a substituted aryl group having a substituted aryl group as a substituent, which itself is substituted by the substituted aryl group, which is further substituted by the substituted aryl group, etc.). In such cases, the maximum number of such substitutions is three. For example, the successive substitutions of substituted aryl groups specifically covered herein are limited to substituted aryl group - (substituted aryl group) - substituted aryl group.

[0315] For any of the groups containing one or more substituents disclosed herein, it should be understood that such groups do not contain any substitutions or substitution patterns that are sterically impractical and / or synthetically infeasible. Furthermore, the subject compounds include all stereochemical isomers resulting from the substitution of these compounds.

[0316] The terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that can exist in a given compound of the present invention, including geometric isomers. It should be understood that substituents can be attached to the chiral center of a carbon atom. The term "chiral" refers to a molecule that has the property of non-overlapping with its mirror partner, while the term "chiral" refers to a molecule that can overlap with its mirror partner. Therefore, the present invention includes enantiomers, diastereomers, or racemates of compounds. An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to refer to racemic mixtures where appropriate. A "diastereomer" is a stereoisomer having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Depending on the direction (right-handed or left-handed) of the plane-polarized light at the wavelength of the sodium D-line of the compound, a resolved compound with an unknown absolute configuration can be designated as (+) or (-). Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0317] Depending on the choice of starting materials and methods, the compound may exist as one of the possible isomers or as mixtures thereof, for example, as a pure optical isomer or as a mixture of isomers, such as racemic mixtures and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). This invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms, except as otherwise specified. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted or trisubstituted double bond, the substituent may be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0318] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers or diastereomers based on the physicochemical differences of the components, for example by chromatography and / or stepwise crystallization.

[0319] Any racemic product or intermediate obtained can be resolved into optical enantiomers by known methods, such as by separating its diastereomer salt (obtained with an optically active acid or base) and releasing the optically active acidic or basic compound. Specifically, the basic moiety can therefore be used to resolve the compounds of the present invention into their optical enantiomers, for example by stepwise crystallization of salts formed from optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluamide tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid). Racemic products can also be resolved by chiral chromatography, such as high-performance liquid chromatography (HPLC) using a chiral stationary phase.

[0320] Furthermore, the compounds of the present invention (including their salts) may also be obtained as their hydrates, or may include other solvents for their crystallization. The compounds of the present invention can inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to cover both solvated and non-solventized forms. The term "solvate" refers to a molecular complex of the compounds of the present invention (including their pharmaceutically acceptable salts) with one or more acids (sulfuric acid, nitric acid, phosphoric acid, etc.).

[0321] Organic acids that can form salts 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, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. Pharmaceutically usable base addition salts can be formed from inorganic and organic bases.

[0322] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0323] Organic solvent molecules. These solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water and ethanol. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0324] The compounds of the present invention, including their salts, hydrates and solvates, can be inherently or designed to form polymorphs.

[0325] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" particularly includes "medicinal salts." The term "medicinal salt" refers to a salt that retains the biological efficacy and properties of the compounds of the present invention and generally does not have undesirable properties biologically or otherwise. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts in the presence of amino and / or carboxyl groups or similar groups.

[0326] Pharmaceutically usable acid addition salts can be formed from inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorates, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, glucohepanoates, glucuronides, glucuronides, hippurates, hydroiodates / iodides, hydroxyethanesulfonates, lactates, lactobionates, lauryl sulfonates, malates, maleates, malonates, mandelates, methanesulfonates, methylsulfonates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonic acids, propionates, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0327] Inorganic acids from which salts can be derived include, for example, hydrochloric acid. Bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Certain organic amines include isopropylamine, benzathine, bile salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and aminobutanetriol.

[0328] The pharmaceutically usable salts of the present invention can be synthesized from the basic or acidic fractions using conventional chemical methods. Generally, such salts are prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of both. Typically, when feasible, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. A list of other suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0329] The compounds and compositions described herein can be administered to individuals who require treatment for proliferative disorders, such as cancer or fibrosis, particularly cancers occurring in organs and tissues of the gastrointestinal and first-pass metabolic systems.

[0330] Individuals treated with the compounds and pharmaceutical compositions of the present invention are typically mammals diagnosed with one or more of these proliferative conditions requiring treatment, and the individuals are typically humans. Typically, the individuals are patients diagnosed with cancers associated with excessive activity of TGFβR1 (also known as Alk5), particularly cancers of the liver, kidneys, and gastrointestinal system. The method comprises administering an effective amount of at least one compound of the present invention; optionally, the compound may be administered in combination with one or more other therapeutic agents, particularly those known to be suitable for treating cancers or proliferative conditions affecting a particular individual.

[0331] The compounds of this invention can be used to treat conditions, symptoms, or diseases as described herein, or to prepare pharmaceutical compositions for treating these diseases. This invention provides methods for treating these diseases using the compounds of this invention or for preparing pharmaceutical compositions having the compounds of this invention for treating these diseases.

[0332] The term "pharmaceutical composition" includes formulations suitable for administration to mammals (e.g., humans). When the compounds of the present invention are administered to mammals (e.g., humans) as medicine, they may be administered either on their own or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of a compound of formula (I) or formula (II), or any subgenus thereof described herein as an active ingredient, and pharmaceutically acceptable excipients, and optionally two or more pharmaceutically acceptable excipients.

[0333] The phrase "pharmaceutical-grade excipient" is understood by those skilled in the art to include pharmaceutically acceptable materials, compositions, or carriers suitable for administration to mammals of the compounds of the present invention. Excipients include liquid or solid fillers, diluents, carriers, solvents, or encapsulating materials relating to the delivery or transport of the subject active agent from one organ or part of the body to another organ or part of the body, or to the preparation of a pharmaceutical product that is easier to formulate, tablet, store, use, or administer. Each excipient must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the patient. 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 tragacanth gum; 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; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotropic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical preparations. Generally, pharmaceutically acceptable excipients are sterile and / or substantially pyrogen-free.

[0334] Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavoring agents and aromas, preservatives and antioxidants may also be present in the composition.

[0335] Examples of pharmaceutically usable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as palmitic acid ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0336] The formulations of this invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations can be conveniently presented in unit dosage forms and can be prepared by any method well known in pharmaceutical technology. The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, based on 100%, this amount will range from about 1% to about 99%, preferably about 5% to about 70%, and most preferably about 10% to about 30% of the active ingredient.

[0337] Methods for preparing these formulations or compositions include the step of combining the compounds of the present invention with a carrier or excipient and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly combining the compounds of the present invention with a liquid excipient or a finely powdered solid excipient, or both, and then shaping, if necessary.

[0338] Formulations of the present invention suitable for oral administration may be in the form of capsules, pouches, pills, tablets, lozenges (using a flavoring base, such as sucrose and gum arabic or tragacanth), powders, granules, or in the form of solutions or suspensions in aqueous or non-aqueous liquids, or in the form of oil-in-water or water-in-oil liquid emulsions, or in the form of elixirs or syrups, or in the form of sugar lozenges (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic) and / or in the form of mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered in the form of injections, licks, or pastes.

[0339] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) of the present invention for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; humectants, such as glycerin; disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; solution blockers, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; humectants, such as cetyl alcohol and glyceryl monostearate; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Excipients such as lactose and high molecular weight polyethylene glycol can also be used to make similar types of solid compositions as fillers in soft-filled and hard-filled gelatin capsules.

[0340] Tablets can be prepared by compression or molding, optionally together with one or more excipient components. Binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants can be used to prepare compressed tablets. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0341] The pharmaceutical compositions of the present invention, in tablet and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, may optionally be obtained or prepared having coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose to provide the desired release characteristics, other polymer matrices, liposomes, and / or microspheres to provide a slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacterial trap filter, or by incorporation with a sterilizing agent in the form of a sterile solid composition soluble in sterile water or some other sterile injectable medium prior to use. These compositions may also optionally contain a light-blocking agent and may be compositions that optionally release the active ingredient in a delayed manner only or preferably in certain portions of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, where appropriate, together with one or more of the above-described excipients.

[0342] Liquid dosage forms of the compounds of the present invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers commonly used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitol and mixtures thereof.

[0343] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0344] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0345] The formulations of the present invention suitable for vaginal application also include formulations containing, for example, pessaries, tampons, creams, gels, pastes, foams or sprays containing carriers known in the art as suitable carriers.

[0346] Dosage forms for topical or transdermal application of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds may be mixed under sterile conditions with pharmaceutically acceptable excipients and any preservatives, buffers, or propellants that may be required.

[0347] In addition to the compounds of this invention, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0348] The scope of this invention also includes ophthalmic preparations, ointments, powders, solutions, etc.

[0349] The pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention and one or more pharmaceutically acceptable carriers (e.g., sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions) or sterile powders that can be reconstituted into sterile injectable solutions or dispersions only immediately before use. The compositions may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the designated recipient.

[0350] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate flowability can be maintained, for example, by using a coating material (e.g., lecithin), by maintaining the desired particle size in the case of a dispersion, and by using a surfactant.

[0351] These compositions may also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolic sorbic acid. It may also be necessary to include isotonic agents, such as sugars and sodium chloride, in the composition. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0352] In some cases, to prolong the effect of a drug, it is necessary to slow down the absorption of the drug after subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate depends on the dissolution rate, which in turn depends on the crystal size and morphology. Alternatively, delayed absorption of parenteral drug formulations can be achieved by dissolving or suspending the drug in an oily carrier.

[0353] The formulations of the present invention can be administered orally, parenterally, topically, or rectally. They are, of course, administered in a form suitable for each route of administration. For example, they can be administered in tablet or capsule form, by injection, by inhalation, as eye wash, ointment, suppository, etc., by injection, infusion, or inhalation, by topical application as a wash or ointment, and by rectal application as a suppository.

[0354] As used herein, the phrases "parenteral administration" and "prescription" refer to a mode of administration other than enteral and local administration, typically by injection, and including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Intravenous infusion is sometimes the preferred method for delivering the compounds of the present invention. Infusion can be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present invention are administered by infusion at time intervals between 15 minutes and 4 hours, typically between 0.5 and 3 hours. This infusion can be used once daily, twice daily, or up to three times daily.

[0355] These compounds may be administered to humans and other animals for treatment via any suitable route of administration, including oral, nasal (e.g., via spray), rectal, vaginal, parenteral, intracerebrospinal, and topical administration, as powders, ointments, or drops, including buccal and sublingual administration.

[0356] Regardless of the chosen route of administration, the compounds of the present invention, which can be used in a suitable hydrated form and / or as pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0357] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed to obtain a certain amount of active ingredient that can effectively achieve the desired therapeutic response for a specific patient, composition and administration mode, without being toxic to the patient.

[0358] The selected dosage level will depend on a variety of factors, including the activity of the specific compound of the present invention or its ester, salt or amide; the route of administration; the time of administration; the excretion rate of the specific compound used; the duration of treatment; other drugs, compounds and / or materials used in combination with the specific compound used; the age, sex, weight, condition, general health and prior medical history of the patient being treated; and similar factors well known in the medical field.

[0359] Physicians or veterinarians skilled in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may begin administering the compound of the invention used in the pharmaceutical composition at a level below that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0360] Generally, the suitable daily dose of the compounds of the present invention is the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose is usually determined by the factors described above. Generally, the intravenous and subcutaneous doses of the compounds of the present invention used in patients, when used according to the specified effect, are in the range of about 0.0001 to about 100 mg / kg body weight per day, more preferably about 0.01 to about 50 mg / kg / day, and even more preferably about 1.0 to about 100 mg / kg / day. The effective amount is the amount that achieves the desired or observable therapeutic effect.

[0361] If necessary, the effective daily dose of the active compound may be administered in sub-dose doses, two, three, four, five, six, or more than six times, administered as unit doses at appropriate intervals throughout the day. Compounds delivered orally or by inhalation are typically administered one to four times daily. Compounds delivered by injection are typically administered once daily or every other day. Compounds delivered by infusion are typically administered one to three times daily.

[0362] While the compounds of the present invention may be administered alone, they are preferably administered in the form of pharmaceutical compositions (such as those described herein).

[0363] Pharmaceutical compositions, combinations and other related uses

[0364] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (II) or any subform thereof as described herein and at least one pharmaceutically acceptable carrier or excipient.

[0365] The compounds described above can be used for any suitable purpose. For example, the compounds of this invention can be used in therapy and / or testing.

[0366] In another aspect, this disclosure provides methods for treating and / or preventing proliferative conditions such as cancer or tumors. The compounds, compositions, and methods are particularly suitable for treating cancers associated with excessive activity of TGFβR1 (also known as Alk5), especially cancers of the liver, kidneys, and gastrointestinal system.

[0367] In another aspect, this disclosure provides the use of the compounds described above for the preparation of pharmaceuticals.

[0368] In another aspect, this disclosure provides a combination product for the treatment and / or prevention of proliferative disorders, the combination product comprising an effective amount of a compound of formula (I) or formula (II) or any subform thereof disclosed herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a second preventive or therapeutic agent for the treatment and / or prevention of proliferative disorders, cancer or tumors or fibrosis, particularly for the treatment of colon cancer, hepatocellular carcinoma (HCC), renal cancer, liver cancer and gastric cancer, as well as fibrosis of the digestive and first-pass metabolic systems, particularly liver fibrosis and renal fibrosis.

[0369] In another aspect, the present invention provides a method for inhibiting the activity of TGFβR1 in an individual, comprising administering to the individual an effective amount of a compound of formula (I) or formula (II) as described herein.

[0370] In another aspect, the present invention provides a method for inhibiting TGFβR1 activity in tissues or cells, comprising contacting the tissues or cells with an effective amount of a compound of formula (I) or formula (II) as described herein.

[0371] In some embodiments, the compound is any of the compounds in the numbered examples disclosed herein.

[0372] preparation

[0373] Any suitable formulation of the compounds described herein can be prepared. See Remington's Pharmaceutical Sciences, (2000) Hoover, JE ed., 20th ed., Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pp. 780-857. Choose a formulation suitable for the appropriate route of administration. The application of the salt form of the compound may be appropriate if the compound is sufficiently acidic to form a stable, non-toxic basic salt. Examples of pharmaceutically acceptable salts are organic acid addition salts formed from acids that form physiologically acceptable anions, such as toluenesulfonates, methanesulfonates, acetates, citrates, malonates, tartrates, succinates, benzoates, ascorbic acid salts, α-ketoglutarate, and α-glycerophosphates. Suitable inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates. Pharmaceutically acceptable salts are obtained using standard methods well known in the art, for example, by reacting a sufficiently basic compound (e.g., an amine) with a suitable acid to obtain a physiologically acceptable anion. It also prepares alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts, as well as amine salts of carboxylic acids and tetrazolium.

[0374] When the intended compound is administered in a pharmacological composition, it is anticipated that the compound can be formulated with pharmaceutically acceptable excipients and / or carriers. For example, the intended compound may be administered orally as a neutral compound or a pharmaceutically acceptable salt, or intravenously in a physiological saline solution. Conventional buffers, such as phosphates, bicarbonates, or citrates, may be used for this purpose. Of course, those skilled in the art can modify the formulation within the teachings of this specification to obtain a variety of formulations for a particular route of administration. Specifically, the intended compound may be modified to make it more soluble in water or other carriers, which can be readily accomplished, for example, with minor modifications (salt formulation, esterification, etc.) that are common to the art. Also common to the art is the selection or modification of the route of administration and dosing regimen of a particular compound to manage the pharmacokinetics of the compounds of the present invention to maximize the beneficial effects in the patient.

[0375] Compounds having formulas I and 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 provides a formulation prepared by mixing compounds having formulas I and II with pharmaceutically acceptable excipients. In one aspect, the formulation can be prepared using a method comprising: a) dissolving the compound in a water-soluble organic solvent, a nonionic solvent, a water-soluble lipid, a vitamin (e.g., tocopherol), a fatty acid, a fatty acid ester, or a combination thereof to obtain a solution; and b) adding physiological saline or a buffer solution containing 1-10% carbohydrate solution. In one example, the carbohydrate comprises dextran. Pharmaceutical compositions obtained using the methods of the present invention are stable and suitable for animal and clinical use.

[0376] Illustrative examples of water-soluble organic solvents used in the methods of the present invention include, but are not limited to, polyethylene glycol (PEG), alcohols, acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or combinations thereof. Examples of alcohols include, but are not limited to, methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[0377] Illustrative examples of water-soluble nonionic surfactants used in the methods of the present invention include, but are not limited to, those used in the present invention. Polyethylene glycol modified (Polyoxyethylene glycol triricinoleate 35), hydrogenated hydrogenation PEG-succinate, polysorbate 20, polysorbate 80 (Polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, (ethoxylated peach kernel oil) (decanoyl-hexanoyl polyethylene glycol-8-glyceride) (glycerides) (PEG 6 caprylic / caprylic glyceride), glycerol, diol-polysorbate, or combinations thereof.

[0378] Illustrative examples of water-soluble lipids used in the methods of the present invention include, but are not limited to, vegetable oils, triglycerides, vegetable oils, or combinations thereof. Examples of lipid oils include, but are not limited to, castor oil, polyethylene glycol castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, triglycerides of coconut oil, palm seed oil, and their hydrogenated forms, or combinations thereof.

[0379] Illustrative examples of fatty acids and fatty acid esters used in the methods of the present invention include, but are not limited to, oleic acid, monoglycerides, diglycerides, mono- or di-fatty acid esters of PEG, or combinations thereof.

[0380] Those skilled in the art can modify formulations within the teachings of this specification to obtain numerous formulations for specific routes of administration. Specifically, compounds can be modified to make them more soluble in water or other carriers. Also within the general art are modifications to the route of administration and dosing regimen of specific compounds to manage the pharmacokinetics of the compounds of the present invention to maximize their beneficial effects in patients.

[0381] Drug combination

[0382] The method of implementation comprises administering an effective amount of at least one exemplary compound of the present invention; optionally, the compound may be administered in combination with one or more other therapeutic agents, particularly those known to be suitable for treating conditions or diseases that cause suffering to an individual.

[0383] Other active ingredients may be administered in a pharmaceutical composition separate from at least one exemplary compound of the present invention, or may be included in a single pharmaceutical composition together with at least one exemplary compound of the present invention. Other active ingredients may be administered simultaneously with, before, or after the administration of at least one exemplary compound of the present invention.

[0384] Methods using exemplary compounds and pharmaceutical compositions thereof

[0385] The present invention also provides pharmaceutical compositions for treating and / or preventing proliferative disorders or cancers (such as those disclosed herein), comprising any compound having formula I or II, or any one of the compounds of Examples 1-110 herein.

[0386] To practice the methods of the present invention, compounds and pharmaceutical compositions thereof may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, via implanted receptacles, or by other methods of administration. As used herein, the term “parenterally” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0387] Sterile injectable compositions, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents. Acceptable carriers and solvents include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Suitable carriers and other pharmaceutical excipients are generally sterile.

[0388] In addition, sterile, non-volatile oils are routinely used as solvents or suspension media (e.g., synthetic monoglycerides or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectable formulations, as are pharmaceutically acceptable oils (e.g., olive oil or castor oil, especially in their polyoxyethylated form). These oil solutions or suspensions may also contain long-chain alcohols as diluents or dispersants, or carboxymethyl cellulose or similar dispersants. Various emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0389] Orally administered compositions can be in any orally acceptable dosage form, including but not limited to tablets, capsules, emulsions, aqueous suspensions, dispersions, and solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants such as magnesium stearate may also be added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in the oil phase in combination with an emulsifier or suspending agent. Certain sweeteners, flavoring agents, or coloring agents may be added if desired. Nasal aerosols or inhalation compositions can be prepared using techniques well known in the pharmaceutical formulation field, and can be prepared as solutions, for example, in physiological saline, using suitable preservatives (e.g., benzyl alcohol), absorption enhancers to improve bioavailability, and / or other solvents or dispersants known in the art.

[0390] Additionally, compounds having formula (I) or formula (II) or any subform thereof may be administered alone or in combination with other therapeutic agents, such as anticancer agents, to treat individuals in need of treatment. Combination therapies according to the invention comprise administration of at least one compound of exemplary formula (I) or formula (II) or any subform thereof as disclosed herein, and at least one other pharmaceutically active ingredient. The compounds and other pharmaceutically active agents of the invention may be administered separately or together. The amounts and relative timing of administration of the compounds and other pharmaceutically active agents of the invention will be selected to achieve the desired combined therapeutic effect.

[0391] The compounds described herein can be synthesized via the following general synthetic route, with specific embodiments described in more detail in the examples.

[0392] Within the scope of this document, unless the context otherwise indicates, only removable groups that are not components of the specific desired end product of the compounds of this invention are designated as “protecting groups”. The protection of functional groups by such protecting groups, the protecting elements themselves, and their cleavage reactions are described in, for example, standard reference works such as Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 (URL: http: / / www.science-of-synthesis.com (electronic version, Vol. 48)); JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; TW Greene and PGM Uts, “Protective Groups in Organic Synthesis”, 3rd edition, Wiley, New York 1999; “The Peptides”; 3rd edition (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981; “Methods of Organic Chemistry”. Chemistry), Houben Weyl, 4th edition, Vol. 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jeschkeit, " Peptide, Protein (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, Basel 1982, and Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate” (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. The protecting group is characterized by its ease of removal, for example, by solvation, reduction, photolysis, or under physiological conditions (e.g., by enzymatic cleavage) (i.e., without undesirable side reactions).

[0393] Salts of the compounds of the present invention having at least one salifying group can be prepared in ways known per se. For example, salts of the compounds of the present invention having an acidic group can be formed, for example, by treatment with various compounds such as metal compounds, such as alkali metal salts of suitable organic carboxylic acids, such as sodium salts of 2-ethylhexanoic acid, organic alkali metal or alkaline earth metal compounds, such as corresponding hydroxides, carbonates or bicarbonates, such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate, corresponding calcium compounds, or preferred salifying agents such as ammonia or suitable organic amines, stoichiometrically or in only a small excess. Acid addition salts of the compounds of the present invention are obtained in a conventional manner, for example by treating the compound with an acid or a suitable anion exchanger. Internal salts of the compounds of the present invention containing groups that form acidic and basic salts, such as free carboxyl groups and free amino groups, can be formed, for example, by neutralizing the salt, such as an acid addition salt, to its isoelectric point (e.g., with a weak base) or by treatment with an ion exchanger.

[0394] Salts can be converted into free compounds by conventional means; metal and ammonium salts can be converted, for example, by treatment with a suitable acid, and acid addition salts can be converted, for example, by treatment with a suitable basic reagent.

[0395] The mixture of isomers obtainable according to the invention can be separated into individual isomers in a manner known per se; diastereomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization and / or chromatographic separation (e.g. via silica gel) or by medium-pressure liquid chromatography, for example via a reversed-phase column; and racemic compounds can be separated, for example, by forming a salt with an optically purified salting agent and separation can be separated, for example, by stepwise crystallization or by chromatography of the obtained diastereomer mixture via an optically active column material.

[0396] Intermediates and final products can be post-processed and / or purified according to standard methods, such as using chromatography, partitioning, (re)crystallization, etc.

[0397] The method steps for synthesizing the compounds of the present invention can be carried out under reaction conditions known per se, including the reaction conditions mentioned below: in the absence or presence of solvents or diluents, including solvents or diluents that are inert to and dissolve the reagents used; in the absence or presence of catalysts, condensing agents or neutralizing agents, such as ion exchangers, such as cation exchangers, which are in the form of H+, depending on the nature of the reaction and / or the reactants; at low temperatures, room temperatures or high temperatures, such as from about -100°C to about 190°C, including, for example, temperatures in the range of from about -80°C to about 150°C; for example, at -80 to -60°C; at room temperature; at -20 to 40°C or at reflux temperature; at atmospheric pressure or in a closed container; under pressure where appropriate; and / or in an inert atmosphere, such as an argon or nitrogen atmosphere.

[0398] At all stages of the reaction, the resulting mixture of isomers can be separated into individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, such as racemates or diastereomers, for example, by methods similar to those described in Science of Synthesis: Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag, Stuttgart, Germany, 2005.

[0399] Unless otherwise indicated in the method description, solvents suitable for any particular reaction may be selected from the following: solvents specifically mentioned, or for example, water; esters, such as lower alkyl-lower alkyl esters, 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-propanol or 2-propanol; nitriles, such as acetonitrile; halogenated hydrocarbons, such as dichloromethane or chloroform; amides, such as dimethylformamide or dimethylacetamide; bases, such as heterocyclic nitrogen bases, such as pyridine or N-methylpyrrolidine-2-one; carboxylic anhydrides, such as lower alkyl anhydrides, such as acetic anhydride; cyclic, straight-chain, or branched hydrocarbons, such as cyclohexane, hexane, or isopentane; or mixtures of these solvents, such as aqueous solutions. Such solvent mixtures may also be used for post-treatment, for example, by chromatography or partitioning.

[0400] Compounds (including their salts) may also be obtained in hydrate form, or their crystals may include, for example, a solvent for crystallization. Different crystalline forms may exist.

[0401] The present invention also relates to methods in which a compound that can be obtained as an intermediate at any stage of the method is used as a starting material and the remaining method steps are carried out, or in which the starting material is formed under reaction conditions or used as a derivative (e.g., in a protected form or in salt form), or in methods that produce a compound that can be obtained by the method according to the invention under method conditions and are further processed in situ.

[0402] Based on the foregoing, the present invention provides, in another aspect:

[0403] A pharmaceutical combination comprising a) a first agent, which is a compound of the present invention, such as a compound of formula (I) or formula (II) or any subform thereof, and b) a co-activator, such as other pharmaceutical activators as defined above.

[0404] A method as defined above, comprising co-administering (e.g., concurrently or sequentially) a therapeutically effective amount of the compound of the present invention, such as a compound of formula I or formula (II) or any subform thereof, and a co-active agent, such as other therapeutic agents as defined above.

[0405] As used herein, the terms “co-administration” or “combination administration” or similar terms mean to cover the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the active agents are not necessarily administered via the same route of administration or at the same time. Fixed combinations are also within the scope of this invention. Administration of the pharmaceutical combinations of this invention produces beneficial effects, such as synergistic therapeutic effects, compared to monotherapy which administers only one of its active pharmaceutical ingredients.

[0406] The components of the combination according to the invention can be applied separately, together, or in any combination thereof.

[0407] The compounds of this invention and any other active agents can be formulated as independent dosage forms. Alternatively, to reduce the number of dosage forms administered to patients, the compounds of this invention and any other active agents can be formulated together in any combination. For example, the inhibitor of the compound of this invention can be formulated as one dosage form and the other active agents as another dosage form. Any independent dosage forms can be administered simultaneously or separately.

[0408] Alternatively, the compositions of the present invention may comprise other active agents as described herein. The components may be present as separate compositions, combined compositions, or single compositions.

[0409] abbreviation

[0410] Acetyl group

[0411] ACN Acetonitrile

[0412] AcOEt / EtOAc Ethyl Acetate

[0413] AcOH (acetic acid)

[0414] aq aqueous solution

[0415] Aryl

[0416] Bn benzyl

[0417] Bu butyl (nBu = n-butyl, tBu = tert-butyl)

[0418] CDI carbonyl diimidazole

[0419] CH3CN Acetonitrile

[0420] DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene

[0421] Boc2O ditert-butyl dicarbonate

[0422] DCE 1,2-Dichloroethane

[0423] DCM dichloromethane

[0424] DiBAl-H diisobutylaluminum hydride

[0425] DIPEA N-Ethyldiisopropylamine

[0426] DMA N,N-dimethylacetamide

[0427] DMAP dimethylaminopyridine

[0428] DMF N,N'-dimethylformamide

[0429] DMSO (dimethyl sulfoxide)

[0430] EI electrospray ionization

[0431] Et2O diethyl ether

[0432] Et3N Triethylamine

[0433] Ether

[0434] EtOAc or EA (ethyl acetate)

[0435] EtOH (ethanol)

[0436] FC rapid chromatography

[0437] h hours

[0438] HATU O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethylureonium hexafluorophosphate

[0439] HBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate

[0440] HCl hydrochloric acid

[0441] HMPA (Hexamethylphosphoramide)

[0442] HOBt 1-hydroxybenzotriazole

[0443] HPLC (High Performance Liquid Chromatography)

[0444] H2O water

[0445] L rise

[0446] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0447] LiHMDS Bis(trimethylsilyl)aminolithium

[0448] mCPBA (m-chloroperoxybenzoic acid)

[0449] MgSO4 Magnesium sulfate

[0450] Me methyl

[0451] MeI iodomethane

[0452] MeOH (methanol)

[0453] mg

[0454] min minutes

[0455] mL

[0456] MS mass spectrometry

[0457] NaHCO3 (Sodium bicarbonate)

[0458] Na2SO4 Sodium sulfate

[0459] NH2OH Hydroxylamine

[0460] Pd / C Palladium / Carbon

[0461] Pd(OH)₂ palladium hydroxide

[0462] PE petroleum ether

[0463] PG protection base

[0464] Ph phenyl

[0465] Ph3P Triphenylphosphine

[0466] Prep preparation type

[0467] Rf shift value

[0468] RP inversion

[0469] Rt retention time

[0470] rt room temperature

[0471] RT room temperature

[0472] SiO2 silica gel

[0473] SOCl2 thionyl chloride

[0474] TBAF Tetrabutylammonium Fluoride

[0475] TBDMS tert-butyldimethylsilyl

[0476] TEA Triethylamine

[0477] TFA (trifluoroacetic acid)

[0478] THF Tetrahydrofuran

[0479] TLC (Thin Layer Chromatography)

[0480] TsCl Toluenesulfonyl chloride

[0481] The compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, referring to the following reaction schemes and examples. General methods for synthesizing compounds of formula (I) and (II) are provided in the following procedures 1 to 3.

[0482] General Synthesis Method

[0483] The compounds of the present invention were prepared from commonly available compounds using methods known to those skilled in the art, according to the embodiments and processes provided herein.

[0484] Process 1.

[0485]

[0486] In process 1, ring A, substituted with an amino group and linked to an ester, is coupled to chloropyridine. The ester can be hydrolyzed to yield a free carboxylic acid. Depending on the choice of R, the product can be a compound of formula (I) or formula (II), or a precursor of such a compound. Ring A corresponds, for example, to the Cy group in compound (I), or the phenyl / pyridyl ring in compound (II).

[0487] Process 2.

[0488]

[0489] In process 2, ring A has an amino group and is linked to a nitrile; after coupling with chloropyridine, the nitrile can be converted to a carboxylic acid group by hydrolysis, or it can be converted to an acidic tetrazolium group by trimethylsilyl azide. Similarly, depending on the choice of R, the product can be a compound of formula (I) or formula (II) or a precursor of such a compound.

[0490] Step 3.

[0491]

[0492] In process 3, the tetrazolium product from process 2 is alkylated with tert-butyl bromoacetate to yield two isomers of carboxymethyltetrazole. Similarly, depending on the choice of R, the product can be a compound of formula (I) or formula (II) or a precursor of such a compound.

[0493] Using these and known alternative starting materials, those skilled in the art can prepare a variety of compounds of formula (I) or formula (II) having carboxylic acid or tetrazolium as acidic groups.

[0494] Intermediate:

[0495] Intermediate A1: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine

[0496]

[0497] This compound was prepared according to the method disclosed in WO2005080377.

[0498] Step 1: (4,5-Dimethylfuran-2-yl)(pyridin-2-yl)methyl ketone

[0499] Under Ar conditions, n-BuLi (1.6 M, 1.3 equivalents) was added dropwise to a solution of 2,3-dimethylfuran (1.0 equivalent) in Et₂O (0.65 M) at 0 °C. The mixture was stirred at 40 °C for 1.5 h and then cooled to -78 °C. A solution of pyridinecarboxynitrile (1.0 equivalent) in Et₂O (2 M) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 1.5 h and then quenched with ice. The pH of the mixture was adjusted to approximately 5 with 2N HCl. The mixture was extracted with DCM. The combined DCM layers were washed with water and dried over Na₂SO₄. The organic solvent was removed, and the residue was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc 10:1) to give the title product as a yellow solid. LC-MS (m / z): [M+1] + =202; 1H NMR (400MHz, CDCl3) δ8.70(d,J=5.2Hz,1H),8.13(d,J=7.6Hz,1H),7.86(t,J=7 .6Hz,1H),7.82(s,1H),7.46(dd,J=7.6,5.2Hz,1H),2.38(s,3H),2.04(s,3H).

[0500] Step 2: 5,6-Dimethyl-[2,2'-bipyridine]-3-ol

[0501] The mixture of the above product (1.0 equivalent) in MeOH (0.033 M) and 28% NH3·H2O (10 mL) was sealed in a test tube and stirred at 170 °C for 8 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc 20:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+1] + =201; 1 HNMR (400MHz, CDCl3) δ13.86 (s, 1H), 8.58 (d, J = 8.0Hz, 1H), 8.47 (d, J = 4.4Hz, 1H), 7. 86(td,J=8.0,1.6Hz,1H),7.28-7.25(m,1H),7.08(s,1H),2.47(s,3H),2.28(s,3H).

[0502] Step 3: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine

[0503] The mixture of the above product (1.0 equivalent), 2,4-dichloropyridine (2.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMSO (0.09 M) was stirred at 180 °C for 5 hours. The mixture was cooled to room temperature. The mixture was quenched with water and extracted with EtOAc. The solvent was removed under reduced pressure. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc 2:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+1] + =312; 1H NMR (400MHz, CDCl3) δ8.57(ddd,J=4.8,2.0,1.2Hz,1H),8.13(d,J=6.0Hz,1H),7.84(dt,J=7.6,1.2Hz,1H),7.70(td,J=7.6,1.6Hz,1H) ,7.27(d,J=6.0Hz,1H),7.20(ddd,J=7.6,4.8,1.2Hz,1H),6.73(d,J=2.0Hz,1H),6.70(dd,J=6.0,2.0Hz,1H),2.63(s,3H),2.38(s,3H).

[0504] Intermediate A2: 3-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine

[0505]

[0506] This compound was prepared according to the method disclosed in WO2009022171. A mixture of 2,6-dimethylpyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.5 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMSO (0.5 M) was stirred at 150 °C for 3 h. The reaction was monitored by TLC. The solution was cooled to room temperature and extracted with EA / H₂O, washed with brine, and dried over Na₂SO₄. The organic phase was concentrated. The residue was purified by silica gel rapid chromatography (petroleum ether / EtOAc 9:1) to give the title compound as a white solid. LC-MS (m / z): [M+H] + =235.3; 1 H NMR (400MHz, CDCl3) δ8.24(d,J=5.6Hz,1H),7.24(d,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),6.74-6.71(m,2H),2.58(s,3H),2.38(s,3H).

[0507] Intermediate A3: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2,2'-bipyridine

[0508]

[0509] This compound was prepared according to the method disclosed in WO2009022171.

[0510] Step 1: 3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine

[0511] A mixture of 2-iodo-6-methylpyridin-3-ol (1.05 equivalents), 2,4-dichloropyridine (1.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.22 M) was stirred at 100 °C for 16 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAC. The filtrate was washed with brine and then dried over Na₂SO₄. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (petroleum ether / EtOAC 8:1) to give a product as a white solid. LC-MS (m / z): [M+H] + =347; 1 H NMR (400MHz, CDCl3) δ8.21 (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).

[0512] Step 2: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2,2'-bipyridine

[0513] A mixture of 3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine (1.0 equivalent), pyridin-2-yl zinc(II) bromide (0.5 M in THF, 1.2 equivalent), and Pd(PPh3)4 (0.1 equivalent) in DMA (0.43 M) was stirred at 120 °C under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature and diluted with EtOAC. The mixture was washed with brine and then dried over Na2SO4. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (100% EtOAc) to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + =298.

[0514] The following compounds were prepared according to the method described for intermediate A3.

[0515]

[0516]

[0517] Intermediate A6: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine

[0518]

[0519] This compound was prepared according to the method disclosed in WO2009022171.

[0520] A mixture of 3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine (1.0 equivalent), phenylboronic acid (1.2 equivalent), Pd(dppf)Cl2 (0.1 equivalent), and Na2CO3 (2.0 equivalent) in dioxane / H2O (5:1, 0.25 M) was stirred at 100 °C for 3 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with brine and then dried over Na2SO4. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (100% EtOAc) to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + =297; 1 H NMR (400MHz, CDCl3) δ8.06 (d, J=6.0Hz, 1H), 7.68 (dd, J=8.0, 1.6Hz, 2H), 7.31-7.24 (m, 4H ), 7.13 (d, J = 8.0Hz, 1H), 6.64 (d, J = 2.4Hz, 1H), 6.59 (dd, J = 6.0, 2.4Hz, 1H), 2.59 (s, 3H).

[0521] The following compounds were prepared according to the method described for intermediate A6.

[0522]

[0523]

[0524] Intermediate A12: 2-chloro-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridine

[0525]

[0526] This compound was prepared according to the method disclosed in WO2016057278.

[0527] Step 1: 2-((2-chloropyridin-4-yl)oxy)-1-(tetrahydro-2H-pyran-4-yl)acet-1-one

[0528] A mixture of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethyl-1-one (1.0 equivalent), 2-chloropyridin-4-ol (1.0 equivalent), and K₂CO₃ (1.5 equivalent) in acetone (0.12 M) was stirred at room temperature for 16 hours. 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.

[0529] Step 2: 2-Chloro-4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridine

[0530] A solution of 2-((2-chloropyridin-4-yl)oxy)-1-(tetrahydro-2H-pyran-4-yl)ethyl-1-one (1.0 equivalent) in DMF-DMA (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 and treated with NH₂NH₂·H₂O (80 wt%, 3.0 equivalent). The resulting mixture was stirred at room temperature 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 Na₂SO₄, and concentrated under reduced pressure to give the title compound as a brown oil. LC-MS (m / z): [M+H] + =280.

[0531] Step 3: 2-Chloro-4-((1-Cyclopropyl-3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridine

[0532] A mixture of pyridine (1.1 equivalents) and Cu(OAc)₂ (1.1 equivalents) in DCE (0.37 M) was stirred at 75 °C for 0.5 h. The mixture was cooled to room temperature, and a solution of the above product (1.0 equivalents) in DCE (0.1 M) was added, followed by the addition of cyclopropylboronic acid (2.0 equivalents) and Na₂CO₃ (2.0 equivalents). The resulting mixture was stirred at 75 °C under an oxygen atmosphere for 16 h. The reaction was monitored by LC-MS. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel rapid 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.

[0533] Intermediate A13: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-cyanopyridine

[0534]

[0535] Step 1: 5-Hydroxy-2-methylpyridine 1-oxide

[0536] m-CPBA (1.2 equivalents) was added to a solution of 6-methylpyridin-3-ol (1.0 equivalent) in DCM (0.5 M). The mixture was stirred at room temperature 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 room temperature and treated with Et2O. The precipitated solid was collected by filtration and dried to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =126.

[0537] Step 2: 3-Hydroxy-6-methyl-2-cyanopyridine

[0538] The mixture of the above product (1.0 equivalent), TMSCN (3.5 equivalent), and TEA (2.5 equivalent) in MeCN (3.0 mL) was sealed into a tubular reactor. The mixture was stirred in a microwave at 150 °C for 2.5 h. 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 (400MHz, DMSO) δ 11.34 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 2.33 (s, 3H).

[0539] Step 3: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-cyanopyridine

[0540] A mixture of the above product (1.0 equivalent), 2,4-dichloropyridine (1.5 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMSO (0.37 M) was stirred at 120 °C for 16 h. 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 rapid 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.

[0541] Intermediate A14: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(trifluoromethyl)pyridine

[0542]

[0543] Step 1: 6-Methyl-2-(trifluoromethyl)pyridine-3-ol

[0544] A mixture of 2-iodo-6-methylpyridin-3-ol (1.0 equivalent), methyl 2-chloro-2,2-difluoroacetate (3.0 equivalent), CuI (1.5 equivalent), KF (2 equivalent), and KBr (2.0 equivalent) in DMF (0.2 M) was stirred at 110 °C under Ar for 16 hours. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc 1:0 to 50:1) to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =178.4.

[0545] Step 2: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(trifluoromethyl)pyridine

[0546] A mixture of 6-methyl-2-(trifluoromethyl)pyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (2.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMSO (0.1 M) was stirred at 140 °C for 3 hours. The reaction mixture was cooled to room temperature, treated with water, and extracted with EtOAc. The solvent was removed under reduced pressure, and the residue was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc 2:1) to give the title compound as a yellow oil. LC-MS (m / z): [M+1] + =289.

[0547] Intermediate A15: 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-methylpyridine

[0548]

[0549] A mixture of 2-ethyl-6-methylpyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (1.5 M) was stirred at 110 °C for 16 h. The reaction was monitored by LC-MS. The mixture was filtered, washed with water, and extracted with EtOAc. The organic layer was washed with brine and dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (petroleum ether / EtOAc 20:1) to give the title compound as a colorless oil. LC-MS (m / z): [M+H] +=249;1H NMR (400MHz, DMSO-d6) δ8.30(d,J=5.6Hz,1H),7.53(d,J=8.0Hz,1H),7.23(d,J=8.0Hz,1H),7.01(d, J=2.0Hz, 1H), 6.91 (dd, J=5.6, 2.4Hz, 1H), 2.60 (q, J=7.6Hz, 2H), 2.50 (s, 3H), 1.13 (t, J=7.6Hz, 3H).

[0550] Intermediate A16: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine

[0551]

[0552] Step 1: 6-Iodo-2-methylpyridin-3-ol

[0553] A mixture of 2-methylpyridin-3-ol (1.0 equivalent), I₂ (1.0 equivalent), and Na₂CO₃ (2.2 equivalent) in H₂O (0.46 M) was stirred at room temperature under Ar for 1 hour. The reaction was monitored by LCMS. The solution was adjusted to pH 6 with HCl (2N). The solid precipitate was filtered, washed with water (10 mL × 2), 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 crystalline solid was filtered and dried to give the title compound as a yellow solid.

[0554] Step 2: 2-Methyl-6-vinylpyridine-3-ol

[0555] A mixture of 6-iodo-2-methylpyridin-3-ol (1.0 equivalent), potassium trifluoro(vinyl)borate (1.0 equivalent), Pd(dppf)Cl2 (0.1 equivalent), and K2CO3 (3.0 equivalent) in 1,4-dioxane-water (20:1, 0.85 M) was stirred at 100 °C under Ar for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography to give the title compound as a yellow oil.

[0556] Step 3: 6-Ethyl-2-methylpyridin-3-ol

[0557] Pd / C (10% by weight, 0.02 equivalents) was added to a solution of 2-methyl-6-vinylpyridin-3-ol (1.0 equivalent) in MeOH (0.35 M). The reaction mixture was stirred at room temperature under H2 for 16 hours. The reaction was monitored by LCMS. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow oil.

[0558] Step 4: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine

[0559] A mixture of 6-ethyl-2-methylpyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.58 M) was stirred at 100 °C for 16 h. The reaction was monitored by LC-MS. The mixture was filtered and washed with water (15 mL), then extracted with EtOAc (15 mL × 3). The organic layer was washed with brine (10 mL × 2) and then dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (petroleum ether / EtOAc 20:1) to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + =249.1;1H NMR (400MHz, DMSO-d6) δ8.30(d,J=5.6Hz,1H),7.55(d,J=8.4Hz,1H),7.24(d,J=8.4Hz,1H),7.00(d, J=2.0Hz, 1H), 6.90 (dd, J=5.6, 2.4Hz, 1H), 2.76 (q, J=7.6Hz, 2H), 2.29 (s, 3H), 1.25 (t, J=7.6Hz, 3H).

[0560] Alternative routes for the preparation of 6-ethyl-2-methylpyridine-3-ol

[0561]

[0562] Step 1: 2-Methyl-6-vinylpyridine-3-amine

[0563] A mixture of 6-bromo-2-methylpyridin-3-amine (1.0 equivalent), C₂H₃BF₃K (1.2 equivalent), K₂CO₃ (3.0 equivalent), and Pd(dppf)Cl₂ (0.05 equivalent) in 1,4-dioxane:H₂O (4:1, 0.27 M) was stirred at 100 °C under Ar for 16 hours. The reaction mixture was cooled to room temperature and diluted with water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 10:1 to 1:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =135.

[0564] Step 2: 6-Ethyl-2-methylpyridin-3-amine

[0565] A mixture of 2-methyl-6-vinylpyridin-3-amine (1.0 equivalent) and Pd / C (10%, 0.01 equivalent) in MeOH (2.1 M) was stirred at room temperature under H2 for 2 hours. The solid was filtered off and the filtrate was concentrated to give the title compound as a white solid.

[0566] Step 3: 6-Ethyl-2-methylpyridin-3-ol

[0567] At 0 °C, a solution of NaNO₂ (1.5 equivalents) in H₂O (3.1 M) was added dropwise to a solution of 6-ethyl-2-methylpyridin-3-amine (1.0 equivalent) in aqueous HCl (1.0 N, 5 equivalents). The reaction mixture was stirred at 0 °C for 1 hour, followed by heating at 70 °C for 16 hours. The reaction mixture was cooled to room temperature and washed twice with EtOAc. The aqueous layer was concentrated, and the pH was adjusted to approximately 7 with 3.0 M NaOH aqueous 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.

[0568] Intermediate A17: 3-((2-chloropyridin-4-yl)oxy)-2-methylquinoline

[0569]

[0570] Step 1: 3-Methoxy-2-methylquinoline

[0571] A mixture of 2-aminobenzaldehyde (1.0 equivalent), 1-methoxyprop-2-one (1.4 equivalent), and KOH (1 equivalent) in EtOH-water (5:1, 0.34 M) was heated at 85 °C for 1 hour. The mixture was cooled to room temperature and post-processed. The crude product was purified by silica gel rapid chromatography (petroleum ether / EtOAc 15:1) to give the title compound as a yellow oil.

[0572] Step 2: 2-Methylquinoline-3-ol

[0573] A solution of 3-methoxy-2-methylquinoline (5.7 g, 32.95 mmol, 1.0 equivalent) in DCM (0.33 M) was cooled to -20 °C. BBr3 (3.0 equivalent) was slowly added under Ar conditions, and the resulting mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS and TLC. After completion, the reaction mixture was cooled below 0 °C, quenched with a saturated aqueous solution of NaHCO3, and extracted with DCM / MeOH. The organic layer was concentrated under reduced pressure to give the title compound as a yellow solid.

[0574] Step 3: 3-((2-chloropyridin-4-yl)oxy)-2-methylquinoline

[0575] A mixture of 2-methylquinoline-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.2 equivalent), and Cs₂CO₃ (3.0 equivalent) in DMSO (0.16 M) was stirred at 150 °C under N₂ for 3 h. The reaction was monitored by TLC. The mixture was cooled to room temperature, treated with water, extracted with EtOAc, and then dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (petroleum ether / EtOAc 4:1) to give the title compound as a yellow oil. 1 H NMR(400MHz, CDCl3)δ8.29(d,J=5.6Hz,1H),8.10(d,J=8.4Hz,1H),7.75-7.71(m,1H), 7.56(t,J=7.2Hz,1H), 6.84(d,J=2.0Hz,1H), 6.82(dd,J=5.6,2.0Hz,1H), 2.61(s,3H).

[0576] Intermediate A18: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-6-methyl-2,2'-bipyridine

[0577]

[0578] Step 1: 2-Methyl-5-nitro-3-vinylpyridine

[0579] A mixture of 3-bromo-2-methyl-5-nitropyridine (1.0 equivalent), potassium trifluoro(vinyl)borate (1.0 equivalent), K₂CO₃ (2.0 equivalent), and Pd(dppf)Cl₂ (0.1 equivalent) in dioxane / H₂O (v / v = 4:1, 0.5 M) was stirred at 100 °C for 16 hours under an Ar atmosphere. The mixture was filtered through a diatomaceous earth layer. The filtrate was diluted with EtOAc, washed with water and brine, and the organic layer was dried over Na₂SO₄. The crude product was purified by rapid silica gel chromatography to give the title compound. LC-MS (m / z): [M+H] + =165.3.

[0580] Step 2: 5-Ethyl-6-methylpyridine-3-amine

[0581] A mixture of 2-methyl-5-nitro-3-vinylpyridine (1.0 equivalent) and Pd / C (10%, 0.01 equivalent) in MeOH (0.3 M) was stirred at room temperature under H2 for 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] + =137.2.

[0582] Step 3: 5-Ethyl-6-methylpyridin-3-ol

[0583] A solution of NaNO₂ (1.0 equivalent) in H₂O (7 M) was added dropwise to a stirred solution of 5-ethyl-6-methylpyridin-3-amine (1.0 equivalent) in 1.0 N HCl aqueous solution (0.7 M). The reaction mixture was stirred at 0 °C for 0.5 h, followed by heating at 70 °C for 2 h. The resulting mixture was stirred at room temperature for 16 h, neutralized with NaHCO₃ to pH approximately 8, and then extracted with EtOAc. The organic layer was washed with brine and then dried over Na₂SO₄. After solvent removal, the title compound was obtained. LC-MS (m / z): [M+H] + =138.2.

[0584] Step 4: 5-Ethyl-2-iodo-6-methylpyridin-3-ol

[0585] A mixture of 5-ethyl-6-methylpyridin-3-ol (1.9 g, 13.8 mmol, 1.0 equivalent), I₂ (3.52 g, 13.8 mmol, 1.0 equivalent), and Na₂CO₃ (3.23 g, 30.5 mmol, 2.2 equivalent) in H₂O (50 mL) was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 10:1 to 5:1) to give the title compound. LC-MS (m / z): [M+H] + =264.2.

[0586] Step 5: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-2-iodo-6-methylpyridine

[0587] A mixture of 5-ethyl-2-iodo-6-methylpyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.05 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.2 M) was stirred at 100 °C under an Ar atmosphere for 16 hours. The mixture was diluted with EtOAc, washed 10 times with brine, and then dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 50:1 to 10:1) to give the title compound. LC-MS (m / z): [M+H] + =375.0.

[0588] Step 6: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-6-methyl-2,2'-bipyridine

[0589] Add pyridin-2-yl zinc(II) bromide (0.5 M in THF, 1.2 equivalents) to a mixture of 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-2-iodo-6-methylpyridine (1.0 equivalent) and Pd(dppf)Cl2 (0.1 equivalent) in DMA (0.4 M). Stir the reaction mixture at 120 °C under Ar for 16 h. Filter the mixture through a diatomaceous earth layer and concentrate the filtrate. Dilute the residue with EtOAc, wash with brine, and then dry with Na2SO4. Purify the crude product by rapid silica gel chromatography to give the title compound. LC-MS (m / z): [M+H] + =326.2.

[0590] The following intermediates are prepared according to the method described in intermediate A18.

[0591]

[0592] Intermediate A20: 3-((2-chloropyridin-4-yl)oxy)-5-isopropyl-6-methyl-2,2'-bipyridine

[0593]

[0594] Step 1: Methyl 5-(hydroxy(pyridin-2-yl)methyl)-2-methylfuran-3-carboxylate

[0595] At 0 °C, pyridinecarboxaldehyde (1.0 equivalent) was added to a suspension of AlBr3 (1.0 equivalent) in anhydrous DCM (0.2 M), and the resulting mixture was stirred at 0 °C under Ar for 30 min. Subsequently, a solution of methyl 2-methylfuran-3-carboxylate (1.0 equivalent) in DCM (0.1 M) was added dropwise. The resulting suspension was stirred at room temperature for 16 h, followed by quenching with a saturated aqueous solution of NaHCO3. The mixture was partitioned between DCM and water, the organic layer was separated, and dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent petroleum ether / EtOAc, 100:1 to 2:1) to give the title compound. LC-MS (m / z): [M+H] + =248.1.

[0596] Step 2: 2-(5-(hydroxy(pyridin-2-yl)methyl)-2-methylfuran-3-yl)prop-2-ol

[0597] CH3MgBr (4.0 equivalents) was added to a solution of methyl 5-(hydroxy(pyridin-2-yl)methyl)-2-methylfuran-3-carboxylate (1.0 equivalent) in THF (0.12 M). The resulting mixture was stirred under Ar at room temperature for 2 hours, followed by quenching with saturated NaHCO3. The mixture was partitioned between EtOAc and water. The organic layer was separated and dried over Na2SO4. After solvent removal, the title compound was obtained and used in the next step without further purification. LC-MS (m / z): [M+H] + =248.1.

[0598] Step 3: (4-(2-hydroxypropyl-2-yl)-5-methylfuran-2-yl)(pyridin-2-yl)methyl ketone

[0599] MnO2 (3.0 equivalents) was added to a solution of 2-(5-(hydroxy(pyridin-2-yl)methyl)-2-methylfuran-3-yl)prop-2-ol (1.0 equivalent) in DCM (0.25 M), and the resulting mixture was stirred overnight at room temperature. The mixture was filtered through a diatomaceous earth layer, the filtrate was concentrated, and purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc, 100:1 to 2:1) to give the title compound as a pale yellow solid. LC-MS (m / z): [M+H] + =246.1.

[0600] Step 4: 5-(2-hydroxypropyl-2-yl)-6-methyl-[2,2'-bipyridine]-3-ol

[0601] A solution of (1.0 equivalent) methyl 4-(2-hydroxypropyl-2-yl)-5-methylfuran-2-yl)(pyridin-2-yl)methyl ketone in NH3·H2O / MeOH (1:1, 0.15 M) was stirred in a sealed tube at 170 °C for 8 hours. The solvent was removed, and the residue was lyophilized to give the title compound as a pale yellow solid. LC-MS (m / z): [M+H] + =245.2.

[0602] Step 5: 6-Methyl-5-(prop-1-en-2-yl)-[2,2'-bipyridine]-3-ol

[0603] A mixture of 5-(2-hydroxypropyl-2-yl)-6-methyl-[2,2'-bipyridine]-3-ol (370 mg, 1.51 mmol, 1.0 equivalent) and p-TsOH (317 mg, 1.67 mmol, 1.1 equivalent) in toluene was refluxed at 135 °C for 16 hours. After the reaction was complete, the mixture was concentrated to give the title compound. LC-MS (m / z): [M+H] + =227.3.

[0604] Step 6: 5-Isopropyl-6-methyl-[2,2'-bipyridine]-3-ol

[0605] A mixture of 6-methyl-5-(prop-1-en-2-yl)-[2,2'-bipyridine]-3-ol (343 mg, 1.52 mmol, 1.0 equivalent) and Pd / C (10%, 0.06 equivalent) in THF / MeOH (5:1, 0.025 M) was stirred at room temperature under H2 for 5 hours. The solid was filtered off, and the filtrate was concentrated to give the title compound. LC-MS (m / z): [M+H] + =229.1.

[0606] Step 7: 3-((2-chloropyridin-4-yl)oxy)-5-isopropyl-6-methyl-2,2'-bipyridine

[0607] A mixture of 5-isopropyl-6-methyl-[2,2'-bipyridine]-3-ol (1.0 equivalent), 2,4-dichloropyridine (2.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMSO (0.1 M) was stirred at 150 °C for 6 hours. The mixture was cooled to room temperature and quenched with water. The crude product was purified by silica gel rapid chromatography (eluent MeOH / DCM 0 to 5%) to give the title compound as a pale yellow solid. LC-MS (m / z): [M+H] + =340.1.

[0608] Intermediate A21: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,2'-bipyridine

[0609]

[0610] The compound was prepared by following the method described in intermediate A1.

[0611] Step 1: (5-Ethylfuran-2-yl)(pyridin-2-yl)methyl ketone

[0612] At 0 °C, n-BuLi (2.5 M, 10.8 mL, 27.1 mmol, 1.3 equivalent) was added dropwise to a stirred solution of 2-ethylfuran (2.0 g, 20.8 mmol, 1.0 equivalent) in Et₂O (80 mL). The mixture was stirred at 40 °C for 1.5 h, then cooled to -78 °C. A solution of pyridinecarboxynitrile (2.4 g, 22.9 mmol, 1.1 equivalent) in Et₂O (20 mL) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature for 1.5 h. The reaction was monitored by LC-MS. The reaction mixture was quenched with ice water. The pH of the mixture was adjusted to approximately 5 with 2N HCl. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried over Na₂SO₄, 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.

[0613] Step 2: 6-Ethyl-[2,2'-bipyridine]-3-ol

[0614] A mixture of (5-ethylfuran-2-yl)(pyridin-2-yl)methyl ketone (1.25 g, 4.97 mmol, 1.0 equivalent), MeOH (10 mL), and NH3·H2O (10 mL) placed in a sealed tube was heated at 170 °C for 8 hours. The mixture was then cooled to room temperature and the solvent was 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

[0615] Step 3: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,2'-bipyridine

[0616] A mixture of 6-ethyl-[2,2'-bipyridine]-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.05 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.4 M) was stirred at 100 °C under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was quenched with water and extracted with EA. The organic layer was dried over Na₂SO₄ and 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.

[0617] The following intermediates are prepared according to the method described in intermediate A21.

[0618]

[0619] Intermediate A23: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-5-methyl-2,2'-bipyridine

[0620]

[0621] Step 1: 2-Bromo-3-methylfuran

[0622] A mixture of 3-methylfuran (1.0 equivalent), NBS (1.0 equivalent), and AIBN (0.08 equivalent) in Et2O (0.5 M) was stirred at 50 °C under an Ar atmosphere for 2 hours. The product was obtained after routine processing and used in the next step without further purification.

[0623] Step 2: (5-bromo-4-methylfuran-2-yl)(pyridin-2-yl)methanol

[0624] AlBr3 (1.0 equivalent) was added fractionally to a solution of 2-bromo-3-methylfuran (1.0 equivalent) in Et2O (0.5 M) at 0 °C. After stirring the mixture at 0 °C for 0.5 h, pyridinecarboxaldehyde (1.0 equivalent) was added. The resulting mixture was stirred under Ar at room temperature for 16 h, followed by quenching with aqueous NaOH solution. The combined organic layers were washed with brine using an EtOAc mixture and then dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 20:1 to 5:1) to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + :268.

[0625] Step 3: (5-Ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanol

[0626] At 0 °C, Et₂Zn (3.0 equivalents) was added dropwise to a mixture of (5-bromo-4-methylfuran-2-yl)(pyridin-2-yl)methanol (1.0 equivalent) and Pd(dppf)Cl₂ (0.05 equivalent) in THF (0.25 M). The mixture was stirred at 70 °C under Ar for 16 hours. The mixture was poured into ice water and filtered through a diatomaceous earth layer. The filtrate was extracted with EtOAc, and the combined organic layers were dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 20:1 to 5:1) to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + :218.

[0627] Step 4: (5-Ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methyl ketone

[0628] A mixture of (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methanol (1.0 equivalent) and MnO2 (5.0 equivalent) in THF (0.2 M) was stirred at 50 °C for 16 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + :216.

[0629] Step 5: 6-Ethyl-5-methyl-[2,2'-bipyridine]-3-ol

[0630] A mixture of (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methyl ketone (1.0 equivalent) and NH3·H2O / MeOH (1:1, 0.2 M) in a sealed tube was heated at 170 °C for 8 hours. The solvent was removed to obtain the title compound, which was used in the next step without further purification. LC-MS (m / z): [M+H] + :215.

[0631] Step 6: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-5-methyl-2,2'-bipyridine

[0632] A mixture of 6-ethyl-5-methyl-[2,2'-bipyridine]-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.5 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.5 M) was stirred at 100 °C under Ar for 16 hours. The mixture was cooled to room temperature, 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 rapid chromatography (eluent: petroleum ether / EtOAc = 10:1 to 1:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + :326.

[0633] Alternative routes for preparing (5-ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methyl ketone:

[0634]

[0635] Step 1: (4-(chloromethyl)-5-ethylfuran-2-yl)(pyridin-2-yl)methyl ketone

[0636] (5-ethylfuran-2-yl)(pyridin-2-yl) methyl ketone (1.0 equivalent), (HCHO) nA mixture of ZnCl2 (4.0 equivalents), HCl / dioxane (10 equivalents) in DCE (0.22 M) was stirred at 50 °C under Ar for 16 hours. Most of the solvent was removed, and the residue was adjusted to pH approximately 8 with 1.0 M NaOH aqueous solution. The mixture was diluted with DCM. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine and then dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 20:1 to 5:1) to give the title compound as a brown oil. LC-MS (m / z): [M+H] + =250.

[0637] Step 2: (5-Ethyl-4-methylfuran-2-yl)(pyridin-2-yl)methyl ketone

[0638] A mixture of (4-(chloromethyl)-5-ethylfuran-2-yl)(pyridin-2-yl) methyl ketone (1.0 equivalent), Pd / C (10%, 0.03 equivalent), and TEA (2.0 equivalent) in EtOAc (0.2 M) was stirred at room temperature under H2 for 2.5 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 10:1 to 5:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =216.

[0639] Intermediate A24: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)pyridine

[0640]

[0641] Step 1: 5,6-Dimethylpyridin-3-ol

[0642] At 0 °C, a solution of NaNO2 (1.0 equivalent) in H2O was added dropwise to a mixture of 5,6-dimethylpyridin-3-amine (1.0 equivalent) in 2 M H2SO4 (0.33 M). The mixture was stirred at room temperature for 30 min, then at 70 °C for 2 h, and subsequently at room temperature for 16 h. The mixture was diluted with EtOAc / H2O. The organic layer was separated and dried over Na2SO4. 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.

[0643] Step 2: 2-Iodo-5,6-dimethylpyridin-3-ol

[0644] I₂ (1.1 equivalent) was added fractionally to a mixture of 5,6-dimethylpyridin-3-ol (1.0 equivalent), Na₂CO₃ (2.0 equivalent), and H₂O / THF (1:4, 0.15 M), and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with DCM / H₂O, the organic layer was separated, and dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 2:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =250.0.

[0645] Step 3: 2-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethylpyridin-3-ol

[0646] A mixture of 2-iodo-5,6-dimethylpyridin-3-ol (1.0 equivalent), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (1.5 equivalent), PdCl2 (dppf) (0.1 equivalent), and Na2CO3 (2.0 equivalent) in dioxane / H2O (10:1, 0.2 M) was stirred under Ar at 100 °C for 16 h. The mixture was diluted with DCM / H2O, the organic layer was separated, and dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 3:1) to give the title compound as a white solid. LC-MS (m / z): [M+H] + =206.4.

[0647] Step 4: 5,6-Dimethyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol

[0648] A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-5,6-dimethylpyridin-3-ol (1.0 equivalent) and Pd / C (20% by weight, 0.05 equivalent) in MeOH (0.1 M) was stirred at room temperature under H2 for 2 hours. 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.

[0649] Step 5: 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)pyridine

[0650] A mixture of 5,6-dimethyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.1 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMSO (0.1 M) was stirred under Ar at 130 °C for 2 hours. The mixture was cooled to room temperature and diluted with EtOA and water. The organic layer was separated and dried over Na₂SO₄. The crude product was purified by preparative TLC (eluent: petroleum ether / EtOAc = 3:1) to give the title compound as a colorless oil. LC-MS (m / z): [M+H] + =319.3.

[0651] Intermediate A25: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(tetrahydro-2H-pyran-4-yl)pyridine

[0652]

[0653] This compound was prepared according to the method described in intermediate A24. LCMS (m / z): [M+1] + =305.

[0654] Intermediate A26: 3-chloro-5-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine

[0655]

[0656] Step 1: 5-Chloro-6-methylpyridine-3-amine

[0657] Zn powder (10 equivalents) and NH4Cl (10 equivalents) were added to a mixture of 3-chloro-2-methyl-5-nitropyridine (1.0 equivalent) in MeOH / H2O (1:1, 0.6 M), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a diatomaceous earth layer, and the solid filter cake 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 rapid chromatography (eluent: petroleum ether / EtOAc = 5:1) to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + =143.1.

[0658] Step 2: 5-Chloro-6-methylpyridin-3-ol

[0659] At 0 °C, a solution of NaNO₂ (1.1 equivalents) in water (3.0 M) was added dropwise to a solution of 5-chloro-6-methylpyridin-3-amine (1.0 equivalent) in 1 M HCl (0.56 M), and the reaction mixture was stirred at 0 °C for 2 h, followed by heating to 70 °C and maintaining the temperature for 16 h. The reaction mixture was quenched with 20 mL of saturated aqueous solution of Na₂CO₃, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: DCM / MeOH = 30:1) to give the title compound as a white solid. LC-MS (m / z): [M+H] + =144.1.

[0660] Step 3: 5-Chloro-2-iodo-6-methylpyridin-3-ol

[0661] I₂ (1.0 equivalent) was added to a mixture of 5-chloro-6-methylpyridin-3-ol (1.0 equivalent), Na₂CO₃ (2.0 equivalent), and water (1.0 M) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with EtOA, and the combined organic layers were dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 5:1) to give the title compound as a white solid. LC-MS (m / z): [M+H] + =270.0.

[0662] Step 4: 5-Chloro-2,6-dimethylpyridin-3-ol

[0663] A mixture of 5-chloro-2-iodo-6-methylpyridin-3-ol (1.0 equivalent), trimethyltriborane (1.1 equivalent), Pd(dppf)Cl2 (0.05 equivalent), and K2CO3 (2.5 equivalent) in dioxane (0.2 M) was stirred at 100 °C under an Ar atmosphere for 16 hours. The reaction mixture was quenched with 10 mL of aqueous NH4Cl solution and filtered through a diatomaceous earth layer. The filtrate was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4. The crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 10:1) to give the title compound as a white solid. LC-MS (m / z): [M+H] + =158.1.

[0664] Step 5: 3-Chloro-5-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine

[0665] 2,4-Dichloropyridine (1.1 equivalents) and Cs₂CO₃ (2.5 equivalents) were added to a solution of 5-chloro-2,6-dimethylpyridin-3-ol (1.0 equivalent) in DMF (0.07 M). After stirring under Ar 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 Na₂SO₄. 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.

[0666] Intermediate A27: 3-((2-chloropyridin-4-yl)oxy)-2,5,6-trimethylpyridine

[0667]

[0668] This compound was prepared according to the method described in intermediate A26. LCMS (m / z): [M+1] + =249.1.

[0669] The following intermediates are prepared according to the method described in intermediate A6.

[0670]

[0671]

[0672]

[0673] Intermediate A41: 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine

[0674]

[0675] Step 1: 3-Cyclopropyl-2-methyl-5-nitropyridine

[0676] A solution of 3-bromo-2-methyl-5-nitropyridine (1.0 equivalent), cyclopropylboronic acid (1.2 equivalent), Na₂CO₃ (2.0 equivalent), and Pd(dppf)Cl₂ (0.1 equivalent) in dioxane / H₂O (10:1, 0.3 M) was stirred at 100 °C under Ar for 16 hours. The mixture was filtered, and the filtrate was diluted with EA, washed with water and brine, and then dried over Na₂SO₄. The crude product was purified by rapid silica gel chromatography to give the title compound. LCMS (m / z): [M+H] + =179.2.

[0677] Step 2: 5-Cyclopropyl-6-methylpyridine-3-amine

[0678] A mixture of 3-cyclopropyl-2-methyl-5-nitropyridine (1.0 equivalent) and Pd / C (10% by weight, 0.1 equivalent) in MeOH (0.3 M) was stirred at room temperature under H2 for 16 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound. LCMS (m / z): [M+H] + =149.2.

[0679] Step 3: 5-Cyclopropyl-6-methylpyridin-3-ol

[0680] A solution of NaNO₂ (1.0 equivalent) in H₂O (2.7 M) was added dropwise to a stirred solution of 5-cyclopropyl-6-methylpyridin-3-amine (1.0 equivalent) in 1 N HCl aqueous solution (0.3 M). The mixture was stirred at 0 °C for 0.5 h, at 70 °C for 2 h, and at room temperature for 16 h. The pH of the mixture was adjusted to approximately 8 with NaHCO₃, followed by extraction with EtOAc. The combined organic layers were dried over Na₂SO₄. After solvent removal, the title compound was obtained. LCMS (m / z): [M+H] + =150.4.

[0681] Step 4: 5-Cyclopropyl-2-iodo-6-methylpyridin-3-ol

[0682] A mixture of 5-cyclopropyl-6-methylpyridin-3-ol (1.0 equivalent), I₂ (1.0 equivalent), and Na₂CO₃ (2.2 equivalent) in H₂O (0.25 M) was stirred at room temperature for 2 hours. The mixture was extracted with EA, and the combined organic layers were dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 10:1 to 5:1) to give the title compound. LCMS (m / z): [M+H] + =276.1.

[0683] Step 5: 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine

[0684] A solution of 5-cyclopropyl-2-iodo-6-methylpyridin-3-ol (1.0 equivalent), phenylboronic acid (1.2 equivalent), Na₂CO₃ (2.0 equivalent), and Pd(dppf)Cl₂ (0.1 equivalent) in dioxane / H₂O (10:1, 0.1 M) was stirred at 100 °C under Ar for 16 hours. The mixture was filtered, and the filtrate was diluted with EA, washed with water and brine, and then dried over Na₂SO₄. The crude product was purified by rapid silica gel chromatography to give the title compound. LCMS (m / z): [M+H]+ =226.3.

[0685] Step 6: 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine

[0686] A mixture of 3-((2-chloropyridin-4-yl)oxy)-5-cyclopropyl-6-methyl-2-phenylpyridine (1.0 equivalent), 2,4-dichloropyridine (1.05 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.1 M) was stirred at 100 °C under Ar for 16 hours. The mixture was diluted with EA and brine. The organic layer was separated and dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 50:1 to 5:1) to give the title compound. LCMS (m / z): [M+H] + =337.1.

[0687] Intermediate A42: 3-((2-chloropyridin-4-yl)oxy)-5-ethyl-6-methyl-2-phenylpyridine

[0688]

[0689] This compound was prepared according to the method described in intermediate A41. LCMS (m / z): [M+H] + =325.1.

[0690] Intermediate A43: 3-((2-chloropyridin-4-yl)oxy)-5-isopropyl-6-methyl-2-phenylpyridine

[0691]

[0692] This compound was prepared by slightly modifying the method described in intermediate A20.

[0693]

[0694] Step 1: Methyl 5-benzoyl-2-methylfuran-3-carboxylate

[0695] Benzoyl chloride (1.05 equivalents) was added to a suspension of FeCl3 (0.013 equivalents) in CCl4 (4.5 M), followed by the addition of methyl 2-methylfuran-3-carboxylate (6.0 g, 42.8 mmol, 1.0 equivalents). The mixture was stirred at 80 °C for 1 hour, and then partitioned between DCM and water. The organic layer was separated and dried over Na2SO4. The crude product was purified by rapid silica gel chromatography (petroleum ether / EtOAc = 1:0 to 10:1) to give the title compound as a yellow oil.

[0696] Step 2: Methyl 5-(hydroxy(phenyl)methyl)-2-methylfuran-3-carboxylate

[0697] At 0 °C, methyl 5-benzoyl-2-methylfuran-3-carboxylate (1.0 equivalent) was added fractionally to a solution of methyl 5-benzoyl-2-methylfuran-3-carboxylate in MeOH (1.0 M), and the mixture was stirred at 0 °C for 2 hours. The reactants were quenched with saturated NH4Cl, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4. The crude product was purified by rapid silica gel chromatography (petroleum ether / EtOAc = 1:0 to 5:1) to give the title compound as a yellow oil.

[0698] The remaining steps were performed according to the method described for intermediate A20 (steps 2-7). The crude product was purified by silica gel rapid chromatography (eluent MeOH / DCM = 0 to 5%) to obtain intermediate A43 as a pale yellow solid. LCMS (m / z): [M+H] + =339.3.

[0699] Intermediate A44: 2-(5-((2-chloropyridin-4-yl)oxy)-2-methyl-6-phenylpyridin-3-yl)prop-2-ol

[0700]

[0701] This compound was prepared according to the method described in intermediate A43. The crude product was purified by silica gel rapid chromatography (eluent: MeOH / DCM = 0 to 5%) to give the title compound as a pale yellow solid. LCMS (m / z): [M+H] + =355.

[0702] Intermediate A45: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-phenylpyridine

[0703]

[0704] Step 1: 2-Phenylidene-3-ol

[0705] A mixture of 2-iodopyridin-3-ol (1.0 equivalent), phenylboronic acid (1.1 equivalent), PdCl2 (dppf) (0.1 equivalent), and Na2CO3 (2.0 equivalent) in dioxane / H2O (10:1, 0.2 M) was stirred at 90 °C under an Ar atmosphere for 16 hours. The mixture was diluted with DCM. The organic layer was separated and dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 3:1) to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =172.2.

[0706] Step 2: 6-Iodo-2-phenylpyridin-3-ol

[0707] I₂ (1.1 equivalent) was added fractionally to a mixture of 2-phenylpyridin-3-ol (1.0 equivalent) and Na₂CO₃ (2.0 equivalent) in THF / H₂O (4:1, 0.15 M), and the mixture was stirred at room temperature for 0.5 h, followed by dilution with DCM. The organic layer was separated, washed with brine, and then dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 4:1) to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =297.9.

[0708] Step 3: 2-Phenylon-6-vinylpyridine-3-ol

[0709] A mixture of 6-iodo-2-phenylpyridin-3-ol (1.0 equivalent), CH2CHBF3K (1.5 equivalent), K2CO3 (2.0 equivalent), and PdCl2 (dppf) (0.1 equivalent) in dioxane / H2O (4:1, 0.1 M) was stirred at 95 °C under an Ar atmosphere for 16 hours. The mixture was diluted with DCM, the organic layer was separated, and then dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 3:1) to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =198.0.

[0710] Step 4: 6-Ethyl-2-phenylpyridine-3-ol

[0711] A mixture of 2-phenyl-6-vinylpyridin-3-ol (1.0 equivalent) and Pd / C (10% by weight, 0.02 equivalent) in MeOH (0.06 M) was stirred at room temperature under H2 for 1 hour. The solid was filtered off, and the filtrate was concentrated to give the title compound as a white solid. LCMS (m / z): [M+H] + =200.0.

[0712] Step 5: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-phenylpyridine

[0713] A mixture of 6-ethyl-2-phenylpyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (2.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMSO (0.1 M) was stirred at 130 °C under Ar for 2 hours. The mixture was diluted with EtOAc and water. The organic layer was separated and dried over Na₂SO₄. The crude product was purified by preparative TLC (eluent: petroleum ether / EtOAc = 4:1) to give the title compound as a colorless oil. LCMS (m / z): [M+H] + =311.1.

[0714] The following intermediates are prepared according to the method described in intermediate A45.

[0715]

[0716]

[0717] Intermediate A49: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,5-dimethylpyridine

[0718]

[0719] Step 1: 2,5-Dimethyl-3-nitropyridine

[0720] A mixture of 2,5-dibromo-3-nitropyridine (1.0 equivalent), trimethyltriborane (3.0 equivalent), Pd(dppf)Cl2 (0.04 equivalent), and K2CO3 (6.0 equivalent) in dioxane (0.25 M) was stirred at 100 °C under an Ar atmosphere for 16 hours. The mixture was then post-treated, and the crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 5:1) to give a yellow oily compound. LCMS (m / z): [M+H] + =153.

[0721] Step 2: 2,5-Dimethylpyridin-3-amine

[0722] A mixture of 2,5-dimethyl-3-nitropyridine (1.0 equivalent) and 10% Pd / C (10% by weight, 0.01 equivalent) in MeOH (0.3 M) was stirred at room temperature under H2 for 16 hours. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =123.

[0723] Step 3: 6-Bromo-2,5-Dimethylpyridin-3-amine

[0724] NBS (1.0 equivalent) was added fractionally to a stirred solution of 2,5-dimethylpyridin-3-amine (1.0 equivalent) in MeCN (0.4 M) at 0 °C under Ar conditions. The mixture was stirred at 0 °C for 1 hour, followed by quenching with water. Acetonitrile was removed, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and then dried over Na2SO4. The title compound was obtained after solvent removal. LCMS (m / z): [M+H] + =201.

[0725] Step 4: 2,5-Dimethyl-6-vinylpyridine-3-amine

[0726] A mixture of 6-bromo-2,5-dimethylpyridin-3-amine (1.0 equivalent), potassium trifluoro(vinyl)borate (1.2 equivalent), Pd(dppf)Cl2 (0.05 equivalent), and K2CO3 (3.0 equivalent) in dioxane / water (14:1, 0.27 M) was stirred at 100 °C under Ar for 16 hours. The mixture was post-treated, and the crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 5:1) to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =150.

[0727] Step 5: 6-Ethyl-2,5-dimethylpyridin-3-amine

[0728] A mixture of 2,5-dimethyl-6-vinylpyridin-3-amine (1.0 equivalent) and Pd / C (10% by weight, 0.01 equivalent) in MeOH (0.32 M) was stirred at room temperature under H2 for 16 hours. The solid was filtered off and the filtrate was concentrated to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =151.

[0729] Step 6: 6-Ethyl-2,5-dimethylpyridin-3-ol

[0730] At 0 °C, a solution of NaNO₂ (1.0 equivalent) in H₂O (2.4 M) was added dropwise to a solution of 6-ethyl-2,5-dimethylpyridin-3-amine (1.0 equivalent) in 1 N HCl (0.16 M). The mixture was stirred at 0 °C for 1 hour, followed by heating to 70 °C and maintaining the temperature for 16 hours. After adjusting the pH to approximately 8 with a 1.0 M NaOH aqueous solution, 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. LCMS (m / z): [M+H] + =152.

[0731] Step 7: 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,5-dimethylpyridine

[0732] A mixture of 6-ethyl-2,5-dimethylpyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.25 M) was stirred at 100 °C under Ar for 16 hours, followed by dilution 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 Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 2:1) to give the title compound as a yellow oil. LCMS (m / z): [M+H] + =263.

[0733] Intermediate A50: 3-chloro-5-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-methylpyridine

[0734]

[0735] Step 1: 5-Chloro-2-methylpyridin-3-amine

[0736] Zn powder (4.0 equivalents) was added to a solution of 5-chloro-2-methyl-3-nitropyridine (30.0 g, 0.17 mol, 1.0 equivalent) in a saturated aqueous solution of EtOH / NH4Cl (1:4, 0.7 M). The reaction mixture was stirred at room temperature for 16 hours, followed by filtration through a diatomaceous earth layer. The filtrate was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: DCM / MeOH = 100:1) to give the title compound as a white solid. LCMS (m / z): [M+H] + =142.0.

[0737] Step 2: 6-Bromo-5-chloro-2-methylpyridin-3-amine

[0738] NBS (1.0 equivalent) was added fractionally to a solution of 5-chloro-2-methylpyridin-3-amine (1.0 equivalent) in acetonitrile (0.5 M) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours, followed by quenching 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 Na₂SO₄. The crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 5:1) to give the title compound as a white solid. LCMS (m / z): [M+H] + =221.0.

[0739] Step 3: 5-Chloro-2-methyl-6-vinylpyridine-3-amine

[0740] A mixture of 6-bromo-5-chloro-2-methylpyridin-3-amine (1.0 equivalent), potassium trifluoro(vinyl)borate (1.2 equivalent), Pd(dppf)Cl2 (0.05 equivalent), and K2CO3 (2.5 equivalent) in dioxane / water (5:1, 0.4 M) was stirred at 80 °C under an atmospheric atmosphere for 2 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was extracted with EtOAc. The combined organic layers were dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 8:1) to give the title compound as a colorless oil. LCMS (m / z): [M+H] + =169.0.

[0741] Step 4: 5-Chloro-6-ethyl-2-methylpyridin-3-amine

[0742] Zn powder (5.0 equivalents) was added to a solution of 5-chloro-2-methyl-6-vinylpyridin-3-amine (1.0 equivalent) and saturated aqueous NH4Cl / EtOH (2:1, 0.5 M). The reaction mixture was stirred at 50 °C for 16 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: 100% DCM) to give the title compound as a colorless oil. LCMS (m / z): [M+H] + =171.0.

[0743] Step 5: 5-Chloro-6-ethyl-2-methylpyridin-3-ol

[0744] At 0 °C, a solution of NaNO₂ (1.5 equivalents) in water (3.0 M) was added dropwise to a solution of 5-chloro-6-ethyl-2-methylpyridin-3-amine (1.0 equivalent) in 1 N HCl aqueous solution (0.25 M), and the mixture was stirred at 0 °C for 2 h, followed by stirring at 70 °C for 16 h. A saturated aqueous solution of NaHCO₃ was added, and the mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: DCM / MeOH = 100:1) to give the title compound as a white solid. LCMS (m / z): [M+H] + =172.0.

[0745] Step 6: 3-Chloro-5-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-methylpyridine

[0746] 2,4-Dichloropyridine (1.2 equivalents) and Cs₂CO₃ (2.5 equivalents) were added to a solution of 5-chloro-6-ethyl-2-methylpyridin-3-ol (1.0 equivalent) in DMF (0.4 M). The reaction mixture was stirred at 100 °C under an Ar atmosphere for 16 hours and then cooled to room temperature. Ice water (100 mL) was added, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and then dried over Na₂SO₄. The crude product was purified by preparative TLC (eluent: petroleum ether / EtOAc = 10:1) to give the title compound as a white solid. LCMS (m / z): [M+H] + =283.1; 1 H NMR (400MHz, CDCl3) δ8.27(d,J=5.6Hz,1H),7.34(s,1H),6.77(d,J=2.0Hz,1H),6.7 4(dd, J=6.0, 2.4Hz, 1H), 2.96 (q, J=7.6Hz, 2H), 2.37 (s, 3H), 1.32 (t, J=7.2Hz, 3H).

[0747] The following intermediates are prepared according to the method described in intermediate A12.

[0748]

[0749]

[0750] Intermediate A56: 2-chloro-4-((1-cyclobutyl-3-phenyl-1H-pyrazol-4-yl)oxy)pyridine

[0751]

[0752] A mixture of 2-chloro-4-((3-phenyl-1H-pyrazol-4-yl)oxy)pyridine (1.0 equivalent), bromocyclobutane (2.0 equivalent), and K₂CO₃ (2.0 equivalent) in dioxane (0.35 M) was stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was separated and dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 5:1 to 1:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =326.

[0753] The following intermediates are prepared according to the method described in intermediate A56.

[0754]

[0755]

[0756] Intermediate A64: 2-chloro-4-((1-(difluoromethyl)-3-phenyl-1H-pyrazol-4-yl)oxy)pyridine

[0757]

[0758] A mixture of 2-chloro-4-((3-phenyl-1H-pyrazol-4-yl)oxy)pyridine (1.0 equivalent), diethyl(bromodifluoromethyl)phosphonite diester (10 equivalent), KF (2.0 equivalent), and NaI (1.0 equivalent) in MeCN (0.2 M) was stirred overnight at 80 °C under an Ar atmosphere. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 5:1) to give the title compound as a yellow oil. LCMS (m / z): [M+1] + =322.1.

[0759] Intermediate A65: 3-((2-chloropyridin-4-yl)oxy)-2-methyl-6-phenylpyridine

[0760]

[0761] Step 1: 2-Methyl-6-phenylpyridin-3-ol

[0762] A mixture of 6-iodo-2-methylpyridin-3-ol (step 1 of intermediate A16, 1.0 equivalent), phenylboronic acid (1.05 equivalent), Pd(dppf)Cl2 (0.1 equivalent), and K2CO3 (3.0 equivalent) in dioxane / H2O (8:1, 0.61 M) was stirred at 115 °C under Ar for 16 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (petroleum ether:EtOAc = 10:1) to give the title compound as a white solid.

[0763] Step 2: 3-((2-chloropyridin-4-yl)oxy)-2-methyl-6-phenylpyridine

[0764] A mixture of 2-methyl-6-phenylpyridin-3-ol (1.0 equivalent), 2,4-dichloropyridine (1.0 equivalent), and Cs₂CO₃ (2.0 equivalent) in DMF (0.36 M) was stirred at 115 °C under Ar for 16 hours. The mixture was filtered, and the filtrate was treated with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (petroleum ether:EtOAc = 20:1) to give the title compound as a colorless oil.

[0765] Intermediate A66: 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)pyridine

[0766]

[0767] A mixture of 3-((2-chloropyridin-4-yl)oxy)-2-iodo-6-methylpyridine (intermediate A3, step 1, 500 mg, 1.45 mmol, 1.0 equivalent), (1-methyl-1H-pyrazol-4-yl)boronic acid (1.2 equivalent), Pd(dppf)Cl2 (0.1 equivalent), and Na2CO3 (2.0 equivalent) in dioxane / H2O (10:1, 0.13 M) was stirred overnight at 100 °C under Ar conditions. The solid was filtered off, and the filtrate was diluted with EtOAc, washed with water and brine, and then dried over Na2SO4. The crude product was purified by rapid silica gel chromatography to give the title compound. LC-MS (m / z): [M+H] + =301.1.

[0768] Intermediate B1: Methyl 3-(3-aminophenyl)propionate

[0769]

[0770] Step 1: 3-(3-nitrophenyl)propionic acid

[0771] At room temperature, TEA (1.4 equivalents) was added dropwise to HCOOH (3.5 equivalents) under stirring. The resulting reagent was added to a solution of 3-nitrobenzaldehyde (1.0 equivalent) and 2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 equivalent) in DMF (2.5 M). The reaction mixture was heated at 130 °C for 3 hours. The solution was cooled to room temperature, diluted with H₂O (200 mL), adjusted to pH 9 with saturated aqueous NaHCO₃ solution, and washed with EtOAc (2 × 50 mL). The aqueous phase was acidified to pH 2 with concentrated 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): [2 M⁻¹] - =389.

[0772] Step 2: Methyl 3-(3-nitrophenyl)propionate

[0773] SOCl2 (2.0 equivalents) was added to a solution of the above product (1.0 equivalent) in MeOH (0.74 M) at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with H2O (150 mL) and extracted with EtOAc (2 × 50 mL). The organic phase was washed with saturated NaHCO3 aqueous solution (2 × 20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc 10:1) to give the title compound as a white solid.

[0774] Step 3: Methyl 3-(3-aminophenyl)propionate

[0775] Pd / C (10% by weight) was added to a stirred solution of the above product (1.0 equivalent) in MeOH (0.5 M), and the mixture was stirred at room temperature under H2 for 16 hours. 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 wet-milled with Et2O (30 mL). The solid was collected by filtration and then dissolved in H2O (100 mL). The solution was adjusted to pH 9 with a saturated aqueous solution of NaHCO3 and extracted with DCM (2 × 50 mL). The DCM layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a pale yellow oil. LC-MS (m / z): [M+1] + =180.

[0776] Intermediate B2: 3-(3-aminophenyl)propionitrile

[0777]

[0778] Step 1: 3-(3-nitrophenyl)propionamide

[0779] HATU (1.2 equivalents) was added to a solution of 3-(3-nitrophenyl)propionic acid (1.0 equivalent) in DCM (0.25 M), and the mixture was stirred at room temperature for 30 minutes. Then, NH4Cl (1.5 equivalents) and DIEA (3.0 equivalents) were added. The mixture was stirred at room temperature for 4 hours, followed by quenching with H2O (50 mL). The aqueous solution was extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4 and 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.

[0780] Step 2: 3-(3-nitrophenyl)propionitrile

[0781] A mixture of 3-(3-nitrophenyl)propionamide (1.0 equivalent) and (CNCl)3 (1.5 equivalent) in DMF (0.25 mM) was stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O (200 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (60 mL) and then dried over Na2SO4. The solvent was removed, and the residue was purified by silica gel rapid 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; 1 H NMR(400MHz, CDCl3)δ8.16(d,J=8.4Hz,1H),8.12(s,1H),7.62(d,J=7.6Hz,1H), 7.55(t,J=8.0Hz,1H), 5.01(s,2H), 3.09(t,J=7.2Hz,2H), 2.72(t,J=7.2Hz,2H).

[0782] Step 3: 3-(3-aminophenyl)propionitrile

[0783] A mixture of 3-(3-nitrophenyl)propionitrile (1.0 equivalent) and Zn (5.0 equivalent) in MeOH / NH4Cl (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 room temperature and filtered. The filtrate was extracted with EA. The combined organic layers were 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; 1 H NMR (400MHz, DMSO) δ6.95 (dd, J=8.4, 7.2Hz, 1H), 6.44 (d, J=0.8Hz, 1H), 6.43-6.39 (m, 2H), 5.01 (s, 2H), 2.73-2.68 (m, 4H).

[0784] Intermediate B3: Methyl 3-(4-aminophenyl)propionate

[0785]

[0786] The compound was obtained according to the method described in intermediate B1. 1 H NMR (400MHz, CDCl3) δ6.98 (d, J = 8.4Hz, 2H), 6.62 (d, J = 8.4Hz, 2H), 3.66 (s, 3H), 2.84 (t, J = 7.6Hz, 2H), 2.57 (t, J = 7.6Hz, 2H).

[0787] Intermediate B4: 3-(4-aminophenyl)propionitrile

[0788]

[0789] Step 1: 3-(4-nitrophenyl)propionamide

[0790] HATU (1.2 equivalents) was added to a solution of 3-(4-nitrophenyl)propionic acid (1.0 equivalent) in DCM (0.4 M) and stirred at room temperature for 30 min, followed by the addition of NH4Cl (1.5 equivalents) and DIEA (3.0 equivalents). The mixture was stirred at room temperature for 4 h, then quenched with H2O (50 mL). The aqueous layer was extracted with DCM (3 × 30 mL) and dried over Na2SO4. The solvent was removed to give the title compound as a yellow oil, which was used directly in the next step without further purification.

[0791] Step 2: 3-(4-nitrophenyl)propionitrile

[0792] A mixture of 3-(4-nitrophenyl)propionamide (1.0 equivalent) and (CNCl)3 (1.5 equivalent) in DMF (0.25 mM) was stirred at room temperature for 2 hours. The solution was quenched with H2O. The aqueous layer was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (60 mL) and dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc 4:1 to 2:1) to give the title compound as a yellow solid. 1 H 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).

[0793] Step 3: 3-(4-aminophenyl)propionitrile

[0794] Pd / C (0.1 equivalent) was added to a solution of 3-(4-nitrophenyl)propionitrile (1.0 equivalent) in MeOH (0.4 M). The mixture was stirred at room temperature under H2 for 3 hours. 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. 1 H NMR (400MHz, DMSO) δ6.92 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 8.4 Hz, 2H), 4.94 (s, 2H), 2.68 (s, 4H).

[0795] Intermediate B5: 2-(3-aminophenyl)-2-methylpropionitrile

[0796]

[0797] Step 1: 2-Methyl-2-(3-nitrophenyl)propionitrile

[0798] t-BuOK (3.0 equivalents) was added fractionally to a solution of 2-(3-nitrophenyl)acetonitrile (1.0 equivalent) in DMF (0.3 M) at 0 °C. The mixture was stirred at 0 °C for 15 min, and MeI (5.0 equivalents) was added dropwise. The mixture was then stirred at room temperature for 2 h. The reaction was monitored by TLC. The mixture was quenched with NH4Cl (50 mL aqueous solution) and extracted with EtOAc (100 mL). The organic phase was washed with brine and dried over Na2SO4. The organic phase was concentrated. The residue was purified by silica gel rapid chromatography (petroleum ether / EtOAc 8:1) to give the title compound as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.24(t,J=2.0Hz,1H),8.14(ddd,J=8.0,2.0,1.2Hz,1H),7.82(ddd,J=8.0, 2.0,1.2Hz,1H),7.54(t,J=8.0Hz,1H),3.74(s,2H),2.83(t,J=7.2Hz,2H),2.57(t,J=7.2Hz,2H).

[0799] Step 2: 2-(3-aminophenyl)-2-methylpropionitrile

[0800] The mixture of the above product (1.0 equivalent), Zn (5.0 equivalent), and NH4Cl (10.0 equivalent) in MeOH-H2O (2:1, 0.15 mM) was stirred at 80 °C for 16 hours. The reaction was monitored by LC-MS. The mixture was filtered and washed with EtOAc (10 mL). The filtrate was extracted with EtOAc (50 mL), and the organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the residue. The residue was purified by silica gel rapid chromatography (petroleum ether / EtOAc 5:1) to give the title product as a yellow oil. LC-MS (m / z): [M+H] + =161. 1 H NMR (400MHz, CDCl3) δ7.08 (t, J = 8.0Hz, 1H), 6.76-6.72 (m, 2H), 6.57-6.53 (m, 1H), 3.38 (s, 2H), 1.61 (s, 6H).

[0801] Intermediate B6: 3-(3-amino-4-fluorophenyl)propionitrile

[0802]

[0803] Step 1: 2-(bromomethyl)-1-fluoro-4-nitrobenzene

[0804] A mixture of 1-fluoro-2-methyl-4-nitrobenzene (1.0 equivalent), NBS (1.1 equivalent), and BPO (benzoyl peroxide, 0.1 equivalent) in CCl4 (0.86 M) was stirred at 95 °C under Ar for 16 hours. 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 rapid chromatography (eluent: petroleum ether / EtOAc 1:0 to 50:1) to give the title compound as a white solid.

[0805] Step 2: Diethyl 2-(2-fluoro-5-nitrobenzyl)malonate

[0806] At 0 °C, a solution of diethyl malonate (2.0 equivalents) in DMF (2 M) was added to a stirred solution of NaH (60% in oil, 1.0 equivalent) in DMF (0.22 M). The mixture was stirred at 0 °C for 0.5 h, followed by dropwise addition of DMF (0.34 M) containing 2-(bromomethyl)-1-fluoro-4-nitrobenzene (1.0 equivalent) to the mixture and stirring 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.

[0807] Step 3: 2-(2-fluoro-5-nitrophenyl)propionic acid

[0808] A mixture of diethyl 2-(2-fluoro-5-nitrobenzyl)malonate (1.0 equivalent) in 6N HCl aqueous solution (31 equivalent, 0.19 M) was heated at 120 °C for 16 h. The reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine and then dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAC 3:1) to give the title compound. 1 H NMR (400MHz, CDCl3) δ8.20-8.12(m,2H),7.26-7.16(m,1H),3.07(t,J=7.6Hz,2H),2.75(t,J=7.6Hz,2H).

[0809] Step 4: 2-(2-fluoro-5-nitrophenyl)propionamide

[0810] A mixture of 1.0 equivalent of 2-(2-fluoro-5-nitrophenyl)propionic acid, 2.0 equivalent of SOCl2, and 1 drop of catalytically added DMF in toluene (0.42 M) was stirred at 85 °C for 1 h. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure. The residue was redissolved in Et2O (0.8 M) and NH3·H2O was added dropwise to a stirred solution (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 and concentrated under reduced pressure to give the title compound.

[0811] Step 5: 2-(2-fluoro-5-nitrophenyl)propionitrile

[0812] TFAA (2.5 equivalents) was added dropwise to a solution of 2-(2-fluoro-5-nitrophenyl)propionamide (1.0 equivalent) and pyridine (2.5 equivalent) in DCM (0.39 M) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. TLC indicated that the reaction was complete. The mixture was washed with 1.0 M HCl aqueous solution and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound.

[0813] Step 6: 2-(5-amino-2-fluorophenyl)propionitrile

[0814] A mixture of 2-(2-fluoro-5-nitrophenyl)propionitrile (1.0 equivalent), Zn (5.0 equivalent), and NH4Cl (10 equivalent) in EtOH / H2O (v / v = 5:1, 0.5 M) 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 Na2SO4 and concentrated under reduced pressure to give the title compound. LCMS (m / z): [M+H] + =165; 1 HNMR (400MHz, CDCl3) δ6.82-8.87(m,2H), 6.52-6.56(m,2H), 2.90(t,J=7.6Hz,2H), 2.62(t,J=7.2Hz,2H).

[0815] The following compounds were prepared according to the method described in intermediate B6.

[0816]

[0817]

[0818] Intermediate B10: Methyl 3-(5-amino-2-fluorophenyl)propionate

[0819]

[0820] Step 1: Methyl 3-(2-fluoro-5-nitrophenyl)propionate

[0821] A solution of 3-(2-fluoro-5-nitrophenyl)propionic acid (1.0 equivalent) in 2.5 M HCl / MeOH (6.7 equivalent, 0.37 M) was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to give the title compound.

[0822] Step 2: Methyl 3-(5-amino-2-fluorophenyl)propionate

[0823] Pd / C (10% by weight, 0.02 equivalents) was added to a solution of methyl 3-(2-fluoro-5-nitrophenyl)propionate (1.0 equivalent) in MeOH (0.35 M). The reaction mixture was stirred under hydrogen at room temperature for 3 hours. 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 (400MHz, CDCl3) δ6.77 (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).

[0824] The following compounds were prepared according to the method described in intermediate B10.

[0825]

[0826]

[0827] Intermediate B14: 3-(6-aminopyridin-2-yl)propionitrile

[0828]

[0829] Step 1: (E)-3-(6-aminopyridin-2-yl)acrylonitrile

[0830] A mixture of 6-bromopyridin-2-amine (1.0 equivalent), acrylonitrile (3.0 equivalent), Pd2(dba)3 (0.1 equivalent), and tri-o-tolylphosphine (0.3 equivalent) in DMF (0.57 M) was heated overnight at 140 °C. The mixture was then cooled to room temperature. The crude product was purified by rapid silica gel chromatography (petroleum ether / EtOAc 1:1) to give the title compound as a yellow solid.

[0831] Step 2: 3-(6-aminopyridin-2-yl)propionitrile

[0832] A mixture of (E)-3-(6-aminopyridin-2-yl)acrylonitrile (1.0 equivalent) and Pd / C (10% by weight, 0.02 equivalent) in MeOH (0.41 M) was stirred at room temperature under H2 for 2 hours. 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 (400MHz, CDCl3) δ7.38 (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).

[0833] The following intermediates are prepared according to the method described in intermediate B14.

[0834]

[0835] Intermediate B17: Methyl 3-(6-aminopyridin-2-yl)propionate

[0836]

[0837] Step 1: (E)-3-(6-aminopyridin-2-yl)methyl acrylate

[0838] A mixture of 6-bromopyridin-2-amine (3.0 g, 17.34 mmol, 1.0 equivalent), methyl acrylate (4.5 mL, 52.02 mmol, 3.0 equivalent), Pd2(dba)3 (0.1 equivalent), and tri-o-tolylphosphine (0.3 equivalent) in DMF (0.58 M) was heated overnight at 140 °C. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel rapid chromatography (petroleum ether / EtOAc 2:1) to give the title compound as a yellow solid.

[0839] Step 2: Methyl 3-(6-aminopyridin-2-yl)propionate

[0840] A mixture of (E)-3-(6-aminopyridin-2-yl)methyl acrylate (1.0 equivalent) and Pd / C (10% by weight, 0.02 equivalent) in MeOH (0.36 M) was stirred at room temperature under H2 for 4 hours. 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. 1H NMR (400MHz, CDCl3) δ7.33(t,J=7.6Hz,1H),6.52(d,J=7.2Hz,1H),6.32(d,J=8. 0Hz, 1H), 4.36 (s, 2H), 3.67 (s, 3H), 2.93 (t, J = 7.2Hz, 2H), 2.73 (t, J = 7.2Hz, 2H).

[0841] The following intermediates are prepared according to the method described in intermediate B17.

[0842]

[0843] Intermediate B20: Ethyl 3-(4-aminopyridin-2-yl)propionate

[0844]

[0845] Step 1: (E)-3-(4-aminopyridin-2-yl)ethyl acrylate

[0846] A mixture of 2-bromopyridin-4-amine (842 mg, 4.86 mmol, 1.0 equivalent), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)acrylate (0.95 equivalent), Pd(PPh3)2Cl2 (0.1 equivalent), and K2CO3 (2.5 equivalent) in dioxane / H2O (5:1, 0.4 M) was heated at 95 °C for 16 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel rapid chromatography (petroleum ether / EtOAc 1:4) to give the title compound as a yellow solid.

[0847] Step 2: Ethyl 3-(4-aminopyridin-2-yl)propionate

[0848] A mixture of (E)-3-(4-aminopyridin-2-yl)ethyl acrylate (1.0 equivalent) and Pd / C (0.02 equivalent) in MeOH (0.3 M) was stirred at room temperature under H2 for 2 hours. 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. 1 H NMR (400MHz, CDCl3) δ8.13 (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).

[0849] Intermediate B21: 3-(5-amino-2-methylphenyl)propionitrile

[0850]

[0851] Step 1: (E)-3-(2-methyl-5-nitrophenyl)acrylonitrile

[0852] A mixture of 2-bromo-1-methyl-4-nitrobenzene (1.0 equivalent), acrylonitrile (1.5 equivalent), Pd2(dba)3 (0.1 equivalent), P(o-Tol)3 (0.2 equivalent), and TEA (3.0 equivalent) in DMF (2.3 M) was stirred at 120 °C under Ar for 16 h. The reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (eluent petroleum ether / EtOAc 20:1 to 5:1) to give the title compound as a brown solid.

[0853] Step 2: 3-(5-amino-2-methylphenyl)propionitrile

[0854] Pd / C (10% by weight, 0.02 equivalents) was added to a solution of (E)-3-(2-methyl-5-nitrophenyl)acrylonitrile (1.0 equivalent) in MeOH (0.15 M). The reaction mixture was stirred at room temperature under H2 for 16 hours. 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. LCMS (m / z): [M+H] + =161; 1 H NMR (400MHz, CDCl3) δ6.96 (d, J = 8.8Hz, 1H), 6.55-6.52 (m, 2H), 3.57 (br s, 2H), 2.88 (t, J = 7.6Hz, 2H), 2.55 (t, J = 8.0Hz, 2H), 2.20 (s, 3H).

[0855] The following intermediates are prepared according to the method described in intermediate B21.

[0856]

[0857] Intermediate B26: Methyl 1-(3-aminophenyl)cyclopropane-1-carboxylate

[0858]

[0859] Step 1: 1-(3-nitrophenyl)cyclopropane-1-carboxynitrile

[0860] An aqueous solution of NaOH (50% wt, 10 equivalents) was added to a mixture of 2-(3-nitrophenyl)acetonitrile (2.0 g, 12.33 mmol, 1.0 equivalent), 1,2-dibromoethane (3.47 g, 18.50 mmol, 1.5 equivalent), and Et3NBnCl (562 mg, 2.47 mmol, 0.2 equivalent) in toluene (1.2 M). The reaction mixture was stirred at 35 °C for 16 h. 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 HCl aqueous solution and brine, and then dried over Na₂SO₄. After solvent removal, title compound 3 (700 mg, 30%) was obtained as a brown solid.

[0861] Step 2: 1-(3-nitrophenyl)cyclopropane-1-carboxylic acid

[0862] A solution of 1-(3-nitrophenyl)cyclopropane (600 mg, 3.19 mmol, 1.0 equivalent) in concentrated 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 an aqueous solution of NaHCO3 and then dried over Na2SO4. 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; 1 H NMR (400MHz, CDCl3) δ6.96 (d, J = 8.8Hz, 1H), 6.55-6.52 (m, 2H), 3.57 (br s, 2H), 2.88 (t, J = 7.6Hz, 2H), 2.55 (t, J = 8.0Hz, 2H), 2.20 (s, 3H).

[0863] Step 3: 1-(3-aminophenyl)cyclopropane-1-carboxylic acid

[0864] Pd / C (20% wt, 0.1 equivalent) was added to a solution of 1-(3-nitrophenyl)cyclopropane-1-carboxylic acid (1.0 equivalent) in MeOH (0.24 M). The mixture was stirred at 35 °C under H2 for 3 hours. 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.

[0865] Step 4: Methyl 1-(3-aminophenyl)cyclopropane-1-carboxylate

[0866] A solution of 1-(3-aminophenyl)cyclopropane-1-carboxylic acid (428 mg, 2.41 mmol, 1.0 equivalent) in 2.5 M HCl / MeOH (1.0 equivalent, 0.24 M) was 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 and washed with aqueous NaHCO3 solution. The organic layer was dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: DCM / MeOH 1:0 to 20:1) to give the title compound as a white solid. LC-MS (m / z): [M+H] + =192.

[0867] Intermediate B27: Methyl 2-(3-aminophenyl)-2-methylpropionate

[0868]

[0869] Step 1: Methyl 2-methyl-2-(3-nitrophenyl)propionate

[0870] t-BuOK (3.0 equivalents) was added fractionally to a solution of methyl 2-(3-nitrophenyl)acetate (1.0 equivalent) in DMF (0.14 M) at 0 °C. The mixture was stirred for 10 min at the same temperature. MeI (5.0 equivalents) was introduced into the mixture while maintaining the temperature below 5 °C. The reaction mixture was quenched with water after stirring at room temperature for 2 h. The resulting solution was extracted with Et2O. The organic layer was combined and concentrated, and the residue was purified by silica gel rapid chromatography (petroleum ether / EtOAc 20:1 to 15:1) to give the title compound as a pale yellow oil.

[0871] Step 2: Methyl 2-(3-aminophenyl)-2-methylpropionate

[0872] NH4Cl (10 equivalents) and Zn (5.0 equivalents) were added to a solution of methyl 2-methyl-2-(3-nitrophenyl)propionate (1.0 equivalent) in MeOH / H2O (1:1, 0.12 M). The reaction mixture was heated at 80 °C for 2 h. The reaction was monitored by TLC. The solid was filtered off, the filtrate was concentrated and extracted with DCM. The organic layers were combined, dried and purified by silica gel rapid chromatography (petroleum ether / EtOAc 15:1 to 8:1) to give the title compound. 1 H NMR (400MHz, CDCl3) δ7.11 (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).

[0873] Intermediate B28: 3-(3-amino-5-methoxyphenyl)propionitrile

[0874]

[0875] The intermediate was prepared according to the method described in intermediate B2. LCMS(m / z): [M+H] + =177; 1 H NMR (400MHz, CDCl3) δ6.18-6.13(m,3H),3.76(s,3H),3.69(s,2H,NH2),2.82(t,J=7.6,2H),2.58(t,J=7.6Hz,2H).

[0876] Intermediate B29: 3-(3-amino-5-fluorophenyl)propionitrile

[0877]

[0878] The intermediate was prepared according to the method described in intermediate B2. LCMS(m / z):[M+1] + =165.2; 1 H NMR (400MHz, CDCl3) δ6.32-6.26 (m, 3H), 3.80 (br s, 2H), 2.83 (t, J = 7.6Hz, 2H), 2.59 (t, J = 7.6Hz, 2H).

[0879] Intermediate B30: 3-(3-amino-5-chlorophenyl)propionitrile

[0880]

[0881] The intermediate was prepared according to the method described in intermediate B6. LCMS(m / z):[M+1] + =181.1.

[0882] Intermediate B31: 3-(3-aminophenyl)-2,2-dimethylpropionitrile

[0883]

[0884] Step 1: 1-(bromomethyl)-3-nitrobenzene

[0885] A solution of 1-methyl-3-nitrobenzene (1 equivalent), NBS (1.05 equivalent), and AIBN (0.03 equivalent) in CCl4 was heated at 95 °C for 16 hours. The reaction was monitored by TLC until completion. The solid was filtered off and the filtrate was concentrated to give a crude product, which was purified by silica gel rapid chromatography (petroleum ether as eluent) to give the title compound.

[0886] Step 2: 2,2-Dimethyl-3-(3-nitrophenyl)propionitrile

[0887] At -78°C, a solution of isobutyronitrile (1.0 equivalent) in THF was added to a solution of LDA (1.1 equivalents) in THF, and the resulting solution was stirred at -78°C for 30 minutes. Then, a solution of 1-(bromomethyl)-3-nitrobenzene (1.0 equivalent) in THF was added, and the reaction mixture was heated to room temperature over 3 hours. After completion, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and purified by rapid silica gel chromatography (100% petroleum ether) to give the title compound.

[0888] Step 3: 3-(3-aminophenyl)-2,2-dimethylpropionitrile

[0889] A mixture of 2,2-dimethyl-3-(3-nitrophenyl)propionitrile (1.0 equivalent) and palladium / carbon (0.03 equivalent) in MeOH was stirred at room temperature under H2 (balloon) for 16 hours. The solid was filtered off, and the filtrate was concentrated to give the title compound. LCMS (m / z): [M+H] + =175; 1 H NMR (400MHz, CDCl3) δ7.11 (t, J = 7.2Hz, 1H), 6.65-6.61 (m, 3H), 3.67 (br s, 2H), 2.72 (s, 2H), 1.34 (s, 6H).

[0890] Intermediate B32: 3-(3-amino-5-methylphenyl)-2,2-dimethylpropionitrile

[0891]

[0892] This intermediate was prepared according to the method described in intermediate B31. LCMS(m / z):[M+1] + =189.3; 1 H NMR (400MHz, CDCl3) δ6.46(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).

[0893] Intermediate B33: 3-(3-aminobenzyl)epoxypropane-3-carboxynitrile

[0894]

[0895] This intermediate was prepared according to the method described in intermediate B31. The final step of reducing the nitro group to the amine was performed using the Zn / NH4Cl method instead of the Pd / C / H2 method. LCMS (m / z): [M+1] + =189.2.

[0896] Intermediate B34: Methyl 3-(3-aminophenyl)-3-methylbutyrate

[0897]

[0898] Step 1: 3-(4-bromophenyl)-3-methylbutyric acid

[0899] A mixture of 3-methylbut-2-enoic acid (1 equivalent), AlCl3 (2 equivalents), and bromobenzene (4 equivalents) was stirred at 65 °C for 1 hour. The mixture was quenched with aqueous NaOH solution and washed with EtOAc (3 × 50 mL). The aqueous phase was neutralized with citric acid solution and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried over NaSO4, and concentrated under vacuum to give the title compound as a yellow solid. LCMS (m / z): [MH] - =255.

[0900] Step 2: 3-(4-bromo-3-nitrophenyl)-3-methylbutyric acid

[0901] A mixture of 3-(4-bromophenyl)-3-methylbutyric acid (1.6 equivalents) and KNO3 (1.0 equivalents) in concentrated H2SO4 (1.2 M) was stirred at -30 °C for 5 min. The mixture was quenched with water and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine and concentrated. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 5 / 1 to 2 / 1) to give the title compound as a yellow solid. LCMS (m / z): [MH] - =300.

[0902] Step 3: 3-(3-aminophenyl)-3-methylbutyric acid

[0903] A mixture of 3-(4-bromo-3-nitrophenyl)-3-methylbutyric acid (1 equivalent) and Pd / C (10%, 0.03 equivalent) in MeOH (0.3 M) was stirred at room temperature for 16 hours. The solid was filtered off, and the filtrate was concentrated to give the title compound as a yellow oil. LCMS (m / z): [M+H] + =194.

[0904] Step 4: Methyl 3-(3-aminophenyl)-3-methylbutyrate

[0905] A solution of 1.55 mmol of 3-(3-aminophenyl)-3-methylbutyric acid in 1 M HCl / MeOH (0.16 M) was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure to give the title compound as a yellow solid. LCMS (m / z): [M+H] + =208.

[0906] Intermediate B35: 3-(3-aminophenyl)-3-methylbutyronitrile

[0907]

[0908] Step 1: 3-(4-bromo-3-nitrophenyl)-3-methylbutyramide

[0909] HATU (1.3 equivalents), DIEA (2.0 equivalents), and NH4Cl (2.0 equivalents) were added to a solution of 1.0 equivalent of 3-(4-bromo-3-nitrophenyl)-3-methylbutyric acid in THF (0.25 M). The mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted with EA (2 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + =301.0.

[0910] Step 2: 3-(4-bromo-3-nitrophenyl)-3-methylbutyronitrile

[0911] A solution of 3-(4-bromo-3-nitrophenyl)-3-methylbutyramide (1.0 equivalent) in DMF (0.66 M) was added with (CNCl)3 (1.2 equivalent), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with aqueous NH4Cl solution and extracted with EA (3 × 20 mL). The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 5:1 to 1:1) to give the title compound as a yellow oil.

[0912] Step 3: 3-(3-aminophenyl)-3-methylbutyronitrile

[0913] 10% Pd / C (10% by weight, 0.03 equivalents) was added to a solution of 3-(4-bromo-3-nitrophenyl)-3-methylbutyronitrile (1.0 equivalent) in MeOH (0.4 M). The mixture was stirred at room temperature under H2 for 16 hours. The solid was filtered off and the filtrate was concentrated under vacuum to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + =175.1.

[0914] Intermediate B36: 2-(3-amino-5-methylphenyl)acetonitrile

[0915]

[0916] Step 1: 1-(bromomethyl)-3-methyl-5-nitrobenzene

[0917] A mixture of 1,3-dimethyl-5-nitrobenzene (1.0 equivalent), NBS (1.1 equivalent), and BPO (0.015 equivalent) in CCl4 (0.5 M) was stirred overnight at 95 °C under Ar conditions. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography (eluent: petroleum ether) to give the title compound as a yellow oil.

[0918] Step 2: 2-(3-methyl-5-nitrophenyl)acetonitrile

[0919] A mixture of 1-(bromomethyl)-3-methyl-5-nitrobenzene (1.0 equivalent) and KCN (2.0 equivalent) in DMSO (0.65 M) was stirred overnight at 40 °C under Ar conditions. Afterward, the reaction mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The crude product was purified by rapid silica gel chromatography (eluent: petroleum ether: EtOAc = 5:1) to give the title compound as a yellow oil.

[0920] Step 3: 3-(3-amino-5-methylphenyl)acetonitrile

[0921] A mixture of 2-(3-methyl-5-nitrophenyl)acetonitrile (1.0 equivalent) and Pd / C (10%, 0.01 equivalent) in MeOH (0.1 M) was stirred at room temperature under H2 (balloon) for 2 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether: EtOAc = 1:1) to give the title compound as a yellow oil. LCMS (m / z): [M+H] + =147.

[0922] Intermediate B37: 2-(3-amino-5-methylphenyl)-2-methylpropionitrile

[0923]

[0924] Step 1: 2-Methyl-2-(3-methyl-5-nitrophenyl)propionitrile

[0925] At 0 °C and under an Ar atmosphere, t-BuOK (3.0 equivalents) was added fractionally to a stirred solution of 2-(3-methyl-5-nitrophenyl)acetonitrile (1.0 equivalent) in DMF (0.13 M), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with ice water and extracted three times with EtOAc. The combined organic layers were washed with brine and then dried over Na2SO4. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 25:1 to 10:1) to give the title compound. 1 HNMR(400MHz, CDCl3)8.09(S,1H),8.02(s,1H),7.69(s,1H),2.51(s,3H),1.78(s,6H).

[0926] Step 2: 2-(3-amino-5-methylphenyl)-2-methylpropionitrile

[0927] Pd / C (10% by weight, 0.04 equivalents) was added to a solution of 2-methyl-2-(3-methyl-5-nitrophenyl)propionitrile (1.0 equivalent) in MeOH (0.06 M), and the resulting mixture was stirred at room temperature under H2 for 6 hours. The solid was filtered off, the filtrate was concentrated, and purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 20:1 to 8:1) to give the title compound as an oil. LCMS (m / z): [M+H] + =175.0.

[0928] Intermediate B38: Methyl 2-(5-amino-2-methylphenyl)acetate

[0929]

[0930] Step 1: 2-(2-methyl-5-nitrophenyl)acetic acid

[0931] At 0 °C, a pre-cooled mixture of concentrated H₂SO₄ (10 mL) and HNO₃ (1.0 mL) was added to a mixture of 2-(o-tolyl)acetic acid (3.5 g, 23.6 mmol, 1.0 equivalence) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 2 hours, followed by pouring into ice water. A white solid was collected by filtration, and the filter cake was washed with water and dried under vacuum. The crude product was further purified by silica gel rapid chromatography (DCM / MeOH = 10:1) to give the title compound.

[0932] Step 2: Methyl 2-(2-methyl-5-nitrophenyl)acetate

[0933] SOCl2 (5.2 g, 5.0 equivalent) was added to a solution of 2-(2-methyl-5-nitrophenyl)acetic acid (1.7 g, 6.52 mmol, 1.0 equivalent) in MeOH (8.0 mL), and the reaction mixture was stirred under Ar at 40 °C for 16 hours. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. After solvent removal, the title compound was obtained as a yellow oil.

[0934] Step 3: Methyl 2-(5-amino-2-methylphenyl)acetate

[0935] A mixture of methyl 2-(2-methyl-5-nitrophenyl)acetate (200 mg, 0.96 mmol, 1.0 equivalent) and Pd / C (10%, 20 mg) in MeOH (20 mL) was stirred at room temperature under H2 (balloon) for 2 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether: EtOAc = 10:1) to give the title compound as a yellow oil. LCMS (m / z): [M+H] + =180.

[0936] Intermediate B39: 2-(5-amino-2-methylphenyl)-2-methylpropionitrile

[0937]

[0938] Step 1: (2-Methyl-5-nitrophenyl)methanol

[0939] CeCl3·7H2O (0.2 equivalents) was added fractionally to a solution of methyl 2-methyl-5-nitrobenzene (1.0 equivalent) in EtOH (0.5 M) at 0 °C, followed by fractional addition of NaBH4 (2.0 equivalent). The resulting mixture was stirred at room temperature for 16 hours, followed by quenching with ice water. The mixture was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. The crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 10:1) to give the title compound as a white solid.

[0940] Step 2: 2-(chloromethyl)-1-methyl-4-nitrobenzene

[0941] SOCl2 (5.0 mL) was added dropwise to a solution of (1.0 equivalent) 2-methyl-5-nitrophenyl)methanol in DCM (0.3 M) at 0 °C. The resulting mixture was stirred at room temperature for 16 minutes, followed by quenching with a cold aqueous solution of NaHCO3. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give a compound as a white solid.

[0942] Step 3: 2-(2-methyl-5-nitrophenyl)acetonitrile

[0943] KCN (2.0 equivalents) was added to a solution of 2-(chloromethyl)-1-methyl-4-nitrobenzene (1.0 equivalent) in DMSO (0.27 M). The mixture was stirred at room temperature for 16 hours, followed by quenching with ice water. The mixture was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. The crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 5:1 to 3:1) to give the title compound as a white solid.

[0944] Step 4: 2-Methyl-2-(2-methyl-5-nitrophenyl)propionitrile

[0945] At 0 °C, 5.0 mL (30% wt) of aqueous NaOH was added to a solution of 1.0 equivalent of 2-(2-methyl-5-nitrophenyl)acetonitrile in 0.5 M DMSO, followed by the addition of 10 equivalents of MeI. The mixture was stirred at 0 °C for 5 minutes, then quenched with aqueous NH4Cl. After post-treatment, the crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 20:1 to 8:1) to give the title compound as a yellow solid.

[0946] Step 5: 2-(5-amino-2-methylphenyl)-2-methylpropionitrile

[0947] A mixture of 2-methyl-2-(2-methyl-5-nitrophenyl)propionitrile (1.0 equivalent) and Pd / C (10% by weight, 0.05 equivalent) in MeOH (0.04 M) was stirred at room temperature under H2 for 1 hour. The solid was filtered off and the filtrate was concentrated to give the title compound. LC-MS (m / z): [M+H] + =175.2.

[0948] Intermediate B40: Methyl 2-(4-aminophenyl)-2-methylpropionate

[0949]

[0950] Step 1: Methyl 2-methyl-2-(4-nitrophenyl)propionate

[0951] At -5 °C, NaH (3.0 equivalents) was added fractionally to a solution of methyl 2-(4-nitrophenyl)acetate (1.0 q) in DMF (0.1 M). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 min. The mixture was cooled again to -5 °C, and MeI (6.0 equivalents) was added dropwise. The resulting mixture was stirred at room temperature for 1 h, followed by quenching with ice water. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine and then dried over Na₂SO₄. After solvent removal, the title compound was obtained as a yellow solid.

[0952] Step 2: Methyl 2-(4-aminophenyl)-2-methylpropionate

[0953] A mixture of methyl 2-methyl-2-(4-nitrophenyl)propionate (1.0 equivalent) and Pd / C (10% by weight, 0.03 equivalent) in MeOH (0.1 M) was stirred at room temperature under H2 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.

[0954] Intermediate B41: Methyl 2-(3-aminophenyl)-2,2-difluoroacetate

[0955]

[0956] Step 1: Methyl 2,2-difluoro-2-(3-nitrophenyl)acetate

[0957] A solution of KHMDS (3.0 equivalents) was added dropwise to a stirred solution of methyl 2-(3-nitrophenyl)acetate (1.0 equivalent) in THF (0.13 M) at -70 °C. The mixture was stirred at -70 °C for 20 min, followed by the slow addition of a solution of FN(SO₂Ph)₂ (3.0 equivalent) in THF (1.5 M). The resulting mixture was stirred at -70 °C for 30 min and then heated to -10 °C. The reactants were quenched with water, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄. The crude product was purified by rapid silica gel chromatography (eluent: petroleum ether / EtOAc = 20:1 to 10:1) to give the title compound as an oil.

[0958] Step 2: Methyl 2-(3-aminophenyl)-2,2-difluoroacetate

[0959] A mixture of methyl 2,2-difluoro-2-(3-nitrophenyl)acetate (1 equivalent) and Pd / C (10%, 0.03 equivalent) in MeOH (0.2 M) was stirred at room temperature under H2 (balloon) for 16 hours. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 10:1 to 5:1) to give the title compound as a brown oil. LCMS (m / z): [M+H] + =202.

[0960] Intermediate B42: 2-(3-aminophenoxy)acetonitrile

[0961]

[0962] A mixture of 3-nitrophenol (1.0 equivalent), 2-bromoacetonitrile (1.2 equivalent), and K₂CO₃ (2.0 equivalent) in CH₃CN (0.5 M) was stirred at room temperature for 16 hours. The solid was filtered off and the filtrate was concentrated to give crude 2-(3-nitrophenoxy)acetonitrile, which was treated with Zn (1.0 equivalent) and saturated NH₄Cl / MeOH (5 mL / 5 mL) at 65 °C for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluent: petroleum ether: EtOAc = 50:1) to give the title compound as a brown oil. LCMS (m / z): [M+1] + =149.0.

[0963] Intermediate B43: 3-(5-amino-2-methoxyphenyl)propionitrile

[0964]

[0965] Step 1: (E)-3-(5-amino-2-methoxyphenyl)acrylonitrile

[0966] A mixture of 3-bromo-4-methoxyaniline (1 equivalent), acrylonitrile (5 equivalents), Pd₂(dba)₃ (0.05 equivalents), and triethylamine (1.25 equivalents) in DMF was purged with argon and heated in a microwave reactor at 100 °C for 1 hour. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (petroleum ether / EtOAc = 6:1) to give the title compound as a brown solid.

[0967] Step 2: 3-(5-amino-2-methoxyphenyl)propionitrile

[0968] A mixture of (E)-3-(5-amino-2-methoxyphenyl)acrylonitrile (1 equivalent) and Pd / C (10% by weight, 0.05 equivalent) in MeOH (0.05 M) was stirred at room temperature under H2 for 16 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography to give the title compound as a brown solid. LCMS (m / z): [M+H] + =177.2; 1 H NMR (400MHz, CDCl3) δ6.72-6.68 (m, 1H), 6.60-6.56 (m, 2H), 3.76 (s, 3H), 2.87 (t, J = 7.4Hz, 2H), 2.60 (t, J = 7.4Hz, 2H).

[0969] Intermediate B44: 3-(4-amino-1H-pyrazol-1-yl)propionitrile

[0970]

[0971] Step 1: 3-(4-nitro-1H-pyrazole-1-yl)propionitrile

[0972] A mixture of 4-nitro-1H-pyrazole (1.0 equivalent), acrylonitrile (1.0 equivalent), and Na₂CO₃ (2.0 equivalent) in H₂O (0.9 M) was stirred at 50 °C under Ar for 12 hours. The reaction mixture was extracted with DCM / i-PrOH = 5:1 (100 mL × 3) and H₂O (100 mL). The combined organic layers were washed with brine and then dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (eluting: 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.

[0973] Step 2: 3-(4-amino-1H-pyrazole-1-yl)propionitrile

[0974] A mixture of 3-(4-nitro-1H-pyrazol-1-yl)propionitrile (1.0 equivalent) and Zn (10.0 equivalent) in saturated aqueous NH4Cl / MeOH (1:2, 0.1 M) was stirred at 80 °C for 1 hour. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel rapid chromatography (elution: DCM / MeOH = 10:1) to give the title compound as a brown oil. LC-MS (m / z): [M+H] + =137.4.

[0975] Intermediate B45: 3-(3-amino-1H-pyrazol-1-yl)propionitrile

[0976]

[0977] This intermediate was prepared according to the method described in intermediate B44, using 3-nitro-1H-pyrazole as the starting material and 1:1 H₂O / THF as the solvent in the first step. LC-MS (m / z): [M+H] + =137.0. Example

[0978] Example 1: 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[0979]

[0980] Step 1: Methyl 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionate

[0981] A mixture of 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine (intermediate A1, 1.0 equivalent), methyl 3-(3-aminophenyl)propionate (intermediate B1, 1.0 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.1 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.064 M) was stirred at 120 °C under Ar for 16 hours. The mixture was cooled to room temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc 5:1 to 0:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+1] + =455.

[0982] Step 2: 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[0983] A solution of methyl 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridinyl]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionate (1.0 equivalent) in THF (0.022 M) was added to an aqueous solution of 1 N NaOH (45 equivalents). The reaction solution was heated to 70 °C and stirred for 2 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (mobile phase: CH3CN / H2O / 0.1% HCOOH). The fraction was collected and the solvent was removed by lyophilization to give the title compound (formate salt) as a white solid. LC-MS (m / z): [M+1] +=441.2; 1 H NMR (400MHz, DMSO) δ8.83 (s, 1H), 8.50 (ddd, J = 4.8, 1.6, 0.8Hz, 1H), 8.23 ​​(s, 0.4H, HCOOH), 7.97 (d, J =5.6Hz,1H),7.84(ddd,J=7.2,4.8,1.2Hz,1H),7.78(d,J=8.0Hz,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=8.0Hz,1H),6.71(d,J=7.6Hz,1H),6.34(dd,J=5.6,2.0H z, 1H), 6.09 (d, J = 2.4Hz, 1H), 2.74 (t, J = 7.6Hz, 2H), 2.53 (s, 3H), 2.48 (t, J = 7.6Hz, 2H), 2.35 (s, 3H).

[0984] The following compounds were prepared using appropriate intermediates according to the method described in Example 1. Compounds not numbered in Example 1 do not belong to formula (I) or (II).

[0985]

[0986]

[0987]

[0988]

[0989] Example 12: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridine-2-amine

[0990]

[0991] Step 1: 3-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile

[0992] A mixture of 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine (intermediate A1, 1.0 equivalent), 3-(3-aminophenyl)propionitrile (intermediate B2, 1.0 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.1 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.06 M) was stirred at 120 °C for 16 h. The mixture was cooled to room temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel rapid 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.

[0993] Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridine-2-amine

[0994] A mixture of the above products (1.0 equivalent), Bu₂SnO (2.0 equivalent), and TMSN₃ (5.0 equivalent) in dioxane (0.08 M) was stirred at 120 °C under Ar for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by HPLC (mobile phase: CH₃CN / H₂O / 0.1% HCOOH). The fraction was collected and the solvent was removed by lyophilization to give the title compound as a yellow solid. LC-MS (m / z): [M+1] + =465.2; 1 H NMR (400MHz, DMSO) δ8.85 (s, 1H), 8.51-8.49 (m, 1H), 8.15 (s, 1H), 7.97 (d, J = 6.0Hz, 1H), 7.84 (td, J=7.6,1.6Hz,1H),7.79(d,J=7.6Hz,1H),7.57(s,1H),7.43(d,J=8.4Hz,1H),7.40(s,1H),7.32(d dd,J=7.2,4.8,1.2Hz,1H),7.11(t,J=8.0Hz,1H),6.70(d,J=7.6Hz,1H),6.35(dd,J=6.0,2.4Hz,1 H), 6.09 (d, J = 2.0Hz, 1H), 3.13 (t, J = 7.6Hz, 2H), 2.96 (t, J = 7.6Hz, 2H), 2.52 (s, 3H), 2.35 (s, 3H).

[0995] The following compounds were prepared using appropriate intermediates according to the method described in Example 12.

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002] Example 34: 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)benzyl)-2H-tetrazol-2-yl)acetic acid (34A) and 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)benzyl)-1H-tetrazol-1-yl)acetic acid (34B)

[1003]

[1004] Step 1: 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)benzyl)-2H-tetrazol-2-yl)tert-butyl acetate and 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)benzyl)-1H-tetrazol-1-yl)tert-butyl acetate

[1005] K₂CO₃ (1.5 equivalents) was added to a stirred solution of N-(3-((1H-tetrazol-5-yl)methyl)phenyl)-4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridine-2-amine (Example 16, 1.0 equivalent) in acetone (0.01 M) at 0 °C under Ar conditions. The resulting mixture was stirred at 0 °C for 30 min, and tert-butyl 2-bromoacetate (1.5 equivalents) was added dropwise. The mixture was slowly heated to room temperature and stirred for 5 h. The mixture was quenched with saturated NH₄Cl. The mixture was partitioned between DCM and water. The organic phase was dried over Na₂SO₄, concentrated, and purified by preparative HPLC (mobile phase: 0.1% TFA / MeCN / H₂O) to give title compounds A and B as yellow oils. LC-MS (m / z): [M+1] + =565.

[1006] Step 2, for the 34A isomer: 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)benzyl)-2H-tetrazole-2-yl)acetic acid

[1007] Add 4N HCl / dioxane (80 equivalents) to a stirred solution of the above mixture (1.0 equivalents) in MeCN (0.2M). Stir the resulting mixture at room temperature for 16 hours. Concentrate the reaction mixture under reduced pressure. Purify the residue by HPLC (mobile phase: MeCN / H2O / 0.1% HCOOH). Collect the fraction and remove the solvent by lyophilization to give the title compound. LC-MS (m / z): [M+1] + =509.2; 1 H NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.48(dd,J=4.8,0.8Hz,1H),7.95(d,J=5.6Hz,1H),7.82( td,J=7.6,2.0Hz,1H),7.77(d,J=7.6Hz,1H),7.59(dd,J=8.0,1.2Hz,1H),7.55(s,1H),7.38(s ,1H),7.31(ddd,J=7.6,4.8,1.6Hz,1H),7.14(t,J=8.0Hz,1H),6.73(d,J=7.6Hz,1H),6.34(dd ,J=6.0,2.4Hz,1H),6.08(d,J=2.4Hz,1H),5.27(s,2H),4.21(s,2H),2.51(s,3H),2.34(s,3H).

[1008] Step 2, for the 34B isomer: 2-(5-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)benzyl)-1H-tetrazole-1-yl)acetic acid

[1009] Add 4N HCl / dioxane (80 equivalents) to a stirred solution of the mixture from step 1 (1.0 equivalents) in MeCN (0.2 M). Stir the resulting mixture at room temperature for 16 hours. Concentrate the reaction mixture under reduced pressure. Purify the residue by HPLC (mobile phase: MeCN / H₂O / 0.1% HCOOH). Collect the fraction and remove the solvent by lyophilization to give the title compound. LC-MS (m / z): [M+1] + =509.2; 1H NMR(400MHz, DMSO-d6)δ8.90(s,1H),8.50(dd,J=4.8,0.4Hz,1H),7.96(d,J=6.0Hz,1H),7.84( td,J=7.6,2.0Hz,1H),7.78(d,J=8.0Hz,1H),7.57(s,1H),7.54(dd,J=9.2,0.8Hz,1H),7.47(s ,1H),7.32(ddd,J=7.2,4.8,1.2Hz,1H),7.14(t,J=8.0Hz,1H),6.75(d,J=7.6Hz,1H),6.34(dd ,J=6.0,2.0Hz,1H),6.09(d,J=2.0Hz,1H),5.59(s,2H),4.16(s,2H),2.52(s,3H),2.35(s,3H).

[1010] The following compounds were prepared according to the method described in Example 34.

[1011]

[1012] Example 36: 3-(5-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2-fluorophenyl)propionic acid

[1013]

[1014] Step 1: Methyl 3-(5-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2-fluorophenyl)propionate

[1015] A mixture of 3-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine (intermediate A2, 1.0 equivalent), methyl 3-(5-amino-2-fluorophenyl)propionate (intermediate B10, 1.3 equivalent), Pd(OAc)2 (0.1 equivalent), Xantphos (0.1 equivalent), and Cs2CO3 (2.0 equivalent) in dioxane (0.29 M) was stirred at 115 °C for 16 h. 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 rapid chromatography (eluent: petroleum ether / EtOAc 10:1 to 3:1) to give the title compound as a yellow oil. LC-MS: [M+H] + =396.2.

[1016] Step 2: 3-(5-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2-fluorophenyl)propionic acid

[1017] A mixture of methyl 3-(5-((4-(((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)-2-fluorophenyl)propionate (1.0 equivalent) and NaOH (5.0 equivalent) in MeOH / H2O (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% NH3·H2O / MeCN / H2O) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =382.2; 1 HNMR(400MHz, DMSO-d6)δ8.93(s,1H),8.04(d,J=6.0Hz,1H),7.55-7.51(m,1H),7.47(d,J=8.0Hz,1H),7.41(dd,J=6.4,2.4Hz,1H),7.21(d,J=8.4Hz, 1H),6.99(t,J=9.2Hz,1H),6.40(dd,J=5.6,2.0Hz,1H),6.02(d,J=2.0Hz,1 H), 2.75 (t, J = 7.6Hz, 2H), 2.47 (s, 3H), 2.37 (t, J = 7.6Hz, 2H), 2.28 (s, 3H).

[1018] The following compounds were prepared using appropriate intermediates according to the method described in Example 36.

[1019]

[1020]

[1021]

[1022] Example 44: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-amine

[1023]

[1024] Step 1: 3-(3-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile

[1025] A mixture of 3-((2-chloropyridin-4-yl)oxy)-2,6-dimethylpyridine (intermediate A2, 1.0 equivalent), 3-(3-aminophenyl)propionitrile (intermediate B2, 1.3 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.1 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.2 M) was stirred at 115 °C for 16 h. The reaction was monitored by LC-MS. The solution was cooled to room temperature and diluted with EtOAc (50 mL). The mixture was washed with brine and then dried over Na₂SO₄. The crude product was purified by silica gel rapid chromatography (petroleum ether / EtOAc 3:2) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =345.

[1026] Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-amine

[1027] A mixture of 3-(3-((4-((2,6-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (1.0 equivalent), TMSN3 (5.0 equivalent), and Bu2SnO (2.0 equivalent) in dioxane (0.06 M) was stirred at 120 °C for 16 h. The reaction was monitored by LC-MS. The mixture was cooled. The organic phase was concentrated. The residue was purified by HPLC (mobile phase: 0.1% HCOOH / MeCN / H2O). The fraction was collected and the solvent was removed by lyophilization to give the title compound (formate) as a white solid. LC-MS (m / z): [M+H] + =388.3; 1 H NMR (400MHz, DMSO) δ8.93 (s, 1H), 8.17 (s, 0.6H, HCOOH), 8.06 (d, J = 5.6Hz, 1H), 7.50-7.43 (m, 3H), 7.22 (d, J = 8.0Hz, 1H), 7.13 (t, J = 8.0Hz, 1H), 6 .72(d,J=7.2Hz,1H),6.43(dd,J=5.6,2.0Hz,1H),6.04(d,J=1.6Hz,1H),3.15(t,J=7.6Hz,2H),2.97(t,J=7.6Hz,2H),2.47(s,3H),2.29(s,3H).

[1028] The following compounds were prepared using appropriate intermediates according to the method described in Example 44.

[1029]

[1030]

[1031]

[1032] Example 52: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-amine

[1033] Step 1: 3-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile

[1034] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (intermediate A6, 1.0 equivalent), 3-(3-aminophenyl)propionitrile (intermediate B2, 1.5 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.1 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.25 M) was stirred at 120 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with brine, and then dried over Na₂SO₄. The organic phase was concentrated to give the title compound as a yellow oil. LC-MS (m / z): [M+H] + =407

[1035] Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-amine

[1036] A mixture of 3-(3-((4-(((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (1.0 equivalent), TMSN3 (5.0 equivalent), and Bu2SnO (2.0 equivalent) in dioxane (0.17 M) was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature 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; 1H NMR (400MHz, DMSO) δ8.89(s,1H),8.00(d,J=6.0Hz,1H),7.78(d,J=8.0Hz,2H),6.66(d,J=8.4Hz,1H),7.44-7.36(m,7H),7.11(t ,J=7.6Hz,1H),6.71(d,J=7.6Hz,1H),6.41-6.39(m,1H),6.09(s,1H),3.11(t,J=7.6Hz,2H),2.95(t,J=7.6Hz,2H),2.58(s,3H).

[1037] The following compounds were prepared using appropriate intermediates according to the method described in Example 52.

[1038]

[1039]

[1040]

[1041]

[1042] Example 66: 3-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[1043]

[1044] A mixture of 3-(3-((4-(((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (Step 1 of Example 52, 1.0 equivalent) and KOH (10.0 equivalent) in dioxane / H₂O (5:1, 0.07 M) was stirred at 120 °C for 16 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature and the dioxane was removed. The residue was adjusted to pH 6-7 with 1N HCl (aqueous solution), and the solid was collected by filtration and washed with H₂O. The solid was purified by silica gel rapid chromatography (DCM / MeOH 8:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =426.4; 1H NMR (400MHz, CDCl3) δ9.64(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. 6,1.6Hz,1H),6.40(d,J=2.0Hz,1H),6.21(dd,J=6.0,2.0Hz,1H),2.95(t,J=6.8Hz,2H),2.66(t,J=6.8Hz,2H),2.65(s,3H).

[1045] Example 67: 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

[1046]

[1047] Step 1: 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile

[1048] A solution of 2-chloro-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridine (intermediate A12, 1.0 equivalent), 3-(3-aminophenyl)propionitrile (intermediate B2, 1.3 equivalent), Pd(OAc)2 (0.1 equivalent), Xantphos (0.1 equivalent), and Cs2CO3 (2.0 equivalent) in dioxane (0.21 M) was stirred at 115 °C for 16 h. The reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid 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.

[1049] 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

[1050] A mixture of 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (1.0 equivalent), TMSN3 (5.0 equivalent), and Bu2SnO (2.0 equivalent) in dioxane (0.12 M) was stirred at 120 °C for 16 h. 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; 1 H NMR (400MHz, DMSO-d6) δ8.96 (s, 1H), 8.02 (d, J = 5.6Hz, 1H), 7.85 (s, 1H), 7.49 (d, J = 8.0Hz, 1H),7.45(s,1H),7.13(t,J=7.6Hz,1H),6.72(d,J=7.6Hz,1H),6.44(dd,J=5.6,2.0Hz,1H), 6.25(d,J=2.0Hz,1H),3.84-3.81(m,2H),3.68-3.63(m,1H),3.34-3.30(m,2H),3.15(t,J= 7.6Hz,2H),2.98(t,J=7.6Hz,2H),2.74-2.69(m,1H),1.67-1.62(m,4H),1.03-0.91(m,4H).

[1051] Example 68: 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[1052] A mixture of 3-(3-((4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (Step 1 of Example 67, 1.0 equivalent) and KOH (5.0 equivalent) in DMSO / H2O (v / v = 1:1, 0.12 M) was stirred at 120 °C for 16 h. The reaction was monitored by LC-MS. The reaction mixture was filtered and the filtrate was adjusted to pH 7 with 1.0 M HCl aqueous solution. The precipitated solid was collected by filtration. The filter cake was washed with water and purified by HPLC (mobile phase: 0.1% NH3·H2O / MeCN / H2O). The fraction was collected and the solvent was removed by lyophilization to give the title compound as a white solid. LC-MS (m / z): [M+H] + =449.4; 1H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.02(d,J=6.0Hz,1H),7.85(s,1H),7.51(d,J=8 .0Hz,1H),7.39(s,1H),7.11(t,J=7.6Hz,1H),6.72(d,J=7.6Hz,1H),6.43(dd,J=5.6, 2.0Hz,1H),6.25(d,J=2.0Hz,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=8.0Hz,2H),1.67-1.62(m,4H),1.03-0.93(m,4H).

[1053] The following compounds were prepared using appropriate intermediates according to the method described in Example 1.

[1054]

[1055]

[1056] Example 70: 2-Methyl-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[1057] Step 1: 2-Methyl-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile

[1058] A solution of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (intermediate A6, 1.0 equivalent), 2-(3-aminophenyl)-2-methylpropionitrile (intermediate B5, 1.5 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.1 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.3 M) was stirred at 120 °C for 16 h. 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 and brine, and then dried over Na₂SO₄. The crude product was purified by silica gel rapid 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 (400MHz, CD3OD) δ7.94(d,J=6.0Hz,1H),7.72-7.70(m,2H),7.61(d,J=8.4Hz,2H),7.42-7.27(m,6H ), 7.10 (d, J = 8.0Hz, 1H), 6.34 (dd, J = 6.0, 2.0Hz, 1H), 6.13 (d, J = 2.0Hz, 1H), 2.63 (s, 3H), 1.71 (s, 6H).

[1059] Step 2: 2-Methyl-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[1060] A solution of 1.0 equivalent of 2-methyl-2-(3-((4-(((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (1.0 equivalent) in concentrated HCl aqueous solution (0.06 M) was stirred in a sealed tube at 110 °C for 16 h. 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; 1 H NMR(400MHz, CD3ODδ7.86(d,J=5.6Hz,1H),7.67(d,J=6.4Hz,2H),7.55(d,J=8.4Hz,1H),7.39-7.29(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).

[1061] Example 71: 2-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionic acid

[1062] Step 1: 2-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionitrile

[1063] A mixture of 3-((2-chloropyridin-4-yl)oxy)-5,6-dimethyl-2,2'-bipyridine (intermediate A1, 1.0 equivalent), 2-(3-aminophenyl)-2-methylpropionitrile (intermediate B5, 1.1 equivalent), Pd(OAc)2 (0.1 equivalent), and Xantphos (0.1 equivalent) in dioxane (0.18 M) was stirred at 120 °C for 16 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature and diluted with EtOAc (50 mL). The mixture was washed with brine and then dried over Na2SO4. The organic phase was concentrated, and the residue was purified by preparative TLC to give the title compound as a pale yellow solid. LC-MS (m / z): [M+H] + =436.3; 1 H NMR (400MHz, CDCl3) δ8.58-8.56(m,1H),7.90(d,J=5.6Hz,1H),7.71(d,J=8.0Hz,1H),7.64-7.60(m,1H),7.29(t,J=1.8Hz,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 .0Hz, 1H), 6.15 (d, J = 2.0Hz, 1H), 2.54 (s, 3H), 2.28 (s, 3H), 1.62 (s, 6H).

[1064] Step 2: 2-(3-((4-((5,6-dimethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionic acid

[1065] The mixture of the above products (1.0 equivalent) in HCl (aqueous solution, 12N) (0.04M) was stirred in a sealed tube at 110°C for 16 hours. The reaction was monitored by LC-MS. The mixture was purified by HPLC (CH3CN / H2O / 0.1% HCOOH) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =455.4; 1H NMR(400MHz,CD3OD)δ8.56(d,J=4.8Hz,1H),8.09(s,1H,HCOOH),(m,1H),7.92(td ,J=7.6,1.2Hz,1H),7.87(d,J=7.6Hz,1H),7.82(d,J=6.4Hz,1H),7.57(s,1H),7.4 2(t,J=5.6Hz,1H),7.33(t,J=8.0Hz,1H),7.28(s,1H),7.21-7.17(m,2H),6.49(dd ,J=6.4,2.4Hz,1H),6.19(d,J=2.4Hz,1H),2.60(s,3H),2.41(s,3H),1.51(s,6H).

[1066] Example 72: 2-Methyl-2-(3-((4-((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[1067] Step 1: 2-Methyl-2-(3-((4-((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile

[1068] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2,2'-bipyridine (intermediate A3, 1.0 equivalent), 2-(3-aminophenyl)-2-methylpropionitrile (intermediate B5, 1.5 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.1 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.033 M) was stirred at 120 °C for 16 h. The reaction mixture was monitored by LC-MS. The reaction mixture was cooled to room temperature 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% NH₃·H₂O / ACN / H₂O) to give a product as a white solid. LC-MS (m / z): [M+H] + =422.3; 1 H NMR (400MHz, CD3OD) δ8.59(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).

[1069] Step 2: 2-Methyl-2-(3-((4-((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionic acid

[1070] A mixture of 2-methyl-2-(3-((4-(((6-methyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (1.0 equivalent) and KOH (20 equivalent) in dioxane-H₂O (1:1, 0.015 M) was stirred at 120 °C for 36 h. The reaction was monitored by LC-MS. The mixture was cooled to room temperature and concentrated. The residue was purified by HPLC (0.1% NH₃·H₂O / ACN / H₂O) to give the title compound as a yellow solid. LC-MS (m / z): [M+H] + =441.4; 1 HNMR(400MHz,DMSO)δ12.25(br,1H),8.89(s,1H),8.52(d,J=2.8Hz,1H),7.95( d,J=5.2Hz,1H),7.86(t,J=7.6Hz,1H),7.76(d,J=8.0Hz,1H),7.69(d,J=8.0Hz, 1H),7.65-7.62(m,1H),7.46(d,J=7.6Hz,1H),7.40-7.34(m,2H),7.15(m,1H),6 .86-6.81(m,1H),6.33(d,J=3.6Hz,1H),6.09(s,1H),2.58(s,3H),1.41(s,6H).

[1071] The following compounds were prepared using appropriate intermediates according to the method described in Example 72.

[1072]

[1073]

[1074] Example 77: 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[1075]

[1076] Step 1: Methyl 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropane-1-carboxylate.

[1077] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (intermediate A6, 1.0 equivalent), methyl 1-(3-aminophenyl)cyclopropane-1-carboxylate (intermediate B26, 1.0 equivalent), Xantphos (0.1 equivalent), Cs₂CO₃ (2.0 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.17 M) was sealed in a tubular reactor. The resulting mixture was stirred at 115 °C under Ar for 16 h. The reaction was monitored by LC-MS. The mixture was filtered, and 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.

[1078] Step 2: 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropane-1-carboxylic acid

[1079] A mixture of methyl 1-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)cyclopropane-1-carboxylate (100 mg, 0.22 mmol, 1.0 equivalent) and aqueous NaOH solution (2.0 M, 5.0 equivalent) in MeOH (0.05 M) was stirred at 50 °C for 2 h. 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 / H2O). The solvent was removed by lyophilization to give the title compound (formate salt) as a white solid. LC-MS (m / z): [M+H] + =438.2; 1 H NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.29(s,1H,HCOOH),8.00(d,J=6.0Hz,1H),7.78(d,J=6.8Hz,2H),7.66(d,J=8.4Hz,1H),7.49(d,J=8.4Hz,1H),7.4 5-7.35(m,5H),7.11(t,J=8.0Hz,1H),6.81(d,J=7.6Hz,1H),6.38(dd,J=6. 0, 2.0Hz, 1H), 6.09 (d, J = 2.0Hz, 1H), 2.58 (s, 3H), 1.39 (m, 2H), 1.03 (m, 2H).

[1080] The following compounds were prepared using appropriate intermediates according to the method described in Example 77.

[1081]

[1082]

[1083] Example 81: 2-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionic acid

[1084]

[1085] Step 1: Methyl 2-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionate

[1086] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine (intermediate A16, 1.0 equivalent), methyl 2-(3-aminophenyl)-2-methylpropionate (intermediate B27, 1.5 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.1 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.1 M) was stirred at 115 °C for 16 h. The reaction mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 10:1 to 1:1) to give the title compound. LC-MS (m / z): [M+H] + =406.2.

[1087] Step 2: 2-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionic acid

[1088] A mixture of methyl 2-(3-((4-(((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2-methylpropionate (1.0 equivalent) and KOH (5.0 equivalent) in MeOH / H₂O (4:1, 0.05 M) was stirred at 50 °C for 16 h. The MeOH was removed under reduced pressure, and the aqueous residue was adjusted to pH approximately 7 with 1.0 M HCl aqueous solution. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine and then dried over Na₂SO₄. The crude product was purified by preparative HPLC (mobile phase: 0.1% NH₃·H₂O / MeCN / H₂O) to give the title compound as a white solid. LC-MS (m / z): [M+H] + =392.3; 1H NMR(400MHz,DMSO-d6)δ12.27(br s,1H),8.98(s,1H),8.06(d,J=6.0Hz,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=8.4Hz,1H),7.18(t,J=8.0 Hz,1H),6.85(d,J=8.0Hz,1H),6.42(dd,J=6.0,2.0Hz,1H),6.07(d,J=2.0Hz ,1H),2.76(q,J=7.6Hz,2H),2.46(s,3H),1.44(s,6H),1.26(t,J=7.6Hz,3H).

[1089] The following compounds were prepared using appropriate intermediates according to the method described in Example 81.

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103] Example 131: 2,2-Difluoro-2-(3-((4-((6-methyl-2-phenylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)acetic acid

[1104]

[1105] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-methyl-2-phenylpyridine (intermediate A6, 1.0 equivalent), methyl 2-(3-aminophenyl)-2,2-difluoroacetate (intermediate B41, 2.2 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.10 equivalent), and Pd(OAc)₂ (0.10 equivalent) in dioxane (0.23 M) was stirred at 110 °C under an Ar atmosphere for 16 hours. 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 (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.24 (s, 0.4H, HCO2H), 8.03 (d, J = 5.6Hz, 1H), 7.82-7.76 (m, 4H), 7.67 (d, J = 8. 4Hz, 1H), 7.43-7.28 (m, 5H), 7.02 (d, J = 7.6Hz, 1H), 6.44 (dd, J = 6.0, 2.0Hz, 1H), 6.11 (d, J = 2.0Hz, 1H), 2.59 (s, 3H).

[1106] Example 132: 2-(3-((4-((1-cyclopropyl-3-phenyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2-difluoroacetic acid

[1107]

[1108] This compound was prepared using intermediates A51 and B41 according to the method described in Example 131. LC-MS (m / z): [M+H] + =463.2; 1 H NMR(400MHz, DMSO-d6)δ9.12(s,1H),8.09(s,1H),8.05(d,J=5.6Hz,1H),7.78(d,J=8.8Hz,1H),7.71-7.68(m,3H),7.36(t,J=7.6Hz,2H),7.29- 7.23(m,2H),6.99(d,J=7.6Hz,1H),6.53(dd,J=5.6,2.4Hz,1H),6.32(d ,J=2.4Hz,1H),3.84-3.77(m,1H),1.17-1.13(m,2H),1.04-1.00(m,2H).

[1109] Example 133: 3-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2-dimethylpropionic acid

[1110]

[1111] Step 1: 3-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2-dimethylpropionitrile

[1112] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2-methylpyridine (intermediate A16, 1.0 equivalent), 3-(3-aminophenyl)-2,2-dimethylpropionitrile (intermediate B31, 1.1 equivalent), Pd(OAc)₂ (0.1 equivalent), Xantphos (0.1 equivalent), and Cs₂CO₃ (2.0 equivalent) in dioxane (0.1 M) was stirred at 110 °C under an Ar atmosphere for 16 hours. The mixture was cooled to room temperature and diluted with DCM / H₂O. The organic layer was separated and dried over Na₂SO₄. 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.

[1113] Step 2: 3-(3-((4-((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2-dimethylpropionic acid

[1114] A mixture of 3-(3-((4-(((6-ethyl-2-methylpyridin-3-yl)oxy)pyridin-2-yl)amino)phenyl)-2,2-dimethylpropionitrile (1.0 equivalent) in concentrated HCl (0.04 M) was stirred at 115 °C for 16 hours. The mixture was concentrated, 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] + =406.3; 1H NMR (400MHz, CD3OD) δ7.97(d,J=6.0Hz,1H),7.46(d,J=8.0Hz,1H),7.26-7.22(m,2H),7.17-7.13(m,2H),6.81(d,J=7.2Hz,1H),6.3 6(dd,J=6.0,2.4Hz,1H),6.11(d,J=2.0Hz,1H),2.81(s,2H),2.80(q,J=7.6Hz,2H),2.38(s,3H),1.29(d,J=7.6Hz,3H),1.14(s,6H).

[1115] The following compounds were prepared using the corresponding intermediates according to the method described in Example 133.

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129] Example 174: 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)epoxypropane-3-carboxylic acid

[1130]

[1131] Step 1: 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)propane-3-carboxynitrile

[1132] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,5-dimethylpyridine (intermediate A49, 1.0 equivalent), 3-(3-aminobenzyl)epoxypropane-3-carboxynitrile (intermediate B33, 1.0 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.2 equivalent), and Pd(OAc)₂ (0.2 equivalent) in dioxane (0.06 M) was stirred at 110 °C under Ar for 16 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated. The residue was redissolved in EtOAc, washed with water and brine, and then dried over Na₂SO₄. The crude product was purified by silica gel rapid 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.

[1133] Step 2: 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)epoxypropane-3-carboxylic acid

[1134] A mixture of 3-(3-((4-((6-ethyl-2,5-dimethylpyridin-3-yl)oxy)pyridin-2-yl)amino)benzyl)epoxypropane-3-carboxynitrile (1.0 equivalent) and KOH (5.0 equivalent) in ethylene glycol / H₂O (v / v = 4:1, 0.02 M) was stirred at 130 °C for 2 h. The mixture was cooled to room temperature and washed with EtOAc. The aqueous layer was adjusted to pH approximately 7 with 1.0 M HCl aqueous solution, and the solvent was removed under reduced pressure. 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] + =434.2; 1 H NMR (400MHz, CD3OD) δ7.97(d,J=6.0Hz,1H),7.33(s,1H),7.27-7.25(m,2H),7.17(t,J=7.6Hz,1H),6.83(d,J=7.6Hz,1H),6.38(dd,J=6.0,2.0Hz ,1H),6.10(d,J=1.6Hz,1H),4.84(d,J=6.4Hz,2H),4.60(d,J=6.0Hz,2H) ,3.27(s,2H),2.82(q,J=7.6Hz,2H),2.34(s,6H),1.24(t,J=7.6Hz,3H).

[1135] Example 175: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-ethyl-[2,2'-bipyridin]-3-yl)oxy)pyridine-2-amine

[1136]

[1137] Step 1: 3-(3-((4-((6-ethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile

[1138] A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-ethyl-2,2'-bipyridine (intermediate A21, 1.0 equivalent), 3-(3-aminophenyl)propionitrile (intermediate B2, 1.0 equivalent), Cs₂CO₃ (2.0 equivalent), Xantphos (0.10 equivalent), and Pd(OAc)₂ (0.1 equivalent) in dioxane (0.1 M) was stirred at 110 °C under an Ar atmosphere for 16 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel rapid chromatography (eluent: petroleum ether / EtOAc = 20:1) to give the title compound as a yellow solid. LC-MS (m / z): [M+1] + =422.3.

[1139] Step 2: N-(3-(2-(2H-tetrazol-5-yl)ethyl)phenyl)-4-((6-ethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-amine

[1140] A mixture of 3-(3-((4-((6-ethyl-[2,2'-bipyridin]-3-yl)oxy)pyridin-2-yl)amino)phenyl)propionitrile (1.0 equivalent), TMSN3 (5.0 equivalent), and Bu2SnO (2.0 equivalent) in dioxane (0.04 M) was stirred at 100 °C under an Ar atmosphere for 16 hours. 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 (400MHz, CD3OD) δ8.58(d,J=4.8Hz,1H),7.89(td,J=8.0,1.6Hz,1H),7.86(d,J=6.0Hz,1H) ,7.82(d,J=8.0Hz,1H),7.68(d,J=8.4Hz,1H),7.49(d,J=8.0Hz,1H),7.43-7.38(m,1H),7.22(s ,1H),7.17-7.10(m,2H),6.76(d,J=6.8Hz,1H),6.32(dd,J=6.0,2.0Hz,1H),6.09(d,J=2.0Hz, 1H), 3.18 (t, J = 7.6Hz, 2H), 3.02 (t, J = 7.6Hz, 2H), 2.90 (q, J = 7.6Hz, 2H), 1.34 (t, J = 7.6Hz, 3H).

[1141] The following compounds were prepared using the corresponding intermediates according to the method described in Example 175.

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152] The following compounds can be prepared using the reaction procedures and methods described in this article.

[1153]

[1154]

[1155]

[1156]

[1157] In some embodiments, the present invention provides compounds selected from the compounds of the embodiments described herein.

[1158] Measurement:

[1159] HEK-Blue TGFβ cell reporter gene assay:

[1160] HEK-Blue TGFβ cells were purchased from Invivogen. 2.5 × 10⁻⁶ cells were prepared using test medium (DMEM containing 0.5% v / v heat-inactivated FBS). 5 Cell suspension at 1 cell / mL. TGF-β working solution (6 ng / mL) was prepared by diluting the TGF-β stock solution (10 μg / mL) with test medium before use. All compounds were obtained at eight different concentrations using a 3× serial dilution method with the TGF-β working solution. 100 μl of test medium (carrier) or test substance or TGF-β working solution was added to each well of a flat-bottomed 96-well plate. 100 μl of HEK-Blue TGF-β cell suspension was added to each well. The plate was incubated at 37°C in a CO2 incubator for 22–23 hours. 150 μl of resuspended QUANTI-Blue was added to each well of a new flat-bottomed 96-well plate. 30 μl of induced HEK-Blue TGF-β cell supernatant was added. Avoid aspirating liquid from the bottom of the wells. The plate was incubated at 37°C for 30–40 minutes. The level of secreted embryonic alkaline phosphatase (SEAP) was measured at 630 nm using a spectrophotometer.

[1161] The suppression is calculated using the following equation:

[1162]

[1163] Activity data:

[1164] HEK-Blue TGFβ cell reporter gene analysis:

[1165]

[1166]

[1167]

[1168]

[1169] Compare the AUC of the selected examples with those of the clinical compounds Galunisertib and LY3200882. 肝脏 / AUC 心脏Tissue exposure was determined in Balb / c mice given PO at 10 mpk. It should be noted that cardiotoxicity was a limiting factor for identification as most relevant to LY3200882 and as Galunisertib. See Stauber et al., J. Clin. Pract., 2014, 4(3), 196.

[1170] General PK strategy:

[1171] Balb / c mice were fasted overnight and given free access to drinking water prior to treatment. The compound was formulated in 0.5% CMC / 0.5% Tween 80 with or without 1 equivalent of NaOH and administered orally at a dose of 10 mg / kg. Liver and heart tissues were collected from mice at 0.5, 1, 3, 5, 7, and 24 hours post-administration (two mice at each time point) by first euthanizing the animals via CO2 inhalation. After rinsing with ice-cold saline and removing excess water from the surface, the liver and heart tissues were weighed and homogenized in 1:5 volume (w / v) water containing 20% ​​methanol. Tissue samples were maintained at -40 to -20°C prior to analysis. The concentrations of the compound in the liver and heart were determined using established liquid chromatography-tandem mass spectrometry (LC-MS / MS) methods. Tissue concentration-time data were processed by linear regression analysis. All pharmacokinetic parameters were calculated using a non-compartmental model in Phrasight Phoenix 8.0.

[1172]

[1173]

[1174]

[1175] As the data demonstrate, when compared to Galunisertib or LY3200882, the compounds of this invention tend to concentrate in the liver more readily than in heart tissue, thus providing a better useful safety margin and therapeutic index than known compounds. Since cardiotoxicity is a major concern in the development of new drugs, the compounds of this invention, exhibiting potent in vitro activity at the target site and significantly better pharmacokinetic properties that enhance safety, demonstrate superiority over compounds known in the art.

[1176] The embodiments described above are provided to assist those skilled in the art in carrying out the invention. However, the scope of the invention as described and claimed herein is not limited to the specific embodiments disclosed herein, as these embodiments are intended to illustrate some aspects of the invention. Any obvious alternatives or other embodiments are intended to fall within the scope of the invention. In fact, various modifications to the invention, other than those shown and described herein, will become apparent to those skilled in the art based on the foregoing description without departing from the spirit or scope of the discoveries of the invention. Such modifications are also intended to fall within the scope of the appended claims.

[1177] All disclosures, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes, to the extent that each individual disclosure, patent, patent application, or other reference specifically and individually indicates that it is incorporated herein by reference in its entirety for all purposes. The citation of references herein should not be construed as an admission that such citations constitute prior art to this invention.

Claims

1. Compound of formula (I): in: Ring A is a 5- or 6-membered heteroaromatic ring, which optionally contains other nitrogen atoms as ring members and is optionally fused with a phenyl or pyridyl ring, and ring A is optionally substituted by one or two independent groups selected from the following groups: halogen, C1-C4 alkyl, phenyl, pyridyl and C3-C6 cycloalkyl; R 1 It is selected from halogens; C1-C4 alkyl groups; C1-C4 haloalkyl groups; phenyl groups; and 5-6-membered heteroaryl groups containing one or two nitrogen atoms as ring members, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, phenyl group, and 5-6-membered heteroaryl group are each optionally surrounded by an R 2 Replace; where R 2 Each time it appears, it is independently selected from halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups; Cy is a phenyl group, and it is optionally further substituted by a group selected from the following: halogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; L is a divalent linker selected from the following: CR2, -(CR2) 2-4 - and -O-(CR2) 1-3 - where R is independently selected from H, F and C1-C4 alkyl groups each time it appears; Or its medicinal salt.

2. The compound of claim 1, wherein R 1 Selected from: C1-C4 alkyl; C1-C4 haloalkyl; phenyl; and pyridyl, wherein the C1-C4 alkyl, C1-C4 haloalkyl, phenyl, and pyridyl are each optionally divided by an R 2 Replacement; or its medicinal salt.

3. The compound of claim 1 or 2, wherein R 1 It is methyl, phenyl, or 2-pyridyl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 or 2, wherein Cy is phenyl and optionally further substituted with a group selected from: halogen, C1-C4 alkyl, C1-C4 haloalkyl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or 2, wherein R is independently selected from H, F and Me in each occurrence; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein L is selected from CH2, -CH2CH2-, C(Me)2, -CHMe-, -CH2CF2-, -CF2CH2-, -CMe2CH2- and -CH2CMe2-; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 or 2, wherein it is a compound of formula (Ib): in R 1 It is methyl, phenyl, or 2-pyridyl; R 4 and R 5 Independently selected from H, halogens, C1-C4 alkyl groups, phenyl groups, and pyridyl groups; Cy is a phenyl group; and L is -CH2CH2-; Or its medicinal salt.

8. The compound of claim 1, wherein the compound is selected from the following list of compounds: Or its medicinal salt.

9. A compound, wherein the compound is selected from the following list of compounds: Or its medicinal salt.

10. A compound, wherein the compound is selected from the following list of compounds: Or its medicinal salt.

11. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-10 and at least one pharmaceutically acceptable carrier or excipient.

12. Use of any compound of claims 1-10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 11 in the preparation of a medicament for treating cancer or fibrosis, wherein said cancer or fibrosis is colon cancer, hepatocellular carcinoma (HCC), kidney cancer, liver cancer, stomach cancer, or fibrosis in the liver or kidney.

13. A pharmaceutical combination comprising an effective amount of the compound as claimed in any one of claims 1-10 or a pharmaceutically acceptable salt thereof, and other therapeutic agents.

14. A pharmaceutical composition comprising the pharmaceutical composition as described in claim 13 and at least one pharmaceutically acceptable excipient.

15. Use of the pharmaceutical composition of claim 14 in the preparation of a medicament for treating cancer or fibrosis, wherein the cancer or fibrosis is colon cancer, hepatocellular carcinoma (HCC), kidney cancer, liver cancer, stomach cancer, or fibrosis in the liver or kidney.

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