Polycyclic heteroaromatic GLP-1 receptor agonists

Abstract

The invention relates to a polycyclic heteroaromatic hydrocarbon GLP-1 (Glucagon Like Peptide-1) receptor agonist. Specifically, the compound disclosed by the invention has a structure as shown in a formula (I), and the definition of each group or substituent group is described in the specification. The invention provides a preparation method of the compound and application of the compound in pharmacy, and further discloses application of the compound in prevention and / or treatment of diseases or symptoms related to GLP-1 receptor signaling pathway disorder.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular, to a polycyclic heteroarene compound, a preparation method thereof and an application thereof in preparing a medicine. The present application further relates to a pharmacological effect of the compound and a pharmaceutical composition containing the compound as a biased GLP-1 receptor agonist, and a use thereof in treating diseases such as diabetes, overweight / obesity, metabolic syndrome, metabolic dysfunction-associated steatohepatitis (MASH), cardiovascular disease, obstructive sleep apnea, chronic kidney disease, dementia, Parkinson's disease, addiction, etc. BACKGROUND

[0002] At present, the world is facing an increasingly severe epidemic of diabetes and obesity. According to the Global Diabetes Map (10th Edition) published by the International Diabetes Federation (IDF), the number of adult diabetes patients worldwide in 2021 was 537 million, about one-tenth of the adult population. It is estimated that the total number of global diabetes patients will increase to 643 million and 783 million by 2030 and 2045. Compared with diabetes, the patient population of obesity is even larger. A study published in the Lancet journal (Lancet. 2024; 403: 1027-1050.) shows that the global obesity population has exceeded 1 billion in 2022, including 879 million adults and 159 million children and adolescents. Diabetes and obesity are prone to induce cardiovascular disease, fatty liver disease, chronic kidney disease, etc., increase the rate of disability and mortality, and are chronic metabolic diseases that seriously endanger human health. Although there are various types of hypoglycemic drugs and weight loss drugs available in the clinic, there are obvious deficiencies in their efficacy, safety, price, treatment compliance, etc., and the demand of patients for safer and more effective new medical means is still very urgent.

[0003] Glucagon-like peptide-1 (GLP-1) is a peptide hormone mainly secreted by intestinal L cells, which exerts diverse biological functions such as promoting insulin secretion, inhibiting glucagon secretion, reducing blood glucose, delaying gastric emptying, and suppressing appetite by activating GLP-1 receptors throughout the body. However, natural GLP-1 is easily degraded and inactivated by dipeptidyl peptidase-4 (DPP-4) in the body, with a very short half-life of only 1-2 minutes. GLP-1 has been improved in metabolic stability through structural modification, becoming a class of drugs with clinical therapeutic value, i.e. GLP-1 receptor agonists. Currently, GLP-1 receptor agonists that have been applied in clinical practice include exenatide, liraglutide, dulaglutide, semaglutide, etc. Due to the strong, blood glucose-dependent, and non-increased risk of hypoglycemia of GLP-1 receptor agonists in reducing blood glucose, its role in the treatment of type 2 diabetes mellitus is increasingly prominent, and it has now become a first-line hypoglycemic drug. In recent years, GLP-1 receptor agonists have also shown great performance in weight loss, for example, semaglutide can reduce the body weight of obese patients by about 15% after 68 weeks of treatment (once a week subcutaneous injection), and it is considered to be a major change in the treatment of obesity. In addition to reducing blood glucose and weight loss, GLP-1 receptor agonists can also lower blood pressure, improve blood lipid disorders, reduce fatty liver disease, and resist Alzheimer's disease and Parkinson's disease, especially, they have protective effects on the heart and kidneys, can significantly reduce the incidence of cardiovascular events, and delay the progression of diabetic nephropathy. In addition, studies have also shown that GLP-1 receptor agonists have good effects in the treatment of alcohol, drug, and nicotine addiction. Because GLP-1 receptors are widely distributed in many organs, tissues, and cells throughout the body, such as the pancreas, kidneys, liver, central nervous system, cardiovascular system, gastrointestinal tract, lungs, skin, immune cells, etc., GLP-1 receptor agonists have potential application value in the treatment of many systemic diseases.

[0004] All the GLP-1 receptor agonists currently on the market are polypeptide drugs, which usually need to be used by subcutaneous injection once a day or once a week, and are expensive, which results in poor patient medication compliance and high drug discontinuation rate. According to a study by the University of Pittsburgh Medical Center (Obesity. 2024; 32: 486-493.), the proportion of patients who still insist on taking semaglutide injection at 3, 6 and 12 months is only 63%, 56% and 40% respectively. In order to overcome the inconvenience of injection preparation, an oral version of semaglutide has also been successfully developed, but because its absorption is easily affected by food, it must be taken on an empty stomach, and it needs to be taken with fasting and water restriction for half an hour after taking the medicine, so the convenience of taking the medicine is not high. In contrast, small molecule drugs are easy to develop into standard oral formulations, have less restrictions on taking the medicine, can be better accepted by patients, have high medication compliance, and are low in price. Therefore, the development of small molecule GLP-1 receptor agonists has been sought after and has become a research hotspot in the field of GLP-1 drugs. At present, small molecule GLP-1 receptor agonists are all in the research and development stage and have not yet been marketed, among which Orforglipron developed by Lilly is the fastest in research progress, which is in the 3rd phase of clinical trials and is testing the therapeutic effect on diabetes, obesity and cardiovascular diseases.

[0005] Patent application US20190225604 discloses GLP-1 receptor agonists represented by the following general formula and their medical uses for treating type 2 diabetes and obesity, wherein Z 1 is selected from Z 2 is selected from C1-6alkyl, C3-15cycloalkyl, 3- to 12-membered heterocyclyl, C6-10aryl and 5- to 10-membered heteroaryl. Compound 67 is a representative compound in the application, which is currently in the clinical trial stage as Orforglipron, and its research code is LY3502970, which is used as a reference compound in the present application.

[0006]

[0007] Therefore, there is an urgent need in the art to develop GLP-1 receptor agonists with excellent oral pharmacokinetic properties, significant hypoglycemic, appetite suppressing and weight reducing effects, and good safety. SUMMARY

[0008] The purpose of the present application is to provide a kind of polycyclic heteroarene GLP-1 receptor agonist with high agonistic activity to GLP-1 receptor Gs pathway, without activating β-arresting pathway, with more optimal oral pharmacokinetic properties compared with prior art, capable of efficiently reducing blood sugar and inhibiting diet, its preparation method and its medical uses for preventing and / or treating diseases related to GLP-1 receptor signal pathway disorder.

[0009] In a first aspect, the present application provides a compound represented by Formula (I), or a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] wherein,

[0012] A ring is selected from the group consisting of C6-C10 aryl, 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, or S, said aryl and heteroaryl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0013] B ring is selected from the group consisting of 11-15 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, or S, 11-18 membered tricyclic or tetracyclic heteroaryl containing 1-5 heteroatoms selected from N, O, or S, said heteroaryl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, oxo, C3-C8 cycloalkyl, haloC3-C8 cycloalkyl, hydroxyl, cyano, C1-C6 alkoxy substituted C1-C6 alkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, C1-C6 alkyl substituted amino;

[0014] C ring is selected from the group consisting of 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, C3-C8 cycloalkyl, said heterocycloalkyl and cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxyl, oxo, cyano;

[0015] R 1a , R 1b are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, or R 1a and R 1b together with the carbon atom to which they are attached form a C3-C8 cycloalkyl;

[0016] R 2a , R 2b are each independently selected from the group consisting of H, C1-C6 alkyl, or R 2a and R 2b together with the carbon atom to which they are attached form a C3-C8 cycloalkyl;

[0017] R 3a , R3b each independently selected from the group consisting of H, C1-C6alkyl, or R 3a and R 3b together with the carbon atom to which they are attached form a C3-C8cycloalkyl or a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, said cycloalkyl and heterocycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, cyano, hydroxy;

[0018] R 4 , R 5 , R 6 each independently H or halogen;

[0019] R 7 selected from the group consisting of H, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy;

[0020] X is NR 8 , O or a bond;

[0021] Y, Z are each independently CH or N;

[0022] R 8 is H or C1-C6alkyl.

[0023] In another preferred embodiment, X in formula (I) is a bond.

[0024] In another preferred embodiment, X in formula (I) is O.

[0025] In another preferred embodiment, at least one ring in the heteroaryl group is aromatic, the other rings being aromatic or non-aromatic.

[0026] In another preferred embodiment, the heteroatoms in the heteroaryl group are in an aromatic ring or in a non-aromatic ring.

[0027] In another preferred embodiment, the ring system of the heteroaryl group is selected from the group consisting of fused, bridged and spirocyclic.

[0028] In another preferred embodiment, the compound has the structure shown in formula (I-0):

[0029]

[0030] wherein,

[0031] A ring is C6-C10aryl, said aryl optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C8cycloalkyl, C2-C6alkynyl;

[0032] B ring is selected from the group consisting of bicyclic or tricyclic heteroaryl groups represented by the following formulae (X-1) to (X-7):

[0033]

[0034] wherein,

[0035] Z1is N or C;

[0036] Z2is N, CR b2 , O or S;

[0037] Z3is selected from the group consisting of:

[0038] Z4is selected from the group consisting of O, NR b2 or CH2;

[0039] Z5and Z6are each independently selected from the group consisting of CH2or C=O;

[0040] R b1 are each independently halogen or C1-C3alkyl;

[0041] each R b2 is each independently selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkyl-C1-C3alkoxy, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0042] k is selected from the group consisting of 0, 1, 2;

[0043] D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0044] is a saturated, partially saturated or aromatic ring; preferably, is an aromatic ring;

[0045] are each independently a single or double bond.

[0046] C ring is a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S, said heterocycloalkyl group being optionally substituted with C1-C6alkyl;

[0047] R 2a , R 2b are each independently selected from the group consisting of H, C1-C6alkyl;

[0048] R 3a , R 3b are each independently selected from the group consisting of H, C1-C6alkyl, or R 3a and R3b with the carbon atom to which they are attached form a C3-C8cycloalkyl group, optionally substituted with one or more groups selected from the group consisting of C1-C6alkyl, haloC1-C6alkyl.

[0049] In another preferred embodiment, the A ring is selected from the group consisting of:

[0050]

[0051] In another preferred embodiment, the C ring is said R c1 or R c2 each independently is H or C1-C3alkyl.

[0052] In another preferred embodiment, the A ring is selected from the group consisting of:

[0053]

[0054] wherein,

[0055] A ring is selected from the group consisting of C6-C10aryl, 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, or S, said aryl and heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C8cycloalkyl, C2-C6alkenyl, C2-C6alkynyl;

[0056] B ring is 9-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O, or S, said heteroaryl optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, oxo, C3-C8cycloalkyl, haloC3-C8cycloalkyl, C1-C6alkoxy substituted C1-C6alkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S;

[0057] C ring is selected from the group consisting of 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, C3-C8cycloalkyl, said heterocycloalkyl and cycloalkyl optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, hydroxyl, oxo, cyano;

[0058] R 1a , R 1b each independently is selected from the group consisting of H, halogen, C1-C6alkyl, or R 1a and R1b together with the carbon atom to which they are attached form a C3-C8cycloalkyl;

[0059] R 2a , R 2b are each independently selected from the group of H, Ci-C6alkyl, or R 2a and R 2b together with the carbon atom to which they are attached form a C3-C8cycloalkyl;

[0060] R 3a , R 3b are each independently selected from the group of H, Ci-C6alkyl, or R 3a and R 3b together with the carbon atom to which they are attached form a C3-C8cycloalkyl or a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, said cycloalkyl and heterocycloalkyl optionally substituted with one or more groups selected from the group of halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, cyano, hydroxy;

[0061] R 4 , R 5 , R 6 are each independently H or halogen;

[0062] R 7 is selected from the group of H, halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy;

[0063] X is NR 8 , O or a chemical bond;

[0064] Y, Z are each independently CH or N;

[0065] R 8 is H or Ci-C6alkyl;

[0066] with the additional proviso that when the C ring is a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S, then,

[0067] a) X is not a chemical bond; or / and

[0068] b) the A ring is selected from the group of C2-C6alkynyl substituted C6-Cio aryl, C2-C6alkynyl substituted 5-10 membered monocyclic or bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, or S, said aryl and heteroaryl further optionally substituted with one or more groups selected from the group of halogen, Ci-C6alkyl; or / and

[0069] c) the B ring is a 9-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O or S, which is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, oxo; or / and

[0070] d) R 1a and R 1b together with the carbon atom to which they are attached form a C3-C8cycloalkyl; or / and

[0071] e) R 2a and R 2b together with the carbon atom to which they are attached form a C3-C8cycloalkyl; or / and

[0072] f) R 3a and R 3b together with the carbon atom to which they are attached form a 4-8 membered heterocycloalkyl; or / and

[0073] g) Y, Z are not simultaneously CH.

[0074] In another preferred embodiment, the B ring is a 9-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O or S, which is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C3alkyl, C3-C5cycloalkyl, C3-C5halocycloalkyl.

[0075] In another preferred embodiment, the B ring has the following structural formula (X-1)~(X-2):

[0076]

[0077] wherein,

[0078] Z1is N or C;

[0079] Z2is selected from the group consisting of N, CR b2 , O or S;

[0080] R b1 each independently is halogen or C1-C3alkyl;

[0081] R b2 is selected from the group consisting of H, C1-C3alkyl, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0082] k is selected from the group consisting of 0, 1, 2;

[0083] D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0084] is a saturated, partially saturated or aromatic ring; preferably, is an aromatic ring;

[0085] each independently is a single or double bond.

[0086] In another preferred embodiment, the B ring has the following structural formulae (X-1-1) to (X-2-2):

[0087]

[0088] wherein,

[0089] Z1is N or C;

[0090] Z2is N or CH;

[0091] R b1 each independently is halogen or C1-C3alkyl;

[0092] k is selected from the group consisting of 0, 1, 2;

[0093] the D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0094] In another preferred embodiment, the B ring is selected from the group consisting of: and is optionally substituted with a halogen atom.

[0095] In another preferred embodiment, the B ring is selected from the group consisting of:

[0096] In another preferred embodiment, the B ring is selected from the group consisting of 11-13 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O or S, 11-15 membered tricyclic or tetracyclic heteroaryl containing 1-3 heteroatoms selected from N, O or S, said heteroaryl being optionally substituted with one or more groups selected from the group consisting of halogen, C1-C3alkyl, oxo, C3-C8cycloalkyl, halogenated C3-C8cycloalkyl, hydroxy.

[0097] In another preferred embodiment, the B ring is fused from a benzene ring and a 7-11 membered heterocycloalkyl or heteroaryl containing 1-3 heteroatoms selected from N, O or S.

[0098] In another preferred embodiment, the B ring is a 12-13 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N or S, said heteroaryl being optionally substituted with one or more groups selected from the group consisting of halogen, C1-C3alkyl, C3-C8cycloalkyl, halogenated C3-C8cycloalkyl.

[0099] In another preferred embodiment, B ring is a 13-15 membered tetra-cyclic heteroaryl containing 1-3 heteroatoms selected from N, O or S, said heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, C1-C3 alkyl, oxo.

[0100] In another preferred embodiment, B ring has the following structural formula (X-3), (X-4), (X-7), (X-8), (X-9):

[0101]

[0102] wherein,

[0103] Z3is selected from the group consisting of:

[0104] R b1 each independently is halogen or C1-C3 alkyl;

[0105] each R b2 each independently is selected from the group consisting of H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyl-C1-C3 alkoxy, C3-C8 cycloalkyl or halogenated C3-C8 cycloalkyl;

[0106] k is selected from the group consisting of 0, 1, 2;

[0107] each independently is a single or double bond.

[0108] In another preferred embodiment, B ring has the following structural formula (X-3-1) ~ (X-9-1):

[0109]

[0110] wherein,

[0111] R b1 each independently is halogen or C1-C3 alkyl;

[0112] each R b2 each independently is selected from the group consisting of H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyl-C1-C3 alkoxy, C3-C8 cycloalkyl or halogenated C3-C8 cycloalkyl;

[0113] k is selected from the group consisting of 0, 1, 2;

[0114] each independently is a single or double bond.

[0115] In another preferred embodiment, B ring is selected from the group consisting of:

[0116] said group is optionally substituted with a halogen atom.

[0117] In another preferred embodiment, the B ring is selected from the group consisting of:

[0118] said group is optionally substituted with a halogen atom.

[0119] In another preferred embodiment, the B ring is selected from the group consisting of:

[0120] said group is optionally substituted with a halogen atom.

[0121] In another preferred embodiment, B is an 11-membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N or O, said heteroaryl is optionally substituted with one or more groups selected from halogen, C1-C3 alkyl, oxo, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl.

[0122] In another preferred embodiment, the B ring has the following structural formulae (X-5) ~ (X-6):

[0123]

[0124] wherein,

[0125] Z4is selected from the group consisting of O, NR b2 or CH2;

[0126] Z5, Z6are each independently selected from the group consisting of CH2or C=O;

[0127] R b1 are each independently halogen or C1-C3 alkyl;

[0128] each R b2 are each independently selected from the group consisting of H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyl-C1-C3 alkoxy, C3-C8 cycloalkyl or halogenated C3-C8 cycloalkyl;

[0129] k is selected from the group consisting of 0, 1, 2.

[0130] In another preferred embodiment, the B ring has the following structural formulae (X-5-1) ~ (X-6-1):

[0131]

[0132] wherein,

[0133] R b1 are each independently halogen or C1-C3 alkyl;

[0134] R b2selected from the group consisting of H, C1-C3alkyl, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0135] k is selected from the group consisting of 0, 1, 2.

[0136] In another preferred embodiment, the B ring is selected from the group consisting of:

[0137] said group is optionally substituted with a halogen atom.

[0138] In another preferred embodiment, the A ring is phenyl, said phenyl being optionally substituted with one or more groups selected from the group consisting of halogen, C1-C3alkyl, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl.

[0139] In another preferred embodiment, the A ring is phenyl, said phenyl being optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, methyl, cyclopropyl, ethynyl.

[0140] In another preferred embodiment, the compound has the structural formula of formula (I-a):

[0141]

[0142] wherein,

[0143] R 9 selected from the group consisting of halogen, C1-C3alkyl, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl;

[0144] m is selected from the group consisting of 1, 2, 3;

[0145] B ring, C ring, R 2a , R 2b , R 3a and R 3b are as described in the first or second aspect of the application.

[0146] In another preferred embodiment, the compound has the structural formula of formula (I-b):

[0147]

[0148] wherein,

[0149] R 9 selected from the group consisting of halogen, C1-C3alkyl, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl;

[0150] R c1 , R c2 , Rc3 R c4 Each is independently an H or C1-C3 alkyl group;

[0151] m is selected from the following groups: 1, 2, 3;

[0152] The definition of ring B is as described in the first or second aspect of this invention.

[0153] In another preferred embodiment, the compound has the structural formulas (Ic) to (Id):

[0154]

[0155] in,

[0156] R 9 Selected from the following group: halogen, C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0157] R c1 R c2 R c3 R c4 Each is independently an H or C1-C3 alkyl group;

[0158] m is selected from the following groups: 1, 2, 3;

[0159] Z1 is either N or C;

[0160] Z2 represents N and CR. b2 , O or S;

[0161] R b1 Each is independently a halogen or a C1-C3 alkyl group;

[0162] R b2 Selected from the following group: H, C1-C3 alkyl, C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl;

[0163] k is selected from the following group: 0, 1, 2;

[0164] The D ring is a C3-C8 cycloalkyl or a halo-C3-C8 cycloalkyl;

[0165] Preferably, ring D is cyclopropyl or halocyclopropyl;

[0166] More preferably, ring D is cyclopropyl.

[0167] In another preferred embodiment, the compound has the structural formulas (Ic-1) to (Id-1):

[0168]

[0169] in,

[0170] R 9 Selected from the following group: halogen, C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0171] R c1 R c2 Each is independently an H or C1-C3 alkyl group;

[0172] m is selected from the following groups: 1, 2, 3;

[0173] Z2 is either N or CH;

[0174] R b1 Each is independently a halogen or a C1-C3 alkyl group;

[0175] k is selected from the following group: 0, 1, 2;

[0176] The D ring is a C3-C8 cycloalkyl or a halo-C3-C8 cycloalkyl;

[0177] Preferably, ring D is cyclopropyl or halocyclopropyl;

[0178] More preferably, ring D is cyclopropyl.

[0179] In another preferred embodiment, the compound has the structure of formula (II):

[0180]

[0181] in,

[0182] X1 is selected from the following group: (CH) n ) p , N, O, S;

[0183] X2 is selected from the following group: (CH) n ) p , N, O, S;

[0184] X3 is selected from the following group: (CH) n ) p , N, O, S;

[0185] X4 is selected from the following group: (CH) n ) p , N, O, S;

[0186] X5 is selected from the following group: (CH) n ) p , N, O, S;

[0187] X6 is selected from the following group: (CH) n ) p , N, O, S;

[0188] X7 is selected from the following group: (CH) n ) p , N, O, S;

[0189] X8 is selected from the following group: (CH) n ) p , N, O, S;

[0190] X9 is selected from the following group: (CH) n ) p , N, O, S;

[0191] X1 to X9 are not simultaneously (CH) n ) p ;

[0192] R 4b R 4c Each is independently selected from the following group: halogen, C1-C6 alkyl, oxo, halogenated C1-C6 alkyl, C3-C8 cycloalkyl;

[0193] R 4d Selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyl, or two Rs 4d Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups or 4-8 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0194] g, h, i, and p are each independently selected from the following groups: 0, 1, 2, 3;

[0195] n is selected from the following group: 0, 1, 2;

[0196] Each can be a single bond or a double bond independently;

[0197] A ring, C ring, R 1a R 1b R 2a R 2b R 3a R 3b R 4 R 5 R 6 R 7 The definitions of Y and Z are as described in the first aspect of this invention.

[0198] In another preferred embodiment, the structure of the compound is selected from the group consisting of (II-a to II-c):

[0199]

[0200] in,

[0201] X1, X2, X3, X4, and X5 are each independently selected from the following groups: (CH n ) p , N, O, S;

[0202] X6, X7, X8, and X9 are each independently selected from the following group: (CH n ) p , N, O, S;

[0203] In equation (II-c), X1 to X5 are not simultaneously (CH) n ) p ;

[0204] R 4b R 4c Each is independently selected from the following group: halogen, C1-C6 alkyl, oxo, halogenated C1-C6 alkyl, C3-C8 cycloalkyl;

[0205] R 4d Selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyl; or two Rs 4d Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups or 4-8 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0206] g, h, i, and p are each independently selected from the following groups: 0, 1, 2, 3;

[0207] n is selected from the following group: 0, 1, 2;

[0208] Each can be a single bond or a double bond independently;

[0209] A ring, C ring, R 1a R 1b R 2a R 2b R 3a R 3b R 4 R 5 R 6 R 7 The definitions of Y and Z are as described in the first aspect of this invention.

[0210] In another preferred embodiment, the compound has the structure of formula (Ⅱ-d):

[0211]

[0212] in,

[0213] X1, X2, X3, X4, and X5 are each independently selected from the following groups: N, O, and S;

[0214] R 4b R 4c R 4d Selected from the following group: halogen, C1-C6 alkyl, oxo, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, hydroxyl;

[0215] g, h, and i are each independently selected from the following groups: 0, 1, 2, 3;

[0216] n is selected from the following group: 0, 1, 2;

[0217] Each can be a single bond or a double bond independently;

[0218] A ring, C ring, R 1a R 1b R 2a R 2b R 3a R 3b R 4 R 5 R 6 R 7 The definitions of Y and Z are as described in the first aspect of this invention.

[0219] In another preferred embodiment, the compound has the structure of formula (II-e) to (II-g):

[0220]

[0221] in,

[0222] R 9 Selected from the following group: halogen, C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0223] R c1 R c2 R c3 R c4 Each is independently selected from H or C1-C3 alkyl groups;

[0224] m is selected from the following groups: 1, 2, 3;

[0225] Z3 is selected from the following group:

[0226] R b1 Each is independently a halogen or a C1-C3 alkyl group;

[0227] Each R b2 Each is independently selected from the group consisting of: H, C1-C3 alkyl, C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl;

[0228] k is selected from the following group: 0, 1, 2;

[0229] Each can be a single bond or a double bond independently.

[0230] In another preferred embodiment, the compound has a structure of formula (Ⅱ-e-1)~(Ⅱ-e-2), (Ⅱ-f-1)~(Ⅱ-f-2) or (Ⅱ-g-1):

[0231]

[0232] in,

[0233] R 9 Selected from the following group: halogen, C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0234] R c1 and R c2 Each is independently selected from H or C1-C3 alkyl groups;

[0235] m is selected from the following groups: 1, 2, 3;

[0236] R b1 Each is independently a halogen or a C1-C3 alkyl group;

[0237] R b2 Selected from the following group: H, C1-C3 alkyl, C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl;

[0238] k is selected from the following group: 0, 1, 2;

[0239] Each can be a single bond or a double bond independently.

[0240] In another preferred embodiment, the compound has the structure of formula (II):

[0241]

[0242] in,

[0243] X1 is selected from the following group: (CH) n ) p , N, O, S;

[0244] X2 is selected from the following group: (CH) n ) p , N, O, S;

[0245] X3 is selected from the following group: (CH) n ) p , N, O, S;

[0246] X4 is selected from the following group: (CH) n ) p , N, O, S;

[0247] X5 is selected from the following group: (CH) n ) p , N, O, S;

[0248] R 4a Selected from the following group: halogen, C1-C6 alkyl, oxo, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, or two Rs 4a Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups, or 4-8 membered heteroalkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0249] m is selected from the following group: 0, 1, 2, 3, 4;

[0250] n is selected from the following group: 0, 1, 2;

[0251] p is selected from the following group: 0, 1, 2, 3;

[0252] A ring, C ring, R 1a R 1b R 2a R 2b R 3a R 3b R 4 R 5 R 6 R 7 The definitions of Y and Z are as described in the first aspect of this invention.

[0253] In another preferred embodiment, the structure of the compound is selected from the group consisting of (III-a, III-b):

[0254]

[0255] in,

[0256] R 4a Selected from the following group: halogen, C1-C6 alkyl, oxo, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, or two Rs 4a Together with the carbon atoms they are attached to, they form C3-C8 cycloalkyl groups, or 4-8 membered heteroalkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0257] m is selected from the following group: 0, 1, 2, 3, 4;

[0258] A ring, C ring, R 1a R 1b R 2a R 2b R3a R 3b R 4 R 5 R 6 R 7 The definitions of Y and Z are as described in the first aspect of this invention.

[0259] In another preferred embodiment, the compound has the structure of formula (III-c) to (III-d):

[0260]

[0261] in,

[0262] R 9 Selected from the following group: halogen, C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0263] R c1 R c2 R c3 R c4 Each is independently selected from H or C1-C3 alkyl groups;

[0264] m is selected from the following groups: 1, 2, 3;

[0265] Z4 is selected from the following groups: O, NR b2 Or CH2;

[0266] Z5 and Z6 are each independently selected from the following group: CH2 or C=O;

[0267] R b1 Each is independently a halogen or a C1-C3 alkyl group;

[0268] R b2 Selected from the following group: H, C1-C3 alkyl, C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl;

[0269] k is selected from the following groups: 0, 1, 2.

[0270] In another preferred embodiment, the compound has the structure of formula (II-c-1):

[0271]

[0272] in,

[0273] R 9 Selected from the following group: halogen, C1-C3 alkyl, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0274] R c1 Rc2 Each is independently selected from H or C1-C3 alkyl groups;

[0275] m is selected from the following groups: 1, 2, 3;

[0276] R b1 Each is independently a halogen or a C1-C3 alkyl group;

[0277] R b2 Selected from the following group: H, C1-C3 alkyl, C3-C8 cycloalkyl or halo-C3-C8 cycloalkyl;

[0278] k is selected from the following groups: 0, 1, 2.

[0279] In another preferred embodiment, the C ring is a 4-8 membered heterocyclic alkyl group containing 1-2 heteroatoms selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more groups selected from the group consisting of halogens and C1-C3 alkyl groups.

[0280] In another preferred embodiment, ring C is selected from the following group:

[0281] in,

[0282] X1 is independently selected from the following groups: N, O, S;

[0283] R 5a Selected from the following group: halogens, C1-C6 alkyl groups, and halogenated C1-C6 alkyl groups;

[0284] v is selected from the following group: 0, 1, 2, 3, 4.

[0285] In another preferred embodiment, ring C is selected from the following group:

[0286] Among them, X1, R 5a The definitions of and v are as described above.

[0287] In another preferred embodiment, the C ring is a C3-C8 cycloalkyl group optionally substituted with a halogen.

[0288] In another preferred embodiment, X in formula (Ⅰ) is a chemical bond.

[0289] In another preferred embodiment, ring A is...

[0290] In another preferred embodiment, ring B is

[0291] In another preferred embodiment, ring B is

[0292] In another preferred embodiment, ring B is

[0293] In another preferred embodiment, ring C is

[0294] In another preferred embodiment, ring C is

[0295] In another preferred embodiment, R 1a R 1b All are H.

[0296] In another preferred embodiment, R 2a For H, R 2b It is a C1-C3 alkyl group.

[0297] In another preferred embodiment, R 2a For H, R 2b It is a methyl group.

[0298] In another preferred embodiment, R 3a and R 3b Together with the carbon atoms to which they are attached, they form C3-C8 cycloalkyl groups, which are either unsubstituted or substituted by C1-C3 alkyl groups.

[0299] In another preferred embodiment, R 3a and R 3b Together with the carbon atoms to which they are attached, they form a cyclopropyl group, wherein the cycloalkyl group is either unsubstituted or substituted with a methyl group.

[0300] In another preferred embodiment, R 4 For H.

[0301] In another preferred embodiment, R 5 For H.

[0302] In another preferred embodiment, R 6 For H.

[0303] In another preferred embodiment, R 7 For H.

[0304] In another preferred embodiment, X is a chemical bond.

[0305] In another preferred example, X is 0.

[0306] In another preferred example, Y is CH.

[0307] In another preferred example, Z is CH.

[0308] In another preferred embodiment, the compound is selected from the group consisting of:

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321] A third aspect of the present invention provides a pharmaceutical composition comprising: the compound described in the first or second aspect of the present invention, or a stereoisomer thereof, a deuterated thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0322] A fourth aspect of the present invention provides the use of the compound described in the first or second aspect of the present invention or the pharmaceutical composition described in the third aspect of the present invention for the preparation of a GLP-1 receptor agonist, or for the preparation of a medicament for the prevention and / or treatment of diseases or symptoms associated with GLP-1 receptor signaling pathway dysregulation.

[0323] In another preferred embodiment, the GLP-1 receptor agonist is a G protein-biased agonist.

[0324] In another preferred embodiment, the diseases or symptoms associated with GLP-1 receptor signaling pathway dysregulation are selected from the group consisting of: diabetes, hyperglycemia, insulin resistance, diabetic complications, overweight / obesity, metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatohepatitis (MASH), hypertension, dyslipidemia, atherosclerosis, coronary heart disease, myocardial infarction, heart failure, cardiomyopathy, endocarditis, arrhythmia, cerebral infarction, stroke, thrombosis, aneurysm, obstructive sleep apnea, gout, chronic kidney disease, dementia, Parkinson's disease, brain inflammation, depression, alcohol addiction, drug addiction, nicotine addiction, autoimmune diseases, and cancer.

[0325] In another preferred embodiment, the disease or symptom associated with GLP-1 receptor signaling pathway dysregulation is type 2 diabetes or overweight / obesity.

[0326] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0327] Figure 1 The agonistic effects of natural GLP-1, LY3502970, compound 6-1, and compound 11-1 on the β-arrestin 1 pathway were demonstrated.

[0328] Figure 2 The agonistic effects of natural GLP-1, LY3502970, compound 6-1, and compound 11-1 on the β-arrestin 2 pathway were demonstrated.

[0329] Figure 3 The changes in cumulative food intake in mice at 3, 6, 12, and 24 hours after oral administration of the positive control LY3502970, compound 6-1, and compound 11-1 are shown (n = 8; means ± SEM; **, p < 0.01 vs. blank control; ***, p < 0.001 vs. blank control).

[0330] Figure 4 The blood glucose concentration-time curves of compounds 6-1 and 11-1 in the oral glucose tolerance test in mice are shown (n=5; means±SEM).

[0331] Figure 5 The area under the blood glucose curve (AUC(0-90)) of compounds 6-1 and 11-1 in mice during oral glucose tolerance tests from 0 to 90 minutes is shown (n=5; means±SEM; ***, p<0.001 vs blank control).

[0332] Figure 6 The effects of compound 15-1 of the present invention, the positive control LY3502970, and compound Ref-3 on the food intake of mice within 24 hours after a single oral administration are shown (n=8; means±SEM; ***, p<0.001 vs blank control; #, p<0.05; ###, p<0.001 vs compound 15-1 0.3 mg / kg).

[0333] Figure 7The effects of LY3502970, compound 15-1, compound Ref-1, and compound Ref-4 at 0.1 mg / kg on food intake in mice within 24 hours after a single oral dose are shown (n = 8; means ± SEM; **, p < 0.01 vs. blank control; ***, p < 0.001 vs. blank control; ##, p < 0.01 vs. compound 15-1; ###, p < 0.001 vs. compound 15-1).

[0334] Figure 8 The effects of LY3502970, compound 96-1, and compound Ref-5 at 1 mg / kg on food intake in mice within 24 hours after a single oral dose are shown (n = 8; means ± SEM; **, p < 0.01 vs. blank control; ***, p < 0.001 vs. blank control; ###, p < 0.001 vs. compound 96-1).

[0335] Figure 9 The blood glucose-time curves (n=5; means±SEM) of LY3502970, compound 15-1 and compound Ref-1 in the oral glucose tolerance test in mice are shown.

[0336] Figure 10 The area under the blood glucose curve (AUC) of LY3502970, compound 15-1 and compound Ref-1 in mice from 0 to 90 minutes after oral glucose administration and the magnitude of the decrease in blood glucose AUC compared with the blank control group are shown (n=5; means±SEM; ***, p<0.001 vs blank control).

[0337] Figure 11 The effects of administration of LY3502970 and compound 15-1 for 21 days on body weight in a diet-induced obesity (DIO) mouse model are shown (n = 9; means ± SEM; ***, p < 0.001 vs. blank control). Detailed Implementation

[0338] Through extensive and in-depth research, including numerous screenings and structural optimizations, the inventors have provided a polycyclic heteroaromatic compound as shown in formula (I). Specifically, regarding the structural modification of the B ring, the inventors not only expanded the rings based on the bicyclic structure but also prepared compounds with tricyclic or tetracyclic heteroaromatic groups. The preparation method of the compound and its use in preventing and / or treating diseases or symptoms related to GLP-1 receptor signaling pathway dysregulation have been disclosed. This invention is based on these findings.

[0339] the term

[0340] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0341] In this invention, the halogen is F, Cl, Br or I.

[0342] In this invention, the term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and n-hexyl.

[0343] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc.

[0344] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and containing at least one double bond, including but not limited to vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl.

[0345] In this invention, the term "C2-C6 ynyl" refers to a straight-chain or branched ynyl group having 2 to 6 carbon atoms and containing at least one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl.

[0346] In this invention, the term "C3-C8 cycloalkyl" represents a cyclic aliphatic hydrocarbon group consisting of 3 to 8 cyclic carbon atoms, and so on. It should be understood that "cycloalkyl" as used in this invention includes not only monocyclic aliphatic hydrocarbon groups, but also fused ring, spiro ring, and bridged ring systems composed of multiple cyclic aliphatic hydrocarbons. "Cycloalkyl" as used in this invention includes not only aliphatic hydrocarbon groups with fully saturated carbon atoms, but also aliphatic hydrocarbon groups with some carbon atoms having unsaturated bonds. Examples of "cycloalkyl" as used in this invention include, but are not limited to: When a cycloalkyl group is used as a substituent, the connection site with the main molecule can occur at any position allowed by the chemical bonds on the cycloalkyl group.

[0347] In this invention, the term "aryl" refers to a monocyclic or bicyclic system consisting of a specific number of carbon atoms that obeys Hückel's rule. It should be understood that when "aryl" in this invention refers to a bicyclic system, it includes not only the case where all rings are aromatic rings, but also the case where only one ring is an aromatic ring and the other ring is a non-aromatic aliphatic ring.

[0348] In this invention, the term "C6-C10 aryl" refers to a cyclic system having 6 to 10 carbon atoms, and at least one ring being an aromatic ring; examples of "aryl" in this invention include, but are not limited to, those described in this invention. When "aryl" is used as a substituent, the connection site with the main molecule occurs on the aromatic ring.

[0349] In this invention, the term "heterocyclic alkyl" refers to a non-aromatic cyclic group that indicates a specific number of cyclic atoms, contains at least one cyclic heteroatom (N, O, or S), and is saturated or partially unsaturated. It should be understood that the "heterocyclic group" described in this invention includes not only monocyclic heterocyclic systems but also polycyclic heterocyclic systems, such as fused rings, spirocyclic rings, and bridged rings. When the "heterocyclic group" is a polycyclic system, at least one ring contains a cyclic heteroatom, and the other rings may contain cyclic heteroatoms or be cyclic alkyl groups. For example, the term "4-8 membered heterocyclic alkyl" refers to a monocyclic or polycyclic system having 4 to 8 cyclic atoms, at least one of which is a heteroatom, and is saturated or partially unsaturated. The definitions of other similar terms follow the same pattern. More preferably, the number of heteroatoms is 1 to 3. This includes (but is not limited to) the following groups: It is important to understand that when a "heterocyclic group" is used as a substituent, the connection site with the main body of the molecule can occur at any position allowed by the chemical bonds on the "heterocyclic group".

[0350] In this invention, the term "heteroaryl" refers to a cyclic group with a specific number of cyclic atoms, containing at least one cyclic heteroatom (N, O, or S), and possessing aromaticity. Unless otherwise defined, the "heteroaryl" in this invention includes not only monocyclic heteroaryl systems but also polycyclic heteroaryl systems, such as bicyclic heteroaryl, tricyclic heteroaryl, and tetracyclic heteroaryl. When the "heteroaryl" is a polycyclic heteroaryl system, at least one ring is aromatic, and the other rings can be aromatic or non-aromatic. The heteroatom can be located in an aromatic ring or a non-aromatic ring. Polycyclic heteroaryl systems include not only fused ring systems but also bridged ring and spiro ring systems.

[0351] In this invention, the term "9-15 membered bicyclic heteroaryl" refers to a group having 9-15 cyclic atoms, at least one of which is a heteroatom; the term "11-18 membered tricyclic heteroaryl" refers to a group having 11-18 membered cyclic atoms; the term "11-18 membered tetracyclic heteroaryl" refers to a group having 11-18 membered cyclic atoms; and other similar terms are defined accordingly. Examples of "heteroaryl" include, but are not limited to, those of [specific type of aryl group]. It is important to understand that when a "heteroaryl" acts as a substituent, the connection site with the main molecule occurs on the aromatic ring.

[0352] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0353] In this invention, the term "optionally" means that when there is a series of candidate groups to choose from, some of them can be selected, or none can be selected.

[0354] In this invention, "each independently" means that when several substituents defined at the same time are selected from the same series of candidate groups, they do not affect each other, and they may be the same or different.

[0355] In this invention, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents at each position may be the same or different. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0356] In this invention, the term "1-6" refers to having 1, 2, 3, 4, 5 or 6, and other similar terms each have a similar meaning independently.

[0357] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0358] compound

[0359] For the first or second aspect of the present invention, general formula (I) indicates that the compound may contain one or more chiral centers, which exist as enantiomers and diastereomers. General formula (I) of the present invention also indicates that the compound may contain many geometric isomers such as alkenes, C=N double bonds, and amides. Unless otherwise specified, all chiral (enantiomers, diastereomers, axial chiral isomers), racemic, cis geometric isomers, trans geometric isomers, mixtures of cis and trans geometric isomers, rotational isomers, and mixtures thereof described above are included within the scope of the present invention. Those skilled in the art can use commonly used laboratory separation or synthesis methods to separate or prepare compounds containing asymmetric centers in the present invention to obtain single isomers. For example, for enantiomers, two enantiomers can be obtained using general chiral resolution methods or asymmetric synthesis methods; for diastereomers, they can be separated by stepwise recrystallization or chromatographic separation, etc., without compromising the novelty of the compounds of the present invention.

[0360] In another preferred embodiment, in the compound, rings A, B, C, and R are... 1a R 1b R 2aR 2b R 3a R 3b R 4 R 4a R 4b R 4c R 4d R 5 R 6 R 7 R 8 Each of X, Y, and Z is an independent group corresponding to the specific compound described in this invention.

[0361] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a positively charged group on a compound of formula (I) and an anion, or a salt formed by a negatively charged group on a compound of formula (I) and a cation. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate, or maleate. Suitable cations include, but are not limited to, sodium, potassium, magnesium, calcium, and ammonium ions.

[0362] In another preferred embodiment, the pharmaceutically acceptable salt of the present invention refers to a salt formed by a compound of general formula (I) with an acid from the group below, such as, but not limited to: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, and fumaric acid. Propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, acetic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid, etc.; or salts formed by compounds of general formula (I) with inorganic bases, such as, but not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, or ammonium salts; or salts formed by compounds of general formula (I) with organic bases, such as, but not limited to, methylamine salts, ethylamine salts, ethanolamine salts, hydroxymethylaminomethane (TRIS) ammonium salts, etc.

[0363] The compounds of general formula (I) of this invention, or pharmaceutically acceptable salts thereof, are obtained by distillation, crystallization, or recrystallization from water or an organic solvent, and may contain solvent molecules used. Furthermore, different crystallization conditions may result in different crystal forms of the compounds. Therefore, compounds of general formula (I) or pharmaceutically acceptable salts thereof containing different chemical dosages of crystallization solvents and all crystal forms are within the scope of this invention.

[0364] Replacing hydrogen atoms with deuterium atoms to alter the physicochemical properties of compounds is a well-known structural modification method among those skilled in the art. Unless otherwise stated, this invention intends to include the deuterated form of compounds represented by general formula (I) in the scope of the invention.

[0365] Preparation method

[0366] The preparation methods of the compounds of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0367] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0368] In this invention, a method for preparing the compound, or its stereoisomer, its deuterated product, or its pharmaceutically acceptable salt, as described in the first or second aspect of this invention is provided.

[0369] The compounds of this invention can be prepared by a variety of synthetic methods. The methods shown in routes A through C below are representative general schemes. They, combined with the synthetic methods of specific compounds in the examples, constitute the preparation methods of the compounds of this invention. It should be understood that the preparation methods of the compounds of this invention are not limited to those shown in routes A through C. They are for explanation only and do not limit the invention in any way.

[0370] In most cases, the compounds of the present invention can be prepared by the method shown in route A below.

[0371] The reaction steps in route A include:

[0372] (a) Intermediate A-1 and A coupling reaction occurs to generate A-2; the coupling reaction is typically carried out in the presence of a palladium or copper catalyst, a ligand, and a base; the palladium or copper catalyst is, for example but not limited to, palladium acetate, tris(dibenzylacetone)palladium, tetra(triphenylphosphine)palladium, Pd(dppf)Cl2, Pd(PPh3)2Cl2, cuprous iodide, cuprous chloride, cuprous bromide, Cu2O, and metallic copper; the ligand is, for example but not limited to, 1,1'-bis(diphenylphosphine)ferrocene and 2-dicyclohexylphosphine-2. ',4',6'-Triisopropylbiphenyl (XPhos), 2-Di-tert-butylphosphino-2',4',6'-Triisopropylbiphenyl (t-BuXPhos), 4,5-Bisdiphenylphosphine-9,9-Dimethyloxanthracene (XantPhos), 2-Dicyclohexylphosphine-2',6'-Diisopropoxy-1,1'-Biphenyl (RuPhos), Tri-tert-butylphosphine, Triphenylphosphine, 1,1'-Binaphthyl-2,2'-Bisdiphenylphosphine (BINAP), (1S,2S)-N 1 N 2 -Dimethylcyclohexane-1,2-diamine, N,N-dimethylethylenediamine, proline, 4-(di-tert-butylphosphino)-N,N-dimethylaniline; the base includes inorganic and organic bases, such as, but not limited to, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine; the reaction is carried out in a suitable organic solvent, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), xylene, chlorobenzene, acetonitrile, tert-butanol; the reaction temperature is generally from room temperature to 200°C.

[0373] (b) Intermediate A-2 undergoes the removal of the tert-butyloxycarbonyl (Boc) protecting group to generate A-3; the reaction is usually carried out in the presence of an acid, such as, but not limited to, trifluoroacetic acid, hydrochloric acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid; the reaction temperature is generally -20 to 50 °C, preferably room temperature; the reaction solvent is, for example, but not limited to, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, etc.

[0374] (c) Intermediate A-4 first reacts with hydroxylamine to form N-hydroxyamidin, which is then acylated and cyclized to form oxadiazolone A-5. The hydroxylamine reaction reagent is typically hydroxylamine hydrochloride, hydroxylamine sulfate, or an aqueous solution of hydroxylamine. The acylation reagent is, for example, but not limited to, N,N'-carbonyldiimidazole, phosgene, triphosgene, diethyl carbonate, and p-nitrophenyl chloroformate. The hydroxylamine and acylation reactions can be carried out continuously or in steps. Both reactions are usually carried out under the action of a base, which includes inorganic and organic bases, such as, but not limited to, potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate, sodium hydroxide, lithium hydroxide, DBU, triethylamine, DIPEA, and pyridine. The reaction solvent is generally a polar solvent, such as, but not limited to, DMF, DMSO, THF, methanol, ethanol, and 1,4-dioxane. The reaction temperature is typically from room temperature to 120°C.

[0375] (d) Intermediate A-5 undergoes hydrolysis or hydrogenation cleavage to generate A-6; hydrolysis can be carried out under alkaline conditions, wherein the alkaline is, for example but not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, lithium hydroxide, and sodium hydroxide; the reaction solvent is generally a polar solvent, for example but not limited to, DMF, DMSO, THF, methanol, ethanol, 1,4-dioxane, ethylene glycol monomethyl ether, and ethylene glycol dimethyl ether; the reaction temperature is generally from room temperature to 150°C; hydrolysis can also be carried out under acidic conditions, wherein the acid reagent is, for example but not limited to, trifluoroacetic acid, hydrochloric acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid; the reaction temperature is generally -2°C. The reaction temperature ranges from 0 to 50°C; the reaction solvents include, but are not limited to, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, and ethanol; the hydrogenation cracking reaction is usually carried out under the catalysis of metals such as palladium / carbon, palladium oxide, platinum oxide, and Raney nickel; the hydrogen source is usually hydrogen gas, but it can also be generated in situ by reagents such as ammonium formate and cyclohexene; the reaction temperature is generally from room temperature to 120°C; the reaction solvents include, but are not limited to, DMF, methanol, ethanol, ethyl acetate, tetrahydrofuran, and 1,4-dioxane; the reaction can be carried out under normal pressure or under pressure, with the pressure for pressurized reactions generally ranging from 0.1 to 30 MPa.

[0376] (e) Intermediates A-3 and A-6 undergo an amide condensation reaction to generate a compound of general formula (I); the reaction is usually carried out in the presence of a condensing agent well known to those skilled in the art, examples of which can be found in the literature or reference books, representative examples including, but not limited to, dicyclohexylcarbodiimide (DCC), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole (ECDI / HOBt), 2-(1H-benzotriazolyl-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (TBTU), N,N'-carbonyldiimidazole ( CDI), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP); the reaction is usually carried out in the presence of a base, which includes inorganic and organic bases. Examples of organic bases include, but are not limited to, pyridine, DIPEA, 4-dimethylaminopyridine (DMAP), triethylamine, DUB, and trihydroxyethylamine. Examples of inorganic bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, and sodium acetate. The solvent can be any solvent that does not adversely affect the reaction, such as, but not limited to, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, DMF, DMA, NMP, and acetonitrile. The reaction temperature is usually from -20 to 120°C.

[0377] Wherein, L1 is a halogen, trifluoromethanesulfonate (OTf), or borate group, and L2 is NR. s1 R s2 OR s1 Or OCH2R s2 R s1 It is a C1-C6 alkyl group, R s2 The phenyl group is unsubstituted or optionally substituted with one or more groups selected from the group consisting of C1-C6 alkyl and C1-C6 alkoxy groups; other substituents are defined as described in the first aspect of the invention.

[0378]

[0379] The reaction steps for route B include:

[0380] (a) Intermediate A-1 is first deprotected by the Boc protecting group to generate B-1, under the reaction conditions described in step b of route A.

[0381] (b) Intermediate B-1 undergoes an amide condensation reaction with A-6 to generate B-2, under the reaction conditions described in step e of route A.

[0382] (c) Intermediate B-2 and A coupling reaction occurs to generate a compound of general formula (I), under the reaction conditions described in step a of route A.

[0383]

[0384] The reaction steps in route C include:

[0385] (a) Intermediate A-4 first undergoes hydrolysis or hydrogenolysis to generate C-1, under the reaction conditions described in step d of route A.

[0386] (b) Intermediate C-1 undergoes an amide condensation reaction with A-3 to generate C-2, under the reaction conditions described in step e of route A.

[0387] (c) Intermediate C-2 reacts with hydroxylamine and then undergoes acylation to generate compound of general formula (I), under the reaction conditions described in step c of route A.

[0388]

[0389] Intermediate A-1 can be prepared by a variety of synthetic methods, with the methods shown in routes D through E below representing representative general approaches. It should be understood that the methods for preparing intermediate A-1 are not limited to those shown in routes D through E; they are for illustrative purposes only and do not limit the invention in any way.

[0390] When both Y and Z in the general formula of intermediate A-1 are CH, it can be prepared by the method shown in route D below.

[0391] The reaction steps in route D include:

[0392] (a) Intermediate D-1 undergoes a nucleophilic substitution reaction with D-2 to generate intermediate D-4; the reaction is usually carried out in the presence of a base, including but not limited to potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate, sodium hydroxide, lithium hydroxide, sodium hydride, DBU, triethylamine, DIPEA, pyridine, etc.; the reaction solvent includes but is not limited to dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, DMF, DMSO, DMA, NMP, acetonitrile, etc.; the reaction temperature is usually from 0 to 120°C.

[0393] (b) When R in the general formula of intermediate A-1 1a When H is present, intermediate D-4 can also be prepared by Michael addition of intermediates D-1 and D-3; the reaction is usually carried out in the presence of an organic base, examples of which include, but are not limited to, pyridine, DIPEA, DMAP, triethylamine, and DUB; the reaction does not require a solvent or is carried out in polar solvents such as DMF, methanol, ethanol, tetrahydrofuran, and 1,4-dioxane; the reaction temperature is usually from room temperature to 120°C.

[0394] (c) The amino group of intermediate D-4 is protected by Boc; the reaction conditions are well known to those skilled in the art, and examples can be found in literature or reference books, such as Protecting Groups in Organic Synthesis (Rong Guobin, East China University of Science and Technology Press).

[0395] (d) Intermediate D-5 undergoes intramolecular condensation under the action of a base to generate intermediate D-6; the base includes, but is not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, and sodium hydride; the reaction solvent includes, but is not limited to, tetrahydrofuran, 1,4-dioxane, DMF, DMSO, tert-butanol, etc.; the reaction temperature is usually from room temperature to 120°C.

[0396] (e) Intermediates D-6 and D-7 undergo a condensation reaction to generate intermediate D-8; the reaction is usually carried out in polar solvents such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane; the reaction temperature is usually room temperature to 120°C, preferably the reflux temperature of the solvent used.

[0397] (f) Intermediate D-8 undergoes an acylation reaction to generate D-10; the acylation reagent is D-9; the reaction is usually carried out under the action of a base, which includes, but is not limited to, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, DBU, triethylamine, DIPEA, pyridine, etc.; the reaction solvent includes, but is not limited to, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, DMF, DMA, NMP, acetonitrile, etc., more preferably DMA; the reaction temperature is usually from 0 to 120°C, more preferably room temperature.

[0398] (g) Intermediate D-10 undergoes intramolecular cyclization under the action of acid to form A-1; the acid reagent is, for example but not limited to, trifluoroacetic acid, hydrochloric acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid; the reaction solvent includes, but is not limited to, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, etc., more preferably tetrahydrofuran; the reaction temperature is usually from room temperature to 120°C, more preferably the reflux temperature of the solvent used.

[0399] Where L3 is a leaving group, such as halogens, sulfonates, etc.; L4 is a leaving group, such as Cl, imidazolyl, p-nitrophenoxy, etc.; R s3 It is a C1-C6 alkyl group; R s4 It is a C1-C6 alkyl group, or two R groups. s4 They are linked together to form C2-C6 alkylene groups; other substituents are defined as described in the first aspect of the invention.

[0400]

[0401] When Y is N and Z is CH in the general formula of intermediate A-1, it can be prepared by the method shown in the following route E.

[0402] The reaction steps in route E include:

[0403] (a) Intermediate D-8 undergoes a three-component condensation reaction with methyl hydrazine and trialkyl orthoformate to generate intermediate A-1; the reaction is usually carried out under the catalysis of an acid or base, the acid reagent being, for example but not limited to, acetic acid, p-toluenesulfonic acid, sodium methoxide, sodium ethoxide, sodium tert-butoxide, etc.; the reaction is usually carried out in polar solvents such as DMF, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, etc.; the reaction temperature is usually from room temperature to 120°C, preferably the reflux temperature of the solvent used.

[0404] (b, c) Intermediate A-1 can also be prepared by another method: Intermediate D-8 first undergoes an acylation reaction to generate the active intermediate E-1, and then undergoes a hydrazinolysis reaction to generate intermediate E2; the acylation reagents include, but are not limited to, CDI, triphosgene, and p-nitrophenyl chloroformate; the reaction is usually carried out in aprotic solvents, such as, but not limited to, dichloromethane, dichloroethane, THF, and 1,4-dioxane; the reaction temperature is usually from -20°C to room temperature; the hydrazinolysis reaction usually uses hydrazine hydrate or hydrazine hydrochloride; the reaction solvents include, but are not limited to, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, etc.; the reaction temperature is usually from room temperature to 120°C.

[0405] (d) Intermediate E-1 undergoes a cyclization reaction to generate A-1; the cyclizing reagent is, for example but not limited to, trialkyl orthoformate and methylamidine; the reaction is usually carried out in polar solvents such as DMF, methanol, ethanol, tetrahydrofuran, and 1,4-dioxane; the reaction temperature is usually 50 to 150 °C.

[0406] Wherein, L5 is a leaving group, such as Cl, imidazolium, p-nitrophenoxy, etc.; R s5 It is a C1-C6 alkyl group; other substituents are defined as described in the first aspect of the invention.

[0407]

[0408] Intermediate A-4 can be prepared by a variety of synthetic methods, with the method shown in route F below being a representative general approach. It should be understood that the preparation method of intermediate A-4 is not limited to that shown in route F; it is for illustrative purposes only and does not limit the invention in any way.

[0409] The reaction steps of the method shown in route F include:

[0410] (a) Intermediate F-1 undergoes a nucleophilic substitution reaction with haloacetonitrile to generate F-2; the reaction conditions are as described in step a of route A.

[0411] (b) Intermediate F-2 undergoes hydrolysis or hydrogenolysis to generate F-3, under the reaction conditions described in step d of route A.

[0412] (c) When L2 is NR s1 R s2 At that time, intermediate F-3 and HNR s1 R s2 An amide condensation reaction occurs to generate intermediate F-4, under the reaction conditions described in step e of route A.

[0413] (d) When L2 and OR s6 Similarly, intermediate F-4 can be directly prepared from F-1 by a substitution reaction with a haloacetonitrile; the reaction conditions are as described in step a of route A.

[0414] (e) Intermediate F-4 and alkylating agent L5-R 3a or / and L6-R 3b The reaction produces A-4; the reaction is usually carried out in the presence of a strong organic base, including but not limited to lithium diisopropylamino (LDA), potassium bis(trimethylsilyl)amino (KHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), lithium bis(trimethylsilyl)amino (LiHMDS), and n-butyllithium; the reaction solvent is usually an aprotic solvent, including but not limited to tetrahydrofuran, 1,4-dioxane, DMF, and dichloromethane, with tetrahydrofuran being more preferred; the reaction temperature is usually from -100°C to room temperature.

[0415] L2 is defined as described in route A, and is NR. s1 R s2 OR s1 Or OCH2R s2 R s1 It is a C1-C6 alkyl group, R s2 The phenyl group is unsubstituted or optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy; R s6 It is a C1-C6 alkyl or benzyl group; L5 and L6 are each independently leaving groups, such as halogens, sulfonates, etc.; other substituents are defined as described in the first aspect of the present invention.

[0416]

[0417] When X in intermediate F-1 is a chemical bond, it can be prepared by the method shown in route G below. It should be understood that the preparation method of intermediate F-1 is not limited to that shown in route G; it is for illustrative purposes only and does not limit the invention in any way.

[0418] The reaction steps of route G include:

[0419] (a) Intermediate G-1 is coupled to F-1 via Suzuki, Negishi, Buchwald-Hartwig, Chan-Lam, etc.; coupling reagents include, but are not limited to, boric acid G-2, borate G-3, organozinc reagent G-4, chlorinated derivative G-5, and cyclic amine G-6; the coupling reaction is usually carried out under the action of palladium or copper catalyst, ligand, and base; the reaction conditions are as described in step a of route A. F-1 can be further converted through functional group transformation, such as hydrogenation reduction, to generate other intermediates that also conform to the general formula F-1.

[0420] Among them, R s6 L7 is a C1-C6 alkyl or benzyl group; L8 is a halogen, OTf, or boric acid; L9 are each independently a halogen; and the other substituents are defined as described in the first aspect of this invention.

[0421]

[0422] Pharmaceutical Compositions and Administration

[0423] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. The term "safe and effective range" indicates that, compared to subjects not receiving treatment at that dose, subjects receiving that dose experience a cure, improvement, effective prevention, or a significant reduction in the incidence of lesions or side effects; furthermore, it includes effective doses that enhance normal physiological function. "Safe" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0424] In the pharmaceutical composition, the compound of the present invention serves as the active ingredient, comprising 0.1% to 99.9% of the total weight of the pharmaceutical composition, with the remainder being pharmaceutical excipients. The preferred ratio of the compound of the present invention to the excipients is: the compound of the present invention as the active ingredient comprises more than 60% of the total weight, with the remainder comprising 0-40% of the total weight, preferably 1-20%, and most preferably 1-10%. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg of active ingredient per dose. Preferably, "one dose" refers to one tablet.

[0425] The term "pharmaceutical excipients" refers to pharmaceutically acceptable carriers, excipients, sustained-release agents, odorants, flavoring agents, etc. "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances suitable for human use, and which must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and blend with the active ingredient of the present invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... ), wetting agents (such as sodium dodecyl sulfate), etc.

[0426] In addition to comprising the compound of general formula (I) as the active ingredient, the pharmaceutical composition may further comprise one or more other therapeutic agents. These "other therapeutic agents" may be therapeutic agents for diabetes, cardiovascular disease, obesity, chronic kidney disease, metabolic disorder-associated steatohepatitis (MASH), dementia, Parkinson's disease, or addiction.

[0427] Adjuvants commonly used in the preparation of pharmaceutical compositions may also include flavoring agents, colorings, preservatives, and antioxidants, such as vitamin E, vitamin C, BHT, and BHA.

[0428] The compounds or pharmaceutical compositions described in this invention can be formulated into various dosage forms, such as tablets, capsules, powders, syrups, solutions, suspensions, sprays, creams, ointments, gels, transdermal patches, microneedles, etc., based on conventional processes in the pharmaceutical formulation field, and can be present in suitable solid or liquid carriers or diluents. The pharmaceutical compositions of this invention can also be stored in suitable sterile injection or infusion apparatus. From the standpoint of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules.

[0429] The compounds or pharmaceutical compositions described in this invention can be used clinically in mammals, including humans and animals. There are no particular limitations on the route of administration; representative routes include, but are not limited to, oral administration, nasal inhalation, topical application, intravenous injection, intramuscular injection, and subcutaneous injection. Preferably, the preferred route of administration for the compounds or pharmaceutical compositions described in this invention is oral administration.

[0430] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0431] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0432] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0433] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0434] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0435] Injectable formulations include, but are not limited to, sterile, injectable, aqueous, oil-containing solutions, suspensions, emulsions, etc. These formulations can also be formulated with suitable parenteral diluents, dispersants, wetting agents, suspending agents, etc. Such injectable formulations can be sterilized by filtration through a bacteria-retaining filter. These formulations can also be formulated with bactericides dissolved or dispersed in an injectable medium or using other methods known in the art.

[0436] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0437] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0438] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0439] When used as a pharmaceutical preparation, the compounds or pharmaceutical compositions shown in this invention may be administered once daily or in divided doses. Regardless of the method of administration, the optimal dosage for an individual should be determined based on the specific treatment. Generally, it is advisable to start with a small dose and gradually increase the dose until the most suitable dosage is found.

[0440] Drug combination

[0441] The compounds of this invention can be administered alone or in combination with other known drugs for treating or improving similar conditions.

[0442] The compounds of the present invention can be used in combination with one or more other drugs to treat, prevent, or improve diseases for which the compounds of the present invention or other drugs may be effective, wherein the combination of these drugs is safer or more effective than the use of any one drug alone. The other drugs may be administered simultaneously with, before, or after the compounds of the present invention via the usual route of administration and dosage. When the compounds of the present invention are used simultaneously with one or more other drugs, a unit dosage form of a pharmaceutical composition comprising the other drug and the compound of the present invention is preferred. However, drug combination may also include therapies in which the compounds described herein and one or more other drugs are administered in different overlapping regimens. When used in combination with one or more other active ingredients, the compounds of the present invention and the other drugs may be used at lower doses than when used alone.

[0443] Drugs or active ingredients that can be used in combination with the compounds described in this invention include, but are not limited to, the following drugs for treating obesity: glucagon-like peptide-1 (GLP-1) analogs (such as semaglutide), glucagon (GCG) analogs, peptide YY (PYY) analogs, gastric acid regulating peptide (OXM) analogs, pancreatic polypeptide (PP) analogs, cholecystokinin (CCK) analogs, leptin analogs, amylin analogs, fibroblast growth factor 21 (FGF21) analogs, neuropeptide Y receptor type 2 (Y-2R) agonists, melanocortin receptor 4 (MC4R) agonists, and glucose-dependent insulinotropic peptides. (GIP) receptor agonists, lipase inhibitors (such as orlistat), AMPK agonists, neuropeptide Y5 receptor antagonists, GPR40 agonists, cannabinoid type 1 receptor blockers, naltrexone / bupropion, lorcaserin, phentermine / topiramate obesity vaccines, or dual or multiple receptor modulators based on the GLP-1 receptor, such as GLP-1 / GIP dual receptor agonists (such as Tirzepatide), GLP-1 receptor agonist / GIP receptor antagonist conjugates, GLP-1 / GCG dual receptor agonists, GLP-1 / GIP / GCG triple receptor agonists, GLP-1 / FGF21 fusion proteins, etc.

[0444] Drugs or active ingredients that can be used in combination with the compounds described in this invention include, but are not limited to, the following drugs for treating diabetes: biguanides, thiazolidinediones, meglitinides, sulfonylureas, DPP4 inhibitors, SGLT1 and / or SGLT2 inhibitors, GPR40 agonists, α-glucosidase inhibitors, glucokinase agonists, insulin, insulin analogs, GLP-1 analogs, or dual or multiple receptor modulators based on the GLP-1 receptor, such as GLP-1 / GIP dual receptor agonists (e.g., Tirzepatide), GLP-1 receptor agonist / GIP receptor antagonist conjugates, GLP-1 / GCG dual receptor agonists, GLP-1 / GIP / GCG triple receptor agonists, GLP-1 / FGF21 fusion proteins, etc.

[0445] Drugs or active ingredients that can be used in combination with the compounds described in this invention include, but are not limited to, the following drugs for treating MASH: FXR receptor agonists, PPARα / δ agonists, fibroblast growth factor 19 / 21 analogs, thyroid hormone receptor β agonists, SGLT1 and / or SGLT2 inhibitors, acetyl-CoA carboxylase inhibitors, chemokine receptor-2 / 5 inhibitors, anti-apoptotic signal-regulated kinase 1 inhibitors, ATP-binding transporter 1 agonists, 5-lipoxygenase inhibitors, or vascular adhesion protein 1 inhibitors.

[0446] Indications

[0447] "Diabetic complications" are complications arising from diabetes or hyperglycemia, and they can be acute or chronic. The term "acute complications" includes ketoacidosis and infectious diseases (such as skin infections, soft tissue infections, biliary tract infections, respiratory infections, and urinary tract infections), while "chronic complications" include, for example, microvascular diseases (such as nephropathy and retinopathy), neuropathy (such as sensory nerve disorders, motor nerve disorders, and autonomic nerve disorders), and gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0448] Coronary heart disease includes asymptomatic myocardial ischemia (silent coronary heart disease), myocardial infarction, angina pectoris, ischemic heart failure (ischemic cardiomyopathy), and sudden death.

[0449] "Dementia" includes, for example, Alzheimer's disease, early-onset dementia (EOD), vascular dementia, and diabetic dementia.

[0450] Compared with the prior art, the present invention has the following main advantages:

[0451] (1) The compounds of the present invention have higher blood drug concentrations, oral exposure and oral bioavailability, and therefore have excellent oral pharmacokinetic properties;

[0452] (2) The compounds of the present invention do not activate the β-arrestin 1 or β-arrestin 2 pathways, and are G protein biased agonists, which have the potential to prepare more efficient and safer new drugs;

[0453] (3) The compounds of the present invention can significantly reduce blood sugar and achieve a significant appetite-suppressing effect, which is beneficial for the treatment of diabetes, overweight / obesity and other related diseases;

[0454] (4) The compounds of the present invention can reduce the dosage and side effects, thereby increasing the clinical benefits to patients to a greater extent and improving clinical efficacy.

[0455] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0456] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0457] Unless otherwise specified in the examples, the room temperature reaction temperature is 20℃~35℃.

[0458] In this invention, all chemical reagents and reaction solvents are purchased from commercial companies and are not further purified before use. 1 H nuclear magnetic resonance (H nuclear magnetic resonance) 1 H NMR) and 13 C nuclear magnetic resonance (C 13 C10 NMR spectra were recorded using a Varian Mercury Plus-300, Bruker Avance III 400, or Bruker Avance III 500 NMR spectrometer, with DMSO-d6, CDCl3, or CD3OD as solvents and trimethylsilane as an internal standard. Chemical shifts are expressed in ppm.

[0459] In this invention, the low-resolution mass spectrometry data are obtained from an Agilent liquid chromatography-mass spectrometry system, which consists of an Agilent 1260 Infinity LC and an Agilent 6120 quadrupole mass spectrometer, using electrospray ionization (ESI) as the ion source.

[0460] In this invention, rapid column chromatography was performed on a CombiFlash Rf 200 (Teledyne Tech., USA), and the chromatographic separation used pre-packed silica columns (4-120 g) purchased from Bonna-Agela Technologies Inc., China.

[0461] In this invention, the preparative liquid chromatography purification is performed on a C18 reversed-phase column (Gemini NX-C18, 5μM, 150×21.2mm, Phenomenex, USA), with a detection wavelength of 240nm or 254nm, and typically using acetonitrile and water (V / V) containing 0.5% trifluoroacetic acid as the mobile phase.

[0462] Preparation of intermediates

[0463] Example 1

[0464] Preparation of (2S)-3-cyano-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (intermediate A6)

[0465]

[0466] Step a: Dissolve A1 (18.0 g, 88.6 mmol) in 300 mL of tetrahydrofuran (THF), cool to 0 °C in an ice bath, then add HATU (40.5 g, 106.5 mmol), ammonium chloride (11.9 g, 222.5 mmol), and N,N-diisopropylethylamine (34.2 g, 264.6 mmol), respectively. Under nitrogen protection, stir overnight at room temperature. After the reaction is complete, dilute the reaction solution with 300 mL of ethyl acetate, wash three times with water, and three times with saturated brine. Dry the organic phase with anhydrous sodium sulfate and filter. Concentrate the filtrate under reduced pressure. Separate the crude product by column chromatography to obtain 11.4 g of intermediate A2.

[0467] Step b: Dissolve A2 (11.4 g, 56.4 mmol) in 8 mL THF, add pyridine (10.7 g, 135.3 mmol), cool in an ice bath to 0–5 °C, then add trifluoroacetic anhydride (14.3 g, 67.9 mmol), and stir at room temperature. After the reaction is complete, quench the reaction with 60 mL of water, extract three times with ethyl acetate, wash three times with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 6.3 g of intermediate A3.

[0468] Step c: Add 59.7 mL of 4 M hydrogen chloride / 1,4-dioxane solution (238.7 mmol) to A3 (6.3 g, 34.1 mmol) and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure and evaporate to dryness to obtain intermediate A4.

[0469] Steps d and e: Dissolve A4 (the concentrate obtained in the previous step) in 40 mL of anhydrous ethanol, add ethyl acrylate (4.1 g, 41.0 mmol) and triethylamine (5.2 g, 51.4 mmol), and react at 70 °C for 3 hours. After the reaction is complete, cool to room temperature, add di-tert-butyl dicarbonate (9.0 g, 41.2 mmol), and stir overnight at room temperature. Concentrate under reduced pressure to remove anhydrous ethanol, extract three times with water and ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 8.0 g of intermediate A5.

[0470] Step f: Dissolve A5 (8.0 g, 28.1 mmol) in 50 mL of anhydrous THF, add potassium tert-butoxide (6.3 g, 56.2 mmol), and stir at room temperature. After the reaction is complete, adjust the pH to 6-7 with dilute hydrochloric acid, extract three times with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 3.3 g of intermediate A6. ESI-MS m / z: 239.3 [M+H] + .

[0471] Example 2

[0472] Preparation of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (intermediate B5)

[0473]

[0474] Step a: Dissolve B1 (10.0 g, 49.2 mmol) in 100 mL of anhydrous THF under nitrogen protection and cool to below -70°C. Slowly add 2.4 M n-butyllithium (22.6 mL, 54.2 mmol) dropwise, controlling the reaction solution temperature to not exceed -70°C. After the addition is complete, stir at -70°C for 1 hour. Then dissolve di-tert-butyl azodicarbonate (11.3 g, 49.2 mmol) in 50 mL of anhydrous toluene and add it dropwise to the reaction solution, controlling the reaction solution temperature to not exceed -40°C. After the addition is complete, stir at -40°C for 30 minutes. Transfer to room temperature and continue the reaction for 1 hour. After the reaction is complete, quench the reaction with 100 mL of saturated ammonium chloride solution, extract three times with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Add 35 mL of n-heptane to the crude product, heat to 70°C, and stir for 30 minutes. The temperature was slowly lowered until a solid precipitated at 20–30°C. The temperature was then further lowered to 0–10°C for 1 hour to allow crystallization. The mixture was filtered, and the filter cake was washed with a small amount of n-heptane and dried at 45°C for about 3 hours to obtain 9.3 g of intermediate B2.

[0475] Steps b and c: Dissolve B2 (6.1 g, 17.2 mmol) in 50 mL of dichloromethane (DCM), add trifluoroacetic acid (39.2 g, 343.8 mmol), and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution under reduced pressure to dryness. Then add 50 mL of anhydrous ethanol, pyridine hydrochloride (198.8 mg, 1.7 mmol), and intermediate A6 (3.3 g, 13.8 mmol), and heat under reflux for 2 hours. After the reaction is complete, concentrate under reduced pressure to remove anhydrous ethanol, extract three times with water and ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 5.5 g of intermediate B3.

[0476] Step d:

[0477] 1) Preparation of N-(2,2-dimethoxyethyl)-1H-imidazolium-1-carboxamide: 3.24 g (20 mmol) of carbonyl diimidazole (CDI) was dissolved in 8 mL of ethyl acetate under nitrogen protection and placed in an ice bath. Then, 2.17 mL (20 mmol) of aminoacetaldehyde dimethyl acetal was added dropwise using a syringe, and the mixture was stirred at room temperature for 3 hours after the addition was complete. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the extracts were combined and washed three times with brine. The solution was dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. 3.07 g of oil was obtained by column chromatography and could be solidified.

[0478] 2) Dissolve B3 (5.5 g, 14.7 mmol) in 40 mL of N,N-dimethylacetamide (DMA), add N-(2,2-dimethoxyethyl)-1H-imidazol-1-carboxamide (3.2 g, 16.1 mmol) and potassium tert-butoxide (4.9 g, 43.7 mmol), and stir overnight at room temperature. After completion, add water, extract three times with ethyl acetate, wash three times with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 4.0 g of intermediate B4.

[0479] Step e: Dissolve B4 (4.0 g, 7.9 mmol) in 40 mL THF, add methanesulfonic acid (759.3 mg, 7.9 mmol), and react at 60 °C for 2 hours. After reaction, cool to room temperature, add potassium phosphate (1.7 g, 7.9 mmol), di-tert-butyl dicarbonate (1.7 g, 7.9 mmol), and 16 mL water, and stir overnight at room temperature. Extract three times with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 2.2 g of intermediate B5. ESI-MS m / z: 442.3 [M+H] + .

[0480] Example 3

[0481] Preparation of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (intermediate C9)

[0482]

[0483] Step a: Add zinc powder (2.93 g, 44.7 mmol) to 12 mL of N,N-dimethylformamide (DMF), and add chlorotrimethylsilane (610 mg, 5.6 mmol) and 1,2-dibromoethane (1.05 g, 5.6 mmol) dropwise under N2 atmosphere. Stir at room temperature for half an hour, then add a solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (5.37 g, 22.4 mmol) dissolved in 6 mL of DMF, and stir at room temperature for half an hour.

[0484] Step b: Add ethyl 5-bromo-1H-indole-2-carboxylic acid C1 (3.00 g, 11.2 mmol), palladium acetate (251 mg, 1.12 mmol), and 4-(di-tert-butylphosphino)-N,N-dimethylaniline (594 mg, 2.24 mmol) to 12 mL of LMF. Under a nitrogen atmosphere, add the mixture from step a to step b, heat to 50 °C, and stir for two hours. After the reaction is complete, place the reaction solution in an ice bath, slowly add 4 M HCl to adjust the pH to 4-5, then add water and extract three times with ethyl acetate. Wash the organic phase three times with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify the crude product by column chromatography to obtain 2.32 g of intermediate C2.

[0485] Step c: Dissolve intermediate C2 (1.41 g, 4.69 mmol) in 12 mL DMF. Cool the reaction solution to 0 °C, add sodium hydride (60% in oil, 376 mg, 9.39 mmol), and stir at 0 °C for one hour. Then add 2-chloroacetonitrile (1.06 g, 14 mmol), slowly restore to room temperature, and stir overnight. After the reaction is complete, slowly pour the reaction solution into water, extract three times with ethyl acetate, wash the organic phase three times with saturated brine to remove residual solvent, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude product. The crude product is purified by column chromatography to obtain 1.5 g of intermediate C3.

[0486] Step d: Dissolve intermediate C3 (1.5 g, 4.42 mmol) in a mixed solvent of THF and water (2:1; 15 mL). Add lithium hydroxide monohydrate (223 mg, 5.3 mmol). After the reaction is complete, dilute the reaction solution with water, add 4 M HCl dropwise to adjust the pH to 7, then evaporate THF. Continue to adjust the pH to 1-3, after which a large amount of solid precipitates. Filter, collect the solid, and dry to obtain 1.07 g of intermediate C4.

[0487] Step e: Dissolve intermediate C4 (1.07 g, 3.43 mmol) in 10 mL of DMF, add HATU (1.95 g, 5.14 mmol) and DIPEA (1.33 g, 10.3 mmol), stir at room temperature for half an hour, then add N-methylaniline (551 mg, 5.14 mmol), and stir at 60 °C for two and a half hours. After the reaction is complete, pour the reaction solution into water, and a large amount of pure solid precipitates. Filter the solid and dry it to obtain 1.1 g of intermediate C5.

[0488] Step f: Add intermediate C5 (1.00 g, 2.49 mmol) and (R)-4-methyl-1,3,2-dioxothiacyclohexane 2,2-dioxide (1.03 g, 7.47 mmol) to N,N-dimethylpropenylurea (10 mL). Replace the N2 in the reaction system, lower the reaction temperature to 0 °C, and slowly add bis(trimethylsilyl)amino potassium (9.96 mL, 9.96 mmol, 1 M). After the addition is complete, stir at 0 °C for three hours. After the reaction is complete, pour the reaction solution into a saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, wash the organic phase three times with saturated brine to remove residual solvent, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by column chromatography to obtain 700 mg of intermediate C6.

[0489] Step g: Dissolve intermediate C6 (297 mg, 672 μmol) in ethanol (3 mL), add hydroxylamine hydrochloride (234 mg, 3.36 mmol) and potassium carbonate (511 mg, 3.7 mmol). Heat the reaction mixture to 100 °C and stir for two hours. After the reaction is complete, add water and extract three times with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain 295 mg of intermediate C7.

[0490] Step h: Intermediate C7 (3.8 g, 8.01 mmol) was dissolved in 1,4-dioxane (38 mL), and N,N'-carbonyldiimidazole (2.26 g, 16.01 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.02 g, 20.02 mmol) were added. The reaction solution was heated to 80 °C and stirred for one hour. After the reaction was completed, the crude product was directly concentrated to obtain the crude product, which was then separated by column chromatography to obtain 3.6 g of intermediate C8.

[0491] Step i: Intermediate C8 (249 mg, 498 μmol) was dissolved in 2-methoxyethanol (3 mL), and potassium hydroxide (279 mg, 4.98 mmol) was added. The reaction mixture was heated to 130 °C and stirred overnight. After the reaction was complete, water was added, and the pH was adjusted to 4 with a 4 M HCl aqueous solution. The mixture was extracted five times with a dichloromethane / methanol (10:1, v / v) mixed solvent. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 186 mg of intermediate C9. ESI-MS m / z: 412.3 [M+H] + .

[0492] Example 4

[0493] Preparation of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (intermediate C9-1)

[0494]

[0495] Intermediate C6 was separated using preparative liquid chromatography (Shimadzu, model: LC-20AT) and a CHIRALPAK AD-H chiral column (Shanghai Daicel, column size: 0.46cm I.D. × 15cm L). Elution was performed using MeOH containing 0.1% diethylamine (V / V) as the mobile phase (flow rate: 1.0 ml / min; detection wavelength: 214 nm). The fractions were collected, and the solvent was removed by rotary evaporation to obtain the chiral isomer C6-1, with a retention time of 5.42 min. The ee value was greater than 98%.

[0496] Intermediate C9-1 was synthesized using the same method as C9, except that intermediate C6-1 was used instead of C6 as the starting material. ESI-MS m / z: 412.3 [M+H] + .

[0497] Example 5

[0498] Preparation of (S)-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (intermediate D5)

[0499]

[0500] Step a: 900 mg (1 equivalent) of 3-cyclopropyl-4-fluoroaniline was suspended in 30 mL of concentrated hydrochloric acid and placed in an ice bath. 493 mg (1.5 equivalent) of sodium nitrite was added, and the mixture was stirred for 0.5 hours. Then, 3.39 g (3 equivalent) of SnCl2 was dissolved in 50 mL of concentrated hydrochloric acid and added dropwise to the reaction mixture. After the addition was complete, stirring was continued for 0.5 hours. After the reaction was complete, 150 mL of water was added to the reaction mixture, and the pH was adjusted to 8 with a 2M sodium hydroxide aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined and washed twice with brine. The solution was dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated to dryness. Then, 5 mL of a 2M hydrogen chloride / methanol solution was added to the residue, and the mixture was stirred for 5 min. 20 mL of diethyl ether was then added to precipitate a solid. The solid was collected by filtration and dried to obtain intermediate D-2.

[0501] Step b: Dissolve 2.3 g (1 equivalent) of intermediate D2, 148 mg of pyridine hydrochloride (0.1 equivalent), and 2.43 g (0.8 equivalent) of intermediate A6 in 25 mL of anhydrous ethanol and heat under reflux for 2 hours. After the reaction is complete, concentrate under reduced pressure to remove the ethanol, and separate the remaining crude product by column chromatography to obtain 2.08 g of intermediate D3.

[0502] Step c: Dissolve 2.08 g (1 equivalent) of intermediate D3 in 16 mL of DMA, then add 1.21 g (1.1 equivalent) of N-(2,2-dimethoxyethyl)-1H-imidazol-1-carboxamide (preparation method as described in Example 2) and 1.81 g (3 equivalent) of potassium tert-butoxide, and stir overnight at room temperature. After the reaction is complete, quench with water, extract three times with ethyl acetate, combine the organic phases, wash three times with saturated brine, and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 2.22 g of intermediate D4.

[0503] Step d: Dissolve 2.22 g (1 equivalent) of intermediate D4 in 23 mL of THF, add 0.36 mL (1.3 equivalent) of methanesulfonic acid, and react at 60 °C for 2 hours. After the reaction is complete, cool to room temperature, add 1.83 g (2 equivalents) of potassium phosphate, 1.03 g (1.1 equivalents) of di-tert-butyl dicarbonate and 9 mL of water, and stir overnight at room temperature. After the reaction is complete, dilute with water, extract three times with ethyl acetate, combine the organic phases, wash three times with saturated brine, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 1.2 g of intermediate D5.

[0504] 1H NMR (600MHz, CDCl3) δ10.35(s,1H,-NH),7.18-7.11(m,1H),7.01(t,1H,J=9.0 ),6.92(dd,1H,J=6.6,1.8),6.35(t,1H,J=2.4),6.10(s,1H),5.41-5.07(m,1H ),4.58-4.20(m,1H),3.22-2.97(m,1H),2.88-2.69(m,2H),2.11-2.03(m,1H), 1.49(s,9H),1.28(d,3H,J=6.6),0.96-0.91(m,2H),0.68-0.61(m,2H); ESI-MS m / z: 454.3 [M+H] + .

[0505] Example 6

[0506] Preparation of (S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (intermediate E5)

[0507] The synthesis method of intermediate E5 is the same as that of intermediate D5, except that 4-fluoro-3-trifluoromethylaniline is used instead of 3-cyclopropyl-4-fluoroaniline as the starting material.

[0508] 1 H NMR (600MHz, CDCl3) δ9.72(s,1H,-NH),7.74(s,1H),7.59(m,1H),7.23(t,1H,J=9.0),6.41(s,1H),6.18(s,1H),5. 41-5.09(m,1H),4.59-4.23(m,1H),3.21-3.30(m,1H),2.88-2.71(m,2H),1.49(s,9H),1.28(d,3H,J=5.4); ESI-MS m / z:482.4[M+H] + .

[0509] Example 7

[0510] Preparation of (S)-2-(3,5-dichloro-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (intermediate F5)

[0511]

[0512] The synthesis method of intermediate F5 is the same as that of intermediate D5, except that 3,5-dichloro-4-fluoroaniline is used instead of 3-cyclopropyl-4-fluoroaniline as the starting material.

[0513] 1 H NMR (500MHz, CDCl3) δ9.95 (s, 1H, -NH), 7.42 (d, 2H, J = 6.0), 6.45 (t, 1H, J = 2.5), 6.20 (s, 1H), 5.40-5.10 ( m,1H),4.57-4.23(m,1H),3.18-2.99(m,1H),2.85-2.69(m,2H),1.49(s,9H),1.26(d,3H,J=6.5); ESI-MS m / z:482.2[M+H] + .

[0514] Example 8

[0515] Preparation of 1-((2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (intermediate G9)

[0516]

[0517] The synthesis method of intermediate G9 is the same as that of intermediate C9, except that 4-iodo-tetrahydro-2H-pyran is used instead of 4-iodo-2,2-dimethyltetrahydro-2H-pyran as the starting material.

[0518] ESI-MS m / z: 384.2 [M+H] + .

[0519] Example 9

[0520] Preparation of tert-butyl(S)-2-(3-bromo-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid ester (intermediate H5)

[0521]

[0522] The synthesis method of intermediate H5 is the same as that of intermediate D5, except that 3-bromo-4-fluoroaniline is used instead of 3-cyclopropyl-4-fluoroaniline as the starting material.

[0523] 1H NMR (500MHz, CDCl3) δ9.53(s,1H,-NH),7.70(dd,1H,J=6.0,2.5),7.30(ddd,1H,J=8.5,4.0,2.5),7.13(t,1H,J=8.5),6.40(t,1H, J=2.5),6.16(s,1H),5.42-5.13(m,1H),4.59-4.22(m,1H),3.21-3.30(m,1H),2.86-2.70(m,2H),1.49(s,9H),1.27(d,3H,J=7.0);

[0524] ESI-MS m / z: 492.2 [M+H] + .

[0525] Preparation of compounds

[0526] Example 1

[0527] Preparation of 3-((1S,2S)-1-(2-(S)-3-(3-(3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 1)

[0528]

[0529] Step a: Add 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 1 equivalent), morpholine (198 mg, 1 equivalent), and potassium carbonate (471 mg, 1.5 equivalent) to 8 mL of DMSO, then stir and heat at 120 °C for 1 h. After cooling, add 50 mL of water to the reaction mixture, extract three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, and dry with anhydrous magnesium sulfate. Filter, and evaporate the filtrate under reduced pressure to dryness to obtain 653 mg of intermediate 1-A, which was used directly in the next reaction without purification.

[0530] Step b: Dissolve intermediate 1-A in a mixed solution of 9 mL ethanol and 1 mL water. Add reduced iron powder (635 mg, 5 equivalents) and glacial acetic acid (205 mg, 1.5 equivalents) to the reaction solution, and then reflux at 90 °C for 1 h. After cooling, add 20 mL water and 20 mL ethyl acetate and stir for 10 min. Filter to remove insoluble matter, and separate the filtrate into organic phases. Extract the aqueous phase with 20 mL ethyl acetate. Combine the organic phases, wash twice with brine, and dry with anhydrous sulfuric acid. Filter, evaporate the filtrate to dryness under reduced pressure, and separate the residue by rapid column chromatography, eluting with a petroleum ether-ethyl acetate solvent system to give 370 mg of solid, i.e., intermediate 1-B. The overall yield of the two steps is 63%.

[0531] Step c: Dissolve 370 mg of intermediate 1-B in 8 mL of ethyl acetate, add 6 mL of 30% hydrogen peroxide solution, and then reflux at 85 °C overnight. After cooling, add 30 mL of saturated Na₂CO₃ solution and stir for 15 minutes, then extract three times with ethyl acetate. Combine the organic phases, wash three times with saturated brine, and dry to anhydrous magnesium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, and separate the residue by rapid column chromatography, eluting with a petroleum ether-ethyl acetate solvent system to give 233 mg of solid, i.e., intermediate 1-C, with a yield of 64%. 1 H NMR (500MHz, CDCl3) δ7.58 (d, 1H, J = 8.5), 7.50 (d, 1H, J = 2.0), 7.39 (dd, 1H, J = 8.5, 1.5), 5.02 (s, 2H), 4.22-4.18 (m, 2H), 4.16-4.12 (m, 2H); ESI-MS m / z:253.1[M+H] + .

[0532] Step d: Add intermediate B5 (60 mg, 1 equivalent), intermediate 1-C (69 mg, 2 equivalent), and (1S,2S)-N to 2 mL of N-methylpyrrolidone (NMP). 1 N 2 Dimethylcyclohexane-1,2-diamine (10 mg, 0.5 equivalents), CuI (5.2 mg, 0.2 equivalents), and potassium carbonate (56 mg, 3 equivalents) were added. The mixture was purged with nitrogen several times, then heated and stirred overnight at 130 °C. After cooling, 30 mL of water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by preparative thin-layer chromatography (TLC) to give 46 mg of a pale yellow solid, intermediate 1-D, in 55% yield. 1H NMR (500MHz, CDCl3) δ7.79(d,1H,J=2.0),7.76(d,1H,J=8.5),7.24(d,1H,J=8 .0),7.10(d,2H,J=6.0),6.75(d,1H,J=3.0),6.30(d,1H,J=3.0),5.46-5.14(m ,1H),5.05(s,2H),4.58-4.26(m,1H),4.26-4.13(m,4H),3.25-3.04(m,1H),2 .88-2.73(m,2H),2.22(d,6H,J=2.0),1.50(s,9H),1.33(d,3H,J=6.5); ESI-MS m / z: 614.4 [M+H] + .

[0533] Steps e and f: Dissolve 46 mg (1 equivalent) of intermediate 1-D in 3 mL of dichloromethane (DCM), add 280 μL of HCl-dioxane solution (4 M, 15 equivalents), stir overnight at room temperature, and then evaporate to dryness under reduced pressure. Redissolve the residue in a small amount of DCM, and evaporate to dryness under reduced pressure again, repeating this process twice. Dissolve the resulting residue in 2.5 mL of dry N,N-dimethylformamide (DMF), then add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 31 mg, 1.1 equivalents), N,N-diisopropylethylamine (DIPEA, 49 mg, 5 equivalents), and intermediate C9 (34 mg, 1.1 equivalents), and stir at room temperature for 2 hours until the reaction is complete. Add 10 mL of water to the reaction solution, and then extract three times with ethyl acetate. Combine the organic phases, wash twice with saturated brine, and then dry with anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by preparative thin-layer chromatography (TLC) or further purified by preparative liquid chromatography, using acetonitrile and water (v / v) containing 0.5% trifluoroacetic acid as the mobile phase. The target product fraction was collected, lyophilized, and yielded 24 mg of an off-white solid, namely compound 1, with a yield of 35%.

[0534] 1¹H NMR (500MHz, CDCl₃, 4:1 rotatimer) δ 11.34 / 11.26 (s, ¹H, -NH), 7.82 / 7.60 (s, ¹H), 7.78 / 7.67 (d, ¹H, J = 8.5), 7.59 / 7.55 (d, ¹H, J = 8.5), 7.52 / 7.48 (s, ¹H), 7.31–7.20 (m, 2H), 7.14 / 7.05 (d, 2H, J = 6.0), 6.80 / 6.65 (d, ¹H, J = 3.0), 6.70 / 6.69 (s, ¹H), 6.33 / 6.11 (d, ¹H, J = 2.5), 5.80 / 5.26 (q, ¹H, J =6.5),5.06 / 5.02(s,2H),4.47 / 4.87(dd,1H,J=13.5,4.5),4.27-4.03( m,4H),3.91-3.77(m,2H),3.60 / 3.40(td,1H,J=13.5,3.5),3.20-2.94( m,3H),2.26 / 2.22(s,6H),1.93-1.71(m,4H),1.68-1.49(m,3H),1.55(d ,3H,J=6.5),1.34 / 1.32(s,3H),1.29(s,3H),1.18 / 1.07(d,3H,J=5.5);

[0535] ESI-MS m / z: 907.5 [M+H] + .

[0536] Example 2

[0537] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-8-yl)-2,3-dihydro-1H-imidazo-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 2)

[0538]

[0539] The synthesis method of compound 2 is the same as that of compound 1, except that piperidine is used instead of morpholine as the starting material.

[0540] 1¹H NMR (500MHz, CDCl₃, 3:1 rotatimer) δ 11.34 / 11.27 (s, ¹H, -NH), 7.73 / 7.62 (d, ¹H, J = 8.0), 7.72 / 7.50 (s, ¹H), 7.60 / 7.57 (d, ¹H, J = 8.5), 7.52 / 7.48 (s, ¹H), 7.31-7.19 (m, 2H), 7.14 / 7.05 (d, 2H, J = 5.5), 6.77 / 6.63 (d, ¹H, J = 2.5), 6.70 / 6.69 (s, ¹H), 6.31 / 6.09 (d, ¹H, J = 2.0), 5.80 / 5.26 (q, ¹H, J = 6. 5),4.47 / 4.87(dd,1H,J=14.0,4.5),4.14 / 3.98(t,2H,J=5.5),3.92-3. 78(m,2H),3.60 / 3.40(td,1H,J=13.0,3.0),3.20-2.94(m,5H),2.26 / 2.2 2(s,6H),2.19-1.98(m,4H),1.93-1.72(m,4H),1.68-1.49(m,3H),1.55( d,3H,J=6.0),1.34 / 1.32(s,3H),1.29(s,3H),1.19 / 1.07(d,3H,J=5.5);

[0541] ESI-MS m / z: 905.6 [M+H] + .

[0542] Example 3

[0543] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(6-fluoro-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 3)

[0544]

[0545] The synthesis method of compound 3 is the same as that of compound 1, except that 1-bromo-2,3-difluoro-4-nitrobenzene is used instead of 4-bromo-2-fluoro-1-nitrobenzene as the starting material.

[0546] 1¹H NMR (500MHz, CDCl₃, 4:1 rotatimer) δ 11.31 (s, ¹H, -NH), 7.59 (d, ¹H, J = 9.0), 7.57 / 7.54 (d, ¹H, J = 8.5), 7.52 / 7.50 (s, ¹H), 7.29–7.21 (m, 2H), 7.17 / 7.08 (d, 2H, J = 6.5), 6.70 / 6.71 (s, ¹H), 6.59 / 6.44 (d, ¹H, J = 3.0), 6.32 / 6.08 (d, ¹H, J = 3.0), 5.79 / 5.26 (q, ¹H, J = 6.5), 5.05 / 5.0 2(s,2H),4.53-4.37(m,3H),4.22 / 4.19(t,2H,J=5.0),3.91-3.79(m,2H),3.60 / 3.39(td,1H,J=13.0,3.5),3.19-2.96(m,3H),2.29 / 2. 25(d,6H,J=1.5),1.94-1.71(m,4H),1.70-1.49(m,3H),1.57(d,3H,J=6.5),1.34 / 1.33(s,3H),1.28(s,3H),1.20 / 1.07(d,3H,J=6.0);

[0547] ESI-MS m / z: 924.6 [M+H] + .

[0548] Example 4

[0549] Preparation of 3-((1S,2S)-1-(2-(S)-3-(3-(3,3-dimethyl-3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 4)

[0550]

[0551] The synthesis method of compound 4 is the same as that of compound 1, except that 2,2-dimethylmorpholine is used instead of morpholine as the starting material.

[0552] 1¹H NMR (500MHz, CDCl₃, 4:1 rotatimer) δ 11.32 (s, ¹H, -NH), 7.78 / 7.67 (d, ¹H, J = 8.5), 7.77 / 7.56 (s, ¹H), 7.59 / 7.55 (d, ¹H, J = 8.5), 7.52 / 7.48 (s, ¹H), 7.29–7.21 (m, 2H), 7.14 / 7.05 (d, 2H, J = 6.0), 6.79 / 6.65 (d, ¹H, J = 3.0), 6.71 / 6.69 (s, ¹H), 6.33 / 6.12 (d, ¹H, J = 2.5), 5.79 / 5.23 (q, ¹H, J = 6.5), 5.06 / 5.03 (s, 2H). 4.47 / 4.87(dd,1H,J=14.0,5.0),4.00 / 3.90(s,2H),3.90-3.77(m,2H),3.60 / 3.39(td,1H,J=13.0,3.5),3.21-2.96(m,3H),2.26 / 2.22(d,6H,J=1.5),1. 93-1.71(m,4H),1.68-1.50(m,3H),1.55(d,3H,J=6.5),1.45 / 1.43(s,3H),1 .44 / 1.42(s,3H),1.34 / 1.32(s,3H),1.29(s,3H),1.19 / 1.08(d,3H,J=5.5);

[0553] ESI-MS m / z: 935.6 [M+H] + .

[0554] Example 5

[0555] Preparation of 3-((1S,2S)-1-(2-(S)-3-(3-(benzo[4,5]imidazo[1,2-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 5)

[0556]

[0557] The preparation method of intermediate 5-C is as described in patent TW201639840.

[0558] The synthesis method of compound 5 is the same as that of compound 1, except that intermediate 5-C is used instead of intermediate 1-C as the raw material.

[0559] 1 ¹H NMR (600MHz, CDCl₃, 7:2 rotatimer) δ 11.36 / 11.26 (s, ¹H, -NH), 8.84–7.90 (m, 6H), 7.95 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.50–7.44 (m, ¹H), 7.30–7.21 (m, ¹H), 7.12 / 7.05 (d, 2H, J = 3.6), 7.04 / 6.89 (s, ¹H), 6.71 / 6.70 (s, ¹H), 6.39 / 6.23 (s, ¹H), 5.8 4 / 5.27(m,1H),4.49 / 4.84(dd,1H,J=13.2,4.2),3.92-3.78(m,2H),3.59 / 3.41(m,1H),3.20-2.97(m,3H),2.27 / 2.22( s,6H),1.93-1.70(m,4H),1.68-1.46(m,3H),1.52(d,3H,J=6.0),1.35(s,3H),1.29(s,3H),1.18 / 1.08(d,3H,J=6.0);

[0560] ESI-MS m / z: 901.5 [M+H] + .

[0561] Example 6

[0562] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 6)

[0563]

[0564] Step b: Under a nitrogen atmosphere, 500 mg (1 equivalent) of starting material 6-A and 10.3 mL of borane-THF solution (1.0 M, 5 equivalents) were heated overnight at 70 °C in 10 mL of dry THF. TLC showed that the reaction was complete. After cooling, 30 mL of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed twice with brine, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to give 440 mg of a white solid, namely intermediate 6-B, which was used directly in the next step of the reaction.

[0565] Step c: Dissolve 440 mg (1 equivalent) of intermediate 6-B in 10 mL of DCM, then add 1.56 g of formaldehyde aqueous solution (37% m / m, 10 equivalents) and 818 mg of NaBH(OAc)3 (1 equivalent), and stir overnight at room temperature. Quench with saturated potassium carbonate solution, stir for 1 h, extract three times with DCM, combine the organic phases, wash once with brine, and dry with anhydrous magnesium sulfate. Filter, evaporate the filtrate to dryness to obtain the crude product, and separate by rapid column chromatography to obtain 350 mg of oil, i.e., intermediate 6-C. 1 H NMR (500MHz, CDCl3) δ7.17(d,1H,J=2.0),7.13(dd,1H,J=8.0,2.0),7.01(d,1 H,J=8.0),4.07(t,2H,J=4.5),3.69(s,2H),2.98(t,2H,J=4.5),2.40(s,2H).

[0566] Step d: The synthesis method of intermediate 6-D is the same as that of 1-D, except that intermediate 6-C is used instead of 1-C as the raw material. 1 HNMR (500MHz, CDCl3) δ7.26-7.19(m,3H),7.07(d,2H,J=6.5),6.65(d,1H,J=3.0 ),6.26(brs,1H),5.41-5.11(m,1H),4.57-4.23(m,1H),4.11(t,2H,J=4.5),3.77 (s,2H),3.24-3.05(m,1H),3.03(t,2H,J=4.5),2.85-2.73(m,2H),2.42(s,3H), 2.21 (d, 6H, J = 2.0), 2.06-1.98 (m, 1H), 1.49 (s, 9H), 1.30 (d, 3H, J = 7.0).; ESI-MS m / z: 602.5 [M+H] + .

[0567] Steps d and f: The synthesis method of compound 6 is the same as that of compound 1, except that intermediate 6-D is used instead of intermediate 1-D as the raw material.

[0568] 1¹H NMR (600MHz, CDCl₃, 4:1 rotatimer) δ 11.28 (s, ¹H, -NH), 7.58 / 7.56 (d, ¹H, J = 8.4), 7.52 / 7.48 (s, ¹H), 7.40 (s, ¹H), 7.35-7.31 (m, 2H), 7.28-7.23 (m, 1H), 7.11 / 7.01 (d, 2H, J = 6.6), 6.73 / 6.57 (d, ¹H, J = 3.0), 6.70 / 6.68 (s, ¹H), 6.31 / 6.09 (d, ¹H, J = 3.0), 5.76 / 5.23 (q, ¹H, J = 6.6), 4.46 / 4.86 (dd, ¹H, J = 13.8, 4. 8),4.26 / 4.18(t,2H,J=4.2),4.10 / 3.99(s,2H),3.90-3.78(m,2H),3.59 / 3 .39(td,1H,J=13.2,3.6),3.34 / 3.26(m,2H),3.18-2.96(m,3H),2.67 / 2.62 (s,3H),2.25 / 2.21(d,6H,J=1.2),1.92-1.70(m,4H),1.65-1.45(m,3H),1. 51(d,3H,J=6.5),1.34 / 1.33(s,3H),1.28(s,3H),1.18 / 1.06(d,3H,J=6.0);

[0569] ESI-MS m / z: 896.6 [M+H] + .

[0570] Example 7

[0571] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 6-1)

[0572]

[0573] The synthesis method of compound 6-1 is the same as that of compound 6, except that the chiral intermediate C9-1 is used instead of C9 as the starting material.

[0574] ESI-MS m / z: 896.6 [M+H]+ .

[0575] Example 8

[0576] Preparation of 8-(3-((4S)-5-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-ethyl-3,4-dihydrobenzo[f][1,4]oxazapyro-5(2H)-one (compound 7)

[0577]

[0578] The preparation method of intermediate 7-C is as described in patent EP3666772.

[0579] The synthesis method of compound 7 is the same as that of compound 1, except that intermediate 7-C is used instead of intermediate 1-C as the raw material.

[0580] ESI-MS m / z: 924.6 [M+H] + .

[0581] Example 9

[0582] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazono-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 8)

[0583]

[0584] The preparation method of intermediate 8-C is the same as that of 6-C, except that 40% (m / m) acetaldehyde aqueous solution is used instead of formaldehyde aqueous solution as raw material.

[0585] The synthesis method of compound 8 is the same as that of compound 1, except that intermediate 8-C is used instead of intermediate 1-C as the raw material.

[0586] ESI-MS m / z: 910.7 [M+H] +.

[0587] Example 10

[0588] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(dibenzo[b,d]furan-2-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 9)

[0589]

[0590] The synthesis method of compound 9 is the same as that of compound 1, except that 2-bromodibenzo[b,d]furan is used instead of intermediate 1-C as the starting material.

[0591] 1 ¹H NMR (500MHz, CDCl₃, 3:1 rotatimer) δ 11.33 / 11.28 (s, ¹H, -NH), 8.16 / 7.96 (d, ¹H, J = 2.0), 7.99 / 7.85 (d, ¹H, J = 7.5), 7.68-7.46 (m, 6H), 7.39 (t, ¹H, J = 7.5), 7.29-7.22 (m, ¹H), 7.16 / 7.07 (d, 2H, J = 6.0), 6.81 / 6.66 (d, ¹H, J = 3.0), 6.71 / 6.69 (s, ¹H), 6.37 / 6.13 (d, ¹H, J = 3.0). 0),5.80 / 5.29(q,1H,J=6.6),4.48 / 4.88(dd,1H,J=13.2,5.4),3.92-3.77(m,2H),3.61 / 3.41(td,1H,J=13.2,3.0),3.20-2.97(m,3H ),2.28 / 2.24(s,6H),1.93-1.70(m,4H),1.68-1.50(m,3H),1.57(d,3H,J=6.6),1.35(s,3H),1.29(s,3H),1.19 / 1.07(d,3H,J=6.0);

[0592] ESI-MS m / z: 901.6 [M+H] + .

[0593] Example 11

[0594] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(benzo[4,5]imidazo[1,2-a]pyridin-8-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 10)

[0595]

[0596] The preparation method of intermediate 10-C is as described in the paper Eur J Org Chem (2011, 27, 5242.).

[0597] The synthesis method of compound 10 is the same as that of compound 1, except that intermediate 10-C is used instead of intermediate 1-C as the raw material.

[0598] 1 ¹H NMR (600MHz, CDCl₃, 4:1 rotatimer) δ 11.37 / 11.24 (s, ¹H, -NH), 8.73–8.67 / 8.46–8.36 (m, ²H), 8.19–8.12 / 8.10–8.02 (m, ²H), 7.77 / 7.72 (t, ¹H, J = 7.8), 7.63 / 7.47 (dd, ¹H) H,J=9.0,1.8),7.59 / 7.57(d,1H,J=9.0),7.53 / 7.46(s,1H),7.29-7.25(m,1H),7. 21(t,1H,J=6.6),7.13 / 7.05(d,2H,J=6.0),6.92 / 6.77(d,1H,J=3.6),6.72 / 6.69( s,1H),6.40 / 6.21(d,1H,J=3.0),5.82 / 5.27(q,1H,J=6.6),4.49 / 4.87(dd,1H,J= 13.8,4.8),3.91-3.80(m,2H),3.60 / 3.41(td,1H,J=13.2,3.6),3.19-2.99(m,3H) ,2.26 / 2.22(d,6H,J=1.2),1.91 / 1.83(t,1H,J=5.4),1.81-1.60(m,4H),1.58-1.4 6(m,2H),1.54(d,3H,J=6.6),1.35(s,3H),1.29(s,3H),1.18 / 1.09(d,3H,J=6.0);

[0599] ESI-MS m / z: 901.6 [M+H] + .

[0600] Example 12

[0601] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(8-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 11)

[0602]

[0603] The synthesis method of compound 11 is the same as that of compound 1, except that 1-bromo-2,3-difluoro-4-nitrobenzene is used instead of 4-bromo-2-fluoro-1-nitrobenzene, and pyrrolidine is used instead of morpholine as the starting material.

[0604] 1 ¹H NMR (600MHz, CDCl₃, 4:1 rotatimer) δ 11.33 / 11.26 (s, ¹H, -NH), 7.67 (d, ¹H, J = 7.8), 7.59 / 7.54 (d, ¹H, J = 8.4), 7.52 / 7.50 (s, ¹H), 7.32 / 7.13 (t, ¹H, J = 7.8), 7.28–7.22 (m, ¹H), 7.16 / 7.07 (d, 2H, J = 6.0), 6.70 (s, ¹H), 6.59 / 6.45 (d, ¹H, J = 3.0), 6.34 / 6.10 (d, ¹H, J = 3.0), 5.78 / 5.25 (q, ¹H, J = 6. .6),4.89-4.32(m,3H),3.91-3.80(m,2H),3.60 / 3.39(td,1H,J=13.2, 3.0),3.29 / 3.24(t,2H,J=7.2),3.18-2.97(m,3H),2.89-2.79(m,2H),2 .29 / 2.25(d,6H,J=1.2),1.93-1.71(m,4H),1.69-1.50(m,3H),1.56(d ,3H,J=6.6),1.35 / 1.34(s,3H),1.28(s,3H),1.20 / 1.07(d,3H,J=6.0);

[0605] ESI-MS m / z: 909.6 [M+H]+ .

[0606] Example 13

[0607] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(8-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 11-1)

[0608]

[0609] The synthesis method of compound 11-1 is the same as that of compound 11, except that chiral intermediate C9-1 is used instead of C9 as the raw material.

[0610] ESI-MS m / z: 909.6 [M+H] + .

[0611] Example 14

[0612] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3,3-difluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 12)

[0613]

[0614] The preparation method of intermediate 12-C is the same as that of 1-C, except that 3,3-difluoropyrrolidine is used instead of morpholine as the starting material.

[0615] 1 H NMR (500MHz, CDCl3) δ7.75(d,1H,J=8.5),7.63(d,1H,J=1.0),7.48(dd,1H,J=8.5,2.0),4.34(t,2H,J=6.5),3.25(m,2H); ESI-MS m / z:273.0[M+H]+ .

[0616] The synthesis method of compound 12 is the same as that of compound 1, except that intermediate 12-C is used instead of 1-C as the raw material.

[0617] 1 ¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.34 (s, ¹H, -NH), 8.05 (s, ¹H), 8.01 (d, ¹H, J = 9.0), 7.59 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.37 (dd, ¹H, J = 9.0, 1.8), 7.28–7.24 (m, ¹H), 7.11 (d, 2H, J = 6.0), 6.84 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.36 (d, ¹H, J = 3.0), 5.80 (q, ¹H, J = 6.6), 4.48 (dd, ¹H, J = 1.8). 13.8,4.8),4.43(t,2H,J=6.0),3.93-3.81(m,2H),3.60(td,1H,J=13. 2,3.6),3.31-3.22(m,2H),3.20-3.12(m,1H),3.08-2.99(m,2H),2.25 (d,6H,J=1.2),1.91(t,1H,J=6.0),1.81-1.72(m,3H),1.69-1.50(m,3 H),1.53(d,3H,J=6.6),1.35(s,3H),1.30(s,3H),1.18(d,3H,J=6.0);

[0618] ESI-MS m / z: 927.5 [M+H] + .

[0619] Example 15

[0620] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-imidazo-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 13)

[0621]

[0622] The synthesis method of compound 13 is the same as that of compound 1, except that 4-bromo-1-fluoro-2-nitrobenzene is used instead of 4-bromo-2-fluoro-1-nitrobenzene, and piperidine is used instead of morpholine as the starting material.

[0623] 1 ¹H NMR (600MHz, major isomer in the CDCl₃, 4:1 rotatory isomer) δ 7.69 (s, ¹H), 7.59 (d, ¹H, J = 8.4), 7.55 (d, ¹H, J = 7.8), 7.52 (s, ¹H), 7.38 (d, ¹H, J = 8.4), 7.23 (m, ¹H), 7.15 (d, 2H, J = 6.6), 6.73 (d, ¹H, J = 3.6), 6.70 (s, ¹H), 6.29 (d, ¹H, J = 3.0), 5.80 (m, ¹H), 4.46 (m,1H),4.13(t,2H,J=6.0),3.85(m,2H),3.60(m,1H),3.14-3.08(m,3H),3.01(m,2H),2.26(s,6H),2.17(m,2H),2. 05(m,2H),1.90(t,1H,J=6.6),1.80-1.50(m,6H),1.56(d,3H,J=6.6),1.33(s,3H),1.29(s,3H),1.19(d,3H,J=6.0);

[0624] ESI-MS m / z: 905.6 [M+H] + .

[0625] Example 16

[0626] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 14)

[0627]

[0628] Step a: 900 mg (1 equivalent) of 4-bromopyridinecarboxaldehyde, 642 mg (1.2 equivalents) of 2-methylpropane-2-sulfinamide, and 3.02 g (3 equivalents) of tetraethyl titanate were dissolved in 18 mL of dry tetrahydrofuran and heated at 75 °C overnight. After cooling, 30 mL of water was added to the reaction mixture, and the mixture was stirred vigorously. The insoluble matter was removed by filtration, and the filtrate was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 720 mg of residue. This residue was redissolved in 15 mL of dry tetrahydrofuran, and 355 mg (4 equivalents) of sodium borohydride was added. The mixture was stirred at room temperature for 3 hours until the reaction was complete. 30 mL of water was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was then extracted three times with ethyl acetate, and the combined organic phases were washed twice with saturated brine and dried over anhydrous magnesium sulfate. The mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was separated by rapid column chromatography to obtain 400 mg of intermediate 14-A.

[0629] Step b: Dissolve 400 mg of intermediate 14-A in 30 mL of trifluoroacetic acid and heat at 40 °C overnight. After the reaction is complete, evaporate to dryness under reduced pressure to obtain 378 mg of residue. Dissolve this residue (1 equivalent) in 4 mL of DMF, then add 840 mg (1.2 equivalent) of HATU, 715 mg (3 equivalent) of DIPEA, and 175 mg (1.1 equivalent) of cyclopropanecarboxylic acid, and stir overnight at room temperature. After the reaction is complete, add 20 mL of water to the reaction solution, extract three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, and dry with anhydrous magnesium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, separate the residue by rapid column chromatography, and then purify by preparative TLC to obtain 90 mg of intermediate 14-B.

[0630] Step c: Dissolve 90 mg of intermediate 14-B in 1 mL of phosphorus oxychloride and heat at 110 °C overnight. After cooling, pour the reaction solution into 10 mL of ice water, stir for half an hour, then extract twice with dichloromethane. Combine the organic phases, wash twice with saturated brine, and dry over anhydrous magnesium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, and separate the residue by preparative TLC to obtain 35 mg of intermediate 14-C.

[0631] The synthesis method of compound 14 is the same as that of compound 1, except that intermediate 14-C is used instead of intermediate 1-C as the raw material. 1¹H NMR (600 MHz, major isomer in the 4:1 CDCl₃ rotational isomer) δ 11.33 (s, ¹H, -NH), 8.22 (d, ¹H, J = 7.8), 7.34 (s, ¹H), 7.68 (s, ¹H), 7.65 (d, ¹H, J = 7.8), 7.59 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.30–7.24 (m, ¹H), 7.10 (d, 2H, J = 6.0), 6.82 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.41 (d, ¹H, J = 2.4), 5.78 (q, ¹H, J = 6.6), 4.4 9(dd,1H,J=13.2,4.8),3.91-3.79(m,2H),3.59(td,1H,J=13.2,3.0) ,3.19-3.11(m,1H),3.08-2.97(m,2H),2.26(s,6H),2.10(m,1H),1.91 (t,1H,J=5.4),1.81-1.71(m,3H),1.68-1.47(m,3H),1.51(d,3H,J=6 .6),1.35(s,3H),1.38-1.23(m,4H),1.29(s,3H),1.18(d,3H,J=5.4);

[0632] ESI-MS m / z: 891.6 [M+H] + .

[0633] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 14-1)

[0634]

[0635] The synthesis method of compound 14-1 is the same as that of compound 14, except that intermediate C9-1 is used instead of intermediate C9 as the raw material.

[0636] Intermediate 14-D. 1H NMR (500MHz, CDCl3) δ8.04(d,1H,J=7.5),7.51(s,1H),7.34(s,1H),7.10-7.02(m,3H),6.68(d,1H,J=3.0),6.32(s,1H),5.44-5.13(m,1 ESI-MS m / z:598.4[M+H] + .

[0637] Compound 14-1. 1 H NMR (600MHz, major isomer in CDCl3, 4:1 rotatable isomer) δ

[0638] 11.31(s,1H,-NH),8.09(d,1H,J=7.8),7.60-7.56(m,2H),7.55(s,1H),7.52(s,1H),7.39(m,1H),7.27(m,1H),7.11(d ,2H,J=6.0),6.74(d,1H,J=3.0),6.70(s,1H),6.35(d,1H,J=3.0),5.77(q,1H,J=6.6),4.48(dd,1H,J=13.8,4.8),3.86 (m,2H),3.59(td,1H,J=13.8,3.6),3.15(m,1H),3.02(m,2H),2.26(d,6H,J=1.8),2.07(m,1H),1.91(t,1H,J=6.0),1.8 0-1.71(m,3H),1.67-1.60(m,2H),1.59-1.49(m,4H),1.34(s,3H),1.28(s,3H),1.26(m,2H),1.20-1.13(m,5H); ESI-MS m / z:881.6[M+H] + .

[0639] Example 17

[0640] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropyl-8-fluoroimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 15)

[0641]

[0642] The preparation method of intermediate 15-C is as described in patent WO2022240830.

[0643] The synthesis method of compound 15 is the same as that of compound 1, except that intermediate 15-C is used instead of intermediate 1-C as the raw material. 1 ¹H NMR (600 MHz, CDCl₃, 4:1 rotator) δ 11.33 / 1.25 (s, ¹H, -NH), 7.93 / 7.73 (d, ¹H, J = 7.2), 7.64 / 7.55 (s, ¹H), 7.59 / 7.57 (d, ¹H, J = 9.0), 7.52 / 7.51 (s, ¹H), 7.50–7.47 (m, 2H), 7.29–7.23 (m, 2H), 7.11 / 7.02 (d, 2H, J = 6.0), 6.70 (s, ¹H), 6.69 / 6.54 (t, ¹H, J = 2.4), 6.34 / 6.14 (d, ¹H, J = 3.6), 5.79 / 5.24 (q, ¹H) ,J=6.6),4.48 / 4.87(dd,1H,J=13.8,4.8),3.91-3.79(m,2H),3.59 / 3.39( td,1H,J=13.2,3.6),3.19-2.97(m,3H),2.28 / 2.24(d,6H,J=1.2),2.10-2 .04(m,1H),1.93-1.70(m,4H),1.68-1.50(m,3H),1.55(d,3H,J=6.6),1.3 5 / 1.33(s,3H),1.32-1.13(m,4H),1.29(s,3H),1.20 / 1.07(d,3H,J=6.0);

[0644] ESI-MS m / z: 909.6 [M+H] + .

[0645] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropyl-8-fluoroimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 15-1)

[0646]

[0647] The synthesis method of compound 15-1 is the same as that of compound 15, except that intermediate C9-1 is used instead of intermediate C9 as the raw material.

[0648] Intermediate 15-D. 1 H NMR (500MHz, CDCl3) δ7.84(d,1H,J=7.5),7.49(s,1H),7.08(d,2H,J=6.0),6.81(t,1H,J=7.0),6.62(t,1H,J=2.0),6.31(s,1H),5.42-5.14(m ,1H),4.58-4.22(m,1H),3.15(m,1H),2.80(m,2H),2.24(d,6H,J=1.5), 2.02(m,1H),1.50(s,9H),1.34(d,3H,J=6.5),1.14-107(m,4H); ESI-MS m / z:616.4[M+H] + .

[0649] Compound 15-1. 1¹H NMR (500MHz, CDCl₃, major isomer in the 3:1 rotatory isomer) δ 11.32 (s, ¹H), 7.89 (d, ¹H, J = 7.5), 7.59 (d, ¹H, J = 8.5), 7.52 (m, 2H), 7.27 (m, ¹H), 7.12 (d, 2H, J = 6.0), 6.85 (t, ¹H, J = 7.0), 6.70 (s, ¹H), 6.66 (dd, ¹H, J = 3.0, 2.0), 6.32 (d, ¹H, J = 3.5), 5.78 (q, ¹H, J = 6.5), 4.47 (dd, ¹H, J = 13) .5,5.0),3.86(m,2H),3.60(td,1H,J=13.0,3.5),3.15(m,1H),3.02(m,2H),2.28(d,6H,J=1.5),2.03(m,1H),1.91(t,1H,J=5.5), ESI-MS m / z:909.6[M+H] + .

[0650] Example 18

[0651] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 16)

[0652]

[0653] The synthesis method of compound 16 is the same as that of compound 1, except that pyrrolidine is used instead of morpholine as the starting material.

[0654] 1¹H NMR (500MHz, CDCl₃, 4:1 rotatimer) δ 11.34 / 11.22 (s, ¹H, -NH), 8.21 (s, ¹H), 8.01 / 7.91 (d, ¹H, J = 9.0), 7.58 / 7.56 (d, ¹H, J = 8.5), 7.52 / 7.48 (s, ¹H), 7.47 / 7.32 (d, ¹H, J = 8.5), 7.30-7.21 (m, ¹H), 7.10 / 7.02 (d, 2H, J = 6.0), 6.86 / 6.72 (d, ¹H, J = 3.0), 6.71 / 6.69 (s, ¹H), 6.38 / 6.22 (d, ¹H, J = 3.0). 0),5.80 / 5.23(q,1H,J=6.5),4.49 / 4.87(dd,1H,J=13.5,5.0),4.46-4 .25(m,2H),3.93-3.78(m,2H),3.64-3.35(m,3H),3.21-2.87(m,5H),2 .25 / 2.20(d,6H,J=1.5),1.93-1.70(m,4H),1.68-1.49(m,3H),1.52(d ,3H,J=6.0),1.35 / 1.32(s,3H),1.29(s,3H),1.18 / 1.07(d,3H,J=5.5);

[0655] ESI-MS m / z: 891.6 [M+H] + .

[0656] Example 19

[0657] Preparation of 3-((1S,2S)-1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-3-(3-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazon-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 17)

[0658]

[0659] Step d: Add 50 mg (1 equivalent) of intermediate D5, 53 mg of intermediate 6-C (2 equivalents), and 7.9 mg (0.5 equivalents) of (1S,2S)-N to 2 mL of NMP. 1 N 2Dimethylcyclohexane-1,2-diamine, 4.2 mg (0.2 equivalents) CuI, and 46 mg (3 equivalents) potassium carbonate were added, and the mixture was stirred overnight at 130 °C after nitrogen purging. After the reaction was complete, 20 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by preparative TLC to give 55 mg of a pale yellow solid, which was intermediate 17-D.

[0660] 1 H NMR (500MHz, CDCl3) δ7.33-7.13(m,4H),7.02(t,1H,J=9.0),6.95(dd,1H,J=6.5,1.5),6.6 7(d,1H,J=3.0),6.25(brs,1H),5.44-5.10(m,1H),4.59-4.23(m,1H),4.14(t,2H,J=4.5), 3.78(s,2H),3.24-3.07(m,1H),3.04(t,2H,J=4.0),2.87-2.74(m,2H),2.44(s,3H),2.11- 2.01(m,1H),1.51(s,9H),1.32(d,3H,J=6.5),0.98-0.92(m,2H),0.68-0.62(m,2H); ESI-MS m / z:615.5[M+H] + .

[0661] Steps e and f: Dissolve 55 mg (1 equivalent) of intermediate 17-D in 1.5 mL of DCM, add 550 μL (4 M, 25 equivalent) of HCl-dioxane solution, stir overnight at room temperature, and then evaporate to dryness under reduced pressure. Redissolve the residue in a small amount of DCM, and evaporate to dryness under reduced pressure again, repeating this process twice. Dissolve the resulting residue in 2 mL of dry DMF, then add 54 mg (1.6 equivalent) of HATU, 110 μL (7 equivalent) of DIPEA, and 58 mg (1.6 equivalent) of intermediate C9, and stir at room temperature for 2 hours until the reaction is complete. Add 10 mL of water to the reaction solution, extract three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, and dry to anhydrous magnesium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, and purify the residue by preparative liquid chromatography, using acetonitrile and water (v / v) containing 0.5% trifluoroacetic acid as the mobile phase. Collect the target product fraction, freeze-dry to give 35 mg of off-white solid, namely compound 17.

[0662] 1¹H NMR (500MHz, CDCl₃, major isomer in the 5:1 rotational isomer) δ 11.29 (s, ¹H, -NH), 7.58 (d, ¹H, J = 8.5), 7.54 (d, ¹H, J = 1.5), 7.51 (s, ¹H), 7.43–7.37 (m, 2H), 7.26 (dd, ¹H, J = 8.5, 1.5), 7.21 (ddd, ¹H, J = 8.5, 4.0, 2.5), 7.06 (t, ¹H, J = 9.0), 6.97 (dd, ¹H, J = 6.5, 2.5), 6.76 (d, ¹H, J = 3.0), 6.69 (s, ¹H), 6.32 (d, ¹H, J = 3.0), 5.74 (q, ¹H, J = 6.5), 4.47 (dd,1H,J=13.0,4.5),4.43-4.20(m,4H),3.92-3.78(m,2H),3.59(td,1H,J=13 .0,3.5),3.19-3.10(m,1H),3.08-2.96(m,2H),2.89(s,3H),2.09(m,1H),1.90 (t,1H,J=5.5),1.80-1.70(m,3H),1.68-1.49(m,3H),1.51(d,3H,J=6.5),1.34 (s,3H),1.29(s,3H),1.18(d,3H,J=5.5),1.00-0.95(m,2H),0.68-0.63(m,2H);

[0663] ESI-MS m / z: 908.6 [M+H] + .

[0664] Example 20

[0665] Preparation of 3-((1S,2S)-1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 18)

[0666]

[0667] The synthesis method of compound 18 is the same as that of compound 17, except that intermediate 1-C is used instead of intermediate 6-C as the raw material.

[0668] 1 ¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.33 (s, ¹H, -NH), 8.24 (s, ¹H), 8.10–7.94 (m, ¹H), 7.59 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.47 (d, ¹H, J = 7.0), 7.29–7.19 (m, 2H), 7.07 (t, ¹H, J = 9.0), 6.95 (dd, ¹H, J = 6.5, 2.5), 6.87 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.36 (d, ¹H, J = 3.0), 5.79 (q, ¹H, J = 6.5), 5.31 (s, 2H), 4.49 ( dd,1H,J=13.5,5.0),4.39(t,2H,J=5.5),4.32(t,2H,J=5.5),3.93-3.79(m ,2H),3.60(td,1H,J=13.5,4.0),3.21-2.95(m,3H),2.10(m,1H),1.91(t,1H ,J=5.5),1.81-1.70(m,3H),1.68-1.47(m,3H),1.52(d,3H,J=6.0),1.35(s, 3H),1.29(s,3H),1.18(d,3H,J=6.0),0.99-0.93(m,2H),0.66-0.61(m,2H);

[0669] ESI-MS m / z: 919.6 [M+H] + .

[0670] Example 21

[0671] Preparation of 3-((1S,2S)-1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 19)

[0672]

[0673] The synthesis method of compound 19 is the same as that of compound 17, except that intermediate 16-C is used instead of intermediate 6-C as the raw material.

[0674] 1¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.31 (s, ¹H, -NH), 8.18 (s, ¹H), 8.03 (d, ¹H, J = 8.5), 7.58 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.50 (d, ¹H, J = 8.5), 7.29–7.19 (m, 2H), 7.07 (t, ¹H, J = 9.0), 6.96 (dd, ¹H, J = 6.0, 2.0), 6.85 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.35 (d, ¹H, J = 3.0), 5.79 (q, ¹H, J = 6.5), 4.49 (dd, ¹H, J = 13.5, 5.0), 4.441 (t,2H,J=6.5),3.91-3.80(m,2H),3.60(td,1H,J=13.5,3.5),3.56-3.47(m,2H) ,3.20-3.11(m,1H),3.08-2.99(m,2H),2.99-2.89(m,2H),2.14-2.07(m,1H),1. 91(t,1H,J=5.0),1.81-1.71(m,3H),1.69-1.48(m,3H),1.52(d,3H,J=7.0),1.3 5(s,3H),1.29(s,3H),1.18(d,3H,J=5.5),0.99-0.94(m,2H),0.66-0.61(m,2H);

[0675] ESI-MS m / z: 903.6 [M+H] + .

[0676] Example 22

[0677] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 20)

[0678]

[0679] The synthesis method of compound 20 is the same as that of compound 1, except that 4-bromo-1-fluoro-2-nitrobenzene is used instead of 4-bromo-2-fluoro-1-nitrobenzene, and pyrrolidine is used instead of morpholine as the starting material.

[0680] 1 ¹H NMR (600MHz, CDCl₃, major isomer in the 3:1 rotatory isomer) δ 11.32 (s, ¹H), 7.76 (s, ¹H), 7.61 (m, ¹H), 7.59 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.41 (d, ¹H, J = 8.4), 7.26 (m, ¹H), 7.14 (d, 2H, J = 6.0), 6.75 (d, 1H, J = 3.0), 6.70 (s, ¹H), 6.30 (d, 1H, J = 3.0), 5.79 (q, ¹H, J = 6.6), 4.46 (dd, ¹H, J = 13.8, 5.4) ),4.19(t,2H,J=7.2),3.85(m,2H),3.59(td,1H,J=13.2,3.6),3.17(t,2H,J=7.2),3.13(m,1H),3.00(m,2H),2.78(m,2H),2.26(d,6H ,J=1.2),1.90(t,1H,J=6.0),1.80-1.71(m,3H),1.68-1.50(m,3H),1.55(d,3H,J=6.6),1.34(s,3H),1.28(s,3H),1.19(d,3H,J=6.0);

[0681] ESI-MS m / z: 891.6 [M+H] + .

[0682] Example 23

[0683] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-4,5,6,7-tetrahydro-2H-pyrazo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 21)

[0684]

[0685] Step a: 748 mg (1 equivalent) of 4-methylpiperazin-2-one was dissolved in 20 mL of dry DMF. At room temperature, 341 mg of sodium hydride (60% by mass dispersed in oil, 1.3 equivalents) was added in portions, and the mixture was stirred for 15 min. Then, 1443 mg (1 equivalent) of 4-bromo-2-fluoronitrobenzene was added, and the reaction was allowed to proceed for 1 hour. The reaction was stopped by TLC. The solution was quenched with 30 mL of saturated saline solution, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was then washed once with saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was separated by rapid column chromatography to obtain 1.34 g of intermediate 21-A.

[0686] Step b: Dissolve 1.34 g (1 equivalent) of intermediate 21-A in 100 mL of an ethanol / water mixture (4:1, v / v), add 1.43 g (6 equivalents) of reduced iron powder and 796 mg (3.5 equivalents) of ammonium chloride, and react at 90 °C for 3 hours. The reaction is stopped by TLC. After cooling, filter to remove insoluble matter, concentrate the filtrate to distill off most of the ethanol. Add 50 mL of water to the residue, extract three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry with anhydrous magnesium sulfate, filter, and evaporate the filtrate to dryness to obtain 1.2 g of intermediate 21-B, which can be directly proceeded to the next reaction without purification.

[0687] Step c: 1.2 g of intermediate 21-B was dissolved in 20 mL of acetic acid, and then heated at 110 °C for 3 hours. The reaction was stopped by TLC. Acetic acid was removed by evaporation, and the residue was redissolved in 30 mL of ethyl acetate, then washed twice with saturated NaHCO3 aqueous solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was separated by rapid column chromatography to obtain 900 mg of intermediate 21-C.

[0688] 1 H NMR (500MHz, CDCl3) δ7.56(d,1H,J=8.5),7.46(d,1H,J=1.5),7.35(dd,1H,J=8.5,1.5),4 .09(t,2H,J=5.5),3.84(s,2H),2.97(t,2H,J=5.5),2.55(s,3H); ESI-MSm / z:266.1[M+H] + .

[0689] The synthesis method of compound 21 is the same as that of compound 1, except that intermediate 21-C is used instead of intermediate 1-C as the raw material.

[0690] 1¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotational isomer) δ 11.35 (s, ¹H, -NH), 7.97 (s, ¹H), 7.89 (d, ¹H, J = 8.5), 7.59 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.33 (dd, ¹H, J = 9.0, 1.5), 7.27 (m, ¹H), 7.12 (d, 2H, J = 6.0), 6.81 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.33 / 6.11 (d, ¹H, J = 2.5), 5.80 (q, ¹H, J = 6.5), 4.48 (dd, ¹H, J = 14.0, 5.0), 4 .28(t,2H,J=5.5),4.07(s,2H),3.88-3.80(m,2H),3.60(td,1H,J=13.0,3 .5),3.20-3.11(m,1H),3.09(t,2H,J=5.5),3.06-2.97(m,2H),2.61(s,3H ),2.25(d,6H,J=1.5),1.91(t,1H,J=5.5),1.80-1.71(m,3H),1.68-1.50( m,3H),1.53(d,3H,J=6.5),1.34(s,3H),1.29(s,3H),1.18(d,3H,J=6.0);

[0691] ESI-MS m / z: 920.6 [M+H] + .

[0692] Example 24

[0693] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(1,1a,8,8a-tetrahydrobenzo[d]cyclopropano[3,4]pyrrolo[1,2-a]imidazol-5-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 22)

[0694]

[0695] The synthesis method of intermediate 22-C is the same as that of intermediate 1-C, except that 3-azabicyclo[3.1.0]hexane is used instead of morpholine as the raw material.

[0696] 1H NMR (500MHz, CDCl3) δ7.51(d,1H,J=8.5),7.35(d,1H,J=2.0),7.28(dd,1H,J=8.5,2.0),4.1 5(dd,1H,J=10.5,5.0),4.06(d,1H,J=11.0),2.54(m,2H),1.50(m,1H),0.82(m,1H); ESI-MS m / z:249.1[M+H] + .

[0697] The synthesis method of compound 22 is the same as that of compound 1, except that intermediate 22-C is used instead of intermediate 1-C as the raw material.

[0698] 1 ¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotational isomer) δ 11.33 (s, ¹H, -NH), 7.75 (d, ¹H, J = 8.5), 7.70 (s, ¹H), 7.59 (d, ¹H, J = 9.0), 7.52 (s, ¹H), 7.27 (m, ¹H), 7.20 (dd, ¹H, J = 8.5, 1.5), 7.12 (d, 2H, J = 6.5), 6.76 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.31 (d, ¹H, J = 3.5), 5.79 (q, ¹H, J = 6.5), 4.47 (dd, ¹H, J = 13.5, 5.0), 4.29-4 .23(m,1H),4.19(d,1H,J=11.0),3.91-3.80(m,2H),3.59(td,1H,J=13.0, 3.0),3.19-3.11(m,1H),3.08-2.97(m,2H),2.70-2.54(m,2H),2.25(d,6H) ,J=1.5),1.91(t,1H,J=5.5),1.81-1.70(m,4H),1.68-1.49(m,3H),1.53( d,3H,J=6.5),1.34(s,3H),1.32(m,1H),1.29(s,3H),1.19(d,3H,J=6.0);

[0699] ESI-MS m / z: 903.6 [M+H] + .

[0700] Example 25

[0701] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]thiazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 23)

[0702]

[0703] The synthesis method of intermediate 23-C is the same as that of intermediate 21-C, except that thiomorpholine-3-one is used instead of 4-methylpiperazin-2-one as the raw material. 1 H NMR (500MHz, CDCl3) δ7.56 (d, 1H, J = 8.5), 7.46 (d, 1H, J = 1.5), 7.38 (dd, 1H, J = 8.5, 2.0), 4.31 (t, 2H, J = 5.5), 4.08 (s, 2H), 3.18 (t, 2H, J = 5.5).

[0704] The synthesis method of intermediate 23-D is the same as that of intermediate 1-D, except that intermediate 23-C is used instead of intermediate 1-C as the raw material.

[0705] 1 H NMR (600MHz, CDCl3) δ7.76 (d, 1H, J = 1.5), 7.73 (d, 1H, J = 8.5), 7.24 (m, 1H) ,7.09(d,2H,J=6.0),6.74(d,1H,J=3.0),6.30(d,1H,J=3.0),5.45-5.15( m,1H),4.38(t,2H,J=5.5),4.11(s,2H),3.19(t,2H,J=5.5),3.15(m,1H), 2.80(m,2H),2.22(d,6H,J=1.5),1.50(s,9H),1.33(d,3H,J=6.5); ESI-MS m / z:630.4[M+H] + .

[0706] The synthesis method of compound 23 is the same as that of compound 1, except that intermediate 23-D is used instead of intermediate 1-D as the raw material.

[0707] 1¹H NMR (500MHz, CDCl₃, major isomer in the 5:1 rotatory isomer) δ 11.37 (s, ¹H, -NH), 8.21 (s, ¹H), 8.01 (d, ¹H, J = 9.0), 7.59 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.45 (dd, ¹H, J = 8.5, 1.5), 7.27 (m, ¹H), 7.10 (d, 2H, J = 6.5), 6.86 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.37 (d, ¹H, J = 3.5), 5.81 (q, ¹H, J = 6.5), 4.54 (m, 2H). 4.49(dd,1H,J=13.5,5.0),4.41(s,2H),3.85(m,2H),3.60(td,1H,J=13.0,3.5),3.30(t,2H,J=5.5),3.16(m,1H),3.03(m,2H),2.25(d, 6H,J=1.5),1.91(t,1H,J=5.5),1.80-1.71(m,3H),1.68-1.50(m,3H),1.52(d,3H,J=6.5),1.35(s,3H),1.29(s,3H),1.18(d,3H,J=6.0);

[0708] ESI-MS m / z: 923.6 [M+H] + .

[0709] Example 26

[0710] Preparation of 3-((1S, 2S)-1-(2-((S)-3-(3-(3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 24)

[0711]

[0712] The preparation method of intermediate 24-C is as described in patent WO202141237.

[0713] The synthesis method of compound 24 is the same as that of compound 1, except that intermediate 24-C is used instead of intermediate 1-C as the raw material.

[0714] 1¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.40 (s, ¹H, -NH), 7.63 (s, ¹H), 7.58 (d, ¹H, J = 8.4), 7.57 (d, ¹H, J = 9.0), 7.52 (s, ¹H), 7.26 (m, ¹H), 7.19 (dd, ¹H, J = 8.4, 1.8), 7.13 (d, 2H, J = 6.0), 6.77 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.30 (d, ¹H, J = 3.0), 5.81 (q, ¹H, J = 6.6), 4.57 (t, 2H, J =5.4),4.47(dd,1H,J=13.2,4.2),4.18(t,2H,J=6.0),3.85(m,2H),3.60(td,1H,J=13.2,3.0),3.14(m,1H),3.02(m,2H),2.37(m,2H),2 .26(s,6H),1.90(t,1H,J=6.0),1.82-1.71(m,3H),1.68-1.50(m,3H),1.54(d,3H,J=6.6),1.34(s,3H),1.28(s,3H),1.19(d,3H,J=6.0);

[0715] ESI-MS m / z: 907.6 [M+H] + .

[0716] Example 27

[0717] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazaphen-9-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 25)

[0718]

[0719] The synthesis method of compound 25 is the same as that of compound 1, except that commercially available reagent 25-C is used instead of intermediate 1-C as the starting material.

[0720] 1¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.32 (s, ¹H, -NH), 8.59 (d, ¹H, J = 9.0), 7.58 (d, ¹H, J = 9.0), 7.54 (s, ¹H), 7.52 (s, ¹H), 7.29 (dd, ¹H, J = 9.0, 1.8), 7.27–7.24 (m, 2H), 7.12 (d, 2H, J = 6.0), 7.04 (s, ¹H), 6.79 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.32 (d, ¹H, J = 3.0), 5.78 (q, ¹H) ,J=6.6),4.52(t,2H,J=4.2),4.44(m,3H),3.85(m,2H),3.59(td,1H,J=13.2,3.0),3.15(m,1H),3.01(m,2H),2.37(m,2H),2.25(dd,6H ,J=1.2),1.90(t,1H,J=6.0),1.80-1.71(m,3H),1.67-1.48(m,3H),1.52(d,3H,J=6.6),1.34(s,3H),1.28(s,3H),1.18(d,3H,J=6.0);

[0721] ESI-MS m / z: 919.6 [M+H] + .

[0722] Example 28

[0723] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-2H-benzo[4,5]thiazo[3,2-a]pyrimidin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 26)

[0724]

[0725] Step a: 300 mg of 2-chloro-5-bromobenzothiazole and 2 mL of 3-amino-1-propanol were added to a sealed tube and heated at 130 °C for 3 hours. The reaction was monitored by TLC until completion. After cooling, 30 mL of water was added to the reaction solution, followed by extraction three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by rapid column chromatography to obtain 311 mg of intermediate 26-A.

[0726] Step b: Add 311 mg of intermediate 26-A to 3 mL of sulfoxide and heat at 70 °C for half an hour. The reaction was monitored by TLC until complete. Evaporate under reduced pressure to dryness to obtain 320 mg of white solid, which is intermediate 26-B. This can be used directly in the next step without further purification.

[0727] Step c: 320 mg of intermediate 26-B and 0.6 mL (3 equivalents) of triethylamine were added to 10 mL of toluene and heated overnight at 100 °C. The reaction was monitored by TLC until complete. The mixture was evaporated to dryness under reduced pressure, and the residue was separated by rapid column chromatography to obtain 230 mg of intermediate 26-C.

[0728] The synthesis method of compound 26 is the same as that of compound 1, except that intermediate 26-C is used instead of intermediate 1-C as the raw material.

[0729] 1 ¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.29 (s, ¹H, -NH), 7.58 (d, ¹H, J = 9.0), 7.52 (s, ¹H), 7.45 (s, ¹H), 7.44 (d, ¹H, J = 8.4), 7.27 (m, 2H), 7.14 (dd, ¹H, J = 8.4, 1.8), 7.11 (d, 2H, J = 6.0), 6.77 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.34 (d, ¹H, J = 3.0), 5.77 (q, ¹H, J = 6.6), 4.47 (dd, ¹H, J = 1 3.8,4.8),3.95(t,2H,J=5.4),3.85(m,2H),3.64(t,2H,J=4.8),3.59(td,1H,J=13.2,3.0),3.15(m,1H),3.02(m,2H),2.25(dd,6H,J=1.2) ,2.14(m,2H),1.91(t,1H,J=6.0),1.80-1.71(m,3H),1.67-1.50(m,3 H),1.52(d,3H,J=6.0),1.34(s,3H),1.28(s,3H),1.18(d,3H,J=6.0);

[0730] ESI-MS m / z: 923.6 [M+H]+ .

[0731] Example 29

[0732] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinazolin-8-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 27)

[0733]

[0734] Step c: 1 g (1 equivalent) of 4-bromo-2-fluorobenzamide (27-A) was mixed with 2.3 g (5 equivalents) of 2-methoxy-1-pyrrolidine (27-B) and heated to 120 °C. The solid initially dissolved slowly, then precipitated, and the solution turned yellowish-brown. After 3 hours, TLC analysis indicated the reaction was complete. The mixture was cooled to room temperature, filtered to collect the solid, washed with a small amount of ethyl acetate, and dried to obtain intermediate 27-C.

[0735] 1 H NMR (500MHz, CDCl3) δ8.11(d,1H,J=8.5),7.53(dd,1H,J=8.5,1.5),7.35(d,1H,J=1.5),4.21(t,2H,J=7.5),3.19(t,2H,J=8.0),2.42(m,2H).

[0736] The synthesis method of compound 27 is the same as that of compound 1, except that intermediate 27-C is used instead of intermediate 1-C as the raw material.

[0737] 1¹H NMR (600MHz, major isomer in CDCl₃, 5:1 rotational isomer) δ 11.38 (s, ¹H, -NH), 8.36 (d, ¹H, J = 9.0), 8.16 (s, ¹H), 7.70 (dd, ¹H, J = 8.4, 1.2), 7.57 (d, ¹H, J = 8.4), 7.26 (m, ¹H), 7.09 (d, 2H, J = 6.0), 7.04 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.42 (d, ¹H, J = 3.0), 5.79 (q, ¹H, J = 6.6), 4.52-4. 42(m,3H),3.90-3.80(m,2H),3.59(td,1H,J=13.2,3.0),3.47(t,2H,J=6.5),3.15(m,1H),3.02(m,2H),2.50(m,2H),2.24(s,6H ),1.89(t,1H,J=6.0),1.80-1.71(m,3H),1.68-1.51(m,3H),1.50(d,3H,J=6.6),1.34(s,3H),1.28(s,3H),1.16(d,3H,J=6.0);

[0738] ESI-MS m / z: 919.6 [M+H] + .

[0739] Example 30

[0740] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(7,8,9,10-tetrahydro-6H-6,9-epoxybenzo[4,5]imidazo[1,2-a]azaphen-2-yl)-2,3-dihydro-1H-imidazo-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 28)

[0741]

[0742] The preparation method of intermediate 28-C is the same as that of 1-C, except that 8-oxa-3-azabicyclo[3.2.1]octane is used instead of morpholine as the starting material.

[0743] 1H NMR (500MHz, CDCl3) δ7.57(d,1H,J=8.5),7.43(d,1H,J=1.5),7.36(dd,1H,J=8.5,2.0),5.40(d,1H,J=6.5),4.97 (m,1H),4.32(dd,1H,J=11.0,4.0),3.80(d,1H,J=11.0),2.44-2.29(m,2H),2.26-2.19(m,1H),1.90-1.83(m,1H).

[0744] The synthesis method of compound 28 is the same as that of compound 1, except that intermediate 28-C is used instead of intermediate 1-C as the raw material.

[0745] 1 ¹H NMR (500MHz, CDCl₃, major isomer in the 5:1 rotational isomer) δ 11.34 (s, ¹H, -NH), 7.90–7.84 (m, 2H), 7.59 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.30 (dt, ¹H, J = 8.5, 2.0), 7.27 (m, ¹H), 7.12 (d, 2H, J = 6.6), 6.80 (m, ¹H), 6.70 (s, ¹H), 6.33 (m, ¹H), 5.80 (q, ¹H, J = 6.5), 5.58 (d, ¹H, J = 6.0), 5.03 (m, ¹H), 4.48 (dd, ¹H, J = 6.0). =13.5,4.5),4.43(dt,1H,J=11.5,4.5),3.96(dd,1H,J=13.5,4.5),3 .87(m,2H),3.59(td,1H,J=13.0,3.5),3.16(m,1H),3.03(m,2H),2.42 (m,2H),2.28(m,2H),2.25(d,6H,J=2.0),1.91(t,1H,J=6.0),1.80-1 .71(m,3H),1.68-1.50(m,6H),1.34(s,3H),1.29(s,3H),1.18(m,3H);

[0746] ESI-MS m / z: 933.6 [M+H] + .

[0747] Example 31

[0748] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 29)

[0749]

[0750] Step b: 500 mg of intermediate 29-A (preparation method as described in patent WO202141237) was added to 5 mL of thionyl chloride, heated at 70 °C for 1 hour, and the reaction was monitored by TLC to confirm completion. The thionyl chloride was removed under reduced pressure, and the residue was reconstituted with ethyl acetate. Then, 1 g of solid NaHCO3 was slowly added, and the mixture was stirred for 10 minutes. The insoluble matter was removed by filtration, and the filtrate was evaporated to dryness to obtain intermediate 29-B, which was directly used in the next reaction.

[0751] Step c: Dissolve 420 mg of intermediate 29-B in 20 mL of DMF, heat at 60 °C overnight, and TLC monitoring showed that the reaction was complete. After cooling, add 30 mL of water to the reaction solution, and then extract three times with ethyl acetate. Combine the organic phases, wash twice with saturated brine, and then dry with anhydrous magnesium sulfate. Filter, evaporate the filtrate to dryness under reduced pressure, and separate the residue by rapid column chromatography to obtain intermediate 29-C.

[0752] 1 H NMR (500MHz, CDCl3) δ7.45 (d, 1H, J = 8.5), 7.35 (d, 1H, J = 2.0), 7.31 (dd, 1H, J = 8.5, 2.0), 4.13 (t, 2H, J = 6.0), 3.22 (t, 2H, J = 6.0), 2.47 (m, 2H).

[0753] The synthesis method of compound 29 is the same as that of compound 1, except that intermediate 29-C is used instead of intermediate 1-C as the raw material.

[0754] 1¹H NMR (500MHz, major isomer in the CDCl₃, 4:1 rotatory isomer) δ 11.35 (s, ¹H, -NH), 7.77 (s, ¹H), 7.70 (d, ¹H, J = 8.5), 7.59 (d, ¹H, J = 9.0), 7.52 (s, ¹H), 7.26 (m, ¹H), 7.19 (dd, ¹H, J = 9.0, 2.0), 7.12 (d, 2H, J = 6.5), 6.78 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.31 (d, ¹H, J = 3.0), 5.80 (q, ¹H, J = 6.5), 4.47 (dd, ¹H, J = 1 3.5,5.0),4.26(t,2H,J=6.0),3.85(m,2H),3.59(td,1H,J=13.5,4.0 ),3.27(t,2H,J=6.0),3.15(m,1H),3.02(m,2H),2.51(m,2H),2.25(d ,6H,J=1.5),1.91(t,1H,J=6.0),1.80-1.71(m,3H),1.68-1.50(m,3H ),1.54(d,3H,J=6.5),1.34(s,3H),1.28(s,3H),1.18(d,3H,J=6.6);

[0755] ESI-MS m / z: 923.6 [M+H] + .

[0756] Example 32

[0757] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-1H-benzo[4,5]imidazo[2,1-c][1,4]oxazin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 30)

[0758]

[0759] The synthesis method of intermediate 30-D is the same as that of intermediate 1-D, except that intermediate E5 is used instead of intermediate B5 as the raw material.

[0760] 1H NMR (500MHz, CDCl3) δ7.76(d,1H,J=9.0),7.75-7.68(m,3H),7.26-7.21(m,2H),6.81(d,1H,J=2.5),6.39(s,1H),5.45-5.13( m,1H),5.04(s,2H),4.59-4.28(m,1H),4.21(m,4H),3.25-3.05(m,1H),2.82(m,2H),1.50(s,9H),1.34(d,3H,J=7.0); ESI-MS m / z:654.4[M+H] + .

[0761] The synthesis method of compound 30 is the same as that of compound 1, except that intermediate 30-D is used instead of intermediate 1-D as the raw material.

[0762] 1 ¹H NMR (600MHz, CDCl₃, major isomer in the 5:1 rotatory isomer) δ 11.27 (s, ¹H, -NH), 7.97 (s, ¹H), 7.95 (d, ¹H, J = 9.0), 7.79 (dd, ¹H, J = 5.4, 1.8), 7.71 (m, ¹H), 7.59 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.40 (dd, ¹H, J = 9.0, 1.8), 7.32–7.26 (m, 2H), 6.90 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.44 (d, ¹H, J = 2.4), 5.79 (q, ¹H, -NH) J=6.6),5.23(s,2H),4.51(dd,1H,J=13.8,5.4),4.30-4.25(m,4H),3.91-3.81(m,2H),3.60(td,1H,J=13.2,3.0),3.21-3.13(m,1H),3.07 -3.00(m,2H),1.92(t,1H,J=5.4),1.81-1.72(m,3H),1.70-1.49(m,3 H),1.54(d,3H,J=6.6),1.35(s,3H),1.29(s,3H),1.18(d,3H,J=6.0);

[0763] ESI-MS m / z: 947.6 [M+H] + .

[0764] Example 33

[0765] Preparation of 3-((1S,2S)-1-(2-((S)-2-(3,5-dichloro-4-fluorophenyl)-3-(3-(8-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 31)

[0766]

[0767] The synthesis method of intermediate 31-D is the same as that of intermediate 1-D, except that intermediate F5 is used instead of intermediate B5 and intermediate 11-C is used instead of intermediate 1-C as raw material.

[0768] 1 H NMR (500MHz, CDCl3) δ7.52(d,1H,J=8.5),7.49(d,2H,J=5.5),7.19(t,1H,J=7.5),6.63(d,1H,J=3.0),6.38(s,1H),5.41-5.16(m,1H),4 .57-4.27(m,1H),4.33(t,2H,J=7.0),3.23-3.02(m,1H),3.09(t,2H,J=7.5),2.86-2.72(m,4H),1.51(s,9H),1.34(d,3H,J=7.0); ESI-MS m / z:656.4[M+H] + .

[0769] The synthesis method of compound 31 is the same as that of compound 1, except that intermediate 31-D is used instead of intermediate 1-D as the raw material.

[0770] 1¹H NMR (600MHz, major isomer in the CDCl₃, 4:1 rotational isomer) δ 11.26 (s, ¹H, -NH), 7.66 (d, ¹H, J = 8.4), 7.59 (d, ¹H, J = 8.4), 7.53 (d, 2H, J = 5.4), 7.52 (s, ¹H), 7.32 (dd, ¹H, J = 8.4, 7.2), 7.27 (m, ¹H), 6.70 (m, 2H), 6.44 (d, ¹H, J = 2.4), 5.77 (q, ¹H, J = 6.6), 4.49 (dd, ¹H, J = 13.8, 5.4), 4.4 5-4.39(m,2H),3.90-3.80(m,2H),3.58(td,1H,J=13.2,3.6),3.26(t,2H,J=7.2),3.18-3.10(m,1H),3.07-2.98(m,2H),2.85(m, 2H),1.92(t,1H,J=6.0),1.81-1.71(m,3H),1.69-1.52(m,3H),1.55(d,3H,J=6.6),1.34(s,3H),1.29(s,3H),1.20(d,3H,J=6.0);

[0771] ESI-MS m / z: 949.5 [M+H] + .

[0772] Example 34

[0773] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(10-methyl-2,3,4,10-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 32)

[0774]

[0775] The synthesis method of intermediate 32-C is the same as that of intermediate 26-C, except that 5-bromo-2-chloro-1-methyl-1H-benzimidazole is used instead of 2-chloro-5-bromobenzothiazole as the raw material.

[0776] 1H NMR (500MHz, DMSO-d6) δ10.12(s,1H,HCl),7.81(s,1H),7.50(m,2H),4.10(t,2H,J=6.0),3.67(s,3H),3.51(t,2H,J=6.0),2.13(m,2H).

[0777] The synthesis method of intermediate 32-D is the same as that of intermediate 1-D, except that intermediate 32-C is used instead of intermediate 1-C as the raw material.

[0778] 1 H NMR (500MHz, CDCl3) δ7.80 (s, 1H), 7.32 (m, 2H), 7.06 (d, 2H, J = 6.0), 6.78 (s, 1H),6.35(d,1H,J=3.0),5.45-5.11(m,1H),4.61-4.23(m,1H),4.13(t,2H,J =5.5),4.00(s,3H),3.78(t,2H,J=5.5),3.25-3.03(m,1H),2.88-2.74(m,2H ),2.27(m,2H),2.22(d,6H,J=1.5),1.50(s,9H),1.30(d,3H,J=6.5); ESI-MS m / z: 637.5 [M+H] + .

[0779] The synthesis method of compound 32 is the same as that of compound 1, except that intermediate 32-D is used instead of intermediate 1-D as the raw material.

[0780] 1¹H NMR (600MHz, CDCl₃, major isomer in the 6:1 rotatory isomer) δ 11.45 (s, ¹H, -NH), 7.73 (d, ¹H, J = 1.2), 7.57 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.45 (dd, ¹H, J = 8.4, 1.8), 7.39 (d, ¹H, J = 8.4), 7.26 (m, ¹H), 7.09 (d, 2H, J = 6.0), 6.83 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.33 (d, ¹H, J = 3.0), 5.80 (q, ¹H, J = 1.2). =6.6),4.47(dd,1H,J=13.8,5.4),4.14(t,2H,J=6.0),3.85(m,2H),3.67(t,2H,J=6.0),3.62(s,3H),3.59(m,1H),3.15(m,1H),3. 02(m,2H),2.25(m,8H),1.89(t,1H,J=6.0),1.80-1.48(m,6H),1.51(d,3H,J=7.2),1.34(s,3H),1.28(s,3H),1.17(d,3H,J=6.0);

[0781] ESI-MS m / z: 920.6 [M+H] + .

[0782] Example 35

[0783] 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(1,2,4,5-tetrahydrobenzo[4,5]imidazo[1,2-d][1,4]oxazolo-9-yl)-2,3-dihydro-1H-imidazo-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-

[0784] c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0785] Synthesis of (Compound 33)

[0786]

[0787] The synthesis method of intermediate 33-C is the same as that of intermediate 21-C, except that 1,4-oxazacycloheptan-5-one is used instead of 4-methylpiperazin-2-one as the starting material.

[0788] The synthesis method of intermediate 33-D is the same as that of intermediate 1-D, except that intermediate 33-C is used instead of intermediate 1-C as the raw material.

[0789] 1 H NMR(500MHz, CDCl3)δ7.76-7.70(m,2H),7.19(d,1H,J=8.0),7.09(d,2H, J=6.0),6.74(d,1H,J=3.0),6.30(d,1H,J=3.0),5.46-5.13(m,1H),4.57 -4.23(m,3H),3.97(m,4H),3.36(t,2H,J=6.0),3.25-3.04(m,1H),2.87- 2.74(m,2H),2.20(d,6H,J=2.0),1.50(s,9H),1.33(d,3H,J=6.5); ESI-MS m / z:628.5[M+H] + .

[0790] The synthesis method of compound 33 is the same as that of compound 1, except that intermediate 33-D is used instead of intermediate 1-D as the raw material.

[0791] 1 ¹H NMR (600MHz, major isomer in the CDCl₃, 4:1 rotational isomer) δ 11.33 (s, ¹H, -NH), 7.79 (d, ¹H, J = 8.4), 7.78 (s, ¹H), 7.59 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.28–7.22 (m, 2H), 7.12 (d, 2H, J = 6.0), 6.80 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.34 (d, ¹H, J = 2.4), 5.79 (q, ¹H, J = 6.6), 4.47 (dd, ¹H, J = 13.2, 4.8) ,4.35(t,2H,J=3.6),4.01-3.95(m,4H),3.85(m,2H),3.60(td,1H,J=13.2,3.6),3.41(t,2H,J=4.8),3.16(m,1H),3.02(m,2H),2.25 (s,6H),1.91(t,1H,J=6.0),1.80-1.72(m,3H),1.69-1.50(m,3H),1.55(d,3H,J=6.6),1.34(s,3H),1.29(s,3H),1.18(d,3H,J=6.0);

[0792] ESI-MS m / z: 921.6 [M+H] + .

[0793] Example 36

[0794] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-1H-[1,4]oxazinco[4,3-a]indol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 34)

[0795]

[0796] Step b: Dissolve 500 mg (1 equivalent) of 6-bromo-1H-indole-2-carboxylic acid in 10 mL of dry tetrahydrofuran. In an ice bath, slowly add 2.1 mL of lithium aluminum hydride / tetrahydrofuran solution (1.0 M, 1 equivalent). After the addition is complete, stir at room temperature for 4 hours. After the reaction is complete, place the solution in an ice bath again and quench with water and then with 15% (m / m) NaOH aqueous solution successively, followed by dilution with 30 mL of water. Extract three times with ethyl acetate, combine the organic phases, wash twice with saturated brine, and then dry with anhydrous magnesium sulfate. Filter, and evaporate the filtrate to dryness under reduced pressure to obtain 460 mg of intermediate 34-B.

[0797] Step c: 1.0 g (1.5 equivalents) of diphenyl(vinyl)sulfonate trifluoromethanesulfonate and 320 mg (3 equivalents) of KOH were suspended in 15 mL of dichloromethane and placed in an ice bath. Intermediate 34-B (1 equivalent) was dissolved in 5 mL of dichloromethane and slowly added dropwise to the reaction solution. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was quenched with water, the organic phase was separated, washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was separated by rapid column chromatography to obtain 300 mg of intermediate 34-C.

[0798] 1 H NMR (600MHz, CDCl3) δ7.43 (s, 1H), 7.42 (d, 1H, J = 8.4), 7.21 (dd, 1H, J = 8.4, 1.8), 6.19 (s, 1H), 4.96 (s, 2H), 4.16 (m, 2H), 4.04 (m, 2H); ESI-MS m / z:252.1[M+H] + .

[0799] The synthesis method of intermediate 34-D is the same as that of intermediate 1-D, except that intermediate 34-C is used instead of intermediate 1-C as the raw material.

[0800] 1H NMR (500MHz, CDCl3) δ7.64 (s, 1H), 7.61 (d, 1H, J = 8.5), 7.15-7.10 (m, 3H), 6 .74(d,1H,J=3.0),6.29(d,1H,J=2.5),6.25(s,1H),5.45-5.19(m,1H),5.01 (s,2H),4.58-4.27(m,1H),4.20(m,2H),4.13(m,2H),3.25-3.06(m,1H),2.8 9-2.76(m,2H),2.24(d,6H,J=1.5),1.59(s,9H),1.36(d,3H,J=6.5); ESI-MS m / z: 613.4 [M+H] + .

[0801] The synthesis method of compound 34 is the same as that of compound 1, except that intermediate 34-D is used instead of intermediate 1-D as the raw material.

[0802] 1 ¹H NMR (500MHz, major isomer in the CDCl₃, 4:1 rotational isomer) δ 11.33 (s, ¹H, -NH), 7.63–7.60 (m, 2H), 7.59 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.26 (m, ¹H), 7.16–7.11 (m, 3H), 7.10 (d, 2H, J = 6.5), 6.77 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.31 (d, ¹H, J = 3.5), 6.25 (s, ¹H), 5.79 (q, ¹H, J = 6.5), 5.0 0(s,2H),4.46(dd,1H,J=13.5,5.0),4.21-4.11(m,4H),3.60(td,1H,J=13.0,3.5),3.15(m,1H),3.02(m,2H),2.26(d,6H,J=1.5 ),1.91(t,1H,J=5.5),1.82-1.71(m,3H),1.69-1.50(m,3H),1.56(d,3H,J=6.5),1.35(s,3H),1.29(s,3H),1.19(d,3H,J=6.0);

[0803] ESI-MS m / z: 906.6 [M+H] + .

[0804] Example 37

[0805] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 35)

[0806]

[0807] The preparation method of intermediate 35-C is as described in the literature (Synthesis. 1981, 6, 461-462.).

[0808] The synthesis method of compound 35 is the same as that of compound 1, except that intermediate 35-C is used instead of intermediate 1-C as the raw material.

[0809] 1 ¹H NMR (600MHz, CDCl₃, major isomer in the 3:1 rotational isomer) δ 11.33 (s, ¹H, -NH), 7.59 (d, ¹H, J = 8.4), 7.52 (s, 2H), 7.30 (d, ¹H, J = 9.0), 7.28–7.24 (m, 2H), 7.17 (d, 2H, J = 6.0), 6.70 (m, 2H), 6.26 (d, ¹H, J = 3.0), 5.79 (q, ¹H, J = 6.6), 4.45 (dd, ¹H, J = 13.2, 5.4), 3.85 (m, 2H) ,3.64(s,3H),3.60(m,1H),3.14(m,1H),3.01(m,2H),2.72(m,4H),2.27(d,6H,J=1.2),1.95(m,2H),1.90(t,1H,J=6.0),1. 86(m,2H),1.80-1.71(m,3H),1.69-1.50(m,3H),1.57(d,3H,J=6.6),1.34(s,3H),1.28(s,3H),1.19(d,3H,J=6.0); ESI-MS m / z:918.6[M+H] + .

[0810] Example 38

[0811] Preparation of 3-((1S,2S)-1-(2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 36)

[0812]

[0813] The synthesis method of compound 36 is the same as that of compound 6, except that intermediate G9 is used instead of intermediate C9 as the raw material.

[0814] 1 ¹H NMR (500MHz, CDCl₃, major isomer in the 3:1 rotational isomer) δ 11.31 (s, ¹H, -NH), 7.60 (d, ¹H, J = 8.5), 7.51 (s, ¹H), 7.40–7.29 (m, ³H), 7.27 (m, ¹H), 7.10 (d, ²H, J = 6.0), 6.72 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.31 (d, ¹H, J = 3.0), 5.76 (q, ¹H, J = 7.0) ,4.47(dd,1H,J=14.0,4.5),4.24(m,2H),4.14-3.92(m,4H),3.56(m,3H),3.25(m,2H),3.14(m,1H),3.00(m, 1H),2.86(m,1H),2.62(s,3H),2.25(d,6H,J=1.5),1.93-1.77(m,4H),1.68-1.50(m,5H),1.18(d,3H,J=6.0);

[0815] ESI-MS m / z: 868.5 [M+H] + .

[0816] Example 39

[0817] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(8-fluoro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 37)

[0818]

[0819] The synthesis method of compound 37 is the same as that of compound 11, except that intermediate G9 is used instead of intermediate C9 as the raw material.

[0820] ESI-MS m / z: 881.5 [M+H] + .

[0821] Example 40

[0822] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(3-ethynyl-4-fluorophenyl)-4-methyl-3-(3-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazon-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 38)

[0823]

[0824] Step b: The synthesis method of intermediate 38-B is the same as that of intermediate 1-D, except that intermediate H5 is used instead of intermediate B5 and intermediate 6-C is used instead of intermediate 1-C as raw material.

[0825] Step c: 57 mg (1 equivalent) of intermediate 38-B, 43 mg (5 equivalents) of trimethylsilylacetylene, 18 mg (0.3 equivalents) of triphenylphosphine palladium chloride, 5 mg (0.3 equivalents) of cuprous iodide, 1.5 mL of triethylamine, and 2.5 mL of DMF were added to a pressure-resistant tube. The tube was degassed with nitrogen for several minutes, sealed, and then heated and stirred overnight at 80 °C. After cooling, the reaction solution was diluted with ethyl acetate, filtered to remove insoluble matter, washed three times with brine, and dried over anhydrous magnesium sulfate. The solution was filtered, evaporated to dryness, and separated by preparative TLC to obtain 70 mg of intermediate 38-C.

[0826] 1 H NMR (500MHz, CDCl3) δ7.57(dd,1H,J=6.0,2.5),7.34(m,1H),7.26(m,1H),7.22(d,1H, J=1.5),7.20(d,1H,J=8.0),7.04(t,1H,J=8.5),6.67(d,1H,J=3.5),6.25(s,1H),5.4 4-5.10(m,1H),4.57-4.22(m,1H),4.11(m,2H),3.77(s,2H),3.22-3.07(m,1H),3.02( m,2H),2.87-2.74(m,2H),2.41(s,3H),1.49(s,9H),1.29(d,3H,J=6.5),0.23(s,9H).

[0827] Step c: Dissolve the above intermediate 38-C in 2 mL of methanol, then add 112 mg of potassium carbonate, and stir at room temperature for 0.5 hours until the reaction is complete. Filter to remove insoluble matter, evaporate the filtrate to dryness, and separate by preparative TLC to obtain 55 mg of intermediate 38-D.

[0828] Steps e and f: Compound 38 is prepared in the same way as compound 1, except that intermediate 38-D is used instead of intermediate 1-D as the raw material.

[0829] 1 ¹H NMR (500MHz, CDCl₃, major isomer in the 5:1 rotational isomer) δ 11.26 (s, ¹H, -NH), 7.61 (dd, ¹H, J = 6.0, 3.0), 7.59 (d, ¹H, J = 9.0), 7.53 (s, ¹H), 7.51 (s, ¹H), 7.45–7.36 (m, ³H), 7.28–7.25 (m, ¹H), 7.15 (t, ¹H, J = 9.0), 6.79 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.37 (d, ¹H, J = 3.0), 5.75 (q, ¹H, J = 6.5), 4.49 ( dd,1H,J=13.0,5.0),4.42-4.20(m,4H),3.92-3.79(m,2H),3.59(td,1H,J=13.5,4.0),3.40(m,2H),3.35(s,1H),3.15(m,1H),3.03(m,2 H),2.90(s,3H),1.91(t,1H,J=5.5),1.85-1.60(m,5H),1.53(m,1H),1.51(d,3H,J=7.0),1.35(s,3H),1.29(s,3H),1.18(d,3H,J=6.0);

[0830] ESI-MS m / z: 892.6 [M+H] + .

[0831] Examples 41 and 42

[0832] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(1H,3H-spiro[benzo[d]pyrrolo[1,2-a]imidazol-2,1'-cyclopropane]-7-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 39)

[0833] Preparation of 3-((1S,2S)-1-(2-((S)-3-(3-(1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,1'-cyclopropane]-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 40)

[0834]

[0835] The synthesis methods of intermediates 39-C and 40-C are the same as those of intermediate 1-C, except that 5-azaspiro[2.4]heptane is used instead of morpholine as the starting material. The two are two isomers produced simultaneously in step c.

[0836] Intermediate 39-C: 1 H NMR (500MHz, CDCl3) δ7.57 (d, 1H, J = 9.0), 7.43 (d, 1H, J = 1.5), 7.33 (dd, 1H, J = 8.5, 1.5), 3.98 (s, 2H), 3.06 (s, 2H), 0.93-0.85 (m, 4H); ESI-MS m / z:263.1[M+H] + .

[0837] Intermediate 40-C: 1H NMR (600MHz, CDCl3) δ7.48(d,1H,J=9.0),7.42(d,1H,J=1.8),7.28(dd,1H,J=9.0,1.8),4.18( t,2H,J=7.2),2.72(t,2H,J=7.2),1.45(dd,2H,J=6.6,4.2),1.11(dd,2H,J=6.6,4.2); ESI-MS m / z:263.1[M+H] + .

[0838] The synthesis methods of compounds 39 and 40 are the same as those of compound 1, except that intermediates 39-C and 40-C are used instead of 1-C as the starting material.

[0839] Compound 39: 1 ¹H NMR (500MHz, CDCl₃, major isomer in the 3:1 rotational isomer) δ 11.34 (s, ¹H, -NH), 7.77 (d, ¹H, J = 8.5), 7.73 (s, ¹H), 7.59 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.27 (m, ¹H), 7.23 (dd, ¹H, J = 8.5, 2.0), 7.13 (d, 2H, J = 6.5), 6.77 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.30 (d, ¹H, J = 3.0), 5.79 (q, ¹H, J = 6. 5),4.47(dd,1H,J=13.5,5.0),4.07(s,2H),3.85(m,2H),3.60(td,1H,J=13.0,3.5),3.15(m,1H),3.10(s,2H),3.02(m,2H),2.26 ESI-MS m / z:917.6[M+H] + .

[0840] Compound 40: 1¹H NMR (600MHz, CDCl₃, major isomer in the 3:1 rotational isomer) δ 11.34 (s, ¹H, -NH), 7.71 (s, ¹H), 7.67 (d, ¹H, J = 9.0), 7.59 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.26 (m, ¹H), 7.19 (dd, ¹H, J = 8.4, 1.8), 7.14 (d, 2H, J = 6.0), 6.77 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.31 (d, ¹H, J = 3.0), 5.80 (q, ¹H, J = 6.6), 4.47 (dd, ¹H, J = 13.8, 4.8) ,4.27(t,2H,J=7.2),3.85(m,2H),3.60(td,1H,J=13.2,3.6),3.15(m,1 H),3.02(m,2H),2.76(t,2H,J=7.2),2.26(d,6H,J=1.2),1.90(t,1H,J= 6.0),1.82-1.72(m,3H),1.68-1.50(m,3H),1.55(d,3H,J=6.6),1.47(m ,2H),1.34(s,3H),1.29(s,3H),1.19(d,3H,J=6.0),1.14(m,2H); ESI-MS m / z:917.6[M+H] + .

[0841] Example 43

[0842] Preparation of 3-((1S,2S)-1-(2-((S)-2-(3-bromo-4-fluorophenyl)-4-methyl-3-(3-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 41)

[0843]

[0844] The synthesis method of compound 41 is the same as that of compound 6, except that intermediate H5 is used instead of intermediate B5 as the raw material.

[0845] 1¹H NMR (500MHz, CDCl₃, major isomer in the 5:1 rotational isomer) δ 11.25 (s, ¹H, -NH), 7.74 (dd, ¹H, J = 5.5, 2.5), 7.59 (d, ¹H, J = 8.5), 7.53 (s, ¹H), 7.52 (s, ¹H), 7.43–7.36 (m, ³H), 7.29–7.25 (m, ¹H), 7.18 (t, ¹H, J = 8.5), 6.81 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.39 (d, ¹H, J = 3.0), 5.75 (q, ¹H, J = 6.5), 4. 49(dd,1H,J=14.0,5.0),4.42-4.19(m,4H),3.92-3.79(m,2H),3.58(td,1H,J=13.5,3.5),3.46-3.31(m,2H),3.15(m,1H),3.03(m,2H ),2.90(s,3H),1.91(t,1H,J=5.5),1.85-1.60(m,5H),1.53(m,1H),1.51(d,3H,J=7.0),1.35(s,3H),1.29(s,3H),1.18(d,3H,J=6.0);

[0846] ESI-MS m / z: 946.5 [M+H] + .

[0847] Example 44

[0848] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(5,5-dibenzo[b,d]thiophene-2-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 42)

[0849]

[0850] The method for synthesizing intermediate 42-C is as described in patent CN111320615.

[0851] The synthesis method of intermediate 42-D is the same as that of intermediate 1-D, except that intermediate 42-C is used instead of intermediate 1-C as the raw material. 1H NMR (500MHz, CDCl3) δ8.33 (s, 1H), 7.88 (d, 1H, J = 8.5), 7.86-7.81 (m, 3H), 7.67 (t ,1H,J=7.5),7.61(d,1H,J=8.0),7.57(t,1H,J=7.5),7.08(d,2H,J=6.0),6.82(d ,1H,J=3.0),6.39(s,1H),5.47-5.14(m,1H),4.59-4.23(m,1H),3.26-3.03(m,1H ),2.90-2.73(m,2H),2.22(d,6H,J=1.5),1.50(s,9H),1.32(d,3H,J=6.5); ESI-MS m / z:656.4[M+H] + .

[0852] The synthesis method of compound 42 is the same as that of compound 1, except that intermediate 42-D is used instead of intermediate 1-D as the raw material.

[0853] 1 ¹H NMR (500MHz, CDCl₃, major isomer in the 3:1 rotatory isomer) δ 11.31 (s, ¹H, -NH), 8.35 (s, ¹H), 7.92 (d, ¹H, J = 8.5), 7.87 (d, ¹H, J = 7.5), 7.85 (d, ¹H, J = 8.0), 7.69 (t, ¹H, J = 7.5), 7.64 (dd, ¹H, J = 8.5, 1.5), 7.62–7.56 (m, 2H), 7.52 (s, ¹H), 7.27 (m, 1H), 7.12 (d, 2H, J = 6.0), 6.87 (d, ¹H, J = 3.5), 6.71 (s, ¹H). 6.42(d,1H,J=3.0),5.79(q,1H,J=6.5),4.49(dd,1H,J=13.0,4.5),3 .85(m,2H),3.60(td,1H,J=13.0,3.0),3.16(m,1H),3.03(m,2H),2.26 (d,6H,J=1.5),1.91(t,1H,J=5.5),1.81-1.72(m,3H),1.68-1.49(m,3 H),1.53(d,3H,J=7.0),1.34(s,3H),1.29(s,3H),1.18(d,3H,J=5.5);

[0854] ESI-MS m / z: 949.5 [M+H] + .

[0855] Example 45

[0856] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-3-(1H,3H-spiro[d]pyrrolo[1,2-a]imidazol-2,1'-cyclobutane]-7-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 43)

[0857]

[0858] The synthesis method of intermediate 43-C is the same as that of intermediate 21-C, except that 6-azaspiro[3.4]octane-7-one is used instead of 4-methylpiperazin-2-one as the raw material. 1 H NMR (500MHz, CDCl3) δ7.54(d,1H,J=8.5),7.44(d,1H,J=1.5),7.31(dd,1H,J= 8.5,1.5),4.08(s,2H),3.15(s,2H),2.23(t,4H,J=6.5),2.06(m,2H); ESI-MS m / z:277.1[M+H] + .

[0859] The synthesis method of compound 43 is the same as that of compound 1, except that intermediate 43-C is used instead of intermediate 1-C as the raw material.

[0860] 1¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotational isomer) δ 11.35 (s, ¹H, -NH), 7.73 (d, ¹H, J = 9.0), 7.72 (s, ¹H), 7.59 (d, ¹H, J = 8.4), 7.52 (s, ¹H), 7.26 (m, ¹H), 7.20 (dd, ¹H, J = 8.4, 1.8), 7.14 (d, 2H, J = 6.0), 6.77 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.31 (d, ¹H, J = 3.0), 5.80 (q, ¹H, J = 6.6), 4.47 (dd, 1H) ,J=13.8,5.4),4.15(s,2H),3.85(m,2H),3.60(td,1H,J=13.2,3.6),3.18(s,2H),3.15(m,1H),3.02(m,2H),2.26(s,6H),2.24(m,4H),2 .05(m,2H),1.91(t,1H,J=6.0),1.80-1.72(m,3H),1.69-1.50(m,3H),1.55(d,3H,J=6.6),1.34(s,3H),1.29(s,3H),1.19(d,3H,J=6.0);

[0861] ESI-MS m / z: 931.6 [M+H] + .

[0862] Example 46

[0863] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(4-methyl-1,2,3,4-tetrahydrocyclopentyl[b]indol-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 44)

[0864]

[0865] The preparation method of intermediate 44-C is as described in patent WO201047982. 1H NMR (500MHz, CDCl3) δ7.52 (d, 1H, J = 1.5), 7.15 (dd, 1H, J = 8.5, 1.5), 7.03 (d, 1H, J = 8.5), 3.59 (s, 3H), 2.80 (m, 4H), 2.50 (m, 2H); ESI-MS m / z:250.1[M+H] + .

[0866] The synthesis method of compound 44 is the same as that of compound 1, except that intermediate 44-C is used instead of intermediate 1-C as the raw material.

[0867] 1 ¹H NMR (500MHz, CDCl₃, major isomer in the 3:1 rotational isomer) δ 11.34 (s, ¹H, -NH), 7.58 (d, ¹H, J = 8.5), 7.52 (s, 2H), 7.50 (d, ¹H, J = 2.0), 7.28 (d, ¹H, J = 9.0), 7.27–7.22 (m, 2H), 7.16 (d, 2H, J = 6.0), 6.70 (m, 2H), 6.26 (d, ¹H, J = 3.0), 5.79 (q, ¹H, J = 6.5), 4.45 (dd, ¹H, J = 13.5, 4.5) ,3.85(m,2H),3.70(s,3H),3.60(td,1H,J=13.0,3.5),3.14(m,1H),3.01(m,2H),2.86(m,4H),2.55(m,2H),2.27(d,6H,J=1.5) ,1.90(t,1H,J=6.0),1.81-1.71(m,3H),1.68-1.50(m,3H),1.56(d,3H,J=6.5),1.34(s,3H),1.29(s,3H),1.19(d,3H,J=6.0);

[0868] ESI-MS m / z: 904.6 [M+H] + .

[0869] Example 47

[0870] Preparation of 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,9-dihydro-3H-benzo[d]imidazol[1,2-a]imidazol-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 45)

[0871]

[0872] The synthesis method of intermediate 45-C is the same as that of intermediate 26-C, except that 5-bromo-2-chloro-1-methyl-1H-benzimidazole is used instead of 2-chloro-5-bromobenzothiazole, and 2-aminoethane-1-ol is used instead of 3-aminopropane-1-ol as the raw material. 1 HNMR(500MHz,DMSO-d6)δ7.05-7.00(m,2H),6.86(d,1H,J=8.0),4.05(t,2H,J=8.0),3.80(t,2H,J=8.0),3.24(s,3H); ESI-MS m / z:252.1[M+H] + .

[0873] The synthesis method of compound 45 is the same as that of compound 1, except that intermediate 45-C is used instead of intermediate 1-C as the raw material.

[0874] 1¹H NMR (600MHz, CDCl₃, major isomer in the 5:1 rotatory isomer) δ 7.59 (d, ¹H, J = 1.2), 7.57 (d, ¹H, J = 8.4), 7.51 (s, ¹H), 7.40 (dd, ¹H, J = 9.0, 1.8), 7.29 (d, ¹H, J = 8.4), 7.25 (m, ¹H), 7.10 (d, 2H, J = 6.0), 6.79 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.31 (d, ¹H, J = 3.0), 5.80 (q, ¹H, J = 6. .6),4.47(dd,1H,J=13.8,4.8),4.35(m,4H),3.85(m,2H),3.60(m,4H),3.15(m,1H),3.01(m,2H),2.25(d,6H,J=1.2),1.8 9(t,1H,J=6.0),1.79-1.71(m,3H),1.67-1.48(m,3H),1.50(d,3H,J=6.6),1.34(s,3H),1.28(s,3H),1.17(d,3H,J=6.0);

[0875] ESI-MS m / z: 906.6 [M+H] + .

[0876] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(9-methyl-2,9-dihydro-3H-benzo[d]imidazol[1,2-a]imidazol-6-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 45-1)

[0877]

[0878] The synthesis method of compound 45-1 is the same as that of compound 45, except that intermediate C9-1 is used instead of intermediate C9 as the raw material. 1¹H NMR (500MHz, CDCl₃, major isomer in the 5:1 rotational isomer) δ 7.64 (d, ¹H, J = 2.0), 7.58 (d, ¹H, J = 8.5), 7.51 (s, ¹H), 7.42 (dd, ¹H, J = 8.5, 2.0), 7.32 (d, ¹H, J = 9.0), 7.25 (m, ¹H), 7.10 (d, 2H, J = 6.0), 6.80 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.32 (d, ¹H, J = 3.0), 5.80 (q, ¹H, J = 6.5) ),4.47(dd,1H,J=13.0,5.0),4.38(m,4H),3.85(m,2H),3.64(m,4H),3.15(m,1H),3.02(m,2H),2.25(d,6H,J=1.0),1.89(t ,1H,J=6.0),1.80-1.70(m,3H),1.70-1.60(m,2H),1.55-1.47(m,4H),1.34(s,3H),1.28(s,3H),1.17(d,3H,J=6.0); ESI-MS m / z:906.6[M+H] + .

[0879] Example 48

[0880] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(imidazol[1,2-a]quinoxalin-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazol[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 46-1)

[0881]

[0882] Step a: Imidazole-2-carboxaldehyde (537 mg, 1 equivalent), 2-iodo-4-bromoaniline (2.5 g, 1.5 equivalent), salicylhydrazide (85 mg, 0.1 equivalent), cesium carbonate (3.65 g, 2 equivalent), and cuprous iodide (53 mg, 0.05 equivalent) were added to 20 mL of DMF. The mixture was stirred and heated at 120 °C for 24 h. After the reaction solution was cooled, 50 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated brine, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by rapid column chromatography and eluted with a petroleum ether-ethyl acetate solvent system to give 790 mg of solid, i.e., intermediate 46-C, with a yield of 57%.1 H NMR (500MHz, CDCl3) δ9.13 (s, 1H), 8.10 (s, 1H), 8.09 (d, 1H, J = 2.0), 8.00 (d, 1H, J = 8.5), 7.86 (s, 1H), 7.71 (dd, 1H, J = 9.0, 2.0); ESI-MS m / z:248.0[M+H] + .

[0883] Step d: Add intermediate B5 (50 mg, 1 equivalent), intermediate 46-C (56 mg, 2 equivalent), and (1S,2S)-N to 2 mL of N-methylpyrrolidone (NMP). 1 N 2 Dimethylcyclohexane-1,2-diamine (8 mg, 0.5 equivalents), CuI (6.5 mg, 0.3 equivalents), and potassium carbonate (47 mg, 3 equivalents) were added. The mixture was purged with nitrogen several times, then heated and stirred overnight at 130 °C. After cooling, 30 mL of water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by preparative thin-layer chromatography (TLC) to give 46 mg of a pale yellow solid, intermediate 46-D, in 67% yield.

[0884] Steps e and f: Dissolve 46 mg (1 equivalent) of intermediate 46-D in 3 mL of dichloromethane (DCM), add 284 μL of HCl / dioxane solution (4 M, 15 equivalents), stir overnight at room temperature, and then evaporate to dryness under reduced pressure. Redissolve the residue in a small amount of DCM, and evaporate to dryness under reduced pressure again, repeating this process twice. Dissolve the resulting residue in 2.5 mL of dry N,N-dimethylformamide (DMF), then add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 31 mg, 1.1 equivalents), N,N-diisopropylethylamine (DIPEA, 49 mg, 5 equivalents), and intermediate C9-1 (34 mg, 1.1 equivalents), and stir at room temperature for 2 hours until the reaction is complete. Add 10 mL of water to the reaction solution, and then extract three times with ethyl acetate. Combine the organic phases, wash twice with saturated brine, and then dry with anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative liquid chromatography using acetonitrile and water (v / v) containing 0.1% trifluoroacetic acid as the mobile phase. The target product fraction was collected, freeze-dried, and yielded 24 mg of an off-white solid, namely compound 46-1, with a yield of 35%. 1¹H NMR (600MHz, CDCl₃, major isomer in the 5:1 rotatory isomer) δ 11.33 (s, ¹H), 9.50 (s, ¹H), 8.89 (s, ¹H), 7.39 (d, ¹H, J = 8.4), 7.78 (d, ¹H, J = 8.4), 7.59 (d, ¹H, J = 9.0), 7.52 (s, ¹H), 7.27 (m, ¹H), 7.12 (d, 2H, J = 5.4), 7.03 (d, ¹H, J = 3.0), 6.72 (s, ¹H), 6.50 (d, ¹H, J = 2.4), 5.80 (q ,1H,J=6.6),4.51(dd,1H,J=13.8,4.8),3.96-3.83(m,2H),3.61(m,1H),3.18(m,1H),3.05(m,2H),2.25(d,6H,J=1.2),1.91( t,1H,J=5.4),1.83-1.74(m,3H),1.71-1.63(m,2H),1.57-1.50(m,4H),1.37(s,3H),1.31(s,3H),1.16(d,3H,J=5.4); ESI-MS m / z:902.6[M+H] + .

[0885] Example 49

[0886] Preparation of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(imidazol[1,2-a]quinazolin-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazol[4,3-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 47-1)

[0887]

[0888] Step a: 1H-imidazol-2-amine (1 g, 1 equivalent), 4-bromo-2-fluorobenzaldehyde (2.45 g, 1 equivalent), and cesium carbonate (5.9 g, 1.5 equivalent) were added to 20 mL of DMF. The mixture was stirred and heated at 120 °C for 6 h. After the reaction solution was cooled, 50 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated brine, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by rapid column chromatography and eluted with a petroleum ether-ethyl acetate solvent system to give 320 mg of solid, i.e., intermediate 47-C, with a yield of 23%. 1HNMR (500MHz, CDCl3) δ8.95 (s, 1H), 8.10 (d, 1H, J = 1.5), 7.92 (d, 1H, J = 1.5), 7.87 (d, 1H, J = 8.5), 7.79 (d, 1H, J = 1.5), 7.70 (dd, 1H, J = 8.5, 2.0); ESI-MS m / z:248.1[M+H] + .

[0889] Step d: Add intermediate B5 (50 mg, 1 equivalent), intermediate 47-C (56 mg, 2 equivalent), and (1S,2S)-N to 2 mL of N-methylpyrrolidone (NMP). 1 N 2 Dimethylcyclohexane-1,2-diamine (8 mg, 0.5 equivalents), CuI (6.5 mg, 0.3 equivalents), and potassium carbonate (47 mg, 3 equivalents) were added. The mixture was purged with nitrogen several times, then heated and stirred overnight at 130 °C. After cooling, 30 mL of water was added to the reaction mixture, followed by extraction three times with ethyl acetate. The organic phases were combined, washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by preparative thin-layer chromatography (TLC) to give 49 mg of a pale yellow solid, intermediate 47-D, in 71% yield. 1 H NMR (500MHz, CDCl3) δ9.01(s,1H),8.61(s,1H),8.11(d,1H,J=8.5),8.08-7.77(m,2H),7.71(d,1H),7.10(d,2H,J=6.0),6.99(s,1H),6.47 (s,1H),5.48-5.17(m,1H),4.60-4.26(m,1H),3.27-3.06(m,1H),2.84(m,2H),2.23(d,6H,J=1.5),1.52(s,9H),1.34(d,3H,J=6.5); ESI-MS m / z:609.4[M+H] + .

[0890] Steps e and f: Dissolve 49 mg (1 equivalent) of intermediate 46-D in 3 mL of dichloromethane (DCM), add 303 μL of HCl / dioxane solution (4 M, 15 equivalents), stir overnight at room temperature, and then evaporate to dryness under reduced pressure. Redissolve the residue in a small amount of DCM, and evaporate to dryness under reduced pressure again, repeating this process twice. Dissolve the resulting residue in 2.5 mL of dry N,N-dimethylformamide (DMF), then add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 33 mg, 1.1 equivalents), N,N-diisopropylethylamine (DIPEA, 52 mg, 5 equivalents), and intermediate C9-1 (36 mg, 1.1 equivalents), and stir at room temperature for 2 hours until the reaction is complete. Add 10 mL of water to the reaction solution, and then extract three times with ethyl acetate. Combine the organic phases, wash twice with saturated brine, and then dry with anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by preparative liquid chromatography using acetonitrile and water (v / v) containing 0.1% trifluoroacetic acid as the mobile phase. The target product fraction was collected, lyophilized, and yielded 24 mg of an off-white solid, compound 47-1, in 26% yield. ESI-MS m / z: 902.6 [M+H] + .

[0891] Example 50

[0892] Preparation of 3-[(1S,2S)-1-(5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(imidazo[1,2-a]quinoxalin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-1H-indol-1-yl)-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 48-1)

[0893]

[0894] The synthesis method of compound 48-1 is the same as that of compound 47-1, except that 5-bromo-2-fluoroaniline and imidazole-2-carboxaldehyde are used instead of 1H-imidazole-2-amine and 4-bromo-2-fluorobenzaldehyde as starting materials.

[0895] Intermediate 48-C. 1H NMR (500MHz, CDCl3) δ9.13 (s, 1H), 8.31 (d, 1H, J = 1.5), 8.11 (s, 1H), 7.85 (s, 1H), 7.82 (d, 1H, J = 8.5), 7.78 (dd, 1H, J = 8.5, 2.0); ESI-MS m / z:248.1[M+H] + .

[0896] Intermediate 48-D. 1 H NMR (500MHz, CDCl3) δ9.21 (s, 1H), 8.33-8.12 (m 3H),8.06-7.93(m,2H),7.10(d,2H,J=6.5),6.85(d,1H,J=3.0),6.38(s,1H),5.46-5.16(m,1H),4.58-4 .23(m,1H),3.26-3.02(m,1H),2.81(m,2H),2.22(d,6H,J=1.5),1.50(s,9H),1.33(d,3H,J=6.5); ESI-MS m / z:609.4[M+H] + .

[0897] Compound 48-1. 1 ¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.32 (s, ¹H), 9.43 (s, ¹H), 8.46 (d, ¹H, J = 8.4), 8.31 (d, ¹H, J = 2.4), 8.27 (s, ¹H), 8.15 (d, ¹H, J = 9.0), 8.01 (s, ¹H), 7.59 (d, ¹H, J = 8.0), 7.52 (s, ¹H), 7.27 (m, ¹H), 7.13 (d, 2H, J = 6.0), 6.96 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.43 (d, 1H) ,J=3.0),5.81(q,1H,J=6.6),4.49(dd,1H,J=13.8,5.4),3.94-3.83(m,2H),3.60(m,1H),3.17(m,1H),3.05(m,2H),2.26(d,6H,J=1.8 ),1.91(t,1H,J=5.4),1.81-1.72(m,3H),1.70-1.63(m,2H),1.56-1.51(m,4H),1.36(s,3H),1.30(s,3H),1.18(d,3H,J=6.0); ESI-MS m / z:902.6[M+H] + .

[0898] Example 51

[0899] Preparation of 3-[(1S,2S)-1-(5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(1-methyl-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazo-6-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-1H-indol-1-yl)-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 49-1)

[0900]

[0901] Step a: 5-Bromo-2-chloro-1H-benzo[d]imidazole (200 mg) was added to 3 mL of N-methylethanolamine and reacted at 130 °C for 3 hours in a sealed tube. After cooling, it was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried with magnesium sulfate, filtered, and the filtrate was purified by Flash column chromatography to obtain intermediate 49-A about 245 mg.

[0902] Step b: Intermediate 49-A (245 mg) was dissolved in 3 mL of thionyl chloride in a sealed tube and reacted at 70 °C for 15 minutes. Ice-cold saturated NaHCO3 aqueous solution was slowly added, followed by extraction with ethyl acetate three times. After drying with magnesium sulfate, the solution was filtered and purified by Flash column chromatography to obtain intermediate 49-B 226 mg.

[0903] Step c: Intermediate 49-B (226 mg, 1 equivalent) was added to a sealed tube with 5 mL of toluene and 350 μL of triethylamine (3 equivalents), and reacted overnight at 100 °C. After the reaction was complete, the mixture was evaporated to dryness and separated by preparative TLC with dichloromethane / methanol (V / V) = 15:1 to obtain 32 mg each of intermediates 49-C and 49-D.

[0904] Intermediate 49-C. 1 H NMR (500MHz, CDCl3) δ7.25(d,1H,J=8.5),7.16(dd,1H,J=8.5,2.0),7.14(d,1H,J= 1.5),4.06(t,2H,J=8.0),3.91(t,2H,J=8.0),3.05(s,3H); ESI-MSm / z:252.1[M+H] + .

[0905] Step df was performed in the same manner as the preparation of compound 46-1, except that intermediate 49-C was used instead of intermediate 46-C as the starting material.

[0906] Intermediate 49-E. 1 H NMR (800MHz, CDCl3) δ7.52-7.35(m,2H),7.10(d,2H,J=5.6),7.01(s,1H),6.68(s,1H),6.26(s,1H),5.42-5.14(m,1H),4.56-4.2 5(m,1H),4.15(m,2H),3.95(t,2H,J=7.2),3.22-3.03(m,4H),2.79(m,2H),2.22(s,6H),1.50(s,9H),1.32(d,3H,J=7.2); ESI-MS m / z:613.4[M+H] + .

[0907] Compound 49-1. 1 H NMR (500MHz, major isomer in CDCl3, 4:1 rotational isomer) δ

[0908] 11.32(s,1H),7.59(d,1H,J=8.5),7.52(s,1H),7.46-7.41(m,2H),7.25(m,1H),7.13(d,2H,J=6.0),7.03(d,1H,J=8. 0),6.72(d,1H,J=3.0),6.70(s,1H),6.27(d,1H,J=3.0),5.80(q,1H,J=6.5),4.46(dd,1H,J=13.5,5.0),4.17(t,2H, J=7.5),3.96(t,2H,J=7.5),3.85(m,2H),3.59(td,1H,J=13.5,3.5),3.15(m,1H),3.09(s,3H),3.01(m,2H),2.26(s, 6H),1.90(t,1H,J=5.5),1.81-1.60(m,5H),1.56-1.50(m,4H),1.34(s,3H),1.28(s,3H),1.19(d,3H,J=6.0); ESI-MS m / z:906.6[M+H] + .

[0909] Example 52

[0910] Preparation of 3-[(1S,2S)-1-[2-[(S)-3-[3-([1,2,4]triazolo[4,3-a]quinoxalin-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 50-1)

[0911]

[0912] Step a: Dissolve 50-A (500 mg, 1.0 eq) in 8 mL of anhydrous ethanol, add hydrazine hydrate (1.13 mL, 4.0 eq), heat to 80 °C and stir for 2–3 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure and evaporate to dryness, add water and stir, filter, wash the filter cake with an appropriate amount of water, and then dry at 50 °C to obtain 495 mg of intermediate 50-A.

[0913] Step b: Add 50-B (495 mg, 1.0 eq) and 7 mL of triethyl orthoformate to the reaction flask, heat to 100 °C and stir for 2–3 hours. After the reaction is complete, quench the reaction with saturated sodium bicarbonate solution, and extract multiple times with a methanol / dichloromethane mixture (V / V = 1:5). Combine the organic phases, wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by column chromatography to obtain intermediate 50-C. 1 H NMR (500MHz, CDCl3) δ10.15(s,1H),9.45(s,1H),8.44(d,1H,J=9.0),8.34(d,1H,J=2.0),8.06(dd,1H,J=8.5,2.0); ESI-MS m / z:249.1[M+H] + .

[0914] Step df was performed using the same synthetic method as compound 46-1, except that intermediate 50-C was used instead of intermediate 46-C as the starting material.

[0915] Intermediate 50-D. 1H NMR (500MHz, CDCl3) δ9.38(s,1H),9.33(s,1H),8.29(dd,1H,J=9.0,2.0),8.24(s,1H),8.05(d,1H,J=8.5),7.10(d,2H,J=6.5),6.86(d,1H,J=3.5 ),6.40(s,1H),5.44-5.16(m,1H),4.57-4.25(m,1H),3.24-3.06(m,1H), 2.80(m,2H),2.22(d,6H,J=1.5),1.50(s,9H),1.33(d,3H,J=7.0); ESI-MS m / z:610.4[M+H] + .

[0916] Compound 50-1. 1 H NMR (600MHz, major isomer in CDCl3, 5:1 rotatable isomer) δ

[0917] 11.29(s,1H),9.40(s,1H),9.39(s,1H),8.36(d,1H,J=9.0),8.29(d,1H,J=1.8),8.13(d,1H,J=8.4),7.59(d,1H,J=8.4), 7.52(s,1H),7.27(m,1H),7.13(d,2H,J=6.0),6.93(d,1H,J=3.0),6.72(s,1H),6.43(d,1H,J=3.0),5.79(q,1H,J=7.2),4 .49(dd,1H,J=13.8,5.4),3.93-3.78(m,2H),3.60(td,1H,J=13.2,3.6),3.17(m,1H),3.04(m,2H),2.26(s,6H),1.91(t,1 H,J=6.0),1.81-1.72(m,3H),1.69-1.63(m,2H),1.57-1.51(m,4H),1.36(s,3H),1.30(s,3H),1.17(d,3H,J=6.0); ESI-MS m / z:903.6[M+H] + .

[0918] Example 53

[0919] Preparation of 3-[(1S,2S)-1-[2-[(S)-3-[3-(1H,3H-benzo[4,5]imidazo[1,2-c]thiazo-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 51)

[0920]

[0921] The synthesis method of intermediate 51-C is the same as that of intermediate 21-C, except that thiazolidin-4-one is used instead of 4-methylpiperazin-2-one as the raw material. 1 H NMR (500MHz, CDCl3) δ7.58(d,1H,J=9.0),7.49(d,1H,J=1.5),7.38(dd,1H,J=9.0,1.5),5.10(s,2H),4.25(s,2H); ESI-MS m / z:255.1[M+H] + .

[0922] The synthesis method of compound 51 is the same as that of compound 1, except that intermediate 51-C is used instead of intermediate 1-C as the raw material. 1 ¹H NMR (600 MHz, major isomer in the CDCl₃, 4:1 rotational isomer) δ 11.33 (s, ¹H), 8.14 (s, ¹H), 7.97 (d, ¹H, J = 8.4), 7.59 (d, ¹H, J = 9.0), 7.52 (s, ¹H), 7.43 (d, ¹H, J = 7.8), 7.27 (m, ¹H), 7.10 (d, 2H, J = 6.0), 6.86 (d, ¹H, J = 3.6), 6.71 (s, ¹H), 6.39 (d, ¹H, J = 3.0), 5.79 (q, ¹H, J = 6.6), 5.32 (m, 2H). H),4.58(s,2H),4.49(dd,1H,J=14.4,5.4),3.94-3.81(m,2H),3.60(td,1H,J=13.2,3.0),3.16(m,1H),3.04(m,2H),2.25(s,6H), 1.91(t,1H,J=5.4),1.82-1.72(m,3H),1.70-1.62(m,2H),1.57-1.50(m,4H),1.36(s,3H),1.30(s,3H),1.18(d,3H,J=5.4); ESI-MS m / z:909.6[M+H]+ .

[0923] Example 54

[0924] 3-[(1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]aza] Preparation of compound 52-1: [-7-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one

[0925]

[0926] Step a: Add 1 g (1 equivalent) of 6-bromo-3,4-dihydronaphthyl-1(2H)-one, 730 mg (2 equivalents) of sodium acetate, and 401 mg (1.3 equivalents) of hydroxylamine hydrochloride to a round-bottom flask containing 30 mL of anhydrous ethanol. Heat to 90 °C and reflux for about 2 hours. Detect the reaction by TLC. Once complete, cool to room temperature and pour into water. A large amount of white solid is produced. Filter and dry to obtain approximately 1.02 g of the intermediate hydroxyoxime. Then, add this intermediate to 15 mL of sulfoxide and heat at 50 °C for 15 minutes. Detect the reaction by TLC. Slowly pour the reaction solution into an ice-cold saturated aqueous solution of NaHCO3. Wait until no more bubbles emerge and the pH test shows weak alkalinity. Extract three times with ethyl acetate, dry with magnesium sulfate, filter, concentrate the filtrate, and purify by Flash column chromatography to obtain approximately 420 mg of intermediate 52-A.

[0927] Step b: Dissolve 200 mg (1 equivalent) of intermediate 52-A in 10 mL of ultra-dry DMF in an ice bath. Add sodium hydride (50 mg, 1.5 equivalents), and after 15 minutes, add iodomethane (65 μL, 1.2 equivalents). React at room temperature for approximately 2 hours, and monitor the reaction for completion by TLC. Pour the reaction solution into a saturated NH4Cl aqueous solution, extract three times with ethyl acetate, dry with magnesium sulfate, and filter. Evaporate the filtrate to dryness to obtain approximately 200 mg of intermediate 52-B, which can be directly proceeded to the next step without purification.

[0928] Step c: Dissolve intermediate 52-B in 20 mL of ultra-dry tetrahydrofuran, add 9-boronbicyclo[3,3,1]-nonane (9-BBN, 420 mg, 2.2 equivalents), and reflux under nitrogen protection for about 5 hours. The reaction mixture was monitored by TLC until completion. The reaction solution was poured into a saturated NaCl aqueous solution, extracted three times with ethyl acetate, dried over magnesium sulfate, filtered, concentrated, and purified by Flash column chromatography to obtain approximately 120 mg of intermediate 52-C.

[0929] Step df was performed using the same synthetic method as compound 46-1, except that intermediate 52-C was used instead of intermediate 46-C as the starting material.

[0930] Compound 52-1. 1 ¹H NMR (500MHz, major isomer in the CDCl₃, 4:1 rotatory isomer) δ 7.63 (d, ¹H, J = 1.5), 7.57 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.40 (dd, ¹H, J = 8.0, 2.0), 7.36 (d, ¹H, J = 8.0), 7.27 (m, ¹H), 7.10 (d, 2H, J = 6.0), 6.75 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.33 (d, ¹H, J = 3.0), 5.76 (q, ¹H, J = 6.5), 4.47 (dd, ¹H, J = 13.5, 5.0). 4.36(s,2H),3.85(m,2H),3.59(td,1H,J=13.5,3.5),3.47(m,2H),3. 15(m,1H),3.09-2.97(m,4H),2.61(s,3H),2.25(d,6H,J=2.0),2.06( m,2H),1.91(t,1H,J=5.5),1.81-1.71(m,3H),1.68-1.60(m,2H),1.55-1.48(m,4H),1.34(s,3H),1.28(s,3H),1.18(d,3H,J=6.0); ESI-MS m / z:894.6[M+H] + .

[0931] Example 55

[0932] Preparation of 3-[(1S,2S)-1-[2-[(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(9-methyl-2,9-dihydro-3H-benzo[d]imidazo[1,2-a]imidazo-6-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 53)

[0933]

[0934] The synthesis method of compound 53 is the same as that of compound 1, except that intermediates 1-D and C9 are used instead of intermediates 45-D and G9, respectively. 1 ¹H NMR (500MHz, CDCl₃, major isomer in the 5:1 rotational isomer) δ 11.28 (s, ¹H), 7.67 (d, ¹H, J = 1.5), 7.58 (d, ¹H, J = 8.5), 7.51 (s, ¹H), 7.44 (dd, ¹H, J = 8.5, 1.5), 7.36 (d, ¹H, J = 9.0), 7.27 (m, ¹H), 7.09 (d, 2H, J = 6.0), 6.80 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.31 (d, 1H, J = 3.0), 5.81 (q, ¹H, J = 6.0). .5),4.47(dd,1H,J=13.5,4.5),4.39(m,4H),4.10(m,2H),3.65-3.51(m,6H),3.15(m,1H),3.04-2.97(m,1H),2.90-2.81(m,1H), 2.25(d,6H,J=1.0),1.91-1.74(m,5H),1.64(m,1H),1.54(m,1H),1.50(d,3H,J=6.5),1.17(d,3H,J=6.0); ESI-MSm / z:878.6[M+H] + .

[0935] Example 56

[0936] Preparation of 3-[(1S,2S)-1-[2-[(S)-3-[3-(2,3-dihydrobenzo[d]imidazo[2,1-b]thiazo-6-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 54-1)

[0937]

[0938] The synthesis method of compound 54-1 is the same as that of compound 49-1, except that 2-chloro-5-bromobenzothiazole and ethanolamine are used instead of 5-bromo-2-chloro-1H-benzo[d]imidazole and N-methylethanolamine, respectively.

[0939] Intermediate 54-C. 1 H NMR (800MHz, CDCl3) δ7.09 (d, 1H, J = 8.0), 7.06 (dd, 1H, J = 8.0, 1.6), 6.81 (d, 1H, J = 1.6), 4.36 (t, 2H, J = 8.8), 3.83 (t, 2H, J = 8.8); ESI-MS m / z:255.1[M+H] + .

[0940] Intermediate 54-D. 1 H NMR (500MHz, CDCl3) δ7.28 (d, 1H, J = 8.5), 7.12 (d, 1H, J = 1.0), 7.07 (d, 2H, J = 6.0),6.97(d,1H,J=8.0),6.67(d,1H,J=3.0),6.29(s,1H),5.49-5.12(m,1H) ,4.59-4.24(m,1H),4.37(t,2H,J=9.0),3.89(t,2H,J=9.0),3.24-3.02(m,1 H), 2.79 (m, 2H), 2.22 (d, 6H, J = 2.0), 1.50 (s, 9H), 1.31 (d, 3H, J = 6.5); ESI-MS m / z: 616.4 [M+H] + .

[0941] Compound 54-1. 1¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotational isomer) δ 11.31 (s, ¹H), 7.58 (d, ¹H, J = 8.5), 7.52 (s, ¹H), 7.31 (d, ¹H, J = 8.0), 7.27 (m, ¹H), 7.11 (m, ³H), 7.01 (m, ¹H), 6.72 (d, ¹H, J = 3.0), 6.70 (s, ¹H), 6.32 (d, ¹H, J = 3.0), 5.76 (q, ¹H, J = 6.5), 4.47 (dd, ¹H, J = 13.5), 6.0),4.38(m,2H),3.94-3.80(m,4H),3.59(td,1H,J=13.5,4.5),3.15(m,1H),3.01(m,2H),2.25(d,6H,J=1.5),1.91(t,1 H,J=5.5),1.80-1.71(m,3H),1.68-1.60(m,2H),1.56-1.50(m,4H),1.34(s,3H),1.28(s,3H),1.18(d,3H,J=6.0); ESI-MS m / z:909.6[M+H] + .

[0942] Example 57

[0943] 8-[3-[(S)-5-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-1H-indole-2-formyl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-4,5-dihydrobenzo[f][1,4]oxynitric acid Preparation of 3(2H)-ketone (compound 55-1)

[0944]

[0945] Step a: Dissolve 1.0 g (4.97 mmol) of 4-bromo-2-hydroxybenzaldehyde in 20 mL of DMF, add 870 μL (5.97 mmol) of tert-butyl bromoacetate and anhydrous potassium carbonate (413 mg, 9.95 mmol), and heat and stir at 70 °C for 5 hours. Add the reaction solution to water, extract three times with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify by column chromatography to obtain 1.41 g of intermediate 55-A.

[0946] Step b: Dissolve intermediate 55-A (1.41 g, 4.47 mmol) in 20 mL of methanol, add methylamine ethanol solution (m / v = 30%, 700 μL), and stir overnight at room temperature. Then add sodium borohydride (203 mg, 5.37 mmol) to the reaction solution and stir at room temperature for 2 hours. Add water to the reaction solution, concentrate under reduced pressure, and extract with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride solution, and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify by column chromatography to obtain 291 mg of intermediate 55-B.

[0947] Step c: Dissolve intermediate 55-B (291 mg, 0.88 mmol) in 5 mL of 1,4-dioxane, add hydrochloric acid / dioxane solution (4 M, 375 μL, 7.05 mmol), and heat and stir overnight at 50 °C. Then, evaporate the reaction solution to dryness, redissolve the residue in 5 mL of DMF, and add HATU (370 mg, 0.97 mmol) and DIPEA (770 μL, 4.42 mmol), and stir overnight at room temperature. Add water to the reaction solution, extract three times with ethyl acetate, combine the organic phases, wash three times with saturated sodium chloride solution, and dry on anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify by column chromatography to obtain 155 mg of intermediate 55-C. 1 H NMR (500MHz, CDCl3) δ7.22 (d, 1H, J = 2.0), 7.18 (dd, 1H, J = 8.0, 2.0), 7.03 (d, 1H, J = 8.0), 4.70 (s, 2H), 4.45 (s, 2H), 3.13 (s, 3H); ESI-MS m / z:256.2[M+H] + .

[0948] The synthesis method of compound 55-1 is the same as that of compound 46-1, except that intermediate 55-C is used instead of intermediate 46-C as the raw material.

[0949] Intermediate 55-D. 1 H NMR (500MHz, CDCl3) δ7.34(d,1H,J=7.5),7.26-7.21(m,2H),7.06(d,2H,J=6.0),6.66(d,1H,J=3.0),6.28(s,1H),5.41-5.11(m,1H) ,4.74(s,2H),4.52(s,2H),4.50-4.23(m,1H),3.15(m,4H),2.79(m,2H),2.21(d,6H,J=2.0),1.49(s,9H),1.30(d,3H,J=6.5); ESI-MS m / z:617.4[M+H] + .

[0950] Compound 55-1. 1 ¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.30 (s, ¹H), 7.58 (d, ¹H, J = 8.5), 7.51 (s, ¹H), 7.38 (dd, ¹H, J = 8.0, 2.0), 7.25 (m, 2H), 7.10 (m, 3H), 6.71 (d, ¹H, J = 3.5), 6.69 (s, ¹H), 6.31 (d, ¹H, J = 3.0), 5.75 (q, ¹H, J = 6.5), 4.77 (s, 2H), 4.54 (s, 2H) ),4.47(m,1H),3.86(m,2H),3.58(td,1H,J=13.5,3.5),3.17-3.11(m,4H),3.03(m,2H),2.25(d,6H,J=1.5),1.90(t,1H ,J=5.5),1.80-1.70(m,3H),1.68-1.61(m,2H),1.55-1.49(m,4H),1.35(s,3H),1.29(s,3H),1.18(d,3H,J=5.5); ESI-MS m / z:910.6[M+H] + .

[0951] Example 58

[0952] Preparation of 3-[(1S,2S)-1-[2-[(S)-3-[3-(benzo[d]imidazo[2,1-b]thiazo-6-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 56-1)

[0953]

[0954] Step a: 5-Bromobenzo[d]thiazol-2-amine (1 g, 1 equivalent), chloroacetaldehyde (822 mg, 2.4 equivalent), and triethylamine (883 mg, 2 equivalent) were added to 20 mL of anhydrous ethanol. The mixture was stirred and heated at 80 °C for 16 h. After the reaction solution was cooled, 50 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated brine, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by rapid column chromatography and eluted with a petroleum ether-ethyl acetate solvent system to give 370 mg of solid, i.e., intermediate 56-C, with a yield of 33%.1 H NMR (500MHz, CDCl3) δ7.78(d,1H,J=1.5),7.69(s,1H),7.57(d,1H,J=8.5),7.47(dd,1H,J=8.5,2.0),7.40(s,1H); ESI-MS m / z:253.1[M+H] + .

[0955] The synthesis method of compound 56-1 is the same as that of compound 46-1, except that intermediate 56-C is used instead of intermediate 46-C as the raw material.

[0956] Intermediate 56-D. 1 H NMR (500MHz, CDCl3) δ8.11(s,1H),7.84-7.67(m,2H),7.49-7.36(m,2H),7.09(d,2H,J=6.0),6.81(d,1H,J=3.0),6.38(s,1H) ,5.47-5.12(m,1H),4.59-4.24(m,1H),3.24-3.03(m,1H),2.81(m,2H),2.22(s,6H),1.50(s,9H),1.33(d,3H,J=7.0); ESI-MS m / z:614.4[M+H] + .

[0957] Compound 56-1. 1 ¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.32 (s, ¹H), 8.51 (s, ¹H), 7.93 (m, 2H), 7.65 (s, ¹H), 7.59 (m, 2H), 7.52 (s, ¹H), 7.27 (m, ¹H), 7.11 (d, 2H, J = 6.0), 6.91 (d, 1H, J = 3.0), 6.71 (s, ¹H), 6.45 (d, 1H, J = 3.0), 5.79 (q, 1H, J = 6.5), 4.50 (dd) ,1H,J=14.0,5.0),3.86(m,2H),3.61(td,1H,J=13.5,3.5),3.17(m,1H),3.05(m,2H),2.26(d,6H,J=1.0),1.91(t,1H, J=5.0),1.81-1.71(m,3H),1.70-1.62(m,2H),1.56-1.50(m,4H),1.36(s,3H),1.30(s,3H),1.18(d,3H,J=5.5); ESI-MS m / z:907.6[M+H] + .

[0958] Example 59

[0959] Preparation of 3-[(1S,2S)-1-[5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-[3-(9-methyl-9H-benzo[d]imidazo[1,2-a]imidazo-6-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 57-1)

[0960]

[0961] Step a: 1.3 g (1 equivalent) of 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one was added to phosphorus oxychloride (13.2 g, 15 equivalents), and the mixture was stirred at 95 °C for 1.5 h until the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and the residue was extracted with dichloromethane by adding ice water. The organic phase was washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by rapid column chromatography, eluted with petroleum ether-ethyl acetate solvent system, to give 1.1 g of solid, i.e., intermediate 57-A, with a yield of 78%. 1 H NMR (500MHz, CDCl3) δ7.83 (d, 1H, J = 1.0), 7.42 (dd, 1H, J = 8.5, 2.0), 7.93 (d, 1H, J = 8.5), 3.78 (s, 3H); ESI-MS m / z: 245.1 [M+H] + .

[0962] Step b: Intermediate 57-A (500 mg, 1 equivalent) was added to aminoacetal diethanol (5.4 g, 25 equivalents), and stirred at 130 °C for 5 h. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was separated by rapid column chromatography, eluting with a dichloromethane-methanol solvent system to give 600 mg of solid, i.e., intermediate 57-B, with a yield of 94%. 1 H NMR (500MHz, CDCl3) δ7.60 (d, 1H, J = 2.0), 7.18 (dd, 1H, J = 8.5, 2.0), 7.18 (d, 1H, J = 8.5) ,4.62(t,1H,J=5.5),4.41(m,1H),3.71(t,2H,J=5.5),3.50(s,3H),3.48(s,6H); ESI-MS m / z:314.1[M+H] + .

[0963] Step c: Intermediate 57-B (100 mg, 1 equivalent) was added to 799 μL of concentrated hydrochloric acid (12 M, 30 equivalents), and stirred at 100 °C for 8 h. After cooling the reaction solution, 50 mL of saturated sodium bicarbonate aqueous solution was added under ice bath conditions to neutralize the excess hydrochloric acid. The mixture was then extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated brine. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by rapid column chromatography, eluting with a petroleum ether-ethyl acetate solvent system to give 60 mg of solid, i.e., intermediate 57-C, with a yield of 75%. 1 H NMR (500MHz, CDCl3) δ7.62(d,1H,J=1.5),7.35(dd,1H,J=8.5,1.5),7.24(d,1H,J=1.5),7.10(d,1H,J=2.0),7.07(d,1H,J=8.5),3.70(s,3H); ESI-MS m / z:250.2[M+H] + .

[0964] The synthesis method of compound 57-1 is the same as that of compound 46-1, except that intermediate 57-C is used instead of intermediate 46-C as the raw material.

[0965] Intermediate 57-D. 1 H NMR(500MHz, CDCl3)δ7.83(d,1H,J=2.0),7.42-7.31(m,2H),7.28(d,1H,J =8.5),7.25-7.13(m,1H),7.09(d,2H,J=6.0),6.71(d,1H,J=3.0),6.31(s, 1H),5.45-5.13(m,1H),4.58-4.22(m,1H),3.79(s,3H),3.23-3.01(m,1H) ,2.79(m,2H),2.21(d,6H,J=1.5),1.49(s,9H),1.33(d,3H,J=7.0); ESI-MS m / z:611.4[M+H] + .

[0966] Compound 57-1. 1¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotational isomer) δ 11.35 (s, ¹H), 8.34 (s, ¹H), 7.64 (d, ¹H, J = 8.4), 7.60 (d, ¹H, J = 9.0), 7.59–7.56 (m, 2H), 7.52 (s, ¹H), 7.39 (s, ¹H), 7.27 (m, ¹H), 7.11 (d, 2H, J = 6.0), 6.89 (d, ¹H, J = 3.0), 6.72 (s, ¹H), 6.43 (d, ¹H, J = 3.0), 5.78 (q, ¹H, J = 6.0), 4 .49(dd,1H,J=13.8,4.8),4.07(s,3H),3.93-3.81(m,2H),3.60(td,1H,J=13.2,3.6),3.17(m,1H),3.04(m,2H),2.25(d,6H,J=1.2) ,1.90(t,1H,J=5.3),1.81-1.72(m,3H),1.69-1.62(m,2H),1.56-1.50(m,4H),1.36(s,3H),1.30(s,3H),1.17(d,3H,J=5.3); ESI-MS m / z:904.6[M+H] + .

[0967] Example 60

[0968] Preparation of 3-(1S,2S)-1-[2-(S)-3-[3-(3-cyclopropylimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 58)

[0969]

[0970] The synthesis method of compound 58 is the same as that of compound 1, except that intermediates 1-D and C9 are used instead of intermediates 1-D and C9, respectively.

[0971] 1¹H NMR (600MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.34 (s, ¹H, -NH), 8.10 (d, ¹H, J = 7.8), 7.60 (d, ¹H, J = 9.0), 7.55 (s, ¹H), 7.52 (s, ¹H), 7.40 (s, ¹H), 7.27 (m, ¹H), 7.11 (d, 2H, J = 6.0), 6.74 (d, ¹H, J = 3.0), 6.71 (s, ¹H), 6.36 (d, ¹H, J = 2.4), 5.78 (q, ¹H, -NH) J=6.6),4.48(dd,1H,J=13.8,4.8),4.11(dd,2H,J=11.4,3.0),3.62-3.52(m,3H),3.15(m,1H),3.01(m,1H),2.86(m,1H ),2.26(d,6H,J=1.2),2.07(m,1H),1.93-1.77(m,5H),1.68-1.47(m,5H),1.35-1.13(m,4H),1.18(d,3H,J=6.0); ESI-MS m / z:863.6[M+H] + .

[0972] Example 61

[0973] Preparation of 3-[(1S,2S)-1-[2-[(S)-3-[3-(3-cyclopropyl-8-fluoroimidazo[1,5-a]pyridin-7-yl)-2-oxo-2,3-dihydro-1H-imidazo-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5-formyl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (compound 59)

[0974]

[0975] The synthesis method of compound 59 is the same as that of compound 1, except that intermediates 1-D and C9 are used instead of intermediates 1-D and C9, respectively.

[0976] 1¹H NMR (500MHz, major isomer in CDCl₃, 4:1 rotatory isomer) δ 11.32 (s, ¹H), 7.89 (d, ¹H, J = 8.0), 7.60 (d, ¹H, J = 8.5), 7.51 (m, 2H), 7.27 (m, ¹H), 7.12 (d, 2H, J = 5.5), 6.86 (t, ¹H, J = 6.5), 6.71 (s, ¹H), 6.66 (m, ¹H), 6.32 (d, ¹H, J = 3.0), 5.79 (q) ,1H,J=6.5),4.48(dd,1H,J=13.5,5.0),4.10(m,2H),3.57(m,3H),3.16(m,1H),3.02(m,1H),2.87(m,1H),2. 28(s,6H),2.04(m,1H),1.93-1.76(m,5H),1.70-1.49(m,5H),1.20(d,3H,J=5.5),1.15-1.03(m,4H); ESI-MS m / z:881.6[M+H] + .

[0977] The compounds in the table below were prepared using the same or similar synthetic methods as compound 1 or compound 46-1:

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995] Test Implementation Examples

[0996] Test Example 1: Determination of GLP-1 receptor-mediated agonistic activity

[0997] (1) Test method

[0998] The compounds were characterized by their effect on cAMP levels in the hGLP-1R / HEK293 cell line. The human GLP-1 receptor gene (hGLP-1R) was amplified from the cDNA of the human colorectal adenocarcinoma cell line NCl-H716 (Chinese Academy of Sciences Cell Bank, #TCHu210) and cloned into the HA-pcDNA3.1 vector (Addgene, #128034), positioning the HA-tag at the N-terminus of hGLP-1R. The hGLP-1R / HA-pcDNA3.1 plasmid was transfected into HEK293 cells to construct a stable hGLP-1R / HEK293 cell line. The hGLP-1R / HEK293 cells were digested, centrifuged, and resuspended in culture medium (DMEM + 0.2% BSA, m / v), and the cell density was adjusted to 2 × 10⁶ cells / mL. 5 Cells / mL, add IBMX (3-isobutyl-1-methylxanthine, final concentration 0.5mM) to the cell suspension, at 5μL (1×10⁻⁶ cells / mL). 3Add cells per well to a 384-well plate. Dissolve the compound in DMSO to prepare a 10 mM stock solution. For experiments, start with a 100 μM concentration and serially dilute 10-fold for a total of 7 spots, with the 8th spot being DMSO. Add 2 μL of different concentrations of the test compound to 98 μL of culture medium, vortex to mix, and then add 5 μL to each 384-well plate (final concentration of test compound 0-100 nM, final concentration of DMSO 1%, v / v). Incubate in a dark incubator (37℃, 5% CO2) for 30 min. Then add 10 μL of cAMP detection reagent (LANCE Ultra cAMP Detection Kit, PerkinElmer, #TRF0264), mix well, and incubate at room temperature in the dark for 1 h. After the reaction, read the HTRF signal using an Envision 2104 multi-functional microplate reader. All samples were tested in triplicate. The receptor-donor excitation signal ratio for each single well was calculated using the formula Ratio = Signal 665 nM / Signal 620 nM. The HTRF signal ratio and the corresponding compound concentration were analyzed using GraphPad Prism 8 software. The EC50 of the compound was calculated by fitting an S-shaped dose-response curve. 50 value.

[0999] (2) Reference compound

[1000] In the chemical structure of LY3502970, the chiral carbon atom on the dimethyltetrahydropyran substitution is in the S-configuration. When this chiral center is not separated, an R-configuration isomer also exists, in which case LY3502970 is a racemic variant. In this invention, LY3502970 and its racemic variant are used as reference compounds.

[1001]

[1002] (3) Activity test results

[1003] The activities of the compounds are shown in Table 1, where "A" indicates 0. <EC 50 ≤1nM, “B” represents 1 <EC 50 ≤10 nM. It can be seen that the compounds of this invention can activate the hGLP-1 receptor at the nanomolar level, and some compounds exhibit activity comparable to the positive control LY3502970 or its racemic mixture, demonstrating good activity.

[1004] Table 1: Effects of the compounds of the present invention on cAMP levels in hGLP-1R / HEK293 cell line

[1005]

[1006]

[1007]

[1008] Table 1-1: EC5 activity of compounds activating hGLP-1R cAMP signaling 50 value

[1009]

[1010]

[1011]

[1012] Table 1-2: Comparison of structure and activity between reference compounds and compounds of the present invention

[1013]

[1014]

[1015]

[1016] This invention systematically modifies the B ring in general formula (I), including in-depth exploration of multiple dimensions such as ring size, shape, hybridization mode, ring fusion mode, heteroatom type and position, and fully optimizes the substituents on the ring. Data in Tables 1-1 and 1-2 show that the compounds of this invention exhibit strong agonistic activity to hGLP-1R at the nanomolar to sub-nanomolar levels, and the activity of several compounds significantly exceeds that of structurally similar reference compounds. These results demonstrate that structural changes to the B ring—even minor adjustments—can significantly affect the biological activity of compounds, thus showcasing the unexpected technical effects of the structural modifications performed in this invention.

[1017] Evaluation of the β-arrestin pathway agonist effect of compound in Test Example 2

[1018] (1) Test method

[1019] The Promega NanoBiT protein-protein reaction system was used to characterize the agonistic effect of compounds on the β-arrestin pathway by detecting the recruitment of β-arrestin 1 and β-arrestin 2 proteins after binding to GLP-1R. The NanoBit protein-protein reaction system is a two-subunit system based on NanoLuc luciferase, used to detect intracellular protein interactions. The LgBiT (17.6 kDa) and SmBiT (11 amino acids) subunits are fused to the target protein. When the target protein interacts, the two subunits come into close proximity to form a catalytically active enzyme capable of catalyzing the luminescence of the luciferase substrate.

[1020] First, the human GLP-1R gene was ligated to the N-terminus of LgBit, and the β-arrestin 1 / 2 gene was cloned into the C-terminus of SmBit. The fusion proteins were then introduced into the pcDNA3.0 vector to construct plasmids expressing the hGLP-1R-LgBit and SmBit-β-arrestin 1 / 2 fusion proteins, respectively. The hGLP-1R-LgBit plasmid and the SmBit-β-arrestin 1 (or SmBit-β-arrestin 2) plasmid were each expressed at a dose of 1 μg plasmid / 2 × 10⁻⁶. 6 HEK293 cells were co-transfected at a ratio of 1:10. Immediately after transfection, the cells were sporadically inoculated at a rate of 4 × 10⁻⁶ cells / year. 5 Cells were added to 96-well white plates at a density of 1000 cells / well and cultured in an incubator (37°C, 5% CO2) for 20 hours.

[1021] After 20 hours, discard the liquid in the wells, add 40 μL of fresh culture medium (DMEM + 0.2% BSA, m / v), then add 10 μL of Nano-Glo Live Cell assay solution (Promega, #N2011), and incubate the cells in an incubator for 10 min. Dissolve the compound in DMSO to prepare a 10 mM stock solution. For experiments, start with a concentration of 100 μM, and after 10-fold serial dilutions, add 3 μL of different concentrations of the test compound to 97 μL of culture medium (GLP-1 final concentration 0-10 μM, other compounds final concentration 0-100 μM, DMSO final concentration 1%, v / v for all). After 10 min of cell incubation, add 25 μL of culture medium containing the compound to each well, incubate at room temperature for 5 min, and then detect the fluorescence signal using an Envision 2104 multi-functional microplate reader (PerkinElmer). All samples were tested in triplicate. Analysis was performed using GraphPad Prism 8 software, with fluorescence signal ratios corresponding to compound concentrations. EC50 of the compounds was calculated by fitting sigmoid dose-response curves. 50 value.

[1022] (2) Test Results

[1023] like Figure 1 and Figure 2 As shown, the agonistic activity of natural GLP-1 on the β-arrestin 1 and β-arrestin 2 pathways is EC10, EC20, and EC20, respectively. 50=147.4 nM and 135.7 nM, while LY3502970, compound 6-1, compound 11-1, compound 15-1, and compound 96-1 do not activate the β-arrestin 1 or β-arrestin 2 pathways. Combined with the data presented in Table 1, this indicates that the compounds of the present invention are G protein biased agonists.

[1024] Test Example 3: Preliminary evaluation of the oral absorbability of the drug

[1025] To investigate the oral absorption properties of the compounds and select compounds for more detailed pharmacokinetic evaluation, the research method adopted in this invention is to first test the plasma drug concentration of the compounds in mice at 1 and 4 hours after oral administration for preliminary evaluation.

[1026] (1) Drug preparation

[1027] The test drug was dissolved in a 2:2:96 (V / V / V) aqueous solution of DMSO / Tween 80 / 0.5% (m / V) methylcellulose A4M, and prepared to the target concentration according to the dosage and volume. It was administered orally (PO) at a volume of 10 mL / kg and a dose of 10 mg / kg.

[1028] (2) Experimental methods

[1029] Three male ICR rats weighing 30-38g were used in each group. They were fasted for 12 hours before the experiment but had free access to water. Four hours after drug administration, they were fed uniformly. One and four hours after gavage administration, 30-40 μL of blood was collected via the jugular or mandibular vein and placed in anticoagulant tubes containing EDTA-K2. After collection, the whole blood was temporarily stored in an ice-water bath and centrifuged at 11,000 rpm for 5 minutes within 30 minutes to separate the plasma. The plasma was then frozen at -70°C for analysis. The drug concentration in the samples was quantitatively determined using LC-MS / MS.

[1030] (3) Test Results

[1031] As can be seen from Table 2, at 1 and 4 hours after oral administration of the same dose (10 mg / kg), the compound of the present invention had higher blood concentrations than the LY3502970 racemate, indicating better oral absorption.

[1032] Table 2: Plasma drug concentrations of the compound after oral administration in mice (mean; N=3)

[1033]

[1034] Test Example 4: Mouse Pharmacokinetics

[1035] (1) Drug preparation

[1036] The test drug was dissolved in a 2:2:96 (V / V / V) aqueous solution of DMSO / Tween 80 / 0.5% (m / V) methylcellulose A4M, and prepared to the target concentration according to the dosage and volume. For intravenous (IV) administration, the volume was 5 mL / kg. For oral (PO) administration, the volume was 10 mL / kg.

[1037] (2) Experimental methods

[1038] Male ICR mice weighing 30-38g, 3 mice per group, were fasted for 12 hours before the experiment but allowed free access to water. They were fed uniformly 4 hours after drug administration. In group IV, the drug was administered via the tail vein, and blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-administration. In group PO, the drug was administered via gavage, and blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-administration. At each time point, 30-40 μL of blood was collected via the jugular or mandibular vein and placed in anticoagulant tubes containing EDTA-K2. After collection, the whole blood was temporarily stored in an ice-water bath and centrifuged at 11000 rpm for 5 minutes within 30 minutes to separate the plasma. The plasma was then frozen at -70°C for analysis. The drug concentration in the samples was quantitatively determined using LC-MS / MS. The relevant pharmacokinetic parameters T were calculated using WinNonlin software. max C max AUC 0-∞ t 1 / 2 wait.

[1039] (3) Test Results

[1040] As can be seen from Table 3, after oral administration at the same dose (10 mg / kg), the compound of the present invention has higher blood concentration, oral exposure and oral bioavailability than LY3502970, and therefore has better pharmacokinetic properties.

[1041] Table 3: Plasma pharmacokinetic parameters of the compounds after oral and intravenous injection in mice (mean values; N=3)

[1042]

[1043] Note: C max Maximum blood drug concentration; T max Time to peak drug concentration; AUC 0-t Area under the drug-time curve from zero time to the last sampling time; CL, plasma clearance rate of the drug; V ss The volume of distribution of a drug at steady state; t 1 / 2 , elimination half-life; F, oral bioavailability; -, not calculated.

[1044] Test Example 5: Diet Suppression Experiment

[1045] (1) Laboratory animals

[1046] Genetically engineered hGLP-1R knock-in mice were purchased from Shanghai Southern Model Biotechnology Co., Ltd. All experimental animals were housed in an SPF-grade environment at the National Compound Sample Bank animal facility, with a temperature of 24±2℃, relative humidity of 40-60%RH, air cleanliness level 7, and a 12h / 12h day / night cycle. They were continuously provided with cobalt-60 radioactively sterilized complete pelleted mouse feed (maintenance feed for mice and rats from Shanghai Shilin Biotechnology Co., Ltd.), with unlimited access. They also had access to tap water (sterilized by autoclaving), with an uninterrupted water supply. The cages were transparent polyetherimide cages (CP-8 mouse cages from Suzhou Fengshi Laboratory Animal Equipment Co., Ltd.), with corn cobs (sterilized by autoclaving from Dezhou Gumei Agricultural Technology Co., Ltd.). Each cage contained 3-5 animals, and the cage tags indicated the IACUC approval number, experiment number, experiment start time, responsible person, experimental personnel, animal origin, group, and animal number. The animal methods used in this experiment were approved by the IACUC Committee of the Shanghai Institute of Materia Medica.

[1047] (2) Drug preparation

[1048] The test drug is dissolved in a 2:2:96 (V / V / V) solution of DMSO / Tween 80 / 0.5% methylcellulose A4M, and prepared to the target concentration according to the dosage and volume. The oral administration volume is usually 10 mL / kg.

[1049] (3) Experimental methods

[1050] hGLP-1R transgenic mice were housed in groups of 6-8, one mouse per cage. They were fasted for 6 hours before the experiment. At the start of the night cycle (7:00 PM), they were administered the prepared test drug via gavage. The blank control group received an equal volume of the above-mentioned DMSO / Tween 80 / 0.5% methylcellulose A4M solution, followed by feeding. Food was weighed in each cage at 0, 3, 6, 12 (at the start of the day cycle at 7:00 AM), and 24 hours after drug administration to calculate the amount of food consumed by the mice.

[1051] (4) Experimental Results

[1052] like Figure 3 As shown, the positive control LY3502970, as well as compounds 6-1 and 11-1 of this invention, significantly inhibited food intake in mice within 0 to 24 hours after oral administration at 3 mg / kg. Among them, the cumulative food intake of compound 11-1 at each time point was slightly lower than that of LY3502970.

[1053] like Figure 6The results show the effects of compound 15-1, the positive control LY3502970, and compound Ref-3 on food intake in mice within 24 hours after a single oral administration. It is evident that compound 15-1 at a dose of 0.3 mg / kg significantly inhibited food intake compared to LY3502970 at 1 mg / kg and 0.3 mg / kg, and also compared to Ref-3 at 1 mg / kg and 0.3 mg / kg. Compound 15-1 exhibited even better food-suppressing effects at a dose of 1 mg / kg.

[1054] like Figure 7 As shown, when compound 15-1 of the present invention was administered orally to mice at a dose of 0.1 mg / kg, its appetite-suppressing effect over 24 hours was significantly superior to that of LY3502970, compound Ref-1, and compound Ref-4 at equivalent doses. The superior appetite-suppressing effect of compound 15-1 is consistent with its superior oral pharmacokinetic properties.

[1055] like Figure 8 As shown, when compound 96-1 of the present invention was administered orally to mice at a dose of 1 mg / kg, its inhibitory effect on food intake within 24 hours was significantly better than that of compound Ref-5 at the same dose.

[1056] Test Example 6: Oral Glucose Tolerance Test (OGTT)

[1057] (1) Drug preparation

[1058] The test drug is dissolved in a 2:2:96 (V / V / V) solution of DMSO / Tween 80 / 0.5% methylcellulose A4M, and prepared to the target concentration according to the dosage and volume. The oral administration volume is usually 10 mL / kg.

[1059] (2) Experimental methods

[1060] Groups of 5-8 hGLP-1R transgenic mice were fasted overnight before the experiment, and fasting blood glucose levels in their tails were measured using a glucometer. At the start of the experiment, mice were administered the prepared test drug via gavage, while the control group received an equal volume of the above-mentioned DMSO / Tween 80 / 0.5% methylcellulose A4M solution. Blood glucose was measured again after 60 or 300 minutes as the zero-point blood glucose level. Immediately afterward, mice were administered 2 g / kg of glucose via gavage, and blood glucose levels were measured at 15, 30, 60, and 90 minutes post-glucose administration.

[1061] (3) Experimental Results

[1062] from Figure 4 and Figure 5 It is evident that compounds 6-1 and 11-1 of the present invention can potently and dose-dependently reduce blood glucose levels and area under the blood glucose curve (AUC) in mice, and therefore have good potential for the treatment of diabetes.

[1063] Figure 9 and Figure 10 The changes in blood glucose levels and AUC after administration of the test compound 5 hours prior to the test and gavage administration of glucose (2 g / kg) at time 0 are shown. It is evident that within 90 minutes after the glucose challenge, compound 15-1 of the present invention significantly inhibited the rise in blood glucose levels at oral doses of 0.01 and 0.1 mg / kg. Compared with the blank control group, the glucose-lowering effect calculated by AUC at both doses reached 42% and 55%, respectively, demonstrating a potent and sustained glucose-lowering effect after a single dose. Furthermore, the glucose-lowering effect of compound 15-1 was slightly greater than that of the reference compound Ref-1 at equivalent doses (36% and 50%, respectively), indicating better potential for diabetes treatment.

[1064] Test Example 7: Cell Membrane Permeability

[1065] (1) Materials and reagents

[1066]

[1067] (2) Cell Culture

[1068] Caco-2 cells were grown in 10cm cell culture dishes using MEM medium (containing 10% FBS) at 37°C with 5% CO2 and 95% humidity. When the cells reached 80-90% confluence, they were digested with 0.25% trypsin (containing EDTA). The digested cells were then incubated at 2×10⁻⁶ cells / day. 5 Cells were seeded at a density of 200 μL / well in Transwell-24 wells, with MEM medium (containing 10% FBS) added to the bottom layer at a volume of 800 μL / well. Cells were incubated in a 37°C CO2 incubator with 5% CO2 concentration and 95% humidity. Fresh medium was added every other day, and the cells were cultured continuously for 21 days for in vitro permeability and efflux transporter (P-gp) substrate studies of the test compound.

[1069] (3) In vitro permeability test

[1070] All solutions used in the experiment were preheated at 37°C for 30 min. Before the experiment, cell monolayers were washed twice with HBSS solution preheated to 37°C, and then equilibrated for 30 min in a 37°C CO2 incubator with 5% CO2 concentration and saturated humidity using HBSS solution at pH 7.4 or a corresponding inhibitor. The incubator was then equilibrated for 30 min. The experiment included a control group and an experimental group. The control group consisted of the low-osmotic compound acyclovir and the high-osmotic compound minoxidil, both at a concentration of 10.0 μM. For compound transport from side A to side B: the solution containing the compound or positive substrate was added to side A as the donor side, while blank HBSS solution was added to side B as the receiver side. For compound transport from side B to side A: the solution containing the compound or positive substrate was added to side B as the donor side, while blank HBSS solution was added to side A as the receiver side. Cell plates were incubated at 37°C in a 5% CO2 incubator with saturated humidity for 120 min. Zero-time point samples before incubation and cell lysates after incubation were also collected for analysis. Each drug concentration was tested in duplicate.

[1071] (4) Analytical instruments and data acquisition software

[1072] Compound concentration was determined by LC-MS / MS: Triple Quad 5500 triple quadrupole tandem mass spectrometer, equipped with an electrospray ionization source (ESI source), AB SCIEX, USA; liquid chromatography system, including infusion pump, high-speed autosampler, column oven, and degasser, Shimadzu Corporation, Japan.

[1073] Data acquisition was performed using AB Sciex's Analyst V1.6.3 software.

[1074] (5) Data Processing and Analysis

[1075] The apparent permeability coefficient (P) is calculated using the following formula. app (cm / s) and Efflux Ratio (ER).

[1076]

[1077] Note: V R This refers to the volume of the solution on the receiving side (200 μL on side A, 1200 μL on side B); Area is the relative surface area of ​​the cell monolayer (0.33 cm²). 2 T is the incubation time (7200s); C0 is the initial concentration at the administration side (nM); C R The final concentration (nM) at the receiving side.

[1078] (6) Test Results

[1079] As shown in Table 4, the apparent permeability coefficient of the compounds of this invention in Caco-2 cells is significantly higher than that of the reference compound LY3502970, indicating that the amplification of the rings leads to an increase in the cell membrane permeability of the compounds. This improved property is consistent with the superior oral pharmacokinetic characteristics exhibited by the compounds of this invention.

[1080] Table 4: Apparent permeability and efflux ratio of compounds in Caco-2 cells

[1081]

[1082] Note: Permeability evaluation criteria: Low permeability, P app ≤Acyclovir; moderate osmotic pressure, P app Between acyclovir and minoxidil; high permeability: P app ≥Minoxidil.

[1083] Test Example 8: Pharmacokinetic Evaluation in Rats

[1084] (1) Evaluation Method

[1085] The drug preparation and experimental methods were the same as in test example 4, except that SD rats weighing 200-280g were used instead of ICR mice as experimental animals.

[1086] (2) Evaluation Results

[1087] As shown in Table 5, compound 15-1 of the present invention, after oral administration to rats at doses of 1.5, 5, 15, and 45 mg / kg, exhibited linear pharmacokinetic characteristics. Blood drug concentration and oral exposure increased with increasing dose, without reaching the absorption ceiling (roof effect). Furthermore, compared to reference compounds Ref-1, Ref-3, LY3502970, and Ref-6, compound 15-1 showed significantly higher blood drug concentration and oral exposure at the same dose (5 mg / kg), indicating superior oral absorption performance. This characteristic is consistent with the superior diet-suppressing effect observed in Test Example 5. In addition, combined with the mouse pharmacokinetic data in Table 3, it can be seen that the structural modifications to the B-ring of the present invention, such as adjusting the position of the nitrogen atom in the heteroaryl group, changing the cyclization mode, and introducing cycloalkyl substituents, have achieved unexpected technical effects in improving the oral absorption performance of the compound.

[1088] Table 5: Plasma pharmacokinetic parameters of the compounds after oral administration in rats (mean values; N=3)

[1089] Note: a Data source: patent WO2025026270; b The data comes from patent US12234236.

[1090]

[1091] Test Example 9: Solubility Test

[1092] (1) Test method

[1093] The analyte was prepared into stock solutions of 50 or 100 mg / mL using DMSO as the solvent. These stock solutions were then transferred to 96-well plates and diluted with phosphate-buffered saline (PBS, pH 7.4) to obtain solutions with a concentration of 100 μg / mL. Two replicates were prepared for each concentration. The mixed solution was placed in a 37°C water bath with a shaker for 2 hours to ensure complete dissolution. Subsequently, the solution was centrifuged at 11,000 rpm for 5 minutes to precipitate undissolved substances. The supernatant was filtered through a 0.22 μm filter to remove particulate matter, and then analyzed by LCMS / MS to determine the concentration of the dissolved compound.

[1094] (2) Test Results

[1095] As shown in Table 6, the compounds of the present invention have higher solubility in PBS solution (pH 7.4) than the reference compounds, which is consistent with the superior oral pharmacokinetic properties of the compounds of the present invention.

[1096] Table 6: Solubility of compounds in PBS solution (pH 7.4)

[1097] Compound Solubility (pg / mL) LY3502970 37.2 Ref-1 37.1 Ref-4 18.8 6-1 31.3 15-1 60.0 59 50.3 96-1 77.4 115-1 53.7

[1098] Test Example 10: Weight Loss Experiment in a Diet-Induced Obesity (DIO) Mouse Model

[1099] (1) Experimental methods

[1100] Forty-week-old hGLP-1R knock-in male mice were fed a high-fat diet (supplier: Research Diets, catalog number D12492) for four weeks. Mice weighing approximately 40g were randomly divided into cages of three mice per cage. The compound was prepared at the prescribed dosage in a 2:2:96 (V / V / V) solution of DMSO / Twenty-Wein 80 / 0.5% methylcellulose A4M, administered at a volume of 10 mL / kg via gavage once daily. The blank control group received only an equal volume of the solvent. The administration continued for 21 days, and the weight of the mice and the amount of food consumed per cage were measured daily.

[1101] (2) Data processing

[1102] All data are expressed as mean ± standard error (mean ± SEM), and graph analysis was performed using Graphpad software. A p < 0.05 (*) indicates a statistically significant difference, a p < 0.01 (**) indicates a statistically significant difference, and a p < 0.001 (***) indicates a highly statistically significant difference. (3) Experimental Results

[1103] like Figure 11 As shown, during the 21-day administration period, the weight of mice in the blank control group continued to increase, while all treatment groups showed significant weight loss. After 21 days of treatment with the reference compound LY3502970 (1 mg / kg / day), the weight of DIO mice decreased by 12.79% from baseline; while compound 15-1 at doses of 0.3 mg / kg / day and 1 mg / kg / day resulted in weight reductions of 13.44% and 15.13%, respectively. These results indicate that the compounds of this invention can achieve superior weight loss effects compared to the reference compound at lower doses. Furthermore, this result is consistent with the superior diet-suppressing effect of compound 15-1 observed in Test Example 5.

[1104] discuss:

[1105] 1. Compared with existing technologies, one of the structural distinguishing features of the compounds of general formula (I) of this invention is that the B ring is expanded from a 5-10 member monocyclic or bicyclic heteroaryl group to an 11-18 member bicyclic, tricyclic, or tetracyclic heteroaryl group, or the B ring is modified to a cycloalkyl-substituted bicyclic or tricyclic heteroaryl group. Surprisingly, the compounds after ring expansion and modification, whether bicyclic, tricyclic, or tetracyclic, still maintain good activity. Many compounds even exhibit activities exceeding those of the reference compounds. Furthermore, compared with the reference compounds, the compounds of this invention show significantly improved oral pharmacokinetic performance, with higher plasma exposure and bioavailability.

[1106] 2. Numerous studies have shown that β-arrestin participates in the internalization and desensitization of GLP-1R, affecting the intensity and persistence of its biological effects. In contrast, biased agonists do not activate β-arrestin, thus maximizing the biological effects of GLP-1R and enhancing efficacy. Therefore, the compounds of this invention are beneficial for preparing more effective hypoglycemic and weight-loss drugs. The results of the OGTT experiment in Test Example 6 confirm this.

[1107] 3. Since the weight-reducing effect of GLP-1 receptor agonists is mainly related to their inhibition of diet, it can be seen from tests 5 and 10 that the compounds of the present invention have better potential for the treatment of overweight / obesity.

[1108] 4. Tests in Examples 7 and 9 demonstrate that the cell membrane permeability or solubility of the compounds of the present invention is significantly improved, further verifying that the compounds have good oral bioavailability and therefore superior oral pharmacokinetic properties.

[1109] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), or a stereoisomer thereof, a deuterated thereof, or a pharmaceutically acceptable salt thereof: in, Ring A is a C6-C10 aryl group, wherein the aryl group is optionally substituted by one or more groups selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, and C2-C6 alkynyl. The B ring is selected from bicyclic or tricyclic heteroaryl groups as shown in formulas (X-1) to (X-7): in, Z1 is either N or C; Z2is N, CR b2 , O or S; Z3is selected from the group consisting of: Z4is selected from the group consisting of O, NR b2 or CH2; Z5 and Z6 are each independently selected from the following group: CH2 or C=O; R b1 each independently halogen or Ci-C3alkyl; each R b2 each independently is selected from the group of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkyl-C1-C3alkoxy, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl; k is selected from the following group: 0, 1, 2; The D ring is a C3-C8 cycloalkyl or a halo-C3-C8 cycloalkyl; is a saturated, partially saturated or aromatic ring; preferably, is an aromatic ring; each independently is a single or double bond; The C ring is a 4-8 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted with a C1-C6 alkyl group; R 1a , R 1b are each H; R 2a , R 2b each independently is selected from the group of H, Ci-C6-alkyl; R 3a , R 3b are each independently selected from the group of H, Ci-C6-alkyl, or R 3a and R 3b together with the carbon atom to which they are attached form a C3-C8-cycloalkyl group, optionally substituted with one or more groups selected from the group of Ci-C6-alkyl, halogenated Ci-C6-alkyl; R 4 , R 5 , R 6 , R 7 are each H; X is a chemical bond; Both Y and Z are CH.

2. The compound of claim 1, wherein Ring B is selected from the following formulas (X-1-1) to (X-9-1): in, Z2 is either N or CH; Z5 and Z6 are each independently selected from the following group: CH2 or C=O; R b1 each independently halogen or Ci-C3alkyl; each R b2 each independently is selected from the group of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkyl-C1-C3alkoxy, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl; k is selected from the following group: 0, 1, 2; The D ring is a C3-C8 cycloalkyl or a halo-C3-C8 cycloalkyl; each independently is a single or double bond.

3. The compound of claim 1, wherein Ring B is selected from the following groups: The B-ring group is optionally substituted with a halogen or a C1-C3 alkoxy group.

4. The compound of claim 1, wherein Ring A is selected from the following groups:

5. The compound of claim 1, wherein C ring is said R c1 or R c2 each independently H or C1-C3alkyl.

6. The compound of claim 1, wherein R 3a and R 3b together with the carbon atom to which they are attached form a cyclopropyl group, which is optionally substituted by C1-C3alkyl.

7. The compound of claim 1, wherein The compound is selected from the following formulas (Ic), (Id), (II-e) to (II-g), (III-c) or (III-d): in, R 9 selected from the group consisting of halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl; R c1 , R c2 , R c3 , R c4 each independently H or C1-C3alkyl; m is selected from the following groups: 1, 2, 3; Z1 is either N or C; Z2is selected from the group consisting of N, CR b2 , O or S; Z3is selected from the group consisting of: Z4is selected from the group consisting of O, NR b2 or CH2; Z5 and Z6 are each independently selected from the following group: CH2 or C=O; R b1 each independently halogen or Ci-C3alkyl; each R b2 each independently is selected from the group of H, C1-C3alkyl, C3-C8cycloalkyl, or halogenated C3-C8cycloalkyl; k is selected from the following group: 0, 1, 2; is a saturated, partially saturated, or aromatic ring; preferably, is an aromatic ring; The D ring is a C3-C8 cycloalkyl or a halo-C3-C8 cycloalkyl; each independently is a single or double bond.

8. The compound of claim 1, wherein The compound is selected from the following formulas: (Ic-1), (Id-1), (II-e-1), (II-e-2), (II-f-1), (II-f-2), (II-g-1), or (III-c-1): in, R 9 selected from the group consisting of halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl; R c1 , R c2 each independently H or C1-C3alkyl; m is selected from the following groups: 1, 2, 3; Z2 is either N or CH; R b1 each independently halogen or Ci-C3alkyl; each R b2 each independently is selected from the group of H, C1-C3alkyl, C3-C8cycloalkyl, or halogenated C3-C8cycloalkyl; k is selected from the following group: 0, 1, 2; The D ring is a C3-C8 cycloalkyl or a halo-C3-C8 cycloalkyl; each independently is a single or double bond.

9. The compound of claim 1, wherein The compounds are selected from the group consisting of:

10. A pharmaceutical composition, characterized by, Include: (i) the compound of any one of claims 1 to 9, or its stereoisomer, its deuterated form, or its pharmaceutically acceptable salt; (ii) Pharmaceutically acceptable carriers.

11. Use of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 10, characterized in that, Used to prepare GLP-1 receptor agonists, or to prepare drugs for the prevention and / or treatment of diseases or symptoms associated with GLP-1 receptor signaling pathway dysregulation.

12. The use of a compound or pharmaceutical composition according to claim 11, wherein The disease or disorder is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, diabetic complications, overweight / obesity, metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatohepatitis (MASH), hypertension, dyslipidemia, atherosclerosis, coronary heart disease, myocardial infarction, heart failure, cardiomyopathy, endocarditis, arrhythmia, cerebral infarction, stroke, thrombosis, aneurysm, obstructive sleep apnea, gout, chronic kidney disease, dementia, Parkinson's disease, brain inflammation, depression, alcohol addiction, drug addiction, nicotine addiction, autoimmune disease, cancer.

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