WO2023061319A1 - 三并环杂环衍生物 - Google Patents
三并环杂环衍生物 Download PDFInfo
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- WO2023061319A1 WO2023061319A1 PCT/CN2022/124333 CN2022124333W WO2023061319A1 WO 2023061319 A1 WO2023061319 A1 WO 2023061319A1 CN 2022124333 W CN2022124333 W CN 2022124333W WO 2023061319 A1 WO2023061319 A1 WO 2023061319A1
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- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- independently
- alkyl
- Prior art date
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- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 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 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 claims description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 229940127272 CD73 inhibitor Drugs 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 150000003573 thiols Chemical class 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000003566 oxetanyl group Chemical group 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- XJLITJHUQRBWPN-UHFFFAOYSA-N 2-acetamidoacetic acid;4-[2-(4-carbamimidoylphenyl)iminohydrazinyl]benzenecarboximidamide Chemical compound CC(=O)NCC(O)=O.C1=CC(C(=N)N)=CC=C1NN=NC1=CC=C(C(N)=N)C=C1 XJLITJHUQRBWPN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 177
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- 239000000243 solution Substances 0.000 description 91
- -1 cyclopropyl Cyclobutyl Chemical group 0.000 description 84
- 238000006243 chemical reaction Methods 0.000 description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000012043 crude product Substances 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
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- 125000006413 ring segment Chemical group 0.000 description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
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- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 4
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- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 3
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
-
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Definitions
- the present invention relates to a series of triacyclic heterocyclic derivatives, in particular to compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
- Tumor microenvironment-mediated immunosuppression plays an important role in tumor immune escape.
- Adenosine is an immunosuppressive metabolite in the tumor microenvironment.
- CD73 extracellular-5'-nucleotidase
- CD39 and CD73 successively convert ATP into adenosine (ADO).
- Adenosine binds to the adenosine receptor expressed on immune cells A2aR and A2bR exert immunosuppressive effects.
- CD73 is overexpressed in a variety of tumors, including pancreatic cancer, triple-negative breast cancer, prostate cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, etc., and is closely related to the progression and poor prognosis of these cancers.
- treatment regimens such as PD-1/PD-L1 monoclonal antibody, radiotherapy and chemotherapy may cause the expression of CD73 in the tumor microenvironment to increase, and then inhibit the immune response through adenosine signaling, resulting in drug resistance.
- Inhibition of CD73 can reduce the production of adenosine in the tumor microenvironment, thereby enhancing the antitumor activity of T cells and NK cells.
- CD73 has received attention as an emerging tumor immunotherapy target.
- several antibodies and small molecule inhibitors against CD73 have entered clinical research, among which the small molecule inhibitor AB680 developed by Arcus Biosciences, Inc. is in phase I clinical research and is being used in combination with chemotherapy and anti-PD1 antibodies It has shown positive therapeutic effect in the early clinical research of pancreatic cancer treatment. Therefore, the development of novel CD73 inhibitors has very important clinical significance.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 , R 2 and R 5 are independently selected from H, C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1-3 alkyl and C 3-6 cycloalkyl are independently any optionally replaced by 1, 2 or 3 R a ;
- R 3 , R 4 , R 6 and R 7 are independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and C 3 -6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are independently optionally substituted by 1, 2 or 3 R b ;
- R 8 and R 9 are independently selected from OH, F, Cl, Br and I;
- R 10 is selected from H, F, Cl, Br, I, C 1-3 alkoxy and C 1-3 alkyl, said C 1-3 alkoxy and C 1-3 alkyl are independently optional Replaced by 1, 2 or 3 R c ;
- R 11 is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R ;
- L is selected from a bond and a C 1-3 alkyl optionally substituted by 1, 2 or 3 R ;
- Each R 12 is independently selected from F, Cl, Br, I, OH, CN, C 1-3 alkoxy and C 1-3 alkyl, and the C 1-3 alkoxy and C 1-3 alkane
- the groups are independently optionally substituted by 1, 2 or 3 R f ;
- Ring A is selected from phenyl, naphthyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, 4-6 membered heterocycloalkyl and 4-6 membered heterocycloalkene base;
- T 1 and T 2 are independently selected from C;
- one of T1 and T2 is selected from C, and the other is selected from N;
- Ring B is selected from 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 4-6 heterocyclic alkenyl, the 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 4-6
- the membered heterocycloalkenyl groups are independently optionally substituted by 1, 2 or 3 Rg ;
- n is selected from 0, 1, 2 and 3;
- Each R a , R b , R c , R d , R e , R f and R g are independently selected from F, Cl, Br, I, CN, OH, C 1-3 alkoxy and C 1-3 Alkyl group, the C 1-3 alkoxy group and C 1-3 alkyl group are independently optionally substituted by 1, 2 or 3 F;
- the "5-10 membered heteroaryl”, “5-6 membered heteroaryl”, “4-6 membered heterocycloalkyl” and “4-6 membered heterocycloalkenyl” independently contain 1, 2 or 3 heteroatoms or heteroatom groups independently selected from NH, N, O and S.
- the "hetero" of the above-mentioned 5-10 membered heteroaryl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and 4-6 membered heterocycloalkenyl independently represent 1, 2 or 3 heteroatoms or heteroatom groups independently selected from NH, N, O and S.
- R a , R b , R c , R d , Re , R f and R g are independently selected from F, CN, OH, CH 3 , CF 3 , OCH 3 and OCF 3 , other variables are as defined in the present invention.
- each of the aforementioned R a , R b , R c , R d , Re , R f and R g is independently selected from F, and other variables are as defined in the present invention.
- R 1 , R 2 and R 5 are independently selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are independently optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
- R 1 , R 2 and R 5 are independently selected from H, and other variables are as defined in the present invention.
- R 3 and R 4 are independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3.
- Cyclopropyl and cyclobutyl, said CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , cyclopropyl and cyclobutyl are independently optionally substituted by 1, 2 or 3 R b , other variables are as defined in the present invention.
- R 3 and R 4 are independently selected from H, and other variables are as defined in the present invention.
- R 6 and R 7 are independently selected from H, and other variables are as defined in the present invention.
- R 8 and R 9 are independently selected from OH, and other variables are as defined in the present invention.
- R 10 is selected from H, F, Cl, CH 3 , OCH 3 , CF 3 and OCF 3 , and other variables are as defined in the present invention.
- R 10 is selected from H, and other variables are as defined in the present invention.
- R 11 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CF 3 and CH 2 CF 3 , and other variables are as defined in the present invention.
- R 11 is selected from H, and other variables are as defined in the present invention.
- R 12 is selected from F, Cl, OH, CN, CH 3 , CF 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCF 3 and OCH 2 CH 3 ,
- Other variables are as defined herein.
- R 12 is selected from F, and other variables are as defined in the present invention.
- the above-mentioned L 1 is selected from a bond, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
- the above-mentioned L 1 is selected from a bond, CH 2 and CH 2 CH 2 , and other variables are as defined in the present invention.
- the above-mentioned ring A is selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, benzopyrazolyl, benzimidazolyl, cyclopropyl Cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, and morpholinyl, other variables are as defined herein.
- the above-mentioned ring A is selected from phenyl and cyclopentyl, and other variables are as defined in the present invention.
- the above-mentioned ring B is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 Rg , and other variables are as defined in the present invention .
- the above-mentioned ring B is selected from thienyl, and the thienyl is optionally substituted by 1, 2 or 3 R g , and other variables are as defined in the present invention.
- the above-mentioned structural units selected from furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxolyl, oxygen heterocycle Hexenyl, azacyclopentenyl, azacyclohexenyl, thiopentenyl and thiopentenyl, the furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, Pyrrolyl, pyrazolyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxolyl, oxepenyl, azacyclopentenyl, azidine, Thiolyl and thiolyl are each independently optionally substituted with 1, 2 or 3 Rg , other variables are as defined here
- the above-mentioned structural units selected from furyl, thienyl, thiazolyl, imidazolyl, cyclopentenyl and thiol, said furyl, thienyl, thiazolyl, imidazolyl, cyclopentenyl and thiol
- the radicals are each independently optionally substituted by 1, 2 or 3 Rg , and other variables are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- R 13 is selected from CH 3 and CH 2 CH 3 , said CH 3 and CH 2 CH 3 are independently optionally substituted by 1, 2 or 3 Re ;
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- ring A, ring B, T 1 , T 2 , R 10 , R 11 , R 12 , n and respectively as defined in the present invention.
- the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to CD73 inhibitors.
- the compound of the present invention has a strong inhibitory activity on CD73, has a strong inhibitory activity on CD73 on the surface of MDA-MB-231 cells, and can significantly reverse the inhibition of ADO on CD8 + T cell IFN- ⁇ secretion and CD8 + T cell proliferation . And has good pharmacokinetic properties.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
- Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
- such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
- the compounds of the invention may exist in particular geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
- cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
- diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
- keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
- tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
- proton tautomers also called prototropic tautomers
- prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
- any variable eg, R
- its definition is independent at each occurrence.
- said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
- substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- one of the variables is selected from a single bond or a bond, it means that the two groups connected are directly connected.
- L in A-L-Z represents a single bond, it means that the structure is actually A-Z; when L in A-L-Z is a bond, it also means that the structure A-Z actually.
- any one or more sites of the group can be linked to other groups through chemical bonds.
- connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
- the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
- the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
- the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
- C 1-3 alkyl by itself or in combination with other terms means a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms, respectively.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-3 alkoxy by itself or in combination with other terms respectively means those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 3-6 cycloalkyl by itself or in combination with other terms represents a saturated monocyclic hydrocarbon group composed of 3 to 6 carbon atoms, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
- Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- C4-6 cycloalkenyl by itself or in combination with other terms respectively means a partially unsaturated monocyclic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond Group, this system is non-aromatic.
- the C 4-6 cycloalkenyl includes C 4-5 or C 5-6 cycloalkenyl and the like; it may be monovalent, divalent or multivalent.
- Examples of C 4-6 cycloalkenyl include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
- 4-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated monocyclic group consisting of 4 to 6 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
- a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
- the 4-6 membered heterocycloalkyl group includes 4-5 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
- 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl
- 4-6 membered heterocycloalkenyl by itself or in combination with other terms respectively means a partially unsaturated monocyclic group consisting of 4 to 6 ring atoms containing at least one carbon-carbon double bond , whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be Oxidation (ie NO and S(O) p , where p is 1 or 2).
- the "4-6 membered heterocycloalkenyl” is non-aromatic.
- 4-6 membered heterocycloalkenyl a heteroatom may occupy the attachment position of the heterocyclenyl to the rest of the molecule.
- the 4-6 membered heterocycloalkenyl includes 4-membered, 5-membered and 6-membered heterocycloalkenyl. Examples of 4-6 membered heterocyclenyl include, but are not limited to,
- 5-10 membered heteroaryl ring and “5-10 membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10 membered heteroaryl” means that there are 5 to 10 rings
- the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
- the 5-10 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
- the 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5-membered and 6-membered heteroaryl groups and the like.
- Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl
- the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
- the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
- the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
- Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.
- aromatic ring is a cyclic group having a conjugated ⁇ -electron system covered by a cloud of delocalized ⁇ -electrons between its atoms.
- the atomic valence state and covalent bond formation rules when the atomic valence state and covalent bond formation rules are met, it can be written in the form of alternating single and double bonds, or it can be written in the form of represents a delocalized ⁇ -electron cloud.
- the formula The structures represented are the same, the structural formula The structures represented are the same, and The structures represented are the same. It can be a single ring or a fused polycyclic ring system in which each ring is aromatic. Unless otherwise specified, the ring optionally contains 0, 1 or more heteroatoms or heteroatom groups independently selected from O, S, NH and N.
- C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
- the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
- SXRD single crystal X-ray diffraction
- DMSO dimethyl sulfoxide
- Bz stands for benzoyl
- CD 3 OD stands for deuterated methanol
- CDCl 3 stands for deuterated chloroform
- AMP stands for adenosine monophosphate
- ADO stands for adenosine.
- the solvent used in the present invention is commercially available.
- Compounds are named according to the conventional naming principles in this field or using The software is named, and the commercially available compounds adopt the supplier catalog name.
- Dissolve compound 1-7 (195mg, 624.27 ⁇ mol, 1eq) in acetonitrile (4mL), add compound 1-8 (472.40mg, 936.41 ⁇ mol, 1.5eq), cool to 0°C, add trimethyl trifluoromethanesulfonate Silicyl ester (166.50mg, 749.13 ⁇ mol, 135.37 ⁇ L, 1.2eq), the reaction solution was slowly heated to 25°C and stirred for 12 hours.
- the filtrate was purified by preparative high-performance liquid chromatography (column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile%: 15%-55%) to obtain the compound 1 trifluoroacetate.
- Dissolve compound 2-7 (100mg, 232.28 ⁇ mol, 1eq) in trimethyl phosphate (1mL), cool to 0°C, and slowly add methylene bisphosphonic dichloride (174mg, 696.83 ⁇ mol, 3eq) in phosphoric acid trimethyl ester (0.5 mL) solution, and the reaction solution was stirred at 25°C for 3 hours. Water (0.5 mL) was added and stirring was continued at 25°C for 20 hours. Acetonitrile (1 mL) was added to the reaction solution for dilution, and the filtrate was collected by filtration.
- the filtrate was purified by preparative high-performance liquid chromatography (column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile%: 0%-30%) to obtain the compound 2 trifluoroacetate.
- reaction solution was freeze-dried, dissolved in water (1mL) and acetonitrile (1mL), and the solution was prepared by high performance liquid chromatography (chromatographic column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)- Acetonitrile]; acetonitrile%: 3%-33%) was purified to obtain the trifluoroacetic acid salt of compound 3. MS: m/z 603.1 [M+H] + .
- reaction solution was freeze-dried, then dissolved in water (1mL) and acetonitrile (1mL), and the solution was prepared by high performance liquid chromatography (column: Welch Xtimate C18 100*40mm*3 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid) - acetonitrile]; acetonitrile %: 0%-28%) was purified to obtain the trifluoroacetate salt of compound 4.
- MS m/z 549.0 [M+H] + .
- CD73 Inhibitor Screening Assay Kit was purchased from BPS Bioscience
- 1X assay buffer preparation Dilute 5X assay buffer with ddH 2 O (double distilled water) to 1X assay buffer, keep on ice for later use.
- the compound to be tested was diluted to 10 ⁇ M with 100% DMSO as the first concentration, and then diluted 5 times to the eighth concentration with a row gun, that is, diluted from 10 ⁇ M to 0.128 nM.
- Example-Min Use the equation (Sample-Min)/(Max-Min)*100% to convert the initial value into an inhibition rate, and the value of IC 50 can be obtained by curve fitting with four parameters (log(inhibitor)vs.response in GraphPad Prism --Variable slope mode derived).
- Max initial value of control well without CD73 enzyme
- Min initial value of control well containing 1% DMSO solvent.
- Table 1 provides the effect of compounds of the present invention on CD73 enzyme activity. The experimental results are shown in Table 1.
- Table 1 The compound of the present invention is to CD73 enzyme in vitro inhibitory activity screening test result
- the compound of the present invention has strong inhibitory activity on CD73.
- human breast cancer cells MDA-MB-231 endogenously expressing CD73 were used to evaluate the inhibitory effect of compounds on CD73 on the cell surface.
- the formula for calculating the inhibition rate is (absorbance value of the blank control well-absorbance value of the compound well)/absorbance value of the blank control well*100%, and the IC 50 value is performed using the log(inhibitor)vs.response--Variable slope mode in GraphPad Prism obtained by curve fitting.
- the experimental results are shown in Table 2.
- the compound of the present invention is to the CD73 inhibitory activity test result of MDA-MB-231 cell surface
- the compound of the present invention has a strong inhibitory activity on CD73 on the surface of MDA-MB-231 cells.
- EDTA anticoagulated whole blood was diluted with the same volume of PBS, 15mL Lymphoprep (human lymphocyte separation medium) was added to a 50mL centrifuge tube, and 30mL diluted blood samples were slowly added to the Lymphoprep, taking care not to damage the interface.
- Lymphoprep human lymphocyte separation medium
- CD8 + T cells were further isolated from PBMCs with EasySep TM Human CD8 + T Cell Isolation Kit.
- CD8 + T cells volume 100 ⁇ L/well
- 96-well U-bottom plate add 25 ⁇ L of the compound to be tested and incubate for 1 h.
- Control wells were added complete medium with equal DMSO content.
- the compounds of the present invention can significantly reverse the inhibition of ADO on the secretion of IFN- ⁇ from CD8 + T cells and the proliferation of CD8 + T cells.
- test compound was dissolved in a solvent of 10% DMSO/10% Solutol/80% water to prepare a clear solution with a concentration of 0.2 mg/mL, which was filtered through a microporous membrane for use.
- Balb/c female mice weighing 19 to 22 grams were selected, and the candidate compound solution was intravenously administered at a dose of 1 mg/kg.
- Whole blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours to prepare plasma.
- the drug concentration was analyzed by LC-MS/MS, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3.
- Table 5 The test results are shown in Table 5.
- T 1/2 half-life
- V dss apparent volume of distribution
- Cl drug clearance
- AUC 0-last area under the time curve
- the compound of the present invention has good pharmacokinetic properties in mice intravenously injected.
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Abstract
公开了一系列三并环杂环衍生物，具体公开了式(I)所示化合物及其药学上可接受的盐。
Description
本发明主张如下优先权：
CN202111183869.0，申请日2021年10月11日；
CN202210885167.5，申请日2022年07月26日。
本发明涉及一系列三并环杂环衍生物，具体涉及式(I)所示化合物及其药学上可接受的盐。
肿瘤微环境介导的免疫抑制在肿瘤免疫逃逸中有重要作用。腺苷是肿瘤微环境中具有免疫抑制作用的代谢物。CD73(胞外-5’-核苷酸酶)是催化腺苷生成的重要催化酶，CD39和CD73先后将ATP转化为腺苷(ADO)，腺苷通过结合免疫细胞上表达的腺苷受体A2aR和A2bR发挥免疫抑制效果。CD73在多种肿瘤中过表达，包括胰腺癌、三阴性乳腺癌、前列腺癌、结直肠癌、非小细胞肺癌、胃癌等，与这些癌症的进展和较差的预后密切相关。此外，PD-1/PD-L1单抗、放化疗等治疗方案可能引起肿瘤微环境CD73表达升高，继而通过腺苷信号抑制免疫反应而发生耐药。抑制CD73可以降低腺苷在肿瘤微环境中的生成，从而增强T细胞和NK细胞的抗肿瘤活性。
因此，CD73作为新兴的肿瘤免疫治疗靶点受到重视。目前已经有多个针对CD73的抗体和小分子抑制剂进入临床研究中，其中Arcus Biosciences,Inc.公司开发的小分子抑制剂AB680处于临床I期研究中，并在与化疗和抗PD1抗体联用于胰腺癌治疗的早期临床研究中表现出积极的治疗作用。因此，开发新型的CD73抑制剂具有非常重要的临床意义。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
其中，
R
1、R
2和R
5分别独立地选自H、C
1-3烷基和C
3-6环烷基，所述C
1-3烷基和C
3-6环烷基分别独立地任选被1、2或3个R
a取代；
R
3、R
4、R
6和R
7分别独立地选自H、F、Cl、Br、I、CN、OH、NH
2、C
1-3烷基、C
1-3烷氧基和C
3-6环烷基，所述C
1-3烷基、C
1-3烷氧基和C
3-6环烷基分别独立地任选被1、2或3个R
b取代；
R
8和R
9分别独立地选自OH、F、Cl、Br和I；
R
10选自H、F、Cl、Br、I、C
1-3烷氧基和C
1-3烷基，所述C
1-3烷氧基和C
1-3烷基分别独立地任选被1、2或3个R
c取代；
R
11选自H和C
1-3烷基，所述C
1-3烷基任选被1、2或3个R
d取代；
L
1选自键和C
1-3烷基，所述C
1-3烷基任选被1、2或3个R
e取代；
各R
12分别独立地选自F、Cl、Br、I、OH、CN、C
1-3烷氧基和C
1-3烷基，所述C
1-3烷氧基和C
1-3烷基分别独立地任选被1、2或3个R
f取代；
环A选自苯基、萘基、5-10元杂芳基、C
3-6环烷基、C
4-6环烯基、4-6元杂环烷基和4-6元杂环烯基；
或者，
选自单键，T
1和T
2其中一个选自C，另一个选自N；
环B选自5-6元杂芳基、C
4-6环烯基和4-6元杂环烯基，所述5-6元杂芳基、C
4-6环烯基和4-6元杂环烯基分别独立地任选被1、2或3个R
g取代；
n选自0、1、2和3；
各R
a、R
b、R
c、R
d、R
e、R
f和R
g分别独立地选自F、Cl、Br、I、CN、OH、C
1-3烷氧基和C
1-3烷基，所述C
1-3烷氧基和C
1-3烷基分别独立地任选被1、2或3个F取代；
所述“5-10元杂芳基”、“5-6元杂芳基”、“4-6元杂环烷基”和“4-6元杂环烯基”分别独立地包含1、2或3个独立选自NH、N、O和S的杂原子或杂原子团。
在本发明的一些方案中，上述5-10元杂芳基、5-6元杂芳基、4-6元杂环烷基和4-6元杂环烯基的“杂”分别独立地表示1、2或3个独立选自NH、N、O和S的杂原子或杂原子团。
在本发明的一些方案中，上述各R
a、R
b、R
c、R
d、R
e、R
f和R
g分别独立地选自F、CN、OH、CH
3、CF
3、OCH
3和OCF
3，其他变量如本发明所定义。
在本发明的一些方案中，上述各R
a、R
b、R
c、R
d、R
e、R
f和R
g分别独立地选自F，其他变量如本发明所定义。
在本发明的一些方案中，上述R
1、R
2和R
5分别独立地选自H、CH
3、CH
2CH
3、CH
2CH
2CH
3和CH(CH
3)
2，所述CH
3、CH
2CH
3、CH
2CH
2CH
3和CH(CH
3)
2分别独立地任选被1、2或3个R
a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R
1、R
2和R
5分别独立地选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述R
3和R
4分别独立地选自H、F、Cl、Br、I、CN、OH、NH
2、CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、环丙基和环丁基，所述CH
3、CH
2CH
3、OCH
3、OCH
2CH
3、环丙基和环丁基分别独立地任选被1、2或3个R
b取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R
3和R
4分别独立地选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述R
6和R
7分别独立地选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述R
8和R
9分别独立地选自OH，其他变量如本发明所定义。
在本发明的一些方案中，上述R
10选自H、F、Cl、CH
3、OCH
3、CF
3和OCF
3，其他变量如本发明所定义。
在本发明的一些方案中，上述R
10选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述R
11选自H、CH
3、CH
2CH
3、CH(CH
3)
2、CF
3和CH
2CF
3，其他变量如本发明所定义。
在本发明的一些方案中，上述R
11选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述R
12选自F、Cl、OH、CN、CH
3、CF
3、CH
2CH
3、CH(CH
3)
2、OCH
3、OCF
3和OCH
2CH
3，其他变量如本发明所定义。
在本发明的一些方案中，上述R
12选自F，其他变量如本发明所定义。
在本发明的一些方案中，上述L
1选自键、CH
3和CH
2CH
3，其他变量如本发明所定义。
在本发明的一些方案中，上述L
1选自键、CH
2和CH
2CH
2，其他变量如本发明所定义。
在本发明的一些方案中，上述环A选自苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、苯并吡唑基、苯并咪唑基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基和吗啡啉基，其他变量如本发明所定义。
在本发明的一些方案中，上述环A选自苯基和环戊基，其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，上述环B选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个R
g取代，其他变量如本发明所定义。
在本发明的一些方案中，上述环B选自噻吩基，所述噻吩基任选被1、2或3个R
g取代，其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
选自呋喃基、噻吩基、噻唑基、噁唑基、咪唑基、吡咯基、吡唑基、环丁烯基、环戊烯基、环己烯基、氧杂环戊烯基、氧杂环己烯基、氮杂环戊烯基、氮杂环己烯基、硫杂环戊烯基和硫杂环己烯基，所述呋喃基、噻吩基、噻唑基、噁唑基、咪唑基、吡咯基、吡唑基、环丁烯基、环戊烯基、环己烯基、氧杂环戊烯基、氧杂环己烯基、氮杂环戊烯基、氮杂环己烯基、硫杂环戊烯基和硫杂环己烯基分别独立地任选被1、2或3个R
g取代，其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
选自呋喃基、噻吩基、噻唑基、咪唑基、环戊烯基和硫杂环戊烯基，所述呋喃基、噻吩基、噻唑基、咪唑基、环戊烯基和硫杂环戊烯基分别独立地任选被1、2或3个R
g取代，其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
选自
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自：
其中，环A、环B、T
1、T
2、L
1、R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、n和
分别如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自：
其中，
R
13选自CH
3和CH
2CH
3，所述CH
3和CH
2CH
3分别独立地任选被1、2或3个R
e取代；
环A、环B、T
1、T
2、R
e、R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、n和
分别如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自：
其中，环A、环B、L
1、T
1、T
2、R
10、R
11、R
12、n和
分别如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自：
其中，环A、环B、T
1、T
2、R
10、R
11、R
12、n和
分别如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明还提供了下列所示化合物或其药学上可接受的盐，
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自：
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗与CD73抑制剂相关疾病的药物中的应用。
技术效果
本发明化合物对CD73有很强的抑制活性，对MDA-MB-231细胞表面的CD73有很强的抑制活性，可以显著逆转ADO对CD8
+T细胞IFN-γ分泌和CD8
+T细胞增殖的抑制。并且具有良好的药代动力学性质。
相关定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型，用直形实线键
和直形虚线键
表示立体中心的相对构型，用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
或直形虚线键
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(
3H)，碘-125(
125I)或C-14(
14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)
0-，表示该连接基团为单键。
当其中一个变量选自单键或键时，都表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z；A-L-Z中L为键时也表示该结构实际上是A-Z。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH
3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
这4种连接方式，即使-N-上画出了H原子，但是
仍包括
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，术语“C
1-3烷基”本身或者与其他术语联合分别表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C
1-3烷氧基”本身或者与其他术语联合分别表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，“C
3-6环烷基”本身或者与其他术语联合分别表示由3至6个碳原子组成的饱和单环碳氢基团，所述C
3-6环烷基包括C
3-5、C
4-5和C
5-6环烷基等；其可以是一价、二价或者多价。C
3-6环烷基的实 例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，术语“C
4-6环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由4至6个碳原子组成的部分不饱和的单环碳氢基团，此体系是非芳香性的。所述C
4-6环烯基包括C
4-5或C
5-6环烯基等；其可以是一价、二价或者多价。C
4-6环烯基的实例包括但不限于，环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)
p，p是1或2)。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括4-5元、5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基或六氢哒嗪基等。
除非另有规定，术语“4-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由4至6个环原子组成的部分不饱和的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)
p，p是1或2)。所述“4-6元杂环烯基”是非芳香性的。此外，就该“4-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述4-6元杂环烯基包括4元、5元和6元杂环烯基。4-6元杂环烯基的实例包括但不限于，
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)
p，p是1或2)。5-10元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-10元杂芳基包括5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-10元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三 唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)
p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，术语“芳香性环”为具有共轭π电子体系的环状基团，其原子间被离域π电子云覆盖。在结构式中，在符合原子价态和共价键成键规则时，可以书写为单双键交替的形式，也可以用
表示离域π电子云。例如，结构式
所表示的结构均相同，结构式
所表示的结构均相同，
与
所表示的结构相同。其可以是单环或稠合多环体系，其中各个环均为芳香性的。除非另有规定，该环任选地包含0、1或多个独立选自O、S、NH和N的杂原子或杂原子团。
除非另有规定，C
n-n+m或C
n-C
n+m包括n至n+m个碳的任何一种具体情况，例如C
1-12包括C
1、C
2、C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11、和C
12，也包括n至n+m中的任何一个范围，例如C
1-12包括C
1-
3、C
1-6、C
1-9、C
3-6、C
3-9、C
3-12、C
6-9、C
6-12、和C
9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和 12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明采用下述缩略词：DMSO代表二甲基亚砜；Bz代表苯甲酰基；CD
3OD代表氘代甲醇；CDCl
3代表氘代氯仿；AMP代表单磷酸腺苷；ADO代表腺苷。
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用
软件命名，市售化合物采用供应商目录名称。
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
第一步
向三氯氧磷(37.95g,247.50mmol,23.00mL,25.75eq)中加入化合物1-1(2.3g,9.61mmol,1eq)，反应液在90℃下搅拌12小时。将反应液冷却至室温，减压浓缩干，加入乙酸乙酯(20mL)稀释，缓慢滴加到冰水(20mL)中淬灭，用乙酸乙酯(20mL×2)萃取，合并有机相，用水(20mL×2)洗涤，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯比例＝0～30％)纯化得到化合物1-2。MS:m/z 275.8[M+H]
+。
第二步
将化合物1-2(1.4g,5.07mmol,1eq)溶于1-甲基-2-吡咯烷酮(14mL)中，加入化合物1-3(705.6mg,5.07mmol,1eq)和N,N-二异丙基乙胺(1.96g,15.21mmol,2.65mL,3eq)，反应液在氮气保护下在110℃下搅拌12小时。向反应液中加入乙酸乙酯(20mL)稀释，有机相用水(20mL×2)洗涤，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯比例＝0～10％)纯化得到化合物1-4。MS:m/z 379.0[M+H]
+。
第三步
将化合物1-4(1.25g,3.30mmol,1eq)溶于二氯甲烷(12.5mL)中，冷却至-78℃下，滴加二异丁基氢化铝(1M的甲苯溶液,9.90mL,3eq)，反应液在氮气保护下在-78℃下搅拌2小时。直接向反应液中加入饱和酒石酸钾钠水溶液(20mL)，搅拌0.5小时，用二氯甲烷(20mL×2)萃取，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝0～20％)得到化合物1-5。MS:m/z 336.9[M+H]
+。
第四步
将化合物1-5(500mg,1.48mmol,1eq)溶于二氯甲烷(5mL)中，加入二氧化锰(1.29g,14.85mmol,10eq)，反应液在25℃下搅拌12小时。向反应液中加入二氯甲烷(10mL)稀释，过滤，滤饼用二氯甲烷(10mL)荡洗，收集滤液，减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝0～10％)得到化合物1-6。MS:m/z 334.9[M+H]
+。
第五步
将化合物1-6(410mg,1.22mmol,1eq)溶于N,N-二甲基甲酰胺(4mL)中，滴加水合肼(2.58g,43.72mmol,2.5mL,85％含量,35.70eq)，然后加入一水合对甲苯磺酸(116.47mg,612.31μmol,0.5eq)，反应液在80℃下搅拌2小时。将反应液减压浓缩干，加入乙酸乙酯(20mL)稀释，有机相用水(20mL×2)洗涤，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝0～30％)得到化合物1-7。MS:m/z 312.9[M+H]
+。
第六步
将化合物1-7(195mg,624.27μmol,1eq)溶于乙腈(4mL)中，加入化合物1-8(472.40mg,936.41μmol,1.5eq)，冷却至0℃，加入三氟甲磺酸三甲基硅酯(166.50mg,749.13μmol,135.37μL,1.2eq)，反应液缓慢升温至25℃下搅拌12小时。向反应液中加入乙酸乙酯(20mL)稀释，有机相用饱和碳酸氢钠水溶液(10mL)洗涤，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯比例＝0～50％)纯化后，再经硅胶板(石油醚:乙酸乙酯＝2:1)纯化得到化合物1-9。MS:m/z 757.2[M+H]
+。
第七步
将化合物1-9(140mg,184.99μmol,1eq)溶于甲醇(2.8mL)中，加入氢氧化钠溶液(1M,555μL,3eq)，反应液在25℃下搅拌12小时。将反应液减压浓缩干，加入乙酸乙酯(10mL)稀释，有机相用水(5mL×2)洗涤，饱和食盐水(5mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝40～100％)得到化合物1-10。MS:m/z 445.1[M+H]
+。
第八步
将化合物1-10(60mg,134.99μmol,1eq)溶于丙酮(1mL)中，加入2,2-二甲氧基丙烷(140.59mg,1.35mmol,165.40μL,10eq)和对甲苯磺酸(30.22mg,175.49μmol,1.3eq)，反应液在25℃下搅拌12小时。向反应液中加入乙酸乙酯(5mL)稀释，有机相用水(5mL×2)洗涤，饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经硅胶板(石油醚:乙酸乙酯＝1:1)纯化得到化合物1-11。MS:m/z 485.1[M+H]
+。
1H NMR(400MHz,CDCl
3)δ7.84(s,1H),7.29-7.34(m,1H),7.29(s,1H),7.25(br d,J＝1.76Hz,1H),7.17(d,J＝6.27Hz,1H),7.10-7.15(m,1H),7.07(dt,J＝1.00,7.53Hz,1H),6.54(d,J＝3.76Hz,1H),5.47-5.56(m,2H),5.27(dd,J＝3.64,5.90Hz,1H),5.11(dd,J＝1.13,5.90Hz,1H),4.51(s,1H),3.92(dd,J＝1.63,12.67Hz,1H),3.75(dd,J＝2.38,12.67Hz,1H),1.77(d,J＝6.02Hz,3H),1.65(s,3H),1.37(s,3H)。
第九步
将化合物1-11(50mg,103.19μmol,1eq)溶于磷酸三甲酯(0.5mL)中，缓慢滴加亚甲基双膦酰二氯(128.88mg,515.95μmol,5eq)的磷酸三甲酯(0.5mL)溶液，反应液在25℃下搅拌3小时。加入水(0.3mL)，反应液 在25℃下搅拌12小时。向反应液中加入乙腈(1mL)稀释，过滤，收集滤液。滤液经制备高效液相色谱(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；梯度：乙腈％:15％-55％)纯化得到化合物1的三氟乙酸盐。MS:m/z 603.1[M+H]
+。
1H NMR(400MHz,CD
3OD)δ8.00(s,1H),7.85(d,J＝6.13Hz,1H),7.42(t,J＝7.69Hz,1H),7.28-7.35(m,2H),7.17-7.24(m,1H),7.12(t,J＝7.38Hz,1H),6.25(d,J＝3.88Hz,1H),5.67(q,J＝6.59Hz,1H),4.74-4.77(m,1H),4.45(t,J＝4.94Hz,1H),4.21(br s,2H),4.00-4.12(m,1H),2.27-2.41(m,2H),1.78(d,J＝6.75Hz,3H)。
实施例2
第一步
将化合物1-2(3.8g,13.76mmol,1eq)溶于1-甲基-2-吡咯烷酮(40mL)，加入环戊胺(1.17g,13.76mmol,1.36mL,1eq)和N,N-二异丙基乙胺(5.34g,41.28mmol,7.19mL,3eq)，在氮气保护下，110℃搅拌12小时。加入乙酸乙酯(100mL)稀释，用水(100mL)洗涤，饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩干得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯比例＝0～20％)纯化得到化合物2-1。MS:m/z 324.9[M+H]
+。
第二步
将化合物2-1(11.5g,35.40mmol,1eq)溶于二氯甲烷(110mL)中，在氮气保护下-78℃下滴加二异丁基氢化铝的甲苯溶液(1M,106.21mL,3eq)，搅拌反应12小时。缓慢向反应液中加入饱和酒石酸钾钠 水溶液(50mL)并搅拌0.5小时，二氯甲烷(50mL)稀释，有机相用水(50mL×2)洗涤，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝0～30％)得到化合物2-2。MS:m/z 282.9[M+H]
+。
第三步
将化合物2-2(10g,35.92mmol,1eq)溶于二氯甲烷(100mL)，加入二氧化锰(31.23g,359.23mmol,10eq)，在45℃搅拌12个小时。将反应液通过硅藻土过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝0～25％)得到化合物2-3。MS:m/z 280.8[M+H]
+。
第四步
将化合物2-3(500mg,1.78mmol,1eq)加入到水合肼(5.19g,88.07mmol,5.04mL,85％含量,49.46eq)中，再加入对甲苯磺酸(183.99mg,1.07mmol,0.6eq)，在氮气保护，130℃下搅拌12小时。用二氯甲烷(20mL)稀释，有机相用水(20mL×2)洗涤，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(甲醇/二氯甲烷＝0～15％)得到化合物2-4。MS:m/z258.9[M+H]
+。
第五步
将化合物2-4(150mg,580.63μmol,1eq)溶于乙腈(3mL)中，加入化合物1-8(439.4mg,870.94μmol,1.5eq)，冷却至0℃，滴加三甲硅基三氟甲磺酸酯(154.9mg,696.75μmol,125.9μL,1.2eq)，反应液缓慢升温至25℃后搅拌12小时。向反应液中加入乙酸乙酯(20mL)稀释，有机相用水(20mL×2)洗涤，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝0～100％)得到化合物2-5。MS:m/z 703.0[M+H]
+。
第六步
将化合物2-5(55mg,78.26μmol,1eq)溶于甲醇(1mL)中，加入氢氧化钠(1M,235μL,3eq)溶液至反应液中，在25℃下搅拌12小时。将反应液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例＝40～100％)得到化合物2-6。MS:m/z 390.9[M+H]
+。
第七步
将化合物2-6(50mg,128.06μmol,1eq)溶于丙酮(1mL)中，加入2,2-二甲氧基丙烷(133.4mg,1.28mmol,156.90μL,10eq)和对甲苯磺酸(28.7mg,166.47μmol,1.3eq)，反应液在25℃下搅拌12小时。向反应液中加入乙酸乙酯(10mL)稀释，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯比例＝0～50％)纯化得到化合物2-7。MS:m/z 431.0[M+H]
+。
第八步
将化合物2-7(100mg,232.28μmol,1eq)溶于磷酸三甲酯(1mL)，冷却至0℃下，缓慢滴加亚甲基双膦酰二氯(174mg,696.83μmol,3eq)的磷酸三甲酯(0.5mL)溶液，反应液在25℃下搅拌3小时。加入水(0.5mL)并在25℃下继续搅拌20小时。向反应液中加入乙腈(1mL)稀释，过滤收集滤液。滤液经制备高效液相色谱(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；梯度:乙腈％:0％-30％)纯化得到化合物2的三氟乙酸盐。MS:m/z 549.1[M+H]
+。
1H NMR(400MHz,CD
3OD)δ8.45(s,1H),7.79(d,J＝6.0Hz,1H),7.34(d,J＝6.4Hz,1H),6.21(d,J＝4.0Hz,1H),4.96-4.91(m,1H),4.69-4.64(m,1H),4.56(t,J＝5.2Hz,1H),4.30-4.20(m,2H),4.17-4.07(m,1H),2.39-2.19(m,4H),1.94-1.75(m,6H)。
实施例3
第一步
将化合物3-1(100g,636.17mmol,1eq)溶于二氯甲烷(1.2L)，再滴加丙二酸甲酯酰氯(104.23g, 763.41mmol,81.43mL,1.2eq)，在40℃下搅拌6小时。反应液冷却后有沉淀析出。然后在25℃下补加丙二酸甲酯酰氯(34.74g,254.47mmol,27.14mL,0.4eq)，升温至40℃，搅拌3小时。向反应液中加入二氯甲烷(700mL)稀释，有机相用水(600mL×2)洗涤，饱和食盐水(600mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干燥得到化合物3-2。MS:m/z 258.0[M+H]
+。
第二步
将化合物3-2(170g,660.80mmol,1eq)溶于四氢呋喃(2L)，在0℃下缓慢滴加叔丁醇钾的四氢呋喃溶液(1M,1.45L,2.2eq)，升温至60℃，搅拌6小时。然后用1M稀盐酸调pH＝6，过滤反应液，将所得固体用乙酸乙酯(800mL)打浆，过滤，固体减压干燥得到化合物3-3。MS:m/z 225.9[M+H]
+。
第三步
将化合物3-3(50g,222.00mmol,1eq)和碳酸氢钠(22.38g,266.41mmol,10.36mL,1.2eq)混合均匀，再分批缓慢加入到三氯氧磷(577.50g,3.77mol,350.00mL,16.97eq)中，升温至90℃下搅拌48小时。将反应液冷却至室温，减压浓缩后的残留物中加入乙酸乙酯(500mL)稀释，缓慢滴加到冰的NaOH溶液(6M)中搅拌下淬灭，用乙酸乙酯(5L×3)萃取，合并有机相，用水(5L×3)洗涤，饱和食盐水(5L×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到化合物3-4。MS:m/z 261.9[M+H]
+。
第四步
将化合物3-4(25.5g,97.29mmol,1eq)溶于二氧六环(200mL)，加入化合物1-3(13.54g,97.29mmol,1eq)和二异丙基乙胺(37.72g,291.86mmol,50.84mL,3eq)，在氮气保护下，110℃搅拌48小时。向反应液中加入乙酸乙酯(500mL)，有机相用水(500mL×2)洗涤，饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩干得到粗品。粗品经快速硅胶柱(0～15％乙酸乙酯/石油醚)纯化，得到化合物3-5。MS:m/z 365.0[M+H]
+。
1H NMR(400MHz,CDCl
3)δ8.13(br d,J＝8.4Hz,1H),7.64(d,J＝5.6Hz,1H),7.29(d,J＝5.6Hz,1H),7.25-7.23(m,1H),7.10-7.05(m,2H),5.76-5.70(m,1H),4.02(s,3H),1.67(d,J＝6.4Hz,3H)。
第五步
将化合物3-5(7g,19.19mmol,1eq)溶于二氯甲烷(400mL)中，在25℃下滴加二异丁基氢化铝的甲苯溶液(1M,57.56mL,3eq)，反应液在氮气保护下反应1小时。缓慢向反应液中加入饱和酒石酸钾钠水溶液(700mL)搅拌1小时，用二氯甲烷(500mL×2)进行萃取，合并有机相，用饱和食盐水洗(500mL)，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(甲醇/二氯甲烷，甲醇的比例＝0～10％)得到化合物3-6。MS:m/z 337.0[M+H]
+。
第六步
将化合物3-6(5.6g,16.63mmol,1eq)溶于二氯甲烷(250mL)，加入二氧化锰(14.45g,166.27mmol, 10eq)，在50℃下搅拌12小时。将反应液过滤，滤液减压浓缩干得到固体。再将固体溶于二氯甲烷(250mL)，重新加入二氧化锰(14.45g,166.27mmol,10eq)，在50℃下继续搅拌6小时。反应液经硅藻土过滤，滤液减压浓缩干得到化合物3-7。MS:m/z 335.0[M+H]
+。
第七步
将化合物3-7(1.56g,4.66mmol,1eq)分批加入到水合肼(5.15g,87.44mmol,5mL,85％含量,18.77eq)中，再加入对甲苯磺酸一水合物(531.80mg,2.80mmol,0.6eq)，在氮气保护，120℃下搅拌12小时。用二氯甲烷(150mL)稀释，有机相用水(100mL)洗涤，饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯的比例＝0～100％)纯化得到化合物3-8。MS:m/z 313.0[M+H]
+。
1H NMR(400MHz,CDCl
3)δ7.94(s,1H),7.71(d,J＝5.6Hz,1H),7.48(d,J＝5.6Hz,1H),7.34(td,J＝7.6,1.6Hz,1H),7.25-7.19(m,1H),7.15-7.09(m,1H),7.06-7.00(m,1H),5.70-5.63(m,1H),1.78(d,J＝6.8Hz,3H)。
第八步
将化合物3-8(2.3g,7.36mmol,1eq)溶于乙腈(60mL)中，加入化合物1-8(5.57g,11.04mmol,1.5eq)，冷却至0℃，滴加三甲硅基三氟甲磺酸酯(1.96g,8.84mmol,1.60mL,1.2eq)，反应液缓慢升温至25℃下搅拌12小时。向反应液中加入乙酸乙酯(200mL)稀释，有机相用饱和碳酸氢钠水溶液(200mL)洗涤，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯的比例＝0～40％)得到化合物3-9。MS:m/z 757.1[M+H]
+。
第九步
将化合物3-9(9.9g,13.08mmol,1eq)溶甲醇(70mL)和二氯甲烷(70mL)的混合溶剂中，再加入氢氧化钠溶液(1M,39.24mL,3eq)，在25℃下搅拌12小时。将反应液用二氯甲烷(200mL×4)萃取，减压浓缩干得到粗品。粗品经快速硅胶柱(流动相：先用乙酸乙酯/石油醚，乙酸乙酯的比例＝0～100％，最后用甲醇/二氯甲烷，甲醇的比例＝0～10％)纯化得到化合物3-10。MS:m/z 445.1[M+H]
+。
第十步
将化合物3-10(4.4g,9.90mmol,1eq)溶于丙酮(180mL)中，加入2,2-二甲氧基丙烷(10.31g,98.99mmol,12.13mL,10eq)和对甲苯磺酸(2.22g,12.87mmol,1.3eq)，反应液在25℃下搅拌12小时。加入乙酸乙酯(300mL×3)稀释，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(流动相：先用乙酸乙酯/石油醚，乙酸乙酯的比例＝0～50％，再用甲醇/二氯甲烷，甲醇的比例＝10％)纯化得到化合物3-11。MS:m/z 485.2[M+H]
+。
第十一步
将化合物3-11(46mg,94.93μmol,1eq)溶于磷酸三甲酯(0.5mL)，在25℃下滴加亚甲基双膦酰二 氯(118.6mg,474.67μmol,5eq)的磷酸三甲酯(0.25mL)溶液，反应液继续搅拌6小时。之后加入水(0.5mL)并在25℃下继续搅拌18小时。向反应液中加入稀盐酸溶液(1M,0.25mL)，在35℃下继续搅拌48小时。将反应液冷冻干燥，用水(1mL)和乙腈(1mL)溶解，溶液经制备高效液相色谱(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；乙腈％:3％-33％)纯化得到化合物3的三氟乙酸盐。MS:m/z 603.1[M+H]
+。
1H NMR(400MHz,CD
3OD)δ8.16(br d,J＝5.2Hz,1H),7.53(br d,J＝4.8Hz,1H),7.44-7.40(m,1H),7.38-7.31(m,1H),7.25-7.12(m,2H),6.21(br d,J＝3.6Hz,1H),5.82(q,J＝6.4Hz,1H),4.89-4.83(m,2H),4.49(br s,1H),4.29(br d,J＝4.0Hz,1H),4.25-4.18(m,1H),4.14-4.03(m,1H),2.31(br t,J＝20.4Hz,2H),1.82(d,J＝6.8Hz,3H)。
实施例4
第一步
将化合物3-4(13g,49.60mmol,1eq)溶于1,4-二氧六环(150mL)，加入环戊胺(4.65g,54.56mmol,5.38mL,1.1eq)和N,N-二异丙基乙胺(19.23g,148.79mmol,25.92mL,3eq)，在氮气保护下，110℃搅拌20小时。加入乙酸乙酯(400mL)稀释，用水(300mL)洗涤，饱和食盐水(300mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯的比例＝0～10％)纯化得到化合物4-1。MS:m/z 311.0[M+H]
+。
第二步
将化合物4-1(17.5g,56.31mmol,1eq)溶于二氯甲烷(700mL)中，在25℃下滴加二异丁基氢化铝的甲苯溶液(1M,168.92mL,3eq)，反应液在氮气保护下反应1小时。缓慢向反应液中加入饱和酒石酸钾钠水溶液(700mL)搅拌1小时，用二氯甲烷(500mL×4)萃取，合并有机相，有机相减压浓缩干得到化合物4-2。MS:m/z 283.0[M+H]
+。
第三步
将化合物4-2(15g,53.04mmol,1eq)溶于二氯甲烷(500mL)，加入二氧化锰(46.12g,530.43mmol,10eq)，在50℃搅拌12个小时。将反应液通过硅藻土过滤，滤液减压浓缩干得到化合物4-3。MS:m/z 281.0[M+H]
+。
第四步
将化合物4-3(24g,85.48mmol,1eq)分批加入到水合肼(241.57g,4.10mol,234.53mL,85％含量,47.99eq)中，再加入对甲苯磺酸(8.83g,51.29mmol,0.6eq)，在氮气保护，120℃下搅拌20小时。用二氯甲烷(500mL)和甲醇(50mL)的混合液稀释，有机相用水(400mL)洗涤，饱和食盐水(400mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(甲醇/二氯甲烷，甲醇的比例＝0～15％)得到化合物4-4。MS:m/z 259.0[M+H]
+。
第五步
将化合物4-4(6g,23.23mmol,1eq)溶于乙腈(140mL)中，加入化合物1-8(17.58g,34.84mmol,1.5eq)，冷却至0℃，滴加三甲硅基三氟甲磺酸酯(7.74g,34.84mmol,6.30mL,1.5eq)，反应液缓慢升温至25℃下搅拌12小时。反应液中加入二氯甲烷(300mL)稀释，有机相用饱和碳酸氢钠水溶液(200mL)洗涤，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(甲醇/二氯甲烷，甲醇的比例＝0～5％)纯化得到产物化合物4-5。MS:m/z 703.2[M+H]
+。
第六步
将化合物4-5(2.9g,4.13mmol,1eq)溶于甲醇(40mL)和二氯甲烷(40mL)的混合溶剂中，再加入氢氧化钠溶液(1M,12.38mL,3eq)，在25℃下搅拌12小时。将反应液减压浓缩干得到粗品。粗品经快速硅胶柱纯化(甲醇/二氯甲烷，甲醇的比例＝0～10％)得到化合物4-6。MS:m/z 391.1[M+H]
+。
第七步
将化合物4-6(473.0mg,1.21mmol,1eq)溶于丙酮(40mL)中，加入2,2-二甲氧基丙烷(1.26g,12.11mmol,1.48mL,10eq)和对甲苯磺酸(271.2mg,1.57mmol,1.3eq)，反应液在25℃下搅拌12小时。向反应液中加入乙酸乙酯(50mL×2)稀释，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经快速硅胶柱(乙酸乙酯/石油醚，乙酸乙酯的比例＝0～50％)纯化得到化合物4-7。MS:m/z 431.1[M+H]
+。
第八步
将化合物4-7(30mg,69.68μmol,1eq)溶于磷酸三甲酯(0.5mL)，在25℃下滴加亚甲基双膦酰二氯(87mg,348.42μmol,5eq)的磷酸三甲酯(0.25mL)溶液，反应液继续搅拌6小时，之后加入水(0.5mL)并在25℃下继续搅拌18小时。向反应液中加入稀盐酸(1M,0.2mL)，在25℃下继续搅拌48小时。将反应液冷冻干燥，再用水(1mL)和乙腈(1mL)溶解，溶液经制备高效液相色谱(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；乙腈％:0％-28％)纯化得到化合物4的三氟乙酸盐。MS:m/z 549.0[M+H]
+。
1H NMR(400MHz,CD
3OD)δ8.52(s,1H),8.23(br d,J＝4.8Hz,1H),7.55(br d,J＝5.2Hz,1H),6.18(br d,J＝2.8Hz,1H),4.78-4.70(m,2H),4.55(t,J＝5.2Hz,1H),4.31-4.28(m,1H),4.26-4.18(m,1H),4.14-4.07(m,1H),2.35-2.20(m,4H),1.91-1.79(m,6H)。
生物测试数据：
实验例1：CD73酶抑制活性测试
实验材料：
CD73 Inhibitor Screening Assay Kit购自BPS Bioscience
实验方法：
1X assay buffer配制(现配现用)：将5X assay buffer用ddH
2O(双蒸水)稀释成1X assay buffer，冰上放置备用。
将待测化合物用100％DMSO稀释到10μM作为第一个浓度，然后再用排枪进行5倍稀释至第8个浓度，即从10μM稀释至0.128nM。
用1X assay buffer将待测化合物各梯度稀释成DMSO为10％的工作液，2.5μL/孔加到对应孔中，设置双复孔实验。1000转，离心1分钟。
用1X assay buffer将CD73酶稀释到0.1ng/μL，取10μL/孔加入到对应孔中，阴性对照孔中加入10μL 1X assay buffer，该步在冰上操作，CD73酶为每孔1ng。
每孔加入7.5μL配制的反应混合液，其中含4.5μL H
2O；3μL 5x CD73 assay buffer。1000转，离心1分钟。反应体系置于37度孵育60分钟做化合物预孵育。
化合物预孵育结束后每孔加入5μL 500μM AMP，反应体系置于37度反应20分钟。此时化合物终浓度梯度为100nM至0.00128nM，底物AMP浓度为100μM。
反应结束后加入每孔50μL Colorimetric检测试剂，37度反应15分钟，结束反应后采用多标记分析仪读取OD 630nm。
利用方程式(Sample-Min)/(Max-Min)*100％将初始值换算成抑制率，IC
50的值即可通过四参数进行曲线 拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。Max:无CD73酶对照孔初始值；Min：含有1％DMSO溶剂对照孔初始值。表1提供了本发明的化合物对CD73酶活的影响。实验结果见表1。
表1本发明化合物对CD73酶体外抑制活性筛选试验结果
| 化合物 | CD73 IC 50(nM) |
| 化合物1的三氟乙酸盐 | 0.040 |
| 化合物2的三氟乙酸盐 | 0.073 |
| 化合物3的三氟乙酸盐 | 0.108 |
| 化合物4的三氟乙酸盐 | 0.090 |
结论：本发明化合物对CD73有很强的抑制活性。
实验例2：化合物对细胞表面的CD73的抑制活性测试
本实验采用内源性表达CD73的人乳腺癌细胞MDA-MB-231来评价化合物对细胞表面的CD73的抑制作用。
实验方法：实验开始前20h左右，将细胞铺于96孔平底培养板进行培养。第二天，用PFB(Phosphate-free buffer，即不含磷酸盐的缓冲液)配制2X浓度梯度的待测药物。用100μL的PFB清洗细胞一次，弃去上清，加入45μL新鲜的PFB，加入50μL 2X浓度梯度的待测药物至相应孔，同时设置只加50μL PFB的空白对照孔，37℃孵育15min。加入5μL预先配制好的AMP(终浓度40μM)并轻轻混匀，盖上盖子并于37℃孵育30-60min。根据试剂盒(Malachite Green Phosphate Detection Kit：R&D systems-DY996)的说明，配制磷酸盐标准曲线(磷酸盐浓度为100至1.56μM)，转移50μL标准曲线的磷酸盐上清液至另一洁净96孔读数板的最左侧一列，计数板样品孔每孔加入25μL 10mM EDTA(用PFB配制)。孵育完成后，转移25μL细胞培养上清至96孔读数板并混匀，每孔加入10μL孔雀绿试剂-A并于室温振荡孵育10min，每孔加入10μL孔雀绿试剂-B并于室温振荡孵育20min。孵育结束后，用微孔板分光光度仪读取620nm吸光值。
数据处理：抑制率计算公式为(空白对照孔吸光值-化合物孔吸光值)/空白对照孔吸光值*100％，IC
50值使用GraphPad Prism中log(inhibitor)vs.response--Variable slope模式进行曲线拟合得出。实验结果见表2。
表2本发明化合物对MDA-MB-231细胞表面的CD73抑制活性测试结果
结论：本发明化合物对MDA-MB-231细胞表面的CD73有很强的抑制活性。
实验例3：化合物逆转ADO介导的CD8
+T细胞抑制测试
实验方法：
1)EDTA抗凝全血以相同体积的PBS稀释，50mL离心管中加入15mL Lymphoprep(人淋巴细胞分离液)，将30mL稀释的血液样本缓慢的加在Lymphoprep上面，注意不破坏界面。
2)加样完毕的离心管室温下1000g离心25min，不使用制动。
3)收集包含PBMC的白细胞层至新的50mL离心管中，用PBS洗两次，350g离心10min。
4)弃上清，用EasySep
TM Buffer重悬细胞。用EasySep
TM Human CD8
+T Cell Isolation Kit从PBMC中进一步分离得到CD8
+T细胞。
5)用终浓度为1μM的CFSE室温避光孵育15min，调整细胞密度为5×10
6/mL，孵育期间颠倒混匀2-3次。
6)用PBS洗涤两次，400g离心5min，离心后弃上清。用完全培养液重悬细胞调整浓度为7.5×10
5/mL。
7)将CD8
+T细胞(体积为100μL/well)加入到96孔U底板中，加入待测化合物25μL孵育1h。对照孔加入DMSO含量相等的完全培养基。
8)加入完全培养液配制的50μL浓度为4mM的AMP(终浓度1mM，AMP经CD73可以代谢生成ADO)；对照孔加入PBS含量相同的完全培养基。再加入25μL CD3/CD28磁珠和hIL-2细胞因子混合物，使得磁珠/细胞比例为1:10，IL-2工作浓度为10ng/ml；对照组加入相同体积的完全培养基。
9)混匀后，置于37℃，5％CO
2培养箱中孵育64h。
10)4℃，350g离心5min；取上清，用ELISA检测IFN-γ表达。
11)板中剩余细胞用PBS洗涤，500g离心5min，弃上清。加入FVS780染色，室温避光孵育10min。
12)加入PBS，350g离心5min，洗涤2遍。用PBS重悬，流式检测细胞增殖。
13)用FlowJo和GraphPad进行数据分析。实验结果见表3和表4。
表3本发明化合物对ADO介导的CD8
+T细胞IFN-γ分泌抑制的逆转作用
表4本发明化合物对ADO介导的CD8T
+细胞增殖抑制的逆转作用
结论：本发明化合物可以显著逆转ADO对CD8
+T细胞IFN-γ分泌和CD8
+T细胞增殖的抑制。
实验例4：小鼠药代动力学性质评价
实验方法：受试化合物溶于10％DMSO/10％Solutol/80％水的溶媒中，制备得到浓度为0.2mg/mL的澄清溶液，微孔滤膜过滤后备用。选取19至22克的Balb/c雌性小鼠，静脉给予候选化合物溶液，剂量为1mg/kg。收集0.083、0.25、0.5、1、2、4、8、24h的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin 6.3计算药代动力学参数。测试结果见表5。
表5：本发明化合物小鼠血浆中的药物代谢动力学(PK)参数
注：T
1/2，半衰期；V
dss，表观分布容积；Cl，药物清除率；AUC
0-last，时间曲线下面积
实验结论：本发明化合物具有良好的小鼠静脉注射体内药代动力学性质。
Claims (23)
- 式(I)所示化合物或其药学上可接受的盐，
其中，R 1、R 2和R 5分别独立地选自H、C 1-3烷基和C 3-6环烷基，所述C 1-3烷基和C 3-6环烷基分别独立地任选被1、2或3个R a取代；R 3、R 4、R 6和R 7分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基分别独立地任选被1、2或3个R b取代；R 8和R 9分别独立地选自OH、F、Cl、Br和I；R 10选自H、F、Cl、Br、I、C 1-3烷氧基和C 1-3烷基，所述C 1-3烷氧基和C 1-3烷基分别独立地任选被1、2或3个R c取代；R 11选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代；L 1选自键和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R e取代；各R 12分别独立地选自F、Cl、Br、I、OH、CN、C 1-3烷氧基和C 1-3烷基，所述C 1-3烷氧基和C 1-3烷基分别独立地任选被1、2或3个R f取代；环A选自苯基、萘基、5-10元杂芳基、C 3-6环烷基、C 4-6环烯基、4-6元杂环烷基和4-6元杂环烯基；选自双键，T 1和T 2分别独立地选自C；
或者，选自单键，T 1和T 2其中一个选自C，另一个选自N；
环B选自5-6元杂芳基、C 4-6环烯基和4-6元杂环烯基，所述5-6元杂芳基、C 4-6环烯基和4-6元杂环烯基分别独立地任选被1、2或3个R g取代；n选自0、1、2和3；各R a、R b、R c、R d、R e、R f和R g分别独立地选自F、Cl、Br、I、CN、OH、C 1-3烷氧基和C 1-3烷基，所述C 1-3烷氧基和C 1-3烷基分别独立地任选被1、2或3个F取代；所述“5-10元杂芳基”、“5-6元杂芳基”、“4-6元杂环烷基”和“4-6元杂环烯基”分别独立地包含1、2或3个独立选自NH、N、O和S的杂原子或杂原子团。 - 根据权利要求1所述化合物或其药学上可接受的盐，其中，各R a、R b、R c、R d、R e、R f和R g分别独立地选自F、OH和CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1、R 2和R 5分别独立地选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2分别独立地任选被1、2或3个R a取代。
- 根据权利要求3所述化合物或其药学上可接受的盐，其中，R 1、R 2和R 5分别独立地选自H。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 3和R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、CH 3、CH 2CH 3、OCH 3、OCH 2CH 3、环丙基和环丁基，所述CH 3、CH 2CH 3、OCH 3、OCH 2CH 3、环丙基和环丁基分别独立地任选被1、2或3个R b取代。
- 根据权利要求5所述化合物或其药学上可接受的盐，其中，R 3和R 4分别独立地选自H。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 6和R 7分别独立地选自H。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 8和R 9分别独立地选自OH。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 10选自H。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 11选自H。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 12选自F。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，L 1选自键、CH 2和CH 2CH 2。
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，环A选自苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、苯并吡唑基、苯并咪唑基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基和吗啡啉基。
- 根据权利要求13所述化合物或其药学上可接受的盐，其中，环A选自苯基和环戊基。
- 根据权利要求1或14所述化合物或其药学上可接受的盐，其中，结构单元选自
- 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元选自呋喃基、噻吩基、噻唑基、噁唑基、咪唑基、吡咯基、吡唑基、环丁烯基、环戊烯基、环己烯基、氧杂环戊烯基、氧杂环己烯基、氮杂环戊烯基、氮杂环己烯基、硫杂环戊烯基和硫杂环己烯基，所述呋喃基、噻吩基、噻唑基、噁 唑基、咪唑基、吡咯基、吡唑基、环丁烯基、环戊烯基、环己烯基、氧杂环戊烯基、氧杂环己烯基、氮杂环戊烯基、氮杂环己烯基、硫杂环戊烯基和硫杂环己烯基分别独立地任选被1、2或3个R g取代。
- 根据权利要求16所述化合物或其药学上可接受的盐，其中，结构单元选自呋喃基、噻吩基、噻唑基、咪唑基、环戊烯基和硫杂环戊烯基，所述呋喃基、噻吩基、噻唑基、咪唑基、环戊烯基和硫杂环戊烯基分别独立地任选被1、2或3个R g取代。
- 根据权利要求17所述化合物或其药学上可接受的盐，其中，结构单元选自
- 根据权利要求18所述化合物或其药学上可接受的盐，其中，结构单元选自
- 根据权利要求1～19任意一项所述化合物或其药学上可接受的盐，其化合物选自，
其中，环A、环B、T 1、T 2、L 1、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、n和分别如权利要求1～19任意一项所定义。
- 下列所示化合物或其药学上可接受的盐，
- 根据权利要求21所述的化合物或其药学上可接受的盐，其选自，
- 权利要求1～22任意一项所述的化合物或其药学上可接受的盐在制备治疗与CD73抑制剂相关疾病的药物中的应用。
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|---|---|---|---|---|
| WO2018183635A1 (en) * | 2017-03-31 | 2018-10-04 | Peloton Therapeutics, Inc. | Cd73 inhibitors and uses thereof |
| CN108697719A (zh) * | 2016-01-08 | 2018-10-23 | 艾库斯生物科学有限公司 | 胞外5′-核苷酸酶的调节剂及其用途 |
| WO2018208980A1 (en) * | 2017-05-10 | 2018-11-15 | Oric Pharmaceuticals, Inc. | Cd73 inhibitors |
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| CN108697719A (zh) * | 2016-01-08 | 2018-10-23 | 艾库斯生物科学有限公司 | 胞外5′-核苷酸酶的调节剂及其用途 |
| WO2018183635A1 (en) * | 2017-03-31 | 2018-10-04 | Peloton Therapeutics, Inc. | Cd73 inhibitors and uses thereof |
| WO2018208980A1 (en) * | 2017-05-10 | 2018-11-15 | Oric Pharmaceuticals, Inc. | Cd73 inhibitors |
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