WO2017101791A1 - Compound and use thereof in preparing drug - Google Patents

Abstract

Disclosed are a compound and a use thereof in preparing a drug, and in particular, provided in the present invention are: the compound as shown in formula (I) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitroxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in formula (I). Also disclosed is the use of the compound in the present invention in preparing a drug for treating cancer.

Description

Compounds and their use in the preparation of medicaments

Priority information

Priority is claimed on Japanese Patent Application No. 201510925699.7, filed on Dec.

Technical field

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.

Background technique

In medicine, cancer refers to a malignant tumor that originates from epithelial tissue and is the most common type of malignant tumor. Correspondingly, 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. Generally speaking, "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.

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.

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.

However, current drugs for the treatment of cancer, especially non-small cell lung cancer, remain to be further studied.

Summary of the invention

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:

Where Q represents C or N;

或任选被C_1～5烷基、C_1～5烷基酯基取代的五元含氮杂环；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;

Each of 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.

In a second aspect of the invention, the invention provides the use of a compound as hereinbefore described in the manufacture of a medicament for the treatment of cancer. Optionally, the cancer is lung cancer. Optionally, the lung cancer is non-small cell lung cancer. Optionally, the non-small cell lung cancer is a BRG1 gene deletion.

Further, 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.

Further, the present invention also provides a composition for treating cancer comprising the aforementioned compound as an activity ingredient.

It should be noted that the features and advantages of the various aspects described above apply equally to other aspects.

The foregoing description is only illustrative of certain aspects of the invention, and is not intended to

Detailed description of the invention

Definitions and general terms

Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.

It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.

Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.

The following definitions used in the present invention should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. The entire content of which is incorporated herein by reference.

The articles "a", "an" and "the" Therefore, the articles used herein are used to refer to the articles of one or more than one (ie, at least one). For example, "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.

The term "subject" as used herein 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.

The term "patient" as used herein refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

"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.

The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry Of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

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. In certain embodiments, 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.

Depending on the choice of starting materials and methods, 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.

The 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. In particular, 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. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "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. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of 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.

As described herein, 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. A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "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. 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. Oxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, cycloalkane Alkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, cycloalkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxy substituted alkyl, hydroxy substituted alkane Amino, cyano substituted alkyl, cyano substituted alkoxy, cyano substituted alkylamino, amino substituted alkyl, alkyl acyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkyl ,heterocyclyl,heterocyclylalkyl,heterocyclylacyl,aryl,arylalkyl,arylamino,heteroaryl,heteroarylalkyl,heteroarylamino,amide,sulfonyl,amino Sulfonyl and the like.

In addition, it should be noted that the descriptions of the "individually" and "individually" and "independently" are interchangeable, unless otherwise explicitly indicated in the present invention. It should be understood in a broad sense, which can mean that the specific options expressed between the same symbols in different groups do not affect each other, and can also represent specific options expressed in the same group and between the same symbols. There is no influence between each other.

In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "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.

The term "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.

Examples of 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(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) _2), 2-methyl-3-pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2,3- dimethyl 2-butyl _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- dimethyl-2-butyl _{(-CH (CH 3) C (} CH 3) 3), n-heptyl Base, just octyl, and so on.

The term "C _xy alkyl" refers to an alkyl group having a C atom number of xy.

The term "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.

Examples of 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 ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), and so on.

The terms "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. Unless otherwise stated, a heterocyclic group can be a carbon or a nitrogen group, and a -CH ₂ - group can be optionally substituted with -C(=O)-. 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. Examples of 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 Daimorpholinyl, (1,1-dioxo)-thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, Oxepane, thiaheptanyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, tetrahydropyridyl. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto group, 3,5-dioxopiperidinyl. 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. When the structure clearly requires a linking group, the Markush variable recited for that group is understood to be a linking group. For example, if the structure requires a linking group and the "Heterocyclyl" is recited for the Markush group definition of the variable, it is understood that the "heterocyclyl" represents a linked heterocyclylene group.

The terms "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. The term "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.

The term "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).

The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "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. The term "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. When the structure clearly requires a linking group, the Markush variable recited for that group is understood to be a linking group. For example, if the structure requires a linking group and the "aryl" is listed for the Markush group definition for this variable, it should be understood that the "aryl" represents a linked arylene group.

The term "prodrug" as used in the present invention 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. In the prior invention, 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. For example, 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. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolic 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. Other pharmaceutically acceptable 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, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. 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.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.

As used herein, the term "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.

The term "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. More specific examples of such cancers include 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.

Description of the compounds of the invention

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:

或任选被C_1～5烷基、C_1～5烷基酯基取代的五元含氮杂环，R6为键，H，C_1～5亚烷基，任选被C_1～5亚烷基取代的五元含氮杂环，或任选被C_1～5亚烷基取代的亚氨基，R7、R8分别独立地为H，C_1～5烷基，或者任选被C_1～5烷基、C_1～5烷氧基、C_1～5亚烷基环烷基、C1～5亚烷基环烯基、芳基、亚烷基芳基、六元杂环、亚烷基六元杂环、氰基、氰基亚氨基C_1～5烷基取代的亚氨基或次氨基；以及R2、R3、R4、R5和R6的每一个分别独立地为H、卤素、羟基、C_1～5烷氧基、胺基、C_1～5羰基亚氨基或者亚氨基、芳基、硝基或者氰基，前提是R2、R3、R4、R5和R6不同时为H；或者R1～R6中相邻的两个连同与其所连接的碳原子构成任选取代的C_1～5烷基、芳基、任选含有氧、硫和氮至少之一的五～七元环或者稠合双环。发明人意外地发现，该化合物能够有效地用于治疗癌症，尤其是非小细胞肺癌。Where Q represents C or N and R1 represents 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, 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; and each of R 2 , R 3 , R 4 , R 5 and R 6 are independently H, halogen, hydroxy, C, respectively. _{a 1-5} alkoxy group, an amine group, a C _1-5 carbonyl imino group or an imino group, an aryl group, a nitro group or a cyano group, provided that R 2 , R 3 , R 4 , R 5 and R 6 are not simultaneously H; or R 1 to R 6 The two adjacent ones 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 or a fused bicyclic ring optionally containing at least one of oxygen, sulfur and nitrogen. The inventors have unexpectedly discovered that the compound can be effectively used for the treatment of cancer, especially non-small cell lung cancer.

Alternatively, R1 is an optionally substituted iminocarbonyl group, a secondary aminocarbonyl group or a five-membered nitrogen-containing heterocyclic ring. Optionally, the halogen is F or Cl. Alternatively, 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. or 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. Alternatively, 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. Alternatively, 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:

In a second aspect of the invention, the invention provides the use of a compound as hereinbefore described in the manufacture of a medicament for the treatment of cancer. Optionally, the cancer is lung cancer. Optionally, the lung cancer is non-small cell lung cancer. Optionally, the non-small cell lung cancer is a BRG1 gene deletion.

Further, 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.

Further, the present invention also proposes a composition for treating cancer comprising the aforementioned compound as an active ingredient.

It should be noted that the features and advantages of the various aspects described above apply equally to other aspects.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites, metabolic precursors, salts and Pharmaceutically acceptable prodrugs are within the scope of the invention.

In particular, the salt is a pharmaceutically acceptable salt. The term "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/hydrogen phosphate/dihydrogen phosphate, polygalactinate, propionate, stearate, succinate, sulfohydrate Salicylate, tartrate, tosylate and trifluoroacetate.

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. In certain embodiments, 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. In general, 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. 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. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., 1985; and "Handbook of Pharmaceutical Salts: Properties, Selection and Use" A list of additional suitable salts can be found in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Further, the compounds disclosed in the present invention, including their salts, 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. 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.

In another aspect, 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. Such 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.

In addition, substitution of heavier isotopes, particularly deuterium (i.e., ² H or D), 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. It should be understood that 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. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If 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.

Pharmaceutical compositions, formulations and administrations of the compounds of the invention

The present invention provides 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.

It will also be appreciated that certain compounds of the invention may exist in free form for treatment or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of 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.

The pharmaceutical 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. Alternatively, 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). When prepared in unit dosage form, 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.

As used 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. In addition, 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. In addition, 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. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function and provide an alternative function depending on how many other excipients are present in the excipient and formulation in the formulation. Agent.

The skilled artisan will have the knowledge and skill in the art to enable them to select the appropriate amount of suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are a number of resources available to the skilled artisan who describe pharmaceutically acceptable excipients and are used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York Various carriers for arranging pharmaceutically acceptable compositions, and well-known techniques for their preparation are disclosed, the respective contents of which are incorporated by reference. It is incorporated into the present invention. In addition to any conventional carrier that is incompatible with the compounds disclosed herein, such as by any undesired biological action, or in a deleterious manner in interaction with any other component of the pharmaceutically acceptable composition, The scope of the invention.

The pharmaceutical 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).

Accordingly, in another aspect, 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.

The compounds disclosed herein are typically formulated in a dosage form suitable for administration to a patient by the desired route. For example, 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.

In one embodiment, 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.

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), consists of two sections, one section being inserted into the other section, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) 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. The liquid, semi-solid and solid dosage forms provided herein 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.

The pharmaceutical 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. For liquid dosage forms, for example, 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.

Other useful 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). These 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.

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.

The pharmaceutical 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. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or palmitoyl residue substituted polyoxyethylene polylysine. Furthermore, 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-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters. Crosslinked or amphiphilic block copolymers of polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.

The pharmaceutical 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.

The pharmaceutical 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.

The pharmaceutical 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. A solid form of the solution or suspension. Such 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).

Pharmaceutical 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.

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.

CyDex,Lenexa,KS)。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. Butyl ether 7-β-cyclodextrin

CyDex, Lenexa, KS).

The pharmaceutical 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.

In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, 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. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product that has been reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

The disclosed pharmaceutical 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. In one embodiment, 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.

In another aspect, 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. In one embodiment, the disclosed pharmaceutical compositions can be formulated in a dosage form suitable for inhalation administration to a patient with a dry powder. In yet another embodiment, 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. Pharmaceutically acceptable excipients 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 inhaler (MDI). Such devices are known to those skilled in the art.

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.

Pharmaceutical 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. For example, the active ingredient can be delivered from the patch by ion permeation as generally described in Pharmaceutical Research, 1986, 3(6), 318.

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams, and gels can be formulated with a water or oil base, and a suitable thickening and/or geling agent and/or solvent. Such a matrix 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.

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.

When treating the eye, or other organs such as the mouth and skin, a composition can be applied as a topical ointment or cream. 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.

Combination therapy

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.

In one aspect, 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. In one embodiment, the combination comprises one or two additional therapeutic agents.

Examples of other therapeutic agents include, but are not limited to, anticancer agents, including chemotherapeutic agents and antiproliferative agents; anti-inflammatory agents; and immunomodulatory or immunosuppressive agents.

treatment method

In one embodiment, 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.

In one embodiment, 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. In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered orally. In another embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered by inhalation. In still another embodiment, the compounds disclosed herein or comprising a compound disclosed herein may be administered intranasally.

In one embodiment, 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. Furthermore, 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. Such skilled artisans will also appreciate that 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.

The pharmaceutical 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. 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.

In one embodiment, 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. In a particular embodiment, 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. In a particular embodiment, the pharmaceutical dosage unit form 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.

Furthermore, the compounds disclosed herein can be administered in the form of a prodrug. In the present invention, 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. When 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.

General synthetic process

In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I).

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated (the route N is collectively described below as a numerical number and will not be described again).

1. (1 indicates Route 1, and Route N is uniformly described as a numerical number, and will not be described again) Synthetic amide compound (3):

Substituted aromatic carboxylic acid (1,1 eq.), Carter condensing agent (BOP, 1.2 eq.) and N,N-diisopropylethylamine (DIEA, 2.5 eq) were added in an appropriate volume of N,N-dimethyl In the formamide solvent. The resulting mixture was stirred at room temperature for 10 min. The amino compound (2, 2.5 eq.) was added dropwise to the reaction mixture in portions or dropwise. The resulting reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction solution was quenched with an equal volume of water and extracted three times with double volume of ethyl acetate. 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.

2. Synthesis of pyrazole compound (7):

The substituted benzaldehyde (4,1 eq.) and alkyl ethyl ketone (5, 1.5 eq.) dissolved in ethanol were added portionwise to an aqueous solution of NaOH (3 eq.). The resulting mixture was refluxed for 4 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 4 to 5 using 2N hydrochloric acid. The resulting mixture was extracted three times with an equal volume of ethyl acetate. After the organic phase was washed with water and brine, dried over anhydrous sodium sulfate. After the sodium sulfate was filtered off and the organic phase was removed using a rotary evaporator, the obtained crude intermediate (6) was used directly in the next step.

The intermediate (6, 1 eq.), p-toluenesulfonylhydrazide (2 eq.) and tetrabutylammonium bromide (TBAB, 1 eq.) were slowly added portionwise to an aqueous solution of NaOH (3 eq.) and stirred while stirring. The resulting mixture was stirred at 95 ° C for 12 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 4 to 5 using 2N hydrochloric acid. The resulting mixture was extracted three times with an equal volume of ethyl acetate. After the organic phase was washed with water and brine, dried over anhydrous sodium sulfate. After the sodium sulfate was filtered off, the organic phase was removed using a rotary evaporator. The obtained crude product was separated and purified by recrystallization or silica gel column chromatography.

3. Synthetic route 2 of hydroxy fluorenone (11) structure:

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. 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.

4. Synthesis route of hydroxyisoquinoline compounds:

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. Compound 12 (1 eq.), NaH (2 eq.) was reacted in solvent tetrahydrofuran for 0.5 h, and iodine R'I (3 eq.) was added. Compound 13 was stirred with an aqueous solution of 48% HBr at 180 ° C overnight to afford compound 14.

5. Synthesis of benzoyl hydrazino (18) and benzoyl hydrazino (20) compounds:

An o-hydroxybenzoic acid compound (15, ₁ eq.) was added to the reaction solvent dichloromethane, and SOCl ₂ (3 eq.) was added dropwise to the solution. The resulting reaction solution was reacted at 50 ° C for 1 h, and then SOCl 2 was removed by rotary evaporation on a rotary evaporator. The obtained crude product was dissolved in dichloromethane, and then a mixture of phenol (phenol, 1 eq.) and triethylamine (TEA, 3 eq.) in dichloromethane was added dropwise. The resulting reaction was stirred at rt for 1 h then quenched with water. It was extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate. After the desiccant is filtered, the organic phase is mixed with silica gel and purified by silica gel chromatography to give Intermediate 16. Intermediate 16 (1 eq.) and 1,1,3,3-tetramethylguanidine (TMG, 1.5 eq.) were added to the reaction solvent N,N-dimethylformamide, and after stirring for 5 min, a mercapto compound was added. 17,1.6 eq.), stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with water, and extracted with ethyl acetate. Intermediate 16 (1 eq.), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU, 1.6 eq.), N,N-diisopropylethylamine (DIEA, 3 eq.) was added to the solvent. In N,N-dimethylformamide. The reaction solution was stirred at room temperature for 30 min, and a mercapto compound (19, 1.2 eq.) was added to the mixture. The reaction solution was stirred at room temperature overnight and then quenched with water. After extraction with ethyl acetate, the benzoyl hydrazide compound (20) can be obtained by silica gel column chromatography.

6. Synthesis of carbazole compound (23):

Substituted fluorobenzonitrile (21, 1 eq.), hydrazine hydrate (4 eq.) and an appropriate amount of solvent n-butanol were placed in a round bottom flask. The reaction was heated to 100 ° C overnight. After completion of the reaction, it was concentrated and filtered to give Intermediate 22, which was used directly to the next step. The intermediate 22 (1 eq.) was dissolved in an appropriate amount of tetrahydrofuran solvent, an aldehyde compound (5 eq.), palladium carbon (0.04 eq.), and then added to the reaction, hydrogen gas was supplied as a hydrogen balloon, and reacted at room temperature overnight, and the reaction was detected by TLC. After completion of the reaction, the palladium carbon was removed by filtration, and the solution was mixed with silica gel and then separated by silica gel column chromatography to obtain the target carbazole compound.

7. Synthesis of triazole (26) compounds:

The substituted salicylamide (24, 1 eq.) was dissolved in acetone, and then triethylamine (Et ₃ N, 1.2 eq.), acetic anhydride (1.1 eq), and heated to reflux for four hours. After the TLC detection reaction was completed, the solvent was removed using a rotary evaporator, and the crude product was purified by silica gel column chromatography to afford Intermediate 26. HClO ₄ (70%, 1 eq.) was added dropwise to acetic anhydride (3 eq.), and the mixture was dropped into an acetic acid solution of Intermediate 25 (1 eq.), and the reaction liquid was heated at 95 ° C for 1.5 h, and the solution became tea. Red, add hydrazine hydrate (2 eq.), reduce the temperature to 80 ° C, and stir for half an hour. After the reaction was cooled to room temperature, it was diluted with ethyl acetate. The acid was washed with saturated sodium hydrogen carbonate aqueous solution, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed on a rotary evaporator and purified by silica gel column chromatography to obtain the target triazole compound. 26.

Synthesis of 8.4-position formyl ester imidazole compound (29):

An aqueous solution of hydroxylamine hydrochloride (4 eq.) and sodium carbonate (2 eq.) was added to a solution of the substituted hydroxybenzonitrile (27, 1 eq.) in ethanol and refluxed for 10 hours. After completion of the reaction, the ethanol was removed by a rotary evaporator, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Ethyl propiolate (2 eq.) was added dropwise to a solution of the intermediate 28 (1 eq.) in ethanol, and the mixture was heated to reflux for 10 hours, and then ethanol was removed by a rotary evaporator, followed by heating at 190 ° C for three hours. After the reaction was stopped, the temperature was lowered to room temperature, and the whole reaction liquid was poured into a larger silica gel column, washed with petroleum ether, and after removing the diphenyl ether, the remaining components were washed out with ethyl acetate. The components were combined, and the silica gel powder was mixed and purified by silica gel column chromatography to obtain the target product imidazole compound 29.

9. Synthesis of 4-position formyl ester imidazole compound (30):

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. After completion of the reaction, 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.

10. Synthesis of quinazolinediones (35):

Compound 32 (1 eq.) was added to a solution of compound 31 (1 eq.) in dichloromethane, and N,N'-carbonyldiimidazole (CDI, 1.3 eq.) and N,N-diisopropylethylamine (DIPEA) , 2 eq.), reacted at room temperature for 6 h, and the dichloromethane was removed by a rotary evaporator. To a solution of the intermediate 33 (1 eq.) in dichloromethane (3 EtOAc). In the reaction system, boron tribromide (3 eq.) was directly added to give a quinazolinedione compound 35.

11. Synthesis of pyrazoloquinoline compounds (KQ76, KQ77):

Compound 36 (1 eq.) was dissolved in acetone, KOH (4 eq.) was added, and dimethyl sulfate (1.5 eq.) was added with stirring. The reaction mixture was stirred for 1 hour, then 1 ml of water was added and stirred for 1.5 h. After completion of the reaction, the mixture was extracted with ethyl acetate. Intermediate 37 (1 eq.) was dissolved in glacial acetic acid, and then EtOAc (2 eq.) was added dropwise, and 98% sulfuric acid (0.1 eq.) was added with stirring, and heated at 80 ° C for 5 h. After completion of the reaction, the mixture was neutralized with aq. sodium hydrogen sulfate, and ethyl acetate was evaporated. Intermediate 38 (1 mmol) was dissolved in 6 mL of Eaton's reagent and the reaction was heated to 65 °C overnight. After completion of the reaction, it was neutralized with a sodium hydroxide solution, and extracted with ethyl acetate. Compound 39 (1 eq.) was dissolved in anhydrous dichloromethane, the reaction flask was replaced with argon, BBr ₃ (5 eq.) was added at -78 ° C, gradually warmed to room temperature, and after 5 h of reaction, it was quenched with saturated sodium hydrogen carbonate solution. The mixture was neutralized, neutralized with ethyl acetate, and the organic phase was dried. Compound 40 (1 eq.) was dissolved in acetone, Cs ₂ CO ₃ (6 eq.) was added, the reaction flask was strictly protected with nitrogen, and chloromethyl methyl ether (3 eq.) was added under ice bath, and the temperature was raised to 10 ° C. Reaction 2h. After completion of the reaction, the reaction was neutralized with 2N hydrochloric acid, and ethyl acetate was evaporated. Compound 41 was dissolved in anhydrous tetrahydrofuran, and LDA (2 eq.) was added at -40 ° C. After half an hour, butyryl chloride (1.1 eq.) was added, the reaction was allowed to rise to room temperature, and the reaction was carried out for 0.5 h. The tetrahydrofuran was spun off, extracted with ethyl acetate, and the organic phase was dried, then the solvent was evaporated, and the crude was dissolved in ethanol, and then hydrazine hydrate (3 eq.) was added and reacted at 60 ° C for 2 h. After completion of the reaction, it was purified by silica gel column chromatography to afford Intermediate 42. Compound 42 (1 eq.) was added to trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hr. The compound 43 was dissolved in dry tetrahydrofuran, and sodium borohydride (5 eq.) was added, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was quenched with water. Purification by silica gel column chromatography gave Compound KQ77.

12. Synthesis of pyrazoloquinolinone compounds (KQ78):

Compound 45 (1 eq.) was placed in a sealed tube, trifluoroacetic acid was added, and then urotropine (1.1 eq.) was added. After the sealed tube was replaced with argon gas, the mixture was heated to 100 ° C, and after reacting for 24 hours, the reaction solution was cooled. Room temperature. An equal volume of 4N hydrochloric acid was added to the reaction mixture and stirred for 1 h. After completion of the reaction, the solvent was evaporated, and an appropriate amount of distilled water was added and extracted with dichloromethane. The crude product was purified by silica gel column chromatography. DBU (2 eq.), iodomethane (3 eq.) was added to a solution of compound 46 (1 eq.) in acetone and stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated to dryness crystall Compound 47 was dissolved in acetone, a saturated solution of sodium chlorite (5 eq.) was added, and then 2N hydrochloric acid (8 eq. After completion of the reaction, the solvent was evaporated to dryness crystall Compound 48 was dissolved in dry dichloromethane, and two drops of DMF were added dropwise, then oxalyl chloride (2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. Compound 49 (1.2 eq.) was dissolved in dry THF. The reaction product of the compound 48 was dissolved in dry THF, and the mixture was poured into the reaction mixture of Compound 49 and stirred at room temperature for 1 hour. After completion of the reaction, a small amount of water was added to quench the reaction. After the solvent was evaporated, the crude product was purified by silica gel column chromatography. Compound 50 was dissolved in ethanol, and hydrazine hydrate (2 eq.) was added thereto, and the mixture was stirred at 60 ° C for 2 h. After completion of the reaction, the solvent was evaporated to dryness. Compound 51 (1 eq.) was dissolved in ethylene glycol dimethyl ether, reduced iron powder (10 eq.) was added, 0.1 N hydrochloric acid (10 eq.) was added, and the mixture was heated to 82 ° C for 5 h. After the reaction was completed, the solvent was dried. The crude product was purified by silica gel column chromatography. Compound 52 was dissolved in ethanol, and an equal volume of 2N-hydrochloric acid was added, and the mixture was stirred and stirred at 40 ° C for 5h to give a white turbid liquid, which was filtered to give a white solid. Compound 53 was dissolved in anhydrous dichloromethane, BBr ₃ (10 eq.) was added at -30 ° C, and the reaction was carried out for 3 days at a temperature of even 40 ° C. After the reaction was completed, the solvent and BBr _{3 were} directly removed under reduced pressure. The crude product was dissolved in ethyl acetate, washed with water and dried over anhydrous magnesium sulfate.

13. Synthesis of cyclopropane-substituted pyrazoloquinoline compound (KQ79):

Compound 53 (1 eq.) was dissolved in dry N,N-dimethylformamide, NaH (60% oil dispersion, 3 eq.) was added, stirred at room temperature for 0.5 h, then benzyl bromide (4 eq.) was added and the reaction was heated for 4 h. . After completion of the reaction, ethyl acetate was added, and the reaction mixture was washed three times with water. Ti(OiPr) ₄ (1 eq.) was dissolved in anhydrous tetrahydrofuran, the reaction flask was replaced with argon gas, and EtMgBr (3M in THF, 3 eq.) was added at -78 ° C. After stirring for 2 min, the compound was slowly added dropwise. A solution of 55 (1 eq.) in tetrahydrofuran was added and the reaction was taken to room temperature and stirred for 5 h. After completion of the reaction, a saturated ammonium chloride solution was added, and the mixture was stirred for 10 min. Compound 56 (1 eq.) was dissolved in methanol, Pd/C (0.1 eq.) was added, the reaction flask was replaced with hydrogen, and a hydrogen balloon was inserted into the reaction flask, and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was filtered to remove Pd. /C, compound 57 was obtained. Compound 57 (1 eq.) was dissolved in dry dichloromethane, BBr ₃ (6 eq.) was added at -78 ° C, the reaction was allowed to warm to room temperature and stirred for 24 h. After completion of the reaction, the solvent was evaporated under reduced pressure The ester was dissolved, washed once with sodium bicarbonate solution, once with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography to afford compound KQ79.

14. Synthesis of dimethyl substituted pyrazoloquinoline compounds (KQ80):

Compound 51 (1 eq.) was dissolved in N,N-dimethylformamide, cesium carbonate (1 eq.), p-toluenesulfonyl chloride (2 eq.), and stirred at room temperature for 5 h. After washing three times with water, the organic phase was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography. Compound 59 was dissolved in ethylene glycol dimethyl ether, reduced iron powder (10 eq.), 0.1N hydrochloric acid (6 eq.), and stirred at room temperature for 15 h. After completion of the reaction, the solvent was evaporated under reduced pressure. Compound 60 was dissolved in anhydrous N,N-dimethylformamide, NaH (1.5 eq.) was added, stirred at room temperature for 15 min, then benzyl bromide (2 eq.) was added and reacted at room temperature for 5 h. Dilute, wash three times with water, dry the organic phase with anhydrous sulfuric acid and purify on silica gel column chromatography to afford compound 61. The compound was dissolved in anhydrous dichloromethane, then DTBMP (1 eq.) was added, trifluoromethanesulfonic acid anhydride (1 eq) was added at -78 ° C, the reaction was allowed to warm to room temperature, stirred for 1 h, and the reaction was again cooled to -78 ° C. After adding methyl Grignard reagent (3 eq.), stirring for 10 min, the reaction was warmed to room temperature and stirred for 5 h. After completion of the reaction, ethyl acetate was added, washed once with water, once with brine, and dried over anhydrous magnesium sulfate. Purification afforded compound 62. Compound 62 (1 eq.) was dissolved in methanol, Pd/C (0.1 eq.) was added, and the benzyl protecting group was removed by reduction in a hydrogen atmosphere. After the reaction is completed, Pd/C is directly removed by filtration. 6N Hydrochloric acid (10 eq.) was added to the filtrate, and the mixture was heated to 50 ° C. After stirring for 5 h, the reaction was cooled to room temperature, and the organic solvent was evaporated under reduced pressure. The product was extracted with ethyl acetate. Compound 63 was obtained. Compound 63 (1 eq.) was dissolved in anhydrous dichloromethane, BBr ₃ (10 eq.) was added at -78 ° C, then the reaction was allowed to warm to room temperature, and reacted for 24 h. After completion of the reaction, the solvent was evaporated under reduced pressure. After the ethyl ester is dissolved, it is washed once with water, once with brine, and the organic phase is dried and purified by silica gel column chromatography to give compound KQ80.

15. Synthesis of benzazepine pyrazole pyrazoles (KQ81):

Compound 65 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. After the reaction was stopped, the temperature was lowered, and the obtained organic phase was concentrated by ethyl acetate. Intermediate 69 (1 eq.) was added to a solution of ferric chloride (5%) in acetonitrile and refluxed for 8 h to remove solvent to afford intermediate 70 which was used directly in the next step. Intermediate 70 (1 eq.) was added to a solution of p-toluenesulfonylhydrazide (1.1 eq.) in methanol, and the mixture was stirred at room temperature overnight, then solvent was evaporated, then NaOH (2 eq.) aqueous solution was added and reacted at 95 ° C for 12 h. After cooling to room temperature, the pH was adjusted to 4 to 5 with 2N hydrochloric acid, extracted with diethyl ether, and the organic phase was combined, and then purified by silica gel column chromatography to afford intermediate 71, intermediate 71 was dissolved in dichloromethane, and BBr ₃ was added at -78 ° C (10 eq .), then the reaction was warmed to room temperature, the reaction was carried out for 24 h. After the reaction was completed, the solvent was evaporated under reduced pressure. The crude material was dissolved in ethyl acetate, washed once with water, and once with brine. .

One skilled in the art can efficiently prepare the corresponding compound according to the structure of the compound to be synthesized, according to the synthetic route described above.

Synthesis example

In the present example, the inventors prepared the compounds listed in Table 1 according to the general synthetic methods described above, and the corresponding synthetic methods are summarized in Table 1. The synthetic identification results of the respective compounds are as follows:

KQ1: ¹ H NMR (400 MHz, d _{6 -} DMSO, ppm) δ 8.03 (br s, 1H), 7.86 (m, 1H), 7.53 (m, 1H), 7.19 (m, 1H), 6.95 (m, 1H), 5.35 (s, 1H), 3.28 (q, 2H, J = 7.2 Hz), 1.04 (t, 3H, J = 7.2 Hz).

KQ2: ¹ H NMR (400 MHz, d _{6 -} DMSO, ppm) δ 8.05 (br s, 1H), 7.92 (m, 1H), 7.59 (m, 1H), 7.19 (m, 1H), 7.17 (m, 1H), 3.83 (s, 3H), 3.26 (q, 2H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.2 Hz).

KQ3: ¹ H NMR (400 MHz, d _{6 -} DMSO, ppm) δ 8.02 (br s, 1H), 7.64 (m, 1H), 7.10 (m, 1H), 6.99 (m, 1H), 6.81 (m, 1H), 6.27 (br s, 2H), 3.23 (q, 2H, J = 7.2 Hz), 1.07 (t, 3H, J = 7.2 Hz).

KQ4: ¹ H NMR (300MHz, CDCl ₃ , ppm) δ 12.11 (s, 1H), 8.16 (d, J = 2.44 Hz, 1H), 7.33 (dd, J = 8.79 Hz, 1H), 7.30 (br s , 1H), 6.92 (d, J = 8.79 Hz, 1H), 2.63 (s, 3H), 2.18 (s, 3H).

KQ5: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) δ 11.65 (s, 1H), 10.29 (br s, 1H), 7.81 (d, 1H, J = 2.6 Hz), 7.49 (dd, 1H, J ₁ = 8.8 Hz, J ₂ = 2.6 Hz), 2.61 (s, 3H).

KQ6: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) δ 8.10 (br s, 1H), 7.09 (m, 1H), 7.06 (m, 1H), 6.89 (m, 1H), 6.83 (m, 1H), 5.35 (s, 1H), 4.47 (s, 2H), 3.29 (s, 2H), 2.51 (m, 4H), 1.68 (m, 4H).

KQ7: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) δ 8.78 (br s, 1H), 7.19-7.14 (m, 1H), 6.74-6.71 (m, 1H), 3.31-3.11 (m, 2H) ), 2.76-2.73 (m, 2H).

KQ8: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 7.55 (d, 1H, J = 8.0 Hz), 7.36-7.28 (m, 2H), 7.03 (d, 1H, J = 7.5 Hz), 3.50 ( q, 2H, J = 7.1 Hz), 1.34 (t, 3H, J = 7.1 Hz).

KQ9: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 9.37 (br s, 1H), 7.07-7.02 (m, 1H), 6.98-6.93 (m, 2H), 3.52 (q, 4H, J=7.1 Hz), 1.28 (t, 6H, J = 7.1 Hz).

KQ10: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 9.40 (br s, 1H), 7.00-6.94 (m, 2H), 6.90-6.86 (m, 1H), 3.50 (q, 2H, J = 7.0 Hz), 3.08 (s, 3H), 1.23 (t, 3H, J = 7.0 Hz).

KQ11: ¹ H NMR (400MHz, CD ₃ Cl, ppm) δ 12.64 (br s, 1H), 7.30-7.27 (m, 1H), 6.82-6.80 (m, 1H), 6.62-6.60 (m, 1H) , 3.58-3.55 (m, 2H), 3.13 (s, 3H), 3.00-2.97 (m, 1H).

KQ12: ¹ H NMR (400MHz, CD ₃ Cl, ppm) δ 12.74 (br s, 1H), 7.30 (d, J = 8.92 Hz, 1H), 6.77 (d, J = 8.92 Hz, 1H), 3.57 ( t, J = 6.88 Hz, 2H), 3.12 (s, 3H), 3.05 (t, J = 6.92 Hz, 2H).

KQ13: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 12.76 (br s, 1H), 7.35-7.31 (m, 1H), 6.67-6.64 (m, 1H), 6.57-6.53 (m, 1H) , 6.21 (br s, 1H), 3.48 (m, 2H), 1.26 (t, 1H, J = 7.2 Hz).

KQ14: ¹ H NMR (400MHz, CD ₃ Cl, ppm) δ 10.79 (br s, 1H), 7.96-7.95 (m, 1H), 7.53-7.51 (m, 1H), 6.89-6.87 (m, 1H) , 4.41 (m, 2H), 1.42 (t, 3H, J = 7.1 Hz).

KQ15: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 12.68 (br s, 1H), 7.12 (d, 1H, J = 8.5 Hz), 6.18 (s, 1H), 6.12 (d, 1H, J) = 8.5 Hz), 5.98 (br s, 1H), 3.97 (br s, 2H), 3.45 (m, 2H), 1.24 (t, 3H, J = 7.2 Hz).

KQ16: ¹ H NMR (400MHz, CD ₃ OD, ppm) δ 7.61 (br s, 1H), 7.20 (d, 1H, J = 8.28 Hz), 6.93 (d, 1H, J = 8.28 Hz), 3.42 ( q, 2H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz).

KQ17: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) δ 12.43 (br s, 1H), 8.81 (br s, 1H), 7.73-7.70 (m, 1H), 7.30-7.25 (m, 1H) , 6.93-6.90 (m, 1H), 3.24 (t, 2H, J = 6.4 Hz), 1.60-1.50 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz).

KQ18: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 12.06 (br s, 1H), 7.13-7.08 (m, 1H), 7.06-7.03 (m, 1H), 6.95-6.91 (m, 1H) , 6.30 (br s, 1H), 3.47-3.42 (m, 2H), 1.65-1.57 (m, 2H), 1.46-1.1.36 (m, 2H), 0.96 (t, 3H, J = 7.3 Hz).

KQ19: ¹ H NMR (400MHz, CD ₃ Cl, ppm) δ 12.40 (br s, 1H), 7.39-7.35 (m, 2H), 6.98-6.96 (m, 1H), 6.84-6.80 (m, 1H) , 6.45 (br s, 1H), 3.43 - 3.38 (m, 2H), 1.69-1.60 (m, 2H), 0.98 (t, 3H, J = 7.4 Hz).

KQ20: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 12.41 (br s, 1H), 7.39-7.34 (m, 2H), 6.98-6.96 (m, 1H), 6.84-6.81 (m, 1H) , 6.40 (br s, 1H), 3.47-3.3.42 (m, 2H), 1.64-1.57 (m, 2H), 1.45-1.36 (m, 2H), 0.95 (t, 3H, J = 7.3 Hz).

KQ21: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 12.37 (br s, 1H), 7.38-7.34 (m, 2H), 6.97-6.95 (m, 1H), 6.83-6.80 (m, 1H) , 6.52 (br s, 1H), 3.44 - 3.3.39 (m, 2H), 1.64-1.57 (m, 2H), 1.35-1.34 (m, 4H), 0.90 (t, 3H, J = 7.4 Hz).

KQ22: ¹ H NMR (400MHz, CD ₃ Cl, ppm) δ 8.07 (s, 1H), 7.86 (br s, 1H), 7.57-7.55 (d, 1H, J = 8.4 Hz), 6.96-6.94 (d , 1H, J = 8.5 Hz), 3.48 (m, 2H), 1.28 (t, 3H, J = 7.2 Hz).

KQ23: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 12.70 (br s, 1H), 7.23 - 7.21 (d, 1H, J = 8.7 Hz), 6.40 (s, 1H), 6.35-6.33 (d , 1H, J = 8.8 Hz), 6.06 (br s, 1H), 3.50 - 3.44 (m, 2H), 1.25 (t, 3H, J = 7.8 Hz).

KQ24: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 7.87 (br s, 1H), 7.37 (d, 1H, J = 8.24 Hz), 7.03 (d, 1H, J = 8.24 Hz), 3.37- 3.31 (m, 2H), 1.65-1.60 (m, 2H), 0.95 (t, 3H, J = 7.32 Hz).

KQ25: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 9.06 (br s, 1H), 7.46 (t, 1H, J = 7.6 Hz), 6.93 (dd, 1H, J ₁ = 8.0 Hz, J ₂ =0.4 Hz), 6.74 (t, 1H, J = 7.6 Hz), 3.12-3.09 (m, 2H), 2.72-2.70 (m, 2H).

KQ26: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 7.16 (m, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 5.64 (m, 1H), 5.35 (br s, 1H) ), 3.65 (s, 1H), 2.74 (m, 2H), 2.64 (m, 2H), 2.26 (s, 3H).

KQ27: ¹ H NMR (400 MHz, d _{6 -} DMSO, ppm) δ 9.97 (s, 1H), 8.34 (t, 1H, J = 5.6 Hz), 7.21. (dd, 1H, J ₁ = J ₂ = 9.2 Hz ), 6.80 (dd, 1H, J ₁ = 4.0 Hz, J ₂ = 9.2 Hz), 3.21 (dq, 2H, J ₁ = 5.6 Hz, J ₂ = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz) ).

KQ28: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 12.47 (br s, 1H), 7.19-7.14 (m, 1H), 6.79-6.75 (m, 1H), 6.13 (br s, 1H), 3.52-3.45 (m, 2H), 1.27 (t, 3H, J = 7.2 Hz).

KQ29: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) δ 9.40 (s, 1H), 8.15 (t, 1H, J = 5.2 Hz), 6.94 (dd, 1H, J ₁ = J ₂ = 9.2 Hz ), 6.65 (dd, 1H, J ₁ = 4.4 Hz, J ₂ = 8.8 Hz), 3.24 - 3.17 (m, 2H), 2.05 (d, 3H, J = 2.0 Hz), 1.08 (t, 3H, J = 7.2Hz).

KQ30: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 12.44 (s, 1H), 7.14 (d, 1H, J = 8.1 Hz), 6.63 (d, 1H, J = 11.0 Hz), 6.12 (s, 1H), 3.52-3.45 (m, 2H), 2.20 (s, 3H), 1.27 (t, 3H, J = 7.2 Hz).

KQ31: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 12.46 (s, 1H), 6.98 (d, 1H, J = 11.6 Hz), 6.27 (d, 1H, J = 7.9 Hz), 6.04 (s, 1H), 3.48-3.41 (m, 2H), 1.24 (t, 3H, J = 7.2 Hz).

^{KQ32: 1 H NMR (400MHz,} CDCl 3, ppm) δ8.24 (br s), 8.08 (m, 1H), 7.59 (m, 1H), 7.52-7.41 (m, 5H), 5.35 (br s, 1H ), 3.42 (t, J = 7.2 Hz, 2H), 1.64 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

KQ33: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 7.41 (d, 2H, J = 8.32 Hz), 7.33 - 7.29 (m, 3H), 6.96 (d, 1H, J = 8.32 Hz), 6.98 ( d, 1H, J = 7.48 Hz), 5.28 (br s, 1H), 3.07 (q, 2H, J = 6.84 Hz), 1.17 (m, 3H), 0.65 (t, 3H, J = 7.4 Hz).

^{KQ34: 1 H NMR (400MHz,} CDCl 3, ppm) δ7.90 (s, 1H), 7.82 (s, 1H), 7.57-7.50 (m, 2H), 7.28 (m, 1H), 6.54 (br s, 1H), 3.48 (q, 2H, J = 6.68 Hz), 1.71 (m, 2H), 1.04 (t, 3H, J = 7.4 Hz).

KQ35: ¹ H NMR (400 MHz, d _{6 -} DMSO, ppm) δ 11.5 (s, 1H), 8.62 (s, 1H), 8.17 (s, 1H), 7.77-7.53 (m, 2H), 7.44 (m) , 1H), 5.35 (br s, 1H).

KQ36: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 7.98-7.91 (m, 2H), 7.77 (m, 1H), 7.75-7.58 (m, 2H), 7.48-7.34 (m, 3H), 6.57 (br s,1H), 3.50 (q, 2H, J = 6.64 Hz), 1.75-1.71 (m, 2H), 1.05 (t, 3H, J = 6.64 Hz).

KQ37: ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.48 (d, 0.2H, J = 2.2 Hz), 8.46 (d, 1H, J = 2.2 Hz), 8.29 - 8.21 (m, 1H), 7.67-7.65 (m, 0.2H), 7.38-7.35 (m, 1H), 6.58-6.55 (m, 0.2H), 3.39-3.35 (m, 0.4H), 3.32-3.26 (m, 2H), 1.68- 1.62 (m, 2H), 1.59-1.46 (m, 2H), 0.99 (t, 0.6H, J = 7.4 Hz), 0.87 (t, 3H, J = 7.4 Hz).

KQ38: ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.84 (s, 1H), 8.26 (m, 1H), 8.03 (br s, 1H), 6.66 (m, 1H), 5.35 (br s, 1H), 3.04 (q, 2H, J = 7.4 Hz), 1.04 (t, 3H, J = 7.4 Hz).

^{KQ39: 1 H NMR (400MHz,} CD 3 OD, ppm) δ8.76 (s, 1H), 8.04 (m, 1H), 8.03 (br s, 1H), 8.02 (s, 1H), 5.35 (m, 1H ), 3.04 (q, 2H, J = 7.4 Hz), 1.04 (t, 3H, J = 7.4 Hz).

^{KQ40: 1 H NMR (400MHz,} CDCl 3, ppm) δ10.54 (br s, 1H), 8.55 (s, 1H), 7.54 (d, 1H, J = 6.1Hz), 7.12 (s, 1H), 6.60 (d, 1H, J = 7.3 Hz), 3.40 (dd, 2H, J = 12.9, 6.8 Hz), 1.65 (dq, 2H, J = 14.5, 7.3 Hz), 1.00 (t, 3H, J = 7.4 Hz) .

KQ41: ¹ H NMR (400MHz, CDCl _3, ppm) δ 8.46 (s, 1H), 8.15 (d, 1H, J = 5.2 Hz), 7.18 (d, 1H, J = 5.2 Hz), 6.58 (br s , 1H), 3.52 (dt, 2H, J = 14.2, 7.2 Hz), 1.29 (t, 3H, J = 7.3 Hz).

^{KQ42: 1 H NMR (400MHz,} CD 3 OD, ppm) δ11.77 (br s, 1H), 10.76 (br s, 1H), 8.01 (s, 1H), 5.60 (s, 1H), 4.25 (q, 2H, J = 7.08Hz), 1.28 (t, 3H, J = 7.12Hz).

KQ43: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 12.02 (br s, 1H), 7.13-7.07 (m, 2H), 6.94-6.90 (m, 1H), 6.74 (br s, 1H), 3.65 -3.61 (m, 2H), 3.58-3.55 (m, 1H), 3.40 (s, 3H).

^{KQ44: 1 H NMR (400MHz,} CDCl 3, ppm) δ12.05 (br s, 1H), 7.16-7.14 (m, 1H), 7.10-7.05 (m, 1H), 6.92-6.88 (m.1H), 6.73 (br s, 1H), 3.24 (t, 2H, J = 6.5 Hz), 1.94-1.84 (m, 1H), 3.40 (d, 6H, J = 6.6 Hz).

KQ45: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 12.11 (br s, 1H), 7.17-7.11 (m, 2H), 7.00-6.98 (m, 1H), 6.34 (br s, 1H), 3.36 -3.33 (m, 2H), 1.10 (m, 1H), 0.65-0.63 (m, 2H), 0.35-0.34 (m, 2H).

^{KQ46: 1 H NMR (400MHz,} CDCl 3, ppm) δ12.07 (br s, 1H), 7.14-7.09 (m, 1H), 7.05-7.02 (m, 1H), 6.95-6.92 (m.1H), 6.30(br s,1H), 3.38(t,2H,J=7.1Hz), 2.20-2.12(m,1H),1.85-1.56(m,8H).

KQ47: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 12.08 (br s, 1H), 7.12-7.07 (m, 2H), 6.94-6.90 (m, 1H), 6.48 (br s, 1H), 3.27 (t, 2H, J = 6.4 Hz), 1.80 - 1.55 (m, 6H), 1.28 - 1.14 (m, 2H), 1.01 - 0.96 (m, 2H).

KQ48: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 12.09 (br s, 1H), 7.14-7.09 (m, 1H), 6.96-6.92 (m, 2H), 6.20 (br s, 1H), 3.53 -3.48 (m, 2H), 2.28-2.24 (m, 2H), 1.68-1.62 (m, 4H), 1.61-1.55 (m, 4H).

^{KQ49: 1 H NMR (400MHz,} CDCl 3, ppm) δ12.09 (br s, 1H), 7.14-7.09 (m, 1H), 7.03-7.00 (m, 1H), 6.95-6.92 (m.1H), 6.17(br s,1H), 3.49-3.44(m,2H),1.76-1.65(m,4H),1.60-1.49(m,2H), 1.39-1.30(m,1H), 1.29-1.14(m, 4H), 1.00-0.91 (m, 2H).

^{KQ50: 1 H NMR (400MHz,} CDCl 3, ppm) δ11.65 (br s, 1H), 7.14-7.09 (m, 1H), 7.07-7.05 (m, 1H), 6.95-6.91 (m, 1H), 3.75 (t, 4H, J = 4.1 Hz), 3.55-3.51 (m, 2H), 2.62 (t, 4H, J = 5.8 Hz), 2.52 (t, 4H, J = 4.2 Hz).

KQ51: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 12.01 (br s, 1H), 7.37-7.29 (m, 2H), 7.27-7.22 (m, 3H), 7.14-7.09 (m, 1H), 6.95-6.92 (m, 1H), 6.88-6.85 (m, 1H), 6.20 (br s, 1H), 3.72-3.69 (m, 2H), 2.96-2.92 (m, 2H).

KQ52: ¹ H NMR (400MHz, CDCl ₃ ppm) δ 12.05 (br s, 1H), 8.02 (d, 1H, J = 8.1 Hz), 7.92-7.86 (m, 2H), 7.60-7.45 (m, 4H) ), 7.13-7.08 (m, 1H), 6.96-6.40 (m, 2H), 6.40 (br s, 1H), 5.7 (d, 2H, J = 5.1 Hz).

KQ53: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 8.03 (br s, 1H), 7.44 (m, 1H), 7.33 - 7.23 (m, 6H), 7.11 (m, 1H), 5.35 (br s , 1H), 4.35 (m, 2H).

KQ54: ¹ H NMR (400M, CDCl ₃ , ppm) δ 11.96 (s, 1H), 7.49-7.32 (m, 5H), 7.12 (dd, 1H, J ₁ = J ₂ = 8.0 Hz), 7.03 (d) , 1H, J = 8.6 Hz), 6.94 (dd, 1H, J ₁ = 9.0 Hz, J ₂ = 4.7 Hz), 6.33 (s, 1H), 5.33-5.26 (m, 1H), 1.63 (d, 1H, J=6.8Hz).

KQ55: ¹ H NMR (400M, CDCl ₃ , ppm) δ 12.01 (s, 1H), 7.27 (d, 2H, J = 8.8 Hz), 7.12 (dd, 1H, J ₁ = J ₂ = 8.7 Hz), 7.00 (d, 1H, J = 8.7 Hz), 6.97-6.93 (m, 1H), 6.90 (d, 2H, J = 7.8 Hz), 6.38 (s, 1H), 4.56 (d, 2H, J = 5.3 Hz) ), 3.81 (s, 3H).

KQ56: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 8.46 (m, 1H), 8.03 (br s, 1H), 7.73 (m, 1H), 7.44 (m, 1H), 7.33-7.23 (m, 3H), 7.11 (m, 1H), 5.35 (br s, 1H), 4.35 (m, 2H).

^{KQ57: 1 H NMR (400MHz,} CDCl 3, ppm) δ8.56 (m, 1H), 8.55 (m, 1H), 8.03 (br s, 1H), 7.44 (m, 1H), 7.35-7.32 (m, 2H), 7.11 (m, 1H), 5.35 (br s, 1H), 4.35 (m, 2H).

KQ58: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 11.96 (br s, 1H), 7.22-7.21 (m, 1H), 7.15-7.10 (m, 1H), 7.00-6.89 (m, 4H), 6.33(br s,1H), 3.75-3.70(m,2H), 3.16(t,2H,J=7.0Hz).

KQ59: ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 7.95 (d, 1H, J = 8.0 Hz), 7.48-7.44 (m, 1H), 6.98 (t, 2H, J = 8.28 Hz), 2.46 (s, 3H).

KQ60: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) δ 15.04 (br s, 0.2H), 14.67 (br s, 0.8H), 9.03 (br s, 0.9H), 8.67 (br s, 0.7) H), 7.83 (m, 1H), 7.28 (m, 1.8H), 7.07 (m, 0.2H), 6.77 (m, 2H), 2.72 (m, 3H). [Tautomeric]

KQ61: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) δ 12.47 (s, 1H), 10.04 (s, 1H), 7.79 (d, 1H, J = 7.9 Hz), 7.37 (t, 1H, J) =7.7Hz), 6.93–6.80 (m, 2H), 2.50 (s, 3H).

KQ62: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 7.53 (dd, 1H, J = 7.7, 1.4 Hz), 7.25 - 7.15 (m, 1H), 7.03 (d, 1H, J = 7.7 Hz), 6.91 (dd, 1H, J = 10.9, 4.0 Hz), 6.44 (s, 1H), 2.40 (s, 3H).

¹³ C NMR (101 MHz, CDCl ₃ , ppm) δ 156.02, 152.63, 139.97, 129.24, 126.59, 119.42, 116.91, 117.06, 101.34, 10.96.

KQ63: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 7.78 (s, 1H), 7.44 - 7.30 (m, 1H), 7.09 (d, 1H, J = 8.3 Hz), 6.90 (t, 1H, J =7.5 Hz), 4.46 (q, 2H, J = 7.1 Hz), 1.45 (t, 3H, J = 7.1 Hz).

¹³ C NMR (101 MHz, CDCl ₃ , ppm) δ 161.07, 158.77, 149.31, 131.89, 131.54, 124.62, 119.20, 118.18, 111.96, 100.12, 61.64, 14.51.

KQ64: ¹ H NMR (400 MHz, d _{6 -} DMSO, ppm) δ 13.09 (s, 1H), 11.81 (s, 1H), 8.36 (s, 1H), 7.90 (d, 1H, J = 6.1 Hz), 7.79 (s, 1H), 7.34 - 7.22 (m, 1H), 6.98 (d, 1H, J = 8.2 Hz), 6.93 (t, 1H, J = 7.5 Hz), 2.77 (t, 3H, J = 11.5 Hz) ).

^{KQ65: 1 H NMR (400MHz,} CDCl 3, ppm) δ11.47 (s, 1H), 7.85 (dd, 1H, J = 7.8,1.4Hz), 7.04 (dd, 1H, J = 8.3,0.6Hz), 6.90–6.82 (m, 1H), 2.82 (q, 2H, J = 7.6 Hz), 1.35 (t, 3H, J = 7.6 Hz).

¹³ C NMR (101 MHz, CDCl 3 , ppm) δ 159.74, 158.80, 156.95, 131.62, 125.97, 119.55, 117.48,

112.65, 20.30, 11.84.

KQ66: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 11.49 (s, 1H), 7.85 (d, 1H, J = 7.8 Hz), 7.28 (dd, 1H, J = 13.7, 6.0 Hz), 7.03 ( d,1H,J=8.3Hz), 6.87(t,1H,J=7.5Hz), 2.77(t,2H,J=7.5Hz),1.87–1.73(m,2H),0.98(t,3H,J =7.3Hz).

KQ67: ¹ H NMR (400MHz, CD ₃ OD, ppm) δ 7.79 (d, 1H, J = 7.8 Hz), 7.72 (s, 1H), 7.29 (t, 1H, J = 7.8 Hz), 7.00 (d) , 1H, J = 8.3 Hz), 6.94 (t, 1H, J = 7.6 Hz), 3.37 (t, 2H, J = 7.2 Hz), 1.73 - 1.60 (m, 2H), 1.00 (t, 3H, J = 7.4Hz).

KQ68: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 10.64 (s, 1H), 7.62 (d, 1H, J = 7.7 Hz,), 7.27 (t, 1H, J = 7.4 Hz,), 7.11 ( d, 1H, J = 8.2 Hz, ), 6.97 (t, 1H, J = 7.5 Hz,), 6.46 (s, 1H), 2.64 (t, 2H, J = 7.6 Hz,), 1.79 - 1.63 (m, 2H), 0.99 (t, 3H, J = 7.3 Hz).

¹³ C NMR (101 MHz, CDCl ₃ , ppm) δ 155.78, 152.16, 144.94, 129.07, 126.54, 119.48, 117.00, 116.93, 100.12, 27.48, 22.34, 13.72.

KQ69: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 7.56 (dd, 1H, J = 7.7, 1.5 Hz), 7.25 - 7.17 (m, 1H), 7.02 (dd, 1H, J = 8.2, 0.7 Hz ), 6.94–6.86 (m, 1H), 6.45 (s, 1H), 2.75 (q, 2H, J = 7.6 Hz), 1.34 (t, 3H, J = 7.6 Hz).

KQ70: ¹ H NMR (400MHz, CDCl ₃ , ppm) δ 8.48 (d, 1H, J = 2.7 Hz), 8.11 (dd, 1H, J = 9.1, 2.7 Hz), 7.07 (d, 1H, J = 9.1 Hz), 6.58 (s, 1H), 2.73 (t, 2H, J = 7.5 Hz), 1.86 - 1.66 (m, 2H), 1.03 (t, 3H, J = 7.4 Hz).

¹³ C NMR (101 MHz, CDCl ₃ , ppm) δ 161.96, 150.73, 145.57, 140.52, 125.07, 122.86, 117.67, 117.09, 100.94, 27.60, 22.37, 13.83.

KQ71: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 9.98 (br s, 2H), 7.50 (d, 1H, J = 2.4 Hz), 7.14 (dd, 1H, J = 2.4 Hz, 8.6 Hz) , 6.95 (d, 1H, J = 8.8 Hz), 6.42 (s, 1H), 2.68 (t, 2H, J = 7.6 Hz), 1.77-1.70 (m, 2H), 1.00 (t, 2H, J = 7.2 Hz).

KQ72: ¹ H NMR (400 MHz, CD ₃ Cl, ppm) δ 9.41 (br s, 2H), 7.24-7.21 (m, 1H), 6.97-6.88 (m, 2H), 6.39 (s, 1H), 2.68 (t, 2H, J = 7.6 Hz), 1.77-1.69 (m, 2H), 1.00 (t, 3H, J = 7.6 Hz).

^{KQ73: 1 H NMR (400MHz,} CDCl 3) δ6.89-6.84 (m, 1H), 6.59 (s, 1H), 6.37-6.34 (m, 1H), 2.66 (t, J = 7.2Hz, 2H), 1.72-1.69 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); ¹³ C NMR (400 MHz, CDCl ₃ ) δ 152.0, 148.3, 147.3, 145.6, 145.0, 133.1, 132.9, 114.9, 114.7, 133.1, 132.9, 114.9, 114.7, 106.5, 105.3, 105.2, 103.2, 27.8, 22.4, 13.9.

KQ74: ¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.68 (s, 1H), 11.54 (s, 1H), 7.96-7.93 (m, 1H), 7.51-7.47 (m, 1H), 6.61-6.56 (m, 1H), 3.95 (t, J = 6.0 Hz, 2H), 3.33-3.30 (m, 2H), 1.72 (s, 3H);

¹³ C NMR (400 MHz, d-DMSO) δ 169.9, 167.5, 160.5, 150.0, 140.6, 137.0, 109.1, 105.2, 100.8, 36.7, 23.0.

KQ75: ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 11.67 (s, 1H), 11.37 (s, 1H), 7.48-7.43 (m, 1H), 6.54 - 6.50 (m, 1H), 3.83 (t , J = 7.2 Hz, 2H), 1.62-1.56 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H); ¹³ C NMR (400 MHz, d-DMSO) δ 166.6, 156.2, 149.6, 142.7, 140.4, 128.2, 128.1, 122.8, 122.6, 108.4, 108.3, 101.4, 101.3, 41.9, 20.9, 11.6.

KQ76: ¹ H NMR (400MHz, CDCl ₃ , ppm) 6.76 (t, 1H, J = 12 Hz), 6.20 (s, 1H), 4.58 (s, 2H), 2.59 (s, 2H), 1.66 (d, 2H) , J = 4 Hz), 0.98 (d, 3H, J = 4 Hz).

KQ77: ¹ H NMR (400 MHz, CD ₃ OD, ppm) 9.12 (s, 1H), 7.33 (dd, 1H, J = 8.4, 10.8 Hz), 6.97 (dd, 1H, J = 3.6, 12.4 Hz), 3.09 (t, 2H, J = 7.6 Hz), 1.91 (m, 2H) 1.04 (t, 3H, J = 7.2 Hz).

KQ78: ¹ H NMR (400 MHz, d ₆ -DMSO, ppm) 13.03 (br s, 1H), 10.88 (br s, 1H), 7.17 (dd, 1H, J = 9.2, 11.2 Hz) 6.57 (dd, 1H, J = 3.6, 8.8 Hz), 2.94 (t, 2H, J = 7.2 Hz), 1.76 (m, 2H,) 0.92 (t, 3H, J = 7.2 Hz). ¹³ C NMR (101 MHz, d ₆ -DMSO, Ppm) 159.57, 151.03, 150.32 (d, J = 2 Hz), 144.24, 141.90, 127.32 (d, J = 4 Hz), 115.51 (d, J = 19 Hz), 108.64, 106.26, 102.38, 29.26, 22.30, 14.16.

KQ79: HRMS (EI ⁺ ): found 273.1276 [M] ⁺ , (Calcd for C ₁₅ H ₁₆ FN ₃ O: 273.1277).

KQ80: HRMS (EI ⁺ ): found 275.1431 [M] ⁺ , (Calcd for C ₁₅ H ₁₈ FN ₃ O: 275.1434).

KQ81: HRMS (EI ⁺ ): found 261.1279 [M] ⁺ , (Calcd for C ₁₄ H ₁₆ FN ₃ O: 261.1277).

Activity test example

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 μL). 96-well plates were incubated for 4 h at 37 °C in a CO ₂ incubator. DMSO (150 μL) 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. Cell viability experiments were tested on large cell lung cancer (belonging to non-small cell lung cancer) 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.

The half-inhibitory concentration (IC ₅₀ ) of each compound (small molecule) was determined according to the conventional detection method, and the results are summarized in Table 1. In 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.

Table 1:

Thus, it can be confirmed that the compounds KQ1 to KQ81 of the present invention can effectively treat cancer, particularly the BRG1 gene-deficient non-small cell lung cancer.

Industrial applicability

The compounds of the present invention are effective for the treatment of cancer, especially the BRG1 gene-deficient non-small cell lung cancer.

It is obvious to those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments, and may be embodied in other specific forms without departing from the essential characteristics. The present embodiments are to be considered in all respects as illustrative and not restrict All changes within this are included in this article.

In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" and the like means a specific feature described in connection with the embodiment or example, A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms does not necessarily mean the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.

Although the embodiments of the present invention have been shown and described, it is understood that the foregoing embodiments are illustrative and not restrictive Case Variations, modifications, alterations and variations of the above-described embodiments are possible within the scope of the invention.

Claims (16)

a compound which is a stereoisomer, a geometric isomer, a tautomer, a racemate, an oxynitride, a hydrate of a compound represented by the formula (I) or a compound of the formula (I). , solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

Where Q is C or N, 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; Each of 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 compound according to claim 1, wherein R1 is an optionally substituted iminocarbonyl group, a secondary aminocarbonyl group or a five-membered nitrogen-containing heterocyclic ring. The compound according to claim 1, wherein the halogen is F or Cl. The compound according to claim 1, wherein 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, optionally containing at least one of oxygen, sulfur and nitrogen. a five- to seven-membered ring or a fused bicyclic ring, or R2 and R3 together with the carbon atom to which they are attached constitute an optionally substituted C _1-5 alkyl group, an aryl group, optionally containing at least one of oxygen, sulfur and nitrogen. A seven-membered ring or a fused double ring. The compound according to claim 1, wherein 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 having from 1 to 3 nitrogen atoms. Optionally, at least one carbonyl group is formed on the ring of the five- to seven-membered ring or the fused bicyclic ring. The compound according to claim 1, wherein the compound is a compound represented by the following formula or a stereoisomer, a geometric isomer, a tautomer, a racemate of a compound represented by the following formula: Nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of cancer. The use according to claim 7, wherein the cancer is lung cancer. The use according to claim 8, wherein the lung cancer is non-small cell lung cancer. The use according to claim 9, wherein the non-small cell lung cancer is a BRG1 gene deletion. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 as an active ingredient. The pharmaceutical composition according to claim 11, further comprising a pharmaceutically acceptable adjuvant. A method for treating cancer, which comprises administering the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to any one of claims 11 to 12 to a cancer patient. The method of claim 13 wherein the cancer is lung cancer. The method of claim 14 wherein said lung cancer is non-small cell lung cancer. The method according to claim 15, wherein the non-small cell lung cancer is a BRG1 gene deletion.