GLP-1 receptor agonists and uses thereof

Abstract

The invention provides a compound as shown in a formula I, or pharmaceutically acceptable salt, stereoisomer or tautomer thereof. The compounds have been demonstrated to be good GLP-1 receptor agonists. In addition, the compound is simple in preparation method and has a certain application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a GLP-1 receptor agonist and uses thereof. Background Art

[0002] Diabetes has become a major public health issue due to its increasing prevalence and associated health risks. A major feature of this disease is the high levels of blood sugar caused by defects in insulin production, insulin action, or both. Two major forms of diabetes have been identified, type 1 and type 2. Type 1 diabetes (T1D) develops when the body's immune system destroys the pancreatic β cells, which are the only cells in the body that make the hormone insulin (regulates blood sugar). In order to survive, people with type 1 diabetes must administer insulin by injection or pump. Type 2 diabetes (commonly known as T2DM) usually begins when insulin resistance occurs or when insulin is not fully produced to maintain acceptable blood sugar levels.

[0003] Various pharmacological approaches are currently available for the treatment of hyperglycemia and, consequently, T2DM (Hampp, C. et al. Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 2014, 37, 1367-1374). These can be grouped into six major categories, each acting through a different primary mechanism: (A) insulin-releasing drugs, including sulfonylureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dulagliptin, d (e.g., utogliptin), linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance insulin secretion by acting on pancreatic β cells. Sulfonyl-ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is also approved for the treatment of obesity. (B) Biguanides (e.g., metformin) are believed to work primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (eg, acarbose) reduce intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones [eg, pioglitazone, rosiglitazone] act on specific receptors (peroxisome proliferator-activated receptor-gamma) in the liver, muscle, and adipose tissue. They modulate lipid metabolism and thereby enhance the responsiveness of these tissues to the action of insulin. Regular use of these drugs may lead to weight gain and may induce edema and anemia.(E) Insulin is used alone or in combination with the aforementioned agents for more severe cases, and regular use may also lead to weight gain and the risk of hypoglycemia. (F) Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dpagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit the reabsorption of glucose in the kidneys and thus lower glucose levels in the blood. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0004] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, these drugs have limited efficacy and do not address the most important issue: the decline in β-cell function and the associated obesity.

[0005] Obesity is a chronic disease, which is highly common and associated with many medical problems in modern society, including hypertension, hypercholesterolemia and coronary heart disease. It is further highly relevant to T2DM and insulin resistance, the latter usually accompanied by hyperinsulinemia or hyperglycemia or both. In addition, T2DM is associated with an increased risk of coronary artery disease by 2 to 4 times. At present, bariatric surgery is the only treatment to eliminate obesity with high efficiency, but the cost of this treatment is expensive and risky. Drug intervention is usually less effective and associated with side effects.

[0006] Therefore, there is a need for more effective pharmaceutical interventions that have fewer side effects and are convenient to administer.

[0007] Although T2DM is most commonly associated with hyperglycemia and insulin resistance, other diseases associated with T2DM include hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and non-alcoholic fatty liver disease (NAFLD).

[0008] NAFLD is the hepatic manifestation of metabolic syndrome and is a spectrum of liver symptoms that encompasses steatosis, nonalcoholic steatosis hepatitis (NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the major fatty liver diseases because they cause the largest proportion of individuals to have elevated liver lipids. The severity of NAFLD / NASH is based on the presence of lipids, inflammatory cell infiltration, hepatocyte ballooning, and the extent of fibrosis. Although not all individuals with steatosis progress to NASH, most do.

[0009] GLP-1 is a 30 amino acid long incretin hormone secreted by intestinal L cells in response to food intake. GLP-1 has been shown to stimulate insulin secretion, reduce glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate beta cell proliferation in a physiological and glucose-dependent manner. In nonclinical trials, GLP-1 promotes sustained beta cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting beta cell neogenesis (Meier et al., Biodrugs. 17(2):93-102, 2013).

[0010] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood sugar levels by stimulating glucose-dependent insulin secretion in the pancreas, thereby increasing peripheral glucose absorption. GLP-1 also inhibits glucagon secretion, which reduces liver glucose excretion. In addition, GLP-1 delays gastric emptying and slows small intestinal motility, thereby delaying food absorption. In people with T2DM, postprandial GLP-1 does not rise normally or the amount of rise is reduced (Vilsboll et al., Diabetes. 50: 609-613, 2001).

[0011] Hoist (Physiol. Rev. 87:1409, 2007) and Meier (Nat. Rev. Endocrinol. 8:728, 2012) describe that GLP-1 receptor agonists (e.g., GLP-1, liraglutide, and exendin-4) have three major pharmacological activities to improve glycemic control in patients with T2DM by lowering fasting and postprandial glucose (FPG and PPG): (i) increased glucose-dependent insulin secretion (improved first and second phases), (ii) glucagon inhibitory activity under hyperglycemic conditions, and (iii) delayed gastric emptying rate, resulting in delayed absorption of meal-derived glucose.

[0012] There remains a need for easily administrable preventive and / or therapeutic agents for cardiometabolic and related diseases. Summary of the invention

[0013] In order to solve the above technical problems, the present invention provides a compound shown in the following formula I, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof:

[0014]

[0015] Wherein, ring A and ring B are the same or different and are independently selected from C 6-12 Aryl or 5-12 membered heteroaryl;

[0016] Ra is independently selected from halogen, OH, COOH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0017] s is 0, 1, 2, 3, 4, or 5;

[0018] R5 is selected from H, OH, COOH, NH2, halogen, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: C 1-12 Alkyl, C 3-12 Cycloalkyl, C 1-12 Alkoxy, -OC 3-12 Cycloalkyl;

[0019] ---Indicates whether two atoms are connected or not;

[0020] When the --- on both sides of ---W--- represent connection, the two Ws are independently selected from O, S, NH, -CH2O- or CH2; X1, X3, X4 are independently selected from N or CH; X2, X5, X6 are selected from C;

[0021] When the --- on both sides of ---W--- means not connected, the W does not exist; X1, X3, X4, X5 are independently selected from N or CH; X2, X6 are selected from C; Rx are independently selected from halogen, OH, COOH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0022] p is 0, 1, 2, or 3;

[0023] Y1 and Y2 are independently selected from N or CH;

[0024] m, n are independently selected from 0, 1 or 2;

[0025] Ry are independently selected from halogen, OH, COOH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C3-12 Cycloalkyl, C 1-12 Alkoxy, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0026] q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0027] L is -S(O)2-, -C(O)- or

[0028] Rz are independently selected from halogen, OH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0029] d is 0, 1, 2, 3, or 4;

[0030] Rb are independently selected from halogen, OH, CN, NH2, oxo (=O), C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, halogenated C 1-12 Alkoxy, halogenated C 3-12 Cycloalkyl, -O-halogenated C 3-12 Cycloalkyl;

[0031] EE is COOH or a carboxyl surrogate, optionally, the carboxyl surrogate is:

[0032]

[0033] R c Selected from hydrogen, deuterium, CN, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 Alkoxy.

[0034] According to an embodiment of the present invention, Formula I is a structure shown in Formula I' below,

[0035]

[0036] wherein Z1, Z3, Z4, and Z6 are independently selected from N or CH; Z2 and Z5 are selected from C;

[0037] Ra, s, ring A, ring B, R5, W, ---, Rx, X1, X2, X3, X4, X5, X6, p, Y1, Y2, m, n, Ry, q, Rz, L, d, and EE are as defined above.

[0038] According to an embodiment of the present invention, in Formula I', Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0039] Ra are independently selected from halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0040] s is 0, 1, 2, 3, 4, or 5;

[0041] R5 is selected from H or C 1-6 alkyl;

[0042] ---Indicates whether two atoms are connected or not;

[0043] When the --- on both sides of ---W--- represent connection, the two Ws are independently selected from O, S, NH, -CH2O- or CH2; X1, X3, X4 are independently selected from N or CH; X2, X5, X6 are selected from C;

[0044] When the --- on both sides of ---W--- indicates no connection, the W does not exist; X1, X3, X4, X5 are independently selected from N or CH; X2, X6 are selected from C; Rx is selected from halogen; p is 0, 1, 2 or 3;

[0045] Y1, Y2 are selected from N;

[0046] m, n are independently selected from 0, 1 or 2;

[0047] Ry is selected from C 1-6 Alkyl; q is 0, 1 or 2;

[0048] L is -S(O)2-;

[0049] Z1, Z3, Z4, Z6 are independently selected from N or CH; Z2 and Z5 are selected from C;

[0050] Rz are independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or -OC 3-6 Cycloalkyl;

[0051] d is 1, 2, or 3;

[0052] EE is COOH.

[0053] According to an embodiment of the present invention, the compound represented by formula I or I' is selected from the compound IX shown below:

[0054]

[0055] Among them, Ra, s, ring A, R5, W, ---, Rx, p, m, n, Ry, q, Z1, Z2, Z3, Z4, Z5, Z6, Rz, and d have the definitions as described above.

[0056] According to an embodiment of the present invention, the compound represented by formula I is selected from compound IY shown below:

[0057]

[0058]

[0059] wherein Ra, s, ring A, R5, W, ---, Rx, p, m, n, Ry, q, Rz, and d have the same definitions as above.

[0060] In some embodiments of the present invention, when the --- on both sides of ---W--- represents connection, and when R5 is selected from C 1-6 When alkyl is present, the formula IY is further represented by the following formula IY':

[0061]

[0062] wherein Ra, s, ring A, R5, W, ---, Rx, p, m, n, Ry, q, Rz, and d have the same definitions as above.

[0063] According to a preferred embodiment of the present invention, the compound represented by formula I is selected from the compounds IZ shown below:

[0064]

[0065] wherein Ra, s, ring A, R5, W, Rx, p, m, n, Ry, q, Rz, and d have the same meanings as described above.

[0066] According to a preferred embodiment of the present invention, the compound represented by formula I is selected from the compounds IZ' shown below:

[0067]

[0068]

[0069] wherein Ra, s, ring A, R5, W, Rx, p, m, n, Ry, q, Rz, and d have the same meanings as described above.

[0070] According to an embodiment of the present invention, the ring A is selected from phenyl or 5-6 membered heteroaryl, for example, ring A is selected from phenyl or pyridyl.

[0071] In some embodiments of the present invention, when the --- on both sides of ---W--- represents connection, and when R5 is selected from C 1-6 When the carbon atoms are alkyl, the carbon atoms connected to two W atoms and R5 are chiral carbon atoms. 1-6 The alkyl group is out of plane, while the other substituent attached to the C faces into the plane.

[0072] According to an embodiment of the present invention, the halogenated C 1-12 Alkyl or halogenated C 1-12 Alkoxy is substituted by F or Cl, and the substitution is substituted by 1, 2, 3 or 4 halogens, such as trifluoromethyl or

[0073] According to an embodiment of the present invention, the W is the same and is selected from O or CH2, preferably both are O.

[0074] According to an embodiment of the present invention, the halogen is preferably F or Cl.

[0075] According to an embodiment of the present invention, the compound of formula I is selected from the compounds shown in the following Ia, Ib, Ic or Id:

[0076]

[0077]

[0078] In the compound represented by Ia, Ib, Ic or Id:

[0079] Ra are the same or different and are independently selected from F, Cl, CN, methoxy, trifluoromethyl, and two Ra in the same general formula are the same or different;

[0080] R5 is methyl;

[0081] Rz are the same or different and are independently F, methoxy, -O-cyclopropyl, Ethyl, ethoxy;

[0082] X is selected from CH, CRa or N; Ra is as defined above;

[0083] Rx is F;

[0084] p is 0 or 1; Ry is methyl;

[0085] q is 0 or 1;

[0086] m and n are each independently selected from 0, 1 or 2, and m and n are not 0 at the same time.

[0087] In a preferred embodiment, in Ia, Ra are the same or different and are independently F, Cl, or CN.

[0088] In a preferred embodiment, in Ia, Rz are the same or different and are independently methoxy or -O-cyclopropyl; for example, one is methoxy and the other is -O-cyclopropyl, or both are methoxy and -O-cyclopropyl.

[0089] In a preferred embodiment, in Ib, X is selected from CH, CRa or N; Ra is the same or different and independently selected from F, Cl, CN, methoxy, trifluoromethyl; R5 is methyl; Rx is F; Ry is methyl.

[0090] In a preferred embodiment, in Ib, Rz are the same or different and are independently selected from methoxy, -O-cyclopropyl, Ethyl, ethoxy.

[0091] In a preferred embodiment, in Ic, X is selected from CH, CRa or N; Ra is the same or different and independently selected from F, Cl, CN, methoxy, trifluoromethyl; and R5 is methyl.

[0092] In a preferred embodiment, in Ic, Rz are the same or different and are independently selected from methoxy, -O-cyclopropyl, ethoxy.

[0093] In a preferred embodiment, in Id, X is selected from CH, CRa or N; Ra is the same or different and independently selected from F, Cl, CN, methoxy, trifluoromethyl; R5 is methyl; Rx is F; Ry is methyl; Rz is the same or different and independently selected from F, methoxy, -O-cyclopropyl, ethoxy.

[0094] As an example, the compound is selected from the following:

[0095]

[0096]

[0097]

[0098] The present invention also provides a method for preparing the compound represented by formula I, comprising the following steps:

[0099] Compound I-1 reacts with compound I-2 to obtain compound I;

[0100] Wherein, Ra, s, Ring A, Ring B, R5, W, ---, Rx, X1, X2, X3, X4, X5, X6, p, Y1, Y2, m, n, Ry, q, Rz, L, d, EE have the definitions as described above;

[0101] Ld is selected from a leaving group, such as a halogen.

[0102] The present invention also provides a pharmaceutical composition, which comprises the compound as described above or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable excipient.

[0103] The present invention also provides the use of the above compound or its pharmaceutically acceptable salt, stereoisomer or tautomer in the preparation of a drug for treating cardiac metabolism and related diseases, wherein the cardiac metabolism and related diseases are T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral fat accumulation, sleep apnea, obesity , dietary abnormalities, weight gain caused by the use of other medications, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular incompliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease Disease), left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, poor glucose metabolism, poor fasting glucose symptoms, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, apo B hyperlipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome and treatment of addiction.

[0104] Beneficial Effects

[0105] The present invention provides a new type of aromatic compound, which is proved to be a good GLP-1 receptor agonist. In addition, the preparation method of the compound is simple and has certain application prospects.

[0106] Definitions and explanations of terms

[0107] Partial Substituents The ligation sites are indicated.

[0108] In this document, the term "halogen" means fluorine, chlorine, bromine and / or iodine. Correspondingly, the term "halo" refers to fluoro, chloro, bromo and / or iodo. Within the scope of this document, when an atom, residue, group or moiety is halogenated, the atom at the halogenated position may be monosubstituted, disubstituted or polysubstituted up to full substitution by halogen atoms, for example, "halo C 1-12 Alkyl" and "halogenated C 1-12 Alkoxy" etc.

[0109] The term "C 1-12 "Alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably C 1-6 Alkyl. "C 1-6 “Alkyl” is understood as meaning preferably a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the radical has 1, 2 or 3 carbon atoms (“C 1-3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0110] The term "C 3-12"Cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or polycyclic hydrocarbon ring (also called condensed hydrocarbon ring) having 3-12 carbon atoms. Bicyclic or polycyclic cycloalkyl groups include paracyclic cycloalkyl, bridged cycloalkyl and spirocyclic cycloalkyl; the paracyclic refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing one bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spirocyclic refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. For example, the C 3-20 The cycloalkyl group may be C 3-8 Monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C 7-12 Cycloalkyl ring, such as decalin ring.

[0111] The term "3-12 membered heterocyclyl" means a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl.

[0112] The term "C 6-12 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0113] The term "5-12 membered heteroaryl" is to be understood as including monovalent mono-, bi- or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contain 1 to 5, preferably 1 to 3 heteroatoms which are each independently selected from N, O and S and which, in addition, in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0114] Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, pyridyl or pyridylene includes pyridine-2-yl, pyridine-2-yl, pyridine-3-yl, pyridine-3-yl, pyridine-4-yl and pyridine-4-yl; thienyl or thienylene includes thien-2-yl, thien-2-yl, thien-3-yl and thien-3-yl.

[0115] The above term “C 1-12 The definition of "alkyl" also applies to groups containing "C 1-12 Other terms for "alkyl", such as the term "halo-C 1-12 Alkyl" or "C 1-12 Alkoxy" or "halogenated C 1-12 Alkoxy" and so on.

[0116] As used herein, "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0117] Pharmaceutically acceptable salts include acid addition salts of compounds of the invention having nitrogen atoms in the chain or ring with sufficient basicity. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, physiologically / pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc.

[0118] According to their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. These compounds may thus exist in racemic form or in optically active form. The compounds of the present invention or their intermediates may be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with optically active resolution agents. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in the R and S forms. Chromatographic enantiomer resolution may also be advantageously performed with the aid of optically active resolution agents (e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0119] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0120] In this application, "abs" means a single configuration. DETAILED DESCRIPTION

[0121] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0122] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0123] Preparation Example 1: Intermediate Compound A

[0124]

[0125] The intermediate compound A-1 (10.0 g, 34.01 mmol) was dissolved in acetonitrile (100 mL), and iodomethane (6.35 mL, 102.03 mmol) and potassium carbonate (23.5 g, 170.05 mmol) were added. The reaction solution was heated to 50 ° C and stirred for 2 hours. After the reaction solution was cooled to room temperature, it was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to obtain the target product intermediate compound A-2 (8.8 g, yield 80%). 1 H NMR (400MHz, CDCl3) δ = 7.17 (s, 2H), 3.95 (s, 6H), 3.94 (s, 3H).

[0126] Under nitrogen atmosphere, the intermediate compound A-2 (4.8 g, 14.90 mmol) was dissolved in dioxane (50 mL), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1725 mg, 2.98 mmol, CAS NO: 161265-03-8), tris(dibenzylideneacetone)dipalladium (1364 mg, 1.49 mmol), N,N-diisopropylethylamine (5778 mg, 44.71 mmol) and benzyl mercaptan (17.46 mL, 149.02 mmol) were added. The reaction solution was heated to 100 ° C and stirred for 16 hours. The reaction solution was then concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to obtain the target product intermediate compound A-3 (4.6 g, yield 97%). 1H NMR (400MHz,CDCl3)δ=7.25-7.10(m,7H),4.06(s,2H),3.92(s,3H),3.86(s,6H).Intermediate compound A-3 (4.6g,14.45mmol) was dissolved in acetic acid / tetrahydrofuran / water (V=8:1:1) (50mL), and N-chlorosuccinimide (4.1g,30.70mmol) was added. The reaction solution was stirred at room temperature for 2 hours. Diluted with water (40mL), extracted with ethyl acetate (50mL x 2). The organic phases were combined, washed with saturated brine (150mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate=100 / 0 to 5 / 1) to obtain the target product intermediate compound A (2.5g, yield 59%). 1 H NMR (400MHz, CDCl3) δ = 7.31 (s, 2H), 4.04 (s, 6H), 3.98 (s, 3H).

[0127] Preparation Example 2: Intermediate Compound B

[0128]

[0129] Dissolve the intermediate compound B-1 (200 mg, 0.92 mmol) in N, N-dimethylformamide (10 mL), add cyclopropyl-1-ol (48 mg, 0.83 mmol) and cesium carbonate (300 mg, 0.92 mmol). The reaction solution was stirred at 50 ° C for 16 hours under nitrogen protection. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to obtain the target product intermediate compound B-2 (130 mg, yield 55%). 1 H NMR (400MHz, CDCl3) δ=7.91-7.81(m,1H),7.53-7.48(m,1H),3.99-3.95(m,4H),0.95-0.84(m,4H).

[0130] The intermediate compound B-2 (1800 mg, 7.05 mmol) was dissolved in dimethyl sulfoxide (12 mL), and an aqueous sodium hydroxide solution (4 mL, 5 N) was added. The reaction solution was stirred at 60 ° C for 16 hours under nitrogen protection. The reaction solution was diluted with water (10 mL), and the pH of the reaction solution was adjusted to 3-4 with 4N HCl and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was dissolved in N, N-dimethylformamide (20 mL), and iodomethane (1.03 mL, 16.56 mmol) and cesium carbonate (7.36 g, 22.58 mmol) were added. The reaction solution was stirred at room temperature for 16 hours under nitrogen protection. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The target product intermediate compound B-3 (1800 mg, yield 96%) was obtained by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 6 / 1). 1 H NMR (400MHz, CDCl3) δ = 7.63 (d, J = 1.2Hz, 1H), 7.33 (d, J = 1.2Hz, 1H), 3.96-3.90 (m, 7H), 0.85-0.83 (m, 4H).

[0131] The intermediate compound B-3 (1.8 g, 6.81 mmol) was dissolved in ethanol (40 mL) and water (4 mL), and iron powder (1.9 g, 34.06 mmol) and ammonium chloride (3.6 g, 67.30 mmol) were added. The reaction solution was stirred at 75 ° C for 1 hour under nitrogen protection. The reaction solution was filtered while hot, concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 6 / 1) to obtain the target product intermediate compound B-4 (1.4 g, yield 87%). LC-MS (ESI + ):m / z 238.0(M+H) + .

[0132] Dissolve the intermediate compound B-4 (1.4 g, 5.90 mmol) in acetonitrile (10 mL), add copper bromide (1318 mg, 5.90 mmol) and tert-butyl nitrite (1217 mg, 11.80 mmol). The reaction solution was stirred at 65 ° C for 0.5 hours under nitrogen protection. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product intermediate compound B-5 (405 mg, yield 23%). 1 H NMR (400MHz, CDCl3) δ = 7.48 (d, J = 1.6Hz, 1H), 7.16 (d, J = 1.6Hz, 1H), 3.95-3.88 (m, 7H), 0.95-0.80 (m, 4H).

[0133] The intermediate compound B-5 (405 mg, 1.35 mmol) was dissolved in dioxane (15 mL), and benzyl mercaptan (0.24 mL, 2.02 mmol), tris(dibenzylideneacetone)dipalladium (123 mg, 0.14 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (156 mg, 0.27 mmol, CAS NO: 161265-03-8) and N,N-diisopropylethylamine (521 mg, 4.04 mmol) were added. The reaction solution was stirred at 100 ° C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 19 / 1) to obtain the target product intermediate compound B-6 (200 mg, yield 43%). LC-MS (ESI+): m / z 345.2 (M+H) + .

[0134] Under ice bath, the intermediate compound B-6 (220 mg, 0.64 mmol) was dissolved in tetrahydrofuran (1 mL), acetic acid (10 mL) and water (1 mL), and N-chlorosuccinimide (179 mg, 1.34 mmol) was added. The reaction solution was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to obtain the target product intermediate compound B (180 mg, yield 88%).

[0135] Preparation Example 3: Intermediate Compound C

[0136]

[0137] Under ice bath, cyclopropyl-1-ol (4.68mL, 79.83mmol) was dissolved in tetrahydrofuran (50mL), and sodium hydrogen (5.2g, 128.97mmol, 60%) was slowly added. The reaction solution was stirred in an ice bath under nitrogen protection for 0.5 hours, and then the intermediate compound C-1 (7.0g, 32.24mmol) was added. The reaction solution was stirred at room temperature under nitrogen protection for 2 hours. Under ice bath, the reaction solution was quenched with water (100mL), and then the pH value of the reaction solution was adjusted to 4 with 4N HCl aqueous solution, and the mixture was extracted with ethyl acetate (50mL x2). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product intermediate compound C-2 (6.0g, yield 67%). LC-MS (ESI - ):m / z 278.0(MH) - .

[0138] The intermediate compound C-2 (6.0 g, 21.49 mmol) was dissolved in N, N-dimethylformamide (60 mL), and iodomethane (6.69 mL, 107.45 mmol) and cesium carbonate (21.0 g, 64.47 mmol) were added. The reaction solution was stirred at room temperature for 16 hours under nitrogen protection. The reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (60 mL x 2). The organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The target product intermediate compound C-3 (4.4 g, yield 70%) was obtained by silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 9 / 1). 1 H NMR (400MHz, CDCl3) δ = 7.64 (s, 2H), 3.97 (s, 3H), 3.97-3.84 (m, 2H), 0.96-0.75 (m, 8H).

[0139]

[0140] The synthesis method of intermediate compound C is similar to that of intermediate compound B, wherein intermediate compound B-3 is replaced by intermediate compound C-3. The crude product of the last step was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to obtain the target product intermediate compound C (140 mg, yield 50%) and was directly used in the next step.

[0141] Preparation Example 4: Intermediate Compound D

[0142]

[0143] Dissolve the intermediate compound D-1 (10.0 g, 50.22 mmol) in N,N-dimethylformamide (60 mL), add cyclopropyl-1-ol (4.77 mL, 81.40 mmol) and cesium carbonate (24.5 g, 75.32 mmol). The reaction solution was stirred at 75 ° C for 16 hours under nitrogen protection. The reaction solution was filtered and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product intermediate compound D-2 (3.5 g, yield 29%). 1 H NMR (400MHz, DMSO-d6) δ = 8.07 (d, J = 1.6 Hz, 1H), 7.99 ( d, J = 8.4 Hz, 1H), 7.71-7.6 9(m,1H),4.30-4.20(m,1H),3.92(s,3H),0.95-0.86(m,2H),0.78-0.73(m,2H).

[0144] The intermediate compound D-2 (4.0 g, 16.86 mmol) was dissolved in ethanol (40 mL) and water (4 mL), and iron powder (4.7 g, 84.32 mmol) and ammonium chloride (9.0 g, 168.63 mmol) were added. The reaction solution was stirred at 75 ° C for 1 hour under nitrogen protection. The reaction solution was filtered while hot, concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product intermediate compound D-3 (3.0 g, yield 86%). LC-MS (ESI+): m / z 208.3 (M+H) + .

[0145] Under ice bath, the intermediate compound D-3 (3.1 g, 14.96 mmol) was dissolved in dichloromethane (30 mL), and N-bromosuccinimide (2.7 g, 14.96 mmol) was added. The reaction solution was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 11 / 1) to obtain the target product intermediate compound D-4 (3.6 g, yield 84%). LC-MS (ESI+): m / z 286.2 (M+H) + .

[0146] The intermediate compound D-4 (3.7 g, 12.93 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), and triethylboron (38.80 mL, 38.80 mmol, 1 M tetrahydrofuran solution), cataCXium A Pd G3 (942 mg, 1.29 mmol, CASNO: 1651823-59-4) and potassium phosphate (8237 mg, 38.80 mmol) were added. The reaction solution was stirred at 80 ° C for 16 hours under nitrogen protection. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column (silica, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product intermediate compound D-5 (2.0 g, yield 66%). LC-MS (ESI+): m / z 236.1 (M+H) + .

[0147]

[0148] The synthesis method of intermediate compound D is similar to that of intermediate compound B, wherein intermediate compound B-4 is replaced by intermediate compound D-5. The crude product of the last step was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product intermediate compound D (126 mg, yield 91%) and was directly used in the next step reaction.

[0149] Preparation Example 5: Intermediate Compound E

[0150]

[0151] The intermediate compound E-1 (1.0 g, 3.24 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (2.1 g, 6.50 mmol) and iodoethane (507 mg, 3.25 mmol) were added. The reaction solution was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 20 / 1) to obtain the target product intermediate compound E-2 (850 mg, yield 78%). LC-MS (ESI + ):m / z336.9(M+H) + . 1HNMR (400MHz, CDCl3) δ = 7.20-7.10 (m, 2H), 4.21-4.14 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 1.51 (t, J = 7.0Hz, 3H).

[0152]

[0153] The synthesis method of intermediate compound E is similar to that of intermediate compound A, wherein intermediate compound A-2 is replaced by intermediate compound E-2. The crude product of the last step was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product intermediate compound E (350 mg, yield 53%). 1 H NMR (400MHz, DMSO-d6) δ = 7.14 (s, 2H), 4.11-4.01 (m, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 1.31-1.24 (m, 3H).

[0154] Preparation Example 6: Intermediate Compound F

[0155]

[0156] The intermediate compound F-1 (300 mg, 0.97 mmol) was dissolved in N, N-dimethylformamide (7 mL), and sodium difluorochloroacetate (371 mg, 2.43 mmol) and cesium carbonate (635 mg, 1.95 mmol) were added. The reaction solution was stirred at 100 ° C for 2 hours under nitrogen protection. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 3 / 1) to obtain the target product intermediate compound F-2 (190 mg, yield 55%). 1 H NMR (400MHz, CDCl3) δ = 7.42 (s, 1H), 7.35 (s, 1H), 6.58 (t, J = 73.0Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H).

[0157]

[0158] The synthesis method of intermediate compound F is similar to that of intermediate compound A, wherein intermediate compound A-2 is replaced by intermediate compound F-2. The crude product of the last step was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product intermediate compound F (99 mg, yield 63%) and was directly used in the next step reaction.

[0159] Preparation Example 7: Intermediate Compound G

[0160]

[0161] The intermediate compound G-1 (5.0 g, 33.99 mmol) was dissolved in N, N-dimethylformamide (20 mL), and N-bromosuccinimide (6655 mg, 37.39 mmol) was slowly added at 0°C. The reaction solution was stirred at 0°C for 1 hour. The reaction solution was diluted with water (60 mL) and extracted with dichloromethane (60 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 20 / 1) to obtain the target product intermediate compound G-2 (6.8 g, yield 89%). 1 H NMR (400MHz, CDCl3) δ = 7.10-6.99 (m, 1H), 3.88 (s, 2H).

[0162] Dissolve the intermediate compound G-2 (6.8 g, 30.09 mmol) in acetic acid (200 mL), and slowly add a solution of sodium perborate (15.3 g, 150.25 mmol) in acetic acid (100 mL). Stir the reaction solution at 55 ° C for 2 hours. Dilute the reaction solution with water (80 mL) and extract with ethyl acetate (80 mL x 3). Combine the organic phases, wash with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was chromatographed on a silica gel column (silica, petroleum ether / ethyl acetate = 100 / 0 to 20 / 1) to obtain the target product intermediate compound G-3 (3420 mg, yield 44%). 1H NMR (400MHz,CDCl3)δ=7.41-7.38(m,1H).Intermediate compound G-3 (2700mg,10.55mmol) was dissolved in methanol (30mL), and sodium methoxide (2278mg,42.19mmol) solid was added. The reaction solution was stirred at 50°C for 16 hours. The reaction solution was diluted with water (30mL) and extracted with ethyl acetate (30mL x 3). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate=100 / 0 to 10 / 1) to obtain the target product intermediate compound G-4 (2180mg, yield 74%). 1 H NMR (400MHz, CDCl3) δ = 6.83 (d, J = 4.8Hz, 1H), 3.98 (d, J = 2.4Hz, 3H), 3.80 (s, 3H).

[0163] The intermediate compound G-4 (2180 mg, 7.79 mmol) was dissolved in methanol (25 mL), and DPPF palladium dichloride (565 mg, 0.78 mmol, CAS No: 72287-26-4) and triethylamine (1576 mg, 15.57 mmol) were added. The reaction solution was stirred at 110 ° C for 16 hours under a carbon monoxide atmosphere. After cooling to room temperature, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 8 / 1) to obtain the target product intermediate compound G-5 (490 mg, yield 24%). 1 H NMR (400MHz, CDCl3) δ = 7.03 (d, J = 5.6Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H).

[0164]

[0165] The synthesis method of intermediate compound G is similar to that of intermediate compound B, wherein intermediate compound B-3 is replaced by intermediate compound G-5. The crude product of the last step was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 5 / 1) to obtain the target product intermediate compound G (140 mg, yield 51%) and was directly used in the next step reaction.

[0166] Preparation Example 8: Intermediate Compound H

[0167]

[0168] The intermediate compound H-1 (2.3 g, 13.29 mmol) was dissolved in N, N-dimethylformamide (40 mL), and 4-chloro-2-fluorobenzyl bromide (3.0 g, 13.42 mmol), potassium carbonate (6.5 g, 46.98 mmol) and potassium iodide (1.1 g, 6.71 mmol) were added. The reaction solution was heated to 90 ° C under nitrogen protection and stirred for 1 hour. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether) to obtain the target product intermediate compound H-2 (2.6 g, yield 62%). 1 H NMR (400MHz, CDCl3) δ=7.49–7.35(m,1H),7.18-7.05(m,5H),6.9-6.87(m,1H),5.05(s,2H).

[0169] The intermediate compound H-2 (300 mg, 0.95 mmol) and tert-butyl piperazine-1-carboxylate (177 mg, 0.95 mmol), sodium tert-butoxide (137 mg, 1.43 mmol), palladium acetate (107 mg, 0.48 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-naphthalene (36 mg, 0.057 mmol) were dissolved in anhydrous dioxane (8 mL). The reaction solution was heated to 90 ° C under nitrogen protection and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to obtain the target intermediate compound H-3 (270 mg, yield 67%). LCMS: MS m / z (ESI) [M+H] + =421.1. 1 H NMR(400MHz, CDCl3)δ=7.51–7.41(m,1H),7.20-7.11(m,4H),6.57-6.48(m, 2H),5.07(s,2H),3.57(t,J=5.0Hz,4H),3.13(t,J=4.8Hz,4H),1.48(s,9H).

[0170] The intermediate compound H-3 (270 mg, 0.64 mmol) was dissolved in 4M hydrochloric acid / 1,4-dioxane (5 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain the target product intermediate compound H (220 mg, crude product). LCMS: MS m / z (ESI) [M+H] + =321.1.

[0171] Example 1

[0172]

[0173] The intermediate compound H (50 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and the intermediate compound A (46 mg, 0.16 mmol) and triethylamine (47 mg, 0.46 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 2 / 1) to obtain the target product 1-1 (16 mg, yield 18%). LC-MS (ESI+): m / z 579.1 (M+H) + .

[0174] Compound 1-1 (16 mg, 0.028 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide monohydrate (6 mg, 0.14 mmol) was added. The reaction solution was stirred at room temperature under nitrogen protection for 16 hours. The reaction solution was diluted with water (3 mL) and the pH value of the reaction solution was adjusted to 5-6 with 2 mol / L hydrochloric acid, and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 20%-50%, 20 minutes) to obtain the target product 1. LCMS: MS m / z (ESI+) [M+H] + =565.0; 1H NMR (400MHz, DMSO-d6)δ=7.65-7.55(m,1H),7.51-7.45(m,1H),7.36-7.33(m,1H),7.22(s,2H),7.1 9-7.04(m,1H),6.59-6.53(m,2H),6.49-6.44(m,1H),5.09(s,2H),3.82(s,6H),3.28-3.18(m,8H).

[0175] Example 4

[0176]

[0177] Compound 4-1 (50 mg, 0.16 mmol) was dissolved in dichloromethane (5 mL), and intermediate compound A (57 mg, 0.19 mmol) and triethylamine (48 mg, 0.47 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel plate (silica, petroleum ether / ethyl acetate = 2 / 1) to obtain the target product 4-2 (50 mg, yield 55%). LC-MS (ESI+): m / z 570.1 (M+H) + .

[0178] Compound 4-2 (50 mg, 0.088 mmol) was dissolved in acetonitrile (2.5 mL) and water (0.5 mL), and lithium bromide (21 mg, 0.24 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were added at 0°C. The reaction solution was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was diluted with water (8 mL), the pH of the reaction solution was adjusted to 4 with 4N HCl, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 0%-100%, 9 minutes) to obtain the target product 4. 1H NMR (400MHz, DMSO-d6) δ=7.92-7.88(m,1H),7.80-7.70(m,2H),7.23(d,J=5.2Hz,2H),7.16-7.11(m,1H) ,6.59-6.56(m,2H),6.52-6.42(m,1H),5.28-5.16(m,2H),3.83(s,3H),3.81(s,3H),3.22-3.19(m,8H).

[0179] Example 5

[0180]

[0181] Compound 5-1 (1236 mg, 6.54 mmol) was dissolved in toluene (6 mL), and 5-chloro-2-ethynylpyridine (900 mg, 6.54 mmol) and triruthenium dodecacarbonyl (84 mg, 0.13 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on a silica gel column (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 19 / 1) to obtain the target product 5-2 (800 mg, yield 37%). 1 H NMR (400MHz, CDCl3) δ = 8.63 (d, J = 2.0Hz, 1H), 7.72-7.69 (m, 1H), 7.61 (d, J = 8.4Hz, 1H), 6.98-6.93 (m, 1H), 6.77-6.70 (m, 2H), 2.11 (s, 3H).

[0182] Compound 5-2 (800 mg, 2.45 mmol) was dissolved in dioxane (6 mL), and 1-Boc-piperazine (456 mg, 2.45 mmol), 2,2'-bis(diphenylphosphino)-1,1'-naphthalene (305 mg, 0.49 mmol), palladium acetate (110 mg, 0.49 mmol) and sodium tert-butoxide (353 mg, 3.68 mmol) were added. The reaction solution was heated to 90 ° C under nitrogen protection and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column (silica, petroleum ether / ethyl acetate = 100 / 0 to 7 / 3) to obtain the target product 5-3 (240 mg, yield 23%). LC-MS (ESI+): m / z 432.2 (M+H)+ .

[0183] Compound 5-3 (240 mg, 0.56 mmol) was dissolved in dioxane (2 mL), and hydrochloric acid / dioxane (4 M, 5 mL) solution was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and dried to obtain the target product 5-4 (184 mg, yield 100%). LC-MS (ESI+): m / z 332.1 (M+H) + .

[0184] Compound 5-4 (100 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), and intermediate compound B (97 mg, 0.30 mmol) and triethylamine (92 mg, 0.91 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 2 / 1) to obtain the target product 5-5 (80 mg, yield 43%). LC-MS (ESI+): m / z 616.1 (M+H) + .

[0185] Compound 5-5 (80 mg, 0.13 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide monohydrate (27 mg, 0.65 mmol) was added. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was diluted with water (10 mL), the pH of the reaction solution was adjusted to 4 with 4N HCl, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 0%-100%, 9 minutes) to obtain the target product 5. LC-MS (ESI + ):m / z 602.0(M+H) + . 1HNMR (400MHz, DMSO-d6) δ=8.71(d,J=2.4Hz,1H),8.05-7.95(m,1H),7.69-7.52(m,2H),7.27(s,1H),6.84–6.72(m,1H),6.57(d,J=8.0 Hz,1H),6.48(d,J=8.8Hz,1H),4.06-4.03(m,1H),3.89(s,3H),3.25-3.24(m,4H),3.17-3.11(m,4H),2.00(s,3H),0.86-0.73(m,4H).

[0186] Example 8

[0187]

[0188] The intermediate compound J (460 mg, 1.34 mmol) was dissolved in toluene (5 mL), and 1-Boc-piperazine (274 mg, 1.47 mmol), 2,2'-bis(diphenylphosphino)-1,1'-dinaphthalene (167 mg, 0.27 mmol), tris[dibenzylideneacetone]dipalladium (123 mg, 0.13 mmol) and cesium carbonate (872 mg, 2.68 mmol) were added. The reaction solution was heated to 90 ° C under nitrogen protection and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to obtain the target product 7-1 (96 mg, yield 16%). LC-MS (ESI+): m / z 449.1 (M+H) + .

[0189]

[0190] Compound 7-1 (50 mg, 0.11 mmol) was dissolved in dioxane (2 mL), and hydrochloric acid / dioxane (5 mL, 4 M) solution was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and dried to obtain the target product 8-1 (39 mg, yield 100%). LC-MS (ESI+): m / z 349.1 (M+H) + .

[0191] Compound 8-1 (200 mg, 0.57 mmol) was dissolved in dichloromethane (8 mL), and intermediate compound A (203 mg, 0.68 mmol) and triethylamine (174 mg, 1.71 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (15 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on a silica gel column (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 7 / 3) to obtain the target product 8-2 (297 mg, yield 86%). LC-MS (ESI+): m / z 607.1 (M+H) + .

[0192] Compound 8-2 (297 mg, 0.49 mmol) was subjected to supercritical fluid chromatography (SFC) (column: OJ 100*3mm 3μm; injection volume: 0.50μL, mobile phase: Supercritical CO2 / MeOH (0.1% DEA) = 85 / 15, flow rate: 1.5mL / min, wavelength: 214nm, column temperature: 35°C, retention time: 2.405min) to prepare the target product 8-3 (120mg, yield 41%). 1 H NMR(400MHz, CDCl3)δ=7.55-7.45(m,1H),7.29(s,2H),7.14-7.09(m,2H),6.84–6.72(m,1H),6.58-6.53 (m,1H),6.43-6.38(m,1H),3.97(s,6H),3.96(s,3H),3.49-3.46(m,4H),3.27-3.21(m,4H),2.05(s,3H).

[0193] Compound 8-3 (120 mg, 0.20 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide monohydrate (25 mg, 0.59 mmol) was added. The reaction solution was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was diluted with water (5 mL), the pH of the reaction solution was adjusted to 5 with 6N HCl, and then extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Boston Prime C18150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 0%-30%, 9 minutes) to obtain the target product 8. LC-MS (ESI+): m / z 593.0 (M+H) +1H NMR (400MHz, DMSO-d6) δ = 13.60 (br.s, 1H), 7.58-7.53 (m, 2H), 7.34-7.32 (m, 1H), 7.26 (s, 2H), 6.87-6.70 (m ,1H),6.59-6.57(m,1H),6.49-6.47(m,1H),3.89(s,6H),3.32-3.28(m,4H),3.19-3.15(m,4H),2.00(s,3H).

[0194] Example 10

[0195]

[0196] Compound 7-1 (150 mg, 0.33 mmol) was dissolved in N, N-dimethylacetamide (3 mL), and zinc cyanide (196 mg, 1.67 mmol), cuprous iodide (64 mg, 0.33 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (24 mg, 0.033 mmol, CAS NO: 72287-26-4) and zinc powder (13 mg, 0.20 mmol) were added. The reaction solution was heated to 120 ° C under nitrogen protection and stirred for 48 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column (silicon dioxide, petroleum ether / ethyl acetate = 10 / 1) to obtain the target product 10-1 (37 mg, yield 25%). LC-MS (ESI+): m / z 440.1 (M+H) + .

[0197] Compound 10-1 (50 mg, 0.11 mmol) was dissolved in dioxane (3 mL), and hydrochloric acid / dioxane (5 mL, 4 M) solution was added. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and dried to obtain the target product 10-2 (39 mg, yield 100%). LC-MS (ESI+): m / z 340.3 (M+H) + .

[0198] Compound 10-2 (39 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), and intermediate compound A (36 mg, 0.12 mmol) and triethylamine (34 mg, 0.33 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water (8 mL) and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 2 / 1) to obtain the target product 10-3 (35 mg, yield 54%). LC-MS (ESI+): m / z 598.1 (M+H) + .

[0199] Compound 10-3 (35 mg, 0.059 mmol) was dissolved in acetonitrile (6 mL) and water (2 mL), and lithium bromide (15 mg, 0.18 mmol) and N,N-diisopropylethylamine (38 mg, 0.30 mmol) were added. The reaction solution was stirred at room temperature for 48 hours. The reaction solution was diluted with water (8 mL), the pH of the reaction solution was adjusted to 4 with 4N HCl, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 0%-100%, 9 minutes) to obtain the target product 10. LC-MS (ESI+): m / z 584.0 (M+H) + . 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=10.4Hz,1H),7.76-7.70(m,2H),7.26-7.19(m,2H),6.84-6.70( m,1H),6.58(d,J=6.8Hz,1H),6.48(d,J=8.4Hz,1H),3.82(s,6H),3.24-3.14(m,8H),2.03(s,3H).

[0200] Embodiment 19

[0201]

[0202] Dissolve compound A-2 (1.4 g, 4.35 mmol) in methanol (3 mL) and add ammonia methanol solution (20 mL, 7 N). The reaction solution was stirred at 60 ° C for 48 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the target product 19-1 (1000 mg, yield 75%). LC-MS (ESI+): m / z 308.0 (M+H) +.

[0203] Under ice bath, compound 19-1 (1.4 g, 4.56 mmol) was dissolved in dichloromethane (40 mL), and triethylamine (692 mg, 6.84 mmol) and trifluoroacetic anhydride (21 mg, 0.098 mmol) were added. The reaction solution was stirred at 0 ° C for 1 hour under nitrogen protection. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 5 / 1) to obtain the target product 19-2 (1.0 g, yield 76%). 1 H NMR (400MHz, DMSO-d6) δ = 7.13 (s, 2H), 3.89 (s, 6H).

[0204] Compound 19-2 (776 mg, 2.68 mmol) was dissolved in dioxane (15 mL), and benzyl mercaptan (3.15 mL, 26.84 mmol), tris(dibenzylideneacetone)dipalladium (246 mg, 0.27 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (311 mg, 0.54 mmol, CAS NO: 161265-03-8) and N,N-diisopropylethylamine (1040 mg, 8.05 mmol) were added. The reaction solution was stirred at 100 ° C for 16 hours under nitrogen protection. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 9 / 1) to obtain the target product 19-3 (750 mg, yield 98%). 1 HNMR (400MHz, CDCl3) δ = 7.13-7.08 (m, 5H), 6.67 (s, 2H), 3.99 (s, 2H), 3.76 (s, 6H).

[0205] Under ice bath, compound 19-3 (961 mg, 3.37 mmol) was dissolved in tetrahydrofuran (1 mL), acetic acid (8 mL) and water (1 mL), and N-chlorosuccinimide (944 mg, 7.07 mmol) was added. The reaction solution was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. Concentrated. The crude product was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain the target product 19-4 (800 mg, yield 91%) and used directly in the next step.

[0206] Compound 19-4 (90 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL), and 8-1 (120 mg, 0.34 mmol) and triethylamine (104 mg, 1.03 mmol) were added. The reaction solution was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was diluted with water (5 mL) and extracted with dichloromethane (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 2 / 1) to obtain the target product 19-5 (120 mg, yield 62%). LC-MS (ESI+): m / z 574.2 (M+H) + .

[0207] Compound 19-5 (100 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium azide (17 mg, 0.26 mmol) and ammonium chloride (14 mg, 0.26 mmol) were added. The reaction solution was stirred at 100 ° C for 16 hours under nitrogen protection. The reaction solution was diluted with water (15 mL), the pH of the reaction solution was adjusted to 2 with 4N HCl, and then extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 0%-95%, 18 minutes) to obtain the target product 19. LC-MS (ESI + ):m / z 617.0(M+H) + . 1 H NMR (400MHz, DMSO-d6)δ=7.59-7.49(m,2H),7.44(s,2H),7.35-7.31(m,1H),6.84-6.70(m,1H),6.58( d,J=7.6Hz,1H),6.50(d,J=8.0Hz,1H)3.95(s,6H),3.31-3.30(m,4H),3.22-3.14(m,4H),2.00(s,3H).

[0208] Embodiment 29

[0209]

[0210] Compound 29-1 (5.0 g, 31.73 mmol) was dissolved in water (180 mL) and concentrated sulfuric acid (30 mL), and a solution of sodium nitrite (2189 mg, 31.73 mmol) in water (10 mL) was slowly added at 0°C. The reaction solution was stirred at 0°C for 45 minutes under nitrogen protection. A solution of potassium iodide (6846 mg, 41.24 mmol) in water (20 mL) was added to the reaction solution at 0°C. The reaction solution was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated sodium thiosulfate solution (80 mL) and saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silicon dioxide, petroleum ether) to obtain the target product 29-2 (6.7 g, yield 79%). 1 HNMR (400MHz, DMSO-d6) δ = 7.76 (d, J = 8.0Hz, 1H), 7.09 (d, J = 2.0Hz, 1H), 6.85-6.83 (m, 1H), 3.86 (s, 3H).

[0211] Compound 29-2 (6.7 g, 24.95 mmol) was dissolved in anhydrous dimethyl sulfoxide (30 mL), and ethynyltrimethylsilane (3431 mg, 34.94 mmol), cuprous iodide (95 mg, 0.50 mmol), bistriphenylphosphine palladium dichloride (777 mg, 1.10 mmol, CASNO: 13965-03-2) and triethylamine (2525 mg, 24.95 mmol) were added. The reaction solution was stirred at room temperature for 4 hours under nitrogen protection. The reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether) to obtain the target product 29-3 (5000 mg, yield 84%). 1 H NMR (400MHz, DMSO-d6) δ = 7.17 (d, J = 8.4Hz, 1H), 6.93 (d, J = 2.0Hz, 1H), 6.78-6.75 (m, 1H), 3.62 (s, 3H), 0.01 (s, 9H).

[0212] Compound 29-3 (5.0 g, 20.94 mmol) was dissolved in tetrahydrofuran (40 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (0.75 mL, 0.75 mmol, 1 mol / L in tetrahydrofuran) was added. The reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether) to obtain the target product 29-4 (3100 mg, yield 89%). 1 H NMR (400MHz, DMSO-d6) δ = 7.42 (d, J = 8.4Hz, 1H), 7.16 (d, J = 1.6Hz, 1H), 7.02-6.95 (m, 1H), 4.32 (s, 1H), 3.85 (s, 3H).

[0213] Compound 29-4 (2600 mg, 15.61 mmol) was dissolved in anhydrous toluene (5 mL), and 3-bromobenzene-1,2-diol (2950 mg, 15.61 mmol) and triruthenium dodecacarbonyl (12 mg, 0.018 mmol) were added. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 0 to 30 / 1) to obtain the target product 29-5 (1190 mg, yield 21%). 1 H NMR (400MHz, CDCl3) δ = 7.51 (d, J = 8.0Hz, 1H), 6.95-6.89 (m, 3H), 6.73-6.65 (m, 2H), 3.92 (s, 3H), 2.12 (s, 3H).

[0214] Compound 29-5 (1000 mg, 2.82 mmol) and tert-butyl piperazine-1-carboxylate (262 mg, 1.41 mmol) were dissolved in toluene (1 mL), and 2,2'-bis(diphenylphosphino)-1,1'-dinaphthalene (350 mg, 0.56 mmol), tris(dibenzylideneacetone)dipalladium (258 mg, 0.28 mmol) and cesium carbonate (1832 mg, 5.62 mmol) were added. The reaction solution was heated to 95 °C under nitrogen protection and stirred for 16 hours. The reaction solution was diluted with water (40 mL x 2) and extracted with ethyl acetate (40 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 13 / 1) to obtain the target product 29-6 (250 mg, yield 38%). 1 H NMR (400MHz, CDCl3) δ = 7.49 (d, J = 8.0Hz, 1H), 6.93-6.89 (m, 2H), 6.84-6.70 (m, 1H), 6.53-6.50 (m, 1 H),6.38-6.36(m,1H),3.89(s,3H),3.60-3.57(m,4H),3.14-3.07(m,4H),2.06(s,3H),1.48(s,9H).

[0215] Compound 29-6 (80 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and dried to obtain the target product 29-7 (60 mg, crude product). LC-MS (ESI+): m / z 361.4 (M+H) + .

[0216] Compound 29-7 (60 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and intermediate compound A (49 mg, 0.17 mmol) and triethylamine (50 mg, 0.49 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 2 / 1) to obtain the target product 29-8 (35 mg, yield 34%). LC-MS (ESI+): m / z 619.1 (M+H) + .

[0217] Compound 29-8 (35 mg, 0.057 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.5 mL), and lithium hydroxide monohydrate (7 mg, 0.17 mmol) was added. The reaction solution was stirred at room temperature under nitrogen protection for 16 hours. The reaction solution was diluted with water (3 mL) and the pH value of the reaction solution was adjusted to 5 with 2 mol / L hydrochloric acid, and then extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 20%-50%, 30 minutes) to obtain the target product 29. LCMS: MS m / z (ESI) [M+H] + =605.1 1 H NMR (400MHz, DMSO-d6) δ = 13.58 (br.s, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.26 (s, 2H), 7.20-7.15 (m, 1H), 7.02-6.99 (m, 1H), 6.84-6.70 ( m,1H),6.54(d,J=7.6Hz,1H),6.42(d,J=8.4Hz,1H),3.89(s,6H),3.87(s,3H),3.30-3.28(m,4H),3.25-3.09(m,4H),1.98(s,3H).

[0218] Embodiment 30

[0219]

[0220] Compound 29-8 (230 mg, 0.37 mmol) was subjected to supercritical fluid chromatography SFC (chromatographic column: chiral IF (IF00CE-RL017), column size: 0.46 cm ID*25 cm L, injection volume 2 μL, mobile phase: MeOH / DCM=60 / 40 (V / V), flow rate: 1.0 mL / min, wavelength: UV 254 nm, column temperature: 35°C, sample retention time: 5.000 min; HPLC equipment: Shimadzu LC-20AT CP-HPLC-09) to prepare the target product 30-1 (89 mg, yield 38%). LCMS: MSm / z(ESI+)[M+Na] + =641.2.

[0221] Compound 30-1 (89 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.5 mL), and lithium hydroxide monohydrate (24 mg, 0.56 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water (5 mL) and the pH value of the reaction solution was adjusted to 5 with 2 mol / L hydrochloric acid, and then extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water-acetonitrile]; B%: 20%-50%, 20 minutes) to obtain the target product 30. LCMS: MS m / z(ESI+)=605.2(M+H) + . 1 H NMR (400MHz, DMSO-d6) δ = 7.43 (d, J = 8.4Hz, 1H), 7.26 (s, 2H), 7.18 (d, J = 1.6Hz, 1H), 7.02-6.99 (m, 1H), 6.80-6.66 (m, 1H), 6.54 (d, J =7.2Hz,1H),6.42(d,J=8.0Hz,1H),3.89(s,6H),3.86(s,3H),3.28-3.26(m,4H),3.22-3.18(m,2H),3.12-3.07(m,2H),1.98(s,3H).

[0222] The compounds shown in Table 1 below were prepared using the same or similar methods as in the above examples:

[0223] Table 1

[0224]

[0225]

[0226]

[0227]

[0228]

[0229] Test Example 1 In vitro activity of test compounds on human GLP-1 receptor

[0230] Methods: Human GLP-1 cells were measured using the LANCE Ultra cAMP assay kit (cAMP Hunter TMThe in vitro activity of the compounds on the human GLP-1 receptor was evaluated by measuring the changes in cAMP in CHO-K1 GLP1R Gs Cell Line, supplier: Eurofins, catalog number: 95-0062C2).

[0231] Table 2 Reagents and consumables

[0232]

[0233] Table 3 Experimental instruments

[0234]

[0235]

[0236] Specific experimental methods:

[0237] 1. Resuscitation of cells

[0238] 1) Soak the cells in complete culture medium (DMEM / F12+10% FBS+500 μg / mL G418) in a 37°C water bath for 30 minutes.

[0239] 2) Take out the GLP-1 cells from the liquid nitrogen tank, quickly thaw them in a 37°C water bath, transfer the cell suspension into a 15 mL centrifuge tube using a pipette, and add 6 mL of complete culture medium.

[0240] 3) After centrifugation at 1000 rpm for 4 minutes, discard the supernatant, resuspend the cell pellet with 5 mL of complete culture medium, transfer to a T75 culture flask, add 10 mL of culture medium, and culture in a 37°C, 5% carbon dioxide incubator.

[0241] 4) The cells are cultured until the confluence is greater than 80%, and then the cells are passaged.

[0242] 2. Cell Passaging

[0243] 1) Take out the T75 culture flask from the incubator and place it in a biosafety cabinet.

[0244] 2) Gently aspirate the culture medium from the T75 flask.

[0245] 3) Add 5 mL of DPBS to the T75 flask and gently tilt the flask left and right to allow the DPBS to cover the entire cell surface. Gently aspirate the DPBS from the flask.

[0246] 4) Add 2 mL of 0.25% trypsin to the T75 flask. Gently shake the flask back and forth to ensure that the surface of the flask is completely covered with trypsin.

[0247] 5) Incubate the flask at 37°C and 5% CO2 for 2-3 minutes or until the cells detach.

[0248] 6) Add 5 mL of fresh culture medium to the T75 flask. Using a pipette, gently rinse the cells from the surface of the flask with the added medium.

[0249] 7) Add fresh culture medium to a new T75 culture flask until the total volume of the T75 is 12 mL, take 1 mL of the cell suspension and add it to the culture flask. Transfer the culture flask to a tissue culture incubator and culture the cells at 37°C and 5% CO2 for 24 hours.

[0250] 8) The cells were passaged twice before use in this cell experiment.

[0251] 3. Compound Preparation

[0252] The compound was prepared with DMSO to a storage concentration of 10mM for future use. The positive drug Exendin-4 was prepared with DMSO to a storage concentration of 5mM for future use. The starting concentration of the compound was 10μM, and all tested compounds were diluted 3 times, 10 concentration points, and two replicates. Use Echo to transfer 100nL to the detection plate (OptiPlate-384).

[0253] 4. Cell Treatment

[0254] 1) Take out the human GLP-1 stably transfected cell line from the incubator and observe the cell status. When the cell density reaches 80% to 90%, discard the culture medium and wash the cells with 5 mL DPBS.

[0255] 2) Remove DPBS, add 2 mL of trypsin, and incubate the flask at 37°C and 5% CO2 for 2-3 minutes or until the cells detach.

[0256] 3) Add 10 mL of complete culture medium to collect cells, centrifuge at 1000 rpm for 4 min, and discard the supernatant.

[0257] 4) Adjust the cell suspension to a density of 1000 cells / well with stimulation buffer.

[0258] Table 4 Stimulation buffer preparation

[0259]

[0260] 5. React

[0261] 1) Transfer 10 μL of cell solution to the assay plate.

[0262] 2) Centrifuge at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes.

[0263] 3) Add cAMP detection kit to the test plate / 5 μL 4X Eu-cAMP tracer solution and 5 μL 4X ULight from Ultra cAMP Kit TM -anti-cAMP solution.

[0264] Table 5 Preparation of detection reagents

[0265]

[0266] 4) Centrifuge at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes.

[0267] 5) cAMP signals were read on a multifunctional microplate reader Envision, and the data were processed using GraphPad Prism 6.0.

[0268] 6. Detection of in vitro agonist activity:

[0269] The concentration of the tested drug was used as the horizontal axis and the measured activation rate was used as the vertical axis to plot the EC value of each compound using GraphPadPrism 6.0 software. 50 .

[0270] GraphPad Prism 6.0 software: Y = Bottom + (Top-Bottom) / (1 + 10^((LogEC 50 -X)*HillSlope)) The activity data of the compounds of the present application are shown in Table 6 below:

[0271] Table 6

[0272]

[0273] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof: in, Ring A and Ring B are the same or different and are independently selected from C 6-12 Aryl or 5-12 membered heteroaryl; Ra is independently selected from halogen, OH, COOH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; s is 0, 1, 2, 3, 4, or 5; R5 is selected from H, OH, COOH, NH2, halogen, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: C 1-12 Alkyl, C 3-12 Cycloalkyl, C 1-12 Alkoxy, -OC 3-12 Cycloalkyl; ---Indicates whether two atoms are connected or not; When the --- on both sides of ---W--- represent connection, the two Ws are independently selected from O, S, NH, -CH2O- or CH2, X1, X3, X4 are independently selected from N or CH; X2, X5, X6 are selected from C; When the --- on both sides of ---W--- means not connected, the W does not exist, X1, X3, X4, X5 are independently selected from N or CH; X2, X6 are selected from C; Rx are independently selected from halogen, OH, COOH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; p is 0, 1, 2, or 3; Y1 and Y2 are independently selected from N or CH; m, n are independently selected from 0, 1 or 2; Ry are independently selected from halogen, OH, COOH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 3-12 Cycloalkyl, C 1-12 Alkoxy, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; q is 0, 1, 2, 3, 4, 5, 6, 7, or 8; L is -S(O)2-, -C(O)- or Rz are independently selected from halogen, OH, NH2, CN, or the following groups which are unsubstituted or optionally substituted by one, two or more Rb: 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; d is 0, 1, 2, 3, or 4; Rb are independently selected from halogen, OH, CN, NH2, oxo (=O), C 1-12 Alkyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, -OC 3-12 Cycloalkyl, halogenated C 1-12 Alkoxy, halogenated C 3-12 Cycloalkyl, -O-halogenated C 3-12 Cycloalkyl; EE is COOH or a carboxyl surrogate, optionally, the carboxyl surrogate is: R c Selected from hydrogen, deuterium, CN, halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl or C 1-12 Alkoxy.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: Formula I is a structure shown in the following formula I', Wherein, Z1, Z3, Z4, and Z6 are independently selected from N or CH; Z2 and Z5 are selected from C; Ra, s, ring A, ring B, R5, W, Rx, X1, X2, X3, X4, X5, X6, p, Y1, Y2, m, n, Ry, q, Rz, L, d, and EE have the definitions described in claim 1.

3. The compound according to claim 2 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: In formula I', ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; Ra are independently selected from halogen, CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy; s is 0, 1, 2, 3, 4, or 5; R5 is selected from H or C 1-6 alkyl; Indicates whether two atoms are connected or not; when On both sides When connected, the two Ws are independently selected from O, S, NH, -CH2O- or CH2, X1, X3, X4 are independently selected from N or CH; X2, X5, X6 are selected from C; when On both sides When it indicates that they are not connected, the W does not exist, X1, X3, X4, and X5 are independently selected from N or CH; X2 and X6 are selected from C; Rx is selected from halogen; p is 0, 1, 2 or 3; Y1, Y2 are selected from N; m, n are independently selected from 0, 1 or 2; Ry is selected from C 1-6 Alkyl; q is 0, 1 or 2; L is -S(O)2-; Z1, Z3, Z4, Z6 are independently selected from N or CH; Z2 and Z5 are selected from C; Rz are independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or -OC 3-6 Cycloalkyl; d is 1, 2, or 3; EE is COOH.

4. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound represented by I' is selected from the compound IX shown below: Among them, Ra, s, ring A, R5, W, Rx, p, m, n, Ry, q, Z1, Z2, Z3, Z4, Z5, Z6, Rz, d have the definitions in claim 2 or 3; Preferably, the compound represented by formula I is selected from compound IY shown below: Among them, Ra, s, ring A, R5, W, Rx, p, m, n, Ry, q, Rz, and d have the definitions as defined in claim 2 or 3.

5. The compound according to claim 4 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound represented by formula I is selected from the compounds IZ shown below: wherein Ra, s, ring A, R5, W, Rx, p, m, n, Ry, q, Rz, and d have the definitions as set forth in claim 4. Preferably, the compound represented by formula I is selected from the compound IZ' shown below: wherein Ra, s, ring A, R5, W, Rx, p, m, n, Ry, q, Rz, and d have the definitions as set forth in claim 4.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The ring A is selected from phenyl or 5-6 membered heteroaryl. Preferably, the halogenated C 1-12 Alkyl or halogenated C 1-12 Alkoxy is substituted by F or Cl, wherein the substitution is substituted by 1, 2, 3 or 4 halogens; Preferably, the W are the same and are selected from O or CH2.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound of formula I is selected from the following compounds represented by Ia, Ib, Ic or Id: In the compound represented by Ia, Ib, Ic or Id: R5 is methyl; Rz are the same or different and are independently F, methoxy, -O-cyclopropyl, Ethyl, ethoxy; X is selected from CH, CRa or N; Ra are the same or different and are independently selected from F, Cl, CN, methoxy, trifluoromethyl, and two Ra in the same general formula are the same or different; Rx is F; p is 0 or 1; Ry is a methyl group; q is 0 or 1; m and n are each independently selected from 0, 1 or 2, and m and n are not 0 at the same time.

8. A compound, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: The compound is represented by any of the following structural formulas:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable excipient.

10. Use of at least one of the compounds according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in the preparation of a medicament for treating cardiometabolism and related diseases, wherein the cardiometabolism and related diseases are T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral fat accumulation, sleep apnea, obesity, abnormal diet, weight gain caused by the use of other agents, excessive sugar addiction, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, Cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular incompliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, poor glucose metabolism, poor fasting glucose symptoms, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, apo B Prevention or treatment of hyperlipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome and treatment of addiction.

Images