CN116236478A - Application of aromatic heterocyclic formamide compound - Google Patents
Application of aromatic heterocyclic formamide compound Download PDFInfo
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- CN116236478A CN116236478A CN202211689067.1A CN202211689067A CN116236478A CN 116236478 A CN116236478 A CN 116236478A CN 202211689067 A CN202211689067 A CN 202211689067A CN 116236478 A CN116236478 A CN 116236478A
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- -1 aromatic heterocyclic formamide compound Chemical class 0.000 title claims abstract description 207
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 108010018033 endothelial PAS domain-containing protein 1 Proteins 0.000 claims abstract description 31
- 239000000556 agonist Substances 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 208000007502 anemia Diseases 0.000 claims abstract description 9
- 208000029462 Immunodeficiency disease Diseases 0.000 claims abstract description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 8
- 230000001684 chronic effect Effects 0.000 claims abstract description 8
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 8
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 8
- 206010061218 Inflammation Diseases 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 230000004054 inflammatory process Effects 0.000 claims abstract description 7
- 206010014561 Emphysema Diseases 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 208000032467 Aplastic anaemia Diseases 0.000 claims description 2
- 201000006474 Brain Ischemia Diseases 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 208000004232 Enteritis Diseases 0.000 claims description 2
- 208000023105 Huntington disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 claims description 2
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- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 206010044302 Tracheitis Diseases 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 2
- 208000029028 brain injury Diseases 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 208000007475 hemolytic anemia Diseases 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 229910052751 metal Chemical class 0.000 claims description 2
- 239000002184 metal Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000002780 morpholines Chemical class 0.000 claims description 2
- 201000008383 nephritis Diseases 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 150000004885 piperazines Chemical class 0.000 claims description 2
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
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- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 201
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 151
- 239000007787 solid Substances 0.000 description 143
- 230000015572 biosynthetic process Effects 0.000 description 83
- 238000003786 synthesis reaction Methods 0.000 description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 40
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 31
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 29
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 238000001308 synthesis method Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- FZIVKDWRLLMSEJ-UITAMQMPSA-N (nz)-n-[(2-chlorophenyl)methylidene]hydroxylamine Chemical compound O\N=C/C1=CC=CC=C1Cl FZIVKDWRLLMSEJ-UITAMQMPSA-N 0.000 description 12
- UVEPOHNXGXVOJE-UHFFFAOYSA-N 3-(2-chlorophenyl)-5-methyl-1,2-oxazole-4-carboxylic acid Chemical compound OC(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl UVEPOHNXGXVOJE-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
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- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 11
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 11
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- KBKYPVNGIPLOGG-NTMALXAHSA-N methyl (z)-2-(2-chlorobenzoyl)-3-(dimethylamino)prop-2-enoate Chemical compound COC(=O)C(=C/N(C)C)\C(=O)C1=CC=CC=C1Cl KBKYPVNGIPLOGG-NTMALXAHSA-N 0.000 description 9
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 8
- 108090000394 Erythropoietin Proteins 0.000 description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
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- NJXPYZHXZZCTNI-UHFFFAOYSA-N 3-aminobenzonitrile Chemical group NC1=CC=CC(C#N)=C1 NJXPYZHXZZCTNI-UHFFFAOYSA-N 0.000 description 7
- YODRRRXGVNGXFN-UHFFFAOYSA-N 4-(2-chlorophenyl)pyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=CN=C1C1=CC=CC=C1Cl YODRRRXGVNGXFN-UHFFFAOYSA-N 0.000 description 7
- RWGBXAQMUBGGKQ-UHFFFAOYSA-N 4-(trifluoromethyl)pyridin-2-amine Chemical group NC1=CC(C(F)(F)F)=CC=N1 RWGBXAQMUBGGKQ-UHFFFAOYSA-N 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- KFKZOQGVNQPBSU-UHFFFAOYSA-N 5-(2-chlorophenyl)-1,2-oxazole-4-carboxylic acid Chemical compound C1=NOC(C=2C(=CC=CC=2)Cl)=C1C(=O)O KFKZOQGVNQPBSU-UHFFFAOYSA-N 0.000 description 6
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 6
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- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 6
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- IGBCIBWBDFNAQC-UHFFFAOYSA-N 5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid Chemical compound N1=COC(C=2C(=CC=CC=2)Cl)=C1C(=O)O IGBCIBWBDFNAQC-UHFFFAOYSA-N 0.000 description 5
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Abstract
The invention provides an application of aromatic heterocyclic formamide compounds, in particular to an application of aromatic heterocyclic formamide and pharmaceutically acceptable salts thereof in preparing HIF-2 alpha agonists. Therefore, the compound can be used as a HIF-2 alpha agonist to be applied to medicines for treating anemia, inflammation, emphysema, immunodeficiency diseases, chronic metabolic diseases and neurodegenerative diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to application of aromatic heterocyclic formamide compounds, in particular to medical application of the aromatic heterocyclic formamide compounds, and particularly relates to application in preparation of hypoxia inducible factor-2 alpha agonist medicines.
Background
Hypoxia inducible factor-2 (HIF-2) is a member of the base-helix-loop-helix (bHLH) -PAS protein family (this family also includes HIF-1 and HIF-3) consisting of an oxygen-dependent HIF-2 alpha subunit and an oxygen-independent aromatic receptor nuclear transport protein ARNT subunit. Under normoxic conditions, specific amino acid residues of HIF-2. Alpha. Proteins are hydroxylated by Prolyl Hydroxylase (PHD), recognized by the Von Hippel-Lindau protein (pVHL), and degraded by ubiquitin-proteasome degradation pathways. Under the anoxic condition, the activity of HIF-PH enzyme is inhibited, the HIF-2 alpha protein enters the cell nucleus and combines with ARNT to form an HIF-2 complex, then the HIF-2 protein combines with coactivator p300/CERB to promote the transcription and expression of hundreds of target genes at the downstream, including Erythropoietin (EPO), vascular Endothelial Growth Factor (VEGF), cyclin (Cyclin 1), glucose transporter (GLUT 1) and the like, and the HIF-2 protein has key effects in physiological processes such as cell growth, metabolism, angiogenesis and the like.
Damage to kidney tissue in Chronic Kidney Disease (CKD) patients can lead to EPO deficiency and iron deficiency leading to renal anemia. Renal anemia not only severely reduces the quality of life of the patient, but is also an important factor in the occurrence of cardiovascular disease and in the increase of mortality. Recombinant human erythropoietin (rHuEPO) or Erythropoiesis Stimulators (ESAs) can treat renal anemia by increasing hemoglobin levels. However, higher hemoglobin targets in clinical trials are positively correlated with the risk of cardiovascular side effects. Currently, an emerging therapy for renal anemia is stabilization of HIF-2 protein by pharmacological inhibition of prolyl hydroxylase PHD to stimulate endogenous EPO production in the kidney or non-kidney tissue. However, the medicines lack selectivity and increase the content of HIF-1 alpha and HIF-3 alpha proteins, so that certain toxic and side effects exist.
Maria et al have found that HIF-2α plays a critical role in maintaining iron balance in organisms by directly regulating transcription of genes encoding divalent metal transporter 1 (DMT 1), the major intestinal iron transporter: activation of HIF-2α may allow iron to mobilize, while its inhibition is beneficial in reducing iron absorption. Thus, direct targeting of the HIF-2 pathway to promote HIF-2 alpha protein expression is potentially valuable for treating renal anemia. The research shows that HIF-2 alpha can be a potential therapeutic target for emphysema, immunodeficiency diseases, chronic metabolic diseases, neurodegenerative diseases and the like.
In 2019, team Wu Dalei first yielded two HIF-2α agonists, M1001 and M1002 (fig. 1), based on affinity selection mass spectrometry (AS-MS) screening. Yu et al have obtained compounds ZG-2006 and ZG-2033 with enhanced HIF-2. Alpha. Agonistic activity by optimizing the structure of M1002. ZG-2033 is the first orally reported HIF-2 alpha agonist, which shows good pharmacokinetic characteristics and in vivo safety, and has synergistic treatment effect on anemia in combination with the PHD inhibitor, namely, vard-stat. The research of HIF-2 alpha agonists has good clinical prospect and development potential, but the structure types of the HIF-2 alpha agonists still lack diversity at present, and the discovery of lead molecules with brand new frameworks is urgently needed.
Disclosure of Invention
Aiming at the characteristic that the structure type of the existing HIF-2 alpha agonist is scarce, the invention aims to provide aromatic heterocyclic formamide and the structural analogue thereof, which are applied to the preparation of HIF-2 alpha agonist medicaments.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides an application of aromatic heterocyclic formamide shown in a formula a and pharmaceutically acceptable salt thereof in preparing HIF-2 alpha agonist,
in formula a:
R 1 selected from nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl or NR a R b Wherein R is a 、R b Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 2-6 Unsaturated aliphatic hydrocarbon groups;
m is 0, 1 or 2; when m is 0, the benzene ring is unsubstituted, and when m is 2, the benzene ring has two identical or different substituents.
Ring A is selected from unsubstituted or substituted by one R 2 Substituted pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl or pyrimidinyl, wherein R 2 Selected from hydroxy, halogen, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Alkoxy or NR c R d Wherein R is c 、R d Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Unsaturated aliphatic hydrocarbon groups;
R 3 、R 4 each independently selected from hydrogen, C 1-6 Alkyl or unsubstituted or substituted by R e Substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl, wherein R e Selected from nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, NR f R g Or SO 2 R x Wherein R is f 、R g 、R x Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 2-6 Unsaturated aliphatic hydrocarbon groups; or R is 3 、R 4 Together with N between them forms unsubstituted or substituted R h Substituted morpholinyl, piperazinyl, or piperidinyl; wherein the method comprises the steps ofR h Is hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-6 Unsaturated aliphatic hydrocarbon group, NR i R j Or SO 2 R y The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is i 、R j 、R y Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-8 Cycloalkyl or C 2-6 Unsaturated aliphatic hydrocarbon groups.
Further, R 1 Preferably nitro, fluoro, chloro, methyl, methoxy, C 1-6 Fluoroalkyl, C 1-6 Fluoroalkoxy or amino.
Further, in formula a
Selected from one of the following heterocycles:
further, R 2 Is hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Fluoroalkyl or NR c R d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is c 、R d Respectively selected from hydrogen, C 1-6 An alkyl group.
Further, R 3 And R is 4 Respectively preferably hydrogen, unsubstituted or R e Substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl; wherein R is e Is fluorine, chlorine, bromine, cyano, C 1-6 Fluoroalkyl, C 1-6 Fluoroalkoxy, NR f R g Or SO 2 R x Wherein R is f 、R g 、R x Respectively hydrogen or C 1-6 An alkyl group.
Further, R 3 、R 4 And N therebetween together form an unsubstituted or substituted R h Substituted morpholinyl, piperazinyl or piperidinyl, wherein R h Is hydroxy, C 1-6 Alkyl, NR i R j Or SO 2 R y The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is i 、R j 、R y Respectively hydrogen,C 1-6 Alkyl or C 1-6 A fluoroalkyl group.
Further preferably, R 1 Is nitro, fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy or amino; r is R 2 Hydrogen, methyl or amino; r is R 3 Is H, R 4 Unsubstituted or substituted by trifluoromethyl, halogen, cyano, -N (CH) 3 ) 2 or-SO 2 CH 3 Substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl, or R 3 、R 4 And N therebetween together form an unsubstituted or substituted hydroxy, methyl, amino, -SO 2 CH 3 or-SO 2 CF 3 Substituted morpholines, piperidines or piperazines.
Preferably, the aromatic heterocyclic formamide shown in the formula a is selected from one of the following:
the "pharmaceutically acceptable salts" in the present invention include, but are not limited to, alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts, and the like.
The invention aims to provide an application of the aromatic heterocyclic formamide compound in preparing HIF-2 alpha agonist medicaments, wherein the medicaments comprise derivatives, pharmaceutically acceptable salts and solvates thereof, or any one or more of the derivatives, pharmaceutically acceptable salts and solvates thereof and pharmaceutically acceptable carriers.
The compound and the pharmaceutical composition thereof can be used as HIF-2 alpha agonists for treating anemia, inflammation, emphysema, immunodeficiency diseases, chronic metabolic diseases and neurodegenerative diseases; the invention provides an application of aromatic heterocyclic formamide shown in the formula a and pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing anemia, inflammation, emphysema, immunodeficiency diseases, chronic metabolic diseases or neurodegenerative diseases. Wherein the anemia comprises secondary anemia, pernicious anemia, hemolytic anemia, iron deficiency anemia, aplastic anemia and the like; the inflammation comprises nephritis, pneumonia, tracheitis, enteritis, arthritis, traumatic infection and the like; the immunodeficiency diseases comprise systemic lupus erythematosus, psoriasis, rheumatic arthritis and the like; the chronic metabolic diseases comprise diabetes, hypertension, obesity and the like; the neurodegenerative diseases comprise cerebral ischemia, brain injury, alzheimer's disease, parkinson's disease, huntington's disease and the like.
The invention has the beneficial effects that: the aromatic heterocyclic formamide compounds with the structural formula can target and excite HIF-2 alpha, and the expression level of a downstream target gene is improved. Therefore, the compound can be used as a HIF-2 alpha agonist to be applied to medicines for treating anemia, inflammation, emphysema, immunodeficiency diseases, chronic metabolic diseases and neurodegenerative diseases.
Drawings
FIG. 1HIF-2 alpha agonists
FIG. 2 Effect of Compounds on EPO and VEGFA mRNA expression in 786-O cells
Detailed Description
The following specific examples are included for illustrative purposes and should not be construed as limiting the scope of the invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Example 1: virtual screening based on molecular docking
By systematic evaluation of the crystal structure of 10 HIF-2 complexes, crystals with PDB number 5UFP were preferred as receptor proteins for molecular docking. And (3) evaluating by adopting a Glide SP scoring mode, and re-scoring and screening 5 ten thousand compounds at the top ranking under XP precision, wherein 1000 compounds are reserved. According to the five-class medicine rule and the Opera rule, molecules possibly containing toxicity, reactivity and other undesirable components are screened out, and 160 small molecules are reserved by cluster analysis. Through structural classification and artificial optimization, 31 compounds are preferably purchased, VEGF protein agonistic activity of the candidate compounds on human kidney transparent cell carcinoma cell line 786-O is evaluated through VEGF Elisa Assay, a small molecular compound with HIF-2 transcription agonistic activity is found from the candidate compounds, and then the aromatic heterocyclic formamide compounds are obtained through structural modification and optimization.
Example 2: synthesis of I series of Compounds
Step 1: 2-chlorobenzaldehyde oxime (Ib-1)
2-chlorobenzaldehyde (25 g,0.18 mol) was dissolved in ethanol (200 mL), hydroxylamine hydrochloride (14.5 g,0.21 mol) and sodium hydroxide (8.4 g,0.21 mol) were dissolved in water (100 mL) and the system was added and heated to 80℃overnight. After the reaction, the organic solvent was distilled off under reduced pressure, the solid was precipitated, suction filtration was performed, the cake was washed with water (2×50 mL), and dried to give 26g of white needle crystals, yield: 93%. 1 H NMR(400MHz,Chloroform-d)δ7.25-7.34(m,2H),7.39(d,J＝8.0Hz,1H),7.82(dd,J＝1.8,7.7Hz,1H),8.42(brs,1H),8.58(s,1H)；ESI-MS:m/z＝154[M-H] - . 2-chloro-6-fluorobenzaldehyde oxime (Ib-2)
The synthesis was identical to Ib-1, substituting 2-chlorobenzaldehyde with 2-chloro-6-fluorobenzaldehyde (1.6 g,0.1 mol) to give 1.7g of a white solid, yield: 96%. ESI-MS: m/z=172 [ M-H ]] - 。
2, 6-dimethyl-aldoxime (Ib-3)
The synthesis was identical to Ib-1, substituting 2-chlorobenzaldehyde with 2, 6-dimethylbenzaldehyde (1.3 g,0.1 mol) to give 1.5g of a white solid, yield: 98%. ESI-MS: m/z=148 [ M-H ]] - 。
3, 4-dichlorobenzaldehyde oxime (Ib-4)
Synthesis method and Ib-1, 2-chlorobenzaldehyde was replaced with 3, 4-dichlorobenzaldehyde (1.8 g,0.1 mol) to give 1.8g of a white solid, yield: 95%. ESI-MS: m/z=188 [ M-H ]] - 。
3, 4-Dimethoxybenzaldehyde oxime (Ib-5)
The synthesis was identical to Ib-1, substituting 2-chlorobenzaldehyde with 3, 4-dimethoxybenzaldehyde (1.7 g,0.1 mol) to give 1.7g of a white solid with a yield of: 96%. ESI-MS: m/z=180 [ M-H ] ] - 。
2-trifluoromethyl Benzoaldoxime (Ib-6)
The synthesis was identical to Ib-1, substituting 2-chlorobenzaldehyde with 2-trifluoromethylbenzaldehyde (1.7 g,0.1 mol) to give 1.8g of a white solid in yield: 97%. ESI-MS: m/z=188 [ M-H ]] - 。
2-fluorobenzaldehyde oxime (Ib-7)
The synthesis was identical to Ib-1, substituting 2-chlorobenzaldehyde with 2-fluorobenzaldehyde (1.2 g,0.1 mol) to give 1.4g of a white solid, yield: 98%. ESI-MS: m/z=138 [ M-H ]] - 。
2-Nitrophenyl aldoxime (Ib-8)
The synthesis method was the same as Ib-1, substituting 2-chlorobenzaldehyde with 2-nitrobenzaldehyde (1.5 g,0.1 mol) to give 1.6g of a white solid, yield: 96%. ESI-MS: m/z=165 [ M-H ]] - 。
2-Difluoromethoxybenzaldehyde oxime (Ib-9)
The synthesis method was the same as that of Ib-1, and 2-chlorobenzaldehyde was replaced with 2-difluoromethoxybenzaldehyde (1.7 g,0.1 mol) to give 1.6g of a white solid, yield: 94%. ESI-MS: m/z=186 [ M-H ]] - 。
2-Methoxybenzaldehyde oxime (Ib-10)
The synthesis method was the same as Ib-1, substituting 2-chlorobenzaldehyde with 2-methoxybenzaldehyde (1.4 g,0.1 mol) to give 1.4g of a white solid with a yield: 95%. ESI-MS: m/z=150 [ M-H ]] - 。
Step 2: 2-chloro-N-hydroxybenzoyl chloride (Ic-1)
Compound Ib-1 (26 g,0.17 mol) is dissolved in DMF (50 mL) and N-chlorosuccinimide (NCS, 22.7g,0.17 mol) is slowly added in portions under an ice water bath, after NCS is completely dissolved, the reaction system is moved to room temperature and stirred continuously until the reaction And (3) completely. Water (50 mL) was added to the system, extracted with ethyl acetate (50 mL. Times.3), the organic layers were combined and washed with water (3X 50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil, 30g, yield: 97%. ESI-MS: m/z=191 [ M+H ]] + 。
2-chloro-6-fluoro-N-hydroxybenzoyl chloride (Ic-2)
The synthesis was carried out in the same manner as Ic-1, except that compound Ib-1 was replaced with Ib-2 (1.7 g,0.096 mol) to give 1.7g of a yellow oil, yield: 87%. ESI-MS: m/z=208 [ M+H ]] + 。
2, 6-dimethyl-N-hydroxybenzoyl chloride (Ic-3)
The synthesis was carried out in the same manner as Ic-1, substituting compound Ib-1 with Ib-3 (1.5 g,0.098 mol) to give 1.7g of yellow oily substance, yield: 93%. ESI-MS: m/z=184 [ M+H ]] + 。
3, 4-dichloro-N-hydroxybenzoyl chloride (Ic-4)
The synthesis was identical to Ic-1, substituting compound Ib-1 for Ib-4 (1.8 g,0.095 mol) to give 2.0g of yellow oil, yield: 96%. ESI-MS: m/z=224 [ M+H ]] + 。
3, 4-dimethoxy-N-hydroxybenzoyl chloride (Ic-5)
The synthesis was carried out in the same manner as Ic-1, except that compound Ib-1 was replaced with Ib-5 (1.7 g,0.096 mol) to give 1.9g of a yellow oil, yield: 94%. ESI-MS: m/z=216 [ M+H ]] + 。
2-trifluoromethyl-N-hydroxybenzoyl chloride (Ic-6)
The synthesis was carried out in the same manner as Ic-1, except that compound Ib-1 was replaced with Ib-6 (1.8 g,0.097 mol) to give 2.1g of a yellow oil, yield: 96%. ESI-MS: m/z=224 [ M+H ] ] + 。
2-fluoro-N-hydroxybenzoyl chloride (Ic-7)
The synthesis was carried out in the same manner as Ic-1, except that compound Ib-1 was replaced with Ib-7 (1.4 g,0.098 mol) to give 1.6g of a yellow oil, yield: 94%. ESI-MS: m/z=174 [ M+H ]] + 。
2-nitro-N-hydroxybenzoyl chloride (Ic-8)
The synthesis was carried out in the same manner as Ic-1, except that compound Ib-1 was replaced with Ib-8 (1.6 g,0.096 mol) to give 1.8g of a yellow oil, yield: 91%. ESI-MS: m/z=201 [ M+H ]] + 。
2-difluoromethoxy-N-hydroxybenzoyl chloride (Ic-9)
The synthesis was carried out in the same manner as Ic-1 except that compound Ib-1 was replaced with Ib-9 (1.6 g,0.094 mol) to give 2.0g of a yellow oil, yield: 94%. ESI-MS: m/z=222 [ M+H ]] + 。
2-methoxy-N-hydroxybenzoyl chloride (Ic-10)
The synthesis was identical to Ic-1, substituting compound Ib-1 for Ib-10 (1.4 g,0.095 mol) to give 1.7g of yellow oil, yield: 96%. ESI-MS: m/z=186 [ M+H ]] + 。
Step 3:3- (2-chlorophenyl) -5-methylisoxazole-4-carboxylic acid (Ie-1)
Sodium hydroxide (9.2 g,0.23 mol) was added to a methanol (100 mL) solution of ethyl acetoacetate (29 mL,0.23 mol) in ice bath, stirred at room temperature for 30min, and the solution was slowly added dropwise to a methanol (50 mL) solution of compound Ic-1 (28.5 g,0.15 mol) in ice bath, and reacted at room temperature for about 2 hours until the starting material completely disappeared. The reaction system was directly added with 50% aqueous sodium hydroxide (50 mL) without post-treatment, the temperature was raised to reflux for 2 hours, the organic solvent was distilled off under reduced pressure, and ethyl acetate (20 mL) and water (30 mL) were added for extraction. The aqueous layer was ph=2 with 6N HCl and solids precipitated. Suction filtration, recrystallization of filter cake with methanol, and drying to obtain pale yellow solid. Yield: 74%. 1 H NMR(400MHz,DMSO-d 6 )δ13.00(brs,1H),7.60-7.56(m,2H),7.48-7.46(m,2H),2.75(s,3H)；ESI-MS:m/z＝239[M+H] + 。
3- (2-chloro-6-fluorophenyl) -5-methylisoxazole-4-carboxylic acid (Ie-2)
The synthesis was carried out in the same manner as for Ie-1, except that compound Ic-1 was replaced with Ic-2 (1.7 g,0.084 mol) to give 1.8g of a yellow solid. Yield: 83%. ESI-MS: m/z=256 [ M+H ]] + 。
3- (2, 6-dimethylphenyl) -5-methylisoxazole-4-carboxylic acid (Ie-3)
The synthesis was carried out in the same manner as for Ie-1, except that compound Ic-1 was replaced with Ic-3 (1.7 g,0.088 mol) to give 1.6g of a yellow solid. Yield: 78%. ESI-MS: m/z=232 [ M+H ]] + 。
3- (3, 4-dichlorophenyl) -5-methylisoxazole-4-carboxylic acid (Ie-4)
The synthesis was identical to Ie-1, substituting Ic-1 for Ic-4 (2.0 g,0.091 mol) to give 2.1g of yellow solid. Yield: 85%. ESI-MS: m/z=272 [ M+H ]] + 。
3- (3, 4-Dimethoxyphenyl) -5-methylisoxazole-4-carboxylic acid (Ie-5)
The synthesis was carried out in the same manner as for Ie-1, except that compound Ic-1 was replaced with Ic-5 (1.9 g,0.090 mol) to give 2.0g of a yellow solid. Yield: 83%. ESI-MS: m/z=264 [ M+H ]] + 。
3- (2-trifluoromethylphenyl) -5-methylisoxazole-4-carboxylic acid (Ie-6)
The synthesis was carried out in the same manner as for Ie-1, except that compound Ic-1 was replaced with Ic-6 (2.1 g,0.093 mol) to give 2.1g of a yellow solid. Yield: 84%. ESI-MS: m/z=272 [ M+H ]] + 。
3- (2-fluorophenyl) -5-methylisoxazole-4-carboxylic acid (Ie-7)
The synthesis was carried out in the same manner as for Ie-1, except that compound Ic-1 was replaced with Ic-7 (1.6 g,0.092 mol) to give 1.7g of a yellow solid. Yield: 85%. ESI-MS: m/z=222 [ M+H ] ] + 。
3- (2-Nitrophenyl) -5-methylisoxazole-4-carboxylic acid (Ie-8)
The synthesis was carried out in the same manner as for Ie-1, except that compound Ic-1 was replaced with Ic-8 (1.8 g,0.087 mol) to give 1.6g of a yellow solid. Yield: 73%. ESI-MS: m/z=249 [ M+H ]] + 。
3- (2-difluoromethoxyphenyl) -5-methylisoxazole-4-carboxylic acid (Ie-9)
The synthesis was carried out in the same manner as for Ie-1, except that compound Ic-1 was replaced with Ic-9 (2.0 g,0.088 mol) to give 2.1g of a yellow solid. Yield: 87%. ESI-MS: m/z=270 [ M+H ]] + 。
3- (2-methoxyphenyl) -5-methylisoxazole-4-carboxylic acid (Ie-10)
The synthesis was identical to Ie-1, substituting compound Ic-1 for Ic-10 (1.7 g,0.091 mol) to give 1.6g of yellow solid. Yield: 75%. ESI-MS: m/z=234 [ M+H ]] + 。
Step 4:3- (2-chlorophenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-1)
Compound Ie-1 (237 mg,1 mmol) was dissolved in thionyl chloride (2 mL) and 1-2 drops of anhydrous DMF was addedAnd (5) refluxing for 30min until the raw materials disappear. The thionyl chloride was distilled off under anhydrous conditions to give a yellow oil, i.e., acid chloride, which was dissolved in anhydrous dichloromethane (5 mL) for further use. Simultaneously, triethylamine (140 mu L) and 3-trifluoromethyl aniline (161 mg,1 mmol) are dissolved in anhydrous dichloromethane (5 mL), the anhydrous dichloromethane and the anhydrous dichloromethane are slowly added into the backup acyl chloride through a constant pressure dropping funnel under ice water bath, the mixture is heated to reflux after no white smoke is generated, the reaction is carried out for 3 hours until the raw materials completely disappear, the reaction liquid is cooled to room temperature, the mixture is concentrated under reduced pressure, and the crude product is purified by column chromatography to obtain 110mg of white solid with the yield: 29%. 1 H NMR(400MHz,Chloroform-d)δ8.21(d,J＝7.8Hz,1H),7.89–7.80(m,2H),7.68–7.60(m,2H),7.49(s,1H),7.44–7.35(m,2H),7.22(s,1H),2.85(s,3H).ESI-MS:m/z＝381[M+H] + 。
3- (2-chloro-6-fluorophenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-2)
Preparation of the target Compound I-2 reference was made to the synthesis of Compound I-1, the only difference being that Compound Ie-1 was replaced with Ie-2 (256 mg,1 mmol) to give 203mg of a white solid. Yield: 51%; 1 H NMR(500MHz,Chloroform-d)δ7.59(td,J＝8.0,6.0Hz,1H),7.55–7.53(m,1H),7.48(dt,J＝8.0,1.0Hz,1H),7.40–7.33(m,2H),7.31–7.27(m,2H),7.02(s,1H),2.86(s,3H).ESI-MS:m/z＝399[M+H] + 。
3- (2, 6-dimethylphenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-3)
Preparation of the target Compound I-3 reference was made to the synthesis of Compound I-1, substituting Compound Ie-1 with Ie-3 (231 mg,1 mmol) to yield 299mg of a white solid. Yield: 80%; 1 H NMR(500MHz,Chloroform-d)δ7.49(t,J＝8.0Hz,1H),7.41(s,1H),7.34–7.27(m,4H),7.09(s,1H),7.03–6.98(m,1H),2.91(s,3H),2.20(s,6H).ESI-MS:m/z＝375[M+H] + 。
3- (3, 4-dichlorophenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-4)
Preparation of the target Compound I-4 reference Synthesis of Compound I-1, compound Ie-1 was replaced with Ie-4 (272 mg,1 mmol) to give 344mg of a white solid. Yield: 83%; 1 H NMR(500MHz,Chloroform-d)δ7.84(d,J＝2.0Hz,1H),7.76(s,1H),7.63(d,J＝8.0Hz,1H),7.53(dd,J＝8.5,2.0Hz,1H),7.46–7.35(m,3H),7.15(s,1H),2.77(s,3H).ESI-MS:m/z＝415[M+H] + .3- (3, 4-Dimethoxyphenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-5)
Preparation of the target Compound I-5 reference Synthesis of Compound I-1, compound Ie-1 was replaced with Ie-5 (263 mg,1 mmol) to give 345mg of a white solid. Yield: 85%; 1 H NMR(500MHz,Chloroform-d)δ7.68(s,1H),7.40–7.34(m,3H),7.30(d,J＝8.0Hz,1H),7.22(dd,J＝8.0,2.0Hz,1H),7.15(d,J＝2.0Hz,1H),7.05(d,J＝8.5Hz,1H),3.98(s,3H),3.89(s,3H),2.80(s,3H).ESI-MS:m/z＝407[M+H] + 。
3- (2-trifluoromethylphenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-6)
Preparation of the target Compound I-6 reference Synthesis of Compound I-1, substituting Compound Ie-1 with Ie-6 (271 mg,1 mmol) gave 364mg of white solid. Yield: 88%; 1 H NMR(400MHz,Chloroform-d)δ7.98(dt,J＝6.8,2.0Hz,1H),7.83–7.80(m,2H),7.63–7.61(m,1H),7.42(s,1H),7.33–7.30(m,2H),7.13–7.09(m,1H),6.67(s,1H),2.86(s,3H).ESI-MS:m/z＝415[M+H] + 。
3- (2-fluorophenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-7)
Preparation of the target Compound I-7 reference synthesis of Compound I-1 Compound Ie-1 was replaced with Ie-7 (221 mg,1 mmol) to give 317mg of a white solid. Yield: 87%; 1 H NMR(400MHz,Chloroform-d)δ7.66–7.60(m,2H),7.57(s,1H),7.40–7.29(m,5H),7.12(s,1H),2.81(s,3H).ESI-MS:m/z＝365[M+H] + 。
3- (2-Nitrophenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-8)
Preparation of target Compound I-8 reference synthesis of Compound I-1 Compound Ie-1 was replaced with Ie-8 (248 mg,1 mmol) to give 278mg of white solid. Yield: 71%; 1 H NMR(400MHz,Chloroform-d)δ8.20(dd,J＝8.0,1.6Hz,1H),7.83–7.73(m,2H),7.62–7.58(m,2H),7.44(s,1H),7.36–7.32(m,3H),2.80(s,3H).ESI-MS:m/z＝392[M+H] + 。
3- (2-difluoromethoxyphenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-9)
Preparation of target Compound I-9 reference Synthesis of Compound I-1, compound Ie-1 was replaced with Ie-9 (267 mg,1 mmol) to give 305mg of a white solid. Yield: 74%; 1 H NMR(500MHz,Chloroform-d)δ7.71–7.59(m,2H),7.58(s,1H),7.47–7.42(m,1H),7.39(d,J＝9.0Hz,1H),7.36(d,J＝7.5Hz,1H),7.35–7.31(m,1H),7.29(dt,J＝7.5,2.0Hz,1H),7.20(m,1H),6.46(t,J＝72.5,1H),2.80(d,J＝4.0Hz,3H).ESI-MS:m/z＝413[M+H] + 。
3- (2-methoxyphenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-10)
Preparation of the target Compound I-10 reference Synthesis of Compound I-1, compound Ie-1 was replaced with Ie-10 (233 mg,1 mmol) to give 312mg of a white solid. Yield: 83%; 1 H NMR(400MHz,DMSO-d 6 )δ7.59(t,J＝8.8Hz,2H),7.55(s,1H),7.51(d,J＝7.6Hz,1H),7.38–7.28(m,3H),7.19(t,J＝7.6Hz,1H),7.09(d,J＝8.4Hz,1H),3.78(s,3H),2.79(s,3H).ESI-MS:m/z＝377[M+H] + 。
3- (2-aminophenyl) -5-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (I-11)
Compound I-8 (62 mg,0.16 mmol) was dissolved in methanol (3 mL), 10% Pd/C (8 mg) was added, the reaction was continued overnight at room temperature with hydrogen till the starting material was completely disappeared, concentrated under reduced pressure, and the crude product was purified by column chromatography to give 28mg of a white solid. Yield: 48%; 1 H NMR(500MHz,DMSO-d 6 )δ10.71(s,1H),8.08(s,1H),7.75(d,J＝8.5Hz,1H),7.59(t,J＝8.0Hz,1H),7.48–7.45(m,1H),7.22(dd,J＝7.5,1.5Hz,1H),7.17(td,J＝7.5,1.5Hz,1H),6.86(dd,J＝8.0,1.0Hz,1H),6.61(td,J＝7.5,1.5Hz,1H),5.78(s,2H),2.61(s,3H).ESI-MS:m/z＝362[M+H] + 。
3- (2-chlorophenyl) -5-methyl-N- (2-fluorophenyl) isoxazole-4-carboxamide (I-12)
Preparation of the target Compound I-12 reference Synthesis of Compound I-1 3-trifluoromethylaniline was replaced with 2-fluoroaniline (111 mg,1 mmol) to give 238mg of a white solid. Yield: 72%; 1 H NMR(500MHz,DMSO-d 6 )δ9.75(s,1H),7.68(s,1H),7.60–7.46(m,4H),7.25–7.14(m,3H),2.70(s,3H).ESI-MS:m/z＝331[M+H] + 。
3- (2-chlorophenyl) -5-methyl-N- (3-cyanophenyl) isoxazole-4-carboxamide (I-13)
Preparation of the target Compound I-13 reference Synthesis of Compound I-1 3-trifluoromethylaniline was replaced with 3-cyanoaniline (118 mg,1 mmol) to give 249mg of a white solid. Yield: 74%; 1 H NMR(500MHz,Chloroform-d)δ7.66(dd,J＝8.5,2.0Hz,1H),7.64(dd,J＝7.0,1.5Hz,1H),7.62–7.58(m,1H),7.58–7.56(m,1H),7.57–7.53(m,1H),7.39–7.31(m,2H),7.28(dt,J＝7.0,2.0Hz,1H),6.98(s,1H),2.85(s,3H).ESI-MS:m/z＝338[M+H] + .3- (2-chlorophenyl) -5-methyl-N- (3-fluoro-5-cyanophenyl) isoxazole-4-carboxamide (I-14)
Preparation of the target Compound I-14 reference Synthesis of Compound I-1 3-trifluoromethylaniline was replaced with 3-fluoro-5-cyanoaniline (136 mg,1 mmol) to give 291mg of a white solid. Yield: 82%; 1 H NMR(500MHz,DMSO-d 6 )δ10.74(s,1H),7.78–7.75(m,2H),7.50–7.58(m,5H),2.70(s,3H).ESI-MS:m/z＝356[M+H] + 。
3- (2-chlorophenyl) -5-methyl-N- (2-fluoro-4-chlorophenyl) isoxazole-4-carboxamide (I-15)
Preparation of the target Compound I-15 reference compound I-1 was synthesized by substituting 2-fluoro-4-chloroaniline (145 mg,1 mmol) for 3-trifluoromethylaniline to obtain 266mg of a white solid. Yield: 73%; 1 H NMR(500MHz,DMSO-d 6 )δ9.89(s,1H),7.73(s,1H),7.59(dd,J＝8.0,1.5Hz,1H)7.56–7.53(m,2H),7.52–7.46(m,2H),7.28(dd,J＝8.0,2.0Hz,1H),2.70(s,3H).ESI-MS:m/z＝365[M+H] + 。
3- (2-chlorophenyl) -5-methyl-N- (3-chloro-4-fluorophenyl) isoxazole-4-carboxamide (I-16)
Preparation of the target Compound I-16 reference Synthesis of Compound I-1 3-trifluoromethylaniline was replaced with 3-chloro-4-fluoroaniline (145 mg,1 mmol) to give 280mg of a white solid. Yield: 77%. 1 H NMR(500MHz,DMSO-d 6 )δ10.39(s,1H),7.84(d,J＝6.5Hz,1H),7.59–7.56(m,2H),7.54(dd,J＝7.5,2.0Hz,1H),7.52–7.47(m,1H),7.44(s,1H),7.39(t,J＝9.0Hz,1H),2.68(s,3H).ESI-MS:m/z＝365[M+H] + 。
3- (2-chlorophenyl) -5-methyl-N-benzyl isoxazole-4-carboxamide (I-17)
Preparation of the target Compound I-17 reference compound I-1 was synthesized by substituting 3-trifluoromethylaniline with benzylamine (107 mg,1 mmol) to give 290mg of a white solid. Yield: 89%; 1 H NMR(500MHz,DMSO-d 6 )δ8.47(t,J＝6.0Hz,1H),7.58(d,J＝7.5Hz,1H),7.54(td,J＝7.5,2.0Hz,1H),7.51(dd,J＝2.0Hz,1H),7.46(t,J＝7.5Hz,1H),7.30(t,J＝7.5Hz,2H),7.24(d,J＝7.5Hz,1H),7.20(t,J＝7.5Hz,2H),4.35(d,J＝6.0Hz,2H),2.62(s,3H).ESI-MS:m/z＝327[M+H] + 。
3- (2-chlorophenyl) -5-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) isoxazole-4-carboxamide (I-18)
Preparation of the target Compound I-18 reference Synthesis of Compound I-1 3-trifluoromethylaniline was replaced with 2-amino-4-trifluoromethylpyridine (162 mg,1 mmol) to give 259mg of a white solid. Yield: 68%; 1 H NMR(500MHz,Chloroform-d)δ8.48(s,1H),8.28(d,J＝5.5Hz,1H),7.74(s,1H),7.61–7.54(m,3H),7.51(td,J＝7.0,2.0Hz,1H),7.20(d,J＝5.0Hz,1H),2.85(s,3H).ESI-MS:m/z＝382[M+H] + 。
(3- (2-chlorophenyl) -5-methylisoxazol-4-yl) (morpholino) methanone (I-19)
Preparation of the target Compound I-19 reference compound I-1 was synthesized by substituting 3-trifluoromethylaniline with morpholine (87 mg,1 mmol) to give 254mg of a white solid. Yield: 83%; 1 H NMR(500MHz,DMSO-d 6 )δ7.64(d,J＝8.0Hz,1H),7.59–7.56(m,1H),7.54–7.48(m,2H),3.47–3.43(m,4H),3.27–3.23(m,4H),2.53(s,3H).ESI-MS:m/z＝307[M+H] + 。
(3- (2-chlorophenyl) -5-methylisoxazol-4-yl) (4-methylpiperazin-1-yl) methanone (I-20)
Preparation of the target Compound I-20 reference compound I-1 was synthesized by substituting 3-trifluoromethylaniline with methylpiperazine (100 mg,1 mmol) to give 278mg of a white solid. Yield: 87%; 1 H NMR(500MHz,DMSO-d 6 )δ7.61(d,J＝8.0Hz,1H),7.58–7.52(m,1H),7.49(dd,J＝7.0,1.5Hz,2H),3.44(s,2H),3.22(s,2H),2.19(s,2H),2.08(s,3H),1.90(s,2H).ESI-MS:m/z＝320[M+H] + 。
example 3: synthesis of IIA series of Compounds
Step 1:3- (2-chlorophenyl) -3-oxopropionic acid methyl ester (IIAb-1)
60% sodium hydride (6.6 g,0.165 mol) was dissolved in toluene (50 mL), dimethyl carbonate (11.1 mL,0.132 mol) was added under ice, and after stirring at room temperature for 30min, a toluene solution (50 mL) of 2-chloroacetophenone (10.2 g,0.066 mol) was added, and the mixture was heated to reflux for 2 hours. Glacial acetic acid (20 mL) was added to the system, ph=5 was adjusted, water (20 mL) was added, extraction with ethyl acetate (100 ml×3), the organic layers were combined and washed with saturated sodium bicarbonate solution (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography to give 11.3g of a white solid with a yield of 80%; ESI-MS: m/z=214 [ M+H ]] + 。
Methyl 3- (2-difluoromethoxyphenyl) -3-oxopropanoate (IIAb-2)
The synthesis method was the same as IIAb-1, substituting 2-chloroacetophenone with 2-difluoromethoxy acetophenone (12.3 g,0.066 mol) to give 8.4g of white solid, yield: 52%. ESI-MS: m/z=245 [ M+H ] ] + 。
3- (2-fluorophenyl) -3-oxopropionic acid methyl ester (IIAb-3)
The synthesis procedure was the same as IIAb-1, substituting 2-chloroacetophenone with 2-fluoroacetophenone (9.1 g,0.066 mol) to give 11.4g of white solid, yield: 88%. ESI-MS: m/z=197 [ M+H ]] + 。
Step 2: (Z) -2- (2-chlorobenzoyl) -3- (dimethylamino) acrylic acid methyl ester (IIAc-1)
Compound IIAb-1 (11.0 g,0.052 mol) was dissolved in DMF-DMA (20 mL) and reacted at 80℃for 3 hours. Cooled to room temperature, water (100 mL) was added, extraction was performed with ethyl acetate (100 mL. Times.3), and the organic layer was washed with water (100 mL. Times.3) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentratedThe crude product was purified by column chromatography to give 9.6g of yellow solid in 69% yield. 1 H NMR(500MHz,Chloroform-d)δ7.79(s,1H),7.38(d,J＝3.2Hz,1H),7.36–7.33(m,1H),7.29–7.26(m,2H),3.46(s,3H),3.32(s,3H),2.96(s,3H).ESI-MS:m/z＝269[M+H] + 。
(Z) -2- (2-Difluoromethoxybenzoyl) -3- (dimethylamino) acrylic acid methyl ester (IIAc-2)
Synthesis method the same as IIAc-1, substituting IIAb-1 for IIAb-2 (8.4 g,0.034 mol) gave a yellow solid, 5.9g, yield: 57%. ESI-MS: m/z=300 [ M+H ]] + 。
(Z) -2- (2-fluorobenzoyl) -3- (dimethylamino) acrylic acid methyl ester (IIAc-3)
Synthesis method the same as IIAc-1, substituting compound IIAb-1 with IIAb-3 (11.4 g,0.058 mol) gave 9.8g of yellow solid, yield: 67%. ESI-MS: m/z=252 [ M+H ]] + 。
Step 3:5- (2-chlorophenyl) isoxazole-4-carboxylic acid methyl ester (IIAd-1)
Compound IIAc-1 (9.5 g,0.035 mol), hydroxylamine hydrochloride (4.9 g,0.07 mol) and sodium acetate (9.6 g,0.07 mol) were dissolved in methanol (50 mL) and reacted at room temperature for 2 hours. Suction filtration, concentration of the filtrate under reduced pressure, and purification of the crude product by column chromatography gave 5.9g of a white solid with a yield of 71%. 1 H NMR(500MHz,Chloroform-d)δ8.67(s,1H),7.55–7.47(m,3H),7.40(td,J＝7.5,1.5Hz,1H),3.78(s,3H).ESI-MS:m/z＝238[M+H] + 。
5- (2-Difluoromethoxyphenyl) isoxazole-4-carboxylic acid methyl ester (IIAd-2)
Synthesis method same as IIAd-1, compound IIAc-1 was replaced with IIAc-2 (5.9 g, 0.020mol) to give 4.1g of a white solid, yield: 78%. ESI-MS: m/z=270 [ M+H ]] + 。
5- (2-fluorophenyl) isoxazole-4-carboxylic acid methyl ester (IIAd-3)
Synthesis method same as IIAd-1, compound IIAc-1 was replaced with IIAc-3 (9.8 g,0.039 mol) to give 6.5g of a white solid, yield: 75%. ESI-MS: m/z=222 [ M+H ]] + 。
Step 4:5- (2-chlorophenyl) isoxazole-4-carboxylic acid (IIAe-1)
Compounds IIAd-1(5.5 g,0.023 mmol) was dissolved in a mixed solvent of 6N hydrochloric acid (125 mL) and glacial acetic acid (85 mL), and the temperature was raised to reflux for 3 hours. Cooled to room temperature, water (150 mL) was added, extracted with ethyl acetate (150 ml×3), the organic layers were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 3.9g of a yellow oil with a yield of 76%. ESI-MS: m/z=224 [ M+H ]] + 。
5- (2-Difluoromethoxyphenyl) isoxazole-4-carboxylic acid (IIAe-2)
The synthesis was identical to IIAe-1, and the compound IIAd-1 was replaced with IIAd-2 (4.1 g,0.015 mol) to give a yellow oil, 2.1g, yield: 54%. ESI-MS: m/z=256 [ M+H ]] + 。
5- (2-fluorophenyl) isoxazole-4-carboxylic acid (IIAe-3)
The synthesis was identical to IIAe-1, and the compound IIAd-1 was replaced with IIAd-3 (6.5 g,0.029 mol) to give 4.6g of a yellow oil, yield: 77%. ESI-MS: m/z=208 [ M+H ]] + 。
Step 5:5- (2-chlorophenyl) -N- (3-trifluoromethylphenyl) isoxazole-4-carboxamide (IIA-1)
Compound IIAe-1 (150 mg,0.67 mmol) was dissolved in thionyl chloride (1.5 mL) and a catalytic amount of anhydrous DMF was added and heated to reflux until the starting material completely disappeared. The thionyl chloride was distilled off under anhydrous conditions to give a yellow oil, i.e., acid chloride, which was dissolved in anhydrous dichloromethane (3 mL) for further use. Simultaneously, triethylamine (102 mu L) and 3-trifluoromethyl aniline (108 mg,0.67 mmol) are dissolved in anhydrous dichloromethane (5 mL), the anhydrous dichloromethane and the anhydrous dichloromethane are slowly added into the standby acyl chloride through a constant pressure dropping funnel under ice water bath, the temperature is raised and the reflux is carried out after no white smoke is generated, the reaction is carried out until the raw materials completely disappear, the reaction is cooled to room temperature, the concentration is carried out under reduced pressure, and the crude product is purified by column chromatography to obtain 110mg of white solid with the yield: 45%. 1 H NMR(500MHz,DMSO-d 6 )δ10.60(s,1H),9.27(s,1H),8.08(s,1H),7.87(dd,J＝8.0,2.0Hz,1H),7.70(dd,J＝7.5,2.0Hz,1H),7.66(dd,J＝8.0,1.0Hz,1H),7.62(td,J＝7.5,2.0Hz,1H),7.58(t,J＝8.0Hz,1H),7.53(td,J＝7.5,1.0Hz,1H),7.46(d,J＝7.5Hz,1H).ESI-MS:m/z＝367[M+H] + 。
5- (2-chlorophenyl) -N- (4- (trifluoromethyl) pyridin-2-yl) isoxazole-4-carboxamide (IIA-2)
Target compoundPreparation of IIA-2 As above, 3-trifluoromethylaniline was replaced by 2-amino-4-trifluoromethylpyridine (109 mg,0.67 mmol) to give 157mg of a white solid. Yield: 64%. 1 H NMR(500MHz,DMSO-d 6 )δ9.87(s,1H),8.64(d,J＝5.0Hz,1H),8.26(s,1H),8.06(d,J＝7.5Hz,1H),7.62(dd,J＝7.5,2.0Hz,1H),7.48(dd,J＝7.5,2.0Hz,1H),7.42–7.32(m,2H),7.24(td,J＝7.5,2.0Hz,1H).ESI-MS:m/z＝368[M+H] + 。
5- (2-chlorophenyl) -N- (3-cyanophenyl) isoxazole-4-carboxamide (IIA-3)
Preparation of the target compound IIA-3 was carried out as above, substituting 3-trifluoromethylaniline with 3-cyanoaniline (79 mg,0.67 mmol) to obtain 102mg of a white solid. Yield: 47%. 1 H NMR(500MHz,DMSO-d 6 )δ9.37(s,1H),8.60(s,1H),8.03(dd,J＝8.0,2.0Hz,1H),7.87(s,1H),7.65(dd,J＝7.5,2.0Hz,1H),7.63–7.60(m,2H),7.56(t,J＝7.5Hz,1H),7.50–7.42(m,2H).ESI-MS:m/z＝324[M+H] + 。
5- (2-chlorophenyl) -N- (3-dimethylaminophenyl) isoxazole-4-carboxamide (IIA-4)
Preparation of the target compound IIA-4 was carried out as above, substituting 3-trifluoromethylaniline with 3-dimethylaminoaniline (91 mg,0.67 mmol) to give 110mg of a white solid. Yield: 48%. ESI-MS: m/z=342 [ M+H ]] + .5- (2-chlorophenyl) -N- (3-methylsulfonylphenyl) isoxazole-4-carboxamide (IIA-5)
Preparation of the target compound IIA-5 was identical, substituting 3-trifluoromethylaniline with 3-methylsulfonylamino (115 mg,0.67 mmol) to give 134mg of a white solid. Yield: 53%. ESI-MS: m/z=377 [ M+H ]] + 。
5- (2-chlorophenyl) -N- (4-aminopyrimidinyl) isoxazole-4-carboxamide (IIA-6)
Preparation of the target compound IIA-6 was carried out as above, substituting 3-trifluoromethylaniline with 4-aminopyrimidine (64 mg,0.67 mmol) to give 70mg of a white solid. Yield: 35%. ESI-MS: m/z=301 [ M+H ] ] + 。
5- (2-chlorophenyl) -N- (2-aminopyrazinyl) isoxazole-4-carboxamide (IIA-7)
Preparation of the target Compound IIA-7 As above, 3-trifluoromethylaniline was replaced by 2-aminopyrazine (64 mg, 0.6)7 mmol) to give 80mg of a white solid. Yield: 40%. ESI-MS: m/z=301 [ M+H ]] + 。
(5- (2-chlorophenyl) isoxazol-4-yl) (morpholinyl) methanone (IIA-8)
Preparation of the target compound IIA-8 was carried out as above, substituting 3-trifluoromethylaniline with morpholine (58 mg,0.67 mmol) to give 131mg of a white solid. Yield: 67%. 1 H NMR(500MHz,Chloroform-d)δ8.31(s,1H),7.50(dd,J＝7.5,2.0Hz,1H),7.43–7.35(m,2H),7.32(td,J＝7.5,2.0Hz,1H),3.61(t,J＝4.5Hz,4H),3.50(t,J＝4.5Hz,4H).ESI-MS:m/z＝293[M+H] + 。
(5- (2-chlorophenyl) isoxazol-4-yl) (4-methylpiperazin-1-yl) methanone (IIA-9)
Preparation of the target compound IIA-9 was carried out as above, substituting 3-trifluoromethylaniline with N-methylpiperazine (67 mg,0.67 mmol) to give 110mg of a white solid. Yield: 54%. 1 H NMR(500MHz,Chloroform-d)δ8.28(s,1H),7.49(dd,J＝7.5,2.0Hz,1H),7.39(td,J＝7.0,2.5Hz,1H),7.35–7.25(m,2H),3.66(t,J＝5.0Hz,4H),3.26(t,J＝5.0Hz,4H),2.32(s,3H).ESI-MS:m/z＝306[M+H] + 。
(5- (2-chlorophenyl) isoxazol-4-yl) (4-hydroxypiperidin-1-yl) methanone (IIA-10)
Preparation of the target compound IIA-10 was carried out as above, substituting 3-trifluoromethylaniline with 4-hydroxypiperidine (68 mg,0.67 mmol) to give 80mg of a white solid. Yield: 39%. 1 H NMR(500MHz,Chloroform-d)δ8.30(s,1H),7.49(dd,J＝7.5,2.0Hz,1H),7.39(td,J＝7.5,2.0Hz,1H),7.36–7.25(m,2H),4.15–4.09(m,2H),3.68–3.53(m,1H),3.08–2.89(m,2H),2.07–1.97(m,2H),1.97–1.86(m,2H),1.47(d,J＝5.0Hz,1H).ESI-MS:m/z＝307[M+H] + 。
(5- (2-chlorophenyl) isoxazol-4-yl) (4-aminopiperidin-1-yl) methanone (IIA-11)
Preparation of the target compound IIA-11 was carried out as above, substituting 3-trifluoromethylaniline with 4-aminopiperidine (67 mg,0.67 mmol) to give 129mg of a white solid. Yield: 63%. 1 H NMR(500MHz,Chloroform-d)δ8.30(s,1H),7.49(dd,J＝7.5,2.0Hz,1H),7.39(td,J＝7.5,2.0Hz,1H),7.36–7.25(m,2H),3.88(dt,J＝12.5,7.0Hz,2H),3.02(dt,J＝12.5,7.0Hz,2H),2.79–2.72(m,1H),2.17–2.11(m,2H),1.84–1.80(m,2H),1.15(s,2H).ESI-MS:m/z＝306[M+H] + 。
(5- (2-chlorophenyl) isoxazol-4-yl) (4- (methylsulfonyl) piperazin-1-yl) methanone (IIA-12)
Preparation of the target compound IIA-12 was carried out as above, substituting 3-trifluoromethylaniline with 1-methanesulfonylpiperazine (110 mg,0.67 mmol) to give 91mg of a white solid. Yield: 37%. 1 H NMR(500MHz,Chloroform-d)δ8.32(s,1H),7.50(dd,J＝7.5,2.0Hz,1H),7.44–7.35(m,2H),7.33–7.26(m,1H),3.45(t,J＝5.0Hz,4H),2.80(s,3H),2.66(t,J＝5.0Hz,4H).ESI-MS:m/z＝370[M+H] + 。
(5- (2-chlorophenyl) isoxazol-4-yl) (4- (trifluoromethanesulfonyl) piperazin-1-yl) methanone (IIA-13)
Preparation of the target compound IIA-13 was as above, substituting 3-trifluoromethylaniline with 1- ((trifluoromethyl) sulfonyl) piperazine (146 mg,0.67 mmol) to give 164mg as a white solid. Yield: 58%. 1 H NMR(500MHz,Chloroform-d)δ8.24(s,1H),7.48(dd,J＝8.0,1.5Hz,1H),7.43–7.35(m,1H),7.33–7.25(m,2H),3.45(t,J＝5.0Hz,4H),2.66(t,J＝5.0Hz,4H).ESI-MS:m/z＝424[M+H] + 。
5- (2- (difluoromethoxy) phenyl) -N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (IIA-14)
Preparation of the target compound IIA-14 was carried out as above, substituting the compound IIAe-1 with IIAe-2 (171 mg,0.67 mmol) to give 155mg of a white solid. Yield: 58%. 1 H NMR(500MHz,Chloroform-d)δ8.78(s,1H),7.72–7.63(m,2H),7.48(s,1H),7.47–7.42(m,1H),7.38(d,J＝9.0Hz,1H),7.36(d,J＝7.5Hz,1H),7.35–7.31(m,1H),7.28(dt,J＝7.5,2.0Hz,1H),7.230(m,1H),6.16(t,J＝73.5,1H).ESI-MS:m/z＝399[M+H] + 。
5- (2-fluorophenyl) -N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (IIA-15)
Preparation of the target compound IIA-15 was the same as above, except that the compound IIAe-1 was replaced with IIAe-3 (139 mg,0.67 mmol) to give 91mg of a white solid. Yield: 39%. 1 H NMR(500MHz,DMSO-d 6 )δ9.86(s,1H),δ7.66–7.60(m,2H),7.58(s,1H),7.53(dd,J＝7.5,2.0Hz,1H),7.43–7.40(m,2H),7.40–7.29(m,2H),7.12(s,1H).ESI-MS:m/z＝351[M+H] + 。
Example 4: synthesis of IIB series of Compounds
Step 1:2- (2-chlorobenzoyl) -3-oxobutanoic acid ethyl ester (IIBc-1)
Ethyl acetoacetate (19.5 mL,154 mmol) was added to petroleum ether (34 mL), 33% strength by mass aqueous sodium hydroxide (7 mL) was added under ice-bath, and stirred for 30min. O-chlorobenzoic acid (30.1 g,192 mmol) was dissolved in thionyl chloride (9 mL) and refluxed and TLC showed spin-dried after complete disappearance of the product. The prepared acid chloride and 33% aqueous sodium hydroxide solution (36 mL) were added dropwise to a petroleum ether solution of ethyl acetoacetate, stirred in an ice water bath for one hour, and then heated to 35℃for a further reaction for one hour. Cooling and filtering. The filter cake was washed with petroleum ether and dried to give a white solid, 30g, yield: 58%. 1 H NMR(500MHz,Methanol-d 4 )δ7.39–7.31(m,1H),7.30–7.19(m,3H),3.73(q,J＝7.0Hz,2H),2.33(s,3H),0.77(t,J＝7.0Hz,3H).ESI-MS:m/z＝369[M+H] + 。
Ethyl 2- (2- (difluoromethoxy) benzoyl) -3-oxobutanoate (IIBc-2)
The synthesis method was the same as IIBc-1, substituting o-chlorobenzoic acid with 2- (difluoromethoxy) benzoic acid (36.1 g,192 mmol) to give a white solid, 31.1g, yield: 54%. ESI-MS: m/z=301 [ M+H ]] + 。
Step 2:5- (2-chlorophenyl) -3-methylisoxazole-4-carboxylic acid ethyl ester (IIBd-1)
Compound IIBc-1 (5 g,18.6 mmol) was dissolved in ethanol (4 mL) and hydroxylamine hydrochloride (4.9 g,71.1 mmol) was dissolved in water (3 mL). An aqueous solution of hydroxylamine hydrochloride was added to the ethanol solution at 60℃overnight. Cooled to room temperature, the organic solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography to give 3.8g of a white solid, yield: 77%. 1 H NMR(500MHz,Methanol-d 4 )δ7.56–7.31(m,4H),4.08(q,J＝7.5Hz,2H),2.58(s,3H),1.05(t,J＝7.5Hz,3H).ESI-MS:m/z＝266[M+H] + 。
5- (2-Difluoromethoxyphenyl) -3-methylisoxazole-4-carboxylic acid ethyl ester (IIBd-2)
The synthesis procedure was the same as IIBd-1, substituting compound IIBc-1 for IIBc-2 (3.5 g,18.6 mmol) to give 3.8g of white solid, yield: 69%. ESI-MS: m/z=298 [ M+H ]] + 。
Step 3:5- (2-chlorophenyl) -3-methylisoxazole-4-carboxylic acid (IIBe-1)
Compound IIBd-1 (1.06 g,4 mmol) and lithium hydroxide monohydrate (336 mg,8 mmol) were added to 15mL THF and 7.5mL water and stirred at room temperature for 3 hours, TLC checked for completion of the reaction, dried by spinning, adjusted to pH 2 with 6N hydrochloric acid solution, the solid precipitated, suction filtered, dried to give 0.68g of white solid in 72% yield. 1 H NMR(500MHz,Methanol-d 4 )δ7.62–7.51(m,3H),7.47(t,J＝7.5Hz,1H),2.53(s,3H).ESI-MS:m/z＝238[M+H] + 。
5- (2-Difluoromethoxyphenyl) -3-methylisoxazole-4-carboxylic acid (IIBe-2)
The synthesis was identical to IIBe-1, and the compound IIBd-1 was replaced with IIBd-2 (1.2 g,4 mmol) to give 0.67g of a white solid, yield: 62%. ESI-MS: m/z=270 [ M+H ]] + 。
Step 4:5- (2-chlorophenyl) -3-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (IIB-1)
Compound IIBe-1 (237 mg,1 mmol) was dissolved in thionyl chloride (2 mL) and a catalytic amount of anhydrous DMF was added and heated under reflux for 30min until the starting material disappeared. The thionyl chloride was distilled off under anhydrous conditions to give a yellow oil, i.e., acid chloride, which was dissolved in anhydrous dichloromethane (5 mL) for further use. Simultaneously, triethylamine (140 mu L) and 3-trifluoromethyl aniline (161 mg,1 mmol) are dissolved in anhydrous dichloromethane (5 mL), the anhydrous dichloromethane and the anhydrous dichloromethane are slowly added into the backup acyl chloride through a constant pressure dropping funnel under ice water bath, the mixture is heated to reflux after no white smoke is generated, the reaction lasts for 3 hours until the raw materials completely disappear, the reaction solution is cooled to room temperature, the mixture is concentrated under reduced pressure, and the crude product is purified through column chromatography to obtain white solid 215mg, and the yield is: 57%. 1 H NMR(500MHz,Chloroform-d)δ7.66–7.59(m,3H),7.58(s,1H),7.52(td,J＝7.5,1.5Hz,1H),7.41–7.33(m,3H),7.13(s,1H),2.62(s,3H).ESI-MS:m/z＝381[M+H] + 。
5- (2-chlorophenyl) -3-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) isoxazole-4-carboxamide (IIB-2)
Referring to the synthesis of compound IIB-1, 3-trifluoromethylaniline was replaced by 4-trifluoromethyl-2-aminopyridine (162 mg,1 mmol) to give 187mg of a white solid. Yield: 49%. ESI-MS: m/z=382 [ M+H ] ] + 。
5- (2-chlorophenyl) -3-methyl-N- (3-cyanophenyl) isoxazole-4-carboxamide (IIB-3)
Referring to the synthesis of compound IIB-1, 3-trifluoromethylaniline was replaced with 3-cyanoaniline (118 mg,1 mmol) to give 199mg of a white solid. Yield: 59%. ESI-MS: m/z=338 [ M+H ]] + 。
5- (2-Difluoromethoxyphenyl) -3-methyl-N- (3- (trifluoromethyl) phenyl) isoxazole-4-carboxamide (IIB-4)
Referring to the synthesis of compound IIB-1, compound IIBe-1 was replaced with IIBe-2 (267 mg,1 mmol) to afford 276mg of a white solid. Yield: 67%. ESI-MS: m/z=413 [ M+H ]] + 。
Example 5: synthesis of III series Compounds
5- (2-chlorophenyl) -N- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxamide (IIIA-1)
To a solution of compound IIA-1 (92 mg,0.25 mmol) in MeOH (1 mL) was slowly added 10% Pd/C (40 mg) and hydrazine hydrate (0.15 mL), stirred at room temperature for 24 hours, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to give 51mg of a white solid. Yield: 56%. 1 H NMR(500MHz,DMSO-d 6 ):δ13.50(s,1H),10.28(s,1H),8.58(s,1H),8.14(s,1H),7.92(d,J＝9.0Hz,1H),7.52(t,J＝8.0Hz,2H),7.45(d,J＝7.5Hz,2H),7.41(d,J＝8.0Hz,1H),7.37(d,J＝8.5Hz,1H).ESI-MS:m/z＝366[M+H] + 。
5- (2-chlorophenyl) -N- (4- (trifluoromethyl) pyridin-2-yl) -1H-pyrazole-4-carboxamide (IIIA-2)
Preparation reference for target compound IIIA-2Synthesis of Compound IIIA-1 Compound IIA-1 was replaced with IIA-2 (92 mg,0.25 mmol) to give 59mg of a white solid. Yield: 64%. ESI-MS: m/z=367 [ M+H ] ] + 。
5- (2-chlorophenyl) -N- (3-cyanophenyl) -1H-pyrazole-4-carboxamide (IIIA-3)
Preparation of the target Compound IIIA-3 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-3 (85 mg,0.25 mmol) to give 35mg of a white solid. Yield: 43%. ESI-MS: m/z=323 [ M+H ]] + 。
5- (2-chlorophenyl) -N- (3-dimethylaminophenyl) -1H-pyrazole-4-carboxamide (IIIA-4)
Preparation of the target Compound IIIA-4 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced with IIA-4 (85 mg,0.25 mmol) to give 40mg of a white solid. Yield: 47%. ESI-MS: m/z=341 [ M+H ]] + 。
5- (2-chlorophenyl) -N- (3-methylsulfonylphenyl) -1H-pyrazole-4-carboxamide (IIIA-5)
Preparation of the target Compound IIIA-5 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-5 (94 mg,0.25 mmol) to give 53mg of white solid. Yield: 57%. ESI-MS: m/z=376 [ M+H ]] + 。
5- (2-chlorophenyl) -N- (4-aminopyrimidinyl) -1H-pyrazole-4-carboxamide (IIIA-6)
Preparation of the target Compound IIIA-6 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-6 (75 mg,0.25 mmol) to give 17mg of a white solid. Yield: 23%. ESI-MS: m/z=300 [ M+H ]] + 。
5- (2-chlorophenyl) -N- (2-aminopyrazinyl) -1H-pyrazole-4-carboxamide (IIIA-7)
Preparation of the target Compound IIIA-7 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-7 (75 mg,0.25 mmol) to give 31mg of a white solid. Yield: 42%. ESI-MS: m/z=300 [ M+H ]] + 。
(5- (2-chlorophenyl) -1H-pyrazol-4-yl) (morpholinyl) methanone (IIIA-8)
Preparation of target Compound IIIA-8 Synthesis of reference Compound IIIA-1 substituting Compound IIA-1 with IIA-8 (73 mg,0.25 mmol) to give white solidBody 41mg. Yield: 57%. ESI-MS: m/z=292 [ M+H ]] + 。
(5- (2-chlorophenyl) -1H-pyrazol-4-yl) (4-methylpiperazin-1-yl) methanone (IIIA-9)
Preparation of the target Compound IIIA-9 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced with IIA-9 (76 mg,0.25 mmol) to give 41mg of white solid. Yield: 54%. ESI-MS: m/z=305 [ M+H ]] + 。
(5- (2-chlorophenyl) -1H-pyrazol-4-yl) (4-hydroxypiperidin-1-yl) methanone (IIIA-10)
Preparation of the target Compound IIIA-10 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-10 (77 mg,0.25 mmol) to give 30mg of a white solid. Yield: 39%. ESI-MS: m/z=306 [ M+H ]] + 。
(5- (2-chlorophenyl) -1H-pyrazol-4-yl) (4-aminopiperidin-1-yl) methanone (IIIA-11)
Preparation of the target Compound IIIA-11 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-11 (76 mg,0.25 mmol) to give 48mg of white solid. Yield: 63%. ESI-MS: m/z=305 [ M+H ] ] + 。
(5- (2-chlorophenyl) -1H-pyrazol-4-yl) (4- (methylsulfonyl) piperazin-1-yl) methanone (IIIA-12)
Preparation of the target Compound IIIA-12 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-12 (92 mg,0.25 mmol) to give 34mg of a white solid. Yield: 37%. ESI-MS: m/z=369 [ M+H ]] + 。
(5- (2-chlorophenyl) -1H-pyrazol-4-yl) (4- (trifluoromethanesulfonyl) piperazin-1-yl) methanone (IIIA-13)
Preparation of the target Compound IIIA-3 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-13 (106 mg,0.25 mmol) to give 61mg of a white solid. Yield: 58%. ESI-MS: m/z=423 [ M+H ]] + 。
5- (2- (difluoromethoxy) phenyl) -N- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxamide (IIIA-14)
Preparation of the target Compound IIIA-14 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-14 (100 mg,0.25 mmol) to give 58mg of white solid. Production ofThe rate is as follows: 58%. ESI-MS: m/z=398 [ M+H ]] + 。
5- (2-fluorophenyl) -N- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxamide (IIIA-15)
Preparation of the target Compound IIIA-15 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIA-15 (88 mg,0.25 mmol) to give 34mg of a white solid. Yield: 39%. ESI-MS: m/z=350 [ M+H ] ] + 。
5- (2-chlorophenyl) -3-methyl-N- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxamide (IIIB-1)
Preparation of the target Compound IIIB-1 reference Synthesis of Compound IIIA-1 IIA-1 was replaced with IIB-1 (95 mg,0.25 mmol) to give 10mg of a white solid. Yield: 11%. 1 H NMR(500MHz,Chloroform-d)δ7.63(d,J＝8.0Hz,1H),7.60–7.53(m,3H),7.52–7.47(m,1H),7.38–7.29(m,2H),7.23(d,J＝8.0Hz,1H),7.08(s,1H),2.28(s,3H).ESI-MS:m/z＝380[M+H] + 。
5- (2-chlorophenyl) -3-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) -1H-pyrazole-4-carboxamide (IIIB-2)
Preparation of the target Compound IIIB-2 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIB-2 (95 mg,0.25 mmol) to give 66mg of white solid. Yield: 69%. ESI-MS: m/z=381 [ M+H ]] + 。
5- (2-chlorophenyl) -3-methyl-N- (3-cyanophenyl) -1H-pyrazole-4-carboxamide (IIIB-3)
Preparation of the target Compound IIIB-3 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIB-3 (84 mg,0.25 mmol) to give a white solid, 50mg. Yield: 59%. ESI-MS: m/z=337 [ M+H ]] + 。
5- (2-Difluoromethoxyphenyl) -3-methyl-N- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxamide (IIIB-4)
Preparation of the target Compound IIIB-4 reference synthesis of Compound IIIA-1 Compound IIA-1 was replaced by IIB-4 (103 mg,0.25 mmol) to give 69mg of white solid. Yield: 67%. ESI-MS: m/z=412 [ M+H ]] + 。
5- (2-chlorophenyl) -1-methyl-N- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxamide (IIIC-1)
Compound IIIA-1 (91.3 mg,0.25 mol) and potassium carbonate (86.4 mg,0.63 mol) were dissolved in DMF (1 mL), and after stirring at room temperature for 30 minutes, methyl iodide (0.25 mL,0.38 mmol) was added dropwise and the mixture was heated to 80℃and stirred for 2 hours. Cooled to room temperature, water was added and extracted with ethyl acetate (3×100 mL), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by column chromatography to give 69mg of a white solid. Yield: 73%. 1 H NMR(500MHz,DMSO-d 6 ):δ8.10(s,1H),7.67(d,J＝8.0Hz,1H),7.60(t,J＝7.5Hz,1H),7.55(s,1H),7.52(t,J＝7.5Hz,1H),7.47(d,J＝6.5Hz,1H),7.43(d,J＝8.0Hz,1H),7.35(t,J＝7.5Hz,1H),7.29(d,J＝7.5Hz,1H),7.09(s,1H),3.72(s,3H).ESI-MS:m/z＝380[M+H] + 。
5- (2-chlorophenyl) -1-methyl-N- (4- (trifluoromethyl) pyridin-2-yl) -1H-pyrazole-4-carboxamide (IIIC-2)
Preparation of the target Compound IIIC-2 reference synthesis of Compound IIIC-1 Compound IIIA-1 was replaced by IIIA-2 (91 mg,0.25 mmol) to give 65mg of white solid. Yield: 68%. ESI-MS: m/z=381 [ M+H ]] + 。
5- (2-Difluoromethoxyphenyl) -1-methyl-N- (3- (trifluoromethyl) phenyl) -1H-pyrazole-4-carboxamide (IIIC-3)
Preparation of the target Compound IIIC-3 reference synthesis of Compound IIIC-1 Compound IIIA-1 was replaced by IIIA-11 (76 mg,0.25 mmol) to give 79mg of a white solid. Yield: 77%. ESI-MS: m/z=412 [ M+H ]] + 。
Example 6: synthesis of IV series of compounds
Step 1: 2-bromo-3- (2-chlorophenyl) -3-oxopropionic acid methyl ester (IVa-1)
To a solution of compound IIAb-1 (5.0 g,23.5 mmol) in DMSO (20 mL) was added NBS (4.6 g,25.8 mmol) and stirred at room temperature for 6 hours. Water (100 mL) was added and extracted with ethyl acetate (100 mL. Times.3), the organic layers were combined, washed with water (100 mL. Times.3) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressureThe crude product was concentrated and purified by column chromatography to give 3.9g of a white solid. Yield: 39%. 1 H NMR(500MHz,Chloroform-d 6 ):δ7.60-7.57(m,1H),7.47-7.45(m,2H),7.36-7.39(m,1H),5.80(s,1H),3.84(s,3H).ESI-MS:m/z＝291[M+H] + 。
2-bromo-3- (2- (difluoromethoxy) phenyl) -3-oxopropanoic acid methyl ester (IVa-2)
The synthesis was identical to IVa-1, and the compound IIAb-1 was replaced with IIAb-2 (5.7 g,23.5 mmol) to give 3.9g of a white solid, yield: 52%. ESI-MS: m/z=324 [ M+H ]] + 。
Step 2: 2-amino-4- (2-chlorophenyl) thiazole-5-carboxylic acid methyl ester (IVb-1)
Compound IVa-1 (2.0 g,7.2 mmol) and thiourea (661mg, 8.7 mmol) were dissolved in EtOH (20 mL) and heated to 80℃for 2h. Cooled to room temperature, concentrated under reduced pressure, aqueous ammonia (20 mL) was added to the residue, filtered, and the filter cake was washed with water and dried under vacuum to give 1.42g of a white solid. Yield: 72%. 1 H NMR(500MHz,Chloroform-d 6 ):δ7.45(dd,J＝7.5,1.5Hz,1H),7.37(dd,J＝7.5,2.0Hz,1H),7.34(dd,J＝7.5,2.0Hz,1H),7.31(td,J＝7.5,1.5Hz,1H),5.96(s,2H),3.69(s,3H).ESI-MS:m/z＝269[M+H] + 。
2-amino-4- (2- (difluoromethoxy) phenyl) thiazole-5-carboxylic acid methyl ester (IVb-2)
The synthesis was identical to IVb-1, substituting IVa-1 for IVa-2 (2.3 g,7.2 mmol) to give 1.26g as a white solid, yield: 58%. ESI-MS: m/z=302 [ M+H ] ] + 。
Step 3: 2-amino-4- (2-chlorophenyl) thiazole-5-carboxylic acid (IVc-1)
Compound IVb-1 (1.07 g,4 mmol) and lithium hydroxide monohydrate (336 mg,8 mmol) were added to 15mL THF and 7.5mL water, stirred at room temperature for 3 hours, TLC checked for completion of the reaction, dried by spin-drying, pH adjusted to 2 with 6N hydrochloric acid solution, solid precipitated, suction filtered, dried to give 680mg of white solid in 67% yield. ESI-MS: m/z=255 [ M+H ]] + 。
2-amino-4- (2- (difluoromethoxy) phenyl) thiazole-5-carboxylic acid (IVc-2)
Synthesis method similar to IVc-1, compound IVb-1 was replaced with IVb-2 (1.2 g,4 mmol) to give 895mg of a white solidYield: 78%. ESI-MS: m/z=288 [ M+H ]] + 。
Step 4: 2-amino-4- (2-chlorophenyl) -N- (3- (trifluoromethyl) phenyl) thiazole-5-carboxamide (IV-1)
Compound IVc-1 (254 mg,1 mmol) was dissolved in thionyl chloride (2 mL) and 1-2 drops of anhydrous DMF was added, and heated under reflux for 30min until the starting material disappeared. The thionyl chloride was distilled off under anhydrous conditions to give a yellow oil, i.e., acid chloride, which was dissolved in anhydrous dichloromethane (5 mL) for further use. Simultaneously, triethylamine (140 mu L) and 3-trifluoromethyl aniline (161 mg,1 mmol) are dissolved in anhydrous dichloromethane (5 mL), the anhydrous dichloromethane and the anhydrous dichloromethane are slowly added into the backup acyl chloride through a constant pressure dropping funnel under ice water bath, the mixture is heated to reflux after no white smoke is generated, the reaction lasts for 3 hours until the raw materials completely disappear, the reaction solution is cooled to room temperature, the mixture is concentrated under reduced pressure, and the crude product is purified through column chromatography to obtain 273mg of white solid with the yield: 69%. 1 H NMR(500MHz,DMSO-d 6 )δ9.63(s,1H),7.91(s,1H),7.78(s,2H),7.66(d,J＝8.5Hz,1H),7.50–7.43(m,3H),7.40–7.34(m,3H).ESI-MS:m/z＝398[M+H] + 。
2-amino-4- (2-chlorophenyl) -N- (4- (trifluoromethyl) pyridin-2-yl) thiazole-5-carboxamide (IV-2)
Preparation of Compound IV-2 Synthesis of reference Compound IV-1, 3-trifluoromethylaniline was replaced with 4-trifluoromethyl-2-aminopyridine (162 mg,1 mmol) to give 235mg of a white solid. Yield: 59%. ESI-MS: m/z=399 [ M+H ]] + 。
2-amino-4- (2-chlorophenyl) -N- (3-cyanophenyl) thiazole-5-carboxamide (IV-3)
Compound IV-3 preparation of reference Compound IV-1 Synthesis of 3-trifluoromethylaniline was replaced with 3-cyanoaniline (118 mg,1 mmol) to give 219mg of a white solid. Yield: 62%. ESI-MS: m/z=355 [ M+H ]] + 。
2-amino-4- (2- (difluoromethoxy) phenyl) -N- (3- (trifluoromethyl) phenyl) thiazole-5-carboxamide (IV-4)
Preparation of Compound IV-4 reference was made to the synthesis of compound IV-1, substituting compound IVc-1 with IVc-2 (287 mg,1 mmol) to give 305mg of a white solid. Yield: 71%. ESI-MS: m/z=430 [ M+H ]] + 。
Example 7: synthesis of V-series compounds
Step 1:5- (2-chlorophenyl) oxazole-4-carboxylic acid ethyl ester (Vc-1)
2-Chlorobenzoic acid (3.0 g,19.2 mmol) was dissolved in thionyl chloride (2 mL), and the mixture was warmed to reflux for 1h, cooled to room temperature, and the thionyl chloride was distilled off under reduced pressure to give an acid chloride intermediate Vb-1. Vb-1 was dissolved in anhydrous THF (3 mL), ethyl isocyanoacetate (2.1 mL,19.2 mmol) and TEA (5.34 mL,38.4 mmol) were added. The reaction was carried out at room temperature overnight. Extraction with ethyl acetate (10 ml×3), combining the organic phases, filtration, concentration under reduced pressure, purification of the crude product by column chromatography gave 1.59g of a white solid, yield: 33%; 1 HNMR(500MHz,Chloroform-d 6 )δ7.99(s,1H),7.53(dd,J＝4.0,1.5Hz,1H),7.51(dd,J＝4.0,1.5Hz,1H),7.45(td,J＝7.5,1.5Hz,1H),7.38(td,J＝7.5,1.5Hz,1H),4.31(q,J＝14.0,7.0Hz,2H),1.26(t,J＝7.5Hz,3H).ESI-MS:m/z＝252[M+H] + .5- (2- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid ethyl ester (Vc-2)
The synthesis method is the same as Vc-1, 2-chlorobenzoic acid is replaced by 2-difluoromethoxybenzoic acid (3.6 g,19.2 mmol) to obtain white solid 2.6g, yield: 48%. ESI-MS: m/z=284 [ M+H ]] + 。
Step 2:5- (2-chlorophenyl) oxazole-4-carboxylic acid (Vd-1)
The compound Vc-1 (1.0 g,4 mmol) and lithium hydroxide monohydrate (336 mg,8 mmol) were added to THF/H 2 In the mixed solvent of O, the reaction is carried out at room temperature until the TLC detection reaction is complete, the organic solvent is distilled off under reduced pressure, the pH is regulated to 2 by using 6N hydrochloric acid solution, the solid is separated out, the filtration is carried out, and the drying is carried out, thus obtaining 553mg of white solid with the yield of 62 percent. ESI-MS: m/z=224 [ M+H ]] + 。
5- (2- (difluoromethoxy) phenyl) oxazole-4-carboxylic acid (Vd-2)
The synthesis method is the same as Vd-1, and compound Vc-1 is replaced by Vc-2 (1.1 g,4 mmol) to obtain 388mg of white solid with yield: 38%. ESI-MS: m/z=256 [ M+H ]] + 。
Step 3:5- (2-chlorophenyl) -N- (3- (trifluoromethyl) phenyl) oxazole-4-carboxamide (V-1)
Compound Vd-1 (223 mg,1 mmol) was dissolved in thionyl chloride (2 mL) and a catalytic amount of anhydrous DMF was added and heated under reflux for 30min until the starting material disappeared. The thionyl chloride was distilled off under anhydrous conditions to give a yellow oil, i.e., acid chloride, which was dissolved in anhydrous dichloromethane (5 mL) for further use. Simultaneously, triethylamine (140 mu L) and 3-trifluoromethyl aniline (161 mg,1 mmol) are dissolved in anhydrous dichloromethane (5 mL), the anhydrous dichloromethane and the 3-trifluoromethyl aniline are slowly added into the backup acyl chloride through a constant pressure dropping funnel under ice water bath, the mixture is heated to reflux after no white smoke is generated, the reaction lasts for 3 hours until the raw materials completely disappear, the reaction solution is cooled to room temperature, the mixture is concentrated under reduced pressure, and the crude product is purified through column chromatography to obtain 241mg of white solid with yield: 66%; 1 H NMR(500MHz,Chloroform-d 6 )δ9.03(s,1H),8.00(d,J＝3.0Hz,2H),7.83(d,J＝8.0Hz,1H),7.66(d,J＝7.5Hz,1H),7.53(d,J＝8.0Hz,1H),7.47(d,J＝7.5Hz,1H),7.44(d,J＝8.5Hz,1H),7.42(d,J＝7.5Hz,1H),7.38(d,J＝8.0Hz,1H).ESI-MS:m/z＝367[M+H] + 。
5- (2-chlorophenyl) -N- (4- (trifluoromethyl) pyridin-2-yl) oxazole-4-carboxamide (V-2)
Preparation of Compound V-2 Synthesis of reference Compound V-1 3-trifluoromethylaniline was replaced with 4-trifluoromethyl-2-aminopyridine (162 mg,1 mmol) to give 209mg of a white solid. Yield: 57%. ESI-MS: m/z=368 [ M+H ]] + 。
5- (2-chlorophenyl) -N- (3-cyanophenyl) oxazole-4-carboxamide (V-3)
Preparation of Compound V-3 reference synthesis of Compound V-1 3-trifluoromethylaniline was replaced with 3-cyanoaniline (118 mg,1 mmol) to give 220mg of a white solid. Yield: 68%. ESI-MS: m/z=324 [ M+H ]] + 。
5- (2- (difluoromethoxy) phenyl) -N- (3- (trifluoromethyl) phenyl) oxazole-4-carboxamide (V-4)
Preparation of Compound V-4 reference synthesis of Compound V-1 Compound Vd-1 was replaced with Vd-2 (255 mg,1 mmol) to yield 295mg of white solid. Yield: 74%. ESI-MS: m/z=399 [ M+H ]] + 。
Example 8: synthesis of VI series of compounds
Step 1:4- (2-chlorophenyl) pyrimidine-5-carboxylic acid methyl ester (VIAa-1)
Compound IIAc-1 (2.0 g,7.45 mmol), formamidine hydrochloride (902 mg,11.2 mmol) and sodium methoxide (760 mg,11.2 mmol) were dissolved in ethanol (40 mL) and heated to 80℃for reaction overnight. Cooled to room temperature, the organic solvent was distilled off under reduced pressure, water (10 mL) was added, filtration, and the cake was washed with water and dried in vacuo to give 1.0g of a white solid, yield: 54%; 1 H NMR(500MHz,Chloroform-d 6 ):δ9.41(s,1H),9.30(s,1H),7.46-7.44(m,2H),7.44-7.43(m,1H),7.43-7.41(m,1H),3.78(s,3H).ESI-MS:m/z＝249[M+H] + 。
4- (2- (difluoromethoxy) phenyl) pyrimidine-5-carboxylic acid methyl ester (VIAa-2)
The synthesis procedure was the same as for VIAa-1, substituting IIAc-1 for IIAc-2 (2.2 g,7.45 mmol) to give 1.2g of a white solid, yield: 58%. ESI-MS: m/z=281 [ M+H ]] + 。
4- (2-fluorophenyl) pyrimidine-5-carboxylic acid methyl ester (VIAa-3)
The synthesis was carried out in the same manner as VIAa-1, except that the compound IIAc-1 was replaced with IIAc-3 (1.9 g,7.45 mmol) to give 1.1g of a white solid, yield: 62%. ESI-MS: m/z=233 [ M+H ]] + 。
2-amino-4- (2-chlorophenyl) pyrimidine-5-carboxylic acid methyl ester (VIBa-1)
The synthesis method was the same as that of VIAa-1, and formamidine hydrochloride was replaced with guanidine hydrochloride (1.1 g,11.2 mmol) to give 1.3g of a white solid, yield: 68%; 1 H NMR(500MHz,Chloroform-d 6 ):δ8.01-7.97(m,1H),7.49-7.47(m,2H),7.35(td,J＝7.5,2.0Hz,2H),3.68(s,3H).ESI-MS:m/z＝264[M+H] + 。
2-amino-4- (2- (difluoromethoxy) phenyl) pyrimidine-5-carboxylic acid methyl ester (VIBa-2)
The synthesis procedure was the same as for VIBa-1, substituting compound IIAc-1 for IIAc-2 (2.2 g,7.45 mmol) to give 1.5g of white solid, yield: 68%. ESI-MS: m/z=296 [ M+H ]] + 。
2-amino-4- (2-fluorophenyl) pyrimidine-5-carboxylic acid methyl ester (VIBa-3)
The synthesis procedure was the same as for VIBa-1, substituting compound IIAc-1 for IIAc-3 (1.9 g,7.45 mmol) to give 1.5g of white solid, yield: 82%. ESI-MS: m/z=248 [ M+H ]] + 。
Step 2:4- (2-chlorophenyl) pyrimidine-5-carboxylic acid (VIAb-1)
The compound VIAa-1 (992 mg,4 mmol) and lithium hydroxide monohydrate (336 mg,8 mmol) were added to THF/H 2 In the mixed solvent of O, the reaction is carried out at room temperature until the TLC detection reaction is complete, the organic solvent is distilled off under reduced pressure, the pH is regulated to 2 by using 6N hydrochloric acid solution, the solid is separated out, the solid is filtered out by suction, and the solid is dried to obtain 489mg of white solid, and the yield is 52%. ESI-MS: m/z=235 [ M+H ]] + 。
4- (2- (difluoromethoxy) phenyl) pyrimidine-5-carboxylic acid (VIAb-2)
The synthesis method is the same as that of VIAb-1, and the compound VIAa-1 is replaced by VIAa-2 (1.12 g,4 mmol) to obtain 404mg of white solid with yield: 38%. ESI-MS: m/z=267 [ M+H ]] + 。
4- (2-fluorophenyl) pyrimidine-5-carboxylic acid (VIAb-3)
The synthesis method is the same as that of VIAb-1, and the compound VIAa-1 is replaced by VIAa-3 (928 mg,4 mmol) to obtain white solid 410mg, yield: 47%. ESI-MS: m/z=219 [ M+H ]] + 。
2-amino-4- (2-chlorophenyl) pyrimidine-5-carbo-x-yl ester (VIBb-1)
The synthesis method was the same as that of VIAb-1, and the compound VIAa-1 was replaced with VIBa-1 (1.05 g,4 mmol) to give 677mg of a white solid, yield: 68%; ESI-MS: m/z=250 [ M+H ]] + 。
2-amino-4- (2- (difluoromethoxy) phenyl) pyrimidine-5-carboxylic acid (VIBb-2)
The synthesis method is the same as that of VIAb-1, and the compound VIAa-1 is replaced by VIBa-2 (1.18 g,4 mmol) to obtain 607mg of white solid with the yield: 54%. ESI-MS: m/z=282 [ M+H ]] + 。
2-amino-4- (2-fluorophenyl) pyrimidine-5-carboxylic acid (VIBb-3)
The synthesis method is the same as that of VIAb-1, and the compound VIAa-1 is replaced by VIBa-3 (992 mg,4 mmol) to obtain white solid 578mg, yield: 62%. ESI-MS: m/z=234 [ M+H ] ] + 。
Step 3:4- (2-chlorophenyl) -N- (3- (trifluoromethyl) phenyl) pyrimidine-5-carboxamide (VIA-1)
Compound VIAb-1 (234 mg,1 mmol) was dissolved in thionyl chloride (2 mL) and a catalytic amount of anhydrous DMF was added and heated under reflux for 30min until the starting material disappeared. The thionyl chloride was distilled off under anhydrous conditions to give a yellow oil, i.e., acid chloride, which was dissolved in anhydrous dichloromethane (5 mL) for further use. Simultaneously, triethylamine (140 mu L) and 3-trifluoromethyl aniline (161 mg,1 mmol) are dissolved in anhydrous dichloromethane (5 mL), the anhydrous dichloromethane and the anhydrous dichloromethane are slowly added into the backup acyl chloride through a constant pressure dropping funnel under ice water bath, the mixture is heated to reflux after no white smoke is generated, the reaction lasts for 3 hours until the raw materials completely disappear, the reaction solution is cooled to room temperature, the mixture is concentrated under reduced pressure, and the crude product is purified through column chromatography to obtain 219mg of white solid with the yield: 58%; 1 H NMR(500MHz,DMSO-d 6 ):δ11.13(s,1H),9.43(s,1H),9.23(s,1H),8.03–8.02(m,1H),7.81(d,J＝8.5Hz,1H),7.57(t,J＝8.0Hz,1H),7.53(dd,J＝6.5,2.5Hz,2H),7.48–7.45(m,3H).ESI-MS:m/z＝378[M+H] + 。
4- (2-chlorophenyl) -N- (4- (trifluoromethyl) pyridin-2-yl) pyrimidine-5-carboxamide (VIA-2)
The title compound VIA-2 was prepared as above, substituting 3-trifluoromethylaniline with 4-trifluoromethyl-2-aminopyridine (162 mg,1 mmol) to give 215mg of a white solid. Yield: 57%. ESI-MS: m/z=379 [ M+H ]] + 。
4- (2-chlorophenyl) -N- (3-cyanophenyl) pyrimidine-5-carboxamide (VIA-3)
The title compound VIA-3 was prepared as above, substituting 3-trifluoromethylaniline with 3-cyanoaniline (118 mg,1 mmol) to give 224mg of a white solid. Yield: 67%. ESI-MS: m/z=335 [ M+H ] ] + .4- (2- (difluoromethoxy) phenyl) -N- (3- (trifluoromethyl) phenyl) pyrimidine-5-carboxamide (VIA-4)
Preparation of the target Compound VIA-4 As above, the Compound VIAb-1 was replaced with VIAb-2 (266 mg,1 mmol) to give 196mg of a white solid. Yield: 48%. ESI-MS: m/z=410 [ M+H ]] + 。
4- (2-fluorophenyl) -N- (3- (trifluoromethyl) phenyl) pyrimidine-5-carboxamide (VIA-5)
Preparation of the target Compound VIA-5 As above, the CompoundVIAb-1 was replaced with VIAb-3 (218 mg,1 mmol) to give 159mg of a white solid. Yield: 44%. ESI-MS: m/z=362 [ M+H ]] + 。
2-amino-4- (2-chlorophenyl) -N- (3- (trifluoromethyl) phenyl) pyrimidine-5-carboxamide (VIB-1)
Preparation of the target compound VIB-1 As above, the compound VIAb-1 was replaced with VIBb-1 (249 mg,1 mmol) to give 278mg of a white solid. Yield: 71%; 1 H NMR(500MHz,DMSO-d6):δ10.57(s,1H),8.70(s,1H),8.03–8.02(m,1H),7.81(d,J＝8.5Hz,1H),7.51(t,J＝8.0Hz,1H),7.44-7.41(m,1H),7.40-7.36(m,6H).ESI-MS:m/z＝393[M+H] + 。
2-amino-4- (2-chlorophenyl) -N- (4- (trifluoromethyl) pyridin-2-yl) pyrimidine-5-carboxamide (VIB-2)
The preparation of the target compound VIB-2 was carried out in the same manner as above, except that 3-trifluoromethylaniline was replaced by 4-trifluoromethyl-2-aminopyridine (162 mg,1 mmol), giving 275mg of a white solid. Yield: 70% of the total weight of the steel sheet; ESI-MS: m/z=394 [ M+H ]] + 。
2-amino-4- (2-chlorophenyl) -N- (3-cyanophenyl) pyrimidine-5-carboxamide (VIB-3)
The preparation method of the target compound VIB-3 was the same as above, except that 3-trifluoromethylaniline was replaced with 3-cyanoaniline (118 mg,1 mmol), to give 216mg of a white solid. Yield: 62%; ESI-MS: m/z=350 [ M+H ] ] + 。
(2-amino-4- (2-chlorophenyl) pyrimidin-5-yl) (morpholinyl) methanone (VIB-4)
The preparation method of the target compound VIB-4 is the same as above, and 3-trifluoromethylaniline is replaced by morpholine (87 mg,1 mmol) to obtain 134mg of a white solid. Yield: 42%; ESI-MS: m/z=319 [ M+H ]] + 。
(2-amino-4- (2-chlorophenyl) pyrimidin-5-yl) (4-methylpiperazin-1-yl) methanone (VIB-5)
The preparation method of the target compound VIB-5 was the same as above, except that 3-trifluoromethylaniline was replaced with N-methylpiperazine (100 mg,1 mmol), to give 142mg of a white solid. Yield: 43%. ESI-MS: m/z=332 [ M+H ]] + 。
2-amino-4- (2- (difluoromethoxy) phenyl) -N- (3- (trifluoromethyl) phenyl) pyrimidine-5-carboxamide (VIB-6)
The preparation method of the target compound VIB-6 is the same as that described above, and the compound VIBb-1 is replaced by VIBb-2 (281mg, 1 mmol) to obtain 310mg of white solid. Yield: 73%; ESI-MS: m/z=425 [ M+H ]] + 。
2-amino-4- (2-fluorophenyl) -N- (3- (trifluoromethyl) phenyl) pyrimidine-5-carboxamide (VIB-7)
The preparation method of the target compound VIB-7 is the same as that described above, and the compound VIBb-1 is replaced with VIBb-3 (233 mg,1 mmol) to obtain 154mg of white solid. Yield: 41%; ESI-MS: m/z=377 [ M+H ]] + 。
Example 9: VEGF Elisa Activity test of the Compounds of the invention (aromatic heterocyclic carboxamides)
In this section, VEGF protein agonistic activity of some of the compounds on human renal clear cell carcinoma cell line 786-O was evaluated using VEGF Elisa Assay using M1002 as a positive control. Other compounds of the present invention have similar beneficial effects to those listed below, but this should not be construed as the compounds of the present invention having only the following beneficial effects.
786-O cells in the logarithmic growth phase were seeded in 96-well plates (Fisher Scientific), 7500 cells per well (180. Mu.L/well), and after culturing for 8 hours, 20. Mu.L of a stock solution of the compound (DMSO dissolved at a concentration of 10 mmol/L) was added to each well to give a final concentration of 10. Mu.M, and 3 multiplex wells were arranged in parallel. After about 24 hours, the medium was removed by aspiration and 180 μl of growth medium was provided to each well. mu.L of freshly prepared 10 Xstock of test compound was added to each well. The cell culture medium was removed by culturing under hypoxic conditions (1% oxygen+5% carbon dioxide+94% nitrogen) for 24 hours. Using R&ELISA kits purchased from DSsystems determine VEGF concentration. The reaction was stopped by adding 50. Mu.LCelltiter Glo reagent to each well and the stop reaction was allowed to proceed well by gently shaking the ELISA plate. Cell titer-Glo luminescent cell viability assay (Promega) was performed on the cell-inoculated plates, and then the light absorbance of each well was measured immediately using a microplate reader at a wavelength of 450 nm. EC was calculated by GraphPadPrism analysis of data using dose-response-inhibition (four parameters) and other formulas 50 Values, results are shown in table 2.
Table 2 VEGF protein agonistic Activity of partial heteroaromatic carboxamides
E 10 10 μm well fluorescence value +.f. blank fluorescence value x 100%; "+". ++'s represents E 10 More than or equal to 200 percent; "+". ++'s represents E 10 More than or equal to 150 percent; "++" represents the activation multiple E 10 More than or equal to 130 percent; "+" represents E 10 ≥100％。
As shown by the experimental results in Table 2, most of the compounds show weaker VEGF protein expression agonist activity, and some of the compounds have better activity compared with positive M1002, so that the compounds have the potential for further development.
Example 10: determination of the Effect of the inventive Compounds on the expression level of the HIF-2 downstream target Gene EPO and VEGF mRNA by qRT-PCR technology
786-O cells in the logarithmic growth phase were seeded in 6-well plates (Fisher Scientific), 1X 10 per well 6 After 8 hours of culture, a stock solution of the compound (DMSO was dissolved at a concentration of 10 mmol/L) was serially diluted, and the diluted solution was added to each well so that the final concentration was 2, 10, 20. Mu.M, respectively. After about 24 hours, 786-O cells were isolated for total RNA using TRIzol (Invitrogen). qRT-PCR analysis of EPO (F: GGAGGCCGAGAATATCACGAC, R: CCCTGCCAGACTTCTACGG) and VEGFA (F: TACCTCCACCATGCCAAGTG, R: ATGATTCTGCCCTCCTCCTTC) was performed using a StepOne System fast real-time PCR System (Applied Biosystems). Beta Action (ACTB) (F: GCACAGAGCCTCGCCTT, R: GTTGTCGACGACGAGCG) was used for normalization. The results are shown in FIG. 2.
As can be seen from the experimental results in FIG. 2, both the compound I-9 and the compound IIIA-1 can up-regulate the expression of the target genes EPO and VEGFA mRNA downstream of the HIF-2 in a dose-dependent manner, and have the potential for further development.
Claims (10)
1. An application of aromatic heterocyclic formamide shown in a formula a or pharmaceutically acceptable salt thereof in preparing HIF-2 alpha agonist,
in formula a:
R 1 selected from nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl or NR a R b Wherein R is a 、R b Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 2-6 Unsaturated aliphatic hydrocarbon groups;
m is 0, 1 or 2;
ring A is selected from unsubstituted or substituted by one R 2 Substituted pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl or pyrimidinyl, wherein R 2 Selected from hydroxy, halogen, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Alkoxy or NR c R d Wherein R is c 、R d Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 2-6 Unsaturated aliphatic hydrocarbon groups;
R 3 、R 4 each independently selected from hydrogen, C 1-6 Alkyl or unsubstituted or substituted by R e Substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl, wherein R e Selected from nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy, C 3-8 Cycloalkyl, NR f R g Or SO 2 R x Wherein R is f 、R g 、R x Each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 2-6 Unsaturated aliphatic hydrocarbon groups; or R is 3 、R 4 Together with N between them forms unsubstituted or substituted R h Substituted morpholinyl, piperazinyl or piperonylA pyridyl group; wherein R is h Is hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 2-6 Unsaturated aliphatic hydrocarbon group, NR i R j Or SO 2 R y The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is i 、R j 、R y Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-8 Cycloalkyl or C 2-6 Unsaturated aliphatic hydrocarbon groups.
2. The use according to claim 1, wherein: r is R 1 Is nitro, fluoro, chloro, methyl, methoxy, C 1-6 Fluoroalkyl, C 1-6 Fluoroalkoxy or amino.
3. The use according to claim 1, wherein: in a
Selected from one of the following heterocycles:
4. the use according to claim 1, wherein: r is R 2 Is hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Fluoroalkyl or NR c R d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is c 、R d Respectively selected from hydrogen, C 1-6 An alkyl group.
5. The use according to claim 1, wherein: r is R 3 And R is 4 Respectively hydrogen, unsubstituted or substituted by R e Substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl; wherein R is e Is fluorine, chlorine, bromine, cyano, C 1-6 Fluoroalkyl, C 1-6 Fluoroalkoxy, NR f R g Or SO 2 R x Wherein R is f 、R g 、R x Respectively hydrogenOr C 1-6 An alkyl group; or R is 3 、R 4 And N therebetween together form an unsubstituted or substituted R h Substituted morpholinyl, piperazinyl or piperidinyl, wherein R h Is hydroxy, C 1-6 Alkyl, NR i R j Or SO 2 R y The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is i 、R j 、R y Respectively is hydrogen, C 1-6 Alkyl or C 1-6 A fluoroalkyl group.
6. The use according to claim 1, wherein: r is R 1 Is nitro, fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy or amino; r is R 2 Hydrogen, methyl or amino; r is R 3 Is H, R 4 Unsubstituted or substituted by trifluoromethyl, halogen, cyano, -N (CH) 3 ) 2 or-SO 2 CH 3 Substituted phenyl, pyridyl, pyrimidinyl or pyrazinyl, or R 3 、R 4 And N therebetween together form an unsubstituted or substituted hydroxy, methyl, amino, -SO 2 CH 3 or-SO 2 CF 3 Substituted morpholines, piperidines or piperazines.
7. The use according to claim 1, wherein: the aromatic heterocyclic formamide shown in the formula a is selected from one of the following:
8. the use according to claim 1, wherein: the pharmaceutically acceptable salts are alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts or amino acid salts.
9. The use according to claim 1, wherein: the application is as follows: the aromatic heterocyclic formamide shown in the formula a and the pharmaceutically acceptable salt thereof are applied to the preparation of drugs for treating or preventing anemia, inflammation, emphysema, immunodeficiency diseases, chronic metabolic diseases or neurodegenerative diseases.
10. The use according to claim 1, wherein: the anemia comprises secondary anemia, pernicious anemia, hemolytic anemia, iron deficiency anemia and aplastic anemia; the inflammation comprises nephritis, pneumonia, tracheitis, enteritis, arthritis and traumatic infection; the immunodeficiency diseases comprise systemic lupus erythematosus, psoriasis and rheumatoid arthritis; the chronic metabolic diseases comprise diabetes, hypertension and obesity; the neurodegenerative diseases comprise cerebral ischemia, brain injury, alzheimer's disease, parkinson's disease and Huntington's disease.
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