Pyrimidine derivative hexokinase inhibitors and their uses

Abstract

The present invention relates to the field of pharmaceutical technology, and specifically relates to pyrimidine derivative hexokinase inhibitors, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof in the preparation of drugs for treating and / or preventing diseases mediated by KHK and related diseases.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to pyrimidine derivative ketohexokinase inhibitor compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof, and the use of the compounds, pharmaceutically acceptable salts thereof, esters thereof or stereoisomers thereof in the preparation of drugs 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 problems attracting much attention. Non-alcoholic steatohepatitis (NASH) is the result of the further development of simple fatty liver, and its pathological manifestations include lipid deposition, infiltration of inflammatory cells, liver tissue necrosis and fibrosis lesions, and further lesions develop into more severe liver cirrhosis and hepatocellular carcinoma (HCC). NAFLD not only affects the hepatobiliary system of patients, but is also closely related to insulin resistance, dyslipidemia, atherosclerosis, fat embolism, hematological diseases, etc. (Friedman SL et al., Nat Med, 2018, 24: 908-22). Since all components of metabolic syndrome are related to liver fat content, patients with metabolic syndrome should be evaluated for the risk of NAFLD. Patients with type 2 diabetes are accompanied by insulin resistance, obesity, dyslipidemia, and abnormal liver enzymes, and the prevalence of NAFLD is also relatively high in people at risk of type 2 diabetes.

[0003] The increasing addition of sugars (usually sucrose and high-fructose corn syrup) in beverages and processed foods has led to an increase in the fructose content in the modern diet. High fructose intake has been shown to cause many adverse metabolic effects and 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 syndrome. (b) Bray GA. Soft drink consumption and obesity: it is 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., Association study of 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 (European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity Clinical Practice Guidelines on Non-alcoholic Fatty Liver Disease 2016). Different from glucose, the metabolism of fructose is not regulated by negative feedback. Fructose is preferentially metabolized relative to other carbohydrates, and its metabolism generates various reactive and signaling metabolites that promote the progression of metabolic diseases.In the absence of KHK, weight gain and insulin resistance induced by fructose consumption 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 the intake of sugar / HFCS (high-fructose corn syrup) and / or blocking the production of uric acid helps 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 gene mutation causes essential fructosuria, a rare and harmless abnormality characterized by the appearance of fructose in urine after ingestion of fructose-containing foods. The high prevalence of T2D, obesity, and NAFLD / NASH and related metabolic diseases such as cardiovascular diseases and strokes has led to an increased demand for both preventive health care and therapeutic interventions.

[0004] Hexokinase (also known as fructokinase) is the basic enzyme for fructose metabolism. The KHK enzyme in the liver phosphorylates the C1 position of fructose with the assistance of ATP (adenosine triphosphate) to produce fructose-1-phosphate (F1P), which enters the normal metabolic pathway; meanwhile, uric acid is produced downstream of ATP. The human hexokinase (hKHK) expressed by two alternative mRNA splice variants encodes two different regional isomer enzymes, KHK-A and KHK-C. KHK-C has a lower Km value, a higher Kcat, and a catalytic efficiency more than 405 times higher, indicating that the affinity and ability of KHK-C for fructose phosphorylation are significantly higher than those of 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 via the polyol pathway through the intermediate sorbitol, generating 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 knockout of KHK protects mice from glucose-induced weight gain, insulin resistance, and steatosis, indicating that under hyperglycemic conditions, endogenously produced fructose can contribute to insulin resistance and steatosis (Lanaspa, M.A. 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 involving alterations in either or both endogenous or ingested fructose.

[0006] Hepatic fructokinase deficiency underlies fructosuria. In contrast to this benign condition, deficiency of aldolase B (the next enzyme in the KHK metabolic pathway for fructose) results in the accumulation of F1P upon fructose ingestion and can lead to lethal depletion of cellular ATP (hereditary fructose intolerance). In the fructose metabolic pathway, the enzyme responsible for breaking down F1P immediately downstream of the KHK step is aldolase (ALDOB), and deficiency of this enzyme results in hereditary fructose intolerance (HFI). A rare disorder affecting approximately 1 in 20,000 people, this mutation causes increased formation of uric acid following F1P accumulation and ATP depletion, the combination of which results in hypoglycemia, hyperuricemia, and lactic acidosis, as well as other metabolic disturbances. HFI blocks the downstream metabolism of fructose and results in acute symptoms such as vomiting, severe hypoglycemia, diarrhea, and abdominal pain, which can lead to long-term growth defects, liver and kidney damage, and potentially death (Ali M et al., J. Med. Genet. May 1998; 35(5); 353-365). Patients typically experience a one-year survival prior to diagnosis, and the only treatment is avoidance of dietary fructose. The conversion of endogenous glucose to endogenous fructose via the polyol pathway and its metabolism in the body also pose a challenge to this treatment modality. The presence of fructose in most foods presents a challenge to the diet. In addition to physical symptoms, many patients face emotional and social isolation due to their unusual diet and need to strictly adhere to dietary restrictions (HFI-INFO Discussion Board, http; / / hfiinfo.proboards.com. Accessed December 14, 2015). Additionally, infusions containing fructose, sorbitol, or invert sugar can be life-threatening to patients. There is a high unmet clinical need for this disorder. SUMMARY OF THE INVENTION

[0007] An object of the present invention is to provide a hexokinase inhibitor of pyrimidine derivatives and its applications. The specific technical solutions are as follows:

[0008] The present invention first provides a compound represented by the general formula (I), its pharmaceutically acceptable salts, esters, or its stereoisomers:

[0009]

[0010] Wherein,

[0011] R 1 , R 2 are each independently selected from hydrogen, halogen, cyano, C 1-6 alkyl optionally substituted with one or more Q1, NR 1a R 1b , C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, -(L)m -C 3-12 cycloalkyl, -(L) m -C 3-12 heterocyclic group, -(L) m -C 6-12 aryl and -(L) m -C 5-12 heteroaryl, or R 1 and R 2 together with the connected carbon atoms form a 4- to 8-membered cycloalkyl, 4- to 8-membered heterocyclic group, phenyl or 5- to 8-membered heteroaryl optionally substituted by one or more Q2;

[0012] R 1a 、R 1b are each independently selected from hydrogen and C 1-6 alkyl optionally substituted by one or more halogen atoms or deuterium atoms;

[0013] R 3 is selected from a 5- to 12-membered spirocyclic group, 5- to 12-membered spiroheterocyclic group, 7- to 12-membered heterocyclic group, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 5- to 12-membered bridged cyclic group, 3- to 10-membered cycloalkyl, 3- to 6-membered monocyclic heterocyclic group,

[0014] provided that: when R 3 is selected from being optionally substituted by one or more Q3 , R 1 and R 2 together with the connected carbon atoms form a 4- to 8-membered cycloalkyl, 4- to 8-membered heterocyclic group, phenyl or 5- to 8-membered heteroaryl optionally substituted by one or more Q2;

[0015] each R 4 、R 5 is each independently selected from hydrogen, -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -C 1-6 alkylamino, halogen, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -(L) m -3- to 8-membered cycloalkyl, -(L) m -3- to 8-membered heterocyclic group, -(L) m -6- to 12-membered aryl, -(L) m -5- to 12-membered heteroaryl, and R 4 、R 5 are not both hydrogen;

[0016] Each of Q1, Q2, and Q3 is independently selected from deuterium, halogen, nitro, cyano, -(L) m -OR 6 、-(L) m -NR 6 R 7 、-(L) m -C(O)OR 6 、-(L) m -CONR 6 R 7 、-(L) m -CONHSO2R 6 、-(L) m -SO2NHCOR 6 、-(L) m -SR 6 、-(L) m -OC(O)R 6 、-(L) m -OC(O)OR 6 、-(L) m -OC(O)NR 6 R 7 、-(L) m -NR 6 C(O)R 7 、-(L) m -NR 6 C(O)OR 7 、-(L) m -OS(O)R 6 、-(L) m -OS(O)OR 6 、-(L) m -OS(O)NR 6 R 7 、-(L) m -S(O)NR 6 R 7 、-(L) m -NR 6 S(O)R 7 、-(L) m -OS(O)2R 6 、-(L) m -S(O)2NR 6 R 7 、-(L) m -NR 6 S(O)2R 7 、-(L) m -P(O)R 6 R 7 、-(L)m -SOR 6 、-(L) m -SO2R 6 、-(L) m -SONR 6 R 7 、-(L) m -C(O)NR 6 R 7 、-(L) m -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, -(L) optionally substituted with one or more substituents m -3- to 10-membered cycloalkyl, -(L) m -3- to 10-membered heterocycloalkyl, -(L) m -6- to 10-membered aryl and -(L) m -5- to 10-membered heteroaryl, said substituents being selected from carboxyl, hydroxyl, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl and halo-C 1-6 alkoxy;

[0017] Each R 6 、R 7 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl and halo-C 1-6 alkoxy;

[0018] Each L is independently selected from C 1-6 alkylene and halo-C 1-6 alkylene;

[0019] Each m is independently an integer from 0 - 6.

[0020] In certain embodiments, a compound of formula (I) as described above, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein,

[0021] R 1 、R 2 are each independently selected from hydrogen, halogen, C 1-4 alkyl optionally substituted with one or more Q1, NR 1a R 1b 、C1-4 Alkoxy, halo-C 1-4 Alkyl, halo-C 1-4 Alkoxy, -(L) m -C 3-8 Cycloalkyl, -(L) m -C 3-8 Heterocyclic group, -(L) m -C 6-10 Aryl and -(L) m -C 5-8 Heteroaryl, or R 1 and R 2 together with the carbon atoms to which they are attached form a 4- to 8-membered cycloalkyl, 4- to 8-membered heterocyclic group, phenyl or 5- to 8-membered heteroaryl optionally substituted by one or more Q2;

[0022] R 1a 、R 1b are each independently selected from hydrogen, C 1-4 alkyl optionally substituted by 1 to 6 halogen atoms or deuterium atoms;

[0023] R 3 is selected from a 5- to 10-membered spirocyclic group, 5- to 10-membered spiroheterocyclic group, 6- to 10-membered aryl, 7- to 9-membered heterocyclic group, 3- to 6-membered monocyclic heterocyclic group optionally substituted by one or more Q3,

[0024] provided that: when R 3 is selected from a optionally substituted by one or more Q3 1 then R 2 and R

[0025] together with the carbon atoms to which they are attached form a 4- to 8-membered cycloalkyl or 4- to 8-membered heterocyclic group optionally substituted by one or more Q2; 4 、R 5 are each independently selected from hydrogen, -(L) m -C 1-4 alkyl, -(L) m -C 1-4 alkoxy, -(L) m -C 1-4 alkylamino, halogen, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and R 4 、R 5 are not both hydrogen;

[0026] each Q1, Q2, Q3 is independently selected from deuterium, halogen, nitro, cyano, -(L) m -OR6 、 -(L) m -NR 6 R 7 、 -(L) m -C(O)OR 6 、 -(L) m -CONR 6 R 7 、 -(L) m -CONHSO2R 6 、 -(L) m -SO2NHCOR 6 、 -(L) m -SR 6 、 -(L) m -OC(O)R 6 、 -(L) m -NR 6 C(O)R 7 、 -(L) m -NR 6 C(O)OR 7 、 -(L) m -S(O)2NR 6 R 7 、 -(L) m -NR 6 S(O)2R 7 、 -(L) m -P(O)R 6 R 7 、 -(L) m -SOR 6 、 -(L) m -SO2R 6 、 -(L) m -SONR 6 R 7 、 -(L) m -C(O)NR 6 R 7 、 -(L) m -C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, -(L) optionally substituted with one or more substituents m -3-8 membered cycloalkyl, -(L) m -3-8 membered heterocyclic group, -(L) m -6-10 membered aryl and -(L) m -5-8 membered heteroaryl, said substituents being selected from carboxyl, hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4Alkyl and halo-C 1-4 alkoxy;

[0027] Each R 6 、R 7 is independently selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo-C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl and halo-C 1-4 alkoxy;

[0028] Each L is independently selected from C 1-4 alkylene and halo-C 1-4 alkylene;

[0029] Each m is independently an integer from 0 - 5.

[0030] In certain embodiments, the compounds, pharmaceutically acceptable salts, esters or stereoisomers thereof of the foregoing general formula (I), wherein,

[0031] R 1 and R 2 together with the carbon atoms to which they are attached form a 4 - 8 membered cycloalkyl, 4 - 8 membered heterocyclic group, phenyl or 5 - 8 membered heteroaryl optionally substituted by one or more Q2;

[0032] R 3 is selected from a 5 - 10 membered spiro group, 5 - 10 membered spiroheterocyclic group, 7 - 9 membered heteroalkyl, 3 - 6 membered monocyclic heterocyclic group,

[0033] Each R 4 、R 5 is independently selected from hydrogen, -(L) m -C 1-4 alkyl, -(L) m -C 1-4 alkoxy, -(L) m -C 1-4 alkylamino, halogen, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, 3 - 6 membered cycloalkyl, 3 - 6 membered heterocyclic group, phenyl, 5 - 8 membered heteroaryl, and R 4 、R 5 are not both hydrogen;

[0034] Each Q2, Q3 is independently selected from deuterium, halogen, -(L) m -OR 6, -(L) m -NR 6 R 7 , -(L) m -C(O)OR 6 , -(L) m -P(O)R 6 R 7 , -(L) m -SOR 6 , -(L) m -SO2R 6 , -(L) m -SONR 6 R 7 , -(L) m -C(O)NR 6 R 7 , -(L) m -C 1-4 alkyl, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, -(L) optionally substituted with 1-5 substituents m -6-10 membered aryl and -(L) m -5-8 membered heteroaryl, said substituents selected from carboxyl, hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkyl and halo-C 1-4 alkoxy;

[0035] Each R 6 , R 7 are each independently selected from hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo-C 1-4 alkyl and halo-C 1-4 alkoxy;

[0036] Each L is independently selected from C 1-4 alkylene and halo-C 1-4 alkylene; Each m is independently an integer from 0-4.

[0037] In certain embodiments, a compound of formula (I) as described above, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein,

[0038] R 1 and R 2 together with the carbon atom to which they are attached form a 5-6 membered cycloalkyl, 5-6 membered heterocyclic or 5-6 membered heteroaryl optionally substituted with 1-4 Q2;

[0039] R 3 selected from 3- to 6-membered monocyclic heterocyclic groups optionally substituted with 1 to 6 Q3s,

[0040] each R 4 、R 5 is independently selected from hydrogen, -(L) m -C 1-4 alkyl, -(L) m -C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, 3- to 6-membered cycloalkyl, phenyl, and R 4 、R 5 are not both hydrogen at the same time;

[0041] each Q2 and Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, -(L) m -P(O)R 6 R 7 、-(L) m -SOR 6 、-(L) m -SO2R 6 、-(L) m -SONR 6 R 7 、-(L) m -C(O)NR 6 R 7 、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo-C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, carboxy-C 1-4 alkyl, halo-C 1-4 alkoxy;

[0042] each R 6 、R 7 is independently selected from hydrogen, hydroxyl, and C 1-4 alkyl;

[0043] each L is independently selected from C 1-4 alkylene; each m is independently an integer from 0 to 3.

[0044] In certain embodiments, the compounds, pharmaceutically acceptable salts, esters, or stereoisomers thereof of the foregoing general formula (I), wherein,

[0045] R3 Selected from oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dihydroimidazolyl, dihydrooxazolyl, dihydrothiazolyl, piperidinyl, tetrahydropyridinyl, piperidinone, tetrahydropyridinone, dihydropiperidinone, piperazinyl, morpholinyl, optionally substituted with 1 to 3 Q3

[0046] R 4 and R 5 are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyclopropyl, phenyl, and R 4 and R 5 are not both hydrogen at the same time;

[0047] Each Q3 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, -CH2P(O)(OH)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, carboxymethyl, carboxyethyl, trifluoromethoxy.

[0048] In certain embodiments, the compound represented by the foregoing general formula (I), its pharmaceutically acceptable salt, its ester, or its stereoisomer, wherein,

[0049] R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl optionally substituted with one or more Q1, NR 1a R 1b , C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -(L) m -C 5-6 cycloalkyl, -(L) m -C 5-6 heterocyclic group, -(L) m -phenyl, and -(L) m -C 5-6 heteroaryl;

[0050] R 1a and R 1b are each independently selected from hydrogen, C 1-4 alkyl optionally substituted with 1 to 4 halogen atoms or deuterium atoms;

[0051] L is selected from C1-4 Alkylene;

[0052] R 3 selected from a 6- to 8-membered spirocyclic group, a 6- to 8-membered spiroheterocyclic group, a 3- to 6-membered monocyclic heterocyclic group, and a 7- to 9-membered heterocyclic group, which are optionally substituted by one or more Q3;

[0053] Each Q1 and Q3 is independently selected from deuterium, halogen, carboxyl, -(L) m -P(O)R 6 R 7 、-(L) m -SOR 6 、-(L) m -SO2R 6 、-(L) m -SONR 6 R 7 、-(L) m -C(O)NR 6 R 7 、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo-C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, carboxy-C 1-4 alkyl, halo-C 1-4 alkoxy, -(L) optionally substituted by 1 to 5 substituents m -3- to 6-membered cycloalkyl, -(L) m -5- to 6-membered heterocyclic group, -(L) m -phenyl and -(L) m -5- to 6-membered heteroaryl, the substituents being selected from carboxyl, hydroxy, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkyl and halo-C 1-4 alkoxy;

[0054] Each R 6 、R 7 is independently selected from hydrogen, hydroxy and C 1-4 alkyl; each m is independently an integer from 0 to 3.

[0055] In certain embodiments, the compounds, pharmaceutically acceptable salts, esters or stereoisomers thereof of the foregoing general formula (I), wherein,

[0056] R 1 、R 2Independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, NR 1a R 1b , methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy;

[0057] R 1a 、R 1b Independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl optionally substituted by 1-3 halogen atoms or deuterium atoms;

[0058] R 3 Selected from 6-8-membered spirocyclic group, 6-8-membered spiroheterocyclic group, 5-6-membered monocyclic heterocyclic group, 7-8-membered heterocyclic group optionally substituted by one or more Q3;

[0059] Each Q1 and Q3 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, -CH2P(O)(OH)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, aminomethyl, carboxymethyl, carboxyethyl, trifluoromethoxy, -(CH2) m -5-6-membered heteroaryl, the substituents being selected from carboxyl, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoromethoxy;

[0060] m is 0, 1 or 2.

[0061] In certain embodiments, the compound represented by the foregoing general formula (I), its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,

[0062] R 1 and R 2 together with the connected carbon atom form a 5-6-membered cycloalkyl group optionally substituted by 1-4 Q2;

[0063] R 3 Selected from 3-6-membered monocyclic heterocyclic group, 7-membered spirocyclic group, 8-membered heterocyclic group optionally substituted by 1-6 Q3,

[0064] Each R 4 、R 5 Independently selected from hydrogen, C 1-4 alkyl, -(L) m -C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4Alkoxy, 3- to 6-membered cycloalkyl, phenyl, and R 4 and R 5 are not simultaneously hydrogen;

[0065] Each Q2 and Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, -(L) m -P(O)(OH)2, -(L) m -SO2(OH), -(L) m -S(O)NH2, -(L) m -CONHOH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, halo C 1-4 alkoxy;

[0066] Each L is independently selected from C 1-4 alkylene; Each m is independently an integer from 0 to 3.

[0067] In certain embodiments, the compounds, pharmaceutically acceptable salts, esters, or stereoisomers thereof of the foregoing general formula (I), wherein,

[0068] R 1 and R 2 together with the carbon atom to which they are attached form a 5- to 6-membered cycloalkyl optionally substituted with 1 to 4 Q2;

[0069] R 3 is selected from 3- to 6-membered monocyclic heterocyclic groups optionally substituted with 1 to 3 Q3,

[0070] R 4 and R 5 are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, 3- to 5-membered cycloalkyl, phenyl, and R 4 and R 5 are not simultaneously hydrogen;

[0071] Each Q2 and Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo C1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, halo C 1-4 alkoxy.

[0072] In certain embodiments, a compound of formula (I) as described above, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein,

[0073] R 3 is selected from optionally substituted by one or more Q3

[0074] provided that: when R 3 is selected from optionally substituted by one or more Q3 then R 1 and R 2 together with the carbon atoms to which they are attached form a 4- to 8-membered cycloalkyl or 4- to 8-membered heterocyclic group optionally substituted by one or more Q2;

[0075] each R 4 , R 5 is independently selected from hydrogen;

[0076] each Q3 is independently selected from -(L) m -P(O)R 6 R 7 、-(L) m -SOR 6 、-(L) m -SO2R 6 、-(L) m -SONR 6 R 7 、-(L) m -C(O)NR 6 R 7 、-(L) m -3- to 8-membered cycloalkyl, -(L) m -3- to 8-membered heterocyclic group, -(L) m -6- to 10-membered aryl and -(L) m -5- to 8-membered heteroaryl;

[0077] each R 6 、R 7 is independently selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C1-4 Alkyl and halo C 1-4 Alkoxy;

[0078] Each L is independently selected from C 1-4 Alkylene and halo C 1-4 Alkylene; each m is independently an integer from 0 - 5.

[0079] In certain embodiments, the compounds, pharmaceutically acceptable salts, esters or stereoisomers thereof of the foregoing general formula (I), wherein,

[0080] R 1 , R 2 are each independently selected from hydrogen, halogen, C optionally substituted with one or more Q1 1-4 alkyl, NR 1a R 1b , C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -(L) m -C 3-8 cycloalkyl, -(L) m -C 3-8 heterocyclyl, -(L) m -C 6-10 aryl and -(L) m -C 5-8 heteroaryl;

[0081] R 1a , R 1b are each independently selected from hydrogen, C alkyl optionally substituted with 1 - 6 halogen atoms or deuterium atoms 1-4 ;

[0082] R 3 is selected from optionally substituted with one or more Q3

[0083] Each R 4 , R 5 are each independently selected from hydrogen;

[0084] Each Q3 is independently selected from -(L) m -P(O)R 6 R 7 , -(L) m -SOR 6 , -(L) m -SO2R 6 , -(L) m -SONR 6 R 7 , -(L) m -C(O)NR 6R 7 、 -(L) m - 3 - to 8 - membered cycloalkyl, -(L) m - 3 - to 8 - membered heterocyclic group, -(L) m - 6 - to 10 - membered aryl and -(L) m - 5 - to 8 - membered heteroaryl;

[0085] Each R 6 、 R 7 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl and halo C 1-6 alkoxy;

[0086] Each L is independently selected from C 1-6 alkylene and halo C 1-6 alkylene; each m is independently an integer from 0 - 5.

[0087] In any of the embodiments of the present invention, the selection of any substituent can be combined with each other, and the technical solutions after combination are still included within the protection scope of the present invention.

[0088] In some embodiments of the present invention, the structures of the compounds, their pharmaceutically acceptable salts, esters or their stereoisomers described by the foregoing general formula (I) are shown in Table 1:

[0089] Table 1

[0090]

[0091]

[0092]

[0093]

[0094] The "pharmaceutically acceptable salts" described in the present invention refer to addition salts of pharmaceutically acceptable acids and bases.

[0095] The "esters" described in the present invention refer to pharmaceutically acceptable esters, especially the following esters, which are hydrolyzed in vivo and include esters that are easily decomposed in the human body to leave the parent compound (the compound described by the general formula (I)) or its salts. In some embodiments of the present invention, the pharmaceutically acceptable esters thereof include: esters derived from pharmaceutically acceptable aliphatic carboxylic acids and phosphoric acid.

[0096] The "stereoisomers" of the compounds represented by the general formula (I) of the present invention refer to enantiomers that are generated when the compounds represented by formula (I) have asymmetric carbon atoms; cis-trans isomers that are generated when the compounds have carbon-carbon double bonds or cyclic structures; and tautomers that are generated when the compounds have ketones or oximes. In some embodiments of the present invention, the stereoisomers include, but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof.

[0097] The present invention also provides a pharmaceutical composition comprising the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutic active agents. Optionally, the pharmaceutical composition further comprises one or more pharmaceutical carriers and / or diluents.

[0098] The present invention also provides a pharmaceutical preparation comprising the compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.

[0099] In some embodiments of the present invention, the above-mentioned pharmaceutical preparation can be administered to patients or subjects in need of such treatment by oral, parenteral, rectal or pulmonary administration, etc. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be formulated into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When formulating into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. For parenteral administration, the above-mentioned pharmaceutical preparation can also be formulated into injections, including injection solutions, sterile powders for injection and concentrated solutions for injection. When formulating into injections, conventional methods in the existing pharmaceutical field can be used for production. When formulating injections, additives may not be added, or suitable additives can be added according to the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For pulmonary administration, the pharmaceutical composition can be formulated into inhalants or sprays, etc.

[0100] The pharmaceutical carriers and / or diluents that can be used in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carriers and / or diluents in the field of pharmaceutical preparations. The selection of a specific carrier and / or diluent will depend on the mode of administration or the type and condition of the disease for treating a specific patient. The preparation methods of suitable pharmaceutical compositions for specific administration modes are completely within the knowledge of those skilled in the pharmaceutical field. For example, the pharmaceutical carriers and / or diluents can include solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, mold release agents, coating agents, flavoring agents, and antioxidants, etc. in the pharmaceutical field. When necessary, flavoring agents, preservatives, sweetening agents, etc. can also be added to the pharmaceutical composition.

[0101] The present invention also provides the use of the compound represented by the foregoing general formula (I), its pharmaceutically acceptable salt, ester or its stereoisomer, the foregoing pharmaceutical preparation or the foregoing pharmaceutical composition in the preparation of a drug 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 steatohepatitis, 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.

[0102] The present invention also provides the application of the compound represented by the foregoing general formula (I), its pharmaceutically acceptable salt, ester or its stereoisomer, the foregoing pharmaceutical preparation or the foregoing pharmaceutical composition in treating / 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 steatohepatitis, 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.

[0103] The present invention also provides a method for treating a disease, which method comprises administering to a patient in need thereof a therapeutically effective amount of the compound represented by the foregoing general formula (I), a pharmaceutically acceptable salt, ester or stereoisomer thereof, the foregoing pharmaceutical preparation or the foregoing pharmaceutical composition, wherein the disease is a KHK-mediated disease and related diseases; the KHK-mediated diseases and related diseases are selected from endocrine disorders, urinary diseases, metabolic diseases, non-alcoholic steatohepatitis, 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.

[0104] In the description and claims of the present application, compounds are named according to chemical structural formulas. If there is a discrepancy between the naming of a compound and its chemical structural formula when representing the same compound, the chemical structural formula shall prevail.

[0105] In the present application, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present application are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in the present application shall prevail.

[0106] As used in the present invention, "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0107] As used in the present invention, "halogenated" means that any hydrogen in the substituent can be replaced by one or more identical or different halogens. "Halogen" is as defined above.

[0108] As used in the present invention, "C 1-6 alkyl" represents a straight-chain or branched-chain alkyl group containing 1-6 carbon atoms, including, for example, "C 1-5 alkyl", "C 1-4 alkyl", "C 1-3 alkyl", "C 1-2 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"Alkyl", etc. 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" in the present invention refers to specific examples of C 1-6 alkyl containing 1-4 carbon atoms.

[0109] The "C 1-6 alkylene" in the present invention refers to the group formed by removing one hydrogen atom from the above-mentioned C 1-6 alkyl, including, 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 alkylene", etc. Specific examples include, but are not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, etc. The "C 1-4 alkylene" in the present invention refers to specific examples of C 1-6 alkylene containing 1-4 carbon atoms.

[0110] The "C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino" described herein refers to the group formed in the manner of C 1-6 alkyl-O-, C 1-6 alkyl-NH-, (C 1-6 alkyl)2-N-, where the definition of "C 1-6 alkyl" is as described above.

[0111] The "C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino" described herein refers to the group formed in the manner of C1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4 alkyl)2-N- groups formed in such a way that the definition of "C 1-4 alkyl" is as described above.

[0112] "Halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, halogenated C 1-6 alkylene, halogenated C 1-6 alkoxy" as described herein refers to a group formed by replacing one or more, for example 1-4, 1-3, 1-2 halogen atoms, hydroxy groups, amino groups, carboxy groups, respectively, in C 1-6 alkyl, C 1-6 alkylene, C 1-6 alkoxy with hydrogen atoms.

[0113] "Halogenated C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl, carboxy C 1-4 alkyl, halogenated C 1-4 alkylene, halogenated C 1-4 alkoxy" as described herein refers to a group formed by replacing one or more, for example 1-4, 1-3, 1-2 halogen atoms, hydroxy groups, amino groups, respectively, in C 1-4 alkyl, C 1-4 alkylene, C 1-4 alkoxy with hydrogen atoms.

[0114] "3-10 membered cycloalkyl" as described in the present invention refers to a saturated or partially saturated and non-aromatic cyclic alkyl group containing 3-10 carbon atoms, including "monocyclic alkyl" and "fused ring alkyl".

[0115] As used herein, the term "monocyclic alkyl" refers to a saturated or partially saturated monocyclic alkyl group that is not aromatic, including "3- to 8-membered saturated cycloalkyl" and "3- to 8-membered partially saturated cycloalkyl"; preferably "3- to 4-membered cycloalkyl", "3- to 5-membered cycloalkyl", "3- to 6-membered cycloalkyl", "3- to 7-membered cycloalkyl", "4- to 5-membered cycloalkyl", "4- to 6-membered cycloalkyl", "4- to 7-membered cycloalkyl", "4- to 8-membered cycloalkyl", "5- to 6-membered cycloalkyl", "5- to 7-membered cycloalkyl", "5- to 8-membered cycloalkyl", "6- to 7-membered cycloalkyl", "6- to 8-membered cycloalkyl", "7- to 8-membered cycloalkyl", "3- to 6-membered saturated cycloalkyl", "4- to 7-membered saturated cycloalkyl", "4- to 8-membered saturated cycloalkyl", "5- to 8-membered saturated cycloalkyl", "5- to 7-membered saturated cycloalkyl", "5- to 6-membered saturated cycloalkyl", "3- to 6-membered partially saturated cycloalkyl", "4- to 7-membered partially saturated cycloalkyl", "4- to 8-membered partially saturated cycloalkyl", "5- to 8-membered partially saturated cycloalkyl", "5- to 7-membered partially saturated cycloalkyl", "5- to 6-membered partially saturated cycloalkyl", and the like. Specific examples of the "3- to 8-membered saturated cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like; specific examples of the "3- to 8-membered partially saturated cycloalkyl" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cycloheptenyl, cyclohepta-1,3-dienyl, cyclohepta-1,4-dienyl, cyclohepta-1,3,5-trienyl, cyclooctenyl, cycloocta-1,3-dienyl, cycloocta-1,4-dienyl, cycloocta-1,5-dienyl, cycloocta-1,3,5-trienyl, cyclooctatetraenyl, and the like.

[0116] The "fused cycloalkyl group" described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other. One of the rings in the fused rings can be an aromatic ring, but the fused rings as a whole do not have aromaticity; the fusion mode can be: 5-6 membered cycloalkyl group fused with 5-6 membered cycloalkyl group, benzo-5-6 membered cycloalkyl group, benzo-5-6 membered saturated cycloalkyl group, etc. Examples thereof include but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl, octahydrobicyclopentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl, 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-tetrahydrobicyclopentadienyl, 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, etc. The "3-6 membered monocyclic heterocyclic group" described in the present invention refers to a saturated or partially saturated and non-aromatic monocyclic group having at least one heteroatom (for example, having 1, 2, 3, 4 or 5) and the number of ring atoms being 3-6. The heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom. Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. Specific examples include but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazireneyl, 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-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidoneyl, tetrahydropyridoneyl, dihydropiperidoneyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazinyl, 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-oneyl, 3,4-dihydro-2H-pyranyl, etc.

[0117] The "7- to 12-membered heterocyclic group" as used in the present invention refers to a saturated or partially saturated and non-aromatic monocyclic or fused-ring cyclic group having at least one heteroatom (e.g., having 1, 2, 3, 4, or 5 heteroatoms) and having 7 to 12 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom, and / or a sulfur atom. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. The "7- to 12-membered heterocyclic group" as used in the present invention includes a "7- to 12-membered saturated heterocyclic group" and a "7- to 12-membered partially saturated heterocyclic group". Preferably, the "7- to 12-membered heterocyclic group" as used in the present invention contains 1 to 3 heteroatoms; preferably, the "7- to 12-membered heterocyclic group" as used in the present invention contains 1 to 2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "7- to 12-membered heterocyclic group" as used in the present invention contains 1 nitrogen atom. The "7- to 12-membered heterocyclic group" is preferably a "7- to 10-membered heterocyclic group", a "7- to 9-membered heterocyclic group", a "7- to 10-membered saturated heterocyclic group", a "7- to 9-membered saturated heterocyclic group", a "7- to 10-membered nitrogen-containing heterocyclic group", a "7- to 10-membered saturated nitrogen-containing heterocyclic group", a "7- to 9-membered nitrogen-containing heterocyclic group", a "7- to 9-membered saturated nitrogen-containing heterocyclic group", etc.Specific examples of the "7-12-membered heterocyclic group" include, but are not limited to: pyrrolidinyl cyclopropyl, cyclopentyl aziridinyl, pyrrolidinyl cyclobutyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl piperidinyl, pyrrolidinyl piperazinyl, pyrrolidinyl morpholinyl, piperidinyl morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridinyl cyclopentyl, pyridinyl cyclohexyl, pyridinyl tetrahydrofuranyl, pyridinyl pyrrolidinyl, pyridinyl imidazolyl, pyridinyl oxazolyl, pyridinyl thiazolyl, pyridinyl isoxazolyl, pyridinyl isothiazolyl, pyridinyl piperidinyl, pyridinyl morpholinyl, pyridinyl piperazinyl, pyridinyl tetrahydropyranyl, pyrimidinyl cyclopentyl, pyrimidinyl cyclohexyl, pyrimidinyl tetrahydrofuranyl, pyrimidinyl pyrrolidinyl, pyrimidinyl imidazolyl, pyrimidinyl oxazolyl, pyrimidinyl thiazolyl, pyrimidinyl isoxazolyl, pyrimidinyl isothiazolyl, pyrimidinyl piperidinyl, pyrimidinyl morpholinyl, pyrimidinyl piperazinyl, pyrimidinyl tetrahydropyranyl; tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[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, hexahydrofuroimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenten[c]pyrrolyl, 4H-1,3-benzoxazinyl, etc.

[0118] The "6-12-membered aryl group" described in the present invention refers to an aromatic cyclic group containing 6-12 ring carbon atoms, including a "6-8-membered monocyclic aryl group" and an "8-12-membered fused-ring aryl group", preferably a 6-10-membered aryl group.

[0119] The "6-8-membered monocyclic aryl group" described in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms, and its examples include, but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0120] The "8-12 membered fused aryl group" described in the present invention refers to an unsaturated and aromatic cyclic group containing 8-12 ring carbon atoms, formed by two or more cyclic structures sharing two adjacent atoms with each other. The "9-10 membered fused aryl group" is preferred, and specific examples include naphthyl group and the like.

[0121] The "5-12 membered heteroaryl group" described in the present invention refers to an aromatic cyclic group containing 5-12 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). It includes "5-8 membered monocyclic heteroaryl group" and "8-12 membered fused heteroaryl group", and the 5-10 membered heteroaryl group is preferred.

[0122] The "5-8 membered monocyclic heteroaryl group" described in the present invention refers to a monocyclic aromatic cyclic group containing 5-8 ring atoms (wherein at least one ring atom 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 can be oxo-substituted. The "5-8 membered monocyclic heteroaryl group" includes, for example, "5-7 membered monocyclic heteroaryl group", "5-6 membered monocyclic heteroaryl group", "5-6 membered nitrogen-containing monocyclic heteroaryl group", "5 membered nitrogen-containing monocyclic heteroaryl group", etc. Specific examples of the "5-8 membered monocyclic heteroaryl group" include, but are not limited to, furyl, 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-pyridone, 4-pyridone, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepine, 1,3-diazepine, azocine, etc. The "5-6 membered heteroaryl group" refers to specific examples of the 5-8 membered heteroaryl group containing 5-6 ring atoms.

[0123] The "8-12 membered fused heteroaryl" as used in the present invention refers to an unsaturated aromatic cyclic structure formed by two or more cyclic structures sharing two adjacent atoms with each other, containing 8-12 ring atoms (where at least one ring atom 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 can be oxo-substituted. It includes "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 fused with 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furanothiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0124] The "5-12 membered bridged cyclic group" as used in the present invention refers to a structure containing 5-12 carbon atoms formed by any two rings sharing two non-directly connected atoms. The "5-12 membered bridged ring" includes 5-12 membered saturated bridged cyclic groups and 5-12 membered partially saturated bridged cyclic groups. Preferred are 5-10 membered bridged cyclic groups, 5-8 membered bridged cyclic groups, 5-10 membered saturated bridged cyclic groups, 5-8 membered saturated bridged cyclic groups, 6-10 membered saturated bridged cyclic groups, 7-12 membered partially saturated bridged cyclic groups. The 5-12 membered bridged cyclic groups include but are 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, dicyclopentadienyl, etc.

[0125] The "5-12 membered spirocyclic group" as used in 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 the 5-12 membered saturated spirocyclic groups include but are not limited to: Groups formed by substituting any replaceable hydrogen atom with cyclic structures such as those above. The 5-12 membered partially saturated spirocyclic group means that at least one of the rings in the spirocyclic group is an unsaturated cyclic group. Specific examples include but are not limited to: A group formed by replacing any replaceable hydrogen atom with a cyclic structure such as etc. A 5- to 10-membered spirocyclic group is preferred, including a "5- to 10-membered saturated spirocyclic group" and a 5- to 10-membered unsaturated spirocyclic group. A 5- to 8-membered spirocyclic group is preferred, including a "5- to 8-membered saturated spirocyclic group" and a 5- to 8-membered unsaturated spirocyclic group.

[0126] The "5- to 12-membered spiroheterocyclic group" as used in the present invention means that at least one ring carbon atom in the 5- to 12-membered spirocyclic group is replaced by a heteroatom selected from O, S, and N, preferably 1 to 3 heteroatoms, and at the same time includes the case where carbon atoms, nitrogen atoms, and sulfur atoms can be oxo. A 5- to 10-membered spiroheterocyclic group, a 5- to 8-membered spiroheterocyclic group, and a 5- to 6-membered spiroheterocyclic group are preferred.

[0127] The "optionally substituted by..." as used in the present invention includes two cases: "substituted" and "unsubstituted".

[0128] The "therapeutically effective amount" as used in the present invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that can at least relieve the symptoms of the patient's disease when administered to the patient. The actual amount containing the "therapeutically effective amount" will vary according to various circumstances, including but not limited to the specific disease being treated, the severity of the disease, the physical and health conditions of the patient, and the route of administration. Skilled medical practitioners can easily determine the appropriate amount using methods known in the medical field.

[0129] Advantages of the invention

[0130] (1) The compounds of the present invention, their pharmaceutically acceptable salts, esters, or their stereoisomers have excellent KHK inhibitory activity and can treat and / or prevent KHK-mediated diseases and related diseases;

[0131] (2) The compounds of the present invention, their pharmaceutically acceptable salts, esters, or their stereoisomers have good pharmacokinetic properties, longer-lasting effects, and high bioavailability;

[0132] (3) The compounds of the present invention, their pharmaceutically acceptable salts, esters, or their stereoisomers have good safety;

[0133] (4) The preparation process of the compounds of the present invention is simple, the drug purity is high, the quality is stable, and it is easy to carry out large-scale industrial production.

[0134] The beneficial effects of the compounds provided in the examples of the present invention are further elaborated through experiments below, but it should not be understood that the compounds provided in the examples of the present invention only have the following beneficial effects.

[0135] Experimental Example 1 In Vitro KHK Kinase Inhibitory Activity Experiment of the Compounds of the Present Invention

[0136] Test sample: The compounds shown in Table 1 of the present invention, and their chemical names and preparation methods can be referred to the preparation examples.

[0137] Control drug: PF-06835919, prepared by the method in the reference (US15 / 381,295).

[0138] Experimental reagents:

[0139]

[0140] Experimental consumables:

[0141]

[0142] Experimental instruments:

[0143]

[0144]

[0145] Experimental methods:

[0146] 1. Compound dilution

[0147] 1) Prepare the compound of the present invention and the control drug to 10 mM using DMSO as the test stock solution.

[0148] 2) Dilute the stock solution of the compound of the present invention 10-fold to 1 mM, and then serially dilute the compound of the present invention 3-fold to 11 concentrations with the highest concentration of 1 mM. Dilute the stock solution of the control drug 100-fold to 0.1 mM, and then serially dilute the control drug 3-fold to 11 concentrations with the highest concentration of 0.1 mM.

[0149] 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 replicates for each concentration, and centrifuge at 1000 rpm for 1 min.

[0150] 2. Enzyme reaction experiment

[0151] 1) Add 5 μL of KHK-C kinase working solution to the 384-well plate, centrifuge at 1000 rpm for 1 min, and then incubate at room temperature (25 °C) for 15 min.

[0152] 2) Add 5 μL of substrate working solution to the 384-well plate to initiate the kinase reaction, centrifuge at 1000 rpm for 1 min, and incubate at room temperature (25 °C) for 60 min.

[0153] 3) The final concentrations of the KHK-C kinase reaction are 1 nM KHK-C, 100 μM ATP, 200 μM D-Fructose, 50 mM HEPES, 10 mM MgCl2, 0.01% Brij35, and the final concentration of DMSO is 1%.

[0154] 4) The final concentrations of the test compounds are 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.

[0155] 5) The final concentrations of the control drugs are 1000 nM, 333.33 nM, 111.11 nM, 37.037 nM, 12.346 nM, 4.115 nM, 1.371 nM, 0.4572 nM, 0.1524 nM, 0.0508 nM, and 0.0169 nM.

[0156] 3. Reaction termination and detection

[0157] 1) Add 10 μL of ADP Glo reagent, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 40 min.

[0158] 2) Add 20 μL of kinase detection reagent, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 40 min.

[0159] 3) After the reaction is completed, read the fluorescence value LUM on Envision.

[0160] 4. Data analysis

[0161] Calculate the inhibition rate inhibition (%) using the following formula:

[0162]

[0163] where Lum HC represents: the luminescence signal intensity of High control (adding the same volume of DMSO as the test compound to the reaction system);

[0164] Lum LC represents: the luminescence signal intensity of Low control (1 μM of the control drug);

[0165] Lum cpd represents: the luminescence signal intensity of the test compound;

[0166] Perform curve fitting using GraphPad Prism 5.0 software to calculate IC 50 .

[0167] Experimental results:

[0168] The inhibitory activity of the compounds shown in Table 1 of the present invention against KHK-C is between 1 nM and 1000 nM, and it can effectively inhibit the kinase activity of KHK-C. For example, the KHK-C inhibitory activity of Compound 5 is 20.33 nM, the KHK-C inhibitory activity of Compound 6 is 2.46 nM, the KHK-C inhibitory activity of Compound 13 is 80.2 nM, and the KHK-C inhibitory activity of Compound 15 is 55.3 nM. They are effective KHK-C kinase inhibitors. Detailed implementation manners

[0169] The technical solutions of the present invention will be described below in conjunction with specific embodiments. The described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0170] The meanings represented by the abbreviations used in the following experiments are as follows:

[0171] 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; DMAP: 4-Dimethylaminopyridine; DCC: Dicyclohexylcarbodiimide.

[0172] Preparation of (S)-2-(2-(2-Methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (Compound 1)

[0173] (1) Preparation of 2-(tert-Butyl)-6-methyl-2-azaspiro[3.3]heptane-2,6-dicarboxylate

[0174]

[0175] Dissolve 2-(tert-Butyl)-2-azaspiro[3.3]heptane-2,6-dicarboxylic acid (200 mg, 0.83 mmol) in methanol (10 mL), add thionyl chloride (2 ml), stir at 0 °C for 2 hours, and spin dry to obtain the product (220 mg, crude product).

[0176] (2) Preparation of Methyl 2-azaspiro[3.3]heptane-6-carboxylate

[0177]

[0178] Dissolve 2-(tert-butyl)-6-methyl-2-azaspiro[3.3]heptane-2,6-dicarboxylate (220 mg, crude) in DCM (5 mL), then add TFA (5 mL), react at 20 °C for 2 hours, add NaHCO3 to adjust the pH to 8, separate the layers, and rotary evaporate the organic phase to obtain the product (140 mg, crude).

[0179] (3) Preparation of methyl 2-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylate

[0180]

[0181] Dissolve methyl 2-azaspiro[3.3]heptane-6-carboxylate (140 mg, crude) and 2,4-dichloro-6-(trifluoromethyl)pyrimidine (280 mg, 1.30 mmol) in DCM (15 mL), stir at -78 °C, add DIEA (4 mL), after addition, react at 20 °C for 5 hours. After the reaction is completed, directly rotary evaporate the system and purify by silica gel column chromatography (PE / EA = 2 / 1) to obtain the product (160 mg, overall yield of three steps 57.4%).

[0182] (4) Preparation of (S)-methyl 2-(2-(2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylate

[0183]

[0184] Dissolve methyl 2-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylate (160 mg, 0.48 mmol) and (S)-2-methylazetidine (105 mg, 1.5 mmol) in acetonitrile (20 mL), add DIEA (2 mL), react at 60 °C for 20 hours, rotary evaporate the solvent and purify by silica gel column chromatography (PE / EA = 2 / 1) to obtain the product (110 mg, yield 61.9%).

[0185] (5) Preparation of (S)-2-(2-(2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid

[0186]

[0187] (S)-Methyl 2-(2-(2-(methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylate (110 mg, 0.29 mmol) was dissolved in 10 mL of THF and 10 mL of water. Then, NaOH (15.0 mg, 0.38 mmol) was added, and the reaction was carried out at 20 °C for 1 hour. The pH of the system was adjusted to less than 7 with 1 N HCl, and the mixture was extracted with MTBE (20 mL). After liquid separation, drying, and solvent evaporation, the product (94 mg, yield 88.8%) was obtained.

[0188] Molecular formula: C 16 H 19 F3N4O2 Molecular weight: 356.2 LC-MS (M / e): 357.2 (M + H + )

[0189] 1 1H-NMR (400 MHz, CDCl3) δ: 5.83 (s, 1H), 4.48 - 4.34 (d, 1H), 4.09 - 3.93 (m, 6H), 3.11 - 3.07 (m, 1H), 2.57 - 2.52 (m, 4H), 2.43 - 2.36 (m, 1H), 1.98 - 1.91 (m, 1H), 1.51 - 1.50 (d, 3H).

[0190] Preparation of (S)-2-(2-(2-(2-(methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)acetic acid (Compound 2)

[0191] (1) Preparation of tert-butyl 6-(2-methoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate

[0192]

[0193] Potassium tert-butoxide (1.3 g, 12 mmol) was dissolved in THF (50 mL), and methyl 2-(diethoxyphosphoryl)acetate (2.2 mL, 12 mmol) was added. The reaction was carried out at 35 °C for 1 hour. Then, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.7 mmol) was added, and the reaction was carried out at 35 °C for 16 hours. The solvent of the system was evaporated, and the product was obtained by silica gel column chromatography (PE:EA = 3:1) (1.2 g, yield 95.6%).

[0194] (2) Preparation of tert-butyl 6-(2-methoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0195]

[0196] Dissolve tert-butyl 6-(2-methoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (1.2 g, 4.5 mmol) in ethanol (120 mL), add Pd / C (360 mg), and react at 25 °C for 16 hours under a hydrogen atmosphere. The system is filtered through diatomaceous earth, and the filtrate is concentrated to obtain 1.5 g of crude product.

[0197] (3) Preparation of methyl 2-(2-azaspiro[3.3]hept-6-yl)acetate trifluoroacetate

[0198]

[0199] Dissolve crude tert-butyl 6-(2-methoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate (268 mg) in DCM (4 mL), then add TFA (4 mL), and react at 25 °C for 1 hour. The system is evaporated to dryness to obtain a crude product (400 mg) directly used for the next step.

[0200] (4) Preparation of methyl 2-(2-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)acetate

[0201]

[0202] Dissolve crude methyl 2-(2-azaspiro[3.3]hept-6-yl)acetate trifluoroacetate (400 mg) in DCM (3 mL), then add 2,4-dichloro-6-(trifluoromethyl)pyrimidine (239 mg, 1.1 mmol), add N,N-diisopropylethylamine (645 mg, 5 mmol) at -78 °C, and react at -78 °C for 1 hour. The system is evaporated to dryness and purified by silica gel column chromatography (PE:EA = 10:1) to obtain the product (320 mg, yield 83.4%).

[0203] (5) Preparation of (S)-methyl 2-(2-(2-(2-(2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)acetate

[0204]

[0205] Methyl 2-(2-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)acetate (320 mg, 0.9 mmol) was added to acetonitrile (5 mL). (S)-2-Methylazetidine trifluoroacetate (72 mg crude) was dissolved in DIPEA (580 mg, 4.5 mmol), and this portion was added to the previous system. The reaction was carried out at 25 °C for 16 hours. The system was directly evaporated to dryness and purified by silica gel column chromatography (PE:EA = 10:1) to give the product (320 mg, yield 92.6%).

[0206] (6) Preparation of (S)-2-(2-(2-(2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)acetic acid

[0207]

[0208] (S)-Methyl 2-(2-(2-(2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)acetate (320 mg, 0.83 mmol) was dissolved in THF (20 mL) and water (20 mL), and then NaOH (44 mg, 1.1 mmol) was added. The reaction was carried out at 25 °C for 2 hours. 1N HCl was added to the system to adjust the pH to 4 - 5, and the mixture was concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:2) to give the product (153 mg, yield 49.6%).

[0209] Molecular formula: C 17 H 21 F3N4O2 Molecular weight: 370.4 LC-MS (M / e): 371.2 (M + H + )

[0210] 1 1H-NMR (400 MHz, CDCl3) δ: 5.82 (s, 1H), 4.50 - 4.39 (m, 1H), 4.11 - 3.97 (m, 3H), 3.96 - 3.88 (m, 3H), 2.65 - 2.55 (m, 1H), 2.50 - 2.35 (m, 5H), 2.02 - 1.88 (m, 3H), 1.50 (d, J = 3.0 Hz, 3H).

[0211] Example 3 Preparation of 2-((R)-1-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl)acetic acid (Compound 5)

[0212] (1) Preparation of tert-butyl (R)-3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[0213]

[0214] (R)-2-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)acetic acid (1 g, 4.4 mmol) was dissolved in dichloromethane / methanol (30 / 1 mL), and DMAP (533 mg, 4.4 mmol) and DCC (908 mg, 4.4 mmol) were added. The reaction was carried out at 25 °C for 16 h. The reaction was quenched by adding an aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane three times. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain 880 mg of the product with a yield of 82%.

[0215] (2) Preparation of methyl (R)-2-(pyrrolidin-3-yl)acetate trifluoroacetate

[0216]

[0217] tert-Butyl (R)-3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (880 mg, 3.6 mmol) was dissolved in trifluoroacetic acid / dichloromethane (10 / 12 mL), and the reaction was carried out at 25 °C for 1 h. The mixture was concentrated to obtain 1.8 g of the crude product.

[0218] (3) Preparation of methyl (R)-2-(1-(2-chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl)acetate

[0219]

[0220] 2,4-Dichloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100 mg, 0.44 mmol) was dissolved in acetonitrile (10 mL), and sodium carbonate (187 mg, 1.76 mmol) was added. Methyl (R)-2-(pyrrolidin-3-yl)acetate trifluoroacetate (229 mg of the crude product) was added at -10 °C, and the reaction was carried out at -10 °C for 2 h. The reaction mixture was directly used for the next step without further purification.

[0221] (4) Preparation of methyl 2-((R)-1-(7,7-difluoro-2-((S)-2-methyl-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl)acetate

[0222]

[0223] Methyl (R)-2-(1-(2-chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl)acetate (crude product, reaction solution from the previous step), cesium carbonate (424 mg, 1.3 mmol) and (S)-2-methylazetidine hydrochloride (86 mg, 0.8 mmol) were added, and the reaction was carried out at 70 °C for 24 hours. The reaction mixture was concentrated, and column chromatography (ethyl acetate / petroleum ether = 0 - 25%) was performed to obtain the product (80 mg, overall yield in two steps: 50%).

[0224] (5) Preparation of 2-((R)-1-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl)acetic acid

[0225]

[0226] Methyl 2-((R)-1-(7,7-difluoro-2-((S)-2-methyl-1-yl)-6,7-dihydro-5H-cyclopentane[d]pyrimidin-4-yl)pyrrolidin-3-yl)acetate (80 mg, 0.22 mmol) was dissolved in MeOH / THF / H2O (3 / 3 / 3 mL), NaOH (35 mg, 0.88 mmol) was added, and the reaction was carried out at 25 °C for 3 hours. The pH was adjusted to 5, the reaction mixture was concentrated, and column chromatography (ACN / H2O = 0 - 65%) was performed to obtain the product (47 mg, 61%).

[0227] Molecular formula: C 17 H 22 F2N4O2 Molecular weight: 352.4 LC-MS (M / e): 353.2 (M+H + )

[0228] 1 1H-NMR (400 MHz, MeOD) δ: 4.45 - 4.36 (m, 1H), 4.12 - 3.52 (m, 5H), 3.42 - 3.31 (m, 1H), 3.15 - 3.02 (m, 2H), 2.69 - 2.2.53 (m, 1H), 2.49 - 2.22 (m, 5H), 2.19 - 2.05 (m, 1H), 1.98 - 1.85 (m, 1H), 1.72 - 1.55 (m, 1H), 1.47 (d, J = 6.0 Hz, 3H).

[0229] Example 4 Preparation of 2-(3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 6)

[0230] (1) Preparation of 1-ethyl 2,3-dimethyl 1-methylcyclopropane-1,2,3-tricarboxylate

[0231]

[0232] At room temperature, dimethyl fumarate (10 g, 69.4 mmol), benzyltriethylammonium chloride (0.16 g, 0.69 mmol) were added to a solution of NaH (60%) (3.6 g, 90.2 mmol) in DMF (100 mL). Ethyl 2-chloropropionate (9.5 g, 69.4 mmol) was slowly added dropwise, and the mixture was stirred at 40 °C overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 16.9 g of a crude product, which was used directly in the next step without further purification.

[0233] (2) Preparation of 1-methylcyclopropane-1,2,3-tricarboxylic acid

[0234]

[0235] At room temperature, an aqueous solution of sodium hydroxide (9.7 g, 242.2 mmol) in water (200 mL) was slowly added dropwise to a solution of 1-ethyl 2,3-dimethyl 1-methylcyclopropane-1,2,3-tricarboxylate (16.9 g, 69.2 mmol) in EtOH (200 mL). After the addition was complete, the mixture was heated to 90 °C and refluxed overnight. After the reaction solution was cooled to room temperature, most of the organic solvents were removed by concentration under reduced pressure. The aqueous phase was adjusted to pH 2 - 3 with 2 M hydrochloric acid, then concentrated under reduced pressure to remove some water. Toluene (50 mL × 2) was added, and the mixture was further concentrated under reduced pressure. Then acetone (50 mL) was added to the residue, and the mixture was heated to reflux for 2 hours, filtered, the filter cake was washed with acetone, and concentrated under reduced pressure to obtain 8.5 g of the target compound, which was used directly in the next step without further purification.

[0236] (3) Preparation of 1-methyl-2,4-dioxo-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

[0237]

[0238] At room temperature, acetic anhydride (4.9 g, 48.4 mmol) was added to a solution of 1-methylcyclopropane-1,2,3-tricarboxylic acid (7.0 g, 37.2 mmol) in acetic acid (15 mL). The resulting mixture was heated to 120 °C and refluxed for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. Toluene (20 mL × 2) was added to the residue, and the mixture was further concentrated under reduced pressure to remove the remaining acetic acid. The resulting residue was directly used in the next step.

[0239] (4) Preparation of 3-benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0240]

[0241] At room temperature, triethylamine (4.1 g, 40.5 mmol) and benzylamine (5.3 g, 49.5 mmol) were successively added to a solution of 1-methyl-2,4-dioxo-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (7.0 g, 441.1 mmol) in acetone (70 mL). After the resulting mixture was stirred at 25 °C for 3 hours, it was concentrated under reduced pressure. Sodium acetate (2.0 g, 24.4 mmol) and acetic anhydride (9.2 g, 90.0 mmol) were added to the residue, and the mixture was heated to reflux for 1 hour. Then it was cooled to 25 °C and stirred for 16 h. It was concentrated under reduced pressure, the residue was quenched with water, the pH was adjusted to 2 - 3 with 2M dilute hydrochloric acid, and it was extracted with dichloromethane (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and rotary evaporated to dryness, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the target compound (3.1 g, 4-step yield 17.3%).

[0242] (5) Preparation of ethyl 3-benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate

[0243]

[0244] At room temperature, concentrated sulfuric acid (0.33 mL) was slowly added dropwise to a solution of 3-benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (3.1 g, 12.0 mmol) in ethanol (45 mL). After the addition was complete, the resulting mixture was heated to 85 °C and refluxed overnight. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting mixture was subjected to silica gel column chromatography (PE:EA = 10:1) to obtain the target compound (2.9 g, 84.1%).

[0245] (6) Preparation of ethyl 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylate

[0246]

[0247] Under ice bath conditions, sodium borohydride (873.2 mg, 23.1 mmol) was dissolved in tetrahydrofuran (30 mL) solution, and boron trifluoride etherate (4.4 g, 30.8 mmol) was slowly added dropwise. After the addition was complete, a solution of ethyl 3-benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (2.2 g, 7.7 mmol) in tetrahydrofuran (6 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred for an additional 10 min, and then the mixture was stirred at 35 °C for 48 h. The reaction solution was cooled to 0 °C, and then ethanol (10 mL) was slowly added dropwise. After the addition was complete, the temperature was allowed to rise to 25 °C naturally and stirred for 5 h, then heated to 70 °C and refluxed for 3 h. After cooling to room temperature, the system was quenched with water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE:EA = 9:1) to obtain the product (670 mg, 33.6%).

[0248] (7) Preparation of 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

[0249]

[0250] At room temperature, an aqueous solution of sodium hydroxide (288.0 g, 7.2 mmol) in water (10 mL) was added to a solution of ethyl 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (634 mg, 2.4 mmol) in methanol (10 mL). The resulting mixture was heated to 65 °C and refluxed for 16 h. After the reaction solution was cooled to room temperature, the system was adjusted to pH 5 - 6 with 2 M dilute hydrochloric acid, concentrated under reduced pressure to remove water, and the residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain the target compound (600 mg, 100%).

[0251] (8) Preparation of (3-benzyl-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)methanol

[0252]

[0253] At 0 °C, lithium aluminum hydride (197.6 mg, 5.2 mmol) was added to a solution of 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (300 mg, 1.3 mmol) in tetrahydrofuran (20 mL). Stirring was continued for 30 min, and the reaction was quenched by adding a saturated aqueous ammonium chloride solution. The mixture was filtered by suction, and the filtrate was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of the target compound (260 mg), which was directly used in the next step of the reaction.

[0254] (9) Preparation of 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde

[0255]

[0256] At 0 °C, Dess-Martin periodinane (593.7 mg, 1.4 mmol) was added to a solution of (3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol (150 mg, 0.69 mmol) in dichloromethane (4 mL). The mixture was stirred at 25 °C for 4 h. The reaction was quenched by adding an aqueous solution of sodium thiosulfate. The mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of the target compound (200 mg), which was directly used in the next step. (10) Preparation of 3-benzyl-6-(2-methoxyvinyl)-1-methyl-3-azabicyclo[3.1.0]hexane

[0257]

[0258] At -78 °C, a solution of sodium bis(trimethylsilyl)amide (2.3 mL, 2 M in THF) was added dropwise to a solution of chloromethoxymethyltriphenylphosphonium (1.6 g, 4.67 mmol) in THF (20 mL). The mixture was stirred for 1 h. A solution of 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde in THF was added dropwise to the mixture, and the mixture was stirred for 30 min. The mixture was allowed to warm to 0 °C and stirred for 1 h. The reaction was quenched by adding an aqueous solution of sodium thiosulfate. The mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 1:5) to obtain the crude product of the target compound (160 mg), which was directly used in the next step.

[0259] (11) Preparation of 2-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetaldehyde

[0260]

[0261] At room temperature, concentrated hydrochloric acid (3 mL) was added to a solution of 3-benzyl-6-(2-methoxyvinyl)-1-methyl-3-azabicyclo[3.1.0]hexane (160 mg, 0.66 mmol) in acetone (4 mL). The mixture was stirred for 10 min. The pH of the system was adjusted to 9 by adding an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of the target compound (105 mg), which was directly used in the next step.

[0262] (12) Preparation of 2-(3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetic Acid

[0263]

[0264] At 0 °C, water (3.5 mL) and potassium dihydrogen phosphate (93.9 mg, 0.69 mmol) were added to a solution of 2-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetaldehyde (105 mg, 0.46 mmol) in tetrahydrofuran (3.5 mL). Stirring was continued for 30 min, then sodium chlorite (117.5 mg, 1.3 mmol) was added to the mixture. The mixture was stirred at 10 °C for 1 h, and the pH of the system was adjusted to 5 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3), and the aqueous phase was concentrated under reduced pressure to obtain the crude product of the target compound (80 mg), which was directly used for the next reaction.

[0265] (13) Preparation of Methyl 2-(3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0266]

[0267] At room temperature, thionyl chloride (0.3 mL) was added to a solution of 2-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (80 mg, 0.33 mmol) in methanol (7 mL). Stirring was continued for 2 h, and the mixture was concentrated under reduced pressure to obtain the crude product of the target compound (77 mg), which was directly used for the next reaction.

[0268] (14) Preparation of Methyl 2-(1-Methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0269]

[0270] At room temperature, Pd / C (45 mg) was added to a solution of 2-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (80 mg, 0.31 mmol) in methanol (7 mL). Stirring was continued for 2 h, then the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the target compound (77 mg), which was directly used for the next reaction.

[0271] (15) Preparation of Methyl 2-(3-(2-Chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0272]

[0273] At 10 °C, to a solution of methyl 2-(1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetate (77 mg, 0.46 mmol) in acetonitrile (3 mL) were added N,N-diisopropylethylamine and 2,4-dichloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (51.5 mg, 0.23 mmol). The mixture was stirred for an additional 30 min, then the system was quenched, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by TLC plate to give the target compound (35 mg, 7.5% yield over 8 steps).

[0274] (16) Preparation of methyl 2-(3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0275]

[0276] At room temperature, to a solution of methyl 2-(3-(2-chloro-7,7-difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetate (35.0 mg, 0.1 mmol) in acetonitrile (8 mL) were added N,N-diisopropylethylamine (38.8 mg, 0.3 mmol) and (S)-2-methylazetidine hydrochloride (14.0 mg, 0.13 mmol). The mixture was reacted at 60 °C for 16 h. The system was quenched, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by TLC plate to give the target compound (20 mg, 52.1%).

[0277] (17) Preparation of 2-(3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0278]

[0279] At room temperature, methyl 2-(3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetate (20 mg, 0.05 mmol) was dissolved in methanol (2 mL) and water (2 mL), and then LiOH (3.6 mg, 0.15 mmol) was added. The mixture was reacted at 25 °C for 2 h. 2 M dilute hydrochloric acid was added to the system to adjust the pH to 4 - 5, concentrated, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by TLC plate to obtain the target compound (3.3 mg, yield 17.4%).

[0280] Molecular formula: C 19 H 24 F2N4O2 Molecular weight: 378.42 LC-MS (M / e): 379.2 (M + H + )

[0281] 1 1H-NMR (400 MHz, MeOH) δ: 4.50 - 4.38 (m, 1H), 4.09 - 4.00 (m, 3H), 3.90 - 3.88 (m, 1H), 3.60 - 3.80 (m, 1H), 3.09 - 3.06 (m, 2H), 2.60 - 2.35 (m, 5H), 2.00 - 1.85 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H), 1.35 (s, 3H), 1.20 - 1.25 (m, 1H), 0.92 - 0.90 (m, 2H).

[0282] Example 5 Preparation of N-hydroxy-2-(((1R,5S,6R)-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetamide (Compound 13)

[0283] (1) Preparation of N-(benzyloxy)-2-(((1R,5S,6R)-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetamide

[0284]

[0285] 2-((1R,5S,6R)-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetic acid (100 mg, 0.28 mmol), N,N-diisopropylethylamine (108 mg, 0.84 mmol), and HATU (159 mg, 0.42 mmol) were dissolved in dichloromethane (3 mL). The reaction was carried out at 10 °C for 5 minutes, then O-benzylhydroxylamine hydrochloride (67 mg, 0.42 mmol) was added, and the reaction was continued at 10 °C for 16 hours. The reaction was quenched with saturated brine (30 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (ethyl acetate / petroleum ether = 0 - 50%) to give the product (120 mg, yield 92.7%).

[0286] (2) Preparation of N-hydroxy-2-(((1R,5S,6R)-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetamide

[0287]

[0288] N-(Benzyloxy)-2-(((1R,5S,6R)-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl)acetamide (95 mg, 0.20 mmol) and 10% wet palladium on carbon (24 mg) were dissolved in methanol (8 mL). The reaction was carried out under hydrogen (15 Psi) at 10 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The product was obtained by medium-pressure preparative RP-HPLC (methanol / water = 0 - 80%) (35 mg, yield 45.8%).

[0289] Molecular formula: C 16 H 20 F3N5O2 Molecular weight: 371.4 LC-MS (M / e): 372.2 (M + H + )

[0290] 1 1H NMR (400 MHz, CDCl3): δ: 5.89 (s, 1H), 4.45 - 4.30 (m, 1H), 4.10 - 3.80 (m, 2H), 3.65 - 3.20 (m, 3H), 2.45 - 2.10 (m, 3H), 1.95 - 1.85 (m, 1H), 1.85 - 1.50 (m, 4H), 1.47 (d, J = 6.0, 3H)

[0291] Compounds 15 and 19 were prepared according to the preparation method of reference compound 13.

[0292] Example 6 Preparation of 2-((1R,5S,6R)-3-(6-(tert-butyl)-2-((S)-2-methylazetidin-1-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid (Compound 18)

[0293] (1) Preparation of 4-(tert-butyl)-2,6-dichloropyrimidine

[0294]

[0295] Dissolve 2,4,6-trichloropyrimidine (200 mg, 1.1 mmol) in dry THF (3 mL), add CuI (10 mg, 0.055 mmol), add tert-butylmagnesium chloride (1.7 M, 0.64 mL, 1.1 mmol) under nitrogen, and react at 0 °C for one hour. Then directly evaporate the solvent of the system and obtain the product (150 mg, yield 67.2%) by silica gel column chromatography (PE:EA = 30:1).

[0296] (2) Preparation of methyl 2-((1R,5S,6s)-3-(6-(tert-butyl)-2-chloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0297]

[0298] Dissolve 4-(tert-butyl)-2,6-dichloropyrimidine (134 mg, 0.65 mmol) in DCM (7 mL), then add methyl 2-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (167 mg, 1.08 mmol), add N,N-diisopropylethylamine (425 mg, 3.3 mmol) at 0 °C, react at 0 °C for 1 hour, evaporate the solvent of the system and obtain the product (160 mg, yield 76.0%) by silica gel column chromatography (PE:EA = 10:1).

[0299] (3) Preparation of methyl 2-(((1R,5S,6R)-3-(6-(tert-butyl)-2-((S)-2-methylazetidin-1-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate

[0300]

[0301] Methyl 2-((1R,5S,6s)-3-(6-(tert-butyl)-2-chloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (160 mg, 0.49 mmol) was added to acetonitrile (8 mL), (S)-2-methylazetidine trifluoroacetate (theoretical amount 1.5 mmol), and DIPEA (0.45 mL, 2.5 mmol) were added, and the reaction was carried out under microwave at 120 °C for 5 hours. The system was directly dried by rotary evaporation and purified by silica gel column chromatography (PE:EA = 20:1) to obtain the product (65 mg, yield 37.1%).

[0302] (4) Preparation of 2-((1R,5S,6R)-3-(6-(tert-butyl)-2-((S)-2-methylazetidin-1-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

[0303]

[0304] Methyl 2-(((1R,5S,6R)-3-(6-(tert-butyl)-2-((S)-2-methylazetidin-1-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetate (65 mg, 0.18 mmol) was dissolved in THF (4 mL) and water (4 mL), then NaOH (9 mg, 0.23 mmol) was added, and the reaction was carried out at 25 °C for 5 hours. 1N HCl was added to the system to adjust the pH to 4 - 5, and the mixture was concentrated. The residue was purified by reverse-phase C18 column chromatography (water:methanol = 1:1) to obtain the product (35 mg, yield 56.4%).

[0305] Molecular formula: C 19 H 28 N4O Molecular weight: 344.5 LC-MS (M / e): 345.1 (M + H + )

[0306] 1 H-NMR (400 MHz, CD3OD) δ: 5.70 (s, 1H), 4.34 - 4.32 (m, 1H), 3.97 - 3.89 (m, 1H), 3.86 - 3.62 (m, 3H), 3.41 - 3.38 (m, 2H), 2.32 - 2.27 (m, 1H), 2.17 - 2.10 (m, 2H), 1.92 - 1.85 (m, 1H), 1.54 - 1.44 (m, 5H), 1.22 (s, 9H), 0.85 (s, 1H).

[0307] The above has introduced in detail the KHK inhibitor provided by the present invention and its applications. Specific embodiments are used herein to elaborate on the principle and implementation manner of the present invention. The description of the above embodiments is only for helping to understand the method of the present invention and its core idea. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt or ester thereof, wherein, R 1 and R 2 together with the attached carbon atom form a 5-membered cycloalkyl group optionally substituted by 1 to 4 Q2; R 3 selected from pyrrolidinyl optionally substituted with 1 to 3 Q3; Each of Q2 and Q3 is independently selected from deuterium, halogen, nitro, cyano, -(L) m -OR 6 、-(L) m -NR 6 R 7 、-(L) m -C(O)OR 6 、-(L) m -CONR 6 R 7 、-(L) m -OC(O)R 6 、-(L) m -P(O)R 6 R 7 、-(L) m -C(O)NR 6 R 7 、-(L) m -C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy; Each R 6 , R 7 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl and halo C 1-6 alkoxy; Each L is independently selected from C 1-6 alkylene; each m is independently an integer from 0 to 6.

2. The compound, a pharmaceutically acceptable salt or ester thereof according to claim 1, wherein, R 1 and R 2 together with the carbon atom to which it is attached form a 5-membered cycloalkyl group optionally substituted by 1 to 3 Q2 groups; R 3 selected from pyrrolidinyl optionally substituted with 1 - 3 Q3s; Each of Q2 and Q3 is independently selected from deuterium, halogen, nitro, cyano, -(L) m -OR 6 、-(L) m -NR 6 R 7 、-(L) m -C(O)OR 6 、-(L) m -CONR 6 R 7 、-(L) m -P(O)R 6 R 7 、-(L) m -C(O)NR 6 R 7 、-(L) m -C 1-4 alkyl, halo-C 1-4 alkyl, halo-C 1-4 alkoxy; Each R 6 and R 7 are each independently selected from hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, amino C 1-4 alkyl and halo C 1-4 alkoxy; Each L is independently selected from C 1-4 alkylene; each m is independently an integer from 0 to 3.

3. The compound, a pharmaceutically acceptable salt or ester thereof according to claim 2, wherein, R 1 and R 2 together with the carbon atom to which it is attached form a 5-membered cycloalkyl group optionally substituted by 1 to 3 Q2; R 3 selected from pyrrolidinyl optionally substituted with 1 to 3 Q3; Each of Q2 and Q3 is independently selected from deuterium, halogen, carboxyl, hydroxyl, -(L) m -P(O)R 6 R 7 、-(L) m -C(O)NR 6 R 7 、C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy; Each R 6 and R 7 are each independently selected from hydrogen, hydroxy and C 1-4 alkyl; Each L is independently selected from C 1-4 alkylene; each m is independently an integer from 0 to 3.

4. The compound, a pharmaceutically acceptable salt or ester thereof according to claim 3, wherein, R 3 selected from pyrrolidinyl optionally substituted with 1 to 3 Q3; each Q3 is independently selected from deuterium, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, -CH2P(O)(OH)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy.

5. The compound, a pharmaceutically acceptable salt or ester thereof according to claim 2, wherein, R 3 selected from pyrrolidinyl optionally substituted with 1 to 3 Q3; each Q3 is independently selected from -CH2C(O)OH.

6. A compound, a pharmaceutically acceptable salt or ester thereof selected from those represented by the following structures:

7. A pharmaceutical preparation comprising the compound, a pharmaceutically acceptable salt or ester thereof according to any one of claims 1 - 6, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.

8. A pharmaceutical composition comprising the compound, a pharmaceutically acceptable salt or ester thereof according to any one of claims 1 - 6, and one or more second therapeutic active agents.

9. The pharmaceutical composition according to claim 8, further comprising one or more pharmaceutical carriers and / or diluents.

10. Use of the compound, a pharmaceutically acceptable salt or ester thereof according to any one of claims 1 - 6, or the pharmaceutical preparation according to claim 7, or the pharmaceutical composition according to claim 8, or the pharmaceutical composition according to claim 9 in the preparation of a drug for the treatment and / or prevention of KHK-mediated diseases.

11. The use according to claim 10, wherein, The KHK-mediated diseases are selected from endocrine disorders, urinary diseases, metabolic diseases, hereditary fructose intolerance, hepatobiliary diseases, fibrotic diseases, cardiovascular and cerebrovascular diseases, immune-inflammatory diseases, central nervous system diseases, gastrointestinal diseases, and hyperproliferative diseases.

12. The use according to claim 11, wherein, The hyperproliferative diseases are selected from cancers.

13. The use according to claim 10, wherein The hepatobiliary diseases are selected from non-alcoholic steatohepatitis.

14. The use according to claim 10, wherein The hepatobiliary diseases are selected from cirrhosis, fatty liver, hepatitis, liver failure.

15. The use according to claim 10, wherein, The hepatobiliary diseases are selected from non-alcoholic fatty liver disease.

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