Polycyclic heteroaryl GLP-1 receptor agonist

Abstract

The present invention relates to a polycyclic heteroaryl GLP-1 receptor agonist. Specifically, a compound has a structure as represented by formula (I), wherein the definition of each group or substituent is as described in the description. Provided are a preparation method for the compound and a pharmaceutical use of the compound. Also disclosed is a use of the compound in preventing and / or treating diseases or symptoms related to dysfunction of a GLP-1 receptor signaling pathway.

Description

Polycyclic heteroarene GLP-1 receptor agonists

[0001] Priority information

[0002] The present disclosure claims priority to and the benefit of Chinese Patent Application No. 2024112579485, filed on September 9, 2024, and Chinese Patent Application No. 2025105281372, filed on April 24, 2025, to the China National Intellectual Property Administration, and incorporates by reference the entire contents of each of the foregoing applications herein. TECHNICAL FIELD

[0003] The present application relates to the field of medicinal chemistry, in particular, to a polycyclic heteroarene compound, a preparation method thereof and an application thereof in the preparation of a medicament. The present application further relates to the pharmacological effect of the compound and a pharmaceutical composition containing the compound as a biased GLP-1 receptor agonist, and the use thereof in the treatment of 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

[0004] Currently, the world is facing an increasingly severe epidemic of diabetes and obesity. According to the International Diabetes Federation (IDF) published Global Diabetes Map (10th Edition), the number of adult diabetes patients worldwide in 2021 was 537 million, about one in ten adults were affected. 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 much larger. A study published in the Lancet journal (Lancet. 2024; 403: 1027-1050.) showed that the global obesity population had 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 for new medical methods that are safer and more effective is still very urgent for patients.

[0005] 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 shown that GLP-1 receptor agonists also 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.

[0006] 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 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.

[0007] 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.

[0008] 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

[0009] The present application aims to provide a kind of polycyclic heteroarene GLP-1 receptor agonist with high agonistic activity to GLP-1 receptor Gs pathway, no activation of β-arresting pathway, more optimal oral pharmacokinetic properties compared with prior art, can efficiently reduce blood sugar and inhibit diet, its preparation method and its medical uses for preventing and / or treating diseases related to GLP-1 receptor signal pathway disorder.

[0010] 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:

[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 , R 3b are each independently selected from the group consisting of H, C1-C6 alkyl, or R3a 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 being 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 is selected from the group consisting of H, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy;

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

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

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

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

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

[0028] In another preferred embodiment, said compound has the structure according to formula (I-0):

[0029] wherein,

[0030] A ring is a C6-C10aryl, said aryl being 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;

[0031] B ring is selected from the group consisting of bicyclic or tricyclic heteroaryls according to formulae (X-1) to (X-7):

[0032] wherein

[0033] Z1is N or C;

[0034] Z2is N, CR b2 , O or S;

[0035] Z3is selected from the group consisting of:

[0036] Z4is selected from the group consisting of O, NR b2 or CH2;

[0037] Z5and Z6are each independently selected from the group consisting of CH2or C=0;

[0038] R b1 are each independently halogen or C1-C3alkyl;

[0039] 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;

[0040] k is selected from the group consisting of 0, 1, 2;

[0041] D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0042] is a saturated, partially saturated or aromatic ring; preferably, is an aromatic ring;

[0043] are each independently a single or double bond.

[0044] C ring is a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, said heterocycloalkyl being optionally substituted with C1-C6alkyl;

[0045] R 2a , R 2b are each independently selected from the group consisting of H, C1-C6alkyl;

[0046] R 3a , R 3b are 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, said cycloalkyl being optionally substituted with one or more groups selected from the group consisting of C1-C6alkyl, halogenated C1-C6alkyl.

[0047] In another preferred embodiment, the A ring is selected from the group consisting of:

[0048] In another preferred embodiment, the C ring is said R c1 or R c2 each independently is H or C1-C3 alkyl.

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

[0050] wherein,

[0051] 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;

[0052] 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 halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, oxo, C3-C8 cycloalkyl, haloC3-C8 cycloalkyl, C1-C6 alkoxy substituted C1-C6 alkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S;

[0053] 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;

[0054] R 1a , R 1b each independently is 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;

[0055] R 2a , R 2b each independently is selected from the group consisting of H, C1-C6 alkyl, or R 2a and R 2btogether with the carbon atom to which they are attached form a C3-C8cycloalkyl or a 4-8 membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O or S, said cycloalkyl and heterocycloalkyl being optionally substituted with one or more groups selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, cyano, hydroxy;

[0056] R 3a , R 3b are 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 comprising 1-3 heteroatoms selected from N, O or S, said cycloalkyl and heterocycloalkyl being optionally substituted with one or more groups selected from halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, cyano, hydroxy;

[0057] R 4 , R 5 , R 6 are each independently H or halogen;

[0058] R 7 is selected from the group consisting of H, halogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy;

[0059] X is NR 8 , O or a chemical bond;

[0060] Y, Z are each independently CH or N;

[0061] R 8 is H or C1-C6alkyl;

[0062] with the proviso that when the C ring is a 4-8 membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O or S, then,

[0063] a) X is not a chemical bond; or / and

[0064] b) the A ring is selected from the group consisting of C2-C6alkynyl substituted C6-C10aryl, C2-C6alkynyl substituted 5-10 membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O or S, said aryl and heteroaryl further being optionally substituted with one or more groups selected from halogen, C1-C6alkyl; or / and

[0065] c) the B ring is a C3-C8cycloalkyl or haloC3-C8cycloalkyl substituted 9-10 membered bicyclic heteroaryl comprising 1-4 heteroatoms selected from N, O or S, said heteroaryl further being optionally substituted with one or more groups selected from halogen, C1-C6alkyl, oxo; or / and

[0066] d) R 1a and R 1btogether with the carbon atom to which they are attached form a C3-C8cycloalkyl; or / and

[0067] e) R 2a and R 2b together with the carbon atom to which they are attached form a C3-C8cycloalkyl; or / and

[0068] f) R 3a and R 3b together with the carbon atom to which they are attached form a C3-C8cycloalkyl; or / and

[0069] g) Y, Z are not simultaneously CH.

[0070] In another preferred embodiment, the B ring is a 9-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O or S, said heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C3alkyl, C3-C5cycloalkyl, C3-C5halocycloalkyl.

[0071] In another preferred embodiment, the B ring has the following structural formulae (X-1) to (X-2):

[0072] wherein,

[0073] Z1is N or C;

[0074] Z2is selected from the group consisting of N, CR b2 , O or S;

[0075] R b1 each independently is halogen or C1-C3alkyl;

[0076] R b2 is selected from the group consisting of H, C1-C3alkyl, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0077] k is selected from the group consisting of 0, 1, 2;

[0078] D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0079] is a saturated, partially saturated or aromatic ring; preferably, is an aromatic ring;

[0080] each independently is a single or double bond.

[0081] In another preferred embodiment, the B ring has the following structural formulae (X-1-1) to (X-2-2):

[0082] wherein,

[0083] Z1is N or C;

[0084] Z2is N or CH;

[0085] R b1 each independently halo or C1-C3alkyl;

[0086] k is selected from the group consisting of 0, 1, 2;

[0087] D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0088] In another preferred embodiment, B ring is selected from the group consisting of: and is optionally substituted with a halo atom.

[0089] In another preferred embodiment, B ring is selected from the group consisting of:

[0090] In another preferred embodiment, 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 is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3alkyl, oxo, C3-C8cycloalkyl, halogenated C3-C8cycloalkyl, hydroxyl.

[0091] In another preferred embodiment, B ring is fused from a phenyl ring with a 7-11 membered heterocycloalkyl or heteroaryl containing 1-3 heteroatoms selected from N, O or S.

[0092] In another preferred embodiment, B ring is a 12-13 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N or S, said heteroaryl is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3alkyl, C3-C8cycloalkyl, halogenated C3-C8cycloalkyl.

[0093] In another preferred embodiment, B ring is a 13-15 membered tetracyclic 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 halo, C1-C3alkyl, oxo.

[0094] In another preferred embodiment, B ring has the following structural formula (X-3), (X-4), (X-7), (X-8), (X-9):

[0095] wherein,

[0096] Z3is selected from the group consisting of:

[0097] R b1each independently halogen or C1-C3 alkyl;

[0098] each R b2 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;

[0099] k is selected from the group consisting of 0, 1, 2;

[0100] each independently a single or double bond.

[0101] In another preferred embodiment, the B ring has the following structural formulae (X-3-1) ~ (X-9-1):

[0102] wherein,

[0103] R b1 each independently halogen or C1-C3 alkyl;

[0104] each R b2 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;

[0105] k is selected from the group consisting of 0, 1, 2;

[0106] each independently a single or double bond.

[0107] In another preferred embodiment, the B ring is selected from the group consisting of: said group is optionally substituted with a halogen atom.

[0108] In another preferred embodiment, the B ring is selected from the group consisting of: said group is optionally substituted with a halogen atom.

[0109] In another preferred embodiment, the B ring is selected from the group consisting of:

[0110] said group is optionally substituted with a halogen atom.

[0111] 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 the group consisting of halogen, C1-C3 alkyl, oxo, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl.

[0112] In another preferred embodiment, the B ring has the following structural formulae (X-5) to (X-6):

[0113] wherein,

[0114] Z4is selected from the group consisting of O, NR b2 or CH2;

[0115] Z5, Z6are each independently selected from the group consisting of CH2or C=O;

[0116] R b1 are each independently halogen or C1-C3alkyl;

[0117] each R b2 are each independently selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkyl-C1-C3alkoxy, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0118] k is selected from the group consisting of 0, 1, 2.

[0119] In another preferred embodiment, the B ring has the following structural formulae (X-5-1) to (X-6-1):

[0120] wherein,

[0121] R b1 are each independently halogen or C1-C3alkyl;

[0122] R b2 are selected from the group consisting of H, C1-C3alkyl, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0123] k is selected from the group consisting of 0, 1, 2.

[0124] In another preferred embodiment, the B ring is selected from the group consisting of:

[0125] said group is optionally substituted with a halogen atom.

[0126] In another preferred embodiment, the A ring is phenyl, which is 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.

[0127] In another preferred embodiment, the A ring is phenyl, which is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, methyl, cyclopropyl, ethynyl.

[0128] In another preferred embodiment, the compound has the structural formula of formula (I-a):

[0129] wherein

[0130] R 9 is selected from the group consisting of halogen, Ci-C3alkyl, halogenated Ci-C3alkyl, halogenated Ci-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl;

[0131] m is selected from the group consisting of 1, 2, 3;

[0132] the definition of 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.

[0133] In another preferred embodiment, the compound has the structural formula of formula (I-b):

[0134] wherein

[0135] R 9 is selected from the group consisting of halogen, Ci-C3alkyl, halogenated Ci-C3alkyl, halogenated Ci-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl;

[0136] R c1 , R c2 , R c3 , R c4 are each independently H or Ci-C3alkyl;

[0137] m is selected from the group consisting of 1, 2, 3;

[0138] the definition of B ring is as described in the first or second aspect of the application.

[0139] In another preferred embodiment, the compound has the structural formula of formula (I-c) to (I-d):

[0140] wherein

[0141] R 9 is selected from the group consisting of halogen, Ci-C3alkyl, halogenated Ci-C3alkyl, halogenated Ci-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl;

[0142] R c1 , R c2 , R c3 , R c4 are each independently H or Ci-C3alkyl;

[0143] m is selected from the group consisting of 1, 2, 3;

[0144] Z1is N or C;

[0145] Z2is N, CR b2 , O or S;

[0146] R b1 each independently is halogen or C1-C3alkyl;

[0147] R b2 is selected from the group consisting of H, C1-C3alkyl, C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0148] k is selected from the group consisting of 0, 1, 2;

[0149] D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0150] Preferably, D ring is cyclopropyl or halogenated cyclopropyl;

[0151] More preferably, D ring is cyclopropyl.

[0152] In another preferred embodiment, the compound has the structural formula of formula (I-c-1)~(I-d-1):

[0153] wherein,

[0154] R 9 is selected from the group consisting of halogen, C1-C3alkyl, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl;

[0155] R c1 , R c2 each independently is H or C1-C3alkyl;

[0156] m is selected from the group consisting of 1, 2, 3;

[0157] Z2is N or CH;

[0158] R b1 each independently is halogen or C1-C3alkyl;

[0159] k is selected from the group consisting of 0, 1, 2;

[0160] D ring is C3-C8cycloalkyl or halogenated C3-C8cycloalkyl;

[0161] Preferably, D ring is cyclopropyl or halogenated cyclopropyl;

[0162] More preferably, D ring is cyclopropyl.

[0163] In another preferred embodiment, the compound has the structure of formula (II):

[0164] wherein

[0165] X1is selected from the group consisting of (CH n ) p , N, O, S;

[0166] X2is selected from the group consisting of (CH n ) p , N, O, S;

[0167] X3is selected from the group consisting of (CH n ) p , N, O, S;

[0168] X4is selected from the group consisting of (CH n ) p , N, O, S;

[0169] X5is selected from the group consisting of (CH n ) p , N, O, S;

[0170] X6is selected from the group consisting of (CH n ) p , N, O, S;

[0171] X7is selected from the group consisting of (CH n ) p , N, O, S;

[0172] X8is selected from the group consisting of (CH n ) p , N, O, S;

[0173] X9is selected from the group consisting of (CH n ) p , N, O, S;

[0174] X1to X9are not simultaneously (CH n ) p ;

[0175] R 4b , R 4c are each independently selected from the group consisting of halogen, Ci-C6-alkyl, oxo, halogenated Ci-C6-alkyl, C3-C8-cycloalkyl;

[0176] R 4d is selected from the group consisting of halogen, Ci-C6-alkyl, halogenated Ci-C6-alkyl, C3-C8-cycloalkyl, hydroxyl, or two R 4d together with the carbon atom to which they are attached form a C3-C8-cycloalkyl or a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0177] g, h, i, p are each independently selected from the group consisting of 0, 1, 2, 3;

[0178] n is selected from the group consisting of 0, 1, 2;

[0179] are each independently a single or double bond;

[0180] A ring, C ring, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , Y, Z are defined as in the first aspect of the present application.

[0181] In another preferred embodiment, the structure of the compound is selected from the group consisting of (II-a ~ II-c):

[0182] wherein,

[0183] X1, X2, X3, X4, X5are each independently selected from the group consisting of (CH n ) p , N, O, S;

[0184] X6, X7, X8, X9are each independently selected from the group consisting of (CH n ) p , N, O, S;

[0185] In formula (II-c), X1~X5are not simultaneously (CH n ) p ;

[0186] R 4b , R 4c are each independently selected from the group consisting of halogen, C1-C6alkyl, oxo, halogenated C1-C6alkyl, C3-C8cycloalkyl;

[0187] R 4d is selected from the group consisting of halogen, C1-C6alkyl, halogenated C1-C6alkyl, C3-C8cycloalkyl, hydroxyl; or two R 4d 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;

[0188] g, h, i, p are each independently selected from the group consisting of 0, 1, 2, 3;

[0189] n is selected from the group consisting of 0, 1, 2;

[0190] each independently is a single or double bond;

[0191] A ring, C ring, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , Y, Z are as described in the first aspect of the present application.

[0192] In another preferred embodiment, the compound has the structure of formula (II-d):

[0193] wherein,

[0194] X1, X2, X3, X4, X5are each independently optionally selected from the group consisting of N, O, S;

[0195] R 4b , R 4c , R 4d is selected from the group consisting of halogen, C1-C6alkyl, oxo, halogenated C1-C6alkyl, C3-C8cycloalkyl, hydroxyl;

[0196] g, h, i are each independently selected from the group consisting of 0, 1, 2, 3;

[0197] n is selected from the group consisting of 0, 1, 2;

[0198] each independently is a single or double bond;

[0199] A ring, C ring, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , Y, Z are as described in the first aspect of the present application.

[0200] In another preferred embodiment, the compound has the structure of formula (II-e)~(II-g):

[0201] wherein,

[0202] R9 halo, C1-C3 alkyl, halo C1-C3 alkyl, halo C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0203] R c1 , R c2 , R c3 , R c4 each independently selected from H or C1-C3 alkyl;

[0204] m is selected from the group consisting of 1, 2, 3;

[0205] Z3is selected from the group consisting of:

[0206] R b1 each independently halo or C1-C3 alkyl;

[0207] each R b2 each independently selected from the group consisting of H, C1-C3 alkyl, C3-C8 cycloalkyl or halo C3-C8 cycloalkyl;

[0208] k is selected from the group consisting of 0, 1, 2;

[0209] each independently a single or double bond.

[0210] In another preferred embodiment, the compound has the structure of formula (II-e-1) ~ (II-e-2), (II-f-1) ~ (II-f-2) or (II-g-1):

[0211] wherein,

[0212] R 9 halo, C1-C3 alkyl, halo C1-C3 alkyl, halo C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0213] R c1 and R c2 each independently selected from H or C1-C3 alkyl;

[0214] m is selected from the group consisting of 1, 2, 3;

[0215] R b1 each independently halo or C1-C3 alkyl;

[0216] R b2 selected from the group consisting of H, C1-C3 alkyl, C3-C8 cycloalkyl or halo C3-C8 cycloalkyl;

[0217] k is selected from the group consisting of 0, 1, 2;

[0218] each independently is a single or double bond.

[0219] In another preferred embodiment, the compound has the structure of Formula (III):

[0220] wherein,

[0221] X1is selected from the group consisting of (CH n ) p , N, O, S;

[0222] X2is selected from the group consisting of (CH n ) p , N, O, S;

[0223] X3is selected from the group consisting of (CH n ) p , N, O, S;

[0224] X4is selected from the group consisting of (CH n ) p , N, O, S;

[0225] X5is selected from the group consisting of (CH n ) p , N, O, S;

[0226] R 4a is selected from the group consisting of halogen, C1-C6alkyl, oxo, halogenated C1-C6alkyl, C3-C8cycloalkyl, or two R 4a together with the carbon atom to which they are attached form a C3-C8cycloalkyl, 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0227] m is selected from the group consisting of 0, 1, 2, 3, 4;

[0228] n is selected from the group consisting of 0, 1, 2;

[0229] p is selected from the group consisting of 0, 1, 2, 3;

[0230] the definitions of A ring, C ring, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , Y, Z are as described in the first aspect of the invention.

[0231] In another preferred embodiment, the compound has a structure selected from the group consisting of (III-a, III-b):

[0232] wherein,

[0233] R 4a is selected from the group consisting of halogen, C1-C6alkyl, oxo, halogenated C1-C6alkyl, C3-C8cycloalkyl, or two R 4a together with the carbon atom to which they are attached form a C3-C8cycloalkyl, a 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0234] m is selected from the group consisting of 0, 1, 2, 3, 4;

[0235] A ring, C ring, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , Y, Z are defined as in the first aspect of the application.

[0236] In another preferred embodiment, the compound has a structure of formula (III-c)~(III-d):

[0237] wherein,

[0238] R 9 is selected from the group consisting of halogen, C1-C3alkyl, halogenated C1-C3alkyl, halogenated C1-C3alkoxy, C3-C5cycloalkyl, C2-C4alkynyl;

[0239] R c1 , R c2 , R c3 , R c4 are each independently selected from H or C1-C3alkyl;

[0240] m is selected from the group consisting of 1, 2, 3;

[0241] Z4is selected from the group consisting of O, NR b2 or CH2;

[0242] Z5, Z6are each independently selected from the group consisting of CH2or C=O;

[0243] R b1 are each independently halogen or C1-C3alkyl;

[0244] R b2H, C1-C3 alkyl, C3-C8 cycloalkyl, or halogenated C3-C8 cycloalkyl;

[0245] k is selected from the group consisting of 0, 1, 2.

[0246] In another preferred embodiment, the compound has the structure of Formula (II-c-1):

[0247] wherein,

[0248] R 9 is selected from the group consisting of halogen, C1-C3 alkyl, halogenated C1-C3 alkyl, halogenated C1-C3 alkoxy, C3-C5 cycloalkyl, C2-C4 alkynyl;

[0249] R c1 , R c2 are each independently selected from H or C1-C3 alkyl;

[0250] m is selected from the group consisting of 1, 2, 3;

[0251] R b1 are each independently halogen or C1-C3 alkyl;

[0252] R b2 is selected from the group consisting of H, C1-C3 alkyl, C3-C8 cycloalkyl, or halogenated C3-C8 cycloalkyl;

[0253] k is selected from the group consisting of 0, 1, 2.

[0254] In another preferred embodiment, the C ring is a 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, or S, which is optionally substituted with one or more groups selected from halogen, C1-C3 alkyl.

[0255] In another preferred embodiment, the C ring is selected from the group consisting of:

[0256] wherein,

[0257] X1are each independently selected from the group consisting of N, O, S;

[0258] R 5a is selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0259] v is selected from the group consisting of 0, 1, 2, 3, 4.

[0260] In another preferred embodiment, the C ring is selected from the group consisting of:

[0261] wherein, X1, R 5a , v are as defined above.

[0262] In another preferred embodiment, C ring is C3-C8cycloalkyl optionally substituted with halogen.

[0263] In another preferred embodiment, X in formula (I) is a bond.

[0264] In another preferred embodiment, A ring is

[0265] In another preferred embodiment, B ring is

[0266] In another preferred embodiment, B ring is

[0267] In another preferred embodiment, B ring is

[0268] In another preferred embodiment, C ring is

[0269] In another preferred embodiment, C ring is

[0270] In another preferred embodiment, R 1a is H. 1b

[0271] In another preferred embodiment, R 2a is H and R 2b is C1-C3alkyl.

[0272] In another preferred embodiment, R 2a is H and R 2b is methyl.

[0273] In another preferred embodiment, R 3a and R 3b together with the carbon atom to which they are attached form C3-C8cycloalkyl, which cycloalkyl is unsubstituted or substituted with C1-C3alkyl.

[0274] In another preferred embodiment, R 3a and R 3b together with the carbon atom to which they are attached form cyclopropyl, which cycloalkyl is unsubstituted or substituted with methyl.

[0275] In another preferred embodiment, R 4 is H.

[0276] In another preferred embodiment, R 5 is H.

[0277] In another preferred embodiment, R 6 is H. ​

[0278] In another preferred embodiment, R 7 is H.

[0279] In another preferred embodiment, X is a chemical bond.

[0280] In another preferred embodiment, X is O.

[0281] In another preferred embodiment, Y is CH.

[0282] In another preferred embodiment, Z is CH.

[0283] In another preferred embodiment, the compound is selected from the group consisting of:

[0284] In a third aspect, the present application provides a pharmaceutical composition comprising: a compound of the first or second aspect of the present application, or a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0285] In a fourth aspect, the present application provides use of a compound of the first or second aspect of the present application or a pharmaceutical composition of the third aspect of the present application, for the manufacture of a GLP-1 receptor agonist, or for the manufacture of a medicament for preventing and / or treating a disease or a symptom associated with a disorder of GLP-1 receptor signaling pathway.

[0286] In another preferred embodiment, the GLP-1 receptor agonist is a G protein-biased agonist.

[0287] In another preferred embodiment, the disease or symptom associated with a disorder of GLP-1 receptor signaling pathway 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 fatty liver hepatitis (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.

[0288] In another preferred embodiment, the disease or condition associated with dysregulation of the GLP-1 receptor signaling pathway is type 2 diabetes, overweight / obesity.

[0289] It should be understood that, within the scope of the present application, all the technical features described above and in the following (e.g. in the examples) of the present application can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0290] Figure 1 shows the agonistic effect of native GLP-1, LY3502970, compound 6-1 and compound 11-1 on the β-arrestin 1 pathway.

[0291] Figure 2 shows the agonistic effect of native GLP-1, LY3502970, compound 6-1 and compound 11-1 on the β-arrestin 2 pathway.

[0292] Figure 3 shows the change in cumulative food intake after 3, 6, 12 and 24 hours after oral administration of the positive control LY3502970, compound 6-1 and compound 11-1 in mice (n = 8; means ± SEM; **, p < 0.01 vs. blank control; ***, p < 0.001 vs. blank control).

[0293] Figure 4 shows the blood glucose concentration-time curve of compound 6-1 and compound 11-1 in the oral glucose tolerance test in mice (n = 5; means ± SEM).

[0294] Figure 5 shows the area under the blood glucose curve AUC(0-90) from 0 to 90 minutes of compound 6-1 and compound 11-1 in the oral glucose tolerance test in mice (n = 5; means ± SEM; ***, p < 0.001 vs. blank control).

[0295] Figure 6 shows the effect of compound 15-1 of the present application, the positive control LY3502970 and compound Ref-3 on food intake in mice within 24 hours after single oral administration (n = 8; means ± SEM; ***, p < 0.001 vs. blank control; #, p < 0.05; ###, p < 0.001 vs. compound 15-1 0.3 mg / kg).

[0296] Figure 7 shows the effect of LY3502970, Compound 15-1, Compound Ref-1 and Compound Ref-4 on food intake in mice within 24 hours after a single oral administration of 0.1 mg / kg (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).

[0297] Figure 8 shows the effect of LY3502970, Compound 96-1 and Compound Ref-5 on food intake in mice within 24 hours after a single oral administration of 1 mg / kg (n = 8; means ± SEM; **, p < 0.01 vs. blank control; ***, p < 0.001 vs. blank control; ###, p < 0.001 vs. Compound 96-1).

[0298] Figure 9 shows the blood glucose level-time curve of LY3502970, Compound 15-1 and Compound Ref-1 in mice oral glucose tolerance test (n = 5; means ± SEM).

[0299] Figure 10 shows the area under the curve (AUC) of blood glucose of LY3502970, Compound 15-1 and Compound Ref-1 in mice from 0 to 90 minutes after oral glucose and the reduction of the AUC of blood glucose compared to the blank control group (n = 5; means ± SEM; ***, p < 0.001 vs. blank control).

[0300] Figure 11 shows the effect of LY3502970 and Compound 15-1 on body weight of mice in a diet-induced obesity (DIO) mouse model after 21 days of administration (n = 9; means ± SEM; ***, p < 0.001 vs. blank control). DETAILED DESCRIPTION

[0301] Through extensive and in-depth research, and through a large number of screening and structural optimization, the present inventors provide a polycyclic heteroarene compound shown in formula (I). Specifically, for the structural modification of ring B, the present inventors not only expand the ring on the basis of the bicyclic ring, but also prepare a compound having a tricyclic or tetracyclic heteroaryl group, and disclose a preparation method of the compound and its use in preventing and / or treating diseases or symptoms related to the disorder of GLP-1 receptor signal pathway. On this basis, the present application is completed.

[0302] Terminology

[0303] In the present application, the terms used have the general meanings known to those skilled in the art, unless otherwise specified.

[0304] In the present application, the halogen is F, CI, Br or I.

[0305] In the present application, 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, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, n-hexyl, and the like.

[0306] In the present application, 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, t-butoxy, and the like.

[0307] In the present application, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms containing at least one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

[0308] In the present application, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms containing at least one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

[0309] In the present application, the term "C3-C8 cycloalkyl" represents a cyclic aliphatic group consisting of 3 to 8 ring-forming carbon atoms, and the like; it is to be understood that the "cycloalkyl" group as used herein encompasses not only monocyclic aliphatic groups, but also fused, spiro, and bridged ring systems consisting of multiple cyclic aliphatic groups; it is to be understood that the "cycloalkyl" group as used herein encompasses not only aliphatic groups in which the carbon atoms are completely saturated, but also aliphatic groups in which some of the carbon atoms have unsaturated bonds; examples of the "cycloalkyl" group as used herein include, but are not limited to: and the like. When the "cycloalkyl" group is used as a substituent, the point of attachment to the main body of the molecule can occur at any position on the "cycloalkyl" group that is chemically permissible.

[0310] In the present application, the term "aryl" refers to monocyclic and bicyclic ring systems consisting of a specified number of carbon atoms that obey the Hückel rule; it is to be understood that when the "aryl" group as used herein is a bicyclic ring system, it includes not only cases in which all of the rings are aromatic, but also cases in which only one of the rings is aromatic and the other ring is a non-aromatic aliphatic ring.

[0311] In the present application, the term "C6-C10 aryl" refers to a cyclic ring system having 6 to 10 carbon atoms, and at least one of the rings is aromatic; examples of the "aryl" group as used herein include, but are not limited to etc.; when "aryl" is used as a substituent, the point of attachment to the molecule's main body occurs on the aromatic ring.

[0312] In the present application, the term "heterocycloalkyl" means a cyclic group with a specified number of ring-forming atoms, containing at least one ring-forming heteroatom (N, O or S), saturated or partially unsaturated, non-aromatic; it is to be understood that "heterocycloalkyl" as used herein encompasses not only monocyclic heterocyclic ring systems, but also polycyclic heterocyclic ring systems, such as fused, spiro and bridged ring systems; when "heterocycloalkyl" is a polycyclic ring system, at least one of the rings contains a ring-forming heteroatom, and the other rings can contain ring-forming heteroatoms or can be cycloalkyl; for example, the term "4-8 membered heterocycloalkyl" means a monocyclic or polycyclic ring system having from 4 to 8 ring-forming atoms, at least one of which is a heteroatom, saturated or partially unsaturated; the definitions of other similar terms are analogous; more preferably, the number of heteroatoms is from 1 to 3. Examples include, but are not limited to, the following: It is to be understood that "heterocycloalkyl" as a substituent can be attached to the molecule's main body at any position allowed by the chemistry of the bonds.

[0313] In the present application, the term "heteroaryl" means a cyclic group with a specified number of ring-forming atoms, containing at least one ring-forming heteroatom (N, O or S), aromatic; unless otherwise specified, "heteroaryl" as used herein encompasses not only monocyclic heteroaromatic ring systems, but also polycyclic heteroaromatic ring systems, such as bicyclic heteroaryl, tricyclic heteroaryl, tetracyclic heteroaryl; when "heteroaryl" is a polycyclic heteroaromatic ring system, at least one of the rings is aromatic, and the other rings can be aromatic or non-aromatic, and the heteroatoms can be in the aromatic rings or in the non-aromatic rings; polycyclic heteroaromatic ring systems include not only fused ring systems, but also bridged and spiro ring systems.

[0314] In the present application, the term "9-15 membered bicyclic heteroaryl" means a ring system having from 9 to 15 ring-forming atoms, at least one of which is a heteroatom; the term "11-18 membered tricyclic heteroaryl" means a ring system having from 11 to 18 ring-forming atoms; the term "11-18 membered tetracyclic heteroaryl" means a ring system having from 11 to 18 ring-forming atoms; the definitions of other similar terms are analogous. Examples of "heteroaryl" include, but are not limited to It is to be understood that "heteroaryl" as a substituent is attached to the molecule's main body at the aromatic ring.

[0315] In the present application, the term "halogen" means substituted by halogen.

[0316] In the present application, the term "optionally" means that when there is a series of candidate groups to choose from, one can choose some or none.

[0317] "each independently" as used herein means that when several substituents are defined simultaneously, they are selected independently from the same list of candidate groups, and they can be the same or different.

[0318] In the present application, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. The specified substituents are those described in the foregoing or those appearing in the various embodiments. Unless otherwise specified, a substituted group can have at one substituent selected from a specified group at any substitutable position on the group, and the substituents can be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present application are those that are stable or chemically feasible.

[0319] In the present application, the term "1-6" means 1, 2, 3, 4, 5 or 6, and other similar terms have similar meanings independently.

[0320] It is understood that when a group is present simultaneously at multiple different positions in a compound, the definition of the group at each position is independent of the others and can be the same or different. That is, the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of".

[0321] Compounds

[0322] For the first or second aspect of the present application, the compounds of general formula (I) can contain one or more chiral centers, and enantiomers and diastereomers exist. The compounds of general formula (I) of the present application can also contain many geometric isomers such as olefin, C=N double bond, amide, etc. Unless otherwise specified, all chiral (enantiomers, diastereomers, axial chiral isomers), racemates, cis geometric isomers, trans geometric isomers, cis and trans geometric isomer mixtures, rotamers and mixtures thereof described above are included in the present application. A person of ordinary skill in the art can use commonly used separation or synthesis methods in the laboratory to separate or prepare the compounds containing asymmetric centers in the present application to obtain single isomers, for example, for enantiomers, two enantiomers can be obtained by using common chiral resolution methods or asymmetric synthesis methods, and for diastereomers, they can be separated by methods such as fractional recrystallization or chromatographic separation, which does not destroy the novelty of the compounds of the present application.

[0323] In another preferred embodiment, in the compound, the A ring, the B ring, the C ring, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R4 R 4a R 4b R 4c R 4d R 5 R 6 R 7 R 8 R

[0324] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed between a positively charged group on a compound of Formula (I) and an anion, or a salt formed between 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, glucuronate, lactate, glutarate, or maleate, and the like. Suitable cations include, but are not limited to, sodium, potassium, magnesium, calcium, ammonium, and the like.

[0325] In another preferred embodiment, the pharmaceutically acceptable salt of the present application refers to a salt formed between a compound of Formula (I) and an acid, such as, but not limited to, hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic 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, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and isethionic acid, and the like; or a salt formed between a compound of Formula (I) and an inorganic base, such as, but not limited to, a sodium salt, a potassium salt, a calcium salt, an aluminum salt, or an ammonium salt; or a salt formed between a compound of Formula (I) and an organic base, such as, but not limited to, a methylamine salt, an ethylamine salt, an ethanolamine salt, a TRIS ammonium salt, and the like.

[0326] The compounds of Formula (I) or their pharmaceutically acceptable salts of the present application can be isolated by distillation, crystallization, or recrystallization from water or an organic solvent, and the compounds can contain solvent molecules used in the isolation. In addition, different crystallization conditions can result in different crystal forms of the compounds. Therefore, all crystal forms of the compounds of Formula (I) or their pharmaceutically acceptable salts containing different amounts of crystallization solvents are within the scope of the present application.

[0327] It is known in the art that replacement of hydrogen atoms by deuterium atoms can alter the physical and chemical properties of a compound. Unless otherwise stated, the application is intended to encompass deuterated forms of the compounds of Formula (I) as well.

[0328] Preparation methods

[0329] The preparation of the compounds of Formula (I) of the present application is described in more detail below, but these specific methods do not limit the present application in any way. The compounds of the present application can also be readily prepared by combining various synthetic methods described in this specification or known in the art, as such combinations can be readily made by one skilled in the art to which the present application pertains.

[0330] Typically, the compounds of the present application are prepared by the following general procedure, wherein the starting materials and reagents used are commercially available unless otherwise specified.

[0331] In the present application, there is provided a method for preparing a compound of the first or second aspect of the present application, or a stereoisomer thereof, a deuterated form thereof, or a pharmaceutically acceptable salt thereof.

[0332] The compounds of the present application can be prepared by a variety of synthetic methods, and the following Route A - Route C represent representative general procedures, which, in combination with the synthesis of specific compounds in the examples, constitute the preparation of the compounds of the present application. It is to be understood that the preparation of the compounds of the present application is not limited to Route A - Route C, which are used for illustration only, and do not limit the present application in any way.

[0333] In most cases, the compounds of the present application can be prepared by the method shown in the following Route A.

[0334] The reaction steps of Route A include:

[0335] (a) intermediate A-1 with The coupling reaction to generate A-2 is usually carried out in the presence of a palladium catalyst or a copper catalyst, a ligand and a base; the palladium catalyst or copper catalyst is for example but not limited to palladium acetate, tris(dibenzylideneacetone) palladium, tetrakis(triphenylphosphine) palladium, Pd(dppf)Cl2, Pd(PPh3)2Cl2, cuprous iodide, cupric chloride, cupric bromide, Cu20, metallic copper; the ligand is for example but not limited to 1,1'-bis(diphenylphosphino) ferrocene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 4,5-bis-diphenylphosphino-9,9-dimethylxanthene (XantPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos), tri-tert-butylphosphine, triphenylphosphine, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (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 bases and organic bases, for example 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 room temperature to 200 °C.

[0336] (b) removal of the tert-butyloxycarbonyl (Boc) protecting group from intermediate A-2 to generate A-3; the reaction is usually carried out in the presence of an acid, for example but not limited to trifluoroacetic acid, hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid; the reaction temperature is generally -20 to 50 °C, more preferably room temperature; the reaction solvent is for example but not limited to dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, etc.

[0337] (c) intermediate A-4 is first reacted with hydroxylamine to form N-hydroxy amidine, and then acylated to form oxadiazolone A-5; the hydroxylamine reagent is usually hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine aqueous solution, etc.; the acylating reagent is, for example but not limited to, N,N'-carbonyldiimidazole, phosgene, triphosgene, diethyl carbonate, p-nitrophenyl chloroformate; the hydroxylamine reaction and the acylation reaction can be carried out continuously or step by step. Both reactions are usually carried out in the presence of a base, which includes inorganic bases and organic bases, such as but not limited to potassium carbonate, sodium carbonate, potassium phosphate, sodium acetate, sodium hydroxide, lithium hydroxide, DBU, triethylamine, DIPEA, pyridine, etc.; the reaction solvent is usually a polar solvent, such as but not limited to DMF, DMSO, THF, methanol, ethanol, 1,4-dioxane; the reaction temperature is usually room temperature to 120°C.

[0338] (d) intermediate A-5 is subjected to hydrolysis or hydrogenolysis to form A-6; the hydrolysis can be carried out under basic conditions, such as but not limited to potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, lithium hydroxide, sodium hydroxide; the reaction solvent is usually a polar solvent, such as but not limited to DMF, DMSO, THF, methanol, ethanol, 1,4-dioxane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether; the reaction temperature is usually room temperature to 150°C; the hydrolysis can also be carried out under acidic conditions, such as but not limited to trifluoroacetic acid, hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid; the reaction temperature is usually -20 to 50°C; the reaction solvent is, for example but not limited to, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, etc.; the hydrogenolysis is usually carried out under the catalysis of palladium on carbon, palladium oxide, platinum oxide, Raney nickel, etc.; the hydrogen source is usually hydrogen gas, or can be generated in situ by using ammonium formate, cyclohexene, etc.; the reaction temperature is usually room temperature to 120°C; the reaction solvent is, for example but not limited to, DMF, methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane; the reaction can be carried out under normal pressure, or under pressurized conditions, and the pressure of the pressurized reaction is usually 0.1 to 30 MPa.

[0339] (e) intermediate A-3 and A-6 undergo an amide condensation reaction to form a compound of general formula (I); the reaction is usually carried out in the presence of a condensing agent, which is well known to those skilled in the art and examples can be found in literature or reference books, representative examples include but are not limited to dicyclohexylcarbodiimide (DCC), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / 1-hydroxybenzotriazole (ECDI / HOBt), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), N,N'-carbonyldiimidazole (CDI), lH-benzotriazole-l-yloxytrispyrrolidino-phosphonium hexafluorophosphate (PyBOP); the reaction is usually carried out in the presence of a base, which includes inorganic bases and organic bases, examples of organic bases include but are not limited to pyridine, DIPEA, 4-dimethylaminopyridine (DMAP), triethylamine, DUB, 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, sodium acetate; the solvent can be any solvent which does not adversely affect the reaction, for example but not limited to dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, DMF, DMA, NMP, acetonitrile, and the like; the reaction temperature is usually in the range of -20 to 120 °C.

[0340] wherein L1is halogen, triflate (OTf) or boronic acid group, L2is NR s1 R s2 , OR s1 , or OCH2R s2 , R s1 is C1-C6 alkyl, R s2 is phenyl, which is unsubstituted or optionally substituted by one or more radicals selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy; and the other substituents are as described in the first aspect of the application.

[0341] The reaction steps of Scheme B include:

[0342] (a) intermediate A-1 is first deprotected to remove the Boc group to form B-1, the reaction conditions are as described in Scheme A step b.

[0343] (b) intermediate B-1 undergoes an amide condensation reaction with A-6 to form B-2, the reaction conditions are as described in Scheme A step e.

[0344] (c) intermediate B-2 undergoes a coupling reaction with to form a compound of general formula (I), the reaction conditions are as described in Scheme A step a.

[0345] The reaction steps of Route C include:

[0346] (a) Intermediate A-4 is first subjected to hydrolysis or hydrogenolysis to form C-1, reaction conditions are as described in step d of Route A.

[0347] (b) Intermediate C-1 is subjected to amide condensation with A-3 to form C-2, reaction conditions are as described in step e of Route A.

[0348] (c) Intermediate C-2 is subjected to acylation after reaction with hydroxylamine to form a compound of general formula (I), reaction conditions are as described in step c of Route A.

[0349] Intermediate A-1 can be prepared by various synthetic methods, the following methods shown in Route D - Route E are representative general schemes. It is understood that the preparation methods of intermediate A-1 are not limited to the methods shown in Route D - Route E, which are only used for explanation, and do not limit the present application in any way.

[0350] When Y and Z in the general formula of intermediate A-1 are both CH, it can be prepared by the method shown in the following Route D.

[0351] The reaction steps of Route D include:

[0352] (a) Intermediate D-1 is subjected to nucleophilic substitution with D-2 to form intermediate D-4; the reaction is usually carried out in the presence of a base, which includes but is 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 0 to 120°C.

[0353] (b) When R 1a is H in the general formula of intermediate A-1, intermediate D-4 can also be prepared by Michael addition of intermediate D-1 with 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, DUB; the reaction can be carried out without solvent or in a polar solvent such as DMF, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, etc.; the reaction temperature is usually room temperature to 120°C.

[0354] (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 "Protective Groups in Organic Synthesis" (Rong Guobin, East China University of Science and Technology Press).

[0355] (d) intramolecular condensation of intermediate D-5 in the presence of a base to form intermediate D-6; the base includes but is not limited to potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, 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 room temperature to 120°C.

[0356] (e) condensation of intermediate D-6 and D-7 to form intermediate D-8; the reaction is usually carried out in polar solvents such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, etc.; the reaction temperature is usually room temperature to 120°C, more preferably the reflux temperature of the solvent used.

[0357] (f) acylation of intermediate D-8 to form D-10; the acylating agent is D-9; the reaction is usually carried out in the presence 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 0 to 120°C, more preferably room temperature.

[0358] (g) intramolecular cyclization of intermediate D-10 in the presence of an acid to form A-1; the acid reagent includes but is not limited to trifluoroacetic acid, hydrochloric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.; 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 room temperature to 120°C, more preferably the reflux temperature of the solvent used.

[0359] wherein L3 is a leaving group such as halogen, sulfonate, etc.; L4 is a leaving group such as Cl, imidazolyl, p-nitrophenoxy, etc.; R s3 is C1-C6 alkyl; R s4 is C1-C6 alkyl, or two R s4 are linked to form a C2-C6 alkylene; the other substituents are as defined in the first aspect of the application.

[0360] 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 Route E as follows.

[0361] The reaction steps of Route E include:

[0362] (a) a three-component condensation reaction of intermediate D-8 with methyl hydrazinecarboxylate and trialkyl orthoformate to form intermediate A-1; the reaction is usually catalyzed by an acid or a base, such as but not limited to acetic acid, p-toluenesulfonic acid, and such as but not limited to sodium methoxide, sodium ethoxide, sodium tert-butoxide; the reaction is usually carried out in a polar solvent such as but not limited to DMF, methanol, ethanol, tetrahydrofuran, 1,4-dioxane; the reaction temperature is usually in the range of room temperature to 120 °C, more preferably at the reflux temperature of the solvent used.

[0363] (b, c) intermediate A-1 can also be prepared by an alternative method: intermediate D-8 is first acylated to form an active intermediate E-1, which is then hydrazinolyzed to form intermediate E-2; the acylating reagent includes but is not limited to CDI, triphosgene, p-nitrophenyl chloroformate; the reaction is usually carried out in an aprotic solvent such as but not limited to dichloromethane, dichloroethane, THF, 1,4-dioxane; the reaction temperature is usually in the range of -20 °C to room temperature; the hydrazinolysis is usually carried out with hydrazine hydrate or hydrazine hydrochloride; the reaction solvent includes but is not limited to dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, and the like; the reaction temperature is usually in the range of room temperature to 120 °C.

[0364] (d) intermediate E-1 is cyclized to form A-1; the cyclizing reagent includes but is not limited to trialkyl orthoformate, methyl amidine; the reaction is usually carried out in a polar solvent such as but not limited to DMF, methanol, ethanol, tetrahydrofuran, 1,4-dioxane; the reaction temperature is usually in the range of 50 to 150 °C.

[0365] wherein L5 is a leaving group such as Cl, imidazolyl, p-nitrophenoxy, and the like; R s5 is C1-C6 alkyl; and other substituents are defined as in the first aspect of the present application.

[0366] Intermediate A-4 can be prepared by a variety of synthetic methods, and the method shown in Route F below is a representative general procedure. It is to be understood that the preparation of intermediate A-4 is not limited to Route F, which is used for illustration only and does not limit the present application in any way.

[0367] The reaction steps of the method shown in Route F include:

[0368] (a) nucleophilic substitution of intermediate F-1 with a haloacetonitrile to form F-2; the reaction conditions are as described in Route A, step a.

[0369] (b) hydrolysis or hydrogenolysis of intermediate F-2 to form F-3; the reaction conditions are as described in Route A, step d.

[0370] (c) when L2 is NR s1 Rs2 Intermediate F-3 is reacted with HNR s1 R s2 to give intermediate F-4 via an amide condensation reaction, reaction conditions are as described in Scheme A, step e.

[0371] (d) when L2is the same as OR s6 , intermediate F-4 can be prepared directly from F-1 via a substitution reaction with haloacetonitrile; reaction conditions are as described in Scheme A, step a.

[0372] (e) intermediate F-4 is reacted with an alkylating agent L5-R 3a or / and L6-R 3b to give A-4; the reaction is usually carried out in the presence of a strong organic base, including but not limited to lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), n-butyllithium; the reaction solvent is usually an aprotic solvent, including but not limited to tetrahydrofuran, 1,4-dioxane, DMF, dichloromethane, more preferably tetrahydrofuran; the reaction temperature is usually from -100 °C to room temperature.

[0373] wherein L2is as defined in Scheme A, and is NR s1 R s2 , OR s1 , or OCH2R s2 , R s1 is C1-C6 alkyl, R s2 is phenyl, which is unsubstituted or optionally substituted with one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy; R s6 is C1-C6 alkyl or benzyl; L5and L6are each independently a leaving group, such as halogen, sulfonate, etc.; other substituents are as defined in the first aspect of the application.

[0374] When X in intermediate F-1 is a bond, it can be prepared by the method shown in Scheme G. It is to be understood that the method of preparing intermediate F-1 is not limited to Scheme G, which is used for illustration only, and does not limit the application in any way.

[0375] The reaction steps of Scheme G include:

[0376] (a) intermediate G-1 is formed by Suzuki, Negishi, Buchwald-Hartwig, Chan-Lam, etc. coupling reaction; coupling reagents include but not limited to boronic acid G-2, boron ester G-3, organozinc reagent G-4, chlorides G-5, cyclic amine G-6; the coupling reaction is usually carried out in the presence of palladium or copper catalyst, ligand and base; reaction conditions are as described in Route A, step a. F-1 can be further transformed by functional group transformation such as hydrogenation reduction to form other intermediates which also conform to the general formula of F-1.

[0377] wherein, R s6 is C1-C6 alkyl or benzyl; L7 is halogen, OTf or boronic acid; L8, L9 are each independently halogen; other substituents are defined as described in the first aspect of the present application.

[0378] Pharmaceutical composition and administration method

[0379] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or its pharmacologically acceptable salt and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means that the subject receiving the dose is cured, improved, effectively prevented or the incidence is significantly reduced in the disease or side effects compared with the subject not receiving the treatment; in addition, it also includes the effective dose for enhancing normal physiological function. "Safe" means that the amount of active ingredient is sufficient to significantly improve the disease without causing serious side effects.

[0380] In the pharmaceutical composition, the compound of the present application is used as an active ingredient, and its weight accounts for 0.1-99.9% of the total weight of the pharmaceutical composition, and the rest is pharmaceutical adjuvant; the preferred ratio of the compound of the present application and the adjuvant is that the compound of the present application as an active ingredient accounts for more than 60% of the total weight, and the rest accounts for 0-40% of the total weight, and the amount of the rest is preferably 1-20%, and most preferably 1-10%. Generally, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, and more preferably 10-200 mg of active ingredient per dose. Preferably, the "one dose" is one tablet.

[0381] The "pharmaceutically acceptable excipient" is a pharmaceutically acceptable carrier, excipient, sustained-release agent, odorant, flavoring agent, etc. The "pharmaceutically acceptable carrier" means one or more compatible solid or liquid filler or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredient of the present application and among themselves 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium dodecyl sulfate), etc.

[0382] The pharmaceutical composition can further comprise one or more other therapeutic agents in addition to the compound represented by the general formula (I) as an active ingredient. Among them, the "other therapeutic agent" is a diabetes treatment agent, a cardiovascular disease treatment agent, an obesity treatment agent, a chronic kidney disease treatment agent, a metabolic dysfunction-associated steatohepatitis (MASH) treatment agent, a dementia treatment agent, a Parkinson's disease treatment agent, an addiction treatment agent.

[0383] Adjuvants commonly used in the preparation of pharmaceutical compositions can also be included, the "adjuvants" being flavoring agents, pigments, preservatives, and antioxidants such as vitamin E, vitamin C, BHT, and BHA.

[0384] The compound or pharmaceutical composition of the present application can be made into various dosage forms based on the conventional processes in the field of pharmaceutical preparations, such as tablets, capsules, powders, syrups, solutions, suspensions, sprays, creams, ointments, gels, transdermal patches, microneedles, etc., and can be present in a suitable solid or liquid carrier or diluent. The pharmaceutical composition of the present application can also be stored in a suitable sterilized injection or infusion device. From the standpoint of ease of preparation and administration, the preferred pharmaceutical composition is a solid composition, especially tablets and solid or liquid-filled capsules.

[0385] The compound or pharmaceutical composition of the present application can be clinically used for mammals, including humans and animals. The mode of administration is not particularly limited, and representative modes of administration include, but are not limited to, oral administration, nasal inhalation, topical administration to the skin, intravenous injection, intramuscular injection, subcutaneous injection, etc. Preferably, the preferred administration route of the compound or pharmaceutical composition of the present application is oral administration.

[0386] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) moisturizing agents, e.g., glycerol and sorbitol; (h) respiration accelerators, e.g., high molecular weight polyethylene glycols; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents.

[0387] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other materials well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0388] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0389] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0390] Suspensions, in addition to the active ingredient, can contain suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbomate, among others.

[0391] 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.

[0392] 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.

[0393] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0394] 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.

[0395] 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.

[0396] Drug combination

[0397] The compounds of this invention can be administered alone or in combination with other known drugs for treating or improving similar conditions.

[0398] 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.

[0399] The drugs or active ingredients that can be combined with the compounds described herein include, but are not limited to, the following drugs for the treatment of obesity: glucagon-like peptide-1 (GLP-1) analogs (such as Semaglutide), glucagon (GCG) analogs, peptide YY (PYY) analogs, oxyntomodulin (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, glucose-dependent insulinotropic polypeptide (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 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, and the like.

[0400] The drugs or active ingredients that can be combined with the compounds described herein include, but are not limited to, the following drugs for the treatment of diabetes: biguanides, thiazolidinediones, glinides, sulfonylureas, DPP4 inhibitors, SGLT1 and / or SGLT2 inhibitors, GPR40 agonists, alpha-glucosidase inhibitors, glucokinase agonists, insulin, insulin analogs, GLP-1 analogs, or dual or multiple receptor modulators based on 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, and the like.

[0401] The drugs or active ingredients that can be combined with the compounds described herein include, but are not limited to, the following drugs for the treatment of MASH: FXR receptor agonists, PPARa / d agonists, fibroblast growth factor 19 / 21 analogs, thyroid hormone receptor beta agonists, SGLT1 and / or SGLT2 inhibitors, acetyl-CoA carboxylase inhibitors, chemokine receptor-2 / 5 inhibitors, anti-apoptotic signal-regulating kinase 1 inhibitors, ATP-binding cassette transporter 1 agonists, 5-lipoxygenase inhibitors, or vascular adhesion protein 1 inhibitors.

[0402] Indications

[0403] "Diabetic complications" are complications caused by diabetes or hyperglycemia, and can be acute complications or chronic complications. The term "acute complications" includes ketosis and infectious diseases (e.g. skin infection, soft tissue infection, biliary system infection, respiratory system infection, urinary tract infection), and "chronic complications" include, for example, microangiopathy (e.g. nephropathy, retinopathy), neuropathy (e.g. sensory nerve disorder, motor nerve disorder, autonomic nerve disorder) and gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

[0404] "Coronary heart disease" includes asymptomatic myocardial ischemia (silent coronary heart disease), myocardial infarction, angina pectoris, ischemic heart failure (ischemic cardiomyopathy) and sudden death.

[0405] "Dementia" includes, for example, Alzheimer's disease, early-onset dementia (EOD), vascular dementia and diabetic dementia.

[0406] Compared with the prior art, the present application has the following main advantages:

[0407] (1) The compound of the present application has higher blood concentration, oral exposure and oral bioavailability, and thus has excellent oral pharmacokinetic properties;

[0408] (2) The compound of the present application does not activate the β-arrestin 1 or β-arrestin 2 pathway, is a G protein-biased agonist, and has the potential to prepare a more efficient and safe new drug;

[0409] (3) The compound of the present application can significantly reduce blood glucose and achieve a significant anorectic effect, which is beneficial for the treatment of diabetes, overweight / obesity and other related diseases;

[0410] (4) The compound of the present application can reduce the dosage, reduce side effects, thereby greatly increase the clinical benefit of patients, and is beneficial to improve the clinical efficacy.

[0411] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The experimental methods in the following examples, if not specified, are generally carried out according to the conventional conditions, such as the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0412] 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.

[0413] Unless otherwise specified in the examples, the room temperature reaction temperature is 20℃~35℃.

[0414] 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.

[0415] In this invention, the low-resolution mass spectrometry data are obtained from an Agilent liquid chromatography-mass spectrometry system consisting of an Agilent 1260 Infinity LC and an Agilent 6120 quadrupole mass spectrometer, using electrospray ionization (ESI) as the ion source.

[0416] 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.

[0417] 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.

[0418] Preparation of intermediates

[0419] Example 1

[0420] Preparation of (2S)-3-cyano-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (intermediate A6)

[0421] 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, protect under nitrogen, stir at room temperature overnight. After the reaction is completed, dilute the reaction solution with 300 mL of ethyl acetate, wash with water three times, wash with saturated brine three times, dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography to obtain 11.4 g of intermediate A2.

[0422] Step b: Dissolve A2 (11.4 g, 56.4 mmol) in 8 mL of THF, add pyridine (10.7 g, 135.3 mmol), cool to 0-5 °C in an ice bath, then add trifluoroacetic anhydride (14.3 g, 67.9 mmol), and stir at room temperature. After the reaction is completed, quench the reaction by adding 60 mL of water, extract three times with ethyl acetate, wash with saturated brine three times, dry the organic phase over 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.

[0423] Step c: Add a 4 M solution of hydrogen chloride in 1,4 dioxane (59.7 mL, 238.7 mmol) to A3 (6.3 g, 34.1 mmol), and stir at room temperature for 3 hours. After the reaction is completed, directly concentrate and evaporate under reduced pressure to obtain intermediate A4.

[0424] Steps d, 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 completed, cool to room temperature, add di-tert-butyl dicarbonate (9.0 g, 41.2 mmol), and stir at room temperature overnight. Concentrate and evaporate the anhydrous ethanol under reduced pressure, add water and extract three times with ethyl acetate, wash with saturated brine, dry the organic phase over 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.

[0425] 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 completed, adjust the pH to 6-7 by adding dilute hydrochloric acid, extract three times with ethyl acetate, wash with saturated brine, dry the organic phase over 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] + .

[0426] Example 2

[0427] Preparation of (S)-tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3- dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate B5)

[0428] Step a: Dissolve B1 (10.0 g, 49.2 mmol) in 100 mL of anhydrous THF, protect with nitrogen, and cool to below -70 °C. Slowly drop in n-butyllithium (22.6 mL, 54.2 mmol) with a concentration of 2.4 M, and control the temperature of the reaction solution to be no more than -70 °C. After dropping, stir for 1 hour at -70 °C. Dissolve di-tert-butyl azodicarboxylate (11.3 g, 49.2 mmol) in 50 mL of anhydrous toluene, and drop into the reaction solution, controlling the temperature of the reaction solution to be no more than -40 °C. After dropping, stir for 30 minutes at -40 °C. Continue to react for 1 hour at room temperature. After the reaction is completed, quench the reaction by adding 100 mL of saturated ammonium chloride solution, extract three times with ethyl acetate, wash with saturated brine, dry the organic phase over 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. Slowly cool, and when the temperature is 20-30 °C, solid precipitates, continue to cool to 0-10 °C, and crystallize for 1 hour. Filter, wash the filter cake with a small amount of n-heptane, and dry at 45 °C for about 3 hours to obtain 9.3 g of intermediate B2.

[0429] Steps b, 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 completed, concentrate and evaporate the reaction solution under reduced pressure. 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 to reflux for 2 hours. After the reaction is completed, concentrate and evaporate the anhydrous ethanol under reduced pressure, add water and extract three times with ethyl acetate, wash with saturated brine, dry the organic phase over 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.

[0430] Step d:

[0431] 1) Preparation of N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide: 3.24 g (20 mmol) of carbonyldiimidazole (CDI) was dissolved in 8 mL of ethyl acetate, protected by nitrogen, and placed in an ice bath. Then 2.17 mL (20 mmol) of aminoacetaldehyde dimethyl acetal was added dropwise using a syringe, and after the dropwise addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate three times, washed with brine three times, dried over sodium sulfate, filtered, and evaporated to dryness to give a crude product, which was separated by column chromatography to give 3.07 g of an oil, which solidified.

[0432] 2) B3 (5.5 g, 14.7 mmol) was dissolved in 40 mL of N,N-dimethylacetamide (DMA), and N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide (3.2 g, 16.1 mmol) and potassium tert-butoxide (4.9 g, 43.7 mmol) were added, and the mixture was stirred at room temperature overnight. After completion, water was added, and the mixture was extracted with ethyl acetate three times, washed with saturated brine three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to give 4.0 g of intermediate B4.

[0433] Step e: B4 (4.0 g, 7.9 mmol) was dissolved in 40 mL of THF, and methylsulfonic acid (759.3 mg, 7.9 mmol) was added, and the mixture was reacted at 60°C for 2 hours. After completion, the mixture was cooled to room temperature, and potassium phosphate (1.7 g, 7.9 mmol), di-tert-butyl dicarbonate (1.7 g, 7.9 mmol), and 16 mL of water were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate three times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to give 2.2 g of intermediate B5. ESI-MS m / z: 442.3 [M+H] + .

[0434] Example 3

[0435] 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)cyclopropyl)-lH-indole-2-carboxylic acid (Intermediate C9)

[0436] Step a: Zinc powder (2.93 g, 44.7 mmol) was added to 12 mL of N,N-dimethylformamide (DMF), and chlorotrimethylsilane (610 mg, 5.6 mmol) and 1,2-dibromoethane (1.05 g, 5.6 mmol) were added dropwise under an N2 atmosphere, and the mixture was stirred at room temperature for half an hour. Then a solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (5.37 g, 22.4 mmol) dissolved in 6 mL of DMF was added, and the mixture was stirred at room temperature for half an hour.

[0437] Step b: To 5-bromo-lH-indole-2-carboxylic acid ethyl ester Cl (3.00 g, 11.2 mmol) in 12 mL of DMF was added palladium acetate (251 mg, 1.12 mmol) and 4-(di-tert-butylphosphino)-N,N-dimethylaniline (594 mg, 2.24 mmol). The mixture from a was added to b under N2atmosphere, warmed to 50 °C and stirred for two hours. After the reaction was complete, the reaction was placed in an ice bath, 4 M HCl was added slowly to adjust the pH to 4-5, water was added and extracted with ethyl acetate three times. The organic phase was washed with saturated brine three times, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography to give 2.32 g of intermediate C2.

[0438] Step c: Intermediate C2 (1.41 g, 4.69 mmol) was dissolved in 12 mL of DMF. The reaction was cooled to 0 °C, sodium hydride (60% in oil, 376 mg, 9.39 mmol) was added and stirred at 0 °C for one hour. Then 2-chloroacetonitrile (1.06 g, 14 mmol) was added, the temperature was slowly increased to room temperature and stirred overnight. After the reaction was complete, the reaction was slowly poured into water, extracted with ethyl acetate three times, the organic phase was washed with saturated brine three times to remove the residual solvent, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography to give 1.5 g of intermediate C3.

[0439] Step d: Intermediate C3 (1.5 g, 4.42 mmol) was dissolved in a mixture of THF and water (2: 1; 15 mL). Lithium hydroxide monohydrate (223 mg, 5.3 mmol) was added. After the reaction was complete, the reaction was diluted with water, 4 M HCl was added dropwise to adjust the pH to 7, the THF was evaporated, the pH was further adjusted to 1-3, a large amount of solid was precipitated, the solid was collected by filtration and dried to give 1.07 g of intermediate C4.

[0440] Step e: Intermediate C4 (1.07 g, 3.43 mmol) was dissolved in 10 mL of DMF, HATU (1.95 g, 5.14 mmol) and DIPEA (1.33 g, 10.3 mmol) were added, stirred at room temperature for half an hour, N-methylaniline (551 mg, 5.14 mmol) was added, moved to 60 °C and stirred for two and a half hours. After the reaction was complete, the reaction was poured into water, a large amount of pure solid was precipitated, the solid was filtered off and dried to give 1.1 g of intermediate C5.

[0441] Step f: Intermediate C5 (1.00 g, 2.49 mmol) and (R)-4-methyl-1,3,2-dithianyl 2,2-dioxide (1.03 g, 7.47 mmol) were added to N,N-dimethylacrylamide (10 mL) and the reaction was purged with N2. The reaction was cooled to 0 °C and potassium bis(trimethylsilyl)amide (9.96 mL, 9.96 mmol, 1 M) was added slowly. After the addition was complete, the reaction was stirred at 0 °C for 3 h. After the reaction was complete, the reaction was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (3x). The organic phase was washed with saturated aqueous brine (3x), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography to give 700 mg of Intermediate C6.

[0442] Step g: Intermediate C6 (297 mg, 672 umol) was dissolved in ethanol (3 mL) and hydroxylamine hydrochloride (234 mg, 3.36 mmol) and potassium carbonate (511 mg, 3.7 mmol) were added. The reaction was heated to 100 °C and stirred for 2 h. After the reaction was complete, water was added and the reaction was extracted with dichloromethane (3x). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 295 mg of Intermediate C7.

[0443] 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 was heated to 80 °C and stirred for 1 h. After the reaction was complete, the reaction was concentrated to give the crude product. The crude product was purified by column chromatography to give 3.6 g of Intermediate C8.

[0444] Step i: Intermediate C8 (249 mg, 498 umol) was dissolved in 2-methoxyethanol (3 mL) and potassium hydroxide (279 mg, 4.98 mmol) was added. The reaction was heated to 130 °C and stirred overnight. After the reaction was complete, water was added and the pH was adjusted to 4 with 4 M aqueous HCl. The reaction was extracted with dichloromethane / methanol (10:1, v / v) (5x). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by column chromatography to give 186 mg of Intermediate C9. ESI-MS m / z: 412.3 [M+H] + .

[0445] Example 4

[0446] 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)

[0447] Intermediate C6 was separated by preparative liquid chromatography (Shimadzu, Model: LC-20AT) and CHIRALPAK AD-H chiral column (Shanghai Daisel, Column size: 0.46 cm I.D. x 15 cm L) with 0.1% diethylamine (V / V) in MeOH as mobile phase (flow rate: 1.0 ml / min; detection wavelength: 214 nm), and the corresponding fractions were collected and rotary evaporated to remove the solvent to give chiral isomer C6-1 with retention time of 5.42 min. The ee value was greater than 98% by detection.

[0448] Intermediate C9-1 was synthesized in the same manner as C9 except that intermediate C6-1 was used instead of C6 as starting material. ESI-MS m / z: 412.3 [M+H] + .

[0449] Example 5

[0450] 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)

[0451] Step a: 900 mg (1 eq) of 3-cyclopropyl-4-fluoroaniline was suspended in 30 mL of concentrated hydrochloric acid and placed in an ice bath, 493 mg (1.5 eq) of sodium nitrite was added, and stirred for 0.5 hours. Then, 3.39 g (3 eq) of SnCl2was dissolved in 50 mL of concentrated hydrochloric acid and added dropwise to the reaction solution, and after the dropwise addition was completed, stirring was continued for 0.5 hours. After the reaction was completed, 150 mL of water was added to the reaction solution, and the pH was adjusted to 8 with a 2M aqueous sodium hydroxide solution. Ethyl acetate was extracted three times, the organic phases were combined, and then washed twice with brine and dried over anhydrous magnesium sulfate. The filtrate was evaporated to dryness, and then 5 mL of a 2M hydrogen chloride / methanol solution was added to the residue, stirred for 5 min, and then 20 mL of diethyl ether was added to precipitate the solid. The solid was collected by filtration and dried to give intermediate D-2.

[0452] Step b: 2.3 g (1 eq) of intermediate D2, 148 mg of pyridine hydrochloride (0.1 eq), and 2.43 g (0.8 eq) of intermediate A6 were dissolved in 25 mL of anhydrous ethanol and heated to reflux for 2 hours. After the reaction was completed, the ethanol was evaporated under reduced pressure, and the remaining crude product was separated by column chromatography to give 2.08 g of intermediate D3.

[0453] Step c: Dissolve 2.08 g (1 eq) of intermediate D3 in 16 mL of DMA, then add 1.21 g (1.1 eq) of N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide (preparation method refer to example 2) and 1.81 g (3 eq) of potassium tert-butoxide, stir at room temperature overnight. After the reaction is completed, quench with water, extract with ethyl acetate for three times, combine the organic phase, wash with saturated brine for three times, dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, separate the crude product by column chromatography to obtain 2.22 g of intermediate D4.

[0454] Step d: Dissolve 2.22 g (1 eq) of intermediate D4 in 23 mL of THF, add 0.36 mL (1.3 eq) of methanesulfonic acid, react at 60 °C for 2 hours. After the reaction is completed, cool to room temperature, add 1.83 g (2 eq) of potassium phosphate, 1.03 g (1.1 eq) of di-tert-butyl dicarbonate and 9 mL of water, stir at room temperature overnight. After the reaction is completed, dilute with water, extract with ethyl acetate for three times, combine the organic phase, wash with saturated brine for three times, dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, separate the crude product by column chromatography to obtain 1.2 g of intermediate D5.

[0455] 1 H NMR (600 MHz, CDC13) δ 10.35 (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] + .

[0456] Example 6

[0457] Preparation of (S)-tert-butyl 2-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH- imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate E5)

[0458] The preparation method of intermediate E5 is the same as that of intermediate D5, except that 4-fluoro-3-trifluoromethyl aniline is used instead of 3-cyclopropyl-4-fluoroaniline as the starting material.

[0459] 1 H NMR (600 MHz, CDC13) δ 9.72 (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] + .

[0460] Example 7

[0461] Preparation of (S)-tert-butyl 2-(3,5-dichloro-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3- dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate F5)

[0462] The synthesis of Intermediate F5 was carried out according to the procedure of Intermediate D5, except that 3,5-dichloro-4-fluoroaniline was used as the starting material instead of 3-cyclopropyl-4-fluoroaniline.

[0463] 1 H NMR (500 MHz, CDC13) δ 9.95 (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] + .

[0464] Example 8

[0465] Preparation of l-((2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- (tetrahydro-2H-pyran-4-yl)-lH-indole-2-carboxylic acid (Intermediate G9)

[0466] The synthesis of Intermediate G9 was carried out according to the procedure of Intermediate C9, except that 4-iodotetrahydro-2H-pyran was used as the starting material instead of 4-iodo-2,2-dimethyltetrahydro-2H-pyran.

[0467] ESI-MS m / z: 384.2 [M+H] + .

[0468] Example 9

[0469] 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-carboxylate (Intermediate H5)

[0470] The synthesis of Intermediate H5 was carried out in the same manner as Intermediate D5, except that 3-bromo-4-fluoroaniline was used instead of 3-cyclopropyl-4-fluoroaniline as the starting material.

[0471] 1 H NMR (500 MHz, CDC13) δ 9.53 (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);

[0472] ESI-MS m / z: 492.2 [M+H] + .

[0473] Preparation of the compound

[0474] Example 1

[0475] 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-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0476] Step a: To 8 mL of DMSO was added 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 1 eq), morpholine (198 mg, 1 eq) and potassium carbonate (471 mg, 1.5 eq) and then heated with stirring at 120 °C for 1 h. After cooling, 50 mL of water was added to the reaction and extracted with ethyl acetate three times, the organic phases were combined and washed with saturated brine twice and dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate under reduced pressure gave 653 mg of intermediate 1-A which was used directly in the next step without further purification.

[0477] Step b: Intermediate 1-A was dissolved in a mixture of 9 mL of ethanol and 1 mL of water, and to the reaction was added reduced iron powder (635 mg, 5 eq) and glacial acetic acid (205 mg, 1.5 eq) and then refluxed at 90 °C for 1 h. After cooling, 20 mL of water and 20 mL of ethyl acetate were added and stirred for 10 min, the insoluble matter was removed by filtration, and the filtrate was separated into an organic phase and an aqueous phase which was extracted with 20 mL of ethyl acetate. The organic phases were combined, washed with brine twice, and dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate under reduced pressure gave a residue which was separated by flash column chromatography using a petroleum ether-ethyl acetate solvent system to give 370 mg of a solid, intermediate 1-B, in a total yield of 63% over two steps.

[0478] Step c: 370 mg of intermediate 1-B was dissolved in 8 mL of ethyl acetate, and to the reaction was added 6 mL of a 30% mass fraction hydrogen peroxide solution and then refluxed at 85 °C overnight. After cooling, 30 mL of saturated Na2CO3 solution was added and stirred for 15 min, and then extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine three times, and dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate under reduced pressure gave a residue which was separated by flash column chromatography using a petroleum ether-ethyl acetate solvent system to give 233 mg of a solid, intermediate 1-C, in a yield of 64%. 1 H NMR (500 MHz, CDC13) δ 7.58 (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] + .

[0479] Step d: To 2 mL of N-methylpyrrolidone (NMP) was added intermediate B5 (60 mg, 1 eq), intermediate 1-C (69 mg, 2 eq), (1S,2S)-N 1 ,N 2- dimethylcyclohexane-1,2-diamine (10 mg, 0.5 equiv), CuI (5.2 mg, 0.2 equiv) and potassium carbonate (56 mg, 3 equiv), nitrogen substitution for several times, then 130 °C stirring heating overnight. After cooling, 30 mL of water was added to the reaction solution, then extracted with ethyl acetate three times. The organic phase was combined, washed with saturated brine twice, and dried over anhydrous magnesium sulfate. Filtration, the filtrate was evaporated under reduced pressure, and the residue was separated by preparative thin layer chromatography (TLC) to obtain 46 mg of light yellow solid, which was intermediate 1-D, with a yield of 55%. 1 H NMR (500 MHz, CDC13) δ 7.79 (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] + .

[0480] Step e, f: 46 mg (1 equiv) of intermediate 1-D was dissolved in 3 mL of dichloromethane (DCM), 280 μL of HCl-dioxane solution (concentration of 4 M, 15 equiv) was added, stirred at room temperature overnight, then evaporated under reduced pressure. The residue was redissolved in a small amount of DCM, and evaporated under reduced pressure again, and repeated twice. The obtained residue was dissolved in 2.5 mL of dry N,N-dimethylformamide (DMF), then 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 31 mg, 1.1 equiv), N,N-diisopropyl ethylamine (DIPEA, 49 mg, 5 equiv) and intermediate C9 (34 mg, 1.1 equiv) were added, and stirred at room temperature for 2 hours until the reaction was completed. 10 mL of water was added to the reaction solution, then extracted with ethyl acetate three times. The organic phase was combined, washed with saturated brine twice, and dried over anhydrous magnesium sulfate. Filtration, the filtrate was evaporated under reduced pressure, and the residue was separated by preparative thin layer chromatography (TLC) or further purified by preparative liquid phase, eluted with acetonitrile and water containing 0.5% trifluoroacetic acid (V / V) as the mobile phase. The target product part was collected and freeze-dried to obtain 24 mg of white solid, which was compound 1, with a yield of 35%.

[0481] 1H NMR (500 MHz, CDC13, 4: 1 rotamers) 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);

[0482] ESI-MS m / z: 907.5 [M+H] + .

[0483] Example 2

[0484] 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-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 2)

[0485] The synthesis of Compound 2 was carried out in the same manner as Compound 1, except that piperidine was used as the starting material instead of morpholine.

[0486] 1H NMR (500 MHz, CDC13, 3:1 rotamers) 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 / 2.22 (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);

[0487] ESI-MS m / z: 905.6 [M+H] + .

[0488] Example 3

[0489] 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-imidazol-1-yl)- 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 3)

[0490] The synthesis of Compound 3 was carried out according to the procedure for Compound 1, except that 1-bromo-2,3-difluoro-4-nitrobenzene was used instead of 4-bromo-2-fluoro-1- nitrobenzene as the starting material.

[0491] 1H NMR (500 MHz, CDC13, 4: 1 rotamers) 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 / 5.02 (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);

[0492] ESI-MS m / z: 924.6 [M+H] + .

[0493] Example 4

[0494] 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-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0495] The synthesis of Compound 4 was carried out according to the procedure of Compound 1, except that 2,2-dimethylmorpholine was used instead of morpholine as the starting material.

[0496] 1H NMR (500 MHz, CDC13, 4: 1 rotamers) 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);

[0497] ESI-MS m / z: 935.6 [M+H] + .

[0498] Example 5

[0499] 3-((1S,2S)-1-(2-(S)-3-(3-(benzo[4,5]imidazo[1,2-a]pyridine-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]pyridine-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)

[0500] The preparation method of intermediate 5-C is referred to that described in patent TW201639840.

[0501] 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.

[0502] 1H NMR (600 MHz, CDC13, 7:2 rotamers) 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), 5.84 / 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);

[0503] ESI-MS m / z: 901.5 [M+H] + .

[0504] Example 6

[0505] 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]oxazepin-8-yl)- 2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 6)

[0506] Step b: 500 mg (1 eq) of starting material 6-A and 10.3 mL of borane-THF solution (1.0 M, 5 eq) in 10 mL of dry THF was heated at 70 °C overnight under nitrogen atmosphere. TLC showed the reaction was complete. After cooling, 30 mL of water was added to the reaction, and the mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine twice and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated to dryness to give 440 mg of white solid, which was intermediate 6-B, and was used directly in the next step.

[0507] Step c: 440 mg (1 eq) of intermediate 6-B was dissolved in 10 mL of DCM, then 1.56 g of formaldehyde aqueous solution (37% m / m, 10 eq) and 818 mg of NaBH(OAc)3(1 eq) were added, and stirred at room temperature overnight. Quenched with saturated potassium carbonate solution, after stirring for 1 h, extracted with DCM three times, combined the organic phase, and washed with brine once, dried over anhydrous magnesium sulfate. Filtered, and the filtrate was evaporated to dryness to give a crude product, which was separated by flash column chromatography to give 350 mg of an oil, which was intermediate 6-C. 1 H NMR (500 MHz, CDC13) δ 7.17 (d, 1 H, J = 2.0), 7.13 (dd, 1 H, J = 8.0, 2.0), 7.01 (d, 1 H, J = 8.0), 4.07 (t, 2 H, J = 4.5), 3.69 (s, 2 H), 2.98 (t, 2 H, J = 4.5), 2.40 (s, 2 H).

[0508] Step d: The synthesis method of intermediate 6-D was the same as that of 1-D, except that intermediate 6-C was used instead of 1-C as the starting material. 1 H NMR (500 MHz, CDC13) δ 7.26-7.19 (m, 3 H), 7.07 (d, 2 H, J = 6.5), 6.65 (d, 1 H, J = 3.0), 6.26 (br s, 1 H), 5.41-5.11 (m, 1 H), 4.57-4.23 (m, 1 H), 4.11 (t, 2 H, J = 4.5), 3.77 (s, 2 H), 3.24-3.05 (m, 1 H), 3.03 (t, 2 H, J = 4.5), 2.85-2.73 (m, 2 H), 2.42 (s, 3 H), 2.21 (d, 6 H, J = 2.0), 2.06-1.98 (m, 1 H), 1.49 (s, 9 H), 1.30 (d, 3 H, J = 7.0).; ESI-MS m / z: 602.5 [M+H] + .

[0509] Step d, f: The synthesis method of compound 6 was the same as that of compound 1, except that intermediate 6-D was used instead of intermediate 1-D as the starting material.

[0510] 1H NMR (600 MHz, CDC13, 4: 1 rotamers) 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);

[0511] ESI-MS m / z: 896.6 [M+H] + .

[0512] Example 7

[0513] 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]oxazepin-8-yl)-2- oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 6-1)

[0514] The synthesis of Compound 6-1 was carried out according to the procedure for Compound 6, except that chiral intermediate C9-1 was used instead of C9 as the starting material.

[0515] ESI-MS m / z: 896.6 [M+H] + .

[0516] Example 8

[0517] 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]oxazepin-5(2H)-one (Compound 7)

[0518] The preparation method of intermediate 7-C is referred to that described in patent EP3666772.

[0519] 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.

[0520] ESI-MS m / z: 924.6 [M+H] + .

[0521] Example 9

[0522] 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]oxazepin-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]pyridine-5-carbonyl)-1H- indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 8)

[0523] 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 the raw material.

[0524] 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.

[0525] ESI-MS m / z: 910.7 [M+H] + .

[0526] Example 10

[0527] 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]pyridine-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)

[0528] The synthesis of Compound 9 was carried out in the same manner as for Compound 1, except that 2-bromodibenzo[b,d]furan was used instead of intermediate 1-C as the starting material.

[0529] 1 H NMR (500 MHz, CDC13, 3:1 rotamers) 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), 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);

[0530] ESI-MS m / z: 901.6 [M+H] + .

[0531] Example 11

[0532] 3-((1S,2S)-1-(2-((S)-3-(3-(benzo[4,5]imidazo[1,2-a]pyridine-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]pyridine-5-carbonyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methyl- cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 10)

[0533] The preparation method of intermediate 10-C refers to the paper Eur J Org Chem (2011, 27, 5242.).

[0534] 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.

[0535] 1 H NMR (600 MHz, CDC13, 4: 1 rotamers) 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, 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), 1.58-1.46 (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);

[0536] ESI-MS m / z: 901.6 [M+H]+ .

[0537] Example 12

[0538] 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-pyrrolo[4,3-c]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 11)

[0539] The synthesis of Compound 11 was the same as Compound 1, except that 1-bromo-2,3- difluoro-4-nitrobenzene was used to replace 4-bromo-2-fluoro-1-nitrobenzene, and pyrrolidine was used to replace morpholine as the starting material.

[0540] 1 H NMR (600 MHz, CDC13, 4:1 rotamers) 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);

[0541] ESI-MS m / z: 909.6 [M+H] + .

[0542] Example 13

[0543] 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]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4- oxadiazol-5(4H)-one (Compound 11-1)

[0544] The synthesis of Compound 11-1 was performed in accordance with the procedure for Compound 11 except that chiral intermediate C9-1 was used instead of C9 as the starting material.

[0545] ESI-MS m / z: 909.6 [M+H] + .

[0546] Example 14

[0547] 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]pyridine-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)

[0548] The synthesis of Intermediate 12-C was performed in accordance with the procedure for 1-C except that 3,3-difluoropyrrolidine was used instead of morpholine as the starting material.

[0549] 1 H NMR (500 MHz, CDC13) δ 7.75 (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] + .

[0550] The synthesis of Compound 12 was performed in accordance with the procedure for Compound 1 except that Intermediate 12-C was used instead of 1-C as the starting material.

[0551] 1 H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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 = 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, 3H), 1.53 (d, 3H, J = 6.6), 1.35 (s, 3H), 1.30 (s, 3H), 1.18 (d, 3H, J = 6.0);

[0552] ESI-MS m / z: 927.5 [M+H] + .

[0553] Example 15

[0554] 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-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 13)

[0555] The synthesis of Compound 13 was carried out according to the procedure of Compound 1, except that 4-bromo-1-fluoro-2-nitrobenzene was used instead of 4-bromo-2-fluoro-1- nitrobenzene and piperidine was used instead of morpholine as the starting material.

[0556] 1H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0557] ESI-MS m / z: 905.6 [M+H] + .

[0558] Example 16

[0559] 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-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]pyridine-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)

[0560] Step a: 900 mg (1 eq) of 4-bromopyridinecarboxaldehyde, 642 mg (1.2 eq) of 2-methylpropane-2-sulfinamide and 3.02 g (3 eq) of tetraethyl titanate were dissolved in 18 mL of dry tetrahydrofuran and heated at 75°C overnight. After cooling, 30 mL of water were added to the reaction and stirred vigorously. The insoluble material was removed by filtration and the filtrate was extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure to obtain 720 mg of a residue. This residue was redissolved in 15 mL of dry tetrahydrofuran, 355 mg (4 eq) of sodium borohydride were added and stirred at room temperature for 3 hours. After completion of the reaction, 30 mL of water were added to the reaction, stirred for 10 minutes and then extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure to obtain 400 mg of intermediate 14-A.

[0561] Step b: 400 mg of intermediate 14-A were dissolved in 30 mL of trifluoroacetic acid and heated at 40°C overnight. After completion of the reaction, it was evaporated under reduced pressure to obtain 378 mg of a residue. This residue (1 eq) was dissolved in 4 mL of DMF and then 840 mg (1.2 eq) of HATU, 715 mg (3 eq) of DIPEA and 175 mg (1.1 eq) of cyclopropanecarboxylic acid were added and stirred at room temperature overnight. After completion of the reaction, 20 mL of water were added to the reaction, extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was separated by flash column chromatography and then purified by preparative TLC to obtain 90 mg of intermediate 14-B.

[0562] Step c: 90 mg of intermediate 14-B were dissolved in 1 mL of phosphorus oxychloride and heated at 110°C overnight. After cooling, the reaction was poured into 10 mL of ice water, stirred for half an hour and then extracted twice with dichloromethane, the organic phases were combined, washed twice with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure and the residue was separated by preparative TLC to obtain 35 mg of intermediate 14-C.

[0563] The synthesis of compound 14 was carried out as for compound 1, except that intermediate 14-C was used instead of intermediate 1-C as starting material. 1H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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), 4.49 (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);

[0564] ESI-MS m / z: 891.6 [M+H] + .

[0565] 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropylimidazo[1,5-a]pyridin-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]pyridine-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)

[0566] The synthesis of Compound 14-1 was performed according to the procedures for Compound 14, except that intermediate C9-1 was used instead of intermediate C9 as the starting material.

[0567] Intermediate 14-D. 1H NMR (500 MHz, CDC13) δ 8.04 (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, 1H), 4.57-4.23 (m, 1H), 3.15 (m, 1H), 2.80 (m, 2H), 2.22 (d, 6H, J = 2.0), 2.03 (m, 1H), 1.50 (s, 9H), 1.31 (d, 3H, J = 6.5), 1.13 (m, 4H); ESI-MS m / z: 598.4 [M+H] + .

[0568] Compound 14-1. 1 H NMR (600 MHz, CDC13, major isomer in 4: 1 rotamers) δ 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), 1.80-1.71 (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] + .

[0569] Example 17

[0570] 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropyl-8-fluoroimidazo[1,5-a]pyridin-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]pyridine-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)

[0571] The preparation method of intermediate 15-C refers to that described in patent WO2022240830.

[0572] 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 H NMR (600 MHz, CDC13, 4:1 rotamers) 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), 1.35 / 1.33 (s, 3H), 1.32-1.13 (m, 4H), 1.29 (s, 3H), 1.20 / 1.07 (d, 3H, J = 6.0);

[0573] ESI-MS m / z: 909.6 [M+H] + .

[0574] 3-((1S,2S)-1-(2-((S)-3-(3-(3-cyclopropyl-8-fluoroimidazo[1,5-a]pyridin-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]pyridine-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)

[0575] The synthesis of Compound 15-1 was carried out according to the procedure for Compound 15, except that intermediate C9-1 was used instead of intermediate C9 as the starting material.

[0576] Intermediate 15-D. 1 H NMR (500 MHz, CDC13) δ 7.84 (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] + .

[0577] Compound 15-1. 1H NMR (500 MHz, CDC13, major isomer of 3: 1 rotamers) 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), 1.81-1.71 (m, 3H), 1.68-1.59 (m, 2H), 1.58-1.50 (m, 4H), 1.35 (s, 3H), 1.28 (s, 3H), 1.20 (d, 3H, J = 6.0), 1.14-1.04 (m, 4H); ESI-MS m / z: 909.6 [M+H] + .

[0578] Example 18

[0579] 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]pyridine-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)

[0580] The synthesis of Compound 16 was carried out according to the procedure of Compound 1, except that pyrrolidine was used instead of morpholine as the starting material.

[0581] 1H NMR (500 MHz, CDC13, 4: 1 rotamers) 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), 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);

[0582] ESI-MS m / z: 891.6 [M+H] + .

[0583] Example 19

[0584] 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]oxazepin-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0585] Step d: To 2 mL of NMP was added 50 mg (1 eq) of Intermediate D5, 53 mg of Intermediate 6-C (2 eq), 7.9 mg (0.5 eq) of (1S,2S)-N 1 ,N 2- dimethylcyclohexane-1,2-diamine, 4.2 mg (0.2 eq) CuI and 46 mg (3 eq) potassium carbonate, nitrogen substitution, stirring at 130 °C overnight. After the reaction is completed, 20 mL of water is added to the reaction solution, extracted with ethyl acetate three times, the organic phase is combined, washed with saturated brine twice, dried over anhydrous magnesium sulfate. Filtration, the filtrate is evaporated under reduced pressure, the residue is separated by preparative TLC to obtain 55 mg of light yellow solid, which is intermediate 17-D.

[0586] 1 H NMR (500 MHz, CDC13) δ 7.33-7.13 (m, 4H), 7.02 (t, 1H, J = 9.0), 6.95 (dd, 1H, J = 6.5, 1.5), 6.67 (d, 1H, J = 3.0), 6.25 (br s, 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] + .

[0587] Step e, f: 55 mg (1 eq) of intermediate 17-D is dissolved in 1.5 mL of DCM, 550 μL (4 M, 25 eq) of HCl-dioxane solution is added, stirred at room temperature overnight, then evaporated under reduced pressure. The residue is redissolved in a small amount of DCM, and evaporated under reduced pressure again, and this is repeated twice. The obtained residue is dissolved in 2 mL of dry DMF, then 54 mg (1.6 eq) of HATU, 110 μL (7 eq) of DIPEA and 58 mg (1.6 eq) of intermediate C9 are added, stirred at room temperature for 2 hours until the reaction is completed. 10 mL of water is added to the reaction solution, extracted with ethyl acetate three times, the organic phase is combined, washed with saturated brine twice, dried over anhydrous magnesium sulfate. Filtration, the filtrate is evaporated under reduced pressure, the residue is separated and purified by preparative liquid phase, eluted with acetonitrile and water containing 0.5% trifluoroacetic acid (V / V) as mobile phase. The target product part is collected and freeze-dried to obtain 35 mg of white solid, which is compound 17.

[0588] 1H NMR (500 MHz, CDC13, major isomer of 5: 1 rotamers) 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);

[0589] ESI-MS m / z: 908.6 [M+H] + .

[0590] Example 20

[0591] 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-imidazol-1-yl)-4- methyl-4, 5, 6, 7-tetrahydro-2H-pyrazolo[4, 3-c]pyridine-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)

[0592] The synthesis of Compound 18 was carried out according to the procedure for Compound 17, except that intermediate 1-C was used instead of intermediate 6-C as the starting material.

[0593] 1H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0594] ESI-MS m / z: 919.6 [M+H] + .

[0595] Example 21

[0596] 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]pyridine-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)

[0597] The synthesis of Compound 19 was carried out according to the procedure of Compound 17, except that intermediate 16-C was used instead of intermediate 6-C as the starting material.

[0598] 1H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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), 1.35 (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);

[0599] ESI-MS m / z: 903.6 [M+H] + .

[0600] Example 22

[0601] 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]pyridine-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)

[0602] The synthesis of Compound 20 was carried out according to the procedure of Compound 1, except that 4-bromo-1-fluoro-2-nitrobenzene was used instead of 4-bromo-2-fluoro-1-nitrobenzene, and pyrrolidine was used instead of morpholine as the starting material.

[0603] 1 H NMR (600 MHz, CDC13, major isomer of 3: 1 rotamers) 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);

[0604] ESI-MS m / z: 891.6 [M+H] + .

[0605] Example 23

[0606] 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-1 H-imidazol-1 -yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine-5-carbonyl)-1 H-indol-1 -yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 21)

[0607] Step a: 748 mg (1 eq) of 4-methylpiperazin-2-one was dissolved in 20 mL of dry DMF, 341 mg of sodium hydride (60% mass fraction dispersed in oil, 1.3 eq) was added portionwise at room temperature, stirred for 15 min, then 1443 mg (1 eq) of 4-bromo-2-fluoronitrobenzene was added, the reaction was allowed to proceed for 1 h, TLC detection showed that the reaction was complete. Quenching was performed with 30 mL of saturated aqueous brine solution, extraction was performed three times with ethyl acetate, the organic phases were combined and washed once with saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, the residue was separated by flash chromatography column to give 1.34 g of intermediate 21-A.

[0608] Step b: 1.34 g (1 eq) of intermediate 21-A was dissolved in 100 mL of a mixture of ethanol / water (4:1, V / V), 1.43 g (6 eq) of reduced iron powder and 796 mg (3.5 eq) of ammonium chloride were added, the reaction was allowed to proceed at 90°C for 3 h, TLC detection showed that the reaction was complete. After cooling, the insoluble material was removed by filtration, the filtrate was concentrated to evaporate most of the ethanol. To the residue, 50 mL of water was added, extraction was performed three times with ethyl acetate, the organic phases were combined and washed twice with saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated to dryness to give 1.2 g of intermediate 21-B, which was used directly in the next step without purification.

[0609] Step c: 1.2 g of intermediate 21-B was dissolved in 20 mL of acetic acid, then heated at 110°C for 3 h, TLC detection showed that the reaction was complete. The acetic acid was evaporated, the residue was redissolved in 30 mL of ethyl acetate, then washed twice with saturated aqueous NaHCO3 solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, the residue was separated by flash chromatography column to give 900 mg of intermediate 21-C.

[0610] 1 H NMR (500 MHz, CDC13) δ 7.56 (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-MS m / z: 266.1 [M+H] + .

[0611] 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.

[0612] 1H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0613] ESI-MS m / z: 920.6 [M+H] + .

[0614] Example 24

[0615] 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]cyclopropa[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]pyridine- 5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 22)

[0616] The synthesis of Intermediate 22-C was performed according to the procedure for Intermediate 1-C, except 3-azabicyclo[3.1.0]hexane was used as starting material instead of morpholine.

[0617] 1H NMR (500 MHz, CDC13) δ 7.51 (d, 1H, J = 8.5), 7.35 (d, 1H, J = 2.0), 7.28 (dd, 1H, J = 8.5, 2.0), 4.15 (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] + .

[0618] The synthesis of compound 22 was carried out according to the procedure of compound 1, except that intermediate 22-C was used instead of intermediate 1-C as the starting material.

[0619] 1 H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0620] ESI-MS m / z: 903.6 [M+H] + .

[0621] Example 25

[0622] 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-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0623] The synthesis of Intermediate 23-C was performed according to the procedure for Intermediate 21-C, except using thiomorpholine-3-one instead of 4-methylpiperazine-2-one as the starting material. 1 H NMR (600 MHz, CDC13) δ 7.76 (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]

[0624] The synthesis of Intermediate 23-D was performed according to the procedure for Intermediate 1-D, except using Intermediate 23-C instead of Intermediate 1-C as the starting material.

[0625] 1 H NMR (600 MHz, CDC13) δ 7.76 (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] + .

[0626] The synthesis of Compound 23 was performed according to the procedure for Compound 1, except using Intermediate 23-D instead of Intermediate 1-D as the starting material.

[0627] 1H NMR (500 MHz, CDC13, major isomer of 5: 1 rotamers) 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);

[0628] ESI-MS m / z: 923.6 [M+H] + .

[0629] Example 26

[0630] 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-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0631] The preparation method of intermediate 24-C is referred to the description in patent WO202141237.

[0632] The synthesis method of compound 24 is the same as compound 1, except that intermediate 24-C is used instead of intermediate 1-C as the raw material.

[0633] 1H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0634] ESI-MS m / z: 907.6 [M+H] + .

[0635] Example 27

[0636] 3-((1S,2S)-1-(2-((S)-3-(3-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-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]pyridine-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)

[0637] The synthesis of Compound 25 was carried out according to the procedure of Compound 1, except that commercially purchased reagent 25-C was used instead of intermediate 1-C as the starting material.

[0638] 1H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0639] ESI-MS m / z: 919.6 [M+H] + .

[0640] Example 28

[0641] 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-2H-benzo[4,5]thiazolo[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]pyrimidin-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)

[0642] Step a: 300 mg of 2-chloro-5-bromobenzothiazole and 2 mL of 3-amino-1-propanol were added into a sealed tube, heated at 130 °C for 3 hours, TLC detection reaction was completed. After cooling, 30 mL of water was added to the reaction solution, then extracted with ethyl acetate three times. The organic phase was combined, washed with saturated brine twice, and dried over anhydrous magnesium sulfate. Filtration, the filtrate was evaporated under reduced pressure, the residue was separated by flash column chromatography, and 311 mg of intermediate 26-A was obtained.

[0643] Step b: 311 mg of intermediate 26-A was added to 3 mL of thionyl chloride and heated at 70 °C for half an hour. The reaction was monitored by TLC. The reaction was evaporated under reduced pressure to give 320 mg of white solid, intermediate 26-B, which was used directly in the next step without further purification.

[0644] Step c: 320 mg of intermediate 26-B and 0.6 mL (3 eq) of triethylamine were dissolved in 10 mL of toluene and heated at 100 °C overnight. The reaction was monitored by TLC. The reaction was evaporated under reduced pressure and the residue was separated by flash column chromatography to give 230 mg of intermediate 26-C.

[0645] The synthesis of compound 26 was carried out according to the procedure of compound 1, except that intermediate 26-C was used instead of intermediate 1-C.

[0646] 1 H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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 = 13.8, 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, 3H), 1.52 (d, 3H, J = 6.0), 1.34 (s, 3H), 1.28 (s, 3H), 1.18 (d, 3H, J = 6.0);

[0647] ESI-MS m / z: 923.6 [M+H] + .

[0648] Example 29

[0649] 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]quinolin-8-yl)- 2,3-dihydro-1 H-imidazol-1 -yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)- 1 H-indol-1 -yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 27)

[0650] Step c: 1 g (1 eq) of 4-bromo-2-fluorobenzamide (27-A) was mixed with 2.3 g (5 eq) of 2-methoxy-1-pyrrolidine (27-B) and heated to react at 120 °C. The solid was dissolved slowly at first and then more solid precipitated out and the solution color turned to tan. After 3 hours, the reaction was checked by TLC and was complete. The solid was collected by filtration after cooling to room temperature, the filter cake was washed with a small amount of ethyl acetate and dried to give intermediate 27-C.

[0651] 1 H NMR (500 MHz, CDC13) δ 8.11 (d, 1 H, J = 8.5), 7.53 (dd, 1 H, J = 8.5, 1.5), 7.35 (d, 1 H, J = 1.5), 4.21 (t, 2 H, J = 7.5), 3.19 (t, 2 H, J = 8.0), 2.42 (m, 2 H).

[0652] Compound 27 was synthesized in the same manner as Compound 1, except that intermediate 27-C was used in place of intermediate 1-C as the starting material.

[0653] 1H NMR (600 MHz, CDC13, major isomer of 5: 1 rotamers) 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);

[0654] ESI-MS m / z: 919.6 [M+H] + .

[0655] Example 30

[0656] 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]azepin-2-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4- oxadiazol-5(4H)-one (Compound 28)

[0657] 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.

[0658] 1H NMR (500 MHz, CDC13) δ 7.57 (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).

[0659] The synthesis of compound 28 was carried out according to the procedure for compound 1, except that intermediate 28-C was used instead of intermediate 1-C as the starting material.

[0660] 1 H NMR (500 MHz, CDC13, major isomer of 5: 1 rotamers) 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 = 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);

[0661] ESI-MS m / z: 933.6 [M+H] + .

[0662] Example 31

[0663] 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-imidazol-1-yl)-2-(4-fluoro-3,5- dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0664] Step b: 500 mg of intermediate 29-A (prepared according to the procedure described in WO202141237) was added to 5 mL of dichlorosulfoxide and heated at 70 °C for 1 h. The reaction was monitored by TLC. The dichlorosulfoxide was removed under reduced pressure and the residue was dissolved in ethyl acetate. Then 1 g of NaHC03 solid was added slowly and stirred for 10 min. The insoluble material was removed by filtration and the filtrate was evaporated to dryness to give intermediate 29-B, which was used directly in the next step.

[0665] Step c: 420 mg of intermediate 29-B was dissolved in 20 mL of DMF and heated at 60 °C overnight. The reaction was monitored by TLC. After cooling, 30 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine twice, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was separated by flash column chromatography to give intermediate 29-C.

[0666] 1 H NMR (500 MHz, CDC13) δ 7.45 (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).

[0667] Compound 29 was synthesized according to the procedure for Compound 1, except that intermediate 29-C was used instead of intermediate 1-C as the starting material.

[0668] 1H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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 = 13.5, 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);

[0669] ESI-MS m / z: 923.6 [M+H] + .

[0670] Example 32

[0671] 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-imidazol-1-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0672] The synthesis of Intermediate 30-D was carried out according to the procedure for Intermediate 1-D, except Intermediate E5 was used in place of Intermediate B5 as the starting material.

[0673] 1H NMR (500 MHz, CDC13) δ 7.76 (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] + .

[0674] The synthesis of compound 30 was carried out according to the procedure of compound 1, except that intermediate 30-D was used instead of intermediate 1-D as the starting material.

[0675] 1 H NMR (600 MHz, CDC13, major isomer of 5: 1 rotamers) 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, 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, 3H), 1.54 (d, 3H, J = 6.6), 1.35 (s, 3H), 1.29 (s, 3H), 1.18 (d, 3H, J = 6.0);

[0676] ESI-MS m / z: 947.6 [M+H] + .

[0677] Example 33

[0678] 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]pyridine-5-carbonyl)-5-(2,2-dimethyltetra- hydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 31)

[0679] The synthesis of Intermediate 31-D was carried out according to the procedure for Intermediate 1-D, except Intermediate F5 was used instead of Intermediate B5, and Intermediate 11-C was used instead of Intermediate 1-C.

[0680] 1 H NMR (500 MHz, CDC13) δ 7.52 (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] + .

[0681] The synthesis of Compound 31 was carried out according to the procedure for Compound 1, except Intermediate 31-D was used instead of Intermediate 1-D.

[0682] 1H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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), 4.45-4.39 (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);

[0683] ESI-MS m / z: 949.5 [M+H] + .

[0684] Example 34

[0685] 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-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 32)

[0686] The synthetic method of Intermediate 32-C is the same as Intermediate 26-C, except using 5-bromo-2-chloro-1-methyl-1H-benzimidazole instead of 2-chloro-5-bromobenzothiazole as the starting material.

[0687] 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H, HC1), 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).

[0688] 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.

[0689] 1 H NMR (500 MHz, CDCl3) δ 7.80 (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] + .

[0690] 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.

[0691] 1H NMR (600 MHz, CDC13, major isomer of 6: 1 rotamers) 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 = 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);

[0692] ESI-MS m / z: 920.6 [M+H] + .

[0693] Example 35

[0694] 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] oxazepin-9-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 33)

[0695] The synthesis of Intermediate 33-C was performed according to the procedure for Intermediate 21-C, except using 1,4-oxazepan-5-one instead of 4-methylpiperazin-2-one as the starting material.

[0696] The synthesis of Intermediate 33-D was performed according to the procedure for Intermediate 1-D, except using Intermediate 33-C instead of Intermediate 1-C as the starting material.

[0697] 1H NMR (500 MHz, CDC13) δ 7.76-7.70 (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] + .

[0698] The synthesis of compound 33 was carried out according to the procedure of compound 1, except that intermediate 33-D was used instead of intermediate 1-D as the starting material.

[0699] 1 H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0700] ESI-MS m / z: 921.6 [M+H] + .

[0701] Example 36

[0702] 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-1H-[1,4]oxazepino[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]pyridine-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)

[0703] Step b: 500 mg (1 eq) of 6-bromo-1H-indole-2-carboxylic acid was dissolved in 10 mL of dry tetrahydrofuran, and 2.1 mL of lithium aluminum hydride / tetrahydrofuran solution (1.0 M, 1 eq) was added dropwise slowly in an ice bath. After the dropwise addition was completed, the reaction was stirred at room temperature for another 4 hours. After the reaction was completed, the reaction was placed in an ice bath again, and quenched with water, 15% (m / m) NaOH aqueous solution, and then diluted with 30 mL of water. The reaction was extracted with ethyl acetate three times, and the organic phase was combined, washed with saturated brine twice, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure to obtain 460 mg of intermediate 34-B.

[0704] Step c: 1.0 g (1.5 eq) of diphenyl(vinyl)sulfonium triflate and 320 mg (3 eq) of KOH were suspended in 15 mL of dichloromethane and placed in an ice bath. Intermediate 34-B (1 eq) was dissolved in 5 mL of dichloromethane, and was added dropwise slowly to the reaction. After the dropwise addition was completed, the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with water, and the organic phase was separated, washed with saturated brine twice, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the residue was separated by flash column chromatography to obtain 300 mg of intermediate 34-C.

[0705] 1 H NMR (600 MHz, CDC13) δ 7.43 (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] + .

[0706] 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.

[0707] 1H NMR (500 MHz, CDC13) δ 7.64 (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), 2.89-2.76 (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] + .

[0708] The synthesis of compound 34 was carried out according to the procedure of compound 1, except that intermediate 34-D was used instead of intermediate 1-D as the starting material.

[0709] 1 H NMR (500 MHz, CDC13) δ 7.64 (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), 2.89-2.76 (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]

[0710] ESI-MS m / z: 906.6 [M+H] + .

[0711] Example 37

[0712] 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]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 35)

[0713] The preparation method of intermediate 35-C refers to the literature (Synthesis. 1981, 6, 461-462.).

[0714] 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.

[0715] 1 H NMR (600 MHz, CDCl3, major isomer in 3:1 rotamers) 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] + .

[0716] Example 38

[0717] 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]oxazepin-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4- yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 36)

[0718] The synthesis of Compound 36 was carried out in the same manner as for Compound 6, except that intermediate G9 was used in place of intermediate C9 as the starting material.

[0719] 1 H NMR (500 MHz, CDC13, major isomer of 3:1 rotamers) 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);

[0720] ESI-MS m / z: 868.5 [M+H] + .

[0721] Example 39

[0722] 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]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 37)

[0723] The synthesis of Compound 37 was the same as Compound 11 except that intermediate G9 was used instead of intermediate C9 as the starting material.

[0724] ESI-MS m / z: 881.5 [M+H] + .

[0725] Example 40

[0726] 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]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 37)

[0727] Step b: The synthesis of intermediate 38-B was the same as intermediate 1-D except that intermediate H5 was used instead of intermediate B5 and intermediate 6-C was used instead of intermediate 1-C as the starting material.

[0728] Step c: 57 mg (1 eq) of intermediate 38-B, 43 mg (5 eq) of trimethylsilyl acetylene, 18 mg (0.3 eq) of triphenylphosphine palladium chloride, 5 mg (0.3 eq) of cuprous iodide, 1.5 mL of triethylamine, 2.5 mL of DMF were added to an autoclave, degassed with nitrogen for several minutes, then sealed, and then heated with stirring at 80°C overnight. After cooling, the reaction solution was diluted with ethyl acetate, filtered to remove insoluble matter, washed with salt water three times, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated to dryness and separated by preparative TLC to obtain 70 mg of intermediate 38-C.

[0729] 1H NMR (500 MHz, CDC13) δ 7.57 (dd, IH, J = 6.0, 2.5), 7.34 (m, IH), 7.26 (m, IH), 7.22 (d, IH, J = 1.5), 7.20 (d, IH, J = 8.0), 7.04 (t, IH, J = 8.5), 6.67 (d, IH, J = 3.5), 6.25 (s, IH), 5.44-5.10 (m, IH), 4.57-4.22 (m, IH), 4.11 (m, 2H), 3.77 (s, 2H), 3.22-3.07 (m, IH), 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).

[0730] Step c: The above intermediate 38-C was dissolved in 2 mL of methanol, then 112 mg of potassium carbonate was added, and stirred at room temperature for 0.5 hours until the reaction was completed. The insoluble matter was removed by filtration, and the filtrate was evaporated to dryness and separated by preparative TLC to give 55 mg of intermediate 38-D.

[0731] Step e, f: The preparation method of compound 38 is the same as that of compound 1, except that intermediate 38-D is used instead of intermediate 1-D as the starting material.

[0732] 1 H NMR (500 MHz, CDC13) δ 7.57 (dd, IH, J = 6.0, 2.5), 7.34 (m, IH), 7.26 (m, IH), 7.22 (d, IH, J = 1.5), 7.20 (d, IH, J = 8.0), 7.04 (t, IH, J = 8.5), 6.67 (d, IH, J = 3.5), 6.25 (s, IH), 5.44-5.10 (m, IH), 4.57-4.22 (m, IH), 4.11 (m, 2H), 3.77 (s, 2H), 3.22-3.07 (m, IH), 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).

[0733] ESI-MS m / z: 892.6 [M+H] + .

[0734] Examples 41 and 42

[0735] 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'- cyclopropan]-7-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 39)

[0736] 3-((1S,2S)-1-(2-((S)-3-(3-(1,2-dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazol-3,1'- cyclopropan]-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]pyridine-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)

[0737] The synthetic method of Intermediate 39-C and Intermediate 40-C is the same as Intermediate 1-C, except that 5-azaspiro[2.4]heptane is used instead of morpholine starting material, and both are two isomers produced simultaneously in step c.

[0738] Intermediate 39-C: 1 H NMR (500 MHz, CDC13) δ 7.57 (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] + .

[0739] Intermediate 40-C: 1H NMR (600 MHz, CDC13) δ 7.48 (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] + .

[0740] The synthesis of compounds 39 and 40 was carried out as for compound 1, except that intermediates 39-C and 40-C, respectively, were used instead of 1-C as starting material.

[0741] Compound 39: 1 H NMR (500 MHz, CDC13, major isomer of 3:1 rotamers) 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 (d, 6H, J = 1.0), 1.90 (t, 1H, J = 5.5), 1.82-1.50 (m, 6H), 1.54 (d, 3H, J = 7.0), 1.34 (s, 3H), 1.28 (s, 3H), 1.18 (d, 3H, J = 6.0); ESI-MS m / z: 917.6 [M+H] + .

[0742] Compound 40: 1H NMR (600 MHz, CDC13, major isomer of 3: 1 rotamers) 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, 1H), 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] + .

[0743] Example 43

[0744] 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]oxazepin-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c]pyridine-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)

[0745] The synthesis of Compound 41 was carried out according to the procedure of Compound 6, except that intermediate H5 was used instead of intermediate B5 as the starting material.

[0746] 1H NMR (500 MHz, CDC13, major isomer of 5: 1 rotamers) 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);

[0747] ESI-MS m / z: 946.5 [M+H] + .

[0748] Example 44

[0749] 3-((1S,2S)-1-(5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(5,5-dioxodibenzo[b,d]thiophen-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]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 42)

[0750] The synthetic method of intermediate 42-C is referred to that described in patent CN111320615.

[0751] The synthetic 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 (500 MHz, CDC13) δ 8.33 (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] + .

[0752] The synthesis of compound 42 was carried out according to the procedure of compound 1, except that intermediate 42-D was used instead of intermediate 1-D as the starting material.

[0753] 1 H NMR (500 MHz, CDC13) δ 8.33 (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]

[0754] ESI-MS m / z: 949.5 [M+H] + .

[0755] Example 45

[0756] 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'- cycloban]-7-yl)-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 43)

[0757] The synthesis of Intermediate 43-C was carried out according to the procedure for Intermediate 21-C, except using 6-azaspiro[3.4]octan-7-one instead of 4-methylpiperazin-2-one as starting material. 1 H NMR (500 MHz, CDC13) δ 7.54 (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] + .

[0758] The synthesis of Compound 43 was carried out according to the procedure for Compound 1, except using Intermediate 43-C instead of Intermediate 1-C as starting material.

[0759] 1H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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);

[0760] ESI-MS m / z: 931.6 [M+H] + .

[0761] Example 46

[0762] 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-tetrahydrocyclopenta[b]indol-7-yl)-2- oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 44)

[0763] The preparation method of intermediate 44-C is referred to the description in patent WO201047982. 1 H NMR (500 MHz, CDC13) δ 7.52 (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]+ .

[0764] The synthesis of compound 44 was carried out according to the procedure for compound 1, except that intermediate 44-C was used instead of intermediate 1-C as the starting material.

[0765] 1 H NMR (500 MHz, CDC13, major isomer of 3:1 rotamers) 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);

[0766] ESI-MS m / z: 904.6 [M+H] + .

[0767] Example 47

[0768] 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]imidazo[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]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4- oxadiazol-5(4H)-one (Compound 45)

[0769] The synthesis of intermediate 45-C was carried out according to the procedure for intermediate 26-C, except that 5-bromo-2-chloro-1-methyl-1H-benzimidazole was used instead of 2-chloro-5-bromobenzothiazole, and 2-aminoethan-1-ol was used instead of 3- aminopropan-1-ol as the starting material.1 HNMR (500 MHz, DMSO-d6) δ 7.05-7.00 (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] + .

[0770] The synthesis of compound 45 was carried out according to the procedure of compound 1, except that intermediate 45-C was used instead of intermediate 1-C as the starting material.

[0771] 1 H NMR (600 MHz, CDC13, major isomer of 5: 1 rotamers) 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), 1.89 (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);

[0772] ESI-MS m / z: 906.6 [M+H] + .

[0773] 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]imidazo[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]pyridine-5- carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 45-1)

[0774] The synthesis of compound 45-1 was carried out in the same manner as compound 45, except that intermediate C9-1 was used instead of intermediate C9 as the starting material. 1 H NMR (500 MHz, CDC13, major isomer of 5: 1 rotamers) 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] + .

[0775] Example 48

[0776] 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-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)- 4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2- methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 46-1)

[0777] Step a: Imidazole-2-carboxaldehyde (537 mg, 1 eq), 2-iodo-4-bromoaniline (2.5 g, 1.5 eq), salicylic hydrazide (85 mg, 0.1 eq), cesium carbonate (3.65 g, 2 eq), cuprous iodide (53 mg, 0.05 eq) were added to 20 mL DMF, stirred and heated at 120 °C for 24 h. After the reaction mixture was cooled, 50 mL water was added to the reaction mixture, extracted with ethyl acetate for 3 times, combined organic phase was washed with saturated brine for 3 times, filtered, the filtrate was evaporated under reduced pressure, the residue was separated by flash column chromatography, eluted with petroleum ether-ethyl acetate solvent system, 790 mg of solid was obtained, which was intermediate 46-C, with a yield of 57%. 1 H NMR (500 MHz, CDC13) δ 9.13 (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] + .

[0778] Step d: To 2 mL N-methyl pyrrolidone (NMP) was added intermediate B5 (50 mg, 1 eq), intermediate 46-C (56 mg, 2 eq), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (8 mg, 0.5 eq), CuI (6.5 mg, 0.3 eq) and potassium carbonate (47 mg, 3 eq), replaced with nitrogen for several times, then stirred and heated at 130 °C overnight. After cooling, 30 mL water was added to the reaction mixture, then extracted with ethyl acetate for three times. The combined organic phase was washed with saturated brine for two times, then dried over anhydrous magnesium sulfate. Filtered, the filtrate was evaporated under reduced pressure, the residue was separated by preparative thin layer chromatography (TLC), 46 mg of light yellow solid was obtained, which was intermediate 46-D, with a yield of 67%.

[0779] Step e, f: Dissolve 46 mg (1 eq) of intermediate 46-D in 3 mL of dichloromethane (DCM), add 284 μL of HCl / dioxane solution (4 M in concentration, 15 eq), stir at room temperature overnight, then evaporate under reduced pressure. Redissolve the residue in a small amount of DCM, and evaporate under reduced pressure again. Repeat twice. Dissolve the residue in 2.5 mL of dry N,N-dimethylformamide (DMF), then add 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 31 mg, 1.1 eq), N,N-diisopropylethylamine (DIPEA, 49 mg, 5 eq), and intermediate C9-1 (34 mg, 1.1 eq), and stir at room temperature for 2 hours until the reaction is completed. Add 10 mL of water to the reaction solution, then extract with ethyl acetate three times. Combine the organic phases, wash with saturated brine twice, and dry over anhydrous magnesium sulfate. Filter, evaporate the filtrate under reduced pressure, and purify the residue by preparative liquid chromatography, eluting with acetonitrile and water containing 0.1% trifluoroacetic acid (V / V) as the mobile phase. Collect the fraction of the target product, and freeze-dry to obtain 24 mg of a white solid, which is compound 46-1, in a yield of 35%. 1 H NMR (600 MHz, CDCl3, major isomer in 5:1 rotamers) 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] + .

[0780] Example 49

[0781] 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]quinazolin-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2- methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 47-1)

[0782] Step a: 1H-imidazol-2-amine (1 g, 1 eq), 4-bromo-2-fluorobenzaldehyde (2.45 g, 1 eq), cesium carbonate (5.9 g, 1.5 eq) were added to 20 mL DMF, heated with stirring at 120 °C for 6 h, the reaction solution was cooled, 50 mL water was added to the reaction solution, extracted with ethyl acetate for 3 times, the organic phase was combined, washed with saturated brine for 3 times, filtered, the filtrate was evaporated under reduced pressure, the residue was separated by flash column chromatography, eluted with petroleum ether-ethyl acetate solvent system, 320 mg of solid was obtained, which was intermediate 47-C, the yield was 23%. 1 H NMR (500 MHz, CDCl3) δ 8.95 (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] + .

[0783] Step d: Intermediate B5 (50 mg, 1 eq), intermediate 47-C (56 mg, 2 eq), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (8 mg, 0.5 eq), CuI (6.5 mg, 0.3 eq) and potassium carbonate (47 mg, 3 eq) were added to 2 mL N-methylpyrrolidone (NMP), replaced with nitrogen for several times, then heated with stirring at 130 °C overnight. After cooling, 30 mL water was added to the reaction solution, then extracted with ethyl acetate for three times. The organic phase was combined, washed with saturated brine twice, and dried over anhydrous magnesium sulfate. Filtration, the filtrate was evaporated under reduced pressure, the residue was separated by preparative thin layer chromatography (TLC), 49 mg of light yellow solid was obtained, which was intermediate 47-D, the yield was 71%. 1H NMR (500 MHz, CDC13) δ 9.01 (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] + .

[0784] Step e, f: 49 mg (1 eq) of intermediate 46-D was dissolved in 3 mL of dichloromethane (DCM), 303 μΐ^of HCl / dioxane solution (4 M in concentration, 15 eq) was added, stirred at room temperature overnight, then evaporated under reduced pressure. The residue was dissolved in a small amount of DCM, then evaporated under reduced pressure, and repeated twice. The obtained residue was dissolved in 2.5 mL of dry N,N-dimethylformamide (DMF), then 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 33 mg, 1.1 eq), N,N-diisopropylethylamine (DIPEA, 52 mg, 5 eq) and intermediate C9-1 (36 mg, 1.1 eq) were added, stirred at room temperature for 2 hours until the reaction was completed. 10 mL of water was added to the reaction solution, then extracted with ethyl acetate three times. The combined organic phase was washed with saturated brine twice, then dried over anhydrous magnesium sulfate. Filtration, the filtrate was evaporated under reduced pressure, the residue was separated and purified by preparative liquid chromatography, eluted with acetonitrile and water containing 0.1% trifluoroacetic acid (V / V) as mobile phase. The target product fraction was collected and freeze-dried to obtain 24 mg of white solid, which was compound 47-1, with a yield of 26%. ESI-MS m / z: 902.6 [M+H] + .

[0785] Example 50

[0786] 3-[(1S,2S)-1-(5-[(S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-2-[(S)-2-(4-fluoro-3,5- dimethylphenyl)-3-[3-(imidazo[l,2-a]quinoxalin-7-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]- 4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-lH-indol-l-yl)-2- methylcyclopropyl]-l,2,4-oxadiazol-5(4H)-one (Compound 48-1)

[0787] The synthesis of compound 48-1 was carried out in the same manner as compound 47-1, except that 5-bromo-2-fluoroaniline and imidazole-2-carboxaldehyde were used instead of 1H-imidazol-2-amine and 4-bromo-2-fluorobenzaldehyde, respectively, as starting materials.

[0788] Intermediate 48-C. 1 H NMR (500 MHz, CDC13) δ 9.13 (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] + .

[0789] Intermediate 48-D. 1 H NMR (500 MHz, CDC13) δ 9.21 (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] + .

[0790] Compound 48-1. 1H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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] + .

[0791] Example 51

[0792] 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]imidazol-6-yl)- 2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carboxamido]-1H-indol-1-yl)-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 49-1)

[0793] Step a: 5-Bromo-2-chloro-1H-benzo[d]imidazole (200 mg) was added to 3 mL of N- methylethanolamine in a sealed tube at 130 °C for 3 hours. After cooling, it was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the filtrate was purified by flash column to give intermediate 49-A about 245 mg.

[0794] Step b: Intermediate 49-A (245 mg) was dissolved in 3 mL of thionyl chloride in a sealed tube at 70 °C for 15 min, then ice-cold saturated aqueous NaHC03solution was added slowly, then extracted with ethyl acetate for 3 times, dried over MgS04and filtered, the filtrate was purified by flash column to give intermediate 49-B 226 mg.

[0795] Step c: Intermediate 49-B (226 mg, 1 eq) was dissolved in 5 mL of toluene, triethylamine (350 μL, 3 eq) in a sealed tube at 100 °C overnight. After the reaction was completed, it was evaporated to dryness, separated by preparative TLC with dichloromethane / methanol (V / V) = 15:1 as eluent to give intermediate 49-C and 49-D each 32 mg.

[0796] Intermediate 49-C. 1 H NMR (500 MHz, CDC13) δ 7.25 (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-MS m / z: 252.1 [M+H] + .

[0797] Step d-f were performed by the same method as described in the preparation of compound 46-1, except that intermediate 49-C was used instead of intermediate 46-C as starting material.

[0798] Intermediate 49-E. 1 H NMR (800 MHz, CDC13) δ 7.52-7.35 (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), 4.56-4.25 (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] + .

[0799] Compound 49-1. 1H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) δ 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] + .

[0800] Example 52

[0801] 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]pyridine-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 50-1)

[0802] Step a: Dissolve the starting material 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 completed, the reaction solution is concentrated under reduced pressure and evaporated to dryness, water is added and stirred, filtered, the filter cake is washed with an appropriate amount of water, and then dried at 50 °C to obtain 495 mg of intermediate 50-A.

[0803] Step b: Into a reaction vial was placed 50-B (495 mg, 1.0 eq) and 7 mL of triethyl orthoformate, heated to 100 °C and stirred for 2-3 hours. Upon completion, the reaction was quenched with saturated sodium bicarbonate solution, extracted with methanol / dichloromethane mixture (V / V = 1:5) for several times. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give intermediate 50-C. 1 H NMR (500 MHz, CDCl3) δ 10.15 (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] + .

[0804] Steps d-f were performed by referring to the same synthetic method as for compound 46-1, except that intermediate 50-C was used in place of intermediate 46-C as the starting material.

[0805] Intermediate 50-D. 1 H NMR (500 MHz, CDCl3) δ 9.38 (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] + .

[0806] Compound 50-1. 1H NMR (600 MHz, CDC13, major isomer of 5: 1 rotamers) δ 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, 1H, 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] + .

[0807] Example 53

[0808] 3-[(1S,2S)-1-[2-[(S)-3-[3-(1H,3H-benzo[4,5]imidazo[1,2-c]thiazol-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]pyridine-5-carbonyl]-5-(2,2-dimethyltetrahydro-2H-pyran-4- yl)-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 51)

[0809] The synthetic method of Intermediate 51-C is the same as Intermediate 21-C, except that thiazolidin-4-one is used as the starting material instead of 4-methylpiperazin-2-one. 1 H NMR (500 MHz, CDC13) δ 7.58 (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] + .

[0810] The synthesis of compound 51 was carried out according to the procedure for compound 1, except that intermediate 51-C was used instead of intermediate 1-C as the starting material. 1 H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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), 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] + .

[0811] Example 54

[0812] 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]azepin-7-yl)-2- oxo-2,3-dihydro-1H-imidazol-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5- carboxamido]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 52-1)

[0813] ​Step a: To a flask containing 30 mL of dry ethanol was added 6-bromo-3,4- dihydronaphthalen-l(2H)-one (1 g, 1 eq), sodium acetate (730 mg, 2 eq), hydroxylamine hydrochloride (401 mg, 1.3 eq), heated to 90 °C and refluxed for about 2 hours, TLC monitored, reaction was complete, cooled to room temperature, poured into water, a large amount of white solid was formed, filtered and dried to give about 1.02 g of intermediate hydroxamic acid. Then, this intermediate was added to 15 mL of dichlorosulfoxide and heated at 50 °C for 15 minutes, TLC monitored, reaction was complete. The reaction was slowly poured into ice-cold saturated aqueous NaHC03solution, waited until no more bubbles were coming out, pH test was weakly basic. Extracted with ethyl acetate 3 times, dried over MgS04, filtered and the filtrate was concentrated, purified by flash column to give about 420 mg of intermediate 52-A.

[0814] Step b: To a flask containing 200 mg (1 eq) of intermediate 52-A was added 10 mL of super dry DMF, ice bath, added sodium hydride (50 mg, 1.5 eq), over 15 minutes, added iodomethane (65 μL, 1.2 eq), room temperature for about 2 hours, TLC monitored, reaction was complete. The reaction was poured into saturated aqueous NH4C1 solution, extracted with ethyl acetate 3 times, dried over MgS04, filtered and the filtrate was evaporated to dryness to give about 200 mg of intermediate 52-B, which was used in the next step without purification.

[0815] Step c: To a flask containing intermediate 52-B was added 20 mL of super dry tetrahydrofuran, added 9-borabicyclo[3,3, l]-nonane (9-BBN, 420 mg, 2.2 eq), refluxed for about 5 hours under nitrogen protection, TLC monitored, reaction was complete. The reaction was poured into saturated aqueous NaCl solution, extracted with ethyl acetate 3 times, dried over MgS04, filtered and the filtrate was concentrated, purified by flash column to give about 120 mg of intermediate 52-C.

[0816] Steps d-f were performed according to the same synthetic procedure as compound 46-1, except that intermediate 52-C was used in place of intermediate 46-C.

[0817] Compound 52-1. 1H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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] + .

[0818] Example 55

[0819] 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]imidazol-6-yl)-2-oxo-2,3-dihydro-1H- imidazol-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(tetrahydro- 2H-pyran-4-yl)-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 53)

[0820] The synthesis of Compound 53 was carried out according to the procedure of Compound 1, except that intermediates 45-D and G9 were used instead of intermediates 1-D and C9, respectively. 1H NMR (500 MHz, CDC13, major isomer of 5: 1 rotamers) 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 = 6.5), 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-MS m / z: 878.6 [M+H] + .

[0821] Example 56

[0822] 3-[(1S,2S)-1-[2-[(S)-3-[3-(2,3-dihydrobenzo[d]imidazo[2,1-b]thiazol-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]pyridine-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 54-1)

[0823] The synthesis of Compound 54-1 was carried out according to the procedure of Compound 49-1, except that 2-chloro-5-bromobenzothiazole and ethanolamine were used instead of 5-bromo-2-chloro-1H-benzo[d]imidazole and N-methylethanolamine, respectively.

[0824] Intermediate 54-C. 1H NMR (500 MHz, CDC13) δ 7.09 (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] + .

[0825] Intermediate 54-D. 1 H NMR (500 MHz, CDC13) δ 7.28 (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, 1H), 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] + .

[0826] Compound 54-1. 1 H NMR (500 MHz, CDC13) δ 7.28 (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, 1H), 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] + .

[0827] Example 57

[0828] 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-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-methyl-4,5-dihydrobenzo[f][1,4]oxazepine -3(2H)-one (Compound 55-1)

[0829] Step a: 4-bromo-2-hydroxybenzaldehyde (1.0 g, 4.97 mmol) was dissolved in 20 mL DMF, tert-butyl bromoacetate (870 μL, 5.97 mmol), anhydrous potassium carbonate (413 mg, 9.95 mmol) were added, and the mixture was heated and stirred at 70 °C for 5 h. The reaction was added to water, extracted with ethyl acetate for 3 times, the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give 1.41 g of intermediate 55-A.

[0830] Step b: Intermediate 55-A (1.41 g, 4.47 mmol) was dissolved in 20 mL of methanol, methylamine ethanol solution (m / v = 30%, 700 μL) was added, and the mixture was stirred at room temperature overnight. Then sodium borohydride (203 mg, 5.37 mmol) was added to the reaction, and the mixture was stirred at room temperature for 2 h. Water was added to the reaction, which was concentrated under reduced pressure, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give 291 mg of intermediate 55-B.

[0831] Step c: Intermediate 55-B (291 mg, 0.88 mmol) was dissolved in 5 mL of 1,4-dioxane, hydrochloric acid / dioxane solution (4 M, 375 μL, 7.05 mmol) was added, and the mixture was heated and stirred at 50 °C overnight. Then the reaction was evaporated to dryness, the residue was dissolved in 5 mL of DMF, and HATU (370 mg, 0.97 mmol) and DIPEA (770 μL, 4.42 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction, which was extracted with ethyl acetate for 3 times, the organic phases were combined, washed with saturated sodium chloride solution for 3 times, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give 155 mg of intermediate 55-C. 1H NMR (500 MHz, CDC13) δ 7.22 (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] + .

[0832] The synthesis of compound 55-1 was carried out according to the procedure for compound 46-1, except that intermediate 55-C was used instead of intermediate 46-C as the starting material.

[0833] Intermediate 55-D. 1 H NMR (500 MHz, CDC13) δ 7.34 (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] + .

[0834] Compound 55-1. 1 H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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] + .

[0835] Example 58

[0836] 3-[(1S,2S)-1-[2-[(S)-3-[3-(benzo[d]imidazo[2,1-b]thiazol-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]pyridine-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 56-1)

[0837] Step a: 5-bromobenzo[d]thiazol-2-amine (1 g, 1 eq), chloroacetaldehyde (822 mg, 2.4 eq), triethylamine (883 mg, 2 eq) were added into 20 mL anhydrous ethanol, heated with stirring at 80 °C for 16 h, the reaction solution was cooled, 50 mL water was added to the reaction solution, extracted with ethyl acetate for 3 times, combined organic phase, washed with saturated brine for 3 times, filtered, the filtrate was evaporated under reduced pressure, the residue was separated by flash column chromatography, eluted with petroleum ether-ethyl acetate solvent system, 370 mg solid was obtained, which was intermediate 56-C, yield 33%. 1 H NMR (500 MHz, CDCl3) δ 7.78 (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] + .

[0838] 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.

[0839] Intermediate 56-D. 1 H NMR (500 MHz, CDCl3) δ 8.11 (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] + .

[0840] Compound 56-1. 1 H NMR (500 MHz, CDC13, major isomer of 4: 1 rotamers) 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] + .

[0841] Example 59

[0842] 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]imidazol-6-yl)-2-oxo- 2,3-dihydro-1H-imidazol-1-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]- 1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 57-1)

[0843] Step a: 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.3 g, 1 eq) was added to phosphorus oxychloride (13.2 g, 15 eq) and stirred at 95 °C for 1.5 h until the reaction was completed. The reaction solution was evaporated under reduced pressure, ice water was added to the residue, and dichloromethane was used to extract the solution. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was separated by flash chromatography column eluted with petroleum ether-ethyl acetate solvent system to give 1.1 g of solid, which was intermediate 57-A with a yield of 78%. 1H NMR (500 MHz, CDC13) δ 7.83 (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] + .

[0844] Step b: Intermediate 57-A (500 mg, 1 eq) was added to aminoacetal dimethanol (5.4 g, 25 eq) and stirred at 130 °C for 5 h. The reaction was evaporated under reduced pressure and the residue was separated by flash column chromatography eluted with dichloromethane-methanol solvent system to give 600 mg of solid, intermediate 57-B, in 94% yield. 1 H NMR (500 MHz, CDC13) δ 7.60 (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] + .

[0845] Step c: Intermediate 57-B (100 mg, 1 eq) was added to 799 μL of concentrated hydrochloric acid (concentration of 12 M, 30 eq) and stirred at 100 °C for 8 h. After the reaction was cooled, 50 mL of saturated aqueous sodium bicarbonate solution was added to the reaction under ice bath conditions to neutralize the excess hydrochloric acid. Then it was extracted with ethyl acetate for 3 times and the organic phase was combined and washed with saturated brine for 3 times. It was filtered and the filtrate was evaporated under reduced pressure. The residue was separated by flash column chromatography eluted with petroleum ether-ethyl acetate solvent system to give 60 mg of solid, intermediate 57-C, in 75% yield. 1 H NMR (500 MHz, CDC13) δ 7.62 (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] + .

[0846] The synthesis of compound 57-1 was the same as compound 46-1 except that intermediate 57-C was used instead of intermediate 46-C as the starting material.

[0847] Intermediate 57-D. 1H NMR (500 MHz, CDC13) δ 7.83 (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] + .

[0848] Compound 57-1. 1 H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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] + .

[0849] Example 60

[0850] 3-(1S,2S)-1-[2-(S)-3-[3-(3-cyclopropylimidazo[1,5-a]pyridin-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]pyridine-5-carbonyl]-5-(tetrahydro-2H-pyran-4-yl)- 1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 58)

[0851] The synthesis of Compound 58 was carried out as for Compound 1, except that intermediates 14-D and G9 were used as starting materials instead of intermediates 1-D and C9, respectively.

[0852] 1 H NMR (600 MHz, CDC13, major isomer of 4: 1 rotamers) 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, 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] + .

[0853] Example 61

[0854] 3-[(1S,2S)-1-[2-[(S)-3-[3-(3-cyclopropyl-8-fluoroimidazo[1,5-a]pyridin-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]pyridine-5-carbonyl]-5-(tetrahydro-2H-pyran-4-yl)-1H- indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one (Compound 59)

[0855] The synthesis of Compound 59 was carried out according to the same procedure as for Compound 1, except that intermediates 15-D and G9 were used instead of intermediates 1-D and C9, respectively.

[0856] 1 H NMR (500 MHz, CDC13, major isomer of 4:1 rotamers) 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] + .

[0857] The compounds in the following table were prepared according to the same or similar synthetic procedures as for Compound 1 or Compound 46-1:

[0858] Test Examples

[0859] Test Example 1: Assay of GLP-1 receptor mediated agonistic activity

[0860] (1) Test method

[0861] The compounds were characterized by their effects on the cAMP levels of hGLP-1R / HEK293 cell strain. The human GLP-1 receptor gene (hGLP-1R) was amplified from the cDNA of human colorectal adenocarcinoma cell line NCl-H716 (Chinese Academy of Sciences Cell Bank, #TCHu210) and cloned into the HA-pcDNA3.1 vector (Addgene, #128034) with the HA-tag at the N-terminus of hGLP-1R. The hGLP-1R / HA-pcDNA3.1 plasmid was transfected into HEK293 cells to construct the hGLP-1R / HEK293 stable cell strain. The hGLP-1R / HEK293 cells were digested, centrifuged and resuspended with culture solution (DMEM + 0.2% BSA, m / v), and the cell density was adjusted to 2x10 5 6 cells / mL, and 5 μL (1x10 3 6 cells) were added to each well of a 384-well plate. The compounds were dissolved in DMSO to prepare a 10 mM stock solution, and the experiment was started at a concentration of 100 μM, with 10-fold gradient dilution, a total of 7 dilution points, and the 8th point being DMSO. 2 μL of the test compound at different concentrations was added to 98 μL of culture solution, and after shaking to mix, 5 μL was added to the 384-well plate (final concentration of test compound 0-100 nM, final concentration of DMSO 1% v / v), and incubated in an incubator (37°C, 5% CO2) for 30 min in the dark, after which 10 μL of cAMP detection reagent (LANCE Ultra cAMP Detection Kit, PerkinElmer, #TRF0264) was added and mixed well, and reacted for 1 h at room temperature in the dark. After the reaction was completed, the HTRF signal was read using an Envision 2104 multifunctional microplate reader. All samples were tested in triplicate, and the ratio of the signal 665 nm to the signal 620 nm was calculated for each single well using the formula Ratio = Signal 665 nm / Signal 620 nm. The HTRF signal ratio and the corresponding compound concentration were analyzed and processed using GraphPad Prism 8 software, and the EC 50 values of the compounds were calculated by S-type dose-response curve fitting.

[0862] (2) Reference compounds

[0863] The chiral carbon atom on the dimethyltetrahydropyran substituent in the chemical structure of LY3502970 is in the S-configuration. When this chiral center is not separated, the R-configuration isomer also exists, and LY3502970 is a racemic mixture at this time. In the present application, LY3502970 and its racemic mixture are used as reference compounds.

[0864] (3) Activity test results

[0865] The activities of the compounds are shown in Table 1, in which "A" represents 0 < EC 50 ≤ 1 nM, and "B" represents 1 < EC 50 ≤ 10 nM. It can be seen that the compounds of the present application can activate the hGLP-1 receptor at the nanomolar level, and some of the compounds have activities comparable to the positive control LY3502970 or its racemic mixture, showing good activity.

[0866] Table 1: Effect of the compounds of the present application on the cAMP level of the hGLP-1R / HEK293 cell strain

[0867] Table 1-1: EC values of the compounds for activating the hGLP-1R cAMP signal 50

[0868] Table 1-2: Comparison of the structures and activities of the reference compounds and the compounds of the present application

[0869] The present application has carried out systematic structural modification on the B ring in general formula (I), including in-depth exploration of multiple dimensions such as ring size, shape, hybridization mode, annulation mode, type and position of heteroatoms, and full optimization of the substituents on the ring. The data in Tables 1-1 and 1-2 show that the compounds of the present application exhibit strong agonistic activity at the nanomolar to sub-nanomolar level for the hGLP-1R, and the activities of many compounds are significantly higher than those of the reference compounds with similar structures. The above results show that the structural changes of the B ring, even minor adjustments, can significantly affect the biological activity of the compounds, thereby embodying the unexpected technical effects of the structural modification carried out in the present application.

[0870] Evaluation of the agonistic effect of the compounds in Test Example 2 on the β-arrestin pathway

[0871] (1) Test method

[0872] ​The recruitment of β-arrestin 1 and β-arrestin 2 proteins after the compound binds to GLP-1R is detected using the Promega NanoBiT protein-protein reaction system to characterize the agonistic effect of the compound on the β-arrestin pathway. The NanoBit protein-protein reaction system is a two-subunit system based on NanoLuc luciferase, which can be used to detect intracellular protein interactions. The LgBiT (17.6 kDa) and SmBiT (11 amino acids) subunits are respectively fused to the target protein, and when the target protein interacts, the two subunits are in close proximity to form a catalytically active enzyme that can catalyze the luminescence of luciferase substrates.

[0873] First, the human GLP-1R gene is linked to the N-terminus of LgBit, and the β-arrestin 1 / 2 gene is cloned to the C-terminus of SmBit, and the fusion protein is introduced into the pcDNA3.0 vector to construct plasmids that can express 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 are co-transfected into HEK293 cells at a ratio of 1 μg plasmid / 2×10 6 5 The cells are then added to a 96-well white plate at a density of 4×10

[0874] After 20 hours, the liquid in the wells is discarded, 40 μL of fresh culture solution (DMEM+0.2% BSA, m / v) is added, followed by 10 μL of Nano-Glo Live Cell detection solution (Promega, #N2011), and then the cells are incubated in an incubator for 10 min. The compounds are dissolved in DMSO to prepare a 10 mM stock solution, and in the experiment, the concentration is started at 100 μM, and after 10-fold gradient dilution, 3 μL of different concentrations of the test compound is added to 97 μL of culture solution (the final concentration of GLP-1 is 0-10 μM, the final concentration of the remaining compounds is 0-100 μM, and the final concentration of DMSO is 1%, v / v). After incubating the cells for 10 min, 25 μL of culture solution containing the compound is added to each well, and incubated at room temperature for 5 min, and then the Envision2104 multifunctional microplate luminometer (PerkinElmer) is used to detect the fluorescence signal. All samples are tested in triplicate, and the fluorescence signal ratio and corresponding compound concentration are analyzed and processed using GraphPad Prism 8 software, and the EC 50 ​Values.

[0875] (2) Test Results

[0876] As shown in Figures 1 and 2, the agonistic activity of native GLP-1 on the β-arrestin 1 and β-arrestin 2 pathways were EC 50 = 147.4 nM and 135.7 nM, while LY3502970, compound 6-1, compound 11-1, compound 15-1, and compound 96-1 did not activate the β-arrestin 1 or β-arrestin 2 pathways. In combination with the data presented in Table 1, it is shown that the compounds of the present application are G protein-biased agonists.

[0877] Preliminary evaluation of oral absorbability of the test compounds

[0878] In order to investigate the oral absorbability of the compounds and select the compounds for more detailed pharmacokinetic evaluation, the present application uses a research method of first testing the plasma drug concentration of the compounds after oral administration to mice for 1 and 4 hours for preliminary evaluation.

[0879] (1) Drug preparation

[0880] The test drug is dissolved in 2:2:96 (V / V / V) DMSO / Tween 80 / 0.5% (m / V) methyl cellulose A4M aqueous solution, and is prepared into the target concentration according to the administration dose and administration volume. Oral (PO) administration, administration volume is 10 mL / kg, administration dose is 10 mg / kg.

[0881] (2) Experimental method

[0882] Male ICR rats weighing 30-38 g, 3 in each group, fasting for 12 h before the experiment, free drinking water, and unified feeding 4 h after administration. 30-40 μL of blood was taken from the jugular vein or mandibular vein 1 and 4 h after intragastric administration, and was placed in an anticoagulant tube containing EDTA-K2. After whole blood collection, it was temporarily stored in an ice water bath, and was centrifuged at 11000 rpm for 5 min within 30 min, and then the plasma was separated and frozen at -70°C in a refrigerator for testing. The drug concentration in the sample was quantitatively detected by LC-MS / MS method.

[0883] (3) Test Results

[0884] As can be seen from Table 2, 1 and 4 hours after oral administration at the same dose (10 mg / kg), the present compounds have higher blood drug concentrations than the LY3502970 racemate, indicating better oral absorbability.

[0885] Table 2: Plasma drug concentration of the compounds after oral administration to mice (average value; N = 3)

[0886] Test Example 4 Mouse Pharmacokinetics

[0887] (1) Drug Preparation

[0888] The drug to be tested was dissolved in 2:2:96 (V / V / V) DMSO / Tween 80 / 0.5% (m / V) methyl cellulose A4M aqueous solution to prepare a target concentration according to the dosage and volume of administration. Intravenous (IV) administration was performed with a volume of 5 mL / kg. Oral (PO) administration was performed with a volume of 10 mL / kg.

[0889] (2) Experimental Method

[0890] Male ICR mice weighing 30-38 g were used, with 3 mice in each group. The mice were fasted for 12 h before the experiment, and were allowed to drink water freely. Four hours after administration, all the mice were fed uniformly. For the IV group, the mice were 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 h after administration. For the PO group, the mice were administered via gavage, and blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 h after administration. At the above time points, 30-40 μL of blood was collected from the jugular vein or the mandibular vein, and was placed in an anticoagulant tube containing EDTA-K2. After the whole blood was collected, it was temporarily stored in an ice water bath, and was centrifuged at 11000 rpm for 5 min within 30 min. The plasma was separated, and was then frozen at -70°C until testing. The drug concentration in the sample was quantitatively detected using LC-MS / MS. The WinNonlin software was used to calculate the relevant pharmacokinetic parameters T max , C max , AUC 0-∞ , t 1 / 2 , etc.

[0891] (3) Test Results

[0892] As can be seen from Table 3, after oral administration at the same dose (10 mg / kg), the compound of the present application has a higher blood drug concentration, oral exposure, and oral bioavailability than LY3502970, and thus has better pharmacokinetic properties.

[0893] Table 3: Plasma pharmacokinetic parameters of the compounds after oral and intravenous administration in mice (average value; N=3)

[0894] Note: C max , maximum blood drug concentration; T max , time to peak drug concentration; AUC 0-t , area under the curve of the drug-time curve from zero to the last sampling time point; CL, plasma clearance rate of the drug; V ss , distribution volume of the drug at steady state; t 1 / 2, clearance half-life; F, oral bioavailability; -, not calculated.

[0895] Dietary inhibition experiment of Test Example 5

[0896] (1) Experimental animals

[0897] Genetically engineered hGLP-1R gene knock-in mice were purchased from Shanghai South Model Organism Technology Co., Ltd. The experimental animals were all raised in the SPF level environment of the National Compound Sample Library Animal Room, with a temperature of 24 ± 2°C, a relative humidity of 40-60% RH, an air cleanliness of level 7, and a day-night alternating time of 12h / 12h; continuously supplied with Co60 radiation sterilized whole grain feed (Shanghai Shilin Biotechnology Co., Ltd., mouse maintenance feed), and free intake; and supplied with tap water (sterilized by high-pressure steam) for free intake. The cage was a transparent polyetherimide cage box (Suzhou Fengshi Experimental Animal Equipment Co., Ltd., CP-8 type mouse cage), the bedding was corn cob (Dezhou Gumeng Agricultural Technology Co., Ltd., sterilized by high-pressure steam), 3-5 animals per cage, and the cage card was marked with the IACUC approval number, experiment number, experiment start time, principal investigator, experiment personnel, animal source, group, and animal number, etc. The animal use method of this experiment was approved by the IACUC committee of Shanghai Institute of Pharmaceutical Industry.

[0898] (2) Drug preparation

[0899] The test drug was dissolved in a 2:2:96 (V / V / V) DMSO / Tween 80 / 0.5% methyl cellulose A4M solution, and the target concentration was prepared according to the dose and volume of the drug. The oral administration volume was usually 10 mL / kg.

[0900] (3) Experimental method

[0901] hGLP-1R transgenic mice, 6-8 per group, were raised in a single cage, fasted for 6 hours before the experiment, and given the prepared test drug by gavage at the time of entering the night cycle (7:00 PM), and the blank control group was given the same volume of the above DMSO / Tween 80 / 0.5% methyl cellulose A4M solution, and then given food. The food weight of each cage was measured at 0, 3, 6, 12 (entering the day cycle 7:00 AM), and 24 hours after administration, and the food intake of the mice was calculated.

[0902] (4) Experimental results

[0903] As shown in Figure 3, the positive control LY3502970 and the compounds 6-1 and 11-1 of the present application can significantly inhibit the food intake of the test 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 is slightly lower than that of LY3502970.

[0904] As shown in Figure 6, the effects of the compound 15-1 of the present application, the positive control LY3502970 and the compound Ref-3 on the food intake of mice within 24 hours after single oral administration. It can be seen that the food intake inhibition effect of compound 15-1 at a dose of 0.3 mg / kg is significantly better than that of LY3502970 at 1 and 0.3 mg / kg, and also better than that of Ref-3 at 1 and 0.3 mg / kg. The food intake inhibition effect of compound 15-1 at a dose of 1 mg / kg is even better.

[0905] As shown in Figure 7, the food intake inhibition effect of the compound 15-1 of the present application at a dose of 0.1 mg / kg is significantly better than that of LY3502970, compound Ref-1 and compound Ref-4 at the same dose after oral administration to mice within 24 hours. The better appetite suppression effect of compound 15-1 is consistent with its better oral pharmacokinetic properties.

[0906] As shown in Figure 8, the food intake inhibition effect of the compound 96-1 of the present application at a dose of 1 mg / kg is significantly better than that of compound Ref-5 at the same dose after oral administration to mice within 24 hours.

[0907] Test Example 6 Oral glucose tolerance test (OGTT)

[0908] (1) Drug preparation

[0909] The test drug was dissolved in a 2:2:96 (V / V / V) DMSO / Tween 80 / 0.5% methyl cellulose A4M solution, and the target concentration was prepared according to the administration dose and administration volume. The oral administration volume is usually 10 mL / kg.

[0910] (2) Experimental method

[0911] hGLP-1R transgenic mice, 5-8 per group, were fasted overnight before the experiment, and the tail blood glucose was measured using a blood glucose meter. After the start of the experiment, the mice were given the prepared test drug by gavage, and the blank control group was given the same volume of the above DMSO / Tween 80 / 0.5% methyl cellulose A4M solution. Wait for 60 or 300 min, measure the blood glucose again as the 0-point blood glucose, then immediately give 2 g / kg of glucose by gavage, and measure the blood glucose at 15, 30, 60 and 90 min after glucose administration.

[0912] (3) Experimental results

[0913] As can be seen from FIG. 4 and FIG. 5, the compounds 6-1 and 11-1 of the present application can effectively and dose-dependently reduce the blood glucose level and the area under the curve (AUC) of the blood glucose in mice, thus having good potential for treating diabetes.

[0914] FIG. 9 and FIG. 10 show the changes of the blood glucose level and AUC after the test compounds are administered 5 hours in advance and the glucose (2 g / kg) is administered by gavage at time point 0. As can be seen, within 90 min after the sugar challenge, the compound 15-1 of the present application can significantly inhibit the increase of the blood glucose level at the oral doses of 0.01 and 0.1 mg / kg. Compared with the blank control group, the glucose-lowering amplitude calculated by AUC reaches 42% and 55% respectively at the two doses, which reflects the strong and persistent glucose-lowering effect after single administration. At the same time, the glucose-lowering amplitude of the compound 15-1 is slightly greater than that of the reference compound Ref-1 (36% and 50% respectively) at the same dose, which shows better potential for treating diabetes.

[0915] Test Example 7 Cell Membrane Permeability

[0916] (1) Materials and Reagents

[0917] (2) Cell Culture

[0918] Caco-2 cells were grown in 10 cm cell culture dishes with MEM medium (containing 10% FBS) in a 37°C incubator with 5% CO2 concentration and 95% humidity. When the cells grew to 80-90% confluence, the cells were digested with 0.25% trypsin (containing EDTA); the digested cells were inoculated in Transwell-24 well plates at a density of 2 x 10 5 cells / mL, with a volume of 200 μL / well, and the lower layer was added with MEM medium (containing 10% FBS) at a volume of 800 μL / well. The cells were cultured in a 37°C carbon dioxide incubator with 5% CO2 concentration and 95% humidity. The medium was replaced every other day, and the cells were continuously cultured for 21 days for the in vitro permeability and P-gp substrate study of the test compounds.

[0919] (3) In vitro Permeability Experiment

[0920] 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.

[0921] (4) Analytical instruments and data acquisition software

[0922] 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.

[0923] Data acquisition was performed using AB Sciex's Analyst V1.6.3 software.

[0924] (5) Data Processing and Analysis

[0925] The apparent permeability coefficient (P) is calculated using the following formula. app (cm / s) and Efflux Ratio (ER).

[0926] 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.

[0927] (6) Test Results

[0928] As shown in Table 4, the apparent permeability coefficients of the compounds of the present application in caco-2 cells are significantly higher than that of the reference compound LY3502970, indicating that the expansion of the ring improves the cell membrane permeability of the compounds. This improvement in the property is consistent with the more optimal oral pharmacokinetic characteristics exhibited by the compounds of the present application.

[0929] Table 4: Apparent permeability coefficients and efflux ratios of compounds in caco-2 cells

[0930] Note: Permeability evaluation criteria: Low permeability, P app ≤ Acyclovir; Moderate permeability, P app between Acyclovir and Minoxidil; High permeability: P app ≥ Minoxidil.

[0931] Test Example 8: Pharmacokinetic evaluation in rats

[0932] (1) Evaluation method

[0933] The drug preparation and experimental method is the same as in Test Example 4, except that SD rats weighing 200-280 g are used instead of ICR mice as experimental animals.

[0934] (2) Evaluation results

[0935] As shown in Table 5, the compound 15-1 of the present application exhibits linear pharmacokinetic characteristics after oral administration to rats at doses of 1.5, 5, 15 and 45 mg / kg, with the blood concentration and oral exposure increasing with increasing dose, and no absorption ceiling (roof effect) being reached. At the same time, compared with the reference compounds Ref-1, Ref-3, LY3502970 and Ref-6, the blood concentration and oral exposure of the compound 15-1 at the same dose (5 mg / kg) are significantly higher, indicating that it has a more optimal oral absorption performance. This characteristic is consistent with the observation in Test Example 5 that the compound 15-1 has a more optimal diet suppression effect. In addition, in combination with the pharmacokinetic data in mice in Table 3, it can be seen that the structural modification of the B ring of the present application, such as adjusting the position of the nitrogen atom in the heteroaryl group, changing the cyclization mode, and introducing a cycloalkyl substituent, has achieved unexpected technical effects in improving the oral absorption performance of the compounds.

[0936] Table 5: Plasma pharmacokinetic parameters of compounds after oral administration to rats (mean value; N=3)

[0937] Notes: a , data from patent WO2025026270; b , data from patent US12234236.

[0938] Test Example 9 Solubility Test

[0939] (1) Test Method

[0940] The test compound was prepared into a stock solution with a concentration of 50 or 100 mg / mL using DMSO as the solvent, and then the stock solution was transferred to a 96-well plate, diluted with phosphate buffered saline (PBS, pH 7.4) to obtain a solution with a concentration of 100 μg / mL, and two duplicate wells were set up for each concentration. The mixed solution was placed in a 37°C water bath shaker for 2 hours to ensure complete dissolution. Subsequently, the solution was centrifuged at 11000 rpm for 5 minutes to precipitate the undissolved substances. The supernatant was filtered through a 0.22 μm filter membrane to remove particulate matter, and then analyzed by LCMS / MS to determine the concentration of the dissolved compound.

[0941] (2) Test Results

[0942] As shown in Table 6, the solubility of the compounds of the present application in PBS solution (pH 7.4) was higher than that of the reference compounds, which is consistent with the better oral pharmacokinetic properties of the compounds of the present application.

[0943] Table 6: Solubility of compounds in PBS solution (pH 7.4)

[0944] Test Example 10 Weight loss experiment on a diet-induced obesity (DIO) mouse model

[0945] (1) Experimental Method

[0946] Forty-week-old hGLP-1R knock-in male mouse mice were fed with high-fat feed (supplier Research Diets, item number D12492) for 4 weeks, and mice with a body weight of about 40 g were selected and randomly divided into cages, 3 mice per cage, 3 cages per group. The compounds were prepared according to the administration dose in a 2:2:96 (V / V / V) DMSO / 0.9% NaCl / 0.5% methylcellulose A4M solution, and the administration volume was 10 mL / kg. The mice were administered intragastrically once a day, and the blank control group was only given an equal volume of solvent. Continuous administration for 21 days, daily measurement of mouse body weight and food intake per cage.

[0947] (2) Data Processing

[0948] All data are expressed as mean ± standard error (mean ± SEM), and graph analysis was performed using Graphpad software. There was a statistically significant difference when p<0.05 (*), a statistically significant difference when p<0.01 (**), and a statistically very significant difference when p<0.001 (***).

[0949] As shown in Figure 11, during the 21-day administration period, the body weight of the blank control group mice continued to increase, while each administration group showed a significant weight loss effect. After 21 days of treatment with the reference compound LY3502970 (1 mg / kg / day), the body weight of the DIO mice decreased by 12.79% compared to the baseline; while compound 15-1 at doses of 0.3 mg / kg / day and 1 mg / kg / day reduced the body weight by 13.44% and 15.13%, respectively. The results show that the compounds of the present application can achieve a weight loss effect better than the reference compound at a lower dose. At the same time, this result is also consistent with the observation in Test Example 5 that compound 15-1 has a more optimal diet suppression effect.

[0950] Discussion:

[0951] 1. Compared with the prior art, one of the structural distinguishing features of the compound of general formula (I) of the present application is that the B ring is expanded from a 5-10 membered monocyclic or bicyclic heteroaryl to an 11-18 membered bicyclic, tricyclic or tetracyclic heteroaryl, or the B ring is modified to a bicyclic or tricyclic heteroaryl substituted with a cycloalkyl. Unexpectedly, after ring expansion and modification, the compounds, whether in the bicyclic, tricyclic or tetracyclic series, still maintain good activity. The activity of many compounds even exceeds that of the reference compound. At the same time, compared with the reference compound, the compounds of the present application have significantly improved oral pharmacokinetic performance, with higher plasma exposure and bioavailability.

[0952] 2. Numerous studies have shown that β-arrestin is involved in the endocytosis and desensitization of GLP-1R, affecting the intensity and duration of its biological effects, and biased agonists do not activate β-arrestin, which can more greatly exert the biological effects of GLP-1R and enhance the efficacy. Therefore, the compounds of the present application are beneficial for preparing more efficient hypoglycemic and weight loss drugs. The results of the OGTT experiment in Test Example 6 confirm this.

[0953] 3. Since the weight loss effect of GLP-1 receptor agonists is mainly related to their diet suppression, as shown by Test Examples 5 and 10, the compounds of the present application have better potential when used to treat overweight / obesity.

[0954] 4. As shown by Test Examples 7 and 9, the cell membrane permeability or solubility of the compounds of the present application is significantly improved, further verifying that the compounds have good oral bioavailability and therefore have more excellent oral pharmacokinetic properties.

[0955] All documents referred to in the present application are incorporated herein by reference as if each were individually incorporated. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding use of the other embodiments. Other embodiments will occur to those skilled in the art upon consideration of this disclosure or can be learned from practice of the application. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, and all changes coming within the meaning and equivalency range of the appended claims are intended to be embraced therein.

Claims

1. A compound of Formula (I), or a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof: wherein, A ring is 6-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; B ring is selected from the group consisting of bicyclic or tricyclic heteroaryl groups represented by the following formulae (X-1) to (X-7): wherein, Z1is 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; Z5and Z6are each independently selected from the group consisting of CH2or 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 group consisting of 0, 1, 2; D ring is C3-C8cycloalkyl or haloC3-C8cycloalkyl; is saturated, partially saturated, or aromatic; preferably, is an aromatic ring; are each independently a single or double bond; C ring is 4-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, said heterocycloalkyl optionally substituted with C1-C6alkyl; 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; Y, Z are each CH.

2. The compound of claim 1, wherein B ring is selected from the following formulae (X-1-1) to (X-9-1): wherein, Z2is N or CH; Z5and Z6are each independently selected from the group consisting of CH2or 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 group consisting of 0, 1, 2; D ring is C3-C8cycloalkyl or haloC3-C8cycloalkyl; are each independently a single or double bond.

3. The compound of claim 1, wherein B ring is selected from the following groups: The B ring group is optionally substituted with halogen, or C1-C3alkoxy.

4. The compound of claim 1, wherein A ring 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 formula (I-c), (I-d), (II-e)~(II-g), (III-c) or (III-d): wherein, 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 group consisting of 1, 2, 3; Z1is 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, Z6are each independently selected from the group consisting of CH2or 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 group consisting of 0, 1, 2; is saturated, partially saturated, or aromatic; preferably, is an aromatic ring; D ring is C3-C8cycloalkyl or haloC3-C8cycloalkyl; are each independently a single or double bond.

8. The compound of claim 1, wherein The compound is selected from the following formula (I-c-1), (I-d-1), (II-e-1), (II-e-2), (II-f-1), (II-f-2), (II-g-1), or (III-c-1): wherein, 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 group consisting of 1, 2, 3; Z2is 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 group consisting of 0, 1, 2; D ring is C3-C8cycloalkyl or haloC3-C8cycloalkyl; are each independently a single or double bond.

9. The compound of claim 1, wherein The compound is selected from the group consisting of:

10. A pharmaceutical composition, characterized by, comprising: (i) a compound of any one of claims 1 to 9, or a stereoisomer thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, and; (ii) a pharmaceutically acceptable carrier.

11. Use of a compound of any one of claims 1 to 9 or a pharmaceutical composition of claim 10, characterized in that, for the preparation of a GLP-1 receptor agonist, or for the preparation of a medicament for the prevention and / or treatment of a disease or condition associated with a dysregulation of the GLP-1 receptor signaling pathway.

12. The use of a compound or pharmaceutical composition according to claim 11, wherein The disease or condition 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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