WO2023061478A1 - Tricyclic compound - Google Patents
Tricyclic compound Download PDFInfo
- Publication number
- WO2023061478A1 WO2023061478A1 PCT/CN2022/125361 CN2022125361W WO2023061478A1 WO 2023061478 A1 WO2023061478 A1 WO 2023061478A1 CN 2022125361 W CN2022125361 W CN 2022125361W WO 2023061478 A1 WO2023061478 A1 WO 2023061478A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- formula
- acceptable salt
- cycloalkyl
- compound represented
- Prior art date
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- JGQPZPLJOBHHBK-UFXYQILXSA-N dBET6 Chemical compound Cc1sc-2c(c1C)C(=N[C@@H](CC(=O)NCCCCCCCCNC(=O)COc1cccc3C(=O)N(C4CCC(=O)NC4=O)C(=O)c13)c1nnc(C)n-21)c1ccc(Cl)cc1 JGQPZPLJOBHHBK-UFXYQILXSA-N 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
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- 210000001672 ovary Anatomy 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
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- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
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- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
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- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
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- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the disclosure belongs to the field of medical technology, and specifically relates to a tricyclic compound, its composition, and its application in the preparation of drugs for treating diseases related to CRBN protein.
- the compound is used to prepare bifunctional PROTAC compounds for treatment of related diseases.
- CRBN Cereblon
- testis spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocytes, colon, brain and retina, while in brain tissue (including retina) and testis The expression in was significantly higher than that in other tissues.
- CRBN is closely related to the metabolism and proliferation of normal cells and tumor cells. On the one hand, its existence ensures the normal metabolic function and normal physiological function of the ion channel, which is very important for maintaining cell growth and proliferation. On the other hand, CRBN is involved in the occurrence of many diseases such as cancer. Shi et al., J. Immunol. Res. Article ID 9130608 (2017). As an important target of anti-tumor and immunomodulator drugs, CRBN has been proven to have clear curative effects in various hematological malignancies such as multiple myeloma and chronic lymphocytic leukemia, and autoimmune diseases such as systemic lupus erythematosus. However, the existing meridamine drugs have many side effects, especially peripheral neuropathy. At present, it is necessary to develop new CRBN modulator drugs to improve clinical treatment effect, reduce clinical side effects, and benefit long-term use of patients.
- CRBN can interact with damaged DNA-binding protein 1 (DDB1), form an E3 ubiquitin ligase complex with Cullin 4 (Cul4A) and the E2-binding protein ROC1 (also known as RBX1), in which, CRBN acts as the substrate receptor of CRBN-CRL4, and after binding to the substrate, the substrate protein undergoes proteolysis through the ubiquitin-proteasome pathway.
- DDB1 DNA-binding protein 1
- Cul4A Cullin 4
- ROC1 also known as RBX1
- the ubiquitin-proteasome pathway is a key pathway for regulating key regulatory proteins and degrading misfolded or abnormal proteins.
- Ubiquitin molecules tag proteins for proteasomal degradation through covalent attachment of E3 ubiquitin ligases to terminal lysine residues, where the protein is digested into small peptides and eventually into its constituent amino acids with as building blocks for new proteins.
- UPP is important for multiple cellular processes, and if defective or out of balance, it contributes to the pathogenesis of a variety of diseases. Defective proteasomal degradation has been shown to be associated with a variety of clinical conditions including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease and cancer, among others.
- PROTAC Proteolysis targeting chimeras
- UFP ubiquitin-proteasome pathway
- PROTAC molecules are bifunctional molecules that can not only bind to target proteins, but also recruit E3 ubiquitin ligase to ubiquitinate target proteins, and then degrade target proteins through proteasomes. Therefore, CRBN ligands can also be used to prepare bifunctional PROTAC (proteolysis-directed chimera) compounds for the treatment of related diseases. Therefore, it is necessary to further develop small molecular compounds that can regulate CRBN and degrade specific proteins for the treatment of tumors. In addition, it is still necessary to find CRBN ligands that can be used as therapeutic agents, and at the same time, CRBN ligands can be further used to prepare bifunctional PROTAC compounds for the treatment of diseases.
- the disclosure provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof:
- Y 1 , Y 2 , Y 3 are independently selected from CR 2 or N;
- X 1 is selected from C, CR 1a or N;
- X 2 is selected from CR 2a , CR 2a R 2b , N or NR 2a ;
- R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, CN, OH, NH 2 , -C(O) Rf , -C(O)N( R f ) 2 , -C(O)OR f , -C(O)ON(R f ) 2 , -NHC(O)R f , -NHC(O)OR f , -NHC(O)N(R f ) 2 , -S(O) 2 (R f ), C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclyl or 5-10 OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocycl
- R 1a , R 4a and the cyclic group they are connected to form a carbon bridged ring or a bridged heterocyclic ring;
- R 1 is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl or 5- 10-membered heteroaryl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered Heteroaryl is optionally substituted by R;
- R 2 is selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl or 5- 10-membered heteroaryl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered Heteroaryl is optionally substituted by R;
- Each R d is independently selected from halogen, CN, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl;
- Each R f is independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl;
- n is independently selected from 0, 1 or 2.
- X 2 is selected from CR 2a , CR 2a R 2b or NR 2a .
- R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, OH, NH 2 , -C(O) Rf , -C( O)N(R f ) 2 , -C(O)OR f , -NHC(O)R f , -NHC(O)OR f , C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl, C 6 -C 10 aryl 4-8 membered heterocyclic group or 5-6 membered heteroaryl group, said OH, NH 2 , C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl, C 6 - C 10 aryl 4-8 membered heterocyclic group or 5-6 membered heteroaryl group is optionally substituted by Rd .
- R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, OH, NH 2 , -C(O)OR f or C 1 - C 6 alkyl, the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted by R d .
- R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, OH, NH 2 , -C(O)OH, or C 1 -C 3 alkyl, the OH, NH 2 or C 1 -C 3 alkyl is optionally substituted by R d .
- R 1a , R 4a and the cyclic group to which they are attached form a carbon-bridged ring.
- R 2a , R 3a and the atoms to which they are attached together form a cycloalkyl group.
- R 2a , R 3a and the atoms to which they are attached together form a C 3 -C 6 cycloalkyl group.
- R 3a , R 3b and the atoms to which they are attached together form a cycloalkyl group.
- R 1 is independently selected from halogen, CN, OH, NH 2 , or C 1 -C 6 alkyl optionally substituted with R d .
- R 2 is selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl optionally substituted with R d .
- R2 is selected from H or halogen.
- R is selected from H or F.
- n is independently selected from 0 or 1.
- the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I') or a pharmaceutically acceptable salt thereof,
- X 1 is selected from CR 1a or N;
- X 2 is selected from CR 2a R 2b or NR 2a ;
- R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n are as defined above.
- the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
- the present disclosure also provides a compound represented by formula (II) and a pharmaceutically acceptable salt thereof:
- [] indicates that L can be connected with X 2 , X 3 , X 4 , Y 1 , Y 2 or Y 3 ;
- X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n are as defined above;
- Y 1 , Y 2 or Y 3 When L is connected with Y 1 , Y 2 or Y 3 , Y 1 , Y 2 or Y 3 is C, when L is connected with X 2 , X 2 is C, CR 2a or N, when L is connected with X 3 , X 3 is CR 3a or N, when L is connected with X 4 , X 3 is CR 4a or N;
- L is selected from the following structural units:
- R 10 is selected from H, OH, NH 2 or C 1 -C 6 alkyl
- R 11 is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl;
- k is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
- q is selected from 0, 1, 2, 3, 4, 5 or 6.
- k is selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9.
- q is selected from 1, 2, 3, 4, 5 or 6.
- L is selected from the following structural units:
- the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5-10 heteroaryl or 4-10 membered heterocyclic group is optionally substituted by R 11 , q is as defined above.
- L is selected from the following structural units:
- L is selected from the following structural units:
- the triazolyl, piperazinyl, cyclohexyl or phenyl is optionally substituted by R 11 , q is as defined above.
- L is selected from the following structural units:
- L is selected from the following structural units:
- the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II') or a pharmaceutically acceptable salt thereof,
- X 1 is selected from CR 1a or N;
- X 2 is selected from CR 2a R 2b or NR 2a ;
- R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, [] are as defined above.
- the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
- the present disclosure also provides a pharmaceutical composition, which comprises the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
- the present disclosure relates to the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating diseases mediated by CRBN.
- the present disclosure relates to the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of diseases mediated by CRBN.
- the present disclosure relates to a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating CRBN-mediated related diseases.
- the present disclosure also relates to a method for treating CRBN-mediated related diseases, the method comprising administering to the patient a therapeutically effective dose of a compound represented by formula (I) or (II) described in the present disclosure or a pharmaceutically acceptable Pharmaceutical preparations of salts.
- the present disclosure provides a method for treating mammals suffering from abnormal cell proliferation diseases, comprising administering a therapeutically effective amount of a compound represented by formula (I) or (II) or a pharmaceutically effective amount thereof to a mammal in need of the treatment, preferably a human. acceptable salts, or pharmaceutical compositions thereof.
- the present disclosure provides the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.
- the present disclosure provides the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating abnormal cell proliferation diseases.
- the present disclosure provides a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.
- the disorder of abnormal cell proliferation is selected from cancer.
- the cancer is selected from solid tumors, adenocarcinomas, or hematological tumors.
- the present disclosure relates to a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, as a synthetic intermediate of a bifunctional compound targeting protein degradation, during the preparation of a bifunctional compound targeting protein degradation ( PROTAC molecules).
- the present disclosure also provides a compound represented by formula (III) and a pharmaceutically acceptable salt thereof:
- the PTM is a targeting protein binding moiety.
- the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from a compound represented by formula (III') or a pharmaceutically acceptable salt thereof:
- X 1 is selected from CR 1a or N;
- X 2 is selected from CR 2a R 2b or NR 2a ;
- R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, PTM, [] are as defined above.
- the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IIIa) or a pharmaceutically acceptable salt thereof:
- X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, and PTM are as defined above.
- the compound shown in formula (III) or its pharmaceutically acceptable salt is selected from the compound shown in formula (IIIb) or its pharmaceutically acceptable salt:
- X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, and PTM are as defined above.
- the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IIIc) or a pharmaceutically acceptable salt thereof:
- X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, and PTM are as defined above.
- the PTM is selected from the binding portion of the following targeting proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP , DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, JAK1, JAK3, KIF18A, KRAS, LCK, MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51 , RBM10, RET, RORA, STAT3, SOS1, TYK2, USP1 or USP14.
- the PTM is selected from the binding portion of the following targeting proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP , DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, JAK1, JAK3, KIF18A, KRAS, LCK, MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51 , RBM10, RET, RORA, SOS1, TYK2, USP1 or USP14.
- the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
- the present disclosure also provides a pharmaceutical composition, which comprises the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
- the present disclosure provides a method for treating mammals suffering from abnormal cell proliferation, comprising administering a therapeutically effective amount of a compound represented by formula (III) or a pharmaceutically acceptable salt thereof to a mammal in need of the treatment, preferably a human , or a pharmaceutical composition thereof.
- the present disclosure provides the use of the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.
- the present disclosure provides the use of the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating abnormal cell proliferation diseases.
- the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.
- the disorder of abnormal cell proliferation is selected from cancer.
- the cancer is selected from solid tumors, adenocarcinomas, or hematological tumors.
- tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
- Compounds of the present disclosure may exhibit tautomerism.
- Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This disclosure encompasses all tautomeric forms of the compounds.
- stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
- the compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
- Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the disclosed compounds.
- asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Compounds of the disclosure are within the definition.
- Compounds of the present disclosure containing asymmetric atoms can be isolated in optically pure or racemic forms, optically pure forms can be resolved from racemic mixtures, or synthesized by using chiral starting materials or chiral reagents .
- substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
- ethyl is “optionally” substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
- any variable eg R a , R b
- its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
- linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
- linking group mentioned herein does not indicate its linking direction
- its linking direction is arbitrary.
- L 1 in is selected from “-C 1 -C 3 alkylene-O-"
- L 1 can be connected with ring Q and R 1 from left to right to form “ring QC 1 -C 3 Alkylene-OR 1 "
- ring Q and R 1 can also be linked from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
- the substituent When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring.
- the structural unit Indicates that R 1 can be substituted at any position on the ring, when R 1 replaces the H of NH, the structure is
- Cm - Cn herein refers to having an integer number of carbon atoms in the range of mn.
- C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
- alkyl refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched.
- C 1 -C 10 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl" can be understood as an
- C 1 -C 3 alkyl is understood to mean a straight-chain or branched saturated alkyl group having 1, 2 or 3 carbon atoms.
- the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl", etc., and the “C 1 -C 6 alkyl” may further include “ C 1 -C 3 alkyl”.
- cycloalkyl refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a double ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
- C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decanyl, etc.
- C 3 -C 10 cycloalkyl may include “C 3 -C 6 cycloalkyl”, and the term “C 3 -C 6 cycloalkyl” can be understood as representing a saturated monocyclic or bicyclic hydrocarbon ring, which has 3-6 carbon atoms, specific examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
- 3-10 membered heterocyclic group refers to a heterocyclic group with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independently selected from the heteroatoms or heteroatom groups described above.
- “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group", wherein, specific examples of 4-membered heterocyclic group include but are not limited to azetidinyl or oxetanyl; 5-membered Specific examples of heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2, 5-dihydro-1H-pyrrolyl; Specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl , trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membere
- the heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
- the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like.
- “4-10 membered heterocyclic group” may include “5-10 membered heterocyclic group”, “4-7 membered heterocyclic group”, “5-6 membered heterocyclic group”, “6-8 membered heterocyclic group” , “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered "Heterocycloalkyl” and other ranges, "4-7 membered heterocyclyl” may further include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl” , “4-6 membered heterocycloalkyl", "5-6 membered
- aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
- the aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
- C 6 -C 20 aryl is understood to mean an aryl group having 6 to 20 carbon atoms.
- C aryl rings with 6 carbon atoms
- C aryl such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 a ring of 3 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or is a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
- C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms.
- C aryl rings with 6 carbon atoms
- C aryl such as phenyl
- C aryl rings with 9 carbon atoms
- C 10 aryl rings with 10 carbon atoms
- C 6 -C 20 aryl may include "C 6 -C 10 aryl"
- heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
- heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
- 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S.
- heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
- benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
- 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S .
- halo or halogen refers to fluorine, chlorine, bromine or iodine.
- hydroxyl refers to a -OH group.
- cyano refers to a -CN group.
- mercapto refers to a -SH group.
- amino refers to a -NH2 group.
- nitro refers to a -NO2 group.
- terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying The amount of a compound of the disclosure required for the onset of one or more symptoms of a particular disease, condition or disorder.
- the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
- composition refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients.
- the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.
- pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
- the disclosure also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature.
- isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
- isotopically labeled compounds of the disclosure are useful in compound and/or substrate tissue distribution assays. Tritiated (ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
- Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
- Isotopically labeled compounds of the disclosure can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- the pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
- Typical routes of administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
- the pharmaceutical composition of the present disclosure can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
- the pharmaceutical composition is in oral form.
- the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to patients.
- Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
- Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
- the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
- the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg /kg body weight, in single or divided doses.
- ratios indicated for mixed solvents are volume mixing ratios.
- % means wt%.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- Step 4 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (1- 6)
- Step 5 3-(2-Oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (1)
- Example 2 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]tri Azolo[4,3-a][1,4]diazoheptin-6-yl)-N-(11-(4-(2,6-dioxopiperidin-3-yl)-5 -Oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinolin-1(2H)-yl)-11-carbonylundecyl)acetamide (compound 2)
- Step 2 tert-butyl 3-((N-(3-bromophenyl)-4-methylphenyl)sulfonylamino)propionate (2-3)
- Step 3 3-((N-(3-bromophenyl)-4-methylphenyl)sulfonylamino)propanoic acid (2-4)
- Step 7 tert-butyl 5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinoline-1(2H)-carboxylate (2-8)
- Step 8 4-(2,6-Bis(benzyloxy)pyridin-3-yl)-5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinone Phenyl-1(2H)-tert-butyl carboxylate (2-9)
- Step 9 4-(2,6-Dicarbonylpiperidin-3-yl)-5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinoline-1 (2H)-tert-butyl carboxylate (2-10)
- Step 10 3-(5-Oxo-2,3,3a,5-tetrahydropyrrolo[2,3,4-de]quinolin-4(1H)-yl)piperidine-2,6-di Ketones (2-11)
- Step 11 (11-(4-(2,6-dioxopiperidin-3-yl)-5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de ]quinolin-1(2H)-yl)-11-carbonylundecyl)carbamate tert-butyl ester (2-12)
- Step 12 3-(1-(11-aminoundecanoyl)-5-oxo-2,3,3a,5-tetrahydropyrrolo[2,3,4-de]quinoline-4(1H )-yl)piperidine-2,6-dione (2-13)
- Step 13 2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazole And[4,3-a][1,4]diazoheptin-6-yl)-N-(11-(4-(2,6-dioxopiperidin-3-yl)-5- Oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinolin-1(2H)-yl)-11-carbonylundecyl)acetamide (Compound 2)
- Step 1 4-Bromo-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (3-1)
- Step 2 Dimethyl 2-(4-bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutarate (3-2 )
- Step 3 2-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutaric acid (3-3)
- Step 4 3-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione ( 3-4)
- Step 5 ((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd]indole- 4-yl) methyl) tert-butyl carbamate (3-5)
- Step 6 3-(4-(Aminomethyl)-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6 - diketone (3-6)
- Step 7 1-(3-Chloro-4-methylphenyl)-3-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6 ,7,8,8a-Hexahydrobenzo[cd]indol-4-yl)methyl)urea (3)
- Step 3 Dimethyl 2-(4-bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutarate (3-2 )
- Step 4 2-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutaric acid (3-3)
- Step 5 3-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione ( 3-4)
- Step 1 (6-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd ]indol-4-yl)methyl)amino)-6-carbonylhexyl)carbamate tert-butyl ester (4-1)
- Step 2 6-Amino-N-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6,7,8,8a-hexahydrobenzo [cd]indol-4-yl)methyl)hexanamide (4-2)
- Step 3 6-(2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4 ]triazolo[4,3-a][1,4]diazoheptin-6-yl)acetamido)-N-((1-(2,6-dioxopiperidin-3-yl )-2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd]indol-4-yl)methyl)caproamide (4)
- the detection kit used in the experiment is a kind of Assay method for quantitative measurement of Cereblon WT ligand.
- the detection principle is based on HTRF technology.
- the specific labeled GST antibody Euroum Cryptate, donor
- the donor triggers fluorescence resonance energy transfer (FRET) to the acceptor, and the acceptor emits fluorescence at a specific wavelength of 665nm. After adding the compound, it competes with XL665-labeled lenalidomide to prevent FRET from occurring.
- FRET signal ratio is inversely proportional to the compound concentration.
- the disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM.
- Gradient dilution of the compound mother solution is carried out through the compound dilution and sample loading program of the Echo instrument.
- the total experimental system of the dilution program is 20 ⁇ L, the initial concentration of the compound to be tested is 100 ⁇ M, the initial concentration of the standard is 200 ⁇ M, 4 times dilution, 8 concentration points, DMSO content 1%.
- HillSlope is the slope coefficient of the curve.
- Test Example 2 MV-4-11 cell anti-proliferation activity experiment
- the culture medium of the target cell MV-4-11 (CBP60522, Kebai) was removed, washed once with PBS, and then digested with trypsin-EDTA (0.25%) for 5 min. After digestion, add 10 mL of complete medium (IMDM+10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 1000 rpm for 5 min, count the cells, and adjust the cell density to 30,000 cells/mL. Take 90 ⁇ L of cell suspension and add it to a 96-well low adsorption plate. Add 200 ⁇ L of PBS to the edge wells of the 96-well plate. Centrifuge at 1000rpm for 5min to aggregate the cells into spheres and place them in a cell culture incubator for overnight culture.
- IMDM+10% FBS complete medium
- the disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM. Before administration, the compound was serially diluted 5-fold with DMSO, and a total of 8 gradient working solutions were used. Take 2 ⁇ L of each working solution of different concentrations, add it to the dilution plate of 198 ⁇ L medium, and mix well by pipetting. Take 10 ⁇ L of the medium containing the compound from the dilution plate and add it to the cell plate containing 90 ⁇ L of the cell suspension laid out the day before. nM.
- the positive control compound is dBET6. Add the diluted compound, 10 ⁇ L per well, and incubate at 37°C, 5% CO 2 for 3 days.
- the cells were taken out of the incubator and returned to room temperature for 30 min. Add 50 ⁇ L of For the Cell Viability Assay reagent, shake and mix for 10 minutes and then read the plate with an Envision microplate reader.
- the anti-proliferation activity of the disclosed compound on MV-4-11 cells is determined by the above test, and the cell growth inhibition rate of each sample well is calculated according to the original data.
- Inhibition rate % 100% * (1 - sample reading / reference average reading)
- HillSlope is the slope coefficient of the curve.
- Table 2 shows the antiproliferative activity of the disclosed compounds on MV-4-11 cells.
- Test example 3 Experiment on the degradation activity of BRD4 protein in MV-4-11 cells
- the culture medium of MV-4-11 (CBP60522, Kebai) was removed, rinsed with PBS, and then digested with trypsin-EDTA (0.25%) for 5 min. After the digestion is complete, add 10 mL of complete medium (IMDM+10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 1000 rpm for 5 min, count the cells, and adjust the cell density to 500,000 cells/mL. Take 2mL of cell suspension and add it to a 12-well plate, and put it in a cell culture incubator for overnight culture.
- complete medium IMDM+10% FBS
- the disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM.
- the compound mother solution was serially diluted (4-fold dilution), with 8 concentration points, DMSO was used as a negative control group, and the DMSO content was 0.1%. Mix the compound and cell suspension and incubate at 37°C, 5% CO 2 for 6 hours.
- the antibody was recovered the next day, and the strip was washed 3 times with PBST (PBS containing 0.1% Tween-20), 10 min each time. After washing, the diluted Goat Anti-Rabbit IgG H&L (goat anti-rabbit secondary antibody) (1:3000) was added and incubated at room temperature for 1 h. The strips were washed 3 times with PBST (PBS containing 0.1% Tween-20). Use SuperSignal West Atto ultra-sensitive ECL luminescent fluid to detect protein.
- the compound of the present disclosure has the BRD4 protein degradation activity in MV-4-11 cells determined by the above test, using the Image J software to read the gray value of the target sample band, and then calculate the protein degradation rate of each sample well according to the original data.
- HillSlope is the slope coefficient of the curve.
- Table 3 shows the measured DC 50 values of the disclosed compounds.
- Test Example 4 Anti-proliferation activity experiment of CAL51 cells
- the culture medium of the target cell CAL51 (CBP60360, Kebai) was removed, washed once with PBS, and then digested with trypsin-EDTA (0.25%) for 5 min. After the digestion is complete, add 10 mL of complete medium (DMEM+10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 300 g for 5 min, count, and adjust the cell density to 40,000 cells/mL. Take 90uL of cell suspension and add it to a 96-well low adsorption plate. Add 200uL of PBS to the edge well. Centrifuge at 300g for 5min to aggregate the cells into spheres and put them in the cell culture incubator overnight.
- complete medium DMEM+10% FBS
- the disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM.
- the DMSO gradient was diluted 10 times, and a total of 6 gradient working solutions were used. Take 2uL of each working solution of different concentrations, add it to the dilution plate of 198uL medium, and mix by pipetting. Take 10uL of the medium containing the compound from the dilution plate and add it to the cell plate containing 90uL of the cell suspension laid out the day before, and the final concentration of each gradient compound is 10,000, 1000, 100, 10, 1, 0.1nM.
- the positive control was CC-885. Add the diluted compound, 10uL per well, centrifuge and put it in a carbon dioxide incubator for 3 days.
- the cells were taken out of the incubator and returned to room temperature for 30 min. Add 50uL of 3D Cell Viability Assay reagent, shake and mix for 10 minutes and then read the plate with Envision microplate reader.
- the anti-proliferation activity of the disclosed compound on CAL51 cells is determined by the above test, and the cell growth inhibition rate of each sample well is calculated according to the original data.
- Inhibition rate % 100% * (1 - sample reading / reference average reading)
- HillSlope is the slope coefficient of the curve.
- Table 4 shows the antiproliferative activity of the disclosed compounds on CAL51 cells.
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Abstract
Provided in the present disclosure are a compound as represented by formula (I) and a pharmaceutically acceptable salt thereof, a composition thereof, and the use thereof in the preparation of a drug for treating diseases related to CRBN protein. The compound can further be used as a synthetic intermediate for a bifunctional compound for targeting protein degradation, and thus can be used for preparing a bifunctional compound for targeting protein degradation.
Description
本申请要求以下在先申请的优先权,以下在先申请的全文通过引用的方式结合于本申请中:This application claims priority to the following earlier application, which is hereby incorporated by reference in its entirety:
2021年10月15日向中国国家知识产权局提交的专利申请号为202111206934.7,发明名称为“三环类化合物”的在先申请。The patent application number submitted to the State Intellectual Property Office of China on October 15, 2021 is 202111206934.7, and the invention name is the prior application of "tricyclic compounds".
本公开属于医药技术领域,具体的涉及一种三环类化合物,及其组合物,以及其在制备治疗与CRBN蛋白相关疾病药物中的应用,所述化合物用于制备双功能PROTAC化合物,用于相关疾病的治疗。The disclosure belongs to the field of medical technology, and specifically relates to a tricyclic compound, its composition, and its application in the preparation of drugs for treating diseases related to CRBN protein. The compound is used to prepare bifunctional PROTAC compounds for treatment of related diseases.
CRBN(Cereblon)是一种在人体内由CRBN基因编码的蛋白质。CRBN广泛地表达在睾丸、脾、前列腺、肝脏、胰腺、胎盘、肾脏、肺、骨骼肌、卵巢、小肠、外周血白细胞、结肠、脑部以及视网膜中,而在脑组织(包括视网膜)以及睾丸中的表达显著高于其他组织。CRBN (Cereblon) is a protein encoded by the CRBN gene in the human body. CRBN is widely expressed in testis, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocytes, colon, brain and retina, while in brain tissue (including retina) and testis The expression in was significantly higher than that in other tissues.
研究发现CRBN与正常细胞以及肿瘤细胞的代谢与增殖紧密相关。一方面,其存在确保离子通道的正常代谢功能与正常生理功能,对于维持细胞生长与增殖相当重要。另一方面,CRBN涉及许多疾病例如癌症的发生。Shietal.,J.Immunol.Res.Article ID 9130608(2017)。CRBN作为抗肿瘤和免疫调节剂药物的重要靶点,已被证实在多发性骨髓瘤、慢性淋巴细胞白血病等多种血液性恶性肿瘤,系统性红斑狼疮等自身免疫性疾病具有明确的疗效。但是现有的度胺类药物都有较多副作用,尤其是周围神经病变。当前需要开发新的CRBN调节剂药物,来提高临床治疗效果,降低临床副作用,利于患者长期使用。Studies have found that CRBN is closely related to the metabolism and proliferation of normal cells and tumor cells. On the one hand, its existence ensures the normal metabolic function and normal physiological function of the ion channel, which is very important for maintaining cell growth and proliferation. On the other hand, CRBN is involved in the occurrence of many diseases such as cancer. Shi et al., J. Immunol. Res. Article ID 9130608 (2017). As an important target of anti-tumor and immunomodulator drugs, CRBN has been proven to have clear curative effects in various hematological malignancies such as multiple myeloma and chronic lymphocytic leukemia, and autoimmune diseases such as systemic lupus erythematosus. However, the existing meridamine drugs have many side effects, especially peripheral neuropathy. At present, it is necessary to develop new CRBN modulator drugs to improve clinical treatment effect, reduce clinical side effects, and benefit long-term use of patients.
此外,CRBN可与受损的DNA结合蛋白1(DDB1)相互作用,与Cullin 4(Cul4A)和E2结合蛋白ROC1(也称为RBX1)形成E3泛素连接酶复合物,在该复合物中,CRBN作为CRBN-CRL4的底物受体,结合底物后使底物蛋白通过泛素-蛋白酶体途径进行蛋白水解。参见,Chang et al.,Int.J.Biochem.Mol.Biol.2(3):287-94(2011)。In addition, CRBN can interact with damaged DNA-binding protein 1 (DDB1), form an E3 ubiquitin ligase complex with Cullin 4 (Cul4A) and the E2-binding protein ROC1 (also known as RBX1), in which, CRBN acts as the substrate receptor of CRBN-CRL4, and after binding to the substrate, the substrate protein undergoes proteolysis through the ubiquitin-proteasome pathway. See, Chang et al., Int. J. Biochem. Mol. Biol. 2(3):287-94 (2011).
泛素-蛋白酶体途径(UPP)是调节关键调节蛋白和降解错折叠或异常蛋白的关键途径。泛素分子通过E3泛素连接酶与末端赖氨酸残基的共价连接对蛋白质进行标记以进行蛋白酶体降解,其中该蛋白质被消化成小肽并最终消化成其组成氨基酸,所述氨基酸用作新蛋白质的构建模块。UPP对于多个细胞过程是重要的,如果有缺陷或失衡,它会导致多种疾病的发病机理。现已证实有缺陷的蛋白酶体降解与多种临床病症有关,所述病症包括阿尔茨海默病、帕金森病、亨廷顿病、肌营养不良、心血管疾病和癌症等。而靶向蛋白降解嵌合体PROTAC(Proteolysis targeting chimeras)是一种基于细胞自身的泛素-蛋白酶体途径(UPP)发展而来的新型靶向降解目标蛋白的技术。PROTAC分子是一种双功能的分子,既能与目标蛋白结合,又能招募E3泛素连接酶,从而将目标蛋白泛素化,进而通过蛋白酶体将目标蛋白降解。因此,还可以利用CRBN配体制备双功能性PROTAC(蛋白水解导向嵌合体)化合物,用于治疗相关疾病。因此,需要进一步开发用于治疗肿瘤的能够调节CRBN并降解特定蛋白的小分子化合物。此外,仍然需要找到可用作治疗剂的CRBN配体,同时可进一步利用CRBN配体制备双功能PROTAC化合物,用于疾病的治疗。The ubiquitin-proteasome pathway (UPP) is a key pathway for regulating key regulatory proteins and degrading misfolded or abnormal proteins. Ubiquitin molecules tag proteins for proteasomal degradation through covalent attachment of E3 ubiquitin ligases to terminal lysine residues, where the protein is digested into small peptides and eventually into its constituent amino acids with as building blocks for new proteins. UPP is important for multiple cellular processes, and if defective or out of balance, it contributes to the pathogenesis of a variety of diseases. Defective proteasomal degradation has been shown to be associated with a variety of clinical conditions including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease and cancer, among others. PROTAC (Proteolysis targeting chimeras) is a new technology for targeting and degrading target proteins developed based on the cell's own ubiquitin-proteasome pathway (UPP). PROTAC molecules are bifunctional molecules that can not only bind to target proteins, but also recruit E3 ubiquitin ligase to ubiquitinate target proteins, and then degrade target proteins through proteasomes. Therefore, CRBN ligands can also be used to prepare bifunctional PROTAC (proteolysis-directed chimera) compounds for the treatment of related diseases. Therefore, it is necessary to further develop small molecular compounds that can regulate CRBN and degrade specific proteins for the treatment of tumors. In addition, it is still necessary to find CRBN ligands that can be used as therapeutic agents, and at the same time, CRBN ligands can be further used to prepare bifunctional PROTAC compounds for the treatment of diseases.
发明内容Contents of the invention
本公开提供了一种式(I)所示化合物及其药学上可接受的盐:The disclosure provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof:
其中,in,
Y
1、Y
2、Y
3独立地选自CR
2或N;
Y 1 , Y 2 , Y 3 are independently selected from CR 2 or N;
X
1选自C、CR
1a或N;
X 1 is selected from C, CR 1a or N;
X
2选自CR
2a、CR
2aR
2b、N或NR
2a;
X 2 is selected from CR 2a , CR 2a R 2b , N or NR 2a ;
X
3选自O、S、C(=O)、C(=S)、S(=O)
2、S(O)、CR
3aR
3b或NR
3a;
X 3 is selected from O, S, C(=O), C(=S), S(=O) 2 , S(O), CR 3a R 3b or NR 3a ;
X
4选自O、S、C(=O)、C(=S)、S(=O)
2、S(O)、CR
4aR
4b或NR
4a;
X 4 is selected from O, S, C(=O), C(=S), S(=O) 2 , S(O), CR 4a R 4b or NR 4a ;
R
1a、R
2a、R
2b、R
3a、R
3b、R
4a、R
4b独立地选自H、卤素、CN、OH、NH
2、-C(O)R
f、-C(O)N(R
f)
2、-C(O)OR
f、-C(O)ON(R
f)
2、-NHC(O)R
f、-NHC(O)OR
f、-NHC(O)N(R
f)
2、-S(O)
2(R
f)、C
1-C
6烷基、C
3-C
10环烷基、C
6-C
10芳基、4-10元杂环基或5-10元杂芳基,所述OH、NH
2、C
1-C
6烷基、C
3-C
10环烷基、C
6-C
10芳基、4-10元杂环基或5-10元杂芳基任选被R
d取代;
R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, CN, OH, NH 2 , -C(O) Rf , -C(O)N( R f ) 2 , -C(O)OR f , -C(O)ON(R f ) 2 , -NHC(O)R f , -NHC(O)OR f , -NHC(O)N(R f ) 2 , -S(O) 2 (R f ), C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclyl or 5-10 OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl Aryl is optionally substituted by R;
或R
1a、R
4a与其连接的环状基团形成碳桥环或桥杂环;
Or R 1a , R 4a and the cyclic group they are connected to form a carbon bridged ring or a bridged heterocyclic ring;
或R
2a、R
3a与其连接的原子共同形成环烷基或杂环基;
Or R 2a , R 3a and the atoms they are connected to together form a cycloalkyl or heterocyclic group;
或R
3a、R
4a与其连接的原子共同形成环烷基或杂环基;
Or R 3a , R 4a and the atoms they are connected to together form a cycloalkyl or heterocyclic group;
或R
2a、R
2b与其连接的原子共同形成环烷基或杂环基;
Or R 2a , R 2b and the atoms they are connected to together form a cycloalkyl or heterocyclic group;
或R
3a、R
3b与其连接的原子共同形成环烷基或杂环基;
Or R 3a , R 3b and the atoms they are connected to together form a cycloalkyl or heterocyclic group;
或R
4a、R
4b与其连接的原子共同形成环烷基或杂环基;
Or R 4a , R 4b and the atoms they are connected to together form a cycloalkyl or heterocyclic group;
R
1独立地选自卤素、CN、OH、NH
2、C
1-C
6烷基、C
3-C
10环烷基、4-8元杂环基、C
6-C
10芳基或5-10元杂芳基,所述OH、NH
2、C
1-C
6烷基、C
3-C
10环烷基、4-8元杂环基、C
6-C
10芳基或5-10元杂芳基任选被R
d取代;
R 1 is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl or 5- 10-membered heteroaryl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered Heteroaryl is optionally substituted by R;
R
2选自H、卤素、CN、OH、NH
2、C
1-C
6烷基、C
3-C
10环烷基、4-8元杂环基、C
6-C
10芳基或5-10元杂芳基,所述OH、NH
2、C
1-C
6烷基、C
3-C
10环烷基、4-8元杂环基、C
6-C
10芳基或5-10元杂芳基任选被R
d取代;
R 2 is selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl or 5- 10-membered heteroaryl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered Heteroaryl is optionally substituted by R;
每一个R
d独立地选自卤素、CN、OH、NH
2、SH、C
1-C
6烷基、C
3-C
10环烷基或4-8元杂环基;
Each R d is independently selected from halogen, CN, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl;
每一个R
f独立地选自H、卤素、CN、OH、NH
2、C
1-C
6烷基、C
3-C
10环烷基或4-8元杂环基;
Each R f is independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl;
n独立地选自0、1或2。n is independently selected from 0, 1 or 2.
在一些实施方案中,X
2选自CR
2a、CR
2aR
2b或NR
2a。
In some embodiments, X 2 is selected from CR 2a , CR 2a R 2b or NR 2a .
在一些实施方案中,X
3选自O、C(=O)、CR
3aR
3b或NR
3a。
In some embodiments, X 3 is selected from O, C(=O), CR 3a R 3b , or NR 3a .
在一些实施方案中,X
3选自C(=O)或CR
3aR
3b。
In some embodiments, X 3 is selected from C(=O) or CR 3a R 3b .
在一些实施方案中,X
4选自O、C(=O)、CR
4aR
4b或NR
4a。
In some embodiments, X 4 is selected from O, C(=O), CR 4a R 4b , or NR 4a .
在一些实施方案中,R
1a、R
2a、R
2b、R
3a、R
3b、R
4a、R
4b独立地选自H、卤素、OH、NH
2、-C(O)R
f、-C(O)N(R
f)
2、-C(O)OR
f、-NHC(O)R
f、-NHC(O)OR
f、C
1-C
6烷基、C
5-C
6环烷基、C
6-C
10芳基4-8元杂环基或5-6元杂芳基,所述OH、NH
2、C
1-C
6烷基、C
5-C
6环烷基、C
6-C
10芳基4-8元杂环基或5-6元杂芳基任选被R
d取代。
In some embodiments, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, OH, NH 2 , -C(O) Rf , -C( O)N(R f ) 2 , -C(O)OR f , -NHC(O)R f , -NHC(O)OR f , C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl, C 6 -C 10 aryl 4-8 membered heterocyclic group or 5-6 membered heteroaryl group, said OH, NH 2 , C 1 -C 6 alkyl, C 5 -C 6 cycloalkyl, C 6 - C 10 aryl 4-8 membered heterocyclic group or 5-6 membered heteroaryl group is optionally substituted by Rd .
在一些实施方案中,R
1a、R
2a、R
2b、R
3a、R
3b、R
4a、R
4b独立地选自H、卤素、OH、NH
2、-C(O)OR
f或C
1-C
6烷基,所述OH、NH
2或C
1-C
6烷基任选被R
d取代。
In some embodiments, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, OH, NH 2 , -C(O)OR f or C 1 - C 6 alkyl, the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted by R d .
在一些实施方案中,R
1a、R
2a、R
2b、R
3a、R
3b、R
4a、R
4b独立地选自H、卤素、OH、NH
2、-C(O)OH或C
1-C
3烷基,所述OH、NH
2或C
1-C
3烷基任选被R
d取代。
In some embodiments, R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, OH, NH 2 , -C(O)OH, or C 1 -C 3 alkyl, the OH, NH 2 or C 1 -C 3 alkyl is optionally substituted by R d .
在一些实施方案中,R
1a、R
4a与其连接的环状基团形成碳桥环。
In some embodiments, R 1a , R 4a and the cyclic group to which they are attached form a carbon-bridged ring.
在一些实施方案中,R
2a、R
3a与其连接的原子共同形成环烷基。
In some embodiments, R 2a , R 3a and the atoms to which they are attached together form a cycloalkyl group.
在一些实施方案中,R
2a、R
3a与其连接的原子共同形成C
3-C
6环烷基。
In some embodiments, R 2a , R 3a and the atoms to which they are attached together form a C 3 -C 6 cycloalkyl group.
在一些实施方案中,R
3a、R
3b与其连接的原子共同形成环烷基。
In some embodiments, R 3a , R 3b and the atoms to which they are attached together form a cycloalkyl group.
在一些实施方案中,R
3a、R
3b与其连接的原子共同形成C
3-C
6环烷基。
In some embodiments, R 3a , R 3b and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group.
在一些实施方案中,R
1独立地选自卤素、CN、OH、NH
2或C
1-C
6烷基,所述OH、NH
2、 C
1-C
6烷基任选被R
d取代。
In some embodiments, R 1 is independently selected from halogen, CN, OH, NH 2 , or C 1 -C 6 alkyl optionally substituted with R d .
在一些实施方案中,R
2选自H、卤素、CN、OH、NH
2、C
1-C
6烷基,所述OH、NH
2、C
1-C
6烷基任选被R
d取代。
In some embodiments, R 2 is selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl optionally substituted with R d .
在一些实施方案中,R
2选自H或卤素。
In some embodiments, R2 is selected from H or halogen.
在一些实施方案中,R
2选自H或F。
In some embodiments, R is selected from H or F.
在一些实施方案中,n独立地选自0或1。In some embodiments, n is independently selected from 0 or 1.
在一些实施方案中,式(I)所示化合物或其药学上可接受的盐选自式(I’)化合物或其药学上可接受的盐,In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I') or a pharmaceutically acceptable salt thereof,
其中,X
1选自CR
1a或N;X
2选自CR
2aR
2b或NR
2a;
Wherein, X 1 is selected from CR 1a or N; X 2 is selected from CR 2a R 2b or NR 2a ;
R
1a、R
2a、R
2b、X
3、X
4、Y
1、Y
2、Y
3、R
1、n如上文的定义。
R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n are as defined above.
在一些实施方案中,式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐:In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
本公开还提供了一种式(II)所示化合物及其药学上可接受的盐:The present disclosure also provides a compound represented by formula (II) and a pharmaceutically acceptable salt thereof:
其中,[]表示L可以与X
2、X
3、X
4、Y
1、Y
2或Y
3连接;
Among them, [] indicates that L can be connected with X 2 , X 3 , X 4 , Y 1 , Y 2 or Y 3 ;
X
1、X
2、X
3、X
4、Y
1、Y
2、Y
3、R
1、n如上文的定义;
X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n are as defined above;
当L与Y
1,Y
2或Y
3连接时,Y
1、Y
2或Y
3为C,当L与X
2连接时,X
2为C、CR
2a或N,当L与X
3连接时,X
3为CR
3a或N,当L与X
4连接时,X
3为CR
4a或N;
When L is connected with Y 1 , Y 2 or Y 3 , Y 1 , Y 2 or Y 3 is C, when L is connected with X 2 , X 2 is C, CR 2a or N, when L is connected with X 3 , X 3 is CR 3a or N, when L is connected with X 4 , X 3 is CR 4a or N;
L选自以下结构单元:L is selected from the following structural units:
-(A
L)
k-;
-(A L ) k -;
A
L独立地选自键、-O-、-S-、-SO-、-SO
2-、-SO
2NR
10-、-C(R
10)
2-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、-C(=S)-、-O-C(=O)-、-OC(O)NR
10-、-C(O)ONR
10-、-CR
10= CR
10-、-C≡C-、-P(O)R
10-、-P(O)OR
10-、
C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基,所述C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基任选地被R
11取代;
AL is independently selected from bond, -O-, -S-, -SO-, -SO 2 -, -SO 2 NR 10 -, -C(R 10 ) 2 -, -(CH 2 ) q -, - (O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, -C(=S)-, -OC(=O)- , -OC(O)NR 10 -, -C(O)ONR 10 -, -CR 10 = CR 10 -, -C≡C-, -P(O)R 10 -, -P(O)OR 10 - , C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered heteroaryl, said C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic Base, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by R 11 ;
R
10选自H、OH、NH
2或C
1-C
6烷基;
R 10 is selected from H, OH, NH 2 or C 1 -C 6 alkyl;
R
11选自卤素、CN、OH、NH
2或C
1-C
6烷基;
R 11 is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl;
k选自1、2、3、4、5、6、7、8、9或10;k is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
q选自0、1、2、3、4、5或6。q is selected from 0, 1, 2, 3, 4, 5 or 6.
在一些实施方案中,k选自1、2、3、4、5、6、7、8或9。In some embodiments, k is selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9.
在一些实施方案中,q选自1、2、3、4、5或6。In some embodiments, q is selected from 1, 2, 3, 4, 5 or 6.
在一些实施方案中,A
L独立地选自-O-、-S-、-SO-、-SO
2-、-SO
2NR
10-、-C(R
10)
2-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、-C(=S)-、-O-C(=O)-、-OC(O)NR
10-、-C(O)ONR
10-、-CR
10=CR
10-、-C≡C-、-P(O)R
10-、-P(O)OR
10-、
C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基,所述C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基任选地被R
11取代。
In some embodiments, AL is independently selected from -O-, -S-, -SO-, -SO 2 -, -SO 2 NR 10 -, -C(R 10 ) 2 -, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, -C(=S)-, -OC( =O)-, -OC(O)NR 10 -, -C(O)ONR 10 -, -CR 10 =CR 10 -, -C≡C-, -P(O)R 10 -, -P(O ) OR 10 -, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered heteroaryl, said C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic radical, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted by R 11 .
在一些实施方案中,A
L独立地选自-O-、-S-、-C(R
10)
2-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基,所述C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基任选地被R
11取代。
In some embodiments, AL is independently selected from -O-, -S-, -C(R 10 ) 2 -, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5- 10-membered heteroaryl, the C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted by R 11 .
在一些实施方案中,A
L独立地选自键、-O-、-S-、-C(R
10)
2-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基,所述C
3-C
10环烷基、4-10元杂环基、C
6-C
10芳基或5-10元杂芳基任选地被R
11取代。
In some embodiments, AL is independently selected from a bond, -O-, -S-, -C(R 10 ) 2 -, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, said C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted by R 11 .
在一些实施方案中,A
L独立地选自-O-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、C
3-C
10环烷基、5-6元杂环基、5-6元杂芳基或C
6-C
10芳基,所述C
3-C
10环烷基、5-6元杂环基、5-6元杂芳基或C
6-C
10芳基任选地被R
11取代。
In some embodiments, AL is independently selected from -O-, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O) -, -C(=O)-, C 3 -C 10 cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6 -C 10 aryl, said C 3 -C 10 Cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6 -C 10 aryl is optionally substituted by R 11 .
在一些实施方案中,A
L独立地选自键、-O-、-C(R
10)
2-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、5-6元杂环基或5-6元杂芳基,所述5-6元杂环基或5-6元杂芳基任选地被R
11取代。
In some embodiments, AL is independently selected from a bond, -O-, -C(R 10 ) 2 -, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, 5-6 membered heterocyclic group or 5-6 membered heteroaryl group, said 5-6 membered heterocyclic group or 5-6 The membered heteroaryl is optionally substituted by R 11 .
在一些实施方案中,A
L独立地选自-O-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、哌嗪基、三唑基、环己基或苯基,所述哌嗪基、三唑基、环己基或苯基任选地被R
11取代。
In some embodiments, AL is independently selected from -O-, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O) -, -C(=O)-, piperazinyl, triazolyl, cyclohexyl, or phenyl optionally substituted by R 11 .
在一些实施方案中,A
L独立地选自键、-O-、-C(R
10)
2-、-(CH
2)
q-、-(O-CH
2-CH
2)
q-、-NR
10-、-NR
10C(=O)-、-C(=O)-、哌嗪基或三唑基。
In some embodiments, AL is independently selected from a bond, -O-, -C(R 10 ) 2 -, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, piperazinyl or triazolyl.
在一些实施方案中,L选自以下结构单元:In some embodiments, L is selected from the following structural units:
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH2)
q-C(=O)NH-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(5-10 heteroaryl)-(CH2) q -C(=O)NH-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NR 10 -;
-(O-CH
2-CH
2)
q-(5-10杂芳基)-(CH
2)
q-O-;
-(O-CH 2 -CH 2 ) q -(5-10 heteroaryl)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(5-10heteroaryl)-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(CH
2)
q-NHC(=O)-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -NHC(=O)-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(5-10 heteroaryl)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-(CH
2)
q-C(=O)-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-(CH 2 ) q -C(=O)-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-;
-NR 10 -(CH 2 ) q -(5-10heteroaryl)-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -;
-(4-10元杂环基)-C(=O)-(CH
2)
q-C(=O)NH-(CH
2)
q-NR
10-;
-(4-10 membered heterocyclyl)-C(=O)-(CH 2 ) q -C(=O)NH-(CH 2 ) q -NR 10 -;
-(5-10杂芳基)-C(=O)-(CH
2)
q-C(=O)NH-(CH
2)
q-NR
10-;
-(5-10 Heteroaryl)-C(=O)-(CH 2 ) q -C(=O)NH-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -;
-O-(CH
2)
q-(5-10杂芳基)-C(=O)-;
-O-(CH 2 ) q -(5-10 heteroaryl)-C(=O)-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;
-O-(CH
2)
q-(CH
2)
q-;
-O-(CH 2 ) q -(CH 2 ) q -;
-NR
10-(CH
2)
q-(CH
2)
q-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -;
-NR
10-(CH
2)
q-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -NR 10 -;
-O-(CH
2)
q-(CH
2)
q-O-;
-O-(CH 2 ) q -(CH 2 ) q -O-;
-O-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-O-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-(CH
2)
q-C(=O)-(CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -(CH 2 ) q -C(=O)-(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -(CH 2 ) q -O-;
-O-C(=O)-(C
3-C
10环烷基)-(CH
2)
q-O-;
-OC(=O)-(C 3 -C 10 cycloalkyl)-(CH 2 ) q -O-;
-O-C(=O)-(C
3-C
10环烷基)-(CH
2)
q-NH-;
-OC(=O)-(C 3 -C 10 cycloalkyl)-(CH 2 ) q -NH-;
-O-C(=O)-(C
3-C
10环烷基)-(CH
2)
q-;
-OC(=O)-(C 3 -C 10 cycloalkyl)-(CH 2 ) q -;
-(CH
2)
q-NHC(=O)-NH-(C
6-C
10芳基)-;
-(CH 2 ) q -NHC(=O)-NH-(C 6 -C 10 aryl)-;
-NR
10-(CH
2)
q-(CH
2)
q-C(=O)-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -C(=O)-;
-NR
10-(CH
2)
q-C(=O)NH-(CH
2)
q-;
-NR 10 -(CH 2 ) q -C(=O)NH-(CH 2 ) q -;
所述C
3-C
10环烷基、C
6-C
10芳基、5-10杂芳基或4-10元杂环基任选地被R
11取代,q如上文的定义。
The C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5-10 heteroaryl or 4-10 membered heterocyclic group is optionally substituted by R 11 , q is as defined above.
在一些实施方案中,L选自以下结构单元:In some embodiments, L is selected from the following structural units:
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH2)
q-C(=O)NH-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(5-10 heteroaryl)-(CH2) q -C(=O)NH-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NR 10 -;
-(O-CH
2-CH
2)
q-(5-10杂芳基)-(CH
2)
q-O-;
-(O-CH 2 -CH 2 ) q -(5-10 heteroaryl)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(5-10heteroaryl)-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(CH
2)
q-NHC(=O)-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -NHC(=O)-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(5-10 heteroaryl)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-(CH
2)
q-C(=O)-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-(CH 2 ) q -C(=O)-;
-NR
10-(CH
2)
q-(5-10杂芳基)-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-;
-NR 10 -(CH 2 ) q -(5-10heteroaryl)-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -;
-(4-10元杂环基)-C(=O)-(CH
2)
q-C(=O)NH-(CH
2)
q-NR
10-;
-(4-10 membered heterocyclyl)-C(=O)-(CH 2 ) q -C(=O)NH-(CH 2 ) q -NR 10 -;
-(5-10杂芳基)-C(=O)-(CH
2)
q-C(=O)NH-(CH
2)
q-NR
10-;
-(5-10 Heteroaryl)-C(=O)-(CH 2 ) q -C(=O)NH-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -;
-O-(CH
2)
q-(5-10杂芳基)-C(=O)-;
-O-(CH 2 ) q -(5-10 heteroaryl)-C(=O)-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;
-O-(CH
2)
q-(CH
2)
q-;
-O-(CH 2 ) q -(CH 2 ) q -;
-NR
10-(CH
2)
q-(CH
2)
q-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -;
-NR
10-(CH
2)
q-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(CH 2 ) q -NR 10 -;
-O-(CH
2)
q-(CH
2)
q-O-;
-O-(CH 2 ) q -(CH 2 ) q -O-;
-O-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-O-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(O-CH
2-CH
2)
q-(CH
2)
q-C(=O)-(CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -(CH 2 ) q -C(=O)-(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-NR
10-;
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -NR 10 -;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-O-;
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -O-;
-NR
10-(CH
2)
q-(4-10元杂环基)-(CH
2)
q-(CH
2)
q-O-。
-NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -(CH 2 ) q -O-.
在一些实施方案中,L选自以下结构单元:In some embodiments, L is selected from the following structural units:
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NH-(CH
2)
q-(CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NH-(CH 2 ) q -(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NH-(CH
2)
q-三唑基-(CH
2)
q-C(=O)NH-(CH
2)
q-O-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -C(=O)NH-(CH 2 ) q -O-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NH-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NH-;
-(O-CH
2-CH
2)
q-三唑基-(CH
2)
q-O-;
-(O-CH 2 -CH 2 ) q -triazolyl-(CH 2 ) q -O-;
-O-(CH
2)
q-(CH
2)
q-O-;
-O-(CH 2 ) q -(CH 2 ) q -O-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;
-NH-(CH
2)
q-三唑基-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-NH-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -NH-;
-NH-(CH
2)
q-(CH
2)
q-NHC(=O)-;
-NH-(CH 2 ) q -(CH 2 ) q -NHC(=O)-;
-O-(CH
2)
q-(CH
2)
q-;
-O-(CH 2 ) q -(CH 2 ) q -;
-NH-(CH
2)
q-三唑基-(CH
2)
q-NH-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NH-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-O-(CH
2)
q-C(=O)-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-(CH 2 ) q -C(=O)-;
-NH-(CH
2)
q-三唑基-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -;
-哌嗪基-C(=O)-(CH
2)
q-C(=O)NH-(CH
2)
q-NH-;
-piperazinyl-C(=O)-( CH2 ) q -C(=O)NH-( CH2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -;
-O-(CH
2)
q-三唑基-C(=O)-;
-O-(CH 2 ) q -triazolyl-C(=O)-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NH-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;
-O-C(=O)-环己基-(CH
2)
q-O-;
-OC(=O)-cyclohexyl-( CH2 ) q -O-;
-O-C(=O)-环己基-(CH
2)
q-NH-;
-OC(=O)-cyclohexyl-( CH2 ) q -NH-;
-O-C(=O)-环己基-(CH
2)
q-;
-OC(=O)-cyclohexyl-(CH 2 ) q -;
-苯基-NHC(=O)-NH-(CH
2)
q-;
-Phenyl-NHC(=O)-NH-(CH 2 ) q -;
-NH-(CH
2)
q-(CH
2)
q-C(=O)-;
-NH-(CH 2 ) q -(CH 2 ) q -C(=O)-;
-NH-(CH
2)
q-C(=O)NH-(CH
2)
q-;
-NH-(CH 2 ) q -C(=O)NH-(CH 2 ) q -;
所述三唑基、哌嗪基、环己基或苯基任选地被R
11取代,q如上文的定义。
The triazolyl, piperazinyl, cyclohexyl or phenyl is optionally substituted by R 11 , q is as defined above.
在一些实施方案中,L选自以下结构单元:In some embodiments, L is selected from the following structural units:
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NH-(CH
2)
q-(CH
2)
q-NHC(=O)-(CH
2)
q-O-;
-NH-(CH 2 ) q -(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;
-NH-(CH
2)
q-三唑基-(CH
2)
q-C(=O)NH-(CH
2)
q-O-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -C(=O)NH-(CH 2 ) q -O-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NH-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NH-;
-(O-CH
2-CH
2)
q-三唑基-(CH
2)
q-O-;
-(O-CH 2 -CH 2 ) q -triazolyl-(CH 2 ) q -O-;
-O-(CH
2)
q-(CH
2)
q-O-;
-O-(CH 2 ) q -(CH 2 ) q -O-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;
-NH-(CH
2)
q-三唑基-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-NH-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -NH-;
-NH-(CH
2)
q-(CH
2)
q-NHC(=O)-;
-NH-(CH 2 ) q -(CH 2 ) q -NHC(=O)-;
-O-(CH
2)
q-(CH
2)
q-;
-O-(CH 2 ) q -(CH 2 ) q -;
-NH-(CH
2)
q-三唑基-(CH
2)
q-NH-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NH-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-O-(CH
2)
q-C(=O)-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-(CH 2 ) q -C(=O)-;
-NH-(CH
2)
q-三唑基-(CH
2)
q-O-(CH
2)
q-C(=O)-(CH
2)
q-;
-NH-(CH 2 ) q -triazolyl-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -;
-哌嗪基-C(=O)-(CH
2)
q-C(=O)NH-(CH
2)
q-NH-;
-piperazinyl-C(=O)-( CH2 ) q -C(=O)NH-( CH2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-O-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -;
-O-(CH
2)
q-三唑基-C(=O)-;
-O-(CH 2 ) q -triazolyl-C(=O)-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-(CH
2)
q-NH-;
-NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NH-;
-NH-(CH
2)
q-(O-CH
2-CH
2)
q-NHC(=O)-。
-NH-( CH2 ) q- (O- CH2 - CH2 ) q -NHC(=O)-.
在一些实施方案中,L选自以下结构单元:In some embodiments, L is selected from the following structural units:
在一些实施方案中,式(II)所示化合物或其药学上可接受的盐选自式(II’)化合物或其药学上可接受的盐,In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II') or a pharmaceutically acceptable salt thereof,
其中,X
1选自CR
1a或N;X
2选自CR
2aR
2b或NR
2a;
Wherein, X 1 is selected from CR 1a or N; X 2 is selected from CR 2a R 2b or NR 2a ;
R
1a、R
2a、R
2b、X
3、X
4、Y
1、Y
2、Y
3、R
1、n、L、[]如上文的定义。
R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, [] are as defined above.
在一些实施方案中,式(II)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐:In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
进一步,本公开还提供了一种药物组合物,所述药物组合物包含式(I)或(II)所示化合物或其药学上可接受的盐,以及药学上可接受的辅料。Further, the present disclosure also provides a pharmaceutical composition, which comprises the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
进一步,本公开涉及式(I)或(II)所示化合物或其药学上可接受的盐,或其药物组合物在制备预防或者治疗与CRBN介导的相关疾病的药物中的用途。Further, the present disclosure relates to the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating diseases mediated by CRBN.
进一步,本公开涉及式(I)或(II)所示化合物或其药学上可接受的盐,或其药物组合物在预防或者治疗与CRBN介导的相关疾病中的用途。Further, the present disclosure relates to the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of diseases mediated by CRBN.
进一步,本公开涉及预防或者治疗CRBN介导的相关疾病的式(I)或(II)所示化合物或其药学上可接受的盐,或其药物组合物。Further, the present disclosure relates to a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating CRBN-mediated related diseases.
进一步,本公开还涉及治疗CRBN介导的相关疾病的方法,该方法包括给以患者治疗上有效剂量的包含本公开所述的式(I)或(II)所示化合物或其药学上可接受的盐的药物制剂。Further, the present disclosure also relates to a method for treating CRBN-mediated related diseases, the method comprising administering to the patient a therapeutically effective dose of a compound represented by formula (I) or (II) described in the present disclosure or a pharmaceutically acceptable Pharmaceutical preparations of salts.
另一方面,本公开提供治疗哺乳动物由异常细胞增殖疾病的方法,包括对需要该治疗的哺乳动物,优选人类,给予治疗有效量的式(I)或(II)所示化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present disclosure provides a method for treating mammals suffering from abnormal cell proliferation diseases, comprising administering a therapeutically effective amount of a compound represented by formula (I) or (II) or a pharmaceutically effective amount thereof to a mammal in need of the treatment, preferably a human. acceptable salts, or pharmaceutical compositions thereof.
另一方面,本公开提供式(I)或(II)所示化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗异常细胞增殖疾病的药物中的用途。In another aspect, the present disclosure provides the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.
另一方面,本公开提供式(I)或(II)所示化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗异常细胞增殖疾病中的用途。In another aspect, the present disclosure provides the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating abnormal cell proliferation diseases.
另一方面,本公开提供预防或者治疗异常细胞增殖疾病的式(I)或(II)所示化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present disclosure provides a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.
在一些实施方案中,所述异常细胞增殖疾病选自癌症。In some embodiments, the disorder of abnormal cell proliferation is selected from cancer.
在一些实施方案中,所述癌症选自实体瘤、腺癌或者血液瘤。In some embodiments, the cancer is selected from solid tumors, adenocarcinomas, or hematological tumors.
进一步,本公开涉及式(I)或(II)所示化合物或其药学上可接受的盐,作为靶向蛋白降解的双功能化合物的合成中间体,在制备靶向蛋白降解的双功能化合物(PROTAC分子)的用途。Further, the present disclosure relates to a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, as a synthetic intermediate of a bifunctional compound targeting protein degradation, during the preparation of a bifunctional compound targeting protein degradation ( PROTAC molecules).
本公开还提供了一种式(III)所示化合物及其药学上可接受的盐:The present disclosure also provides a compound represented by formula (III) and a pharmaceutically acceptable salt thereof:
其中,[]、X
1、X
2、X
3、X
4、Y
1、Y
2、Y
3、R
1、L、n如上文的定义;
Wherein, [], X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , L, and n are as defined above;
所述PTM是靶向蛋白结合部分。The PTM is a targeting protein binding moiety.
在一些实施方案中,式(III)所示化合物或其药学上可接受的盐选自式(III’)所示化合物或其药学上可接受的盐:In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from a compound represented by formula (III') or a pharmaceutically acceptable salt thereof:
其中,X
1选自CR
1a或N;X
2选自CR
2aR
2b或NR
2a;
Wherein, X 1 is selected from CR 1a or N; X 2 is selected from CR 2a R 2b or NR 2a ;
R
1a、R
2a、R
2b、X
3、X
4、Y
1、Y
2、Y
3、R
1、n、L、PTM、[]如上文的定义。
R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, PTM, [] are as defined above.
在一些实施方案中,式(III)所示化合物或其药学上可接受的盐选自式(IIIa)所示化合物或其药学上可接受的盐:In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IIIa) or a pharmaceutically acceptable salt thereof:
其中,X
1、X
2、X
3、X
4、Y
1、Y
2、Y
3、R
1、n、L、PTM如上文的定义。
Wherein, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, and PTM are as defined above.
在一些实施方案中,式(III)所示化合物或其药学上可接受的盐选自式(IIIb)所示化合物 或其药学上可接受的盐:In some embodiments, the compound shown in formula (III) or its pharmaceutically acceptable salt is selected from the compound shown in formula (IIIb) or its pharmaceutically acceptable salt:
其中,X
1、X
2、X
3、X
4、Y
1、Y
2、Y
3、R
1、n、L、PTM如上文的定义。
Wherein, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, and PTM are as defined above.
在一些实施方案中,式(III)所示化合物或其药学上可接受的盐选自式(IIIc)所示化合物或其药学上可接受的盐:In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IIIc) or a pharmaceutically acceptable salt thereof:
其中,X
1、X
2、X
3、X
4、Y
1、Y
2、Y
3、R
1、n、L、PTM如上文的定义。
Wherein, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, and PTM are as defined above.
在一些实施方案中,PTM选自以下靶向蛋白的结合部分:ALK,AR,BET1,BRAF,BRCA2,BRD4,BRD9,BTK,CBL,CCNE1,CCNE2,CCR4,CCR7,CCR9,CD47,CLDN18,CYP,DDR1,DMPK,EGFR,ERBB2,ERBB3,ERBB4,FGFR1,FGFR2,FGFR3,FGFR4,GSPT1,JAK1,JAK3,KIF18A,KRAS,LCK,MET,NTRK1,NTRK2,NTRK3,PCSK9,PKMYT1,PARP7,PARP14,RAD51,RBM10,RET,RORA,STAT3,SOS1,TYK2,USP1或USP14。In some embodiments, the PTM is selected from the binding portion of the following targeting proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP , DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, JAK1, JAK3, KIF18A, KRAS, LCK, MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51 , RBM10, RET, RORA, STAT3, SOS1, TYK2, USP1 or USP14.
在一些实施方案中,PTM选自以下靶向蛋白的结合部分:ALK,AR,BET1,BRAF,BRCA2,BRD4,BRD9,BTK,CBL,CCNE1,CCNE2,CCR4,CCR7,CCR9,CD47,CLDN18,CYP,DDR1,DMPK,EGFR,ERBB2,ERBB3,ERBB4,FGFR1,FGFR2,FGFR3,FGFR4,GSPT1,JAK1,JAK3,KIF18A,KRAS,LCK,MET,NTRK1,NTRK2,NTRK3,PCSK9,PKMYT1,PARP7,PARP14,RAD51,RBM10,RET,RORA,SOS1,TYK2,USP1或USP14。In some embodiments, the PTM is selected from the binding portion of the following targeting proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK, CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP , DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, JAK1, JAK3, KIF18A, KRAS, LCK, MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51 , RBM10, RET, RORA, SOS1, TYK2, USP1 or USP14.
在一些实施方案中,式(III)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐:In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
另一方面,本公开还提供了一种药物组合物,所述药物组合物包含式(III)所示化合物或其药学上可接受的盐,以及药学上可接受的辅料。On the other hand, the present disclosure also provides a pharmaceutical composition, which comprises the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
另一方面,本公开提供治疗哺乳动物由异常细胞增殖疾病的方法,包括对需要该治疗的哺乳动物,优选人类,给予治疗有效量的式(III)所示化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present disclosure provides a method for treating mammals suffering from abnormal cell proliferation, comprising administering a therapeutically effective amount of a compound represented by formula (III) or a pharmaceutically acceptable salt thereof to a mammal in need of the treatment, preferably a human , or a pharmaceutical composition thereof.
另一方面,本公开提供式(III)所示化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗异常细胞增殖疾病的药物中的用途。In another aspect, the present disclosure provides the use of the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.
另一方面,本公开提供式(III)所示化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗异常细胞增殖疾病中的用途。In another aspect, the present disclosure provides the use of the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating abnormal cell proliferation diseases.
另一方面,本公开提供预防或者治疗异常细胞增殖疾病的式(III)所示化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.
在一些实施方案中,所述异常细胞增殖疾病选自癌症。In some embodiments, the disorder of abnormal cell proliferation is selected from cancer.
在一些实施方案中,所述癌症选自实体瘤、腺癌或者血液瘤。In some embodiments, the cancer is selected from solid tumors, adenocarcinomas, or hematological tumors.
除非另有说明,本公开中所用的术语具有下列含义,本公开中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化 合物的定义等,可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照本领域普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。Unless otherwise stated, terms used in this disclosure have the following meanings, definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, examples The definitions of specific compounds in and etc. may be combined and combined with each other arbitrarily. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明,用楔形键和虚楔键
表示一个立体中心的绝对构型,用黑实键和虚键
表示一个立体中心的相对构型(如脂环化合物的顺反构型)。
Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, with wedge and dotted keys Indicates the absolute configuration of a stereocenter with black real and virtual bonds Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在,尝试分离单一互变异构体时通常产生一种混合物,其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如,在很多脂族醛和酮如乙醛中,酮型占优势;而在酚中,烯醇型占优势。本公开包含化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This disclosure encompasses all tautomeric forms of the compounds.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和非对映异构体。The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键,因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,以及其外消旋混合物或其它混合物,例如对映异构体或非对映体富集的混合物,以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子,所有取代基中涉及到的这些异构体以及它们的混合物,也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来,光学活性纯的形式可以从外消旋混合物拆分,或通过使用手性原料或手性试剂合成。The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the disclosed compounds. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Compounds of the disclosure are within the definition. Compounds of the present disclosure containing asymmetric atoms can be isolated in optically pure or racemic forms, optically pure forms can be resolved from racemic mixtures, or synthesized by using chiral starting materials or chiral reagents .
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即=O)时,意味着两个氢原子被取代,氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxo (ie, =0), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生,该描述包括发生所述事件或情况和不发生所述事件或情况。例如,乙基“任选”被卤素取代,是指乙基可以是未被取代的(CH
2CH
3)、单取代的(CH
2CH
2F、CH
2CH
2Cl等)、多取代的(CHFCH
2F、CH
2CHF
2、CHFCH
2Cl、CH
2CHCl
2等)或完全被取代的(CF
2CF
3、CF
2CCl
3、CCl
2CCl
3等)。本领域技术人员可理解,对于包含一个或多个取代基的任何基团,不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
The term "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that description includes that said event or circumstance occurs and that it does not. For example, ethyl is "optionally" substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
当任何变量(例如R
a、R
b)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。例如,如果一个基团被2个R
b所取代,则每个R
b都有独立的选项。
When any variable (eg R a , R b ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
当一个连接基团的数量为0时,比如-(CH
2)
0-,表示该连接基团为键。
When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
当其中一个变量选自化学键或不存在时,表示其连接的两个基团直接相连,比如A-L-Z中L代表键时表示该结构实际上是A-Z。When one of the variables is selected from chemical bond or absence, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a bond, it means that the structure is actually A-Z.
当本文中涉及到的连接基团若没有指明其连接方向,则其连接方向是任意的。例如当结构单元
中的L
1选自“-C
1-C
3亚烷基-O-”时,此时L
1既可以按照与从左到右的方向连接环Q和R
1构成“环Q-C
1-C
3亚烷基-O-R
1”,也可以按照从右到左的方向连接环Q和R
1构 成“环Q-O-C
1-C
3亚烷基-R
1”。
When the linking group mentioned herein does not indicate its linking direction, its linking direction is arbitrary. For example when the structural unit When L 1 in is selected from "-C 1 -C 3 alkylene-O-", at this time L 1 can be connected with ring Q and R 1 from left to right to form "ring QC 1 -C 3 Alkylene-OR 1 ", ring Q and R 1 can also be linked from right to left to form "ring QOC 1 -C 3 alkylene-R 1 ".
当一个取代基的键交叉连接到一个环上的两个原子时,这种取代基可以与这个环上的任意原子相键合。例如,结构单元
表示R
1可在环上任意位置发生取代,当R
1取代NH的H时,结构为
When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring. For example, the structural unit Indicates that R 1 can be substituted at any position on the ring, when R 1 replaces the H of NH, the structure is
本文中的C
m-C
n是指具有m-n范围中的整数个碳原子。例如“C
1-C
10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
Cm - Cn herein refers to having an integer number of carbon atoms in the range of mn. For example, "C 1 -C 10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
本文中,由实线和虚线描绘的键
表示单键或双键。例如,结构单元
包含
In this paper, the bonds depicted by solid and dashed lines Indicates a single or double bond. For example, the structural unit Include
术语“烷基”是指通式为C
nH
2n+1的烃基,该烷基可以是直链或支链的。术语“C
1-C
10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等;术语“C
1-C
6烷基”可理解为表示具有1至6个碳原子的烷基,具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C
1-C
3烷基”可理解为表示具有1、2或3个碳原子的直链或支链饱和烷基。所述“C
1-C
10烷基”可以包含“C
1-C
6烷基”或“C
1-C
3烷基”等范围,所述“C
1-C
6烷基”可以进一步包含“C
1-C
3烷基”。
The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched. The term "C 1 -C 10 alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl" can be understood as an alkyl group having 1 to 6 carbon atoms, specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C 1 -C 3 alkyl" is understood to mean a straight-chain or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C 1 -C 10 alkyl" may include "C 1 -C 6 alkyl" or "C 1 -C 3 alkyl", etc., and the "C 1 -C 6 alkyl" may further include " C 1 -C 3 alkyl".
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示,该碳环通常为3至10元环。术语“C
3-C
10环烷基”可理解为表示饱和的单环、并环、螺环或桥环,其具有3、4、5、6、7、8、9或10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基,降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C
3-C
10环烷基”可以包含“C
3-C
6环烷基”,术语“C
3-C
6环烷基”可理解为表示饱和的单环或双环烃环,其具有3~6个碳原子,具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。
The term "cycloalkyl" refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a double ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C 3 -C 10 cycloalkyl" is understood to mean a saturated monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of said cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decanyl, etc. The term "C 3 -C 10 cycloalkyl" may include "C 3 -C 6 cycloalkyl", and the term "C 3 -C 6 cycloalkyl" can be understood as representing a saturated monocyclic or bicyclic hydrocarbon ring, which has 3-6 carbon atoms, specific examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、并环、螺环或桥环基团,其环原子中含有12、3、4或5个杂原子或杂原子团(即含有杂原子的原子团),所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(=O)
2-、-S(=O)-、-P(=O)
2-、-P(=O)-、-NH-、-S(=O)(=NH)-、-C(=O)NH-或-NHC(=O)NH-等。术语“3-10元杂环基”是指环原子数目为3、4、5、6、7、8、9或10的杂环基,且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。“3-10元杂环基”包括“4-7元杂环基”,其中,4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基;5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基;6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基;7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基,其中,5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯 -2(1H)-基;5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地,所述杂环基可以是上述4-7元杂环基的苯并稠合环基,具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围,“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本公开中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环,但所述杂环基整体上仍是无芳香性的。
The term "heterocyclic group" refers to a fully saturated or partially saturated (heteroaromatic not aromatic as a whole) monocyclic, cyclic, spiro or bridged ring group containing 12, 3, 4 or 5 heteroatoms or heteroatom groups (ie, heteroatom-containing atomic groups), said "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atom (P), boron atom (B), -S(=O) 2 -, -S(=O)-, -P(=O) 2 -, -P(=O)-, -NH-, - S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "3-10 membered heterocyclic group" refers to a heterocyclic group with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independently selected from the heteroatoms or heteroatom groups described above. "3-10 membered heterocyclic group" includes "4-7 membered heterocyclic group", wherein, specific examples of 4-membered heterocyclic group include but are not limited to azetidinyl or oxetanyl; 5-membered Specific examples of heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2, 5-dihydro-1H-pyrrolyl; Specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl , trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl. The heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like. "4-10 membered heterocyclic group" may include "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group" , "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered "Heterocycloalkyl" and other ranges, "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocyclyl" , "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl" and other ranges. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic groups as a whole are non-aromatic.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子,6-14个碳原子或6-12个碳原子。术语“C
6-C
20芳基”可理解为具有6~20个碳原子的芳基。特别是具有6个碳原子的环(“C
6芳基”),例如苯基;或者具有9个碳原子的环(“C
9芳基”),例如茚满基或茚基;或者具有10个碳原子的环(“C
10芳基”),例如四氢化萘基、二氢萘基或萘基;或者具有13个碳原子的环(“C
13芳基”),例如芴基;或者是具有14个碳原子的环(“C
14芳基”),例如蒽基。术语“C
6-C
10芳基”可理解为具有6~10个碳原子的芳基。特别是具有6个碳原子的环(“C
6芳基”),例如苯基;或者具有9个碳原子的环(“C
9芳基”),例如茚满基或茚基;或者具有10个碳原子的环(“C
10芳基”),例如四氢化萘基、二氢萘基或萘基。术语“C
6-C
20芳基”可以包含“C
6-C
10芳基”
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. The term "C 6 -C 20 aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. Especially rings with 6 carbon atoms (“C aryl ”), such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 a ring of 3 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or is a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl. The term "C 6 -C 10 aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. Especially rings with 6 carbon atoms (“C aryl ”), such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "C 6 -C 20 aryl" may include "C 6 -C 10 aryl"
术语“杂芳基”是指具有芳香性的单环或稠合多环体系,其中含有至少一个选自N、O、S的环原子,其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系:其具有5、6、7、8、9或10个环原子,特别是5或6或9或10个环原子,且其包含、2、3、4或5个,优选1、2或3个独立选自N、O和S的杂原子。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基或噻二唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基或异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物,例如喹啉基、喹唑啉基或异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系,且其包含1、2或3个,优选1-2个独立选自N、O和S的杂原子。The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthalene Pyridyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S .
术语“卤”或“卤素”是指氟、氯、溴或碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”是指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to a -CN group.
术语“巯基”是指-SH基团。The term "mercapto" refers to a -SH group.
术语“氨基”是指-NH
2基团。
The term "amino" refers to a -NH2 group.
术语“硝基”是指-NO
2基团。
The term "nitro" refers to a -NO2 group.
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍,(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状,或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变,但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying The amount of a compound of the disclosure required for the onset of one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐,包括化合物与无机酸或有机酸形成的盐,以及化合物与无机碱或有机碱形成的盐。The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的 混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用,而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的,例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义,即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising can be interpreted in an open and non-exclusive sense, ie "including but not limited to".
本公开还包括与本文中记载的那些相同的,但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素,诸如分别为
2H、
3H、
11C、
13C、
14C、
13N、
15N、
15O、
17O、
18O、
31P、
32P、
35S、
18F、
123I、
125I和
36Cl等。
The disclosure also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
某些同位素标记的本公开化合物(例如用
3H及
14C标记)可用于化合物和/或底物组织分布分析中。氚化(即
3H)和碳-14(即
14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素,诸如
15O、
13N、
11C和
18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序,通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。
Certain isotopically labeled compounds of the disclosure (eg, with3H and14C ) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备,例如可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
本公开的药物组合物可以采用本领域众所周知的方法制造,如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present disclosure can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
在一些实施方案中,药物组合物是口服形式。对于口服给药,可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合,来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如,可通过下述方法获得:将所述的活性化合物与固体辅料混合,任选地碾磨所得的混合物,如果需要则加入其它合适的辅料,然后将该混合物加工成颗粒,得到了片剂或糖衣剂的核心。适合的辅料包括但不限于:粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating. Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
药物组合物还可适用于肠胃外给药,如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
本文所述的通式Ⅰ化合物的所有施用方法中,每天给药的剂量为0.01mg/kg到200mg/kg体重,优选为0.05mg/kg到50mg/kg体重,更优选0.1mg/kg到30mg/kg体重,以单独或分开剂量的形式。In all methods of administration of the compound of general formula I described herein, the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg /kg body weight, in single or divided doses.
下面通过实施例对发明进行详细描述,但并不意味着对本公开的任何不利限制。本文已经详细地描述了本公开,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种改变和改进将是显而易见的。本公开所使用的所有试剂是市售的,无需进一步纯化即可使用。The invention will be described in detail through the examples below, but it does not imply any unfavorable limitation to the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. will be obvious. All reagents used in this disclosure are commercially available and used without further purification.
除非另作说明,混合溶剂表示的比例是体积混合比例。Unless otherwise specified, the ratios indicated for mixed solvents are volume mixing ratios.
除非另作说明,否则,%是指wt%。Unless otherwise stated, % means wt%.
化合物经手工或
软件命名,市售化合物采用供应商目录名称。
compound by hand or The software is named, and the commercially available compounds adopt the supplier catalog name.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为 10
-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等,内标为四甲基硅烷(TMS);“IC
50”指半数抑制浓度,指达到最大抑制效果一半时的浓度。
Compound structures were determined by nuclear magnetic resonance (NMR) and/or mass spectroscopy (MS). The unit of NMR shift is 10 -6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); concentration.
本公开式(f)所示化合物或其药学上可接受的盐的制备方法,具体如下:The preparation method of the compound represented by the formula (f) of the present disclosure or a pharmaceutically acceptable salt thereof is as follows:
本公开式(f’)所示化合物或其药学上可接受的盐的制备方法,具体如下:The preparation method of the compound represented by the present disclosure formula (f') or a pharmaceutically acceptable salt thereof is as follows:
实施例1:3-(2-羰基-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)哌啶-2,6-二酮Example 1: 3-(2-Carbonyl-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione
步骤1:6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(1-2)Step 1: 6,7,8,8a-Tetrahydrobenzo[cd]indol-2(1H)-one (1-2)
将苯并[cd]吲哚-2(1H)-酮(2.0g,11.8mmol)溶解三氟乙酸(10mL)中,加入钯碳(200mg,10%wt),置换氢气三次,加热至50℃,反应过夜,冷却至室温,过滤,浓缩干,反相纯化得6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(950mg,收率50%,纯度96%)。m/z(ESI):174[M+H]
+。
Dissolve benzo[cd]indol-2(1H)-one (2.0g, 11.8mmol) in trifluoroacetic acid (10mL), add palladium carbon (200mg, 10%wt), replace hydrogen three times, and heat to 50°C , reacted overnight, cooled to room temperature, filtered, concentrated to dryness, and reversed-phase purified to obtain 6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (950mg, yield 50%, purity 96%). m/z (ESI): 174[M+H] + .
步骤2:2,6-二(苄氧基)吡啶(1-4)Step 2: 2,6-Bis(benzyloxy)pyridine (1-4)
室温下,将苄醇(1.1g,10.2mmol)加入到N,N-二甲基甲酰胺中(10mL),然后加入氢化 钠(680mg,17mmol),室温下反应1小时。将化合物2,6-二氯吡啶(0.5g,3.4mmol)加入,室温下反应过夜。将反应液加入到冰水中(30mL)。所得混合物用乙酸乙酯萃取(20mL*3),将有机相合并后用饱和食盐水洗涤(50mL),并用无水硫酸钠干燥,过滤,减压蒸馏除去溶剂后得2,6-二(苄氧基)吡啶(960mg)。m/z(ESI):292[M+H]
+。
Benzyl alcohol (1.1g, 10.2mmol) was added into N,N-dimethylformamide (10mL) at room temperature, and then sodium hydride (680mg, 17mmol) was added to react at room temperature for 1 hour. Compound 2,6-dichloropyridine (0.5 g, 3.4 mmol) was added and reacted overnight at room temperature. The reaction solution was added to ice water (30 mL). The resulting mixture was extracted with ethyl acetate (20mL*3), the combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 2,6-bis(benzyl oxy)pyridine (960 mg). m/z(ESI):292[M+H] + .
步骤3:2,6-二(苄氧基)-3-碘吡啶(1-5)Step 3: 2,6-Bis(benzyloxy)-3-iodopyridine (1-5)
室温下,将2,6-二(苄氧基)吡啶(960mg,3.3mmol)和1-碘吡咯烷-2,5-二酮(900mg g,4.0mmol)加入乙腈(10ml)中,所得混合物在80℃搅拌加热反应8h。将反应液冷却至室温,浓缩干反相柱层析(洗脱剂为水:乙腈=1:1)纯化得2,6-二(苄氧基)-3-碘吡啶(550mg,两步收率39%,纯度95%)。m/z(ESI):418[M+H]
+。
At room temperature, 2,6-bis(benzyloxy)pyridine (960mg, 3.3mmol) and 1-iodopyrrolidine-2,5-dione (900mg g, 4.0mmol) were added to acetonitrile (10ml), and the resulting mixture The reaction was stirred and heated at 80°C for 8h. The reaction solution was cooled to room temperature, concentrated to dryness and purified by reverse-phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain 2,6-bis(benzyloxy)-3-iodopyridine (550 mg, two steps Yield 39%, purity 95%). m/z (ESI): 418[M+H] + .
步骤4:1-(2,6-二(苄氧基)吡啶-3-基)-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(1-6)Step 4: 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (1- 6)
于干燥反应管中加入6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(10mg,57.8μmol),2,6-二(苄氧基)-3-碘吡啶(36mg,86.7μmol),碘化亚铜2(2.2mg,11.6μmol)和碳酸钾(24mg,173.4μmol)溶解于DMF(1mL),加入配体反式-N,N'-二甲基-1,2-环己二胺(3.3mg,23.2μmol),抽真空换氩气三次,加热至100℃,反应30min,冷却至室温,反相柱层析(水:乙腈=1:1)纯化得1-(2,6-二(苄氧基)吡啶-3-基)-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(21mg,收率79%)。LC-MS:m/z(ESI):463[M+H]
+。
Add 6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (10 mg, 57.8 μmol), 2,6-bis(benzyloxy)-3- Iodopyridine (36 mg, 86.7 μmol), copper iodide 2 (2.2 mg, 11.6 μmol) and potassium carbonate (24 mg, 173.4 μmol) were dissolved in DMF (1 mL), and the ligand trans-N,N'-dimethyl Diamino-1,2-cyclohexanediamine (3.3 mg, 23.2 μmol), vacuumed and replaced argon three times, heated to 100 ° C, reacted for 30 min, cooled to room temperature, reversed-phase column chromatography (water: acetonitrile = 1:1 ) was purified to obtain 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (21mg, Yield 79%). LC-MS: m/z (ESI): 463 [M+H] + .
步骤5:3-(2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)哌啶-2,6-二酮(1)Step 5: 3-(2-Oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (1)
将1-(2,6-二(苄氧基)吡啶-3-基)-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(21mg,45.4umol)加入到乙醇(5mL)中,加入钯碳(20mg,100%wt),抽真空换氢气三次,室温下反应过夜,垫硅藻土过滤,滤液浓缩干反相柱层析(洗脱剂为水:乙腈=1:1)纯化得3-(2-羰基-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)哌啶-2,6-二酮(12mg,收率93%)。m/z(ESI):285[M+H]
+.
1-(2,6-bis(benzyloxy)pyridin-3-yl)-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (21mg, 45.4umol ) was added into ethanol (5mL), palladium carbon (20mg, 100%wt) was added, vacuum was changed for three times for hydrogen, room temperature was reacted overnight, pad diatomaceous earth was filtered, and the filtrate was concentrated and dried by reverse phase column chromatography (eluent was Water: acetonitrile = 1:1) to obtain 3-(2-carbonyl-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-di Ketone (12 mg, yield 93%). m/z(ESI):285[M+H] + .
1H NMR(300MHz,DMSO)δ10.94(s,1H),7.43(dd,J=16.3,7.5Hz,3H),5.03–4.77(m,1H),4.43(dd,J=11.2,3.7Hz,1H),3.07–2.55(m,6H),2.44–2.25(m,1H),2.08–1.88(m,3H).
1 H NMR (300MHz, DMSO) δ10.94(s, 1H), 7.43(dd, J=16.3, 7.5Hz, 3H), 5.03–4.77(m, 1H), 4.43(dd, J=11.2, 3.7Hz ,1H),3.07–2.55(m,6H),2.44–2.25(m,1H),2.08–1.88(m,3H).
实施例2:2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]重氮基庚英-6-基)-N-(11-(4-(2,6-二氧代哌啶-3-基)-5-氧代-3,3a,4,5-四氢吡咯并[2,3,4-脱]喹啉-1(2H)-基)-11-羰基十一烷基)乙酰胺(化合物2)Example 2: 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]tri Azolo[4,3-a][1,4]diazoheptin-6-yl)-N-(11-(4-(2,6-dioxopiperidin-3-yl)-5 -Oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinolin-1(2H)-yl)-11-carbonylundecyl)acetamide (compound 2)
步骤1:3-(3-溴苯胺基)丙酸叔丁酯(2-2)Step 1: tert-butyl 3-(3-bromoanilino)propionate (2-2)
将化合物2-1(30g,174mmol),丙烯酸叔丁酯(22.4g,174mmol)和乙酸(2.09g,34.9mmol)加至250mL反应瓶中,90℃下搅拌反应12h。反应结束后,反应液浓缩得粗品化合物2-2(50g),直接用于下一步反应。m/z(ESI):300[M+H]
+。
Compound 2-1 (30g, 174mmol), tert-butyl acrylate (22.4g, 174mmol) and acetic acid (2.09g, 34.9mmol) were added to a 250mL reaction flask, and stirred at 90°C for 12h. After the reaction, the reaction solution was concentrated to obtain crude compound 2-2 (50 g), which was directly used in the next reaction. m/z (ESI): 300[M+H] + .
步骤2:3-((N-(3-溴苯基)-4-甲基苯基)磺酰氨基)丙酸叔丁酯(2-3)Step 2: tert-butyl 3-((N-(3-bromophenyl)-4-methylphenyl)sulfonylamino)propionate (2-3)
将化合物2-2(20g,66.6mmol)溶于吡啶(100mL)中,在0℃下缓慢滴加对甲苯磺酰氯(25.4g,133mmol)。在25℃下搅拌反应2h。反应结束后缓慢滴加饱和氯化铵水溶液(100mL),使用乙酸乙酯(50mL*3)萃取反应液,收集有机相,饱和氯化铵水溶液(50mL)洗涤,无水硫酸钠干燥有机相,过滤,滤液浓缩得粗产品,再经柱层析(洗脱剂为石油醚:乙酸乙酯=10:1)得化合物2-3(15g,收率50%)。m/z(ESI):454[M+H]
+。
Compound 2-2 (20 g, 66.6 mmol) was dissolved in pyridine (100 mL), and p-toluenesulfonyl chloride (25.4 g, 133 mmol) was slowly added dropwise at 0°C. The reaction was stirred at 25 °C for 2 h. After the reaction, slowly add saturated ammonium chloride aqueous solution (100mL) dropwise, use ethyl acetate (50mL*3) to extract the reaction solution, collect the organic phase, wash with saturated ammonium chloride aqueous solution (50mL), dry the organic phase over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to obtain a crude product, which was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 as eluent) to obtain compound 2-3 (15 g, yield 50%). m/z (ESI): 454[M+H] + .
步骤3:3-((N-(3-溴苯基)-4-甲基苯基)磺酰氨基)丙酸(2-4)Step 3: 3-((N-(3-bromophenyl)-4-methylphenyl)sulfonylamino)propanoic acid (2-4)
将化合物2-3(15g,33.0mmol)溶于三氟乙酸(15mL)和二氯甲烷(30mL)的混合溶液中,在25℃下搅拌反应12h。反应液浓缩得粗产品2-4(14g),直接用于下一步反应。m/z(ESI):398[M+H]
+。
Compound 2-3 (15g, 33.0mmol) was dissolved in a mixed solution of trifluoroacetic acid (15mL) and dichloromethane (30mL), and stirred at 25°C for 12h. The reaction solution was concentrated to obtain crude product 2-4 (14 g), which was directly used in the next reaction. m/z(ESI):398[M+H] + .
步骤4:5-溴-2,3-二氢喹啉-4(1H)-酮(2-5)Step 4: 5-Bromo-2,3-dihydroquinolin-4(1H)-one (2-5)
将多聚磷酸(75g,191mmol)加热至80℃,加入化合物2-4(15g,36.9mmol)后,升温至110℃,反应0.5h。反应结束后,将反应液倒入到水(150mL)中,使用乙酸乙酯(80mL*3)萃取反应液,收集有机相,饱和氯化铵水溶液(50mL)洗涤,无水硫酸钠干燥有机相,过滤,滤液浓缩得粗产品,再经柱层析(洗脱剂为石油醚:乙酸乙酯=5:1)得化合物2-5(4.2g,收率25%)。m/z(ESI):226[M+H]
+。
Polyphosphoric acid (75g, 191mmol) was heated to 80°C, compound 2-4 (15g, 36.9mmol) was added, the temperature was raised to 110°C, and the reaction was carried out for 0.5h. After the reaction, pour the reaction solution into water (150mL), extract the reaction solution with ethyl acetate (80mL*3), collect the organic phase, wash with saturated ammonium chloride aqueous solution (50mL), and dry the organic phase with anhydrous sodium sulfate , filtered, and the filtrate was concentrated to obtain a crude product, and then subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain compound 2-5 (4.2 g, yield 25%). m/z(ESI):226[M+H] + .
步骤5:5-溴-4-氧代-3,4-二氢喹啉-1(2H)-羧酸叔丁酯(2-6)Step 5: tert-butyl 5-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2-6)
将化合物2-5(4.2g,18.5mmol)溶于二氯甲烷(40mL)中,再加入4-二甲氨基吡啶(113mg,0.9mmol),二异丙基乙胺(3.6g,27.9mmol)和二碳酸二叔丁酯(4.05g,18.6mmol)。反应液加热至50℃回流反应16h。反应结束后,反应液浓缩得粗品,经柱层析(洗脱剂为石油醚:乙酸乙酯=5:1)得化合物2-6(2.32g,收率77%)。m/z(ESI):326[M+H]
+。
Compound 2-5 (4.2g, 18.5mmol) was dissolved in dichloromethane (40mL), then added 4-dimethylaminopyridine (113mg, 0.9mmol), diisopropylethylamine (3.6g, 27.9mmol) and di-tert-butyl dicarbonate (4.05 g, 18.6 mmol). The reaction solution was heated to 50°C and refluxed for 16h. After the reaction, the reaction solution was concentrated to obtain a crude product, which was subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain compound 2-6 (2.32 g, yield 77%). m/z(ESI):326[M+H] + .
步骤6:4-氨基-5-溴-3,4-二氢喹啉-1(2H)-羧酸叔丁酯(2-7)Step 6: tert-butyl 4-amino-5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (2-7)
将化合物2-6(2.1g,6.44mmol)和醋酸铵(6.6g,85.6mmol)溶于甲醇(20mL)中,在60℃下反应6h,加入氰基硼氢化钠(2.43g,38.6mmol),在60℃下反应10h。反应结束后,向反应液中缓慢加入饱和氯化铵水溶液(50mL)中,使用乙酸乙酯(80mL*3)萃取反应液,收集有机相,饱和氯化铵水溶液(50mL)洗涤,无水硫酸钠干燥有机相,过滤,滤液浓缩得粗产品,再经柱层析(洗脱剂为石油醚:乙酸乙酯=5:1,加0.5%(体积比)三乙胺)得化合物2-7(0.75g,收率29%)。m/z(ESI):327[M+H]
+。
Dissolve compound 2-6 (2.1g, 6.44mmol) and ammonium acetate (6.6g, 85.6mmol) in methanol (20mL), react at 60°C for 6h, add sodium cyanoborohydride (2.43g, 38.6mmol) , Reacted at 60°C for 10h. After the reaction, slowly add saturated ammonium chloride aqueous solution (50mL) to the reaction solution, extract the reaction solution with ethyl acetate (80mL*3), collect the organic phase, wash with saturated ammonium chloride aqueous solution (50mL), anhydrous sulfuric acid The organic phase was dried with sodium, filtered, and the filtrate was concentrated to obtain a crude product, and then subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 5:1, plus 0.5% (volume ratio) triethylamine) to obtain compound 2-7 (0.75g, yield 29%). m/z(ESI):327[M+H] + .
步骤7:5-氧代-3,3a,4,5-四氢吡咯并[2,3,4-脱]喹啉-1(2H)-羧酸叔丁酯(2-8)Step 7: tert-butyl 5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinoline-1(2H)-carboxylate (2-8)
将化合物2-7(0.75g,2.2mmol),1,1'-双(二苯基膦)二茂铁(211mg,0.38mmol),三乙胺(577mg,5.70mmol),甲醇(0.3mL)和乙酸钯(42.7mg,0.19mmol)依次加至DMF(3mL)中,置换一氧化碳三次,在一氧化碳(15psi)条件下加热至80℃反应12h。反应结束后,向反应液中加入水(10mL),使用乙酸乙酯(20mL*3)萃取反应液,收集有机相,饱和氯化铵水溶液(30mL)洗涤,无水硫酸钠干燥有机相,过滤,滤液浓缩得粗产品,再经柱层析(洗脱剂为石油醚:乙酸乙酯=1:2)得化合物2-8(0.42g,收率75%)。m/z(ESI):275[M+H]
+。
Compound 2-7 (0.75g, 2.2mmol), 1,1'-bis(diphenylphosphino)ferrocene (211mg, 0.38mmol), triethylamine (577mg, 5.70mmol), methanol (0.3mL) and palladium acetate (42.7mg, 0.19mmol) were sequentially added to DMF (3mL), carbon monoxide was replaced three times, and heated to 80°C under carbon monoxide (15psi) for 12h. After the reaction, add water (10mL) to the reaction solution, extract the reaction solution with ethyl acetate (20mL*3), collect the organic phase, wash with saturated ammonium chloride aqueous solution (30mL), dry the organic phase with anhydrous sodium sulfate, filter , the filtrate was concentrated to obtain a crude product, and then subjected to column chromatography (eluent: petroleum ether: ethyl acetate = 1:2) to obtain compound 2-8 (0.42 g, yield 75%). m/z(ESI):275[M+H] + .
步骤8:4-(2,6-二(苄氧基)吡啶-3-基)-5-氧代-3,3a,4,5-四氢吡咯并[2,3,4-脱]喹啉-1(2H)-羧酸叔丁酯(2-9)Step 8: 4-(2,6-Bis(benzyloxy)pyridin-3-yl)-5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinone Phenyl-1(2H)-tert-butyl carboxylate (2-9)
氮气条件下,将化合物2-8(150mg,0.54mmol),碘化亚铜(34.7mg,0.11mmol)和化合物1-5(342mg,0.82mmol)溶于1,4-二氧六环(2mL)中,在100℃反应12h。反应结束后,浓缩得粗产品,经柱层析(洗脱剂为甲醇:二氯甲烷=1:20)得到化合物2-9(120mg,收率39%)。m/z(ESI):564[M+H]
+。
Under nitrogen, compound 2-8 (150mg, 0.54mmol), cuprous iodide (34.7mg, 0.11mmol) and compound 1-5 (342mg, 0.82mmol) were dissolved in 1,4-dioxane (2mL ), react at 100°C for 12h. After the reaction was completed, the crude product was concentrated to obtain compound 2-9 (120 mg, yield 39%) by column chromatography (eluent: methanol: dichloromethane = 1:20). m/z(ESI):564[M+H] + .
步骤9:4-(2,6-二羰基哌啶-3-基)-5-氧代-3,3a,4,5-四氢吡咯并[2,3,4-脱]喹啉-1(2H)-羧酸叔丁酯(2-10)Step 9: 4-(2,6-Dicarbonylpiperidin-3-yl)-5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinoline-1 (2H)-tert-butyl carboxylate (2-10)
将化合物2-9(150mg,0.26mmol)溶于乙醇(10mL)中,加入钯/碳(16mg),置换氢气3次,在氢气(15psi)条件下,25℃反应16h。反应结束后,过滤得粗产品化合物2-10(90mg),直接用于下一步反应。m/z(ESI):386[M+H]
+。
Compound 2-9 (150mg, 0.26mmol) was dissolved in ethanol (10mL), palladium/carbon (16mg) was added, hydrogen was replaced 3 times, and reacted at 25°C for 16h under hydrogen (15psi). After the reaction, the crude product compound 2-10 (90mg) was obtained by filtration, which was directly used in the next reaction. m/z(ESI):386[M+H] + .
步骤10:3-(5-氧代-2,3,3a,5-四氢吡咯并[2,3,4-脱]喹啉-4(1H)-基)哌啶-2,6-二酮(2-11)Step 10: 3-(5-Oxo-2,3,3a,5-tetrahydropyrrolo[2,3,4-de]quinolin-4(1H)-yl)piperidine-2,6-di Ketones (2-11)
氮气条件下,将化合物2-10(60mg,0.15mmol)溶于TFA(1mL)和DCM(5mL),得混合溶液中,在25℃反应1h。反应结束后,浓缩得粗产品,经反相柱层(洗脱剂为水:乙腈=1:1)析纯化得化合物2-11(38mg,收率85%)。m/z(ESI):286[M+H]
+。
Under nitrogen, compound 2-10 (60mg, 0.15mmol) was dissolved in TFA (1mL) and DCM (5mL) to obtain a mixed solution, and reacted at 25°C for 1h. After the reaction, the crude product was concentrated and purified by reverse-phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 2-11 (38 mg, yield 85%). m/z(ESI):286[M+H] + .
1H NMR(400MHz,DMSO-d
6)δ10.93(br s,1H),7.14(dt,J=2.4,7.6Hz,1H),6.81–1 6.74(m,1H),6.63–6.55(m,1H),6.25–6.13(m,1H),5.05–4.78(m,1H),4.54–4.38(m,1H),3.54–3.44(m,1H),2.93–2.78(m,1H),2.60(br d,J=1.3Hz,2H),2.43–2.36(m,1H),2.32–2.10(m,1H),2.06-1.95(m,1H),1.22–1.02(m,1H).
1 H NMR (400MHz, DMSO-d 6 ) δ10.93 (br s, 1H), 7.14 (dt, J=2.4, 7.6Hz, 1H), 6.81–1 6.74 (m, 1H), 6.63–6.55 (m ,1H),6.25–6.13(m,1H),5.05–4.78(m,1H),4.54–4.38(m,1H),3.54–3.44(m,1H),2.93–2.78(m,1H),2.60 (br d,J=1.3Hz,2H),2.43–2.36(m,1H),2.32–2.10(m,1H),2.06-1.95(m,1H),1.22–1.02(m,1H).
步骤11:(11-(4-(2,6-二氧代哌啶-3-基)-5-氧代-3,3a,4,5-四氢吡咯并[2,3,4-脱]喹啉-1(2H)-基)-11-羰基十一烷基)氨基甲酸叔丁酯(2-12)Step 11: (11-(4-(2,6-dioxopiperidin-3-yl)-5-oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de ]quinolin-1(2H)-yl)-11-carbonylundecyl)carbamate tert-butyl ester (2-12)
将11-(叔丁氧羰基氨基)十一烷酸(10mg,0.03mmol)溶于氯化亚砜(1mL)中,加热至70℃反应10min后浓缩,再加入二氯甲烷(2mL)。将化合物2-11(1mg,0.03mmol)加至上述反应液中,再加入三乙胺(1mg,0.09mmol)。在25℃反应1h。反应结束后,浓缩得粗产品化合物2-12(17mg),直接用于下一步反应中。m/z(ESI):569[M+H]
+。
Dissolve 11-(tert-butoxycarbonylamino)undecanoic acid (10mg, 0.03mmol) in thionyl chloride (1mL), heat to 70°C for 10min and concentrate, then add dichloromethane (2mL). Compound 2-11 (1 mg, 0.03 mmol) was added to the above reaction solution, and then triethylamine (1 mg, 0.09 mmol) was added. React at 25°C for 1h. After the reaction was completed, the crude product compound 2-12 (17 mg) was obtained by concentration, which was directly used in the next reaction. m/z(ESI):569[M+H] + .
步骤12:3-(1-(11-氨基十一烷酰)-5-氧代-2,3,3a,5-四氢吡咯并[2,3,4-脱]喹啉-4(1H)-基)哌啶-2,6-二酮(2-13)Step 12: 3-(1-(11-aminoundecanoyl)-5-oxo-2,3,3a,5-tetrahydropyrrolo[2,3,4-de]quinoline-4(1H )-yl)piperidine-2,6-dione (2-13)
将化合物2-12(17mg,0.03mmol)溶于二氯甲烷(2mL)中,后加入氯化氢/1,4-二氧六环溶液(4M,1mL),在25℃反应1h。反应结束后,浓缩得粗产品化合物2-13(15mg,盐酸盐),直接用于下一步反应。m/z(ESI):469[M+H]
+。
Compound 2-12 (17mg, 0.03mmol) was dissolved in dichloromethane (2mL), then hydrogen chloride/1,4-dioxane solution (4M, 1mL) was added, and reacted at 25°C for 1h. After the reaction was completed, the crude product compound 2-13 (15 mg, hydrochloride) was obtained by concentration, which was directly used in the next reaction. m/z (ESI): 469[M+H] + .
步骤13:2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]重氮基庚英-6-基)-N-(11-(4-(2,6-二氧代哌啶-3-基)-5-氧代-3,3a,4,5-四氢吡咯并[2,3,4-脱]喹啉-1(2H)-基)-11-羰基十一烷基)乙酰胺(化合物2)Step 13: 2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazole And[4,3-a][1,4]diazoheptin-6-yl)-N-(11-(4-(2,6-dioxopiperidin-3-yl)-5- Oxo-3,3a,4,5-tetrahydropyrrolo[2,3,4-de]quinolin-1(2H)-yl)-11-carbonylundecyl)acetamide (Compound 2)
将化合物2-13(10mg,0.02mmol),(S)-2-[2,3,9-三甲基-4-(4-氯苯基)-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂卓-6-基]乙酸(9mg,0.02mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(8mg,0.02mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入二异丙基乙胺(8mg,0.06mmol),在25℃反应1h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物2(4mg,收率24%)。m/z(ESI):851[M+H]
+。
Compound 2-13 (10mg, 0.02mmol), (S)-2-[2,3,9-trimethyl-4-(4-chlorophenyl)-6H-thieno[3,2-f] [1,2,4]Triazolo[4,3-a][1,4]diazepine-6-yl]acetic acid (9mg, 0.02mmol) and 2-(7-azobenzotriazole Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8mg, 0.02mmol) was dissolved in N,N-dimethylformamide (2mL), and diisopropylethylamine was added (8mg, 0.06mmol), react at 25°C for 1h. After the reaction, compound 2 (4 mg, yield 24%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1: 1). m/z(ESI):851[M+H] + .
1H NMR(400MHz,DMSO-d
6)δ11.02(s,1H),8.49(s,1H),8.19(t,J=5.6Hz,1H),7.57–7.37(m,7H),5.01(ddd,J=51.6,12.9,4.9Hz,1H),4.58–4.50(m,2H),3.27(dd,J=14.9,8.4Hz,2H),3.22–3.04(m,4H),2.97–2.83(m,1H),2.70(td,J=4.5,3.7,2.6Hz,1H),2.66–2.58(m,7H),2.45-2.44(m,1H),2.43(s,3H),2.36-2.34(m,1H),2.09-2.01(m,1H),1.65(s,3H),1.37–1.20(m,14H).
1 H NMR (400MHz, DMSO-d 6 ) δ11.02(s, 1H), 8.49(s, 1H), 8.19(t, J=5.6Hz, 1H), 7.57–7.37(m, 7H), 5.01( ddd, J=51.6, 12.9, 4.9Hz, 1H), 4.58–4.50(m, 2H), 3.27(dd, J=14.9, 8.4Hz, 2H), 3.22–3.04(m, 4H), 2.97–2.83( m,1H),2.70(td,J=4.5,3.7,2.6Hz,1H),2.66–2.58(m,7H),2.45-2.44(m,1H),2.43(s,3H),2.36-2.34( m,1H),2.09-2.01(m,1H),1.65(s,3H),1.37–1.20(m,14H).
实施例3:1-(3-氯-4-甲基苯基)-3-((1-(2,6-二氧代哌啶-3-基)-2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-基)甲基)脲Example 3: 1-(3-chloro-4-methylphenyl)-3-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2, 6,7,8,8a-Hexahydrobenzo[cd]indol-4-yl)methyl)urea
步骤1:4-溴-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(3-1)Step 1: 4-Bromo-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (3-1)
将硝酸银(980mg,5.77mmol)溶于水(4mL)中后加至溶有化合物1-2(1g,5.77mmol)的乙酸(8mL)溶液中,将硝酸(363mg,5.77mmol)和液溴(6.46g,40.41mmol)加至反应液中,在25℃反应16h。反应结束后,滴加饱和亚硫酸钠水溶液洗涤至溶液澄清,使用乙酸乙酯(20mL*3)萃取反应液,收集有机相,饱和氯化铵水溶液(30mL)洗涤,无水硫酸钠干燥有机相,过滤,滤液浓缩得粗产品,再经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-1(0.5g,收率34%)。m/z(ESI):252[M+H]
+。
Silver nitrate (980mg, 5.77mmol) was dissolved in water (4mL) and added to a solution of compound 1-2 (1g, 5.77mmol) in acetic acid (8mL) solution, nitric acid (363mg, 5.77mmol) and liquid bromine (6.46g, 40.41mmol) was added to the reaction solution and reacted at 25°C for 16h. After the reaction, add saturated sodium sulfite aqueous solution dropwise to wash until the solution is clear, use ethyl acetate (20mL*3) to extract the reaction solution, collect the organic phase, wash with saturated ammonium chloride aqueous solution (30mL), dry the organic phase with anhydrous sodium sulfate, filter , the filtrate was concentrated to obtain a crude product, which was then purified by reverse-phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 3-1 (0.5 g, yield 34%). m/z(ESI):252[M+H] + .
步骤2:2-(4-溴-2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)戊二酸二甲酯(3-2)Step 2: Dimethyl 2-(4-bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutarate (3-2 )
将化合物3-1(100mg,0.4mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入氢化钠(20mg,0.5mmol)在25℃搅拌0.5h,加入2-溴戊二酸二甲酯(140mg,0.6mmol)后,在25℃反应1h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-2(100mg,收率61%)。m/z(ESI):410[M+H]
+。
Dissolve compound 3-1 (100mg, 0.4mmol) in N,N-dimethylformamide (2mL), add sodium hydride (20mg, 0.5mmol) and stir at 25°C for 0.5h, add 2-bromoglutaric acid After dimethyl ester (140mg, 0.6mmol), react at 25°C for 1h. After the reaction, compound 3-2 (100 mg, yield 61%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1). m/z (ESI): 410[M+H] + .
步骤3:2-(4-溴-2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)戊二酸(3-3)Step 3: 2-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutaric acid (3-3)
将化合物3-2(50mg,0.12mmol)溶于四氢呋喃(2mL)和水(2mL)中,加入氢氧化锂(9mg,0.36mmol),在25℃反应2h。反应结束后,使用浓盐酸调节pH至3左右,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-3(40mg,收率85%)。m/z(ESI):382[M+H]
+。
Compound 3-2 (50mg, 0.12mmol) was dissolved in tetrahydrofuran (2mL) and water (2mL), lithium hydroxide (9mg, 0.36mmol) was added, and reacted at 25°C for 2h. After the reaction, the pH was adjusted to about 3 with concentrated hydrochloric acid, and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 3-3 (40 mg, yield 85%). m/z (ESI): 382[M+H] + .
步骤4:3-(4-溴-2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)哌啶-2,6-二酮(3-4)Step 4: 3-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione ( 3-4)
氮气条件下,将化合物3-3(40mg,0.1mmol),三乙胺(32mg,0.3mmol),1-羟基苯并三唑(32mg,0.24mmol)溶于二氯甲烷(2mL)中,加入三氟乙酰胺(12mg,0.1mmol),反应液温度降至0℃后,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(44mg,0.23mmol),在25℃反应16h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-4(30mg,收率82%)。m/z(ESI):363[M+H]
+。
Under nitrogen, compound 3-3 (40mg, 0.1mmol), triethylamine (32mg, 0.3mmol), 1-hydroxybenzotriazole (32mg, 0.24mmol) were dissolved in dichloromethane (2mL), and added Trifluoroacetamide (12mg, 0.1mmol), after the temperature of the reaction solution dropped to 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44mg, 0.23mmol) was added , Reacted at 25°C for 16h. After the reaction, compound 3-4 (30 mg, yield 82%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1). m/z(ESI):363[M+H] + .
步骤5:((1-(2,6-二氧代哌啶-3-基)-2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-基)甲基)氨基甲酸叔丁酯(3-5)Step 5: ((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd]indole- 4-yl) methyl) tert-butyl carbamate (3-5)
氮气条件下,将化合物3-4(50mg,0.13mmol),[(叔丁氧羰基氨基)甲基]三氟硼酸钾(65mg,0.27mmol),乙酸钯(6mg,0.027mmol),正丁基二(1-金刚烷基)膦(20mg,0.55mmol)和碳酸铯(134mg,0.41mmol)溶于1,4-二氧六环(2mL)和水(0.2mL)中,在100℃反应1h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-5(40mg, 收率70%)。m/z(ESI):414[M+H]
+。
Under nitrogen, compound 3-4 (50mg, 0.13mmol), [(tert-butoxycarbonylamino)methyl] potassium trifluoroborate (65mg, 0.27mmol), palladium acetate (6mg, 0.027mmol), n-butyl Bis(1-adamantyl)phosphine (20mg, 0.55mmol) and cesium carbonate (134mg, 0.41mmol) were dissolved in 1,4-dioxane (2mL) and water (0.2mL), and reacted at 100°C for 1h . After the reaction, compound 3-5 (40 mg, yield 70%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1: 1). m/z (ESI): 414[M+H] + .
步骤6:3-(4-(氨基甲基)-2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)哌啶-2,6-二酮(3-6)Step 6: 3-(4-(Aminomethyl)-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6 - diketone (3-6)
将化合物3-5(40mg)溶于二氯甲烷(2mL)中,加入氯化氢/1,4-二氧六环溶液(4M,1mL),在25℃反应1h。反应结束后,浓缩得粗产品化合物3-6(33mg),直接用于下一步反应。m/z(ESI):314[M+H]
+。
Compound 3-5 (40mg) was dissolved in dichloromethane (2mL), hydrogen chloride/1,4-dioxane solution (4M, 1mL) was added, and reacted at 25°C for 1h. After the reaction, it was concentrated to obtain the crude product compound 3-6 (33 mg), which was directly used in the next reaction. m/z (ESI): 314[M+H] + .
步骤7:1-(3-氯-4-甲基苯基)-3-((1-(2,6-二氧代哌啶-3-基)-2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-基)甲基)脲(3)Step 7: 1-(3-Chloro-4-methylphenyl)-3-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6 ,7,8,8a-Hexahydrobenzo[cd]indol-4-yl)methyl)urea (3)
将化合物3-6(10mg,0.028mmol),三乙胺(9mg,0.085mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入3-氯-4-甲基苯异氰酸酯(6mg,0.037mmol),在25℃反应1h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3(5mg,收率36%)。m/z(ESI):481[M+H]
+。
Dissolve compound 3-6 (10mg, 0.028mmol), triethylamine (9mg, 0.085mmol) in N,N-dimethylformamide (2mL), add 3-chloro-4-methylbenzene isocyanate (6mg ,0.037mmol), reacted at 25°C for 1h. After the reaction, compound 3 (5 mg, yield 36%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1). m/z (ESI): 481[M+H] + .
1H NMR(600MHz,DMSO-d
6)δ10.95(s,1H),8.74(s,1H),7.66(d,J=2.3Hz,1H),7.49(dd,J=12.1,7.7Hz,1H),7.39(dd,J=8.3,3.3Hz,1H),7.18(d,J=8.3Hz,1H),7.13(d,J=8.4Hz,1H),6.84–6.65(m,1H),4.91(ddd,J=99.9,13.3,4.9Hz,1H),4.44(dd,J=12.0,4.5Hz,1H),4.36(dd,J=15.7,5.9Hz,1H),4.28(dt,J=16.2,4.5Hz,1H),2.96(dt,J=17.1,8.2Hz,1H),2.84(qd,J=15.7,13.7,9.6Hz,1H),2.70(dt,J=18.0,8.9Hz,1H),2.62–2.56(m,2H),2.46–2.28(m,1H),2.23(s,3H)2.17-2.10(m,1H),2.06–1.90(m,2H),1.15-1.04(m,1H).
1 H NMR (600MHz, DMSO-d 6 )δ10.95(s, 1H), 8.74(s, 1H), 7.66(d, J=2.3Hz, 1H), 7.49(dd, J=12.1, 7.7Hz, 1H),7.39(dd,J=8.3,3.3Hz,1H),7.18(d,J=8.3Hz,1H),7.13(d,J=8.4Hz,1H),6.84–6.65(m,1H), 4.91(ddd, J=99.9, 13.3, 4.9Hz, 1H), 4.44(dd, J=12.0, 4.5Hz, 1H), 4.36(dd, J=15.7, 5.9Hz, 1H), 4.28(dt, J= 16.2,4.5Hz,1H),2.96(dt,J=17.1,8.2Hz,1H),2.84(qd,J=15.7,13.7,9.6Hz,1H),2.70(dt,J=18.0,8.9Hz,1H ),2.62–2.56(m,2H),2.46–2.28(m,1H),2.23(s,3H)2.17-2.10(m,1H),2.06–1.90(m,2H),1.15-1.04(m, 1H).
化合物3-4的合成方法2:Synthetic method 2 of compound 3-4:
步骤1:N-(6-溴-1,2,3,4-四氢萘-1-基)甲基吡啶酰胺(3-c)Step 1: N-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)picolinamide (3-c)
将化合物3-b(3g,13.27mmol),2-吡啶甲酸(1.96g,15.92mmol),1-羟基苯并三唑(2.15g,15.92mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(3.05g,15.92mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入N,N-二异丙基乙胺(4.29g,33.17mmol),在25℃下搅拌反应16小时。反应结束后,反应液浓缩,经柱层析(石油醚:乙酸乙酯=10:1)得化合物3-c(4g,收率91%)。m/z(ESI):331[M+H]+。Compound 3-b (3g, 13.27mmol), 2-pyridinecarboxylic acid (1.96g, 15.92mmol), 1-hydroxybenzotriazole (2.15g, 15.92mmol), 1-(3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (3.05g, 15.92mmol) was dissolved in N,N-dimethylformamide (20mL), N,N-diisopropylethylamine (4.29g, 33.17mmol), stirred and reacted at 25°C for 16 hours. After the reaction, the reaction liquid was concentrated, and compound 3-c (4 g, yield 91%) was obtained by column chromatography (petroleum ether: ethyl acetate = 10:1). m/z (ESI): 331 [M+H]+.
步骤2:4-溴-6,7,8,8a-四氢苯并[cd]吲哚-2(1H)-酮(3-1)Step 2: 4-Bromo-6,7,8,8a-tetrahydrobenzo[cd]indol-2(1H)-one (3-1)
将化合物3-c(200mg,0.6mmol),四水乙酸钴(150mg,0.6mmol),碳酸银(499mg,1.81mmol),特戊酸(185mg,1.81mmol),偶氮二甲酸二乙酯(420mg,2.42mmol)溶于三氟乙醇(1.5mL),并置于聚四氟乙烯封管中。反应液在130℃下搅拌反应16小时。反应结束后, 反应液过滤,滤液经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-1(40mg,收率26%)。m/z(ESI):252[M+H]+。Compound 3-c (200mg, 0.6mmol), cobalt acetate tetrahydrate (150mg, 0.6mmol), silver carbonate (499mg, 1.81mmol), pivalic acid (185mg, 1.81mmol), diethyl azodicarboxylate ( 420mg, 2.42mmol) was dissolved in trifluoroethanol (1.5mL) and placed in a polytetrafluoroethylene sealed tube. The reaction solution was stirred and reacted at 130° C. for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was purified by reverse-phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 3-1 (40 mg, yield 26%). m/z(ESI):252[M+H]+.
步骤3:2-(4-溴-2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)戊二酸二甲酯(3-2)Step 3: Dimethyl 2-(4-bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutarate (3-2 )
将化合物3-1(100mg,0.4mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入氢化钠(20mg,0.5mmol)在25℃下搅拌0.5h,加入2-溴戊二酸二甲酯(140mg,0.6mmol)后,在25℃下反应1h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-2(100mg,收率61%)。m/z(ESI):410[M+H]
+。
Dissolve compound 3-1 (100mg, 0.4mmol) in N,N-dimethylformamide (2mL), add sodium hydride (20mg, 0.5mmol) and stir at 25°C for 0.5h, add 2-bromopentanedi Dimethyl ester (140mg, 0.6mmol) was reacted at 25°C for 1h. After the reaction, compound 3-2 (100 mg, yield 61%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1). m/z (ESI): 410[M+H] + .
步骤4:2-(4-溴-2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)戊二酸(3-3)Step 4: 2-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)glutaric acid (3-3)
将化合物3-2(50mg,0.12mmol)溶于四氢呋喃(2mL)和水(2mL)中,加入氢氧化锂(9mg,0.36mmol),在25℃下反应2h。反应结束后,使用浓盐酸调节pH至3左右,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-3(40mg,收率85%)。m/z(ESI):382[M+H]
+。
Compound 3-2 (50mg, 0.12mmol) was dissolved in tetrahydrofuran (2mL) and water (2mL), lithium hydroxide (9mg, 0.36mmol) was added, and reacted at 25°C for 2h. After the reaction, the pH was adjusted to about 3 with concentrated hydrochloric acid, and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 3-3 (40 mg, yield 85%). m/z (ESI): 382[M+H] + .
步骤5:3-(4-溴-2-氧代-6,7,8,8a-四氢苯并[cd]吲哚-1(2H)-基)哌啶-2,6-二酮(3-4)Step 5: 3-(4-Bromo-2-oxo-6,7,8,8a-tetrahydrobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione ( 3-4)
氮气条件下,将化合物3-3(40mg,0.1mmol),三乙胺(32mg,0.3mmol),1-羟基苯并三唑(32mg,0.24mmol)溶于二氯甲烷(2mL)中,加入三氟乙酰胺(12mg,0.1mmol),反应液温度降至0℃后,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(44mg,0.23mmol),在25℃反应16h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物3-4(30mg,收率82%)。m/z(ESI):363[M+H]
+。
Under nitrogen, compound 3-3 (40mg, 0.1mmol), triethylamine (32mg, 0.3mmol), 1-hydroxybenzotriazole (32mg, 0.24mmol) were dissolved in dichloromethane (2mL), and added Trifluoroacetamide (12mg, 0.1mmol), after the temperature of the reaction solution dropped to 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44mg, 0.23mmol) was added , Reacted at 25°C for 16h. After the reaction, compound 3-4 (30 mg, yield 82%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1). m/z(ESI):363[M+H] + .
实施例4:6-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]重氮基庚英-6-基)乙酰氨基)-N-((1-(2,6-二氧代哌啶-3-基)-2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-基)甲基)己酰胺Example 4: 6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2, 4] Triazolo[4,3-a][1,4]diazoheptin-6-yl)acetamido)-N-((1-(2,6-dioxopiperidine-3- Base)-2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd]indol-4-yl)methyl)caproamide
步骤1:(6-(((1-(2,6-二氧代哌啶-3-基)-2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-基)甲基)氨基)-6-羰基己基)氨基甲酸叔丁酯(4-1)Step 1: (6-(((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd ]indol-4-yl)methyl)amino)-6-carbonylhexyl)carbamate tert-butyl ester (4-1)
将化合物3-6(33mg,0.094mmol),叔丁氧羰酰基6-氨基己酸(22mg,0.094mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(39mg,0.1mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入二异丙基乙胺(36mg,0.28mmol),在25℃反应1h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1)纯化得化合物4-1(40mg,收率80%)。m/z(ESI):527[M+H]
+。
Compound 3-6 (33mg, 0.094mmol), tert-butoxycarbonyl 6-aminocaproic acid (22mg, 0.094mmol) and 2-(7-azobenzotriazole)-N,N,N', N'-Tetramethyluronium hexafluorophosphate (39mg, 0.1mmol) was dissolved in N,N-dimethylformamide (2mL), diisopropylethylamine (36mg, 0.28mmol) was added, and at 25°C Reaction 1h. After the reaction, compound 4-1 (40 mg, yield 80%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1: 1). m/z(ESI):527[M+H] + .
步骤2:6-氨基-N-((1-(2,6-二氧代哌啶-3-基)-2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-基)甲基)己酰胺(4-2)Step 2: 6-Amino-N-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2,6,7,8,8a-hexahydrobenzo [cd]indol-4-yl)methyl)hexanamide (4-2)
将化合物4-1(40mg)溶于二氯甲烷(2mL)中,加入氯化氢/1,4-二氧六环溶液(4M,1mL),在25℃反应1h。反应结束后,浓缩得粗产品化合物4-2(30mg),直接用于下一步反应。m/z(ESI):427[M+H]
+。
Compound 4-1 (40mg) was dissolved in dichloromethane (2mL), hydrogen chloride/1,4-dioxane solution (4M, 1mL) was added, and reacted at 25°C for 1h. After the reaction, it was concentrated to obtain the crude product compound 4-2 (30 mg), which was directly used in the next reaction. m/z (ESI): 427[M+H] + .
步骤3:6-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]重氮基庚英-6-基)乙酰氨基)-N-((1-(2,6-二氧代哌啶-3-基)-2-氧代-1,2,6,7,8,8a-六氢苯并[cd]吲哚-4-基)甲基)己酰胺(4)Step 3: 6-(2-((S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4 ]triazolo[4,3-a][1,4]diazoheptin-6-yl)acetamido)-N-((1-(2,6-dioxopiperidin-3-yl )-2-oxo-1,2,6,7,8,8a-hexahydrobenzo[cd]indol-4-yl)methyl)caproamide (4)
将化合物4-2(30mg,0.064mmol),(S)-2-[2,3,9-三甲基-4-(4-氯苯基)-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂卓-6-基]乙酸(26mg,0.064mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(29mg,0.077mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入二异丙基乙胺(25mg,0.19mmol),在25℃反应1h。反应结束后,经反相柱层析(洗脱剂为水:乙腈=1:1纯化得化合物4(3mg,收率5%)。m/z(ESI):809[M+H]
+。
Compound 4-2 (30mg, 0.064mmol), (S)-2-[2,3,9-trimethyl-4-(4-chlorophenyl)-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl]acetic acid (26mg, 0.064mmol) and 2-(7-azobenzotriazole Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29mg, 0.077mmol) was dissolved in N,N-dimethylformamide (2mL), and diisopropylethylamine was added (25mg, 0.19mmol), react at 25°C for 1h. After the reaction, compound 4 (3 mg, yield 5%) was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1). m/z (ESI): 809[M+H] + .
1H NMR(600MHz,DMSO-d
6)δ10.95(d,J=7.0Hz,1H),8.29(t,J=6.0Hz,1H),8.19(t,J=5.7Hz,1H),7.49(d,J=8.2Hz,2H),7.47–7.44(m,1H),7.42(d,J=8.1Hz,2H),7.31(dd,J=7.8,4.2Hz,1H),5.06–4.79(m,1H),4.51(t,J=7.1Hz,1H),4.42(dd,J=11.9,4.5Hz,1H),4.33(dt,J=16.0,5.1Hz,1H),4.24(dt,J=15.4,4.8Hz,1H),3.27-3.23(m,1H),3.20-3.17(m,1H),3.15-3.09(m,1H),2.86-2.80(m,1H),2.70–2.55(m,7H),2.41(s,3H),2.17(t,J=7.5Hz,2H),2.13-2.05(m,1H),2.03-1.97(m,3H),1.93-1.91(m,1H),1.62(s,3H),1.56(t,J=7.5Hz,2H),1.48-1.43(m,2H),1.31(t,J=7.8Hz,2H),1.07(dd,J=17.1,12.1Hz,1H).
1 H NMR (600MHz, DMSO-d 6 ) δ10.95(d, J=7.0Hz, 1H), 8.29(t, J=6.0Hz, 1H), 8.19(t, J=5.7Hz, 1H), 7.49 (d,J=8.2Hz,2H),7.47–7.44(m,1H),7.42(d,J=8.1Hz,2H),7.31(dd,J=7.8,4.2Hz,1H),5.06–4.79( m,1H),4.51(t,J=7.1Hz,1H),4.42(dd,J=11.9,4.5Hz,1H),4.33(dt,J=16.0,5.1Hz,1H),4.24(dt,J =15.4,4.8Hz,1H),3.27-3.23(m,1H),3.20-3.17(m,1H),3.15-3.09(m,1H),2.86-2.80(m,1H),2.70–2.55(m ,7H),2.41(s,3H),2.17(t,J=7.5Hz,2H),2.13-2.05(m,1H),2.03-1.97(m,3H),1.93-1.91(m,1H), 1.62(s,3H),1.56(t,J=7.5Hz,2H),1.48-1.43(m,2H),1.31(t,J=7.8Hz,2H),1.07(dd,J=17.1,12.1Hz ,1H).
除了在实施例1-4中合成的化合物之外的其它化合物可以通过参考实施例1-4中的合成路径和源材料合成得到。Compounds other than those synthesized in Examples 1-4 can be synthesized by referring to the synthesis routes and source materials in Examples 1-4.
生物学活性及相关性质测试例Biological activity and related properties test cases
测试例1、Cereblon结合实验Test example 1, Cereblon binding experiment
1、实验仪器及材料1. Experimental instruments and materials
仪器名称equipment name | 设备厂家Equipment manufacturers | 型号model |
振荡器oscillator | BoxunBoxun | BSD-YX3400BSD-YX3400 |
读板仪Plate reader | PerkinElmerPerkinElmer | EnvisionEnvision |
离心机centrifuge | EppendorfEppendorf | Eppendorf MixmateEppendorf Mixmate |
化合物稀释及加样仪Compound Dilution and Sampler | PerkinElmerPerkinElmer | EchoEcho |
实验所用的检测试剂盒(HTRF Human Cereblon Binding Kits)是一种使用
技术定量测量Cereblon WT配体的检测方法。检测原理基于HTRF技术,特定标记的GST抗体(Euroum Cryptate,供体)同时与带有GST标记的人Cereblon WT配体和XL665标记的来那度胺示踪剂(受体)结合,用光源激发供体引发向受体的荧光共振能量转移(FRET),受体在特定波长665nm发出荧光,加入化合物后与XL665标记的来那度胺竞争而阻止FRET发生。FRET信号比与化合物浓度成反比。
The detection kit (HTRF Human Cereblon Binding Kits) used in the experiment is a kind of Assay method for quantitative measurement of Cereblon WT ligand. The detection principle is based on HTRF technology. The specific labeled GST antibody (Euroum Cryptate, donor) is simultaneously combined with GST-labeled human Cereblon WT ligand and XL665-labeled lenalidomide tracer (acceptor), and excited by light source The donor triggers fluorescence resonance energy transfer (FRET) to the acceptor, and the acceptor emits fluorescence at a specific wavelength of 665nm. After adding the compound, it competes with XL665-labeled lenalidomide to prevent FRET from occurring. The FRET signal ratio is inversely proportional to the compound concentration.
实验所需其它试剂及耗材信息如下:Other reagents and consumables required for the experiment are as follows:
试剂Reagent | 品牌brand | 货号Item No. |
HTRF Human Cereblon Binding KitsHTRF Human Cereblon Binding Kits | PromegaPromega | 64BDCRBNPEG64BDCRBNPEG |
384孔板384-well plate | PerkinElmerPerkinElmer | 60072996007299 |
2、实验步骤2. Experimental steps
将本公开化合物溶解于DMSO中,母液储存浓度为10mM。通过Echo仪器的化合物稀释及加样仪程序进行化合物母液梯度稀释,稀释程序实验总体系20μL,待测化合物起始浓度100μM,标准品起始浓度200μM,4倍稀释,8个浓度点,DMSO含量为1%。程序结束后,每孔加入5μL试剂盒里的1×9#稀释液,然后加入5μL GST标记的人Cereblon WT配体,充分混匀后加入10μL的HTRF检测试剂,室温孵育3小时。使用Envision读板仪测量 每个孔中的HTRF信号。100%结合抑制定义为200μM标准品来那度胺处理下信号比。The disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM. Gradient dilution of the compound mother solution is carried out through the compound dilution and sample loading program of the Echo instrument. The total experimental system of the dilution program is 20 μL, the initial concentration of the compound to be tested is 100 μM, the initial concentration of the standard is 200 μM, 4 times dilution, 8 concentration points, DMSO content 1%. After the program is over, add 5 μL of the 1×9# dilution in the kit to each well, then add 5 μL of GST-labeled human Cereblon WT ligand, mix well, add 10 μL of HTRF detection reagent, and incubate at room temperature for 3 hours. The HTRF signal in each well was measured using an Envision plate reader. 100% binding inhibition was defined as the signal ratio under 200 μM standard lenalidomide treatment.
3、数据分析3. Data analysis
计算每个孔的受体和供体发射信号的比率:Calculate the ratio of acceptor and donor emission signals for each well:
Ratio=Signal 665nm/Signal 620nm(比率=665nm信号/620nm信号)Ratio=Signal 665nm/Signal 620nm (ratio=665nm signal/620nm signal)
CV(%)=Standard deviation/Mean Ratio(偏差系数(%)=标准差/平均比率)CV(%)=Standard deviation/Mean Ratio (Deviation Coefficient (%)=Standard Deviation/Mean Ratio)
Cereblon binding inhibition%=100%-100%*(Sample-Average_L)/(Average_H-L),即Cereblon结合抑制率(%)=100%-100%×(Sample-L)/(H-L)Cereblon binding inhibition%=100%-100%*(Sample-Average_L)/(Average_H-L), that is, Cereblon binding inhibition rate (%)=100%-100%×(Sample-L)/(H-L)
其中:in:
H=Ave(DMSO处理组);H=Ave (DMSO treatment group);
L=Ave(200μM来那度胺标准品处理组)。L=Ave (200 μM lenalidomide standard treatment group).
通过GraphPad Prism 9进行数据分析处理,浓度-效应曲线采用非线性四参数曲线拟合,并计算化合物的IC
50:
The data was analyzed and processed by GraphPad Prism 9, the concentration-effect curve was fitted with a nonlinear four-parameter curve, and the IC 50 of the compound was calculated:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
其中:in:
X:Log of cpd concentration(Log化合物浓度);X: Log of cpd concentration (Log compound concentration);
Y:Percent inhibition(%inhibition)(抑制百分比(%));Y:Percent inhibition(%inhibition)(inhibition percentage(%));
Bottom为最小抑制百分比;Bottom is the minimum suppression percentage;
Top为最大抑制百分比;Top is the maximum inhibition percentage;
HillSlope为曲线斜率系数。HillSlope is the slope coefficient of the curve.
本公开化合物对Cereblon的结合能力通过以上的试验进行测定,测得的IC
50值见表1。
The binding ability of the disclosed compounds to Cereblon was determined by the above tests, and the measured IC 50 values are shown in Table 1.
表1Table 1
化合物编号Compound number | IC 50(μM) IC50 (μM) |
化合物1Compound 1 | BB |
A:<0.5μM;B:0.5-10μM;C:10-100μM;D:>100μM.A:<0.5μM; B:0.5-10μM; C:10-100μM; D:>100μM.
测试例2:MV-4-11细胞抗增殖活性实验Test Example 2: MV-4-11 cell anti-proliferation activity experiment
1、实验仪器及材料1. Experimental instruments and materials
仪器与设备Instruments and Equipment
仪器名称equipment name | 型号model | 设备厂家Equipment manufacturers |
离心机centrifuge | 58005800 | EppendorfEppendorf |
细胞计数仪cell counter | IC1000IC1000 | Count starCount star |
倒置显微镜Inverted microscope | TS2TS2 | NikonNikon |
细胞培养箱cell culture incubator | 1IVIOS 250i1IVIOS 250i | ThermoThermo |
Envision酶标仪Envision microplate reader | Envision2105Envision2105 | Perkin ElmerPerkin Elmer |
实验试剂与耗材Experimental reagents and consumables
2、实验步骤2. Experimental steps
(1)细胞铺板(1) Cell plating
将靶细胞MV-4-11(CBP60522,科佰)的培养基去除,加入PBS润洗一遍,再加入胰酶(Trypsin-EDTA(0.25%))消化5min。消化过后,加入10mL的完全培养基(IMDM+10% FBS),中和胰酶,吹打细胞,收集细胞,1000rpm离心5min,对细胞进行计数,将细胞密度调到30,000个/mL。取90μL细胞悬液加入到96孔低吸附板中。96孔板边缘孔加入200μL的PBS。1000rpm离心5min,使细胞聚集成球状,放入细胞培养箱中过夜培养。The culture medium of the target cell MV-4-11 (CBP60522, Kebai) was removed, washed once with PBS, and then digested with trypsin-EDTA (0.25%) for 5 min. After digestion, add 10 mL of complete medium (IMDM+10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 1000 rpm for 5 min, count the cells, and adjust the cell density to 30,000 cells/mL. Take 90 μL of cell suspension and add it to a 96-well low adsorption plate. Add 200 μL of PBS to the edge wells of the 96-well plate. Centrifuge at 1000rpm for 5min to aggregate the cells into spheres and place them in a cell culture incubator for overnight culture.
(2)细胞加药(2) Cell dosing
将本公开化合物溶解于DMSO中,母液储存浓度为10mM。给药前,使用DMSO将化合物进行5倍梯度稀释,共8个梯度的工作液。不同浓度工作液各取2μL,加入198μL培养基的稀释板中,吹打混匀。从稀释板中取10μL含有化合物的培养基,加入到前一天铺好的含有90μL细胞悬液的细胞板中,各梯度化合物终浓度为1000、200、40、8、1.6、0.32、0.064、0.0128nM。阳性对照化合物为dBET6。加入已经稀释好的化合物,每孔10μL,在37℃,5%CO
2条件下培养3天。
The disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM. Before administration, the compound was serially diluted 5-fold with DMSO, and a total of 8 gradient working solutions were used. Take 2 μL of each working solution of different concentrations, add it to the dilution plate of 198 μL medium, and mix well by pipetting. Take 10 μL of the medium containing the compound from the dilution plate and add it to the cell plate containing 90 μL of the cell suspension laid out the day before. nM. The positive control compound is dBET6. Add the diluted compound, 10 μL per well, and incubate at 37°C, 5% CO 2 for 3 days.
将细胞从培养箱中取出,30min恢复至室温。加入50μL的
Cell Viability Assay试剂,震荡混匀10min之后Envision酶标仪读板。
The cells were taken out of the incubator and returned to room temperature for 30 min. Add 50 μL of For the Cell Viability Assay reagent, shake and mix for 10 minutes and then read the plate with an Envision microplate reader.
3、数据分析3. Data analysis
本公开化合物对MV-4-11细胞的抗增殖活性通过以上的试验进行测定,根据原始数据计算每个样品孔的细胞生长抑制率。The anti-proliferation activity of the disclosed compound on MV-4-11 cells is determined by the above test, and the cell growth inhibition rate of each sample well is calculated according to the original data.
抑制率%=100%*(1-样品读数/参照平均读数)Inhibition rate % = 100% * (1 - sample reading / reference average reading)
通过GraphPad Prism 9进行数据分析处理,浓度-效应曲线采用非线性四参数曲线拟合,并计算化合物的IC
50:
The data was analyzed and processed by GraphPad Prism 9, the concentration-effect curve was fitted with a nonlinear four-parameter curve, and the IC 50 of the compound was calculated:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
其中:in:
X:Log化合物浓度;X: Log compound concentration;
Y:抑制率(%);Y: inhibition rate (%);
Bottom为最小抑制百分比;Bottom is the minimum suppression percentage;
Top为最大抑制百分比;Top is the maximum inhibition percentage;
HillSlope为曲线斜率系数。HillSlope is the slope coefficient of the curve.
本公开化合物对MV-4-11细胞的抗增殖活性如表2。Table 2 shows the antiproliferative activity of the disclosed compounds on MV-4-11 cells.
表2本公开化合物对MV-4-11细胞抗增殖活性Table 2 Compounds of the present disclosure have antiproliferative activity on MV-4-11 cells
化合物编号Compound number | IC 50(nM) IC 50 (nM) |
化合物2Compound 2 | 13.3613.36 |
化合物4Compound 4 | 15.9815.98 |
测试例3:对MV-4-11细胞内BRD4蛋白降解活性实验Test example 3: Experiment on the degradation activity of BRD4 protein in MV-4-11 cells
1、实验仪器及材料1. Experimental instruments and materials
仪器与设备Instruments and Equipment
仪器名称equipment name | 设备厂家Equipment manufacturers | 型号model |
离心机centrifuge | EppendorfEppendorf | 58005800 |
细胞计数仪cell counter | Count starCount star | IC1000IC1000 |
倒置显微镜Inverted microscope | NikonNikon | TS2TS2 |
细胞培养箱cell culture incubator | ThermoThermo | 1IVIOS 250i1IVIOS 250i |
电泳仪Electrophoresis | Bio-RadBio-Rad | 16450501645050 |
转膜仪Film transfer instrument | Bio-RadBio-Rad | Trans-Blot Turbo(1704150)Trans-Blot Turbo(1704150) |
Azure WB成像系统Azure WB imaging system | Azure biosystemsAzure biosystems | SapphireSapphire |
实验试剂与耗材Experimental reagents and consumables
2、实验步骤2. Experimental steps
(1)细胞铺板(1) Cell plating
将MV-4-11(CBP60522,科佰)的培养基去除,加入PBS润洗一遍,再加入胰酶(Trypsin-EDTA(0.25%))消化5min。消化完成后,加入10mL的完全培养基(IMDM+10%FBS),中和胰酶,吹打细胞,收集细胞,1000rpm离心5min,对细胞进行计数,将细胞密度调到500,000个/mL。取2mL细胞悬液加入到12孔板中,放入细胞培养箱中过夜培养。The culture medium of MV-4-11 (CBP60522, Kebai) was removed, rinsed with PBS, and then digested with trypsin-EDTA (0.25%) for 5 min. After the digestion is complete, add 10 mL of complete medium (IMDM+10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 1000 rpm for 5 min, count the cells, and adjust the cell density to 500,000 cells/mL. Take 2mL of cell suspension and add it to a 12-well plate, and put it in a cell culture incubator for overnight culture.
(2)细胞加药(2) Cell dosing
将本公开化合物溶解于DMSO中,母液储存浓度为10mM。将化合物母液进行梯度稀释(4倍稀释),8个浓度点,DMSO作为阴性对照组,DMSO含量为0.1%。将化合物和细胞悬液混匀后在37℃,5%CO
2条件下培养6小时。
The disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM. The compound mother solution was serially diluted (4-fold dilution), with 8 concentration points, DMSO was used as a negative control group, and the DMSO content was 0.1%. Mix the compound and cell suspension and incubate at 37°C, 5% CO 2 for 6 hours.
(3)Western Blot(3) Western Blot
给药处理6小时后,丢弃上清,用1000μL预冷PBS洗涤细胞,然后加入100μL RIPA裂解液(25mM Tris-HCl,pH=7.5,150mM NaCl,1%NP-40,1mM EDTA,pH=8.0,1mM PMSF,1mM Na
3VO
4和1x Protease Inhibitor Cocktail-P2714,Sigma),放置于冰上裂解10min。收取细胞裂解后样品于12000rpm,4℃离心30min,使用BCA试剂盒测定每个蛋白样品浓度,进行蛋白质定量。在收集的蛋白样品中加入适量5x SDS-PAGE蛋白上样缓冲液,100℃金属浴加热10min,以充分变性蛋白。将蛋白样品上样到SDS-PAGE胶加样孔内,120V恒压电泳60min。电泳结束后将胶转移到PVDF膜上使用Bio-bad转膜仪进行转膜,转膜过后根据目的蛋白大小裁剪条带,放置于5%BSA中室温封闭1h,随后分别加入BRD4(1:3000)和β-actin(1:3000)抗体,4℃孵育过夜。次日回收抗体,用PBST(含0.1%Tween-20的PBS)洗涤条带3次,每次10min。洗涤过后加入稀释好的Goat Anti-Rabbit IgG H&L(山羊抗兔二抗)(1:3000),常温孵育1h。PBST(含0.1%Tween-20的PBS)洗涤条带3次。使用SuperSignal West Atto超敏ECL发光液来检测蛋白。
After 6 hours of drug treatment, discard the supernatant, wash the cells with 1000 μL pre-cooled PBS, and then add 100 μL RIPA lysate (25 mM Tris-HCl, pH=7.5, 150 mM NaCl, 1% NP-40, 1 mM EDTA, pH=8.0 , 1mM PMSF, 1mM Na 3 VO 4 and 1x Protease Inhibitor Cocktail-P2714, Sigma), placed on ice for 10min to lyse. The samples after cell lysis were collected and centrifuged at 12,000 rpm at 4°C for 30 min, and the concentration of each protein sample was determined using a BCA kit for protein quantification. Add an appropriate amount of 5x SDS-PAGE protein loading buffer to the collected protein samples, and heat in a metal bath at 100°C for 10 minutes to fully denature the proteins. Load the protein sample into the sample hole of the SDS-PAGE gel, and electrophoresis at a constant voltage of 120V for 60min. After the electrophoresis, the gel was transferred to the PVDF membrane using a Bio-bad membrane transfer instrument. After the membrane was transferred, the bands were cut according to the size of the target protein, placed in 5% BSA for blocking at room temperature for 1 hour, and then BRD4 (1:3000 ) and β-actin (1:3000) antibodies, incubated overnight at 4°C. The antibody was recovered the next day, and the strip was washed 3 times with PBST (PBS containing 0.1% Tween-20), 10 min each time. After washing, the diluted Goat Anti-Rabbit IgG H&L (goat anti-rabbit secondary antibody) (1:3000) was added and incubated at room temperature for 1 h. The strips were washed 3 times with PBST (PBS containing 0.1% Tween-20). Use SuperSignal West Atto ultra-sensitive ECL luminescent fluid to detect protein.
3、数据分析3. Data analysis
本公开化合物对MV-4-11细胞内BRD4蛋白降解活性通过以上的试验进行测定,使用Image J软件读取目的样品条带灰度值,再根据原始数据计算每个样品孔的蛋白降解率。The compound of the present disclosure has the BRD4 protein degradation activity in MV-4-11 cells determined by the above test, using the Image J software to read the gray value of the target sample band, and then calculate the protein degradation rate of each sample well according to the original data.
降解率(%)=100%*(1-样品读数/DMSO参照读数)Degradation rate (%)=100%*(1-sample reading/DMSO reference reading)
其中:in:
所有的原始数据通过GraphPad Prism 9进行数据分析处理,浓度-效应曲线采用非线性四参数曲线拟合,并计算化合物的DC
50:
All raw data were analyzed and processed by GraphPad Prism 9, and the concentration-effect curve was fitted with a nonlinear four-parameter curve, and the DC 50 of the compound was calculated:
Y=Bottom+(Top-Bottom)/(1+10^((LogDC
50-X)*HillSlope))
Y=Bottom+(Top-Bottom)/(1+10^((LogDC 50 -X)*HillSlope))
其中:in:
X:Log化合物浓度;X: Log compound concentration;
Y:降解率(%);Y: degradation rate (%);
Bottom为最小降解百分比;Bottom is the minimum degradation percentage;
Top为最大降解百分比;Top is the maximum degradation percentage;
HillSlope为曲线斜率系数。HillSlope is the slope coefficient of the curve.
本公开化合物测得的DC
50值如表3。
Table 3 shows the measured DC 50 values of the disclosed compounds.
表3本公开化合物对BRD4蛋白降解活性Table 3 Compounds of the present disclosure have activity on BRD4 protein degradation
化合物编号Compound number | 最大降解率(%)Maximum degradation rate (%) | DC 50(nM) DC 50 (nM) |
化合物2Compound 2 | 88.1388.13 | 3.373.37 |
化合物4Compound 4 | 78.5778.57 | 6.656.65 |
测试例4:CAL51细胞抗增殖活性实验Test Example 4: Anti-proliferation activity experiment of CAL51 cells
1、实验仪器及材料1. Experimental instruments and materials
仪器与设备Instruments and Equipment
仪器名称equipment name | 型号model | 设备厂家Equipment manufacturers |
离心机centrifuge | 58005800 | EppendorfEppendorf |
细胞计数仪cell counter | IC1000IC1000 | Count starCount star |
倒置显微镜Inverted microscope | TS2TS2 | NikonNikon |
细胞培养箱cell culture incubator | 1IVIOS 250i1IVIOS 250i | ThermoThermo |
Envision酶标仪Envision microplate reader | Envision2105Envision2105 | Perkin ElmerPerkin Elmer |
实验试剂与耗材Experimental reagents and consumables
2、实验步骤2. Experimental steps
(1)细胞铺板(1) Cell plating
将靶细胞CAL51(CBP60360,科佰)的培养基去除,加入PBS润洗一遍,再加入胰酶(Trypsin-EDTA(0.25%))消化5min。消化完成后,加入10mL的完全培养基(DMEM+10%FBS),中和胰酶,吹打细胞,收集细胞,300g离心5min,计数,将细胞密度调到40,000个/mL。取90uL细胞悬液加入到96孔低吸附板中。边缘孔加入200uL的PBS。300g离心5min,使细胞聚集成球状,放入细胞培养箱中过夜。The culture medium of the target cell CAL51 (CBP60360, Kebai) was removed, washed once with PBS, and then digested with trypsin-EDTA (0.25%) for 5 min. After the digestion is complete, add 10 mL of complete medium (DMEM+10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 300 g for 5 min, count, and adjust the cell density to 40,000 cells/mL. Take 90uL of cell suspension and add it to a 96-well low adsorption plate. Add 200uL of PBS to the edge well. Centrifuge at 300g for 5min to aggregate the cells into spheres and put them in the cell culture incubator overnight.
(2)细胞加药(2) Cell dosing
将本公开化合物溶解于DMSO中,母液储存浓度为10mM。给药前,DMSO梯度10倍稀释,共6个梯度的工作液。不同浓度工作液各取2uL,加入198uL培养基的稀释板中,吹打混匀。从稀释板中取10uL含有化合物的培养基,加入到前一天铺好的含有90uL细胞悬液的细胞板中,各梯度化合物终浓度为10,000、1000、100、10、1、0.1nM。阳性对照为CC-885。加入已经稀释好的化合物,每孔10uL,离心后放入二氧化碳培养箱培养3天。The disclosed compound was dissolved in DMSO, and the stock concentration of the stock solution was 10 mM. Before administration, the DMSO gradient was diluted 10 times, and a total of 6 gradient working solutions were used. Take 2uL of each working solution of different concentrations, add it to the dilution plate of 198uL medium, and mix by pipetting. Take 10uL of the medium containing the compound from the dilution plate and add it to the cell plate containing 90uL of the cell suspension laid out the day before, and the final concentration of each gradient compound is 10,000, 1000, 100, 10, 1, 0.1nM. The positive control was CC-885. Add the diluted compound, 10uL per well, centrifuge and put it in a carbon dioxide incubator for 3 days.
将细胞从培养箱中取出,30min恢复至室温。加入50uL的
3D Cell Viability Assay试剂,震荡混匀10min之后Envision酶标仪读板。
The cells were taken out of the incubator and returned to room temperature for 30 min. Add 50uL of 3D Cell Viability Assay reagent, shake and mix for 10 minutes and then read the plate with Envision microplate reader.
3、数据分析3. Data analysis
本公开化合物对CAL51细胞的抗增殖活性通过以上的试验进行测定,根据原始数据计算每个样品孔的细胞生长抑制率。The anti-proliferation activity of the disclosed compound on CAL51 cells is determined by the above test, and the cell growth inhibition rate of each sample well is calculated according to the original data.
抑制率%=100%*(1-样品读数/参照平均读数)Inhibition rate % = 100% * (1 - sample reading / reference average reading)
通过GraphPad Prism 9进行数据分析处理,浓度-效应曲线采用非线性四参数曲线拟合,并计算化合物的IC
50:
The data was analyzed and processed by GraphPad Prism 9, the concentration-effect curve was fitted with a nonlinear four-parameter curve, and the IC 50 of the compound was calculated:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
其中:in:
X:Log化合物浓度;X: Log compound concentration;
Y:抑制率(%);Y: inhibition rate (%);
Bottom为最小抑制百分比;Bottom is the minimum suppression percentage;
Top为最大抑制百分比;Top is the maximum inhibition percentage;
HillSlope为曲线斜率系数。HillSlope is the slope coefficient of the curve.
参考WO2008027542中5.76合成方法制备化合物CC-885,其结构如下:Compound CC-885 is prepared with reference to 5.76 synthetic method in WO2008027542, and its structure is as follows:
本公开化合物对CAL51细胞的抗增殖活性如表4。Table 4 shows the antiproliferative activity of the disclosed compounds on CAL51 cells.
表4本公开化合物对CAL51细胞抗增殖活性Table 4 Compounds of the present disclosure have antiproliferative activity on CAL51 cells
化合物编号Compound number | IC 50(nM) IC 50 (nM) |
化合物3Compound 3 | 889889 |
Claims (27)
- 一种式(I)所示化合物及其药学上可接受的盐:A compound shown in formula (I) and pharmaceutically acceptable salts thereof:其中,in,Y 1、Y 2、Y 3独立地选自CR 2或N; Y 1 , Y 2 , Y 3 are independently selected from CR 2 or N;X 1选自C、CR 1a或N; X 1 is selected from C, CR 1a or N;X 2选自CR 2a、CR 2aR 2b、N或NR 2a; X 2 is selected from CR 2a , CR 2a R 2b , N or NR 2a ;X 3选自O、S、C(=O)、C(=S)、S(=O) 2、S(O)、CR 3aR 3b或NR 3a; X 3 is selected from O, S, C(=O), C(=S), S(=O) 2 , S(O), CR 3a R 3b or NR 3a ;X 4选自O、S、C(=O)、C(=S)、S(=O) 2、S(O)、CR 4aR 4b或NR 4a; X 4 is selected from O, S, C(=O), C(=S), S(=O) 2 , S(O), CR 4a R 4b or NR 4a ;R 1a、R 2a、R 2b、R 3a、R 3b、R 4a、R 4b独立地选自H、卤素、CN、OH、NH 2、-C(O)R f、-C(O)N(R f) 2、-C(O)OR f、-C(O)ON(R f) 2、-NHC(O)R f、-NHC(O)OR f、-NHC(O)N(R f) 2、-S(O) 2(R f)、C 1-C 6烷基、C 3-C 10环烷基、C 6-C 10芳基、4-10元杂环基或5-10元杂芳基,所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、C 6-C 10芳基、4-10元杂环基或5-10元杂芳基任选被R d取代; R 1a , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are independently selected from H, halogen, CN, OH, NH 2 , -C(O) Rf , -C(O)N( R f ) 2 , -C(O)OR f , -C(O)ON(R f ) 2 , -NHC(O)R f , -NHC(O)OR f , -NHC(O)N(R f ) 2 , -S(O) 2 (R f ), C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclyl or 5-10 OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl Aryl is optionally substituted by R;或R 1a、R 4a与其连接的环状基团形成碳桥环或桥杂环; Or R 1a , R 4a and the cyclic group they are connected to form a carbon bridged ring or a bridged heterocyclic ring;或R 2a、R 3a与其连接的原子共同形成环烷基或杂环基; Or R 2a , R 3a and the atoms they are connected to together form a cycloalkyl or heterocyclic group;或R 3a、R 4a与其连接的原子共同形成环烷基或杂环基; Or R 3a , R 4a and the atoms they are connected to together form a cycloalkyl or heterocyclic group;或R 2a、R 2b与其连接的原子共同形成环烷基或杂环基; Or R 2a , R 2b and the atoms they are connected to together form a cycloalkyl or heterocyclic group;或R 3a、R 3b与其连接的原子共同形成环烷基或杂环基; Or R 3a , R 3b and the atoms they are connected to together form a cycloalkyl or heterocyclic group;或R 4a、R 4b与其连接的原子共同形成环烷基或杂环基; Or R 4a , R 4b and the atoms they are connected to together form a cycloalkyl or heterocyclic group;R 1独立地选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、C 6-C 10芳基或5-10元杂芳基,所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选被R d取代; R 1 is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl or 5- 10-membered heteroaryl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered Heteroaryl is optionally substituted by R;R 2选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、C 6-C 10芳基或5-10元杂芳基,所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基、4-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选被R d取代; R 2 is selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclyl, C 6 -C 10 aryl or 5- 10-membered heteroaryl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-8 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered Heteroaryl is optionally substituted by R;每一个R d独立地选自卤素、CN、OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基; Each R d is independently selected from halogen, CN, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl;每一个R f独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-8元杂环基; Each R f is independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-8 membered heterocyclyl;n独立地选自0、1或2。n is independently selected from 0, 1 or 2.
- 根据权利要求1所述式(I)所示化合物或其药学上可接受的盐,其中:X 2选自CR 2a、CR 2aR 2b或NR 2a。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X 2 is selected from CR 2a , CR 2a R 2b or NR 2a .
- 根据权利要求1或2所述式(I)所示化合物或其药学上可接受的盐,其中:X 3选自O、C(=O)、CR 3aR 3b或NR 3a;或者,其中X 3选自C(=O)或CR 3aR 3b。 According to claim 1 or 2, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: X 3 is selected from O, C(=O), CR 3a R 3b or NR 3a ; or, wherein X 3 is selected from C(=O) or CR 3a R 3b .
- 根据权利要求1-3中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:X 4选自O、C(=O)、CR 4aR 4b或NR 4a。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein: X 4 is selected from O, C(=O), CR 4a R 4b or NR 4a .
- 根据权利要求1-4中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:R 1a、R 4a与其连接的环状基团形成碳桥环。 According to any one of claims 1-4, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1a , R 4a and the cyclic group connected to them form a carbon-bridged ring.
- 根据权利要求1-5中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:R 2a、R 3a与其连接的原子共同形成C 3-C 6环烷基。 According to any one of claims 1-5, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 2a , R 3a and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group.
- 根据权利要求1-6中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:R 3a、R 3b与其连接的原子共同形成C 3-C 6环烷基。 According to any one of claims 1-6, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 3a , R 3b and the atoms they are connected to together form a C 3 -C 6 cycloalkyl group.
- 根据权利要求1-7中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:R 1独立地选自卤素、CN、OH、NH 2或C 1-C 6烷基,所述OH、NH 2或C 1-C 6烷基任选地被R d取代。 According to any one of claims 1-7, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is independently selected from halogen, CN, OH, NH 2 or C 1 -C 6 Alkyl, the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted by R d .
- 根据权利要求1-8中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:R 2选自H、卤素、CN、OH、NH 2或C 1-C 6烷基,所述OH、NH 2或C 1-C 6烷基任选地被R d取代。 According to any one of claims 1-8, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from H, halogen, CN, OH, NH 2 or C 1 -C 6 Alkyl, the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted by R d .
- 根据权利要求1-9中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:n独立地选自0或1。The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein: n is independently selected from 0 or 1.
- 根据权利要求1-10中任一项所述式(I)所示化合物或其药学上可接受的盐,其中:式(I)所示化合物或其药学上可接受的盐选自式(I’)化合物或其药学上可接受的盐,According to the compound shown in formula (I) or its pharmaceutically acceptable salt according to any one of claims 1-10, wherein: the compound shown in formula (I) or its pharmaceutically acceptable salt is selected from formula (I) ') compound or a pharmaceutically acceptable salt thereof,其中,X 1选自CR 1a或N;X 2选自CR 2aR 2b或NR 2a; Wherein, X 1 is selected from CR 1a or N; X 2 is selected from CR 2a R 2b or NR 2a ;R 1a、R 2a、R 2b、X 3、X 4、Y 1、Y 2、Y 3、R 1、n如权利要求1-10任一项的定义。 R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , and n are as defined in any one of claims 1-10.
- 根据权利要求1所述式(I)所示化合物或其药学上可接受的盐,其中:式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐:According to claim 1, the compound shown in formula (I) or its pharmaceutically acceptable salt, wherein: the compound shown in formula (I) or its pharmaceutically acceptable salt is selected from the following compounds or its pharmaceutically acceptable salt Salt:
- 一种式(II)所示化合物及其药学上可接受的盐:A compound represented by formula (II) and a pharmaceutically acceptable salt thereof:其中,[]表示L可以与X 2、X 3、X 4、Y 1、Y 2或Y 3连接; Among them, [] indicates that L can be connected with X 2 , X 3 , X 4 , Y 1 , Y 2 or Y 3 ;X 1、X 2、X 3、X 4、Y 1、Y 2、Y 3、R 1、n如权利要求1的定义; X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n are as defined in claim 1;当L与Y 1,Y 2或Y 3连接时,Y 1、Y 2或Y 3为C,当L与X 2连接时,X 2为C、CR 2a或N,当L与X 3连接时,X 3为CR 3a或N,当L与X 4连接时,X 3为CR 4a或N; When L is connected with Y 1 , Y 2 or Y 3 , Y 1 , Y 2 or Y 3 is C, when L is connected with X 2 , X 2 is C, CR 2a or N, when L is connected with X 3 , X 3 is CR 3a or N, when L is connected with X 4 , X 3 is CR 4a or N;L选自以下结构单元:L is selected from the following structural units:-(A L) k-; -(A L ) k -;A L独立地选自键、-O-、-S-、-SO-、-SO 2-、-SO 2NR 10-、-C(R 10) 2-、-(CH 2) q-、-(O-CH 2-CH 2) q-、-NR 10-、-NR 10C(=O)-、-C(=O)-、-C(=S)-、-O-C(=O)-、-OC(O)NR 10-、-C(O)ONR 10-、-CR 10= CR 10-、-C≡C-、-P(O)R 10-、-P(O)OR 10-、 C 3-C 10环烷基、4-10元杂环基、C 6-C 10芳基或5-10元杂芳基,所述C 3-C 10环烷基、4-10元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被R 11取代; AL is independently selected from bond, -O-, -S-, -SO-, -SO 2 -, -SO 2 NR 10 -, -C(R 10 ) 2 -, -(CH 2 ) q -, - (O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, -C(=S)-, -OC(=O)- , -OC(O)NR 10 -, -C(O)ONR 10 -, -CR 10 = CR 10 -, -C≡C-, -P(O)R 10 -, -P(O)OR 10 - , C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered heteroaryl, said C 3 -C 10 cycloalkyl, 4-10 membered heterocyclic Base, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by R 11 ;R 10选自H、OH、NH 2或C 1-C 6烷基; R 10 is selected from H, OH, NH 2 or C 1 -C 6 alkyl;R 11选自卤素、CN、OH、NH 2或C 1-C 6烷基; R 11 is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl;k选自1、2、3、4、5、6、7、8、9或10;k is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;q选自0、1、2、3、4、5或6。q is selected from 0, 1, 2, 3, 4, 5 or 6.
- 根据权利要求13所述式(II)所示化合物或其药学上可接受的盐,其中:A L独立地选自键、-O-、-S-、-C(R 10) 2-、-(CH 2) q-、-(O-CH 2-CH 2) q-、-NR 10-、-NR 10C(=O)-、-C(=O)-、C 3-C 10环烷基、4-10元杂环基、C 6-C 10芳基或5-10元杂芳基,所述C 3-C 10环烷基、4-10元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被R 11取代; According to claim 13, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein: AL is independently selected from bond, -O-, -S-, -C(R 10 ) 2 -, - (CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C(=O)-, C 3 -C 10 cycloalkane base, 4-10 membered heterocyclic group, C 6 -C 10 aryl group or 5-10 membered heteroaryl group, the C 3 -C 10 cycloalkyl group, 4-10 membered heterocyclic group, C 6 -C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by R 11 ;或者,A L独立地选自键、-O-、-C(R 10) 2-、-(CH 2) q-、-(O-CH 2-CH 2) q-、-NR 10-、-NR 10C(=O)-、-C(=O)-、5-6元杂环基或5-6元杂芳基,所述5-6元杂环基或5-6元杂芳基任选地被R 11取代; Alternatively, AL is independently selected from a bond, -O-, -C(R 10 ) 2 -, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, - NR 10 C(=O)-, -C(=O)-, 5-6 membered heterocyclic group or 5-6 membered heteroaryl group, the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group optionally substituted by R 11 ;或者,A L独立地选自键、-O-、-C(R 10) 2-、-(CH 2) q-、-(O-CH 2-CH 2) q-、-NR 10-、-NR 10C(=O)-、-C(=O)-、哌嗪基或三唑基; Alternatively, AL is independently selected from a bond, -O-, -C(R 10 ) 2 -, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, - NR 10 C(=O)-, -C(=O)-, piperazinyl or triazolyl;或者,A L独立地选自-O-、-(CH 2) q-、-(O-CH 2-CH 2) q-、-NR 10-、-NR 10C(=O)-、-C(=O)-、C 3-C 10环烷基、5-6元杂环基、5-6元杂芳基或C 6-C 10芳基,所述C 3-C 10环烷基、5-6元杂环基、5-6元杂芳基或C 6-C 10芳基任选地被R 11取代。 Alternatively, AL is independently selected from -O-, -(CH 2 ) q -, -(O-CH 2 -CH 2 ) q -, -NR 10 -, -NR 10 C(=O)-, -C (=O)-, C 3 -C 10 cycloalkyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl or C 6 -C 10 aryl, said C 3 -C 10 cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl or C 6 -C 10 aryl is optionally substituted by R 11 .
- 根据权利要求13或14所述式(II)所示化合物或其药学上可接受的盐,其中:L选自以下结构单元:According to the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to claim 13 or 14, wherein: L is selected from the following structural units:-NR 10-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;-NR 10-(CH 2) q-(CH 2) q-NHC(=O)-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;-NR 10-(CH 2) q-(5-10杂芳基)-(CH2) q-C(=O)NH-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(5-10 heteroaryl)-(CH2) q -C(=O)NH-(CH 2 ) q -O-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-(CH 2) q-NR 10-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NR 10 -;-(O-CH 2-CH 2) q-(5-10杂芳基)-(CH 2) q-O-; -(O-CH 2 -CH 2 ) q -(5-10 heteroaryl)-(CH 2 ) q -O-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;-NR 10-(CH 2) q-(5-10杂芳基)-(CH 2) q-O-(CH 2) q-C(=O)-(CH 2) q-NR 10-; -NR 10 -(CH 2 ) q -(5-10heteroaryl)-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -NR 10 -;-NR 10-(CH 2) q-(CH 2) q-NHC(=O)-; -NR 10 -(CH 2 ) q -(CH 2 ) q -NHC(=O)-;-NR 10-(CH 2) q-(5-10杂芳基)-(CH 2) q-NR 10-; -NR 10 -(CH 2 ) q -(5-10 heteroaryl)-(CH 2 ) q -NR 10 -;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-NR 10-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NR 10 -;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-O-(CH 2) q-C(=O)-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-(CH 2 ) q -C(=O)-;-NR 10-(CH 2) q-(5-10杂芳基)-(CH 2) q-O-(CH 2) q-C(=O)-(CH 2) q-; -NR 10 -(CH 2 ) q -(5-10heteroaryl)-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -;-(4-10元杂环基)-C(=O)-(CH 2) q-C(=O)NH-(CH 2) q-NR 10-; -(4-10 membered heterocyclyl)-C(=O)-(CH 2 ) q -C(=O)NH-(CH 2 ) q -NR 10 -;-(5-10杂芳基)-C(=O)-(CH 2) q-C(=O)NH-(CH 2) q-NR 10-; -(5-10 Heteroaryl)-C(=O)-(CH 2 ) q -C(=O)NH-(CH 2 ) q -NR 10 -;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-O-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -;-O-(CH 2) q-(5-10杂芳基)-C(=O)-; -O-(CH 2 ) q -(5-10 heteroaryl)-C(=O)-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-(CH 2) q-NR 10-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NR 10 -;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;-O-(CH 2) q-(CH 2) q-; -O-(CH 2 ) q -(CH 2 ) q -;-NR 10-(CH 2) q-(CH 2) q-; -NR 10 -(CH 2 ) q -(CH 2 ) q -;-NR 10-(CH 2) q-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(CH 2 ) q -O-;-NR 10-(CH 2) q-(CH 2) q-NR 10-; -NR 10 -(CH 2 ) q -(CH 2 ) q -NR 10 -;-O-(CH 2) q-(CH 2) q-O-; -O-(CH 2 ) q -(CH 2 ) q -O-;-O-(CH 2) q-(O-CH 2-CH 2) q-O-; -O-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-O-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-O-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;-NR 10-(CH 2) q-(O-CH 2-CH 2) q-(CH 2) q-C(=O)-(CH 2) q-NHC(=O)-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(O-CH 2 -CH 2 ) q -(CH 2 ) q -C(=O)-(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;-NR 10-(CH 2) q-(4-10元杂环基)-(CH 2) q-NR 10-; -NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -NR 10 -;-NR 10-(CH 2) q-(4-10元杂环基)-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -O-;-NR 10-(CH 2) q-(4-10元杂环基)-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -O-;-NR 10-(CH 2) q-(4-10元杂环基)-(CH 2) q-(CH 2) q-O-; -NR 10 -(CH 2 ) q -(4-10 membered heterocyclyl)-(CH 2 ) q -(CH 2 ) q -O-;-O-C(=O)-(C 3-C 10环烷基)-(CH 2) q-O-; -OC(=O)-(C 3 -C 10 cycloalkyl)-(CH 2 ) q -O-;-O-C(=O)-(C 3-C 10环烷基)-(CH 2) q-NH-; -OC(=O)-(C 3 -C 10 cycloalkyl)-(CH 2 ) q -NH-;-O-C(=O)-(C 3-C 10环烷基)-(CH 2) q-; -OC(=O)-(C 3 -C 10 cycloalkyl)-(CH 2 ) q -;-(CH 2) q-NHC(=O)-NH-(C 6-C 10芳基)-; -(CH 2 ) q -NHC(=O)-NH-(C 6 -C 10 aryl)-;-NR 10-(CH 2) q-(CH 2) q-C(=O)-; -NR 10 -(CH 2 ) q -(CH 2 ) q -C(=O)-;-NR 10-(CH 2) q-C(=O)NH-(CH 2) q-; -NR 10 -(CH 2 ) q -C(=O)NH-(CH 2 ) q -;所述C 3-C 10环烷基、C 6-C 10芳基、5-10杂芳基或4-10元杂环基任选地被R 11取代, The C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5-10 heteroaryl or 4-10 membered heterocyclic group is optionally substituted by R 11 ,q如权利要求13或14的定义。q is as defined in claim 13 or 14.
- 根据权利要求13-15中任一项所述式(II)所示化合物或其药学上可接受的盐,其中:L选自以下结构单元:According to the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 13-15, wherein: L is selected from the following structural units:-NH-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-(CH 2) q-O-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;-NH-(CH 2) q-(CH 2) q-NHC(=O)-(CH 2) q-O-; -NH-(CH 2 ) q -(CH 2 ) q -NHC(=O)-(CH 2 ) q -O-;-NH-(CH 2) q-三唑基-(CH 2) q-C(=O)NH-(CH 2) q-O-; -NH-(CH 2 ) q -triazolyl-(CH 2 ) q -C(=O)NH-(CH 2 ) q -O-;-NH-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-(CH 2) q-NH-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NH-;-(O-CH 2-CH 2) q-三唑基-(CH 2) q-O-; -(O-CH 2 -CH 2 ) q -triazolyl-(CH 2 ) q -O-;-O-(CH 2) q-(CH 2) q-O-; -O-(CH 2 ) q -(CH 2 ) q -O-;-NH-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;-NH-(CH 2) q-三唑基-(CH 2) q-O-(CH 2) q-C(=O)-(CH 2) q-NH-; -NH-(CH 2 ) q -triazolyl-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -NH-;-NH-(CH 2) q-(CH 2) q-NHC(=O)-; -NH-(CH 2 ) q -(CH 2 ) q -NHC(=O)-;-O-(CH 2) q-(CH 2) q-; -O-(CH 2 ) q -(CH 2 ) q -;-NH-(CH 2) q-三唑基-(CH 2) q-NH-; -NH-(CH 2 ) q -triazolyl-(CH 2 ) q -NH-;-NH-(CH 2) q-(O-CH 2-CH 2) q-NH-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NH-;-NH-(CH 2) q-(O-CH 2-CH 2) q-O-(CH 2) q-C(=O)-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-(CH 2 ) q -C(=O)-;-NH-(CH 2) q-三唑基-(CH 2) q-O-(CH 2) q-C(=O)-(CH 2) q-; -NH-(CH 2 ) q -triazolyl-(CH 2 ) q -O-(CH 2 ) q -C(=O)-(CH 2 ) q -;-哌嗪基-C(=O)-(CH 2) q-C(=O)NH-(CH 2) q-NH-; -piperazinyl-C(=O)-( CH2 ) q -C(=O)NH-( CH2 ) q -NH-;-NH-(CH 2) q-(O-CH 2-CH 2) q-O-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -O-;-NH-(CH 2) q-(O-CH 2-CH 2) q-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -;-O-(CH 2) q-三唑基-C(=O)-; -O-(CH 2 ) q -triazolyl-C(=O)-;-NH-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-(CH 2) q-NH-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-(CH 2 ) q -NH-;-NH-(CH 2) q-(O-CH 2-CH 2) q-NHC(=O)-; -NH-(CH 2 ) q -(O-CH 2 -CH 2 ) q -NHC(=O)-;-O-C(=O)-环己基-(CH 2) q-O-; -OC(=O)-cyclohexyl-( CH2 ) q -O-;-O-C(=O)-环己基-(CH 2) q-NH-; -OC(=O)-cyclohexyl-( CH2 ) q -NH-;-O-C(=O)-环己基-(CH 2) q-; -OC(=O)-cyclohexyl-(CH 2 ) q -;-苯基-NHC(=O)-NH-(CH 2) q-; -Phenyl-NHC(=O)-NH-(CH 2 ) q -;-NH-(CH 2) q-(CH 2) q-C(=O)-; -NH-(CH 2 ) q -(CH 2 ) q -C(=O)-;-NH-(CH 2) q-C(=O)NH-(CH 2) q-; -NH-(CH 2 ) q -C(=O)NH-(CH 2 ) q -;所述三唑基、哌嗪基、环己基或苯基任选地被R 11取代, The triazolyl, piperazinyl, cyclohexyl or phenyl is optionally substituted by R,q如权利要求13-15任一项的定义。q is as defined in any one of claims 13-15.
- 根据权利要求13-16中任一项所述式(II)所示化合物或其药学上可接受的盐,其中:k 选自1、2、3、4、5、6、7、8或9。The compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 13-16, wherein: k is selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9 .
- 根据权利要求13-17中任一项所述式(II)所示化合物或其药学上可接受的盐,其中:式(II)所示化合物或其药学上可接受的盐选自式(II’)化合物或其药学上可接受的盐,According to any one of claims 13-17, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein: the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from the group consisting of formula (II) ') compound or a pharmaceutically acceptable salt thereof,其中,X 1选自CR 1a或N;X 2选自CR 2aR 2b或NR 2a; Wherein, X 1 is selected from CR 1a or N; X 2 is selected from CR 2a R 2b or NR 2a ;R 1a、R 2a、R 2b、X 3、X 4、Y 1、Y 2、Y 3、R 1、n、L、[]如权利要求13-17任一项的定义。 R 1a , R 2a , R 2b , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , n, L, [] are as defined in any one of claims 13-17.
- 根据权利要求13所述式(II)所示化合物或其药学上可接受的盐,其中:式(II)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐:According to claim 13, the compound shown in formula (II) or its pharmaceutically acceptable salt, wherein: the compound shown in formula (II) or its pharmaceutically acceptable salt is selected from the following compounds or its pharmaceutically acceptable salt Salt:
- 一种药物组合物,所述药物组合物包含权利要求1-19任一项式(I)或式(II)所示化合物或其药学上可接受的盐,以及药学上可接受的辅料。A pharmaceutical composition, which comprises the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, and pharmaceutically acceptable auxiliary materials.
- 权利要求1-19中任一项式(I)或(II)所示化合物或其药学上可接受的盐,或权利要求20 所述药物组合物在制备预防或者治疗与CRBN介导的相关疾病的药物中的用途。The compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof in any one of claims 1-19, or the pharmaceutical composition of claim 20 is used in the preparation of prevention or treatment of related diseases mediated by CRBN use in medicines.
- 权利要求1-19中任一项式(I)或(II)所示化合物或其药学上可接受的盐,作为靶向蛋白降解的双功能化合物的合成中间体,在制备靶向蛋白降解的双功能化合物的用途。The compound shown in any one of claims 1-19 formula (I) or (II) or a pharmaceutically acceptable salt thereof, as the synthetic intermediate of the bifunctional compound targeting protein degradation, in the preparation of targeting protein degradation Use of bifunctional compounds.
- 一种式(III)所示化合物及其药学上可接受的盐:A compound represented by formula (III) and pharmaceutically acceptable salts thereof:其中,[]、X 1、X 2、X 3、X 4、Y 1、Y 2、Y 3、R 1、L、n如权利要求13-17任一项的定义; Wherein, [], X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , R 1 , L, n are as defined in any one of claims 13-17;所述PTM是靶向蛋白结合部分。The PTM is a targeting protein binding moiety.
- 根据权利要求23所述式(III)所示化合物或其药学上可接受的盐,其中:PTM选自以下靶向蛋白的结合部分:ALK,AR,BET1,BRAF,BRCA2,BRD4,BRD9,BTK,CBL,CCNE1,CCNE2,CCR4,CCR7,CCR9,CD47,CLDN18,CYP,DDR1,DMPK,EGFR,ERBB2,ERBB3,ERBB4,FGFR1,FGFR2,FGFR3,FGFR4,GSPT1,JAK1,JAK3,KIF18A,KRAS,LCK,MET,NTRK1,NTRK2,NTRK3,PCSK9,PKMYT1,PARP7,PARP14,RAD51,RBM10,RET,RORA,STAT3,SOS1,TYK2,USP1或USP14。According to claim 23, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein: PTM is selected from the following binding parts of targeting proteins: ALK, AR, BET1, BRAF, BRCA2, BRD4, BRD9, BTK , CBL, CCNE1, CCNE2, CCR4, CCR7, CCR9, CD47, CLDN18, CYP, DDR1, DMPK, EGFR, ERBB2, ERBB3, ERBB4, FGFR1, FGFR2, FGFR3, FGFR4, GSPT1, JAK1, JAK3, KIF18A, KRAS, LCK , MET, NTRK1, NTRK2, NTRK3, PCSK9, PKMYT1, PARP7, PARP14, RAD51, RBM10, RET, RORA, STAT3, SOS1, TYK2, USP1 or USP14.
- 根据权利要求23所述式(III)所示化合物或其药学上可接受的盐,其中:式(III)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐:According to claim 23, the compound represented by formula (III) or its pharmaceutically acceptable salt, wherein: the compound represented by formula (III) or its pharmaceutically acceptable salt is selected from the following compounds or its pharmaceutically acceptable salt Salt:
- 一种药物组合物,所述药物组合物包含权利要求23-25中任一项所述的式(III)所示化合物或其药学上可接受的盐,以及药学上可接受的辅料。A pharmaceutical composition, comprising the compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 23-25, and pharmaceutically acceptable auxiliary materials.
- 权利要求1-19任一项式(I)或(II)所示化合物或其药学上可接受的盐,或权利要求20所述的药物组合物,或者权利要求23-25中任一项所述式(III)所示化合物或其药学上可接受的盐,或权利要求26所述的药物组合物在制备预防或者治疗异常细胞增殖疾病的药物中的用途。The compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, or the pharmaceutical composition described in claim 20, or the pharmaceutical composition described in any one of claims 23-25 Use of the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26 in the preparation of medicines for preventing or treating abnormal cell proliferation diseases.
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CN101578277A (en) * | 2006-08-30 | 2009-11-11 | 细胞基因公司 | 5-substituted isoindoline compounds |
CN102112463A (en) * | 2008-05-30 | 2011-06-29 | 细胞基因公司 | 5-substituted isoindoline compounds |
WO2020210630A1 (en) * | 2019-04-12 | 2020-10-15 | C4 Therapeutics, Inc. | Tricyclic degraders of ikaros and aiolos |
WO2021127586A1 (en) * | 2019-12-20 | 2021-06-24 | Calico Life Sciences Llc | Protein tyrosine phosphatase degraders and methods of use thereof |
WO2022081925A1 (en) * | 2020-10-14 | 2022-04-21 | C4 Therapeutics, Inc. | Tricyclic ligands for degradation of ikzf2 or ikzf4 |
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CN101578277A (en) * | 2006-08-30 | 2009-11-11 | 细胞基因公司 | 5-substituted isoindoline compounds |
CN102112463A (en) * | 2008-05-30 | 2011-06-29 | 细胞基因公司 | 5-substituted isoindoline compounds |
WO2020210630A1 (en) * | 2019-04-12 | 2020-10-15 | C4 Therapeutics, Inc. | Tricyclic degraders of ikaros and aiolos |
WO2021127586A1 (en) * | 2019-12-20 | 2021-06-24 | Calico Life Sciences Llc | Protein tyrosine phosphatase degraders and methods of use thereof |
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