CN113861161A - Aryl aromatic heterocyclic derivative and preparation method and application thereof - Google Patents
Aryl aromatic heterocyclic derivative and preparation method and application thereof Download PDFInfo
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- CN113861161A CN113861161A CN202010621956.9A CN202010621956A CN113861161A CN 113861161 A CN113861161 A CN 113861161A CN 202010621956 A CN202010621956 A CN 202010621956A CN 113861161 A CN113861161 A CN 113861161A
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- Prior art keywords
- substituted
- unsubstituted
- compound
- group
- alkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 278
- 239000000203 mixture Substances 0.000 claims abstract description 71
- 125000001424 substituent group Chemical group 0.000 claims abstract description 63
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 8
- 229940044665 STING agonist Drugs 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 230000001900 immune effect Effects 0.000 claims abstract description 4
- 239000012646 vaccine adjuvant Substances 0.000 claims abstract description 4
- 229940124931 vaccine adjuvant Drugs 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 70
- 150000002367 halogens Chemical class 0.000 claims description 70
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 61
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 48
- 238000006467 substitution reaction Methods 0.000 claims description 48
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 32
- -1 hydroxy, methoxy, amino, carboxy Chemical group 0.000 claims description 32
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 22
- 206010003402 Arthropod sting Diseases 0.000 claims description 18
- 208000003014 Bites and Stings Diseases 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 108010014726 Interferon Type I Proteins 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
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- 206010039491 Sarcoma Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
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- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
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- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
- 208000008938 Rhabdoid tumor Diseases 0.000 claims description 3
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- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 208000009956 adenocarcinoma Diseases 0.000 claims description 3
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- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 208000024348 heart neoplasm Diseases 0.000 claims description 3
- 201000005787 hematologic cancer Diseases 0.000 claims description 3
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
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- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 230000003211 malignant effect Effects 0.000 claims description 3
- 208000006178 malignant mesothelioma Diseases 0.000 claims description 3
- 201000011519 neuroendocrine tumor Diseases 0.000 claims description 3
- 210000004994 reproductive system Anatomy 0.000 claims description 3
- 201000011096 spinal cancer Diseases 0.000 claims description 3
- 208000014618 spinal cord cancer Diseases 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 claims 1
- 208000021309 Germ cell tumor Diseases 0.000 claims 1
- 208000009889 Herpes Simplex Diseases 0.000 claims 1
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- 206010052399 Neuroendocrine tumour Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims 1
- 229910021386 carbon form Inorganic materials 0.000 claims 1
- 201000010175 gallbladder cancer Diseases 0.000 claims 1
- 201000010235 heart cancer Diseases 0.000 claims 1
- 208000002672 hepatitis B Diseases 0.000 claims 1
- 208000010710 hepatitis C virus infection Diseases 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
- 201000010982 kidney cancer Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
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- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
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- 201000001275 rectum cancer Diseases 0.000 claims 1
- 201000000849 skin cancer Diseases 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 241
- 238000006243 chemical reaction Methods 0.000 description 179
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- 239000000243 solution Substances 0.000 description 111
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 86
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 86
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 82
- 235000019439 ethyl acetate Nutrition 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 239000007787 solid Substances 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
- 230000015572 biosynthetic process Effects 0.000 description 54
- 238000003786 synthesis reaction Methods 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- 239000012074 organic phase Substances 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
- 238000000605 extraction Methods 0.000 description 30
- 239000000047 product Substances 0.000 description 29
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- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 26
- 229910052757 nitrogen Inorganic materials 0.000 description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
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- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 20
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
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- 239000004480 active ingredient Substances 0.000 description 12
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The invention discloses an aryl aromatic heterocyclic derivative and a preparation method and application thereof, wherein the structure is shown as a formula I, and in the formula, the definition of each substituent group is described in the specification and the claims. The compounds of the invention can be used as STING agonists, in the treatment of diseases including tumors, infectious diseases, or as immunological compositions or vaccine adjuvants.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to an aryl aromatic heterocyclic derivative and a preparation method and application thereof.
Background
Innate immunity is the first line of defense of the body against pathogen infection, and plays a crucial role in inhibiting tumor growth and the pathogenesis of autoimmunity. In recent years, cGAS-STING-TBK1 has attracted much attention as a natural immune regulator, and when cGAS (cyclic GMP-AMP synthase) is a DNA receptor and senses pathogen DNA, cGAMP (cyclic GMP-AMP) is induced to be produced, which causes activation of Interferon gene stimulating factors (stimulants of Interferon genes, STING), recruits TANK-binding kinase 1(TANK-binding kinase 1, TBK1) to phosphorylate Interferon regulatory Factor 3(Interferon regulatory Factor 3, IRF3), induces production of type I Interferon and cytokines, and activates the adaptive immune system through a series of cascade reactions, activating T cells, and thereby exerting an antitumor immune effect.
STING agonists not only induce the expression of type i interferon genes, but also play an important role in the natural immune signaling pathway. It can also activate immunostimulatory cells including dendritic cells, alter the tumor microenvironment and induce the production of tumor specific T cells, thereby killing tumor cells. Research has shown that: in different mouse tumor models (including the B16 melanoma model, the 4T1 breast cancer and the CT26 colon cancer model), primary tumor growth and distant lesions were prevented by intratumoral or intravenous injection of STING agonists. These findings suggest that achieving anti-tumor effects by activating STING has become one of the important strategies for anti-tumor immunotherapy.
To date, STING small molecule agonist studies are in the initiative and few compounds are available for clinical trial studies, with ADU-S100 (phase II) developed by the adoro company and MK1454 (phase I) developed by the merck company, both cyclic dinucleotide analogs and administration being intratumoral. The drugs have the defects of large molecular weight, poor cell membrane permeability, negative phosphate group contained in the structure, very easy hydrolysis of a phosphate bond, very poor pharmacokinetic property and the like, and the clinical use of the compounds is severely limited. In 2018, the GSK company reports the first benzimidazole STING agonist capable of being administered by intravenous injection, but the compounds still have serious metabolic problems. Therefore, there is a need to develop a novel small molecule with simple structure, convenient synthesis, stable metabolism and high safety, which can activate interferon gene-stimulated protein and induce the production of type i interferon beta. The STING agonist can be widely used for treating tumors and infectious diseases, or used as an immune composition or a vaccine adjuvant.
Disclosure of Invention
The invention aims to provide a compound shown in a formula (I) and application of a preparation method thereof in the aspects of resisting tumors and infectious diseases.
In a first aspect of the invention, there is provided a compound of formula (I), or an enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt thereof,
in the formula (I), the compound is shown in the specification,
A1、X1each independently is N or CRx;RxIs H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -L-M; the substituted is substituted by a substituent selected from the group consisting of: halogen, hydroxy, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;
W1is NH, S or O; y is1Is N or CRy;RyIs H, -L-M or absent;
R1、R2independently selected from halogen, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylacyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C4 alkylamido, substituted or unsubstituted C1-C4 alkylamino, -L-M; r1、R2Wherein said substitution is with a substituent selected from group a: one or more of halogen, hydroxyl, methoxyl, amino and carboxyl;
R3is F, R4Is H, halogen, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; or R3And R4Form, with the C atom to which they are attached, a 3-6 membered heterocyclyl or C3-C8 cycloalkyl; or R3And R4Taken together to form ═ O; or R4Is H, R3And Y1And forms a 5-7 membered heterocyclic group with the C atom therebetween; at this time Y1Is C;
R5、R6、R7、R8each independently is H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C4 alkanoylamino; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 3-6 membered heterocyclyl;
or R5、R6Taken together with the attached carbon to form a substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7、R8Taken together with the attached carbon to form a substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: c1-C6 alkyl, hydroxy, halogen;
T1is-C (O) R9、-SO2R9、5-7 membered heteroaryl unsubstituted or substituted by a substituent selected from group B, C1-C6 alkyl unsubstituted or substituted by a substituent selected from group B; r9Selected from the group consisting of H, hydroxy, C1-C6 alkoxy, -NHCO- (C1-C6 alkyl), C1-C6 alkyl unsubstituted or substituted with a substituent selected from group B, amino unsubstituted or substituted with a substituent selected from group B, and 5-8 membered heteroaryl unsubstituted or substituted with a substituent selected from group B; group B substituents include: halogen, hydroxy, C1-C6 alkyl, -SO2CH3;
And when A1、X1、Y1Is CH, W1Is S, T1is-C (O) R9And R is1And R2When none is-L-M, R5、R6、R7、R8Cannot be all H at the same time;
and A is1R in (1)x、X1R in (1)x、R1、R2、RyAny two of which are not simultaneously-L-M;
l is selected from- (CH)2)m-(Q)i-(CH2)n-、-O-(CH2)m-(Q)i-(CH2)n-O-、-O-(CH2)m-(Q)i-(CH2)n-、-(CH2)m-(Q)i-(CH2)n-O-,; m and n are respectively and independently selected from integers of 0-5; i is 0 or 1; and m, n and i are not 0 at the same time; q is selected from-CH ═ CH-, -C ≡ C-, -C (O) -NH-, -NH-C (O) -, -N ═ CH-, O, 3-8 membered heterocyclyl, 3-8 membered heteroaryl;
m is selected from the following structures:
A2、X2each independently is N or CRx’;Rx' is H or halogen; rx' is H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl; a substituted or unsubstituted C1-C6 alkoxy group; the substituted is substituted by a substituent selected from the group consisting of: halogen, hydroxy, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;
W2o, S, NH; y is2Is N or CRy’;Ry' is H or absent;
R1’、R2' is independently selected from halogen, hydroxy, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C4 alkylamido, substituted or unsubstituted C1-C4 alkylamino; r1’、R2The substitution in' means substitution by one or more selected from halogen, hydroxyl and methoxy;
R3' is F, R4' is H, halogen, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; or R3' and R4' forms a 3-6 membered heterocyclic group with the C atom to which they are attached; or R3' and R4Together form ═ O; or R4' is H, R3' and Y1And forms a 5-7 membered heterocyclic group with the C atom therebetween; at this time Y2Is C;
R5’、R6’、R7’、R8' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C4 alkanoylamino; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 3-6A heterocyclic group;
or R5’、R6' taken together with the attached carbon to form a substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7’、R8' taken together with the attached carbon to form a substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
T2is-C (O) R9、-SO2R9、5-7 membered heteroaryl unsubstituted or substituted by a substituent selected from group B, C1-C6 alkyl unsubstituted or substituted by a substituent selected from group B; r9Selected from the group consisting of H, hydroxy, C1-C6 alkoxy, -NHCO- (C1-C6 alkyl), C1-C6 alkyl unsubstituted or substituted with a substituent selected from group B, amino unsubstituted or substituted with a substituent selected from group B, and 5-8 membered heteroaryl unsubstituted or substituted with a substituent selected from group B;
T3is 5-7 membered heteroaryl, unsubstituted or substituted by a substituent selected from group B;
group B substituents include: halogen, hydroxy, C1-C6 alkyl, -SO2CH3;
T4And T4' are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C8 cycloalkyl; the substituted means substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, amino, carboxyl, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 3-8 membered heterocyclic group, C6-C10 aryl.
In a preferred embodiment, A1、X1Each independently is N or CRx;RxH, F, Cl, -L-M; a. the2、X2Each independently is N or CRx’;Rx' is H, F, Cl; y is1Is N or CRy;RyIs H, -L-M or absent; y is2Is N or CH; w1、W2Each independently is NH or S; r1、R2Each independently is fluorine, chlorine, bromine or C1-C4 alkoxy, -L-M; r1’、R2' are each independently fluorine, chlorine, bromine or C1-C4 alkoxy; and A is1R in (1)x、X1R in (1)x、R1、R2、RyAny two of which are not simultaneously-L-M.
In a preferred embodiment, R3And R4Are all F; or R3And R4Form, with the C atom to which they are attached, a 3-6 membered heterocyclyl or C3-C8 cycloalkyl; or R3And R4Taken together to form ═ O; or R4Is H, R3And Y1And forms a 5-7 membered heterocyclic group with the C atom therebetween; at this time Y1Is C;
in a preferred embodiment, R3' and R4' both are F; or R3' and R4' forms a 3-6 membered heterocyclic group or a C3-C8 cycloalkyl group with the C atom to which they are attached; or R3' and R4Together form ═ O; or R4' is H, R3' and Y2And forms a 5-7 membered heterocyclic group with the C atom therebetween; at this time Y2Is C;
in a preferred embodiment, R5、R6、R7、R8Each independently is H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 4-6 membered heterocyclyl;
or R5、R6Together with the carbon to which they are attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstitutedSubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7、R8Together with the carbon to which they are attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
R5’、R6’、R7’、R8' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 4-6 membered heterocyclyl;
or R5’、R6' taken together with the carbon to which it is attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7’、R8' taken together with the carbon to which it is attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxyl and halogen.
In a preferred embodiment, the compound of formula (I) has a structure selected from the group consisting of:
wherein the content of the first and second substances,
A1、X1、A2、X2each independently is N or CRx;RxIs H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; the takingSubstituted is substituted by a substituent selected from the group consisting of: halogen, hydroxy, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;
Y1、Y2each independently is N or CH; w1、W2Each independently is NH or S;
R1、R2independently selected from halogen, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; r1、R2Wherein the substitution is substituted by one or more selected from halogen, hydroxyl and methoxy;
l is selected from- (CH)2)m-(Q)i-(CH2)n-、-O-(CH2)m-(Q)i-(CH2)n-O-; m and n are respectively and independently selected from integers of 1-5; i is 0 or 1; q is selected from-CH ═ CH-, -C ≡ C-, -C (O) -NH-, -NH-C (O) -, -N ═ CH-, O, and,
R3、R4、R5、R6、R7、R8、T1、R1’、R2’、R3’、R4’、R5’、R6’、R7’、R8’、T2And T3The definition of (A) is as described above.
In a preferred embodiment, the compound is selected from the group consisting of:
in a first aspect of the invention, there is provided a compound of formula (I), or an enantiomer, diastereomer, racemate, or mixture thereof, or a pharmaceutically acceptable salt thereof.
The compounds of the present invention have asymmetric centers, chiral axes and chiral planes, and can exist in the form of racemates, R-isomers or S-isomers. The person skilled in the art is able to obtain the R-isomer and/or the S-isomer by resolution of the racemate by means of customary technical measures.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the first aspect or enantiomers, diastereomers, racemates and mixtures thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
The present invention provides a novel compound which can be used alone or in admixture with pharmaceutically acceptable adjuvants (e.g., excipients, diluents, etc.) to prepare tablets, capsules, granules, syrups, and the like for oral administration. The pharmaceutical composition can be prepared according to a conventional method in pharmacy.
In another preferred embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent. Preferably, the at least one other therapeutic agent comprised in the pharmaceutical composition is selected from the group consisting of other anti-cancer agents, immunomodulators, anti-allergic agents, antiemetics, pain relieving agents, cytoprotective agents and combinations thereof.
In a third aspect of the invention, there is provided a use of the compound of formula (I) according to the first aspect or the pharmaceutical composition according to the second aspect for the preparation of a STING agonist, an immunological composition or a vaccine adjuvant;
or for the prevention and/or treatment of STING-dependent type I interferon-related diseases.
In another preferred embodiment, the STING-dependent type I interferon-related diseases are tumor and infectious diseases.
In another preferred embodiment, the tumor is selected from the group consisting of: brain and spinal cancers, head and neck cancers, leukemias and blood cancers, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, esophageal cancers, nasopharynx cancers, pancreatic cancers, rectal cancers, hepatocellular cancers, cholangiocarcinomas, gallbladder cancers, colon cancers, multiple myeloma, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, adenocarcinomas, thyroid cancers, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline tract cancers, and unknown primary cancers (i.e., cancers in which metastatic cancers are found but the location of the original cancer is unknown).
In another preferred embodiment, the infectious disease is selected from: viral infections such as human immunodeficiency virus, herpes simplex virus, hepatitis b virus, hepatitis c virus; infection by pathogenic microorganisms.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have extensively and intensively studied to develop a 4- (arylbenzothiophene) -4, 4-difluoro-polysubstituted butyric acid derivative. The invention carries out multi-site methyl or fluorination modification on benzene ring or butyric acid side chain of a benzothiophene compound to obtain a multi-substituted derivative, and can simultaneously and efficiently activate human (human) sting (hsting) and mouse (mouse) sting (mSTING). In particular, the drug metabolism (PK) properties of compound S1 containing both methyl and three fluorine atom substitutions are significantly improved, thereby enabling the compound to be orally administered and avoiding the development of special dosage forms in later studies. On the basis of this, the present invention has been completed.
Term(s) for
In the present invention, when the valence bond of the group has a wavy lineWhen, for example, inThe wavy line in (a) indicates the point of attachment of the group to the rest of the molecule.
In the present invention, the halogen is F, Cl, Br or I.
In the present invention, unless otherwise specified, the terms used have the ordinary meanings well known to those skilled in the art.
In the present invention, the term "C1-C6" means having 1,2, 3, 4, 5, or 6 carbon atoms, "C1-C8" means having 1,2, 3, 4, 5,6, 7, or 8 carbon atoms, and so on. "3-8 membered" means having 3-8 ring atoms, and so on, "3-6 membered", and so on.
In the present invention, the term "alkyl" denotes a saturated linear or branched hydrocarbon moiety, for example the term "C1-C6 alkyl" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "alkoxy" denotes a-O- (C1-6 alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
In the present invention, the term "alkenyl" denotes a straight or branched chain hydrocarbon moiety comprising at least one double bond, for example the term "C2-C6The alkenyl group "means a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, and includes, but is not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
In the present invention, the term "cycloalkyl" denotes a saturated cyclic hydrocarbon moiety, for example the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.
In the present invention, the term "heterocyclyl" denotes a cyclic group comprising at least one carbon atom and at least one (e.g., 1 to 3) ring heteroatom selected from N, O, S, such as 3-8 membered heterocyclyl, 3-6 membered heterocyclyl and the like; such as tetrahydrofuranyl, pyrrolidinyl, oxetanyl, oxacyclohexyl, azetidinyl, oxiranyl, aziridinyl, thietanyl, 1, 2-dithianobutyl, 1, 3-dithianobutyl, azepanyl, oxepanyl, and the like.
In the present invention, the term "5-7 membered heteroaryl" refers to a cyclic aromatic hydrocarbon group having 5,6 or 7 ring atoms, which contains at least one (e.g., 1-3) ring heteroatom (S) independently selected from N, O and S (e.g., N) in the ring, the remaining ring atoms being carbon atoms; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2, 4-triazolyl, etc.; preferred are five-membered heteroaryl groups such as imidazolyl, isoxazolyl, 1,2, 4-triazolyl, benzoxazolyl, imidazopyridinyl, triazolopyridinyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolinyl, isoquinidinyl, and the like.
Unless otherwise specified, alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on the alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocyclyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylsulfino, C1-C10 alkylsulfino, arylsulfonylimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, cyano, acyl, thioacyl, acyloxy, carboxyl, and carboxylic acid ester groups. In another aspect, cycloalkyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl groups can also be fused to each other.
In the invention, the substitution is mono-substitution or multi-substitution, and the multi-substitution is di-substitution, tri-substitution, tetra-substitution or penta-substitution. By disubstituted is meant having two substituents and so on.
The pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium.
In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or a sodium, magnesium, potassium, calcium, aluminum, manganese or ammonium salt of a compound of formula (I) with an inorganic base; or the methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the general formula (I) and organic base.
The invention carries out multi-site methyl or fluorination modification on benzene ring or butyric acid side chain of a benzothiophene compound to obtain a multi-substituted derivative, and can simultaneously and efficiently activate human (human) sting (hsting) and mouse (mouse) sting (mSTING). In particular, the drug metabolism (PK) properties of compound S1 containing both methyl and three fluorine atom substitutions are significantly improved, thereby enabling the compound to be orally administered and avoiding the development of special dosage forms in later studies.
In particular, the advantages of representative compounds S1 of the present invention compared to compounds IA, which do not contain methyl and fluorine atom substitutions, and compounds IB, which contain only methyl groups but no fluorine atom substitutions in the side chains, are represented by:
1. half-life T1/2 reached 1.56 hours, 2.4 times that of compound IA and 2 times that of IB;
2. the exposure of oral administration is obviously improved and is 7.5 times of that of the compound IA and 5.8 times of that of the compound IB;
3. the exposure of intravenous administration is significantly improved, 10.4 times that of compound IA and 7.2 times that of compound IB.
Therefore, the compound containing a plurality of special group substitutions simultaneously has high agonistic activity to hSTING or mSTING and is remarkably improved in metabolism property in rats, so that the drug effect of the compound is fully exposed in the process of intravenous administration or oral administration when the compound enters in vivo pharmacodynamics and safety evaluation, and the compound has remarkable advantages and further development potential compared with the STING inhibitor reported so far.
Pharmaceutical composition
The invention also provides a pharmaceutical composition comprising a safe and effective amount of the active ingredient, and a pharmaceutically acceptable carrier.
The active ingredient refers to the compound of the formula I.
The active ingredient and the pharmaceutical composition are used for preparing the drugs for treating tumors and infectious diseases. The active ingredients and the pharmaceutical composition can be used as STING agonists to activate STING.
The tumor is selected from: brain and spinal cancers, head and neck cancers, leukemias and blood cancers, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, esophageal cancers, nasopharynx cancers, pancreatic cancers, rectal cancers, hepatocellular cancers, cholangiocarcinomas, gallbladder cancers, colon cancers, multiple myeloma, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, adenocarcinomas, thyroid cancers, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline tract cancers, and unknown primary cancers (i.e., cancers in which metastatic cancers are found but the location of the original cancer is unknown).
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient.Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other therapeutic agents, such as antineoplastic agents.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures for which specific conditions are not indicated in the following examples are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Preparation of the Compound of example 1
1. Synthesis of Compound S1
Step 1: the compound 1a (1eq) was dissolved in toluene in a sealed tube, and rhodanine (1.1eq) and ammonium acetate (2eq) were added, and the temperature was raised to 160 ℃ for 20 minutes.After the reaction is completed, cooling the reaction solution, precipitating a large amount of solid, adding a proper amount of ethanol for dilution, filtering, washing a filter cake with water, pulping with ethanol, and drying to obtain the compound 1 b.1H NMR(400MHz,CDCl3)δ9.24(s,1H),7.83(s,1H),7.17–7.07(m,1H),6.82(d,J=9.0Hz,1H),3.95(s,6H).
Step 2: compound 1b (1eq) was suspended in 2.5M aqueous sodium hydroxide (2.5eq), and the reaction was allowed to proceed at 75 ℃ for 30 minutes, whereupon the reaction solution became clear. Adding a proper amount of activated carbon, stirring for 15 minutes, and filtering while the solution is hot. And dropwise adding the filtrate into 6N hydrochloric acid in an ice bath, filtering after solid is fully separated out, pulping the filter cake with water, and drying to obtain a compound 1 c.1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.64(t,J=8.4Hz,1H),6.80(dd,J=9.0,1.5Hz,1H),4.67(s,1H),3.93(s,6H).
And step 3: the compound 1c (1eq) is placed in a sealed tube and dissolved in 1, 4-dioxane, the iodine simple substance (1.5eq) is added, and the temperature is raised to 150 ℃ for reaction overnight. After the reaction solution is cooled, the reaction solution is poured into water, a proper amount of saturated sodium thiosulfate solution is dropwise added for decolorization, ethyl acetate is used for extraction, and the compound 1d is obtained after column chromatography purification.1H NMR(400MHz,DMSO)δ13.50(s,1H),7.92(s,1H),7.58(s,1H),3.91(s,3H),3.84(s,3H).
And 4, step 4: dissolving the compound 1d (1eq) in N-methylpyrrolidone, adding silver carbonate (1.2eq) and phenanthroline (0.1eq), and heating to 170 ℃ for reacting for 1 hour. And (3) after the reaction liquid is cooled, passing through diatomite, extracting the filtrate by using ethyl acetate, and purifying by a column to obtain a compound 1 e.1H NMR(400MHz,CDCl3)δ7.33(d,J=5.5Hz,1H),7.27(d,J=4.5Hz,1H),7.13(s,1H),3.99–3.97(m,3H),3.94(s,3H).
And 5: (S) -methylsuccinic anhydride (1.5eq) and aluminum chloride (2eq) were suspended in 1, 2-dichloroethane, and a solution of compound 1e (1eq) in dichloroethane was added dropwise at-10 ℃. After the dropwise addition, the temperature was raised to 45 ℃ to react overnight. After the reaction solution was cooled, the reaction solution was poured into ice water, and a suitable amount of 4N hydrochloric acid was added, followed by extraction with ethyl acetate and column purification to obtain mixtures 1f and 1 g.
Step 6: the mixture 1f and 1g (1eq) were dissolved in anhydrous methanol, thionyl chloride (10eq) was added slowly in an ice bath, and after the addition was completed, the mixture was allowed to warm to room temperature for 1 hour. After the reaction is completed, the solvent is removed by spinning, the pH value of the residual oily substance is adjusted to 7-8 by using a saturated sodium bicarbonate solution, the residual oily substance is extracted by using ethyl acetate, washed by salt, dried by anhydrous sodium sulfate and then dried by spinning to obtain a mixture of 1h and 1 i.
And 7: under the protection of nitrogen, the mixture 1j and 1k (1eq) are dissolved in ultra-dry dichloromethane, 1, 3-propanedithiol (2eq) and boron trifluoride diethyl etherate (1eq) are added under ice bath, and after 2 hours of reaction, the mixture is moved to room temperature for 48 hours. After the reaction is completed, a proper amount of saturated sodium bicarbonate solution is used for quenching the reaction, ethyl acetate is used for extraction, and the pure products 1j and 1k are obtained through column purification. Compound 1 j:1H NMR(400MHz,CDCl3) δ 7.46(s,1H),7.02(s,1H),3.96(d, J ═ 0.7Hz,3H),3.93(s,3H),3.41(s,3H), 3.00-2.93 (m,2H), 2.87-2.71 (m,4H), 2.09-1.99 (m,2H), 1.97-1.87 (m,1H),1.13(d, J ═ 6.8Hz,3H). compound 1 k:1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.02(s,1H),3.97(s,3H),3.93(s,3H),3.63(s,3H),3.04–2.90(m,3H),2.76(d,J=14.9Hz,2H),2.70–2.65(m,1H),2.25(dd,J=15.8,10.7Hz,1H),2.04–1.98(m 1H),1.94–1.82(m,1H),1.14(d,J=6.7Hz,3H).
and 8: compound 1j (1eq) was dissolved in ultra-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 5 hours. After the reaction is completed, the mixture is quenched by saturated ammonium chloride solution, extracted by dichloromethane and purified by a column to obtain 1l of a compound.1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.07(s,1H),3.97(s,3H),3.94(s,3H),3.65(s,3H),2.96–2.80(m,2H),2.37–2.24(m,1H),1.28(d,J=6.8Hz,3H).
And step 9: 1l (1eq) of the compound was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (3eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S1 is obtained after column purification. Compound S1:1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.08(s,1H),3.97(s,3H),3.94(s,3H),2.98–2.83(m,2H),2.39–2.26(m,1H),1.34(d,J=6.6Hz,3H).
2. synthesis of Compound S2
Step 1: compound 1k (1eq) was dissolved in ultra-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 5 hours. After the reaction is completed, quenching the mixture by using a saturated ammonium chloride solution, extracting the mixture by using dichloromethane, and purifying the mixture by using a column to obtain a compound 2 a.1H NMR(400MHz,CDCl3)δ7.45(s,1H),7.08(s,1H),3.98(s,3H),3.95(s,3H),3.69(s,3H),2.89(br,1H),2.76(dd,J=15.9,3.9Hz,1H),2.31(dd,J=16.1,9.8Hz,1H),1.13(d,J=6.9Hz,3H).
Step 2: compound 2a (1eq) was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (3eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S2 is obtained after column purification. Compound S2:1H NMR(400MHz,CDCl3)δ7.45(s,1H),7.08(s,1H),3.98(s,3H),3.94(s,3H),2.93–2.85(m,1H),2.82(dd,J=16.5,3.6Hz,1H),2.35(dd,J=16.3,9.7Hz,1H),1.16(d,J=6.9Hz,3H).
3. synthesis of Compound S3
In addition to the replacement of (S) -methylsuccinic anhydride by itaconic anhydride, the compound S1 was synthesized. Compound S3:1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.07(s,1H),6.32(s,1H),5.80(s,1H),3.98(s,3H),3.96(s,3H),2.95–2.86(m,2H).
4. synthesis of Compound S4
In addition to the replacement of (S) -methylsuccinic anhydride by itaconic anhydride, the compound S2 was synthesized. Compound S4:1H NMR(400MHz,CDCl3)δ7.51(s,1H),7.12(s,1H),6.77(s,1H),5.91(s,1H),3.99(s,3H),3.98(s,3H),3.02(s,2H).
5. synthesis of Compound S5
Step 1: (S) - (-) -2-acetoxysuccinic anhydride (1.5eq) and aluminum chloride (2eq) were suspended in 1, 2-dichloroethane, and a solution of compound 1e (1eq) in dichloroethane was added dropwise at-10 ℃. After the dropwise addition, the temperature was raised to 45 ℃ to react overnight. After the reaction solution is cooled, the reaction solution is poured into ice water, a proper amount of 4N hydrochloric acid is added, ethyl acetate is used for extraction, and the mixture is subjected to column chromatography purification to obtain a mixture 5a and a mixture 5 b.
Step 2: the mixtures 5a and 5b (1eq) were dissolved in anhydrous methanol, thionyl chloride (10eq) was added slowly in an ice bath, and after the addition was completed, the mixture was allowed to warm to room temperature for 1 hour. After the reaction is completed, the solvent is removed by spinning, the pH of the residual oily substance is adjusted to 7-8 by using a saturated sodium bicarbonate solution, the residual oily substance is extracted by using ethyl acetate, washed by salt, dried by anhydrous sodium sulfate and then dried by spinning to obtain a mixture 5c and a mixture 5 d.
And step 3: under the protection of nitrogen, the mixture 5c and 5d (1eq) were dissolved in ultra-dry dichloromethane, 1, 3-propanedithiol (2eq) and boron trifluoride diethyl etherate (1eq) were added under ice bath, and after 2 hours of reaction, the mixture was allowed to move to room temperature for 48 hours. After the reaction is completed, a proper amount of saturated sodium bicarbonate solution is used for quenching the reaction, ethyl acetate is used for extraction, and pure products 5e and 5f are obtained through column purification.
And 4, step 4: compound 5e (1eq) was dissolved in ultra-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 5 hours. After the reaction is completed, quenching the mixture by using a saturated ammonium chloride solution, extracting the mixture by using dichloromethane, and purifying the mixture by using a column to obtain a compound 5 f.
And 5: dissolving compound 5f (1eq) in tetrahydrofuran, adding an aqueous solution of lithium hydroxide monohydrate (5eq) at room temperatureThe reaction was carried out for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S5 is obtained after column purification. Compound S5:1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.05(s,1H),4.28–4.19(m,1H),3.94(s,3H),3.87(s,3H),2.41–2.38(m,2H).
6. synthesis of Compound S6
Step 1: compound 5d (1eq) was dissolved in ultra-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 5 hours. After the reaction is completed, quenching the mixture by using a saturated ammonium chloride solution, extracting the mixture by using dichloromethane, and purifying the mixture by using a column to obtain a compound 6 a.
Step 2: compound 6a (1eq) was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (5eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S6 is obtained after column purification. Compound S6:1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.08(s,1H),4.79–4.65(m,1H),3.95(s,3H),3.86(s,3H),2.52–2.46(m,2H).
7. synthesis of Compound S7
Step 1: the mixtures 5a and 5b (1eq) were dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (3eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is added dropwise to adjust the pH value to 6-7, ethyl acetate is used for extraction, and compound mixtures 7a and 7b are obtained through column purification.
Step 2: the mixtures 7a and 7b (1eq) were dissolved in anhydrous methanol, thionyl chloride (10eq) was added slowly in an ice bath, and after the addition was completed, the mixture was allowed to warm to room temperature for 1 hour. After the reaction is completed, the solvent is removed by spinning, the pH of the residual oily substance is adjusted to 7-8 by using a saturated sodium bicarbonate solution, the residual oily substance is extracted by using ethyl acetate, washed by salt, dried by anhydrous sodium sulfate and then dried by spinning to obtain a mixture 7c and a mixture 7 d.
And step 3: under the protection of nitrogen, the mixture 7c and 7d (1eq) were dissolved in ultra-dry dichloromethane, 1, 3-propanedithiol (2eq) and boron trifluoride diethyl etherate (1eq) were added under ice bath, and after 2 hours of reaction, the mixture was allowed to move to room temperature for 48 hours. After the reaction is completed, a proper amount of saturated sodium bicarbonate solution is used for quenching the reaction, ethyl acetate is used for extraction, and the pure products 7e and 7f are obtained through column purification.
And 4, step 4: compound 7e (1eq) was dissolved in ultra-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 5 hours. After the reaction is completed, the mixture is quenched by saturated ammonium chloride solution, extracted by dichloromethane and purified by a column to obtain a compound 7 f.
And 5: compound 7f (1eq) was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (3eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S7 is obtained after column purification. Compound S7:1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.07(s,1H),4.81–3.78(m,1H),3.93(s,3H),3.86(s,3H),2.85–2.76(m,2H).
8. synthesis of Compound S8
Except that (S) - (-) -2-acetoxysuccinic anhydride was replaced with (R) - (+) -2-acetoxysuccinic anhydride, the compound S5 was synthesized. Compound S8:1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.06(s,1H),4.29–4.22(m,1H),3.93(s,3H),3.86(s,3H),2.43–2.39(m,2H).
9. synthesis of Compound S9
Except that (S) - (-) -2-acetoxysuccinic anhydride was replaced with (R) - (+) -2-acetoxysuccinic anhydride, the compound S7 was synthesized. Compound S9:1H NMR(400MHz,CDCl3)δ7.45(s,1H),7.08(s,1H),4.78–3.67(m,1H),3.92(s,3H),3.85(s,3H),2.86–2.78(m,2H).
10. synthesis of Compound S10
Compound S1 was synthesized except that (S) -methylsuccinic anhydride was replaced by (S) -methoxysuccinic anhydride. Compound S10:1H NMR(400MHz,CDCl3)δ7.41(s,1H),7.14(s,1H),4.48–4.40(m,1H),3.92(s,3H),3.86(s,3H),3.47(s,3H),2.89–2.79(m,2H).
11. synthesis of Compound S11
Except that (S) -methylsuccinic acid is replaced by (S) -methoxysuccinic anhydrideAnhydrides, other synthetic compounds S2. Compound S11:1H NMR(400MHz,CDCl3)δ7.52(s,1H),7.13(s,1H),5.05–4.99(m,1H),3.93(s,3H),3.86(s,3H),3.51(s,3H),2.74–2.63(m,2H).
12. synthesis of Compound S12
Step 1: compound 7c (1eq) was dissolved in tetrahydrofuran and sodium hydride (2eq) was added under ice bath for 2 hours. Bromoacetonitrile (3eq) was then added dropwise and reacted overnight. After the reaction is completed, water is added for quenching, ethyl acetate is used for extraction, and the compound 12a is obtained through column purification.
Step 2: to compound 12a (1eq) was added a 33% hydrobromic acid solution in acetic acid and the reaction was carried out at room temperature for 1 hour. After the reaction is completed, neutralizing the reaction solution with a proper amount of saturated sodium bicarbonate solution, extracting with ethyl acetate, and purifying by a column to obtain a compound 12 b.
And step 3: under the protection of nitrogen, compound 12b (1eq) is dissolved in super-dry dichloromethane, 1, 3-propanedithiol (2eq) and boron trifluoride diethyl etherate (1eq) are added under ice bath, and after 2 hours of reaction, the mixture is moved to room temperature for reaction overnight. After the reaction is completed, a proper amount of saturated sodium bicarbonate solution is used for quenching the reaction, ethyl acetate is used for extraction, and the compound 12c is obtained through column purification.
And 4, step 4: compound 12c (1eq) was dissolved in super-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 2 hours. After the reaction is completed, the mixture is quenched by saturated ammonium chloride solution, extracted by dichloromethane and purified by a column to obtain a compound 12 d.
And 5: compound 12d (1eq) was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (3eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S12 is obtained after column purification. Compound S12:1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.21(s,1H),6.98(br,2H),4.26–4.17(m,1H),4.09(s,2H),3.91(s,3H),3.86(s,3H),2.85–2.75(m,2H).
13. synthesis of Compound S13
In addition to the replacement of (S) -methylsuccinic anhydride by 2, 2-dimethylsuccinic anhydride, the compound S1 was synthesized. Compound S13:1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.16(s,1H),3.90(s,3H),3.83(s,3H),2.64–2.51(m,2H),1.23(s,6H).
14. synthesis of Compound S14
Step 1: compound 9c (1eq, intermediate of compound S8) was dissolved in N, N-dimethylformamide, ethyl 2-chloroacetate (1.5eq) and potassium carbonate (3eq) were added, and the mixture was heated to 60 ℃ for reaction overnight. After the reaction is completed, water is added for dilution, ethyl acetate is used for extraction, and the compound 14a is obtained through column purification.
Step 2: under the protection of nitrogen, compound 14a (1eq) is dissolved in super-dry dichloromethane, 1, 3-propanedithiol (2eq) and boron trifluoride diethyl etherate (1eq) are added under ice bath, and after 2 hours of reaction, the mixture is moved to room temperature for reaction overnight. After the reaction is completed, a proper amount of saturated sodium bicarbonate solution is used for quenching the reaction, ethyl acetate is used for extraction, and the compound 14b is obtained through column purification.
And step 3: compound 14b (1eq) was dissolved in super-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 6 hours. After the reaction is completed, the mixture is quenched by saturated ammonium chloride solution, extracted by dichloromethane and purified by a column to obtain a compound 14 c.
And 4, step 4: compound 14c (1eq) was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (5eq) was added to the solution to react at room temperature for 5 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S14 is obtained after column purification. Compound S14:1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.19(s,1H),4.20–4.15(m,1H),3.90(s,3H),3.84(s,3H),3.70–3.56(m,4H),2.85–2.75(m,2H).
15. synthesis of Compound S15
The compound S14 was synthesized except that ethyl 2-chloroacetate was replaced with 3-chloropropylacetate. Compound S15:1H NMR(400MHz,CDCl3)δ7.48(s,1H),7.18(s,1H),4.52–4.48(m,1H),3.92(s,3H),3.87(s,3H),3.69–3.57(m,4H),2.76–2.63(m,2H),1.91–1.84(m,2H).
16. synthesis of Compound S16
Step 1: the Z-aspartic anhydride (1.5eq) and aluminum chloride (2eq) were suspended in 1, 2-dichloroethane and a solution of compound 1e (1eq) in dichloroethane was added dropwise at-10 ℃. After the dropwise addition, the temperature was raised to 45 ℃ to react overnight. After the reaction solution is cooled, the reaction solution is poured into ice water, a proper amount of 4N hydrochloric acid is added, ethyl acetate is used for extraction, and the compound 16a is obtained after column chromatography purification.
Step 2: dissolving the compound 16a (1eq) in absolute methanol, slowly adding thionyl chloride (10eq) under ice bath, and moving to room temperature for reaction for 1 hour after the addition is finished. After the reaction is completed, the solvent is removed by spinning, the pH value of the residual oily substance is adjusted to 7-8 by using saturated sodium bicarbonate solution, the residual oily substance is extracted by using ethyl acetate, washed by salt, dried by anhydrous sodium sulfate and then dried by spinning to obtain a compound 16 b.
And step 3: under the protection of nitrogen, compound 16b (1eq) is dissolved in super-dry dichloromethane, 1, 3-propanedithiol (2eq) and boron trifluoride diethyl etherate (1eq) are added under ice bath, and after 2 hours of reaction, the mixture is moved to room temperature for 48 hours. After the reaction is completed, a proper amount of saturated sodium bicarbonate solution is used for quenching the reaction, ethyl acetate is used for extraction, and the compound 16c is obtained through column purification.
And 4, step 4: compound 16c (1eq) was dissolved in super-dry dichloromethane, and diethylaminosulfur trifluoride (20eq) was added to the solution to react at room temperature for 5 hours. After the reaction is completed, the mixture is quenched by saturated ammonium chloride solution, extracted by dichloromethane and purified by a column to obtain a compound 16 d.
And 5: compound 16d (1eq) was dissolved in anhydrous methanol and reacted at room temperature for 6 hours with the addition of 10% Pd/C, usually under hydrogen pressure. After the reaction was completed, the reaction mixture was passed through celite, and the filtrate was spin-dried to obtain compound 16 e.
Step 6: compound 16e (1eq) was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (3eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S16 is obtained after column purification. Compound S16:1H NMR(400MHz,CDCl3)δ7.42(s,1H),7.14(s,1H),4.08–3.97(m,1H),3.94(s,2H),3.90(s,3H),3.84(s,3H),2.78–2.66(m,2H).
17. synthesis of Compound S17
Step 1: under the protection of nitrogen, compound 16e (1eq) was dissolved in 1, 4-dioxane, and methylboronic acid (1.5eq), copper acetate (1.5eq), and pyridine (4eq) were added and reacted at 120 ℃ for 3 hours. After the reaction is completed, water is added for dilution, ethyl acetate is used for extraction, and the compound 16c is obtained through column purification.
Step 2: compound 16c (1eq) was dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide monohydrate (3eq) was added to the solution to react at room temperature for 3 hours. After the reaction is completed, 1N hydrochloric acid is dropwise added to adjust the pH value to 6-7, ethyl acetate is used for extraction, and the compound S17 is obtained after column purification. Compound S17:1H NMR(400MHz,CDCl3)δ7.43(s,1H),7.18(s,1H),4.32–4.27(m,1H),4.01(s,1H),3.91(s,3H),3.85(s,3H),2.67–2.59(m,2H),2.39(s,3H).
18. synthesis of Compound S18
In addition to the replacement of (S) -methylsuccinic anhydride by cyclopropylsuccinic anhydride, the compound S1 was synthesized. Compound S18:1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.17(s,1H),3.88(s,3H),3.82(s,3H),2.63–2.51(m,2H),1.28–1.16(m,4H).
19. synthesis of Compound S19
Except using 5, 6-dimethoxythiophene [2,3-b ]]Pyridine-2-carboxylic acid (compound 19a, synthetic reference: WO 2019195063A 1) was substituted for 4-fluoro-5, 6-dimethoxybenzothiophene-2-carboxylic acid (compound 1d), and compound S1 was synthesized. Compound S19:1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.56(s,1H),4.03(s,3H),3.89(s,3H),3.01–2.85(m,2H),2.38–2.29(m,1H),1.32(d,J=6.8Hz,3H).
20. synthesis of Compound S20
Except using 6-bromo-5-methoxythiophene [3,2-b ]]Pyridine (compound 20a, synthetic reference: WO 2019195063A 1) was substituted for 4-fluoro-5, 6-dimethoxybenzothiophene (compound 1e), and compound S1 was synthesized. Compound S20:1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.21(s,1H),4.04(s,3H),3.03–2.89(m,2H),2.69–2.56(m,1H),1.35(d,J=6.9Hz,3H).
21. synthesis of Compound S21
Except using 2, 3-dimethoxythiophene [2,3-b ]]Pyrazine-6-carboxylic acid (synthesis reference: WO 2019195063A 1) was substituted for 4-fluoro-5, 6-dimethoxybenzothiophene-2-carboxylic acid (Compound 1d), and compound S1 was synthesized. Compound S21:1H NMR(400MHz,CDCl3)δ8.29(s,1H),4.03(s,3H),3.99(s,3H),3.13–2.88(m,2H),2.65–2.59(m,1H),1.28(d,J=6.7Hz,3H).
22. synthesis of Compound S22
Except using 5, 6-dimethoxythiophene [3,2-b ]]Pyridine-2-carboxylic acid (compound 22a, synthetic reference: WO 2019195063A 1) was substituted for 4-fluoro-5, 6-dimethoxybenzothiophene-2-carboxylic acid (compound 1d), and compound S1 was synthesized. Compound S22:1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.41(s,1H),4.03(s,3H),3.98(s,3H),3.13–2.89(m,2H),2.76–2.64(m,1H),1.36(d,J=6.6Hz,3H).
23. synthesis of Compound S23
Compound S1 was synthesized except that 4-fluoro-5, 6-dimethoxybenzothiophene-2-carboxylic acid (Compound 1d) was replaced with 5, 6-dimethoxybenzothiophene-2-carboxylic acid (Compound 23 a). Compound S23:1H NMR(500MHz,CDCl3)δ7.35(s,1H),7.25(s,1H),7.20(s,1H),3.95(s,3H),3.94(s,3H),2.89(q,J=13.6Hz,2H),2.36–2.24(m,1H),1.33(d,J=6.8Hz,3H).
24. synthesis of Compound S24
Step 1: in addition to the replacement of (S) -methylsuccinic anhydride by succinic anhydride, the compound S23 was synthesized.
Step 2: under nitrogen protection, compound S1(1eq) was dissolved in N, N-dimethylformamide, and 3-aminopropionitrile (1.2eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.5eq), 1-hydroxybenzotriazole (1.5eq), and N, N-diisopropylethylamine (4eq) were added and reacted at room temperature overnight. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and purified by column chromatography to obtain compound 24 f.
And step 3: under the protection of nitrogen, the compound 24f (1eq) and triphenylphosphine (2.5eq) are dissolved in ultra-dry acetonitrile, cooled to 0 ℃ and stirred for about 10 minutes, then diisopropyl azodicarboxylate (2.5eq) is added dropwise, azidotrimethylsilane (3eq) is added dropwise after about 5 minutes, and after stirring for about 1 hour at 0 ℃, the temperature is raised to 50 ℃ for reaction overnight. After the reaction is completed, cooling the reaction liquid to 0 ℃, adding a proper amount of sodium nitrite aqueous solution, stirring for about 20 minutes, adding cerium ammonium nitrate aqueous solution, stirring for 30 minutes, then adding water for dilution, extracting with ethyl acetate, and purifying by a column to obtain a compound S24. Compound S24:1H NMR(400MHz,CDCl3)δ7.38(s,1H),7.26–7.24(m,1H),7.21(s,1H),4.55(t,J=6.6Hz,2H),3.97(s,3H),3.95(s,3H),3.25–3.18(m,2H),3.09(t,J=6.6Hz,2H),2.99(ddd,J=23.0,15.6,7.7Hz,2H).
25. synthesis of Compound S25
Step 1: under the protection of nitrogen, dissolving a compound S25(1eq) in super-dry dichloromethane, adding 1, 8-diazabicycloundecen-7-ene (7eq) to react at room temperature for about 4 hours, adding water to dilute after the reaction is completed, extracting with ethyl acetate, and purifying by a column to obtain a compound S25. Compound S25:1H NMR(400MHz,DMSO-d6)δ7.65(s,1H),7.62(s,1H),7.42(s,1H),3.84(s,3H),3.82(s,3H),3.12(dd,J=9.2,6.5Hz,2H),2.99–2.83(m,2H).
26. synthesis of Compound H26
In a dry 25mL round-bottomed flask, compound 1(70mg,0.22mmol), HATU (100mg,0.27mmol) were added in this order at room temperature in N, N-dimethylformamide (2mL), and a solution of methylamine in tetrahydrofuran (4N,0.6mL) was added to the above reaction flask. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction by LCMS, direct concentration and subsequent purification of the resulting residue on a reverse phase column gave product H26(67mg, white solid) in yield: 92.5 percent. LCMS (ESI) M/z 310.1[ M-19+ H]+;1H-NMR(400MHz,DMSO-d6):7.87-7.86(brs,1H),7.60(s,1H),7.59(s,1H),7.41(s,1H),3.83(s,3H),3.81(s,3H),2.62-2.58(m,2H),2.55(s,3H),2.30-2.26(m,2H).
27. Synthesis of Compound H27
In a dry 25mL round bottom flask was added compound 24d (60mg,0.18mmol), (trifluoromethyl) trimethylsilane (258mg,1.82mmol) dissolved in tetrahydrofuran (20mL) in sequence at room temperature, placed under a nitrogen atmosphere, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1N,0.02mL) was added to the flask in a-78 deg.C dry ice bath. The reaction mixture was stirred at room temperature for 2 hours. After completion of the TLC detection, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined. Washed with saturated brine (100mL × 1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with a reverse phase system to give compound H27(6mg, white solid) in yield: 9.1 percent. LCMS (ESI) M/z 367.0[ M-H ]]+;1H-NMR(DMSO-d6,400MHz):7.44(s,1H),7.43(s,1H),7.37(s,1H),3.90(s,3H),3.89(s,3H),2.46-2.42(m,2H),1.98-1.94(m,2H).
28. Synthesis of Compound H28
Step 1: EtOAc (800mg, 9.08mmol) is added dropwise to a solution of LiHMDS (9.08mL, 9.08mmol) in THF (30mL) at-78 ℃. After the addition, the stirring was continued for 1 hour while keeping the temperature constant. 4- (5, 6-dimethoxybenzo [ b ] is reacted at-78 DEG C]Thien-2-yl) -4, 4-difluorobutanoic acid methyl ester 24d (300mg, 0.9mmol) was added dropwise to the above solution. After the reaction solution was stirred for 1 hour, the temperature was raised to 0 ℃ and saturated aqueous NH4Cl solution was added to quench. The reaction was extracted with EtOAc, the organic layer was concentrated, and silica gel column separation (PE/EA ═ 1/1) gave compound 28a (100mg, white waxy solid) in 28.5% yield. LCMS (ESI) M/z 386.2[ M + H [ ]]+.
Step 2: to 1mL of 6- (5, 6-dimethoxybenzo [ b ] at room temperature]To a solution of thien-2-yl) -6, 6-difluoro-3-oxohexanoic acid ethyl ester (50mg, 0.13mmol) in ethanol was added hydrazine hydrate (7mg, 0.14 mmol). Stirring was carried out at room temperature for 2 hours under nitrogen. Purification by reverse phase HPLC gave H28(6mg, white solid) in 13.1% yield. LCMS (ESI) M/z 353.0[ M-H ]]-;1H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.61(s,1H),7.42(s,1H),5.36(s,1H),3.83(s,3H),3.82(s,3H),2.68–2.66(m,4H).
29. Synthesis of Compound H29
Reacting NH4OH hydrochloride (10mg, 0.15mmol) dissolved in MeOH/H2In a solution in O (2mL, 1/1), the temperature was maintained at 0 ℃. Then 0.5mL of aqueous NaOH (12mg, 0.31mmol) was added dropwise to the solution. After stirring for 5 minutes, 0.5mL of 6- (5, 6-dimethoxybenzo [ b ] was added]Thien-2-yl) -6, 6-difluoro-3-oxohexanoic acid ethyl ester 28a (60mg, 0.15mmol) in methanol. Stirring was continued for 2 hours at 0 ℃ under nitrogen protection. The reaction was purified by reverse phase HPLC to give H29(16mg, white solid)) The yield thereof was found to be 29.0%. LCMS (ESI) M/z 354.1[ M-H ]]-;1H NMR(400MHz,DMSO-d6)δ7.64(s,1H),7.62(s,1H),7.42(s,1H),3.86–3.82(m,7H),2.78–2.66(m,4H).
30. Synthesis of Compound H30
Compound H27(90mg,0.24mmol) was added in tetrahydrofuran (5mL) in a dry 25mL three-necked flask at room temperature, placed under a nitrogen atmosphere, and a solution of lithium triethylborohydride in tetrahydrofuran (1N,0.7mL) was added to the above reaction flask in a-78 deg.C dry ice bath. The reaction mixture was stirred at room temperature for 2 hours. After completion of the TLC detection, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined. The residue was purified by washing with saturated brine (100 mL. times.1), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to give the product H30(6mg, white solid) in 6.8% yield.1H-NMR(400MHz,MeOD-d4)δ7.44(s,2H),7.37(s,1H),4.00-3.98(m,1H),3.97-3.95(m,6H),2.58-2.53(m,2H),1.88-1.72(m,2H).
31. Synthesis of Compound H31
Compound H27(120mg,0.33mmol), (trifluoromethyl) trimethylsilane (460mg,3.26mmol) dissolved in tetrahydrofuran (3mL) was added sequentially at room temperature in a dry 25mL round bottom flask, placed under a nitrogen atmosphere, and tetrabutylammonium fluoride in tetrahydrofuran (1N,0.03mL) was added to the flask in a-78 deg.C dry ice bath. The reaction mixture was stirred at room temperature for 2 hours. After completion of the TLC detection, 20mL of water was added, extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined. The extract was washed with saturated brine (100 mL. times.1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase to give H31(15mg, yellow solid) in 10.4% yield. LCMS (ESI) M/z 436.9[ M-H ]]-;1H NMR(MeOD-d4,400MHz)δ7.45-7.44(m,2H),7.37(s,1H),3.90-3.89(m,6H),2.61-2.49(m,2H),2.15-2.11(m,2H).
32. Synthesis of Compound H32
Step 1: in a dry 500mL single-necked flask, compound 32a (10g, 71.9mmol), N-bromosuccinimide (15.3g, 86.3mmol) were added in this order, dissolved in dry N, N-dimethylformamide (20mL), and then reacted at room temperature overnight. The reaction was monitored by LCMS and, after completion, extracted 2 times with ethyl acetate and the organic phase was concentrated by drying to give compound 32b (12g, yellow oil) in yield: 80 percent. LCMS (ESI) M/z 219.9[ M + H [ ]]+.
Step 2: compound 32b (6g, 27.6mmol) was added to a dry 250mL three-necked flask and dissolved in dry tetrahydrofuran (60 mL). Nitrogen was purged 3 times using a nitrogen balloon, and then N-butyllithium (20.4ml, 33.2mmol) was slowly added thereto and reacted at-78 ℃ for one hour, followed by addition of N, N-dimethylformamide (6g, 82.8mmol) and reaction at-78 ℃ for one hour. The reaction was monitored by LCMS and, after completion, extracted 2 times with ethyl acetate and the organic phase was concentrated by drying to afford compound 32c (3.1g, yellow solid) in yield: 80 percent. LCMS (ESI) M/z 168.2[ M + H]+.
And step 3: compound 32c (3.1g, 18.5mmol) was added sequentially to a dry 250mL single vial, dissolved in methanol (30mL), and the reaction stirred for 10 minutes in an ice water bath, followed by addition of sodium borohydride (2.1g,55.6mmol) and reaction at room temperature for about one hour. The reaction was monitored by LCMS, after completion, it was extracted 2 times with dichloromethane, the organic phase was dried and concentrated to give compound 32d(1.3g, yellow oil), yield: and 43 percent. LCMS (ESI) M/z 170.2[ M + H ]]+.
And 4, step 4: in a dry 500mL single-necked flask, compound 32d (2.5g, 14.8mmol), N-bromosuccinimide (3.9g, 22.2mmol) were added in this order, dissolved in dry N, N-dimethylformamide (20mL), and then reacted at room temperature overnight. The reaction was monitored by LCMS and, after completion, extracted 2 times with ethyl acetate, the organic phase was dried and concentrated and isolated on silica gel to give compound 32e (2.1g, white solid) in yield: 58 percent. LCMS (ESI) M/z 249.9[ M + H ]]+.
And 5: in a dry 250mL single neck flask were added 32e (2.1g,8.5mmol) and manganese dioxide (7.4g,85mmol) in the order named dissolved in dichloromethane (20 mL). Stir at room temperature for two hours. Reaction was monitored by LCMS and after completion, concentrated by filtration to give compound 32f (1.9g, white solid). LCMS (ESI) M/z 246.0[ M + H [ ]]+.
Step 6: in a dry 250mL single neck flask were added 32f (2.4g,9.79mmol), methyl thioglycolate (1.6g,14.7mmol) and potassium carbonate (4.1g,29.4mmol) in that order dissolved in N, N-dimethylformamide (20mL) and stirred at 60 ℃ for five hours. The reaction was monitored by LCMS and, after completion, extracted 2 times with ethyl acetate and the organic phase was concentrated by drying to give 32g (1.7g, white solid) of compound, yield: 54 percent. LCMS (ESI) M/z 254.0[ M + H ]]+.
And 7: in the dry stateIn a dry 250mL single-neck flask were added 32g (2.4g,9.79mmol), sodium hydroxide (1.7g,6.72mmol), dissolved in tetrahydrofuran (10mL) and water (10mL) in that order, and the mixture was stirred at room temperature for 12 hours. The reaction was monitored by LCMS and after completion, the pH was adjusted to 5-6 with HCl and filtered to give a filter cake for 32h (1.28g, white solid). Yield: 80 percent. LCMS (ESI) M/z 240.0[ M + H ]]+.
And 8: to a dry 250mL single-neck flask were added in sequence 32h (1.28g,5.44mmol), 1, 10-phenanthroline (979mg,5.44mmol), silver carbonate (1.5g,5.44mmol) dissolved in N-methylpyrrolidone (15mL) at 150 ℃ and stirred for 2 h. The reaction was monitored by LCMS and, after completion, extracted 2 times with ethyl acetate and the organic phase was concentrated by drying to give compound 32i (742mg, white solid). Yield: 70 percent. LCMS (ESI) M/z 196.0[ M + H ]]+.
And step 9: compound 32i (700mg, 3.59mmol) was added to a dry 250mL three-necked flask and dissolved in dry tetrahydrofuran (20 mL). Nitrogen was purged 3 times using a nitrogen balloon, and then n-butyllithium (3.4ml, 5.39mmol) was slowly added thereto, and reacted at-78 ℃ for one hour, followed by addition of succinic anhydride (1.1g, 10.78mmol) and reaction at room temperature for one hour. The reaction was monitored by LCMS and after completion, PH was adjusted to 5-6 with HCl and the organic phase was concentrated twice with ethyl acetate to afford compound 32j (200mg, yellow solid) in yield: 20 percent. LCMS (ESI) M/z 296.0[ M + H [ ]]+.
Step 10: 32j (180mg,0.65mmol) and dichloromethylenemaple (162mg, 1.36mmol) were added sequentially to a dry 250mL single-neck flask, dissolved in methanol (15mL) and stirred at 80 ℃ for 2 hours. LCMS monitors the reaction, and after the reaction is finished, the organic phase is coherentDry concentration on column afforded compound 32k (140mg, yellow solid), yield: 72 percent. LCMS (ESI) M/z 310.0[ M + H [ ]]+.
Step 11: 32k (180mg,0.65mmol), 1, 3-propanedithiol (97mg, 0.9mmol) and boron trifluoride diethyl etherate (128mg, 0.9mmol) were dissolved in tetrahydrofuran (10mL) in this order in a dry 250mL single-neck flask and stirred at room temperature for 16 hours. The reaction was monitored by LCMS and after completion the organic phase was concentrated by drying to give 32l (65mg, white solid) of compound. Yield: 36 percent. LCMS (ESI) M/z 400.0[ M + H ]]+.
Step 12: 32l (65mg,0.16mmol) of diethylaminosulfur trifluoride (53mg, 0.33mmol) were added in this order to a dry 250mL single-neck flask, dissolved in dichloromethane (5mL) and stirred at room temperature for 2 hours. The reaction was monitored by LCMS and after completion the organic phase was concentrated by drying to give compound 32m (35mg, yellow solid). Yield: 70 percent. LCMS (ESI) M/z 332.0[ M + H ]]+.
Step 13: 32m (35mg,0.1 mmol), lithium hydroxide (3mg, 0.3mmol) were added in this order to a dry 250mL single-necked flask, dissolved in tetrahydrofuran (3mL) and water (3mL), and stirred at room temperature for 1 hour. LCMS to monitor the reaction, after completion of the reaction, compound H32(10mg, white solid) was prepared in yield: 30 percent. LCMS (ESI) M/z 318.0[ M + H [ ]]+;1H NMR(DMSO-d6,400MHz)δ12.42(s,1H),7.75(s,1H),7.61(s,1H),3.76(s,3H),3.74(s,3H),2.62(t,J=12.0Hz,2H),2.47(t,J=12.0Hz,2H).
33. Synthesis of Compound H33
The synthesis of H33 is similar to that of H32.
Compound H33: a white solid. LCMS (ESI) M/z 349.2[ M-H ]]-;1H NMR(400MHz,MeOD)δ7.54(s,1H),7.52(s,1H),3.94(s,3H),3.86(s,3H),2.60-2.70(m,2H),2.52-2.56(m,2H).
Intermediate 33d was synthesized as follows:
step 1: in a dry 100mL single-neck flask were added compound 33a (5.0g, 27.2mmol) and 40mL 98% sulfuric acid in that order, and heated to 95 ℃ for 4 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. After concentration of the organic phase, silica gel chromatography (petroleum ether/ethyl acetate 5/1) afforded the product 33b (3.95g, white solid) in yield: 85.5 percent.1H NMR(400MHz,CDCl3):δ10.16(s,1H),7.34(d,J=6.8Hz,1H),6.66(d,J=15.2Hz,1H),5.28(brs,1H),3.93(s,3H).
Step 2: in a dry 100mL single-neck flask, compound 33b (3.80g, 22.35mmol) and 40mL of N, N-dimethylformamide were added sequentially, and NCS (2.97g, 22.35mmol) was added in portions. The reaction was carried out at room temperature overnight. After completion of the reaction, ethyl acetate (150mL) and water (40mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and dried by spinning. Column chromatography over silica gel (petroleum ether/ethyl acetate ═ 5/1) afforded product 33c (4.0g, white solid), yield: 87.7 percent.1H NMR(400MHz,CDCl3):δ10.34(s,1H),6.63(d,J=11.6Hz,1H),5.79(s,1H),3.99(s,3H).
And step 3: in a dry 100mL single-neck flask were added compound 33c (4.0g, 19.6mmol), methyl iodide (8.35g,58.8mmol), potassium carbonate (8.11g,58.8mmol) and 40mL of N, N-dimethylformamide in that order. The reaction was carried out at room temperature overnight. After completion of the reaction, ethyl acetate (150mL) and water (40mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and dried by spinning. Silica gel column chromatography (petroleum ether/ethyl acetate 5/1) afforded product 33d (3.52g, white solid) in yield: 82.4 percent. LCMS (ESI) M/z 219.1[ M + H]+.
34. Synthesis of Compound H34
In a dry 250mL three-necked flask, 24a (100mg,0.34mmol), sodium hydride (16mg,0.68mmol), and trimethylthioiodide (138mg,0.68mmol) were dissolved in dimethylsulfoxide (10mL) and tetrahydrofuran (10mL) in this order, and the mixture was stirred at room temperature for 16 hours. LCMS monitoring of the reaction, after completion, compound H34(5mg, white solid) was prepared in reverse phase, yield: 4.5 percent. LCMS (ESI) M/z 309.1[ M + H [ ]]+;1H NMR(MeOD,400MHz)δ7.39(s,1H),7.30(s,1H),7.21(s,1H),3.95-3.91(m,1H),3.87(s,6H),3.81-3.78(m,1H),2.68-2.56(m,4H).
35. Synthesis of Compound H35
The synthesis of H35 is similar to that of H32.
Compound H35: a white solid. LCMS (ESI) M/z 383.0[ M-H ]]-;1H NMR(MeOD,400MHz)δ7.69(s,1H),3.98(s,3H),3.95(s,3H),2.67-2.73(m,2H),2.54-2.57(m,2H).
Intermediate 35b was synthesized as follows:
in a dry 100mL single-neck flask were added compound 35a (2.0g, 6.99mmol) and 15mL of N, N-dimethylformamide in that order, and N-chlorosuccinimide (0.93g, 6.99mmol) was added in portions. The reaction was carried out at room temperature overnight. After completion of the reaction, ethyl acetate (50mL) and water (20mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and dried by spinning. Column chromatography over silica gel (petroleum ether/ethyl acetate 5/1) afforded product 35b (1.85g, white solid) in yield: 82.6 percent.1H NMR(CDCl3,400MHz)δ8.14(s,1H),4.01(s,3H),3.96(s,6H).
36. Synthesis of Compound H37
In a dry 25mL round bottom flask, compound 28b (50mg,0.16mmol), HATU (72mg,0.19mmol) were added sequentially at room temperature in N, N-dimethylformamide (3mL), and a solution of ammonia in tetrahydrofuran (4N,0.4mL) was added to the reaction flask. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction by LCMS, direct concentration and subsequent purification of the resulting residue on a reverse phase column gave product H37(21mg, white solid) in yield: 41.6 percent. LCMS (ESI) M/z 296[ M-19 ]]+;1H NMR(DMSO-d6,400MHz)δ7.60-7.59(brs,2H),7.41(s,1H),7.39(s,1H),6.89(s,1H),3.83-3.81(m,6H),2.61-2.58(m,2H),2.30-2.26(m,2H).
37. Synthesis of Compound H38
The synthesis of H38 is similar to that of H32.
Intermediate 38d was synthesized as follows:
step 1: in a dry 1L single neck flask, compound 38a (36.51g,245mmol) and 600mL of methanol were added and stirred at room temperature until compound 38a was completely dissolved. Then, the reaction solution was stirred in an ice-water bath, and sodium methoxide (119g,2.21mol) was added to the reaction solution in portions, followed by completion of the addition, and the reaction solution was allowed to react overnight at room temperature. The reaction was diluted with dichloromethane, filtered, the organic phase concentrated and then water was added, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give product 38b (31g, white solid) in yield: 90.3 percent.1H NMR(400MHz,CDCl3)δ7.62(s,2H),4.02(s,6H).
Step 2: in a dry 1L single-necked flask, compound 38b (31g, 221mmol) and 300mL of N, N-dimethylformamide were added in this order, and NBS (47.2g, 265mmol) was added in portions. The reaction was carried out at 40 ℃ overnight. After the reaction, ethyl acetate and water are added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and dried by spinning. Crude product was chromatographed to give product 38c (26.8g, white solid), yield: and (5) 55.3%.1H NMR(400MHz,CDCl3)δ7.72(s,1H),4.03(s,3H),4.00(s,3H).
Step (ii) of3:2, 2,6, 6-tetramethylpiperidine (43mL, 269.06mmol) and anhydrous tetrahydrofuran (200mL) were added in this order to a dry 500mL three-necked flask, and stirred at-78 ℃ under nitrogen, n-butyllithium (107mL, 269.06mmol, 2.5mol/L) was slowly added dropwise, and after completion of the addition, stirring was continued at this temperature for 15 minutes, and then stirred at zero degrees centigrade for 20 minutes. The reaction was cooled to-78 ℃ again, and compound 38c (26.8g, 122.3mmol) was dissolved in anhydrous tetrahydrofuran (40mL) and slowly added to the reaction mixture, after the addition was completed, the mixture was stirred at this temperature for 1 hour, then anhydrous N, N-dimethylformamide (9mL) was added, and after the addition was completed, the mixture was heated to zero degrees centigrade and stirred for 20 minutes, glacial acetic acid (27mL) was added, and the mixture was left overnight at room temperature after the addition was completed. The reaction was quenched with water under stirring in an ice bath, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on silica gel to give the product 38d (2.6g, white solid) in yield: 8.6 percent.1H NMR(400MHz,CDCl3)δ10.17(s,1H),4.15(s,3H),4.11(s,3H).
38. Synthesis of Compound H39
Step 1: in a dry 100mL single neck round bottom flask, compound 24e (300g, 0.95mmol), N-methoxymethyl amine hydrochloride (93mg,0.95mmol) and diisopropylethylamine (490mg,1.14mmol) were added sequentially at room temperature. After cooling to 0 ℃,2- (7-azabenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (432mg,1.14mmol) was added to the above solution in portions, the reaction was stirred at room temperature for 16 hours, and TLC monitored that the starting material did not react completely. Water was added thereto, and extracted three times with ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by column (petroleum ether/ethyl acetate: 1/1) to give the product 39a (300mg, yellow solid) in yield: 88 percent.1H NMR(400MHz,CDCl3)δ7.37(s,1H),7.26(s,1H),7.21(s,1H),3.98(s,1H),3.94(s,3H),3.68(s,3H),3.18(s,3H),2.72-2.65(m,4H).
Step 2: in a dry 100mL single-neck round-bottom flaskCompound 39b (2.0g,29.41mmol), pyridine (5mL,62.03mmol) and dry dichloromethane (30mL) were added sequentially at room temperature. After cooling to 0 ℃, a solution of p-toluenesulfonyl chloride (6.9g, 36.3mmol) in dichloromethane was slowly added dropwise to the above solution, and after completion of the dropwise addition, the reaction was stirred at room temperature for 2 hours, and TLC monitored that the starting material did not react completely. Water was added thereto, and methylene chloride was extracted three times. The organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by column (petroleum ether/ethyl acetate 1/1) to give the product 39c (4.5g, white solid) in yield: and 69 percent.1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.90(d,J=8.4Hz,2H),7.22(s,1H),7.33(d,J=8.0Hz,2H),6.39(s,1H),2.42(s,3H).
And step 3: in a dry 50mL three-necked round-bottomed flask at room temperature, compound 39c (50mg, 0.225mmol) and anhydrous tetrahydrofuran (5mL) were added in this order, and the mixture was cooled to-78 ℃ after purging with nitrogen three times. After t-BuLi (0.19mL,1.3N,0.247mmol) was slowly added dropwise to the solution and stirred at this temperature for 45 minutes, then compound 39a (89mg, 0.248mmol) in anhydrous tetrahydrofuran was added dropwise to the solution and stirring was continued at-78 ℃ for 1 hour, after TLC monitoring the reaction was completed, saturated ammonium chloride solution was quenched, diluted with water, extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by prep-TLC, PE/EA ═ 1/1 developed to give 39d (25mg, light yellow solid), yield: 82.1% and H39(4.6mg, white solid), yield: 5.6 percent.
39d:1H NMR(CDCl3,400MHz)δ8.01(d,J=8.4Hz,2H),7.68(s,1H),7.37-7.34(m,3H),7.26(s,1H),7.21(s,1H),6.67(s,1H),3.97(s,3H),3.95(s,3H),3.20-3.16(m,2H),2.82-2.74(m,2H),2.43(s,3H).
H39:1H NMR(CDCl3,400MHz)δ10.7(brs,1H),7.62(s,1H),7.38(s,1H),7.26(s,1H),7.20(s,1H),6.68(s,1H),3.97(s,3H),3.94(s,3H),3.31-3.27(m,2H),2.83-2.71(m,2H).
39. Synthesis of Compound H40
The synthesis of H40 is similar to that of H32.
Wherein intermediate 40d was synthesized as follows:
step 1: in a single neck round bottom flask with 150mL of methanol was added the compound 12-fluoro-4-methoxybenzaldehyde 40a (10g, 64.93mmol) at room temperature, followed by dropwise addition of liquid bromine (15.58g, 97.40mmol) under ice bath. After the reaction was stirred at room temperature for 3 hours after the completion of the dropwise addition, LCMS was used to monitor the completion of the basic reaction, sodium sulfite solution was added to quench, then 200mL of water was added, the solution was filtered, the filter cake was washed with water, and then the filter cake was spin-dried to give compound 40b (12g, white solid), yield: 79.31 percent. LCMS (ESI) M/z 233.0,235.0[ M + H [ ]]+.
Step 2: compound 40b (12g, 51.50mmol) and methyl 2-mercaptoacetate (6.0g, 56.65mmol) were added at room temperature to a single neck round bottom flask containing 150mL of DMF, followed by potassium carbonate (10.66g, 77.25 mmol). Heating under argon protection at 60 ℃ for 5h, monitoring by LCMS after the reaction is finished, adding 150mL of water, filtering the solution, washing the filter cake with water for 2 times, and spin-drying the filter cake to obtain a crude product, namely a compound 40c (13g, white solid), wherein the yield is as follows: 84.14 percent. LCMS (ESI) M/z 301.0,303.0[ M + H [ ]]+.
Step 2: after adding compound 40c (13g, 43.19mmol) and lithium hydroxide (9.07g, 216mmol) to a 500mL single neck flask containing 150mL of tetrahydrofuran and 60mL of water at room temperature and stirring at 50 ℃ for 3 hours, lcms (esi) monitors the completion of the reaction, concentrates the solution, adjusts pH to-4 by adding dilute hydrochloric acid, and washes the filter cake of the solution three times with water and spin-dries under reduced pressure to obtain the product compound 40d (8g, white solid) in yield: 64.54 percent. LCMS (ESI) M/z 287.0,289.0(M + H)+.1H NMR(400MHz,DMSO-d6):δ8.25(s,1H),7.96(s,1H),7.79(s,1H),3.93(s,3H).
H40 yellow solid. LCMS (ESI) M/z 325.1,327.1[ M + H-40 [)]+;1H NMR(400MHz,MeOD):δ8.05(s,1H),7.58(s,1H),7.48(s,1H),3.94(s,3H),2.69-2.63(m,2H),2.55-2.52(m,2H).
40. Synthesis of Compound H41
Step 1: compound 24d (344mg,1.0mmol) was dissolved in THF/H2O (1/1), then adding lithium hydroxide (72mg,3.0mmol), reacting at room temperature for half an hour, adjusting the pH to 5-6 with 1N hydrochloric acid, extracting with chloroform, collecting the organic phase, drying, concentrating, and separating with a column to obtain the compound 41a (165mg, white solid) with a yield of 52%. LCMS (ESI) M/z 317.0[ M + H [ ]]+;1H NMR(400MHz,CDCl3)δ7.35(s,1H),7.25(s,1H),7.20(s,1H),3.96(s,3H),3.94(s,3H),2.70–2.58(m,4H).
Step 2: after compound 41a (30mg, 0.094mmol) and 1 drop of DMF were sequentially added at room temperature to a dry 50mL three necked round bottom flask containing anhydrous dichloromethane, cooled to 0 deg.C, oxalyl chloride (0.2mL) was added to the above solution, and after completion of addition, the reaction was stirred at 0 deg.C for 1 hour to obtain a solution of 41b which was directly used for the next reaction.
And step 3: in a dry 50mL three-necked flask containing anhydrous dichloromethane, N-methylmethanesulfonamide (12mg, 0.104mmol), a catalytic amount of 4-N, N-lutidine and triethylamine (29mg, 0.284mmol) were sequentially added at room temperature, after cooling to 0 ℃ under nitrogen protection, the previously prepared acid chloride solution was added dropwise thereto, after completion of dropwise addition, stirring at room temperature for 1 hour, LCMS was used to monitor the substantial completion of the reaction, the reaction solution was diluted with water, dichloromethane was extracted, the organic phase was washed with water and saturated ammonium chloride solution in turn, dried over anhydrous sodium sulfate, filtered, and concentrated, then PREP-HPLC (hydrochloric acid system) was purified to obtain the final compound H41(10mg, white solid) with yield: 26 percent.1H NMR(400MHz,CDCl3,):δ7.34(s,1H),7.26(s,1H),7.21(s,1H),3.97(s,3H),3.95(s,3H),3.30(s,3H),3.24(s,3H),2.93-2.89(m,2H),2.75-2.71(m,2H).
41. Synthesis of Compound H42
Synthesis of H42 was performed with compound H41. H42 (white solid).1H NMR(400MHz,MeOD):δ7.46(s,1H),7.45(s,1H),7.37(s,1H),3.90(s,3H),3.89(s,3H),3.31(s,3H),2.65-2.54(m,4H).
42. Synthesis of Compounds H45 and H46
Step 1: compound 40g (2.0g, 5.58mmol) and allyl tetrabutyl-15-stannane (4.33g, 11.17mmol) were added to a three-necked flask containing 50mL of 1,4 dioxane at room temperature followed by tetratriphenylphosphine palladium (1.29g, 1.12mmol), the reaction was stirred at 80 ℃ under argon atmosphere overnight, lcms (esi) was monitored for completion of the reaction, 150mL of water was added, quenched with KF solution, extracted with ethyl acetate (3 × 100mL)3 times, the combined organic phases were dried over anhydrous sodium sulfate, separated on a silica gel column, and eluted with petroleum ether/ethyl acetate 4/1 to give compound 45a (1.5g, white solid) in yield: 84.43 percent. LCMS (ESI) M/z 319.1[ M + H]+;1H NMR(400MHz,DMSO-d6):δ8.27(s,1H),7.73(s,1H),7.62(s,1H),6.03-5.97(m,1H),5.09-5.05(m,2H),3.94(s,3H),3.60(s,3H),3.41(d,J=6.8Hz,2H),3.34-3.31(m,2H),2.69-2.66(t,J=6.4Hz,2H).
Step 2: in a single neck flask with 50mL of dichloromethane, compound 45a (750mg, 2.35mmol) and Grubbs catalyst 2G catalyst (283mg, 0.47mmol) were added at room temperature, the reaction was stirred under argon protection at 50 ℃ overnight lcms (esi) to monitor the end of the reaction, prep-TLC preparative separation, and petroleum ether/ethyl acetate 1/1 developed to give a mixture of compounds 45b and 45 b' (600mg, brown powder), yield: 80.0 percent. LCMS (ESI) M/z 595.2,609.2[ M + H [ ]]+.
And step 3: in a single neck flask containing 100mL of dichloromethane, a mixture of compounds 45b and 45b '(200 mg,0.33mmol) and palladium on carbon catalyst (50mg) were added at room temperature, stirred under hydrogen protection overnight, reaction was monitored by LCMS for completion, the combined organic phases were filtered and dried to give a mixture of crude 45c and 45 c' (150mg, white solid) yield: 74.76%。LCMS(ESI):m/z 597.2,611.2[M+H]+.
and 4, step 4: in a single-neck flask containing 10mL of tetrahydrofuran, a mixture of 45c and 45 c' (150mg,0.24mmol) and 1, 3-propanedithiol (133mg,1.23mmol) were added at room temperature, followed by dropwise addition of 2mL of boron trifluoride diethyl etherate. The reaction was stirred overnight at 50 ℃ under argon, LCMS monitored for reaction completion, 50mL of water was added and pH adjusted with sodium bicarbonate solution, extracted with ethyl acetate, the combined organic phases were dried by spinning, and petroleum ether was purified using a thin layer chromatography plate: ethyl acetate 3:1 gave a mixture of 45d and 45 d' (80mg, brown oil), yield: 46.47 percent. LCMS (ESI) M/z 701.3,687.3[ M + H [ ]]+.
And 5: in a single neck flask containing 10mL of dichloromethane, 45d and 45 d' (80mg, 0.11mmol) were added at room temperature and DAST (184mg,1.14mmol) was added dropwise, the reaction was stirred at room temperature under argon atmosphere for 1 hour, LCMS (ESI) was used to monitor the end of the reaction, 50mL of water was added to adjust the pH with sodium bicarbonate solution, extraction was performed with ethyl acetate, and the combined organic phases were dried by rotary drying. The residue was separated on a thin layer chromatography plate and developed with petroleum ether/ethyl acetate 3/1 to give compounds 45e and 45 e' (45mg, brown oil), yield: 60.21 percent. LCMS (ESI) M/z 655.2,641.3[ M + H [ ]]+.
And 5: compounds 45e and 45 e' (45mg, 0.068mmol) and lithium hydroxide (15mg,0.34mmol) were added to a single-neck flask containing 10mL of tetrahydrofuran and 2mL of water at room temperature, the reaction was stirred at room temperature overnight, LCMS monitored for reaction completion, the solution was concentrated, and the compound was isolated and purified by reverse phase preparative isolation:
h45(7mg, yellow solid), yield: 16.20 percent. LCMS (ESI) M/z 627.2[ M + H ]]+;1H NMR(400MHz,MeOD):δ8.04(s,1H),7.63(s,1H),7.54(s,1H),7.420(s,1H),7.37(s,2H),3.89(s,3H),3.85(s,3H),2.73-2.60(m,6H),2.58-2.51(m,4H),1.67(s,4H),1.32-1.29(m,2H).
H46(3mg, yellow solid), yield: 7.09 percent. LCMS (ESI) M/z 613.2[ M + H]+;1H NMR(400MHz,MeOD):δ8.06(s,1H),7.66(s,1H),7.57(s,1H),7.42(s,1H),7.38-7.37(m,2H),3.89(s,3H),3.87(s,3H),2.77-2.60(m,8H),2.58-2.51(m,2H),2.03-1.94(m,2H),1.67-1.59(m,2H).
43. Synthesis of Compound H47
Step 1: a dry 250mL three-necked flask was charged with 40g (800mg,2.24mmol) of the compound pinacol bisborate (1.7g,6.74mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (161mg,0.22mmol), potassium acetate (161mg,0.22mmol), dissolved in dry 1, 4-dioxane (30 mL). The reaction system was purged with nitrogen 3 times and reacted at 100 ℃ for 16 hours. Lcms (esi) and after completion of the reaction, extraction with ethyl acetate 2 times, dry concentration of the organic phase and silica gel column separation gave compound 47a (470mg, yellow solid) in yield: 52 percent. LCMS (ESI) M/z 323.0[ M-82+ H]+.
Step 2: in a dry 250mL single-neck flask, compound 47a (470mg, 1.46mmol) and hydrogen peroxide (99mg, 2.92mmol) were added in this order, dissolved in dry ethanol (10mL), and reacted at 80 ℃ for 2 hours. The reaction was monitored by lcms (esi), after completion, the organic phase was concentrated by drying to give compound 47b (320mg, yellow solid) in yield: 75 percent. LCMS (ESI) M/z 295.4[ M + H]+.
And step 3: in a dry 250mL single-necked flask, compound 47b (100mg,0.34mmol), 1, 3-dibromopropane (136mg, 0.68mmol), potassium carbonate (94mg, 0.68mmol) were sequentially added, dissolved in dry N, N-dimethylformamide (10mL), and then reacted at room temperature for 16 hours. The reaction was monitored by LCMS and, after completion, extracted 2 times with ethyl acetate, the organic phase was concentrated by drying and the crude product was chromatographed to give compound 47c (80mg, yellow solid) in yield: 75 percent. LCMS (ESI) M/z 415.3[ M + H]+.
And 4, step 4: in a dry 500mL single-necked flask, compound 47c (50mg,0.12mmol), compound 47b (35mg,0.12mmol), sodium hydride (6mg,0.24mmol) were sequentially added, dissolved in dry N, N-dimethylformamide (10mL), and then reacted at room temperature for 4 hours. The reaction was monitored by LCMS (ESI), after completion, extracted 2 times with ethyl acetate, the organic phase was concentrated by drying and isolated on silica gel to give compound 47d (25mg, yellow solid) which gaveRate: 34 percent. LCMS (ESI) M/z 628.8[ M + H [ ]]+.
And 5: 47d (25mg,0.04mmol), lithium hydroxide (8m g,0.12mmol) dissolved in tetrahydrofuran (5mL) and water (5mL) were added sequentially to a dry 50mL single neck flask and stirred at room temperature for two hours. Lcms (esi) monitored the reaction and, upon completion, compound H47(2mg, white solid) was prepared. Yield: 8 percent. LCMS (ESI) M/z 600.9[ M + H [ ]]+.
44. Synthesis of Compound H51
Step 1: in a dry 50mL three-necked flask, compound 47b (500mg,1.70mmol),1, 3-propanedithiol (184mg,3.40mmol) dissolved in dry tetrahydrofuran (10mL) were sequentially charged at room temperature, and a boron trifluoride ether solution (2mL) was charged into the above reaction flask. The mixture was stirred at 50 ℃ and reacted overnight. After LCMS detection reaction was completed, the reaction solution was added with ice water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a crude product, and the obtained residue was purified with Flash silica gel column to obtain product 51a (180mg, yellow solid) with yield: 27.5 percent. LCMS (ESI) M/z 384.8[ M + H ]]+.
Step 2: compound 51a (180mg, 0.47mmol) was dissolved in dry dichloromethane (10mL) in a dry 25mL three-necked flask under ice-bath conditions, and diethylaminosulfur trifluoride (226mg,1.41mmol) was added to the above reaction flask. The reaction was stirred in an ice bath for 3 hours. After the TLC detection reaction was completed, the reaction solution was added with ice water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate and evaporated to dryness to obtain a crude product, which was purified by silica gel plate preparation to obtain product 51b (80mg, yellow oil) with yield: 53.8 percent
And step 3: in a dry 25mL three-necked flask under ice-bath conditions, compound 51b (80mg, 0.25mmol), potassium iodide (42mg, 0.25mmol) and cesium carbonate (162mg, 0.50mmol) were dissolved in dry N-methylpyrrolidone (10mL) and 4- (5- (3-bromopropoxy) -6-methoxybenzo [ b ] b]Thien-2-yl) -4-oxobutanoic acid methyl ester (226mg,1.41mmol) was added to the above reaction flask. The reaction was stirred at room temperature for 3 hours. After the reaction was completed by LCMS detection,the reaction solution was added with ice water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give a crude product, which was purified by silica gel plate preparation to give product 51c (80mg, yellow solid) with yield: 49.2 percent. LCMS (ESI) M/z 630.8[ M-19+ H]+.
And 4, step 4: compound 51c (80mg,0.12mmol) was dissolved in tetrahydrofuran/water (3/1, 4mL) in a dry 25mL three-necked flask under ice-bath conditions, and lithium hydroxide (12mg,0.49mmol) was added to the reaction flask. The reaction was stirred in an ice bath for 3 hours. After LCMS detection of the reaction, the reaction was adjusted to PH 7 by the addition of acetic acid, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to give a crude product which was then purified on a reverse phase preparative column to give the product H51(20mg, yellow solid) in yield: 26.7 percent. LCMS (ESI) M/z 623.1[ M + H [ ]]+;1H NMR(400MHz,MeOD-d4):δ7.86(s,1H),7.60-7.27(m,5H),4.27-4.21(m,4H),3.84-3.82(m,6H),3.26-3.23(m,2H),2.70-2.50(m,6H),2.33-2.28(m,2H).
45. Synthesis of compound H59:
step 1: in a dry 50mL three-necked round-bottomed flask, compound 61b (100mg, 0.24mmol), compound 61a (95mg, 0.32mmol), cesium carbonate anhydrous (157mg,0.48mmol), potassium iodide (40mg,0.24mmol) and N-methylpyrrolidone (4mL) were added in this order at room temperature. Stirring for 4 hours at 20-25 ℃ under the protection of nitrogen. After TLC monitoring the reaction was complete, it was quenched with ice water, extracted with ethyl acetate, the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the residue was purified on column (dichloromethane-dichloromethane: methanol ═ 0-5%) to give product 59a (90mg, light yellow solid) in yield: and (5) 59.6%. LCMS (ESI) M/z 629.3[ M + H [ ]]+.
Step 2: in a dry 50mL three-necked round-bottomed flask, compound 59a (135mg, 0.21mmol), propanedithiol (91mg, 0.84mmol), boron trifluoride diethyl etherate (120mg,0.84mmol) and anhydrous tetrahydrofuran (4mL) were added in this order at room temperature. Nitrogen protectionStirring for 16 hours at the temperature of 20-25 ℃ under protection. After TLC monitoring the reaction was complete, it was quenched with ice water, extracted with ethyl acetate, the organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the residue was purified on column (dichloromethane-dichloromethane/methanol 0-2%) to give product 59b (130mg, light yellow solid) in yield: 76.5 percent. LCMS (ESI) M/z [ M + H]+.
And step 3: in a dry 50mL three-necked round bottom flask, compound 59b (130mg, 0.16mmol), dichloromethane (4mL) were added sequentially at room temperature. DAST (105mg, 0.64mmol) was added dropwise with cooling in an ice-water bath, and after the end of the addition, the reaction was continued for 1 hour with stirring with cooling in an ice-water bath, and the completion of the reaction of the starting material was monitored by TLC. Quenched with ice water, extracted with dichloromethane, the organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the residue was purified on column (dichloromethane-dichloromethane/methanol ═ 0-2%) to give product 59c (90mg, yellow solid) in yield: 83.3 percent.
And 4, step 4: in a dry 50mL three-necked round bottom flask, compound 59c (90mg, 0.13mmol), tetrahydrofuran (4mL) and water (1mL) were added sequentially at room temperature. Lithium hydroxide hydrate (22mg, 0.52mmol) was added and after the addition was complete, the reaction was continued at 20-25 ℃ for 3-4 hours with stirring and the completion of the starting material reaction was monitored by TLC. Quenching with ice water, extraction with dichloromethane, washing the organic phase successively with saturated sodium bicarbonate and saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure and purification of the residue by prep-HPLC gave the product H59(15mg, light yellow solid) in yield: 17.9 percent. LCMS (ESI) M/z 643.1[ M-H ]]-.1H-NMR(400MHz,DMSO-d6):δ12.35(s,2H),7.67(s,2H),7.61(s,2H),7.43(s,2H),4.23(t,4H),3.83(d,6H),2.63(td,4H),2.45(t,4H),2.31–2.18(m,2H).
46. Synthesis of Compound H61
Step 1: in a dry 250mL portion of tris buffer containing 100mL of methylene chlorideCompound 24a (5.3g,17.2mmol), aluminum chloride (11.4g,86.0mmol) were added sequentially in a vial under ice-bath. After stirring at 0 ℃ for 10 minutes, the reaction mixture was reacted at room temperature for three hours. LC-MS monitored the reaction was completed and the reaction was slowly poured into 1M dilute hydrochloric acid, extracted twice with dichloromethane, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, slurried with tetrahydrofuran and methyl tert-butyl ether (3/1, V/V) to give product 61a (2.5g, white solid), yield: 49.4 percent. LCMS (ESI) M/z 551.3[ M + H [)]+.1H NMR(400MHz,CDCl3):δ7.88(s,1H),7.33(s,1H),7.23(s,1H),6.07(s,1H),3.98(s,3H),3.71(s,3H),3.32(t,2H),2.79(t,2H).
Step 2: in a dry 100mL three-necked round-bottomed flask at room temperature were added compound 61a (220mg, 0.75mmol), 1, 3-dibromopropane (182mg, 0.90mmol), anhydrous potassium carbonate (156mg, 1.13mmol) and anhydrous N, N-dimethylformamide (12mL) in this order, and stirred at 20-25 ℃ for 16 hours under nitrogen. After TLC monitoring the reaction was complete, it was quenched with ice water, extracted with ethyl acetate, the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the residue was purified by column (petroleum ether-petroleum ether: ethyl acetate 0-15%) to give the product 61b (180mg, off-white solid) in yield: 57.9 percent. LCMS (ESI) M/z 414.9[ M + H [ ]]+.
And step 3: in a single-neck flask containing 10mL of N-methylpyrrolidone, compound 61b (40mg, 0.096mmol) and 4, 4-difluoro-4- (6-hydroxy-5-methoxybenzo [ b ] were added at room temperature]Thiophen-2-yl) butyric acid methyl ester (30mg,0.096mmol), then cesium carbonate (63mg,0.192mmol), potassium iodide (16mg,0.096mmol) were added and stirred at room temperature overnight, the reaction was monitored by LCMS for completion, 50mL of water was added and extracted 3 times with ethyl acetate (3 × 50mL), the organic phases were combined and spun dry, and petroleum ether was purified using thin layer chromatography: ethyl acetate 2:1 gave compound 61c (35mg, yellow oil), yield: 55.86 percent. LCMS (ESI) M/z 631.3[ M + H-20 [ ]]+.
And 4, step 4: in a single-neck flask containing 8mL of tetrahydrofuran and 2mL of water, compound 61c (35mg, 0.054mmol) and lithium hydroxide (23mg,0.54mmol) were added at room temperature, and the reaction was stirred at room temperature for 4 hours, LCMS monitoring the end of the reaction, the solution was concentrated and purified by reverse phase preparative separation to give H61(6mg, yellow solid) in yield: 17.92 percent. LCMS (ESI) M/z 583.2[ M + H-40 [)]+;1H NMR(400MHz,DMSO-d6):δ8.20(s,1H),7.66(d,J=3.6Hz,2H),7.61(s,1H),7.49(s,1H),7.43(s,1H),4.27-4.19(m,4H),3.86(s,3H),3.82(s,3H),3.27-3.24(m,4H),2.68-2.58(m,3H),2.46-2.43(m,1H)2.29-2.25(m,2H).
47. Synthesis of compound H62:
step 1: in a 100mL three-necked flask containing 20mL of tetrahydrofuran, compound 61a (500mg,1.7 mmol),1, 2-dithiol (2mL) and boron trifluoride diethyl etherate (5mL) were added in this order at room temperature. Reacting at room temperature overnight, monitoring the reaction by TLC, diluting the reaction solution with water, extracting twice with ethyl acetate, collecting the organic phase, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. Column chromatography (petroleum ether/ethyl acetate 5/1) gave product 62a (460mg, white solid) in: 70.4 percent. LCMS (ESI) M/z 385.1[ M + H [ ]]+.
Step 2: in a dry 100mL single-neck flask containing 15mL of methylene chloride, compound 62a (400mg, 1.04mmol) and diethylaminosulfur trifluoride (251mg, 1.56mmol) were added in this order at 0 ℃. The reaction was carried out at 0 ℃ for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was quenched by adding saturated sodium bicarbonate solution, extracted twice with dichloromethane, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (petroleum ether/ethyl acetate 5/1) gave product 62b (160mg, white wax) in: 40 percent. LCMS (ESI) M/z297.1[ M + H-F]+.
And step 3: in a single-neck flask containing 8mL of methylene chloride, compound 62b (30mg, 0.063mmol), methyl 4- (6- (2-hydroxyethoxy) -5-methoxybenzothiophen-2-yl) -4-oxobutanoate (32mg, 0.063mmol), diisopropyl azodicarboxylate (58mg, 0.28mmol) and triphenylphosphine (75mg, 0.28mmol) were added in this order at room temperature. Reacting at room temperature overnight, and reactingThe solution was diluted with water, extracted twice with dichloromethane, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (petroleum ether/ethyl acetate-1/1) gave crude 62c (15mg, yellow solid) in: 24.8 percent. LCMS (ESI) M/z 617.0[ M-F + H]+.
And 4, step 4: in a dry 50mL single neck flask containing 3mL of tetrahydrofuran and 1mL of water was added compound 62c (15mg, 0.024mmol), lithium hydroxide (4mg, 0.094mmol) in that order at room temperature. The reaction was carried out at room temperature for three hours. After TLC monitoring the reaction was complete, the reaction was concentrated and sent to preparation to afford product H62(6mg, yellow solid) in yield: 40 percent. LCMS (ESI) M/z 569.1[ M + H-2F]+.1H NMR(400MHz,DMSO-d6):δ8.22(s,1H),7.73(d,J=4.8Hz,2H),7.63(s,1H),7.52(s,1H),7.46(s,1H),4.47(s,4H),3.83(d,J=8.0Hz,6H),3.28(d,J=6.4Hz,2H),2.67-2.59(m,4H),2.51-2.44(m,2H).
Example 2: cell screening experiment for activating interferon gene stimulating protein and promoting IFN-beta expression by compound
Human cell assay for STING activation by compounds
The detection method and the principle are as follows: THP1-Blue-ISG cells of human origin, into which IFN-. beta.containing reporter systems have been transferred, which induce the expression of downstream alkaline phosphatase and whose content is determined by the chromogenic reaction that OD650 reflects when alkaline phosphatase is secreted outside the cells. After the compound is added into the cells, if the interferon gene stimulating protein is activated, the expression of IFN-beta can be promoted, and further the increase of downstream alkaline phosphorylation secretion and the increase of the absorbance of a color reaction are promoted.
The test method comprises the following steps:
1. adding a compound: 20. mu.L of a compound diluted with physiological saline was added to each well of a 96-well cell culture plate at a concentration of 100. mu.M, in 2 duplicate wells. The positive control compound was ADU-S100 at a concentration of 100. mu.M. No-drug control group was added with 20. mu.L of physiological saline containing 1% DMSO.
2. Adding cells: THP1-Blue-ISG cell count, adjusting cell concentration to 5X 105mL, add 180. mu.l of cells per well for incubation. Due to the fact thatThe final volume of each test well was 200. mu.L, DMSO content was 0.1%, and the test concentration of the compound was 10. mu.M. The positive control compound is ADU-S100, the final concentration is 10 mu M, and the positive control compound is incubated for 24 hours for detection; another blank group was added with 180. mu.L of culture solution.
3. Detecting a color development reaction: after 24 hours, 20. mu.L of the culture medium was transferred to a new 96-well plate, 200. mu.L of color developing solution Quanti-Blue was added thereto, the plate was placed in an incubator at 37 ℃ and the OD650 value was measured after 0.5 to 2 hours.
4. Screening concentration of compound: 10 μ M.
5. And (4) analyzing results:
where Compound OD650 is the OD650 value of the Compound of the present invention, Blank OD650 is the OD650 value of the medium, and Control OD650 is the OD650 value of the Control group without the Compound of the present invention (cells only and 0.1% DMSO).
6. And (4) evaluating the result: the activation multiple (Fold change) is more than or equal to 2. Thus, representative compounds all showed significant ability to activate hSTING.
TABLE 1 ability of partial compounds to activate hSTING in THP1 cells
Note: the structures of compound ADU-S100, compound IA and compound IB are as follows:
second, testing of Compounds on STING-activated murine cells
The detection method and the principle are as follows: murine Raw-lucia cells into which an ISG-containing reporter system has been transferred. The reporter system induces the activation of the ISG promoter and produces luciferase, which is present in the cell supernatant and is capable of passing through the luciferaseDetection reagent QUANTI-LucTMAnd (5) detecting and quantifying. When the cells are added with the compound, the expression of ISG can be promoted if STING is activated, and the secretion of downstream luciferase is further promoted to be increased.
Reagents, consumables and instruments:
in the experiment, Raw-lucia cells were purchased from InvivoGen, DMEM culture solution was purchased from Thermo Fisher Scientific, FBS was purchased from Gibco, Australia, and luciferase assay reagent QUANTI-LucTMIs purchased from InvivoGen company, and the microplate reader is a multifunctional microplate reader produced by Envision company
Compound preparation:
centrifuging compound 12000 g for 5min, adding DMSO to prepare 10mM stock solution, vortexing uniformly, and then performing ultrasonic treatment for 10min for later use, and storing at-20 ℃.
The test method comprises the following steps:
1. adding cells: raw-lucia cell count, adjusting cell concentration to 5X 105mL, add 180. mu.l of cells per well for incubation.
2. Adding a compound: after the cells adhere to the wall, 20 μ L of a compound diluted with physiological saline is added to each well of a 96-well cell culture plate, the concentration of the compound is 50 μ M, the positive control compound is DMXAA, the concentration is 50 μ M, the control group is physiological saline without DMSO, and 3 duplicate wells are respectively arranged. And incubating for 24h for detection.
3. Detecting a color development reaction: after 24 hours, 20. mu.L of the culture broth per well was transferred to a new bottom-transmitting 96-well plate, and the luciferase assay reagent QUANTI-Luc was addedTM50 μ l, fluorescence was measured immediately (protected from light).
Screening concentration of compound: 50 μ M
5. Experimental batches: 2 times (one time)
6. And (4) analyzing results:
Fold Change=Compound Luminescence/Control Luminescence
7. and (4) evaluating the result: the effective Fold change is more than or equal to 2.
TABLE 2 ability of partial compounds to activate mSTING in Raw-lucia cells
Note: the structures of compound DMXAA, compound IA and compound IB are as follows:
EXAMPLE 3 Metabolic (PK) profiling of Compound S1
In order to show the special group effect of multi-substituted compounds containing fluorine, methyl and the like, a compound IA which does not contain methyl and does not contain three fluorine atoms in the Merck (Merck) published patent PCT/US2017/054688, and a compound IB which only contains methyl but does not contain fluorine atoms in the side chain are compared with the metabolic properties of a representative compound S1 in the multi-substituted compounds described in the patent in the rat body.
1. Dosing regimens
SD rats 18, male, weighing 200-:
group of | Compound (I) | Route of administration | Administration dose (mg/kg) | Volume administered (mL/kg) |
1 | ⅠA | Is administered orally | 3 | 10 |
2 | ⅠA | Vein | 1 | 5 |
3 | ⅠB | Is administered orally | 3 | 10 |
4 | ⅠB | Vein | 1 | 5 |
5 | S1 | Is administered orally | 3 | 10 |
6 | S1 | Vein | 1 | 5 |
Fasted for 12h before the test, water was freely available. The diets were uniformly fed 2h after dosing.
2. Blood sampling time points and sample treatment:
oral administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;
intravenous administration: 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;
at the set time point, 0.3mL of venous blood is taken from the retrobulbar venous plexus of the rat, the venous blood is placed in a heparinized test tube, the centrifugal treatment is carried out for 5min at 11000rpm, and the plasma is separated and frozen in a refrigerator at the temperature of 20 ℃ below zero.
3. Sample testing and data analysis
The concentrations of IA, IB and S1 in rat plasma were determined by LC/MS/MS.
Pharmacokinetic parameters after administration were calculated using a non-compartmental model of WinNonlin 6.3 software (Pharsight, usa).
Peak concentration of CmaxAnd time to peak TmaxIs an actual measurement value;
area under the time curve AUC0-tThe value: calculating by adopting a trapezoidal method; AUC0-∞=AUC0-t+Ct/ke,CtThe blood concentration at the last measurable time point, keTo eliminate the rate constant;
elimination of half-life t1/2=0.693/ke;
Clearance rate CL ═ D/AUC0-∞;
Volume V of steady state distributionss=CL×MRT
Absolute bioavailability F ═ AUC (AUC)Is administered orally×DVein)/(AUCVein×DIs administered orally)×100%
4. The results are shown in Table 3.
TABLE 3 comparison of pharmacokinetic Properties of Compound S1 with IA and IB in rats
(administration dose: p.o.3mg/kg, i.v.1mg/kg)
The data show that Merck compound IA has poor metabolic properties and half-life (T) despite its strong activating activity on both murine and human STING1/2) Short peak time (T)max) Short, low exposure (AUC), especially for intravenous administration. The compound IB introduces fluorine atoms on benzene rings in the mother nucleus of dimethoxy benzothiophene, so that the pharmacokinetic properties are improved to a certain extent, but the improvement effect is not obvious. However, the invention obtains a multi-substituted structure with a novel structure based on the multi-site modification strategies such as methylation and fluorination of the benzothiophene compounds, and the properties of the representative compound S1 are remarkably improved, which are specifically shown in the following steps:
half life T1/2Up to 1.56 hours, 2.4 times as high as compound ia, 2 times as high as ib (ia: ib: S1 ═ 0.656:0.783:1.56 h);
the exposure was significantly increased by oral administration, 7.5 times that of compound ia and 5.8 times that of ib (ia: ib: S1: 3419:4363:25508h ng/mL);
the exposure to intravenous administration was significantly increased, 10.4-fold higher than compound ia and 7.2-fold higher than ib (ia: ib: S1: 1646:2370:16674h ng/mL).
Therefore, the compounds containing methyl, polyfluoro and other groups for substitution have higher activation capability on hSTING or mSTING and are remarkably improved in the in vivo metabolic property of rats, so that the drug effect of the compounds is fully exposed in the in vivo pharmacodynamics and safety evaluation process of intravenous administration or oral administration, and the compounds have remarkable advantages and further development potential compared with the STING inhibitors reported so far.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A compound shown in a general formula (I), or enantiomer, diastereoisomer, racemate and mixture thereof, or pharmaceutically acceptable salt thereof,
in the formula (I), the compound is shown in the specification,
A1、X1each independently is N or CRx;RxIs H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -L-M; the substituted is substituted by a substituent selected from the group consisting of: halogen, hydroxy, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;
W1is NH, S or O; y is1Is N or CRy;RyIs H, -L-M or absent;
R1、R2independently selected from halogen, hydroxyl, carboxyl, amino, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylacyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C4 alkylamido, substituted or unsubstituted C1-C4 alkylamino, -L-M; r1、R2Wherein said substitution is by one or more substituents selected from the following group a: halogen, hydroxy, methoxy, amino, carboxy;
R3is F, R4Is H, halogen, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; or R3And R4Form, with the C atom to which they are attached, a 3-6 membered heterocyclyl or C3-C8 cycloalkyl; or R3And R4Taken together to form ═ O; or R4Is H, R3And Y1And together with the C atom between them form a 5-7 membered heterocyclic group; at this time Y1Is C;
R5、R6、R7、R8each independently is H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxySubstituted or unsubstituted C1-C4 alkanoylamino; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 3-6 membered heterocyclyl;
or R5、R6Taken together with the attached carbon to form a substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7、R8Together with the attached carbon form a group selected from the group consisting of: substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
T1is-C (O) R9、-SO2R9、5-7 membered heteroaryl unsubstituted or substituted by a substituent selected from group B, C1-C6 alkyl unsubstituted or substituted by a substituent selected from group B; r9Selected from the group consisting of H, hydroxy, C1-C6 alkoxy, -NHCO- (C1-C6 alkyl), C1-C6 alkyl unsubstituted or substituted with a substituent selected from group B, amino unsubstituted or substituted with a substituent selected from group B, and 5-8 membered heteroaryl unsubstituted or substituted with a substituent selected from group B; group B substituents include: halogen, hydroxy, C1-C6 alkyl, -SO2CH3;
And when A1、X1、Y1Is CH, W1Is S, T1is-C (O) R9And R is1And R2When none is-L-M, R5、R6、R7、R8Cannot be all H at the same time;
and A is1R in (1)x、X1R in (1)x、R1、R2、RyAny two of which are not simultaneously-L-M;
l is selected from- (CH)2)m-(Q)i-(CH2)n-、-O-(CH2)m-(Q)i-(CH2)n-O-、-O-(CH2)m-(Q)i-(CH2)n-、-(CH2)m-(Q)i-(CH2)n-O-,; m and n are respectively and independently selected from integers of 0-5; i is 0 or 1; and m, n and i are not 0 at the same time; q is selected from-CH ═ CH-, -C ≡ C-, -C (O) -NH-, -NH-C (O) -, -N ═ CH-, O, 3-8 membered heterocyclyl, 3-8 membered heteroaryl;
m is selected from the following structures:
A2、X2each independently is N or CRx’;Rx' is H or halogen; rx' is H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl; a substituted or unsubstituted C1-C6 alkoxy group; the substitution means substitution with a substituent selected from the group consisting of: halogen, hydroxy, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;
W2o, S, NH; y is2Is N or CRy’;Ry' is H or absent;
R1’、R2' is independently selected from halogen, hydroxy, cyano, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkanoyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C4 alkylamido, substituted or unsubstituted C1-C4 alkylamino; r1’、R2The substitution in' means substitution by one or more selected from halogen, hydroxyl and methoxy;
R3' is F, R4' is H, halogen, hydroxy, C1-C4 alkyl or C1-C4 alkoxy; or R3' and R4' forms a 3-6 membered heterocyclic group with the C atom to which they are attached; or R3' and R4Together form ═ O; or R4' is H, R3' and Y1And forms a 5-7 membered heterocyclic group with the C atom therebetween; at this time Y2Is C;
R5’、R6’、R7’、R8' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C4 alkanoylamino; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 3-6 membered heterocyclyl;
or R5’、R6' taken together with the attached carbon to form a substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7’、R8' taken together with the attached carbon to form a substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
T2is-C (O) R9、-SO2R9、5-7 membered heteroaryl unsubstituted or substituted by a substituent selected from group B, C1-C6 alkyl unsubstituted or substituted by a substituent selected from group B; r9Selected from H, hydroxy, C1-C6 alkoxy, -NHCO- (C1-C6 alkyl), C1-C6 alkyl which is unsubstituted or substituted by a substituent selected from group B, amino which is unsubstituted or substituted by a substituent selected from group B5-8 membered heteroaryl substituted with a substituent selected from group B;
T3is 5-7 membered heteroaryl, unsubstituted or substituted by a substituent selected from group B;
group B substituents include: halogen, hydroxy, C1-C6 alkyl, -SO2CH3;
T4And T4' are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C8 cycloalkyl; the substituted means substituted by one or more substituents selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, 3-8 membered heterocyclyl, C6-C10 aryl; .
2. A compound of formula (I) according to claim 1, or enantiomers, diastereomers, racemates thereof and mixtures thereof, or pharmaceutically acceptable salts thereof,
A1、X1each independently is N or CRx;RxH, F, Cl, -L-M;
A2、X2each independently is N or CRx’;Rx' is H, F, Cl;
Y1is N or CRy;RyIs H, -L-M or absent; y is2Is N or CH;
W1、W2each independently is NH or S;
R1、R2each independently is fluorine, chlorine, bromine or C1-C4 alkoxy, -L-M;
R1’、R2' are each independently fluorine, chlorine, bromine or C1-C4 alkoxy;
and A is1R in (1)x、X1R in (1)x、R1、R2、RyAny two of which are not simultaneously-L-M.
3. A compound of formula (I) according to claim 1, or enantiomers, diastereomers, racemates thereof and mixtures thereof, or pharmaceutically acceptable salts thereof,
R3and R4Are all F; or R3And R4Form, with the C atom to which they are attached, a 3-6 membered heterocyclyl or C3-C8 cycloalkyl; or R3And R4Taken together to form ═ O; or R4Is H, R3And Y1And forms a 5-7 membered heterocyclic group with the C atom therebetween; at this time Y1Is C;
R3' and R4' both are F; or R3' and R4' forms a 3-6 membered heterocyclic group or a C3-C8 cycloalkyl group with the C atom to which they are attached; or R3' and R4Together form ═ O; or R4' is H, R3' and Y2And forms a 5-7 membered heterocyclic group with the C atom therebetween; at this time Y2Is C.
4. A compound of formula (I) according to claim 1, or enantiomers, diastereomers, racemates thereof and mixtures thereof, or pharmaceutically acceptable salts thereof,
R5、R6、R7、R8each independently is H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 4-6 membered heterocyclyl;
or R5、R6Together with the carbon to which they are attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7、R8Together with the carbon to which they are attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl orA substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
R5’、R6’、R7’、R8' are each independently H, halogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; the substitution is substituted by one or more substituents selected from the group consisting of: halogen, -C (O) NH2Hydroxy, C1-C4 alkyl, C1-C4 alkoxy, amino, 4-6 membered heterocyclyl;
or R5’、R6' taken together with the carbon to which it is attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxy, halogen;
or R7’、R8' taken together with the carbon to which it is attached to form- (CH ═ CH)2) Substituted or unsubstituted C3-C8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocyclyl; the substitution is substituted by one or more substituents selected from the group consisting of: C1-C6 alkyl, hydroxyl and halogen.
5. The compound of claim 1, having a structure selected from any one of the following groups:
wherein the content of the first and second substances,
A1、X1、A2、X2each independently is N or CRx;RxIs H, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; said substitutionIs substituted by a substituent selected from the group consisting of: halogen, hydroxy, C6-C10 aryl, C3-C8 cycloalkyl, 5-7 membered heteroaryl, 3-8 membered heterocyclyl;
Y1、Y2each independently is N or CH; w1、W2Each independently is NH or S;
R1、R2independently selected from halogen, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; r1、R2Wherein the substitution is substituted by one or more selected from halogen, hydroxyl and methoxy;
l is selected from-O- (CH)2)m-(Q)i-(CH2)n-O-、-(CH2)m-(Q)i-(CH2)n-; m and n are respectively and independently selected from integers of 1-5; i is 0 or 1; q is selected from-CH ═ CH-, -C ≡ C-, -C (O) -NH-, -NH-C (O) -, -N ═ CH-, O, and,
R3、R4、R5、R6、R7、R8、T1、R1’、R2’、R3’、R4’、R5’、R6’、R7’、R8’、T2And T3Is as defined in claim 1.
7. a pharmaceutical composition, comprising:
a compound of general formula (I) according to any one of claims 1 to 6, or enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.
8. Use of a compound of general formula (I) according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the preparation of a STING agonist, an immunological composition or a vaccine adjuvant;
or for the preparation of a medicament for the prevention and/or treatment of STING-dependent type I interferon-related diseases.
9. The use according to claim 8, wherein the STING-dependent type I interferon-related diseases are tumors and infectious diseases.
10. The use of claim 9, wherein the tumor is selected from the group consisting of: brain and spinal cord cancer, head and neck cancer, leukemia and blood cancer, skin cancer, cancer of the reproductive system, cancer of the gastrointestinal system, cancer of the esophagus, cancer of the nasopharynx, pancreatic cancer, rectal cancer, hepatocellular cancer, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline tract cancer, and cancer of unknown primary;
and the infectious disease is selected from the group consisting of: human immunodeficiency virus infection, herpes simplex virus infection, hepatitis B virus infection, and hepatitis C virus infection.
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