Novel triazole-pyridine substituted pyrrolidinyl and tetrahydro-2H-pyranyl acetic acid compounds as LPA antagonists

Abstract

The present application relates to novel triazole-pyridine substituted pyrrolidinyl, tetrahydro-2H-pyranyl, cyclohexyl, and piperidinyl acetic acid compounds, their preparation, pharmaceutical compositions containing them, and their use as medicaments for treating diseases associated with dysregulation of the lysophosphatidic acid receptor (LPA).

Description

[Technical Field]

[0001] This application claims priority to PCT International Application No. PCT / CN2021 / 091510, filed April 30, 2021, the entire contents of which are incorporated herein by reference.

[0002] Field This application relates to novel triazole-pyridine substituted pyrrolidinyl, tetrahydro-2H-pyranyl, cyclohexyl, and piperidinyl acetic acid compounds and related compounds, their preparation, pharmaceutical compositions containing them, and their use as medicaments for treating diseases associated with dysregulation of the lysophosphatidic acid receptor (LPA). [Background technology]

[0003] background Lysophosphatidic acid (LPA) is a small glycerol phospholipid (1- or 2-acyl-sn-glycerol triphosphate) with a molecular weight of 430 to 480 daltons, consisting of a phosphate group and a glycerol backbone esterified with fatty acids of variable chain length and degree of saturation (Yang and Chen, World J Gastroenterol 24:4132-4151, 2018). LPA can be formed from precursor molecules in plasma, serum, or tissues (membrane phospholipids) through several pathways: (1) hydrolysis of the choline group from lysophosphatidylcholine by lysophospholipase D (lysoPLD or autotaxin), (2) hydrolysis of the fatty acyl chain from phosphatidic acid to generate 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). In tissues or cells, LPA represents a mixture of 1- or 2-acyl-sn-glycerol 3-phosphates.

[0004] 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 (LPARs 1-6) that are expressed in various tissues and / or cells. Through binding to its receptors, LPA plays an important role in pathophysiological processes such as autoimmune diseases, fibrotic diseases, cancer, inflammation, and neuropathic pain (Budd and Qian, Future Med Chem 5:1935-52, 2013 (Non-Patent Document 3); Valdes-Rives and Gonzalez-Arenas, Mediators Inflamm 2017:9173090, 2017 (Non-Patent Document 4); Lopane et al., Biochim Biophys Acta Rev Cancer 1868:277-282, 2017 (Non-Patent Document 5); Ueda H. Pain 158 Suppl 1:S55-S65, 2017 (Non-Patent Document 6)).

[0005] Fibrosis is a repair (or "healing") process characterized by the excessive accumulation of extracellular matrix (ECM). When tissue damage (caused by infection, autoimmune reactions, mechanical injury, etc.) is chronic, the continuous production of profibrotic mediators leads to an uncontrolled healing process, and replacement of damaged cells occurs with connective tissue associated with the overproduction of ECM (Weiskirchen et al., Molecular Aspects Med. 65:2-15, 2019). Because fibrosis alters organ structure and function, it is closely associated with and often causes morbidity and mortality. It is estimated that 45% of all deaths in the developed world are attributable to several types of chronic fibrosis, such as idiopathic pulmonary fibrosis, systemic sclerosis, liver cirrhosis, chronic cardiovascular disease, progressive kidney disease (renal fibrosis), or diabetes (Wynn TANat. Rev. Immunol. 4:583-594, 2004).

[0006] The profibrotic effects of LPA, via binding to its receptor LPAR1, have been established in the lung, liver, and other organs or tissues with two major characteristics: 1) the presence of a positive correlation between the appearance of fibrotic markers and increased LPA production associated with increased LPAR1 expression; and 2) attenuation of fibrosis in LPAR1- / - mice or by treatment with an LPAR antagonist (Rancoule et al., Expert Opin. Investig. Drugs 20:657667, 2011). For example, in a bleomycin model of pulmonary fibrosis, LPA levels were significantly increased in bronchoalveolar lavage fluid 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). Treatment with a small molecule LPAR1 antagonist can reduce pulmonary fibrosis in a bleomycin mouse model (Swanet et al., Br. J. Pharmacol. 160:1699-1713, 2010). More recently, in a rat model of chemically induced liver cirrhosis and HCC, Lapr1 expression was significantly increased in hepatic stellate cells, while lysoPLD (autotaxin) expression was higher in hepatocytes (Nakagawa et al., Cancer Cell. 30:879-890, 2016). Transcriptome analysis of human and rat liver tissues demonstrated that the LPA pathway, mediated by activation of LPAR1, was a functional driver of liver cirrhosis and HCC. Accordingly, inhibition of LPAR1 and lysoPLD by chemical inhibitors attenuated the progression of fibrosis and reduced HCC nodules in a cirrhosis-driven HCC rat model (Id.). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Yang and Chen, World J Gastroenterol 24:4132-4151, 2018

Non-Patent Document 2

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Non-Patent Document 4

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Non-Patent Document 12

Summary of the Invention

[0008] overview In one aspect, the present invention provides a compound of formula (I): TIFF2024517769000001.tif62128 or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, The A ring is: TIFF2024517769000002.tif82144; and L 1 is a covalent bond, NH, O, or S, with the proviso that L 1 is a covalent bond, the A ring is selected from formula (A1), (A2), (A3), (A4), or (A5); and 1 is NH or S, the A ring is selected from formula (A6) or (A7), and further, L 1 is O, with the proviso that ring A is selected from formula (A6): L 2 is a covalent bond or (CR 7 R 7 ) p and L 3 is a covalent bond, O, or NR 7 where L 2 and L 3 is not a covalent bond; Q is C(=O)NR 9 R 10 , C(=O)OR 10 or a 5- or 6-membered heteroaryl group or a 5- or 6-membered heterocyclyl group, wherein the ring contains at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the oxygen may be a ring member and / or an oxo group (═O) bonded to a ring member, and the ring is selected from (R 3 ) n and one R 4is replaced by X 1 is N, O, or CR 6a and X 2 is N or NR 6 and X 3 is N, NR 6 , or CR 6 where the dashed circle indicates the bond that forms the five-membered aromatic ring, Y 1 , Y 2 , Y 3 , and Y 4 are each independently N or CR 5 where Y 1 , Y 2 , Y 3 , and Y 4 at least one but not more than two of Z 1 , Z 2 , Z 3 , and Z 4 are each independently CH2 or O, with the proviso that Z 1 , Z 2 , Z 3 , and Z 4 is O, 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-membered heterosilyl, or R 1 and R 1 together with the carbon atom to which they are attached form a ketone (C=O), R 2 represents, independently at each occurrence, hydrogen, deuterium, C1~4 Alkyl, C 3~5 cycloalkyl or R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 3 is, in each occurrence, independently hydrogen, halogen, CN, C 1~6 Alkyl, or C 3~7 is cycloalkyl, R 4 is 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q - a 5- to 7-membered heterocyclyl ring, wherein each phenyl is independently optionally substituted with 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 5 represents, in each occurrence, hydrogen, halogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, OH, C 1~6 Alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6Alkoxy, HaloC 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 independently represents hydrogen, halogen, CN, C 1~4 alkyl, or cyclopropyl; R 7 is, in each occurrence, independently hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 9 and R 10 Each occurrence of is independently selected from hydrogen, one to four R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q- a 5- to 7-membered heterocyclyl ring, or R 9 and R 10 are composed of 1 to 4 R groups together with the nitrogen atom to which they are attached. 11 forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R 11 is, in each occurrence, independently hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, or O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 12 is, in each occurrence, independently hydrogen, C 1~4 Alkyl or C 3~7 cycloalkyl or R 12 and R 12 together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R a and R b Each occurrence of is independently hydrogen or C 1~6 alkyl, and R a and R btogether with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; p in each occurrence is independently 1, 2, 3, or 4; q is independently 0, 1, 2, 3, or 4 in each occurrence.

[0009] In another aspect, the present invention provides a compound of formula (IV) TIFF2024517769000003.tif54128 or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, 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-membered heterosilyl, or R 1 and R 1 together with the carbon atom to which they are attached form a ketone (C=O), R 5 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, C 1~6 Alkyl-C1~6 Alkoxy, HaloC 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b and X 1 But N or CR 6a and R 6a is hydrogen or methyl, R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L 2 is (CR 7 R 7 ) p and The Q ring is TIFF2024517769000004.tif20128, each of which is (R 3 ) n and one R 4 is replaced by R 3 is, in each occurrence, independently hydrogen, halogen, CN, C 1~6 Alkyl, or C 3~7 is cycloalkyl, R 4 But hydrogen, halogens, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl, O(CH2) p-C 3~7 Cycloalkyl, 1 to 4 R 11 substituted with (CH2) q - 5-6 membered heteroaryl ring, 1-4 R 11 substituted with (CH2) q - a 5- to 7-membered heterocyclyl ring, wherein each phenyl independently optionally contains 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 7 is, in each occurrence, independently hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 11 is, in each occurrence, independently hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R a and R b Each occurrence of is independently hydrogen or C 1~6 alkyl, and R a and R btogether with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; n is 0, 1, or 2; t is 0, 1, 2, or 3; p in each occurrence is independently 1, 2, 3, or 4; and q in each occurrence is independently 0, 1, 2, 3, or 4.

[0010] The present invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and (IV), their preparation, and their use as medicaments for treating diseases associated with lysophosphatidic acid receptor 1 (LPAi) dysregulation. Thus, the compounds of formula (I) and (IV) are useful for treating pathological fibrosis (e.g., pulmonary, hepatic, renal, cardiac, cutaneous, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description In one aspect, the present invention provides compounds and pharmaceutically acceptable forms thereof, including, but not limited to, salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotopically labeled derivatives thereof.

[0012] In another aspect, the present invention provides methods for treating and / or managing various diseases and disorders, comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, isomer, sterioisomer, enantiomer, prodrug, and isotopically labeled derivative). Non-limiting examples of diseases and disorders are described herein.

[0013] In another aspect, the present invention provides methods for preventing various diseases and disorders, comprising administering to a patient in need of such prevention a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, isomer, sterioisomer, prodrug, and isotopically labeled derivative). Non-limiting examples of diseases and disorders are described herein.

[0014] In another aspect, the compounds provided herein, or pharmaceutically acceptable forms thereof (e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotopically labeled derivatives), can be administered in combination with another drug (a "second active agent") or treatment. Second active agents include small molecules and large molecules (e.g., proteins and antibodies).

[0015] Also provided herein are pharmaceutical compositions (e.g., single unit dosage forms) that can be used in the methods 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 isotopically labeled derivative), and optionally one or more second active agents.

[0016] While specific embodiments are discussed, this specification is illustrative only and not restrictive. Many variations of the disclosure will become apparent to those of skill in the art upon review of this specification.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0018] definition As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0019] As used herein, "drug," "biologically active agent," or "second active agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. 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. A variety of compounds can be synthesized, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides), as well as synthetic organic compounds based on various core structures. In addition, a variety of natural sources can provide active compounds, such as, for example, plant or animal extracts. One of ordinary skill in the art can readily recognize that there is no limit as to the structural nature of the agents of the present disclosure.

[0020] "Administration" of the disclosed compounds encompasses delivery of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, as discussed herein.

[0021] As used herein, the terms "co-administration," "administered in combination with," and their grammatical equivalents include administration of two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0022] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to affect the intended use, including, but not limited to, disease treatment, as described 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. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. This term also applies to a dosage that will induce a response in target cells, such as reduced cell migration. A particular dosage will vary depending, for example, on the selected compound, the subject's species and their age / existing health conditions or risk to health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0023] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0024] As used herein, the terms "treatment," "treating," "alleviating," "managing," and "ameliorating" are used interchangeably herein. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient, even though the patient may still suffer from the underlying disease. For prophylactic benefit, pharmaceutical compounds and / or compositions may be administered to patients at risk of developing a disease or to patients who report one or more physiological symptoms of a disease, even if a diagnosis of the disease has not been made.

[0025] As used herein, the terms "preventing" and "prophylaxis" refer to administering a pharmaceutical compound or medicament, or a composition containing a pharmaceutical compound or medicament, to a subject before a disease, disorder, or condition fully manifests itself, to prevent the appearance and / or reduce the severity of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will recognize that the term "prevent" is not an absolute term. In the medical field, it is understood to refer to 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 terms as used in this disclosure.

[0026] A "therapeutic effect," as that term is used herein, encompasses therapeutic and / or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0027] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female 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., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys.

[0028] The term "in vivo" refers to events that take place inside a subject's body. In vivo also includes events that occur in rodents, such as rats, mice, guinea pigs, etc.

[0029] The term "in vitro" refers to events that occur outside of a subject's body. For example, an in vitro assay includes any assay performed outside of a subject. In vitro assays include cell-based assays in which cells, living or dead, are used. In vitro assays also include cell-free assays in which no intact cells are used.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, 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. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. 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 with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, organic acids from which salts can be derived include, for example, 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, salicylic acid, and the like.

[0031] 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. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4 alkyl) 4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0032] As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Solvates can consist of the disclosed compounds, or pharmaceutically acceptable salts thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that can include, 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.

[0033] 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 yield a pharmaceutically acceptable form of the disclosed compound or compounds. A prodrug may be inactive when administered to a subject but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, a prodrug has improved physical and / or delivery properties relative to the parent compound. A prodrug can increase the bioavailability of the compound when administered to a subject (e.g., by enabling enhanced absorption into the blood after oral administration) or enhance delivery to a desired biological compartment (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced aqueous solubility or active transport across the intestinal membrane compared to the parent compound.

[0034] Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium 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 incorporated herein by reference in their entireties. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced aqueous solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the gastrointestinal tract, or it can enhance drug stability for long-term storage.

[0035] The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is 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 modifications are cleaved to the parent active compound, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that cleaves to form 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, acetate, formate, and benzoate derivatives of alcohols, such as in active compounds, or acetamide, formamide, and benzamide derivatives 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).

[0036] For example, if a disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, the prodrug may be a compound selected from the group consisting of a hydrogen atom of the acid group and a (C 1~8 ) alkyl, (C 1~12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 10 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 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 ) alkyl, or the like, to form pharmaceutically acceptable esters.

[0037] Similarly, when a disclosed compound contains an alcohol functional group, the prodrug may be a compound selected from the group consisting of a hydrogen atom of the alcohol group and a (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 α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from naturally occurring L-amino acids, -P(O)(OH), -P(O)(O(C 1~6) alkyl) 2, or glycosyl (a radical resulting from removal of the hydroxyl group of a hemiacetal form of a carbohydrate).

[0038] When the disclosed compounds incorporate an amine functional group, prodrugs can be prepared by combining a hydrogen atom in the amine group with a hydroxyl group in which R and R′ are each 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 ) alkyl, or benzyl, -C(OH)C(O)OY 1 ;Y 2 However, (C 1~4 ) alkyl, and 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 is H or methyl, and Y 5 However, mono-N- or di-N-(C 1~6 ) alkylamino -C(Y 4 )Y 5 , morpholino, piperidin-1-yl, or pyrrolidin-1-yl groups.

[0039] In some embodiments, the disclosed compounds may include isomers. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric and stereoisomers. For example, "isomer" includes geometric double bond cis and trans isomers, also referred to as E and Z isomers, R and S enantiomers, diastereomers, (d) isomers and (l) isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the present disclosure.

[0040] Geometric isomers are represented by symbols representing bonds which may be single, double or triple bonds as described herein. TIFF2024517769000005.tif2128. Provided herein are various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbon ring. Substituents around a carbon-carbon double bond are designated as being of the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers.

[0041] Alternatively, substituents around a carbon-carbon double bond may be designated "cis" or "trans," with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring may also be designated "cis" or "trans." The term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are disposed on both the same and opposite sides of the plane of the ring is designated "cis / trans."

[0042] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportions may be known as a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is an enantiomer, the stereochemistry at each chiral carbon may be specified as either R or S. Resolved compounds of unknown absolute configuration may be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that the compound rotates plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- in terms of the absolute stereochemistry at each asymmetric atom. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using, for example, chiral synthons or chiral reagents, or resolved using conventional techniques.

[0043] In some embodiments, an enantiomer is provided partially or substantially free of the corresponding enantiomer and may be referred to as "optically enriched," "enantiomerically enriched," "enantiomerically pure," and "non-racemic," when used interchangeably herein. The "enantiomeric excess" or "% enantiomeric excess" of 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% Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. 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 the S enantiomer, or a range between and including any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the S enantiomer over the R enantiomer. In other embodiments, some 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 the R enantiomer, or a range between any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the R enantiomer over the S enantiomer. When the enrichment of one enantiomer is much greater than about 80% by weight, the composition is referred to as a "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic" preparation.

[0044] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. 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 the S enantiomer, or a range between and including any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the S enantiomer over the R enantiomer. In other embodiments, some 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 the R enantiomer, or a range between any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the R enantiomer over the S enantiomer. When the enrichment of one enantiomer is much greater than about 80% by weight, the composition is referred to as a "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic" preparation.

[0045] Optical isomers can be obtained according to conventional processes, for example, by the formation of diastereomeric salts, by treatment with optically active acids or bases, or by resolution of racemic mixtures. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Separation of the diastereomeric mixture by crystallization, followed by liberation of the optically active base from the salt, results in separation of the isomers. Another method involves the synthesis of covalent diastereomeric molecules by reacting the disclosed compounds with optically pure acids in activated form or with optically pure isocyanates. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to deliver enantiomerically enriched compounds. Optically active compounds can also be obtained by using active starting materials. In some embodiments, these isomers can be in the form of free acids, free bases, esters, or salts.

[0046] 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 migration of at least one of the hydrogen atoms 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 prototropic tautomerism, which are considered a subset of acid-base chemistry. "Prototropic tautomerism" or "prototropic tautomerism" involves the migration of a proton with a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. When tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. Tautomerism (i.e., the reaction providing the tautomeric pair) can be catalyzed by an acid or base, or can occur without the action or presence of an external agent. Exemplary tautomers include, but are not limited to, keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different) enamine tautomers. A specific example of keto-enol tautomerism is the interconversion of the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of the tautomers of pyridin-4-ol and pyridin-4(1H)-one.

[0047] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0048] The present disclosure also encompasses pharmaceutically acceptable forms that are "isotopically labeled derivatives," which are compounds identical to those enumerated herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include, 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 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl. Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can allow for ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, can confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that may also contain unnatural proportions of atomic isotopes at one or more of the atoms comprising such compounds. All isotopic variations of compounds as disclosed herein, whether radioactive or not, are encompassed within the scope of the present disclosure. In some embodiments, radiolabeled compounds are useful for studying the metabolism and / or tissue distribution of compounds, or for altering the rate or pathway of metabolism or other aspects of biological function.

[0049] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. A pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compounds and is non-toxic when administered in dosages 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. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated.Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and non-toxic compatible lubricants such as sodium lauryl sulfate and stearin. magnesium stearate; colorants; release agents; coating agents; sweetening, flavoring, and fragrance agents; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as da tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymeric delivery matrices; serum proteins, such as human serum albumin; 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, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyacrylates, waxes, and polyethylene-polyoxypropylene-block polymers. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrin, or other solubilized derivatives, can also be used to enhance delivery of the compounds described herein.

[0050] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sansalito, 1999; Smith and 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.

[0051] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value and subrange falling within the range, unless otherwise stated herein, and each separate value and subrange is incorporated herein as if it were individually recited 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 5~6Alkyl is intended to be included.

[0052] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated linear alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups, while saturated branched alkyls 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, 2,3-dimethylbutyl, etc. The alkyl is attached to the parent molecule by a single bond. Unless otherwise stated herein, the alkyl group may be optionally substituted with one or more of the substituents disclosed herein. In a non-limiting embodiment, the substituted alkyl may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0053] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 10 carbon atoms (i.e., C 2~10Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; for example, "2 to 10 carbon atoms" means that the alkenyl group can consist of up to 10 carbon atoms, such as 2 carbon atoms, 3 carbon atoms, etc. In some embodiments, the alkenyl comprises 2 to 8 carbon atoms. In other embodiments, the alkenyl comprises 2 to 6 carbon atoms (e.g., C 2~6 Alkenyls include alkyl groups such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and penta-1,4-dienyl. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), 2-methylprop-2-enyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), 2,3-dimethyl-2-butenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless stated otherwise herein, alkenyl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0054] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and having from 2 to 10 carbon atoms (i.e., C 2~10Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; for example, "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, or up to 10 carbon atoms. In some embodiments, the alkynyl comprises 2 to 8 carbon atoms. In other embodiments, the alkynyl comprises 2 to 6 carbon atoms (e.g., C 2~6 Alkynyl groups include alkynyl groups, which are attached to the parent molecular structure by a single bond and are, for example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentenyl, hexynyl, and the like. Unless stated otherwise herein, alkynyl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0055] "Alkoxy" refers to the group -O-alkyl containing 1 to 10 carbon atoms of a straight, branched, saturated, cyclic configuration, and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbons. In some embodiments, C 1~4 Alkoxy is an alkoxy group that includes both straight- and branched-chain alkyls of 1 to 4 carbon atoms. Unless otherwise stated herein, an alkoxy group may be optionally substituted with one or more of the substituents disclosed herein. The terms "alkenoxy" and "alkynoxy" mirror the above description of "alkoxy," with the prefix "alk" replacing "alkene" or "alkyne," respectively, and the parent "alkenyl" or "alkynyl" terms as described herein.

[0056] "Aromatic" or "aryl" refers to a radical having 6 to 14 ring atoms (e.g., C 6~14In some embodiments, aryl refers to C 6~10 An aryl group. For example, a divalent radical formed from a substituted benzene derivative and having a free valence on a ring atom is named a substituted phenylene radical. In another embodiment, a divalent radical derived from a monovalent polycyclic hydrocarbon radical ending in "-yl" by removing one hydrogen atom from the carbon atom having the free valence is named by adding "idene" to the name of the corresponding monovalent radical; for example, a naphthyl group having two attachment points is called naphthylidene. Whenever it appears herein, a numerical range such as "6 to 14 aryl" refers to each integer in the given range; for example, "6 to 14 ring atoms" means that the aryl group can consist of up to 14 ring atoms, such as 6 ring atoms, 7 ring atoms, etc. This term includes monocyclic or fused-ring polycyclic (i.e., rings sharing pairs of adjacent ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In polycyclic groups, only one ring is required to be aromatic, and thus groups such as indanyl are encompassed by the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless otherwise stated herein, aryl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0057] "Cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic radical that contains only carbon and hydrogen and can be saturated or partially unsaturated. A partially unsaturated cycloalkyl group can be referred to as a "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or as a "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. A cycloalkyl group is a group having 3 to 13 ring atoms (i.e., C 3~13

[0023] Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can consist of up to 13 carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to a C 3~8 In some embodiments, "cycloalkyl" is a C 3~5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: C 3~6 Carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~7 An example of a carbocyclyl group is norbornyl (C7). 3~8 Examples of carbocyclyl groups include the aforementioned C 3~7 Examples include carbocyclyl groups, cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. 3~13 Examples of carbocyclyl groups include the aforementioned C 3~8Examples of cycloalkyl groups include carbocyclyl groups, and octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless stated otherwise herein, cycloalkyl groups may be optionally substituted with one or more of the substituents disclosed herein. The terms "cycloalkenyl" and "cycloalkynyl" reflect the above description of "cycloalkyl," with the prefix "alk" replacing "alkene" or "alkyne," respectively, and the parent "alkenyl" or "alkynyl" terms as described herein. For example, cycloalkenyl groups can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, cycloalkynyl groups can have 5 to 13 ring atoms.

[0058] "Halo," "halide," or alternatively, "halogen" means fluoro, chloro, bromo, or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof, preferably substituted with one, two, or three halo groups. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2 trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, -O-CHF2, and the like. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and may be optionally further substituted as defined herein.

[0059] "Heteroaryl," or alternatively, "heteroaromatic," refers to the radical of a 5- to 18-membered 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) having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 18-membered heteroaryl"). Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; for example, "5 to 18 ring atoms" means that the heteroaryl group can consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, etc. In some cases, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, heteroaryls have divalent radicals derived from monovalent heteroaryl radicals whose names end in "-yl", e.g., by removing one hydrogen atom from the atom with the free valence, and are named by adding "-ene" to the name of the corresponding monovalent radical, e.g., a pyridyl group with two points of attachment is pyridylene.

[0060] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring 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. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxide. A heteroaryl is attached to the parent molecular structure through any atom of the ring.

[0061] "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment to the parent molecular structure being on either the aryl or heteroaryl ring, or in which a heteroaryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, with the point of attachment to the parent molecular structure being on the heteroaryl ring. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment to the parent molecular structure can be on either ring, i.e., either the ring containing a heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl). In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system ("5- to 10-membered heteroaryl") having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system ("5- to 8-membered heteroaryl") having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system ("5- to 6-membered heteroaryl") having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0062] Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzopyranonyl, and benzofuranyl. Lazanil, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, 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-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzyl benzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[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, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8- Methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2, Examples of heteroaryl groups include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated herein, heteroaryl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0063] "Heterocyclyl," "heterocycloalkyl," or "heterocarbocyclyl" each refer 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 fused, bridged, or spiro ring systems. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. Heterocyclyl groups can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups can be referred to as "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, a numerical range such as "5 to 18" refers to each integer in the given range; for example, "5 to 18 ring atoms" means that the heterocyclyl group can consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, etc. Divalent radicals derived from monovalent heterocyclyl radicals whose names end in "-yl", e.g., by removing one hydrogen atom from the atom having the free valence, are named by adding "-ene" to the name of the corresponding monovalent radical; e.g., a piperidine group having two points of attachment is piperidylene.

[0064] An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom. The heteroatoms in the heterocyclyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quaternized. Heterocyclyl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxide. A heterocyclyl is attached to the parent molecular structure through any atom of any of the rings.

[0065] "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment to the parent molecular structure being on the heterocyclyl ring. In some embodiments, a heterocyclyl group is a 5- to 14-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5- to 14-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "3- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0066] A "heterocyclyl" may contain one or more ketone groups (-C(=O)-) as part of the ring. Examples of ketone-containing heterocycles include, but are not limited to, pyridin-2(1H)-one, pyrazin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, pyridin-4(1H)-one, imidazolidin-2-one, 1,3-dihydro-2H-imidazol-2-one, 2,4-dihydro-3H-1,2,4-triazol-3-one, oxazol-2(3H)-one, and oxazolidin-2-one. Ketone-containing heterocyclyls can be obtained by removing a hydrogen atom from the corresponding ketone-containing heterocycle at any available NH or CH position.

[0067] Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, thiazolidinyl, and dithiolanyl. Exemplary 5-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, diazolonyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, phenanthridinyl, indolyl, and the like. nyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH- These include, but are not limited to, pyrrolo[2,3-b]pyridinyl, hydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0068] Unless stated otherwise specifically, a heterocyclyl group may be optionally substituted with one or more of the substituents disclosed herein.

[0069] Where substituent groups are specified by their conventional chemical formula written from left to right, they equally encompass the chemically identical substituent that would result from writing the structure from right to left; for example, -CHO- is equivalent to -OCH-.

[0070] A "leaving group or atom" is any group or atom that, under reaction conditions, is cleaved from a starting material, thereby facilitating reaction at a specific site. Suitable non-limiting examples of such groups, unless otherwise specified, include halogen atoms, mesyloxy, p-nitrobenzenesulfonyloxy, trifluoromethyloxy, and tosyloxy groups.

[0071] The term "protecting group" has its traditional meaning in organic synthesis: a group that selectively blocks one or more reactive sites in a multifunctional compound so that a chemical reaction can be selectively performed at an otherwise unprotected reactive site, and so that the group can be easily removed after the selective reaction is complete. Non-limiting examples of functional groups that can be masked by a protecting group include amine, hydroxy, thiol, carboxylic acid, and aldehyde. For example, a hydroxy-protected form is when at least one of the hydroxy groups present in a 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 regarding protecting group methodology (materials, methods, and strategies for protection and deprotection) and other synthetic chemical transformations useful in 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 entireties.

[0072] The term "substituted" or "substituted" means that at least one hydrogen present on a group atom (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon displacement by hydrogen, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group can have a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. Substituents include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, 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 (wherein t is 1 or 2), -P(=O)(R a )(Ra ), or -OP(=O)(OR a )2, wherein each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties (other than hydrogen) can be optionally substituted with one or more substituents (up to six, valences allowed) selected from OH, NH, oxo, halo, nitro, COOH, C(O)NH, or cyano. For example, a cycloalkyl substituent can have a halide substituted on one or more ring carbons, etc. Protecting groups that can form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.

[0073] Suitable substituents include, but are not limited to, haloalkyl and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -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-NRa C(NR a )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 (wherein M is C 1~6 alkyl group).

[0074] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with several substituents varying within an explicitly defined range, it is understood that the total number of substituents does not exceed the normally available valences under the existing conditions. Thus, for example, a phenyl ring substituted with a "p" substituent (where "p" ranges from 0 to 5) can have 0 to 5 substituents, while a pyridinyl ring substituted with a "p" substituent is understood to have several substituents ranging from 0 to 4. The maximum number of substituents that a group in a disclosed compound may have can be readily determined. Substituted groups encompass only those combinations of substituents and variables that result in stable or chemically feasible compounds. Stable or chemically feasible compounds are those that have sufficient stability to permit their preparation and detection, among other factors. In some embodiments, the disclosed compounds are sufficiently stable that they remain substantially unchanged when maintained at a temperature of 40° C. or less 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 other chemically reactive conditions for, e.g., 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.

[0075] The terms "combining, combining, to combine, combination" refer to the act of adding at least one chemical to another chemical, either sequentially or simultaneously. In some embodiments, bringing these chemicals together can result in the conversion of the first chemical into one or more different chemicals. This conversion can occur through one or more chemical reactions, such as, for example, covalent bonds being formed, broken, or rearranged. A non-limiting example can include hydrolysis of an ester to an alcohol and a carboxylic acid, which can result from combining an ester with a suitable base. In another non-limiting example, an aryl fluoride can be combined with an amine to provide an aryl amine through a substitution process. These terms also include changes associated with charged chemicals and the production of charged chemicals, such as, but not limited to, N-oxide formation, acid addition salt formation, base addition salt formation, etc. These terms include the production and / or conversion of radical chemicals and isotopically labeled chemicals.

[0076] The terms "convert, converting, to convert, conversion" 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 to another functional group. For example, conversion includes, but is not limited to, using a reducing agent to convert a nitro functional group on a chemical to an amine. Conversion also includes the alteration of charged chemicals, radical chemicals, and isotopically labeled chemicals. However, the term "convert" does not include the alteration of conserved bonds in the disclosed genera and compounds.

[0077] compound In one aspect, the present invention provides a compound of formula (I): TIFF2024517769000006.tif51128 or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, The A ring is: TIFF2024517769000007.tif83145; and L 1 is a covalent bond, NH, O, or S, with the proviso that L 1 is a covalent bond, the A ring is selected from formula (A1), (A2), (A3), (A4), or (A5); and 1 is NH or S, the A ring is selected from formula (A6) or (A7), and further, L 1 is O, with the proviso that ring A is selected from formula (A6): L 2 is a covalent bond or (CR 7 R 7 ) p and L 3 is a covalent bond, O, or NR 7 where L 2 and L 3 is not a covalent bond; Q is C(=O)NR 9 R 10 , C(=O)OR 10 or a 5- or 6-membered heteroaryl group or a 5- or 6-membered heterocyclyl group, wherein the ring contains at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the oxygen may be a ring member and / or an oxo group (═O) bonded to a ring member, and the ring is selected from (R 3 ) n and one R 4 is replaced by X 1 is N, O, or CR 6a and X 2 is N or NR 6 and X 3 is N, NR 6 , or CR 6 where the dashed circle indicates the bond that forms the five-membered aromatic ring, Y 1 , Y 2 , Y 3 , and Y 4 are each independently N or CR 5 where Y 1 , Y 2 , Y 3 , and Y 4 at least one but not more than two of Z 1 , Z 2 , Z 3 , and Z 4 are each independently CH2 or O, with the proviso that Z 1 , Z 2 , Z 3 , and Z 4 is O, 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-membered heterosilyl, or R 1 and R 1 together with the carbon atom to which they are attached form a ketone (C=O), R 2 represents, independently at each occurrence, hydrogen, deuterium, C 1~4 Alkyl, C 3~5 cycloalkyl or R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 3 is, in each occurrence, independently hydrogen, halogen, CN, C 1~6 Alkyl, or C 3~7 is cycloalkyl, R4 is 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q - a 5- to 7-membered heterocyclyl ring, wherein each phenyl is independently optionally substituted with 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 5 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, C 1~6 Alkyl-C 1~6 Alkoxy, HaloC 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 independently represents hydrogen, halogen, CN, C 1~4alkyl, or cyclopropyl; R 7 is, in each occurrence, independently hydrogen, C 1~4 Alkyl or C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 9 and R 10 Each occurrence of is independently selected from hydrogen, one to four R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q - a 5- to 7-membered heterocyclyl ring, or R 9 and R 10 together with the nitrogen atom to which they are attached, 1 to 4 R 11 forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R 11is, in each occurrence, independently hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, or O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 12 is, in each occurrence, independently hydrogen, C 1~4 Alkyl, C 3~7 cycloalkyl or R 12 and R 12 together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R a and R b Each occurrence of is independently hydrogen or C 1~6 alkyl, and R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; p in each occurrence is independently 1, 2, 3, or 4; q is independently 0, 1, 2, 3, or 4 in each occurrence.

[0078] In some embodiments, the A ring is selected from formula (A1). In certain other embodiments, the A ring is selected from formula (A2). In still other embodiments, the A ring is selected from formula (A3). In still other embodiments, the A ring is selected from formula (A4). In still other embodiments, the A ring is selected from formula (A5). In still other embodiments, the A ring is selected from formula (A6). In still other embodiments, the A ring is selected from formula (A7).

[0079] In some embodiments, formula (A1) is represented by formula (A1a): TIFF2024517769000008.tif27128.

[0080] In some other embodiments, Formula (A1) is Formula (A1b): TIFF2024517769000009.tif27128.

[0081] In some embodiments, formula (A3) is represented by formula (A3a): The file is TIFF2024517769000010.tif24128.

[0082] In some other embodiments, Formula (A3) is Formula (A3b): The file is TIFF2024517769000011.tif24128.

[0083] In any embodiment, L 1 is a covalent bond. In certain other embodiments, L 1 is NH. In yet another embodiment, L 1 is O. In yet another embodiment, L 1 is S.

[0084] In any embodiment, R 1 is independently hydrogen at each occurrence. In certain other embodiments, R 1 is independently at each occurrence halogen. In still other embodiments, m is 2 and one R 1 is hydrogen, and the other R 1 In yet another embodiment, m is 2 and one R 1 is hydrogen, and the other R 1 is F. In yet other embodiments, m is 2 and R 1 is independently F in each occurrence.

[0085] In any embodiment, R 2 is, at each occurrence, independently hydrogen or deuterium. In certain other embodiments, R 2 is independently C in each occurrence. 1~4 In yet another embodiment, R 2 is independently C in each occurrence. 3~5 In yet another embodiment, R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring. 2 is hydrogen, and the other R 2 is methyl. In yet other embodiments, one R 2 is hydrogen, and the other R 2 is ethyl or propyl. In yet other embodiments, one R 2 is hydrogen, and the other R 2 is cyclopropyl. In yet another embodiment, R 2 and R 2 together with the carbon atoms to which they are attached form a cyclopropyl ring.

[0086] In any embodiment, Y 2 is N and Y 1 , Y 3 , and Y 4 Each of the 5In certain other embodiments, Y 1 is CR 5 and Y 2 is N and Y 3 and Y 4 Each of Y is independently CH. 1 is CR 5 and Y 2 is N and Y 3 is N and Y 4 is CH.

[0087] In any embodiment, R 5 is independently hydrogen at each occurrence. In certain other embodiments, R 5 is independently methyl at each occurrence. 5 is independently ethyl at each occurrence. 5 is independently at each occurrence halogen. In still other embodiments, R 5 is, at each occurrence, independently CHF2 or CF3. In still other embodiments, R 5 is independently CN at each occurrence. In any embodiment, R 5 is, in each occurrence, independently hydrogen or C 1~6 It is alkyl.

[0088] In any embodiment, X 1 is N and X 2 is N and X 3 is NR 6 In certain other embodiments, X 1 is CH and X 2 is N and X 3 is NR 6 In yet another embodiment, X 1 is O and X 2 is N and X 3 is CR 6 is.

[0089] In any embodiment, R 6is methyl, ethyl, or propyl. In any embodiment, R 6 is methyl. In certain other embodiments, R 6 is hydrogen. In yet another embodiment, R 6 is ethyl.

[0090] In any embodiment, R 6a is methyl, ethyl, or propyl. In any embodiment, R 6a is methyl. In certain other embodiments, R 6a is hydrogen. In yet another embodiment, R 6a is ethyl.

[0091] In any embodiment, L 2 is a covalent bond. In certain other embodiments, L 2 is (CR 7 R 7 ) p In yet another embodiment, L 2 is CH2.

[0092] In any embodiment, L 3 is a covalent bond. In certain other embodiments, L 3 is O. In yet another embodiment, L 3 is NR 7 is.

[0093] In any embodiment, R 9 is C 1~4 It is alkyl.

[0094] In any embodiment, R 10 is 1 to 4 R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q-C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q -5- to 7-membered heterocyclyl ring. In certain other embodiments, R 10 is C 1~6 In yet another embodiment, R 10 is (CH2) p -C 3~7 In yet another embodiment, R 9 and R 10 are composed of 1 to 4 R groups together with the nitrogen atom to which they are attached. 11 and forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with , which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0095] In some embodiments, Q is C(=O)NR 9 R 10 In certain other embodiments, Q is C(═O)OR 10 In still other embodiments, Q is a ring selected from a 5- or 6-membered heteroaryl group or a 5- or 6-membered heterocyclyl group, wherein the ring members contain at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the oxygen may be an oxo group (═O) attached to a ring member and / or a ring member, and the ring is 3 ) n and one R 4In yet other embodiments, the Q ring is substituted with: TIFF2024517769000012.tif40153, each of which can be placed at any available carbon or nitrogen position (R 3 ) n and one R 4 In yet other embodiments, the Q ring is substituted with: TIFF2024517769000013.tif64166, each of which can be placed at any available carbon or nitrogen position (R 3 ) n and one R 4 is replaced by .

[0096] In any embodiment, R 3 is, in each occurrence, independently hydrogen, halogen, or C 1~4 In certain other embodiments, R 3 is independently C in each occurrence. 1~4 In yet another embodiment, R 3 is methyl in each occurrence.

[0097] In any embodiment, R 4 is hydrogen, C 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C1~6 In certain other embodiments, R 4 is 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q In yet another embodiment, R 4 is C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, or C 2~6 Alkenyl-C 3~7 It is cycloalkyl.

[0098] In any embodiment, m is 0. In certain other embodiments, m is 1. In still other embodiments, m is 2. In still other embodiments, m is 3.

[0099] In any embodiment, n is 0. In certain other embodiments, n is 1. In still other embodiments, n is 2.

[0100] In any embodiment, p is 1. In certain other embodiments, p is 2. In still other embodiments, p is 3. In still other embodiments, p is 4.

[0101] In any embodiment, q is 0. In certain other embodiments, q is 1. In still other embodiments, q is 2. In still other embodiments, q is 3. In still other embodiments, q is 4.

[0102] In some embodiments, the compound of formula (I) is a compound of formula (II): TIFF2024517769000014.tif42128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, The A ring is: TIFF2024517769000015.tif27151; a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from 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-membered heterosilyl, or R 1 and R 1 together with the carbon atom to which they are attached form a ketone (C=O), R 2 represents, independently at each occurrence, hydrogen, deuterium, C 1~4 Alkyl, C 3~5 cycloalkyl or R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; Z 1 , Z 2 , Z 3 , and Z 4 are each independently CH or O, with the proviso that Z 1 , Z 2 , Z 3 , and Z 4 is O, R 5 is, in each occurrence, independently hydrogen, halogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, OH, C 1~6 Alkyl-OH, C1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, HaloC 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b and X 1 But N or CR 6a and R 6a is hydrogen or methyl, R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L 2 is a covalent bond or (CR 7 R 7 ) p and L 3 is a covalent bond, O, or NR 7 where L 2 and L 3 is not a covalent bond; The Q ring is selected from 5-membered heteroaryl or heterocyclyl and 6-membered heteroaryl or heterocyclyl, the Q ring contains one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the Q ring is selected from (R 3 ) n and one R 4 is replaced by R 3 is, in each occurrence, independently hydrogen, halogen, CN, C 1~6 Alkyl, or C 3~7 is cycloalkyl, R 4 is 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 1~6Alkoxy, 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 Cycloalkyl, 1 to 4 R 11 substituted with (CH2) q - 5-6 membered heteroaryl ring, 1-4 R 11 substituted with (CH2) q - a 5- to 7-membered heterocyclyl ring, wherein each phenyl is independently optionally substituted with 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 7 is, in each occurrence, independently hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 11 is, in each occurrence, independently hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R a and R b Each occurrence of is independently hydrogen or C 1~6 alkyl, and R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; t is 0, 1, 2, or 3; p, in each occurrence, is independently 1, 2, 3, or 4; q is independently 0, 1, 2, 3, or 4 in each occurrence.

[0103] In some embodiments, the compound of formula (II) has the formula (IIa): TIFF2024517769000016.tif54128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, Symbols (Q, X 1 , L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n, t) can have any of the values ​​disclosed herein.

[0104] In some embodiments, the compound of formula (II) has formula (IIb): TIFF2024517769000017.tif52128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, Symbols (Q, X 1 , L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n, t) can have any of the values ​​disclosed herein.

[0105] In some embodiments, the compound of Formula (II) has the formula (IIc): TIFF2024517769000018.tif53128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, Symbols (Q, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n, t) can have any of the values ​​disclosed herein.

[0106] In any embodiment (including but not limited to compounds of Formula I, II, II(a), II(b), and II(c)), R 1 is independently at each occurrence hydrogen. In certain other embodiments, R 1 is independently at each occurrence halogen. In still other embodiments, m is 2 and one R 1 is hydrogen, and the other R 1 In yet another embodiment, m is 2 and one R 1 is hydrogen, and the other R1 is F. In yet other embodiments, m is 2 and R 1 is independently F in each occurrence.

[0107] In any embodiment, R 2 is, at each occurrence, independently hydrogen or deuterium. In certain other embodiments, R 2 is independently C in each occurrence. 1~4 In yet another embodiment, R 2 is independently C in each occurrence. 3~5 In yet another embodiment, R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring. 2 is hydrogen, and the other R 2 is methyl. In yet other embodiments, one R 2 is hydrogen, and the other R 2 is ethyl or propyl. In yet other embodiments, one R 2 is hydrogen, and the other R 2 is cyclopropyl. In yet another embodiment, R 2 and R 2 together with the carbon atoms to which they are attached form a cyclopropyl ring.

[0108] In any embodiment, the moiety TIFF2024517769000019.tif20128 is TIFF2024517769000020.tif20128.

[0109] In any embodiment, R 5 is, in each occurrence, independently hydrogen, halogen, C 1~6 Alkyl or haloC 1~6 In certain other embodiments, R 5 is independently C in each occurrence. 1~6 In certain other embodiments, R 5is independently methyl at each occurrence. 5 is independently ethyl at each occurrence. 5 is, at each occurrence, independently CHF2 or CF3. In still other embodiments, R 5 is independently hydrogen at each occurrence. 5 is independently at each occurrence halogen. In still other embodiments, R 5 is independently CN in each occurrence.

[0110] In any embodiment, X 1 is N. In certain other embodiments, X 1 is CH.

[0111] In any embodiment, R 6 is methyl. In certain other embodiments, R 6 is ethyl.

[0112] In any embodiment, R 6a is methyl. In certain other embodiments, R 6a is ethyl.

[0113] In any embodiment, L 2 L 2 is (CR 7 R 7 ) p In certain other embodiments, L 2 is CH2.

[0114] In any embodiment, L 3 is a covalent bond. In certain other embodiments, L 3 is O. In yet another embodiment, L 3 is NR 7 is.

[0115] In any embodiment, the Q ring is TIFF2024517769000021.tif58166, each of which can be placed at any available carbon or nitrogen position (R 3 ) n and one R 4 and n is 0, 1, or 2. In certain other embodiments, the Q ring is substituted with (R 3 ) n and one R 4 replaced with TIFF2024517769000022.tif17128, and n is 0, 1, or 2. In yet other embodiments, the Q ring is TIFF2024517769000023.tif61166, each of which can be placed at any available carbon or nitrogen position (R 3 ) n and one R 4 and n is 0, 1, or 2.

[0116] In any embodiment, R 3 is, in each occurrence, independently hydrogen, halogen, or C 1~4 In certain other embodiments, R 3 is independently C in each occurrence. 1~4 In yet another embodiment, R 3 is independently ethyl in each occurrence.

[0117] In any embodiment, R 4 is hydrogen, C 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 In certain other embodiments, R 4 is 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q In yet another embodiment, R 4 is C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, or C 2~6 Alkynyl-C 3~7 It is cycloalkyl.

[0118] In some embodiments, the compound of formula (I) has formula (III): TIFF2024517769000024.tif43128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, The A ring is: TIFF2024517769000025.tif27152; a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from R 1 is, in each occurrence, independently hydrogen, halogen, keto (=O), C 1~6 Alkyl, HaloC 1~6 Alkyl, OH, C 1~6 Alkyl-OH, C 1~6 Alkoxy, HaloC 1~6 Alkoxy, CN, C 3~7Cycloalkyl, NR a R b , C 1~6 Alkyl-NR a R b or 4- to 6-membered heterosilyl; R 2 represents, independently at each occurrence, hydrogen, deuterium, C 1~4 Alkyl, C 3~5 cycloalkyl or R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; Z 1 , Z 2 , Z 3 , and Z 4 are each independently CH or O, with the proviso that Z 1 , Z 2 , Z 3 , and Z 4 is O, R 5 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, C 1~6 Alkyl-C 1~6 Alkoxy, HaloC 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b and X 1 But N or CR 6a and R 6a is hydrogen or methyl, R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L 2 is a covalent bond or (CR 7 R 7 ) p and L 3 is a covalent bond, O, or NR 7 where L 2 and L 3 is not a covalent bond; R 7 is, in each occurrence, independently hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 9 and R 10 Each occurrence of is independently selected from hydrogen, one to four R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q - a 5- to 7-membered heterocyclyl ring, or R 9 and R 10 together with the nitrogen atom to which they are attached, 1 to 4 R 11forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R 11 is, in each occurrence, independently hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 12 is, in each occurrence, independently hydrogen, C 1~4 Alkyl, C 3~7 cycloalkyl or R 12 and R 12 together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R a and R b Each occurrence of is independently hydrogen or C 1~6 alkyl, and R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; t is 0, 1, 2, or 3; p in each occurrence is independently 1, 2, 3, or 4; and q in each occurrence is independently 0, 1, 2, 3, or 4.

[0119] In some embodiments, the compound of formula (III) has the formula (IIIa): TIFF2024517769000026.tif55128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, Symbol (X 1 , L 2 , L 3 , R 1 , R 2 , R 5 , R 6 , R 9 , R 10 , m, t) can have any of the values ​​disclosed herein.

[0120] In some embodiments, the compound of formula (III) has formula (IIIb): TIFF2024517769000027.tif52128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, Symbol (X 1 , L 2 , L 3 , R 1 , R 2 , R 5 , R 6 , R 9 , R 10 , m, t) can have any of the values ​​disclosed herein.

[0121] In some embodiments, the compound of formula (III) has the formula (IIIc): TIFF2024517769000028.tif53128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, Symbol (X 1 , Z 1 , Z 2 , Z 3 , Z 4 , L 2 , L 3 , R 1 , R 2 , R 5 , R 6 , R 9 , R 10 , m, t) can have any of the values ​​disclosed herein.

[0122] In any embodiment of any compound disclosed herein, R 1 is independently at each occurrence hydrogen. In certain other embodiments, R 1 is independently at each occurrence halogen. In a further embodiment, one R 1 is hydrogen, and the other R 1 is halogen. In a further embodiment, one R 1 is hydrogen, and the other R 1 is F. In a further embodiment, R 1 is, at each occurrence independently, F.

[0123] In any embodiment, the moiety TIFF2024517769000029.tif20128 is TIFF2024517769000030.tif20128.

[0124] In any embodiment, R 5 is, in each occurrence, independently hydrogen, halogen, or C 1~6 In certain other embodiments, R 5 is independently C in each occurrence. 1~6 In yet another embodiment, R 5is independently methyl at each occurrence. 5 is independently ethyl at each occurrence. 5 is independently hydrogen at each occurrence. 5 is independently at each occurrence halogen. In still other embodiments, R 5 is independently CN in each occurrence.

[0125] In any embodiment, X 1 is N. In certain other embodiments, X 1 is CH.

[0126] In any embodiment, R 6 is methyl.

[0127] In any embodiment, L 2 is (CR 7 R 7 ) p In certain other embodiments, L 2 is CH2.

[0128] In any embodiment, L 3 is a covalent bond. In certain other embodiments, L 3 is O. In yet another embodiment, L 3 is NR 7 is.

[0129] In any embodiment, R 9 is C 1~4 It is alkyl.

[0130] In any embodiment, R 10 is 1 to 4 R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q -5- to 7-membered heterocyclyl ring. In certain other embodiments, R 10 is C 1~6 In yet another embodiment, R 10 is (CH2) q -C 3~7 In yet another embodiment, R 9 and R 10 are composed of 1 to 4 R groups together with the nitrogen atom to which they are attached. 11 and forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with , which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0131] In some embodiments, the compound of formula (I) is: Selected from TIFF2024517769000031.tif171146.

[0132] In another aspect, the present invention provides a compound of formula (IV) TIFF2024517769000032.tif54128 or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, R 1is, 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-membered heterosilyl, or R 1 and R 1 together with the carbon atom to which they are attached form a ketone (C=O), R 5 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, C 1~6 Alkyl-C 1~6 Alkoxy, HaloC 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b and X 1 is N or CR 6a and R 6a is hydrogen or methyl, R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L 2 is (CR 7 R 7 ) p and The Q ring is TIFF2024517769000033.tif20128, each of which is (R 3 ) n and one R 4 is replaced by R 3 is, in each occurrence, independently hydrogen, halogen, CN, C 1~6 Alkyl, or C 3~7 is cycloalkyl, R 4 is 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1 to 4 R 11 substituted with (CH2) q - 5-6 membered heteroaryl ring, 1-4 R 11 substituted with (CH2) q - a 5- to 7-membered heterocyclyl ring, wherein each phenyl is independently optionally substituted with 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 7 is, in each occurrence, independently hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 11 is, in each occurrence, independently hydrogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, 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 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R a and R b Each occurrence of is independently hydrogen or C 1~6 alkyl, and R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; t is 0, 1, 2, or 3; p in each occurrence is independently 1, 2, 3, or 4; and q in each occurrence is independently 0, 1, 2, 3, or 4.

[0133] In some embodiments, the compound of formula (IV) has the formula (IVa): TIFF2024517769000034.tif54128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, Symbol (X 1 , L 2 , Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , n, m, t) can have any of the values ​​disclosed herein.

[0134] In some embodiments, m is 0. In certain other embodiments, m is 1.

[0135] In some embodiments, the moiety TIFF2024517769000035.tif20128 is TIFF2024517769000036.tif20128.

[0136] In any embodiment, R 5 is, in each occurrence, independently hydrogen, halogen, or C 1~6 In certain other embodiments, R 5 is independently C in each occurrence. 1~6 In yet another embodiment, R 5 is independently, at each occurrence, methyl or ethyl. In still other embodiments, R 5 is, at each occurrence, independently CHF2 or CF3. In still other embodiments, R 5 is independently hydrogen at each occurrence. 5 is independently at each occurrence halogen. In still other embodiments, R 5 is independently CN in each occurrence.

[0137] In any embodiment, X 1 is N. In certain other embodiments, X1 is CH.

[0138] In any embodiment, R 6 is methyl.

[0139] In any embodiment, L 2 is CH2.

[0140] In any embodiment, the Q ring may be (R 3 ) n and one R 4 replaced with The file is TIFF2024517769000037.tif17128.

[0141] In any embodiment, R 3 is, in each occurrence, independently hydrogen, halogen, or C 1~4 In certain other embodiments, R 3 is independently C in each occurrence. 1~4 In yet another embodiment, R 3 is independently ethyl in each occurrence.

[0142] In some embodiments, n is 0. In certain other embodiments, n is 1.

[0143] In any embodiment, R 4 is hydrogen, C 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C3~7 Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 In certain other embodiments, R 4 is 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q In yet another embodiment, R 4 is C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, or C 2~6 Alkynyl-C 3~7 It is cycloalkyl.

[0144] In some embodiments, the compound of formula (I) is: Selected from TIFF2024517769000038.tif67128.

[0145] In some embodiments, the present invention relates to compounds of Formulas (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), and (IVa), including each exemplary compound, in which at least one hydrogen (H) is replaced with deuterium (D). Enriching with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. In some other embodiments, the compounds provided herein may have an isotopic enrichment factor for each deuterium present at a site designated as a potential deuterium site on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0146] In another aspect, the invention relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0147] In yet another aspect, the present invention relates to a method for treating a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein. In some embodiments, the disease is pathological fibrosis (e.g., fibrosis of the lung, liver, kidney, heart, skin, eye, or pancreas), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.

[0148] In yet another aspect, the present invention relates to processes for making compounds of Formula (I), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), and (IVa), including each exemplary compound and intermediate described herein.

[0149] General synthesis method The compounds of the present invention can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those exemplary schemes and working examples described below. All substituents are as defined herein above unless otherwise indicated. Reactions are carried out in a solvent or solvent mixture appropriate to the reagents and materials used and suitable for the proposed transformation. This will often require judgment to modify the order of synthetic steps or select a particular process scheme over another to obtain the desired compounds of the present invention.

[0150] It will be appreciated that another major consideration in planning any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functional groups present in the compounds described in this invention. An authoritative account describing many alternatives for the trained practitioner is by Greene et al., Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014). It will also be appreciated that the names of compounds referred to in the descriptions of Schemes 1-3 are for convenience only and do not reflect the actual chemical names of those compounds.

[0151] Scheme 1 TIFF2024517769000039.tif92165 Scheme 1 shows the carbonyl azine L 2The synthesis of L-azolecyclo-acid 6 is described. PG1 and PG2 each represent a protecting group, and L 2 is (CR 7 R 7 ) p (e.g., CH). Deprotection of the protected hydroxyl-azole 1 yields hydroxyl-azole 2, which is then reacted with MsCl (or PBr) to give mesylate (or Br) 3. Treatment of mesylate (or Br) 3 with 2-hydroxyazine 4 in the presence of a suitable base (e.g., KCO, nucleophilic substitution reaction) gives the corresponding carbonylazine azole cyclocarboxylate 5, which then undergoes ester deprotection to give the desired carbonylazine L. 2 -azolecyclo-acid 6 is obtained.

[0152] Scheme 2 Scheme 2 describes the synthesis of oxyQ-ring N-heteroaryl-cyclo-acids 9, where Q-ring represents a 5-membered heteroaryl or heterocyclyl or a 6-membered heteroaryl or heterocyclyl. The base-mediated S-coupling of hydroxyl azole 2 with an appropriate halo- or methylsulfonyl-substituted Q-ring 7 (X is halo or methylsulfonyl) is then carried out. N The Ar reaction affords the oxy-Q-ring N-heteroaryl cyclo-carboxylate 8, which then undergoes ester deprotection to give the desired oxy-Q-ring N-heteroaryl cyclo-acid 9.

[0153] Scheme 3 TIFF2024517769000041.tif100132 Scheme 3 describes the synthesis of carbamoyloxymethyl azole N-heteroaryl cyclo-acid 13. Hydroxylmethyl azole 4 is reacted with 4-nitrophenyl chloroformate in the presence of a suitable base to give the corresponding 4-nitrophenyl carbonate 10, which is then reacted with amine 11 in the presence of a suitable base to give carbomate 12. Subsequent deprotection of ester 12 affords carbamoyloxymethyl azole N-heteroaryl cyclo-acid 13.

[0154] Pharmaceutical Compositions and Methods The compounds used in the methods described herein can be formulated into pharmaceutically acceptable compositions together with a pharmaceutically acceptable carrier or adjuvant prior to administration to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise an effective amount of an additional therapeutic agent, including those described herein, to achieve modulation of the disease or disease symptoms.

[0155] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a subject together with a compound of the invention, which does not destroy its pharmacological activity and which is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[0156] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can 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 pharmaceutical dosage forms, such as Tween or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, 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 substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0157] The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably by oral administration or injection. The pharmaceutical compositions of the present invention may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. Optionally, 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, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0158] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated using suitable dispersing or wetting agents (such as Tween 80) and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any smooth fixed oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethylcellulose, or similar dispersing agents commonly used in the formulation 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.

[0159] The pharmaceutical compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For oral tablets, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and / or emulsions are orally administered, the active ingredient can be suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If necessary, certain sweeteners and / or flavorings and / or coloring agents can be added.

[0160] The pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0161] Topical administration of the pharmaceutical compositions of the present invention is useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredients suspended or dissolved in a carrier. 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 wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifiers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically transdermal patches are also included in the present invention.

[0162] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0163] When the compositions of the present invention include a combination of a compound of the formulae described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels that are about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds of the present invention as part of a multiple-dose regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition.

[0164] The compounds described herein can be administered, for example, by injection, intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous administration, or in oral, buccal, nasal, transmucosal, topical, or ophthalmic preparations, or by inhalation, at dosages ranging from about 0.5 to about 100 mg / kg of body weight every 4 to 120 hours, alternatively at dosages of 1 mg to 1000 mg per dose, or according to the requirements of the drug. The methods herein contemplate administration of an effective amount of a compound or compound composition to achieve the desired or described effect. Typically, pharmaceutical compositions of the present invention will be administered about 1 to about 6 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0165] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any subject will depend on a variety of factors, including the activity of the particular compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition, or symptom, the subject's disposition to the disease, condition, or symptom, and the judgment of the treating physician.

[0166] When the condition of the subject is improved, if necessary, the compound, composition or combination of the present invention can be administered in a maintenance dose.Then, the dosage or frequency of administration, or both, can be reduced according to the function of symptoms, until the condition is maintained at a level at which the improved condition is maintained when the condition is alleviated to a desired level.However, the subject may need to be treated intermittently on a long-term basis based on any recurrence of disease symptoms.

[0167] The pharmaceutical compositions comprising the compounds of Formulae (I) to (IV) may further comprise another therapeutic agent 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., fibrosis of the lung, liver, kidney, heart, skin, eye, or pancreas), idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.

[0168] All publications, patents, and patent applications mentioned in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0169] The examples herein are provided to illustrate the advantages of the present invention and to further assist those of ordinary skill in preparing or using the compounds of the present invention or their salts, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures, or tautomeric forms. The examples herein are also presented to more fully illustrate preferred aspects of the present invention. The examples should not be construed in any way as limiting the scope of the invention, as defined by the appended claims. The examples may include or incorporate any of the variations, aspects, or embodiments of the present invention described above. Each of the variations, aspects, or embodiments described above may also further include or incorporate variations of any or all other variations, aspects, or embodiments of the present invention. [Example]

[0170] The abbreviations used herein are as follows: TIFF2024517769000042.tif227167

[0171] General Conditions and Procedures In the following examples, chemical reagents were purchased from commercial 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.

[0172] Flash chromatography was performed on an Ez Purifier III column with 200-300 mesh silica gel particles. Analytical and preparative thin-layer chromatography plates (TLC) were HSGF254 (0.15-0.2 mm thick, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were recorded at approximately 20-30 °C using a Brucker AMX-300 or AMX-400 NMR (Brucker, Switzerland) unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublet; ddd, doublet of doublet of doublet; dt, doublet of triplet; bs, broad signal. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were performed by electrospray ionization (ESI) from a Waters LCT TOF mass spectrometer (Waters, USA). Compound purification was performed using a variety of conventional methods, including, but not limited to, preparative chromatography using either normal-phase or reverse-phase HPLC or flash columns, or Prep-TLC plates, under acidic, neutral, or basic conditions as appropriate.

[0173] Preparative HPLC: Unless otherwise noted, compounds were purified using a WATERS Fractionlynx system equipped with a YMC Pack Pro d8 column (5 μm, 120 A, 50 × 20 mm) and the following solvent systems: HO, AcCN, and 2% TFA in HO. The specific elution gradients were based on retention times obtained by analytical LC-MS, but generally all elution gradients of HO and MeCN were run over a 7-minute run time using a flow rate of 35 mL / min. An autoblend method was used to ensure a concentration of 0.1% TFA throughout each run. The specific elution gradients were based on retention times obtained by analytical LC / MS, but generally all elution gradients of HO and MeCN were run over an 8-minute run time using a flow rate of 50 mL / min.

[0174] Analytical LC / MS: Analytical LC / MS was performed on a WATERS Acquity UPLC / MS instrument equipped with an ACQUITY UPLC BEH Ci8 column (2.1 x 50 mm, 1.7 μηι) using a column temperature of 45 °C and the following solvent systems: Solvent A: 0.1% HCOOH in HO, and Solvent B: 0.1% HCOOH in AcCN. All compounds were run using the same elution gradient, i.e., 5% to 95% solvent B, with a flow rate of 0.6 mL / min over a run time of 1.5 min.

[0175] Preparative chiral SFC separation: Stereoisomeric mixtures were separated using a Berger Minigram SFC instrument on one of the following columns: ChiralPak AS-H (10 x 250 mm), ChiralPak IA (10 x 250 mm), ChiralPak AD-H (21 x 250 mm), Phenomenex Lux-2 (21.2 x 250 mm), or ChiralPak IC (10 x 250 mm). Elution was performed with either 0.1% diethylamine in MeOH / CO, or 0.1% diethylamine in EtOH / CO, or 0.1% diethylamine in isopropanol / CO, using a flow rate of 2.5 mL / min and a column temperature of 35°C.

[0176] Analytical chiral SFC separations: Stereoisomeric mixtures or single enantiomers were analyzed using a JASCO analytical SFC instrument on one of the following columns: ChiralPak AS-H (4.6 x 250 mm), ChiralPak IA (4.6 x 250 mm), ChiralPak AD-H (4.6 x 250 mm), Phenomenex Lux-2 (4.6 x 250 mm), or ChiralPak IC (4.6 x 250 mm). Elution was performed with either 0.1% diethylamine in MeOH / C02, or 0.1% diethylamine in EtOH / C02, or 0.1% diethylamine in isopropanol / C02, using a flow rate of 6.0 μL / min and a column temperature of 35°C.

[0177] Intermediate 1: 3-bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine TIFF2024517769000043.tif86160 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 min. MeI (46.5 mL, 0.75 mol) was added to the above mixture, and the resulting mixture was stirred at -50 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (500 mL) at 0 °C and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica column chromatography (PE:DCM = 300:1 to 200:1) to give the title compound (47 g, 59.1% yield) as a yellow oil. 1 H NMR (400MHz, CD3OD) δ 7.61-7.59(d,J=8Hz,1H),7.61-7.59(d,J=8.4Hz,1H),2.94-2.88(q,2H),1.38-1.27(t,3H).

[0178] Step 2: 3-(5-bromo-6-ethylpyridin-2-yl)prop-2-yn-1-ol To a solution of 3,6-dibromo-2-ethylpyridine (47 g, 0.177 mol) in THF (0.65 L) were added prop-2-yn-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). The mixture was degassed under N2 atmosphere three times and stirred at room temperature under N2 atmosphere for 16 h. The mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica column chromatography (DCM:EtOAc = 10:1 to 4:1) to give the title compound (40 g, 94.1% yield) as a brown solid. LC / MS(ESI)m / z:240 / 242(M+H) + .

[0179] Step 3: (4-(5-bromo-6-ethylpyridin-2-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)methanol To a solution of the intermediate 3-(5-bromo-6-ethylpyridin-2-yl)prop-2-yn-1-ol (20 g, 0.083 mol) in THF (400 mL) was added chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II) (3.5 g, 4.16 mmol) and TMS-methyl azide (14 g, 0.108 mol) under a N atmosphere at 0 °C. The mixture was degassed three times under a N atmosphere and stirred at room temperature for 16 h. The mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was concentrated to dryness to give the crude product, which was triturated with PE / EtOAc (1000 mL, 10 / 1 v / v) to give the title compound (28 g, 91.3% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ 8.03-8.01(d,J=8.4Hz,1H),7.95-7.93(d,J=8.4Hz,1H),6.77-6.74(t,J=6.8Hz,1H),4.79-4. 78(d,J=6.8Hz,1H),3.80(s,3H),3.03-3.01(q,1H),1.34-1.30(t,J=7.6Hz,3H),0.20(s,9H).

[0180] Step 4: (4-(5-bromo-6-ethylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol To a solution of (4-(5-bromo-6-ethylpyridin-2-yl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)methanol (25 g, 67.7 mmol) in THF (300 mL) was added TBAF.3H2O (25.6 g, 81.2 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (500 mL), washed with saturated aqueous NH4Cl (3 × 50 mL) and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica column chromatography (DCM:EtOAc = 8:1 to 4:1) to give the title compound (19 g, 94.4% yield) as a gray solid. LC / MS (ESI) m / z: 297 / 299 (M+H). + .

[0181] Step 5: 3-Bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine To a mixture of (4-(5-bromo-6-ethylpyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (25 g, 0.084 mol) and TosOH (2.2 g, 12.6 mmol) in DCM (300 mL) was added DHP (10.6 g, 0.126 mol) at 0° C., and the mixture was stirred at room temperature for 16 h. The mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica column chromatography (DCM: EtOAc = 8:1) to give the title compound (30 g, 93.6% yield) as a yellow solid. LC / MS (ESI) m / z: 381 / 383 (M+H) + . 1 H NMR(400MHz,CDCl3)δ 7.91(d,J=8.3Hz,1H),7.86(d,J=8.3Hz,1H),5.36(dd,J=36.5,12.8Hz,2H),4.75-4.67(m,1H),4.16(s,3H),3.88-3.80(m,1) H),3.55-3.46(m,1H),3.00(q,J=7.5Hz,2H),1.84-1.67(m,2H),1.65-1.58(m,2H),1.54-1.45(m,2H),1.34(t,J=7.5Hz,3H).

[0182] Intermediate 2: 3-Bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine Intermediate 2 was synthesized following the same sequence as used to synthesize Intermediate 1. LC / MS (ESI) m / z: 367 / 369 (M+H) + . 1H NMR(400MHz,CDCl3)δ 7.73(d,J=8.3Hz,1H),7.69(d,J=8.3Hz,1H),5.15(q,J=12.7Hz,2H),4.61-4.54(m,1H),3.99(s,3H),3.7 4-3.64(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).

[0183] Intermediate 3: 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine To a solution of 3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (1 g, 2.72 mmol, Intermediate 2) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (840 mg, 3.3 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl (99 mg, 0.136 mmol) and KOAc (400 mg, 4.08 mmol), and the mixture was degassed three times under N atmosphere and stirred at 100 °C for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (890 mg, 78.9% yield) as a pale yellow solid. LC / MS (ESI) m / z: 415 (M+H). + .

[0184] Intermediate 4: 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine To a solution of 3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (2 g, 5.25 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.73 g, 6.82 mmol) in 1,4-dioxane (30 mL) was added Pd(dppf)Cl (200 mg, 0.27 mmol) and KOAc (800 mg, 8.2 mmol), and the mixture was degassed three times under N atmosphere and stirred at 100 °C for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (1.91 g, 84.9% yield) as a pale yellow solid. LC / MS (ESI) m / z: 429 (M+H). + .

[0185] Intermediate 5: 4-(cyclopropylmethyl)-3-methylpyridin-2(1H)-one TIFF2024517769000047.tif71149Step 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) was added KPO (14.23 g, 67.0 mmol), Pd(dppf)Cl (1.63 g, 2.23 mmol) under N atmosphere, and the mixture was degassed three times under N atmosphere and stirred at 100 °C for 2 h under N atmosphere. The mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (eluted with PE: EtOAc = 50:1 to 10:1) to give the title compound (3 g, 90% yield) as a pale yellow oil. LC / MS (ESI) m / z: 150 (M+H) + .

[0186] Step 2: 2-Methoxy-5-propylpyridine To a solution of 5-allyl-2-methoxypyridine (3 g, 20.1 mmol) in MeOH (30 mL) was added Pd(OH) / C (0.28 g, 10 wt%) under a N atmosphere. After the addition, the mixture was degassed three times under a N atmosphere and stirred at 25 °C under a H balloon for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (2.74 g, 90.1% yield) as a colorless oil, which was used directly in the next step. LC / MS (ESI) m / z: 152 (M+H). + .

[0187] Step 3: 5-Propylpyridin-2(1H)-one (4) To a solution of 2-methoxy-5-propylpyridine (2.74 g, 18.12 mmol) in EtOH (27 mL) was added aqueous HBr (27 mL, 40 wt%), and the mixture was stirred at 85 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (eluted with PE: EtOAc = 10:1 to 1:1) to give the title compound (723 mg, 29.1% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 13.21(s,1H),7.35(dd,J=9.2,2.5Hz,1H),7.14(d,J=2.2Hz,1H),6.55(d,J=9.2Hz,1H),2 .35(t,J=7.6Hz,1H),1.60-1.48(m,1H),0.92(t,J=7.2Hz,2H).LC / MS(ESI)m / z:138(M+H) + .

[0188] Intermediate 6: 2-chloro-4-cyclobutylpyrimidine 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) was added AgNO (890 mg, 5.2 mmol), followed by the portionwise addition of (NH)SO (6.0 g, 26.2 mmol) at room temperature, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with DCM (50 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound (2.2 g, 49.8% yield) as a colorless oil. LC / MS (ESI) m / z: 169 (M+H). + . 1H NMR(400MHz, CDCl3)δ 8.49(d,J=5.2Hz,1H),7.11(d,J=5.2Hz,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).

[0189] Example 1: 2-[(3S)-1-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]pyrrolidin-3-yl]acetic acid TIFF2024517769000049.tif97164 Step 1: 2-[(3S)-pyrrolidin-3-yl]acetate methyl hydrochloride To a solution of 2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]acetic acid (1 g, 4.36 mmol) in MeOH (10 mL) was added SOCl (2 mL, 27.6 mmol) dropwise at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (720 mg, 92% yield) as a pale yellow solid. LC / MS (ESI) m / z: 144 (M+H). + .

[0190] Step 2: 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]acetate methyl To a solution of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (300 mg, 0.79 mmol) in 1,4-dioxane (20 mL) was added methyl 2-[(3S)-pyrrolidin-3-yl]acetate (169 mg, 1.18 mmol), followed by CsCO (769 mg, 2.36 mmol), Pd(dba) (64 mg, 0.08 mmol), and Ru-phos (37 mg, 0.08 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 120 °C for 16 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (260 mg, 74.5% yield) as a yellow solid. LC / MS (ESI) m / z: 444 (M+H) + .

[0191] Step 3: 2-[(3S)-1-{2-ethyl-6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]pyridin-3-yl}pyrrolidin-3-yl]methyl acetate To a solution of methyl 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]acetate (260 mg, 0.58 mmol) in MeOH (15 mL) was added PPTS (295 mg, 1.17 mmol). The reaction mixture was stirred at 50 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over Na SO , filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (0-80% EtOAc in PE) to give the title compound (130 mg, 61.7% yield) as a yellow solid. LC / MS (ESI) m / z: 360 (M+H). + .

[0192] Step 4: 2-[(3S)-1-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]pyrrolidin-3-yl]methyl acetate To a solution of methyl 2-[(3S)-1-{2-ethyl-6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]pyridin-3-yl}pyrrolidin-3-yl]acetate (60 mg, 0.17 mmol) in THF (5 mL) was added t-BuOK (0.37 mL, 0.33 mmol, 1.0 M in THF) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NH4Cl at 0 °C, and the mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–70% EtOAc in PE) to give the title compound (60 mg, 73.1% yield) as a white solid. LC / MS(ESI)m / z:492(M+H) + .

[0193] Step 5: 2-[(3S)-1-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]pyrrolidin-3-yl]acetic acid To a solution of methyl 2-[(3S)-1-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]pyrrolidin-3-yl]acetate (70 mg, 0.14 mmol) in THF (4 mL) / HO (1 mL) / MeOH (1 mL) was added LiOH.HO (60 mg, 1.42 mmol) and the reaction was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was diluted with HO (5 mL). The mixture was adjusted to pH 4 with 1 N aqueous HCl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 5-95% in HO with 0.1% HCOOH, MeCN) to give the title compound (25 mg, 36.8% yield) as a white solid. LC / MS (ESI) m / z: 478 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 8.41(d,J=5.1Hz,1H),7.76(d,J=8.4Hz,1H),7.32(d,J=8.5Hz,1H),6.98(d,J=5.1Hz,1H) ,6.23-6.14(m,2H),4.22(s,3H),3.57-3.47(m,1H),3.40-3.33(m,2H),3.28-3.21(m,1H) ,3.09-3.02(m,1H),2.88-2.78(m,2H),2.72-2.60(m,1H),2.49(d,J=7.3Hz,2H),2.28-2. 18(m,5H),2.08-1.96(m,1H),1.88-1.76(m,1H),1.74-1.64(m,1H),1.22(t,J=7.4Hz,3H).

[0194] Example 2: 2-(1-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)acetic acid TIFF2024517769000050.tif111157 Step 1: 2-(1-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)ethyl acetate To a solution of 3-bromo-2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (0.3 g, 0.82 mmol) in 1,4-dioxane (30 mL) was added ethyl 2-(pyrrolidin-3-yl)acetate (0.13 g, 0.82 mmol), followed by CsCO (0.80 g, 2.45 mmol), Pd(dba) (0.07 g, 0.08 mmol), and Ru-phos (0.04 g, 0.08 mmol) under N atmosphere with stirring, and the mixture was stirred at 120 °C for 16 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness to give a residue, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) to give the title compound (280 mg, 77.3% yield) as a yellow solid.

[0195] Step 2: Ethyl 2-(1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)pyrrolidin-3-yl)acetate To a solution of ethyl 2-(1-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)acetate (260 mg, 0.59 mmol) in MeOH (10 mL) was added PPTS (147 mg, 0.59 mmol), and the reaction mixture was stirred at 60 °C for 2 h. The mixture was concentrated to dryness, and the residue was diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (0-50% EtOAc in PE) to give the title compound (170 mg, 80.7% yield) as a yellow solid. LC / MS (ESI) m / z: 360 (M+H) + .

[0196] Step 3: 2-(1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)ethyl acetate To a stirred solution of ethyl 2-(1-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)pyrrolidin-3-yl)acetate (50 mg, 0.14 mmol) in DCM (5 mL) was added MsCl (38 mg, 0.28 mmol), followed by TEA (42 mg, 0.42 mmol) at 0 °C under a N atmosphere. The reaction mixture was stirred at room temperature for 30 min until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NaHCO at 0 °C, and the mixture was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (60 mg, 98.6% yield) as a yellow oil, which was used directly in the next step. LC / MS(ESI)m / z:438(M+H) + .

[0197] Step 4: 2-(1-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)ethyl acetate To a mixture of ethyl 2-(1-(2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)acetate (50 mg, 0.114 mmol) and 5-propyl-1,2-dihydropyridin-2-one (19 mg, 0.14 mmol) in toluene (5 mL) and HO (1 mL) was added KCO (47 mg, 0.34 mmol) and TBAF (3 mg, 0.011 mmol). The reaction was stirred at 100° C. for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (10 mL), washed with water and brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (50 mg, 91.4% yield) as a yellow solid, which was used directly in the next step. LC / MS(ESI)m / z:479(M+H) + .

[0198] Step 5: 2-(1-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)acetic acid To a solution of methyl 2-(1-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)acetate (50 mg, 0.10 mmol) in THF (4 mL) / HO (1 mL) / MeOH (1 mL) was added LiOH.HO (44 mg, 1.0 mmol) and the reaction was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was diluted with HO (5 mL). The mixture was adjusted to pH 4 with 1 N aqueous HCl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 5-95% in HO with 0.1% HCOOH, MeCN) to give the title compound (10 mg, 21.2% yield) as a white solid. LC / MS (ESI) m / z: 451 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.83(d,J=2.0Hz,1H),7.70(d,J=8.4Hz,1H),7.36(dd,J=9.2,2.5Hz,1H),7.27(d,J=8. 5Hz,1H),6.47(d,J=9.2Hz,1H),5.75(s,2H),4.22(s,3H),3.49-3.36(m,2H),3.17-3.0 8(m,1H),2.77-2.65(m,1H),2.63(s,3H),2.51(d,J=7.4Hz,2H),2.24(t,J=7.4Hz,3H), 1.77-1.65(m,1H),1.44-1.30(m,2H),0.78(t,J=7.3Hz,3H).LC / MS(ESI)m / z:451(M+H) + .

[0199] The following examples in Table 1 were prepared from appropriate starting materials by using methods similar to those used to prepare the examples described herein.

[0200] (Table 1) TIFF2024517769000051.tif153167TIFF2024517769000052.tif220167

[0201] Example 8: (R)-2-((S)-1-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)pyrrolidin-3-yl)propanoic acid TIFF2024517769000053.tif121165 Step 1: tert-Butyl (3S)-3-{2-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylate To a solution of 2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]acetic acid (3.7 g, 16.1 mmol) in THF (80 mL) was added TEA (2.71 g, 26.8 mmol), followed by the dropwise addition of pivaloyl chloride (3.23 g, 26.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and (4R)-4-benzyl-1,3-oxazolidin-2-one (1.9 g, 10.7 mmol) and LiCl (40 mg, 0.872 mmol) were added to the mixture. The resulting mixture was stirred at 70 °C for 16 hours. The mixture was poured into saturated aqueous NH Cl and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-35% EtOAc in PE) to give the title compound (2.9 g, 69.6% yield) as a colorless oil. LC / MS (ESI) m / z: 389 (M+H) + .

[0202] Step 2: tert-butyl (3R)-3-{1-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-oxopropan-2-yl}pyrrolidine-1-carboxylate To a solution of tert-butyl (3R)-3-{2-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl}pyrrolidine-1-carboxylate (1.5 g, 3.9 mmol) in THF (30 mL) was added dropwise over 30 min at −78 °C under a N atmosphere, and the mixture was stirred at −78 °C for 1 h. MeI (28.3 g, 199.3 mmol) was added dropwise to the mixture over a 30 min period, maintaining the temperature below −70 °C. After stirring at −70 °C for 1 h, the reaction mixture was further stirred at room temperature for 2 h until disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched at 0 °C with saturated aqueous NH Cl and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (850 mg, 54.7% yield) as a white solid. LC / MS (ESI) m / z: 403 (M+H). + .

[0203] Step 3: 2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]propanoic acid To a solution of tert-butyl (3R)-3-{1-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-oxopropan-2-yl}pyrrolidine-1-carboxylate (400 mg, 0.99 mmol) in THF (10 mL) was added LiOH (125 mg, 2.98 mmol), followed by HO (2 mL, 65.3 mmol, 30 wt%), and the mixture was stirred at 0 °C for 2 h. The mixture was concentrated to 1 / 5 volume and diluted with water (10 mL). The mixture was washed with EtOAc (2 × 10 mL), and the aqueous layer was acidified with 1 N aqueous HCl to pH 4 and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered and concentrated to dryness to give the title compound (200 mg, 82.7% yield) as a white solid. LC / MS (ESI) m / z: 244 (M+H).+ .

[0204] Step 4: (2R)-2-[(3S)-pyrrolidin-3-yl]propanoic acid methyl ester hydrochloride To a solution of (2R)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]propanoic acid (200 mg, 0.82 mmol) in MeOH (10 mL) was added SOCl (1 mL, 12.35 mmol) at 0 °C under a N atmosphere. After the addition, the resulting solution was stirred at room temperature for an additional 16 h. The reaction was concentrated to dryness under reduced pressure to give the title compound (160 mg, 100% yield) as a colorless solid, which was used directly in the next reaction without purification. LC / MS (ESI): m / z: 158 (M+H). + .

[0205] Step 5: Methyl (2R)-2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]propanoate To a solution of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (300 mg, 0.79 mmol) and (2R)-2-[(3S)-pyrrolidin-3-yl]propanoic acid hydrochloride (153 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added CsCO (769 mg, 2.36 mmol), Pd(dba) (64 mg, 0.08 mmol), and Ru-Phos (37 mg, 0.08 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 120 °C for 16 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (270 mg, 75% yield) as a yellow solid. LC / MS (ESI) m / z: 458 (M+H) + .

[0206] Step 6: Methyl (2R)-2-[(3S)-1-{2-ethyl-6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]pyridin-3-yl}pyrrolidin-3-yl]propanoate To a solution of methyl (2R)-2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]propanoate (270 mg, 0.590 mmol) in MeOH (5 mL) was added PPTS (297 mg, 1.18 mmol), and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in EtOAc (20 mL). The mixture was washed with brine, dried over Na SO , filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (0-80% EtOAc in PE) to give the title compound (170 mg, 80.7% yield) as a yellow solid. LC / MS (ESI) m / z: 374 (M+H). + .

[0207] Step 7: (2S)—N-(6-bromo-3-methylpyridin-2-yl)-2-(methylamino)hex-5-enamide To a solution of methyl (2R)-2-[(3S)-1-{2-ethyl-6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]pyridin-3-yl}pyrrolidin-3-yl]propanoate (80 mg, 0.21 mmol) in THF (5 mL) was added t-BuOK (0.43 mL, 0.43 mmol, 1.0 M in THF) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NH Cl at 0 °C, and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (80 mg, 73.9% yield) as a yellow solid. LC / MS (ESI) m / z: 506 (M+H) + .

[0208] Step 8: (2R)-2-[(3S)-1-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]pyrrolidin-3-yl]propanoic acid To a solution of methyl (2R)-2-[(3S)-1-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]pyrrolidin-3-yl]propanoate (70 mg, 0.14 mmol) in THF (4 mL) / HO (1 mL) / MeOH (1 mL) was added LiOH.HO (58 mg, 1.38 mmol), and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was diluted with HO (5 mL). The mixture was adjusted to pH 4 with 1 N aqueous HCl and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 5-95% in HO with 0.1% HCOOH, MeCN) to give the title compound (25 mg, 36.7% yield) as a white solid. LC / MS (ESI) m / z: 492 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 8.41(d,J=5.1Hz,1H),7.76(d,J=8.4Hz,1H),7.30(d,J=8.5Hz,1H),6.98(d,J=5.1Hz ,1H),6.18(d,J=4.5Hz,2H),4.22(s,3H),3.57-3.45(m,1H),3.42-3.33(m,1H),3.28 -3.23(m,1H),3.21-3.10(m,2H),2.81(q,J=7.4Hz,2H),2.48-2.37(m,2H),2.27-2.1 4(m,5H),2.08-1.95(m,1H),1.85-1.76(m,1H),1.75-1.64(m,1H),1.26-1.19(m,6H).

[0209] The following examples in Table 2 were prepared from appropriate starting materials using methods similar to those used to prepare the examples described herein.

[0210] (Table 2) TIFF2024517769000054.tif153167TIFF2024517769000055.tif228167

[0211] Example 14: 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-4,5-dihydro-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoic acid TIFF2024517769000056.tif144166 Step 1: (3S)-3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate tert-butyl To a solution of 2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]acetic acid (1.5 g, 6.5 mmol) in DMF (20 mL) was added KCO (2.71 g, 19.6 mmol) followed by MeI (0.81 mL, 13.1 mmol) under a N atmosphere at 0 °C. The reaction was stirred at room temperature for 16 h. The mixture was quenched with saturated aqueous NHCl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (1.5 g, 94.2% yield) as a yellow oil. LC / MS (ESI) m / z: 244 (M+H). + .

[0212] Step 2: tert-butyl (3S)-3-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (3S)-3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (200 mg, 0.82 mmol) in THF (10 mL) was added t-BuOK (2.5 mL, 2.5 mmol, 1 M in THF) dropwise over 20 min at −70° C. under a N atmosphere, and the mixture was stirred at −70° C. for 1 h. MeI (583 mg, 4.11 mmol) was added dropwise to the mixture over a 10 min period, maintaining the temperature below −70° C. The reaction mixture was further stirred at room temperature for 16 h until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (120 mg, 53.8% yield) as a yellow oil. LC / MS (ESI) m / z: 272 (M+H) + .

[0213] Step 3: Methyl 2-methyl-2-[(3S)-pyrrolidin-3-yl]propanoate TFA salt To a solution of tert-butyl (3S)-3-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (120 mg, 0.44 mmol) in DCM (3 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the title compound (110 mg, 100% yield) as a colorless oil, which was used directly in the next step. LC / MS (ESI) m / z: 172 (M+H). + .

[0214] Step 4: Methyl 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoate To a solution of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (167 mg, 0.44 mmol) in 1,4-dioxane (5 mL) was added methyl 2-methyl-2-[(3S)-pyrrolidin-3-yl]propanoate TFA salt (110 mg, 0.44 mmol), followed by CsCO (428 mg, 1.31 mmol), Pd(dba) (40 mg, 0.044 mmol), and RuPhos (20 mg, 0.044 mmol) under a N atmosphere. The reaction mixture was degassed three times under a N atmosphere and stirred at 120 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluted with PE: EtOAc = 10:1 to 1:2) to give the title compound (80 mg, 38.7% yield) as a yellow solid. LC / MS (ESI) m / z: 472 (M+H) + .

[0215] Step 5: Methyl 2-[(3S)-1-{2-ethyl-6-[5-(hydroxymethyl)-1-methyl-4,5-dihydro-1H-1,2,3-triazol-4-yl]pyridin-3-yl}pyrrolidin-3-yl]-2-methylpropanoate To a solution of methyl 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-4,5-dihydro-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoate (80 mg, 0.17 mmol) in MeOH (3 mL) was added PPTS (128 mg, 0.51 mmol). The reaction was stirred at 60 °C for 16 h. The mixture was concentrated to dryness, and the residue was diluted with EtOAc (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (0-70% EtOAc in PE) to give the title compound (50 mg, 76.0% yield) as a yellow solid. LC / MS (ESI) m / z: 388 (M+H). + .

[0216] Step 6: Methyl 2-[(3S)-1-(2-ethyl-6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoate To a stirred solution of methyl 2-[(3S)-1-{2-ethyl-6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]pyridin-3-yl}pyrrolidin-3-yl]-2-methylpropanoate (50 mg, 0.13 mmol) in DCM (10 mL) was added MsCl (30 mg, 0.26 mmol), followed by TEA (39 mg, 0.39 mmol) under a N atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NaHCO at 0 °C and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (50 mg, 83.2% yield) as a yellow solid, which was used directly in the next step. LC / MS(ESI)m / z:466(M+H) + .

[0217] Step 7: Methyl 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoate To a mixture of methyl 2-[(3S)-1-(2-ethyl-6-{5-[(methanesulfonyloxy)methyl]-1-methyl-4,5-dihydro-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoate (50 mg, 0.11 mmol) and 5-propyl-1,2-dihydropyridin-2-one (29 mg, 0.22 mmol) in toluene (5 mL) and HO (1 mL) was added KCO (44.5 mg, 0.32 mmol) followed by TBAF (3 mg, 0.01 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (10 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness to give the title compound (50 mg, 91.9% yield) as a yellow sloid, which was used directly in the next step. LC / MS (ESI) m / z: 507 (M+H). + .

[0218] Step 8: 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-4,5-dihydro-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoic acid To a solution of methyl 2-[(3S)-1-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-4,5-dihydro-1H-1,2,3-triazol-4-yl}pyridin-3-yl)pyrrolidin-3-yl]-2-methylpropanoate (50 mg, 0.098 mmol) in THF (4 mL) / HO (1 mL) / MeOH (1 mL) was added LiOH.HO (41 mg, 0.98 mmol), and the reaction was stirred at room temperature for 2 h. The volatiles were removed in vacuo, and the residue was diluted with HO (5 mL). The mixture was adjusted to pH 4 with 1 N aqueous HCl and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 5-95% in HO with 0.1% HCOOH, MeCN) to give the title compound (13 mg, 26.7% yield) as a white solid. LC / MS (ESI) m / z: 493 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.77(d,J=8.5Hz,1H),7.66(d,J=2.0Hz,1H),7.40-7.33(m,2H),6.52(d,J=9.2Hz,1H), 5.92-5.79(m,2H),4.16(s,3H),3.40-3.32(m,1H),3.23-3.10(m,2H),2.94(q,J=7.5Hz ,2H),2.70-2.57(m,1H),2.20(t,J=7.5Hz,2H),2.12-2.02(m,1H),1.94-1.81(m,1H),1 .36(dd,J=14.9,7.4Hz,2H),1.29(t,J=7.5Hz,3H),1.25(s,6H),0.76(t,J=7.3Hz,3H).

[0219] Example 15: (S)-2-methyl-2-(1-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)propanoic acid TIFF2024517769000057.tif74128 The title compound was prepared from the appropriate starting materials using the same synthetic sequence used to synthesize Example 14. LC / MS(ESI)(m / z): 479(M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.82(d,J=2.0Hz,1H),7.71(d,J=8.4Hz,1H),7.36(dd,J=9.2,2.5Hz,1H),7.29(d ,J=8.5Hz,1H),6.47(d,J=9.2Hz,1H),5.79-5.70(m,2H),4.22(s,3H),3.42-3.34 (m,2H),3.25-3.14(m,3H),2.68-2.59(m,4H),2.24(t,J=7.5Hz,2H),2.10-2.02( m,1H),1.93-1.83(m,1H),1.42-1.33(m,2H),1.25(s,6H),0.78(t,J=7.3Hz,3H).

[0220] Example 16: (R)-2-(1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)-2-methylpropanoic acid TIFF2024517769000058.tif78128 The title compound was prepared from the appropriate starting materials using the same synthetic sequence used to synthesize Example 14. LC / MS(ESI)(m / z): 493(M+H) + . 1H NMR(400MHz,CD3OD)δ 7.79(d,J=8.5Hz,1H),7.68(d,J=2.1Hz,1H),7.43-7.32(m,2H),6.53(d,J=9.2Hz,1H),5.88(d,J=3.0Hz, 2H),4.17(s,3H),3.37(dd,J=8.8,6.7Hz,1H),3.31-3.30(m,1H),3.21(td,J=8.4,3.0Hz,1H),3.16(t,J=8 .7Hz,1H),2.96(q,J=7.5Hz,2H),2.72-2.61(m,1H),2.22(t,J=7.5Hz,2H),2.12-2.04(m,1H),1.94-1.85 (m,1H),1.38(dd,J=14.9,7.4Hz,2H),1.31(t,J=7.5Hz,3H),1.27(d,J=0.5Hz,6H),0.78(t,J=7.3Hz,3H).

[0221] Example 17 and Example 18: (S) or (R)-2-((S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid, and (R) or (S)-2-((S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid TIFF2024517769000059.tif108161 Step 1: (R)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate tert-butyl To a solution of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.3 g, 11.4 mmol) in DCM (30 mL) was added pyridine (2.8 mL, 34.3 mmol) and TosCl (3.3 g, 17.2 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (3.7 g, 91.1% yield) as a white solid. LC / MS (ESI) m / z: 300 (M+H −56). + .

[0222] Step 2: (R)-tert-butyl 3-(cyanomethyl)pyrrolidine-1-carboxylate To a solution of (R)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (3.7 g, 10.4 mmol) in DMSO (20 mL) was added KCN (1.36 g, 20.8 mmol), and the reaction mixture was stirred at 100° C. for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (1.9 g, 87% yield) as a white solid. LC / MS (ESI) m / z: 155 (M+H-56). + .

[0223] Step 3: (3S)-tert-butyl 3-(1-cyanopropyl)pyrrolidine-1-carboxylate To a solution of (R)-tert-butyl 3-(cyanomethyl)pyrrolidine-1-carboxylate (1 g, 4.76 mmol) in THF (15 mL) was added LDA (7.1 mL, 7.1 mmol, 1 M in THF) dropwise at -70 °C. Then, a solution of EtI (965 mg, 6.2 mmol) in THF (3 mL) was added dropwise, and the resulting mixture was stirred at -70 °C to room temperature for 16 h. The mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (400 mg, 35.3% yield) as a yellow oil. LC / MS (ESI) m / z: 183 (M+H-56). + .

[0224] Step 4: tert-Butyl (3S)-3-(1-amino-1-oxobutan-2-yl)pyrrolidine-1-carboxylate To a solution of tert-butyl (3S)-3-(1-cyanopropyl)pyrrolidine-1-carboxylate (400 mg, 1.68 mmol) in EtOH (5 mL) and HO (3 mL) was added KOH (282 mg, 5.04 mmol), and the mixture was stirred at 120 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give the title compound (220 mg, 51.2% yield) as a yellow oil. LC / MS (ESI) m / z: 201 (M+H-56). + .

[0225] Step 5: 2-((S)-Pyrrolidin-3-yl)butanoic acid hydrobromide A solution of tert-butyl (S)-3-((S)-1-amino-1-oxobutan-2-yl)pyrrolidine-1-carboxylate (220 mg, 0.86 mmol) in aqueous HBr (4 mL, 40 wt%) was stirred at 120° C. for 16 h. The mixture was concentrated to dryness to give the title compound (150 mg, 81.5% yield) as a yellow solid. LC / MS (ESI) m / z: 158 (M+H). + .

[0226] Step 6: Methyl 2-((S)-pyrrolidin-3-yl)butanoate hydrochloride To a solution of 2-((S)-pyrrolidin-3-yl)butanoic acid hydrobromide (100 mg, 0.64 mmol) in MeOH (3 mL) was added SOCl (0.14 mL, 1.91 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the title compound (120 mg, 92% yield) as a yellow solid. LC / MS (ESI) m / z: 172 (M+H) + .

[0227] Step 7: Methyl 2-((3S)-1-(2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate To a mixture of 3-bromo-2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (180 mg, 0.47 mmol) and methyl 2-((S)-pyrrolidin-3-yl)butanoate hydrochloride (116 mg, 0.56 mmol) in 1,4-dioxane (8 mL) was added CsCO (308 mg, 0.94 mmol) followed by Ru-Phos (44 mg, 0.1 mmol) and Pd(dba) (43 mg, 0.1 mmol) under a N atmosphere. The mixture was then degassed three times under a N atmosphere and stirred at 120 °C for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (150 mg, 67.4% yield) as a yellow oil. LC / MS (ESI) m / z: 472 (M+H) + .

[0228] Step 8: Methyl 2-((S)-1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate To a solution of methyl 2-((3S)-1-(2-ethyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate (150 mg, 0.32 mmol) in MeOH (6 mL) was added PPTS (240 mg, 0.95 mmol), and the mixture was stirred at 60 °C for 3 h. The mixture was diluted with DCM (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (100 mg, 81.4% yield) as a yellow oil. LC / MS (ESI) m / z: 388 (M+H). + .

[0229] Step 9: Methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate To a solution of methyl 2-((S)-1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate (50 mg, 0.13 mmol) in DCM (3 mL) was added TEA (39.2 mg, 0.39 mmol) followed by MsCl (22 mg, 0.19 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (55 mg, 92% yield) as a yellow oil. LC / MS (ESI) m / z: 466 (M+H) + .

[0230] Step 10: Methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate To a mixture of methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate (55 mg, 0.12 mmol) and 5-propylpyridin-2(1H)-one (24 mg, 0.18 mmol) in toluene (3 mL) and HO (0.3 mL) under a N atmosphere, KCO (49 mg, 0.35 mmol) and TBAF (3 mg, 0.012 mmol) were added. The reaction mixture was stirred at 100 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (45 mg, 73.8% yield) as a white solid. LC / MS (ESI) m / z: 507 (M+H) + .

[0231] Step 11: (S) or (R)-2-((S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid, and (R) or (S)-2-((S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid To a solution of methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate (45 mg, 0.09 mmol) in MeOH (2 mL), THF (2 mL), and HO (1 mL) was added NaOH (36 mg, 0.9 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness, and the residue was dissolved in water (5 mL). The mixture was washed with EtOAc (2 × 5 mL), acidified with 1 N aqueous HCl to pH 3, and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, 45-95% acetonitrile in HO containing 0.1% trifluoroacetic acid) to give Example 17 (11 mg, 25% yield) and Example 18 (10 mg, 22.4% yield) as white solids. Example 17: LC / MS (ESI) m / z: 492 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.94(d,J=8.9Hz,1H),7.85(s,1H),7.74(d,J=9.0Hz,1H),7.57(dd,J=9.2,2.3Hz,1H),6.61(d,J=9.2Hz ,1H),5.56-5.47(m,2H),4.15(s,3H),3.66-3.60(m,1H),3.56-3.49(m,2H),3.42-3.35(m,1H),3.26-3. 19(m,2H),2.62-2.52(m,1H),2.47-2.43(m,2H),2.39-2.27(m,2H),1.85-1.66(m,3H),1.62-1.56(m,2H) ),1.37(t,J=7.5Hz,3H),0.99(t,J=7.4Hz,3H),0.94(t,J=7.3Hz,3H).Example 18: LC / MS(ESI)m / z:492(M+H) + . 1H NMR(400MHz,CD3OD)δ 7.92(d,J=8.8Hz,1H),7.80(s,1H),7.68(d,J=8.9Hz,1H),7.56-7.50(m,1H),6.59(d,J=9.2Hz,1H ),5.60(s,2H),4.15(s,3H),3.63-3.50(m,2H),3.47-3.41(m,1H),3.29-3.26(m,1H),3.15(dt,J=5 .0,4.4Hz,2H),2.58-2.50(m,1H),2.43-2.32(m,3H),2.25-2.14(m,1H),1.88-1.79(m,1H),1.73-1 .64(m,2H),1.59-1.49(m,2H),1.35(t,J=7.5Hz,3H),0.98(t,J=7.4Hz,3H),0.90(t,J=7.3Hz,3H).

[0232] Example 19 and Example 20: (S) or (R)-2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid, and (R) or (S)-2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid TIFF2024517769000060.tif104161 Step 1: Methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate To a solution of methyl 2-((S)-1-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate (50 mg, 0.13 mmol) in DCM (3 mL) was added pyridine (50 mg, 0.65 mmol) and 4-nitrophenyl chloroformate (78 mg, 0.39 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (80 mg, 100% yield) as a yellow solid, which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 553 (M+H). + .

[0233] Step 2: Methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate To a solution of methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate (80 mg, 0.13 mmol) in THF (3 mL) was added DIPEA (65 mg, 0.5 mmol) and N-methylpropan-1-amine (22 mg, 0.3 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (35 mg, 55.7% yield) as a yellow solid. LC / MS(ESI)m / z:487(M+H) + .

[0234] Step 3: (S) or (R)-2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid and (R) or (S)-2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoic acid To a solution of methyl 2-((S)-1-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrrolidin-3-yl)butanoate (35 mg, 0.07 mmol) in MeOH (2 mL), THF (2 mL), and HO (1 mL) was added NaOH (36 mg, 0.9 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness, and the residue was dissolved in water (5 mL). The mixture was washed with EtOAc (2 × 5 mL), acidified with 1 N aqueous HCl to pH 3, and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, 45-95% acetonitrile in H2O with 0.1% TFA) to give Compound Example 19 (6 mg, 18% yield) and Compound Example 20 (1.5 mg, 4.5% yield) as white solids.

[0235] Example 19: LC / MS (ESI) m / z: 473 (M+H) + . 1H NMR(400MHz,CD3OD)δ 8.00(dd,J=8.9,2.9Hz,1H),7.81(dd,J=8.9,3.3Hz,1H),5.50(s,2H),4.24(d,J=2.1Hz,3H), 3.68-3.60(m,2H),3.55-3.51(m,1H),3.39-3.34(m,1H),3.27-3.22(m,4H),2.93(d,J=19.8H) z,3H),2.60-2.50(m,1H),2.38-2.32(m,1H),2.24-2.18(m,1H),1.90-1.80(m,1H),1.73-1.6 6(m,2H),1.60-1.52(m,2H),1.39(t,J=7.5Hz,3H),0.99(t,J=7.4Hz,3H),0.92-0.82(m,3H).

[0236] Example 20: LC / MS (ESI) m / z: 473 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.72(d,J=8.5Hz,1H),7.28(d,J=8.5Hz,1H),5.75(s,2H),4.17(s,3H),3.18-3.08(m,3H),2.89-2.80(m,5H),2.51-2.44(m ,1H),2.33-2.13(m,H),1.75-1.65(m,3H),1.57-1.50(m,1H),1.38-1.27(m,6H),0.98(t,J=7.1Hz,3H),0.89-0.68(m,3H).

[0237] Example 21: 2-(rel-(2S,6R)-6-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetic acid TIFF2024517769000061.tif119163 Step 1: 3,6-Dibromo-2-ethylpyridine To a solution of 3,6-dibromo-2-methylpyridine (20 g, 79.7 mmol) in THF (250 mL) was added dropwise NaHMDS (95.6 mol, 47.8 mL, 2 M in THF) over 30 min at −50° C. under a N atmosphere, and the mixture was stirred at −50° C. for 1 h. MeI (28.3 g, 199.3 mmol) was added dropwise to the mixture over a 30 min period, maintaining the temperature below −40° C. The reaction mixture was further stirred at −50° C. for 1 h until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NH4Cl at 0° C. The mixture was extracted with EtOAc (2×200 mL), and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-2% EtOAc in PE) to give the title compound (14 g, 66.3% yield) as a yellow oil. LC / MS (ESI) m / z: 266 (M+H) + . 1 H NMR(400MHz, CDCl3)δ 7.62(d,J=8.3Hz,1H),7.18(d,J=8.3Hz,1H),2.94(q,J=7.5Hz,2H),1.28(t,J=7.5Hz,3H).

[0238] Step 2: 1-(6-bromo-2-ethylpyridin-3-yl)-5-hydroxypentan-1-one To a solution of 3,6-dibromo-2-ethylpyridine (7 g, 26.4 mmol) in THF (100 mL) was added n-BuLi (10.6 mL, 26.4 mmol, 2.5 M in hexane) dropwise over 30 min at −78 °C under a N atmosphere, and the mixture was stirred at −78 °C for 1 h. Tetrahydro-2H-pyran-2-one (5.3 g, 52.8 mmol) in THF (20 mL) was added dropwise over a 30 min period, maintaining the temperature below −60 °C. The reaction mixture was further stirred at −78 °C for 1 h until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NH Cl at 0 °C. The reaction mixture was extracted with EtOAc (2 × 50 mL), and the combined organic layers were washed with water and brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (3.6 g, 47.6% yield) as a yellow solid. LC / MS (ESI) m / z: 287 (M+H) + .

[0239] Step 3: 5-(6-bromo-2-ethylpyridin-3-yl)-5-oxopentanal To a solution of 1-(6-bromo-2-ethylpyridin-3-yl)-5-hydroxypentan-1-one (3.6 g, 12.6 mmol) in DCM (50 mL) was added Dess-Martin periodinane (8.00 g, 18.9 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated aqueous NaHCO and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (1.7 g, 47.7% yield) as a yellow oil. LC / MS (ESI) m / z: 286 (M+H). + . 1H NMR(400MHz,CDCl3)δ 9.81(t,J=1.2Hz,1H),7.71(d,J=8.2Hz,1H),7.40(d,J=8.2Hz,1H),2.96(q,J=7.5Hz,3H),2.92( t,J=7.1Hz,2H),2.60(td,J=6.9,1.1Hz,2H),2.05(dd,J=13.9,7.0Hz,2H),1.28(t,J=7.5Hz,3H).

[0240] Step 4: (E)-7-(6-bromo-2-ethylpyridin-3-yl)-7-oxohept-2-enoate methyl ester To a solution of 5-(6-bromo-2-ethylpyridin-3-yl)-5-oxopentanal (1.7 g, 6.0 mmol) in DCM (20 mL) was added methyl 2-(triphenyl-15-phosphanylidene)acetate (2.4 g, 7.2 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-35% EtOAc in PE) to give the title compound (1.8 g, 88.4% yield) as a yellow oil. LC / MS (ESI) m / z: 341 (M+H). + .

[0241] Step 5: (E)-7-(6-bromo-2-ethylpyridin-3-yl)-7-hydroxyhept-2-enoate methyl ester To a solution of methyl (E)-7-(6-bromo-2-ethylpyridin-3-yl)-7-oxohept-2-enoate (1.8 g, 5.3 mmol) in MeOH (20 mL) was added NaBH (200 mg, 5.3 mol) in portions at 0 °C, and the mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous NH Cl at 0 °C and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (1.5 g, 82.8% yield) as a white solid. LC / MS (ESI) m / z: 343 (M+H). + .

[0242] Step 6: Methyl 2-(6-(6-bromo-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate To a solution of methyl (E)-7-(6-bromo-2-ethylpyridin-3-yl)-7-hydroxyhept-2-enoate (1.5 g, 4.4 mmol) in THF (20 mL) was added t-BuOK (4.4 mL, 4.4 mmol, 1 M in THF) dropwise over 10 min at 0 °C under a N atmosphere. The mixture was stirred at 0 °C for 30 min until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NH Cl at 0 °C. The mixture was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with water and brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (1.3 g, 86.7% yield) as a yellow solid. LC / MS (ESI) m / z: 343 (M+H). + .

[0243] Step 7: Methyl 2-(6-(2-ethyl-6-(3-hydroxyprop-1-yn-1-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate To a solution of methyl 2-(6-(6-bromo-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate (1.3 g, 3.8 mmol) in MeCN (30 mL) was added triethylamine (1.6 mL, 11.4 mmol), followed by Pd(PPh3)2Cl2 (590 mg, 0.76 mmol) and prop-2-yn-1-ol (0.45 mL, 7.6 mmol) at 0 °C, and the mixture was stirred at room temperature under a N2 atmosphere for 16 h. The reaction mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-65% EtOAc in PE) to give the title compound (1.1 g, 91.2% yield) as a yellow oil. LC / MS (ESI) m / z: 318 (M+H). + .

[0244] Step 8: 2-(6-(2-ethyl-6-(5-(hydroxymethyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate methyl To a solution of methyl 2-(6-(2-ethyl-6-(3-hydroxyprop-1-yn-1-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate (1.1 g, 3.5 mmol) in 1,4-dioxane (20 mL) was added TMSCHN (1.1 g, 8.7 mmol), followed by CuI (70 mg, 0.35 mmol) and pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride (280 mg, 0.35 mmol) at 0 °C. The mixture was stirred at 60 °C under a N atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (750 mg, 48.4% yield) as a yellow oil. LC / MS(ESI)m / z:447(M+H) + .

[0245] Step 9: 2-(rel-(2S,6R)-6-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)methyl acetate (10) and 2-((2S,6S) or (2R,6R)-6-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)methyl acetate (10-1) and 2-((2R,6R) or (2S,6S)-6-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)methyl acetate To a solution of methyl 2-(6-(2-ethyl-6-(5-(hydroxymethyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate (750 mg, 1.7 mmol) in THF (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 to 70% EtOAc in PE) to give compound 10 (50 mg, 8.3% yield) and a mixture of compounds 10-1 and 10-2 (520 mg, 82.7% yield) as a white solid. The mixture was separated by chiral SFC to give compound 10-1 (200 mg, 31.8% yield) (peak 1, retention time: 2.909 min) and compound 10-2 (210 mg, 33.4% yield) (peak 2, retention time: 3.566 min) as white solids. SFC conditions: Column: ChiralPak AD, 250 × 21.2 mm ID, 5 μm; Mobile phase: A with CO and B with methanol (0.1% NH OH); Gradient: B 30%; Flow rate: 50 mL / min; Column temperature: 35 °C.

[0246] Step 10: 2-(rel-(2S,6R)-6-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate methyl To a mixture of 2-(rel-(2S,6R)-6-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)methyl acetate (50 mg, 0.13 mmol) and 2-chloro-4-cyclobutylpyrimidine (34 mg, 0.2 mmol) in THF (5 mL) was added t-BuOK (0.25 mL, 0.25 mmol, 1.0 M in THF) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NH Cl at 0 °C, and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (35 mg, 51.7% yield) as a yellow solid. LC / MS (ESI) m / z: 507 (M+H) + .

[0247] Step 11: 2-(rel-(2S,6R)-6-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetic acid To a mixture of methyl 2-(rel-(2S,6R)-6-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetate (35 mg, 0.07 mmol) in THF (4 mL) / HO (1 mL) / MeOH (1 mL) was added LiOH.HO (29 mg, 0.69 mmol) and the reaction was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was diluted with HO (5 mL). The mixture was adjusted to pH 4 with 1 N aqueous HCl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 5-95% in HO containing 0.1% HCOOH, MeCN) to give the title compound (12 mg, 35.3% yield) as a white solid. LC / MS (ESI) m / z: 493 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 8.49(d,J=5.0Hz,1H),7.94(d,J=8.1Hz,1H),7.81(d,J=8.1Hz,1H),7.04(d,J=5.0Hz,1H),6.09 (dd,J=27.1,12.6Hz,2H),4.58(d,J=10.9Hz,1H),4.16(s,3H),3.98-3.88(m,1H),3.53(dd,J=1 7.0,8.5Hz,1H),2.82-2.66(m,2H),2.45-2.33(m,2H),2.23-2.15(m,4H),2.02-1.93(m,1H),1. 92-1.86(m,1H),1.80-1.65(m,4H),1.50-1.40(m,1H),1.35-1.22(m,1H),1.08(t,J=7.4Hz,3H).

[0248] Example 22: 2-((2S,6S) or (2R,6R)-6-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetic acid The title compound was synthesized from compound 10-1 of Example 21 using the same synthetic sequence used to synthesize Example 21. LC / MS (ESI) m / z: 493 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.40(d,J=5.1Hz,1H),7.87(d,J=8.4Hz,2H),6.98(d,J=5.1Hz,1H),6.27-6.1 6(m,2H),4.69-4.63(m,1H),4.23(s,3H),4.07-3.98(m,1H),3.56-3.45(m,1H) ,2.95-2.73(m,2H),2.58-2.48(m,2H),2.26-2.15(m,4H),2.08-1.97(m,2H),1 .87-1.73(m,4H),1.62-1.52(m,1H),1.45-1.35(m,1H),1.22(t,J=7.5Hz,3H).

[0249] Example 23: 2-((2R,6R) or (2S,6S)-6-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetic acid The title compound was synthesized from compound 10-2 of Example 21 using the same synthetic sequence used to synthesize Example 21. LC / MS (ESI) m / z: 493 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 8.40(d,J=5.1Hz,1H),7.99-7.82(m,2H),6.98(d,J=5.1Hz,1H),6.27-6.12(m ,2H),4.72-4.62(m,1H),4.23(s,3H),4.09-3.96(m,1H),3.59-3.44(m,1H),2 .95-2.73(m,2H),2.57-2.46(m,2H),2.26-2.15(m,4H),2.09-1.95(m,2H),1. 86-1.72(m,4H),1.65-1.52(m,1H),1.47-1.34(m,1H),1.22(t,J=7.5Hz,3H).

[0250] Example 24: 2-((2S,6S) or (2R,6R)-6-(2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetic acid The title compound was synthesized from compound 10-1 in Example 21 using the same synthetic sequence used to synthesize Example 14. LC / MS (ESI) m / z: 480 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.91(d,J=8.2Hz,1H),7.89(d,J=8.2Hz,1H),7.66(d,J=2.2Hz,1H),7.38(dd,J=9.2,2.5Hz,1H),6. 52(d,J=9.3Hz,1H),5.88(s,2H),4.72-4.66(m,1H),4.16(s,3H),4.09-4.01(m,1H),3.00-2.87(m,2 H),2.52(d,J=6.5Hz,2H),2.21(t,J=7.5Hz,2H),2.04-1.98(m,1H),1.88-1.75(m,3H),1.64-1.53(m ,1H),1.41(dd,J=12.0,4.6Hz,1H),1.38-1.32(m,2H),1.30(t,J=7.5Hz,3H),0.75(t,J=7.3Hz,3H).

[0251] Example 25: 2-((2S,6S) or (2R,6R)-6-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetic acid The title compound was synthesized from compound 10-2 in Example 21 using the same synthetic sequence used to synthesize Example 14. LC / MS (ESI) m / z: 460 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.85(s,2H),5.76(s,2H),4.69-4.63(m,1H),4.18(s,3H),4.07-3.99(m,1H),3.21(t,J=7.0H z,1H),3.09(t,J=7.0Hz,1H),2.93(dd,J=14.9,7.5Hz,1H),2.87(d,J=7.6Hz,1H),2.85-2.79 (m,3H),2.51(d,J=6.5Hz,2H),2.03-1.96(m,1H),1.87-1.75(m,3H),1.55(dt,J=12.3,9.4Hz ,2H),1.41(dd,J=11.6,7.7Hz,1H),1.36(d,J=9.6Hz,2H),1.32(d,J=7.3Hz,2H),0.77(m,3H).

[0252] Example 26: 2-(2-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetic acid TIFF2024517769000066.tif106166Step 1: 6-Bromo-2-methylnicotinaldehyde To a solution of 3,6-dibromo-2-methylpyridine (10 g, 39.9 mmol) in THF (110 mL) was added n-BuLi (20.7 mL, 51.8 mmol, 2.5 M in hexane) at −78 °C under a N atmosphere. The reaction mixture was stirred at −78 °C for 20 min. DMF (6.17 mL, 79.7 mmol) was then added dropwise, and the mixture was stirred at −78 °C for 30 min. The mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (4 g, 50.2% yield) as a yellow solid. LC / MS(ESI)m / z:201(M+H) + .

[0253] Step 2: 2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-ol To a mixture of 6-bromo-2-methylnicotinaldehyde (4 g, 20 mmol) and but-3-en-1-ol (3.48 mL, 40 mmol), sulfuric acid (14.25 g, 80 mmol) was added at 0 °C, and the mixture was stirred for 30 min. The reaction mixture was adjusted to pH 9 with saturated aqueous NaOH and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (870 mg, 16.1% yield) as a yellow oil. LC / MS (ESI) m / z: 273 (M+H). + .

[0254] Step 3: 2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-4H-pyran-4-one To a solution of 2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-ol (870 mg, 3.20 mmol) in DCM (10 mL) was added Dess-Martin periodinate (1.86 g, 9.59 mol) and NaHCO (1.07 g, 12.8 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The mixture was filtered through a Celite pad, and the filtrate was diluted with saturated aqueous NaHCO and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (660 mg, 76.4% yield) as a yellow solid. LC / MS (ESI) m / z: 271 (M+H). + .

[0255] Step 4: (Z)-2-(2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-4H-pyran-4-ylidene)acetate methyl To a solution of 2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-4H-pyran-4-one (660 mg, 2.4 mmol) in toluene (8 mL), methyl 2-(triphenyl-15-phosphanylidene)acetate (1.6 g, 4.9 mmol) was added, and the mixture was stirred at 100 °C for 3 h. The solution was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (750 mg, 94.6% yield) as a yellow solid. LC / MS (ESI) m / z: 326 (M+H). + .

[0256] Step 5: Methyl 2-(2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate To a solution of (Z)-2-(2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-4H-pyran-4-ylidene)methyl acetate (750 mg, 2.3 mmol) in EtOAc (10 mL) was added PtO (70 mg, 0.03 mmol) at room temperature. The mixture was degassed three times under N and stirred under a H balloon at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness to give the title compound (680 mg, 90% yield) as a yellow solid, which was used in the next step without further purification. LC / MS (ESI) m / z: 328 (M+H). + .

[0257] Step 6: Methyl 2-(2-(6-(3-hydroxyprop-1-yn-1-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate To a solution of methyl 2-(2-(6-bromo-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate (680 mg, 2.1 mmol) in acetonitrile (10 mL) under a N atmosphere was added bis(triphenylphosphine)palladium(II) chloride (292 mg, 0.42 mmol), CuI (79.2 mg, 0.42 mmol), TEA (0.87 mL, 6.24 mmol), and prop-2-yn-1-ol (0.24 mL, 4.16 mmol). The reaction was degassed three times under a N atmosphere and stirred at room temperature for 5 h. The mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (540 mg, 85.7% yield) as a yellow oil. LC / MS (ESI) m / z: 304 (M+H) + .

[0258] Step 7: 2-(2-(6-(5-(hydroxymethyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate methyl To a solution of methyl 2-(2-(6-(3-hydroxyprop-1-yn-1-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate (540 mg, 1.78 mmol) in 1,4-dioxane (8 mL) was added Cp*RuCl(PPh) (141.7 mg, 0.18 mmol), cuprous iodide (34 mg, 0.18 mmol), and trimethylsilylmethyl azide (0.56 mL, 4.1 mmol) under a N atmosphere at room temperature. The reaction mixture was degassed three times under a N atmosphere and stirred at 50 °C for 2 h. The solution was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (320 mg, 41.6% yield) as a yellow oil. LC / MS(ESI)m / z:433(M+H) + .

[0259] Step 8: Methyl 2-(2-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate To a solution of methyl 2-(2-(6-(5-(hydroxymethyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate (320 mg, 0.74 mmol) in THF (15 mL) was added TBAF (194 mg, 0.74 mmol), and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-70% EtOAc in PE) to give the title compound (230 mg, 86.1% yield) as a yellow oil. LC / MS (ESI) m / z: 361 (M+H). + .

[0260] Step 9: 2-(2-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate methyl To a mixture of methyl 2-(2-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate (65 mg, 0.18 mmol) and 2-chloro-4-cyclobutylpyrimidine (45.5 mg, 0.27 mmol) in THF (8 mL) was added t-BuOK (0.36 mL, 0.36 mmol, 1.0 M in THF) dropwise at 0 °C, and the reaction was stirred at 0 °C for 1 h. The mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (80 mg, 89.9% yield) as a yellow oil. LC / MS (ESI) m / z: 493 (M+H) + .

[0261] Step 10: 2-(2-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetic acid To a solution of methyl 2-(2-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)acetate (80 mg, 0.16 mmol) in MeOH (2 mL), THF (2 mL), and HO (1 mL) was added LiOH (68 mg, 1.6 mol), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness, and the residue was dissolved in water (8 mL). The mixture was washed with EtOAc (2 × 5 mL), acidified with 1 N aqueous HCl to pH 3, and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, 30-95% in HO with 0.1% HCOOH, MeCN) to give the title compound (16 mg, 21% yield) as a white solid. LC / MS (ESI) m / z: 479 (M+H) + . 1H NMR(400MHz,CD3OD)δ 8.40(d,J=5.1Hz,1H),7.91-7.84(m,2H),6.98(d,J=5.1Hz,1H),6.23-6.12(m,2H),4.83-4.81(m,0.5 H),4.59(dd,J=11.1,1.9Hz,0.5H),4.24(s,3H),4.14(dd,J=11.5,3.4Hz,0.5H),3.90 -3.83(m,1H),3.73-3.66(m,0.5H),3.54-3.44(m,1H),2.77-2.61(m,1H),2.56-2.52(m ,0.5H),2.50-2.48(m,3H),2.32-2.26(m,1H),2.24-2.18(m,4.5H),2.07-1.95(m,2H) ,1.83-1.74(m,2.5H),1.56-1.52(m,0.5H),1.48-1.37(m,0.5H),1.31-1.22(m,0.5H).

[0262] Example 27: 2-[2-(2-methyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)oxan-4-yl]acetic acid TIFF2024517769000067.tif118152 Step 1: 2-[(4S)-2-(6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl}-2-methylpyridin-3-yl)oxan-4-yl]acetic acid ethyl ester To a stirred solution of methyl 2-(2-{6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridin-3-yl}oxan-4-yl)acetate (60 mg, 0.16 mmol) in DCM (5 mL) was added MsCl (37 mg, 0.32 mmol), followed by TEA (49 mg, 0.48 mmol) under a N atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 30 min until the disappearance of the starting material was confirmed by TLC analysis. The reaction was quenched with saturated aqueous NaHCO at 0 °C, and the mixture was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (65 mg, 89.6% yield) as a yellow oil, which was used directly in the next step. LC / MS(ESI)m / z:453(M+H) + .

[0263] Step 2: Ethyl 2-[(4S)-2-(2-methyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)oxan-4-yl]acetate To a mixture of ethyl 2-[(4S)-2-(6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridin-3-yl)oxan-4-yl]acetate (50 mg, 0.11 mmol) and 5-propyl-1,2-dihydropyridin-2-one (18 mg, 0.13 mmol) in toluene (5 mL) and HO (1 mL) was added KCO (46 mg, 0.33 mmol) followed by TBAF (3 mg, 0.01 mmol), and the reaction was stirred at 100 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc (10 mL), washed with water and brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (50 mg, 91.7% yield) as a yellow solid, which was used directly in the next step. LC / MS(ESI)m / z:494(M+H) + .

[0264] Step 3: 2-[2-(2-methyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)oxan-4-yl]acetic acid To a solution of ethyl 2-[2-(2-methyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)oxan-4-yl]acetate (50 mg, 0.10 mmol) in THF (4 mL) / HO (1 mL) / MeOH (1 mL) was added LiOH.HO (43 mg, 1.01 mmol) and the reaction was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was diluted with HO (5 mL). The mixture was adjusted to pH 4 with 1 N aqueous HCl and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 5-95% in HO with 0.1% HCOOH, MeCN) to give the title compound (10 mg, 21.2% yield) as a white solid. LC / MS (ESI) m / z: 466 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.92-7.81(m,3H),7.36(dd,J=9.2,2.4Hz,1H),6.47(d,J=9.3Hz,1H),5.77(s,2H),4.66-4.56(m,0.5 H),4.23(d,J=0.5Hz,3H),4.17-4.09(m,0.5H),3.90(dd,J=7.9,3.0Hz,1H),2.80-2.65(m,1H),2.63(d ,J=6.4Hz,3H),2.61-2.47(m,1H),2.33-2.18(m,4H),2.09-1.95(m,1H),1.86-1.80(m,1H),1.78(d,J= 14.2Hz,0.5H),1.55(d,J=14.9Hz,0.5H),1.42-1.34(m,2H),1.34-1.16(m,1H),0.78(t,J=7.3Hz,3H).

[0265] Example 28: 2-{5-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl]oxan-3-yl}acetic acid TIFF2024517769000068.tif88165 Step 1: 5-oxo-5,6-dihydro-2H-pyran-3-yl trifluoromethanesulfonate To a solution of 2H-pyran-3,5(4H,6H)-dione (2.3 g, 20 mmol) in THF (40 mL) was added t-BuOK (22 mL, 1 M in THF) dropwise at 0 °C. After the addition, the mixture was stirred at 0 °C for an additional 0.5 h. N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-trifluoromethanesulfonyl methanesulfonamide (8.8 g, 22 mmol) in THF (20 mL) was added dropwise to the above mixture at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) to give the title compound (1.2 g, 25% yield) as a colorless oil. LC / MS(ESI)m / z:247(M+1) + . 1 H NMR (400MHz, CDCl3) δ 6.24(t,J=1.4Hz,1H),4.47(s,2H),4.17(s,2H).

[0266] Step 2: 5-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2H-pyran-3(6H)-one To a mixture of 5-oxo-5,6-dihydro-2H-pyran-3-yl trifluoromethanesulfonate (1.2 g, 5 mmol), 2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.3 g, 3.2 mmol), and NaCO (860 mg, 8.1 mmol) in 1,4-dioxane (20 mL) and HO (4 mL) was added Pd(PPh) (155 mg, 0.13 mmol) under a N atmosphere. After the addition, the mixture was degassed three times under a N atmosphere and stirred at 60 °C for an additional 3 h. The mixture was diluted with EtOAc (30 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (920 mg, 78.6% yield) as a pale yellow solid. LC / MS (ESI) m / z: 385 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.09(d,J=8.1Hz,1H),7.65(d,J=1.4Hz,1H),6.22(t,J=1.6Hz,1H),5.42-5.27(m,2H),4.83-4.71(m,1H),4.56(d,J=0.9Hz,2H),4.27(s,2H) ),4.17(s,3H),3.88(ddd,J=11.3,8.0,3.0Hz,1H),3.62-3.48(m,1H),2.60(d,J=4.8Hz,3H),1.71(dt,J=5.6,4.5Hz,2H),1.63-1.49(m,4H).

[0267] Step 3: (E)-2-(5-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2H-pyran-3(6H)-ylidene)methyl acetate A mixture of 5-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2H-pyran-3(6H)-one (385 mg, 1.0 mmol) and methyl (triphenylphosphoranylidene)acetate (500 mg, 1.5 mmol) in toluene (8 mL) was stirred at 110° C. for 16 h. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (310 mg, 70.4% yield) as a white solid. LC / MS (ESI) m / z: 441 (M+1). + .

[0268] Step 4: 2-(5-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate methyl To a solution of methyl (E)-2-(5-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-2H-pyran-3(6H)-ylidene)acetate (310 mg, 0.7 mmol) in MeOH (10 mL) was added Pd / C (15 mg, 10 wt%), and the mixture was degassed three times under N2 atmosphere and stirred at room temperature under a H2 balloon for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (230 mg, 73.5% yield) as a white solid. LC / MS (ESI) m / z: 445 (M+H). + .

[0269] Step 5: Methyl 2-(5-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate To a solution of methyl 2-(5-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate (230 mg, 0.5 mmol) in MeOH (10 mL) was added PPTS (262 mg, 1.0 mmol), and the mixture was stirred at 60 °C for 16 h. The mixture was diluted with DCM (10 mL), washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (75 mg, 40.2% yield) as a colorless oil. LC / MS (ESI) m / z: 361 (M+H). + .

[0270] Step 6: 2-(5-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate methyl To a mixture of methyl 2-(5-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate (20 mg, 0.05 mmol) and 2-chloro-4-cyclobutylpyrimidine (18 mg, 0.1 mmol) in THF (4 mL) was added t-BuOK (0.1 mL, 1 M in THF) at 0° C. After the addition, the mixture was stirred at room temperature for 16 h. The reaction was quenched with ice-cold saturated aqueous NH4Cl solution and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (15 mg, 55.4% yield) as a white solid. LC / MS (ESI) m / z: 493 (M+H) + .

[0271] Step 7: 2-(5-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetic acid To a solution of methyl 2-(5-(6-(5-(((4-cyclobutylpyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate (15 mg, 0.03 mmol) in THF (2 mL), MeOH (1 mL), and HO (1 mL) was added LiOH (10 mg, 0.2 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness, and the residue was dissolved in water (5 mL). The mixture was washed with EtOAc (2 × 3 mL), acidified with 1 N aqueous HCl to pH 4, and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 0-90% acetonitrile in HO containing 0.1% HCOOH) to give the title compound (4 mg, 27.5% yield) as a white solid. LC / MS (ESI) m / z: 479 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 8.40(dd,J=5.1,1.0Hz,1H),7.81-7.84(m,2H),6.97(d,J=5.1Hz,1H),6.22-6.12(m,2H),4.24(s,3H),4.08-3.78(m,2H),3.71- 3.63(m,1H),3.55-3.45(m,1H),3.30-3.11(m,3H),2.60-2.48(m,4H),2.24-2.17(m,5H),2.08-1.96(m,2H),1.95-1.61(m,2H).

[0272] Example 29: 2-[(5R)-5-(2-ethyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)oxan-3-yl]acetic acid TIFF2024517769000069.tif103150 Step 1: Methyl 2-[5-(6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl}-2-methylpyridin-3-yl)oxan-3-yl]acetate To a solution of methyl 2-(5-(6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate (30 mg, 0.08 mmol) in DCM (4 mL) was added TEA (25 mg, 0.25 mmol), followed by the addition of MsCl (20 mg, 0.18 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (10 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (32 mg, 87.7% yield) as a colorless oil, which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 439 (M+H). + .

[0273] Step 2: 2-(5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate methyl To a mixture of methyl 2-[5-(6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl}-2-methylpyridin-3-yl)oxan-3-yl]acetate (32 mg, 0.07 mmol) and 5-propylpyridin-2(1H)-one (10 mg, 0.07 mmol) in toluene (4 mL) and HO (1 mL) was added TBAF (5 mg, 0.019 mmol) and KCO (25 mg, 0.18 mmol), and the resulting mixture was stirred at 110 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (30 mg, 83.3% yield) as a yellow solid. LC / MS(ESI)m / z:480(M+H) + .

[0274] Step 3: 2-(5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetic acid To a solution of methyl 2-(5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-3-yl)acetate (30 mg, 0.061 mmol) in THF (2 mL), MeOH (1 mL), and HO (1 mL) was added LiOH (10 mg, 0.2 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness, and the residue was dissolved in water (5 mL). The mixture was washed with EtOAc (2 × 3 mL), acidified with 1 N aqueous HCl to pH 4, and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 0-90% acetonitrile in HO containing 0.1% TFA) to give the title compound (9.5 mg, 32.6% yield) as a white solid. LC / MS (ESI) m / z: 466 (M+H)+ . 1 H NMR(400MHz,CD3OD)δ 7.96-7.70(m,3H),7.36(dd,J=9.3,2.3Hz,1H),6.47(d,J=9.3Hz,1H),5.77(d,J=1.4 Hz,2H),4.23(d,J=1.4Hz,3H),4.07-3.81(m,2H),3.71-3.64(m,1H),3.49-3.33(m,1 H),3.23-3.14(m,1H),2.68(d,J=10.3Hz,3H),2.57-2.45(m,1H),2.30-2.19(m,4H), 2.11-1.97(m,1H),1.93-1.53(m,1H),1.44-1.34(m,2H),0.78(td,J=7.3,1.6Hz,3H).

[0275] Example 30: 2-(4-{2-ethyl-6-[1-methyl-5-({[methyl(propyl)carbamoyl]oxy}methyl)-1H-1,2,3-triazol-4-yl]pyridin-3-yl}oxan-2-yl)acetic acid TIFF2024517769000070.tif98160 Step 1: Ethyl (E)-3-(but-3-en-1-yloxy)acrylate To a mixture of ethyl prop-2-ynoate (10 mL, 0.1 mol) and 4-methylmorpholine (11 mL, 0.1 mol) in DCM (150 mL), but-3-en-1-ol (8.7 mL, 0.1 mol) was added dropwise over 15 min at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (12.3 g, 72.3% yield) as a colorless oil. LC / MS (ESI) m / z: 171 (M+1). + . 1H NMR(400MHz,CDCl3)δ 7.60(d,J=12.6Hz,1H),5.80(ddt,J=17.0,10.2,6.7Hz,1H),5.20(d,J=12.6Hz,1H),5.17-5.08( m,2H),4.16(q,J=7.1Hz,2H),3.89(t,J=6.6Hz,2H),2.47(q,J=6.7Hz,2H),1.27(t,J=7.1Hz,3H).

[0276] Step 2: 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate methyl To a solution of (E)-ethyl 3-(but-3-en-1-yloxy)acrylate (5.1 g, 30 mmol) in dry DCM (100 mL) was added TFA (12 mL) dropwise over 30 min at 0 °C, and the mixture was stirred at 0 °C for 2 h. After completion, the reaction mixture was concentrated to dryness and diluted with EtOAc (100 mL). The mixture was washed with ice-cold 1N aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was dissolved in MeOH (80 mL), and KCO (13 g, 92 mmol) was added. The resulting mixture was stirred at 25 °C for 30 min. The pH of the mixture was adjusted to 7 with 1N aqueous AcOH, and the mixture was extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness under vacuum. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (2.3 g, 40% yield) as a colorless oil.

[0277] Step 3: 2-(4-oxotetrahydro-2H-pyran-2-yl)acetate methyl To a mixture of ethyl 2-(4-hydroxyoxan-2-yl)acetate (1.5 g, 8.0 mmol) in acetone (20 mL) was added freshly prepared Jones reagent (10 mL), and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc (30 mL), washed with saturated aqueous NaHSO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (1.1 g, 74.1% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 4.35-4.24(m,1H),4.12-4.01(m,1H),3.72(s,3H),3.72-3.65(m,1H),2.69(dd ,J=15.5,7.8Hz,1H),2.65-2.56(m,1H),2.56-2.45(m,2H),2.43-2.31(m,2H).

[0278] Step 4: (Z)-2-(4-(2-tosylhydrazono)tetrahydro-2H-pyran-2-yl)acetate methyl A mixture of ethyl 2-(4-oxoxooxan-2-yl)acetate (900 mg, 5.0 mmol) and 4-methylbenzenesulfonohydrazide (970 mg, 5.0 mmol) in EtOH (20 mL) was stirred at room temperature for 3 h. The mixture was diluted with EtOAc (30 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (1.5 g, 78.7% yield) as a pale yellow solid. LC / MS (ESI) m / z: 341 (M+1). + .

[0279] Step 5: Methyl 2-[4-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)oxan-2-yl]acetate To a mixture of 3-bromo-2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridine (760 mg, 2.0 mmol), ethyl 2-[(3R)-piperidin-3-yl]acetate (420 mg, 2.0 mmol) in 1,4-dioxane (20 mL), K2CO3 (830 mg, 6.0 mmol) was added, and the mixture was stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (170 mg, 30.6% yield) as a yellow solid. LC / MS (ESI) m / z: 459 (M+1). + . 1 H NMR(400MHz,CDCl3)δ 8.00(d,J=8.1Hz,1H),7.55(s,1H),5.46(dd,J=12.7,1.9Hz,1H),5.33(dd,J=12.7,1.7Hz,1H),4.79-4.69(m,1H),4.16( s,3H),4.15-4.10(m,1H),4.00-3.91(m,1H),3.86(dd,J=13.9,5.8Hz,1H),3.71(s,3H),3.65(td,J=11.7,2.5Hz,1H),3.5 0(dd,J=11.2,4.2Hz,1H),3.08(ddd,J=12.0,8.2,3.8Hz,1H),2.90(q,J=7.5Hz,2H),2.63(dd,J=15.3,7.8Hz,1H),2.47(d d,J=15.3,5.1Hz,1H),1.87-1.74(m,3H),1.70(td,J=9.5,4.4Hz,3H),1.59(dd,J=8.5,4.1Hz,3H),1.35(t,J=7.5Hz,3H).

[0280] Step 6: Ethyl 2-(4-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)morpholin-2-yl)acetate To a mixture of methyl 2-[4-(2-ethyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)oxan-2-yl]acetate (340 mg, 0.8 mmol) in MeOH (10 mL) was added PPTS (600 mg, 2.4 mmol), and the mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with DCM (20 mL), washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel: 0-40% EtOAc in PE) to give the title compound (210 mg, 75.6% yield) as a white solid. LC / MS (ESI) m / z: 375 (M+1]). + The title compound was further purified by chiral SFC to give four diastereomers as follows: Compound 7-1 (peak 1, retention time: 2.510 min), Compound 7-2 (peak 2, retention time: 2.798 min), Compound 7-3 (peak 3, retention time: 3.647 min), and Compound 7-4 (peak 4, retention time: 4.346 min). SFC conditions: Column: ChiralCel OJ, 250 × 21.2 mm ID, 5 μm; Mobile phase: A for CO and B for MeOH + 0.1% NH H O; Flow rate: 50 mL / min; Column temperature: 35 °C.

[0281] Step 7: 2-(4-{2-ethyl-6-[1-methyl-5-({[(4-nitrophenoxy)carbonyl]oxy}methyl)-1H-1,2,3-triazol-4-yl]pyridin-3-yl}oxan-2-yl)acetate methyl To a mixture of ethyl 2-(4-(2-ethyl-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)morpholin-2-yl)acetate (40 mg, 0.1 mmol) and pyridine (50 mg, 0.6 mmol) in DCM (5 mL) was added a solution of 4-nitrophenyl chloroformate (73 mg, 0.4 mmol) in DCM (1 mL) dropwise at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (80 mg, 100% yield) as a yellow solid, which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 540 (M+1). + .

[0282] Step 8: Methyl 2-(4-{2-ethyl-6-[1-methyl-5-({[methyl(propyl)carbamoyl]oxy}methyl)-1H-1,2,3-triazol-4-yl]pyridin-3-yl}oxan-2-yl)acetate To a mixture of methyl 2-(4-{2-ethyl-6-[1-methyl-5-({[(4-nitrophenoxy)carbonyl]oxy}methyl)-1H-1,2,3-triazol-4-yl]pyridin-3-yl}oxan-2-yl)acetate (80 mg, 0.1 mmol) and DIPEA (66 mg, 0.5 mmol) in THF (4 mL) was added methyl(propyl)amine (22 mg, 0.3 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (10 mL), washed with 1N aqueous NaOH and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (32 mg, 66.3% yield) as a white solid. LC / MS (ESI) m / z: 474 (M+1). + .

[0283] Step 9: 2-(4-(2-ethyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)tetrahydro-2H-pyran-2-yl)acetic acid To a solution of methyl 2-(4-{2-ethyl-6-[1-methyl-5-({[methyl(propyl)carbamoyl]oxy}methyl)-1H-1,2,3-triazol-4-yl]pyridin-3-yl}oxan-2-yl)acetate (32 mg, 0.7 mmol) in MeOH (1 mL), water (1 mL), and THF (4 mL) was added LiOH (21 mg, 0.5 mmol), and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated to dryness, and the residue was dissolved in water (10 mL). The mixture was washed with EtOAc, acidified with 1 N aqueous HCl to pH 3, and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 0-90% acetonitrile in HO containing 0.1% TFA) to give the title compound (18.1 mg, 53.3% yield) as a white solid. LC / MS (ESI) m / z: 460 (M+1) + . 1 H NMR(400MHz,CD3OD)δ 7.85(d,J=7.9Hz,1H),7.75(dd,J=20.9,8.2Hz,1H),5.77(d,J=4.7Hz,2H),4.19( s,3H),4.15-4.00(m,1H),3.99-3.88(m,1H),3.84-3.63(m,1H),3.29-3.05(m,4H ),2.96(dd,J=13.4,6.0Hz,2H),2.83(d,J=17.6Hz,3H),2.52-2.48(m,1H),1.88- 1.67(m,3H),1.59-1.39(m,2H),1.39-1.29(m,4H),0.77(dt,J=79.5,7.5Hz,3H).

[0284] The following examples in Table 3 were prepared from appropriate starting materials by using methods similar to those used to prepare the examples described herein.

[0285] (Table 3) TIFF2024517769000071.tif174170TIFF2024517769000072.tif168170TIFF2024517769000073.tif179170TIFF2024517769000074.tif88167

[0286] Example 38: 2-[3-(2-methyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)cyclohexyl]acetic acid TIFF2024517769000075.tif112165 Step 1: 3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate To a solution of cyclohexane-1,3-dione (2 g, 17.8 mmol) in THF (20 mL) was added t-BuOK (21.4 mL, 21.4 mmol) dropwise at 0 °C. The mixture was stirred at this temperature for 30 min. Subsequently, N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-trifluoromethanesulfonyl methanesulfonamide (8.4 g, 21.4 mmol) was added in portions. The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (3.2 g, 73.5% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ 6.07(t,J=1.3Hz,1H),2.69(td,J=6.2,1.3Hz,2H),2.50-2.42(m,2H),2.18-2.08(m,2H).

[0287] Step 2: 5-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-3,6-dihydro-2H-pyran-3-one To a mixture of 5-oxo-5,6-dihydro-2H-pyran-3-yl trifluoromethanesulfonate (330 mg, 1.3 mmol) and 2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (667 mg, 1.6 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added NaCO (426 mg, 4.0 mmol) and Pd(PPh) (155 mg, 0.13 mmol) under a N atmosphere. After the addition, the mixture was degassed three times under a N atmosphere and stirred at 60 °C for 2 h. The mixture was diluted with water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (480 mg, 93.1% yield) as a yellow oil. LC / MS (ESI) m / z: 385 (M+H). + .

[0288] Step 3: 2-[(1Z)-3-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)cyclohex-2-en-1-ylidene]acetate To a solution of ethyl 2-(trimethylsilyl)acetate (0.3 mL, 1.6 mmol) in THF (10 mL) was added dropwise LDA (2.4 mL, 4.7 mmol) at −70° C. After stirring at this temperature for 30 min, a solution of 3-(2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)cyclohex-2-en-1-one (600 mg, 1.6 mmol) in THF (5 mL) was added, and the resulting mixture was stirred at −70° C. for 30 min. The reaction mixture was quenched with ice-cold saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (500 mg, 70.4% yield) as a pale yellow solid. LC / MS (ESI) m / z: 453 (M+H) + .

[0289] Step 4: Ethyl 2-[3-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)cyclohexyl]acetate To a solution of ethyl 2-[(1Z)-3-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)cyclohex-2-en-1-ylidene]acetate (500 mg, 1.1 mmol) in MeOH (10 mL), Pd / C (30 mg, 0.2 mmol, 10 wt%) was added at 0 °C, and the mixture was degassed three times under N atmosphere and stirred at room temperature for 16 h under a H balloon. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (460 mg, 91.2% yield) as a white semi-solid. LC / MS (ESI) m / z: 457 (M+H). + .

[0290] Step 5: Ethyl 2-(3-{6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridin-3-yl}cyclohexyl)acetate To a solution of ethyl 2-[(1Z)-3-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)cyclohex-2-en-1-ylidene]acetate (460 mg, 1 mmol) in MeOH (10 mL) was added PPTS (1.2 g, 5.1 mmol), and the mixture was stirred at 50° C. for 16 h. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by chromatography on silica gel (PE:EtOAc=1:1) to give the title compound (270 mg, 72.3% yield) as a pale yellow solid. LC / MS (ESI) m / z: 373 (M+H). + . 1 H NMR(400MHz,CDCl3)δ 8.11(dd,J=8.1,1.3Hz,1H),7.70-7.64(m,1H),4.85(s,2H),4.18-4.11(m,2H),4.08(d,J=7.4Hz,3H),3.00-2.74(m,1H),2.64-2.58(m,3H) ),2.54(d,J=6.7Hz,1H),2.31-2.20(m,1H),2.01-1.81(m,3H),1.78-1.58(m,4H),1.43-1.30(m,1H),1.28-1.23(m,4H),1.20-1.04(m,1H).

[0291] Step 6: 2-(4-{5-[3-(2-ethoxy-2-oxoethyl)cyclohexyl]-6-methylpyridin-2-yl}-1-methyl-1H-1,2,3-triazol-5-yl)ethane-1-sulfonic acid To a solution of ethyl 2-(3-{6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridin-3-yl}cyclohexyl)acetate (30 mg, 0.08 mmol) in DCM (5 mL) was added TEA (0.1 mL, 0.24 mmol), followed by MsCl (0.1 mL, 0.1 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. TLC showed the reaction was complete, so the mixture was diluted with ice water and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (33 mg, 90.4% yield) as a yellow solid. LC / MS (ESI) m / z: 451 (M+H) + .

[0292] Step 7: 2-(4-{5-[3-(2-ethoxy-2-oxoethyl)cyclohexyl]-6-methylpyridin-2-yl}-1-methyl-1H-1,2,3-triazol-5-yl)ethane-1-sulfonic acid To a mixture of ethyl 2-[3-(6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl}-2-methylpyridin-3-yl)cyclohexyl]acetate (35 mg, 0.07 mmol) and 5-propyl-1,2-dihydropyridin-2-one (13 mg, 0.1 mmol) in toluene (4 mL) and water (1 mL) was added KCO (32 mg, 0.2 mmol) and TBAF (2.0 mg, 0.01 mmol), and the mixture was stirred at 100° C. for 16 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (30 mg, 78.5% yield) as a yellow solid. LC / MS (ESI) m / z: 492 (M+H). + .

[0293] Step 8: 2-[3-(2-methyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)cyclohexyl]acetic acid To a solution of ethyl 2-[3-(2-methyl-6-{1-methyl-5-[(2-oxo-5-propyl-1,2-dihydropyridin-1-yl)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)cyclohexyl]acetate (35 mg, 0.07 mmol) in MeOH (1 mL), water (1 mL), and THF (2 mL) was added LiOH (30 mg, 0.7 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was acidified with 1 M aqueous HCl and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 0–90% acetonitrile in HO with 0.1% TFA) to give the title compound (20 mg, 60.6% yield) as a white solid. LC / MS(ESI)m / z:464(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 7.84(d,J=8.1Hz,1H),7.82(s,1H),7.75-7.68(m,1H),7.29(dd,J=9.3,2.5Hz,1H),6.35(d,J=9.2H z,1H),5.62(d,J=16.3Hz,2H),4.19(d,J=11.8Hz,3H),2.88(dd,J=48.2,11.8Hz,1H),2.61(d,J=1. 3Hz,3H),2.48-2.30(m,1H),2.17(dd,J=9.3,5.4Hz,3H),1.90-1.70(m,3H),1.60(dd,J=26.6,14.9 Hz,3H),1.45(dd,J=26.5,14.4Hz,1H),1.38-1.13(m,3H),1.13-0.82(m,1H),0.71(t,J=7.3Hz,3H).

[0294] Example 39: 2-{3-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl]cyclohexyl}acetic acid TIFF2024517769000076.tif50165 Step 1: 2-{3-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl]cyclohexyl}ethyl acetate To a mixture of ethyl 2-(3-{6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridin-3-yl}cyclohexyl)acetate (40 mg, 0.11 mmol) and 2-chloro-4-cyclobutylpyrimidine (27 mg, 0.16 mmol) in THF (5 mL) was added t-BuOK (0.16 mL, 0.16 mmol, 1 M in THF) at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (48 mg, 88.6% yield) as a yellow solid. LC / MS (ESI) m / z: 505 (M+H). + .

[0295] Step 2: 2-{3-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl]cyclohexyl}acetic acid To a solution of ethyl 2-{3-[6-(5-{[(4-cyclobutylpyrimidin-2-yl)oxy]methyl}-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl]cyclohexyl}acetate (48 mg, 0.1 mmol) in MeOH (1 mL), water (1 mL), and THF (4 mL) was added LiOH (40 mg, 0.9 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to dryness. The residue was diluted with water (10 mL) and washed with EtOAc (2 × 5 mL). The aqueous layer was acidified with 1 M aqueous HCl to pH 3 and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (10 mg, 22.1% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ 8.39(d,J=5.1Hz,1H),7.83(d,J=8.1Hz,1H),7.71(t,J=9.3Hz,1H),6.96(d,J=5.1Hz,1H),6.21-6.1 1(m,2H),4.23(s,3H),3.48(q,J=8.6Hz,1H),2.92(dt,J=66.1,11.7Hz,1H),2.70-2.53(m,1H),2.51( s,3H),2.47(d,J=13.8Hz,1H),2.22(ddd,J=17.3,7.8,3.1Hz,5H),2.04-1.94(m,2H),1.91-1.84(m, 2H),1.83-1.72(m,2H),1.68(s,1H),1.61-1.35(m,2H),1.30-1.02(m,2H).LC / MS(ESI)m / z:477(M+H) + .

[0296] Example 40 and Example 41: (R) or (S)-2-(3,3-difluoro-5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-1-yl)acetic acid and (S) or (R)-2-(3,3-difluoro-5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-1-yl)acetic acid TIFF2024517769000077.tif114164 Step 1: Ethyl 2-[benzyl(2-oxopropyl)amino]acetate To a mixture of ethyl 2-(benzylamino)acetate (9.7 mL, 51.7 mmol) and aqueous NaHCO3 (25.8 mL, 103.2 mmol, 4 M in water) in THF (100 mL) was added 1-chloropropan-2-one (4.9 mL, 62.1 mmol) dropwise over 15 min at 0 °C. After the addition, the resulting solution was stirred at 80 °C overnight. After cooling to 0 °C, the reaction mixture was treated with EtOAc (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organics were concentrated to dryness under vacuum, and the residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (6.6 g, 51.2% yield) as a colorless oil. LC / MS (ESI) m / z: 250 (M+H). + .

[0297] Step 2: 1-benzyl-5-oxo-1,2,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate To a solution of ethyl 2-[benzyl(2-oxopropyl)amino]acetate (5.6 g, 22.5 mmol) in THF (60 mL) was added t-BuOK (22.5 mL, 22.5 mmol, 1 M in THF) dropwise over 15 min at 0 °C. After the addition, the mixture was stirred at 0 °C for an additional 0.5 h. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-trifluoromethanesulfonyl methanesulfonamide (8.8 g, 22.5 mmol) in THF (20 mL) was added to the above mixture over 15 min at 0 °C, and the resulting solution was stirred at 0 °C for 1 h. The reaction mixture was treated with EtOAc (50 mL) and water (50 mL), the organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were concentrated to dryness under reduced pressure, and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (1.8 g, 23.9% yield) as a colorless oil. LC / MS (ESI) m / z: 336 (M+H). + .

[0298] Step 3: 1-benzyl-2'-methyl-6'-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-1,6-dihydro-[3,3'-bipyridin]-5(2H)-one To a mixture of 1-benzyl-5-oxo-1,2,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate (990 mg, 2.9 mmol), 2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.1 g, 2.7 mmol), and NaCO (853 mg, 8.1 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh) (155 mg, 0.13 mmol) under a N atmosphere at 0° C. After the addition, the resulting solution was degassed three times under N and stirred at 60° C. for 3 h. The mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-100% EtOAc in PE) to give the title compound (760 mg, 59.5% yield) as a white solid. LC / MS (ESI) m / z: 474 (M+H). + . 1 H NMR(400MHz,CDCl3)δ 8.03(d,J=8.0Hz,1H),7.48(d,J=8.1Hz,1H),7.35(d,J=4.4Hz,4H),7.33-7.27(m,1H),6.14(t,J=1.4Hz,1H),5.41-5.25(m,2H),4.79- 4.73(m,1H),4.16(s,3H),3.91-3.82(m,1H),3.75(s,2H),3.55-3.47(m,1H),3.44(s,2H),3.30(s,2H),2.50(s,3H),1.70-1.49(m,6H).

[0299] Step 4: 1-benzyl-2'-methyl-6'-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-1,2,5,6-tetrahydro-[3,3'-bipyridin]-5-ol To a solution of 1-benzyl-5-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-1,2,3,6-tetrahydropyridin-3-one (630 mg, 1.3 mmol) in MeOH (10 mL) was added NiCl (428 mg, 2.7 mmol), followed by the portionwise addition of NaBH (113 mg, 2.7 mmol) at 0 °C. After the addition, the mixture was stirred at room temperature for an additional 3 h. The reaction mixture was poured into ice-cold saturated aqueous NH Cl and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water and brine, dried over Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (430 mg, 68% yield) as a colorless oil. LC / MS (ESI) m / z: 476 (M+H) + .

[0300] Step 5: tert-butyl 3-hydroxy-5-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidine-1-carboxylate To a mixture of 1-benzyl-5-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-1,2,3,6-tetrahydropyridin-3-ol (430 mg, 0.9 mmol) and BocO (456 mg, 2.0 mmol) in MeOH (20 mL) was added Pd / C (50 mg, 10 wt%), and the mixture was degassed three times under N and stirred under a H balloon at room temperature for 16 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (0-40% EtOAc in PE) to give the title compound (320 mg, 72.9% yield) as a colorless oil. LC / MS (ESI) m / z: 488 (M+H). + .

[0301] Step 6: (S)-N-(6-bromo-3-methylpyridin-2-yl)-2-(N-methyl-4-nitrophenylsulfonamido)hex-5-enamide To a solution of DMSO (0.2 mL, 2.5 mmol) in DCM (5 mL) was added oxalyl chloride (0.1 mL, 1.3 mmol) dropwise at −70° C. After the addition, the mixture was stirred at −70° C. for another 10 minutes. A solution of tert-butyl 3-hydroxy-5-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidine-1-carboxylate (250 mg, 0.5 mmol) in DCM (2 mL) was added dropwise to the above mixture at −70° C. for 10 minutes, and the reaction mixture was stirred at this temperature for 1 hour. TEA (0.4 mL, 2.8 mmol) was added dropwise to the above mixture at −70° C., and the resulting mixture was stirred at −70° C. for 1 hour until room temperature. The mixture was diluted with DCM (10 mL), washed with water and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (210 mg, 80.3% yield) as a colorless oil. LC / MS (ESI) m / z: 486 (M+H). + . 1 H NMR(400MHz,CDCl3)δ 7.94(d,J=8.1Hz,1H),7.44(d,J=8.2Hz,1H),5.34-5.24(m,2H),4.73-4.67(m,1H),4.22(m,1H),4.08(s,3H),3.92-3.77(m,2H), 3.49-3.40(m,2H),3.27(s,1H),2.97(m,1H),2.77-2.61(m,2H),2.57(s,3H),1.73-1.60(m,2H),1.54-1.45(m,4H),1.40(s,9H).

[0302] Step 7: tert-butyl 3,3-difluoro-5-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidine-1-carboxylate To a solution of tert-butyl 3-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)-5-oxopiperidine-1-carboxylate (180 mg, 0.37 mmol) in DCM (5 mL) was added DAST (187 mg, 0.8 mmol) dropwise at 0 °C. After the addition, the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice-cold saturated aqueous NaHCO3 solution and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (0–50% EtOAc in PE) to give the title compound (145 mg, 77.1% yield) as a colorless oil. LC / MS (ESI) m / z: 508 (M+H). + . 1 H NMR (400 MHz, CDCl3) δ 8.02(dd,J=8.1,4.0Hz,1H),7.50(t,J=6.7Hz,1H),5.45-5.32(m,2H),4.78-4 .76(m,1H),4.36(dd,J=24.0,8.2Hz,1H),4.16(s,3H),3.89(t,J=9.3Hz,1H),3 .53(dd,J=10.4,4.5Hz,1H),3.32-3.20(m,1H),3.09-2.91(m,1H),2.67(s,3H) ,2.64(s,1H),2.38(s,1H),1.84-1.64(m,4H),1.62-1.54(m,4H),1.50(s,9H).

[0303] Step 8: {4-[5-(5,5-difluoropiperidin-3-yl)-6-methylpyridin-2-yl]-1-methyl-1H-1,2,3-triazol-5-yl}methanol hydrochloride To a solution of tert-butyl 3,3-difluoro-5-(2-methyl-6-{1-methyl-5-[(oxan-2-yloxy)methyl]-1H-1,2,3-triazol-4-yl}pyridin-3-yl)piperidine-1-carboxylate (150 mg, 0.3 mmol) in DCM (5 mL) was added HCl / 1,4-dioxane (0.5 mL, 2 mmol, 4 M) at 0° C. After stirring at room temperature for 2 h, the mixture was concentrated to dryness under reduced pressure to give the title compound (110 mg, 100% yield) as a yellow solid, which was used directly in the next reaction. LC / MS (ESI) m / z: 304 (M+H). + .

[0304] Step 9: Ethyl 2-(3,3-difluoro-5-{6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridin-3-yl}piperidin-1-yl)acetate To a mixture of {4-[5-(5,5-difluoropiperidin-3-yl)-6-methylpyridin-2-yl]-1-methyl-1H-1,2,3-triazol-5-yl}methanol hydrochloride (94 mg, 0.26 mmol) and DIPEA (0.16 mL, 1 mmol) in THF (5 mL), 2-bromoethyl acetate (48 mg, 0.3 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (55 mg, 51.1% yield) as a colorless oil. LC / MS (ESI) m / z: 410 (M+H). + . 1 H NMR(400MHz,CDCl3)δ 8.14(d,J=8.2Hz,1H),7.65(d,J=8.2Hz,1H),7.53(d,J=10.5Hz,1H),4.83(s,2H),4.19(m,2H),4.08(s,3H),3.47(s,2H) ,3.39(m,1H),3.22(m,1H),2.97(m,2H),2.72(m,1H),2.66(s,3H),2.34(m,1H),2.06-1.87(m,1H),1.28(t,J=7.1Hz,3H).

[0305] Step 10: Ethyl 2-[3,3-difluoro-5-(6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl}-2-methylpyridin-3-yl)piperidin-1-yl]acetate To a solution of ethyl 2-(3,3-difluoro-5-{6-[5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl]-2-methylpyridin-3-yl}piperidin-1-yl)acetate (55 mg, 0.14 mmol) in DCM (5 mL), TEA (0.1 mL, 0.7 mmol) and MsCl (24 mg, 0.2 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (5 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness to give the title compound (60 mg, 88.4% yield) as a yellow solid. LC / MS (ESI) m / z: 488 (M+H). + .

[0306] Step 11: (R) or (S)-2-(3,3-difluoro-5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-1-yl)ethyl acetate (12-P1) and (S) or (R)-2-(3,3-difluoro-5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-1-yl)ethyl acetate (12-P2) A solution of 2-[3,3-difluoro-5-(6-{5-[(methanesulfonyloxy)methyl]-1-methyl-1H-1,2,3-triazol-4-yl}-2-methylpyridin-3-yl)piperidin-1-yl]ethyl acetate (60 mg, 0.12 mmol) and 5-propyl-1,2-dihydropyridin-2-one ( To a mixture of 12-P1 (peak 1, retention time: 4.88 min) (16 mg, 25% yield) and 12-P2 (peak 2, retention time: 5.08 min) (22 mg, 34.6% yield) were added KCO (55.2 mg, 0.4 mmol) and TBAF (5 mg, cat.), and the mixture was stirred at 110° C. for 3 h. The mixture was diluted with EtOAc (5 mL), washed with water and brine, dried over NaSO, filtered, and concentrated to dryness to give the racemic product, which was purified by chiral SFC to give compound 12-P1 (peak 1, retention time: 4.88 min) (16 mg, 25% yield) and compound 12-P2 (peak 2, retention time: 5.08 min) (22 mg, 34.6% yield) as yellow solids. LC / MS (ESI) m / z: 529 (M+H). + Absolute stereochemistry not assigned. SFC conditions: Column: ChiralPak OJ, 250 x 21.2 mm ID, 5 μm; Mobile phase: A with CO2 and B with methanol (0.1% NH4OH); Gradient: 30% B; Flow rate: 50 mL / min; Column temperature: 35 °C.

[0307] Example 40: (R) or (S)-2-(3,3-difluoro-5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-1-yl)acetic acid To a solution of compound 12-P1 (16 mg, 0.03 mmol) in THF (1 mL), MeOH (0.5 mL), and HO (0.5 mL) was added LiOH (5 mg, 0.1 mmol), and the mixture was stirred at room temperature for 3 h. The reaction was treated with 1N aqueous HCl to pH 4 and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 0–90% acetonitrile in HO containing 0.1% HCOOH) to give the title compound (5.8 mg, 35.3% yield) as a white solid. LC / MS (ESI) m / z: 501 (M+H). + . 1H NMR(400MHz,CD3OD)7.92(d,J=8.3Hz,2H),7.84(d,J=8.2Hz,1H),7.44-7.3 7(m,1H),6.50(d,J=9.1Hz,1H),5.74(s,2H),4.22(s,3H),3.55(s,2H),3.50 (s,1H),3.40(d,J=10.0Hz,1H),3.12(s,1H),2.97(m,1H),2.76-2.67(m,4H ),2.37-2.27(m,3H),2.26-2.09(m,1H),1.42(m,2H),0.81(t,J=7.3Hz,3H).

[0308] Example 41: (S) or (R)-2-(3,3-difluoro-5-(2-methyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)piperidin-1-yl)acetic acid The title compound was prepared from compound 12-P2 of Example 40 using the same method for the synthesis of Example 40. LC / MS (ESI) m / z: 501 (M+H) + . 1 H NMR(400MHz,CD3OD)7.92(d,J=8.3Hz,2H),7.84(d,J=8.2Hz,1H),7.44-7.3 7(m,1H),6.50(d,J=9.1Hz,1H),5.74(s,2H),4.22(s,3H),3.55(s,2H),3.50 (s,1H),3.40(d,J=10.0Hz,1H),3.12(s,1H),2.97(m,1H),2.76-2.67(m,4H ),2.37-2.27(m,3H),2.26-2.09(m,1H),1.42(m,2H),0.81(t,J=7.3Hz,3H).

[0309] Example 42: (1S,3S)-3-((6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxoimidazolidin-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid TIFF2024517769000078.tif110165 Step 1: 2-Methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol To a solution of 3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine (1 g, 2.72 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (840 mg, 3.3 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl (99 mg, 0.136 mmol) and KOAc (400 mg, 4.08 mmol). The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 16 h. The mixture was cooled to 0 °C, and aqueous HO (3 mL, 30 wt%) was added dropwise. The resulting mixture was stirred from 0 °C to room temperature for 2 h. The mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaSO and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (560 mg, 67.6% yield) as a pale yellow solid. LC / MS (ESI) m / z: 305 (M+H). + .

[0310] Step 2: (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate isopropyl To a solution of 2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol (500 mg, 1.64 mmol) in DCM (20 mL) was added (1S,3R)-3-hydroxycyclohexane-1-carboxylate propan-2-yl (612 mg, 3.29 mmol) and PPh3 (1.29 g, 4.93 mmol), followed by dropwise addition of DIAD (0.98 mL, 4.93 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness, and the residue was purified by chromatography on silica gel (PE: EtOAc = 3:1) to give the title compound (310 mg, 39.9% yield) as a pale yellow solid. LC / MS (ESI) m / z: 473 (M+H). + .

[0311] Step 3: (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate isopropyl To a solution of isopropyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (310 mg, 0.66 mmol) in MeOH (10 mL) was added PPTS (330 mg, 1.3 mmol), and the mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by chromatography on silica gel (PE:EtOAc=1:1) to give the title compound (174 mg, 68.3% yield) as a pale yellow solid. LC / MS (ESI) m / z: 389 (M+H) + .

[0312] Step 4: (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate isopropyl To a solution of isopropyl (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate (170 mg, 0.438 mmol) in DCM (6 mL) was added TEA (0.18 mL, 1.3 mmol) and MsCl (0.068 mL, 0.88 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (5 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by chromatography on silica gel (PE:EtOAc=2:1) ​​to give the title compound (152 mg, 74.4% yield) as a yellow solid. LC / MS (ESI) m / z: 467 (M+H) + .

[0313] Step 5: (1S,3S)-3-((6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxoimidazolidin-1-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid To a solution of 5-(cyclopropylmethyl)-1-methylimidazolidin-2-one (44.6 mg, 0.29 mmol) in DMF (2 mL) was added NaH (19.3 mg, 0.48 mmol, 60% dispersion in mineral oil) in portions at 0 °C, and the mixture was stirred at 0 °C for 30 min under a N atmosphere. A solution of isopropyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (150 mg, 0.32 mmol) was added at 0 °C, and the mixture was stirred at room temperature under a N atmosphere for 2 h. The reaction mixture was quenched with ice water, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness, and the residue was dissolved in HO (10 mL). The mixture was washed with MTBE (2 × 5 mL), acidified with 1N aqueous HCl to pH ∼4, and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C18, 10–80% in HO with 0.1% HCOOH, MeCN) to give the title compound (50 mg, 32.2% yield) as a white solid. LC / MS (ESI) m / z: 483 (M+H). + . 1 H-NMR (400 MHz, CD3OD) δ 7.81(d,J=8.5Hz,1H),7.45-7.42(m,1H),5.01(s,2H),4.11(s,3H),3.50- 3.41(m,2H),3.09-3.04(m,1H),2.80-2.74(m,4H),2.56-2.47(m,3H),2.1 4-2.08(m,1H),1.95-1.90(m,3H),1.79-1.55(m,3H),1.51-1.43(m,2H),1 .40-1.29(m,1H),0.49-0.43(m,1H),0.38-0.30(m,2H),0.03-0.01(m,2H).

[0314] Example 43: (1S,3S)-3-((2-ethyl-6-(1-methyl-5-((2-oxo-5-propylpyridin-1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylic acid The title compound was synthesized using the same synthetic sequence used to synthesize Examples 2 and 42. LC / MS (ESI) m / z: 480 (M+H) + . 1 H NMR(400MHz,CD3OD)δ 7.84-7.81(d,J=8.6Hz,1H),7.68-7.66(d,J=2.0Hz,1H),7.47-7.44(d,J=8.7Hz,1H),7.34-7.40(m 1H),6.51-6.49(d,J=9.2Hz,1H),5.82(s,2H),4.82-4.78(m,1H),4.18(s,3H),2.97-2.93(m,2H),2.80-2.75(m,1H),2.23-2.19(m,2H) ,2.13-2.09(m,1H),1.98-1.92(m,3H),1.79-1.64(m,4H),1.41-1.33(m,2H),1.31-1.28(t,J=7.6Hz,3H),0.77-0.73(t,J=7.6Hz,3H).

[0315] Example 44: (1S,3S)-3-((6-(5-((5-(cyclopropylmethyl)-2-oxopyridin-1(2H)-yl)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)oxy)cyclohexanecarboxylic acid The title compound was synthesized using the same synthetic sequence used to synthesize Examples 2 and 42. LC / MS (ESI) m / z: 492 (M+H) + . 1H NMR(400MHz,CD3OD)δ 7.88-7.85(d,J=8.6Hz,1H),7.71-7.69(d,J=2.0Hz,1H),7.48-7.44(d,J=8.7Hz,1H),7.43-7. 40(m,1H),6.53-6.50(d,J=9.3Hz,1H),5.90(s,2H),4.79-4.82(m,1H),4.16(s,3H),2.95-2.91 (m,2H),2.81-2.72(m,1H),2.16-2.14(d,J=6.9Hz,2H),2.14-2.07(m,1H),2.00-1.89(m,3H), 1.79-1.60(m,4H),1.26-1.32(m,3H),0.70-0.56(m,1H),0.31-0.23(m,2H),0.10-0.07(m,2H).

[0316] Biological assays LPA1 calcium flux assay The effectiveness of the compounds of the present invention as LPA1 inhibitors can be determined in an LPA1 functional antagonist assay as follows.

[0317] PathHunter® CHO-K1 EDG2 β-Arrestin Cell Line (Eurofins DiscoverX Corporation, Catalog No. 93-0644C2) was plated overnight (11,500 cells / well) in poly-D-lysine-coated 384-well microplates (Corning, Catalog No. 356697) in AssayComplete™ Cell Plating 35 Reagent (Eurofins DiscoverX Corporation, Catalog No. 93-0563R35). After overnight culture, cells were loaded with calcium indicator dye from the HitHunter Calcium No WashPLUS Assay Kit (Eurofins DiscoverX Corporation, Catalog No. 93-0091) at 37°C for 45 minutes. Test compounds solubilized in DMSO (Sigma, Cat. No. 276855) on a 384-well polypropylene microplate (Greiner bio-one, Cat. No. 781280) were then diluted to intermediate concentrations using assay buffer [1× HBSS calcium / magnesium (Corning, Cat. No. 21-023-CM) and 20 mM HEPES (Corning, Cat. No. 25-060-Cl)] and added to the cells at a final concentration of 0.4% DMSO using an Agilent Velocity 11. After compound addition, the assay plate was equilibrated to room temperature for 30 minutes. Cells were then stimulated by adding an EC concentration of LPA (catalog number 10010093) in assay buffer containing 1× HBSS calcium / magnesium (Corning, catalog number 21-023-CM), 20 mM HEPES (Corning, catalog number 25-060-Cl), and 0.1% BSA (Sigma, catalog number A8806) using a Molecular Devices FLIPR Tetra PLUS®. IC values ​​were determined by Chemical and Biological Information System from ChemInnovation Software, Inc.

[0318] Compounds of the present invention were tested for their activity to inhibit LPA1, as determined in the LPA1 functional antagonist assay as described herein. The results of the LPA1 assay are shown in Table 4.

[0319] (Table 4) Activity data in LPA1 assay * * A:<100nM, B:100~500nM, C:500~5000nM, D:5000nM~10mM TIFF2024517769000081.tif152128TIFF2024517769000082.tif23558TIFF2024517769000083.tif28128

[0320] The present technology may include, but is not limited to, the features and combinations of features listed in the following numbered paragraphs, and it is understood that the following paragraphs should not be construed as limiting the scope of the claims appended hereto or as mandating that all such features must necessarily be included within the scope of such claims. 1) Formula (I) TIFF2024517769000084.tif52128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, The A ring is: TIFF2024517769000085.tif83150; a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from L 1 is a covalent bond, NH, O, or S, with the proviso that L 1 is a covalent bond, the A ring is selected from formula (A1), (A2), (A3), (A4), or (A5); and 1 is NH or S, the A ring is selected from formula (A6) or (A7), and further, L 1 is O, with the proviso that ring A is selected from formula (A6): L 2 is a covalent bond or (CR 7 R 7 ) p and L 3 is a covalent bond, O, or NR 7 where L 2 and L 3 is not a covalent bond; Q is C(=O)NR 9 R 10 , C(=O)OR 10 or a 5- or 6-membered heteroaryl group or a 5- or 6-membered heterocyclyl group, wherein the ring members contain 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 oxygen may be a ring member and / or an oxo group bonded to the ring member, and the ring is 3 ) n and one R 4 is replaced by X 1 is N, O, or CR 6a and X 2 But N or NR 6 and X 3 But N, NR 6 , or CR 6 where the dashed circle indicates the bond that forms the five-membered aromatic ring; Y 1 , Y 2 , Y 3 , and Y 4 are each independently N or CR 5 where Y 1 , Y 2 , Y 3 , and Y 4 at least one but not more than two of Z 1 , Z 2 , Z 3 , and Z 4 are each independently CH2 or O, with the proviso that Z 1, Z 2 , Z 3 , and Z 4 is O, R 1 may, in each occurrence, independently represent 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-membered heterosilyl, or R 1 and R 1 together with the carbon atom to which they are attached to form a ketone (C=O), R 2 In each occurrence, independently, hydrogen, deuterium, C 1~4 Alkyl, C 3~5 cycloalkyl or R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 3 may, in each occurrence, independently represent hydrogen, halogen, CN, C 1~6 Alkyl, or C 3~7 is cycloalkyl, R 4 But hydrogen, halogens, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 Cycloalkyl, 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q - a 5- to 7-membered heterocyclyl ring, wherein each phenyl independently optionally contains 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 5 may, in each occurrence, independently represent hydrogen, halogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, OH, C 1~6 Alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, HaloC 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 independently represents hydrogen, halogen, CN, C 1~4 alkyl, or cyclopropyl; R 7 may, in each occurrence, independently be hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 9 and R 10 each occurrence of is independently hydrogen, one to four R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q - a 5- to 7-membered heterocyclyl ring, or R 9 and R 10 together with the nitrogen atom to which they are attached, 1 to 4 R 11 forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R 11 may, in each occurrence, independently be hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C2~6 Alkynyl-C 3~7 Cycloalkyl, or O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 12 may, in each occurrence, independently be hydrogen, C 1~4 Alkyl or C 3~7 cycloalkyl or R 12 and R 12 together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R a and R b each occurrence is independently hydrogen or C 1~6 alkyl, and R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; p, in each occurrence, is independently 1, 2, 3, or 4; q, in each occurrence, is independently 0, 1, 2, 3, or 4; The compound, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof. 2) The compound of item 1, wherein the A ring is selected from formula (A1). 3) The compound of item 1, wherein the A ring is selected from formula (A2). 4) The compound of item 1, wherein the A ring is selected from formula (A3). 5) The compound of item 1, wherein the A ring is selected from formula (A4). 6) The compound of item 1, wherein the A ring is selected from formula (A5). 7) The compound of item 1, wherein the A ring is selected from formula (A6). 8) The compound of item 1, wherein the A ring is selected from formula (A7). 9)L 1 is a covalent bond. 10)L 1 The compound of any one of items 1 to 8, wherein is NH. 11)L 1 is O. 12)L 1 The compound of any one of items 1 to 8, wherein is S. 13)R 1 The compound of any one of items 1 to 12, wherein, in each occurrence, is independently hydrogen. 14)R 1 The compound of any one of items 1 to 12, wherein, in each occurrence, is independently a halogen. 15) m is 2 and one R 1 is hydrogen, and the other R 1 is a halogen. 16) m is 2 and one R 1 is hydrogen, and the other R 1 The compound of any one of items 1 to 12, wherein 17) m is 2 and R 1 is, in each occurrence, independently F. 18)R 2 The compound of any one of items 1 to 17, wherein, in each occurrence, is independently hydrogen. 19)R 2 But in each occurrence, independently, C 1~4 18. The compound of any one of items 1 to 17, wherein the alkyl is alkyl. 20)R 2 But in each occurrence, independently, C 3~5 18. The compound of any one of items 1 to 17, wherein the compound is cycloalkyl. 21)R2 and R 2 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring. 22) One R 2 is hydrogen, and the other R 2 is methyl. 23) One R 2 is hydrogen, and the other R 2 18. The compound of any one of items 1 to 17, wherein is ethyl or propyl. 24) One R 2 is hydrogen, and the other R 2 18. The compound of any one of items 1 to 17, wherein is cyclopropyl. 25)R 2 and R 2 together with the carbon atom to which they are attached form a cyclopropyl ring. 26)Y 2 is N and Y 1 , Y 3 , and Y 4 Each of these independently 5 The compound of any one of items 1 to 25, 27)Y 1 But, CR 5 and Y 2 is N and Y 3 and Y 4 26. The compound of any one of items 1 to 25, wherein each of is independently CH. 28)Y 1 But, CR 5 and Y 2 is N and Y 3 is N and Y 4 The compound of any one of items 1 to 25, wherein is CH. 29)R 5 29. The compound of any one of items 1 to 28, wherein is methyl or ethyl. 30)R 5 29. The compound of any one of items 1 to 28, wherein is CHF2 or CF3. 31)R 529. The compound of any one of items 1 to 28, wherein is hydrogen or CN. 32)X 1 is N and X 2 is N and X 3 But NR 6 The compound of any one of items 1 to 31, 33)X 1 is CH and X 2 is N and X 3 But NR 6 The compound of any one of items 1 to 31, 34)X 1 is O and X 2 is N and X 3 But, CR 6 The compound of any one of items 1 to 31, 35)R 6 The compound of any one of items 1 to 34, wherein is methyl. 36)L 2 is a covalent bond. 37)L 2 However, (CR 7 R 7 ) p The compound of any one of items 1 to 35, 38)L 2 The compound of any one of items 1 to 35, wherein is CH2. 39)L 3 is a covalent bond. 40)L 3 The compound of any one of items 1 to 38, wherein 41)L 3 But NR 7 39. The compound of any one of items 1 to 38, wherein 42) The compound of any one of items 1 to 41, wherein q is 0. 43) The compound of any one of items 1 to 41, wherein q is 1. 44) The compound of any one of items 1 to 41, wherein q is 2. 45)R 9 But C 1~445. The compound of any one of items 1 to 44, wherein the compound is alkyl. 46)R 10 However, 1 to 4 R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q - The compound of any one of items 1 to 45, wherein the ring is a 5- to 7-membered heterocyclyl ring. 47)R 10 But C 1~6 46. ​​The compound of any one of items 1 to 45, wherein the compound is alkyl. 48)R 10 But (CH2) p -C 3~7 46. ​​The compound of any one of items 1 to 45, wherein the compound is cycloalkyl. 49)R 9 and R 10 together with the nitrogen atom to which they are attached, 1 to 4 R 11 46. ​​The compound of any one of items 1 to 45, wherein R 1 is a substituted or unsaturated 3- to 7-membered heterocyclic ring, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. 50) Q is C(=O)NR 9 R 10 49. The compound of any one of items 1 to 49, 51) Q is a ring selected from a 5- or 6-membered heteroaryl group or a 5- or 6-membered heterocyclyl group, wherein the ring members contain at least one carbon atom, at least one nitrogen atom, and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the oxygen may be a ring member and / or an oxo group bonded to the ring member, and the ring is 3 ) n and one R 4 49. The compound of any one of items 1 to 49, substituted with 52) Q-ring is TIFF2024517769000086.tif40150, each of which can be used with (R 3 ) n and one R 4 5. The compound of item 51, wherein the compound is substituted with 53) Q-ring is TIFF2024517769000087.tif44161, each of which is (R 3 ) n and one R 4 5. The compound of item 51, wherein the compound is substituted with 54)R 3 is, in each occurrence, independently hydrogen, halogen, or C 1~4 54. The compound of any one of items 1 to 53, wherein the alkyl is alkyl. 55)R 3 But in each occurrence, independently, C 1~4 54. The compound of any one of items 1 to 53, wherein the alkyl is alkyl. 56)R 3 The compound of any one of items 1 to 53, wherein, in each occurrence, is methyl. 57)R 4 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Alkoxy, (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 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 57. The compound of any one of items 1 to 56, optionally substituted with alkoxy. 58)R 4 However, 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q - The compound of any one of items 1 to 56, wherein the ring is a 5- to 7-membered heterocyclyl ring. 59)R 4 But C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, or C 2~6 Alkenyl-C 3~7 The compound of any one of items 1 to 56, wherein the compound is cycloalkyl. 60) Formula (II) It has the structure TIFF2024517769000088.tif42128, During the ceremony, The A ring is: TIFF2024517769000089.tif27151; a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from X 1 But N or CR 6a and R 6a is hydrogen or methyl, R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; The Q ring is selected from 5-membered heteroaryl or heterocyclyl and 6-membered heteroaryl or heterocyclyl, the Q ring contains 1 nitrogen atom and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the Q ring is selected from (R 3 ) n and one R 4 is replaced by t is 0, 1, 2, or 3; Item 1, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof. 61) Formula (IIa) The compound in item 60 has the structure TIFF2024517769000090.tif55128. 62) Formula (IIb) The compound in item 60 has the structure TIFF2024517769000091.tif52128. 63) Formula (IIc) The compound in item 60 has the structure TIFF2024517769000092.tif53128. 64)R 1 The compound of any one of items 60 to 63, wherein, in each occurrence, is independently hydrogen. 65)R 1 The compound of any one of items 60 to 63, wherein, in each occurrence, is independently a halogen. 66) m is 2 and one R 1 is hydrogen, and the other R 1 The compound of any one of items 60 to 63, wherein is a halogen. 67) m is 2 and one R 1 is hydrogen, and the other R 1 The compound of any one of items 60 to 63, wherein 68) m is 2 and R 1 is, in each occurrence, independently F. 69)R 2 The compound of any one of items 60 to 68, wherein, in each occurrence, is independently hydrogen. 70)R 2 But in each occurrence, independently, C 1~4 69. The compound of any one of items 60 to 68, wherein the compound is alkyl. 71)R 2 But in each occurrence, independently, C 3~5 69. The compound of any one of items 60 to 68, which is cycloalkyl. 72)R 2 and R 2 together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring. 73) One R 2 is hydrogen, and the other R 2 The compound of any one of items 60 to 68, wherein is methyl. 74) One R 2 is hydrogen, and the other R 2 The compound of any one of items 60 to 68, wherein is ethyl or propyl. 75) One R 2 is hydrogen, and the other R 2 The compound of any one of items 60 to 68, wherein is cyclopropyl. 76)R 2 and R 2 together with the carbon atom to which they are attached form a cyclopropyl ring. 77) Part TIFF2024517769000093.tif20128 is Any one of the compounds listed in items 60 to 76, which is TIFF2024517769000094.tif20128. 78)R 5 may, in each occurrence, independently represent hydrogen, halogen, C 1~6 Alkyl or haloC 1~6 78. The compound of any one of items 60 to 77, wherein the compound is alkyl. 79)R 5 But in each occurrence, independently, C 1~6 78. The compound of any one of items 60 to 77, wherein the compound is alkyl. 80)R 5 is, at each occurrence, independently methyl or ethyl. 81)R 5 is, at each occurrence, independently CHF2 or CF3. 82)X 1 The compound of any one of items 60 to 80, wherein 83)X 1 The compound of any one of items 60 to 80, wherein is CH. 84)R 6 The compound of any one of items 60 to 83, wherein is methyl. 85)L 2 However, (CR 7 R 7 ) p The compound of any one of items 60 to 84, 86)L 2 The compound of any one of items 60 to 84, wherein is CH2. 87)L 3 is a covalent bond. 88)L 3 The compound of any one of items 60 to 86, wherein 89)L 3 But NR 7 The compound of any one of items 60 to 86, 90) Q-ring is TIFF2024517769000095.tif40150, each of which can be used with (R 3 ) n and one R4 89. The compound of any one of items 60 to 89, wherein n is 0, 1, or 2, and is substituted with 91) The Q ring is (R 3 ) n and one R 4 replaced with TIFF2024517769000096.tif17128, and n is 0, 1, or 2. 92) Q-ring is TIFF2024517769000097.tif44160, each of which can be used at any available carbon or nitrogen position (R 3 ) n and one R 4 89. The compound of any one of items 60 to 89, wherein n is 0, 1, or 2, and is substituted with 93)R 3 is, in each occurrence, independently hydrogen, halogen, or C 1~4 The compound of any one of items 60 to 92, wherein the compound is alkyl. 94)R 3 But in each occurrence, independently, C 1~4 The compound of any one of items 60 to 92, wherein the compound is alkyl. 95)R 3 The compound of any one of items 60 to 92, wherein, in each occurrence, is independently methyl. 96)R 4 But hydrogen, C 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 The compound of any one of items 60 to 95, optionally substituted with alkoxy. 97)R 4 However, 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q - The compound of any one of items 60 to 95, wherein the ring is a 5- to 7-membered heterocyclyl ring. 98)R 4 But C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, or C 2~6 Alkynyl-C 3~7 The compound of any one of items 60 to 95, which is cycloalkyl. 99) Formula (III) It has the structure TIFF2024517769000098.tif43128, During the ceremony, The A ring is: TIFF2024517769000099.tif27151; a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from R 1 may, in each occurrence, independently be hydrogen, halogen, keto (=O), 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 , C1~6 Alkyl-NR a R b or 4- to 6-membered heterosilyl; R 2 In each occurrence, independently, hydrogen, deuterium, C 1~4 Alkyl, C 3~5 cycloalkyl or R 2 and R 2 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; Z 1 , Z 2 , Z 3 , and Z 4 are each independently CH or O, with the proviso that Z 1 , Z 2 , Z 3 , and Z 4 is O, R 5 may, in each occurrence, independently represent hydrogen, halogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, OH, C 1~6 Alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, HaloC 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b and X 1 But N or CR 6a and R 6a is hydrogen or methyl, R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L 2 is a covalent bond or (CR 7 R 7 ) p and L 3 is a covalent bond, O, or NR7 where L 2 and L 3 is not a covalent bond; R 7 may, in each occurrence, independently be hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 9 and R 10 each occurrence of is independently hydrogen, one to four R 11 C replaced with 1~6 Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q - a 5- to 7-membered heterocyclyl ring, or R 9 and R 10 together with the nitrogen atom to which they are attached, 1 to 4 R 11forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R 11 may, in each occurrence, independently be hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 12 may, in each occurrence, independently be hydrogen, C 1~4 Alkyl, C 3~7 cycloalkyl or R 12 and R 12 together with the carbon atoms to which they are attached form a 3- to 6-membered cycloalkyl ring; R a and R b each occurrence is independently hydrogen or C 1~6 alkyl, and R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; t is 0, 1, 2, or 3; p, in each occurrence, is independently 1, 2, 3, or 4; q, in each occurrence, is independently 0, 1, 2, 3, or 4; Item 1, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof. 100) Formula (IIIa) Compound item 99, with structure TIFF2024517769000100.tif55128. 101) Formula (IIIb) Compound 99, with structure TIFF2024517769000101.tif52128. 102) Formula (IIIc) Compound item 99, with structure TIFF2024517769000102.tif53128. 103)R 1 The compound of any one of items 99 to 102, wherein, in each occurrence, is independently hydrogen. 104)R 1 The compound of any one of items 99 to 102, wherein, in each occurrence, is independently a halogen. 105) One R 1 is hydrogen, and the other R 1 The compound of any one of items 99 to 102, wherein is a halogen. 106) One R 1 is hydrogen, and the other R 1 The compound of any one of items 99 to 102, wherein 107)R 1 The compound of any one of items 99 to 102, wherein, in each occurrence, is independently F. 108) Part TIFF2024517769000103.tif20128 is Any one of the compounds listed in items 99 to 107, which is TIFF2024517769000104.tif20128. 109)R 5 is, in each occurrence, independently hydrogen, halogen, or C 1~6 The compound of any one of items 99 to 108, wherein the compound is alkyl. 110)R 5 But in each occurrence, independently, C 1~6 The compound of any one of items 99 to 108, wherein the compound is alkyl. 111)R 5 The compound of any one of items 99 to 108, wherein, at each occurrence, is independently methyl or ethyl. 112)X 1 The compound of any one of items 99 to 111, wherein 113)X 1 The compound of any one of items 99 to 111, wherein is CH. 114)R 6 The compound of any one of items 99 to 113, wherein is methyl. 115)L 2 However, (CR 7 R 7 ) p The compound of any one of items 99 to 114, 116)L 2 The compound of any one of items 99 to 114, wherein is CH2. 117)L 3 is a covalent bond. 118)L 3 The compound of any one of items 99 to 116, wherein 119)L 3 But NR 7 The compound of any one of items 99 to 116, 120)R 9 But C 1~4 The compound of any one of items 99 to 119, wherein the compound is alkyl. 121)R 10 However, 1 to 4 R 11 C replaced with 1~6Alkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 2~6 Alkynyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -C 3~7 Cycloalkyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q -phenyl, 1 to 4 R 11 Replaced with (CR 12 R 12 ) q - 5-6 membered heteroaryl ring, 1-4 R 11 Replaced with (CR 12 R 12 ) q - The compound of any one of items 99 to 120, wherein the ring is a 5- to 7-membered heterocyclyl ring. 122)R 10 But C 1~6 The compound of any one of items 99 to 120, wherein the compound is alkyl. 123)R 10 But (CH2) q -C 3~7 The compound of any one of items 99 to 120, which is cycloalkyl. 124)R 9 and R 10 together with the nitrogen atom to which they are attached, 1 to 4 R 11 121. The compound of any one of items 99 to 120, wherein R 1 is a substituted or unsaturated 3- to 7-membered heterocyclic ring, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. 125) The following: The compound of item 1 selected from TIFF2024517769000105.tif170146. 126) Formula (IV) TIFF2024517769000106.tif54128, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, R 1 may, in each occurrence, independently represent 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-membered heterosilyl, or R 1 and R 1 together with the carbon atom to which they are attached to form a ketone (C=O), R 5 may, in each occurrence, independently represent hydrogen, halogen, C 1~6 Alkyl, HaloC 1~6 Alkyl, OH, C 1~6 Alkyl-OH, C 1~6 Alkoxy, C 1~6 Alkyl-C 1~6 Alkoxy, HaloC 1~6 Alkoxy, CN, C 3~7 Cycloalkyl, NR a R b , or C 1~6 Alkyl-NR a R b and X 1 But N or CR 6a and R 6a is hydrogen or methyl, R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L 2 However, (CR 7 R 7 ) p and The Q ring is TIFF2024517769000107.tif20128, each of which is (R 3 ) n and one R 4 is replaced by R 3 may, in each occurrence, independently represent hydrogen, halogen, CN, C 1~6 Alkyl, or C 3~7 is cycloalkyl, R 4 But hydrogen, halogens, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl, O(CH2) p -C 3~7 Cycloalkyl, 1 to 4 R 11 substituted with (CH2) q - 5-6 membered heteroaryl ring, 1-4 R 11 substituted with (CH2) q - a 5- to 7-membered heterocyclyl ring, wherein each phenyl independently optionally contains 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R 7 may, in each occurrence, independently be hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R 7 and R 7 together with the carbon atoms to which they are attached form a 3- to 5-membered cycloalkyl ring; R 11 may, in each occurrence, independently be hydrogen, 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 optionally substituted with alkoxy; R a and R b each occurrence is independently hydrogen or C 1~6 alkyl, and R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1~4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; t is 0, 1, 2, or 3; p, in each occurrence, is independently 1, 2, 3, or 4; and q, in each occurrence, is independently 0, 1, 2, 3, or 4; The compound, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof. 127) Formula (IVa) The compound in item 126 has the structure TIFF2024517769000108.tif54128. 128) The compound of item 126 or 127, wherein m is 0. 129) Part TIFF2024517769000109.tif20128 is Any one of the compounds listed in items 126 to 128, which is TIFF2024517769000110.tif20128. 130)R 5 may, in each occurrence, independently represent hydrogen, halogen, C 1~6 Alkyl or haloC 1~6 129. The compound of any one of items 126 to 129, wherein the alkyl is 131)R 5 But in each occurrence, independently, C 1~6 129. The compound of any one of items 126 to 129, wherein the alkyl is 132)R 5 is, at each occurrence, independently methyl or ethyl. 133)R 5 is, at each occurrence, independently CHF2 or CF3. 134)X 1 The compound of any one of items 126 to 133, wherein 135)X 1 The compound of any one of items 126 to 133, wherein is CH. 136)R 6 The compound of any one of items 126 to 135, wherein is methyl. 137)L 2 The compound of any one of items 126 to 136, wherein is CH2. 138) The Q ring is (R 3 ) n and one R 4 replaced with Any one of the compounds listed in items 126 to 137, TIFF2024517769000111.tif17128. 139)R 3 is, in each occurrence, independently hydrogen, halogen, or C 1~4 139. The compound of any one of items 126 to 138, wherein the compound is alkyl. 140)R 3 But in each occurrence, independently, C 1~4 139. The compound of any one of items 126 to 138, wherein the compound is alkyl. 141)R 3 The compound of any one of items 126 to 138, wherein, at each occurrence, is independently methyl. 142)R 4 But hydrogen, C 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 3~7 Cycloalkyl, C 2~6 Alkenyl-C 3~7 Cycloalkyl, C 2~6 Alkynyl-C 3~7 Cycloalkyl, O(CH2) p -C 3~7 cycloalkyl, wherein each phenyl is independently optionally selected from 1 to 3 halogens, C 1~6 Alkyl, or C 1~6 142. The compound of any one of items 126 to 141, optionally substituted with alkoxy. 143)R 4 However, 1 to 4 R 11 substituted with (CH2) q - a 5- to 6-membered heteroaryl ring, or 1 to 4 R 11 substituted with (CH2) q - The compound of any one of items 126 to 141, wherein the ring is a 5- to 7-membered heterocyclyl ring. 144)R 4 But C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkoxy, (CH2) p -C 1~6 Alkoxy, C 3~7 Cycloalkyl, (CH2) p -C 3~7 Cycloalkyl, or C 2~6 Alkynyl-C 3~7 142. The compound of any one of items 126 to 141, which is cycloalkyl. 145) The following: The compound of item 126 selected from TIFF2024517769000112.tif67128. 146) A pharmaceutical composition comprising a compound of any one of items 1 to 145 and a pharmaceutically acceptable carrier. 147) A method for treating a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of items 1 to 145. 148) The method of item 147, wherein the disease is pathological fibrosis (e.g., fibrosis of the lung, liver, kidney, heart, skin, eye, or pancreas), idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.

Claims

1. Formula (I) or a pharma- ceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony, The A ring is as follows: is a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from L １ is a covalent bond, NH, O, or S, with the proviso that L １ is a covalent bond, the A ring is selected from formula (A1), (A2), (A3), (A4), or (A5); and １ is NH or S, the A ring is selected from formula (A6) or (A7); １ is O, then ring A is selected from formula (A7): L ２ is a covalent bond or (CR ７ R ７ ) ｐ and L ３ is a covalent bond, O, or NR ７ where L ２ and L ３ is not a covalent bond; Q is C(=O)NR ９ R １０ , C(=O)OR １０ or a 5- or 6-membered heteroaryl group or a 5- or 6-membered heterocyclyl group, the ring members containing 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, the oxygen may be a ring member, and / or an oxo group bonded to the ring members, said ring being selected from (R ３ ) ｎ and one R ４ is replaced by X １ is N, O, or CR ６ａ and X ２ But N or NR ６ and X ３ But, N, NR ６ , or C.R. ６ with the dashed circle indicating the bonds forming a 5-membered aromatic ring; Y １ , Y ２ , Y ３ , and Y ４ each independently represents N or CR ５ where Y １ , Y ２ , Y ３ , and Y ４ is N; Z １ , Z ２ , Z ３ , and Z ４ Each independently represents CH ２ or O, with the proviso that Z １ , Z ２ , Z ３ , and Z ４ is O; R １ is, in each occurrence, independently selected from 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-membered heterocyclyl, or R １ and R １ together with the carbon atom to which they are attached form a ketone (C=O), R ２ may, in each occurrence, independently represent hydrogen, deuterium, C １～４ Alkyl or C ３～５ cycloalkyl or R ２ and R ２ together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring; R ３ is, in each occurrence, independently, hydrogen, halogen, CN, C １～６ Alkyl, or C ３～７ is cycloalkyl, R ４ But hydrogen, halogen, C １～６ Alkyl, haloC １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, 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 Alkynyl-C ３～７ Cycloalkyl, O(CH ２ ) ｐ -C ３～７ cycloalkyl, 1 to 4 R １１ (CH ２ ) ｑ - a 5- to 6-membered heteroaryl ring, or 1 to 4 R １１ (CH ２ ) ｑ - a 5- to 7-membered heterocyclyl ring, each phenyl independently and optionally containing 1 to 3 halogens, C １～６ Alkyl, or C １～６ optionally substituted with alkoxy; R ５ is, in each occurrence, independently selected from hydrogen, halogen, C １～６ Alkyl, haloC １～６ Alkyl, OH, C １～６ Alkyl-OH, C １～６ Alkoxy, C １～６ Alkyl-C １～６ Alkoxy, HaloC 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 independently represents hydrogen, halogen, CN, C １～４ alkyl, or cyclopropyl; R ７ is, in each occurrence, independently, hydrogen, C １～４ Alkyl or C ３～５ cycloalkyl or R ７ and R ７ together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring; R ９ and R １０ each occurrence of is independently hydrogen, 1 to 4 R １１ C substituted with １～６ Alkyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ -C ２～６ alkenyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ -C ２～６ alkynyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ -C ３～７ cycloalkyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ -phenyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ - a 5- to 6-membered heteroaryl ring, or 1 to 4 R １１ (CR １２ R １２ ) ｑ - a 5- to 7-membered heterocyclyl ring, or R ９ and R １０ together with the nitrogen atom to which they are attached, 1 to 4 R １１ forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with, said ring optionally containing 1 or 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R １１ is, in each occurrence, independently, hydrogen, C １～６ Alkyl, haloC １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, 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 Alkynyl-C ３～７ Cycloalkyl, or O(CH ２ ) ｐ -C ３～７ cycloalkyl, each phenyl independently optionally containing 1 to 3 halogens, C １～６ Alkyl, or C １～６ optionally substituted with alkoxy; R １２ is, in each occurrence, independently, hydrogen, C １～４ Alkyl or C ３～７ cycloalkyl or R １２ and R １２ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring; R ａ and R ｂ Each occurrence of 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 heterocyclic ring containing 3 to 7 ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C １～４ optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; p, in each occurrence, is independently 1, 2, 3, or 4; q, in each occurrence, is independently 0, 1, 2, 3, or 4; The compound or a pharma- ceutically acceptable salt, tautomer, and / or stereoisomer thereof.

2. L １ The compound of claim 1 , wherein is a covalent bond.

3. R １ 2. The compound of claim 1, wherein, at each occurrence, is independently hydrogen or halogen.

4. m is 2; (a) One R １ is hydrogen, and the other R １ is a halogen; (b) one R 1 is hydrogen and the other R 1 is F; or (c) R 1 , at each occurrence, is independently F; The compound of claim 1.

5. R ２ The compound of claim 1, wherein, at each occurrence, is independently hydrogen, C 1-4 alkyl, or C 3-5 cycloalkyl.

6. R ２ and R ２ The compound according to claim 1, wherein together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring, preferably a cyclopropyl ring.

7. (a) One of R ２ is hydrogen, and the other R ２ is methyl, or (b) one R 2 is hydrogen and the other R 2 is ethyl or propyl; or (c) one R 2 is hydrogen and the other R 2 is cyclopropyl; The compound of claim 1.

8. (a) Y ２ is N and Y １ , Y ３ , and Y ４ Each of the above is independently CR ５ or (b) Y 1 is CR 5 , Y 2 is N, and each of Y 3 and Y 4 is independently CH; or (c) Y 1 is CR 5 , Y 2 is N, Y 3 is N and Y 4 is CH; The compound of claim 1.

9. (a) R ５ is methyl or ethyl, or (b) R 5 is CHF 2 or CF 3 , or (c) R 5 is hydrogen or CN; The compound of claim 1.

10. (a)X １ is N and X ２ is N and X ３ But, N.R. ６ or (b) X 1 is CH, X 2 is N and X 3 is NR 6 ; or (c) X 1 is O, X 2 is N and X 3 is CR 6 ; The compound of claim 1.

11. R ６ The compound of claim 1 , wherein is methyl.

12. L ２ 2. The compound of claim 1, wherein: is a covalent bond or CH2; and / or L3 is a covalent bond, O, or NR7.

13. The compound of claim 1 , wherein q is 0, 1, or 2.

14. R ９ But, C １～４ and / or R 10 is C 1-6 alkyl.

15. R ９ and R １０ together with the nitrogen atom to which they are attached, 1 to 4 R １１ 2. The compound of claim 1, wherein the ring optionally contains one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

16. The Q ring is each of which is selected from the group consisting of (R ３ ) ｎ and one R ４ 2. The compound of claim 1 , substituted with:

17. R ３ is, in each occurrence, independently hydrogen, halogen, or C １～４ The compound of claim 1 , wherein the aryl group is an alkyl group.

18. (a) R ４ is hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, 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 Alkynyl-C ３～７ Cycloalkyl, or O(CH ２ ) ｐ -C ３～７ cycloalkyl, each phenyl independently optionally containing 1 to 3 halogens, C １～６ Alkyl, or C １～６ Optionally substituted with alkoxy, or (b) R 4 is a (CH 2 ) q -5- to 6-membered heteroaryl ring substituted with one to four R 11 , or a (CH 2 ) q -5- to 7-membered heterocyclyl ring substituted with one to four R 11 ; or (c) R 4 is C 1-6 alkyl, C 2-6 alkynyl, 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 cycloalkyl; The compound of claim 1.

19. Formula (II) The structure is During the ceremony, The A ring is as follows: is a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from X １ But N or CR ６ａ and R ６ａ is hydrogen or methyl; R ６ is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; The Q ring is selected from 5-membered heteroaryl or heterocyclyl and 6-membered heteroaryl or heterocyclyl, the Q ring contains one nitrogen atom and optionally 1 to 4 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the Q ring is selected from (R ３ ) ｎ and one R ４ is replaced by t is 0, 1, 2, or 3; 2. A compound according to claim 1, or a pharma- ceutically acceptable salt, tautomer, and / or stereoisomer thereof.

20. Formula (IIa) or Formula (IIb) or Formula (IIc) having the structure 20. The compound of claim 19.

21. Formula (III) The structure is During the ceremony, The A ring is as follows: is a 5-membered heterocyclyl or a 6-membered cyclohexyl or heterocyclyl selected from R １ is, in each occurrence, independently selected from hydrogen, halogen, keto (=O), 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 4-6 membered heterosilyl; R ２ may, in each occurrence, independently represent hydrogen, deuterium, C １～４ Alkyl or C ３～５ cycloalkyl or R ２ and R ２ together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring; Z １ , Z ２ , Z ３ , and Z ４ each independently represents CH ２ or O, with the proviso that Z １ , Z ２ , Z ３ , and Z ４ is O; R ５ is, in each occurrence, independently selected from hydrogen, halogen, C １～６ Alkyl, haloC １～６ Alkyl, OH, C １～６ Alkyl-OH, C １～６ Alkoxy, C １～６ Alkyl-C １～６ Alkoxy, HaloC １～６ Alkoxy, CN, C ３～７ Cycloalkyl, NR ａ R ｂ , or C １～６ Alkyl-NR ａ R ｂ and X １ But N or CR ６ａ and R ６ａ is hydrogen or methyl; R ６ is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L ２ is a covalent bond or (CR ７ R ７ ) ｐ and L ３ is a covalent bond, O, or NR ７ where L ２ and L ３ is not a covalent bond; R ７ is, in each occurrence, independently, hydrogen, C １～４ Alkyl or C ３～５ cycloalkyl or R ７ and R ７ together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring; R ９ and R １０ each occurrence of is independently hydrogen, 1 to 4 R １１ C substituted with １～６ Alkyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ -C ２～６ alkenyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ -C ２～６ alkynyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ -phenyl, 1 to 4 R １１ (CR １２ R １２ ) ｑ - a 5- to 6-membered heteroaryl ring, or 1 to 4 R １１ (CR １２ R １２ ) ｑ - a 5- to 7-membered heterocyclyl ring, or R ９ and R １０ together with the nitrogen atom to which they are attached, 1 to 4 R １１ forming a saturated or unsaturated 3- to 7-membered heterocyclic ring substituted with, said ring optionally containing 1 or 2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; R １１ is, in each occurrence, independently, hydrogen, C １～６ Alkyl, haloC １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, 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 Alkynyl, or O(CH ２ ) ｐ -C ３～７ cycloalkyl, each phenyl independently optionally containing 1 to 3 halogens, C １～６ Alkyl, or C １～６ optionally substituted with alkoxy; R １２ is, in each occurrence, independently, hydrogen, C １～４ Alkyl or C ３～７ cycloalkyl or R １２ and R １２ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl ring; R ａ and R ｂ Each occurrence of 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 heterocyclic ring containing 3 to 7 ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C １～４ optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; t is 0, 1, 2, or 3; p, in each occurrence, is independently 1, 2, 3, or 4; and q, in each occurrence, is independently 0, 1, 2, 3, or 4; 2. A compound according to claim 1, or a pharma- ceutically acceptable salt, tautomer, and / or stereoisomer thereof.

22. Formula (IIIa) or Formula (IIIb) or Formula (IIIc) having the structure 22. The compound of claim 21.

23. below:

2. The compound of claim 1 , selected from:

24. Formula (IV) The structure is During the ceremony, R １ is, in each occurrence, independently selected from 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 4-6 membered heterosilyl, or R １ and R １ together with the carbon atom to which they are attached form a ketone (C=O), R ５ is, in each occurrence, independently selected from hydrogen, halogen, C １～６ Alkyl, haloC １～６ Alkyl, OH, C １～６ Alkyl-OH, C １～６ Alkoxy, C １～６ Alkyl-C １～６ Alkoxy, HaloC １～６ Alkoxy, CN, C ３～７ Cycloalkyl, NR ａ R ｂ , or C １～６ Alkyl-NR ａ R ｂ and X １ But N or CR ６ａ and R ６ａ is hydrogen or methyl; R ６ is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; L ２ However, (CR ７ R ７ ) ｐ and The Q ring is At any available carbon position (R ３ ) ｎ and one R ４ has been replaced with and R ３ is, in each occurrence, independently, hydrogen, halogen, CN, C １～６ Alkyl, or C ３～７ is cycloalkyl, R ４ But hydrogen, halogen, C １～６ Alkyl, haloC １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, 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 Alkynyl, O(CH ２ ) ｐ -C ３～７ cycloalkyl, 1 to 4 R １１ (CH ２ ) ｑ - a 5- to 6-membered heteroaryl ring, or 1 to 4 R １１ (CH ２ ) ｑ - a 5- to 7-membered heterocyclyl ring, each phenyl independently and optionally containing 1 to 3 halogens, C １～６ Alkyl, or C １～６ optionally substituted with alkoxy; R ７ is, in each occurrence, independently, hydrogen, C １～４ Alkyl or C ３～５ cycloalkyl or R ７ and R ７ together with the carbon atom to which they are attached form a 3- to 5-membered cycloalkyl ring; R １１ is, in each occurrence, independently, hydrogen, C １～６ Alkyl, haloC １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, 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 Alkynyl, or O(CH ２ ) ｐ -C ３～７ cycloalkyl, each phenyl independently optionally containing 1 to 3 halogens, C １～６ Alkyl, or C １～６ optionally substituted with alkoxy; R ａ and R ｂ Each occurrence of 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 heterocyclic ring containing 3 to 7 ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C １～４ optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; t is 0, 1, 2, or 3; p, in each occurrence, is independently 1, 2, 3, or 4; and q, in each occurrence, is independently 0, 1, 2, 3, or 4; 2. A compound according to claim 1, or a pharma- ceutically acceptable salt, tautomer, and / or stereoisomer thereof.

25. Formula (IVa) and optionally having the structure:

25. The compound of claim 24, selected from:

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 and a pharma- ceutically acceptable carrier.

27. The pharmaceutical composition of claim 26 for treating a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi), optionally wherein the disease is pathological fibrosis (e.g., pulmonary, hepatic, renal, cardiac, cutaneous, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.

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