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CN114656472B - Pyrazolopyrimidine compound, isomer or salt, and preparation method and application thereof - Google Patents

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

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CN114656472B
CN114656472B CN202210448072.7A CN202210448072A CN114656472B CN 114656472 B CN114656472 B CN 114656472B CN 202210448072 A CN202210448072 A CN 202210448072A CN 114656472 B CN114656472 B CN 114656472B
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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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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a compound shown in a formula (I), or stereoisomers, geometric isomers, tautomers, oxynitride compounds, hydrates, solvent compounds, metabolites and pharmaceutically acceptable salts of the compound shown in the formula (I). The invention also provides application of the compound, stereoisomer or pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing diseases related to the TRPA1 receptor, in particular to application in preparing medicaments for treating and/or preventing cough, asthma, pain and sleep apnea.

Description

Pyrazolopyrimidine compound, isomer or salt, and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a novel pyrazolopyrimidine compound or salt and isomer thereof, a preparation method thereof and application of a pharmaceutical composition thereof in preparation of a medicament for treating and/or preventing diseases related to TRPA1 receptors, and especially application in treatment and/or prevention of respiratory diseases and nervous system diseases.
Background
Transient receptor potential (Transient Receptor Potential, TRP) channels are a non-selective cation channel. TRP ion channels in mammals can be divided into 7 subfamilies, TRPC (7 members), TRPM (8 members), TRPV (6 members), TRPA (ANKTM 1, unique member), TRPML (3 members), TRPP (5 members) and TRPN, based on TRP sequence homology. The TRP family is involved in a variety of cellular functions including sensory perception and signal transduction. Among them, TRPA1 receptors are associated with temperature, pain sensation, hyperalgesia and neurogenic inflammation.
TRPA1 is widely found in trigeminal nerves, dorsal roots, ganglion, expressed on primary sensory neurons of aδ and C fibers. Expression is also on non-neural cells such as inner ear hair cells, intestinal chromaffin cells, vascular endothelial cells, dental pulp fibroblast keratinocytes, islet cells, etc. The channel can be activated by noxious cold stimulus below 17 ℃, a series of chemical substance stimulus and inflammatory medium, generates transmembrane voltage change mainly of calcium ion inflow, participates in cold formation of noxious cold stimulus, and has the functions of regulating inflammatory reaction, apoptosis necrosis and mediating pain. Recent studies indicate that the receptor for TRPA1 is also a "switch" for coughing. Activation of TRPA1 receptors is therefore associated with a variety of diseases, such as showing significant therapeutic effects on pain, neuralgia, asthma, airway inflammation, bronchoconstriction and cough.
Among them, cough is one of the most common symptoms clinically. In 2006, a survey of 1087 college students in Guangzhou area of China showed a cough incidence of 10.9%, with a chronic cough incidence of 3.3%, presumably the community population would be higher. There is currently no approved drug for the treatment of chronic cough. Common antitussive therapeutic agents include codeine, dextromethorphan, etc., but central antitussive agents often have side effects such as constipation and somnolence. Pain is one of the most common pain in humans and one of the most common and intolerable symptoms in the clinic. The incidence of world pain is about 35-45%, and the incidence of the elderly is high, about 75-90%. At present, two main types of medicines are COX inhibitors (with weak analgesic effect and relatively high safety) and opioid receptors are excited (with strong analgesic effect, constipation, addiction and respiratory depression), and the two main types of medicines have advantages and disadvantages and cannot meet clinical requirements. In addition, about 16% of diabetics develop painful diabetic neuropathy. Drugs for the treatment of painful DPN mainly include tricyclic antidepressants, selective 5-hydroxytryptamine and norepinephrine reuptake inhibitors, opioids and antiepileptics. Available treatment regimens are not completely palliative, nor are they effective in all patients, and more than 50% pain relief is achieved in only about one third of patients.
TRPA1 antagonists are currently in clinical use in only two varieties, ISC-17536 at stage 2 (diabetic peripheral neuropathy, pain, respiratory disease) and LY-3526318 at stage 1 (pain). The IC50 value of ISC-17536 at inhibiting calcium current through TRPA1 is about 70 nM. The final point of clinical research on refractory cough developed in Europe is finally not reached, the antagonism IC50 of LY-3526318 on TRPA1 is 5-6 uM, the activity is weak, the TRPA1 antagonist is a potential therapeutic drug for various diseases, and the fields of pain, asthma, cough and the like have great unmet clinical demands, so that the antagonist with high activity on the TRPA1 is more needed clinically, a higher activity and safer drug selection opportunity are provided for patients, and the development of the TRPA1 antagonist has great market value and academic value.
Disclosure of Invention
The compound is a novel pyrazolopyrimidine compound, and most of the example compounds show good cough relieving effect and TRPA1 in vitro affinity in animals. In the cough test of mice, when 60mg/kg of the compound of the invention is orally administered, the compound has extremely 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 DEST_PATH_IMAGE001
wherein,,
ring a is selected from a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted aromatic heterocyclic ring;
R 1 selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylamino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted cycloamino, substituted or unsubstituted aryloxy, or substituted or unsubstituted arylaminoA base;
R 2 、R 3 independently selected from hydrogen, deuterium, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, - (CH) 2 )fNRR’、—O-(CH 2 ) fNRR ', -C (=o) fNRR' or carboxyl, wherein:
f is selected from integers from 1 to 4;
each R is independently selected from hydrogen or lower alkyl;
each R' is independently selected from hydrogen, lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.
Further, the structure of the compound represented by the above formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof is defined as follows:
ring A is selected from substituted or unsubstituted 5-6 membered aromatic heterocycle;
R 1 selected from hydrogen, hydroxy, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkylamino, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkylthio, or substituted or unsubstituted 3-to 10-membered cyclic amino;
R 2 、R 3 independently selected from hydrogen, deuterium, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, or C1-C3 perfluoroalkoxy.
Further, the structure of the compound represented by the above formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof is defined as follows:
ring a is selected from substituted or unsubstituted pyrimidine, substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiadiazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted thiophene, substituted or unsubstituted 1,2, 3-triazole, or substituted or unsubstituted 1,2, 4-triazole; preferably, ring a is selected from substituted or unsubstituted pyrimidine, substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted thiadiazole, or substituted or unsubstituted oxadiazole;
R 1 selected from hydrogen, halogen, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, C1-C6 alkyl, or optionally selected from the following rings:
Figure DEST_PATH_IMAGE002
wherein:
x is selected from: o, NH or CHR 7 ；
Each R 4 、R 5 、R 6 、R 7 Independently 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 group, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy or carboxyl;
additionally or alternatively, two R's attached to the same ring carbon 4 Or two R 5 Or two R 6 Substituents may together form oxo (i.e.: =o) or C3-C7 spirocyclic groups; and additionally or alternatively, two R's attached to different ring carbons 4 Or two R 5 Or two R 6 Substituents may together form a ring, wherein two R 6 The rings formed when taken together have from 4 to 7 ring atoms, including from 0 to 3 ring heteroatoms;
n is an integer from 0 to 4;
a is selected from integers from 0 to 3;
b. c is independently selected from integers from 0 to 2;
m and p are independently selected from integers of 1 to 3;
q, r are independently integers selected from 0 to 3;
R 2 、R 3 independently selected from the group consisting ofThe group: hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, substituted or unsubstituted aryl, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy.
Further, R is as described above 1 Selected from hydrogen, halogen, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, C1-C6 alkyl, or is selected from 1 to 2R 8 Substituted ring:
Figure DEST_PATH_IMAGE003
wherein each R 8 Independently 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 group, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy or carboxyl.
Further, R is as described above 8 Selected from the group consisting of: hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, substituted or substituted aryl, C3-C6 cyclic alkyl, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy; preferably, R is as defined above 8 Selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy.
Further, 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 lower alkylamino, substituted or unsubstituted lower alkanoylamino, substituted or unsubstituted ester group, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy or carboxyl.
Further, the substituents of the ring A are selected from the group consisting of: hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, substituted or unsubstituted aryl, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy.
Further, R is as described above 2 、R 3 Independently selected from: hydroxy, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C3 perfluoroalkyl or C1-C3 perfluoroalkoxy.
Further, a compound represented by the above formula (i), a stereoisomer or a pharmaceutically acceptable salt thereof, an exemplary compound is as follows:
Figure DEST_PATH_IMAGE004
Figure DEST_PATH_IMAGE005
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE007
Figure DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE009
。
further, the compounds of the present invention also include geometric isomers, tautomers, nitroxide compounds, hydrates, solvates, metabolites or prodrugs of the compounds of formula (I) above.
Further, the compounds of the present invention also include the compounds described above, stereoisomers, pharmaceutically acceptable salts, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites or prodrugs thereof, wherein the hydrogen may be substituted with one or more deuterium.
Further, the invention also provides a preparation method of the compound shown in the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises the following steps:
Figure DEST_PATH_IMAGE010
wherein the ring A, R 1 、R 2 、R 3 Is defined as defined in any one of the preceding claims;
step 1: the starting material (R) -methyl 2- (methylsulfonyloxy) propionate and 1-methyl-3, 4,5, 7-tetrahydro-1H-purine-2, 6-dione undergo substitution reaction to obtain an intermediate b: (S) -methyl 2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1 h-pyrazolo [4,3-d ] pyrimidin-1-yl) propanoate;
step 2: the intermediate b undergoes hydrolysis reaction to obtain a key intermediate c;
step 3: and (3) carrying out condensation reaction on the key intermediate c and the key intermediate a to obtain the compound shown in the formula I.
In another aspect, the present invention also provides the use of the above-mentioned compound, stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing a disease associated with TRPA1 receptors.
Further, the above-mentioned TRPA1 receptor-related diseases are selected from respiratory diseases or nervous system diseases.
Further, the above-mentioned TRPA1 receptor-related diseases are selected from cough, asthma, pain or sleep apnea; cough is preferred.
Term interpretation:
the "alkyl" includes straight-chain and branched alkyl groups.
The above "lower alkyl" is: C1-C16 straight or branched alkyl.
The definition of "lower alkoxy", "lower alkylamino", "lower alkylthio", "lower alkanoylamino" in the above-mentioned "lower alkyl" is the same as the definition of "lower alkyl" in relation to the alkyl moiety.
The "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and is exemplified by methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl.
The alkyl moiety in the "C1-C6 alkoxy" and the "C1-C6 alkylamino" is the same as that in the "C1-C6 alkyl".
The term "perfluoro" in the above-mentioned "C1-C3 perfluoroalkyl group" means that hydrogen on a carbon atom is substituted with fluorine. Such as trifluoromethyl, -CF 2 CF 3 、—CFCF 3 CF 3 、—CF 2 CF 2 CF 3 。
The term "perfluoro" in the above-mentioned "C1-C3 perfluoroalkoxy" is as defined above.
The "substituent" in the above "substituted or unsubstituted" is selected from the group consisting of, unless otherwise specified: 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 alkanoylamino, substituted or unsubstituted ester, C3-C6 cycloalkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, or carboxyl; preferably, the "substituents" are selected from: hydrogen, halogen, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl.
The term "C1 to C16" means a compound containing 1 to 16 carbon atoms. Other similar writing methods are similarly explained.
The above-mentioned "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 single ring, a bridged ring, at least 1 heteroatom in number, all heteroatoms being N, or comprising N and S and/or O. As part of the R1 substituent, this moiety is preferably a 5-to 8-membered cyclic amino group; more preferably a 5-to 6-membered cyclic amino group; most preferred is a 5 membered cyclic amino group.
The above "halogen" is: fluorine, chlorine, bromine.
The "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.
Such "solvates" include, but are not limited to, organic solvents or inorganic solvents, including, but not limited to, methanol, ethanol, acetone, heptane, and the like.
The "hydrates" include, but are not limited to, monohydrate, dihydrate, trihydrate, and the like.
The term "nitroxide" includes, but is not limited to, any or at least one nitrogen atom on the parent nucleus being oxidized to form an N.fwdarw.O bond.
The beneficial effects are 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 the following examples and experimental examples, which are only for illustrating the technical scheme of the present invention, but not for limiting the present invention, and any equivalent substitution in the art according to the disclosure of the present invention shall fall within the scope of the present invention.
The compounds of the present invention, stereoisomers or pharmaceutically acceptable salts thereof may be prepared by the synthetic routes of the examples, and the conventional conditions of the reaction starting materials and reaction solvents may be adjusted according to the substituents or salt-forming requirements, which may be accomplished by one skilled in the art based on the present disclosure. In addition, the column chromatography of the present invention refers to silica gel column chromatography unless otherwise specified, and the eluting solvent may be a single or mixed eluting solvent determined by combining the reaction solvent with common knowledge or common means of a person skilled in the art.
The structure of the compound is nuclear magnetic resonance 1 H NMR) or liquid mass spectrometry (LC-MS).
The liquid chromatography-mass spectrometer (LC-MS) is Agilent G6120B (matched with liquid phase Agilent 1260); nuclear magnetic resonance apparatus 1 H NMR) was Bruker AVANCE-400 or Bruker AVANCE-800,nuclear magnetic resonance 1 H NMR) shift [ ]δ) Given in parts per million (ppm), the assay solvent is DMSO, the internal standard is Tetramethylsilane (TMS), and the chemical shift is 10 -6 (ppm) is given as a unit.
The term "room temperature" according to the invention means a temperature between 10 and 25 ℃.
Example 1: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (5- (3-fluoro-4- (S) -2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-yl) propionamide:
Figure DEST_PATH_IMAGE011
step one: preparation of methyl (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1 h-pyrazolo [4,3-d ] pyrimidin-1-yl) propionate
Figure DEST_PATH_IMAGE012
1-methyl-3, 4,5, 7-tetrahydro-1H-purine-2, 6-dione (690 mg,4.15 mmol) and K are added to a 25ml three-necked flask 2 CO 3 (0.573 g,4.15 mmol) DMF (7 mL) was stirred. Methyl (R) -2- (methylsulfonyloxy) propionate (0.5 g,3.2 mmoL) was added, the reaction was stirred at room temperature overnight, and the reaction was completed, followed by saturated NH 4 Cl (20 ml) was quenched. The resulting mixture was extracted with EA (3X 20 mL). The combined organic phases were washed with water (3X 50 mL) and brine. Anhydrous Na for organic phase 2 SO 4 Dried and concentrated. The residue was purified by chromatography (MeOH: dcm=1:100), the product was collected and concentrated to dryness to give the title product as a white solid (500 mg, 50%), yield 50% purity 97.89%.
ESI-MS: m/z = 267.1(M+H) + 。
Step two: preparation of (2S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1 h-pyrazolo [4,3-d ] pyrimidin-1-yl) propionic acid
Figure DEST_PATH_IMAGE013
Into a 25mL reaction flask was charged methyl (2S) - (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1 h-pyrazolo [4,3-d ] pyrimidin-1-yl) propionate (0.35 g,1.31 mmol), dioxane (4 mL), 6N HCl (2 mL). The reaction was refluxed for 3h, cooled to room temperature, concentrated to dryness, added with 3ml of water, stirred in ice bath to precipitate a solid, filtered and dried to 250mg of a white solid product with a yield of 75.4% and a purity of 97.39%.
ESI-MS:m/z=253(M+H) + 。
Step three: preparation of methyl (S) -3-fluoro-4- (2-methylpyrrolidin-1-yl) benzoate
Figure DEST_PATH_IMAGE014
To a 50ml reaction flask was added methyl 3, 4-difluorobenzoate (1 g,5.81 mmol), (S) -2-methylpyrrolidine (0.54 g,6.39 mmol), potassium carbonate (0.88 g,6.39 mmol), DMSO (10 ml), and the mixture was heated to 80℃to react for 5 hours. After the reaction was completed, it was cooled to room temperature, water (15 ml) was added, and EA (15 ml×2) was extracted twice. The organic phases were combined, washed twice with saturated NaCl solution (15 ml x 2), separated and concentrated to dryness to give 1.3g of product in 94.2% yield with 97.50% purity.
ESI-MS:m/z=238.2(M+H) + 。
Step four: preparation of (S) -3-fluoro-4- (2-methylpyrrolidin-1-yl) benzoic acid
Figure DEST_PATH_IMAGE015
Methyl (S) -3-fluoro-4- (2-methylpyrrolidin-1-yl) benzoate (1.3 g,5.48 mmol) was added to a 25ml reaction flask, lithium hydroxide monohydrate (0.46 g,10.96 mmol) was dissolved in 5ml water and added dropwise to the reaction flask, and reacted overnight at room temperature. After the reaction, water, EA and 10% citric acid are added to adjust the pH to be acidic, the layers are separated, the organic phase is dried with anhydrous sodium sulfate, filtered and concentrated to obtain 0.9g of a product with the yield of 95.6% and the purity of 97.90%.
ESI-MS:m/z=224.1(M+H) + 。
Step five: preparation of (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine
Figure DEST_PATH_IMAGE016
To a 25ml reaction flask was added (S) -3-fluoro-4- (2-methylpyrrolidin-1-yl) benzoic acid (0.5 g,2.24 mmol), thiosemicarbazide (0.25 g,2.69 mmol), phosphorus oxychloride (4 ml), and the mixture was heated to 75℃to react overnight. At the end of the reaction, the dry phosphorus oxychloride was concentrated, DCM was added, water. Adjusting to ph=8 with sodium hydroxide solution, separating, concentrating the organic phase, purifying with silica gel column (PE: ea=2:1→1:2), collecting the product, concentrating to dryness to obtain 379mg of the product, yield 60.9%, purity 98.87%.
ESI-MS:m/z=279.1(M+H) + 。
Step six: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (5- (3-fluoro-4- (S) -2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-yl) propanamide
Figure DEST_PATH_IMAGE017
A25 ml reaction flask was charged with (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine (155 mg,0.62 mmol), (2S) -2- (1-methyl-2, 6-dioxo-3, 4,5, 6-tetrahydro-1H-purin-7 (2H) -yl) propionic acid (114 mg,0.41 mmol), HOAT (112 mg,0.82 mmol), 5ml DCM, stirred and cooled to-10℃and N-methylmorpholine (207 mg,2.05 mmol), EDCI (157 mg,0.82 mmol) was added and the reaction was maintained at 0-10℃for 2H. At the end of the reaction, water was added, DCM was extracted, the organic phase was dried by drying, column purified by silica gel chromatography (PE: ea=1:1→1:5), the product was collected and dried by concentration to give 170mg of a yellow solid product with a yield of 80.9% and a purity of 99.10%.
ESI-MS:m/z=513.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ:13.13 (s, 1H), 7.66 (s, 1H), 7.60 – 7.56 (dd, 1H), 7.52– 7.49 (dd, 1H), 6.83 – 6.79 (t, 1H), 5.80 – 5.74 (q, 1H), 4.12 – 4.07 (m 1H), 3.59 – 3.53 (m, 1H), 3.30– 3.25 (m, 1H), 3.18(s, 3H) , 3.06 (s, 3H), 2.13 – 2.04 (m, 1H), 2.02 – 1.92(m, 1H), 1.91 – 1.80 (m, 4H), 1.65 – 1.58 (m, 1H), 1.10 – 1.08(d, 3H)。
Example 2: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (4- (3-fluoro-4- (S) -2-methylpyrrolidin-1-yl) phenyl) thiazol-2-yl) propanamide
Figure DEST_PATH_IMAGE018
Step one: preparation of (S) -1- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) ethan-1-one
Figure DEST_PATH_IMAGE019
A25 ml reaction flask was charged with (S) -dimethylpyrrolidine (190 mg,2.23 mmol), 3, 4-difluoroacetophenone (317 mg,2.03 mmol), potassium carbonate (309 mg,2.23 mmol) and heated to 80℃for reaction overnight. After the reaction, the temperature was lowered to room temperature, water was added, and the mixture was extracted with EA, and the mixture was separated into layers, dried and concentrated to dryness to give 400mg of a yellow oily product with a yield of 88.9% and a purity of 98.16%.
ESI-MS:m/z=222.2(M+H) + 。
Step two: preparation of (S) -2-bromo-1- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) ethan-1-one
Figure DEST_PATH_IMAGE020
A25 ml reaction flask was charged with (S) -1- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) ethan-1-one (400 mg,1.81 mmol), anhydrous THF (5 ml), acetic acid (1 ml) and stirred to reduce the temperature to 0 ℃. Pyridinium tribromide (803 mg,2.51 mmol) was added in portions and the reaction was allowed to proceed to room temperature for 5h after completion of the addition. After the reaction, the reaction mixture was concentrated to remove THF, water was added thereto, EA was added thereto to extract, and the organic phase was dried and concentrated to dryness. Purification by silica gel column (PE: ea=15:1→5:1), collection of the product, and concentration to dryness afforded 370mg of the product as a yellow oil in 68.2% yield.
ESI-MS:m/z=301.2(M+H) + 。
Step three: preparation of (S) -4- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) thiazol-2-amine
Figure DEST_PATH_IMAGE021
A25 ml reaction flask was charged with (S) -2-bromo-1- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) ethan-1-one (370 mg,1.23 mmol), thiourea (112.6 mg,1.48 mmol), ethanol (5 ml) and heated to 80℃for 2h. After the reaction, ethanol is removed by concentration, water is added, EA extraction is carried out, and the organic phase is dried and concentrated to dryness. Purification by silica gel chromatography (PE: ea=10:1→2:1), collecting the product, concentrating to dryness gave 300mg of the product as a yellow oil in a yield of 87.7% and purity of 98.59%.
ESI-MS:m/z=278.2(M+H) + 。
The title compound was prepared in the same manner as in example 1 by substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar (S) -4- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) thiazol-2-amine to give the title compound as a pale yellow solid in yield: 66.3% and 97.20% purity.
ESI-MS: m/z = 512.2(M+H) + 。
1 HNMR (400 MHz, DMSO-d6) δ: 12.72 (s, 1H), 7.67 (s, 1H), 7.59 – 7.51 (m, 2H), 7.43 (s, 1H), 6.78 (t, 1H), 5.76 (d, 1H), 4.02 (d, 1H), 3.52 (d, 1H), 3.21 (d, 1H), 3.16 (s, 3H), 3.06 (s, 3H), 2.08 (m, 1H), 1.94 (m, 1H), 1.85 (d, 4H), 1.58 (dd, 1H), 1.06 (d, 3H)。
Example 3: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (2- (3-fluoro-4- (S) -2-methylpyrrolidin-1-yl) phenyl) pyrimidin-4-yl) propionamide
Figure DEST_PATH_IMAGE022
Step one: preparation of (S) -3-fluoro-4- (2-methylpyrrolidin-1-yl) benzimidazole
Figure DEST_PATH_IMAGE023
A25 ml three-necked flask was charged with 3, 4-difluorobenzamide hydrochloride (308 mg,1.60 mmol), (S) -dimethylpyrrolidine (150 mg,1.76 mmol), K 2 CO 3 (664 mg,4.81 mmol), DMSO (5 ml), was heated to 100deg.C with stirring and reacted for 5h. TLC monitored complete reaction of the starting material, cooling to room temperature, adding water, EA extraction, and concentrating the organic phase to dryness. The concentrate was purified by chromatography (MeOH: dcm=2:100), the product was collected and concentrated to dryness to give 180mg of the title product in 51% yield and 98.50% purity.
ESI-MS: m/z = 222.1(M+H) + 。
Step two: preparation of (S) -2- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) pyrimidin-4-amine
Figure DEST_PATH_IMAGE024
To a 25ml three-necked flask was added (S) -3-fluoro-4- (2-methylpyrrolidin-1-yl) benzimidazole (130 mg,0.59 mmol), (E) -3-ethoxyacrylonitrile (284 mg,2.94 mmol), DMSO (0.5 ml), and the mixture was heated to 130℃with stirring to react for 24 hours, and the TLC showed that most of the starting material had reacted. The reaction was cooled to room temperature, water was added, extracted with DCM and the organic phase concentrated to dryness. The concentrate was purified by column chromatography (PE: ea=2:1), the product was collected and concentrated to dryness to give 70mg of the title product in 44% yield with a purity of 96.89%.
ESI-MS: m/z = 273.1(M+H) + 。
The procedure for the preparation of the title compound was as in example 1 substituting equimolar amounts of (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine for (S) -2- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) pyrimidin-4-amine in step six to give the title compound as a white solid in yield: 51.3% and 97.50% purity.
ESI-MS: m/z = 507.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 12.35 (s, 1H), 7.67 (d, 1H), 8.22 (d, 1H), 7.80 (dd, 1H), 7.72 (dd, 1H), 7.47 (d, 1H), 7.06 (dd, 1H), 5.76 (d, 1H), 3.71 – 3.60 (m, 2H), 3.38 (s, 3H), 3.18 (s, 4H), 1.96 – 1.82 (m, 1H), 1.87 – 1.72 (m, 2H), 1.67 (d, 3H), 1.56 – 1.44 (m, 1H), 1.22 (d, 3H)。
Example 4: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (4- (3-fluoro-4- (S) -2-methylpyrrolidin-1-yl) phenyl) -5-methylthiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE025
Preparation of intermediate (S) -4- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -5-methylthiazol-2-amine
Figure DEST_PATH_IMAGE026
The preparation method of the intermediate is the same as that of the example 2, the 3, 4-difluoroacetophenone in the first step is replaced by equimolar 3, 4-difluoropropiophenone, the second step and the third step are the same, and the yellow oily intermediate compound is obtained, and the three-step reaction yield is: 43.9% and purity 98.11%.
ESI-MS: m/z = 292.2 (M+H) + 。
The title compound was prepared in the same manner as in example 1 by substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar (S) -4- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -5-methylthiazol-2-amine to give the title compound as a white solid in yield: 66.3% and 97.20% purity.
ESI-MS: m/z = 526.2 (M+H) + 。
1 HNMR (400 MHz, DMSO-d6) δ:12.54 (s, 1H), 7.66 (s, 1H), 7.35 – 7.27 (m, 2H), 6.79 (t, 1H), 5.73 (q, 1H), 4.07 – 3.96 (m, 1H), 3.53 (d, 1H), 3.21 (d, 1H), 3.17 (s, 3H), 3.04 (s, 3H), 2.41 (s, 3H), 2.08 (m, 1H), 1.95 (d, 1H), 1.83 (d, 4H), 1.59 (dt, 1H), 1.07 (d, 3H)。
Example 5: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (5- (3-fluoro-4- (S) -2- (trifluoromethyl) pyrrolidin-1-yl) -1,3, 4-oxadiazol-2-yl) propionamide
Figure DEST_PATH_IMAGE027
Preparation of intermediate (S) -5- (3-fluoro-4- (2- (trifluoromethyl) pyrrolidin-1-yl) phenyl) -1,3, 4-oxadiazol-2-amine
Figure DEST_PATH_IMAGE028
The preparation method is the same as that of example 1, the (S) -2-methylpyrrolidine in the third step is replaced by equimolar (S) -2- (trifluoromethyl) pyrrolidinyl, the hydrolysis operation method in the fourth step is the same, the thiosemicarbazide in the fifth step is replaced by equimolar semicarbazide, and an intermediate compound is obtained, and the three-step reaction yield is: 17.9%.
ESI-MS: m/z =317.1 (M+H) + 。
The procedure for the preparation of the title compound was as in example 1 substituting equimolar amounts of (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with (S) -5- (3-fluoro-4- (2- (trifluoromethyl) pyrrolidin-1-yl) phenyl) -1,3, 4-oxadiazol-2-amine to give the title compound as a white solid in yield: 60.5% and purity 98.30%.
ESI-MS: m/z = 551.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 12.42 (s, 1H), 7.66 (s, 1H), 7.59 – 7.51 (m, 2H), 6.78 (t, 1H), 5.76 (d, 1H), 4.02 (d, 1H), 3.52 (d, 1H), 3.21 (d, 1H), 3.16 (s, 3H), 3.04 (s, 3H), 2.08 (m, 1H), 1.94 (m, 1H), 1.85 (d, 4H), 1.58 (dd, 1H), 1.06 (d, 3H)。
Example 6: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (4- (3-fluoro-4- (S) -2- (trifluoromethyl) pyrrolidin-1-yl) phenyl) -5-methoxy-2-propionamide
Figure DEST_PATH_IMAGE029
Preparation of intermediate (S) -4- (3-fluoro-4- (2-trifluoromethylpyrrolidin-1-yl) phenyl) -5-methyloxazol-2-amine
Figure DEST_PATH_IMAGE030
The preparation method is the same as that of example 2, wherein 3, 4-difluoroacetophenone is replaced by equimolar 3, 4-difluoropropiophenone, and (S) -2-methylpyrrolidine is replaced by equimolar (S) -2- (trifluoromethyl) pyrrolidinyl, and thiourea is replaced by equimolar urea in the second and third steps, so as to obtain an intermediate compound, and the three steps of reaction yield: 56.9%.
ESI-MS: m/z = 330.1 (M+H) + 。
The title compound was prepared in the same manner as in example 1 by substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar (S) -4- (3-fluoro-4- (2-trifluoromethylpyrrolidin-1-yl) phenyl) -5-methyl oxazol-2-amine to give the title compound as a white solid in yield: 76.3 percent and the purity is 98.50 percent.
ESI-MS: m/z = 564.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ:12.64 (s, 1H),7.66 (s, 1H), 7.35 – 7.27 (m, 2H), 6.79 (t, 1H), 5.73 (q, 1H), 4.07 – 3.96 (m, 1H), 3.53 (d, 1H), 3.21 (d, 1H), 3.17 (s, 3H), 3.07 (s, 3H),2.51 (s, 3H), 2.08 (m, 1H), 1.95 (d, 1H), 1.83 (d, 4H), 1.59 (m, 1H), 1.07 (d, 3H)。
Example 7: preparation of (S) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) -N- (5-fluoro-4- (3-fluoro-4- (S) -2-methylpyrrolidin-1-yl) phenyl) thiazole-2-propionamide
Figure DEST_PATH_IMAGE031
Preparation of intermediate (S) -5-fluoro-4- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) thiazol-2-amine
Figure DEST_PATH_IMAGE032
A10 ml reaction flask was charged with (S) -4- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) thiazol-2-amine (250 mg,0.89 mmol), acetonitrile (2.5 ml), cooled to-25℃and SelectFluor (349 mg,0.98 mmol) was added, TLC monitored until the starting material had reacted, the reaction was complete, water was added, DCM was used for extraction, the layers were separated and the organic phase was concentrated. Purification by silica gel chromatography (PE: ea=8:1→1:1) afforded the product as a yellow oil, 100mg, 37.6% yield, as a concentrated dry.
ESI-MS:m/z=296.1(M+H) + 。
The title compound was prepared in the same manner as in example 1 by substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar (S) -5-fluoro-4- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) thiazol-2-amine to give the title compound as a yellow solid in yield: 57.6% and purity of 98.80%.
ESI-MS: m/z = 530.2 (M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 12.86 (s, 1H), 7.66 (s, 1H), 7.59 – 7.51 (m, 2H), 6.78 (t, 1H), 5.76 (d, 1H), 4.02 (d, 1H), 3.52 (d, 1H), 3.21 (d, 1H), 3.16 (s, 3H), 3.06 (s, 3H), 2.08 (m, 1H), 1.94 (m, 1H), 1.85 (d, 4H), 1.58 (dd, 1H), 1.06 (d, 3H)。
Example 8: preparation of (S) -N- (4- (2, 4-difluoro-3- (trifluoromethyl) phenyl) thiazol-2-yl) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) propanamide
Figure DEST_PATH_IMAGE033
Preparation of intermediate 4- (2, 4-difluoro-3- (trifluoromethyl) phenyl) thiazol-2-amine
Figure DEST_PATH_IMAGE034
The preparation method is the same as that of example 2, and (S) -1- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) ethane-1-ketone in the second step is replaced by equimolar 1- (2, 4-difluoro-3- (trifluoromethyl) phenyl) ethane-1-ketone, and the three steps are the same, so that a reddish brown solid intermediate compound is obtained, and the two-step reaction yield is: 65.9%.
ESI-MS: m/z = 281.0 (M+H) + 。
The title compound was prepared in the same manner as in example 1 by substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar 4- (2, 4-difluoro-3- (trifluoromethyl) phenyl) thiazol-2-amine to give the title compound as a white solid in yield: 60.3% and the purity is 96.90%.
ESI-MS:m/z=515.1(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 12.87 (s, 1H), 7.67 (d, 2H), 7.67 (d, 1H), 7.50 (t, 1H), 5.78 (q, 1H), 3.16 (s, 3H), 3.09 (s, 3H), 1.86 (d, 3H)。
Example 9: preparation of (S) -N- (4- (4- (4-aza-1-yl) -3-fluorophenyl) -5-methylthiazol-2-yl) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) propionamide
Figure DEST_PATH_IMAGE035
Preparation of intermediate 4- (4- (azepin-1-yl) -3-fluorophenyl) -5-methylthiazol-2-amine
Figure DEST_PATH_IMAGE036
The preparation method is the same as that of example 2, wherein 3, 4-difluoroacetophenone in the first step is replaced by equimolar 3, 4-difluoropropiophenone, and (S) -dimethylpyrrolidine is replaced by equimolar heptaazone, the second and third steps are the same, a yellow oily intermediate compound is obtained, and the three-step reaction yield is: 57.5%.
ESI-MS: m/z =306.1(M+H) + 。
The procedure for the preparation of the title compound was as in example 1 substituting equimolar amounts of (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine with 4- (4- (azepin-1-yl) -3-fluorophenyl) -5-methyl-thiazol-2-amine in step six to give the title compound as a white solid in yield: 66.3% and 97.20% purity.
ESI-MS: m/z = 540.2 (M+H) + 。
1 H NMR (400 MHz, DMSO-d6)δ: 12.78 (s, 1H), 8.32 (s, 1H), 7.59 – 7.51 (1H), 7.43 (s, 1H), 6.78 (t, 1H), 5.70 (d, 1H), 3.38 (s, 3H), 3.33 (m, 4H), 3.16 (s, 3H), 2.48 (s, 3H), 1.83 – 1.72 (m, 4H), 1.67 (d, 3H), 1.63 – 1.50 (m, 4H)。
Example 10: preparation of (S) -N- (4- (3, 5-difluoro-4- (S) -2-methylpyrrolidin-1-yl) -5-methylthiazol-2-yl) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) propionamide
Figure DEST_PATH_IMAGE037
Preparation of intermediate (S) -5-methyl-4- (3, 5-difluoro-4- (2-methylpyrrolidin-1-yl) phenyl) thiophen-2-amine
Figure DEST_PATH_IMAGE038
The preparation method is the same as that of example 2, the 3, 4-difluoroacetophenone in the first step is replaced by equimolar 3',4',5' -trifluoroacetophenone, the second step and the third step are the same, and the yellow oily intermediate compound is obtained, and the three-step reaction yield is: 16.3% and a purity of 96.90%.
ESI-MS: m/z = 310.1 (M+H) + 。
The title compound was prepared in the same manner as in example 1 by substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar (S) -4- (3, 5-difluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -5-methylthiazol-2-amine to give the title compound as a white solid in yield: 49.3% and the purity is 97.60%.
ESI-MS: m/z = 544.2 (M+H) + 。
1 H NMR(400 MHz, DMSO-d6)δ:12.84 (s, 1H), 7.66 (s, 1H), 7.35 – 7.27 (m, 2H), 5.73 (q, 1H), 4.07 – 3.96 (m, 1H), 3.53 (d, 1H), 3.21 (d, 1H), 3.17 (s, 3H), 3.04 (s, 3H),2.41 (s, 3H), 2.08 (m, 1H), 1.95 (d, 1H), 1.83 (d, 4H), 1.59 (m, 1H), 1.07 (d, 3H)。
Example 11: preparation of (2S) -N- (4- (4- (3, 6-diazabicyclo [3.1.1] hept-6-yl) -3-fluorophenyl) -5-methylthiazol-2-yl) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) propionamide
Figure DEST_PATH_IMAGE039
Preparation of intermediate 6- (4- (2-amino-5-methylthiazol-4-yl) -2-fluorophenyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylic acid tert-butyl ester
Figure DEST_PATH_IMAGE040
The intermediate preparation method is the same as that of example 2, wherein 3, 4-difluoroacetophenone in the first step is replaced by equimolar 3, 4-difluoropropiophenone, (S) -dimethylpyrrolidine is replaced by equimolar 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane, the second step and the third step are the same, and the intermediate compound is obtained in a yellow oil form, and the total yield of the three-step reaction: 45.1% and 97.76% purity.
ESI-MS: m/z =405.2(M+H) + 。
The procedure for the preparation of the title compound was identical to that of example 1 substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar tert-butyl 6- (4- (2-amino-5-methyl-thiazol-4-yl) -2-fluorophenyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylate to give tert-butyl 6- (4- (2- ((S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide) -5-methyl-thiazol-4-yl) -2-fluorophenyl) -3, 6-diazabicyclo [3.1.1] heptane-3-carboxylate and removing the Boc protecting group with trifluoroacetic acid to give the title compound in two-step reaction yield: 36.9% and a purity of 98.83%.
ESI-MS: m/z = 539.2 (M+H) + 。
1 H NMR(400 MHz, DMSO-d6) δ:12.98 (s, 1H), 7.66 (s, 1H), 7.59 – 7.51 (m, 1H), 7.43 (s, 1H), 6.78 (t, 1H), 5.79 (d, 1H), 4.01 (m, 2H), 3.38 (s, 3H), 3.16 (s, 3H),3.01 – 2.86 (m, 4H), 2.51 – 2.43 (m, 1H), 2.48(s, 3H) ,2.13 (dt, 1H), 1.99 (dt, 1H), 1.67 (d, 3H)。
Example 12: preparation of (2S) -N- (4- (4- (3, 8-diazabicyclo [3.2.1] Xin Tan-8-yl) -3-fluorophenyl) -5-methylthiazol-2-yl) -2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-D ] pyrimidin-1-yl) propionamide
Figure DEST_PATH_IMAGE041
Preparation of intermediate 8- (4- (2-amino-5-methylthiazol-4-yl) -2-fluorophenyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester
Figure DEST_PATH_IMAGE042
The intermediate preparation method is the same as the preparation method of example 2, wherein 3, 4-difluoroacetophenone in the first step is replaced by equimolar 3, 4-difluoropropiophenone, and (S) -dimethylpyrrolidine is replaced by equimolar 3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester, and the second and third steps are the same to obtain the yellow oily intermediate compound, and the three-step reaction yield is: 39.7% and a purity of 98.64%.
ESI-MS: m/z = 419.2(M+H) + 。
The title compound was prepared in the same manner as in example 1 by substituting (S) -5- (3-fluoro-4- (2-methylpyrrolidin-1-yl) phenyl) -1,3, 4-thiadiazol-2-amine in step six with equimolar tert-butyl 8- (4- (2-amino-5-methyl-thiazol-4-yl) -2-fluorophenyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylate to give tert-butyl 8- (4- (2- ((S) -2- (1, 3-dimethyl-2, 6-dioxo-1, 2,3, 6-tetrahydro-7H-purin-7-yl) propionamide) -5-methyl-thiazol-4-yl) -2-fluorophenyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylate and removing the Boc protecting group with trifluoroacetic acid to give the title compound in two reaction yields: 29.6% and purity of 98.80%.
ESI-MS: m/z = 553.2 (M+H) + 。
1 H NMR(400 MHz, DMSO-d6) δ:12.65 (s, 1H), 8.32 (s, 1H), 7.59 – 7.51 (m, 1H), 7.43 (s, 1H), 6.78 (t, 1H), 5.76 (d, 1H), 3.89 (m, 2H), 3.38 (s, 3H), 3.16 (s, 3H), 3.01 (m, 2H), 2.90 (m, 2H), 2.78 (q, 1H), 2.48(s, 3H) ,2.02 – 1.87 (m, 2H), 1.86 – 1.71 (m, 2H), 1.67 (d, 3H)。
Comparative example 1: preparation of N- (4- (2, 4-difluoro-3- (trifluoromethyl) phenyl) thiazol-2-yl) -2- (1, 3-dimethyl-2, 4-dioxo-1, 2,3, 4-tetrahydrothiophene [2,3-d ] imi-din-5-yl) acetamide
Figure DEST_PATH_IMAGE043
Synthesized according to the method described in patent WO2013183035A2, purity: 98.9%.
ESI-MS: m/z = 517.1(M+H) + 。
1 H NMR (300 MHz, DMSO-d6)δ: 12.48 (brs, 1H), 8.30-8.37 (q, 1H) , 7.61 (s, 1H), 7.48-7.54 (t, 1H), 7.07 (s, 1H), 4.07 (s, 2H), 3.46 (s, 3H),3.19 (s, 3H)。
Comparative example 2: preparation of (S) -3- (3- (4-chlorobenzyl) -4- (4- (3-fluoropyridin-2-yloxy) phenyl) amino) -2, 6-dioxa-3, 6-dihydropyrimidin-1 (2H) yl) -2-methylpropanoic acid
Figure DEST_PATH_IMAGE044
Synthesized according to the method described in patent WO2010075353A1, purity: 98.5%.
ESI-MS: m/z = 498.2(M+H) + 。
1 H 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
Test material for sexual function
Basic information of test article
The compounds of examples 1 to 12 (laboratory synthesis of the present invention), the compound of comparative example 1 (CRC 17536, positive control, laboratory synthesis of the present invention), and the compound of comparative example 2 (laboratory synthesis of the present invention).
Test reagent of the second aspect
Normal saline and ammonia water.
Sulfurus experimental animal
Healthy adult KM mice are male and female, 6 mice in each group, and the weight is about 28-30 g.
⒊ test method
The method comprises the steps of designing dosage and using amount of a sample
The animal cough model reported in the literature mostly adopts methods such as mechanical, chemical, electrical stimulation and the like to stimulate nerves and receptors of animals so as to cause cough. And (3) establishing a mouse cough modeling test by initially selecting a strong ammonia water induction method according to the characteristics of the candidate compound and the existing similar target compound as references.
Preparation method of test article
The preparation method of 50% ammonia water solution comprises the following steps: 2.5ml of ammonia water is measured and dissolved in 5ml of 0.9% sodium chloride injection, and the mixture is fully and uniformly mixed.
Comparative example 1 solution formulation method: 18mg of comparative example 1 was weighed and dissolved in 3ml of 0.5% CMC-Na solution, and the mixture was thoroughly mixed to prepare a solution of 6 mg/ml.
Comparative example 2 solution formulation method: 18mg of comparative example 2 was weighed and dissolved in 3ml of 0.5% CMC-Na solution, and the mixture was thoroughly mixed to prepare a solution of 6 mg/ml.
Example solution formulation method: 18mg of the examples were weighed into 3ml of 0.5% CMC-Na solution, and mixed well to prepare a solution of 6 mg/ml.
⒊ experimental operation method
6 KM mice were taken per group: comparative example 1 group, comparative example 2 group, example group, vehicle group. The mice of comparative example 1, comparative example 2 and example 1 were respectively given comparative example 1 compound (60 mg/kg), comparative example 2 compound (60 mg/kg) and example compound (60 mg/kg) by gavage, and the vehicle group was given an equal volume of 0.5% CMC-Na solution. After 30min of administration, the mice were placed in 500ml beakers, and 1 cotton ball (weight: 100.+ -. 5 mg) containing 0.3ml of 50% aqueous ammonia was placed in each beaker. Mice were observed for the number of typical coughs that occurred within 3min (typical coughing actions: abdominal muscle contraction or chest constriction, with simultaneous large mouth opening, with coughing).
⒋ results and discussion
Multi-level data processing system
(1) Cough criterion:
cough manifests as: the abdominal muscles contract or contract the chest, and simultaneously open the large mouth with cough.
(2) The number of coughs (times) in 3min of the mice was recorded by stopwatch, statistical analysis was performed by software, each group of data was statistically described by mean ± standard deviation, multi-group single factor analysis of variance was performed, and P <0.05 was statistically significant.
Discussion of results of the following
The cough times of the mice after 30min of administration of 60mg/kg of the compound of the examples are shown in the following table:
Figure DEST_PATH_IMAGE045
note that: (1) * Representation P compared to model set<0.05； ** Representation P compared to model set<0.01； # Represents P compared with comparative example 1 group<0.05; (2) The compounds used in the group of comparative example 1 and the group of example 1 represent the compound of comparative example 1 and the compound of example 1, respectively, and the other are similarly explained.
As shown in the above table, the number of coughs was significantly reduced in the compounds of the examples of the present invention compared to the model group, and the number of coughs was significantly reduced in the compounds of the examples 2,4, 7, and 9 compared to the compound of the comparative example 1, and also reduced compared to the compound of the comparative example 2, and was statistically significant.
Test example 2: serum biomarker study for rat hepatotoxicity
1. Test materials
Test article: the compounds of examples 2,4, 7, 9, 10, comparative example 2 (laboratory synthesis of the present inventors);
test reagent: 0.5% CMC-Na solution (lot number: G1226001).
Sulfurus experimental animal
Healthy adult SD rats weighing 180-200 g, 6-9 weeks of week old, total females, 6 animals per group.
⒊ test method
Preparation method of test piece
Preparation method of example compound and comparative example compound: precisely weighing a proper amount of medicine, adding 0.5% CMC-Na, and mixing by ultrasonic and vortex; formulated to a drug concentration of 12.5 mg/ml.
Experimental operation method
The method comprises the steps of taking 6 healthy adult SD rats, after taking food overnight (free drinking), taking blank serum from jugular vein for 200 microliter blood supply biochemical detection, respectively carrying out tail vein injection after blood collection, carrying out single administration of 50mg/kg, observing and recording the toxic reaction condition and death condition of each rat after administration, taking blood again from jugular vein for 24 hours after administration, detecting blood biochemical indexes (AST and ALT), and placing the rats back to a feeder cage after blood collection is finished to continuously observe the condition after administration.
⒋ results and discussion
The blood biochemical index before and after administration of each group of rats was counted as shown in the following table:
Figure DEST_PATH_IMAGE046
as is clear from the above table, the blood biochemical indicators (AST, ALT) of the mice in the examples 2,4, 7, 9 and 10 were not significantly changed before and after administration, whereas the blood biochemical indicators (AST, ALT) of the comparative example 2 were increased by 4.22 times and 9.52 times respectively after administration. The compounds of examples 2,4, 7, 9, 10 according to the present invention were shown to be significantly safer than the compound of comparative example 2 without causing liver toxicity.
The above 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 color changes made in the main design concept and spirit of the present invention are still consistent with the present invention, and all the technical problems to be solved are included in the scope of the present invention.

Claims (8)

1. A compound of formula (i) or a pharmaceutically acceptable salt thereof:
Figure FDA0004152949680000011
wherein,,
ring a is selected from substituted or unsubstituted thiazoles; the substituent of the ring A is selected from hydrogen, halogen or C1-C6 alkyl;
R 1 selected from 1 to 2R 8 Substituted ring:
Figure FDA0004152949680000012
wherein R is 8 Independently selected from hydrogen or C1-C6 alkyl;
R 2 、R 3 independently selected from hydrogen, deuterium or halogen.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from the group consisting of: hydrogen or C1-C4 alkyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:
Figure FDA0004152949680000013
4. the compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein hydrogen in the compound is substituted with one or more deuterium.
5. A process for the preparation of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure FDA0004152949680000021
wherein the ring A, R 1 、R 2 、R 3 Is defined as corresponding to claim 1;
step 1: the starting material (R) -methyl 2- (methylsulfonyloxy) propionate and 1-methyl-3, 4,5, 7-tetrahydro-1H-purine-2, 6-dione undergo substitution reaction to obtain an intermediate b: (S) -methyl 2- (4, 6-dimethyl-5, 7-dioxo-4, 5,6, 7-tetrahydro-1 h-pyrazolo [4,3-d ] pyrimidin-1-yl) propanoate;
step 2: the intermediate b undergoes hydrolysis reaction to obtain a key intermediate c;
step 3: the key intermediate c and the key intermediate a undergo condensation reaction to obtain the compound shown in the formula (I).
6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of a disease associated with TRPA1 receptor.
7. The use according to claim 6, wherein the TRPA1 receptor related disease is selected from respiratory diseases or neurological diseases.
8. The use according to claim 6, wherein the TRPA1 receptor related disease is selected from cough, asthma, pain or sleep apnea.
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