Triazole-pyridinyl-substituted azacyclohexylacetic acid compounds as LPA receptor antagonists

Abstract

The present invention provides compounds and pharmaceutical compositions for treating or preventing diseases associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi). [Solution] Compound of formula (I): TIFF2026086696000265.tif51128 Alternatively, pharmaceutically acceptable salts, tautomers, or stereoisomers thereof are provided.

Description

[Technical Field]

[0001] field This application relates to novel substituted azacyclohexylacetic acid compounds and analogues, their manufacture, pharmaceutical compositions comprising them, and their use as pharmaceuticals for the treatment of diseases associated with dysregulation of lysophosphatidic acid receptors (LPARs). [Background technology]

[0002] background Lysophosphatidic acid (LPA) is a small glycerol phospholipid (1- or 2-acyl-sn-glycerol-3-phosphate) with a molecular weight of 430-480 daltons, consisting of a phosphate group and a glycerol skeleton esterified with a fatty acid having variable chain length and saturation (Yang and Chen, World J Gastroenterol 24:4132-4151, 2018 (Non-Patent Literature 1)). LPA can be formed from precursor molecules in plasma, serum, or tissue (membrane phospholipids) via several pathways. (1) Hydrolysis of the choline group from lysophosphatidylcholine by lysophospholipase D (lysoPLD or autotaxin), (2) Hydrolysis of the fatty acid acyl chain from phosphatidic acid to produce 2-acyl or 1-acyl LPA by phospholipase A1 or A2, and (3) De novo synthesis from glycerol-3-phosphate by acyltransferase (Kihara et al, Experimental Cell Res 333:171-177, 2015 (Non-patent Literature 2)). In tissues or cells, LPA represents a mixture of 1- or 2-acyl-sn-glycerol-3-phosphates.

[0003] Lysophosphatidic acid (LPA) acts as a signaling molecule and exerts its effects by binding to G protein-coupled receptors called LPA receptors (LPARs). To date, there are six identified LPA receptors (LPAR1-6) that are expressed in various tissues and / or cells. LPA plays a crucial role in pathophysiological processes such as autoimmune diseases, fibrous diseases, cancer, inflammation, and neuropathic pain through its binding to receptors (Budd and Qian, Future Med Chem 5:1935-52, 2013 (Non-Patent Literature 3), Valdes-Rives and Gonzalez-Arenas, Mediators Inflamm 2017:9173090, 2017 (Non-Patent Literature 4), Lopane et al., Biochim Biophys Acta Rev Cancer 1868:277-282, 2017 (Non-Patent Literature 5), Ueda H. Pain 158 Suppl 1:S55-S65, 2017 (Non-Patent Literature 6)).

[0004] Fibrosis is a repair (or "healing") process characterized by an excessive accumulation of extracellular matrix (ECM). When tissue damage (caused by infection, autoimmune reactions, mechanical injury, etc.) is chronic, the sustained production of pro-fibrotic mediators leads to an uncontrolled healing process in which replacement of damaged cells occurs along with connective tissue associated with ECM overproduction (Weiskirchen et al., Molecular Aspects Med. 65:2-15, 2019 (Non-Patent Literature 7)). Because it alters the structure and function of organs, fibrosis is closely linked to and often causes morbidity and mortality. It is estimated that 45% of all deaths in developed countries worldwide are due to several types of chronic fibrosis, such as idiopathic pulmonary fibrosis, systemic sclerosis, cirrhosis, chronic cardiovascular disease, progressive kidney disease (renal fibrosis), or diabetes (Wynn TANat. Rev. Immunol. 4:583-594, 2004 (Non-Patent Literature 8)).

[0005] The profibrotic effect of LPA via binding to its receptor LPAR1 has been established to have two main characteristics in the lungs, liver, and other organs or tissues: 1) the presence of a positive correlation between the appearance of fibrosis markers and increased LPA production associated with increased LPAR1 expression, and 2) attenuation of fibrosis in LPAR1- / - mice or by treatment with LPAR antagonists (Rancoule et al., Expert Opin.Investig.Drugs 20:657-667, 2011 (Non-Patent Literature 9)). For example, in a bleomycin model of pulmonary fibrosis, LPA levels in bronchoaveolar lavage fluid increased significantly after lung injury, and mice lacking the LPAR1 gene (LPAR1- / - mice) were significantly protected from fibrosis and mortality (Tager et al., Nat.Med.14:45-54, 2008 (Non-Patent Literature 10)). Treatment with small molecule LPAR1 antagonists can reduce pulmonary fibrosis in a bleomycin mouse model (Swanet et al., Br.J.Pharmacol. 160:1699-1713, 2010 (Non-Patent Literature 11)). More recently, in a chemo-induced cirrhosis and HCC rat model, Lapr1 expression was significantly increased in hepatic stellate cells, while lysoPLD (autotaxin) was higher in hepatocytes (Nakagawa et al., Cancer Cell. 30:879-890, 2016 (Non-Patent Literature 12)). Transcriptome analysis of human and rat liver tissues showed that the LPA pathway, mediated by LPAR1 activation, was a functional driving factor for cirrhosis and HCC. Therefore, inhibition of LPAR1 and lysoPLD with chemical inhibitors attenuated fibrosis progression and reduced HCC nodules in a cirrhosis-driven HCC rat model (Id.). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Yang and Chen, World J Gastroenterol 24:4132-4151, 2018

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Summary of the Invention

[0007] In one aspect, the present invention relates to a compound of formula (I), TIFF2026086696000001.tif51128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, L 1 is a covalent bond or CH2 optionally substituted by one or two methyl groups, L 2 is a covalent bond or (CR 7 R 7 ) p wherein, L 3 is a covalent bond, O or NR 7 wherein, provided that at least one of L 2 and L 3 is not a covalent bond, Q is a ring selected from C(=O)NR 9 R 10 , C(=O)OR 10 , or a 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl group, the ring containing at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, oxygen being an oxo group bonded to a ring member and / or a ring member, the ring being substituted by (R 3 ) n and one R 4 wherein, X 1 is N, O, or CR 6a wherein, X 2 is N or NR 6 wherein, X 3 is N, NR 6 or CR 6 wherein the dashed circle represents a bond forming a 5-membered aromatic ring, Y 1 Y 2 Y 3 and Y 4 are each independently N or CR 5And, however, Y 1 , Y 2 , Y 3 , and Y 4 The condition is that at least one of them is present, but two or fewer are N. Z is either CH2 or O. R 1 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b , or a 4-6 member heterosilyl, or two R 1 The groups, together with the carbon atoms to which they bond, form a C=O group. R 2 (CR 7 R 7 ) q -R 8 And, R 3 In each of these entities, independently, hydrogen, halogen, CN, and C are present. 1~6 Alkyl, or C 3~7 It is a cycloalkyl, R 4 These are, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1 to 4 Rs 11 Substituted (CH2) by q -5- to 6-membered heteroaryl ring, 1 to 4 Rs 11 Substituted (CH2) by q -5- to 7-membered heterocyclyl ring, and each phenyl is, independently, optionally substituted by 1 to 3 of halogen, C 1~6 alkyl, or C 1~6 alkoxy, R 5 is, in each occurrence, independently, hydrogen, halogen, C 1~6 alkyl, halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 alkoxy, C 1~6 alkyl-C 1~6 alkoxy, halo C 1~6 alkoxy, CN, C 3~7 cycloalkyl, NR a R b or C 1~6 alkyl-NR a R b and<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, P(=O)(OH)2, or The filename is TIFF2026086696000002.tif14128. R 9 and R 10 Each of these entities independently contains hydrogen, 1 to 4 R atoms. 11 C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5 to 7 member heterocyclyl rings, or R 9 and R 10 Along with the nitrogen atom to which they bond, there are 1 to 4 R 11 A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2)p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 12 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~7 It is either cycloalkyl or has two R's 12 The groups, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkyl ring. R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three groups, which may be the same or different, selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. m is either 1 or 2. n is 0, 1, or 2. p is independently 1, 2, 3, or 4 in each existence. q is independently 0, 1, 2, 3, or 4 in each existence.

[0008] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), the preparation thereof, and its use as a pharmaceutically acceptable treatment for diseases associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi). Accordingly, the compound of formula (I) is useful in the treatment of pathological fibrosis (e.g., pulmonary, hepatic, renal, cardiac, dermal, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, or systemic sclerosis. [Modes for carrying out the invention]

[0009] Detailed explanation In one embodiment, the technology provides compounds and pharmaceutically acceptable forms thereof, including but not limited to salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotope-labeled derivatives thereof.

[0010] In another embodiment, the present technology provides a method for treating and / or managing various diseases and disorders, which involves administering to a patient a therapeutically effective amount of the compounds provided herein, or their pharmaceutically acceptable forms (e.g., salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotope-labeled derivatives). A non-limiting example of diseases and disorders is described herein.

[0011] In another embodiment, the present technology provides a method for preventing various diseases and disorders, which involves administering to a patient in need of such prevention a prophylactically effective amount of the compound provided herein, or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotope-labeled derivatives). A non-limiting example of diseases and disorders is described herein.

[0012] In another embodiment, the Art, the compounds provided herein, or their pharmaceutically acceptable forms (e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotope-labeled derivatives) may be administered in combination with another drug ("second activator") or treatment. Examples of second activators include small and large molecules (e.g., proteins and antibodies).

[0013] This specification also provides pharmaceutical compositions (e.g., single-unit dosage forms) that can be used in the manner provided herein. In one embodiment, the pharmaceutical composition comprises a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., a salt, hydrate, solvate, isomer, sterioisomer, prodrug, and isotope-labeled derivative), and optionally one or more second activators.

[0014] While specific embodiments are discussed, this specification is illustrative and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon reviewing this specification.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this specification belongs.

[0016] definition As used herein and in the claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise.

[0017] As used herein, “agent,” “additional agent,” “therapeutic agent,” or “second activator” refers to a biological, pharmaceutical, or chemical compound or another part thereof. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamins, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds, and their metabolites. Various compounds, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides), as well as synthetic organic compounds based on various core structures, can be synthesized. In addition, various natural sources, such as plant or animal extracts, can provide active compounds. Those skilled in the art will readily recognize that there are no limitations regarding the structural properties of the agents described herein.

[0018] The “administration” of the disclosed compounds includes, as discussed herein, the delivery of the compounds described herein, or their prodrugs or other pharmaceutically acceptable derivatives, to a subject using any suitable formulation or route of administration.

[0019] As used herein, the terms “co-administration,” “administered in combination,” and their grammatical equivalents encompass the administration of two or more drugs to a subject such that both drugs and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at separate times in separate compositions, or administration in a composition in which both drugs are present.

[0020] The terms “effective dose” or “therapeutic effective dose” refer to the amount of the compound or pharmaceutical composition described herein that is sufficient to affect the intended use, including but not limited to disease treatment, as set forth below. In some embodiments, this amount is effective for detectable inhibition of LPA1, which can be determined, for example, by an LPA1 functional antagonist assay. The therapeutic effective dose may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, e.g., the subject’s weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by those skilled in the art. The term also applies to the dose that will induce a response in target cells, e.g., a reduction in cell migration. A particular dose will vary, for example, depending on the selected compound, the species of subject and their age / pre-existing health status or risk to their health status, the drug regimen to be followed, the severity of the disease, whether it is administered in combination with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is carried.

[0021] All methods described herein may be carried out in any preferred order, unless otherwise indicated herein or unless the context clearly contradicts it.

[0022] As used herein, the terms “treatment,” “to treat,” “to alleviate,” “to manage,” and “to achieve remission” are interchangeable herein. These terms refer to approaches to achieve beneficial or desired outcomes, including but not limited to therapeutic and / or preventive benefits. A therapeutic benefit means the eradication or remission of the underlying disease being treated. A therapeutic benefit is achieved by the eradication or remission of one or more physiological symptoms associated with the underlying disease, even though the patient may still suffer from the underlying disease, as improvement is observed in the patient. For a preventive benefit, pharmaceutical compounds and / or compositions may be administered to patients at risk of developing the disease, or to patients reporting one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0023] As used herein, the terms “prevention” and “preventive measures” mean administering a pharmaceutical compound or medicine, or a composition containing a pharmaceutical compound or medicine, to a subject before the disease, disorder, or condition itself fully manifests, in order to prevent the appearance of one or more symptoms of the disease, disorder, or condition and / or reduce its severity. Those skilled in the art will recognize that the term “prevention” is not an absolute term. In the medical field, it is understood to mean the prophylactic administration of a drug to substantially reduce the likelihood or severity of a disease, disorder, or condition, or its symptoms, and this is the meaning of such term as used in this disclosure.

[0024] When the term “therapeutic effect” is used herein, it encompasses the therapeutic and / or preventive benefits described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0025] The "targets" to which the drug is intended to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or other primates (e.g., crab-eating macaques, rhesus macaques); rodents (e.g., mice, rats), mammals including cattle, pigs, horses, sheep, goats, cats, and / or dogs, and / or birds including chickens, ducks, geese, quail, and / or turkeys.

[0026] The term "in vivo" refers to events that occur within the body of a subject. In vivo also includes events that occur in rodents, such as rats, mice, and guinea pigs.

[0027] The term "in vitro" refers to an event that occurs outside the body of the subject. For example, an in vitro assay encompasses any assay performed outside the subject. In vitro assays include cell-based assays that use living or dead cells. In vitro assays also include cell-free assays that do not use intact cells.

[0028] As used herein, the term “pharmaceutically acceptable salt” refers to salts that, within the bounds of sound medical judgment, are suitable for use in contact with the target tissue without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (incorporated herein by reference) describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Examples of pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or using organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, besilate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfate. Examples include nitrates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamonates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.In some embodiments, examples of organic acids from which salts may be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0029] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Suitable pharmaceutically acceptable salts derived from a suitable base include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4 Alkyl) 4 Examples include salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Furthermore, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0030] As used herein, the term “solvate” refers to a compound further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. A solvate may consist of the disclosed compound or a pharmaceutically acceptable salt thereof. If the solvent is water, the solvate is a “hydrate.” A pharmaceutically acceptable solvate and hydrate is a complex that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term “compound” will be understood to encompass compounds and solvates of compounds, as well as mixtures thereof.

[0031] In some embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” refers to a compound that is transformed in vivo to obtain the disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound by, for example, hydrolysis (e.g., hydrolysis in the blood). In certain cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can enhance the bioavailability of the compound when administered to a subject (e.g., by enabling enhanced absorption into the blood after oral administration) or by enhancing delivery to a biological compartment of interest (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compound having enhanced water solubility or active transport across the mesenteric membrane compared to the parent compound.

[0032] Prodrug compounds often offer advantages in mammalian organisms, such as solubility, histocompatibility, or delayed release (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACSSymposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated herein by reference. Illustrative advantages of prodrugs include, but are not limited to, their physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or their ability to enhance absorption from the gastrointestinal tract, or their ability to enhance drug stability for long-term storage.

[0033] The term “prodrug” also means that such a prodrug includes any covalently bonded carrier that releases the active compound in vivo when administered to a subject. Prodrugs of active compounds as described herein can be prepared by modifying functional groups present in the active compound in such a way that the modification is cleaved relative to the parent active compound, either in a routine operation or in vivo. Prodrugs include compounds to which a hydroxy, amino, or mercapto group is bonded, which is cleaved to any group that forms a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, derivatives of acetates, formates, and benzoates of alcohols in active compounds, or derivatives of acetamides, formamides, and benzamides of amine functional groups. Other examples of prodrugs include compounds containing -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995) and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985).

[0034] For example, if the disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, the prodrug is a hydrogen atom of the acid group and (C1-8) alkyl, (C1- 12) Alkanoyloxymethyl, 1-(alkanoyloxy)ethyl with 4-9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl with 5-10 carbon atoms, alkoxycarbonyloxymethyl with 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl with 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl with 5-10 carbon atoms, N-(alkoxycarbonyl)aminomethyl with 3-9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl with 4-10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C 1~2 ) Alkylamino(C 2~3 )alkyl (e.g., [3-dimethylaminoethyl]), carbamoyl-(C 1~2 ) alkyl, N,N-di(C 1~2 ) Alkylcarbamoyl-(C 1~2 ) alkyl, and piperidino-, pyrrolidino-, or morpholino (C 2~3 This may include pharmaceutically acceptable esters formed by substitution with groups such as alkyl groups.

[0035] Similarly, if the disclosed compound contains an alcohol functional group, the prodrug is a hydrogen atom of the alcohol group and (C 1~6 ) Alkanoyloxymethyl, 1-((C 1~6 )Alkanoyloxy)ethyl, 1-methyl-1-((C 1~6 )Alkanoyloxy)ethyl, (C 1~6 ) Alkoxycarbonyloxymethyl, N-(C 1~6 ) Alkoxycarbonylaminomethyl, succinoyl, (C 1~6 ) Alkanoyl, α-amino(C 1~4 )Alkanoyl, arylacyl, and each α-aminoacyl group are independently selected from naturally occurring L-amino acids, resulting in α-aminoacyl, or α-aminoacyl-α-aminoacyl, -P(O)(OH)2, -P(O)(O(C 1~6It can be formed by substitution with groups such as alkyl2 or glycosyl (radicals obtained from the removal of hydroxyl groups from hemiacetal carbohydrates).

[0036] If the disclosed compound incorporates an amine functional group, the prodrug is such that the hydrogen atoms in the amine group and R and R' are independently (C 1~10 ) alkyl, (C 3~7 ) R-carbonyl, RO-carbonyl, NRR'-carbonyl, Y selected from cycloalkyl, benzyl, natural α-aminoacyl, or natural α-aminoacyl-natural α-aminoacyl 1 However, H, (C 1~6 -C(OH)C(O)OY, which is alkyl or benzyl 1 ;Y 2 However, (C 1~4 ) is alkyl, Y 3 However, (C 1~6 ) alkyl, carboxy(C 1~6 ) alkyl, amino(C 1~4 )alkyl, or mono-N- or di-N,N-(C 1~6 ) alkylaminoalkyl -C(OY 2 )Y 3 ; and Y 4 However, it is H or methyl, and Y 5 However, mono-N- or di-N-(C 1~6 ) an alkylamino -C(Y 4 )Y 5 It can be formed by substitution with groups such as morpholino, piperidine-1-yl, or pyrrolidine-1-yl.

[0037] In some embodiments, the disclosed compounds may encompass isomers. “Isomer” refers to different compounds having the same molecular formula. “Stereoisomer” refers to isomers that differ only in the way their atoms are arranged in space. As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomer” includes geometric double-bond cis and trans isomers, R and S enantiomers, diastereomers, (d) isomers and (l) isomers, racemic mixtures thereof, and other mixtures thereof as applicable to the scope of this disclosure.

[0038] Geometric isomers are symbols indicating bonds that may be single, double, or triple bonds as described herein. This may be represented by TIFF2026086696000003.tif2128. This specification provides various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as "Z" or "E" configurations, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures exhibiting a double bond encompass both "E" and "Z" isomers.

[0039] Alternatively, substituents around a carbon-carbon double bond may be referred to as "cis" or "trans," where "cis" refers to a substituent on the same side of the double bond and "trans" refers to a substituent on the opposite side of the double bond. The arrangement of substituents around a carbon ring may also be designated as "cis" or "trans." The term "cis" refers to a substituent on the same side of the ring plane, and the term "trans" refers to a substituent on the opposite side of the ring plane. A mixture of compounds in which substituents are located on both the same and opposite sides of the ring plane is designated as "cis / trans."

[0040] An enantiomer is a pair of stereoisomers that are mirror images of each other and cannot overlap. A diastereoisomer is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other. Absolute stereochemistry is determined according to the Cahn-Ingold-Prelog RS system. If a compound is an enantiomer, the stereochemistry at each chiral carbon may be determined by either R or S. A divided compound whose absolute configuration is unknown may be designated as (+) or (-) depending on the direction in which the compound rotates plane polarization at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein contain one or more chiral centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry at each chiral atom. The chemical entities, pharmaceutical compositions, and methods described herein include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or they can be separated using conventional techniques.

[0041] A mixture of a pair of enantiomers in any proportion may be known as a "racemic" mixture. The term TIFF2026086696000004.tif4128 is used to specify a racemic mixture as needed. In some embodiments, the compounds of the Art are a racemic mixture of (S)- and (R)-isomers. In some embodiments, the racemic mixture has equal amounts of two enantiomers.

[0042] In some embodiments, enantiomers are provided partially or substantially without the corresponding enantiomers and may be referred to as “optically concentrated,” “enantiomerically concentrated,” “enantiomerically pure,” and “non-racemic,” as used interchangeably herein. The “enantiomery excess” or “enantiomery excess%” of such a composition may be calculated using the equation shown below. In the example shown below, the composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, e.g., the R enantiomer. ee = (90 - 10) / 100 = 80%. Therefore, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an 80% enantiomeric excess. In some embodiments, the compositions described herein contain an enantiomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of S enantiomers, or an enantiomeric excess between any two of the aforementioned values ​​and a range including them (e.g., 50-99.5%ee). In other words, the composition contains an enantiomeric excess of S enantiomers exceeding R enantiomers. In other embodiments, some compositions described herein contain at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of R enantiomers, or an enantiomer excess in a range between any two of the aforementioned values ​​(e.g., 50–99.5%ee). In other words, the composition contains an enantiomer excess of R enantiomers exceeding S enantiomers. If the concentration of one enantiomer far exceeds about 80% by weight, the composition is referred to as a “substantially enantiomerically concentrated,” “substantially enantiomerically pure,” or “substantially non-racemic” preparation.

[0043] Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC), chiral salt formation, and crystallization, or they can be prepared by asymmetric synthesis. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Stereochemistry of Carbon Compounds (ELEliel, Ed., McGraw-Hill, NY, 1962), and Tables of Resolving Agents and Optical Resolutions p.268 (ELElM, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

[0044] Optical isomers can be obtained by conventional processes, for example, by the formation of diastereoisomer salts, by treatment with an optically active acid or base, or by the separation of a racemic mixture. Suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid, and camphorsulfonic acid. Separation of the diastereoisomer mixture by crystallization, followed by the liberation of an optically active base from these salts, results in the separation of the isomers. Another method involves the synthesis of covalent diastereoisomer molecules by reacting the disclosed compound with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to deliver enantiomerically concentrated compounds. Optically active compounds can also be obtained by using active starting materials. In some embodiments, these isomers may be in the form of free acids, free bases, esters, or salts.

[0045] In any embodiment, the pharmaceutically acceptable form is a tautomer. As used herein, the term “tautomer” refers to a type of isomer comprising two or more interconvertible compounds resulting from the formal transfer of at least one hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). “Tautomerism” includes prototropic tautomerism or proton transfer tautomerism, which are considered a subset of acid-base chemistry. “Prototropic tautomerism” or “proton transfer tautomerism” involves the transfer of protons with a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerism (i.e., the reaction that provides the tautomer pair) can be catalyzed by an acid or a base, or it can occur without the action or presence of an external agent. Exemplary tautomerisms include, but are not limited to, tautomerisms from keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different) enamine. A specific example of keto-enol tautomerism is the interconversion of tautomers of pentan-2,4-dione and 4-hydroxypenta-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of tautomers of pyridine-4-ol and pyridine-4(1H)-one.

[0046] Unless otherwise stated, the structures shown herein also mean that they contain different compounds only in the presence of one or more isotopically enriched atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having this structure, excluding carbon substitution with 13C-enriched carbon, are within the scope of this disclosure.

[0047] This disclosure also encompasses pharmaceutically acceptable forms of "isotope-labeled derivatives," which are identical compounds to those enumerated herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl. Specific isotope-labeled disclosed compounds (e.g., 3 H and 14 Those labeled with 1C are useful for tissue distribution assays of compounds and / or substrates. Tritiation (i.e., 3 H) and carbon 14 (i.e., 14 C) Isotopes can be made easy to prepare and detectable. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), can result in certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced required dosage). The isotope-labeled compounds disclosed can generally be prepared by substituting an isotope-labeled reagent for an unlabeled reagent. In some embodiments, compounds are provided herein that may also contain one or more atomic isotopes in non-natural proportions among the atoms constituting such compounds. All isotopic variants of compounds disclosed herein, whether radioactive or not, are encompassed within the scope of this disclosure. In some embodiments, radioactively labeled compounds are useful for studying the metabolism and / or tissue distribution of compounds, or for altering metabolic rates or pathways or other aspects of biological function.

[0048] Examples of "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption retarders. pharmaceutically acceptable carriers or excipients do not impair the pharmacological activity of the disclosed compound and are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions such as those disclosed herein is intended.Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter, and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., polyethylene glycol, and propylene glycol; esters, e.g., ethyl oleate, and ethyl laurate; agar; buffers, e.g., magnesium hydroxide, and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and non-toxic compatible lubricants, e.g., sodium lauryl sulfate, and stearin. Magnesium sulfate; colorants; release agents; coating agents; sweeteners, flavoring agents and fragrances; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), e.g., da tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, e.g., Tween or other similar polymer delivery matrices; serum proteins, e.g., human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based materials; polyacrylates, waxes, and polyethylene-polyoxypropylene-block polymers. Cyclodextrins, such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives, such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-cyclodextrin, or other solubilized derivatives, may also be used to enhance the delivery of the compounds described herein.

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the cover of Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional group moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sansalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th ed., John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.

[0050] The enumeration of value ranges in this specification is intended solely as a simplified method for individually referring to each separate value and subrange that falls within the range, unless otherwise indicated herein, and each separate value and subrange is incorporated herein as if it were individually enumerated herein. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6It is intended to include alkyl groups.

[0051] "Alkyl" is a linear or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, without unsaturation, and having 1 to 10 carbon atoms (e.g., C 1~10 This refers to alkyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer within a given range, for example, "1 to 10 carbon atoms" means that an alkyl group can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, but this definition also covers the existence of the term "alkyl" for which no numerical range is specified. In some embodiments, an alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Examples of typical saturated linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. On the other hand, examples of saturated branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, and 2,3-dimethylbutyl. The alkyl group is bonded to the parent molecule by a single bond. Unless otherwise specified herein, the alkyl group may be substituted with one or more substituents disclosed herein. In non-limiting embodiments, the substituted alkyl group may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0052] "Alkenyl" is a linear or branched hydrocarbon chain radical group (i.e., C) consisting only of carbon and hydrogen atoms, containing at least one double bond, and having 2 to 10 carbon atoms. 2~10This refers to an alkenyl. Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer within a given range, for example, "2 to 10 carbon atoms" means that the alkenyl group may consist of 10 or fewer carbon atoms, such as 2 carbon atoms, 3 carbon atoms, etc. In any embodiment, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 6 carbon atoms (e.g., C 2~6 It contains alkenyls. Alkenyls are attached to the parent molecule structure by single bonds, such as ethenyl (i.e., vinyl), propa-1-enyl (i.e., allyl), buta-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. One or more carbon-carbon double bonds may be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), 2-methylpropa-2-enyl (C4), and butadienyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and 2,3-dimethyl-2-butenyl (C6). Additional examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified herein, alkenyl groups may be substituted with one or more substituents disclosed herein.

[0053] "Alkynyl" is a linear or branched hydrocarbon chain radical group (i.e., C) consisting only of carbon and hydrogen atoms, containing at least one triple bond, and having 2 to 10 carbon atoms. 2~10This refers to an alkynyl group. Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer within a given range, for example, "2 to 10 carbon atoms" means that the alkynyl group may consist of 10 or fewer carbon atoms, such as 2 carbon atoms, 3 carbon atoms, etc. In any embodiment, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 6 carbon atoms (e.g., C 2~6 The molecules have an alkynyl group. The alkynyl group is attached to the parent molecule structure by a single bond, and examples include ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentenyl, and hexynyl. Unless otherwise specified herein, the alkynyl group may be optionally substituted with one or more substituents disclosed herein.

[0054] "Alkoxy" refers to an -O-alkyl group containing 1 to 10 carbon atoms in a linear, branched, saturated cyclic structure, or combination thereof, bonded to the parent molecular structure via oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, and cyclohexyloxy. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms. In some embodiments, C 1~4 Alkoxy groups are alkoxy groups that include both linear and branched alkyl groups with 1 to 4 carbon atoms. Unless otherwise specified herein, alkoxy groups may be substituted with one or more substituents disclosed herein. The terms “alkenoxy” and “alkynoxy” reflect the above description of “alkoxy,” with the prefix “alk” being replaced by “alkene” or “alkyne,” respectively, and the parent terms “alkenyl” or “alkynyl” as described herein.

[0055] "Aromatic" or "aryl" refers to a radical having 6 to 14 ring atoms (e.g., C) having at least one ring (e.g., phenyl, fluorenyl, and naphthyl) with a conjugated pi-electron system that is carbocyclic. 6~14 Aromatic or C6~14 This refers to the aryl. In some embodiments, the aryl is C 6~10 These are aryl groups. For example, a divalent radical formed from a substituted benzene derivative and having free valence on the ring atoms is named a substituted phenylene radical. In other embodiments, a divalent radical derived from a monovalent polycyclic hydrocarbon radical whose name ends in "-yl" by removing one hydrogen atom from a carbon atom with free valence is named by adding "-idene" to the name of the corresponding monovalent radical; for example, a naphthyl group having two bond points is called naphthylidene. Whenever it appears herein, numerical ranges such as "6 to 14 aryls" refer to each integer within a given range; for example, "6 to 14 ring atoms" means that the aryl group may consist of 14 or fewer ring atoms, such as 6 ring atoms, 7 ring atoms, etc. This term includes monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent ring atoms) groups. Examples of polycyclic aryl groups include bicyclic, tricyclic, and tetracyclic groups. In polycyclic groups, only one ring is required for aromaticity; therefore, groups such as indanyl are encompassed by the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenantrenyl, anthracenyl, fluorenyl, indolyl, and indanyl. Unless otherwise specified herein, aryl groups may be substituted with one or more substituents disclosed herein.

[0056] "Cycloalkyl" and "carbocykyl" refer to monocyclic or polycyclic radicals that contain only carbon and hydrogen and may be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups may be called "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups are groups having 3 to 13 ring atoms (i.e., C 3~13This term includes cycloalkyl groups. Whenever it appears herein, numerical ranges such as "3 to 10" refer to each integer within a given range, for example, "3 to 13 carbon atoms" means that a cycloalkyl group may consist of 13 or fewer carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. The term "cycloalkyl" also includes bridged and spiro-condensed cyclic structures that do not contain heteroatoms. The term also includes monocyclic or condensed polycyclic (i.e., rings that share pairs of adjacent ring atoms) groups. Examples of polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, and the like. In some embodiments, "cycloalkyl" means C 3~8 It may be a cycloalkyl radical. In some embodiments, "cycloalkyl" is C 3~5 It may be a cycloalkyl radical. Exemplary examples of cycloalkyl groups include, but are not limited to, the following: C 3~6 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~7 An example of a carbocyclyl group is norbornyl (C7). 3~8 An example of a carbocyclyl group is the aforementioned C 3~7 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. 3~13 An example of a carbocyclyl group is the aforementioned C 3~8Examples include carbocyl groups, and octahydro-1H-indenyl, decahydronaphthalenyl, and spiro[4.5]decanyl. Unless otherwise specified herein, cycloalkyl groups may be substituted with one or more substituents disclosed herein. The terms “cycloalkenyl” and “cycloalkynyl” reflect the above description of “cycloalkyl,” where the prefix “alk” is replaced with “alkene” or “alkyne,” respectively, and the parent terms “alkenyl” or “alkynyl” are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group may have 5 to 13 ring atoms.

[0057] "Halo," "halide," or "halogen" means fluoro, chloro, bromo, or iodine. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted by one or more halo groups or combinations thereof, preferably by one, two, or three halo groups. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups where the halo is fluorine, for example, but not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, -O-CHF2, etc. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and may be further substituted as defined herein.

[0058] "Heteroaryl" or "heteroaromatic" refers to a radical of an aromatic ring system ("5-18 membered heteroaryl") which is a monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement), wherein each heteroatom independently has a ring carbon atom provided in the aromatic ring system, selected from nitrogen, oxygen, phosphorus, and sulfur, and 1 to 6 ring heteroatoms. A heteroaryl polycyclic ring system may contain one or more heteroatoms in one or both rings. Whenever it appears herein, numerical ranges such as "5-18" refer to each integer within a given range, for example, "5-18 ring atoms" means that the heteroaryl group may consist of 18 or fewer ring atoms, such as 5 ring atoms, 6 ring atoms, etc. In some cases, a heteroaryl may have 5 to 14 ring atoms. In some embodiments, heteroaryls have a divalent radical derived from a monovalent heteroaryl radical whose name ends in "-yl" by, for example, removing one hydrogen atom from an atom having free valence, and are named by adding "-ene" to the name of the corresponding monovalent radical, for example, a pyridyl group having two bonds is pyridylene.

[0059] For example, the nitrogen-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the ring's skeletal atoms is a nitrogen atom. One or more heteroatoms in a heteroaryl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. Heteroaryls also include ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxides. Heteroaryls are bonded to the parent molecular structure via any atom of the ring.

[0060] "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, and the bond site to the parent molecule structure is either an aryl or heteroaryl ring, or ring systems in which a heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclyl groups, and the bond site to the parent molecule structure is located on the heteroaryl ring. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site to the parent molecule structure can be on either ring, i.e., a ring containing a heteroatom (e.g., 2-indolyl) or a ring not containing a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system ("5- to 10-membered heteroaryl") in which each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur, and has a ring carbon atom and 1 to 4 ring heteroatoms in the aromatic ring system. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") in which each heteroatom independently provides a ring carbon atom and 1-4 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur to the aromatic ring system. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") in which each heteroatom independently provides a ring carbon atom and 1-4 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur to the aromatic ring system. In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0061] Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzoxazolyl, benzopyranol, benzofuranil, benzopyranonil, benzof Lazanil, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5Hbenzo[6,7]cyclohepta[1,2-c]pyrimidinyl, gibe Nzofuranil, dibenzothiophenyl, furanil, furazanil, furanonil, flo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8- Methano-5,6,7,8-tetrahydroquinazolinyl, naphthilidinyl, 1,6-naphthilidinol, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimudinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2, Examples include, but are not limited to, [3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranil, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyrimidinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl groups may be optionally substituted with one or more substituents disclosed herein.

[0062] "Heterocyclyl," "heterocycloalkyl," or "heterocarbocyclyl" each refers to any 3- to 18-membered non-aromatic radical monocyclic or polycyclic moiety containing at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. Heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and polycyclic ring systems can be condensed, bridging, or spirocyclic ring systems. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. Heterocyclyl groups can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups may be called "heterocycloalkenyl" if the heterocyclyl contains at least one double bond, or "heterocycloalkynyl" if the heterocyclyl contains at least one triple bond. Whenever it appears herein, numerical ranges such as “5 to 18” refer to each integer within a given range, for example, “5 to 18 ring atoms” means that a heterocyclyl group can consist of 18 or fewer ring atoms, such as 5 ring atoms, 6 ring atoms, and so on. For example, by removing one hydrogen atom from an atom with free valence, a divalent radical derived from a monovalent heterocyclyl radical whose name ends in “-yl” is named by adding “-ene” to the name of the corresponding monovalent radical, for example, a piperidine group with two bond sites is piperidylene.

[0063] The nitrogen-containing heterocyclyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom. Heteroatoms in the heterocyclyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quaternized. Heterocyclyls also include ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxides. Heterocyclyls are bonded to the parent molecular structure via any atom on any of the rings.

[0064] A "heterocyclyl" is a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyrill groups, and the bond site is located on either the carbocyrill or heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, and the bond site to the parent molecular structure is located on the heterocyclyl ring. In some embodiments, the heterocyclyl group is a 5-14 membered non-aromatic ring system ("5-14 membered heterocyclyl") in which each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur, and has a ring carbon atom and 1-4 ring heteroatoms. In some embodiments, the heterocyclyl group is a 3-10 membered non-aromatic ring system ("3-10 membered heterocyclyl") in which each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur, and has a ring carbon atom and 1-4 ring heteroatoms. In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system ("5-8 membered heterocyclyl") having a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system ("5-6 membered heterocyclyl") having a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0065] A "heterocyclyl" may contain one or more ketone groups (-C(=O)-) as part of a ring. Examples of ketone-containing heterocycles include, but are not limited to, pyridine-2(1H)-one, pyrazine-2(1H)-one, pyrimidine-2(1H)-one, pyrimidine-4(3H)-one, pyridazine-3(2H)-one, pyridine-4(1H)-one, imidazolidine-2-one, 1,3-dihydro-2H-imidazole-2-one, 2,4-dihydro-3H-1,2,4-triazole-3-one, oxazole-2(3H)-one, and oxazolidine-2-one. Ketone-containing heterocyclyls can be obtained by removing a hydrogen atom from the corresponding corepsoning ketone-containing heterocycle at any available NH or CH position.

[0066] Examples of three-membered heterocyclines containing one heteroatom include, but are not limited to, azildinyl, oxyranil, and thiorenyl. Examples of four-membered heterocyclines containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclines containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclines containing two heteroatoms include, but are not limited to, dioxolanil, oxathiolanil, thiazolidinyl, and dithiolanil. Examples of five-membered heterocyclines containing three heteroatoms include, but are not limited to, triazolinyl, diazolonil, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, thiomorpholinil, dithianyl, dioxanil, and triazinanil. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl.Examples of bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanil, benzopyrrolidinyl, benzopiperidinyl, benzoxolanil, benzothiolanil, benzothianil, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-1H-benzimidazole-2-one, (1-substituted)-2-oxo-benzimidazole-3-yl, octahydroclomenyl, octahydroisoclomenyl, decahydronaphthilidinyl, decahydro-1,8-naphthilidinyl, octahydropyrrolo[3,2-b]pyrrole, phenantridinyl, indolinyl Nyl, phthalimidyl, naphthalimidyl, chromanil, clomenil, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-fl[3,2-b]pyrrolyl, 6,7-dihydro-5H-fl[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H- Examples include, but are not limited to, pyrrolo[2,3-b]pyridinyl, hydroflo[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydroflo[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, and 1,2,3,4-tetrahydro-1,6-naphthilidinyl.

[0067] Unless otherwise specified herein, heterocyclyl groups may be substituted with one or more substituents disclosed herein.

[0068] When a substituent group is identified by its conventional chemical formula written from left to right, it equally encompasses chemically identical substituents that would result from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0069] A “leaving group or leaving atom” is any group or atom that, under reaction conditions, is cleaved from the starting material and thereby facilitates the reaction at a particular site. Preferred non-limiting examples of such groups include, unless otherwise specified, halogen atoms, mesyloxy, p-nitrobenzenesulfonyloxy, trifluoromethyloxy, and tosyloxy groups.

[0070] The term "protecting group" has traditionally had a related meaning in organic synthesis, namely, a group that selectively blocks one or more reaction sites in a polyfunctional compound so that a chemical reaction can be selectively carried out at another unprotected reaction site, and so that the group can be easily removed after the selective reaction is complete. Non-limiting embodiments of functional groups that can be masked by protecting groups include amines, hydroxys, thiols, carboxylic acids, and aldehydes. For example, the hydroxy-protected form is when at least one of the hydroxyl groups present in the compound is protected by a hydroxy-protecting group. Various protecting groups are disclosed, for example, in Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014), which is incorporated herein by reference in its entirety. For additional background information on protecting group methodologies (materials, methods, and strategies for protection and deprotection) and other synthetic chemical transformations useful for producing the compounds described herein, see R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). These references are incorporated herein by reference in their entirety.

[0071] The terms “substituted” or “substituted” mean that at least one hydrogen atom present on a base atom (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, such as one that, upon substitution of hydrogen, results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, exclusion, or other reactions. Unless otherwise indicated, a “substituted” group may have substituents at one or more of its substituted positions, and if two or more positions in any given structure are substituted, the substituents are either identical or different at each position. Substituents include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo (i.e., F, Cl, Br, I), haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(Ra )(R a ), or -OP(=O)(OR a )2 includes one or more groups selected individually and independently, where each R a These are independently hydrogen, alkyl, haloalkyl, carbocyl, carbocylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where each of these parts (other than hydrogen) may be substituted with one or more substituents (up to six, valence-permissible) selected from OH, NH2, oxo, halo, nitro, COOH, C(O)NH2, or cyano. For example, a cycloalkyl substituent may have a halide substituted with one or more ring carbons. Protecting groups that can form protected derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts mentioned above.

[0072] Preferred substituents include haloalkyl and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocyclic, -M-aryl, and -M-OR a -M-SR a , -MN(R a )2, -M-OC(O)N(R a )2, -MC(=NR a )N(R a )2, -MC(=NR a )OR a ,-MP(O)(R a )2, Si(R a )3, -M-NR a C(O)R a -M-NR a C(O)OR a ,-MC(O)R a ,-MC(=S)R a -MC(=S)NR a R a ,-MC(O)N(R a )2, -MC(O)NR a -MN(R a )2, -M-NR a C(NRa )N(R a )2, -M-NR a C(S)N(R a )2,-MS(O)2R a ,-MC(O)R a ,-M-OC(O)R a -MC(O)SR a -MS(O)2N(R a )2, -C(O)-MC(O)R a -MCO2R a , -MC(=O)N(R a )2, -MC(=NH)N(R a )2, and -M-OC(=NH)N(R a )2(In the formula, M is C 1~6 Examples include, but are not limited to, alkyl groups.

[0073] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with several substituents that vary within an explicitly defined range, it is understood that the total number of substituents does not exceed the normal available valence under the existing state. Therefore, for example, a phenyl ring substituted with a "p" substituent (where "p" is in the range of 0-5) may have 0-5 substituents, while a pyridinyl ring substituted with a "p" substituent may have several substituents in the range of 0-4. The maximum number of substituents a group in a disclosed compound may have can be easily determined. The substituted groups include only combinations of substituents and variables that result in a stable or chemically feasible compound. A stable or chemically feasible compound is, among other factors, one that possesses sufficient stability to allow its preparation and detection. In some embodiments, the disclosed compounds are sufficiently stable to remain substantially unchanged for, for example, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, or at least about 6 weeks when maintained at a temperature of 40°C or below in the absence of moisture (e.g., less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.5%) or in the absence of other chemical reaction conditions.

[0074] The terms “combining,” “combining,” “for combining,” and “combining” refer to the act of adding at least one chemical substance to another chemical substance, either sequentially or simultaneously. In some embodiments, combining these chemical substances can result in the conversion of the initial chemical substance into one or more different chemical substances. This conversion may occur through one or more chemical reactions, such as the formation, breaking, or reconstruction of covalent bonds. A non-limiting example is the hydrolysis of esters to alcohols and carboxylic acids, which may result from combinations of esters with suitable bases. Another non-limiting example is the combination of aryl fluorides with amines to provide arylamines via a substitution process. These terms also include the generation and / or conversion of charged chemical substances, such as, but not limited to, N-oxide formation, acid addition salt formation, base addition salt formation, etc. These terms also include the generation and / or conversion of radical chemical substances and isotope-labeled chemical substances.

[0075] The terms “convert,” “transform,” “in order to convert,” and “convert” refer to a subset of “combination” and its grammatical equivalents, where the action of one or more reagents converts one or more functional groups on a chemical substance to another functional group. For example, a conversion is the conversion of a nitro functional group on a chemical substance to an amine using a reducing agent, but is not limited to these. Conversions also include changes in charged chemicals, radical chemicals, and isotopically labeled chemicals. However, the term “convert” does not include changes in conserved bonds in the disclosed genera and compounds.

[0076] compound In one embodiment, the present invention relates to a compound of formula (I), With respect to TIFF2026086696000005.tif51128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, Z is either CH2 or O. Y 1 , Y 2 , Y3 , and Y 4 Each of these is independently N or CR 5 And, however, Y 1 , Y 2 , Y 3 , and Y 4 The condition is that at least one of them is present, but two or fewer are N. X 1 is N, O, or CR 6a And, X 2 is N or NR 6 And, X 3 N, NR 6 or CR 6 The dashed circle indicates the bond that forms a 5-membered aromatic ring. L 1 CH2 may be substituted by a covalent bond or by one or two methyl groups. L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, Q is C(=O)NR 9 R 10 , C(=O)OR 10 , or a ring selected from a 5 or 6-membered heteroaryl group or a 5 or 6-membered heterocyclyl group, wherein the ring comprises at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the oxygen may be an oxo group bonded to the ring member and / or to the ring member, and the ring is (R 3 ) n and one R 4 It has been replaced by, R 1 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C1~6 alkyl-OH, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b , or a 4-6 member heterosilyl, or two R 1 The groups, together with the carbon atoms to which they bond, form a C=O group. R 2 (CR 7 R 7 ) q -R 8 And, R 3 In each of these entities, independently, hydrogen, halogen, CN, and C are present. 1~6 Alkyl, or C 3~7 It is a cycloalkyl, R 4 These are, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1-4 R 11 (CH2) replaced by q -5-6 member heteroaryl ring, 1-4 R 11 (CH2) replaced by q - A 5- to 7-membered heterocyclyl ring, where each phenyl group independently contains a halogen, C 1~6Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a and R 6 Each of these entities is independently hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or has two R's 7 The groups, together with the carbon atoms to which they are bonded, form a 3- to 5-membered cycloalkyl ring. R 8 C(=O)OR 7 , C(=O)NR a R b , CN, C(=O)NHC(=O)R 7 , C(=O)NHS(=O)2R 7 , C(=O)NHS(=O)R 7 , S(=O)2R 7 , P(=O)(OH)2, or The filename is TIFF2026086696000006.tif14128. R 9 and R 10 Each of these entities independently contains hydrogen, 1 to 4 R atoms. 11 C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 )q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5 to 7 member heterocyclyl rings, or R 9 and R 10 Along with the nitrogen atom to which they bond, there are 1 to 4 R 11 A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7Cycloalkyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 12 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~7 It is either cycloalkyl or has two R's 12 The groups, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkyl ring. R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. m is either 1 or 2. n is 0, 1, or 2. p is independently 1, 2, 3, or 4 in each existence. q is independently 0, 1, 2, 3, or 4 in each existence.

[0077] In some embodiments, the compound of formula (I) is the compound of formula (II), TIFF2026086696000007.tif57128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, L 1 CH2 may be substituted by a covalent bond or by one or two methyl groups. L 2 is covalent or (CR 7 R7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, Q is a ring selected from the group consisting of 5-membered heteroaryls, 5-membered heterocyclyls, 6-membered heteroaryls, and 6-membered heterocyclyls, wherein the ring comprises at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the oxygen may be oxo (=O) bonded to the ring member and / or to the ring member, and the ring is (R 3 ) n and one R 4 It has been replaced by, X 1 is N, or CR 6a And, Z is either CH2 or O. R 1 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b , or a 4-6 member heterosilyl, or two R 1 The groups, together with the carbon atoms to which they bond, form a C=O group. R 3 In each of these entities, independently, hydrogen, halogen, CN, and C are present. 1~6 Alkyl, or C 3~7 It is a cycloalkyl, R 4 These are, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1-4 R 11 (CH2) replaced by q -5-6 member heteroaryl ring, 1-4 R 11 (CH2) replaced by q - A 5- to 7-membered heterocyclyl ring, where each phenyl group independently contains a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C3~5 It is either cycloalkyl or R 7 and R 7 Together with the carbon atoms to which they are bonded, they form a 3-5 membered cycloalkyl ring. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 13 In each existence, independently, hydrogen and C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. n is 0, 1, or 2. p is independently 1, 2, 3, or 4 in each existence. t is 0, 1, 2, or 3. w is 0 or 1, except L 1 If the bond is covalent, then the condition is that w is 1, and further, L 1 However, if the CH2 is substituted with one or two methyl groups, then the condition is that w is 0.

[0078] In some embodiments, the compound of formula I is a compound of formula (IIa) or (IIaa), TIFF2026086696000008.tif53128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, Q is a ring selected from the group consisting of 5-membered heteroaryls, 5-membered heterocyclyls, 6-membered heteroaryls, and 6-membered heterocyclyls, wherein the ring comprises at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the oxygen may be an oxo bonded to the ring member and / or to the ring member, and the ring is (R 3 ) n and one R 4 It has been replaced by, X 1 is N, or CR 6a And, R 1 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b , or a 4-6 member heterosilyl, or two R 1 The groups, together with the carbon atoms to which they bond, form a C=O group. R 3 In each of these entities, independently, hydrogen, halogen, CN, and C are present. 1~6 Alkyl, or C 3~7 It is a cycloalkyl, R 4 These are, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1-4 R 11 (CH2) replaced by q -5-6 member heteroaryl ring, 1-4 R 11 (CH2) replaced by q - A 5- to 7-membered heterocyclyl ring, where each phenyl group independently contains a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or R 7 and R 7 Together with the carbon atoms to which they are bonded, they form a 3-5 membered cycloalkyl ring. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6It may be substituted with 1 to 3 of the alkoxy groups. R 13 In each existence, independently, hydrogen and C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. n is 0, 1, or 2. p is independently 1, 2, 3, or 4 in each existence. t is 0, 1, 2, or 3.

[0079] In some embodiments, the compound of formula I is the compound of formula (IIb) or (IIbb), TIFF2026086696000009.tif53128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, Q is a ring selected from the group consisting of 5-membered heteroaryls, 5-membered heterocyclines, 6-membered heteroaryls, and 6-membered heterocyclines, wherein the ring comprises at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the ring is (R 3 ) n and one R 4 It has been replaced by, X 1 is N, or CR 6a And, R 3 In each of these entities, independently, hydrogen, halogen, CN, and C are present. 1~6 Alkyl, or C 3~7 It is a cycloalkyl, R 4 These are, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1-4 R 11 (CH2) replaced by q -5-6 member heteroaryl ring, 1-4 R 11 (CH2) replaced by q - A 5- to 7-membered heterocyclyl ring, where each phenyl group independently contains a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or R 7 and R 7 Together with the carbon atoms to which they are bonded, they form a 3-5 membered cycloalkyl ring. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 13 In each existence, independently, hydrogen and C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. n is 0, 1, or 2. p is independently 1, 2, 3, or 4 in each existence. t is 0, 1, 2, or 3.

[0080] In some embodiments, the compound of formula I is the compound of formula (IIc) or (IIcc), TIFF2026086696000010.tif53128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, Q is a ring selected from the group consisting of 5-membered heteroaryls, 5-membered heterocyclines, 6-membered heteroaryls, and 6-membered heterocyclines, wherein the ring contains at least one carbon atom, at least one nitrogen atom, and optionally contains 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the ring is (R 3 ) n and one R 4 It has been replaced by, X 1 is N, or CR 6a And, R 3 In each of these entities, independently, hydrogen, halogen, CN, and C are present. 1~6 Alkyl, or C 3~7 It is a cycloalkyl, R 4 is hydrogen, halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl, O(CH2) p -C 3~7 Cycloalkyl, 1-4 R 11 (CH2) replaced by q -5-6 member heteroaryl rings, or 1-4 R groups 11 (CH2) replaced by q - A 5- to 7-membered heterocyclyl ring, where each phenyl group independently contains a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 5In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or R 7 and R 7 Together with the carbon atoms to which they are bonded, they form a 3-5 membered cycloalkyl ring. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 13 In each existence, independently, hydrogen and C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. n is 0, 1, or 2. p is independently 1, 2, 3, or 4 in each existence. t is 0, 1, 2, or 3.

[0081] In some embodiments, the compound of formula I is the compound of formula (IId) or (IIdd), TIFF2026086696000011.tif56128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, In formula (IIdd), * represents a chiral center having an R or S configuration. L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, Q is a ring selected from the group consisting of 5-member heteroaryl, 5-member heterocyclyl, 6-member heteroaryl, and 6-member heterocyclyl, the ring containing at least 1 carbon atom, at least 1 nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, oxygen being able to be an oxo(=O) bonded to a ring member and / or a ring member, the ring being (R 3 ) n and one R 4 substituted by, X 1 is N, or CR 6a and R 1 is, in each occurrence, independently, hydrogen, halogen, C 1~6 alkyl, haloC 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 alkoxy, haloC 1~6 alkoxy, CN, C 3~7 cycloalkyl, NR a R b , C 1~6 alkyl-NR a R b , or 4- to 6-member heterosilyl, or two R 1 groups together with the carbon atom to which they are attached form C=O, R 3 is, in each occurrence, independently, hydrogen, halogen, CN, C 1~6 alkyl, or C 3~7 cycloalkyl, R 4 is, independently, hydrogen, halogen, C 1~6 alkyl, haloC 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, (CH2) p -C 1~6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 cycloalkyl, (CH2) p -C 3~7Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl, O(CH2) p -C 3~7 Cycloalkyl, 1-4 R 11 (CH2) replaced by q -5-6 member heteroaryl ring, 1-4 R 11 (CH2) replaced by q - A 5- to 7-membered heterocyclyl ring, where each phenyl group independently contains a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or has two R's 7 The groups, together with the carbon atoms to which they are bonded, form a 3- to 5-membered cycloalkyl ring. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C1~6 alkoxy, (CH2) p -C 1~6 alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 cycloalkyl, (CH2) p -C 3~7 cycloalkyl, C 2~6 alkenyl-C 3~7 cycloalkyl, C 2~6 alkynyl-C 3~7 cycloalkyl, O(CH2) p -C 3~7 is cycloalkyl, and each phenyl is independently substituted by 1 to 3 of halogen, C 1~6 alkyl, or C 1~6 alkoxy, and may be optionally substituted, R a and R b each presence of which is independently hydrogen or C 1~6 alkyl, or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, the ring may optionally contain an additional 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by 1 to 3 identical or different groups selected from the group consisting of C1-4 alkyl, phenyl, and benzyl, n is 0, 1, or 2, p is independently 1, 2, ③, or 4 in each presence, t is 0, 1, 2, or 3. [[ID=①]]

[0082] [[ID=②]] [[ID=③]] In some embodiments, the compound of formula I comprises a compound of formula (III), TIFF2026086696000012.tif57128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein, X 1 is N, or CR 6a and is, Note: There seems to be a typo in the original text where "③" appears in "p is independently 1, 2, ③, or 4 in each presence" and "①", "②" in other parts which might be incorrect or incomplete notations. I've translated it as it is for the purpose of following the instruction. Z is either CH2 or O. L 1 CH2 may be substituted by a covalent bond or by one or two methyl groups. L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, R 1 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b , or a 4-6 member heterosilyl, or two R 1 The groups, together with the carbon atoms to which they bond, form a C=O group. R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or has two R's 7 The groups, together with the carbon atoms to which they are bonded, form a 3- to 5-membered cycloalkyl ring. R 9 and R 10 Each of these entities independently contains hydrogen, 1 to 4 R atoms. 11 C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5 to 7 member heterocyclyl rings, or R 9 and R 10 Along with the nitrogen atom to which they bond, there are 1 to 4 R 11 A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R 11In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 12 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~7 It is either cycloalkyl or has two R's 12 The groups, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkyl ring. R 13 In each existence, independently, C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R bTogether with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. p is independently 1, 2, 3, or 4 in each existence. q is independently 0, 1, 2, 3, or 4 in each existence. t is 0, 1, 2, or 3. w is 0 or 1, except L 1 If the bond is covalent, then the condition is that w is 1, and further, L 1 However, the condition is that w is 0 if the CH2 molecule may be substituted with 1 or 2 methyl groups.

[0083] In some embodiments, the compound of formula I is a compound of formula (IIIa) or (IIIaa), TIFF2026086696000013.tif53128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, X 1 is N, or CR 6a And, R 1 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, Halo C1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b , or a 4-6 member heterosilyl, or two R 1 The groups, together with the carbon atoms to which they bond, form a C=O group. R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or has two R's 7 The groups, together with the carbon atoms to which they are bonded, form a 3- to 5-membered cycloalkyl ring. R 9 and R 10 Each of these entities independently contains hydrogen, 1 to 4 R atoms. 11 C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R11 Replaced by (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5 to 7 member heterocyclyl rings, or R 9 and R 10 Along with the nitrogen atom to which they bond, there are 1 to 4 R 11 A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R in each existence 11 , independently, hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 12 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~7 It is either cycloalkyl or R 12 and R 12 Together with the carbon atoms to which they are bonded, they form a 3-6 membered cycloalkyl ring. R 13 In each existence, independently, hydrogen and C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. t is 0, 1, 2, or 3. p is independently 1, 2, 3, or 4 in each existence. q is independently 0, 1, 2, 3, or 4 in each existence.

[0084] In some embodiments, the compound of formula I is a compound of formula (IIIb) or (IIbb), TIFF2026086696000014.tif53128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3Provided that at least one of them is not a covalent bond, X 1 is N, or CR 6a And, R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 Each of these entities independently contains hydrogen and C. 1~4 Alkyl, C 3~5 It is either cycloalkyl or R 7 and R 7 Together with the carbon atoms to which they are bonded, they form a 3-5 membered cycloalkyl ring. R 9 and R 10 Each of these entities independently contains hydrogen, 1 to 4 R atoms. 11 C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R 11 Replaced by (CR 12 R 12 )q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5 to 7 member heterocyclyl rings, or R 9 and R 10 Along with the nitrogen atom to which they bond, there are 1 to 4 R 11 A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R 11 Each of these entities independently contains hydrogen and C. 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 12 Each of these entities independently contains hydrogen and C. 1~4 Alkyl, C 3~7It is either cycloalkyl or R 12 and R 12 Together with the carbon atoms to which they are bonded, they form a 3-6 membered cycloalkyl ring. R 13 In each existence, independently, hydrogen and C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. t is 0, 1, 2, or 3. p is independently 1, 2, 3, or 4 in each existence. q is independently 0, 1, 2, 3, or 4 in each existence.

[0085] In some embodiments, the compound of formula I is the compound of formula (IIIc) or (IIIcc), TIFF2026086696000015.tif53128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, X 1 is N, or CR6a And, R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~5 It is either cycloalkyl or R 7 and R 7 Together with the carbon atoms to which they are bonded, they form a 3-5 membered cycloalkyl ring. R 9 and R 10 Each of these entities independently contains hydrogen, 1 to 4 R atoms. 11 C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5 to 7 member heterocyclyl rings, or R 9 and R 10 Along with the nitrogen atom to which they bond, there are 1 to 4 R 11 A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R 11 In each existence, independently, hydrogen and C 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 12 In each existence, independently, hydrogen and C 1~4 Alkyl, C 3~7 It is either cycloalkyl or R 12 and R12 Together with the carbon atoms to which they are bonded, they form a 3-6 membered cycloalkyl ring. R 13 In each existence, independently, hydrogen and C 1~4 Alkyl, or C 3~5 It is a cycloalkyl, R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. t is 0, 1, 2, or 3. p is independently 1, 2, 3, or 4 in each existence. q is independently 0, 1, 2, 3, or 4 in each existence.

[0086] In some embodiments, the compound of formula I is the compound of formula (IIId) or (IIIdd), TIFF2026086696000016.tif56128 or its pharmaceutically acceptable salts, tautomers, or stereoisomers, During the ceremony, In formula (IIIdd), * represents a chiral center having an R or S configuration. L 2 is covalent or (CR 7 R 7 ) p And, L 3 is a covalent bond, O or NR 7 And, however, L 2 and L 3 Provided that at least one of them is not a covalent bond, X 1is N, or CR 6a And, R 1 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b , or a 4-6 member heterosilyl, or two R 1 The groups, together with the carbon atoms to which they bond, form a C=O group. R 5 In each of these entities, independently, hydrogen, halogen, and C 1~6 Alkyl, Halo C 1~6 alkyl, OH, C 1~6 alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, Halo C 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b And, R 6a is hydrogen or methyl, R 6 These are hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R 7 Each of these entities independently contains hydrogen and C. 1~4 Alkyl, C 3~5 It is either cycloalkyl or R 7 and R 7 Together with the carbon atoms to which they are bonded, they form a 3-5 membered cycloalkyl ring. R 9 and R 10 Each of these entities independently contains hydrogen, 1 to 4 R atoms. 11C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5 to 7 member heterocyclyl rings, or R 9 and R 10 Along with the nitrogen atom to which they bond, there are 1 to 4 R 11 A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R 11 Each of these entities independently contains hydrogen and C. 1~6 Alkyl, Halo C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxy groups. R 12 Each of these entities independently contains hydrogen and C. 1~4 Alkyl, C 3~7 It is either cycloalkyl or R 12 and R 12 Together with the carbon atoms to which they are bonded, they form a 3-6 membered cycloalkyl ring. R a and R b Each of these entities independently contains hydrogen or C 1~6 Alkyl or R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted by one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl. t is 0, 1, 2, or 3. p is independently 1, 2, 3, or 4 in each existence. q is independently 0, 1, 2, 3, or 4 in each existence.

[0087] In any embodiment, Z is CH2. In certain other embodiments, Z is O.

[0088] In any embodiment, L 1 It is a covalent bond. In certain other embodiments, L 1 This is a CH2 which may be substituted with 1 or 2 methyl groups. In other embodiments, L 1This is CH2.

[0089] In any embodiment, L 1 It is a covalent bond, and w is 1. In some other specific embodiments, L 1 w is a CH2 molecule which may be substituted with 1 or 2 methyl groups, and w is 0.

[0090] In any embodiment, R 1 Each of these entities is independently hydrogen. In certain other embodiments, R 1 Each of these entities is independently a halogen. In other embodiments, m is 2, and one of R 1 is hydrogen, and the other is R 1 is a halogen. In other embodiments, m is 2, and one of R is 1 is hydrogen, and the other is R 1 In other embodiments, R 1 Each of these entities is independently F.

[0091] In any embodiment, Y 2 N is Y 1 , Y 3 , and Y 4 Each of them independently performs CR 5 In certain other embodiments, Y 1 CR 5 Y 2 N is Y 3 and Y 4 Each of these is independently CH. In other embodiments, Y 1 CR 5 Y 2 N is Y 3 N is Y 4 It is CH.

[0092] In any embodiment, the parts in formulas (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), and (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), and (IIIdd) TIFF2026086696000017.tif21128 is, The filename is TIFF2026086696000018.tif21128.

[0093] In any embodiment, R 5 is methyl or ethyl. In certain other embodiments, R 5 This is CHF2 or CF3. In other embodiments, R 5 It is hydrogen or CN.

[0094] In any embodiment, t is 0. In a certain other embodiment, t is 1. In another embodiment, t is 2. In another embodiment, t is 3.

[0095] In any embodiment, X 1 is N and X 2 is N and X 3 , NR 6 In certain other embodiments, X 1 CH is, X 2 is N and X 3 , NR 6 In other embodiments, X 1 is O, and X 2 is N and X 3 CR 6 That is the case.

[0096] In any embodiment, R 6 is hydrogen. In certain other embodiments, R 6 R is methyl. In other embodiments, R 6 R is ethyl. In other embodiments, R 6 It is cyclopropyl.

[0097] In any embodiment, R 6a is hydrogen. In certain other embodiments, R 6a R is methyl. In other embodiments, R 6a R is ethyl. In other embodiments, R 6a It is cyclopropyl.

[0098] In any embodiment, L 2 It is a covalent bond. In certain other embodiments, L 2 (CR 7 R 7 ) p In other embodiments, L 2 This is CH2.

[0099] In any embodiment, L 3 It is a covalent bond. In certain other embodiments, L 3 In other embodiments, L 3 , NR 7 That is the case.

[0100] In any embodiment, R 7 Each of these entities is independently hydrogen. In certain other embodiments, R 7 Each of these entities is independently C 1~4 It is alkyl. In other embodiments, R 7 Each of these entities is independently C 3~5 It is a cycloalkyl. In other embodiments, R 7 Each of these entities is independently either hydrogen or methyl.

[0101] In any embodiment, q is 0. In a certain other embodiment, q is 1. In another embodiment, q is 2.

[0102] In any embodiment, R 8 COOH is.

[0103] In any embodiment, R 9 C1~4 It is alkyl. In certain other embodiments, R 9 R is methyl. In other embodiments, R 9 It is ethyl.

[0104] In any embodiment, R 10 This is 1 to 4 R 11 C replaced by 1~6 Alkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 2~6 Alkinyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q - Phenyl, 1-4 R 11 Replaced by (CR 12 R 12 ) q -5-6 member heteroaryl ring, 1-4 R 11 Replaced by (CR 12 R 12 ) q - It is a 5- to 7-membered heterocyclyl ring. 10 C 1~6 It is alkyl. 10 (CH2) p -C 3~7 It is a cycloalkyl. In other embodiments, R 9 and R 10 Along with the nitrogen atom to which they are bonded, there are 1 to 4 R 11The substituted saturated or unsaturated 3- to 7-membered heterorings are formed, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0105] In any embodiment, Q is C(=O)NR 9 R 10 In certain other embodiments, Q is a ring (also referred to herein as the "Q ring") selected from the group consisting of 5-membered heteroaryls, 5-membered heterocyclyls, 6-membered heteroaryls, and 6-membered heterocyclyls, the ring comprising at least one nitrogen atom on at least one carbon atom, and optionally 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the oxygen may be an oxo bonded to the ring member and / or to the ring member, and the ring is (R 3 ) n and R 4 It has been replaced by [this].

[0106] In any embodiment, Q is TIFF2026086696000019.tif57166, and each of them has (R) at any available carbon or nitrogen position. 3 ) n and one R 4 It has been replaced by [this].

[0107] In any embodiment, Q is at any available carbon position (R 3 ) n and one R 4 Replaced by The filename is TIFF2026086696000020.tif17128.

[0108] In any embodiment, Q is TIFF2026086696000021.tif65165, and each of them has (R at any available carbon or nitrogen position) 3 ) n and one R 4 It has been replaced by [this].

[0109] In any embodiment, R3 Each of these entities is independently hydrogen, halogen, or C 1~4 It is alkyl. In certain other embodiments, R 3 Each of these entities is independently C 1~4 It is alkyl. In other embodiments, R 3 Each of these entities is independently methyl.

[0110] In any embodiment, n is 0. In a certain other embodiment, n is 1. In another embodiment, n is 2.

[0111] In any embodiment, R 4 These are, independently, hydrogen and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, phenyl, (CH2) p -phenyl, O(CH2) p -phenyl, CN, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, C 2~6 Alkenil-C 3~7 Cycloalkyl, C 2~6 Alkinyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 It is a cycloalkyl group, and each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 of the alkoxys. In certain other embodiments, R 4 These are independently 1 to 4 R 11 (CH2) replaced by q -5-6 member heteroaryl rings, or 1-4 R groups 11 (CH2) replaced by q -It is a 5- to 7-membered heterocyclyl ring. In other embodiments, R 4 Independently, C 1~6 Alkyl, C 2~6Alkinyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, or C 2~6 Alkenil-C 3~7 It is a cycloalkyl group.

[0112] In any embodiment, R 11 Each of these entities is independently hydrogen. In certain other embodiments, R 11 Each of these entities is independently C 1~6 It is alkyl. In other embodiments, R 11 Each of these entities is independently C 1~6 It is an alkoxy. In other embodiments, R 11 Each of these entities is independently (CH2) p -C 1~6 In other embodiments, R 11 Each of these entities is independently phenyl. In other embodiments, R 11 Each of these entities is independently (CH2) p -Phenyl is used in other embodiments. 11 Each of these entities is independently C 3~7 It is a cycloalkyl. In other embodiments, R 11 Each of these entities is independently (CH2) p -C 3~7 It is a cycloalkyl. In other embodiments, R 11 Each of these entities is independently C 2~6 Alkinyl-C 3~7 It is a cycloalkyl. In other embodiments, R 11 Each of these entities is independently O(CH2) p -C 3~7 It is a cycloalkyl group. In any embodiment, each phenyl group is independently a halogen, C 1~6 Alkyl, or C 1~6 It may be substituted with 1 to 3 alkoxy groups.

[0113] In any embodiment, R12 Each of these entities is independently hydrogen. In certain other embodiments, R 12 Each of these entities is independently C 1~4 It is alkyl. In other embodiments, R 12 Each of these entities is independently C 3~7 It is a cycloalkyl. In other embodiments, R 12 and R 12 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkyl ring.

[0114] In any embodiment, R a and R b Each of these entities is independently hydrogen. In certain other embodiments, R a and R b Each of these entities is independently C 1~6 It is alkyl. In other embodiments, R 12 Each of these entities is independently C 3~7 It is a cycloalkyl. In other embodiments, R a and R b Together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may be substituted with one to three identical or different groups selected from the group consisting of C1 to C4 alkyl, phenyl, and benzyl.

[0115] In any embodiment, in formulas (II) and (III) The TIFF2026086696000022.tif23128 part is This is TIFF2026086696000023.tif23128. In certain other embodiments, the formulas (II) and (III) The TIFF2026086696000024.tif23128 part is The filename is TIFF2026086696000025.tif23128, and w is 1.

[0116] In any embodiment, R 13 is hydrogen. In certain other embodiments, R 13 R is methyl. In other embodiments, R 13 It is cyclopropyl.

[0117] In any embodiment, the compound is Selected from TIFF2026086696000026.tif119132.

[0118] In any embodiment, the compound is Selected from TIFF2026086696000027.tif126137.

[0119] In any embodiment, the compound is Selected from TIFF2026086696000028.tif113150.

[0120] In any embodiment, the compound is Selected from TIFF2026086696000029.tif102163.

[0121] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0122] In another embodiment, the present invention relates to a method for treating a subject in need of treatment for a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi), comprising administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the disease is pathological fibrosis (e.g., pulmonary, hepatic, renal, cardiac, cutaneous, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, or systemic sclerosis.

[0123] In another embodiment, the present invention relates to a process for producing compounds of formulas (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (III), (IIIa), (IIIaa), (IIIb), (IIIbb), (IIIc), (IIIcc), (IIId), and (IIIdd), including each of the exemplary compounds and intermediates described herein.

[0124] In any embodiment, the present invention is This concerns intermediates selected from TIFF2026086696000030.tif19128.

[0125] General synthesis methods The compounds of the present invention can be synthesized using the methods described herein, together with known synthetic methods in the field of synthetic organic chemistry, or in modified forms thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the exemplary schemes and working examples described below. All substituents are as defined above herein unless otherwise indicated. The reactions are carried out in solvents or solvent mixtures suitable for the reagents and materials used for the proposed transformations. This will often require modifying the order of the synthetic steps or making judgments to select a particular process scheme from others in order to obtain the desired compounds of the present invention.

[0126] Another key consideration in planning any synthetic route in this field will be recognized as the wise selection of protecting groups used to protect the reactive functional groups present in the compounds described in this invention. An authoritative explanation describing many alternatives for trained practitioners is provided by Greene et al., Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014). It will also be recognized that the names of the compounds mentioned in the descriptions of Schemes 1-12 are for convenience only and do not reflect the actual chemical names of those compounds.

[0127] Scheme 1 Scheme 1 of TIFF2026086696000031.tif90165 describes the synthesis of carbonyl azine azole N-heteroaryl azacyclohexylacetic acid 8. PG1 and PG2 represent protecting groups, respectively. 2 (CR 7 R 7 ) p (e.g., CH2). Haloadine derivative 1 is reacted with piperidine acetate ester 2 under Buckwald conditions by a suitable catalyst (e.g., Pd(OAc)2 / BINAP), a nucleophilic aromatic substitution reaction, or a Ullmann reaction to obtain the corresponding carbonyladine N-heteroaryl-piperidine acetate carboxylate 3. Deprotection of the protected hydroxylmethylazole 3 yields hydroxylmethylazole 4, which then reacts with MsCl (or PBr3) to obtain mesylate (or Br) 5. Treatment of mesylate (or Br) 5 with 2-hydroxyadine 6 in the presence of a suitable base (e.g., K2CO3, nucleophilic substitution reaction) yields the corresponding carbonyladine N-heteroaryl-piperidine acetate carboxylate 7, which then undergoes deprotection of the ester to obtain the desired carbonyladine L 2 -Azole N-heteroaryl-azacyclohexylacetic acid 8 is obtained.

[0128] Scheme 2 Scheme 2 of TIFF2026086696000032.tif83170 describes an alternative synthetic route to carbonylazine N-heteroaryl-azacyclohexylacetic acid 8. PG1 and PG2 represent protecting groups, respectively. 2 (CR 7 R 7 ) p (e.g., CH2). Deprotection of the protected hydroxymethylazole derivative 1 yields hydroxymethylazole 9, which is then reacted with MsCl (or PBr3) to obtain mesylate (or Br) 10. Treatment of mesylate (or Br) 10 with 2-hydroxyazine in the presence of a suitable base (e.g., K2CO3, nucleophilic substitution reaction) yields the corresponding N-substituted carbonylazine 11. Haloazine derivative 11 is reacted with piperidine acetate carboxylate under Buckwald conditions by a suitable catalyst (e.g., Pd(OAc)2 / BINAP), a nucleophilic aromatic substitution reaction, or an Ullmann reaction to obtain the corresponding piperidine acetate carboxylate 7, which is then deprotected from the ester to obtain the desired carbonylazine L 2 -Azole N-heteroaryl-azacyclohexylacetic acid 8 is obtained.

[0129] Scheme 3 Scheme 3 of TIFF2026086696000033.tif51164 describes the synthesis of N-substituted aza-heterocyclopentyl ketone N-heteroaryl-azacyclohexylacetic acid 13. In the presence of a suitable base (e.g., t-BuOK, nucleophilic substitution reaction), mesylate (or Br) 5 is treated with aza-heterocyclopentyl ketone 6a to obtain the corresponding N-substituted aza-cyclopentyl ketone 12, which is then deprotected by the ester to obtain the desired N-substituted aza-cyclopentyl ketone N-heteroaryl-azacyclohexylacetic acid 13.

[0130] Scheme 4 Scheme 4 of TIFF2026086696000034.tif52164 describes the synthesis of oxy-Q ring N-heteroaryl-azacyclohexylacetic acid 16, where Q represents a 5-membered heteroaryl or heterocyclyl, or a 6-membered heteroaryl or heterocyclyl. Base mediation of hydroxylmethylazole 4 with a suitable halo or methylsulfonyl-substituted Q ring 14 (where X is halo or methylsulfonyl) S N The Ar reaction yields oxy-Q ring N-heteroarylpiepridin acetate 15, which is then deprotected to obtain the desired oxy-Q ring N-heteroaryl-azacyclohexyl acetate 16.

[0131] Scheme 5 Scheme 5 of TIFF2026086696000035.tif86165 describes an alternative synthesis of oxy-Q ring N-heteroaryl-azacyclohexylacetic acid 16, where Q represents a 5-membered heteroaryl or heterocyclyl, or a 6-membered heteroaryl or heterocyclyl. Base-mediated synthesis of hydroxylmethylazole 9 with a suitable halo or methylsulfonyl-substituted Q ring 14 (where X is halo or methylsulfonyl) S N The Ar reaction yields the oxy-Q ring 17, which is then reacted with a piperidine ethyl ester derivative under Buckwald conditions using a catalyst (e.g., Pd(OAc)2 / BINAP), a nucleophilic aromatic substitution reaction, or a Ullmann reaction to obtain the corresponding oxy-Q ring N-heteroarylpiepridin acetate 15. Subsequently, the ester is deprotected to obtain the desired oxy-Q ring N-heteroaryl-azacyclohexylacetic acid 16.

[0132] Scheme 6 Scheme 6 of TIFF2026086696000036.tif93165 describes the synthesis of amino Q-ring N-heteroaryl-azacyclohexylacetic acid 21. Hydroxylmethylazole 4 is reacted with MsCl using a suitable base (e.g., TEA) to obtain the corresponding mesylate 17. Mesylate 17 is replaced with NaN3 (or other azide reagent) to obtain azide 18, which is then reduced (e.g., by Staudinger reduction with PPh3 / water) to obtain amine 19. Amine 19 is then reacted with a halo- or methylsulfonyl-substituted Q-ring 14 (where X is halo- or methylsulfonyl) in the presence of a suitable base or via Pd-catalyzed amination to obtain amino-azinpiepridin acetate 20, which is then deprotected to obtain the desired amino Q-ring N-heteroaryl-azacyclohexylacetic acid 21.

[0133] Scheme 7 Scheme 7 of TIFF2026086696000037.tif45164 describes the synthesis of oxy-azole N-heteroaryl-azacyclohexylacetic acid 24. Hydroxylmethylazole 4 is reacted (nucleophilic aromatic substitution) with a suitable haloazole or methylsulfonylazole 22 (which is a five-membered heteroaryl ring containing at least one nitrogen and potentially containing an additional 1 to 3 heteroatoms selected from N, O, and S) in the presence of a suitable base to obtain oxy-azole N-heteroarylpiepridin acetate 23, which is then deprotected to obtain the desired oxy-azole N-heteroaryl-azacyclohexylacetic acid 24.

[0134] Scheme 8 Scheme 8 of TIFF2026086696000038.tif94165 describes the synthesis of amino-azole N-heteroaryl-azacyclohexylacetic acid 28. Hydroxylmethylazole 4a is oxidized to the corresponding aldehyde 25 (e.g., by Dess-Martin periodinane or Swern oxidation). Aldehyde 25 is then subjected to reductive amination by a suitable amino-azole 26 (a five-membered heteroaryl ring containing at least one nitrogen and potentially containing an additional 1-3 heteroatoms selected from N, O, and S) to obtain amino-azole N-heteroarylpiepridin ethetic ester 27. Subsequent deprotection of ester 27 yields amino-azole N-heteroaryl-azacyclohexylacetic acid 28.

[0135] Scheme 9 Scheme 9 of TIFF2026086696000039.tif105157 describes the synthesis of alkylated triazole N-heteroaryl-azacyclohexylacetic acid 32. Alkylated triazole 30 is obtained by treating a mesylate or Br-substituted compound 10 with triazole 29 in the presence of a suitable base. Halo-azine 30 is then reacted with piperidine acetate 2 under Buckwald conditions using a suitable catalyst (e.g., Pd(OAc)2 / BINAP) to obtain the corresponding alkylated triazole N-heteroarylpiepridine acetate 31, which is then deprotected to obtain the desired alkylated triazole N-heteroaryl-azacyclohexylacetic acid 32.

[0136] Scheme 10 Scheme 10 of TIFF2026086696000040.tif112164 describes the synthesis of alkylated tetrazole N-heteroaryl-azacyclohexylacetic acid 36 and 37. Hydroxylmethylazole 4 is reacted with tetrazole 33 under Mitsunobu conditions to yield positional isomers tetrazole 34 and 35. Deprotected piepridin acetate 34 and 35 yield positional isomers alkylated tetrazole N-heteroaryl-azacyclohexylacetic acid 36 and 37.

[0137] Scheme 11 Scheme 11 of TIFF2026086696000041.tif121165 describes the synthesis of carbamoyloxymethylazole N-heteroaryl-azacyclohexylacetic acid 41. Hydroxylmethylazole 4 is reacted with 4-nitrophenyl chloroformate in the presence of a suitable base to obtain the corresponding 4-nitrophenyl carbonate 38, which is then reacted with amine 39 in the presence of a suitable base to obtain carbomate 40. Subsequent deprotection of ester 40 yields carbamoyloxymethylazole N-heteroaryl-azacyclohexylacetic acid 41.

[0138] Scheme 12 Scheme 12 describes the synthesis of 1-azinmethyl-piperidine-3-carboxylic acids 48, 49, and 50. By carbonyl insertion of azinmethyl 1 in methanol in the presence of CO gas and a suitable catalyst, azinmethyl carboxylate 42 is obtained, and then by reduction with a suitable reducing agent, azinmethyl alcohol 43 is obtained. By treatment of azinmethyl alcohol 43 with MsCl in the presence of a suitable base, the corresponding mesylate 44 is obtained. Alkylated piperidine carboxylate 45 by mesylate 44 in the presence of a suitable base yields azinmethyl-piperidine-3-carboxylate 46. By deprotection of azinmethyl-piperidine-3-carboxylate 46, hydroxylmethylazole 47 is obtained, and then, over several steps, by similar methods described herein, it is converted to the corresponding acids 48, 49, and 50.

[0139] Pharmaceutical compositions and methods Compounds used in the methods described herein may be formulated into a pharmaceutically acceptable composition together with a pharmaceutically acceptable carrier or adjuvant before administration to a subject. In another embodiment, such a pharmaceutically acceptable composition further comprises an additional therapeutic agent, including those described herein, in an amount effective to achieve the modulation of a disease or disease symptom.

[0140] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a subject together with the compound of the present invention, which does not destroy its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0141] Examples of pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in the pharmaceutical dosage form, such as Tween or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffers, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. Cyclodextrins, such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives, such as 2- and 3-hydroxypropyl-β-cyclodextrins, hydroxyalkylcyclodextrins, or other solubilized derivatives, may also be advantageously used to enhance the delivery of compounds of the formulas described herein.

[0142] The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, intraoral buccal, vaginally, or via an implanted reservoir, preferably by oral or injectable administration. The pharmaceutical compositions of the present invention may contain any conventional non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-bursal, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques.

[0143] Pharmaceutical compositions may be in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to known art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oils have conventionally been used as solvents or suspension media. For this purpose, any smooth fixative oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, particularly in their polyoxyethylated forms, are useful in the preparation of injectable preparations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose, or similar dispersing agents commonly used in formulations of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants, such as Tween or Span, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0144] The pharmaceutical compositions of the present invention include, but are not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions, and can be administered orally in any orally acceptable dosage form. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. Specific sweeteners and / or flavorings and / or colorings may be added as needed.

[0145] The pharmaceutical compositions of the present invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature, and therefore melt in the rectum to release the active components. Examples of such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0146] Topical administration of the pharmaceutical compositions of the present invention is useful when the desired treatment involves an area or organ that is easily reachable by topical application. For topical application to the skin, the pharmaceutical compositions should be formulated using a suitable ointment containing the active components suspended or dissolved in a carrier. Suitable carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical compositions may be formulated using a suitable lotion or cream containing the active compounds suspended or dissolved in a carrier together with a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention may also be applied topically to the lower intestinal tract by rectal suppository formulations or in suitable enema formulations. Topical transdermal patches are also included in the present invention.

[0147] The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared in accordance with well-known techniques in the field of pharmaceutical formulations, and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art.

[0148] If the composition of the present invention comprises a compound of the formula described herein in combination with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at a dosage level of about 1 to 100%, more preferably about 5 to 95%, of the dosage typically administered in a monotherapy regimen. The additional agents may be administered separately from the compound of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form and mixed together with the compound of the present invention in a single composition.

[0149] The compounds described herein may be administered, for example, by injection, intravenous, intra-arterial, subdermal, intraperitoneal, intramuscular, or subcutaneous, or orally, intraoral buccal, nasally, transmucosally, topically, in ophthalmic preparations, or by inhalation, in doses ranging from about 0.5 to about 100 mg / kg of body weight, alternatively 1 mg to 1000 mg / dose, or according to the requirements of the drug. The methods described herein are intended to administer an effective amount of the compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions of the present invention will be administered about 1 to about 6 times per day, or as continuous infusions. Such administration may be used as chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the mode of administration. Typical preparations will contain about 5% to about 95% (w / w) of the active compound. Alternatively, such preparations may contain approximately 20% to 80% of the active compound.

[0150] Lower or higher doses than those listed above may be required. Specific dosages and treatment regimens for any given subject will depend on a variety of factors, including the activity of the particular compound used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combinations, severity and progression of the disease, condition, or symptom, the subject's temperament to the disease, condition, or symptom, and the judgment of the treating physician.

[0151] To improve the condition of the subject, a maintenance dose of the compound, composition, or combination of the present invention may be administered as needed. The dosage, frequency, or both of these can then be reduced as a function of the symptoms to a level at which the improved condition is maintained when the symptoms are alleviated to the desired level. However, the subject may require long-term, intermittent treatment based on any recurrence of disease symptoms.

[0152] The above-mentioned pharmaceutical compositions comprising the compound of formula (I) may further comprise other therapeutic agents useful for treating diseases associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi). In particular, such combinations may be useful for treating pathological fibrosis (e.g., pulmonary, hepatic, renal, cardiac, cutaneous, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, or systemic sclerosis.

[0153] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. In the event of any conflict, this application, including any definition herein, shall prevail.

[0154] The examples herein illustrate the advantages of the Art and are provided to further assist those skilled in the art in preparing or using the compounds or salts thereof, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures, or tautomers of the Art. The examples herein are also presented to more fully illustrate preferred embodiments of the Art. The examples should never be construed as limiting the scope of the Art as defined by the appended claims. The examples may include or incorporate any of the above-described variations, embodiments, or forms of the Art. Each of the above-described variations, embodiments, or forms may also further include or incorporate any or all other variations, embodiments, or forms of the Art. [Examples]

[0155] The abbreviations used in this specification are as follows: TIFF2026086696000043.tif224154TIFF2026086696000044.tif123151

[0156] General conditions and procedures In the following examples, chemical reagents were purchased from commercially available sources (e.g., Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification. THF was continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen, and dichloromethane was continuously refluxed and freshly distilled from CaH2 under nitrogen.

[0157] Flash chromatography was performed in an Ez Purifier III via a column with 200–300 mesh silica gel particles. Analytical and preparative thin-layer chromatography plates (TLCs) were HSGF254 (0.15–0.2 mm thick, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were recorded using a Brucker AMX-300 or AMX-400 NMR (Brucker, Switzerland) at approximately 20–30°C unless otherwise specified. The following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; dd, doublet-doublet; ddd, doublet-doublet-doublet; dt, triplet-doublet; bs, broadband signal. Chemical shifts were reported in parts per million (ppm, δ) from tetramethylsilane to low field. Mass spectroscopy was performed by electrospray ionization (ESI) from a Waters LCT TOF mass spectrometer (Waters, USA). Compound purification was carried out using a variety of conventional methods, including, but not limited to, preparative chromatography using normal-phase or reverse-phase HPLC, flash columns, or Prep-TLC plates, as needed, under acidic, neutral, or basic conditions.

[0158] Preparative HPLC: Unless otherwise specified, compounds were purified using a WATERS Fractionlynx system with a YMC Pack Pro d8 column (5 μm, 120 A, 50 × 20 mm) and the following solvent systems: H2O, AcCN, and 2% TFA in H2O. Specific elution gradients were based on retention times obtained by analytical LC-MS; however, generally, all elution gradients for H2O and MeCN were performed over a 7-minute run at a flow rate of 35 mL / min. An autoblending method was used to ensure a 0.1% TFA concentration throughout each run. Specific elution gradients were based on retention times obtained by analytical LC-MS; however, generally, all elution gradients for H2O and MeCN were performed over an 8-minute run at a flow rate of 50 mL / min.

[0159] Analytical LC-MS was performed using a WATERS Acquity UPLC-MS instrument equipped with an ACQUITY UPLC BEH Ci8 column (2.1 × 50 mm, 1.7 μIη) at a column temperature of 45°C, and with the following solvent systems: Solvent A: 0.1% HCOOH in H2O, and Solvent B: 0.1% HCOOH in AcCN. All compounds were analyzed using the same elution gradient, i.e., 5% to 95% solvent B, at a flow rate of 0.6 mL / min for a run time of 1.5 minutes.

[0160] Preparative chiral SFC separation: Stereoisomer mixtures were separated using a Berger Minigram SFC instrument on one of the following columns: ChiralPak AS-H (10x250mm), ChiralPak IA (10x250mm), ChiralPak AD-H (21x250mm), Phenomenex Lux-2 (21.2x250mm), or ChiralPak IC (10x250mm). Elution was performed with 0.1% diethylamine in MeOH / CO2, 0.1% diethylamine in EtOH / CO2, or 0.1% diethylamine in isopropanol / CO2, using a flow rate of 2.5 mL / min and a column temperature of 35°C.

[0161] Analytical chiral SFC separation: Stereoisomer mixtures or single enantiomers were analyzed using a JASCO analytical SFC instrument on one of the following columns: ChiralPak AS-H (4.6x250mm), ChiralPak IA (4.6x250mm), ChiralPak AD-H (4.6x250mm), Phenomenex Lux-2 (4.6x250mm), or ChiralPak IC (4.6x250mm). Elution was performed using a flow rate of 6.0 ml / min and a column temperature of 35°C with either 0.1% diethylamine in MeOH / CO2, 0.1% diethylamine in EtOH / CO2, or 0.1% diethylamine in isopropanol / CO2.

[0162] Intermediate 1: 3-bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine TIFF2026086696000045.tif68128 Step 1: 3,6-Dibromo-2-ethylpyridine To a solution of 3,6-dibromo-2-methylpyridine (75 g, 0.299 mol) in THF (1 L), NaHMDS (180 mL, 0.36 mol, 2 M in THF) was added dropwise at -50°C, and the mixture was stirred at this temperature for 30 minutes. MeI (46.5 mL, 0.75 mol) was added to the above mixture, and the resulting mixture was stirred at -50°C to room temperature for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (500 mL) at 0°C and extracted with ₹ (2 x 500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by silica column chromatography (PE:DCM = 300:1~200:1) to obtain the title compound (47 g, yield 59.1%) as a yellow oil. 1H NMR (400 MHz, CD3OD) δ 7.61-7.59(d,J=8 Hz,1H),7.61-7.59(d,J=8.4 Hz,1H),2.94-2.88(q,2H),1.38-1.27(t,3H).

[0163] Step 2: 3-(5-bromo-6-ethylpyridine-2-yl)prop-2-in-1-ol To a solution of 3,6-dibromo-2-ethylpyridine (47 g, 0.177 mol) in THF (0.65 L), prop-2-in-1-ol (11.9 g, 0.212 mol), CuI (3.4 g, 17.7 mmol), DIPEA (35.1 mL, 0.212 mol), and Pd(PPh3)2Cl2 (12.4 g, 17.7 mmol) were added. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature under an N2 atmosphere for 16 hours. The mixture was diluted with SiO2 (500 mL) and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by silica column chromatography (DCM: SiO2 = 10:1 to 4:1) to obtain the title compound (40 g, yield 94.1%) as a brown solid. LC / MS(ESI)m / z:240 / 242(M+H) + .

[0164] Step 3: (4-(5-bromo-6-ethylpyridine-2-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole-5-yl)methanol To a solution of the intermediate 3-(5-bromo-6-ethylpyridine-2-yl)prop-2-in-1-ol (20 g, 0.083 mol) in THF (400 mL), chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II) (3.5 g, 4.16 mmol) and TMS-methyl azide (14 g, 0.108 mol) were added at 0°C under an N2 atmosphere. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 16 hours. The mixture was diluted with ELISA (500 mL) and filtered. The filtrate was concentrated until dry to obtain the crude product, which was pulverized with PE / ELISA (1000 mL, 10 / 1 v / v) to obtain the title compound (28 g, yield 91.3%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 8.03-8.01(d,J=8.4 Hz,1H),7.95-7.93(d,J=8.4 Hz,1H),6.77-6.74(t,J=6.8 Hz,1H),4.79-4.78(d,J=6.8 Hz,1H),3.80(s,3H),3.03-3.01(q,1H),1.34-1.30(t,J=7.6 Hz,3H),0.20(s,9H).

[0165] Step 4: (4-(5-bromo-6-ethylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol To a solution of (4-(5-bromo-6-ethylpyridine-2-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole-5-yl)methanol (25 g, 67.7 mmol) in THF (300 mL), TBAF (3 H2 O) (25.6 g, 81.2 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was diluted with RINKAN (500 mL), washed with saturated NH4Cl aqueous solution (3 × 50 mL) and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by silica column chromatography (DCM: RINKAN = 8:1~4:1) to obtain the title compound (19 g, yield 94.4%) as a gray solid. LC / MS (ESI) m / z: 297 / 299 (M+H) + .

[0166] Step 5: 3-Bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine A mixture of (4-(5-bromo-6-ethylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol (25 g, 0.084 mol) and TosOH (2.2 g, 12.6 mmol) in DCM (300 mL) was mixed with DHP (10.6 g, 0.126 mol) at 0°C, and the mixture was stirred at room temperature for 16 hours. The mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by silica column chromatography (DCM: Â=8:1) to obtain the title compound (30 g, yield 93.6%) as a yellow solid. LC / MS (ESI) m / z: 381 / 383 (M+H) + . 1 H NMR(400 MHz,CDCl3)δ 7.91(d,J=8.3 Hz,1H),7.86(d,J=8.3 Hz,1H),5.36(dd,J=36.5,12.8 Hz,2H),4.75-4.67(m,1H),4.16(s,3H),3.88-3.80(m,1H),3.55-3.46(m,1H),3.00(q,J=7.5 Hz,2H),1.84-1.67(m,2H),1.65-1.58(m,2H),1.54-1.45(m,2H),1.34(t,J=7.5 Hz,3H).

[0167] Intermediate 2: 3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine Intermediate 2 was synthesized in the same order as the intermediate 1 used in the synthesis of TIFF2026086696000046.tif29128. LC / MS(ESI) m / z:367 / 369(M+H) + . 1H NMR(400 MHz,CDCl3)δ 7.73(d,J=8.3 Hz,1H),7.69(d,J=8.3 Hz,1H),5.15(q,J=12.7 Hz,2H),4.61-4.54(m,1H),3.99(s,3H),3.74-3.64(m,1H),3.38-3.30(m, 1H), 2.51 (s, 3H), 1.66-1.50 (m, 2H), 1.46-1.40 (m, 2H), 1.39-1.32 (m, 2H).

[0168] Intermediate 3: (4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol TIFF2026086696000047.tif30135 Step 1: 2-Ethyl-3-iodo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine To a mixture of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazole-4-yl}pyridine (7.2 g, 18.9 mmol) and NaI (14.2 g, 94.4 mmol) in 1,4-dioxane (80 mL), N1,N2-dimethylethane-1,2-diamine (1.55 g, 11.3 mmol) and CuI (1.80 g, 9.44 mmol) were added. The mixture was degassed three times under an N2 atmosphere and stirred at 110°C for 20 hours. The mixture was filtered, and the filter cake was washed with ELISA (2 × 50 mL). The combined filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry to obtain the crude product. The crude product was purified by silica gel chromatography (PE:SiO = 4:1 to 1:1) to obtain the title compound (6.1 g, 74.2%) as a pale yellow solid. LC / MS (ESI) (m / z): 429 (M+H) + . 1H NMR(400 MHz,CDCl3)δ 8.11-8.09(d,J=8.4 Hz,1H),7.75-7.73(d,J=8.3 Hz,1H),5.42-5.29(q,J=12.7 Hz,2H),4.72-4.70(m,1H),4.16(s,3H),3.84-3.82(m,1H),3.56-3.49(m,1H),3.02-2.97(q,J=7.2 2H),1.63-1.59(m,2H),1.56-1.53(m,4H),1.34-1.30(t,J=7.6 Hz,3H).

[0169] Step 2: (4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol (6) To a solution of 2-ethyl-3-iodo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine (1.0 g, 2.34 mmol) in MeOH (10 mL), PPTS (0.59 g, 2.34 mmol) was added, and the mixture was stirred at 60°C for 16 hours. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:ethyl = 20:1 to 2:1) to obtain the title compound (698 mg, yield 86.9%) as a white solid. LC / MS (ESI) m / z: 345 (M+H) + .

[0170] Intermediate 4: 5-bromo-4-ethyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole-4-yl)pyrimidine TIFF2026086696000048.tif33137 Step 1: 5-Bromo-2-chloro-4-ethylpyrimidine To a solution of 5-bromo-2-chloropyrimidine (60 g, 0.31 mol) in THF (600 mL), EtMgCl (186 mL, 0.37 mol, 2 M in THF) was added dropwise at 10°C under an N2 atmosphere, and the resulting mixture was stirred at this temperature for 1 hour. TEA (43 mL, 0.31 mol) was added dropwise to the mixture at 0°C under an N2 atmosphere. After stirring at 0°C for 20 minutes, a solution of iodine (79.0 g, 0.31 mol) in THF (120 mL) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction products were quenched with water and extracted with SiO2 (2 × 300 mL). The combined organic layers were washed with saturated Na2SO3 aqueous solution and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel column chromatography (Â:PE = 0-200:1) to obtain the title compound (35.3 g, yield 51.4%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 2.89-2.83 (q, J = 7.5 Hz, 2H), 1.22-1.18 (t, J = 7.5 Hz, 3H).

[0171] Step 2: 5-bromo-4-ethyl-2-iodopyrimidine To a solution of 5-bromo-2-chloro-4-ethylpyrimidine (20 g, 0.09 mol) in DCM (50 mL), aqueous solution HI (200 mL, 57 wt%) was added dropwise, followed by the dropwise addition of NaI (30 g, 0.2 mol) at 0°C. The mixture was stirred at 5°C for 16 hours. The reaction mixture was quenched with saturated aqueous solution of Na2S2O3 (100 mL) and extracted using DCM (2 × 200 mL). The combined organic layers were concentrated under reduced pressure to obtain a colorless residue. The resulting residue was purified by silica gel column chromatography (PE:HCl = 4:1) to obtain the title compound (25.3 g, yield 89.8%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 2.82-2.75 (q, J = 7.5 Hz, 2H), 1.19-1.16 (t, J = 7.5 Hz, 3H).

[0172] Step 3: 5-bromo-4-ethyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole-4-yl)pyrimidine To a solution of 5-bromo-4-ethyl-2-iodopyrimidine (17.5 g, 55.9 mmol) and 1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.8 g, 46.6 mmol, prepared as per WO2014 / 081619) in 1,4-dioxane (300 mL) and water (60 mL), Na2CO3 (9.9 g, 93.2 mmol) and Pd(dppf)Cl2 (1.7 g, 2.3 mmol) were added all at once under an N2 atmosphere. The mixture was degassed three times under N2 and stirred at 75°C for 16 hours under an N2 atmosphere. The mixture was poured into ice water and extracted using DCM (2 × 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure until dry. The resulting residue was purified by silica gel chromatography (PE:HCl=10:1) to obtain the title compound (12.7 g, 59.6% yield) as a yellow solid. LC / MS(ESI) m / z:381 / 383(M+H) + . 1 H NMR(400 MHz,DMSO-d6)δ 8.80(s,1H),8.01(s,1H),5.32-5.29(d,J=12 Hz,1H),5.14-5.11(d,J=12 Hz,1H),4.73-4.69(m,1H),3.90(s,3H),3.79-3.72(m,1H),3.45-3.41(m,1H),2.88-2.83(q,J=7.4 Hz,2H),1.68-1.55(m,2H),1.55-1.42(m,4H),1.28-1.24(t,J=7.5 Hz,3H).

[0173] Intermediate 5: Methyl(S)-2-(5,5-difluoropiperidine-3-yl)acetate (Intermediate 5A) TIFF2026086696000049.tif58148 Step 1: Benzyl 5-(2-diazoacetyl)-3,3-difluoropiperidine-1-carboxylate To a solution of 1-((benzyloxy)carbonyl)-5,5-difluoropiperidine-3-carboxylic acid (51 g, 0.17 mol) in DCM (500 mL), DMF (2 mL) was added, followed by the dropwise addition of (COCl)2 (43 g, 0.34 mol) at 0°C. The mixture was stirred at 0°C to room temperature for 2 hours. The reaction mixture was concentrated until dry, and the residue was evaporated three times with toluene. The residue was dissolved in THF (500 mL), and TMSCHN2 solution (250 mL, 0.5 mol, 2 M in hexane) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with AcOH (60 mL) at 0°C, and the mixture was concentrated until dry to obtain the title compound (55 g, 100% yield) as a yellow oil, which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 324 (M + H) + .

[0174] Step 2: Benzyl(S)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (3A) and benzyl(R)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (3B) To a solution of benzyl 5-(2-diazoacetyl)-3,3-difluoropiperidine-1-carboxylate (55 g, 0.17 mol) in MeOH (500 mL), CF3COOAg (7.4 g, 0.03 mol) and TEA (67.6 g, 0.67 mol) were added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated until dry, and the residue was purified by silica gel chromatography (PE:HCl=3:1) to obtain the title compound (37 g, yield 62.9%) as a pale yellow oil. LC / MS (ESI) m / z: 328 (M+H) +The two enantiomers were separated by chiral SFC to obtain benzyl(S)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (peak 2, retention time: 4.414 mins) (13.8 g, yield 24.8%) and benzyl(R)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (peak 1, retention time: 4.109 mins) (16.1 g, yield 28.9%) as pale yellow oils. 1 ¹H NMR (400 MHz, CDCl3) δ 7.41-7.28 (m, 5H), 5.15 (s, 2H), 4.25-3.94 (m, 2H), 3.66 (d, J=25.3 Hz, 3H), 3.30-3.12 (m, 1H), 2.91-2.67 (m, 1H), 2.42-2.23 (m, 4H), 1.75-1.60 (m, 1H). SFC conditions: Column: ChiralPak IC-H, 250 × 4.6 mm inner diameter, 5 μm; Mobile phase: A for CO2, and B (0.05% NH4OH) for methanol; Gradient: B 5%~40%; Flow rate: 50 mL / min;

[0175] Step 3: Methyl(S)-2-(5,5-difluoropiperidine-3-yl)acetate To a solution of benzyl(S)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (4.2 g, 12.83 mmol) in  (40 mL), Pd / C (300 mg, 10 wt%) was added at 0°C. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 2 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (2.37 g, 95.6%) as an off-white solid. LC / MS (ESI) (m / z): 194 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.18-3.06 (m, 2H), 2.85-2.65 (m, 1H), 2.36-2.20 (m, 5H), 1.62-1.48 (m, 1H).

[0176] Intermediate 6: Methyl(R)-2-(5,5-difluoropiperidine-3-yl)acetate The title compound was prepared from benzyl(R)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate using the same procedure as for methyl(S)-2-(5,5-difluoropiperidine-3-yl)acetate. LC / MS(ESI)(m / z):194(M+H) + .

[0177] Intermediate 7: Methyl(S)-2-(5,5-difluoro-1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)piperidine-3-yl)acetate TIFF2026086696000051.tif37128 Step 1: 2-((3S)-5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid To a mixture of 3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine (1.5 g, 4.1 mmol) and methyl(S)-2-(5,5-difluoropiperidine-3-yl)acetate (790 mg, 4.1 mmol) in dried 1,4-dioxane (30 mL), Cs2CO3 (2.66 g, 8.2 mmol), RuPhos (381 mg, 0.82 mmol), and RuPhos-Pd-G3 (342 mg, 0.41 mmol) were added under an N2 atmosphere. The mixture was degassed three times under an N2 atmosphere and stirred at 100°C for 16 hours under an N2 atmosphere. The mixture was filtered and the filtrate was concentrated until dry. The residue was purified by flash chromatography (0-50% ethyl acetate in PE) to obtain the title compound (1.6 g, yield 81.7%) as a pale yellow solid. LC / MS (ESI) m / z: 480 (M+H) + . 1H NMR(400 MHz,CDCl3)δ 7.97(d,J=8.3 Hz,1H),7.33(d,J=8.3 Hz,1H),5.38-5.26(m,2H),4.77(t,J=3.2 Hz,1H),4.15(s,3H),3.92-3.85(m,1H),3.70(s,3H),3.57-3.50(m,1H),3.32-3.22(m,2H),3.03-2.93(m,1H),2.63-2.53(m,2H) ,2.57(s,3H),2.44-2.41(m,2H),2.35-2.25(m,1H),1.84-1.77(m,1H),1.75-1.67(m,2H),1.62-1.55(m,2H),1.54-1.45(m,2H).

[0178] Step 2: Methyl(S)-2-(5,5-difluoro-1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine-3-yl)piperidine-3-yl)acetate To a solution of methyl 2-((3S)-5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (1.6 g, 3.3 mmol) in MeOH (20 mL), PPTS (1.6 g, 6.6 mmol) was added, and the mixture was stirred at 50°C for 16 hours. The mixture was concentrated until dry, and the residue was dissolved in ELISA (20 mL). The mixture was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-60% ELISA in PE) to obtain the title compound (1.2 g, yield 90.0%) as a pale yellow solid. LC / MS(ESI)m / z:396(M+H) + . 1H NMR(400 MHz,CDCl3)δ 8.11(d,J=8.4 Hz,1H),7.44(d,J=8.4 Hz,1H),4.82(s,2H),4.08(s,3H),3.70(s,3H),3.36-3.21(m,2H),3.06-2.96(m,1H),2 .65-2.56(m,2H),2.61(s,3H),2.46-2.40(m,2H),2.37-2.28(m,1H),1.78-1.70(m,1H).

[0179] Intermediate 8: Methyl(S)-2-(1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate Intermediate 8 was synthesized in the same order as used for the synthesis of intermediate 7. (TIFF2026086696000052.tif39128) + . 1 H NMR(400 MHz,CDCl3)δ 8.12(d,J=8.4 Hz,1H),7.48(d,J=8.4 Hz,1H),4.84(s,2H),4.08(s,3H),3.70(s,3H),3.30-3.17(m,2H),3.07-2.99(m,1H),2.99-2.93( m,2H),2.63-2.58(m,2H),2.48-2.38(m,2H),2.36-2.28(m,1H),1.74-1.63(m,1H),1.34(t,J=7.5 Hz,3H).

[0180] Intermediate 9: Methyl(S)-2-(1-(4-ethyl-2-(5-(hydroxymethyl)-1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)-5,5-difluoropiperidine-3-yl)acetate TIFF2026086696000053.tif38128 Step 1: Methyl 2-((3S)-5,5-difluoro-1-(4-methyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole-4-yl)pyrimidine-5-yl)piperidine-3-yl)acetate To a solution of 5-bromo-4-ethyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole-4-yl)pyrimidine (420 mg, 1.1 mmol) in toluene (5 mL), methyl(S)-2-(5,5-difluoropiperidine-3-yl)acetate (212 mg, 1.1 mmol) was added, followed by the addition of Cs2CO3 (710 mg, 2.2 mmol), BINAP (135 mg, 0.20 mmol), and Pd(OAc)2 (49 mg, 0.22 mmol) under an N2 atmosphere. The reaction mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The mixture was diluted with ELISA (10 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-50% ethyl acetate in PE) to obtain the title compound (160 mg, 28.7% yield) as a yellow oil. LC-MS(ESI) m / z 494(M+H) + .

[0181] Step 2: Methyl(S)-2-(1-(4-ethyl-2-(5-(hydroxymethyl)-1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)-5,5-difluoropiperidine-3-yl)acetate Intermediate 9 was synthesized following the same sequence as used in the synthesis of intermediate 5. LC / MS(ESI)m / z:410(M+H) + .

[0182] Intermediate 10: Ethyl(R)-2-(1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine-3-yl)piperidine-3-yl)acetate Intermediate 10 was synthesized from commercially available ethyl(R)-2-(piperidine-3-yl)acetate following the same sequence used in the synthesis of intermediate 7. LC / MS(ESI)m / z:374(M+H) + . 1H NMR(400 MHz,CDCl3)δ 8.07(d,J=8.4 Hz,1H),7.43(d,J=8.4 Hz,1H),4.81(s,2H),4.14(q,J=7.1 Hz,2H),4.07(s,3H),3.21-3.14(m,1H),3.09-3.02(m,1H),2.72-2.67(m,1H),2.57(s,3H) ,2.48-2.39(m,1H),2.35-2.26(m,3H),1.93-1.86(m,1H),1.84-1.68(m,2H),1.26(t,J=7.1 Hz,3H),1.23-1.15(m,1H).

[0183] Intermediate 11: Ethyl(R)-2-(1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate Intermediate 11 was synthesized from commercially available ethyl(R)-2-(piperidine-3-yl)acetate following the same sequence used in the synthesis of intermediate 7. LC / MS(ESI)m / z:388(M+H) + . 1 H NMR(400 MHz,CDCl3)δ 8.09(d,J=8.4 Hz,1H),7.47(d,J=8.4 Hz,1H),4.83(s,2H),4.14(q,J=7.5 Hz,2H),4.08(d,J=6.8 Hz,3H),3.12(d,J=10.8 Hz,1H),3.05-2.98(m,1H),2.92(q,J=7.5 Hz,2H),2.73-2.67(m,1H),2.50-2.40(m,1H),2.35-2.25(m,3H),1.95-1.85(m,1H),1.84-1.80(m,1H),1.79-1.71(m,1H),1.33(t,J=7.5 Hz,3H),1.26(t,J=7.5,0.7 Hz,3H),1.23-1.13(m,1H).

[0184] Intermediate 12: Methyl 5,5-difluoro-1-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine-3-yl)methyl)piperidine-3-carboxylate TIFF2026086696000056.tif79144 Step 1: Methyl 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)nicotinate To a solution of 3-bromo-2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazole-4-yl}pyridine (5.0 g, 13.6 mmol) in MeOH (50 mL), TEA (9.5 mL, 68.1 mmol) was added, followed by Pd(dppf)Cl2 (1.0 g, 1.4 mmol). The mixture was degassed three times under an N2 atmosphere and stirred at 70°C for 16 hours under 60 psi of CO gas. The mixture was filtered through a Celite pad, and the filtrate was concentrated until dry. The residue was purified by flash chromatography (0-50% ethyl phosphate in PE) to obtain the title compound (3.8 g, yield 80.6%) as a yellow solid. LC-MS(ESI) m / z 347(M+H) + . 1 H NMR(400 MHz,CDCl3)δ 8.28(d,J=8.2 Hz,1H),8.10(d,J=8.2 Hz,1H),5.39(dd,J=29.2,12.7 Hz,2H),4.77-4.75(m,1H),4.17(s,3H),3.93(s,3H),3.90-3.83(m,1H),3.55-3. 50(m,1H),2.86(s,3H),1.84-1.66(m,2H),1.65-1.57(m,2H),1.55-1.48(m,2H).

[0185] Step 2: (2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)methanol To a solution of methyl 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)nicotinate (1.50 g, 4.33 mmol) in THF (20 mL), LiBH4 (5.20 mL, 10.40 mmol, 2 M in THF) was added dropwise at 0°C. After addition, the mixture was stirred at 55°C for 3 hours. The mixture was poured into a saturated NH4Cl aqueous solution and extracted with ELISA (2 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash chromatography (0-50% ELISA in PE) to obtain the title compound (1.3 g, yield 94.3%) as a pale yellow solid. LC / MS(ESI)(m / z):319(M+H) + . 1 H NMR(400 MHz,CDCl3)δ 8.00(d,J=7.9 Hz,1H),7.74(d,J=8.0 Hz,1H),5.34(dd,J=33.4,12.6 Hz,2H),4.80-4.75(m,1H),4.74(s,2H),4.16(s,3H),3.92-3.84(m,1H) ,3.55-3.48(m,1H),2.57(s,3H),1.82-1.71(m,2H),1.58-1.48(m,4H).

[0186] Step 3: 3-(chloromethyl)-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine To a solution of (2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)methanol (1.3 g, 4.1 mmol) in DCM (30 mL), TEA (1.7 mL, 12.25 mmol) was added, followed by dropwise addition of MsCl (0.70 g, 6.1 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash chromatography (0-50% butyl in PE) to obtain the title compound (1.7 g, yield 87.3%) as a yellow solid. LC / MS(ESI)(m / z):367(M+H) + . 1 H NMR(400 MHz,CDCl3)δ 8.03(d,J=8.0 Hz,1H),7.68(d,J=8.0 Hz,1H),5.35(dd,J=33.2,12.7 Hz,2H),4.80-4.73(m,1H),4.62(s,2H),4.16(s,3H),3.93-3.82(m,1H) ,3.56-3.42(m,1H),2.66(s,3H),1.81-1.67(m,2H),1.61-1.49(m,4H).

[0187] Step 4: Methyl 5,5-difluoro-1-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)methyl)piperidine-3-carboxylate To a solution of 3-(chloromethyl)-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine (935 mg, 2.78 mmol) in CH3CN (20 mL), methyl 5,5-difluoropiperidine-3-carboxylate (994 mg, 3.6 mmol) was added, followed by the addition of DIPEA (1.2 mL, 7.1 mmol), and the reaction mixture was stirred at 80°C for 3.5 hours. The mixture was diluted with RINKAN (10 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash chromatography (0-50% RINKAN in PE) to obtain the title compound (800 mg, yield 60.1%) as a yellow oil. LC / MS(ESI)(m / z):480(M+H) + . 1 H NMR(400 MHz,CDCl3)δ 7.98(d,J=7.9 Hz,1H),7.62(d,J=7.9 Hz,1H),5.43-5.30(m,2H),4.78-4.76(m,1H),4.15(s,3H),3.93-3.85(m, 1H),3.68(s,3H),3.65-3.57(m,2H),3.56-3.49(m,1H),3.12-3.01(m,2H) ,2.92-2.85(m,1H),2.81-2.75(m,1H),2.58(s,3H),2.42-2.35(m,1H),2. 32-2.22(m,1H),1.93-1.86(m,1H),1.82-1.66(m,2H),1.62-1.48(m,4H).

[0188] Step 5: Methyl 5,5-difluoro-1-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine-3-yl)methyl)piperidine-3-carboxylate To a solution of methyl 5,5-difluoro-1-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)methyl)piperidine-3-carboxylate (800 mg, 1.67 mmol) in MeOH (15 ml), PPTS (0.84 g, 3.34 mmol) was added, and the reaction mixture was stirred at 50°C for 16 hours. The mixture was concentrated until dry, and the residue was diluted with ELISA (10 mL). The mixture was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-60% ELISA in PE) to obtain the title compound (620 mg, yield 94.0%) as a yellow oil. LC / MS(ESI)(m / z):396(M+H) + . 1 H NMR(400 MHz,CDCl3)δ 8.14(d,J=8.0 Hz,1H),7.73(d,J=8.0 Hz,1H),4.85(s,2H),4.09(s,3H),3.69(s,3H),3.62(d,J=3.2 Hz,2H),3.12-2.97(m,2H),2.95-2.83(m,1H),2.62(s,3H),2.48-2.38(m,2H),2.34-2.28(m,1H),2.03-1.86(m,1H).

[0189] Intermediate 13: Methyl 1-((2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)methyl)-5,5-difluoropiperidine-3-carboxylate The title compound was prepared from 3-bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine using the same sequence as in the synthesis of intermediate 12. LC / MS(ESI)(m / z):410(M+H) + . 1H NMR(400 MHz,CDCl3)δ 8.13(d,J=8.0 Hz,1H),7.75(d,J=8.0 Hz,1H),4.85(s,2H),4.10(s,3H),3.69(s,3H),3.64(s,2H),3.12-3.00(m,2H),2.94-2.88(m,2H),2.44-2.37(m,2H),2.33-2.27 m,1H),2.07-1.86(m,2H),1.31(t,J=7.6 Hz,3H).

[0190] Intermediate 14: 4-(cyclopropylmethyl)-3-methylpyridine-2(1H)-one TIFF2026086696000058.tif26133 Step 1: Cyclopropyl(2-fluoro-3-methylpyridine-4-yl)methanol To a solution of 2-fluoro-4-iodo-3-methylpyridine (4 g, 16.9 mmol) in THF (40 mL), i-Pr-MgCl (16.9 mmol, 8.4 mL, 2 M in THF) was added dropwise under N2 at 0°C, and the mixture was stirred at room temperature for 1 hour. Cyclopropanecarboxyl (1.18 g, 16.9 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice water (20 mL) and extracted with SiO2 (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:SiO2 = 100:1 to 10:1) to obtain the title compound (2.37 g, yield 77.6%) as a colorless oil. LC / MS (ESI) m / z: 182 (M + H) + .

[0191] Step 2: 4-(cyclopropylmethyl)-2-fluoro-3-methylpyridine To a solution of cyclopropyl(2-fluoro-3-methylpyridine-4-yl)methanol (810 mg, 4.47 mmol) in CH3CN (8 mL), NaI (2.68 g, 17.9 mmol) and TFA (2.61 g, 22.4 mmol) were added. Subsequently, Et3SiH (2.60 g, 22.4 mmol) was added dropwise at 0°C under an N2 atmosphere, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted with SiO2 (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:SiO2 = 100:1 to 10:1) to obtain the title compound (420 mg, yield 56.9%) as a colorless oil. LC / MS(ESI)m / z:166(M+H) + .

[0192] Step 3: 4-(cyclopropylmethyl)-3-methylpyridine-2(1H)-one To a solution of 4-(cyclopropylmethyl)-2-fluoro-3-methylpyridine (420 mg, 2.54 mmol) in 1,4-dioxane (4.2 mL) and water (4.2 mL), aqueous HCl (0.84 mL, 36 wt%) was added, and the mixture was stirred at 100°C for 16 hours. The mixture was diluted with water and extracted using DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:HCl = 20:1 to 2:1) to obtain the title compound (322 mg, yield 77.6%) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 11.13(s,1H),6.95(d,J=6.8 Hz,1H),5.97(d,J=6.8 Hz,1H),2.19(d,J=6.8 Hz,2H),1.75(s,3H),0.78-0.67(m,1H),0.32-0.23(m,2H),0.02--0.04(m,2H). LC / MS(ESI)m / z:164(M+H) + .

[0193] Intermediate 15: 4-(cyclopropylmethyl)-3-methylpyridine-2(1H)-one TIFF2026086696000059.tif23137 Step 1: 5-Allyl-2-methoxypyridine To a solution of 5-bromo-2-methoxypyridine (4.2 g, 22.3 mmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.63 g, 33.5 mmol) in 1,4-dioxane (42 mL) and water (8.4 mL), K3PO4 (14.23 g, 67.0 mmol) and Pd(dppf)Cl2 (1.63 g, 2.23 mmol) were added under an N2 atmosphere. The mixture was degassed three times under an N2 atmosphere and stirred at 100°C for 2 hours under an N2 atmosphere. The mixture was diluted with RINKAN (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (elution using PE:HCl = 50:1 to 10:1) to obtain the title compound (3 g, 90% yield) as a pale yellow oil. LC / MS (ESI) m / z: 150 (M+H) + .

[0194] Step 2: 2-Methoxy-5-propylpyridine To a solution of 5-allyl-2-methoxypyridine (3 g, 20.1 mmol) in MeOH (30 mL), Pd(OH)2 / C (0.28 g, 10 wt%) was added under an N2 atmosphere. After addition, the mixture was degassed three times under an N2 atmosphere and stirred at 25°C for 16 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (2.74 g, yield 90.1%) as a colorless oil, which was used directly in the next step. LC / MS (ESI) m / z: 152 (M+H) + .

[0195] Step 3: 5-Propylpyridine-2(1H)-one(4) To a solution of 2-methoxy-5-propylpyridine (2.74 g, 18.12 mmol) in EtOH (27 mL), HBr aqueous solution (27 mL, 40 wt%) was added, and the mixture was stirred at 85°C for 16 hours. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted using DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:siRNA = 10:1 to 1:1) to obtain the title compound (723 mg, yield 29.1%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 13.21(s,1H),7.35(dd,J=9.2,2.5 Hz,1H),7.14(d,J=2.2 Hz,1H),6.55(d,J=9.2 Hz,1H),2.35(t,J=7.6 Hz, 1H), 1.60-1.48 (m, 1H), 0.92 (t, J=7.2 Hz, 2H). LC / MS(ESI)m / z:138(M+H) + .

[0196] Intermediate 16: 5-(cyclopropylmethyl)pyridine-2(1H)-one TIFF2026086696000060.tif53128 Step 1: N'-[(1E)-cyclopropylmethylidene]-4-methylbenzene-1-sulfonohydrazide To a solution of 4-methylbenzene-1-sulfonohydrazide (1 g, 5.4 mmol) in MeOH (10 mL), cyclopropanecarbaldehyde (0.40 mL, 5.4 mmol) was added dropwise at 0°C, and the mixture was stirred at 70°C for 10 minutes. The mixture was concentrated until dry, and the residue was purified by flash chromatography (0-40% siRNA in PE) to obtain the title compound (1.1 g, yield 86.0%) as a white solid. LC-MS (ESI) m / z 239(M+H) + .

[0197] Step 2: 5-(cyclopropylmethyl)-2-methoxypyridine A mixture of N'-[(1E)-cyclopropylmethylidene]-4-methylbenzene-1-sulfonohydrazide (1 g, 4.2 mmol) and (6-methoxypyridine-3-yl)boronic acid (0.64 g, 4.2 mmol) in 1,4-dioxane (10 mL) was mixed with K2CO3 (580 mg, 4.2 mmol), and the mixture was stirred at 110°C for 16 hours. The mixture was diluted with ELISA (15 mL), washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-5% ELISA in PE) to obtain 5-(cyclopropylmethyl)-2-methoxypyridine (210 mg, yield 30.7%) as a colorless oil. LC-MS(ESI) m / z 164(M+H) + . 1 H NMR(400 MHz,CDCl3)δ 8.03(d,J=1.9 Hz,1H),7.48(dd,J=8.4,1.9 Hz,1H),6.68(d,J=8.4 Hz,1H),3.92(s,3H),2.46(d,J=6.9 Hz,2H),1.01-0.84(m,1H),0.57-0.46(m,2H),0.20-0.17(m,2H).

[0198] Step 3: 5-(cyclopropylmethyl)pyridine-2(1H)-one To a mixture of 5-(cyclopropylmethyl)-2-methoxypyridine (200 mg, 1.2 mmol) in MeCN (5 mL), NaI (367 mg, 2.5 mmol) and TMSCl (0.31 mL, 2.5 mmol) were added, and the reaction mixture was stirred at 70°C for 16 hours. The mixture was diluted with ethyl acetate (5 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-50% ethyl acetate in PE) to obtain 5-(cyclopropylmethyl)pyridine-2(1H)-one (50 mg, yield 27.4%) as a colorless oil. LC-MS(ESI) m / z 150(M+H) + .

[0199] Intermediate 17: 5-(cyclobutylmethyl)pyridine-2(1H)-one The title compound was prepared from cyclobutanecarbaldehyde using the same sequence as the synthesis of intermediate 16. LC-MS(ESI)m / z164(M+H) + .

[0200] Intermediate 18: 5-(cyclobutylmethyl)pyridine-2(1H)-one The title compound was prepared from isobutyraldehyde using the same sequence as the synthesis of intermediate 16. LC-MS(ESI)m / z 152(M+H) + .

[0201] Intermediate 19: 5-Isopropylpyridine-2(1H)-one TIFF2026086696000063.tif32128 Step 1: 2-Methoxy-5-(prop-1-en-2-yl)pyridine To a solution of 5-bromo-2-methoxypyridine (1.0 g, 5.32 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.34 g, 7.98 mmol) in 1,4-dioxane (10 ml) and water (2 mL), K2CO3 (1.47 g, 10.64 mmol) and Pd(PPh3)4 (0.61 g, 0.53 mmol) were added under an N2 atmosphere. After addition, the mixture was degassed three times under an N2 atmosphere and stirred at 100°C for 16 hours. The mixture was diluted with water and extracted with SiO2 (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (elution using PE:Â=200:1~20:1) to obtain the title compound (600 mg, yield 75.6%) as a colorless oil. LC / MS(ESI) m / z:150(M+H) + . 1H NMR(400 MHz,CDCl3)δ 8.25(d,J=2.4 Hz,1H),7.69(dd,J=8.6,2.6 Hz,1H),6.71(dd,J=8.6,0.6 Hz,1H),5.29(s,1H),5.05-5.01(m,1H),3.94(s,1H),2.13(d,J=0.5 Hz,1H).

[0202] Step 2: 5-Isopropyl-2-methoxypyridine To a solution of 2-methoxy-5-(prop-1-en-2-yl)pyridine (600 mg, 4.02 mmol) in MeOH (6 mL), Pd(OH)2 (50 mg, 10 wt%) was added under an N2 atmosphere. After addition, the mixture was degassed three times under an N2 atmosphere and stirred at 25°C for 16 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (290 mg, yield 47.7%) as a colorless oil, which was used directly in the next step. 1 H NMR(400 MHz,CD3OD)δ 7.95(d,J=2.4 Hz,1H),7.59(dd,J=8.6,2.5 Hz,1H),6.74(d,J=8.6 Hz,1H),3.87(s,3H),2.93-2.85(m,1H),1.24(d,J=6.9 Hz,6H). LC / MS(ESI)m / z:152(M+H) + .

[0203] Step 3: 5-Isopropylpyridine-2(1H)-ONE To a solution of 5-isopropyl-2-methoxypyridine (150 mg, 0.99 mmol) in EtOH (1.5 mL), an aqueous HBr solution (1.5 mL, 40 wt%) was added under a N2 atmosphere, and the mixture was stirred at 85°C for 16 hours. The mixture was quenched with saturated aqueous NaHCO3 solution and extracted using DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (115 mg, yield 84.5%) as a white solid. LC / MS (ESI) m / z: 138 (M + H) + .

[0204] Intermediate 20: 5-Cyclobutylpyridine-2(1H)-one TIFF2026086696000064.tif27128 Step 1: 1-(6-methoxypyridine-3-yl)cyclobutan-1-ol To a stirred solution of 5-bromo-2-methoxypyridine (1.38 mL, 10.6 mmol) in dry THF (25 mL), n-BuLi (5.5 mL, 13.8 mmol) was added dropwise at -78°C. After stirring at this temperature for 30 minutes, cyclobutanone (1.2 mL, 15.9 mmol) was added, and the resulting mixture was stirred at -78°C for 30 minutes and then at room temperature for 30 minutes. The mixture was quenched with ice water and extracted with toluene (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated to dry, and the residue was purified by flash chromatography (PE:toluene = 10:1) to obtain the title compound (1.5 g, yield 78.6%). LC / MS (ESI) m / z: 180 (M + H) + . 1 H NMR(400 MHz,CDCl3)δ 8.29(d,J=2.2 Hz,1H),7.72(dd,J=8.6,2.6 Hz,1H),6.76(dd,J=8.6,0.6 Hz,1H),3.94(s,3H),2.62-2.46(m,2H),2.41-2.32(m,2H),2.08-1.94(m,2H),1.69-1.59(m,2H).

[0205] Step 2: 5-Cyclobutyl-2-methoxypyridine To a solution of 1-(6-methoxypyridine-3-yl)cyclobutan-1-ol (1 g, 5.5 mmol) in MeOH (3 mL), concentrated H2SO4 (1 mL) was added, followed by the addition of Pd / C (80 mg, 10 wt%) at 0°C. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 1 hour under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry. The residue was purified by flash chromatography (PE:Â=10:1~5:1) to obtain the title compound (300 mg, yield 32.9%) as a pale yellow oil. LC / MS(ESI)(m / z):164(M+H)+ . 1 H NMR(400 MHz,CDCl3)δ 7.98(t,J=4.4 Hz,1H),7.47(dd,J=8.5,2.5 Hz,1H),6.69(d,J=8.5 Hz,1H),3.91(s,3H),3.46(dd,J=17.4,8.7 Hz, 1H), 2.40-2.28 (m, 2H), 2.16-2.02 (m, 3H), 1.91-1.82 (m, 1H).

[0206] Step 3: 5-Cyclobutylpyridine-2-ol To a solution of 5-cyclobutyl-2-methoxypyridine (100 mg, 0.6 mmol) in EtOH (5 mL), HBr aqueous solution (2 mL, 48 wt%) was added, and the mixture was stirred at 70°C for 16 hours under an N2 atmosphere. The mixture was poured into ice-cooled saturated NaHCO3 aqueous solution and extracted using DCM (2 × 5 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry to obtain the title compound (70 mg, yield 76.5%). LC / MS (ESI) (m / z): 150 (M + H) + . 1 H NMR(400 MHz,CDCl3)δ 12.76(s,1H),7.42(dd,J=9.3,2.4 Hz,1H),7.14(d,J=1.8 Hz,1H),6.56(d,J=9.3 Hz,1H),3.34-3.23(dt,J=17.2,8.7 Hz, 1H), 2.27-2.23 (m, 2H), 2.06-1.92 (m, 3H), 1.89-1.76 (m, 1H).

[0207] Intermediate 21: 5-Cyclopropyl-4-methylpyridine-2(1H)-one TIFF2026086696000065.tif26128 Step 1: 5-Cyclopropyl-2-Methoxy-4-Methylpyridine To a solution of 5-bromo-2-methoxy-4-methylpyridine (2 g, 9.90 mmol) and cyclopropylboronic acid (1.11 g, 12.87 mmol) in toluene (30 mL) and water (3 mL), K3PO4 (6.30 g, 29.67 mmol), tricyclohexylphosphine (0.28 g, 0.99 mmol), and Pd(OAc)2 (0.11 g, 0.50 mmol) were added under an N2 atmosphere. After addition, the mixture was degassed three times under an N2 atmosphere and stirred at 100°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with toluene (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (elution using PE:SiO=200:1~10:1) to obtain the title compound (1.42 g, yield 88.1%) as a yellow oil. LC / MS(ESI) m / z:164(M+H) + .

[0208] Step 2: 5-Cyclopropyl-4-methylpyridine-2(1H)-one(3) To a solution of 5-cyclopropyl-2-methoxy-4-methylpyridine (1 g, 6.12 mmol) in CH3CN (10 mL), NaI (1.84 g, 12.25 mmol) and TMSCl (1.33 g, 12.25 mmol) were added. The mixture was stirred overnight at 70°C. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted with toluene (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:toluene = 20:1 to 1:1) to obtain the title compound (525 mg, yield 57.4%) as a brown solid. 1 H-NMR(400 MHz,DMSO-d6)δ 10.96(s,1H),6.67(s,1H),5.91(s,1H),1.97(d,J=0.6 Hz, 1H), 1.38-1.27 (m, 1H), 0.56-0.46 (m, 1H), 0.24-0.16 (m, 1H). LC / MS(ESI)m / z:150(M+H)+ .

[0209] Intermediate 22: 4-Cyclopropyl-5-methylpyridine-2(1H)-one TIFF2026086696000066.tif34128 Step 1: 2-Chloro-4-cyclopropyl-5-methylpyridine A mixture of 4-bromo-2-chloro-5-methylpyridine (700 mg, 3.39 mmol), K3PO4 (2.15 g, 10.17 mmol), and cyclopropylboronic acid (349 mg, 4.07 mmol) in 1,4-dioxane (25 mL) was mixed with Pd(OAc)2 (38 mg, 0.17 mmol) and tricyclohexylphosphine (95 mg, 0.34 mmol) under an N2 atmosphere. The mixture was stirred at 110°C for 16 hours. The mixture was diluted with HCl (10 mL) and filtered. The filtrate was concentrated until dry, and the residue was purified to the title compound (420 mg, yield 73.9%) as a colorless oil by flash chromatography (silica gel, PE with 0-100% HCl). LC / MS (ESI) m / z: 168 (M+H) + .

[0210] Step 2: 4-Cyclopropyl-5-methyl-2-[2-(trimethylsilyl)ethoxy]pyridine To a solution of 2-chloro-4-cyclopropyl-5-methylpyridine (250 mg, 1.49 mmol) in toluene (5 mL), 2-(trimethylsilyl)ethane-1-ol (2.1 mL, 14.91 mmol), Cs2CO3 (1.46 g, 4.47 mmol), Pd(OAc)2 (33 mg, 0.15 mmol), and t-BuPhos (89 mg, 0.15 mmol) were added. The mixture was degassed three times under N2 and stirred at 110°C for 16 hours. The reaction mixture was concentrated until dry, and the residue was purified by flash chromatography (silica gel, PE with 0-30% Â) to obtain the title compound (201 mg, yield 54.0%) as a pale yellow oil. LC / MS (ESI) m / z: 250 (M+H) + .

[0211] Step 3: 4-Cyclopropyl-5-methylpyridine-2-ol To a solution of 4-cyclopropyl-5-methyl-2-[2-(trimethylsilyl)ethoxy]pyridine (200 mg, 0.80 mmol) in THF (3 mL), TBAF (418 mg, 1.60 mmol) was added, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was diluted with ₹ (10 mL), washed with saturated water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated until dry. The residue was purified by flash chromatography (silica gel, 0-20% MeOH in DCM) to obtain the title compound (56 mg, yield 46.8%) as a white solid. LC / MS (ESI) m / z: 150 (M+H) + . 1 H NMR(400 MHz,DMSO-d6)δ 11.12(s,1H),7.08(s,1H),5.83(s,1H),2.08(d,J=0.8 Hz, 3H), 1.80-1.72 (m, 1H), 0.97-0.91 (m, 2H), 0.68-0.62 (m, 2H).

[0212] Intermediate 23: 5-(cyclopropylethynyl)pyridine-2(1H)-one TIFF2026086696000067.tif24132 Step 1: 5-(2-cyclopropylethynyl)-2-methoxypyridine To a solution of 5-iodo-2-methoxypyridine (1 g, 4.26 mmol) in CH3CN (20 mL), TEA (1.8 mL, 12.77 mmol) was added. Subsequently, under N2 conditions, bis(triphenylphosphine)palladium(II) chloride (0.17 g, 0.21 mmol), CuI (0.16 g, 0.85 mmol), and ethinylcyclopropane (0.43 mL, 5.11 mmol) were added with stirring. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated until dry. The residue was purified by flash chromatography (silica gel, PE with 0-30% siRNA) to obtain the title compound (700 mg, yield 95.0%) as a white solid. LC / MS (ESI) m / z: 174 (M+H) +.

[0213] Step 2: 5-(2-cyclopropylethynyl)-1,2-dihydropyridine-2-one To a solution of 5-(2-cyclopropylethynyl)-2-methoxypyridine (500 mg, 2.89 mmol) in CH3CN (10 mL), NaI (865 mg, 5.78 mmol) and TMSCl (0.74 mL, 5.773 mmol) were added, and the reaction mixture was stirred at 70°C for 16 hours. The mixture was diluted with  (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-5% MeOH in DCM) to obtain 5-(2-cyclopropylethynyl)-1,2-dihydropyridine-2-one (300 mg, yield 65.3%) as a yellow solid. LC / MS (ESI) m / z: 160 (M+H) + .

[0214] Intermediate 24: 4-(cyclopropylethynyl)pyridine-2(1H)-one Intermediate 24 was prepared from 4-iodo-2-methoxypyridine using the same sequence as used to synthesize intermediate 23. LC / MS(ESI) m / z:160(M+H) + .

[0215] Intermediate 25: 5-Cyclopropoxypyridine-2(1H)-one TIFF2026086696000069.tif22128 Step 1: 2-(benzyloxy)-5-cyclopropoxypyridine A mixture of 6-(benzyloxy)pyridine-3-ol (300 mg, 1.5 mmol) and bromocyclopropane (1.2 mL, 14.9 mmol) in NMP (5 mL) was mixed with CS2CO3 (1.4 g, 4.4 mmol). The resulting solution was stirred in an autoclave at 150 °C for 8 hours. The mixture was cooled to room temperature, diluted with SiO2 (10 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-50% SiO2 in PE) to obtain the title compound (180 mg, 50% yield) as a pale yellow oil. LC / MS(ESI) m / z 242 [M+1] + .

[0216] Step 2: 5-Cyclopropoxypyridine-2(1H)-ONE To a solution of 2-(benzyloxy)-5-cyclopropoxypyridine (180 mg, 0.7 mmol) in MeOH (3 mL), Pd / C (20 mg, 10 wt%) was added at 0°C. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 1 hour under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry. The residue was purified by preparative TLC (PE:Â=2:1) ​​to obtain the title compound (40 mg, yield 35.4%) as a white, foamy solid. LC / MS (ESI) (m / z): 152 (M+H) + .

[0217] Intermediate 26: 5-propoxypyridine-2(1H)-one Intermediate 26 was synthesized in the same order as used for the synthesis of intermediate 25. LC / MS(ESI)(m / z):154(M+H) + .

[0218] Intermediate 27: 5-propoxypyridine-2(1H)-one Intermediate 27 was synthesized in the same order as used for the synthesis of intermediate 25. LC / MS(ESI)(m / z):140(M+H)+ .

[0219] Intermediate 28: 5-(azetidine-1-yl)pyridine-2(1H)-one TIFF2026086696000072.tif28128 Step 1: 5-(azetidine-1-yl)-2-(benzyloxy)pyridine To a solution of 2-(benzyloxy)-5-bromopyridine (850 mg, 3.2 mmol) in 1,4-dioxane (5 mL), azetidine (0.65 mL, 9.6 mmol) was added, followed by the addition of CS2CO3 (2.1 g, 6.4 mmol), RuPhos (300 mg, 0.64 mmol), and Pd2(dba)3 (260 mg, 0.3 mmol). The mixture was degassed three times under an N2 atmosphere and stirred in a CEM reactor at 100°C for 2 hours. The mixture was diluted with RINKAN (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-50% RINKAN in PE) to obtain the title compound (650 mg, yield 84.3%) as a yellow oil. LC-MS(ESI)m / z241(M+H) + .

[0220] Step 2: 5-(azetidine-1-yl)pyridine-2-ol To a solution of 5-(azetidine-1-yl)-2-(benzyloxy)pyridine (400 mg, 1.7 mmol) in MeOH (10 mL), Pd / C (50 mg, 10 wt%) was added. The mixture was degassed under an N2 atmosphere and stirred at room temperature for 3 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (230 mg, 90% yield) as a yellow solid. LC-MS(ESI)m / z151(M+H) + .

[0221] Intermediate 29: 5-Propylpyrazine-2-ol TIFF2026086696000073.tif50128 Step 1: 5-Allylpyrazine-2-amine A mixture of 5-bromopyrazine-2-amine (500 mg, 2.87 mmol) and 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (0.81 mL, 4.31 mmol) in DMF (10 mL) was mixed with CsF (1.3 g, 8.6 mmol) and Pd(dppf)Cl2 (430 mg, 0.57 mmol). The mixture was degassed three times under an N2 atmosphere and stirred at 100°C for 9 hours under an N2 atmosphere. The mixture was diluted with RINKAN (10 mL), washed with water and brine, dried, and concentrated until dry. The residue was purified by flash chromatography (PE:RINKAN = 4:1) to obtain the title compound (250 mg, yield 64.1%) as a yellow oil. LC / MS (ESI) (m / z): 135 (M+H) + .

[0222] Step 2: 5-Propylpyrazine-2-amine To a solution of 5-allylpyrazine-2-amine (240 mg, 1.78 mmol) in MeOH (10 mL), Pd / C (20 mg, 10 wt%) was added. The mixture was degassed three times under an H2 atmosphere and stirred at room temperature for 16 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (200 mg, yield 82.1%) as a yellow oil. LC / MS (ESI) (m / z): 138 (M+H) + .

[0223] Step 3: 5-Propylpyrazine-2-ol To a solution of NaNO2 (3 g, 43.74 mmol) in concentrated H2SO4 (10 mL), propylpyrazine-2-amine (1 g, 7.3 mmol) was added in fractions at 0°C, and the mixture was stirred at 100°C for 2 hours. The mixture was diluted with ice water, neutralized to pH=5 with 1 M NaOH aqueous solution, and extracted using DCM (2 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography on silica gel (eluted using DCM:MeOH = 15:1) to obtain the title compound (320 mg, yield 31.8%). LC / MS(ESI)(m / z):139[M+H] + .

[0224] Intermediate 30: 5-Propylpyrimidine-2(1H)-one TIFF2026086696000074.tif14128 A solution of 2-chloro-5-propylpyrimidine (500 mg, 3.19 mmol) in EtOH (5 mL) was mixed with concentrated HCl (5 mL) at 0 °C, and the mixture was stirred at 100 °C for 16 hours under an N2 atmosphere. The mixture was diluted with ice water (10 mL), neutralized to pH=7 with saturated NaHCO3 aqueous solution, and extracted using DCM (2 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography on silica gel (eluted using DCM:MeOH = 15:1) to obtain the title compound (200 mg, yield 45.3%) as a yellow oil. LC / MS (ESI) m / z: 139 (M + H) + .

[0225] Intermediate 31: 6-Propylpyrimidine-4(3H)-one TIFF2026086696000075.tif17128 A mixture of ethyl 3-oxohexanoate (1.6 mL, 10 mmol) and formamidine acetate (1 g, 10 mmol) in MeOH (10 mL) was to be added dropwise with MeONa (7.5 mL, 1.5 M in MeOH) at 0°C, and the mixture was stirred overnight at 60°C. The reaction mixture was diluted with DCM (20 mL), washed with water, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-100% ethyl in PE) to obtain the title compound (410 mg, yield 29.0%) as a white solid. LC / MS (ESI) m / z: 139 (M+H) + .

[0226] Intermediate 32: 4-Propylpyridazine-3(2H)-one TIFF2026086696000076.tif21128 Step 1: 6-Chloro-4-propylpyridazine-3(2H)-one A solution of 3,6-dichloro-4-propylpyridazine (1.00 g, 5.23 mmol) in AcOH (10 mL) was stirred at 120°C for 5 hours under an N2 atmosphere. The mixture was concentrated until dry, and the residue was neutralized with saturated NaHCO3 aqueous solution. The mixture was extracted with toluene (2 × 20 mL), and the combined organic layers were washed with brie, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:toluene = 8:1~5:1) to obtain the title compound (550 mg, yield 60.9%) as a yellow oil. LC / MS (ESI) m / z: 173 (M+H) + .

[0227] Step 2: 4-Propylpyridazine-3(2H)-ONE To a solution of 6-chloro-4-propylpyridazine-3(2H)-one (500 mg, 2.90 mmol) in  (5 mL), TEA (0.05 mL, 0.360 mmol) and Pd / C (60 mg, 10 wt%) were added. The mixture was degassed three times under an N2 atmosphere and stirred at 0°C for 3 hours under an H2 balloon. The reaction product was filtered, and the filtrate was concentrated until dry. The residue was purified by column chromatography (PE: = 5:1 to 1:1) to obtain the title compound (75 mg, yield 18.7%) as an off-white solid. LC / MS (ESI) m / z: 139 (M + H) + .

[0228] Intermediate 33: 6-Propylpyridazine-3-ol TIFF2026086696000077.tif65128 Step 1: 3-Allyl-6-chloropyridazine A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (705 mg, 4.2 mmol) and 3-chloro-6-iodopyridazine (1 g, 4.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was mixed with K2CO3 (1.74 g, 12.582 mmol) and Pd(dppf)Cl2 (153.44 mg, 0.210 mmol) under an N2 atmosphere. The reaction mixture was then stirred at 75°C for 16 hours. The mixture was diluted with water and extracted with SiO2 (2 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, and concentrated under reduced pressure until dry. The residue was purified by chromatography (PE:SiO2 = 5:1) on silica gel to obtain the title compound (130 mg, yield 20.3%) as a yellow oil. LC / MS(ESI)(m / z):155(M+H) + .

[0229] Step 2: 6-allylpyridazine-3-ol A solution of 3-allyl-6-chloropyridazine (130 mg, 0.85 mmol) in AcOH (6 mL) was stirred at 120°C for 2 hours. The reaction mixture was concentrated until dry, and the residue was purified by chromatography (PE:Â=3:1) on silica gel to obtain the title compound (70 mg, yield 61.3%) as a yellow solid. LC / MS(ESI)(m / z):137(M+H) + .

[0230] Step 3: 6-Propylpyridazine-3-ol To a solution of 6-allylpyridazine-3-ol (70 mg, 0.459 mmol) in MeOH (3 mL), Pd / C (20 mg, 10 wt%) was added at 0°C. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 2 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (32 mg, yield 51.2%) as a yellow solid. LC / MS (ESI) (m / z): 139 (M+H) + .

[0231] Intermediate 34: 6-(cyclopropylmethyl)pyridazine-3-ol TIFF2026086696000078.tif31131 Step 1: Dimethyl(3-cyclopropyl-2-oxopropyl)phosphonate To a solution of dimethylmethylphosphonate (652 mg, 5.25 mmol) in THF (5 mL), n-BuLi (2.62 mL, 5.25 mmol, 2 M in THF) was added dropwise at -70°C, and the mixture was stirred at this temperature for 15 minutes. A solution of methyl 2-cyclopropyl acetate (300 mg, 2.62 mmol) in THF (3 mL) was added to the above mixture at -70°C, and the resulting mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution at 0°C and extracted with ₹ (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (460 mg, yield 84.9%) as a yellow solid. LC / MS (ESI) m / z: 207 (M + H) + .

[0232] Step 2: Ethyl(2Z)-5-cyclopropyl-4-oxopenta-2-enoate To a solution of dimethyl(3-cyclopropyl-2-oxopropyl)phosphonate (460 mg, 2.23 mmol) in t-BuOH (5 mL), t-BuOK (250 mg, 2.23 mmol) and ethyl 2-oxoacetate (0.22 mL, 2.23 mmol) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with ethyl (10 mL), washed with saturated NH4Cl aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (silica gel, PE with 0-5% ethyl) to obtain the title compound (81 mg, yield 19.9%) as a yellow oil. LC / MS (ESI) m / z: 183 (M+H) + . 1 H NMR(400 MHz,CDCl3)δ 6.55(d,J=12.1 Hz,1H),6.02(d,J=12.1 Hz,1H),4.21(q,J=7.2 Hz,2H),2.52(d,J=7.0 Hz,2H),1.29(dd,J=9.4,4.8 Hz,3H),1.01(dd,J=13.9,6.1 Hz,1H),0.59(q,J=5.3 Hz,2H),0.17(q,J=5.0 Hz,2H).

[0233] Step 3: 6-(cyclopropylmethyl)pyridazine-3-ol To a solution of methyl(2Z)-5-cyclopropyl-4-oxopenta-2-enoate (80 mg, 0.47 mmol) in EtOH (6 mL) and H2O (2 mL), hydrazine hydrate (0.1 mL) and AcOH (2 mL) were added, and the mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with ELISA (5 mL), washed with saturated NH4Cl aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to obtain the title compound (32 mg, yield 44.8%) as a white solid. LC / MS (ESI) m / z: 151 (M+H) + . 1 H NMR(400 MHz,DMSO-d6)δ 12.55(s,1H),7.22(d,J=9.7 Hz,1H),6.63(d,J=9.7 Hz,1H),2.22(d,J=7.0 Hz,2H),0.80-0.70(m,1H),0.27(dt,J=7.7,4.9 Hz,2H),-0.01(q,J=4.9 Hz,2H).

[0234] Intermediate 35: 5-(1H-pyrazole-1-yl)pyridine-2(1H)-one TIFF2026086696000079.tif21128 Step 1: 2-(benzyloxy)-5-(1H-pyrazole-1-yl)pyridine A mixture of 2-(benzyloxy)-5-bromopyridine (1 g, 3.79 mmol) and 1H-pyrazole (392 mg, 5.68 mmol) in DMSO (10 mL) was mixed with CuI (145 mg, 0.76 mmol), L-proline (87 mg, 0.757 mmol), and K2CO3 (1047 mg, 7.57 mmol) under an N2 atmosphere. The mixture was stirred at 120°C for 16 hours under an N2 atmosphere. The mixture was diluted with water and extracted with RINKAN (2 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography (PE:RINKAN = 5:1) on silica gel to obtain the title compound (350 mg, yield 36.8%) as a white solid. LC / MS(ESI)(m / z):252(M+H) + .

[0235] Step 2: 5-(1H-pyrazole-1-yl)pyridine-2-ol To a solution of 2-(benzyloxy)-5-(1H-pyrazole-1-yl)pyridine (450 mg, 1.791 mmol) in MeOH (10 mL), Pd / C (45 mg, 10 wt%) was added. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 3 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (290 mg, yield 100.5%) as a colorless oil. LC / MS (ESI) m / z: 162 (M+H) + .

[0236] Intermediate 36: (R)-5-(cyclopropylmethyl)-1-methylimidazolidined-2-one TIFF2026086696000080.tif83144 Step 1: (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid To a solution of (2R)-2-amino-3-cyclopropylpropanoic acid (6 g, 46.4 mmol) in THF (60 mL) and water (60 mL), NaHCO3 (11.1 g, 139.2 mmol) and di-tert-butyl decarbonate (12.9 mL, 60.4 mmol) were added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography (DCM:MeOH = 10:1) on silica gel to obtain the title compound (10 g, yield 93.9%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 6.04(s,1H),5.30(d,J=7.7 Hz,1H),4.35(d,J=6.0 Hz,1H),1.68-1.65(m,2H),1.43-1.42(m,9H),0.73-0.74(m,1H),0.47-0.46(m,2H),0.10-0.12(m,2H). LC / MS(ESI)(m / z):174(M+H-56) + .

[0237] Step 2: (R)-tert-butyl(1-cyclopropyl-3-hydroxypropan-2-yl)carbamate To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid (6 g, 17.4 mmol) in THF (50 mL), BH3-THF complex (52.3 mL, 52.3 mmol, 1 M in THF) was added dropwise at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction product was quenched with MeOH at 0°C and concentrated until dry. The residue was purified by chromatography (DCM:MeOH = 10:1) on silica gel to obtain the title compound (2 g, yield 35.5%) as a yellow oil. LC / MS (ESI) (m / z): 160 (M + H - 56) + .

[0238] Step 3: (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropylmethanesulfonate To a solution of (R)-tert-butyl(1-cyclopropyl-3-hydroxypropan-2-yl)carbamate (2.0 g, 9.3 mmol) in DCM (30 mL), TEA (3.9 mL, 27.9 mmol) was added, followed by dropwise addition of MsCl (1.44 mL, 18.6 mmol) at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (10 mL) and extracted using DCM (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography (PE:HCl=5:1) on silica gel to obtain the title compound (2.0 g, yield 73.4%) as a yellow oil. LC / MS(ESI)(m / z):238(M+H-56) + .

[0239] Step 4: (R)-tert-butyl(1-azido-3-cyclopropylpropan-2-yl)carbamate To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropylmethanesulfonate (1.5 g, 5.1 mmol) in DMSO (20 mL), NaN3 (1.0 g, 15.3 mmol) was added, and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography (PE:ethyl = 5:1) on silica gel to obtain the title compound (525 mg, yield 42.7%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 4.64(d,J=5.2 Hz,1H),3.82(s,1H),3.54-3.45(m,2H),1.63(s,1H),1.45(s,10H),0.71-0.64(m,1H),0.52-0.47(m,2H),0.11-0.08(m,2H).

[0240] Step 5: (R)-tert-butyl(1-azido-3-cyclopropylpropan-2-yl)(methyl)carbamate To a solution of (R)-tert-butyl(1-azido-3-cyclopropylpropan-2-yl)carbamate (525 mg, 2.19 mmol) in DMF (10 mL), NaH (114 mg, 2.84 mmol, 60% dispersion in mineral oil) was added in portions at 0°C, and the mixture was stirred at 0°C for 1 hour. Then, MeI (0.33 mL, 4.37 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with toluene (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography (PE:toluene = 5:1) on silica gel to obtain the title compound (480 mg, yield 86.4%) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 4.21(s,1H),3.52-3.22(m,2H),2.78(s,3H),1.62-1.54(m,1H),1.48(s,9H) ,1.33-1.26(m,1H),0.68-0.58(m,1H),0.48-0.46(m,2H),0.1-0.03(m,2H). LC / MS(ESI)(m / z):199(M+H-56) + .

[0241] Step 6: (R)-tert-butyl(1-amino-3-cyclopropylpropan-2-yl)(methyl)carbamate To a solution of (R)-tert-butyl(1-azido-3-cyclopropylpropan-2-yl)(methyl)carbamate (480 mg, 1.89 mmol) in MeOH (6 mL), Pd / C (80 mg, 10 wt%) was added at 0°C. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 2 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (230 mg, yield 53.4%) as a yellow solid. LC / MS (ESI) (m / z): 229 (M+H) + .

[0242] Sytep7:(R)-3-cyclopropyl-N2-methylpropane-1,2-diamine To a solution of (R)-tert-butyl(1-amino-3-cyclopropylpropan-2-yl)(methyl)carbamate (230 mg, 1.0 mmol) in DCM (4 mL), TFA (4 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure until dry, and the title compound (120 mg, yield 92.9%) was obtained as a yellow oil. LC / MS (ESI) (m / z): 129 (M+H) + .

[0243] Step 8: (S)-5-(cyclopropylmethyl)-1-methylimidazolidined-2-one To a solution of (R)-3-cyclopropyl-N2-methylpropane-1,2-diamine (120 mg, 0.94 mmol) in DCM (5 mL), TEA (0.39 mL, 2.8 mmol) and CDI (152 mg, 0.94 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (5 mL) and extracted using DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure until dry. The residue was purified by chromatography (PE:₹=1:2) on silica gel to obtain the title compound (120 mg, yield 82.7%) as a white solid. LC / MS (ESI) (m / z): 155 (M+H) + . 1 H-NMR(400 MHz, CDCl3)δ 4.57(s,1H),3.64-3.53(m,2H),3.22-3.18(m,1H),2.75(s,3H),1.65- 1.50(m,2H),0.69-0.59(m,1H),0.52-0.50(m,2H),0.12-0.07(m,2H).

[0244] Intermediate 37: (S)-5-(cyclopropylmethyl)-1-methylimidazolidined-2-one Intermediate 37 was prepared from (S)-2-amino-3-cyclopropylpropanoic acid using the same sequence of synthesis used to synthesize intermediate 36. LC / MS(ESI)(m / z):155(M+H) + .

[0245] Intermediate 38: 1-(cyclopropylmethyl)-1,3-dihydro-2H-imidazole-2-one To a solution of 1-methyl-2,3-dihydro-1H-imidazole-2-one (1 g, 10.2 mmol) in DMF (10 mL), NaH (410 mg, 10.2 mmol, a 60% dispersion in mineral oil) was added in portions at 0°C, and the mixture was stirred at this temperature for 30 minutes. (Bromomethyl)cyclopropane (1.2 mL, 12.2 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with siRNA (20 mL), washed with saturated aqueous NH4Cl solution and brine, dried on anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by chromatography (PE:siRNA = 6:1) on silica gel to obtain the title compound (450 mg, yield 31.9%) as a colorless oil. LC / MS(ESI)(m / z):139(M+H) + . 1 H NMR(400 MHz, CDCl3)δ 10.34(s,1H),6.35-6.22(m,2H),3.52-3.45(m,2H),1.11(s,1H),0.62-0.53(m,2H),0.33(t,J=5.3 Hz,2H).

[0246] Intermediate 39: 1-Isobutyl-1,3-dihydro-2H-imidazole-2-one Intermediate 39 was prepared from 1-methyl-2,3-dihydro-1H-imidazole-2-one and 1-bromo-2-methylpropane, following the synthesis of intermediate 38. LC / MS(ESI)(m / z):141(M+H) + .

[0247] Intermediate 40: 1-(sec-butyl)-1,3-dihydro-2H-imidazole-2-one Intermediate 40 was prepared from 1-methyl-2,3-dihydro-1H-imidazole-2-one and 2-bromobutane, following the synthesis of intermediate 38. LC / MS(ESI)(m / z):141(M+H) + .

[0248] Intermediate 41: 4-Chloro-6-(1H-pyrazole-1-yl)pyrimidine A mixture of 4,6-dichloropyrimidine (1 g, 6.71 mmol) and 1H-pyrazole (457 mg, 6.71 mmol) in 20 mL of DMF was mixed with Cs2CO3 (4.37 g, 13.4 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with SiO4 (40 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was ground with SiO4 (10 mL) and filtered. The filtered cake was dried under vacuum to obtain the title compound (660 mg, yield 54.4%) as a white solid. LC / MS (ESI) m / z: 181 (M+H) + . 1 H NMR(400 MHz,CDCl3)δ 8.79-8.79(d,J=0.8 Hz,1H),8.55-8.57(dd,J=2.7,0.5 Hz,1H),7.97-7.98(d,J=1.0 Hz,1H),7.81(d,J=1.0 Hz,1H),6.53-6.54(dd,J=2.7,1.6 Hz,1H).

[0249] Intermediate 42: 2-Chloro-4-cyclobutylpyrimidine TIFF2026086696000086.tif22128 To a mixture of 2-chloropyrimidine (3 g, 26.2 mmol) and cyclobutanecarboxylic acid (2.3 mL, 23.6 mmol) in DCM (15 mL) and water (15 mL), AgNO3 (890 mg, 5.2 mmol) was added, followed by the addition of (NH4)2S2O8 (6.0 g, 26.2 mmol) at room temperature in separate additions. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with DCM (50 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (PE:siRNA = 5:1 to 1:1) to obtain the title compound (2.2 g, yield 49.8%) as a colorless oil. LC / MS(ESI)m / z:169(M+H) + . 1 H-NMR(400 MHz,CDCl3)δ 8.49(d,J=5.2 Hz,1H),7.11(d,J=5.2 Hz, 1H), 3.70-3.53 (m, 1H), 2.41-2.30 (m, 4H), 2.15-2.03 (m, 1H), 1.99-1.92 (m, 1H).

[0250] Intermediate 43: 2-Chloro-4-isopropylpyrimidine Intermediate 43 was prepared from 2-chloropyrimidine and isobutyric acid using the same synthetic method as intermediate 42. LC / MS(ESI) m / z: 157(M+H) + . 1 H NMR(400 MHz,CD3OD)δ 8.52(d,J=5.1 Hz,1H),7.17(d,J=5.1 Hz,1H),3.06-2.99(m,1H),1.32(d,J=7.0 Hz,6H).

[0251] Intermediate 44: 2-Chloro-4-cyclopropylpyrimidine Intermediate 44 was prepared from 2-chloropyrimidine and cyclopropanecarboxylic acid using the same synthetic method as intermediate 42. LC / MS(ESI) m / z:155(M+H)+ .

[0252] Intermediate 45: 4-chloro-6-cyclobutylpyrimidine TIFF2026086696000089.tif19128 Step 1: 6-Propyl-3,4-dihydropyrimidine-4-one To a solution of methyl 3-cyclobutyl-3-oxopropanoate (2 g, 12.81 mmol) and formamidine acetate (1.33 g, 19.98 mmol) in MeOH (30 mL), 7.7 mL of 5 N MeONa / MeOH solution (38.5 mmol) was added dropwise at 0°C. After addition, the mixture was stirred at 70°C for 4 hours. After cooling to 0°C, the reaction product was filtered and treated with DCM (100 mL) and water (100 mL) to separate the organic layer, and the aqueous layer was extracted using DCM (50 mL). The combined organic compounds were concentrated until dry, and the residue was purified by flash chromatography (0-80% ethyl acetate in PE) to obtain the title compound (400 mg, yield 29.0%) as a white solid. LC / MS (ESI) m / z: 151 (M+H) + .

[0253] Step 2: 4-chloro-6-cyclobutylpyrimidine A stirred solution of 6-cyclobutyl-3,4-dihydropyrimidine-4-one (100 mg, 0.666 mmol) in POCl3 (2 mL) was stirred at 120°C for 2 hours. The solution was concentrated under reduced pressure until dry. The residue was purified by flash chromatography (0-10% ethyl acetate in PE) to obtain the title compound (70 mg, yield 62.3%) as a pale yellow oil. LC / MS (ESI) m / z: 169 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 8.91(s,1H),7.20(s,1H),3.63-3.59(m,1H),2.40-2.30(m,4H),2.12-2.07(m,1H),1.96-1.93(m,1H).

[0254] Intermediate 46: 3-Chloro-5-cyclopropyl-1,2,4-oxadiazole TIFF2026086696000090.tif41128 Step 1: N-Cyanocyclopropanecarboxamide To a solution of sodium cyanamide hydrogen (1.25 g, 19.51 mmol) in THF (10 mL), cyclopropane carbonyl chloride (1.02 g, 9.76 mmol) was added at 0°C under an N2 atmosphere, and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated until dry, and the residue was dissolved in H2O (10 mL). The mixture was washed with siRNA (2 × 3 mL), acidified to approximately pH 2 with 1N aqueous HCl solution, and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (564 mg, yield 52.5%) as a colorless oil, which was used directly in the next step.

[0255] Step 2: 5-Cyclopropyl-1,2,4-Oxadiazole-3-amine A mixture of N-cyanocyclopropanecarboxamide (525 mg, 4.77 mmol) and hydroxylamine hydrochloride (497.0 mg, 7.15 mmol) in EtOH (6 mL) was mixed with pyridine (1.51 g, 19.07 mmol) under an N2 atmosphere, and the mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (10 mL) and extracted using DCM (3 × 5 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (429 mg, yield 71.9%) as a white solid, which was used directly in the next step. LC / MS (ESI) m / z: 126 (M + H) + . 1 H NMR (400 MHz, CDCl3) δ 4.28 (s, 1H), 2.05 (tt, J=7.0, 6.0 Hz, 1H), 1.19-1.12 (m, 2H).

[0256] Step 3: 3-Chloro-5-cyclopropyl-1,2,4-oxadiazole A solution of 5-cyclopropyl-1,2,4-oxadiazole-3-amine (200 mg, 1.60 mmol) in an aqueous HCl solution (2 mL, 36 wt%) was added dropwise to a solution of NaNO2 (276 mg, 4.00 mmol) in water (2 mL), and the mixture was stirred at 0°C for 2 hours. The mixture was diluted with water and extracted using DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:siRNA = 200:1 to 20:1) to obtain the title compound (78 mg, yield 33.8%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 2.24-2.15(m, 1H), 1.34-1.25(m, 5H).

[0257] Intermediate 47: 3-Chloro-5-(cyclopropylmethyl)-1,2,4-oxadiazole The title compound was prepared from 2-cyclopropylacetyl chloride using the same procedure as for intermediate 46 (TIFF2026086696000091.tif17128). LC / MS(ESI) m / z:159(M+H) + .

[0258] Intermediate 48: 3-Chloro-5-cyclobutyl-1,2,4-oxadiazole The title compound was prepared from cyclobutane carbonyl chloride using the same procedure as for intermediate 46 in TIFF2026086696000092.tif14128. LC / MS(ESI) m / z:159(M+H) + .

[0259] Intermediate 49: 5-bromo-1-propyl-1H-1,2,4-triazole TIFF2026086696000093.tif17128 A mixture of 3-bromo-4H-1,2,4-triazole (1 g, 6.76 mmol), 1-iodopropane (1.0 mL, 10.13 mmol), and TBAF (10 mg, catalyst) in toluene (10 mL) was mixed with a solution of KOH (750 mg, 13.5 mmol) in water (2 mL), and the mixture was stirred at 60 °C for 16 hours. The mixture was diluted with water (10 mL) and extracted with toluene (2 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous sodium 2 SO4, filtered, and concentrated until dry. The residue was purified by chromatography on silica gel (eluted using PE:HCl = 6:1) to obtain the title compound (400 mg, yield 31.3%) as a yellow oil. LC / MS(ESI)m / z:190 / 192(M+H) + . 1 H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 4.14 (t, J = 2.4 Hz, 2H), 1.91 (m, 2H), 0.95 (t, J = 2.4 Hz, 2H).

[0260] Intermediate 50: 5-bromo-1-(cyclopropylmethyl)-1H-1,2,4-triazole The title compound was prepared from 3-bromo-4H-1,2,4-triazole and (bromomethyl)cyclopropane using the same procedure as for intermediate 49 (TIFF2026086696000094.tif16128). LC / MS(ESI) m / z:202 / 204(M+H) + .

[0261] Intermediate 51: 5-bromo-1-isobutyl-1H-1,2,4-triazole The title compound was prepared from 3-bromo-4H-1,2,4-triazole and 1-iodo-2-methylpropane using the same procedure as for intermediate 49 (TIFF2026086696000095.tif16128). LC / MS(ESI) m / z:204 / 206(M+H) + . 1H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 3.97 (d, J = 7.2 Hz, 2H), 2.35-2.86 (m, 1H), 0.95 (d, J = 6.8 Hz, 6H).

[0262] Example 1: (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid TIFF2026086696000096.tif92129 Step 1: Methyl(S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate To a solution of methyl(S)-2-(5,5-difluoro-1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)piperidine-3-yl)acetate (40 mg, 0.1 mmol) in DCM (1 mL), TEA (20 mg, 0.2 mmol) was added, followed by the addition of MsCl (17 mg, 0.15 mmol) at 0°C. The mixture was stirred at this temperature for 2 hours. The mixture was diluted with DCM (2 mL), washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, and concentrated until dry to obtain the title compound (43 mg, yield 91%) as a pale yellow solid, which was used directly in the next reaction without purification. LC / MS(ESI)(m / z):474(M+H) + .

[0263] Step 2: Methyl(S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate A mixture of methyl(S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (43 mg, 0.091 mmol) and 3-methyl-5-propyl-1,2-dihydropyridine-2-one (16.5 mg, 0.11 mmol) was mixed with toluene (3 mL) and water (1 mL). K2CO3 (25 mg, 0.182 mmol) and TBAF (3 mg, catalytic amount) were added, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (3 mL) and extracted with butyl (2 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (35 mg, 72.9% yield) as a pale yellow solid. LC / MS(ESI)(m / z): 529(M+H) + .

[0264] Step 3: (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid A solution of methyl(S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((3-methyl-2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (35 mg, 0.066 mmol) in THF (1 mL) and methanol (2 mL) was added at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated until dry, and the residue was dissolved in water (3 mL). The mixture was washed twice with MTBE, the aqueous layer was acidified to approximately pH 2 with 1 N aqueous HCl solution, and extracted with ELISA (2 × 2 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated until dry. The residue was purified by preparative HPLC (C18, 10-95% in H2O containing 0.1% HCOOH, MeCN) to obtain the title compound (22 mg, yield 64.6%) as a white solid. LC / MS(ESI)(m / z): 515(M+H) + . 1 H NMR(400 MHz,DMSO-d6)δ 7.82(d,J=8.3 Hz,1H),7.62(d,J=1.7 Hz,1H),7.55(d,J=8.4 Hz,1H),7.17-7.16(m,1H),5.56(s,2H),4.23(s,3H),3.20-3.04(m,4H),2.60-2.55(m,4H),2.39-2.27(m,4H),2.15(t,J=7.4 Hz,2H),1.95(s,3H),1.84-1.68(m,1H),1.35-1.26(m,2H),0.71(t,J=7.3 Hz,3H).

[0265] Example 2: (S)-2-(1-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridine-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetic acid TIFF2026086696000097.tif86128 Step 1: 3-Bromo-6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridine To a solution of (4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol (500 mg, 1.76 mmol) in DCM (10 mL), PBr3 (717 mg, 2.65 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C to room temperature for 3 hours. The mixture was diluted with DCM (10 mL), washed with ice-cooled saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the crude product. This was purified by flash chromatography (silica gel, PE with 0-30% Â) to obtain the title compound (510 mg, yield 83.7%) as a white solid. LC / MS (ESI) m / z: 347 (M+H) + .

[0266] Step 2: 1-((4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methyl)-4-(cyclopropylmethyl)-3-methylpyridine-2(1H)-one To a mixture of 3-bromo-6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine (200 mg, 0.58 mmol) and 4-(cyclopropylmethyl)-3-methyl-1,2-dihydropyridine-2-one (136 mg, 0.83 mmol) in toluene (5 mL) and H2O (1 mL), K2CO3 (230 mg, 1.66 mmol) and TBAF (10 mg, catalyst) were added, and the mixture was stirred at 100°C for 3 hours. The reaction mixture was diluted with ethyl acetate (5 mL), washed with brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (silica gel, 0-56% ethyl acetate in PE) to obtain the title compound (220 mg, yield 88.9%) as a white solid. LC / MS(ESI)m / z:428 / 430(M+H)+ .

[0267] Step 3: Methyl(S)-2-(1-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridine-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate Ru-phos-Pd-G3 (30 mg, 0.036 mmol) was added to a mixture of 1-((4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methyl)-4-(cyclopropylmethyl)-3-methylpyridine-2(1H)-one (78 mg, 0.18 mmol), methyl 2-[(3S)-5,5-difluoropiperidine-3-yl]acetate (35 mg, 0.18 mmol), Cs2CO3 (177 mg, 0.54 mmol), and Ru-phos (17 mg, 0.036 mmol) in 1,4-dioxane (2 mL). The mixture was then degassed three times under an N2 atmosphere and stirred at 110°C for 16 hours under an N2 atmosphere. The reaction mixture was poured into ice water and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate in PE) to obtain the title compound (35 mg, yield 35.5%) as a yellow solid. LC / MS (ESI) m / z: 541 (M + H) + .

[0268] Step 4: (S)-2-(1-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridine-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetic acid To a solution of methyl(S)-2-(1-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridine-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate (35 mg, 0.065 mmol) in MeOH (1 mL), H2O (1 mL), and THF (4 mL), LiOH (50 mg, 2.1 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was acidified to approximately pH 3 with 1 N aqueous HCl solution and extracted using DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by preparative HPLC (C18, 10-95% in H2O containing 0.1% HCOOH, MeCN) to obtain the title compound (15 mg, yield 43.8%) as a white solid. LC / MS (ESI) m / z: 527 (M+H) + . 1 H NMR(400 MHz,CD3OD)δ 7.83(d,J=8.4 Hz,1H),7.75(d,J=7.1 Hz,1H),7.52(d,J=8.4 Hz,1H),6.30(d,J=7.2 Hz,1H),5.73(s,2H),4.21(s,3H),3.28-3.23(m,2H),3.15-3.00(m,1H),2.62-2.56(m,1H),2.59(s,3H),2.54-2.48(m,1H),2 .43-2.39(m,4H),2.36-2.26(m,1H),2.04(s,3H),1.81-1.64(m,1H),0.90-0.87(m,1H),0.52-0.46(m,2H),0.18-0.14(m,2H).

[0269] The examples in the table below were prepared using similar reactants and the methods shown. TIFF2026086696000098.tif139151TIFF2026086696000099.tif230159TIFF2026086696000100.tif230159TIFF2026086696000101.tif230159TIFF2026086696000102.tif230159TIFF2026086696000103.tif230159TIFF2026086696000104.tif230159TIFF2026086696000105.tif230159TIFF2026086696000106.tif230159TIFF2026086696000107.tif230159TIFF2026086696000108.tif230159TIFF2026086696000109.tif230159TIFF2026086696000110.tif230159TIFF2026086696000111.tif230159TIFF2026086696000112.tif230159TIFF2026086696000113.tif230159TIFF2026086696000114.tif230159TIFF2026086696000115.tif230159TIFF2026086696000116.tif230159TIFF2026086696000117.tif230159TIFF2026086696000118.tif230159TIFF2026086696000119.tif230159TIFF2026086696000120.tif230159TIFF2026086696000121.tif230159TIFF2026086696000122.tif230159TIFF2026086696000123.tif230159TIFF2026086696000124.tif230159TIFF2026086696000125.tif230159TIFF2026086696000126.tif230159TIFF2026086696000127.tif230159TIFF2026086696000128.tif205154

[0270] Example 43: (S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridine-1(4H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid TIFF2026086696000129.tif71128 Step 1: 4-(benzyloxy)-3-bromopyridine To a solution of 3-bromopyridine-4-ol (0.13 mL, 1.16 mmol) in DMF (2 mL), NaH (92 mg, 2.30 mmol, 60% dispersion in mineral oil) was added in divided portions at 0°C under an N2 atmosphere, and the reaction mixture was stirred at 0°C for 20 minutes. BnBr (0.21 mL, 1.76 mmol) was added to the above mixture, and the resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (20 mL) at 0°C, and the mixture was extracted with RINKAN (3 × 15 mL). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated until dry. The residue was purified by column chromatography (PE:RINKAN = 50:1 to 20:1) to obtain the title compound (300 mg, yield 98.6%) as a pale yellow solid. LC / MS(ESI)m / z:264(M+H) + .

[0271] Step 2: 3-Allyl-4-(benzyloxy)pyridine A mixture of 4-(benzyloxy)-3-bromopyridine (300 mg, 1.14 mmol), thiobutyl(vinyl)tin (0.53 mL, 1.71 mmol), and LiCl (121 mg, 2.85 mmol) was mixed with Pd(PPh3)4 (132 mg, 0.114 mmol) under an N2 atmosphere. After addition, the mixture was degassed at 100°C for 16 hours under an N2 atmosphere. The mixture was diluted with RINKAN (10 mL), washed with saturated aqueous KF solution and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by column chromatography (DCM:MeOH = 50:1~20:1) to obtain the title compound 3 (205 mg, yield 80.2%) as a yellow oil. LC / MS (ESI) m / z: 226 (M+H)+ .

[0272] Step 3: 3-Propylpyridine-4-ol To a solution of 3-allyl-4-(benzyloxy)pyridine (150 mg, 0.67 mmol) in MeOH (3 mL), Pd(OH)2 / C (20 mg, 10 wt%) was added at 25°C under an N2 atmosphere. The mixture was degassed three times under an N2 atmosphere and stirred at 25°C for 5 hours under an H2 balloon. The mixture was filtered, and the filter cake was washed with MeOH (2 × 5 mL). The filtrate was concentrated until dry, and the residue was purified by column chromatography (DCM:MeOH = 20:1 to 10:1) to obtain compound 4 (50 mg, yield 54.7%) as a colorless oil. LC / MS (ESI) m / z: 138 (M + H) + .

[0273] Step 4: Methyl(R)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridine-1(4H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate To a mixture of 3-propylpyridine-4-ol (15.7 mg, 0.114 mmol) and methyl(S)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (36 mg, 0.076 mmol) in toluene (2 mL) and H2O (1 mL), K2CO3 (31.5 mg, 0.23 mmol) was added, followed by the addition of TBAF (2 mg, 0.008 mmol), and the reaction mixture was heated at 80°C for 16 hours. The mixture was diluted with toluene (3 mL), washed with water and brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated until dry to obtain the title compound (50 mg, 100% yield) as a yellow solid, which was used directly in the following reaction: LC / MS (ESI) m / z: 515 (M + H) + .

[0274] Step 5: (R)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridine-1(4H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid To a solution of methyl(R)-2-(5,5-difluoro-1-(2-methyl-6-(1-methyl-5-((4-oxo-3-propylpyridine-1(4H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (50 mg, 0.097 mmol) in THF (2 mL), MeOH (0.50 mL), and water (0.5 mL), LiOH.H2O (42 mg, 1.00 mmol) was added at 25°C, and the mixture was stirred at 25°C for 16 hours. The reaction product was concentrated until dry, and the residue was diluted with water (5 mL). The mixture was basicized to approximately pH 14 with 1 N NaOH aqueous solution and washed with ELISA (2 × 2 mL). The aqueous layer was acidified to approximately pH 3 with a 1N HCl aqueous solution and extracted using DCM (2 × 3 mL). The combined organic layer was washed with brine, dried on anhydrous Na₂SO₄, filtered, and concentrated until dry. The residue was purified by preparative HPLC to obtain the title compound (5.2 mg, 10.7%) as a white solid. LC / MS(ESI) m / z: 501(M+H) + . 1 H NMR(400 MHz,DMSO)δ 7.90(d,J=8.3 Hz,1H),7.84-7.75(m,2H),7.59(d,J=8.4 Hz,1H),6.03(d,J=7.3 Hz,1H),5.69(s,2H),4.10(s,3H),3.21-3.07(m,3H),2.59-2.56(m,1H),2.52(s,3H),2.40-2.25( m,4H),2.22-2.15(m,2H),2.03-1.95(m,1H),1.80-1.73(m,1H),1.40-1.31(m,2H),0.78(t,J=7.4 Hz,3H).

[0275] Example 44: 2-[5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazine-1-yl)ethyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)piperidine-3-yl]acetic acid TIFF2026086696000130.tif90128 Step 1: 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]acetonitrile To a solution of 3-bromo-6-[5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridine (1.1 g, 3.18 mmol) in CH3CN (10 mL), NaCN (260 mg, 5.31 mmol) in DMSO (10 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then partitioned between butyl and water. The aqueous phase was extracted with butyl (3 × 20 mL). The combined organic extract was concentrated and washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0% to 100% butyl in PE) to obtain the title compound (680 mg, yield 73.2%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.92 (q, J = 8.4 Hz, 2H), 4.64 (s, 2H), 4.19 (s, 3H), 2.69 (s, 3H), 1.66 (s, 2H).

[0276] Step 2: 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]acetic acid To a solution of 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]acetonitrile (630 mg, 2.16 mmol) in ethanol (10 mL) and H2O (10 mL), KOH (483 mg, 8.63 mmol) was added, and the resulting mixture was refluxed for 16 hours. Ethanol was removed under reduced pressure, and the solution was then cooled to below 10°C and acidified to approximately pH 1 with concentrated aqueous HCl. The mixture was extracted with toluene (2 × 10 mL), the combined organic extract was concentrated and washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated until dry to obtain the title compound (680 mg, yield 101.4%) as a white solid. LC / MS (ESI) m / z: 312 / 314 (M + H) + .

[0277] Step 3: 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]ethane-1-ol A mixture of 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]acetic acid (450 mg, 1.45 mmol) in THF was mixed with BH3.THF complex (4.3 mL, 1 M in THF) dropwise at 0°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched by dropwise addition of MeOH (5 mL) at 0°C, and the resulting mixture was concentrated until dry to obtain the title compound (250 mg, yield 58.2%) as a white solid. LC / MS (ESI) m / z: 298 / 300 (M+H) + .

[0278] Step 4: 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]ethylmethanesulfonate To a stirred solution of 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]ethane-1-ol (250 mg, 0.84 mmol) in DCM (10 mL), MsCl (0.1 mL, 1.26 mmol) and TEA (0.35 mL, 2.52 mmol) were added at 0°C under an N2 atmosphere. After stirring at room temperature for 3 hours, the reaction mixture was quenched with H2O (10 mL) and extracted using DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:Â=9:1~4:1) to obtain the title compound (270 mg, yield 85.5%) as a yellow solid. LC / MS(ESI)m / z:376 / 378(M+H) + .

[0279] Step 5: 2-{2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]ethyl}4-propyl-2,3-dihydropyridazine-3-one To a solution of 2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]ethylmethanesulfonate (120 mg, 0.32 mmol) and 4-propyl-2,3-dihydropyridazine-3-one (66 mg, 0.48 mmol) in toluene (2 mL), K2CO3 (132 mg, 0.96 mmol) in H2O (2 mL) was added, followed by the addition of TBAF (8 mg, 0.03 mmol), and the mixture was stirred at 100°C for 16 hours. The reaction mixture, diluted with siRNA (10 mL), was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-25% siRNA in PE) to obtain the title compound (40 mg, yield 30.0%) as a brown solid. LC / MS(ESI)m / z:418 / 420(M+H) + .

[0280] Step 6: Methyl 2-[(3R)-5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazin-1-yl)ethyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)piperidine-3-yl]acetate To a mixture of 2-{2-[4-(5-bromo-6-methylpyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]ethyl}-4-propyl-2,3-dihydropyridazine-3-one (40 mg, 0.10 mmol) and methyl 2-[(3R)-5,5-difluoropiperidine-3-yl]acetate (22 mg, 0.12 mmol), Cs2CO3 (62 mg, 0.19 mmol) was added, followed by the addition of BINAP (6 mg, 0.01 mmol) and Pd(OAc)2 (2 mg, 0.01 mmol) under an N2 atmosphere. The reaction mixture was degassed three times under an N2 atmosphere and stirred in a CEM microwave reactor at 110°C for 2 hours. The mixture was diluted with toluene (5 mL), washed with water and brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-55% toluene in PE) to obtain the title compound (10 mg, yield 19.7%) as a yellow solid. LC / MS (ESI) m / z: 531 (M+H) + .

[0281] Step 7: 2-[5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazin-1-yl)ethyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)piperidine-3-yl]acetic acid A solution of methyl 2-[5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazine-1-yl)ethyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)piperidine-3-yl]acetate (10 mg, 0.02 mmol) was added to a solution of LiOH (8 mg, 0.2 mmol) in H2O (1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was acidified to approximately pH 3 with 1 N aqueous HCl solution and extracted using DCM (2 × 2 mL). The combined organic layers were washed with brine and concentrated until dry. The residue was purified by preparative HPLC (C18, 0-90% acetonitrile in H2O containing 0.1% formic acid) to obtain 2-[5,5-difluoro-1-(2-methyl-6-{1-methyl-5-[2-(6-oxo-5-propyl-1,6-dihydropyridazine-1-yl)ethyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)piperidine-3-yl]acetic acid (2.2 mg, yield 22.6%) as a white solid. LC / MS (ESI) m / z: 517 (M+H) + . 1 H NMR(400 MHz,CD3OD)δ 7.65(d,J=8.3 Hz,1H),7.57(d,J=4.2 Hz,1H),7.44(d,J=8.3 Hz,1H),6.99(d,J=4.2 Hz,1H),4.61(s,3H),4.50(t,J=7.3 Hz,2H),4.06(s,3H),3.78(t,J=6.6 Hz,2H),3.14-2.99(m,1H),2.56(s,3H),2.54-2.47(m,1H),2.42-2.35(m,4 H),2.34-2.25(m,1H),1.83-1.64(m,1H),1.57-1.45(m,2H),0.92(t,J=7.4 Hz,3H).

[0282] Examples 45 and 46: 2-((3R,5R), or (3S,5S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl)acetic acid, and 2-((3S,5S), or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl)acetic acid TIFF2026086696000131.tif115147 Step 1: Cis-methyl 5-hydroxypiperidine-3-carboxylate To a solution of cis-1-benzyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (8 g, 27.3 mmol) in toluene (100 mL), Pd / C (1 g, 10 wt%) was added. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 16 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (4.3 g, 99% yield) as a colorless oil. LC / MS (ESI) m / z: 160 (M+1) + .

[0283] Step 2: cis-methyl-1-benzyl-5-hydroxypiperidine-3-carboxylate A mixture of cis-methyl 5-hydroxypiperidine-3-carboxylate (4.3 g, 27.0 mmol) and K2CO3 (7.5 g, 54.1 mmol) in DMF (50 mL) was mixed with BnBr (7.4 g, 40.5 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with RINKAN (100 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-100% PEG in PE) to obtain the title compound (3.85 g, yield 57.2%) as a yellow oil. LC / MS (ESI) m / z: 250 (M+1) + .

[0284] Step 3: Trans-methyl 1-benzyl 5-fluoropiperidine 3-carboxylate To a mixture of cis-methyl-1-benzyl-5-hydroxypiperidine-3-carboxylate (3.85 g, 15.4 mmol) in DCM (50 mL), DAST (4.1 mL, 30.9 mmol) was added dropwise at -78°C, and the mixture was stirred at -78°C at room temperature for 16 hours. The mixture was quenched with saturated NaHCO3 aqueous solution at 0°C and extracted using DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-100% PE, ethylethanol) to obtain the title compound (3.2 g, yield 82.5%) as a yellow oil. LC / MS (ESI) m / z: 252 (M+1) + .

[0285] Step 4: Trans-methyl 5-fluoropiperidine-3-carboxylate To a mixture of trans-methyl 1-benzyl-5-fluoropiperidine-3-carboxylate (3.2 g, 12.7 mmol) in MeOH (50 mL), Pd(OH)2 (400 mg, 10 wt%) and AcOH (3 drops) were added. The mixture was degassed three times under N2 and stirred at room temperature for 16 hours under an H2 balloon. The mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (2.5 g, 100% yield) as a colorless oil. LC / MS (ESI) m / z: 162 (M+1) + .

[0286] Step 5: Trans-1-benzyl 3-methyl 5-fluoropiperidine-1,3-dicarboxylate A mixture of trans-methyl 5-fluoropiperidine-3-carboxylate (2.5 g, 15.5 mmol) and saturated NaHCO3 aqueous solution (15 mL) in THF (30 mL) was to be added dropwise with CbzCl (5.27 g, 31.0 mmol) at 0°C, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with RINKAN (2 × 20 mL), and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-50% PEG, RINKAN) to obtain the title compound (3.7 g, yield 80.8%) as a yellow oil. LC / MS (ESI) m / z: 296 (M+1) + .

[0287] Step 6: Trans-1-((benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid A solution of trans-1-benzyl 3-methyl 5-fluoropiperidine-1,3-dicarboxylate (3.7g, 12.5 mmol) in MeOH (40 mL), THF (20 mL), and H2O (20 mL) is mixed with LiOH. · H2O (2.63 g, 62.6 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated until dry, the residue was dissolved in water (50 mL), and washed with toluene (2 × 10 mL). The aqueous layer was acidified to approximately pH 4 with 1 N aqueous HCl solution and extracted with dihydrogen methylcellulose (DCM) (3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated until dry, and the title compound (3.1 g, yield 88%) was obtained as a white solid. LC / MS (ESI) m / z: 282 (M+1) + .

[0288] Step 7: Trans-benzyl 3-(chlorocarbonyl)-5-fluoropiperidine-1-carboxylate To a solution of 1-[(benzyloxy)carbonyl]-5-fluoropiperidine-3-carboxylic acid (3.1 g, 11.0 mmol) and DMF (0.085 mL, 1.10 mmol) in DCM (31 mL), oxalyl chloride (2.80 g, 22.0 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated until dry, and the residue was dissolved in THF (40 mL). A solution of TMSCHN2 (16.5 mL, 2 M in toluene) was added to the above mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with AcOH (6 mL), concentrated until dry, and a yellow residue was obtained. The residue was dissolved in MeOH (50 mL), and F3CCOOAg (0.48 g, 2.16 mmol) and TEA (6 mL) were added. The reaction mixture was sonicated at room temperature for 1 hour. The mixture was concentrated until dry, and the residue was purified by flash chromatography (silica gel (40g), 0-100% of PE, ethyl acetate) to obtain the title compound (2.0g, 60% yield) as a yellow oil. LC / MS (ESI) m / z: 310 (M+1) + .

[0289] Step 8: Trans-methyl 2-(5-fluoropiperidine-3-yl) acetate To a mixture of trans-benzyl 3-fluoro-5-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (2 g, 6.46 mmol) in siRNA (50 mL), Pd / C (200 mg, 10 wt%) was added. The mixture was degassed three times under an N2 atmosphere and stirred at room temperature for 2 hours under an H2 balloon. The reaction mixture was filtered, and the filtrate was concentrated until dry to obtain the title compound (1.1 g, 97% yield) as an off-white solid. LC / MS (ESI) m / z: 176 (M+1) + .

[0290] Step 9: Trans-methyl 2-(1-(2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl)acetate A mixture of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazole-4-yl}pyridine (600 mg, 1.57 mmol), trans-methyl 2-(5-fluoropiperidine-3-yl)acetate (276 mg, 1.58 mmol), Ru-phos (147 mg, 0.315 mmol), and Cs2CO3 (1.0 mg, 3.14 mmol) in 1,4-dioxane (15 mL) was mixed with Pd2(dba)3 (216 mg, 0.236 mmol) under an N2 atmosphere. The mixture was degassed three times under N2 and stirred at 120°C for 3 hours. The mixture was filtered and the filtrate was concentrated until dry. The residue was purified by flash chromatography (silica gel, PE containing 0-40% ethyl acetate) to obtain the title compound (430 mg, yield 57.5%) as a yellow solid. LC / MS(ESI) m / z: 476 (M+1) + .

[0291] Step 10: Methyl 2-((3S,5S), or (3R,5R)-1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl) acetate (14-P1), and methyl 2-((3R,5R), or (3S,5S)-1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl) acetate (14-P2) A mixture of methyl 2-[1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)-5-fluoropiperidine-3-yl]acetate (430 mg, 0.904 mmol) in MeOH (10 mL) was mixed with PPTS (454 mg, 1.81 mmol). After stirring at 50°C for 16 hours, the mixture was poured into a saturated NH4Cl aqueous solution and extracted with ELISA (3 × 10 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was subjected to preparative HPLC (C) 18The mixture was purified by 10-95% (MeCN) in H2O containing 0.1% HCOOH to obtain a racemic product, which was then purified by chiral SFC to obtain compound 14-P1 (peak 1, retention time: 5.48 min) (64 mg, yield 18%) and 14-P2 (peak 2, retention time: 5.83 min) (92 mg, yield 26%) as white solids. LC / MS (ESI) m / z: 392.5 (M+1) + SFC conditions: Column: ChiralPak OJ, 250 × 21.2 mm inner diameter, 5 μm; Mobile phase: A for CO2, and B (0.1% NH4OH) for methanol; Gradient: B 40%; Flow rate: 50 mL / min; Column temperature: 35°C.

[0292] Step 11: Methyl 2-((3S,5S), or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl)acetate A mixture of compound 14-P1 (64 mg, 0.16 mmol) and TEA (0.07 mL, 0.510 mmol) in DCM (3 mL) was mixed with MsCl (0.025 mL, 0.33 mmol) at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was diluted with DCM (5 mL), washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (76 mg, 99% yield) as a yellow solid. LC / MS(ESI) m / z: 470 (M+1) + .

[0293] Step 12: Methyl 2-((3S,5S), or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl)acetate 5-Propyl-1,2-dihydropyridine-2-one (12 mg, 0.089 mmol) was added to a mixture of compound 15 (35 mg, 0.075 mmol) and K2CO3 (21 mg, 0.151 mmol) in toluene (2 mL) and H2O (0.4 mL). After stirring at 100 °C for 2 hours, the reaction mixture was diluted with RINKAN (5 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain the title compound (38 mg, 99.8% yield) as a yellow solid. LC / MS (ESI) m / z: 511 (M+1) + .

[0294] Step 13: 2-((3S,5S), or (3R,5R)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl)acetic acid A solution of compound 16 (38 mg, 0.074 mmol) in THF (2 mL), H2O (0.5 mL), and MeOH (0.5 mL) is prepared by adding LiOH · H2O (31 mg, 0.740 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was acidified to approximately pH 6 with 1N aqueous HCl solution and extracted using DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was subjected to preparative HPLC (C). 18 The compound was purified by 10-95% LC / MS (ESI) in H2O containing 0.1% HCOOH, using MeCN, to obtain the title compound (8.5 mg, yield 23%) as a white solid. LC / MS (ESI) m / z: 497 (M+1) + . 1H NMR(400 MHz,CD3OD)δ 7.88(d,J=8.3 Hz,1H),7.66(d,J=1.7 Hz,1H),7.60(d,J=8.4 Hz,1H),7.38(dd,J=9.3,2.4 Hz,1H),6.52(d,J=9.2 Hz,1H),5.87(s,2H),4.82-4.63(m,1H),4.16(s,3H),3.21-3.12(m,1H),3.02-2. 90(m,2H),2.89-2.79(m,1H),2.54-2.40(m,3H),2.39-2.27(m,2H),2.21(t,J=7.5 Hz, 2H), 1.48-1.28 (m, 7H), 0.76 (t, J=7.3 Hz, 3H).

[0295] Example 46: 2-((3R,5R), or (33,5S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5-fluoropiperidine-3-yl)acetic acid The title compound was prepared from compound 14-P2 in the same order as in the synthesis of Example 45. LC / MS(ESI)m / z:497(M+1) + . 1 H NMR(400 MHz,CD3OD)δ 7.88(d,J=8.4 Hz,1H),7.66(d,J=2.0 Hz,1H),7.60(d,J=8.4 Hz,1H),7.38(dd,J=9.3,2.5 Hz,1H),6.52(d,J=9.2 Hz,1H),5.87(s,2H),4.73(d,J=4.6 Hz,1H),4.16(s,3H),3.33(s,1H),3.20-3.14(m,1H),3.01-2.90(m,2H) ,2.88-2.81(m,1H),2.54-2.40(m,3H),2.39-2.26(m,2H),2.21(t,J=7.6 Hz,2H),1.50-1.40(m,1H),1.39-1.33(m,2H),1.31(t,J=7.5 Hz,3H),0.76(t,J=7.3 Hz,3H).

[0296] Example 47: 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid TIFF2026086696000132.tif95128 Step 1: 6-Bromo-3-fluoro-2-methylpyridine 1-oxide To a solution of 6-bromo-3-fluoro-2-methylpyridine (10 g, 52.6 mmol) in TFA (100 mL), H2O2 (40 mL, 353 mmol) was added at 0°C under an N2 atmosphere, and the mixture was stirred at 70°C for 20 hours. The reaction product was cooled to 0°C and quenched with saturated Na2S2O3 aqueous solution. The mixture was extracted with RINKAN (3 × 100 mL), and the combined organic layers were washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:RINKAN = 10:1 to 0:1) to obtain the title compound (8.2 g, yield 75.6%) as a yellow solid.

[0297] Step 2: 6-bromo-3-fluoro-2-methyl-4-nitropyridine 1-oxide To a solution of 6-bromo-3-fluoro-2-methylpyridine 1-oxide (7 g, 34.0 mmol) in concentrated H2SO4 (70 mL, 731 mmol), KNO3 (1.96 g, 19.4 mmol) was added in fractions at 0°C, and the mixture was stirred at 120°C for 6 hours. The reaction mixture was poured into ice water and extracted with HCl (3 × 100 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was recrystallized in HCl to obtain the title compound (2.57 g, yield 30.1%) as a yellow solid. LC / MS(ESI) m / z: 251(M+H) + .

[0298] Step 3: 6-Bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidine-1-yl)-2-methyl-4-nitropyridine-1-oxide To a solution of 6-bromo-3-fluoro-2-methyl-4-nitropyridine 1-oxide (1.2 g, 4.78 mmol) in THF (5 mL), TEA (0.7 mL, 5.04 mmol) and a solution of ethyl 2-(piperidine-3-yl) acetate (0.9 g, 5.26 mmol) in THF (5 mL) were added at 0°C, and the reaction mixture was stirred at 25°C for 24 hours. The mixture was diluted with siRNA (20 mL), washed with water and brine, dried over Na₂SO₄, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:siRNA = 10:1-3:1) to obtain the title compound (1.55 g, yield 82.8%) as a red solid. LC / MS (ESI) m / z: 402 (M+H) + .

[0299] Step 4: Ethyl 2-(1-(6-bromo-2-methyl-4-nitropyridine-3-yl)piperidine-3-yl)acetate To a solution of 6-bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidine-1-yl)-2-methyl-4-nitropyridine 1-oxide (1.55 g, 4.13 mmol) in DCM (15 mL), a solution of PBr3 (0.91 mL, 9.63 mmol) in DCM (2 mL) was added at 0°C under an N2 atmosphere, and the mixture was stirred at 16°C for 3 hours. The reaction product was poured into an ice-cooled saturated NaHCO3 aqueous solution and extracted using DCM (3 × 50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:Â=30:1~10:1) to obtain the title compound (1.52 g, yield 93.9%) as a red oil. LC / MS(ESI) m / z:386(M+H) + .

[0300] Step 5: Ethyl 2-(1-(6-bromo-4-fluoro-2-methylpyridine-3-yl)piperidine-3-yl)acetate To a solution of ethyl 2-(1-(6-bromo-2-methyl-4-nitropyridine-3-yl)piperidine-3-yl)acetate (1.5 g, 3.88 mmol) in DMSO (15 mL), KF (1.13 g, 19.4 mmol) was added, and the reaction mixture was stirred at 140 °C for 3 hours under an N2 atmosphere. The mixture was poured into ice water and extracted with RINKAN (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:RINKAN = 20:1~10:1) to obtain the title compound (700 mg, yield 50.2%) as a yellow solid. LC / MS (ESI) m / z: 359 (M+H) + .

[0301] Step 6: Ethyl 2-(1-(4-fluoro-6-(3-hydroxyprop-1-in-1-yl)-2-methylpyridine-3-yl)piperidine-3-yl)acetate To a mixture of ethyl 2-(1-(6-bromo-4-fluoro-2-methylpyridine-3-yl)piperidine-3-yl)acetate (830 mg, 2.31 mmol) and TEA (0.96 mL, 6.93 mmol) in MeCN (8 mL), CuI (10 mg, 0.046 mmol) and Pd(PPh3)2Cl2 (32.4 mg, 0.046 mmol) were added at 16°C under an N2 atmosphere. Then, prop-2-in-1-ol (0.27 mL, 4.62 mmol) was added, and the resulting mixture was degassed three times under an N2 atmosphere and stirred at 25°C for 22 hours. The mixture was diluted with ELISA (20 mL) and filtered. The filtrate was concentrated until dry, and the residue was purified by silica gel chromatography (PE:Â=10:1~1:1) to obtain the title compound (430 mg, yield 55.7%) as a yellow oil. LC / MS(ESI) m / z:335(M+H) + .

[0302] Step 7: Ethyl 2-(1-(4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)piperidine-3-yl)acetate To a solution of ethyl 2-(1-(4-fluoro-6-(3-hydroxyprop-1-in-1-yl)-2-methylpyridine-3-yl)piperidine-3-yl)acetate (430 mg, 1.29 mmol) in 1,4-dioxane (10 mL), TMSCH2N3 (332 mg, 2.57 mmol), Cp*RuCl(PPh3)2 (51 mg, 0.064 mmol), and cuprous iodide (12.25 mg, 0.064 mmol) were added under an N2 atmosphere. The mixed reaction product was degassed three times under an N2 atmosphere and stirred at 50°C for 16 hours under an N2 atmosphere. The mixture was concentrated until dry, the residue was dissolved in THF (10 mL), and TBAF (336 mg, 1.29 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with toluene (10 mL), washed with water and brine, dried over Na₂SO₄, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (DCM:toluene = 6:1) to obtain the title compound (200 mg, yield 39.7%) as a yellow solid. LC / MS (ESI) (m / z): 392 (M + H) + .

[0303] Step 8: Ethyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate To a solution of ethyl 2-(1-(4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)-2-methylpyridine-3-yl)piperidine-3-yl) acetate (200 mg, 0.511 mmol) in DCM (10 mL), TEA (0.213 mL, 1.53 mmol) and MsCl (0.079 mL, 1.02 mmol) were added at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted using DCM (2 × 5 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title compound (210 mg, yield 87.5%) as a yellow solid. LC / MS (ESI) (m / z): 470 (M + H) + .

[0304] Step 9: Ethyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate To a mixture of ethyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (135 mg, 0.29 mmol) and 5-propyl-1,2-dihydropyridine-2-one (59 mg, 0.43 mmol) in toluene (4 mL) and H2O (1 mL), K2CO3 (80 mg, 0.57 mmol) and TBAF (7.5 mg, 0.03 mmol) were added under an N2 atmosphere, and the mixture was stirred at 70°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl phosphate (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:SiO = 5:1 to 2:1) to obtain the title compound (70 mg, 47.7% yield) as a yellow oil. LC / MS (ESI) (m / z): 511 (M+H) + .

[0305] Step 10: 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid To a solution of ethyl 2-(1-(4-fluoro-2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (50 mg, 0.098 mmol) in THF (2 mL) and MeOH (3 mL), a solution of LiOH (23.5 mg, 0.98 mmol) in water (1 mL) was added at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to 1 / 5 volume, diluted with water, and washed twice with ethyl acetate. The aqueous layer was acidified to approximately pH 3 with 1 N aqueous HCl solution and extracted with ELISA (2 × 5 mL). The combined organic layers were washed with brine, dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure until dry. The residue was purified by preparative HPLC (C18, 25-95% in H2O containing 0.1% HCOOH, MeCN) to obtain the title compound (10 mg, yield 21.2%) as a white solid. LC / MS (ESI) m / z: 483 (M+H) + . 1 H NMR(400 MHz,CD3OD)δ 7.83(d,J=2.1 Hz,1H),7.60(d,J=13.0 Hz,1H),7.38(dd,J=9.2,2.5 Hz,1H),6.47(d,J=9.2 Hz,1H),5.72(s,2H),4.23(s,3H),3.14(t,J=11.7 Hz,2H),3.06-3.03(m,2H),2.63(s,3H),2.31-2.26(m,4H),1.96-1.90(m,1H),1.84(d,J=12.9 Hz,2H),1.51-1.36(m,4H),0.80(t,J=7.3 Hz,3H).

[0306] Example 48: 2-(1-(2-ethyl-4-fluoro-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid TIFF2026086696000133.tif93133 Step 1: 6-Bromo-2-ethyl-3-fluoropyridine To a mixture of 6-bromo-3-fluoro-2-methylpyridine (7.9 g, 41.6 mmol) and DMPU (6.5 mL, 54.1 mmol) in THF (80 mL), LDA (27 mL, 54.1 mmol, 2 M in THF) was added dropwise at -70°C under an N2 atmosphere, and the mixture was stirred at -70°C for 1 hour. MeI (3.37 mL, 54.1 mmol) was added to the mixture, and the resulting mixture was stirred at -70°C for 3 hours and at room temperature for 16 hours. The reaction product was quenched with saturated NH4Cl aqueous solution and extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (eluted using PE) to obtain the title compound (2 g, yield 21.2%) as a colorless oil. LC / MS(ESI)m / z:204 / 206(M+H) + .

[0307] Step 2: 6-bromo-2-ethyl-3-fluoropyridine 1-oxide To a solution of 6-bromo-2-ethyl-3-fluoropyridine (2 g, 10.5 mmol) in TFA (20 mL), H2O2 (8 mL, 70.6 mmol) was added, and the mixture was stirred at 70°C for 16 hours under an N2 atmosphere. The reaction mixture was cooled to 0°C and quenched with saturated Na2S2O3 aqueous solution. The mixture was extracted with RINKAN (3 × 50 mL), and the combined organic layer was washed with saturated NaHCO3 aqueous solution and brine (50 mL), dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by column chromatography (PE:RINKAN = 10:1~5:1) to obtain the title compound (1.5 g, yield 65.0%) as a yellow solid. LC / MS (ESI) m / z: 220 / 222 (M+H) + .

[0308] Step 3: 6-bromo-2-ethyl-3-fluoro-4-nitropyridine 1-oxide To a solution of 6-bromo-2-ethyl-3-fluoropyridine 1-oxide (5.0 g, 22.7 mmol) in concentrated H2SO4 (50 mL), KNO3 (9.19 g, 90.9 mmol) was added in fractions at 0°C, and the mixture was stirred at 120°C for 4 hours. The mixture was poured into ice water and extracted with RINKAN (3 × 50 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:RINKAN = 5:1~3:1) to obtain the title compound (380 mg, yield 6.31%) as a yellow solid. LC / MS (ESI) m / z: 265 / 267 (M+H) + .

[0309] Step 4: 6-Bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidine-1-yl)-2-ethyl-4-nitropyridine-1-oxide To a solution of 6-bromo-2-ethyl-3-fluoro-4-nitropyridine 1-oxide (380 mg, 1.43 mmol) and ethyl 2-(piperidine-3-yl) acetate (318 mg, 1.86 mmol) in THF (5 mL), TEA (0.60 mL, 4.30 mmol) was added, and the mixture was stirred at 25°C for 4 hours. The mixture was concentrated until dry, and the residue was purified by silica gel chromatography (PE:Â=10:1~3:1) to obtain the title compound (480 mg, yield 80.4%) as a yellow oil. LC / MS (ESI) m / z: 416 / 418 (M+H) + .

[0310] Step 5: Ethyl 2-(1-(6-bromo-2-ethyl-4-nitropyridine-3-yl)piperidine-3-yl)acetate To a solution of 6-bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidine-1-yl)-2-ethyl-4-nitropyridine 1-oxide (480 mg, 1.15 mmol) in DCM (5 mL), a solution of PBr3 (0.11 mL, 1.15 mmol) in DCM (1 mL) was added at 0°C under an N2 atmosphere, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice-cooled saturated NaHCO3 aqueous solution and extracted using DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:Â=30:1~20:1) to obtain the title compound (435 mg, yield 94.3%) as a yellow solid. LC / MS(ESI) m / z:400 / 402(M+H) + .

[0311] Step 6: Ethyl 2-(1-(6-bromo-2-ethyl-4-fluoropyridine-3-yl)piperidine-3-yl)acetate To a solution of ethyl 2-(1-(6-bromo-2-ethyl-4-nitropyridine-3-yl)piperidine-3-yl)acetate (435 mg, 1.09 mmol) in DMF (5 mL), TBAF (5.43 mL, 5.43 mmol, 1 M in THF) was added, and the reaction mixture was stirred at 50°C for 1 hour. The mixture was poured into ice water and extracted with RINKAN (2 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (PE:RINKAN = 30:1~20:1) to obtain the title compound (220 mg, yield 54.2%) as a yellow solid. LC / MS (ESI) m / z: 373 / 375 (M+H) + .

[0312] Step 7: Ethyl 2-(1-(2-ethyl-4-fluoro-6-(3-hydroxyprop-1-in-1-yl)pyridine-3-yl)piperidine-3-yl)acetate A mixture of ethyl 2-(1-(6-bromo-2-ethyl-4-fluoropyridine-3-yl)piperidine-3-yl) acetate (220 mg, 0.59 mmol) and prop-2-in-1-ol (0.10 mL, 1.77 mmol) in CH3CN (5 mL) was mixed with TEA (0.25 mL, 1.77 mmol), Pd(PPh3)2Cl2 (41.4 mg, 0.059 mmol), and CuI (11.2 mg, 0.059 mmol) at 0°C under an N2 atmosphere. The mixture was stirred at 25°C for 16 hours under an N2 atmosphere. The mixture was concentrated until dry, and the residue was purified by silica gel chromatography (PE:Â=10:1~2:1) to obtain the title compound (167 mg, yield 81.3%) as a yellow solid. LC / MS(ESI) m / z:349(M+H) + .

[0313] Step 8: Ethyl 2-(1-(2-ethyl-4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate A mixture of ethyl 2-(1-(2-ethyl-4-fluoro-6-(3-hydroxyprop-1-in-1-yl)pyridine-3-yl)piperidine-3-yl) acetate (167 mg, 0.48 mmol) and TMSCH2N3 (0.14 mL, 0.96 mmol) in 1,4-dioxane (3 mL) was mixed with Cp*RuCl(PPh3)2 (38 mg, 0.05 mmol) and CuI (9.1 mg, 0.05 mmol) under an N2 atmosphere. The reaction mixture was degassed and stirred at 50°C for 16 hours under an N2 atmosphere. The mixture was concentrated until dry, the residue was dissolved in THF (10 mL), and then TBAF (1.5 mL, 3 mmol, 2 M in THF) was added. The mixture was diluted with toluene (10 mL), washed with water and brine, dried on anhydrous sodium 2SO4, filtered, and concentrated until dry. The residue was purified by silica gel chromatography (DCM: toluene = 100:0-1:1) to obtain the title compound (100 mg, yield 51.4%) as a yellow oil. LC / MS (ESI) m / z: 406 (M+H) + .

[0314] Step 9: Ethyl 2-(1-(2-ethyl-4-fluoro-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate To a solution of ethyl 2-(1-(2-ethyl-4-fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetate (40 mg, 0.099 mmol) in DCM (2 mL), TEA (0.10 mL, 0.719 mmol) and MsCl (0.05 mL, 0.646 mmol) were added at 0°C under an N2 atmosphere, and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM (5 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry to obtain the title compound (50 mg, yield 100%), which was used directly in the next step. LC / MS (ESI) m / z: 484 (M+H) + .

[0315] Step 10: 2-(1-(2-ethyl-4-fluoro-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid The title compound was prepared according to the procedure described for the synthesis of Example 47. LC / MS(ESI)m / z:497(M+H) + . 1 H NMR(400 MHz,CD3OD)δ 7.69-7.62(m,2H),7.48-7.30(m,1H),6.53-6.49(d,J=9.2 Hz,1H),5.84(s,2H),4.16(s,3H),3.21-3.13(m,2H),3.06-2.98(m,4H),2.31-2.28(d,J=7.0 Hz,2H),2.21-2.26(m,2H),1.98-1.88(m,1H),1.80-1.86(m,2H),,1.51-1.36(m,4H),1.32-1.26(m,3H),0.80-0.75(m,3H).

[0316] Example 49: (S)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetic acid TIFF2026086696000134.tif84137 Step 1: 3,6-Dibromopicolinoyl Chloride A solution of 3,6-dibromopicolinic acid (1 g, 3.56 mmol) in SOCl2 (10 mL) was stirred at 85°C for 3 hours. The reaction mixture was concentrated until dry, and the title compound (1.0 g, 95.0% yield) was obtained as a yellow oil, which was used directly in the next step.

[0317] Step 2: 3,6-Dibromopicolinamide To a solution of 3,6-dibromopyridine-2-carbonyl chloride (1 g, 3.34 mmol) in DCM (10 mL), NH4OH (10 mL) was added dropwise at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was poured into ice water and extracted using DCM (2 × 10 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (900 mg, 90% yield). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 5.59 (s, 2H). LC / MS(ESI)m / z:281(M+H) + .

[0318] Step 3: 3,6-Dibromopicolinonitrile To a solution of 3,6-dibromopicolinamide (900 mg, 3.21 mmol) in DCM (10 mL), pyridine (1.3 mL, 16 mmol) was added, followed by the addition of TFAA (1.25 mL, 9 mmol) at 0°C. The mixture was stirred at this temperature for 1 hour. The mixture was poured into ice water and extracted using DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated until dry. The residue was purified by chromatography on silica gel (eluted using PE:HCl = 30:1 to 5:1) to obtain the title compound (650 mg, yield 77.2%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H).

[0319] Step 3: 3-Bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-in-1-yl)picolinonitrile A mixture of 3,6-dibromopicolinonitrile (2.3 g, 8.7 mmol) and 2-(prop-2-in-1-yloxy)oxane (1.5 g, 10.54 mmol) in MeCN (20 mL) was mixed with TEA (3.7 mL, 26.34 mmol), CuI (84 mg, 0.44 mmol), and Pd(PPh3)2Cl2 (310 mg, 0.44 mmol). The mixture was degassed three times under an N2 atmosphere and stirred at room temperature under an N2 atmosphere for 16 hours. The mixture was diluted with ice water and extracted with SiO2 (2 × 10 mL). The combined organic layers were washed with brine, dried on anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by chromatography (PE:SiO2 = 2:1) on silica gel to obtain the title compound (2.2 g, yield 54.4%) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ 7.97(d,J=8.4 Hz,1H),7.48(d,J=8.4 Hz,1H),4.86(t,J=3.2 Hz,1H),4.50(q,J=16.4 Hz,2H),3.93-3.81(m,1H),3.62-3.51(m,1H),1.91-1.72(m,2H),1.75-1.60(m,3H). LC(ESI)m / z:238(M+H-84) + .

[0320] Step 4: 3-Bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)picolinonitrile To a solution of 3-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-in-1-yl)picolinonitrile (2.2 g, 6.85 mmol) in 1,4-dioxane (5 mL), (azidomethyl)trimethylsilane (1.1 g, 8.22 mmol), CuI (65 mg, 0.34 mmol), and Cp*RuCl(PPh3)2 (270 mg, 0.34 mmol) were added. The mixture was degassed three times under an N2 atmosphere and stirred at 50°C for 16 hours under an N2 atmosphere. The mixture was concentrated until dry, and the residue was dissolved in THF (10 mL). TBAF (1.8 g, 13.7 mmol) was added to the mixture, and the resulting mixture was stirred at 0°C for 10 minutes. The mixture was diluted with toluene (5 mL), washed with water and brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated until dry to obtain the crude product. This was purified by flash chromatography (PE:toluene = 4:1) to obtain the title compound (1.6 g, yield 51.8%) as a white solid. LC / MS (ESI) (m / z): 294 (M + H - 84) + .

[0321] Step 6: Methyl 2-((3S)-1-(2-cyano-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate To a mixture of 1,4-dioxane (7.5 mL), 3-bromo-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)picolinonitrile (80 mg, 0.21 mmol) and methyl(S)-2-(5,5-difluoropiperidine-3-yl)acetate (40.9 mg, 0.21 mmol) was added under an N2 atmosphere to Cs2CO3 (137.8 mg, 0.42 mmol), Ru-Phos Pd G3 (35 mg, 0.04 mmol), and Ru-phos (20 mg, 0.04 mmol). The mixture was degassed three times under an N2 atmosphere and stirred overnight at 110°C under an N2 atmosphere. The mixture was diluted with toluene (5 mL), washed with water and brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (PE:toluene = 2:1) to obtain the title compound (70 mg, yield 67.5%) as a yellow solid. LC / MS (ESI) m / z: 491 (M + H) + .

[0322] Step 7: Methyl(S)-2-(1-(2-cyano-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate To a solution of methyl 2-((3S)-1-(2-cyano-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl) acetate (70 mg, 0.14 mmol) in MeOH (5 mL), PPTS (72 mg, 0.28 mmol) was added, and the mixture was stirred at 50°C for 16 hours. The mixture was concentrated until dry, and the residue was purified by chromatography (elution using PE:Â=1:1) on silica gel to obtain the title compound (55 mg, yield 94.8%) as a yellow solid. LC / MS (ESI) m / z: 407 (M+H) + .

[0323] Step 8: Methyl(S)-2-(1-(2-cyano-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate To a solution of methyl(S)-2-(1-(2-cyano-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl) acetate (60 mg, 0.15 mmol) in DCM (2 mL), TEA (0.06 mL, 0.44 mmol) was added, followed by the addition of MsCl (25 mg, 0.22 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with ice water and extracted using DCM (2 × 3 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated until dry to obtain the title compound (65 mg, yield 90.8%) as a yellow solid. LC / MS (ESI) m / z: 485 (M + H) + .

[0324] Step 9: Methyl(S)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate To a mixture of methyl(S)-2-(1-(2-cyano-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate (70 mg, 0.14 mmol) and 5-propylpyridine-2(1H)-one (20 mg, 0.14 mmol) in toluene (5 mL) and water (1 mL), K2CO3 (40 mg, 0.29 mmol) and TBAF (3.4 mg, catalyst) were added, and the mixture was stirred at 110°C for 1.5 hours. The reaction mixture was diluted with dimethyl ammonium (5 mL), washed with brine, dried over anhydrous sodium ammonium ammonium 1, and filtered. The mixture was concentrated until dry to obtain the title compound (65 mg, yield 88.4%) as a yellow solid. LC / MS(ESI)m / z:526(M+H) + .

[0325] Step 10: (S)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetic acid (12) To a solution of methyl(S)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-5,5-difluoropiperidine-3-yl)acetate (35 mg, 0.067 mmol) in MeOH (1 mL), water (1 mL), and THF (4 mL), LiOH (28 mg, 0.67 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was acidified with 1 M aqueous HCl and extracted with RINKAN (3 × 3 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated until dry. The residue was purified by preparative HPLC to obtain the title compound (20 mg, yield 58.7%) as a white solid. 1H NMR(400 MHz,CD3OD)δ 8.21(d,J=9.2 Hz,1H),7.91(d,J=2.0 Hz,1H),7.80(d,J=9.2 Hz,1H),7.39(dd,J=9.2,2.0 Hz,1H),6.41(d,J=9.2 Hz,1H),5.55(s,2H),4.31(s,3H),3.98-3.74(m,2H),3.57-3.32(m,4H),3.03-2.91( m,1H),2.59-2.32(m,6H),1.90-1.74(m,6H),1.55-1.45(m,1H),0.88(t,J=7.2,3H). LC / MS(ESI)m / z:512(M+H) + .

[0326] Example 50: (R)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid The title compound was prepared according to the procedure described in the synthesis of Example 49 (TIFF2026086696000135.tif46128). LC / MS(ESI) m / z: 476(M+H) + . 1 H NMR(400 MHz,CD3OD)δ 8.17-8.14(d,J=8.9 Hz,1H),7.91(s,1H),7.71-7.68(d,J=9.0 Hz,1H),7.41-7.37(m,1H),6.42-6.39(d,J=9.2 Hz,1H),5.54(s,2H),4.30(s,3H),3.77-3.65(m,2H),3.02-2.96(m,1H),2.81-2.74(m,1H),2 .46-2.39(m,3H),2.27-2.24(m,2H),1.99-1.81(m,3H),1.59-1.46(m,3H),0.89-0.85(m,3H).

[0327] Example 51: (S)-2-(1-(2-cyano-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)piperidine-3-yl)acetic acid The title compound was prepared according to the procedure described in the synthesis of Example 49 (TIFF2026086696000136.tif45128). LC / MS(ESI) m / z: 476(M+H) + . 1 H NMR(400 MHz,CD3OD)δ 8.21(d,J=9.2 Hz,1H),7.91(d,J=2.0 Hz,1H),7.80(d,J=9.2 Hz,1H),7.39(dd,J=9.2,2.0 Hz,1H),6.41(d,J=9.2 Hz,1H),5.55(s,2H),4.31(s,3H),3.98-3.74(m,2H),3.57-3.32(m,4H),3.03-2.91( m,1H),2.59-2.32(m,6H),1.90-1.74(m,6H),1.55-1.45(m,1H),0.88(t,J=7.2,3H).

[0328] Examples 52 and 53: (R) or (S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetic acid, and (S) or (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetic acid TIFF2026086696000137.tif72128 Step 1: (4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methylmethanesulfonate To a solution of (4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol (1 g, 2.91 mmol) in DCM (10 mL), TEA (590 mg, 5.8 mmol) was added, followed by dropwise addition of MsCl (0.40 g, 3.49 mmol) at 0°C. The mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted using DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (1.27 g, yield 103.5%) as a yellow oil, which was used directly in the next step. LC / MS(ESI) m / z: 423(M+H) + .

[0329] Step 2: 1-((4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methyl)-5-propylpyridine-2(1H)-one To a mixture of (4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methylmethanesulfonate (1.27 g, 3.01 mmol) and 5-propylpyridine-2(1H)-one (0.54 g, 3.91 mmol) in toluene (15 mL) and water (3 mL), K2CO3 (1.25 g, 9.02 mmol) and TBAF (80 mg, 0.30 mmol) were added, and the mixture was stirred at 100°C for 16 hours. The mixture was diluted with siRNA (20 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:siRNA = 20:1 to 1:1) to obtain the title compound (1.06 g, yield 76.1%) as a yellowed solid. LC / MS(ESI)m / z:464(M+H) + .

[0330] Step 3: Ethyl(R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetate, and Ethyl(S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetate To a mixture of 1,4-dioxane (3 mL), 1-((4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methyl)-5-propylpyridine-2(1H)-one (120 mg, 0.26 mmol), and ethyl 2-(2-oxopiperidine-3-yl) acetate (48 mg, 0.26 mmol), Cs2CO3 (253 mg, 0.78 mmol), N1,N2-dimethylethane-1,2-diamine (2.3 mg, 0.026 mmol), and CuI (9.9 mg, 0.052 mmol) were added under an N2 atmosphere. After the addition, the mixture was degassed three times under an N2 atmosphere and stirred at 110°C for 16 hours under an N2 atmosphere. The mixture was diluted with 10 mL of ethyl, washed with water and brine, dried over anhydrous sodium 2 SO4, filtered, and concentrated until dry. The residue was purified by chiral SFC and optionally allocated ethyl(R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetate (peak 1, retention time: 6.782 mins) (37 mg, yield A yield of 27.4% was obtained, along with ethyl(S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl) acetate (peak 2, retention time: 7.367 minutes) (37 mg, yield 27.4%), as a white solid. LC / MS (ESI) m / z: 521 (M+H) +SFC equipment: Waters Thar 80-minute SFC, Column: ChiralPak IA, 250×21.2mm inner diameter, 5μm, Mobile phase: A for CO2, and B for MEOH + 0.1% NH3H2O, Gradient: B 35%, Flow rate: 50mL / min, Column temperature: 35℃, Wavelength: 220nm.

[0331] Step 4: (R) or (S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetic acid To a solution of ethyl(R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetate (37 mg, 0.071 mmol) in THF (2 mL), MeOH (0.5 mL), and water (0.5 mL), lithium hydroxide monohydrate (30 mg, 0.71 mmol) was added, and the reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated until dry, and the residue was dissolved in water. The mixture was washed with siRNA (2 × 3 mL), and the aqueous layer was acidified to pH=3 with 1 N aqueous HCl and extracted with siRNA (3 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated until dry. The residue was purified by preparative HPLC (C18, 10-95% in H2O containing 0.1% HCOOH, MeCN) to obtain the title compound (14.7 mg, yield 42.0%) as a white solid. LC / MS (ESI) m / z: 493 (M+H) + . 1H NMR(400 MHz,CD3OD)δ 8.03(dd,J=8.2,1.9 Hz,1H),7.76-7.65(m,1H),7.41(dd,J=9.3,2.5 Hz,1H),6.55(d,J=9.2 Hz,1H),5.91(s,1H),4.14(s,1H),3.82-3.46(m,1H),2.88-2.68(m,2H),2.27-2. 22(m,1H),2.15-1.96(m,1H),1.47-1.36(m,1H),1.31-1.25(m,1H),0.79(t,J=7.2 Hz,1H).

[0332] Example 53: (S) or (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-2-oxopiperidine-3-yl)acetic acid The title compound was prepared according to the procedure described for the synthesis of Example 53. LC / MS(ESI)m / z:493(M+H) + . 1 H NMR(400 MHz,CD3OD)δ 8.03(dd,J=8.3,1.8 Hz,1H),7.77-7.64(m,2H),7.41(dd,J=9.2,2.5 Hz,1H),6.55(d,J=9.2 Hz,1H),5.91(s,2H),4.14(s,3H),3.81-3.46(m,2H),2.89-2.70(m,5H),2.25(t,J=7.6 Hz,2H),2.16-1.93(m,4H),1.47-1.37(m,2H),1.31-1.25(m,3H),0.79(t,J=7.2 Hz,3H).

[0333] Examples 54 and 55: (R) or (S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-6-oxopiperidine-3-yl)acetic acid, and (S) or (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-6-oxopiperidine-3-yl)acetic acid TIFF2026086696000138.tif64160 Step 1: tert-butyl 3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate A mixture of ethyl 2-(piperidine-3-yl)acetate (1 g, 5.8 mmol) and di-tert-butyl dicarbonate (1.9 mL, 8.8 mmol) in DCM (25 mL) was mixed with TEA (1.6 mL, 11.7 mmol) at 0°C, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated until dry, and the residue was purified by flash chromatography (0-20% butyl in PE) to obtain the title compound (1.3 g, yield 82.3%) as a yellow oil. LC-MS (ESI) m / z 272 (M+H) + .

[0334] Step 2: tert-butyl 5-(2-ethoxy-2-oxoethyl)-2-oxopiperidine-1-carboxylate To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (1.3 g, 4.8 mmol) in butyl (10 mL), a solution of NaIO4 (5.1 g, 24.0 mmol) in H2O (10 mL) was added, followed by the addition of ruthenium(IV) oxide hydrate (70 mg, 0.45 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with butyl (2 × 5 mL). The filtrate was washed with saturated Na2SO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-30% butyl in PE) to obtain the title compound (1.1 g, yield 80.1%) as a yellow oil. LC-MS(ESI)m / z286(M+H) + .

[0335] Step 3: Ethyl 2-(6-oxopiperidine-3-yl)acetate To a solution of tert-butyl 5-(2-ethoxy-2-oxoethyl)-2-oxopiperidine-1-carboxylate (1.1 g, 3.9 mmol) in 1,4-dioxane (5 mL), HCl / 1,4-dioxane (4.8 mL, 4 M) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated until dry, and the residue was basicized with saturated NaHCO3 aqueous solution. The mixture was extracted with ELISA (2 × 10 mL), the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated until dry to obtain the title compound (640 mg, yield 89.6%) as a yellow syrup. LC-MS(ESI)m / z186(M+H) + .

[0336] Step 4: Ethyl(R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-6-oxopiperidine-3-yl)acetate, and Ethyl(S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-6-oxopiperidine-3-yl)acetate To a solution of 1-{[4-(6-ethyl-5-iodopyridine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl]methyl}-5-propyl-1,2-dihydropyridine-2-one (250 mg, 0.5 mmol) in 1,4-dioxane (10 mL), ethyl 2-(6-oxopiperidine-3-yl) acetate (150 mg, 0.8 mmol) was added, followed by the addition of Cs2CO3 (527 mg, 1.6 mmol), CuI (21 mg, 0.11 mmol), and N1,N2-dimethylethane-1,2-diamine (15 mg, 0.11 mmol). The reaction mixture was stirred at 120°C for 16 hours. The mixture was filtered through a Celite pad, and the filter cake was washed with ELISA (10 mL). The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (0-50% ethyl in PE), further separated by chiral SFC, and optionally assigned ethyl 2-[(3R)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridine-1-yl)methyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)-6-oxopiperidine-3-yl]acetate (peak 1 (Retention time: 4.123 minutes) (35 mg, yield 9.2%) and ethyl 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridine-1-yl)methyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)-6-oxopiperidine-3-yl]acetate (peak 2, retention time: 4.669 minutes) (40 mg, yield 10.3%) were obtained as white solids. LC-MS(ESI)m / z521(M+H) + SFC conditions: Column: ChiralPak IA, 250 × 21.2 mm inner diameter, 5 μm; Mobile phase: A for CO2, and B (0.1% NH4OH) for methanol; Gradient: B 30%; Flow rate: 50 mL / min; Column temperature: 35°C.

[0337] Step 5: (R) or (S)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-6-oxopiperidine-3-yl)acetic acid To a solution of ethyl 2-[(3R)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridine-1-yl)methyl]-1H-1,2,3-triazole-4-yl}pyridine-3-yl)-6-oxopiperidine-3-yl]acetate (35 mg, 0.06 mmol) in THF (4 mL) and MeOH (1 mL), LiOH (28 mg, 0.7 mmol) in H2O (1 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated until dry, the residue was diluted with water (5 mL), and washed twice with ELISA (2 × 3 mL). The aqueous layer was acidified to approximately pH 3 with 1 N aqueous HCl and extracted using DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated until dry. The residue was purified by perp-HPLC (C18, 0-90% acetonitrile in H2O containing 0.1% formic acid) to obtain the title compound (7 mg, yield 21.2%) as a white solid. LC-MS(ESI)m / z493(M+H) + . 1 H NMR(400 MHz,CD3OD)δ 8.06-8.03(m,1H),7.78-7.71(m,1H),7.66-7.65(t,J=2.6 Hz,1H),7.442-7.29(dd,J=9.3,2.5 Hz,1H),6.55(d,J=9.3 Hz,1H),5.91(d,J=1.8 Hz,2H),4.15(s,3H),3.87-3.41(m,2H),2.81-2.67(m,3H),2.62-2.49(m,1H),2.45-2.43(m,2H),2.35-2.32(m,1H),2.26-2.22(t,J=7.5 Hz,2H),2.20-2.09(m,1H),1.89-1.78(m,1H),1.47-1.36(m,2H),1.32-1.26(q,J=7.6 Hz,3H),0.80-0.77(t,J=7.3 Hz,3H).

[0338] Example 55: (S) or (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyridine-3-yl)-6-oxopiperidine-3-yl)acetic acid The title compound was prepared according to the procedure described for the synthesis of Example 54. 1 H NMR(400 MHz,CD3OD)δ 7.98-7.91(m,1H),7.67-7.60(m,1H),7.56(t,J=2.6 Hz,1H),7.34-7.27(m,1H),6.45(d,J=9.3 Hz,1H),5.81(d,J=1.7 Hz,2H),4.05(s,3H),3.76-3.34(m,2H),2.72-2.58(m,3H),2.53-2.39(m,1H),2.39-2.32(m,2H),2.28-2.18(m,1H),2.15(t,J=7.5 Hz,2H),2.06(d,J=13.6 Hz,1H),1.82-1.65(m,1H),1.38-1.26(m,2H),1.19(q,J=7.6 Hz,3H),0.69(t,J=7.3 Hz,3H). LC / MS(ESI)m / z:493(M+H) + .

[0339] Example 56: (R)-2-(5,5-difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyrazine-2-yl)piperidine-3-yl)acetic acid TIFF2026086696000139.tif64128 Step 1: 3-(5-bromopyrazine-2-yl)prop-2-in-1-ol To a solution of 2,5-dibromopyrazine (1.6 g, 6.73 mmol) and prop-2-in-1-ol (0.38 g, 6.73 mmol) in MeCN (16 mL), TEA (2.0 g, 20.18 mmol), CuI (30 mg, 0.14 mmol), and Pd(PPh3)2Cl2 (90 mg, 0.14 mmol) were added under an N2 atmosphere. After addition, the mixture was degassed three times under an N2 atmosphere and stirred at 25°C for 16 hours. The mixture was diluted with water and extracted with SiO2 (2 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:SiO2 = 20:1 to 2:1) to obtain the title compound (453 mg, yield 31.6%) as a yellowed solid. LC / MS(ESI)m / z:213 / 215(M+H) + .

[0340] Step 2: (4-(5-bromopyrazine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol To a solution of 3-(5-bromopyrazine-2-yl)prop-2-in-1-ol (453 mg, 2.13 mmol) and TMSCH2N3 (493.76 mg, 3.83 mmol) in 1,4-dioxane (5 mL), CuI (20.3 mg, 0.11 mmol) and chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium(II) (84.7 mg, 0.11 mmol) were added under an N2 atmosphere. After addition, the mixture was degassed three times under an N2 atmosphere and stirred at 50°C for 16 hours. The mixture was concentrated until dry, and the residue was dissolved in THF (5 mL). TBAF (1 M in THF, 4.3 mL) was added, and the resulting mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with SiO2 (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (eluted using PE:siRNA = 20:1 to 2:1) to obtain the title compound (205 mg, yield 35.7%) as a yellowed solid. LC / MS (ESI) m / z: 270 / 272 (M+H) + .

[0341] Step 3: (4-(5-bromopyrazine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methylmethanesulfonate To a solution of (4-(5-bromopyrazine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methanol (205 mg, 0.76 mmol) in DCM (2 mL), TEA (230.4 mg, 2.28 mmol) and MsCl (104.3 mg, 0.91 mmol) were added at 0°C under an N2 atmosphere, and the mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted using DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (295 mg, yield 111.6%) as a yellow solid, which was used directly in the next step. LC / MS(ESI) m / z: 348 / 350(M+H) + .

[0342] Step 4: 1-((4-(5-bromopyrazine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methyl)-5-propylpyridine-2(1H)-one To a solution of (4-(5-bromopyrazine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methylmethanesulfonate (295 mg, 0.85 mmol) and 5-propylpyridine-2(1H)-one (174.3 mg, 1.27 mmol) in toluene (5 mL) and H2O (1 mL), K2CO3 (351 mg, 2.54 mmol) and TBAF (22 mg, 0.085 mmol) were added at room temperature under an N2 atmosphere, and the mixture was stirred at 100°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with RINKAN (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by flash chromatography (elution using PE:Â=20:1~2:1) to obtain title compound 6 (130 mg, yield 39.4%) as a yellowed solid. LC / MS(ESI) m / z:389 / 391(M+H) + .

[0343] Step 5: Methyl(S)-2-(5,5-difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyrazine-2-yl)piperidine-3-yl)acetate To a solution of 1-((4-(5-bromopyrazine-2-yl)-1-methyl-1H-1,2,3-triazole-5-yl)methyl)-5-propylpyridine-2(1H)-one (30 mg, 0.077 mmol) and methyl(S)-2-(5,5-difluoropiperidine-3-yl)acetate (14.9 mg, 0.077 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (49 mg, 0.15 mmol), Ru-Phos Pd G3 (13 mg, 0.015 mmol), and Ru-Phos (7.2 mg, 0.015 mmol) were added under an N2 atmosphere. After the addition, the mixture was degassed three times under an N2 atmosphere and stirred at 110°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with ELISA (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry to obtain the title compound (30 mg, 77.6% yield) as a white solid, which was used directly in the next step. LC / MS(ESI) m / z: 502(M+H) + .

[0344] Step 6: (S)-2-(5,5-difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyrazine-2-yl)piperidine-3-yl)acetic acid A solution of methyl(S)-2-(5,5-difluoro-1-(5-(1-methyl-5-((2-oxo-5-propylpyridine-1(2H)-yl)methyl)-1H-1,2,3-triazole-4-yl)pyrazine-2-yl)piperidine-3-yl)acetate (30 mg, 0.06 mmol) was added to THF (2 mL), MeOH (0.5 mL), and H2O (0.5 mL) at 25°C. LiOH.H2O (25 mg, 0.60 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated until dry, and the residue was dissolved in water (5 mL). The mixture was washed with ethyl acetate (2 × 3 mL), and the aqueous layer was acidified to pH=4 with 1 N aqueous HCl solution and extracted with ethyl acetate (3 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated until dry. The residue was purified by preparative HPLC (C18, 10-95% in H2O containing 0.1% HCOOH, MeCN) to obtain the title compound (3.6 mg, yield 12.3%) as a white solid. LC / MS(ESI) m / z: 488(M+H) + . 1 H NMR(400 MHz,CD3OD)δ 8.68(s,1H),8.41(s,1H),7.71(d,J=2.4 Hz,1...

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, During the ceremony, L １ CH may be substituted by a covalent bond or by one or two methyl groups. ２ And, L ２ However, covalent or (CR ７ R ７ ) ｐ And, L ３ is a covalent bond, O or NR ７ wherein, provided that L ２ and L ３ at least one of which is not a covalent bond Q is C(=O)NR ９ R １０ , C (=O) OR １０ , or a ring selected from a 5 or 6-membered heteroaryl group or a 5 or 6-membered heterocyclyl group, wherein the ring comprises at least one carbon atom, at least one nitrogen atom, and optionally one to four additional heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the oxygen may be an oxo group bonded to the ring member and / or the ring member, and the ring is (R ３ ) ｎ and one R ４ It has been replaced by, X １ However, N, O, or CR ６ａ And, X ２ However, N or NR ６ And, X ３ However, N, NR ６ or CR ６ The dashed circle indicates the bond that forms a five-membered aromatic ring. Y １ , Y ２ , Y ３ , and Y ４ However, each independently, N or CR ５ And, however, Y １ , Y ２ , Y ３ , and Y ４ The condition is that at least one of them is present, but two or fewer are N. Z is CH ２ or O, R １ However, in each entity, independently, hydrogen, halogen, and C １～６ Alkyl, Halo C １～６ Alkyl, OH, C １～６ Alkyl-OH, C １～６ Alkoxy, Halo C １～６ Alkoxy, CN, C ３～７ Cycloalkyl, NR ａ R ｂ , C １～６ Alkyl-NR ａ R ｂ , or a 4-6 member heterosilyl, or two R １ The groups, together with the carbon atoms to which they bond, form a C=O. R ２ However, (CR ７ R ７ ) ｑ -R ８ And, R ３ However, in each of these entities, hydrogen, halogen, CN, and C exist independently. １～６ Alkyl, or C ３～７ It is a cycloalkyl, R ４ However, independently, hydrogen, halogen, C １～６ Alkyl, Halo C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, (CH ２ ) ｐ -C １～６ Alkoxy, phenyl, (CH ２ ) ｐ - Phenyl, O(CH ２ ) ｐ - Phenyl, CN, C ３～７ Cycloalkyl, (CH ２ ) ｐ -C ３～７ Cycloalkyl, C ２～６ Alkenyl-C ３～７ Cycloalkyl, C ２～６ Alkinyl-C ３～７ Cycloalkyl, O(CH ２ ) ｐ -C ３～７ Cycloalkyl, 1 to 4 R １１ (CH ２ ) ｑ - 5-6 member heteroaryl ring, 1-4 R １１ (CH ２ ) ｑ - A 5- to 7-membered heterocyclyl ring, where each phenyl group independently contains a halogen, C １～６ Alkyl, or C １～６ It may be substituted with 1 to 3 alkoxy groups. R ５ is, in each occurrence, independently hydrogen, halogen, C １～６ alkyl, halo C １～６ alkyl, OH, C １～６ alkyl-OH, C １～６ alkoxy, C １～６ alkyl-C １～６ alkoxy, halo C １～６ alkoxy, CN, C ３～７ cycloalkyl, NR ａ R ｂ or C １～６ alkyl-NR ａ R ｂ wherein R ６ａ and R ６ Each of these entities is independently hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl. R ７ However, in each existence, hydrogen and C exist independently. １～４ Alkyl, C ３～５ It is either cycloalkyl or has two R's ７ The groups, together with the carbon atoms to which they are bonded, form a 3- to 5-membered cycloalkyl ring. R ８ is C(=O)OR ７ C(=O)NR ａ R ｂ CN, C(=O)NH C(=O)R ７ C(=O)NH S(=O) ２ R ７ C(=O)NH S(=O)R ７ S(=O) ２ R ７ P(=O)(OH) ２ or And, R ９ and R １０ Each of these entities independently contains hydrogen, 1 to 4 R １１ C replaced by １～６ Alkyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ２～６ Alkenyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ２～６ Alkinyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ３～７ Cycloalkyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ - Phenyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ - 5-6 member heteroaryl ring, 1-4 R １１ Replaced by (CR １２ R １２ ) ｑ - A 5- to 7-membered heterocyclyl ring, or R ９ and R １０ However, along with the nitrogen atom to which they bond, there are 1 to 4 R １１ A saturated or unsaturated 3- to 7-membered heteroring is formed by substitution, and the ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. R １１ However, in each existence, hydrogen and C exist independently. １～６ Alkyl, Halo C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, (CH ２ ) ｐ -C １～６ Alkoxy, phenyl, (CH ２ ) ｐ - Phenyl, O(CH ２ ) ｐ - Phenyl, CN, C ３～７ Cycloalkyl, (CH ２ ) ｐ -C ３～７ Cycloalkyl, C ２～６ Alkenyl-C ３～７ Cycloalkyl, C ２～６ Alkinyl-C ３～７ Cycloalkyl, O(CH ２ ) ｐ -C ３～７ It is a cycloalkyl group, and each phenyl group is independently a halogen, C １～６ Alkyl, or C １～６ It may be substituted with 1 to 3 alkoxy groups. R １２ However, in each existence, hydrogen and C exist independently. １～４ Alkyl, C ３～７ It is either cycloalkyl or has two R's １２ The groups, together with the carbon atoms to which they are bonded, form a 3- to 6-membered cycloalkyl ring. R ａ and R ｂ Each of these entities independently contains hydrogen or C １～６ Alkyl or R ａ and R ｂ However, together with the nitrogen atom to which they are bonded, they form a saturated or unsaturated heterocycle containing 3 to 7 ring atoms, and the ring may optionally contain an additional 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and C １ ~ ４ It may be substituted with one to three identical or different groups selected from the group consisting of alkyl, phenyl, and benzyl. m is 1 or 2, n is 0, 1, or 2, p is independently 1, 2, 3, or 4 in each existence, and q is independently 0, 1, 2, 3, or 4 in each existence. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

2. Z is CH ２ The compound according to claim 1.

3. The compound according to claim 1, wherein Z is O.

4. L １ The compound according to any one of claims 1 to 3, wherein the bond is covalent.

5. L １ However, CH may be substituted with one or two methyl groups. ２ The compound according to any one of claims 1 to 3.

6. L １ However, CH ２ The compound according to any one of claims 1 to 3.

7. R １ The compound according to any one of claims 1 to 6, wherein each of the elements present is independently hydrogen.

8. R １ The compound according to any one of claims 1 to 6, wherein each of the elements present is independently a halogen.

9. m is 2, and on the other hand, R １ However, it is hydrogen, and the other R １ The compound according to any one of claims 1 to 6, wherein the compound is a halogen.

10. m is 2, and on the other hand, R １ However, it is hydrogen, and the other R １ The compound according to any one of claims 1 to 6, wherein F.

11. m is 2, R １ The compound according to any one of claims 1 to 6, wherein each of the elements present is F.

12. Y ２ However, N is Y １ , Y ３ , and Y ４ Each of them independently ５ The compound according to any one of claims 1 to 11.

13. Y １ However, CR ５ Y ２ However, N is Y ３ and Y ４ The compound according to any one of claims 1 to 11, wherein each of them is independently CH.

14. Y １ However, CR ５ Y ２ However, N is Y ３ However, N is Y ４ A compound according to any one of claims 1 to 11, wherein the compound is CH.

15. R ５ The compound according to any one of claims 1 to 14, wherein, in each presence, it is independently hydrogen, methyl, or ethyl.

16. R ５ However, in each entity, independently, hydrogen, CHF ２ , or CF ３ The compound according to any one of claims 1 to 14.

17. R ５ The compound according to any one of claims 1 to 14, wherein, in each presence, it is independently hydrogen or CN.

18. X １ However, N is X ２ However, N is X ３ However, NR ６ The compound according to any one of claims 1 to 17.

19. X １ However, CH and X ２ However, N is X ３ However, NR ６ The compound according to any one of claims 1 to 17.

20. X １ However, O and X ２ However, N is X ３ However, CR ６ The compound according to any one of claims 1 to 17.

21. R ６ The compound according to any one of claims 1 to 20, wherein the compound is methyl.

22. L ２ The compound according to any one of claims 1 to 21, wherein the bond is covalent.

23. L ２ However, (CR ７ R ７ ) ｐ The compound according to any one of claims 1 to 21.

24. L ２ However, CH ２ The compound according to any one of claims 1 to 21.

25. L ３ The compound according to any one of claims 1 to 24, wherein the bond is covalent.

26. L ３ The compound according to any one of claims 1 to 24, wherein the compound is O.

27. L ３ However, NR ７ The compound according to any one of claims 1 to 24.

28. The compound according to any one of claims 1 to 27, wherein q is 0.

29. The compound according to any one of claims 1 to 27, wherein q is 1.

30. The compound according to any one of claims 1 to 27, wherein q is 2.

31. R ８ The compound according to any one of claims 1 to 30, wherein the compound is a COOH group.

32. R ９ However, C １～４ A compound according to any one of claims 1 to 31, wherein it is alkyl.

33. R １０ However, 1 to 4 R １１ C replaced by １～６ Alkyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ２～６ Alkenyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ２～６ Alkinyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ３～７ Cycloalkyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ - Phenyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ - 5-6 member heteroaryl ring, 1-4 R １１ Replaced by (CR １２ R １２ ) ｑ A compound according to any one of claims 1 to 32, wherein the compound is a 5- to 7-membered heterocyclyl ring.

34. R １０ However, C １～６ A compound according to any one of claims 1 to 33, wherein it is alkyl.

35. R １０ However, (CH ２ ) ｐ -C ３～７ A compound according to any one of claims 1 to 33, wherein it is a cycloalkyl compound.

36. R ９ and R １０ However, along with the nitrogen atom to which they are bonded, there are 1 to 4 R １１ The compound according to any one of claims 1 to 33, wherein it forms a saturated or unsaturated 3- to 7-membered heteroring substituted by, and the ring may optionally contain an additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

37. Q is C(=O)NR ９ R １０ The compound according to any one of claims 1 to 36.

38. Q is a ring selected from a 5-membered heteroaryl or heterocyclyl and a 6-membered heteroaryl or heterocyclyl, wherein the ring contains at least one nitrogen atom on at least one carbon atom, and optionally 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the oxygen may be a carbonyl bonded to the ring member and / or to the ring member, and the ring is (R ３ ) ｎ and R ４ A compound according to any one of claims 1 to 36, which is substituted by...

39. Q is, And each of them is at any available carbon or nitrogen position (R ３ ) ｎ and one R ４ The compound according to claim 38, which is substituted by [the specified compound].

40. Q is, And each of them is at any available carbon or nitrogen position (R ３ ) ｎ and one R ４ The compound according to claim 38, which is substituted by [the specified compound].

41. R ３ Each of these entities independently contains hydrogen, halogen, or C １～４ A compound according to any one of claims 1 to 40, wherein it is alkyl.

42. R ３ Each entity independently of C １～４ A compound according to any one of claims 1 to 40, wherein it is alkyl.

43. R ３ The compound according to any one of claims 1 to 40, wherein each of the elements present is independently methyl.

44. R ４ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, (CH ２ ) ｐ -C １～６ Alkoxy, phenyl, (CH ２ ) ｐ - Phenyl, O(CH ２ ) ｐ - Phenyl, CN, C ３～７ Cycloalkyl, (CH ２ ) ｐ -C ３～７ Cycloalkyl, C ２～６ Alkenyl-C ３～７ Cycloalkyl, C ２～６ Alkinyl-C ３～７ Cycloalkyl, O(CH ２ ) ｐ -C ３～７ It is a cycloalkyl group, and each phenyl group is independently a halogen, C １～６ Alkyl, or C １～６ The compound according to any one of claims 1 to 43, which may be substituted with one to three alkoxy groups.

45. R ４ However, independently, 1 to 4 R １１ (CH ２ ) ｑ - 5-6 member heteroaryl ring, or 1-4 R １１ (CH ２ ) ｑ A compound according to any one of claims 1 to 43, wherein the compound is a 5- to 7-membered heterocyclyl ring.

46. R ４ However, independently, C １～６ Alkyl, C ２～６ Alkinyl, C １～６ Alkoxy, (CH ２ ) ｐ -C １～６ Alkoxy, C ３～７ Cycloalkyl, (CH ２ ) ｐ -C ３～７ Cycloalkyl, or C ２～６ Alkenyl-C ３～７ A compound according to any one of claims 1 to 43, wherein it is a cycloalkyl compound.

47. Having the structure of formula (II), During the ceremony, Q is a ring selected from the group consisting of 5-membered heteroaryls, 5-membered heterocyclines, 6-membered heteroaryls, and 6-membered heterocyclines, wherein the ring comprises at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the oxygen may be an oxo bonded to the ring member and / or to the ring member, and the ring is (R ３ ) ｎ and one R ４ It has been replaced by, X １ However, N, or CR ６ａ And, R ６ａ However, it is hydrogen or methyl, R ６ However, it is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl, R １３ However, in each existence, hydrogen and C exist independently. １～４ Alkyl, or C ３～５ It is a cycloalkyl, t is 0, 1, 2, or 3, w is 0 or 1, provided that L １ If the bond is covalent, then the condition is that w is 1, and furthermore, L １ However, CH may be substituted with one or two methyl groups. ２ If that is the case, then the condition is that w is 0, The compound according to any one of claims 1 to 46.

48. Z is CH ２ The compound according to claim 47.

49. The compound according to claim 47, wherein Z is O.

50. L １ The compound according to any one of claims 47 to 49, wherein the bond is covalent.

51. L １ However, CH may be substituted with one or two methyl groups. ２ The compound according to any one of claims 47 to 49.

52. L １ However, CH ２ The compound according to any one of claims 47 to 49.

53. R １ The compound according to any one of claims 47 to 52, wherein each of the elements present is independently hydrogen.

54. R １ The compound according to any one of claims 47 to 52, wherein each of the elements present is independently a halogen.

55. One side of the １ However, it is hydrogen, and the other R １ The compound according to any one of claims 47 to 52, wherein the compound is a halogen.

56. One side of the １ However, it is hydrogen, and the other R １ The compound according to any one of claims 47 to 52, wherein F.

57. R １ The compound according to any one of claims 47 to 52, wherein each of the elements is independently F.

58. portion but, The compound according to any one of claims 47 to 57.

59. Each R ５ However, independently, hydrogen, halogen, C １～６ Alkyl, or halo C １～６ A compound according to any one of claims 47 to 58, wherein it is alkyl.

60. Each R ５ However, C １～６ A compound according to any one of claims 47 to 58, wherein it is alkyl.

61. Each R ５ The compound according to any one of claims 47 to 58, wherein the compound is independently methyl or ethyl.

62. Each R ５ However, CHF became independent. ２ or CF ３ The compound according to any one of claims 47 to 58.

63. X １ The compound according to any one of claims 47 to 62, wherein N is present.

64. X １ The compound according to any one of claims 47 to 62, wherein the compound is CH.

65. R ６ The compound according to any one of claims 47 to 64, wherein the compound is methyl.

66. L ２ However, (CR ７ R ７ ) ｐ The compound according to any one of claims 47 to 65.

67. L ２ However, CH ２ The compound according to any one of claims 47 to 65.

68. L ３ The compound according to any one of claims 47 to 65, wherein the bond is covalent.

69. L ３ The compound according to any one of claims 47 to 65, wherein the compound is O.

70. L ３ However, NR ７ The compound according to any one of claims 47 to 65.

71. Q is, And each of them is at any available carbon or nitrogen position (R ３ ) ｎ and one R ４ The compound according to any one of claims 47 to 70, wherein it is substituted by and n is 0, 1, or 2.

72. Q is at any available carbon or nitrogen position (R ３ ) ｎ and one R ４ Replaced by The compound according to claim 71, wherein n is 0, 1, or 2.

73. Q is, And each of them is at any available carbon or nitrogen position (R ３ ) ｎ and one R ４ The compound according to any one of claims 47 to 70, wherein it is substituted by and n is 0, 1, or 2.

74. R ３ Each of these entities independently contains hydrogen, halogen, or C １～４ The compound according to any one of claims 47 to 73, wherein it is alkyl.

75. R ３ Each entity independently of C １～４ The compound according to any one of claims 47 to 73, wherein it is alkyl.

76. R ３ The compound according to any one of claims 47 to 73, wherein each of the elements present is independently methyl.

77. R ４ However, independently, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, (CH ２ ) ｐ -C １～６ Alkoxy, phenyl, (CH ２ ) ｐ - Phenyl, O(CH ２ ) ｐ - Phenyl, CN, C ３～７ Cycloalkyl, (CH ２ ) ｐ -C ３～７ Cycloalkyl, C ２～６ Alkenyl-C ３～７ Cycloalkyl, C ２～６ Alkinyl-C ３～７ Cycloalkyl, O(CH ２ ) ｐ -C ３～７ It is a cycloalkyl group, and each phenyl group is independently a halogen, C １～６ Alkyl, or C １～６ The compound according to any one of claims 47 to 76, which may be substituted with one to three alkoxys.

78. R ４ However, independently, 1 to 4 R １１ (CH ２ ) ｑ - 5-6 member heteroaryl ring, or 1-4 R １１ (CH ２ ) ｑ A compound according to any one of claims 47 to 76, wherein the compound is a 5- to 7-membered heterocyclyl ring.

79. R ４ However, independently, C １～６ Alkyl, C ２～６ Alkinyl, C １～６ Alkoxy, (CH ２ ) ｐ -C １～６ Alkoxy, C ３～７ Cycloalkyl, (CH ２ ) ｐ -C ３～７ Cycloalkyl, or C ２～６ Alkinyl-C ３～７ A compound according to any one of claims 47 to 76, wherein it is a cycloalkyl compound.

80. The part is The compound according to any one of claims 47 to 79.

81. R １３ The compound according to any one of claims 47 to 80, wherein the compound is hydrogen.

82. R １３ The compound according to any one of claims 47 to 80, wherein the compound is methyl.

83. R １３ The compound according to any one of claims 47 to 80, wherein the compound is cyclopropyl.

84. It has the structure of formula (III), During the ceremony, X １ However, N, or CR ６ａ And, R ６ａ However, it is hydrogen or methyl, R ６ However, it is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl, R １３ However, in each existence, hydrogen and C exist independently. １～４ Alkyl, or C ３～５ It is a cycloalkyl, t is 0, 1, 2, or 3, w is 0 or 1, provided that L １ If the bond is covalent, then the condition is that w is 1, and furthermore, L １ However, CH may be substituted with one or two methyl groups. ２ If that is the case, then the condition is that w is 0, The compound according to any one of claims 1 to 46 or 48 to 83.

85. Z is CH ２ The compound according to claim 84.

86. The compound according to claim 84, wherein Z is O.

87. L １ The compound according to any one of claims 84 to 86, wherein the bond is covalent.

88. L １ However, CH may be substituted with one or two methyl groups. ２ The compound according to any one of claims 84 to 86.

89. L １ However, CH ２ The compound according to any one of claims 84 to 86.

90. R １ The compound according to any one of claims 84 to 89, wherein each of the elements is independently hydrogen.

91. R １ The compound according to any one of claims 84 to 89, wherein each of the elements present is independently a halogen.

92. One side of the １ However, it is hydrogen, and the other R １ The compound according to any one of claims 84 to 89, wherein the compound is a halogen.

93. One side of the １ However, it is hydrogen, and the other R １ The compound according to any one of claims 84 to 89, wherein F is present.

94. R １ The compound according to any one of claims 84 to 89, wherein each of the elements is independently F.

95. portion but, The compound according to any one of claims 84 to 94.

96. Each R ５ However, independently, hydrogen, halogen, or C １～６ The compound according to any one of claims 84 to 95, wherein it is alkyl.

97. Each R ５ However, C １～６ The compound according to any one of claims 84 to 95, wherein it is alkyl.

98. Each R ５ The compound according to any one of claims 81 to 95, wherein the compound is independently methyl or ethyl.

99. X １ The compound according to any one of claims 84 to 98, wherein N is present.

100. X １ The compound according to any one of claims 84 to 98, wherein the compound is CH.

101. R ６ The compound according to any one of claims 84 to 100, wherein the compound is methyl.

102. L ２ However, (CR ７ R ７ ) ｐ The compound according to any one of claims 84 to 101.

103. L ２ However, CH ２ The compound according to any one of claims 84 to 101.

104. L ３ The compound according to any one of claims 84 to 101, wherein the bond is covalent.

105. L ３ The compound according to any one of claims 84 to 101, wherein the compound is O.

106. L ３ However, NR ７ The compound according to any one of claims 84 to 101.

107. R ９ However, C １～４ The compound according to any one of claims 84 to 106, wherein it is alkyl.

108. R １０ However, 1 to 4 R １１ C replaced by １～６ Alkyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ２～６ Alkenyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ２～６ Alkinyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ -C ３～７ Cycloalkyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ - Phenyl, 1 to 4 R １１ Replaced by (CR １２ R １２ ) ｑ - 5-6 member heteroaryl ring, 1-4 R １１ Replaced by (CR １２ R １２ ) ｑ A compound according to any one of claims 84 to 107, wherein the compound is a 5- to 7-membered heterocyclyl ring.

109. R １０ However, C １～６ The compound according to any one of claims 84 to 107, wherein it is alkyl.

110. R １０ However, (CH ２ ) ｑ -C ３～７ A compound according to any one of claims 84 to 107, wherein it is a cycloalkyl compound.

111. R ９ and R １０ However, along with the nitrogen atom to which they are bonded, there are 1 to 4 R １１ The compound according to any one of claims 84 to 107, wherein it forms a saturated or unsaturated 3- to 7-membered heteroring substituted by, and the ring may optionally contain an additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

112. The part is The compound according to any one of claims 84 to 111.

113. R １３ The compound according to any one of claims 84 to 112, wherein the compound is hydrogen.

114. R １３ The compound according to any one of claims 84 to 112, wherein the compound is methyl.

115. R １３ The compound according to any one of claims 84 to 112, wherein the compound is cyclopropyl. A compound according to claim 1, selected from

116. . A compound according to claim 1, selected from

117. . A compound according to claim 1, selected from

118. . A compound according to claim 1, selected from

119. .

120. A pharmaceutical composition comprising a compound according to any one of claims 1 to 119 and a pharmaceutically acceptable carrier.

121. A method for treating or preventing a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi) in a subject in need, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 119.

122. The method according to claim 121, wherein the disease is pathological fibrosis (e.g., lung, liver, kidney, heart, skin (dernal), eye, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, or systemic sclerosis.

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