Benzimidazole compound as well as preparation method, composition and application thereof

Abstract

The invention provides a benzimidazole compound as well as a preparation method, a composition and application thereof. Specifically provided is a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. The compound provided by the invention has one or more of the following advantages: (1) novel structure, (2) good GLP-1 receptor agonistic activity, (3) good metabolic stability, (4) good GLP-1 receptor specificity, and (5) good medicinal safety. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a benzimidazole compound, a preparation method thereof, a composition and uses thereof. Background Art

[0002] Diabetes is a metabolic disease characterized by hyperglycemia, which is characterized by high blood glucose levels caused by defects or deficiencies in insulin production, insulin action, or both, and can further lead to chronic damage or dysfunction of organs and tissues such as the eyes, kidneys, heart, blood vessels, nerves, etc. Depending on the pathogenesis, diabetes is divided into type I and type II. Type I diabetes (T1D) develops when the body's immune system destroys pancreatic beta cells, which are the only cells in the body that produce insulin, a hormone that regulates blood glucose levels. Treatment of type I diabetes mainly involves injecting or pumping insulin. Type II diabetes (commonly referred to as T2DM) often begins with insulin resistance or when pancreatic beta cell function declines, resulting in insufficient insulin production to maintain an acceptable glucose level, and is the main type of diabetes.

[0003] Currently, there are different pharmacological methods for treating hyperglycemia and T2DM (Diabetes Care 2014, 37, 1367 - 1374). These drugs can be classified into six major categories according to different mechanisms of action: (1) Biguanides (such as metformin), which mainly act by reducing hepatic glucose production, and are often limited in further use due to gastrointestinal disorders and lactic acidosis. (2) α-Glucosidase inhibitors (such as acarbose), whose mechanism of action is to reduce intestinal glucose absorption, but can cause gastrointestinal disorders. (3) Thiazolidinediones (such as pioglitazone and rosiglitazone), which mainly act on peroxisome proliferator-activated receptor γ in the liver, muscle, and adipose tissues, regulate lipid metabolism, and enhance the response of these tissues to insulin action. However, the frequent use of such drugs can induce edema, anemia, and weight gain. (4) Insulin, either alone or in combination with drugs with other mechanisms of action, can lead to the risks of hypoglycemia and obesity. (5) Sodium-glucose linked transporter co-transporter-2 (SGLT-2) inhibitors, such as dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, etc., which mainly inhibit glucose reabsorption in the kidneys, thereby reducing blood glucose levels, but such drugs may be associated with ketoacidosis and urinary tract infections. (6) Insulin secretagogues, which enhance insulin secretion by acting on pancreatic β cells, including sulfonylureas [glipizide, glimepiride, glyburide], meglitinides [such as nateglidine, repaglinide], dipeptidyl peptidase-4 (DPP-IV) inhibitors [sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxagliptin], glucagon-like peptide-1 receptor (GLP-1R) agonists [such as liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide].Sulfonylureas and meglitinides have limited efficacy and tolerance, often inducing hypoglycemia and causing weight gain. DPP-IV inhibitors have limited efficacy, while GLP-1 receptor agonists are all macromolecular peptide drugs, usually administered by subcutaneous injection. Although oral semaglutide developed by Novo Nordisk was launched in 2019, it is subject to various adverse limitations such as administration time, dose, and gastrointestinal disturbances, and has low oral bioavailability.

[0004] T2DM is most commonly associated with hyperglycemia and insulin resistance, and is also related to other diseases including obesity, coronary artery disease, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, dyslipidemia, hypertension, hyperinsulinemia, and non-alcoholic fatty liver disease (NAFLD). Bariatric surgery, as a highly effective treatment for eliminating obesity, is expensive and risky, while pharmacological interventions are usually less effective and associated with significant side effects. Therefore, weight-loss drugs with higher efficiency, fewer side effects, and convenient administration are urgently needed. NAFLD is the hepatic manifestation of metabolic syndrome, including steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. The severity of NAFLD / NASH is based on the presence of lipids, inflammatory cell infiltration, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with steatosis progress to NASH, most do. Except for GLP-1 receptor agonists and SGLT2 inhibitors, other diabetes-related drugs have limited efficacy and fail to address β-cell function decline and related obesity. GLP-1 receptor agonists have drugs approved for the treatment of obesity, and currently, there are also various T2DM-related indications in clinical trials.

[0005] The GLP-1 receptor belongs to the G protein-coupled receptor family B, and its natural agonist ligand GLP-1 is an incretin with a length of 30 amino acids secreted by intestinal L cells in response to food intake. GLP-1 stimulates insulin secretion, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates β-cell proliferation in a physiological and glucose-dependent manner. In non-clinical trials, GLP-1 promotes sustained β-cell function by stimulating gene transcription important for glucose-dependent insulin secretion and by promoting β-cell neogenesis (Biodrugs. 2003; 17(2): 93-102). In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose levels. By stimulating glucose-dependent insulin secretion in the pancreas, it leads to increased peripheral glucose uptake. At the same time, it inhibits glucagon secretion, resulting in a decrease in hepatic glucose output, delays gastric emptying, and slows down small intestine motility to delay food absorption. In people with T2DM, the normal postprandial rise in GLP-1 does not occur or is reduced (Diabetes. 2001. 50; 609-613). GLP-1 receptor agonists improve glycemic control in T2DM patients by reducing fasting and postprandial glucose (FPG and PPG) mainly through three pharmacological activities: (i) increased glucose-dependent insulin secretion (improved first and second phases), (ii) glucagon inhibitory activity under hyperglycemic conditions, (iii) delayed gastric emptying rate, resulting in delayed absorption of dietary-derived glucose (Physiol. Rev. 2007, 87, 1409; Nat. Rev. Endocrinol. 2012, 8, 728).

[0006]

[0007] Currently, there are no small molecule GLP-1 drugs on the market. Among the GLP-1R small molecule agonists in clinical research, only PF-06882961, TTP273, and TTP-054 have announced early and mid-stage clinical data. PF-06882961 has good safety in clinical phase I, and preliminary efficacy in reducing blood glucose and body weight has been observed (a 1.2% reduction in HbA1c with 50 mg bid), and the safety tolerance is good. TTP054 has been discontinued because it is not as good as TTP273. However, the phase II study completed by TTP273 in 2017 showed good safety. Although the reduction in glycated hemoglobin HbA1c reached statistical significance (a 0.6% reduction with 150 mg bid, p < 0.001), it was not as expected by the company (a 7.5-10% reduction in HbA1c compared to baseline). Therefore, in the development of small molecule GLP-1 drugs, it is still very necessary to obtain hypoglycemic drugs that, like liraglutide and empagliflozin, have potential cardiovascular benefits or greater cardiovascular safety. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the defect that the types of GLP-1 receptor agonists are limited in the prior art. For this purpose, a benzimidazole compound, a preparation method thereof, a composition thereof and uses thereof are provided. The compounds of the present invention satisfy one or more of the following advantageous effects: (1) novel structure, (2) good GLP-1 receptor agonist activity, (3) good metabolic stability, (4) good GLP-1 receptor specificity, and (5) good pharmaceutical safety.

[0009] The present invention provides a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof;

[0010]

[0011] In formula (I),

[0012] R 1-1 is hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by one or more R 1-1-1 ;

[0013] Each R 1-1-1 is independently C6-C 10 aryl;

[0014] R 2 is one of the following cases (i) or (ii):

[0015] Case (i): R 2 is C1-C6 alkyl substituted by one or more R 2-1 ;

[0016] Each R 2-1 is independently -CN or halogen;

[0017] Case (ii): R 2 is C1-C6 alkyl substituted by one or more R 2-2 ;

[0018] Each R 2-2 is independently -CN, halogen or 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are selected from one or more of N, S and O, and the number is 1, 2, 3 or 4;

[0019] R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl or C1-C6 alkyl substituted by one or more R 4-2 ;

[0020] Each R 4-2 is independently a halogen;

[0021] When R 2 is in case (i), L 1 is

[0022] a single bond or a double bond;

[0023] When it is a single bond, X 1 is CH or N; When it is a double bond, X 1 is C;

[0024] Each X 2 and X 3 are each independently CR X-2 or N;

[0025] Each R X-2 is independently hydrogen or a halogen;

[0026] n is 0, 1 or 2;

[0027] Each R X-1 is independently a halogen;

[0028] Each X 4 is independently selected from one of O, S and NH;

[0029] When R 2 is in case (ii), L 1 is

[0030] a single bond or a double bond;

[0031] When it is a single bond, each Y 1 is independently CH or N; When it is a double bond, each Y 1 is C;

[0032] Each Y 8 is independently CH or N;

[0033] Each Y 2 、Y 3 、Y 4 、Y 5 and Y 6 are each independently CR Y-2 or N;

[0034] Each R Y-2 is independently hydrogen or a halogen;

[0035] Each Y 7 is independently selected from one of a chemical bond, O, S, and NH;

[0036] m is 0, 1, or 2;

[0037] Each R Y-1 is independently a halogen;

[0038] R Y-3 , R Y-4 , R Y-5 and R Y-6 Among them, any two groups (such as R Y-3 and R Y-6 , R Y-3 and R Y-5 , R Y-4 and R Y-5 , R Y-4 and R Y-6 , R Y-3 and R Y-4 , R Y-5 and R Y-6 ) are connected together to form -(CH2) p -, and the remaining groups are hydrogen;

[0039] Each R Y-7 , R Y-8 , R Y-9 and R Y-10 are independently hydrogen;

[0040] Or, among R Y-7 , R Y-8 , R Y-9 and R Y-10 , any two groups are connected together to form -(CH2) p -, and the remaining groups are hydrogen;

[0041] p is 1, 2, or 3;

[0042] In formula (II),

[0043] R 1-2 and R 1-3 are independently hydrogen, an alkali metal ion, a C1-C6 alkyl group, or a C1-C6 alkyl group substituted by one or more R 1-2-1 ;

[0044] Each R 1-2-1 is independently a C6-C 10 aryl;

[0045] R 2a is a C1-C6 alkyl group substituted by one or more R 2a-1 ;

[0046] Each R 2a-1 is independently -CN, a halogen, or a 3- to 6-membered heterocycloalkyl group; the heteroatoms in the 3- to 6-membered heterocycloalkyl group are selected from one or more of N, S, and O, and the number is 1, 2, 3, or 4;

[0047] R 3a , R 4a , R 5a , R 6a and R 7a are each independently hydrogen, -CN, a halogen, a C1-C6 alkyl group, an -O-C1-C6 alkyl group, or a C1-C6 alkyl group substituted by one or more R 4a-2 ;

[0048] Each R 4a-2 is independently a halogen;

[0049] L 2 is

[0050] a single bond or a double bond;

[0051] When it is a single bond, Z 1 is CH or N; When it is a double bond, Z 1 is C;

[0052] Each Z 2 and Z 3 are each independently CR Z-3 or N;

[0053] Each R Z-3 is each independently hydrogen or a halogen;

[0054] Each Z 4 is each independently selected from one of O, S, and NH;

[0055] q is 0, 1, or 2;

[0056] Each R Z-1 is each independently a halogen;

[0057] Alternatively, R Z-1 is located at the ortho position of Z 4 , and R Z-1 and Z 4 form a 5- to 6-membered heteroalkenyl group with the carbon atom to which they are attached, and the heteroatoms in the 5- to 6-membered heteroalkenyl group are selected from one or more of N, S, and O, and the number is 1, 2, 3, or 4.

[0058] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are defined as follows. For groups not mentioned, they are the same as those described in any embodiment of the present invention (abbreviated as "in certain embodiments of the present invention").

[0059] In some embodiments, R 2 in the C1-C6 alkyl group substituted by one or more R 2-1 and the C1-C6 alkyl group in the C1-C6 alkyl group substituted by one or more R 2-2 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, ethyl or isopropyl.

[0060] In some embodiments, R 2-1 in which the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0061] In some embodiments, R 2-2 in which the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0062] In some embodiments, R 2-2 in which the heteroatom in the 3-6 membered heteroalkyl group is selected from one or two of N, S and O; the number of heteroatoms in the 3-6 membered heteroalkyl group is preferably 1 or 2; the 3-6 membered heteroalkyl group can be a 3-membered, 4-membered, 5-membered or 6-membered heteroalkyl group; more preferably For example

[0063] In some embodiments, R 3 , R 4 , R 5 , R 6 and R 7 in which the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0064] In some embodiments, R X-1 in which the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0065] In some embodiments, R Y-1 in which the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0066] In some embodiments, R 2a in the C1-C6 alkyl group substituted by one or more R 2a-1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0067] In some embodiments, R 2a-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0068] In some embodiments, R 2a-1 , the heteroatom in the 3-6 membered heteroalkyl is selected from one or two of N, S and O; the number of heteroatoms in the 3-6 membered heteroalkyl is preferably 1 or 2; the 3-6 membered heteroalkyl can be a 3-membered, 4-membered, 5-membered or 6-membered monocyclic heteroalkyl; more preferably For example

[0069] In some embodiments, R 3a , R 4a , R 5a , R 6a and R 7a , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0070] In some embodiments, R Z-1 , the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0071] In some embodiments, R Z-1 and Z 4 form a 5-6 membered heteroalkenyl with the carbon atom to which they are attached. In the 5-6 membered heteroalkenyl, the heteroatom is selected from one or two of N, S and O; the number of heteroatoms in the 5-6 membered heteroalkenyl is preferably 1 or 2; the 5-6 membered heteroalkenyl is more preferably a 5-membered monocyclic heteroalkenyl; the 5-membered monocyclic heteroalkenyl is for example Also for example (The 5-6 membered heteroalkenyl forms a fused ring with the main body through ).

[0072] In some embodiments, R Y-3 , R Y-4 , R Y-5 and R Y-6 , in R Y-3 and R Y-6 form -(CH2) p -, R Y-4 and R Y-5 are hydrogen;

[0073] R Y-3 and R Y-5 form -(CH2) p (-), R Y-4 and R Y-6 are hydrogen;

[0074] RY-4 and R Y-5 form -(CH2) p -, R Y-3 and R Y-6 is hydrogen.

[0075] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof as shown below:

[0076]

[0077] R 1-1 , R 2 , L 1 , R 3 and R 5 are as defined above.

[0078] In some embodiments, in formula (I-1), R 1-1 is as defined above;

[0079] When R 2 is in case (i), L 1 is

[0080] a single bond or a double bond;

[0081] When it is a single bond, X 1 is CH; When it is a double bond, X 1 is C;

[0082] Each X 2 and X 3 is independently CR X-2 or N;

[0083] Each R X-2 is independently hydrogen;

[0084] n is 0, 1 or 2;

[0085] Each R X-1 is independently halogen;

[0086] X 4 is O;

[0087] When R 2 is in case (ii), L 1 is

[0088] a single bond or a double bond;

[0089] When it is a single bond, each Y 1 is independently CH or N; When it is a double bond, each Y 1 is independently C;

[0090] Each Y 8 is independently N;

[0091] Each Y 2 、Y 3 、Y 4 、Y 5 and Y 6 are independently CR Y-2 or N;

[0092] Each R Y-2 is independently hydrogen or halogen;

[0093] Each Y 7 is independently selected from one of a chemical bond, O, S, and NH;

[0094] m is 0, 1, or 2;

[0095] Each R Y-1 is independently halogen;

[0096] R Y-3 、R Y-4 、R Y-5 and R Y-6 Among them, any two groups (for example, R Y-3 and R Y-6 、R Y-3 and R Y-5 、R Y-4 and R Y-5 、R Y-4 and R Y-6 、R Y-3 and R Y-4 、R Y-5 and R Y-6 ) are connected together to form -(CH2) p -, and the remaining groups are hydrogen;

[0097] Each R Y-7 、R Y-8 、R Y-9 and R Y-10 are independently hydrogen;

[0098] p is 1, 2, or 3;

[0099] R 3 is hydrogen or halogen;

[0100] R 5-CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4-2 ;

[0101] Each R 4-2 is independently halogen.

[0102] Preferably, R 3 is halogen; R 5 is -CN.

[0103] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof shown as follows:

[0104]

[0105] R 1-2 , R 1-3 , R 2a , L 2 , R 3a and R 5a are as defined above.

[0106] In some embodiments, formula (II-1) is formula (II-1a), formula (II-1b), or formula (II-1c):

[0107]

[0108] Wherein, R 1-2 , R 1-3 , R 2a , Z 2 , Z 3 , Z 4 , q, R Z-1 , R 3a and R 5a are as defined above.

[0109] In some embodiments, in formula (II-1a), formula (II-1b), and formula (II-1c), R 1-2 , R 1-3 and R 2a are as defined above;

[0110] R 3a is hydrogen or halogen;

[0111] R 5a is -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more R 4a-2 ;

[0112] Each R4a-2 is independently a halogen;

[0113] Each Z 2 and Z 3 are each independently CR Z-3 or N;

[0114] Each R Z-3 is independently hydrogen or a halogen;

[0115] Each Z 4 is independently selected from one of O, S, and NH;

[0116] q is 0, 1, or 2;

[0117] Each R Z-1 is independently a halogen; preferably, R 3a is a halogen; R 5a is -CN.

[0118] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-2) or formula (I-3) or a pharmaceutically acceptable salt thereof:

[0119]

[0120] In formula (I-2) and formula (I-3), R 1-1 , R 2 , R 3 , R 5 , X 1 , X 2 , X 3 , X 4 , R x-1 and n are as defined above.

[0121] In some embodiments, in formula (I-2) and formula (I-3), R 1-1 , R 3 , R 5 and X 4 are as defined above;

[0122] R 2 is a C1-C6 alkyl group substituted by one or more -CN;

[0123] is a single bond or a double bond;

[0124] X 1 is CH or C;

[0125] Each X 2 and X 3 are each independently CH or N;

[0126] n is 0.

[0127] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-4) or a pharmaceutically acceptable salt thereof:

[0128]

[0129] R 2 , X 1 , X 2 , X 3 , X 4 , R x-1 and the definitions of n are as described above.

[0130] In some embodiments, in formula (I-4),

[0131] R 2 is C1-C6 alkyl substituted with one or more -CN;

[0132] is a single bond or a double bond;

[0133] X 1 is CH or C;

[0134] Each X 2 and X 3 are each independently CH or N;

[0135] n is 0;

[0136] X 4 is selected from one of O, S, and NH;

[0137] Preferably, in formula (I-4), X 4 is O.

[0138] In some embodiments, in formula (I), R 1-1 is hydrogen.

[0139] In some embodiments, in formula (I), in case (i), R 2 is preferably

[0140] In some embodiments, in formula (I), in case (ii), R 2 is preferably

[0141] In some embodiments, in formula (I), R 3 is F.

[0142] In some embodiments, in formula (I), R 4 is -CN.

[0143] In some embodiments, in formula (I), when R 2 is in case (i), L 1 is

[0144]

[0145] In some embodiments, in formula (I), when R 2 is in case (ii), L 1 is

[0146]

[0147]

[0148] In some embodiments, in formula (II), R 1-2 and R 1-3 are each independently hydrogen.

[0149] In some embodiments, in formula (II), R 2a is In some embodiments, in formula (II), R 3a is F.

[0150] In some embodiments, in formula (II), R 4a is -CN.

[0151] In some embodiments, in formula (II), L 2 is

[0152]

[0153] In some embodiments, the compound represented by formula (I) or formula (II) is any of the following compounds:

[0154]

[0155]

[0156] In some embodiments, the compound represented by formula (I) or formula (II) is any of the following compounds:

[0157]

[0158] The present invention also provides a method for preparing a compound represented by formula (I) as described above, which comprises the following steps: subjecting the compound represented by formula (IV-1) to a substitution reaction with the compound represented by formula (III-1) as shown below to obtain the compound represented by formula (I);

[0159]

[0160] wherein: R 1-1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and L 1 are as defined in any one of the present invention.

[0161] The present invention also provides a pharmaceutical composition, which comprises the compound represented by formula (I) or a pharmaceutically acceptable salt thereof (effective therapeutic amount), or the compound represented by formula (II) or a pharmaceutically acceptable salt thereof (effective therapeutic amount) and a pharmaceutically acceptable carrier.

[0162] The present invention also provides the use of a substance A in the preparation of a medicament for treating and / or preventing cardiometabolic diseases and related diseases, wherein the related diseases are T2DM, insulin resistance, sclerosis, cardiovascular diseases, colitis or addiction; preferably prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, hepatocellular carcinoma, atherosclerosis, coronary artery disease, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, thrombosis, transient ischemic attack, glucose metabolism disorder, impaired fasting glucose condition, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, short bowel syndrome, Crohn's disease, irritable bowel syndrome and polycystic ovary syndrome;

[0163] The substance A is a compound represented by formula (I) or formula (II) as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above.

[0164] The present invention also provides the use of a substance A in the preparation of a medicament for treating or preventing GLP-1-related diseases; the substance A is the same as described above.

[0165] In some embodiments, the GLP-1-related diseases are T2DM, insulin resistance, sclerosis, cardiovascular diseases, colitis or addiction.

[0166] In some embodiments, the GLP-1 related diseases are pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, hepatocellular carcinoma, atherosclerosis, coronary artery disease, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, thrombosis, transient ischemic attack, glucose metabolism disorder, impaired fasting glucose condition, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, short bowel syndrome, Crohn's disease, irritable bowel syndrome, and polycystic ovary syndrome.

[0167] The present invention also provides the use of a substance A in the preparation of a GLP-1 receptor agonist (in vivo or in vitro); the substance A is as described above.

[0168] Term Explanation

[0169] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0170] In the present invention, in the structural fragment it means that this structural fragment is connected to the rest of the molecule through this bond. For example, is cyclopropyl.

[0171] In the present invention, the "-" at the end of a group means that the group is connected to the rest of the molecule through this site. For example, -OH means hydroxyl group.

[0172] In the present invention, the term "one or more" means 1, 2, 3, 4 or 5, for example 1, 2 or 3.

[0173] In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0174] In the present invention, the term "alkyl" means a straight-chain or branched-chain, saturated monovalent hydrocarbon group having a specified number of carbon atoms (for example, C1-C6). Alkyl includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0175] In the present invention, the term "heterocycloalkyl" means a cyclic, saturated monovalent group having a specified number of ring atoms (for example, 3-12 membered, 3-6 membered, 3 membered, 4 membered, 5 membered or 6 membered), a specified number of heteroatoms (for example, 1, 2 or 3), a specified type of heteroatoms (one or more of N, O and S). The heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes but is not limited to: etc.

[0176] The term "heterocycloalkenyl" means a cyclic, unsaturated hydrocarbon group having a specified number of ring atoms (for example, 5-10 membered, 5-6 membered), a specified number of heteroatoms (for example, 1, 2 or 3), a specified type of heteroatoms (one or more of N, O and S), and having one or more (for example, 1, 2 or 3) carbon-carbon sp 2 double bonds, which is monocyclic and non-aromatic. The heterocycloalkenyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkenyl includes but is not limited to:

[0177] In the present invention, the term "aryl" means a cyclic, unsaturated hydrocarbon group having a specified number of carbon atoms (for example, C6-C 10 )), which is monocyclic or polycyclic (for example, 2 or 3). When it is polycyclic, two atoms and one bond are shared between the single rings, and each ring has aromaticity. The aryl is connected to the rest of the molecule through a carbon atom. Aryl includes but is not limited to: phenyl, naphthyl.

[0178] In the present invention, the term "pharmaceutically acceptable excipients" refers to all substances contained in a pharmaceutical preparation except the active pharmaceutical ingredient, and is generally divided into two categories: excipients and additives. For details, reference can be made to Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0179] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0180] The reagents and raw materials used in the present invention are all commercially available.

[0181] The positive and progressive effects of the present invention are as follows: the compounds of the present invention meet one or more of the following effect advantages: novel structure, good GLP-1 receptor agonist activity, good metabolic stability, good GLP-1 receptor specificity, and good pharmaceutical safety. Detailed implementation mode

[0182] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.

[0183] Unless otherwise stated, the raw materials are usually obtained from market sources such as Titan Chemical, Bide Pharmatech, J&K Scientific, Aladdin, Aldrich-sigma, TCI Chemicals, Alfa Aesar, Acros Organics, etc. Commercial solvents and reagents are used without further purification. Certain common abbreviations and acronyms have been used, which may include: AcOH (acetic acid), DCM (dichloromethane), THF (tetrahydrofuran), DMF (N,N'-dimethylformamide), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), EtOAc or EA (ethyl acetate), ACN (acetonitrile), PE (petroleum ether), EtOH (ethanol), MeOH (methanol), IPA (isopropanol), TEA (triethylamine), DIPEA (N,N-diisopropylethylamine), DMAP (4-dimethylaminopyridine), KHMDS (potassium hexamethyldisilazide), NaHMDS (sodium hexamethyldisilazide), LiHMDS (lithium hexamethyldisilazide), NaBH(OAc)3 (sodium triacetoxyborohydride), Boc2O (di-tert-butyl dicarbonate), TFA (trifluoroacetic acid), TsOH (p-toluenesulfonic acid), Pd2(dba)3 [tris(dibenzylideneacetone)dipalladium], Ruphos Pd G2: {[2'-(amino)[1,1'-biphenyl]-2-yl][[2',6'-bis(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride}, X-phos (2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl), G or g (gram), H or h (hour), L or l (liter), mL (milliliter), mg (milligram), RH (relative humidity), RT or rt (room temperature, which is the same as the ambient temperature (about 20 to 25 °C)). The terms "concentrate", "evaporate", and "concentrate in vacuo" mean removing the solvent on a rotary evaporator at a bath temperature below 60 °C under reduced pressure. The term "TLC" refers to thin-layer chromatography, "room temperature or ambient temperature" means a temperature between 18 and 25 °C, "LCMS" refers to liquid chromatography - mass spectrometry, and "HPLC" refers to high-performance liquid chromatography.

[0184] Intermediate Synthesis Examples

[0185] Synthesis of (S)-tert-butyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate IIa)

[0186]

[0187] Step 1: Synthesis of tert-butyl 3-fluoro-4-nitrobenzoate (IIa-1)

[0188] To a solution of 3-fluoro-4-nitrobenzoic acid (10 g, 54.02 mmol) in tetrahydrofuran (115.83 mL) was added di-tert-butyl dicarbonate (17.69 g, 81.03 mmol, 18.60 mL) and 4-(N,N-dimethylamino)pyridine (6.60 g, 54.02 mmol), and the mixture was stirred at 40 °C for 3 h. After completion of the reaction, the solvent was removed, and the residue was purified by silica gel column chromatography (PE:EA = 8:1) to give the title compound IIa-1 (7.2 g). LC-MS (ESI, m / z) 242 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.08 (dd, 1H), 7.91 - 7.85 (m, 2H), 1.61 (s, 9H).

[0189] Step 2: Synthesis of tert-butyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (IIa-2)

[0190] To a solution of compound IIa-1 (3.6 g, 14.92 mmol) in acetonitrile (50 mL) was added triethylamine (2.27 g, 22.39 mmol) and (S)-oxetan-2-ylmethanamine (1.56 g, 17.91 mmol), and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was removed, and the residue was purified by silica gel column chromatography (PE:EA = 5∶1) to give the title compound IIa-2 (3.56 g). LC-MS (ESI, m / z) 309 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.20 (d, 1H), 7.58 (d, 1H), 7.20 (dd, 1H), 5.15 (m, 1H), 4.80 - 4.71 (m, 1H), 4.63 (dt, 1H), 3.64 - 3.61 (m, 2H), 2.80 - 2.73 (m, 1H), 2.64 - 2.55 (m, 1H), 1.60 (s, 9H).

[0191] Step 3: Synthesis of tert-butyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (IIa-3)

[0192] Compound IIa-2 (3.56 g, 11.55 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and water (10 mL). Iron powder (3.87 g, 69.28 mmol) and ammonium chloride (2.47 g, 46.18 mmol, 1.61 mL) were added. The temperature was raised to 80 °C and the mixture was stirred for 16 hours. After filtration and concentration, the residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the title compound IIa-3 (2.70 g). LC-MS (ESI, m / z) 279 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.42 (dd, 1H), 7.35 (d, 1H), 6.66 (d, 1H), 5.13 - 5.07 (m, 1H), 4.76 - 4.71 (m, 1H), 4.63 - 4.58 (m, 1H), 3.48 (s, 2H), 3.45 - 3.41 (m, 1H), 3.37 - 3.32 (m, 1H), 2.78 - 2.70 (m, 1H), 2.61 - 2.53 (m, 1H), 1.57 (s, 9H).

[0193] Step 4: (S)-tert-butyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (IIa)

[0194] Compound IIa-3 (2.7 g, 9.70 mmol) was dissolved in acetonitrile (20 mL). 2-Chloro-1,1,1-trimethoxyethane (1.50 g, 9.70 mmol) and p-toluenesulfonic acid (167.04 mg, 970.02 μmol) were added. The temperature was raised to 70 °C and the mixture was stirred for 4 hours. After the reaction was completed, the solvent was removed. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the title compound IIa (2.65 g). LC-MS (ESI, m / z) 337 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.95 (dd, 1H), 7.76 (d, 1H), 5.23 - 5.17 (m, 1H), 5.03 (s, 2H), 4.65 - 4.58 (m, 2H), 4.54 - 4.49 (m, 1H), 4.36 - 4.31 (m, 1H), 2.79 - 2.71 (m, 1H), 2.46 - 2.37 (m, 1H), 1.62 (s, 9H).

[0195] Example 2 Synthesis of tert-butyl 2-(chloromethyl)-1-(cyanomethyl)-1H-benzoimidazole-6-carboxylate (Intermediate IIb)

[0196]

[0197] Step 1: tert-Butyl 3-((cyanomethyl)amino)-4-nitrobenzoate (IIb-1)

[0198] Dissolve compound IIa-1 (9.7 g, 104.47 mmol) in dimethyl sulfoxide (220 mL), add triethylamine (17.62 g, 174.12 mmol), and aminoacetonitrile hydrochloride (21.0 g, 87.06 mmol). Heat the mixture to 80 °C and stir for 12 hours. Pour the reaction mixture into water, extract with ethyl acetate (500 mL × 3), combine the organic phases, wash with saturated brine (500 mL × 3), dry over anhydrous sodium sulfate, filter and concentrate. Purify by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound IIb-1 (5.0 g). LC-MS (ESI, m / z) 278 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (t, 1H), 8.22 (d, 1H), 7.58 (d, 1H), 7.31 - 7.28 (m, 1H), 4.63 (d, 2H), 1.57 (s, 9H).

[0199] Step 2: tert-Butyl 4-amino-3-((cyanomethyl)amino)benzoate (IIb-2)

[0200] Dissolve compound IIb-1 (5 g, 18.03 mmol) in 50 mL of methanol, then add palladium on carbon (1.92 g, 18.03 mmol). Carry out the hydrogenation reaction at room temperature and atmospheric pressure for 2 hours. TLC shows that the reaction is complete. Then evaporate the solvent to dryness and mix the sample. Purify by silica gel column chromatography (PE:EA = 2:1) to obtain the title compound IIb-2 (2.9 g). LC-MS (ESI, m / z) 248 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.23 - 7.21 (m, 1H), 7.13 (d, 1H), 6.60 (d, 1H), 5.40 - 5.37 (m, 3H), 4.27 (d, 2H), 1.51 (s, 9H).

[0201] Step 3: tert-Butyl 2-(chloromethyl)-1-(cyanomethyl)-1H-benzoimidazole-6-carboxylate (IIb)

[0202] Compound IIb-2 (2.9 g, 11.73 mmol) was dissolved in 40 mL of acetonitrile, then methyl chloroacetate (2.72 g, 17.59 mmol) and TsOH (201.94 mg, 1.17 mmol) were added. The temperature was raised to 110 °C and the reaction was stirred for 12 hours. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate (300 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE:EA = 2:1) to obtain the title compound (2.60 g). LC-MS (ESI, m / z) 306 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.90 - 7.88 (m, 1H), 7.78 (d, 1H), 5.82 (s, 2H), 5.17 (s, 2H), 1.59 (s, 9H).

[0203] Example 3 Synthesis of tert-butyl 2-(chloromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate IIc)

[0204]

[0205] Step 1: tert-butyl 4-nitro-3-((2,2,2-trifluoroethyl)amino)benzoate (IIc-1)

[0206] Compound IIa-1 (1.0 g, 4.15 mmol) was dissolved in dimethyl sulfoxide (9.42 mL), triethylamine (1.26 g, 12.44 mmol, 1.73 mL) and 2,2,2-trifluoroethylamine (1.23 g, 12.44 mmol, 989.52 μL) were added. The temperature was raised to 100 °C and the reaction was stirred for 16 hours. After the reaction was completed, the mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, dried and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the title compound IIc-1 (1.23 g). LC-MS (ESI, m / z) 321 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.23 (d, 1H), 8.16 (s, 1H), 7.61 (s, 1H), 7.34 (dd, 1H), 4.07 - 3.99 (m, 2H), 1.61 (s, 9H).

[0207] Step 2: tert-butyl 4-amino-3-((2,2,2-trifluoroethyl)amino)benzoate (IIc-2)

[0208] To a solution of compound IIc-1 (1.23 g, 3.84 mmol) in MeOH (15 mL) was added 10% palladium on carbon (200 mg), and the mixture was hydrogenated at room temperature under atmospheric pressure for 16 h. After completion of the reaction, the mixture was filtered and the filtrate was concentrated to give the title compound IIc-2 (1.16 g). LC-MS (ESI, m / z) 391 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.50 (dd, 1H), 7.39 (d, 1H), 6.71 (d, 1H), 3.73 (q, 2H), 3.49 (s, 2H), 1.57 (s, 9H).

[0209] Step 3: Synthesis of tert-butyl 2-(chloromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carboxylate (IIc)

[0210] Compound IIc-2 (1.13 g, 3.89 mmol) was dissolved in acetonitrile (15 mL), methyl chloroacetate (902.69 mg, 5.84 mmol) and p-toluenesulfonic acid (67.03 mg, 389.28 μmol) were added, and the mixture was stirred at 70 °C for 2 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by column (PE:EA = 5:1) to give the title compound IIc (1.32 g). LC-MS (ESI, m / z) 349 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 8.00 (dd, 1H), 7.78 (dd, 1H), 4.95 (q, 2H), 4.89 (s, 2H), 1.63 (s, 9H).

[0211] Example 4 Synthesis of di-tert-butyl (S)-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonate (Intermediate IId)

[0212]

[0213] Step 1: 5-Bromo-2-nitro-N-(oxetan-2-ylmethyl)aniline (IId-1)

[0214] To a solution of 2-fluoro-4-bromonitrobenzene (20.0 g, 90.91 mmol) in acetonitrile (220 mL) was added triethylamine (13.8 g, 136.37 mmol) and (S)-oxetan-2-ylmethanamine (9.5 g, 109.09 mmol), and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was removed, and the residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound IId-1 (3.56 g). LC-MS (ESI, m / z) 287 [M+H] + .

[0215] Step 2: Di-tert-butyl (S)-(4-nitro-3-((oxetan-2-ylmethyl)amino)phenyl)phosphonate (IId-2)

[0216] Under nitrogen protection, compound IId-1 (10.0 g, 34.83 mmol) and di-tert-butyl phosphite (7.44 g, 38.31 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), and palladium acetate (196 mg, 0.87 mmol, 5 mol%), 1,1'-bis(diphenylphosphino)ferrocene (965 mg, 1.74 mmol), potassium acetate (342 mg, 3.48 mmol) and triethylamine (4.23 g, 41.80 mmol) were added. The temperature was raised to 68 °C and the reaction was stirred for 15 h. After cooling to room temperature, it was diluted with dichloromethane (200 mL), filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to give the target product IId-2 (6.87 g), LCMS (m / z): 401 (M+H + ). 1 H NMR (400 MHz, DMSO) δ 8.38 (t, 1H), 8.15 (dd, 4.5 Hz, 1H), 7.46–7.33 (m, 1H), 6.90 (ddd, 8.7, 1.4 Hz, 1H), 4.99 (ddd, 1H), 4.55 (ddd, 1H), 4.42 (dt, 1H), 3.71–3.57 (m, 2H), 2.75–2.60 (m, 1H), 2.58–2.52 (m, 1H), 1.43 (s, 18H).

[0217] Step 3: Di-tert-butyl (S)-(4-amino-3-((oxetan-2-ylmethyl)amino)phenyl)phosphonate (IId-3)

[0218] Dissolve IId-2 (3.56 g, 11.55 mmol) in a mixed solvent of ethanol (50 mL) and water (10 mL), add iron powder (3.87 g, 69.28 mmol) and ammonium chloride (2.47 g, 46.18 mmol), and heat to 80 °C with stirring for 16 hours. Filter and concentrate, and purify the residue by silica gel column chromatography (PE:EA = 2:1) to obtain the title compound IId-3 (2.70 g). LC-MS (ESI, m / z) 371 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.55 (m, 1H), 6.79 (dd, 1H), 6.69 (d, 1H), 6.55 (dd, 1H), 5.14 (s, 2H), 4.91 - 4.88 (m, 1H), 4.53 - 4.42 (m, 2H), 3.31–3.21 (m, 2H), 2.69 - 2.42 (m, 2H), 1.36 (s, 18H).

[0219] Step 4: (S)-tert-Butyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (IIa)

[0220] Dissolve IId-3 (2.7 g, 9.70 mmol) in acetonitrile (20 mL), add 2-chloro-1,1,1-trimethoxyethane (1.50 g, 9.70 mmol) and p-toluenesulfonic acid (167.04 mg, 970.02 μmol), and heat to 70 °C with stirring for 4 hours. After the reaction is completed, remove the solvent, and purify the residue by silica gel column chromatography (PE:EA = 3:1) to obtain the title compound IId (2.65 g). LC-MS (ESI, m / z) 429 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (d, 1H), 7.73 (dd, 1H), 7.53–7.49 (m, 1H), 5.11 (d, 2H), 5.08–5.03 (m, 1H), 4.78–4.72 (m, 1H), 4.62 (dd, 1H), 4.49–4.44 (m, 1H), 4.32–4.26 (m, 1H), 2.71 - 2.67 (m, 1H), 2.38 - 2.33 (m, 1H), 1.39 (s, 18H).

[0221] Example 5 Di-tert-butyl (2-(chloromethyl)-1-(cyanomethyl)-1H-benzo[d]imidazol-6-yl)phosphonate (IIe)

[0222]

[0223] Step 1: Synthesis of 2-((5-bromo-2-nitrophenyl)amino)acetonitrile (IIe-1)

[0224] To a solution of 2-fluoro-4-bromonitrobenzene (20.0 g, 90.91 mmol) in acetonitrile (220 mL) was added triethylamine (13.8 g, 136.37 mmol) and aminoacetonitrile (6.12 g, 109.09 mmol), and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was removed, and the residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound IIe-1 (12.47 g). LC-MS (ESI, m / z) 256 [M+H] + .

[0225] Step 2: Synthesis of di-tert-butyl (3-((cyanomethyl)amino)-4-nitrophenyl)phosphonate (IIe-2)

[0226] Under nitrogen protection, compound IIe-1 (10.0 g, 39.05 mmol) and di-tert-butyl phosphite (8.4 g, 42.96 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), and palladium acetate (219 mg, 0.976 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.08 g, 1.95 mmol), potassium acetate (383 mg, 3.91 mmol) and triethylamine (4.74 g, 46.86 mmol) were added. The temperature was raised to 68 °C and the reaction was stirred for 15 h. After cooling to room temperature, it was diluted with dichloromethane (200 mL), filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to give the target product IIe-2 (7.28 g), LCMS (m / z): 370 [M+H] + .

[0227] Step 3: Synthesis of di-tert-butyl (4-amino-3-((cyanomethyl)amino)phenyl)phosphonate (IIe-3)

[0228] Compound IIe-2 (5.0 g, 13.54 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and water (10 mL), and iron powder (7.56 g, 135.37 mmol) and ammonium chloride (7.24 g, 135.37 mmol) were added. The temperature was raised to 80 °C and the reaction was stirred for 16 h. After filtration and concentration, the residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the title compound IIe-3 (3.44 g). LC-MS (ESI, m / z) 340 [M+H] + .

[0229] Step 4: Di-tert-butyl (2-(chloromethyl)-1-(cyanomethyl)-1H-benzo[d]imidazol-6-yl)phosphonate (IIe)

[0230] Compound IIe-3 (2.7 g, 9.70 mmol) was dissolved in acetonitrile (20 mL), 2-chloro-1,1,1-trimethoxyethane (1.50 g, 9.70 mmol) and p-toluenesulfonic acid (167.04 mg, 970.02 μmol) were added, and the temperature was raised to 70 °C and stirred for reaction for 4 hours. After the reaction was completed, the solvent was removed, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the title compound IIe (2.65 g). LC-MS (ESI, m / z) 398 [M+H] + .

[0231] Example 6 Synthesis of 3-Fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate IIIa)

[0232]

[0233] Step 1: 4-(((6-Bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (IIIa-1)

[0234] 2-Fluoro-4-cyanobenzyl alcohol (2.00 g, 13.23 mmol) was dissolved in 1,4-dioxane (20 mL), 2-fluoro-6-bromopyridine (1.32 g, 13.23 mmol) and potassium tert-butoxide (1.78 g, 15.88 mmol) were added, and the temperature was raised to 40 °C and stirred for reaction for 0.5 hour. The reaction was quenched by adding water, and extracted with ethyl acetate (100 mL * 3). The organic phases were combined, dried and concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound IIIa-1 (3.6 g). LC-MS (ESI, m / z) 307 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 7.67 - 7.64 (m, 1H), 7.50 - 7.45 (m, 2H), 7.40 - 7.37 (m, 1H), 7.13 - 7.11 (m, 1H), 6.78 - 6.76 (m, 1H), 5.48 (s, 2H).

[0235] Step 2: tert-Butyl 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (IIIa-2)

[0236] Compound IIIa-1 (1.8 g, 5.86 mmol) was dissolved in a mixed solvent of 1,4-dioxane (19 mL) and water (5 mL). 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.17 g, 7.03 mmol), sodium carbonate (2.4 g, 23.44 mol), and tetrakis(triphenylphosphine)palladium (67.73 mg, 58.61 mmol) were added. The reaction mixture was heated to 85 °C under nitrogen protection and stirred for 12 hours. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried, and concentrated. The title compound IIIa-2 (2.1 g) was obtained by purification through silica gel column chromatography (PE:EA = 5:1). LC-MS (ESI, m / z) 410 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.55 (m, 2H), 7.46 - 7.44 (m, 1H), 7.40 - 7.37 (m, 1H), 6.98 (d, 1H), 6.71 (d, 1H), 6.68 - 6.63 (m, 1H), 5.54 (s, 2H), 4.15 - 4.09 (m, 2H), 3.63 (t, 2H), 2.57 - 2.54 (m, 2H), 1.49 (s, 9H).

[0237] Step 3: tert-Butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (IIIa-3)

[0238] Compound IIIa-2 (500 mg, 1.22 mmol) was dissolved in toluene (10 mL). 10% palladium on carbon (129.95 mg, 1.22 mmol) was added. The reaction mixture was hydrogenated at room temperature and atmospheric pressure for 12 hours. After TLC showed that the reaction was complete, the palladium on carbon was filtered off, and the solvent was evaporated to dryness to obtain the title compound IIIa-3 (480 mg). LC-MS (ESI, m / z) 412 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.53 - 7.48 (m, 1H), 7.47 - 7.43 (m, 1H), 7.13 - 7.09 (m, 2H), 6.71 (d, 1H), 6.61 (d, 1H), 5.42 (s, 2H), 2.91 - 2.67 (m, 4H), 2.26 (d, 1H), 1.92 - 1.84 (m, 2H), 1.78 - 1.67 (m, 2H), 1.49 (s, 9H).

[0239] Step 4: 3-Fluoro-4-((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (IIIa)

[0240] Dissolve compound IIIa-3 (480 mg, 1.17 mmol) in dichloromethane (1 mL), add 4 M hydrochloric acid dioxane solution (2 mL), stir the reaction at room temperature for 2 hours. After completion of the reaction as indicated by TLC, evaporate the solvent under reduced pressure, redissolve in dichloromethane, wash with saturated sodium bicarbonate, dry over anhydrous sodium sulfate, filter and concentrate to obtain the title compound IIIa (350 mg). LC-MS (ESI, m / z) 312 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.93 (m, 1H), 7.85 - 7.72 (m, 3H), 6.95 (d, 1H), 6.82 (d, 1H), 5.53 (s, 2H), 3.37 (d, 2H), 3.07 - 2.93 (m, 4H), 2.04 - 1.93 (m, 4H).

[0241] Example 7 Synthesis of 3-Fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)oxy)methyl)benzonitrile (IIIb)

[0242]

[0243] Dissolve compound IIIa-2 (480 mg, 1.17 mmol) in dichloromethane (1 mL), add 4 M hydrochloric acid dioxane solution (2 mL), stir the reaction at room temperature for 2 hours. After completion of the reaction as indicated by TLC, evaporate the solvent under reduced pressure, redissolve in dichloromethane, wash with saturated sodium bicarbonate, dry over anhydrous sodium sulfate, filter and concentrate to obtain the title compound IIIa (350 mg). LC-MS (ESI, m / z) 310 [M+H] + .

[0244] Example 8 Synthesis of 4-(((6-(2-azabicyclo[2.2.1]hept-5-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (Intermediate IIIc)

[0245]

[0246] Step 1: tert-Butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (IIIc-1)

[0247] Compound IIIa-1 (1.8 g, 5.86 mmol) was dissolved in a mixed solvent of 1,4-dioxane (19 mL) and water (5 mL). tert-Butyl 2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (1.37 g, 7.03 mmol), sodium carbonate (2.4 g, 23.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (67.73 mg, 58.61 μmol) were added. The reaction mixture was heated to 85 °C under nitrogen protection and stirred for 12 h. TLC showed that the reaction was complete. After cooling to room temperature, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (PE:EA = 5:1) gave the title compound IIIc-1 (1.2 g). LC-MS (ESI, m / z) 424 [M+H] + 。

[0248] Step 2: 4-(((6-(2-Azabicyclo[2.2.1]hept-5-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (IIIc)

[0249] Compound IIIc-1 (470 mg, 1.14 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. After TLC showed that the reaction was complete, the solvent was removed in vacuo, and the residue was redissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound IIIc (345 mg). LC-MS (ESI, m / z) 324 [M+H] + 。

[0250] Example 9 Synthesis of 3-Fluoro-4-((6-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzonitrile (Intermediate IIId)

[0251]

[0252] Step 1: tert-Butyl 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (IIId-1)

[0253] Dissolve 6-bromo-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.03 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (753.28 mg, 2.44 mmol) in a mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). Add cesium carbonate (1.65 g, 5.08 mmol) and RuPhos Pd G2 (78.84 mg, 101.51 μmol). Heat the reaction mixture to 110 °C under nitrogen protection and stir for 17 hours. After the reaction is completed, cool it to room temperature, quench with water (50 mL), extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (gradient elution with PE / EA) to obtain the title compound IIId-1 (420 mg). LC-MS (ESI, m / z) 300 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.90 (d, 1H), 7.41 (t, 1H), 7.31 (d, 1H), 6.58 (s, 1H), 6.41 (dd, 1H), 4.04 (s, 2H), 3.55 (t, 2H), 2.64 (m, 2H), 1.43 (s, 9H).

[0254] Step 2: tert-Butyl 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (IIId-2)

[0255] Dissolve compound IIId-1 (500 mg, 1.67 mmol) in ethyl acetate (10 mL), add 10% palladium on carbon (497.68 mg, 4.68 mmol), introduce hydrogen gas, and carry out hydrogenation reaction at room temperature and atmospheric pressure for 19 hours. Filter and concentrate to obtain the title compound IIId-2 (573 mg). LC-MS (ESI, m / z) 302 [M+H] + .

[0256] Step 3: tert-Butyl 4-(1-(4-cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidine-1-carboxylate (IIId-3)

[0257] Compound IIId-2 (573 mg, 1.53 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride (66.17 mg, 2.76 mmol) was added. After stirring at room temperature for 0.5 h, 4-(bromomethyl)-3-fluorobenzonitrile (426.22 mg, 1.99 mmol) was added, and the reaction was continued with stirring for 19 h. The reaction was quenched by adding water (50 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EA = 6 / 1) to obtain the title compound IIId-3 (456 mg). LC-MS (ESI, m / z) 435 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, 1H), 7.39 - 7.36 (m, 1H), 7.34 - 7.31 (m, 1H), 7.21 (t, 1H), 7.17 (d, 1H), 6.97 (d, 1H), 6.46 (d, 1H), 5.55 (s, 2H), 2.94 - 2.83 (m, 3H), 1.96 - 1.76 (m, 5H), 1.49 (s, 9H).

[0258] Step 4: 3-Fluoro-4-((6-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzonitrile (IIId)

[0259] Compound IIId-3 (450 mg, 1.04 mmol) was dissolved in ethyl acetate (2 mL), and 4 M hydrogen chloride in ethyl acetate solution (5 mL, 2.0 mmol) was added. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed, redissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried and concentrated to obtain the title compound IIId (385.6 mg). LC-MS (ESI, m / z) 335 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.87 (dd, 1H), 7.66 (dd, 1H), 7.57 (d, 1H), 7.31 (t, 1H), 7.03 (d, 1H), 6.51 (d, 1H), 5.58 (s, 2H), 3.4 (d, 2H), 3.10 - 2.94 (m, 3H), 2.02 - 1.97 (m, 4H).

[0260] Example 10 Synthesis of 3-Fluoro-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzonitrile (Intermediate IIIe)

[0261]

[0262] Step 1: tert-Butyl 4-[1-[(4-cyano-2-fluorophenyl)methyl]-1H-indol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (IIIe-1)

[0263] Dissolve compound IIId-1 (800 mg, 2.68 mmol) in anhydrous N,N-dimethylformamide (10 mL), add 60% sodium hydride (96.51 mg, 4.02 mmol), stir for 30 min, then add 4-(bromomethyl)-3-fluorobenzonitrile (631.25 mg, 2.95 mmol), and continue to stir the reaction at room temperature for 19 h. Quench with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound IIIe-1 (613 mg). LC-MS (ESI, m / z) 433 [M+H] + .

[0264] Step 2: tert-Butyl 4-[1-[(4-cyano-2-fluorophenyl)methyl]-1H-indol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (IIIe)

[0265] Dissolve compound IIIe-1 (200 mg, 0.46 mmol) in anhydrous dichloromethane (1 mL), add trifluoroacetic acid (2 mL), and stir the mixture at room temperature for 5 h. After the reaction is completed, concentrate the mixture to obtain the title compound IIIe (140 mg). LC-MS (ESI, m / z) 333 [M+H] + .

[0266] Synthesis of Example 11 3-Fluoro-4-((6-(piperidin-4-yl)-1H-indol-1-yl)methyl)benzonitrile (Intermediate IIIf)

[0267]

[0268] Step 1: Synthesis of tert-Butyl 4-(1H-indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (IIIf-1)

[0269] 6-Bromo-1H-indole (3 g, 15.30 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4.26 g, 13.77 mmol) were dissolved in a mixed solvent of 1,4-dioxane (130 mL) and water (13 mL). Ruphos Pd G2 (594.3 mg, 765.14 μmol) and cesium carbonate (12.46 g, 38.26 mmol) were added. The mixture was heated to 65 °C under nitrogen protection and stirred for 3 hours. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound IIIf-1 (2.8 g). LC-MS (ESI, m / z) 299 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.59 (d, 1H), 7.38 (s, 1H), 7.22 - 7.19 (m, 2H), 6.54 - 6.52 (m, 1H), 6.05 - 6.04 (m, 1H), 4.10 (d, 2H), 3.67 (t, 2H), 2.63 - 2.58 (m, 2H), 1.50 (s, 9H).

[0270] Step 2: Synthesis of tert-butyl 4-(1H-indol-6-yl)piperidine-1-carboxylate (IIIf-2)

[0271] Compound IIIf-1 (1 g, 3.35 mmol) was dissolved in ethyl acetate (15 mL). 10% palladium on carbon (1.07 g, 10.05 mmol) was added. The mixture was hydrogenated at room temperature and atmospheric pressure for 17 hours. After completion of the reaction, the mixture was filtered and concentrated to obtain the title compound IIIf-2 (924 mg). LC-MS (ESI, m / z) 301 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.57 (d, 1H), 7.22 (s, 1H), 7.17 (t, 1H), 6.99 (dd, 1H), 6.52 - 6.51 (m, 1H), 4.26 (s, 2H), 2.90 - 2.71 (m, 3H), 1.91 - 1.85 (m, 2H), 1.73 - 1.64 (m, 2H), 1.50 (s, 9H).

[0272] Step 3: tert-Butyl 4-(1-(4-cyano-2-fluorobenzyl)-1H-indol-6-yl)piperidine-1-carboxylate (IIIf-3)

[0273] Compound IIIf-2 (924 mg, 3.08 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). 60% sodium hydride (110.72 mg, 4.61 mmol) was added, and the mixture was stirred at room temperature for half an hour. Then 4-(bromomethyl)-3-fluorobenzonitrile (724 mg, 3.38 mmol) was added, and the reaction was continued with stirring for 19 hours. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound IIIf-3 (856 mg). LC-MS (ESI, m / z) 434 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.61 - 7.58 (m, 1H), 7.41 (dd, 1H), 7.29 (dd, 1H), 7.09 (d, 1H), 7.05 - 7.00 (m, 2H), 6.78 (t, 1H), 6.57 (dd, 1H), 5.41 (s, 2H), 2.90 - 2.66 (m, 4H), 1.86 - 1.80 (m, 2H), 1.70 - 1.61 (m, 3H), 1.48 (s, 9H).

[0274] Step 4: 3-Fluoro-4-((6-(piperidin-4-yl)-1H-indol-1-yl)methyl)benzonitrile (IIIf)

[0275] Compound IIIf-3 (200 mg, 0.46 mmol) was dissolved in anhydrous dichloromethane (5 mL). Trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, it was concentrated, redissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound IIIf (150 mg). LC-MS (ESI, m / z) 334 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, 1H), 7.61 (dd, 1H), 7.53 (d, 1H), 7.44 (d, 1H), 7.26 (s, 1H), 7.00 - 6.93 (m, 2H), 6.49 (d, 1H), 5.58 (s, 2H), 3.06 - 2.77 (m, 5H), 1.88 - 1.80 (m, 4H).

[0276] Example 12 Synthesis of 3-Fluoro-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]indol-1-yl)methyl)benzonitrile (Intermediate IIIg)

[0277]

[0278] Step 1: Synthesis of tert-butyl 4-(1-(4-cyano-2-fluorobenzyl)-1H-indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (IIIg-1)

[0279] Dissolve compound IIIf-1 (800 mg, 2.68 mmol) in anhydrous N,N-dimethylformamide (10 mL), add 60% sodium hydride (96.51 mg, 4.02 mmol), stir at room temperature for half an hour, then add 4-(bromomethyl)-3-fluorobenzonitrile (631.25 mg, 2.95 mmol), and continue stirring for 19 hours. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate, and purify the residue by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound IIIg-1 (613 mg). LC-MS (ESI, m / z) 432 [M+H] + .

[0280] Step 2: 3-Fluoro-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl)methyl)benzonitrile (IIIg)

[0281] Add 4M hydrogen chloride dioxane solution (1 mL) to a solution of compound IIIf-1 (200 mg, 463.50 μmol) in anhydrous dichloromethane (6 mL), and stir the mixture at room temperature for 5 hours. After the reaction is completed, concentrate, redissolve in dichloromethane, wash with saturated sodium bicarbonate, dry over anhydrous sodium sulfate, filter and concentrate to obtain the title compound IIIg (140 mg). LC-MS (ESI, m / z) 332 [M+H] + .

[0282] Synthesis of Example 13 3-Fluoro-4-((6-(piperazin-1-yl)-1H-indol-1-yl)methyl)benzonitrile (Intermediate IIIh)

[0283]

[0284] Step 1: tert-Butyl 4-(1H-indol-6-yl)piperazine-1-carboxylate (IIIh-1)

[0285] 6-Bromo-1H-indole (1 g, 5.10 mmol) and tert-butyl piperazine-1-carboxylate (1.14 g, 6.12 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL). Pd2(dba)3 (46.71 mg, 51.01 μmol), X-phos (80.27 mg, 102.02 μmol) and LiHMDS (1.71 g, 10.20 mmol) were added. The mixture was heated to 65 °C under nitrogen protection and stirred for 18 hours. After cooling to room temperature, the reaction was quenched with water, and the pH value was adjusted to 8 with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, filtered and concentrated. The residue was purified by column chromatography (PE:EA = 5:1) to obtain the title compound IIIh-1 (1.38 g). LC-MS (ESI, m / z) 302 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.38 (d, 1H), 7.15 (d, 1H), 6.85 (s, 1H), 6.78 (dd, 1H), 6.29 - 6.27 (m, 1H), 3.48 (t, 4H), 3.01 (t, 4H), 1.42 (s, 9H).

[0286] Step 2: tert-Butyl 4-(1-(4-cyano-2-fluorobenzyl)-1H-indol-6-yl)piperazine-1-carboxylate (IIIh-2)

[0287] Compound IIIh-1 (1.66 g, 5.51 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL). 60% sodium hydride (198.27 mg, 8.26 mmol) was added, and the mixture was stirred at room temperature for half an hour. Then 4-(bromomethyl)-3-fluorobenzonitrile (724 mg, 3.38 mmol) was added, and the reaction was continued for 19 hours. After the reaction was completed, the reaction was quenched with water and then with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound IIIh-2 (1.36 g). LC-MS (ESI, m / z) 435 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 1H), 7.41 (dd, 1H), 7.29 (d, 1H), 7.02 (d, 1H), 6.90 (dd, 1H), 6.67 (s, 1H), 6.51 (d, 1H), 5.36 (s, 2H), 3.59 (t, 4H), 3.07 (t, 4H), 1.48 (s, 9H).

[0288] Step 3: Synthesis of 3-Fluoro-4-((6-(piperazin-1-yl)-1H-indol-1-yl)methyl)benzonitrile (IIIh)

[0289] Dissolve compound IIIh-2 (201 mg, 462.60 μmol) in anhydrous dichloromethane (4 mL), add 4M dioxane hydrochloride solution (1 mL, 4 mmol), and stir the reaction at room temperature for 8 hours. After the reaction is completed, concentrate the mixture, redissolve it in dichloromethane, dry it over anhydrous sodium sulfate, filter and concentrate to obtain the title compound (150 mg). LC-MS (ESI, m / z) 335 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.31 (d, 1H), 7.05 (s, 1H), 6.95 - 6.83 (m, 2H), 6.43 (d, 1H), 5.55 (s, 2H), 3.34 - 3.31 (m, 4H), 3.24 - 3.22 (m, 4H), 1.91 (s, 1H).

[0290] Example 14 Synthesis of 3-Fluoro-4-((6-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile (Intermediate IIIi)

[0291]

[0292] Step 1: tert-Butyl 4-(1H-benzo[d]imidazol-6-yl)piperazine-1-carboxylate (IIIi-1)

[0293] Dissolve 6-bromo-1H-benzoimidazole (200 mg, 1.02 mmol) in tetrahydrofuran (4 mL), add tert-butyl piperazine-1-carboxylate (208 mg, 1.12 mmol), X-phos (24 mg, 0.03 mmol) and Pd2(dba)3 (10 mg, 0.01 mmol), heat to 65 °C and stir for 4 hours under nitrogen protection. After LCMS shows the reaction is complete, add water and ethyl acetate (100 mL * 3) for extraction, then rotary evaporate and mix the samples, and obtain the title compound IIIi-1 (300 mg) by column chromatography (DCM:MeOH = 20:1). LC-MS (ESI, m / z) 303 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.58 (d, 1H), 7.12 (d, 1H), 7.04 (dd, 1H), 3.62 (t, 4H), 3.12 (t, 4H), 1.49 (s, 9H).

[0294] Step 2: tert-Butyl 4-(1-(4-cyano-2-fluorobenzyl)-1H-benzo[d]imidazol-6-yl)piperazine-1-carboxylate (IIIi-2)

[0295] Dissolve compound IIIi-1 (300 mg, 0.99 mmol) in N,N-dimethylformamide (4 mL), add 4-(bromomethyl)-3-fluorobenzonitrile (254.83 mg, 1.19 mmol) and potassium carbonate (274.24 mg, 1.98 mmol), and stir at 60 °C for 1 hour. LCMS shows that the reaction is complete. Add water and ethyl acetate (100 mL * 3) for extraction, then evaporate to dryness and mix the sample. Compound IIIi-2 (335 mg) is obtained by column chromatography (DCM:MeOH = 10:1). LC-MS (ESI, m / z) 436 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, 2H), 7.91 (s, 1H), 7.72 (d, 1H), 7.46 - 7.42 (M, 2H), 7.39 (s, 1H), 7.37 (s, 1H), 7.34 (d, 1H), 7.16 (d, 1H), 7.07 - 6.98 (m, 4H), 6.70 (d, 1H), 5.44 (s, 2H), 5.42 (s, 2H), 3.60 (q, 8H), 3.14 - 3.07 (m, 8H), 1.48 (s, 8H), 1.48 (s, 9H).

[0296] Step 3: 3-Fluoro-4-((6-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile (IIIi)

[0297] Dissolve compound IIIi-2 (335 mg, 769.24 μmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. LCMS shows that the reaction is complete. Evaporate to dryness, redissolve in dichloromethane, wash with saturated sodium bicarbonate, dry over anhydrous sodium sulfate, filter and concentrate to obtain the title compound IIIi (250 mg). LC-MS (ESI, m / z) 336 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.63 (s, 1H), 7.98 (t, 1H), 7.97 - 7.94 (m, 1H), 7.76 (d, 2H), 7.74 - 7.72 (m, 2H), 7.63 (t, 1H), 7.56 (t, 1H), 7.42 - 7.39 (m, 2H), 7.38 - 7.37 (m, 1H), 7.26 (d, 1H), 5.91 (s, 2H), 5.90 (s, 2H), 3.48 - 3.45 (t, 8H), 3.22 (s, 8H).

[0298] Example 15 Synthesis of 3-Fluoro-4-(((3-fluoro-6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (IIIj)

[0299]

[0300] Step 1: 4-(((6-Chloro-3-fluoropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (IIIj-1)

[0301] Dissolve 3-fluoro-4-(hydroxymethyl)benzonitrile (10 g, 66.16 mmol) in 300 mL of acetonitrile, then add 2,6-dichloro-3-fluoropyridine (10.98 g, 66.16 mmol), cesium carbonate (43.12 g, 132.32 mmol), stir at 80 °C for 16 h. After LCMS shows the reaction is complete, obtain the title compound IIIj-1 (5 g) by column chromatography (PE:EA = 5:1). LC-MS (ESI, m / z) 281 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H), 7.84 (dd, 1H), 7.79 - 7.73 (m, 2H), 7.19 (dd, 1H), 5.52 (s, 2H).

[0302] Step 2: tert-Butyl 6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (IIIj-2)

[0303] Compound IIIj-1 (1.5 g, 5.34 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.65 g, 5.34 mmol) were dissolved in 15 mL of 1,4-dioxane and 1.5 mL of water. Then cesium carbonate (4.35 g, 13.36 mmol) and Ruphos Pd G2 (415.13 mg, 534.46 μmol) were added. Under nitrogen protection, the mixture was stirred at 65 °C for several hours. After the LCMS showed that the reaction was completed, the title compound IIIj-2 (1.1 g) was obtained by column chromatography (PE:EA = 5:1). LC-MS (ESI, m / z) 428 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.90 (m, 1H), 7.77 - 7.72 (m, 3H), 7.15 - 7.12 (m, 1H), 6.64 (s, 1H), 5.59 (s, 2H), 4.03 (s, 2H), 3.52 (t, 2H), 2.46 (s, 2H), 1.43 (s, 9H).

[0304] Step 3: tert-Butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperidine-1-carboxylate (IIIj-3)

[0305] Compound IIIj-2 (1.1 g, 2.57 mmol) was dissolved in ethyl acetate (15 mL), and palladium on carbon (10% wt, 254 mg, 0.26 mmol) was added. The mixture was hydrogenated under normal pressure at room temperature for 17 hours. After the reaction was completed, the mixture was filtered and concentrated to obtain the title compound IIIj-3 (0.9 g). LC-MS (ESI, m / z) 430 [M+H] + .

[0306] Step 4: 3-Fluoro-4-(((3-fluoro-6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (IIIj)

[0307] Compound IIIj-3 (400 mg, 935.80 μmol) was dissolved in 3 mL of dichloromethanol and 1 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours. After the LCMS showed that the reaction was completed, the reaction solution was evaporated to dryness to obtain the title compound IIIj (300 mg). LC-MS (ESI, m / z) 330 [M+H] + .

[0308] Example 16 Synthesis of 3-Fluoro-4-(((5-fluoro-2-(piperidin-4-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile (IIIk)

[0309]

[0310] Step 1: 4-(((2-chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (IIIk-1)

[0311] Dissolve 3-fluoro-4-(hydroxymethyl)benzonitrile (8 g, 52.93 mmol) in THF (100 mL), cool to 0 °C in an ice bath, add sodium hydride (3.17 g, 79.40 mmol), stir at room temperature for 0.5 h, add 2,4-dichloro-5-fluoropyrimidine (13.26 g, 79.40 mmol), and stir at room temperature for 2 h. Add water (50 mL), extract with ethyl acetate (30 mL × 3), separate the layers, combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (PE:EA = 5:1) to obtain the title compound IIIk-1 (3.0 g). LC-MS (ESI, m / z) 282 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.27 (d, 1H), 7.67 (t, 1H), 7.52 (dd, 1H), 7.43 (dd, 1H), 5.61 (d, 2H).

[0312] Step 2: tert-Butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (IIIk-2)

[0313] Dissolve compound IIIk-1 (700 mg, 2.49 mmol) in 1,4-dioxane (10 mL), H2O (3 mL), add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (768.50 mg, 2.49 mmol), Pd(dppf)Cl2 (90.93 mg, 124.27 μmol), potassium phosphate (1.58 g, 7.46 mmol), displace with nitrogen 3 times, heat to 90 °C and stir for 16 h. Cool, concentrate the reaction solution, and purify by column chromatography (DCM:MeOH = 20:1) to obtain the target compound IIIk-2 (910 mg). LC-MS (ESI, m / z) 429 [M+H] + . 11H NMR (400 MHz, Chloroform-d) δ 8.26 (d, 1H), 7.58 (t, 1H), 7.43 (dd, 1H), 7.35 (dd, 1H), 5.56 (s, 2H), 5.23 (s, 1H), 4.08 (q, 2H), 3.54 (t, 2H), 2.57 (s, 2H), 1.42 (d, 10H).

[0314] Step 3: tert-Butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperidine-1-carboxylate (IIIk-3)

[0315] Dissolve IIIk-2 (0.91 g, 2.12 mmol) in ethyl acetate (15 mL), add palladium on carbon (10% wt, 294 mg, 0.21 mmol), and perform hydrogenation reaction at normal pressure at room temperature for 17 hours. After the reaction is completed, filter and concentrate the mixture to obtain the title compound IIIk-3 (0.8 g). LC-MS (ESI, m / z) 431 [M+H] + .

[0316] Step 4: 3-Fluoro-4-(((5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile (IIIk)

[0317] Dissolve compound IIIk-3 (400 mg, 933.6 μmol) in DCM (9 mL), add TFA (3 mL), and stir at 25 °C for 2 hours. Filter and concentrate the reaction solution to obtain the title compound IIIk (301 mg). LC-MS (ESI, m / z) 331 [M+H] + .

[0318] Example 17 Synthesis of 3-Fluoro-4-(((5-fluoro-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)oxy)methyl)benzonitrile (IIIL)

[0319]

[0320] Dissolve compound IIIj-2 (400 mg, 935.80 μmol) in 3 mL of dichloromethane and 1 mL of trifluoroacetic acid, stir at room temperature for 2 hours. After LCMS shows that the reaction is complete, concentrate the reaction solution under reduced pressure to obtain the title compound IIIL (300 mg). LC-MS (ESI, m / z) 328 [M+H] + .

[0321] Synthesis of Example 18 3-Fluoro-4-(((5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile (IIIm)

[0322]

[0323] Dissolve compound IIIk-2 (400 mg, 933.6 μmol) in DCM (9 mL), add TFA (3 mL), stir at 25 °C for 2 hours, concentrate the reaction solution under reduced pressure to obtain the title compound IIIm (300 mg). LC-MS (ESI, m / z) 329 [M+H] + .

[0324] Synthesis of Compounds

[0325] Synthesis of Example 1 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-1)

[0326]

[0327] Step 1: tert-Butyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazole-6-carboxylate (I-1-1)

[0328] Dissolve compound IIIa (120 mg, 385.41 μmol) in acetonitrile (3 mL), add compound IIb (117.84 mg, 385.41 μmol), potassium carbonate (159.80 mg, 1.16 mmol) and potassium iodide (6.40 mg, 38.54 μmol), heat to 50 °C and stir for 4 hours. LCMS shows the reaction is complete, filter, concentrate, and purify the residue by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-1 (50 mg). LC-MS (ESI, m / z) 581 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.89 - 7.83 (m, 2H), 7.73 - 7.62 (m, 4H), 6.86 (d, 1H), 6.70 (d, 1H), 5.75 (s, 2H), 5.45 (s, 2H), 3.91 (s, 2H), 3.17 (d, 2H), 2.89 (d, 2H), 2.70 - 2.58 (m, 1H), 1.86 - 1.72 (m, 4H), 1.59 (s, 9H).

[0329] Step 2: ((4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-1)

[0330] Dissolve compound I-1-1 (50 mg, 86.11 μmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. LCMS shows that the reaction is complete. Evaporate the solvent under reduced pressure, and purify the crude product by preparative chromatography to obtain the target product (15.7 mg). LC-MS (ESI, m / z) 525 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.42 (s, 1H), 8.02 - 7.78 (m, 3H), 7.75 - 7.66 (m, 3H), 6.92 (d, 1H), 6.77 (d, 1H), 5.81 (s, 2H), 5.49 (s, 2H), 3.31 - 3.25 (m, 4H), 2.98 - 2.71 (m, 2H), 2.61 - 2.55 (m, 1H), 2.04 - 1.88 (m, 4H).

[0331] Example 2 Synthesis of 2-((4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-2)

[0332]

[0333] Step 1: tert-Butyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1H-benzoimidazole-6-carboxylate (I-2-1)

[0334] Dissolve compound IIIa (170 mg, 546.00 μmol) in acetonitrile (3 mL), add compound IIc (228.50 mg, 655.21 μmol), potassium carbonate (226.38 mg, 1.64 mmol) and potassium iodide (9.06 mg, 54.60 μmol), and stir at 50 °C for 4 hours. LCMS shows that the reaction is complete. Filter, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the target product I-2-1 (110 mg). LC-MS (ESI, m / z) 624 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.90 - 7.79 (m, 2H), 7.74 - 7.61 (m, 4H), 6.88 (d, 1H), 6.72 (d, 1H), 5.75 (s, 1H), 5.67 - 5.60 (m, 2H), 5.47 (s, 2H), 3.89 (s, 2H), 2.89 (d, 2H), 2.21 (t, 2H), 1.77 - 1.69 (m, 4H), 1.58 (s, 9H).

[0335] Step 2: 2-(4-(4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1H-benzoimidazole-6-carboxylic acid (I-2)

[0336] Dissolve compound I-2-1 (110 mg, 176.38 μmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir the reaction at room temperature for 2 hours. Rotate the reaction solution to dryness, and purify the crude product by preparative chromatography to obtain the target product I-2 (34.93 mg). LC-MS (ESI, m / z) 568 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.36 (s, 1H), 7.89 (d, 2H), 7.74 - 7.63 (m, 4H), 6.90 (d, 1H), 6.74 (d, 1H), 5.67 - 5.61 (m, 2H), 5.48 (s, 2H), 3.89 (s, 2H), 2.91 (s, 2H), 2.67 - 2.52 (m, 1H), 2.29 - 2.10 (m, 2H), 1.85 - 1.62 (m, 4H).

[0337] Example 3 Synthesis of 2-((5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-3)

[0338]

[0339] Step 1: 2-((5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (I-3-1)

[0340] Compound IIIb (170 mg, 546.00 μmol) was dissolved in acetonitrile (3 mL), and compound IIa (228.50 mg, 655.21 μmmol), potassium carbonate (226.38 mg, 1.64 mmol) and potassium iodide (9.06 mg, 54.60 μmol) were added. The mixture was heated to 50 °C and stirred for 4 hours. LCMS showed that the reaction was complete. The mixture was filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the target product I-3-1 (110 mg). LC-MS (ESI, m / z) 624 [M+H] + .

[0341] Step 2: 2-((5-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-3)

[0342] Compound I-3-1 (110 mg, 176.38 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. It was concentrated under reduced pressure and purified by preparative chromatography to obtain the target product I-3 (34.9 mg). LC-MS (ESI, m / z) 568 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 8.02 (d, 1H), 7.75 (d, 1H), 7.70 - 7.50 (m, 4H), 6.96 (d, 1H), 6.78 (d, 1H), 5.55 (s, 2H), 5.30 - 5.19 (m, 1H), 4.83 - 4.59 (m, 6H), 4.47 - 4.41 (m, 1H), 4.15 (s, 1H), 3.37 - 3.36 (m, 1H), 3.18 - 3.14 (m, 1H), 2.90 - 2.77 (m, 1H), 2.70 (s, 1H), 2.59 - 2.46 (m, 1H), 2.45 - 2.33 (m, 1H), 2.32 - 2.20 (m, 1H), 2.10 (d, 1H), 1.90 (d, 1H).

[0343] Synthesis of Comparative Example (S)-2-((4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-4, i.e., PF-06882961)

[0344]

[0345] Step 1: Synthesis of tert-butyl (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-4-1)

[0346] Dissolve compound IIIa (100 mg, 321.18 μmol) in acetonitrile (2 mL), add compound IIa (129.81 mg, 385.41 μmmol), potassium carbonate (133.17 mg, 963.54 μmmol) and potassium iodide (5.33 mg, 32.12 μmol), heat to 50 °C and stir the reaction for 4 hours. TLC shows that the reaction is complete. Quench with water, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-4-1 (35 mg). LC-MS (ESI, m / z) 612 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.89 (d, 1H), 7.76 (d, 1H), 7.70 (d, 2H), 7.64 (d, 2H), 6.89 (d, 1H), 6.73 (d, 1H), 5.48 (s, 2H), 5.14 - 5.09 (m, 1H), 4.83 - 4.77 (m, 1H), 4.69 - 4.64 (m, 1H), 4.52 - 4.47 (m, 1H), 4.43 - 4.37 (m, 1H), 3.95 (d, 1H), 3.78 (d, 1H), 2.98 (d, 1H), 2.83 (d, 1H), 2.74 - 2.68 (m, 1H), 2.60 (d, 1H), 2.45 (d, 1H), 2.27 - 2.11 (m, 2H), 1.83 - 1.64 (m, 4H), 1.57 (s, 9H).

[0347] Step 2: (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-4, i.e., PF-06882961)

[0348] Compound I-4-1 (35 mg, 65.00 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative chromatography to obtain the target product (9.34 mg). LC-MS (ESI, m / z) 556 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.37 (s, 1H), 7.90 (d, 2H), 7.80 (d, 1H), 7.75 - 7.70 (m, 3H), 6.95 (d, 1H), 6.79 (d, 1H), 5.50 (s, 2H), 5.08 - 5.04 (m, 1H), 4.85 - 4.79 (m, 2H), 4.68 (d, 1H), 4.52 - 4.47 (m, 1H), 4.37 - 4.31 (m, 1H), 3.88 - 3.66 (m, 2H), 2.92 (s, 1H), 2.76 - 2.67 (m, 1H), 2.54 (t, 3H), 2.38 - 2.28 (m, 1H), 2.05 (s, 4H).

[0349] Synthesis of Example 4 (S)-2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-5)

[0350]

[0351] Step 1: (S)-2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (I-5-1)

[0352] Compound IIId (173 mg, 517.36 μmol) was dissolved in acetonitrile (5 mL), and Compound IIa (209.10 mg, 620.83 μmol), potassium iodide (8.59 mg, 51.74 μmol) and potassium carbonate (214.51 mg, 1.55 mmol) were added. The reaction was stirred at 50 °C for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the title compound I-5-1 (200 mg). LC-MS (ESI, m / z) 635 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.94 - 7.84 (m, 2H), 7.76 (d, 1H), 7.69 - 7.56 (m, 2H), 7.52 (d, 1H), 7.18 (t, 1H), 7.03 (d, 1H), 6.48 (d, 1H), 5.57 (s, 2H), 5.11 (d, 1H), 4.79 (dd, 1H), 4.66 (dd, 1H), 4.51 - 4.36 (m, 2H), 3.95 (d, 1H), 3.77 (d, 1H), 3.00 (d, 1H), 2.84 (d, 1H), 2.75 - 2.65 (m, 2H), 2.45 (s, 1H), 2.21 (dd, 2H), 1.77 (d, 4H), 1.57 (s, 9H).

[0353] Step 2: (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-5)

[0354] Compound I-5-1 (180 mg, 283.58 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 2 hours. Concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain the title compound I-5 (59 mg). LC-MS (ESI, m / z) 579 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, 1H), 7.93 - 7.83 (m, 2H), 7.80 (dd, 1H), 7.63 - 7.57 (m, 2H), 7.52 (d, 1H), 7.18 (t, 1H), 7.03 (d, 1H), 6.48 (d, 1H), 5.57 (s, 2H), 5.11 (m, 1H), 4.79 (dd, 1H), 4.66 (dd, 1H), 4.47 (td, 1H), 4.39 (dt, 1H), 3.95 (d, 1H), 3.77 (d, 1H), 3.00 (d, 1H), 2.86 (d, 1H), 2.77 - 2.64 (m, 2H), 2.48 - 2.40 (m, 1H), 2.22 (m, 2H), 1.80 (m, 4H).

[0355] Synthesis of Example 5 (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-indol-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-6)

[0356]

[0357] Step 1: Synthesis of tert-butyl (S)-2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-indol-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-6-1)

[0358] Dissolve compound IIIf (150 mg, 0.45 mmol) and compound IVa (181.84 mg, 1.35 mmol) in acetonitrile (2 mL), add potassium carbonate (186.54 mg, 1.35 mmol) and potassium iodide (7.47 mg, 0.04 mmol), heat to 50 °C and stir for 5 hours. Cool to room temperature, add ethyl acetate to dilute the reaction solution, filter and concentrate, and purify the residue by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-6-1 (192 mg). LC-MS (ESI, m / z) 634 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, 1H), 7.88 (dd, 1.6 Hz, 1H), 7.75 (dd, 1H), 7.63 (d, 1H), 7.61 - 7.58 (m, 1H), 7.47 (d, 1H), 7.38 (d, 1H), 7.30 (s, 1H), 6.97 (q, 2H), 6.45 (d, 1H), 5.75 (s, 1H), 5.56 (s, 2H), 5.12 - 5.07 (m, 1H), 4.82 - 4.76 (m, 1H), 4.66 (dd, 1H), 4.49 (t, 1H), 4.40 - 4.36 (m, 1H), 3.94 (d, 1H), 3.78 (d, 1H), 3.57 (s, 1H), 3.00 (d, 1H), 2.84 (s, 1H), 2.68 (d, 1H), 2.26 - 2.15 (m, 2H), 1.74 (d, 2H), 1.68 - 1.60 (m, 2H), 1.57 (s, 9H).

[0359] Step 2: (S)-2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-indol-6-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-6)

[0360] Compound I-6-1 (170 mg, 268.24 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.0 mL, 13.07 mmol) was added, and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative chromatography to obtain the title compound I-6 (150.1 mg). LC-MS (ESI, m / z) 578 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.52 (s, 4H), 8.26 (s, 1H), 7.97 (d, 1H), 7.64 - 7.56 (m, 2H), 7.49 (d, 1H), 7.41 (dd, 1H), 7.23 (d, 1H), 7.16 (s, 1H), 6.98 (dd, 1H), 6.89 (t, 1H), 6.48 (d, 1H), 5.52 (s, 2H), 5.27 (d, 1H), 4.72 (dd, 2H), 4.66 - 4.55 (m, 3H), 4.47 (dt, 1H), 4.02 (d, 1H), 3.91 (d, 1H), 3.07 (d, 1H), 2.97 (d, 1H), 2.79 (dt, 1H), 2.65 - 2.49 (m, 2H), 2.32 (dt, 2H), 2.03 (d, 1H), 1.77 (d, 1H).

[0361] Synthesis of Example 6 (S)-2-((4-(1-(4-cyanobenzyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-7)

[0362]

[0363] Step 1: (S)-2-((4-(1-(4-cyanobenzyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (I-7-1)

[0364] Compound IIIg (106 mg, 448.58 μmol) and compound IIa (129.28 mg, 383.84 μmol) were dissolved in acetonitrile (5 mL), potassium carbonate (132.62 mg, 953.61 μmol) and potassium iodide (5.31 mg, 31.99 μmol) were added, and the mixture was heated to 50 °C and stirred for reaction for 17 h. After cooling to room temperature, ethyl acetate was added to dilute the reaction solution, filtered and concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-7-1 (90 mg). LC-MS (ESI, m / z) 632 [M+H] + .

[0365] Step 2: (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-indol-6-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-7)

[0366] Compound I-7-1 (90 mg, 252.07 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL, 26.14 mmol) was added, and the mixture was stirred at room temperature for reaction for 1.5 h. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-7 (10.0 mg). LC-MS (ESI, m / z) 576 [M+H] + .

[0367] Example 7 Synthesis of (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-indol-6-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-8)

[0368]

[0369] Step 1: (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-indol-6-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (I-8-1)

[0370] Compound IIIh (150 mg, 448.58 μmol) and compound IIa (181.30 mg, 538.29 μmol) were dissolved in acetonitrile (2 mL), potassium carbonate (185.99 mg, 1.35 mmol) and potassium iodide (7.45 mg, 44.86 μmol) were added, and the mixture was heated to 50 °C and stirred for 5 hours. After cooling to room temperature, it was diluted with ethyl acetate, filtered and concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-8-1 (188 mg). LC-MS (ESI, m / z) 635 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.24 - 8.20 (m, 1H), 7.87 (dd, 1H), 7.76 (dd, 1H), 7.64 (d, 1H), 7.60 (dd, 1H), 7.39 (d, 1H), 7.25 (d, 1H), 6.93 (dd, 2H), 6.80 (dd, 1H), 6.38 (d, 1H), 5.50 (s, 2H), 5.09 (tt, 1H), 4.78 (dd, 1H), 4.68 - 4.62 (m, 1H), 4.51 - 4.46 (m, 1H), 4.38 (dt, 1H), 3.99 (d, 1H), 3.82 (d, 1H), 3.07 (s, 4H), 2.64 (dt, 6H), 1.57 (s, 9H).

[0371] Step 2: (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-indol-6-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-8)

[0372] Compound I-8-1 (160 mg, 252.1 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. It was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the title compound I-8 (58 mg). LC-MS (ESI, m / z) 579 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.30 (s, 1H), 7.88 (dd, 1H), 7.83 (d, 1H), 7.68 (d, 1H), 7.60 (dd, 1H), 7.41 (d, 1H), 7.26 (d, 1H), 6.97 - 6.89 (m, 2H), 6.82 (dd, 1H), 6.39 (d, 1H), 5.52 (s, 2H), 5.11 - 5.04 (m, 1H), 4.80 (dd, 1H), 4.66 (dd, 1H), 4.51 - 4.46 (m, 1H), 4.37 (dt, 1H), 3.13 (s, 4H), 2.76 - 2.59 (m, 3H), 2.41 (d, 1H).

[0373] Synthesis of Example 8 (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-9)

[0374]

[0375] Step 1: (S)-2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid tert-butyl ester (I-9-1)

[0376] Dissolve Compound IIIi (250 mg, 745.43 μmol) in acetonitrile (3 mL), add Compound IIa (301.28 mg, 894.51 μmol), potassium carbonate (309.07 mg, 2.24 mmol) and potassium iodide (12.37 mg, 74.54 μmol), heat to 50 °C and stir the reaction for 5 hours. Cool to room temperature, dilute with ethyl acetate, filter and concentrate. The residue is purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-9-1 (117 mg). LC-MS (ESI, m / z) 636 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.23 (d, 1H), 8.13 (s, 1H), 7.91 - 7.88 (m, 1H), 7.77 - 7.75 (m, 1H), 7.68 - 7.60 (m, 2H), 7.49 (d, 1H), 7.23 (t, 1H), 7.03 - 6.91 (m, 2H), 5.59 (s, 2H), 5.10 - 5.08 (m, 1H), 4.81 - 4.75 (m, 1H), 4.67 - 4.62 (m, 1H), 4.52 - 4.44 (m, 1H), 4.41 - 4.36 (m, 1H), 3.99 (d, 1H), 3.82 (d, 1H), 3.17 (d, 2H), 3.09 (d, 4H), 2.68 - 2.59 (m, 4H), 1.57 (s, 9H).

[0377] Step 2: (S)-2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-9)

[0378] Dissolve compound I-9-1 (117 mg, 0.18 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. LCMS shows that the reaction is complete. Concentrate under reduced pressure, and the crude product is obtained as the title compound I-9 (19.94 mg) by preparative chromatography. LC-MS (ESI, m / z) 580 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, 2H), 7.92 - 7.89 (m, 1H), 7.81 - 7.78 (m, 1H), 7.67 - 7.65 (m, 1H), 7.51 (t, 2H), 7.25 (t, 1H), 6.99 (d, 1H), 6.96 - 6.92 (m, 1H), 5.60 (s, 2H), 5.11 - 5.09 (m, 1H), 4.78 - 4.72 (m, 1H), 4.64 - 4.60 (m, 1H), 4.53 - 4.46 (m, 1H), 4.41 - 4.35 (m, 1H), 3.97 (d, 1H), 3.81 (d, 1H), 3.11 (t, 4H), 2.74 - 2.60 (m, 5H), 2.44 (t, 1H).

[0379] Example 9 Synthesis of 2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-10)

[0380]

[0381] Step 1: tert-Butyl 2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carboxylate (I-10-1)

[0382] Dissolve compound IIId (173 mg, 517.36 μmol) in acetonitrile (5 mL), add compound IIc (216.5 mg, 620.83 μmol), potassium iodide (8.59 mg, 51.74 μmol, 2.75 μL) and potassium carbonate (214.51 mg, 1.55 mmol), heat to 50 °C and stir for reaction for 16 hours. Cool to room temperature, dilute with ethyl acetate, filter and concentrate, and purify the residue by silica gel column chromatography (PE:EA = 1:1) to obtain the title compound I-10-1 (252 mg). LC-MS (ESI, m / z) 647 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.97 (d, 1H), 7.83 (d, 1H), 7.74 (d, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.16 (d, 1H), 6.97 (d, 1H), 6.46 (d, 1H), 5.56 (s, 2H), 5.39 - 5.29 (m, 2H), 3.97 (s, 2H), 2.95 (d, 2H), 2.81 (s, 1H), 2.34 (t, 2H), 1.98 - 1.87 (m, 4H), 1.63 (s, 9H).

[0383] Step 2: 2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-10)

[0384] Dissolve I-10-1 (180 mg, 283.58 μmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), stir at room temperature for reaction for 2 hours. Concentrate under reduced pressure, and purify the crude product by preparative liquid chromatography to obtain the title compound I-10 (70 mg). LC-MS (ESI, m / z) 591 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.92 - 7.83 (m, 3H), 7.71 (d, 1H), 7.60 (dd, 1H), 7.53 (d, 1H), 7.22 (t, 1H), 7.02 (d, 1H), 6.47 (d, 1H), 5.65 (q, 2H), 5.56 (s, 2H), 3.89 (s, 2H), 2.92 (d, 2H), 2.73 (m, 1H), 2.25 (m, 2H), 1.86 - 1.74 (m, 4H).

[0385] Example 10 Synthesis of 2 - ((6 - ((4 - cyano - 2 - fluorobenzyl)oxy) - 3',6' - dihydro - [2,4' - bipyridin] - 1'(2'H) - yl)methyl) - 1 - (cyanomethyl) - 1H - benzo[d]imidazole - 6 - carboxylic acid (I - 11)

[0386]

[0387] Step 1: tert - Butyl 2 - ((6 - ((4 - cyano - 2 - fluorobenzyl)oxy) - 3',6' - dihydro - [2,4' - bipyridin] - 1'(2'H) - yl)methyl) - 1 - (cyanomethyl) - 1H - benzo[d]imidazole - 6 - carboxylate (I - 11 - 1)

[0388] Dissolve compound IIIb (140 mg, 452.58 μmol) in acetonitrile (3 mL), add compound IIb (166.06 mg, 543.10 μmmol), potassium carbonate (187.65 mg, 1.36 mmol) and potassium iodide (7.51 mg, 45.26 μmol), heat to 50 °C and stir the reaction for 4 hours. Cool to room temperature, dilute with ethyl acetate, filter and concentrate. Purify the residue by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I - 11 - 1 (220 mg). LC - MS (ESI, m / z) 579 [M + H] + . 1 1H NMR (400 MHz, DMSO - d6) δ 8.28 (d, 1H), 7.90 - 7.85 (m, 2H), 7.74 - 7.68 (m, 4H), 7.10 (d, 1H), 6.78 (d, 1H), 6.72 (s, 1H), 5.75 (s, 2H), 5.50 (s, 2H), 4.03 (d, 2H), 3.28 (s, 2H), 2.67 (t, 2H), 2.53 (s, 2H), 1.60 (s, 9H).

[0389] Step 2: 2-((6-((4-Cyano-2-fluorobenzyl)oxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-12)

[0390] Dissolve compound I-12-1 (220 mg, 380.21 μmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), stir at room temperature for 2 hours, concentrate under reduced pressure, and purify the crude product by preparative liquid chromatography to obtain the title compound I-11 (75.91 mg). LC-MS (ESI, m / z) 523 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, 1H), 7.92 - 7.85 (m, 2H), 7.73 - 7.62 (m, 4H), 7.09 (d, 1H), 6.76 (d, 1H), 6.71 (d, 1H), 5.71 (s, 2H), 5.49 (s, 2H), 4.00 (s, 2H), 3.31 - 3.22 (m, 4H), 2.66 (t, 2H).

[0391] Example 11 Synthesis of 2-((4-(1-(4-Cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazole-6-carboxylic acid (I-12)

[0392]

[0393] Step 1: tert-Butyl 2-((4-(1-(4-cyano-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-1-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazole-6-carboxylate (I-12-1)

[0394] Dissolve compound IIId (173 mg, 517.36 μmol) in acetonitrile (3 mL), add compound IIb (205.64 mg, 672.57 μmol), potassium carbonate (214.51 mg, 1.55 mmol) and potassium iodide (8.59 mg, 51.74 μmol), heat to 50 °C and stir for 16 hours. Cool to room temperature, dilute with ethyl acetate, filter and concentrate, and purify the residue by silica gel column chromatography (PE:EA = 1:1) to obtain the title compound I-12-1 (260 mg). LC-MS (ESI, m / z) 604 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H), 8.00 (dd, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.41 - 7.26 (m, 3H), 7.17 (d, 1H), 6.98 (d, 1H), 6.45 (d, 1H), 5.66 - 5.47 (m, 4H), 4.00 (s, 2H), 3.00 - 2.78 (m, 3H), 2.4 - 2.34 (m, 2H), 2.07 - 1.98 (m, 4H), 1.64 (s, 9H).

[0395] Step 2: 2 - ((4 - (1 - (4 - Cyano - 2 - fluorobenzyl) - 1H - pyrrolo[2,3 - b]pyridin - 6 - yl)piperidin - 1 - yl)methyl) - 1 - (cyanomethyl) - 1H - benzo[d]imidazole - 6 - carboxylic acid (I - 12)

[0396] Dissolve I - 12 - 1 (240 mg) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir the reaction at room temperature for 2 hours. Concentrate under reduced pressure, and purify the crude product by preparative liquid chromatography to obtain the title compound I - 12 (70 mg). LC - MS (ESI, m / z) 548 [M + H] + . 1 1H NMR (400 MHz, DMSO - d6) δ 12.97 (s, 1H), 8.39 (s, 1H), 7.97 - 7.83 (m, 3H), 7.82 - 7.70 (m, 1H), 7.60 (dd, 1H), 7.53 (d, 1H), 7.24 (t, 1H), 7.03 (d, 1H), 6.49 (d, 1H), 5.79 (s, 2H), 5.56 (s, 2H), 4.14 - 3.70 (m, 2H), 3.09 - 2.61 (m, 3H), 2.47 - 2.11 (m, 2H), 2.07 - 1.75 (m, 4H).

[0397] Example 12 Synthesis of 2 - ((4 - (1 - (4 - Cyano - 2 - fluorobenzyl) - 1H - indol - 6 - yl)piperazin - 1 - yl)methyl) - 1 - (cyanomethyl) - 1H - benzo[d]imidazole - 6 - carboxylic acid (I - 13)

[0398]

[0399] Step 1: 2 - ((4 - (1 - (4 - Cyano - 2 - fluorobenzyl) - 1H - indol - 6 - yl)piperazin - 1 - yl)methyl) - 1 - (cyanomethyl) - 1H - benzo[d]imidazole - 6 - tert - butyl ester

[0400] Compound IIIh (188 mg, 562.22 μmol) was dissolved in acetonitrile (3 mL), and compound IIb (206.28 mg, 674.66 μmol), potassium carbonate (233.11 mg, 1.69 mmol) and potassium iodide (9.33 mg, 56.22 μmol) were added. The mixture was heated to 50 °C and stirred for 5 h. After cooling to room temperature, it was diluted with ethyl acetate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the title compound I-13-1 (262 mg). LC-MS (ESI, m / z) 604 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 1.5 Hz, 1H), 7.88 - 7.83 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 7.9, 1.6 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 3.2 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H), 6.91 - 6.86 (m, 1H), 6.79 (dd, J = 8.7, 2.0 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 5.75 (s, 2H), 5.50 (s, 2H), 3.95 (s, 2H), 3.12 (d, J = 5.2 Hz, 4H), 2.60 (t, J = 4.9 Hz, 4H), 1.59 (s, 9H).

[0401] Step 2: 2 - ((4 - (1 - (4 - cyano - 2 - fluorobenzyl)-1H - indol - 6 - yl)piperazin - 1 - yl)methyl)-1 - (cyanomethyl)-1H - benz[d]imidazole - 6 - carboxylic acid (I - 13)

[0402] Compound I - 13 - 1 (255 mg, 422.40 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. It was concentrated under reduced pressure, and the crude product was purified by preparative liquid chromatography to obtain the title compound I - 13 (135 mg). LC-MS (ESI, m / z) 548 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.37 (d, 1H), 7.91 (dd, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 7.59 (dd, 1H), 7.41 (d, 1H), 7.26 (d, 1H), 6.97 - 6.90 (m, 2H), 6.81 (dd, 1H), 6.39 (d, 1H), 5.77 (s, 2H), 5.51 (s, 2H), 4.08 (s, 2H), 3.18 (s, 4H), 2.95 - 2.58 (m, 4H).

[0403] Example 13 Synthesis of 2 - ((6 - ((4 - cyano - 2 - fluorobenzyl)oxy) - 5 - fluoro - 3',6'-dihydro - [2,4'-bipyridin] - 1'(2'H)-yl)methyl) - 1 - (cyanomethyl) - 1H - benzo[d]imidazole - 6 - carboxylic acid (I - 14)

[0404]

[0405] Step 1: tert - butyl 2 - (6 - ((4 - cyano - 2 - fluorobenzyl)oxy) - 5 - fluoro - 3,6 - dihydro - [2,4 - bipyridin] - 1 - cyanomethyl) - 1 - cyanomethyl - 1H - benzoimidazole - 6 - carboxylate

[0406] Dissolve compound IIIL (300 mg, 916.51 μmol) in acetonitrile (5 mL), add compound IIb (280.23 mg, 916.51 μmmol), potassium carbonate (380 mg, 2.75 mmol), potassium iodide (15.21 mg, 91.65 μmol), and stir at 50 °C for 3 hours. LCMS shows that the reaction is complete, then concentrate under reduced pressure and purify by column chromatography (DCM:MeOH = 20:1) to obtain the title compound I - 14 - 1 (322 mg). LC - MS (ESI, m / z) 597 [M + H] + .

[0407] Step 2: 2 - ((6 - ((4 - cyano - 2 - fluorobenzyl)oxy) - 5 - fluoro - 3',6'-dihydro - [2,4'-bipyridin] - 1'(2'H)-yl)methyl) - 1 - (cyanomethyl) - 1H - benzo[d]imidazole - 6 - carboxylic acid

[0408] Dissolve I - 14 - 1 (300 mg, 502.83 μmol) in 3 mL of dichloromethane and 1 mL of trifluoroacetic acid, and stir at room temperature for 2 hours. LCMS shows that the reaction is complete, concentrate under reduced pressure, and purify the crude product by Prep - HPLC to obtain the title compound I - 14 (66.79 mg). LC - MS (ESI, m / z) 541 [M + H]+ ; 1 H NMR(400MHz, DMSO-d6) δ 8.26(d, 1H), 7.92 - 7.87(m, 2H), 7.74 - 7.61(m, 4H), 7.11(dd, 1H), 6.64(t, 1H), 5.70(s, 2H), 5.57(s, 2H), 4.00(s, 2H), 3.26(d, 4H), 2.66(t, 2H).

[0409] Example 14 Synthesis of 2 - ((4 - (4 - ((4 - cyano - 2 - fluorobenzyl)oxy)-5 - fluoropyrimidin - 2 - yl)-3,6 - dihydropyridin - 1(2H)-yl)methyl)-1-(cyanomethyl)-1H - benzo[d]imidazole - 6 - carboxylic acid (I - 15)

[0410]

[0411] Step 1: tert - butyl 2 - ((4 - (4 - ((4 - cyano - 2 - fluorobenzyl)oxy)-5 - fluoropyrimidin - 2 - yl)-3,6 - dihydropyridin - 1(2H)-yl)methyl)-1-(cyanomethyl)-1H - benzo[d]imidazole - 6 - carboxylate (I - 15 - 1)

[0412] Dissolve compound IIIm (161.07 mg, 490.58 μmol) in acetonitrile (10 mL), add compound IIb (150.00 mg, 490.58 μmol), K2CO3 (203.40 mg, 1.47 mmol), KI (8.14 mg, 49.06 μmol), and heat to 60 °C with stirring for 2 hours. Cool the reaction solution, concentrate to remove the solvent, and purify the crude product by silica gel column chromatography (PE:EA = 2:1) to obtain the title compound I - 15 - 1 (245 mg). LC - MS (ESI, m / z) 598 [M + H] + . 1 H NMR(400MHz, Chloroform - d) δ 8.32(d, 1H), 8.12 - 8.10(m, 1H), 8.02(dd, 1H), 7.77(dd, 1H), 7.64(t, 1H), 7.49(dd, 1H), 7.40(dd, 1H), 7.05(s, 1H), 5.61(s, 2H), 4.14(s, 2H), 2.93 - 2.65(m, 4H), 1.64(s, 9H).

[0413] Step 2: 2 - ((4 - (4 - ((4 - cyano - 2 - fluorobenzyl)oxy)-5 - fluoropyrimidin - 2 - yl)-3,6 - dihydropyridin - 1(2H)-yl)methyl)-1-(cyanomethyl)-1H - benzo[d]imidazole - 6 - carboxylic acid (I - 15)

[0414] Compound I-15-1 (240 mg, 401.60 μmol) was added to DCM (6 mL), and TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour. It was concentrated, and the crude product was purified by Prep-HPLC to obtain Compound I-15 (63.19 mg). LC-MS (ESI, m / z) 542 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.32 (d, 1H), 7.91 (td, 2H), 7.80 - 7.68 (m, 3H), 7.06 (d, 1H), 5.73 (s, 2H), 5.66 (s, 2H), 4.03 (s, 2H), 2.67 (t, 2H), 2.59 (s, 2H), 2.52 (s, 2H).

[0415] Synthesis of Example 15 (S)-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-16)

[0416]

[0417] Step 1: (S)-4-(((6-(1-((6-(6-bromo-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-16-1)

[0418] Compound IIIa (300 mg, 963.5 μmol) was dissolved in DMF (8 mL), and Compound IId (413 mg, 963.5 μmol) and DIPEA (373.6 mg, 2.89 mmol) were added. The mixture was stirred at room temperature for 4 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound I-16-1 (322 mg). LC-MS (ESI, m / z) 590 [M+H] + .

[0419] Step 2: Di-tert-butyl (S)-(2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonate (IId-2)

[0420] Under nitrogen protection, dissolve compound IId-1 (300 mg, 508.05 μmol) and di-tert-butyl phosphite (148 mg, 762.07 μmol) in anhydrous tetrahydrofuran (8 mL), add palladium acetate (11.4 mg, 50.80 μmol), 1,1'-bis(diphenylphosphino)ferrocene (65 mg, 101.61 μmol), potassium acetate (100 mg, 1.02 mmol) and triethylamine (132 μL, 1.0 mmol), and raise the temperature to 68 °C and stir the reaction for 15 hours. Cool to room temperature, dilute with dichloromethane (200 mL), filter and concentrate. The crude product is purified by silica gel column chromatography (ethyl acetate / n-hexane) to obtain the target product IId-2 (168 mg), LCMS (m / z): 704 (M+H + ).

[0421] Step 3: (S)-(2-((4-(6-((4-Cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-16-1)

[0422] Dissolve I-16-1 (150 mg, 213.1 μmol) in DCM (4.5 mL), add TFA (1.5 mL), stir at 25 °C for 12 hours, concentrate the reaction solution, and purify the crude product by Prep-HPLC to obtain the title compound I-16 (38 mg). LC-MS (ESI, m / z) 592 [M+H] + .

[0423] Example 16 Synthesis of (S)-(2-((6-((4-Cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-17)

[0424]

[0425] Step 1: Di-tert-butyl (S)-(2-((6-((4-Cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonate (I-17-1)

[0426] Dissolve compound IIIb (300 mg, 969.8 μmol) in DMF (8 mL), add compound IId (416 mg, 969.8 μmol), DIPEA (376 mg, 2.91 mmol), and stir at room temperature for 3 hours. Add water (20 mL), extract with ethyl acetate (20 mL × 2), separate the layers, dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound I-17-1 (322 mg). LC-MS (ESI, m / z) 702 [M+H] + .

[0427] Step 2: (S)-(2-((6-((4-Cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-17)

[0428] Dissolve compound I-17-1 (150 mg, 213.7 μmol) in DCM (4.5 mL), add TFA (1.5 mL), stir at 25 °C for 12 hours, concentrate the reaction solution, and purify the crude product by Prep-HPLC to obtain the title compound I-17 (42 mg). LC-MS (ESI, m / z) 590 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, 2H), 7.72–7.65 (m, 3H), 7.53 (d, 2H), 7.07 (d, 1H), 6.76 (d, 1H), 6.69 (s, 1H), 5.48 (s, 2H), 4.97 (s, 1H), 4.61 (s, 1H), 4.51 (s, 1H), 4.38 (s, 1H), 4.28 (s, 1H), 4.01 (d, 1H), 3.86 (d, 1H), 3.16 (d, 4H), 2.68 (d, 2H), 2.46 (d, 1H), 2.32 (s, 1H).

[0429] Synthesis of Example 17 (S)-(2-((6-((4-Cyano-2-fluorobenzyl)oxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-18)

[0430]

[0431] Step 1: Di-tert-butyl (S)-(2-((6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonate (I-18-1)

[0432] Dissolve IIIL (300 mg, 916.5 μmol) in DMF (8 mL), add IId (393.08 mg, 916.5 μmol) and DIPEA (355 mg, 2.75 mmol), stir at 25 °C for 3 h. Add water (20 mL), extract with ethyl acetate (20 mL x 2), separate the layers, dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound I-18-1 (302 mg). LC-MS (ESI, m / z) 720 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.06 - 8.00 (m, 1H), 7.89 (d, 1H), 7.76–7.60 (m, 4H), 7.55–7.42 (m, 1H), 7.13–7.09 (d, 1H), 6.63 (s, 1H), 5.58 (s, 2H), 5.11 (d, 1H), 5.08–5.03 (m, 2H), 4.79–4.70 (m, 1H), 4.66–4.56 (m, 1H), 4.47–4.42 (m, 1H), 4.33 - 4.27 (m, 1H), 3.25 - 3.18 (m, 2H), 2.73 - 2.59 (m, 2H), 2.49 - 2.33 (m, 4H), 1.39 (s, 18H).

[0433] Step 2: (S)-(2-((6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-18)

[0434] Dissolve I-18-1 (150 mg, 208.4 μmol) in DCM (4.5 mL), add TFA (1.5 mL), stir at 25 °C for 12 h, concentrate the reaction solution, and purify the crude product by Prep-HPLC to obtain the title compound I-18 (35 mg). LC-MS (ESI, m / z) 608 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.93–7.87 (m, 2H), 7.73–7.70 (m, 2H), 7.66 (dd, J = 8.2 Hz, 1H), 7.58 (s, 1H), 7.55–7.46 (m, 1H), 7.10 (dd, 1H), 6.63 (s, 1H), 5.57 (s, 2H), 5.01 (s, 1H), 4.73–4.64 (m, 1H), 4.56 (d, 1H), 4.46–4.40 (m, 1H), 4.33 (dd, 1H), 4.03 (d, 1H), 3.89 (d, 1H), 3.21 (s, 4H), 2.74–2.66 (m, 2H), 2.46 (s, 1H), 2.35 (s, 1H).

[0435] Synthesis of Example 18 (2-((6-((4-Cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-19)

[0436]

[0437] Step 1: Di-tert-butyl (2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]

[0438] imidazol-6-yl)phosphonate (I-19-1)

[0439] Dissolve compound IIIb (300 mg, 969.8 μmol) in DMF (8 mL), add compound IIe (416 mg, 969.8 μmol), DIPEA (376 mg, 2.91 mmol), and stir at 25 °C for 3 hours. Add water (20 mL), extract with ethyl acetate (20 mL x 2), separate the layers, dry the organic layer over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the title compound I-19-1 (314 mg). LC-MS (ESI, m / z) 671 [M+H] + .

[0440] Step 2: (2-((6-((4-Cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-1-(cyanomethyl)-1H-benzo[d]imidazol-6-yl)phosphonic acid (I-19)

[0441] Dissolve I-19-1 (150 mg, 213.7 μmol) in DCM (4.5 mL), add TFA (1.5 mL), stir at 25 °C for 12 h, concentrate the reaction solution, and purify the crude product by Prep-HPLC to obtain the title compound I-19 (41 mg). LC-MS (ESI, m / z) 559 [M+H] + .

[0442] Effect Example 1, In vitro Activity Evaluation of GLP-1 Receptor Agonist

[0443] Characterize the agonist activity of the compound by the change in cAMP content of CHO cells (Eurofins, 95-0062C2) stably expressing GLP-1R. Use a cAMP detection kit (Cisbio), and the test principle can be referred to the instruction manual of Cisbio CAMP-GSDYNAMIC KIT.

[0444] 1. Prepare the compound:

[0445] Dissolve the compound in DMSO, dilute it to 10 μM with PBS buffer, and dilute it in a 3-fold gradient. Take 10 data points for each. Transfer 100 nL of the compound to an OptiPlate-384 well plate and mix at 2000 rpm for 60 sec.

[0446] 2. Cell culture:

[0447] 1) Take out the GLP-1 stable cell line from the incubator and observe the cell state. When the cell density reaches 80% - 90%, remove the culture medium and wash the cells with 5 mL of DPBS.

[0448] 2) Remove DPBS, add 3 mL of 0.25% Trypsin-EDTA, and then incubate at 37 °C for 2 - 5 minutes.

[0449] 3) Add 10 mL of complete culture medium to the culture dish, then centrifuge at 1000 rpm for 4 minutes and remove the supernatant.

[0450] 4) Adjust the concentration of the cell suspension to 1000 cells per well using the stimulation buffer.

[0451] 3. HTRF cAMP Assay of the Agonist:

[0452] 1) Transfer 10 μl of the cell solution to a 384 well plate.

[0453] 2) Centrifuge at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes.

[0454] 3) Add 5 μL of 4-fold diluted Eu-cAMP tracer solution and 5 μL of 4-fold diluted ULight TM -anti-cAMP solution into a 384-well plate.

[0455] 4) Centrifuge at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes.

[0456] 5) Detect the cAMP signal using Envision.

[0457] 4. Data processing: Use GraphPad Prism (version 6.0) for data analysis and calculate the EC 50 value.

[0458] The results show that the compounds of the embodiments of the present invention have a significant agonist effect on the GLP-1 receptor, and their EC 50 values reach the nM level (see Table 1), and can be used alone as a drug for the treatment of diabetes.

[0459] Table 1. EC of some compounds of the embodiments of the present invention 50 data

[0460]

[0461]

[0462] The above embodiments of the present invention are merely examples for clearly illustrating the present invention, rather than limitations on the embodiments of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all the embodiments here. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; In formula (I), R 1-1 is hydrogen, C1-C6 alkyl or is replaced by one or more R 1-1-1 Substituted C1-C6 alkyl; Each R 1-1-1 Independently C6-C 10 Aryl; R 2 (i) or (ii) below: Case (i): R 2 For one or more R 2-1 Substituted C1-C6 alkyl; Each R 2-1 are independently -CN or halogen; Case (ii): R 2 For one or more R 2-2 Substituted C1-C6 alkyl; Each R 2-2 are independently -CN, halogen or 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are selected from one or more of N, S and O, and the number is 1, 2, 3 or 4; R 3 , R 4 , R 5 , R 6 and R 7 Each is independently hydrogen, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl or replaced by one or more R 4-2 Substituted C1-C6 alkyl; Each R 4-2 are independently halogen; When R 2 In case (i), L 1 for is a single bond or a double bond; When it is a single bond, X 1 is CH or N; When it is a double bond, X 1 is C; Each X 2 and X 3 Each independently is CR X-2 or N; Each R X-2 are each independently hydrogen or halogen; n is 0, 1 or 2; Each R X-1 are each independently a halogen; Each X 4 Each is independently selected from one of O, S and NH; When R 2 In case (ii), L 1 for is a single bond or a double bond; When it is a single bond, each Y 1 are each independently CH or N; When there is a double bond, each Y 1 is C; Each Y 8 are each independently CH or N; Each Y 2 , Y 3 , Y 4 , Y 5 and Y 6 Each independently is CR Y-2 or N; Each R Y-2 are each independently hydrogen or halogen; Each Y 7 Each is independently selected from one of a chemical bond, O, S and NH; m is 0, 1 or 2; Each R Y-1 are each independently a halogen; R Y-3 , R Y-4 , R Y-5 and R Y-6 Any two groups are linked together to form -(CH2) p -, the remaining groups are hydrogen; Each R Y-7 , R Y-8 , R Y-9 and R Y-10 each independently is hydrogen; Or, R Y-7 , R Y-8 , R Y-9 and R Y-10 Any two groups are linked together to form -(CH2) p -, the remaining groups are hydrogen; p is 1, 2, or 3; In formula (II), R 1-2 and R 1-3 Each independently represents hydrogen, an alkali metal ion, a C1-C6 alkyl group or one or more R 1-2-1 Substituted C1-C6 alkyl; Each R 1-2-1 Independently C6-C 10 Aryl; R 2a For one or more R 2a-1 Substituted C1-C6 alkyl; Each R 2a-1 are independently -CN, halogen or 3-6 membered heterocycloalkyl; the heteroatoms in the 3-6 membered heterocycloalkyl are selected from one or more of N, S and O, and the number is 1, 2, 3 or 4; R 3a , R 4a , R 5a , R 6a and R 7a Each is independently hydrogen, -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or substituted by one or more R 4a-2 Substituted C1-C6 alkyl; Each R 4a-2 are independently halogen; L 2 for is a single bond or a double bond; When Z is a single bond, 1 is CH or N; When Z is a double bond, 1 is C; Each Z 2 and Z 3 Each independently is CR Z-3 or N; Each R Z-3 are each independently hydrogen or halogen; Each Z 4 Each is independently selected from one of O, S and NH; q is 0, 1, or 2; Each R Z-1 are each independently a halogen; Or, R Z-1 Located in Z 4 The adjacent position, R Z-1 and Z 4 The carbon atoms connected to them form a 5-6 membered heterocycloalkenyl group, wherein the heteroatoms in the 5-6 membered heterocycloalkenyl group are selected from one or more of N, S and O, and the number of the heteroatoms is 1, 2, 3 or 4.

2. The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1)R 2 In the above, the one or more R 2-1 The C1-C6 alkyl in the substituted C1-C6 alkyl and the 2 -2 The C1-C6 alkyl in the substituted C1-C6 alkyl is each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, ethyl or isopropyl; (2)R 2-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (3)R 2-2 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (4)R 2-2 wherein the heteroatoms in the 3-6 membered heterocycloalkyl are selected from one or two of N, S and O; the number of heteroatoms in the 3-6 membered heterocycloalkyl is preferably 1 or 2; the 3-6 membered heterocycloalkyl may be a 3-membered, 4-membered, 5-membered or 6-membered monocyclic heterocycloalkyl; more preferably For example (5)R 3 , R 4 , R 5 , R 6 and R 7 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (6)R X-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (7)R Y-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (8)R 2a In the above, the one or more R 2a-1 The C1-C6 alkyl group in the substituted C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (9)R 2a-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (10)R 2a-1 wherein the heteroatoms in the 3-6 membered heterocycloalkyl are selected from one or two of N, S and O; the number of heteroatoms in the 3-6 membered heterocycloalkyl is preferably 1 or 2; the 3-6 membered heterocycloalkyl may be a 3-membered, 4-membered, 5-membered or 6-membered monocyclic heterocycloalkyl; more preferably For example (11)R 3a , R 4a , R 5a , R 6a and R 7a wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (12)R Z-1 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (13)R Z-1 and Z 4 The carbon atoms connected to them form a 5-6 membered heterocycloalkenyl group, wherein the heteroatoms in the 5-6 membered heterocycloalkenyl group are selected from one or two of N, S and O; the number of heteroatoms in the 5-6 membered heterocycloalkenyl group is preferably 1 or 2; the 5-6 membered heterocycloalkenyl group is more preferably a 5-membered monocyclic heterocycloalkenyl group; the 5-membered monocyclic heterocycloalkenyl group is, for example, Another example is and (14)R Y-3 , R Y-4 , R Y-5 and R Y-6 In, R Y-3 and R Y-6 Formation of -(CH2) p -, R Y-4 and R Y-5 is hydrogen; R Y-3 and R Y-5 Formation of -(CH2) p -, R Y-4 and R Y-6 is hydrogen; R Y-4 and R Y-5 Formation of -(CH2) p -, R Y-3 and R Y-6 For hydrogen.

3. The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof: R 1-1 , R 2 , R 3 , R 5 and L 1 as defined in claim 1 or 2; Preferably, When R 2 In case (i), L 1 for is a single bond or a double bond; When it is a single bond, X 1 for CH; When it is a double bond, X 1 is C; Each X 2 and X 3 Each independently is CR X-2 or N; Each R X-2 each independently is hydrogen; n is 0, 1 or 2; Each R X-1 are each independently a halogen; X 4 is O; When R 2 In case (ii), L 1 for is a single bond or a double bond; When it is a single bond, each Y 1 are each independently CH or N; When there is a double bond, each Y 1 Each is independently C; each Y 8 Each independently is N; Each Y 2 , Y 3 , Y 4 , Y 5 and Y 6 Each independently is CR Y-2 or N; Each R Y-2 are each independently hydrogen or halogen; Each Y 7 Each is independently selected from one of a chemical bond, O, S and NH; m is 0, 1 or 2; Each R Y-1 are each independently a halogen; R Y-3 , R Y-4 , R Y-5 and R Y-6 Any two groups are linked together to form -(CH2) p -, the remaining groups are hydrogen; each R Y-7 , R Y-8 , R Y-9 and R Y-10 each independently is hydrogen; p is 1, 2, or 3; R 3 is hydrogen or halogen; R 5 is -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is replaced by one or more R 4-2 Substituted C1-C6 alkyl; Each R 4-2 are independently halogen; More preferably, R 3 is halogen; R 5 is -CN; The compound of formula (II) or a pharmaceutically acceptable salt thereof is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof: R 1-2 , R 1-3 , R 2a , R 3a , R 5a and L 2 as defined in claim 1 or 2; Preferably, formula (II-1) is formula (II-1a), formula (II-1b) or formula (II-1c): More preferably, in formula (II-1a), formula (II-1b) and formula (II-1c), R 3a is hydrogen or halogen; R 5a is -CN, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, or is replaced by one or more R 4a-2 Substituted C1-C6 alkyl; Each R 4a-2 are independently halogen; Each Z 2 and Z 3 Each independently is CR Z-3 or N; Each R Z-3 are each independently hydrogen or halogen; Each Z 4 Each is independently selected from one of O, S and NH; q is 0, 1, or 2; Each R Z-1 are each independently a halogen; More preferably, R 3a is halogen; R 5a It is -CN.

4. The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof is the following scheme a or b; Scheme a: The compound of formula (I-1) or a pharmaceutically acceptable salt thereof is a compound of formula (I-2) or formula (I-3) or a pharmaceutically acceptable salt thereof: In formula (I-2) and formula (I-3), R 1-1 , R 2 , R 3 , R 5 , X 1 , X 2 , X 3 , X 4 , R x-1 and n is defined as in claim 3; Preferably, in formula (I-2) and formula (I-3), R 2 is a C1-C6 alkyl group substituted by one or more -CN; is a single bond or a double bond; X 1 is CH or C; Each X 2 and X 3 are each independently CH or N; n is 0; Scheme b: The compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-4) or a pharmaceutically acceptable salt thereof: R 2 , X 1 , X 2 , X 3 , X 4 , R x-1 and n is defined as in claim 3; Preferably, in formula (I-4), R 2 is a C1-C6 alkyl group substituted by one or more -CN; is a single bond or a double bond; X 1 is CH or C; Each X 2 and X 3 are each independently CH or N; n is 0; X 4 One selected from O, S and NH; More preferably, in formula (I-4), X 4 is O.

5. The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In formula (I), R 1-1 is hydrogen; (2) In formula (I), in case (i), R 2 for Preferably (3) In formula (I), in case (ii), R 2 for Preferably (4) In formula (I), R 3 is F; (5) In formula (I), R 4 is -CN; (6) In formula (I), when R 2 In case (i), L 1 for (7) In formula (I), when R 2 In case (ii), L 1 for (8) In formula (II), R 1-2 and R 1-3 each independently is hydrogen; (9) In formula (II), R 2a for (10) In formula (II), R 3a is F; (11) In formula (II), R 4a is -CN; (12) In formula (II), L 2 for 6. The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The compound represented by formula (I) or formula (II) is any of the following compounds:

7. The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that: The compound represented by formula (I) or formula (II) is any of the following compounds:

8. A method for preparing a compound of formula (I) as claimed in any one of claims 1 to 7, characterized in that: The method comprises the following steps: subjecting a compound represented by formula (IV-1) to a substitution reaction as shown below with a compound represented by formula (III-1) to obtain a compound represented by formula (I); Where: R 1-1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and L 1 The definition as described in any one of claims 1 to 7.

9. A pharmaceutical composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

10. Use of a substance A in the preparation of a medicament for treating and / or preventing cardiometabolic diseases and related diseases, wherein the related diseases are T2DM, insulin resistance, cirrhosis, cardiovascular disease, colitis or addiction; Preferred are prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other drugs, excessive sugar addiction, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, hepatocellular carcinoma, atherosclerosis, coronary artery disease, peripheral vascular disease, endothelial dysfunction, damaged blood vessels compliance, congestive heart failure, myocardial infarction, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, thrombosis, transient ischemic attack, poor glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, short bowel syndrome, Crohn's disease, irritable bowel syndrome, and polycystic ovary syndrome; The substance A is a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, or a pharmaceutical composition as described in claim 9.

11. Use of a substance A in the preparation of a drug for treating or preventing a disease associated with GLP-1; the substance A is as described in claim 10; the disease associated with GLP-1 is preferably T2DM, insulin resistance, cirrhosis, cardiovascular disease, colitis or addiction.

12. Use of substance A in the preparation of a GLP-1 receptor agonist; the substance A is as described in claim 10.

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