heteroaryl [4,3-c] pyrimidine-5-amine derivatives, method of preparing them, and medical uses thereo

专利摘要:
a heteroaryl [4,3-c] pyrimidin-5-amine derivative, a method of preparing it, and medical uses of it. specifically, a heteroaryl [4,3-c] pyrimidin-5-amine derivative represented by a general formula (i), a method of preparing the same, a pharmaceutical composition containing the derivative, and uses thereof as therapeutic agents in particular, a use as an a2a receptor antagonist and a use in the preparation of a medicament for the treatment of conditions or symptoms that are ameliorated by inhibition of the a2a receptor; various substituent groups in the general formula (i) have the meanings identical to those in the specification.
公开号:BR112019017108A2
申请号:R112019017108
申请日:2018-03-15
公开日:2020-04-07
发明作者:Lu Biao；He Feng；Wang Shenglan；Tao Weikang；Shen Xiaodong
申请人:Jiangsu Hengrui Medicine Co；Shanghai hengrui pharmaceutical co ltd；
IPC主号:

专利说明:

Invention Patent Descriptive Report for HETEROARY DERIVATIVES [4,3-C] PYRIMIDIN-5-AMINE, METHOD OF PREPARATION OF THE SAME, AND MEDICAL USES OF THE SAME. FIELD OF THE INVENTION [001] The present invention belongs to the field of medicine and relates to a heteroaryl [4,3-c] pyrimidine-5-amine derivative of formula (I), a method for preparing the same, a pharmaceutical composition comprising the same, a use thereof as a therapeutic agent, in particular as an A2a receptor antagonist, and a use thereof in the preparation of a medicament for the treatment of a disease or condition improved by inhibition of the A _2a receptor.
BACKGROUND OF THE INVENTION [002] Adenosine is a naturally occurring purine nucleoside, and is an endogenous regulator of most physiological functions. It plays an important role in regulating the cardiovascular system, central nervous system, respiratory system, kidney, fat and platelets.
[003] The action of adenosine is mediated by a family of receptors coupled to protein G. It is now known that there are at least four subtypes of adenosine receptors, which are classified into Ai, A2a, A2b and A3. Among them, the A1 and A3 receptors inhibit the activity of the adenylate cyclase enzyme, while the A2a and A2b receptors stimulate the activity of the same enzyme, thereby modulating the level of cyclic AMP in cells. Adenosine regulates a wide range of physiological functions through these receptors.
[004] The A2a receptor (A2aR) is widely distributed in the body, and is mainly expressed in the striatum in the central nervous system, and is also expressed in tissues such as the periphery, heart, lung and kidney. Several subclinical studies show that the receiving agonists
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2/119 adenosine A2a tor surprisingly has efficacy in the treatment of neurodegenerative diseases, mainly Parkinson's disease, Huntington's disease or Alzheimer's disease (Trends in Neurosci. 2006, 29 (11), 647-654; Expert Opinion on Therapeutic Patents, 2007, 17, 979-991 and the like). In addition, adenosine A2a receptor antagonists can also be used to treat other diseases related to the central nervous system (CNS) such as depression, restless syndrome, sleep disorders and anxiety disorders (Clin. Neuropharmacol. 2010, 33, 55 -60; J. Neurosci. 2010, 30 (48), 1628416292; Parkinsonisn Report Disord. 2010, 16 (6), 423-426; and references in these: Mov. Disorders, 2010, 25 (2), S305). In addition, adenosine A2a receptor antagonists also have therapeutic potential as neuroprotective agents (see, Jenner P. J Neuro I. 2000; 24 7Supp12: 1143-50).
[005] Recent studies indicate that the activation of the A2a adenosine receptor can exert an important immunomodulatory effect in many pathological processes such as ischemia, hypoxia, inflammation, trauma, transplantation and the like, which may be related to the higher level of expression of the receptor A2a in various immune cells such as T cells, B cells, monocyte, macrophages, neutrophils and the like. In addition, activation of the A2a receptor can stimulate the body to generate immune tolerance, and participate closely in the formation of immune escape or immunosuppression of tumor cells, thereby creating a favorable condition for the occurrence and development of tumors. Lokshin and colleagues (Cancer Res. 1 August 2006; 66 (15): 7758-65) demonstrate that activation of A2aR in natural killer cells can inhibit tumor cell death by natural killer cells by increasing cAMP and activation of PKA. Studies also show that A2a receptor activation can promote the proliferation of tumor cells such as cells
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A375 melanoma, NIH3T3 fibroblast cells, PC12 pheochromocytoma cells and the like, which may be related to the fact that A2a receptor activation in T cells can inhibit T cell activation, proliferation, tumor cell adhesion, and produce effect cytotoxic in tumor cells. However, in A2a receptor knockout mice, the anti-tumor immunity of CD8 ⁺ T cells can be enhanced, and tumor proliferation is significantly inhibited. Therefore, A2a receptor antagonists can also be used in the treatment of tumor.
[006] Although compounds with significant biological activity in a variety of adenosine receptor subtypes can have a therapeutic effect, they can cause unwanted side effects. For example, during tissue ischemia / hypoxia, when cells of the central system, circulatory system, digestive system and skeletal muscle are in an environment of anoxic and hypoxic stress, aggregate extracellular adenosine initiates a mechanism activating the Ai adenosine receptor on the cell membrane , thereby increasing the tolerance of cells to apoxia and hypoxia. The Ai receptor located in immune cells can promote immune responses in a hypoxic environment. In addition, the Ai receptor can also reduce free fatty acids and triglycerides, and is involved in the regulation of blood glucose. Therefore, the continued blockage of the Ai receptor can cause several adverse effects on body tissues (Chinese Pharmacological Bulletin, 2008, 24 (5), 573-576). For example, it is reported that blocking the Ai receptor will cause adverse effects, such as anxiety, arousal and the like in animal models (Basic & Clinicai Pharmacology & Toxicology, 2011, 109 (3), 203-7). Adenosine released by the A3 adenosine receptor during myocardial ischemia has a strong protective effect on the heart (as described by Gessi S et al, Pharmacol. Ther. 117 (1), 2008, 123-140). Continued blocking of
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4/119 receptor A3 can increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease such as angina or heart failure.
[007] Currently, many compounds have been developed as A2a receptor antagonists for the treatment of various diseases, as described in W02007116106, W02009080197, WO2011159302, WO2011095625, W201110101373 and WO2015031221. However, there are still problems, such as low solubility, photosensitivity, low activity, low selectivity and low bioavailability.
[008] The present invention provides a structure of heteroaryl [4,3-c] pyrimidine-5-amine as an adenosine A2a receptor antagonist, and finds that compounds having such a structure have potent inhibitory activity, high selectivity, low concentration of free drug in the brain, weak ability to cross the blood-brain barrier, and less side effects that are likely to be generated after the drug enters the brain.
SUMMARY OF THE INVENTION [009] The purpose of the present invention is to provide a compound of formula (I):
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, [0010] where:
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5/119 [0011] G is N or CR ⁴ ;
[0012] ring A is selected from the group consisting of cycloalkyl, aryl and heteroaryl;
[0013] each R ¹ is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
[0014] R ² is selected from the group consisting of alkoxy, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, in which the alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, C (O) OR ⁵ and R ^b ;
[0015] R ³ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
[0016] R ⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
[0017] R ⁵ is selected from the group consisting of hydrogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
[0018] R ^b is heterocyclylalkyl, wherein the heterocyclyl of the heterocyclylalkyl is optionally substituted by one or more substituents selected from the group consisting of alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl, heteroaryl and C (O) OR ⁵ ; and [0019] right 1,2, 3 or 4.
[0020] In a preferred embodiment of the present invention, in the compound of formula (I), R ² is selected from the group consisting of
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6/119 cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, in which cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, oxo, cycloalkyl, heterocyclyl and R ^b ; R ^b is heterocyclylalkyl, wherein the heterocyclyl of the heterocyclylalkyl is optionally substituted by one or more alkyls.
[0021] In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (II):
(H) [0022] or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, [0023] where:
[0024] ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
[0025] each R ⁶ is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl , C (O) OR ⁵ and R ^b ;
[0026] seO, 1,2, 3 or 4; and [0027] ring A, G, R ¹ , R ³ , R ⁵ , R ^{b and} n are as defined in the formula (D [0028] In a preferred embodiment of the present invention, the
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7/119 compound of formula (I) is a compound of formula (III):
(Hl) [0029] or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, [0030] where:
[0031] each R ⁶ is identical or different and each is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, oxo, cycloalkyl, heterocyclyl and R ^b ; R ^b is heterocyclylalkyl, wherein the heterocyclyl of the heterocyclylalkyl is optionally substituted by one or more alkyl;
[0032] ring A, ring B, R ¹ , R ³ , nes are as defined in formula (II).
[0033] In a preferred embodiment of the present invention, in the compound of formula (II), ring B is selected from the group consisting of phenyl, 5 to 6 membered heterocyclyl and 5 to 10 membered heteroaryl, and preferably phenyl, pyridyl , pyrazolyl, pyridin-2-one, imidazolyl, pyrrolyl, furyl, thienyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, isoquinolyl, quinolyl, quinoxalinyl, indolyl, indazolyl, benzofuranyl and benzothienyl.
[0034] In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (III '):
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(III ') [0035] or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, [0036] where:
[0037] each R ⁶ is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, oxo, cycloalkyl, heterocyclyl and R ^b ; R ^b is heterocyclylalkyl, wherein the heterocyclyl of the heterocyclylalkyl is optionally substituted by one or more alkyl;
[0038] s is 0, 1, 2, 3 or 4; ring A, R ¹ , R ^{3 and} n are as defined in formula (I).
[0039] In a preferred embodiment of the present invention, in the compound of formula (I), ring A is aryl or heteroaryl, and preferably phenyl or furyl.
[0040] In a preferred embodiment of the present invention, in the compound of formula (I), R ¹ is selected from the group consisting of hydrogen, halogen and alkyl.
[0041] In a preferred embodiment of the present invention, in the compound of formula (I), R ³ is selected from the group consisting of hydrogen, halogen and alkyl.
[0042] Typical compounds of the present invention include, but are not limited to:
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Example No. Structure and name of the compound 1 CM mi. u. U- ^{z =} 8- (2-Methyl-6- (trifluoromethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine1 2 HN I I jf _n ^ n ^ nh ₂ 27-Phenyl-8- (1/7-pyrazol-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 2 3 O r 1 Ί T Γ if n ^ n nh ₂ 37-Phenyl-8- (quinolin-6-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 3 4 Q n η jl JI I if N ^ N nh ₂ 48- (2-Chloro-6-methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 4 5 / AO f if N, N NH ₂ 58- (8-Methylquinolin-6-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 5 6 CM z / = ZEZ'z8- (7-Fluoro-1/7-indazol-5-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 6
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7 CM «Λ / ΛΟ8- (8-Fluoroquinolin-6-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 7 8 / N% T Ji 1 1 i if O nh ₂ 19 = ⁷ 88- (2-Methyl-6- (trifluoromethyl) pyridin-4-yl) -7- (5-methylfuran-2-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 8 9 F ^ F η IL] ^N CCCI V ^s N Γ if n, n nh ₂ 19 = ⁷ 97-Phenyl-8- (7- (trifluoromethyl) -1 / 7-indazol-5-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine9 10 Η O N l · if n ^ n ^ nh ₂ 19 = ⁷ 108- (1/7-lndazol-5-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 10 11 I [X Ji JJ ^ I j · n ^ n ^ nh ₂ N ^ ⁷ 118- (2,6-D imethyl Ipirid in-4-i l) -7-phen i l- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 11 12 á HJJ _s ^ rj · nJ'Jn nh ₂ 19 = ⁷ 128- (2-Methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 12
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13 0 X XX _n ^ n ^ nh ₂ 13 5-Amino-7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidine-8-carbonitrile 13 14 T fj N η jl 1 1 JT n ^ n ^ nh ₂ 14 7- (4-Chlorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 14 15 F Ò N '^ ηρ jl Ί I r jr / ^{N nh} 2 15 8- (2-Chloro-6-methylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5amine 15 16 φΐ TO jl I Γ if n ^ n nh ₂ 19 = ⁷ 16 7- (4-Fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 16 17 T Γ j) r jr ^N vJ ^N ^ ^NH2 17 8- (2-Methyl I-6- (trifluoro methyl) p iridi n-4-i l) -7-phenyl mid azo [1,2-c] pyrimidin-5-amine 17 18 F f FÜ / F T Γ jl NO JLXL JL I if n ^ n nh ₂ 18 7- (2,4-Difluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 18
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19 <NTLL Z 8- (2,6-D imethylpyridin-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 19 20 F NA VA jl JI l · if _n ^ n nh ₂ 20 8- (2- (Difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 20 21 i O Ti J 1 I i _n - ^ ^x N - ^ 'NH ₂ 21 8- (2,6-Dimethylpyridin-4-yl) -2-methyl-7-phenylimidazo [1,2-c] pyrimidin-5-amine 21 22 i ΓΊ jl T n .X / Á Q _N „, I 22 8- (2-Methyl-6 - ((4-methylpiperazin-1-yl) methyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3c] pyrimidin-5-amine 22 23 AO νΆ yo nJ n nh ₂ 23 8- (2-Chloro-6- (trifluoromethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5amine 23 24 Q jl 4 1 i jr _n - ^ n ^ nh ₂ 24 8- (2-Chloro-6-methylpyridin-4-yl) -7-phenylimidazo [1,2-c] pyrimidin-5-amine 24
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25 A Ο Ί 1 1 Γ if ν / ν νη ₂ Ν— '25 8- (2-Methoxy-6-methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 25 26 Ί Cj] ϊ II Γ if ν ^ ν νη ₂ 26 8- (2-Ethyl-6-methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 26 27 Ol N ^ i T ^ F jl JI l · if _n ^ n ^ nh ₂ 27 8- (2-Chloro-6-methylpyridin-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5amine 27 28 F IM] jl I Γ if N ^ N nh ₂ 28 8- (2,6-Dimethylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 28 29 l Γ Ϊ n <^ n nh ₂ N = 1 29 7- (3-Fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 29 30 II I jf _n ^ n ^ nh ₂ 30 8- (2-Cyclopropyl-6-methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 30
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31 γ ^ ji 1 I l · if ^N vJ ^{N NH2} 31 8- (2,6-Dimethylpyridin-4-yl) -7-phenylimidazo [1,2-c] pyrimidin-5-amine 31 32 FΝ · γ Y ^jl I l · ifN ^ N ^ NHj32 8- (2,6-Dimethylpyridin-4-yl) -7- (4-fluorophenyl) imidazo [1,2-c] pyrimidin-5-amine 32 33 I U_ z / = C / ^{z =} ^ ----- f ---- K 11 CO ~ z = 7- (2-Fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 33 34 F A ^N ll l ^ ^F l · Jf n ^ n ^ nh ₂ 34 8- (2-Chloro-6-methylpyridin-4-yl) -7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5amine 34 35 A ò A JL ^ Α ^ γ ^ Ν Γ if n ^ n nh ₂ 35 8- (2-Chloro-6-methylpyridin-4-yl) -7- (p-tolyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 35
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36 Cl Δ AAA 1 if N ^ N ^ NH ₂ 36 8- (2-Chloro-6-methylpyridin-4-yl) -7- (4-chlorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine36 37 OJI z z = Z = J 7-Phenyl-8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 37 38 o N ^ i π 1 I l · if _n ^ n nh ₂ N = ^ 38 8- (2-Chloropyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 38 39 ΦΛ T L1 N ^ l Τ'Τ AAA Γ if n ^ n nh ₂ Ά 39 8- (2-Chloro-6- (trifluoromethyl) pyridin-4-yl) -7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 39 40 F ^N il | ^ ^F Γ if n ^ n ^ nh ₂ 40 7- (2,4-Difluorophenyl) -8- (2,6-dimethylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5amine 40
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41 F A Ól T ^ F 1 if n ^ n nh ₂ 41 7- (2,4-Difluorophenyl) -8- (2-methoxy-6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5amine 41 42 F ^ F T Γ j 1 1 1 if _n ^ n nh ₂ N = y 42 3-Methyl-8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin5-amine 42 43 CM o 5- (5-Amino-7-phenyl- [1,2,4] tri azo Io [4,3-c] p iri mid i n-8-yl) -1 - isopropyl pyrid i n-2 (1 H ) -one 43 44 F Y ΓΊ N ^ j ji Ί I l · if _n ^ n nh ₂ N = ^ 44 8- (2-Cyclopropyl-6-methylpyridin-4-yl) -7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 44
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45 F Ν ^ ι Τ'Τ HJ 1 Γ if n ^ n nh ₂ N = ^ 45 7- (2,4-Difluorophenyl) -8- (2-methylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 45 46 T Cl jji 1 I Γ if Z n nh ₂ N = ^ 46 7- (2-Chloro-4-fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 46 47 ckL ^z / - 8- (2-Chloro-6- (morpholinomethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5amine 47 48 i Q] N ^ | T 1 1 NI JÍ (η n ^ n ^ nh ₂ M ' ^N 48 8- (2-Methyl-6- (morpholinomethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5amine 48 49 ϋ A ji JI l · if _n Z'n ^x ^ NH ₂ 49 7- (4-Chloro-2-fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 49
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50 Cl a dl Ji II l · jf n ^ n nh ₂ N = ^ 50 7- (4-Chloro-2-fluorophenyl) -8- (2-chloro-6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 50 51 F F ^ F / L TO aJL I Γ If _n ^ n nh ₂ N = ^ 51 8- (2- (Difluoromethyl) -6-methylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 51 52 Cl K / F jl JI l · if _n ^ n nh ₂ N = ^ 52 7- (4-Chlorophenyl) -8- (2- (difluoromethyl) -6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 52 53 Cl ^F A xlx 1 o JD J 1 Γ If n ^ n nh ₂ Ν = ^ 53 7- (4-Chlorophenyl) -8- (2- (fluoromethyl) -6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin5-amine 53 54 Cl i Cj Ji 1 1 Γ if N <^ N nh ₂ Ν = ^ 54 7- (4-Chlorophenyl) -8- (2,6-dimethylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 54
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55 FX o riTΓ Jf N ^ N ^ NHj iZ55 8- (2- (Fluoromethyl) -6-methylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin5-amine 55 56 F / F jl J 1 Γ jf _n ^< ^ n '^ nh ₂ hZ 56 8- (2- (Difluoromethyl) -6-methylpyridin-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 56 57 k Z ITIN) 8- (2- (Fluoromethyl) -6-methylpyridin-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin5-amine 57 58 F X o ^N il Γ if n ^ n nh ₂ 58 7- (2,4-Difluorophenyl) -8- (2- (fluoromethyl) -6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 58 59 Cl ^F ^ - ^F Zx X Li n'Z T I Γ if n ^ n- ^ nh, 59 7- (4-Chloro-2-fluorophenyl) -8- (2- (difluoromethyl) -6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 59
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt of
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20/119 same.
[0043] In another aspect, the present invention relates to a compound of formula (IV):
N ^x N /
G ^ k (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, [0044] where:
[0045] X is a halogen;
[0046] ring A, G, R ¹ , R ^{3 and} n are as defined in formula (I).
[0047] Typical compounds of the present invention include, but are not limited to:
Example No.
Structure and name of the compound hf N NH ₂ N ^
2c
8-Bromo-7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 2c
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11/21
8e [jf n nh ₂ 8e 8-Bromo-7- (5-methylfuran-2-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 8e 14d Cl Ó ^Br > X [χ _n ^ n nh ₂ N = ^ 14d 8-Bromo-7- (4-chlorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 14d 15f F Ó ^Br > X Γ χ N ^ N nh ₂ 15f 8-Bromo-7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 15f 17e 0 ^Br UN í X _n ^ n ^ nh ₂ 17e 8-Bromo-7-phenylimidazo [1,2-c] pyrimidin-5-amine 17e
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11/22
18th F OL ^β Μν [Ϊ _n ^ n nh ₂ 18e 8-Bromo-7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 18e 19d CM T Ll Z / = C / ^{z =} <m 8-Bromo-7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 19d 21g 0 Br Jx N _n ^ n nh ₂ 21g 8-Bromo-2-methyl-7-phenylimidazo [1,2-c] pyrimidin-5-amine 21 g 29b M Γ _n ^ N ^ NH ₂ N = ^ 29b 8-Bromo-7- (3-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 29b
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11/23
32c F 0 ^Br > A Γ if _n ^ n nh ₂ 32c 8-Bromo-7- (4-fluorophenyl) imidazo [1,2-c] pyrimidin-5-amine 32c 35b CM X z / = z = / f / v Z ⁰⁰ Z z ' 8-Bromo-7- (p-tolyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 35b 46a F VO I if n ^ n nh ₂ N ^ ⁷ 46a 8-Bromo-7- (2-chloro-4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 46a 49a Cl γψ Br A [if n ^ n nh ₂ N ^ ⁷ 49a 8-Bromo-7- (4-chloro-2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 49a
[0048] In another aspect, the present invention relates to a
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24/119 method for preparing the compound of formula (II), comprising a step of:
(IV) (li) reacting a compound of formula (IV) with a compound of formula (V) to obtain the compound of formula (II), in which:
[0049] X is a halogen;
OH, P ^ Z 4-b 4® Ti
W is OH or ⁰ ;
Ring A, ring B, G, R ¹ , R ³ , R ⁶ , nes are as defined in formula (I).
In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt pharmaceutically acceptable carrier, and one or more pharmaceutically acceptable carriers, diluents or excipients.
[0051] The present invention also relates to a use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in the preparation of a drug for A2a receptor inhibition.
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25/119 [0052] The present invention also relates to a use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same in the preparation of a medicament for the treatment of a disease or condition improved by inhibition of the A2a receptor.
[0053] In the present invention, the disease or condition improved by inhibition of the Aia receptor is selected from the group consisting of tumor, depression, cognitive function disorder, neurodegenerative disorder (Parkinson's disease, Huntington's disease, Alzheimer's disease or lateral sclerosis) amyotrophic and the like), attention-related disorder, extrapyramidal syndrome, abnormal movement disorder, cirrhosis, liver fibrosis, fatty liver, dermal fibrosis, sleep disorder, stroke, brain injury, neuroinflammation and addictive behavior, and preferably tumor. [0054] The present invention also relates to a use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in the preparation of a drug for the treatment of tumor, depression, cognitive function disorder, neurodegenerative disorder (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis and the like), attention-related disorder, extrapyramidal syndrome, abnormal movement disorder, cirrhosis, liver fibrosis, fatty liver, dermal fibrosis, sleep disorder, stroke, brain injury, neuroinflammation and addictive behavior, and preferably tumor.
[0055] The present invention also relates to a use of the
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26/119 post of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in the preparation of a medicament for the treatment tumor.
The present invention also relates to a method for inhibiting the A2a receptor, comprising a step of administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same.
[0057] The present invention also relates to a method for the treatment of a disease or condition improved by inhibition of the A2a receptor, comprising a step of administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I) , or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same.
[0058] The present invention relates to a method for the treatment of tumor, depression, cognitive function disorder, neurodegenerative disorder (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis and the like), disorder related attention, extrapyramidal syndrome, abnormal movement disorder, cirrhosis, liver fibrosis, fatty liver, dermal fibrosis, sleep disorder, stroke, brain injury, neuroinflammation and addictive behavior, and preferably tumor, comprising a step of administering to a patient in need for a therapeutically effective amount
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27/119 of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same.
[0059] The present invention also relates to the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same, for use as a medicine.
[0060] The present invention also relates to the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same, for use as an A2a receptor antagonist.
[0061] The present invention also relates to the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same, for use in the treatment of a disease or condition improved by inhibition of the A2a receptor.
[0062] The present invention also relates to the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same, for use in the treatment of tumor, depression, cognitive function disorder, neurodegenerative disorder (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis and the like), attention-related disorder, extrapyramidal syndrome, abnormal movement disorder, cirrhosis , liver fibrosis, fatty liver, dermal fibrosis, sleep disorder, accident
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28/119 Cerebral vascular, brain injury, neuroinflammation and addictive behavior, and preferably tumor.
[0063] The present invention also relates to the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same, for use in tumor treatment.
[0064] The tumor described in the present invention is selected from the group consisting of melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, tumor thyroid, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, chorionic epithelium and pediatric tumor, and preferably lung cancer [0065] The pharmaceutical composition containing the active ingredient may be in the form suitable for oral administration, for example, a tablet, troches, rhombus, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir. An oral composition can be prepared according to any method known in the art for the preparation of the pharmaceutical composition. Such a composition may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorings and preservatives, in order to provide a pleasant and palatable pharmaceutical formulation. The tablet contains the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets.
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11/29
These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. The tablet may be uncoated or coated using a known technique to mask the taste of the drug or delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby providing prolonged release over a long period of time.
[0066] An oral formulation can also be supplied as soft gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, or the active ingredient is mixed with a water-soluble vehicle or an oily medium.
[0067] An aqueous suspension contains the active ingredient in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension can also contain one or more preservatives, one or more dyes, one or more flavoring agents and one or more sweeteners.
[0068] An oily suspension can be formulated by suspending the active ingredient in a vegetable oil or mineral oil. The oily suspension may contain a thickener. Sweetening and flavoring agents can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant.
[0069] The active ingredient in admixture with dispersing or wetting agents, suspending agent or one or more preservatives can be prepared as dispersible powders or granules for the preparation of an aqueous suspension by adding water. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring and coloring agents, powder
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11/309 must also be added. These compositions can be preserved by adding an antioxidant, such as ascorbic acid.
[0070] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifying agents can also be naturally occurring phospholipids. The emulsion can also contain a sweetening agent, flavoring agent, preservative and antioxidant. Such a formulation may also contain a demulcent, preservative, dye and antioxidant.
[0071] The pharmaceutical composition of the present invention can be in the form of a sterile aqueous solution for injection. Acceptable vehicles or solvents that can be used are water, Ringer's solution or isotonic sodium chloride solution. The sterile injectable formulation can be an injectable oil-in-water microemulsion, in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion can be introduced into the patient's bloodstream by local bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. In order to maintain this constant concentration, a continuous release device can be used. An example of such a device is the Deltec CADD-PLUS intravenous injection pump. TM. 5400.
[0072] The pharmaceutical composition of the present invention can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. Such a suspension can be formulated with suitable dispersing or wetting agents and suspending agents as described above according to known techniques. The sterile injectable formulation can also be used
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11/31 solution or suspension for injection prepared in a non-toxic parenterally acceptable diluent or solvent. In addition, stable fixed oils can easily be used as a solvent or suspending medium. For this purpose, any mixed fixed oil can be used. In addition, fatty acids can also be used to prepare injections.
[0073] The compound of the present invention can be administered in the form of a suppository for rectal administration. This pharmaceutical composition can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures, but liquid in the rectum, thereby melting in the rectum to release the drug.
[0074] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors including, but not limited to, the following factors: activity of a specific compost, age of the patient, weight of the patient, general health of the patient, patient behavior, patient diet, time of administration, routine of administration, rate of excretion, combination of drug and the like. In addition, the ideal treatment, such as method of treatment, daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt thereof can be verified by traditional therapeutic regimens.
DETAILED DESCRIPTION OF THE INVENTION [0075] Unless otherwise stated, the terms used in the specification and claims have the meanings described below.
[0076] The term alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group comprising from 1 to 20 carbon atoms, preferably an alkyl having from 1 to 12 carbon atoms, and more preferably
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32/119 an alkyl having from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-
2-methylpropyl, 1,1,2-trimethyl propyl, 1,1-dimethylbutyl, 1,2-d imethyl butyl,
2.2- dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl,
3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, an alkyl group is a lower alkyl having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, ferc-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl,
1.2- dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl group can be substituted or unsubstituted. When substituted, the substituting group (s) can be replaced at any available connection point. The substituent group (s) is preferably one or more groups independently selected optionally from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and C (O) OR ⁵ .
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33/119 [0077] The term alkoxy refers to a group -O- (alkyl) or -O (unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituent group (s) is preferably one or more groups independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C (O) OR ⁵ .
[0078] The term cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, a fused ring or a bridged ring. Cycloalkyl can be substituted or unsubstituted. When substituted, the substituting group (s) can be replaced at any available connection point. The substituent group (s) is preferably one or more groups independently selected optionally from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl and -C (O) OR ⁵ .
[0079] The term heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group of 3 to 20 members, where one or more ring atoms are hetero atoms
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34/119 selected from the group consisting of N, O and S (O) _m (where m is an integer from 0 to 2), but excluding -OO-, -0-S- or -S-Sin the ring, with the remaining ring atoms being carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, where 1 to 4 atoms are hetero atoms, more preferably, 3 to 10 ring atoms where 1 to 4 atoms are hetero atoms, and more preferably 5 to 6 ring atoms, where 1 to 3 atoms are hetero atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring.
[0080] The heterocyclyl ring can be fused to the aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl. Non-limiting examples of these include:
[0081] Heterocyclyl can be substituted or unsubstituted. When substituted, the substituting group (s) can be substituted ^) at any available connection point. The substituent group (s) is (are) preferably one or more groups independently selected optionally from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl , heterocyclyl, aryl, heteroaryl and C (O) OR ⁵ .
[0082] The term aryl refers to a 6- to 14-membered monocyclic ring or polycyclic fused ring (that is, each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) having a π- conjugated electron, preferably 6 to 10 membered aryl, for example, phenyl and naphthyl.
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11/35
The aryl ring can be fused to the heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring. Non-limiting examples of these include:


[0083] Aryl can be substituted or not substituted. When substituted, the substituting group (s) can be replaced at any available connection point. The substituent group (s) is (are) preferably one or more groups independently selected optionally from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl , heterocyclyl, aryl, heteroaryl and -C (O) OR ⁵ .
[0084] The term heteroaryl refers to a 5 to 14 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of O, S and N. The heteroaryl is preferably 5 to 10 membered heteroaryl, more preferably, 5- or 6-membered heteroaryl, e.g., furanyl, thienyl, pyridyl, pyrrolyl, Nalquylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tetrazolyl and the like. The heteroaryl ring can be fused to the aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. Non-limiting examples of it include:
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36/119
[0085] Heteroaryl can be substituted or unsubstituted. When substituted, the substituting group (s) can be substituted ^) at any available connection point. The substituent group (s) is (are) preferably one or more groups independently selected optionally from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl , heterocyclyl, aryl, heteroaryl and C (O) OR ⁵ .
[0086] The term oxo refers to a group = o.
[0087] The term cycloalkyloxy refers to a cycloalkyl-O- group, [0088] The term heterocyclylalkyl refers to an alkyl group substituted by one or more heterocyclyl, where alkyl and heterocyclyl are as defined above. The term haloalkyl refers to an alkyl group substituted by one or more halogens, where alkyl is as defined above.
[0089] The term hydroxy refers to an -OH group.
[0090] The term hydroxyalkyl refers to an alkyl group substituted by hydroxy (s), where alkyl is as defined above.
[0091] The term halogen refers to fluorine, chlorine, bromine or iodine. [0092] The term amino refers to a group -NH2.
[0093] The term cyan refers to a group -CN.
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37/119 [0094] The term nitro refers to a -NO2 group.
[0095] Optionally or optionally means that the event or circumstance described later may, but need not, occur, and that description includes the situation in which the event or circumstance does not occur. For example, heterocyclyl optionally substituted by an alkyl means that an alkyl group may be, but need not be, present, and such description includes the situation of a heterocyclyl being replaced by an alkyl and a heterocyclyl not being substituted by an alkyl.
[0096] Substituted refers to one or more hydrogen atoms in a group, preferably up to 5, and more preferably 1 to 3 hydrogen atoms, independently replaced by a corresponding number of substituents. Needless to say, the substituents only exist in their possible chemical position. The person skilled in the art is able to determine whether substitution is possible or impossible by experiment or theory without paying excessive effort. For example, the combination of amino or hydroxy having free hydrogen and carbon atoms having unsaturated bonds (such as olefins) can be unstable.
[0097] A pharmaceutical composition refers to a mixture of one or more compounds according to the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutically acceptable vehicles and excipients . The purpose of the pharmaceutical composition is to facilitate the administration of a compound to an organism, which is conducive to the absorption of the active ingredient in order to show biological activity.
[0098] A pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is safe and effective in mammals
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38/119 and has the desired biological activity.
[0099] Where: R ⁵ is as defined in formula (I).
Synthesis Method of the Compound of the Present Invention [00100] In order to achieve the aim of the present invention, the present invention applies the following technical solutions:
Scheme I [00101] A method for preparing the compound of formula (II) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following step of :
(iv) (ii) a compound of formula (IV) and a compound of formula (V) are subjected to a Suzuki coupling reaction in the presence of a catalyst under an alkaline condition to obtain the compound of formula (II).
[00102] Where:
[00103] The reagent that provides an alkaline condition includes organic bases and inorganic bases. Organic bases include, but are not limited to, triethylamine, A /, / V-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amine, potassium acetate, potassium acetate, tert -sodium butoxide, potassium tert-butoxide and sodium n-butoxide. Inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonate
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39/119 cesium, sodium hydroxide and lithium hydroxide.
[00104] The catalyst includes, but is not limited to, Pd / C, Raney's Ni, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, bis (dibenzylidene acetone) palladium, chlorine (2-dicyclohexylphosphine2 ', 4 ', 6'-triisopropyl I-1,1' -biphenyl) [2- (2'-amino-1,1 '-biphenyl I)] palladium, [1,1bis (diphenylphosphino) ferrocene] dichloropalladium , 1,1'-bis (dibenzylphosphoryl) ferrocene and tris (dibenzylideneacetone) dipaladium palladium chloride, and preferably [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium.
[00105] The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane , glycol dimethyl ether, water, A /, A / -dimethylformamide, and mixtures thereof.
[00106] Where:
[00107] X is a halogen;
OH / B
Wé ^0H or ring A, ring B, G, R ¹ , R ³ , R ⁶ , nes are as defined in formula (II). Scheme II [00108] A method for preparing the compound of formula (III) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of :
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11/40
Legend: step in step 1, a compound of formula (II1-1) is reacted with hydrazine hydrate to obtain a compound of formula (III-2);
in step 2, the compound of formula (III-2) is reacted with a compound of formula (III-3) to obtain a compound of formula (IIIA);
in step 3, the compound of formula (IIIA) and a compound of formula (V) are subjected to a Suzuki coupling reaction in the presence of a catalyst under an alkaline condition to obtain the compound of formula (III).
[00109] Where:
[00110] The reagent that provides an alkaline condition includes organic bases and inorganic bases. Organic bases include, but are not limited to, triethylamine, A /, / V-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amine, potassium acetate, potassium acetate, ferc -sodium butoxide, potassium fer-butoxide and sodium n-butoxide. Inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
[00111] The catalyst includes, but is not limited to, Pd / C, Raney's Ni, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, bis (dibenzylidene acetone) palladium, chlorine (2-dicyclohexylphosphine2 ', 4 ', 6'-triisopropyl I-1,1' -biphenyl) [2- (2'-amino-1,1 '-biphenyl I)] palladium, [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium , palladium chloride of 1, Tbis (dibenzylphosphoryl) ferrocene and tris (dibenzylideneacetone) dipaladium, and
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41/119 preferably [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium.
[00112] The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4dioxane, glycol dimethyl ether, water, A /, A / -dimethylformamide, and mixtures thereof.
[00113] Where:
[00114] X is a halogen;
OH / B
Wé ^0H or ring A, ring B, R ¹ , R ³ , R ⁶ , nes are as defined in formula (III). Scheme III [00115] A method for preparing the compound of formula (III) of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps of :
Legend: step [00116] in step 1, a compound of formula (111-1) is reacted with hydrazine hydrate to obtain a compound of formula (III-2);
[00117] in step 2, the compound of formula (III-2) and a compound of formula (V) are subjected to a Suzuki coupling reaction in the presence of a catalyst under an alkaline condition to obtain a
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42/119 compound of formula (I I IB);
[00118] in step 3, the compound of formula (IIIB) is reacted with a compound of formula (III-3) to obtain the compound of formula (III).
[00119] Where:
[00120] The reagent that provides an alkaline condition includes organic bases and inorganic bases. Organic bases include, but are not limited to, triethylamine, A /, / V-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amine, potassium acetate, potassium acetate, ferc -sodium butoxide, potassium fer-butoxide and sodium n-butoxide. Inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
[00121] The catalyst includes, but is not limited to, Pd / C, Raney's Ni, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, bis (dibenzylidene acetone) palladium, chlorine (2-dicyclohexylphosphine2 ', 4 ', 6'-triisopropyl I-1,1' -biphenyl) [2- (2'-amino-1,1 '-biphenyl I)] palladium, [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium , 1 palladium chloride, Tbis (dibenzylphosphoryl) ferrocene and tris (dibenzylideneacetone) dipaladium, and preferably [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium.
[00122] The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4dioxane, glycol dimethyl ether, water, A /, / V-dimethylformamide, and mixtures thereof.
[00123] Where:
[00124] X is a halogen;
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OH / B
W is ^0H or ring A, ring B, R ¹ , R ³ , R ⁶ , nes are as defined in formula (III). Scheme IV [00125] A method for preparing the compound of formula (III ') of the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the following steps in:

Legend: Step [00126] In step 1, a compound of formula (111-1) is reacted with hydrazine hydrate to obtain a compound of formula (111-2);
[00127] in step 2, the compound of formula (111-2) and a compound of formula (lll'a) are subjected to a Suzuki coupling reaction in the presence of a catalyst under an alkaline condition to obtain a compound of formula ( IIl'b);
[00128] in step 3, the compound of formula (ll'b) is reacted with a compound of formula (111-3) to obtain the compound of formula (III ').
[00129] Where:
[00130] The reagent that provides an alkaline condition includes organic bases and inorganic bases. Organic bases include, but are not limited to, triethylamine, A /, A / -di-isopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amine, potassium acetate, potassium acetate, erc -sodium butoxide, ions-butoxide
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44/119 potassium and sodium n-butoxide. Inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
[00131] The catalyst includes, but is not limited to, Pd / C, Raney Ni, tetra-triphenylphosphine palladium, palladium chloride, palladium acetate, bis (dibenzylidene acetone) palladium, chlorine (2-dicyclohexylphosphine2 ', 4 ', 6'-triisopropyl I-1,1' -biphenyl) [2- (2'-amino-1,1 '-biphenyl I)] palladium, [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium , 1 palladium chloride, Tbis (dibenzylphosphoryl) ferrocene and tris (dibenzylideneacetone) dipaladium, and preferably [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium.
[00132] The above reaction is preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4dioxane, glycol dimethyl ether, water, A /, / V-dimethylformamide, and mixtures thereof.
[00133] Where:
[00134] X is a halogen;
OH / B
Wé ^0H or [00135] Ring A, R ¹ , R ³ , R ⁶ , nes are as defined in formula (III).
PREFERRED EMBODIMENTS [00136] The present invention will also be described with reference to the following examples, however the examples are not to be considered as limiting the scope of the present invention.
EXAMPLES [00137] The structures of the compounds were identified by res
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45/119 nuclear magnetic resonance (NMR) and / or mass spectrometry (EM). NMR shifts (δ) are provided at 10 ' ⁶ (ppm). NMR was determined by a Bruker AVANCE-400 machine. The solvents for determination were deuterated dimethyl sulfoxide (DMSO-de), deuterated chloroform (CDCh) and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TEM).
[00138] EM was determined by a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, type: Finnigan LCQ advantage MAX).
[00139] High performance liquid chromatography (HPLC) was determined on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 chromatographic column 150x4.6 mm) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 chromatographic column 150x4.6 mm).
[00140] Chiral HPLC analysis was determined on an LC-10A vp (Shimadzu) or analytical SFC (Berger Instruments Inc.).
[00141] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as the thin layer silica gel chromatography (TLC) plate. The size of the silica gel plate used in TLC was 0.15 mm to 0.2 mm, and the size of the silica gel plate used in product purification was 0.4 mm to 0.5 mm.
[00142] 200 to 300 mesh Yantai Huanghai silica gel was generally used as a vehicle for column chromatography.
[00143] Prep Star SD-1 (Varian Instruments Inc.) or SFCmultigram (Berger Instruments Inc.) was used for preparative chiral column chromatography.
[00144] CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).
[00145] Average kinase inhibition rates and IC50 values were determined by a NovoStar ELISA (BMG Co., Germany).
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46/119 [00146] The known starting materials of the present invention can be prepared by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc., or Dari chemical Company, etc.
[00147] Unless otherwise stated, reactions were carried out under an argon atmosphere or a nitrogen atmosphere. [00148] Argon atmosphere or nitrogen atmosphere means that the reaction flask is equipped with an argon or nitrogen flask (about 1 L).
[00149] Hydrogen atmosphere means that a reaction flask is equipped with a hydrogen flask (about 1 L).
[00150] Pressurized hydrogenation reactions were performed on a Parr 3916EKX hydrogenation instrument and a Qinglan QL-500 hydrogen generator or HC2SS hydrogenation instrument.
[00151] In hydrogenation reactions, the reaction system was generally subjected to vacuum and charged with hydrogen, and the above operation was repeated three times.
[00152] Microwave reactor type CEM Discover-S 908860 was used in microwave reactions.
[00153] Unless otherwise stated, the solution refers to an aqueous solution.
[00154] Unless otherwise stated, the reaction temperature is an ambient temperature of 20 ° C to 30 ° C.
[00155] The reaction process in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reactions, the eluting system in column chromatography and the developing solvent system in thin layer chromatography for purification of the compounds included: A: dichloromethane / me system
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47/119 tanol, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: acetone, E: dichloromethane / acetone system, F: ethyl acetate / dichloromethane system , G: ethyl acetate / dichloromethane / n-hexane, and H: ethyl acetate / dichloromethane / acetone. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and a small amount of alkaline reagent such as triethylamine or acidic reagent such as acetic acid can also be added for adjustment.
Example 1 [00156] 8- (2-Methyl 1- 6- (trifluoromethyl) pyrid in-4-yl) -7-phenyl 1- [1,2,4] triazolo [4,3-c] pyrimidin -5-amine 1
F

1a 1b 1c 1d ie 1
Figure caption: Stage
Step 1 [00157] 4-Chloro-5-iodo-6-phenylpyrimidin-2-amine 1b [00158] 4-Chloro-6-phenylpyrimidin-2-amine 1a (2 g, 9.75 mmol, prepared according to known method described in Bioorganic & Medicinal Chemistry Letters, 2011, 21 (8), 2497-2501) and A / -iodosuccinimide (2.6 g, 11.7 mmol) were dissolved in 30 ml of acetic acid. Upon completion of the addition, the reaction solution was stirred for 16 hours. The reaction solution was added with 200 ml of saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 ml * 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over sulfate
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48/119 aqueous sodium, and filtered to collect the filtrate. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel with eluent system B to obtain the title compound 1b (2.88 g, yield: 89%).
[00159] MS m / z (ESI): 332.2 [M + 1]
Step 2 [00160] 4-C loro-5- (2-methyl l-6- (trifluoromethyl) pyrid in-4-yl) -6phenylpyrimidin-2-amine 1d [00161] Compound 1b (2.88 g , 8.7 mmol), 2-methyl-4- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) -6- (trifluoromethyl) pyridine 1c (2.7 g, 9, 17 mmol, prepared according to the known method described in Journal of Medicinal Chemistry, 2012, 55 (5), 1898-1903), [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium (0.64 g, 0.87 mmol) and potassium carbonate (3.6 g, 26.1 mmol) were dissolved successively in 66 mL of a mixed solution of 1,4-dioxane and water (V / V = 10: 1) under an atmosphere of nitrogen. The reaction solution was heated to 83 ° C, and stirred for 3 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered. The filtrate was added with 200 ml of ethyl acetate, washed with saturated sodium chloride solution (100 ml), dried over aqueous sodium sulfate, and filtered to collect the filtrate. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel with eluent system B to obtain the title compound 1d (2.4 g, yield: 76%).
[00162] MS m / z (ESI): 365.4 [M + 1]
Step 3 [00163] 4-Hydrazinyl-5- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) -6-phenylpyrimidin-2-amine 1e [00164] Compound 1d (100 mg, 0.275 mmol) and 85 % hydrazine hydrate (62 mg, 2.747 mmol) was dissolved successively in
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49/119 mL of ethanol. The reaction solution was stirred at reflux for 17 hours. The reaction was stopped, and the reaction solution was cooled to room temperature. The reaction solution was added with 30 ml of water, and extracted with ethyl acetate (30 ml * 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL * 2), dried over aqueous sodium sulfate, and filtered to collect the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude title compound 1e (85 mg), which was used directly in the next step without purification.
[00165] MS m / z (ESI): 361.4 [M + 1]
Step 4 [00166] 8- (2-Methyl 1- 6- (trifluoromethyl) pyrid in -4-yl) -7-phenyl 1- [1,2,4] triazolo [4,3-c] pyrimidin -5-amine 1 [00167] Crude compound 1e (85 mg, 0.275 mmol) was added to 2 ml of (tri) ethyl orthoformate. The reaction solution was stirred at 140 ° C for 0.5 hour. The reaction was stopped, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to obtain the title 1 compound (6 mg, yield: 6.9%).
[00168] MS m / z (ESI): 371.4 [M + 1] [00169] ¹ H NMR (400MHz, DMSO-cfe) δ 9.38 (s, 1H), 8.42 (brs, 2H) , 7.59 (s, 1H), 7.42 (s, 1H), 7.35-7.31 (m, 5H), 2.48 (s, 3H).
Example 2 [00170] 7-Phenyl-8- (1 H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-c] pyrimid in-5amine 2
N.
HN
N ^Z N
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11/50

2a 2b
Caption: step
Step 1 [00171] 5-Bromo-4-chloro-6-phenylpyrimidin-2-amine 2a [00172] Compound 1a (500 mg, 2.431 mmol) and / V-bromosuc cinimide (519 mg, 2.918 mmol) were dissolved in 16 mL of Λ /, Λ / dimethylformamide. Upon completion of the addition, the reaction solution was stirred for 1 hour. The reaction solution was added with 50 ml of water, and extracted with ethyl acetate (50 mlx3). The organic phases were combined, washed with water (100 ml * 3) and saturated sodium chloride solution (200 ml) successively, dried over aqueous sodium sulfate, and filtered to collect the filtrate. The filtrate was concentrated under reduced pressure to obtain crude title compound 2a (698 mg), which was used directly in the next step without purification.
[00173] MS m / z (ESI): 284.2 [M + 1]
Step 2 [00174] 5-Bromo-4-hydrazinyl-6-phenylpyrimidin-2-amine 2b [00175] Crude compound 2a (692 mg, 2.432 mmol) and 85% hydrazine hydrate (1.432 mg, 24.32 mmol ) were dissolved successively in 20 ml of ethanol. The reaction solution was stirred at reflux for 1 hour. The reaction solution was cooled to room temperature, and stirred for 0.5 hour. The reaction solution was filtered, and the filtered mass was washed with ethanol (3 ml * 2) and ether (3 ml x 2) successively. The filtered mass was collected and dried to obtain the crude title compound 2b (480 mg), which was used directly in the next step without purification.
[00176] MS m / z (ESI): 280.3 [M + 1]
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Step 3 [00177] 8-Bromo-7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 2c [00178] Crude compound 2b (480 mg, 1.713 mmol) was added to 5 ml of (tri) ethyl orthoformate. The reaction solution was stirred at 140 ° C for 15 minutes. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered. The filtered mass was washed with ethanol (3 ml * 3) and diethyl ether (5 ml * 3) successively. The filtered mass was collected and dried to obtain the title compound 2c (348 mg, yield: 62.4%).
[00179] EM m / z (ESI): 290.3 [M + 1]
Step 4 [00180] 7-Phenol-8- (1 H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-c] pyrimid in-5amine 2 [00181] Compound 2c (120 mg, 0.414 mmol), 4- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) -1H-pyrazole 2d (120 mg, 0.620 mmol, prepared according to the known method described in Journal of the American Chemical Society, 2014, 136 (11), 4287-4299), [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium (30 mg, 0.041 mmol) and potassium carbonate (171 mg, 1,241 mmol) were dissolved successively in 6 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 3 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (30 ml * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title 2 compound (33 mg, yield: 28.7%).
[00182] MS m / z (ESI): 278.4 [M + 1] [00183] ¹ H NMR (400 MHz, DMSO-cfe) δ 12.79 (brs, 1H), 9.32 (s, 1H ), 7.98 (brs, 2H), 7.41-7.37 (m, 7H).
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Example 3 [00184] 7-Fen i l-8- (q u inol in-6-i l) - [1,2,4] triazolo [4,3-c] pyrimid i n-5amine 3

2c 3a 3 [00185] Compound 2c (100 mg, 0.345 mmol), 6- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) quinoline 3a (106 mg, 0.414 mmol, prepared according to the known method described in Journal of the American Chemical Society, 2013, 135 (50), 18730-18733), [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.034 mmol) and potassium carbonate (143 mg, 1.034 mmol) were dissolved successively in 6 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (50 ml * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel with eluent system A to obtain the title compound 3 (49 mg, yield: 41.9%).
[00186] MS m / z (ESI): 339.2 [M + 1] [00187] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.38 (s, 1H), 8.88-8.87 (m, 1H), 8.29-8.27 (m, 1H), 8.20 (brs, 2H), 8.05-8.04 (m, 1H), 7.88-7.85 (m , 1H), 7.54-7.50 (m, 2H), 7.37-7.34 (m, 2H), 7.24-7.20 (m, 3H).
Example 4
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53/119 [00188] 8- (2-Chloro-6-methyl Pyrid in-4-yl) -7-phenyl 1- [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 4

[00189] Compound 2c (100 mg, 0.345 mmol), 2-chloro-6-methyl-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 4a (105 mg, 0.414 mmol, prepared according to the known method described in Organic Syntheses, 2005, 82, 126-133), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.034 mmol) and potassium carbonate (143 mg, 1.034 mmol) were dissolved successively in 10 mL of a mixed solution of 1,4-dioxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 3 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (30 mlx4). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 4 (20.7 mg, yield: 17.8%).
[00190] MS m / z (ESI): 337.4 [M + 1] [00191] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.36 (s, 1H), 8.38 (brs, 2H ), 7.36-7.32 (m, 5H), 7.19-7.14 (m, 2H), 2.35 (s, 3H).
Example 5 [00192] 8- (8-Methylquinolin-6-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-
5-amine 5
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Figure caption: Stage
Step 1 [00193] 8-Methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline
5c [00194] 6-Bromo-8-methylquinoline 5b (444 mg, 2.00 mmol, prepared according to the known method described in Journal of Organic Chemistry, 2014, 79 (11), 5379-5385), 4.4 , 4 ', ^{4, 5,5,5,} 5-2,2'bi -octametil (1,3,2-dioxaborolane) 5a (508 mg, 2.00 mmol), [1,1'- bis (diphenylphosphino) ferrocene] dichloropalladium (292 mg, 0.40 mmol) and potassium acetate (588 mg, 6.00 mmol) were dissolved successively in 10 mL of glycol dimethyl ether under an argon atmosphere. The reaction solution was heated to 80 ° C, and stirred for 12 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered. The filtrate was added with 20 ml of ethyl acetate, washed successively with water (10 ml) and saturated sodium chloride solution (10 ml), dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent system B to obtain the title compound 5c (320 mg, yield: 59.5%).
[00195] MS m / z (ESI): 270.1 [M + 1]
Step 2
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55/119 [00196] 8- (8-Methylquinolin-6-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin5-amine 5 [00197] Compound 2c (100 mg , 0.345 mmol), 5c (130 mg, 0.482 mmol), [1, T-bis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.034 mmol) and potassium carbonate (143 mg, 1.034 mmol) were successively dissolved in 5 mL of a mixed solution of 1,4-dioxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (30 ml * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 5 (32 mg, yield: 26.4%).
[00198] MS m / z (ESI): 353.2 [M + 1] [00199] ¹ H NMR (400 MHz, DMSO-cfe) δ 19.37 (s, 1H), 8.90-8.89 (m, 1H), 8.21-8.19 (m, 3H), 7.78 (s, 1H), 7.51-7.49 (m, 2H), 7.37-7.36 (m , 2H), 7.22-7.20 (m, 3H), 2.60 (s, 3H).
Example 6 [00200] 8- (7-Fluoro-1 H-indazol-5-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 6


2c 6
Caption: Stage
Step 1
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56/119 [00201] 7-Fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 Hindazol 6b [00202] 5-Bromo-7-fluoro -1H-indazole 6a (1.27 g, 5.90 mmol, prepared according to the method described in patent application WO2012037410), compound 5a (2.25 g, 8.86 mmol), [1.1 ' bis (diphenylphosphino) ferrocene] dichloropalladium (432 mg, 0.56 mmol) and potassium acetate (1.74 g, 17.7 mmol) were successively dissolved in 40 ml of dimethyl ether glycol under an argon atmosphere. The reaction solution was heated to 80 ° C, and stirred for 12 hours. The reaction was stopped. The reaction solution was cooled to room temperature, added with 10 ml of ethyl acetate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel with eluent system B to obtain the title compound 6b (1.178 g, yield: 76.0%).
[00203] EM m / z (ESI): 263.2 [M + 1]
Step 2 [00204] 8- (7-Fluoro-1 H-indazol-5-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 6 [00205] Compound 2c (117 mg, 0.348 mmol), 6b (100 mg, 0.382 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.034 mmol) and potassium carbonate (192 mg, 1.387 mmol) ) were dissolved successively in 10 mL of a mixed solution of 1,4dioxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (30 ml * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 6 (13 mg, yield: 10.8%).
[00206] MS m / z (ESI): 346.4 [M + 1]
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57/119 [00207] ¹ H NMR (400 MHz, DMSO-cfe) δ 13.65 (brs, 1H), 9.34 (s, 1H), 8.13-8.11 (m, 3H), 7.55 (s, 1H), 7.35-7.33 (m, 2H), 7.23-7.22 (m, 3H), 7.05-7.02 (m, 1H).
Example 7 [00208] 8- (8-Fluoroquinolin-6-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin5-amine 7
Caption: Stage
Step 1 [00209] 8-Fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) quinoline 7b [00210] 6-Bromo-8-fluoroquinoline 7a (226 mg, 1 , 00 mmol, prepared according to the known method described in Journal of Medicinal Chemistry, 2010, 53 (10), 4066-4084), compound 5a (305 mg, 1.20 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (146 mg, 0.20 mmol) and potassium acetate (294 mg, 3.00 mmol) were dissolved successively in 10 mL of glycol dimethyl ether under an argon atmosphere. The reaction solution was heated to 80 ° C, and stirred for 12 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by a rapid preparation instrument CombiFlash with eluent system B to obtain the title compound 7b (220 mg, yield: 80.1%).
[00211] MS m / z (ESI): 274.1 [M + 1]
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11 589
Step 2 [00212] 8- (8-Fluoroquinol in-6-yl) -7-phenyl 1- [1,2,4] triazolo [4,3-c] pyrimid in5-amine 7 [00213] Compound 2c (100 mg, 0.345 mmol), 7b (100 mg, 0.414 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.034 mmol) and potassium carbonate (143 mg, 1.034 mmol) were dissolved successively in 6 mL of a mixed solution of 1,4dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 3 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (40 ml * 4). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 7 (20 mg, yield: 16.3%).
[00214] MS m / z (ESI): 357.2 [M + 1] [00215] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.38 (s, 1H), 8.94-8.93 (m, 1H), 8.35-8.33 (m, 1H), 8.26 (brs, 2H), 7.86 (s, 1H), 7.62-7.59 (m, 1H), 7.40-7.36 (m, 3H), 7.26-7.24 (m, 3H).
Example 8 [00216] 8- (2-Methyl-6- (trifluoromethyl) pyridin-4-yl) -7- (5-methylfuran-2-yl) - [1,2,4] triazolo [4,3-c ] pyrimidin-5-amine 8
F __ /
4 ^ 0 y ^ N Γ If n ^ n nh ₂

Caption: Stage
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Step 1 [00217] 5-Bromo-4-chloro-6- (5-methylfuran-2-yl) pyrimidin-2-amine 8c [00218] 5-Bromo-4,6-dichloropyrimidin-2-amine 8a (5 g , 20.585 mmol, prepared according to the method described in patent application US20100331294), 4,4,5,5-tetramethyl-2- (5-methylfuran-2-yl) -1,3,2-dioxaborolane 8b (4,283 g, 20.585 mmol, prepared according to the known method described in Organometallics, 2015, 34 (7), 13071320), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (1.506 g, 2.058 mmol) and potassium carbonate (8.535 g, 61.756 mmol) were dissolved successively in 150 ml of a mixed solution of 1,4dioxane and water (V / V = 4: 1) under an argon atmosphere, and stirred for 2 hours. The reaction was stopped, and the reaction solution was added with 200 ml of water and extracted with ethyl acetate (200 mlx3). The organic phase was added with 100 to 200 mesh silicon dioxide, and concentrated under reduced pressure. The residue was purified by a rapid preparation instrument CombiFlash with eluent system B to obtain the title compound 8c (2.0 g, yield: 33.7%).
[00219] MS m / z (ESI): 288.2 [M + 1]
Step 2 [00220] 5-Bromo-4-hydrazinyl-6- (5-methylfuran-2-yl) pyrimidin-2-amine
8d [00221] Compound 8c (1.88 g, 6.516 mmol) and 15 mL of 85% hydrazine hydrate were dissolved successively in 120 mL of ethanol. The reaction solution was stirred for 17 hours. The reaction was stopped, and the reaction solution was filtered. The filtered mass was dried to obtain the crude title compound 8d (1.5 g), which was used directly in the next step without purification.
[00222] MS m / z (ESI): 284.3 [M + 1]
Step 3
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60/119 [00223] 8-Bromo-7- (5-methylfuran-2-yl) - [1,2,4] triazolo [4,3-c] pyrimidin5-amine 8e [00224] The crude product 8d (1 , 5 g, 5.279 mmol) was added to 20 mL of (tri) ethyl orthoformate. The reaction solution was stirred at 140 ° C for 15 minutes. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered. The filtered mass was washed with n-hexane (20 ml * 2), and dried to obtain the crude title compound 8e (1.13 g, yield: 72.8%).
[00225] MS m / z (ESI): 294.3 [M + 1]
Step 4 [00226] 8- (2-Methyl-6- (trifluoromethyl) pyridin-4-yl) -7- (5-methylfuran-2-yl) - [1,2,4] triazolo [4,3-c ] pyrimidin-5-amine 8 [00227] The crude product 8e (140 mg, 0.476 mmol), 2-methyl-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -6- (trifluoromethyl) pyridine 8f (205 mg, 0.714 mmol, prepared according to the known method described in Journal of Medicinal Chemistry, 2012, 55 (5), 1898-1903), [1,1'-bis (diphenylphosphino ) ferrocene] dichloropalladium (35 mg, 0.048 mmol) and potassium carbonate (197 mg, 1.428 mmol) were dissolved successively in 6 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2.5 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (50 ml * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 8 (80 mg, yield: 44.9%).
[00228] MS m / z (ESI): 375.4 [M + 1] [00229] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.30 (s, 1H), 8.26 (brs, 2H ), 7.68 (s, 1H), 7.64 (s, 1H), 6.70-6.69 (m, 1H), 6.20-6.19 (m, 1H), 2.60 ( s, 3H), 2.03 (s, 3H).
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Example 9 [00230] 7-Phenyl-8- (7- (trifluoromethyl) -1 H-indazol-5-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 9
Step 1
Br
H N
O
Caption: Stage
Step 1 [00231] 5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -7 (trifluoromethyl) -1 H-indazole 9b [00232] 5-Bromo-7- (trifluoromethyl) -1 / - / - indazole 9a (0.5 g, 1.88 mmol, prepared according to the method described in patent application WO2012056372), compound 5a (575 mg, 2.26 mmol), [1 , 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (275 mg, 0.38 mmol) and potassium acetate (554 mg, 5.66 mmol) were dissolved successively in 10 ml of dimethyl ether glycol under an argon atmosphere. The reaction solution was heated to 80 ° C, and stirred for 2 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by a rapid preparation instrument CombiFlash with eluent system C to obtain the title compound 9b (270 mg, yield: 45.9%).
[00233] MS m / z (ESI): 313.2 [M + 1]
Step 2 [00234] 7-Phenyl-8- (7- (trifluoromethyl) -1 H-indazol-5-yl) Petition 870190079675, of 8/16/2019, p. 81/150
62/119 [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 9 [00235] Compound 2c (117 mg, 0.348 mmol), 9b (35 mg, 0.11 mmol), [ 1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.035 mmol) and potassium carbonate (192 mg, 1.387 mmol) were dissolved successively in 5 ml of a mixed solution of 1,4dioxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction was stopped, and the reaction solution was added with 10 ml of water and extracted with a mixed solution of dichloromethane and methanol (V / V = 8: 1) (20 mlx3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 6 (10 mg, yield: 22%).
[00236] MS m / z (ESI): 396.4 [M + 1] [00237] ¹ H NMR (400 MHz, DMSO-cfe) δ 13.66 (s, 1H), 9.36 (s, 1H ), 8.25-8.09 (m, 4H), 7.53 (s, 1H), 7.33-7.31 (m, 2H), 7.25-7.23 (m, 3H). Example 10 [00238] 8- (1 H-in dazol-5-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrim id in-5amine 10
Ν = ^ 10
Br.
B ' ⁰ ·
OV [00239] Compound 2c (140 mg, 0.482 mmol), 5- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) -1H-indazole 10a (141 mg, 0.579 mmol, prepared according to the known method described in Journal of Medicinal Chemistry, 2014, 57 (9), 3856-3873), [1, T-bis (differ
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63/119 nilphosphino) ferrocene] dichloropalladium (35 mg, 0.048 mmol) and potassium carbonate (200 mg, 1.448 mmol) were dissolved successively in 12 mL of a mixed solution of 1,4-dioxane and water (V / V = 5 : 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 3 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with a mixed solution of dichloromethane and water (V / V = 8: 1) (30 ml * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title 10 compound (8.6 mg, yield: 5.4%).
[00240] MS m / z (ESI): 328.1 [M + 1] [00241] ¹ H NMR (400 MHz, DMSO-cfe) δ 13.05 (brs, 1H), 9.33 (s, 1H ), 8.05-8.01 (m, 3H), 7.75 (s, 1H), 7.53-7.41 (m, 1H), 7.35-7.33 (m, 2H), 7.20-7.07 (m, 4H).
Example 11 [00242] 8- (2,6-Dimethylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 11

[00243] Compound 2c (100 mg, 0.345 mmol), 2,6-dimethyl-4- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 11a (91 mg, 0.414 mmol , prepared according to the known method described in Organic Letters, 2009, 11 (16), 3586-3589), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.034 mmol) and potassium carbonate ( 143 mg,
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1.034 mmol) were dissolved successively in 6 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 3 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (30 mlx3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 11 (27 mg, yield: 24.8%).
[00244] MS m / z (ESI): 317.5 [M + 1] [00245] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.35 (s, 1H), 8.25 (brs, 2H ), 7.32-7.30 (m, 5H), 6.97 (s, 2H), 2.32 (s, 6H).
Example 12 [00246] 8- (2-Methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5amine 12
[00247] Compound 2c (100 mg, 0.345 mmol), 2-methyl-4- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 12a (91 mg, 0.414 mmol, prepared according to the known method described in Journal of the American Chemical Society, 2014, 136 (11), 4133-4136), [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium (25 mg, 0.034 mmol) and potassium carbonate ( 143 mg, 1.034 mmol) were dissolved successively in 6 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was
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65/119 heated to 90 ° C, and stirred for 3 hours. The reaction was stopped, and the reaction solution was added with 50 ml of water and extracted with ethyl acetate (30 ml * 3). The organic phase was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to obtain the title compound 12 (6.8 mg, yield: 6.5%).
[00248] MS m / z (ESI): 303.4 [M + 1] [00249] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.35 (s, 1H), 8.29-8.26 (m, 3H), 7.32-7.25 (m, 6H), 6.99 (s, 1H), 2.39 (s, 3H).
Example 13 [00250] 5-Amino-7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidine-8-carbonitrile
[00251] Compound 2c (1.0 g, 3.45 mmol), zinc cyanide (484 mg, 4.13 mmol), zinc (22 mg, 0.34 mmol), [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (124 mg, 0.17 mmol) and tris (dibenzylidenoacetone) dipaladium (156 mg, 0.17 mmol) were dissolved in 30 mL of A /, / V-dimethylformamide under an argon atmosphere, and stirred at 60 ° C for 12 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtered mass was washed with methanol. The filtrate was added with 30 ml of water, and extracted with a mixed solution of dichloromethane and methanol (V / V = 8: 1) (30 ml * 3). The organic phases were combined, washed with chloride solution
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66/119 of saturated sodium, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 13 (650 mg, yield: 80.0%).
[00252] MS m / z (ESI): 237.0 [M + 1] [00253] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.24 (brs, 1H), 8.83 (brs, 1H ), 8.64 (s, 1H), 7.92-7.89 (m, 2H), 7.59-7.57 (m, 3H).
Example 14 [00254] 7- (4-Chlorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5 -amine 14
Cl FO [if rf'N nh ₂

Step 1 [00255] 5-Bromo-4-chloro-6- (4-chlorophenyl) pyrimidin-2-amine 14b [00256] 4-Chloro-6- (4-chlorophenyl) pyrimidin-2-amine 14a (11 g, 38.03 mmol, prepared according to the method described in patent application DE102006008880A1) and / V-bromosuccinimide (7.11 g, 39.93 mmol) were dissolved in 300 ml of A /, / V-dimethylformamide. Upon completion of the addition, the reaction solution was stirred for 2 hours. The reaction solution was added with 1 L of water, and extracted with ethyl acetate (300 mL * 4). The organic phases were combined, washed with water (100 mL * 3) and saturated sodium chloride solution
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67/119 (200 ml_x2) successively, dried over aqueous sodium sulfate, and filtered to collect the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude title compound 14b (12 g), which was used directly in the next step without purification.
[00257] EM m / z (ESI): 318.2 [M + 1]
Step 2 [00258] 5-Bromo-4- (4-chlorophenyl) -6-hydrazinylpyrimidin-2-amine 14c [00259] The crude compound 14b (12 g, 37.62 mmol) and 40 mL of 85% hydrate hydrazine were dissolved successively in 400 ml of ethanol. The reaction solution was stirred for 17 hours. The reaction solution was filtered, and the filtered mass was washed with ethanol (50 ml) and n-hexane (100 ml * 2) successively. The filtered mass was collected and dried to obtain the crude title compound 14c (10.28 g), which was used directly in the next step without purification.
[00260] MS m / z (ESI): 314.3 [M + 1]
Step 3 [00261] 8-Bromo-7- (4-chlorophenyl) - [1,2,4] triazolo [4,3-c] pirim id in-5amine 14d [00262] The crude compound 14c (2 g, 6 , 36 mmol) and 1.16 mL of (tri) ethyl orthoformate (1.04 g, 6.99 mmol) were added to 50 mL of ethanol. The reaction solution was stirred at reflux for 4 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was added with 51 ml of a mixed solution of ethanol and n-hexane (V / V = 1:50), stirred and filtered. The filtered mass was collected to obtain the title compound 14d (2 g, yield: 96.9%).
[00263] MS m / z (ESI): 324.3 [M + 1]
Step 4 [00264] 7- (4-Chlorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5 -amine 14
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68/119 [00265] Compound 14d (250 mg, 770.27 pmol), compound 1c (265.36 mg, 924.32 pmol), [1, T-bis (diphenylphosphino) ferrocene] dichloropalladium (56.36 mg, 77.03 pmol) and potassium carbonate (319.36 mg, 2.31 mmol) were added successively to 10 ml of a mixed solution of 1,4-dioxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by a rapid preparation instrument CombiFlash with eluent B system. The resulting crude product was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the compound of title 14 (64.4 mg, yield: 20.7%).
[00266] MS m / z (ESI): 405.5 [M + 1] [00267] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.39 (s, 1H), 8.46 (brs, 2H ), 7.58 (s, 1H), 7.49 (s, 1H), 7.43-7.35 (m, 4H), 2.50 (s, 3H).
Example 15 [00268] 8- (2-Chloro-6-methylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 15
Cl
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Caption: Stage
Step 1 [00269] 4-Chloro-6- (4-fluorophenyl) pyrimidin-2-amine 15c [00270] 4,6-Dichloropyrimidin-2-amine 15a (10 g, 60.98 mmol,
Adamas Reagent Ltd.), (4-fluorophenyl) boronic acid 15b (8.53 g, 60.98 mmol, Accela ChemBio (Shanghai) Inc.), [1,1-bis (diphenylphosphino) iron ceno] dichloropalladium (4, 46 g, 6.10 mmol) and potassium carbonate (16.83 g, 121.96 mmol) were added successively to 250 mL of a mixed solution of 1,4-dioxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 60 ° C, and stirred for 3 hours. The reaction solution was cooled to room temperature, added with 300 ml of water, and extracted with ethyl acetate (150 ml * 3). The organic phases were combined, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with eluent system B to obtain the title compound 15c (11.0 g, yield: 76.0%).
[00271] MS m / z (ESI): 224.3 [M + 1]
Step 2 [00272] 5-Bromo-4-chloro-6- (4-fluorophenyl) pyrimidin-2-amine 15d [00273] Compound 15c (11.0 g, 49.19 mmol) was dissolved in 100 ml of A /, / V-dimethylformamide. The reaction solution was added with
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70/119 / V-bromosuccinimide (8.75 g, 49.19 mmol) in batches, and stirred for 1 hour. The reaction solution was added with 400 ml of water, and extracted with ethyl acetate (100 ml * 3). The organic phases were combined, washed with water (100 ml * 3) and saturated sodium chloride solution (200 ml) successively, dried over aqueous sodium sulfate, and filtered to collect the filtrate. The filtrate was concentrated under reduced pressure to obtain the crude title compound 15d (6.0 g), which was used directly in the next step without purification.
[00274] MS m / z (ESI): 301.9 [M + 1]
Step 3 [00275] 5-Bromo-4- (4-fluorophenyl) -6-hydrazinylpyrimidin-2-amine 15e [00276] The crude compound 15d (5.5 g, 18.18 mmol) and 10 mL of 85% hydrazine hydrate were dissolved successively in 20 ml of ethanol. The reaction solution was stirred at reflux for 1 hour. The reaction solution was cooled to room temperature, and stirred for 0.5 hour. The reaction solution was filtered, and the filtered mass was washed with ethanol (3 ml * 2) and diethyl ether (3 ml * 2) successively. The filtered mass was collected and dried in vacuum to obtain the crude title compound 15e (4.4 g), which was used directly in the next step without purification.
MS m / z (ESI): 298.1 [M + 1]
Step 4
8-Bromo-7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 15f [00277] The crude compound 15e (500 mg, 1.68 mmol) and (tri) ethyl orthoformate (497 mg, 3.35 mmol) was added successively to 20 ml of ethanol. The reaction solution was heated to reflux for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtered mass was washed with 2 ml of ethanol once, and then collected to obtain the crude title compound
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15f (460 mg), which was used directly in the next step without purification.
[00278] EM m / z (ESI): 307.9 [M + 1]
Step 5 [00279] 8- (2-Chloro-6-methylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 15 [00280] Crude compound 15f (120 mg, 389.47 pmol), compound 4a (138.24 mg, 545.26 pmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (28.50 mg, 38.95 pmol) and potassium carbonate (161.48 mg, 1.17 mmol) were added successively to 6.0 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction solution was cooled to room temperature, added with 50 ml of water, and extracted with ethyl acetate (30 mlx3). The organic phases were combined, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the title compound 15 (22 mg, yield: 15.9%).
[00281] MS m / z (ESI): 355.1 [M + 1] [00282] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.35 (s, 1H), 8.38 (brs, 2H ), 7.40-7.37 (m, 2H), 7.20-7.18 (m, 4H), 2.37 (s, 3H).
Example 16 [00283] 7- (4-Fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5 -amine 16
N
N
N ^Z N
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[00284] Compound 15f (100 mg, 324.56 pmol), compound 1c (111.81 mg, 389.47 pmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (23.73 mg, 32.46 pmol) and potassium carbonate (89.71 mg, 649.12 pmol) were added successively to 6.0 ml of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction solution was cooled to room temperature, added with 20 ml of water, and extracted with ethyl acetate (10 mlx3). The organic phases were combined, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the title compound 16 (34 mg, yield: 26.9%).
[00285] MS m / z (ESI): 389.4 [M + 1] [00286] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.35 (s, 1H), 8.40 (brs, 2H ), 7.56 (s, 1H), 7.43 (s, 1H), 7.34-7.37 (m, 2H), 7.13-7.17 (m, 2H), 2.49 ( s, 3H).
Example 17 [00287] 8- (2-Methyl-6- (trifluoromethyl) pyridin-4-yl) -7-phenylimidazo [1,2c] pyrimidin-5-amine 17
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^17a 17b 17c 17d 17e ¹⁷
Caption: Stage
Step 1 [00288] 5-Bromo-2- (methylthio) -6-phenylpyrimidin-4-amine 17b [00289] 2- (Methylthio) -6-phenylpyrimidin-4-amine 17a (1.2 g, 5.5 mmol , prepared according to the known method described in Chemical & Pharmaceutical Bulletin, 1981, 29 (4), 948-54) and / V-bromosuccinimide (1.1 g, 6.1 mmol) were added successively to 20 ml of A /, A / -dimethylformamide. The reaction solution was stirred for 1 hour. The reaction solution was added with water, and extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 17b (550 mg), which was used directly in the next step without purification.
[00290] MS m / z (ESI): 296.0 [M + 1]
Step 2 [00291] 8-Bromo-5- (methylthio) -7-phenylimidazo [1,2-c] pyrimidine at 17c [00292] Crude compound 17b (250 mg, 0.84 mmol) was dissolved in 10 mL 1,4-dioxane. The reaction solution was added dropwise with chloroacetaldehyde (249 mg, 1.27 mmol), and stirred at 90 ° C for 36 hours. The reaction solution was cooled to room temperature, added with saturated sodium bicarbonate solution, and extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by
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74/119 thin layer chromatography with developing solvent system A to obtain the title compound 17c (195 mg, yield: 72%).
[00293] EM m / z (ESI): 320.1 [M + 1]
Step 3 [00294] 8-Bromo-5- (methylsulfonyl) -7-phenylimidazo [1,2-c] pyrimidine 17d [00295] Compound 17c (195 mg, 0.61 mmol) was dissolved in 10 ml of dichloromethane. The reaction solution was added with m-chloroperoxybenzoic acid (316 mg, 1.83 mmol) in batches, and stirred for 3 hours. The reaction solution was added with saturated sodium bicarbonate solution, and extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 17d (210 mg), which was used directly in the next step without purification.
[00296] MS m / z (ESI): 352.1 [M + 1]
Step 4 [00297] 8-Bromo-7-phenylimidazo [1,2-c] pyrimidin-5-amine 17e [00298] Crude compound 17d (210 mg, 0.59 mmol) was dissolved in 10 mL of 1.4 -dioxane. The reaction solution was added dropwise with 1 ml of 30% ammonia, and stirred for 1 hour. The reaction solution was added with water, and extracted with a mixed solution of dichloromethane and methanol (V / V = 10: 1) three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 17e (172 mg, yield: 46%).
[00299] MS m / z (ESI): 289.1 [M + 1]
Step 5
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75/119 [00300] 8- (2-Methyl-6- (trifluoromethyl) pyridin-4-yl) -7-phenylimidazo [1,2c] pyrimidin-5-amine 17 [00301] Compound 17e (80 mg, 0 , 28 mmol), compound 1c (95 mg, 0.332 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (20 mg, 28 pmol) and potassium carbonate (87 mg, 0.56 mmol) successively added to 10 mL of a mixed solution of 1,4diaxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 3 hours. The reaction solution was cooled to room temperature, added with water, and extracted with a mixed solution of dichloromethane and methanol (V / V = 8: 1) three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 17 (15 mg, yield: 14%).
[00302] MS m / z (ESI): 370.1 [M + 1] [00303] ¹ H NMR (400 MHz, DMSO-cfe) δ 8.02 (s, 1H), 7.99 (brs, 2H ), 7.57 (s, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.30 (brs, 5H), 2.45 (s, 3H).
Example 18 [00304] 7- (2,4-Difluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin -5-amine 18
N NH.
N ^z N NH.
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F
18a 18b
Figure caption: Stage
Step 1 [00305] 4-Chloro-6- (2,4-difluorophenyl) pyrimidin-2-amine 18b [00306] Compound 15a (11 g, 63.72 mmol), boronic acid (2,4-difluorophenyl) 18a (10.06 g, 63.72 mmol, Shanghai Bepharm Ltd.), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (4.66 g, 6.37 mmol) and potassium carbonate (26.42 g , 191.17 mmol) were added successively to 500 mL of a mixed solution of 1,4-dioxane and water (V / V = 4: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction solution was filtered, and the filtrate was separated into two phases. The aqueous phase was extracted with ethyl acetate (200 ml * 2). The organic phases were combined, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with eluent system B to obtain the title compound 18b (14.04 g, yield: 91.2%).
[00307] EM m / z (ESI): 242.3 [M + 1]
Step 2 [00308] 5-Bromo-4-chloro-6- (2,4-difluorophenyl) pyrimidin-2-amine 18c [00309] Compound 18b (14.04 g, 58.11 mmol) was dissolved in 300 mL of A /, A / -dimethylformamide. The reaction solution was added with / V-bromosuccinimide (11.38 g, 63.92 mmol), and stirred for 1 hour. The reaction solution was poured into 1 L of water, stirred for 30 minutes, and filtered. The filtered mass was collected and dried in vacuo to obtain the crude title compound 18c (16 g), which was used directly in the next step without purification.
[00310] EM m / z (ESI): 320.0 [M + 1]
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Step 3 [00311] 5-Bromo-4- (2,4-difluorophenyl) -6-hydrazinylpyrimidin-2-amine
18d [00312] Crude compound 18c (16 g, 49.92 mmol) was dissolved in 250 ml of ethanol. The reaction solution was added with 50 ml of 85% hydrazine hydrate, and stirred for 17 hours. The reaction solution was filtered. The filtered mass was washed with ethanol (20 ml * 2) and n-hexane (20 ml * 2) successively, and dried to obtain the title compound 18d (12 g, yield: 76.1%).
[00313] MS m / z (ESI): 316.0 [M + 1]
Step 4 [00314] 8-Bromo-7- (2,4-difluorophenyl) - [1,2,4] triazole [4,3-c] pyrimidine n-5amine 18e [00315] Compound 18d (4 g , 12.65 mmol) and (tri) ethyl orthoformate (2.25 g, 15.18 mmol) were dissolved in 50 mL of ethanol. The reaction solution was stirred at reflux for 2 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was suspended in 5 ml of ethanol for 0.5 hour, and filtered. The filtered mass was washed with anhydrous diethyl ether (10 ml * 2), and dried to obtain the title compound 18e (3.85 g, yield: 93.4%).
[00316] MS m / z (ESI): 326.2 [M + 1]
Step 5 [00317] 7- (2,4-Difluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin -5-amine 18 [00318] Compound 18e (110 mg, 337.32 pmol), compound 1c (145.26 mg, 505.98 pmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium ( 24.7 mg, 33.73 pmol) and potassium carbonate (93.1 mg, 674.64 pmol) were added successively to 12 ml of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere.
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The reaction solution was heated to 90 ° C, and stirred for 3 hours. The reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate (20 ml_ * 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the title compound 18 (31 mg, production : 22.6%).
[00319] MS m / z (ESI): 407.4 [M + 1] [00320] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.41 (s, 1H), 8.50 (brs, 2H ), 7.55 (brs, 2H), 7.44 (s, 1H), 7.20-7.18 (m, 2H), 2.49 (s, 3H).
Example 19 [00321] 8- (2,6-D i methylpyrid in-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 19
Caption: Stage
Step 1 [00322] 5-Bromo-4-chloro-6- (2,4-difluorophenyl) pyrimidin-2-amine 19b [00323] 4-Chloro-6- (2-fluorophenyl) pyrimidin-2-amine 19a (1 , 5 g, 6.71 mmol, prepared according to the method described in patent application WO 2014162039ΑΓ) was dissolved in 20 ml of Λ /, Λ /
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79/119 dimethylformamide. The reaction solution was added with Λ / bromosuccinimide (1.31 g, 7.38 mmol), and stirred for 1 hour. The reaction solution was added with 120 ml of water, stirred and filtered. The filtered mass was collected and dried in vacuo to obtain the crude title compound 19b (1.9 g), which was used directly in the next step without purification.
[00324] MS m / z (ESI): 301.9 [M + 1]
Step 2 [00325] 5-Bromo-4- (2-fluorophenyl) -6-hydrazinylpyrimidin-2-amine 19c [00326] The crude compound 19b (1.9 g, 6.28 mmol) was dissolved in 30 ml of ethanol . The reaction solution was added with 85% hydrazine hydrate (125.61 mmol, 7.18 ml), and stirred at 60 ° C for 1 hour. The reaction solution was filtered. The filtered mass was washed with ethanol (20 ml * 2), and dried to obtain the title compound 19c (1.7 g, yield: 90.8%).
[00327] MS m / z (ESI): 297.8 [M + 1]
Step 3 [00328] 8-Bromo-7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5amine 19d [00329] Compound 19c (1.7 g, 5, 70 mmol) was added to 10 mL of (tri) ethyl orthoformate. The reaction solution was stirred at 130 ° C for 0.5 hour. The reaction solution was cooled to room temperature and filtered. The filtered mass was added with ethyl acetate, stirred and filtered. The filtered mass was dried to obtain the title compound 19d (1.1 g, yield: 62.6%).
[00330] MS m / z (ESI): 307.9 [M + 1]
Step 4 [00331] 8- (2,6-D i methylpyrid in-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 19 [00332] Compound 19d (200 mg, 649.12 pmol), compound 11a
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80/119 (151.32 mg, 649.12 pmol), [1, T-bis (diphenylphosphino) ferrocene] dichloropalladium (47.45 mg, 64.91 pmol) and potassium carbonate (179.16 mg, 1, 30 mmol) were added successively to 12 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 80 ° C, and stirred for 3 hours. The reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the title compound 19 (26 mg, production : 12%).
[00333] MS m / z (ESI): 335.4 [M + 1] [00334] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.38 (s, 1H), 8.30 (s, 2H ), 7.41 (brs, 2H), 7.19-7.22 (m, 1H), 7.09-7.13 (m, 1H), 6.91 (s, 2H), 2.29 ( s, 6H).
Example 20 [00335] 8- (2- (Difluoromethyl) -6-methylpyridin-4-yl) -7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin- 5-amine 20

20th to 18th
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81/119 [00336] 2- (Difluoromethyl) -6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 20a (247.56 mg, 919 , 96 pmol, prepared according to the method described in patent application WO2011095625A1), compound 18e (200 mg, 613.31 pmol), [1, Tbis (diphenylphosphino) ferrocene] dichloropalladium (44.88 mg, 61.33 pmol) and potassium carbonate (254.29 mg, 1.84 mmol) were added successively to 12 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 90 ° C, and stirred for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by a rapid CombiFlash preparation instrument with eluent B system. The resulting crude product was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the compound titer 20 (26 mg, yield: 12%).
[00337] MS m / z (ESI): 389.5 [M + 1] [00338] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.40 (s, 1H), 8.44 (brs, 2H ), 7.54 (s, 1H), 7.40-7.18 (m, 4H), 6.96-6.69 (m, 1H), 2.44 (s, 3H).
Example 21 [00339] 8- (2,6-Dimethylpyridin-4-yl) -2-methyl-7-phenylimidazo [1,2c] pyrimidin-5-amine 21
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21g 21
Caption: Stage
Step 1 [00340] 2 - ((2- (Methylthio) -6-phenylpyrimidin-4-yl) amino) propan-1-ol 21 b [00341] 4-Chloro-2-methylthio-6-phenyl-pyrimidine 21a ( 1.5 g, 6.34 mmol, prepared according to the known method described in Tetrahedron, 1994, 50 (34), 10299-308) was dissolved in 40 ml of acetonitrile. The reaction solution was added with 2-aminopropan-1ol (713.91 mg, 9.50 mmol) and A /, A / -di-isopropylethylamine (1.64 g, 12.67 mmol), and stirred at 75 ° C for 72 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 21b (1.5 g, yield: 86%).
[00342] MS m / z (ESI): 276.2 [M + 1]
Step 2 [00343] 2 - ((5-Bromo-2- (methylthio) -6-phenylpyrimidin-4-yl) amino) propan-1ol 21c [00344] Compound 21b (1.5 g, 5.45 mmol) was dissolved in 30 ml of A /, A / -dimethylformamide. The reaction solution was added with / V-bromosuccinimide (969.50 mg, 5.45 mmol) in batches, and stirred for 1 hour. The reaction solution was added with 150 ml of water, and extracted with a mixed solution of dichloromethane and methanol
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83/119 (V / V = 8: 1) three times. The organic phases were combined, washed with water and saturated sodium chloride solution successively, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 21c (1.2 g, yield: 62.2%).
[00345] MS m / z (ESI): 354.1 [M + 1]
Step 3 [00346] 8-Bromo-2-methyl-5- (methylthio) -7-phenyl-2,3-dihydroimidazo [1,2c] pyrimidine 21d [00347] Compound 21c (2.3 g, 6 , 49 mmol) was dissolved in 40 ml of dichloromethane. The reaction solution was added with triethylamine (983.59 mg, 9.74 mmol), added dropwise with methanesulfonyl chloride (892.44 mg, 7.79 mmol), and stirred overnight. The reaction solution was added with saturated sodium bicarbonate solution, and extracted with dichloromethane three times (30 mL * 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 21 d (1.2 g, yield: 55%).
[00348] MS m / z (ESI): 336.0 [M + 1]
Step 4 [00349] 8-Bromo-2-methyl-5- (methylthio) -7-phenylimidazo [1,2-c] pyrimidine
21e [00350] Compound 21d (1.2 g, 3.57 mmol) was added to 1.4dioxane. The reaction solution was added with manganese dioxide (3.14 g, 35.69 mmol), and stirred at 90 ° C for 36 hours. The reaction solution was cooled to room temperature, and filtered through celite. The filtered mass was washed with methanol, and the filtrate was concentrated
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84/119 under reduced pressure. The residue was purified by column chromatography on silica gel with eluent system A to obtain the title compound 21 e (750 mg, yield: 62.9%).
[00351] MS m / z (ESI): 334.1 [M-1]
Step 5 [00352] 8-Bromo-2-methyl-5- (methylsulfonyl) -7-phenylimidazo [1,2c] pyrimidine 21f [00353] Compound 21 e (320 mg, 957.41 pmmol) was dissolved in 5 ml of trifluoroacetic acid. The reaction solution was added dropwise with hydrogen peroxide (0.5 ml, 957.41 pmmol), and stirred for 1 hour. The reaction solution was neutralized with saturated sodium carbonate solution, and extracted with dichloromethane (30 mL * 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the 21 f crude title compound (350 mg), which was used directly in the next step without purification.
Step 6 [00354] 8-Bromo-2-methyl-7-phenylimidazo [1,2-c] pyrimidin-5-amine 21 g [00355] The crude compound 21f (350 mg, 955.68 pmmol) was dissolved in 10 ml of 1,4-dioxane. The reaction solution was added with ammonia monohydrate (1.0 mL, 955.68 pmmol), and stirred at 40 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, added with water, and extracted with a mixed solution of dichloromethane and methanol (V / V = 8: 1) three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 21g (215 mg, yield: 74.2%).
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Step 7 [00356] 8- (2,6-Dimethylpyridin-4-yl) -2-methyl-7-phenylimidazo [1,2c] pyrimidin-5-amine 21 [00357] Compound 21g (215 mg, 709.20 pmmol), compound 11a (247.99 mg, 1.06 mmol), [1, T-bis (diphenylphosphino) ferrocene] dichloropalladium (51.84 mg, 70.92 pmmol) and sodium bicarbonate (131.06 mg, 1.56 mmol) were added successively to 12 mL of a mixed solution of 1,4-dioxane and water (V / V = 5: 1) under an argon atmosphere. The reaction solution was heated to 80 ° C, and stirred for 2 hours. The reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the title compound 21 (45 mg, production : 19.3%).
[00358] MS m / z (ESI): 330.4 [M + 1] [00359] ¹ H NMR (400 MHz, DMSO-cfe) δ 7.68 (s, 1H), 7.65 (s, 2H ), 7.28 (s, 2H), 7.24 (s, 3H), 6.89 (s, 2H), 2.31 (s, 6H), 2.27 (s, 3H).
Example 22 [00360] 8- (2-Methyl-6 - ((4-methylpiperazin-1-yl) methyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3- c] pyrimidin-5-amine 22
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Caption: Stage
Step 1 [00361] 1-Methyl-4 - (((6-methylpyridin-2-yl) methyl) piperazine 22c [00362] 2- (Chloromethyl) -6-methylpyridine 22b (1 g, 7.06 mmol) and carbonate potassium (1.46 g, 10.59 mmol) were dissolved in 40 mL of acetonitrile. The reaction solution was added with 1 methylpiperazine 22a (848.57 mg, 8.47 mmol, 939.72 µL), and stirred at 80 ° C for 17 hours. The reaction solution was purified by column chromatography on silica gel with eluent system A to obtain the title compound 22c (1 g, yield: 69%).
[00363] MS m / z (ESI): 206.4 [M + 1]
Step 2 [00364] 1-Methyl-4 - (((6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl) pyridin-2-yl) methyl) piperazine 22d [00365] Compound 22c (1 g, 4.87 mmol), compound 5a (146.13 pmmol) and (1,5-cyclooctadiene) (methoxy) iridium (I) dimer (78.44 mg, 292.26 pmmol) were dissolved in 40 mL of n-hexane under an argon atmosphere. The reaction solution was stirred at 80 ° C for 17 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent B system to obtain the title compound 22d (217 mg, yield: 13.5%).
[00366] According to the synthetic routine of Example 5, starting material 5b in step 1 was replaced with 22d, consequently, the title compound 22 (27.6 mg) was prepared.
[00367] MS m / z (ESI): 415.5 [M + 1]
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87/119 [00368] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.34 (s, 1H), 8.26 (brs, 2H), 7.32-7.28 (m, 6H), 6 , 85 (s, 1H), 3.38 (s, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.19-2.09 (m, 8H).
Example 23 [00369] 8- (2-Chloro-6- (trifluoromethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 23
Cl [00370] According to the synthetic routine of Example 4, the starting material 4a in step 1 was replaced with 2-chloro-4- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2- il) -6- (trifluoromethyl) pyridine 23a (prepared according to the known method described in Research on Chemical Intermediates, 2013, 39 (4), 1917-1926), therefore, the title compound 23 (11.8 mg) was prepared.
[00371] MS m / z (ESI): 391.4 [M + 1] [00372] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.40 (s, 1H), 8.58 (brs, 2H ), 7.82 (s, 1H), 7.65 (s, 1H), 7.40-7.36 (m, 5H).
Example 24 [00373] 8- (2-Chloro-6-methylpyridin-4-yl) -7-phenylimidazo [1,2-c] pyrimidin5-amine 24
Cl [00374] According to the synthetic routine of Example 17, the starting material 1c in step 5 was replaced with compound 4a, consequently, the title compound 24 (32 mg) was prepared.
[00375] MS m / z (ESI): 336.4 [M + 1]
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88/119 [00376] ¹ H NMR (400 MHz, DMSO-cfe) δ 8.00 (s, 1H), 7.93 (s, 2H),
7.55 (s, 1H), 7.31 (s, 5H), 7.14 (d, 2H), 2.33 (s, 3H).
Example 25 [00377] 8- (2-Methoxy-6-methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3c] pyrimidin-5-amine 25
[00378] According to the synthetic routine of Example 4, the starting material 4a in step 1 was replaced with 2-methoxy-6-methyl-4 (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) pyridine 25a (prepared according to the known method described in Chemistry - A European Journal, 2017, 23 (24), 5663-5667), therefore, the title compound 25 (11.8 mg) was prepared.
[00379] MS m / z (ESI): 333.2 [M + 1] [00380] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.33 (s, 1H), 8.24 (brs, 2H ), 7.36-7.29 (m, 5H), 6.76 (s, 1H), 6.48 (s, 1H), 3.77 (s, 3H), 2.29 (s, 3H) . Example 26 [00381] 8- (2-Ethyl-6-methylpyrid in-4-yl) -7-phenyl- [1,2,4] triazolo [4,3c] pyrimidin-5-amine 26

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89/119 [00382] 2-Ethyl-6-methylpyridine 26a (1 g, 8.25 mmol, Accela ChemBio (Shanghai) Inc.), compound 5a (2.31 g, 9.08 mmol), (1Z, 5Z) -cycloocta1,5-diene; iridium; methyloxonium (164.10 mg, 247.57 pmmol) and 4-fer-butyl-2 (4-fer-butyl-2-pyridyl) pyridine (588 mg, 6.00 mmol) were added successively to 40 ml of n-hexane under an argon atmosphere. The reaction solution was heated to 80 ° C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent B system to obtain 2-ethyl-6-methyl-4- (4,4,5,5-tetramethyl-1 , 3,2dioxaborolan-2-yl) pyridine 26b (809 mg, yield: 39.7%).
[00383] EM m / z (ESI): 248.2 [M + 1] [00384] According to the synthetic routine of Example 4, the starting material 4a in step 1 was replaced with 26b, consequently, the compound of title 26 (136.6 mg) was prepared.
[00385] MS m / z (ESI): 331.1 [M + 1] [00386] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.35 (s, 1H), 8.25 (brs, 2H ), 7.32-7.28 (m, 5H), 7.12 (s, 1H), 6.80 (s, 1H), 2.57-2.55 (m, 2H), 2.37 ( s, 3H), 1.03-1.00 (m, 3H).
Example 27 [00387] 8- (2-Chloro-6-methylpyridin-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 27
Cl
N NH N = ^ [00388] According to the synthetic routine of Example 19, the starting material 11a in step 4 was replaced with compound 4a, consequently, the title compound 27 (73 mg) was prepared.
[00389] MS m / z (ESI): 355.4 [M + 1] [00390] ¹ H NMR (400 MHz, DMSO-cfe) δ 8.39 (s, 1H), 8.44 (s, 2H ),
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7.49-7.45 (m, 2H), 7.28-7.24 (m, 1H), 7.17-7.14 (m, 2H), 7.11 (s, 1H),
2.33 (s, 3H).
Example 28 [00391] 8- (2,6-Dimethylpyrid in-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 28
[00392] According to the synthetic routine of Example 15, the starting material 4a in step 5 was replaced with compound 11a, consequently, the title compound 28 (38 mg) was prepared.
[00393] MS m / z (ESI): 335.4 [M + 1] [00394] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.34 (s, 1H), 8.24 (brs, 2H ), 7.39-7.35 (m, 2H), 7.16-7.11 (m, 2H), 6.95 (s, 2H), 2.33 (s, 6H).
Example 29 [00395] 7- (3-Fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5 -amine 29
[00396] According to the synthetic routine of Example 15, the starting material 15b in step 1 was replaced with acid (3-fluorophenyl)
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91/119 boronic 29a, consequently, the compound 8-bromo-7- (3-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 29b was prepared;
[00397] The starting material 4a in step 5 of Example 15 was replaced with compound 1c, consequently, the title compound 29 (28 mg) was prepared.
[00398] MS m / z (ESI): 389.4 [M + 1] [00399] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.39 (s, 1H), 8.46 (brs, 2H ), 7.60 (s, 1H), 7.48 (s, 1H), 7.36-7.34 (m, 1H), 7.23-7.19 (m, 2H), 7,107.08 ( m, 1H), 2.49 (s, 3H).
Example 30 [00400] 8- (2-Cyclopropyl-6-methylpyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3c] pyrimidin-5-amine 30
N ^z N NH. N = ^ [00401] According to the synthetic routine of Example 11, the starting material 11a in step 1 was replaced with 2-cyclopropyl-6-methyl-4 (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) pyridine 30a (prepared according to the method described in patent application WO2011070131A1), consequently, the title compound 30 (43 mg) was prepared.
[00402] MS m / z (ESI): 343.2 [M + 1] [00403] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.34 (s, 1H), 8.23 (brs, 2H ), 7.47-7.31 (m, 5H), 6.92-6.87 (m, 2H), 2.28 (s, 3H), 1.98-1.90 (m, 1H), 0.84-0.72 (m, 4H).
Example 31 [00404] 8- (2,6-Dimethylpyridin-4-yl) -7-phenylimidazo [1,2-c] pyrimidin-5amine 31
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[00405] According to the synthetic routine of Example 17, starting material 1c in step 5 was replaced with compound 11a, consequently, the title compound 31 (40 mg) was prepared.
[00406] MS m / z (ESI): 316.4 [M + 1] [00407] ¹ H NMR (400 MHz, DMSO-cfe) δ 8.00 (s, 1H), 7.99 (s, 2H ), 7.51 (d, 1H), 7.31-7.29 (m, 2H), 7.26-7.25 (m, 3H), 6.91 (s, 2H), 2.30 ( s, 6H).
Example 32 [00408] 8- (2,6-Dimethylpyridin-4-yl) -7- (4-fluorophenyl) imidazo [1,2-c] pyrimidin-5-amine 32
[00409] 6-Chloro-2- (methylthio) pyrimidin-4-amine 32a (2.0 g, 11.39 mmol, Shanghai Bide Pharmatech Ltd.) and boronic acid (4-fluorophenyl) (2.39 g, 17 , 08 mmol) were dissolved in 50 mL of toluene under an argon atmosphere. Tetra (triphenylphosphine) palladium (657.60 mg, 569.35 pmmol), sodium carbonate (2.41 g, 22.77 mmol) and 10 mL of water
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93/119 were added successively. The reaction solution was stirred at 90 ° C for 3 hours, then added with water, and extracted with ethyl acetate three times (50 ml_3). The organic phases were combined, washed with saturated sodium chloride solution, dried over aqueous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was added with methanol, stirred and filtered. The filtered mass was collected to obtain 6- (4fluorophenyl) -2- (methylthio) pyrimidin-4-amine 32b (1.3 g, yield: 48.5%). [00410] According to the synthetic routine of Example 17, the starting material 17a in step 1 was replaced with 32b, consequently, 8-bromo-7- (4-fluorophenyl) imidazo [1,2-c] pyrimidin-5 -amine 32c was prepared.
[00411] The starting compound 1c in step 5 of Example 17 was replaced with compound 11a, consequently, the title compound 32 (70 mg) was prepared.
[00412] MS m / z (ESI): 334.4 [M + 1] [00413] ¹ H NMR (400 MHz, DMSO-cfe) δ 7.98 (d, 1H), 7.82 (s, 2H ), 7.52 (d, 1H), 7.35-7.32 (m, 2H), 7.28-7.08 (m, 2H), 6.92 (s, 2H), 2.32 ( s, 6H).
Example 33 [00414] 7- (2-Fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5 -amine 33
F.
FT
F [00415] According to the synthetic routine of Example 19, starting material 11a in step 4 was replaced with compound 1c, consequently, the title compound 33 (25 mg) was prepared.
[00416] MS m / z (ESI): 389.4 [M + 1]
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94/119 [00417] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.43 (s, 1H), 8.48 (brs, 2H), 7.55 (s, 1H), 7.50-7 , 44 (m, 2H), 7.42 (s, 1H), 7.28-7.26 (m, 1H), 7,157.12 (m, 1H), 2.46 (s, 3H)
Example 34 [00418] 8- (2-Chloro-6-methyl pyrid in-4-yl) -7- (2,4-d if fluorophenyl) - [1,2,4] triazolo [4,3- c] pyrimidin-5-amine 34
[00419] According to the synthetic routine of Example 18, starting material 1c in step 5 was replaced with compound 4a, consequently, the title compound 34 (30.4 mg) was prepared.
[00420] MS m / z (ESI): 373.3 [M + 1] [00421] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.39 (s, 1H), 8.46 (brs, 2H ), 7.55-7.54 (m, 1H), 7.25-7.14 (m, 4H), 2.36 (s, 3H).
Example 35 [00422] 8- (2-Chloro-6-methylpyridin-4-yl) -7- (p-tolyl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 35

[00423] According to the synthetic routine of Example 15, the material
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Starting 95/119 15b in step 1 was replaced with p-tolylboronic acid 35a (Shanghai Dari chemical Ltd.), hence 8-bromo-7- (p-tolyl) - [1,2,4] triazole [4, 3-c] pyrimidin-5-amine 35b was prepared.
[00424] The starting compound 15f in step 5 of Example 15 was replaced with compound 35b, consequently, the title compound 35 (21.3 mg) was prepared.
[00425] MS m / z (ESI): 351.1 [M + 1] [00426] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.34 (s, 1H), 8.33 (brs, 2H ), 7.26-7.13 (m, 6H), 2.36 (s, 3H), 2.30 (s, 3H).
Example 36 [00427] 8- (2-Chloro-6-methylpyridin-4-yl) -7- (4-chlorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 36
Cl [00428] According to the synthetic routine of Example 14, starting compound 1c in step 4 was replaced with compound 4a, consequently, the title compound 36 (45.9 mg) was prepared.
[00429] MS m / z (ESI): 371.4 [M + 1] [00430] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.36 (s, 1H), 8.40 (brs, 2H ), 7.43-7.35 (m, 4H), 7.20-7.18 (m, 2H), 2.38 (s, 3H).
Example 37 [00431] 7-Fen i l-8- (pyrid in-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine
N ^Z , ^N
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96/119 [00432] According to the synthetic routine of Example 2, the starting compound 2d in step 4 was replaced with 4- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) pyridine 37a (Shanghai Bide Pharmatech Ltd.), consequently, the title compound 37 (20 mg) was prepared.
[00433] MS m / z (ESI): 289.0 [M + 1] [00434] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.35 (s, 1H), 8.47-8.46 (m, 2H), 8.29 (brs, 2H), 7.33-7.29 (m, 7H).
Example 38 [00435] 8- (2-Chloropyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5amine 38 ci
N
II
N
I h n ^ n | F N NH.
N = ^ [00436] According to the synthetic routine of Example 2, the starting compound 2d in step 4 was replaced with 2-chloro-4- (4,4,5,5tetramethyl-1,3,2-dioxaborolan- 2-yl) pyridine 38a (Adamas Reagent Ltd.), consequently, the title compound 38 (20 mg) was prepared.
[00437] MS m / z (ESI): 323.1 [M + 1] [00438] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.36 (s, 1H), 8.40 (brs, 2H ), 8.28-8.27 (m, 1H), 7.47 (s, 1H), 7.38-7.31 (m, 5H), 7.23-7.22 (m, 1H).
Example 39 [00439] 8- (2-Chloro-6- (trifluoromethyl) pyridin-4-yl) -7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin -5-amine 39
Cl
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97/119 [00440] According to the synthetic routine of Example 18, starting compound 1c in step 5 was replaced with 2-chloro-4- (4,4,5,5tetramethyl-1,3,2-dioxaborolan- 2-yl) -6- (trifluoromethyl) pyridine (prepared according to the known method described in Research on Chemical Intermediates, 2013, 39 (4), 1917-1926), therefore, the title compound 39 (19.8 mg ) was prepared.
[00441] MS m / z (ESI): 427.4 [M + 1] [00442] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.66 (s, 1H), 8.80 (brs, 2H ), 7.80 (s, 1H), 7.70 (s, 1H), 7.65-7.59 (m, 1H), 7.29-7.22 (m, 2H).
Example 40 [00443] 7- (2,4-Difluorophenyl) -8- (2,6-dimethylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 40
N ^z N NH N = 1 [00444] According to the synthetic routine of Example 18, starting compound 1c in step 5 was replaced with compound 11a, consequently, the title compound 40 (40 mg) was prepared.
[00445] MS m / z (ESI): 353.1 [M + 1] [00446] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.54 (s, 1H), 8.43 (brs, 2H ), 7.51-7.45 (m, 1H), 7.21-7.10 (m, 2H), 6.92 (s, 2H), 2.31 (s, 6H).
Example 41 [00447] 7- (2,4-Difluorophenyl) -8- (2-methoxy-6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 41
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98/119 [00448] According to the synthetic routine of Example 18, starting compound 1c in step 5 was replaced with compound 25a, consequently, the title compound 41 (10.6 mg) was prepared.
[00449] MS m / z (ESI): 369.5 [M + 1] [00450] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.37 (s, 1H), 8.33 (brs, 2H ), 7.50-7.48 (m, 1H), 7.22-7.13 (m, 2H), 6.76 (s, 1H), 6.45 (s, 1H), 3.76 ( s, 3H), 2.30 (s, 3H).
Example 42 [00451] 3-Methyl-8- (2-methyl-6- (trifluoromethyl) pyrid in-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 42
[00452] According to the synthetic routine of Example 1, the (tri) ethyl orthoformate starting compound in step 4 was replaced with triethyl orthoacetate, therefore, the title compound 42 (52 mg) was prepared.
[00453] MS m / z (ESI): 385.1 [M + 1] [00454] ¹ H NMR (400 MHz, DMSO-cfe) δ 7.69 (brs, 2H), 7.55 (s, 1H ), 7.41 (s, 1H), 7.35-7.31 (m, 5H), 2.96 (s, 3H), 2.46 (s, 3H).
Example 43 [00455] 5- (5-Amino-7-phenyl- [1,2,4] triazolo [4,3-c] pi rim id in-8-i) -1 isopropylpyridin-2 (1 H) -one 43
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99/119 [00456] According to the synthetic routine of Example 4, starting compound 4a in step 1 was replaced with 1-isopropyl-5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan- 2-yl) pyridine-2 (1 / - /) - one 43a (prepared according to the method described in patent application WO2011143426A1), consequently, the title compound 43 (31 mg) was prepared.
[00457] MS m / z (ESI): 347.1 [M + 1] [00458] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.33 (s, 1H), 8.13 (brs, 2H ), 7.47-7.33 (m, 7H), 6.38-6.35 (m, 1H), 4.97-4.90 (m, 1H), 0.99-0.97 (m , 6H).
Example 44 [00459] 8- (2-Cyclopropyl-6-methylpyridin-4-yl) -7- (2,4-difluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 44 _N 'N NH.
_N 'N NH.
[00460] According to the synthetic routine of Example 18, starting compound 1c in step 5 was replaced with compound 30a, consequently, the title compound 44 (79.4 mg) was prepared.
[00461] MS m / z (ESI): 379.5 [M + 1] [00462] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.38 (s, 1H), 8.33 (brs, 2H ), 7.52-7.46 (m, 1H), 7.21-7.11 (m, 2H), 6.90-6.85 (m, 2H), 2.28 (s, 3H), 1.95-1.85 (m, 1H), 0.85-0.83 (m, 2H), 0.72-0.70 (m, 2H).
Example 45 [00463] 7- (2,4-Difluorophenyl) -8- (2-methylpyridin-4-yl) - [1,2,4] triazolo [4,3c] pyrimidin-5-amine 45
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[00464] According to the synthetic routine of Example 18, starting compound 1c in step 5 was replaced with compound 12a, consequently, the title compound 45 (79.4 mg) was prepared.
[00465] MS m / z (ESI): 339.4 [M + 1] [00466] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.46 (s, 1H), 8.40 (brs, 2H ), 8.31-8.30 (m, 1H), 7.53-7.47 (m, 1H), 7.22-7.11 (m, 3H), 6.98-6.97 (m , 1H), 2.39 (s, 3H).
Example 46 [00467] 7- (2-Chloro-4-fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4yl) - [1,2,4] triazolo [4,3-c] pyrimidin -5-amine 46

[00468] According to the synthetic routine of Example 15, starting compound 15b in step 1 was replaced with boronic acid (2-chloro-4-fluorophenyl) (Accela ChemBio (Shanghai) Inc.), therefore, 8-bromo-7 - (2-chloro-4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 46a was prepared.
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101/119 [00469] The starting compound 4a in step 5 of Example 15 was replaced with compound 1c, consequently, the title compound 46 (32 mg) was prepared.
[00470] MS m / z (ESI): 423.3 [M + 1] [00471] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.43 (s, 1H), 8.54 (brs, 2H ), 7.54 (s, 1H), 7.53-7.49 (m, 2H), 7.47 (s, 1H), 7.40-7.28 (m, 1H), 2.47 ( s, 3H).
Example 47 [00472] 8- (2-Chloro-6- (morpholinomethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 47
[00473] According to the synthetic routine of Example 22, starting compound 22c was replaced with 4 - ((6-chloropyridin-2yl) methyl) morpholine (prepared according to the method described in patent application US20150361100A1), consequently , the title compound 47 (34.8%) was prepared.
[00474] MS m / z (ESI): 422.4 [M + 1] [00475] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.37 (s, 1H), 7.58 (s, 1H ), 7.48-7.33 (m, 5H), 7.05 (s, 1H), 3.35-3.28 (m, 6H), 2.11 (s, 2H), 1.901.87 ( m, 4H).
Example 48 [00476] 8- (2-Methyl-6- (morpholinomethyl) pyridin-4-yl) -7-phenyl- [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 48
[00477] According to the synthetic routine of Example 43, the com
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102/119 starting point 43a in step 1 was replaced with morpholine 48a, consequently, the title compound 48 (30.8 mg) was prepared.
[00478] MS m / z (ESI): 402.5 [M + 1] [00479] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.34 (s, 1H), 8.23 (brs, 2H ), 7.35-7.28 (m, 6H), 6.85 (s, 1H), 3.42-3.35 (m, 6H), 2.44 (s, 3H), 2,132.05 ( m, 4H).
Example 49 [00480] 7- (4-Chloro-2-fluorophenyl) -8- (2-methyl-6- (trifluoromethyl) pyridin-4yl) - [1,2,4] triazolo [4,3-c] pyrimidin -5-amine
[00481] According to the synthetic routine of Example 15, starting compound 15b in step 1 was replaced with boronic acid (4-chloro-2-fluorophenyl) (Accela ChemBio (Shanghai) Inc.), therefore, 8-bromo-7 - (4-chloro-2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 49a was prepared.
[00482] The starting compound 4a in step 5 of Example 15 was replaced with compound 1c, consequently, the title compound 49 (20 mg) was prepared.
[00483] MS m / z (ESI): 422.7 [M + 1] [00484] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.43 (s, 1H), 8.54 (brs, 2H ), 7.56-7.52 (m, 2H), 7.45 (s, 1H), 7.42-7.38 (m, 2H), 2.48 (s, 3H).
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Example 50 [00485] 7- (4-Chloro-2-fluorophenyl) -8- (2-chloro-6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin- 5-amine 50
Cl
[00486] According to the synthetic routine of Example 15, the starting compound 15b in step 1 was replaced with boronic acid (4-chloro-2-fluorophenyl) (Accela ChemBio (Shanghai) Inc.), therefore, the title compound 50 (30 mg) was prepared.
[00487] MS m / z (ESI): 389.4 [M + 1] [00488] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.41 (s, 1H), 8.47 (brs, 2H ),
7.54-7.50 (m, 1H), 7.44-7.39 (m, 2H), 7.18 (s, 1H), 7.14 (s, 1H), 2.36 (s, 3H).
Example 51 [00489] 8- (2- (Difluoromethyl) -6-methylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 51

15f 20a
[00490] Compound 15f (1.00 g, 3.25 mmol), compound 20a (1.05 g, 3.90 mmol), [1, T-bis (diphenylphosphino) ferrocene] dichloropalladium (238 mg,
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324.6 μιτιοΙ) and sodium bicarbonate (682 mg, 8.11 mmol) were added successively to 55 ml of a mixed solution of 1,4dioxane and water (V / V = 9: 2) under an argon atmosphere. The reaction solution was heated to 95 ° C, and stirred for 17 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: sodium bicarbonate, water, acetonitrile) to obtain the title compound 51 (50 mg).
[00491] MS m / z (ESI): 371.2 [M + 1] [00492] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.37 (s, 1H), 8.38 (brs, 2H ), 7.44 (s, 1H), 7.39-7.36 (m, 2H), 7.32 (s, 1H), 7.19-7.14 (m, 2H), 6,986.70 ( m, 1H), 2.46 (s, 3H).
Example 52 [00493] 7- (4-Chlorophenyl) -8- (2- (difluoromethyl) -6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 52 [00494] In accordance with the synthetic routine of Example 14, starting compound 1c was replaced with compound 20a, consequently, the title compound 52 (32 mg) was prepared.
[00495] MS m / z (ESI): 387.0 [M + 1] [00496] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.37 (s, 1H), 8.39 (brs, 2H ), 7.40-7.43 (m, 2H), 7.33-7.38 (m, 4H), 6.84 (t, 1H), 2.46 (s, 3H).
Example 53 [00497] 7- (4-Chlorophenyl) -8- (2- (fluoromethyl) -6-methylpyridin-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 53
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[00498] According to the synthetic routine of Example 14, starting compound 1c was replaced with compound 2- (fluoromethyl) -6methyl-4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) pyridine 53a (prepared according to the method described in patent application WO201195625A1), consequently, the title compound 53 (4 mg) was prepared.
[00499] MS m / z (ESI): 369.1 [M + 1] [00500] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.36 (s, 1H), 8.36 (brs, 2H ), 7.42-7.32 (m, 3H), 7.19 (s, 1H), 5.42-5.30 (m, 2H), 7.19-7.14 (m, 2H), 2.40 (s, 3H).
Example 54 [00501] 7- (4-Chlorophenyl) -8- (2,6-d imethylpyrid in-4-yl) - [1,2,4] triazolo [4,3-c] pyrimidin-5-amine 54
[00502] According to the synthetic routine of Example 14, starting compound 1c was replaced with compound 11a, consequently, the title compound 54 (47.5 mg) was prepared.
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106/119 [00503] MS m / z (ESI): 351.1 [M + 1] [00504] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.34 (s, 1H), 8.27 ( brs, 2H), 7.39-7.33 (m, 4H), 6.96 (s, 2H), 2.34 (s, 6H).
Example 55 [00505] 8- (2- (Fluoromethyl) -6-methylpyridin-4-yl) -7- (4-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 55
N NH _: N = ^ [00506] According to the synthetic routine of Example 15, starting compound 4a was replaced with compound 53a, consequently, the title compound 55 (20 mg) was prepared.
[00507] MS m / z (ESI): 353.2 [M + 1] [00508] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.36 (s, 1H), 8.31 (brs, 2H ), 7.40-7.36 (m, 2H), 7.20-7.13 (m, 4H), 5.42-5.31 (m, 2H), 2.41 (s, 3H).
Example 56 [00509] 8- (2- (Difluoromethyl) -6-methylpyridin-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin-5- amine 56
N * N NH _: [00510] According to the synthetic routine of Example 19, starting compound 11a was replaced with compound 20a, consequently, the title compound 56 (105.6 mg) was prepared.
[00511] MS m / z (ESI): 371.1 [M + 1] [00512] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.53 (s, 1H), 8.50 (brs, 2H ), 7.47-7.42 (m, 2H), 7.37 (s, 1H), 7.31 (s, 1H), 7.26-7.24 (m, 1H), 7.13 Petition 870190079675 , of 16/08/2019, p. 126/150
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7.11 (m, 1 Η), 6.94-6.66 (m, 1 Η), 2.41 (s, 3H).
Example 57 [00513] 8- (2- (Fluoromethyl) -6-methylpyrid in-4-yl) -7- (2-fluorophenyl) - [1,2,4] triazolo [4,3-c] pyrimidin- 5-amine 57
N NH _:
N NH _: N = ^ 57 [00514] According to the synthetic routine of Example 19, starting compound 11a was replaced with compound 53a, consequently, the title compound 57 (58 mg) was prepared.
[00515] MS m / z (ESI): 353.2 [M + 1] [00516] ¹ H NMR (400 MHz, METANOL-ch) δ 9.29 (s, 1H), 7.51-7.48 (m, 1H), 7.43-7.41 (m, 1H), 7.26-7.21 (m, 3H), 7.04-6.99 (m, 1H), 5.375.25 (m , 2H), 2.45 (s, 3H).
Example 58 [00517] 7- (2,4-Difluorophenyl) -8- (2- (fluoromethyl) -6-methylpyridin-4-yl) [1,2,4] triazolo [4,3-c] pyrimidin-5 -amine 58 tf n nh ₂
N NH [00518] According to the synthetic routine of Example 18, the starting compound 1c was replaced with compound 53a, consequently, the title compound 58 (30 mg) was prepared.
[00519] MS m / z (ESI): 371.1 [M + 1] [00520] ¹ H NMR (400 MHz, CD ₃ OD) δ 9.29 (s, 1H), 7.59-7.55 (m, 1H), 7.27-7.25 (m, 2H), 7.06-7.02 (m, 1H), 6.91-6.86 (m, 1H), 5.40-5 , 28 (m, 2H), 2.48 (s, 3H).
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Example 59 [00521] 7- (4-Chloro-2-fluorophenyl) -8- (2- (difluoromethyl) -6-methylpyridin-4yl) - [1,2,4] triazolo [4,3-c] pyrimidin- 5-amine 59 ^F [00522] According to the synthetic routine of Example 49, starting compound 1c was replaced with compound 20a, consequently, the title compound 59 (49.1 mg) was prepared.
[00523] MS m / z (ESI): 405.1 [M + 1] [00524] ¹ H NMR (400 MHz, DMSO-cfe) δ 9.42 (s, 1H), 7.54-7.50 (m, 1H), 7.40-7.30 (m, 4H), 6.97-6.69 (m, 1H), 3.43 (brs, 2H), 2.44 (s, 3H).
Test Examples:
Biological Assay [00525] Test Example 1. Determination of the inhibitory activity of the compounds of the present invention on the adenosine Aia receptor (A2aR) cAMP signaling pathway, the adenosine A2b (A2bR) cAMP signaling pathway, a adenosine Ai receptor cAMP (AiR) signaling pathway and adenosine A3 receptor (A3R) cAMP signaling pathway.
[00526] The inhibitory activity of the compounds of the present invention on the adenosine A1c receptor cAMP signaling pathway, the adenosine A2b receptor cAMP signaling pathway, the adenosine A1 receptor cAMP signaling pathway adenosine A3 receptor cAMP signaling pathway was determined by the following method. The experimental method is briefly described as follows:
I. Experimental instruments and materials
1. CHO-K1 / A _2a R cells (NM 000675.5) or CHO cells
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K1 / A _2b R (NM_000676.2) or CHO-KI / A1R cells (NM_000674.2) or CHO-KI / A3R cells (NM_000677.3)
2. Fetal bovine serum (Gibco, 10099-141)
3. Bleomycin (Thermo, R25001) or G418 (ENZO, ALX380-013-G005) or puromycin (Thermo, 10687-010)
4. DMEM / F12 medium (GE, SH30023.01)
5. Cell separation buffer (Thermo Fisher, 13151014)
6. HEPES (Gibco, 42360-099)
7. Bovine serum albumin (MP Biomedicals, 219989725)
8. Rolipram (sigma, R6520-10MG)
9. Adenosine deaminase (sigma, 10102105001)
10. Forskolin (sigma, F6886)
11. 2CI-IB-MECA (Tocrics, 1104/10)
12. N6-cyclopentyladenosine (Tocris, 1702/50)
13. Balanced salt buffer (Thermo, 14025-092)
14. Dynamic cAMP kit 2 (Cisbio, 6 _2a M4PEB)
15. 384-well plate (Corning, 4514) or (Nunc, 267462 #)
16. Ethyl carbazole (Torcis, 1691/10)
17. PHERAstar multifunction microplate reader (Cisbio, 6 _2a M4PEB)
II. Experimental procedures
2.1 Adenosine A _2a receptor [00527] CHO-K1 / A _2a R cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 800 pg / ml bleomycin. The cells were digested with cell separation buffer during the experiment. The cells were resuspended in the balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin and counted, and the cell density was adjusted
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110/119 for 10 ⁶ cells / ml. In the 384-well plate, each well was added with 5 pl of cell suspension, and 2.5 μΙ of test compound (4x concentration) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% serum albumin bovine, 54 μΜ of rolipram and 2.7 U / ml of adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. Each well was then added with 2.5 μΙ of ethyl carbazole (4x concentration) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μΜ rolipram and 2.7 U / ml adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. The final concentrations of the compounds were: 10,000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, and 0.001024 nM. The final concentration of ethyl carbazole was 20 nM. Intracellular cAMP concentration was detected with the dynamic cAMP kit 2. cAMP-d2 and Anti-cAMP-Eu-Cryptate were diluted respectively with the cAMP lysis buffer in a 1: 4 ratio. Each well was added with 5 μΙ of diluted cAMP-d2, followed by the addition of 5 μΙ of diluted Anti-cAMP-Eu-Cryptate, and the plate was incubated at room temperature in the dark for 1 hour. The HTRF signal values were read by the PHERAstar multifunction microplate reader. The ICso values of inhibition activity of the compounds were calculated by Graphpad Prism software, and are shown in Table 1.
2.2 Ai adenosine receptor [00528] CHO-KI / A1R cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1 mg / ml G418. The cells were digested with 0 cell separation buffer during the experiment. The cells were then resuspended in the balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin and counted, and the cell density was adjusted to 5x10 ⁵
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111/119 cells / ml. In the 384-well plate, each well was added with 12.5 μΙ of cell suspension, and 6.25 μΙ of test compound (4x concentration) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% albumin of bovine serum, 54 μΜ of rolipram and 2.7 U / ml of adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. Each well was then added with 6.25 μΙ of forskolin and N6-cyclopentyladenosine (4x concentration) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μΜ rolipram and 2 , 7 U / ml adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. The final concentrations of the compounds were: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM. The final concentration of forskolin was 10 μΜ. The final CPA concentration was 10 nM. Intracellular cAMP concentration was detected with the dynamic cAMP kit 2. cAMP-d2 and Anti-cAMP-Eu-Cryptate were diluted respectively with cAMP lysis buffer in a ratio of 1: 4, Each well was added with 12, 5 μΙ of diluted cAMP-d2, followed by the addition of 12.5 μΙ of diluted Anti-cAMP-Eu-Cryptate, and the plate was incubated at room temperature in the dark for 1 hour. The HTRF signal values were read by the PHERAstar multifunction microplate reader. The IC 50 values of inhibition activity of the compounds were calculated by Graphpad Prism software, and are shown in Table 2.
2.3 Adenosine A3 receptor [00529] CHO-KI / A3R cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 10 pg / ml puromycin. The cells were digested with cell separation buffer during the experiment. The cells were resuspended in the balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin and counted, and the cell density was adjusted
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112/119 for 5χ10 ⁵ cells / ml. In the 384-well plate, each well was added with 12.5 pl of cell suspension, and 6.25 μΙ of test compound (4x concentration) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% albumin of bovine serum, 54 μΜ of rolipram and 2.7 U / ml of adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. Each well was then added with 6.25 μΙ of forskolin and 2CI-IB-MECA (4x concentration) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μΜ rolipram and 2.7 U / ml adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. The final concentrations of the compounds were: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM. The final concentration of forskolin was 10 μΜ. The final concentration of 2CIIB-MECA was 5 nM. Intracellular cAMP concentration was detected with the dynamic cAMP kit 2. cAMP-d2 and Anti-cAMP-Eu-Cryptate were diluted respectively with cAMP lysis buffer in a 1: 4 ratio, each well was added with 12, 5 μΙ of diluted cAMP-d2, followed by the addition of 12.5 μΙ of diluted Anti-cAMP-EuCriptato, and the plate was incubated at room temperature in the dark for 1 hour. The HTRF signal values were read by the PHERAstar multifunction microplate reader. The IC 50 values of inhibition activity of the compounds were calculated by Graphpad Prism software, and are shown in Table 2.
2.4 Adenosine A2b receptor (A2bR) [00530] CHO-K1 / A2bR cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1 mg / ml G418. The cells were digested with cell separation buffer during the experiment. The cells were resuspended in the balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin and counted, and the cell density was adjusted to 10 ⁶
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113/119 cells / ml. In the 384-well plate, each well was added with 5 μΙ of cell suspension, and 2.5 μΙ of test compound (4x concentration) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% serum albumin bovine, 54 μΜ of rolipram and 2.7 U / ml of adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. Each well was then added with 2.5 μΙ of ethyl carbazole (4x concentration) (Torcis, 1691/10) formulated with the balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 μΜ rolipram and 2.7 U / ml adenosine deaminase, and the plate was incubated at room temperature for 30 minutes. The final concentrations of the compounds were: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM. The final concentration of ethyl carbazole was 1 μΜ. Intracellular cAMP concentration was detected with the dynamic cAMP kit 2. cAMP-d2 and Anti-cAMP-Eu-Cryptate were diluted with cAMP lysis buffer in a 1: 4 ratio, respectively, each well was added with 5 μΙ of diluted cAMP-d2, followed by the addition of 5 μΙ of diluted AnticAMP-Eu-Cryptate, and the plate was incubated at room temperature in the dark for 1 hour. The HTRF signal values were read by the PHERAstar multifunction microplate reader. The IC50 values of inhibition activity of the compounds were calculated by Graphpad Prism software, and are shown in Table 3.
Table 1. IC50 values of the inhibition activity of the compounds of the present invention on the adenosine A2a receptor cAMP signaling pathway
Example No. ICso / nM (A ₂ aR) 1 0.23 3 0.07 4 0.08 5 0.09 6 0.14 7 0.16 8 0.18 9 0.25
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114/119
10 0.26 11 0.15 12 0.63 14 1.56 15 0.17 16 0.63 17 0.75 18 3.96 19 0.96 20 2.33 21 2.46 23 0.23 24 0.27 25 0.32 26 0.42 27 0.5 28 0.52 29 0.55 30 0.77 31 0.93 32 1 33 1.77 34 2.04 35 0.18 36 3.47 37 2.11 38 2.18 40 1.75 43 0.2 50 3.55 51 0.36 52 0.48 53 0.35 54 0.48 55 1.04 56 1.68 57 2.59 59 3.05
[00531] Conclusion: The compounds of the present invention have significant inhibitory activity on the adenosine A _2a receptor cAMP signaling pathway.
Table 2. IC 50 values of the inhibitory activity of the compounds of the present invention on the adenosine Ai receptor cAMP signaling pathway and the adenosine A3 receptor cAMP signaling pathway.
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115/119
Ex.At the. ICso / nM (A _2a R) ICso / nM (AiR) IC ₅₀ ratio (At R / A _2a R) ICso / nM (A ₃ R) IC ₅₀ ratio (A ₃ R / A _2a R) 3 0.07 18 257 2x10 ³ 2.9x10 ⁴ 4 0.08 37 463 > 10 ⁴ > 1.3x10 ⁵ 5 0.09 12 133 1.4x10 ³ 1.5x10 ⁴ 7 0.16 16 100 5x10 ³ 3.1x10 ⁴ 11 0.15 102 680 > 10 ⁴ > 6.7x10 ⁴ 18 3.96 409 103 > 10 ⁴ > 2.5x10 ³ 19 0.96 173 180 > 10 ⁴ > 10 ⁴ 20 2.33 519 223 > 10 ⁴ > 4.3x10 ³ 27 0.5 71 142 > 10 ⁴ > 2x10 ⁴ 28 0.52 66 127 > 10 ⁴ > 1.9x10 ⁴ 51 0.36 418 1161 > 10 ⁴ > 10 ⁴ 52 0.48 41 85 > 10 ⁴ > 10 ⁴ 55 1.04 222.5 214 > 10 ⁴ > 10 ³ 56 1.68 248 148 > 10 ⁴ > 10 ³ 57 2.59 302.4 117 > 10 ⁴ > 10 ³ 59 3.05 1009 330 > 10 ⁴ > 10 ³
[00532] Conclusion: The compounds of the present invention have weak inhibitory activity on the adenosine Ai receptor and the adenosine A3 receptor, indicating that the compounds of the present invention are highly selective for the adenosine A _2a receptor.
Table 3. IC 50 values of the inhibitory activity of the compounds of the present invention on the adenosine A2b receptor cAMP signaling pathway.
Example No. ICso / nM (A _2a R) ICso / nM (A _2b R) ICso ratio (A _2b R / A _2a R) 1 0.23 58.5 254 4 0.08 82.6 1032 8 0.18 202.6 1125 10 0.26 91 350 15 0.17 98.9 582 16 0.63 122.2 194 18 0.75 793.1 1057 19 0.96 85.4 89 20 2.33 522.3 224 29 0.55 86.3 157 30 0.77 70.9 92 33 1.77 134.5 76 34 2.04 169.9 83 50 3.55 254.7 72 55 1.04 78.2 75 56 1.68 111.9 67 57 2.59 209.2 81 59 3.05 883.8 290
[00533] Conclusion: The compounds of the present invention have poor inhibitory activity on the A2b adenosine receptor, indican
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116/119 than the compounds of the present invention are highly selective for the adenosine A _2a receptor.
[00534] Test Example 2. Determination of cerebral permeability of the compounds of the present invention in mice [00535] The cerebral permeability of the compounds of the present invention in mice was determined by the following experimental method:
I. Experimental instruments and materials
1. RED Device Inserts (Thermo Scientific, QL21291110)
2. API 4000 Q-trap linear ion trap mass spectrometer (Applied BiosysteEM)
3. LC-30A Ultra High Pressure Liquid Chromatography System (Shimadzu)
4. pH 7.4 PBS (100 mM, stored at 4 ° C in a refrigerator)
5. C57 mice, supplied by Jiesijie Laboratory Animal Co., LTD, with Certificate No.: SCXK (Shanghai) 2013-0006.
II. Treatment of test animals [00536] Four female C57 mice maintained on a 12-hour light / 12-hour dark cycle, at a constant temperature of 24 ± 3 ° C and a humidity of 50-60%, and have free access to food and water. The compounds were administered intragastrically to the mice after fasting overnight. The dosage for administration was 20 mg / kg. The drug administration group was sacrificed after blood collection at 0.5 h after drug administration (volume of blood collected: 0.5 ml). The blood sample was stored in heparinized tubes, and centrifuged for 10 minutes at 3500 rpm to separate the plasma, which was marked as plasma 1 and stored at -80 ° C. Normal saline was infused into the heart of the sacrificed animal to remove excess blood from brain tissue. O
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117/119 brain tissue was removed, and residual blood in the brain tissue was sucked up with filter paper. Brain tissue was marked as brain tissue 1, and stored at -80 ° C. Another three animals were apprehended for null plasma and brain tissue 2, and the treatment method was the same as that of the drug administration group.
III. Plasma protein binding balance dialysis process
3.1 Sample preparation [00537] The drug compounds were dissolved in DMSO to 20 mM to obtain the raw material solution I. An appropriate amount of raw material solution I was apprehended and diluted with methanol to obtain 200 μΜ of solution of diluted raw material II. 10 μΙ of raw material solution II was taken to a 1.5 ml Eppendorf tube, added with 990 μΙ of plasma, and mixed well to obtain 2 μΜ of plasma sample 2 (DMSO concentration <0.2%), which were used to determine the plasma protein binding rate at this concentration. 50 μΙ of the plasma sample formulated above were apprehended, marked as To, and stored at -4 ° C in a refrigerator for testing.
3.2 Experimental procedures [00538] The RED Device Inserts balance dialysis tube was inserted into a 96-well plate. 300 μΙ of the plasma sample 2 formulated above containing the test compound and the corresponding null plasma was added to a well marked red (plasma chamber). 500 μΙ of phosphate buffer solution (pH 7.4) was added to another well (plasma chamber) side by side with the well marked red. According to the above procedures, each concentration of each compound has 2 samples. Then, the 96-well plate was covered with a sealing tape, and the entire plate in a heat mixer and equilibrated at 37 ° C at 400 rpm for 4 h. The 96-well plate device has been removed
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118/119 of the heat mixer after incubation to obtain equilibrium dialysis. 25 μΙ of balanced plasma sample or dialyzed sample was added with 25 μΙ of the corresponding unbalanced drug-free phosphate buffer solution or drug-free null plasma, and then added with 200 μΙ of internal standard (formulated with acetonitrile), mixed by swirling for 5 min, and centrifuged for 10 minutes (4000 rpm). The supernatant was apprehended for LC / MS / MS analysis. The To sample was not subjected to incubation. The chromatographic peak area relationships of the total drug (plasma chamber) and the free drug (buffer chamber) to the internal standard were determined directly by the LC / MS / EM method established respectively, and the free percentage (f _u piasma% ) was calculated.
IV. Brain tissue protein binding balance dialysis process [00539] Brain tissue protein binding balance dialysis process: null brain tissue 2 was formulated into a null brain homogenate with PBS (pH 7.4) accordingly with a dilution factor of 11, and added with the compound to formulate 2 μΜ of cerebral homogenate. Other procedures were the same as those for plasma protein binding. Area ratios d chromatographic peak of total drug (Brain Homo chamber) and the free drug (buffer chamber) to the internal standard were determined by LC / MS / MS established respectively, and the percentage (F _u homo cerebral% ) WAS CALCULATED.
V. Method of calculating data from the cerebral permeability test [00540] 5.1 The drug concentrations in plasma 1 and brain tissue 1 of mice 0.5 h after drug administration were determined by the established LC / MS / MS method, respectively, which were the total concentration (Ctotai, _P and Ctotai, b);
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119/119 [00541] 5.2 The protein binding rates of the compound in the mouse plasma and brain tissue were determined respectively by the equilibrium dialysis method with the RED Device Inserts device, in order to calculate the free percentage (f _u plasma% , cerebral fu%);
Plasma free percentage (plasma _u %) ^- Buffer / Plasma * 100%;
Percent free brain homogenate (brain homo% f _u) ^- Cbuffer / Chomo brain x100%;
Percentage free of brain tissue (brain _u %) - cerebral homo fu / (Df- (Df1) Xfu homo cerebral) ^χ 100%, COITI Df ⁼ 1 1, [00542] 5.3 The Kp-unbound hematoencephalic index was calculated using the following formula.
Off
SAW. Test results and description [00543] The brain permeability indices of the compounds of the present invention are shown below:
Example No. blood-brain permeability index (Kp-unbound) Example 18 0.010 Example 20 0.015
[00544] Conclusion: The compounds of the present invention have a low concentration of free drug in the brain, the ability to cross the blood-brain barrier is weak, and few drugs enter the brain, which can have low side effects.

权利要求:
Claims (17)
[1]
1. Compound characterized by the fact that it presents the formula (I):

[2]
2/10 amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R ⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R ⁵ is selected from the group consisting of hydrogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R ^b is heterocyclylalkyl, where the heterocyclyl of the heterocyclylalkyl is optionally substituted by one or more substituents selected from the group consisting of alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, cycloalkyloxy, heterocyclyl, aryl, heteroaryl and C (O ) OR ⁵ ; and n is 1,2, 3 or 4,
2. A compound of formula (I) according to claim 1, characterized by the fact that R ² is selected from the group consisting of cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, in which cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, oxo, cycloalkyl, heterocyclyl and R ^b ; R ^b is heterocyclylalkyl, wherein the heterocyclyl of the heterocyclylalkyl is optionally substituted by one or more alkyl.
[3]
3. A compound of formula (I) according to claim 1, characterized by the fact that it is a compound of formula (II):

[4]
Compound of formula (I) according to any one of claims 1 to 3, characterized in that it is a compound of formula (III):

[5]
A compound of formula (II) according to claim 3 or 4, characterized by the fact that ring B is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyridin-2-one, imidazolyl, pyrrolyl, furyl, thienyl, piperidinyl, tetrahydropyridyl, isoquinolyl, quinolyl, quinoxalinyl, indolyl, indazolyl, benzofuranyl and benzothienyl.
[6]
A compound of formula (I) according to any one of claims 1 to 5, characterized in that it is a compound of formula (III '):

[7]
A compound of formula (I) according to any one of claims 1 to 6, characterized by the fact that ring A is aryl or heteroaryl, and preferably phenyl or furyl.
[8]
A compound of formula (I) according to any one of claims 1 to 7, characterized by the fact that R ¹ is selected from the group consisting of hydrogen, halogen and alkyl.
[9]
A compound of formula (I) according to any one of claims 1 to 8, characterized by the fact that R ³ is selected from the group consisting of hydrogen, halogen and alkyl.
[10]
10. Compound of formula (I) according to any one of claims 1 to 9, characterized in that it is selected from the group consisting of:

[11]
11. Compound characterized by the fact that it presents the formula (IV):
Petition 870190079675, of 16/08/2019, p. 146/150
8/10

[12]
12. Compound of formula (IV) according to claim 11, characterized by the fact that it is selected from the group consisting of:

[13]
13. Method for preparing the compound of formula (II) as defined in claim 3, characterized in that it comprises a step of:

[14]
14. Pharmaceutical composition, characterized by the fact that it comprises a therapeutically effective amount of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or a pharmaceutical salt
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10/10 ceutetically acceptable thereof as defined in any one of claims 1 to 10, and one or more pharmaceutically acceptable vehicles, diluents or excipients.
[15]
15. Use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 10, or composition pharmaceutical as defined in claim 14, characterized in that it is in the preparation of a drug for inhibition of the A _2a receptor.
[16]
16. Use of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof as defined in any of claims 1 to 10, or composition pharmaceutical as defined in claim 14, characterized in that it is in the preparation of a medicament for the treatment of a disease or condition improved by inhibition of the A _2a receptor.
[17]
17. Use according to claim 16, characterized by the fact that the disease or condition improved by inhibition of the A _2a receptor is selected from the group consisting of tumor, depression, cognitive function disorder, neurodegenerative disorder, attention-related disorder, extrapyramidal syndrome, abnormal movement disorder, cirrhosis, liver fibrosis, fatty liver, dermal fibrosis, sleep disorder, stroke, brain injury, neuroinflammation and addictive behavior, and preferably tumor.

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法律状态:
2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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CN201710156742|2017-03-16|

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CN201710982734|2017-10-20|

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PCT/CN2018/079086|WO2018166493A1|2017-03-16|2018-03-15|Heteroaryl[4,3-c]pyrimidine-5-amine derivative, preparation method therefor, and medical uses thereof|

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