Naphthyridine derivatives as ATR inhibitors and method for preparing same

Abstract

Disclosed are naphthyridine derivatives as ATR inhibitors, their preparation methods and their use.Specifically, the present invention relates to naphthyridine compounds of general formula (1), their preparation methods, and the use of the compounds of general formula (1) and their isomers, crystals, pharmaceutically acceptable salts, hydrates or solvates as ATR inhibitors.The compounds of the present invention and their isomers, crystals, pharmaceutically acceptable salts, hydrates or solvates can be used for the preparation of medicaments for treating or preventing related diseases mediated by ATR protein kinase. [Formula 1] TIFF2024529070000099.tif33168

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 202110919812.6 (filed on August 11, 2021), Chinese Patent Application No. 202111188963.5 (filed on October 12, 2021), and Chinese Patent Application No. 202210918443.3 (filed on August 1, 2022), which are incorporated by reference in their entireties.

[0002] The present invention relates to the field of formulation chemistry, and in particular to a class of novel naphthyridine derivatives, methods for their preparation, and uses thereof. [Background technology]

[0003] Ataxia telangiectasia and Rad3-related (ATR) proteins, members of the PIKK family, are a class of protein kinases involved in genome stability and DNA damage repair. ATR is activated by stalled replication forks and DNA single-strand breaks (SSBs). Activated ATR recruits repair proteins or factors to repair the damaged areas and delays the mitotic process, especially the G2 / M phase of mitosis. This not only stabilizes replication forks but also ensures genome stability.

[0004] Moreover, the DNA damage repair system in most tumor cells is abnormal and certain repair pathways (e.g., P53 and ATM mutations) are usually defective, making tumor cells more dependent on ATR for survival. However, in normal cells, the repair pathways are robust and intact, so inhibiting ATR kinase alone does not have a significant effect. Therefore, inhibition of ATR may have a greater effect on the treatment of cancer without significant toxicity and side effects on normal cells.

[0005] DNA damage repair, which occurs during the S phase of the cell cycle, is mainly accomplished by the ATR pathway, suggesting that ATR is crucial for ensuring cell proliferation. Analysis of clinical tumor samples has shown that elevated ATR expression levels are observed in various tumor tissues, including gastric, hepatic, colorectal, ovarian, and pancreatic cancers. Moreover, high ATR levels are usually associated with relatively poor survival rates in patients with ovarian and pancreatic cancer.

[0006] Furthermore, ATR inhibition can be combined with radiation therapy or chemotherapy drugs to synergistically enhance the effect. A wide variety of chemotherapy drugs include metabolic antagonists (e.g., gemcitabine), DNA cross-linking agents (e.g., cisplatin and carboplatin), alkylating agents (e.g., temozolomide), topoisomerase inhibitors (e.g., irinotecan), etc. When affected by chemotherapy or radiation therapy, tumor cells activate the ATR signaling pathway more to repair damaged DNA. Therefore, when treating cancer with radiation therapy or chemotherapy drugs, simultaneous inhibition of ATR can greatly enhance the therapeutic effect against cancer. From the above studies, it can be seen that ATR is an important target for effective tumor treatment.

[0007] Compounds such as AstraZeneca's AZD6738, Merck's VE822, and Bayer's BAY1895344 are currently in Phase I / II clinical trials. Summary of the Invention [Problem to be solved by the invention]

[0008] Taken together, these studies suggest that ATR is an important target for effective tumor therapy. [Means for solving the problem]

[0009] (overview) The present invention provides a compound of general formula (1), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In general formula (1), X is CH or N; R 1 teeth, [ka] and R 2 and R 3 are each independently -H, -D, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C3-C10) cycloalkyl, (C3-C10) cycloalkenyl, (3-10 membered) heterocycloalkyl, (3-10 membered) heterocycloalkenyl, (C6-C10) aryl or (5-10 membered) heteroaryl, wherein said (C1-C6) alkyl is the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C1-C6) alkoxy, the (C3-C10) cycloalkyl, the (C3-C10) cycloalkenyl, the (3-10 membered) heterocycloalkyl, the (3-10 membered) heterocycloalkenyl, the (C6-C10) aryl or the (5-10 membered) heteroaryl each independently represents the following group: -H, -D, halogen, -OH, -R 6 , -NR 4 R 5 , -C(O)OR 4 , -C(O)NR 4 R 5 , -S(O) P R 4 , -S(O)NR 4 R 5 , -P(O)(OR 4 )2, -P(O)(R 4 )2, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (3-10 membered)heterocycloalkyl, (3-10 membered)heterocycloalkenyl, (C6-C10)aryl or (5-10 membered)heteroaryl; Or, R 2 and R 3 together with the carbon atom to which they are attached form a (C3-C15)cycloalkyl or a (3-15 membered)heterocycloalkyl, wherein said (C3-C15)cycloalkyl or said (3-15 membered)heterocycloalkyl each independently comprises one or more R 6 may be optionally substituted with R 4 and R 5 are each independently -H, -D, (C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C3-C10) cycloalkyl, (C3-C10) cycloalkenyl, (3-10 membered) heterocycloalkyl, (3-10 membered) heterocycloalkenyl, (C6-C10) aryl or (5-10 membered) heteroaryl; Or, R 4 and R 5 together with the N atom to which it is attached, form a (3-10 membered)heterocycloalkyl, wherein said (3-10 membered)heterocycloalkyl is selected from the following groups: -H, -D, halogen, -OH, -NR 7 R 8 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O) P R 7 , -S(O)NR 7 R 8 , -P(O)(OR 7 )2, -P(O)(R 7 )2, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (3-10 membered)heterocycloalkyl, (3-10 membered)heterocycloalkenyl, (C6-C10)aryl, or (5-10 membered)heteroaryl; Each R 6 are independently -H, -D, halogen, -OH, -NR 7 R8 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -(CH2) n -S(O) P R 7 , -(CH2) n -S(O)2NR 7 R 8 , -P(O)(OR 7 )2, -P(O)(R 7 )2, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (3-10 membered)heterocycloalkyl, (3-10 membered)heterocycloalkenyl, (C6-C10)aryl or (5-10 membered)heteroaryl, wherein said (C1-C6)alkyl, said (C2-C6) alkenyl, the (C2-C6)alkynyl, the (C1-C6)haloalkyl, the (C1-C6)alkoxy, the (C3-C10)cycloalkyl, the (C3-C10)cycloalkenyl, the (3-10 membered)heterocycloalkyl, the (3-10 membered)heterocycloalkenyl, the (C6-C10)aryl, or the (5-10 membered)heteroaryl each independently represents the following group: -H, -D, halogen, -OH, -NR 7 R 8 , -C(O)OR 7 , -C(O)NR 7 R 8 , -(CH2) n -S(O) P R7, -(CH2) n -S(O)2NR 7 R 8 , -P(O)(OR 7 )2, -P(O)(R 7)2, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (3-10 membered)heterocycloalkyl, (3-10 membered)heterocycloalkenyl, (C6-C10)aryl or (5-10 membered)heteroaryl; R 7 and R 8 are each independently -H, -D, (C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C3-C10) cycloalkyl, (C3-C10) cycloalkenyl, (3-10 membered) heterocycloalkyl, (3-10 membered) heterocycloalkenyl, (C6-C10) aryl or (5-10 membered) heteroaryl; p is 0, 1, or 2; n is 0, 1, 2, or 3.

[0010] In another embodiment of the present invention, in general formula (1), X is CH.

[0011] In another embodiment of the present invention, in general formula (1), R 1 teeth, [ka] It is.

[0012] In another embodiment of the present invention, in general formula (1), R 2 and R 3are each independently -H, -D, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C3) alkoxy, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl, (3-8 membered) heterocycloalkyl, (3-8 membered) heterocycloalkenyl, (C6-C10) aryl or (5-10 membered) heteroaryl, wherein said (C1-C3) aryl the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C1-C3) alkoxy, the (C3-C6) cycloalkyl, the (C3-C6) cycloalkenyl, the (3-8 membered) heterocycloalkyl, the (3-8 membered) heterocycloalkenyl, the (C6-C10) aryl or the (5-10 membered) heteroaryl each independently represents the following group: -H, -D, -F, -Cl, -Br, -I, -OH, -R 6 , -NR 4 R 5 , -C(O)OR 4 , -C(O)NR 4 R 5 , -S(O) P R 4 , -S(O)NR 4 R 5 , -P(O)(OR 4 )2, -P(O)(R 4 )2, (C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C3)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, (3-8 membered)heterocycloalkyl, (3-8 membered)heterocycloalkenyl, (C6-C10)aryl or (5-10 membered)heteroaryl, or R 2 and R 3 together with the carbon atoms to which they are attached form a (C3-C15)cycloalkyl or a (3-15 membered)heterocycloalkyl, wherein said (C3-C15)cycloalkyl or said (3-15 membered)heterocycloalkyl each independently represent one or more R 6 may be optionally substituted with

[0013] In another embodiment of the present invention, in general formula (1), R 2 and R 3 are each independently -H, -D, -F, -Cl, -Br, -I, -CH3, [ka] and preferably R 2 is -H or -CH3, R 3 -H, -F, -Cl, -CH3, [ka] and more preferably, R 2 is -H or -CH3, R 3 -H, -CH3, [ka] It is.

[0014] In another embodiment of the present invention, in general formula (1), R 2 and R 3 The (C3-C15)cycloalkyl or the (3-15 membered)heterocycloalkyl formed together with the carbon atom to which they are bonded is [ka] and Preferably, [ka] wherein the (C3-C15)cycloalkyl or the (3-15 membered)heterocycloalkyl is selected from the following groups: -H, -F, -CH3, -CH2CH3, -OH, [ka] -NH2, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -OCH3, -OCH2CH3, [ka] Preferably, -H, -F, -CH3, -CH2CH3, -OH, [ka] -NH2, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -OCH3, -OCH2CH3, [ka] may be optionally substituted with one or more of:

[0015] In another embodiment of the present invention, in general formula (1), R 4 and R 5 are each independently -H, -D, -CH3, [ka] It is.

[0016] In another embodiment of the present invention, in general formula (1), R 4 and R 5 are each independently -H or -CH3.

[0017] In another embodiment of the present invention, in general formula (1), R 6 are -H, -F, -CH3, -CH2CH3, -OH, [ka] -NH2, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -OCH3, -OCH2CH3, [ka] and Preferably, -H, -F, -CH3, -CH2CH3, -OH, [ka] -NH2, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -OCH3, -OCH2CH3, [ka] It is.

[0018] In another embodiment of the present invention, in general formula (1), R 7 and R 8 are each independently -H or -CH3.

[0019] In another particular embodiment of the present invention, the compound of general formula (1) has the following structure: [ka] It has one of the following: TIFF2024529070000020.tif204168TIFF2024529070000021.tif243168TIFF2024529070000022.tif227168TIFF2024529070000023.tif215168

[0020] Another object of the present invention is to provide a pharmaceutical composition containing a pharma- ceutically acceptable carrier, diluent and / or excipient and, as an active ingredient, a compound of the general formula (1) of the present invention or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0021] The present invention further intends to provide the use of a compound of the present invention represented by general formula (1), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or the above pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with ATP protein kinase.

[0022] The present invention further intends to provide a method for treating, regulating or preventing a related disease mediated by ATR protein kinase, comprising administering to a subject a therapeutically effective amount of a compound of the present invention represented by general formula (1), or an isomer, crystalline form, pharma-ceutically acceptable salt, hydrate or solvate thereof, or the above pharmaceutical composition.

[0023] It is to be understood that both the foregoing general description and the following detailed description of the invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] (Synthesis of Compounds) Methods for preparing the compound of the general formula (1) of the present invention are specifically described below, but these specific methods do not limit the present invention in any way.

[0025] The compounds of general formula (1) above can be synthesized using standard synthetic techniques in combination with the methods described herein, or well-known techniques. Furthermore, the solvents, temperatures and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds can be obtained synthetically or commercially. The compounds described herein and other related compounds with different substituents are described in March, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rd Ed., (Wiley 1999). General methods for preparing compounds may be modified by using appropriate reagents and conditions to introduce various groups into the molecular formulas provided herein.

[0026] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the following description. In addition, the compounds of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains. In one embodiment, the present invention further provides a method for preparing a compound of general formula (1), where the compound of general formula (1) can be prepared using the following method A, method B, or method C.

[0027] Method A [ka]

[0028] Compounds of general formula (1) can be prepared according to method A, where R 1 , R 2 and R 3 is as defined above.

[0029] Method A includes the following steps: first, compound A1 is reacted under alkaline conditions to produce compound A2, compound A2 is further subjected to a metal-catalyzed coupling reaction to produce compound A3, compound A3 is deprotected under acidic conditions to produce A4, A4 is reacted with a cyanation reagent to produce A5, A5 is reacted with a strong alkali and a halogenation reagent to produce A6, and A6 is subjected to a coupling reaction to produce target compound A7.

[0030] Method B [ka]

[0031] Compounds of general formula (1) can be prepared according to method B, in which n and m represent 0, 1, 2 or 3, PG represents an N-protecting group, and R1 and R 6 is as defined above.

[0032] Method B includes the following steps: first, compound A5 is reacted with fragment B1 under the action of strong alkali to generate B2, B2 is subjected to coupling reaction to generate B3, B3 is deprotected under appropriate conditions to generate B4, and B4 is further reacted to obtain target compound B6.

[0033] Method C [ka]

[0034] Compounds of general formula (1) may be prepared according to method C, where n and m represent 0, 1, 2 or 3; R 1 and R 6 is as defined above.

[0035] Method C includes the following steps: first, compound A5 is reacted with fragment C1 under the action of strong alkali to generate C2, C2 is subjected to deprotection with acid to generate C3, C3 is subjected to coupling reaction to generate C4, and C4 is reacted under appropriate conditions to obtain target compound C5.

[0036] Further forms of the compound As used herein, "pharmaceutical acceptable" refers to a relatively non-toxic substance, such as a carrier or diluent, that does not cause a loss of biological activity or properties of a compound. For example, when a substance is administered to an individual, the substance does not cause undesired biological effects or adverse interactions with any of its components.

[0037] The term "pharmaceutical acceptable salt" refers to the existing form of a compound that does not cause significant irritation to the receiving organism or eliminate the biological activity and properties of the compound.In certain embodiments, the pharmaceutical acceptable salt is obtained by reacting the compound of general formula (1) with an acid, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

[0038] It is to be understood that pharma- ceutically acceptable salts include solvent addition forms or crystal forms, particularly solvates or polymorphs. Solvates include stoichiometric or non-stoichiometric amounts of solvent and are preferentially formed during crystallization in pharma- ceutical acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of the compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of the compounds of general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds described herein may exist in either unsolvated or solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0039] In other specific examples, the compound of general formula (1) is prepared in different forms, including but not limited to amorphous, milled, and nanoparticle forms. Furthermore, the compound of general formula (1) may be a polymorph, including crystalline forms. A polymorph includes different lattice arrangements of the same elements of a compound. The polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal morphology, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in a single predominant crystalline form.

[0040] In another embodiment, the compounds of general formula (1) may have chiral centers and / or axial asymmetry and may therefore exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers and cis-trans isomers. Each chiral center or axial asymmetry independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomers of these compounds.

[0041] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) and C-14( 14 The deuterated pharmaceutical composition may be labeled with a radioisotope such as 1,2-dihydro-1,3-trifluoroethylene (1,2,3,4-trifluoroethylene) or 1,2-dihydro-1,3-trifluoroethylene (1,2,3,4-trifluoroethylene). As another example, deuterium may be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon. Compared to non-deuterated pharmaceuticals, deuterated pharmaceuticals generally have the advantages of reduced toxic effects and side effects, improved pharmaceutical stability, enhanced efficacy, and extended pharmaceutical in vivo half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0042] Explanation of terms Unless otherwise specified, the terms used in this application, including those used in the specification and claims, are defined as follows. Please note that in this specification and the appended claims, the singular forms "a" and "an" include the plural meaning unless otherwise specified in the context. Conventional methods such as mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used unless otherwise specified. "Or" or "and" as used herein means "and / or" unless otherwise specified.

[0043] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched groups, having 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl, are preferred. As used herein, "alkyl" includes unsubstituted and substituted alkyls, particularly alkyls substituted with one or more halogens. Preferred alkyls are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t is selected from Bu.

[0044] Unless otherwise specified, "alkylene" refers to a divalent alkyl as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0045] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups containing 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl, are preferred.

[0046] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, and includes straight-chain and branched groups containing 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl, are preferred.

[0047] Unless otherwise noted, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic); partially unsaturated cycloalkyls may be referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond, or "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. Cycloalkyls may include monocyclic or polycyclic groups, as well as spirocycles (e.g., having 2, 3, or 4 fused rings). In some embodiments, cycloalkyls are monocyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. Ring carbon atoms of cycloalkyls may be optionally oxidized to form oxo or sulfido groups. Cycloalkyls further include cycloalkylene. In some embodiments, cycloalkyls include 0, 1, or 2 double bonds. In some embodiments, cycloalkyls include 1 or 2 double bonds (partially unsaturated cycloalkyls). In some embodiments, cycloalkyls may be fused with aryls, heteroaryls, cycloalkyls, and heterocycloalkyls. In some embodiments, cycloalkyl may be fused with aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl and cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0048] Unless otherwise indicated, "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy are OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0049] Unless otherwise specified, "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group, for example, a monocyclic aryl ring may be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0050] Unless otherwise noted, "aryloxy" refers to an aryl group attached to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0051] Unless otherwise noted, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, and phenanthrylene.

[0052] Unless otherwise specified, "heteroaryl" refers to an aromatic group that contains one or more heteroatoms (O, S, or N), and the "heteroaryl" is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [ka] These include, but are not limited to:

[0053] Unless otherwise stated, "heterocycloalkyl" refers to a non-aromatic ring or ring system having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus, which may optionally include one or more alkenylenes as part of the ring structure. Partially unsaturated heterocycloalkyls may be referred to as "heterocycloalkenyls" when the heterocycloalkyl contains at least one double bond, and "heterocycloalkynyls" when the heterocycloalkyl contains at least one triple bond. Heterocycloalkyls may include monocyclic, bicyclic, spirocyclic, or polycyclic systems (e.g., having two fused or bridged rings). In some embodiments, heterocycloalkyls are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring carbon atoms and heteroatoms of a heterocycloalkyl may be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl may be bonded through a ring carbon atom or a ring heteroatom. In some embodiments, a heterocycloalkyl contains 0-3 double bonds. In some embodiments, a heterocycloalkyl contains 0-2 double bonds. Further included within the definition of a heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., sharing a bond) to the heterocycloalkyl ring, e.g., benzo derivatives such as piperidine, morpholine, azepine, thienyl, etc. Heterocycloalkyls that contain fused aromatic rings may be bonded through any ring atom, including the ring atoms of the fused aromatic rings.Examples of heterocycloalkyl include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-isopropyl ether, and the like. midazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanyl, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro[3.3]heptanyl, indolinyl, [ka] These include, but are not limited to:

[0054] Unless otherwise stated, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a radical name indicates that the radical is partially or fully halogenated, i.e., substituted by F, Cl, Br or I, preferably F or Cl, in any combination.

[0055] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0056] The substituent "-O-CH2-O-" means that the two oxygen atoms in the substituent are attached to two adjacent carbon atoms in a heterocycloalkyl, aryl, or heteroaryl, for example: [ka]

[0057] When the number of a linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0058] When one of the variables is selected from a chemical bond, it means that the two groups connected by this variable are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0059] The term "membered ring" includes any cyclic structure. The term "membered" is intended to refer to the number of main chain atoms that form the ring. For example, cyclohexyl, pyridinyl, pyranyl, and thiopyranyl are 6-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[0060] The term "moiety" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to refer to a chemical substance contained in or attached to a molecule.

[0061] Unless otherwise indicated, the absolute configuration of a stereocenter is represented by a solid wedge bond. [ka] and wedge-shaped dashed bond [ka] The relative configuration of the stereocenters is represented by a straight solid bond [ka] and straight dashed bond [ka] It is expressed by:

[0062] Wavy line [ka] is a solid wedge connection [ka] or wedge-shaped dashed bond [ka] or a wavy line [ka] is a straight solid line connection [ka] or straight dashed bond [ka] Represents.

[0063] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0064] Specific pharmaceutical and medical terms The term "acceptable" as used herein means that a formulation component or active ingredient does not have an excessive and deleterious effect on the general health of the treated subject.

[0065] The terms "treatment", "course of treatment" and "treatment" as used herein include alleviating, inhibiting or ameliorating a disease symptom or condition, inhibiting the occurrence of a complication, improving or preventing the underlying metabolic syndrome, inhibiting the occurrence of a disease or condition (e.g., controlling the progression of a disease or condition), relieving a disease or condition, regressing a disease or condition, and alleviating complications caused by a disease or condition, or preventing or treating symptoms caused by a disease or condition. As used herein, a compound or pharmaceutical composition, when administered, can alleviate a disease, symptom or condition, and in particular can improve the severity, delay the onset, delay the progression, or shorten the duration of a disease. Fixed or episodic administration, or continuous or intermittent administration, can result from or relate to administration.

[0066] "Active ingredient" refers to compounds of general formula (1) and pharma- ceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial asymmetry) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0067] As used herein, terms such as "compound," "composition," "agent," or "medicine or pharmaceutical agent" are used interchangeably and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of eliciting a desired pharmacological and / or physiological response through local and / or systemic action.

[0068] The terms "administered, administering, or administration" as used herein refer to direct administration of a compound or composition, or to administration of a prodrug, derivative, analog, etc. of an active compound.

[0069] Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the relevant values ​​set forth in certain embodiments are set forth herein as precisely as possible. However, any numerical value inherently contains a standard deviation that necessarily results from certain testing methods. Here, "about" generally means that the actual value is within a particular value or range ±10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual numerical value is within an acceptable standard error of the mean value, as would be understood by one of ordinary skill in the art. Except in experimental examples or unless otherwise indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, proportions of amounts, etc.) are understood to be modified by the term "about". Thus, unless otherwise indicated, all numerical parameters set forth in this specification and the appended claims are approximations that may be varied as desired. At the very least, these numerical parameters should be interpreted as numerical values ​​obtained using the significant digits given or conventional rounding rules.

[0070] Scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein include their plurals, unless otherwise contradicted by context, and plural nouns used herein also include their singulars.

[0071] therapeutic use The present invention provides methods for treating diseases including, but not limited to, conditions in which ATR protein kinase is implicated (e.g., cancer) using a compound of general formula (1) or a pharmaceutical composition of the present invention.

[0072] In some embodiments, a method of treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of structural general formula (1). In some embodiments, the compound of general formula (1) may be used in combination with an additional anti-cancer agent. In some embodiments, the compound of general formula (1) may be used in combination with gemcitabine. In some embodiments, the cancer is mediated by ATR protein kinase. In other embodiments, the cancer includes, but is not limited to, blood cancer and solid tumors, including leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

[0073] Route of administration The compound of the present invention and its pharmaceutically acceptable salt can be prepared into various formulations containing a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier, where "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious adverse effects.The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject to be treated.

[0074] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use, have sufficient purity, and have sufficiently low toxicity. As used herein, "compatible" means that the components of the composition are capable of being mixed with the compounds of the present invention without significantly reducing the pharmaceutical effectiveness of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0075] The compounds of the present invention may be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0076] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or the following ingredients: (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, said dosage forms may further comprise buffering agents.

[0077] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art.These may contain opacifying agents, and the active compound or compounds in such compositions can be released in a certain part of the digestive tract in a delayed manner.The examples of embedding components that can be used include polymeric materials and wax-based materials.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0078] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0079] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0080] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar-agar, or mixtures of these substances.

[0081] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0082] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required as required.

[0083] The compound of the present invention may be administered alone or in combination with other pharma- ceutically acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) to be treated, and the dosage is a pharma- ceutical effective dose. For a 60 kg human, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. In determining the specific dosage, factors such as the route of administration and the patient's health condition are also taken into consideration, but these are well known to those skilled in the art.

[0084] The features described in the present invention or the features described above in the embodiments can be combined in any combination. All features disclosed herein can be used in any composition, and the various features disclosed herein can be replaced with any alternative features that provide the same, equivalent or similar purpose. Thus, unless otherwise specified, the features disclosed herein are merely generic examples of equivalent or similar features.

[0085] (Detailed Description) Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions are described in detail as follows, which will make the contents of the present invention very clear. It should be understood that the following detailed description and examples are for reference purposes only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present application as defined herein.

[0086] In all examples, 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts are expressed in δ (ppm). Unless otherwise specified, 200-300 mesh silica gel was used for separation, and the ratio of eluents was by volume.

[0087] In the present invention, the following abbreviations are used: Ar is argon; AcCl is acetyl chloride; AcOH is glacial acetic acid; Acetone is acetone; CDCl3 is deuterated chloroform; conc HCl is concentrated hydrochloric acid; DIPEA is diisopropylethylamine; DCE is 1,2-dichloroethane; DCM is dichloromethane; dioxane is 1,4-dioxane; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; EA or EtOAc is ethyl acetate; h is hour; K3PO4 is anhydrous potassium phosphate; KOH is potassium hydroxide; K2CO3 is anhydrous potassium carbonate; LC-MS is liquid chromatography mass spectrometry; MeI is iodomethane; MeOH is anhydrous methanol; mL is milliliter; min is minute; MS is mass spectrometry; NaH is sodium hydride; Na2SO4 is sodium sulfate; NaBH4 is sodium borohydride; NaBH(OAc)3 is triacetate. Sodium diborohydride; NH(CH3)2 is dimethylamine; NMR is nuclear magnetic resonance; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(dtbpf)Cl2 is dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II); PE is petroleum ether; THF is tetrahydrofuran; TFA is trifluoroacetic acid; TfOH is trifluoromethanesulfonic acid; Tf2O is trifluoromethanesulfonic anhydride; Tol is methylbenzene; prep-HPLC is preparative high performance liquid chromatography; and Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. EXAMPLES

[0088] Example 1: Synthesis of (R)-2-(2-(3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)acetonitrile (Compound 1) [ka] [ka]

[0089] Step 1: Synthesis of 1-2 In a 250 mL one-neck flask, 1-1 (2.4 g, 8.58 mmol), DCM (60 mL) and DIPEA (2.77 g, 21.47 mmol) were added. After purging the system with Ar, N-phenylbis(trifluoromethanesulfonyl)imide (4.6 g, 12.87 mmol) was added and the mixture was stirred at room temperature for 5 h. After the completion of the reaction was confirmed by LC-MS, water (50 mL) was added to quench the mixture, and the resulting mixture was stirred and separated. The aqueous phase was extracted with DCM (50 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 mL) and concentrated. The residue was purified by column chromatography (EA:PE=10:0→10:1→5:1) to give a yellowish oily product (2.7 g, yield: 77.1%). ESI-MS m / z: 412.1 [M+H] + .

[0090] Step 2: Synthesis of 1-3 In a 250 mL one-neck flask, 1-2 (2.7 g, 6.55 mmol), K3PO4 (2.78 g, 13.1 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.29 g, 6.55 mmol), Diox (60 mL), and water (12 mL) were added. After purging the system with Ar, Pd(dtbpf)Cl2 (427 mg, 0.655 mmol) was added. The mixture was purged with argon, heated to 80 °C, and stirred for 2.5 h. After completion of the reaction was confirmed by LC-MS, the mixture was filtered. EA (100 mL) and water (50 mL) were added to the filtrate, and the resulting mixture was stirred and liquid separation was performed. The organic phase was washed with saturated aqueous sodium chloride solution (50 mL) and concentrated. The residue was purified by column chromatography (EA:PE=10:0→10:1→5:1) to give a yellowish oily product (700 mg, yield: 32.0%). ESI-MS m / z: 334.2 [M+H] + .

[0091] Step 3: Combining 1-4 Into a 100 mL one-neck flask, 1-3 (700 mg, 2.1 mmol), THF (30 mL) and concentrated hydrochloric acid (3 mL) were added. The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was confirmed by LC-MS, DCM (30 mL) was added to the mixture, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate, the resulting mixture was stirred and the liquid was separated. The aqueous phase was then extracted with DCM (20 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brownish yellow oily product (730 mg, yield: >100%). ESI-MS m / z: 306.1 / 324.1 [M+H] + .

[0092] Step 4: Combining 1-5 In a 100 mL one-neck flask, 1-4 (730 mg, crude product, 2.1 mmol), ethyl (E)-N-((methylsulfonyl)oxy)acetimidate (1.42 g, 6.0 mmol), and DCM (30 mL) were added. After purging the system with argon, trifluoromethanesulfonic acid (340 mg, 2.26 mmol) was added, and the mixture was stirred at room temperature for 20 h. After the completion of the reaction was confirmed by LC-MS, the mixture was added with saturated aqueous sodium bicarbonate to adjust the pH to 7-8, and the resulting mixture was stirred and separated. The aqueous phase was then extracted with DCM (20 mL). The organic phases were combined, washed with saturated aqueous sodium chloride (20 mL), and concentrated. The residue was purified by flash to give a brownish yellow solid product (400 mg, yield: 62.9%). ESI-MS m / z: 303.1 [M+H] + .

[0093] Step 5: Synthesis of compound 1: In a 100 mL one-neck flask, 1-5 (50 mg, 0.153 mmol), K3PO4 (80 mg, 0.377 mmol), pyrazole-3-boronic acid (30 mg, 0.25 mmol), Diox (5 mL) and water (1 mL) were added. After purging the system with Ar, Pd(dtbpf)Cl2 (13 mg, 0.02 mmol) was added. The mixture was purged with argon, heated to 80 °C and stirred for 1.5 h. After LC-MS confirmed the completion of the reaction, the mixture was filtered and concentrated. The residue was purified by flash to give a yellowish solid product (10 mg, yield: 19.5%). ESI-MS m / z: 335.1 [M+H] + .

[0094] 1 H NMR (400 MHz, cdcl3) δ 8.78 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 5.5 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.38 (d, J= 5.5 Hz, 1H), 7.34 (s, 1H), 6.52 (dd, J = 2.6, 1.7 Hz, 1H), 4.44 (s, 1H), 4.14 - 4.05 (m, 4H), 3.86 (d, J = 11.5 Hz, 1H), 3.76 (d, J = 3.1 Hz, 1H), 3.63 (td, J = 12.0, 3.2 Hz, 1H), 3.40 (td, J = 12.7, 3.8 Hz, 1H), 1.37 (d, J = 6.8 Hz, 3H).

[0095] Example 2 and Example 3: Synthesis of 2-(2-((R)-3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)propionitrile (Compound 2) and (R)-2-methyl-2-(2-(3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)propionitrile (Compound 3) [ka] [ka]

[0096] Step 1: Synthesis of 2-1 In a 100 mL one-neck flask, 1-5 (100 mg, 0.331 mmol) and DMF (10 mL) were added. After purging the system with argon, the mixture was cooled to 0-5°C in an ice bath, and NaH (26 mg, 60%, 0.662 mmol) was added. The mixture was stirred at room temperature for 15 min, and then MeI (70 mg, 0.497 mmol) was added. The mixture was purged with argon and stirred at room temperature for 2 h. After completion of the reaction was confirmed by LC-MS, the mixture was poured into a 10 mL mixture of ice and water. EA (20 mL) was added, and the resulting mixture was stirred and liquid separation was performed. The aqueous phase was then extracted with EA (10 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily product (127 mg, yield: >100%). ESI-MS m / z:316.2 [M+H] + and 330.2 [M+H] + .

[0097] Step 2: Synthesis of Compound 2 and Compound 3 In a 100 mL single-neck flask, 2-1 (127 mg, crude product, 0.331 mmol), K3PO4 (160 mg, 0.754 mmol), pyrazole-3-boronic acid (56 mg, 0.497 mmol), Diox (10 mL) and water (2 mL) were added. After purging the system with Ar, Pd(dtbpf)Cl2 (25 mg, 0.038 mmol) was added. The mixture was purged with argon, heated to 80 °C and stirred for 1.5 h. After the reaction was completed by LC-MS, the mixture was filtered and concentrated. The residue was purified by flash to give a yellowish solid mixture. The mixture was purified by preparative HPLC to give compound 2 (10 mg, yield: 8.7%), ESI-MS m / z: 349.2 [M+H] + and compound 3 (17 mg, yield: 14.2%), ESI-MS m / z: 363.2 [M+H] + obtained.

[0098] Examples 4 to 24: Synthesis of Compounds 4 to 24 Compounds 4 to 24 in Table 1 were obtained according to the same synthesis method as in Example 2, using different starting materials.

[0099] [Table 1] TIFF2024529070000046.tif218168

[0100] Example 25: Synthesis of (R)-1-(2-(3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-ylmethyl)cyclohexane-1-carbonitrile (Compound 25) [ka] [ka]

[0101] Step 1: Synthesis of 25-1 In a 100 mL one-neck flask, 1-5 (100 mg, 0.331 mmol) and DMF (10 mL) were added. After purging the system with argon, the mixture was cooled to 0-5°C in an ice bath, and NaH (26 mg, 60%, 0.662 mmol) was added. The mixture was stirred at room temperature for 15 min, and then 1,5-dibromohexane (76 mg, 0.331 mmol) was added. The mixture was stirred at room temperature for 2 h. After completion of the reaction was confirmed by LC-MS, the mixture was poured into a 10 mL mixture of ice and water. EA (20 mL) was added, and the resulting mixture was stirred and liquid separation was performed. The aqueous phase was then extracted with EA (10 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily product (140 mg, yield: >100%). ESI-MS m / z:371.2 [M+H] + .

[0102] Step 2: Synthesis of compound 25 In a 100 mL one-neck flask, 25-1 (140 mg, crude product, 0.331 mmol), K3PO4 (160 mg, 0.754 mmol), pyrazole-3-boronic acid (56 mg, 0.497 mmol), dioxane (10 mL) and water (2 mL) were added. After purging the system with Ar, Pd(dtbpf)Cl2 (25 mg, 0.038 mmol) was added. The mixture was purged with argon, heated to 80 °C and stirred for 1.5 h. After the reaction was completed by LC-MS, the mixture was filtered and concentrated. The residue was purified by flash to give a yellowish solid product (46 mg, yield: 34.5%). ESI-MS m / z: 403.3 [M+H] + .

[0103] 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 5.7 Hz, 1H), 8.04 (d, J = 5.7 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.21 (s, 1H), 4.42 (d, J = 5.0 Hz, 1H), 4.17 (dd, J = 11.5, 3.8 Hz, 1H), 4.00 - 3.94 (m, 1H), 3.91 (s, 1H), 3.85 (dd, J = 11.6, 3.1 Hz, 1H), 3.71 (td, J = 11.8, 3.0 Hz, 1H), 3.55 (td, J = 12.4, 3.9 Hz, 1H), 2.55 (d, J = 12.7 Hz, 2H), 2.02 (d, J = 11.4 Hz, 6H), 1.85 (dd, J = 12.7, 4.1 Hz, 2H), 1.44 (d, J = 6.8 Hz, 3H).

[0104] Examples 26 to 32: Synthesis of Compounds 26 to 32 Compounds 26 to 32 in Table 2 were obtained using different starting materials and following the same synthetic method as in Example 25.

[0105] [Table 2]

[0106] Example 33: Synthesis of (R)-4-hydroxy-1-(2-(3-methylmorpholine)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)cyclohexane-1-carbonitrile (Compound 33) [ka] [ka]

[0107] Step 1: Synthesis of 33-1 In a 500 mL one-neck flask, 1-5 (2.0 g, 6.6 mmol) and DMF (200 mL) were added. After purging the system with argon, the mixture was cooled to 0-5°C in an ice bath, and NaH (528 mg, 60%, 13.2 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then 2,2-bis(2-bromoethyl)-1,3-dioxolane (2.85 g, 9.9 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the completion of the reaction was confirmed by LC-MS, the mixture was poured into a mixture of ice and water (200 mL). EA (200 mL) was added, and the resulting mixture was stirred and liquid separation was performed. The aqueous phase was then extracted with EA (100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown oily product (2.12 g, yield: 75%). ESI-MS m / z: 429.1 [M+H] + .

[0108] Step 2: Synthesis of 33-2: In a 500 mL one-neck flask, 33-1 (2.12 g, 4.94 mmol), acetone (50 mL) and 0.5 N HCl (20 mL) were added. The mixture was purged with Ar, heated to 50 °C and stirred for 5 h. After completion of the reaction was confirmed by LC-MS, the mixture was concentrated to half its volume, EA (100 mL) was added, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate, the resulting mixture was stirred and the liquid was separated. The aqueous phase was then extracted with EA (50 mL). The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a brown oily product (1.81 g, yield: 95%). ESI-MS m / z: 385.0 [M+H] + .

[0109] Step 3: Synthesis of 33-3 In a 500 mL one-neck flask, 33-2 (1.81 g, 4.7 mmol), K3PO4 (2.99 g, 14.1 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid (1.38 g, 7.05 mmol), dioxane (160 mL) and water (32 mL) were added. After purging the system with argon, Pd(dtbpf)Cl2 (309 mg, 0.47 mmol) was added. The mixture was purged with Ar, heated to 80 °C and stirred for 2 h. After the reaction was completed by LC-MS, the mixture was filtered and concentrated. The residue was purified by flash to give a yellowish solid product (1.67 g, yield: 71%). ESI-MS m / z: 501.3 [M+H] + .

[0110] Step 4: Synthesis of 33-4 Into a 100 mL single-neck flask were added 33-3 (100 mg, 0.2 mmol), THF (10 mL), MeOH (5 mL) and NaBH4 (6 mg, 0.16 mmol). The mixture was stirred at room temperature for 2 h. After completion of the reaction was confirmed by LC-MS, water (2 mL) was added to quench the mixture, and the resulting mixture was concentrated under reduced pressure to give the crude product. ESI-MS m / z: 503.3 [M+H] + .

[0111] Step 5: Synthesis of 33 In a 100 mL one-neck flask, the above crude product 33-4, THF (10 mL) and 2N HCl (3 mL) were added. The mixture was purged with Ar and stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was concentrated under reduced pressure. The residual liquid was purified by flash to give the product (8 mg, yield: 9.5%). ESI-MS m / z: 419.3 [M+H] + .

[0112] 1 H NMR (400 MHz, cdcl3) δ 8.50 (d, J = 5.8 Hz, 1H), 8.00 (d, J = 5.8 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.32 (d, J= 1.9 Hz, 1H), 7.20 (s, 1H), 4.42 (d, J = 7.0 Hz, 1H), 4.18 (dd, J= 11.4, 3.8 Hz, 1H), 4.01 - 3.95 (m, 1H), 3.93 (d, J= 11.4 Hz, 1H), 3.85 (dd, J = 11.5, 3.1 Hz, 1H), 3.80 - 3.65 (m, 2H), 3.55 (td, J = 12.4, 3.8 Hz, 1H), 2.62 (d, J= 12.2 Hz, 2H), 2.27 (d, J = 12.9 Hz, 2H), 2.12 - 1.92 (m, 4H), 1.44 (s, 3H).

[0113] Example 34: Synthesis of (R)-4-(dimethylamino)-1-(2-(3-methylmorpholine)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)cyclohexane-1-carbonitrile (Compound 34) [ka] [ka]

[0114] Step 1: Synthesis of 34-1 Into a 100 mL single-neck flask were added 33-3 (100 mg, 0.205 mmol), DCE (10 mL), AcOH (38 mg, 0.63 mmol), and dimethylamine (0.5 mL, 2 M in THF, 1.0 mmol). The mixture was stirred at room temperature for 30 min, and then NaBH(OAc)3 (87 mg, 0.41 mmol) was added. The mixture was heated to 50° C. and stirred for 3 h. After the reaction was essentially complete by LC-MS, the mixture was concentrated. The residue was purified by flash to give the product (32 mg, yield: 29.5%). ESI-MS m / z: 530.3 [M+H] + .

[0115] Step 2: Synthesis of 34 In a 100 mL one-neck flask, 34-1 (32 mg, 0.06 mmol), DCM (10 mL) and TFA (0.2 mL) were added. The mixture was purged with Ar and stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was concentrated under reduced pressure. The residual liquid was purified by flash to give the product (12 mg, yield: 44.9%). ESI-MS m / z: 446.3 [M+H] + .

[0116] 1H NMR (400 MHz, chloroform-d) δ 8.49 (d, J= 5.7 Hz, 1H), 8.01 (d, J = 5.7 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.20 (s, 1H), 4.46 - 4.38 (m, 1H), 4.17 (dd, J = 11.4, 3.8 Hz, 1H), 3.97 (dd, J= 12.5, 2.9 Hz, 1H), 3.92 (d, J = 11.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.70 (td, J = 11.8, 3.0 Hz, 1H), 3.55 (td, J = 12.4, 3.9 Hz, 1H), 2.65 (d, J = 12.7 Hz, 2H), 2.44 (d, J = 11.2 Hz, 1H), 2.39 (s, 6H), 2.15 (d, J = 13.0 Hz, 2H), 2.09 - 1.99 (m, 2H), 1.93 (t, J = 12.0 Hz, 2H), 1.44 (d, J = 6.8 Hz, 3H).

[0117] Example 35 and Example 36: Synthesis of Compound 35 and Compound 36 Compounds 35 and 36 in Table 3 were obtained using different starting materials and following the same synthetic method as in Example 34.

[0118] [Table 3]

[0119] Example 37: Synthesis of (R)-4-(2-(3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)piperidine-4-carbonitrile (Compound 37) [ka] [ka]

[0120] Step 1: Synthesis of 37-2 In a 500 mL one-neck flask, 1-5 (2.0 g, 6.6 mmol) and DMF (200 mL) were added. After purging the system with argon, the mixture was cooled to 0-5°C in an ice bath, and NaH (528 mg, 60%, 13.2 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then N,N-bis(2-bromoethyl)-2,2,2-trifluoroacetamide (3.24 g, 9.9 mmol) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction was confirmed by LC-MS, the mixture was poured into a mixture of ice and water (200 mL). EA (200 mL) was added, and the resulting mixture was stirred and liquid separation was performed. The aqueous phase was then extracted with EA (100 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown oily product (1.61 g, yield: 52%). ESI-MS m / z: 467.3 [M+H] + .

[0121] Step 2: Synthesis of 37-3: In a 500 mL one-neck flask, 37-2 (1.61 g, crude product, 3.44 mmol), K3PO4 (1.66 g, 7.84 mmol), (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid (1.01 g, 5.164 mmol), dioxane (160 mL) and water (32 mL) were added. After purging the system with Ar, Pd(dtbpf)Cl2 (250 mg, 0.38 mmol) was added. The mixture was purged with argon, heated to 80 °C and stirred for 2 h. After the reaction was completed by LC-MS, the mixture was filtered and concentrated. The residue was purified by flash to give a yellowish solid product (1.63 g, yield: 81%). ESI-MS m / z: 584.3 [M+H] + .

[0122] Step 3: Synthesis of 37-4 In a 500 mL one-neck flask, 37-3 (1.60 g, 2.742 mmol), MeOH (50 mL) and 1N KOH (4 mL, 4 mmol) were added. The mixture was purged with Ar and stirred at room temperature for 20 h. After the reaction was confirmed to be complete by LC-MS, 1N HCl (2 mL) was added to the mixture, and the resulting mixture was concentrated to a small volume under reduced pressure. The residual liquid was purified by flash to give a yellowish solid product (1.0 g, yield: 75%). ESI-MS m / z: 488.3 [M+H] + .

[0123] Step 4: Synthesis of 37 Into a 100 mL one-neck flask were added 37-4 (50 mg, 0.103 mmol), DCM (5 mL) and TFA (0.2 mL). The mixture was purged with Ar and stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was concentrated under reduced pressure. The residual liquid was purified by flash to give the product (11 mg, yield: 26.6%). ESI-MS m / z: 404.2 [M+H] + .

[0124] Example 38: Synthesis of (R)-1-acetyl-4-(2-(3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)piperidine-4-carbonitrile (Compound 38) [ka] [ka]

[0125] Step 1: Synthesis of 38-1 In a 100 mL one-neck flask, 37-4 (100 mg, 0.205 mmol), DCM (10 mL) and DIPEA (79 mg, 0.615 mmol) were added. After purging the system with Ar, acetyl chloride (24 mg, 0.306 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature for 2 h. After the reaction was confirmed to be substantially complete by LC-MS, water (10 mL) was added to the mixture and the liquid was separated. The aqueous phase was then extracted with DCM (10 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the product (120 mg, yield: >100%). ESI-MS m / z: 530.3 [M+H] + .

[0126] Step 2: Synthesis of 38 In a 100 mL one-neck flask, 38-1 (120 mg, crude product, 0.205 mmol), DCM (10 mL) and TFA (0.5 mL) were added. The mixture was purged with Ar and stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was concentrated under reduced pressure. The residue was purified by flash to give the product (45 mg, yield: 49.3%). ESI-MS m / z: 446.2 [M+H] + .

[0127] Example 39 and Example 40: Synthesis of Compound 39 and Compound 40 Compound 39 and Compound 40 in Table 4 were obtained according to the same synthetic methods as in Example 37 and Example 38 using different starting materials.

[0128] [Table 4]

[0129] Example 41: Synthesis of (R)-4-(2-(3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)-1-(2,2,2-trifluoroethyl)piperidine-4-carbonitrile (Compound 41) [ka] [ka]

[0130] Step 1: Synthesis of 41-1 In a 100 mL one-neck flask, 37-4 (100 mg, 0.205 mmol), DMF (5 mL) and K2CO3 (85 mg, 0.615 mmol) were added. After purging the system with Ar, trifluoroiodoethane (65 mg, 0.31 mmol) was added and the mixture was stirred at room temperature for 20 h. After completion of the reaction was confirmed by LC-MS, EA (20 mL) and water (10 mL) were added to the mixture, the mixture was stirred and the liquid was separated. The aqueous phase was then extracted with EA (10 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown oily product (201 mg, yield: >100%, containing DMF). ESI-MS m / z: 570.3 [M+H] + .

[0131] Step 2: Synthesis of 41 In a 100 mL one-neck flask, 41-1 (201 mg, 0.205 mmol, crude product), DCM (10 mL) and TFA (0.5 mL) were added. The mixture was purged with Ar and stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was concentrated under reduced pressure. The residual liquid was purified by flash to give the product (16 mg, yield: 16.1%). ESI-MS m / z: 486.2 [M+H] + .

[0132] Examples 42 to 44: Synthesis of Compounds 42 to 44 Compounds 42 to 44 in Table 5 were obtained according to the same synthesis method as in Example 41 using different starting materials.

[0133] [Table 5]

[0134] Example 45: Synthesis of (R)-1-(4-chlorophenyl)-4-(2-(3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)piperidine-4-carbonitrile (Compound 45) [ka] [ka]

[0135] Step 1: Synthesis of 45-1 A 100 mL single-neck flask was charged with 37-4 (100 mg, 0.205 mmol), DMF (5 mL), Cs2CO3 (200 mg, 0.615 mmol), Xantphos (24 mg, 0.041 mmol), 4-chloroiodobenzene (98 mg, 0.41 mmol), and Pd2(dba)3 (19 mg, 0.021 mmol). The mixture was purged with Ar, heated to 120 °C, and stirred for 5 h. After the reaction was essentially complete by LC-MS, the mixture was filtered. The filtrate was purified by flash to give the product (35 mg, yield: 28.5%). ESI-MS m / z: 598.1 [M+H] + .

[0136] Step 2: Synthesis of 45 In a 100 mL one-neck flask, 45-1 (35 mg, 0.059 mmol), DCM (10 mL) and TFA (0.2 mL) were added. The mixture was purged with Ar and stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was concentrated under reduced pressure. The residual liquid was purified by flash to give the product (19 mg, yield: 63.2%). ESI-MS m / z: 514.1 [M+H] + .

[0137] Examples 46 to 50: Synthesis of Compounds 46 to 50 Compounds 46 to 50 in Table 6 were obtained using different starting materials and following the same synthetic method as in Example 45.

[0138] [Table 6]

[0139] Example 51 and Example 52: Synthesis of Compound 51 and Compound 52 Compound 51 and compound 52 in Table 7 were obtained according to the same synthetic method as in Example 25 using different starting materials.

[0140] [Table 7]

[0141] Example 53: Synthesis of (R)-4-methoxy-1-(2-(3-methylmorpholine)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)cyclohexane-1-carbonitrile (Compound 53) [ka] [ka]

[0142] Step 1: Synthesis of 53-1 To a 50 mL one-neck flask, 33-4 (52 mg, 0.103 mmol) and DMF (5 mL) were added. After purging the system with Ar, NaH (6.2 mg, 60% in mineral oil, 0.155 mmol) was added. The mixture was stirred at room temperature for 10 min, and then MeI (22 mg, 0.155 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was essentially complete by LC-MS, the mixture was used directly in the next step.

[0143] Step 2: Synthesis of 53 THF (2 mL) and 1N HCl solution (2 mL, 2 mmol) were added to the above reaction mixture, and the mixture was stirred at room temperature for 2 h. After the reaction was completed by LC-MS, the mixture was purified by flash to give the product (16 mg, yield: 35.9%). ESI-MS m / z: 433.2 [M+H] + .

[0144] Examples 54 to 59: Synthesis of Compounds 54 to 59 Compounds 54 to 59 in Table 8 were obtained using different starting materials and following the same synthetic method as in Example 53.

[0145] [Table 8]

[0146] Examples 60 to 65: Synthesis of Compounds 60 to 65 Compounds 60 to 65 in Table 9 were obtained using different starting materials and following the same synthetic method as in Example 34.

[0147] [Table 9]

[0148] Examples 66-84: Synthesis of compounds 66-84 Compounds 66 to 84 in Table 10 were obtained using different starting materials and following the same synthetic method as in Example 41.

[0149] [Table 10] TIFF2024529070000072.tif227168TIFF2024529070000073.tif110168

[0150] Example 85: Synthesis of 3-(2-((R)-3-methylmorpholino)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl)-8-oxabicyclo[3.2.1]octane-3-carbonitrile (Compound 85) [ka] [ka]

[0151] Step 1: Synthesis of 85-1 In a 100 mL one-neck flask, (tetrahydrofuran-2,5-diyl)dimethanol (500 mg, 3.783 mmol), triphenylphosphine (3.97 g, 15.133 mmol), imidazole (1.29 g, 18.915 mmol), and DCM (25 mL) were added. The mixture was cooled to 0-5 °C in an ice bath under argon atmosphere, and iodine (3.84 g, 15.132 mmol) was added in batches. After the addition, the mixture was stirred at room temperature overnight. After the completion of the reaction was confirmed by LC-MS, a saturated sodium thiosulfate solution (25 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes, and liquid separation was performed. The aqueous phase was then extracted with DCM (25 mL). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash to give the product (536 mg, yield: 40.3%).

[0152] Step 2: Synthesis of 85-2 In a 100 mL one-neck flask, 1-5 (100 mg, 0.331 mmol) and DMF (10 mL) were added. After purging the system with argon, Cs2CO3 (216 mg, 0.662 mmol) and 85-1 (116 mg, 0.331 mmol) were added. The mixture was stirred at room temperature for 20 h. The product was detected by LC-MS, and the mixture was purified by flash purification to give a brown oily product (22 mg, yield: 16.7%). ESI-MS m / z: 399.2 [M+H] + .

[0153] Step 3: Synthesis of compound 85 In a 50 mL one-neck flask, 85-2 (22 mg, 0.055 mmol), K3PO4 (35 mg, 0.165 mmol), pyrazole-3-boronic acid (10 mg, 0.089 mmol), dioxane (5 mL) and water (1 mL) were added. After purging the system with Ar, Pd(dtbpf)Cl2 (10 mg, 0.015 mmol) was added. The mixture was purged with argon, heated to 80 °C and stirred for 1.5 h. After the reaction was completed by LC-MS, the mixture was filtered and concentrated. The residue was purified by flash to give a yellowish solid product (6 mg, yield: 25.3%). ESI-MS m / z: 431.2 [M+H] + .

[0154] The nuclear magnetic resonance (NMR) spectra of some of the compounds of the invention are shown in Table 11 below.

[0155] [Table 11]

[0156] Example 86: In vitro antiproliferative activity of compounds of the invention against MIA PaCa-2 cells MIA PaCa-2 cells were seeded in 384-well plates at 3000 cells / well. After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting from 5 μM were added. Viability was assessed 72 hours after administration by measuring intracellular ATP content. The inhibition rate of viable cells by compounds was calculated compared to the DMSO group and was expressed as IC 50 The values ​​were calculated and the results are shown in Table 12 below.

[0157] [Table 12]

[0158] Example 87: In vitro antiproliferative activity of compounds of the invention in combination with gemcitabine against MIA PaCa-2 cells MIA PaCa-2 cells were seeded in 384-well plates at 3000 cells / well and treated with 20 nM gemcitabine. After overnight adherent culture, DMSO or compounds serially diluted 1:5 starting at 100 nM were added. Viability was assessed 72 hours after treatment by measuring intracellular ATP content. The inhibition rate of viable cells by compounds was calculated compared to the DMSO group and IC 50 The values ​​were calculated and the results are shown in Table 13 below.

[0159] [Table 13]

[0160] As can be seen from the data in Table 13, compounds of the invention in combination with gemcitabine exhibited significantly improved in vitro antiproliferative activity against MIA PaCa-2 cells compared to the control compound BAY1895344 in combination with gemcitabine.

[0161] Example 88: Liver microsomal stability of some of the compounds of the present invention After incubating 1 μM of a compound with 500 μg / mL human liver microsomes or mouse liver microsomes and an NADPH regenerating system at 37°C for different periods of time, the remaining amount of the compound was analyzed using LC-MS-MS. 1 / 2 The results are shown in Table 14 below.

[0162] [Table 14]

[0163] Example 89: In vivo pharmacokinetic studies of some of the compounds of the invention Female CD-1 mice aged 7–10 weeks were administered 2 mg / kg intravenously and 10 mg / kg orally, respectively. Mice were fasted for at least 12 hours before dosing, fed 4 hours after dosing, and allowed free access to water throughout the experiment.

[0164] On the day of the experiment, animals in the intravenous group were given a single injection of the corresponding compound at a dose of 10 mL / kg via the tail vein, and animals in the oral group were given a single intragastric injection of the corresponding compound at a dose of 10 mL / kg. Before administration, the animals were weighed, and the dose was calculated according to the body weight. The sample collection times were 0.083 hours, 0.167 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. Approximately 200 μL of whole blood was collected from the orbital venous plexus at each time point and used to prepare plasma for concentration measurement by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). Plasma concentrations were processed using the noncompartmental model of WinNonlin pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. The results are shown in Table 15 below.

[0165] [Table 15]

[0166] Example 90: Pharmacokinetic evaluation of some of the compounds of the present invention in rats SPF grade SD female rats aged 7-10 weeks were administered the compound intravenously and orally at doses of 1 mg / kg and 10 mg / kg, respectively. The rats were fasted for at least 12 hours before dosing, given food 4 hours after dosing, and allowed free access to water throughout the experiment.

[0167] On the day of the experiment, animals in the intravenous group were given a single injection of the corresponding compound at a dose of 2 mL / kg via the tail vein, and animals in the oral group were given a single intragastric injection of the corresponding compound at a dose of 10 mL / kg. Before administration, animals were weighed and the dose was calculated according to their body weight. Sample collection times were 0.083 hours (intravenous group only), 0.125 hours (oral group only), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours. Approximately 200 μL of whole blood (EDTA-K2 anticoagulated) was collected from the jugular vein or other suitable vein at each time point and used to prepare plasma for concentration measurement by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). After collection of the PK sample at the last time point, all animals were killed by CO2 asphyxiation. Plasma concentrations were processed using a noncompartmental model in WinNonlin™ version 8.2 (Pharsight, Mountain View, Calif.) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[0168] The results are shown in Table 16 below.

[0169] [Table 16]

[0170] Example 91: In vivo efficacy testing of some of the compounds of the invention Human colon cancer LOVO cells were routinely cultured in 1640 medium containing 10% fetal bovine serum in an incubator at 37°C and 5% CO2. After subculture, cells were harvested when they reached the desired number. 7 LOVO cells were injected into the left dorsal side of each nude mouse until tumors grew to 100–200 mm 3After the mice had grown to 100 mm, the animals were randomly divided into groups for administration. The groups consisted of 8 mice in the solvent control group and 8 mice in the compound administration group. The compounds were orally administered 3 days a week with 4 days off for 21 consecutive days. The vehicle was a 0.5% MC suspension containing 1% tween-80. The tumor volume and body weight of the mice were measured every Tuesday and Thursday, and the nude mice were sacrificed on the 21st day after administration. The test results are shown in the table below. The tumor growth inhibition ability of the compounds was evaluated by tumor growth inhibition rate (TGI) = 1-(tumor volume on the 21st day of administration group-tumor volume on the 1st day of administration group) / (administration volume on the 21st day of control group-tumor volume on the 1st day of control group). The toxicity of the compounds was evaluated based on the body weight of the mice.

[0171] The groups are as follows: 1) Solvent control group, 2) Compound 25 group, 3) Compound 27 group, 4) Compound 29 group, 5) Compound 33 group, 6) Compound 34 group, 7) Compound 43 group, 8) Control compound (BAY1895344) group.

[0172] The results are shown in Table 17 below.

[0173] [Table 17]

[0174] Example 92: In vivo efficacy testing of some of the compounds of the invention Human colon cancer HT29 cells were routinely cultured in 1640 medium containing 10% fetal bovine serum in an incubator at 37°C and 5% CO2. After subculture, the cells were harvested when they reached the desired amount. 7 HT29 cells were injected into the left dorsal side of each nude mouse, and tumors were grown to 100–200 mm 3After the mice had grown to 100 mm, the animals were randomly divided into groups for administration. The administration groups were a vehicle control group of 6 mice, a single-drug administration group of gemcitabine (GMC) 15 mg / kg, and a combination administration group of gemcitabine 15 mg / kg and the compound. Gemcitabine was intraperitoneally administered once a week using PBS as a vehicle. The compound was administered 3 days a week with 4 days off (3 on / 4 off), for 21 consecutive days, and the vehicle was a 0.5% MC suspension containing 1% tween-80. The tumor volume and body weight of the mice were measured every Tuesday and Thursday, and the nude mice were sacrificed on the 21st day after administration. The test results are shown in the table below. The tumor growth inhibition ability of the compound was evaluated by tumor growth inhibition rate (TGI) = 1 - (tumor volume on the 21st day of the administration group - tumor volume on the 1st day of the administration group) / (administration volume on the 21st day of the control group - tumor volume on the 1st day of the control group). The toxicity of the compounds was assessed based on the body weight of the mice.

[0175] The groups are as follows: 1) Vehicle control group, 2) Vehicle + GMC group, 3) Compound 25 group, 4) Compound 25 + GMC group, 5) Compound 29 group, 6) Compound 29 + GMC group, 7) Compound 33 group, 8) Compound 33 + GMC group, 9) Compound 34 group, 10) Compound 34+GMC group, 11) Compound 43 group, 12) Compound 43+GMC group, 13) Control compound (BAY1895344) group, 14) Control compound (BAY1895344)+GMC group.

[0176] The results are shown in Table 18 below.

[0177] [Table 18]

[0178] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1), or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof. 【Chemical 1】 (In general formula (1), X is CH or N; R １ teeth, 【Chemistry 2】 and R ２ and R ３ are each independently -H, -D, halogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C3-C10) cycloalkyl, (C3-C10) cycloalkenyl, (3- to 10-membered) heterocycloalkyl, (3- to 10-membered) heterocycloalkenyl, (C6-C10) aryl, or (5- to 10-membered) heteroaryl, wherein said (C1-C6) aryl alkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C1-C6) alkoxy, the (C3-C10) cycloalkyl, the (C3-C10) cycloalkenyl, the (3- to 10-membered) heterocycloalkyl, the (3- to 10-membered) heterocycloalkenyl, the (C6-C10) aryl or the (5- to 10-membered) heteroaryl are each independently one of the following groups: -H, -D, halogen, -OH, -R ６ , -NR ４ R ５ , -C(O)OR ４ , —C(O)NR ４ R ５ , -S(O) Ｐ R ４ , -S(O) ２ NR ４ R ５ , -P(O)(OR ４ ) ２ , -P(O)(R ４ ) ２ , (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (3-10 membered)heterocycloalkyl, (3-10 membered)heterocycloalkenyl, (C6-C10)aryl or (5-10 membered)heteroaryl; Or, R ２ and R ３ together with the carbon atoms to which they are attached form a (C3-C15)cycloalkyl or a (3- to 15-membered)heterocycloalkyl, wherein said (C3-C15)cycloalkyl or said (3- to 15-membered)heterocycloalkyl each independently comprise one or more R ６ optionally substituted with R ４ and R ５ are each independently -H, -D, (C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C3-C10) cycloalkyl, (C3-C10) cycloalkenyl, (3- to 10-membered) heterocycloalkyl, (3- to 10-membered) heterocycloalkenyl, (C6-C10) aryl, or (5- to 10-membered) heteroaryl; Or, R ４ and R ５ together with the N atom to which it is attached form a (3- to 10-membered) heterocycloalkyl, wherein said (3- to 10-membered) heterocycloalkyl is selected from the following groups: -H, -D, halogen, -OH, -NR ７ R ８ , -C(O)OR ７ , —C(O)NR ７ R ８ , -S(O) Ｐ R ７ , -S(O) ２ NR ７ R ８ , -P(O)(OR ７ ) ２ , -P(O)(R ７ ) ２ , (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (3-10 membered)heterocycloalkyl, (3-10 membered)heterocycloalkenyl, (C6-C10)aryl, or (5-10 membered)heteroaryl; Each R ６ are independently —H, —D, halogen, —OH, or —NR ７ R ８ , -C(O)R ７ , -C(O)OR ７ , —C(O)NR ７ R ８ , -(CH ２ ) ｎ -S(O) Ｐ R ７ , -(CH ２ ) ｎ -S(O) ２ NR ７ R ８ , -P(O)(OR ７ ) ２ , -P(O)(R ７ ) ２ , (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C10) cycloalkyl, (C3-C10) cycloalkenyl, (3- to 10-membered) heterocycloalkyl, (3- to 10-membered) heterocycloalkenyl, (C6-C10) aryl or (5- to 10-membered) heteroaryl, wherein said (C1-C6) alkyl, said (C2-C6) alkynyl The (C2-C6)alkenyl, the (C1-C6)alkynyl, the (C1-C6)haloalkyl, the (C1-C6)alkoxy, the (C3-C10)cycloalkyl, the (C3-C10)cycloalkenyl, the (3- to 10-membered)heterocycloalkyl, the (3- to 10-membered)heterocycloalkenyl, the (C6-C10)aryl, or the (5- to 10-membered)heteroaryl each independently represent the following groups: -H, -D, halogen, -OH, -NR ７ R ８ , -C(O)OR ７ , —C(O)NR ７ R ８ , -(CH ２ ) ｎ -S(O) Ｐ R ７ , -(CH2) ｎ -S(O) ２ NR ７ R ８ , -P(O)(OR ７ ) ２ , -P(O)(R ７ ) ２ , (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkenyl, (3-10 membered)heterocycloalkyl, (3-10 membered)heterocycloalkenyl, (C6-C10)aryl or (5-10 membered)heteroaryl; R ７ and R ８ are each independently -H, -D, (C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C3-C10) cycloalkyl, (C3-C10) cycloalkenyl, (3- to 10-membered) heterocycloalkyl, (3- to 10-membered) heterocycloalkenyl, (C6-C10) aryl, or (5- to 10-membered) heteroaryl; p is 0, 1, or 2; n is 0, 1, 2, or 3.

2. 2. The compound according to claim 1, wherein in general formula (1), X is CH, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

3. In general formula (1), R １ but, 【Chemistry 3】 2. The compound of claim 1, wherein:

4. In general formula (1), R ２ and R ３ are each independently -H, -D, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C3) alkoxy, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl, (3- to 8-membered) heterocycloalkyl, (3- to 8-membered) heterocycloalkenyl, (C6-C10) aryl, or (5- to 10-membered) heteroaryl, wherein said (C1-C3) aryl The alkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C1-C3) alkoxy, the (C3-C6) cycloalkyl, the (C3-C6) cycloalkenyl, the (3- to 8-membered) heterocycloalkyl, the (3- to 8-membered) heterocycloalkenyl, the (C6-C10) aryl or the (5- to 10-membered) heteroaryl are each independently selected from the following groups: -H, -D, -F, -Cl, -Br, -I, -OH, -R ６ , -NR ４ R ５ , -C(O)OR ４ , —C(O)NR ４ R ５ , -S(O) Ｐ R ４ , -S(O) ２ NR ４ R ５ , -P(O)(OR ４ ) ２ , -P(O)(R ４ ) ２ , (C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C3)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl, (3- to 8-membered)heterocycloalkyl, (3- to 8-membered)heterocycloalkenyl, (C6-C10)aryl or (5- to 10-membered)heteroaryl; Or, R ２ and R ３ together with the carbon atoms to which they are attached form a (C3-C15)cycloalkyl or a (3- to 15-membered)heterocycloalkyl, wherein said (C3-C15)cycloalkyl or said (3- to 15-membered)heterocycloalkyl each independently comprise one or more R ６ 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with:

5. In general formula (1), R ２ and R ３ are each independently —H, —F, —Cl, or —CH ３ , 【Chemistry 4】 2. The compound of claim 1, wherein:

6. In general formula (1), R ２ and R ３ together with the carbon atom to which they are bonded to form the (C3-C15)cycloalkyl or the (3- to 15-membered)heterocycloalkyl, 【Chemistry 5】 wherein said (C3-C15)cycloalkyl or said (3- to 15-membered)heterocycloalkyl is selected from the following groups: -H, -F, -CH ３ , -CH ２ CH ３ , -OH, 【Chemistry 6】 、-NH ２ 、-NH(CH ３ )、-N(CH ３ ) ２ 、-N(CH ２ CH ３ ) ２ 、-OCH ３ 、-OCH ２ CH ３ 、 【Chemistry 7】 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with one or more of:

7. In general formula (1), R ４ and R ５ are each independently —H, —D, or —CH ３ , 【Chemistry 8】 2. The compound of claim 1, wherein:

8. In general formula (1), R ４ and R ５ are each independently —H or —CH ３ 8. The compound of claim 7, wherein:

9. In general formula (1), R ６ -H, -F, -CH ３ , -CH ２ CH ３ , -OH, 【Chemistry 9】 -NH ２ 、-NH(CH ３ )、-N(CH ３ ) ２ 、-N(CH ２ CH ３ ) ２ 、-OCH ３ 、-OCH ２ CH ３ 、 【Chemistry 10】 2. The compound of claim 1, wherein:

10. In general formula (1), R ７ and R ８ are each independently —H or —CH ３ 2. The compound of claim 1, wherein:

11. The compound has the following structure: 【Chemistry 11】 【change】 【change】 【change】 【change】 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, having one of the following formulas:

12. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and the compound of claim 1 or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.

13. 10. Use of a compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for treating a disease associated with ATP protein kinase.

14. 14. The use according to claim 13, wherein the disease is cancer, and the cancer is a blood cancer or a solid tumor.

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