PARP1 and ULK1 double-target inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a PARP1 and ULK1 double-target inhibitor as well as a preparation method and application thereof. The compound as shown in the formula I or pharmaceutically acceptable salt, solvate, active metabolite, polymorphic substance, ester, optical isomer or prodrug of the compound, and a composition containing the compound as shown in the formula I show a very strong inhibition effect on PARP1 and ULK1; the compound prepared by the invention has a good inhibition effect on a plurality of tumors, such as triple negative breast cancer, liver cancer, ovarian cancer and the like, which are caused by Parp1 inhibitor induced autophagy and cause Parp1 inhibitor primary drug resistance.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a PARP1 and ULK1 dual-target inhibitor, a preparation method thereof and an application thereof. Background Art

[0002] Poly (ADP-ribose) polymerase (PARP) is a multifunctional post-translational modification enzyme of proteins present in most eukaryotic cells, and there are 18 subtypes in its family. Among them, PARP-1 accounts for the largest proportion and plays a major role in DNA damage repair [Peraltaleal A, et al., Free Radical Biology and Medicine 2009, 47(1): 13-26].

[0003] In DNA damage, the most severe damages are single-strand breaks (SSBs) and double-strand breaks (DSBs), with single-strand breaks being more common. If these breaks cannot be repaired promptly and accurately, the genome will become unstable, which can lead to carcinogenesis or directly cause cell death. To maintain normal physiological functions, cells have multiple DNA damage detection and repair mechanisms. The repair of single-strand break damage mainly relies on PARP, among which PARP1 plays more than 90% of the functions [Langelier M, et al., Nucleic Acids Research 2014, 42(12): 7762-7775]. For double-strand breaks, although the occurrence is rare but the consequences are serious. If not repaired in time, the cell DNA will become unstable and eventually die. Homologous recombination (HR) is a high-fidelity and error-free repair method for DNA double-strand break repair. The proteins involved in this repair include BRCA, ATM, RAD51, etc. The most well-known is the BRCA protein. The risk of developing malignant tumors in people carrying familial hereditary BRCA1 / 2 mutations is significantly increased, especially in breast cancer and ovarian cancer. BRCA1 / 2 are key proteins for double-strand break homologous recombination repair. BRCA1 / 2 mutations lead to obstruction of DNA double-strand break repair, causing genomic instability and then cancer. Due to the survival mechanism of cells, the obstruction of double-strand break repair will make cells more dependent on PARP-mediated single-strand break repair. Compared with tumor cells with perfect BRCA function, the sensitivity of BRCA-deficient tumor cells to PARP inhibitors is 100 times that of the former. The successful application of PARP inhibitors in cancer patients with BRCA deficiency is a typical case of "synthetic lethality" in DNA damage repair response (DDR) [Bryant H E., Nature 2005, 434(7035): 913-917; Farmer H, et al., Nature 2005, 434(7035): 917-921]. Currently, the successfully marketed PARP inhibitors include Olaparib, Rucaparib, Niraparib, and Talazoparib.

[0004] Autophagy is a conserved intracellular degradation process that determines which organelles, proteins, and invading microorganisms are degraded by lysosomes. This conserved process is involved in the cell's response to nutrient deprivation and other stresses, as well as the homeostasis and defense against pathogens during appropriate cell and tissue embryonic development. Defects in the autophagy pathway are associated with certain human pathologies, including infectious diseases, neurodegenerative diseases, and cancer.

[0005] Autophagy is a multi-step pathway initiated by the ULK (unc-51-like autophagy activating kinase) pre-initiation complex, which consists of unc-51-like autophagy activating kinase 1 (ULK1) or its homolog ULK2, autophagy related protein 13 (ATG13), ATG101, and focal adhesion kinase (FAK) family interacting protein (FIP200) [Hosokawa N., et al., Autophagy 2009, 5:973-979; Ganley I G, et al., J Biol Chem 2009, 5:973-979]. Autophagy is activated by AMPK under stress conditions and inhibited by mTOR under non-stress conditions [Laplante M, et al., Cell 2012, 149:274-293]. AMPK activates autophagy through two mechanisms: first, by phosphorylating the mTOR complex components raptor and TSC2 to inhibit mTOR activity; second, by directly phosphorylating multiple sites at the N-terminus of ULK1 / 2 to the mTOR phosphorylation sites, activating ULK1 / 2. Conversely, mTOR inhibits autophagy by directly phosphorylating and inhibiting the function of ULK1 / 2.

[0006] As the only serine / threonine kinase in the autophagy signaling pathway, ULK1 / 2 plays a key role in autophagy by phosphorylating three proteins (ATG13, ATG101, and FIP200) in the ULK1 / 2 pre-initiation complex at positions 9-11 and initiating the protein complex (Beclin1, VPS34, ATG9, and ATG16L1) of downstream Beclin1 [Papinski D, et al., Mol.Cell 2014, 53:471-483; Papinski D, et al., J Mol Biol 2016, 428:1725-1741; Egan D, et al., Mol Cell 2015, 59:285-297; Alsaadi R, EMBO Rep. 2019, 20:No.e46885].

[0007] Knockout of ULK1 or the use of small molecule ULK1 inhibitors can effectively inhibit autophagy, induce apoptosis, and inhibit the growth of tumor cells [Si-Tu Xue, et al., Autophagy 2020, 16(10):1823-1837; Huiyu R, et al., J.Med.Chem. 2020, 63:14609-14625].

[0008] PARP1 inhibitor-induced autophagy is the main cause of primary resistance to PARP1 inhibitors. The combined use of PARP1 inhibitors and autophagy inhibitors has shown strong synergistic anti-cancer effects in different tumors [Pai Bellare G, et al., Cancer 2021, 124: 1260-1274; Fu X T, et al., Cancer Cell Int. 2019, 19: 71; Luo T, et al., Autophagy 2016, 12: 1355-1371; Lu S, et al., Cell Death Dis. 2018, 9: 646; Liu Y, et al., AMB Expr 2019, 9: 108; Janice M S-O, et al., Cancer 2020, 126: 894-907].

[0009] Therefore, the development of a dual-target inhibitor that can simultaneously inhibit PARP1 and ULK1 will provide a new, safe, and effective anti-cancer drug. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide, in view of the deficiencies of the prior art, a novel compound of a PARP1 and ULK1 dual-target inhibitor that has not been reported in the literature, its pharmaceutically acceptable salts, solvates, active metabolites, polymorphs, esters, optical isomers, or prodrugs, the use of the compound in pharmaceuticals, and a method for preventing or treating diseases related to abnormal activities of PARP1 and ULK1 in humans or mammals using the compound of the present invention.

[0011] To solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0012] The present invention discloses a compound of formula I or its pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer, or prodrug;

[0013]

[0014] Wherein,

[0015] R 1 is selected from halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, alkoxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, halo C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;

[0016] R2 Selected from -NR 5 R 6 、-NHNR 5 R 6 、-NR 5 OR 6 、-OR 5 、-ONR 5 R 6 or -SR 5 ; wherein,

[0017] R 5 、R 6 are each independently selected from H, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-9 heteroaryl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-7 heterocycloalkyl, or R 5 、R 6 and -NR 5 R 6 form a 3 - 6 - membered heterocycle with the N in; wherein, the said substitution is selected from being substituted by halogen, cyano, hydroxyl, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 3-7 cycloamino, C 3-7 heterocycloamino, C 4-7 cycloamido, C 1-3 alkyl, halo - C 1-3 alkyl, C 1-3 alkoxy or halo - C 1-3 alkoxy substitution;

[0018] R 3 is selected from any one of the following groups:

[0019]

[0020] wherein, R 4 is selected from H, halogen, cyano, C 1-6 alkyl, halo - C 1-6 alkyl, C 1-3 alkoxy or halo - C 1-3 alkoxy;

[0021] The L - ring is selected from substituted or unsubstituted 5 - 6 - membered aromatic rings, or substituted or unsubstituted 5 - 6 - membered heteroaromatic rings; wherein, the said substitution is selected from being substituted by halogen, cyano, hydroxyl, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy or halo-C 1-3 alkoxy substitution;

[0022] W is selected from N or CH.

[0023] Specifically, preferably, R 1 is selected from halogen, C 1-3 alkyl, halo-C 1-3 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl.

[0024] Specifically, preferably, R 2 is selected from -NR 5 R 6 or -OR 5 ; wherein,

[0025] R 5 , R 6 are each independently selected from H, substituted or unsubstituted C6 aryl, substituted or unsubstituted C 3-5 heteroaryl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocycloalkyl, or R 5 , R 6 and the N in -NR 5 R 6 form a 3-6 membered heterocycle; wherein, the said substitution is selected from being substituted by halogen, cyano, hydroxy, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 4-7 cyclic amide group, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy or halo-C 1-3 alkoxy substitution.

[0026] Specifically, preferably, R 3 is selected from any one of the following groups:

[0027]

[0028] wherein, R 4 is selected from H or halogen.

[0029] Specifically, preferably, the L ring is selected from substituted or unsubstituted 5-6 membered aromatic rings, or substituted or unsubstituted 5-6 membered heteroaromatic rings; wherein, the said substitution is selected from being substituted by halogen.

[0030] Specifically, preferably, W is selected from N.

[0031] Specifically, preferably:

[0032] R 1 is selected from halo C 1-3 alkyl;

[0033] R 2 is selected from -NR 5 R 6 ; wherein,

[0034] R 5 and R 6 are each independently selected from H, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocycloalkyl; wherein, the substitution is selected from being substituted with an amino group or a pyrrolidone group;

[0035] R 3 is selected from any one of the following groups:

[0036]

[0037] wherein, R 4 is selected from H or fluorine;

[0038] The L ring is selected from a substituted or unsubstituted 6-membered aromatic ring, or an unsubstituted 6-membered heteroaromatic ring; wherein, the substitution is selected from being substituted with fluorine;

[0039] W is selected from N;

[0040] Specifically, further preferably:

[0041] R 1 is selected from trifluoromethyl;

[0042] R 2 is selected from any one of the following groups:

[0043]

[0044] R 3 is selected from any one of the following groups:

[0045]

[0046] The L ring is selected from any one of the following groups:

[0047]

[0048] W is selected from N.

[0049] Specifically, more preferably, the compound is selected from any of the following structures:

[0050]

[0051] Furthermore, the present invention provides a method for preparing the above compound, which is characterized by comprising the following steps:

[0052] Step 1: Nucleophilic substitution of compound A-1 with compound B to obtain compound A-2;

[0053] Step 2: Coupling of compound A-2 with compound C to generate compound I;

[0054]

[0055] Wherein, the compound B is selected from amine, hydroxylamine, hydrazine, alcohol or thiol; the compound C is

[0056] Wherein,

[0057] R 1 is selected from halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, alkoxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;

[0058] R 2 is selected from -NR 5 R 6 、-NHNR 5 R 6 、-NR 5 OR 6 、-OR 5 、-ONR 5 R 6 or -SR 5 ; wherein,

[0059] R 5 、R 6 are each independently selected from H, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-9 heteroaryl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-7 heterocycloalkyl, or R 5 、R 6-NR 5 R 6 forms a 3- to 6-membered heterocycle with the N therein; wherein, the substitution is selected from being substituted by halogen, cyano, hydroxyl, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 3-7 cyclic amino, C 3-7 heterocyclic amino, C 4-7 cyclic amide, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkoxy substitution;

[0060] R 3 is selected from any one of the following groups:

[0061]

[0062] wherein, R 4 is selected from H, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1-3 alkoxy or halo C 1-3 alkoxy;

[0063] The L ring is selected from a substituted or unsubstituted 5- to 6-membered aromatic ring, or a substituted or unsubstituted 5- to 6-membered heteroaromatic ring; wherein, the substitution is selected from being substituted by halogen, cyano, hydroxyl, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkoxy substitution;

[0064] W is selected from N or CH.

[0065] Specifically, in step 1, compound A-1 undergoes nucleophilic substitution with compound B to obtain compound A-2; wherein, the molar ratio of compound A-1 to compound B is 1:(0.80 - 4.00), preferably 1:(0.80 - 3.00), and more preferably 1:(0.90 - 2.00); the reaction temperature of the nucleophilic substitution is room temperature; preferably, the solvent used in the reaction process of the nucleophilic substitution is methanol or dichloromethane; a first base is added for catalysis in the nucleophilic substitution reaction; the first base is a trialkyl tertiary amine; preferably, the trialkyl tertiary amine is N,N-diisopropylethylamine; the molar ratio of compound A-1 to the first base is 1:(1.50 - 4.00), preferably 1:(1.50 - 3.50), and more preferably 1:(1.90 - 2.46); wherein, when compound B is cyclopropylamine, no first base needs to be added to the nucleophilic substitution reaction system.

[0066] Specifically, in step 2, compound A-2 undergoes coupling with compound C to form compound I; wherein, the molar ratio of compound A-2 to compound C is 1:(0.80 - 4.00), preferably 1:(0.80 - 2.00), and more preferably 1:(0.80 - 1.20); the coupling catalytic system for compound A-2 to undergo coupling with compound C to form compound I selects one of the following catalytic systems:

[0067] Catalytic system 1: A catalytic system containing a palladium catalyst, an organophosphorus ligand, and a second base; wherein, preferably, the palladium catalyst is tris(dibenzylideneacetone)dipalladium; preferably, the organophosphorus ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; preferably, the second base is cesium carbonate; the molar ratio of compound A-2 to the palladium catalyst, the organophosphorus ligand, and the second base is 1:(0.08 - 0.40):(0.08 - 0.80):(1.50 - 6.00), preferably 1:(0.08 - 0.35):(0.08 - 0.60):(1.80 - 4.00), and more preferably 1:(0.08 - 0.25):(0.08 - 0.45):(2.00 - 3.20).

[0068] Wherein, when the catalytic system used in the coupling process is catalytic system 1, the solvents used in the coupling process include but are not limited to 1,4-dioxane, isopropanol, and N,N-dimethylformamide, preferably 1,4-dioxane, the coupling reaction is carried out under the protection of an inert gas, the reaction temperature of the coupling reaction is 100 - 140 °C, preferably 125 - 135 °C, and more preferably 130 °C; wherein, the inert gas is nitrogen.

[0069] Or,

[0070] Catalytic system 2: A catalytic system containing a first acid; wherein, the first acid is methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid or hydrochloric acid; when the first acid is methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid, the molar ratio of compound A-2 to the first acid is 1:(0.60 - 1.20), preferably 1:(0.70 - 1.00), more preferably 1:(0.80 - 0.95); when the first acid is hydrochloric acid, the amount of the first acid used is in excess, preferably, the molar ratio of compound A-2 to the first acid is 1:18 - 24.

[0071] Wherein, when the catalytic system used in the coupling process is catalytic system 2, the solvents used in the coupling process include but are not limited to N,N-dimethylformamide, 1,4-dioxane and isopropanol, and the reaction temperature of the coupling reaction is 80 - 140 °C, preferably 90 - 120 °C.

[0072] Specifically, in step 2, compound A-2 and compound C are coupled to form compound I; when the R in 3 is selected from When R in 3 is such that the N atom on it has high activity, the N atom is protected with tert-butyl, and after the coupling reaction is completed, deprotection is carried out under the action of a second acid to obtain compound I; preferably, the second acid is trifluoroacetic acid; the reaction temperature for deprotection is 80 - 100 °C, preferably 85 - 100 °C, more preferably 90 - 100 °C.

[0073] Specifically, step 1: Compound A-1 and compound B undergo nucleophilic substitution to obtain compound A-2; step 2: Compound A-2 and compound C are coupled to form compound I; when R in compound A-2 ( ) is selected from 2 When the N atom of the heterocyclic alkyl or the N atom of the substituted amino group on the cycloalkyl has high activity, the N atom is protected with tert-butoxycarbonyl (Boc), and after the coupling reaction is completed, deprotection is carried out under the action of a third acid to obtain compound I; preferably, the third acid is trifluoroacetic acid or hydrochloric acid; the reaction temperature for deprotection is room temperature.

[0074] Each product obtained from the reaction in the above method can be obtained by conventional separation techniques, which include but are not limited to filtration, distillation, crystallization, chromatographic separation, etc. The starting materials required for the synthesis can be synthesized by oneself or obtained from commercial institutions, such as, but not limited to, Adrich or Sigma. These raw materials can be characterized by conventional means, such as physical constants and spectroscopic data. The compounds described in the present invention can be obtained as a single optical isomer or a mixture of optical isomers using synthetic methods.

[0075] In the present invention, superscripts on letters represent group labels, and subscripts represent the number of atoms of that kind. For example: R 1 、R 2 、R 3 represent the 1st to 3rd R groups, and C 1-4 alkyl represents an alkyl group containing 1 to 4 carbon atoms. The number of carbon atoms in the substituent is not counted in the main chain.

[0076] Furthermore, the present invention provides a pharmaceutical composition comprising the compound represented by the above formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0077] Furthermore, the present invention provides a pharmaceutical preparation which comprises a therapeutically effective amount of the compound represented by the above formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0078] Among them, the said pharmaceutical preparation is formulated for an administration route selected from oral administration, parenteral administration, oral cavity administration, nasal cavity administration, topical administration or rectal administration.

[0079] Furthermore, the use of the above compound or the above pharmaceutical composition or the above pharmaceutical preparation in the preparation of a poly(ADP-ribose) polymerase 1 inhibitor is also within the protection scope of the present invention.

[0080] Furthermore, the use of the above compound or the above pharmaceutical composition or the above pharmaceutical preparation in the preparation of an unc-51-like autophagy activating kinase 1 inhibitor is also within the protection scope of the present invention.

[0081] Furthermore, the use of the above compound or the above pharmaceutical composition or the above pharmaceutical preparation in the preparation of a drug for preventing or treating a disease related to abnormal enzyme activity of poly(ADP-ribose) polymerase 1 and / or unc-51-like autophagy activating kinase 1 is also within the protection scope of the present invention.

[0082] Among them, the poly (ADP-ribose) polymerase 1 is abbreviated as Parp1; the unc-51-like autophagy activating kinase 1 is abbreviated as ULK1.

[0083] Specifically, the diseases related to the abnormal enzymatic activities of poly (ADP-ribose) polymerase 1 and / or unc-51-like autophagy activating kinase 1 are tumors.

[0084] Specifically, preferably, the tumors include solid tumors or malignant hematological tumors; more preferably, the solid tumors are breast cancer tumors or liver cancer tumors.

[0085] Among them, the above-mentioned compound or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation is used for preventing or treating diseases or conditions related to the abnormal enzymatic activities of poly (ADP-ribose) polymerase 1 and / or unc-51-like autophagy activating kinase 1, including administering the above-mentioned compound or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation to a person or mammal in need, and the diseases related to the abnormal enzymatic activities of poly (ADP-ribose) polymerase 1 and / or unc-51-like autophagy activating kinase 1 are cancers.

[0086] Among them, the present invention includes the step of contacting the above-mentioned compound or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation with PARP1 / ULK1, and the contacting step includes in vitro or in vivo tests.

[0087] Beneficial effects:

[0088] The compound prepared in this application shows strong inhibitory effects on both PARP1 and ULK1. The compound prepared in this application will have good inhibitory effects on many tumors that are resistant to Parp1 inhibitors due to the induction of autophagy by Parp1 inhibitors, such as triple-negative breast cancer, liver cancer, ovarian cancer, etc. Specific embodiments

[0089] According to the following embodiments, the present invention can be better understood. However, those skilled in the art can easily understand that the content described in the embodiments is only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0090] Example 1: Synthesis of intermediate A-2-1

[0091] Synthesis route of 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (Compound A-2-1):

[0092]

[0093] To a solution of compound A-1-1 (1.447 g, 6.7 mmol) in methanol (20 mL) was added compound B-1 (649 mg, 11.3 mmol) at 0 °C to obtain a mixed solution. The mixed solution was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted twice with ethyl acetate (2 x 10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with ethyl acetate / petroleum ether = 1:20 to obtain product A-2-1, 200 mg, with a yield of 12.6%.

[0094] The 1H NMR data of product A-2-1 are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1H); 7.27 (s, 1H); 2.93 - 2.99 (m, 1H); 0.90 - 1.02 (m, 2H); 0.60 - 0.68 (m, 2H).

[0095] Example 2: Synthesis of intermediate A-2-2

[0096] Synthetic route of 2-chloro-N-cyclobutyl-5-(trifluoromethyl)pyrimidin-4-amine (compound A-2-2):

[0097]

[0098] To a solution of compound A-1-1 (3.0 g, 13.9 mmol) and DIEA (4.41 g, 34.2 mmol) in DCM (30 mL) was added compound B-2 (1.0 g, 14.0 mmol) at 0 °C to obtain a mixed solution. The mixed solution was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), extracted three times with ethyl acetate (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with ethyl acetate / petroleum ether = 1:25 to obtain product A-2-2, 1.7 g, with a yield of 48.6%.

[0099] The 1H NMR data of product A-2-2 are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.24 (s, 1H); 5.49 (s, 1H); 4.63 - 4.69 (m, 1H); 2.44 - 2.52 (m, 2H); 1.90 - 1.97 (m, 2H); 1.78 - 1.85 (m, 2H).

[0100] Example 3: Synthesis of intermediate A-2-3

[0101] Synthetic route of 2-chloro-N-(oxetan-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (Compound A-2-3):

[0102]

[0103] To a solution of Compound A-1-1 (3.0 g, 13.9 mmol) and DIEA (4.41 g, 34.2 mmol) in DCM (30 mL) was added Compound B-3 (1.0 g, 13.7 mmol) at 0 °C to obtain a mixed solution. The mixed solution was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted three times with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography using ethyl acetate / petroleum ether = 1:25 to obtain Product A-2-3, 0.88 g, with a yield of 25.0%.

[0104] The 1H NMR data of Product A-2-3 are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.33 (s, 1H); 5.84 (s, 1H); 5.22 - 5.30 (m, 1H); 5.01 - 5.06 (m, 2H); 4.57 - 4.60 (m, 2H).

[0105] Example 4: Synthesis of Intermediate A-2-5

[0106] (1R,4R)-tert-Butyl 4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)cyclohexylcarbamate (Compound A-2-5) synthetic route:

[0107]

[0108] To a solution of Compound A-1-1 (1.0 g, 4.6 mmol) and DIEA (1.2 g, 9.2 mmol) in DCM (10 mL) was added Compound B-5 (1.0 g, 4.6 mmol) at 0 °C to obtain a mixed solution. The mixed solution was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted three times with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography using ethyl acetate / petroleum ether = 1:5 to obtain Product A-2-5, 1.1 g, with a yield of 60.7%.

[0109] The 1H NMR data of Product A-2-5 are as follows: 11H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1H); 5.07 - 5.09 (m, 1H); 4.30 - 4.40 (m, 1H); 3.90 - 4.10 (m, 1H); 3.30 - 3.50 (m, 1H); 1.95 - 2.10 (m, 4H); 1.15 - 1.30 (m, 4H); 1.52 (s, 9H).

[0110] Example 5: Synthesis of Intermediate A-2-6

[0111] Synthesis route of 2-chloro-N-(tetrahydrofuran-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (Compound A-2-6):

[0112]

[0113] To a solution of Compound A-1-1 (2.5 g, 11.6 mmol) and DIEA (2.96 g, 23.0 mmol) in DCM (30 mL) was added Compound B-6 (1.0 g, 11.5 mmol, Mw = 87.122) at 0 °C to obtain a mixed solution; the mixed solution was warmed to room temperature and stirred for 12 hours; after the reaction was completed, the reaction solution was poured into water (30 mL), extracted three times with ethyl acetate (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with ethyl acetate / petroleum ether = 1:5 to obtain Product A-2-6, 0.39 g, with a yield of 12.6%.

[0114] The 1H NMR data of Product A-2-6 are as follows: 1 1H NMR (400 MHz, CDCl3): δ = 8.29 (s, 1H); 5.51 (s, 1H); 4.80 - 4.90 (m, 1H); 3.90 - 4.10 (m, 2H); 3.80 - 3.90 (m, 1H); 3.70 - 3.80 (m, 1H); 2.30 - 2.50 (m, 1H); 1.80 - 1.90 (m, 1H).

[0115] Example 6: Synthesis of Intermediate A-2-7

[0116] Synthesis route of 2-chloro-N-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyrimidin-4-amine (Compound A-2-7):

[0117]

[0118] To a solution of compound A-1-1 (2.2 g, 10.2 mmol) and DIEA (2.6 g, 20.0 mmol) in DCM (30 mL) was added compound B-7 (1.0 g, 10.0 mmol) at 0 °C to obtain a mixed solution. The mixed solution was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted three times with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with ethyl acetate / petroleum ether = 1:5 to obtain product A-2-7, 1.3 g, with a yield of 45.4%.

[0119] The 1H NMR data of product A-2-7 are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1H); 5.15 (s, 1H); 4.20 - 4.40 (m, 1H); 3.90 - 4.00 (m, 2H); 3.50 - 3.70 (m, 2H); 1.90 - 2.00 (m, 2H); 1.40 - 1.60 (m, 2H).

[0120] Example 7: Synthesis of intermediate A-2-8

[0121] Synthetic route of tert-butyl 4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)piperidine-1-carboxylate (compound A-2-8):

[0122]

[0123] To a solution of compound A-1-1 (1.09 g, 5.0 mmol) and DIEA (1.3 g, 10.0 mmol) in DCM (10 mL) was added compound B-8 (1.0 g, 5.0 mmol) at 0 °C to obtain a mixed solution. The mixed solution was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted three times with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography with ethyl acetate / petroleum ether = 1:10 to obtain product A-2-8, 0.47 g, with a yield of 24.7%.

[0124] The 1H NMR data of product A-2-8 are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1H); 5.20 (m, 1H); 4.20 - 4.40 (m, 1H); 3.95 - 4.15 (m, 2H); 2.90 - 3.00 (m, 2H); 1.95 - 2.10 (m, 2H); 1.62 (s, 9H); 1.30 - 1.50 (m, 2H).

[0125] Example 8: Synthesis of Intermediate A-2-9

[0126] Synthesis route of tert-butyl 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)pyrrolidine-1-carboxylate (Compound A-2-9):

[0127]

[0128] To a solution of Compound A-1-1 (1.16 g, 5.37 mmol) and DIEA (1.38 g, 10.74 mmol) in DCM (12 mL) was added Compound B-9 (1.0 g, 5.37 mmol) at 0 °C to obtain a mixed solution; the mixed solution was warmed to room temperature and stirred for 12 hours; after the reaction was completed, the reaction solution was poured into water (30 mL), and extracted three times with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography using ethyl acetate / petroleum ether = 1:7 to obtain Product A-2-9, 0.93 g, with a yield of 47.3%.

[0129] The 1H NMR data of Product A-2-9 are as follows: 1 H NMR(400MHz,CDCl3): δ = 8.23(s,1H); 5.30(m,1H); 4.65 - 4.75(m,1H); 3.65 - 3.75(m,1H); 3.35 - 3.50(m,2H); 3.10 - 3.30(m,1H); 2.20 - 2.35(m,1H); 1.80 - 1.90(m,1H); 1.41(s,9H).

[0130] Example 9: Synthesis of Intermediate A-2-10

[0131] (1S,3S)-tert-butyl 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)cyclopentanecarboxylate (Compound A-2-10) synthesis route:

[0132]

[0133] To a solution of compound A-1-1 (0.27 g, 1.25 mmol) and DIEA (0.32 g, 2.5 mmol) in DCM (5 mL) was added compound B-10 (0.25 g, 1.25 mmol) at 0 °C to obtain a mixture. The mixture was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), and extracted three times with ethyl acetate (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography using ethyl acetate / petroleum ether = 1:3 to obtain product A-2-10, 0.24 g, with a yield of 50.5%.

[0134] The 1H NMR data of product A-2-10 are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.26 (s, 1H); 5.33 (m, 1H); 4.50 - 4.70 (m, 2H); 4.00 - 4.15 (m, 1H); 2.30 - 2.40 (m, 1H); 2.15 - 2.30 (m, 1H); 2.00 - 2.10 (m, 1H); 1.85 - 2.00 (m, 1H); 1.40 - 1.6 (m, 2H); 1.49 (s, 9H).

[0135] Example 10: Synthesis of intermediate A-2-11

[0136] Synthetic route of 1-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)propyl)pyrrolidin-2-one (compound A-2-11):

[0137]

[0138] To a solution of compound A-1-1 (1.53 g, 7.08 mmol) and DIEA (1.8 g, 14.0 mmol) in DCM (15 mL) was added compound B-11 (1.0 g, 7.04 mmol) at 0 °C to obtain a mixture. The mixture was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (30 mL), and extracted three times with ethyl acetate (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography using ethyl acetate / petroleum ether = 1:1 to obtain product A-2-11, 1.23 g, with a yield of 53.9%.

[0139] The 1H NMR data of product A-2-11 are as follows: 11H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1H); 7.28 (m, 1H); 3.44 - 3.49 (m, 2H); 3.30 - 3.40 (m, 2H); 3.25 - 2.30 (m, 2H); 2.38 - 2.42 (m, 2H); 1.95 - 2.10 (m, 2H); 1.65 - 1.75 (m, 2H).

[0140] Example 11: Synthesis of Intermediate C-1

[0141] Synthetic route of compound C-1:

[0142]

[0143] (1) Synthesis of 2-(4-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound M-3)

[0144] Dissolve compound M-1 (0.86 g, 5.70 mmol), M-2 (1 g, 6.17 mmol), HATU (1.4 g, 3.68 mmol), and DIEA (0.88 g, 6.79 mmol) in DMF (10 mL), and stir at room temperature overnight. After the reaction is completed, add 60 mL of water to the reaction solution, filter, and dry the filter cake; add the filter cake to 12 mL of AcOH, reflux at 120 °C for 4 hours. After the reaction is completed, cool to room temperature, add 60 mL of water, extract with EA (2 × 40 mL), dry the organic phase, concentrate, and purify the crude product by column chromatography (DCM:MeOH = 50:1) to obtain product M-3, 0.92 g, with a yield of 57.2%. LCMS of product M-3: m / z = 282.9 [M+1] + 。

[0145] (2) Synthesis of 2-(4-aminophenyl)-1H-benzo[d]imidazole-4-carboxamide (C-1)

[0146]

[0147] Mix the M-3 (0.4 g, 1.42 mmol) prepared in step (1), Fe (0.395 g, 7.1 mmol), NH4Cl (0.385 g, 7.1 mmol), EtOH (6 mL), and H2O (1.2 mL), reflux at 70 °C for 4 hours. After the reaction is completed, cool the reaction solution to room temperature, concentrate, add 8 mL of water, extract with EA (3 × 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (eluted with EA) to obtain product C-1, 0.3 g, with a yield of 83.8%. LCMS of product C-1: m / z = 252.9 [M+1] + 。

[0148] Example 12: Synthesis of Intermediate C-2

[0149] Synthesis route of Compound C-2:

[0150]

[0151] (1) Synthesis of 2-(3-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound M-5)

[0152] Dissolve Compound M-1 (0.86 g, 5.7 mmol), M-4 (1 g, 6.17 mmol), HATU (1.4 g, 3.68 mmol), and DIEA (0.88 g, 6.79 mmol) in DMF (10 mL), and stir overnight at room temperature. After the reaction is completed, add 60 mL of water to the reaction solution, filter, and dry the filter cake; add the filter cake to 12 mL of AcOH, reflux and react at 120 °C for 4 hours. After the reaction is completed, cool to room temperature, add 60 mL of water, extract with EA (2 × 40 mL), dry the organic phase, concentrate, and purify the crude product by column chromatography (DCM:MeOH = 50:1) to obtain the product M-5, 0.95 g, with a yield of 59.1%. LCMS of product M-5: m / z = 282.9 [M+1] + .

[0153] (2) Synthesis of 2-(3-aminophenyl)-1H-benzo[d]imidazole-4-carboxamide (C-2)

[0154]

[0155] Mix the M-5 (0.4 g, 1.42 mmol) prepared in step (1), Fe (0.395 g, 7.1 mmol), NH4Cl (0.385 g, 7.1 mmol), EtOH (6 mL), and H2O (1.2 mL), reflux and react at 70 °C for 4 hours. After the reaction is completed, cool the reaction solution to room temperature, concentrate, add 8 mL of water, extract with EA (3 × 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (eluted with EA) to obtain the product C-2, 0.28 g, with a yield of 78.2%.

[0156] LCMS of product C-2: m / z = 253.0 [M+1] + .

[0157] Example 13: Synthesis of Intermediate C-3

[0158] Synthesis route of Compound C-3:

[0159]

[0160] (1) Synthesis of 2-(2-Fluoro-4-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound M-7)

[0161] Dissolve Compound M-1 (0.86 g, 5.7 mmol), M-6 (1 g, 5.41 mmol), HATU (1.4 g, 3.68 mmol), and DIEA (0.88 g, 6.79 mmol) in DMF (10 mL), and stir overnight at room temperature. After the reaction is completed, add 60 mL of water to the reaction solution, filter, and dry the filter cake; add the filter cake to 12 mL of AcOH, reflux and react at 120 °C for 4 hours. After the reaction is completed, cool to room temperature, add 60 mL of water, extract with EA (2 × 40 mL), dry the organic phase, concentrate, and purify the crude product by column chromatography (DCM:MeOH = 50:1) to obtain Product M-7, 0.89 g, with a yield of 52.0%. LCMS of Product M-7: m / z = 300.9 [M+1] + 。

[0162] (2) Synthesis of 2-(4-Amino-2-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound C-3)

[0163]

[0164] Mix the M-7 (0.43 g, 1.43 mmol) prepared in step (1), Fe (0.395 g, 7.1 mmol), NH4Cl (0.385 g, 7.1 mmol), EtOH (6 mL), and H2O (1.2 mL), reflux and react at 70 °C for 4 hours. After the reaction is completed, cool the reaction solution to room temperature, concentrate, add 8 mL of water, extract with EA (3 × 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (eluted with EA) to obtain Product C-3, 0.28 g, with a yield of 72.5%. LCMS of Product C-3: m / z = 270.9 [M+1] + 。

[0165] Example 14: Synthesis of Intermediate C-4

[0166] Synthesis route of Compound C-4:

[0167]

[0168] (1) Synthesis of 2-(2-Fluoro-5-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound M-9)

[0169] Compound M-1 (0.77 g, 5.10 mmol), M-8 (1 g, 5.41 mmol), HATU (1.23 g, 3.24 mmol), and DIEA (0.76 g, 5.94 mmol) were dissolved in DMF (10 mL) and stirred overnight at room temperature. After the reaction, 60 mL of water was added to the reaction solution, and the mixture was filtered. The filter cake was dried. The filter cake was added to 12 mL of AcOH, and the mixture was refluxed at 120 °C for 4 hours. After the reaction, the mixture was cooled to room temperature, 60 mL of water was added, and the mixture was extracted with EA (2 × 40 mL). The organic phase was dried, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 50:1) to obtain product M-9, 0.87 g, with a yield of 56.9%. LCMS of product M-9: m / z = 300.9 [M+1] + 。

[0170] (2) Synthesis of 2-(5-amino-2-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound C-4)

[0171]

[0172] M-9 (0.43 g, 1.43 mmol) prepared in step (1), Fe (0.395 g, 7.1 mmol), NH4Cl (0.385 g, 7.1 mmol), EtOH (6 mL), and H2O (1.2 mL) were mixed and refluxed at 70 °C for 4 hours. After the reaction, the reaction solution was cooled to room temperature, concentrated, 8 mL of water was added, and the mixture was extracted with EA (3 × 20 mL). The organic phase was dried, mixed with silica gel, and purified by column chromatography (eluted with EA) to obtain product C-4, 0.28 g, with a yield of 72.5%. LCMS of product C-4: m / z = 270.9 [M+1] + 。

[0173] Example 15: Synthesis of Intermediate C-5

[0174] Synthetic route of Compound C-5:

[0175]

[0176] (1) Synthesis of 2-(5-nitropyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound M-11)

[0177] Compound M-1 (0.86 g, 5.7 mmol), M-10 (1 g, 5.95 mmol), HATU (1.4 g, 3.57 mmol), and DIEA (0.85 g, 6.55 mmol) were dissolved in DMF (10 mL) and stirred overnight at room temperature. After the reaction was completed, 60 mL of water was added to the reaction solution, and the mixture was filtered. The filter cake was dried. The filter cake was added to 12 mL of AcOH, and the mixture was refluxed at 120 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, 60 mL of water was added, and the mixture was extracted with EA (2 × 40 mL). The organic phase was dried, concentrated, and the crude product was purified by column chromatography (DCM:MeOH = 50:1) to obtain product M-11, 0.83 g, with a yield of 51.5%. LCMS of product M-11: m / z = 305.8 [M+23] + 。

[0178] (2) Synthesis of 2-(5-aminopyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound C-5)

[0179]

[0180] M-11 (0.4 g, 1.41 mmol) prepared in step (1), Fe (0.395 g, 7.1 mmol), NH4Cl (0.385 g, 7.1 mmol), EtOH (6 mL), and H2O (1.2 mL) were mixed and refluxed at 70 °C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, 8 mL of water was added, and the mixture was extracted with EA (3 × 20 mL). The organic phase was dried, mixed with silica gel, and purified by column chromatography (eluted with EA) to obtain product C-5, 0.11 g, with a yield of 30.8%. LCMS of product C-5: m / z = 253.9 [M+1] + 。

[0181] Example 16: Synthesis of Intermediate C-6

[0182] Synthesis route of Compound C-6:

[0183]

[0184] (1) Synthesis of 2-(5-nitropyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound M-13)

[0185] Dissolve compound M-1 (0.86 g, 5.7 mmol), M-12 (1 g, 5.95 mmol), HATU (1.4 g, 3.57 mmol), and DIEA (0.85 g, 6.55 mmol) in DMF (10 mL), and stir overnight at room temperature. After the reaction is completed, add 60 mL of water to the reaction solution, filter, and dry the filter cake; add the filter cake to 12 mL of AcOH, reflux at 120 °C for 4 hours, cool to room temperature after the reaction is completed, add 60 mL of water, extract with EA (2 × 40 mL), dry the organic phase, concentrate, and purify the crude product by column chromatography (DCM:MeOH = 50:1) to obtain product M-13, 0.75 g, with a yield of 46.5%. LCMS of product M-13: m / z = 305.8 [M+23] + 。

[0186] (2) Synthesis of 2-(5-aminopyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound C-6)

[0187]

[0188] Mix M-13 (0.4 g, 1.41 mmol) prepared in step (1), Fe (0.395 g, 7.1 mmol), NH4Cl (0.385 g, 7.1 mmol), EtOH (6 mL), and H2O (1.2 mL), reflux at 70 °C for 4 hours, cool the reaction solution to room temperature after the reaction is completed, concentrate, add 8 mL of water, extract with EA (3 × 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (eluted with EA) to obtain product C-6, 0.12 g, with a yield of 33.6%. LCMS of product C-6: m / z = 253.9 [M+1] + 。

[0189] Example 17: Synthesis of Intermediate C-7

[0190] Synthesis route of compound C-7:

[0191]

[0192] (1) Synthesis of N-tert-butyl-2-(4-nitrophenyl)-2H-indazole-7-carboxamide (Compound M-16)

[0193] Dissolve M-14 (5.0 g, 23.04 mmol), M-15 (3.25 g, 23.04 mmol), and K2CO3 (6.36 g, 46.08 mmol) in DMF (70 mL), and reflux the reaction mixture at 200 °C for 2 h. After the reaction is completed, cool the reaction solution to room temperature, add 60 mL of water, filter, and dry the filter cake; add the filter cake to 12 mL of AcOH, reflux the reaction mixture at 120 °C for 4 h, cool to room temperature after the reaction is completed, add 60 mL of water, extract with EA (2 × 40 mL), dry the organic phase, concentrate, and rotary evaporate to obtain 4.0 g of product M-16.

[0194] (2) Synthesis of 2-(4-aminophenyl)-N-tert-butyl-2H-indazole-7-carboxamide (Compound C-7)

[0195]

[0196] Mix M-16 (0.51 g, 1.5 mmol) prepared in step (1), Fe (0.42 g, 7.5 mmol), NH4Cl (0.41 g, 7.5 mmol), EtOH (10 mL), and H2O (2 mL), reflux the reaction mixture at 70 °C for 4 h. After the reaction is completed, cool the reaction solution to room temperature, concentrate, add 8 mL of water, extract with EA (3 × 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (eluted with EA) to obtain 0.37 g of product C-7. LCMS of product C-7: m / z = 310.0 [M+1] + 。

[0197] Example 18: Synthesis of Intermediate C-8

[0198] Synthesis route of Compound C-8:

[0199]

[0200] (1) Synthesis of N-tert-butyl-2-(3-nitrophenyl)-2H-indazole-7-carboxamide (Compound M-19)

[0201] Dissolve M-14 (1.0 g, 4.6 mmol), M-18 (1.25 g, 7.5 mmol), Cu(OAc)2 (6.36 g, 31.9 mmol), and Py (12.43 mmol, 1 mL) in DMF (70 mL), and reflux the reaction mixture in air at 80 °C for 12 h. After the reaction is completed, cool the reaction solution to room temperature, add 60 mL of water, extract with EA (3 × 100 mL), dry the organic phase, concentrate. Purify by column chromatography, rotary evaporate, and obtain 0.6 g of product M-19.

[0202] (2) Synthesis of 2-(3-aminophenyl)-N-tert-butyl-2H-indazole-7-carboxamide (C-8)

[0203]

[0204] Mix M-19 (0.338 g, 1.0 mmol), Fe (0.28 g, 5.0 mmol), NH4Cl (0.27 g, 5.0 mmol), EtOH (5 mL), and H2O (1 mL) prepared in step (1), and reflux the reaction mixture at 70 °C for 4 h. After the reaction is completed, cool the reaction solution to room temperature, concentrate it, add 8 mL of water, extract with EA (3 × 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (PE:EA = 1:1) to obtain 0.2 g of product C-8. LCMS of product C-8: m / z = 309.0 [M+1] + 。

[0205] Example 19: Synthesis of Intermediate C-9

[0206] Synthetic route of compound C-9:

[0207]

[0208] (1) Synthesis of 2-(4-nitrophenyl)-8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (Compound M-23)

[0209] Dissolve M-21 (0.4 g, 1.42 mmol), M-22 (0.237 g, 1.42 mmol), PdCl2(dppf) (0.1 g, 0.14 mmol), and Na2CO3 (300 mg, 2.84 mmol, 2 eq) in Dioxane (7 mL), and reflux the reaction mixture at 90 °C for 2 h. After the reaction is completed, cool the reaction solution to room temperature, add 20 mL of water, extract with EA (3 × 30 mL), dry the organic phase, and concentrate. Purify by column chromatography to obtain 0.21 g of product M-23.

[0210] (2) Synthesis of 2-(4-aminophenyl)-8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (C-9)

[0211]

[0212] Mix M-23 (0.21 g, 0.65 mmol), Fe (0.18 g, 3.35 mmol), NH4Cl (0.179 g, 3.35 mmol), EtOH (5 mL), and H2O (1 mL) prepared in step (1), reflux the mixture at 70 °C for 4 hours. After the reaction, cool the reaction solution to room temperature, concentrate it, add 8 mL of water, extract with EA (3 * 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (DCM:MeOH = 8:1) to obtain 0.08 g of product C-9. LCMS of product C-9: m / z = 296.0 [M+1] + 。

[0213] Example 20: Synthesis of Intermediate C-10

[0214] Synthesis route of compound C-10:

[0215]

[0216] (1) Synthesis of 2-(3-nitrophenyl)-8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (Compound M-25)

[0217] Dissolve M-21 (0.4 g, 1.41 mmol), M-24 (0.237 g, 1.42 mmol), PdCl2(dppf) (0.1 g, 0.14 mmol), and Na2CO3 (300 mg, 2.84 mmol, 2 eq) in Dioxane (7 mL), and reflux the reaction mixture at 90 °C for 2 h. After the reaction, cool the reaction solution to room temperature, add 20 mL of water, extract with EA (3 * 30 mL), dry the organic phase, and concentrate. Purify by column chromatography to obtain 0.24 g of product M-25.

[0218] (2) Synthesis of 2-(3-aminophenyl)-8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (Compound C-10)

[0219]

[0220] Mix M-25 (0.13 g, 0.4 mmol), Fe (0.112 g, 2.0 mmol), NH4Cl (0.108 g, 2.0 mmol), EtOH (3 mL), and H2O (0.6 mL) prepared in step (1), reflux the mixture at 70 °C for 6 hours. After the reaction, cool the reaction solution to room temperature, concentrate it, add 8 mL of water, extract with EA (3 * 20 mL), dry the organic phase, mix with silica gel, and purify by column chromatography (PE:EA = 1:5) to obtain product C-10, 0.018 g. LCMS of product C-10: m / z = 296.0 [M+1] + 。

[0221] Example 21: Synthesis of Intermediate C-11

[0222] Synthesis route of compound C-11:

[0223]

[0224] (1) Synthesis of 7-fluoro-9-nitro-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one (compound M-28)

[0225] Stir and react a mixture containing M-26 (1.5 g, 5.40 mmol), M-27 (1.07 g, 8.01 mmol), and triethylamine (3 mL, 21.58 mmol) in DMA (6 mL) at 100 °C for 1 h. After the reaction, cool the reaction solution, dilute it with EA (100 mL), wash with water (2 x 50 mL), wash with saturated NaCl solution (2 x 20 mL), dry the organic phase, filter, concentrate, and purify the residue by column chromatography, eluting with PE / EA (2:1) to obtain product M-28, 0.8 g, with a yield of 65.8%. LCMS of product M-28: m / z = 225.9 [M+1] + 。

[0226] (2) Synthesis of 9-amino-7-fluoro-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one (compound M-29)

[0227] Dissolve M-28 (2 g, 8.89 mmol) prepared in step (1) in MeOH / AcOH (15 mL / 2 mL), add Pd / C (100 mg, 5%) to the solution, stir and react at room temperature under hydrogen (1 atm) for 16 h. After the reaction, filter off the catalyst, concentrate the reaction solution, and purify the residue by column chromatography, eluting with DCM / MeOH (5:1) to obtain product M-29, 450 mg, with a yield of 26%. LCMS of product M-29: m / z = 195.9 [M+1] + 。

[0228] (3) Synthesis of 1-(4-nitrophenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benz[cd]azulen-6-one (Compound M-31)

[0229] Dissolve M-30 (480 mg, 2.88 mmol) in thionyl chloride (5 mL), and reflux the reaction mixture at 90 °C for 1 h. After the reaction is completed, concentrate the reaction solution to dryness. Dissolve the residue in DCM (5 mL), add a mixture containing the raw material M-29 (510 mg, 2.61 mmol) obtained in step (2) and Py (0.5 mL, 6.21 mmol, density 0.983 g / cm 3 ) in DCM (2 mL), stir the reaction mixture at room temperature for 1 h. After the reaction is completed, concentrate the reaction solution. Add TsOH (0.9 g, 5.22 mmol) and MeOH (10 mL) to the residue, and reflux the reaction mixture at 90 °C for 3 h. After the reaction is completed, cool the reaction solution, concentrate it, dissolve it in EA (100 mL), wash it with saturated NaHCO3 (2 x 50 mL), wash it with 1N HCl (2 x 50 mL), dry the organic phase, filter, concentrate, purify the residue by column chromatography, elute with EA, and obtain the product M-31, 418 mg, with a yield of 49%. LCMS of product M-31: m / z = 326.9 [M+1] + .

[0230] (4) Synthesis of 1-(4-aminophenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benz[cd]azulen-6-one (Compound C-11)

[0231]

[0232] Dissolve M-31 (418 mg, 1.28 mmol) obtained in step (3) and Pd / C (42 mg, 0.04 mmol, 10%) in MeOH (20 mL), and stir the reaction mixture at room temperature under hydrogen (1 atm) for 24 h. After the reaction is completed, filter off the catalyst, concentrate, purify the residue by column chromatography, elute with DCM / MeOH (5:1), and obtain the product C-11, 220 mg, with a yield of 58%. LCMS of product C-11: m / z = 296.9 [M+1] + .

[0233] Example 22: Synthesis of Intermediate C-12

[0234] Synthesis route of Compound C-12:

[0235]

[0236] (1) Synthesis of 2-Fluoro-N-(7-fluoro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)-4-nitrobenzamide (Compound M-33)

[0237] Dissolve M-29 (500 mg, 2.56 mmol), M-32 (474 mg, 2.56 mmol), HATU (1.46 g, 3.84 mmol) and DIEA (0.67 mL, 3.97 mmol, density 0.766 g / mL) in DMF (10 mL) to obtain a mixed solution; stir and react the mixed solution at 120 °C for 12 h. After the reaction is completed, cool the reaction solution, dilute it with water (50 mL), filter the generated solid, wash it with water, and dry it to obtain product M-33, 601 mg, with a yield of 65%. LCMS of product M-33: m / z = 362.8 [M+1] + 。

[0238] (2) Synthesis of 1-(4-Nitro-2-fluoro-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Compound M-34)

[0239] Dissolve M-33 (601 mg, 1.66 mmol) obtained in step (1) in AcOH (10 mL) to obtain a mixed solution; stir and react the mixed solution at 110 °C for 12 h. After the reaction is completed, cool the reaction solution to room temperature, concentrate it, wash the residue with water and DCM, and dry it to obtain product M-34, 516 mg, with a yield of 90%. LCMS of product M-34: m / z = 344.8 [M+1] + 。

[0240] (3) Synthesis of 1-(4-Amino-2-fluoro-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (C-12)

[0241]

[0242] Dissolve M-34 (516 mg, 1.5 mmol) obtained in step (2) and Pd / C (104 mg, 0.2 mmol, 20%) in MeOH / DCM (300 mL / 100 mL), and stir and react the obtained mixed solution under hydrogen (1 atm) at room temperature for 24 h. After the reaction is completed, filter off the catalyst, wash it with DCM / MeOH (2:1), and concentrate the organic phase to obtain product C-12, 467 mg, with a yield of 99%. LCMS of product C-12: m / z = 314.9 [M+1] + 。

[0243] Example 23: Synthesis of Intermediate C-13

[0244] Synthesis route of Compound C-13:

[0245]

[0246] (1) Synthesis of 3-Fluoro-N-(7-fluoro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)-4-nitrobenzamide (Compound M-36)

[0247] Dissolve M-29 (500 mg, 2.56 mmol), M-35 (474 mg, 2.56 mmol), HATU (1.17 g, 3.07 mmol) and DIEA (0.67 mL, 3.97 mmol, density 0.766 g / mL) in DMF (10 mL) to obtain a mixed solution; stir the mixed solution at 120 °C for 12 h. After the reaction is completed, cool the reaction solution, dilute it with water (50 mL), filter the generated solid, wash it with water, and dry it to obtain the product M-36, 570 mg, with a yield of 61%. LCMS of product M-36: m / z = 362.8 [M+1] + .

[0248] (2) Synthesis of 1-(4-Nitro-3-fluoro-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Compound M-37)

[0249] Dissolve the M-36 (570 mg, 1.57 mmol) obtained in step (1) in AcOH (10 mL) to obtain a mixed solution; stir the mixed solution at 110 °C for 12 h. After the reaction is completed, cool the reaction solution to room temperature, concentrate it, wash the residue with water and DCM, and dry it to obtain the product M-37, 373 mg, 69%. LCMS of product M-37: m / z = 344.8 [M+1] + .

[0250] (3) Synthesis of 1-(4-Amino-3-fluoro-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Compound C-13)

[0251]

[0252] M-37 (373 mg, 1.08 mmol) obtained in step (2) and Pd / C (76 mg, 0.14 mmol, 20%) were dissolved in MeOH / DCM (200 mL / 80 mL), and the resulting mixture was stirred and reacted under hydrogen (1 atm) at room temperature for 24 h. After the reaction was completed, the catalyst was filtered off, washed with DCM / MeOH (2:1), and the organic phase was concentrated to obtain product C-13, 336 mg, 99%. LCMS of product C-13: m / z = 314.9 [M+1] + 。

[0253] Example 24: Synthesis of Intermediate C-14

[0254] Synthesis route of compound C-14:

[0255]

[0256] (1) Synthesis of N-(7-fluoro-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)-5-nitropyridinecarboxamide (Compound M-39)

[0257] M-29 (500 mg, 2.56 mmol), M-38 (430 mg, 2.56 mmol), HATU (1.17 g, 3.07 mmol) and DIEA (0.67 mL, 3.97 mmol, density 0.766 g / mL) were dissolved in DMF (10 mL) to obtain a mixture; the mixture was stirred and reacted at 120 °C for 12 h. After the reaction was completed, the reaction solution was cooled, diluted with water (50 mL), the resulting solid was filtered, washed with water, and dried to obtain product M-39, 635 mg, with a yield of 72%. LCMS of product M-39: m / z = 345.8 [M+1] + 。

[0258] (2) Synthesis of 1-(5-nitro-pyridin-2-yl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triazabenzo[cd]azulen-6-one (Compound M-40)

[0259] The M-39 (635 mg, 1.84 mmol) prepared in step (1) was dissolved in AcOH (10 mL) to obtain a mixture; the mixture was stirred and reacted at 110 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and the residue was washed with water, washed with DCM, and dried to obtain product M-40, 480 mg, with a yield of 80%. LCMS of product M-40: m / z = 327.8 [M+1] + 。

[0260] (3) Synthesis of 1-(5-Amino-pyridin-2-yl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benz[cd]azulene-6-one (Compound C-14)

[0261]

[0262] M-40 (481 mg, 1.47 mmol) obtained in step (2) and Pd / C (48 mg, 0.05 mmol, 10%) were dissolved in MeOH / DCM (200 mL / 80 mL), and the resulting mixture was stirred at room temperature under hydrogen (1 atm) for 24 h. After the reaction, the catalyst was filtered off, washed with DCM / MeOH (2:1), and the organic phase was concentrated to give product C-14, 360 mg, with a yield of 82.4%. LCMS of product C-14: m / z = 297.9 [M+1] + 。

[0263] Example 25: Synthesis of Intermediate C-15

[0264] Synthetic route of Compound C-15:

[0265]

[0266] (1) Synthesis of 4-Hydroxy-5-nitronicotinic acid (Compound M-42)

[0267] Concentrated nitric acid (60 mL) was added dropwise to a solution of M-41 (24 g, 172.5 mmol) in concentrated sulfuric acid (200 mL) at 0 °C over 30 min. Then the temperature was slowly raised to room temperature, and the mixture was stirred at 100 °C for 20 h. After the reaction, the reaction mixture was cooled to room temperature, poured into ice water (1 L), and stirred vigorously. The resulting solid was filtered, washed with water (1 L), and dried to give product M-42, 10 g, with a yield of 31.5%. LCMS of product M-42: m / z = 184.9 [M+1] + 。

[0268] (2) Synthesis of Methyl 4-chloro-5-nitronicotinate (Compound M-43)

[0269] To a mixed solution of DCE / DMF (150 mL / 1 mL) containing M-42 (10 g, 54.3 mmol, prepared in step (1)), thionyl chloride SOCl₂ (28 mL, 386 mmol, density 1.638 g / mL) was slowly added dropwise to obtain a mixed solution. The mixed solution was stirred and refluxed at 84 °C for 24 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and the residue was dissolved in DCM (25 mL) and then slowly added dropwise to a mixed solution of anhydrous methanol / TEA (200 mL / 2 mL) at -10 °C. The mixture was stirred and reacted for 2 h. After the reaction was completed, water (100 mL) was added for dilution, and the mixture was extracted with DCM (400 mL). The organic phase was washed with brine and dried to obtain product M-43, 8.51 g, with a yield of 72.5%. LCMS of product M-43: m / z = 216.9 [M+1] + 。

[0270] (3) Synthesis of 9-nitro-1,2,3,4-tetrahydropyrido[4,3-e][1,4]diazepin-5-one (Compound M-44)

[0271] A solution of M-43 (8 g, 37.0 mmol) prepared in step (2), M-27 (5.38 g, 40.7 mmol), and sodium carbonate (8.63 g, 81.4 mmol) in acetonitrile (150 mL) was stirred and reacted at 90 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, washed with water, and dried to obtain product M-44, 3.25 g, with a yield of 42.3%. LCMS of product M-44: m / z = 208.9 [M+1] + 。

[0272] (4) Synthesis of 9-amino-1,2,3,4-tetrahydropyrido[4,3-e][1,4]diazepin-5-one (Compound M-45)

[0273] M-44 (3 g, 14.4 mmol) prepared in step (3) and Pd / C (0.3 g, 0.28 mmol, 10%) were dissolved in MeOH / DCM (300 mL / 150 mL), and the mixture was stirred and reacted at room temperature under hydrogen (1 atm) for 24 h. After the reaction was completed, the catalyst was filtered off and washed with DCM / MeOH (100 mL / 100 mL). The filtrate was concentrated to obtain product M-45, 2.56 g, with a yield of 99%. LCMS of product M-45: m / z = 179.0 [M+1] + 。

[0274] (5) Synthesis of 1-(4-nitrophenyl)-8,9-dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-one (Compound M-46)

[0275] To a solution of M-30 (2.4 g, 14.38 mmol) in DCE (25 mL) was added dropwise thionyl chloride (10 mL, 138 mmol, density 1.638 g / mL) and DMF (1 mL) at room temperature. Then the mixture was refluxed at 85 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and the residue was dissolved in DCE (50 mL). It was added dropwise to a solution of M-45 (2.56 g, 14.38 mmol, prepared in step (4)) and DIEA (2 mL, 11.85 mmol, density 0.766 g / mL) in DCE (100 mL) at room temperature. The mixture was stirred at 90 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated to dryness, MeOH (100 mL) and MeSO3H (2.76 g, 28.76 mmol) were added to the residue, and the mixture was refluxed at 85 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and the residue was purified by column chromatography, eluted with EA / MeOH (10:1) to obtain the product M-46, 286 mg, with a yield of 6.4%. LCMS of product M-46: m / z = 309.7 [M+1] + 。

[0276] (6) Synthesis of 1-(4-aminophenyl)-8,9-dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-one (Compound C-15)

[0277]

[0278] M-46 (286 mg, 0.93 mmol) prepared in step (5) and Pd / C (28.6 mg, 0.03 mmol, 10%) were dissolved in MeOH / DCM (200 mL / 100 mL) to obtain a mixture. The mixture was stirred at room temperature under hydrogen (1 atm) for 12 h. After the reaction was completed, the catalyst was removed by filtration, and the product C-15, 257 mg, was obtained by concentration with a yield of 99%. LCMS of product C-15: m / z = 279.9 [M+1] + 。

[0279] Example 26: Synthesis of Compound I-1

[0280] Synthetic route of Compound I-1:

[0281]

[0282] (1) Synthesis of 2-(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound I-1)

[0283]

[0284] A mixed solution of compound A-2-1 (0.1 g, 0.42 mmol, prepared in Example 1), compound C-1 (0.1 g, 0.4 mmol, prepared in Example 11), Pd2dba3 (37 mg, 0.042 mmol), Xantphos (24.3 mg, 0.042 mmol) and Cs2CO3 (0.27 g, 0.84 mmol) in Dioxane (3 mL) was stirred and reacted under nitrogen protection at 130 °C for 12 hours. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 2) to obtain product I-1, 4.6 mg. LCMS of product I-1: m / z = 454.8 [M+1] + 。

[0285] The 1H NMR data of product I-1 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 9.20 (s, 1H), 8.64 (s, 1H), 8.12 (m, 1H), 7.95 (m, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.40 (m, 2H), 7.30 (m, 2H), 6.57 - 6.59 (s, 1H), 5.66 (s, 2H), 2.03 (m, 1H), 0.85 (m, 2H), 0.52 (m, 2H).

[0286] Example 27: Synthesis of compound I-2

[0287] Synthetic route of compound I-2:

[0288]

[0289] (1) Synthesis of 2-(3-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-benzo[d]imidazole-4-carboxamide (compound I-2)

[0290]

[0291] A mixed solution of compound A-2-1 (0.1 g, 0.42 mmol, prepared in Example 1), compound C-2 (0.1 g, 0.4 mmol, prepared in Example 12), Pd2dba3 (38 mg, 0.042 mmol), Xantphos (24.3 mg, 0.042 mmol) and Cs2CO3 (0.27 g, 0.84 mmol) in Dioxane (3 mL) was stirred and reacted under nitrogen protection at 130 °C for 12 hours. After the reaction was completed, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 4) to obtain 8 mg of product I-2. LCMS of product I-2: m / z = 454.6 [M+1] + 。

[0292] The 1H NMR data of product I-2 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 13.30 (s, 1H), 9.91 (s, 1H), 9.33 (s, 1H), 8.74 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.75 - 7.87 (m, 4H), 7.19 - 7.52 (m, 3H), 2.03 (s, 1H), 0.65 (s, 4H).

[0293] Example 28: Synthesis of compound I-3

[0294] Synthetic route of compound I-3:

[0295]

[0296] (1) Synthesis of 2-(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide (compound I-3)

[0297]

[0298] A mixed solution of compound A-2-1 (0.1 g, 0.42 mmol, prepared in Example 1), compound C-3 (0.107 g, 0.4 mmol, prepared in Example 13), Pd2dba3 (38 mg, 0.042 mmol), Xantphos (24.3 mg, 0.042 mmol) and Cs2CO3 (0.27 g, 0.84 mmol) in Dioxane (3 mL) was stirred and reacted at 130 °C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 2) to obtain 10 mg of product I-3. LCMS of product I-3: m / z = 471.8 [M+1] + 。

[0299] The 1H NMR data of product I-3 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 12.52 - 13.00 (m, 2H), 9.29 - 9.45 (s, 1H), 8.74 (s, 1H), 8.45 - 8.50 (s, 1H), 8.02 - 8.31 (s, 1H), 7.75 - 7.87 (m, 3H), 7.19 - 7.52 (m, 3H), 2.03 (s, 1H), 0.83 - 0.90 (m, 4H).

[0300] Example 29: Synthesis of compound I-4

[0301] Synthetic route of compound I-4:

[0302]

[0303] (1) Synthesis of 2-(5-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide (compound I-4)

[0304]

[0305] A mixed solution of compound A-2-1 (0.1 g, 0.42 mmol, prepared in Example 1), compound C-4 (0.107 g, 0.4 mmol, prepared in Example 14), Pd2dba3 (38 mg, 0.042 mmol), Xantphos (24.3 mg, 0.042 mmol) and Cs2CO3 (0.27 g, 0.84 mmol) in Dioxane (3 mL) was stirred and reacted at 130 °C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 2) to obtain product I-4, 6.8 mg. LCMS of product I-4: m / z = 471.9 [M+1] + 。

[0306] The 1H NMR data of product I-4 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 13.03 (s, 1H), 10.02 (s, 1H), 9.25 (s, 1H), 8.83 (s, 1H), 8.07 - 8.20 (s, 1H), 7.75 - 7.82 (m, 4H), 7.21 - 7.49 (m, 3H), 2.085 (s, 1H), 0.65 (s, 4H).

[0307] Example 30: Synthesis of compound I-5

[0308] Synthetic route of compound I-5:

[0309]

[0310] (1) Synthesis of 2-(5-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide (compound I-5)

[0311]

[0312] A mixed solution of compound A-2-1 (0.1 g, 0.42 mmol prepared in Example 1), compound C-5 (0.1 g, 0.4 mmol prepared in Example 15), Pd2dba3 (38 mg, 0.042 mmol), Xantphos (24.3 mg, 0.042 mmol) and Cs2CO3 (0.27 g, 0.84 mmol) in Dioxane (3 mL) was stirred at 130 °C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (DCM / MeOH = 16 / 1) to obtain 8 mg of product I-5. LCMS of product I-5: m / z = 454.8 [M+1] + 。

[0313] The 1H NMR data of product I-5 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 9.14 (s, 1H), 8.62 (s, 1H), 7.72 - 8.20 (m, 8H), 7.42 - 7.49 (m, 1H), 7.01 - 7.07 (m, 1H), 2.03 (m, 1H), 0.49 - 0.51 (s, 4H).

[0314] Example 31: Synthesis of compound I-6

[0315] Synthetic route of compound I-6:

[0316]

[0317] (1) Synthesis of 2-(5-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide (compound I-6)

[0318]

[0319] A mixed solution of compound A-2-1 (0.1 g, 0.42 mmol, prepared in Example 1), compound C-6 (0.1 g, 0.4 mmol, prepared in Example 16), Pd2dba3 (38 mg, 0.042 mmol), Xantphos (24.3 mg, 0.042 mmol) and Cs2CO3 (0.27 g, 0.84 mmol) in Dioxane (3 mL) was stirred at 130 °C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (DCM / MeOH = 16 / 1) to obtain product I-6, 6.6 mg. LCMS of product I-6: m / z = 454.8 [M+1] + 。

[0320] The 1H NMR data of product I-6 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 13.54 (s, 1H), 10.11 (s, 1H), 9.13 - 9.20 (m, 3H), 8.93 (s, 1H), 8.28 (s, 1H), 7.75 - 7.90 (m, 3H), 7.27 - 7.40 (m, 2H), 2.03 (m, 1H), 0.52 - 0.69 (s, 4H).

[0321] Example 32: Synthesis of compound I-7

[0322] Synthetic route of compound I-7:

[0323]

[0324] (1) Synthesis of N-tert-butyl-2-(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-2H-indazole-7-carboxamide (compound M-17)

[0325] A mixed solution containing compound A-2-1 (0.1 g, 0.42 mmol, prepared in Example 1), compound C-7 (0.12 g, 0.4 mmol, prepared in Example 17), Pd2dba3 (38 mg, 0.042 mmol), Xantphos (24.3 mg, 0.042 mmol) and Cs2CO3 (0.27 g, 0.84 mmol) in Dioxane (3 mL) was stirred and reacted under nitrogen protection at 130 °C for 12 hours. After the reaction was completed, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 1) to obtain 30 mg of product M-17. LCMS of product M-17: m / z = 509.9 [M+1] + 。

[0326] (2) Synthesis of 2-(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-2H-indazole-7-carboxamide (Compound I-7)

[0327]

[0328] M-17 (0.031 g, 0.06 mmol) prepared in step (1) was dissolved in TFA (1.5 mL) and refluxed at 100 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, saturated NaHCO3 solution (5 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA / MeOH = 1 / 5 / 0.1) to obtain 4.5 mg of product I-7. LCMS of product I-7: m / z = 453.9 [M+1] + 。

[0329] 1H NMR data of product I-7 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 11.62 (m, 1H), 10.00 (s, 1H), 9.23 (m, 1H), 8.58 (m, 1H), 8.10 - 8.25 (m, 3H), 8.06 - 8.16 (m, 3H), 7.89 - 7.99 (m, 1H), 7.23 - 7.27 (m, 2H), 2.02 (s, 1H), 0.70 - 0.90 (m, 4H).

[0330] Example 33: Synthesis of Compound I-8

[0331] Synthesis route of Compound I-8:

[0332]

[0333] (1) Synthesis of N-tert-butyl-2-(3-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-2H-indazole-7-carboxamide (Compound M-20)

[0334] A mixed solution of Dioxane (3 mL) containing Compound A-2-1 (0.071 g, 0.3 mmol, prepared in Example 1), Compound C-8 (0.092 g, 0.3 mmol, prepared in Example 18), Pd2dba3 (27 mg, 0.03 mmol), Xantphos (34 mg, 0.06 mmol) and Cs2CO3 (0.195 g, 0.6 mmol) was stirred and reacted under nitrogen protection at 130 °C for 12 hours. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 1) to obtain 38 mg of Product M-20. LCMS of Product M-20: m / z = 509.9 [M+1] + 。

[0335] (2) Synthesis of 2-(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-2H-indazole-7-carboxamide (Compound I-8)

[0336]

[0337] M-20 (0.025 g, 0.05 mmol) prepared in step (1) was dissolved in TFA (1.0 mL) and refluxed at 100 °C overnight. After the reaction, the reaction solution was cooled to room temperature, saturated NaHCO3 solution (5 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA / MeOH = 1 / 5 / 0.1) to obtain 9 mg of Product I-8. LCMS of Product I-8: m / z = 453.8 [M+1] + 。

[0338] The 1H NMR data of Product I-8 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 9.88 (s, 1H), 8.37 - 8.45 (m, 2H), 8.16 - 8.23 (d, 1H), 7.72 - 7.93 (m1H), 7.65 - 7.70 (m, 2H), 7.50 - 7.52 (s, 1H), 7.23 - 7.35 (m, 3H), 7.10 - 7.20 (m, 2H), 2.02 (s, 1H), 0.43 (s, 2H), 0.185 (s, 2H).

[0339] Example 34: Synthesis of Compound I-9

[0340] Synthesis route of Compound I-9:

[0341]

[0342] (1) Synthesis of 2-(4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (Compound I-9)

[0343]

[0344] A mixed solution of Compound A-2-1 (0.065 g, 0.271 mmol, prepared in Example 1), Compound C-9 (0.08 g, 0.271 mmol, prepared in Example 19), Pd2dba3 (50 mg, 0.054 mmol), Xantphos (62 mg, 0.108 mmol) and Cs2CO3 (0.176 g, 0.542 mmol) in Dioxane (3 mL) was stirred under nitrogen protection at 130 °C for 12 hours. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA / MeOH = 1 / 4 / 0.1) to obtain 25 mg of Product I-9. LCMS of Product I-9: m / z = 496.8 [M+1] + 。

[0345] 1H NMR data of Product I-9 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 11.56 (s, 1H); 9.89 (s, 1H), 8.21 - 8.24 (m, 2H), 8.07 - 8.10 (m, 2H), 7.56 - 7.58 (m, 2H), 7.39 - 7.42 (m, 1H), 7.30 - 7.35 (m, 1H), 7.28 (s, 1H), 3.39 (m, 2H), 3.04 (m, 2H), 2.88 (m, 1H), 0.85 - 0.86 (m, 2H), 0.76 - 0.79 (m, 2H).

[0346] Example 35: Synthesis of Compound I-10

[0347] Synthesis route of Compound I-10:

[0348]

[0349] (1) Synthesis of 2-(3-(4-(Cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one (Compound I-10)

[0350]

[0351] A mixed solution of Compound A-2-1 (0.015 g, 0.06 mmol, prepared in Example 1), Compound C-10 (0.018 g, 0.06 mmol, prepared in Example 20), Pd2dba3 (6 mg, 0.006 mmol), Xantphos (6 mg, 0.012 mmol) and Cs2CO3 (0.059 g, 0.18 mmol) in Dioxane (3 mL) was stirred under nitrogen protection at 130 °C for 4 hours. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (PE / EA / MeOH = 1 / 5 / 0.1) to obtain 6 mg of Product I-10. LCMS of Product I-10: m / z = 496.9 [M+1] + 。

[0352] The 1H NMR data of Product I-10 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 11.60 (s, 1H), 9.84 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.99 - 8.02 (s, 1H), 7.11 - 7.45 (m, 6H), 3.31 - 3.39 (d, 2H), 2.85 - 3.03 (d, 2H), 2.02 (m, 1H), 0.83 - 0.87 (m, 2H), 0.58 - 0.61 (m, 2H).

[0353] Example 36: Synthesis of Compound I-11

[0354] Synthesis route of Compound I-11:

[0355]

[0356] (1) Synthesis of 1-(4-(Cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benz[cd]azulen-6-one (Compound I-11)

[0357]

[0358] A mixed solution of compound A-2-1 (50 mg, 0.21 mmol, prepared in Example 1), C-11 (63 mg, 0.21 mmol, prepared in Example 21), Pd2dba3 (19 mg, 0.021 mmol), Xantphos (12 mg, 0.021 mmol) and Cs2CO3 (137 mg, 0.42 mmol) in Dioxane (3 mL) was stirred and reacted at 130 °C for 12 hours under nitrogen protection. After the reaction, the reaction solution was cooled, water (6 mL) was added, and it was extracted with EA (10 mL * 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography and eluted with EA / MeOH (20:1) to obtain product I-11, 8.2 mg, with a yield of 7.9%. LCMS of product I-11: m / z = 497.8 [M+1] + 。

[0359] The 1H NMR data of product I-11 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 10.05 (s, 1H); 8.61 (s, 1H), 8.26 (s, 1H), 8.15 - 8.16 (m, 2H), 7.81 - 7.83 (m, 2H), 7.71 - 7.73 (m, 1H), 7.56 - 7.58 (m, 1H), 7.29 (s, 1H), 4.49 (m, 2H), 3.55 (m, 2H), 2.89 (m, 1H), 0.86 (m, 2H), 0.71 (m, 2H).

[0360] Example 37: Synthesis of compound I-12

[0361] Synthetic route of compound I-12:

[0362]

[0363] (1) Synthesis of 1-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benz[cd]azulene-6-one (compound I-12)

[0364]

[0365] Compound A-2-1 (99 mg, 0.42 mmol, prepared in Example 1), C-12 (120 mg, 0.38 mmol, prepared in Example 22), and MeSO3H (37 mg, 0.38 mmol) were dissolved in DMF (2 mL) to obtain a mixed solution. The mixed solution was stirred at 120 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated sodium bicarbonate (20 mL) was added to form a solid, which was filtered, washed with water, washed with DCM, and the residue was purified by column chromatography and eluted with EA / MeOH (20:1) to obtain product I-12, 18.2 mg, with a yield of 8.4%. LCMS of product I-12: m / z = 515.8 [M+1] + 。

[0366] The 1H NMR data of product I-12 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 10.28 (s, 1H), 8.62 (s, 1H), 8.4 (d, 1H), 7.73 - 7.75 (m, 2H), 7.64 - 7.66 (m, 2H), 7.64 (s, 1H), 4.26 (s, 2H), 3.56 (s, 2H), 2.85 (s, 1H), 0.85 - 0.86 (m, 3H), 0.72 - 0.85 (s, 2H).

[0367] Example 38: Synthesis of Compound I-13

[0368] Synthetic route of Compound I-13:

[0369]

[0370] (1) Synthesis of 1-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-fluoro-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulene-6-one (Compound I-13)

[0371]

[0372] A-2-1 (99 mg, 0.42 mmol, prepared in Example 1), C-13 (120 mg, 0.38 mmol, prepared in Example 23), and MeSO3H (37 mg, 0.38 mmol) were dissolved in DMF (2 mL) to obtain a mixed solution; the mixed solution was stirred at 120 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated sodium bicarbonate (20 mL) was added to form a solid, which was filtered, washed with water, washed with DCM, and the residue was purified by column chromatography and eluted with EA / MeOH (20:1) to obtain product I-13, 12 mg, with a yield of 6.1%. LCMS of product I-13: m / z = 515.8 [M+1] + 。

[0373] 1H NMR data of product I-13 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 9.39 (s, 1H), 8.62 (m, 1H), 8.42 (m, 1H), 8.24 (s, 1H), 7.69 - 7.76 (m, 3H), 7.58 - 7.61 (d, J = 12 Hz, 1H), 7.24 (s, 1H), 4.5 (m, 2H), 3.56 (m, 2H), 2.82 (m, 1H), 0.74 - 0.86 (m, 4H).

[0374] Example 39: Synthesis of Compound I-14

[0375] Synthetic route of compound I-14:

[0376]

[0377] (1) Synthesis of 1-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-pyridyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulene-6-one (Compound I-14)

[0378]

[0379] Compound A-2-1 (105 mg, 0.44 mmol, prepared in Example 1), C-14 (120 mg, 0.40 mmol, prepared in Example 24), and MeSO3H (39 mg, 0.40 mmol) were dissolved in DMF (2 mL) to obtain a mixed solution; the mixed solution was stirred and reacted at 120 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated sodium bicarbonate (20 mL) was added to form a solid, which was filtered, washed with water, washed with DCM, and the residue was purified by column chromatography, eluted with EA / MeOH (30:1) to obtain product I-14, 65 mg, with a yield of 32.6%. LCMS of product I-14: m / z = 498.8 [M+1] + 。

[0380] The 1H NMR data of product I-14 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 10.25 (s, 1H), 9.13 (s, 1H), 8.70 - 8.73 (s, 1H), 8.59 (s, 1H), 8.27 - 8.29 (s, 2H), 7.73 - 7.75 (d, J = 8 Hz, 1H), 7.61 - 7.64 (d, J = 12 Hz, 1H), 7.37 (s, 1H), 3.26 (m, 2H), 2.89 (m, 2H), 1.99 (m, 1H), 0.85 (m, 2H), 0.72 (m, 2H).

[0381] Example 40: Synthesis of Compound I-15

[0382] Synthesis route of Compound I-15:

[0383]

[0384] (1) Synthesis of 1-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino-phenyl)-8,9-dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6-one (Compound I-15)

[0385]

[0386] Compound A-2-1 (140 mg, 0.59 mmol, prepared in Example 1), C-15 (150 mg, 0.54 mmol, prepared in Example 25), and methanesulfonic acid (52 mg, 0.54 mmol) were dissolved in DMF (2.5 mL) to obtain a mixed solution; the mixed solution was stirred at 120 °C for 6 h. After the reaction, the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate was added, stirred for 2 h, the precipitated solid was filtered, washed with water, washed with DCM, and dried to obtain product I-15, 84.7 mg, with a yield of 32.7%. LCMS of product I-15: m / z = 480.9 [M+1] + 。

[0387] The 1H NMR data of product I-15 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 10.08 (s, 1H); 9.07 (s, 1H), 8.81 (s, 1H), 8.59 - 8.60 (m, 1H), 8.27 (s, 1H), 8.17 - 8.19 (m, 2H), 7.85 - 7.87 (m, 2H), 7.31 (s, 1H), 4.51 (m, 2H), 3.58 (m, 2H), 2.89 (m, 1H), 0.86 - 0.88 (m, 2H), 0.71 (m, 2H).

[0388] Example 41: Synthesis of Compound I-16

[0389] Synthetic route of Compound I-16:

[0390]

[0391] (1) Synthesis of 5-(4-(4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-8-fluoro-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one (Compound I-16)

[0392]

[0393] Compound A-2-2 (0.102 g, 0.407 mmol, prepared in Example 2), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), TsOH (0.06 g, 0.334 mmol) and Dioxane (2 mL) were mixed and refluxed at 80 °C for 12 h. After the reaction, the reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (20 * 3 mL), dried, concentrated, and chromatographed on a plate with PE / EA = 25 / 1 to obtain product I-16, 0.06 g. LCMS of product I-16: m / z = 510.8 (M+1)+ .

[0394] The 1H NMR data of product I-16 are as follows: 1 H NMR(400MHz,DMSO-d6): δ = 11.50(s,1H), 9.92(s,1H), 8.22 - 8.24(m,2H), 7.91 - 7.93(d,2H), 7.51 - 7.59(d,2H), 7.40(m,1H), 7.3(m,1H), 7.06(m,1H), 4.7(m,1H), 3.5(m,2H), 3.1(m,2H), 2.2 - 2.4(m,4H), 1.73(m,2H).

[0395] Example 42: Synthesis of Compound I-17

[0396] Synthesis route of Compound I-17:

[0397]

[0398] (1) Synthesis of 8-fluoro-5-(4-(4-(oxetan-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-3,4-dihydro-2H-azacyclo[5,4,3-cd]indol-1(6H)-one (Compound I-17)

[0399]

[0400] Compound A-2-3 (0.103 g, 0.407 mmol, prepared in Example 3), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), TsOH (0.06 g, 0.334 mmol) and Dioxane (2 mL) were mixed and refluxed at 80 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added, and it was extracted with ethyl acetate (20 * 3 mL), dried, concentrated, and purified by TLC (PE / EA = 25 / 1) to obtain product I-17, 0.013 g. The LCMS of product I-17: m / z = 512.8 (M+1) + .

[0401] The 1H NMR data of product I-17 are as follows: 1 H NMR(400MHz,DMSO-d6): δ = 11.68(s,1H), 9.83(s,1H), 8.42(s,1H), 8.29(s,1H), 7.83 - 7.85(d,2H), 7.60 - 7.66(s,3H), 7.25 - 7.33(m,2H), 4.69 - 4.82(m,4H), 3.33(s,3H), 3.05(s,2H).

[0402] Example 43: Synthesis of Compound I-18

[0403] Synthetic route of Compound I-18:

[0404]

[0405] (1) Synthesis of 5-(4-(4-((1r,4r)-4-aminocyclohexylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-8-fluoro-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one (Compound I-18)

[0406]

[0407] Compound A-2-5 (0.157 g, 0.407 mmol, prepared in Example 4), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), Pd2dba3 (0.031 g, 0.0334 mmol), Xantphos (20 mg, 0.034 mmol) and Cs2CO3 (326 mg, 1 mmol) were dissolved in Dioxane (2 mL). The reaction was refluxed at 130 °C for 12 h under nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, 10 mL of water was added, and it was extracted with ethyl acetate (20 × 3 mL), dried, concentrated, and purified by column chromatography with PE / EA = 1 / 4 to obtain 0.03 g of the intermediate. The obtained intermediate was added with HCl / dioxane (4 M, 2 mL), and the reaction was stirred at room temperature overnight. After the reaction, the reaction solution was concentrated to obtain 4.8 mg of Product I-18. LCMS: m / z = 553.5 (M+1) + 。

[0408] Example 44: Synthesis of Compound I-19

[0409] Synthetic route of Compound I-19:

[0410]

[0411] (1) Synthesis of 8-fluoro-5-(4-(4-(tetrahydrofuran-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-3,4-dihydro-2H-azeto[5,4,3-cd]indol-1(6H)-one (Compound I-19)

[0412]

[0413] Compound A-2-6 (0.107 g, 0.407 mmol, prepared in Example 5), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), Pd2dba3 (0.031 g, 0.0334 mmol), Xantphos (20 mg, 0.034 mmol) and Cs2CO3 (326 mg, 1 mmol) were dissolved in Dioxane (2 mL), and the mixture was refluxed at 130 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 * 3 mL), dried, concentrated, and purified by TLC with PE / EA = 1 / 4 to obtain product I-19, 0.025 g. LCMS: m / z = 527.8 (M+1) + 。

[0414] The 1H NMR data of product I-19 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 11.65 (s, 1H), 9.85 (s, 1H), 8.15 - 8.26 (m, 2H), 7.88 - 7.90 (d, 2H), 7.7.57 - 7.59 (d, 2H), 7.25 - 7.42 (m, 3H), 3.34 - 3.97 (m, 6H), 3.04 (s, 3H), 2.16 - 2.24 (m, 2H).

[0415] Example 45: Synthesis of Compound I-20

[0416] Synthetic route of Compound I-20:

[0417]

[0418] (1) Synthesis of 8-fluoro-5-(4-(4-(tetrahydro-2H-pyran-4-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one (Compound I-20)

[0419]

[0420] Compound A-2-7 (0.112 g, 0.407 mmol, prepared in Example 6) and C-9 (0.1 g, 0.334 mmol, prepared in Example 19) were dissolved in HCl / Dioxane (4 M, 2 mL), and the mixture was sealed and reacted at 80 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added, the pH was adjusted to 7 - 8, and the mixture was extracted with ethyl acetate (20 * 3 mL), dried, concentrated, and purified by TLC with PE / EA = 1 / 4 to obtain product I-20, 0.07 g. LCMS: m / z = 540.8 (M+1)+ 。

[0421] The 1H NMR data of Product I-20 are as follows: 1 H NMR(400MHz,DMSO-d6): δ=11.37(s,1H),9.85(s,1H),8.16 - 8.25(m,2H),7.56 - 7.58(d,2H),7.22 - 7.39(m,5H),3.94(d,2H),3.33 - 3.50(s,4H),2.90 - 3.10(m,3H),1.81 - 1.80(m,4H).

[0422] Example 46: Synthesis of Compound I-21

[0423] Synthetic route of Compound I-21:

[0424]

[0425] (1) Synthesis of 8-Fluoro-5-(4-(4-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one (Compound I-21)

[0426]

[0427] Dissolve Compound A-2-8 (0.152 g, 0.407 mmol, Example 7), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), Pd2dba3 (0.031 g, 0.0334 mmol), Xantphos (20 mg, 0.034 mmol) and Cs2CO3 (326 mg, 1 mmol) in Dioxane (2 mL), reflux the reaction mixture under nitrogen protection at 130 °C for 12 h. After the reaction is completed, cool the reaction solution to room temperature, add 10 mL of water, adjust the pH to 7 - 8, extract with ethyl acetate (20 * 3 mL), dry, concentrate, and perform column chromatography with PE / EA = 1 / 4 to obtain 0.06 g of the intermediate. Add HCl / dioxane (4 M, 2 mL) to the obtained intermediate and stir the reaction mixture overnight at room temperature. After the reaction is completed, concentrate the reaction solution to obtain 60 mg of Product I-21. LCMS: m / z = 540.8 (M+1) + 。

[0428] The 1H NMR data of Product I-21 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 11.78 (s, 1H), 9.00 (s, 1H), 8.26 (s, 2H), 8.33 (s, 1H), 7.78 - 7.86 (d, 2H), 7.62 - 7.64 (d, 2H), 7.26 - 7.36 (m, 2H), 3.30 - 3.45 (m, 4H), 2.98 - 3.05 (m, 5H), 1.83 - 2.02 (d, 5H).

[0429] Example 47: Synthesis of Compound I-22

[0430] Synthetic route of Compound I-22:

[0431]

[0432] (1) Synthesis of 8-Fluoro-5-(4-(4-(pyrrolidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one (Compound I-22)

[0433]

[0434] Compound A-2-9 (0.146 g, 0.407 mmol, prepared in Example 8), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), Pd2dba3 (0.031 g, 0.0334 mmol), Xantphos (20 mg, 0.034 mmol) and Cs2CO3 (326 mg, 1 mmol) were dissolved in Dioxane (2 mL). The reaction was refluxed at 130 °C for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added, the pH was adjusted to 7 - 8, and it was extracted with ethyl acetate (20 * 3 mL), dried, concentrated, and chromatographed on a plate with PE / EA = 1 / 4 to obtain 0.048 g of the intermediate. The obtained intermediate was added with HCl / dioxane (4 M, 2 mL), and the reaction was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain 30 mg of Product I-22. LCMS: m / z = 526.8 (M + 1) + 。

[0435] The 1H NMR data of Product I-22 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 11.85 (s, 1H), 9.83 (s, 1H), 8.21 - 8.24 (s, 2H), 7.88 - 7.98 (s, 2H), 7.53 - 7.58 (d, 2H), 7.26 - 7.40 (m, 3H), 3.45 - 3.72 (m, 4H), 2.78 - 3.09 (m, 5H), 2.01 - 2.08 (d, 3H).

[0436] Example 48: Synthesis of Compound I-23

[0437] Synthetic route of Compound I-23:

[0438]

[0439] (1) Synthesis of 5-(4-(4-((1S,3S)-3-aminocyclopentylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-8-fluoro-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one (Compound I-23)

[0440]

[0441] Dissolve Compound A-2-10 (0.152 g, 0.407 mmol, prepared in Example 9), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), Pd2dba3 (0.031 g, 0.0334 mmol), Xantphos (20 mg, 0.034 mmol) and Cs2CO3 (326 mg, 1 mmol) in Dioxane (2 mL). Under nitrogen protection, reflux the reaction mixture at 130 °C for 12 h. After the reaction is completed, cool the reaction solution to room temperature, add 10 mL of water, adjust the pH to 7 - 8, extract with ethyl acetate (20 * 3 mL), dry, concentrate, and purify by column chromatography (PE / EA = 1 / 4) to obtain 0.07 g of the intermediate. Add HCl / dioxane (4 M, 2 mL) to the obtained intermediate and stir the reaction mixture overnight at room temperature. After the reaction is completed, concentrate the reaction solution to obtain 35 mg of Product I-23. LCMS: m / z = 539.9 (M + 1) + 。

[0442] The 1H NMR data of Product I-23 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 11.62 (s, 1H), 9.81 (s, 1H), 8.19 - 8.21 (s, 2H), 7.93 - 7.95 (s, 2H), 7.55 - 7.7 (d, 2H), 7.26 - 7.42 (m, 3H), 3.47 (m, 2H), 2.98 - 3.15 (m, 4H), 2.08 - 2.20 (m, 2H), 1.85 - 2.02 (m, 2H), 1.45 - 1.82 (m, 4H).

[0443] Example 49: Synthesis of Compound I-24

[0444] Synthetic route of Compound I-24:

[0445]

[0446] (1) Synthesis of 8-Fluoro-5-(4-(4-(3-(2-oxopyrrolidin-1-yl)propylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-3,4-dihydro-2H-azepino[5,4,3-cd]indol-1(6H)-one (Compound I-24)

[0447]

[0448] Compound A-2-11 (0.129 g, 0.407 mmol, prepared in Example 10), C-9 (0.1 g, 0.334 mmol, prepared in Example 19), TsOH (0.06 g, 0.334 mmol) and Dioxane (3 mL) were mixed and refluxed at 80 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added, the pH was adjusted to 7 - 8, and it was extracted with ethyl acetate (20 * 3 mL), dried, concentrated, and purified by TLC (DCM / EA = 1 / 3), and then concentrated to obtain 20 mg of product I-24. LCMS: m / z = 582.0 (M+1) + 。

[0449] The 1H NMR data of product I-24 are as follows: 1 1H NMR (400 MHz, DMSO-d6): δ = 11.62 (s, 1H), 9.82 (s, 1H), 8.23 (s, 2H), 7.90 - 7.92 (d, 2H), 7.51 - 7.59 (d, 2H), 7.22 - 7.34 (m, 2H), 6.67 (s, 1H), 3.32 - 3.45 (m, 4H), 2.85 - 3.15 (m, 2H), 2.15 - 2.25 (m, 2H), 1.56 - 2.05 (m, 4H), 1.1 - 1.32 (m, 4H).

[0450] Example 50: Synthesis of Compound I-25

[0451] Synthetic route of Compound I-25:

[0452]

[0453] (1) Synthesis of 1-(4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benz[cd]azulen-6-one (Compound I-25)

[0454]

[0455] Compound A-2-2 (30 mg, 0.12 mmol, prepared in Example 2), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction, the reaction solution was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, the pH was adjusted to 7 - 8, filtered, the filtrate was layered, the filter cake and the organic phase were combined, concentrated, and chromatographed on a plate with DCM / MeOH = 10 / 1 to obtain 7 mg of product I-25. LCMS: m / z = 511.8 (M+1) + 。

[0456] The 1H NMR data of product I-25 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 9.96 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.01 (d, 2H), 7.74 - 7.81 (d, 2H), 7.71 - 7.74 (m, 1H), 7.56 - 7.59 (d, 1H), 7.12 (s, 1H), 4.49 (s, 2H), 3.56 (s, 2H), 3.01 - 3.21 (m, 1H), 2.01 - 2.45 (m, 4H), 1.70 - 1.73 (m, 2H).

[0457] Example 51: Synthesis of Compound I-26

[0458] Synthetic route of Compound I-26:

[0459]

[0460] (1) Synthesis of 1-(4-(oxetan-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino-phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benz[cd]azulen-6-one (Compound I-26)

[0461]

[0462] Compound A-2-3 (30 mg, 0.12 mmol, prepared in Example 3), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction, the reaction solution was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, the pH was adjusted to 7 - 8, filtered, the filtrate was layered, the filter cake and the organic phase were combined, concentrated, and chromatographed on a plate with DCM / MeOH = 10 / 1 to obtain 8 mg of product I-26. LCMS: m / z = 513.8 (M+1) + 。

[0463] The 1H NMR data of product I-26 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 9.45 (s, 1H), 8.62 (s, 1H), 8.12 (s, 2H), 7.92 - 8.1 (m, 4H), 7.62 - 7.83 (m, 2H), 4.35 - 4.45 (m, 2H), 4.02 - 4.18 (d, 2H), 3.88 - 3.92 (d, 2H), 3.52 - 3.68 (m, 3H).

[0464] Example 52: Synthesis of Compound I-27

[0465] Synthesis route of Compound I-27:

[0466]

[0467] (1) Synthesis of 1-(4-(4-((1r,4r)-4-aminocyclohexylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Compound I-27)

[0468]

[0469] Compound A-2-5 (50 mg, 0.12 mmol, prepared in Example 4), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed, and the reaction was carried out in a sealed tube at 100 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, 5 mL of petroleum ether / ethyl acetate (1 / 1) was added, and the mixture was slurried, filtered. The filter cake was added with 2 mL of TFA / DCM (1 / 1), and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated, 5 mL of water and 5 mL of ethyl acetate were added, and the pH was adjusted to 7-8. After filtration, the filtrate was separated into layers. The filter cake and the organic phase were combined, concentrated, and chromatographed on a plate with DCM / MeOH = 10 / 1 to obtain 5 mg of product I-27. LCMS: m / z = 554.8 (M+1) + 。

[0470] The 1H NMR data of product I-27 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 10.04 (s, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 8.01 - 8.21 (m, 3H), 7.81 - 7.84 (d, 2H), 7.73 - 7.74 (d, 1H), 7.712 - 7.718 (d, 1H), 4.49 (s, 2H), 3.56 (s, 2H), 2.9 - 3.01 (m, 1H), 2.56 - 2.62 (m, 1H), 1.98 - 2.15 (m, 5H), 1.45 - 1.62 (m, 5H).

[0471] Example 53: Synthesis of Compound I-28

[0472] Synthetic route of Compound I-28:

[0473]

[0474] (1) Synthesis of 1-(4-(4-(tetrahydrofuran-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulene-6-one (Compound I-28)

[0475]

[0476] Compound A-2-6 (32 mg, 0.12 mmol, prepared in Example 5), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction, the reaction solution was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, the pH was adjusted to 7-8, filtered, the filtrate was separated, the filter cake and the organic phase were combined, concentrated, and chromatographed on a plate with DCM / MeOH = 10 / 1 to obtain product I-28, 8 mg. LCMS: m / z = 527.8 (M+1) + 。

[0477] The 1H NMR data of product I-28 are as follows: 1 H NMR (400 MHz, DMSO-d6): δ = 10.01 (s, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 7.97 - 7.99 (d, 2H), 7.81 - 7.84 (d, 2H), 7.71 - 7.713 (d, 1H), 7.756 - 7.58 (d, 1H), 6.88 - 6.90 (s, 1H), 4.48 - 4.49 (s, 2H), 3.56 - 4.1 (m, 5H), 1.98 - 2.25 (m, 4H).

[0478] Example 54: Synthesis of Compound I-29

[0479] Synthetic route of Compound I-29:

[0480]

[0481] (1) Synthesis of 1-(4-(4-(tetrahydro-2H-pyran-4-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulene-6-one (Compound I-29)

[0482]

[0483] Compound A-2-7 (31 mg, 0.12 mmol, prepared in Example 6), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction, the reaction solution was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, the pH was adjusted to 7-8, filtered, the filtrate was separated, the filter cake and the organic phase were combined, concentrated, and chromatographed on a plate with DCM / MeOH = 10 / 1 to obtain product I-29, 6 mg. LCMS: m / z = 542.8 (M+1) + 。

[0484] The 1H NMR data of product I-29 are as follows: 1 H NMR(400MHz,DMSO-d6): δ=10.10(s,1H),8.69(s,1H),8.29(s,1H),7.98 - 8.02(d,2H),7.82 - 7.85(d,2H),7.79 - 7.796(d,1H),7.61 - 7.64(m,1H),6.87 - 6.90(s,1H),4.51(s,2H),4.35(s,1H),3.93 - 3.95(d,2H),3.30 - 3.52(m,4H),1.75 - 1.80(s,4H).

[0485] Example 55: Synthesis of Compound I-30

[0486] Synthesis route of Compound I-30:

[0487]

[0488] (1) Synthesis of 1-(4-(4-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Compound I-30)

[0489]

[0490] Compound A-2-8 (46 mg, 0.12 mmol, prepared in Example 7), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was concentrated and 5 mL of petroleum ether / ethyl acetate (1 / 1) was added, and then slurried and filtered. The filter cake was added with 2 mL of TFA / DCM (1 / 1) and reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated and 5 mL of water and 5 mL of ethyl acetate were added, and the pH was adjusted to 7 - 8. Then it was filtered, and the filtrate was separated into layers. The filter cake and the organic phase were combined, concentrated, and purified by TLC with DCM / MeOH = 10 / 1 to obtain 5 mg of product I-30. LCMS: m / z = 540.9 (M+1) + .

[0491] The 1H NMR data of product I-30 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 10.07 (s, 1H), 8.95 (s, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 7.98 - 8.02 (d, 2H), 7.82 - 7.85 (d, 2H), 7.79 - 7.796 (d, 1H), 7.61 - 7.64 (m, 1H), 6.87 - 6.90 (s, 1H), 4.51 (s, 2H), 4.35 (s, 1H), 3.52 - 3.70 (s, 2H), 3.28 - 3.35 (s, 1H), 2.95 - 3.12 (s, 3H), 1.1.82 - 2.03 (m, 4H).

[0492] Example 56: Synthesis of Compound I-31

[0493] Synthetic route of Compound I-31:

[0494]

[0495] (1) Synthesis of 1-(4-(4-(Pyrrolidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Compound I-31)

[0496]

[0497] Compound A-2-9 (44 mg, 0.12 mmol, prepared in Example 8), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was concentrated and 5 mL of petroleum ether / ethyl acetate (1 / 1) was added, and then slurried and filtered. The filter cake was added to 2 mL of TFA / DCM (1 / 1) and reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated and 5 mL of water and 5 mL of ethyl acetate were added, and the pH was adjusted to 7 - 8. After filtration, the filtrate was separated into layers. The filter cake and the organic phase were combined, concentrated, and purified by preparative TLC (DCM / MeOH = 9 / 1) to obtain 10 mg of product I-31. LCMS: m / z = 526.8 (M+1) + .

[0498] The 1H NMR data of product I-31 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 10.11 (s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 7.96 - 8.02 (d, 2H), 7.85 - 7.87 (d, 2H), 7.79 - 7.796 (d, 1H), 7.61 - 7.64 (d, 1H), 7.19 (s, 1H), 3.45 - 3.72 (m, 4H), 2.78 - 3.09 (m, 5H), 2.01 - 2.08 (d, 3H).

[0499] Example 57: Synthesis of Compound I-32

[0500] Synthetic route of Compound I-32:

[0501]

[0502] (1) Synthesis of 1-(4-(4-((1S,3S)-3-aminocyclopentylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Compound I-32)

[0503]

[0504] Compound A-2-10 (46 mg, 0.12 mmol, prepared in Example 9), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was concentrated and 5 mL of petroleum ether / ethyl acetate (1 / 1) was added, and then slurried and filtered. The filter cake was added to 2 mL of TFA / DCM (1 / 1) and reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated and 5 mL of water and 5 mL of ethyl acetate were added, and the pH was adjusted to 7 - 8. After filtration, the filtrate was separated into layers. The filter cake and the organic phase were combined, concentrated, and chromatographed on a plate with DCM / MeOH = 9 / 1 to obtain 7 mg of product I-32. LCMS: m / z = 540.8 (M+1) + .

[0505] The 1H NMR data of product I-32 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 10.07 (s, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 7.96 - 8.02 (d, 2H), 7.85 - 7.87 (d, 2H), 7.79 - 7.796 (d, 1H), 7.61 - 7.64 (d, 1H), 6.95 (s, 1H), 3.47 (m, 2H), 2.98 - 3.15 (m, 4H), 2.08 - 2.20 (m, 2H), 1.85 - 2.02 (m, 2H), 1.45 - 1.82 (m, 4H).

[0506] Example 58: Synthesis of Compound I-33

[0507] Synthetic route of Compound I-33:

[0508]

[0509] (1) Synthesis of 1-(4-(4-(3-(2-oxopyrrolidin-1-yl)propylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-4-fluoro-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulene-6-one (Compound I-33)

[0510]

[0511] Compound A-2-11 (39 mg, 0.12 mmol, prepared in Example 10), C-11 (30 mg, 0.1 mmol, prepared in Example 21), TFA (12 mg, 0.1 mmol) and IPA (2 mL) were mixed and reacted in a sealed tube at 100 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 5 mL of water and 5 mL of ethyl acetate were added, the pH was adjusted to 7 - 8, filtered, the filtrate was layered, the filter cake and the organic phase were combined, concentrated, and chromatographed on a plate with DCM / MeOH = 10 / 1 to obtain 12 mg of product I-33. LCMS: m / z = 582.8 (M+1) + .

[0512] The 1H NMR data of product I-33 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 9.98 (s, 1H); 8.60 - 8.61 (m, 1H), 8.26 (s, 1H), 7.97 - 8.00 (m, 2H), 7.82 - 7.84 (m, 2H), 7.72 - 7.74 (m, 1H), 7.56 - 7.59 (m, 1H), 7.28 (m, 1H), 4.50 (m, 2H), 3.56 (m, 2H), 3.46 (m, 2H), 3.25 - 3.32 (m, 4H), 2.50 (m, 2H), 1.90 - 1.92 (m, 2H), 1.78 - 1.81 (m, 2H).

[0513] Example 59: Synthesis of Compound I-34

[0514] Synthetic route of Compound I-34:

[0515]

[0516] (1) Synthesis of 1-(4-(4-(3-(2-oxopyrrolidin-1-yl)propylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-8,9-dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6-one (Compound I-34)

[0517]

[0518] Compound A-2-11 (254 mg, 0.79 mmol, prepared in Example 10), C-15 (201 mg, 0.72 mmol, prepared in Example 25) and methanesulfonic acid (69 mg, 0.72 mmol) were dissolved in DMF (2.5 mL) to obtain a mixed solution; the mixed solution was stirred at 120 °C for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred for 2 h. The precipitated solid was filtered, washed with water and DCM, and dried to obtain Product I-34, 85.8 mg, with a yield of 21%. LCMS: m / z = 565.8 (M+1) + .

[0519] 1H NMR data of Product I-34 are as follows: 11H NMR (400 MHz, DMSO-d6): δ = 10.01 (s, 1H); 9.08 (s, 1H), 8.81 (s, 1H), 8.59 - 8.60 (m, 1H), 8.26 (s, 1H), 7.98 - 8.02 (m, 2H), 7.86 - 7.89 (m, 2H), 7.28 (m, 1H), 4.51 (m, 2H), 3.58 (m, 2H), 3.48 (m, 2H), 3.20 - 3.30 (m, 4H), 2.20 (m, 2H), 1.90 - 1.92 (m, 2H), 1.78 - 1.81 (m, 2H).

[0520] Example 60: Determination of the in vitro inhibitory activities (IC50 values) of different compounds against Parp1 and ULK1

[0521] 1. Determination of the in vitro inhibitory activity (IC50 value) of different compounds against Parp1

[0522] The PARP1 enzyme activity transfers ADP - ribose from the NAD+ substrate to the PAR chain of the histone substrate. The amount of NAD+ remaining after the enzymatic reaction is quantitatively determined using the Promega NAD / NADH - Glo TM detection kit as the endpoint PARP1 activity.

[0523] 1.1 Reagents: Reaction buffer: 50 mM Tris - HCl (pH 8.0), 50 mM NaCl, 10 mM MgCl2, 0.01% Brij35, 1 mM DTT, 1% DMSO and 10 mg / mL activated DNA (Sigma cat#D4522).

[0524] 1.2 Substrates: Chicken core histones, NAD.

[0525] 1.3 Standard reaction conditions:

[0526] PARP1: 2.5 nM (RBC CAT#PAR - 21 - 346);

[0527] Chicken core histones: 0.01 mg / mL (RBC CAT#HMT - 35 - 435);

[0528] NAD: 0.5 mM (Sigma - Aldrich CAT#N1636);

[0529] Detection kit: NAD / NADH - Glo TM (Promega CAT#G9071).

[0530] 1.4 Reaction steps:

[0531] (i) Add 10 mL of a 1X enzyme / histone substrate mixture prepared in reaction buffer to the wells of a reaction plate (Corning 3572, untreated). For the total NAD+ signal wells (without enzyme), add the histone substrate prepared in reaction buffer.

[0532] (ii) Add compounds dissolved in 100% DMSO (prepared from Examples 26 to 59, respectively) to the enzyme mixture by acoustic technology (Echo550; nanoliter range). Add 100% DMSO to the control wells without compound / DMSO. Spin the reaction plate down to mix and pre-incubate at room temperature for 20 minutes.

[0533] (iii) Use the reaction liquid handler of Mantis to add 100 nl of 100X NAD to initiate the reaction. Spin the reaction plate down to mix. Seal the reaction plate and incubate at room temperature for 2 hours.

[0534] (iv) Add 10 mL of NAD / NADH-GloTM prepared according to the detection kit instructions to all the detection wells. Spin the reaction plate down to mix. Seal the reaction plate and incubate in the dark at room temperature for 30 minutes (with black lid).

[0535] (v) Read the endpoint fluorescence value at 30 minutes.

[0536] 1.5. Data analysis:

[0537] Subtract the average NAD signal from the enzyme-free wells from the fluorescence signal of each assay well to calculate the signal loss due to NAD+ consumption caused by PARP1 enzyme activity.

[0538] Calculate the % enzyme activity in each assay well (at different compound concentrations) relative to the wells without compound / DMSO (the wells with maximum enzyme activity).

[0539] Use Graphpad Prism software to perform non-linear regression curve fitting of "S-shaped dose response (variable slope)"; 4 parameters with slope to obtain the IC50 value of the compound.

[0540] Constraints:

[0541] Bottom = constant equal to 0;

[0542] Top = must be less than 120.

[0543] 2. Determination of the in vitro inhibitory activity (IC50 value) of different compounds against ULK1

[0544] 2.1. Experimental method

[0545] The substrate solution was prepared by adding the substrate poly(Glu,Tyr) sodium salt (Sigma Aldrich, St. Louis, MO) to the substrate reaction buffer (20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO) (the final concentration of the substrate in the reaction was 0.2 μM). The test compounds (compounds prepared in Examples 26 to 59, respectively) were each formulated into a stock solution at a concentration of 10 mM with 100% DMSO, and 10-fold serial dilutions of 3-fold doses were performed in a 384-well cyclic olefin copolymer LDV microtiter plate. ULK1 kinase (recombinant human full-length protein, histidine-tagged, expressed in insect cells, Invitrogen, Carlsbad, CA) was added to the substrate solution and gently mixed (the final concentration of ULK1 in the reaction solution was 8 nM). Then, 100% DMSO containing the test compounds (compounds prepared in Examples 26 to 59, respectively) was added to the kinase reaction mixture by acoustic liquid transfer technology (Echo 550; nanoliter range) (Labcyte Inc, Sunnyvale, CA), and incubated at room temperature for 20 minutes. 33P-ATP (specific activity 10 μCi / μl) was added to the reaction mixture to initiate the reaction, and then incubated at room temperature for 2 hours. A small portion of the reaction solution was spotted on P-81 ion exchange filter paper (Whatman). After washing the unbound phosphate on the filter paper with 0.75% phosphate buffer (three times) and drying, the radioactivity remaining on the filter paper was measured.

[0546] 2.2 Data analysis

[0547] The ULK1 kinase activity data was expressed as the percentage of the remaining kinase activity in the test sample compared to the vehicle (dimethyl sulfoxide) blank reaction. Prism (GraphPad Software) software was used to perform curve fitting on the obtained data to calculate the IC50 value.

[0548] 3 Experimental results

[0549] Table 1 Inhibition results of Parp1 and ULK1 enzyme activities

[0550]

[0551]

[0552] Note: A: Enzyme activity inhibition ≤ 100 nM; B: 100 nM < enzyme activity inhibition ≤ 1 μM; C: 1 μM < enzyme activity inhibition.

[0553] As shown in Table 1, most of the representative compounds (Compound I-1 to Compound I-34) of the present invention showed strong inhibitory effects (<100 nM) on both Parp1 and ULK1.

[0554] Example 61: Determination of in vitro cell proliferation inhibitory activity (IC50 value) of Huh-7 and MDA-MB-468 cells

[0555] 1. Experimental method

[0556] (i) Resuscitate and culture cells Huh-7 and MDA-MB-468, passage them more than 2 times, harvest the cells to prepare single-cell suspensions, inoculate a transparent 96-well plate according to the cell layout diagram, 103 cells / well;

[0557] (ii) The next day, prepare a drug working solution using complete medium, add the test drugs (Compound I-11 prepared in Example 36, Compound I-9 prepared in Example 34, Compound I-14 prepared in Example 39, and the commercially purchased positive control compound Olaparib) according to the cell layout diagram. The highest drug concentration is 10 μM, diluted 3.16-fold, with a total of 9 concentrations, 3 replicates for each concentration, and set a DMSO control;

[0558] (iii) Place the 96-well plate in a CO2 incubator and culture at 37 °C for 120 hours;

[0559] (iv) After the culture is completed, add an equal volume of Reagent to each well;

[0560] (v) Use an orbital shaker to mix for 2 minutes to induce cell lysis;

[0561] (vi) Incubate the plate at room temperature for 10 minutes to stabilize the luminescence signal;

[0562] (vii) Transfer the supernatant to a white opaque 96-well plate and record the luminescence signal using a microplate reader.

[0563] 2. Experimental results

[0564] After co-incubating the test compounds (Compound I-11 prepared in Example 36, Compound I-9 prepared in Example 34, Compound I-14 prepared in Example 39) and the positive control compound Olaparib with cells MDA-MB-468 and Huh-7 for 120 hours, the cell viability was detected by the CTG method. With the drug concentration as the X-axis and the cell viability as the Y-axis, the dose-effect curve was obtained by applying non-linear S-curve regression to fit the data, and the IC50 was calculated.

[0565] Table 2. IC50 values of the test compounds against cells

[0566]

[0567] As shown in Table 2, some of the compounds described in the present invention exhibit stronger growth inhibitory effects on cancer cells MDA-MB-468 and Huh-7 than the reference compound Olaparib.

[0568] The present invention provides a dual-target inhibitor of PARP1 and ULK1, as well as ideas and methods for its preparation and application. There are many specific methods and ways to implement this technical solution. The above description is only a preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention. Each component not clearly defined in this embodiment can be realized by existing technologies.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof; Wherein, R 1 selected from halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, alkoxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, halo-C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; R 2 selected from -NR 5 R 6 , -NHNR 5 R 6 , -NR 5 OR 6 , -OR 5 , -ONR 5 R 6 or -SR 5 ; wherein, R 5 and R 6 are each independently selected from H, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-9 heteroaryl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-7 heterocycloalkyl, or R 5 and R 6 together with the N in -NR 5 R 6 form a 3- to 6-membered heterocycle; wherein, the said substitution is selected from being substituted by halogen, cyano, hydroxy, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 3-7 cyclic amino, C 3-7 heterocyclic amino, C 4-7 cyclic amide, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkoxy substitution; R 3 Any one selected from the following groups: wherein, R 4 is selected from H, halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-3 alkoxy or halo-C 1-3 alkoxy; The L ring is selected from a substituted or unsubstituted 5- to 6-membered aromatic ring, or a substituted or unsubstituted 5- to 6-membered heteroaromatic ring; wherein, the substitution is selected from being substituted by halogen, cyano, hydroxyl, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy or halo-C 1-3 alkoxy substitution; W is selected from N or CH.

2. The compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to claim 1, characterized in that, R 1 selected from halogen, C 1-3 alkyl, halo-C 1-3 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl.

3. The compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to claim 1, characterized in that, R 2 selected from -NR 5 R 6 or -OR 5 ; wherein, R 5 and R 6 are each independently selected from H, substituted or unsubstituted C6 aryl, substituted or unsubstituted C 3-5 heteroaryl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocycloalkyl, or R 5 and R 6 together with the N in -NR 5 R 6 form a 3- to 6-membered heterocycle; wherein the substitution is selected from being substituted by halogen, cyano, hydroxy, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 4-7 cyclic amide group, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkoxy substitution.

4. The compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to claim 1, characterized in that, R 3 Any one selected from the following groups: wherein, R 4 is selected from H or halogen.

5. The compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to claim 1, characterized in that, The L ring is selected from a substituted or unsubstituted 5- or 6-membered aromatic ring, or a substituted or unsubstituted 5- or 6-membered heteroaromatic ring; wherein, the substitution is selected from being substituted by a halogen.

6. The compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to claim 1, characterized in that, W is selected from N.

7. The compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to claim 1, characterized in that, R 1 selected from halo-C 1-3 alkyl; R 2 selected from -NR 5 R 6 ; wherein, R 5 、R 6 are each independently selected from H, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocycloalkyl; wherein, the substitution is selected from being substituted by an amino group or a pyrrolidone group; R 3 Any one selected from the following groups: wherein, R 4 is selected from H or fluorine; The L ring is selected from a substituted or unsubstituted 6-membered aromatic ring, or an unsubstituted 6-membered heteroaromatic ring; wherein, the substitution is selected from being substituted by fluorine; W is selected from N; Preferably, R 1 Selected from trifluoromethyl; R 2 Any one selected from the following groups: R 3 Any one selected from the following groups: The L ring is selected from any one of the following groups: W is selected from N.

8. The compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to claim 1, characterized in that, The compound is selected from any of the following structures:

9. A process for preparing the compound according to any one of claims 1 to 8, characterized in that, Comprising the following steps: Step 1: Nucleophilic substitution of compound A-1 with compound B to obtain compound A-2; Step 2: Coupling of compound A-2 with compound C to generate compound I; Among them, the compound B is selected from amines, hydroxylamines, hydrazines, alcohols or thiols; the compound C is Wherein, R 1 selected from halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, alkoxy-substituted C 1-6 alkyl, C 3-6 cycloalkyl, halo-C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; R 2 selected from -NR 5 R 6 、-NHNR 5 R 6 、-NR 5 OR 6 、-OR 5 、-ONR 5 R 6 or -SR 5 ; wherein, R 5 and R 6 are each independently selected from H, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 3-9 heteroaryl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-7 heterocycloalkyl, or R 5 and R 6 together with the N in -NR 5 R 6 form a 3- to 6-membered heterocycle; wherein the substitution is selected from being substituted by halogen, cyano, hydroxy, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 3-7 cycloamino, C 3-7 heterocycloamino, C 4-7 cycloamido, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkoxy substitution; R 3 Any one selected from the following groups: wherein, R 4 is selected from H, halogen, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-3 alkoxy or halo-C 1-3 alkoxy; The L ring is selected from a substituted or unsubstituted 5- to 6-membered aromatic ring or a substituted or unsubstituted 5- to 6-membered heteroaromatic ring; wherein the substitution is selected from being substituted by halogen, cyano, hydroxy, amino, mono(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy or halo-C 1-3 alkoxy. W is selected from N or CH.

10. A pharmaceutical composition, characterized in that, Comprising the compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to any one of claims 1 to 8, and one or more pharmaceutically acceptable carriers.

11. A pharmaceutical preparation, characterized in that, It contains a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier, diluent or excipient.

12. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 10 or the pharmaceutical preparation according to claim 11 in the preparation of a poly(ADP-ribose) polymerase 1 inhibitor.

13. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 10 or the pharmaceutical preparation according to claim 11 in the preparation of an unc-51-like autophagy activating kinase 1 inhibitor. Use of the compound according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 10, or the pharmaceutical preparation according to claim 11, in the preparation of a medicament for preventing or treating a disease associated with abnormal enzyme activity of poly (ADP-ribose) polymerase 1 and / or unc-51-like autophagy activating kinase 1.

15. The use according to claim 14, characterized in that, The disease associated with abnormal enzyme activity of poly (ADP-ribose) polymerase 1 and / or unc-51-like autophagy activating kinase 1 is a tumor.

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