CN114671876A - Novel theophylline compound, isomer or salt, and preparation method and application thereof - Google Patents

Novel theophylline compound, isomer or salt, and preparation method and application thereof Download PDF

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CN114671876A
CN114671876A CN202210448131.0A CN202210448131A CN114671876A CN 114671876 A CN114671876 A CN 114671876A CN 202210448131 A CN202210448131 A CN 202210448131A CN 114671876 A CN114671876 A CN 114671876A
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CN114671876B (en
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曾燕群
周广林
朱绪成
付海霞
牟霞
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Chengdu Shibeikang Biological Medicine Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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Abstract

The invention discloses a compound shown in formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide compound, a hydrate, a solvent compound, a metabolite or a pharmaceutically acceptable salt of the compound shown in formula (I)A salt is accepted. The invention also provides application of the compound, the stereoisomer or the pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing diseases related to the TRPA1 receptor, in particular application in preparing medicaments for treating and/or preventing cough, asthma, pain and sleep apnea.

Description

Novel theophylline compound, isomer or salt, and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to application of a novel theophylline compound or a salt and an isomer thereof, a preparation method thereof and a pharmaceutical composition thereof in preparing medicines for treating and/or preventing diseases related to TRPA1 receptors, especially application in treating and/or preventing respiratory diseases and nervous system diseases.
Background
The Transient Receptor Potential (TRP) channel is a non-selective cation channel. TRP ion channels in mammals can be divided into 7 subfamilies based on TRP sequence homology, namely TRPC (7 members), TRPM (8 members), TRPV (6 members), TRPA (ANKTM 1, the only member), TRPML (3 members), TRPP (5 members) and TRPN. The TRP family is involved in a variety of cellular functions, including sensory perception and signal transduction. Among them, the TRPA1 receptor is associated with temperature, pain sensation, hyperalgesia and neurogenic inflammation.
TRPA1 is widely found in trigeminal nerve, dorsal root, nodose, and is expressed on primary sensory neurons of a δ and C fibers. Expression is also found in non-neuronal cells, such as inner ear hair cells, enterochromaffin cells, vascular endothelial cells, dental pulp fibroblasts, keratinocytes, islet cells, and the like. The channel can be activated by nociceptive cold stimulation at a temperature lower than 17 ℃, a series of chemical substance stimulation and inflammatory mediators, generates transmembrane voltage change mainly based on calcium ion influx, participates in cold sensation formation of noxious cold stimulation, and has the functions of regulating inflammatory response, apoptosis and necrosis and mediating pain. Recent studies have shown that receptors for TRPA1 are also "switches" for cough. Thus, activation of TRPA1 receptor has been associated with various diseases, such as pain, neuralgia, asthma, airway inflammation, bronchoconstriction and cough, showing significant therapeutic effects.
Among them, cough is one of the most common symptoms in clinical practice. There is currently no approved drug for the treatment of chronic cough. Common antitussive agents include codeine, dextromethorphan and the like, but central antitussives often have side effects such as constipation and somnolence. Pain is one of the most common pains in human beings and one of the most common symptoms in clinic and most unbearable for patients. The incidence rate of the world pain is about 35-45%, and the incidence rate of the old people is higher, about 75% -90%. The therapeutic drugs mainly have two types, namely COX inhibitors (weak in analgesic effect and relatively high in safety), opioid receptor agonists (strong in analgesic effect, constipation, addiction and respiratory depression), and have advantages and disadvantages, and clinical requirements cannot be met. In addition, painful diabetic neuropathy occurs in about 16% of diabetic patients. The drugs used to treat painful DPN include tricyclic antidepressants, selective 5-hydroxytryptamine and norepinephrine reuptake inhibitors, opioids, and antiepileptics. And available treatment regimens are not completely effective in all patients, with more than 50% pain relief being achieved in only about one third of patients. Therefore, TRPA1 antagonists are potential therapeutic agents for a variety of diseases and there is a great unmet clinical need in the areas of pain, asthma, cough, and the like.
TRPA1 antagonists currently only two varieties are clinically under investigation, clinical stage 2 ISC-17536 (diabetic peripheral neuropathy, pain, respiratory disease) and clinical stage 1 LY-3526318 (pain). The IC50 value of ISC-17536 was about 70 nM when it inhibited calcium current through TRPA 1. In the clinical study of intractable cough carried out in Europe, the terminal point is not reached finally, and the failure is ended, so that the antagonism IC50 of LY-3526318 on TRPA1 is 5-6 uM, and the activity is weak. Therefore, antagonists with high TRPA1 activity are more clinically needed, and provide patients with higher activity and safer drug selection opportunities, and development of TRPA1 antagonists has great market value and academic value.
Disclosure of Invention
The compound is a novel theophylline compound, and most of the compounds in the embodiment show good cough relieving effect and in-vitro affinity of TRPA1 in animals. In a mouse cough-relieving experiment, when 60mg/kg of the compound is orally administered, the compound has a very strong cough-relieving effect, and has statistical significance compared with a model group.
In one aspect, the present invention provides a compound of formula (i), a stereoisomer, or a pharmaceutically acceptable salt thereof:
Figure 100002_DEST_PATH_IMAGE001
wherein,
the ring A is selected from a substituted or unsubstituted 5-membered heterocyclic ring, a substituted or unsubstituted 7-to 12-membered aromatic heterocyclic ring, or a substituted or unsubstituted benzene; preferably, ring a is selected from a substituted or unsubstituted 5-membered aromatic heterocyclic ring, or a substituted or unsubstituted benzene;
R1selected from the group consisting of hydrogen, deuterium, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, substituted or unsubstituted cyclic amino, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heterocycloalkyl, - (CH- (CH)2)fNR2R3、—O-(CH2)fN R2R3、—C(=O)fNR2R3Or a carboxyl group, wherein:
f is an integer from 1 to 4;
each R2Independently selected from hydrogen or lower alkyl;
each R3Independently selected from hydrogen, lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.
Further, the compound, stereoisomer or pharmaceutically acceptable salt shown in the formula (I) has the following structural definition:
ring a is selected from substituted or unsubstituted benzene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyrrole, substituted or unsubstituted 1,2, 3-triazole, or substituted or unsubstituted 1,2, 4-triazole; preferably, ring a is selected from substituted or unsubstituted benzene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiadiazole, or substituted or unsubstituted oxadiazole;
R1selected from the group consisting of hydrogen, deuterium, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted 3-to 10-membered cyclic amino, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heterocycloalkyl.
Further, the above R1Selected from hydrogen, deuterium, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, or freely selected from the following rings:
Figure 100002_DEST_PATH_IMAGE002
wherein:
x is selected from: o, NH or CHR7；
Each R4、R5、R6、R7Independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted lower alkylamino, substituted or unsubstituted alkylamido, substituted or unsubstituted ester group, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, or carboxy;
additionally or alternatively, two R's attached to the same ring carbon4Or two R5Or two R6The substituents may together form an oxo group (i.e.: O) or a C3-C7 spiro ring group; and additionallyOr alternatively, two R's attached to different ring carbons4Or two R5Or two R6The substituents may together form a ring, wherein two R' s6When taken together, form a ring having 4 to 7 ring atoms, including 0 to 3 ring heteroatoms;
n is an integer from 0 to 4;
a is selected from an integer of 0 to 3;
b. c is independently an integer selected from 0 to 2;
m and p are independently selected from integers of 1 to 3;
q and r are independently selected from integers of 0 to 3.
Further, the above R1Selected from hydrogen, halogen, methyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, C1-C6 alkyl, or selected from the group consisting of 1 to 2R8Substituted of the following rings:
Figure 100002_DEST_PATH_IMAGE003
wherein each R is8Independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted ester, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, or carboxy.
Further, the above R8Selected from the group consisting of: hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy; preferably, R is as defined above8Selected from the group consisting of: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy.
Further, the substituents of the above ring a include, but are not limited to: hydrogen, halogen, hydroxy, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamido, substituted or unsubstituted ester group, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, or carboxy.
Further, the substituents of the above ring a are selected from: hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy.
Further, the compounds represented by the above formula (i), stereoisomers or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:
Figure 100002_DEST_PATH_IMAGE004
Figure DEST_PATH_IMAGE005
Figure 100002_DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE007
Figure 100002_DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE009
Figure DEST_PATH_IMAGE010
Figure DEST_PATH_IMAGE011
Figure DEST_PATH_IMAGE012
Figure DEST_PATH_IMAGE013
Figure DEST_PATH_IMAGE014
。
further, the compounds of the present invention also include geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites or prodrugs of the above compounds.
Further, the hydrogen in the above compounds, stereoisomers thereof, pharmaceutically acceptable salts, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites or prodrugs thereof may be substituted with one or more deuterium.
Further, the invention provides a pharmaceutical composition of the compound, the stereoisomer and the pharmaceutically acceptable salt thereof, which is characterized by further comprising pharmaceutically acceptable auxiliary materials.
In another aspect, the present invention also provides the use of the above compounds, stereoisomers thereof, and pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and/or prevention of diseases associated with the TRPA1 receptor.
Further, the above-mentioned diseases related to TRPA1 receptor are selected from respiratory diseases or nervous system diseases; respiratory diseases are preferred.
Further, the above-mentioned diseases related to TRPA1 receptor are selected from cough, asthma, pain or sleep apnea; cough is preferred.
Interpretation of terms:
the above "alkyl" includes straight-chain and branched-chain alkyl groups.
The above "lower alkyl" is: C1-C16 straight chain or branched chain alkyl.
The definition of the alkyl moiety in the above-mentioned "lower alkoxy", "lower alkylamino", "lower alkylthio", "lower alkanoylamino" is the same as that of the above-mentioned "lower alkyl".
The above-mentioned "C1-C6 alkyl group": refers to a straight or branched alkyl group having 1 to 6 carbon atoms, illustratively such as: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl.
The alkyl moiety of the "C1-C6 alkoxy group" and the "C1-C6 alkylamino group" is the same as the "C1-C6 alkyl group".
The "perfluoro" group in the above-mentioned "C1-C3 perfluoroalkyl group" means that all the hydrogens on the carbon atoms of the alkyl group are replaced with fluorine. Such as trifluoromethyl, -CF2CF3、—CFCF3CF3、—CF2CF2CF3。
The "perfluoro group" in the above-mentioned "C1-C3 perfluoroalkoxy group" is as defined above.
The "substituent" in the above "substituted or unsubstituted" is selected from the group consisting of: hydrogen, halogen, hydroxy, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamido, substituted or unsubstituted ester group, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, or carboxy; preferably, the "substituents" are selected from: hydrogen, halogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl.
The above-mentioned "C1 to C16" indicates that the carbon number is 1 to 16. Other similar writing methods are similarly explained.
The "3-to 10-membered cyclic amino group" is: a nitrogen-containing heterocyclic ring having 3 to 10 ring atoms; the heterocyclic ring includes, but is not limited to, a monocyclic ring, a bridged ring, the number of heteroatoms is at least 1, the heteroatoms are all N, or comprise N and S and/or O. As part of the R1 substituent, the moiety is preferably a 5-to 8-membered cyclic amino group; more preferably 5 to 6-membered cyclic amino; most preferably a 5-membered cyclic amino group.
The above "halogen" is: fluorine, chlorine, bromine.
The above "pharmaceutically acceptable salts" include, but are not limited to, organic acid salts or inorganic acid salts; such acids include, but are not limited to, hydrochloric acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, 1, 5-naphthalenedisulfonic acid, trifluoroacetic acid, acetic acid, malic acid, tartaric acid, hydrobromic acid, and the like.
The above "solvate" includes, but is not limited to, organic solvents or inorganic solvents, including, but not limited to, methanol, ethanol, acetone, heptane, and the like.
The "hydrates" mentioned above include, but are not limited to, monohydrate, dihydrate, trihydrate and the like.
The above "nitroxide" includes, but is not limited to, any or at least one nitrogen atom on the parent nucleus that is oxidized to form a N → O bond.
The above "pharmaceutically acceptable excipients" include, but are not limited to, pharmaceutically acceptable additives including, but not limited to, fillers, disintegrants, lubricants, solubilizers, binders, diluents, glidants, and the like.
The above "pharmaceutical composition" includes but is not limited to active ingredients and pharmaceutically acceptable excipients, and is formulated into certain dosage forms by conventional preparation methods in the art, such as tablets, capsules, injections, microparticles, aerosols, ointments, and the like. Routes of administration include, but are not limited to, oral, intravenous, and the like.
Has the advantages that: compared with the prior art, the invention has better cough relieving effect and higher safety.
Detailed Description
The present invention will be described in further detail with reference to examples and experimental examples, which are provided for illustration of the technical solution of the present invention and are not intended to limit the present invention, and any equivalent replacement in the field made in accordance with the disclosure of the present invention is within the scope of the present invention.
The compounds of the present invention, stereoisomers or pharmaceutically acceptable salts thereof can be prepared by selecting the synthetic routes of the examples, and the conventional conditions of the reaction raw materials and the reaction solvent are adjusted according to the requirements of substituents or salt formation, which can be realized by those skilled in the art based on the present disclosure. In addition, the column chromatography of the present invention refers to silica gel column chromatography without specific description, and the elution solvent without specific description may be combined with a reaction solvent and common knowledge or common means of those skilled in the art to determine a single or mixed elution solvent.
The structure of the compound is nuclear magnetic resonance (1H NMR) or liquid mass spectrometry (LC-MS).
The liquid mass spectrometer (LC-MS) is Agilent G6120B (used with liquid Agilent 1260); nuclear magnetic resonance apparatus (1H NMR is Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance: (1H NMR) shifts (δ) Given in parts per million (ppm), the assay solvent is DMSO, the internal standard is Tetramethylsilane (TMS), and the chemical shifts are given as 10-6(ppm) is given as a unit.
The term "room temperature" in the present invention means a temperature of 10 to 25 ℃.
Example 1: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (5- (4- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) -1,3, 4-thiadiazol-2-yl) propionamide:
Figure DEST_PATH_IMAGE015
the method comprises the following steps: preparation of methyl (S) -2-2- (1-methyl-2, 6-dioxo-3, 4,5, 6-tetrahydro-1H-purin-7 (2H) -yl) propionate
Figure DEST_PATH_IMAGE016
A25 ml three-necked flask was charged with 1-methyl-3, 4,5, 7-tetrahydro-1H-purine-2, 6-dione (747.7mg, 4.15mmol) and K2CO3(0.573g, 4.15mmol) and DMF (7mL) were stirred and mixed well. Adding (R) -2- (A)Methylsulfonyloxy) propionic acid methyl ester (0.58 g, 3.2 mmoL), the reaction was stirred at room temperature overnight, the reaction was complete, and saturated NH was used4Cl (20ml) quench. The resulting mixture was extracted with EA (3X 20 mL). The combined organic phases were washed with water (3X 50mL) and brine. Anhydrous Na for organic phase2SO4Dried and concentrated. The residue was purified by column separation (MeOH: DCM = 1: 100) and the product was collected and concentrated to dryness to give the title product as a white solid (552mg) in 50% yield and 97.89% purity.
ESI-MS: m/z = 267.1(M+H) +。
Step two: preparation of (S) -2-2- (1-methyl-2, 6-dioxo-3, 4,5, 6-tetrahydro-1H-purin-7 (2H) -yl) propionic acid
Figure DEST_PATH_IMAGE017
A25 mL reaction flask was charged with methyl (S) -2-2- (1-methyl-2, 6-dioxo-3, 4,5, 6-tetrahydro-1H-purin-7 (2H) -yl) propanoate (0.35g, 1.31mmol), dioxane (4mL), 6N HCl (2 mL). The reaction was refluxed for 3h, cooled to room temperature, concentrated to dryness, added 3ml of water, stirred in an ice bath to precipitate a solid, filtered, and dried to a white solid product of 250mg, yield 75.4%, purity 97.39%.
ESI-MS:m/z=253(M+H)+。
Step three: preparation of (S) -N- (5-bromo-1, 3, 4-thiadiazol-2-yl) -2- (1, 3-dimethyl-2, 6-dioxy-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide
Figure DEST_PATH_IMAGE018
A25 ml three-necked flask was charged with (S) -2-2- (1-methyl-2, 6-dioxo-3, 4,5, 6-tetrahydro-1H-purin-7 (2H) -yl) propionic acid (200 mg, 0.8 mmol), 5-bromo-1, 3, 4-thiadiazol-2-amine (170 mg, 0.8 mmol), acetonitrile (2ml), NMI (197 mg, 2.4 mmol), dissolved by stirring, added TCFH (301 mg, 1.2 mmol) in portions, and allowed to react at room temperature overnight. EA was added after the reaction was completed, and the mixture was extracted with water, dried, concentrated and dried, and passed through a silica gel column to obtain 220mg of a product with a yield of 66.98%.
ESI-MS:m/z=415.0(M+H)+。
Step four: preparation of (S) -2- (2-methylpyrrolidin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine
Figure DEST_PATH_IMAGE019
A50 ml three-necked flask was charged with 2-chloropyrimidine-5-boronic acid pinacol ester (1.0 g, 4.16 mmol), (S) -2-methylpyrrolidine (0.35g, 4.16 mmol), and DMF (10 ml), cooled to-5 ℃, and DIEA (1.65 g, 12.5 mmol) was added dropwise with stirring, and after completion of the dropwise addition, the reaction was allowed to proceed at room temperature overnight. After the reaction is finished, EA is added, water is used for extraction and washing, and the organic phase is dried, concentrated and dried to obtain 1.0g of a product, wherein the yield is 83.1 percent and the product is directly used in the next step.
ESI-MS:m/z=290.1(M+H)+。
Step five: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (5- (4- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) -1,3, 4-thiadiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE020
A25 mL three-necked flask was charged with ((S) -N- (5-bromo-1, 3, 4-thiadiazol-2-yl) -2- (1, 3-dimethyl-2, 6-dioxy-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide (120 mg, 0.29 mmol), (S) -2- (2-methylpyrrolidin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (125.7 mg, 0.43 mmol), Pd (dppf) Cl2`C2HCl2(46mg, 0.056mmol), DMF (1.5 ml), water (0.5 ml), caesium carbonate (281.6 mg, 0.87 mmol), N2After three times of replacement, the mixture is heated to 95 ℃ for reaction for 6 hours. After the reaction is finished, EA is added, water is extracted and washed, and the organic phase is dried, concentrated and dried. Purification on a silica gel column (PE: EA = 1: 1 → 1: 5), collection of the product, concentration to dryness to give 70mg of the product as a yellow solid in 48.7% yield and purityThe degree was 96.50%.
ESI-MS:m/z=497.2(M+H)+。
1H NMR (400 MHz, DMSO-d6) δ:12.20 (s, 1H), 8.78(s, 2H), 8.22 (d, 1H), 5.86 (d, 1H), 4.30 (s, 1H), 3.59 (m, 1H), 3.46 (s, 3H), 3.19 (s, 3H),2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, 3H), 1.72 (s, 1H), 1.24 (d, 3H)。
Example 2: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (2- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE021
The method comprises the following steps: preparation of (S) -4- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-amine
Figure DEST_PATH_IMAGE022
A25 mL three-necked flask was charged with (S) -2- (2-methylpyrrolidin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (200 mg, 0.69 mmol), 4-bromothiazol-2-amine (124 mg, 0.69 mmol), Pd (Ph)3P）4(80 mg, 0.069 mmol), potassium carbonate (286 mg, 2.07 mmol), dioxane (3 ml), water (0.6 ml), N2After three times of replacement, the mixture is heated to 1055 ℃ for reaction for 6 hours. After the reaction, EA was added, water was extracted and washed, the organic phase was dried, concentrated and dried, and the product was passed through a silica gel column to obtain 100mg of a yellow oily product with a yield of 55.3%.
ESI-MS: m/z = 262.1(M+H) +。
Step two: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (2- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE023
A25 ml reaction flask was charged with (S) -2-2- (1-methyl-2, 6-dioxo-3, 4,5, 6-tetrahydro-1H-purin-7 (2H) -yl) propionic acid (136 mg, 0.54 mmol), (S) -4- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-amine (140 mg, 0.54 mmol), HOBT (146 mg, 1.08 mmol), dried pyridine (2ml), EDCI (206 mg, 1.08 mmol) was added in portions, and the reaction was stirred at room temperature overnight. After the reaction was complete, EA was added, water was extracted, washed, the organic phase was dried and concentrated to dryness, and the product was purified by silica gel column chromatography (DCM: MeOH =100:1 → 100: 5), collected and concentrated to dryness to give 80mg of a yellow solid product in 29.9% yield and 98.40% purity.
ESI-MS:m/z=496.2(M+H)+。
1HNMR (400 MHz, DMSO-d6) δ: 12.81 (s, 1H), 8.80 (s, 2H), 8.32 (s, 1H), 7.48 (s, 1H), 5.76 (m, 1H), 4.26 – 4.20 (m, 1H), 3.56 (d, 1H), 3.48 (d, 1H), 3.44 (s, 3H), 3.16 (s, 3H), 2.05 – 2.00 (m, 2H), 1.85 (d, 4H), 1.66 (d, 1H), 1.19 (d, 3H)。
Example 3: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (4- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) -5-methylthiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE024
The procedure is as in example 2 except that 4-bromothiazol-2-amine is replaced with equimolar 4-bromo-5-methylthiazol-2-amine in step one and the procedure is the same in step two to give the title compound as a yellow solid in two reaction yields: 30.5 percent and the purity is 98.02 percent.
ESI-MS: m/z =510.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ:12.75 (s, 1H), 8.56 (s, 2H), 8.22 (d, 1H), 5.88 (d, 1H), 4.30 (s, 1H), 3.59 (m, 1H), 3.46 (s, 3H), 3.19 (s, 3H), 2.48 (s, 3H),2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, 3H), 1.72 (s, 1H), 1.24 (d, 3H)。
Example 4: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (3- (2- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) phenyl) propionamide
Figure DEST_PATH_IMAGE025
The procedure was as in example 2 except that 4-bromothiazole-2-amine was replaced with equimolar m-bromoaniline in the first step and the procedure in the second step to give the title compound in two-step yield: 25.3 percent and the purity is 97.22 percent.
ESI-MS: m/z =489.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ:11.35 (s, 1H), 8.66 (s, 2H), 8.22 (d, 1H), 8.06 (t, 1H), 7.67 (ddd, 1H), 7.51 (ddd, 1H), 7.39 (t, 1H), 5.85 (d, 1H), 4.30 (s, 1H), 3.59 (m, 1H), 3.46 (s, 3H), 3.19 (s, 3H), 2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, 3H), 1.72 (s, 1H), 1.24 (d, 3H)。
Example 5: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (5- (2- (S) -2- (trifluoromethyl) pyrrolidin-1-yl) pyrimidin-5-yl) -1,3, 4-thiadiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE026
Preparation the same as in example 1 was used to replace (S) -2-methylpyrrolidine in step four with an equimolar amount of (S) -2- (trifluoromethyl) pyrrolidine to give the title compound as a yellow solid in yield: 35.1% and the purity is 97.9%.
ESI-MS: m/z = 551.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ:11.16(s, 1H),8.87 (s, 2H), 8.22(d, 1H),5.82(q, 1H),5.12(t, 1H),3.70(m, 2H),3.47(s, 3H),3.16(s，3H),2.10(m. 4H),1.88(d, 3H)。
Example 6: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (4- (S) -2- (trifluoromethyl) pyrrolidin-1-yl) pyrimidin-5-yl) -5-methylthiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE027
Preparation method the same as preparation example 1, substituting 4-bromothiazol-2-amine for equimolar 4-bromo-5-methylthiazol-2-amine in step one and (S) -2-methylpyrrolidine for equimolar (S) -2- (trifluoromethyl) pyrrolidine in step four gave the title compound in yield: 43.6% and the purity is 97.26%.
ESI-MS: m/z =564.2(M+H) +。
1H NMR(400 MHz, DMSO-d6) δ: 12.21 (s, 1H),8.75 (s, 2H), 8.22 (d, 1H),5.82(q, 1H),5.12(t, 1H),3.70(m, 2H),3.47(s, 3H),3.16(s, 3H),2.48 (s, 3H),2.10(m, 4H),1.88(d, 3H)。
Example 7: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (5- (4- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) -1,3, 4-oxadiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE028
Preparation the same as preparation of example 2, substituting 4-bromothiazol-2-amine for equimolar 5-bromo-1, 3, 4-oxadiazol-2-amine in step one gave the title compound in yield: 45.2 percent and the purity is 98.48 percent.
ESI-MS: m/z = 481.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ:12.11 (s, 1H), 9.02(s, 2H), 8.29 (d, 1H), 5.56 (d, 1H), 4.30 (s, 1H), 3.59 (m, 1H), 3.46 (s, 3H), 3.19 (s, 3H),2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, 3H), 1.72 (s, 1H), 1.24 (d, 3H)。
Example 8: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxy-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (2- ((S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) -5- (trifluoromethyl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE029
Preparation the same as preparation of example 2, substituting 4-bromothiazol-2-amine for equimolar 4-bromo-5- (trifluoromethyl) thiazol-2-amine in step one gave the title compound in yield: 52.7 percent and the purity of 98.06 percent.
ESI-MS: m/z =564.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ:12.21 (s, 1H), 8.77(s, 2H), 8.27 (d, 1H), 5.80 (d, 1H), 4.30 (s, 1H), 3.59 (m, 1H), 3.46 (s, 3H), 3.19 (s, 3H),2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, 3H), 1.72 (s, 1H), 1.24 (d, 3H)。
Example 9: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (5-fluoro-4- (4- (S) -2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE030
Preparation of intermediate (S) -5-fluoro-4- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-amine
Figure DEST_PATH_IMAGE031
A10 ml reaction flask was charged with (S) -4- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-amine (200 mg, 0.77 mmol), acetonitrile (2.5 ml), cooled to-25 deg.C, charged with Selectfluor (328 mg, 0.92 mmol), TLC monitored until the starting material had reacted, water was added, DCM was added and the organic phase was concentrated. Purification on a silica gel column (PE: EA = 8: 2 → 1: 2) and collection of the product, concentration to dryness, gave 140mg of product, 39.9% yield.
ESI-MS:m/z=280.1(M+H)+。
Preparation method the same as preparation example 2 was used to replace (S) -4- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-amine in step two with equimolar (S) -5-fluoro-4- (2- (2-methylpyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-amine to give the title compound in yield: 45.7 percent and the purity is 97.46 percent.
ESI-MS: m/z = 514.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ:12.21 (s, 1H), 8.77(s, 2H), 8.27 (d, 1H), 5.80 (d, 1H), 4.12 (s, 1H), 3.77 – 3.67 (m, 1H), 3.62 – 3.51 (m, 1H), 3.46 (s, 3H), 3.38 (s, 3H), 2.01 – 1.83 (m, 2H), 1.87 – 1.76 (m, 1H), 1.67 (d, 3H), 1.64 – 1.53 (m, 1H), 1.20 (d, 3H)。
Example 10: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxy-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (2-methylpyrimidin-5-yl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE032
Preparation method the same as preparation example 2 was used to replace in step one (S) -2- (2-methylpyrrolidin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine with an equimolar amount of 2-methylpyrimidine-5-boronic acid pinacol ester to give the title compound in yield: 58.9 percent and the purity of 98.55 percent.
ESI-MS: m/z = 427.1(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ:12.10 (s, 1H),8.99 (s, 2H), 8.22 (d, 1H), 7.38 (s, 1H), 5.78 (d, 1H), 3.46 (s, 3H), 3.38 (s, 3H), 2.46 (s, 3H), 1.67 (d, 3H)。
Example 11: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (2- (piperidin-1-yl) pyrimidin-5-yl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE033
Preparation method 5-bromo-1, 3, 4-thiadiazol-2-amine was replaced with equimolar 4-bromothiazol-2-amine in step three and (S) -2-methylpyrrolidine was replaced with equimolar piperidine hydrochloride in the same manner as in example 1 to give the title compound as a yellow solid in yield: 55.8 percent and the purity is 97.86 percent.
ESI-MS: m/z = 496.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.77 (s, 2H), 8.22 (d, 1H), 7.38 (s, 1H), 5.80(d, 1H), 3.68 (m, 4H), 3.46 (s, 3H), 3.38 (s, 3H), 1.70 – 1.54 (m, 9H)。
Example 12: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (2- (trifluoromethyl) pyrimidin-5-yl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE034
Preparation method the same as preparation example 2 was used to replace in step one (S) -2- (2-methylpyrrolidin-1-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine with an equimolar amount of 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyrimidine to give the title compound in yield: 58.9 percent and the purity of 98.55 percent.
ESI-MS: m/z = 481.1(M+H) +。
1H NMR (400 MHz, DMSO-d6)δ: 12.31 (s, 1H),9.03 (s, 2H), 8.22 (d, 1H), 7.39 (s, 1H), 5.80 (d, 1H), 3.46 (s, 3H), 3.38 (s, 3H), 1.87 (d, 3H)。
Example 13: preparation of (S) -2-N- (4- (2- (2, 5-diazabicyclo [2.2.1] hept-2-yl) pyrimidin-5-yl) thiazol-2-yl) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide
Figure DEST_PATH_IMAGE035
Preparation method the same as example 1, 5-bromo-1, 3, 4-thiadiazole-2-amine in step three was replaced with equimolar 4-bromothiazole-2-amine, and (S) -2-methylpyrrolidine in step four was replaced with equimolar tert-butyl 2, 5-diazacyclo [2.2.1] heptane-2-carboxylate to give tert-butyl 5- (5- (2- ((S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamido) thiazol-4-yl) pyrimidin-2-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate, removal of the Boc protecting group with trifluoroacetic acid gave the title compound in yield: 45.9 percent and the purity is 98.63 percent.
ESI-MS: m/z = 509.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ: 12.11 (s, 1H), 8.78 (s, 2H), 8.22 (d, 1H), 7.38 (s, 1H), 5.79(d, 1H), 4.29 (m, 1H), 3.94 (m, 2H), 3.46 (s, 3H), 3.38 (s, 3H), 3.23 (m, 1H), 3.17 – 3.02 (m, 2H), 2.15 (m, 1H), 2.08 – 1.99 (m, 1H), 1.90 – 1.81 (m, 1H), 1.67 (d, 3H)。
Example 14: preparation of (S) -2-N- (4- (2- (3, 8-diazabicyclo [3.2.1] octan-8-yl) pyrimidin-5-yl) thiazol-2-yl) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide
Figure DEST_PATH_IMAGE036
Preparation method is the same as example 1, 5-bromo-1, 3, 4-thiadiazole-2-amine in step three is replaced with equimolar 4-bromothiazole-2-amine, and (S) -2-methylpyrrolidine in step four is replaced with equimolar 3, 8-diazacyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester to obtain 8- (5- (2- ((S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionylamino) thiazol-4-yl) pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester, removal of the Boc protecting group with trifluoroacetic acid gave the title compound in yield: 45.9 percent and the purity is 98.63 percent.
ESI-MS: m/z = 523.2(M+H) +。
1H NMR(400 MHz, DMSO-d6) δ: 12.06 (s, 1H),8.75 (s, 2H), 8.22 (d, 1H), 7.38 (s, 1H), 5.75 (d, 1H), 4.13 (m, 2H), 3.46 (s, 3H), 3.38 (s, 3H), 3.12 – 3.05 (m, 1H), 3.08 – 3.03 (m, 1H), 2.98 (m, 2H), 2.85 (m, 1H), 2.05 – 1.78 (m, 4H), 1.67 (d, 3H)。
Example 15: preparation of (S) -N- (4- (2- (2-aza-1-yl) pyrimidin-5-yl) thiazol-2-yl) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide
Figure DEST_PATH_IMAGE037
Preparation the same as in example 1 was used to replace 5-bromo-1, 3, 4-thiadiazol-2-amine with equimolar 4-bromothiazol-2-amine in step three and (S) -2-methylpyrrolidine with equimolar heptamethine in step four to give the title compound in yield: 65.9 percent and the purity of 98.77 percent.
ESI-MS: m/z = 510.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ: 11.06 (s, 1H), 8.77 (s, 2H), 8.22 (d, 1H), 7.38 (s, 1H), 5.68 (d, 1H), 3.56 (m, 4H), 3.46 (s, 3H), 3.38 (s, 3H), 1.78 – 1.64 (m, 7H), 1.63 – 1.49 (m, 4H)。
Example 16: preparation of (S) -2-N- (4- (2- (3, 6-diazabicyclo [3.1.1] hept-6-yl) pyrimidin-5-yl) thiazol-2-yl) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide
Figure DEST_PATH_IMAGE038
Preparation method the same as example 1, 5-bromo-1, 3, 4-thiadiazol-2-amine was replaced with an equimolar amount of 4-bromothiazol-2-amine in step three, and (S) -2-methylpyrrolidine was replaced with an equimolar amount of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane in step four, to give tert-butyl 6- (5- (2- ((S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionylamino) thiazol-4-yl) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylate, removal of the Boc protecting group with trifluoroacetic acid gave the title compound in yield: 56.2 percent and the purity of 98.94 percent.
ESI-MS: m/z = 509.2(M+H) +。
1H NMR(400 MHz, DMSO-d6) δ: 11.36 (s, 1H), 8.75 (s, 2H), 8.22 (d, 1H), 7.38 (s, 1H), 5.69 (d, 1H), 4.43 (m, 2H), 3.46 (s, 3H), 3.38 (s, 3H) 3.16 – 3.02 (m, 4H), 2.71 – 2.63 (m, 1H), 2.19 (d, 1H), 2.04 (d, 1H), 1.67 (d, 3H)。
Example 17: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (4- (2- ((S) -3-methoxypyrrolidin-1-yl) pyrimidin-5-yl) -5-methylthiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE039
Preparation method the same as preparation example 1, substituting 4-bromothiazol-2-amine for equimolar 4-bromo-5-methylthiazol-2-amine in step one and (S) -2-methylpyrrolidine for equimolar (S) -3-methoxypyrrolidine in step four, gave the title compound in yield: 43.6% and the purity is 97.26%.
ESI-MS: m/z = 526.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ:11.30 (s, 1H), 8.69 (s, 2H), 8.22 (d, 1H), 5.68 (d, 1H), 4.39 (m, 1H), 4.03 – 3.94 (m, 1H), 3.82 – 3.69 (m, 2H), 3.53 – 3.41 (m, 1H), 3.46 (s, 3H), 3.38 (s, 3H),3.20 (d, 3H), 2.48 (s, 3H), 2.08 – 1.96 (m, 1H), 1.83 (m, 1H), 1.67 (d, 3H)。
Example 18: preparation of (S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) -N- (5-methyl-4- (2- ((S) -3- (trifluoromethoxy) pyrrolidin-1-yl) pyrimidin-5-yl) thiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE040
Preparation method the same as preparation example 1, substituting 4-bromothiazol-2-amine for equimolar 4-bromo-5-methylthiazol-2-amine in step one and (S) -2-methylpyrrolidine for equimolar (S) -3-trifluoromethoxy pyrrolidine in step four, gave the title compound in yield: 46.9 percent and the purity is 97.84 percent.
ESI-MS: m/z = 580.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ:11.69 (s, 1H), 8.69 (s, 2H), 8.22 (d, 1H), 5.68 (d, 1H), 4.95 (m, 1H), 4.08 (m, 1H), 3.88 – 3.75 (m, 2H), 3.53 – 3.43 (m, 1H), 3.46 (s, 3H), 3.38 (s, 3H), 2.48 (s, 3H), 2.14 – 2.03 (m, 1H), 1.85 (m, 1H), 1.67 (d, 3H)。
Comparative example 1: preparation of N- (4- (2, 4-difluoro-3- (trifluoromethyl) pyrimidin-5-yl) thiazol-2-yl) -2- (1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydrothiophene [2,3-d ] pyrimidin-5-yl) acetamide
Figure DEST_PATH_IMAGE041
Synthesized according to the method described in patent WO2013183035a2, purity: 98.9 percent.
ESI-MS: m/z = 517.1(M+H) +。
1H NMR (300 MHz, DMSO- d6) δ:3.19 (s, 3H), 3.46 (s, 3H), 4.07 (s, 2H), 7.07 (s, 1H), 7.48-7.54 (t, 1H), 7.61 (s, 1H), 8.30-8.37 (q, 1H), 12.48 (br s, 1H)。
Comparative example 2: preparation of (S) -3- (3- (4-chlorobenzyl) -4- (4- (3-fluoropyridin-2-oxy) pyrimidin-5-yl) amino) -2, 6-dioxa-3, 6-dihydropyrimidin-1 (2H) yl) -2-methylpropionic acid
Figure DEST_PATH_IMAGE042
Synthesized according to the method described in patent WO2010075353a1, purity: 98.5 percent.
ESI-MS: m/z = 498.2(M+H) +。
1H NMR (400 MHz, DMSO-d6) δ: 12.87 (s, 1H), 8.03 (s, 1H), 7.68 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 7.06 (dd, 1H), 5.32 (d, 2H), 3.71 – 3.60 (m, 2H), 3.46 (m, 4H), 3.38 (s, 3H), 1.96 – 1.82 (m, 1H), 1.87 – 1.72 (m, 2H), 1.56 – 1.44 (m, 1H), 1.22 (d, 3H)。
Test example 1: cough test in mice
Working test material
Test article basic information
Examples 1-18 (synthesized in our laboratory), comparative example 1 (CRC 17536, positive control, our laboratory), and comparative example 2 (synthesized in our laboratory).
A reagent for experiments
Normal saline and ammonia water.
Perfect animal experiment
Healthy adult KM mice are half male and female, 6 mice in each group and have the weight of about 28-30 g.
⒊ test method
First dosage design and test article use amount
The animal cough model reported in the literature at present mostly adopts methods such as mechanical, chemical and electrical stimulation to stimulate nerves and receptors of animals to cause cough. According to the characteristics of the candidate compound and the existing similar target compounds as references, a mouse cough modeling test is established by primarily selecting a strong ammonia water induction method.
Preparation method of test articles
The preparation method of the 50% ammonia water solution comprises the following steps: 2.5ml of ammonia water is measured and dissolved in 5ml of 0.9 percent sodium chloride injection, and the mixture is fully and evenly mixed.
Comparative example 1 solution preparation method: 18mg of comparative example 1 was dissolved in 3ml of 0.5% CMC-Na solution and mixed well to prepare a solution of 6 mg/ml.
Comparative example 2 solution preparation method: 18mg of comparative example 2 was dissolved in 3ml of 0.5% CMC-Na solution and mixed well to prepare a solution of 6 mg/ml.
Examples solution formulation methods: 18mg of the example was dissolved in 3ml of 0.5% CMC-Na solution and mixed well to prepare a solution of 6 mg/ml.
Experimental operation method for obtaining three
6 KM mice were taken per group: comparative example 1 group, comparative example 2 group, example group, model group. Mice in the comparative example 1 group, comparative example 2 group and example group were each gavaged with the compound of comparative example 1 (60 mg/kg), the compound of comparative example 2 (60 mg/kg) and the compound of example (60 mg/kg), and the model group was administered with an equal volume of 0.5% CMC-Na solution. After administration for 30min, the mice were placed in 500ml beakers, into which 1 cotton ball (100. + -.5 mg by weight) containing 0.3ml of 50% ammonia water was placed, respectively. The number of typical coughs that occurred within 3min was observed in the mice (typical coughing action: contraction of abdominal muscles or chest contraction while mouth enlargement with coughing sound).
⒋ results and discussion
First result judgment standard
A cough judgment standard:
the manifestations of cough are: the abdominal muscles contract or contract the chest while the mouth is enlarged, with a cough.
Secondly, a stopwatch is used for timing, the number of coughing of the mice within 3min is recorded, statistical analysis is carried out by software, all groups of data are statistically described by means of mean values plus or minus standard deviations, single-factor variance analysis is carried out among multiple groups, and P <0.05 is a difference which has statistical significance.
Discussion of the results
The number of coughs of mice coughed 30min after administration of 60mg/kg of the example compound is shown in the following table:
Figure DEST_PATH_IMAGE043
note: (1)*representing P compared to the model set<0.05；**Representing P compared to the model set<0.01；#Represents P in comparison with the group of comparative example 1<0.05; (2) group of comparative example 1, group of example 1 the compounds used for representing this group are the compound of comparative example 1, the compound of example 1, respectively, and the others are explained similarly.
As shown in the above table, the compounds of the examples of the present invention showed a significant decrease in the number of coughs as compared with the model group, and the compounds of the examples 1,2,3, 5, 6 and 12 showed a significant decrease in the number of coughs as compared with the compounds of the comparative example 1, and also showed a decrease in the number of coughs as compared with the compounds of the comparative example 2, and had statistical significance.
Test example 2: rat hepatotoxicity serum biomarker study
Working test material
And (3) testing the sample: examples 1,2,3, 5, 6, 12, 13 groups of compounds, comparative example 2 compound (laboratory synthesis by the present inventors);
test reagents: 0.5% CMC-Na solution (batch No. G1226001).
Perfect animal experiment
Healthy adult SD rats weighing 180-200 g, 6-9 weeks old per week, all females, and 6 rats per group.
⒊ test method
Preparation method of test articles
Example 5 group of compounds and comparative example compound formulation method: accurately weighing appropriate amount of the medicine, adding 0.5% CMC-Na, ultrasonic treating, and mixing; the drug concentration of 12.5mg/ml is prepared.
Method for experimental operation
Healthy adult SD rats, 6 rats in each group, after fasting overnight (free drinking water), collecting blank serum of 200 microliters respectively for blood supply biochemical detection from jugular veins, respectively injecting and administering tail veins after blood collection, administering 50mg/kg once, observing the toxic reaction condition and death condition of each rat after administration, recording, collecting blood from jugular veins again 24h after administration to detect blood biochemical indexes (AST and ALT), and after blood collection, placing the rats back to the rearing cage to continuously observe the condition after administration.
⒋ results and discussion
The biochemical blood indicators before and after administration of the drug to the rats in each group are counted as shown in the following table: the blood biochemical indicators (AST, ALT) of the mice in the groups of examples 1,2,3, 5, 6, 12 and 13 are not obviously changed before and after the administration, while the blood biochemical indicators (AST, ALT) of the mice in the group of comparative example 2 after the administration are respectively increased by 4.22 times and 9.52 times compared with the blood biochemical indicators before the administration. It is shown that the compounds of examples 1,2,3, 5, 6, 12, 13 of the present invention do not cause hepatotoxicity and are significantly safer than the compound of comparative example 2.
Figure DEST_PATH_IMAGE044
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.

Claims (10)

1. A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:
Figure DEST_PATH_IMAGE001
wherein,
the ring A is selected from a substituted or unsubstituted 5-membered heterocyclic ring, a substituted or unsubstituted 7-to 12-membered aromatic heterocyclic ring, or a substituted or unsubstituted benzene; preferably, ring a is selected from a substituted or unsubstituted 5-membered aromatic heterocyclic ring, or a substituted or unsubstituted benzene;
R1selected from the group consisting of hydrogen, deuterium, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, substituted or unsubstituted cyclic amino, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heterocycloalkyl, - (CH- (CH)2)fNR2R3、—O-(CH2)fN R2R3、—C(=O)fNR2R3Or a carboxyl group, wherein:
f is an integer from 1 to 4;
each R2Independently selected from hydrogen or lower alkyl;
each R3Independently selected from hydrogen, lower alkyl, substituted or unsubstitutedSubstituted aryl, or substituted or unsubstituted aralkyl.
2. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein in formula (i):
ring a is selected from substituted or unsubstituted benzene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted pyrrole, substituted or unsubstituted 1,2, 3-triazole, or substituted or unsubstituted 1,2, 4-triazole; preferably, ring a is selected from substituted or unsubstituted benzene, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiadiazole, or substituted or unsubstituted oxadiazole;
R1selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, substituted or unsubstituted 3-to 10-membered cyclic amino, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heterocycloalkyl.
3. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein R1Selected from hydrogen, deuterium, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, or freely selected from the following rings:
Figure DEST_PATH_IMAGE002
wherein:
x is selected from: o, NH or CHR7；
Each R4、R5、R6、R7Independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted ester, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, or carboxy;
additionally or alternatively, two R's attached to the same ring carbon4Or two R5Or two R6The substituents may together form an oxo group (i.e.: O) or a C3-C7 spiro ring group; and additionally or alternatively, two R's attached to different ring carbons4Or two R5Or two R6The substituents may together form a ring, wherein two R' s6When taken together, form a ring having 4 to 7 ring atoms, including 0 to 3 ring heteroatoms;
n is an integer from 0 to 4;
a is selected from an integer of 0 to 3;
b. c is independently selected from an integer of 0 to 2;
m, p are independently selected from integers from 1 to 3;
q and r are independently selected from integers of 0 to 3.
4. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, wherein R is1Selected from hydrogen, halogen, methyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, C1-C6 alkyl, or selected from the group consisting of 1 to 2R8Substituted of the following rings:
Figure DEST_PATH_IMAGE003
wherein each R is8Independently selected from the group consisting of: hydrogen, halogen, hydroxy, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted ester, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, or carboxy.
5. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 4, wherein R is8Selected from the group consisting of: hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy; preferably, said R is8Selected from the group consisting of: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy.
6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the compound is:
Figure DEST_PATH_IMAGE004
Figure 787556DEST_PATH_IMAGE005
Figure DEST_PATH_IMAGE006
Figure 584610DEST_PATH_IMAGE007
Figure DEST_PATH_IMAGE008
Figure 131129DEST_PATH_IMAGE009
。
7. the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein hydrogen in the compound is substituted with one or more deuterium.
8. The compound, the stereoisomer or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
9. Use of a compound of any one of claims 1 to 8, a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of a disease associated with the TRPA1 receptor.
10. The use as claimed in claim 9, wherein the TRPA1 receptor related disease is selected from respiratory diseases; preferably, the disease associated with the TRPA1 receptor is selected from cough, asthma, pain or sleep apnea.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014113671A1 (en) * 2013-01-18 2014-07-24 Cubist Pharmaceuticals, Inc. Inhibiting the transient receptor potential a1 ion channel
CN106573934A (en) * 2014-04-23 2017-04-19 海德拉生物科学公司 Inhibiting the transient receptor potential A1 ion channel
CN106715430A (en) * 2014-09-19 2017-05-24 海德拉生物科学公司 Inhibiting the transient receptor potential A1 ion channel
CN111655693A (en) * 2018-01-31 2020-09-11 伊莱利利公司 Inhibition of transient receptor potential A1 ion channels

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014113671A1 (en) * 2013-01-18 2014-07-24 Cubist Pharmaceuticals, Inc. Inhibiting the transient receptor potential a1 ion channel
CN106573934A (en) * 2014-04-23 2017-04-19 海德拉生物科学公司 Inhibiting the transient receptor potential A1 ion channel
CN106715430A (en) * 2014-09-19 2017-05-24 海德拉生物科学公司 Inhibiting the transient receptor potential A1 ion channel
CN111655693A (en) * 2018-01-31 2020-09-11 伊莱利利公司 Inhibition of transient receptor potential A1 ion channels

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