Compounds as Src Inhibitors

Abstract

A group of compounds is disclosed as Src inhibitors.Specifically, the present invention relates to the compound of general formula (1), its preparation method, and the use of the compound of general formula (1) and its isomers, crystals, pharmaceutically acceptable salts, hydrates or solvates as Src inhibitors.The compound of the present invention and its isomers, crystals, pharmaceutically acceptable salts, hydrates or solvates can be used in the preparation of medicines for treating or preventing diseases related to Src protein. [Formula 1] TIFF2024544558000120.tif51168

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 202111350842.6, filed on November 15, 2021, which is incorporated by reference in its entirety herein.

[0002] The present invention belongs to the field of pharmaceutical chemistry, and in particular relates to a group of compounds having inhibitory activity against Src protein, a method for their preparation, and the use of said compounds in the preparation of medicines for treating or preventing related diseases mediated by Src. [Background technology]

[0003] Src belongs to the SFK family of non-receptor tyrosine kinases (SFKs) and plays important roles in multiple signaling pathways in cells. Src is composed of seven functional domains, including: 1. an N-terminal myristoylation sequence associated with an SH4 domain (Src homology 4), 2. an Src-specific domain, 3. an SH3 domain (Src homology 3), 4. an SH2 domain (Src homology 2), 5. a liner region capable of intramolecular binding with the SH3 domain, and 6. a kinase domain also known as an SH1 domain (Src homology 1). Structural changes in the Src protein determine the active or inactive state of Src kinase. In normal tissues, Src is generally in an inactive state. In tumor tissues, Src is generally overexpressed or aberrantly activated.

[0004] Src is involved in multiple cell signaling processes. Src can be activated by G protein-coupled receptors (GPCRs), adhesion receptors, cytokine receptors, and receptor tyrosine kinases (RTKs, such as EGFR, VEGFR, HER2, and PDGFR). As an effector of RTK signaling pathways, Src plays an important signaling role in the EGFR / -ERK pathway, PI3K / -Akt / mTOR pathway, and JAK / -STAT pathway, promoting cancer development by promoting cell proliferation, differentiation, and migration. Summary of the Invention [Problem to be solved by the invention]

[0005] Src has been shown to be associated with various diseases, and intensive research on Src has found overexpression or abnormal activation of Src in various tumors, including breast cancer, non-small cell lung cancer, intestinal cancer, head and neck squamous cell carcinoma, pancreatic cancer, ovarian cancer, etc. Therefore, there is an urgent need to research and discover compounds with excellent activity targeting Src. [Means for solving the problem]

[0006] (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 the general formula (1), X 1 CR a1 or N, X 2 CR a2 or N, Y 1 is H or F, Y 2 is H or F, L 1 -C(O)-, -NR 2 C(O)-, -NR 2C(O)O-, -OC(O)NR 2 -, -C(O)NR 2 -, -NR 3 C(O)NR 2 -, -NR 2 S(O)2-, -S(O) p -, -S(O)NR 2 -, or -NR 3 S(O)2NR 2 - and R 1 is -H, -OH, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, phenyl, (5-membered to 9-membered) heteroaryl, or (4-membered to 6-membered) heterocycloalkyl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C6) cycloalkyl, the phenyl, the (5-membered to 9-membered) heteroaryl, or the (4-membered to 6-membered) heterocycloalkyl are each independently selected from the following groups: -H, halogen, -OH, -OR 5 , -CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; L 2 is (C1-C6) alkylene, wherein the (C1-C6) alkylene is independently selected from the following groups: -H, halogen, -OH, -OR 5 , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, and [ka] may be optionally substituted by one, two, three or four of Z is -OR 7 , -NR 7 R 8 , -NR 6 (CH2) m OR 7 , -NR 6 (CH2) m NR 7 R 8, -O(CH2) m OR 6 , -O(CH2) m NR 7 R 8 or (4- to 12-membered)heterocycloalkyl, wherein the (4- to 12-membered)heterocycloalkyl are each independently selected from the following groups: -H, halogen, -OH, -OR 4 , -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C6) cycloalkyl, -NR 7 R 8 , -NR 6 (CH2) m OR 7 , -O(CH2) m OR 6 , -O(CH2) m NR 7 R 8 , -NR 6 (CH2) m NR 7 R 8 , -(CH2) m OR 7 , -(CH2) m NR 7 R 8 and R 9 , optionally substituted by one, two, three or four of R a1 and R a2 are each independently -H, -OR 5 , -CN, or halogen; R 2 and R 3 are each independently -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or (C3-C6) cycloalkyl; R 4 is -H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or (C3-C6) cycloalkyl; R 5 is -H, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C6) cycloalkyl; R 6 , R 7 and R 8 are each independently -H, a (C1-C6) alkyl, a (C1-C6) haloalkyl, a (C2-C6) alkenyl, a (C2-C6) alkynyl, a (C3-C6) cycloalkyl, a (4-membered to 12-membered) heterocycloalkyl, a phenyl, or a (5-membered to 6-membered) heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C6) cycloalkyl, the (4-membered to 12-membered) heterocycloalkyl, the phenyl, or the (5-membered to 6-membered) heteroaryl are each independently one of the following groups: -H, halogen, -OH, -OR 10 , -CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; or R 7 and R 8 may form, together with the N atom to which they are attached, a (4- to 12-membered)heterocycloalkyl, wherein said (4- to 12-membered)heterocycloalkyl is selected from the following groups: -H, halogen, -OH, -OR 10 , -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) cycloalkyl, -NR 10 R 11 , -NR 10 (CH2) m OR 11 , -O(CH2) m OR 10 , -O(CH2) m NR 10 R 11 , -NR 10 (CH2) m NR 11 R 12 , -(CH2) m OR 7 , -(CH2) m NR 7 R 8 and R 9 , optionally substituted by one, two, three or four of R 9is -H or (4- to 9-membered)heterocycloalkyl, wherein said (4- to 9-membered)heterocycloalkyl is independently selected from the following groups: -H, -OH, -OR 10 , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, or (C3-C6)cycloalkyl; R 10 , R 11 and R 12 are each independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, or (4- to 6-membered)heterocycloalkyl; p is an integer of 0, 1, or 2, and m is an integer of 1, 2, or 3.

[0007] In another preferred embodiment, in general formula (1), L 1 is -C(O)-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2-, -S(O)2 NH-, -NHS(O)2NH-, -N(CH3)C(O)-, -N(CH3)C(O)O-, -OC(O)N(CH3)-, -C(O)N(CH3)-, -N(CH 3)C(O)NH-, -NHC(O)N(CH3)-, -N(CH3)C(O)N(CH3)-, -N(CH3)S(O)2-, -S(O)2-, -S(O)-, - S-, -S(O)2N(CH3)-, -N(CH3)S(O)2NH-, -NHS(O)2N(CH3)- or -N(CH3)S(O)2N(CH3)-, and L 1 is preferably -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHC(O)O-, -OC(O)NH- or -C(O)NH-, and L 1 is more preferably -NHC(O)-, -NHC(O)O-, or -NHC(O)NH-, and L 1 is more preferably -NHC(O)O-.

[0008] In another preferred embodiment, in the general formula (1), R 1is -H, -OH, -CN, (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C3-C6)cycloalkyl, phenyl, (5-membered to 9-membered)heteroaryl, or (4-membered to 6-membered)heterocycloalkyl, wherein the (C1-C5)alkyl, the (C1-C5)haloalkyl, the (C2-C5)alkenyl, the (C2-C5)alkynyl, the (C3-C6)cycloalkyl, the phenyl, the (5-membered to 9-membered)heteroaryl, or the (4-membered to 6-membered)heterocycloalkyl may each independently be optionally substituted with one, two, three, or four of the following groups: -H, -F, -Cl, -Br, -OH, -OCH3, -CN, (C1-C3)alkyl, and (C1-C3)haloalkyl.

[0009] In another preferred embodiment, in the general formula (1), R 1 are -H, -OH, -CN, [ka] and preferably [ka] and more preferably [ka] and more preferably [ka] and more preferably [ka] It is.

[0010] In another preferred embodiment, in general formula (1), L 2is (C1-C4) alkylene, wherein the (C1-C4) alkylene is each independently selected from the following groups: -H, -F, -OH, -OCH3, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, and [ka] may be optionally substituted with one, two, three or four of:

[0011] In another preferred embodiment, in general formula (1), L 2 teeth, [ka] and preferably [ka] and more preferably [ka] It is.

[0012] In another preferred embodiment, in the general formula (1), Z is -NR 7 R 8 , -NR 6 (CH2)2OR 7 , -NR 6 (CH2)2NR 7 R 8 , -O(CH2)2OR 6 , -O(CH2)2NR 7 R 8 or (4- to 11-membered)heterocycloalkyl, wherein the (4- to 11-membered)heterocycloalkyl is independently selected from the following groups: -H, -F, -OH, -OCH3, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, -NR 7 R 8 , -NR 6 (CH2)2OR 7 , -O(CH2)2OR 6 , -O(CH2)2NR 7 R8 , -NR 6 (CH2)2NR 7 R 8 , -(CH2)2OR 7 , -(CH2)2NR 7 R 8 , -CH2OR 7 , -CH2NR 7 R 8 and R 9 , which may be optionally substituted with one, two, three or four of:

[0013] In another preferred embodiment, in the general formula (1), R 6 , R 7 and R 8 are each independently -H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, (4-membered to 9-membered)heterocycloalkyl, phenyl, or (5-membered to 6-membered)heteroaryl, wherein the (C1-C3)alkyl, the (C1-C3)haloalkyl, the (C3-C6)cycloalkyl, the (4-membered to 9-membered)heterocycloalkyl, the phenyl, or the (5-membered to 6-membered)heteroaryl are each independently optionally substituted with one, two, three, or four of the following groups: -H, -F, -OH, -OCH3, -CN, (C1-C3)alkyl, and (C1-C3)haloalkyl; or R 7 and R 8 can form, together with the N atom to which they are attached, a (4- to 11-membered)heterocycloalkyl, wherein said (4- to 11-membered)heterocycloalkyl is selected from the following groups: -H, -F, -OH, -OCH3, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)cycloalkyl, -NR 10 R 11 , -NR 10 (CH2)2OR 11 , -O(CH2)2OR 10 , -O(CH2)2NR 10 R 11 , -NR 10 (CH2)2NR 11 R 12 , -(CH2)2OR7 , -(CH2)2NR 7 R 8 , -CH2OR 7 , -CH2NR 7 R 8 , and R 9 , which may be optionally substituted with one, two, three or four of:

[0014] In another preferred embodiment, in the general formula (1), Z is [ka] and preferably [ka] and more preferably [ka] It is.

[0015] In another preferred embodiment, in the general formula (1), R a1 and R a2 are each independently -H, -OCH3, -CN or -F, preferably -H or -F, and more preferably -H.

[0016] In another preferred embodiment, in the general formula (1), Y 1 and Y 2 are each independently -H or -F, preferably -H.

[0017] In another specific embodiment of the present invention, the compound of general formula (1) has the following structure: [ka] It has one of the following: TIFF2024544558000017.tif231168TIFF2024544558000018.tif231168TIFF2024544558000019.tif171168.

[0018] The present invention further provides a compound of general formula (2), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In the general formula (2), R 13 is (C1-C6) alkyl, (C3-C6) cycloalkyl or (4-membered to 6-membered) heterocycloalkyl, wherein the (C1-C6) alkyl, the (C3-C6) cycloalkyl or the (4-membered to 6-membered) heterocycloalkyl are each independently selected from the following groups: -H, halogen, -OH, -OR 16 , -CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; R 14 and R 15 are each independently -H, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, or the (C3-C6) cycloalkyl are each independently the following groups: -H, halogen, -OH, -OR 16 , -CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; R 13 When is (C1-C6) alkyl, R 14 and R 15 must be (C3-C6)cycloalkyl; R 16 is -H, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C6) cycloalkyl.

[0019] In another preferred embodiment, in the general formula (2), R 13is a (C1-C6)alkyl, a (C3-C6)cycloalkyl, or a (4-membered to 6-membered)heterocycloalkyl, wherein said (C1-C6)alkyl, said (C3-C6)cycloalkyl, or said (4-membered to 6-membered)heterocycloalkyl may each independently be optionally substituted with one, two, three, or four of the following groups: H, -F, -Cl, -Br, -OH, -OCH3, -CN, (C1-C3)alkyl, and (C1-C3)haloalkyl.

[0020] In another preferred embodiment, in the general formula (2), R 13 teeth, [ka] and preferably [ka] and more preferably [ka] and more preferably [ka] and more preferably [ka] It is.

[0021] In another preferred embodiment, in the general formula (2), R 14 and R 15 are each independently -H, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C3-C6)cycloalkyl, wherein said (C1-C3)alkyl, said (C1-C3)haloalkyl, or said (C3-C6)cycloalkyl are each independently optionally substituted with one, two, three, or four of the following groups: -H, -F, -OH, -OCH3, -CN, (C1-C3)alkyl, and (C1-C3)haloalkyl; R 13When is (C1-C6) alkyl, R 14 and R 15 One of the groups must be a (C3-C6)cycloalkyl.

[0022] In another preferred embodiment, in the general formula (2), the structural unit: [ka] teeth, [ka] is selected from, preferably [ka] and more preferably [ka] and more preferably [ka] It is.

[0023] In another specific embodiment of the present invention, the compound of general formula (2) has the following structure: [ka] has one of the following:

[0024] 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 general formula (1) or general formula (2) of the present invention or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0025] The present invention further aims to provide the use of a compound of general formula (1) or general formula (2) of the present invention, or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with Src protein, wherein said disease is preferably cancer, and said cancer is a hematological cancer or a solid cancer.

[0026] The present invention further contemplates providing a method for treating, regulating or preventing a disease associated with Src protein, comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) or general formula (2) of the present invention, or an isomer, crystal form, pharma-ceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition described above.

[0027] 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.

[0028] Compound synthesis

[0029] 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.

[0030] The compounds of formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, in combination with the methods described herein. Additionally, the solvents, temperatures and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds may be obtained synthetically or commercially available. 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 thEd., 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 described herein.

[0031] 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 determined 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 general reaction scheme 1, and the compound of general formula (2) can be prepared using the following general reaction scheme 2.

[0032] General reaction scheme 1

[0033] [ka]

[0034] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 1, wherein R 1 , L 1 , L 2 , Z, X 1 , X 2 , Y 1 and Y 2is as defined above, X represents iodine or bromine, N represents nitrogen, O represents oxygen, and B represents boron. As shown in General Reaction Scheme 1, compound 1-1 and compound 1-2 are coupled in the presence of Pd(dppf)Cl2 to produce compound 1-3, and compound 1-3 and compound 1-4 are coupled in the presence of Pd(OAc)2 and PPh3 to produce target compound 1-5.

[0035] General reaction scheme 2

[0036] [ka]

[0037] Embodiments of compounds of general formula (2) may be prepared according to General Reaction Scheme 2, wherein R 13 , R 14 , and R 15 is as defined above, X represents iodine or bromine, N represents nitrogen, O represents oxygen, and B represents boron. As shown in General Reaction Scheme 2, compound 2-1 and compound 2-2 are coupled in the presence of Pd(dppf)Cl2 to produce compound 2-3, and compound 2-3 and compound 2-4 are coupled in the presence of Pd(OAc)2 and PPh3 to produce target compound 2-5.

[0038] Further forms of the compound

[0039] As used herein, the term "pharmaceutical acceptable" refers to a relatively non-toxic substance, such as a carrier or diluent, that does not cause the loss of biological activity or properties of a compound, e.g., when administered to an individual, the substance does not cause undesirable biological effects or adverse interactions with any of its components.

[0040] The term " pharmaceutically acceptable salt " refers to the form of a compound that does not cause significant stimulation to the organism receiving the compound or does not destroy the biological activity and properties of the compound.In certain embodiments, said pharmaceutically acceptable salt is obtained by reacting the compound of general formula with acid, for example, inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, etc.; organic acid 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; acidic amino acid such as aspartic acid and glutamic acid.

[0041] It should 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 selectively formed during crystallization in pharma-ceutically acceptable solvents such as water and ethanol. When the solvent is water, hydrates are formed, and when the solvent is ethanol, alcoholates are formed. Solvates of compounds of the general formula are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of the general formula 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, 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.

[0042] In other particular embodiments, the compound of the general formula is prepared in various forms, including but not limited to amorphous, pulverized, and nanoparticle forms.Furthermore, the compound of the general formula may be in polymorphic form, including crystalline form.Polymorphs include different lattice arrangements of the same elements of a compound.Polymorphs generally have different X-ray diffraction patterns, 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.

[0043] In another embodiment, the compounds of the general formula above may have chiral centers and / or axial asymmetry and therefore may 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.

[0044] 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 (1H-tetrafluoroethylene) or 1,2-dihydro-1,3-trifluoroethylene (1H-tetrafluoroethylene). As another example, deuterium may be used to replace a hydrogen atom to form a deuterated compound. The bond formed by deuterium and carbon is stronger than the bond formed by normal 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 increased 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.

[0045] Explanation of terms

[0046] Unless otherwise specified, the terms used herein, including those described in the specification and claims, are defined as follows. It should be noted that in this specification and the appended claims, the singular forms "a" and "an" include the plural meaning unless otherwise specified. Conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used unless otherwise specified. In this specification, "or" or "and" means "and / or" unless otherwise specified.

[0047] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups with straight and branched chain groups containing 1 to 6 carbon atoms. Lower alkyl groups containing 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 alkyl and substituted alkyl, particularly alkyl 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.

[0048] Unless otherwise specified, "alkylene" refers to a divalent alkyl as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0049] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon double bond, including straight-chain 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.

[0050] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl as defined above.

[0051] Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups with a carbon-carbon triple bond, including 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.

[0052] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl as defined above.

[0053] 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 (e.g., having 2, 3, or 4 fused rings) and spirocycles. In some embodiments, cycloalkyls are monocyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. The ring carbon atoms of a cycloalkyl may be optionally oxidized to form an oxo or sulfide group. 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, cycloalkyl may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. 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.

[0054] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl as defined above.

[0055] 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, and t- BuO.

[0056] Unless otherwise specified, "aryl" refers to an aromatic hydrocarbon group that is monocyclic or polycyclic. For example, a monocyclic aryl ring can be fused with one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0057] Unless otherwise noted, "aryloxy" refers to an aryl group attached to the remainder of the molecule through an ether oxygen atom. Examples of said aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0058] Unless otherwise noted, "arylene" refers to a divalent aryl as defined above. Examples of arylene include, but are not limited to, phenylene, naphthylene, phenanthrylene, and the like.

[0059] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), said "heteroaryl" being 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 pyridyl, 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:

[0060] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl as defined above.

[0061] 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 an oxo or sulfide group or other oxidized bond (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. Also included in the definition of heterocycloalkyl are moieties (also called partially unsaturated heterocycles) that have one or more aromatic rings fused (i.e., sharing bonds) 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-imidazo[ 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:

[0062] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl as defined above.

[0063] 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.

[0064] "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.

[0065] 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]

[0066] When the number of the linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0067] When one of the variables is selected from a chemical bond, it means that the two groups linked by this variable are directly linked, for example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0068] The term "membered ring" includes any cyclic structure. The term "membered" refers 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.

[0069] 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.

[0070] 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 represented by the 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.

[0071] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0072] 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.

[0073] 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 ameliorate 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.

[0074] "Active ingredient" refers to compounds of the general formula and pharma- ceutically acceptable inorganic or organic salts of compounds of the general formula. 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. Possible asymmetric centers may exist depending on the properties of 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.

[0075] 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.

[0076] The terms "administered, administering, or administration" as used herein refer to direct administration of a compound or composition, or administration of a prodrug, derivative, analog, etc. of an active compound.

[0077] 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.

[0078] 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.

[0079] therapeutic use

[0080] The present invention provides the use of a compound of the general formula of the present invention or a pharmaceutical composition in the inhibition of Src protein and thus in the treatment of one or more disorders related to the activity of Src protein.Accordingly, in a particular embodiment, the present invention provides a method for treating a disorder mediated by Src protein, the method comprising administering a compound of the general formula of the present invention or a pharma- ceutically acceptable composition thereof to a patient in need thereof.

[0081] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1).In some embodiments, cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, and myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative familial syndrome), solid cancers (carcinomas such as prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, renal cancer, ovarian cancer, and soft tissue cancer, osteosarcoma, and stromal tumors), and the like.

[0082] Route of administration

[0083] 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 side 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.

[0084] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and low toxicity. "Compatible" as used herein means that the components of the composition are capable of being mixed with the compounds of the present invention without significantly reducing the pharmaceutical efficacy 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, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0085] The compounds of the present invention may be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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. Of course, the specific dosage will take into account factors such as the route of administration and the patient's health condition, but these are well known to those skilled in the art.

[0094] 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 various features disclosed herein can be replaced with any alternative features that provide the same, equivalent or similar purpose.Thus, unless otherwise stated, the features disclosed herein are merely generic examples of equivalent or similar features. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] Detailed Description

[0096] Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions will be 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 only and describe specific examples. 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.

[0097] In all examples, 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm). Unless otherwise specified, 200-300 mesh silica gel was used for separation, and the ratio of eluents was expressed by volume.

[0098] The following abbreviations are used in the present invention: (Boc)2O is di-tert-butyl dicarbonate; CDCl3 is deuterated chloroform; Cs2CO3 is cesium carbonate; EtOAc is ethyl acetate; Hexane is n-hexane; HPLC is high performance liquid chromatography; MeCN is acetonitrile; DCM is dichloromethane; DIPEA is diisopropylethylamine; Dioxane is 1,4-dioxane; DMF is N,N-dimethylformamide; DMAP is 4-(dimethylamino)pyridine; DMSO is dimethylsulfoxide; EtOH is ethanol; h is hour; IPA is isopropanol; ISCO® is Biotage Isolera Prime flash preparative liquid chromatography; min is minutes; K2CO3 is potassium carbonate; KOAc is potassium acetate; KOH is potassium hydroxide; K3PO4 is potassium phosphate; LiBH4 is lithium borohydride; min is minutes; MeOH is methanol; MS is mass spectrometry; NaBH(OAc)3 is sodium triacetoxyborohydride; NaH is sodium hydride; NMR is nuclear magnetic resonance; NIS is iodosuccinimide; Pd / C is palladium on carbon; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium; Pd(OAc)2 is palladium acetate ;Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE is petroleum ether; PPh3 is triphenylphosphine; TEA is triethylamine; TFA is trifluoroacetic acid; TsOH is p-toluenesulfonic acid; XantPhos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TfOH is trifluoromethanesulfonic acid; TLC is thin layer chromatography; XPhos is 2-dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl.

[0099] Example 1: Synthesis of Compound 1

[0100] [ka]

[0101] Step 1: Synthesis of compound int_1-3

[0102] [ka]

[0103] int_1-2 (12.6 g, 36.1 mmol) and calcium carbonate (4.27 g, 42.7 mmol) were dissolved in a mixed solvent of methanol (70 mL) and dichloromethane (140 mL), and int_1-1 (4.50 g, 32.8 mmol) was added to the reaction at 30 °C. After the addition was complete, the reaction was stirred at 30 °C for 1.5 h. LC-MS monitoring showed that the reaction was complete. Water (300 mL) was added to the reaction. The aqueous phase was extracted with dichloromethane (300 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 0 to 4 / 1) to give a yellow solid (4.29 g, 49.3% yield). 1 H NMR: (400 MHz, CHLOROFORM-d) δ 6.93 (d, J = 8.5 Hz, 1H), 6.17 (d, J = 8.5 Hz, 1H), 5.98 (s, 2H), 3.58 (br s, 2H). ESI-MS m / z: 264 [M+H] + .

[0104] Step 2: Synthesis of compounds int_1-4 [ka] int_1-3 (200 mg, 0.76 mmol) was dissolved in THF (10 mL) and (Boc)2O (216 mg, 0.99 mmol) was added at room temperature. The reaction was allowed to react at 80° C. for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to remove THF to give the crude product (260 mg), which was used directly in the next step. ESI-MS m / z: 364 [M+H] + .

[0105] Step 3: Synthesis of compounds int_1-6 [ka]

[0106] int_1-4 (50 mg, 0.138 mmol) was dissolved in DMF (3 mL) and int_1-5 (42 mg, 0.165 mmol), Pd(dppf)Cl2 (8 mg, 0.011 mmol), and potassium acetate (27 mg, 0.275 mmol) were added. The reaction was purged with nitrogen three times, heated to 100 °C, and stirred under nitrogen atmosphere for 6 h. LC-MS monitoring showed the reaction was complete. The reaction was cooled to room temperature and water (20 mL) was added slowly to the reaction. The aqueous phase was extracted with ethyl acetate (20 mL × 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH = 98 / 2) to give a solid (10 mg, 20% yield). ESI-MS m / z: 364, 264 [M+H] + .

[0107] Step 4: Synthesis of compounds int_1-9 [ka]

[0108] int_1-7 (15 g, 57.4 mmol) and int_1-8 (11.3 g, 57.4 mmol) were dissolved in DMF. NaH (2.29 g, 57.4 mmol, 60%) was added. The reaction was heated to 100 °C and reacted for 6 h. LC-MS monitoring showed the reaction was complete. After the reaction was cooled to room temperature, the reaction was directly concentrated under reduced pressure to remove the solvent to give the crude product (5.37 g). The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=95 / 5) to give a solid (14 g, 64.6% yield). ESI-MS m / z: 378 [M+H] + .

[0109] Step 5: Synthesis of compounds int_1-10 [ka]

[0110] Int_1-9 (1 g, 2.65 mmol) was dissolved in TFA (3 mL) and water (3 mL). The reaction was heated to 100° C. and reacted for 1 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product (1 g), which was used directly in the next step. ESI-MS m / z: 304 [M+H] + .

[0111] Step 6: Synthesis of compound int_1-12 [ka]

[0112] int_1-10 (500 mg, 1.64 mmol) and int_1-11 (210.2 mg, 1.64 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (347.5 mg, 1.64 mmol), DIPEA (317.9 mg, 2.46 mmol) and acetic acid (150 mg, 2.46 mmol) were added to the reaction. The reaction was allowed to react at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. Water (20 mL) was added slowly to the reaction. The aqueous phase was extracted with dichloromethane (20 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) to give a solid (580 mg, 85.1% yield). MS (ESI): 416 [M+H] + .

[0113] Step 7: Synthesis of Compound 1 [ka]

[0114] int_1-6 (100 mg, 0.275 mmol) and int_1-12 (171 mg, 0.413 mmol) were dissolved in dioxane (3 mL) and H2O (0.5 mL). Palladium acetate (4 mg, 0.014 mmol), PPh3 (144 mg, 0.551 mmol) and potassium carbonate (76 mg, 0.551 mmol) were added to the reaction. The reaction was heated to 120 °C in a microwave and reacted under nitrogen atmosphere for 0.5 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) and then by preparative HPLC to give a solid (10 mg, 7% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.19 (s, 1H), 7.13 (d, J= 8.6 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.07 (s, 2H), 4.39 (t, J = 6.8 Hz, 2H), 2.92 (d, J = 11.2 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.16 (d, J = 3.2 Hz, 6H), 2.12 - 2.01 (m, 1H), 2.01 - 1.87 (m, 2H), 1.66 (d, J = 11.7 Hz, 2H), 1.45 (s, 6H), 1.23 (ddt, J= 30.8, 11.6, 6.2 Hz, 2H). MS (ESI): 525 [M+H] + .

[0115] Examples 2 to 58: Synthesis of Compounds 2 to 58 Compounds 2 to 58 in Table 1 were obtained using different starting materials and according to the above synthesis method.

[0116] [Table 1] TIFF2024544558000057.tif248168TIFF2024544558000058.tif200168TIFF2024544558000059.tif248168TIFF2024544558000060.tif228168 TIFF2024544558000061.tif198168TIFF2024544558000062.tif200168TIFF2024544558000063.tif200168TIFF2024544558000064.tif200168

[0117] Example 59: Synthesis of Compound 59 [ka]

[0118] Step 1: Synthesis of compound int_59-3 [ka] int_59-2 (300 mg, 2.22 mmol) was dissolved in dichloromethane (5 mL) and int_59-1 (186 mg, 0.74 mmol) and DIPEA (581.6 mg, 4.5 mmol) were added to the reaction at 0 °C. After the addition was complete, the reaction was stirred at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. Water (10 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (10 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH = 98 / 2) to give a solid (35 mg, yield: 4.5%). ESI-MS m / z: 348 [M+H] + .

[0119] Step 2: Synthesis of compound 59 [ka] int_59-3 (30 mg, 0.086 mmol) and int_1-12 (54 mg, 0.130 mmol) were dissolved in dioxane (3 mL) and H2O (0.5 mL). Palladium acetate (1 mg, 0.004 mmol), PPh3 (45 mg, 0.173 mmol) and potassium carbonate (24 mg, 0.173 mmol) were added to the reaction. The reaction was heated to 120 °C in a microwave and reacted under nitrogen atmosphere for 0.5 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) and then by preparative HPLC to give a solid (5 mg, yield: 11.4%). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.21 (d, J = 5.9 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 4.41 (t, J = 6.8 Hz, 2H), 3.84 (s, 3H), 2.93 (s, 2H), 2.75 (d, J = 6.9 Hz, 2H), 2.17 (s, 6H), 2.00 - 1.90 (m, 3H), 1.68 (d, J= 12.3 Hz, 2H), 1.52 (s, 3H), 1.26 (dd, J= 12.0, 3.6 Hz, 2H), 0.88 - 0.83 (m, 2H), 0.68 - 0.62 (m, 2H). MS (ESI): 509 [M+H] + .

[0120] Example 60: Synthesis of Compound 60 [ka]

[0121] Step 1: Synthesis of compound int_60-2 [ka] int_60-1 (200 mg, 1.486 mmol) was dissolved in dichloromethane (5 mL), and int_59-1 (325 mg, 1.341 mmol) and DIPEA (550 mg, 4.245 mmol) were added to the reaction at 0 °C. After the addition was complete, the reaction was stirred at room temperature for 16 h. LC-MS monitoring showed that the reaction was complete. Water (10 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH = 98 / 2) to give a solid (106 mg, yield: 22.7%). ESI-MS m / z: 348 [M+H] + .

[0122] Step 2: Synthesis of compound 60 [ka] int_60-2 (100 mg, 0.288 mmol) and int_1-12 (120 mg, 0.288 mmol) were dissolved in dioxane (3 mL) and H2O (0.5 mL). Palladium acetate (4 mg, 0.014 mmol), PPh3 (151 mg, 0.576 mmol) and potassium carbonate (80 mg, 0.576 mmol) were added to the reaction. The reaction was heated to 120 °C in a microwave and reacted under nitrogen atmosphere for 0.5 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) and further purified by preparative HPLC to give a solid (25 mg, yield: 17%). 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.22 (s, 1H), 7.84 (d, J= 8.1 Hz, 1H), 7.23 - 7.16 (m, 2H), 4.92 (p, J = 7.5 Hz, 1H), 4.41 (t, J= 6.8 Hz, 2H), 3.86 (s, 3H), 2.93 (d, J= 11.0 Hz, 2H), 2.74 (t, J = 6.8 Hz, 2H), 2.28 (dddt, J = 9.8, 7.6, 5.3, 2.6 Hz, 2H), 2.12 (s, 6H), 2.09 - 1.89 (m, 5H), 1.77 - 1.55 (m, 4H), 1.25 (tt, J = 12.1, 6.1 Hz, 2H). MS (ESI): 509 [M+H] + .

[0123] Example 61: Synthesis of Compound 61 [ka]

[0124] Step 1: Synthesis of compound int_61-2 [ka]

[0125] int_61-1 (150 mg, 1.00 mmol) was dissolved in dichloromethane (5 mL) and int_59-1 (125 mg, 0.505 mmol) and DIPEA (258.4 mg, 2 mmol) were added to the reaction at 0 °C. After the addition was complete, the reaction was stirred at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. Water (10 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (10 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH = 98 / 2) to give a solid (95 mg, yield: 52%). ESI-MS m / z: 362 [M+H] + .

[0126] Step 2: Synthesis of compound 61 [ka]

[0127] int_61-2 (95 mg, 0.263 mmol) and int_1-12 (163 mg, 0.394 mmol) were dissolved in dioxane (3 mL) and H2O (0.5 mL). Palladium acetate (3 mg, 0.013 mmol), PPh3 (138 mg, 0.526 mmol) and potassium carbonate (73 mg, 0.526 mmol) were added to the reaction. The reaction was heated to 120 °C in a microwave and reacted under nitrogen atmosphere for 0.5 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) and further purified by preparative HPLC to give a solid (49 mg, yield: 35.6%). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.22 (s, 1H), 7.87 (d, J= 8.2 Hz, 1H), 7.23 - 7.15 (m, 2H), 4.41 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 2.95 (d, J = 10.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 2.31 (dt, J = 12.3, 9.4 Hz, 2H), 2.18 (s, 6H), 2.08 (dtd, J= 9.5, 8.1, 4.0 Hz, 3H), 1.95 (td, J= 11.6, 2.3 Hz, 2H), 1.82 - 1.61 (m, 4H), 1.55 (s, 3H), 1.28 (qd, J = 12.0, 3.7 Hz, 2H). MS (ESI): 523 [M+H] + .

[0128] Example 62: Synthesis of Compound 62 [ka]

[0129] Step 1: Synthesis of compound int_62-2 [ka]

[0130] int_59-1 (450 mg, 1.80 mmol) was dissolved in THF (20 mL) and (Boc)2O (788 mg, 3.613 mmol) was added at room temperature. The reaction was allowed to react at 80° C. for 16 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to remove THF to give the crude product (500 mg), which was used directly in the next step. ESI-MS m / z: 350, 295 [M+H] + .

[0131] Step 2: Synthesis of compound int_62-3 [ka]

[0132] int_1-10 (100 mg, 0.33 mmol) and int_62-2 (80 mg, 0.49 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (280 mg, 1.32 mmol), DIPEA (170.6 mg, 1.32 mmol) and acetic acid (79.2 mg, 1.32 mmol) were added to the reaction. The reaction was allowed to react at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. Water (20 mL) was added slowly to the reaction. The aqueous phase was extracted with dichloromethane (20 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) to give a solid (120 mg, yield: 82.4%). MS (ESI): 442 [M+H] + .

[0133] Step 3: Synthesis of compound 62 [ka]

[0134] int_62-1 (50 mg, 0.143 mmol) and int_62-3 (94 mg, 0.215 mmol) were dissolved in dioxane (3 mL) and H2O (0.5 mL). Palladium acetate (1.5 mg, 0.007 mmol), PPh3 (75 mg, 0.286 mmol) and potassium carbonate (40 mg, 0.286 mmol) were added to the reaction. The reaction was heated to 120 °C in a microwave and reacted under nitrogen atmosphere for 0.5 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) and then purified by preparative HPLC to give a solid (8 mg, yield: 10.4%). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.03 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.23 - 7.18 (m, 2H), 4.41 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 2.96 (d, J = 10.9 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.30 (t, J = 11.5 Hz, 1H), 2.18 (s, 3H), 1.95 (t, J = 11.3 Hz, 2H), 1.74 - 1.63 (m, 3H), 1.46 (s, 9H), 1.41 - 1.29 (m, 2H), 0.43 - 0.36 (m, 2H), 0.27 - 0.18 (m, 2H). MS (ESI): 537 [M+H] + .

[0135] Example 63: Synthesis of Compound 69 [ka]

[0136] Step 1: Synthesis of compound int_59-3 [ka]

[0137] int_59-2 (300 mg, 2.22 mmol) was dissolved in dichloromethane (5 mL), and int_59-1 (186 mg, 0.74 mmol) and DIPEA (581.6 mg, 4.5 mmol) were added to the reaction at 0 °C. After the addition was complete, the reaction was stirred at room temperature for 16 h. LC-MS monitoring showed the reaction was complete. Water (10 mL) was added to the reaction. The aqueous phase was extracted with ethyl acetate (10 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH = 98 / 2) to give a solid (35 mg, yield: 4.5%). ESI-MS m / z: 348 [M+H] + .

[0138] Step 2: Synthesis of compound 69 [ka]

[0139] int_59-3 (50 mg, 0.144 mmol) and int_62-3 (64 mg, 0.144 mmol) were dissolved in dioxane (3 mL) and H2O (0.5 mL). Palladium acetate (3 mg, 0.014 mmol), PPh3 (75 mg, 0.288 mmol) and potassium carbonate (60 mg, 0.432 mmol) were added to the reaction. The reaction was heated to 120 °C in a microwave and reacted under nitrogen atmosphere for 2 h. LC-MS monitoring showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative column chromatography (SiO2, DCM / MeOH=90 / 10) and then by preparative HPLC to give a solid (4 mg, yield: 5.2%). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 7.0 Hz, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 4.41 (t, J = 6.5 Hz, 2H), 3.84 (s, 3H), 2.96 (d, J = 10.4 Hz, 2H), 2.75 (q, J = 7.3 Hz, 3H), 2.30 (s, 1H), 2.15 (d, J = 23.4 Hz, 3H), 1.96 (d, J = 12.9 Hz, 2H), 1.74 - 1.65 (m, 2H), 1.52 (s, 3H), 1.21 (s, 2H), 0.84 (d, J= 6.4 Hz, 2H), 0.68 - 0.63 (m, 2H), 0.38 (dd, J = 6.8, 4.7 Hz, 2H), 0.25 - 0.16 (m, 2H). MS (ESI): 535 [M+H] + .

[0140] Examples 64 to 70: Synthesis of Compounds 64 to 70 Using different starting materials and following the above synthesis methods, the target compounds 63-68 and compound 70 in Table 2 were obtained.

[0141] [Table 2] TIFF2024544558000082.tif65168

[0142] Example 71: In vitro assay of compounds of the present invention for inhibiting Src kinase activity Compounds serially diluted in DMSO were incubated with Src recombinant protein for 10 min at room temperature, and then biotin-labeled TK substrate and ATP were added to initiate the reaction. The mixture was left at room temperature for 40 min, after which Sa-XL665 and cryptate-labeled antibody were added. Fluorescence values ​​at 615 nm and 665 nm were measured, and the ratio of 665 nm to 615 nm was calculated. Compound inhibition rate and IC 50 was calculated in comparison with the DMSO group. The results are shown in Table 3 below.

[0143] [Table 3]

[0144] Example 72: In vitro antiproliferative activity of compounds of the invention against PC3 cells PC3 cells were mixed with 0.4% agarose at 1200 cells / well, and the mixture was seeded on 0.6% agarose. Serially diluted compounds were added and cultured for 7 days, after which the cell numbers were measured. Compound inhibition rates and IC 50 was calculated in comparison with the DMSO group. The results are shown in Table 4 below.

[0145] [Table 4]

[0146] As can be seen from the data in Table 4, compounds of the present invention have unexpectedly strong in vitro antiproliferative activity against PC3 cells.

[0147] Example 73: In vivo Pharmacodynamic Study - Mouse PC3 Subcutaneous Xenograft Tumor Model 10 × 10 for each nude mouse 6 PC3 cells were subcutaneously transplanted. The tumor size was 100–200 mm 3When the tumors had grown to 100 mm, the compound was orally administered once a day, and the tumor volume was measured twice a week and at the end of administration. The tumor growth inhibition rate of the compound was calculated according to the following formula: tumor growth inhibition rate (TGI) = 1 - (tumor volume of treatment group on day 17 - tumor volume of treatment group on day 1) / (tumor volume of vehicle control group on day 17 - tumor volume of treatment group on day 1). The results are shown in Table 5.

[0148] [Table 5]

[0149] As can be seen from Table 5, the compounds of the present invention were able to inhibit tumor growth in a mouse PC3 subcutaneous xenograft tumor model.

[0150] Example 74: In vivo pharmacokinetic studies of compounds of the present invention The compounds were administered intravenously and orally to 7-10 week-old CD-1 female mice at doses of 2 mg / kg and 10 mg / kg, respectively. The mice were fasted for at least 12 hours before administration, fed 4 hours after administration, and allowed to drink water ad libitum throughout the experiment. On the day of the experiment, animals in the intravenous administration group were injected once with the corresponding compound at a dose of 10 mL / kg via the tail vein. Animals in the oral administration group were administered once with the corresponding compound at a dose of 10 mL / kg via intragastric injection. The animals were weighed before administration, and the dose was calculated according to their body weight. The sample collection times were 0.083 hours (injection group), 0.167 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours, and approximately 200 μL of whole blood was collected from the submandibular 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). All animals were euthanized with CO2 anesthesia after PK samples were taken at the final time point. Plasma concentrations were processed using a non-compartmental model in the pharmacokinetic software Phoenix WinNonlin™ version 8.3 (Certara), and pharmacokinetic parameters were calculated using the log-linear trapezoidal method. In vivo pharmacokinetic results are shown in Table 6 below.

[0151] [Table 6]

[0152] Compound A is compound 506 in WO2016185160A1 and has the following chemical structure: [ka]

[0153] As can be seen from the data in Table 6, in the pharmacokinetic study in mice, compared with compound A, compound 59 of the present invention has a half-life T 1 / 2 , indicating that compound A has similar metabolic stability as compound 59. However, compound 59 exhibits a significant increase in Vdss, indicating that compound 59 is less distributed in plasma and more distributed in other tissues, which is of great advantage in the treatment of solid cancers. Thus, compound 59 has unexpectedly improved pharmacokinetic properties compared to compound A.

[0154] Example 75: Stability Studies 5 mg each of Compound 59 and Compound A was dissolved in a pH 2 aqueous hydrochloric acid solution (5 mL), and the mixture was stirred at room temperature. After 0.5 hours, a sample was taken and subjected to HPLC assay under the following assay conditions. The results of the HPLC assay are shown in Table 7.

[0155] Instrument: Agilent 1260 infinity 2 Column: Xtimate C18 4.6 * 150mm, 3um Temperature: 25℃ Wavelength: 210nm / 254nm Mobile phase A: H2O (0.1%TFA) Mobile phase B: MECN (0.1%TFA) TIFF2024544558000088.tif60168

[0156] [Table 7]

[0157] As can be seen from Table 7, compound 59 of the present invention is more stable under acidic conditions compared to compound A.

[0158] 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. 【Chemistry 1】 (In general formula (1), X １ is CR ａ１ or N, X ２ is CR ａ２ or N, Y １ is H or F, Y ２ is H or F, L １ is -C(O)-, -NR ２ C(O)-, -NR ２ C(O)O-, -OC(O)NR ２ -, -C(O)NR ２ -, -NR ３ C(O)NR ２ -, -NR ２ S (O) ２ -, -S(O) ｐ -, -S(O) ２ NR ２ - or -NR ３ S (O) ２ NR ２ - and R １ is —H, —OH, —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C6) cycloalkyl, phenyl, (5- to 9-membered) heteroaryl, or (4- to 6-membered) heterocycloalkyl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C6) cycloalkyl, the phenyl, the (5- to 9-membered) heteroaryl, or the (4- to 6-membered) heterocycloalkyl are each independently selected from the following groups: —H, halogen, —OH, —OR ５ , —CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; L ２ is (C1-C6) alkylene, wherein said (C1-C6) alkylene is independently selected from the following groups: -H, halogen, -OH, -OR ５ , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, and 【Chemistry 2】 and optionally substituted with one, two, three or four of Z is -OR ７ , -NR ７ R ８ , -NR ６ (CH ２ ) ｍ OR ７ , -NR ６ (CH ２ ) ｍ NR ７ R ８ , -O(CH ２ ) ｍ OR ６ , -O(CH ２ ) ｍ NR ７ R ８ or (4- to 12-membered) heterocycloalkyl, wherein each of said (4- to 12-membered) heterocycloalkyl is independently selected from the following groups: —H, halogen, —OH, —OR ４ , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C6) cycloalkyl, —NR ７ R ８ , -NR ６ (CH ２ ) ｍ OR ７ , -O(CH ２ ) ｍ OR ６ , -O(CH ２ ) ｍ NR ７ R ８ , -NR ６ (CH ２ ) ｍ NR ７ R ８ , -(CH ２ ) ｍ OR ７ , -(CH ２ ) ｍ NR ７ R ８ , and R ９ optionally substituted with one, two, three or four of R ａ１ and R ａ２ are each independently —H, —OR ５ , —CN or halogen R ２ and R ３ are each independently —H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or (C3-C6)cycloalkyl; R ４ is —H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or (C3-C6)cycloalkyl; R ５ is —H, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C6) cycloalkyl; R ６ , R ７ and R ８ are each independently —H, a (C1-C6) alkyl, a (C1-C6) haloalkyl, a (C2-C6) alkenyl, a (C2-C6) alkynyl, a (C3-C6) cycloalkyl, a (4- to 12-membered) heterocycloalkyl, a phenyl, or a (5- to 6-membered) heteroaryl, wherein the (C1-C6) alkyl, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C6) cycloalkyl, the (4- to 12-membered) heterocycloalkyl, the phenyl, or the (5- to 6-membered) heteroaryl are each independently one of the following groups: —H, halogen, —OH, —OR １０ , —CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; or R ７ and R ８ may together with the N atom to which they are attached form a (4- to 12-membered) heterocycloalkyl, wherein said (4- to 12-membered) heterocycloalkyl is selected from the following groups: —H, halogen, —OH, —OR １０ , —CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) cycloalkyl, —NR １０ R １１ , -NR １０ (CH ２ ) ｍ OR １１ , -O(CH ２ ) ｍ OR １０ , -O(CH ２ ) ｍ NR １０ R １１ , -NR １０ (CH ２ ) ｍ NR １１ R １２ , -(CH ２ ) ｍ OR ７ , -(CH ２ ) ｍ NR ７ R ８ and R ９ optionally substituted with one, two, three or four of R ９ is —H, or a (4- to 9-membered)heterocycloalkyl, wherein said (4- to 9-membered)heterocycloalkyl is independently selected from the following groups: —H, —OH, —OR １０ , —CN, (C1-C6)alkyl, (C1-C6)haloalkyl, or (C3-C6)cycloalkyl; R １０ , R １１ and R １２ are each independently —H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, or (4- to 6-membered)heterocycloalkyl; p is an integer of 0, 1, or 2, and m is an integer of 1, 2, or 3.

2. In general formula (1), L １ is -C(O)-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -C(O)NH-, -NHC(O)NH-, -NHS(O) ２ -, -S(O) ２ NH-, -NHS(O) ２ NH-, -N(CH ３ )C(O)-,-N(CH ３ )C(O)O-, -OC(O)N(CH ３ )-, -C(O)N(CH ３ ) -, -N(CH ３ )C(O)NH-, -NHC(O)N(CH ３ ) -, -N(CH ３ )C(O)N(CH ３ ) -, -N(CH ３ ) S (O) ２ -, -S(O) ２ -, -S(O)-, -S-, -S(O) ２ N (CH ３ ) -, -N(CH ３ ) S (O) ２ NH-, -NHS(O) ２ N (CH ３ ) - or -N(CH ３ ) S (O) ２ N (CH ３ )- and L １ is preferably —NHC(O)—, —NHC(O)O—, —NHC(O)NH—, —NHC(O)O—, —OC(O)NH— or —C(O)NH—, and L １ is more preferably —NHC(O)—, —NHC(O)O—, or —NHC(O)NH—, and L １ is more preferably —NHC(O)O—, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

3. In general formula (1), R １ is —H, —OH, —CN, (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, (C3-C6) cycloalkyl, phenyl, (5- to 9-membered) heteroaryl, or (4- to 6-membered) heterocycloalkyl, wherein the (C1-C5) alkyl, the (C1-C5) haloalkyl, the (C2-C5) alkenyl, the (C2-C5) alkynyl, the (C3-C6) cycloalkyl, the phenyl, the (5- to 9-membered) heteroaryl, or the (4- to 6-membered) heterocycloalkyl are each independently selected from the following groups: —H, —F, —Cl, —Br, —OH, —OCH ３ , —CN, (C1-C3)alkyl, and (C1-C3)haloalkyl; Preferably, R 1 is —H, —OH, —CN, 【Transformation 3】 and Preferably, 【Chemistry 4】 and More preferably, 【Transformation 5】 and more preferably 【Transformation 6】 and more preferably 【Transformation 7】 2. The compound of claim 1, wherein:

4. In general formula (1), L ２ is (C1-C4) alkylene, wherein the (C1-C4) alkylene is each independently selected from the following groups: -H, -F, -OH, -OCH ３ , —CN, (C1-C3) alkyl, (C1-C3) haloalkyl, and 【Transformation 8】 and optionally substituted with one, two, three or four of Preferably, L 2 is 【Chemistry 9】 and Preferably, 【Chemistry 10】 and More preferably, 【Chemistry 11】 2. The compound of claim 1, wherein:

5. In the general formula (1), Z is —NR ７ R ８ , -NR ６ (CH ２ ) ２ OR ７ , -NR ６ (CH ２ ) ２ NR ７ R ８ , -O(CH ２ ) ２ OR ６ , -O(CH ２ ) ２ NR ７ R ８ or (4- to 11-membered)heterocycloalkyl, wherein said (4- to 11-membered)heterocycloalkyl is independently selected from the following groups: —H, —F, —OH, —OCH ３ , —CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl, —NR ７ R ８ , -NR ６ (CH ２ ) ２ OR ７ , -O(CH ２ ) ２ OR ６ , -O(CH ２ ) ２ NR ７ R ８ , -NR ６ (CH ２ ) ２ NR ７ R ８ , -(CH ２ ) ２ OR ７ , -(CH ２ ) ２ NR ７ R ８ , -CH ２ OR ７ , -CH ２ NR ７ R ８ and R ９ 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with one, two, three or four of:

6. In general formula (1), R ６ , R ７ and R ８ are each independently —H, a (C1-C3) alkyl, a (C1-C3) haloalkyl, a (C3-C6) cycloalkyl, a (4- to 9-membered) heterocycloalkyl, a phenyl, or a (5- to 6-membered) heteroaryl, wherein the (C1-C3) alkyl, the (C1-C3) haloalkyl, the (C3-C6) cycloalkyl, the (4- to 9-membered) heterocycloalkyl, the phenyl, or the (5- to 6-membered) heteroaryl are each independently one of the following groups: —H, —F, —OH, —OCH ３ , —CN, (C1-C3)alkyl and (C1-C3)haloalkyl, or R ７ and R ８ can form together with the N atom to which they are attached a (4- to 11-membered) heterocycloalkyl, wherein said (4- to 11-membered) heterocycloalkyl is selected from the following groups: -H, -F, -OH, -OCH ３ , —CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) cycloalkyl, —NR １０ R １１ , -NR １０ (CH ２ ) ２ OR １１ , -O(CH ２ ) ２ OR １０ , -O(CH ２ ) ２ NR １０ R １１ , -NR １０ (CH ２ ) ２ NR １１ R １２ , -(CH ２ ) ２ OR ７ , -(CH ２ ) ２ NR ７ R ８ , -CH ２ OR ７ , -CH ２ NR ７ R ８ , and R ９ 6. The compound of claim 5, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, optionally substituted with one, two, three or four of:

7. In the general formula (1), Z is 【Chemistry 12】 and preferably 【Chemistry 13】 and more preferably, 【Chemistry 14】 6. The compound of claim 5, wherein:

8. In general formula (1), R ａ１ and R ａ２ are each independently —H or —OCH ３ , —CN or —F, preferably —H or —F; and Y 1 and Y 2 are each independently —H or —F, preferably —H; 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

9. In the general formula (1), the compound has the following structure: 【Chemistry 15】 【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:

10. A compound of general formula (2), or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 16】 (In the general formula (2), R １３ is a (C1-C6) alkyl, a (C3-C6) cycloalkyl, or a (4- to 6-membered) heterocycloalkyl, wherein said (C1-C6) alkyl, said (C3-C6) cycloalkyl, or said (4- to 6-membered) heterocycloalkyl are each independently selected from the following groups: —H, halogen, —OH, —OR １６ , —CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; R １４ and R １５ are each independently —H, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl, said (C1-C6) haloalkyl, or said (C3-C6) cycloalkyl are each independently one of the following groups: —H, halogen, —OH, —OR １６ , —CN, (C1-C6)alkyl, and (C1-C6)haloalkyl; R １３ is (C1-C6) alkyl, R １４ and R １５ must be (C3-C6)cycloalkyl; R １６ is —H, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C6) cycloalkyl.

11. In general formula (2), R １３ is a (C1-C6) alkyl, a (C3-C6) cycloalkyl, or a (4- to 6-membered) heterocycloalkyl, wherein said (C1-C6) alkyl, said (C3-C6) cycloalkyl, or said (4- to 6-membered) heterocycloalkyl are each independently selected from the following groups: H, —F, —Cl, —Br, —OH, —OCH ３ , —CN, (C1-C3)alkyl, and (C1-C3)haloalkyl; Preferably, R 13 is 【Chemistry 17】 and preferably [Chemistry 18] and more preferably, 【Chemistry 19】 and more preferably, 【Chemistry 20】 and more preferably, 【Chemistry 21】 11. The compound of claim 10, wherein:

12. In general formula (2), R １４ and R １５ are each independently —H, (C1-C3) alkyl, (C1-C3) haloalkyl, or (C3-C6) cycloalkyl, wherein said (C1-C3) alkyl, said (C1-C3) haloalkyl, or said (C3-C6) cycloalkyl are each independently selected from the following groups: —H, —F, —OH, —OCH ３ , —CN, (C1-C3)alkyl, and (C1-C3)haloalkyl; R １３ is (C1-C6) alkyl, R １４ and R １５ or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein one of

13. In the general formula (2), the structural unit: 【Chemistry 22】 but, 【Chemistry 23】 is selected from, preferably 【Chemistry 24】 and more preferably, 【Chemistry 25】 and more preferably, 【Chemistry 26】 13. The compound of claim 12, wherein:

14. In the general formula (2), the compound has the following structure: 【Chemistry 27】 11. The compound of claim 10, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, having one of:

15. 15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound according to any one of claims 1 to 14, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

Images