Naphthylamide 1H-indazole derivative as well as preparation and application thereof

Abstract

The invention provides a naphthamide 1H-indazole derivative with a structure as shown in a formula (I) as well as preparation and application of the naphthamide 1H-indazole derivative. Through prodrug molecule design, the solubility of the compound is greatly improved, so that the compound is more suitable for development of various dosage forms; meanwhile, the introduced functional groups can be removed under the action of metabolic enzymes in organisms, active pharmaceutical molecules are obtained, and the biological activity of the compounds is guaranteed. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular, relates to a naphthamide 1H-indazole derivative and a preparation method and application thereof. Background Art

[0002] Oral administration is the most convenient and common route of administration due to its ease of administration, high patient compliance, low cost, and fewer restrictions in dosage form design. However, the main challenge of oral administration is low bioavailability. Its bioavailability depends on several factors, including aqueous solubility, drug permeability, dissolution rate, first-pass elimination, and first-pass metabolism. Among them, the most common reasons for low oral bioavailability are poor solubility and low permeability.

[0003] Solubility improvement technologies can be divided into physical modification of drugs, chemical modification and other technologies. Physical modification: particle size reduction, such as micronization and nanosuspension, change of crystal form such as polymorphism, amorphous form and co-crystal, dispersion of drugs in carriers, such as co-crystal mixtures, solid dispersions and solid solutions. Chemical modification: changes in pH, use of buffers, derivatization, complexation and salt formation, etc. Other technologies: supercritical fluid process, use of adjuvants such as surfactants, solubilizers, co-solvents, hydrolysis, and new excipients.

[0004] Chinese patent CN104860885B records a class of naphthamide compounds, the structural formula of which is shown below:

[0005]

[0006] The compounds are used as VEGFR inhibitors to prevent and / or treat diseases associated with abnormal angiogenesis, including tumors, rheumatoid arthritis, age-related macular degeneration and psoriasis.

[0007] Chinese patent CN114246864 A records the use of naphthamide compounds in drugs for treating diseases related to the CSF1R kinase signal transduction pathway or in regulating immunity.

[0008] The compounds described in the patent have poor solubility and need to be solubilized to improve the absorption level of such drugs in the body. The poor solubility also limits the development and use of the formulations of such compounds.

[0009] It is urgent to improve the bioavailability of this type of compound to facilitate the development of more clinically applicable dosage forms. Summary of the invention

[0010] The invention studies and develops a derivative with good fat solubility or water solubility by chemically modifying naphthamide 1H-indazole compounds, thereby improving the bioavailability of naphthamide 1H-indazole compounds and making them suitable for the development and utilization of multiple dosage forms.

[0011] In one aspect of the present invention, there is provided a compound represented by the following formula (I) or its tautomer, optical isomer, or pharmaceutically acceptable salt:

[0012]

[0013] in:

[0014] R 1 and R 2 Each is independently selected from the following groups: hydrogen, -LR 4 ;

[0015] L is selected from a bond, -C(=O)-, *-OC(=O)-, *-CH=CHC(=O)-, *-C(=O)CH=CHC(=O)-, *-OC(=O)CH=CHC(=O)-, *-CH(NHR b )C(=O)-, the * end represents the end connected to R4;

[0016] R 4 Ra, or the following groups optionally substituted by 1, 2, 3, 4, 5 or 6 Ra: C1~C12 alkyl, C3~C12 cycloalkyl, 3~12 membered heterocycloalkyl, C6~C10 aryl, 5~10 membered heteroaryl, C3~C12 cycloalkyl-C1~C6 alkyl-, 3~12 membered heterocycloalkyl-C1~C6 alkyl-, C1~C6 alkyl-3~12 membered heterocycloalkyl-C1~C6 alkyl-, sulfonic acid-C1~C6 alkyl-3~12 membered heterocycloalkyl-C1~C6 alkyl-, C6~C10 aryl-C1~C6 alkyl-, 5~10 membered heteroaryl-C1~C6 alkyl-;

[0017] Ra is selected from halogen, amino, hydroxyl, cyano, nitro, carboxyl, sulfonic acid, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-3 halogens, C1-C6 alkoxy substituted with 1-3 halogens, -S(=O) 2 ONa, optionally 1 to 5 R c Substituted: glycosyl, aminoglycosyl, glycoacyl;

[0018] R bSelected from hydrogen, the following groups optionally substituted by 1, 2 or 3 Ra: C6-C10 aryl-C(=O)-, 6-10 membered heteroaryl-C(=O)-, C1-C6 alkyl-C(=O)-, C3-C12 cycloalkyl-C(=O)-, 3-12 membered heterocycloalkyl-C(=O)-;

[0019] R c is selected from a hydroxy protecting group or an amino protecting group;

[0020] R 1 and R 2 Not at the same time hydrogen;

[0021] R 3 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted phenyl and substituted or unsubstituted 5-10 membered heteroaryl containing 1 to 5 heteroatoms selected from N, O and S, and in the case of substitution, the substituents are 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, halo C1-C3 alkoxy, hydroxy, amino, nitro and halogen;

[0022] The "hetero" of the heteroaryl and heterocycloalkyl groups are independently selected from the following heteroatoms or heteroatoms: -NH-, -S-, -N=, -O-, -C(=O), -NH-C(=O)-, -OC(=O)-, -S(=O)2-, -S(=O)-, -C(=O)-NH-;

[0023] In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1, 2, 3, 4 or 5.

[0024] In some embodiments, R 3 is selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, in the case of substitution, the substituents are 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br, and the other variables are as defined herein;

[0025] In some embodiments, R 3 is selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, in the case of substitution, the substituents are 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br, and the other variables are as defined in the present invention;

[0026] In some embodiments, R 3 is selected from substituted or unsubstituted: phenyl and a 5-6 membered heteroaryl group containing 1 N atom and 1 O atom, in the case of substitution, the substituents are 1-3 substituents, each of which is independently selected from C1-C3 alkyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br, and the other variables are as defined in the present invention;

[0027] In some embodiments, R 3 is selected from substituted or unsubstituted: phenyl and a 5-6 membered heteroaryl group containing 1 N atom and 1 O atom, in the case of substitution, the substituents are 1-3 substituents, each of which is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br, and the other variables are as defined in the present invention;

[0028] In some embodiments, R 3 is selected from substituted or unsubstituted: phenyl, oxazolyl and isoxazolyl, in the case of substitution, the substituents are 1-3 substituents, each of which is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br, and the other variables are as defined in the present invention;

[0029] In some embodiments, R 3 is selected from substituted or unsubstituted: phenyl and isoxazolyl, in the case of substitution, the substituent is 1 or 2 substituents, the substituents are each independently selected from methyl, methoxy, F and Cl, and the other variables are as defined in the present invention;

[0030] In some embodiments, R 3 Selected from:

[0031] Other variables are as defined herein.

[0032] In some embodiments, R 4 Ra, or the following groups optionally substituted by 1, 2, 3, 4, 5 or 6 Ra: C1~C12 alkyl, C3~C8 cycloalkyl, 3~8 membered heterocycloalkyl, phenyl, 5~8 membered heteroaryl, C3~C8 cycloalkyl-C1~C3 alkyl-, 3~8 heterocycloalkyl-C1~C3 alkyl-, phenyl-C1~C3 alkyl-, C1~C3 alkyl-5~8 membered heterocycloalkyl-C1~C3 alkyl-, sulfonic acid-C1~C3 alkyl-5~8 membered heterocycloalkyl-C1~C3 alkyl-, 5~8 membered heteroaryl-C1~C3 alkyl-, and the other variables are as defined in the present invention;

[0033] In some embodiments, Ra is selected from halogen, amino, hydroxyl, cyano, nitro, carboxyl, sulfonic acid, oxo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl substituted with 1-3 halogens, C1-C3 alkoxy substituted with 1-3 halogens, -S(=O) 2 ONa, and optionally 1 to 5 R c Substituted with the following groups: glycosyl, aminoglycosyl, glycoacyl, other variables are as defined in the present invention;

[0034] In some embodiments, Ra is selected from halogen, amino, hydroxy, cyano, nitro, carboxyl, oxo, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, -S(=O), 2 ONa, and optionally 1 to 5 R c Substituted with the following groups: Other variables are as defined in the present invention;

[0035] In some embodiments, Ra is selected from amino, carboxyl, oxo, methyl, -S(=O) 2 ONa, The other variables are as defined herein; in some embodiments, at least one Ra is selected from the group consisting of: amino, hydroxyl, carboxyl, sulfonic acid, -S(=O) 2 ONa, and optionally 1 to 5 R c Substituted following groups: glycosyl, aminoglycosyl, glycoacyl, other Ra and other variables are as defined in the present invention;

[0036] In some embodiments, at least one Ra is selected from the group consisting of: amino, hydroxy, carboxyl, sulfonic acid, -S(=O) 2 ONa, and optionally 1 to 5 R c Substituted with the following groups: Other Ra and other variables are as defined in the present invention;

[0037] In some embodiments, R b is selected from hydrogen, the following groups optionally substituted by 1, 2 or 3 Ra: phenyl-C(=O)-, 5-6 membered heteroaryl-C(=O)-, -C1-C3 alkyl-C(=O)-, C3-C8 cycloalkyl-C(=O)-, 3-8 membered heterocycloalkyl-C(=O)-, and the other variables are as defined in the present invention;

[0038] In some embodiments, R b Selected from hydrogen, the following groups optionally substituted by 1, 2 or 3 Ra: phenyl-C(=O)-, C1-C3 alkyl-C(=O)-, and the other variables are as defined in the present invention;

[0039] In some embodiments, R b Selected from hydrogen, Other variables are as defined in the present invention;

[0040] In some embodiments, R c Selected from CH 3 C(=O)-, other variables are as defined in the present invention;

[0041] In some embodiments, R 1 and R 2 Each independently selected from the following groups: hydrogen, ethyl, cyclohexyl, phenyl,

[0042]

[0043] Other variables are as defined in the present invention;

[0044] In some embodiments, R 1 Selected from the following groups:

[0045] Other variables are as defined in the present invention;

[0046] In some embodiments, R 1 Selected from the following groups: ethyl, cyclohexyl, Other variables are as defined in the present invention;

[0047] In some embodiments, R 2 Selected from the following groups: hydrogen, ethyl, Other variables are as defined herein.

[0048] In some embodiments, the number of the heteroatoms or heteroatom groups is independently selected from 1, 2, 3 or 4, respectively.

[0049] In some embodiments, the compounds of the present invention include the following specific compounds or their tautomers, optical isomers, and pharmaceutically acceptable salts:

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] Another aspect of the present invention provides a pharmaceutical composition comprising the compound represented by the above formula (I) or its tautomer, optical isomer, pharmaceutically acceptable salt, and optionally a pharmaceutically acceptable carrier.

[0060] Another aspect of the present invention provides use of the compound represented by the above formula (I) or its tautomers, optical isomers, and pharmaceutically acceptable salts in the preparation of VEGFR inhibitor drugs and / or CSF1R inhibitor drugs.

[0061] The compound of the present application is a prodrug of the naphthamide compound described in CN104860885B, and can be at least partially metabolized into the original drug in the body, thereby exerting the efficacy of the original drug.

[0062] In some embodiments, the compound represented by formula (I) or its tautomer, optical isomer, or pharmaceutically acceptable salt is used in a drug for preventing and / or treating diseases associated with abnormal angiogenesis.

[0063] In some embodiments, the disease associated with abnormal angiogenesis is selected from tumors, rheumatoid arthritis, age-related macular degeneration and psoriasis.

[0064] In some embodiments, the tumor is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma and lymphoma.

[0065] In some embodiments, the compound represented by formula (I) or its tautomer, optical isomer, pharmaceutically acceptable salt is used for preparing a drug for treating meningioma.

[0066] In some embodiments, the compound represented by formula (I) or its tautomer, optical isomer, pharmaceutically acceptable salt is used for preparing a drug for treating diseases related to the CSF1R kinase signal transduction pathway.

[0067] In some embodiments, the CSF1R kinase signal transduction pathway-related diseases include cancer or tumors, hyperplasia, immune disorders, inflammation, etc.; in some embodiments, the disease is cancer or tumor. In some specific embodiments, the cancer or tumor is CSF1 / CSF1R-dependent cancer or tumor or TAMs-enriched tumor; in some more specific embodiments, CSF1 / CSF1R-dependent cancer or tumor includes CSF1 / CSF1R-dependent leukemia, tenosynovial giant cell tumor, etc.; TAMs-enriched tumors include but are not limited to brain glioma, brain metastasis or colorectal cancer.

[0068] In some embodiments, the compound represented by formula (I) or its tautomer, optical isomer, or pharmaceutically acceptable salt is used to prepare an anti-tumor drug in combination with an immune checkpoint drug; in some embodiments, the immune checkpoint drug is an anti-PD-1 antibody or an anti-PD-L1 antibody; in some embodiments, the tumor includes but is not limited to a brain glioma, a brain metastasis, or a colorectal cancer.

[0069] In another aspect, the present invention provides a method for preparing the compound represented by formula (I) or its tautomers, optical isomers, and pharmaceutically acceptable salts, comprising the following steps:

[0070]

[0071] Compound A and R 1 -LG1 undergoes condensation reaction, or reacts with the corresponding R 1 -LG1 and R 2 LG2 undergoes condensation reaction simultaneously or sequentially to obtain the compound of formula (I).

[0072] Among them, R 1 , R 2 , R 3 As defined above, LG1 and LG2 are leaving groups, LG1 is preferably halogen, tert-butoxy, trifluoromethanesulfonyloxy, mesyloxy, anhydride fragment, hydroxyl, carboxylic acid hydroxyl activated group (such as imidazole, 1-hydroxybenzotriazole, etc.), more preferably hydroxyl or carboxylic acid hydroxyl activated group (such as imidazole, 1-hydroxybenzotriazole, etc.). LG2 is preferably halogen, trifluoromethanesulfonyloxy, mesyloxy, anhydride fragment, more preferably halogen (such as Br, Cl or I).

[0073] The condensation reaction temperature is 15-60°C, preferably 25-45°C.

[0074] The reaction solvent is tetrahydrofuran, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,4-dioxane, dichloromethane (DCM), methanol, etc.

[0075] definition

[0076] The terms "optional", "optionally", "optionally" or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0077] Unless otherwise specified, the term "optionally substituted" or "arbitrarily substituted" means that the substituents are independently selected from one or more hydroxyl, halogen, amino, nitro, thiol, cyano, azido, carboxyl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH-C 1-6 Alkyl, -NHC(O)-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl group; wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 The aryl or 5-12 membered heteroaromatic ring group may be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 The present invention is substituted by one or more alkoxy groups.

[0078] The term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond, ie, =0.

[0079] Unless otherwise specified, the term "carbocyclyl" refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 4-6-membered (e.g., 5-6-membered) saturated carbocyclic ring and a 5-6-membered partially unsaturated carbocyclic ring. In one embodiment, the carbocyclyl is a 3-4-membered monocyclic ring, a 3-5-membered monocyclic ring, a 3-6-membered monocyclic ring, a 3-8-membered monocyclic ring, a 3-10-membered monocyclic ring, a 5-8-membered monocyclic ring, a 5-6-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system. Carbocyclic rings include bridged rings or spirocyclic rings. The limiting examples of carbocyclic radical include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo [3.2.1] octanyl, bicyclo [5.2.0] nonanyl, tricyclo [5.3.1.1] dodecyl, adamantyl or spiral [3.3] heptyl etc.Carbocyclic radical can be optionally substituted.When substituted, substituent is preferably 1 to 5, and the substituent is independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano and amino.

[0080] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl), such as "C 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0081] Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), 2-5 carbon atoms (i.e. C 2-5 alkenyl), 2-4 carbon atoms (i.e. C 2-4 alkenyl), 2-3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e. C 2alkenyl), such as "C 2-6 "Alkenyl" means that the group is an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl, etc.

[0082] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2-5 carbon atoms (i.e. C 2-5 Alkynyl), 2-4 carbon atoms (i.e. C 2-4 Alkynyl), 2-3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl), such as "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl, etc.

[0083] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 Cycloalkyl), preferably 3 to 7 carbon atoms (C 3-7 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0084] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, wherein the alkyl is as defined above, i.e., contains 1-20 carbon atoms, preferably, contains 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0085] Unless otherwise specified, the term "alkylthio" refers to -S-alkyl, wherein the alkyl is as defined above, i.e., contains 1-20 carbon atoms, preferably, contains 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, tert-butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, and the like.

[0086] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I. CH 2 CF 3 CF 2 CF 3 wait.

[0087] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to 4 or more ring heteroatoms, containing 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, and the hydrogen on the heteroatom or carbon atom can be substituted with oxygen, specifically, the heteroatom or heteroatom group is selected from:

[0088] -NH-, -S-, -N=, -O-, -C(=O), -NH-C(=O)-, -OC(=O)-, -S(=O)2-, -S(=O)-, -C(=O)-NH-. It preferably contains 3 to 12 ring atoms (3-12 membered heterocyclic group), and further preferably contains 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, and more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Heterocyclyl" can be monocyclic ("monocyclic heterocyclyl") or a fused ("fused heterocyclyl" or "heterofused cyclyl"), bridged ("heterobridged cyclyl" or "bridged heterocyclyl") or spiro-fused ("heterospirocyclyl" or "spiro heterocyclyl") ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, or cycloalkyl rings as defined above are fused with one or more heteroaryl groups, wherein the point of attachment is on the heterocyclyl or cycloalkyl ring, and in such cases, the number of members of the heterocyclyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridine, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic radicals containing 1 heteroatom include, but are not limited to azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic radicals containing 1 heteroatom include, but are not limited to tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic radicals containing 2 heteroatoms include, but are not limited to dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic radicals containing 3 heteroatoms include, but are not limited to triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclic radical groups containing 1 heteroatom include, but are not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Exemplary 6-membered heterocyclic radical groups containing 2 heteroatoms include, but are not limited to piperazinyl, morpholinyl, dithianyl and dioxanyl. Exemplary 6-membered heterocyclic radical groups containing 3 heteroatoms include, but are not limited to triazacyclohexane, oxadiazine alkyl, thiadiazine alkyl, oxathiazine alkyl and dioxaazacyclohexane alkyl (dioxazinanyl). Exemplary 7-membered heterocyclic radical groups containing 1 heteroatom include, but are not limited to azepanyl, oxanyl and thianyl. Exemplary 8-membered heterocyclic radical groups containing 1 heteroatom include, but are not limited to azocyclooctanyl, oxanyl and thianyl. Fused to one C. 6 Exemplary 5-membered heterocyclyl groups on an aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0089] Unless otherwise specified, "heterocycloalkyl" refers to a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, with the same definition of ring atoms as above, i.e., containing 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), the number of heteroatoms is 1 to 5, preferably 1 to 4 (1, 2, 3 or 4), more preferably 1 to 3 (1, 2 or 3), wherein the heteroatom is each independently selected from N, O or S, and the hydrogen on the heteroatom or carbon atom may be substituted with oxygen, specifically, the heteroatom or heteroatom group is selected from: -NH-, -S-, -N=, -O-, -C(=O), -NH-C(=O)-, -OC(=O)-, -S(=O)2-, -S(=O)-, -C(=O)-NH-. Preferably, it contains 3 to 12 ring atoms ("3-12 membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), even more preferably 5 to 6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). Some exemplary "heterocycloalkyl" groups are given in the "heterocyclyl" or "heterocycle" section above, and also include, but are not limited to, aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiolanyl, oxazolidinyl, dioxanyl, dithiolanyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, and the like.

[0090] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms, and the term "aryl" can be used interchangeably with the term "aromatic ring group". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl, etc.

[0091] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing a 5-14 membered structure, or preferably a 5-10 membered structure, or preferably a 5-8 membered structure, and more preferably a 5-6 membered structure, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the hydrogen on the heteroatom or carbon atom can be oxidized. Specifically, the heteroatom or heteroatom group is selected from: -NH-, -S-, -N=, -O-, -C(=O), -NH-C(=O)-, -OC(=O)-, -S(=O)2-, -S(=O)-, -C(=O)-NH-, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0092] Unless otherwise specified, the terms "glycosyl" and "aminoglycosyl" refer to monovalent free radicals or substituent structures obtained after removing the hemiacetal hydroxyl group of a cyclic monosaccharide, amino sugar or oligosaccharide. The monosaccharides include but are not limited to glucose, galactose, arabinose, mannose, sorbose, fructose, glyceraldehyde, erythrose, thulose, rhamnose, xylose, lyxose, ribose, deoxyribose; the aminoglycosyls include but are not limited to glucosamine, aminogalactose, etc.; the monosaccharides may be chain sugars or cyclic sugars, and the cyclic sugars include but are not limited to pyranose and furanose, such as pyranose glucose and furanose glucose. The oligosaccharides include but are not limited to lactose. The term "sugar acid" refers to a carboxylic acid formed by oxidation of the aldehyde group of an aldose to a carboxyl group; the term "sugar acyl" refers to a group formed by the removal of the hydroxyl group from a sugar acid condensation reaction.

[0093] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt suitable for contact with mammalian tissues, especially human tissues, without excessive toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment, and refers to a salt suitable for use as a drug formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include salts derived from inorganic or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, perchloric acid, formic acid, acetic acid, malonic acid, glycolic acid, salicylic acid, citric acid, maleic acid, tartaric acid, fumaric acid, succinic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, etc.; and salts derived from inorganic or organic bases, such as sodium salts, potassium salts, calcium salts, ammonium salts or tetrafluoroborate salts. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent. Exemplary preferred salts include, but are not limited to, sodium salts, hydrochlorides.

[0094] The compounds of the present invention also include their "isotopic derivatives". Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotope: 15 O. 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H) substitution can enhance metabolic stability, prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis like non-isotope-labeled compounds.

[0095] The compounds of the present invention also include their "solvates" and "solvates". Unless otherwise specified, the terms "solvate" and "solvate" mean the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" covers solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Solvation methods are well known in the art.

[0096] Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical constitution but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization based on the differences in the physical and chemical properties of the components.

[0097] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0098] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0099] The compounds of the present invention also include their "nitrogen oxides". Unless otherwise specified, the term "nitrogen oxide" means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides on nitrogen atoms of nitrogen-containing heterocycles.

[0100] Unless otherwise specified, the term "pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.

[0101] There is no particular limitation on the administration of the pharmaceutical composition of the present invention. Representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

[0102] Accordingly, the drug of the present invention can be prepared into various clinically acceptable dosage forms, including oral dosage forms, injection dosage forms, local administration dosage forms or external dosage forms, etc.; preferably, it is an oral dosage form, such as a solid dosage form or an oral liquid, and more preferably, it is an oral liquid.

[0103] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound in such compositions may be delayed in a certain part of the digestive tract. If necessary, the active compound may also be formed into microencapsulated form with one or more of the above excipients.

[0104] Oral liquid dosage forms may include solutions, syrups, emulsions, suspensions, etc., preferably emulsions, more preferably self-microemulsifying preparations. The self-microemulsifying agent excipients include oil phase, emulsifier, co-emulsifier, and may also include antioxidants. The oil phase includes medium chain triglycerides (MCT), monocaprylin, dicaprylin, monoolein, monolinolein, corn oil, castor oil, sesame oil, peanut oil, olive oil, etc. The emulsifier includes polyoxyethylene (40) hydrogenated castor oil (RH40), polyoxyethylene (35) castor oil (Cremophor EL), vitamin E succinate polyethylene glycol ester (TPGS1000), polyethylene glycol stearate (HS15), linoleoyl polyoxyethylene (6) glyceride, linoleoyl polyoxyethylene (6) glyceride, caprylic acid capric acid polyethylene glycol glyceride (Labrasol ALF), etc. The auxiliary emulsifier is selected from: polyethylene glycol (PEG), diethylene glycol monoethyl ether (Transcutol HP), propylene glycol, glycerol, etc. The antioxidant is selected from: butylated hydroxytoluene, butylated hydroxyanisole, vitamin E, propyl gallate. The self-microemulsifying preparation can also be prepared into capsules or tablets.

[0105] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0106] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier (including any preservatives, buffers, or propellants that may be required as necessary).

[0107] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable anti-tumor drugs (such as chemotherapeutic drugs, targeted therapy drugs, immunotherapy drugs) or other treatment methods (such as radiotherapy, surgery).

[0108] The therapeutically effective amount of the present invention refers to the effective dosage considered in medicine, that is, the amount of active compound is sufficient to significantly improve the condition without causing serious side effects. The specific dosage and frequency of administration should take into account factors such as the route of administration and the patient's health status, which can be determined by skilled physicians based on routine skills. In the first human dose escalation study (Phase I study), the most sensitive animal species is selected based on preclinical toxicology studies to calculate the maximum recommended starting dose for clinical trials. The starting dose is calculated according to the calculation method recommended by the "Technical Guidelines for Non-clinical Research of Anti-tumor Drugs" and other guidelines. In the Phase I clinical trial of a parent compound of the compound of formula (I), in order to ensure the safety of the subjects, combined with the operability of the clinical trial and the formulation specifications, the Phase I clinical starting dose of the parent compound is designed to be 5 mg. According to the results of the animal long-term toxicity test, according to the human body weight of 60 kg, the maximum tolerated dose of the human body is converted to 200 mg. In the Phase I clinical trial of the parent compound, the safety, tolerability and efficacy of the continuous administration regimen of 5 mg to 200 mg per day are studied. For a person with a body weight of 60 kg, the daily dosage of the parent compound is preferably 5 to 30 mg, more preferably 10 to 25 mg, more preferably 10 to 20 mg, and further preferably 10 mg, 15 mg, 20 mg or 25 mg. It can be administered in a single dose once a day, can be administered multiple times a day, or can be used at intervals, preferably in a single dose once a day. Preferably, the administration cycle is continuous administration for 21 days, and optionally, multiple cycles of administration can be repeated. The therapeutically effective amount of the compound of formula (I) can be carried out with reference to the parent compound.

[0109] Compared with the prior art, the present invention has the following main advantages:

[0110] The present invention greatly improves the solubility of the compound through the design of prodrug molecules, making it more suitable for the development of various dosage forms; at the same time, the introduced functional groups can be removed under the action of metabolic enzymes in the body to obtain active drug molecules, thereby ensuring the biological activity of the compound. DETAILED DESCRIPTION

[0111] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0112] The following examples are further details of the present invention.

[0113] Specific synthetic routes of the compounds (the bases, solvents and acid-binding agents listed in the routes are merely exemplary and do not constitute limitations of the present invention).

[0114] The abbreviations used in this application are defined as follows:

[0115]

[0116] Preparation Example: Preparation of Intermediates

[0117]

[0118] To a reaction flask were added 2.0 g (7.68 mmol, 1.0 eq) of sodium 2-(4-(2-hydroxyethyl)piperazine-1-yl)ethyl-1-sulfonate, 15 mL of tetrahydrofuran, 1.31 g (8.1 mmol, 1.05 eq) of carbonyldiimidazole, and 0.82 g (8.1 mmol, 1.05 eq) of triethylamine. The mixture was stirred at T=30-35° C. for 6 hours. According to TLC analysis, the reaction was complete to obtain intermediate 1, which was directly subjected to the next step without further treatment.

[0119] Referring to the preparation method of the preparation example, the following intermediate was prepared:

[0120]

[0121] Example 1: tert-Butyl 3-amino-4-(5-(phenylcarbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylate (Compound 1-1)

[0122]

[0123] Add 30g 6-(3-amino-1H-indazol-4-yl)-N-phenyl-1-naphthamide, 17.0g di-tert-butyl dicarbonate, 7.9g triethylamine, 300mL tetrahydrofuran into the reaction bottle and react at room temperature overnight. TLC analysis (developing solvent: DCM: MeOH = 10: 1) After the reaction is completed, filter and dry to obtain compound 1-1, weighing 22.3g, with a yield of 58.8%.

[0124] 1H NMR (600MHz, DMSO-d6) δ10.42 (s, 1H), 8.37–8.28 (m, 1H), 8.25 (t, J = 1.9Hz, 1H), 8. 16(dt,J=7.7,1.7Hz,1H),7.98(dd,J=7.6,1.3Hz,1H),7.94–7.87(m,2H),7.81(dd ,J=7.3,1.0Hz,1H),7.79–7.73(m,1H),7.68(dq,J=7.6,1.5Hz,2H),7.55(t,J=7.4 Hz,1H),7.39–7.22(m,2H),7.05(tt,J=7.1,1.3Hz,1H),6.14(s,2H),1.61(s,9H). ESI-MSm / z: 479.23(M+H) + .

[0125] Example 2: Sodium 2-(4-(2-((3-amino-4-(5-((4-fluoro-3-methylphenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carbonyl)oxy)ethyl)piperazin-1-yl)ethyl-1-sulfonate (Compound 1-2)

[0126]

[0127] The preparation process is as follows:

[0128] In the reaction bottle of the intermediate 1 obtained in the preparation example, 1.6 g (3.9 mmol, 0.5 eq) of 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, NMP (15 mL), and 0.82 g (8.1 mmol, 1.05 eq) of triethylamine were added, and the reaction was carried out at T = 35 ° C for 15 hours. After TLC analysis, the reaction was completed, and the mixture was concentrated to dryness. 20 mL of ethyl acetate was added, and 100 mL of n-hexane was used for crystallization. The crude product was filtered off and purified by column chromatography (DCM: MeOH volume ratio from 10: 1 to 2: 1) to obtain compound 1-2, weighing 2.1 g, with a yield of 77.2%.

[0129] 1 H NMR (600 MHz, DMSO-d 6)δ10.64(s,1H),8.36(d,J=8.7Hz,1H),8.24–8.14(m,3H),7.83(ddd,J=22.1,7.1,1.9Hz,2H),7.75–7.63(m,4H),7.30 (d,J=7.2Hz,1H),7.16(t,J=9.2Hz,1H),5.14(s,2H),4.49(t,J=5.7Hz,2H),2.81–2.53(m,14H),2.28(d,J=1.9Hz,3H). ESI-MSm / z: 673.22(M-Na) - .

[0130] Example 3: Sodium 2-(4-(2-((3-amino-4-(5-((3-methylphenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carbonyl)oxy)ethyl)piperazin-1-yl)ethyl-1-sulfonate (Compound 1-3)

[0131]

[0132] Referring to the preparation method of Example 2, only 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(3-methylphenyl)-1-naphthamide to obtain compound 1-3, weighing 2.1 g, with a yield of 75.8%.

[0133] 1 H NMR (600 MHz, Methanol-d 4 )δ9.26(s,1H),8.32–8.23(m,2H),8.18(dt,J=7.9,1.7Hz,1H),7.97(dd,J=7.6,1.0Hz,1H),7.9 1(ddd,J=8.2,3.9,1.8Hz,2H),7.84(dd,J=7.3,1.3Hz,1H),7.76(t,J=7.8Hz,1H),7.62–7.51(m, 3H),7.17(t,J=7.7Hz,1H),6.96–6.89(m,1H),6.24(s,2H),4.37(t,J=5.3Hz,2H),3.20(t,J=7. 7Hz, 2H), 3.00–2.87 (m, 4H), 2.67 (qdd, J=12.5, 5.8, 3.5Hz, 4H), 2.60–2.44 (m, 4H), 2.32 (s, 3H). ESI-MSm / z: 655.23(M-Na) - .

[0134] Example 4: 3-amino-4-(5-((4-fluorophenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylic acid benzyl ester (Compound 1-4)

[0135]

[0136] Referring to the preparation method of Example 2, only 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide, and intermediate 1 was replaced by intermediate 2 to obtain compound 1-4, weighing 1.98 g, with a yield of 92.5%.

[0137] 1 H NMR (600 MHz, DMSO-d 6 )δ9.42(s,1H),8.41–8.28(m,1H),8.25(t,J=1.9Hz,1H),8.16(dt,J=7.9,1.6Hz,1 H),7.98(dd,J=7.6,1.3Hz,1H),7.92(ddd,J=8.5,6.3,1.8Hz,2H),7.81(dd,J=7.3, 1.0Hz,1H),7.79–7.74(m,1H),7.74–7.68(m,2H),7.55(t,J=7.4Hz,1H),7.38–7.3 1(m,4H),7.31–7.26(m,1H),7.14–7.06(m,2H),6.14(s,2H),5.34(d,J=1.0Hz,2H). ESI-MSm / z: 531.17(M+H) + .

[0138] Example 5: 3-amino-4-(5-((4,3-dichlorophenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylic acid cyclohexyl ester (Compound 1-5)

[0139]

[0140] Referring to Example 2, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(3,4-dichlorophenyl)-1-naphthamide, and intermediate 1 was replaced with intermediate 3 to obtain compound 1-5, weighing 1.49 g, with a yield of 72.7%.

[0141] 1 H NMR (600 MHz, DMSO-d 6)δ9.46(s,1H),8.36–8.29(m,1H),8.25(t,J=1.9Hz,1H),8.16(dt,J=8.1,1.7Hz,1H),8.0 3(d,J=2.3Hz,1H),7.98(dd,J=7.6,1.3Hz,1H),7.95–7.88(m,2H),7.81(dd,J=7.3,1.0Hz ,1H),7.79–7.73(m,1H),7.66(dd,J=8.1,2.2Hz,1H),7.55(t,J=7.4Hz,1H),7.46(d,J=7. 9Hz,1H),6.14(s,2H),4.91(p,J=4.6Hz,1H),2.00–1.85(m,2H),1.81–1.62(m,4H),1.59–

[0142] 1.34(m,4H). ESI-MSm / z: 573.14(M+H) + .

[0143] Example 6: 3-amino-4-(5-((4-fluoro-3-methylphenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylic acid dodecyl ester (Compound 1-6)

[0144]

[0145] Referring to the preparation method of Example 2, only intermediate 1 was replaced by intermediate 4 to obtain compound 1-6, weighing 2.19 g, with a yield of 90.3%.

[0146] 1 H NMR (600 MHz, DMSO-d 6 )δ10.61(s,1H),8.35(d,J=8.7Hz,1H),8.24–8.10(m,3H),7.89–7.76(m,2H ),7.76–7.58(m,4H),7.30(d,J=7.2Hz,1H),7.17(t,J=9.2Hz,1H),5.13(s, 2H),4.38(t,J=6.6Hz,2H),2.28(s,3H),1.75(q,J=7.0Hz,2H),1.40(q,J=7 .5Hz,2H),1.33(t,J=7.4Hz,2H),1.30–1.17(m,14H),0.84(t,J=6.8Hz,3H). ESI-MS m / z: 623.33 (M+H)+.

[0147] Example 7: 3-(4-methylpiperazin-1-yl)propyl 3-amino-4-(5-((4-fluorophenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylate (Compound 1-7)

[0148]

[0149] (1) Preparation of free base of compound 1-7

[0150] Referring to Example 2, only 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide, and intermediate 1 was replaced by intermediate 5 to obtain compound 1-7 free base, weighing 2.01 g, with a yield of 85.9%.

[0151] (2) Preparation of Compound 1-7

[0152] Take 420 mg (0.71 mmol) of the above 1-7 free base, add 20 mL DCM, dissolve it, add 0.2 mL (0.78 mmol) of dioxane hydrochloric acid solution, stir for 10-30 min, and concentrate to dryness to obtain 440 mg of compound 1-7, with a yield of 99%.

[0153] 1 H NMR(500MHz,Chloroform-d)δ9.80(s,1H),8.38(s,1H),8.30(d,J=8.4Hz,1H),8.22(t,J=2.2Hz,1H),8.15 –8.12(m,1H),7.92(dd,J=8.1,1.2Hz,1H),7.87(dd,J=8.3,2.3Hz,1H),7.76(t,J=7.9Hz,1H),7.71(dd,J= 7.2,1.2Hz,1H),7.67(dd,J=7.5,1.3Hz,1H),7.62–7.57(m,2H),7.53(t,J=7.4Hz,1H),7.13–7.08(m,2H), 5.87(s,2H),4.33(t,J=5.9Hz,2H),2.65(t,J=6.7Hz,2H),2.57–2.44(m,8H),1.90(tt,J=6.6,5.9Hz,2H). ESI-MSm / z: 581.26(M+H) + .

[0154] Example 8: 3-(4-methylpiperazin-1-yl)propyl-3-amino-4-(5-((4-fluoro-3-methylphenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylate hydrochloride (Compound 1-8)

[0155]

[0156] Referring to the preparation method of Example 7, only 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide to obtain compound 1-8, weighing 0.52 g, with a yield of 98.1%.

[0157] 1 H NMR (600 MHz, DMSO-d 6 )δ10.66(s,1H),8.36(d,J=8.7Hz,1H),8.26–8.06(m,3H),7.83(dd,J=24.3,7.0Hz,2H),7.69(ddt,J=29.8,13.6,7.4Hz,4H),7.31 (d,J=7.3Hz,1H),7.17(t,J=9.1Hz,1H),5.16(s,2H),4.45(t,J=6.4Hz,2H),3.07(s,10H),2.70(s,3H),2.28(s,3H),2.08(s,2H).

[0158] ESI-MS m / z: 595.31 (M+H) + .

[0159] Example 9: 1-9: 3-(4-methylpiperazin-1-yl)propyl 3-amino-4-(5-((3-methoxyphenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylate (Compound 1-9)

[0160]

[0161] Referring to the preparation method of Example 7, only 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(3-methoxyphenyl)-1-naphthamide to obtain compound 1-9, weighing 520 mg, with a yield of 98.1%.

[0162] 1H NMR(500MHz,Chloroform-d)δ9.80(s,1H),8.86(s,1H),8.30(d,J=8.4Hz,1H),8.22(t,J=2.2Hz,1H),8.14(dt,J=7.9,1.3Hz,1H), 7.92(dd,J=8.1,1.2Hz,1H),7.87(dd,J=8.3,2.3Hz,1H),7.76(t,J=7.9Hz,1H),7.71(dd,J=7.2,1.2Hz,1H),7.67(dd,J=7.5,1.3Hz ,1H),7.53(t,J=7.4Hz,1H),7.38(ddd,J=8.0,2.2,1.1Hz,1H),7.25(t,J=2.2Hz,1H),7.22(t,J=7.9Hz,1H),6.91(ddd,J=7.9,2.2, 1.2Hz,1H),5.87(s,2H),4.33(t,J=5.9Hz,2H),3.82(s,3H),2.65(t,J=6.7Hz,2H),2.56–2.45(m,8H),1.90(tt,J=6.7,5.9Hz,2H).

[0163] ESI-MS m / z: 593.30 (M+H) + .

[0164] Example 10: 2-Morpholinoethyl 3-amino-4-(5-((4-fluoro-3-methylphenyl)carbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylate (Compound 1-10)

[0165]

[0166] Referring to the preparation method of Example 7, only 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, and intermediate 5 was replaced by intermediate 6 to obtain compound 1-10, weighing 0.53 g, with a yield of 99.6%.

[0167] 1 H NMR (600 MHz, DMSO-d 6)δ11.66(s,1H),10.64(s,1H),8.36(d,J=8.7Hz,1H),8.23–8.18(m,2H),8.17(d,J=1 .9Hz,1H),7.85(dd,J=7.0,1.2Hz,1H),7.80(dd,J=7.1,2.7Hz,1H),7.76–7.67(m,3H ),7.64(ddd,J=8.1,4.5,2.8Hz,1H),7.33(d,J=7.2Hz,1H),7.17(t,J=9.2Hz,1H),5. 16(s,2H),4.83(s,2H),3.98(s,2H),3.86(s,2H),3.58(s,6H),2.28(d,J=1.9Hz,3H).

[0168] ESI-MS m / z: 568.23 (M+H) + .

[0169] Example 11: 6-(1-acetyl-3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 2-1)

[0170]

[0171] Add 2g (4.87mmol) 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide, 0.3g (5.0mmol) glacial acetic acid, HOBT (5.93mmol), 20mL DMF to the reaction bottle, slowly add 1.25g EDCI (6.52mmol), react at room temperature, after the reaction is completed, slowly add 10mL methanol, 20mL 3N HCl, dropwise, crystallize for 1 hour, filter, and rinse the filter cake with water until it is neutral. The solid is dried to obtain 1.91g, with a yield of 86.8%.

[0172] 1 H NMR (600 MHz, DMSO-d 6)δ10.61(s,1H),8.41–8.33(m,2H),8.20(d,J=8.2Hz,1H),8.17(d,J=1.9Hz,1H),7.84(dd,J=7.0,1.2Hz,1H),7.80(dd,J=7.1,2.7Hz,1H),7.78–7 .66(m,3H),7.64(ddd,J=8.0,4.5,2.7Hz,1H),7.34(dd,J=7.3,0.9Hz,1H ), 7.17 (t, J = 9.2Hz, 1H), 5.18 (s, 2H), 2.58 (s, 3H), 2.28 (d, J = 1.9Hz, 3H). ESI-MSm / z: 453.12(M+H) +

[0173] Example 12: 6-(3-amino-1-trimethylacetyl-1H-indazol-4-yl)-N-(3-methylphenyl)-1-naphthamide (Compound 2-2)

[0174]

[0175] Referring to the preparation method of Example 11, only 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(3-methylphenyl)-1-naphthamide, and glacial acetic acid was replaced by pivalic acid to obtain compound 2-2, weighing 1.88 g, with a yield of 77.2%.

[0176] 1 H NMR(500MHz,Chloroform-d)δ8.57(s,1H),8.30(d,J=8.4Hz,1H),8.22(t,J=2.2Hz,1H), 8.14(dt,J=7.6,1.3Hz,1H),7.92(dd,J=8.1,1.3Hz,1H),7.87(dd,J=8.3,2.3Hz,1H),7. 81(dd,J=7.4,1.2Hz,1H),7.76(t,J=8.0Hz,1H),7.71(dd,J=7.2,1.2Hz,1H),7.58–7.50 (m,3H),7.17(t,J=7.7Hz,1H),6.93–6.87(m,1H),5.86(s,2H),2.33(s,3H),1.31(s,9H). ESI-MSm / z: 477.21(M+H) + .

[0177] Example 13: 2-3: 6-(3-amino-1-(cyclopentanecarbonyl)-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide (Compound 2-3)

[0178]

[0179] Referring to the preparation method of Example 11, only 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (reference substance 2) was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide, and glacial acetic acid was replaced with cyclopentanoic acid to obtain compound 2-3, weighing 2.24 g, with a yield of 90.4%.

[0180] 1 H NMR (600 MHz, DMSO-d 6 )δ10.59(s,1H),8.41(d,J=8.3Hz,1H),8.35(d,J=8.7Hz,1H),8.21–8.15(m,2H),7.83(dd,J=7.1 ,1.2Hz,1H),7.79(dd,J=7.1,2.7Hz,1H),7.74(dd,J=8.7,1.9Hz,1H),7.72–7.60(m,4H),7.32(d ,J=7.2Hz,1H),7.16(t,J=9.2Hz,1H),5.14(s,2H),3.87(p,J=8.1Hz,1H),2.03–1.95(m,2H),1.8 5(dq,J=12.5,7.9Hz,2H), 1.73(tdd,J=10.4,6.2,4.1Hz,2H), 1.63(dtd,J=11.8,7.5,3.3Hz,2H). ESI-MSm / z: 493.16(M+H) + .

[0181] Example 14: 6-(3-amino-1-(3-phenylpropionyl)-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 2-4)

[0182]

[0183] Referring to the preparation method of Example 11, only glacial acetic acid was replaced with phenylpropionic acid to obtain compound 2-4, weighing 2.43 g, with a yield of 91.9%.

[0184] 1 H NMR (600 MHz, DMSO-d 6)δ10.62(s,1H),8.41(d,J=8.3Hz,1H),8.36(d,J=8.6Hz,1H),8.22–8.16(m,2H ),7.87–7.82(m,1H),7.80(dd,J=7.2,2.7Hz,1H),7.75(dd,J=8.7,1.9Hz,1H), 7.73–7.65(m,2H),7.67–7.61(m,1H),7.39–7.28(m,5H),7.24–7.14(m,2H),5. 19 (s, 2H), 3.36 (t, J = 7.7Hz, 2H), 3.06 (t, J = 7.7Hz, 2H), 2.28 (d, J = 1.9Hz, 3H). ESI-MS m / z: 543.17 (M+H) + .

[0185] Example 15: 6-(3-amino-1-octanoyl-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 2-5)

[0186]

[0187] Referring to the preparation method of Example 11, only 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, and glacial acetic acid was replaced by octanoic acid to obtain compound 2-5, weighing 2.5 g, with a yield of 95.6%.

[0188] 1 H NMR (600 MHz, DMSO-d 6 )δ10.61(s,1H),8.40(d,J=8.3Hz,1H),8.35(d,J=8.6Hz,1H),8.20(d,J=8.2Hz,1H),8. 17(d,J=1.9Hz,1H),7.84(dd,J=7.0,1.2Hz,1H),7.80(dd,J=7.2,2.7Hz,1H),7.77–7.6 1(m,4H),7.33(d,J=7.2Hz,1H),7.17(t,J=9.2Hz,1H),5.17(s,2H),3.00(t,J=7.4Hz,2 H), 2.28 (d, J = 2.0Hz, 3H), 1.72 (p, J = 7.4Hz, 2H), 1.42–1.24 (m, 8H), 0.90–0.84 (m, 3H).

[0189] ESI-MS m / z: 537.25 (M+H) + .

[0190] Example 16: 6-(3-amino-1-decanoyl-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 2-6)

[0191]

[0192] Referring to the preparation method of Example 11, only 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, and glacial acetic acid was replaced by decanoic acid to obtain compound 2-6, weighing 2.6 g, with a yield of 94.6%.

[0193] 1 H NMR (600 MHz, DMSO-d 6 )δ10.61(s,1H),8.40(d,J=8.4Hz,1H),8.35(d,J=8.7Hz,1H),8.20(d,J=8.3Hz,1H),8.17 (d,J=2.1Hz,1H),7.84(d,J=7.0Hz,1H),7.80(dd,J=7.1,2.7Hz,1H),7.77–7.61(m,4H),7 .33(dd,J=7.4,2.1Hz,1H),7.17(td,J=9.2,1.7Hz,1H),5.16(s,2H),3.00(td,J=7.5,1.7 Hz, 2H), 2.28 (s, 3H), 1.77–1.67 (m, 2H), 1.40–1.24 (m, 12H), 0.86 (dt, J = 7.1, 3.4Hz, 3H).

[0194] ESI-MS m / z: 565.27 (M+H) + .

[0195] Example 17: 2-7: 6-(3-amino-1-benzoyl-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 2-7)

[0196]

[0197] Referring to the preparation method of Example 11, only glacial acetic acid was replaced with benzoic acid to obtain compound 2-7, weighing 2.31 g, with a yield of 92.2%.

[0198] 1 H NMR (600 MHz, DMSO-d 6)δ10.62(s,1H),8.54(d,J=8.3Hz,1H),8.41–8.33(m,1H),8.25–8.17(m,2H),7.98(dd,J=8.1,1.6Hz,2H),7.85(d,J=7.0Hz,1H),7.83–7 .68(m,4H),7.67–7.58(m,2H),7.54(dd,J=8.3,6.8Hz,2H),7.43–7.38(m,1H),7.17(t,J=9.2Hz,1H),5.21(s,2H),2.28(d,J=1.9Hz,3H).

[0199] ESI-MS m / z: 515.16 (M+H) + .

[0200] Example 18: 2-8: 6-(3-amino-1-(furan-2-carbonyl)-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide (Compound 2-8)

[0201]

[0202] Referring to the preparation method of Example 11, only 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide, and glacial acetic acid was replaced by 2-furancarboxylic acid to obtain compound 2-8, weighing 2.32 g, with a yield of 94.1%.

[0203] 1 H NMR (600 MHz, DMSO-d 6 )δ10.62(s,1H),8.51(d,J=8.3Hz,1H),8.37(d,J=8.7Hz,1H),8.21(dd,J=5.2,3.3Hz, 2H),8.15–8.10(m,2H),8.07(d,J=3.5Hz,1H),7.86(dd,J=7.1,1.2Hz,1H),7.79(ddd,J =10.7,8.0,2.3Hz,2H),7.73(dt,J=8.2,6.5Hz,2H),7.64(ddd,J=8.0,4.4,2.6Hz,1H), 7.39 (d, J=7.2Hz, 1H), 7.18 (t, J=9.2Hz, 1H), 6.82 (dd, J=3.5, 1.7Hz, 1H), 5.33 (s, 2H).

[0204] ESI-MS m / z: 491.12 (M+H) + .

[0205] Example 19: 6-(3-amino-1-cinnamoyl-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 2-9)

[0206]

[0207] Referring to the preparation method of Example 11, only glacial acetic acid was replaced with trans-cinnamic acid to obtain compound 2-9, weighing 2.28 g, with a yield of 86.6%.

[0208] 1 H NMR (600 MHz, DMSO-d 6 )δ10.62(s,1H),8.54(d,J=8.3Hz,1H),8.37(d,J=8.6Hz,1H),8.24–8.16(m,2H),7.98–7.84(m,3H),7.84–7.68(m,6H),7.67–

[0209] 7.61(m,1H),7.57–7.45(m,3H),7.39(d,J=7.4Hz,1H),7.17(t,J=9.2Hz,1H),5.30(s,2H),2.28(d,J=1.9Hz,3H). ESI-MSm / z: 541.15(M+H) +

[0210] Example 20: 6-(3-amino-1-(2-morpholinoacetyl)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide hydrochloride (Compound 2-10)

[0211]

[0212] Referring to the preparation method of Example 11, only 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, and glacial acetic acid was replaced by 2-morpholineacetic acid to obtain compound 2-10, weighing 2.1 g, with a yield of 98.6%.

[0213] 1 H NMR (600 MHz, DMSO-d 6)δ11.23(s,1H),10.67(s,1H),8.38(t,J=9.0Hz,2H),8.25–8.17(m,2H),7.89–7.85(m,1H),7.85–7.68(m,4H),7.70–7.63(m,1H ),7.44(d,J=7.3Hz,1H),7.17(t,J=9.1Hz,1H),5.47(s,2H),4.91(s,2H),3.99(s,2H),3.64–3.61(m,6H),2.28(d,J=2.0Hz,3H).

[0214] ESI-MS m / z: 538.19 (M+H) + .

[0215] Example 21: (R)-6-(3-amino-1-(tetrahydrofuran-2-carbonyl)-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 2-11)

[0216]

[0217] Referring to the preparation method of Example 11, only glacial acetic acid was replaced with R-tetrahydrofurancarboxylic acid to obtain compound 2-11, weighing 2.1 g, with a yield of 84.9%.

[0218] 1 H NMR (600 MHz, DMSO-d 6 )δ10.62(s,1H),8.37(dd,J=15.6,8.5Hz,2H),8.25–8.17(m,2H),7.85(dd,J=7.0,1.2Hz,1 H),7.80(dd,J=7.1,2.7Hz,1H),7.75(dd,J=8.7,1.9Hz,1H),7.71(dt,J=8.3,7.0Hz,2H),7. 64(ddd,J=8.0,4.6,2.8Hz,1H),7.36(d,J=7.2Hz,1H),7.17(t,J=9.2Hz,1H),5.40(dd,J=8. 5,5.2Hz,1H),5.24(s,2H),4.02(q,J=7.2Hz,1H),3.92(td,J=7.5,5.7Hz,1H),2.38(dtd,J=

[0219] 12.5, 8.5, 6.5Hz, 1H), 2.28 (d, J = 1.9Hz, 3H), 2.09–2.01 (m, 1H), 2.00–1.86 (m, 2H). ESI-MSm / z: 509.17(M+H) + .

[0220] Example 22: 6-(3-amino-1-valyl-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide hydrochloride (Compound 3-1)

[0221]

[0222] The synthetic route is as follows:

[0223]

[0224] To the reaction bottle, 5 g (12.2 mmol) of 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, 1.98 g (14.65 mmol) of HOBT, 2.91 g (13.39 mmol) of Boc-L-valine, 2.80 g (14.61 mmol) of EDCI and 50 mL of DMF were added and reacted at room temperature. After the reaction was completed, 25 mL of methanol and 50 mL of 3N HCl were slowly added dropwise. The mixture was crystallized for 1 hour and filtered. The filter cake was rinsed with water until it was neutral. After the filter cake was dried, 15 mL of DCM and 15 mL of trifluoroacetic acid were added, and the reaction was carried out at room temperature. After the reaction was completed, it was concentrated to dryness, 30 mL of DCM was added, 30 mL of purified water was added, and the pH value was adjusted to 9-10 with 20% sodium hydroxide. The layers were allowed to stand and the DCM layer was washed with 30 mL of purified water and 30 ml of saturated sodium chloride in turn. The organic layer was concentrated to dryness under reduced pressure to obtain 5.7 g of compound 3-1 free base, with a yield of 91.9%.

[0225] Take 1 g (1.96 mmol) of the free base of compound 3-1, add 20 mL of DCM, dissolve it, add 0.54 mL (2.16 mmol) of dioxane hydrochloric acid solution, stir for 10-30 min, and concentrate to dryness to obtain compound 3-1, weighing 1.0 g, with a yield of 93.5%.

[0226] 1 H NMR (600 MHz, DMSO-d 6)δ10.65(s,1H),8.43(d,J=8.3Hz,1H),8.37(d,J=8.7Hz,1H),8.23–8.17(m,2H),7.88–7.8 4(m,1H),7.81(dd,J=7.1,2.6Hz,1H),7.78–7.69(m,3H),7.65(ddd,J=7.9,4.5,2.7Hz,1H), 7.41(d,J=7.3Hz,1H),7.17(t,J=9.2Hz,1H),6.88(s,3H),5.36(s,2H),4.64(s,1H),2.37( dt,J=13.2,6.6Hz,1H),2.28(d,J=2.0Hz,3H),1.04(d,J=6.9Hz,3H),0.97(d,J=6.9Hz,3H). ESI-MSm / z: 510.19(M+H) + .

[0227] Example 23: 3-2: 6-(3-amino-1-(D-phenylalanyl)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide hydrochloride (Compound 3-2)

[0228]

[0229] Referring to the preparation method of Example 22, only Boc-L-valine was replaced with Boc-D-phenylalanine to obtain compound 3-2, weighing 1.71 g, with a yield of 80.2%.

[0230] 1 H NMR (600 MHz, DMSO-d 6 )δ10.64(s,1H),8.40(dd,J=11.3,8.5Hz,2H),8.24–8.18(m,2H),7.87(d,J=7.0Hz,1H),7.82(dd,J=7.1,2 .7Hz,1H),7.77(dd,J=8.7,1.9Hz,1H),7.75–7.68(m,2H),7.66(ddd,J=7.9,4.4,2.7Hz,1H),7.38(d,J=7. 3Hz,1H),7.29(d,J=5.4Hz,4H),7.23(ddd,J=8.7,5.8,3.1Hz,1H),7.18(t,J=9.2Hz,1H),5.34(s,2H),4.8 3(dd,J=7.9,4.9Hz,1H), 3.26(dd,J=13.7,4.9Hz,1H), 2.96(dd,J=13.7,7.9Hz,1H), 2.29(d,J=2.0Hz,3H).

[0231] ESI-MS m / z: 558.23 (M+H) +

[0232] Example 24: 6-(3-amino-1-(L-phenylalanyl)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide hydrochloride (Compound 3-3)

[0233]

[0234] Referring to the preparation method of Example 22, only Boc-L-valine was replaced with Boc-L-phenylalanine to obtain compound 3-3, weighing 1.78 g, with a yield of 83.4%.

[0235] 1 H NMR (600 MHz, DMSO-d 6 )δ10.64(s,1H),8.40(dd,J=21.1,8.5Hz,2H),8.27–8.16(m,2H),7.89–7.64(m,6H),7.36(d,J=7.3Hz,1H),7.32–7.23(m,4H),7.23 –7.09(m,2H),5.28(s,2H),4.70(dd,J=7.8,5.1Hz,1H),3.18(d,J=5.1Hz,1H),2.85(dd,J=13.5,7.9Hz,1H),2.29(d,J=2.1Hz,3H).

[0236] ESI-MS m / z: 558.23 (M+H) + .

[0237] Example 25: (R)-6-(3-amino-1-prolyl-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 3-4)

[0238]

[0239] Referring to the preparation method of Example 22, only 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide, and Boc-L-valine was replaced by Boc-L-proline to obtain compound 3-4, weighing 1.79 g, with a yield of 72.6%. 1 H NMR (600 MHz, DMSO-d 6)δ10.57(s,1H),8.36(t,J=8.1Hz,1H),8.19(dd,J=8.2,5.1Hz,1H),8.14(dd,J=11.7,1.9Hz,1H),7.81(d dd,J=19.8,7.2,3.2Hz,2H),7.77–7.67(m,2H),7.63(dd,J=8.3,4.2Hz,1H),7.37–7.29(m,2H),7.17(t,J= 9.2Hz,1H),6.74–6.67(m,1H),6.39(d,J=8.5Hz,2H),5.59(ddd,J=18.6,9.0,4.2Hz,1H),3.52–3.40(m,2 H),2.49–2.39(m,2H),2.28(d,J=1.9Hz,3H),2.09–2.00(m,1H),1.90(ddq,J=20.7,13.1,7.3,6.6Hz,2H).

[0240] ESI-MS m / z: 508.16 (M+H) + .

[0241] Example 26: 6-(3-amino-1-(benzoyl-L-phenylalanyl)-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide (Compound 4-1)

[0242]

[0243] Referring to the method for preparing the free base in Example 22, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide, and Boc-L-valine was replaced with Boc-L-phenylalanine to prepare 4-1, which was then prepared with benzoic acid by the method of Example 11 to obtain 4-1, weighing 2.48 g,

[0244] Yield: 75.8%.

[0245] 1 H NMR (600 MHz, DMSO-d 6 )δ10.64(s,1H),8.97(d,J=8.1Hz,1H),8.40(dd,J=12.8,8.5Hz,2H),8.28–8.20(m,2H),7.92–7.78(m, 6H),7.73(dd,J=8.3,7.2Hz,2H),7.65(ddt,J=8.9,7.2,3.5Hz,1H),7.57(dd,J=7.8,1.8Hz,1H),7.57–

[0246] 7.50(m,2H),7.49(t,J=7.6Hz,2H),7.46–7.35(m,1H),7.33(t,J=7.6Hz,2H),7.27–7.15 (m,2H),5.87(ddd,J=11.2,8.1,2.9Hz,1H),5.41(s,2H),3.18(dd,J=13.8,11.2Hz,1H).

[0247] ESI-MS m / z: 648.23 (M+H) + .

[0248] Example 27: 6-(3-amino-1-(benzoyl-D-phenylalanyl)-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide (Compound 4-2)

[0249]

[0250] Referring to Example 22, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced by 6-(3-amino-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide, and Boc-L-valine was replaced by Boc-D-phenylalanine to prepare 4-2, which was then prepared with benzoic acid using the method of Example 11 to obtain compound 4-2, weighing 2.3 g, with a yield of 70.2%.

[0251] 1 H NMR (600 MHz, DMSO-d 6)δ10.63(s,1H),8.97(d,J=8.1Hz,1H),8.40(dd,J=13.9,8.5Hz,2H),8.25–8.21(m,2H),7.87(td,J=7.3,6.5,1.2 Hz,4H),7.81(dt,J=8.7,2.1Hz,2H),7.73(dd,J=8.3,7.2Hz,2H),7.65(ddd,J=8.0,4.5,2.7Hz,1H),7.59–7.53(m ,2H),7.55–7.52(m,1H),7.49(dd,J=8.3,6.9Hz,2H),7.40(d,J=7.2Hz,1H),7.33(t,J=7.7Hz,2H),7.25–7.15(m, 2H), 5.86 (ddd, J=11.1, 8.1, 2.9Hz, 1H), 5.40 (s, 2H), 3.41 (dd, J=13.9, 2.9Hz, 1H), 3.17 (dd, J=13.8, 11.2Hz, 1H). ESI-MSm / z: 648.23(M+H) + .

[0252] Example 28: 6-(3-amino-1-(glycyl-D-phenylalanyl)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 5-1)

[0253]

[0254] Referring to the preparation method of Example 22, the free base of compound 3-2 obtained in the preparation process of Example 24 was reacted with Boc-protected glycine, and Boc was removed by trifluoroacetic acid to prepare compound 5-1, weighing 806 mg, with a yield of 73.3%.

[0255] 1 H NMR (600 MHz, DMSO-d 6)δ10.63(s,1H),8.95(d,J=8.2Hz,1H),8.40–8.35(m,2H),8.24–8.19(m,2H),7.87(d,J=7.0Hz,1H),7.79(ddd ,J=14.6,7.9,2.3Hz,2H),7.77–7.70(m,2H),7.64(dt,J=7.9,3.6Hz,1H),7.46(s,3H),7.41(d,J=7.3Hz,1H), 7.37(d,J=7.7Hz,2H),7.32(t,J=7.5Hz,2H),7.25(t,J=7.3Hz,1H),7.18(t,J=9.1Hz,1H),5.81–5.74(m,1H), 5.42(s,2H),3.61(d,J=16.3Hz,1H),3.52(d,J=16.3Hz,1H),2.95(dd,J=14.0,10.0Hz,1H),2.30–2.27(m,3H). ESI-MSm / z: 615.3(M+H) + .

[0256] Example 29-30: 6-(3-amino-1-(glycyl-L-phenylalanyl)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 5-2)

[0257]

[0258]

[0259] Referring to the preparation method of Example 28, only the free base of compound 3-2 was replaced by the free base of compound 3-3 obtained in the preparation process of Example 23 to obtain compound 5-2, weighing 828 mg, with a yield of 75.3%.

[0260] 1 H NMR (600 MHz, DMSO-d 6)δ10.63(s,1H),9.00(d,J=8.2Hz,1H),8.40–8.36(m,2H),8.22(d,J=7.9Hz,2H),7.87(d,J=7.0Hz,1H),7.84(s,1H),7. 82–7.78(m,3H),7.78(dd,J=8.6,1.9Hz,1H),7.74(q,J=7.2Hz,2H),7.64(dt,J=7.8,3.7Hz,1H),7.41(d,J=7.3Hz,1H), 7.38(d,J=7.5Hz,2H),7.32(t,J=7.5Hz,2H),7.25(t,J=7.3Hz,1H),7.18(t,J=9.2Hz,1H),5.78(ddt,J=8.3,5.8,3.3Hz ,1H),5.42(s,2H),3.65(d,J=16.3Hz,1H),3.56(d,J=16.3Hz,1H),2.94(dd,J=14.0,10.1Hz,1H),2.28(d,J=2.0Hz,3H). ESI-MSm / z: 615.3(M+H) + .

[0261] Compound 5-2 was reacted with hydrochloric acid to obtain the hydrochloride of compound 5-2, namely compound 5-3, weighing 421 mg, with a yield of 99.3%.

[0262] 1 H NMR (600 MHz, DMSO-d 6 )δ10.69(d,J=4.4Hz,1H),9.16(d,J=7.8Hz,1H),8.38(d,J=8.4Hz,2H),8.22(d,J=7.3Hz,4H),7.87(d,J=7.0Hz,1H),7.85–

[0263] 7.79(m,1H),7.78(d,J=8.8Hz,1H),7.73(q,J=7.8Hz,2H),7.66(dt,J=8.1,3.9Hz,1 H),7.40(t,J=7.3Hz,3H),7.32(t,J=7.4Hz,2H),7.24(t,J=7.4Hz,1H),7.17(t,J=9. 1Hz,1H),5.76(dt,J=8.9,5.8Hz,1H),5.42(s,2H),3.66(d,J=16.2Hz,1H),3.56(d,J =16.3Hz,1H),2.96(dd,J=13.9,10.0Hz,1H),2.90(s,1H),2.74(s,1H),2.28(s,3H). ESI-MSm / z: 615.3(M+H) + .

[0264] Example 31: 3-amino-4-(3-amino-4-(5-((4-fluoro-3-methylphenyl)carbamoyl)naphthalen-2-yl)-1H-indazol-1-yl)-4-oxobutyric acid hydrochloride (Compound 6-1)

[0265]

[0266] The preparation process is as follows:

[0267]

[0268] Step 1:

[0269] Add 2g (4.87mmol) 6-(3-amino-1H-indazole-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, FMOC-aspartic acid-4-tert-butyl ester 2.2g, HOBT 0.8g (5.93mmol), EDCI 1.25g (6.54mmol), 20mL NMP to the reaction bottle, react at room temperature, after the reaction is completed, slowly add 10mL methanol, 20mL 3N HCl, dropwise addition, crystallize for a small test, filter with suction, and rinse the filter cake with water until it is neutral. The filter cake is dried to obtain intermediate A, weighing 3.9g, with a yield of 99.7%.

[0270] Step 2:

[0271] The intermediate A was added to a reaction bottle, and 20 mL of DMF and 5 g of piperidine were added. After reacting for 1 hour, TLC analysis showed that the reaction was complete. The intermediate was added to 100 mL of water and crystallized for 1 hour. The mixture was filtered, washed with water until neutral, and dried to obtain an intermediate B weighing 2.8 g with a yield of 99.3%.

[0272] Step 3:

[0273] The intermediate B was added to a reaction bottle, and 10 mL (4 M) of dioxane hydrochloric acid solution was added. The reaction was stirred for 1 hour. TLC analysis showed that the reaction was complete. The crude product was concentrated to dryness and purified by column (the volume ratio of mobile phase DCM: MeOH was 1:50 to 1:5) to obtain compound 6-1, weighing 1.74 g, with a yield of 64.4%.

[0274] 1 H NMR (600 MHz, DMSO-d 6 )δ13.01(s,1H),10.67(s,1H),8.79(s,3H),8.42–

[0275] 8.32(m,2H),8.24–8.16(m,2H),7.86(dd,J=7.1,1.2Hz,1H),7.83–7.68(m,4H),7.68–7.60(m,1H),7.43(dd,J=7.4,0.9Hz,1H),7.17(t,J =9.2Hz,1H),5.46(s,2H),5.08(dd,J=7.3,4.9Hz,1H),3.18(dd,J=17.7,7.3Hz,1H),3.13(dd,J=17.7,7.3Hz,1H),2.28(d,J=2.0Hz,3H). ESI-MSm / z: 526.19(M+H) + .

[0276] Example 32: 6-(1-(5-(((2R, 3R, 4R, 5R, 6R)-3-acetylamino-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanoyl)-3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 7-1)

[0277]

[0278] 7-1 The preparation process is as follows:

[0279]

[0280] Step 1. Referring to the preparation method of Example 11, 6-(3-amino-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, and glacial acetic acid was replaced with 5-(((2R, 3R, 4R, 5R, 6R)-3-acetylamino-4,5-bis((benzyloxy)carbonyl)oxy)-6-(((benzyloxy)carbonyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)pentanoic acid to obtain benzyloxy-protected compound 7-1.

[0281] Step 2: Dissolve the benzyloxy-protected compound 7-1 obtained in step 1 in methanol, add 0.1 g Pd / C, replace hydrogen, and hydrogenate for 3 hours. After the reaction is completed, filter and concentrate the filtrate to dryness under reduced pressure to obtain compound 7-1, weighing 3.3 g, with a total yield of 94.8%.

[0282] 1 H NMR(500MHz,Chloroform-d)δ8.52(s,1H),8.30(d,J=8.4Hz,1H),8.22(t,J=2.2Hz,1H),8.14(dt,J=7.8,1.6Hz,1H),7.92(dd,J=8.1,1.2Hz, 1H),7.87(dd,J=8.3,2.3Hz,1H),7.76(t,J=7.9Hz,1H),7.70(ddd,J=12.4,7.3,1.2Hz,2H),7.58–7.49(m,3H),7.08–7.02(m,2H),5.81(s,2H ),5.15(d,J=4.7Hz,1H),4.96(d,J=6.2Hz,1H),4.63(d,J=4.8Hz,1H),4.03(ddd,J=8.0,7.3,4.8Hz,1H),3.87(ddd,J=12.1,4.5,3.4Hz,1H), 3.78–3.53(m,5H),3.48(td,J=8.3,6.1Hz,1H),3.21(dt,J=7.7,3.5Hz ,1H),3.14–2.96(m,2H),2.29(s,3H),1.99(s,3H),1.79–1.60(m,4H). ESI-MSm / z:714.29(M+H) + .

[0283] Example 33: 6-(3-amino-1-((2R, 3S, 4R, 5R)-2,3,4,5,6-pentahydroxyhexanoyl)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 8-1)

[0284]

[0285] The preparation method is as follows:

[0286] Calcium gluconate (0.7 g, 1.63 mmol) and 10 mL of methanol were added to the reaction flask, cooled in an ice-water bath, and SOCl was slowly added. 2 (0.39 g, 3.30 mmol). After the addition, the temperature was gradually raised to room temperature, stirred overnight, and concentrated under reduced pressure to dryness to obtain a white solid, which was dissolved in 10 mL of methanol and set aside.

[0287] 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (1 g, 2.44 mmol) was dissolved in 10 mL DMF. After the solution was clear, the above 10 mL methanol solution was slowly added and reacted at room temperature overnight. The reaction solution was slowly added to 10 mL water, filtered, and the filter cake was washed with 10 mL water and dried to obtain compound 8-1, weighing 0.3 g, with a yield of 21%.

[0288] 1 H NMR (600 MHz, DMSO-d 6 )δ10.61(s,1H),8.31(d,J=8.7Hz,1H),8.19(d,J=8.2Hz,1H),8.14(d,J=1.9Hz,1H),7.80(d,J=6.8Hz,2H),7.76(dd,J=8.7,1.9Hz,1H),7. 68(t,J=7.6Hz,1H),7.66–7.61(m,1H),7.36(d,J=3.9Hz,2H),7.17(t,J=9.1Hz,1H),6.95(q,J=5.0,4.4Hz,1H),5.07(d,J=8.6Hz,1H),4.44

[0289] (t,J=6.7Hz,1H),4.32(s,2H),δ4.28(d,J=9.7Hz,1H),4.17(d,J=7.9Hz,1H),4.12(d,J=9.0Hz,1H),4.08( d,J=9.7Hz,1H),3.78(t,J=10.4Hz,1H),3.69(q,J=6.7Hz,1H),3.45-3.37(m,3H),2.28(d,J=1.9Hz,3H).

[0290] ESI-MS m / z: 589.21 (M+H) + .

[0291] Example 34: 9-1: ((2R, 3R, 4S, 5R, 6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl (Z)-4-(3-amino-4-(5-((3-methoxyphenyl)carbamoyl)naphthalen-2-yl)-1H-indazol-1-yl)-4-oxobut-2-enoic acid (Compound 9-1)

[0292]

[0293] The preparation process is as follows:

[0294]

[0295] Add diacetone galactose (2g, 7.7mmol), maleic anhydride (0.8g, 8.2mmol), pyridine 20mL to the reaction bottle, T = 110-115℃, react for 5-6 hours, concentrate under reduced pressure until no obvious liquid, and then drag with 10mL toluene. After dragging, add DMF 20mL, HOBT (1.3g, 9.6mmol), 6-(3-amino-1H-indazol-4-yl)-N-(3-methoxyphenyl)-1-naphthamide (3.1g, 7.6mmol), EDCI (1.9g, 9.9mmol) in sequence, react at room temperature overnight, then slowly add the reaction solution into 40mL water, stir and crystallize for 2 hours, filter and dry to obtain a white solid. Add the obtained solid to the reaction bottle, add 10mL glacial acetic acid and 10mL dioxane, stir and react at room temperature, after the reaction is completed, concentrate under reduced pressure to dryness to obtain compound 9-1, weighing 1.0g, yield 19.6%.

[0296] 1H NMR(500MHz,Chloroform-d)δ8.86(s,1H),8.30(d,J=8.4Hz,1H),8.22(t,J=2.2Hz,1H ),8.14(dt,J=7.8,1.4Hz,1H),7.92(dd,J=8.1,1.2Hz,1H),7.87(dd,J=8.3,2.3Hz,1H ),7.78–7.69(m,3H),7.53(t,J=7.3Hz,1H),7.38(ddd,J=8.0,2.2,1.1Hz,1H),7.25(t ,J=2.2Hz,1H),7.22(t,J=7.9Hz,1H),6.91(ddd,J=7.9,2.2,1.2Hz,1H),6.88(d,J=11 .2Hz,1H),6.59(d,J=11.2Hz,1H),5.85(s,2H),5.21(d,J=6.0Hz,1H),5.01(dq,J=4.8 ,3.8Hz,1H),4.82(d,J=4.8Hz,1H),4.79(d,J=5.9Hz,1H),4.48–4.39(m,2H),4.20(d, J=6.2Hz,1H),3.82(s,3H),3.75(dtdd,J=6.1,4.8,3.7,2.4Hz,1H),3.70(qd,J=5.9,3 .8Hz, 1H), 3.58 (dddd, J=11.9, 5.9, 4.1, 2.3Hz, 1H), 3.48 (ddt, J=9.9, 6.2, 3.8Hz, 1H).

[0297] ESI-MS m / z: 669.23 (M+H) + .

[0298] Example 35: (3R, 4R, 5S)-2-((R)-1,2-dihydroxyethyl)-4,5-dihydroxytetrahydrofuran-3-yl (Z)-4-(3-amino-4-(5-((3-methoxyphenyl)carbamoyl)naphthalen-2-yl)-1H-indazol-1-yl)-4-oxobut-2-enoic acid (Compound 9-2)

[0299]

[0300] Referring to the preparation method of Example 34, diacetone galactose was replaced with diacetone glucose to obtain compound 9-2, weighing 1.3 g, with a yield of 25.5%.

[0301] 1H NMR(500MHz,Chloroform-d)δ8.86(s,1H),8.30(d,J=8.4Hz,1H),8.22(t,J=2.2Hz,1H),8.14(dt,J=7.9,1.3Hz,1H),7.92(dd,J=8.1,1.2Hz,1H),7.87(dd, J=8.3,2.3Hz,1H),7.78–7.69(m,3H),7.53(t,J=7.3Hz,1H),7.38(ddd,J=8.0 ,2.2,1.1Hz,1H),7.25(t,J=2.2Hz,1H),7.22(t,J=7.9Hz,1H),6.91(ddd,J=7 .9,2.2,1.2Hz,1H),6.86(d,J=11.5Hz,1H),6.61(d,J=11.4Hz,1H),5.85(s,2 H),5.10(ddd,J=4.0,3.3,0.8Hz,1H),4.93(ddd,J=7.4,6.6,0.9Hz,1H),4.65 (d,J=3.8Hz,1H),4.45(dd,J=7.0,5.9Hz,2H),4.15(d,J=5.9Hz,1H),4.03(dd d,J=7.3,5.9,3.3Hz,1H),3.99–3.91(m,2H),3.82(s,3H),3.74–3.63(m,2H).

[0302] ESI-MS m / z: 669.21 (M+H) + .

[0303] Example 36: (2R, 3R, 4R, 5R, 6R)-5-acetylamino-2-(acetoxymethyl)-6-((5-(3-amino-4-(5-((4-fluoro-3-methylphenyl)carbamoyl)naphthalen-2-yl)-1H-indazol-1-yl)-5-oxopentyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate (Compound 9-3)

[0304]

[0305] The preparation process is as follows:

[0306]

[0307] 1.2 g (2.68 mmol) of 4-(((1R, 2S, 3R, 4S, 5R)-2-acetylamino-3,4-diacetoxy-5-(acetoxymethyl)cyclohexyl)oxy)butyric acid, 0.4 g (2.96 mmol) of HOBT, 1 g (2.44 mmol) of 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, 10 mL of NMP, and 0.65 g (3.4 mmol) of EDCI were added to the reaction bottle and reacted at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was slowly dripped into 20 mL of water. After stirring for 1 hour, the mixture was filtered and the filter cake was dried to obtain compound 9-3, weighing 1.8 g with a yield of 90.0%.

[0308] 1 H NMR (600 MHz, DMSO-d 6 )δ10.61(s,1H),8.40(d,J=8.3Hz,1H),8.35(d,J=8.7Hz,1H),8.20(d,J=8.2Hz,1H),8.17(d,J=1.9Hz,1H),7.86–7.82(m,2H),7.80(dd,J=7. 1,2.7Hz,1H),7.77–7.66(m,3H),7.63(ddd,J=8.0,4.6,2.7Hz,1H),7.34(d,J=7.2Hz,1H),7.17(t,J=9.2Hz,1H),5.23(d,J=3.4Hz,1H),5.17( s,2H),4.99(dd,J=11.2,3.4Hz,1H),4.54(d,J=8.5Hz,1H),4.05(s,3H),3.91(dt,J=11.2,8.8Hz,1H),3.78(dt,J=9.8,6.1Hz,1H),3.51(dt,J =10.0,6.5Hz,1H),3.02(td,J=7.3,2.0Hz,2H),2.28(d,J=2.1Hz,3H), 2.12(s,3H),2.01(s,3H),1.90(s,3H),1.79(s,3H),1.68–1.53(m,4H). ESI-MSm / z: 824.35(M+H) + .

[0309] Examples 37-38: 6-(1-ethyl-3-(ethylamino)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 10-1) and 6-(3-(ethylamino)-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide (Compound 10-2)

[0310]

[0311] The preparation process is as follows:

[0312]

[0313] 3g (7.31mmol) 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide, 2.4g (15.7mmol) iodoethane, 20mL DMF, 1.5g (17.86mmol) sodium bicarbonate were added to the reaction bottle, the temperature was raised to T = 60°C, the reaction was allowed to proceed overnight, 10mL methanol was added to the reaction solution, 40mL purified water was slowly added, the mixture was stirred for 2 hours, the mixture was filtered, the filter cake was washed until neutral, and the filter cake was subjected to column chromatography to obtain compound 10-1, weighing 1.65g, with a yield of 51.6%, and compound 10-2, weighing 0.85g, with a yield of 25.0%. The identification data are as follows:

[0314] 10-1: 1 H NMR (600 MHz, DMSO-d 6 )δ10.61(s,1H),8.42(d,J=8.7Hz,1H),8.24–8.17(m,2H),7.92–7.87(m,2H),7.84(d,J=8.6Hz ,1H),7.81(dd,J=7.1,2.8Hz,1H),7.76(dd,J=8.7,1.9Hz,1H),7.73(dd,J=8.3,7.1Hz,1H),7. 65(ddd,J=11.8,5.3,3.0Hz,1H),7.32(d,J=7.1Hz,1H),7.18(t,J=9.2Hz,1H),4.46(dq,J=19. 8,7.0Hz,4H),3.18(s,1H),2.28(d,J=2.0Hz,3H),1.29(t,J=7.1Hz,3H),1.00(t,J=6.9Hz,3H). ESI-MSm / z: 467.19(M+H) + .

[0315] 10-2: 1 H NMR (600 MHz, DMSO-d 6 )δ11.87(s,1H),10.62(s,1H),8.35(d,J=8.7Hz,1H),8.20(d,J=8.2Hz,1H),8.16(d,J=1.9Hz,1H),7.84–7.80(m,2H),7.83–

[0316] 7.75(m,1H),7.72–7.62(m,2H),7.40–7.34(m,2H),7.17(t,J=9.2Hz,1H),6.95(dd,J=4.8,3.0 Hz,1H),3.72(t,J=5.7Hz,1H),3.21–3.13(m,2H),2.29(d,J=2.0Hz,3H),1.00(t,J=7.1Hz,3H). ESI-MSm / z: 439.15(M+H) + .

[0317] Example 39: 6-(3-amino-1-cyclohexyl-1H-indazol-4-yl)-N-(3,5-dichlorophenyl)-1-naphthamide (Compound 10-3)

[0318]

[0319] Referring to the preparation methods of Examples 37 and 38, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with 6-(3-amino-1H-indazol-4-yl)-N-(3,4-dichlorophenyl)-1-naphthamide, and iodoethane was replaced with 1-iodocyclohexane to obtain compound 10-3, weighing 2.17 g, with a yield of 61.1%.

[0320] 1 H NMR(500MHz,Chloroform-d)δ8.77(s,1H),8.30(d,J=8.4Hz,1H),8.20(t,J=2.2Hz,1H),8.15–8.10(m,1 H),7.92(dd,J=8.0,1.4Hz,1H),7.84–7.78(m,3H),7.76(t,J=8.0Hz,1H),7.72(dd,J=7.2,1.2Hz,1H),7 .56(dd,J=7.7,1.3Hz,1H),7.48(t,J=7.4Hz,1H),7.27(d,J=4.4Hz,1H),5.84(s,2H),4.44(p,J=3.7Hz, 1H), 2.00(dddd,J=12.4,7.8,5.3,3.7Hz,2H),1.92–1.81(m,2H),1.74–1.64(m,2H),1.62–1.41(m,4H). ESI-MSm / z: 529.15(M+H) + .

[0321] Example 40: 6-(1-cyclohexyl-3-(ethylamino)-1H-indazol-4-yl)-N-(3,5-dichlorophenyl)-1-naphthamide (Compound 10-4)

[0322]

[0323] Referring to the preparation method of Example 37, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with 6-(3-amino-1-cyclohexyl-1H-indazol-4-yl)-N-(3,5-dichlorophenyl)-1-naphthamide to obtain compound 10-4, weighing 0.5 g, with a yield of 47.6%.

[0324] 1 H NMR(500MHz,Chloroform-d)δ8.77(s,1H),8.33(d,J=7.7Hz,1H),8.23(t,J=2.0Hz,1H),8.14(dt,J=7.9,1.6Hz,1H) ,7.92(ddd,J=8.3,6.8,1.7Hz,2H),7.80(d,J=2.2Hz,2H),7.76(t,J=8.0Hz,1H),7.70(dd,J=5.1,3.3Hz,1H),7.58–

[0325] 7.51(m,2H),7.27(t,J=2.2Hz,1H),6.39(t,J=3.4Hz,1H),4.52(p,J=3.7Hz,1H),3.54(qd,J=6.6,3.5Hz,2H),2.00(d ddd,J=12.4,7.8,5.3,3.7Hz,2H),1.92–1.83(m,2H),1.75–1.64(m,2H),1.62–1.53(m,2H),1.56–1.48(m,1H),1.51–

[0326] 1.41(m,1H),1.33(t,J=6.5Hz,3H). ESI-MSm / z: 557.17(M+H) + .

[0327] Example 41: 6-(3-amino-1-phenyl-1H-indazol-4-yl)-N-(5-methylisoxazol-3-yl)-1-naphthamide (Compound 10-5)

[0328]

[0329] The preparation process is as follows:

[0330]

[0331] CsOAc (0.63 g, 3.26 mmol), CuI (0.25 g, 1.31 mmol), DMF (10 mL), iodobenzene (0.27 g, 1.31 mmol, 1.0 eq), 6-(3-amino-1H-indazol-4-yl)-N-(5-methylisoxazol-3-yl)-1-naphthamide (1 g, 2.61 mmol, 2.0 eq) were added to the reaction bottle at T = 90 ° C. The reaction was kept at this temperature for 24 hours, cooled to room temperature, and dichloromethane and saturated NH 4 Cl solution and saturated NaCl solution, stirred sufficiently, filtered, rinsed the filter cake with dichloromethane, separated the filtrate, concentrated the dichloromethane phase to dryness under reduced pressure, and separated by column purification to obtain compound 10-5, weighing 0.8 g, with a yield of 66.7%.

[0332] 1 H NMR (600 MHz, DMSO-d 6 )δ11.16(s,1H),8.31(dd,J=8.2,0.7Hz,1H),8.24(t,J=2.1Hz,1H),8.16(dt,J=7 .5,1.6Hz,1H),7.93(ddd,J=7.2,6.0,1.1Hz,2H),7.87(dd,J=8.3,2.3Hz,1H),7.8 2(dd,J=7.3,1.0Hz,1H),7.77(t,J=8.0Hz,1H),7.68–7.64(m,2H),7.56–7.47(m, 3H), 7.38 (tt, J=7.3, 1.3Hz, 1H), 6.71 (d, J=0.8Hz, 1H), 5.66 (s, 2H), 2.39 (s, 3H). ESI-MSm / z: 460.17(M+H) + .

[0333] Example 42: 6-(3-(ethylamino)-1-phenyl-1H-indazol-4-yl)-N-(5-methylisoxazol-3-yl)-1-naphthamide (Compound 10-6)

[0334]

[0335] Referring to the preparation methods of Examples 37 and 38, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with compound 10-5 to obtain compound 10-6, weighing 0.36 g, with a yield of 67.9%.

[0336] 1 H NMR (600 MHz, DMSO-d 6)δ11.16(s,1H),8.36–8.32(m,1H),8.27(t,J=2.1Hz,1H),8.16(dt,J=7.9, 1.7Hz,1H),7.99–7.90(m,3H),7.81–7.74(m,2H),7.69–7.65(m,2H),7.58– 7.50(m,3H),7.38(tt,J=7.4,1.3Hz,1H),7.11(t,J=3.5Hz,1H),6.71(d,J= 0.8Hz, 1H), 3.52 (tt, J = 6.3, 3.1Hz, 2H), 2.39 (s, 3H), 1.33 (t, J = 6.6Hz, 3H). ESI-MS m / z: 488.19 (M+H) + .

[0337] Example 43: tert-Butyl 3-(ethylamino)-4-(5-(phenylcarbamoyl)naphthalen-2-yl)-1H-indazole-1-carboxylate (Compound 10-7)

[0338]

[0339] Referring to the preparation method of Example 37, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with 3-amino-4-(5-(phenylcarbamoyl)naphthalene-2-yl)-1H-indazole-1-carboxylic acid tert-butyl ester to obtain compound 10-7, weighing 0.7 g, with a yield of 66%.

[0340] 1 H NMR (600 MHz, DMSO-d 6 )δ10.42(s,1H),8.38–8.33(m,1H),8.28(t,J=2.0Hz,1H),8.16(dt,J=7.9,1.8Hz,1H ),8.03–7.98(m,2H),7.92(dd,J=8.1,1.1Hz,1H),7.83–7.74(m,2H),7.68(dq,J=7.6 ,1.5Hz,2H),7.60(t,J=7.4Hz,1H),7.37–7.27(m,2H),7.11(t,J=3.5Hz,1H),7.05(t t,J=7.1,1.3Hz,1H),3.52(qd,J=6.6,3.5Hz,2H),1.61(s,9H),1.33(t,J=6.6Hz,3H).

[0341] ESI-MS m / z: 507.21 (M+H) + .

[0342] Example 44: 6-(1-(Cyclopentanecarbonyl)-3-(ethylamino)-1H-indazol-4-yl)-N-(4-fluorophenyl)-1-naphthamide (Compound 10-8)

[0343]

[0344] Referring to the preparation method of Example 37, 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide was replaced with compound 2-3 to obtain compound 10-8 with a weight of 0.65 and a yield of 61.3%.

[0345] 1 H NMR(500MHz,Chloroform-d)δ8.38(s,1H),8.33(d,J=8.2Hz,1H),8.25(t,J=2.0Hz,1H),8.16–8.11( m,1H),7.97(dd,J=8.3,2.3Hz,1H),7.92(dd,J=8.0,1.4Hz,1H),7.79–7.73(m,2H),7.69(dd,J=7.3,1 .1Hz,1H),7.62–7.56(m,3H),7.13–7.07(m,2H),6.41(t,J=3.4Hz,1H),3.69(p,J=5.1Hz,1H),3.54(q d,J=6.6,3.5Hz,2H),2.02–1.93(m,2H),1.91–1.82(m,2H),1.74–1.63(m,4H),1.33(t,J=6.5Hz,3H). ESI-MSm / z: 521.21(M+H) + .

[0346] Example 45: 6-(3-acetylamino-1-acetyl-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 11-1)

[0347]

[0348] The preparation process is as follows:

[0349]

[0350] Compound 2-1 (0.5 g, 1.3 mmol), DMF (5 mL), triethylamine (0.14 g, 1.4 mmol) and acetyl chloride (0.11 g, 1.4 mmol) were added to the reaction bottle. After reacting for 4 hours, 10 mL of purified water was slowly added and purified by column chromatography to obtain compound 11-10.31 g with a yield of 56.8%.

[0351] 1 H NMR (600 MHz, DMSO-d 6 )δ10.31(s,1H),9.29(s,1H),8.40–8.31(m,1H),8.28(t,J=1.9Hz,1H),8.16(dt,J=7.7,1. 6Hz,1H),8.01(dd,J=8.4,2.1Hz,1H),7.92(dd,J=8.2,1.1Hz,1H),7.87(dd,J=7.4,1.2Hz,1 H),7.80(dd,J=7.3,1.0Hz,1H),7.79–7.74(m,1H),7.64–7.54(m,2H),7.43(dd,J=8.9,2.4 Hz, 1H), 7.19 (ddq, J = 8.9, 5.0, 1.0 Hz, 1H), 2.61 (s, 3H), 2.26 (d, J = 1.0 Hz, 3H), 2.20 (s, 3H).

[0352] ESI-MS m / z: 495.18 (M+H) + .

[0353] Example 46: 6-(3-Acetylamino-1-pivaloyl-1H-indazol-4-yl)-N-(m-tolyl)-1-naphthamide (Compound 11-2)

[0354]

[0355] Referring to the preparation method of Example 45, compound 2-1 was replaced by compound 2-2 to obtain compound 11-2 weighing 0.35 g and with a yield of 64.3%.

[0356] 1 H NMR (600 MHz, DMSO-d 6 )δ10.33(s,1H),9.32(s,1H),8.38–8.31(m,1H),8.28(t,J=1.9Hz,1H),8.16(dt, J=7.8,1.8Hz,1H),8.06–7.98(m,2H),7.92(dd,J=8.2,1.1Hz,1H),7.81(dd,J=7.4 ,1.2Hz,1H),7.79–7.74(m,1H),7.61(t,J=7.3Hz,1H),7.58–7.53(m,2H),7.16(t, J=7.7Hz,1H),6.90(dq,J=7.5,1.4Hz,1H),2.32(s,3H),2.20(s,3H),1.32(s,9H). ESI-MSm / z: 519.23(M+H) + .

[0357] Example 47: N-(3-fluoro-4-methylphenyl)-6-(3-(3-phenylpropionamido)-1-(3-phenylpropionyl)-1H-indazol-4-yl)-1-naphthamide (Compound 11-3)

[0358]

[0359] Referring to the preparation method of Example 45, compound 2-1 was replaced by compound 2-4, and acetyl chloride was replaced by phenylpropionyl chloride to obtain compound 11-3, weighing 0.32 g, with a yield of 51.6%. 1 H NMR (600 MHz, DMSO-d 6 )δ10.39(s,1H),9.29(s,1H),8.35(d,J=8.3Hz,1H),8.28(t,J=2.0Hz,1H),8.16(dt,J=7.3,1.6Hz,1H),8.0 1(dd,J=8.4,2.1Hz,1H),7.92(ddd,J=7.6,3.6,1.3Hz,2H),7.81(dd,J=7.2,1.3Hz,1H),7.79–7.73(m,1H), 7.61(t,J=7.4Hz,1H),7.58(dd,J=8.1,2.1Hz,1H),7.43(dd,J=8.9,2.4Hz,1H),7.28–7.17(m,11H),3.20(d ,J=15.4Hz,2H),2.99(t,J=7.7Hz,2H),2.90(t,J=8.1Hz,2H),2.73(t,J=8.1Hz,2H),2.26(d,J=1.4Hz,3H). ESI-MSm / z: 675.23(M+H) + .

[0360] Example 48: 6-(1-benzoyl-3-propionamido-1H-indazol-4-yl)-N-(3-fluoro-4-methylphenyl)-1-naphthamide (Compound 11-4)

[0361]

[0362] Referring to the preparation method of Example 45, compound 2-1 was replaced by compound 2-7, and acetyl chloride was replaced by propionyl chloride to obtain compound 11-4, weighing 0.24 g, with a yield of 43.6%.

[0363] 1 H NMR (600 MHz, DMSO-d 6)δ10.43(s,1H),9.29(s,1H),8.37–8.33(m,1H),8.28(t,J=1.9Hz,1H),8.16(dt,J=7.9,1.7Hz,1H),8.04–7.99(m,2H),7.98–

[0364] 7.94(m,2H),7.92(dd,J=8.3,1.2Hz,1H),7.81(dd,J=7.3,1.3Hz,1H),7.79–

[0365] 7.74(m,1H),7.62(t,J=7.4Hz,1H),7.58(dd,J=8.1,2.1Hz,1H),7.54–7.48(m,3H),7.43(dd,J=8.9,2. 4Hz, 1H), 7.19 (ddq, J = 8.9, 5.0, 1.0Hz, 1H), 2.44 (q, J = 7.0Hz, 2H), 2.26 (s, 3H), 1.16 (t, J = 7.1Hz, 3H). ESI-MSm / z: 571.21(M+H) + .

[0366] Test Example 1: Determination of fat solubility

[0367] 1. Experimental method 1: Add 10 mL of corn oil, MCT or soybean oil to a test tube. Add an appropriate amount of compound, put it into an oscillator, T = 37°C, shake for 2 hours, and measure the solubility by HPLC.

[0368] The experimental results of the example compounds are as follows:

[0369]

[0370] It can be seen from the experimental results that the lipid solubility of some compounds of the present invention (such as compound 1-6 and compound 2-2) is significantly improved compared with their corresponding parent compounds (original drugs).

[0371] 2. Experimental method 2: Solubility experiments were further conducted on compounds 1-6 with better solubility in different solvent ratios of MCT and RH40. The following solvents were added to 10 mL sample tubes, as shown in the following table:

[0372] Serial number 1 2 3 4 MCT (mL) 1 2 3 4 RH40(mL) 4 3 2 1

[0373] 80 mg of compound 1-6 was added to tubes 1 to 4, heated at T = 60°C for 5 min, shaken well, and the solubility was determined by HPLC.

[0374] The results of the measurement are as follows:

[0375] Serial number 1 2 3 4 MCT: RH40 1：4 2：3 3：2 4：1 Solubility (mg / mL) 9.50 13.63 12.02 8.48

[0376] The experimental results showed that when the MCT:RH40 ratio was 2:3 to 3:2, the solubility of compounds 1-6 was high, and oil-soluble preparations could be further developed.

[0377] Test Example 2: Determination of solubility in water, pre-meal simulated liquid, and post-meal simulated liquid

[0378] Test samples: Compounds 5-2 and 5-3

[0379] Reference substance (original drug, parent compound): 6-(3-amino-1H-indazol-4-yl)-N-(4-fluoro-3-methylphenyl)-1-naphthamide

[0380] Solution preparation:

[0381] 1. Preparation method of pre-meal simulation solution:

[0382] Step 1. Preparation of FaSSIF-V2 buffer

[0383] Dissolve 1.39 g NaOH, 2.22 g maleic acid, and 4.01 g NaCl in about 0.9 L purified water;

[0384] Step 2: Adjust the pH of the buffer solution

[0385] The pH of the solution was adjusted to 6.5 with 1N NaOH or 1N HCl, and the buffer volume was made up to 1 L with purified water at room temperature.

[0386] Step 3: Add FaSSIF-V2 powder to prepare FaSSIF-V2 solution

[0387] Add 1.79 g FaSSIF-V2 powder to about 0.5 L buffer; stir until the powder is completely dissolved; make up the volume (1 L) with buffer at room temperature;

[0388] Step 4: Let stand

[0389] The prepared solution was allowed to stand for 1 hour to obtain a ready-to-use FaSSIF-V2 solution.

[0390] 2. Preparation method of postprandial simulation solution:

[0391] Step 1. Preparation of FeSSIF-V2 buffer

[0392] Dissolve 3.27 g NaOH, 6.39 g maleic acid, and 7.33 g NaCl in about 0.9 L purified water;

[0393] Step 2: Adjust the pH of the buffer solution

[0394] The pH of the solution was adjusted to 5.8 with 1N NaOH or 1N HCl, and the buffer volume was made up to 1 L with purified water at room temperature.

[0395] Step 3: Add FeSSIF-V2 powder to prepare FeSSIF-V2 solution

[0396] Add 9.76 g of FeSSIF-V2 powder to about 0.5 L of buffer; stir until the powder is completely dissolved; make up the volume (1 L) with buffer at room temperature;

[0397] Step 4: Let stand

[0398] The prepared solution was allowed to stand for 1 hour to obtain a usable FeSSIF-V2 solution.

[0399] Experimental method: Weigh an appropriate amount of sample, add a certain amount of water, pre-meal simulated solution and post-meal simulated solution respectively, place in a shaker at 37°C for 24 hours. All of them are supersaturated solutions. Take the upper solution and determine the solubility by HPLC.

[0400] The results are as follows:

[0401]

[0402] The experimental results show that in water, pre-meal simulated fluid and post-meal simulated fluid, the solubility of the compounds of the present invention is significantly improved compared with the original drug (reference substance), among which compound 5-3 has the best solubility, followed by compound 5-2, and the reference substance has the worst solubility.

[0403] Test Example 3: Determination of water solubility

[0404] Test method: Add 10 mL of purified water to a test tube, add an appropriate amount of compound, put it into an oscillator, and shake it at room temperature for 2 hours. If it is completely dissolved, calculate the solubility directly. If it is not dissolved, determine the solubility by HPLC.

[0405] The solubility results of the exemplary compounds are as follows:

[0406]

[0407]

[0408]

[0409] The solubility of the compounds of the present invention in water is significantly improved compared to the parent compounds (original drugs, reference substances 1-3). Among them, compound 1-2, compound 1-7, compound 1-8 and compound 1-9 have good solubility, all greater than 30 mg / mL, and compound 1-10 and compound 3-1 also have good solubility, reaching 2 mg / mL.

[0410] Test Example 4: In vivo PK test in Beagle dogs

[0411] Experimental animals: Beagle dogs, 6, male.

[0412] Test drug: Compound 5-3 capsules

[0413] Test method: Compound 5-3 (15 or 25 mg) was mixed with pharmaceutical excipients and granulated, and then filled into capsules (see the formula in the table below). Beagle dogs were divided into pre-meal and post-meal groups (3 in each group), and the filled capsules were fed to the Beagle dogs orally. 2 mL of blood was collected from the forelimb vein and placed in a K2-EDTA tube, and the concentrations of compound 5-3 and reference substance 1 in plasma were determined by LC-MS / MS.

[0414] After testing, compound 5-3 was not detected in the plasma of Beagle dogs in the pre-meal and post-meal groups, and only its original drug reference substance 1 was detected.

[0415] composition Proportion(%) Compound 5-3 25.0 Microcrystalline cellulose pH102 69.0 Sodium starch glycolate 5.0 Magnesium Stearate 1.0 total 100.0 .

Claims

1. A compound represented by formula (I) or its tautomer, optical isomer, or pharmaceutically acceptable salt, in: R1 and R2 are each independently selected from the following groups: hydrogen, -L-R4; L is selected from a bond, -C(=O)-, *-OC(=O)-, *-CH=CHC(=O)-, *-C(=O)CH=CHC(=O)-, *-OC(=O)CH=CHC(=O)-, *-CH(NHR b )C(=O)-, the * end represents the end connected to R4; R4 is selected from Ra, or the following groups optionally substituted by 1, 2, 3, 4, 5 or 6 Ra: C1~C12 alkyl, C3~C12 cycloalkyl, 3~12 membered heterocycloalkyl, C6~C10 aryl, 5~10 membered heteroaryl, C3~C12 cycloalkyl-C1~C6 alkyl-, 3~12 membered heterocycloalkyl-C1~C6 alkyl-, C1~C6 alkyl-3~12 membered heterocycloalkyl-C1~C6 alkyl-, sulfonic acid-C1~C6 alkyl-3~12 membered heterocycloalkyl-C1~C6 alkyl-, C6~C10 aryl-C1~C6 alkyl-, 5~10 membered heteroaryl-C1~C6 alkyl-; Ra is selected from halogen, amino, hydroxyl, cyano, nitro, carboxyl, sulfonic acid, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with 1-3 halogens, C1-C6 alkoxy substituted with 1-3 halogens, -S(=O)2ONa, optionally substituted with 1-5 R c Substituted glycosyl, aminoglycosyl, glycoacyl; R b Selected from hydrogen, the following groups optionally substituted by 1, 2 or 3 Ra: C6-C10 aryl-C(=O)-, 6-10 membered heteroaryl-C(=O)-, C1-C6 alkyl-C(=O)-, C3-C12 cycloalkyl-C(=O)-, 3-12 membered heterocycloalkyl-C(=O)-; R c is selected from a hydroxy protecting group or an amino protecting group; R1 and R2 are not hydrogen at the same time; R3 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted phenyl and substituted or unsubstituted 5-10 membered heteroaryl containing 1 to 5 heteroatoms selected from N, O and S, and in the case of substitution, the substituents are 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, halo C1-C3 alkoxy, hydroxy, amino, nitro and halogen; The "hetero" of the heteroaryl and heterocycloalkyl groups are independently selected from the following heteroatoms or heteroatoms: -NH-, -S-, -N=, -O-, -C(=O), -NH-C(=O)-, -OC(=O)-, -S(=O)2-, -S(=O)-, -C(=O)-NH-; In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1, 2, 3, 4 or 5.

2. The compound represented by formula (I) according to claim 1 or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: R3 is selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, and in the case of substitution, the substituents are 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br; or R3 is selected from substituted or unsubstituted phenyl and substituted or unsubstituted 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, and in the case of substitution, the substituents are 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br; or R3 is selected from substituted or unsubstituted: phenyl and 5-6 membered heteroaryl containing 1 N atom and 1 O atom, in the case of substitution, the substituents are 1-3 substituents, each of which is independently selected from C1-C3 alkyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br; or R3 is selected from substituted or unsubstituted: phenyl and 5-6 membered heteroaryl containing 1 N atom and 1 O atom, in the case of substitution, the substituents are 1-3 substituents, each of which is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxy, amino, nitro, F, Cl and Br; or R3 is selected from substituted or unsubstituted: phenyl, oxazolyl and isoxazolyl, in the case of substitution, the substituents are 1-3 substituents, each of which is independently selected from methyl, methoxy, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, nitro, F, Cl and Br; or R3 is selected from substituted or unsubstituted: phenyl and isoxazolyl, in the case of substitution, the substituent is 1 or 2 substituents, the substituents are each independently selected from methyl, methoxy, F and Cl; or R3 is selected from:

3. The compound of formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: R4 is selected from Ra, or the following groups optionally substituted by 1, 2, 3, 4, 5 or 6 Ra: C1~C12 alkyl, C3~C8 cycloalkyl, 3~8 membered heterocycloalkyl, phenyl, 5~8 membered heteroaryl, C3~C8 cycloalkyl-C1~C3 alkyl-, 3~8 heterocycloalkyl-C1~C3 alkyl-, phenyl-C1~C3 alkyl-, C1~C3 alkyl-5~8 membered heterocycloalkyl-C1~C3 alkyl-, sulfonic acid-C1~C3 alkyl-5~8 membered heterocycloalkyl-C1~C3 alkyl-, 5~8 membered heteroaryl-C1~C3 alkyl-.

4. The compound represented by formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, pharmaceutically acceptable salt, characterized in that: Ra is selected from halogen, amino, hydroxyl, cyano, nitro, carboxyl, sulfonic acid, oxo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl substituted with 1-3 halogens, C1-C3 alkoxy substituted with 1-3 halogens, -S(=O)2ONa, and the following groups optionally substituted with 1-5 Rc: glycosyl, aminoglycosyl, glycoacyl; or Ra is selected from halogen, amino, hydroxy, cyano, nitro, carboxyl, oxo, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, -S(=O)2ONa, and optionally substituted by 1 to 5 R c Substituted with the following groups: or Ra is selected from amino, carboxyl, oxo, methyl, -S(=O)2ONa, 5. The compound represented by formula (I) according to claim 4 or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: At least one Ra is selected from the group consisting of amino, hydroxyl, carboxyl, sulfonic acid, -S(=O)2ONa, and optionally 1 to 5 R c Substituted with the following groups: glycosyl, aminoglycosyl, glycoacyl; or At least one Ra is selected from the group consisting of amino, hydroxyl, carboxyl, sulfonic acid, -S(=O)2ONa, and optionally 1 to 5 R c Substituted with the following groups:

6. The compound of formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: Rb is selected from hydrogen, the following groups optionally substituted by 1, 2 or 3 Ra: phenyl-C(=O)-, 5-6 membered heteroaryl-C(=O)-, -C1-C3 alkyl-C(=O)-, C3-C8 cycloalkyl-C(=O)-, 3-8 membered heterocycloalkyl-C(=O)-; or Rb is selected from hydrogen, phenyl-C(=O)-, C1-C3 alkyl-C(=O)-, optionally substituted by 1, 2 or 3 Ra; or Rb is selected from hydrogen, 7. The compound of formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: Rc is selected from CH3C(=O)-.

8. The compound of formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: R1 and R2 are each independently selected from the following groups: hydrogen, ethyl, cyclohexyl, phenyl, 9. The compound of formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: R1 is selected from the following groups:

10. The compound of formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: R1 is selected from the following groups: ethyl, cyclohexyl, 11. The compound of formula (I) according to any one of the preceding claims, or its tautomer, optical isomer, or pharmaceutically acceptable salt, characterized in that: R2 is selected from the following groups: hydrogen, ethyl, 12. A compound having the following structure or its tautomer, optical isomer, or pharmaceutically acceptable salt:

13. A pharmaceutical composition, characterized in that: It comprises the compound represented by formula (I) according to any one of claims 1 to 12 or its tautomer, optical isomer, pharmaceutically acceptable salt, and optionally a pharmaceutically acceptable carrier.

14. Use of the compound represented by formula (I) according to any one of claims 1 to 12 or its tautomer, optical isomer, pharmaceutically acceptable salt or the pharmaceutical composition according to claim 13 in the preparation of a VEGFR inhibitor and / or a CSF1R inhibitor.

15. Use of the compound represented by formula (I) according to any one of claims 1 to 12 or its tautomer, optical isomer, pharmaceutically acceptable salt or the pharmaceutical composition according to claim 13 in a drug for preventing and / or treating diseases associated with abnormal angiogenesis; Preferably, the disease associated with abnormal angiogenesis is selected from tumors, rheumatoid arthritis, age-related macular degeneration and psoriasis; Preferably, the tumor is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, lymphoma and meningioma.

16. Use of the compound represented by formula (I) according to any one of claims 1 to 12 or its tautomer, optical isomer, pharmaceutically acceptable salt or the pharmaceutical composition according to claim 13 in the preparation of a drug for treating diseases related to the CSF1R kinase signal transduction pathway; Preferably, the CSF1R kinase signal transduction pathway-related diseases include cancer or tumor, hyperplasia, immune disorders, inflammation; Preferably, the cancer or tumor is a CSF1 / CSF1R-dependent cancer or tumor or a TAMs-enriched tumor; Preferably, CSF1 / CSF1R-dependent cancers or tumors include CSF1 / CSF1R-dependent leukemia and tenosynovial giant cell tumor; TAMs-enriched tumors include but are not limited to gliomas, brain metastases or colorectal cancer.

17. Use of the compound of formula (I) according to any one of claims 1 to 12 or its tautomer, optical isomer, pharmaceutically acceptable salt or the pharmaceutical composition according to claim 13 in the preparation of an anti-tumor drug in combination with an immune checkpoint drug; Preferably, the immune checkpoint drug is an anti-PD-1 antibody or an anti-PD-L1 antibody; Preferably, the tumor includes but is not limited to glioma, brain metastasis or colorectal cancer.

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