WO2023138541A1 - Picolinamide parp inhibitor, and preparation method therefor and medical use thereof - Google Patents

Abstract

Disclosed are a picolinamide PARP inhibitor, and a preparation method therefor and the medical use thereof. Specifically, the present invention relates to a new compound as represented by general formula (1) and/or a pharmaceutically acceptable salt thereof, and a composition containing the compound as represented by general formula (1) and/or a pharmaceutically acceptable salt thereof, and a preparation method therefor and the use thereof as a PARP inhibitor in the preparation of an anti-tumor drug.

Description

Pyridinamide PARP inhibitors, preparation method and medical application thereof

This application claims the priority of the Chinese patent application 202210067335.X with the filing date on January 20, 2022, the Chinese patent application 202210206331.5 on March 1, 2022, the Chinese patent application 202210642141.8 on June 7, 2022, and the Chinese patent application 202211494319.5 on November 25, 2022 right. This application cites the full text of the above-mentioned Chinese patent application.

technical field

The invention belongs to the field of medicinal chemistry, and more specifically relates to a class of pyridine amide PARP inhibitors, a preparation method and a medical application thereof.

Background technique

Poly(ADP-ribose) polymerase (PARP) is expressed in most eukaryotic cells. It uses nicotinamide adenine dinucleotide (NAD+) as a substrate to catalyze the formation of ADP-ribose units or polymers (PAR) on specific amino acid residues of itself or other proteins, and PAR modification of proteins, thereby regulating protein degradation and function. The PARP family consists of 7 isozymes, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), tankyrases such as PARP-5 (TANK-1, TANK-2, and TANK-3), PARP-7, and PARP-10 [de la Lastra CA. et al., Curr Pharm Des., 13(9), 933-962, 2007] . Although there are many kinds of enzymes in the PARP family, PARP-1 is responsible for more than 90% of ADP-ribosylation (PAR) in cells. PARPs play an important role in regulation of chromosome structure, gene transcription, DNA replication and recombination, and DNA repair. Among them, PARP-1 promotes ADP-ribosylation and polymerization in DNA repair, initiates DNA repair and regulates the recruitment and level of DNA repair proteins.

When the DNA of tumor cells is damaged by chemotherapeutic drugs or ionizing radiation, PARP-1 is quickly activated, and uses NAD+ as a substrate to synthesize a large amount of PAR at the site of DNA damage and modify histones. DNA repair proteins are then recruited to initiate DNA repair. PARP-1 is primarily involved in the repair of single-strand DNA breaks (SSBs). When PARP-1 is inhibited by PARP inhibitors, SSBs cannot be repaired. During S-phase DNA replication, SSBs are converted into double strand breaks (DSBs, Double strand breaks). Inhibiting the function of PARP-1 leads to the accumulation of intracellular DSBs. The body repairs DSBs mainly through two methods: homologous recombination (HR) and non-homologous DNA end joining (NHEJ, Non-Homologous End Joining), among which homologous recombination repair is the main method of DSB repair in S phase, and the repair reliability is high. BRCA1 and BRCA2 play an important role in homologous recombination repair. Loss of BRCA1 and BRAC2 results in restricted DSB repair. Studies have found that BRCA1/2 mutations are found in ovarian cancer, breast cancer, and prostate cancer, and cancer cells with BRCA1 and 2 deletions are particularly sensitive to PARP inhibitors. This may be due to the inhibition of PARP-1 by PAPR inhibitors and the induction of DSBs, while the repair is blocked due to the loss of BRCA1/2, thereby inducing cell death. For this reason, PARP inhibitors It has good clinical effect in the treatment of BRCA1/2-deficient tumors. In addition to being used as a single drug, PARP inhibitors can also be used in combination with chemotherapy drugs and radiotherapy drugs, so as to achieve the purpose of reducing the dose and improving the efficacy. Olaparib is the first PARP inhibitor approved for marketing. As the indications of PARP inhibitors continue to expand, the application of PARP inhibitors is also deepening, not only around tumors, but also has certain effects on stroke, myocardial ischemia, inflammation and diabetes.

Although efforts to develop PARP inhibitors for the treatment of cancer and other diseases have been ongoing, such inhibitors lack certain specificity for PAPR family proteins, have non-negligible toxic and side effects, and are prone to drug resistance. Therefore, the development of specific and highly active PARP-1 inhibitors has important clinical value.

Contents of the invention

The technical problem to be solved by the present invention is that current PARP inhibitors lack certain specificity to PAPR family proteins, have non-negligible toxic and side effects, and are prone to drug resistance. Therefore, the present invention provides pyridine amide PARP inhibitors, a preparation method and a medical application thereof.

The present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (1):

X ¹ and X ² are each independently CH or N;

R ¹ is H, (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy, wherein said (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy can be substituted by one or more of the following groups: -H, halogen;

R ² is halogen or (C1-C4) alkyl;

R ³ is -H, halogen or (C1-C4) alkyl, wherein said (C1-C4) alkyl can be substituted by one or more of the following groups: -H, halogen;

When X ^is N, R is -H, (C1-C4) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C4) alkyl or (C3-C6) cycloalkyl may be substituted by one ^or more of the following groups: -H, -D, halogen; or

When X ² is CH, R ⁴ is -CD ₃ or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl can be substituted by one or more of the following groups: -H, halogen.

In another preferred example, wherein in the general formula (1), R is ^H , (C1-C3) alkyl, (C3-C4) cycloalkyl or (C1-C3) alkoxy, wherein the (C1-C3) alkyl, (C3-C4) cycloalkyl or (C1-C3) alkoxy can be substituted by one or more of the following groups: H or F.

In another preferred example, in the general formula (1), R ¹ is H, -CH ₃ , -CH ₂ CH ₃ , -OMe, -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OEt, preferably -CH ₃ , -CH ₂ CH ₃ , or -OMe.

In another preferred example, in the general formula (1), R ² is F, Cl or (C1-C3) alkyl.

In another preferred example, in the general formula (1), R ² is F, Cl, -Me or -Et, preferably F, Cl, -Me.

In another preferred example, in the general formula (1), R ³ is H, halogen or (C1-C3) alkyl, wherein the (C1-C3) alkyl can be substituted by one or more of the following groups: H or F.

In another preferred example, in the general formula (1), R ³ is H, F, Cl, -Me, -CH ₂ CH ₃ , Preferably H, F, Cl, -Me or

In another preferred example, in the general formula (1), when X ² is N, R ⁴ is -H, (C1-C3) alkyl or (C3-C4) cycloalkyl, wherein the (C1-C3) alkyl or (C3-C4) cycloalkyl can be substituted by one or more of the following groups: -H, -D or -F.

In another preferred example, in the general formula (1), when X ² is N, R ⁴ is H, -CH ₃ , -CD ₃ , -CH ₂ CH ₃ , Preferably -CH ₃ , -CD ₃ , More preferably -CH ₃ , -CD ₃ , More preferably -CH ₃ , more preferably -CD ₃ , more preferably more preferably

In another preferred example, when X ² is CH in the general formula (1), R ⁴ is -CD ₃ , (C3-C4)cycloalkyl, wherein the (C3-C4)cycloalkyl can be substituted by one or more of the following groups: H or F.

In another preferred example, in the general formula (1), when X ² is CH, R ⁴ is -CD ₃ , Preferably -CD ₃ ,

The present invention provides a compound represented by general formula (2) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (2):

X ¹ and X ² are each independently CH or N;

R ¹ is H, (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy, wherein said (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy can be substituted by one or more of the following groups: -H, halogen;

R ³ is -H, halogen or (C1-C4)alkyl, wherein the (C1-C4)alkyl may be substituted by one or more of the following groups: -H, halogen.

In another specific embodiment of the present invention, the compound of the present invention has one of the following structures:

Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the present invention or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

Another object of the present invention is to provide the compound of the present invention or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions for the purposes of preparing medicines for treating, regulating or preventing diseases related to PARP. Wherein, said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.

Another object of the present invention is also to provide a method for treating, regulating or preventing related diseases mediated by PARP, comprising administering to a subject a therapeutically effective amount of the indicated compound of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

compound synthesis

The preparation method of the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.

The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY ^4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY ^4th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PRO Methods in TECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.

In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below. Compound of the present invention The compound can also optionally be prepared by combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared using the following general reaction scheme 1:

General reaction scheme 1

Compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ and X ² are as defined above. As shown in general reaction scheme 1, compound 1-1 reacts with thionyl chloride to generate compound 1-2, and compound 1-2 undergoes substitution reaction with 1-3 to generate target compound (1).

Further forms of compounds

"Pharmaceutically acceptable" here refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., does not cause unwanted biological effects or interact in a deleterious manner with any of the components it contains when administered to an individual.

The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and that does not abolish the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of formula with an acid or base including, but not limited to, the acids and bases found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1 ^st Ed., (Wiley, 2002).

References to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In summary, for purposes of the compounds and methods provided herein, the solvated forms Considered equivalent to the unsolvated form.

In other embodiments, compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.

In another aspect, the compounds of general formula (1) may exhibit chiral centers and/or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently give rise to 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 compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs usually have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and prolonging the half-life of drugs in vivo. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

the term

Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.

Unless otherwise specified, "alkyl" means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl ^groups are selected from _CH3 , _CH3CH2 , _CF3 , _CHF2 , _{CF3CH2 , CF3} ( _CH3 )CH, _iPr , ^nPr , ^iBu , ^nBu or ^tBu .

Unless otherwise specified, "cycloalkyl" means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic) that may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic. in some embodiments In, cycloalkyl is monocyclic or bicyclic. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form oxo or thioxo. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

Unless otherwise specified, "alkoxy" means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from OCH ₃ , OCF ₃ , CHF ₂ O, CF ₃ CH ₂ O, ^i- PrO, ^n- PrO, ^i- BuO, ^n- BuO or ^t- BuO.

Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substitution") appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I, preferably F or Cl, in any combination.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Unless otherwise specified, it is to be understood that the word "comprising", or variations thereof such as "comprises" or "containing", refers to the inclusion of a stated element or integer, or group of elements or integers, but not to the exclusion of any other element or integer, or group of elements or integers.

The substituent "-O-CH ₂ -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a single bond.

When one of the variables is selected from a chemical bond, it means that the two groups connected are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.

The term "membered ring" includes any ring structure. The term "member" is meant to indicate the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.

The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.

Unless otherwise noted, keys with wedge-shaped solid lines and dotted wedge keys represents the absolute configuration of a stereocenter, with straight solid line key and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key

Unless otherwise specified, use Indicates a single or double bond.

Certain pharmaceutical and medical terms

The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.

The terms "treatment", "course of treatment" or "therapy" as used herein include alleviating, inhibiting or ameliorating a symptom or condition of a disease; inhibiting the development of complications; ameliorating or preventing an underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.

"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axichiral) and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to 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 "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to an individual (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

The term "administered, administering, or administration" herein refers to direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. 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 mean, as considered by those skilled in the art. Except for the experimental examples, or unless otherwise expressly stated, when understandable All ranges, amounts, values and percentages used herein (eg, to describe amounts of materials, periods of time, temperatures, operating conditions, ratios of quantities and the like) are modified by the word "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood as the number of significant digits indicated plus the usual rounding method.

Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.

therapeutic use

The present invention provides methods for treating diseases using compounds of the general formula or pharmaceutical compositions of the present invention, including but not limited to conditions involving PARP (such as cancer, ischemic disease, ischemia-reperfusion injury, inflammation, nerve injury, vascular disease and diabetes, etc.).

In some embodiments, a method for treating cancer is provided, the method comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of the general formula to an individual in need. In some embodiments, the cancer is mediated by PARP. In other embodiments, the cancer is a blood cancer and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

Route of administration

The compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the range of safe and effective amounts and pharmaceutically acceptable excipients or carriers. Wherein "safe and effective amount" refers to: the amount of the compound is sufficient to obviously improve the condition without producing serious side effects. The safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.

"Pharmaceutically acceptable excipients or carriers" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

When the compounds of the present invention are administered, they can 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; Potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances and the like.

Besides such inert diluents, the compositions can also contain 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, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and 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 non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention 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 present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, and for a person with a body weight of 60kg, the daily dosage is usually 1 to 2000mg, preferably 50-1000mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

Detailed ways

In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail, so that the content of the present invention becomes very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined in the present application.

In all the examples, ¹ H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.

The synthesis of embodiment 1 compound 1

Step 1: Synthesis of compound int_1-2:

Under nitrogen protection, methyl 5-bromo-6-methylpyridine-2-carboxylate (6.5g, 28mmol), tert-butyl piperazine-1-carboxylate (8.4g, 45mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (879mg, 1.05mmol ) and cesium carbonate (19.6 g, 60 mmol) were mixed in 1,4-dioxane (60 mL). The reaction solution was heated to 110°C and stirred for 6 hours. After cooling, it was diluted with water (100 mL), extracted with ethyl acetate (200 mL×3), and the organic phases were combined. The organic phase was washed with water (100 mL) and saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel chromatography to obtain intermediate int_1-2.

LC-MS (ESI): 336 [M+H] ⁺ .

Step 2: Synthesis of compound int_1-3:

The intermediate int_1-2 (6.00g, 17.91mmol) was dissolved in methanol (120mL) at room temperature, cyclopropylamine (2.04g, 35.8mmol) was added, and stirred overnight at room temperature. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by recrystallization (dichloromethane/petroleum ether) to obtain a pale yellow intermediate int_1-3.

LC-MS (ESI): 361 [M+H] ⁺ .

Step 3: Synthesis of compound int_1-4:

Intermediate int_1-3 (6.30 g, 17.50 mmol) was dissolved in dichloromethane (15 mL) at room temperature. at 0°C Next, trifluoroacetic acid (15 mL) was added dropwise, and stirred for 0.5 hours. Quenched with saturated aqueous sodium bicarbonate (30 mL), extracted with dichloromethane (50 mL×3), combined organic phases, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was purified by recrystallization (dichloromethane/petroleum ether) to obtain the yellow intermediate int_1-4.

LC-MS (ESI): 261 [M+H] ⁺ .

Step 4: Synthesis of compound 1:

Intermediate int_1-5 (35 mg, 0.157 mmol) was dissolved in dichloromethane (3 mL) at room temperature, N,N-dimethylformamide (1 drop) and thionyl chloride (0.1 mL) were added, and stirred at room temperature for 2 hours. Concentrated to dryness under reduced pressure, the residue was dissolved in acetonitrile (3 mL), N,N-diisopropylethylamine (59 mg, 0.456 mmol) and intermediate int_1-4 (41 mg, 0.157 mmol) were added, and the reaction solution was heated to 70°C and stirred for 15 hours. After cooling, it was concentrated under reduced pressure, and the residue was separated and purified by C18 reverse phase chromatography to obtain compound 1.

LC-MS (ESI): 465 [M+H] ⁺ .

The synthesis of embodiment 2-52 compound 2-52

The target compound 2-52 in Table 1 can be obtained by using the synthesis method of the above-mentioned Example 1, or using other similar routes and using different raw materials.

Table 1

Example 53 The compound of the present invention inhibits the activity of poly (ADP-ribose) polymerase [PARP-1 enzyme] in vitro

Histones were coated on a 384-well plate overnight for 4 nights, washed three times with PBST buffer, and blocked for 1 hour at room temperature. After 1 hour, rinse again three times with PBST, add DMSO or serially diluted compounds, and a mixture containing PARP-1 enzyme and DNA, and incubate at 25°C for 10 minutes. After 10 minutes, NAD ⁺ was added to start the reaction. After reacting at room temperature for 60 minutes, rinse with PBST three times, add poly/mono-ADP ribose antibody conjugated with horseradish peroxidase (HRP), and detect the level of poly/mono-ADP ribose on histone. After incubation at room temperature for 1 hour, HRP substrates ECL A and B were added, and Envision quantified chemiluminescence. Compared with the control group DMSO, the calculated pH of the compound percentage and IC ₅₀ . The results are shown in Table 2 below.

Table 2. Inhibitory activity of compounds of the present invention on PARP-1 (IC ₅₀ , nM)

+++ means IC ₅₀ less than or equal to 10nM

++ indicates an _IC50 of 10nM to 50nM

+ means _IC50 greater than 50nM

Example 54 The compound of the present invention inhibits the proliferation of MDA-MB-436 cells in vitro

1200 MDA-MB-436 cells per well were planted in 96-well low-adsorption plates. After overnight attachment, gradiently diluted compounds were added. After incubation for 10 days, the ATP level of cells was detected by CTG to evaluate cell growth. Comparing with the DMSO group, the percentage of growth inhibition and _IC50 of the compound were calculated. The specific results are shown in Table 3 below.

Table 3. The inhibitory activity (IC ₅₀ , nM) of the compounds of the present invention on MDA-MB-436 cells

Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these implementations without departing from the principle and essence of the present invention. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (17)

1. A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
   
   In general formula (1):

   X ¹ and X ² are each independently CH or N;

   R ¹ is H, (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy, wherein said (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy can be substituted by one or more of the following groups: -H, halogen;

   R ² is halogen or (C1-C4) alkyl;

   R ³ is -H, halogen or (C1-C4) alkyl, wherein said (C1-C4) alkyl can be substituted by one or more of the following groups: -H, halogen;

   When X ^is N, R is -H, (C1-C4) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C4) alkyl or (C3-C6) cycloalkyl may be substituted by one ^or more of the following groups: -H, -D, halogen; or

   When X ² is CH, R ⁴ is -CD ₃ or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl can be substituted by one or more of the following groups: -H, halogen.
2. The compounds such as claim 1 or their own different structures, various crystal, and pharmaceuticals are acceptable to salt, aquarmers, or solvent compounds. Among them, ^R1 is -H, (C1-C3) alkyl, (C3-C4) cyclotic alkyl or (C1-C3) alkyl, (C3-C4) cyclotrophtan alkyl or (C1-C3) alky oxygen, where (C1-C3) Alky oxygen can be replaced by one or more groups: -H or -F.
3. The compound according to claim 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ¹ is -H, -CH ₃ , -CH ₂ CH ₃ , -OMe, -OCF ₃ , -OCHF ₂ , -OCH ₂ F or -OEt, Preferably -CH ₃ , -CH ₂ CH ₃ , or -OMe.
4. The compound according to any one of claims 1-3 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ² is -F, -Cl or (C1-C3) alkyl.
5. The compound as claimed in claim 4 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ² is -F, -Cl, -Me or -Et, preferably -F, -Cl, -Me.
6. The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ^R3 is -H, halogen or (C1-C3) alkyl, wherein the (C1-C3) alkyl can be substituted by one or more of the following groups: -H or -F.
7. The compound as claimed in claim 6 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ³ is -H, -F, -Cl, -Me, -CH ₂ CH ₃ , Preferably -H, -F, -Cl, -Me or
8. The compound according to any one of claims 1-7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when ^X2 is N, ^R4 is -H, (C1-C3) alkyl or (C3-C4) cycloalkyl, wherein the (C1-C3) alkyl or (C3-C4) cycloalkyl can be substituted by one or more of the following groups: -H, -D or -F.
9. The compound according to claim 8 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when X ² is N, R ⁴ is H, -CH ₃ , -CD ₃ , -CH ₂ CH ₃ , Preferably -CH ₃ , -CD ₃ , better Selected as -CH ₃ , -CD ₃ , More preferably -CH ₃ , more preferably -CD ₃ , more preferably more preferably
10. The compound according to any one of claims 1-7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when ^X2 is CH, ^R4 is _-CD3 , (C3-C4)cycloalkyl, wherein the (C3-C4)cycloalkyl can be substituted by one or more of the following groups: H or F.
11. The compound according to claim 10 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when X ² is CH, R ⁴ is -CD ₃ , Preferably -CD ₃ ,
12. The compound according to any one of claims 1-11 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:
    
13. A compound represented by general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
    
    In general formula (2):

    X ¹ and X ² are each independently CH or N;

    R ¹ is H, (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy, wherein said (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy can be substituted by one or more of the following groups: -H, halogen;

    R ³ is -H, halogen or (C1-C4)alkyl, wherein the (C1-C4)alkyl may be substituted by one or more of the following groups: -H, halogen.
14. The compound as claimed in claim 13 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or Solvates, wherein the compound has one of the following structures:
    
15. A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-14, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.
16. A compound as described in any one of claims 1-14, or each isomer thereof, each crystal form, a pharmaceutically acceptable salt, hydrate or solvate, or a pharmaceutical composition as claimed in claim 15 is used in the preparation of a drug for treating, regulating and/or preventing diseases related to poly(ADP-ribose) polymerase (PARP).
17. The use according to claim 16, wherein said disease is cancer, and said cancer is hematological cancer and solid tumor.