CN117924258A - Pyridone compound derivative and application thereof - Google Patents

Pyridone compound derivative and application thereof Download PDF

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Publication number
CN117924258A
CN117924258A CN202311392382.2A CN202311392382A CN117924258A CN 117924258 A CN117924258 A CN 117924258A CN 202311392382 A CN202311392382 A CN 202311392382A CN 117924258 A CN117924258 A CN 117924258A
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王永辉
卢伟强
祝晨宇
谢琼
迮书茵
周荣辉
杨新宇
王豪杰
刘明耀
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Fudan University
East China Normal University
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Fudan University
East China Normal University
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Abstract

The invention provides a pyridone compound derivative and application thereof, wherein the pyridone compound derivative has a chemical structural general formula (I) shown in the specification, and the pyridone compound derivative provided by the invention is used as a novel adenosine A 2A R inhibitor, has adenosine A 2A R inhibition activity, and can be used for preparing medicines for preventing or treating diseases related to A 2A R.

Description

Pyridone compound derivative and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a pyridone compound derivative and application thereof as an adenosine A 2A receptor (A 2A R) inhibitor, wherein the compound has adenosine A 2A R inhibition activity and is expected to be used for preparing medicaments for preventing or treating diseases related to A 2A R.
Background
Adenosine, as an endogenous purine nucleoside, is involved in a number of physiological and pathological processes: it is an essential precursor for the synthesis of Adenosine Triphosphate (ATP), a major molecule that stores cellular energy, an important metabolic intermediate for the synthesis of nucleotides. Since 1983, four subtypes of adenosine receptors (a 1R、A2AR、A2B R and a 3 R) were cloned, and extracellular adenosine acts by modulating these four types of receptors. Adenosine receptors (adenosine receptor, AR) belong to a class of G protein-coupled receptors (GPCRs) that are widely distributed in the body and play diverse roles, including: vasodilation and ischemia reperfusion, angiogenesis, heart rhythm and circulation, sleep and arousal, neurodegenerative diseases, inflammation. Targeting adenosine receptors in the hope of achieving clinical efficacy has long been apparent. Adenosine itself is used clinically as a mimetic (trade name Adenocard or Adenoscan) for the treatment of supraventricular tachycardia and caffeine is also used in some clinical settings for the apnea of premature infants, and many clinical drugs (dipyridamole, methotrexate) are likely to exert their corresponding effects via the adenosine receptor. Regadenoson (trade name Lexiscan) was approved by the us FDA as a myocardial blood perfusion imaging agent for the diagnosis of coronary artery disease, and itratheophylline (trade name Nouriast) is marketed in japan for the treatment of early parkinsonism symptoms, which more demonstrates the possibility of a 2A R as a target for drug development.
Adenosine is a potent endogenous neuromodulator in the Central Nervous System (CNS), which controls the release of many neurotransmitters, and thus is involved in affecting motor function, sleep, anxiety, pain, and psychomotor activity. The major adenosine receptor subtypes in the brain are a 1 R and a 2A R. Adenosine a 1 receptors (a 1 R) are distributed throughout the brain at high density. Inhibitors of the a 1 receptor may lower seizure thresholds and have potential for convulsive effects (e.g., cotter G, et al, 2008, j. Card. Fail. 14:631-640). The a 2A receptor (a 2A R) distribution is more localized, with a high density distribution over the basal ganglia striatum (caudate putamen, nucleus accumbens, olfactory tuberculosis), and is located on striatal output neurons along with the dopamine D 2 receptor. Discrete distribution of A 2A receptor on striatum and its inhibition on dopamine D 2 receptor, which makes A 2A receptor inhibitor exhibit improved movement disorder caused by neurodegenerative diseases such as Parkinson's disease, alzheimer's disease, huntington's chorea and psychosis (e.g.,Rodrigo C,et al.,Curr.Pharm.Des.2008,14:1512-24;Tuite P,et al.,Expert Opin.Investig.Drugs2003,12:1335-52;Popoli P.et al.,J.Neurosci.2002,22:1967-75).
These dyskinesias may often be the result of brain lesions. Diseases involving basal ganglia that cause dyskinesia include Parkinson's disease, huntington's disease, and Wilson's disease. Parkinson's disease is characterized by progressive degeneration of the nigrostriatal dopaminergic pathway. The reduced striatal dopamine levels are responsible for the symptoms of dyskinesia. Tremor, stiffness, movement disorders and posture changes are four typical symptoms of parkinson's disease, but the disease is also associated with sleep disorders, depression, anxiety, psychosis, dementia and impaired overall cognitive ability (e.g., jankovic J, et al, j.neuro.neuro.psychiatry 2008, 79:368-376). Although drugs may be used to alleviate symptoms and/or slow down the progression of the disease, parkinson's disease is a progressive and currently incurable disease and there is no definitive prophylactic treatment. Current therapies are dopamine replacement therapies based on presynaptic terminals, for example, direct stimulation of the postsynaptic D 2 receptor by using the dopamine precursor levodopa (L-DOPA) or inhibition of dopamine metabolism by using type B monoamine oxidase (MAO-B) or catechol-O-methyltransferase (COMT). Although L-DOPA is the primary means of treating parkinson's disease, the need for new therapies is still high due to tolerability problems and numerous adverse reactions, including involuntary movements and vomiting, and this adverse reaction can become more and more severe with continued treatment. To this end, highly selective inhibitors of the a 2A receptor have been shown to have efficacy in alleviating motor symptoms associated with neurodegenerative diseases such as parkinson's disease (e.g., shook and Jackson, ACS chem. Neurosci.2011, 2:555-567).
Inhibitors of the a 2A receptor may also be potentially useful therapies for the treatment of addiction. Drugs that cause mainly addiction (opiates, cocaine, ethanol, etc.) directly or indirectly regulate dopamine signaling in neurons, especially in the nucleus accumbens. Whereas the presence of high levels of the a 2A receptor in the nucleus accumbens, adenosine signaling pathway activation showed an enhancement of drug dependence, a 2A receptor inhibitor could reduce craving for addictive substances (e.g., stephen H, macdonald C, crit. Rev. Neurobiol.2003, 15:235-274).
In recent years, cancer immunotherapy has gained academic circles, industrial favor and investment of various large commercial capital, and immunological drugs of toxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are also marketed successively, so that immunotherapy will become another revolution after radiotherapy and chemotherapy and targeted therapy, and create a new situation for tumor therapy. Although immunotherapy has met with some success in various types of cancer, there are a number of compensatory immunosuppressive mechanisms in the tumor microenvironment (tumor microenvironment, TME), resulting in a lower response rate for immunotherapy. Adenosine signaling pathway plays an important role in immunoinflammatory regulation of TME, becoming a key negative feedback loop for down-regulating anti-tumor immunity. High-concentration adenosine is an important marker of TME, and activates A 2A R expressed on immune cells such as T lymphocytes, NK cells, monocytes and dendritic cells, thereby inhibiting innate immune function and adaptive immune function of the immune cells. The A 2A R inhibitor can block the combination of adenosine and A 2A R so as to reverse the immunosuppressive effect of the adenosine, and can activate anti-tumor immunity as a small molecule immune microenvironment regulator (almost all current cancer immunotherapy is polypeptide, antibody and cell medicine), and the A 2A R inhibitor has huge potential and market value as a cancer immunotherapy medicine development.
Disclosure of Invention
The invention aims to provide a compound which is used as a novel adenosine A 2A receptor (A 2A R) inhibitor, has the adenosine A 2A R inhibition activity and is expected to be used for preparing medicines for preventing or treating diseases related to A 2A R.
In a first aspect, the present invention provides a compound of the general chemical structural formula (I) or a pharmaceutically acceptable salt thereof:
X 1 is selected from N or C-R 1, preferably X 1 is N or C-R 1,R1 is selected from hydrogen, halogen, C 1-3 alkyl, halogen substituted C 1-3 alkyl, aryl or heteroaryl, more preferably R 1 is selected from hydrogen, fluorine or chlorine.
X 2 is selected from N or C-R 2, wherein R 2 is selected from hydrogen, halogen, C 1-3 alkyl, halogen substituted C 1-3 alkyl, preferably R 2 is hydrogen, cl or F.
Y is selected from O or S.
Ar is selected from an unsubstituted or substituted aryl or heteroaryl group, the substituents being selected from at least one of halogen, C 1-3 alkyl, C 1-3 alkoxy, halogen substituted C 1-3 alkyl, halogen substituted C 1-3 alkoxy and cyano; preferably Ar is an aryl or heteroaryl group which is unsubstituted or has 1 to 2 substituents, e.gWherein R 3、R4、R5 is independently selected from at least one of hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, halogen substituted C 1-3 alkyl, halogen substituted C 1-3 alkoxy, and cyano, X 3 is O, S or NH, e.g., ar is selected from/> More preferably, ar ring is unsubstituted, or substituted with F at any position, or substituted with meta-position and unsubstituted at other positions of the aromatic ring, or substituted with meta-position and a small volume ortho-position to the adjacent aromatic ring; the meta substituent is preferably selected from cyano, methyl, F, cl, methoxy; the low-volume substituents are preferably selected from methyl or F, for example Ar is selected from/>Most preferably Ar meta has cyano substitution and the other position is unsubstituted or ortho to the aromatic ring adjacent to the cyano group with methyl or F substitution, e.g. Ar is selected from/>
R a is selected from unsubstituted or substituted aryl or heteroaryl, the substituent is selected from at least one of halogen, cyano, hydroxy, C 1-6 alkoxyalkylene, C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen and hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, hydroxy substituted C 3-6 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, carboxy substituted C 1-6 alkoxy, ester substituted C 1-6 alkoxy, sulfamoyl, C 1-6 alkyl sulfone and ester; preferably, R a is aryl or heteroaryl, unsubstituted or having 1-2 substituents, e.g R 6、R7、R8 is independently selected from at least one of hydrogen, halogen, cyano, hydroxy, C 1-6 alkoxyalkylene, C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen and hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, hydroxy substituted C 3-6 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, carboxy substituted C 1-6 alkoxy, ester substituted C 1-6 alkoxy, sulfamoyl, C 1-6 alkyl sulfone, and ester, X 4 is CH or N; for example, R a is selected from More preferably, R 6、R7、R8 is independently selected from hydrogen, C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen and hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, hydroxy and/or halogen substituted C 3-6 cycloalkyl. Most preferably, R 6、R7、R8 is independently selected from hydrogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, halogen and hydroxy substituted C 1-4 alkyl, C 3-4 cycloalkyl, hydroxy and/or halogen substituted C 3-4 cycloalkyl.
R b is selected from hydrogen or halogen, preferably hydrogen, fluorine or chlorine.
L is selected from C 1-6 alkylene, preferably methylene or ethylene.
Preferably, X 2 is N or C-R 2,R2 is selected from hydrogen, fluorine or chlorine.
Preferably, the compound is selected from the following compounds:
in a second aspect, the present invention provides a process for the preparation of a compound as described above, or a pharmaceutically acceptable salt thereof, comprising the following four synthetic schemes:
The first synthesis scheme (applicable to compounds where X 2 is N and Y is O):
reagents and conditions: (a) 4, 6-dichloropyrimidin-2-amine derivative, potassium bicarbonate, bis (triphenylphosphine) palladium (II) dichloride, ethanol, 78 ℃,4 hours, 57-67%; (b) Tetrakis (triphenylphosphine) palladium, cesium carbonate, 1, 4-dioxane, 100 ℃,12 hours, 73-79%; (c) 48% hydrogen bromide aqueous solution, ethanol, reflux at 100 ℃,6 hours, 95% -100%; (d) Corresponding to bromo (R a -L-Br), N, N-dimethylformamide at 50℃for 16 hours, 62-79%;
Scheme 1 represents a general synthetic route for a portion of compounds of formula (I), starting material 1.1 is substituted with 4, 6-dichloropyrimidin-2-amine derivative via a coupling reaction to afford single substituted intermediate 1.2, which is then coupled with 2-methoxy-4-pyridineboronic acid pinacol ester to afford intermediate 1.3, which is then refluxed in 48% aqueous hydrobromic acid for 6 hours, and demethylated to afford intermediate 1.4. Finally, carrying out nucleophilic reaction with corresponding bromide to obtain a final product 1.5;
The second synthesis scheme (applicable to compounds wherein X 1 is C-R 1,X2 is N and Y is O):
Reagents and conditions: (a) Potassium bicarbonate, bis (triphenylphosphine) palladium (II) dichloride, ethanol, 78 ℃,4 hours, 57%; (b) N-iodosuccinimide, glacial acetic acid, 25 ℃ for 12 hours, 35%; (c) Potassium bicarbonate, bis (triphenylphosphine) palladium (II) chloride, 1, 4-dioxane/water, 95 ℃,12 hours, 60%; (d) Tetrakis (triphenylphosphine) palladium, cesium carbonate, 1, 4-dioxane, 100 ℃,12 hours, 70-75%; (e) 48% hydrogen bromide aqueous solution, ethanol, reflux, 6 hours, 95% -100%; (f) Corresponding to bromo (R a -L-Br), N, N-dimethylformamide at 50℃for 16 hours, 53-63%;
Scheme 2 represents a general synthetic route for a portion of compounds of formula (I), starting material 1.1 is substituted with 4, 6-dichloropyrimidin-2-amine via a coupling reaction to afford monosubstituted intermediate 1.2, which is then iodinated at the 5-position of the pyrimidine ring by N-iodosuccinimide (NIS) to afford intermediate 2.1; coupling with aryl pinacol borate to obtain an intermediate 2.2; coupling with 2-methoxy-4-pyridine pinacol borate to obtain an intermediate 2.3, refluxing in 48wt.% hydrobromic acid water solution for 6 hours, and removing methyl to obtain an intermediate 2.4; finally, carrying out nucleophilic substitution reaction on the obtained product and the corresponding bromide to obtain a final product 2.5;
Third synthetic scheme (applicable to compounds where X 1 is N, X 2 is C-F, Y is O):
Reagents and conditions: (a) Ammonia (80%), ethanol, room temperature, 48 hours, 75%; (b) Potassium bicarbonate, bis (triphenylphosphine) palladium (II) dichloride, acetonitrile, 90 ℃,4 hours, 75-80%; (c) Tetrakis (triphenylphosphine) palladium, cesium carbonate, 1, 4-dioxane, 100 ℃,12 hours, 70-75%; (d) 48% hydrogen bromide aqueous solution, ethanol, reflux, 6 hours, 95% -100%; (e) Corresponding to bromo (R a -L-Br), N, N-dimethylformamide, potassium carbonate, 50 ℃,16 hours, 52%;
Scheme 3 represents a general synthetic route for a portion of compounds of formula (I), starting material 3.1 being reacted with an aqueous ethanol solution of ammonia to afford intermediate 3.2;3.2 is coupled with aryl pinacol borate to obtain an intermediate 3.3;3.3 and 2-methoxy-4-pyridine boronic acid pinacol ester are subjected to a coupling reaction to obtain an intermediate 3.4, and then the intermediate 3.5 is obtained by refluxing in 48wt.% hydrobromic acid aqueous solution for 6 hours and removing methyl; finally, carrying out nucleophilic substitution reaction on the obtained product and the corresponding bromide to obtain a final product 3.6;
Fourth synthetic scheme (applicable to compounds where Y is S):
reagents and conditions: lawson reagent, toluene, reflux, 0.5 hours, 50-55%;
Scheme 4 represents a general synthetic route for a portion of compounds having the general chemical formula (I); intermediate 4.1 and the lawson reagent were refluxed in toluene for 0.5 hours to give the desired product 4.2.
Unless otherwise indicated, the groups and terms described in the above synthetic schemes have the same meaning as in the compounds of formula I.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a fourth aspect, the present invention provides the use of a pyridone derivative or a pharmaceutically acceptable salt thereof as described above in the manufacture of a medicament for the treatment or prophylaxis of a 2A R-related disease.
Preferably, the disease is selected from at least one of cancer, parkinson's disease, amyotrophic lateral sclerosis, coronary artery disease, mild cognitive impairment, multiple sclerosis, pericardial pseudocirrhosis, rheumatoid arthritis, bipolar disorder, experimental endotoxemia and schizophrenia.
In a fifth aspect, the invention provides an adenosine a 2A R inhibitor comprising a compound as described above, or a pharmaceutically acceptable salt thereof.
The invention provides a pyridone compound derivative which is used as a novel adenosine A 2A R inhibitor, has the adenosine A 2A R inhibition activity and can be used for preparing medicines for preventing or treating diseases related to A 2A R.
Drawings
FIGS. 1-3 illustrate the in vivo efficacy of compound 38 of the present invention in a mouse MC38 transplant tumor model; wherein, figure 1 is a graph showing tumor volume trend in MC38 colon cancer model for model group and dosing group (compound 38,100mg/kg, p.o., 1 time per day); figure 2 is the change in body weight of mice during dosing; figure 3 is a profile display after tumor sampling.
Detailed Description
The invention will be further described with reference to the accompanying drawings and the following embodiments, it being understood that the drawings and the following embodiments are only for illustrating the invention, not for limiting the invention. The same or corresponding reference numerals in the drawings denote the same parts, and a repetitive description thereof will be omitted.
The above synthetic schemes are only exemplified as methods for preparing some of the compounds of the present invention, and those skilled in the art can use similar methods to synthesize the compounds of the present invention based on the above synthetic schemes with reference to the conventional technical means and prior art.
The term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.
The "compounds" described herein may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically pure or racemic form; optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The "compounds" of the present invention also include tautomeric forms; tautomers originate from the exchange of one single bond with an adjacent double bond and accompany the migration of one proton.
The invention also includes all isotopic atoms, whether in intermediates or final compounds; the atoms of the isotope include isotopes having the same atomic number but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium. Also, if desired, for example for particular therapeutic or diagnostic treatments, the compounds of the present invention may incorporate isotopes or radioisotopes known in the art, such as 3H、15O、13 C or 13 N isotopes.
The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt which can improve physicochemical properties or metabolic properties while maintaining the pharmacological activity of the parent compound. Such salts include acid addition salts and base addition salts prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, inorganic bases), or mixtures of both. In the present invention, suitable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; suitable organic acids are, for example, acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, salicylic acid, stearic acid, muconic acid, or the like.
The compounds according to the invention may also be present in the form of solvates thereof. Such as hydrates (hemihydrate, monohydrate, dihydrate, trihydrate, etc.).
In the present invention, the terms used have the following meanings, except for the specific description.
The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "cyano" refers to-CN.
The term "hydroxy" refers to-OH.
The term "hydroxymethyl" refers to-CH 2 OH.
The term "trifluoromethyl" refers to-CF 3.
The term "alkoxy" refers to an-O-alkyl group.
The term "trifluoromethoxy" refers to-OCF 3.
The term "alkoxyalkylene", commonly known as "ether", refers to an-alkylene-O-alkyl group.
The term "carboxy" refers to-COOH.
The term "ester group" refers to a-COO-alkyl group.
The term "aminosulfonyl" refers to-SO 2NH2.
The term "alkylsulfonyl" refers to-SO 2 -alkyl.
The term "alkyl" refers to a straight or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as a C 1-C20 alkyl group, preferably a C 1-C6 alkyl group, for example methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl and the like. The alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (fused, spiro or bridged) cyclic hydrocarbon substituent, cycloalkyl containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, spiro [3.4] octyl, bicyclo [3.1.1] hexyl, and the like. The cycloalkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, halogen, sulfonyl, sulfinyl, for example, forming a halocycloalkyl group, preferably a C 3-C8 halocycloalkyl group, more preferably a C 3-C6 halocycloalkyl group.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, typically having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, and most preferably having 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, halo-substituted alkyl, alkoxy, halo-substituted alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, aralkyl, amino, halo, sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms containing 1 to 4 ring atoms selected from N, O, S, the remaining ring atoms being C and having a fully conjugated pi-electron system, including but not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrahydropyrrolyl. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, halo-substituted alkyl, alkoxy, halo-substituted alkoxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heterocycloalkyl.
The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (fused, spiro, or bridged) cyclic hydrocarbon substituent containing 1 or more heteroatoms N, O or S, the heterocycloalkyl containing 3 to 8 ring atoms, 1-3 of which are heteroatoms; preferably containing 3 to 6 ring atoms, of which 1-2 are heteroatoms. Typically a 3-6 membered heterocyclyl containing 1 or more heteroatoms of N, O or S, for example aziridin-1-yl, oxetan-3-yl, azetidin-1-yl, pyrrolidinyl, tetrahydrofuranyl, piperidino, piperazino, tetrahydropyranyl, tetrahydrothiopyranyl, dioxotetrahydrothiopyranyl, morpholino and derivatives thereof. The heterocycloalkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, halogen, sulfonyl, sulfinyl, oxo, for example, to form a halogenated heterocycloalkyl group, preferably a halogenated heterocycloalkyl group containing 3 to 8 ring atoms.
The term "alkylene" refers to a divalent radical resulting from the loss of one hydrogen atom from an alkyl group, wherein alkyl is as defined above. The alkylene group contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. For example, methylene, ethylene, propylene, butylene, and the like.
"Treatment" means any treatment of a disease in a mammal, including: (1) Preventing disease, i.e., causing no development of symptoms of clinical disease; (2) inhibiting the disease, i.e., arresting the development of clinical symptoms; (3) alleviation of the disease, i.e. causing regression of clinical symptoms.
The invention also provides a pharmaceutical composition comprising a compound as described above or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.
The term "pharmaceutical composition" as used herein refers to a formulation of one or more compounds of the present invention or salts thereof with a carrier commonly accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate the delivery of drug delivery to an organism.
The term "pharmaceutically acceptable carrier" refers to a substance co-administered with and facilitating administration of an active ingredient, including but not limited to any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring enhancers, surfactants, wetting agents, dispersing agents, disintegrants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
The pharmaceutical composition of the invention can be prepared into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, pastes, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolution, granulation, sugarcoated pill, milling, emulsification, lyophilization, and the like.
The administration route of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof includes, but is not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient. For example, a pharmaceutical composition for oral administration can be obtained as a tablet in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and processed into a mixture or granulate, if necessary with the addition of small amounts of excipients, to form tablets or cores. The tablet cores may be processed into coated formulations that are more readily absorbed by the organism (e.g., human) in combination with an optionally enteric coating material.
Pharmaceutically acceptable salts of the compounds of the invention include conventional non-toxic salts formed by reaction of basic and inorganic or organic acids. I.e. by salifying the free base of the compound with an inorganic or organic acid. The inorganic or organic acid may be selected from hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like.
If the inventive compounds are acidic, the appropriate "pharmaceutically acceptable salts" refers to salts prepared with pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Can be selected from aluminum salt, ammonium salt, lithium salt, magnesium salt, sodium salt, etc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine and caffeine and the like.
The invention also provides an application of the compound or pharmaceutically acceptable salt or solvate thereof or the pharmaceutical composition in preparing an adenosine A 2A R inhibitor.
The invention also provides application of the compound or pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as an adenosine A 2A R inhibitor in preparing medicines for treating or preventing diseases related to A 2A R.
The aforementioned A 2A R-related disease is selected from cancer (cancer), parkinson's disease, amyotrophic lateral sclerosis (amyotrophic lateral sclerosis; ALS), coronary artery disease (acroary ARTERY DISEASE), mild cognitive impairment (mild cognitive impairment), multiple sclerosis (mμ Ltiple sclerosis), pericardial pseudo-cirrhosis (Pick's disease), rheumatoid arthritis (rheumatoid arthritis), bipolar disorder (bipolar disorder), experimental endotoxemia (experimental endotoxemia), schizophrenia (schizophrenia), or a combination of the aforementioned.
In conclusion, the invention provides a compound with a structure shown in a general formula (I), and researches show that the compound can effectively inhibit an adenosine A 2A receptor, so that the level of intracellular cyclic adenosine monophosphate (cAMP) in an immune microenvironment is regulated, the immune physiological response of an organism is regulated, and the compound can be used as a medicament for treating or preventing diseases related to A 2A R.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the present invention can be prepared using the reactions shown in the schemes below. Accordingly, the following illustrative schemes are for purposes of illustration and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims and for clarity the definition of single substituents attached to the structural formula of this patent allows compounds with multiple substituents.
The present invention will be described in further detail with reference to the following examples. It is also to be understood that the following examples are given solely for the purpose of illustration and are not to be construed as limitations upon the scope of the invention, since numerous insubstantial modifications and variations will now occur to those skilled in the art in light of the foregoing disclosure. The specific process parameters and the like described below are also merely examples of suitable ranges, i.e., one skilled in the art can make a suitable selection from the description herein and are not intended to be limited to the specific values described below.
In the preparation method of the target compound, column chromatography adopts silica gel (300-400 meshes) produced by the solar desiccant Limited company in the mastia; thin layer chromatography using GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) was measured using a Varian-400 NMR; liquid chromatography (LC/MS) uses Agilent Technologies 6120 liquid chromatography.
In addition, all operations involving readily oxidizable or hydrolyzable feedstocks are performed under nitrogen protection. Unless otherwise indicated, the starting materials used in the present invention are all commercially available and can be used without further purification, but it is understood that they can be used after purification.
PE: petroleum ether;
EA: ethyl acetate;
DCM: dichloromethane;
CH 3 CN: acetonitrile;
MeOH: methanol;
EtOH: ethanol;
DMF: n, N' -dimethylformamide;
HOAc: glacial acetic acid;
KHCO 3: potassium bicarbonate;
K 2CO3: potassium carbonate;
Cs 2CO3: cesium carbonate;
pd (PPh 3)4: tetrakis (triphenylphosphine) palladium;
PdCl 2(PPh3)2: bis (triphenylphosphine) palladium (II) dichloride;
NIS: n-iodosuccinimide;
TLC: thin-layer silica gel plate (G254) analysis;
P-TLC: and (5) preparing a thin-layer silica gel plate.
Embodiment one: preparation of Compound 1
Preparation of 4- (2-amino-6- (5-methylfuran-2-yl) pyrimidin-4-yl) -1-benzylpyridin-2 (1H) -one
Step 1: preparation of 4-chloro-6- (5-methylfuran-2-yl) pyrimidin-2-amine
4, 5-Tetramethyl-2- (5-methylfuran-2-yl) -1,3, 2-dioxaborane (1.04 g,5 mmol), 4, 6-dichloropyrimidin-2-amine (480 mg,5 mmol), potassium bicarbonate (1 g,10 mmol), bis triphenylphosphine palladium dichloride (702 mg,1 mmol) were taken separately in a 100mL flask, 20mL ethanol was added and a sufficient nitrogen substitution was performed. Then, the reaction was carried out in an oil bath at 78℃for 4 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with ethyl acetate and then washed with water and then with saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (576 mg, 55%) by column chromatography (dichloromethane/ethyl acetate=100/1 to 40/1).
Step 2: preparation of 4- (2-methoxypyridin-4-yl) -6- (5-methylfuran-2-yl) pyrimidin-2-amine
The product of step 1, 4-chloro-6- (5-methylfuran-2-yl) pyrimidin-2-amine (576 mg,2.75 mmol), 2-methoxypyridine-4-pentanoylboronic acid (775.5 mg,3.3 mmol), cesium carbonate (1.8 g,5.5 mmol), and tetrakis triphenylphosphine palladium (635 mg,0.55 mmol) were separately taken in a 100mL flask, and 15mL dioxane was added with 3mL water, followed by a complete nitrogen substitution. Then, the reaction was carried out in an oil bath at 100℃for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (605 mg, 78%) by column chromatography (dichloromethane/ethyl acetate=10/1 to 3/1).
Step 3: preparation of 4- (2-amino-6- (5-methylfuran-2-yl) pyrimidin-4-yl) pyridin-2 (1H) -one
The product of step 2, 4- (2-methoxypyridin-4-yl) -6- (5-methylfuran-2-yl) pyrimidin-2-amine (605 mg,2.1 mmol), was placed in a 50mL flask, 2mL ethanol was added, and 4mL 48wt.% aqueous hydrobromic acid was added. Then, the reaction was carried out in an oil bath at 100℃for 6 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Neutralization was carried out using 8mmol/mL aqueous sodium hydroxide until the pH was 8-9. At this time, the product precipitated as a solid. The overweight product (610 mg, containing partial salts) was obtained by filtration and dried and was used in the next step without further purification, based on 100% conversion.
Step 4: preparation of 4- (2-amino-6- (5-methylfuran-2-yl) pyrimidin-4-yl) -1-benzylpyridin-2 (1H) -one
The product of step 3, 4- (2-amino-6- (5-methylfuran-2-yl) pyrimidin-4-yl) pyridin-2 (1H) -one (300 mg), benzyl bromide (205 mg,1.2 mmol), potassium carbonate (276 mg,2 mmol) was placed in a 50mL flask and 5mL of N, N-dimethylformamide was added. Then, the reaction was carried out in an oil bath at 50℃for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (143 mg, 40%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.93(d,J＝7.1Hz,1H),7.42(s,1H),7.39–7.26(m,6H),7.19(d,J＝1.8Hz,1H),6.96–6.83(m,3H),6.34(dd,J＝3.3,0.8Hz,1H),5.16(s,2H),2.39(s,3H).13C NMR(101MHz,DMSO-d6)δ163.79,161.60,161.48,156.98,154.92,150.05,148.02,139.27,137.29,128.59,127.64,127.54,117.14,113.90,108.96,103.28,100.40,51.05,13.60.ESI(m/z):[M+H]+358.9.
Embodiment two: preparation of Compound 2
Preparation of 4- (2-amino-6-phenylpyrimidin-4-yl) -1-benzyl-pyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 4, 5-tetramethyl-2-phenyl-1, 3, 2-dioxaborane. The product was isolated as a white solid (180 mg, 19%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.25(dd,J＝6.7,3.0Hz,2H),7.96(d,J＝7.1Hz,1H),7.76(s,1H),7.56–7.50(m,3H),7.39–7.28(m,6H),7.03(dd,J＝7.1,1.9Hz,1H),6.91(s,2H),5.18(s,2H).13C NMR(101MHz,DMSO-d6)δ165.47,163.94,162.12,161.66,148.14,139.18,137.29,136.91,130.69,128.62,128.57,127.65,127.52,127.10,117.48,103.46,102.60,51.07.ESI(m/z):[M+H]+354.9.
Embodiment III: preparation of Compound 3
Preparation of 4- (2-amino-6- (o-tolyl) pyrimidin-4-yl) -1-benzyl-pyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 4, 5-tetramethyl-2- (o-tolyl) -1,3, 2-dioxaborane. The product was isolated as a white solid (90 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.92(d,J＝7.1Hz,1H),7.47(d,J＝7.6Hz,1H),7.38–7.26(m,9H),7.20(d,J＝1.7Hz,1H),6.94(dd,J＝7.1,1.9Hz,1H),6.89(s,2H),5.16(s,2H),2.40(s,3H).13C NMR(101MHz,DMSO-d6)δ169.07,163.59,161.57,161.23,148.04,139.23,138.50,137.27,135.53,130.69,129.16,128.97,128.57,127.68,127.53,125.79,117.32,106.42,103.37,51.04,20.10.ESI(m/z):[M+H]+368.9.
Embodiment four: preparation of Compound 4
Preparation of 4- (2-amino-6- (m-tolyl) pyrimidin-4-yl) -1-benzylpyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 4, 5-tetramethyl-2- (m-tolyl) -1,3, 2-dioxaborane. The product was isolated as a white solid (105 mg, 15%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),8.04(d,J＝7.7Hz,1H),7.95(d,J＝7.1Hz,1H),7.73(s,1H),7.42–7.28(m,8H),7.02(dd,J＝7.1,1.6Hz,1H),6.89(s,2H),5.18(s,2H),2.41(s,3H).13C NMR(101MHz,DMSO-d6)δ165.55,163.92,162.03,161.66,148.17,139.16,137.83,137.31,136.85,131.31,128.58,128.50,127.64,127.52,124.27,117.45,103.46,102.59,51.05,21.02.ESI(m/z):[M+H]+368.9.
Fifth embodiment: preparation of Compound 5
Preparation of 4- (2-amino-6- (p-tolyl) pyrimidin-4-yl) -1-benzylpyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 4, 5-tetramethyl-2- (p-tolyl) -1,3, 2-dioxaborane. The product was isolated as a white solid (125 mg, 16%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝8.2Hz,2H),7.95(d,J＝7.1Hz,1H),7.72(s,1H),7.34(dt,J＝7.9,4.6Hz,8H),7.02(dd,J＝7.1,1.9Hz,1H),6.85(s,2H),5.18(s,2H),2.39(s,3H).13C NMR(101MHz,DMSO-d6)δ165.35,163.88,161.94,161.64,148.20,140.56,139.13,137.30,134.12,129.21,128.57,127.64,127.51,127.03,117.39,103.45,102.25,51.03,20.95.ESI(m/z):[M+H]+368.9.
Example six: preparation of Compound 6
Preparation of 4- (2-amino-6- (3-methoxyphenyl) pyrimidin-4-yl) -1-benzylpyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 2- (3-methoxyphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane. The product was isolated as a white solid (110 mg, 15%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝7.2Hz,1H),7.85(d,J＝7.9Hz,1H),7.80(d,J＝2.1Hz,1H),7.76(s,1H),7.44(t,J＝8.0Hz,1H),7.40–7.27(m,6H),7.11(dd,J＝8.1,2.2Hz,1H),7.04(dd,J＝7.1,1.9Hz,1H),6.93(s,2H),5.19(s,2H),3.86(s,3H).13C NMR(101MHz,DMSO-d6)δ165.29,163.89,162.30,162.17,161.68,159.61,148.14,139.15,138.44,137.31,129.70,128.58,127.66,127.53,119.53,117.56,116.48,112.24,103.51,102.79,55.29,51.08.ESI(m/z):[M+H]+384.9.
Embodiment seven: preparation of Compound 7
Preparation of 4- (2-amino-6- (3- (trifluoromethoxy) phenyl) pyrimidin-4-yl) -1-benzylpyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 4, 5-tetramethyl-2- (3- (trifluoromethoxy) phenyl) -1,3, 2-dioxaborane. The product was isolated as a white solid (87 mg, 10%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝8.0Hz,1H),8.25(s,1H),7.96(d,J＝7.1Hz,1H),7.85(s,1H),7.67(t,J＝8.0Hz,1H),7.54(d,J＝8.2Hz,1H),7.39–7.28(m,6H),7.05–6.96(m,3H),5.18(s,2H).13C NMR(101MHz,DMSO-d6)δ163.90,163.57,162.62,161.66,148.85,147.90,139.32,139.21,137.29,130.70,128.58,127.63,127.52,126.18,123.11,121.40,119.52,118.85,117.69,103.39,102.75,51.07.ESI(m/z):[M+H]+438.9.
Example eight: preparation of Compound 8
Preparation of 4- (2-amino-6- (3- (trifluoromethyl) phenyl) pyrimidin-4-yl) -1-benzylpyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 4, 5-tetramethyl-2- (3- (trifluoromethyl) phenyl) -1,3, 2-dioxaborane. The product was isolated as a white solid (90 mg, 11%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.62–8.56(m,2H),7.96(d,J＝7.1Hz,1H),7.90(d,J＝6.9Hz,2H),7.79(d,J＝7.8Hz,1H),7.40–7.27(m,6H),7.08–6.96(m,3H),5.18(s,2H).13CNMR(101MHz,DMSO-d6)δ163.93,163.64,162.70,161.65,147.90,139.19,137.93,137.28,131.07,129.81,129.73,129.41,128.56,127.62,127.51,127.12,127.08,125.53,123.53,123.49,122.82,117.72,103.40,102.74,51.07.ESI(m/z):[M+H]+422.9.
Example nine: preparation of Compound 9
Preparation of 4- (2-amino-6- (3-fluorophenyl) pyrimidin-4-yl) -1-benzyl-pyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 2- (3-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane. The product was isolated as a white solid (75 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.58(d,J＝8.1Hz,1H),7.99(dd,J＝12.3,7.4Hz,2H),7.92(s,1H),7.75(t,J＝7.9Hz,1H),7.41–7.32(m,6H),7.07–7.01(m,3H),5.19(s,2H).13C NMR(101MHz,DMSO-d6)δ163.96(t,J＝9.9Hz),162.56(s),161.74(s),161.43(s),148.03(s),139.55(d,J＝7.7Hz),139.28(s),137.37(s),130.72(d,J＝8.1Hz),128.66(s),127.67(d,J＝11.7Hz),123.22(s),117.68(d,J＝8.5Hz),117.42(s),113.89(s),113.66(s),103.48(s),102.82(s),54.98(s),51.16(s).ESI(m/z):[M+H]+372.9.
Example ten: preparation of Compound 10
Preparation of 3- (2-amino-6- (1-benzyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) benzonitrile
Reference is made to the synthetic route of example one. The starting material was selected from 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile. The product was isolated as a white solid (120 mg, 14%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.58(d,J＝8.1Hz,1H),7.99(dd,J＝12.3,7.4Hz,2H),7.92(s,1H),7.75(t,J＝7.9Hz,1H),7.41–7.32(m,6H),7.07–7.01(m,3H),5.19(s,2H).13C NMR(101MHz,DMSO-d6)δ163.93,163.19,162.69,161.66,147.83,139.22,137.99,137.27,134.00,131.47,130.81,129.96,128.57,127.63,127.52,118.59,117.72,111.93,103.33,102.73,51.10.ESI(m/z):[M+H]+379.9.
Example eleven: preparation of Compound 11
Preparation of 3- (2-amino-6- (1-benzyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example one. The starting material was selected from 22-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile. The product was isolated as a white solid (160 mg, 16%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.97–7.87(m,2H),7.82–7.76(m,1H),7.52(t,J＝7.7Hz,1H),7.40–7.26(m,6H),7.22(d,J＝1.8Hz,1H),7.01(s,2H),6.94(dd,J＝7.1,1.9Hz,1H),5.15(s,2H),2.55(d,J＝4.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ167.30,163.61,161.75,161.54,147.74,139.85,139.31,139.27,137.24,133.93,133.32,128.56,127.66,127.53,126.86,117.97,117.51,113.16,106.53,103.26,51.06,18.33.ESI(m/z):[M+H]+393.9.
Embodiment twelve: preparation of Compound 12
Preparation of 5- (2-amino-6- (1-benzyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example one. The starting material was selected from 2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile. The product was isolated as a white solid (80 mg, 9%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝1.7Hz,1H),8.47(dd,J＝8.2,1.8Hz,1H),7.96(d,J＝7.1Hz,1H),7.88(s,1H),7.63(d,J＝8.3Hz,1H),7.39–7.28(m,6H),7.03(dd,J＝7.1,1.9Hz,1H),6.97(s,2H),5.17(s,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ163.88,163.13,162.54,161.66,147.88,143.94,139.20,137.28,135.32,131.26,131.06,130.85,128.58,127.63,127.52,117.75,117.65,112.35,103.33,102.40,51.07,19.89.ESI(m/z):[M+H]+393.9.
Embodiment thirteen: preparation of Compound 13
Preparation of 3- (2-amino-6- (1-benzyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -5-methylbenzonitrile
Reference is made to the synthetic route of example one. The starting material was selected from 3-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile. The product was isolated as a white solid (78 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.42(s,1H),7.97(d,J＝7.1Hz,1H),7.88(s,1H),7.82(s,1H),7.39–7.30(m,6H),7.05–6.98(m,3H),5.18(s,2H),2.46(s,3H).13C NMR(101MHz,DMSO-d6)δ163.91,163.26,162.62,161.67,147.85,139.87,139.22,137.89,137.28,134.15,132.16,128.58,128.03,127.63,127.53,118.69,117.69,111.75,103.33,102.70,51.09,20.62.ESI(m/z):[M+H]+393.9.
Fourteen examples: preparation of Compound 14
Preparation of 3- (2-amino-6- (1-benzyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -4-methylbenzonitrile
Reference is made to the synthetic route of example one. The starting material was selected from 4-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile. The product was isolated as a white solid (85 mg, 9%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.99(d,J＝1.0Hz,1H),7.96(d,J＝7.1Hz,1H),7.83(dd,J＝7.9,1.3Hz,1H),7.54(d,J＝8.0Hz,1H),7.41(s,1H),7.32(ddd,J＝18.5,9.3,4.1Hz,6H),7.02(s,2H),6.98(dd,J＝7.1,1.6Hz,1H),5.17(s,2H),2.51(s,3H).13C NMR(101MHz,DMSO-d6)δ166.94,163.56,161.87,161.61,147.85,142.11,139.38,139.31,137.27,132.95,132.39,132.01,128.59,127.68,127.56,118.67,117.57,108.93,106.46,103.35,51.10,20.53.ESI(m/z):[M+H]+393.9.
Example fifteen: preparation of Compound 15
Preparation of 3- (2-amino-6- (2-oxo-1-phenethyl-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. And selecting bromophenylethane for substitution reaction in the step 4. The product was isolated as a white solid (76 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.90(dd,J＝7.7,0.9Hz,1H),7.78(d,J＝7.7Hz,1H),7.63(d,J＝7.1Hz,1H),7.52(t,J＝7.7Hz,1H),7.34–7.27(m,3H),7.26–7.18(m,4H),7.01(s,2H),6.82(dd,J＝7.1,1.9Hz,1H),4.15(t,J＝7.4Hz,2H),2.98(t,J＝7.4Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.30,163.60,161.78,161.49,147.49,139.86,139.28,138.08,133.94,133.31,128.80,128.43,126.87,126.45,117.99,117.15,113.15,106.47,102.59,54.90,50.00,34.28,18.34.ESI(m/z):[M+H]+407.9.
Example sixteen: preparation of Compound 16
Preparation of 3- (2-amino-6- (1- (4- (2-hydroxypropan-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 2- (4- (bromomethyl) phenyl) propan-2-ol was selected for substitution at step 4.
1H NMR(400MHz,DMSO)δ7.95–7.89(m,2H),7.81–7.77(m,1H),7.53(t,J＝7.7Hz,1H),7.44(d,J＝8.3Hz,2H),7.34(s,1H),7.26(d,J＝8.3Hz,2H),7.21(d,J＝1.8Hz,1H),7.00(s,2H),6.93(dd,J＝7.1,1.9Hz,1H),5.12(s,2H),4.99(s,1H),2.56(s,3H),1.40(s,6H).
Example seventeenth: preparation of Compound 17
Preparation of 3- (2-amino-6- (1- (4- (2-fluoropropane-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -4- (2-fluoroprop-2-yl) benzene was selected for substitution at step 4.
1H NMR(400MHz,DMSO)δ7.96(d,J＝7.2Hz,1H),7.91(dd,J＝7.7,0.9Hz,1H),7.79(d,J＝6.9Hz,1H),7.52(dd,J＝13.6,5.8Hz,1H),7.40(d,J＝8.3Hz,2H),7.33(d,J＝7.6Hz,3H),7.22(d,J＝1.8Hz,1H),7.01(s,2H),6.95(dd,J＝7.1,1.9Hz,1H),5.16(s,2H),2.56(s,3H),1.66(s,3H),1.60(s,3H).
Example eighteenth: preparation of Compound 18
Preparation of 3- (2-amino-6- (1- (2, 4-difluorobenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -2, 4-difluorobenzene was selected for substitution at step 4.
1H NMR(400MHz,DMSO)δ7.91(dd,J＝10.4,3.9Hz,2H),7.79(d,J＝7.8Hz,1H),7.53(t,J＝7.8Hz,1H),7.35(s,1H),7.31(dd,J＝8.7,1.7Hz,1H),7.29–7.26(m,1H),7.21(d,J＝1.8Hz,1H),7.09(td,J＝8.5,2.1Hz,1H),7.01(s,2H),6.97(dd,J＝7.2,1.9Hz,1H),5.16(s,2H),2.57(s,3H).
Example nineteenth: preparation of Compound 19
Preparation of 3- (2-amino-6- (1- ((6- (1, 3-hexafluoro-2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
With reference to the synthetic route of example eleven, the final step was to select 2- (6- (bromomethyl) pyridin-2-yl) -1, 3-hexafluoropropan-2-ol for substitution. The product was isolated as a white solid (20 mg, 19%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.22(dd,J＝6.7,3.0Hz,2H),7.92(d,J＝7.1Hz,1H),7.74(s,1H),7.58–7.52(m,3H),7.36–7.25(m,6H),7.02(dd,J＝7.1,1.9Hz,1H),6.93(s,2H),5.19(s,2H).ESI(m/z):[M+H]+561.0
Example twenty: preparation of Compound 20
Preparation of 3- (2-amino-6- (1- (2-methylbenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -2-toluene was selected for substitution at step 4. The product was isolated as a white solid (50 mg, 7%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝7.6Hz,1H),7.78(dd,J＝15.6,7.4Hz,2H),7.52(t,J＝7.7Hz,1H),7.37(s,1H),7.29–7.12(m,4H),6.99(dd,J＝15.0,13.6Hz,3H),6.84(d,J＝7.3Hz,1H),5.15(s,2H),2.57(s,3H),2.32(s,3H).13C NMR(101MHz,DMSO-d6)δ167.35,163.64,161.77,161.62,147.75,139.88,139.30,139.25,135.68,134.97,133.96,133.35,130.21,127.33,126.89,126.44,126.07,118.01,117.42,113.18,106.56,103.36,48.92,35.78,30.77,18.74,18.37.ESI(m/z):[M+H]+407.9.
Example twenty-one: preparation of Compound 21
Preparation of 3- (2-amino-6- (1- (3-methylbenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -3-toluene was selected for substitution at step 4. The product was isolated as a white solid (75 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.94–7.88(m,2H),7.80–7.76(m,1H),7.52(t,J＝7.8Hz,1H),7.34(s,1H),7.26–7.20(m,2H),7.15–7.08(m,3H),7.02(s,2H),6.93(dd,J＝7.1,1.9Hz,1H),5.11(s,2H),2.55(s,3H),2.28(s,3H).13C NMR(101MHz,DMSO-d6)δ167.32,163.63,161.76,161.55,147.72,139.87,139.34,137.75,137.20,133.97,133.36,128.52,128.24,128.21,126.91,124.80,118.01,117.51,113.17,106.55,103.25,50.98,21.01,18.36.ESI(m/z):[M+H]+407.9.
Example twenty two: preparation of Compound 22
Preparation of 3- (2-amino-6- (1- (4-methylbenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
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Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -4-toluene was selected for substitution at step 4. The product was isolated as a white solid (55 mg, 7%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.92–7.88(m,2H),7.80–7.76(m,1H),7.51(t,J＝7.7Hz,1H),7.33(s,1H),7.21(dd,J＝9.9,4.9Hz,3H),7.15(d,J＝8.0Hz,2H),7.00(s,2H),6.92(dd,J＝7.1,1.9Hz,1H),5.10(s,2H),2.55(s,3H),2.27(s,3H).13C NMR(101MHz,DMSO-d6)δ167.29,163.60,161.76,161.51,147.65,139.85,139.27,139.20,136.79,134.24,133.93,133.31,129.10,127.77,126.86,117.97,117.47,113.15,106.51,103.19,50.76,20.65,18.33.ESI(m/z):[M+H]+407.9.
Example twenty-three: preparation of Compound 23
Preparation of methyl 2- (4- (2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl) -2-oxopyridin-1 (2H) -yl) methyl) benzoate
Reference is made to the synthetic route of example eleven. Methyl 2- (bromomethyl) benzoate is selected for substitution reaction in step 4. The product was isolated as a white solid (80 mg, 7%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.96(dd,J＝7.7,0.9Hz,1H),7.93–7.89(m,1H),7.88(d,J＝7.2Hz,1H),7.80(d,J＝7.6Hz,1H),7.55(dt,J＝15.1,4.4Hz,2H),7.43(t,J＝7.5Hz,1H),7.38(s,1H),7.26(d,J＝1.7Hz,1H),7.04(s,2H),7.00(dd,J＝7.1,1.9Hz,1H),6.89(d,J＝7.8Hz,1H),5.49(s,2H),3.89(s,3H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ167.37,166.87,163.65,161.72,148.01,139.88,139.70,139.30,138.14,133.98,133.37,132.83,130.52,128.49,127.40,126.90,126.70,118.02,117.52,113.19,106.59,103.46,54.93,52.29,50.11,18.38.ESI(m/z):[M+H]+451.9.
Example twenty-four: preparation of Compound 24
Preparation of methyl 3- (4- (2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl) -2-oxopyridin-1 (2H) -yl) methyl) benzoate
Reference is made to the synthetic route of example eleven. In step 4, methyl 3- (bromomethyl) benzoate is selected for substitution reaction. The product was isolated as a white solid (98 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝7.2Hz,1H),7.94(s,1H),7.93–7.86(m,2H),7.82–7.76(m,1H),7.63(d,J＝7.8Hz,1H),7.52(t,J＝7.7Hz,2H),7.35(s,1H),7.23(d,J＝1.8Hz,1H),7.01(s,2H),6.97(dd,J＝7.2,1.9Hz,1H),5.23(s,2H),3.85(s,3H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.33,165.98,163.61,161.68,161.54,147.90,139.84,139.33,139.27,137.95,133.93,133.32,132.70,129.89,129.09,128.36,126.86,117.97,117.53,113.16,106.56,103.44,52.20,50.91,18.33.ESI(m/z):[M+H]+451.9.
Example twenty-five: preparation of Compound 25
Preparation of methyl 4- ((4- (2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl) -2-oxopyridin-1 (2H) -yl) methyl) benzoate
Reference is made to the synthetic route of example eleven. Methyl 4- (bromomethyl) benzoate was selected for substitution at step 4. The product was isolated as a white solid (68 mg, 6%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.96(dd,J＝9.5,7.8Hz,3H),7.90(dd,J＝7.7,0.9Hz,1H),7.81–7.76(m,1H),7.52(t,J＝7.8Hz,1H),7.42(d,J＝8.3Hz,2H),7.36(s,1H),7.24(d,J＝1.7Hz,1H),7.02(s,2H),6.97(dd,J＝7.1,1.9Hz,1H),5.24(s,2H),3.84(s,3H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.34,165.94,163.62,161.66,161.54,147.95,142.63,139.85,139.44,139.28,133.94,133.34,129.46,128.76,127.72,126.88,117.98,117.55,106.56,103.44,52.13,51.03,18.35.ESI(m/z):[M+H]+451.9.
Example twenty-six: preparation of Compound 26
Preparation of 3- (2-amino-6- (1- (3-fluorobenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -3-fluorobenzene is selected for substitution reaction in step 4. The product was isolated as a white solid (58 mg, 5%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝7.2Hz,1H),7.93–7.89(m,1H),7.79(d,J＝6.9Hz,1H),7.52(t,J＝7.8Hz,1H),7.41(td,J＝8.0,6.5Hz,1H),7.35(s,1H),7.23(d,J＝1.7Hz,1H),7.19–7.11(m,3H),7.03(s,2H),6.96(dd,J＝7.1,1.9Hz,1H),5.16(s,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.34,163.63,161.69,161.54,147.91,140.07,139.99,139.86,139.35,139.30,133.97,133.36,130.68,130.60,126.90,123.74,123.71,118.01,117.54,114.66,114.52,114.44,114.32,113.17,106.58,103.43,50.71,18.36.ESI(m/z):[M+H]+411.9.
Example twenty-seventh: preparation of Compound 27
Preparation of 3- (2-amino-6- (1- (3-chlorobenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -3-chlorobenzene was selected for substitution reaction at step 4. The product was isolated as a white solid (70 mg, 6%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝7.2Hz,1H),7.90(dd,J＝7.7,0.8Hz,1H),7.78(d,J＝7.7Hz,1H),7.51(t,J＝7.8Hz,1H),7.41–7.36(m,3H),7.35(s,1H),7.29(d,J＝6.9Hz,1H),7.22(d,J＝1.7Hz,1H),7.02(s,2H),6.96(dd,J＝7.2,1.9Hz,1H),5.15(s,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ167.34,163.63,161.68,161.54,147.94,139.85,139.68,139.33,133.95,133.35,133.14,130.51,127.60,127.57,126.89,126.43,118.00,117.54,113.18,106.59,103.48,50.70,18.36.ESI(m/z):[M+H]+427.9.
Example twenty-eight: preparation of Compound 28
Preparation of 3- (2-amino-6- (1- (3-bromobenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1-bromo-3- (bromomethyl) benzene was selected for substitution at step 4. The product was isolated as a white solid (90 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝7.2Hz,1H),7.90(dd,J＝7.7,1.0Hz,1H),7.81–7.76(m,1H),7.56–7.48(m,3H),7.37–7.32(m,3H),7.22(d,J＝1.8Hz,1H),7.01(s,2H),6.96(dd,J＝7.2,1.9Hz,1H),5.15(s,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.32,163.60,161.66,161.51,147.93,139.92,139.84,139.31,139.27,133.93,133.33,130.78,130.46,126.87,126.80,121.72,117.97,117.52,113.16,106.57,103.46,50.63,18.34.ESI(m/z):[M+H]+471.9.
Example twenty-nine: preparation of Compound 29
Preparation of 3- (2-amino-6- (1- (3-cyanobenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 3- (bromomethyl) benzonitrile is selected for substitution reaction at step 4. The product was isolated as a white solid (90 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝7.2Hz,1H),7.92–7.88(m,1H),7.80(d,J＝4.7Hz,2H),7.77(s,1H),7.66(d,J＝7.9Hz,1H),7.58(t,J＝7.7Hz,1H),7.52(t,J＝7.8Hz,1H),7.35(s,1H),7.22(d,J＝1.7Hz,1H),7.02(s,2H),6.97(dd,J＝7.2,1.9Hz,1H),5.19(s,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ167.34,163.62,161.64,161.55,148.00,139.85,139.34,138.76,133.95,133.35,132.70,131.42,129.90,126.89,118.59,117.99,117.54,113.16,111.47,106.58,103.55,50.73,18.34.ESI(m/z):[M+H]+418.9.
Example thirty: preparation of Compound 30
Preparation of 3- ((4- (2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl) -2-oxopyridin-1 (2H) -yl) methyl) benzenesulfonamide
Reference is made to the synthetic route of example eleven. 3- (bromomethyl) benzenesulfonamide was selected for substitution at step 4. The product was isolated as a white solid (69 mg, 5%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.00(d,J＝7.2Hz,1H),7.90(dd,J＝7.7,0.9Hz,1H),7.80–7.75(m,3H),7.58–7.49(m,3H),7.40(s,2H),7.36(s,1H),7.24(d,J＝1.7Hz,1H),7.02(s,2H),6.98(dd,J＝7.2,1.9Hz,1H),5.24(s,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.37,163.63,161.68,161.54,147.94,144.48,139.87,139.38,139.30,138.20,133.96,133.36,131.11,129.30,126.91,124.94,124.51,118.01,117.59,113.18,106.58,103.49,50.93,18.36.ESI(m/z):[M+H]+472.9.
Example thirty-one: preparation of Compound 31
Preparation of 3- (2-amino-6- (1- (3- (methylsulfonyl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
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Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -3- (methylsulfonyl) benzene was selected for substitution at step 4. The product was isolated as a white solid (85 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝7.2Hz,1H),7.94–7.86(m,3H),7.81–7.77(m,1H),7.66(d,J＝6.0Hz,2H),7.52(t,J＝7.8Hz,1H),7.36(s,1H),7.24(d,J＝1.7Hz,1H),7.02(s,2H),6.98(dd,J＝7.2,1.9Hz,1H),5.27(s,2H),3.22(s,3H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.36,163.62,161.64,161.56,147.99,141.14,139.85,139.37,139.29,138.72,133.95,133.35,132.82,129.82,126.89,126.24,125.92,117.99,117.56,113.17,106.58,103.54,50.87,43.46,18.35.ESI(m/z):[M+H]+471.9.
Example thirty-two: preparation of Compound 32
Preparation of 3- (2-amino-6- (1- (3-hydroxybenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 3- (bromomethyl) phenol was selected for substitution at step 4. The product was isolated as a white solid (30 mg, 4%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),7.90(dd,J＝11.4,4.0Hz,2H),7.79(d,J＝7.7Hz,1H),7.52(t,J＝7.7Hz,1H),7.34(s,1H),7.22(d,J＝1.7Hz,1H),7.13(t,J＝7.7Hz,1H),7.02(s,2H),6.94(dd,J＝7.1,1.9Hz,1H),6.70(dd,J＝24.2,7.8Hz,3H),5.07(s,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.32,163.63,161.77,161.55,157.55,147.73,139.87,139.38,139.30,138.64,133.96,133.35,129.59,126.90,118.11,118.00,117.49,114.47,114.30,113.17,106.54,103.22,50.87,18.36.ESI(m/z):[M+H]+409.9.
Example thirty-three: preparation of Compound 33
Preparation of 3- (2-amino-6- (1- (3-methoxybenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -3-methoxybenzene was selected for substitution reaction at step 4. The product was isolated as a white solid (65 mg, 6%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.91(dd,J＝11.3,4.1Hz,2H),7.80–7.76(m,1H),7.52(t,J＝7.7Hz,1H),7.34(s,1H),7.26(t,J＝7.9Hz,1H),7.21(d,J＝1.8Hz,1H),7.01(s,2H),6.93(dd,J＝7.2,1.9Hz,1H),6.91–6.84(m,3H),5.11(s,2H),3.73(s,3H),2.55(s,3H).13CNMR(101MHz,DMSO-d6)δ167.31,163.62,161.74,161.54,159.38,147.75,139.87,139.31,139.28,138.79,133.96,133.35,129.74,126.89,119.73,118.00,117.49,113.61,113.16,112.78,106.55,103.25,55.04,50.90,18.35.ESI(m/z):[M+H]+423.9.
Example thirty-four: preparation of Compound 34
Preparation of 3- (2-amino-6- (1- (3- (hydroxymethyl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. (3- (bromomethyl) phenyl) methanol was selected for substitution reaction at step 4. The product was isolated as a white solid (20 mg, 2%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.96–7.88(m,2H),7.78(d,J＝7.7Hz,1H),7.52(t,J＝7.7Hz,1H),7.34(s,1H),7.29(d,J＝7.7Hz,2H),7.25–7.17(m,3H),7.01(s,2H),6.94(dd,J＝7.1,1.9Hz,1H),5.21(t,J＝5.7Hz,1H),5.15(s,2H),4.47(d,J＝5.7Hz,2H),2.56(s,3H).13CNMR(101MHz,DMSO-d6)δ167.31,163.62,161.76,161.54,147.71,139.86,139.33,139.28,137.06,133.94,133.33,128.30,126.88,126.08,125.67,125.60,124.74,117.99,117.52,113.17,106.54,103.25,62.95,62.72,51.06,13.85.ESI(m/z):[M+H]+423.9.
Example thirty-five: preparation of Compound 35
Preparation of 3- (2-amino-6- (1- (3- (methoxymethylene) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -3- (methoxymethylene) benzene was selected for substitution at step 4. The product was isolated as a white solid (50 mg, 4%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.97–7.88(m,2H),7.80–7.76(m,1H),7.52(t,J＝7.7Hz,1H),7.36–7.20(m,6H),7.01(s,2H),6.94(dd,J＝7.1,1.9Hz,1H),5.15(s,2H),4.38(s,2H),3.28(s,3H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ167.31,163.61,161.73,161.53,147.74,139.86,139.32,139.27,138.71,137.30,133.94,133.33,128.51,126.88,126.82,126.69,126.66,117.98,117.51,113.16,106.54,103.28,73.44,57.58,51.00,18.34.ESI(m/z):[M+H]+437.9.
Example thirty-six: preparation of Compound 36
Preparation of 2- (3- ((4- (2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl) -2-oxopyridin-1 (2H) -yl) methyl) phenoxy) acetic acid
Compound 37 (120 mg,0.25 mmol) and lithium hydroxide monohydrate (10 mg,0.25 mmol) were placed in a 50mL flask, 5mL EtOH and 0.5mL water were added and stirred at room temperature for 6h. The reaction was monitored by TLC. After the reaction is completed. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (18 mg, 28%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.98–7.87(m,2H),7.79(d,J＝7.0Hz,1H),7.52(t,J＝7.7Hz,1H),7.34(s,1H),7.28–7.18(m,2H),7.02(s,2H),6.93(dd,J＝7.1,1.8Hz,1H),6.91–6.84(m,2H),6.83–6.78(m,1H),5.11(s,2H),4.56(s,2H),4.03(s,1H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ170.29,167.32,163.63,161.79,161.57,158.15,147.78,139.87,139.33,138.72,133.98,133.35,129.64,126.90,120.01,118.02,117.50,114.33,113.18,113.04,106.59,103.32,65.04,50.86,34.01,18.37.ESI(m/z):[M+H]+467.9.
Example thirty-seven: preparation of Compound 37
Preparation of methyl 2- (3- ((4- (2-amino-6- (3-cyano-2-methylphenyl) pyrimidin-4-yl) -2-oxopyridin-1 (2H) -yl) methyl) phenoxy) acetate
Reference is made to the synthetic route of example eleven. Methyl 2- (3- (bromomethyl) phenoxy) acetate was selected for substitution at step 4. The product was isolated as a white solid (136 mg, 12%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.91(dd,J＝12.8,4.2Hz,2H),7.81–7.76(m,1H),7.52(t,J＝7.7Hz,1H),7.34(s,1H),7.27(t,J＝7.9Hz,1H),7.22(d,J＝1.7Hz,1H),7.01(s,2H),6.96–6.90(m,2H),6.88(s,1H),6.85(dd,J＝8.2,2.4Hz,1H),5.11(s,2H),4.77(s,2H),3.68(s,3H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ169.11,167.31,163.62,161.74,161.53,157.71,147.77,139.86,139.31,139.28,138.88,133.95,133.34,129.75,126.89,120.49,117.99,117.49,114.19,113.17,106.55,103.27,64.52,51.80,50.83,18.35.ESI(m/z):[M+H]+481.9.
Example thirty-eight: preparation of Compound 38
Preparation of 3- (2-amino-6- (1- (3- (2-hydroxypropan-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 2- (3- (bromomethyl) phenyl) propan-2-ol was selected for substitution at step 4. The product was isolated as a white solid (170 mg, 15%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.95–7.88(m,2H),7.78(d,J＝7.0Hz,1H),7.51(dd,J＝13.8,5.8Hz,2H),7.39–7.33(m,2H),7.26(t,J＝7.7Hz,1H),7.22(d,J＝1.7Hz,1H),7.10(d,J＝7.6Hz,1H),7.02(s,2H),6.94(dd,J＝7.1,1.9Hz,1H),5.15(s,2H),5.03(s,1H),2.56(s,3H),1.40(s,6H).13C NMR(101MHz,DMSO-d6)δ167.33,163.63,161.77,161.56,150.98,147.69,139.87,139.37,139.30,136.64,133.98,133.36,128.01,126.90,125.17,123.94,123.90,118.02,117.51,113.17,106.55,103.23,70.54,51.23,31.96,18.37.ESI(m/z):[M+H]+451.9.
Example thirty-nine: preparation of Compound 39
Preparation of 3- (2-amino-6- (1- (3- (2-fluoropropane-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Compound 38 (112 mg,0.25 mmol) and DAST (40 mg,0.25 mmol) were placed in a 50mL flask, 5mL of methylene chloride was added thereto, nitrogen was sufficiently replaced, and the mixture was reacted at room temperature for 4 hours. After the reaction is completed. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (25 mg, 22%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝7.2Hz,1H),7.90(dd,J＝7.7,1.0Hz,1H),7.81–7.76(m,1H),7.52(t,J＝7.7Hz,1H),7.43(s,1H),7.38–7.31(m,3H),7.21(t,J＝4.4Hz,2H),7.01(s,2H),6.95(dd,J＝7.1,1.9Hz,1H),5.17(s,2H),2.56(s,3H),1.63(d,J＝22.2Hz,6H).13C NMR(101MHz,DMSO-d6)δ167.33,163.62,161.73,161.56,147.78,146.00,145.79,139.87,139.36,137.31,133.96,133.35,128.59,126.89,126.50,123.16,123.07,122.97,118.00,117.51,113.16,106.56,103.31,96.54,94.87,51.13,29.13,28.88,18.35.ESI(m/z):[M+H]+453.9.
Example forty: preparation of Compound 40
Preparation of 3- (2-amino-6- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 2- (6- (bromomethyl) pyridin-2-yl) propan-2-ol was selected for substitution at step 4. The product was isolated as a white solid (146 mg, 13%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.97–7.87(m,2H),7.82–7.70(m,2H),7.57–7.48(m,2H),7.36(s,1H),7.21(d,J＝1.7Hz,1H),7.06–6.95(m,4H),5.20(d,J＝17.8Hz,3H),2.57(s,3H),1.36(s,6H).13C NMR(101MHz,DMSO-d6)δ167.72,167.34,163.62,161.80,161.58,154.06,147.86,140.24,139.86,139.29,137.30,133.96,133.32,126.87,118.94,117.99,117.22,117.18,113.16,106.51,102.64,72.26,52.86,30.58,18.34.ESI(m/z):[M+H]+452.9.
Example forty-one: preparation of Compound 41
Preparation of 3- (2-amino-6- (1- ((6- (2-fluoropropane-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example thirty-nine. The reactions were performed by choosing examples forty and DAST. The product was isolated as a white solid (23 mg, 20%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.97–7.89(m,2H),7.86–7.78(m,2H),7.52(t,J＝7.8Hz,1H),7.44(d,J＝7.8Hz,1H),7.37(s,1H),7.22(d,J＝1.7Hz,1H),7.14(d,J＝7.7Hz,1H),7.03(s,2H),6.99(dd,J＝7.1,1.9Hz,1H),5.25(s,2H),2.57(s,3H),1.58(d,J＝22.1Hz,6H).13CNMR(101MHz,DMSO-d6)δ167.37,163.64,162.69,162.42,161.79,161.61,155.07,147.96,140.26,139.87,139.31,138.01,133.99,133.36,126.90,120.21,118.02,117.22,116.61,116.52,113.17,106.54,102.77,97.47,95.80,52.87,27.70,27.46,18.36.ESI(m/z):[M+H]+454.9.
Examples forty-two: preparation of Compound 42
Preparation of 3- (2-amino-5-fluoro-6- (1- (3- (2-hydroxypropan-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example thirty-eight. 4, 6-dichloro-5-fluoropyrimidine-2-amine is selected for the coupling reaction in step 1. The product was isolated as a white solid (116 mg, 15%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝6.9Hz,2H),7.76(d,J＝7.6Hz,1H),7.54(t,J＝7.8Hz,1H),7.49(s,1H),7.37(d,J＝7.8Hz,1H),7.27(t,J＝7.6Hz,1H),7.10(d,J＝7.5Hz,1H),6.99(d,J＝13.4Hz,3H),6.73(d,J＝7.2Hz,1H),5.16(s,2H),5.03(s,1H),2.44(s,3H),1.40(s,6H).13C NMR(101MHz,DMSO-d6)δ161.09,159.85,159.81,155.07,154.90,151.01,149.71,149.60,148.09,145.59,144.37,144.33,139.64,139.35,136.48,134.77,134.14,133.93,128.03,126.91,125.18,123.96,120.10,120.03,117.70,113.05,104.55,104.50,70.54,51.33,31.95,17.86,17.84.ESI(m/z):[M+H]+469.9.
Example forty-three: preparation of Compound 43
Preparation of 3- (2-amino-6- (1- (3- (2-hydroxypropan-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) -5-methylpyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example thirty-eight. 4, 6-dichloro-5-methylpyrimidine-2-amine is selected for the coupling reaction in the step 1. The product was isolated as a white solid (96 mg, 12%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.90–7.86(m,2H),7.57(dd,J＝7.7,1.1Hz,1H),7.53–7.46(m,2H),7.37(d,J＝7.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.09(d,J＝7.6Hz,1H),6.75(s,2H),6.57(d,J＝1.7Hz,1H),6.42(dd,J＝7.0,1.8Hz,1H),5.15(s,2H),5.03(s,1H),2.30(s,3H),1.79(s,3H),1.40(s,6H).13C NMR(101MHz,DMSO-d6)δ166.80,164.18,161.38,161.08,150.97,149.82,139.95,139.04,138.46,136.65,132.85,132.71,128.02,126.89,125.07,123.86,119.02,117.91,113.25,112.70,105.86,70.52,51.21,31.94,17.59,14.38.ESI(m/z):[M+H]+465.9.
Example forty-four: preparation of Compound 44
Preparation of 3- (2-amino-6- (1- (3- (2-hydroxypropan-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) -5- (pyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Step 1: preparation of 3- (2-amino-6-chloro-5-iodopyrimidin-4-yl) -2-tolunitrile
Step 1 of Synthesis example eleven, 3- (2-amino-6-chloropyrimidin-4-yl) -2-tolunitrile (2.44 g,10 mmol) and NIS (2.24 g,10 mmol) were placed in a 50mL flask, 10mL acetic acid was added and reacted at room temperature for 12h. The reaction was monitored by TLC. After the reaction is completed. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a brown solid (2.59 g, 70%) by column chromatography (dichloromethane/ethyl acetate=100/1 to 30/1).
Step 2: preparation of 3- (2-amino-6-chloro-5- (pyridin-4-yl) pyrimidin-4-yl) -2-tolunitrile
The product of step 1,3- (2-amino-6-chloro-5-iodopyrimidin-4-yl) -2-tolunitrile (2.59 g,7 mmol), pinacol 4-pyridineborate (1.43 g,7 mmol), potassium bicarbonate (1.4 g,14 mmol), bis triphenylphosphine palladium dichloride (982 mg,1.4 mmol) was taken in a 100mL flask, 20mL dioxane and 2mL water were added and a full nitrogen substitution was performed. Then, the reaction was carried out in an oil bath at 95℃for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with ethyl acetate and then washed with water and then with saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a brown solid (1.36 g, 60%) by column chromatography (dichloromethane/ethyl acetate=100/1 to 40/1).
The subsequent steps are the same as in thirty-eighth embodiment. The product was isolated as a white solid (80 mg, 8%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.28(d,J＝5.9Hz,2H),7.73–7.69(m,1H),7.66(d,J＝7.0Hz,1H),7.41(d,J＝7.0Hz,1H),7.35(d,J＝6.5Hz,2H),7.30–7.22(m,4H),7.02–6.97(m,2H),6.89(d,J＝7.6Hz,1H),6.29(d,J＝1.7Hz,1H),6.11(dd,J＝7.0,1.8Hz,1H),5.03(s,3H),2.26(s,3H),1.38(s,6H).13C NMR(101MHz,DMSO-d6)δ165.65,163.36,162.28,160.72,150.92,149.34,148.98,143.92,139.19,138.69,138.50,136.52,133.60,132.67,127.94,126.24,125.70,124.60,123.76,123.51,119.89,118.61,117.71,112.33,105.93,70.49,59.74,51.03,31.92,17.88.ESI(m/z):[M+H]+528.9.
Example forty-five: preparation of Compound 45
Preparation of 4- (2-amino-6- (2-fluorophenyl) pyrimidin-4-yl) -1-benzyl-pyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 2- (2-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane. The product was isolated as a white solid (75 mg, 9%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.96(dd,J＝11.3,4.4Hz,2H),7.61–7.54(m,1H),7.45(d,J＝1.8Hz,1H),7.41–7.38(m,1H),7.37(d,J＝3.8Hz,2H),7.35(d,J＝3.2Hz,3H),7.33(d,J＝1.2Hz,1H),7.15(d,J＝1.7Hz,1H),6.99(s,2H),6.89(dd,J＝7.1,1.9Hz,1H),5.17(s,2H).ESI(m/z):[M+H]+372.9
Example forty-six: preparation of Compound 46
Preparation of 4- (2-amino-6- (4-fluorophenyl) pyrimidin-4-yl) -1-benzyl-pyridin-2 (1H) -one
Reference is made to the synthetic route of example one. The starting material was selected from 2- (4-fluorophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborane. The product was isolated as a white solid (87 mg, 12%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.37–8.28(m,2H),7.95(d,J＝7.1Hz,1H),7.76(s,1H),7.39(s,1H),7.37(d,J＝2.2Hz,2H),7.35(d,J＝3.2Hz,3H),7.32(d,J＝1.6Hz,2H),7.02(dd,J＝7.1,1.9Hz,1H),6.90(s,2H),5.18(s,2H).ESI(m/z):[M+H]+372.9
Example forty-seventh: preparation of Compound 47
Preparation of 3- (2-amino-6- (1- (naphthalen-2-ylmethyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 2- (bromomethyl) naphthalene was selected for substitution at step 4. The product was isolated as a white solid (90 mg, 11%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝7.2Hz,1H),7.91(dt,J＝13.4,5.4Hz,4H),7.80(dd,J＝6.7,5.8Hz,2H),7.52(ddd,J＝8.3,6.8,3.6Hz,4H),7.36(s,1H),7.26(d,J＝1.8Hz,1H),7.01(s,2H),6.97(dd,J＝7.2,1.9Hz,1H),5.32(d,J＝9.3Hz,2H),2.57(s,3H).ESI(m/z):[M+H]+444.1
Example forty-eight: preparation of Compound 48
Preparation of 3- (2-amino-6- (1- (naphthalen-1-ylmethyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) naphthalene was selected for substitution at step 4. The product was isolated as a white solid (95 mg, 13%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝7.8Hz,1H),8.03–7.98(m,1H),7.91(dd,J＝10.6,4.2Hz,2H),7.82–7.77(m,2H),7.61(qd,J＝6.8,3.6Hz,2H),7.56–7.47(m,2H),7.36(s,1H),7.31(d,J＝1.8Hz,1H),7.21(d,J＝7.0Hz,1H),7.01(s,2H),6.95(dd,J＝7.2,1.9Hz,1H),5.67(s,2H),2.57(s,3H).ESI(m/z):[M+H]+444.1
Examples forty-nine: preparation of Compound 49
Preparation of 3- (2-amino-6- (1- (4-isopropylbenzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example eleven. 1- (bromomethyl) -4-isopropylbenzene was selected for substitution reaction at step 4. The product was isolated as a white solid (35 mg, 24%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.91(dd,J＝12.7,4.3Hz,2H),7.81–7.77(m,1H),7.53(t,J＝7.8Hz,1H),7.34(s,1H),7.28–7.20(m,5H),7.00(s,2H),6.93(dd,J＝7.1,1.9Hz,1H),5.11(s,2H),2.87(dt,J＝13.8,6.9Hz,1H),2.56(s,3H),1.19(s,3H),1.18(s,3H).ESI(m/z):[M+H]+435.9
Example fifty: preparation of Compound 50
Preparation of 3- (4-amino-5-fluoro-6- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile
Step 1: preparation of 2, 6-dichloro-5-fluoropyrimidin-4-amine
10ML of an ethanol solution of 2,4, 6-trichloro-5-fluoropyrimidine (664.6 mg,3.3 mmol) and 2 mol/L80% aqueous ammonia were taken respectively, and the reaction was stirred at room temperature for 6-7 hours. The reaction was monitored by TLC. After completion of the reaction, ethyl acetate was added to the reaction mixture to dilute the mixture, followed by washing with water and saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (447.9 mg, 75%) by column chromatography (petroleum ether/ethyl acetate=10/1 to 3/1).
Step 2: preparation of 3- (4-amino-6-chloro-5-fluoropyrimidin-2-yl) -2-methylbenzonitrile
2, 6-Dichloro-5-fluoropyrimidin-4-amine (400 mg,2.2 mmol), 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile (850.5 mg,3.5 mmol), potassium bicarbonate (600 mg,6.0 mmol) and ditriphenylphosphine palladium dichloride (193 mg,0.28 mmol) were separately taken in a 100mL flask, 10mL acetonitrile was added and the flask was thoroughly replaced with nitrogen. Then the mixture was placed in an oil bath at 90℃and reacted for 4 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was added to 100mL of water, extracted with ethyl acetate, and then washed with saturated brine. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (449.5 mg, 78%) by column chromatography (dichloromethane/ethyl acetate=40/1 to 20/1).
Step 3: preparation of 3- (6-amino-5-fluoro-2- (2-methoxypyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
3- (4-Amino-6-chloro-5-fluoropyrimidin-2-yl) -2-methylbenzonitrile (400 mg,1.5 mmol), 2-methoxy-4-pyridineboronic acid pinacol ester (423.0 mg,1.8 mmol), cesium carbonate (975.0 mg,3.0 mmol), and tetrakis triphenylphosphine palladium (77 mg,0.067 mmol) were separately taken in a 100mL flask, and 15mL dioxane and 3mL water were added to perform a sufficient nitrogen substitution. Then the mixture was placed in an oil bath at 100℃and reacted for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with ethyl acetate and then washed with water and then with saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (351.7 mg, 70%) by column chromatography (dichloromethane/ethyl acetate=100/1 to 40/1).
The subsequent steps are the same as in thirty-eighth embodiment. The product was isolated as a white solid (15 mg, 50%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.99–7.83(m,2H),7.73(t,J＝7.8Hz,2H),7.59–7.42(m,2H),7.04(d,J＝7.4Hz,2H),6.88(d,J＝19.4Hz,1H),6.71(d,J＝25.6Hz,1H),5.21(s,2H),5.16(s,1H),4.24(d,J＝7.1Hz,1H),1.35(s,6H),1.23(s,3H).ESI(m/z):[M+H]+471.1
Example fifty-one: preparation of Compound 51
Preparation of 3- (4-amino-5-chloro-6- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile
Reference is made to the synthetic route of example fifty. And selecting perchloric pyrimidine for subsequent reaction in the step1. The product was isolated as a white solid (45 mg, 15%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.92(d,J＝6.9Hz,2H),7.86(d,J＝6.9Hz,1H),7.79–7.59(m,3H),7.53(t,J＝7.5Hz,2H),7.21(s,1H),7.04–6.93(m,2H),5.19(s,2H),5.15(s,1H),2.34(s,3H),1.34(s,6H).ESI(m/z):[M+H]+487.1
Example fifty two: preparation of Compound 52
Preparation of 3- (2-amino-6- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -2-thioxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Compound 38 (100 mg,0.2 mmol), L.Lawson reagent (202.2 mg,0.5 mmol) and 5mL toluene were taken separately in 25mL flasks and refluxed for 0.5 hours, and TLC monitored the reaction. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a colourless oil (46.8 mg, 50%) by column chromatography (dichloromethane/ethyl acetate=10/1 to 3/1).
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.25(s,1H),7.89(d,J＝8.0Hz,1H),7.75(d,J＝7.0Hz,1H),7.64(s,1H),7.44(dd,J＝31.7,6.1Hz,3H),7.15–7.03(m,3H),6.99(s,1H),5.78(d,J＝20.8Hz,2H),3.77(s,1H),1.26(d,J＝25.1Hz,6H),1.08(s,3H).ESI(m/z):[M+H]+469.2
Example fifty-three: preparation of Compound 53
Preparation of 3- (2-amino-6- (1- (1-methyl-1H-pyrazol-3-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, 3- (bromomethyl) -1-methyl-1H-pyrazole was selected for substitution at step 4. The product was isolated as a white solid (32 mg, 12%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.89(d,J＝7.1Hz,1H),7.83–7.73(m,2H),7.60(s,1H),7.51(t,J＝7.8Hz,1H),7.30(s,1H),7.15(s,1H),6.98(s,2H),6.88(d,J＝6.7Hz,1H),6.13(s,1H),5.05(s,2H),3.77(d,J＝7.4Hz,3H),2.54(s,3H).ESI(m/z):[M+H]+398.1
Example fifty-four: preparation of Compound 54
Preparation of 3- (2-amino-6- (1- (1-isopropyl-1H-pyrazol-3-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, 3- (bromomethyl) -1-isopropyl-1H-pyrazole was selected for substitution at step 4. The product was isolated as a white solid (25 mg, 15%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.89(d,J＝7.5Hz,1H),7.84–7.74(m,2H),7.69(s,1H),7.51(t,J＝7.5Hz,1H),7.31(s,1H),7.17(s,1H),6.89(d,J＝7.1Hz,1H),6.10(s,1H),5.07(s,2H),4.49–4.39(m,1H),3.33(s,2H),2.54(s,3H),1.38(s,3H),1.37(s,3H).ESI(m/z):[M+H]+426.1
Example fifty-five: preparation of Compound 55
Preparation of 3- (4-amino-5-fluoro-6- (1- (1-isopropyl-1H-pyrazol-3-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-2-yl) -2-methylbenzonitrile
Referring to the synthetic route of example fifty, the final step selects 3- (bromomethyl) -1-isopropyl-1H-pyrazole for substitution reaction. The product was isolated as a white solid (25 mg, 16%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝7.2Hz,1H),7.75(dd,J＝15.2,7.2Hz,2H),7.68(s,2H),7.54(t,J＝8.0Hz,1H),7.17(s,1H),6.93(d,J＝7.0Hz,1H),6.08(s,1H),5.75(s,1H),5.05(s,2H),4.48–4.39(m,1H),2.43(s,3H),1.38(s,3H),1.36(s,3H).ESI(m/z):[M+H]+444.1
Example fifty-six: preparation of Compound 56
Preparation of 3- (2-amino-6- (1- (2-methylphenylethyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, the final step was to select 1- (2-bromoethyl) -2-methylbenzene for substitution. The product was isolated as a white solid (20 mg, 13%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ7.91(dd,J＝7.7,1.1Hz,1H),7.83–7.74(m,1H),7.64(d,J＝7.1Hz,1H),7.52(t,J＝7.7Hz,1H),7.39–7.25(m,2H),7.21–7.07(m,6H),6.83(dd,J＝7.1,1.9Hz,1H),4.08(dd,J＝17.6,9.9Hz,2H),3.03–2.91(m,2H),2.55(d,J＝6.7Hz,3H),2.32(s,3H).ESI(m/z):[M+H]+422.2
Example fifty-seven: preparation of Compound 57
Preparation of 3- (2-amino-6- (1- (3-methylphenylethyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, the final step was to select 1- (2-bromoethyl) -3-methylbenzene for substitution. The product was isolated as a white solid (26 mg, 20%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ7.97–7.86(m,1H),7.79(d,J＝7.8Hz,1H),7.63(d,J＝7.1Hz,1H),7.51(dd,J＝15.1,7.3Hz,1H),7.32(s,1H),7.17(t,J＝5.3Hz,1H),7.11(s,4H),6.99(s,1H),6.82(dd,J＝7.1,1.9Hz,1H),4.12(t,J＝7.4Hz,2H),2.92(dd,J＝14.2,7.0Hz,2H),2.73(d,J＝7.6Hz,1H),2.56(s,3H),2.27(s,3H).ESI(m/z):[M+H]+422.2
Example fifty-eight: preparation of Compound 58
Preparation of 3- (2-amino-6- (1- (4-methylphenylethyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, the final step was to select 1- (2-bromoethyl) -4-methylbenzene for substitution. The product was isolated as a white solid (25 mg, 18%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ7.90(d,J＝7.7Hz,1H),7.79(d,J＝6.8Hz,1H),7.67(d,J＝7.1Hz,1H),7.52(t,J＝7.8Hz,1H),7.33(s,1H),7.22–7.15(m,2H),7.04(dd,J＝17.5,8.5Hz,3H),6.83(dd,J＝7.1,1.9Hz,1H),4.16–4.09(m,2H),2.92(dd,J＝14.3,7.2Hz,2H),2.70–2.65(m,1H),2.56(s,3H),2.36–2.31(m,1H),2.28(s,3H).ESI(m/z):[M+H]+422.2
Example fifty-nine: preparation of Compound 59 preparation of 3- (2-amino-6- (1- (3-methoxyphenylethyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, the final step was to select 1- (2-bromoethyl) -3-methoxybenzene for substitution. The product was isolated as a white solid (19 mg, 17%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ7.90(dd,J＝7.7,1.1Hz,1H),7.79(d,J＝6.8Hz,1H),7.64(d,J＝7.2Hz,1H),7.52(t,J＝7.7Hz,1H),7.32(s,1H),7.22–7.16(m,2H),6.92–6.86(m,1H),6.71(dd,J＝7.1,1.9Hz,1H),6.55(d,J＝14.3Hz,1H),4.47(t,J＝7.0Hz,1H),4.14(dd,J＝16.8,9.2Hz,3H),3.72(d,J＝2.5Hz,3H),3.01(d,J＝7.0Hz,1H),2.94(d,J＝7.2Hz,2H),2.55(d,J＝7.0Hz,3H).ESI(m/z):[M+H]+438.1
Example sixty: preparation of Compound 60
Preparation of 3- (2-amino-6- (1- (4-methoxyphenylethyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, the final step was to select 1- (2-bromoethyl) -4-methoxybenzene for substitution. The product was isolated as a white solid (27 mg, 10%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ7.90(dd,J＝7.7,1.1Hz,1H),7.78(d,J＝6.8Hz,1H),7.62(d,J＝7.1Hz,1H),7.52(t,J＝7.8Hz,1H),7.32(s,1H),7.16(dd,J＝15.9,5.2Hz,3H),6.86(d,J＝8.6Hz,2H),6.82(dd,J＝7.1,1.9Hz,1H),4.11(t,J＝7.4Hz,3H),3.72(s,3H),2.91(t,J＝7.3Hz,3H),2.55(d,J＝8.7Hz,3H).ESI(m/z):[M+H]+438.1
Example sixty-one: preparation of Compound 61
Preparation of 3- (2-amino-6- (1- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, the final step was to select 1- (3- (bromomethyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol for substitution. The product was isolated as a white solid (15 mg, 16%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ7.90(d,J＝7.2Hz,1H),7.78(dd,J＝7.4,2.8Hz,2H),7.61(d,J＝2.1Hz,1H),7.52(t,J＝7.7Hz,2H),7.31(d,J＝7.3Hz,2H),7.18(d,J＝1.7Hz,1H),6.92–6.82(m,2H),6.16(d,J＝2.2Hz,1H),5.08(s,2H),3.96(d,J＝10.4Hz,2H),2.56(s,3H),1.05(d,J＝11.2Hz,6H).ESI(m/z):[M+H]+456.2
Examples sixty two: preparation of Compound 62
Preparation of 3- (2-amino-6- (1- ((6- (1-hydroxycyclobutyl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile
Referring to the synthetic route of example eleven, the final step was to select 1- (6- (bromomethyl) pyridin-2-yl) cyclobutan-1-ol for substitution. The product was isolated as a white solid (29 mg, 20%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ7.95(t,J＝5.8Hz,1H),7.91(d,J＝7.5Hz,1H),7.79(t,J＝8.0Hz,1H),7.74(t,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),7.44(t,J＝7.8Hz,1H),7.38–7.30(m,1H),7.20(dd,J＝6.6,1.8Hz,1H),7.12(d,J＝7.6Hz,1H),7.03–6.93(m,1H),5.25(d,J＝10.9Hz,2H),4.57(s,1H),2.56(d,J＝8.5Hz,3H),2.45–2.37(m,2H),2.21–2.09(m,2H),1.81–1.63(m,2H),1.28–1.20(m,2H).ESI(m/z):[M+H]+465.2
Example sixty-three: preparation of Compound 63
Preparation of 3- (2-amino-6- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-fluorobenzonitrile
Step one: preparation of 3- (2-amino-6-chloropyrimidin-4-yl) -2-fluorobenzonitrile
2-Fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile (1.45 g,6 mmol), 4, 6-dichloropyrimidin-2-amine (800 mg,5 mmol), potassium bicarbonate (1 g,10 mmol), bis triphenylphosphine palladium dichloride (702 mg,1 mmol) were taken separately in a 100mL flask, and 20mL ethanol was added to perform a sufficient nitrogen substitution. Then the mixture was placed in an oil bath at 78 ℃ for 4 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with ethyl acetate and then washed with water and then with saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (730 mg, 60%) by column chromatography (dichloromethane/ethyl acetate=100/1 to 40/1).
Step two: preparation of 3- (2-amino-6- (2-methoxypyridin-4-yl) pyrimidin-4-yl) -2-fluorobenzonitrile
The product of step 1, 3- (2-amino-6-chloropyrimidin-4-yl) -2-fluorobenzonitrile (730 mg,3.0 mmol), 2-methoxypyridine-4-pentanoylboronic acid (775.5 mg,3.3 mmol), cesium carbonate (1.8 g,5.5 mmol), and tetrakis triphenylphosphine palladium (635 mg,0.55 mmol) were separately taken in a 100mL flask, and 15mL dioxane was added with 3mL water, followed by a complete nitrogen substitution. Then the mixture was placed in an oil bath at 100℃and reacted for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (660 mg, 70%) by column chromatography (dichloromethane/ethyl acetate=10/1 to 3/1).
Step three: preparation of 3- (2-amino-6- (2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-fluorobenzonitrile
The product of step 2, 3- (2-amino-6- (2-methoxypyridin-4-yl) pyrimidin-4-yl) -2-fluorobenzonitrile (660 mg,2.0 mmol), was placed in a 50mL flask, 2mL ethanol was added, and 4mL 48wt.% aqueous hydrobromic acid was added. Then the mixture was placed in an oil bath at 100℃and reacted for 6 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Neutralization was carried out using 8mmol/mL aqueous sodium hydroxide until the pH was 8-9. At this time, the product precipitated as a solid. The crude product (710 mg, containing some salt) was obtained by filtration and dried and was used in the next step without further purification, based on 100% conversion.
Step four: preparation of 3- (2-amino-6- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-fluorobenzonitrile
The product of step 3, 3- (2-amino-6- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) -2-fluorobenzonitrile (100 mg), 2- (6- (bromomethyl) pyridin-2-yl) propan-2-ol (90 mg,0.40 mmol) was taken separately, and potassium carbonate (90 mg,0.65 mmol) was placed in a 50mL flask and 5mL of N, N-dimethylformamide was added. Then the mixture was placed in an oil bath at 50℃and reacted for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature. Diluted with dichloromethane and then washed with water and then saturated brine in this order. The organic phase was taken and dried over anhydrous sodium sulfate. After concentration, the product was isolated as a white solid (74 mg, 50%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(400MHz,DMSO)δ8.25(td,J＝7.7,1.6Hz,1H),8.14–8.05(m,1H),7.96(d,J＝7.1Hz,1H),7.75(t,J＝7.8Hz,1H),7.63–7.51(m,3H),7.17(d,J＝1.8Hz,1H),7.10(s,1H),7.05(d,J＝7.6Hz,1H),6.94(dd,J＝7.1,1.9Hz,1H),5.76(s,1H),5.23(s,3H),1.35(d,J＝10.1Hz,6H).ESI(m/z):[M+H]+457.2
Example sixty-four: preparation of Compound 64
Preparation of 3- (2-amino-6- (1- (3- (2-hydroxypropan-2-yl) benzyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-fluorobenzonitrile
Referring to the synthetic route of example sixty three, the final step selects 2- (3- (bromomethyl) phenyl) propan-2-ol for substitution reaction. The product was isolated as a white solid (20 mg, 18%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(600MHz,DMSO)δ8.28–8.22(m,1H),8.12–8.05(m,1H),7.94(d,J＝7.1Hz,1H),7.58(t,J＝7.8Hz,1H),7.54(d,J＝1.4Hz,1H),7.49(s,1H),7.36(t,J＝10.0Hz,1H),7.27(t,J＝7.7Hz,1H),7.18(d,J＝1.8Hz,1H),7.13–7.06(m,1H),6.91(dd,J＝7.0,1.9Hz,1H),5.16(s,2H),2.61(dd,J＝10.6,8.9Hz,1H),2.42–2.35(m,1H),2.19(t,J＝7.4Hz,1H),1.40(s,3H),1.24(s,3H).ESI(m/z):[M+H]+456.1
Examples sixty-five: preparation of Compound 65
Preparation of 3- (2-amino-6- (1- ((1-isopropyl-1H-pyrazol-3-yl) methyl) -2-oxo-1, 2-dihydropyridin-4-yl) pyrimidin-4-yl) -2-fluorobenzonitrile
Referring to the synthetic route of example sixty-three, the final step selects 3- (bromomethyl) -1-isopropyl-1H-pyrazole for substitution reaction. The product was isolated as a white solid (12 mg, 13%) by column chromatography (dichloromethane/methanol=300/3 to 300/6).
1H NMR(600MHz,DMSO)δ8.25(td,J＝7.7,1.6Hz,1H),8.12–8.06(m,1H),7.83(d,J＝7.2Hz,1H),7.70(d,J＝2.2Hz,1H),7.58(t,J＝7.8Hz,1H),7.53(d,J＝1.7Hz,1H),7.15(d,J＝1.9Hz,1H),6.91–6.85(m,1H),6.13(d,J＝2.2Hz,1H),5.09(s,2H),4.47–4.42(m,1H),2.64–2.60(m,1H),2.41–2.37(m,1H),1.39(d,J＝6.7Hz,3H),1.24–1.23(m,3H).ESI(m/z):[M+H]+430.0
Examples sixty-six: test of Compounds for inhibitory Activity on the A 2A R-cAMP Signal pathway
HEK293 cells in 10cm dishes were co-transfected with 3.0. Mu.g of human A 2A R plasmid and 3.0. Mu. g pGloSensor-22F cAMP plasmid (Promega, USA) for 24 hours using Polyethylenimine (PEI) (18. Mu.L, yeasen, china). Cells were harvested and re-inoculated into 384 Kong Baiban (2×10 4 cells/well) (Costar, USA) equilibrated with CO 2 independent medium (Gibco, USA) containing 1% glosense camp reagent (Promega, USA). After 1.5 hours of incubation at room temperature, the cells were pre-treated with different concentrations of the compound for a further 30 minutes and then stimulated with 5' -N-ethylcarboxamido adenosine (NECA) (MCE, USA). Luminescence signals were measured continuously using Cytation imaging reader (BioTek, USA). The measurement results are shown in tables 1 and 2.
TABLE 1A 2A R cAMP inhibitory Activity of some of the example compounds (inhibition @ 1. Mu.M, @ 10. Mu.M)
In table 1: ++ indicates inhibition rate 90% or more; ++ means that the inhibition ratio is 50% or more and less than 90%; ++ means that the inhibition ratio is 10% or more and less than 50%; + represents an inhibition rate of less than 10%; measured at a NECA concentration of 20 nM.
TABLE 2A 2A R cAMP inhibitory Activity of some of the example compounds (IC 50, nM)
In table 2: ++ and representing IC 50 is less than 10nM; ++ + + and representation of IC 50 is larger than equal to 10nM and less than 60nM; ++ + representing IC 50 is greater than equal to 60nM and less than 300nM; ++ means IC 50 is 300nM or more and less than 1000nM; + represents IC 50 of 1000nM or more; measured at a NECA concentration of 20 nM.
From the experimental results of A 2A R-cAMP signal channels in tables 1 and 2, the compound of the invention has better inhibition activity on A 2A R. It can be seen that for the compounds of formula (I), when Ar to the left of the formula is an aromatic ring, it is preferred that the aromatic ring has no substituents or 1 to 2 less sterically hindered substituents, e.g., CN, methyl, F, cl, methoxy; in the case of monosubstituted, the position of the substituent is preferably meta; in the case of a disubstituted substituent, the substituent positions are preferably two adjacent ortho-and meta-positions; when the substituent is F, the activities of the o-, m-and p-substituents are equivalent; particularly, when the meta substituent is a cyano group and the other positions are not substituted or have only a small volume of substituents such as methyl or F at the ortho position adjacent thereto, the inhibitory activity against a 2A R is particularly excellent. For the intermediate aromatic amine ring of formula (I), a structure in which one of X 1 and X 2 is N, especially a structure in which X 2 is N and X 1 is CH, is preferred. For Ra (aryl or heteroaryl) to the right of formula (I), it is preferred that Ra ring has no substituent or meta substituent, which is more excellent when meta contains a branched alkyl or cycloalkyl group with some steric hindrance, especially when meta contains a hydroxy and/or F substituted branched alkyl or cycloalkyl group.
Example sixty-seven: compound 38 in vivo pharmacokinetic studies in mice
Male C57BL/6 mice were selected as the test mice. Oral gavage administration was performed using compound 38 at 2mg/kg (5% dmso+10% solutol+85% saline) and 10mg/kg (5% dmso+10% solutol+85% saline). Following dosing, blood samples were collected over a 24 hour period and centrifuged to obtain plasma. The resulting plasma samples were precipitated with acetonitrile and analyzed for compounds by LC-MS/MS system. Each pharmacokinetic parameter was calculated from the plasma concentration-time curve using non-compartmental model analysis. The results are detailed in Table 3.
TABLE 3 in vivo pharmacokinetic parameters of Compound 38 mice
From the results of in vivo pharmacokinetic experiments in mice of table 3, it was shown that compound 38 has good oral bioavailability and high in vivo exposure.
Examples sixty-eight: compound 38 in vivo pharmacodynamics study in mice
C57BL/6 female mice (6 to 8 weeks old) were used purchased from National Rodent Laboratory Animal Resources (China). To establish a xenograft model, 8×10 5 MC38 cells were subcutaneously injected into the right back of C57BL/6 mice. When the average tumor volume reached about 100mm 3, the mice were randomized into model and compound 38 treatment groups. The compound 38 treatment group adopts an oral administration route, the administration frequency is 1 time a day, and the administration dosage is 100mg/kg. Tumor volume and mouse body weight were measured and tumor inhibition rate was calculated. The results are shown in FIGS. 1-3.
The results of in vivo pharmacodynamic studies in mice shown in FIGS. 1-3 indicate that compound 38 achieves 56% tumor inhibition at a dose of 100mg/kg in the mouse MC38 engraftment tumor model and exhibits superior safety.
The above embodiments further describe the objects, technical solutions and advantageous effects of the present invention in detail, it should be understood that the above is only one embodiment of the present invention and is not limited to the scope of the present invention, and the present invention may be embodied in various forms without departing from the gist of the essential characteristics of the present invention, and thus the embodiments of the present invention are intended to be illustrative and not limiting, since the scope of the present invention is defined by the claims rather than the specification, and all changes falling within the scope defined by the claims or the equivalent scope of the scope defined by the claims should be construed to be included in the claims. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A compound of the general chemical structural formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
X 1 is selected from N or C-R 1,R1 is selected from hydrogen, halogen, C 1-3 alkyl, halogen substituted C 1-3 alkyl, aryl or heteroaryl;
X 2 is selected from N or C-R 2,R2 is selected from hydrogen, halogen, C 1-3 alkyl, halogen substituted C 1-3 alkyl;
Y is selected from O or S;
Ar is selected from an unsubstituted or substituted aryl or heteroaryl group, the substituents being selected from at least one of halogen, C 1-3 alkyl, C 1-3 alkoxy, halogen substituted C 1-3 alkyl, halogen substituted C 1-3 alkoxy and cyano;
r a is selected from unsubstituted or substituted aryl or heteroaryl, the substituent is selected from at least one of halogen, cyano, hydroxy, C 1-6 alkoxyalkylene, C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, halogen and hydroxy substituted C 1-6 alkyl, C 3-6 cycloalkyl, hydroxy substituted C 3-6 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, carboxy substituted C 1-6 alkoxy, ester substituted C 1-6 alkoxy, sulfamoyl, C 1-6 alkyl sulfone and ester;
R b is selected from hydrogen or halogen;
L is selected from C 1-6 alkylene.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X 1 is N or C-R 1,R1 is selected from hydrogen, fluoro or chloro.
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 2 is N or C-R 2,R2 is selected from hydrogen, fluoro or chloro.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R b is selected from hydrogen, fluoro or chloro.
5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R a is selected from
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ar is selected from
7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein L is selected from methylene or ethylene.
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. Use of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a 2A R-related disease; preferably, the disease is selected from at least one of cancer, parkinson's disease, amyotrophic lateral sclerosis, coronary artery disease, mild cognitive impairment, multiple sclerosis, pericardial pseudocirrhosis, rheumatoid arthritis, bipolar disorder, experimental endotoxemia and schizophrenia.
CN202311392382.2A 2022-10-26 2023-10-25 Pyridone compound derivative and application thereof Pending CN117924258A (en)

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CN2022113208322 2022-10-26
CN202211320832 2022-10-26

Publications (1)

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CN117924258A true CN117924258A (en) 2024-04-26

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