Ketokinase inhibitors and uses thereof

Abstract

The present invention relates to the field of medical technology, and specifically to a ketohexokinase inhibitor compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a method for preparing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, and use of the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof in preparing a drug for treating and / or preventing diseases mediated by KHK and related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and specifically to a ketohexokinase inhibitor compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a method for preparing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, and use of the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof in preparing a drug for treating and / or preventing diseases mediated by KHK and related diseases. Background Art

[0002] NAFLD / NASH is the hepatic manifestation of metabolic syndrome. Changes in diet and lifestyle have led to the prevalence of obesity and metabolic syndrome in Western countries and many Asian countries, resulting in a significant increase in the incidence of NAFLD, which has become one of the public health issues of great concern. Nonalcoholic steatohepatitis (NASH) is the result of the further development of simple fatty liver. Its pathological manifestations are lipid deposition, inflammatory cell infiltration, liver tissue necrosis and fibrotic lesions, and further lesions are more severe cirrhosis and hepatocellular carcinoma (HCC). NAFLD not only affects the patient's hepatobiliary system, but is also closely related to insulin resistance, dyslipidemia, atherosclerosis, fat embolism, blood system diseases, etc. (Friedman SL et al., Nat Med, 2018, 24: 908-22). Because all components of metabolic syndrome are related to liver fat content, patients with metabolic syndrome should be assessed for NAFLD risk. Patients with type 2 diabetes are accompanied by insulin resistance, obesity, dyslipidemia, and abnormal liver enzymes. The prevalence of NAFLD in people at risk of type 2 diabetes is also high.

[0003] The fructose content of the modern diet has increased due to the increasing addition of sugars (usually sucrose and high fructose corn syrup) to beverages and processed foods. High fructose intake has been shown to cause many adverse metabolic effects, and it plays a role in the development of obesity and metabolic syndrome, such as weight gain, hyperlipidemia, hypertension, and insulin resistance ((a) Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ. Fructose, weight gain, and the insulin resistance syn-drome. (b) Bray GA. Soft drink consumption and obesity: inflammation all about fructose. Current opinion in lipidology. 2010; 21(1): 51–7. (c) The American journal of clinical nutrition. 2002; 76(5): 911–22. and cardiovascular disease. The American journal of clinical nutrition. 2007; 86(4): 899–906.). Fructose promotes the occurrence and development of NAFLD, and exacerbates the development and deterioration of NAFLD (Shi Hongbin et al., Study on the association between fructose and non-alcoholic fatty liver disease, Medical Recapitulate 2017 23(9), 1685-1689). At the same time, high fructose intake increases the risk of NASH and advanced liver fibrosis (2016 European Association for the Study of the Liver, European Association for Diabetes and European Association for Obesity Clinical Practice Guidelines: Non-alcoholic fatty liver disease). Unlike glucose, the metabolism of fructose is not regulated by negative feedback. Fructose is metabolized preferentially relative to other carbohydrates, and its metabolism produces various reaction and signal metabolites that promote the progression of metabolic diseases.In the absence of KHK, fructose consumption-induced weight gain and insulin resistance were blocked (George Marek,1Varinderpal Pannu,1Prashanth Shanmugham,1Brianna Pancione,1Dominic Mascia,1Sean Crosson,1Takuji Ishimoto,2and Yuri Y. Sautin1; Adiponectin Resistance and Proinflammatory Changes in the Visceral Adipose Tissue Induced by Fructose Consumption via Ketohexokinase-Dependent Pathway; Diabetes 2015;64:508–518). Reducing sugar / HFCS (high fructose corn syrup) intake and / or blocking uric acid production can help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease (Thomas Jensen et al., Fructose and Sugar: A Major Mediator of Nonalcoholic Fatty Liver Disease, J Hepatol. 2018 May; 68(5): 1063–1075.). Meanwhile, human genetic mutations lead to basic fructose diabetopathy, a rare, harmless abnormality characterized by the appearance of fructose in the urine after ingestion of fructose-containing foods. The high prevalence of T2D, obesity, and NAFLD / NASH and related metabolic diseases such as cardiovascular disease and stroke has led to an increased need for both preventive care and therapeutic interventions.

[0004] Hexulose kinase (also known as fructokinase) is a basic enzyme for fructose metabolism. The KHK enzyme in the liver phosphorylates fructose at the C1 position with the assistance of ATP (adenosine triphosphate) to produce fructose-1-phosphate (F1P), which enters the normal metabolic pathway; at the same time, uric acid is produced downstream of ATP. Human hexulose kinase (hKHK) expressed by two alternative mRNA splicing forms encodes two different regional isomeric enzymes KHK-A and KHK-C. KHK-C has a lower Km value, a higher Kcat, and a catalytic efficiency that is higher than 405 times, indicating that KHK-C has a significantly higher affinity and ability for fructose phosphorylation than KHK-A. Although KHK-A is widely expressed and KHK-C is distributed in the liver, kidney, and intestine, KHK-C is the main metabolic site of fructose in the body.

[0005] In the human body, glucose is converted to fructose through the polyol pathway via the intermediate sorbitol to produce endogenous fructose (Mingule A et al., Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome, Nat Commun. 2013; 4: 2434.), and the activity of this pathway increases with hyperglycemia. Studies have shown that KHK knockout mice are protected from glucose-induced weight gain, insulin resistance, and steatosis, indicating that endogenously produced fructose can contribute to insulin resistance and steatosis under hyperglycemic conditions (Lanaspa, MA et al., Nature Comm. 4, 2434, 2013). Fructose is the only common carbohydrate that produces uric acid during its metabolism, and fructose also stimulates the synthesis of uric acid from amino acid precursors. Therefore, it is speculated that inhibiting KHK is beneficial for many diseases in which changes in either or both of endogenous or ingested fructose are involved.

[0006] Hepatic fructokinase deficiency underlies fructosuria. In contrast to this benign condition, deficiency in aldolase B, the next enzyme in the fructose metabolic pathway via KHK, results in the accumulation of F1P on fructose ingestion and can lead to lethal depletion of cellular ATP (hereditary fructose intolerance). The enzyme responsible for breaking down F1P immediately downstream of the KHK step in the fructose metabolic pathway is aldolase (ALDOB), the absence of which results in hereditary fructose intolerance (HFI). A rare condition affecting approximately 1 in 20,000 people, the mutation results in the accumulation of F1P, increased uric acid formation following ATP depletion, a combination of which results in hypoglycemia, hyperuricemia, and lactic acidosis, among other metabolic disturbances. HFI blocks the downstream metabolism of fructose and causes acute symptoms such as vomiting, severe hypoglycemia, diarrhea and abdominal pain, which in turn leads to long-term growth defects, liver and kidney damage and potentially death (Ali M et al., J. Med. Genet. 1998 May: 35(5); 353-365). Patients usually survive for one year before diagnosis, and the only treatment is to avoid fructose in the diet. However, the body's glucose is converted into endogenous fructose through the polyol pathway and metabolized in the body, which is also a challenge to this treatment. The presence of fructose in most foods poses a challenge to diet. In addition to physical symptoms, many patients face emotional and social isolation due to their unusual diets and need to strictly adhere to dietary restrictions (HFI-INFO Discussion Board, http: / / hfiinfo.proboards.com. Visited on December 14, 2015). In addition, infusions containing fructose, sorbitol or invert sugar can also endanger patients' lives. This disease has a high unmet clinical need. Summary of the invention

[0007] The object of the present invention is to provide a hexokine kinase inhibitor and its application. The specific technical scheme is as follows:

[0008] The present invention first provides a compound represented by general formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof:

[0009]

[0010] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer,

[0011] X, Y, and Z are independently selected from -CR 4 -and-N-;

[0012] Ring A is selected from 3-10 membered cycloalkyl and 3-10 membered heterocyclyl;

[0013] R 1 Selected from -(L)m -C(O)OR a 、-(L) m -CONR a R b 、-(L) m -CONHSO 2 R a 、-(L) m -SO 2 R a 、-(L) m -SO 2 NHCOR a 、-(L) m -OR a 、-(L) m -NR a R b 、-(L) m -C(O)R a 、-(L) m -OC(O)R a 、-(L) m -NR a C(O)R b 、-(L) m -NR a C(O)OR b 、-(L) m -OS(O) 2 R a 、-(L) m -S(O) 2 NR a R b 、-(L) m -NR a S(O) 2 R b , and -(L) optionally substituted by 1 to 4 Q1 m -C 1-4 Alkyl and -(L) m -C 1-4 Alkoxy;

[0014] L is selected from C 1-3 Alkylene and halogenated C 1-3 Alkylene;

[0015] R 2 is selected from 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-8 membered heteroaryl, 6-8 membered aryl, 5-8 membered spirocyclyl, 5-8 membered spiroheterocyclyl and N(C 1-4 Alkyl)(C 3-6 Cycloalkyl);

[0016] Each R3 are independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C optionally substituted with 1-4 Q3 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 Alkoxy;

[0017] Each R a , R b are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 Alkoxy;

[0018] Each Q1, Q2, Q3 is independently selected from hydroxyl, amino, halogen, nitro, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 Alkoxy;

[0019] m and n are each independently an integer of 0-4.

[0020] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X, Y, and Z are independently selected from -CR 4 -and-N-;

[0021] Ring A is selected from 4-8 membered cycloalkyl and 4-8 membered heterocyclyl;

[0022] R 1 Selected from -(L) m -C(O)OR a 、-(L) m -CONR a R b 、-(L) m -SO 2 Ra 、-(L) m -OR a 、-(L) m -NR a R b 、-(L) m -C(O)R a 、-(L) m -OC(O)R a 、-(L) m -NR a C(O)R b 、-(L) m -S(O) 2 NR a R b 、-(L) m -NR a S(O) 2 R b , optionally substituted with 1 to 3 Q1 -(L) m -C 1-4 Alkyl and -(L) m -C 1-4 Alkoxy;

[0023] L is C 1-3 Alkylene;

[0024] R 2 is selected from 3-6 membered heterocyclyl, 5-8 membered spiroheterocyclyl, 5-6 membered heteroaryl and N(C 1-4 Alkyl)(C 3-6 Cycloalkyl);

[0025] Each R 3 are independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl and carboxyl;

[0026] Each R a , R b are independently selected from hydrogen and C 1-4 alkyl;

[0027] Each Q1 and Q2 are independently selected from hydroxyl, amino, halogen, nitro, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 Alkoxy;

[0028] m and n are each independently an integer of 0-3.

[0029] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X, Y and Z are independently -N-;

[0030] Ring A is a 4-7 membered cycloalkyl group;

[0031] R 1 Selected from -(L) m -C(O)OR a 、-(L) m -CONR a R b 、-(L) m -SO 2 R a 、-(L) m -OR a 、-(L) m -NR a R b 、-(L) m -C(O)R a , optionally substituted with 1 to 3 Q1 -(L) m -C 1-4 Alkyl and -(L) m -C 1-4 Alkoxy;

[0032] L is a methylene group;

[0033] R 2 is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, furanyl, pyranyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,

[0034] Each R 3 are independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl and carboxyl;

[0035] Each R a , R b are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl;

[0036] Each Q1, Q2 is independently selected from hydroxy, amino, fluorine, chlorine, bromine, iodine, nitro, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;

[0037] m and n are independently 0, 1, 2 or 3.

[0038] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X, Y and Z are independently -N-;

[0039] Ring A is a 4-7 membered cycloalkyl group;

[0040] R 1 Selected from -(L) m -C(O)OR a 、-(L) m -CONR a R b 、-(L) m -SO 2 R a 、-(L) m -OR a 、-(L) m -NR a R b 、-(L) m -C(O)R a 、-(L) m -OC(O)R a , optionally substituted with 1 to 3 Q1 -(L) m -C 1-4 Alkyl and -(L) m -C 1-4 Alkoxy;

[0041] L is C 1-3 Alkylene;

[0042] R 2 is selected from 4-6 membered heterocyclyl, 5-6 membered heteroaryl and N(C 1-4 Alkyl)(C 3-6 Cycloalkyl);

[0043] Each R 3 are independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl and carboxyl;

[0044] Each R a , R b are independently selected from hydrogen and C 1-4 alkyl;

[0045] Each Q1 and Q2 are independently selected from hydroxyl, amino, halogen, nitro, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl and halogenated C 1-4 Alkoxy;

[0046] m and n are each independently an integer of 0-3.

[0047] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X, Y and Z are independently -N-;

[0048] Ring A is a 4-7 membered cycloalkyl group;

[0049] R 1 Selected from -(L) m -C(O)OR a 、-(L) m -CONR a R b 、-(L) m -SO 2 R a 、-(L) m -OR a 、-(L) m -NR a R b 、-(L) m -C(O)R a , optionally substituted with 1 to 3 Q1 -(L) m -C 1-4 Alkyl and -(L) m -C 1-4 Alkoxy;

[0050] L is a methylene group;

[0051] R 2 is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, furanyl, pyranyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,

[0052] Each R 3 are independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl and carboxyl;

[0053] Each R a , R b are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl;

[0054] Each Q1, Q2 is independently selected from hydroxy, amino, fluorine, chlorine, bromine, iodine, nitro, cyano, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;

[0055] m and n are independently 1, 2 or 3.

[0056] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer,

[0057] Wherein, ring A is a 5-6 membered cycloalkyl group, preferably a 5-6 membered partially saturated cycloalkyl group or a 5-6 membered saturated cycloalkyl group.

[0058] The selection of any substituent in any embodiment of the present invention can be combined with each other, and the technical solution after the combination is still included in the protection scope of the present invention.

[0059] In some embodiments of the present invention, the structures of the compounds of the aforementioned general formula (I), their pharmaceutically acceptable salts, esters or stereoisomers thereof are shown in Table 1:

[0060] Table 1

[0061]

[0062]

[0063]

[0064] The "pharmaceutically acceptable salt" described in the present invention refers to pharmaceutically acceptable acid and base addition salts.

[0065] The "ester" of the present invention refers to a pharmaceutically acceptable ester, and in particular refers to an ester that is hydrolyzed in vivo and includes an ester that is easily decomposed in the human body to leave the parent compound (the compound described in general formula (I)) or its salt. In some embodiments of the present invention, the pharmaceutically acceptable ester includes: derived from pharmaceutically acceptable aliphatic carboxylic acids and phosphoric acids.

[0066] The "stereoisomer" of the compound represented by the general formula (I) of the present invention means that when the compound represented by the formula (I) has an asymmetric carbon atom, enantiomers will be produced; when the compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers will be produced; when the compound has a ketone or oxime, tautomers will be produced. In some embodiments of the present invention, stereoisomers include but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof.

[0067] The embodiments of the present invention also provide two methods for preparing the above-mentioned compound, but are not limited to the following methods. The reaction equation of the preparation method 1 is as follows:

[0068]

[0069] Step 1 Preparation of Intermediate 1

[0070] Prepare intermediate 1 yourself.

[0071] Step 2 Preparation of Intermediate 2

[0072] The preparation was carried out according to the preparation method of reference (US15 / 381,295).

[0073] Step 3 Preparation of Intermediate 3

[0074] Intermediate 1 is dissolved in a suitable solvent (such as NMP), and intermediate 2 and an alkaline substance (such as potassium carbonate) are added, reacted at 70-100° C. for 10-40 hours, water is added, extracted with a suitable organic solvent (such as ethyl acetate), the organic phase is concentrated, and intermediate 3 is obtained by a suitable method (such as silica gel column chromatography).

[0075] Step 4 Preparation of Intermediate 4

[0076] Intermediate 3 is dissolved in a suitable solvent (e.g., dichloromethane), and m-chloroperbenzoic acid is added. The reaction is carried out at 10-30° C. for 0.5-5 hours. A suitable substance (e.g., sodium thiosulfate) is added to quench the reaction. The reaction is washed with a suitable reagent (e.g., saturated sodium carbonate, saturated brine), dried, concentrated, and subjected to a suitable method (e.g., silica gel column chromatography) to obtain intermediate 4.

[0077] Step 5 Preparation of the compound of general formula (I) of the present invention

[0078] Intermediate 4 was dissolved in a suitable solvent (such as NMP), DIEA and HR were added. 2 or R 2 The salt is reacted at 100-200°C for 1-5 hours, water is added, and an appropriate organic solvent (such as ethyl acetate) is extracted, and the dried product is dissolved in an appropriate solvent (such as THF / H 2O), add an alkaline reagent (such as NaOH, KOH, etc.), react at 10-50° C. for 0.2-5 hours, adjust the pH to 4.5-5.5, concentrate, and obtain the compound of the general formula (I) of the present invention by an appropriate method (such as silica gel column chromatography).

[0079] The above preparation process can also be simply summarized into the following steps:

[0080] reacting the compound represented by formula (II) with the compound represented by formula (III) to obtain the compound represented by formula (IV);

[0081] The sulfhydryl group in the compound represented by formula (IV) undergoes a functional group conversion reaction to obtain a compound represented by formula (V);

[0082] The compound represented by formula (V) is reacted to obtain the compound represented by general formula (I).

[0083] The reaction equation of preparation method 2 is as follows:

[0084]

[0085] Step 1 Preparation of intermediate 1-1

[0086] Intermediate 1-1 was prepared in-house.

[0087] Step 2 Preparation of Intermediate 2

[0088] The preparation was carried out according to the preparation method of reference (US15 / 381,295).

[0089] Step 3 Preparation of intermediate 3-1

[0090] Intermediate 1-1 is dissolved in a suitable solvent (such as acetonitrile), and intermediate 2 and a basic substance (such as DIPEA) are added, reacted at 70-100° C. for 10-30 hours, and dried by spin drying. Intermediate 3-1 is obtained by a suitable method (such as silica gel column chromatography).

[0091] Step 4 Preparation of the compound of general formula (I) of the present invention

[0092] Intermediate 3-1 is dissolved in a suitable solvent (e.g. dioxane) and HR is added 2 , Pd(pph 3 )Cl 2 , x-phos, react at 80-200°C for 10-20 hours under nitrogen protection, cool to 10-30°C, spin dry, and obtain the product by appropriate method (such as silica gel column chromatography), dissolve the product in an appropriate organic solvent (such as tetrahydrofuran and water), add an alkaline reagent (such as NaOH, KOH, etc.), react at 10-30°C for 0.5-5 hours, adjust the pH to acidic, and filter to obtain the compound of general formula (I) of the present invention.

[0093] The above preparation process can also be simply summarized into the following steps:

[0094] The compound represented by formula (II-1) is reacted with the compound represented by formula (III) to obtain the compound represented by formula (IV-1);

[0095] The compound represented by formula (IV-1) is reacted to obtain the compound represented by general formula (I).

[0096] The "functional group conversion reaction" can be achieved by known chemical synthesis methods, including but not limited to substitution reactions, addition reactions, elimination reactions, dehydration reactions, hydrolysis reactions, oxidation reactions and esterification reactions, etc. These reactions are well known to those skilled in the art of chemistry and are not limited herein by the present invention. In the specific implementation process, it can be achieved by a one-step reaction or by a multi-step reaction.

[0097] In addition, some necessary starting materials, such as materials for synthesizing intermediates, can be synthesized according to similar steps and methods described in organic chemistry handbooks, and the present invention is not further limited herein.

[0098] The substituent G in the above reaction equation is a halogen; R 1 , R 2 , R 3 , X, Y, Z, n and ring A are as defined above.

[0099] The present invention also provides an intermediate for synthesizing the compound represented by general formula (I), which has the following structural formula:

[0100]

[0101] Wherein, the substituent G is a halogen; R 1 , R 3 , X, Y, Z, n and ring A are as defined above.

[0102] The present invention also provides a pharmaceutical composition, which contains the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutically active agents. Optionally, the pharmaceutical composition also contains one or more pharmaceutically acceptable carriers and / or diluents.

[0103] The present invention also provides a pharmaceutical preparation, which contains the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, ester or stereoisomer, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation is in any dosage form that is clinically or pharmaceutically acceptable.

[0104] In some embodiments of the present invention, the above-mentioned pharmaceutical preparations can be administered to patients or subjects who need such treatment by oral, parenteral, rectal or pulmonary administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, adhesives, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparations can also be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, additives can be omitted or appropriate additives can be added according to the properties of the drugs. When used for rectal administration, the pharmaceutical composition can be made into suppositories, etc. When used for pulmonary administration, the pharmaceutical composition can be made into inhalants or sprays, etc.

[0105] The pharmaceutical carrier and / or diluent available in the pharmaceutical composition of the present invention or the pharmaceutical preparation can be any conventional carrier and / or diluent in the pharmaceutical preparation field, and the selection of specific carrier and / or diluent will depend on the mode of administration or disease type and state for treating a specific patient. The preparation method of the suitable pharmaceutical composition for a specific mode of administration is completely within the knowledge of the pharmaceutical field technician. For example, the pharmaceutical carrier and / or diluent can include conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. in the pharmaceutical composition. If necessary, flavoring agents, preservatives, and sweeteners, etc. can also be added to the pharmaceutical composition.

[0106] The present invention also provides the use of the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing KHK-mediated diseases and related diseases; the KHK-mediated diseases and related diseases are selected from endocrine disorders, urinary diseases, metabolic diseases, non-alcoholic fatty hepatitis, cirrhosis, fatty liver, hepatitis, liver failure, hereditary fructose intolerance, non-alcoholic fatty liver disease, hepatobiliary diseases, fibrosis diseases, cardiovascular and cerebrovascular diseases, immune inflammatory diseases, central nervous system diseases, gastrointestinal diseases, hyperproliferative diseases such as cancer, etc.

[0107] The present invention also provides the use of the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment and / or prevention of KHK-mediated diseases and related diseases; the KHK-mediated diseases and related diseases are selected from endocrine disorders, urinary diseases, metabolic diseases, non-alcoholic fatty hepatitis, cirrhosis, fatty liver, hepatitis, liver failure, hereditary fructose intolerance, non-alcoholic fatty liver disease, hepatobiliary diseases, fibrosis diseases, cardiovascular and cerebrovascular diseases, immune inflammatory diseases, central nervous system diseases, gastrointestinal diseases, hyperproliferative diseases such as cancer, etc.

[0108] The present invention also provides a method for treating a disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition, wherein the disease is a KHK-mediated disease and related diseases; the KHK-mediated disease and related diseases are selected from endocrine disorders, urinary diseases, metabolic diseases, non-alcoholic fatty hepatitis, cirrhosis, fatty liver, hepatitis, liver failure, hereditary fructose intolerance, non-alcoholic fatty liver disease, hepatobiliary diseases, fibrotic diseases, cardiovascular and cerebrovascular diseases, immune inflammatory diseases, central nervous system diseases, gastrointestinal diseases, hyperproliferative diseases such as cancer, etc.

[0109] In the specification and claims of the present application, compounds are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when representing the same compound, the chemical structural formula shall prevail.

[0110] In this application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, but in order to better understand the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in this application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in this application shall prevail.

[0111] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0112] The term "halogenated" as used herein means that any hydrogen in the substituent may be replaced by one or more halogens which may be the same or different. "Halogen" is as defined above.

[0113] The "C 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, "C 1-5 Alkyl", "C 1-4 Alkyl", "C 1-3 Alkyl", "C1-2 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 2-4 Alkyl", "C 2-3 Alkyl", "C 3-6 Alkyl", "C 3-5 Alkyl", "C 3-4 Alkyl", "C 4-6 Alkyl", "C 4-5 Alkyl", "C 5-6 Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The “C 1-4 "Alkyl" refers to C 1-6 Specific examples of alkyl groups contain 1 to 4 carbon atoms.

[0114] The "C 1-6 "Alkylene" refers to the above-mentioned C 1-6 The radical formed by removing a hydrogen atom from an alkyl group includes, for example, "C 1-5 Alkylene", "C 1-4 Alkylene", "C 1-3 Alkylene", "C 1-2 Alkylene", "C 2-6 Alkylene", "C 2-5 Alkylene", "C 2-4 Alkylene", "C 2-3 Alkylene", "C 3-6 Alkylene", "C 3-5 Alkylene", "C 3-4 Alkylene", "C 4-6 Alkylene", "C 4-5 Alkylene", "C 5-6 Specific examples include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. The “C 1-4 "Alkylene" refers to C 1-6 Specific examples of the alkylene group contain 1 to 4 carbon atoms.

[0115] The “C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 "Alkyl)amino" refers to a C1-6 Alkyl-O-, C 1-6 Alkyl-NH-, (C 1-6 alkyl) 2 -N-, where "C 1-6 "Alkyl" is as defined above.

[0116] The “C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 "Alkyl)amino" refers to a C 1-4 Alkyl-O-, C 1-4 Alkyl-NH-, (C 1-4 alkyl) 2 -N-, where "C 1-4 "Alkyl" is as defined above.

[0117] The "halogenated C 1-6 Alkyl, halogenated C 1-6 Alkylene, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 "Alkoxy" refers to one or more, for example, 1-4, 1-3, 1-2 halogen atoms, hydroxyl groups, amino groups, etc., which are substituted by C 1-6 Alkyl, C 1-6 Alkylene, C 1-6 A group formed by the hydrogen atoms in an alkoxy group.

[0118] The "halogenated C 1-4 Alkyl, halogenated C 1-4 Alkylene, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, halogenated C 1-4 "Alkoxy" refers to one or more, for example, 1-4, 1-3, 1-2 halogen atoms, hydroxyl groups, amino groups, etc., which are substituted by C 1-4 Alkyl, C 1-4 Alkylene, C 1-4 A group formed by the hydrogen atoms in an alkoxy group.

[0119] The "3-14 membered cycloalkyl" mentioned in the present invention refers to a saturated or partially saturated non-aromatic cyclic alkyl group containing 3-14 carbon atoms, including "3-8 membered cycloalkyl" and "8-14 membered condensed cycloalkyl", preferably "3-12 membered cycloalkyl" and "3-10 membered cycloalkyl".

[0120] The "3-8 membered cycloalkyl" of the present invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-8 carbon atoms and not having aromaticity, including "3-8 membered saturated cycloalkyl" and "3-8 membered partially saturated cycloalkyl"; preferably "3-4 membered cycloalkyl", "3-5 membered cycloalkyl", "3-6 membered cycloalkyl", "3-7 membered cycloalkyl", "4-5 membered cycloalkyl", "4-6 membered cycloalkyl", "4-7 membered cycloalkyl", "4-8 membered cycloalkyl", "5-6 membered cycloalkyl", "5-7 membered cycloalkyl", "5-8 membered cycloalkyl" "," 6-7 membered cycloalkyl," "6-8 membered cycloalkyl," "7-8 membered cycloalkyl," "3-6 membered saturated cycloalkyl," "4-7 membered saturated cycloalkyl," "4-8 membered saturated cycloalkyl," "5-8 membered saturated cycloalkyl," "5-7 membered saturated cycloalkyl," "5-6 membered saturated cycloalkyl," "3-6 membered partially saturated cycloalkyl," "4-7 membered partially saturated cycloalkyl," "4-8 membered partially saturated cycloalkyl," "5-8 membered partially saturated cycloalkyl," "5-7 membered partially saturated cycloalkyl," "5-6 membered partially saturated cycloalkyl," etc. Specific examples of the “3-8 membered saturated cycloalkyl” include, but are not limited to, cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentanyl (cyclopentyl), cyclohexanyl (cyclohexyl), cycloheptanyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the “3-8 membered partially saturated cycloalkyl” include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0121] The "8-14 membered fused ring group" described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-14 ring atoms formed by two or more cyclic structures sharing two adjacent carbon atoms. One ring in the fused ring can be an aromatic ring, but the fused ring as a whole does not have aromaticity; it includes "8-12 membered fused ring group", "8-10 membered fused ring group", "8-9 membered fused ring group", "9-10 membered fused ring group", etc., and the fusion mode can be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, etc. Examples include, but are not limited to, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrenyl, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydropentalenyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl and the like.

[0122] The "3-14 membered heterocyclic group" of the present invention refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom (e.g., 1, 2, 3, 4 or 5) and 3-14 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxidized. The "3-14 membered heterocyclic group" includes "3-8 membered heterocyclic group" and "8-14 membered fused heterocyclic group", preferably 3-12 membered heterocyclic group and 3-10 membered heterocyclic group.

[0123] The "3-8 membered heterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic group without aromaticity, which contains at least one heteroatom (e.g., 1, 2, 3, 4 or 5) and has 3-8 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxidized. The "3-8 membered heterocyclic group" of the present invention includes "3-8 membered saturated heterocyclic group" and "3-8 membered partially saturated heterocyclic group". Preferably, the "3-8 membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered heterocyclic group" of the present invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-8 membered heterocyclic group" of the present invention contains 1 nitrogen atom. The “3-8 membered heterocyclic group” is preferably a “3-7 membered heterocyclic group”, “3-6 membered heterocyclic group”, “4-7 membered heterocyclic group”, “4-6 membered heterocyclic group”, “6-8 membered heterocyclic group”, “5-7 membered heterocyclic group”, “5-6 membered heterocyclic group”, “3-6 membered saturated heterocyclic group”, “4-6 membered saturated heterocyclic group”, “5-6 membered saturated heterocyclic group”, “3-6 membered nitrogen-containing heterocyclic group”, “3-6 membered saturated nitrogen-containing heterocyclic group”, “4-6 membered nitrogen-containing heterocyclic group”, “4-6 membered saturated nitrogen-containing heterocyclic group”, “5-6 membered nitrogen-containing heterocyclic group”, “5-6 membered saturated nitrogen-containing heterocyclic group” and the like. Specific examples of the “3- to 8-membered heterocyclic group” include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, etc.

[0124] The "8-14 membered fused heterocyclic group" of the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 8-14 ring atoms formed by two or more cyclic structures sharing two adjacent atoms, and at least one ring atom is a heteroatom, wherein one of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxidized, including but not limited to The invention is limited to "8-9 membered fused heterocyclic group", "9-10 membered fused heterocyclic group", etc., and the fused mode can be 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heterocyclic group and 5-6 membered cycloalkyl group, benzo 5-6 membered heterocyclic group, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclic group; 5-6 membered heteroaryl is as defined above; specific examples of the "8-10 membered fused heterocyclic group" include but are not limited to: pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine , pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridocyclopentyl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyranyl pyrimidinyl, pyridoimidazolidinyl, pyridooxazolidinyl, pyridothiazolidinyl, pyridoisoxazolidinyl, pyridoisothiazolidinyl, pyridopiperdinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidoisoxazolidinyl, pyrimidoisothiazolidinyl, pyrimidopiperdinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl;tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H- Furano[3,4-d]imidazolyl, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuranoimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-1,3-benzoxazinyl, etc. ;

[0125] The "6-12 membered aryl group" described in the present invention refers to an aromatic cyclic group containing 6-12 ring carbon atoms, including "6-8 membered monocyclic aryl group" and "8-12 membered condensed ring aryl group", preferably a 6-10 membered aryl group.

[0126] The "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0127] The "8-12 membered fused ring aromatic group" described in the present invention refers to an unsaturated aromatic cyclic group containing 8-12 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms, preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl and the like.

[0128] The "5-12 membered heteroaryl" of the present invention refers to an aromatic cyclic group containing 5-12 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). It includes "5-8 membered single heteroaryl" and "8-12 membered fused heteroaryl", preferably a 5-10 membered heteroaryl.

[0129] The "5-8-membered single heteroaryl" of the present invention refers to a monocyclic cyclic group with aromaticity containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo-substituted. "5-8-membered single heteroaryl" includes, for example, "5-7-membered single heteroaryl", "5-6-membered single heteroaryl", "5-6-membered nitrogen-containing single heteroaryl", "5-membered nitrogen-containing single heteroaryl" and the like. Specific examples of “5-8 membered monocyclic heteroaryl” include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like. The "5- to 6-membered heteroaryl" refers to a specific example of a 5- to 8-membered heteroaryl containing 5 to 6 ring atoms.

[0130] The "8-12 membered fused heteroaryl" of the present invention refers to an unsaturated aromatic cyclic structure formed by two or more cyclic structures sharing two adjacent atoms, containing 8-12 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxo-substituted. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., and the fusion mode can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furathiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0131] The "5-12-membered bridged ring group" of the present invention refers to a structure containing 5-12 carbon atoms formed by two atoms not directly connected to each other shared by any two rings, and the "5-12-membered bridged ring" includes a 5-12-membered saturated bridged ring group and a 5-12-membered partially saturated bridged ring group. Preferably, the 5-10-membered bridged ring group, the 5-8-membered bridged ring group, the 5-10-membered saturated bridged ring group, the 5-8-membered saturated bridged ring group, the 6-10-membered saturated bridged ring group, and the 7-12-membered partially saturated bridged ring group are used. The 5-12-membered bridged ring group includes but is not limited to bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.2.1]hept-5-enyl, bicyclo[3.2.1]oct-6-enyl, bicyclopentadienyl, etc.

[0132] The "5-12 membered bridged heterocyclic group" described in the present invention means that at least one ring carbon atom in the above 5-12 membered bridged heterocyclic group is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms, and also includes the case where the carbon atoms, nitrogen atoms and sulfur atoms can be oxo-substituted, preferably a 5-10 membered bridged heterocyclic group, a 5-8 membered bridged heterocyclic group.

[0133] The "5-12-membered spirocyclic group" of the present invention refers to a structure containing 5-12 carbon atoms formed by at least two rings sharing one atom. It includes 5-12-membered saturated spirocyclic groups and 5-12-membered partially saturated spirocyclic groups. Specific examples of 5-12-membered saturated spirocyclic groups include but are not limited to: A 5-12 membered partially saturated spirocyclic group refers to a cyclic group in which at least one ring of the spirocyclic group is unsaturated. Specific examples include but are not limited to: The group formed by replacing any substitutable hydrogen atom with a cyclic structure such as the above. Preferably, the 5-10 membered spirocyclic group includes "5-10 membered saturated spirocyclic group" and "5-10 membered unsaturated spirocyclic group". Preferably, the 5-8 membered spirocyclic group includes "5-8 membered saturated spirocyclic group" and "5-8 membered unsaturated spirocyclic group".

[0134] The "5-12-membered spiro heterocyclic group" of the present invention refers to a 5-12-membered spiro heterocyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms, and includes the case where the carbon atom, nitrogen atom, and sulfur atom may be oxo-substituted. Preferably, the 5-10-membered spiro heterocyclic group, the 5-8-membered spiro heterocyclic group, and the 5-6-membered spiro heterocyclic group are used.

[0135] The "optionally substituted by..." mentioned in the present invention includes two situations: "substituted" and "unsubstituted".

[0136] The "therapeutically effective amount" of the present invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that can at least alleviate the symptoms of the patient's condition when administered to the patient. The actual amount comprising the "therapeutically effective amount" will vary depending on a variety of circumstances, including but not limited to the specific condition being treated, the severity of the condition, the patient's physical and health condition, and the route of administration. A skilled medical practitioner can easily determine the appropriate amount using methods known in the medical field.

[0137] Advantageous Effects of the Invention

[0138] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have excellent KHK inhibitory activity and can treat and / or prevent KHK-mediated diseases and related diseases;

[0139] (2) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good pharmacokinetic properties, longer-lasting effects and high bioavailability;

[0140] (3) The compounds of the present invention, their pharmaceutically acceptable salts, esters or stereoisomers thereof have good safety;

[0141] (4) The compound of the present invention has a simple preparation process, high drug purity, stable quality, and is easy to carry out large-scale industrial production.

[0142] The following experiments further illustrate the beneficial effects of the compounds provided in the embodiments of the present invention, but this should not be understood as the compounds provided in the embodiments of the present invention only having the following beneficial effects.

[0143] Experimental Example 1 In vitro KHK kinase inhibitory activity experiment of the compounds provided in the examples of the present invention

[0144] Test sample: the compound provided in the examples of the present invention. For its chemical name and preparation method, please refer to the preparation example of each compound.

[0145] Control drug: PF-06835919, prepared according to the method in reference (US15 / 381,295).

[0146] Experimental reagents:

[0147]

[0148] Experimental consumables:

[0149]

[0150] Experimental instruments:

[0151]

[0152] Experimental method 1:

[0153] 1. Compound dilution

[0154] 1) The compounds of the present invention and control drugs were prepared with DMSO to 10 mM as test stock solutions.

[0155] 2) The stock solutions of the compound of the present invention and the control drug were diluted 10-fold to 1 mM, and then the compound of the present invention and the control drug were diluted 3-fold to 11 concentrations, with the highest concentration being 1 mM.

[0156] 3) Use Echo550 to transfer 0.1 μL of the diluted compound of the present invention and the control drug to a 384-well plate, set 2 replicate wells for each concentration, and centrifuge at 1000 rpm for 1 min.

[0157] 2. Enzyme reaction experiment

[0158] 1) Add 5 μL of KHK-C kinase working solution to a 384-well plate, centrifuge at 1000 rpm for 1 min, and then incubate at room temperature 25°C for 15 min.

[0159] 2) Add 5 μL of substrate working solution to a 384-well plate to start the kinase reaction, centrifuge at 1000 rpm for 1 min, and incubate at room temperature at 25°C for 60 min.

[0160] 3) The final concentration of KHK-C kinase reaction is 1nM KHK-C, 100μM ATP, 200μM D-Fructose, HEPES50mM, MgCl 2 10 mM, Brij35 0.01%, final DMSO concentration 1%.

[0161] 4) The final concentrations of the test compounds and control drugs were 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.457 nM, 41.15 nM, 13.71 nM, 4.572 nM, 1.524 nM, 0.508 nM, and 0.169 nM.

[0162] 3. Reaction termination and detection

[0163] 1) Add 10 μL ADP Glo reagent, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 40 min.

[0164] 2) Add 20 μL of kinase detection reagent, centrifuge at 1000 rpm for 1 min, and incubate at room temperature 25°C for 40 min.

[0165] 3) After the reaction is completed, read the fluorescence value LUM on Envision.

[0166] 4. Data Analysis

[0167] The inhibition rate (%inh) was calculated using the following formula:

[0168]

[0169] Among them, Lum HC Indicates: Luminescent signal intensity of High control (DMSO with the same volume as the test compound is added to the reaction system);

[0170] Lum LC Indicates: Luminescent signal intensity of Low control (control drug 10 μM);

[0171] Lum cpd Indicates: Indicates the luminescent signal intensity of the test compound;

[0172] GraphPad Prism 5.0 software was used for curve fitting and IC 50 .

[0173] Experimental results:

[0174] Table 2 Inhibitory activity of compounds of the present invention on KHK-C

[0175]

[0176] It can be seen from the above experimental results that the compounds provided in the embodiments of the present invention can effectively inhibit the activity of KHK-C kinase and are effective KHK-C kinase inhibitors.

[0177] Experimental method 2:

[0178] 1. Compound dilution

[0179] 1) The compounds of the present invention and control drugs were prepared with DMSO to 10 mM as test stock solutions.

[0180] 2) The stock solution of the compound of the present invention was diluted 10-fold to 1 mM, and then the compound of the present invention was diluted 3-fold to 11 concentrations, with the highest concentration being 1 mM. The stock solution of the control drug was diluted 100-fold to 0.1 mM, and then the control drug was diluted 3-fold to 11 concentrations, with the highest concentration being 0.1 mM.

[0181] 3) Use Echo550 to transfer 0.1 μL of the diluted compound of the present invention and the control drug to a 384-well plate, set 2 replicate wells for each concentration, and centrifuge at 1000 rpm for 1 min.

[0182] 2. Enzyme reaction experiment

[0183] 1) Add 5 μL of KHK-C kinase working solution to a 384-well plate, centrifuge at 1000 rpm for 1 min, and then incubate at room temperature 25°C for 15 min.

[0184] 2) Add 5 μL of substrate working solution to a 384-well plate to start the kinase reaction, centrifuge at 1000 rpm for 1 min, and incubate at room temperature at 25°C for 60 min.

[0185] 3) The final concentration of KHK-C kinase reaction is 1nM KHK-C, 100μM ATP, 200μM D-Fructose, HEPES50mM, MgCl 2 10 mM, Brij35 0.01%, final DMSO concentration 1%.

[0186] 4) The final concentrations of the test compounds were 10000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.457 nM, 41.15 nM, 13.71 nM, 4.572 nM, 1.524 nM, 0.508 nM, and 0.169 nM.

[0187] 5) The final concentrations of the control drugs were 1000nM, 333.33nM, 111.11nM, 37.037nM, 12.346nM, 4.115nM, 1.371nM, 0.4572nM, 0.1524nM, 0.0508nM, and 0.0169nM.

[0188] 3. Reaction termination and detection

[0189] 1) Add 10 μL ADP Glo reagent, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 40 min.

[0190] 2) Add 20 μL of kinase detection reagent, centrifuge at 1000 rpm for 1 min, and incubate at room temperature 25°C for 40 min.

[0191] 3) After the reaction is completed, read the fluorescence value LUM on Envision.

[0192] 4. Data Analysis

[0193] The inhibition rate (%inh) was calculated using the following formula:

[0194]

[0195] Among them, Lum HC Indicates: Luminescent signal intensity of High control (DMSO with the same volume as the test compound is added to the reaction system);

[0196] Lum LC Indicates: Luminescent signal intensity of Low control (control drug 1 μM);

[0197] Lum cpd Indicates: Indicates the luminescent signal intensity of the test compound;

[0198] GraphPad Prism 5.0 software was used for curve fitting and IC 50 .

[0199] Experimental results:

[0200] Table 3 Inhibitory activity of compounds of the present invention on KHK-C

[0201]

[0202] The above experimental method was used to further test the inhibitory activity of other specific compounds against KHK-C kinase. Test compounds 1-2, compound 5-1, compound 7, compound 10, compound 14, compound 15, etc. all showed good inhibitory activity against KHK-C (1 nM to 0.3 μM).

[0203] It can be seen from the above experimental results that the compounds provided in the embodiments of the present invention can effectively inhibit the activity of KHK-C kinase and are effective KHK-C kinase inhibitors.

[0204] Experimental Example 2 In vitro cell inhibition activity experiment of the compounds provided in the examples of the present invention

[0205] Test sample: the compound provided in the examples of the present invention. For its chemical name and preparation method, please refer to the preparation example of each compound.

[0206] Control drug: PF-06835919, prepared according to the method in reference (US15 / 381,295).

[0207] Experimental reagents:

[0208] Reagent Vendor Cat No. MEM medium Gibco 10370-021 HepG2 liver cancer cell line ATCC HB-8065 Sodium pyruvate Gibco 11360-070 Glutamine Gibco 35050-061 Fetal bovine serum (FBS) Gibco 10091-148 DPBS buffer Gibco 14200-075 0.25% pancreatin (with EDTA) Gibco 25200-072 DMSO Sigma D4540 Penicillin-Streptomycin Gibco 10378016 Ammonium acetate TEDIA AS0139-028 D-fructose Sigma F3510-100G

[0209] Experimental instruments:

[0210] Instrument Vendor Cat No. <![CDATA[CO 2 Incubator]]> SANYO MCO-15A4 Biological Safety Cabinets Shanghai Lishen Technology Instrument Co., Ltd. 1200A2 Refrigerated centrifuge Eppendorf Centrifuge5840R microscope Nikon TS100-F

[0211] Experimental methods:

[0212] 1. Cell culture and inoculation

[0213] 1) Collect HepG2 cells in the logarithmic growth phase and count the cells using a platelet counter. Detect cell viability using the trypan blue exclusion method to ensure that the cell viability is above 90%.

[0214] 2) Adjust the concentration of HepG2 cells and add 81 μL of basal medium without FBS (starvation treatment) to each 96-well plate. The cell inoculation volume of the test well is 5×10 4 indivual.

[0215] 3) Place the HepG2 cells in a 96-well plate at 37°C and 5% CO 2 , and cultured overnight under 95% humidity conditions.

[0216] 2. Dosing

[0217] 1) Before adding drugs, add 9 μL FBS to the test wells of the 96-well plate to stop the starvation treatment.

[0218] 2) Prepare 10-fold compound solution with the highest concentration of 100 μM, 8 concentrations, and 3-fold gradient dilution. Add 10 μL of drug solution to each well of a 96-well plate seeded with cells, set up three replicate wells for each drug concentration, and add 10 μL of 1% DMSO solution to the solvent control group, and set up three replicate wells.

[0219] 3) Place the cells in the 96-well plate with the drug added at 37°C and 5% CO 2 , and incubate for 30 min under 95% humidity conditions.

[0220] 4) Prepare 11-fold D-Fructose solution with a concentration of 220 mM, add 10 μL D-Fructose solution to each well of a 96-well plate seeded with HepG2 cells, set up 3 replicates, and add 10 μL 11% DPBS solution to the solvent control group, set up 3 replicates.

[0221] 5) The cells in the 96-well plate to which D-fructose had been added were incubated at 37° C., 5% CO 2 , and 95% humidity for 3 h.

[0222] 3. Sample processing

[0223] The culture medium in the 96-well plate was removed, and the cells in the well plate were washed three times with cold DPBS (200 μl / well). Then, 30 μL of cold 10 mM ammonium acetate (pH 7.4) was added to each well to lyse the cells (hypotonic lysis). After lysis on ice for 5 min, the cells were thoroughly blown and the cell lysate was taken for LC-MS analysis.

[0224] 4. Data Analysis

[0225] The data were analyzed using GraphPad Prism 5.0 software, and the dose-effect curve was fitted using nonlinear S-curve regression to obtain the EC50 value.

[0226] 5. Experimental results:

[0227] Table 4 Inhibitory effect of the compounds of the present invention on D-Fructose-induced fructose-1-phosphate production in HepG2 cells

[0228]

[0229] The expression level of KHK-C kinase is the highest in the liver. At the same time, KHK-C kinase can specifically metabolize fructose to produce fructose-1-phosphate. From the above experimental results, it can be seen that the example compounds of the present invention can effectively inhibit D-Fructose-induced HepG2 cells from producing fructose-1-phosphate, and are effective KHK-C inhibitors. DETAILED DESCRIPTION

[0230] The technical solution of the present invention will be described below in conjunction with specific embodiments, and the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0231] The abbreviations used in the following experiments have the following meanings:

[0232] PE: petroleum ether; EA: ethyl acetate; DAST: diethylaminosulfur trifluoride; THF: tetrahydrofuran; NMP: N-methylpyrrolidone; DCM: dichloromethane; DCE: 1,2-dichloroethane; mCPBA: m-chloroperbenzoic acid; EtONa: sodium ethoxide; DBN: 1,5-diazabicyclo[4.3.0]non-5-ene; DIEA: N,N-diisopropylethylamine.

[0233] Preparation Example

[0234] Example 1 Preparation of 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 1)

[0235]

[0236] (1) Preparation of 1-ethyl 2,4-dimethyl 1-oxobutane-1,2,4-tricarboxylate

[0237]

[0238] Sodium metal (4.3 g, 186.9 mmol) was added to ethanol (200 mL). After complete dissolution, the mixture was spin-dried and suspended in tetrahydrofuran (200 mL). Diethyl oxalate (27.4 g, 187.5 mmol) was slowly added to the solution, followed by dimethyl glutarate (30.0 g, 187.3 mmol). The mixture was reacted at 25°C for 16 hours. The reaction was detected by TLC (Rf = 0.5, PE:EA = 1:1). The mixture was spin-dried, and water (300 mL) and methyl tert-butyl ether (200 mL) were added. The mixture was separated, the aqueous phase was adjusted to pH = 1, and the mixture was extracted with 3 × 200 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was directly used in the next step.

[0239] (2) Preparation of 2-oxoadipic acid

[0240]

[0241] 1-Ethyl 2,4-dimethyl 1-oxobutane-1,2,4-tricarboxylate (the crude product from the previous step) was added to 4N hydrochloric acid (230 mL, 920 mmol), heated to 65°C for 6 hours, and then spin-dried to obtain 21.0 g of compound 1, with a two-step yield of 70.0%.

[0242] (3) Preparation of 6-methoxy-5,6-dioxohexanoic acid

[0243]

[0244] At 0°C, 2-oxoadipic acid (10.0 g, 62.5 mmol) was added to a solution of DBN (9.3 g, 74.9 mmol) in acetone (100 mL), and dimethyl sulfate (7.9 g, 62.6 mmol) was added dropwise. The mixture was incubated at 25°C for 16 hours, and then dried by spin drying. Water (50 mL) was added to adjust the pH to 2-3, and the mixture was extracted with 3×100 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was directly used in the next step.

[0245] (4) Preparation of dimethyl 2-oxoadipate

[0246]

[0247] Dissolve 6-methoxy-5,6-dioxohexanoic acid (the crude product from the previous step) in dichloromethane (100 mL), add 2 drops of N,N-dimethylformamide, add oxalyl chloride (15.9 g, 125.2 mmol) at 0°C, incubate at 25°C for 16 hours, spin dry, add methanol (40 mL) to the residue at 0°C, incubate at 25°C for 2 hours, spin dry, and chromatograph the residue (PE:EA=5:1) to obtain the product (7.9 g, two-step yield: 66.9%).

[0248] (5) Preparation of dimethyl 2,2-difluoroadipate

[0249]

[0250] Dimethyl 2-oxoadipate (4.8 g, 25.5 mmol) was dissolved in chloroform (50 mL) and added to DAST. The mixture was reacted at 25 °C for 48 hours. Water was added to quench the reaction. The mixture was extracted with 3 × 100 ml of ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain the product (2.0 g, 37.0%).

[0251] (6) Preparation of methyl 3,3-difluoro-2-oxocyclopentane-1-carboxylate

[0252]

[0253] Sodium hydride (60%) (0.57 g, 14.2 mmol) was dissolved in THF (40 mL), and a THF solution (10 mL) of dimethyl 2,2-difluoroadipate (2.0 g, 9.5 mmol) was added. The mixture was reacted at 20 °C for 16 hours, and water was added to quench the reaction. The pH was adjusted to 5-6, and the mixture was extracted with 3 × 100 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and used directly in the next step (product 1.6 g, yield: 94.1%).

[0254] (7) Preparation of 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol

[0255]

[0256] Methyl 3,3-difluoro-2-oxocyclopentane-1-carboxylate (2.4 g, 13.5 mmol) was dissolved in water (40 mL), and methyl isothiourea sulfate (3.8 g, 20.2 mmol) and sodium carbonate (2.85 g, 26.9 mmol) were added. The mixture was reacted at 25 °C for 16 hours, and the pH was adjusted to 2 with 1N hydrochloric acid. The mixture was extracted with 3×100 ml of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.4 g of crude product, which was directly used in the next step.

[0257] (8) Preparation of 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

[0258]

[0259] 7,7-Difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (2.4 g crude product) was dissolved in phosphorus oxychloride (5 mL) / 1,2-dichloroethane (10 mL), reacted at 110°C for 16 h, concentrated, adjusted to pH 7-8 with saturated sodium bicarbonate, extracted with 3×80 ml ethyl acetate, combined the organic phases, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to give 1.4 g of the compound, with a two-step yield of 43.8%.

[0260] (9) Preparation of methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0261]

[0262] 4-Chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.84 mmol) was dissolved in NMP (5 mL), and methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (160 mg, 1.03 mmol) and potassium carbonate (260 mg, 1.88 mmol) were added. The mixture was reacted at 90 °C for 16 hours, and water was added. The mixture was extracted with 3×50 ml of ethyl acetate. The organic phases were combined and concentrated, and the crude product was used directly in the next step.

[0263] (10) Preparation of methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0264]

[0265] Methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetate (the crude product from the previous step) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (80%) (400 mg, 1.85 mmol) was added, and the mixture was reacted at 20°C for 3 hours. Saturated sodium carbonate solution was added, and the mixture was separated. The aqueous phase was extracted with 2×30 ml of dichloromethane, and the organic phases were combined, dried by spin drying, and subjected to column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain 160 mg of the compound, with a two-step yield of 48.6%.

[0266] (11) Preparation of methyl 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0267]

[0268] 2-((1R,5S,6s)-3-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (100 mg, 0.26 mmol) was dissolved in NMP (3 mL), DIEA (0.5 ml) and (S)-2-methylazetidine trifluoroacetate (107 mg, 0.58 mmol) were added, and the mixture was reacted by microwave at 160 ° C for 2 hours. Water was added, and the mixture was extracted with 2×30 ml of ethyl acetate. The organic phases were combined, dried by spin drying, and purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to give 60 mg of the compound. Yield: 61.4%.

[0269] (12) Preparation of 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0270]

[0271] 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (60 mg, 0.16 mmol) was dissolved in MeOH / THF / H 2 O (3 / 3 / 3 mL), add NaOH (26 mg, 0.65 mmol), and react at 25°C for 3 hours. Adjust pH to 5 with 1N hydrochloric acid, concentrate, and column chromatography (ACN / H 2 O=40:60) to give the product (38 mg, 65.8%).

[0272] Molecular formula: C 18 H 22 F 2 N 4 O 2 Molecular weight: 364.4 LC-MS (M / e): 365.0 (M+H + )

[0273] 1 HNMR(400MHz,MeOD): δ:4.38-4.43(m,1H),3.98-4.05(m,3H),3.84-3.91(m,1H),3.61-3.68(m,2H),3.04-3.09(m,2H ),2.31-2.48(m,3H),2.30(d,J=7.2Hz,2H),1.90-1.96(m,1H),1.56(s,2H),1.48(d,J=6.4Hz,3H),0.85-0.89(m,1H).

[0274] Example 1-1 Preparation of 2-((1R,5S,6s)-3-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 1-1)

[0275] (1) Preparation of methyl 2-((1R,5S,6s)-3-(2-chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0276]

[0277] 2,4-Dichloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100 mg, 0.44 mmol) and methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (70 mg, 0.45 mmol) were dissolved in acetonitrile (10 ml), and N,N-diisopropylethylamine (0.5 ml) was added. The mixture was incubated at 25°C for 6 h, and then dried by spin drying. The mixture was purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to give 120 mg of the compound. Yield: 78.6%.

[0278] (2) Preparation of methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0279]

[0280] 2-((1R,5S,6s)-3-(2-chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (80 mg, 0.23 mmol) and 2-methylazetidine trifluoroacetate (100 mg, 0.54 mmol) were dissolved in acetonitrile (10 ml), and N,N-diisopropylethylamine (0.5 ml) was added. The mixture was heated to 70°C for 16 h, and then dried by spin drying. Column chromatography (ethyl acetate: petroleum ether = 1:2) was performed to obtain 50 mg of the compound. Yield: 56.8%.

[0281] (3) Preparation of 2-((1R,5S,6s)-3-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0282]

[0283] 2-((1R,5S,6s)-3-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (50 mg, 0.13 mmol) was dissolved in MeOH / H 2 O (5 / 0.5 mL), add NaOH (21 mg, 0.52 mmol), react at 25° C. for 3 hours, adjust pH to 4-5 with 1N hydrochloric acid, spin dry, separate on a preparative plate (dichloromethane: methanol = 20:1) to obtain 23 mg of the compound, yield: 47.9%.

[0284] Molecular formula: C 18 H 22 F 2 N 4 O 2 Molecular weight: 364.4 LC-MS (M / e): 365.2 (M+H + )

[0285] 1 HNMR(400MHz, CDCl3): δ:4.41-4.44(m,1H),3.94-4.03(m,4H),3.61-3.69(m,2H),3.04-3.09(m,2H),2.50 -2.59(m,3H),2.38-2.47(m,2H),1.94-2.00(m,1H),1.55(s,2H),1.51(d,J=6.0Hz,3H),0.90-0.99(m,1H).

[0286] Compound 1-2 was prepared by referring to the above preparation method. The relevant characterization data are as follows:

[0287] 1 HNMR(400MHz,DMSO): δ:12.11(s,br,1H),4.30-4.21(m,1H),3.88-3.72(m,4H),3.58(s,br,2H),3.02-2.99(m,2H),2.49- 2.21(m,3H),2.20-2.17(d,J=7.2Hz,2H),1.90-1.81(m,1H),1.51(s,2H),1.40-1.39(d,J=6.0Hz,3H),0.77-0.72(m,1H).

[0288] Example 2 Preparation of 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (Compound 2)

[0289]

[0290] (1) Preparation of 1-ethyl 2,5-dimethyl-1-oxopentane-1,2,5-tricarboxylate

[0291]

[0292] Dissolve metallic sodium (2.07 g, 90 mmol) in anhydrous ethanol (32 mL) and stir until clear. Concentrate the solvent to obtain white solid EtONa. Dissolve EtONa in THF (60 mL), add diethyl oxalate (13.2 g, 90 mmol) dropwise, stir for 30 min after addition, add dimethyl adipate (15.7 g, 90 mmol), react at 25 ° C for 14 h. Add water (100 mL) and extract with EA (100 mL). Separate the liquids, wash the organic phase with water (100 mL), combine the aqueous phases, and adjust the pH to 1 with concentrated HCl. Extract with EA (100 mL × 3), combine the organic phases, dry and concentrate to obtain 19 g, with a yield of 76.6%.

[0293] (2) Preparation of 2-oxopimelic acid

[0294]

[0295] 1-Ethyl 2,5-dimethyl 1-oxopentane-1,2,5-tricarboxylate (14.0 g, 51.1 mmol) was dissolved in 4N HCl (75 mL), added and reacted at 65°C for 12 h. The solvent was concentrated to obtain 7.9 g of the title compound with a yield of 88.9%.

[0296] (3) Preparation of 7-methoxy-6,7-dioxoheptanoic acid

[0297]

[0298] Dissolve 2-oxopimelic acid (7.9 g, 45.4 mmol) in acetone (100 mL), add DBN (6.2 g, 49.9 mmol), add dimethyl sulfate (7.0 g, 55.4 mmol) at 0°C, and react at 25°C for 12 hours after the addition is complete. Quench the reaction with 2M hydrochloric acid, extract with EA, combine the organic phases, dry and concentrate to obtain 9.0 g of the title compound, which is used directly in the next step.

[0299] (4) Preparation of dimethyl 2-oxopimelate

[0300]

[0301] Dissolve 7-methoxy-6,7-dioxoheptanoic acid (9.0 g, 47.8 mmol) in methanol (150 mL), add thionyl chloride (15 mL) dropwise at 0°C, and react at 65°C for 12 h. Concentrate the solvent to obtain 6.6 g of the title compound with a two-step yield of 72%.

[0302] (5) Preparation of dimethyl 2,2-difluoroheptanedioate

[0303]

[0304] Dimethyl 2-oxopimelate (1.4 g, 6.93 mmol) was dissolved in dichloromethane (25 mL), DAST (5.6 g, 34.65 mmol) was added at 0°C, and the mixture was reacted at 20°C for 16 hours. Water was added to quench the reaction, and the mixture was concentrated and subjected to column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain the product (1.1 g, yield 71%). (6) Preparation of methyl 3,3-difluoro-2-oxocyclohexane-1-carboxylate

[0305]

[0306] Sodium hydride (300 mg, 60%, 7.5 mmol) was dissolved in THF (20 mL), and a THF solution (10 mL) of dimethyl 2,2-difluoroheptanedioate (1 g, 4.46 mmol) was added. The mixture was reacted at 20 °C for 16 hours, and 2 M hydrochloric acid was added to quench the reaction. The pH was adjusted to 5, and the mixture was extracted with ethyl acetate, washed with water, and concentrated to obtain a crude product which was directly used in the next step.

[0307] (7) Preparation of 8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol

[0308]

[0309] 3,3-Difluoro-2-oxocyclohexane-1-carboxylic acid methyl ester (crude product) was dissolved in water (20 mL), methyl isothiourea sulfate (1.8 g, 7.55 mmol) and sodium carbonate (945 mg, 8.92 mmol) were added, and the mixture was reacted at 30°C for 16 hours. Concentration column chromatography (ACN / H 2 O=0-40%) to obtain a crude product for the next reaction.

[0310] (8) Preparation of 4-chloro-8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline

[0311]

[0312] 8,8-Difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol (crude product) was dissolved in phosphorus oxychloride (8 mL) / 1,2-dichloroethane (4 mL), reacted at 110°C for 16 h, concentrated, diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the product (100 mg, three-step yield 9%).

[0313] (9) Preparation of methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0314]

[0315] 4-Chloro-8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline (100 mg, 0.4 mmol) was dissolved in NMP (5 mL), and methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (81 mg, 0.48 mmol) and potassium carbonate (110 mg, 0.8 mmol) were added. The mixture was reacted at 90 °C for 30 hours and then purified by column chromatography (ACN / H 2 O=0-70%) to give the product (90 mg, yield 61%).

[0316] (10) Preparation of methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0317]

[0318] Methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetate (90 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (159 mg, 0.92 mmol) was added, and the mixture was reacted at 20°C for 2 hours. Sodium thiosulfate was added to quench the reaction, and the mixture was washed with saturated sodium carbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated, and used directly in the next step (120 mg crude product).

[0319] (11) Preparation of methyl 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl))-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0320]

[0321] 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (80 mg, crude product) was dissolved in NMP (5 mL), DIEA (125 mg, 0.97 mmol) and (S)-2-methylazetidine (107 mg, 0.239 mmol) were added, and microwave reaction was performed at 160°C for 1 hour. Column chromatography (ACN / H 2 O = 0-60%) to give 40 mg of the product.

[0322] (12) Preparation of 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid

[0323]

[0324] 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl))-3-azabicyclo[3.1.0]hexan-6-yl)acetate (30 mg, 0.076 mmol) was dissolved in THF / H 2O (3 / 3 mL), add NaOH (20 mg, 0.5 mmol), react at 30 ° C for 1 hour. Adjust pH = 5, concentrate, and column chromatography (ACN / H 2 O=0-65%) to obtain the product (7.9 mg, yield 27.5%). Molecular formula: C 19 H 24 F 2 N 4 O 2 Molecular weight: 378.4 LC-MS (M / e): 379.2 (M+H + )

[0325] 1 H-NMR (400MHz, Methanol-D4) δ: 4.45-4.36 (m, 1H), 4.12-3.97 (m, 3H), 3.87 (q, J = 8.0Hz, 1H), 3.65-3.52 (m, 2H), 2.65-2.75 ( m,2H),2.43-2.12(m,5H),1.99-1.88(m,1H),1.85-1.78(m,2H),1.57-1.49(s,2H),1.47(d,J=8.0Hz,3H),0.92-0.85(m,1H).

[0326] Example 3-1 Preparation of 2-((1R,5S,6s)-3-(8,8-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 3-1)

[0327]

[0328] (1) Preparation of methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0329]

[0330] 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetic acid methyl ester (50 mg, 0.12 mmol, preparation method reference Example 2), dissolved in NMP (2 mL), added with DIEA (77 mg, 0.6 mmol), 3-fluoro-2-methylazetidine hydrochloride (47 mg, 0.37 mmol), microwave reaction at 160 ° C for 2 hours. Column chromatography (ACN / H 2 O = 0-80%) to give the product (20 mg, yield 41%).

[0331] (2) Preparation of 2-((1R,5S,6s)-3-(8,8-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0332]

[0333] 2-((1R,5S,6s)-3-(8,8-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (20 mg, 0.048 mmol) was dissolved in THF / H 2 O (2 / 2 mL), add NaOH (4 mg, 0.097 mmol), and react at 20°C for 3 hours. Adjust pH to 5, concentrate, and separate on a preparative plate (MeOH / CH 2 Cl 2 =1 / 15) to give the product (9 mg, yield 47%).

[0334] Molecular formula: C 19 H 23 F 3 N 4 O 2 Molecular weight: 396.4 LC-MS (M / e): 379.2 (M+H + )

[0335] 1 H-NMR (400MHz, CDCl 3)δ:5.05-4.86(m,1H),4.55-4.30(m,3H),4.15-3.95(m,3H),3.72-3.57(m,2H),2.70(s,1H ),2.38(m,2H),2.35-2.15(m,2H),1.95-1.81(m,2H),1.62-1.48(m,5H),1.09-0.98(m,2H).

[0336] Example 4-1 Preparation of 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (Compound 4-1)

[0337]

[0338] (1) Preparation of methyl 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0339]

[0340] 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetic acid methyl ester (100 mg, 0.25 mmol, preparation method reference Example 2), dissolved in NMP (2 mL), added with DIEA (97 mg, 0.75 mmol), 3,3-difluoro-2-methylazetidine hydrochloride (72 mg, 0.5 mmol), microwave reaction at 160°C for 2 hours, additional 3,3-difluoro-2-methylazetidine hydrochloride (72 mg, 0.5 mmol), continued microwave reaction at 160°C for 2 hours. Column chromatography (ACN / H 2 O = 0-85%) to give the product (50 mg, yield 47%).

[0341] (2) Preparation of 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid

[0342]

[0343] 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (50 mg, 0.117 mmol) was dissolved in THF / H 2 O (3 / 3 mL), add NaOH (9 mg, 0.234 mmol), react at 20 ° C for 3 hours. Adjust pH = 5, concentrate, and prepare plate separation (MeOH / CH 2 Cl 2 =1 / 20) to give the product (24 mg, yield 50%).

[0344] Molecular formula: C 19 H 22 F 4 N 4 O 2 Molecular weight: 414.4 LC-MS (M / e): 415.2 (M+H + )

[0345] 1 H-NMR (400MHz, CDCl 3 )δ:4.70-4.55(m,1H),4.34(t,J=12Hz,2H),4.12-4.02(m,2H),3.69-3.57(m,2H),2.75-2.65(m ,2H),2.46-2.18(m,4H),1.95-1.82(m,2H),1.52(m,3H),1.40-1.25(m,2H),1.09-0.98(m,1H).

[0346] Example 4-2 Preparation of a single configuration isomer of 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid

[0347] (1) Preparation of methyl 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0348]

[0349] Methyl 2-((1R,5S,6s)-3-(2-chloro-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetate (300 mg, 0.84 mmol) was dissolved in ACN (10 mL), DIEA (542 mg, 4.2 mmol) and 2-methyl 3,3-difluoroazetidine hydrochloride (150 mg, 1.04 mmol) were added, and the mixture was reacted at 80° C. for 16 hours. The product (150 mg, 42%) was obtained by column chromatography (EA / PE=30%).

[0350] (2) Preparation of a single configuration isomer of 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid

[0351]

[0352] 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (150 mg, 0.35 mmol) was dissolved in THF / H 2 O (8 / 8 mL), add NaOH (28 mg, 0.7 mmol), react at 20°C for 16 hours. Adjust pH to 5, concentrate, and column chromatography (ACN / H 2 O=0-70%) to obtain the product (100 mg, yield 69%). After separation by chiral column IG-3 (IG30CD-WE016), compound 4-2 (retention time: 20.987) and compound 4-3 (retention time: 19.762) were obtained.

[0353] Among them, one of compound 4-2 and compound 4-3 is compound 4, and the structure of the other single configuration is:

[0354]

[0355] Molecular formula: C 19 H 22 F 4 N 4 O 2 Molecular weight: 414.4 LC-MS (M / e): 415.2 (M+H + )

[0356] Compound 4-2: 1 H-NMR (400MHz, CDCl3 )δ:4.70-4.55(m,1H),4.34(t,J=12Hz,2H),4.12-4.02(m,2H),3.69-3.57(m,2H),2.75-2.65(m ,2H),2.46-2.18(m,4H),1.95-1.82(m,2H),1.52(m,3H),1.40-1.25(m,2H),1.09-0.98(m,1H).

[0357] Compound 4-3: 1 H-NMR (400MHz, CDCl 3 )δ:4.70-4.55(m,1H),4.34(t,J=12Hz,2H),4.12-4.02(m,2H),3.69-3.57(m,2H),2.75-2.65(m ,2H),2.46-2.18(m,4H),1.95-1.82(m,2H),1.52(m,3H),1.40-1.25(m,2H),1.09-0.98(m,1H).

[0358] Example 5-1 Preparation of 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 5-1)

[0359]

[0360] (1) Preparation of methyl 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0361]

[0362] 2-((1R,5S,6s)-3-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid methyl ester (70 mg, 0.18 mmol, preparation method reference Example 1) was dissolved in N-methylpyrrolidone (2 mL), diisopropylaminoethylamine (93.1 mg, 0.72 mmol) and 3,3-difluoro-2-methylazetidine hydrochloride (57.4 mg, 0.40 mmol) were added, and microwave reaction was performed at 150° C. for 2 hours, diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography (30% ethyl acetate / petroleum ether) was performed to obtain the product (40 mg, yield 53%).

[0363] (2) Preparation of 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0364]

[0365] Methyl 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (40 mg, 0.097 mmol) was dissolved in methanol (1 mL), 5N sodium hydroxide (0.025 mL, 0.125 mmol) was added, and the mixture was reacted at 10°C for 16 hours. The pH was adjusted to 4 with 1N hydrochloric acid, and the mixture was extracted with 10 mL of ethyl acetate. The mixture was washed with saturated brine, and the organic phase was spin-dried. The product (6.5 mg, yield 17%) was obtained by column chromatography (5% methanol / dichloromethane).

[0366] Molecular formula: C 18 H 20 F 4 N 4 O 2 Molecular weight: 400.4 LC-MS (M / e): 401.2 (M+H + )

[0367] 1 H-NMR (400MHz, CDCl 3)δ:4.68-4.62(m,1H),4.38(t,J=12.0,2H),4.06(t,J=12.0,2H),3.73-3.66(m, 2H),3.10-3.07(m,2H),2.52-2.40(m,4H),1.61-1.33(m,5H),1.03-1.00(m,1H).

[0368] Example 6-1 Preparation of 2-((1R,5S,6s)-3-(7,7-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 6-1)

[0369]

[0370] (1) Preparation of methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0371]

[0372] 2-((1R,5S,6s)-3-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid methyl ester (50 mg, 0.13 mmol, preparation method reference Example 1) was dissolved in N-methylpyrrolidone (2 mL), diisopropylaminoethylamine (50.4 mg, 0.39 mmol) and 3-fluoro-2-methylazetidine hydrochloride (19.5 mg, 0.15 mmol) were added, and microwave reaction was performed at 150° C. for 2 hours, diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography (30% ethyl acetate / petroleum ether) was performed to obtain the product (30 mg, yield 59%).

[0373] (2) Preparation of 2-((1R,5S,6s)-3-(7,7-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0374]

[0375] Methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (30 mg, 0.076 mmol) was dissolved in methanol (1 mL) and water (0.3 mL), and sodium hydroxide (3.94 mg, 0.098 mmol) was added. The mixture was reacted at 10°C for 16 hours, and the pH was adjusted to 4 with 1N hydrochloric acid. The mixture was extracted with 10 mL of ethyl acetate and washed with saturated brine. The organic phase was spin-dried and the product was obtained by column chromatography (5% methanol / dichloromethane) (14 mg, yield 48%).

[0376] Molecular formula: C 18 H 21 F 3 N 4 O 2 Molecular weight: 382.4 LC-MS (M / e): 383.2 (M+H + )

[0377] 1 H-NMR (400MHz, CDCl 3 )δ:5.32-5.30(m,0.5H),4.99-4.97(m,0.5H),4.46-4.29(m,2H),4.08-3.97(m,3H),3.69 -3.62(m,2H),3.07-3.01(m,2H),2.52-2.37(m,5H),1.57-1.53(m,5H),1.02-0.59(m,1H).

[0378] Example 7 Preparation of 2-((1R,5S,6R)-3-(9,9-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 7)

[0379]

[0380] (1) Preparation of 1-ethyl 2,6-dimethyl 1-oxohexane-1,2,6-tricarboxylate

[0381]

[0382] Sodium ethoxide (2.0 g, 29.3 mmol) was dissolved in THF (20 mL), and diethyl oxalate (3.9 g, 26.6 mmol) and dimethyl pimelate (5.0 g, 26.6 mmol) were added, and the mixture was reacted at 25°C for 16 hours. After the reaction, the system was distilled under reduced pressure, and water and EA were added for separation. The aqueous phase was adjusted to pH = 1, extracted with EA, and the organic phase was distilled under reduced pressure and directly used for the next reaction.

[0383] (2) Preparation of 2-oxosubanedioic acid

[0384]

[0385] 1-Ethyl 2,6-dimethyl 1-oxohexane-1,2,6-tricarboxylate (crude product 7.7 g) was dissolved in 4M HCl (66 ml), and the mixture was added and reacted at 65° C. for 10 hours. After the reaction was completed, the system was directly spin-dried and used directly in the next reaction.

[0386] (3) Preparation of 8-methoxy-7,8-dioxooctanoic acid

[0387]

[0388] Dissolve DBN (4.0 g, 31.9 mmol) in acetone (60 mL), add 2-oxosuberic acid (crude product 5.0 g) and dimethyl sulfate (3.4 g, 26.6 mmol), and react at 25°C for 16 hours. After the reaction, the system is directly spin-dried and EA is added, and the organic phase is washed with 1N HCl, and the organic phase is distilled under reduced pressure and directly used in the next reaction.

[0389] (4) Preparation of dimethyl 2-oxosuberate

[0390]

[0391] Dissolve 8-methoxy-7,8-dioxooctanoic acid (crude product 5.4 g) in DCM (40 ml) and add (COCl) 2 (5.1 g, 40.0 mmol), react at 25°C for 6 hours, add MeOH (20 ml), react for 16 hours, and after the reaction is completed, directly distill under reduced pressure and use it directly in the next step.

[0392] (5) Preparation of dimethyl 2,2-difluorooctanedioate

[0393]

[0394] Dissolve 2-oxosuberic acid dimethyl ester (crude product 5.7g) in DCM (50ml), add dast (10.0ml, 79.8mmol). After the addition is complete, react at 25℃ for 48 hours. After the reaction is completed, add 50ml of water, extract with EA, and perform normal phase column chromatography (EA:PE=1:8) to obtain 1.9g of the product, with a five-step yield of 30%.

[0395] (6) Preparation of methyl 3,3-difluoro-2-oxocycloheptane-1-carboxylate

[0396]

[0397] 60% NaH (480.0 mg, 12.0 mmol) was dissolved in THF, and dimethyl 2,2-difluorooctanedioate (1.9 g, 8.0 mmol) was added, and the mixture was reacted at 50°C for 16 hours. After the reaction was completed, the system was cooled to 20°C, water was added to quench, and column chromatography (EA:PE=1:10) was performed to obtain 680 mg of the product with a yield of 41%.

[0398] (7) Preparation of 9,9-difluoro-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-ol

[0399]

[0400] Dissolve 3,3-difluoro-2-oxocycloheptane-1-carboxylic acid methyl ester (1.0 g, 4.8 mmol) in water (30 ml), add S-methylisothiourea sulfate (1.0 g, 7.2 mmol), Na 2 CO 3 (1.0 g, 9.6 mmol), the system was reacted at 25°C for 16 hours. After the reaction, the pH was adjusted to 5, and the mixture was directly used for the next step after post-treatment.

[0401] (8) Preparation of 4-chloro-9,9-difluoro-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine

[0402]

[0403] 9,9-Difluoro-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-ol (crude product 3.5 g) was dissolved in DCE (10 ml) and POCl 3 (20 ml), and reacted at 110°C for 16 hours. After the reaction was completed, the system was evaporated under reduced pressure, and saturated NaHCO 3 The pH was adjusted to 8, and the product was extracted with EA and subjected to column chromatography (EA:PE=1:5) to obtain 650 mg of the product with a two-step yield of 51%.

[0404] (9) 2-((1R,5S,6s)-3-(9,9-difluoro-2-(methylthio)-6,7,8,9-tetrahydro-5H-cycloheptyl[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)

[0405] Preparation of methyl acetate

[0406]

[0407] 4-Chloro-9,9-difluoro-2-(methylthio)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine (300.0 mg, 1.14 mmol) was dissolved in NMP (10 ml), methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)acetate (264.0 mg, 1.7 mmol) was added, and K 2 CO 3 (315.0 mg, 2.3 mmol), react at 90°C for 3 hours. After the reaction, quench with water, extract with EA, and perform column chromatography (EA:PE=1:5) to obtain 350 mg of the product with a yield of 83%.

[0408] (10) Preparation of methyl 2-((1R,5S,6s)-3-(9,9-difluoro-2-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0409]

[0410] 2-((1R,5S,6s)-3-(9,9-difluoro-2-(methylthio)-6,7,8,9-tetrahydro-5H-cycloheptyl[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (350.0 mg, 0.9 mmol) was dissolved in DCM (90 ml), and m-CPBA (80%) (392.0 mg, 1.8 mmol) was added and reacted at 25°C for 3 hours. After the reaction was completed, saturated NaHCO 3 The reaction was quenched, extracted with DCM, and purified by column chromatography (EA:PE=2:1) ​​to obtain 250 mg of the product with a yield of 67%.

[0411] (11) Preparation of methyl 2-((1R,5S,6R)-3-(9,9-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0412]

[0413] 2-((1R,5S,6s)-3-(9,9-difluoro-2-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid methyl ester (250.0 mg, 0.6 mmol) was dissolved in NMP (6 ml), (S)-2-methylazetidine (0.5 ml, 3.0 mmol) was added, and the mixture was reacted at 160° C. for 8 hours in a microwave oven. After the reaction was completed, water was added, EA was extracted, and column chromatography (EA:PE=1:3) was performed to obtain 120 mg of the product with a yield of 49%.

[0414] (12) Preparation of 2-((1R,5S,6R)-3-(9,9-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0415]

[0416] Methyl 2-((1R,5S,6R)-3-(9,9-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (120.0 mg, 0.3 mmol) was dissolved in THF (3 ml) and H 2 O (3 ml), add NaOH (17.7 mg, 0.4 mmol), and react at 25° C. for 3 hours. After the reaction, adjust the pH to weak acidity, prepare a silica gel plate (DCM: MeOH = 15: 1) to obtain 60 mg of the product, with a yield of 53%.

[0417] Molecular formula: C 20 H 26 F 2 N 4 O 2 Molecular weight: 392.45 LC-MS (M / e): 393.0 (M+H + )

[0418] 1 H-NMR (400MHz, MeOD) δ: 4.47-4.40 (m, 1H), 4.05-3.87 (m, 4H), 3.49 (t, J = 11.2Hz, 2H), 2.68-2.66 (m, 2H), 2 .43-2.35(m,1H),2.35-2.16(m,4H),2.00-1.88(m,3H),1.65(m,2H),1.50-1.48(m,5H),0.86-0.83(m,1H).

[0419] Example 8 Preparation of 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 10)

[0420]

[0421] (1) Preparation of methyl 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl))-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0422]

[0423] 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetic acid methyl ester (120.0 mg, 0.3 mmol, preparation method refers to steps (1)-(10) of Example 2), dissolved in NMP (3 mL), added with DIEA (155.0 mg, 1.2 mmol), (S)-2-methylpiperidine (59.0 mg, 0.6 mmol), and reacted at 170°C for 2 hours by microwave. Diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography (EA / PE=1 / 5) to obtain the product (10.0 mg, yield 7.9%).

[0424] (2) Preparation of 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0425]

[0426] 2-((1R,5S,6R)-3-(8,8-difluoro-2-((S)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl))-3-azabicyclo[3.1.0]hexan-6-yl)acetate (24.0 mg, 0.057 mmol) was dissolved in THF / H 2 O (2 / 2 mL), add NaOH (4.6 mg, 0.11 mmol), react at 20° C. for 30 minutes, adjust pH to 6-7, concentrate, and column chromatography DCM:MeOH=20:1 to obtain the product (7.2 mg, yield 31.1%).

[0427] Molecular formula: C 21 H 28 F 2 N 4 O 2 Molecular weight: 406.5 LC-MS (M / e): 407.0 (M+H + )

[0428] 1 H-NMR (400MHz, CDCl 3 )δ:5.03-4.90(m,1H),4.59-4.48(m,1H),4.00-3.76(m,2H),3.64-3.09 (m,2H),2.91-2.70(m,1H),2.65-2.57(m,2H),2.47-2.38(m,2H),2.36-2 .18(m,2H),1.85-1.75(m,2H),1.75-1.51(m,5H),1.56-1.45(m,2H),1.4 9-1.40(m,1H),1.39-1.29(m,1H),1.09-1.18(m,3H),0.96-1.08(m,1H).

[0429] Example 9 Preparation of 2-((1R,5S,6S)-3-(8,8-difluoro-2-((R)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 11)

[0430]

[0431] (1) Preparation of methyl 2-((1R,5S,6S)-3-(8,8-difluoro-2-((R)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl))-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0432]

[0433] Methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (200 mg, 0.5 mmol) was dissolved in NMP (1 mL), DIEA (322 mg, 2.5 mmol) and (R)-2-methylpiperidine (99 mg, 1 mmol) were added, and microwave reaction was performed at 180°C for 2 hours. The mixture was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the product (35 mg, yield 17%) was obtained by column chromatography (EA / PE=1 / 5).

[0434] (2) Preparation of 2-((1R,5S,6S)-3-(8,8-difluoro-2-((R)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0435]

[0436] 2-((1R,5S,6S)-3-(8,8-difluoro-2-((R)-2-methylpiperidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl))-3-azabicyclo[3.1.0]hexan-6-yl)acetate (35 mg, 0.083 mmol) was dissolved in THF / H 2 O (3 / 3 mL), add NaOH (17 mg, 0.42 mmol), react at 20 ° C for 3 hours. Adjust pH = 5, concentrate, and reverse phase column chromatography ACN / H 2 O=0-60% gave the product (5.9 mg, yield 17%).

[0437] Molecular formula: C 21 H 28 F 2 N 4 O 2 Molecular weight: 406.5 LC-MS (M / e): 407.2 (M+H + )

[0438] 1 H-NMR (400MHz, CDCl 3 )δ:5.02-4.85(m,1H),4.58-4.42(m,1H),4.00-3.75(m,2H),3.64-3.09(m,5H),2.89-2.70 (m,1H),2.65-2.42(m,2H),2.25-1.89(m,4H),1.82-1.15(m,7H),1.09(m,3H),0.8(s,1H).

[0439] Example 10 Preparation of 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 12)

[0440]

[0441] (1) Preparation of methyl 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0442]

[0443] 2-((1R,5S,6s)-3-(2-chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (80 mg, 0.23 mmol) was dissolved in acetonitrile (2 mL), DIEA (0.5 ml) and (S)-2-methylpiperidine (50 mg, 0.50 mmol) were added, and the mixture was reacted by microwave at 90 ° C for 6 hours. The reaction was detected by TLC (petroleum ether: ethyl acetate = 2:1), and the mixture was spin-dried. The mixture was separated by preparative plate (petroleum ether: ethyl acetate = 2:1) to obtain 30 mg of the compound. The yield was 31.9%.

[0444] (2) Preparation of 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0445]

[0446] 2-((1R,5S,6R)-3-(7,7-difluoro-2-((S)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (30 mg, 0.07 mmol) was dissolved in MeOH / THF / H 2 O (2 / 2 / 0.2 mL), add NaOH (20 mg, 0.5 mmol), react at 25° C. for 3 hours, adjust pH to 4-5 with 1N hydrochloric acid, concentrate, and separate on a preparative plate (dichloromethane: methanol = 20:1) to obtain 20 mg of the compound, with a yield of 69.0%.

[0447] Molecular formula: C 20 H 26 F 2 N 4 O 2 Molecular weight: 392.4 LC-MS (M / e): 393.0 (M+H + )

[0448] 1 HNMR (400MHz, MeOD): δ4.88-5.00 (m, 1H), 4.50-4.54 (m, 1H), 4.02 (dd, J = 10.8Hz, 4.4Hz, 2H),

[0449] 3.64-3.67(m,2H),3.03-3.09(m,2H),2.93(td,J=10.8Hz,2.8Hz,1H),2.42-2.49(m,2H),2.32(d,J=7.2H z,2H),1.70-1.73(m,3H),1.57-1.67(m,4H),1.42-1.47(m,1H),1.17(d,J=7.2Hz,3H),0.89-0.92(m,1H).

[0450] Example 11 Preparation of 2-((1R,5S,6S)-3-(7,7-difluoro-2-((R)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 13)

[0451]

[0452] (1) Preparation of methyl 2-((1R,5S,6S)-3-(7,7-difluoro-2-((R)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0453]

[0454] 2-((1R,5S,6s)-3-(7,7-difluoro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (100 mg, 0.26 mmol, preparation method as described in Example 1) was dissolved in NMP (2 mL), DIEA (0.5 ml), 4-dimethylaminopyridine (5 mg, 0.04 mmol), (R)-2-methylpiperidine (51 mg, 0.51 mmol) were added, microwave reaction was performed at 160° C. for 4 hours, water (10 ml) was added, and the mixture was extracted with 3×5 ml of ethyl acetate. The organic phases were combined, dried by spin drying, and purified by column chromatography (ethyl acetate: petroleum ether=1:2) to give 9 mg of the compound, with a yield of 8.6%.

[0455] (2) Preparation of 2-((1R,5S,6S)-3-(7,7-difluoro-2-((R)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0456]

[0457] 2-((1R,5S,6S)-3-(7,7-difluoro-2-((R)-2-methylpiperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (9 mg, 0.022 mmol) was dissolved in MeOH / THF / H 2 O (2 / 2 / 0.2 mL), add NaOH (5 mg, 0.12 mmol), react at 25° C. for 4 hours, adjust pH to 6-7 with 1N hydrochloric acid, concentrate, and separate on a preparative plate (dichloromethane: methanol = 20:1) to obtain 3.0 mg of the compound, with a yield of 34.5%.

[0458] Molecular formula: C 20 H 26 F 2 N 4 O 2 Molecular weight: 392.4 LC-MS (M / e): 393.0 (M+H + )

[0459] 1HNMR (400MHz, MeOD): δ4.88-5.00(m,1H),4.50-4.54(m,1H),4.01(dd,J=10.8Hz,4.0Hz,2H),3.62-3.65(m,2H),3.02-3.06(m,2H),2.90-2.91( m,1H),2.38-2.43(m,2H),2.29-2.31(m,2H),1.69-1.71(m,3H),1.55-1 .60(m,4H),1.28-1.33(m,1H),1.15(d,J=7.2Hz,3H),0.89-0.92(m,1H).

[0460] Example 12 Preparation of 2-((1R,5S,6s)-3-(2-(cyclobutyl(methyl)amino)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (Compound 14)

[0461]

[0462] (1) Preparation of methyl 2-((1R,5S,6s)-3-(2-(cyclobutyl(methyl)amino)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0463]

[0464] Methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(methylsulfonyl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (100 mg, 0.25 mmol) was dissolved in NMP (2 mL), DIEA (161 mg, 1.25 mmol) and N-cyclobutylmethylamine hydrochloride (61 mg, 0.5 mmol) were added, and microwave reaction was performed at 160°C for 2 hours. The mixture was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the product (30 mg, yield 30%) was obtained by column chromatography (EA / PE=1 / 5).

[0465] (2) Preparation of 2-((1R,5S,6s)-3-(2-(cyclobutyl(methyl)amino)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid

[0466]

[0467] 2-((1R,5S,6s)-3-(2-(cyclobutyl(methyl)amino)-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (30 mg, 0.074 mmol) was dissolved in THF / H 2 O (3 / 3 mL), add NaOH (15 mg, 0.37 mmol), react at 20 ° C for 3 hours. Adjust pH = 5, concentrate, and reverse phase column chromatography ACN / H 2 O=0-80% gave the product (5.9 mg, yield 20%).

[0468] Molecular formula: C 20 H 26 F 2 N 4 O 2 Molecular weight: 392.45 LC-MS (M / e): 393.2 (M+H + )

[0469] 1 H-NMR (400MHz, CDCl 3 )δ:5.11-4.95(m,1H),3.99-3.85(m,2H),3.55-3.41(m,2H),3.02(s,3H),2.95-2 .48(m,5H),2.25-2.12(m,6H),1.83-1.55(m,4H),1.39-1.28(m,2H),0.89(s,1H).

[0470] Example 13 Preparation of 2-((1R,5S,6s)-3-(8,8-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 15)

[0471]

[0472] (1) Preparation of 8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol

[0473]

[0474] Dissolve methyl 3,3-difluoro-2-oxocyclohexane-1-carboxylate (2.0 g, 10.4 mmol) in water (50 mL), add methyl isothiourea (2.2 g, 15 mmol), Na 2 CO 3(2.2 g, 20.8 mmol), react at 20 °C for 16 hours, adjust pH to acidic with dilute hydrochloric acid, extract with EA, dry over anhydrous sodium sulfate, and distill under reduced pressure for direct use in the next step.

[0475] (2) Preparation of 8,8-difluoro-5,6,7,8-tetrahydroquinazoline-2,4-diol

[0476]

[0477] 8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4-ol (1.8 g crude product) was dissolved in ethanol (40 mL), and 6M HCl (40 ml) was added. After the addition was complete, the mixture was reacted at 85° C. for 8 hours. After the reaction was completed, the system was directly spin-dried and used for the next reaction.

[0478] (3) Preparation of 2,4-dichloro-8,8-difluoro-5,6,7,8-tetrahydroquinazoline

[0479]

[0480] 8,8-difluoro-5,6,7,8-tetrahydroquinazoline-2,4-diol (1.6 g crude product) was dissolved in phosphorus oxychloride (50 mL), and DIPEA (5 ml) was added. After the addition was complete, the reaction was carried out at 110° C. for 16 hours. After the reaction was completed, the system was directly spin-dried and purified by column chromatography (EA:PE=1:5) to obtain 1.5 g of the product, with a three-step yield of 61%.

[0481] (4) Preparation of methyl 2-((1R,5S,6s)-3-(2-chloro-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetate

[0482]

[0483] Dissolve 2,4-dichloro-8,8-difluoro-5,6,7,8-tetrahydroquinazoline (500.0 mg, 2.1 mmol) in acetonitrile (10 ml), add methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexane-6-yl)acetate (391.0 mg, 2.5 mmol), DIPEA (1.9 ml, 10.5 mmol), and react at 25°C for 16 hours. After the reaction is completed, spin dry, and normal phase column chromatography (EA:PE=1:2) is performed to obtain 640 mg of the product with a yield of 85%.

[0484] (5) Preparation of methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0485]

[0486] 2-((1R,5S,6s)-3-(2-chloro-8,8-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetate (320.0 mg, 0.9 mmol) was dissolved in dioxane (10 ml), 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (368.0 mg, 0.99 mmol), Pd (pph) were added. 3 )Cl 2 (19.0 mg, 0.027 mmol), x-phos (13.0 mg, 0.027 mmol), after addition, the system was heated to N 2 Under protection, the reaction was carried out at 100°C for 16 hours. After the reaction was completed, the system was cooled to 20°C, dried in a spin-drying machine, and subjected to normal phase column chromatography (EA:PE=2:1) ​​to obtain 220 mg of the product with a yield of 60%.

[0487] (6) Preparation of 2-((1R,5S,6s)-3-(8,8-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0488]

[0489] Methyl 2-((1R,5S,6s)-3-(8,8-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (200.0 mg, 0.5 mmol) was dissolved in THF (4 ml) and H 2 O (4 ml), add NaOH (30.0 mg, 0.75 mmol). After the addition is complete, the system is reacted at 25°C for 2 hours. After the reaction is completed, adjust the pH to acidic, and filter to obtain 150 mg of the product with a yield of 77%.

[0490] Molecular formula: C 18 H 20 F 2 N 6 O 2Molecular weight: 390.4 LC-MS (M / e): 391.0 (M+H + )

[0491] 1 H-NMR (400MHz, DMSO) δ: 8.19 (s, 1H), 4.38 (s, 3H), 4.07 (d, J = 11.2Hz, 2H), 3.78 (d, J = 10 .4Hz,2H),2.94(s,2H),2.31-2.24(m,4H),1.82(s,2H),1.60(s,2H),0.85-0.83(m,1H).

[0492] Example 14 Preparation of 2-((1R,5S,6s)-3-(7,7-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 16)

[0493]

[0494] (1) Preparation of 1-methyl-5-(tributyltinyl)-1H-1,2,3-triazole

[0495]

[0496] 1-Methyl-1H-1,2,3-triazole (300.0 mg, 3.6 mmol) was dissolved in THF (5 mL), n-BuLi (2.0 ml, 5 mmol) was added at -78 °C and reacted for 2 hours, tributyltin chloride (1.1 ml, 4 mmol) was added at -78 °C and reacted for 1 hour, the system was heated to 20 °C, reacted for 1 hour, directly spin-dried, petroleum ether was added, filtered, and the filtrate was distilled under reduced pressure to obtain 1.5 g of crude product, which was directly used in the next step reaction.

[0497] (2) Preparation of methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0498]

[0499] 2-((1R,5S,6s)-3-(2-chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (70.0 mg, 0.2 mmol) was dissolved in dioxane (2 mL), and 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (82.0 mg crude), Pd (pph) were added. 3 ) 2 Cl 2 (4.2 mg, 0.006 mmol), x-phos (2.9 mg, 0.006 mmol, after addition, under N 2 The reaction was carried out at 100° C. for 3 hours. After the reaction was completed, the product was filtered, washed with methanol, and the filtrate was distilled under reduced pressure and purified on a silica gel plate (DCM:MeOH=20:1) to obtain 71 mg of the product with a yield of 91%.

[0500] (3) Preparation of 2-((1R,5S,6s)-3-(7,7-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0501]

[0502] Methyl 2-((1R,5S,6s)-3-(7,7-difluoro-2-(1-methyl-1H-1,2,3-triazol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (100.0 mg, 0.26 mmol) was dissolved in THF (3 ml) and H 2 O (3 ml), add NaOH (16.0 mg, 0.39 mmol), react at 20 ° C for 2 hours, adjust the pH to acidic, extract with EA, and distill the organic phase under reduced pressure to obtain a solid, which is washed with methanol to obtain 53 mg of the product with a yield of 54%.

[0503] Molecular formula: C 17 H 18 F 2 N 6 O 2 Molecular weight: 376.37 LC-MS (M / e): 377.0 (M+H + )

[0504] 1H-NMR (400MHz, MeOD) δ: 8.29 (s, 1H), 4.48 (s, 3H), 4.16 (d, J = 11.2Hz, 2H), 3.91-3.69 (m, 2H), 3 .31(t,J=1.6Hz,2H),2.57-2.54(m,2H),2.35(d,J=7.2Hz,2H),1.67(s,2H),0.96-0.94(m,1H).

[0505] The KHK inhibitor provided by the present invention and its application are described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention, and the description of the above examples is only used to help understand the method of the present invention and its central idea. It should be pointed out that for those of ordinary skill in the art, without departing from the principles of the present invention, the present invention can also be improved and modified in a number of ways, and these improvements and modifications also fall within the protection of the claims of the present invention.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in, X, Y, and Z are each independently selected from -N-; Ring A is selected from 4-7 membered cycloalkyl; R 1 selected from -(L) m -C(O)OR a ; L is selected from C 1-3 Alkylene and halogenated C 1-3 Alkylene; R 2 is selected from 3-6 membered heterocyclyl, 5-6 membered heteroaryl and N(C 1-4 Alkyl)(C 3-6 Cycloalkyl); Each R 3 are independently selected from hydrogen, halogen, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and halogenated C 1-4 Alkoxy; R a Selected from hydrogen; Each Q2 is independently selected from amino, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and halogenated C 1-4 Alkoxy; m is 1 or 2; n is an integer from 0 to 3.

2. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, in, X, Y, and Z are each independently selected from -N-; Ring A is selected from 5-7 membered cycloalkyl; R 1 selected from -(L) m -C(O)OR a ; L is C 1-3 Alkylene; R 2 is selected from azetidinyl, piperidinyl, thienyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl and Each R 3 are independently selected from hydrogen and halogen; R a is hydrogen; Each Q2 is independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and halogenated C 1-4 Alkoxy; m is 1 or 2; n is an integer from 0 to 3.

3. The compound according to claim 2, its pharmaceutically acceptable salt or its stereoisomer, in, X, Y, and Z are each independently -N-; Ring A is a 5-6 membered cycloalkyl group; R 1 selected from -(L) m -C(O)OR a ; L is a methylene group; R 2 is selected from azetidinyl, piperidinyl, triazolyl, Each R 3 are each independently selected from halogen; R a Selected from hydrogen; Each Q2 is independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl and trifluoromethoxy; m is 1 or 2; n is 1, 2 or 3.

4. A pharmaceutical preparation comprising the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers and / or diluents; the pharmaceutical preparation is in any dosage form that is clinically or pharmaceutically acceptable.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and / or diluents.

6. Use of the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical preparation according to claim 4, or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating and / or preventing a KHK-mediated disease.

7. The use according to claim 6, wherein The KHK-mediated disease is selected from cirrhosis, fatty liver, hepatitis, and liver failure.

8. A method for preparing the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or its stereoisomer, comprising the following steps: reacting the compound represented by formula (II) with the compound represented by formula (III) to obtain the compound represented by formula (IV); The sulfhydryl group in the compound represented by formula (IV) undergoes a functional group conversion reaction to obtain a compound represented by formula (V); The compound represented by formula (V) is reacted to obtain the compound represented by formula (I); Wherein, G is a halogen; R 1 , R 2 , R 3 , X, Y, Z, n and ring A are as defined in any one of claims 1 to 3.

9. A method for preparing the compound as claimed in any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, comprising the following steps: The compound represented by formula (II-1) is reacted with the compound represented by formula (III) to obtain the compound represented by formula (IV-1); The compound represented by formula (IV-1) is reacted to obtain the compound represented by formula (I); Wherein, G is a halogen; R 1 , R 2 , R 3 , X, Y, Z, n and ring A are as defined in any one of claims 1 to 3.

10. An intermediate of the compound of general formula (I) as claimed in claim 1, having the following structure: in, R 1 , R 3 , X, Y, Z, n and ring A are as defined in any one of claims 1 to 3.

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