Heterocyclic compounds as glp-1 agonists and uses thereof

Abstract

The present application relates to the technical field of drugs, in particular to heterocyclic compounds for use as GLP-1 agonists and uses thereof. The GLP-1 agonists of the present application have high activity and bioavailability.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and more specifically, to heterocyclic compounds used as GLP-1 agonists and their applications. Background Technology

[0002] Incretin metabolism hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are crucial in the regulation of glucose homeostasis. Drugs targeting this intestinal peptide family, such as GLP-1 agonists, have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety.

[0003] Diabetes mellitus is a group of metabolic disorders characterized by persistently high blood sugar. The most common form, type 2 diabetes mellitus (T2DM), is an acquired condition that typically develops in obese or sedentary adults and begins to show insulin resistance. Although lifestyle modifications can effectively manage the disease, patients with T2DM may need to take antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0004] In healthy individuals, the glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) of incretin hormones tandemly regulate the secretory response of insulin to glucose uptake. Although the incretin effect is significantly diminished (if fully present) in cases of type 2 diabetes mellitus (T2DM), GLP-1 retains its insulinotropic properties even if the endocrine pancreas's response to GIP is effectively terminated. Therefore, incretin mimics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. Summary of the Invention

[0005] This application provides heterocyclic compounds represented by formula (I), pharmaceutical compositions comprising said heterocyclic compounds, and their pharmaceutical uses.

[0006] On the one hand, this application provides a heterocyclic compound represented by formula (I),

[0007] Formula (I)

[0008] Or its pharmaceutically acceptable salt, wherein: R 1 To R4 and R 6 To R 13 Each is independently chosen from the following groups: hydrogen; deuterium; halogens; optionally chosen from deuterium, halogens, and C. 1-6 At least one substituent of the group consisting of alkyl groups substituted with C 1-12 Alkyl groups; and optionally, free from deuterium, halogens, and C. 1-6At least one substituent in the group consisting of alkyl groups substituted C 1-12 Alkoxy; R 5 Selected from 3- to 12-membered heterocyclic alkyl groups; C 3-12 The group consisting of cycloalkyl groups; and 5- to 10-membered heteroaryl groups, wherein the heterocycloalkyl group, the cycloalkyl group, and the heteroaryl group are each optionally selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 At least one substituent in the group consisting of alkoxy groups is substituted; Ring A is selected from 3- to 12-membered heterocyclic alkyl groups; C 3-12 The group consisting of cycloalkyl groups; and 5- to 10-membered heteroaryl groups, wherein the heterocycloalkyl group, the cycloalkyl group, and the heteroaryl group are each optionally selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 At least one substituent in the group consisting of alkoxy, (IX-1), (IX-2), (IX-3), and (IX-4) is substituted:

[0009] R 9a R 9b R 9c R 9d and R 9e Each is independently selected from the following groups: H; deuterium; optionally halogenated and / or C. 1-6 alkoxy-substituted C 1-6 Alkyl groups; and C(=O)(C 1-6 alkyl); X 1 To X 3 Each independently chooses freely -C(R) a R b )-、=C(R c )-、-N(R d The group consisting of )- and =N-; X 1 To X 3 At least one of them is selected from -N(R) d The group consisting of )- and =N-; R a and R b Each is independently chosen from the following groups: hydrogen; deuterium; halogens; optionally chosen from deuterium, halogens, and C. 1-6 At least one substituent in the group consisting of alkyl groups substituted C 1-12 alkyl; R cEach of the following groups is independently selected: hydrogen; deuterium; halogen; -L 1 -R e ; and C(=O)OR f ; R d Choose from the following groups: hydrogen; deuterium; halogens; and -L 1 -R e ; R c and R d At least one of them is -L 1 -R e ; L 1 Choose from the following groups: single bonds; C 1-12 Alkylene; C 3-12 Cycloalkylene; and 3-12 membered heteroalkylene, wherein the alkylene, the cycloalkylene, and the heteroalkylene are each optionally selected from deuterium, halogen, and C. 1-6 At least one substituent is substituted in the group consisting of alkyl groups; R e Choose C freely 3-12 The group consisting of cycloalkyl groups; and 3-12 membered heterocyclic alkyl groups, wherein the cycloalkyl groups and the heterocyclic alkyl groups are each optionally selected from deuterium, halogens and C. 1-6 At least one substituent is substituted in the group consisting of alkyl groups; R f C is a C that is optionally substituted with at least one substituent selected from the group consisting of deuterium and halogens. 1-12 Alkyl groups; and Indicates the connection site.

[0010] On the one hand, this application provides a pharmaceutical composition comprising a heterocyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] On the other hand, this application provides the use of the heterocyclic compound or the pharmaceutical composition in the preparation of a medicament for treating or preventing a disease. Detailed Implementation

[0012] definition

[0013] As used herein, instances of the term "halogen" may include fluorine, chlorine, bromine, or iodine.

[0014] As used in this article, the term "C1- 12The "alkyl group" can be a straight-chain or branched monovalent aliphatic hydrocarbon group having one to twelve carbon atoms (e.g., one to ten, two to eight, three to six, or four to six carbon atoms), and examples of such groups may include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, sec-butyl groups, isobutyl groups, tert-butyl groups, n-pentyl groups, tert-pentyl groups, neopentyl groups, isopentyl groups, sec-pentyl groups, 3-pentyl groups, sec-isopentyl groups, n-hexyl groups, isohexyl groups, sec-hexyl groups, tert-hexyl groups, n-heptyl groups, isoheptyl groups, sec-heptyl groups, tert-heptyl groups, n-octyl groups, isooctyl groups, sec-octyl groups, tert-octyl groups, n-nonyl groups, isononyl groups, sec-nonyl groups, tert-nonyl groups, n-decyl groups, isodel groups, sec-decyl groups, and tert-decyl groups, but embodiments of this disclosure are not limited thereto.

[0015] As used in this article, the term "C1-C" 12 "alkylene group" can be a group with C1-C2... 12 Divalent groups with the same structure as alkyl groups.

[0016] As used in this article, the term "C1-C" 12 "Alkoxy" can refer to an oxygen atom bonded to a C1- as defined above. 12 Alkyl groups. Examples of alkoxy groups may include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentoxy, hexoxy, octoxy, nonoxy, decoxy, etc., but the embodiments of this disclosure are not limited thereto.

[0017] As used in this article, the term "C3-C" 12 "Cycloalkyl" can mean a cyclic alkyl group having three to twelve carbon atoms (e.g., 3 to 10, 4 to 9, 5 to 8, or 4 to 6 carbon atoms). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornel, 1-adamantyl, 2-... -Adamantyl group, isoborneol group, bicycloheptanyl group, bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc., but the embodiments of this disclosure are not limited to these.

[0018] As used in this article, the term "C3-C" 12 "Cycloalkylene" can be a compound with C3-C666.12 Divalent groups with the same structure as cycloalkyl groups.

[0019] As used herein, the term "3-12-membered heterocyclic alkyl" can mean a 3- to 12-membered (e.g., 3- to 10-, 4- to 8-, 5- to 7-, or 3- to 6-membered) monovalent cyclic group having a carbon atom and further comprising at least one (e.g., 1 to 10, 2 to 8, 3 to 7, or 3 to 6) heteroatom as a cyclic atom. Examples of heterocyclic alkyl groups can include 1,2,3,4-oxatriazolyl groups, oxacyclopropane groups, thiocyclopropane groups, pyrrolyl groups, piperidinyl groups, tetrahydrofuran groups, tetrahydrothiophene groups, thiocyclohexane groups, tetrahydropyran groups, 1,4-dioxacyclohexane groups, piperazine groups, pyrrolyl groups, dioxane groups, morpholinyl groups, tetrahydrofuranyl groups, 2-azabicyclo[1.1.0]butane, 2-Azabicyclo[2.1.0]pentane, 2-Azabicyclo[1.1.1]pentane, 3-Azabicyclo[3.1.0]hexane, 5-Azabicyclo[2.1.1]hexane, 3-Azabicyclo[3.2.0]heptane, octahydrocyclopentano[c]pyrrole, 3-Azabicyclo[4.1.0]heptane, 7-Azabicyclo[2.2.1]heptane, 6-Azabicyclo[3.1.1]heptane 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]... [2.0]Heptane, 3-oxabicyclo[4.1.0]Heptane, 7-oxabicyclo[2.2.1]Heptane, 6-oxabicyclo[3.1.1]Heptane, 7-oxabicyclo[4.2.0]Octane, 2-oxabicyclo[2.2.2]Octane, 3-oxabicyclo[3.2.1]Octane, 2-azaspiro[2.2]Pentane, 4-azaspiro[2.5]Octane, 1-azaspiro[3.5] Nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, etc., but the embodiments disclosed herein are not limited to these.

[0020] As used herein, the term "3-12-membered heterocyclic alkyl group" can be a divalent group having the same structure as a 3-12-membered heterocyclic alkyl group.

[0021] As used herein, the term "5- to 10-membered heteroaryl" can refer to a 5- to 10-membered monovalent group having a heterocyclic aromatic system having 1 to 9 carbon atoms (e.g., 1 to 8, 2 to 6, 2 to 5, 2 to 4, or 1 to 3 carbon atoms) and further comprising at least one heteroatom of B, O, N, P, Si, and S (e.g., 1 to 9, 2 to 8, 3 to 6, 2 to 4) as a cyclic atom. Examples of heteroaryl groups may include quinoxalinyl, phthalazinyl, thiopheneyl, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroleyl, imidazoleyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiopheneyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazoleyl, indolyl, and isoquinoline. The compounds include, but the embodiments disclosed herein are not limited to, such as, isothiazolyl, naphridyl, purine, thienopyridyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxacyclohexadiene, benzo[d][1,3]m-dioxacyclopentene, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxothionecyclohexadiene, isoindoline, etc., but the embodiments disclosed herein are not limited to these.

[0022] As used in this article, the term "C" 1-6 "Halogenated alkyl" can refer to C as defined above. 1-6 An alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms. Examples of alkyl halogens may include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, iodomethyl, etc., but embodiments thereof are not limited thereto.

[0023] As used in this article, This indicates the site to be connected.

[0024] As used herein, the term "compound" means all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein as a particular tautomer by name or structure are intended to include other tautomers.

[0025] As used herein, the term “pharmaceutically acceptable” indicates that a compound or its salt or composition is chemically and / or toxicologically compatible with the other components constituting the formulation and / or with the patients treated thereunder.

[0026] As used herein, the terms “administration” or “drug administration” refer to a method of giving a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). Methods of administration can vary depending on various factors, such as the composition of the pharmaceutical composition, the site of disease, and the severity of the disease.

[0027] As used herein, the terms “effective amount” or “effective dose” or “pharmaceutically effective amount” or “therapeutic effective amount” mean a sufficient amount of a chemical entity to alleviate one or more symptoms of a disease or condition for which treatment is being administered, and may include curative treatment.

[0028] As used herein, “cure” means the elimination of symptoms of an active disease. Results include reduction and / or alleviation of signs, symptoms, or causes of the disease, or any other desired changes in the biological system. For example, an “effective amount” for therapeutic use is the amount of a composition comprising compounds as disclosed herein required to achieve a clinically significant reduction in the symptoms of a disease. The appropriate “effective” amount in any individual case is determined using any suitable technique, such as dose escalation studies. In some embodiments, a “therapeuticly effective amount” of the compounds provided herein refers to the amount of a compound that is effective as a monotherapy or in combination therapy.

[0029] As used herein, the term "excipient" or "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable substance, composition, or mediator, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating substance. In some embodiments, a component is "pharmaceutically acceptable" in the sense that it is compatible with other components of the pharmaceutical formulation and suitable for contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0030] As used herein, the term "pharmaceutical composition" refers to a mixture of heterocyclic compounds represented by formula (I) as described herein, or pharmaceutically acceptable salts or solvates thereof, with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. Pharmaceutical compositions facilitate the administration of compounds to a living organism. Various techniques for administering compounds exist in this field, including but not limited to: rectal, oral, intravenous, aerosol, non-enteral, ocular, pulmonary, and topical administration.

[0031] In the context of treating a disease, symptom, or condition, the term "treatment" means the relief or elimination of one or more of the symptom, disease, or condition or symptoms associated with said symptom, disease, or condition; or the slowing of the progression, spread, or worsening of the disease, symptom, or condition or one or more of its symptoms.

[0032] As used herein, the term “prevention” means complete or partial prevention of the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0033] As used herein, the terms “subject,” “patient,” or “individual” are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans.

[0034] In some implementations, the patient is a human. In some implementations, the subject has experienced and / or exhibits at least one symptom of a disease, condition, or symptom to be treated and / or prevented.

[0035] As used herein, the terms “treatment regimen” and “administration procedure” are used interchangeably to refer to the dosage and timing of the various therapeutic agents administered in the combinations of the present invention.

[0036] As used herein, the term "drug combination" refers to a drug treatment obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0037] As used herein, the term “combination therapy” refers to a regimen of administration of two different therapeutic agents (i.e., components or combinations thereof), wherein the therapeutic agents are administered together or separately in a manner prescribed by a healthcare professional or as defined herein by a regulatory body.

[0038] As used herein, the term “regulation” means control or adjustment (e.g., increase or decrease) and may include, for example, activating, partially activating or antagonizing effects.

[0039] On the one hand, this application provides a heterocyclic compound represented by formula (I),

[0040] Formula (I)

[0041] Or its pharmaceutically acceptable salt, wherein: R 1 To R4 and R 6 To R 13 Each is independently chosen from the following groups: hydrogen; deuterium; halogens; optionally chosen from deuterium, halogens, and C. 1-6 At least one substituent of the group consisting of alkyl groups substituted with C 1-12 Alkyl groups; and optionally, free from deuterium, halogens, and C. 1-6 At least one substituent in the group consisting of alkyl groups substituted C 1-12 Alkoxy; R 5 Selected from 3- to 12-membered heterocyclic alkyl groups; C 3-12 The group consisting of cycloalkyl groups; and 5- to 10-membered heteroaryl groups, wherein the heterocycloalkyl group, the cycloalkyl group, and the heteroaryl group are each optionally selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 At least one substituent in the group consisting of alkoxy groups is substituted; Ring A is selected from 3- to 12-membered heterocyclic alkyl groups; C 3-12 The group consisting of cycloalkyl groups; and 5- to 10-membered heteroaryl groups, wherein the heterocycloalkyl group, the cycloalkyl group, and the heteroaryl group are each optionally selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 At least one substituent in the group consisting of alkoxy, (IX-1), (IX-2), (IX-3), and (IX-4) is substituted:

[0042] R 9a R 9b R 9c R 9d and R 9e Each is independently selected from the following groups: H; deuterium; optionally halogenated and / or C. 1-6 alkoxy-substituted C 1-6 Alkyl groups; and C(=O)(C 1-6 alkyl); X 1 To X 3 Each independently chooses freely -C(R) a R b )-、=C(R c )-、-N(R d The group consisting of )- and =N-; X 1 To X 3 At least one of them is selected from -N(R) d The group consisting of )- and =N-; R a and R b Each is independently chosen from the following groups: hydrogen; deuterium; halogens; optionally chosen from deuterium, halogens, and C. 1-6 At least one substituent in the group consisting of alkyl groups substituted C 1-12 alkyl; R c Each of the following groups is independently selected: hydrogen; deuterium; halogen; -L 1 -R e ; and C(=O)OR f ; R d Choose from the following groups: hydrogen; deuterium; halogens; and -L 1 -R e ; R c and R d At least one of them is -L 1 -R e ; L 1 Choose from the following groups: single bonds; C 1-12 Alkylene; C 3-12 Cycloalkylene; and 3-12 membered heteroalkylene, wherein the alkylene, the cycloalkylene, and the heteroalkylene are each optionally selected from deuterium, halogen, and C. 1-6 At least one substituent is substituted in the group consisting of alkyl groups; R e Choose C freely 3-12 The group consisting of cycloalkyl groups; and 3-12 membered heterocyclic alkyl groups, wherein the cycloalkyl groups and the heterocyclic alkyl groups are each optionally selected from deuterium, halogens and C. 1-6 At least one substituent is substituted in the group consisting of alkyl groups; R f C is a C that is optionally substituted with at least one substituent selected from the group consisting of deuterium and halogens. 1-12 Alkyl groups; and Indicates the connection site.

[0043] In the implementation scheme, in formula (I) Some selections are made from the following groups: ; ;as well as .

[0044] In the implementation plan, L 1 Select free single key; C1-6 Alkylene; C 3-6 Cycloalkylene groups; and the group consisting of 3-6 membered heterocyclic alkylene groups, wherein each of the alkylene groups, the cycloalkylene groups, and the heterocyclic alkylene groups is optionally selected from deuterium, halogen, and C. 1-3 At least one substituent in the group consisting of alkyl groups is substituted.

[0045] In the implementation plan, R e Choose C freely 3-6 The group consisting of cycloalkyl groups; and 3-6 membered heterocyclic alkyl groups, wherein the cycloalkyl groups and the heterocyclic alkyl groups are each optionally selected from deuterium, halogens and C. 1-3 At least one substituent in the group consisting of alkyl groups is substituted.

[0046] In the implementation plan, R 5 Selected from 3- to 6-membered heterocyclic alkyl groups; and C 3-6 A group consisting of cycloalkyl groups, wherein the heterocycloalkyl groups and the cycloalkyl groups are each optionally selected from deuterium, halogen, C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 At least one substituent in the group consisting of alkoxy groups is substituted.

[0047] In the implementation scheme, ring A is selected from 3- to 6-membered heterocyclic alkyl groups; C 3-6 The group consisting of cycloalkyl groups; and 5- to 8-membered heteroaryl groups, wherein the heterocycloalkyl group, the cycloalkyl group, and the heteroaryl group are each optionally selected from C10. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 At least one substituent from the group consisting of alkoxy, (IX-1), (IX-2), (IX-3) and (IX-4) is substituted.

[0048] In the implementation scheme, the heterocyclic compound represented by formula (I) is selected from the group consisting of the following compounds: , , , , , , , , , , , , , , , , , and .

[0049] On the other hand, this application provides a pharmaceutical composition comprising the heterocyclic compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0050] On the other hand, this application provides the use of the heterocyclic compound or the pharmaceutical composition in the preparation of a medicament for treating or preventing a disease.

[0051] On the other hand, this application provides the heterocyclic compound or the pharmaceutical composition for treating or preventing diseases.

[0052] On the other hand, this application provides a method for treating or preventing a disease, the method comprising administering a therapeutically effective amount of the heterocyclic compound or the pharmaceutical composition to a subject in need.

[0053] In the implementation plan, the disease is a GLP-1-related disease. Specifically, the GLP-1-related diseases include: type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes, atypical diabetes mellitus with juvenile onset, adult-onset diabetes in adolescents, latent autoimmune diabetes in adults, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, and blood... Restenosis after tubuloplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome, or any combination thereof.

[0054] In some embodiments, the heterocyclic compound represented by formula (I) is selected from the group consisting of the compounds in Table 1 or their pharmaceutically acceptable salts.

[0055] Table 1

[0056] Heterocyclic compounds represented by formula (I) include their pharmaceutically acceptable salts. Furthermore, heterocyclic compounds represented by formula (I) may also include other salts of such compounds, which may not be pharmaceutically acceptable salts and may be suitable as intermediates for the preparation and / or purification of heterocyclic compounds represented by formula (I) and / or the isolation of enantiomers of heterocyclic compounds represented by formula (I). Non-limiting examples of pharmaceutically acceptable salts of heterocyclic compounds represented by formula (I) include trifluoroacetate salts.

[0057] It should be further understood that heterocyclic compounds represented by formula (I) or their salts can be isolated in solvate form, and accordingly, any such solvates are included within the scope of this invention. For example, compounds represented by formula (I) and their salts can exist in non-solvate form as well as in solvate form formed with pharmaceutically acceptable solvents such as water, ethanol and the like.

[0058] Example

[0059] The invention is further described in the following synthetic examples and embodiments, which do not limit the scope of the invention as described in the claims.

[0060] Synthesis Example 1: Synthesis of Intermediate 2

[0061] 5-bromo-4-fluoro-1 H Indazole (1.0 g, 4.65 mmol, 1.0 eq), cyclopropylboronic acid (832.4 mg, 9.30 mmol, 2.0 eq), and sodium carbonate (985.7 mg, 9.30 mmol, 2.0 eq) were added to 20 mL of 1,2-dichloroethane, followed by the addition of 2,2'-bipyridine (726.2 mg, 4.65 mmol, 1.0 eq) and anhydrous copper acetate (844.6 mg, 4.65 mmol, 1.0 eq). The resulting reaction system was kept at an external temperature of 70 °C. o React at C for 2 hours. TLC (PE / EA = 2 / 1) shows the starting material has disappeared. Cool to room temperature, filter to remove insoluble matter, and wash the filter cake thoroughly with DCM. Dissolve the filtrate in water (50 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product was purified by column chromatography (silica gel, 200-300 mesh, PE / EA = 20 / 1-15 / 1-10 / 1-8 / 1) to give 5-bromo-1-cyclopropyl-4-fluoro-1- H -Indazole (640 mg, yield: 53.8%), pale yellow solid.

[0062] 5-Bromo-1-cyclopropyl-4-fluoro-1 H -Indazole

[0063] 1 H NMR (600 MHz, chloroform-) d ) δ 7.98 (s, 1H), 7.45 (dt, J = 6.2, 2.0 Hz,1H), 7.32-7.26 (m, 1H), 3.60-3.57 (m, 1H), 1.24-1.16 (m, 4H)

[0064] Synthesis Example 2: Synthesis of Intermediates 3 and 4

[0065] 5-bromo-4-fluoro-1 H Indazole (280 mg, 1.308 mmol, 1.0 eq), iodocyclobutane (250 mg, 1.374 mmol, 1.05 eq), and cesium carbonate (639.2 mg, 1.962 mmol, 1.5 eq) were added to DMF (5 mL). The resulting system was heated to 60 °C under argon protection. o The reaction was carried out at C for 4 hours. TLC (PE / EA = 4 / 1) showed that the starting material disappeared. The mixture was cooled to room temperature, and 10 mL of water was added to the reactants, followed by EtOAc (10 mL). 3) Extraction. The organic phase is extracted with saturated saline solution (10 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (silica gel, 200-300 mesh, PE / EA=30 / 1) to give 5-bromo-1-cyclobutyl-4-fluoro ... H -Indazole (160 mg, yield: 45.7%), a yellow oil and 5-bromo-2-cyclobutyl-4-fluoro-2 H -Indazole (100 mg, yield: 28.5%), pale yellow solid.

[0066] 5-Bromo-1-cyclobutyl-4-fluoro-1 H -Indazole

[0067] 1H NMR (400 MHz, chloroform-) d ) δ 8.07 (s, 1H), 7.41 (dd, J = 8.8, 6.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 5.00 (q, J = 8.3 Hz, 1H), 2.83-2.73 (m, 2H), 2.60-2.46 (m, 2H), 2.05-1.87 (m, 2H)

[0068] 5-Bromo-2-cyclobutyl-4-fluoro-2 H -Indazole

[0069] 1 H NMR (400 MHz, chloroform-) d ) δ 8.03 (s, 1H), 7.40 (d, J = 9.1 Hz, 1H), 7.31 (dd, J = 9.1, 6.5 Hz, 1H), 5.04 (p, J = 8.4 Hz, 1H), 2.78-2.57 (m, 4H), 2.06-1.90 (m, 2H)

[0070] Synthesis Example 3: Synthesis of Intermediates 5 to 12

[0071] Following the methods used to synthesize intermediates 3 and 4, intermediates 5 to 12 were synthesized.

[0072] 5-Bromo-1-cyclopentyl-4-fluoro-1 H -Indazole

[0073] Yellow oily substance, yield: 43%.

[0074] 1 H NMR (400 MHz, chloroform-) d ) δ 8.03 (s, 1H), 7.42 (dd, J = 8.9, 6.2 Hz,1H), 7.15-7.11 (m, 1H), 4.93 (p, J = 7.2 Hz, 1H), 2.24-2.06 (m, 4H), 2.04-1.90 (m, 2H), 1.82-1.68 (m, 2H)

[0075] 5-Bromo-2-cyclopentyl-4-fluoro-2 H -Indazole

[0076] Colorless oily substance, yield: 27.8%.

[0077] 1 H NMR (400 MHz, chloroform-) d ) δ 8.03 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.30 (dd, J = 9.1, 6.4 Hz, 1H), 4.93 (p, J = 7.2 Hz, 1H), 2.36-2.26 (m, 2H), 2.22-2.11 (m, 2H), 2.03-1.90 (m, 2H), 1.85-1.72 (m, 2H).

[0078] 5-Bromo-4-fluoro-1-(oxetane-3-yl)-1 H -Indazole

[0079] White solid, yield: 42.3%.

[0080] 1 H NMR (400 MHz, chloroform-) d ) δ 8.15 (s, 1H), 7.49 (dd, J = 8.8, 6.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 5.75 (p, J = 7.0 Hz, 1H), 5.26 (t, J = 6.5 Hz, 3H), 5.15 (t, J = 7.3 Hz, 3H)

[0081] 5-Bromo-4-fluoro-2-(oxetane-3-yl)-2 H -Indazole

[0082] Yellow oily substance, yield: 13.2%.

[0083] 1 H NMR (400 MHz, chloroform-) d) δ 8.16 (s, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 6.4 Hz, 1H), 5.71 (p, J = 6.8 Hz, 1H), 5.25-5.10 (m, 4H)

[0084] 5-Bromo-1-(cyclopropylmethyl)-4-fluoro-1 H -Indazole

[0085] Yellow oily substance, yield: 45.3%.

[0086] 1 H NMR (400 MHz, chloroform-) d ) δ 8.04 (s, 1H), 7.43 (dd, J = 8.8, 6.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.24 (d, J = 6.9 Hz, 2H), 1.38-1.26 (m, 1H), 0.63-0.56 (m, 2H), 0.44-0.38 (m, 2H)

[0087] 5-Bromo-2-(cyclopropylmethyl)-4-fluoro-2 H -Indazole

[0088] Yellow solid, yield: 32%.

[0089] 1 H NMR (400 MHz, chloroform-) d ) δ 8.12 (s, 1H), 7.39 (d, J = 9.1 Hz, 1H), 7.32 (dd, J = 9.2, 6.3 Hz, 1H), 4.27 (d, J = 7.3 Hz, 2H), 1.50-1.38 (m, 1H), 0.80-0.69 (m, 2H), 0.52-0.45 (m, 2H)

[0090] 5-Bromo-1-(cyclopropylmethyl)-1 Hmethyl indazole-3-carboxylate

[0091] White solid, yield: 37.2%.

[0092] 1 H NMR (400 MHz, chloroform-) d ) δ 8.20 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.42 (dt, J = 9.0, 1.4 Hz, 1H), 4.75 (d, J = 7.3 Hz, 2H), 4.04 (s, 3H), 1.58-1.45 (m, 1H), 0.59-0.46 (m, 4H)

[0093] 5-Bromo-2-(cyclopropylmethyl)-2 H methyl indazole-3-carboxylate

[0094] Colorless oily substance, yield: 43.7%.

[0095] 1 H NMR (400 MHz, chloroform-) d ) δ 8.40 (s, 1H), 7.53 (dt, J = 9.0, 1.5 Hz, 2H), 7.39 (d, J = 8.9 Hz, 1H), 4.35 (d, J = 7.0 Hz, 3H), 4.04 (d, J = 1.1 Hz,4H), 1.44-1.34 (m, 1H), 0.64-0.56 (m, 2H), 0.48-0.41 (m, 2H)

[0096] Synthesis Example 4: Synthesis of Intermediates 13 and 14

[0097] At room temperature, 1-hydroxy-adamantane (849.5 mg, 5.58 mmol, 1.2 eq) was dispersed in 85% phosphoric acid (51 mL), and then 5-bromo-4-fluoro-1-oxohydrogen phosphate was added. H -Indazole (1.0 g, 4.65 mmol, 1.0 eq). The resulting system was heated to 60 °C. oC, reaction for 48 hours. TLC (PE / EA=10 / 1) showed a small amount of starting material remaining. The reaction was stopped, cooled to room temperature, and 150 mL of water was added to the system. A large amount of white solid precipitated. The solid was filtered, and the filter cake was washed with saturated sodium carbonate aqueous solution until neutral, then dried under vacuum overnight. The crude product was purified by column chromatography (silica gel, 200-300 mesh, PE / EA=250 / 1-200 / 1) to give 1-(adamantane-1-yl)-5-bromo-4-fluoro-1-yl H -Indazole (450 mg, yield: 27.7%), white solid. Increasing the eluent polarity (PE / EA = 150 / 1-100 / 1-80 / 1) yields 2-(adamantane-1-yl)-5-bromo-4-fluoro-2- H -Indazole (680 mg, yield: 41.8%), white solid.

[0098] 1-(adamantane-1-yl)-5-bromo-4-fluoro-1 H -Indazole

[0099] 1 H NMR (400 MHz, chloroform-) d ) δ 8.00 (s, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.35 (dd, J = 9.0, 6.4 Hz, 1H), 2.44-2.34 (m, 6H), 2.33-2.24 (m, 3H), 1.88-1.74 (m, 6H).

[0100] 2-(adamantane-1-yl)-5-bromo-4-fluoro-2 H -Indazole

[0101] 1 H NMR (400 MHz, chloroform-) d ) δ 8.11 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.30 (dd, J = 9.1, 6.5 Hz, 1H), 2.31 (s, 9H), 1.82 (s, 6H)

[0102] Synthesis Example 5: Synthesis of Intermediates 17 and 18

[0103] 5-bromo-4-fluoro-1 HIndole (450 mg, 2.10 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), and 1,3-dichloro-5,5-dimethylhydantoin (227.8 mg, 1.15 mmol, 0.55 eq) was added at room temperature. The resulting system was stirred for 3 hours. TLC (PE / EA = 10 / 1) showed that the starting material disappeared. 20 mL of water was added to the system, and a yellow solid precipitated. The solid was filtered, the filter cake was thoroughly washed with water, and then dried under vacuum overnight to give 5-bromo-3-chloro-4-fluoro-1- H -Indole (490 mg, yield: 93.8%), yellow solid.

[0104] 1 H NMR (400 MHz, chloroform-) d ) δ 8.21 (br. s, 1H), 7.30 (dd, J = 8.5, 6.6Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 8.7 Hz, 1H), 3.71 (s, 1H).

[0105] At room temperature, 5-bromo-3-chloro-4-fluoro-1 H Indole (260 mg, 1.05 mmol, 1.0 eq), 3-iodoxetane (231 mg, 1.25 mmol, 1.2 eq), and cesium carbonate (684 mg, 2.10 mmol, 2.0 eq) were added to DMF (5 mL). The resulting system was heated to 75°C. o Stirred overnight at C. TLC (PE / EA=3 / 1) showed the starter had disappeared. Cool to room temperature, add 10 mL of ice water, and a brownish-yellow solid precipitated. Filter, wash the filter cake thoroughly with water, and then vacuum dry overnight to give 5-bromo-3-chloro-4-fluoro-1-(oxetane-3-yl)-1 H -Indole (175 mg, yield: 54.7%), brownish-yellow solid.

[0106] 1 H NMR (400 MHz, chloroform-) d ) δ 7.41-7.40 (m, 1H), 7.31 (ddd, J = 8.4,6.4, 1.5 Hz, 1H), 7.17 (d, J= 8.7 Hz, 1H), 6.70-6.63 (m, 1H), 5.56-5.46 (m,1H), 5.24-5.14 (m, 2H), 5.08-5.01 (m, 2H).

[0107] At room temperature, 5-bromo-3-chloro-4-fluoro-1 H Indole (260 mg, 1.05 mmol, 1.0 eq), cyclopropylboronic acid (180.4 mg, 2.10 mmol, 2.0 eq), and sodium carbonate (222.6 mg, 2.10 mmol, 2.0 eq) were added to 1,2-dichloroethane (10 mL), and the mixture was stirred for 5 minutes under air. Then, 2,2'-bipyridine (164 mg, 1.05 mmol, 1.0 eq) and anhydrous copper acetate (190.7 mg, 1.05 mmol, 1.0 eq) were added. The resulting reaction mixture was heated to 70°C. o React at C for 3 hours. TLC (PE / EA = 5 / 1) showed the starting material had disappeared. Cool to room temperature, add 10 mL of water to the system, and separate the layers. Use DCM (10 mL) for the aqueous phase. 3) Extraction. Combine the organic phases and extract with saturated saline (20 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (silica gel, 200-300 mesh, PE / EA=50 / 1) to give 5-bromo-3-chloro-1-cyclopropyl-4-fluoro-1- H -Indole (253 mg, yield: 83.5%), white solid.

[0108] 1 H NMR (400 MHz, chloroform-) d ) δ 7.30-7.24 (m, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 3.33 (tt, J = 7.3,3.8 Hz, 1H), 1.12-1.05 (m, 2H), 1.02-0.96 (m, 2H)

[0109] Synthesis Example 6: Synthesis of Intermediates 19 and 20

[0110] At room temperature, 5-bromo-4-fluoro-1H Indole (250 mg, 1.168 mmol, 1.0 eq), cyclopropylboronic acid (200.7 mg, 2.336 mmol, 2.0 eq), and sodium carbonate (247.6 mg, 2.10 mmol, 2.0 eq) were added to 1,2-dichloroethane (5 mL), and stirred for 5 minutes under air. Then, 2,2'-bipyridine (182.4 mg, 1.168 mmol, 1.0 eq) and anhydrous copper acetate (212 mg, 1.168 mmol, 1.0 eq) were added. The resulting reaction system was heated to an external temperature of 70°C. o React at C for 4 hours. TLC (PE / EA = 10 / 1) showed the starting material had disappeared. Cool to room temperature, add 10 mL of water to the system, and separate the layers. Use DCM (10 mL) for the aqueous phase. 3) Extraction. Combine the organic phases and extract with saturated saline (20 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (silica gel, 200-300 mesh, PE / EA=50 / 1) to give 5-bromo-1-cyclopropyl-4-fluoro-1- H -Indole (200 mg, yield: 67.4%), colorless oil.

[0111] 1 H NMR (400 MHz, chloroform-) d ) δ 7.35-7.27 (m, 1H), 7.20 (dd, J = 8.8, 1.2Hz, 1H), 7.04 (s, 1H), 3.30 (tt, J = 7.1, 3.9 Hz, 1H), 1.13-1.06 (m, 2H), 1.02-0.95 (m, 2H).

[0112] At room temperature, 5-bromo-4-fluoro-1 H Indole (250 mg, 1.168 mmol, 1.0 eq), 3-iodoxetane (258 mg, 1.402 mmol, 1.2 eq), and cesium carbonate (761 mg, 2.336 mmol, 2.0 eq) were added to DMF (5 mL). The resulting system was heated to 75°C. o Stir overnight at C. TLC (PE / EA=10 / 1) showed a small amount of reactant remaining. Stop the reaction, cool to room temperature, and add 10 mL of ice water and EtOAc (10 mL) to the system. 3) Extraction. The organic phase was washed with saturated brine (10 mL). 3) The product was dried over anhydrous sodium sulfate and then evaporated to obtain the crude product. The crude product was purified by column chromatography (silica gel, 200-300 mesh, PE / EA=15 / 1-12 / 1-10 / 1-8 / 1) to give 5-bromo-4-fluoro-1-(oxetane-3-yl)-1 H -Indole (150 mg, yield: 47.5%), pale yellow solid.

[0113] 1 H NMR (400 MHz, chloroform-) d ) δ 7.38 (s, 1H), 7.33 (dd, J = 8.9, 6.3 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 5.47 (p, J = 6.7 Hz, 1H), 5.17 (t, J = 7.4 Hz, 2H), 4.97 (t, J = 6.6 Hz, 2H)

[0114] Synthesis Example 7: Synthesis of Intermediate 25

[0115] At room temperature, 2-amino-3-nitrophenol (25 g, 162.2 mmol, 1.0 eq) was dissolved in 1,4-dioxane (300 mL), followed by the dropwise addition of liquid bromine (8.3 mL, 162.2 mmol, 1.0 eq), while maintaining the internal temperature below 15°C. o C, A large amount of solid is formed during the dropwise addition process. The resulting mixture is at 25°C. o The reaction was carried out at C overnight. TLC (PE / EA = 4 / 1) showed that the starting material disappeared. The mixture was filtered, and the filter cake was washed with 1,4-dioxane (300 mL) and petroleum ether (500 mL), and then dried under vacuum overnight to give 2-amino-5-bromo-3-nitrophenol hydrobromide (54.6 g, yield: 100%), a yellow solid, which was used directly in the next reaction.

[0116] 1 H NMR (400 MHz, DMSO- d 6) δ 11.01 (br. s, 1H), 7.58 (s, 1H), 6.97 (s,1H), 6.05 (br. s, 3H)

[0117] 2-Amino-5-bromo-3-nitrophenol hydrobromide (20 g, 63.7 mmol, 1.0 eq) and 1,2,-dibromoethane (71.8 g, 382.2 mmol, 6.0 eq) were added to DMF (120 mL), and solid KOH (12.6 g, 191.1 mmol, 3.0 eq) was added in portions at room temperature. The resulting reaction system was heated to 140 °C under argon protection. o The reaction was carried out at C for 10 hours. After cooling to room temperature, 200 mL of water was added to the system, followed by EtOAc (200 mL). 3) Extraction. The organic phase is extracted with saturated brine (200 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (silica gel, 200-300 mesh, PE / EA=10 / 1-8 / 1-6 / 1-4 / 1) to give 7-bromo-5-nitro-3,4-dihydro-2- H -Benzo[b][1,4]oxazine (12 g, yield: 72.7%), red solid.

[0118] 1 H NMR (400 MHz, chloroform-) d ) δ 7.91 (d, J = 2.5 Hz, 2H), 7.09 (d, J = 2.3Hz, 1H), 4.25 (t, J = 4.6 Hz, 1H), 3.66-3.63 (m, 1H)

[0119] 7-bromo-5-nitro-3,4-dihydro-2 H Benzo[b][1,4]oxazine (12 g, 46.3 mmol, 1.0 eq) and ammonium chloride (22.3 g, 416.7 mmol, 9.0 eq) were added to a mixed solvent of methanol (100 mL) and water (100 mL), followed by the addition of reduced iron powder (15.6 g, 278.6 mmol, 6.0 eq) in portions. The resulting reaction system was heated to 55 °C. o React at C for 2 hours. TLC (PE / EA = 2 / 1) showed the starting material had disappeared. Cool to room temperature, filter with diatomaceous earth, and wash the filter cake thoroughly with EtOAc. Concentrate the filtrate to remove methanol, and wash the remaining aqueous phase with EtOAc (100 mL). 4) Extraction. The organic phase is extracted with saturated brine (100 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (silica gel, 200-300 mesh, PE / EA=8 / 1-6 / 1-4 / 1-3 / 1) to give 7-bromo-3,4-dihydro-2-bromosulfonate. H -Benzo[b][1,4]oxazine-5-amine (5.3 g, yield: 50%), reddish-brown oily substance.

[0120] 1 H NMR (400 MHz, chloroform-) d ) δ 6.52 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.1Hz, 1H), 4.16-4.14 (m, 2H), 3.40-3.38 (m, 2H), 3.29(br. s, 3H)

[0121] 7-bromo-3,4-dihydro-2 H Benzo[b][1,4]oxazine-5-amine (500 mg, 2.18 mmol, 1.0 eq) and p-toluenesulfonic acid (7.5 mg, 0.0436 mmol, 0.02 eq) were dissolved in trimethyl orthoformate (2 mL). The mixture was heated to reflux for 1 hour, and TLC (PE / EA = 2 / 1) showed that the starting material disappeared. The mixture was cooled to room temperature and concentrated to remove the solvent. The residue was directly purified by column chromatography (silica gel, 200-300 mesh, DCM / MeOH = 100 / 1-80 / 1) to give 7-bromo-3,4-dihydro-5-oxa-1,2a-diazanaphthene (0.2 g, yield: 38.4%), a yellow solid.

[0122] 1H NMR (400 MHz, chloroform- d ) δ 7.87 (s, 1H), 7.55 (d, J = 1.2 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 4.51 (dd, J = 5.7, 3.8 Hz, 2H), 4.40 (dd, J = 5.8, 3.7 Hz, 2H)

[0123] Synthesis Example 8: Synthesis of Intermediate 27

[0124] 7-bromo-3,4-dihydro-2 HBenzo[b][1,4]oxazine-5-amine (340 mg, 1.484 mmol, 1.0 eq), cyclopropionic acid (127.8 mg, 1.484 mmol, 1.0 eq), and DIPEA (0.78 mL, 4.453 mmol, 3.0 eq) were dissolved in DMF (5 mL), and then HATU (620.7 mg, 1.63 mmol, 1.1 eq) was added. The resulting system was heated at 25 °C. o The reaction proceeds at C for 3 hours. TLC (DCM / MeOH = 30 / 1, 1 drop of ammonia) shows the disappearance of the starting material. 20 mL of water is added to the system, and a yellow solid precipitates. The mixture is filtered, and the filter cake is thoroughly washed with water to remove DMF. The filter cake is then dissolved in EtOAc (20 mL) and saturated saline solution (20 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain N-(7-bromo-3,4-dihydro-2-) H 1,4-benzo[b][1,4]oxazine-5-yl)cyclopropionamide (340 mg, yield: 77.1%), yellow solid.

[0125] 1 H NMR (400 MHz, chloroform-) d ) δ 7.36 (br. s, 1H), 7.02 (s, 1H), 6.86 (s, 1H), 4.14 (t, J = 4.4 Hz, 2H), 4.09 (br. s, 1H), 3.38 (t, J = 4.4 Hz, 2H), 1.57-1.51 (m, 1H), 1.11-1.05 (m, 2H), 0.92-0.83 (m, 2H).

[0126] N-(7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)cyclopropionamide (290 mg, 0.976 mmol, 1.0 eq) was dispersed in AcOH (8 mL) and then heated to 80 °C. o React at C overnight. TLC (DCM / MeOH = 30 / 1, 1 drop of ammonia) showed the starting material disappeared. Cool to room temperature and concentrate to remove glacial acetic acid. Add saturated sodium carbonate solution to the residue to pH 8-9, then use EtOAc (20 mL) 3) Extraction. The organic phase is extracted with saturated saline solution (20 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain crude product. The crude product was purified by column chromatography (silica gel, 200-300 mesh, DCM / MeOH=200 / 1-150 / 1) to give 7-bromo-3,4-dihydro-5-oxa-1,2a-diazanene (220 mg, yield: 80.8%), a yellow solid.

[0127] 1 H NMR (400 MHz, chloroform-) d ) δ 7.37 (s, 1H), 6.84 (s, 1H), 4.50 (t, J =4.7 Hz, 2H), 4.34 (t, J = 4.7 Hz, 2H), 1.90 (tt, J = 8.7, 4.8 Hz, 2H), 1.30-1.23 (m, 2H), 1.17-1.10 (m, 2H)

[0128] Synthesis Example 9: Synthesis of Intermediate 31

[0129] 5-bromo-4-fluoro-1 H -Indazole (1.0 g, 4.65 mmol, 1.0 eq), tert-butyl 3-bromozacyclobutane-1-carboxylate (1.21 g, 5.12 mmol, 1.1 eq), Cs₂CO₃ (2.27 g, 5.12 mmol, 1.5 eq), and NaI (0.1 g, cat.) were added to DMF (15 mL). The resulting system was heated to 60 °C. o The reaction was carried out at C for 5 hours. TLC (PE / EA = 4 / 1) showed that the starting material had disappeared. The mixture was then cooled to room temperature, and 30 mL of ice water and 20 mL of EtOAc were added to the system. 3) Extraction. The organic phase is extracted with saturated saline solution (20 mL). 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain a yellow oily substance. The crude product was purified by column chromatography (silica gel, 200-300 mesh, PE / EA=15 / 1-12 / 1-10 / 1) to give 3-(5-bromo-4-fluoro-1-) H 3-Indazole-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (650 mg, yield: 37.8%), white solid. Increasing the eluent polarity (PE / EA = 8 / 1) gives 3-(5-bromo-4-fluoro-2-) H 2-Indazole-2-yl) tert-butyl 1-carboxylate (478 mg, yield: 27.8%), a yellow foamy solid.

[0130]

[0131] 3-(5-bromo-4-fluoro-1- H -Indazole-1-yl)Zetane-1-carboxylic acid tert-butyl ester

[0132] 1 H NMR (400 MHz, chloroform-) d ) δ 8.12 (s, 1H), 7.48 (dd, J = 8.9, 6.2 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 5.33 (h, J = 6.0, 5.3 Hz, 1H), 4.47 (q, J =8.9, 7.6 Hz, 4H), 1.48 (s, 9H)

[0133] 3-(5-bromo-4-fluoro-2-) H -Indazole-2-yl)Zetane-1-carboxylic acid tert-butyl ester

[0134] 1 H NMR (400 MHz, chloroform-) d ) δ 8.13 (s, 1H), 7.41 (d, J = 9.1 Hz, 1H), 7.35 (dd, J = 9.2, 6.3 Hz, 1H), 5.30 (ddd, J = 13.1, 7.6, 5.6 Hz, 1H), 4.55-4.41 (m, 4H), 1.47 (s, 9H)

[0135] 3-(5-bromo-4-fluoro-1 H tert-butyl 1-indazole-1-yl)azacyclobutane-1-carboxylate (650 mg, 1.75 mmol, 1.0 eq) was dissolved in DCM (10 mL), and HCl (g) / 1,4-dioxane (4 M, 4.4 mL, 17.6 mmol, 10 eq) was added dropwise under an ice-water bath. The resulting system was reacted at room temperature for 1 hour under argon protection. TLC (PE / EA = 1 / 1) showed the disappearance of the starting material. The solvent was removed by concentration, and saturated sodium bicarbonate solution was added to the residue under an ice-water bath to adjust the pH to 8-9, followed by EtOAc (20 mL). 3) Extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 1-(azacyclobutane-3-yl)-5-bromo-4-fluoro-1-yl H -Indazole (380 mg, yield: 80.4%), yellow solid.

[0136]

[0137] 1-(azacyclobutan-3-yl)-5-bromo-4-fluoro-1 H Indazole (380 mg, 1.407 mmol, 1.0 eq), cyclopropylboronic acid (241.7 mg, 2.814 mmol, 2.0 eq), and sodium carbonate (298 mg, 2.814 mmol, 2.0 eq) were added to 1,2-dichloroethane (10 mL), followed by 2,2'-bipyridine (219.7 mg, 1.407 mmol, 1.0 eq) and anhydrous copper acetate (255.6 mg, 1.407 mmol, 1.0 eq). The resulting reaction mixture was heated to an external temperature of 75°C. o React at C overnight. TLC (DCM / MeOH = 20 / 1, 1 drop of ammonia) showed the starting material disappeared. Cool to room temperature, filter with diatomaceous earth to remove insoluble matter, and wash the filter cake thoroughly with DCM. Dilute the filtrate with 20 mL of saturated saline solution. 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (silica gel, 200-300 mesh, DCM / MeOH = 250 / 1) to give 5-bromo-1-(1-cyclopropylazacyclobutane-3-yl)-4-fluoro-1-yl H -Indazole (175 mg, yield: 40.1%), pale yellow solid.

[0138] 1 H NMR (400 MHz, chloroform-) d ) δ 8.18 (s, 1H), 7.52 (dd, J = 8.9, 6.3 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H), 5.70-5.54 (m, 1H), 4.75 (t, J = 8.2 Hz, 2H), 4.37 (t, J = 8.2 Hz, 2H), 2.91 (br. s, 1H), 1.21-1.08 (m, 2H), 0.94-0.78 (m,2H)

[0139] Synthesis Example 10: Synthesis of Intermediate 33

[0140] 3-(5-bromo-4-fluoro-2- H 470 mg (1.27 mmol, 1.0 eq) of tert-butyl 1-indazole-2-yl)azacyclobutane-1-carboxylate (DCM) was dissolved in 10 mL of DCM. HCl (g) / 1,4-dioxane (4 M, 3.2 mL, 12.8 mmol, 10 eq) was added dropwise under an ice-water bath. The resulting system was reacted at room temperature for 2 hours under argon protection. TLC (PE / EA = 1 / 1) showed the disappearance of the starting material. The solvent was removed by concentration, and a saturated sodium bicarbonate aqueous solution was added to the residue under an ice-water bath until the pH reached 8-9. Then, EtOAc (20 mL) was added. 3) Extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 2-(azacyclobutane-3-yl)-5-bromo-4-fluoro-2-ylylene(2-ylylene) ...bromo-5-bromo-4-fluoro-2-ylylene(2-ylylylene)bromo-5 H -Indazole (220 mg, yield: 64.1%), yellow solid.

[0141]

[0142] 2-(azacyclobutan-3-yl)-5-bromo-4-fluoro-2 H Indazole (220 mg, 0.815 mmol, 1.0 eq), cyclopropylboronic acid (140 mg, 1.63 mmol, 2.0 eq), and sodium carbonate (172.8 mg, 1.63 mmol, 2.0 eq) were added to 1,2-dichloroethane (10 mL), followed by 2,2'-bipyridine (127.3 mg, 0.815 mmol, 1.0 eq) and anhydrous copper acetate (148 mg, 0.815 mmol, 1.0 eq). The resulting reaction system was heated to an external temperature of 70 °C. o React at C for 2 hours. TLC (DCM / MeOH = 20 / 1, 1 drop of ammonia) showed the starting material disappeared. Cool to room temperature, filter with diatomaceous earth to remove insoluble matter, and wash the filter cake thoroughly with DCM. Dilute the filtrate with 20 mL of saturated saline solution. 3) Wash, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (silica gel, 200-300 mesh, DCM / MeOH = 200 / 1-160 / 1-120 / 1) to give 5-bromo-2-(1-cyclopropylazacyclobutane-3-yl)-4-fluoro-2-yl H -Indazole (90 mg, yield: 35.6%), pale yellow solid.

[0143] 1 H NMR (400 MHz, chloroform-) d) δ 8.18 (s, 1H), 7.40 (d, J = 9.1 Hz, 1H), 7.33 (dd, J = 9.1, 6.4 Hz, 1H), 5.16 (p, J = 6.7 Hz, 1H), 3.94 (t, J = 7.2Hz, 2H), 3.79 (t, J = 7.1 Hz, 2H), 2.05 (td, J = 6.2, 3.4 Hz, 1H), 0.53-0.31(m, 4H)

[0144] Synthesis Example 11: Synthesis of Compound FY801

[0145] 3-((1) S ,2 S )-1-(5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-2-(( S )-4-methyl-3-(2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazolo[4,3-c]pyridine-5-carbonyl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-Ketone (770 mg, 0.945 mmol, 1.0 eq), 5-bromo-1-cyclopropyl-4-fluoro-1 H -Indazole (361.5 mg, 1.42 mmol, 1.5 eq), (1 S ,2 S )-(+)- N , N' Dimethyl-1,2-cyclohexanediamine (201.6 mg, 1.42 mmol, 1.5 eq) and potassium carbonate (261.2 mg, 1.89 mmol, 2.0 eq) were dispersed in anhydrous NMP (10 mL), followed by the addition of CuI (270.4 mg, 1.42 mmol, 1.5 eq). The reaction system was incubated at 130 °C under argon protection. o React at step C for 1 hour. After cooling to room temperature, add 20 mL of saturated sodium carbonate aqueous solution; a solid precipitates. Filter, and wash the filter cake thoroughly with 10 mL of water. 5), then vacuum dried overnight to obtain the crude product. The crude product was purified by column chromatography (silica gel, 200-300 mesh, DCM / MeOH = 200 / 1-160 / 1-120 / 1) to obtain 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(1-cyclopropyl-4-fluoro-1 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone (172 mg, yield 18.4%), yellow solid.

[0146] 1 H NMR (600 MHz, DMSO- d 6) δ 12.30 (br. s, 0.30H), 11.75 (br. s,0.76H), 8.32-8.18 (m, 1H), 8.13-8.00 (m, 2H), 7.71-7.32 (m, 6H), 7.26 (d, J =8.5Hz, 1H), 7.21-7.00 (m, 1.8H), 6.98-6.88 (m, 1H), 6.75 (br. s, 0.3H) 5.6-5.55 (m, 0.8H), 5.28 (br. s, 0.2H), 4.40 (d, J = 13.0 Hz, 1H)), 3.89-3.60 (m,4H), 3.27-3.17 (m, 1H), 3.07-2.99 (m, 1H), 2.98-2.90 (m, 1H), 1.83-1.48 (m,7H), 1.47-1.37 (m, 2H), 1.36-1.22 (m, 5H), 1.21-1.05 (m, 9H)

[0147] HRMS: m / z 989.3343 (M+H) +

[0148] Synthesis Example 12: Synthesis of Compound FY802

[0149] Following the method of Synthesis Example 11, compound FY802 was synthesized: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(1-cyclobutyl-4-fluoro-1 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 18.4%.

[0150] 1 H NMR (400 MHz, chloroform-) d ) δ 11.29 (br. s, 0.80H), 11.24 (br. s,0.19H), 8.18 (s, 0.80H), 8.09 (s, 0.22H), 7.89-7.78 (m, 2H), 7.67-7.49 (m,4H), 7.44 (t, J = 7.8 Hz, 1H), 7.35-7.29 (m, 1H), 7.29-7.15 (m, 1H), 6.74-6.53 (m, 2H), 6.42-6.14 (m, 1H), 5.83-5.26 (m, 1H), 5.13-4.99(m, 1H), 4.92-4.45 (m, 1H), 3.92-3.78 (m, 2H), 3.65-3.53 (m, 1H), 3.22-2.97 (m, 3H), 2.87-2.71 (m, 2H), 2.61-2.47 (m, 2H), 2.06-1.88 (m, 3H), 1.82-1.62 (m, 5H), 1.58-1.49 (m, 4H), 1.34 (s, 3H), 1.31-1.24 (m, 4H), 1.22-1.03 (m, 3H)

[0151] HRMS: m / z 1025.3403 (M+Na) +

[0152] Synthesis Example 13: Synthesis of Compound FY803

[0153] Following the method of Synthesis Example 11, compound FY803 was synthesized: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(2-cyclobutyl-4-fluoro-2 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 22.7%.

[0154] 1 H NMR (400 MHz, chloroform-) d ) δ 11.29 (br. s, 0.72H), 11.24 (br. s,0.21H), 8.18 (s, 0.76H), 8.09 (s, 0.21H), 7.89-7.78 (m, 2H), 7.69-7.40 (m,5H), 7.35-7.29 (m, 2H), 6.74-6.53 (m, 2H), 6.42-6.10 (m, 1H), 5.83-5.26 (m,1H), 5.14-5.01 (m, 1H), 4.92-4.45 (m, 1H), 3.92-3.78 (m, 2H), 3.65-3.53 (m,1H), 3.22-2.97 (m, 3H), 2.81-2.53 (m, 4H), 2.06-1.88(m, 3H), 1.82-1.62 (m,5H), 1.58-1.49 (m, 4H), 1.38-1.16 (m, 6H), 1.22-1.03 (m, 3H)

[0155] HRMS: m / z 1025.3398 (M+Na) +

[0156] Synthesis Example 14: Synthesis of Compound FY804

[0157] Following the method of Synthesis Example 11, compound FY804 was synthesized: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(1-cyclopentyl-4-fluoro-1 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 16%.

[0158] 1 H NMR (400 MHz, chloroform-) d ) δ 11.29 (br. s, 0.71H), 11.24 (br. s,0.22H), 8.14 (s, 0.78H), 8.05 (s, 0.21H), 7.91-7.78 (m, 2H), 7.66-7.40 (m,5H), 7.38-7.31 (m, 1H), 7.30-7.17 (m, 1H), 6.76-6.56 (m, 2H), 6.43-6.13 (m,1H), 5.83-5.26 (m, 1H), 4.99 (p, J = 8.1, 7.6 Hz, 1H), 4.93-4.43 (m, 1H), 3.92-3.78 (m, 2H), 3.65-3.53 (m, 1H), 3.24-2.97 (m, 3H), 2.26-2.10 (m, 4H), 2.05-1.94 (m, 2H), 1.82-1.65 (m, 6H), 1.56-1.51 (m, 2H), 1.38-1.16 (m, 10H), 1.22-1.03 (m, 3H)

[0159] HRMS: m / z 1039.3562 (M+Na) +

[0160] Synthesis Example 15: Synthesis of Compound FY805

[0161] Following the method of Synthesis Example 11, compound FY805 was synthesized: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(2-cyclopentyl-4-fluoro-2 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 15.5%.

[0162] 1 H NMR (400 MHz, chloroform-) d ) δ 11.29 (br. s, 0.73H), 11.24 (br. s,0.22H), 8.15 (s, 0.75H), 8.07 (s, 0.20H), 7.91-7.76 (m, 2H), 7.68-7.39 (m,5H), 7.32-7.21 (m, 2H), 6.76-6.49 (m, 2H), 6.43-6.13 (m, 1H), 5.83-5.26 (m,1H), 4.99 (p, J = 8.1, 7.6 Hz, 1H), 4.93-4.43 (m, 1H), 3.92-3.78 (m, 2H), 3.65-3.50 (m, 1H), 3.24-2.97 (m, 3H), 2.40-2.26 (m, 2H), 2.24-2.10 (m, 2H),2.05-1.94 (m, 2H), 1.87-1.62 (m, 6H), 1.58-1.51 (m, 2H), 1.38-1.16 (m, 10H),1.22-1.03 (m, 3H)

[0163] HRMS: m / z 1039.3555 (M+Na) +

[0164] Synthesis Example 16: Synthesis of Compound FY806

[0165] Following the method of Synthesis Example 11, compound FY806 was synthesized: 3-((1 S ,2 S )-1-(5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-2-(( S )-3-(3-(4-fluoro-1-(oxetane-3-yl)-1 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 13.8%.

[0166] 1 H NMR (600 MHz, DMSO- d 6) δ 12.31 (br. s, 0.27H), 11.75 (br. s,0.74H), 8.54-8.40 (m, 1H), 8.14-8.00 (m, 2H), 7.73-7.48 (m, 4H), 7.44-7.32(m, 1H), 7.29-7.14 (m, 2H), 6.98-6.60 (m, 2H), 6.16-6.04 (m, 1H), 5.82-5.55(m, 1H), 5.30-4.78 (m, 5H), 4.70-4.34 (m, 1H), 3.78-3.57 (m, 3H), 3.27-3.17(m, 1H), 3.07-2.99 (m, 1H), 2.98-2.90 (m, 1H), 1.83-1.48 (m, 7H), 1.47-1.37(m, 2H), 1.36-1.03 (m, 10H)

[0167] HRMS: m / z 1027.3198 (M+Na) +

[0168] Synthesis Example 17: Synthesis of Compound FY807

[0169] Following the method of Synthesis Example 11, compound FY807 was synthesized: 3-((1 S ,2 S)-1-(5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-2-(( S )-3-(3-(4-fluoro-2-(oxetane-3-yl)-2 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 10.3%.

[0170] 1 H NMR (400 MHz, chloroform-) d ) δ 11.29 (br. s, 0.73H), 11.24 (br. s,0.22H), 8.32-8.20 (m, 1H), 7.91-7.76 (m, 2H), 7.70-7.45 (m, 5H), 7.40-7.16(m, 2H), 6.76-6.49 (m, 2H), 6.43-6.13 (m, 1H), 5.82-5.70 (m, 1H), 5.46-5.11(m, 5H), 4.54-4.42 (m, 1H), 3.92-3.78 (m, 2H), 3.76-3.68 (m, 1H), 3.65-3.54(m, 1H), 3.24-2.97 (m, 3H), 2.26-2.17 (m, 1H), 2.03-1.90 (m, 2H), 1.83-1.63(m, 4H), 1.38-1.16 (m, 11H)

[0171] HRMS: m / z 1027.3196 (M+Na) +

[0172] Synthesis Example 18: Synthesis of Compound FY808

[0173] Following the method of Synthesis Example 11, compound FY808 was synthesized: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(1-(cyclopropylmethyl)-4-fluoro-1 H-Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 23.2%.

[0174] 1 H NMR (400 MHz, chloroform-) d ) δ 11.29 (br. s, 0.76H), 11.24 (br. s,0.21H), 8.16 (s, 0.78H), 8.06 (s, 0.19H), 7.90-7.78 (m, 2H), 7.67-7.41 (m,5H), 7.35-7.13 (m, 2H), 6.76-6.53 (m, 2H), 6.46-6.11 (m, 1H), 5.83-5.26 (m,1H), 4.92-4.43 (m, 1H), 4.35-4.22 (m, 2H), 3.92-3.78 (m, 2H), 3.67-3.54 (m,1H), 3.24-2.97 (m, 3H), 1.94-1.63 (m, 6H), 1.59-1.49(m, 4H), 1.38-1.20 (m,7H), 1.22-1.05 (m, 3H), 0.65-0.55 (m, 2H), 0.47-0.37 (m, 2H)

[0175] HRMS: m / z 1025.3420 (M+Na) +

[0176] Synthesis Example 19: Synthesis of Compound FY809

[0177] Following the method of Synthesis Example 11, compound FY809 was synthesized: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(2-(cyclopropylmethyl)-4-fluoro-2 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H-imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 24.4%.

[0178] 1 H NMR (400 MHz, chloroform-) d ) δ 11.29 (br. s, 0.77H), 11.24 (br. s,0.20H), 8.16 (s, 0.82H), 8.06 (s, 0.20H), 7.90-7.78 (m, 2H), 7.67-7.40 (m,5H), 7.35-7.23 (m, 2H), 6.76-6.53 (m, 2H), 6.42-6.11 (m, 1H), 5.83-5.26 (m,1H), 4.92-4.43 (m, 1H), 4.35-4.25 (m, 2H), 3.92-3.78 (m, 2H), 3.67-3.54 (m,1H), 3.24-2.97 (m, 3H), 1.94-1.63 (m, 6H), 1.58-1.40(m, 6H), 1.38-1.23 (m,5H), 1.21-1.06 (m, 3H), 0.80-0.72 (m, 2H), 0.53-0.45 (m, 2H)

[0179] HRMS: m / z 1025.3412 (M+Na) +

[0180] Synthesis Example 20: Synthesis of Compound FY810

[0181] Following the method of Synthetic Example 11, compound FY810 was synthesized: 1-(cyclopropylmethyl)-5-(3-( S )-5-(5-((S)-2,2-dimethyltetrahydro-2 H -pyran-4-yl)-1-((1 S ,2 S )-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1 H-indole-2-carbonyl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -Pyrazole[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-1 H methyl indazole-3-carboxylate, pale yellow solid, yield: 19.3%.

[0182] 1 H NMR (400 MHz, chloroform-) d ) δ 11.27 (br. s, 0.72H), 11.23 (br. s,0.24H), 8.20 (s, 0.76H), 7.99 (s, 0.20H), 7.95-7.76 (m, 3H), 7.67-7.46 (m,5H), 7.31-7.28 (m, 1H), 6.94-6.74 (m, 1H), 6.70 (br. s, 1H), 6.46-6.16 (m,1H), 5.83-5.26 (m, 1H), 4.83-4.72 (m, 2H), 4.55-4.44 (m, 1H), 4.05-3.96 (m,3H), 3.92-3.78 (m, 2H), 3.67-3.54 (m, 1H), 3.24-2.97 (m, 3H), 2.08-1.69 (m,6H), 1.68-1.63 (m, 2H), 1.56-1.48 (m, 5H), 1.37-1.15 (m, 4H), 1.19-1.06 (m,3H), 0.60-0.48 (m, 4H)

[0183] HRMS: m / z 1065.3563 (M+Na) +

[0184] Synthesis Example 21: Synthesis of Compound FY811

[0185] Following the method of Synthetic Example 11, compound FY811 was synthesized: 2-(cyclopropylmethyl)-5-(3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2-) H -pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1 H -indole-2-carbonyl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H-Pyrazole[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-2 H methyl indazole-3-carboxylate, pale yellow solid, yield: 37.5%.

[0186] 1 H NMR (400 MHz, DMSO- d 6) δ 12.35 (br. s, 0.22H), 11.76 (br. s,0.75H), 8.41-7.92 (m, 4H), 7.83-7.57 (m, 3H), 7.56-7.31 (m, 3H), 7.30-7.20(m, 1H), 7.18-6.71 (m, 2H), 5.70-5.23 (m, 1H), 4.73-4.33 (m, 3H), 3.97-3.83(m, 3H), 3.78-3.57 (m, 3H), 3.31-3.15 (m, 1H), 3.09-2.88 (m, 2H), 1.84-1.45(m, 7H), 1.43-1.21 (m, 8H), 1.20-1.09 (m, 5H), 0.58-0.34 (m, 4H)

[0187] HRMS: m / z 1065.3560 (M+Na) +

[0188] Synthesis Example 22: Synthesis of Compound FY812

[0189] Following the method of Synthesis Example 11, compound FY812 was synthesized: 3-((1 S ,2 S )-1-(2-((S)-3-(3-(1-(adamantyl-1-yl)-4-fluoro-1 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, yellow solid, yield: 17.7%.

[0190] 1H NMR (400 MHz, chloroform-) d ) δ 11.40-11.17 (m, 1H), 8.14-8.00 (m, 1H), 7.90-7.76 (m, 2H), 7.68-7.35 (m, 6H), 7.30-7.10 (m, 1H), 6.76-6.51 (m, 2H),6.42-6.13 (m, 1H), 5.85-5.26 (m, 1H), 4.91-4.42 (m, 1H), 3.92-3.78 (m, 2H),3.67-3.54 (m, 1H), 3.42-2.96 (m, 4H), 2.48-2.24 (m, 9H), 1.83 (br. s, 6H),1.94-1.24 (m, 15H), 1.22-1.03 (m, 3H)

[0191] HRMS: m / z 1083.4155 (M+H) +

[0192] Synthesis Example 23: Synthesis of Compound FY813

[0193] Following the method of Synthesis Example 11, compound FY813 was synthesized: 3-((1 S ,2 S )-1-(2-((S)-3-(3-(2-(adamantyl-1-yl)-4-fluoro-2 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, yellow solid, yield: 12.4%.

[0194] 1 H NMR (400 MHz, chloroform-) d) δ 11.38-11.22 (m, 1H), 8.28-8.12 (m, 1H), 7.91-7.76 (m, 2H), 7.68-7.38 (m, 6H), 7.30-7.10 (m, 1H), 6.76-6.51 (m, 2H),6.42-6.10 (m, 1H), 5.85-5.26 (m, 1H), 4.91-4.42 (m, 1H), 3.92-3.78 (m, 2H),3.65-3.54 (m, 1H), 3.42-2.96 (m, 4H), 2.40-2.24 (m, 9H), 1.83 (br. s, 6H),1.94-1.24 (m, 15H), 1.22-1.03 (m, 3H)

[0195] HRMS: m / z 1083.4169(M+H) +

[0196] Synthesis Example 24: Synthesis of Compound FY822

[0197] Following the method of Synthesis Example 11, compound FY822: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(2-(1-cyclopropylazetane3-yl)-4-fluoro-2 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 16.5%.

[0198] 1 H NMR (400 MHz, chloroform-) d) δ 11.28 (br. s, 1H), 8.31 (br. s, 0.73H), 8.22 (br. s, 0.29H), 7.90-7.75 (m, 2H), 7.67-7.49 (m, 4H), 7.38-6.96 (m, 3H),6.74-6.53 (m, 2H), 6.42-6.13 (m, 1H), 5.81-5.32 (m, 1H), 5.23-5.18 (m, 1H),4.93-4.45 (m, 1H), 4.05-3.73 (m, 6H), 3.65-3.54 (m, 1H), 3.43-2.94 (m, 4H),2.12-1.87 (m, 3H), 1.82-1.25 (m, 13H), 1.22-1.04 (m, 3H), 0.52-0.38 (m, 4H)

[0199] HRMS: m / z 1044.3799 (M+H) +

[0200] Synthesis Example 25: Synthesis of Compound FY823

[0201] Following the method of Synthesis Example 11, compound FY823: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(1-cyclopropyl-4-fluoro-1 H -indol-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, yellow solid, yield: 6.6%.

[0202] 1 H NMR (400 MHz, chloroform-) d) δ 11.30 (br. s, 0.77H), 11.26 (br. s,0.26H), 7.89-7.79 (m, 2H), 7.68-7.49 (m, 4H), 7.45-7.39 (m, 1H), 7.32-7.19(m, 2H), 7.20-7.13 (m, 1H), 6.75-6.66 (m, 2H), 6.60-6.52 (m, 1H), 6.40-6.08(m, 1H), 5.81-5.28 (m, 1H), 4.92-4.45 (m, 1H), 3.92-3.76 (m, 2H), 3.65-3.54(m, 1H), 3.43-3.30 (m, 1H), 3.22-2.96 (m, 4H), 1.95-1.87 (m, 1H), 1.82-0.96(m, 18H), 1.21-1.05 (m, 3H)

[0203] HRMS: m / z 988.3418 (M+H) +

[0204] Synthesis Example 26: Synthesis of Compound FY824

[0205] Following the method of Synthesis Example 11, compound FY824: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(3-chloro-1-cyclopropyl-4-fluoro-1) H -indol-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, yellow solid, yield: 2.8%.

[0206] 1 H NMR (400 MHz, chloroform-) d) δ 11.28 (br. s, 1H), 7.90-7.78 (m, 2H), 7.67-7.48 (m, 4H), 7.45-7.30 (m, 2H), 7.15-6.96 (m, 2H), 6.74-6.53(m, 2H),6.41-6.10 (m, 1H), 5.81-5.32 (m, 1H), 4.93-4.45 (m, 1H), 3.92-3.76 (m, 2H),3.64-3.54 (m, 1H), 3.43-3.30 (m, 1H), 3.22-2.96 (m, 4H), 2.26-2.18 (m, 1H),2.07-1.95 (m, 3H), 1.82-1.04 (m, 15H), 1.21-1.05 (m, 3H)

[0207] HRMS: m / z 1022.3027 (M+H) +

[0208] Synthesis Example 27: Synthesis of Compound FY825

[0209] Following the method of Synthesis Example 11, compound FY825 was synthesized: 3-((1 S ,2 S )-1-(5-((S)-2,2-dimethyltetrahydro-2 H -pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-(epoxybutane-3-yl)-1 H -indol-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, yellow solid, yield: 6.1%.

[0210] 1 H NMR (400 MHz, chloroform-) d) δ 11.29 (br. s, 0.77H), 11.26 (br. s,0.26H), 7.94-7.76 (m, 2H), 7.68-7.40 (m, 5H), 7.40-7.20 (m, 3H), 6.80-6.51(m, 3H), 3.92-3.76 (m, 2H), 3.65-3.54(m, 1H), 3.22-2.96 (m, 3H), 2.07-1.97 (m, 1H), 1.95-1.87 (m, 1H), 1.82-1.22(m, 14H), 1.21-1.05 (m, 3H)

[0211] HRMS: m / z 1004.3367 (M+H) +

[0212] Synthesis Example 28: Synthesis of Compound FY826

[0213] Following the method of Synthesis Example 11, compound FY826: 3-((1 S ,2 S )-1-(2-((S)-3-(3-(3-chloro-4-fluoro-1-(epoxybutane-3-yl)-1 H -indol-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, yellow solid, yield: 5.5%.

[0214] 1 H NMR (400 MHz, chloroform-) d) δ 11.29 (br. s, 0.65H), 11.26 (br. s,0.24H), 7.92-7.79 (m, 2H), 7.66-7.40 (m, 5H), 7.38-7.20 (m, 3H), 6.77-6.54(m, 2H), 6.43-6.12 (m, 1H), 5.81-5.28 (m, 1H), 5.56-5.45 (m, 1H), 5.25-5.13(m, 2H), 5.09-4.99 (m, 2H), 4.92-4.43 (m, 1H), 3.92-3.79 (m, 2H), 3.65-3.54(m, 1H), 3.22-2.96 (m, 3H), 2.06-1.97 (m, 1H), 1.95-1.87 (m, 1H), 1.82-1.22(m, 14H), 1.21-1.05 (m, 3H)

[0215] HRMS: m / z 1038.2981 (M+H) +

[0216] Synthesis Example 29: Synthesis of Compound FY828

[0217] Following the method of Synthesis Example 11, compound FY828: 3-((1 S ,2 S )-1-(2-(( S )-3-(3-(1-(1-cyclopropylazetane3-yl)-4-fluoro-1 H -Indazole-5-yl)-2-oxo-2,3-dihydro-1 H -imidazol-1-yl)-4-methyl-2-(4-(pentafluorothio)phenyl)-4,5,6,7-tetrahydro-2 H -pyrazole[4,3-c]pyridine-5-carbonyl)-5-(( S )-2,2-Dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4) H )-ketone, pale yellow solid, yield: 7.8%.

[0218] 1 H NMR (400 MHz, chloroform-) d) δ 11.28 (br. s, 1H), 8.23 ​​(br. s, 0.68H), 8.14 (br. s, 0.25H), 7.94-7.75 (m, 2H), 7.69-7.43 (m, 4H), 7.38-6.96 (m, 3H),6.74-6.53 (m, 2H), 6.44-6.13 (m, 1H), 5.81-5.32 (m, 1H), 5.43-5.18 (m, 1H),4.93-4.45 (m, 1H), 4.20-3.75 (m, 5H), 3.67-3.54 (m, 1H), 3.23-2.96 (m, 3H),2.24-2.20 (m, 1H), 2.07-1.87 (m, 3H), 1.82-1.04 (m, 19H), 0.92-0.78 (m, 2H)

[0219] HRMS: m / z 1044.3789 (M+H) +

[0220] Example 1: h-GLP-1 activity assay (EC) 50 )

[0221] 1. Experimental materials

[0222] (1) Cell line

[0223] (2) Sample information

[0224] Test samples: 5-fold dilution, 9 concentration gradients (50.00 nM, 10.00 nM, 2.000 nM, 0.4000 nM, 0.08000 nM, 0.01600 nM, 0.003200 nM, 0.0006400 nM, 0.0001280 nM).

[0225] Positive control drug: Semaglutide, 5-fold dilution, 9 concentration gradients (50.00 nM, 10.00 nM, 2.000 nM, 0.4000 nM, 0.08000 nM, 0.01600 nM, 0.003200 nM, 0.0006400 nM, 0.0001280 nM).

[0226] 2. Experimental Methods

[0227] The steps for detecting luciferase activity in cells using the luciferase reporter gene method are as follows: (1) Collect cells in the logarithmic growth phase, count them with a cell counter, and adjust the concentration to the required level with culture medium at 30,000 cells per well.

[0228] (2) Add 80 to each well of the 96-well plate. L cell suspension, add 150 ml around the perimeter LPBS.

[0229] (3) Place the laid 96-hole plate at 37°C. Incubate overnight in a C incubator.

[0230] (4) Dilute the test sample and positive control stock solution with the complete culture medium corresponding to the cell line, starting with the initial dilution concentration, and then dilute 5 times to 9 concentrations.

[0231] (5) Take out the 96-well plate, add 20 μL of culture medium containing the drug to be tested per well, and perform 3 replicates for each concentration. Add 20 μL of culture medium (containing the same concentration of solvent) to wells without drug.

[0232] (6) Place the 96-well plate in an incubator and incubate for 6 h.

[0233] (7) Equilibrate the 96-well plate for 30 min at room temperature.

[0234] (8) Add 100 μL of Bio-Luc firefly luciferase reporter gene detection reagent to a 96-well plate, mix and lyse for 5 min, incubate at room temperature for 10 min, and then pipette 150 μL into each well of a white 96-well plate in sequence.

[0235] (9) Use an enzyme-linked immunosorbent assay (ELISA) reader to measure the luminescence signal value.

[0236] 3. Experimental Data Processing and Statistical Analysis

[0237] The data were graphically processed using GraphPad Prism 8.0 software. Four-parameter nonlinear regression analysis was performed to match the appropriate dose-response curves and calculate EC. 50 .

[0238] The results are shown in Table 1, which illustrates the agonistic (EC) effects of the compounds provided in some of the synthetic examples of this invention and the control compound FY111. 50 ).

[0239] Table 1: Experimental results of the agonistic effects of the compounds

[0240] Results and Discussion: As shown in Table 1, the compounds of the present invention exhibit superior agonistic activity against GLP-1 receptors. (“A” means >0 nM and ≤ 20 nM; “B” means > 20 nM and ≤ 100 nM).

[0241] Compound FY111 was obtained according to the method described in Chinese patent application 202411690743.6, and its structure is shown below: .

[0242] Example 2: Pharmacokinetic Study in Mice

[0243] 1. Experimental Materials and Instruments

[0244] CD-1 mice: male, 6-8 weeks old, weighing 25-30 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0245] Liquid chromatography system: SHIMADZU Nexera LC-40D

[0246] Mass spectrometer: AB SCIEX Triple Quad 5500+

[0247] 2. Experimental Methods

[0248] The compound was weighed and dissolved in DMSO-ELP (polyoxyethylene castor oil)-PEG400-0.1 mol / L glycine (pH adjusted to 8 with 0.1 mol / L sodium hydroxide solution). CD-1 mice were administered the test compound via intravenous injection (iv) or oral gavage (po). Blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Plasma was separated by centrifugation, and the concentration of the plasma compound was detected by LC / MS. Pharmacokinetic parameters were calculated using WinNolin 8.3.5 pharmacokinetic software with a non-compartmental model statistical moment method.

[0249] Intravenous dose: 1 mg / kg; Oral gavage dose: 5 mg / kg.

[0250] Assay method: After pretreatment by protein precipitation, quantitative analysis was performed using an LC / MS system.

[0251] 3. Data Processing

[0252] Using WinNonlin 8.3.5 pharmacokinetic software, the statistical moment method of the non-compartmental model was selected to calculate pharmacokinetic parameters, eliminating the half-life T. 1 / 2 Peak time T maxPharmacokinetic parameters such as area under the curve (AUC) were obtained, and the results are shown in Table 2. Table 2 shows the pharmacokinetic parameters of mice administered compound FY801 of the present invention and compound A as a control.

[0253] Table 2. Experimental results of pharmacokinetic parameters of the compounds.

[0254] Results and Discussion: The experimental results show that the compound of the present invention is well absorbed orally in mice. Compared with compound A, it has a higher exposure level (AUC) in both intravenous injection and oral gavage, demonstrating excellent bioavailability.

[0255] Compound A was obtained according to the method described in Chinese patent application 202480003075.7, and its structure is shown below: .

[0256] Example 3: Pharmacokinetic Study in Rats

[0257] 1. Experimental Materials and Instruments

[0258] SD rats: male, 6-8 weeks old, weighing 250-300 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0259] Liquid chromatography system: SHIMADZU Nexera LC-40D

[0260] Mass spectrometer: AB SCIEX Triple Quad 5500+

[0261] 2. Experimental Methods

[0262] The compound was weighed and dissolved in DMSO-ELP (polyoxyethylene castor oil)-PEG400-0.1 mol / L glycine (pH adjusted to 8 with 0.1 mol / L sodium hydroxide solution). SD rats were administered the test compound via intravenous injection (iv) or oral gavage. Blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Plasma was separated by centrifugation, and the compound concentration was detected by LC-MS. Pharmacokinetic parameters were calculated using WinNolin 8.3.5 pharmacokinetic software with a non-compartmental model statistical moment method.

[0263] Intravenous dose: 1 mg / kg; Oral gavage dose: 5 mg / kg.

[0264] Assay method: After pretreatment by protein precipitation, quantitative analysis was performed using an LC / MS system.

[0265] Using WinNonlin 8.3.5 pharmacokinetic software, the statistical moment method of the non-compartmental model was selected to calculate pharmacokinetic parameters, including the eliminated half-life T. 1 / 2 Peak time T max Peak concentration C max Pharmacokinetic parameters such as area under the curve (AUC) were obtained. Results are shown in Table 3, which presents the pharmacokinetic parameters of rats administered compound FY801 of this invention and compound 16 as a control.

[0266] Table 3. Experimental results of pharmacokinetic parameters of the compounds.

[0267] Results and Discussion: The experimental results show that the compounds of this invention are well absorbed orally in rats. Compared with compound B, FY801 has a higher exposure level (AUC), demonstrating excellent bioavailability.

[0268] Compound B was obtained according to the method described in PCT international application PCT / CN2025 / 086812, and its structure is shown below: .

[0269] Example 4: Stability in liver microsomes

[0270] 1. Experimental materials

[0271] 2. Experimental Methods

[0272] 2.1 Transfer 0.800 mL of microsome stock solution, dilute with 15.2 mL of PB to prepare a 2.00 mg / mL microsome working solution; 2.2 Transfer 4.00 μL of the 10.0 mM compound stock solution, dilute it with 396 μL of DMSO, and prepare a 100 μM compound working solution; 2.3 Prepare eight 96-well sample plates, named T0, T5, T15, T30, T45, T60, NCF60 and Blank respectively; 2.4 Add 100 μL of microparticle working solution to the corresponding sample wells of the sample plate; 2.5 For Blank and T0 sample plates, first add 600 μL of stop solution to the corresponding well; second, add 2.00 μL of the solvent and working solution of the compound, respectively; finally, add 98.0 μL of coenzyme factor and shake the sample plate well. 2.6 For T5, T15, T30, T45, T60, and NCF60 sample plates, first add 2.00 μL of the compound working solution to the corresponding well of the sample plate; second, pre-incubate the sample plate in a 37 °C water bath for about 10 min; finally, for T5, T15, T30, T45, and T60 sample plates, add 98.0 μL of coenzyme factor to the corresponding well of the sample plate to start the reaction; for NCF60 sample plates, add 98.0 μL of LPB to the corresponding well of the sample plate to start the reaction. 2.7 After reacting for 5, 15, 30, 45 and 60 minutes, 600 μL of stop solution was added to the corresponding well of the sample plate to terminate the reaction. 2.8 Mix all sample plates thoroughly and centrifuge at 3200×g for 20 minutes; 2.9 Add 100 μL of supernatant to 100 μL of ultrapure water, shake well, and then perform LC-MS / MS analysis.

[0273] 3. Data Processing

[0274] The remaining percentage (residual rate) of the compound is calculated using the following formula:

[0275] T 1 / 2 The formula for calculating (half-life) is as follows:

[0276] CL in vitro The formula for calculating (in vitro clearance rate) is as follows:

[0277] CL int The formula for calculating (intrinsic clearance rate) is as follows:

[0278] CL hep The formula for calculating (liver clearance rate) is as follows:

[0279] In the above formula: liver weight / body weight = 25.7 g / kg; liver blood flow Q = 20.7 mL / min / kg; microsomal protein weight / liver weight = 45.0 mg / g.

[0280] Table 4: Experimental results on the stability of compounds in human liver microparticles

[0281] Note: Testosterone is a control compound. A residual rate exceeding 80.0% at the maximum incubation time is considered within the acceptable range of experimental variation (i.e., CV = 20.0%), therefore the corresponding T... 1 / 2 The reported value is >186 minutes, corresponding to CL. in vitro The reported value is < 7.45 μL / min / mg.

[0282] It should be noted that this application is not limited to the above-described implementation schemes or examples. The above-described implementation schemes and examples are merely illustrative, and any structure or manner that has the same essential technical concept and achieves the same effect within the scope of the technical solution of this application is included within the technical scope of this application.

[0283] Furthermore, without departing from the spirit of this application, various modifications that can be conceived by those skilled in the art to the implementation scheme, and other ways of constructing by combining some of the constituent elements of the implementation scheme, are also included within the scope of this application.

Claims

1. A heterocyclic compound represented by formula (I), Formula (I) Or its pharmaceutically acceptable salt. in: In formula (I) Some selections are made from the following groups: , ,as well as ; R 1 To R 4 and R 6 To R 10 Each of the following groups is independently selected: hydrogen; deuterium; halogen; and C atoms optionally substituted with at least one substituent selected from the group consisting of deuterium and halogen. 1-12 alkyl; R 5 It is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally selected from deuterium, halogen and C. 1-6 At least one substituent is substituted in the group consisting of alkyl groups; Ring A is a cyclopropyl group, which is substituted with 1X-2 and optionally selected from deuterium, halogen, and C. 1-6 At least one substituent in the group consisting of alkyl groups is substituted: ； R 9b Choose the following groups: H; and deuterium; R c Each of the following groups is independently chosen: hydrogen; deuterium; halogens; and C(=O)OR f ; L 1 Choose from the following groups: single bonds; C 1-6 Alkylene; and 3-6-membered heterocyclic alkylene, wherein the heteroatom in the 3-6-membered heterocyclic alkylene is N, and the alkylene and the heterocyclic alkylene are each optionally selected from deuterium, halogen and C. 1-6 At least one substituent is substituted in the group consisting of alkyl groups; R e Choose C freely 3-12 The group consisting of cycloalkyl groups; and 3-6 membered heterocyclic alkyl groups, wherein the cycloalkyl groups and the heterocyclic alkyl groups are each optionally selected from deuterium, halogens and C. 1-6 At least one substituent is substituted in the group consisting of alkyl groups; R f C is a C that is optionally substituted with at least one substituent selected from the group consisting of deuterium and halogens. 1-6 Alkyl groups; and Indicates the connection site.

2. The heterocyclic compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , and .

3. A pharmaceutical composition comprising a heterocyclic compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. Use of the heterocyclic compound of claim 1 or 2 or the pharmaceutical composition of claim 3 in the preparation of a medicament for treating or preventing a disease. The disease mentioned is a GLP-1-related disease.

5. The use according to claim 4, wherein the disease is type 1 diabetes, type 2 diabetes, juvenile-onset atypical diabetes, adolescent-onset adult-onset diabetes, adult-onset latent autoimmune diabetes, obesity, gout, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, transient ischemic attack, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, restenosis, hypertension, intermittent... Sexual claudication, hyperglycemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, alcohol use disorder, metabolic syndrome, premenstrual syndrome, angina pectoris, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, primary polydipsia, nonalcoholic fatty liver disease, inflammatory bowel disease, irritable bowel syndrome, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome, or any combination thereof.

6. The use according to claim 4, wherein the disease is early-onset type 2 diabetes, idiopathic type 1 diabetes, hypertriglyceridemia, hemorrhagic stroke, ischemic stroke, restenosis after angioplasty, hepatic insulin resistance, ulcerative colitis, Crohn's disease, non-alcoholic steatohepatitis, chronic renal failure, glomerulosclerosis, postprandial lipemia, or any combination thereof.

7. The use according to claim 4, wherein the disease is atherosclerotic cardiovascular disease, pulmonary hypertension, diabetic nephropathy, psoriasis, colitis, or any combination thereof.

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