CN118027016A - PARG inhibitor and preparation method and application thereof - Google Patents
PARG inhibitor and preparation method and application thereof Download PDFInfo
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- CN118027016A CN118027016A CN202311366845.8A CN202311366845A CN118027016A CN 118027016 A CN118027016 A CN 118027016A CN 202311366845 A CN202311366845 A CN 202311366845A CN 118027016 A CN118027016 A CN 118027016A
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- alkyl
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- parg
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a PARG inhibitor and a preparation method and application thereof, in particular to a compound shown as a formula (1), a preparation method thereof, a composition containing the compound shown as the formula (1) and/or pharmaceutically acceptable salt thereof, a preparation method and application thereof as the PARG inhibitor in preparation of antitumor drugs.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a PARG inhibitor with a structure shown as a formula (1), a preparation method thereof and application of the PARG inhibitor in preparing a pharmaceutical composition for treating, regulating and/or preventing related diseases mediated by PARG.
Background
Polyadenylation [ Poly (ADP-ribosyl) ation, PAR ] is the process by which a Poly (A-DPP) multimer is covalently linked to the glutamic and aspartic acid residues of a receptor protein under the catalysis of a Poly (A-DPP) polymerase in eukaryotic cells, through which post-translational modification of the protein is achieved. There are two classes of enzymes involved in this modification process: one is responsible for modified Poly (ADP-ribose) polymerase, PARP, and the other is responsible for unmodified Poly (ADP-ribose) hydrolase, glycohyfrolase, PARG.
The DNA fragmentation activates PARP, which recognizes and binds to the DNA strand gap, activates PARP, and catalyzes the synthesis of PAR, causing itself and related nucleoprotein to be PARated; PAR and protein transmit DNA fragmentation signals to activate a DNA repair system, and self-modified PARP loses affinity with DNA and falls off from the DNA, so that DNA repair enzyme can approach a damaged part, and DNA chain gaps are excised and repaired; finally, PARG degrades PAR on PARP nucleoprotein, so that PAR is restored to unmodified form, and the whole repair process is completed. The biological functions of PARG are various, such as participating in the processes of cell cycle regulation, spindle concentration in mitosis, development, differentiation, cell death, DNA repair and the like, and the prior researches find that PARG is closely related to clinical diseases such as tumor, inflammation, autoimmune diseases and the like.
PARG gene silencing reduces cell proliferation and enhances cell sensitivity to chemotherapeutic agents, and thus PARG inhibitors have received considerable attention for the development of tumors. Studies have shown that ovarian cancer cell lines and in vitro models derived from patient living tissue are sensitive to PARG inhibitors, which lead to synthetic lethality by inhibiting DNA replication factors due to replication fork quiescence and sustained replication pressure caused by DNA replication loopholes [ CANCER CELL,2019,35:519-533]. Additional studies have found that PARG can act as an oncogene in hepatocellular carcinoma (HCC) by modulating PARG/DDB1/c-Myc signaling and can be used as a biomarker to identify HCC patients who may benefit from anti-PD-1 treatment. The results of this study demonstrate that the combined inhibition of PARG and PD-1 is an effective novel combination strategy for HCC patients [ J.Hepatol,2022,77:140-151]. Still further studies have shown that PARG is a potential target for the treatment of Pancreatic Ductal Adenocarcinoma (PDAC), and knocking down PARG can significantly inhibit PDAC tumor growth in PDAC cell lines and mouse models, and cells with homologous repair defects are more sensitive to PARG inhibitors than cells with homologous repair normal [ Cancer res.,2019,79:4491-4502].
The development of PARG inhibitors is a major unmet clinical need, but the PARG inhibitors reported before are mainly tannic acid, gallic acid and other compounds, and the compounds have the defects of poor specificity, low oral bioavailability and other patent drug properties. Patent WO2021055744 discloses a new class of PARG inhibitors of the structure which have better enzymatic activity in vivo for PARG inhibitors, representative compounds such as Ref-01 (patent example 38, hereinafter used as control compounds).
However, the existing PARG inhibitors have the disadvantages of insufficient activity or poor oral absorption, so that there is an urgent need in the art to develop new PARG inhibitors with high activity and excellent oral absorption.
Disclosure of Invention
The invention aims to provide a novel PARG inhibitor with high activity and excellent oral absorption, and a preparation method and application thereof.
In a first aspect of the present invention, there is provided a compound having the structure shown in formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
In the formula (1):
X 1 is N or CH;
X 2 is O or S;
R 1 is H, CN, C 1-3 alkyl or C 1-3 haloalkyl;
R 2 is H, C 1-3 alkyl or C 1-3 haloalkyl;
R 3 is H or C 1-3 alkyl;
r 4 is Wherein m is 1 or 2, N is 1 or 2, p is 1 or 2, R 5 is H, halogen, hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy or N (C 1-3 alkyl) 2,R6 and R 7 are independently H or C 1-3 alkyl, or R 6 and R 7 form a C 3-6 cycloalkyl group with the C atom to which they are attached, R 8a、R8b and R 8c are independently H or C 1-3 alkyl, R 9 is H, halogen, CN or C 1-3 alkyl, R 10a and R 10b are independently H or C 1-3 alkyl, or R 9 and R 10b form a C 4-6 cycloalkenyl group with a common double bond carbon atom, or R 10a and R 10b form a divalent C 3-6 cycloalkyl group with a common double bond carbon atom, or R 10a and R 10b form a divalent 4-6 membered heterocycloalkyl group with a common double bond carbon atom, and R 11 is H or C 1-3 alkyl.
In another preferred embodiment, wherein R 1 is H, CN, me, et or CH 2 F.
In another preferred embodiment, wherein R 2 is H, me, CH 2 F, or CHF 2.
In another preferred embodiment, wherein R 3 is H, me or Et.
In another preferred embodiment, wherein R 4 is
In another preferred embodiment, wherein the compound has one of the following structures:
In a second aspect of the present invention there is provided a pharmaceutical composition for the treatment, modulation and/or prophylaxis of a related disorder mediated by PARG, the pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and as active ingredient a compound according to the first aspect of the present invention, or a variant, pharmaceutically acceptable salt, hydrate or solvate thereof.
In another preferred embodiment, the PARG mediated related disorder is cancer selected from the group consisting of: breast cancer, liver cancer, pancreatic ductal adenocarcinoma, ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer.
In a third aspect of the present invention there is provided the use of a compound according to the first aspect of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a pharmaceutical composition for the treatment, modulation and/or prophylaxis of a related disorder mediated by PARG.
In a fourth aspect of the invention there is provided a process for the preparation of a compound according to the first aspect of the invention comprising the steps of:
(1) Reacting a compound of formula (a) with a compound of formula (b) to give a compound of formula (1):
or (i) deprotection of a compound of formula (A) to give a compound of formula (B):
(ii) The compound of formula (1) is prepared by using the compound of formula (B) as a raw material.
In a fifth aspect of the present invention, there is provided a method of treating, modulating and/or preventing a related disorder mediated by PARG comprising the steps of: administering to a subject in need thereof a compound according to the first aspect of the invention, or an isomer, each crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof.
In another preferred embodiment, the subject includes a human and a non-human mammal.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The present inventors have conducted extensive and intensive studies and, through extensive screening and testing, have found for the first time a class of compounds of formula (1), which have a remarkable therapeutic effect on related diseases mediated by PARG. The compound has good inhibitory activity on PARG enzyme and good cell proliferation inhibitory activity on ZR-75-1 cell line. And the compound has good pharmacokinetic properties, and the compound is expected to have remarkable tumor inhibiting effect and patentability. The present invention has been completed on the basis of this finding.
Compounds of the invention and their synthesis
The present invention provides inhibitors of PARG, i.e. compounds of formula (1), or individual isomers, crystalline forms, pharmaceutically acceptable salts (inorganic or organic), hydrates or solvates thereof. Preferably, the compound of the invention is as described in the first aspect.
The invention also provides a preparation method of the compound shown as the formula (1). The process for preparing the compound of the general formula (1) of the present invention is specifically described below, but these specific processes do not constitute any limitation on the present invention.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared by the following general reaction scheme 1 or scheme 2:
General reaction scheme 1:
Embodiments of compounds of formula (1) may be prepared according to general reaction scheme 1, wherein Y 1、Y2、Y3 alone is halogen, R 1、R2、R3、R4、X1 and X 2 are as defined hereinabove.
General reaction scheme 2:
Embodiments of compounds of formula (1) may be prepared according to general reaction scheme 2, wherein Y 1、Y2、Y3 alone is halogen, R 1、R2、R3、R4、X1 and X 2 are as defined hereinabove.
Correlation definition
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomerically enriched mixtures of enantiomers, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.
Unless otherwise stated, "(D)" or "(+)" means right-handed, "(L)" or "(-)" means left-handed, "(DL)" or "(±)" means racemic.
Unless otherwise indicated, with solid wedge bondsAnd wedge dotted bond/>Representing the absolute configuration of a stereogenic center, using straight solid keys/>And straight dotted bond/>Representing the relative configuration of the stereogenic centers, using wavy lines/>Representing wedge solid bond/>Or wedge dotted bond/>Or by wavy lines/>Representing straight solid line bond/>And straight dotted line key
Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee) is 80%.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as tritium (3 H), iodine-125 (125 I), or C-14 (14 C). For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When the number of one linking group is 0, for example- (CH 2)0) -means that the linking group is a single bond.
When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.
Unless otherwise specified, C n-n+m or C n-Cn+m include any of the specific cases of n to n+m carbons, e.g., C 1-12 includes C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11 and C 12, as well as any of the ranges of n to n+m, e.g., C 1-12 includes C 1-3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12 and C 9-12, etc.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring and 12-membered ring, and any one of the ranges of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring and 6-10-membered ring, etc.
Unless otherwise specified, "C 1-3 alkyl" is used to denote a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups and the like; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). Non-limiting examples of C 1-3 alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, and the like.
Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic aliphatic hydrocarbon group consisting of 3 to 6 carbon atoms, which includes both monocyclic and bicyclic ring systems. The C 3-6 cycloalkyl group includes C 3-5、C4-5 and C 5-6 cycloalkyl groups and the like; it may be monovalent, divalent or multivalent. Non-limiting examples of C 3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Unless otherwise specified, a "C 1-3 alkoxy" group is attached to those alkyl groups containing 1 to 3 carbon atoms in the remainder of the molecule through one oxygen atom. The C 1-3 alkoxy group includes C 1-2、C2 and C 3 alkoxy groups and the like; non-limiting examples of C 1-3 alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like.
Unless otherwise specified, "C 4-6 cycloalkenyl" means a partially unsaturated cyclic aliphatic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond, which includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. Any ring of this system is non-aromatic. The C 4-6 cycloalkenyl includes C 4-5、C5-6 and C 5 cycloalkenyl and the like; it may be monovalent, divalent or multivalent. Non-limiting examples of C 4-6 cycloalkenyl include cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
Unless otherwise specified, "4-6 membered heterocycloalkyl" by itself or in combination with other terms, refers to a saturated cyclic group consisting of 4-6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur atoms may optionally be oxidized (i.e., C (=o), NO, SO and SO 2), respectively. It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, fused and bridged rings. In addition, in the case of the "4-6 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 4-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Non-limiting examples of 4-6 membered heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuranyl-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.
"Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
"Hydroxy" refers to-OH.
"Cyano" refers to-CN.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
"Active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the invention may contain one or more asymmetric centers (axichirality) and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition that is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).
The term "administration (ADMINISTERED, ADMINISTERING or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a precursor (prodrug), derivative (derivative), or analog (analog) of the active compound, and the like.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.
Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. Furthermore, as used in this specification, the singular noun encompasses the plural version of the noun without conflict with the context; plural nouns as used also encompasses singular versions of the noun.
Route of administration
The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
"Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), and emulsifying agent (such as) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the invention include:
(a) Unexpectedly, the compound of formula (1) of the present invention shows a very good in vitro activity compared to the control compound Ref-1, while also showing better in vivo pharmacokinetic properties, and is more suitable for development as a drug.
(B) The compound of the invention has good patentability.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present application. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present application will become apparent to those skilled in the art upon reading the description of the application, and such equivalents are intended to fall within the scope of the application.
The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray pure diffraction (SXRD), the single crystal grown is collected by using a Bruker D8 culture diffractometer, the light source is CuK alpha phase, and the scanning mode is adopted: After scanning and collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shelxs, 97).
The solvent used in the present invention is commercially available. Compounds are named according to the general naming principles in the art or using ChemDraw@software, and commercially available compounds are referred to by the vendor catalog name.
In all examples 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance apparatus and the chemical shifts were expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
The invention adopts the following abbreviations: CAN stands for acetonitrile; acOH represents acetic acid; DEG C represents DEG C; CHCl 3 represents chloroform; cs 2CO3 represents cesium carbonate; CD 3 OD represents deuterated methanol; EA (EtOAc) represents ethyl acetate; DCM represents dichloromethane; DIEA (DIPEA) represents diisopropylethylamine; dioxane represents 1, 4-Dioxane; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide; h represents hours; LC-MS stands for liquid phase-mass spectrometer; liOH represents lithium hydroxide; meOH represents methanol; MS stands for mass spectrum; NMR represents nuclear magnetic resonance; pd 2(dba)3 represents tris (dibenzylideneacetone) dipalladium; py represents pyridine; POCl 3 represents phosphorus oxychloride; TFA represents trifluoroacetic acid; TLC stands for thin layer chromatography; ruphos-Pd-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II); ruphos represents 2-bicyclohexylphosphine-2 ',6' -diisopropyloxybiphenyl.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Preparation example 1: synthesis of N- (1-cyanocyclopropyl) -1- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -4- (piperazin-1-yl) -1H-indazole-6-sulfonamide (intermediate 1)
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Step 1: synthesis of intermediate 1-1
6-Bromo-4-chloro-1H-indazole (5 g,21.6 mmol) and benzyl mercaptan (8.05 g,64.8 mmol) were dissolved in dioxane (150 mL), nitrogen protection was added Xantphos(1.25g,2.16mmol),DIEA(8.36g,64.8mmol),Pd2(dba)3.CHCl3(990mg,1.08mmol),, the temperature was raised to 100deg.C for reaction, and LC-MS monitoring was performed, after the reaction of the starting materials was completed. The reaction mixture was quenched with water (200 mL), extracted with EA (150 mL. Times.3), the combined organic phases dried, filtered, concentrated and column chromatographed (PE/EA=10/1 to 1/1) to give 1-1 (5.1 g, 86% yield) as a pale yellow solid as product, ESI-MS m/z 274.9[ M+H ] +.
Step 2: synthesis of intermediate 1-2
1-1 (5.1 G,18.56 mmol) and 2-bromo-5- (difluoromethyl) -1,3, 4-thiadiazole (7.98 g,37.12 mmol) were dissolved in DMF (100 mL) and Cs 2CO3 (6.05 g,18.56 mmol) was added thereto, nitrogen blanket, and the temperature was raised to 60℃for reaction. LC-MS monitoring, wherein the reaction of the raw materials is finished. The reaction mixture was quenched with water (200 mL), extracted with EA (100 mL. Times.3), the combined organic phases dried, filtered, concentrated and column chromatographed (PE/EA=10/1 to 1/1) to give product 1-2 (7.1 g, 94% yield) as a yellow solid, ESI-MS m/z 408.9[ M+H ] +.
Step 3: synthesis of intermediates 1-3
1-2 (7.1 G,17.4 mmol) was dissolved in ACN (50 mL), HOAc (1 mL) and water (2 mL) were added, 1, 3-dichloro-5, 5-dimethylhydantoin (5.14 g,26.1 mmol) was slowly added at 0deg.C, the reaction was completed while maintaining 0deg.C, and LC-MS monitoring was performed to complete the reaction of the starting materials. Direct concentration gave brown solid 1-3 (9.8 g, crude), ESI-MS m/z 384.8[ M+H ] +.
Step 4: synthesis of intermediates 1-4
1-3 (9.8 G,17.4mmol, crude) and 1-amino-1-cyclopropylnitrile hydrochloride (2.06 g,17.4 mmol) were dissolved in pyridine (50 mL) at 0deg.C and allowed to react at room temperature, monitored by LC-MS, and the starting material was complete. Direct concentration to remove pyridine, 1M HCl to adjust pH to about 5, EA extraction (100 mL. Times.3), combining the organic phases, drying, filtration, concentration, and column chromatography (PE/EA=5/1 to 1/1) afforded white solid product 1-4 (5.8 g, 78% yield), ESI-MS M/z:430.8[ M+H ] +.
Step 5: synthesis of intermediates 1-5
1-4 (2G, 4.65 mmol) and 1-t-butoxycarbonyl piperazine (953 mg,5.12 mmol) were dissolved in 1, 4-dioxane (30 mL), ruphos-Pd-G3 (393 mg,0.47 mmol), ruphos (433 mg,0.93 mmol) and cesium carbonate (3.05G, 9.3 mmol) were added and reacted at 90℃with LC-MS monitoring the completion of the reaction. The reaction mixture was quenched with water (100 mL), extracted with EA (50 mL. Times.3), the combined organic phases were dried, filtered, concentrated, and column chromatographed (PE/EA=5/1 to 1/1) to give product 1-5 (1.9 g, 70% yield) as a white solid, ESI-MS m/z 581.0[ M+H ] +.
Step 6: synthesis of intermediate 1
1-5 (1.9 G,3.28 mmol) was dissolved in DCM (30 mL), TFA (5 mL) was added and the reaction was allowed to proceed at room temperature, monitored by LC-MS, and the starting material reacted. The reaction mixture was concentrated directly to give intermediate 1 (1.7 g, crude) as a pale yellow solid, ESI-MS m/z 481.0[ M+H ] +.
Intermediates 2-10 can be synthesized in a similar manner to intermediate 1.
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Example 1: synthesis of 4- (4- (bicyclo [1.1.1] pentane-1-carbonyl) piperazin-1-yl) -N- (1-cyanocyclopropyl) -1- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1H-indazole-6-sulfonamide (Compound 1)
Intermediate 1 (50 mg,0.104 mmol) and bicyclo [1.1.1] pentane-1-carboxylic acid ((13 mg,0.115 mmol) were dissolved in DMF (3 mL) and DIEA (27 mg,0.208 mmol) and HATU (59 mg,0.156 mmol) were added followed by room temperature reaction, LC-MS monitoring the reaction, pouring into water (20 mL), EA extraction (10 mL. Times.3), combining the organic phases, drying, concentrating, column chromatography (DCM/MeOH=50/1 to 20/1) to give compound 1 as a yellow solid (38 mg, 65% yield).
1H NMR(400MHz,CD3OD)δ:8.73(d,J=14.4Hz,2H),7.44-7.11(m,2H),4.07-3.98(m,2H),3.93-3.83(m,2H),3.58-3.47(m,4H),2.54(s,1H),2.30-2.24(m,6H),1.56-1.48(m,2H),1.48-1.40(m,2H);ESI-MS m/z:575.1[M+H]+.
Examples 2 to 30: synthesis of Compounds 2-10, 12-31
Starting from intermediate 1 and the corresponding carboxylic acid, the target compounds 2-10, 12-31 were obtained according to a similar synthetic method as in example 1.
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Example 31: synthesis of N- (1-cyanocyclopropyl) -1- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -4- (4- (2, 4-trimethylpent-3-enyl) piperazin-1-yl) -1H-indazole-6-sulfonamide (Compound 11)
Step 1: synthesis of intermediate 11-1
Ethyl 2-bromo-2-methylpropionate (1 g,5.13 mmol) and isobutyraldehyde (369 mg,5.13 mmol) were dissolved in THF (30 mL), zinc powder was added thereto, nitrogen protection was applied, the reaction was performed at 70℃and monitored by LC-MS, and the reaction of the starting materials was completed. Suction filtration, EA extraction of the filtrate (30 mL. Times.3), combining the organic phases, drying and concentration gave 11-1 (1.4 g, crude) as a pale yellow liquid, ESI-MS m/z 188.9[ M+H ] +.
Step2: synthesis of intermediate 11-2
11-1 (1.4 G,5.13mmol, crude product) was dissolved in pyridine (5 mL), POCl 3 (2.5 mL) was slowly added, nitrogen was purged, the temperature was raised to 100deg.C, LC-MS monitoring, and the reaction of the starting materials was completed. The reaction solution was slowly poured into ice water, extracted with EA (30 ml. Times.3), washed once with 1M HCl, washed once with saturated aqueous sodium bicarbonate, the organic phases were combined, dried, and concentrated, and column chromatography (PE/ea=100/1 to 10/1) gave 11-2 (420 mg, yield 48%) as colorless liquid, ESI-MS M/z:170.8[ m+h ] +.
Step 3: synthesis of intermediate 11-3
11-2 (420 Mg,2.47 mmol) was dissolved in MeOH/H 2 O (10/1 mL) and LiOH (118 mg,4.94 mmol) was added and reacted at room temperature. LC-MS monitoring, wherein the reaction of the raw materials is finished. The pH was adjusted to about 5 with 1M HCl, the organic phases were combined, dried and concentrated to give 11-3 (280 mg, crude) as a pale yellow solid.
Step 4: synthesis of Compound 11
Starting from intermediates 1 and 11-3, the desired compound 11 was obtained according to a similar synthetic method as in example 1.
1H NMR:(400MHz,CD3OD)δ:8.81-8.66(m,2H),7.45-7.10(m,2H),6.15(s,1H),3.98-3.88(m,4H),3.52-3.43(m,4H),2.28(s,6H),1.56-1.49(m,2H),1.47-1.40(m,2H),1.35(s,6H);ESI-MS m/z:605.1[M+H]+.
Examples 32 to 43: synthesis of Compounds 32-43
Starting from intermediate 2-intermediate 10 and the corresponding carboxylic acid, the target compounds 32-43 were obtained according to a similar synthetic method as in example 1.
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EXAMPLE 44 PARG enzyme Activity Screen
This study evaluates the ability of the compounds of the present invention to inhibit PARG protease activity in vitro. The experiment used HTRF analysis to characterize PARG inhibitors at 80nM PARylation (Ice-Biosci). In this experiment, the final concentration of enzyme was 150pM and the final concentration of substrate was 80nM.
The compound was dissolved in DMSO to give a stock solution at a concentration of 10 mM. Dose-gradient reactions were prepared to have an initial compound concentration of 10 μm, followed by four-fold dilutions in DMSO (three-fold dilutions of control compound) for a total of ten data points. Transfer 0.1 μl of the diluted compound solution to 384 assay plates (Cornning) using ECHO sonic pipetting (LABCYTE), add 2.5 μ LPARylation working solution to 384 well assay plates, centrifuge 1000prm 1min, incubate for 60 min at 25 ℃, then add 5 μl of His-Tb (Cisbio) and SA-XL665 (Cisbio) mixture for reaction, incubate for 50 min at 25 ℃. The detection is then carried out under an HTS high throughput drug screening multifunctional enzyme labeling machine (BMG) and HTRF signals are read.
The inhibition ratio of the compound to PARG protein activity inhibition was calculated using the following formula, percent inhibition (%) =100 (average of negative control group-average of compound)/(average of negative control group-average of positive control group). And the IC 50 curve of the compound was fitted by software Graphpad 8.0 according to the nonlinear regression equation. Table 1 provides the inhibitory activity of the compounds of the invention against PARG proteins.
EXAMPLE 45 screening of Compounds for anti-proliferative Activity on ZR-75-1 cells
The present study uses cell proliferation assays to analyze cytotoxicity of ZR-75-1 breast cancer cells four days after PARG inhibitor action. ZR-75-1 cell line was purchased from the Withansai Life technologies Co., ltd, and cultured in a cell incubator (Thermo) at 37℃with 5% carbon dioxide using 1640 medium (Viva cell). In this experiment, PARG inhibitors were dissolved in DMSO to an initial concentration of 30 μm and three-fold dilutions were made in DMSO for a total of eight data points. The final concentration of DMSO was 0.5%.
ZR-75-1 cells were seeded in white 96-well plates, 80. Mu.L of cell suspension per well, containing 5000 ZR-75-1 cells. The cell plates were placed in a carbon dioxide incubator overnight, then 20 μl of PARG inhibitor solution of different concentrations was added to the well plates, and 96 well plates were placed in the incubator for four days of incubation. A cell plate was also prepared and the signal value read on the day of dosing as the maximum value (Max value in the following equation) was used in the data analysis. To this plate, 25. Mu.L of cell viability chemiluminescent detection reagent was added per well and incubated at room temperature for 10 minutes to stabilize the luminescent signal. Multiple marker analyzer readings were used.
The raw data is converted to inhibition rate using equation (Sample-Min)/(Max-Min) ×100%, and the value of IC 50 can be obtained by curve fitting four parameters (obtained in "log (inhibitor) vs. response-Variable slope" mode in GRAPHPAD PRISM). Min:0.5% dmso-treated cell wells; max: day0 well. Table 1 provides the inhibitory activity of the compounds of the invention on ZR-75-1 cell proliferation.
TABLE 1 PARG enzyme inhibitory Activity of Compounds (IC 50) and antiproliferative Activity against ZR-75-1 cells (IC 50)
From the above table data, the compounds of the present invention have strong PARG enzyme activity inhibition and also have strong antiproliferative activity on ZR-75-1 cells. In particular, compounds 9, 10, 14, 16, 17, 36 and 37, etc., have stronger PARG enzyme activity inhibition and antiproliferative activity on ZR-75-1 cells than the control drug Ref-01.
Example 46: in vivo pharmacokinetic assessment in mice
The compound is orally administrated by gastric lavage, the administration dosage is 10mg/kg, the final concentration of the test product is 0.4mg/mL, and the prepared solvent is 5% DMSO+45% PEG400+50% aqueous solution or suspension. 9 ICR mice, male, were selected for each group, and 3 discrete time points were collected for each mouse, with 3 mice at each time point. Sampling time points are 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h post-administration, and mice were bled at about 80 μl from the orbit or heart at each time point post-administration. All whole blood samples were collected in tubes containing EDTA K 2, centrifuged at 4℃for 10min (4000 rmp/min) and plasma was isolated at a storage temperature below-40℃for sample analysis. The concentration of the compound in the plasma was determined by liquid chromatography-tandem mass spectrometry, and the corresponding pharmacokinetic parameters were determined from the plasma concentration-time curve.
TABLE 2 pharmacokinetic parameters of Compound 17 and Ref-01 mice
As can be seen from the above table, the compound 17 has good oral absorption characteristics, and the metabolic parameters such as the maximum blood concentration (C max) and the area under the drug time curve (AUC 0-t) are superior to those of the control drug Ref-01. The oral absorption property is significant in improving the drug effect, reducing the dosage, saving the cost and the like.
Further experiments prove that other compounds of the invention also have good oral absorption characteristics, and the metabolic parameters such as the maximum blood concentration (C max) and the area under the curve (AUC 0-t) are better than the control drug Ref-01.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. A compound having the structure shown in formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
In the formula (1):
X 1 is N or CH;
X 2 is O or S;
R 1 is H, CN, C 1-3 alkyl or C 1-3 haloalkyl;
R 2 is H, C 1-3 alkyl or C 1-3 haloalkyl;
R 3 is H or C 1-3 alkyl;
r 4 is Wherein m is 1 or 2, N is 1 or 2, p is 1 or 2, R 5 is H, halogen, hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy or N (C 1-3 alkyl) 2,R6 and R 7 are independently H or C 1-3 alkyl, or R 6 and R 7 form a C 3-6 cycloalkyl group with the C atom to which they are attached, R 8a、R8b and R 8c are independently H or C 1-3 alkyl, R 9 is H, halogen, CN or C 1-3 alkyl, R 10a and R 10b are independently H or C 1-3 alkyl, or R 9 and R 10b form a C 4-6 cycloalkenyl group with a common double bond carbon atom, or R 10a and R 10b form a divalent C 3-6 cycloalkyl group with a common double bond carbon atom, or R 10a and R 10b form a divalent 4-6 membered heterocycloalkyl group with a common double bond carbon atom, and R 11 is H or C 1-3 alkyl.
2. The compound of claim 1, wherein R 1 is H, CN, me, et or CH 2 F.
3. The compound of any one of claims 1-2, wherein R 2 is H, me, CH 2 F, or CHF 2.
4. A compound according to any one of claims 1 to 3 wherein R 3 is H, me or Et.
5. The compound of any one of claims 1-4, wherein R 4 is
6. The compound of any one of claims 1-5, wherein the compound has one of the following structures:
7. A pharmaceutical composition for the treatment, modulation and/or prevention of related diseases mediated by PARG, characterized in that the pharmaceutical composition comprises a pharmaceutically acceptable excipient or carrier and as active ingredient a compound according to any one of claims 1-6, or an individual isomer, pharmaceutically acceptable salt, hydrate or solvate thereof.
8. Use of a compound according to any one of claims 1 to 6, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a pharmaceutical composition for the treatment, modulation and/or prevention of a related disorder mediated by PARG.
9. A process for preparing a compound according to any one of claims 1 to 6, comprising the steps of:
(1) Reacting a compound of formula (a) with a compound of formula (b) to give a compound of formula (1):
or (i) deprotection of a compound of formula (A) to give a compound of formula (B):
(ii) The compound of formula (1) is prepared by using the compound of formula (B) as a raw material.
10. A method of treating, modulating and/or preventing a related disorder mediated by PARG comprising the steps of: administering to a subject in need thereof a compound of any one of claims 1-6, or an isomer, each crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof.
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