CN117430610A - Deuterated condensed heterocyclic compound and preparation method and application thereof - Google Patents
Deuterated condensed heterocyclic compound and preparation method and application thereof Download PDFInfo
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- CN117430610A CN117430610A CN202311315785.7A CN202311315785A CN117430610A CN 117430610 A CN117430610 A CN 117430610A CN 202311315785 A CN202311315785 A CN 202311315785A CN 117430610 A CN117430610 A CN 117430610A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 6
- RNOAOAWBMHREKO-QFIPXVFZSA-N (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical class C(C=C)(=O)N1CCC(CC1)[C@@H]1CCNC=2N1N=C(C=2C(=O)N)C1=CC=C(C=C1)OC1=CC=CC=C1 RNOAOAWBMHREKO-QFIPXVFZSA-N 0.000 claims abstract description 27
- 229940124291 BTK inhibitor Drugs 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 221
- 239000003960 organic solvent Substances 0.000 claims description 70
- 238000002156 mixing Methods 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 238000007363 ring formation reaction Methods 0.000 claims description 22
- 150000001408 amides Chemical class 0.000 claims description 20
- 230000009615 deamination Effects 0.000 claims description 16
- 238000006481 deamination reaction Methods 0.000 claims description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 16
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 14
- 238000006482 condensation reaction Methods 0.000 claims description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 238000003379 elimination reaction Methods 0.000 claims description 11
- 238000007069 methylation reaction Methods 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 238000005915 ammonolysis reaction Methods 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 9
- -1 bis ([ 1,1' -biphenyl ] -2-yl) glyoxalic amide Chemical compound 0.000 claims description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical class OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 8
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims description 8
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 8
- 235000011009 potassium phosphates Nutrition 0.000 claims description 8
- CAKYGVXUEFBCLI-QHCPKHFHSA-N CC=CN(CC1)CCC1[C@H](CCNC1=C2C(N)=O)N1N=C2C(C=C1)=CC=C1OC1=CC=CC=C1 Chemical class CC=CN(CC1)CCC1[C@H](CCNC1=C2C(N)=O)N1N=C2C(C=C1)=CC=C1OC1=CC=CC=C1 CAKYGVXUEFBCLI-QHCPKHFHSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 5
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
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- 230000003113 alkalizing effect Effects 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 238000000034 method Methods 0.000 claims 7
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical class NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims 1
- 230000004913 activation Effects 0.000 abstract description 8
- 210000003719 b-lymphocyte Anatomy 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 230000035578 autophosphorylation Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 abstract description 2
- 235000018417 cysteine Nutrition 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 239000012295 chemical reaction liquid Substances 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 27
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- 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- 238000000605 extraction Methods 0.000 description 19
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- 101100042680 Mus musculus Slc7a1 gene Proteins 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 5
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 102100038183 Tyrosine-protein kinase SYK Human genes 0.000 description 3
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 2
- 102000001332 SRC Human genes 0.000 description 2
- 108060006706 SRC Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 102000000551 Syk Kinase Human genes 0.000 description 2
- 108010016672 Syk Kinase Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- 239000000706 filtrate Substances 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- PZYFJWVGRGEWGO-UHFFFAOYSA-N trisodium;hydrogen peroxide;trioxido(oxo)vanadium Chemical compound [Na+].[Na+].[Na+].OO.OO.OO.[O-][V]([O-])([O-])=O PZYFJWVGRGEWGO-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102000010995 Pleckstrin homology domains Human genes 0.000 description 1
- 108050001185 Pleckstrin homology domains Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
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- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
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- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 1
- VKRWRNVGVPSVLA-UHFFFAOYSA-N n,n'-bis(2-phenylphenyl)oxamide Chemical compound C=1C=CC=C(C=2C=CC=CC=2)C=1NC(=O)C(=O)NC1=CC=CC=C1C1=CC=CC=C1 VKRWRNVGVPSVLA-UHFFFAOYSA-N 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a deuterated condensed heterocyclic compound, and a preparation method and application thereof. The deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with the structure shown in the formula I or the formula II can be irreversibly combined with cysteine 481 at the active site of BTK through a covalent bond, so that the autophosphorylation of Y223 is inhibited to prevent the complete activation of BTK and inhibit downstream signals, and therefore, the derivative has a very good inhibition effect on BTK, can be used for preparing BTK inhibitors, and plays an important role in the occurrence and development of various B cell malignant tumors.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a deuterated condensed heterocyclic compound, and a preparation method and application thereof.
Background
Bruton's tyrosine kinase (Bruton tyrosine kinase, BTK) is a key kinase of B Cell Receptor (BCR) signaling pathway, playing an important role in the occurrence and development of various B cell malignancies, and currently BTK inhibitors (Bruton tyrosine kinase inhibitors, BTKi) are widely used in the treatment of chronic lymphocytic leukemia and mantle cell lymphoma due to their outstanding therapeutic effects.
BTK consists of 659 amino acids, comprising 5 domains, PH domain (pleckstrin homologydomain), TH domain (TEC homology domain), SH 3domain (SRC homo log 3 domain), SH2 domain (SRC homo log 2 domain) and catalytic domain, in order from N-terminus to C-terminus. BTK has 2 key tyrosine phosphorylation sites, tyrosine 223 (Y223) located on the SH 3domain and tyrosine 551 (Y551) located on the catalytic domain, respectively. Upon activation of the BCR signaling pathway, SYK enhances the catalytic activity of BTK by phosphorylating Y551, contributing to subsequent autophosphorylation of Y223. Because of the important role of BCR in CLL signaling and the central role of BTK in BCR signaling pathways, targeted inhibition of BTK is a rational strategy for treating B cell tumors. All current covalent and non-covalent BTKi bind to the catalytic domain of BTK and act by inhibiting autophosphorylation of Y223.
After antigen stimulation, BCR aggregates, recruits CD79 a and CD79 β and migrates to lipid rafts, binding to the dense LYN kinase (SRC family kinase members) on the lipid rafts, which phosphorylates CD79 a/β heterodimers, resulting in recruitment and phosphorylation of spleen tyrosine kinase (spleen tyrosine kinase, SYK). The activated SYK and LYN further phosphorylate the immunoreceptor tyrosine activation motif (immunoreceptor tyrosine-based activationmotifs, ITAMs), leading to activation of downstream BTK and phosphoinositide 3-kinase (PI 3K). Upon activation of BTK, downstream phosphophospholipase cγ2 (plcγ2) is activated, further amplifying BCR signal. These BCR signaling pathway early events trigger downstream signaling pathway molecular activation, thereby activating downstream related kinases and signaling pathways, leading to related factor-mediated transcriptional activation, ultimately promoting a range of cell physiological activities including integrin activation, chemokine-mediated cell migration, and B-cell proliferation, differentiation, apoptosis, etc.
Disclosure of Invention
The invention aims to provide a deuterated condensed heterocyclic compound, a preparation method and application thereof, and the deuterated condensed heterocyclic compound provided by the invention has a very good inhibition effect on BTK, can be used for preparing a BTK inhibitor and is applied to the treatment of various B cell malignant tumors.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative, which has a structure shown in a formula I or a formula II:
the invention provides a preparation method of deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives, which comprises the following steps:
(a) Mixing a structural compound shown in a formula III, a structural compound shown in a formula IV, potassium phosphate, cuprous iodide and N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) glyoxalic amide in an organic solvent, and carrying out substitution reaction to obtain the structural compound shown in the formula V;
(b) Carrying out hydrolysis reaction on a structural compound shown in a formula V and alkali in a mixed solvent of water and alcohol to obtain a structural compound shown in a formula VI;
(c) Mixing a structural compound shown in a formula VI, malononitrile, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole in an organic solvent for reaction to obtain a structural compound shown in a formula VII;
(d) Mixing a structural compound shown in a formula VII with trimethyl orthoformate in an organic solvent, and performing methylation reaction to obtain the structural compound shown in the formula VIII;
(e) Mixing a structural compound shown in a formula VIII with hydrazine hydrate in an organic solvent, and performing a ring closure reaction to obtain a structural compound shown in a formula IX;
(f) Mixing a structural compound shown in a formula X with N, N-dimethylformamide dimethyl acetal in an organic solvent, and performing addition elimination reaction to obtain a structural compound shown in a formula I-1; step (f) is not time sequential with any one of steps (a) - (e);
(g) Mixing a structural compound shown in a formula IX, a structural compound shown in a formula I-1 and acid in an organic solvent, and performing cyclization reaction to obtain a structural compound shown in a formula I-2;
(h) In hydrogen atmosphere, mixing a structural compound shown in a formula I-2 with a catalyst in an organic solvent, and carrying out reduction reaction to obtain a structural compound shown in a formula I-3;
(i) Mixing a structural compound shown in a formula I-3 with an organic solution of hydrogen chloride, and carrying out deamination protecting group reaction to obtain deamination protecting group reaction solution; alkalizing the deamination protecting group reaction solution by adding alkali to obtain a compound with a structure shown in a formula I-4;
(j) Mixing a structural compound shown in a formula I-4 with D- (+) -dibenzoyl tartaric acid in an organic solvent, and carrying out chiral resolution to obtain a structural compound shown in a formula I-5;
(k) Mixing a structural compound shown in a formula I-5 with methanesulfonic acid, and carrying out ammonolysis reaction to obtain a structural compound shown in a formula I-6;
(l) Mixing a structural compound shown in a formula I-6 with acryloyl chloride in an organic solvent, and performing an amide condensation reaction to obtain a deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in the formula I;
(m) mixing a structural compound shown in a formula I-6 with perdeuterated acrylic acid in an organic solvent to perform an amide condensation reaction to obtain a deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in a formula II;
Preferably, in step (a): the mol ratio of the structural compound shown in the formula III to the structural compound shown in the formula IV to the potassium phosphate to the cuprous iodide to the N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) glyoxalic amide is 1 (1.0-1.2): 1.0-1.5): 0.3-1.2: (1.0-1.2); the temperature of the substitution reaction is 25-90 ℃ and the time is 5-10 h;
in step (b): the mol ratio of the structural compound shown in the formula V to the alkali is 1 (1.0-10); the temperature of the hydrolysis reaction is 25-100 ℃ and the time is 2-10 h.
Preferably, in step (c): the mol ratio of the structural compound shown in the formula VI, malononitrile, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole is 1 (1.0-1.2): 1.0-1.5): 1.0-2; the reaction temperature is 0-60 ℃ and the reaction time is 3-5 h;
in step (d): the mol ratio of the structural compound shown in the formula VII to trimethyl orthoformate is 1 (0.5-1.5); the temperature of the methylation reaction is 0-60 ℃ and the time is 3-5 h.
Preferably, in step (e): the mol ratio of the structural compound shown in the formula VIII to the hydrazine hydrate is 1 (1.5-2.0); the temperature of the ring closing reaction is 0-80 ℃ and the time is 3-5 h;
in step (f): the mol ratio of the structural compound shown in the formula X to the N, N-dimethylformamide dimethyl acetal is 1 (1.0-200); the temperature of the addition elimination reaction is 0-130 ℃ and the time is 4-5 h.
Preferably, in step (g): the mol ratio of the structural compound shown in the formula IX, the structural compound shown in the formula I-1 and the acid is 1 (1.0-1.3): 1.0-10; the temperature of the cyclization reaction is 0-130 ℃ and the time is 2-5 h;
in step (h): the catalyst is palladium carbon or Raney nickel; the mol ratio of the structural compound shown in the formula I-2 to the catalyst is 1 (0.3-1.3); the temperature of the reduction reaction is 0-130 ℃ and the time is 2-5 h.
Preferably, in step (i): the mol ratio of the structural compound shown in the formula I-3 to the hydrogen chloride to the alkali is 1 (1.0-100): 1.0-1.2; the reaction temperature of the deamination protecting group is 0-60 ℃ and the reaction time is 2-10 h;
in step (j): the mol ratio of the structural compound shown in the formula I-4 to the D- (+) -dibenzoyl tartaric acid is 1 (1.0-1.2); the chiral resolution temperature is 0-60 ℃ and the chiral resolution time is 2-10 h.
Preferably, in step (k): the mol ratio of the structural compound shown in the formula I-5 to the methylsulfonic acid is 1 (1.0-100); the ammonolysis reaction is carried out at the temperature of 0-120 ℃ for 2-10 h;
in step (l): the mol ratio of the structural compound shown in the formula I-6 to the acryloyl chloride is 1 (1.0-1.5); the temperature of the amide condensation reaction is 0-60 ℃ and the time is 2-5 h;
In step (m): the mol ratio of the structural compound shown in the formula I-6 to the total deuterated acrylic acid is 1 (1.0-1.5); the temperature of the amide condensation reaction is 0-60 ℃ and the time is 2-5 h.
The invention provides application of deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives or deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives prepared by the preparation method described in the technical scheme in preparation of BTK inhibitors.
The invention provides application of deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives or deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives prepared by the preparation method of the technical scheme and pharmaceutically acceptable salts thereof in preparation of medicines for treating chronic lymphocytic leukemia or medicines for treating mantle cell lymphoma.
The invention provides a deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative, which has a structure shown in a formula I or a formula II. The deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with the structure shown in the formula I or the formula II provided by the invention has the advantages that alkenyl can be irreversibly combined with cysteine 481 (C481) of a BTK active site through a covalent bond, so that autophosphorylation of Y223 is inhibited to prevent complete activation of BTK, and downstream signals are inhibited, so that the derivative has a very good inhibition effect on BTK, can be used for preparing BTK inhibitors, and plays an important role in generation and development of various B cell malignant tumors.
Drawings
FIG. 1 is a synthetic scheme of deuterated (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives provided in an embodiment of the invention.
Detailed Description
The invention provides a deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative, which has a structure shown in a formula I or a formula II:
The invention provides a preparation method of deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives, which comprises the following steps:
(a) Mixing a structural compound shown in a formula III, a structural compound shown in a formula IV, potassium phosphate, cuprous iodide and N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) glyoxalic amide in an organic solvent, and carrying out substitution reaction to obtain the structural compound shown in the formula V;
(b) Carrying out hydrolysis reaction on a structural compound shown in a formula V and alkali in a mixed solvent of water and alcohol to obtain a structural compound shown in a formula VI;
(c) Mixing a structural compound shown in a formula VI, malononitrile, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole in an organic solvent for reaction to obtain a structural compound shown in a formula VII;
(d) Mixing a structural compound shown in a formula VII with trimethyl orthoformate in an organic solvent, and performing methylation reaction to obtain the structural compound shown in the formula VIII;
(e) Mixing a structural compound shown in a formula VIII with hydrazine hydrate in an organic solvent, and performing a ring closure reaction to obtain a structural compound shown in a formula IX;
(f) Mixing a structural compound shown in a formula X with N, N-dimethylformamide dimethyl acetal in an organic solvent, and performing addition elimination reaction to obtain a structural compound shown in a formula I-1; step (f) is not time sequential with any one of steps (a) - (e);
(g) Mixing a structural compound shown in a formula IX, a structural compound shown in a formula I-1 and acid in an organic solvent, and performing cyclization reaction to obtain a structural compound shown in a formula I-2;
(h) In hydrogen atmosphere, mixing a compound with a structure shown in a formula I-2 with a catalyst in an organic solvent, and carrying out reduction reaction to obtain a compound with a structure shown in a formula I-3;
(i) Mixing a structural compound shown in a formula I-3 with an organic solution of hydrogen chloride, and carrying out deamination protecting group reaction to obtain deamination protecting group reaction solution; alkalizing the deamination protecting group reaction solution by adding alkali to obtain a compound with a structure shown in a formula I-4;
(j) Mixing a structural compound shown in a formula I-4 with D- (+) -dibenzoyl tartaric acid in an organic solvent, and carrying out chiral resolution to obtain a structural compound shown in a formula I-5;
(k) Mixing a structural compound shown in a formula I-5 with methanesulfonic acid, and carrying out ammonolysis reaction to obtain a structural compound shown in a formula I-6;
(l) Mixing a structural compound shown in a formula I-6 with acryloyl chloride in an organic solvent, and performing an amide condensation reaction to obtain a deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in the formula I;
(m) mixing a structural compound shown in a formula I-6 with full deuterated acrylic acid in an organic solvent to perform an amide condensation reaction to obtain deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in a formula II;
in the present invention, all preparation materials/components are commercially available products well known to those skilled in the art unless specified otherwise.
The invention mixes the structural compound shown in the formula III, the structural compound shown in the formula IV, potassium phosphate, cuprous iodide and N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) oxalamide in an organic solvent (hereinafter referred to as a first organic solvent) for substitution reaction to obtain the structural compound shown in the formula V. In the present invention, the first organic solvent is preferably N, N-Dimethylformamide (DMF) and/or Tetrahydrofuran (THF), more preferably N, N-dimethylformamide. The molar ratio of the structural compound of formula III, the structural compound of formula IV, potassium phosphate, cuprous iodide and N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) oxalamide is preferably 1 (1.0-1.2): 1.0-1.5): 0.3-1.2: (1.0-1.2), more preferably 1:1:1:0.5:1 or 1:1.2:1.2:1:1. The invention has no special requirement on the dosage of the first organic solvent, and ensures that the substitution reaction is carried out smoothly. The temperature of the substitution reaction is preferably 25 to 90 ℃, more preferably 90 ℃; the time is preferably 5 to 10 hours, more preferably 8 hours. After the substitution reaction is finished, a substitution reaction liquid is obtained, and the substitution reaction liquid is preferably diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and organic phases are combined, dried and concentrated in sequence to obtain a concentrated reaction liquid; and (3) purifying the concentrated reaction liquid by column chromatography to obtain the compound with the structure shown in the formula V. The number of extractions is preferably 3. The eluent used for the column chromatography purification is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 6:1.
After the structural compound shown in the formula V is obtained, the structural compound shown in the formula V and alkali are subjected to hydrolysis reaction in a mixed solvent of water and alcohol to obtain the structural compound shown in the formula VI. In the present invention, the base is preferably sodium hydroxide. The alcohol is preferably ethanol. The molar ratio of the structural compound of formula V to the base is preferably 1 (1.0 to 10), more preferably 1:10. The invention has no special requirement on the dosage of the mixed solvent of water and alcohol, and ensures that the structural compound shown in the formula V and alkali are completely dissolved and the hydrolysis reaction is smoothly carried out. The temperature of the hydrolysis reaction is preferably 25 to 100 ℃, more preferably 100 ℃; the time is preferably 2 to 10 hours. The hydrolysis reaction is carried out under reflux. After the hydrolysis reaction is finished, obtaining hydrolysis reaction liquid, preferably mixing the hydrolysis reaction liquid with acid to adjust the pH value of the mixed reaction liquid to 3-4, and obtaining acid reaction liquid; the acidic reaction solution is extracted by ethyl acetate, and the organic phases are combined, dried and concentrated in sequence to obtain the structural compound shown in the formula VI. The number of extractions is preferably 3.
After obtaining the structural compound represented by formula VI, the present invention mixes the structural compound represented by formula VI, malononitrile, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT) in an organic solvent (hereinafter referred to as a second organic solvent) and reacts to obtain the structural compound represented by formula VII. In the present invention, the second organic solvent is preferably N, N-Dimethylformamide (DMF), tetrahydrofuran (THF) or Dichloromethane (DCM), more preferably N, N-dimethylformamide. The molar ratio of the structural compound of formula VI, malononitrile, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably 1 (1.0-1.2): 1.0-1.5): 1.0-2, more preferably 1:1.0:1.0:1.0 or 1:1.2:1.3:1.1. The invention has no special requirement on the dosage of the second organic solvent, and ensures that the reaction is carried out smoothly. The temperature of the reaction is preferably 0 to 60 ℃, more preferably room temperature; the time is preferably 3 to 5 hours. And after the reaction is finished, obtaining a reaction liquid. In the invention, the reaction liquid is preferably diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and the organic phases are combined and then dried and concentrated in sequence to obtain a concentrated reaction liquid; and (3) purifying the concentrated reaction liquid by column chromatography to obtain the compound with the structure shown in the formula VII. The number of extractions is preferably 3. The eluent used for the column chromatography purification is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 2:1.
After obtaining the compound having the structure represented by formula VII, the present invention mixes the compound having the structure represented by formula VII with trimethyl orthoformate in an organic solvent (hereinafter referred to as a third organic solvent) to perform a methylation reaction, thereby obtaining the compound having the structure represented by formula VIII. In the present invention, the third organic solvent is preferably N, N-Dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM) or acetonitrile, more preferably acetonitrile. The molar ratio of the structural compound of formula VII to trimethyl orthoformate is preferably 1 (0.5 to 1.5), more preferably 1:1.0. The invention has no special requirement on the dosage of the third organic solvent, and ensures that the methylation reaction is smoothly carried out. The temperature of the methylation reaction is preferably 0-60 ℃, more preferably room temperature; the time is preferably 3 to 5 hours. And after the methylation reaction is finished, a methylation reaction liquid is obtained. In the invention, the methylation reaction liquid is preferably diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and the organic phases are combined and then dried and concentrated in sequence to obtain a concentrated reaction liquid; and (3) purifying the concentrated reaction liquid by column chromatography to obtain the compound with the structure shown in the formula VIII. The number of extractions is preferably 3. The eluent used for the column chromatography purification is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 4:1.
After the compound having the structure represented by formula VIII is obtained, the present invention mixes the compound having the structure represented by formula VIII with hydrazine hydrate in an organic solvent (hereinafter referred to as a fourth organic solvent) to perform a ring-closure reaction to obtain the compound having the structure represented by formula IX. In the present invention, the fourth organic solvent is preferably ethanol or methanol, more preferably ethanol. The molar ratio of the structural compound of formula VIII to hydrazine hydrate is preferably 1 (1.5 to 2.0), more preferably 1:2.0. The temperature of the ring closure reaction is preferably 0-80 ℃, more preferably room temperature; the time is preferably 3 to 5 hours, more preferably 4 hours. The ring closure reaction is preferably carried out under reflux conditions. And after the ring closing reaction is finished, obtaining a ring closing reaction liquid. In the invention, the ring-closing reaction liquid is preferably diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and the organic phases are combined, dried and concentrated in sequence to obtain the structural compound shown in the formula IX. The number of extractions is preferably 3.
The invention mixes the structural compound shown in the formula X and N, N-dimethylformamide dimethyl acetal (DMF-DMA) in an organic solvent (hereinafter referred to as a fifth organic solvent) to carry out addition elimination reaction, thus obtaining the structural compound shown in the formula I-1. In the present invention, the fifth organic solvent is preferably dichloromethane or tetrahydrofuran or acetonitrile, more preferably dichloromethane. The molar ratio of the structural compound of formula X to DMF-DMA is preferably 1 (1.0-200), more preferably 1:200. The invention has no special requirement on the dosage of the fifth organic solvent, and ensures that the addition elimination reaction is smoothly carried out. The temperature of the addition elimination reaction is preferably 0 to 130 ℃, more preferably room temperature; the time is preferably 4 to 5 hours. And after the addition elimination reaction is finished, obtaining an addition elimination reaction liquid. In the invention, the addition elimination reaction liquid is preferably diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and the organic phases are combined and then dried and concentrated in sequence to obtain the structural compound shown in the formula I-1. The number of extractions is preferably 3.
After obtaining the structural compound represented by formula IX and the structural compound represented by formula I-1, the present invention mixes the structural compound represented by formula IX, the structural compound represented by formula I-1 and an acid in an organic solvent (hereinafter referred to as a sixth organic solvent) to perform a cyclization reaction to obtain the structural compound represented by formula I-2. In the present invention, the sixth organic solvent is preferably benzene or xylene, more preferably xylene. The acid is preferably acetic acid, hydrochloric acid (HCl) or sulfuric acid (H) 2 SO 4 ). The acid is preferably hydrochloric acid (HCl) or sulfuric acid (H) 2 SO 4 ) When the present invention is used preferably in the form of an aqueous acid solution, the concentration of the aqueous acid solution is not particularly limited. The molar ratio of the structural compound shown in the formula IX, the structural compound shown in the formula I-1 and the acid is 1 (1.0-1.3): (1.0-10), and more preferably 1:1.3:10. The invention has no special requirement on the dosage of the sixth organic solvent, and ensures that the cyclization reaction is carried out smoothly. The temperature of the cyclization reaction is preferably 0 to 130 ℃, more preferably 100 ℃; the time is preferably 2 to 5 hours. After the cyclization reaction is completed, a cyclization reaction liquid is obtained. In the invention, the cyclization reaction liquid is preferably diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and the organic phases are combined and then dried and concentrated in sequence to obtain a concentrated reaction liquid; purifying the concentrated reaction liquid by column chromatography to obtain the compound with the structure shown in the formula I-2. The number of extractions is preferably 3. The eluent used for the column chromatography purification is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 4:1.
After obtaining the compound with the structure shown in the formula I-2, the invention mixes the compound with the structure shown in the formula I-2 and the catalyst in an organic solvent (hereinafter referred to as a seventh organic solvent) in hydrogen atmosphere, and carries out reduction reaction to obtain the compound with the structure shown in the formula I-3. In the present invention, the seventh organic solvent is preferably methanol or ethanol, more preferably methanol. The catalyst is preferably palladium carbon or Raney nickel. The molar ratio of the structural compound of formula I-2 to the catalyst is preferably 1 (0.3 to 1.3), more preferably 1:0.8. The temperature of the reduction reaction is preferably 0 to 130 ℃ and the time is preferably 2 to 5 hours. The reduction reaction is carried out under reflux conditions. And obtaining a reduction reaction liquid after the reduction reaction is finished. The reduction reaction liquid is preferably filtered by diatomite, and the obtained filtrate is pressurized and concentrated to obtain a concentrated reaction liquid; purifying the concentrated reaction liquid by column chromatography to obtain the compound with the structure shown in the formula I-3. The eluent used for the column chromatography purification is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 3:1.
After obtaining a structural compound shown in a formula I-3, mixing the structural compound shown in the formula I-3 with an organic solution of hydrogen chloride, and carrying out deamination protecting group reaction to obtain deamination protecting group reaction solution; alkalizing the deamination protecting group reaction liquid by adding alkali to obtain the compound with the structure shown in the formula I-4. In the present invention, the organic solution of hydrogen chloride is preferably an ethyl acetate solution of hydrogen chloride, a dioxane solution of hydrogen chloride or a dichloromethane solution of hydrogen chloride, more preferably a dioxane solution of hydrogen chloride. The base is preferably sodium hydroxide. The molar ratio of the structural compound of the formula I-3, hydrogen chloride and base is preferably 1 (1.0 to 100): (1.0 to 1.2), more preferably 1:100:1. The invention has no special requirement on the dosage of the organic solvent in the organic solution of hydrogen chloride. The temperature of the deamination protecting group reaction is preferably 0 to 60 ℃, and the time is preferably 2 to 10 hours, more preferably 5 hours. Before the alkalization, the present invention preferably concentrates the obtained deamination protecting group reaction solution, and the obtained concentrated solution is alkalized by adding alkali. And after the alkalization is finished, obtaining an alkalization reaction liquid. The alkalization reaction liquid is preferably extracted by ethyl acetate, and the organic phases are combined and then dried and concentrated in sequence to obtain the structural compound shown in the formula I-4. The number of extractions is preferably 3.
After the structural compound shown in the formula I-4 is obtained, the structural compound shown in the formula I-4 and D- (+) -dibenzoyl tartaric acid are mixed in an organic solvent (hereinafter referred to as an eighth organic solvent) and chiral resolution is carried out, so that the structural compound shown in the formula I-5 is obtained. In the present invention, the eighth organic solvent is preferably methanol, or a mixed solution of ethanol, water and acetic acid, or trifluoroacetic acid, and in a specific embodiment of the present invention, the eighth organic solvent is preferably a mixed solution of ethanol, water and acetic acid. The invention optimizes the special requirement on the volume ratio of the ethanol, the water and the acetic acid in the mixed solution of the ethanol, the water and the acetic acid, and ensures that the structural compound shown in the formula I-4 and the D- (+) -dibenzoyl tartaric acid are completely dissolved. The molar ratio of the structural compound of formula I-4 to D- (+) -dibenzoyltartaric acid is preferably 1 (1.0 to 1.2), more preferably 1:1.2. The invention has no special requirement on the dosage of the eighth organic solvent, and ensures that the chiral resolution is smoothly carried out. The temperature of the chiral resolution is preferably 0-60 ℃, and the time is preferably 2-10 h, more preferably 5h. In the invention, the chiral resolution reaction liquid is obtained by chiral resolution, preferably, the chiral resolution reaction liquid is concentrated into supersaturated solution, the supersaturated solution is mixed with the structural compound seed crystal shown in the formula I-5, and then the structural compound shown in the formula I-5 is cooled and crystallized from the initial temperature to the final temperature, and is obtained by solid-liquid separation. The structural compound shown in the formula I-5 is an optically pure levorotatory compound. The temperature of the concentration was 60 ℃. The initial temperature is preferably 60 ℃, the final temperature is preferably 40 ℃, and the cooling rate of the cooling crystallization is preferably 1.67 ℃/h.
After the structural compound shown in the formula I-5 is obtained, the structural compound shown in the formula I-5 is mixed with methanesulfonic acid, and ammonolysis reaction is carried out to obtain the structural compound shown in the formula I-6. In the present invention, the molar ratio of the structural compound represented by the formula I-5 to methanesulfonic acid is preferably 1 (1.0 to 100), more preferably 1:100. The temperature of the ammonolysis reaction is preferably 0-120 ℃, more preferably room temperature; the time is preferably 2 to 10 hours. And obtaining an ammonolysis reaction liquid after the ammonolysis reaction is finished. The invention preferably dilutes the ammonolysis reaction liquid by water to obtain diluted reaction liquid, extracts the diluted reaction liquid by ethyl acetate, combines organic phases, and sequentially dries and concentrates to obtain the structural compound shown in the formula I-6. The number of extractions is preferably 3.
After obtaining the structural compound shown in the formula I-6, the structural compound shown in the formula I-6 and the acryloyl chloride are mixed in an organic solvent (hereinafter referred to as a ninth organic solvent) to perform an amide condensation reaction to obtain the deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with the structure shown in the formula I. In the present invention, the ninth organic solvent is preferably methylene chloride, acetonitrile, tetrahydrofuran, anhydrous dioxane or toluene, more preferably methylene chloride. The molar ratio of the structural compound of formula I-6 to the acryloyl chloride is 1 (1.0 to 1.5), more preferably 1:1.3. The temperature of the amide condensation reaction is 0-60 ℃, and the time is preferably 2-5 h. And (3) obtaining an amide condensation liquid after the amide condensation is finished. In the invention, preferably, the amide condensation liquid is diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and the organic phases are combined and then dried and concentrated in sequence to obtain a concentrated reaction liquid; the concentrated reaction liquid is purified by column chromatography to obtain deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in a formula I. The number of extractions is preferably 3. The eluent used for the column chromatography purification is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 2:1.
After obtaining the structural compound shown in the formula I-6, the structural compound shown in the formula I-6 and the perdeuterated acrylic acid are mixed in an organic solvent (hereinafter referred to as tenth organic solvent) to perform an amide condensation reaction to obtain the deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with the structure shown in the formula II. In the present invention, the tenth organic solvent is preferably thionyl chloride and an eleventh organic solvent; the eleventh organic solvent is preferably dichloromethane, acetonitrile, tetrahydrofuran, anhydrous dioxane or toluene, more preferably dichloromethane. The molar ratio of the structural compound of formula I-6 to the perdeuterated acrylic acid is preferably 1 (1.0 to 1.5), more preferably 1:1.2. The molar ratio of the structural compound of formula I-6 to thionyl chloride is preferably 1 (1.0 to 5.0), more preferably 1:2.0. The temperature of the amide condensation reaction is preferably 0 to 60 ℃ and the time is preferably 2 to 5 hours. And (3) obtaining an amide condensation liquid after the amide condensation is finished. In the invention, preferably, the amide condensation liquid is diluted by adding water, the obtained diluted reaction liquid is extracted by ethyl acetate, and the organic phases are combined and then dried and concentrated in sequence to obtain a concentrated reaction liquid; the concentrated reaction liquid is purified by column chromatography to obtain deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in a formula II. The number of extractions is preferably 3. The eluent used for the column chromatography purification is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 2:1.
The invention provides application of deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives or deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives prepared by the preparation method in the technical scheme and pharmaceutically acceptable salts thereof in preparation of Btk inhibitors.
The invention provides application of deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives or deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives prepared by the preparation method of the technical scheme and pharmaceutically acceptable salts thereof in preparation of medicines for treating chronic lymphocytic leukemia or medicines for treating mantle cell lymphoma.
The technical solutions provided by the present invention are described in detail below in conjunction with examples for further illustrating the present invention, but they should not be construed as limiting the scope of the present invention.
The following examples were prepared according to the synthetic scheme of fig. 1.
Example 1
(a) Deuterated phenol (100 mg,1 mmol) methyl p-bromobenzoate (compound of the structure shown in formula III, 258mg,1.2 mmol), potassium phosphate (254 mg,1.2 mmol), cuprous iodide (190 mg,1 mmol), N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) ethanediamide (390 mg,1 mmol) were added to N, N-dimethylformamide (20 mL), reacted at 90℃for 8 hours, 60mL of water was added, extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried, concentrated, and the residue was purified by column chromatography with an eluent of petroleum ether and ethyl acetate in a volume ratio of petroleum ether to ethyl acetate of 6:1, to give the compound of the structure shown in formula V.
(b) The compound of formula V (233 mg,1 mmol) and sodium hydroxide (40 mg,10 mmol) were added to a mixed solvent of water and ethanol (10 mL) and refluxed for 2 hours, diluted hydrochloric acid was added to adjust pH to 3.5.+ -. 0.5, ethyl acetate (30 mL. Times.3) was added to extract, and the organic phases were combined, dried and concentrated to give the compound of formula VI.
(c) The structural compound (219 mg,1 mmol) represented by formula VI was reacted with malononitrile (80 mg,1.2 mmol), EDCI (248 mg,1.3 mmol), HOBT (148 mg,1.1 mmol) in DMF at room temperature for 5 hours, 60mL of water was added, followed by extraction with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried, concentrated, and the residue was purified by column chromatography with an eluent of petroleum ether and ethyl acetate in a volume ratio of petroleum ether and ethyl acetate of 2:1 to give the structural compound represented by formula VII.
(d) The structural compound (281mg, 1 mmol) shown in formula VII and trimethyl orthoformate (106 mg,1 mmol) are added into acetonitrile (5 mL), the mixture is reacted for 3 hours at room temperature, 20mL of water is added, then ethyl acetate (30 mL multiplied by 3) is used for extraction, the organic phases are combined, dried and concentrated, the residue is purified by column chromatography, and the volume ratio of petroleum ether to ethyl acetate is 4:1, so that the structural compound shown in formula VIII is obtained.
(e) The structural compound of formula VIII (295 mg,1 mmol) and hydrazine hydrate (100 mg,2 mmol) were added to ethanol and refluxed for 4 hours. 20mL of water was added, followed by extraction with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried, and concentrated to give the structural compound of formula IX.
(f) The structural compound (227 mg,1 mmol) represented by formula X was reacted with DMF-DMA (23800 mg,200 mmol) in dichloromethane (5 mL), at room temperature for 4 hours, 10mL of water was added, followed by extraction with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried, and concentrated to give the structural compound represented by formula I-1.
(g) The structural compound (281mg, 1 mmol) shown in the formula IX, the structural compound (365 mg,1.3 mmol) shown in the formula I-1 and acetic acid (600 mg,10 mmol) are added into xylene 20mL, the reaction is carried out for 2 hours at 100 ℃, water 20mL is added, then ethyl acetate (30 mL multiplied by 3) is used for extraction, the organic phases are combined, dried and concentrated, the residue is purified by column chromatography, eluent is petroleum ether and ethyl acetate, the volume ratio of petroleum ether and ethyl acetate is 4:1, and the structural compound shown in the formula I-2 is obtained.
(h) Refluxing the structural compound (500 mg,1 mmol) shown in the formula I-2 and palladium carbon (85 mg,0.8 mmol) in methanol for 3 hours in a hydrogen atmosphere, filtering by diatomite, concentrating the filtrate under reduced pressure, purifying the residue by column chromatography, wherein the eluent is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 3:1, so as to obtain the structural compound shown in the formula I-3.
(i) The compound (504 mg,1 mmol) of the structure shown in the formula I-3 is added into dioxane solution of hydrogen chloride, the reaction is carried out for 5 hours at room temperature, the concentration is reduced pressure, the aqueous solution of sodium hydroxide (1 mmol) is added for alkalinity adjustment, the ethyl acetate (30 mL multiplied by 3) is used for extraction, the organic phases are combined, and the drying and the concentration are carried out, thus obtaining the compound of the structure shown in the formula I-4.
(j) Reacting a structural compound (404 mg,1 mmol) shown in I-4 with D- (+) -dibenzoyltartaric acid (430 mg,1.2 mmol) in a mixed solvent of ethanol, water and acetic acid for 5 hours at a temperature of 60 ℃ to obtain chiral resolution reaction liquid, concentrating the chiral resolution reaction liquid at 60 ℃ to obtain supersaturated solution, adding a structural compound (L-rotation) seed crystal shown in the formula I-5 into the supersaturated solution, slowly cooling to 40 ℃ for 12 hours from the initial temperature of 60 ℃ for crystallization, and rapidly separating to obtain the structural compound shown in the formula I-5.
(k) The structural compound (404 mg,1 mmol) represented by I-5 was added to 6.5mL of methanesulfonic acid, reacted at room temperature for 10 hours, added with 30mL of water, extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, dried and concentrated to obtain the structural compound represented by formula I-6.
(l) The structural compound (422 mg,1 mmol) shown in formula I-6 and acryloyl chloride (117 mg,1.3 mmol) are added into dichloromethane to react for 5 hours at room temperature, 20mL of water is added, then ethyl acetate (30 mL multiplied by 3) is used for extraction, the organic phases are combined, dried and concentrated, the residue is purified by column chromatography, and the eluent is petroleum ether and ethyl acetate with the volume ratio of petroleum ether to ethyl acetate being 2:1, so as to obtain deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative shown in formula I.
1 H NMR(400MHz,DMSO-d6)δ7.50(d,J＝8.8Hz,2H),7.46-7.38(m,2H),7.17(t,J＝7.6Hz,1H),7.08(d,J＝7.6Hz,2H),7.05(d,J＝8.8Hz,2H),6.83-6.76(m,1H),6.68(br s,1H),6.07(d,J＝18.4Hz,1H),5.64(d,J＝10.4Hz,1H),4.52-4.42(m,1H),4.11-3.98(m,2H),3.33-3.24(m,2H),3.04-2.94(m,1H),2.67-2.55(m,1H),2.33-2.25(m,1H),2.01-1.93(m,2H),1.78-1.66(m,1H),1.61-1.50(m,1H),1.30-1.18(m,2H).
Example 2
The preparation method of example 1 was followed to obtain a compound of the structure shown in formula I-6.
(m) the structural compound (422 mg,1 mmol) of formula I-6, total deuterated acrylic acid (86 mg,1.2 mmol) and thionyl chloride (236 mg,2 mmol) were added to dichloromethane and reacted at room temperature for 5 hours, 20mL of water was added, followed by extraction with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried, concentrated and the residue was purified by column chromatography, eluting with petroleum ether and ethyl acetate in a volume ratio of petroleum ether to ethyl acetate of 2:1 to give deuterated (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative of formula II.
1 H NMR(400MHz,DMSO-d6)δ7.50(d,J＝8.8Hz,2H),7.46-7.38(m,2H),7.17(t,J＝7.6Hz,1H),7.08(d,J＝7.6Hz,2H),7.05(d,J＝8.8Hz,2H),6.83-6.76(m,1H),6.68(br s,1H),6.07(d,J＝18.4Hz,1H),5.64(d,J＝10.4Hz,1H),4.52-4.42(m,1H),4.11-3.98(m,2H),3.33-3.24(m,2H),3.04-2.94(m,1H),2.67-2.55(m,1H),2.33-2.25(m,1H),2.01-1.93(m,2H),1.78-1.66(m,1H),1.61-1.50(m,1H),1.30-1.18(m,2H).
Test case
(1) BTK biochemical assay.
Recombinant BTK and Compound at room temperature in 50mM Tris pH 7.4, 10mM MgCl 2 ，2mM MnCl 2 The incubation was performed in the assay buffer of 0.1mM EDTA,1mM DTT,20nM SEB,0.1%BSA,0.005%tween-20 for 1 hour. The reaction consists of ATP (ATP Km concentration) and peptide substrate (BiotinAVLESEEELYSSARQ-NH 2 ) Is initiated by the addition of (3). After 1 hour incubation at room temperature, an equal volume of stop solution containing 50mM HEPES pH 7.0, 800mM KF,20mM EDTA,0.1%BSA,Eu-cryptconjugated p-Tyr66 anti and streptavidine-labed XL665 was added. Incubation was further performed for 1 hour at room temperature, and then the TR-FRET signal was read on a BMG PHERAstarFS instrument.
(2) BTKpY223 cell assay
With 1mM of Pervanadate (PV) or Na 3 VO 4 (OV) cells were stimulated for 20 min and then lysed. mu.L of each cell lysate was mixed with 2. Mu.L of a 1-fold antibody mixture prepared by diluting anti-btk-d 2 and anti-pbtk in the detection buffer. After gentle mixing and brief rotation, the dishes were sealed and stored overnight in the dark. Fluorescence emissions at two different wavelengths (665 nm and 620 nm) were measured on compatible HTRF readers (PHERAstar FS, BMG). The potency of the compounds was calculated from the inhibition ratio between 665nm and 620nm signal intensities.
(3) Rec1 cell viability assay
Measurement of growth inhibitory Activity of IDE Compounds in Rec-1 cells using CellTiter-Glo fluorescent cell viability assay (Promega) example 1 and example 2. Cells are treated with an increasing concentration of the compound. After 6 days of exposure to the compound, addCell titer-glo reagent was added in a volume equal to the volume of cell culture medium per well. The mixture was mixed on an orbital shaker for 2 minutes to lyse the cells, then incubated for 10 minutes to allow a luminescent signal to form and stabilize, which corresponds to the amount of ATP and thus the number of metabolically active cells. Luminescence signals were measured using a PHERAstar FS reader (BMG Labtech). IC for determining cell viability using GraphPad Prism software 50 Values.
BTK (IC) in table 1 50 nM) is the result of the BTK biochemical assay of test (1), BTK pY223 (IC) in Table 1 50 nM) is the result of the BTK pY223 cell assay in test (2), rec-1 cell Viability (IC) in Table 1 50 nM) is the result of the Rec1 cell viability assay in test (3).
Table 1 kinase activity and cell viability of examples 1 and 2
| Compounds of formula (I) | BTK(IC 50 ,nM) | BTK pY223(IC 50 ,nM) | Rec-1 cell Viability(IC 50 ,nM) |
| Example 1 | 0.4 | 2.0 | 0.33 |
| Example 2 | 0.3 | 1.7 | 0.30 |
As can be seen from table 1: the compounds prepared in example 1 and the compounds prepared in example 2 have good inhibitory activity against BTK and BTK pY223 at the molecular level, and at the same time, the compounds prepared in example 1 and the compounds prepared in example 2 have good inhibitory activity against Rec-1 tumor cells at the cellular level. Thus, it was confirmed that the compound prepared in example 1 and the compound prepared in example 2 of the present invention can be used for preparing drugs against mantle cell lymphoma.
(4) Pharmacokinetic testing in animals
Preliminary pharmacokinetic studies (as shown in Table 2) were performed in SD rats with the compound of example 1 (25 mg/kg, lavage; 100mg/kg, lavage) and the compound of example 2 (25 mg/kg, lavage; 100mg/kg, lavage), respectively. And plasma samples (n=3 for each group) were collected at 5min, 10min, 15min, 30min, 60min, 90min, 120min, 4h, 6h, 12h, 24h, 36h, 48h, and their pharmacokinetic profile was evaluated.
Table 2 pharmacokinetic parameters of the compounds of example 1 and example 2
a D 2 ＝intragastric administration of 25 mg/kg. b D 3 ＝intragastric administration of 100mg/kg.
As can be seen from Table 2, the compounds of example 1 and example 2 have low clearance, long half-life and high bioavailability at doses of 25mg/kg and 100mg/kg, respectively, for oral gavage. Whereas the biological potency F (%) =23.6, t of zebutinib, similar to the present structure 1/2 ＝0.53h(Guo,Yunhang et al.Discovery of Zanubrutinib,a Novel,Potent,and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. Journal of medicinal chemistry vol.62,17 (2019): 7923-7940.) thus demonstrating the superior in vivo pharmacokinetic properties of the compounds prepared in example 1 and example 2 of the present invention.
Although the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments may be obtained according to the present embodiments without departing from the scope of the invention.
Claims (10)
1. A deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative having the structure according to formula I or formula II:
2. the process for the preparation of deuterated (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives according to claim 1, comprising the steps of:
(a) Mixing a structural compound shown in a formula III, a structural compound shown in a formula IV, potassium phosphate, cuprous iodide and N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) glyoxalic amide in an organic solvent, and carrying out substitution reaction to obtain the structural compound shown in the formula V;
(b) Carrying out hydrolysis reaction on a structural compound shown in a formula V and alkali in a mixed solvent of water and alcohol to obtain a structural compound shown in a formula VI;
(c) Mixing a structural compound shown in a formula VI, malononitrile, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole in an organic solvent for reaction to obtain a structural compound shown in a formula VII;
(d) Mixing a structural compound shown in a formula VII with trimethyl orthoformate in an organic solvent, and performing methylation reaction to obtain the structural compound shown in the formula VIII;
(e) Mixing a structural compound shown in a formula VIII with hydrazine hydrate in an organic solvent, and performing a ring closure reaction to obtain a structural compound shown in a formula IX;
(f) Mixing a structural compound shown in a formula X with N, N-dimethylformamide dimethyl acetal in an organic solvent, and performing addition elimination reaction to obtain a structural compound shown in a formula I-1; step (f) is not time sequential with any one of steps (a) - (e);
(g) Mixing a structural compound shown in a formula IX, a structural compound shown in a formula I-1 and acid in an organic solvent, and performing cyclization reaction to obtain a structural compound shown in a formula I-2;
(h) In hydrogen atmosphere, mixing a structural compound shown in a formula I-2 with a catalyst in an organic solvent, and carrying out reduction reaction to obtain a structural compound shown in a formula I-3;
(i) Mixing a structural compound shown in a formula I-3 with an organic solution of hydrogen chloride, and carrying out deamination protecting group reaction to obtain deamination protecting group reaction solution; alkalizing the deamination protecting group reaction solution by adding alkali to obtain a compound with a structure shown in a formula I-4;
(j) Mixing a structural compound shown in a formula I-4 with D- (+) -dibenzoyl tartaric acid in an organic solvent, and carrying out chiral resolution to obtain a structural compound shown in a formula I-5;
(k) Mixing a structural compound shown in a formula I-5 with methanesulfonic acid, and carrying out ammonolysis reaction to obtain a structural compound shown in a formula I-6;
(l) Mixing a structural compound shown in a formula I-6 with acryloyl chloride in an organic solvent, and performing an amide condensation reaction to obtain a deuterated (S) -7- (1-acryloylpiperidine-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in the formula I;
(m) mixing a structural compound shown in a formula I-6 with full deuterated acrylic acid in an organic solvent to perform an amide condensation reaction to obtain deuterated (S) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivative with a structure shown in a formula II;
3. the method of claim 2, wherein in step (a): the mol ratio of the structural compound shown in the formula III to the structural compound shown in the formula IV to the potassium phosphate to the cuprous iodide to the N1, N2 bis ([ 1,1' -biphenyl ] -2-yl) glyoxalic amide is 1 (1.0-1.2): 1.0-1.5): 0.3-1.2: (1.0-1.2); the temperature of the substitution reaction is 25-90 ℃ and the time is 5-10 h;
in step (b): the mol ratio of the structural compound shown in the formula V to the alkali is 1 (1.0-10); the temperature of the hydrolysis reaction is 25-100 ℃ and the time is 2-10 h.
4. The method of claim 2, wherein in step (c): the mol ratio of the structural compound shown in the formula VI, malononitrile, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole is 1 (1.0-1.2): 1.0-1.5): 1.0-2; the reaction temperature is 0-60 ℃ and the reaction time is 3-5 h;
in step (d): the mol ratio of the structural compound shown in the formula VII to trimethyl orthoformate is 1 (0.5-1.5); the temperature of the methylation reaction is 0-60 ℃ and the time is 3-5 h.
5. The method of claim 2, wherein in step (e): the mol ratio of the structural compound shown in the formula VIII to the hydrazine hydrate is 1 (1.5-2.0); the temperature of the ring closing reaction is 0-80 ℃ and the time is 3-5 h;
in step (f): the mol ratio of the structural compound shown in the formula X to the N, N-dimethylformamide dimethyl acetal is 1 (1.0-200); the temperature of the addition elimination reaction is 0-130 ℃ and the time is 4-5 h.
6. The method according to claim 2, wherein in step (g): the mol ratio of the structural compound shown in the formula IX, the structural compound shown in the formula I-1 and the acid is 1 (1.0-1.3): 1.0-10; the temperature of the cyclization reaction is 0-130 ℃ and the time is 2-5 h;
In step (h): the catalyst is palladium carbon or Raney nickel; the mol ratio of the structural compound shown in the formula I-2, the catalyst and the hydrogen is 1 (0.3-1.3); the temperature of the reduction reaction is 0-130 ℃ and the time is 2-5 h.
7. The method of claim 2, wherein in step (i): the mol ratio of the structural compound shown in the formula I-3 to the hydrogen chloride to the alkali is 1 (1.0-100): 1.0-1.2; the reaction temperature of the deamination protecting group is 0-60 ℃ and the reaction time is 2-10 h;
in step (j): the mol ratio of the structural compound shown in the formula I-4 to the D- (+) -dibenzoyl tartaric acid is 1 (1.0-1.2); the chiral resolution temperature is 0-60 ℃ and the chiral resolution time is 2-10 h.
8. The method of claim 2, wherein in step (k): the mol ratio of the structural compound shown in the formula I-5 to the methylsulfonic acid is 1 (1.0-100); the ammonolysis reaction is carried out at the temperature of 0-120 ℃ for 2-10 h;
in step (l): the mol ratio of the structural compound shown in the formula I-6 to the acryloyl chloride is 1 (1.0-1.5); the temperature of the amide condensation reaction is 0-60 ℃ and the time is 2-5 h;
in step (m): the mol ratio of the structural compound shown in the formula I-6 to the total deuterated acrylic acid is 1 (1.0-1.5); the temperature of the amide condensation reaction is 0-60 ℃ and the time is 2-5 h.
9. Use of deuterated (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives as defined in claim 1 or deuterated (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives as defined in any one of claims 2 to 8 and pharmaceutically acceptable salts thereof for the preparation of BTK inhibitors.
10. Use of deuterated (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives as described in claim 1 or deuterated (S) -7- (1-propenylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrimidine-3-carboxamide derivatives as described in any one of claims 2 to 8 as a medicament for the treatment of chronic lymphocytic leukemia or a medicament for the treatment of mantle cell lymphoma as a pharmaceutically acceptable salt thereof.
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