CN116789636A - Bifunctional compound, preparation method, pharmaceutical composition and application thereof - Google Patents

Bifunctional compound, preparation method, pharmaceutical composition and application thereof Download PDF

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Publication number
CN116789636A
CN116789636A CN202210249285.7A CN202210249285A CN116789636A CN 116789636 A CN116789636 A CN 116789636A CN 202210249285 A CN202210249285 A CN 202210249285A CN 116789636 A CN116789636 A CN 116789636A
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fluoro
dihydro
inden
hydroxy
methylsulfonyl
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Inventor
尹大伟
孙效华
杨阳
邹方亮
赵宋强
周小军
米桢
杨津兰
吴俊燏
陈平运
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Beijing Konruns Pharmaceutical Co Ltd
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Beijing Konruns Pharmaceutical Co Ltd
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Abstract

The application relates to a bifunctional compound, a preparation method thereof, a pharmaceutical composition and application thereof, wherein the compound has the following general formula:

Description

Bifunctional compound, preparation method, pharmaceutical composition and application thereof
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a difunctional compound, a preparation method, a pharmaceutical composition and application thereof.
Background
Renal cell carcinoma (Renal Cell Carcinoma, RCC) is the second leading cause of mortality in urinary system cancers, and metastasis and chemotherapy resistance are the main features of renal cell carcinoma. 85% of patients with renal cell carcinoma are clear cell renal cell carcinoma (clear cell Renal Cell Carcinoma, ccRCC). Molecular biology studies indicate that 90% of clear cell renal cell carcinoma has an inactivation of the VHL gene, which is considered to be a driver of clear cell renal cell carcinoma. The VHL protein is a constituent of the E3 ubiquitin ligase complex, which is capable of recognizing and ubiquitinating hypoxia inducible factor 1α (Hypoxia Inducible Factors 1α, HIF-1α) and hypoxia inducible factor 2α (Hypoxia Inducible Factors 2α, HIF-2α) and is further degraded by the proteasome. Studies have shown that VHL gene inactivation increases HIF-2. Alpha. Expression in clear cell kidney cell carcinoma cells, HIF-2. Alpha. Being a transcription factor, increased expression of which results in increased expression of downstream regulated genes, e.g., increased expression and secretion of VEGFA, thereby promoting angiogenesis; increasing the expression of cyclin (CCDN 1), promoting cell proliferation; increasing the expression of glucose transporter, and thus enhancing the metabolism of cells, etc., and the above results may promote the growth, metastasis, etc. of tumors. In addition to renal cell carcinoma, studies have shown that up-regulation of HIF-2 alpha expression in liver cancer, breast cancer and colorectal cancer due to hypoxia in tumor tissue also contributes to the development and progression of cancer.
Because HIF-2α is a transcription factor, and does not have an endogenous small molecule ligand bound thereto, HIF-2α is considered a difficult target for patent. In 2009, scientists research and find that a cavity with a certain size exists in the protein, small molecules can be combined, and a compound with a certain inhibition activity is obtained through screening of a compound library, but the compound is difficult to prepare medicine due to insufficient affinity.
Disclosure of Invention
The application aims to overcome the defects, and provides a difunctional compound, a preparation method, a pharmaceutical composition and application thereof, wherein the difunctional compound can solve the problem that hypoxia inducible factor 2 alpha is difficult to prepare, thereby being used for treating diseases related to high HIF-2 alpha expression.
In a first aspect, embodiments of the present application provide bifunctional compounds having the general formula:
in the above formula: the L is a linker;
the R is 1 Selected from halogen, -NO 2 、-CN、-S(O) 2 R a 、-S(O)R a and-P (O) R b R c Any one of Ra, R b And R is c Each independently selected from any one of C1-C6 alkyl and C1-C6 haloalkyl;
the R is 2 And R is 3 Each independently selected from any one of H, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl;
said X is selected from the group consisting of-C (O) -and-CH 2 -any one of the following;
the R is 4 Selected from any one of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.
With reference to the first aspect, the linker L has the following general formula (ii):
the L is 1 By passing throughAnd R is R 1 Covalently linked to the benzene ring, said L 4 By->And R is R 4 Covalently linking the linked benzene rings;
said L1 is absent or selected from-NR d -、-O-、-S-、-NHCH 2 -、-NH(CH 2 ) q C (O) -and-OC (O) -wherein q is an integer of 0 to 6, and R d Any one selected from H, C-C3 alkyl and C1-C3 haloalkyl;
the L is 2 And/or L 3 Absent or selected from- (CH) 2 ) m -、-NR e -、-(CH 2 CH 2 O) n -、-(NH) o (CH 2 ) p C (O) -and-C (O) (CH 2 ) p (NH) o -any one of the above, wherein m is an integer from 0 to 12, n is an integer from 0 to 6, o is 0 or 1, p is an integer from 0 to 6, R e Any one selected from H, C-C3 alkyl and C1-C3 haloalkyl;
the L is 4 Absent or selected from-O-, -S-and-NR f -any one of said R f Any one selected from H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy;
the A, B and C are each independently selected from any one of absent, C3-C7 cycloalkyl, 5-to 7-membered heterocyclyl containing 1-3 atoms independently selected from O, N and S atoms, C5-C10 aryl, and 5-to 10-membered heteroaryl containing 1-3 atoms independently selected from O, N and S atoms.
In a second aspect, the present application discloses a pharmaceutical composition comprising a bifunctional compound of the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug or solvate thereof, and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.
In a third aspect, the application discloses the use of a bifunctional compound according to the first or second aspect for the preparation of a medicament for tumour or cancer.
Compared with the prior art, the technical scheme has at least the following technical effects:
the compound comprises a part combined with HIF-2 alpha protein and a part combined with E3 ubiquitin ligase CRBN through a linker L coupling or connecting, wherein the left part of L is a small molecule part combined with the HIF-2 alpha protein, and the right part of L is a small molecule ligand combined with ubiquitin ligase.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application as claimed.
Detailed Description
In order to better understand the technical solution of the present application, the following detailed description of the embodiments of the present application is provided with reference to the specific embodiments.
It should be understood that the described embodiments are merely some, but not all, embodiments of the application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
The terminology used in the embodiments of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
It should be understood that the term "and/or" as used herein is merely one relationship describing the association of the associated objects, meaning that there may be three relationships, e.g., a and/or B, may represent: a exists alone, A and B exist together, and B exists alone. In addition, the character "/" herein generally indicates that the front and rear associated objects are an "or" relationship.
It should be noted that the "halogen" described in the embodiments of the present invention means F, cl, br, I, at.
"C1-C6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms, which may be straight or branched, for example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like. Wherein the hydrogen atom on the C1-6 alkyl carbon may be further substituted with a specified substituent.
"C1-C6 haloalkyl" refers to an alkyl chain having 1 to 6 carbon atoms, which may be straight or branched, for example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., wherein a hydrogen atom on an alkyl carbon is substituted with at least one halogen atom.
"C1-C6 alkoxy" refers to an alkyl chain having 1 to 6 carbon atoms, which may be straight or branched, and which is attached to the position through an oxygen atom.
"C3-C7 cycloalkyl" refers to cycloalkyl chains having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The hydrogen atom on the carbon atom in the cycloalkyl group may be substituted with a prescribed substituent.
"heterocyclyl" means a mono-or bicyclic group having 1 to 3 carbon-carbon single bonds independently selected from the group consisting of oxygen, nitrogen and sulfur atoms; the hydrogen atom on the carbon may be substituted with halogen, C1-C3 alkyl, C1-C3 alkoxy or the like.
"aryl" means an aromatic monocyclic or bicyclic ring having all carbon atoms, such as benzene rings, naphthalene rings, wherein the hydrogen atom may be substituted with halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and the like.
"heteroaryl" means an aromatic monocyclic or bicyclic ring having at least one heteroatom, such as quinolinyl, isoquinolinyl, pyridinyl, furanyl, thiophenyl, pyrrolyl, and the like; the hydrogen atom on the ring may be substituted with halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or the like;
"haloalkoxy" refers to a haloalkyl chain having 1 to 3 carbon atoms, which may be straight or branched, and which is attached to said position through an oxygen atom;
"C1-C3 alkanoyl" means MeC (O) -, etC (O) -, CH 3 CH 2 CH 2 C(O)-，(CH 3 ) 2 CHC(O)-；
"C1-C3 alkylsulfonyl" means MeS (O) 2 -，EtS(O) 2 -，CH 3 CH 2 CH 2 S(O) 2 -，(CH 3 ) 2 CHS(O) 2 -；
The term "prodrug" refers to derivatives that are converted to the compounds of the present invention under physiological conditions by enzymatic oxidation, reduction, hydrolysis, and the like in vivo.
The term "isotopic derivative" means a compound comprising the structure of the present invention comprising one or more isotopic atoms in non-natural proportions. Such as deuterium (2H or D), carbon-13 (13C) and nitrogen-15 (15N).
The term "solvate" refers to a form of a solvent complex formed by the physical association of a compound of the present application with a solvent molecule. The physical bonding comprises hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, tetrahydrofuran, ethyl acetate, acetonitrile, and the like. The compounds of the present application may be prepared in crystalline form and may be in the form of solvates (including hydrate forms).
The term "pharmaceutically acceptable salt" comprises one or more basic or acidic groups, in particular pharmaceutically usable salts thereof. Such as alkali metal salts, alkaline earth metal salts, ammonium salts. More precisely, it may be a sodium salt, potassium salt, calcium salt, magnesium salt or an organic amine such as ethylamine, ethanolamine, triethylamine or an amino acid salt. The compounds of the present application may form protonated compounds of formula (I) with inorganic or organic acids, examples of which include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, tartaric acid, and the like, as well as other acids known to those skilled in the art.
HIF-2 alpha is a transcription factor, and does not have an endogenous small molecule ligand bound thereto, and therefore HIF-2 alpha is considered as a target site for difficult patent medicine. At present, no medicine for degrading HIF-2 alpha protein by constructing a bifunctional compound is marketed.
Accordingly, the present application provides a bifunctional compound having the following general formula (I):
in the above formula: l is a linker.
R 1 Selected from halogen, -NO 2 、-CN、-S(O) 2 R a 、-S(O)R a and-P (O) R b R c Any one of, wherein R a ,R b And R is c Each independently selected from any one of C1-C6 alkyl and C1-C6 haloalkyl.
R 2 And R is 3 Each independently selected from any one of H, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl.
X is selected from the group consisting of-C (O) -and-CH 2 -any one of the following.
R 4 Selected from any one of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.
In the above technical scheme, the compound of the application comprises a part which is coupled or connected through a linker L and binds to HIF-2 alpha protein and a part which binds to E3 ubiquitin ligase CRBN, wherein the left part of L is a small molecule part which binds to HIF-2 alpha protein, and the right part of L is a small molecule ligand which binds to ubiquitin ligase.
The ubiquitination of proteins is performed under the synergistic action of Ubiquitin activating enzyme (Ubiquitin activating enzyme) E1, ubiquitin binding enzyme (Ubiquitin conjugating enzyme) E2 and E3 Ubiquitin ligase (Ubiquitin ligase). First, ubiquitin is linked to ubiquitin in an activated state on E1 through the carboxyl group on its C-terminal glycine and the necessary cysteine sulfhydryl group on ubiquitin activating enzyme E1 to form a high energy thioester bond; second, the activated ubiquitin is transferred from ubiquitin activating enzyme E1 to ubiquitin binding enzyme E2; finally, under the action of E3 ubiquitin ligase, ubiquitin molecules connected to ubiquitin conjugated enzyme E2 are connected to HIF-2 alpha protein through covalent connection mode of isopeptide bond, and after the HIF-2 alpha protein is ubiquitinated, the protein is degraded in a proteasome.
The right part of formula I is the part that is linked to the E3 ubiquitin ligase CRBN, specifically, the right part of formula I is the ligand that can bind to the CRBN gene, CRBN is a part of the E3 ubiquitin ligase and acts as a substrate receptor (substrate receptor, SRs) to recognize the substrate protein and thereby initiate the degradation process, the right part of formula I has a hexacyclic piperidine dione structure that can bind to the E3 ubiquitin ligase in a manner that is generally non-covalent linkage, while the left part of L contains a structural fragment of a HIF-2 alpha small molecule inhibitor that can recognize the HIF-2 alpha protein and that interacts with the HIF-2 alpha protein such that the HIF-2 alpha protein approaches the E3 ubiquitin ligase protein and thereby promotes degradation of the HIF-2 alpha protein.
In some embodiments, preferably, R a Selecting any one of methyl and halogenated methyl. The halomethyl group may be CH, for example 3 F、CH 3 Cl、 CH 3 Br、CH 3 I and CH 3 At, etc.
In some embodiments, preferably, R2 and/or R3 are each independently selected from any one of H and halogen.
In some embodiments, the L linker has the following formula II:
wherein: l (L) 1 By passing throughAnd R in formula I 1 Covalently linked to the benzene ring, L 4 By->And R in formula I 4 The attached benzene rings are covalently linked. Specifically, linker L passes adjacent to L 1 Is->And R is R 1 Covalently binding the para-position of linker L through proximity L 4 Is->Covalent bonding is carried out in the ortho or meta position to the C atom to which X is attached.
L 1 Absent or selected from: -NR d -、-O-、-S-、-NHCH 2 -、-NH(CH 2 ) q C (O) -, -OC (O) -, wherein q is an integer of 0 to 6, R d Selected from any one of H, C-C3 alkyl and C1-C3 haloalkyl.
L 2 And/or L 3 Absent or selected from- (CH) 2 ) m -、-NR e -、-(CH 2 CH 2 O) n -、-(NH) o (CH 2 ) p C (O) -and-C (O) (CH 2 ) p (NH) o -any one of the following; wherein m is an integer of 0 to 12, n is an integer of 0 to 6, o is 0 or 1, p is an integer of 0 to 6, R e Selected from any one of H, C-C3 alkyl and C1-C3 haloalkyl.
L 4 Absent or selected from-O-, -S-and-NR f -any one of the following; wherein R is f Any one selected from H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
A. B and C are each independently selected from any one of absent, C3-C7 cycloalkyl, 5-to 7-membered heterocyclyl containing 1-3 atoms independently selected from O, N and S, C5-C10 aryl, and 5-to 10-membered heteroaryl containing 1-3 atoms independently selected from O, N and S. Preferably:
a is absent or selected from any one of the following groups:
wherein Z is selected from the group consisting of-N-and-CH 2 -any one of which, a, represents a bond to the group adjacent to the left of the group A in formula (II), and β represents a bond to the group adjacent to the right of the group A in formula (II), if L 1 And L 2 Are all present, then alpha represents and L 1 Covalently linked, β represents a bond with L 2 Covalent bond connection.
B is absent or selected from any one of the following groups:
wherein gamma represents the connection to the group adjacent to the left of the B group in formula (II), delta represents the connection to the group adjacent to the right of the B group in formula (II), if L 2 And L 3 Are all present, gamma represents a group corresponding to L 2 Through covalent linkage, delta represents and is connected with L 3 Through covalent bonds.
C is absent or selected from any one of the following groups:
wherein L is 5 Absent or selected from-CH 2 -、-O-、-NR g -, -C (O) -and-O (CH) 2 ) r C (O) -wherein r is an integer of 0 to 6; r is R g Selected from any one of H, C-C3 alkyl, C1-C3 alkanoyl and C1-C3 alkylsulfonyl.
R 5 Selected from any one of H, deuterium, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.
R 6 Selected from H, -CN, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and-NR h -any one of the following. Wherein R is h Selected from any one of H and C1-C3 alkyl.
Pi represents a bond to the group adjacent to the left of the C group in formula (II), and θ represents a bond to the group adjacent to the right of the C group in formula (II), specifically, if L 3 And L 4 Are all present, then pi represents and L 3 Through covalent bond connection, θ represents and L 4 Through covalent bonds.
The linker L connects two parts of the bifunctional molecule, can form a ternary complex of HIF-2 alpha protein, small molecules and E3 ubiquitin ligase, and simultaneously, the linker L has certain flexibility, can regulate the conformation of the ternary complex, so that the E3 ubiquitin ligase can catalyze the ubiquitination of substrate protein, and in addition, the linker L can influence the physicochemical property of the whole molecule, so that the ligand has better drug property. The linker L can pull the distance between the HIF-2 alpha protein and the E3 ubiquitin ligase, promote the ubiquitination of the protein, and has irreplaceable effect on degrading target protein.
The application also provides a preparation method of the difunctional compound, which comprises any one of the following reaction routes:
route a:
step 1: providing a reaction substrate A1, and reacting the reaction substrate A1 with the reaction substrate A1 in a solvent under the action of sodium hydride to obtain A-2.
Step 2: under the action of p-toluenesulfonic acid, the A-2 is heated in a solvent for reaction to obtain an intermediate A-3.
Step 3: the A-3 and the reaction substrate A2 are heated in a solvent for reaction to obtain A-4.
Step 4: under the catalysis of monovalent copper, the A-4 and a reaction substrate A3 are heated in a solvent to react to obtain an intermediate A-5;
step 5: and A-5, adding formic acid and triethylamine under the catalysis of a chiral ruthenium catalyst, wherein the formic acid and the triethylamine are used as hydrogen sources, and reacting in a solvent under a protective atmosphere to obtain a target product A-6.
In the preparation process, the solvent for the reaction is at least one selected from N, N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1, 4-dioxane, methanol, ethanol, water, acetone and acetonitrile.
The monovalent copper is selected from any one of cuprous iodide, cuprous bromide, cuprous chloride and a compound generated in situ from cupric sulfate and sodium ascorbate.
The chiral ruthenium reagent is selected from any one of [ (R, R) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II) and [ (S, S) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II).
The atmosphere of the protective atmosphere includes at least one of argon and nitrogen.
The temperature of the temperature-raising reaction is 60℃to 100℃and may be 60℃65℃70℃75℃80℃85℃90℃95℃100℃or the like, although the temperature-raising reaction may be other values within the above range, and the present application is not limited thereto.
Route B:
step 1: providing a reaction substrate B1, and reacting the reaction substrate B-1 with the reaction substrate B1 in a solvent under the action of sodium hydride to obtain B-2.
Step 2: under the action of p-toluenesulfonic acid, the B-2 is heated in a solvent for reaction to obtain an intermediate B-3.
Step 3: and (3) heating the B-3 and a reaction substrate B2 in a solvent to react to obtain B-4.
Step 4: b-4 is reacted with triphenylphosphine to obtain an intermediate B-5 in a solvent;
step 5: under the action of alkali, the B-5 and a reaction substrate B3 react in a solvent at a temperature rise to obtain an intermediate B-6;
step 6: and B-6, adding formic acid and triethylamine under the catalysis of a chiral ruthenium catalyst, and reacting the formic acid and the triethylamine serving as hydrogen sources in a solvent under a protective atmosphere to obtain a target product B-7.
In the preparation process, the solvent for the reaction is at least one selected from N, N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1, 4-dioxane, methanol, ethanol, water, acetone and acetonitrile.
The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.
The chiral ruthenium reagent is selected from any one of [ (R, R) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II) and [ (S, S) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II).
The atmosphere of the protective atmosphere includes at least one of argon and nitrogen.
The temperature of the temperature-raising reaction is 60℃to 100℃and may be 60℃65℃70℃75℃80℃85℃90℃95℃100℃or the like, although the temperature-raising reaction may be other values within the above range, and the present application is not limited thereto.
Route C:
step 1: c-1 and cyano diphenol are in solvent, and intermediate C-2 is obtained under the action of alkali;
step 2: c-2 and a reaction substrate C1 are in a solvent, and an intermediate C-3 is obtained under the action of alkali;
step 3: c-3 in a solvent, and under the condition of acid, heating to react to obtain an intermediate C-4;
step 4: c-4 reacts with a reaction substrate C2 in a solvent to obtain C-5;
step 5: under the catalysis of monovalent copper, C-5 and a reaction substrate C3 are heated in a solvent to react to obtain an intermediate C-6;
Step 6: under the catalysis of chiral ruthenium catalyst, formic acid and triethylamine are added, and the formic acid and the triethylamine are used as hydrogen sources to react in a solvent under the protection atmosphere, so that a target product C-7 is obtained.
In the preparation process, the solvent for the reaction is at least one selected from N, N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1, 4-dioxane, methanol, ethanol, water, acetone and acetonitrile.
The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate and trifluoroacetic acid.
The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.
The chiral ruthenium reagent is selected from any one of [ (R, R) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II) and [ (S, S) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II).
The atmosphere of the protective atmosphere includes at least one of argon and nitrogen.
The temperature of the temperature-raising reaction is 60℃to 100℃and may be 60℃65℃70℃75℃80℃85℃90℃95℃100℃or the like, although the temperature-raising reaction may be other values within the above range, and the present application is not limited thereto.
Route D:
step 1: d-1, a reaction substrate D1 reacts with sodium hydride in a solvent to obtain an intermediate D-2;
step 2: under the acidic condition, D-2 is heated in a solvent to react to obtain an intermediate D-3;
step 3: the intermediate D-3 reacts with a reaction substrate D2 in a solvent to obtain D-4;
step 4: under the catalysis of monovalent copper, D-5 and a reaction substrate D3 are heated in a solvent to react to obtain an intermediate D-6;
step 5: dissolving the intermediates D-6 and D-4 in a solvent, adding alkali, and carrying out heating reaction to obtain an intermediate D-7;
step 6: and D-7, adding formic acid and triethylamine under the catalysis of a chiral ruthenium catalyst, and reacting the formic acid and the triethylamine serving as hydrogen sources in a solvent under a protective atmosphere to obtain a target product D-8.
In the preparation process, the solvent for the reaction is at least one selected from N, N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1, 4-dioxane, methanol, ethanol, water, acetone and acetonitrile.
The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate and trifluoroacetic acid.
The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.
The chiral ruthenium reagent is selected from any one of [ (R, R) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II) and [ (S, S) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II).
The atmosphere of the protective atmosphere includes at least one of argon and nitrogen.
The temperature of the temperature-raising reaction is 60℃to 100℃and may be 60℃65℃70℃75℃80℃85℃90℃95℃100℃or the like, although the temperature-raising reaction may be other values within the above range, and the present application is not limited thereto.
Route E:
step 1: e-1 and a reaction substrate E1 are dissolved in a solvent, and then alkali is added for heating reaction to obtain an intermediate E-2;
step 2: under the acidic condition, E-2 is heated in a solvent to react to obtain an intermediate E-3;
step 3: e-3 is dissolved in a solvent, and trifluoroacetic acid is added to obtain an intermediate E-4;
step 4: intermediate E-4 and reaction substrate E2 are dissolved in a solvent, and alkali is added for heating reaction to obtain intermediate E-5;
step 5: and E-5, adding formic acid and triethylamine as hydrogen sources under the catalysis of a chiral ruthenium catalyst, and reacting in a solvent under a protective atmosphere to obtain a target product E-6.
In the preparation process, the solvent for the reaction is at least one selected from N, N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1, 4-dioxane, methanol, ethanol, water, acetone and acetonitrile.
The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate and trifluoroacetic acid.
The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.
The chiral ruthenium reagent is selected from any one of [ (R, R) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II) and [ (S, S) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II).
The atmosphere of the protective atmosphere includes at least one of argon and nitrogen.
The temperature of the temperature-raising reaction is 60℃to 100℃and may be 60℃65℃70℃75℃80℃85℃90℃95℃100℃or the like, although the temperature-raising reaction may be other values within the above range, and the present application is not limited thereto.
Route F:
step 1: f-1 and a reaction substrate F1 are dissolved in a solvent, and alkali is added for heating reaction to obtain an intermediate F-2;
Step 2: dissolving the intermediate F-2 in a solvent, and adding trifluoroacetic acid to perform a reaction to obtain an intermediate F-3;
step 3: dissolving the intermediate F-3 and a reaction substrate F2 in a solvent, and adding a condensing agent and alkali for reaction to obtain an intermediate F-4;
step 4: under the catalysis of chiral ruthenium catalyst, formic acid and triethylamine are added, and the formic acid and the triethylamine are used as hydrogen sources to react in a solvent under the protection atmosphere, so that a target product F-5 is obtained.
In the preparation process, the solvent for the reaction is at least one selected from N, N-dimethylformamide, dichloromethane, ethyl acetate, dimethyl sulfoxide, 1, 4-dioxane, methanol, ethanol, water, acetone and acetonitrile.
The acid is selected from any one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate and trifluoroacetic acid.
The base is selected from any one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine and diisopropylethylamine.
The chiral ruthenium reagent is selected from any one of [ (R, R) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II) and [ (S, S) -N- (2-amino-1, 2-diphenyl ethyl) -p-methylbenzenesulfonamide ] ruthenium (p-cymene) chloride (II).
The atmosphere of the protective atmosphere includes at least one of argon and nitrogen.
The temperature of the temperature-raising reaction is 60℃to 100℃and may be 60℃65℃70℃75℃80℃85℃90℃95℃100℃or the like, although the temperature-raising reaction may be other values within the above range, and the present application is not limited thereto.
Condensing agents include any of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) or (1-propylphosphoric acid cyclic anhydride) T3P.
The present application also provides a pharmaceutical composition comprising an effective amount of the above bifunctional compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, solvate thereof, and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient. The above drugs are drugs for regulating HIF-2α content and function, preferably degradation agents for HIF-2α. It will be appreciated that based on the core skeleton of the bifunctional compounds of the present application, those skilled in the art can make appropriate modifications to adapt them to the various forms or types of action targets described above, thereby better exerting therapeutic effects, and also being able to act as recruitment of target proteins (HIF-2α) and thus promote degradation of the target proteins.
The pharmaceutical compositions of the present application, when used as a medicament, refer to compositions of the compounds of formula (I) of the present application, and salts, isotopic derivatives, prodrugs, solvates thereof, with or without biologically active agents, useful in the treatment or prevention of HIF-2α related disorders.
In order to adapt to different administration modes, the pharmaceutical composition of the application can be prepared into various dosage forms. Specifically, the preparation form of the pharmaceutical composition of the application can be an oral preparation or an injection.
The bifunctional compounds or pharmaceutical compositions of the present application are useful for treating cancers or tumors arising from proliferation of a target protein (HIF-2α), including any of renal cell carcinoma, lung carcinoma, skin carcinoma, head and neck cancer, and breast cancer. The tumor includes any one of a hematological tumor including any one of acute lymphoblastic leukemia, chronic myelogenous leukemia, and mantle cell lymphoma, a glioma including any one of esophageal cancer, gastric cancer, and colorectal cancer, a digestive system tumor including any one of ovarian cancer and endometrial cancer, a reproductive system tumor including any one of brain glioma and optical neuroblastoma, and a nervous system tumor including any one of brain glioma and optical neuroblastoma, it being understood that the cancers and tumors may be induced by the upregulation of HIF-2α expression.
The following examples are provided to further illustrate embodiments of the application. The embodiments of the present application are not limited to the following specific embodiments. The modification can be appropriately performed within the scope of the main claim.
Example 1
Compound 1-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione
Compound 1-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Step A: preparation of intermediate 1-A:
2- (2-azidyloxy) ethyl-1-ol (2 mmol) was dissolved in 5mL of anhydrous DMF, sodium hydride (2.4 mmol) was added under ice-water bath, stirred in ice-water bath for 30min, 4-fluoro-7- (methylsulfonyl) -2, 3-dihydro spiro [ indene-1, 2' - [1,3] dioxolane ] (2 mmol) was added and reacted at room temperature for 1h. After the reaction is finished, quenching the saturated ammonium chloride solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and spin-drying to obtain an intermediate 1-A;
Step B: preparation of intermediate 1-B:
1-A was dissolved in a mixed solvent of 8mL of acetone and 2mL of water, and pyridine p-toluenesulfonate (PPTS, 1 mmol) was added thereto, followed by a reflux reaction for 1h. After the reaction is finished, cooling to room temperature, removing acetone by rotary evaporation, adding 20mL of saturated sodium carbonate solution, extracting by ethyl acetate, drying by anhydrous sodium sulfate, and rotary drying to obtain an intermediate 1-B;
step C: preparation of intermediate 1-C:
1-B was dissolved in 10mL of methanol, selectFluoro reagent (3 mmol) was added, and the mixture was reacted at 70℃for 2 hours in a sealed bottle. After the reaction, cooling to room temperature, removing methanol by rotary evaporation, dissolving solid residues in dichloromethane, filtering, spin-drying filtrate, dissolving in 5mL of acetonitrile, adding 2mL of diluted hydrochloric acid (2M), stirring at room temperature for 1h, after the reaction is finished, removing acetonitrile by rotary evaporation, adding 20mL of saturated sodium carbonate solution, extracting by ethyl acetate, drying by anhydrous sodium sulfate, and obtaining an intermediate 1-C (300 mg, three-step total yield 42%) by column chromatography.
Step D: preparation of intermediate 1-D:
1-C (0.1 mmol), 2- (2, 6-dioxopiperidin-3-yl) -4- (prop-2-yn-1-ylamino) isoindoline-1, 3-dione (0.1 mmol), anhydrous copper sulfate (0.05 mmol), sodium ascorbate (0.2 mmol) were dissolved in a mixed solvent of 4mL DMF and 0.5mL water and reacted at 70℃under argon for 6h. After the completion of the reaction, the mixture was cooled to room temperature, 20mL of a saturated chlorinated solution was added, extraction was performed with ethyl acetate, and drying was performed with anhydrous sodium sulfate, followed by column chromatography to obtain intermediate 1-D (40 mg, yield 59.8%).
Step E:1-1 and 1-2:
formic acid (20. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (30. Mu.L) was added thereto under ice-water bath, followed by stirring for 10 minutes. The above solution was added to a 1-D methylene chloride solution, and ruthenium (II) (5% mol) was reacted at room temperature under the protection of argon gas by adding a catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] chloride (p-cymene) for 8 hours. After the completion of the reaction, 20mL of methylene chloride was added, followed by washing with saturated sodium bicarbonate, drying, purification by high performance liquid chromatography, and freeze-drying, to give the objective products 1-1 (10 mg) and 1-2 (6 mg).
1 H-NMR(1-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),8.00(s,1H),7.73(d,J＝8.7Hz,1H),7.56(dd,J＝8.5, 7.1Hz,1H),7.16(d,J＝8.6Hz,1H),7.10(d,J＝8.7Hz,1H),7.01-7.06(m,2H),5.42(dd,J＝7.0,5.0Hz,1H), 5.22(dq,J＝52.1,5.6Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.49-4.58(m,4H),4.13-4.18(m,2H),3.88(t,J＝ 5.2Hz,2H),3.70-3.77(m,2H),3.27(s,3H),2.81-3.14(m,4H),2.55-2.58(m,2H),1.98-2.05(m,1H)；MS:[M+1] + : 671.2。
1 H-NMR(1-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),8.00(s,1H),7.75(d,J＝8.6Hz,1H),7.55(dd,J＝8.5, 7.1Hz,1H),7.15(dd,J＝10.6,8.6Hz,2H),7.00-7.06(m,2H),5.50(d,J＝16.5Hz,1H),5.18(dd,J＝50.5,4.7Hz, 1H),5.05(dd,J＝12.8,5.4Hz,1H),4.49-4.58(m,4H),4.16-4.22(m,2H),3.88(t,J＝5.2Hz,2H),3.72-3.79(m, 2H),3.23(s,3H),2.80-2.95(m,2H),2.52-2.62(m,2H),1.96-2.05(m,1H)；MS:[M+1] + :671.2。
Example 2
Compound 2-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compound 2-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compounds 2-1 and 2-2 were synthesized in a similar manner to compound 1-1 as shown in example 1-1.
1 H-NMR(2-1)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.99(s,1H),7.73(d,J＝8.7Hz,1H),7.56(dd,J＝8.6, 7.1Hz,1H),7.16(d,J＝8.6Hz,1H),7.12(d,J＝8.8Hz,1H),7.02-7.07(m,2H),5.78(d,J＝7.0Hz,1H),5.42(q, J＝6.3Hz,1H),5.12-5.29(m,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.57(d,J＝6.0Hz,2H),4.48(t,J＝5.2Hz,2H), 4.15-4.21(m,2H),3.79(t,J＝5.2Hz,2H),3.70(t,J＝4.5Hz,2H),3.47-3.57(m,3H),3.27(s,3H),2.82-3.12(m, 4H),2.53-2.62(m,2H),1.95-2.05(m,1H)；MS:[M+1] + :715.2。
1 H-NMR(2-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.98(s,1H),7.75(d,J＝8.6Hz,1H),7.56(dd,J＝8.6, 7.1Hz,1H),7.12-7.22(m,2H),7.02-7.08(m,2H),6.02(d,J＝6.3Hz,1H),5.49(dd,J＝16.6,6.1Hz,1H),5.18 (dd,J＝50.5,4.6Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.57(d,J＝6.1Hz,2H),4.48(t,J＝5.2Hz,2H),4.17- 4.24(m,2H),4.09(q,J＝5.3Hz,2H),3.79(t,J＝5.2Hz,2H),3.67-3.74(m,2H),3.48-3.56(m,2H),3.22(s,3H), 2.81-2.97(m,3H),2.53-2.62(m,2H),1.95-2.05(m,1H)；MS:[M+1] + :715.2。
Example 3
Compound 3-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compound 3-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compounds 3-1 and 3-2 were synthesized in a similar manner to compound 1-1 as shown in example 1-1.
1 H-NMR(3-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.99(s,1H),7.73(d,J＝8.6Hz,1H),7.57(dd,J＝8.6, 7.1Hz,1H),7.02-7.18(m,2H),7.03-7.07(d,J＝7.0Hz,2H),5.76-5.80(m,1H),5.42(td,J＝7.0,5.0Hz,1H),5.21 (dq,J＝52.1,5.6Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.58(d,J＝6.0Hz,2H),4.47(t,J＝5.2Hz,2H),4.18- 4.24(m,2H),3.72-3.80(m,4H),3.52-3.58(m,2H),3.43-3.50(m,5H),3.27(s,3H),2.82-3.14(m,4H),2.52-2.62 (m,2H),1.97-2.05(m,1H)；MS:[M+1] + :759.2。
1 H-NMR(3-2)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.98(s,1H),7.75(d,J＝8.6Hz,1H),7.57(dd,J＝8.5, 7.1Hz,1H),7.15-7.20(m 2H),7.02-7.07(m,2H),6.02(d,J＝6.4Hz,1H),5.49(dd,J＝16.5,6.4Hz,1H),5.18(dd, J＝50.6,4.8Hz,1H),5.02-5.09(m,1H),4.59(d,J＝6.0Hz,2H),4.47(t,J＝5.2Hz,2H),4.24(t,J＝4.6Hz,2H), 3.76(q,J＝5.5Hz,4H),3.52-3.57(m,2H),3.42-3.48(m,5H),3.23(s,3H),2.81-2.95(m,3H),2.54-2.69(m,3H), 1.97-2.06(m,1H)；MS:[M+1] + :759.2。
Example 4
Compound 4-1: cis-2- (2, 6-dioxacyclopenta-3-yl) -4- ((2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) amino) isoindoline-1, 3-dione.
Compound 4-2: trans-2- (2, 6-dioxacyclopenta-3-yl) -4- ((2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) amino) isoindoline-1, 3-dione.
Step A: preparation of intermediate 4-A:
4- (2- (2- (2-Azidoethoxy) ethoxy) -2-fluoro-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-1-one (1 mmol), triphenylphosphine (1.5 mmol) was dissolved in a mixed solvent of 5mL tetrahydrofuran and 1mL water and reacted overnight at room temperature.
Step B: preparation of intermediate 4-B:
4-A (100 mg), 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione (74 mg), DIPEA (34 mg) was dissolved in 3mL DMF and reacted at 90℃for 2h. After the completion of the reaction, the mixture was cooled to room temperature, 20mL of a saturated sodium chloride solution was added thereto, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate, followed by column chromatography to give intermediate 4-B (45 mg, yield 27%).
Step C:4-1 and 4-2:
the target compounds 4-1 and 4-2 were synthesized similarly to Step E in 1-1 synthesis.
1 H NMR(4-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),8.27(t,J＝4.9Hz,1H),7.73(d,J＝9.3Hz,1H),7.54 (dd,J＝7.9,7.0Hz,1H),7.39(dd,J＝6.9,1.2Hz,1H),7.18(dd,J＝7.9,1.1Hz,1H),6.87(d,J＝9.3Hz,1H),5.48 (m,1H),5.23(dt,J＝25.3,5.2Hz,1H),5.00-5.15(m,1H),4.30(m,1H),4.16(m,3H),3.75(m,3H),3.59–3.69 (m,8H),3.20(s,3H),3.16(d,J＝5.4Hz,1H),3.11(d,J＝5.3Hz,1H),2.51-2.66(m,2H),2.10-2.20(m,1H),1.73- 1.81(m,1H).MS:[M+1] + :634.5.
1 H NMR(4-2)：(400MHz,DMSO-d 6 )11.09(s,1H),δ8.29(t,J＝4.9Hz,1H),7.70(d,J＝9.3Hz,1H),7.52 (dd,J＝7.9,7.0Hz,1H),7.38(dd,J＝6.9,1.2Hz,1H),7.13(dd,J＝7.9,1.1Hz,1H),6.82(d,J＝9.3Hz,1H),5.40 (m,1H),5.17-5,27(m),4.87-5.02(m,1H),4.46(d,J＝5.5Hz,1H),4.16(t,J＝4.9Hz,2H),3.72-3.78(m,2H),3.45 –3.65(m,8H),3.16–3.26(m,4H),3.00-3.10(m,1H),2.51-2.66(m,2H),2.14-2.22(m,1H),1.75-1.80(m,1H). MS:[M+1] + :634.5.
Example 5
Compound 5-1: cis-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide.
Compound 5-2: trans-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide.
Step A: preparation of intermediate 5-A:
2- (2, 6-Dioxypiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione (2 mmol), glycine tert-butyl ester (2.2 mmol), DIPEA (4 mmol) were dissolved in DMF and reacted at 90℃for 2h. After the completion of the reaction, the mixture was cooled to room temperature, 20mL of a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, and drying was performed with anhydrous sodium sulfate, followed by column chromatography to obtain intermediate 5-A (600 mg, 77.5%).
Step B: preparation of intermediate 5-B:
intermediate 5-A (600 mg) was dissolved in 10mL of methylene chloride, and 5mL of trifluoroacetic acid was added thereto for reaction at room temperature for 4 hours. After the reaction is completed, the intermediate 5-B is dried by spin and directly used for subsequent synthesis.
Step C: preparation of intermediate 5-C:
intermediate 5-B (100 mg), EDCI (116 mg), HOBT (82 mg), DIPEA (78 mg) were dissolved in DMF (5 mL), and after stirring at room temperature for 20min, intermediate 4-A (113 mg) was added and reacted at room temperature for 8h. After the completion of the reaction, 20mL of a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and intermediate 5-C (40 mg, yield 19%) was obtained by reverse phase column chromatography.
Step D:5-1 and 5-2: the target compounds 5-1 and 5-2 were synthesized similarly to Step E in 1-1 synthesis.
1 H-NMR(5-1)：(400MHz,DMSO-d 6 )δ11.10(s,1H),8.16(t,J＝5.6Hz,1H),7.74(d,J＝8.6Hz,1H),7.54- 7.62(m,1H),7.15(d,J＝8.7Hz,1H),7.06(d,J＝7.1Hz,1H),6.94(t,J＝5.6Hz,1H),6.85(d,J＝8.5Hz,1H), 5.78(d,J＝6.9Hz,1H),5.37-5.47(m,1H),5.13-5.31(m,1H),5.07(dd,J＝13.0,5.4Hz,1H),4.21-4.26(m,2H), 3.93(d,J＝5.6Hz,2H),3.74-3.81(m,2H),3.57-3.65(m,2H),3.48-3.55(m,2H),3.43-3.46(m,2H),3.22-3.27(m, 5H),2.83-3.15(m,4H),2.54-2.63(m,1H),1.95-2.05(m,1H)；MS:[M+1] + :691.2.
1 H-NMR(5-2)：(400MHz,DMSO-d 6 )δ11.15(s,1H),8.19(t,J＝5.6Hz,1H),7.69(d,J＝8.6Hz,1H),7.50- 7.58(m,1H),7.09(d,J＝8.7Hz,1H),7.03(d,J＝7.1Hz,1H),6.94(t,J＝5.6Hz,1H),6.80(d,J＝8.5Hz,1H), 5.68(d,J＝6.9Hz,1H),5.30-5.44(m,1H),5.25-5.31(m,1H),4.95(dd,J＝13.0,5.4Hz,1H),4.18-4.27(m,2H), 3.89(d,J＝5.6Hz,2H),3.76-3.84(m,2H),3.54-3.68(m,2H),3.48-3.55(m,2H),3.43-3.46(m,2H),3.28-3.34(m, 5H),2.90-3.15(m,4H),2.46-2.58(m,1H),1.95-2.05(m,1H)；MS:[M+1] + :691.2.
Example 6
Compound 6-1: cis-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide.
Compound 6-2: trans-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide.
Compounds 6-1 and 6-2 were synthesized as shown in example 5-1 using a procedure analogous to that used for synthesis 5-1.
1 H-NMR(6-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),8.16(t,J＝5.6Hz,1H),7.70-7.78(m,1H),7.59(t,J＝ 7.8Hz,1H),7.15(d,J＝8.7Hz,1H),7.07(d,J＝7.1Hz,1H),6.94(t,J＝5.7Hz,1H),6.86(d,J＝8.5Hz,1H),5.78 (d,J＝6.9Hz,1H),5.42(q,J＝6.4Hz,1H),5.22(dq,J＝51.9,5.7Hz,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.18- 4.28(m,2H),3.93(d,J＝5.6Hz,2H),3.77(t,J＝4.4Hz,2H),3.56-3.65(m,2H),3.47-3.56(m,6H),3.42(t,J＝5.8 Hz,2H),3.22-3.30(m,5H),2.82-3.18(m,4H),2.52-2.64(m,1H),1.99-2.08(m,1H)；MS:[M+1] + :735.2。
1 H-NMR(6-2)：(400MHz,DMSO-d 6 )δ11.10(s,1H),8.16(t,J＝5.7Hz,1H),7.75(d,J＝8.6Hz,1H),7.59 (t,J＝7.8Hz,1H),7.19(d,J＝8.6Hz,1H),7.07(d,J＝7.1Hz,1H),6.94(t,J＝5.6Hz,1H),6.86(d,J＝8.6Hz, 1H),6.03(d,J＝6.4Hz,1H),5.50(dd,J＝16.5,6.4Hz,1H),5.19(dd,J＝50.4,4.6Hz,1H),5.07(dd,J＝12.9,5.4 Hz,1H),4.25(t,J＝4.7Hz,2H),3.93(d,J＝5.6Hz,2H),3.78(t,J＝4.6Hz,2H),3.56-3.63(m,2H),3.45-3.55(m, 6H),3.42(t,J＝5.7Hz,2H),3.20-3.27(m,5H),2.82-2.97(m,2H),2.52-2.63(m,3H),1.97-2.06(m,1H)；MS: [M+1] + :735.2。
Example 7
Compound 7-1: cis-4- ((1- (2- (2- (2- ((1S) -7- ((difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.
Compound 7-2: trans-4- ((1- (2- (2- (2- ((1S) -7- ((difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione.
Step A: preparation of intermediate 7-A:
4-fluoro-7-mercapto-2, 3-dihydro-1H-indene-1-one (10 mmol) was dissolved in 50mL of acetone, an aqueous solution (50 mL) of potassium hydroxide (200 mmol) was added, the temperature was lowered to-78 ℃, diethyl bromodifluoromethylphosphonate (20 mmol) was added, the temperature was slowly raised to room temperature, and the reaction was carried out at room temperature for 2 hours. After the completion of the reaction, 100mL of water was added, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and column chromatography was performed to obtain intermediate 7-A (8 mmol, yield 80%).
Step B: preparation of intermediate 7-B:
7-A (8 mmol), sodium periodate (20 mmol) and ruthenium trichloride (0.2 mmol) were dissolved in a mixed solvent of acetonitrile (30 mL), carbon tetrachloride (30 mL) and water (30 mL) and reacted at room temperature for 5 hours. After the reaction, the solid was removed by filtration, part of the solvent was removed by rotary evaporation, 100mL of water was added, extraction was performed with methylene chloride, and drying was performed with anhydrous sodium sulfate, and intermediate 7-B (crude 7.2mmol, yield 90%) was obtained by rotary drying, and was directly used for the subsequent synthesis.
Step C: preparation of intermediate 7-C:
7-B (1 mmol) was dissolved in 5mL of toluene, 2mL of ethylene glycol was added, and the reaction was refluxed for 12h. After the completion of the reaction, the mixture was cooled to room temperature, part of the solvent was removed by rotary evaporation, 20mL of water was added, extraction was performed with ethyl acetate, and drying was performed with anhydrous sodium sulfate, followed by column chromatography to give intermediate 7-C (0.4 mmol, yield 40%).
Step D-H is synthesized by a similar method to 1-1 to obtain target compounds 7-1 and 7-2.
1 H-NMR(7-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.99(s,1H),7.84(d,J＝8.8Hz,1H),7.56(dd,J＝8.6, 7.1Hz,1H),7.24(d,J＝8.8Hz,1H),7.13-7.19(m,1H),7.16(t,J＝53.6Hz,1H),7.02-7.07(m,2H),5.15-5.39(m, 2H),5.05(dd,J＝12.8,5.4Hz,1H),4.57(d,J＝6.0Hz,2H),4.48(t,J＝5.2Hz,2H),4.18-4.27(m,2H),3.79(t,J ＝5.2Hz,2H),3.71(dd,J＝5.7,3.4Hz,2H),3.47-3.55(m,4H),2.81-3.16(m,4H),2.52-2.62(m,2H),1.97-2.05(m, 1H)；MS:[M+1] + :751.2。
1 H-NMR(7-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.99(s,1H),7.85(d,J＝8.7Hz,1H),7.52-7.60(m, 1H),7.28(d,J＝8.8Hz,1H),7.16(d,J＝8.6Hz,1H),7.07(t,J＝53.1Hz,1H),7.01-7.09(m,2H),5.38(d,J＝16.6 Hz,1H),5.20(dd,J＝50.6,4.8Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.58(d,J＝6.1Hz,2H),4.48(t,J＝5.2Hz, 2H),4.20-4.30(m,2H),3.79(t,J＝5.2Hz,2H),3.72(t,J＝4.5Hz,2H),3.48-3.56(m,4H),3.22-3.25(m,1H),2.83- 2.94(m,3H),2.55-2.62(m,2H),1.97-2.10(m,1H)；MS:[M+1] + :751.2。
Example 8
Compound 8-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compound 8-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
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Compounds 8-1 and 8-2 were synthesized in a similar manner to compound 1-1 as shown in example 1-1.
1 H-NMR(8-1)：(400MHz,DMSO-d 6 )δ11.05(s,1H),7.99(s,1H),7.73(d,J＝8.7Hz,1H),7.52-7.58(m, 2H),7.12(d,J＝8.8Hz,1H),7.05(d,J＝2.1Hz,1H),6.94(dd,J＝8.4,2.1Hz,1H),5.38-5.45(m,1H),5.21(dq,J ＝52.1,5.6Hz,1H),5.02(dd,J＝12.9,5.4Hz,1H),4.42-4.53(m,4H),4.12-4.22(m,2H),3.79(t,J＝5.2Hz,2H), 3.70(t,J＝4.6Hz,2H),3.48-3.57(m,4H),3.27(s,3H),2.80-3.16(m,4H),2.52-2.61(m,2H),1.94-2.01(m,1H)； MS:[M+1] + :715.2。
1 H-NMR(8-2)：(400MHz,DMSO-d 6 )δ11.05(s,1H),7.99(s,1H),7.75(d,J＝8.6Hz,1H),7.52-7.60(m, 2H),7.16(d,J＝8.7Hz,1H),7.06(d,J＝2.1Hz,1H),6.94(dd,J＝8.4,2.2Hz,1H),5.49(d,J＝16.5Hz,1H),5.18 (dd,J＝50.4,4.6Hz,1H),5.03(dd,J＝12.9,5.4Hz,1H),4.43-4.52(m,4H),4.21(t,J＝4.7Hz,2H),3.79(t,J＝ 5.2Hz,2H),3.68-3.74(m,2H),3.49-3.56(m,4H),3.18-3.27(m,5H),2.80-2.96(m,2H),2.52-2.61(m,2H),1.94- 2.02(m,1H)；MS:[M+1] + :715.2。
Example 9
Compound 9-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((1- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compound 9-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((1- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compounds 9-1 and 9-2 were synthesized in a similar manner to compound 1-1 as shown in example 1-1.
1 H-NMR(9-1)：(400MHz,DMSO-d 6 )δ11.06(s,1H),7.96(s,1H),7.73(d,J＝8.6Hz,1H),7.57(d,J＝10.1 Hz,1H),7.42(m,1H),7.22(d,J＝7.2Hz,1H),7.12(d,J＝8.7Hz,1H),5.78(d,J＝6.9Hz,1H),5.37-5.45(m,1H), 5.22(dq,J＝52.1,5.6Hz,1H),5.04(dd,J＝12.7,5.4Hz,1H),4.55(d,J＝6.0Hz,2H),4.48(t,J＝5.2Hz,2H), 4.10-4.22(m,2H),3.78(t,J＝5.2Hz,2H),3.69(t,J＝4.6Hz,2H),3.45-3.55(m,4H),3.28(s,3H),2.80-3.13(m, 4H),2.50-2.60(m,1H),1.95-2.02(m,1H)；MS:[M+1] + :733.2。
1 H-NMR(9-2)：(400MHz,DMSO-d 6 )δ11.06(s,1H),7.95(s,1H),7.75(d,J＝8.6Hz,1H),7.58(d,J＝10.2 Hz,1H),7.37-7.45(m,1H),7.22(d,J＝7.2Hz,1H),7.16(d,J＝8.7Hz,1H),6.03(d,J＝6.2Hz,1H),5.50(dd,J ＝16.6,4.7Hz,1H),5.18(dd,J＝50.5,4.6Hz,1H),5.04(dd,J＝12.7,5.4Hz,1H),4.56(d,J＝6.1Hz,2H),4.48(t, J＝5.2Hz,3H),4.21(t,J＝4.6Hz,2H),3.78(t,J＝5.2Hz,2H),3.70(dd,J＝5.7,3.5Hz,2H),3.45-3.55(m,4H), 3.18-3.27(m,5H),2.80-2.96(m,2H),2.52-2.60(m,1H),1.95-2.02(m,1H)；MS:[M+1] + :733.2。
Example 10
Compound 10-1: cis-3- (4- ((1- (2- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione.
Compound 10-2: trans-3- (4- ((1- (2- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione
Compounds 10-1 and 10-2 were synthesized in a similar manner to compound 1-1 as shown in example 1-1.
1 H-NMR(10-1)：(400MHz,DMSO-d 6 )δ10.98(s,1H),7.93(s,1H),7.74(d,J＝8.6Hz,1H),7.25(t,J＝7.7 Hz,1H),7.12(d,J＝8.7Hz,1H),6.95(d,J＝7.4Hz,1H),6.82(d,J＝8.1Hz,1H),6.19(t,J＝5.9Hz,1H),5.79(d, J＝7.0Hz,1H),5.42(q,J＝6.5Hz,1H),5.05-5.30(m,2H),4.46(t,J＝5.2Hz,2H),4.40(d,J＝5.8Hz,2H),4.10- 4.27(m,4H),3.78(t,J＝5.2Hz,2H),3.69(t,J＝4.5Hz,2H),3.50(m,4H),3.28(s,3H),2.85-3.16(m,3H),2.54- 2.67(m,1H),2.20-2.35(m,1H),1.95-2.05(m,1H)；MS:[M+1] + :701.2。
1 H-NMR(10-2)：(400MHz,DMSO-d 6 )δ10.99(s,1H),7.93(s,1H),7.75(d,J＝8.6Hz,1H),7.25(t,J＝7.7 Hz,1H),7.15(d,J＝8.7Hz,1H),6.95(d,J＝7.4Hz,1H),6.82(d,J＝8.1Hz,1H),6.20(t,J＝5.9Hz,1H),6.00- 6.08(m,1H),5.45-5.55(m,1H),5.06-5.26(m,2H),4.46(t,J＝5.2Hz,2H),4.41(d,J＝5.9Hz,2H),4.10-4.30(m, 4H),3.78(t,J＝5.2Hz,2H),3.70(t,J＝4.6Hz,2H),3.51(m,4H),3.24-3.28(m,1H),3.23(s,3H),2.81-2.97(m, 2H),2.52-2.65(m,1H),2.22-2.33(m,1H),2.01(m,1H)；MS:[M+1] + :701.2。
Example 11
Compound 11-1: cis-3- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile.
Compound 11-2: trans-3- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile.
Step A: preparation of intermediate 11-A
4-fluoro-7- (methylsulfonyl) -2, 3-dihydro-spiro [ indene-1, 2' - [1,3] dioxolane ] (2 mmol), 3, 5-dihydroxybenzonitrile (4 mmol) and potassium carbonate (4 mmol) were dissolved in DMF (8 mL) and reacted by microwave at 100℃for 2h. After the completion of the reaction, the mixture was cooled to room temperature, 50mL of a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and spin-drying was performed to obtain intermediate 11-A (1.54 mmol, yield 77%) by column chromatography.
Step B: preparation of intermediate 11-B
11-A (1.54 mmol) was dissolved in anhydrous DMF (8 mL), sodium hydride (2 mmol) was added under ice-water bath, stirred in ice-water bath for 30min, 2- (2-azidoethoxy) ethyl 4-methylbenzenesulfonate (1.54 mmol) was added, and the reaction was carried out at room temperature for 4h. After the reaction was completed, 40mL of ice water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried to give intermediate 11-B.
The synthesis of Step C-F was similar to the reactions associated with the 1-1 synthesis to give compounds 11-1 and 11-2.
1 H-NMR(11-1)：(400MHz,DMSO-d 6 )δ8.00(s,1H),7.78(d,J＝8.6Hz,1H),7.55(dd,J＝8.8,6.9Hz,1H), 7.28-7.33(m,1H),7.13-7.19(m,2H),7.00-7.08(m,4H),5.45-5.52(m,1H),5.17-5.36(m,1H),5.05(dd,J＝12.9, 5.4Hz,1H),4.47-4.59(m,4H),4.10-4.15(m,2H),3.84(t,J＝5.2Hz,2H),3.68-3.72(m,2H),2.82-3.30(m,7H), 2.54-2.66(m,2H),1.95-2.05(m,1H)；MS:[M+1] + :788.2。
1 H-NMR(11-2)：(400MHz,DMSO-d 6 )δ8.00(s,1H),7.79(d,J＝8.6Hz,1H),7.55(dd,J＝8.5,7.1Hz,1H), 7.30-7.34(m,1H),7.20-7.24(m,1H),7.16(d,J＝8.6Hz,2H),7.00-7.10(m,4H),5.56(d,J＝16.3Hz,1H),5.23 (dd,J＝50.4,4.7Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.47-4.60(m,4H),4.08-4.16(m,2H),3.85(t,J＝5.2Hz, 2H),3.67-3.73(m,2H),3.40-3.50(m,2H),3.29(s,3H),2.82-3.06(m,2H),2.54-2.66(m,2H),1.97-2.10(m,1H)； MS:[M+1] + :788.2。
Example 12
Compound 12-1: cis-3- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile.
Compound 12-2: trans-3- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile.
12-1 and 12-2 were synthesized as described in the synthesis of example 11-1, using a procedure similar to 11-1.
1 H-NMR(12-1)：(400MHz,DMSO-d 6 )δ11.06(s,1H),7.99(s,1H),7.78(d,J＝8.7Hz,1H),7.56(dd,J＝ 8.6,7.1Hz,1H),7.31(dd,J＝2.3,1.3Hz,1H),7.12-7.19(m,2H),7.01-7.08(m,4H),5.95(d,J＝6.7Hz,1H),5.49 (q,J＝6.8Hz,1H),5.27(dq,J＝52.1,5.4Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.57(d,J＝6.1Hz,2H),4.48(t, J＝5.2Hz,2H),4.12(dd,J＝5.7,3.3Hz,2H),3.78(t,J＝5.2Hz,2H),3.65(dd,J＝5.3,3.3Hz,2H),3.49(s,3H), 3.33-3.35(m,3H),2.82-3.21(m,4H),2.52-2.62(m,2H),1.98-2.05(m,1H)；MS:[M+1] + :832.2。
1 H-NMR(12-2)：(400MHz,DMSO-d 6 )δ11.07(s,1H),7.99(s,1H),7.78(d,J＝8.6Hz,1H),7.52-7.60(m, 1H),7.32-7.34(m,1H),7.20-7.22(m,1H),7.16(d,J＝8.6Hz,1H),7.01-7.10(m,3H),6.18(d,J＝5.7Hz,1H), 5.56(dd,J＝16.3,5.3Hz,1H),5.23(dd,J＝50.4,4.7Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.57(d,J＝6.0Hz, 2H),4.48(t,J＝5.2Hz,2H),4.10-4.15(m,2H),3.78(t,J＝5.2Hz,2H),3.63-3.69(m,2H),3.49(s,3H),3.34-3.46 (m,2H),3.29(m,3H),2.81-3.05(m,2H),2.54-2.65(m,2H),1.95-2.05(m,1H)；MS:[M+1] + :832.2。
Example 13
Compound 13-1: cis-3- (2- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile.
Compound 13-2: trans-3- (2- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile.
12-1 and 12-2 were synthesized as described in the synthesis of example 11-1, using a procedure similar to 11-1.
1 H-NMR(13-1)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.99(s,1H),7.78(d,J＝8.6Hz,1H),7.52-7.60(m, 1H),7.30-7.34(m,1H),7.13-7.20(m,2H),7.01-7.08(m,4H),5.90-6.00(m,1H),5.45-5.55(m,1H),5.27(dq,J＝ 51.9,5.4Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.58(d,J＝6.0Hz,2H),4.47(t,J＝5.2Hz,2H),4.12-4.17(m, 2H),3.77(t,J＝5.2Hz,2H),3.65-370(m,2H),3.41-3.55(m,7H),3.30(s,3H),2.81-3.23(m,4H),2.52-2.62(m, 2H),1.96-2.06(m,1H)；MS:[M+1] + :876.2。
1 H-NMR(13-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.99(s,1H),7.79(d,J＝8.5Hz,1H),7.56(dd,J＝ 8.6,7.1Hz,1H),7.32-7.36(m,1H),7.20-7.23(m,1H),7.16(d,J＝8.6Hz,1H),7.01-7.11(m,4H),6.15-6.25(m, 1H),5.56(d,J＝15.9Hz,1H),5.23(dd,J＝50.3,4.6Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),4.58(d,J＝6.1Hz, 2H),4.47(t,J＝5.2Hz,2H),4.10-4.17(m,2H),3.77(t,J＝5.2Hz,2H),3.65-3.72(m,2H),3.41-3.55(m,9H),3.29 (s,3H),2.83.05(m,2H),2.52-2.62(m,2H),1.97-2.04(m,1H)；MS:[M+1] + :876.2。
Example 14
Compound 14-1: cis 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (4- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) piperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione.
Compound 14-2: trans 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (4- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) piperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione.
Step A: preparation of intermediate 14-A
4-fluoro-7- (methylsulfonyl) -2, 3-dihydro-spiro [ indene-1, 2' - [1,3] dioxolane ] (2 mmol), methyl 3-fluoro-5-hydroxybenzoate (2 mmol) and cesium carbonate (4 mmol) were dissolved in DMF (8 mL) and reacted by microwave at 100℃for 2h. After the reaction was completed, it was cooled to room temperature to intermediate 14-A (1 mmol, yield 50%).
Step B: preparation of intermediate 14-B
14-A (1 mmol) was dissolved in a mixed solvent of 8mL of acetone and 2mL of water, and pyridinium p-toluenesulfonate (0.5 mmol) was added thereto and reacted under reflux for 2h. After the reaction was completed, the mixture was cooled to room temperature, a part of the solvent was removed by rotary evaporation, 20mL of saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and intermediate 14-B was obtained by rotary drying.
Step C: preparation of intermediate 14-C
The crude product obtained in Step B was dissolved in 8mL of anhydrous methanol, and the SelectFluoro reagent (1.5 mmol) was added thereto and the reaction was refluxed for 4 hours. After the reaction was completed, cooled to room temperature, dried by spin-drying, and the residue was dissolved in dichloromethane and filtered. The filtrate was dried by spin-drying, dissolved in 5mL of acetonitrile, 1mL of diluted hydrochloric acid (2M) was added, and stirred at room temperature for 1h. After the reaction was completed, 20mL of saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and spin drying was performed, to obtain intermediate 14-C (0.4 mmol, 40% in two steps) by column chromatography.
Step D: preparation of intermediate 14-D
14-C (0.4 mmol) was dissolved in a mixed solvent of 4mL of tetrahydrofuran and 1mL of water, and lithium hydroxide (1 mmol) was added thereto and reacted at room temperature for 2 hours. After the reaction is finished, the pH is regulated to 4-5 by dilute hydrochloric acid, 10mL of water is added, ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying, and the intermediate 14-D is obtained by spin drying.
Step E: preparation of intermediate 14-E
2- (2, 6-Dioxypiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (2 mmol), tert-butyl 4- (piperidin-4-yl) piperazine-1-carboxylate (2 mmol), DIPEA (3 mmol) were dissolved in DMSO (8 mL) and reacted at 90℃for 2h. After the reaction is completed, the mixture is cooled to room temperature, 30mL of saturated sodium chloride solution is added, the mixture is extracted by ethyl acetate, and the mixture is dried by anhydrous sodium sulfate and spin-dried to obtain an intermediate 14-F.
Step F: synthesis of intermediate 14-F
Intermediate 14-E from Step E was dissolved in 10mL of methylene chloride, 5mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 3 hours. After the reaction is completed, the solvent is dried by spin to obtain an intermediate 14-F.
Step G: synthesis of intermediate 14-G
14-D (0.1 mmol), EDCI (0.2 mmol), HOBT (0.2 mmol) and triethylamine (0.2 mmol) were dissolved in DMF (4 mL), and after stirring at room temperature for 30min, 14-G (0.11 mmol) was added and reacted at room temperature for 8h. After the completion of the reaction, 20ml of a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, drying was performed over anhydrous sodium sulfate, and spin drying was performed, whereby intermediate 14-G (0.05 mmol, yield 50%) was obtained by column chromatography.
Step H:14-1 and 14-2 Synthesis
Formic acid (20. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (30. Mu.L) was added to the solution in an ice-water bath and stirred for 10 minutes. The above solution was added to a 1-H (0.05 mmol) dichloromethane solution, and the catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-toluenesulfonamide ] ruthenium (II) (5% mol) chloride, under argon, was added and reacted at room temperature for 8 hours. After the completion of the reaction, 20mL of methylene chloride was added, followed by washing with saturated sodium bicarbonate, drying, purification by high performance liquid chromatography, and freeze-drying, to give the objective products 1-1 (15 mg) and 1-2 (10 mg).
1 H-NMR(14-1)：(400MHz,DMSO-d 6 )δ11.07(s,1H),7.80(d,J＝8.6Hz,1H),7.65(d,J＝8.5Hz,1H),7.32 (d,J＝2.2Hz,1H),7.24(dd,J＝8.7,2.3Hz,1H),7.07-7.18(m,3H),6.91(t,J＝1.8Hz,1H),5.46-5.56(m,1H), 5.27(dq,J＝52.2,5.5Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.07(d,J＝12.9Hz,2H),3.56(m,2H),3.33(s,3H), 2.82-3.22(m,8H),2.54-2.68(m,7H),1.95-2.05(m,1H),1.82(d,J＝12.4Hz,2H),1.37-1.50(m,2H)；MS:[M+1] + : 792.2.
1 H-NMR(14-2)：(400MHz,DMSO-d 6 )δ11.07(s,1H),7.81(d,J＝8.5Hz,1H),7.65(d,J＝8.6Hz,1H),7.32 (d,J＝2.3Hz,1H),7.10-7.26(m,4H),6.92-6.95(m,1H),5.57(d,J＝16.3Hz,1H),5.23(dd,J＝50.3,4.6Hz,1H), 5.06(dd,J＝12.9,5.4Hz,1H),4.07(d,J＝13.0Hz,2H),3.50-3.60(m,2H),3.30(s,3H),2.82-3.06(m,6H),2.50- 2.65(m,9H),1.97-2.05(m,1H),1.82(d,J＝12.3Hz,2H),1.45(q,J＝11.3Hz,2H)；MS:[M+1] + :792.2.
Example 15
Compound 15-1: cis 2- (2, 6-dioxopiperidin-3-yl) -5- (6- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) -2, 6-diazaspiro [3.3] hept-2-yl) isoindoline-1, 3-dione.
Compound 15-2: trans 2- (2, 6-dioxopiperidin-3-yl) -5- (6- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) -2, 6-diazaspiro [3.3] hept-2-yl) isoindoline-1, 3-dione.
As shown in example 14-1, 15-1 and 15-2 were synthesized in a similar manner to 14-1.
1 H-NMR(15-1)：(400MHz,DMSO-d 6 )δ11.06(s,1H),7.81(d,J＝8.6Hz,1H),7.65(d,J＝8.3Hz,1H),7.29- 7.34(m,1H),7.22-7.27(m,1H),7.14(s,1H),7.09(d,J＝8.6Hz,1H),6.81(d,J＝2.1Hz,1H),6.67(dd,J＝8.3, 2.1Hz,1H),5.45-5.55(m,1H),5.28(dq,J＝51.9,5.5Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.54(s,2H),4.13- 4.30(m,6H),3.33(s,3H),2.80-3.25(m,4H),2.53-2.63(m,2H),1.95-2.05(m,1H)；MS:[M+1] + :721.2.
1 H-NMR(15-2)：(400MHz,DMSO-d 6 )δ11.06(s,1H),7.82(d,J＝8.6Hz,1H),7.65(d,J＝8.3Hz,1H),7.27- 7.35(m,2H),7.16(t,J＝1.7Hz,1H),7.11(d,J＝8.5Hz,1H),6.80(d,J＝2.1Hz,1H),6.67(dd,J＝8.3,2.2Hz, 1H),5.57(d,J＝16.3Hz,1H),5.24(dd,J＝50.3,4.7Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.54(s,2H),4.14- 4.29(m,6H),3.44(dd,J＝18.4,4.9Hz,2H),3.30(s,3H),2.82-3.07(m,2H),2.52-2.62(m,2H),1.95-2.05(m,1H)； MS:[M+1] + :721.2.
Example 16
Compound 16-1: cis-N- (2- (4- (1- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-5-yl) piperidin-4-yl) piperazin-1-yl) -2-oxoethyl) -3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzamide;
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Compound 16-2: trans-N- (2- (4- (1- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-5-yl) piperidin-4-yl) piperazin-1-yl) -2-oxoethyl) -3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzamide;
step A: preparation of intermediate 16-A
14-D (1 mmol), tert-butyl glycinate (1.1 mmol), EDCI (2 mmol), HOBT (2 mmol) and triethylamine (2 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 8h. After the completion of the reaction, 30mL of a saturated sodium chloride solution was added, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate and spin-drying, followed by column chromatography to give intermediate 16-A (0.6 mmol, yield 60%).
Step B: preparation of intermediate 16-B
The crude 16-A product obtained in Step A was dissolved in methylene chloride (5 mL), 3mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the solvent was removed by spin-drying to obtain intermediate 16-B.
Step C and Step D: the target compounds 16-1 and 16-2 were synthesized in a similar manner as described in example 14-1.
1 H-NMR(16-1)：(400MHz,DMSO-d 6 )δ11.07(s,1H),8.77(t,J＝5.7Hz,1H),7.79(d,J＝8.6Hz,1H),7.66 (d,J＝8.5Hz,1H),7.53-7.60(m,1H),7.42-7.44(m,1H),7.22-7.35(m,3H),7.08(d,J＝8.6Hz,1H),5.45-5.55(m, 1H),5.29(dq,J＝51.9,5.4Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.00-4.15(m,4H),2.82-3.50(m,14H),2.46- 2.62(m,6H),1.97-2.05(m,1H),1.83(d,J＝12.4Hz,2H),1.40-1.52(m,2H)；MS:[M+1] + :849.2.
1 H-NMR(16-2)：(400MHz,DMSO-d 6 )δ11.07(s,1H),8.78(t,J＝5.7Hz,1H),7.80(d,J＝8.6Hz,1H),7.66 (d,J＝8.6Hz,1H),7.55-7.60(m,1H),7.45-7.49(m,1H),7.32-7.37(m,2H),7.25(dd,J＝8.6,2.3Hz,1H),7.09(d, J＝8.6Hz,1H),5.57(d,J＝16.3Hz,1H),5.24(dd,J＝50.4,4.7Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.02-4.15 (m,4H),3.40-3.50(m,6H),3.30(s,3H),2.82-3.08(m,5H),2.45-2.61(m,6H),1.97-2.05(m,1H),1.83(d,J＝12.3 Hz,2H),1.40-1.52(m,2H)；MS:[M+1] + :849.2.
Example 17
Compound 17-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compound 17-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Step A: preparation of intermediate 17-A
3-Hydroxyazetidine-1-carboxylic acid tert-butyl ester (5 mmol) was dissolved in anhydrous DMF (10 mL), sodium hydride (6 mmol) was added under ice-water bath to react for 30min, 4-fluoro-7- (methylsulfonyl) -2, 3-dihydro spiro [ indene-1, 2' - [1,3] dioxolane ] (5 mmol) was added and reacted at room temperature for 4h. After the completion of the reaction, a saturated ammonium chloride solution (50 mL) was added, followed by ethyl acetate extraction, drying over anhydrous sodium sulfate and spin-drying to give intermediate 17-A.
Step B: preparation of intermediate 17-B
The crude 17-A product obtained in Step A was dissolved in a mixed solvent of 15mL of acetone and 3mL of water, and pyridine p-toluenesulfonate (PPTS, 2 mmol) was added thereto for reflux reaction. After the completion of the reaction, a part of the solvent was removed by rotary evaporation, and 40mL of a saturated sodium bicarbonate solution was added to conduct ethyl acetate extraction, drying over anhydrous sodium sulfate and rotary drying in this order to obtain intermediate 17-B.
Step C: preparation of intermediate 17-C
The crude 17-B product obtained in Step B was dissolved in 15mL of methanol, and SelectFluoro reagent (7.5 mmol) was added thereto and the reaction was refluxed for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was removed by rotary evaporation, the residue was dissolved in methylene chloride, the mixture was filtered, the filtrate was dried by rotary evaporation, and the filtrate was dissolved in 15mL of acetonitrile, 3mL of diluted hydrochloric acid (2M) was added, the reaction mixture was reacted at room temperature for 3 hours, and after the completion of the reaction, the filtrate was dried by rotary evaporation. The residue was dissolved in 20mL of methylene chloride, and the organic phase was washed with saturated sodium hydrogen chloride solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried by spin-drying, followed by column chromatography to give intermediate 17-C (2.5 mmol, comprehensive yield 50%).
Step D: preparation of intermediate 17-D
2- (2, 6-Dioxypiperidin-3-yl) -4- (prop-2-yn-1-ylamino) isoindoline-1, 3-dione (0.5 mmol), 2- (2-azidoethoxy) ethyl 4-methylbenzenesulfonate (0.5 mmol), copper sulfate (0.25 mmol) and sodium ascorbate (1.5 mmol) were dissolved in a mixed solvent of DMF (5 mL) and water (1 mL) and reacted at 70℃under argon for 4h. After the completion of the reaction, the mixture was cooled to room temperature, 30mL of a saturated sodium chloride solution was added, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and spin-drying was performed, whereby intermediate 17-D (0.3 mmol, yield 60%) was obtained by column chromatography.
Step E: preparation of intermediate 17-E
Intermediate 17-C (0.05 mmol), intermediate 17-D (0.05 mmol) and N, N-diisopropylethylamine DIPEA (0.1 mmol) were dissolved in DMSO (3 mL) and reacted at 80℃for 2h. After completion of the reaction, a saturated sodium chloride solution (20 mL) was added, extraction was performed with ethyl acetate, drying was performed over anhydrous sodium sulfate, and column chromatography was performed to obtain intermediate 17-E (20 mg, yield 55%).
Step F:17-1 and 17-2 preparation
Formic acid (10. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (15. Mu.L) was added thereto under ice-water bath, followed by stirring for 10 minutes. The above solution was added to a dichloromethane solution of 17-E (20 mg), and ruthenium (II) (5% mol) chloride (p-cymene) was added as a catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-methylbenzenesulfonamide ] and reacted at room temperature under argon atmosphere for 8 hours. After the completion of the reaction, 20mL of methylene chloride was added, followed by washing with saturated sodium bicarbonate, drying, purification by high performance liquid chromatography, and freeze-drying, to give the objective products 17-1 (5 mg) and 17-2 (4 mg).
1 H-NMR(17-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),8.23(s,1H),8.00(s,1H),7.70(d,J＝8.6Hz,1H), 7.56(dd,J＝8.5,7.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.00-7.10(m,2H),6.86(d,J＝8.7Hz,1H),5.42(dd,J＝7.3, 5.0Hz,1H),5.22(dq,J＝52.0,5.6Hz,1H),5.04(ddd,J＝12.8,5.4,2.0Hz,1H),4.77-4.87(m,1H),4.58(d,J＝6.1 Hz,2H),4.48(t,J＝5.1Hz,2H),3.74(t,J＝5.1Hz,2H),3.60-3.68(m,3H),3.33-3.37(m,2H),3.28(s,3H),2.79- 3.17(m,7H),2.53-2.60(m,1H),1.94-2.04(m,1H)；MS:[M+1] + :726.2.
1 H-NMR(17-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),8.29(s,1H),8.00(s,1H),7.72(d,J＝8.6Hz,1H), 7.56(dd,J＝8.6,7.1Hz,1H),7.17(d,J＝8.6Hz,1H),7.00-7.10(m,2H),6.89(d,J＝8.6Hz,1H),5.50(d,J＝16.5 Hz,1H),5.19(dd,J＝50.4,4.7Hz,1H),5.04(dd,J＝12.8,5.4Hz,1H),4.82-4.87(m,1H),4.58(d,J＝6.0Hz,2H), 4.48(t,J＝5.1Hz,2H),3.74(t,J＝5.2Hz,2H),3.60-3.68(m,3H),3.25-3.33(m,2H),3.23(s,3H),2.82-3.01(m, 5H),2.52-2.61(m,3H),1.95-2.02(m,1H)；MS:[M+1] + :726.2.
Example 18
Compound 18-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compound 18-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
As shown in example 17-1, the target compounds 18-1 and 18-2 were synthesized in a similar manner to 17-1.
1 H-NMR(18-1)：(400MHz,DMSO-d 6 )δ8.02(s,1H),7.70(d,J＝8.6Hz,1H),7.50-7.58(m,1H),7.16(d,J ＝8.6Hz,1H),7.01-7.11(m,2H),6.87(d,J＝8.7Hz,1H),5.81(s,1H),5.42(t,J＝6.0Hz,1H),5.22(dq,J＝52.1, 5.6Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.88(p,J＝5.6Hz,1H),4.60(d,J＝6.0Hz,2H),4.32(t,J＝5.9Hz, 2H),3.65-3.72(m,2H),3.28(s,3H),2.97-3.18(m,5H),2.85-2.95(m,3H),2.52-2.57(m,1H),1.97-2.06(m,1H)； MS:[M+1] + :682.2.
1 H-NMR(18-2)：(400MHz,DMSO-d 6 )δ8.02(s,1H),7.72(d,J＝8.5Hz,1H),7.54(t,J＝7.8Hz,1H),7.16 (d,J＝8.6Hz,1H),7.01-7.11(m,2H),6.91(d,J＝8.6Hz,1H),6.07(s,1H),5.50(d,J＝16.5Hz,1H),5.19(dd,J ＝50.4,4.6Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.90(p,J＝5.6Hz,1H),4.60(d,J＝6.1Hz,2H),4.33(t,J＝ 5.9Hz,2H),3.65-3.75(m,2H),3.23(s,3H),2.95-3.07(m,3H),2.82-2.94(m,4H),2.52-2.63(m,2H),1.97-2.07(m, 1H)；MS:[M+1] + :682.2.
Example 19
Compound 19-1:2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (4- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) piperidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
19 was synthesized as described in example 17-1 using a synthesis method similar to 17-1.
1 H NMR(19-1)：(400MHz,DMSO-d 6 )δ9.80(s,1H),8.38(t,J＝5.4Hz,1H),7.74(d,J＝9.7Hz,1H),7.63 (s,1H),7.54(dd,J＝7.9,7.0Hz,1H),7.39(dd,J＝6.9,1.2Hz,1H),7.20(dd,J＝7.9,1.1Hz,1H),6.94(d,J＝9.7 Hz,1H),5.48(t,J＝3.6Hz,1H),5.18-5.28(m,1H),5.00-5.15(m,1H),4.62(dd,J＝5.4,1.9Hz,2H),4.44-4.50(m, 1H),4.30(d,J＝5.7Hz,1H),4.21(t,J＝4.2Hz,2H),3.79(m,2H),3.55(m,2H),3.20(s,3H),3.14-3.18(m,1H), 3.09-3.12(m,1H),2.80-2.90(m,2H),2.67-2.75(m,2H),2.51-2.66(m,4H),2.14-2.22(m,1H),1.92-1.98(m,2H), 1.83-1.91(m,2H),1.74-1.80(m,1H).MS:[M+1] + :754.3。
Example 20
Compound 20-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- ((1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Compound 20-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- ((1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione.
Step A: preparation of intermediate 20-A
2- (2, 6-Dioxypiperidin-3-yl) -4, 7-difluoroisoindoline-1, 3-dione (3 mmol), propargylamine (1.5 mmol) and DIPEA (3 mmol) were dissolved in DMSO (5 mL) and reacted at 90℃for 2h. After the completion of the reaction, the reaction mixture was cooled to room temperature, and 40mL of a saturated sodium chloride solution was added thereto, followed by ethyl acetate extraction, drying over anhydrous sodium sulfate and column chromatography to obtain intermediate 20-A (1.3 mmol, yield 86.7%).
Step B-D: as shown in example 17-1, the target compounds 20-1 and 20-2 were synthesized using a synthesis method similar to that of 17-1.
1 H-NMR(20-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),8.00(s,1H),7.70(d,J＝8.6Hz,1H),7.47(t,J＝9.0 Hz,1H),7.23(dd,J＝9.4,3.3Hz,1H),7.03(t,J＝6.1Hz,1H),6.86(d,J＝8.7Hz,1H),5.42(dd,J＝7.3,5.0Hz, 1H),5.22(dq,J＝52.2,5.6Hz,1H),5.05(ddd,J＝12.8,5.4,1.9Hz,1H),4.83(p,J＝5.5Hz,1H),4.57(d,J＝6.0 Hz,2H),4.48(t,J＝5.1Hz,2H),3.74(t,J＝5.2Hz,2H),3.60-3.65(m,2H),3.36(t,J＝5.4Hz,2H),3.28(s,3H), 3.12(ddd,J＝16.1,14.0,6.4Hz,1H),2.80-3.05(m,5H),2.52-2.60(m,3H),1.95-2.05(m,1H)；MS:[M+1] + :744.2。
1 H-NMR(20-2)：(400MHz,DMSO-d 6 )δ11.11(s,1H),8.00(s,1H),7.72(d,J＝8.5Hz,1H),7.46(t,J＝9.0 Hz,1H),7.23(dd,J＝9.3,3.3Hz,1H),7.03(t,J＝6.1Hz,1H),6.90(d,J＝8.6Hz,1H),5.49(d,J＝16.6Hz,1H), 5.19(dd,J＝50.5,4.6Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.86(p,J＝6.0Hz,1H),4.57(d,J＝6.1Hz,2H), 4.48(t,J＝5.1Hz,2H),3.74(t,J＝5.2Hz,2H),3.62-3.70(m,2H),3.25-3.30(m,2H),3.23(s,3H),2.81-3.03(m, 4H),2.51-2.60(m,5H),1.96-2.03(m,1H)；MS:[M+1] + :744.2。
Example 21
Compound 21-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 21-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) piperazin-1-yl) isoindoline-1, 3-dione.
Step A: preparation of intermediate 21-A
2, 4-difluoro-1, 1-dimethoxy-7- (methylsulfonyl) -2, 3-dihydro-1H-indene (1 mmol), tert-butyl 4- (azetidin-3-yl) piperazine-1-carboxylate (1 mmol) and cesium bicarbonate (2 mmol) were dissolved in DMSO (3 mL) and reacted by microwave at 90℃for 2H. After the completion of the reaction, the mixture was cooled to room temperature, saturated sodium chloride solution (30 mL) was added thereto, extraction was performed with ethyl acetate, and drying was performed with anhydrous sodium sulfate, whereby intermediate 21-A (0.31 mmol, yield 31%) was obtained by column chromatography.
Step B: preparation of intermediate 21-B
Intermediate 21-A (0.31 mmol), pyridine p-toluenesulfonate (0.1 mmol) was dissolved in a mixed solvent of acetone (5 mL) and water (1 mL) and reacted under reflux for 1h. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was dried by spinning, methylene chloride (20 mL) was dissolved, and the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried by spinning to give intermediate 21-B, which was directly used for the subsequent synthesis.
Step C: preparation of intermediate 21-C
Formic acid (40. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (85. Mu.L) was added thereto under ice-water bath, followed by stirring for 10 minutes. The solution was added to the above-mentioned dichloromethane solution of 21-B, and ruthenium (II) (5% mol) was reacted at room temperature under the protection of argon gas by adding a catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-methylbenzenesulfonamide ] chloride (p-cymene) for 8 hours. After the reaction was completed, 20mL of methylene chloride was added, washed with saturated sodium bicarbonate, dried, purified by high performance liquid chromatography, and freeze-dried to obtain intermediate 21-C (0.17 mmol, comprehensive yield: 55%).
Step D: preparation of intermediate 21-D
Intermediate 21-C (0.17 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added at room temperature, reacted for 1h at room temperature, and spin-dried to dissolve to give intermediate 21-D, which was used directly in the subsequent synthesis.
Step E:21-1 and 21-2 preparation
Intermediate 21-D was dissolved in DMF (3 mL), 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.17 mmol), DIPEA (0.34 mmol) was added and reacted at 90℃for 2h. After the reaction was completed, the mixture was cooled to room temperature, saturated sodium chloride solution was added thereto, extraction was performed with ethyl acetate, and drying was performed with anhydrous sodium sulfate, whereby the target compounds 21-1 (11 mg) and 21-2 (7 mg) were obtained by purification of the preparative high-performance liquid phase.
1 H-NMR(21-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.71(t,J＝7.8Hz,1H),7.56(d,J＝8.6Hz,1H), 7.32-7.40(m,2H),6.42(d,J＝8.7Hz,1H),5.36(t,J＝5.1Hz,1H),5.04-5.24(m,2H),4.19(q,J＝7.5Hz,2H), 3.90-4.00(m,2H),2.80-3.50(m,13H),2.53-2.64(m,5H),1.98-2.05(m,1H)；MS:[M+1]+:626.2。
1 H-NMR(21-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.67-7.75(m,1H),7.57(d,J＝8.5Hz,1H),7.32- 7.38(m,2H),6.44(d,J＝8.6Hz,1H),5.45(d,J＝16.6Hz,1H),5.04-5.20(m,2H),4.20(q,J＝8.1Hz,2H),3.92- 4.02(m,2H),3.39-3.55(m,4H),3.17(s,3H),2.82-3.10(m,4H),2.53-2.62(m,7H),1.98-2.06(m,1H)；MS:[M+1]+: 626.2。
Example 22
Compound 22-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 22-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 22-1 and 22-2 were synthesized as described in example 21-1, using a similar procedure as 21-1.
1 H-NMR(22-1)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.67(t,J＝8.2Hz,1H),7.35(d,J＝2.3Hz,1H),7.27 (dd,J＝8.6,2.3Hz,1H),7.01(d,J＝8.7Hz,1H),5.42(t,J＝4.9Hz,1H),5.03-5.23(m,2H),3.42-3.57(m,6H), 3.25(s,3H),3.02-3.15(m,2H),2.79-2.95(m,2H),2.64-2.71(m,5H),2.53-2.63(m,3H),1.98-2.05(m,1H),1.85- 1.95(m,2H),1.52-1.70(m,2H)；MS:[M+1] + :654.2。
1 H-NMR(22-2)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.68(dd,J＝8.5,2.5Hz,2H),7.35(d,J＝2.3Hz,1H), 7.24-7.30(m,1H),7.05(d,J＝8.6Hz,1H),5.49(d,J＝15.3Hz,1H),5.04-5.25(m,2H),3.42-3.59(m,7H),3.22(s, 3H),2.82-2.93(m,3H),2.51-2.73(m,8H),1.85-2.05(m,3H),1.49-1.69(m,2H)；MS:[M+1] + :654.2。
Example 23
Compound 23-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 23-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Step A: preparation of intermediate 23-A
2, 4-difluoro-1, 1-dimethoxy-7- (methylsulfonyl) -2, 3-dihydro-1H-indene (250 mg), tert-butyl 4- (azetidin-3-ylmethyl) piperazine-1-carboxylate (218 mg), and potassium carbonate (236 mg) were dissolved in DMF (5 mL) and reacted at 90℃for 2 hours. After the completion of the reaction, the mixture was cooled to room temperature, saturated sodium chloride solution (30 mL) was added thereto, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain intermediate 23-A (400 mg, yield 88%).
Step B: preparation of intermediate 23-B
Intermediate 23-A (400 mg) was dissolved in a mixed solvent of acetone (8 mL) and water (2 mL) and reacted under reflux for 1h. After the reaction, cooling to room temperature, removing part of solvent by rotary evaporation, adding saturated sodium bicarbonate solution (20 mL), extracting by ethyl acetate, drying by anhydrous sodium sulfate, and rotary drying to obtain an intermediate 23-B, which is directly used for subsequent synthesis.
Step C: preparation of intermediate 23-C
Intermediate 23-B obtained in Step B was dissolved in methylene chloride (10 mL), and trifluoroacetic acid (5 mL) was added thereto for reaction at room temperature for 2h. After the reaction is finished, the intermediate 23-C is dried by spin drying and is directly used for subsequent synthesis.
Step D: synthesis of intermediate 23-D
Intermediate 23-C (50 mg), 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione (37 mg), DIPEA (34 mg) was dissolved in DMSO (2 mL) and reacted at 90℃for 2h. After completion of the reaction, the mixture was cooled to room temperature, saturated sodium chloride solution (20 mL) was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and isolated by preparative thin layer chromatography as intermediate 23-D (23 mg, yield 28%).
Step E: preparation of 23-1 and 23-2
Formic acid (10. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (15. Mu.L) was added thereto under ice-water bath, followed by stirring for 10 minutes. The above solution was added to a dichloromethane solution of 23-D (23 mg), and ruthenium (II) (5% mol) chloride (p-cymene) was added as a catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-methylbenzenesulfonamide ] and reacted at room temperature under argon atmosphere for 8 hours. After the completion of the reaction, 20mL of methylene chloride was added, followed by washing with saturated sodium bicarbonate, drying, purification by high performance liquid chromatography, and freeze-drying, to give the objective products 23-1 (7 mg) and 23-2 (5 mg).
1 H-NMR(23-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.67-7.75(m,1H),7.54(d,J＝8.6Hz,1H),7.30-7.40 (m,2H),6.40(d,J＝8.7Hz,1H),5.35(t,J＝5.0Hz,1H),5.02-5.22(m,2H),4.21(q,J＝7.6Hz,2H),3.77(t,J＝ 6.7Hz,2H),2.80-3.40(m,13H),2.54-2.68(m,7H),1.97-2.06(m,1H)；MS:[M+1] + :640.2。
1 H-NMR(23-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.71(dd,J＝8.4,7.2Hz,1H),7.55(d,J＝8.5Hz,1H), 7.35(m,2H),6.41(d,J＝8.6Hz,1H),5.44(d,J＝16.5Hz,1H),5.02-5.20(m,2H),4.23(q,J＝8.1Hz,2H),3.78 (m,2H),3.26-3.56(m,6H),3.16(s,3H),2.82-3.07(m,4H),2.53-2.69(m,7H),1.99-2.06(m,1H)；MS:[M+1] + : 640.2。
Example 24
Compound 24-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 24-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 24-1 and 24-2 were synthesized as described in example 23-1, using a procedure similar to 23-1.
1 H-NMR(24-1)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.69(d,J＝8.5Hz,1H),7.37(m,1H),7.28(d,J＝8.3 Hz,1H),6.39(d,J＝8.6Hz,1H),5.60(d,J＝6.4Hz,1H),5.35(q,J＝5.3Hz,1H),5.01-5.23(m,2H),4.22(q,J＝ 7.8Hz,2H),3.72-3.82(m,2H),3.40-3.52(m,4H),3.07-3.23(m,6H),2.82-2.92(m,2H),2.55-2.70(m,7H),1.97- 2.05(m,1H)；MS:[M+1] + :640.2。
1 H-NMR(24-2)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.68(d,J＝8.5Hz,1H),7.55(d,J＝8.5Hz,1H),7.35 (d,J＝2.3Hz,1H),7.27(dd,J＝8.7,2.4Hz,1H),6.41(d,J＝8.6Hz,1H),5.44(d,J＝16.5Hz,1H),5.02-5.20(m, 2H),4.22(q,J＝7.8Hz,2H),3.74-3.82(m,2H),3.42-3.53(m,6H),3.16(s,3H),2.82-3.08(m,3H),2.55-2.70(m, 8H),1.97-2.05(m,1H)；MS:[M+1] + :640.2。
Example 25
Compound 25-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 25-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Target compounds 25-1 and 25-2 were synthesized as described in example 23-1, using a similar procedure as 23-1.
1 H-NMR(25-1)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.73(d,J＝11.4Hz,1H),7.54(d,J＝8.6Hz,1H), 7.46(d,J＝7.4Hz,1H),6.39(d,J＝8.7Hz,1H),5.59(d,J＝6.4Hz,1H),5.31-5.37(m,1H),5.02-5.22(m,2H), 4.21(q,J＝7.7Hz,2H),3.76(t,J＝6.7Hz,2H),3.22-3.27(m,4H),3.05-3.21(m,5H),2.82-3.00(m,2H),2.52-2.68 (m,8H),1.98-2.05(m,1H)；MS:[M+1] + :658.2。
1 H-NMR(25-2)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.73(d,J＝11.4Hz,1H),7.55(d,J＝8.5Hz,1H), 7.46(d,J＝7.4Hz,1H),6.41(d,J＝8.6Hz,1H),5.85(m,1H),5.44(d,J＝16.5Hz,1H),5.02-5.20(m,2H),4.22 (q,J＝7.9Hz,2H),3.75-3.82(m,2H),3.38-3.52(m,1H),3.25(m,4H),3.16(s,3H),2.82-3.07(m,3H),2.52-2.69 (m,8H),1.97-2.06(m,1H)；MS:[M+1] + :658.2。
Example 26
Compound 26-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 26-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 26-1 and 26-2 were synthesized as described in example 23-1, using a procedure analogous to 23-1.
1 H-NMR(26-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.63-7.75(m,2H),7.30-7.40(m,2H),7.00(d,J＝8.7 Hz,1H),5.63-5.75(m,1H),5.42(t,J＝4.8Hz,1H),5.03-5.24(m,2H),3.45-3.52(m,2H),3.30-3.35(m,2H),3.25 (s,3H),3.02-3.19(m,2H),2.77-2.92(m,2H),2.52-2.71(m,8H),2.27(d,J＝7.1Hz,2H),1.99-2.06(m,1H),1.70- 1.90(m,3H),1.16-1.37(m,3H)；MS:[M+1] + :668.2。
1 H-NMR(26-2)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.64-7.75(m,2H),7.30-7.40(m,2H),7.03(d,J＝8.6 Hz,1H),5.85-6.00(m,1H),5.49(d,J＝15.4Hz,1H),5.05-5.25(m,2H),3.44-3.54(m,2H),3.30-3.40(m,3H),3.22 (s,3H),2.77-2.93(m,3H),2.52-2.69(m,8H),2.27(d,J＝7.1Hz,2H),1.99-2.06(m,1H),1.71-1.92(m,3H),1.18- 1.40(m,3H)；MS:[M+1] + :668.2。
Example 27
Compound 27-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 27-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 27-1 and 27-2 were synthesized as described in example 23-1, using a procedure analogous to 23-1.
1 H-NMR(27-1)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.60(t,J＝8.8Hz,1H),7.54(d,J＝8.6Hz,1H),7.40 (dd,J＝9.2,3.6Hz,1H),6.39(d,J＝8.6Hz,1H),5.36(m,1H),5.03-5.22(m,2H),4.21(q,J＝7.6Hz,2H),3.76(t, J＝6.7Hz,2H),3.21-3.23(m,4H),3.20(s,3H),2.81-3.12(m,5H),2.53-2.69(m,7H),1.96-2.06(m,1H)；MS: [M+1] + :658.2。
1 H-NMR(27-2)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.60(t,J＝8.9Hz,1H),7.55(d,J＝8.5Hz,1H),7.40 (dd,J＝9.3,3.7Hz,1H),6.41(d,J＝8.6Hz,1H),5.44(d,J＝16.6Hz,1H),5.12(dd,J＝50.7,4.5Hz,1H),5.09 (dd,J＝12.8,5.5Hz,1H),4.23(q,J＝8.1Hz,2H),3.75-3.83(m,2H),3.20-3.25(m,4H),3.16(s,3H),2.82-3.06 (m,5H),2.66(d,J＝7.5Hz,2H),2.53-2.62(m,5H),1.98-2.07(m,1H)；MS:[M+1] + :658.2。
Example 28
Compound 28-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 28-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 28-1 and 28-2 were synthesized as described in example 23-1, using a similar procedure as 23-1.
1 H-NMR(28-1)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.67(t,J＝8.6Hz,2H),7.35(d,J＝2.3Hz,1H),7.26 (dd,J＝8.7,2.3Hz,1H),7.00(d,J＝8.7Hz,1H),5.71(d,J＝6.5Hz,1H),5.42(dt,J＝6.6,4.8Hz,1H),5.03-5.23 (m,2H),3.42-3.53(m,6H),3.25(s,3H),2.99-3.18(m,2H),2.78-2.95(m,2H),2.53-2.71(m,6H),2.26(d,J＝7.1 Hz,2H),1.98-2.05(m,1H),1.72-1.90(m,3H),1.17-1.37(m,3H)；MS:[M+1] + :668.2。
1 H-NMR(28-2)：(400MHz,DMSO-d 6 )δ11.07(s,1H),7.68(dd,J＝8.5,2.7Hz,2H),7.35(d,J＝2.2Hz,1H), 7.26(dd,J＝8.6,2.3Hz,1H),7.03(d,J＝8.6Hz,1H),5.94(s,1H),5.49(d,J＝15.3Hz,1H),5.03-5.26(m,2H), 3.42-3.53(m,6H),3.22(s,3H),2.77-2.94(m,4H),2.53-2.68(m,6H),2.26(d,J＝7.1Hz,2H),1.98-2.03(m,1H), 1.70-1.90(m,3H),1.18-1.40(m,3H)；MS:[M+1] + :668.2。
Example 29
Compound 29-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 29-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 29-1 and 29-2 were synthesized as described in example 23-1, using a similar procedure as 23-1.
1 H-NMR(29-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.73(d,J＝11.4Hz,1H),7.66(d,J＝8.5Hz,1H), 7.46(d,J＝7.4Hz,1H),7.00(d,J＝8.7Hz,1H),5.71(s,1H),5.37-5.46(m,1H),5.04-5.24(m,2H),3.18-3.30(m, 8H),3.00-3.14(m,2H),2.77-2.95(m,2H),2.53-2.73(m,8H),2.27(d,J＝7.1Hz,2H),2.00-2.07(m,1H),1.7-1.90 (m,3H),1.15-1.35(m,2H)；MS:[M+1] + :686.2。
1 H-NMR(29-2)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.73(d,J＝11.4Hz,1H),7.68(d,J＝8.5Hz,1H), 7.46(d,J＝7.4Hz,1H),7.03(d,J＝8.6Hz,1H),5.94(d,J＝6.2Hz,1H),5.49(dd,J＝15.2,4.6Hz,1H),5.04-5.26 (m,2H),3.44-3.54(m,2H),3.25-3.30(m,5H),3.22(s,3H),2.77-2.96(m,3H),2.53-2.67(m,8H),2.28(d,J＝7.1 Hz,2H),2.00-2.08(m,1H),1.70-1.90(m,3H),1.18-1.41(m,2H)；MS:[M+1] + :686.2。
Example 30
Compound 30-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 30-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 30-1 and 30-2 were synthesized as described in example 23-1, using a similar procedure as 23-1.
1 H-NMR(30-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.63-7.75(m,2H),7.30-7.40(m,2H),7.00(d,J＝8.6 Hz,1H),5.42(t,J＝4.8Hz,1H),5.02-5.22(m,2H),3.26-3.35(m,4H),3.25(s,3H),3.00-3.16(m,3H),2.75-2.92 (m,3H),2.53-2.69(m,7H),2.42(t,J＝6.9Hz,2H),1.98-2.07(m,1H),1.75-1.85(m,2H),1.20-1.55(m,6H)；MS: [M+1] + :682.2。
1 H-NMR(30-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.64-7.75(m,2H),7.30-7.37(m,2H),7.03(d,J＝8.6 Hz,1H),5.49(d,J＝15.4Hz,1H),5.06-5.25(m,2H),3.26-3.35(m,4H),3.22(s,3H),2.77-2.94(m,4H),2.52-2.67 (m,7H),2.39-2.45(m,2H),1.97-2.07(m,1H),1.81(t,J＝13.6Hz,2H),1.21-1.59(m,6H)；MS:[M+1] + :682.2。
Example 31
Compound 31-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 31-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione.
The target compounds 31-1 and 31-2 were synthesized as described in example 23-1, using a similar procedure as 23-1.
1 H-NMR(31-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.73(d,J＝11.4Hz,1H),7.66(d,J＝8.5Hz,1H), 7.46(d,J＝7.4Hz,1H),7.00(d,J＝8.6Hz,1H),5.42(t,J＝4.8Hz,1H),5.03-5.22(m,2H),3.47(d,J＝12.3Hz, 2H),3.34(d,J＝11.8Hz,2H),3.25(s,3H),2.98-3.18(m,3H),2.74-2.95(m,3H),2.53-2.68(m,7H),2.37-2.45(m, 2H),2.00-2.08(m,1H),1.81(d,J＝12.4Hz,2H),1.20-1.53(m,6H)；MS:[M+1] + :700.2。
1 H-NMR(31-2)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.73(d,J＝11.4Hz,1H),7.67(d,J＝8.5Hz,1H), 7.46(d,J＝7.4Hz,1H),7.03(d,J＝8.6Hz,1H),5.49(d,J＝15.4Hz,1H),5.06-5.26(m,2H),3.33-3.51(m,7H), 3.22(s,3H),2.77-2.95(m,3H),2.53-2.67(m,7H),2.41(t,J＝7.2Hz,2H),2.00-2.07(m,1H),1.81(t,J＝12.9Hz, 2H),1.21-1.58(m,6H)；MS:[M+1] + :700.2。
Example 32
Compound 32-1: cis-5- (4- ((1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione.
Compound 32-2: trans-5- (4- ((1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione.
Step A: preparation of intermediate 32-A
7- (difluoromethyl) sulfonyl) -4-fluoro-2, 3-dihydro-1H-inden-1-one (1 mmol) and SelectFluoro reagent (1.5 mmol) were dissolved in methanol (10 mL) and reacted under reflux for 6H. After the reaction was completed. Cooled to room temperature, the solvent was removed by rotary evaporation, the residue was dissolved in dichloromethane, filtered, and the filtrate was rotary dried to give intermediate 32-A, which was used directly in the subsequent synthesis (0.89 mmol, yield 89%).
Step B: preparation of intermediate 32-B
Intermediate 32-A (100 mg), tert-butyl 4- (azetidin-3-ylmethyl) piperazine-1-carboxylate (90 mg), triethylamine (72 mg) were dissolved in DMSO (3 mL) and reacted at 90 ℃. After the completion of the reaction, the mixture was cooled to room temperature, saturated sodium chloride solution (20 mL) was added, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give intermediate 32-B (120 mg, yield 65.6%).
Step C: preparation of intermediate 32-C
Intermediate 32-B (120 mg) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (2 mL) was added thereto for reaction at room temperature. After completion, spin-drying to obtain intermediate 32-C, which is directly used for subsequent synthesis.
Step D: preparation of intermediate 32-D
Intermediate 32-C (80 mg), 2- (2, 6-dioxopiperidin-3-yl) -5, 6-difluoroisoindoline-1, 3-dione (113 mg), DIPEA (50 mg) was dissolved in DMSO (3 mL) and reacted at 90℃for 2h. After the completion of the reaction, a saturated sodium chloride solution (20 mL) was added, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, and column chromatography to give intermediate 32-D (25 mg, yield 18.8%).
Step E: preparation of Compounds 32-1 and 32-2
Formic acid (10. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (15. Mu.L) was added thereto under ice-water bath, followed by stirring for 10 minutes. The above solution was added to a dichloromethane solution of 32-D (25 mg), and ruthenium (II) (5% mol) chloride (p-cymene) was added as a catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-methylbenzenesulfonamide ] and reacted at room temperature under argon atmosphere for 8 hours. After the completion of the reaction, 20mL of methylene chloride was added, followed by washing with saturated sodium bicarbonate, drying, purification by high performance liquid chromatography, and freeze-drying, to give the objective products 32-1 (7 mg) and 32-2 (5 mg).
1 H-NMR(32-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.73(d,J＝11.3Hz,1H),7.57(d,J＝8.7Hz,1H), 7.46(d,J＝7.4Hz,1H),7.03(t,J＝53.9Hz,1H),6.42(d,J＝8.8Hz,1H),5.07-5.28(m,3H),4.30(t,J＝8.1Hz, 2H),3.87(t,J＝6.8Hz,2H),3.22-3.30(m,5H),2.83-3.19(m,4H),2.53-2.70(m,8H),1.98-2.08(m,1H)；MS: [M+1] + :694.2。
1 H-NMR(32-2)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.73(d,J＝11.4Hz,1H),7.57(d,J＝8.6Hz,1H), 7.46(d,J＝7.4Hz,1H),6.94(t,J＝53.7Hz,1H),6.44(d,J＝8.8Hz,1H),5.29(d,J＝16.9Hz,1H),5.03-5.20(m, 2H),4.25-4.39(m,2H),3.85-3.93(m,2H),3.50-3.60(m,1H),3.20-3.30(m,4H),2.81-3.14(m,4H),2.52-2.75(m, 8H),1.98-2.08(m,1H)；MS:[M+1] + :694.2。
Example 33
Compound 33-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 33-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compounds 33-1 and 33-2 were synthesized as described in example 23-1 using a procedure similar to 23-1.
1 H-NMR(33-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.74(dd,J＝8.4,7.2Hz,1H),7.56(d,J＝8.6Hz,1H), 7.41(d,J＝7.1Hz,1H),7.36(d,J＝8.4Hz,1H),6.45(d,J＝8.6Hz,1H),5.61(d,J＝6.5Hz,1H),5.35(q,J＝5.4 Hz,1H),5.04-5.23(m,2H),4.31(q,J＝8.1Hz,2H),4.21(t,J＝6.9Hz,2H),3.85-3.95(m,1H),3.65-3.73(m,2H), 3.50-3.58(m,2H),3.25-3.28(m,2H),3.05-3.24(m,5H),2.82-2.96(m,1H),2.53-2.65(m,3H),2.00-2.07(m,1H)； MS:[M+1] + :654.2。
1 H-NMR(33-2)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.74(dd,J＝8.4,7.2Hz,1H),7.57(d,J＝8.5Hz,1H), 7.41(d,J＝7.1Hz,1H),7.37(d,J＝8.4Hz,1H),6.47(d,J＝8.6Hz,1H),5.85-5.91(m,1H),5.44(dd,J＝16.5,4.4 Hz,1H),5.04-5.21(m,2H),4.33(dt,J＝15.4,8.1Hz,2H),4.23(q,J＝7.5Hz,2H),3.85-3.95(m,1H),3.65-3.75 (m,2H),3.52-3.58(m,2H),3.42-3.51(m,2H),3.17(s,3H),2.83-3.08(m,3H),2.52-2.65(m,3H),2.00-2.07(m, 1H)；MS:[M+1] + :654.2。
Example 34
Compound 34-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 34-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compounds 34-1 and 34-2 were synthesized as described in example 23-1 using a procedure similar to 23-1.
1 H-NMR(34-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.78(d,J＝11.2Hz,1H),7.56(d,J＝8.6Hz,1H), 7.50(d,J＝7.3Hz,1H),6.46(d,J＝8.6Hz,1H),5.62(d,J＝6.6Hz,1H),5.36(q,J＝5.4Hz,1H),5.05-5.24(m, 2H),4.31(q,J＝8.1Hz,2H),4.21(t,J＝6.9Hz,2H),3.84-3.96(m,1H),3.65-3.70(m,2H),3.50-3.56(m,2H), 3.18-3.28(m,5H),2.82-3.13(m,3H),2.52-2.65(m,3H),2.00-2.10(m,1H)；MS:[M+1] + :672.2。
1 H-NMR(34-2)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.78(d,J＝11.2Hz,1H),7.57(d,J＝8.5Hz,1H), 7.50(d,J＝7.3Hz,1H),6.47(d,J＝8.6Hz,1H),5.83-5.90(m,1H),5.44(d,J＝16.4Hz,1H),5.05-5.21(m,2H), 4.33(dt,J＝13.8,8.1Hz,2H),4.23(q,J＝7.6Hz,2H),3.88-3.97(m,1H),3.63-3.70(m,2H),3.49-3.59(m,2H), 2.82-3.21(m,8H),2.53-2.62(m,2H),2.00-2.08(m,1H)；MS:[M+1] + :672.2。
Example 35
Compound 35-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -2-oxoethyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 35-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -2-oxoethyl) piperazin-1-yl) isoindoline-1, 3-dione.
Step A: preparation of intermediate 35-A
2- (2, 6-Dioxypiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (1 mmol), tert-butyl 2- (piperazin-1-yl) acetate (1 mmol) and DIPEA (2 mmol) were dissolved in DMSO (6 mL), reacted at 90℃for 2h, cooled to room temperature after the reaction was completed, saturated sodium chloride solution (40 mL) was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spun dry to give intermediate 35-A, which was directly used for the subsequent synthesis.
Step B: preparation of intermediate 35-B
The product from Step A was dissolved in methylene chloride (10 mL), and trifluoroacetic acid (5 mL) was added thereto for reaction at room temperature. After the reaction is finished, the solvent is dried by spinning to obtain an intermediate 35-B, which is directly used for subsequent synthesis.
Step C: preparation of intermediate 35-C
Intermediate 35-B (30 mg), intermediate 17-C (22.5 mg), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDCI (29 mg) and 1-hydroxybenzotriazole HOBT (20 mg) were dissolved in DMF (3 mL) and reacted at room temperature. After the completion of the reaction, a saturated sodium chloride solution (20 mL) was added, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, and column chromatography to give intermediate 35-C (37 mg, yield 71%).
Step D: preparation of Compounds 35-1 and 35-2
Formic acid (20. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (30. Mu.L) was added thereto under ice-water bath to stir for 10min. The above solution was added to a 35-C (37 mg) methylene chloride solution, and ruthenium (II) (5% mol) chloride (p-cymene) catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-methylbenzenesulfonamide ] was added thereto, followed by reaction at room temperature under argon atmosphere for 8 hours. After the completion of the reaction, 20mL of methylene chloride was added, followed by washing with saturated sodium bicarbonate, drying, purification by high performance liquid chromatography, and freeze-drying to give the target products 35-1 (13 mg) and 35-2 (8 mg).
1 H-NMR(35-1)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.74(d,J＝8.6Hz,1H),7.68(d,J＝8.4Hz,1H),7.35 (d,J＝2.3Hz,1H),7.25(dd,J＝8.8,2.3Hz,1H),6.92(d,J＝8.6Hz,1H),5.85(d,J＝6.9Hz,1H),5.40-5.48(m, 1H),5.14-5.35(m,2H),5.07(dd,J＝12.9,5.4Hz,1H),4.68-4.76(m,1H),4.35-4.44(m,1H),4.18-4.25(m,1H), 3.80-3.90(m,1H),3.40-3.50(m,4H),3.29(s,3H),2.82-3.20(m,6H),2.54-2.65(m,5H),1.96-2.06(m,1H)；MS: [M+1] + :684.2。
1 H-NMR(35-2)：(400MHz,DMSO-d 6 )δ11.08(s,1H),7.76(d,J＝8.6Hz,1H),7.68(d,J＝8.5Hz,1H),7.35 (d,J＝2.3Hz,1H),7.25(d,J＝8.7Hz,1H),6.92-6.99(m,1H),6.09(t,J＝5.5Hz,1H),5.51(dd,J＝16.5,5.7Hz, 1H),5.14-5.29(m,2H),5.07(dd,J＝12.9,5.4Hz,1H),4.70-4.78(m,1H),4.36-4.43(m,1H),4.20-4.30(m,1H), 3.88(d,J＝10.9Hz,1H),3.40-3.50(m,4H),3.25(s,3H),2.81-3.12(m,6H),2.52-2.68(m,5H),1.97-2.05(m,1H)； MS:[M+1] + :684.2。
Example 36
Compound 36-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) piperidin-1-yl) isoindoline-1, 3-dione.
Compound 36-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) piperidin-1-yl) isoindoline-1, 3-dione.
Compounds 36-1 and 36-2 were synthesized as described in example 23-1 using a procedure similar to 23-1.
1 H-NMR(36-1)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.74(d,J＝8.6Hz,1H),7.70(d,J＝11.4Hz,1H), 7.43(d,J＝7.4Hz,1H),6.92(d,J＝8.7Hz,1H),5.79-5.90(m,1H),5.40-5.48(m,1H),5.04-5.36(m,3H),4.63(m, 1H),4.35(m,1H),4.15(m,1H),3.76-3.85(m,1H),3.59(d,J＝12.0Hz,2H),3.30(s,3H),2.79-3.21(m,4H),2.50- 2.63(m,2H),2.14(m,2H),1.99-2.07(m,1H),1.78(d,J＝12.6Hz,2H),1.49(m,3H),1.20-1.35(m,3H)；MS: [M+1] + :669.2。
1 H-NMR(36-2)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.76(d,J＝8.6Hz,1H),7.70(d,J＝11.4Hz,1H), 7.43(d,J＝7.4Hz,1H),6.95(d,J＝8.6Hz,1H),6.05-6.14(m,1H),5.52(d,J＝16.5Hz,1H),5.05-5.31(m,3H), 4.58-4.58(m,1H),4.30-4.40(m,1H),4.12-4.20(m,1H),3.83(d,J＝10.7Hz,1H),3.59(d,J＝12.0Hz,2H),3.25 (s,3H),2.80-3.05(m,4H),2.53-2.67(m,2H),2.15(t,J＝7.4Hz,2H),1.99-2.06(m,1H),1.78(d,J＝12.6Hz,2H), 1.40-1.53(m,3H),1.20-1.35(m,3H)；MS:[M+1] + :669.2。
Example 37
Compound 37-1: cis-N- (2- (4- (2, 6-dioxapiperidin-3-yl) -6-fluoro-1, 3-dioxaindol-5-yl) piperazin-1-yl) -2-oxoethyl) -1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carboxamide;
step A: preparation of intermediate 37-A
1- ((benzyloxy) carbonyl) azetidine-3-carboxylic acid (100 mg), tert-butyl glycine (56 mg), EDCI (163 mg), HOBT (115 mg) and triethylamine (85 mg) were dissolved in DMF (3 mL) and reacted at room temperature. After the reaction, saturated sodium chloride solution (30 mL) is added, ethyl acetate extraction, anhydrous sodium sulfate drying and spin drying are sequentially carried out to obtain an intermediate 37-A, which is directly used for subsequent synthesis.
Step B: preparation of intermediate 37-B
Intermediate 37-A obtained in Step A was dissolved in methanol (8 mL), followed by addition of palladium hydroxide (50 mg), and reaction was carried out under hydrogen overnight. After the reaction is finished, filtering, and spin-drying filtrate to obtain an intermediate 37-B, which is directly used for subsequent synthesis.
Step C: preparation of intermediate 37-C
Intermediate 37-B (40 mg), 2, 4-difluoro-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-1-one (46 mg) and potassium carbonate (53 mg) obtained in Step B were dissolved in DMF (2 mL) and reacted at 80 ℃. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then a saturated sodium chloride solution (20 mL) was added thereto, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, and column chromatography to give intermediate 37-C (15 mg, yield 18.2%).
Step D: preparation of intermediate 37-D
Intermediate 37-C (15 mg) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (2 mL) was added to react at room temperature. After the reaction is finished, the solvent is dried by spinning to obtain an intermediate 37-D, which is directly used for subsequent synthesis.
Step E: synthesis of intermediate 37-E
2- (2, 6-Dioxypiperidin-3-yl) -5, 6-difluoroisoindoline-1, 3-dione (50 mg), tert-butylpiperazine-1-carboxylate (22 mg) and DIPEA (22 mg) were dissolved in DMSO (2 mL) and reacted at 90℃for 1h. After the reaction is finished, cooling to room temperature, adding saturated sodium chloride solution (20 mL), sequentially extracting with ethyl acetate, drying with anhydrous sodium sulfate, and spin-drying to obtain an intermediate 37-E, which is directly used for subsequent synthesis.
Step F: synthesis of intermediate 37-F
The 37-E obtained in Step E was dissolved in methylene chloride (3 mL), trifluoroacetic acid (1 mL) was added to react at room temperature, and after the reaction was completed, the intermediate 37-F was obtained by spin-drying and used directly for the subsequent synthesis.
Step G: synthesis of intermediate 37-G
Intermediate 37-D obtained in Step D, intermediate 37-G, EDCI (15 mg) obtained in Step G and HOBT (10 mg) were dissolved in DMF (2 mL), reacted at room temperature, and after the reaction was completed, a saturated sodium chloride solution was added, followed by ethyl acetate extraction, drying over anhydrous sodium sulfate, and column chromatography to obtain intermediate 37-G (15 mg).
Step H: synthesis of Compound 37-1
Formic acid (10. Mu.L) was dissolved in 1mL of methylene chloride, and triethylamine (15. Mu.L) was added thereto under ice-water bath, followed by stirring for 10 minutes. The above solution was added to a dichloromethane solution of 37-G (15 mg), and ruthenium (II) (5% mol) chloride (p-cymene) was added as a catalyst [ (R, R) -N- (2-amino-1, 2-diphenylethyl) -p-methylbenzenesulfonamide ] and reacted at room temperature under argon atmosphere for 8 hours. After the completion of the reaction, 20mL of methylene chloride was added, followed by washing with saturated sodium bicarbonate, drying, purification by high performance liquid chromatography, and freeze-drying to give the objective product 37-1 (3 mg).
1 H-NMR(37-1)：(400MHz,DMSO-d 6 )δ11.10(s,1H),8.24(t,J＝5.3Hz,1H),7.77(d,J＝11.3Hz,1H),7.56 (d,J＝8.5Hz,1H),7.50(d,J＝7.3Hz,1H),6.43(d,J＝8.6Hz,1H),5.61(d,J＝6.8Hz,1H),5.31-5.39(m,1H), 5.03-5.23(m,2H),4.18-4.30(m,2H),4.03-4.14(m,3H),3.58-3.67(m,4H),3.03-3.26(m,7H),2.83-2.94(m,2H), 2.56-2.69(m,4H),2.32-2.37(m,1H),1.95-2.05(m,1H)；MS:[M+1] + :729.2。
Example 38
Compound 38-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (4- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -4-oxobutyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 38-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (4- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -4-oxobutyl) piperazin-1-yl) isoindoline-1, 3-dione.
1 H-NMR(38-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),8.32(s,1H),7.68-7.77(m,2H),7.44(d,J＝7.4Hz, 1H),6.92(d,J＝8.7Hz,1H),5.40-5.44(m,1H),5.05-5.31(m,3H),4.55-4.65(m,1H),4.30-4.40(m,1H),4.10-4.20 (m,1H),3.78-3.84(m,1H),3.20-3.30(m,7H),2.81-3.15(m,5H),2.55-2.64(m,3H),2.29-2.35(m,2H),2.12(t,J ＝7.2Hz,2H),2.00-2.07(m,1H),1.63-1.75(m,2H)；MS:[M+1] + :730.2。
1 H-NMR(38-2)：(400MHz,DMSO-d 6 )δ11.10(s,1H),8.41(s,2H),7.67-7.78(m,2H),7.44(dd,J＝7.5,1.9 Hz,1H),6.95(d,J＝8.6Hz,1H),5.45-5.55(m,1H),5.06-5.28(m,3H),4.63(t,J＝8.0Hz,1H),4.30-4.40(m,1H), 4.18(dt,J＝10.7,5.5Hz,1H),3.84(dd,J＝10.5,3.8Hz,1H),3.20-3.25(m,7H),2.82-3.03(m,5H),2.67(m,1H), 2.54-2.63(m,3H),2.28-2.36(m,2H),2.08-2.15(m,2H),2.00-2.07(m,1H),1.65-1.73(m,2H)；MS:[M+1] + :730.2。
Example 39
Compound 39-1: cis-5- (4- (4- (4- ((1- ((1S) -7- ((difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -4-oxobutyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione.
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1 H-NMR(39-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.72(d,J＝11.5Hz,1H),7.57(d,J＝8.8Hz,1H), 7.45(d,J＝7.4Hz,1H),7.03(t,J＝54.0Hz,1H),6.41(d,J＝8.8Hz,1H),5.06-5.26(m,3H),4.28(t,J＝7.8Hz, 2H),3.84(t,J＝7.0Hz,2H),3.10-3.60(m,10H),2.83-2.97(m,3H),2.52-2.63(m,8H),2.25-2.40(m,8H),1.98- 2.04(m,1H),1.62-1.76(m,2H)；MS:[M+1] + :849.3。
Example 40
Compound 40-1: cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione.
Compound 40-2: trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione.
Step A: preparation of intermediate 40-A
Tert-butylmethyl (2- (methylamino) ethyl) carbamate (1 g) and benzyl 3-oxo-azetidine-1-carboxylate (1.09 g) were dissolved in dichloromethane (20 mL), and after stirring at room temperature for 1h, sodium acetoxyborohydride (1.13 g) was added and stirred at room temperature overnight. After completion of the reaction, saturated sodium bicarbonate solution (40 mL) and dichloromethane (20 mL) were added, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried to give intermediate 40-a, which was directly used for the subsequent synthesis.
Step B: preparation of intermediate 40-B
Intermediate 40-A was dissolved in methanol (20 mL), palladium hydroxide (200 mg) was added, and the mixture was reacted at room temperature under hydrogen. After the reaction is finished, the intermediate 40-B is filtered and dried in a spinning way and is directly used for subsequent synthesis.
Step C-G：
The target compounds 40-1 and 40-2 were synthesized as described in example 23-1, using a similar procedure as 23-1.
1 H-NMR(40-1)：(400MHz,DMSO-d 6 )δ11.07(s,1H),7.51-7.61(m,2H),7.28(d,J＝8.7Hz,1H),7.21(d, J＝7.0Hz,1H),6.34(d,J＝8.6Hz,1H),5.60(d,J＝6.3Hz,1H),5.30-5.38(m,1H),5.02-5.22(m,2H),4.02-4.15 (m,2H),3.60-3.75(m,4H),3.21(s,3H),3.08-3.18(m,2H),3.05(s,3H),2.80-2.92(m,2H),2.53-2.69(m,4H),2.10 (s,3H),1.94-2.04(m,1H)；MS:[M+1] + :628.2。
1 H-NMR(40-2)：(400MHz,DMSO-d 6 )δ11.07(s,1H),7.51-7.61(m,2H),7.28(d,J＝8.6Hz,1H),7.21(d, J＝7.0Hz,1H),6.34(d,J＝8.6Hz,1H),5.60(d,J＝6.5Hz,1H),5.35(q,J＝5.2Hz,1H),5.02-5.23(m,2H),4.04- 4.15(m,2H),3.62-3.75(m,4H),3.21(s,3H),3.05-3.18(m,2H),3.05(s,3H),2.82-2.92(m,2H),2.52-2.68(m,4H), 2.10(s,3H),1.96-2.03(m,1H)；MS:[M+1] + :628.2。
Example 41
Compound 41-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione.
Compound 41-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione.
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Compounds 41-1 and 41-2 were synthesized as described in example 40-1 using a similar procedure as 40-1.
1 H-NMR(41-1)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.65(d,J＝12.6Hz,1H),7.52(d,J＝8.5Hz,1H), 7.29(d,J＝7.8Hz,1H),6.34(d,J＝8.6Hz,1H),5.59(m,1H),5.34(t,J＝5.0Hz,1H),5.00-5.22(m,2H),4.07- 4.16(m,2H),3.69-3.76(m,2H),3.52(t,J＝6.9Hz,2H),3.35-3.45(m,2H),3.01-3.24(m,9H),2.82-2.92(m,1H), 2.54-2.65(m,2H),2.17(s,3H),1.97-2.05(m,1H)；MS:[M+1] + :646.2。
1 H-NMR(41-2)：(400MHz,DMSO-d 6 )δ11.09(s,1H),7.65(d,J＝12.7Hz,1H),7.54(d,J＝8.5Hz,1H), 7.30(d,J＝7.7Hz,1H),6.36(d,J＝8.6Hz,1H),5.85(m,1H),5.43(d,J＝16.6Hz,1H),4.98-5.18(m,2H),4.05- 4.18(m,2H),3.68-3.83(m,2H),3.38-3.56(m,5H),3.17(s,3H),3.08(s,3H),2.82-3.02(m,3H),2.52-2.63(m,2H), 2.18(s,3H),1.96-2.05(m,1H)；MS:[M+1] + :646.2。
Example 42
Compound 42-1: cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (6- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -6-oxohexyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compound 42-2: trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (6- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -6-oxohexyl) piperazin-1-yl) isoindoline-1, 3-dione.
Compounds 42-1 and 42-2 were synthesized as described in example 38-1 using a similar procedure to 38-1.
1 H-NMR(42-1)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.67-7.76(m,2H),7.45(d,J＝7.4Hz,1H),6.91(d, J＝8.7Hz,1H),5.44(dd,J＝7.6,5.0Hz,1H),5.07-5.34(m,3H),4.60(m,1H),4.34(m,1H),4.12(m,1H),3.80 (m,1H),3.29(s,3H),3.20-3.28(m,5H),2.82-3.18(m,5H),2.52-2.68(m,4H),2.31(t,J＝7.5Hz,2H),2.00-2.13 (m,3H),1.40-1.55(m,4H),1.20-1.35(m,2H)；MS:[M+1] + :758.2。
1 H-NMR(42-2)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.68-7.77(m,2H),7.45(d,J＝7.4Hz,1H),6.95(d, J＝8.6Hz,1H),5.51(d,J＝16.5Hz,1H),5.06-5.29(m,3H),4.59-4.63(m,1H),4.30-4.38(m,1H),4.10-4.18(m, 1H),3.78-3.86(m,1H),3.18-3.31(m,10H),2.82-3.04(m,3H),2.52-2.68(m,4H),2.31(t,J＝7.1Hz,2H),1.97- 2.13(m,3H),1.40-1.55(m,4H),1.22-1.35(m,2H)；MS:[M+1] + :758.2。
Example 43
Compound 43:5- (4- ((1- ((S) -2, 2-difluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperazin-3-yl) -6-fluoroisoindoline-1, 3-dione.
Step A: preparation of intermediate 43-A
2, 4-trifluoro-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-1-one (100 mg), tert-butyl 4- (azetidin-3-ylmethyl) piperazine-1-carboxylate (997 mg) and triethylamine (57 mg) were dissolved in DMSO (3 mL) and reacted at 90 ℃. After the completion of the reaction, the mixture was cooled to room temperature, saturated sodium chloride solution (30 mL) was added thereto, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and column chromatography was performed to obtain the objective compound (130 mg, yield 69%).
Step B-D：
Compound 43 was synthesized as described in example 23-1 using a procedure analogous to 23-1.
1 H-NMR(43)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.73(d,J＝11.4Hz,1H),7.58(d,J＝8.6Hz,1H),7.46 (d,J＝7.4Hz,1H),6.43(d,J＝8.7Hz,1H),5.25(d,J＝13.4Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.23(q,J＝7.8Hz,2H),3.79(t,J＝6.4Hz,2H),3.32-3.62(m,6H),3.17(s,3H),2.82-3.01(m,2H),2.52-2.70(m,8H),1.98- 2.08(m,1H)；MS:[M+1] + :676.2。
Example 44
Compound 44-1: cis-5- (4- (1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -3-fluoroazetidin-3-carbonyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione.
Compound 44-2: trans-5- (4- (1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -3-fluoroazetidin-3-carbonyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione.
Step A: preparation of intermediate 44-A
1- ((benzyloxy) carbonyl) -3-hydroxyazetidine-3-carboxylic acid (200 mg), tert-butylpiperazine-1-carboxylic acid ester (148 mg), EDCI (300 mg), HOBT (215 mg) and triethylamine (160 mg) were dissolved in DMF (5 mL) to react at room temperature, and after the reaction was completed, saturated sodium chloride solution (35 mL) was added, followed by ethyl acetate extraction, anhydrous sodium sulfate drying, and column chromatography to obtain intermediate 44-A (180 mg, yield 54%).
Step B: preparation of intermediate 44-B
Intermediate 44-A (180 mg) was dissolved in ultra-dry dichloromethane, and diethylaminosulfur trifluoride DAST (103 mg) was added to react at room temperature. After completion of the reaction, methylene chloride (20 mL) was added thereto, and the mixture was washed with a saturated sodium hydrogencarbonate solution, a saturated sodium chloride solution, and dried over anhydrous sodium sulfate, followed by column chromatography to give intermediate 44-B (130 mg, yield 72%).
Step C-F：
Compounds 44-1 and 44-2 were synthesized as described in example 32-1 using a similar procedure as 32-1.
1 H-NMR(44-1)：(400MHz,DMSO-d 6 )δ11.11(s,1H),7.79(d,J＝11.2Hz,1H),7.65(d,J＝8.7Hz,1H), 7.52(d,J＝7.3Hz,1H),7.08(t,J＝53.9Hz,1H),6.60(d,J＝8.8Hz,1H),5.88(m,1H),5.24-5.30(m,1H),5.07- 5.15(m,1H),4.79-4.89(m,2H),4.49-4.63(m,2H),3.71(m,2H),3.58(m,2H),3.13-3.26(m,5H),2.82-2.95(m, 1H),2.53-2.64(m,4H),2.01-2.10(m,1H)；MS:[M+1] + :726.2.
1 H-NMR(44-2)：(400MHz,DMSO-d 6 )δ11.10(s,1H),7.90(d,J＝11.2Hz,1H),7.68(d,J＝8.7Hz,1H), 7.47(d,J＝7.3Hz,1H),6.90(d,J＝8.8Hz,1H),6.65(t,J＝53.9Hz,1H),5.92(m,1H),5.20-5.30(m,1H),4.90- 5.10(m,1H),4.60(m,1H),4.10-4.25(m,4H),3.76(m,2H),3.65(m,2H),3.45-3.55(m,4H),3.00-3.18(m,2H), 2.15-2.20(m,1H),2.50-2.65(m,2H),1.75-1.80(m,1H)；MS:[M+1] + :726.2.
Performance measurement:
(one) HIF-2. Alpha. Degradation Rate determination
The method for measuring the degradation rate of HIF-2 alpha by adopting an immune western blotting method comprises the following steps:
1) 768-O cells were plated in T25 flasks with about 6mL of medium per flask and a cell count of about 1.2 x 10 6 . The confluence rate is ensured to be about 80-90% on the same day of dosing.
2) Overnight incubation at 37deg.C, 5% CO 2 In an incubator.
3) The compounds prepared in examples 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and 44 were dissolved in DMSO to obtain compound solutions.
4) Adding 6 μl of the compound solution (or DMSO) obtained in step 3) into a culture flask, culturing at 37deg.C under 5% CO 2 The incubator was maintained for 6 hours.
5) Cells were collected 6 hours after dosing (lysis method referred to RIPA instructions provided by thermosfisher).
6) Preparing cell lysate, adding 1 piece of protease inhibitor and 1 piece of phosphatase inhibitor into each 10mL of RIPA buffer, and uniformly mixing for later use.
7) The supernatant from the flask was discarded and washed 2 times with PBS.
8) Each flask of cells was added with 100. Mu.L of pre-chilled RIPA, and the flask was spun to allow uniform plating in the flask, which was kept on ice for 15 minutes.
9) The protein lysate was collected by a cell scraper and transferred to a 1.5ml centrifuge tube and centrifuged at 14000r/min for 15 minutes.
10 The supernatant was transferred to a clean pre-chilled 1.5ml centrifuge tube for further use.
11 Protein quantification assay procedure reference BCA protein quantification kit instructions.
12 Sample loading: 30 ug/well (pre-gel, bio-rad,26 wells, 4-15%).
13 Electrophoresis: electrophoresis was carried out at 70 volts until the bromophenol blue dye reached the end of the gel bottom, for a period of about 2.5 hours.
14 Film transfer): firstly, methanol is used for preactivating the PVDF film, and a sandwich structure is assembled, wherein the structure is formed by sequentially: filter paper-gum-membrane-filter paper. Wet-turn, 60 minutes, 280mA.
15 Closing: 5% skim milk/TBS/0.1% T solution, incubated for 1 hour at room temperature.
16 Film washing: TBS/0.1% T solution, 5 min, 3 times.
17 Primary antibody: primary antibody was diluted with 5% skim milk/TBS/0.1% t solution and incubated overnight at 4 ℃.
18 Film washing: TBS/0.1% T solution, 5 min, 3 times.
19 Secondary antibody: each corresponding secondary antibody was diluted with 5% skim milk/TBS/0.1% T solution, diluted 1:250, incubated for 1 hour at room temperature, protected from light.
20 Film washing: TBS/0.1% T solution, 5 min, 3 times.
21 Detecting: scanning detection or Tanon5200 imaging with Odyssey at 700nm or 800nm wavelength respectively, the detection results are shown in Table 1.
TABLE 1 degradation of HIF-2. Alpha. Ratio at 1. Mu.M compound concentration for each example
In the table above: A. b and C represent degradation rate, wherein A is larger than or equal to 50%, B is larger than or equal to 30% and smaller than 50%; c is more than or equal to 10 percent and less than 30 percent.
As can be seen from table 1: the difunctional compound disclosed by the application has a higher degradation HIF-2 alpha ratio, and shows that the difunctional compound disclosed by the application can well reduce the expression quantity of HIF-2 alpha in tumor cells, can be used for treating tumors or cancer diseases related to high expression of HIF-2 alpha, and has a good application prospect.
The foregoing description of the preferred embodiments of the application is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the application.

Claims (10)

1. A bifunctional compound, characterized in that it has the following general formula (i):
in the above formula: the L is a linker;
the R is 1 Selected from halogen, -NO 2 、-CN、-S(O) 2 R a 、-S(O)R a and-P (O) R b R c Any one of, wherein R a 、R b And R is c Each independently selected from any one of C1-C6 alkyl and C1-C6 haloalkyl;
the R is 2 And R is 3 Each independently selected from any one of H, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl;
said X is selected from the group consisting of-C (O) -and-CH 2 -any one of the following;
the R is 4 Selected from any one of H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy.
2. The bifunctional compound of claim 1, wherein the linker L has the following general formula (ii):
in the above formula: the L is 1 By passing throughAnd R is R 1 Covalently linked to the benzene ring, said L 4 By->And R is R 4 Covalently linking the linked benzene rings;
said L1 is absent or selected from-NR d -、-O-、-S-、-NHCH 2 -、-NH(CH 2 ) q C (O) -and-OC (O) -wherein q is an integer of 0 to 6, and R d Any one selected from H, C-C3 alkyl and C1-C3 haloalkyl;
the L is 2 And/or L 3 Absent or selected from- (CH) 2 ) m -、-NR e -、-(CH 2 CH 2 O) n -、-(NH) o (CH 2 ) p C (O) -and-C (O) (CH 2 ) p (NH) o -any one of the above, wherein m is an integer from 0 to 12, n is an integer from 0 to 6, o is 0 or 1, p is an integer from 0 to 6, R e Any one selected from H, C-C3 alkyl and C1-C3 haloalkyl;
the L is 4 Absent or selected from-O-, -S-and-NR f -any one of said R f Any one selected from H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy;
the A, B and C are each independently selected from any one of absent, C3-C7 cycloalkyl, 5-to 7-membered heterocyclyl containing 1-3 atoms independently selected from O, N and S atoms, C5-C10 aryl, and 5-to 10-membered heteroaryl containing 1-3 atoms independently selected from O, N and S atoms.
3. The bifunctional compound of claim 2, wherein a is selected from any one of the following groups:
wherein Z is selected from the group consisting of-N-and-CH 2 -any one of said α represents a linkage to the group adjacent to the left of the a group in formula (ii) and said β represents a linkage to the group adjacent to the right of the a group in formula (ii).
4. A bifunctional compound according to claim 2 or 3, said B being selected from at least one of the following groups:
wherein, γ represents a linkage to a group adjacent to the left of the B group in formula (II), and δ represents a linkage to a group adjacent to the right of the B group in formula (II).
5. The bifunctional compound of any one of claims 2 to 4, wherein the C group is selected from any one of the following groups:
wherein the L is 5 Absent or selected from-CH 2 -、-O-、-NR g -、-C(O)-、-O(CH 2 ) r C (O) -, wherein R is an integer of 0 to 6, and R g Any one selected from H, C-C3 alkyl, C1-C3 alkanoyl and C1-C3 alkylsulfonyl;
the R is 5 Any one selected from H, deuterium, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl and C1-C3 alkoxy;
the R is 6 Selected from H, -CN, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and-NR h -any one of the above, wherein the R h Selected from H or C1-C3 alkyl;
the pi represents the linkage to the group adjacent to the left of the C group in formula (II), and the θ represents the linkage to the group adjacent to the right of the C group in formula (II).
6. The bifunctional compound of any one of claims 1 to 5, wherein the bifunctional compound is selected from any one of the following compounds:
cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
Cis-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxacyclopenta-3-yl) -4- ((2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxacyclopenta-3-yl) -4- ((2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) amino) isoindoline-1, 3-dione;
cis-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide;
Trans-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide;
cis-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide;
trans-2- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) -N- (2- (2- (2- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) acetamide;
cis-4- ((1- (2- (2- (2- ((1S) -7- ((difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
trans-4- ((1- (2- (2- (2- ((1S) -7- ((difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
Cis-2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5- ((1- (2- (2- (2- (2- ((((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((1- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((1- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
cis-3- (4- ((1- (2- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
Trans-3- (4- ((1- (2- (2- (2- (2- (((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
cis-3- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile;
trans-3- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile;
cis-3- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile;
trans-3- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile;
Cis-3- (2- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile;
trans-3- (2- (2- (2- (2- (4- ((2- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindolin-4-yl) amino) methyl) -1H-1,2, 3-triazol-1-yl) ethoxy) -5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzonitrile;
cis 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (4- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) piperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione;
trans 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (4- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) piperazin-1-yl) piperidin-1-yl) isoindoline-1, 3-dione;
cis 2- (2, 6-dioxopiperidin-3-yl) -5- (6- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) -2, 6-diazaspiro [3.3] hept-2-yl) isoindoline-1, 3-dione;
Trans 2- (2, 6-dioxopiperidin-3-yl) -5- (6- (3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzoyl) -2, 6-diazaspiro [3.3] hept-2-yl) isoindoline-1, 3-dione;
cis-N- (2- (4- (1- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-5-yl) piperidin-4-yl) piperazin-1-yl) -2-oxoethyl) -3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzamide;
trans-N- (2- (4- (1- (2, 6-dioxapiperidin-3-yl) -1, 3-dioxaindol-5-yl) piperidin-4-yl) piperazin-1-yl) -2-oxoethyl) -3-fluoro-5- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) benzamide;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
Cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((1- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- (1- (2- (2- (4- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) piperidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- ((1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- ((1- (2- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethoxy) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) amino) isoindoline-1, 3-dione;
Cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
Trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
Trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
Trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) methyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (2- (1- (2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) piperidin-4-yl) ethyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-5- (4- ((1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
Trans-5- (4- ((1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (1- (1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carbonyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -2-oxoethyl) piperazin-1-yl) isoindoline-1, 3-dione;
Trans-2- (2, 6-dioxopiperidin-3-yl) -5- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -2-oxoethyl) piperazin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) piperidin-1-yl) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- (4- (2- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) ethyl) piperidin-1-yl) isoindoline-1, 3-dione;
n- (2- (4- (2, 6-dioxapiperidin-3-yl) -6-fluoro-1, 3-dioxaindol-5-yl) piperazin-1-yl) -2-oxoethyl) -1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidine-3-carboxamide;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (4- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -4-oxobutyl) piperazin-1-yl) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (4- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -4-oxobutyl) piperazin-1-yl) isoindoline-1, 3-dione;
5- (4- (4- (4- ((1- ((1S) -7- ((difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -4-oxobutyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -4- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -4- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione;
trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((2- ((1- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) (methyl) amino) ethyl) (methyl) amino) isoindoline-1, 3-dione;
cis-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (6- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -6-oxohexyl) piperazin-1-yl) isoindoline-1, 3-dione;
Trans-2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (4- (6- (3- ((1S) -2-fluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) azetidin-1-yl) -6-oxohexyl) piperazin-1-yl) isoindoline-1, 3-dione;
5- (4- ((1- ((S) -2, 2-difluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) azetidin-3-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperazin-3-yl) -6-fluoroisoindoline-1, 3-dione;
cis-5- (4- (1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -3-fluoroazetidin-3-carbonyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
trans-5- (4- (1- ((1S) -7- (difluoromethyl) sulfonyl) -2-fluoro-1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -3-fluoroazetidin-3-carbonyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione.
7. A pharmaceutical composition comprising a bifunctional compound of any one of claims 1-6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, prodrug, or solvate thereof, and at least one pharmaceutically acceptable carrier, additive, adjuvant, or excipient.
8. Use of the pharmaceutical composition according to claim 7 for the treatment of tumors or cancers.
9. The use of a pharmaceutical composition according to claim 8 for the treatment of tumors or cancers, wherein said cancers comprise at least one of renal cell carcinoma, skin carcinoma, lung carcinoma and breast carcinoma.
10. The use of a pharmaceutical composition according to claim 8 for the treatment of tumors or cancers, wherein said tumors comprise at least one of hematological tumors, glioma, digestive system tumors, reproductive system tumors, lymphomas and nervous system tumors.
CN202210249285.7A 2022-03-14 2022-03-14 Bifunctional compound, preparation method, pharmaceutical composition and application thereof Pending CN116789636A (en)

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