CN111423420A - Fused ring compounds as ketohexokinase inhibitors - Google Patents
Fused ring compounds as ketohexokinase inhibitors Download PDFInfo
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- CN111423420A CN111423420A CN202010366415.6A CN202010366415A CN111423420A CN 111423420 A CN111423420 A CN 111423420A CN 202010366415 A CN202010366415 A CN 202010366415A CN 111423420 A CN111423420 A CN 111423420A
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- Prior art keywords
- alkyl
- compound
- cycloalkyl
- pharmaceutically acceptable
- acceptable salt
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 129
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- 108010062852 Ketohexokinase Proteins 0.000 title description 20
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- 201000010099 disease Diseases 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- -1 Tetrazol-5-yl Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 19
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Abstract
The invention also provides a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof or the stereoisomer or isotope labeled compound thereof, and application of the compound or the pharmaceutically acceptable salt thereof or the stereoisomer or isotope labeled compound thereof in preparing medicaments for treating diseases such as T1D, T2D, L ADA, EOD, YOAD, MODY, malnutrition related diabetes, gestational diabetes and the like.
Description
Technical Field
The invention relates to a novel compound, pharmaceutically acceptable salts, stereoisomers and isotopes thereof, in particular to a compound capable of inhibiting ketohexokinase, pharmaceutically acceptable salts, stereoisomers and isotopes thereof.
Background
Ketohexokinase (KHK) is a basic enzyme involved in fructose metabolism in vivo, plays a very important role in fructose metabolism, catalyzes the reaction of fructose and ATP to convert fructose into fructose-1-phosphate (F1P). ketohexokinase has two important subtypes in human body, namely ketohexokinase A (KHKa) and ketohexokinase C (KHKc). although KHKa is more widely expressed in vivo, KHKc is more highly expressed in major metabolic organs in human body, such as liver, kidney and intestine (Ishimoto, L anaspa et al, PNAS109,4320-4325,2012), and thus KHKc has a more significant effect on fructose metabolism regulation.
Epidemiological studies have shown that dietary sugar consumption has a clear correlation with the incidence of metabolic syndrome and obesity. Experiments have shown that fructose administration to rats is characteristic of inducing metabolic syndrome, weight gain, and increased body fat.
Metabolic syndrome and obesity seriously affect the quality of life of people. The data published by the WHO showed that the number of obese people worldwide has increased almost two-fold since 1975. More than 19 billion overweight people in 2016 among adults over 18 years of age worldwide, with more than 6.5 million people being obese (https:// www.who.int/en/news-room/fact-s heets/detail/obesity-and-overweight). Obesity is combined with hypertension, hyperlipidemia and hyperglycemia and is called as a death quartet, and the obesity can become the first killer in the 21 st century. At least 280 million people die annually from being overweight or obese.
Diabetes belongs to one of metabolic syndromes, patients are widely distributed, 4.63 million people are estimated to have Diabetes in the population of 20-79 years in the world, and most of Diabetes mellitus is type 2 (IDF Diabetes mellitus Atlas indication 2019 published by the International Diabetes Association in 9 th Edition).
The metabolic-related fatty liver disease (MAF L D) has attracted extensive attention in recent years, the global incidence rate is about 25%, inflammation is generated in further development, and then liver fibrosis and even liver cancer are likely to be further worsened, so that the metabolic-related fatty liver disease becomes a worldwide chronic liver disease which is increasingly common, and is the first cause of liver transplantation in the united states at present, but unfortunately, no medicine is officially approved for the metabolic-related fatty liver disease at present, and a huge unmet clinical demand exists.
Fructose significantly increases lipid de novo synthesis (Stanhope, k. L., Schwarz et al, (2009), J ClinInvest 119,1322-1334), fructose uptake in large amounts leads to an increase in hepatic triglycerides and after cessation of fructose uptake can reverse hepatic triglyceride accumulation (Schwarz, j.m., nomoolski et al, (2015), J Clin EndocrinolMetab 100, 2434) -in diabetes, the polyol pathway (the pathway that converts glucose to fructose via sorbitol as an intermediate) leads to endogenous fructose production and the more active the pathway is, the more severe hyperglycemia the no KHK mice are protected from glucose induced weight gain, insulin resistance and hepatic steatosis, which suggests that in case of hyperglycemia endogenously produced fructose may lead to insulin resistance and to kh steatosis (L anaspapa, m.a. et al, Nature m.4, 2434), 2013 may be used in the treatment of obesity and other related disorders by inhibition of fructose metabolism, and thus may provide a significant inhibition of fructose metabolism in humans, and also a corresponding inhibition of glucose uptake in vivo mutations, and thus may lead to the inhibition of obesity and the relevant metabolic disorders of fructose metabolism in humans.
As for compounds of ketohexokinase inhibitors, the Dougeny company published the utility of pyrimidopyrimidines in inhibiting ketohexokinase activity (ACS Med. chem. L ett.2011,2, 538-543), wherein the 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 12 nM. WO2017/115205 discloses a compound that can be an inhibitor of ketohexokinase and discloses the use of said compound in the treatment of obesity, type ii diabetes, metabolic-related fatty liver disease and the like.
Disclosure of Invention
The invention aims to provide a novel compound capable of inhibiting ketohexokinase, a pharmaceutically acceptable salt thereof, a stereoisomer thereof and an isotope labeled compound thereof aiming at the defects of the prior art; in addition, the invention also provides a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof or the stereoisomer or isotope labeled compound thereof and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that: a compound or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof, said compound having a structural formula shown in formula i below:
wherein X is N or CR5；R5Is H, halogen, -CN, -C1-3Alkyl, -0C1-3Alkyl, C substituted by 1 to 3 halogen atoms1-3Alkyl, or-C3-4Cycloalkyl radicals
Y is N or C-CN or CF;
z is N or CH;
and at least one of X, Y, Z is N;
R1is cyclopropyl, cyclobutyl, cyano, or-C which may be substituted in valence number by 0 to 5 halogen atoms1-3An alkyl group;
R2is C3-7Cycloalkyl, 4-to 7-membered heterocycle, N (C)1-3Alkyl radical)2、NH(C1-3Alkyl) or NH (C)3-4Cycloalkyl groups); wherein the 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur; said C is3-7Cycloalkyl or 4-to 7-membered heterocycle having 0 to 3 substituents selected from-C1-3Alkyl and a substituent of-0H, and the number of substituents of-0H is not more than 1; the N (C)1-3Alkyl radical)2、NH(C1-3Alkyl), NH (C)3-4Cycloalkyl) each C1-3Alkyl is substituted with 0 to 1H;
R3is- (L)m-C0N(RN)2、-(L)m-S02RS、-L-(CH2)nS02RS、-L-(CH2)nC02H、-L-(CH2)nP03H、-L-(CH2)nC(0)RC、-L-(CH2)nC0NHS02RS、-L-(CH2)nS02NHC0RS、-L-(CH2)nSO2NHCONH2or-L- (CH)2)nTetrazol-5-yl; m is 0 or 1; n is 0 or 1; rNIs H or-C1-3An alkyl group; rSIs H or-C1-3Alkyl L is CH2CHF or CF2；RCis-C1-4Alkoxy, -C1-4alkoxy-carbonyloxy-C1-4Alkoxy or-C1-4alkylcarbonyloxy-C1-4An alkoxy group;
R4is hydrogen, halogen, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl or a 4-to 7-membered heterocycle, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions; the 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur;
R6is hydrogen, halogen, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl or a 4-to 7-membered heterocycle, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions; the 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur;
the R is4、R6Not hydrogen at the same time.
In the research process, the inventor of the application finds that a novel structural compound generated by introducing an aliphatic or aromatic substituent group into a fused ring in a molecule disclosed in WO2017/115205 can still better maintain the activity, the pharmacological property and the like of the compound compared with the compound disclosed in WO2017/115205, and is even better than the compound disclosed in WO2017/115205 in certain aspects.
As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically labeled compound thereof, said
X is N or CR5；R5Is H, halogen, -CN, -C1-3Alkyl, -0C1-3Alkyl, C substituted by 1 to 3 halogen atoms1-3Alkyl, or-C3-4Cycloalkyl radicals
Y is N, C-CN;
z is N or CH;
and at least one of X, Y, Z is N;
R1allowed to be substituted by 0 to 5 halogen atoms for valence-C1-3An alkyl group;
R2is C3-7Cycloalkyl 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, sulfur, C3-7Cycloalkyl or 4-to 7-membered heterocycle having 0 to 3 substituents selected from-C1-3Alkyl and-0H, and-0HThe number of the (C) is not more than 1;
R3is- (L)m-C0N(RN)2、-(L)m-S02RS、-L-(CH2)nS02RS、-L-(CH2)nC02H、-L-(CH2)nP03H、-L-(CH2)nC(0)RC、-L-(CH2)nC0NHS02RS、-L-(CH2)nS02NHC0RSor-L- (CH)2)nTetrazol-5-yl; m is 0 or 1; n is 0 or 1; rNIs H or-C1-3An alkyl group; rSIs H or-C1-3Alkyl L is CH2CHF or CF2；RCis-C1-4Alkoxy, -C1-4alkoxy-carbonyloxy-C1-4Alkoxy or-C1-4alkylcarbonyloxy-C1-4An alkoxy group;
R4is H, F, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions;
R6is H, F, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions; and R is4、R6Not 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 isotopically labeled compound thereof, said
X is CR5；R5Is H, halogen, -CN, -C1-3Alkyl, -0C1-3Alkyl, C substituted by 1 to 3 halogen atoms1-3Alkyl, or-C3-4A cycloalkyl group;
y is N;
z is N;
R1allowed to be substituted by 0 to 5 halogen atoms for valence-C1-3An alkyl group;
R2is C3-7Cycloalkyl or a 4-to 7-membered heterocyclic ring, wherein said 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur, said C3-7Cycloalkyl or 4-to 7-membered heterocycle having 0 to 3 substituents selected from-C1-3Alkyl and a substituent of-0H, and the number of substituents of-0H is not more than 1;
R3is- (L)m-C0N(RN)2、-(L)m-S02RS、-L-(CH2)nS02RS、-L-(CH2)nC02H、-L-(CH2)nP(O)(0H)2、-L-(CH2)nC(0)RC、-L-(CH2)nC0NHS02RS、-L-(CH2)nS02NHC0RSor-L- (CH)2)nTetrazol-5-yl; m is 0 or 1; n is 0 or 1; rNIs H or-C1-3An alkyl group; rSIs H or-C1-3Alkyl L is CH2CHF or CF2；RCis-C1-4Alkoxy, -C1-4alkoxy-carbonyloxy-C1-4Alkoxy or-C1-4alkylcarbonyloxy-C1-4An alkoxy group;
R4is H, F, -C1-3Alkyl, wherein said-C1-3Alkyl contains 0 to 5F atom substitutions;
R6is H, F, -C1-3Alkyl, wherein said-C1-3Alkyl contains 0 to 5F atom substitutions;
the R is4、R6Not 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 isotopically-labeled compound thereof, said RSIs H or-CH3。
As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically-labeled compound thereof, said R3is-CH2C02H、-CH2P03H、-CH2CO2CH3or-CH2CO2CH2CH3。
As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically-labeled compound thereof, said R5Is H, -Cl, -CH3, -CH2CH3、-O-CH3Cyclopropyl or CN;
as a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically-labeled compound thereof, said R1is-CF3、-CHF2or-CF2CH3。
As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically-labeled compound thereof, said R2Is a 4-to 7-membered heterocyclic ring selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, said 4-to 7-membered heterocyclic ring of pyrrolidin-1-yl and piperidin-1-yl having 0 to 3 substituents selected from-C1-3Alkyl and a substituent of-0H, and the number of substituents of-0H does not exceed 1.
As a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically-labeled compound thereof, said R4、R6Each independently is H, F, or-C1-3Alkyl radical of formula (I), said1-3Alkyl contains 0 to 5F atoms substituted, and R4、R6Not hydrogen at the same time; and both Y and Z are N. As a more preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, said R2Is of 1 to 2-CH3And an azetidin-1-yl substituted with 0 to 1-0H substituents; and Y is C-CN and Z is N, or Y and Z are both N.
As a preferred embodiment of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically labeled compound thereof, wherein X, Y and Z are selected from any one of the following:
as a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically labeled compound thereof, said compound is selected from the following structural formulae:
as a preferred embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically labeled compound thereof, said compound is selected from the following structural formulae:
as preferred embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically-labeled compound thereof, 2- (1-methyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hexan-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] hexan-6-yl) acetic acid, ((1, 5-dimethyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hex-6-yl) methyl) phosphoric acid, ((1-methyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hex-6-yl) methyl) phosphoric acid, or a prodrug form thereof.
As a preferred embodiment of the compound of the present invention or the pharmaceutically acceptable salt thereof or the stereoisomer or isotope-labeled compound thereof, the structure of the compound is shown as a compound of formula I (a)
Wherein R is3Substituent and R4And R6In the same plane, wherein X, Y, Z, R1、R2、R3、R4、R6Are selected as described above, and R4、R6Not hydrogen at the same time.
In addition, the invention also provides a pharmaceutical composition which contains the compound or the pharmaceutically acceptable salt thereof or the stereoisomer or isotopically labeled compound thereof.
Finally, the present invention also provides the use of a compound as described above or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically labeled compound thereof in the manufacture of a medicament for the treatment of diseases including T1D, T2D, L ADA, EOD, YOAD, MODY, malnutrition-associated diabetes mellitus, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, acute nephropathy, tubular dysfunction, proinflammatory changes in proximal tubules, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, excessive carbohydrate craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia, increased total cholesterol, L D L cholesterol, low HD L cholesterol, hyperinsulinemia, metabolic-related fatty liver disease, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, coronary artery disease, vascular failure, hypertension, endothelial dysfunction, vascular thrombosis, peripheral vascular disease, ischemic stroke, stroke.
One way to accomplish this is to administer the compounds of formula I in the form of prodrugs. Thus, certain derivatives of a compound of formula I which may themselves have little or no pharmacological activity, when administered in vivo or on the body, are converted to a compound of formula I having the desired activity, for example by hydrolytic cleavage, particularly esterase or peptidase-promoted hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'.
The corresponding Prodrugs are obtained by those skilled in the art by modifying the appropriate functional groups present in the compounds of formula I (H.Bundgaard, Design of Prodrugs, Elsevier, 1985).
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. Unless otherwise specified, all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, are part of the present invention.
The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula I, wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and may therefore be preferred in certain circumstances.
The term "alkyl" as used herein means a group of the formula-CnH(2n+1)A straight or branched chain monovalent hydrocarbon group. Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1-dimethylethyl, pentyl, and hexyl.
The term "cycloalkyl" as used herein means a compound of formula-C containing at least three carbon atomsnH(2n-1)A cyclic monovalent hydrocarbon group of (1). Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "alkoxy" as used herein means an alkyl substituent attached through an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy.
The term "alkoxycarbonyloxy", as used herein, means an alkoxy group attached through a carbonyl (-C0-). Non-limiting examples include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl.
The term "alkylcarbonyloxy", as used herein, means an alkyl group attached through a carbonyloxy (-C (═ 0) -0-). Representative examples include methylcarbonyloxy, ethylcarbonyloxy and t-butylcarbonyloxy.
The term "alkoxycarbonyloxy-alkoxy" as used herein means an alkoxycarbonyloxy group linked through an alkoxy group. The term halogen as used herein refers to F, Cl, Br, I.
The term "heterocycle" as used herein refers to aliphatic and aromatic heterocycles having 4 to 7 carbon atoms in which the cyclomethylene (-CH) group of the aliphatic heterocycle is2-) has been replaced by a group selected from-0-, -S-or-N-, wherein the valence requirement for-N-is satisfied by H or by being a point of attachment, and a heteroaromatic ring refers to a 5-or 6-membered heterocyclic ring system containing 1 to 2 atoms selected from O, S, N atoms, which conforms to the Houckel rule (H ü ckel' S rule).
Aryl refers to a functional group or substituent derived from a simple aromatic ring (e.g., benzene, naphthalene, etc.) that does not contain heteroatoms.
General abbreviations used in this application: ADP is adenosine diphosphate; ATP is adenosine triphosphate; CDC13Is deuterated chloroform; c02Et is ethyl carboxylate; DCM is dichloromethane; DIPEA is N, N-diisopropylethylamine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; EtOAc is ethyl acetate; h or H or hr is hour; HEPES is 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid; KCl is potassium chloride; min is Min; MgCl2Is magnesium chloride; NaHCO 23Is a carbon dioxide tube; na (Na)2S04Is sodium sulfate; NADH is nicotinamide adenine dinucleotide (reduced form); NAD + is nicotinamide adenine dinucleotide (in oxidized form) PEP is phosphoenolpyruvate; RT or RT is room temperature; TCEP is tris (2-carboxyethyl) phosphoniumHydrogen is gasified; TFA is trifluoroacetic acid; THF is tetrahydrofuran.
The compound or its pharmaceutically acceptable salt or its stereoisomer or isotope labeled compound has good inhibitory effect on ketohexokinase, and can be used for preparing medicaments for treating T1D, T2D, L ADA, EOD, YOAD, MODY, diabetes related to malnutrition, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, acute nephropathy, tubular dysfunction, proinflammatory changes in proximal tubules, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, excessive carbohydrate craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia, total cholesterol increase, L D L cholesterol, HD L cholesterol lowering, hyperinsulinemia, metabolic-related fatty liver disease, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, HFI, coronary artery disease, vascular disease, hypertension, endothelial cell dysfunction, vascular endothelial failure, vascular endothelial dysfunction, vascular hypertension, ischemic stroke, atherosclerosis-induced cardiovascular disease, ischemic stroke, diabetic retinopathy, cardiovascular diseases, cardiovascular atherosclerosis, cardiovascular diseases, cardiovascular atherosclerosis, cardiovascular diseases after ischemic stroke, cardiovascular diseases, ischemic stroke, myocardial ischemia-induced cardiovascular diseases, chronic atherosclerosis, myocardial ischemia-induced hypertension, chronic atherosclerosis.
Drawings
FIG. 1 is a scheme showing the synthesis of the compound of example 1 of the present invention.
FIG. 2 is a scheme showing the synthesis of the compound described in example 2 of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present application will be further described with reference to specific examples.
Example 1
The structural formula of 2- (1-methyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hex-6-yl) acetic acid is shown below:
the synthesis scheme of the compound described in this example is shown in fig. 1, and the specific preparation method of the compound described in this example comprises:
step 1: 1-methylcyclopropane-1-carboxylic acid ethyl ester-2, 3-carboxylic acid methyl ester
Dimethyl fumarate (10g,69.38mmol) and benzyltriethylammonium chloride (0.16g,0.69mmol) were added to a solution of NaH (2.16g,90.2mmol) in DMF (100m L) at room temperature, ethyl 2-chloropropionate (10.42g,76.32mmol) was added dropwise slowly, and the reaction was stirred at 40 ℃ overnight.
The reaction solution was poured into ice water (30m L), extracted with methyl tert-butyl ether (30m L× 2), and the organic phases were combined, washed with saturated brine (80m L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil 14.80g, which was used in the next step without further purification.
Step 2: 1-methylcyclopropane-1, 2, 3-tricarboxylic acid
At room temperature, slowly dripping an aqueous solution (200M L) of sodium hydroxide (8.48g,40.5mmol) into a solution of (2R,3R) -1-methylcyclopropane-1-ethyl formate-2, 3-methyl formate (14.8g,60.6mmol) in EtOH (200M L) at room temperature, heating to reflux overnight, cooling the reaction solution to room temperature, concentrating under reduced pressure to remove most of the organic solvent, adjusting the pH of the aqueous phase to 2-3 with 2M hydrochloric acid, then concentrating under reduced pressure to remove part of water, adding toluene (50M L), continuing to concentrate under reduced pressure, repeating the above step for 2 times, adding acetone (30M L) to the residue, heating to reflux for 2 hours, filtering, washing the filter cake with acetone, concentrating under reduced pressure to obtain 10.0g of a pale yellow solid target compound, and directly using the product in the next step without further purification.
And step 3: 1-methyl-2, 4-dioxo-3-oxabicyclo [3.1.0] hexane-6-carboxylic acid
Acetic anhydride (6.62m L, 70.16mmol) was added to a solution of (2S,3S) -1-methylcyclopropane-1, 2, 3-tricarboxylic acid (10g,53.15mmol) in acetic acid (20m L) at room temperature, and the resulting mixture was heated to reflux for 2 hours, and after the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was added to toluene (20m L), and further concentrated under reduced pressure to remove the residual acetic acid, and the residue was directly put to the next step in 100% yield.
Step 4, 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylic acid is prepared by adding triethylamine (7.4M L, 53.15mmol) and benzylamine (6.9g,63.78mmol) to a solution of 1-methyl-2, 4-dioxo-3-oxabicyclo [3.1.0] hexane-6-carboxylic acid (9.1g, 53.15mmol) in acetone (40M L) at room temperature, stirring the resulting mixture at room temperature for 3 hours, concentrating under reduced pressure, adding sodium acetate (2.64g,32.26mmol) and acetic anhydride (24.4M L, 115mmol) to the residue, heating under reflux for 1 hour, cooling to room temperature, stirring overnight, concentrating under reduced pressure, adding water (50M L) to the residue, adjusting the pH to 2-3 with 2M dilute hydrochloric acid, extracting with dichloromethane (60M L×), combining the organic phases, drying, filtering under reduced pressure, concentrating, adding toluene (50M L), filtering to obtain a solid, filtering the filtrate at room temperature, and filtering the filtrate to obtain a gray solid (0.1.590.9%).
MS(ESI,neg.ion)m/z:258.0[M-H]-
And 5: 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester
Concentrated sulfuric acid (0.9m L) is slowly dropped into a solution of 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylic acid in ethanol (50m L) at room temperature, after dropping, the obtained mixture is heated under reflux for overnight reaction, after the reaction solution is cooled to room temperature, most of the ethanol is removed by concentration under reduced pressure, the residue is diluted with water (50m L), the pH is adjusted to 8-9 with saturated sodium bicarbonate, dichloromethane (50m L× 3) is extracted, the organic phases are combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained mixture is subjected to silica gel column chromatography (PE: EA is 10:1) to obtain a pale yellow oily target compound (5.0g, 50%).
1H NMR(600MHz,CDCl3)7.36–7.29(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＝3.0Hz,1H),1.57(s,3H),1.29(t,J＝7.2Hz,3H).
Step 6: 3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester
Under ice bath conditions, boron trifluoride diethyl etherate (21.02g, 69.61mmol) was slowly added dropwise to a tetrahydrofuran (50m L) solution of sodium borohydride (1.98g,52.21mmol), and after dropwise addition, a tetrahydrofuran (30m L) solution of 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (5.0g,17.4mmol) was slowly added dropwise, and after dropwise addition, the reaction mixture was stirred overnight at room temperature, followed by slowly adding ethanol (50m L) dropwise, after dropwise addition, the reaction mixture was naturally warmed to room temperature and stirred for 5 hours, heated under reflux for 3 hours (generation of a large amount of gas), cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, the system was diluted with water (100m L), extracted with dichloromethane (100m L× 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE EA: 10:1) to obtain a pale yellow solid (3.66 g, 3.66%).
LC-MS(ESI,pos.ion)m/z:260.1.0[M+H]+
And 7: 3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid
To a solution of ethyl 3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylate (3.01g,11.57mmol) in methanol (50M L) at room temperature was added an aqueous solution of sodium hydroxide (1.39g,34.7mmol) (50M L), the resulting mixture was heated to reflux overnight, after the reaction was cooled to room temperature, most of the organic solvent was removed under reduced pressure, diluted with water (50M L), the pH was adjusted to 5-6 by adding 1M diluted hydrochloric acid, water was removed under reduced pressure, the residue was subjected to column chromatography (DCM: MeOH ═ 10:1) to give the objective compound (2.30g, 86%)
And 8: 1- (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) -2-diazomethane-1-one
Under ice bath conditions, 3 drops of DMF were added to a solution of 3-phenyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (2.30g,9.94mmol) in dichloromethane (50m L), then oxalyl chloride (1.68m L, 19.89mmol) was slowly added dropwise, the reaction was stirred at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in THF (50m L) and acetonitrile (50m L), triethylamine (2.07m L, 14.9mmol) was added at 0 ℃, trimethylsilyl diazomethane (14.9m L, 29.79mmol) was slowly added dropwise, the reaction was stirred at 0 ℃ overnight, a saturated aqueous solution of sodium bicarbonate (80m L) was added to the reaction mixture and the mixture was quenched, ethyl acetate (50m L× 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE: EA 4: 1g, 80g of the objective compound (71%).
MS(ESI,pos.ion)m/z:256.2[M+H]+
And step 9: 2- (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) acetic acid methyl ester
To a solution of 1- (3-phenyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) -2-diazomethane-1-one (1.80g,7.05mmol) in MeOH (50m L) were added triethylamine (2.45m L, 17.62mmol) and silver benzoate (0.16g,0.7mmol), the reaction was stirred at room temperature overnight, the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1: 1) to give the title compound (0.75g, 41%) as a yellow liquid
Step 10, add Pd/C (80mg) to a solution of methyl 2- (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) acetate (0.75g,2.89mmol) in methanol (50m L) at room temperature, replace hydrogen for 3 times, fill 4MPa of hydrogen, stir at room temperature overnight, filter the reaction mixture through celite to remove the catalyst, and concentrate under reduced pressure to obtain the title compound as a pale yellow oil (0.19g, 38%).
Step 11 methyl 2- (3- (2-chloro-6- (trifluoromethyl) pyrimidin-4-yl) -1-methyl-3-azabicyclo [3.1.0] hexan-6-yl) acetate a solution of methyl 2- (1-methyl-3-azabicyclo [3.1.0] hexan-6-yl) acetate (0.75g,4.43mmol) in dichloromethane (30m L) was slowly added dropwise at-75 deg.c to a solution of methyl 2- (1-methyl-3-azabicyclo [3.1.0] hexan-6-yl) acetate (0.75g,4.43mmol) in dichloromethane (20m L), and after the addition, DIPEA (2.2m L, 13.3mmol) was added dropwise thereto, the temperature was raised to-65 deg.c, stirring was continued for 1 hour, then naturally raised to room temperature and stirred to the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: 4: 1), to give the title compound as a pale yellow solid (0.9 g).
LC-MS(ESI,pos.ion)m/z:350.1[M+H]+
1H NMR(400MHz,CDCl3)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) -3-azabicyclo [3.1.0] hexan-6-yl) acetic acid methyl ester
To a solution of methyl 2- (3- (2-chloro-6- (trifluoromethyl) pyrimidin-4-yl) -1-methyl-3-azabicyclo [3.1.0] hex-6-yl) acetate (0.9g,2.57mmol) in acetonitrile (20m L) at room temperature were added hydrochloride of (S) -2-methylazetidine (0.55g,5.15mmol) and DIPEA (1.28g,7.72mmol), the resulting mixture was heated to 80 ℃ and stirred overnight, the reaction solution was cooled and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (PE: EA ═ 5: 1) to give the objective compound (0.65g, 66%) as a colorless oil.
LC-MS(ESI,pos.ion)m/z:385.1[M+H]+
1H NMR(400MHz,CDCl3)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] hexan-6-yl) acetic acid
To a solution of methyl 2- (1-methyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hexan-6-yl) acetate (0.65g,1.69mmol) in THF (20m L) and water (20m L) was added sodium hydroxide (0.14g,3.38mmol) portionwise at room temperature, the resulting mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure to remove most of the tetrahydrofuran, water (20m L) was added for dilution, the aqueous phase was adjusted to pH 5 to 6 with dilute hydrochloric acid, ethyl acetate (30m L× 3) was extracted, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (PE: EA ═ 3: 1) to obtain the objective compound (80mg, 13%) as a white solid.
MS(ESI,pos.ion)m/z:371.3[M+H]+
1H NMR(400MHz,CDCl3)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-d4) Acetic acid
The structural formula is as follows:
the synthesis scheme of the compound described in this example is shown in fig. 2, and the specific preparation method of the compound described in this example comprises:
step 1: 3-benzyl-1-methyl-3-azabicyclo [3.1.0]Hexane-6-Carboxylic acid Ethyl ester-2, 2,4,4-d4
Boron trifluoride diethyl etherate (22.10g, 73.18mmol, 47%) was slowly added dropwise to a tetrahydrofuran (50m L) solution of sodium borodeuteride (2.3g,54.89mmol) at 0 deg.C, and 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] was slowly added dropwise thereto after completion of dropwise addition]After dropwise addition of a solution of hexane-6-carboxylic acid ethyl ester (5.0g,18.03mmol) in tetrahydrofuran (30m L), the reaction mixture was stirred at room temperature overnight, then cooled in an ice bath, ethanol (50m L) was slowly added dropwise, after dropwise addition, the mixture was naturally warmed to room temperature and stirred for reaction for 5 hours,heating reflux reaction for 3 hours, cooling the reaction solution to room temperature, concentrating under reduced pressure to remove most of the solvent, adding water (100M L) to dilute the system, extracting with dichloromethane (100M L× 3), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained residue by silica gel column chromatography (PE: EA ═ 10:1) to obtain a pale yellow solid target compound (4.13g, yield: 87%). 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-d4
At room temperature, in 3-benzyl-1-methyl-3-azabicyclo [ 3.1.0%]Hexane-6-Carboxylic acid Ethyl ester-2, 2,4,4-d4(4.13g,16.04mmol) in methanol (50M L) was added an aqueous solution of sodium hydroxide (48.13mmol,50M L), the reaction was heated to reflux overnight, most of the organic solvent was removed under reduced pressure after the reaction was cooled to room temperature, water was added to dilute the reaction mixture (50M L), 1M diluted hydrochloric acid was added to adjust the pH to 5-6, water was removed by concentration under reduced pressure, and the resulting residue was subjected to column chromatography (DCM: MeOH. RTM. 10:1) to give the title compound as a white solid (3.19g, yield: 84%).
And step 3: 3-benzyl-1-methyl-3-azabicyclo [3.1.0]Hexane-6-formyl chloride-2, 2,4,4-d4
At 0 ℃ in 3-benzyl-1-methyl-3-azabicyclo [3.1.0 ℃]Hexane-6-carboxylic acid-2, 2,4,4-d4To a solution of (3.9g,13.56mmol) in anhydrous dichloromethane (50m L) was added 3 drops of DMF, then oxalyl chloride (2.29m L, 27.11mmol) was slowly added dropwise, after completion of the addition, the reaction was stirred at room temperature for 3 hours, and the reaction mixture was concentrated under reduced pressure to give 3.50g of the objective compound as a pale yellow solid, which was used in the next step without further purification (yield was 100%).
And 4, step 4: 1- (3-benzyl-1-methyl-3-azabicyclo [ 3.1.0)]Hexane-6-yl-2, 2,4,4-d4) -2-Dimethin-1-one
At 0 ℃ under the protection of nitrogen, in 3-benzyl-1-methyl-3-azabicyclo [3.1.0 ℃]Hexane-6-formyl chloride-2, 2,4,4-d4Triethylamine (2.83m L, 20.33mmol) was added to a solution of (3.50g,13.56mmol) in THF (30m L) and acetonitrile (30m L), followed by dropwise addition of trimethylsilyldiazomethane (20.33m L, 40.67mmol) slowly, stirring was continued at 0 ℃ overnight, the reaction mixture was concentrated under reduced pressure to remove most of the reaction solutionAdding saturated sodium bicarbonate water solution (50m L) into the organic solvent system, quenching, extracting with ethyl acetate (50m L× 3), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing silica gel column chromatography (PE: EA ═ 4: 1) to obtain light yellow solid target compound (2.11g, 60%)
MS(ESI,pos.ion)m/z:260.3[M+H]+
And 5: 2- (3-benzyl-1-methyl-3-azabicyclo [ 3.1.0)]Hexane-6-yl-2, 2,4,4-d4) Acetic acid methyl ester
In the presence of 1- (3-benzyl-1-methyl-3-azabicyclo [3.1.0]]Hexane-6-yl-2, 2,4,4-d4) To a solution of (e) -2-dimethylin-1-one (2.11g,8.14mmol) in methanol (50m L) were added triethylamine (2.83m L, 20.38mmol) and silver benzoate (0.93g,4.08mmol), and the mixture was 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 give the title compound (2.10g, 98%) as a yellow liquid.
Step 6: 2- (1-methyl-3-azabicyclo [ 3.1.0)]Hexane-6-yl-2, 2,4,4-d4) Acetic acid methyl ester
At room temperature, in 2- (3-benzyl-1-methyl-3-azabicyclo [3.1.0]]Hexane-6-yl-2, 2,4,4-d4) To a solution of methyl acetate (2.10g,7.97mmol) in methanol (50m L), Pd/C (200mg) was added to replace hydrogen for 3 times, then hydrogen at 4MPa was charged, the mixture was heated to 50 ℃ and stirred to react overnight, after naturally cooling to room temperature, the catalyst was removed by filtration and concentrated under reduced pressure to give 0.75g of the objective compound as a pale yellow solid, which was used in the next step without further purification.
And 7: 2- (3- (2-chloro-6- (trifluoromethyl) pyrimidin-4-yl) -1-methyl-3-azabicyclo [3.1.0]Hexane-6-yl-2, 2,4,4-d4) Acetic acid methyl ester
At-75 deg.C in 2- (1-methyl-3-azabicyclo [3.1.0]]Hexane-6-yl-2, 2,4,4-d4) Slowly dripping a dichloromethane (30m L) solution of 2, 4-dichloro-6- (trifluoromethyl) pyrimidine (1.44g,6.65mmol) into a dichloromethane (0.55g,3.14mmol) solution of methyl acetate (0.55g,3.14mmol), continuously dripping DIPEA (1.56m L, 9.42mmol) at the temperature after dripping, then raising the temperature to-65 ℃, continuously stirring for 1 hour, naturally raising the temperature to room temperature, stirring for reaction overnight, and reducing the temperatureThe solvent was removed by pressure concentration, and the resulting residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4: 1) to give the title compound (0.38g, 34%) as a pale yellow solid.
MS(ESI,pos.ion)m/z:354.1[M+H]+
And 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-d4) Acetic acid methyl ester
To 2- (3- (2-chloro-6- (trifluoromethyl) pyrimidin-4-yl) -1-methyl-3-azabicyclo [3.1.0] at room temperature]Hexane-6-yl-2, 2,4,4-d4) Methyl acetate (0.38g,1.07mmol) in acetonitrile (20M L) was added (S) -2-methylazetidine hydrochloride (0.23g,2.12mmol) and DIPEA (0.52g,3.18mmol), the resulting mixture was heated to 80 ℃ and stirred overnight, the reaction was concentrated under reduced pressure after the reaction solution was cooled to room temperature, and the resulting residue was purified by column chromatography (PE: EA: 5: 1) to give the objective compound (0.31g, yield: 75%) L C-MS (ESI, pos.ion) M/z:389.2[ M + H.]+
And 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-d4) Acetic acid
At room temperature 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-d4) To a solution of methyl acetate (0.31g,0.80mmol) in THF (20m L) and water (20m L) was added sodium hydroxide (0.064g,1.6mmol), the reaction was stirred at room temperature until completion, the reaction was concentrated under reduced pressure to remove most of tetrahydrofuran, the residual aqueous phase was adjusted to pH 5 to 6 with dilute hydrochloric acid, ethyl acetate (30m L× 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE: EA ═ 3: 1) to obtain the title compound (90mg, 30%) as a white solid.
MS(ESI,pos.ion)m/z:375.2[M+H]+
1H NMR(400MHz,CDCl3)5.93(s,1H),4.51–4.37(m,1H),4.04(td,J＝8.8,5.0Hz,1H),3.96(dd,J＝16.1,8.7Hz,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 enzymatic Activity experiments
Ketohexokinase has two isoforms, KHKc and KHKa, wherein KHKc is more than ten times as capable of phosphorylating fructose as compared to KHKa.
According to the metabolic pathway of fructose, the enzyme function of KHK is to consume ATP to convert fructose into fructose-1-phosphate, while producing ADP. The consumption of NADH and the end product NAD can be detected by ATP depletion, ADP color, or by subsequent reaction+The inhibition of the reaction can be effectively measured.
And continuously measuring the absorbance at 340nm to monitor the content of NADH, and preliminarily judging the inhibition condition of the candidate compound on KHK according to the consumption of NADH. The method relates to a coupling enzyme system, and the 3 steps of reactions are as follows:
the KHKc inhibitor preliminary screening involves 3 steps of reaction (KHKc hexulophosphokinase; PK pyruvate kinase; L DH lactate dehydrogenase)
To screen candidate compounds for their inhibitory efficiency against KHKc enzyme, absorbance monitoring was performed in a continuous mode at 340nm wavelength in 96 well Corning3599 cell culture plates using a microplate reader under incubation conditions at 37 deg.C.Compound was prepared in the solvent DMSO as a stock solution of 10mM stock solution, followed by gradient dilution with 50mM PIPES buffer using a triple dilution scheme.A reaction system of 200. mu. L contained 50mM PIPES buffer, 6mM MgCl2100mM KCl, 5mM fructose, 2mM phosphoenolpyruvate (PEP), 5mM ATP, 0.6mM reduced coenzyme I (NADH), 40U/m L pyruvate kinase-lactate dehydrogenase and 10mM recombinant KHKC. the compound to be screened was mixed well with all reagents except for the trigger ATP in the reaction system, incubated at 37 ℃ for 15min, after which 50mM ATP was added to the reaction system to start the trigger reaction, incubated at 37 ℃ with a microplate reader for 2 hours for kinetic monitoring, measured every 5min at 340nm wavelength,the inhibition was calculated as the difference in measured absorbance (△ OD values) and then IC50 values for KHK were calculated for the test substances using Graphpad software the reagent concentrations provided were based on a final mix volume of 200. mu. L, i.e., the final concentration.
Comparison: n8- (cyclopropylmethyl) -N4- (2- (methylthio) phenyl) -2- (piperazin-1-yl) pyrimido [5,4-d ] pyrimidine-4, 8-diamine (CAS: 1303469-70-6) at a final concentration of 2 μ M served as a high percent inhibition control (HPE) and the drug-free group (buffer instead) served as a zero percent effect control (FOC).
Measuring absorbance at the wavelength of 340nm by the enzyme-labeling instrument within 1min and at 0.5h, 1h and 2h after ATP is added, calculating the inhibition rate by measuring the absorbance difference (△ OD value), and calculating the inhibition rate of the test substance on KHK according to the following formula:
percent inhibition [ [ (FOC)△ OD valueAdministration group△ OD value)/(FOC△ OD value-HPE△ OD value)]×100％。
Logarithmic transformation was performed using GraphPad Prism software according to the inhibition rate corresponding to each drug concentration, and the data was fitted to "selection criteria-nonlinear regression-variable slope (parameter set)" using nonlinear regression analysis to obtain IC50The value is obtained. For the different compounds determined, the IC obtained50Is an average based on at least two independent experiments performed at different times.
With different monitoring points of 0.5h, 1h and 2h in the reaction process as test A, test B and test C respectively, the reaction rate and IC were calculated as described above50The value is obtained.
The biological data of the compound described in example 1 of the present invention and the compound numbered PF-06835919, respectively, were tested as described above, wherein the structural formula of the compound numbered PF-06835919 is as follows:
the test results are shown in table 1.
TABLE 1 biological data for test A, B, C
From the test results, it is clear that the compound of example 1 has a good inhibitory effect on ketohexokinase.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A compound or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof, said compound having a structural formula shown in formula i below:
wherein X is N or CR5；R5Is H, halogen, -CN, -C1-3Alkyl, -0C1-3Alkyl, C substituted by 1 to 3 halogen atoms1-3Alkyl, or-C3-4Cycloalkyl radicals
Y is N or C-CN or CF;
z is N or CH;
and at least one of X, Y, Z is N;
R1is cyclopropyl, cyclobutyl, cyano, or-C which may be substituted in valence number by 0 to 5 halogen atoms1-3An alkyl group;
R2is C3-7Cycloalkyl, 4-to 7-membered heterocycle, N (C)1-3Alkyl radical)2、NH(C1-3Alkyl) or NH (C)3-4Cycloalkyl groups); wherein the 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur; said C is3-7Cycloalkyl or 4-to 7-membered heterocycle having 0 to 3 substituents selected from-C1-3Alkyl and a substituent of-0H, and the number of substituents of-0H is not more than 1; the N (C)1-3Alkyl radical)2、NH(C1-3Alkyl), NH (C)3-4Cycloalkyl) each C1-3Alkyl is substituted with 0 to 1H;
R3is- (L)m-C0N(RN)2、-(L)m-S02RS、-L-(CH2)nS02RS、-L-(CH2)nC02H、-L-(CH2)nP03H、-L-(CH2)nC(0)RC、-L-(CH2)nC0NHS02RS、-L-(CH2)nS02NHC0RS、-L-(CH2)nSO2NHCONH2or-L- (CH)2)nTetrazol-5-yl; m is 0 or 1; n is 0 or 1; rNIs H or-C1-3An alkyl group; rSIs H or-C1-3Alkyl L is CH2CHF or CF2；RCis-C1-4Alkoxy, -C1-4alkoxy-carbonyloxy-C1-4Alkoxy or-C1-4alkylcarbonyloxy-C1-4An alkoxy group;
R4is hydrogen, halogen, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl or a 4-to 7-membered heterocycle, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions; the 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur;
R6is hydrogen, halogen, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl or a 4-to 7-membered heterocycle, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions; the 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur;
the R is4、R6Not hydrogen at the same time.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof, wherein the compound is a pharmaceutically acceptable salt thereof
X is N or CR5；R5Is H, halogen, -CN, -C1-3Alkyl, -0C1-3Alkyl, C substituted by 1 to 3 halogen atoms1-3Alkyl, or-C3-4Cycloalkyl radicals
Y is N, C-CN;
z is N or CH;
and at least one of X, Y, Z is N;
R1allowed to be substituted by 0 to 5 halogen atoms for valence-C1-3An alkyl group;
R2is C3-7Cycloalkyl 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, sulfur, C3-7Cycloalkyl or a 4-to 7-membered heterocycle having a ring selected from-C1-3Alkyl and 0 to 3 substituents of-0H, and no more than one-OH substituent is present;
R3is- (L)m-C0N(RN)2、-(L)m-S02RS、-L-(CH2)nS02RS、-L-(CH2)nC02H、-L-(CH2)nP03H、-L-(CH2)nC(0)RC、-L-(CH2)nC0NHS02RS、-L-(CH2)nS02NHC0RSor-L- (CH)2)nTetrazol-5-yl; m is 0 or 1; n is 0 or 1; rNIs H or-C1-3An alkyl group; rSIs H or-C1-3Alkyl L is CH2CHF or CF2；RCis-C1-4Alkoxy, -C1-4alkoxy-carbonyloxy-C1-4Alkoxy or-C1-4alkylcarbonyloxy-C1-4An alkoxy group;
R4is H, F, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions;
R6is H, F, -C1-3Alkyl radical, C3-7Cycloalkyl, aryl, wherein said-C1-3Alkyl, aryl and C3-7Cycloalkyl contains 0 to 5 fluorine atom substitutions;
and R is4、R6Not hydrogen at the same time.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof, wherein the compound is a pharmaceutically acceptable salt thereof
X is CR5；R5Is H, halogen, -CN, -C1-3Alkyl, -0C1-3Alkyl, C substituted by 1 to 3 halogen atoms1-3Alkyl, or-C3-4A cycloalkyl group;
y is N;
z is N;
R1allowed to be substituted by 0 to 5 halogen atoms for valence-C1-3An alkyl group;
R2is C3-7Cycloalkyl or a 4-to 7-membered heterocyclic ring, wherein said 4-to 7-membered heterocyclic ring contains 1 to 2 atoms selected from nitrogen, oxygen, sulfur, said C3-7Cycloalkyl or a 4-to 7-membered heterocycle having a ring selected from-C1-3Alkyl and 0 to 3 substituents of-0H, and no more than one-OH substituent is present;
R3is- (L)m-C0N(RN)2、-(L)m-S02RS、-L-(CH2)nS02RS、-L-(CH2)nC02H、-L-(CH2)nP(O)(0H)2、-L-(CH2)nC(0)RC、-L-(CH2)nC0NHS02RS、-L-(CH2)nS02NHC0RSor-L- (CH)2)nTetrazol-5-yl; m is 0 or 1; n is 0 or 1; rNIs H or-C1-3An alkyl group; rSIs H or-C1-3Alkyl L is CH2CHF or CF2；RCis-C1-4Alkoxy, -C1-4alkoxy-carbonyloxy-C1-4Alkoxy or-C1-4alkylcarbonyloxy-C1-4An alkoxy group;
R4is H, F, -C1-3Alkyl, wherein said-C1-3Alkyl contains 0 to 5F atom substitutions;
R6is H, F, -C1-3Alkyl, wherein said-C1-3Alkyl contains 0 to 5F atom substitutions;
the R is4、R6Not hydrogen at the same time.
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer or isotopically-labeled compound thereof, wherein R isSIs H or-CH3；
Preferably, said R is3is-CH2C02H、-CH2P03H、-CH2CO2CH3or-CH2CO2CH2CH3；
Preferably, said R is5Is H, -Cl, -CH3, -CH2CH3、-O-CH3Cyclopropyl or CN;
preferably, said R is1is-CF3、-CHF2or-CF2CH3；
Preferably, said R is2Is a 4-to 7-membered heterocyclic ring selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, said 4-to 7-membered heterocyclic ring of pyrrolidin-1-yl and piperidin-1-yl having 0 to 3 substituents selected from-C1-3Alkyl and a substituent of-0H, and the number of substituents of-0H is not more than 1;
preferably, said R is4、R6Each independently is H, F, or-C1-3Alkyl radical of formula (I), said1-3Alkyl contains 0 to 5F atoms substituted, and R4、R6Not hydrogen at the same time; and both Y and Z are N.
5. The compound of claim 4, or a pharmaceutically acceptable salt or stereoisomer or isotopically-labeled compound thereof, wherein R is2Is of 1 to 2-CH3Substituted and having 0 to 1-0H substituentSubstituted azetidin-1-yl; and Y is C-CN and Z is N, or Y and Z are both N.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof, wherein the compound is selected from the following structural formulae:
7. the compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof, wherein the compound is selected from the following structural formulae:
8. the compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer or isotopically-labeled compound thereof, wherein the compound is 2- (1-methyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hex-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] hex-6-yl) acetic acid, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof, ((1, 5-dimethyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hex-6-yl) methyl) phosphoric acid ((1-methyl-3- (2- ((S) -2-methylazetidin-1-yl) -6- (trifluoromethyl) pyrimidin-4-yl) -3-azabicyclo [3.1.0] hex-6-yl) methyl) phosphoric acid or a prodrug form thereof.
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer or isotopically-labeled compound thereof.
10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a stereoisomer or isotopically labeled compound thereof for the manufacture of a medicament for the treatment of a disease selected from the group consisting of T1D, T2D, L ADA, EOD, YOAD, MODY, malnutrition-associated diabetes mellitus, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, acute nephropathy, tubular dysfunction, proximal tubular alterations, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, excessive carbohydrate craving, dyslipidemia, hyperlipidemia, hypertriglyceridemia, increased total cholesterol, L D L cholesterol, HD L cholesterol, hyperinsulinemia, metabolic-related fatty liver disease, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, HFI, coronary artery disease, vascular disease, hypertension, endothelial dysfunction, peripheral vascular endothelial dysfunction, peripheral arterial thrombosis, ischemic stroke, ischemic stroke, diabetic retinopathy, atherosclerosis, ischemic stroke, ischemic stroke, diabetic retinopathy, peripheral arterial restenosis, ischemic stroke, diabetic retinopathy, ischemic stroke, diabetic retinopathy, peripheral arterial restenosis, ischemic stroke, diabetic retinopathy, ischemic stroke, diabetic retinopathy.
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| PCT/CN2020/090463 WO2021217734A1 (en) | 2020-04-30 | 2020-05-15 | Fused ring compound used as ketohexokinase inhibitor |
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| CN113149968A (en) * | 2020-04-30 | 2021-07-23 | 广州博济医药生物技术股份有限公司 | Compound serving as ketohexokinase inhibitor and application thereof |
| CN114181198A (en) * | 2020-09-15 | 2022-03-15 | 山东轩竹医药科技有限公司 | Pyrimidine derivative ketohexokinase inhibitor and application thereof |
| WO2022135390A1 (en) * | 2020-12-25 | 2022-06-30 | 四川海思科制药有限公司 | Ketohexokinase inhibitor and use thereof |
| WO2022212194A1 (en) | 2021-03-29 | 2022-10-06 | Gilead Sciences, Inc. | Khk inhibitors |
| WO2022262841A1 (en) * | 2021-06-17 | 2022-12-22 | 杭州中美华东制药有限公司 | Salt form and crystal form of spiro compound and preparation method therefor |
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| CN114315494B (en) * | 2021-12-29 | 2023-09-22 | 苏州楚凯药业有限公司 | Preparation method of (S) -2-methylazetidine hydrochloride |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113149968A (en) * | 2020-04-30 | 2021-07-23 | 广州博济医药生物技术股份有限公司 | Compound serving as ketohexokinase inhibitor and application thereof |
| CN113149968B (en) * | 2020-04-30 | 2024-06-04 | 博济医药科技股份有限公司 | Compound serving as ketohexokinase inhibitor and application thereof |
| CN114181198A (en) * | 2020-09-15 | 2022-03-15 | 山东轩竹医药科技有限公司 | Pyrimidine derivative ketohexokinase inhibitor and application thereof |
| WO2022135390A1 (en) * | 2020-12-25 | 2022-06-30 | 四川海思科制药有限公司 | Ketohexokinase inhibitor and use thereof |
| WO2022212194A1 (en) | 2021-03-29 | 2022-10-06 | Gilead Sciences, Inc. | Khk inhibitors |
| WO2022262841A1 (en) * | 2021-06-17 | 2022-12-22 | 杭州中美华东制药有限公司 | Salt form and crystal form of spiro compound and preparation method therefor |
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| WO2021217734A1 (en) | 2021-11-04 |
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