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WO2017101791A1 - Composé et son utilisation pour la préparation de médicaments - Google Patents

Composé et son utilisation pour la préparation de médicaments Download PDF

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Publication number
WO2017101791A1
WO2017101791A1 PCT/CN2016/109961 CN2016109961W WO2017101791A1 WO 2017101791 A1 WO2017101791 A1 WO 2017101791A1 CN 2016109961 W CN2016109961 W CN 2016109961W WO 2017101791 A1 WO2017101791 A1 WO 2017101791A1
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compound
group
cancer
ring
nmr
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Chinese (zh)
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何伟
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Tsinghua University
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Tsinghua University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C235/66—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and singly-bound oxygen atoms, bound to the same carbon skeleton
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    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/20—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having nitrogen atoms of amidino groups acylated
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a novel compound and the use of the novel compound in preparing a medicament.
  • cancer refers to a malignant tumor that originates from epithelial tissue and is the most common type of malignant tumor.
  • malignant tumors originating from mesenchymal tissue are collectively referred to as sarcomas.
  • a few malignant tumors are not named according to the above principles, such as nephroblastoma, malignant teratoma and so on.
  • cancer is used to refer to all malignant tumors.
  • Tumors are new organisms formed by the body's cells under the action of various tumorigenic factors, which lose the normal regulation of their growth at the genetic level and lead to abnormal proliferation and differentiation. Once a new organism is formed, it will not stop growing due to the elimination of the cause. His growth is not regulated by the normal body, but the normal tissues and organs are destroyed. This is especially true in malignant tumors. Compared with benign tumors, malignant tumors grow fast, invasive growth, prone to bleeding, necrosis, ulcers, etc., and often have distant metastasis, causing body weight loss, weakness, anemia, loss of appetite, fever and severe organs. Impaired function, etc., eventually causing death.
  • Non-small cell lung cancer is one of the most common malignant tumors in the world, and it has become the number one cause of death in malignant tumors in urban population in China.
  • Non-small cell lung cancer includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, and large cell carcinoma. Compared with small cell carcinoma, its cancer cells grow slowly and have a relatively slow diffusion and metastasis.
  • Non-small cell lung cancer accounts for about 80% of all lung cancers, and about 75% of patients are already in the advanced stage, and the 5-year survival rate is very low.
  • Brg1 gene As a new tumor suppressor gene, Brg1 gene has been found to be an important tumor suppressor gene in many tumor research. Many tumors are related to their functional inactivation or gene mutation and deletion. It is also found to be involved in signal transduction during mitosis and is closely related to many important tumor suppressor genes such as Rb gene and CD44.
  • the present invention provides a compound which is a stereoisomer, a geometric isomer, a tautomer, a racemate, an oxynitride of a compound represented by the formula (I) or a compound of the formula (I). , hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:
  • R1 means H, Or a five-membered nitrogen-containing heterocyclic ring optionally substituted by a C 1-5 alkyl group or a C 1-5 alkyl ester group;
  • R6 is a bond, H, C 1 ⁇ 5 alkylene group, optionally substituted C 1 ⁇ 5 alkylene 5-membered nitrogen heterocycle, or optionally substituted C 1 ⁇ 5 alkylene imino group;
  • R7 and R8 are each independently H, C 1-5 alkyl, or optionally C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkylcycloalkyl, C 1-5 An alkylcycloalkenyl group, an aryl group, an alkylene aryl group, a six-membered heterocyclic ring, an alkylene six-membered heterocyclic ring, a cyano group, a cyanoimino C 1-5 alkyl substituted imino group or a minor amino group;
  • R2, R3, R4, R5 and R6 is independently H, halogen, hydroxy, C 1-5 alkoxy, amine, C 1-5 carbonyl imino or imino, aryl, nitro or Cyano group, provided that R2, R3, R4, R5 and R6 are not H at the same time;
  • Adjacent two of R1 to R6 together with the carbon atom to which they are attached constitute an optionally substituted C 1-5 alkyl group, an aryl group, a five to seven membered ring optionally containing at least one of oxygen, sulfur and nitrogen or a thick Double ring.
  • the inventors have unexpectedly discovered that the compound can be effectively used for the treatment of cancer, especially non-small cell lung cancer.
  • the invention provides the use of a compound as hereinbefore described in the manufacture of a medicament for the treatment of cancer.
  • the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • the non-small cell lung cancer is a BRG1 gene deletion.
  • the present invention also provides a method for treating cancer comprising administering a compound or a composition containing the compound to a subject, such as a patient.
  • the present invention also provides a composition for treating cancer comprising the aforementioned compound as an activity ingredient.
  • the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • subject refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, The subject is a human.
  • primates eg, humans, males or females
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a person (including adults and children) or other animal. In some embodiments, “patient” refers to a human.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds may be used interchangeably.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group.
  • substituents When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • the substituents described therein may be, but are not limited to, hydrazine, fluorine, chlorine, bromine, iodine, cyano, hydroxy, nitro, amino, carboxy, alkyl, alkoxy, alkoxyalkyl, alkane.
  • C 1 -C 5 alkyl or “C 1-5 alkyl” refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 and C 5 alkyl groups.
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains from 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CHCH
  • C xy alkyl refers to an alkyl group having a C atom number of xy.
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH
  • heterocyclyl and “heterocycle” are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein monocyclic, bicyclic or tricyclic
  • the ring does not contain an aromatic ring, and at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydrogen Pyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, (1-oxo)-sulfur Daimorpholiny
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a 1,1-dioxothiomorpholinyl group.
  • the heterocyclyl group can be optionally substituted with one or more substituents described herein.
  • fused bicyclic and “fused bicyclic” are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a bicyclic system.
  • bridged ring means that any two rings share two atoms that are directly or not directly connected. For example, as described by the following formulas a and b, ring A and ring A' share two directly connected C atoms, and ring B and ring B' share two C atoms which are not directly connected.
  • Each of the fused bicyclic rings is either a carbocyclic ring or a heterocyclic ring.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • aryl can be used interchangeably with the term "aromatic ring”. Examples of the aryl group may include a phenyl group, a decyl group, a naphthyl group, and an anthracene group.
  • the aryl group may be independently and optionally substituted with one or more substituents described herein.
  • the Markush variable recited for that group is understood to be a linking group.
  • the "aryl" is listed for the Markush group definition for this variable, it should be understood that the "aryl” represents a linked arylene group.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • treating any disease or condition, in some embodiments, “treating” refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms). In other embodiments, “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both. In other embodiments, “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • cancer refers to or describes a physiological condition in a patient that is typically characterized by uncontrolled cell growth.
  • a “tumor” contains one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies.
  • squamous cell carcinoma such as squamous cell carcinoma
  • lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma
  • peritoneal cancer Hepatocellular cancer
  • gastric or stomach cancer including gastrointestinal cancer
  • pancreatic cancer malignant glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma (hepatoma) ), breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer ( Hepatic carcinoma), anal cancer, penile cancer, and head and neck cancer.
  • the present invention provides a compound which is a stereoisomer, a geometric isomer, a tautomer, a racemate, an oxynitride of a compound represented by the formula (I) or a compound of the formula (I). , hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:
  • R 6 is a bond, H, C 1-5 alkylene group, optionally C 1-5 An alkyl-substituted five-membered nitrogen-containing heterocyclic ring, or an imino group optionally substituted by a C 1-5 alkylene group, wherein R 7 and R 8 are each independently H, C 1-5 alkyl, or optionally C 1 ⁇ 5- alkyl, C 1-5 alkoxy, C 1-5 alkylcycloalkyl, C 1-5 alkylcycloalkenyl, aryl, alkylene aryl, six-membered heterocyclic, alkylene a six-membered heterocyclic ring, a cyano group, a cyanoimino C 1-5 alkyl group substituted imino group or a secondary amino group
  • R1 is an optionally substituted iminocarbonyl group, a secondary aminocarbonyl group or a five-membered nitrogen-containing heterocyclic ring.
  • the halogen is F or Cl.
  • R1 and R2 together with the carbon atom to which they are attached constitute an optionally substituted C 1-5 alkyl group, an aryl group, a five to seven membered ring optionally containing at least one of oxygen, sulfur and nitrogen or a fused bicyclic ring.
  • R2 and R3 together with the C atom to which they are attached form a carbon optionally substituted with 1 to 5 alkyl group, an aryl group, optionally containing oxygen, or a 5- to 7-membered rings fused bicyclic at least one of sulfur and nitrogen.
  • R1 and R2 together with the carbon atom to which they are attached constitute an optionally substituted five- to seven-membered ring or a fused bicyclic ring containing from 1 to 3 nitrogen atoms, optionally a five to seven-membered ring or fused At least one carbonyl group is formed on the bicyclic ring.
  • the compound is a stereoisomer, a geometric isomer, a tautomer, a racemate, an oxynitride, a hydrate or a solvate of a compound represented by the following formula or a compound represented by the formula: , metabolites and pharmaceutically acceptable salts or prodrugs:
  • the invention provides the use of a compound as hereinbefore described in the manufacture of a medicament for the treatment of cancer.
  • the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer.
  • the non-small cell lung cancer is a BRG1 gene deletion.
  • the present invention also provides a method for treating cancer comprising administering a compound or a composition containing the compound to a subject, such as a patient.
  • the present invention also proposes a composition for treating cancer comprising the aforementioned compound as an active ingredient.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically relevant to the other components of the formulation and to the mammal being treated.
  • Salts of the compounds of the invention also include salts for the preparation or purification of intermediates of the compounds of formula (I) or enantiomers of the compounds of formula (I), but are not necessarily pharmaceutically acceptable Salt.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/ Carbonate, hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, Portuguese Saccharate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, Malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, Oleate, oxalate, palmitate, pamoate, phosphate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid. , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds disclosed in the present invention may also be obtained in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.) for their crystallization.
  • solvents e.g., ethanol, DMSO, etc.
  • the compounds disclosed herein may form solvates either intrinsically or by design with pharmaceutically acceptable solvents, including water; thus, the invention is intended to include both solvated and unsolvated forms.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy.
  • 18 F enriched compounds are particularly desirable for PET or SPECT studies.
  • the isotopically enriched compound of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • the hydrazine in the present invention is regarded as a substituent of the compound represented by the formula (I).
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • isotopic enrichment factor refers to the ratio between the isotope abundance and the natural abundance of a given isotope.
  • a substituent of a compound of the invention is designated as hydrazine
  • the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D 2 O, acetone -d 6, DMSO-d 6 solvate of those.
  • compositions, formulations and administrations of the compounds of the invention are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof.
  • the amount of the compound in the pharmaceutical composition disclosed in the present invention means an amount effective to detect inhibition of protein kinase in a biological sample or a patient.
  • compositions of the invention may exist in free form for treatment or, if appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or can be provided directly or indirectly to a patient in need thereof. Any additional adduct or derivative of the compound or its metabolite or residue.
  • compositions disclosed herein can be prepared and packaged in a bulk form in which a safe and effective amount can be extracted The compound of formula (I) is then administered to the patient in the form of a powder or syrup.
  • the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I).
  • the pharmaceutical compositions disclosed herein can generally contain, for example, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of the compounds disclosed herein.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, mixture or vehicle that is associated with the administration of a dosage form or pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions which would greatly reduce the efficacy of the compounds disclosed herein when administered to a patient and result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction.
  • each excipient must be pharmaceutically acceptable, for example, of sufficiently high purity.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • pharmaceutically acceptable excipients can be selected based on their particular function in the composition. For example, certain pharmaceutically acceptable excipients can be selected which can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected which can aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients that facilitate the carrying or transport of a compound of the present invention from one organ or part of the body to another organ or part of the body upon administration to a patient may be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents,
  • compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the present invention is directed to a process for preparing a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients.
  • Pharmaceutical compositions comprising the compounds disclosed herein can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.
  • dosage forms include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.
  • routes of administration include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3)
  • the compounds disclosed herein can be formulated into oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhaled dosage form. In another embodiment, the compounds disclosed herein may be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated in a transdermal dosage form. In still another embodiment, the compounds disclosed herein may be formulated for topical administration.
  • the pharmaceutical composition provided by the present invention can be provided as a compressed tablet, a developed tablet, a chewable tablet, a fast-dissolving tablet, a reconstituted tablet, or an enteric coated tablet, a sugar-coated tablet or a film-coated tablet.
  • the enteric coated tablet is a compressed tablet coated with a substance which is resistant to gastric acid but which dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach.
  • Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate.
  • the sugar-coated tablet is a compressed tablet surrounded by a sugar coating which can be used to mask an unpleasant taste or odor and to prevent oxidation of the tablet.
  • the film coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble substance.
  • Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating.
  • the compressed tablet is a compressed tablet prepared over more than one compression cycle, including a multilayer tablet, and a press-coated or dry-coated tablet.
  • the tablet dosage form can be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including carriers Decomposing agents, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.
  • Exemplary pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose And methyl cellulose; western yellow gum powder; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; synthetic oil; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olives Oil and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; phosphate buffer solution; emulsifiers, such as Tween; wetting agents, such as sodium lauryl sulfate Colorant; flavoring agent; compressed tablet; stabilizer; antioxidant; preservative; pyrogen-free water; isotonic saline; and phosphate buffer solution.
  • sugars such
  • the pharmaceutical composition provided by the present invention may be provided in a soft capsule or a hard capsule, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.
  • the hard gelatin capsule also known as dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • Soft elastic capsules are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol or similar polyols.
  • Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those as described herein, including methylparaben and paraben, and sorbic acid.
  • liquid, semi-solid and solid dosage forms can be encapsulated in a capsule.
  • suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides.
  • Capsules containing such a solution can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545.
  • the capsules may also employ coatings as known to those skilled in the art to improve or maintain dissolution of the active ingredient.
  • compositions provided herein can be provided in liquid and semisolid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups.
  • the emulsion is a two-phase system in which one liquid is completely dispersed in the form of pellets in another liquid, which may be an oil-in-water or water-in-oil type.
  • the emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives.
  • Suspensions can include pharmaceutically acceptable suspending agents and preservatives.
  • the aqueous alcohol solution may include a pharmaceutically acceptable acetal such as a di(lower alkyl) acetal of a lower alkyl aldehyde such as acetaldehyde diethyl acetal; and a water soluble solvent having one or more hydroxyl groups, such as Propylene glycol and ethanol.
  • the tincture is a clear, sweet, hydroalcoholic solution.
  • a syrup is an aqueous solution of a concentrated sugar such as sucrose, and may also contain a preservative.
  • solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier such as water for precise and convenient administration.
  • liquid and semisolid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and the secondary mono- or poly-alkylene glycols, the mono- or poly-alkylene glycols comprising: 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-two Methyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, 750 refers to the approximate average molecular weight of polyethylene glycol).
  • formulations may further comprise one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin. , cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamate.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin.
  • cephalin ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamate.
  • Dosage unit formulations for oral administration can be microencapsulated as appropriate. It may also be prepared as a composition for prolonged or sustained release, for example by coating or embedding the particulate material in a polymer, wax or the like.
  • the oral pharmaceutical compositions provided herein can also be provided in the form of liposomes, micelles, microspheres or nanosystems.
  • the micellar dosage form can be prepared by the method described in U.S. Pat. No. 6,350,458.
  • compositions provided herein can be provided as non-effervescent or effervescent granules and powders to reconstitute a liquid dosage form.
  • the pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • the pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Colorants and flavoring agents can be used in all of the above dosage forms.
  • the compounds disclosed herein can also be combined with soluble polymers as targeted drug carriers.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or palmitoyl residue substituted polyoxyethylene polylysine.
  • the compounds disclosed herein can be combined with a class of biodegradable polymers used in the controlled release of drugs, for example, polylactic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters. Crosslinked or amphiphilic block copolymers of polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.
  • compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.
  • compositions provided herein can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with a substance that complements the intended effect.
  • compositions provided by the present invention can be administered parenterally by injection, infusion or implantation for topical or systemic administration.
  • Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and in liquids prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous carriers, water miscible vehicles, nonaqueous vehicles, antibiotics Microbial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, multivalent Chelating or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters, and inert gases.
  • aqueous carriers water miscible vehicles, nonaqueous vehicles, antibiotics Microbial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, multivalent Chelating or chelating agents, antifreeze agents, cryoprotectants, thicken
  • Suitable aqueous vehicles include, but are not limited to, water, saline, saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose, and Lactated Ringers injection.
  • Non-aqueous vehicles include, but are not limited to, plant-derived non-volatile oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil. Chain triglycerides, and palm seed oil.
  • Water miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl- 2-pyrrolidone, N,N-dimethylacetamide and dimethyl sulfoxide.
  • Suitable antimicrobial or preservatives include, but are not limited to, phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl and propylparaben, thiomersal, benzalkonium chloride (eg benzethonium chloride), methylparaben and propylparaben and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and glucose.
  • Suitable buffering agents include, but are not limited to, phosphates and citrates.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
  • Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to, EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfonate.
  • cyclodextrins including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfonate.
  • compositions provided by the present invention may be formulated for administration in single or multiple doses.
  • the single dose formulation is packaged in an ampoule, vial or syringe.
  • the multi-dose parenteral formulation must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.
  • the pharmaceutical composition is provided as a ready-to-use sterile solution.
  • the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powders and subcutaneously injected tablets, which are reconstituted with a vehicle prior to use.
  • the pharmaceutical composition is formulated as a ready-to-use sterile suspension.
  • the pharmaceutical composition is formulated as a sterile dry insoluble product that has been reconstituted with a vehicle prior to use.
  • the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.
  • compositions can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.
  • the pharmaceutical compositions can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implanted reservoir.
  • the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric film that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.
  • Suitable internal substrates include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized Polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone Carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, crosslinked polyvinyl alcohol and partially hydrolyzed polyvinyl acetate of the trainer.
  • Suitable external polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, chloroprene Rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polymer polyethylene terephthalate, butyl rubber chlorohydrin Rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene/vinyloxyethanol copolymer.
  • the pharmaceutical compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, aerosol, suspension or solution composition.
  • the disclosed pharmaceutical compositions can be formulated in a dosage form suitable for inhalation administration to a patient with a dry powder.
  • the disclosed pharmaceutical compositions can be formulated in a dosage form suitable for inhalation administration to a patient by a nebulizer.
  • Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the invention and one or more finely divided pharmaceutically acceptable excipients.
  • compositions which are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g. micronised) compound can be (e.g., as measured by laser diffraction method) is defined by the D 50 value from about 1 to 10 microns.
  • Aerosol formulations can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant.
  • Suitable propellants include chlorinated hydrocarbons, hydrocarbons, and other liquefied gases.
  • Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1 , 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoro Pentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a metered dose
  • Aerosols may contain additional pharmaceutically acceptable excipients, such as surfactants, lubricants, cosolvents, and other excipients, which may be used by MDIs to improve the physical stability of the formulation, improve valve characteristics, Improve solubility or improve taste.
  • excipients such as surfactants, lubricants, cosolvents, and other excipients, which may be used by MDIs to improve the physical stability of the formulation, improve valve characteristics, Improve solubility or improve taste.
  • compositions suitable for transdermal administration can be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time.
  • the active ingredient can be delivered from the patch by ion permeation as generally described in Pharmaceutical Research, 1986, 3(6), 318.
  • compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • ointments, creams, and gels can be formulated with a water or oil base, and a suitable thickening and/or geling agent and/or solvent.
  • a suitable thickening and/or geling agent and/or solvent may include water, and/or oils such as liquid liquid paraffin and vegetable oils (such as peanut oil or castor oil), or solvents such as polyethylene glycol.
  • Thickeners and gels for use depending on the nature of the matrix include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or single Stearic acid glycerides and/or nonionic emulsifiers.
  • Lotions may be formulated with water or oil bases and usually contain one or more emulsifying, stabilizing, dispersing, suspending or thickening agents.
  • the topical powder can be formed in the presence of any suitable powder base such as talc, lactose or starch. Drops can be formulated with an aqueous or non-aqueous base comprising one or more dispersing agents, solubilizing agents, suspending agents or preservatives.
  • suitable powder base such as talc, lactose or starch.
  • Drops can be formulated with an aqueous or non-aqueous base comprising one or more dispersing agents, solubilizing agents, suspending agents or preservatives.
  • the topical preparation can be administered by applying one or more times per day to the affected area; a closed dressing covering the skin is preferably used.
  • Adhesive depot systems enable continuous or extended administration.
  • a composition When treating the eye, or other organs such as the mouth and skin, a composition can be applied as a topical ointment or cream.
  • a composition When formulated as an ointment, the compounds disclosed herein can be used with paraffin or water soluble ointment bases. Alternatively, the compounds disclosed herein can be formulated as a cream with an oil-in-water cream base or an oil-in-water base.
  • the compounds of the invention may be administered as separate active agents or may be administered in combination with other therapeutic agents, including other compounds having the same or similar therapeutic activity and which are determined to be safe and effective for such combination administration.
  • the invention provides a method of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the invention and one or more therapeutically active agents.
  • the combination comprises one or two additional therapeutic agents.
  • therapeutic agents include, but are not limited to, anticancer agents, including chemotherapeutic agents and antiproliferative agents; anti-inflammatory agents; and immunomodulatory or immunosuppressive agents.
  • the methods of treatment disclosed herein comprise administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • Embodiments of the present disclosure include methods of treating the above mentioned diseases by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered by any suitable route of administration, including systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration Administration, transdermal administration and rectal administration.
  • Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion.
  • Topical administration includes administration to the skin as well as intraocular, otic, intravaginal, inhalation, and intranasal administration.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered orally.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered by inhalation.
  • the compounds disclosed herein or comprising a compound disclosed herein may be administered intranasally.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered at a time, or several times at different time intervals, over a specified period of time, depending on the dosage regimen. For example, administration once, twice, three times or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, the administration is twice daily. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the compounds disclosed herein depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, as determined by the skilled artisan.
  • suitable dosage regimens of the disclosed compounds or pharmaceutical compositions comprising the compounds of the present invention including the duration of implementation of the regimen, depend on the condition being treated, the severity of the condition being treated, the age of the subject being treated, and The physical condition, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc., are within the knowledge and experience of the skilled person.
  • the dosage regimen for the adjustment may be required for individual patient responses to the dosage regimen, or for individual patient needs to change over time.
  • the compounds disclosed herein can be administered simultaneously with, or before or after, one or more other therapeutic agents.
  • the compounds of the invention may be administered separately or in combination with other therapeutic agents by the same or different routes of administration.
  • compositions and combinations disclosed herein may comprise from about 1 to 1000 mg, or from about 1 to 500 mg, or from about 1 to 250 mg, or from about 1 to 150 mg, or from about 0.5 to 100 mg, or from about 50 to 70 kg of the individual, or A unit dosage form of about 1-50 mg of the active ingredient.
  • the therapeutically effective amount of a compound, pharmaceutical composition, or combination thereof will depend on the species, weight, age, and individual condition of the individual, the disorder or disease being treated, or the severity thereof. Physicians, clinicians, or veterinarians with common skills can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the development of a disease or disease.
  • the dosage characteristics cited above have been demonstrated in in vitro and in vivo assays using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and specimens.
  • advantageous mammals e.g., mice, rats, dogs, monkeys
  • the compounds disclosed in the present invention are used in vitro in the form of a solution, for example, an aqueous solution, and may also be used, for example, in the form of a suspension or an aqueous solution in the intestine of the body, parenterally, especially intravenously.
  • a therapeutically effective amount of a compound disclosed herein is from about 0.1 mg to about 2,000 mg per day.
  • the pharmaceutical composition thereof should provide a dose of from about 0.1 mg to about 2,000 mg of the compound.
  • the pharmaceutical dosage unit form is prepared to provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the primary active ingredient or per dosage unit form.
  • the combination of the main ingredients is prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the main active ingredient.
  • a prodrug of a compound disclosed herein is a functional derivative which, when administered to a patient, ultimately releases the compound of the present invention in vivo.
  • a compound disclosed herein is administered in a prodrug form
  • one of skill in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; Changing the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound.
  • Typical functional derivatives for the preparation of prodrugs including variants of compounds which are cleaved chemically or enzymatically in vivo. These variants comprising the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates are well known to those skilled in the art.
  • the ethyl acetate phase was combined and the organic phase was washed with water and brine and dried over anhydrous sodium sulfate. After filtration, ethyl acetate was removed using a rotary evaporator, and the obtained crude product was mixed with silica gel powder, dried, and separated and purified by silica gel column chromatography.
  • the phenolic compound (8, 1 eq.) was dissolved in solvent dichloromethane (DCM) and the reaction flask was filled with argon and protected with an argon balloon. Pyridine (1.2 eq.) was added using a syringe at room temperature. 3-Chloropropanoyl chloride (9, 1.1 eq.) was slowly added dropwise to the reaction vial via a syringe. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was quenched with water. After liquid separation, the dichloromethane phase was washed with water and brine.
  • DCM solvent dichloromethane
  • the methylene chloride phase was dried over anhydrous magnesium sulfate, filtered, and the organic solvent was removed on a rotary evaporator.
  • the intermediate (10, 1 eq.) and AlCl 3 (3 eq.) were added to the reaction flask and heated to 180 ° C for 6 h without solvent. After the reaction was cooled to room temperature, it was quenched with ice cold 2M hydrochloric acid and stirred to dissolve a black solid. It was extracted three times with ethyl acetate. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and then evaporated and evaporated.
  • the hydroxy fluorenone compound (11, 1 eq.) was added to ice-cold concentrated hydrochloric acid, and NaN 3 (2 eq.) was slowly added portionwise.
  • the reaction solution was stirred at 0 ° C to rt for 20 h. After the reaction was completed, the reaction solution was quenched with water. The aqueous phase was extracted three times with dichloromethane and the organic phase dried over anhydrous magnesium sulfate. After the desiccant was filtered, the organic phase was mixed with silica gel and purified by silica gel column chromatography to give hydroxyisoquinoline compound 12.
  • the 4-position of the formyl ester imidazole compound 29 (1 eq.) was dissolved in a mixed solvent of tetrahydrofuran and water, and then a 40% aqueous solution of methylamine (20 eq.) was added dropwise thereto, and the mixture was heated at 60 ° C for 4 hours.
  • tetrahydrofuran was removed under reduced pressure using a rotary evaporator, and the aqueous layer was extracted with ethyl acetate.
  • the combined organic phases were dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic phase was mixed with silica gel, and purified by silica gel column chromatography to give the title compound.
  • intermediate 66 is reduced by Pd/C to give intermediate 66.
  • the intermediate 66 (1 eq.) was dissolved in a tetrahydrofuran solution, and trifluoroacetic anhydride (1 eq.) was slowly added dropwise to the above solution in an ice bath, and reacted for 1 hour, followed by dichloromethane extraction, and the obtained organic phase was removed by a rotary evaporator. Dissolved, finally obtained intermediate 67, which was used directly in the next step.
  • Compound 68 (3 eq.) was slowly added dropwise to a solution of intermediate 67 (1 eq.) and potassium carbonate (5 eq.) in N,N-dimethylformamide.
  • NMR Chemical Displacement Perturbation Test Affinity (K D ): The NMR HSQC titration method detects protein amino acid residues that are perturbed by small molecule compounds and detects the binding affinity of small molecules and proteins by a perturbation signal.
  • the bromodomain of the 15 N-labeled BRM of 0.05 mM to 0.2 mM was titrated separately from the molar ratio of the small molecule compound from 0.0 to 4.0.
  • the HSQC pattern for each titration data point was acquired using a 500 MH or 700 MHz Agilent nuclear magnetic instrument for 18 min at 293 K. The results are summarized in Table 1.
  • Cell viability assay The effect of small molecules on cell viability was detected using the MTT assay.
  • the cells were placed in 96-well plates, and different concentrations of test small molecule samples, KQ70 (negative control), and DMSO (blank control) were administered for 3 to 4 days, followed by addition of MTT stock solution (5 mg/ml, 20 ⁇ L).
  • MTT stock solution 5 mg/ml, 20 ⁇ L.
  • 96-well plates were incubated for 4 h at 37 °C in a CO 2 incubator.
  • DMSO 150 ⁇ L was added to each well and mixed until all crystals were dissolved.
  • the OD value at 490 nm was tested using a SpectraMax M5 (Molecular Devices, CA, USA). It was calculated by nonlinear regression analysis of the concentration values of 50% inhibition IC.
  • H1299 cells and lung adenocarcinoma cells (belonging to non-small cell lung cancer) A549 cells, respectively.
  • Both H1299 cells and A549 cells are BRG1 gene deletion (BRG1 - ), and BRM gene (BRM + ) non-deleted cell line.
  • the cell line cannot express BRG1 protein, but can express BRM protein normally.
  • a small molecule that blocks the interaction of a BRM protein with a chromosome in a cell prevents the BRM protein from performing intracellular functions. According to the synergistic lethality rule, in the BRG1 gene-deficient cells, blocking the function of the BRM protein leads to cell death and the effect of small molecules killing cancer cells.
  • IC 50 half-inhibitory concentration of each compound (small molecule) was determined according to the conventional detection method, and the results are summarized in Table 1.
  • Table 1 +++ represents a strong inhibitory activity, and ++ represents a moderate inhibition.
  • the activity, + represents a lower inhibitory activity, but still has a significantly better inhibitory activity than the known compounds.
  • the compounds KQ1 to KQ81 of the present invention can effectively treat cancer, particularly the BRG1 gene-deficient non-small cell lung cancer.
  • the compounds of the present invention are effective for the treatment of cancer, especially the BRG1 gene-deficient non-small cell lung cancer.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé et une utilisation associée dans la préparation d'un médicament, et en particulier, la présente invention concerne : le composé représenté par la formule (I) ou un stéréoisomère, un isomère géométrique, un tautomère, un racémate, un nitroxyde, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament du composé tel que représenté en formule (I). L'invention concerne également l'utilisation du composé dans la préparation d'un médicament pour le traitement du cancer.
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CN114814020A (zh) * 2022-04-20 2022-07-29 安康市农产品质量安全检验监测中心 一种农产品中残留有机磷农药的分析方法
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CN111635310A (zh) * 2020-05-21 2020-09-08 大连理工大学 一种用于防护铜在弱碱性介质中腐蚀的水杨酸酰胺型缓蚀剂及制备方法
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US12037344B2 (en) 2018-04-25 2024-07-16 Innate Tumor Immunity, Inc NLRP3 modulators
CN110840876A (zh) * 2019-11-18 2020-02-28 青海民族大学 圆孢蘑菇中的没食子酸在cdc25磷酸蛋白酶上应用
CN114814020A (zh) * 2022-04-20 2022-07-29 安康市农产品质量安全检验监测中心 一种农产品中残留有机磷农药的分析方法
CN114814020B (zh) * 2022-04-20 2023-08-29 安康市农产品质量安全检验监测中心 一种农产品中残留有机磷农药的分析方法

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