WO2019056950A1 - 噻吩并二氮杂卓衍生物及其应用 - Google Patents
噻吩并二氮杂卓衍生物及其应用 Download PDFInfo
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- WO2019056950A1 WO2019056950A1 PCT/CN2018/104345 CN2018104345W WO2019056950A1 WO 2019056950 A1 WO2019056950 A1 WO 2019056950A1 CN 2018104345 W CN2018104345 W CN 2018104345W WO 2019056950 A1 WO2019056950 A1 WO 2019056950A1
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- HMSCTFNKQVCBHA-MUAVYFROSA-N C[C@@]1(Cc2cc(NC(C[C@@H](c3nnc(C)[n]3-c3c4c(C)c(C)[s]3)N=C4c(cc3)ccc3Cl)=O)ccc2C1)O Chemical compound C[C@@]1(Cc2cc(NC(C[C@@H](c3nnc(C)[n]3-c3c4c(C)c(C)[s]3)N=C4c(cc3)ccc3Cl)=O)ccc2C1)O HMSCTFNKQVCBHA-MUAVYFROSA-N 0.000 description 1
- VTABBHSIVMJZJJ-QCDSWUKFSA-N C[C@](C1)(Cc2c1ccc(NC(C[C@@H](c1nnc(C)[n]1-c1c3c(C)c(C)[s]1)N=C3c(cc1)ccc1Cl)=C)c2)O Chemical compound C[C@](C1)(Cc2c1ccc(NC(C[C@@H](c1nnc(C)[n]1-c1c3c(C)c(C)[s]1)N=C3c(cc1)ccc1Cl)=C)c2)O VTABBHSIVMJZJJ-QCDSWUKFSA-N 0.000 description 1
- HMSCTFNKQVCBHA-IADCTJSHSA-N C[C@]1(Cc2cc(NC(C[C@@H](c3nnc(C)[n]3-c3c4c(C)c(C)[s]3)N=C4c(cc3)ccc3Cl)=O)ccc2C1)O Chemical compound C[C@]1(Cc2cc(NC(C[C@@H](c3nnc(C)[n]3-c3c4c(C)c(C)[s]3)N=C4c(cc3)ccc3Cl)=O)ccc2C1)O HMSCTFNKQVCBHA-IADCTJSHSA-N 0.000 description 1
- QMUNGVHKZHNRLG-UHFFFAOYSA-N Cc(c(COC1)c1cc1)c1N Chemical compound Cc(c(COC1)c1cc1)c1N QMUNGVHKZHNRLG-UHFFFAOYSA-N 0.000 description 1
- SLIAPOPSOWGOSF-UHFFFAOYSA-N Cc1c(C)[s]c(NC(CCl)=O)c1C(c(cc1)ccc1Cl)=O Chemical compound Cc1c(C)[s]c(NC(CCl)=O)c1C(c(cc1)ccc1Cl)=O SLIAPOPSOWGOSF-UHFFFAOYSA-N 0.000 description 1
- DLPDCIBSOXBBQB-QFIPXVFZSA-N Cc1c(C)[s]c-2c1C(c(cc1)ccc1Cl)=N[C@@H](CC(Nc(cc1OCCOCCO)ccc1O)=O)c1nnc(C)[n]-21 Chemical compound Cc1c(C)[s]c-2c1C(c(cc1)ccc1Cl)=N[C@@H](CC(Nc(cc1OCCOCCO)ccc1O)=O)c1nnc(C)[n]-21 DLPDCIBSOXBBQB-QFIPXVFZSA-N 0.000 description 1
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- DEIGEZJUGBLTEZ-QHCPKHFHSA-N Cc1c(C)[s]c-2c1C(c(cc1)ccc1Cl)=N[C@@H](CC(Nc1ccc(COC3)c3c1C)=O)c1nnc(C)[n]-21 Chemical compound Cc1c(C)[s]c-2c1C(c(cc1)ccc1Cl)=N[C@@H](CC(Nc1ccc(COC3)c3c1C)=O)c1nnc(C)[n]-21 DEIGEZJUGBLTEZ-QHCPKHFHSA-N 0.000 description 1
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- JQFGSFILBJVXFJ-UHFFFAOYSA-N Cc1c(CCCC2)c2ccc1N Chemical compound Cc1c(CCCC2)c2ccc1N JQFGSFILBJVXFJ-UHFFFAOYSA-N 0.000 description 1
- BVHNUULIORBKNO-UHFFFAOYSA-N Cc1c(C[O](C)C2)c2ccc1N Chemical compound Cc1c(C[O](C)C2)c2ccc1N BVHNUULIORBKNO-UHFFFAOYSA-N 0.000 description 1
- ISMUWQMUWFPFBZ-UHFFFAOYSA-N Nc(cc1CO2)ccc1C2=O Chemical compound Nc(cc1CO2)ccc1C2=O ISMUWQMUWFPFBZ-UHFFFAOYSA-N 0.000 description 1
- PJJADJURZCRWDL-UHFFFAOYSA-N Nc1ccc(CC(C2)(F)F)c2c1 Chemical compound Nc1ccc(CC(C2)(F)F)c2c1 PJJADJURZCRWDL-UHFFFAOYSA-N 0.000 description 1
- QAOIFHOSWFCDIF-UHFFFAOYSA-N Nc1ccc(CC2(COC2)C2)c2c1 Chemical compound Nc1ccc(CC2(COC2)C2)c2c1 QAOIFHOSWFCDIF-UHFFFAOYSA-N 0.000 description 1
- ZIJZDNKZJZUROE-UHFFFAOYSA-N Nc1ccc(COC2=O)c2c1 Chemical compound Nc1ccc(COC2=O)c2c1 ZIJZDNKZJZUROE-UHFFFAOYSA-N 0.000 description 1
- QRRRCGVZMSOTEB-UHFFFAOYSA-N [O-][N+](c1ccc(CC(C2)F)c2c1)=O Chemical compound [O-][N+](c1ccc(CC(C2)F)c2c1)=O QRRRCGVZMSOTEB-UHFFFAOYSA-N 0.000 description 1
- RNWGZXAHUPFXLL-UHFFFAOYSA-N [O-][N+](c1ccc(COC2=O)c2c1)=O Chemical compound [O-][N+](c1ccc(COC2=O)c2c1)=O RNWGZXAHUPFXLL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to a class of thienodiazepine derivatives and their use in the manufacture of a medicament for the treatment of diseases associated with BET Bromodomain inhibitors. Specifically, it relates to a compound of the formula (I), (II) and a pharmaceutically acceptable salt thereof.
- the recognition of histone lysine acetylation is a key step in histone acetylation involved in epigenetic regulation.
- the acetylated histone lysine can be specifically recognized by bromodomains (BRDs) domain, thereby recruiting chromatin regulation. Factor to specific regions, synergistically complete gene expression regulation.
- BRDs bromodomains
- BET extra-terminal
- the BET bromodomain family includes four proteins containing a series of Bromo domain domains: BRD2, BRD3, BRD4 and BRDT.
- the present invention provides a compound of the formula (I), (II), an isomer thereof or a pharmaceutically acceptable salt thereof,
- T is selected from: CH or N;
- R 1 is selected from C 1 1-3 alkyl, C 1-3 alkoxy optionally substituted by 1, 2 or 3 R;
- R 2 , R 3 , R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-6 alkyl, C 1-6 heteroalkyl;
- R 5 is selected from H or is selected from C 1 - 3 alkyl optionally substituted by 1, 2 or 3 R;
- R 6 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl;
- Ring A is selected from the group consisting of: C 3-7 cycloalkyl, 5- to 12-membered heterocycloalkyl, 5- to 6-membered heteroaryl;
- Ring B is selected from the group consisting of: 4 to 7 membered heterocycloalkyl
- Structural unit Not selected from:
- n is selected from: 0, 1, 2, 3, 4, 5 or 6;
- R is independently selected from: F, Cl, Br, I, OH, NH 2 , CN, or selected from C 1 1-6 alkyl, C 1 - 6 optionally substituted by 1, 2 or 3 R' Heteroalkyl
- R' is independently selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me;
- a carbon atom with a "*" is a chiral carbon atom, in the form of a single enantiomer of (R) or (S) or in the form of one enantiomer;
- the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
- the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R', C 1-3 alkoxy, other variables are as defined in the present invention.
- R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Other variables are as defined by the present invention.
- the above R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et, Other variables are as defined by the present invention.
- R 1 is selected from the group consisting of: 1, 2 or 3 R: Me, Et, Other variables are as defined by the present invention.
- R 1 is selected from the group consisting of Me, Et, CF 3 , Other variables are as defined by the present invention.
- R 2 , R 3 , and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or are independently selected from the group consisting of 1, 2 , respectively.
- R 2 , R 3 , and R 4 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined by the present invention.
- R 5 is selected from the group consisting of H and Me, and other variables are as defined in the present invention.
- said R 6 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. : C 1-3 alkyl, C 1-3 heteroalkyl, other variables are as defined in the present invention.
- said R 6 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. :Me, Et, Other variables are as defined by the present invention.
- R 6 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, Et, Other variables are as defined by the present invention.
- the above ring A is selected from the group consisting of C 4-6 cycloalkyl, pyrrolidin-2-one, pyrimidine-4(3H)-one, 5-azaspiro[2.4]heptane- 4-keto, 4-azaspiro[2.4]heptane-5-one, tetrahydrothiophene-1,1-dioxide, tetrahydrothiophene-1-oxide, tetrahydrofuranyl, pyrrolidinyl , dihydrothiophene-2(3H)-keto, 2-oxaspiro[3.4]octyl, dihydrofuran-2(3H)-one, 1,4,7,10-tetraoxane Alkyl, 1,2,5-oxadiazolyl, 7-oxabicyclo[2.2.1]heptane, pyrrolidine-2,5-dione, 5,5-dimethyldihydrofuran-2 (3H)
- the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- T 2 is independently selected from: -NH-, -O-, -S-;
- R 1 to R 6 are as defined in the present invention.
- the carbon atom bearing a "*" is a chiral carbon atom and is present as a single enantiomer of (R) or (S) or as an enantiomer.
- the present invention also provides the following compounds, isomers thereof, or pharmaceutically acceptable salts thereof, selected from the group consisting of:
- the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
- the present invention also provides the use of the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a BET Bromodomain inhibitor-related drug.
- the BET Bromodomain inhibitor related drug is a drug for antitumor.
- pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
- pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
- such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
- the compounds of the invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
- Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
- enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
- cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
- wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
- straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
- tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
- proton tautomers also known as prototropic tautomers
- prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
- the valence tautomer includes the mutual transformation of some of the bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
- the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
- the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
- optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
- a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art.
- the diastereomers are resolved and the pure enantiomer is recovered.
- the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
- radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
- hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
- the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
- deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
- substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
- Oxygen substitution does not occur on the aromatic group.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with at most two R, and each case has an independent option.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
- one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
- a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
- the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
- substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
- the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
- 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
- ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
- heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
- the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
- the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
- the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
- the nitrogen atom in the heterocycle is optionally quaternized.
- a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
- aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
- the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
- the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
- bridged rings are also included in the definition of heterocycles.
- a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
- Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
- heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofurylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, ind
- hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
- the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
- C 1-12 is selected from C 1
- Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
- An aromatic hydrocarbon group such as benzene, naphthalene or the like.
- hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
- saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
- a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
- the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
- heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
- heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
- the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
- the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
- Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
- cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
- a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
- cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
- alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
- alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
- a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
- Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
- halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
- haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
- halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
- examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
- alkoxy represents attached through an oxygen bridge
- C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
- alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
- aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
- heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
- aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
- aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
- alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
- leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
- substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
- hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
- Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl and t-butyl groups
- acyl groups such as alkanoyl groups (e.g., acetyl)
- arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
- the solvent used in the present invention is commercially available.
- the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
- the compound of the present invention has remarkable BET Bromodomain inhibitory activity; has a remarkable antitumor effect, and the animal has good tolerance; and the compound of the present invention has low pharmacological clearance rate and good absorption.
- N,N-diisopropylethylamine (48.36 mg, 374.19 ⁇ mol) was slowly added dropwise to the compound 1-11 (50.00 mg, 124.73 ⁇ mol), 6-amino-isoindoline-1 under nitrogen at 30 ° C.
- a solution of the ketone (27.72 mg, 187.10 ⁇ mol) and HATU (71.14 mg, 187.10 ⁇ mol) in anhydrous dichloromethane (15.00 ml) was added and reacted at 30 ° C for 12 hours. The reaction mixture was washed with EtOAcq. Purification by preparative chromatography gave Compound 1.
- Example 2 The synthesis method of Example 2 is referred to Example 1.
- Methylmagnesium bromide (3M, 6.30 mL) was added to 10 mL of dry diethyl ether, and the mixture was stirred three times with nitrogen, and a solution of compound 3-1 (2.00 g, 15.13 mmol) in 40 ml of anhydrous ether was slowly added dropwise. The mixture was stirred under a nitrogen atmosphere at 25 ° C for 3 hours. The reaction solution was poured into 50 g of ice water under stirring, and stirred for 5 minutes by adding 50 ml of a saturated NH 4 Cl solution. The liquid phase was separated, and the aqueous phase was extracted with 50 ml of ethyl acetate.
- Nitric acid (118.46 mg, 1.88 mmol, 84.61 ⁇ L, 1.00 eq) was slowly added dropwise to the compound 9-2 (300.00 mg, 1.88 mmol, 1.00 eq) and concentrated sulfuric acid (184.85 mg, 1.88 mmol) under -15 ° C under nitrogen.
- 100.46 ⁇ L, 1.00 eq. of dichloromethane (4.00 ml) was added, the mixture was warmed to 27 ° C and then stirred for 10 hours.
- the reaction mixture was quenched with EtOAc (3 g), EtOAc (EtOAc) It was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and evaporated.
- Trifluoroacetic acid (3.08 g, 27.01 mmol, 2.00 mL, 333.41 eq) was added to a solution of compound 18-3 (50.00 mg, 81.02 ⁇ mol, 1.00 eq) in anhydrous dichloromethane (6.00 mL). The mixture was stirred at 15 ° C for 4 hours. The reaction mixture was directly concentrated to dryness, and the mixture was evaporated to dryness with EtOAc EtOAc EtOAc. Dry over anhydrous sodium sulfate, filter, and the filtrate was evaporated to dryness. The crude product was purified by preparative chromatography to give compound 18.
- Triethylamine (948.78 mg, 9.38 mmol, 1.30 mL, 2.96 eq) was added to a solution of compound 17-2 (520.00 mg, 3.17 mmol, 1.00 eq) in dichloromethane (5.00 mL).
- methanesulfonyl chloride 370.00 mg, 3.23 mmol, 250.00 uL, 1.02 eq was slowly added dropwise to the reaction mixture, and the mixture was heated to 15 ° C and stirred for 2 hours.
- the reaction solution was directly concentrated under reduced pressure, and the crude material was purified using a flash column apparatus to afford compound 19-1.
- Example 26 The synthesis method of Example 26 is referred to Example 25.
- POCl3 (133.87 mg, 873.08 ⁇ mol, 81.13 uL, 5 eq) was slowly added dropwise to compound 28-6 (40 mg, 235.84 ⁇ mol, 1.35 eq) and compound 1-11 (70 mg, 174.62 ⁇ mol, 1.00 eq) of pyridine at 0 °C. (3 ml) in a solution, stirred at 0 ° C under nitrogen for a few hours. The reaction solution was stirred for 3 ml of ice water, and the mixture was adjusted to pH 6 with 0.5 M diluted aqueous hydrochloric acid, and extracted with 3 ⁇ 5 ml of ethyl acetate. Dry, filter, and concentrate the filtrate under reduced pressure.
- Potassium nitrate (878.27 mg, 8.69 mmol, 1 eq) was added to a concentrated sulfuric acid (10 ml) solution, and then compound 29-4 (1.2) was concentrated with concentrated sulfuric acid (5 ml) cooled in a -10 ° C ice salt bath. g, 8.69 mmol, 1 eq) was dissolved and added to the above reaction solution under ice salt bath, and then reacted for 30 minutes at -10 ° C in an ice salt bath. The reaction mixture was slowly added dropwise to dry ice (100 ml) and filtered to give a pale brown solid. The crude product was dissolved in ethyl acetate (50 ml).
- Trifluoroacetic acid (3.85 g, 33.77 mmol, 2.5 mL, 18.30 eq) was added to compound 32-2 (0.46 g, 1.85 mmol, 1 eq) in anhydrous dichloromethane (20 mL). Reaction for 12 hours. The reaction mixture was washed with water (20 ml), and then the aqueous phase was adjusted to pH 7 with saturated aqueous sodium hydrogen carbonate, and the aqueous phase was extracted with dichloromethane (10 ml ⁇ 2). Spin dry. The compound 32-3 was obtained directly used in the next reaction without further purification. LCMS (ESI) m/z: 149.8 (M+1).
- POCl3 (76.50 mg, 498.90 ⁇ mol, 46.36 ⁇ L, 2 eq) was added to compound 1-11 (100 mg, 249.45 ⁇ mol, 1 eq) and compound 32-3 (44.65 mg, 299.34 ⁇ mol, 1.2 eq) of pyridine (2) at 0 °C.
- the reaction was carried out by heating to 20 ° C for 1.5 hours.
- Water (3 ml) was added to the reaction mixture to quench the reaction.
- the aqueous phase was adjusted to pH 7 with 2N hydrochloric acid, and the aqueous phase was extracted with dichloromethane (5 ml ⁇ 3). Spin dry.
- Example 36 The synthesis method of Example 36 is referred to Example 1.
- Methylmagnesium bromide (3M, 9.39 mL, 3 eq) was slowly added dropwise to a solution of compound 37-1 (2 g, 9.39 mmol, 1 eq) in anhydrous tetrahydrofuran (20 mL). The mixture was heated to 30 ° C and stirred under nitrogen for 3 hours. The reaction mixture was cooled to 0 ° C, and then the mixture was evaporated, evaporated, evaporated, evaporated. The filtrate was concentrated to dryness under reduced pressure. Compound 37-2 was obtained, which was directly transferred to the next reaction without purification.
- Tris(dibenzylideneacetone)dipalladium 380.00 mg, 414.98 ⁇ mol, 0.1 eq
- 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxime 240.0 mg, 414.78) Molmol, 0.1 eq
- cesium carbonate 2.70 g, 8.29 mmol, 2 eq
- the solution was stirred for 2 hours under nitrogen at 100 ° C in a solution of 1,4-dioxane (10 ml).
- Trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL, 18.73 eq) was slowly added dropwise to a solution of compound 37-4 (1 g, 3.61 mmol, 1 eq) in anhydrous dichloromethane (10 ml). hour.
- Compound 37-5 was obtained and was directly taken to the next reaction without purification.
- Phosphorus oxychloride (140.00 mg, 913.05 ⁇ mol, 84.85 uL, 5.23 eq) was slowly added dropwise to compound 1-11 (70 mg, 174.62 ⁇ mol, 1.00 eq) and compound 37-5 (40 mg, 225.73 ⁇ mol, 1.29) at 0 °C.
- Aq. pyridine (2 mL) was stirred at 0 ° C for 1 hour under nitrogen.
- Compound dilution was done by Echo and diluted 3 times to 10 concentrations: 20000, 6666.67, 2222.22, 740.74, 246.91, 82.305, 27.435, 9.145, 3.048, 1.016 nM.
- the experimental plate was prepared using ECHO prepared before the experiment using a gradient of compound concentration and the corresponding DMSO solution:
- the compounds of the invention have significant BET Bromodomain inhibitory activity.
- Human breast cancer MDA-MB-231_luc cells were cultured in vitro, culture conditions were RPMI-1640 medium (supplier: Gibco; article number: 22400-089; production batch number: 4868546) plus 10% fetal bovine serum, 100U/ml Penicillin and 100 ⁇ g/ml streptomycin were incubated at 37 ° C 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and inoculated.
- the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
- Tumor diameters were measured twice a week using vernier calipers.
- TGI (%) [(1 - mean tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group)) / (average tumor at the end of treatment of the solvent control group) Volume-solvent control group average tumor volume at the start of treatment)] ⁇ 100%.
- T weight and C weight indicate the tumor weights of the drug-administered group and the vehicle control group, respectively.
- Statistical analysis included mean and standard error (SEM) of tumor volume at each time point for each group.
- the treatment group showed the best therapeutic effect on the 21st day after the administration at the end of the trial, and therefore statistical analysis was performed based on this data to evaluate the difference between the groups.
- T-test was used for comparison between the two groups, and one-way ANOVA was used for comparison between three groups or groups. If there was a significant difference in F values, the Games-Howell method was used for the test. If there is no significant difference in F values, the Dunnet (2-sided) method is used for analysis. All data analysis was performed with SPSS 17.0. A significant difference was considered at p ⁇ 0.05.
- the preparation method of the test substance is the same as Table 2, and the animal grouping and administration scheme are the same as Table 3.
- Human prostate cancer PC-3 cells were cultured in vitro in a single layer, culture conditions were F-12K medium (supplier: Gibco; article number: 21127-022; production batch number: 1868870) plus 10% fetal bovine serum, 100 U/mL penicillin Incubate with 100 ⁇ g/mL streptomycin at 37 ° C 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and inoculated.
- mice Female Balb/c mice were used as test animals, and the concentration of the drug in plasma at different times after intravenous administration and intragastric administration of Compound 32 was determined by LC/MS/MS. The pharmacokinetic behavior of Compound 32 in mice was investigated and its pharmacokinetic profile was evaluated.
- mice Eight female Balb/c mice were divided into two groups. After overnight fasting, the first group was administered intravenously at a dose of 2.5 mL/kg at a dose of 1 mg/kg. The second group was administered by intragastric administration. The administration volume was 5 mL/kg and the dose was 2 mg/kg.
- the content of the test compound in plasma after intravenous and intragastric administration in mice was determined by LC/MS/MS.
- the linear range of the method was 2.00-6000 nmol/L; plasma samples were analyzed by acetonitrile precipitation protein analysis.
- the results of pharmacokinetic parameters are shown in Table 4.
- Mouse colon cancer MC38 cells (Heyuan Biotechnology Co., Ltd.) were cultured in vitro in a single-layer culture medium containing 10% fetal bovine serum in DMEM medium (Gibco, Cat. No. 12100) in a 37 ° C 5% CO 2 incubator. to cultivate. Passage was routinely digested with 0.25% trypsin-EDTA. When the cells are in the exponential growth phase and the saturation is 80% to 90%, the cells are collected, counted, and inoculated.
- 0.1 mL of 2 ⁇ 10 5 MC38 cells were subcutaneously inoculated into the right back of each mouse, and when the average tumor volume reached ⁇ 70 mm 3 , random administration was performed according to the tumor volume.
- Tumor diameters were measured twice a week using vernier calipers.
- TGI percent tumor growth rate
- T/C percent tumor proliferation rate
- T/C percent tumor proliferation rate
- TGI (%) [(1 - mean tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group)) / (median tumor volume at the end of treatment of the solvent control group - treatment of the solvent control group started) Time average tumor volume)] ⁇ 100%.
- Tumor weights were measured after the end of the experiment, and the percentage of T weight / C weight was calculated, and T weight and C weight indicate the tumor weights of the drug-administered group and the vehicle control group, respectively.
- Animals in each of the administration groups had significant antitumor effects as well as good tolerance.
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Abstract
Description
Claims (23)
- 式(Ⅰ)、(Ⅱ)所示化合物、其异构体或其药学上可接受的盐,其中,T选自CH或N;R 1选自任选被1、2或3个R取代的:C 1-3烷基或C 1-3烷氧基;R 2、R 3、R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN,或分别独立地选自任选被1、2或3个R取代的:C 1-6烷基或C 1-6杂烷基;R 5选自H,或选自任选被1、2或3个R取代的C 1-3烷基;R 6分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN,或分别独立地选自任选被1、2或3个R取代的:C 1-6烷基或C 1-6杂烷基;或者,连接在相同C原子上的两个R 6与相连的C原子一起组成C(=O);环A选自:C 3-7环烷基、5~12元杂环烷基或5~6元杂芳基;环B是4~7元杂环烷基;n选自0、1、2、3、4、5或6;R分别独立地选自F、Cl、Br、I、OH、NH 2、CN,或选自任选被1、2或3个R’取代的:C 1-6烷基或C 1-6杂烷基;R’分别独立地选自F、Cl、Br、I、OH、NH 2、CN或Me;带“*”碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在;所述C 1-6杂烷基、5~12元杂环烷基、5-6元杂芳基、4~7元杂环烷基之“杂”选自N、-O-、-S-、-NH-、-C(=O)NH-、-C(=O)-、-C(=O)O-、-S(=O) 2-、-S(=O)-、-C(=O)S-;上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。
- 根据权利要求1所述化合物、其异构体或其药学上可接受的盐,其中,R选自F、Cl、Br、I、OH、NH 2、CN,或选自任选被1、2或3个R’取代的:C 1-3烷基或C 1-3烷氧基。
- 根据权利要求1~4任意一项所述化合物、其异构体或其药学上可接受的盐,其中,R 2、R 3、R 4分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN,或分别独立地选自任选被1、2或3个R取代的:C 1-3烷基或C 1-3烷氧基。
- 根据权利要求1~4任意一项所述化合物、其异构体或其药学上可接受的盐,其中,R 5选自H或Me。
- 根据权利要求1~4任意一项所述化合物、其异构体或其药学上可接受的盐,其中,R 6分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN,或分别独立地选自任选被1、2或3个R取代的:C 1-3烷基或C 1-3杂烷基。
- 根据权利要求1~4任意一项所述化合物、其异构体或其药学上可接受的盐,其中,环A选自C 4-6环烷基、吡咯烷-2-酮基、嘧啶-4(3H)-酮基、5-氮杂螺[2.4]庚烷-4-酮基、4-氮杂螺[2.4]庚烷-5-酮基、四氢噻吩-1,1-二氧化物基、四氢噻吩-1-氧化物基、四氢呋喃基、吡咯烷基、二氢噻吩-2(3H)-酮基、2-氧杂螺[3.4]辛烷基、二氢呋喃-2(3H)-酮基、1,4,7,10-四氧环十二烷基、1,2,5-恶二唑基、7-氧杂二环[2.2.1]庚烷、吡咯烷-2,5-二酮或5,5-二甲基二氢呋喃-2(3H)-酮基。
- 一种药物组合物,包括治疗有效量的根据权利要求1~20任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
- 根据权利要求1~20任意一项所述的化合物或其药学上可接受的盐或者权利要求21的组合物在制备BET Bromodomain抑制剂相关药物上的应用。
- 根据权利要求22所述的应用,其特征在于,所述BET Bromodomain抑制剂相关药物是用于抗肿瘤的药物。
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US16/649,964 US11312726B2 (en) | 2017-09-22 | 2018-09-06 | Thienodiazepine derivatives and application thereof |
JP2020516591A JP7417519B2 (ja) | 2017-09-22 | 2018-09-06 | チエノジアゼピン誘導体とその応用 |
CA3076759A CA3076759A1 (en) | 2017-09-22 | 2018-09-06 | Thienodiazepine derivatives and application thereof |
EP18859140.8A EP3686204A4 (en) | 2017-09-22 | 2018-09-06 | THIENODIAZEPIN DERIVATIVES AND THEIR USES |
CN201880061661.1A CN111372937B (zh) | 2017-09-22 | 2018-09-06 | 噻吩并二氮杂卓衍生物及其应用 |
KR1020207011709A KR20200058483A (ko) | 2017-09-22 | 2018-09-06 | 티에노디아제핀 유도체 및 그의 적용 |
AU2018334788A AU2018334788B2 (en) | 2017-09-22 | 2018-09-06 | Thienodiazepine derivatives and application thereof |
RU2020113587A RU2795005C2 (ru) | 2017-09-22 | 2018-09-06 | Тиенодиазепиновые производные и их применение |
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Cited By (4)
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WO2020177762A1 (zh) * | 2019-03-07 | 2020-09-10 | 南京明德新药研发有限公司 | 同时具有BET Bromodomain蛋白抑制和PD-L1基因调控作用的化合物 |
WO2020192637A1 (zh) * | 2019-03-22 | 2020-10-01 | 石药集团中奇制药技术(石家庄)有限公司 | 固体形式的brd4抑制剂化合物及其制备方法与应用 |
WO2021180055A1 (zh) * | 2020-03-09 | 2021-09-16 | 石药集团中奇制药技术(石家庄)有限公司 | 一种brd4抑制剂的用途 |
WO2022048685A1 (zh) * | 2020-09-07 | 2022-03-10 | 南京明德新药研发有限公司 | 苯并四氢呋喃肟类化合物的晶型及其制备方法 |
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WO2023113456A1 (ko) * | 2021-12-14 | 2023-06-22 | (주)프레이저테라퓨틱스 | 폴리유비퀴틴화에 의한 표적 단백질 또는 폴리펩티드의 분해용 신규 화합물 |
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EP3347020A4 (en) | 2015-09-11 | 2019-08-14 | Dana-Farber Cancer Institute, Inc. | ACETAMIDE THIENOTRIAZOLDIAZEPINES AND USES THEREOF |
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- 2018-09-06 WO PCT/CN2018/104345 patent/WO2019056950A1/zh unknown
- 2018-09-06 CN CN201880061661.1A patent/CN111372937B/zh active Active
- 2018-09-06 CA CA3076759A patent/CA3076759A1/en active Pending
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WO2020177762A1 (zh) * | 2019-03-07 | 2020-09-10 | 南京明德新药研发有限公司 | 同时具有BET Bromodomain蛋白抑制和PD-L1基因调控作用的化合物 |
WO2020192637A1 (zh) * | 2019-03-22 | 2020-10-01 | 石药集团中奇制药技术(石家庄)有限公司 | 固体形式的brd4抑制剂化合物及其制备方法与应用 |
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WO2021180055A1 (zh) * | 2020-03-09 | 2021-09-16 | 石药集团中奇制药技术(石家庄)有限公司 | 一种brd4抑制剂的用途 |
CN115190800A (zh) * | 2020-03-09 | 2022-10-14 | 石药集团中奇制药技术(石家庄)有限公司 | 一种brd4抑制剂的用途 |
WO2022048685A1 (zh) * | 2020-09-07 | 2022-03-10 | 南京明德新药研发有限公司 | 苯并四氢呋喃肟类化合物的晶型及其制备方法 |
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CA3076759A1 (en) | 2019-03-28 |
EP3686204A1 (en) | 2020-07-29 |
CN111372937B (zh) | 2021-10-01 |
AU2018334788A1 (en) | 2020-04-16 |
US20210017190A1 (en) | 2021-01-21 |
US11312726B2 (en) | 2022-04-26 |
RU2020113587A (ru) | 2021-10-25 |
AU2018334788B2 (en) | 2022-11-24 |
RU2020113587A3 (zh) | 2022-03-30 |
JP2020534317A (ja) | 2020-11-26 |
KR20200058483A (ko) | 2020-05-27 |
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