Azakinolione derivatives, method for preparing the same, and use thereof

Abstract

An azaquinolinone compound having the structure of the following formula (I) as an enzyme inhibitor for the poly(ADP-ribose) polymerase (PARP) family, and a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide drug thereof, a method for preparing the same, and its use. 【Chemical 1】 TIFF2025519219000138.tif35140

Description

Technical Field

[0001] The present application relates to azakynolinone compounds as enzyme inhibitors for the poly(ADP-ribose) polymerase (PARP) family, pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions thereof, methods for preparing the same, and uses thereof.

Background Art

[0002] PARP1 and PARP2 (PARP1 / 2) bind to DNA damage sites and catalyze the synthesis of poly(ADP-ribose) chains in protein substrates, thereby recruiting other DNA repair proteins to the damage sites to repair DNA damage together, while inducing the release of PARP1 / 2 from DNA. PARP inhibitors "trap" PARP1 / 2 on DNA by binding to the PARP1 / 2 catalytic site, whereby PARP1 / 2 cannot detach from the DNA damage site, thus inducing stalling of DNA replication forks and interfering with the smooth implementation of DNA replication. At this point, cells typically correct this error by the homologous repeat repair (HRR) method. Proteins such as BRCA1 / 2 play important roles in the HRR process, while in BRCA-mutated cells, HRR is dysfunctional, and the presence of PARP inhibitors blocks the DNA damage repair effect, thus leading to cell death.

[0003] Olaparib is the first PARP inhibitor developed by AstraZeneca and approved for sale worldwide, and is approved by the FDA for the treatment of various cancers. Since then, rucaparib, niraparib, talazoparib, etc. have also been approved for sale. On the other hand, there are multiple inhibitors in the clinical stage. PARP inhibitors have shown excellent clinical efficacy in patients with BRCA deficiency, but all of these compounds have shown obvious hematotoxicity including anemia, neutropenia, and thrombocytopenia, regardless of whether they are used in monotherapy or combination therapy. Hematotoxicity limits the use of first-generation PARP inhibitors and clinically requires dose reduction, discontinuation, or interruption of administration.

[0004] Recent studies indicate that the inhibition of PARP2 is closely associated with hematotoxicity. Rather than PARP1, PARP2 is essential for the survival of mouse hematopoietic stem / progenitor cells (HSPCs) and is used to maintain hematopoietic homeostasis. Moreover, the synthetic lethality of BRCA mutations is driven only by PARP1 without the need to "trap" PARP2 to DNA. Since PARP1 and PARP2 are highly homologous, most current PARP inhibitors lack selectivity for PARP1. Therefore, the development of highly selective PARP1 inhibitors encourages reducing hematotoxicity and improving the therapeutic index.

[0005] Compared with other PARP1 / 2 inhibitors, PARP1 inhibitors with high selectivity are expected to improve efficacy and reduce toxicity. Therefore, there is an unmet medical need for effective and safe PARP inhibitors. Currently, there are no PARP1 inhibitors with high selectivity on the market. AZD5305, a selective PARP1 inhibitor, has entered clinical phase I / II. AZD9574, a PARP1 inhibitor with higher selectivity than AZD5305, has also entered clinical phase I / II. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] The compounds and experimental drugs disclosed in the prior art still have uncertainties in terms of effectiveness, safety, etc. Therefore, it is still necessary to select compounds with excellent performance from the perspectives of effectiveness, safety, selectivity, etc. as PARP1 inhibitors. MEANS FOR SOLVING THE PROBLEM

[0007] To solve the above problems of the prior art, the object of the present application is to provide azakynolinone compounds and pharmaceutically acceptable salts or stereoisomers thereof, and to select compounds with excellent performance from the perspectives of effectiveness, safety, selectivity, etc. as PARP1 inhibitors.

[0008] To achieve this object of the present application, the following technical solutions are adopted in the present application.

[0009] In some embodiments, the present application provides a compound having the structure of formula (I):

[0010]

Chemical formula

[0011]

Chemical formula

[0012] R z is, in each occurrence, independently selected from hydrogen, C 1~4 alkyl, C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl, where C 1~4 alkyl, C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from F, cyano, hydroxy, C 1~4 alkyl, -O-(C 1~4 alkyl) or fluorinated C 1~4 alkyl.

[0013] In some embodiments, X is selected from N, CH or CR a where R a is selected from F, Cl, Br, C 1~4 alkyl, C 3~6 cycloalkyl, -OMe or fluorinated C 1~4 alkyl.

[0014] In some preferred embodiments, R a is selected from F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, -OMe, -CF3, -CHF2 or -CH2F, more preferably, R ais selected from F, Cl, Br, methyl, cyclopropyl, -OMe, -CHF2 or -CH2F, Y is N, CH or CR b selected from, where R b is selected from F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, oxacyclohexyl or -OR z selected from, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or oxacyclohexyl is unsubstituted or independently substituted with one or more substituents selected from fluoro, cyano, hydroxy, methyl or -OMe.

[0015] In some preferred embodiments, R b is selected from F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z selected from, where methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or independently substituted with one or two substituents selected from fluoro, cyano, hydroxy or methyl, provided that when X is selected from N or CH, Y is CR b selected from, when X is selected from CR a selected from, Y is N, CH or CR b selected from.

[0016] In some embodiments, R 1 is hydrogen, F, Cl, Br, cyano, methyl, ethyl, isopropyl, -OMe, -O-(fluorinated C 1~4 alkyl) or fluorinated C 1~4 alkyl selected from.

[0017] In some preferred embodiments, R 1 is selected from hydrogen, F, Cl, methyl, -OMe, -CHF2 or -CH2F.

[0018] In some embodiments, R 2 is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, cyclopropyl, -OMe or fluorinated C 1~4 alkyl.

[0019] In some preferred embodiments, R 2 is selected from hydrogen, F, Cl, Br, methyl, cyclopropyl, -OMe, -CHF2 or -CH2F.

[0020] In some embodiments, R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, methyl, cyclopropyl, -OMe or fluorinated C 1~4 alkyl.

[0021] In some preferred embodiments, R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or two substituents selected from F, cyano, -OMe, -CHF2 or -CH2F.

[0022] In some embodiments, Q is selected from N or CR c , where R c is selected from F, hydroxy, cyano, methyl, ethyl, -OMe or fluorinated C 1~4 alkyl.

[0023] In some preferred embodiments, Q is selected from N or CR c , where R c is selected from F, hydroxy, cyano, methyl, -OMe, -CHF2 or -CH2F.

[0024] In some more preferred embodiments, Q is N or CR c selected from, where R c is selected from F, hydroxy, -OMe or methyl.

[0025] In some embodiments, R 4 and R 5 are each independently selected from hydrogen, methyl or ethyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring.

[0026] In some preferred embodiments, R 4 and R 5 are each independently selected from hydrogen or methyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring to

[0027]

Chemical formula

[0028] In some more preferred embodiments, R 4 and R 5 are each independently selected from hydrogen or methyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring to

[0029]

Chemical formula

[0030] In some embodiments,

[0031]

Chemical formula

[0032] In some preferred embodiments,

[0033]

Chemical formula

[0034] In some more preferred embodiments,

[0035]

Chemical formula

[0036]

Chemical formula

[0037] In some embodiments, R 6 is, in each occurrence, independently selected from hydrogen, F, Cl, Br, cyano, -OR z , -C(=O)-R z , -C(=O)-NH-R z , methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, hydroxy, methyl, -OMe, -CF3 or -CHF2.

[0038] In some preferred embodiments, R 6 is, in each occurrence, independently selected from hydrogen, F, Cl, Br, cyano, -OR z , -C(=O)-R z , -C(=O)-NH-R z, independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or independently substituted with one or two substituents selected from F, hydroxy or -OMe.

[0039] In some embodiments, R z is, in each occurrence, independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or oxacyclopentyl, where methyl, ethyl, cyclopropyl, cyclobutyl or oxacyclopentyl is unsubstituted or independently substituted with one or more substituents selected from fluoro, cyano, hydroxy, -OMe, oxetanyl or methyl.

[0040] In some preferred embodiments, R z is, in each occurrence, independently selected from hydrogen, methyl, ethyl, cyclopropyl, oxetanyl, oxacyclopentyl, methylene-oxetanyl, -CF3, -CF2H or -CH2F.

[0041] In some embodiments, n is 1 or 2.

[0042] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof having the structure of formula (II):

[0043]

Chemical formula

[0044]

Chemical formula

[0045]

Chemical formula

[0046] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof having the structure of formula (III):

[0047] [wherein, R is selected from hydrogen, F, Cl, methyl, -OMe, -CHF2 or -CH2F, R 1 is selected from hydrogen, halogen, cyano, C R 2 is selected from hydrogen, halogen, cyano, C 1~4 alkyl, C 3~6Cycloalkyl, -O-(C 1~4 alkyl) or halogenated C 1~4 alkyl, selected from R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or two substituents selected from F, cyano, methyl, cyclopropyl or -OMe, R b is selected from F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z where methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or is independently substituted with one or two substituents selected from fluoro, cyano, hydroxy or methyl, R 4 and R 5 are each independently selected, in each occurrence, from hydrogen or C 1~4 alkyl, or R 4 and R 5 are connected to each other to form a ring to

[0048]

Chemical formula

[0049]

Chemical formula

[0050]

Chemical formula

[0051] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof having the structure of formula (IV):

[0052] [wherein, R is selected from hydrogen, F, Cl, Br, cyano, C 2 alkyl, C 1~4 cycloalkyl, -O-(C 3~6 alkyl) or fluorinated C 1~4 alkyl, 1~4 and R 3 ​is selected from cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or 4- to 6-membered heterocyclyl, where methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, methyl or -OMe, R b is selected from F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z wherein methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or is independently substituted with one or two substituents selected from fluoro, cyano, hydroxy or methyl, R 4 and R 5 are each independently selected from hydrogen, methyl or ethyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring,

[0053]

Chemical formula

[0054] In some specific embodiments, the present application

[0055]

Chemical formula

[0056] In another aspect, the present application further relates to a pharmaceutical composition comprising an effective dose of any one of the compounds of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, and a pharmaceutically acceptable carrier and / or excipient, or further comprising one or more other therapeutic agents.

[0057] In another aspect, the present application provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, or a pharmaceutical composition of a compound of the present application, in the preparation of a PARP1 inhibitor.

[0058] In another aspect, the present application provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, in the preparation of a medicament for treating cancer, wherein the cancer is a PARP1-mediated BRCA gene-deficient tumor.

[0059] More specifically, the present application provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, in the preparation of a medicament for treating cancer or other diseases related to PARP1, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, colorectal cancer, bladder cancer, gastrointestinal cancer, lung cancer or blood cancer.

[0060] Definitions Hereinafter, unless otherwise defined, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technologies used herein are intended to refer to technologies commonly understood in the art, including variations or equivalent substitutes of technologies that are obvious to one of ordinary skill in the art. The following terms are considered to be understood by one of ordinary skill in the art, but the following definitions are provided for a more detailed explanation of the present application.

[0061] The compounds described in the present application are named according to the chemical structural formula. When representing the same compound, if the naming of the compound does not match the chemical formula, the chemical formula shall take precedence.

[0062] The terms "comprise", "include", "have", "contain" or "relate to" and their other variants used herein are inclusive or open-ended and do not exclude other elements or method steps not listed.

[0063] As used herein, the term "alkylene" represents a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylidene, propylidene or butylidene.

[0064] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, alkyl has 1 to 12 carbon atoms, such as 1 to 6 carbon atoms. For example, as used herein, the term "C 1~6 alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which may optionally be substituted with one or more (e.g., 1 to 3) suitable substituents, such as halogen (the group is then referred to as "haloalkyl (halogenated alkyl)") (e.g., CH2F, CHF2, CF3, CCl3, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1~4 alkyl" refers to a straight or branched chain aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0065] As used herein, the term "alkenyl" means a (C 2~5 alkenyl) straight or branched chain monovalent hydrocarbon group having one double bond and 2 to 5 carbon atoms. Alkenyl includes, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-alkenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present application contain alkylene, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form or any mixture thereof.

[0066] As used herein, the term "alkynyl" includes one triple bond and has 2 to 5 carbon atoms (C 2~5 alkynyl), and means a straight-chain or branched-chain monovalent hydrocarbon group. Alkynyl includes, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-2-propynyl, and 4-methyl-3-pentynyl.

[0067] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including a spirocyclic, fused or bridged system (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, etc.)), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. Cycloalkyl has 3 to 15 carbon atoms. For example, the term "C 3~6 cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with one or more (e.g., up to 3) suitable substituents, for example, cyclopropyl substituted with methyl.

[0068] As used herein, the terms "cyclohydrocarbylene" and "cyclohydrocarbyl" refer to a saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (preferably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, which includes, but is not limited to, cyclopropyl(en), cyclobutyl(en), cyclopentyl(en), cyclohexyl(en), cycloheptyl(en), cyclooctyl(en), cyclononyl(en), cyclohexenyl(en), etc.

[0069] As used herein, the terms "heterocyclyl" and "heterocyclylene" refer to a cyclic group in which at least one cyclic atom is a heteroatom selected from N, O, and S and the remaining cyclic atoms are C, for example, a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds in the ring) cyclic group having 3 to 10 (preferably 3 to 8, more preferably 3 to 6) cyclic atoms. For example, "3- to 10-membered heterocyclyl(en)" refers to a saturated or partially unsaturated heterocyclyl(en) having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) cyclic carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocyclylene and heterocyclyl include, but are not limited to, oxiranyl(en), aziridinyl(en), azetidinyl(en), oxetanyl(en), tetrahydrofuryl(en), dioxolinyl(en), pyrrolidinyl(en), pyrrolidonyl(en), imidazolidinyl(en), pyrazolidinyl(en), pyrrolinyl(en), tetrahydropyranyl(en), piperidyl(en), morpholinyl(en), dithianyl(en), thiomorpholinyl(en), piperazinyl(en), or trithianyl(en). Heterocyclylene and heterocyclyl may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0070] As used herein, the term "halo (halogenated)" or "halogen" group is defined to include F, Cl, Br, or I.

[0071] As used herein, the term "nitrogen-containing heterocycle" has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least 1 nitrogen atom in the ring, and one or more (e.g., 1, 2, 3, or 4) ring members selected from N, O, C=O, S, S=O, and S(=O)2 may optionally be included, and refers to a saturated or unsaturated monocyclic or bicyclic group, and the remainder of the molecule is connected via any one of the nitrogen atom in the nitrogen-containing heterocycle and other ring atoms. The nitrogen-containing heterocycle may optionally be benzo-fused, and the remainder of the molecule is connected via any one of the nitrogen atom in the nitrogen-containing heterocycle and a carbon atom in the fused benzene ring.

[0072] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the specified atom are replaced by selection from the specified group, under the proviso that the normal valence of the specified atom is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variable elements are only permitted if such combinations form stable compounds.

[0073] When a substituent is described as "each independently selected from" one group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from another (other) substituent.

[0074] As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, or 10, under reasonable conditions.

[0075] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be derived from any suitable position of the substituent.

[0076] When the attachment of a substituent is shown to pass through a bond connecting two atoms in a ring, such a substituent may be attached to any one of the ring-forming atoms of the ring that can be substituted.

[0077] This application further includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of this application except that one or more atoms are replaced by atoms having an atomic mass or mass number different from that of the atoms having the same atomic number but being predominant in nature. Examples of isotopes suitable for inclusion in the compounds of this application are isotopes of hydrogen (e.g., deuterium ( 2 H) and tritium ( 3 H)), isotopes of carbon (e.g., 11 C, 13 C and 14 C), isotopes of chlorine (e.g., 36 Cl), isotopes of fluorine (e.g., 18 F), isotopes of iodine (e.g., 123 I and 125 I), isotopes of nitrogen (e.g., 13 N and 15 N), isotopes of oxygen (e.g., 15 O, 17 O and 18 O), isotopes of phosphorus (e.g., 32 P) and isotopes of sulfur (e.g., 35 S) (including but not limited to these).

[0078] The term "stereoisomer" refers to isomers formed by at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereoisomer mixtures, and single diastereoisomers can be formed. Certain individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present application can exist as mixtures of two or more different structural forms in rapid equilibrium (generally referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is understood that the scope of the present application includes all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%).

[0079] Solid line

[0080]

Chem.

[0081]

Chem.

[0082]

Chem.

[0083] This application includes all possible crystalline forms or polymorphic forms of the compounds of the present application, which may be a single polymorphic form or a mixture of any proportion of more than one polymorphic form.

[0084] It should also be understood that some of the compounds of the present application may exist in the free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present application, pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that can directly or indirectly provide the compounds of the present application or their metabolites or residues after administration to a patient in need thereof. Thus, when referred to herein, "the compounds of the present application" is also intended to include the various derivative forms of the compounds described above.

[0085] The pharmaceutically acceptable salts of the compounds of the present application include their acid addition salts and alkali addition salts.

[0086] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate / carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitate, and other similar salts.

[0087] Suitable alkali addition salts are formed from alkalis that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.

[0088] For a general overview of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection and Use" (Wiley-VCH, 2002). Pharmaceutically acceptable salts used to prepare the compounds of this application are known to those skilled in the art.

[0089] As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in this application and includes physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release the compounds of this application in the form of free acids or alcohols). The compounds of this application themselves may be esters.

[0090] The compounds of this application may exist in the form of solvates (preferably hydrates), where the compounds of this application include polar solvents, especially, for example, water, methanol, or ethanol, as structural elements of the crystal lattice of the compound. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.

[0091] One skilled in the art would understand that not all nitrogen-containing heterocycles can form N-oxides since a lone pair of electrons is required to oxidize nitrogen to an oxide, and one skilled in the art would recognize nitrogen-containing heterocycles that can form N-oxides. One skilled in the art would also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art. These include oxidation of heterocycles and tertiary amines with peracids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides are widely described and summarized in the literature, for example, T. L. Gilehrist, Comprehensive Organic Synthesis, Volume 7, pages 748 - 750; edited by A. R. Katritzky and A. J. Boulton, Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, Volume 22, pages 390 - 392. See A. R. Katritzky and A. J. Boulton, Academic Press.

[0092] Metabolites of the compounds of the present application, i.e., substances formed in the body when the compounds of the present application are administered, are also included within the scope of the present application. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. Accordingly, the present application includes metabolites of the compounds of the present application and compounds prepared by a method of contacting the compounds of the present application with a mammal for a sufficient time to produce those metabolites.

[0093] This application further includes prodrugs of the compounds of this application within its scope. The prodrugs may themselves have little or no pharmacological activity and can be converted into the compounds of this application having the desired activity, for example, by cleavage such as hydrolysis, when administered in the body or on the body surface. They are certain derivatives of the compounds of this application. Generally, such prodrugs are functional group derivatives of the compounds that can be easily converted in vivo into compounds having the desired therapeutic activity. Other information about the use of prodrugs may be referred to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of this application can be prepared, for example, by replacing appropriate functional groups present in the compounds of this application with certain parts known to those skilled in the art as "pro parts" (for example, as described in "Design of Prorugs", H. Bundgaard (Elsevier, 1985)).

[0094] This application also includes compounds of this application containing protecting groups. In any method of preparing the compounds of this application, it may be necessary and / or desirable to protect sensitive or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of this application. This can be achieved by conventional protecting groups, for example, those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. These reference documents are incorporated herein by reference. The protecting groups can be removed at an appropriate subsequent stage by methods known in the art.

[0095] The term "about" refers to within ±10% of the defined numerical value, preferably within ±5%, more preferably within ±2%.

Modes for Carrying Out the Invention

[0096] [Examples] The present application will be described in more detail below in conjunction with examples, but the present application is not limited thereto. Any equivalent substitution in the art made in accordance with the disclosure of the present application is within the protection scope of the present application.

[0097] The structure of the compound is determined by mass spectrometry (MS) or nuclear magnetic resonance ( 1 HNMR).

[0098] Nuclear magnetic resonance ( 1 HNMR) is measured with a Bruker AVANCE 400 nuclear magnetic spectrometer. The measurement solvent is deuterated chloroform (CDCl3), the internal standard is tetramethylsilane (TMS), and the chemical shift is recorded in units of 10 -6 (ppm).

[0099] Mass spectrometry (MS) is measured with a FINNIGAN LCQ Ad (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ Advantage MAX).

[0100] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used as the thin-layer silica gel.

[0101] Yantai Huanghai silica gel, which is 200 - 300 mesh silica gel, is generally used as the carrier in column chromatography.

[0102] Unless otherwise specified in the present application, all reactions mentioned in the present application are carried out under N2 protection or in a nitrogen atmosphere.

[0103] The terms "N2 protection" or "nitrogen atmosphere" in the present application refer to, for example, connecting the reaction flask to a nitrogen balloon with a volume of 1 L.

[0104] Unless otherwise specified in the present application, the solutions mentioned in the reactions of the present application are aqueous solutions.

[0105] The term "room temperature" in this application refers to a temperature between 10°C and 25°C.

[0106] [Table 1]

[0107] [Example A1] Preparation of the dihydrochloride of the intermediate N-methyl-5-(piperazin-1-yl)picolinamide (Int-1)

[0108] [Chemical Formula] Step 1: Preparation of the compound tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (Int-1b) Compound Int-1a (10.0 g, 46.3 mmol), tert-butyl piperazine-1-carboxylate (9.07 g, 48.6 mmol) and Cs2CO3 (30.0 g, 92.6 mmol) were weighed into a round-bottom flask, 1,4-dioxane (180 mL) was added, Ruphos Pd G3 (1.36 g, 1.62 mmol) was added under N2 protection. After the addition was complete, the temperature was raised to 80°C for the reaction. After the reaction was complete, water and ethyl acetate were added to the reaction system for dilution and liquid separation. The aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and subjected to suction filtration. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product of the compound was purified by column chromatography to obtain the title compound Int-1b (8.18 g, yield: 55%). MS m / z (ES): 322.2 [M+H] + .

[0109] Step 2: Preparation of the compound tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (Int-1c) Compound Int-1b (12.1 g, 37.3 mmol) was dissolved in methanol (50 mL), then added to an aqueous solution of 40% methylamine (33 mL, 0.38 mol), and stirred at room temperature. After the reaction was completed, the reaction system was concentrated, and the residue was diluted with saturated ammonium chloride solution and DCM for liquid separation. The aqueous phase was extracted 3 times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-1c (12.0 g, yield: 100%). MS m / z (ES): 321.2 [M+H] + .

[0110] Step 3: Preparation of compound N-methyl-5-(piperazin-1-yl)picolinamide (Int-1) Compound Int-1c (12.0 g, 37.3 mmol) was dissolved in MeOH (100 mL), and a 1,4-dioxane solution of HCl (4 M, 50 mL, 200 mmol) was added at 0 °C, then slowly warmed to room temperature and stirred. After the reaction was completed, ethyl ether was added to the reaction system for dilution. The solid was precipitated from the system, filtered, and washed with ethyl ether. The solid was collected and subjected to vacuum drying to obtain the dihydrochloride salt of the title compound Int-1 (11.1 g, yield: 99%). MS m / z (ES): 221.1 [M+H] + .

[0111] [Example A2] Preparation of hydrochloride salt of intermediate 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N,6-dimethylpicolinamide (Int-A2)

[0112] [Chemical formula] Step 1: Preparation of compound tert-butyl 3-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Int-A2b) The crude product of compound Int-A2b was synthesized by the same method as described in step 1 of Example A1, except that compound Int-A2a was used instead of compound Int-1a in step 1 of Example A1. The obtained crude product was purified by column chromatography to obtain the title compound Int-A2b (1.90 g, yield: 79%). MS m / z (ES): 348.2 [M+H] + .

[0113] Step 2: Preparation of compound tert-butyl 3-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Int-A2c) Compound Int-A2b (1.90 g, 5.48 mmol) was dissolved in methanol (10 mL), then 33% methylamine ethanol solution (5 mL, 54.8 mol) was added, and the mixture was stirred at room temperature. After the reaction was completed, the reaction system was concentrated to obtain the crude product of the title compound Int-A2c (1.83 g), and the obtained crude product was directly used in the next step without further purification. MS m / z (ES): 347.1 [M+H] + .

[0114] Step 3: Preparation of compound 5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N,6-dimethylpicolinamide (Int-A2) The crude product of compound Int-A2 was synthesized by the same method as described in Example A1, except that compound Int-A2c was used instead of compound Int-1c in step 3 of Example A1. Ethyl ether was added to the crude product for dilution. The solid was precipitated from the system, filtered, and washed with ethyl ether. The solid was collected and subjected to vacuum drying to obtain the hydrochloride salt of the title compound Int-A2 (1.24 g, 2-step yield: 92%). MS m / z (ES): 247.2 [M+H] + .

[0115] [Example A3] Preparation of intermediate 5-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N,6-dimethylpicolinamide (Int-A3)

[0116] [Chemical formula] Step 1: Preparation of compound tert-butyl (1R,4R)-5-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Int-A3b) Compound Int-A3a (3.0 g, 13.1 mmol), tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.8 g, 14.4 mmol) and Cs2CO3 (12.1 g, 39.3 mmol) were weighed into a round-bottom flask, 1,4-dioxane (20 mL) was added, Ruphos Pd G3 (0.5 g, 0.65 mmol) was added under N2 protection. After the addition was complete, the temperature was raised to 90 °C for the reaction. After the reaction was complete, water and ethyl acetate were added to the reaction system for dilution and liquid separation. The aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and subjected to suction filtration. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product of the compound was purified by column chromatography to obtain the title compound Int-A3b (3.8 g, yield: 84%). MS m / z (ES): 347.1 [M+H] + .

[0117] Step 2: Preparation of compound 5-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N,6-dimethylpicolinamide (Int-A3) Compound Int-A3b (200 mg, 0.57 mmol) was dissolved in a 1,4-dioxane solution (2 mL), and a 1,4-dioxane solution of HCl (4 M, 1.5 mL, 5.7 mmol) was added thereto at 0 °C. Then, the mixture was slowly warmed to room temperature and stirred. After the reaction was completed, petroleum ether was added to the reaction system for dilution. The solid was precipitated from the system, filtered, and washed with petroleum ether. The solid was collected and subjected to vacuum drying to obtain the hydrochloride salt of the title compound Int-A3 (123 mg, yield: 86%). MS m / z (ES): 247.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.26 (s, 1H), 8.66 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.56 (s, 1H), 4.39 (s, 1H), 3.75 (d, J = 10.0 Hz, 1H), 3.60 (d, J = 10.4 Hz, 1H), 3.40 - 3.30 (m, 1H), 3.30 - 3.18 (m, 1H), 2.81 (d, J = 4.4 Hz, 3H), 2.55 (s, 3H), 2.11 (d, J = 10.8 Hz, 1H), 1.98 (d, J = 10.8 Hz, 1H).

[0118] Referring to the synthesis methods in Examples A1, A2, or A3, under the same reaction conditions, appropriate aryl halides and amino compounds were used instead of the raw materials and amino compounds in the reaction of Step 1 to synthesize the hydrochloride salts of the following intermediate compounds.

[0119]

Table 2

[0120] [Example A4] Preparation of Intermediate 6-Chloro-N-methyl-5-(piperazin-1-yl)picolinamide (Int-A8)

[0121]

Chem.

[0122] Step 2: Preparation of compound methyl 6-chloro-5-(piperazin-1-yl)picolinate (Int-A8c) Compound Int-A8b (1.45 g, 7.57 mmol) was dissolved in acetonitrile (50 mL), then anhydrous piperazine (1.8 g, 21.0 mmol) was added, and after the addition was complete, the reaction was carried out at 80 °C. After the reaction was complete, the reaction system was concentrated to obtain the crude product of compound Int-A8c, and the obtained crude product was directly used in the next step without further purification. MS m / z (ES): 256.1 [M+H] + .

[0123] Step 3: Preparation of compound 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide (Int-A8) The crude product of compound Int-A8c in the above step was dissolved in EtOH (10 mL), then 33% methylamine ethanol solution (9.8 mL, 78 mmol) was added, and the mixture was stirred at room temperature for the reaction. After the reaction was completed, concentration was carried out to obtain the title compound Int-A8 (1.9 g, two-step yield: 98%). MS m / z (ES): 255.1 [M+H] + .

[0124] [Example A5] Preparation of intermediate 3-(6-methyl-5-(piperazin-1-yl)pyridin-2-yl)oxetan-3-ol (Int-A9)

[0125]

Chemical formula

[0126] Step 2: Preparation of Compound 3-(6-Methyl-5-(piperazin-1-yl)pyridin-2-yl)oxetan-3-ol (Int-A9) Compound Int-A9c (500 mg, 2.1 mmol), piperazine (361 mg, 4.2 mmol), RuPhosPdG3 (176 mg, 0.21 mmol) and Cs2CO3 (2.05 g, 6.3 mmol) were dissolved in 1,4-dioxane (20 mL), the reaction system was placed at 120 °C, and the reaction was carried out for 4 hours under a nitrogen atmosphere. After monitoring the completion of the reaction by LCMS, water was added to quench the reaction, and then extraction with ethyl acetate was carried out 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound (Int-A9) (60 mg, yield: 11%). MS m / z (ES): 250.1 [M+H] + .

[0127] [Example A6] Preparation of Hydrochloride of Intermediate N-Methyl-5-(piperazin-1-yl)thiazole-2-carboxamide Hydrochloride (Int-A13)

[0128] [Chemical Formula] Step 1: Preparation of Compound 5-Bromo-N-methylthiazole-2-carboxamide (Int-A13b) Compound Int-A13a (3.0 g, 14.4 mmol) and methylamine hydrochloride (1.46 g, 21.6 mmol) were dissolved in N,N-dimethylformamide (30 mL), DIPEA (4.64 g, 36.0 mmol) and HATU (13.69 g, 36.0 mmol) were added at 0 °C, and the reaction system was warmed to room temperature for the reaction. After monitoring by LCMS that the reaction was completed, water (50 mL) was added to quench the reaction, and then extraction was performed 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound (Int-A13b) (2.5 g, yield: 79%). MS m / z (ES): 220.9 [M+H]

[0129] Step 2: Preparation of compound tert-butyl 4-(2-(methylcarbamoyl)thiazol-5-yl)piperazine-1-carboxylate (Int-A13c) Compound Int-A13b (300 mg, 1.36 mmol), tert-butyl piperazine-1-carboxylate (454 mg, 2.04 mmol) and cesium carbonate (1.33 g, 4.08 mmol) were dissolved in N,N-dimethylformamide (5 mL), the reaction system was heated to 120 °C and stirred. After monitoring by LCMS that the reaction was completed, water (10 mL) was added thereto to quench the reaction, and then extraction was performed 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-A13c (70 mg, yield: 16%). MS m / z (ES): 327.0 [M+H] + .

[0130] Step 3: Preparation of hydrochloride salt of compound N-methyl-5-(piperazin-1-yl)thiazole-2-carboxamide (Int-A13) Compound Int-A13c (70 mg, 0.21 mmol) was dissolved in MeOH (5 mL), and a 1,4-dioxane solution of HCl (4 M, 0.53 mL, 2.1 mmol) was added, followed by stirring at room temperature. After monitoring the completion of the reaction by LCMS, the reaction solution was concentrated to obtain a crude product (60 mg) of the title compound Int-A13, and the obtained crude product was directly used in the next reaction without further purification. MS m / z (ES): 227.0 [M+H] + .

[0131] [Example A7] Preparation of hydrochloride of intermediate N-methyl-2-(piperazin-1-yl)thiazole-5-carboxamide (Int-A14)

[0132]

Chemical formula

[0133] [Example A8] Preparation of hydrochloride of intermediate N-cyclopropyl-5-(piperazin-1-yl)picolinamide (Int-A15)

[0134]

Chemical formula

[0135] [Example A9] Preparation of hydrochloride salt of intermediate 1-(6-(difluoromethyl)-2-methylpyridin-3-yl)piperazine (Int-A17)

[0136]

Chemical formula

[0137] Steps 2 to 3: Preparation of hydrochloride salt of intermediate 1-(6-(difluoromethyl)-2-methylpyridin-3-yl)piperazine (Int-A17) The crude product of the hydrochloride salt of the title compound Int-A17 was synthesized in the same manner as described in Steps 1 to 2 of Example A3, except that compound Int-A17b was used instead of compound Int-A3a in Step 1 of Example A3, and tert-butyl piperazine-1-carboxylate was used instead of tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in Step 1 of Example A3. The obtained crude product was used directly in the next reaction without further purification. MS m / z (ES): 228.1 [M+H] + .

[0138] [Example A10] Preparation of the hydrochloride salt of intermediate 2-fluoro-4-(piperazin-1-yl)benzonitrile (Int-A20)

[0139]

Chemical formula

[0140] Step 2: Preparation of compound 2-fluoro-4-(piperazin-1-yl)benzonitrile (Int-A20) Compound Int-A20b (2.2 g, 7.2 mmol) was dissolved in a 1,4-dioxane solution (10 mL), and a 1,4-dioxane solution of HCl (4 M, 15 mL, 60 mmol) was added thereto at 0 °C, then slowly warmed to room temperature and stirred. After the reaction was completed, petroleum ether was added to the reaction system for dilution. The solid was precipitated from the system, filtered, and washed with petroleum ether. The solid was collected and subjected to vacuum drying to obtain the hydrochloride salt of the title compound Int-A20 (1.5 g, yield: 86%). MS m / z (ES): 206.1 [M+H] + .

[0141] [Example A11] Preparation of hydrochloride salt of intermediate 2-(piperazin-1-yl)thiazole-5-carbonitrile (Int-A21)

[0142] [Chemical formula] Step 1: Preparation of compound tert-butyl 4-(5-cyanothiazol-2-yl)piperazine-1-carboxylate (Int-A21b) Compound Int-A21a (2.1 g, 11.0 mmol), tert-butyl piperazine-1-carboxylate (2.5 g, 13.1 mmol) and cesium carbonate (10.7 g, 32.9 mmol) were weighed into a round-bottom flask, 1,4-dioxane (30 mL) was added, and the reaction system was heated to 110 °C and reacted overnight. After the reaction was completed, water and ethyl acetate were added to the reaction system for dilution and liquid separation. The aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The filtrate was concentrated to obtain a crude product of the compound. The obtained crude product was purified by silica gel column to obtain the title compound Int-A21b (2.6 g, yield: 80%). MS m / z (ES): 295.1 [M+H] + .

[0143] Step 2: Preparation of Intermediate 2-(Piperazin-1-yl)thiazole-5-carbonitrile (Int-A21) A crude product of the hydrochloride salt of the title compound Int-A21 was synthesized by a method similar to that described in Step 2 of Example A10, except that compound Int-A21b was used instead of Int-A20b in Step 2 of Example A10. The obtained crude product was directly used in the next reaction without further purification. MS m / z (ES): 195.1 [M+H] + .

[0144] [Example A12] Preparation of the hydrochloride salt of Intermediate N-(2-Methoxyethyl)-6-methyl-5-(piperazin-1-yl)picolylamide (Int-A22)

[0145] [Chemical formula] Step 1: Preparation of Compound 5-Bromo-N-(2-methoxyethyl)-6-methylpicolylamide (Int-A22b) Compound Int-A22a (5.0 g, 23.1 mmol), 2-methoxyethylamine (3.48 g, 46.3 mmol), HATU (17.6 g, 46.3 mmol) and DIPEA (5.97 g, 46.3 mmol) were dissolved in DMF (40 mL), and the reaction system was stirred at room temperature. After monitoring the completion of the reaction by LCMS, water (50 mL) was added thereto to quench the reaction, and then extraction was performed 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-A22b (5.3 g, yield: 73%). MS m / z (ES): 273.0 [M+H] + .

[0146] Steps 2 - 3: Preparation of Intermediate N-(2-Methoxyethyl)-6-methyl-5-(piperazin-1-yl)picolylamide (Int-A22) The crude product of the hydrochloride salt of the title compound Int-A22 was synthesized by the same method as described in Steps 1 - 2 of Example A3, except that compound Int-A22b was used instead of Int-A3a in Step 1 of Example A3. The obtained crude product was directly used in the next reaction without further purification. MS m / z (ES): 279.1 [M+H] + .

[0147] Referring to the synthesis method in Example A12, the following intermediate compounds were synthesized under the same reaction conditions.

[0148]

Table 3

[0149] [Example B] Preparation of 7-(Bromomethyl)-5-fluoro-3-methylquinoxalin-2(1H)-one (Int-2) Route 1:

[0150]

Chem.

[0151] Step 2: Preparation of Compound 7-Bromo-5-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-2c) Compound Int-2b (3.50 g, 10.9 mmol) and sodium dithionite (5.70 g, 32.7 mmol) were dissolved in DMSO (80 mL), and the reaction system was heated to 120 °C and reacted for 4 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, water (200 mL) was slowly added thereto to quench the reaction, and then extraction with ethyl acetate was carried out 3 times. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-2c (734 mg, yield: 26%). MS m / z (ES): 259.0 [M+H] + .

[0152] Step 3: Preparation of Compound 7-Bromo-5-fluoro-3-methylquinolin-2(1H)-one (Int-2d) Compound Int-2c (700 mg, 2.70 mmol) and DDQ (683 mg, 3.01 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution (20 mL) was added to the obtained solid crude product. After stirring for 2 hours, it was filtered and washed with water and saturated sodium bicarbonate solution to obtain the title compound Int-2d (624 mg, yield: 90%). MS m / z (ES): 257.0 [M+H] + .

[0153] Step 4: Preparation of Compound 5-Fluoro-3-methyl-7-vinylquinolin-2(1H)-one (Int-2e) Compound Int-2d (300 g, 1.17 mmol) and tributylvinyltin (740 mg, 2.33 mmol) were dissolved in toluene (10 mL), Pd(PPh3)4 (136 mg, 0.12 mmol) was added under N2 protection, and the mixture was heated to 100 °C and reacted overnight. The reaction solution was concentrated to obtain a crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-2e (228 mg, yield: 95%). MS m / z (ES): 205.1 [M+H] + .

[0154] Step 5: Preparation of compound 8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (Int-2f) Compound Int-2e (800 mg, 3.86 mmol), potassium osmate dihydrate (60 mg, 0.193 mmol), 2,6-dimethylpyridine (0.9 mL, 7.72 mmol) and NaIO4 (4.13 g, 19.3 mmol) were dissolved in THF (30 mL) and water (20 mL), and reacted overnight at room temperature. When the reaction was complete, a saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, and then extraction with dichloromethane was carried out 3 times. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-2f (711 mg, yield: 89%). MS m / z (ES): 207.1 [M+H] + .

[0155] Step 6: Preparation of compound 5-fluoro-7-hydroxymethyl-3-methylquinoxalin-2(1H)-one (Int-2g) At 0 °C, compound Int-2f (700 mg, 3.35 mmol) was dissolved in methanol (20 mL), and NaBH4 (253 mg, 6.70 mmol) was added. After the addition was complete, the reaction was carried out at 0 °C for 1 hour. When the reaction was complete, water (2 mL) was slowly added thereto to quench the reaction at 0 °C, and the reaction solution was concentrated to obtain a crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-2g (504 mg, yield: 72%). MS m / z (ES): 209.1 [M+H] + .

[0156] Step 7: Preparation of compound 7-(bromomethyl)-5-fluoro-3-methylquinoxalin-2(1H)-one (Int-2) At 0 °C, compound Int-2 (600 mg, 2.87 mmol), carbon tetrabromide (1.90 g, 5.74 mmol) and PPh3 (1.51 g, 5.74 mmol) were dissolved in DCM (30 mL) and stirred at 0 °C. When the reaction was complete, the reaction solution was concentrated to obtain a crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-2 (163 mg, yield: 21%). MS m / z (ES): 271.0 [M+H] + .

[0157] Route 2:

[0158]

Chemical Structure

[0159] Step 2: Preparation of Compound 7-Bromo-5-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-2c) Compound Int-2b (6.20 g, 19.4 mmol) and NH4Cl (20.7 g, 388 mmol) were dissolved in MeOH / H2O (70 mL / 7 mL). The reaction system was cooled to 0 °C, zinc powder was added. After the addition was complete, the reaction system was warmed to 25 °C and reacted for 6 hours. When the reaction was complete, the reaction system was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain the crude product of the compound. The obtained crude product of compound Int-2-3 (4.7 g) was directly used in the next reaction. MS m / z (ES): 259.0 [M+H] + .

[0160] Step 3: Preparation of Compound 7-Bromo-5-fluoro-3-methylquinolin-2(1H)-one (Int-2d) The crude product of the compound was obtained by the same procedure as in Step 3 of Route 1. The obtained crude product of the compound was purified by column chromatography to obtain Int-2d (2.5 g, two-step yield: 50%). MS m / z (ES): 257.0 [M+H] + .

[0161] Step 4: Preparation of Compound 5-Fluoro-7-hydroxymethyl-3-methylquinoxalin-2(1H)-one (Int-2g) Compound Int-2d (300 mg, 1.17 mmol) and (tributylstannyl)methanol (450 mg, 1.41 mmol) were dissolved in dioxane (10 mL). Xphos Pd G2 (92 mg, 0.12 mmol) was added under N2 protection, heated to 80 °C, stirred and reacted overnight. The reaction solution was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-2g (190 mg, yield: 78%). MS m / z (ES): 209.1 [M+H] + .

[0162] Step 5: Preparation of Compound 7-(Bromomethyl)-5-fluoro-3-methylquinoxalin-2(1H)-one (Int-2) The crude product of the compound was obtained by the same procedure as in Step 7 of Route 1. The obtained crude product of the compound was purified by column chromatography to obtain Int-2 (148 mg, yield: 60%). MS m / z (ES): 271.0 [M+H] + .

[0163] [Example C] Preparation of 5-Bromo-7-(bromomethyl)-3-methylquinoxalin-2(1H)-one (Int-3)

[0164] [Chemical formula] Step 1: Preparation of Compound Methyl 3-Bromo-4-fluoro-5-nitrobenzoate (Int-3b) At 0 °C, Compound Int-3a (5.0 g, 18.9 mmol) was dissolved in MeOH (100 mL), and then SOCl2 (4.1 mL, 56.7 mmol) was added dropwise thereto. The reaction system was warmed to room temperature and reacted overnight. After the reaction was completed, saturated sodium bicarbonate (200 mL) was added at 0 °C for dilution, extraction was performed 3 times with ethyl acetate, drying was performed with anhydrous sodium sulfate, filtration was performed, and the filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-3b (4.47 g, yield: 86%). MS m / z (ES): 278.0 [M+H] + .

[0165] Step 2: Preparation of Compound Methyl 3-Bromo-4-(1-methoxy-1-oxopropan-2-yl)amino-5-nitrobenzoate (Int-3c) Compound Int-3b (4.4 g, 15.8 mmol), methyl alaninate hydrochloride (4.41 g, 31.6 mmol), and NaHCO3 (4.0 g, 47.4 mmol) were dissolved in THF (70 mL). The reaction system was allowed to react overnight at room temperature. After the reaction was completed, water (150 mL) was added for dilution, and extraction was performed 3 times with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-3c (5.1 g, yield: 89%). MS m / z (ES): 361.0 [M+H] + .

[0166] Steps 3 to 4: Preparation of compound methyl 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Int-3e) A crude product of compound Int-3e was synthesized in the same manner as described in Steps 2 to 3 of Example B, except that compound Int-3c was used instead of compound Int-2b in Step 2 of Example B. The obtained crude product was purified by column chromatography to obtain the title compound Int-3e (1.4 g, yield: 25%). MS m / z (ES): 297.0 [M+H] + .

[0167] Step 5: Preparation of compound 5-bromo-7-hydroxymethyl-3-methylquinoxalin-2(1H)-one (Int-3f) Compound (Int-3e) (400 mg, 1.34 mmol) was dissolved in DCM (10 mL). After cooling the reaction solution to 0 °C, DIBAL-H (1 M in hexane, 4.04 mL, 4.04 mmol) was added to the reaction system. After the addition was complete, the reaction was carried out overnight at room temperature. After the reaction was complete, a saturated aqueous solution of sodium potassium tartrate (40 mL) was added to the reaction system at 0 °C to quench the reaction, and dichloromethane was added for liquid separation. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by silica gel column to obtain the title compound (Int-3f) (220 mg, yield: 61%). MS m / z (ES): 269.0 [M+H] + .

[0168] Step 6: Preparation of compound 5-bromo-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (Int-3) A crude product of compound Int-3 was synthesized by the same method as described in Step 7 of Example B, except that compound Int-3f was used instead of compound Int-2g in Step 7 of Example B. The obtained crude product was purified by preparative silica gel plate to obtain the title compound Int-3 (120 mg, yield: 31%). MS m / z (ES): 471.1 [M+H] + .

[0169] [Example D] Preparation of compound 7-(bromomethyl)-5,6-difluoro-3-methylquinoxalin-2(1H)-one (Int-4)

[0170]

Chemical Structure

[0171] Step 2: Preparation of compound methyl 7,8-difluoro-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Int-4c) The crude product of compound Int-4b (5.41 g, 17.0 mmol) and sodium dithionite (8.87 g, 51.0 mmol) were dissolved in DMSO (80 mL), and the reaction system was heated to 120 °C and stirred. After the reaction was completed, the reaction solution was cooled to 0 °C, water (200 mL) was slowly added thereto to quench the reaction, and then extraction was performed 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-4c (1.63 g, 2-step yield: 37%). MS m / z (ES): 257.0 [M+H] + .

[0172] Step 3: Preparation of compound methyl 7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Int-4d) Compound (Int-4c) (1.63 g, 6.36 mmol) and DDQ (1.6 g, 7.00 mmol) were dissolved in 1,4-dioxane (40 mL) and stirred at room temperature. After the reaction was completed, the reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution (20 mL) was added to the obtained solid crude product. After stirring for 2 hours, it was filtered. The filter cake was washed with water and saturated sodium bicarbonate solution. The solid was collected and dried to obtain the title compound Int-4d (1.17 g, yield: 72%). MS m / z (ES): 255.0 [M+H] + .

[0173] Step 4: Preparation of compound 5,6-difluoro-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (Int-4e) Compound (Int-4d) (1.17 g, 4.60 mmol) was dissolved in DCM (30 mL), cooled to 0 °C in an ice-water bath, and then DIBAL-H (1 M in toluene, 13.8 mL, 13.8 mmol) was added to the reaction system. After the addition was completed, stirring was carried out at 0 °C. After the reaction was completed, saturated aqueous sodium potassium tartrate solution (40 mL) was added to the reaction system at 0 °C to quench the reaction, dichloromethane was added for dilution, and stirring was carried out for 30 minutes for liquid separation. The aqueous phase was extracted 3 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The filtrate was concentrated to obtain the crude product of the compound. The obtained crude product was purified by silica gel column to obtain the title compound (Int-4e) (800 mg, yield: 77%). MS m / z (ES): 227.0 [M+H] + .

[0174] Step 5: Preparation of compound 7-(bromomethyl)-5,6-difluoro-3-methylquinoxalin-2(1H)-one (Int-4) At 0 °C, PPh3 (401 mg, 1.53 mmol) was added to a solution of compound Int-4e (115 mg, 0.51 mmol) and carbon tetrabromide (505 mg, 1.53 mmol) in DCM (10 mL), and the reaction system was stirred at 0 °C. After the reaction was completed, the reaction solution was concentrated to obtain a crude product of the compound. The obtained crude product was purified by column chromatography to obtain the title compound Int-4 (110 mg, yield: 75%). MS m / z (ES): 289.0 [M+H] + .

[0175] [Example E] Preparation of 7-(Bromomethyl)-3,5-dimethylquinoxalin-2(1H)-one (Int-5)

[0176] [Chemical formula] Step 1: Preparation of compound methyl (4-bromo-2-methyl-6-nitrophenyl)-L-alaninate (Int-5b) Compound Int-5a (5.0 g, 21.4 mmol), methyl L-alaninate hydrochloride (4.47 g, 32.1 mmol) and DIPEA (14.6 mL, 84.0 mmol) were dissolved in 1,4-dioxane (70 mL), and the reaction system was heated to 110 °C for reaction and stirred. After the reaction was completed, the reaction system was cooled to room temperature, and water and ethyl acetate were added to the system for dilution and liquid separation. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and subjected to suction filtration. The filtrate was concentrated to obtain a crude product (6.6 g) of the title compound (Int-5b). The obtained crude product was directly used in the next reaction without further purification. MS m / z (ES): 317.0 [M+H] + .

[0177] Step 2: Preparation of compound (S)-7-bromo-3,5-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (Int-5c) The crude product of compound Int-5b (6.6 g, 20.8 mmol) was dissolved in THF / EtOH (100 mL / 100 mL), cooled to 0 °C, and tin dichloride (11.8 g, 62.2 mmol) was added under a nitrogen atmosphere. Then it was warmed to room temperature and stirred. After the reaction was completed, the reaction solution was concentrated, and the residue was diluted with water and dichloromethane. Subsequently, the pH of the aqueous phase was adjusted to 9 - 10 with saturated sodium bicarbonate solution. Filtration was carried out through diatomaceous earth to remove insoluble substances. The filter cake was washed with dichloromethane. The filtrate was subjected to liquid separation. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product (4.2 g) of the title compound Int-5c. The obtained crude product was directly used in the next reaction without further purification. MS m / z (ES): 255.0 [M+H] + .

[0178] Step 3: Preparation of compound 7-bromo-3,5-dimethylquinoxalin-2(1H)-one (Int-5d) The crude product of compound Int-5c (4.2 g, 16.5 mmol) was dissolved in dichloromethane (100 mL), and manganese dioxide (7.2 g, 82.8 mmol) was added and reacted at room temperature overnight. After the reaction was completed, filtration was carried out through diatomaceous earth. The filter cake was washed three times with methanol. The filtrate was concentrated to dryness to obtain the crude product (4.0 g) of the title compound Int-5d. The obtained crude product was directly used in the next reaction without further purification. MS m / z (ES): 253.0 [M+H] + .

[0179] Steps 4 - 5: Preparation of compound 7-(bromomethyl)-3,5-dimethylquinoxalin-2(1H)-one (Int-5) The crude product of compound Int-5 was synthesized by the same method as described in Steps 4 to 5 of Route 2 of Example B, except that compound Int-5d was used instead of compound Int-2d in Step 4 of Route 2 of Example B. The obtained crude product was purified by column chromatography to obtain the title compound Int-5 (760 mg, 5-step yield: 13%). MS m / z (ES): 267.0 [M+H] + .

[0180] [Example F] Preparation of Compound 7-(Bromomethyl)-3,6-dimethylquinoxalin-2(1H)-one (Int-6)

[0181]

Chemical Structure

[0182] Steps 4 to 5: Preparation of Compound 7-(Bromomethyl)-3,6-dimethylquinoxalin-2(1H)-one (Int-6) The crude product of compound Int-6 was synthesized by the same method as described in Steps 4 to 5 of Example D, except that compound Int-6d was used instead of compound Int-4d in Step 4 of Example D. The obtained crude product was purified by column chromatography to obtain the title compound Int-6 (101 mg, 2-step yield: 41%). MS m / z (ES): 267.0 [M+H] + .

[0183] [Example G] Preparation of Compound 7-(Bromomethyl)-5-chloro-3-methylquinoxalin-2(1H)-one (Int-9)

[0184] [Chemical formula] Steps 1 to 2: Preparation of Compound (S)-7-bromo-5-chloro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-9c) The crude product (2.41 g) of compound Int-9c was synthesized by the same method as described in Steps 1 to 2 of Route 2 of Example B, except that compound Int-9a was used instead of compound Int-2a in Step 1 of Route 2 of Example B. The obtained crude product was used directly in the next step without further purification. MS m / z (ES): 274.9 [M+H] + .

[0185] Step 3: Preparation of Compound (S)-5-chloro-7-hydroxymethyl-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-9d) The crude product of compound Int-9d was synthesized by the same method as described in Step 4 of Route 2 of Example B, except that compound Int-9c was used instead of compound Int-2d in Step 4 of Route 2 of Example B. The obtained crude product was purified by column chromatography to obtain the title compound Int-9d (157 mg, 3-step yield: 35%). MS m / z (ES): 227.0 [M+H] + .

[0186] Step 4: Preparation of compound 5-chloro-7-hydroxymethyl-3-methylquinoxalin-2(1H)-one (Int-9e) The crude product of compound Int-9e was synthesized by a method similar to that described in Step 3 of Route 2 of Example B, except that compound Int-9d was used instead of compound Int-2c in Step 3 of Route 2 of Example B. The obtained crude product was purified by column chromatography to obtain the title compound Int-9e (53 mg, yield: 34%). MS m / z (ES): 225.0 [M+H] + .

[0187] Step 5: Preparation of compound 7-(bromomethyl)-5-chloro-3-methylquinoxalin-2(1H)-one (Int-9) The crude product of compound Int-9 was synthesized by a method similar to that described in Step 5 of Route 2 of Example B, except that compound Int-9e was used instead of compound Int-2g in Step 5 of Route 2 of Example B. The obtained crude product was purified by column chromatography to obtain the title compound Int-9 (64 mg, yield: 93%). MS m / z (ES): 286.9 [M+H] + .

[0188] With reference to the synthesis methods in Examples B to G, the following intermediate compounds were synthesized under the same reaction conditions.

[0189]

Table 4

[0190] [Example 1] Preparation of 5-(4-(8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (1)

[0191] [Chemical formula] Step 1: Preparation of 5-(4-(8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (1) Compound Int-2 (50 mg, 0.185 mmol), compound Int-1 (41 mg, 0.185 mmol) and DIPEA (0.10 mL, 0.57 mmol) were dissolved in acetonitrile (4 mL). The reaction system was heated to 70 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product of the compound. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 1 (21.04 mg, yield: 28%). MS m / z (ES): 411.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.40 (q, J = 4.4 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1H), 7.13 - 7.06 (m, 2H), 3.60 (s, 2H), 3.39 - 3.31 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H), 2.59 - 2.53 (m, 4H), 2.41 (s, 3H).

[0192] [Example 2] Preparation of 5-(4-((8-Bromo-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (2)

[0193] [Chemical formula] The crude product of Compound 2 was synthesized in the same manner as described in Example 1, except that Compound Int-3 was used instead of Compound Int-2 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 2 (9.33 mg). MS m / z (ES): 471.1 [M+H] + .

[0194] [Example 3] Preparation of 5-(6-(8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-N,6-dimethylpicolinamide (3)

[0195] [Chemical formula] The crude product of Compound 3 was synthesized in the same manner as described in Example 1, except that Compound Int-A2 was used instead of Compound Int-1 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 3 (8.04 mg). MS m / z (ES): 437.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (q, J = 5.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 7.04 (d, J = 12.4 Hz, 1H), 3.72 - 3.61 (m, 6H), 3.39 (d, J = 10.8 Hz, 2H), 2.81 (d, J = 4.8 Hz, 3H), 2.63 (s, 3H), 2.53 - 2.51 (m, 1H), 2.37 (s, 3H), 1.86 (d, J = 8.0 Hz, 1H).

[0196] [Example 4] Preparation of compound 5-((1S,4S)-5-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N,6-dimethylpicolinamide (4)

[0197] [Chemical formula] A crude product of compound 4 was synthesized in the same manner as described in Example 1, except that compound Int-A4 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 4 (11.5 mg). MS m / z (ES): 437.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.29 (q, J = 4.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 7.05 (d, J = 12.8 Hz, 1H), 4.24 (s, 1H), 3.74 (s, 2H), 3.65 - 3.57 (m, 1H), 3.53 (s, 1H), 3.36 - 3.30 (m, 1H), 2.87 - 2.81 (m, 1H), 2.79 (d, J = 4.8 Hz, 3H), 2.77 - 2.71 (m, 1H), 2.51 (s, 3H), 2.39 (s, 3H), 1.97 -1.90 (m, 1H), 1.85 - 1.78 (m, 1H).

[0198] [Example 5] Preparation of compound 5-(6-(8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-methylpicolinamide (5)

[0199]

Chem.

[0200] [Example 6] Preparation of 5-(4-((8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (6)

[0201]

Chem.

[0202] [Example 7] Preparation of Compound 6-chloro-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (7)

[0203]

Chemical Structure

[0204] [Example 8] Preparation of compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (8)

[0205] [Chemical formula] The crude product of compound 8 was synthesized in the same manner as described in Example 1, except that compound Int-4 was used instead of compound Int-2 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 8 (8.11 mg). MS m / z (ES): 429.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.40 (q, J = 4.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1H), 7.08 - 7.04 (m, 1H), 3.68 (s, 2H), 3.39 - 3.31 (m, 4H), 2.78 (d, J = 4.8 Hz, 3H), 2.61 - 2.56 (m, 4H), 2.37 (s, 3H).

[0206] [Example 9] Preparation of Compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (9)

[0207]

Chemical Structure

[0208] [Example 10] Preparation of Compound 5-(4-((2,8-dimethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (10)

[0209]

Chemical Structure

[0210] [Example 11] Preparation of 3-ethyl-5-fluoro-7-((4-(6-(3-hydroxyoxetan-3-yl)-2-methylpyridin-3-yl)piperazin-1-yl)methyl)quinoxalin-2(1H)-one (11)

[0211]

Chemical formula

[0212] [Example 12] Preparation of compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methylpyridinonitrile (12)

[0213] [Chemical formula] Except for using compound Int-A18 instead of compound Int-1 in Example 1, the crude product of compound 12 was synthesized by the same method as described in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 12 (45.17 mg). MS m / z (ES): 393.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.12 - 7.07 (m, 2H), 3.62 (s, 2H), 3.05 - 2.97 (m, 4H), 2.63 - 2.54 (m, 4H), 2.46 (s, 3H), 2.41 (s, 3H).

[0214] [Example 13] Preparation of Compound 5-(4-((8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinonitrile (13)

[0215]

Chem.

[0216] [Example 14] Preparation of Compound 5-(4-((8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methoxy-N-methylpicolinamide (14)

[0217]

Chem.

[0218] [Example 15] Preparation of compound 4-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylthiazole-2-carboxamide (15)

[0219] [Chemical formula] Except for using compound Int-A12 instead of compound Int-1 in Example 1, the crude product of compound 15 was synthesized by the same method as described in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 15 (12.8 mg). MS m / z (ES): 417.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.54 (q, J = 4.4 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.57 (s, 1H), 3.60 (s, 2H), 3.32 - 3.26 (m, 4H), 2.77 (d, J = 4.8 Hz, 3H), 2.56 - 2.52 (m, 4H), 2.41 (s, 3H).

[0220] [Example 16] Preparation of compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylthiazole-2-carboxamide (16)

[0221] [Chemical formula] A crude product of compound 16 was synthesized in the same manner as described in Example 1, except that compound Int-A13 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 16 (15.78 mg). MS m / z (ES): 417.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.38 (q, J = 4.4 Hz, 1H), 7.13 (s, 1H), 7.11 - 7.05 (m, 2H), 3.60 (s, 2H), 3.27 - 3.18 (m, 4H), 2.74 (d, J = 4.8 Hz, 3H), 2.59 - 2.53 (m, 4H), 2.41 (s, 3H).

[0222] [Example 17] Preparation of compound 2-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide (17)

[0223] [Chemical formula] A crude product of compound 17 was synthesized in the same manner as described in Example 1, except that compound Int-A14 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 17 (15.78 mg). MS m / z (ES): 417.1 [M+H] + .

[0224] [Example 18] Preparation of compound 2-fluoro-4-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)benzonitrile (18)

[0225] [Chemical formula] The crude product of compound 18 was synthesized in the same manner as described in Example 1, except that compound Int-A20 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 18 (5.92 mg). MS m / z (ES): 396.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.95 (dd, J = 14.0, 2.4 Hz, 1H), 6.85 (dd, J = 9.2, 2.4 Hz, 1H), 3.59 (s, 2H), 3.44 - 3.36 (m, 4H), 2.51 - 2.47 (m, 4H), 2.41 (s, 3H).

[0226] [Example 19] Preparation of compound 4-(4-((2,8-dimethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-2-fluorobenzonitrile (19)

[0227] [Chemical formula] A crude product of compound 19 was synthesized in the same manner as described in Example 18, except that compound Int-5 was used instead of compound Int-2 in Example 18. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 19 (4.63 mg). MS m / z (ES): 392.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 7.62 - 7.56 (m, 1H), 7.12 - 7.07 (m, 2H), 6.94 (dd, J = 14.0, 2.4 Hz, 1H), 6.85 (dd, J = 9.2, 2.4 Hz, 1H), 3.54 (s, 2H), 3.43 - 3.36 (m, 4H), 2.54 (s, 3H), 2.51 - 2.45 (m, 4H), 2.41 (s, 3H).

[0228] [Example 20] Preparation of Compound N-Cyclopropyl-5-(4-((8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide (20)

[0229]

Chemical Structure

[0230] [Example 21] Preparation of compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)-6-methylpicolinamide (21)

[0231] [Chemical formula] The crude product of compound 21 was synthesized by the same method as described in Example 1, except that compound Int-A22 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 21 (4.0 mg). MS m / z (ES): 469.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.44 - 8.35 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.14 - 7.06 (m, 2H), 3.62 (s, 2H), 3.49 - 3.42 (m, 4H), 3.27 (s, 3H), 3.04 - 2.89 (m, 4H), 2.64 - 2.55 (m, 4H), 2.49 (s, 3H), 2.41 (s, 3H).

[0232] [Example 22] Preparation of compound 5-(4-((2,8-dimethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)-6-methylpicolinamide (22)

[0233] [Chemical formula] The crude product of compound 22 was synthesized in the same manner as described in Example 21, except that compound Int-5 was used instead of compound Int-2 in Example 21. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 22 (10.0 mg). MS m / z (ES): 465.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 8.43 - 8.36 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 7.11 (s, 1H), 3.58 (s, 2H), 3.49 - 3.41 (m, 4H), 3.27 (s, 3H), 3.00 - 2.91 (m, 4H), 2.62 - 2.53 (m, 4H), 2.55 (s, 3H), 2.41 (s, 3H).

[0234] [Example 23] Preparation of compound 2-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)thiazole-5-carbonitrile (23)

[0235] [Chemical formula] A crude product of compound 23 was synthesized in the same manner as described in Example 1, except that compound Int-A21 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 23 (4.0 mg). MS m / z (ES): 385.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.02 (s, 1H), 7.12 - 7.05 (m, 2H), 3.61 (s, 2H), 3.59 - 3.53 (m, 4H), 2.57 - 2.50 (m, 4H), 2.41 (s, 3H).

[0236] [Example 24] Preparation of compound (S)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl)-N-methylpicolinamide (24)

[0237] [Chemical formula] A crude product of compound 24 was synthesized in the same manner as described in Example 1, except that compound Int-A11 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 24 (7.00 mg). MS m / z (ES): 425.2 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.36 (q, J = 4.8 Hz, 1H), 8.21 (d, J = 3.0 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 9.0, 3.0 Hz, 1H), 7.13 (s, 1H), 7.11 (d, J = 11.4 Hz, 1H), 4.25 - 4.20 (m, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.60 (d, J = 12.0 Hz, 1H), 3.52 (d, J = 14.4 Hz, 1H), 3.10 (td, J = 12.0, 3.6 Hz, 1H), 2.92 (d, J = 10.2 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.72 (d, J = 10.8 Hz, 1H), 2.41 (s, 3H), 2.33 (dd, J = 11.4, 3.6 Hz, 1H), 2.22 (td, J = 11.4, 3.6 Hz, 1H), 1.15 (d, J = 6.0 Hz, 3H).

[0238] [Example 25] Preparation of compound (R)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl)-N-methylpicolinamide (25)

[0239] [Chemical formula] The crude product of compound 25 was synthesized by the same method as described in Example 1, except that compound Int-A5 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 25 (3.66 mg). MS m / z (ES): 425.2 [M+H] + . 11H NMR (600 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.36 (q, J = 4.8 Hz, 1H), 8.21 (d, J = 3.0 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 9.0, 3.0 Hz, 1H), 7.13 (s, 1H), 7.11 (d, J = 11.4 Hz, 1H), 4.25 - 4.20 (m, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.60 (d, J = 12.0 Hz, 1H), 3.52 (d, J = 14.4 Hz, 1H), 3.10 (td, J = 12.0, 3.6 Hz, 1H), 2.92 (d, J = 10.2 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.72 (d, J = 10.8 Hz, 1H), 2.41 (s, 3H), 2.33 (dd, J = 11.4, 3.6 Hz, 1H), 2.22 (td, J = 11.4, 3.6 Hz, 1H), 1.15 (d, J = 6.0 Hz, 3H).

[0240] [Example 26] Preparation of Compound 7-((4-(6-(Difluoromethyl)-2-methylpyridin-3-yl)piperazin-1-yl)methyl)-5-fluoro-3-methylquinoxalin-2(1H)-one (26)

[0241] [Chemical Structure] The crude product of Compound 26 was synthesized by the same method as described in Example 1, except that Compound Int-A17 was used instead of Compound Int-1 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 26 (12.62 mg). MS m / z (ES): 418.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.81 (t, J = 55.2 Hz, 1H), 3.61 (s, 2H), 3.00 - 2.89 (m, 4H), 2.65 - 2.53 (m, 4H), 2.46 (s, 3H), 2.40 (s, 3H).

[0242] [Example 27] Preparation of compound 7-((4-(6-(difluoromethyl)pyridin-3-yl)piperazin-1-yl)methyl)-5-fluoro-3-methylquinoxalin-2(1H)-one (27)

[0243] [Chemical formula] The crude product of compound 27 was synthesized by the same method as described in Example 1, except that compound Int-A16 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 27 (50.20 mg). MS m / z (ES): 403.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.81 (t, J = 55.2 Hz, 1H), 3.60 (s, 2H), 3.36 - 3.29 (m, 4H), 2.59 - 2.52 (m, 4H), 2.41 (s, 3H).

[0244] [Example 28] Preparation of compound N-(2,2-difluoroethyl)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (28)

[0245]

Chem.

[0246] [Example 29] Preparation of compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-fluoroethyl)-6-methylpicolinamide (29)

[0247]

Chem.

[0248] [Example 30] Preparation of 5-(4-((2-Ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-fluoroethyl)-6-methylpicolinamide (30)

[0249] [Chemical formula] A crude product of compound 30 was synthesized by the same method as described in Example 29, except that compound Int-7 was used instead of compound Int-2 in Example 29. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 30 (9.83 mg). MS m / z (ES): 471.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.15 - 7.07 (m, 2H), 4.54 (dt, J = 47.6, 5.2 Hz, 2H), 3.68 - 3.50 (m, 4H), 3.02 - 2.91 (m, 4H), 2.81 (q, J = 7.4 Hz, 2H), 2.65 - 2.55 (m, 4H), 2.51 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).

[0250] [Example 31] Preparation of compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)-6-methylpicolinamide (31)

[0251] [Chemical formula] The crude product of compound 31 was synthesized in the same manner as described in Example 30, except that compound Int-A26 was used instead of compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 31 (5.80 mg). MS m / z (ES): 469.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.40 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.09 - 7.00 (m, 2H), 4.79 (s, 1H), 3.62 (s, 2H), 3.54 - 3.47 (m, 2H), 3.39 - 3.33 (m, 2H), 3.01 - 2.91 (m, 4H), 2.79 (q, J = 7.2 Hz, 2H), 2.64 - 2.55 (m, 4H), 2.49 (s, 3H), 1.21 (t, J = 7.6 Hz, 3H).

[0252] [Example 32] Preparation of compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (32)

[0253] [Chemical formula] The crude product of compound 32 was synthesized in the same manner as described in Example 30, except that compound Int-A7 was used instead of compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 32 (9.00 mg). MS m / z (ES): 439.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.41 (q, J = 4.8 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J = 11.2 Hz, 1H), 3.59 (s, 2H), 3.00 - 2.90 (m, 4H), 2.80 (d, J = 4.8 Hz, 3H), 2.76 (q, J = 7.6 Hz, 2H), 2.63 - 2.54 (m, 4H), 2.48 (s, 3H), 1.19 (t, J = 7.6 Hz, 3H).

[0254] [Example 33] Preparation of compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(oxetan-3-ylmethyl)picolinamide (33)

[0255] [Chemical formula] The crude product of compound 33 was synthesized by the same method as described in Example 30, except that compound Int-A25 was used instead of compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 33 (6.6 mg). MS m / z (ES): 495.2 [M+H] + .

[0256] [Example 34] Preparation of compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)-6-methylpicolinamide (34)

[0257] [Chemical formula] The crude product of Compound 34 was synthesized in the same manner as described in Example 30, except that Compound Int-A22 was used instead of Compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 34 (13.70 mg). MS m / z (ES): 483.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.36 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.13 - 7.04 (m, 2H), 3.63 (s, 2H), 3.48 - 3.43 (m, 4H), 3.27 (s, 3H), 3.00 - 2.91 (m, 4H), 2.81 (q, J = 7.6 Hz, 2H), 2.65 - 2.55 (m, 4H), 2.50 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).

[0258] [Example 35] Preparation of Compound 4-(4-((2-Ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-2-fluorobenzonitrile (35)

[0259]

Chemical formula

[0260] [Example 36] Preparation of compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)-6-methylpicolinamide (36)

[0261] [Chemical formula] The crude product of compound 36 was synthesized in the same manner as described in Example 8, except that compound Int-A22 was used instead of compound Int-1 in Example 8. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 36 (13.58 mg). MS m / z (ES): 487.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.36 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 3.73 (s, 2H), 3.48 - 3.43 (m, 4H), 3.27 (s, 3H), 3.01 - 2.91 (m, 4H), 2.67 - 2.56 (m, 4H), 2.49 (s, 3H), 2.43 (s, 3H).

[0262] [Example 37] Preparation of compound 6-chloro-5-(4-((7-methoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (37)

[0263] [Chemical formula] The crude product of compound 37 was synthesized in the same manner as described in Example 7, except that compound Int-8 was used instead of compound Int-2 in Example 7. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 37 (1.06 mg). MS m / z (ES): 457.1 [M+H] + .

[0264] [Example 38] Preparation of compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,3-dimethylpicolinamide (38)

[0265] [Chemical formula] The crude product of compound 38 was synthesized in the same manner as described in Example 1, except that compound Int-A36 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 38 (9.72 mg). MS m / z (ES): 425.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.31 (q, J = 4.8 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.19 - 7.05 (m, 3H), 3.60 (s, 2H), 3.35 - 3.29 (m, 4H), 2.74 (d, J = 4.8 Hz, 3H), 2.60 - 2.51 (m, 7H), 2.41 (s, 3H).

[0266] [Example 39] Preparation of compound 3-fluoro-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (39)

[0267] [Chemical formula] A crude product of compound 39 was synthesized by the same method as described in Example 1, except that compound Int-A37 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 39 (2.81 mg). MS m / z (ES): 429.1 [M+H] + .

[0268] [Example 40] Preparation of compound 5-(4-((2,7-dimethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (40)

[0269] [Chemical formula] A crude product of compound 40 was synthesized by the same method as described in Example 6, except that compound Int-6 was used instead of compound Int-2 in Example 6. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 40 (1.35 mg). MS m / z (ES): 421.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.42 (q, J = 4.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 3.59 (s, 2H), 3.01 - 2.91 (m, 4H), 2.80 (d, J = 5.2 Hz, 3H), 2.65 - 2.55 (m, 4H), 2.50 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H).

[0270] [Example 41] Preparation of compound 5-(4-((7-methoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (41)

[0271] [Chemical formula] A crude product of compound 41 was synthesized in the same manner as described in Example 40, except that compound Int-8 was used instead of compound Int-6 in Example 40. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 41 (7.19 mg). MS m / z (ES): 437.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.42 (q, J = 4.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 3.85 (s, 3H), 3.63 (s, 2H), 3.02 - 2.91 (m, 4H), 2.80 (d, J = 4.8 Hz, 3H), 2.67 - 2.57 (m, 4H), 2.50 (s, 3H), 2.39 (s, 3H).

[0272] [Example 42] Preparation of compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(oxetan-3-yl)picolinamide (42)

[0273] [Chemical formula] The crude product of compound 42 was synthesized by the same method as described in Example 30, except that compound Int-A30 was used instead of compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 42 (8.23 mg). MS m / z (ES): 481.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.08 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.15 - 7.08 (m, 2H), 5.08 - 4.95 (m, 1H), 4.73 (t, J = 6.4 Hz, 2H), 4.66 (t, J = 6.8 Hz, 2H), 3.63 (s, 2H), 3.03 - 2.92 (m, 4H), 2.81 (q, J = 7.6 Hz, 2H), 2.66 - 2.56 (m, 4H), 2.53 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H).

[0274] [Example 43] Preparation of compound N-cyclopropyl-5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (43)

[0275] [Chemical formula] The crude product of compound 43 was synthesized by the same method as described in Example 30, except that compound Int-A29 was used instead of compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 43 (5.86 mg). MS m / z (ES): 465.2 [M+H] + .

[0276] [Example 44] Preparation of compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1s,3s)-3-hydroxycyclobutyl)-6-methylpicolinamide (44)

[0277] [Chemical formula] The crude product of Compound 44 was synthesized in the same manner as described in Example 30, except that Compound Int-A32 was used instead of Compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 44 (7.83 mg). MS m / z (ES): 495.2 [M+H] + .

[0278] [Example 45] Preparation of Compound 5-(4-((2-Ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((1r,3r)-3-hydroxycyclobutyl)-6-methylpicolinamide (45)

[0279] [Chemical formula] The crude product of Compound 45 was synthesized in the same manner as described in Example 30, except that Compound Int-A31 was used instead of Compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 45 (4.56 mg). MS m / z (ES): 495.2 [M+H] + .

[0280] [Example 46] Preparation of Compound (R)-5-(4-((8-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide (46)

[0281] [Chemical formula] A crude product of compound 46 was synthesized by the same method as described in Example 1, except that compound Int-A33 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 46 (2.38 mg). MS m / z (ES): 481.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.13 - 7.06 (m, 2H), 4.52 - 4.38 (m, 1H), 3.91 - 3.77 (m, 2H), 3.76 - 3.67 (m, 1H), 3.62 (s, 2H), 3.59 (dd, J = 8.8, 4.4 Hz, 1H), 3.03 - 2.91 (m, 4H), 2.64 - 2.55 (m, 4H), 2.50 (s, 3H), 2.41 (s, 3H), 2.23 - 2.11 (m, 1H), 1.99 - 1.88 (m, 1H).

[0282] [Example 47] Preparation of compound (R)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide (47)

[0283]

Chemical formula

[0284] [Example 48] Preparation of compound (R)-5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)-6-methylpicolinamide (48)

[0285] [Chemical formula] The crude product of compound 48 was synthesized in the same manner as described in Example 30, except that compound Int-A28 was used instead of compound Int-A24 in Example 30. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 48 (4.62 mg). MS m / z (ES): 483.2 [M+H] + .

[0286] [Example 49] Preparation of compound (S)-5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-hydroxypropyl)-6-methylpicolinamide (49)

[0287]

Chem.

[0288] [Example 50] Preparation of compound N-(2-hydroxyethyl)-5-(4-((7-methoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (50)

[0289]

Chem.

[0290] [Example 51] Preparation of compound 5-(4-((8-chloro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (51)

[0291] [Chemical formula] A crude product of Compound 51 was synthesized in the same manner as described in Example 40, except that Compound Int-9 was used instead of Compound Int-6 in Example 40. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 51 (3.19 mg). MS m / z (ES): 441.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (q, J = 5.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.08 - 6.98 (m, 2H), 3.55 (s, 2H), 3.02 - 2.87 (m, 4H), 2.80 (d, J = 4.8 Hz, 3H), 2.64 - 2.54 (m, 4H), 2.48 (s, 3H), 2.32 (s, 3H).

[0292] [Example 52] Preparation of Compound (R)-5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide (52)

[0293] [Chemical formula] A crude product of Compound 52 was synthesized in the same manner as described in Example 46, except that Compound Int-4 was used instead of Compound Int-2 in Example 46. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 52 (6.85 mg). MS m / z (ES): 499.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 4.4 Hz, 1H), 4.51 - 4.40 (m, 1H), 3.91 - 3.79 (m, 2H), 3.75 - 3.67 (m, 3H), 3.59 (dd, J = 8.8, 4.4 Hz, 1H), 3.01 - 2.89 (m, 4H), 2.67 - 2.58 (m, 4H), 2.50 (s, 3H), 2.40 (s, 3H), 2.23 - 2.11 (m, 1H), 2.00 - 1.88 (m, 1H).

[0294] [Example 53] Preparation of compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(oxetan-3-ylmethyl)picolinamide (53)

[0295] [Chemical formula] A crude product of compound 53 was synthesized in the same manner as described in Example 52, except that compound Int-A25 was used instead of compound Int-A33 in Example 52. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 53 (3.99 mg). MS m / z (ES): 499.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 5.2 Hz, 1H), 4.60 (dd, J = 7.6, 6.0 Hz, 2H), 4.34 (t, J = 6.0 Hz, 2H), 3.72 (s, 2H), 3.56 (t, J = 6.8 Hz, 2H), 3.21 - 3.12 (m, 1H), 3.01 - 2.89 (m, 4H), 2.67 - 2.58 (m, 4H), 2.50 (s, 3H), 2.42 (s, 3H).

[0296] [Example 54] Preparation of compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-fluoroethyl)-6-methylpicolinamide (54)

[0297] [Chemical formula] The crude product of compound 54 was synthesized by the same method as described in Example 52, except that compound Int-A24 was used instead of compound Int-A33 in Example 52. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 54 (8.88 mg). MS m / z (ES): 475.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.61 (t, J = 5.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 4.54 (dt, J = 47.6, 4.4 Hz, 2H), 3.67 - 3.52 (m, 4H), 3.08 - 2.88 (m, 4H), 2.77 - 2.57 (m, 4H), 2.51 (s, 3H), 2.44 (s, 3H).

[0298] [Example 55] Preparation of compound N-cyclopropyl-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methylpicolinamide (55)

[0299] [Chemical formula] A crude product of compound 55 was synthesized in the same manner as described in Example 1, except that compound Int-A29 was used instead of compound Int-1 in Example 1. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 55 (6.01 mg). MS m / z (ES): 451.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.32 (d, J = 4.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.14 - 7.06 (m, 2H), 3.62 (s, 2H), 3.03 - 2.91 (m, 4H), 2.89 - 2.80 (m, 1H), 2.63 - 2.55 (m, 4H), 2.48 (s, 3H), 2.41 (s, 3H), 0.72 - 0.66 (m, 2H), 0.66 - 0.60 (m, 2H).

[0300] [Example 56] Preparation of compound 5-(4-((2-cyclopropyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (56)

[0301] [Chemical formula] A crude product of compound 55 was synthesized in the same manner as described in Example 6, except that compound Int-10 was used instead of compound Int-2 in Example 6. The obtained crude product was purified by a preparative silica gel plate to obtain the title compound 55 (40.2 mg). MS m / z (ES): 451.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.46 - 8.37 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.12 - 7.02 (m, 2H), 3.61 (s, 2H), 3.01 - 2.89 (m, 4H), 2.80 (d, J = 4.8 Hz, 3H), 2.73 - 2.64 (m, 1H), 2.63 - 2.54 (m, 4H), 2.49 (s, 3H), 1.12 - 1.03 (m, 4H).

[0302] [Example 57] Preparation of compound 6-chloro-5-(4-((2-cyclopropyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (57)

[0303] [Chemical formula] The crude product of compound 57 was synthesized in the same manner as described in Example 56, except that compound Int-A8 was used instead of compound Int-A7 in Example 56. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 57 (13.4 mg). MS m / z (ES): 471.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.46 - 8.38 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.11 - 7.04 (m, 2H), 3.61 (s, 2H), 3.20 - 3.04 (m, 4H), 2.79 (d, J = 4.8 Hz, 3H), 2.73 - 2.64 (m, 1H), 2.63 - 2.54 (m, 4H), 1.12 - 1.03 (m, 4H).

[0304] Pharmacological test evaluation Test Example 1: Proliferation inhibition test of BRCA1 mutant MDA-MB-436 cells 1. Test principle CCK-8 was used to measure the content of mitochondrial dehydrogenase in cells at different drug concentrations, and the luminescence intensity was used to reflect cell activity. The IC 50 values of various compounds against BRCA1 mutant MDA-MB-436 cells were calculated using the survival rate, and the growth inhibitory effect of the compounds of the present disclosure against BRCA1 mutant MDA-MB-436 cells was studied to evaluate the antitumor efficacy of the test compounds at the cell level.

[0305] 2. Test materials 2.1. Test reagents and equipment: Culture medium (DMEM) dedicated to MDA-MB-436 cells, Procell, Fetal bovine serum (FBS), Hyclone, Phosphate buffered saline (PBS), Gibico, Dimethyl sulfoxide: DMSO, Sigma, CCK-8, Beyotime, 96-well cell culture plate, Coring, Centrifuge, Eppendorf, CO2 incubator, Thermo Scientific, Microscope, OLYMMPUS, Automatic cell counter, Gibco, Multifunctional microplate reader (Omega), BMG.

[0306] 2.2. Test cells: MDA-MB-436 cells, purchased from Procell.

[0307] 2.3. Compounds Test drugs: Compounds AZD5305 and AZD9574 were purchased from Chengdu Dingdangchem Medical Technology Co., Ltd, Test drugs: Compounds 1 - 57 were sequentially prepared by the synthesis methods in Examples 1 - 57, respectively.

[0308] 3. Test methods 3.1. Test steps - On the first day, cells were inoculated into a 96-well cell culture plate at a fixed cell density and then placed in a 5% CO2 cell incubator at 37°C overnight for culture.

[0309] On the 0th day, the compounds to be tested were prepared into a 10 mM stock solution and diluted to nine concentration points of 1,000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM in two duplicate wells. A fixed volume of the diluted compound was added to the 96-well cell culture plate and then placed in a 5% CO2 cell incubator at 37°C for 5 days for culture.

[0310] On the 5th day, a fixed volume of CCK-8 was added to a 96-well cell culture plate and incubated at 37°C for 1.5 hours in a 5% CO2 cell incubator, and the plate was read by the chemiluminescence module of a multifunctional microplate reader.

[0311] 3.2. Data Analysis Calculation formula:

[0312]

Number

[0313] 4. Test Results The inhibitory activity of the compounds against the proliferation of BRCA1-mutant MDA-MB-436 cells was determined according to the above method. The results are shown in Table 1.

[0314]

Table 5

[0315] 5. Test Conclusion: As can be seen from the test data of the inhibitory activity of the compounds against BRCA1-mutant MDA-MB-436 cells in Table 1, the compounds of the present application have strong cell proliferation inhibitory activity against BRCA1-mutant MDA-MB-436 cells and have obvious advantages compared with the positive control AZD9574.

[0316] Test Example 2: Proliferation Inhibition Test of BRCA1-Mutant HCC1395 Cells 1. Test Principle Using CCK-8, the content of mitochondrial dehydrogenase in cells at different drug concentrations was measured, and the cell viability was reflected using the luminescence intensity. The IC 50 values of various compounds against BRCA1 mutant HCC1395 cells were calculated using the survival rate, and the growth inhibitory effect of the compounds of the present disclosure against BRCA1 mutant HCC1395 cells was studied to evaluate the antitumor efficacy of the test compounds at the cellular level.

[0317] 2. Test Materials 2.1. Test Reagents and Instruments: RPMI-1640 culture medium, Hyclone, Fetal bovine serum (FBS), Gibco, Phosphate buffered saline (PBS), Wisent Biotechnology (Nanjing) Co., Ltd, Dimethyl sulfoxide: DMSO, Sigma, CCK-8, Beyotime, 96-well cell culture plate, Coring, Centrifuge, Eppendorf, CO2 incubator, Thermo Scientific, Microscope, OLYMMPUS, Automatic cell counter, Gibco, Multifunctional microplate reader (Omega), BMG.

[0318] 2.2. Test Cells: HCC1395 cells, purchased from ATCC.

[0319] 2.3. Compounds The test compounds were obtained by the same method as recorded in Test Example 1.

[0320] 3. Test Methods 3.1. Test Steps - On the first day, the cells were inoculated into a 96-well cell culture plate at a fixed cell density and then placed in a 5% CO2 cell incubator at 37 °C overnight for culture.

[0321] On the 0th day, the compound to be tested was prepared in a 10 mM stock solution and diluted to nine concentration points of 1,000 nM, 300 nM, 100 nM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, and 0.1 nM in two duplicate wells. A fixed volume of the diluted compound was added to a 96-well cell culture plate and then placed in a 5% CO2 cell incubator at 37 °C for 5 days for culturing.

[0322] On the 5th day, a fixed volume of CCK-8 was added to the 96-well cell culture plate, incubated in a 5% CO2 cell incubator at 37 °C for 1.5 hours, and the plate was read by the chemiluminescence module of a multifunctional microplate reader.

[0323] 3.2. Data analysis Calculation formula:

[0324]

Number

[0325] 4. Test results The inhibitory activity of the compound against the proliferation of BRCA1-mutant HCC1395 cells was determined according to the above method. The results are shown in Table 2.

[0326]

Table 6

[0327] 5. Test conclusion: As can be seen from the test data of the inhibitory activity of the compounds against BRCA1 mutant HCC1395 cells in Table 2, the compounds of the present application have strong cell growth inhibitory activity against BRCA1 mutant HCC1395 cells and have certain advantages compared with the positive control AZD9574.

[0328] Test Example 3: PARP1 and PARP2 Enzyme Activity Test 1. Test Purpose This test was used to evaluate the effect of the test compound on PARP1 and PARP2 enzyme activities, and the IC 50 values of the test compound against PARP1 and PARP2 enzymes were calculated using the inhibition rate.

[0329] 2. Test Materials 2.1. Compounds: The test compounds were obtained by the same method as recorded in Test Example 1.

[0330] 2.2. Test Reagents and Instruments PARP1 Chemiluminescence Assay Kit, BPS, 80551, PARP2 Chemiluminescence Assay Kit, BPS, 80552, PBS, in-house, 20210819, Tween-20, Sigma, P9416, 96-well polypropylene plate, Nunc, 249944, Centrifuge, XiangYi, TDZ5-WS, Plate reader, BMG, PHERAstar FSX.

[0331] 3. Test Method 3.1. Preparation of Compounds Preparation of 10 mM compound stock solution: The compound powder was dissolved in 100% DMSO to prepare 10 mM compound stock solutions respectively.

[0332] 3.2. Enzyme Reaction Process (1) The 5× histone mixture was diluted 1:5 with PBS and added to each well at 50 μL and incubated overnight at 4°C. (2) Wash three times with 200 μL of PBST buffer and incubate in blocking buffer for 90 minutes. (3) Wash three times with 200 μL of PBST buffer. (4) Add 5 μL of inhibitor solution to each well. (5) Add 20 μL of diluted PARP to each well. (6) Add 25 μL of biotinylated substrate to each well and incubate at room temperature for 1 hour. (7) Wash the wells three times with 200 μL of PBST buffer and blot dry with a clean paper towel. (8) Add 50 μL of diluted streptavidin-HRP to each well and incubate for 30 minutes. (9) Wash three times with 200 μL of PBST buffer. (10) Add 100 μL of a mixture of ELISA ECL substrate A and ELISA ECL substrate B to each well. (11) Immediately read the chemiluminescence signal value.

[0333] 3.3. Data analysis Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) × Hill slope)) Using the logarithm of the compound concentration as the X-axis and the chemiluminescence signal as the Y-axis, Top and Bottom are platforms with the same unit as Y, LogIC50 is in the same logarithmic unit as X, the Hill slope is the slope factor or Hill slope, and the IC value is fitted using a non-linear regression equation. 50 value was fitted.

[0334] 4. Test results The enzyme inhibitory activities of the compounds of the present application against PARP1 and PARP2 were determined according to the above method. The results are shown in Table 3.

[0335]

Table 7

[0336] 5. Test conclusion: As can be seen from the test data of the enzymatic inhibitory activity of the compounds against PARP1 and PARP2 in Table 3, the compounds of the present application have strong inhibitory activity against PARP1 and weak inhibitory effects against PARP2 at the enzymatic level, and the enzymatic selectivity of some compounds against PARP1 and PARP2 is equivalent to that of the positive control AZD9574. The compounds of the present application have obvious advantages compared with the compound AZD5305 and can reduce the hematotoxicity induced by PARP2.

[0337] Test Example 4: Study on the pharmacokinetics of rats 1. Test principle Using SD rats as test animals, the plasma concentrations of the compounds of the present application in the plasma of rats at different time points after oral administration were determined by the LC-MS / MS method. The pharmacokinetic parameters of the compounds of the present application in rats were obtained to study the pharmacokinetic characteristics.

[0338] 2. Test materials 2.1. Compounds: The test compounds were obtained by the same method as recorded in Test Example 1.

[0339] 2.2. Test equipment: Shimadzu Corporation LC-30A AB API4500 tandem mass spectrometer, vacuum blood collection tube, blood collection needle, filter paper, syringe, etc.

[0340] 2.3. Test animals SD rats, female, body weight 180 - 220 g, 3 rats per group. After purchase, the animals were fed in the animal house for at least 3 days of adaptation period, and then used in the test after passing quarantine.

[0341] 3. Test method 3.1. Grouping: SD rats were randomly grouped according to Table 4, and there was no statistical difference in body weight among the groups after grouping.

[0342]

Table 8

[0343] 3.2. Vehicle: 10% DMSO and 90% (20% SBE-β-CD in physiological saline).

[0344] 3.3. Collection and determination of blood samples: According to Table 4, each compound was prepared in a clear solution added with the vehicle, and the test drug corresponding to each group was administered by gavage. Before administration, and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, a fixed volume of blood was collected via the jugular foramen, placed in an EDTA-K2 anticoagulant tube, and centrifuged at 4,000 rpm for 10 minutes to separate plasma in the centrifuge tube. The plasma was frozen in a freezer at -80°C.

[0345] 3.4. Analytical method The plasma stored at -80°C at each time point was taken out, and a fixed volume of acetonitrile was added thereto. After vortexing at 1,500 rpm for 2 minutes, it was centrifuged for 15 minutes (3,500 revolutions per minute). A fixed volume of the solution supernatant was collected for LC-MS / MS analysis.

[0346] 4. Calculation of pharmacokinetic parameters: The pharmacokinetic behavior of the test compound was fitted to a non-compartmental model, and the main pharmacokinetic parameters were calculated using DAS 3.31 software. The results are shown in Table 5.

[0347]

Table 9

[0348] 5. Test conclusion: As can be seen from the test results in Table 5, compared with the positive control AZD9574, the multiple compounds of the present application have higher blood exposure, higher maximum plasma concentration and lower clearance in animals, and thus have better pharmacokinetic properties.

Claims

1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof: 【Chemical 1】 [Wherein, X is N, CH or CR a and is selected from, where R a is halogen, C 1～4 alkyl, C 3～6 cycloalkyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl and is selected from Y is N, CH or CR b and is selected from, where R b is halogen, cyano, C 1～4 alkyl, C 2～6 alkenyl, C 3～6 cycloalkyl, 4- to 6-membered heterocyclyl or -OR z and is selected from, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from fluoro, cyano, hydroxy, C 1～4 alkyl or -O-(C 1～4 alkyl), However, when X is selected from N or CH, Y is CR b is selected from When X is CR a when selected from, Y is N, CH or CR b selected from, and R 1 is selected from hydrogen, halogen, cyano, C 1～4 alkyl, -O-(C 1～4 alkyl), -O-(halogenated C 1～4 alkyl) or halogenated C 1～4 alkyl, R 2 is selected from hydrogen, F, Cl, Br, cyano, C 1～4 alkyl, C 3～6 cycloalkyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl, R 3 is selected from cyano, C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, C 1～4 alkyl, C 3～6 cycloalkyl, 4- to 6-membered heterocyclyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl, respectively, Q is N or CR c is selected from, where R c is F, hydroxy, cyano, C 1～4 alkyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl is selected from, R 4 and R 5 in each occurrence, is independently selected from hydrogen or C 1～4 alkyl, or R 4 and R 5 are connected to each other to form a ring, 【Chemical 2】 is selected from phenyl, or a 5- or 6-membered heteroaryl containing 1 to 2 atoms selected from N, O or S, R 6 is, in each occurrence, hydrogen, halogen, cyano, -OR z , -C(=O)-R z , -C(=O)-NH-R z , C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl, each independently selected, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, hydroxy, C 1～4 alkyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl, n is 1, 2 or 3, R z is, in each occurrence, independently selected from hydrogen, C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from F, cyano, hydroxy, C 1～4 alkyl, -O-(C 1～4 alkyl) or fluorinated C 1～4 alkyl).

2. X is N, CH or CR a and is selected from the group consisting of, where R a is F, Cl, Br, C 1～4 alkyl, C 3～6 cycloalkyl, -OMe or fluorinated C 1～4 alkyl, preferably R a is selected from F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, -OMe, -CF 3 , -CHF 2 or -CH 2 F, more preferably R a is selected from F, Cl, Br, methyl, cyclopropyl, -OMe, -CHF 2 or -CH 2 F, and Y is N, CH or CR b is selected from, where R b is F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, oxacyclohexyl or -OR z is selected from, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or oxacyclohexyl is unsubstituted or independently substituted with one or more substituents selected from fluoro, cyano, hydroxy, methyl or -OMe, preferably R b is F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z is selected from, where methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or independently substituted with one or two substituents selected from fluoro, cyano, hydroxy or methyl, However, when X is selected from N or CH, Y is CR b selected from X is CR a When selected from, Y is N, CH or CR b selected from A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, characterized in that.

3. R 1 is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, isopropyl, -OMe, -O-(fluorinated C 1～4 alkyl) or fluorinated C 1～4 alkyl, and preferably, R 1 is selected from hydrogen, F, Cl, methyl, -OMe, -CHF 2 or -CH 2 F A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, characterized in that.

4. R 2 is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, cyclopropyl, -OMe or fluorinated C 1～4 alkyl, preferably, R 2 is selected from hydrogen, F, Cl, Br, methyl, cyclopropyl, -OMe, -CHF 2 or -CH 2 F A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, characterized in that.

5. R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, methyl, cyclopropyl, -OMe or fluorinated C 1～4 alkyl, Preferably, R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or two substituents selected from F, cyano, -OMe, -CHF 2 or -CH 2 F A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, characterized in that.

6. Q is N or CR c is selected from, where R c is F, hydroxy, cyano, methyl, ethyl, -OMe or fluorinated C 1～4 alkyl is selected from, Preferably, Q is N or CR c is selected from, where R c is F, hydroxy, cyano, methyl, -OMe, -CHF 2 or -CH 2 F is selected from, More preferably, Q is N or CR c is selected from, where R c is selected from F, hydroxy, -OMe or methyl, R 4 and R 5 in each occurrence, is independently selected from hydrogen, methyl or ethyl, or R 4 and R 5 are connected to each other to form a ring, Preferably, R 4 and R 5 are each independently selected from hydrogen or methyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring, [Chemical Formula 3] forming More preferably, R 4 and R 5 are each independently selected from hydrogen or methyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring, 【Chemical 4】 forming A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, characterized in that.

7. 【Fig. 5】 is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl or thiazolyl, preferably, 【Chemical Formula 6】 is selected from phenyl, pyridyl, pyrazolyl, oxazolyl, thienyl or thiazolyl, more preferably, 【Chemical 7】 is, [Chemical Formula 8] selected from, R 6 is, at each occurrence, hydrogen, F, Cl, Br, cyano, -OR z , -C(=O)-R z , -C(=O)-NH-R z , methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, each independently selected, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, hydroxy, methyl, -OMe, -CF 3 or -CHF 2 and is thus independently substituted with one or more substituents selected therefrom, Preferably, R 6 is, in each occurrence, hydrogen, F, Cl, Br, cyano, -OR z , -C(=O)-R z , -C(=O)-NH-R z , methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, each independently selected, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or independently substituted with one or two substituents selected from F, hydroxy or -OMe, R z is, in each occurrence, independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or oxacyclopentyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxacyclopentyl is unsubstituted or is independently substituted with one or more substituents selected from fluoro, cyano, -OH, -OMe, oxetanyl or methyl, n is 1 or 2 A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, characterized in that.

8. A compound having the structure of formula (II), or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof: 【Chemical Formula 9】 [Wherein, R 1 is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, isopropyl or -OMe, R 2 is selected from hydrogen, halogen, cyano, C 1～4 alkyl, C 3～6 cycloalkyl, -O-(C 1～4 alkyl) or fluorinated C 1～4 alkyl, R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, methyl, cyclopropyl or -OMe, R b is selected from F, Cl, Br, cyano, C 1～4 alkyl, C 3～6 cycloalkyl, 4- to 6-membered heterocyclyl or -OR z , wherein C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from fluoro, cyano, hydroxy, C 1～4 alkyl or -O-(C 1～4 alkyl), R 4 and R 5 each occurrence, is independently selected from hydrogen or C 1～4 alkyl, or R 4 and R 5 are connected to each other to form a ring, 【Chemical 10】 forming 【Chemical 11】 is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl or thiazolyl, R 6 is, in each occurrence, hydrogen, halogen, cyano, -OR z , -C(=O)-R z , -C(=O)-NH-R z , C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl, each independently selected, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, hydroxy, C 1～4 alkyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl, respectively. n is 1, 2 or 3, R z is, in each occurrence, independently selected from hydrogen, C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from F, cyano, hydroxy, C 1～4 alkyl, -O-(C 1～4 alkyl), 4- to 6-membered heterocyclyl or fluorinated C 1～4 alkyl).

9. A compound having the structure of formula (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof: 【Chemical Formula 12】 [Wherein, R 1 is selected from hydrogen, F, Cl, methyl, -OMe, -CHF 2 or -CH 2 F, and R 2 is selected from hydrogen, halogen, cyano, C 1～4 alkyl, C 3～6 cycloalkyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl, R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, where methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or is independently substituted with one or two substituents selected from F, cyano, methyl, cyclopropyl or -OMe, R b is selected from F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z wherein methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or is independently substituted with one or two substituents selected from fluoro, cyano, hydroxy or methyl R 4 and R 5 in each occurrence, is independently selected from hydrogen or C 1～4 alkyl, or R 4 and R 5 are connected to each other to form a ring, 【Chemical 13】 forming 【Chemical 14】 is, 【Chemical 15】 selected from, R 7 is selected from hydrogen, F, Cl, Br, cyano, C 1～4 alkyl, C 3～6 cycloalkyl, 4- to 6-membered heterocyclyl or -OR z wherein C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, hydroxy, C 1～4 alkyl, -O-(C 1～4 alkyl) or halogenated C 1～4 alkyl, respectively, n is 1 or 2, R z is, in each occurrence, independently selected from hydrogen, C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from F, cyano, hydroxy, C 1～4 alkyl, -O-(C 1～4 alkyl), 4- to 6-membered heterocyclyl or fluorinated C 1～4 alkyl).

10. A compound having the structure of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof: 【Chemical Formula 16】 [wherein, R 2 is selected from hydrogen, F, Cl, Br, cyano, C 1～4 alkyl, C 3～6 cycloalkyl, -O-(C 1～4 alkyl) or fluorinated C 1～4 alkyl, R 3 is selected from cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or 4- to 6-membered heterocyclyl, where methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or 4- to 6-membered heterocyclyl is unsubstituted or is each independently substituted with one or more substituents selected from F, cyano, methyl or -OMe, R b is selected from F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z wherein methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or is independently substituted with one or two substituents selected from fluoro, cyano, hydroxy or methyl R 4 and R 5 is, in each occurrence, independently selected from hydrogen, methyl or ethyl, respectively, or R 4 and R 5 are connected to each other to form a ring, 【Chemical 17】 forms, R 7 is selected from hydrogen, halogen, cyano, -OR z , C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl, where C 1～4 alkyl, C 3～6 cycloalkyl or 4- to 6-membered heterocyclyl is unsubstituted or is independently substituted with one or more substituents selected from F, hydroxy, methyl, ethyl, methoxy or ethoxy, n is 1 or 2, R z is, in each occurrence, independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or oxacyclopentyl, where methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl is unsubstituted or is independently substituted with one or more substituents selected from F, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, oxetanyl or fluoromethyl].

11. The compound is 【Chemical 18】 [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 The compound according to any one of claims 1, 8, 9 or 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, selected from

12. A pharmaceutical composition comprising an effective amount of the compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, and a pharmaceutically acceptable carrier and / or excipient, or further comprising one or more other therapeutic agents.

13. Use of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, or the pharmaceutical composition according to claim 12, in the preparation of a PARP1 inhibitor, wherein the PARP1 inhibitor is used in the preparation of a drug for treating cancer, preferably the cancer is a PARP1-mediated BRCA gene-deficient tumor, more preferably the tumor is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, colorectal cancer, bladder cancer, gastrointestinal cancer, lung cancer or blood cancer.

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