WO2021217734A1 - Fused ring compound used as ketohexokinase inhibitor - Google Patents

Abstract

A compound or a pharmaceutically acceptable salt thereof or a stereoisomer or isotope labeled compound thereof. The compound has a good inhibition effect on ketohexokinase. Provided are a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof or the stereoisomer or isotope labeled compound thereof, and an application of the compound or the pharmaceutically acceptable salt thereof or the stereoisomer or isotope labeled compound thereof in preparation of drugs for treating diseases such as T1D, T2D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes and gestational diabetes.

Description

Compounds as hexulose kinase inhibitors Technical field

The present invention relates to a new compound, its pharmaceutically acceptable salt, its stereoisomer and isotope-labeled compound, especially a compound that can inhibit pentulose kinase, its pharmaceutically acceptable salt, Its stereoisomers and isotopically labeled compounds.

Background technique

Hexokinase (KHK) is a basic enzyme involved in the metabolism of fructose in the body. It plays a very important role in the metabolism of fructose, catalyzing the reaction between fructose and ATP to convert fructose-1-phosphate (F1P). There are two important subtypes of hexulose kinase in the human body, namely hexulose kinase A (KHKa) and hexulose kinase C (KHKc). Although KHKa is more widely expressed in the body, KHKc is more highly expressed in the main metabolic organs of the human body (such as liver, kidney and intestine) (Ishimoto, Lanaspa et al., PNAS109, 4320-4325, 2012), so KHKc is The regulation of fructose metabolism is more significant.

Epidemiological studies have shown that there is a clear correlation between dietary sugar consumption and the incidence of metabolic syndrome and obesity. Experiments have shown that administration of fructose to rats has shown that it can induce metabolic syndrome, weight gain, and the characteristics of increasing body fat.

Metabolic syndrome and obesity seriously affect people's quality of life. According to data released by the WHO, the number of obese people in the world has almost tripled since 1975. In 2016, more than 1.9 billion adults over the age of 18 were overweight in the world, of which more than 650 million were obese patients (https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight) . Obesity and hypertension, hyperlipidemia, and hyperglycemia are collectively called the "quartet of death," which may become the number one killer in the 21st century. At least 2.8 million people die every year from being overweight or obese.

Diabetes is a type of metabolic syndrome, and its patients are widely distributed. Globally, it is estimated that 463 million people aged 20 to 79 have diabetes, and most of them are type 2 diabetes (International Diabetes Federation issued the 9th edition "Global Diabetes Map (IDF Diabetes Atlas Ninth Edition 2019)". Although there are more diabetes treatment drugs on the market, there are still unmet clinical needs.

Metabolism-related fatty liver disease (MAFLD) has received extensive attention in recent years. The global incidence rate is about 25%. Further development will cause inflammation, which may further deteriorate to form liver fibrosis and even liver cancer. At present, metabolism-related fatty liver disease has It has become an increasingly common worldwide chronic liver disease and is currently the number one cause of liver transplantation in the United States. Unfortunately, no drugs have been officially approved for metabolic-related fatty liver disease, and there is a huge unmet clinical need.

Fructose can significantly increase lipid de novo synthesis (Stanhope, KL, Schwarz, et al., (2009), J Clin Invest 119, 1322-1334). A large intake of fructose will increase liver triglycerides and stop the intake of fructose Later, it can reverse the accumulation of triglycerides in the liver (Schwarz, JM, Noworolski et al. (2015), J Clin Endocrinol Metab 100, 2434-2442). In diabetes, the polyol pathway (the pathway that converts glucose into fructose through sorbitol as an intermediate) leads to the production of endogenous fructose, and the more severe the hyperglycemia, the greater the activity of this pathway. KHK-free mice are protected from glucose-induced weight gain, insulin resistance and liver steatosis, which indicates that in the case of hyperglycemia, endogenously produced fructose can lead to insulin resistance and liver steatosis (Lanaspa, MA, etc.) People, Nature Comm. 4, 2434, 2013). By inhibiting hexulose kinase, thereby inhibiting the metabolism of fructose in the body, it can be used to treat obesity and metabolic-related fatty liver disease, and provide new treatment options for corresponding diseases. Moreover, the loss of function caused by human KHK-related gene mutations is ingested. After sugar, there were no significant adverse effects except for the appearance of fructose in the urine.

Regarding hexulose kinase inhibitor compounds, Johnson & Johnson of the United States announced the function of pyrimidopyrimidine compounds in inhibiting the activity of hexulose kinase (ACS Med.Chem.Lett.2011, 2,538-543), in which compound N8-( Cyclopropylmethyl)-N4-(2-(methylthio)phenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine in vitro activity (IC ₅₀₎ was 12nM. WO2017/115205 discloses a compound that can be used as a hexulose kinase inhibitor, and discloses the application of the compound in the treatment of obesity, type 2 diabetes, metabolic-related fatty liver disease and the like.

Summary of the invention

The purpose of the present invention is to provide a new compound that can inhibit hexulose kinase, its pharmaceutically acceptable salt, its stereoisomer and isotope-labeled compound in view of the above-mentioned shortcomings of the prior art; in addition, The present invention also provides a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt, or a stereoisomer or isotope-labeled compound, and an application thereof.

In order to achieve the above-mentioned object, the technical solution adopted by the present invention is: a compound or a pharmaceutically acceptable salt or a stereoisomer or an isotopically-labeled compound, the compound has the structural formula shown in the following formula I:

Wherein X is N or CR ⁵ ; R ⁵ is H, halogen, -CN, -C _1-3 alkyl, -OC _{1-3 alkyl, -C 1-3} alkane substituted by 1 to 3 halogen atoms Group, or -C _3-4 cycloalkyl

Y is N or C-CN or CF;

Z is N or CH;

And at least one of X, Y, and Z is N;

R ¹ _{is cyclopropyl, cyclobutyl, cyano, or -C 1-3} alkyl whose valence may be substituted with 0 to 5 halogen atoms;

R ² is C _3-7 cycloalkyl, 4-membered to 7-membered heterocycle, N (C _1-3 alkyl) ₂ , NH (C _1-3 alkyl) or NH (C _3-4 cycloalkyl) Wherein the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur; the C _3-7 cycloalkyl or 4- to 7-membered heterocyclic ring has 0 to 3 options From -C _1-3 alkyl and -OH substituents, and the number of -OH substituents does not exceed one; the N (C _1-3 alkyl) ₂ , NH (C _1-3 alkyl), _{Each C 1-3} alkyl group in NH (C _3-4 cycloalkyl) is substituted with 0 to 1 OH;

R ³ is -(L) _m -C0N(R ^N ) ₂ , -(L) _m -S0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ R ^S , -L-(CH ₂ ) _n C0 ₂ H, -L-(CH ₂ ) _n P0 ₃ H, -L-(CH ₂ ) _n C(0)R ^C , -L-(CH ₂ ) _n C0NHS0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ NHC0R ^S , -L-(CH ₂ ) _n SO ₂ NHCONH ₂ or -L-(CH ₂ ) _n tetrazol-5-yl; m is 0 or 1; n is 0 or 1; R ^N is H Or -C _1-3 alkyl; R ^S is H or -C _1-3 alkyl; L is CH ₂ , CHF or CF ₂ ; R ^C is -C _1-4 alkoxy, -C _1-4 alkane Oxycarbonyloxy-C _1-4 alkoxy or -C _1-4 alkylcarbonyloxy-C _1-4 alkoxy;

R ⁴ is hydrogen, halogen, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl or 4- to 7-membered heterocycle, wherein said -C _1-3 alkyl, aryl and C _{3 -7} cycloalkyl contains 0 to 5 fluorine atoms substituted; the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur;

R ⁶ is hydrogen, halogen, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl or 4- to 7-membered heterocycle, wherein said -C _1-3 alkyl, aryl and C _{3 -7} cycloalkyl contains 0 to 5 fluorine atoms substituted; the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur;

The R ⁴ and R ^{6 are} not hydrogen at the same time.

In the course of research, the inventor of the present application discovered that the new structure compound produced by introducing aliphatic or aromatic substituents on the parallel ring of the molecule disclosed in WO2017/115205 is compared with the compound disclosed in WO2017/115205. The activity and pharmacokinetic properties can still be better maintained, and in some aspects are even better than the compounds disclosed in WO2017/115205.

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound, the

X is N or CR ⁵ ; R ⁵ is H, halogen, -CN, -C _1-3 alkyl, -OC _{1-3 alkyl, -C 1-3} alkyl substituted by 1 to 3 halogen atoms, Or -C _3-4 cycloalkyl

Y is N, C-CN;

Z is N or CH;

And at least one of X, Y, and Z is N;

R ¹ _{is a -C 1-3} alkyl group whose valence is allowed to be substituted by 0 to 5 halogen atoms;

R ² is a C _3-7 cycloalkyl group or a 4- to 7-membered heterocyclic ring, wherein the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur, and the C _{3- The 7-} cycloalkyl group or the 4- to 7-membered heterocyclic ring has 0 to 3 substituents selected from -C _1-3 alkyl and -OH, and the number of -OH substituents does not exceed 1;

R ³ is -(L) _m -C0N(R ^N ) ₂ , -(L) _m -S0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ R ^S , -L-(CH ₂ ) _n C0 ₂ H, -L-(CH ₂ ) _n P0 ₃ H, -L-(CH ₂ ) _n C(0)R ^C , -L-(CH ₂ ) _n C0NHS0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ NHC0R ^S or -L-(CH ₂ ) _n tetrazol-5-yl; m is 0 or 1; n is 0 or 1; R ^N is H or -C _1-3 alkyl; R ^S is H Or -C _1-3 alkyl; L is CH ₂ , CHF or CF ₂ ; R ^C is -C _1-4 alkoxy, -C _1-4 alkoxycarbonyloxy-C _1-4 alkoxy Or -C _1-4 alkylcarbonyloxy-C _1-4 alkoxy;

R ⁴ is H, F, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl, wherein the -C _1-3 alkyl, aryl and C _3-7 cycloalkyl contain 0 to Replaced by 5 fluorine atoms;

R ⁶ is H, F, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl, wherein the -C _1-3 alkyl, aryl and C _3-7 cycloalkyl contain 0 to 5 fluorine atoms are substituted; and R ⁴ and R ^{6 are} not hydrogen at the same time.

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound, the

X is CR ⁵ ; R ⁵ is H, halogen, -CN, -C _1-3 alkyl, -OC _{1-3 alkyl, -C 1-3} alkyl substituted by 1 to 3 halogen atoms, or- C _3-4 cycloalkyl;

Y is N;

Z is N;

R ¹ _{is a -C 1-3} alkyl group whose valence is allowed to be substituted by 0 to 5 halogen atoms;

R ² is a C _3-7 cycloalkyl group or a 4- to 7-membered heterocyclic ring, wherein the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur, and the C _3-7 Cycloalkyl or 4- to 7-membered heterocycle has 0 to 3 substituents selected from -C _1-3 alkyl and -OH, and the number of -OH substituents does not exceed 1;

R ³ is -(L) _m -C0N(R ^N ) ₂ , -(L) _m -S0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ R ^S , -L-(CH ₂ ) _n C0 ₂ H, -L-(CH ₂ ) _n P(O)(0H) ₂ , -L-(CH ₂ ) _n C(0)R ^C , -L-(CH ₂ ) _n C0NHS0 ₂ R ^S , -L- (CH ₂ ) _n S0 ₂ NHC0R ^S or -L-(CH ₂ ) _n tetrazol-5-yl; m is 0 or 1; n is 0 or 1; R ^N is H or -C _1-3 alkyl ; R ^S is H or -C _1-3 alkyl; L is CH ₂ , CHF or CF ₂ ; R ^C is -C _1-4 alkoxy, -C _1-4 alkoxycarbonyloxy-C _{1 -4} alkoxy or -C _1-4 alkylcarbonyloxy-C _1-4 alkoxy;

R ⁴ is H, F, -C _1-3 alkyl, wherein the -C _1-3 alkyl contains 0 to 5 F atoms substituted;

R ⁶ is H, F, -C _1-3 alkyl, wherein the -C _1-3 alkyl contains 0 to 5 F atoms substituted;

The R ⁴ and R ^{6 are} not hydrogen at the same time.

As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotope-labeled compound, the R ^S is H or -CH ₃ .

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound, the R ³ is -CH ₂ C0 ₂ H, -CH ₂ P0 ₃ H,- CH ₂ CO ₂ CH ₃ or -CH ₂ CO ₂ CH ₂ CH ₃ .

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound, the R ⁵ is H, -Cl, -CH3, -CH ₂ CH ₃ ,- O-CH ₃ , cyclopropyl or CN;

As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer or isotope-labeled compound, the R ¹ is -CF ₃ , -CHF ₂ or -CF ₂ CH ₃ .

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound, said R ² is selected from azetidin-1-yl, pyrrolidine-1 4-membered to 7-membered heterocycles of -yl and piperidin-1-yl, the 4-membered to 7-membered heterocycles of said pyrrolidin-1-yl and piperidin-1-yl have 0 to 3 selected from -C _1-3 alkyl and -OH substituents, and the number of -OH substituents does not exceed one.

As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotope-labeled compound, the R ⁴ and R ⁶ are each independently H, F, or -C _1-3 Alkyl group, the -C _1-3 alkyl group contains 0 to 5 F atoms substituted, and R ⁴ and R ^{6 are} not hydrogen at the same time; the Y and Z are both N. As a more preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, the R ² is an azetidine having 1 to 2 -CH ₃ substituents and 0 to 1 -OH substituents -1-yl; said Y is C-CN and Z is N, or both Y and Z are N.

As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotope-labeled compound, the X, Y, and Z are selected from any one of the following:

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound, the compound is selected from the following structural formulas:

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound, the compound is selected from the following structural formulas:

As a preferred embodiment of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or isotopically labeled compound, the compound is 2-(1-methyl-3-(2-((S )-2-Methylazetidine-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid , 2-(1,5-Dimethyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl )-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid, ((1,5-dimethyl-3-(2-((S)-2-methylazetidine) -1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)phosphoric acid, ((1-methyl- 3-(2-((S)-2-Methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0] Hexane-6-yl)methyl)phosphoric acid or their prodrug forms.

As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotope-labeled compound, the structure of the compound is the compound of formula I(a)

Wherein R ³ substituents are in the same plane as R ⁴ and R ⁶ , wherein X, Y, Z, R ¹ , R ² , R ³ , R ⁴ , and R ⁶ are selected as described above, and R ⁴ , R ^{6 are} not At the same time it is hydrogen.

In addition, the present invention also provides a pharmaceutical composition, which contains the above-mentioned compound or a pharmaceutically acceptable salt or stereoisomer or isotope-labeled compound.

Finally, the present invention also provides the application of the above-mentioned compound or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound in the preparation of medicines for the treatment of diseases, including T1D, T2D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, acute kidney disease, renal tubular dysfunction, proximal Pro-inflammatory changes in the telomere, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia, increased total cholesterol , High LDL cholesterol, low HDL cholesterol, hyperinsulinemia, metabolic-related fatty liver disease, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial cells Dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-meal lipemia , Metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerular sclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome Symptoms, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders , Foot ulcer, ulcerative colitis, overload of apolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive decline, inflammatory bowel disease, ulcerative colitis, Crohn's disease and bowel disease Excited syndrome.

One way to achieve the present invention is to administer the compound of formula I in the form of a prodrug. Therefore, certain derivatives of the compound of formula I, which may have little or no pharmacological activity per se, will (for example) undergo hydrolytic cleavage, especially esterase or peptidase-promoted hydrolytic cleavage, to convert into A compound of formula I having the desired activity. Such derivatives are called ‘prodrugs’.

Those skilled in the art obtain the corresponding prodrugs by modifying appropriate functional groups existing in the compound of formula I (H. Bundgaard, Design of Prodrugs, Elsevier, 1985).

The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. Unless otherwise specified, all stereoisomeric forms of the compounds of the present invention and their mixtures, including racemic mixtures, are part of the present invention.

The present invention includes all pharmaceutically acceptable isotope-labeled compounds of formula I, in which one or more atoms are replaced by atoms having the same atomic number but whose atomic mass or mass number is different from the atomic mass or mass number commonly found in nature . Substitution by heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or decreased dosage requirements, and may therefore be preferred in certain situations.

The term "alkyl" as used in this application means a linear or branched monovalent hydrocarbon group of the _{formula -C n} H _(2n+1). Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl and hexyl.

The term "cycloalkyl" as used in this application means a cyclic monovalent hydrocarbon group _{of formula -C n} H _{(2n-1) containing at least three carbon atoms.} Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "alkoxy" as used in this application means an alkyl substituent attached through an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy.

The term "alkoxycarbonyloxy" as used in this application means an alkoxy group linked through a carbonyl group (-CO-). Non-limiting examples include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl.

The term "alkylcarbonyloxy" as used in this application means an alkyl group linked through a carbonyloxy group (-C(=0)-0-). Representative examples include methylcarbonyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.

The term "alkoxycarbonyloxy-alkoxy" as used in this application means an alkoxycarbonyloxy group linked through an alkoxy group. The term halogen used in this application refers to F, Cl, Br, I.

The term "heterocyclic ring" as used in this application refers to aliphatic heterocyclic ring and aromatic heterocyclic compounds having 4 to 7 carbon atoms, wherein _{one or more of the cyclomethylene group (-CH 2} -) of the aliphatic heterocyclic ring One has been replaced by a group selected from -0-, -S- or -N-, where the valence requirement of -N- is satisfied by H or by serving as a point of attachment; aromatic heterocycle refers to Hückel's rule A 5-membered or 6-membered heterocyclic ring system containing 1-2 atoms selected from O, S, N.

The aryl group refers to a functional group or substituent derived from a simple aromatic ring (such as a benzene ring, a naphthalene ring, etc.) that does not contain a heteroatom.

The general abbreviations used in this application: ADP is adenosine diphosphate; ATP is adenosine triphosphate; CDC1 ₃ is deuterated chloroform; CO ₂ Et is ethyl carboxylate; DCM is methylene chloride; DIPEA is N,N- Diisopropylethylamine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; EtOAc is ethyl acetate; H or h or hr is hours; HEPES is 4-(2-hydroxyethyl)-1 -Piperazine ethanesulfonic acid; KCl is potassium chloride; Min is minutes; MgCl ₂ is magnesium chloride; NaHCO ₃ is sodium bicarbonate; Na ₂ S0 ₄ is sodium sulfate; NADH is nicotinamide adenine dinucleotide (reduced Form); NAD+ is nicotinamide adenine dinucleotide (oxidized form) PEP is phosphoenolpyruvate; RT or rt is room temperature; TCEP is tris (2-carboxyethyl) phosphine; TFA is trifluoro Acetic acid; THF is tetrahydrofuran.

The compound described in this application or its pharmaceutically acceptable salt or its stereoisomer or isotope-labeled compound has a good inhibitory effect on hexulose kinase and can be used to prepare and treat T1D, T2D, LADA, EOD, YOAD , MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, acute kidney disease, renal tubular dysfunction, proximal tubules Pro-inflammatory changes, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL Cholesterol, low HDL cholesterol, hyperinsulinemia, metabolism-related fatty liver disease, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, HFI, coronary artery disease, peripheral vascular disease, hypertension, endothelial cell dysfunction, Impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-meal lipemia, metabolic Acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris , Thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, foot ulcers , Ulcerative colitis, apolipoprotein B overload lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, ulcerative colitis, Crohn's disease and irritable bowel syndrome The drugs provide new drug options for the treatment of these diseases.

Description of the drawings

Figure 1 is a synthetic route diagram of the compound described in Example 1 of the present invention.

Figure 2 is a synthetic route diagram of the compound described in Example 2 of the present invention.

Detailed ways

In order to better illustrate the objectives, technical solutions, and advantages of the present invention, the application will be further described below in conjunction with specific embodiments.

Example 1

2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3- The structural formula of azabicyclo[3.1.0]hexane-6-yl)acetic acid is as follows:

The synthetic route diagram of the compound described in this example is shown in Figure 1. The specific preparation method of the compound described in this example includes:

Step 1: Ethyl 1-methylcyclopropane-1-carboxylate-2,3-methyl carboxylate

At room temperature, add dimethyl fumarate (10g, 69.38mmol) and benzyltriethylammonium chloride (0.16g, 0.69mmol) to NaH (2.16g, 90.2mmol) in DMF (100mL) solution, slowly Ethyl 2-chloropropionate (10.42g, 76.32mmol) was added dropwise, and the reaction was stirred overnight at 40°C.

The reaction solution was poured into ice water (30mL), methyl tert-butyl ether (30mL×2) was extracted, the organic phases were combined, washed with saturated brine (80mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain The title compound was 14.80 g of pale yellow oil, which was used in the next step without further purification.

Step 2: 1-Methylcyclopropane-1,2,3-tricarboxylic acid

At room temperature, in (2R,3R)-1-methylcyclopropane-1-ethyl carboxylate-2,3-methyl carboxylate and (2S,3S)-1-methylcyclopropane-1-ethyl carboxylate- An aqueous solution (200 mL) of sodium hydroxide (8.48 g, 40.5 mmol) was slowly dropped into a solution of methyl 2,3-formate (14.8 g, 60.6 mmol) in EtOH (200 mL). After dropping, the solution was heated to reflux and reacted overnight. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove most of the organic solvents, the aqueous phase was adjusted to pH 2-3 with 2M hydrochloric acid, and then concentrated under reduced pressure to remove part of the water; then toluene (50 mL) was added, and concentration under reduced pressure was continued. Repeat the above steps twice, then add acetone (30 mL) to the residue, heat to reflux for 2 hours, filter, wash the filter cake with acetone, and concentrate under reduced pressure to obtain 10.0 g of the light yellow solid target compound, which is used directly without further purification Next step.

Step 3: 1-Methyl-2,4-dioxo-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid

At room temperature, in (2S,3S)-1-methylcyclopropane-1,2,3-tricarboxylic acid and (2R,3R)-1-methylcyclopropane-1,2,3-tricarboxylic acid (10g, Add acetic anhydride (6.62mL, 70.16mmol) to a solution of 53.15mmol) in acetic acid (20mL). The resulting mixture was heated to reflux and reacted for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was added to toluene (20mL) and continued The residual acetic acid was removed by concentration under reduced pressure, and the obtained residue was directly put into the next step at a yield of 100%.

Step 4: 3-benzyl-1-methyl-2,4-diox-3-azabicyclo[3.1.0]hexane-6-carboxylic acid Oxy-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (9.1g, 53.15mmol) in acetone (40mL) was added with triethylamine (7.4mL, 53.15mmol) and benzylamine (6.9g) , 63.78mmol), the resulting mixture was stirred and reacted at room temperature for 3 hours, and then concentrated under reduced pressure. Sodium acetate (2.64g, 32.26mmol) and acetic anhydride (24.4mL, 115mmol) were added to the residue, and the mixture was heated to reflux for 1 hour. Then it was cooled to room temperature and the reaction was stirred overnight. Concentrate under reduced pressure, quench the residue with water (50 mL), adjust the pH to 2-3 with 2M dilute hydrochloric acid, extract with dichloromethane (60 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. An oily substance was obtained, and then toluene (100 mL) was added and stirred at 0°C for 1 hour. A large amount of solid was precipitated, filtered, the filter cake was washed with toluene, and dried in vacuo to obtain the gray solid target compound (9.0 g, 64%).

MS(ESI,neg.ion)m/z:258.0[MH] ^-

Step 5: Ethyl 3-benzyl-1-methyl-2,4-diox-3-azabicyclo[3.1.0]hexane-6-carboxylate

At room temperature, slowly drop concentrated sulfuric acid ( 0.9mL), after dropping, the resulting mixture was heated and refluxed overnight. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove most of the ethanol. The residue was diluted with water (50mL), and the pH was adjusted to 8-9 with saturated sodium bicarbonate. Extract with methyl chloride (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting mixture is subjected to silica gel column chromatography (PE:EA=10:1) to obtain the light yellow oily target compound (5.0 g, 50%).

¹ H NMR(600MHz,CDCl3)δ7.36–7.29(m,5H),4.57–4.50(m,2H),4.21(q,J=7.1Hz,2H), 2.84(d,J=3.0Hz,1H ), 2.25 (d, J = 3.0 Hz, 1H), 1.57 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H).

Step 6: Ethyl 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylate

Under ice bath conditions, slowly drip boron trifluoride ether (21.02g, 69.61mmol) into a solution of sodium borohydride (1.98g, 52.21mmol) in tetrahydrofuran (50mL), and then slowly drip 3-benzyl- A solution of 1-methyl-2,4-diox-3-azabicyclo[3.1.0]hexane-6-ethyl carboxylate (5.0g, 17.4mmol) in tetrahydrofuran (30mL), drip it, and stir overnight at room temperature . The reaction solution was cooled in an ice bath, and then ethanol (50 mL) was slowly added dropwise. After the dripping was completed, it was naturally warmed to room temperature and stirred for 5 hours, then heated to reflux for 3 hours (generating a large amount of gas), after cooling to room temperature, concentrated under reduced pressure to remove most of it Solvent, the system was diluted with water (100mL), extracted with dichloromethane (100mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (PE:EA=10: 1) Purification to obtain the target compound (3.0 g, 66%) as a pale yellow solid.

LC-MS(ESI,pos.ion)m/z:260.1.0[M+H]+

Step 7: 3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid

At room temperature, add sodium hydroxide to a solution of ethyl 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (3.01g, 11.57mmol) in methanol (50mL) (1.39 g, 34.7 mmol) in water (50 mL), and the resulting mixture was heated to reflux overnight. After the reaction solution was cooled to room temperature, most of the organic solvent was removed under reduced pressure, diluted with water (50mL), 1M diluted hydrochloric acid was added to the system to adjust the pH to 5-6, concentrated under reduced pressure to remove water, and the residue was column chromatographed (DCM:MeOH =10:1) white solid target compound (2.30g, 86%) is obtained

Step 8: 1-(3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-2-diazomethane-1-one

Under ice bath conditions, add 3 to a solution of 3-phenyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (2.30g, 9.94mmol) in dichloromethane (50mL) DMF was dropped, and then oxalyl chloride (1.68 mL, 19.89 mmol) was slowly dropped. After the dropping, the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in THF (50mL) and acetonitrile (50mL). Triethylamine (2.07mL, 14.9mmol) was added at 0°C, and trimethylsilyldiazomethane (14.9mL) was slowly added dropwise. , 29.79mmol), after dripping, the reaction was stirred overnight at 0°C. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (80 mL), extracted with ethyl acetate (50 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography ( PE:EA=4:1) was purified to obtain the target compound (1.80 g, 71%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:256.2[M+H]+

Step 9: Methyl 2-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl)acetate

MeOH in 1-(3-phenyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-2-diazomethane-1-one (1.80g, 7.05mmol) (50mL) Triethylamine (2.45mL, 17.62mmol) and silver benzoate (0.16g, 0.7mmol) were added to the solution, and the reaction was stirred overnight at room temperature. The reaction solution was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (0.75 g, 41%) as a yellow liquid

Step 10: Methyl 2-(1-methyl-3-azabicyclo[3.1.0]hexane-6-yl)acetate is heated in 2-(3-benzyl-1-methyl-3- Add Pd/C (80mg) to a methanol (50mL) solution of methyl azabicyclo[3.1.0]hexane-6-yl)acetate (0.75g, 2.89mmol), replace hydrogen for 3 times, and then charge 4MPa Hydrogen, stirring at room temperature overnight. The reaction solution was filtered through Celite to remove the catalyst, and concentrated under reduced pressure to obtain the target compound (0.19 g, 38%) as a pale yellow oil.

Step 11: 2-(3-(2-Chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl) Methyl acetate in 2-(1-methyl-3-azabicyclo[3.1.0]hexane-6-yl) methyl acetate (0.75g, 4.43mmol) in dichloromethane ( 30mL) slowly dropwise add 2,4-dichloro-6-(trifluoromethyl)pyrimidine (1.44g, 6.65mmol) in dichloromethane (20mL) solution to the solution, after the dripping, continue to add DIPEA dropwise at this temperature (2.2mL, 13.3mmol). After the addition, the temperature was increased to -65°C and the stirring was continued for 1 hour, then it was naturally raised to room temperature and stirred until the reaction was overnight, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography ( Petroleum ether: ethyl acetate = 4: 1) to obtain the title compound (0.9 g, 58%) as a pale yellow solid.

LC-MS(ESI,pos.ion)m/z:350.1[M+H]+

¹ H NMR (400MHz, CDCl ₃ ) δ 6.48 (s, 1H), 4.15-4.04 (m, 1H), 3.73 (s, 3H), 3.70-3.61 (m, 2H), 3.49-3.36 (m, 1H) ), 2.56–2.35(m,2H), 1.35(d,J=5.2Hz,3H), 1.32–1.27(m,1H), 1.02–0.91(m,1H).

Step 12: 2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl) Methyl-3-azabicyclo[3.1.0]hexane-6-yl)acetate

At room temperature, to 2-(3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl ) A solution of methyl acetate (0.9g, 2.57mmol) in acetonitrile (20mL) was added (S)-2-methylazetidine hydrochloride (0.55g, 5.15mmol) and DIPEA (1.28g, 7.72mmol) ), the resulting mixture was heated to 80°C and stirred overnight. After the reaction solution was cooled, it was concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE:EA=5:1) to obtain the colorless oily target compound (0.65g, 66 %).

LC-MS(ESI,pos.ion)m/z:385.1[M+H]+

¹ H NMR (400MHz, CDCl ₃ ) δ 5.92 (s, 1H), 4.50-4.37 (m, 1H), 4.07-3.90 (m, 3H), 3.72 (s, 3H), 3.65-3.45 (m, 2H) ), 3.32–3.24(m,1H), 2.46–2.40(m,2H), 2.41–2.33(m,1H), 2.01–1.88(m,1H), 1.51(d,J=6.2Hz,3H), 1.32(s,3H), 1.19(s,1H), 0.99-0.92(m,1H).

Step 13: 2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl) -3-azabicyclo[3.1.0]hexane-6-yl)acetic acid

At room temperature in 2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl) -3-Azabicyclo[3.1.0] hexane-6-yl) methyl acetate (0.65g, 1.69mmol) in THF (20mL) and water (20mL) solution was added sodium hydroxide (0.14g, 3.38mmol), the resulting mixture was stirred at room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure to remove most of the tetrahydrofuran, diluted with water (20mL), the aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid, extracted with ethyl acetate (30mL×3), dried over anhydrous sodium sulfate, filtered, and reduced under reduced pressure. After pressure concentration, the obtained residue was purified by column chromatography (PE:EA=3:1) to obtain the target compound (80 mg, 13%) as a white solid.

MS(ESI,pos.ion)m/z:371.3[M+H]+

¹ H NMR (400MHz, CDCl ₃ ) δ 5.93 (s, 1H), 4.51-4.37 (m, 1H), 4.10-3.87 (m, 3H), 3.69-3.46 (m, 2H), 3.28 (d, J = 10.7Hz, 1H), 2.55–2.35(m, 3H), 2.00–1.91(m, 1H), 1.51(d, J = 6.2Hz, 3H), 1.35(s, 3H), 1.25–1.19(m, 1H),1.00–0.94(m,1H).

Example 2

2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3- Azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )acetic acid

The structural formula is as follows:

The synthetic route diagram of the compound described in this example is shown in Figure 2. The specific preparation method of the compound described in this example includes:

Step 1: 3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-ethyl carboxylate-2,2,4,4-d ₄

At 0°C, slowly drip boron trifluoride ether (22.10g, 73.18mmol, 47%) into a solution of sodium borodeuteride (2.3g, 54.89mmol) in tetrahydrofuran (50mL). Benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-ethyl carboxylate (5.0g, 18.03mmol) in tetrahydrofuran (30mL) solution, dropwise , The reaction was stirred overnight at room temperature. The reaction solution was cooled in an ice bath, and then ethanol (50 mL) was slowly added dropwise. After the dripping was completed, it was naturally warmed to room temperature and stirred for 5 hours, and then heated and refluxed for 3 hours. Part of the solvent, the system was diluted with water (100mL), extracted with dichloromethane (100mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (PE:EA=10:1) , A light yellow solid target compound (4.13 g, yield: 87%) was obtained. MS(ESI,pos.ion)m/z:264.2[M+H] ⁺

Step 2: 3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid-2,2,4,4-d ₄

At room temperature, in 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-ethyl carboxylate- _{2,2,4,4-d 4} (4.13g, 16.04mmol) An aqueous solution of sodium hydroxide (48.13 mmol, 50 mL) was added to the methanol (50 mL) solution, and the reaction solution was heated to reflux and reacted overnight. After the reaction solution was cooled to room temperature, most of the organic solvents were removed under reduced pressure, diluted with water (50 mL), 1M diluted hydrochloric acid was added to the system to adjust the pH to 5-6, concentrated under reduced pressure to remove water, and the resulting residue was column chromatographed (DCM:MeOH = 10:1) The target compound (3.19 g, yield: 84%) was obtained as a white solid.

Step 3: 3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carbonyl chloride-2,2,4,4-d ₄

At 0℃, in 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid- _{2,2,4,4-d 4} (3.9g, 13.56mmol) Add 3 drops of DMF to the anhydrous dichloromethane (50mL) solution, and then slowly add oxalyl chloride (2.29mL, 27.11mmol). After the dripping is completed, the reaction is stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure to obtain a pale yellow solid target Compound 3.50g was used directly in the next step without further purification (yield was calculated as 100%).

Step 4: 1-(3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )-2-dimethylene Amine-1-one

0℃, under nitrogen protection, in 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-formyl chloride-2,2,4,4-d ₄ (3.50g, 13.56mmol) in THF (30mL) and acetonitrile (30mL) solution was added triethylamine (2.83mL, 20.33mmol), and then slowly dripped trimethylsilyldiazomethane (20.33mL, 40.67mmol), the dripping was completed, After stirring overnight at 0°C, the reaction solution was concentrated under reduced pressure to remove most of the organic solvents. The system was quenched by adding saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, filtered, and reduced After pressure concentration, the residue obtained was subjected to silica gel column chromatography (PE:EA=4:1) to obtain the target compound as a pale yellow solid (2.11g, 60%)

MS(ESI,pos.ion)m/z:260.3[M+H] ⁺

Step 5: Methyl 2-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )acetate

To 1-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )-2-dimethylimine- Triethylamine (2.83 mL, 20.38 mmol) and silver benzoate (0.93 g, 4.08 mmol) were added to the methanol (50 mL) solution of 1-ketone (2.11 g, 8.14 mmol), and stirred at room temperature until the reaction was completed. The system was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (2.10 g, 98%) as a yellow liquid.

Step 6: Methyl 2-(1-methyl-3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )acetate

At room temperature, in 2-(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )methyl acetate ( 2.10g, 7.97mmol) in methanol (50mL) solution, add Pd/C (200mg), replace hydrogen 3 times, fill with 4MPa hydrogen, heat to 50°C and stir to react overnight. After being naturally cooled to room temperature, the catalyst was removed by filtration, and concentrated under reduced pressure to obtain 0.75 g of the light yellow solid target compound, which was directly used in the next step without further purification.

Step 7: 2-(3-(2-Chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl- 2,2,4,4-d ₄ ) Methyl acetate

At -75℃, in 2-(1-methyl-3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ ) methyl acetate (0.55g, 3.14mmol) in dichloromethane (30mL) solution slowly dropwise add 2,4-dichloro-6-(trifluoromethyl)pyrimidine (1.44g, 6.65mmol) in dichloromethane (20mL) solution, dropwise finish, Continue to add DIPEA (1.56mL, 9.42mmol) dropwise at this temperature, then increase the temperature to -65°C and continue stirring for 1 hour, then naturally rise to room temperature and stir for overnight reaction. Concentrate under reduced pressure to remove the solvent, and use a silica gel column for the residue. Purification by chromatography (petroleum ether: ethyl acetate=4:1) to obtain the title compound (0.38 g, 34%) as a pale yellow solid.

MS(ESI,pos.ion)m/z:354.1[M+H] ⁺

Step 8: 2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl) -3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )methyl acetate

At room temperature, to 2-(3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-yl -2,2,4,4-d ₄ ) Methyl acetate (0.38g, 1.07mmol) in acetonitrile (20mL) solution was added (S)-2-methylazetidine hydrochloride (0.23g, 2.12mmol) and DIPEA (0.52g, 3.18mmol), the resulting mixture was heated to 80°C and stirred overnight. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (PE:EA=5:1) to obtain the colorless oily target compound (0.31 g, yield: 75%). LC-MS(ESI,pos.ion)m/z:389.2[M+H] ⁺

Step 9: 2-(1-methyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl) -3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )acetic acid

At room temperature in 2-(1-methyl3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)- 3-azabicyclo[3.1.0]hexane-6-yl-2,2,4,4-d ₄ )methyl acetate (0.31g, 0.80mmol) in THF (20mL) and water (20mL) Add sodium hydroxide (0.064g, 1.6mmol), stir at room temperature until the reaction is complete. Concentrate under reduced pressure under reduced pressure to remove most of the tetrahydrofuran, adjust the pH of the remaining aqueous phase to 5-6 with dilute hydrochloric acid, extract with ethyl acetate (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE:EA=3:1) to obtain the target compound (90mg, 30%) as a white solid.

MS(ESI,pos.ion)m/z:375.2[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ )δ5.93(s,1H),4.51–4.37(m,1H),4.04(td,J＝8.8,5.0Hz,1H),3.96(dd,J＝16.1,8.7 Hz,1H),2.51–2.33(m,3H),1.95(tt,J=9.0,7.0Hz,1H),1.51(d,J=6.2Hz,3H),1.35(s,3H),1.25–1.19 (m,1H),1.00–0.94(m,1H).

Biological data

Example A: In vitro enzyme activity experiment

Hexokinase has two isoforms, KHKc and KHKa, and KHKc has more than ten times the ability to phosphorylate fructose than KHKa.

According to the metabolic pathway of fructose, the enzyme function of KHK is to consume ATP to convert fructose into 1-phosphate fructose and produce ADP at the same time. The ATP depletion method, ADP color method, or subsequent reactions can be used to detect the consumption of NADH and the production of the final product NAD ⁺ , which can effectively determine the inhibitory effect of the reaction.

The content of NADH was monitored by continuously measuring the absorbance at 340nm, and the inhibition of KHK by the candidate compound was preliminarily judged based on the consumption of NADH. This method involves a coupled enzyme system, and the three-step reaction involved is as follows:

The 3-step reaction involved in the preliminary screening of KHKc inhibitors (KHKc hexulose phosphokinase; PK pyruvate kinase; LDH lactate dehydrogenase)

In order to screen the inhibitory efficiency of candidate compounds on KHKc enzyme, in a 96-well Corning3599 cell culture plate, the absorbance value was monitored in a continuous mode at 37°C incubation at a wavelength of 340nm using a microplate reader. The compound was prepared as a 10 mM stock solution in DMSO as a stock solution, followed by a three-fold dilution scheme with 50 mM PIPES buffer for serial dilution. A 200μL reaction system contains 50mM PIPES buffer, 6mM MgCl ₂ , 100mM KCl, 5mM fructose, 2mM phosphoenolpyruvate (PEP), 5mM ATP, 0.6mM reducing coenzyme I (NADH), 40U/mL pyruvate kinase -Lactate dehydrogenase and 10mM recombinant KHKC. Mix the compound to be screened with all the reagents in the reaction system except the trigger ATP, and incubate at 37°C for 15 minutes. After that, 50mM ATP was added to the reaction system to trigger the reaction. Incubate at 37°C in the microplate reader for continuous kinetic monitoring for 2 hours, and measure at 340nm wavelength every 5 minutes to calculate the inhibition by measuring the difference in absorbance (△OD) Then use Graphpad software to calculate the IC50 value of the test substance to KHK. The reagent concentration provided is based on a final mixture volume of 200 μL, which is the final concentration.

Control: N8-(cyclopropylmethyl)-N4-(2-(methylthio)phenyl)-2-(piperazin-1-yl)pyrimido[5,4-d] at a final concentration of 2μM Pyrimidine-4,8-diamine (CAS: 1303469-70-6) was used as a high percentage inhibition control (HPE), and the drug-free group (replaced with buffer) was used as a zero percentage effect control (FOC).

The microplate reader measures the absorbance at the wavelength of 340nm within 1 min and 0.5h, 1h, 2h after adding ATP, and calculates the inhibition rate by the measured absorbance difference (△OD value), and calculates the test substance against KHK according to the following formula The inhibition rate:

Inhibition rate %=[(FOC _{△OD value} -administration group _{△OD value} )/(FOC _{△OD value-} HPE _{△OD value} )]×100%.

According to the inhibition rate corresponding to each drug concentration, use GraphPad Prism software to perform logarithmic conversion, and use nonlinear regression analysis to fit the data to "Selection Criteria-Nonlinear Regression-Variable Slope (Parameter Setting)" to obtain the IC ₅₀ value . Measured for different compounds, the IC ₅₀ of the obtained based on the average of at least two independent experiments performed at different times.

Taking the different monitoring points 0.5h, 1h, and 2h during the reaction process as test A, test B, and test C, respectively, the reaction rate and IC ₅₀ value were calculated according to the above description.

The biological data of the compound described in Example 1 of the present invention and the compound numbered PF-06835919 were tested as described above, and the structural formula of the compound numbered PF-06835919 is as follows:

The test results are shown in Table 1.

Table 1 Biological data of test A, B, C

It can be seen from the test results that the compound of Example 1 has a good inhibitory effect on hexulose kinase.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that, The technical solution of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solution of the present invention.

Claims (10)

1. A compound or a pharmaceutically acceptable salt or a stereoisomer or an isotopically-labeled compound, the compound has the structural formula shown in the following formula I:

   

   Wherein X is N or CR ⁵ ; R ⁵ is H, halogen, -CN, -C _1-3 alkyl, -OC _{1-3 alkyl, -C 1-3} alkane substituted by 1 to 3 halogen atoms Group, or -C _3-4 cycloalkyl

   Y is N or C-CN or CF;

   Z is N or CH;

   And at least one of X, Y, and Z is N;

   R ¹ _{is cyclopropyl, cyclobutyl, cyano, or -C 1-3} alkyl whose valence may be substituted with 0 to 5 halogen atoms;

   R ² is C _3-7 cycloalkyl, 4-membered to 7-membered heterocycle, N (C _1-3 alkyl) ₂ , NH (C _1-3 alkyl) or NH (C _3-4 cycloalkyl) Wherein the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur; the C _3-7 cycloalkyl or 4- to 7-membered heterocyclic ring has 0 to 3 options From -C _1-3 alkyl and -OH substituents, and the number of -OH substituents does not exceed one; the N (C _1-3 alkyl) ₂ , NH (C _1-3 alkyl), _{Each C 1-3} alkyl group in NH (C _3-4 cycloalkyl) is substituted with 0 to 1 OH;

   R ³ is -(L) _m -C0N(R ^N ) ₂ , -(L) _m -S0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ R ^S , -L-(CH ₂ ) _n C0 ₂ H, -L-(CH ₂ ) _n P0 ₃ H, -L-(CH ₂ ) _n C(0)R ^C , -L-(CH ₂ ) _n C0NHS0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ NHC0R ^S , -L-(CH ₂ ) _n SO ₂ NHCONH ₂ or -L-(CH ₂ ) _n tetrazol-5-yl; m is 0 or 1; n is 0 or 1; R ^N is H Or -C _1-3 alkyl; R ^S is H or -C _1-3 alkyl; L is CH ₂ , CHF or CF ₂ ; R ^C is -C _1-4 alkoxy, -C _1-4 alkane Oxycarbonyloxy-C _1-4 alkoxy or -C _1-4 alkylcarbonyloxy-C _1-4 alkoxy;

   R ⁴ is hydrogen, halogen, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl or 4- to 7-membered heterocycle, wherein said -C _1-3 alkyl, aryl and C _{3 -7} cycloalkyl contains 0 to 5 fluorine atoms substituted; the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur;

   R ⁶ is hydrogen, halogen, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl or 4- to 7-membered heterocycle, wherein said -C _1-3 alkyl, aryl and C _{3 -7} cycloalkyl contains 0 to 5 fluorine atoms substituted; the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur;

   The R ⁴ and R ^{6 are} not hydrogen at the same time.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotope-labeled compound, wherein the

   X is N or CR ⁵ ; R ⁵ is H, halogen, -CN, -C _1-3 alkyl, -OC _{1-3 alkyl, -C 1-3} alkyl substituted by 1 to 3 halogen atoms, Or -C _3-4 cycloalkyl

   Y is N, C-CN;

   Z is N or CH;

   And at least one of X, Y, and Z is N;

   R ¹ _{is a -C 1-3} alkyl group whose valence is allowed to be substituted by 0 to 5 halogen atoms;

   R ² is a C _3-7 cycloalkyl group or a 4- to 7-membered heterocyclic ring, wherein the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur, and the C _{3- The 7} -cycloalkyl or 4- to 7-membered heterocycle has _{0 to 3 substituents selected from -C 1-3} alkyl and -OH, and there is no more than one -OH substituent;

   R ³ is -(L) _m -C0N(R ^N ) ₂ , -(L) _m -S0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ R ^S , -L-(CH ₂ ) _n C0 ₂ H, -L-(CH ₂ ) _n P0 ₃ H, -L-(CH ₂ ) _n C(0)R ^C , -L-(CH ₂ ) _n C0NHS0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ NHC0R ^S or -L-(CH ₂ ) _n tetrazol-5-yl; m is 0 or 1; n is 0 or 1; R ^N is H or -C _1-3 alkyl; R ^S is H Or -C _1-3 alkyl; L is CH ₂ , CHF or CF ₂ ; R ^C is -C _1-4 alkoxy, -C _1-4 alkoxycarbonyloxy-C _1-4 alkoxy Or -C _1-4 alkylcarbonyloxy-C _1-4 alkoxy;

   R ⁴ is H, F, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl, wherein the -C _1-3 alkyl, aryl and C _3-7 cycloalkyl contain 0 to Replaced by 5 fluorine atoms;

   R ⁶ is H, F, -C _1-3 alkyl, C _3-7 cycloalkyl, aryl, wherein the -C _1-3 alkyl, aryl and C _3-7 cycloalkyl contain 0 to Replaced by 5 fluorine atoms;

   And R ⁴ and R ^{6 are} not hydrogen at the same time.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotope-labeled compound, wherein the

   X is CR ⁵ ; R ⁵ is H, halogen, -CN, -C _1-3 alkyl, -OC _{1-3 alkyl, -C 1-3} alkyl substituted by 1 to 3 halogen atoms, or- C _3-4 cycloalkyl;

   Y is N;

   Z is N;

   R ¹ _{is a -C 1-3} alkyl group whose valence is allowed to be substituted by 0 to 5 halogen atoms;

   R ² is a C _3-7 cycloalkyl group or a 4- to 7-membered heterocyclic ring, wherein the 4- to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, and sulfur, and the C _3-7 Cycloalkyl or 4- to 7-membered heterocycle has _{0 to 3 substituents selected from -C 1-3} alkyl and -OH, and there is no more than one -OH substituent;

   R ³ is -(L) _m -C0N(R ^N ) ₂ , -(L) _m -S0 ₂ R ^S , -L-(CH ₂ ) _n S0 ₂ R ^S , -L-(CH ₂ ) _n C0 ₂ H, -L-(CH ₂ ) _n P(O)(0H) ₂ , -L-(CH ₂ ) _n C(0)R ^C , -L-(CH ₂ ) _n C0NHS0 ₂ R ^S , -L- _{(CH 2) n S0 2 NHC0R} S or -L- (CH _{2) n-tetrazol-5-yl;} m is 0 or 1; n is 0 or 1; R ^N is H or -C _1-3 alkyl ; R ^S is H or -C _1-3 alkyl; L is CH ₂ , CHF or CF ₂ ; R ^C is -C _1-4 alkoxy, -C _1-4 alkoxycarbonyloxy-C _{1 -4} alkoxy or -C _1-4 alkylcarbonyloxy-C _1-4 alkoxy;

   R ⁴ is H, F, -C _1-3 alkyl, wherein the -C _1-3 alkyl contains 0 to 5 F atoms substituted;

   R ⁶ is H, F, -C _1-3 alkyl, wherein the -C _1-3 alkyl contains 0 to 5 F atoms substituted;

   The R ⁴ and R ^{6 are} not hydrogen at the same time.
4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotope-labeled compound, wherein the R ^S is H or -CH ₃ ;

   Preferably, the R ³ is -CH ₂ CO ₂ H, -CH ₂ P0 ₃ H, -CH ₂ CO ₂ CH ₃ or -CH ₂ CO ₂ CH ₂ CH ₃ ;

   Preferably, the R ⁵ is H, -Cl, -CH3, -CH ₂ CH ₃ , -O-CH ₃ , cyclopropyl or CN;

   Preferably, the R ¹ is -CF ₃ , -CHF ₂ or -CF ₂ CH ₃ ;

   Preferably, the R ² is a 4- to 7-membered heterocyclic ring selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, the pyrrolidin-1-yl and The 4- to 7-membered heterocycle of piperidin-1-yl has 0 to 3 substituents selected from -C _1-3 alkyl and -OH, and the number of -OH substituents does not exceed 1;

   Preferably, the R ⁴ and R ⁶ are each independently H, F, or -C _1-3 alkyl, and the -C _1-3 alkyl contains 0 to 5 F atoms substituted, and R ⁴ , R ⁶ It is not hydrogen at the same time; the Y and Z are both N.
5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotope-labeled compound, wherein the R ² has 1 to 2 -CH ₃ substituents and has 0 Azetidin-1-yl to 1 -OH substituent; said Y is C-CN and Z is N, or both Y and Z are N.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically labeled compound, wherein the compound is selected from the following structural formulas:

   
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically labeled compound, wherein the compound is selected from the following structural formulas:

   
8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotope-labeled compound, wherein the compound is 2-(1-methyl-3-(2-( (S)-2-Methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl )Acetic acid, 2-(1,5-dimethyl-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidine-4 -Yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid, ((1,5-dimethyl-3-(2-((S)-2-methylazacyclo) Butane-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)phosphoric acid ((1-methyl -3-(2-((S)-2-Methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0 ]Hexane-6-yl)methyl)phosphoric acid or their prodrug forms.
9. A pharmaceutical composition, characterized in that the pharmaceutical composition contains the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotope-labeled compound.
10. The use of the compound or a pharmaceutically acceptable salt or stereoisomer or isotope-labeled compound of any one of claims 1 to 8 in the preparation of a medicine for the treatment of a disease, wherein the disease comprises T1D , T2D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, acute kidney disease, kidney Tubular dysfunction, pro-inflammatory changes in proximal tubules, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, excessive sugar craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia Syndrome, increased total cholesterol, high LDL cholesterol, low HDL cholesterol, hyperinsulinemia, metabolism-related fatty liver disease, steatosis, NASH, fibrosis, liver cirrhosis, hepatocellular carcinoma, HFI, coronary artery disease, peripheral vascular disease, Hypertension, endothelial cell dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, Post-dietary lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, X syndrome Symptoms, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting blood sugar, hyperuricemia, gout, erectile dysfunction, Skin and connective tissue disorders, foot ulcers, ulcerative colitis, overload apolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive decline, inflammatory bowel disease, ulcerative colitis, Crowe Faint disease and irritable bowel syndrome.

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