Pyridinamide parp inhibitors, methods of making and medical uses thereof

Abstract

The application discloses a pyridine amide PARP inhibitor, a preparation method and medical application thereof. Specifically, the application relates to a new compound as shown in a general formula (1) and / or a pharmaceutically acceptable salt thereof, a composition containing the compound as shown in the general formula (1) and / or a pharmaceutically acceptable salt thereof, a preparation method and a use of the compound as a PARP inhibitor in preparation of an antitumor drug.

Description

[0001] This application claims priority to Chinese Patent Application No. 202210067335.X, filed on January 20, 2022, Chinese Patent Application No. 202210206331.5, filed on March 1, 2022, Chinese Patent Application No. 202210642141.8, filed on June 7, 2022, and Chinese Patent Application No. 202211494319.5, filed on November 25, 2022. This application incorporates the entirety of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the field of medicinal chemistry, more specifically, it relates to a class of pyridine amide PARP inhibitors, and the preparation method and medical use thereof. BACKGROUND

[0003] Poly(ADP-ribose) polymerase (PARP) is expressed in most eukaryotic cells, which catalyzes the formation of ADP-ribose units or its polymer (PAR) on specific amino acid residues of itself or other proteins using nicotinamide adenine dinucleotide (NAD+) as substrate, and then regulates the degradation and function of proteins through PAR modification. PARP family consists of 7 isozymes, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), end anchoring polymerases 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 types of PARP family enzymes, PARP-1 is responsible for more than 90% of intracellular ADP-ribosylation (PAR). PARPs play an important role in chromatin structure regulation, 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.

[0004] When tumor cell DNA is damaged by chemotherapy drugs or ionizing radiation, PARP-1 is quickly activated to synthesize a large amount of PAR from NAD+ at the DNA damage site, and to modify histones. In turn, it recruits DNA repair proteins to initiate DNA repair. PARP-1 is mainly involved in the repair of single-strand DNA breaks (SSB). When PARP-1 is inhibited by PARP inhibitors, SSB cannot be repaired, and SSB is converted to double-strand breaks (DSB) during the S phase of DNA replication. Inhibition of PARP-1 function leads to accumulation of DSB in cells. The body repairs DSB mainly through two ways: homologous recombination (HR) and non-homologous DNA end linking (NHEJ, Non-Homologous End Joining), among which homologous recombination repair is the main way of S phase DSB repair, and the repair reliability is high. BRCA1 and BRCA2 play an important role in homologous recombination repair. The deletion of BRCA1 and BRCA2 leads to limited DSB repair. Studies have found that mutations in BRCA1 / 2 are found in ovarian cancer, breast cancer, and prostate cancer, and cancer cells with BRCA1 / 2 deletion are particularly sensitive to PARP inhibitors. This may be due to the inhibition of PARP-1 by PAPR inhibitors, which induces DSB, and due to the deletion of BRCA1 / 2, the repair is blocked, and then the cell death is induced. Therefore, PARP inhibitors have good effects in the clinical 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 to reduce the dose and improve the therapeutic effect. Olaparib is the first PARP inhibitor approved for marketing. With the continuous expansion of the indications of PARP inhibitors, the application of PARP inhibitors is also continuously deepening, not only around tumors, but also has certain effects on stroke, myocardial ischemia, inflammation and diabetes.

[0005] Although efforts to develop PARP inhibitors for the treatment of cancer and other diseases are ongoing, such inhibitors lack a certain specificity for PAPR family proteins, have non-negligible toxic side effects, and are prone to drug resistance. Therefore, it is of great clinical value to develop specific and highly active PARP-1 inhibitors. SUMMARY

[0006] The technical problem to be solved by the present application is that the current PARP inhibitors lack a certain specificity for PAPR family proteins, have non-negligible toxic side effects, and are prone to drug resistance. To this end, the present application provides pyridine amide PARP inhibitors, and a preparation method and medical use thereof.

[0007] The present application provides a compound represented by general formula (1) or each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:

[0008]

[0009] In general formula (1) R1is

[0010] X 1 , X 2 are each independently CH or N;

[0011] R 1 is H, (C1-C4)alkyl, (C3-C6)cycloalkyl, or (C1-C4)alkoxy, wherein the (C1-C4)alkyl, (C3-C6)cycloalkyl, or (C1-C4)alkoxy can be substituted with one or more -H, halogen;

[0012] R 2 is halogen or (C1-C4)alkyl;

[0013] R 3 is -H, halogen, or (C1-C4)alkyl, wherein the (C1-C4)alkyl can be substituted with one or more -H, halogen;

[0014] X 2 R 4 is -H, (C1-C4)alkyl, or (C3-C6)cycloalkyl, wherein the (C1-C4)alkyl or (C3-C6)cycloalkyl can be substituted with one or more -H, -D, halogen; or

[0015] X 2 R 4 is -CD3or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl can be substituted with one or more -H, halogen.

[0016] In another preferred embodiment, wherein in general formula (1) R1is 1 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 with one or more H or F.

[0017] In another preferred embodiment, wherein in general formula (1) R1is 1 H, -CH3, -CH2CH3, -OMe, -OCF3, -OCHF2, -OCH2F, or -OEt, preferably -CH3, -CH2CH3, -OMe, -OCF3, -OCHF2, -OCH2F, or -OEt, preferably -CH3, -CH2CH3,

[0018] In another preferred embodiment, wherein in the general formula (1) R 2 is F, CI or (Ci-C3)alkyl.

[0019] In another preferred embodiment, wherein in the general formula (1) R 2 is F, CI, -Me or -Et, preferably F, CI, -Me.

[0020] In another preferred embodiment, wherein in the general formula (1) R 3 is H, halogen or (Ci-C3)alkyl, wherein the (Ci-C3)alkyl can be substituted by one or more -H or -F.

[0021] In another preferred embodiment, wherein in the general formula (1) R 3 is H, F, CI, -Me, -CH2CH3, preferably H, F, CI, -Me or

[0022] In another preferred embodiment, wherein in the general formula (1) X 2 is N, R 4 is -H, (Ci-C3)alkyl or (C3-C4)cycloalkyl, wherein the (Ci-C3)alkyl or (C3-C4)cycloalkyl can be substituted by one or more -H, -D or -F.

[0023] In another preferred embodiment, wherein in the general formula (1) X 2 is N, R 4 is H, -CH3, -CD3, -CH2CH3, preferably -CH3, -CD3, more preferably -CH3, -CD3, more preferably -CH3, more preferably -CD3, more preferably more preferably

[0024] In another preferred embodiment, wherein in the general formula (1) X 2 is CH, R 4 is -CD3, (C3-C4)cycloalkyl, wherein the (C3-C4)cycloalkyl can be substituted by one or more -H or -F.

[0025] In another preferred embodiment, wherein in the general formula (1) X 2 is CH, R 4 is -CD3, preferably -CD3,

[0026] The present application provides a compound represented by general formula (2) or each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:

[0027]

[0028] In general formula (2):

[0029] X 1 , X 2 each independently is CH or N;

[0030] R 1 is H, (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkoxy, wherein the (C1-C4)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkoxy can be substituted with one or more of the following: -H, halogen;

[0031] R 3 is -H, halogen or (C1-C4)alkyl, wherein the (C1-C4)alkyl can be substituted with one or more of the following: -H, halogen.

[0032] In another specific embodiment of the present application, the compound of the present application has one of the following structures:

[0033]

[0034]

[0035]

[0036] Another object of the present application provides a pharmaceutical composition containing a pharmaceutically acceptable carrier, diluent and / or excipient, and the compound of the present application or each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an active ingredient.

[0037] Still another object of the present application provides the use of the compound of the present application or each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof or the above pharmaceutical composition for the manufacture of a medicament for treating, regulating or preventing a disease related to PARP. Preferably, the disease is cancer, and the cancer is a hematological cancer and a solid tumor.

[0038] Still another object of the present application also provides a method for treating, regulating or preventing a disease related to PARP mediation, which comprises administering to a subject a therapeutically effective amount of the compound of the present application or each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof or the above pharmaceutical composition.

[0039] It is to be understood that both the foregoing general description and the following detailed description of the present application are exemplary and explanatory and are intended to provide further explanation of the application as claimed.

[0040] Synthesis of Compounds

[0041] The preparation of the compounds of the present application of general formula (1) is described in detail below, but these specific methods do not limit the present application in any way.

[0042] The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques and methods incorporated herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein can be varied. The starting materials used for the synthesis of the compounds can be obtained by synthesis or from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce the different groups in the formula provided herein.

[0043] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as the reactants, solvents, bases, amounts of compounds used, reaction temperatures, times required for the reaction, etc. are not limited to the explanations below. The compounds of the present application can also be prepared conveniently by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily made by those skilled in the art. In one aspect, the present application also provides a method for preparing the compounds of general formula (1) described herein, wherein the compounds of general formula (1) can be prepared using the following general reaction scheme 1:

[0044] General Reaction Scheme 1

[0045]

[0046] The compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R4 , X 1 and X 2 as defined above. As shown in General Reaction Scheme 1, compound 1-1 is reacted with thionyl chloride to form compound 1-2, which is subjected to a substitution reaction with 1-3 to form the target compound of general formula (1).

[0047] Further forms of the compounds

[0048] "Pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds, and is relatively non-toxic, i.e., the material is not biologically or otherwise undesirable, i.e., the material is not deleterious to the individual to whom it is administered.

[0049] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause important pharmacological, physiological, or other biological activities when administered to an organism, and does not cause the biological activity or properties of the compound to be abrogated. In certain embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of the general formula with an acid or a 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).

[0050] It is understood that reference to a pharmaceutically acceptable salt includes solvate or crystalline forms, especially solvate or polymorph. Solvates contain either stoichiometric or non-stoichiometric amounts of the solvent, 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 the compounds of general formula (1) are readily prepared and formed according to methods described herein. For example, hydrates of the compounds of general formula (1) are readily prepared by recrystallization from a mixture of water / organic solvent, including but not limited to, tetrahydrofuran, acetone, ethanol, or methanol. In addition, the compounds referred to herein can exist in unsolvated and solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0051] In other embodiments, the compounds of Formula (1) are prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms. In addition, the compounds of Formula (1) include crystalline forms, which can also exist as polymorphs. Polymorphs include different lattice arrangements of the same elemental constituents of the compounds. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvent, rate of crystallization, and storage temperature can cause a single crystal form to dominate.

[0052] In another aspect, the compounds of Formula (1) can possess chiral centers and / or axes, and therefore exist in racemic, racemic mixtures, single enantiomeric, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axis will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures are intended to be within the scope of the present application. The present application is meant to include all such isomeric forms of these compounds.

[0053] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) and carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen present in the compounds of the present application to form deuterium-containing compounds. Deuterium-containing compounds often have increased stability over non-deuterium-containing compounds due to the increased bond strength of deuterium relative to ordinary hydrogen. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.

[0054] The terms

[0055] The terms

[0056] Unless otherwise specified, "alkyl" means a saturated aliphatic hydrocarbon group including straight-chain and branched groups having 1 to 6 carbon atoms. Preferred is lower alkyl containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-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 the group consisting of CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0057] Unless otherwise specified, "cycloalkyl" means a non-aromatic hydrocarbon ring system (single ring, bi- or polycyclic), and partially unsaturated cycloalkyl groups can be referred to as "cycloalkenyl" if the carbon ring contains at least one double bond, or "cycloalkynyl" if the carbon ring contains at least one triple bond. Cycloalkyl groups can include single ring or multiple ring (e.g., with 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The ring-forming carbon atoms of the cycloalkyl group can optionally be oxidized to form oxo or thioxo groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, the cycloalkyl group can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, the cycloalkyl group can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, the cycloalkyl group can be fused to aryl and heterocycloalkyl groups. In some embodiments, the cycloalkyl group can be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0058] Unless otherwise specified, "alkoxy" means an alkyl group linked through an ether oxygen atom to the rest of the molecule. Representative alkoxy groups are alkoxyl groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propyloxy, isopropoxy, butoxy, isobutyloxy, sec-butyloxy, and t-butyloxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from the group consisting of OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO ort- BuO.

[0059] Unless otherwise specified, "halogen" (or halogeno) means fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before a group denotes that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I, in any combination, preferably with F or Cl.

[0060] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0061] Unless otherwise specified, it is to be understood that the word "comprising" or variations such as "comprise", "comprises" or "comprised of", as used herein, mean including but not limited to, and not necessarily limited to, the elements or integers conjured.

[0062] The substituent "-O-CH2-O-" means that the two oxygen atoms of the substituent are attached to two adjacent carbon atoms of the heterocycloalkyl, aryl or heteroaryl group, such as:

[0063] When the number of linking groups is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0064] When one of the variables is selected from a bond, it means that the two groups to which it is attached are directly connected, such as L represents a bond in X-L-Y means that the structure is actually X-Y.

[0065] The term "membered ring" includes any cyclic structure. The term "member" is intended to indicate the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl and thienyl are five-membered rings.

[0066] The term "moiety" refers to a specific part or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity that is included in or attached to a molecule.

[0067] Unless otherwise indicated, a wavy line and a dashed wavy line represents the absolute configuration of a stereocenter, a straight line and a dashed straight line represents the relative configuration of a stereocenter, a wavy line represents a wavy line or a dashed wavy line or a straight line represents a straight line or a dashed straight line

[0068] Unless otherwise indicated, the use of the term denotes a single or double bond.

[0069] Certain pharmaceutical and medical terms

[0070] The term "acceptable", as used herein, means having no excessive deleterious effect on the health of the general treatment population.

[0071] The terms "treatment", "treatment regime" or "therapy", as used herein, include alleviating, inhibiting or ameliorating a disease symptom or condition; inhibiting the development of complications; ameliorating or preventing a latent metabolic syndrome; inhibiting the disease or symptom, such as controlling the disease or condition development; relieving the disease or symptom; causing regression of the disease or symptom; relieving a complication caused by the disease or symptom, or preventing or treating a sign caused by the disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration to a subject, can cause an improvement of a disease, symptom or condition, particularly an improvement in its severity, a delay in onset, a slowing of progression, or a decrease in the duration of the condition, whether fixed or contingent, continuous or intermittent.

[0072] "Active ingredient" means a compound according to Formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compounds according to Formula (1). The compounds of the present application can contain one or more asymmetric centers (chiral centers or axes of chirality) and therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and as individual diastereomers. The asymmetric centers that can exist in the molecules are dependent on the nature of the various substituents. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures are intended, as well as their pure or partially purified individual isomers. The present application is meant to include all such isomeric forms of these compounds.

[0073] The terms "compound", "composition", "agent" or "medicine" or "medicament" are used interchangeably herein and refer to a compound or composition which, when administered to a subject (human or animal), is capable of eliciting a desired pharmacological and / or physiologic effect by local and / or systemic action.

[0074] The term "administered," "administering" or "administration" means either directly administering the compound or composition described, or administering a prodrug, derivative, or analog of the active compound, and the like.

[0075] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The term "about" is used herein to describe and account for small variations. Alternatively, the term "about" means that the value in question can be "a little above" or "a little below" the value stated as the preferred value. Unless otherwise clear from context, all ranges provided herein are intended to be "about" ranges. Unless otherwise indicated, all ranges, numbers, values, and percentages (such as amounts of materials, durations, temperatures, and other similar metrics) stated herein are to be understood as approximations as opposed to being absolute. Thus, unless otherwise indicated, the numerical parameters are approximations and can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the present disclosure. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0076] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Further, the terms "comprises", "comprising", "includes", "including" and the like can be used herein. Unless otherwise expressly stated, all ranges encompass endpoints, single values between endpoints, single values that fall under the purview of the term "about", and, where applicable, combinations of ranges.

[0077] Therapeutic uses

[0078] The present application provides methods of treating diseases using the compounds or pharmaceutical compositions of the present application, including but not limited to conditions involving PARP (e.g., cancer, ischemic diseases, ischemia-reperfusion injury, inflammation, nerve injury, vascular diseases, and diabetes, etc.).

[0079] In some embodiments, methods for treating cancer are provided, the method comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of the structural formula. In some embodiments, the cancer is mediated by PARP. In other embodiments, the cancer is a hematological 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 metastasis of all cancers.

[0080] Routes of administration

[0081] The compounds of the present application and their pharmaceutically acceptable salts can be prepared into various formulations comprising a safe and effective amount of the compound of the present application or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient or carrier. By "safe and effective amount" is meant an amount of the compound sufficient to significantly induce a desired effect, without causing serious side effects. The safe and effective amount of the compound is determined by the age, condition, treatment period, and the like of the subject.

[0082] "Pharmacologically acceptable excipient or carrier" means one or more compatible solid or liquid filler or gel materials, which are suitable for human use, and which must have sufficient purity and low toxicity. By "compatible" is meant that the components of the composition are capable of being commingled with the compounds of the present application, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the compounds. Examples of pharmacologically acceptable excipients or carriers include celluloses and their derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., lecithin), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0083] The compounds of the present application can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0084] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such 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 such ingredients as: (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin and bentonite; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, buffering agents can be included.

[0085] ​Solid dosage forms such as tablets, sugar coated tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other well-known materials. They can contain opacifying agents and can also be of a composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0086] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0087] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0088] Suspensions, in addition to the active compounds, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, as well as mixtures thereof.

[0089] The compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol glycols, and suitable mixtures thereof.

[0090] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required. Ointments or

[0091] The compounds of the present application can be administered alone, or in combination with other pharmaceutically acceptable compounds. When administered as a pharmaceutical composition, a safe and effective amount of the compound of the present application is administered to a mammal (e.g., human) in need of treatment, wherein the amount is a pharmaceutically effective amount, and the amount is typically 1-2000 mg, preferably 50-1000 mg, per day for a 60 kg body weight adult. The specific dose level and frequency of dosage will vary depending on the nature of the pharmaceutical composition, the age, weight and general condition of the patient, the nature of the disease and the like. Such can be determined by the skilled practitioner.

[0092] The above-mentioned features of the present application, or features mentioned in the embodiments, can be combined in any manner. All features disclosed in the specification can be used in any combination, and each feature disclosed in the specification can be replaced by any alternative feature that serves the same, equivalent or similar purpose. Thus, unless specifically noted, the features disclosed are merely exemplary of the generic nature of the features and are not restrictive. DETAILED DESCRIPTION

[0093] The various specific aspects, features and advantages of the compounds, methods, and pharmaceutical compositions described above will become apparent to those of ordinary skill in the art upon reading the following description and examples. It is understood that the detailed description and examples described herein are given for illustrative purposes only and are not intended to limit the application. Various modifications and alterations to this application will become apparent to those of ordinary skill in the art upon reading the description and examples that follow. It is understood that all such modifications and alterations are within the scope and spirit of the application.

[0094] In all examples, 1 H-NMR was recorded on a Varian Mercury 400 NMR spectrometer, chemical shifts are expressed in δ (ppm); silica gel used for separation was 200-300 mesh unless otherwise stated, and the ratio of eluent was volume ratio.

[0095] Synthesis of compound 1 of example 1

[0096]

[0097] Step 1: Synthesis of compound int_1-2:

[0098]

[0099] Methyl 5-bromo-6-methylpyridine-2-carboxylate (6.5 g, 28 mmol), piperazine-1- carboxylate tert-butyl ester (8.4 g, 45 mmol), 2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl (2-amino-1,1'-biphenyl-2-yl)palladium(II) (879 mg, 1.05 mmol) and cesium carbonate (19.6 g, 60 mmol) were mixed in 1,4-dioxane (60 mL) under nitrogen protection. The reaction was heated to 110 °C and stirred for 6 hours. After cooling, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3), and the organic phases were combined. The organic phase was washed with water (100 mL) and saturated sodium chloride aqueous solution (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 purified by silica gel chromatography to obtain intermediate int_1-2.

[0100] LC-MS (ESI): 336 [M+H] + .

[0101] Step 2: Synthesis of compound int_1-3:

[0102]

[0103] Intermediate int_1-2 (6.00 g, 17.91 mmol) was dissolved in methanol (120 mL) at room temperature, and cyclopropylamine (2.04 g, 35.8 mmol) was added. The reaction was stirred at room temperature overnight. The organic solvent was removed by concentration, and the residue was purified by recrystallization (dichloromethane / petroleum ether) to give yellowish intermediate int_1-3.

[0104] LC-MS (ESI): 361 [M+H] + .

[0105] Step 3: Synthesis of compound int_1-4:

[0106]

[0107] Intermediate int_1-3 (6.30 g, 17.50 mmol) was dissolved in dichloromethane (15 mL) at room temperature. Trifluoroacetic acid (15 mL) was added dropwise at 0 °C, and the reaction was stirred for 0.5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (30 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined, 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 give yellow intermediate int_1-4.

[0108] LC-MS (ESI): 261 [M+H] + .

[0109] Step 4: Synthesis of compound 1:

[0110]

[0111] Intermediate int_1-5 (35 mg, 0.157 mmol) was dissolved in dichloromethane (3 mL) at room temperature, and N,N-dimethylformamide (1 drop) and dichlorosulfoxide (0.1 mL) were added. The reaction was stirred at room temperature for 2 h. The residue was dissolved in acetonitrile (3 mL), and N,N-diisopropylethylamine (59 mg, 0.456 mmol) and intermediate int_1-4 (41 mg, 0.157 mmol) were added. The reaction was heated to 70 °C and stirred for 15 h. After cooling, the residue was purified by C18 reverse-phase chromatography to give compound 1.

[0112] LC-MS (ESI): 465 [M+H] + .

[0113] Example 2 - Synthesis of compound 2-52

[0114] Using the synthetic procedure described in Example 1 above, or other similar routes, using different starting materials, the target compounds 2-52 in Table 1 can be obtained.

[0115] Table 1

[0116]

[0117]

[0118]

[0119]

[0120] Example 53 In vitro inhibition of poly(ADP-ribose) polymerase [PARP-1 enzyme] activity assay of compounds of the present application

[0121] Histones were coated on 384-well plates overnight at 4°C, rinsed with PBST buffer three times, and blocked for 1 hour at room temperature. After 1 hour, rinsed with PBST three times again, added DMSO or gradient diluted compounds, and mixed with PARP-1 enzyme and DNA, incubated for 10 minutes at 25°C. After 10 minutes, added NAD + to start the reaction. After 60 minutes of reaction at room temperature, rinsed with PBST three times, added poly / mono-ADP ribose antibody conjugated with horseradish peroxidase (HRP) to detect the level of poly / mono-ADP ribose on histones. After 1 hour of incubation at room temperature, added HRP substrate ECL A and B for Envision quantitative chemiluminescence. Calculated the percentage of inhibition and IC 50 of compounds compared to the control group DMSO. The results are shown in Table 2 below.

[0122] Table 2. Inhibition activity (IC 50 , nM) of compounds of the present application on PARP-1

[0123]

[0124] +++ indicates IC 50 less than or equal to 10 nM

[0125] ++ indicates IC 50 from 10 nM to 50 nM

[0126] + indicates IC 50 more than 50 nM

[0127] Example 54: In vitro inhibition experiment of the compound of the present invention on the proliferation of MDA-MB-436 cells.

[0128] 1200 MDA-MB-436 cells per well were seeded in 96-well low-absorption plates. After overnight adhesion, serially diluted compounds were added, and incubation continued for 10 days. Cell growth was evaluated by measuring ATP levels using CTG. Compared with the DMSO group, the percentage of growth inhibition and IC50 of the compounds were calculated. 50 The specific results are shown in Table 3 below.

[0129] Table 3. Inhibitory activity of the compounds of the present invention against MDA-MB-436 cells (IC50) 50 ,nM)

[0130]

[0131] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof: ； In general formula (1): X 1 is CH; X 2 is N or CH; R 1 is -CH2CH3or ; R 2 is -F, -Cl or -Me; R 3 -H, halogen, or (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one or more -H, halogen; R 4 is (C1-C4)alkyl or (C3-C6)cycloalkyl, wherein said (C1-C4)alkyl or (C3-C6)cycloalkyl is optionally substituted with one or more -H, -D, halogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), R 3 is -H, halogen, or (Ci-C3)alkyl, wherein the (Ci-C3)alkyl is optionally substituted with one or more -H or -F.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), R 3 is -H, -F, -CI, -Me, -CH2CH3, , .

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), R 3 is -H, -F, -CI, -Me, or .

5. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein in the general formula (1), R 4 is (Ci-C3)alkyl or (C3-C4)cycloalkyl, wherein the (Ci-C3)alkyl or (C3-C4)cycloalkyl is optionally substituted with one or more -H, -D, or -F.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), R 4 For -CH3, -CD3, -CH2CH3, , , , , , , , , , , or .

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), R 4 For -CH3, -CD3, or .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures: 、 、 、 、 、 、 、 、 , or .

9. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a compound or a pharmaceutically acceptable salt thereof as any one of claims 1-8 as an active ingredient.

10. Use of a compound as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9, in the preparation of a medicament for treating, modulating, and / or preventing diseases associated with poly-ADP-ribose polymerase.

11. The use as claimed in claim 10, wherein the disease is cancer, and the cancer is a hematologic malignancy or a solid tumor.

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