WO2022135610A1

WO2022135610A1 - Tetracyclic compound, pharmaceutical composition thereof and use thereof

Info

Publication number: WO2022135610A1
Application number: PCT/CN2022/070423
Authority: WO
Inventors: 方华祥; 杨秀眉
Original assignee: 武汉誉祥医药科技有限公司
Priority date: 2020-12-25
Filing date: 2022-01-06
Publication date: 2022-06-30
Also published as: CN114685531A; CN114685531B

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and relates to a tetracyclic compound, a pharmaceutical composition thereof and use thereof. The compound is a tetracyclic compound as shown in formula I, or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, a tautomer, a metabolite or a prodrug thereof, wherein R₁-R₆ and L₁, L₂, L₃, Z₁, Z₂, and X and Y groups are as defined in the description. The compound and the pharmaceutical composition comprising same in the present invention have good SOS1 inhibitory activity, and therefore can be used as an SOS1 inhibitor, and can be used for preparing drugs for treating and/or preventing diseases caused by overexpression of SOS1, such as cancer, thereby being applied in the field of medicines. The tetracyclic compound in the present invention exhibits excellent biological activity and druggability, and has great prospects for drug development.

Description

Tetracyclic compounds and their pharmaceutical compositions and applications

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of tetracyclic compounds, pharmaceutical compositions containing the compounds and their application in the field of medicine.

Background technique

Since the discovery in late 1982 of the RAS family GTPases (which include members KRAS, NRAS, and HRAS) associated with cancer, the incidence in human cancers is as high as 20% to 30%. RAS proteins act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state. Activated by the guanine nucleotide exchange factor (GEF), RAS in its GTP-bound state interacts with a number of effectors. The return to an inactive state is driven by GTPase activating proteins (GAPs), which downregulate active RAS by accelerating weak intrinsic GTPase activity by up to 5 orders of magnitude.

Whether mutant RAS proteins require GEF activity for full activation remains to be well studied and may vary with specific mutations. The most studied protein of RAS sevenless son (SOS), two human isoforms, SOS1 and SOS2, are known. Attempted to recognize RAS-SOS interactions of hydrocarbon-bound peptides by inhibiting peptide mimicry with nanomolar affinity orthotopic SOS helices, but with only low cellular activity. Fragment-based screening, rationally designed, and high-throughput screening methods led to the identification of small-molecule-addressed KRAS-SOS1 interactions, resulting in moderate micromolar affinities.

The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multi-domain protein with two tandem N-terminal histone domains (HD) followed by Dbl homology domain (DH), Pleckstrin ) homeodomain (PH), helical linker (HL), RAS exchange motif (REM), CDC25 homeodomain and C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins; a catalytic site, which binds GDP-bound RAS family proteins to facilitate guanine nucleotide exchange; and an allosteric site, which binds GTP-bound RAS family protein, which leads to a further increase in the catalytic GEF function of SOS1. Published data suggest that SOS1 is critically involved in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168). Depleting SOS1 levels reduced the proliferation rate and survival of KRAS-mutated tumor cells, whereas no effect was observed in KRAS wild-type cell lines. The effects of SOS1 loss could not be compensated by introducing catalytic site-mutated SOS1, demonstrating the important role of SOS1GEF activity in KRAS-mutant cancer cells.

SOS1 is critically involved in the activation of RAS family protein signaling in cancer through mechanisms other than RAS family protein mutation. SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1/Grb2 complex binds to activated/phosphorylated receptor tyrosine kinases (eg, EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/ 3. IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56 ). SOS1 is also recruited to other phosphorylated cell surface receptors, such as T cell receptor (TCR), B cell receptor (BCR), and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75). This localization of SOS1 to the plasma membrane proximal to RAS family proteins enables SOS1 to promote RAS family protein activation. SOS1 activation by RAS family proteins can also be mediated through the interaction of SOS1/Grb2 with the BCR-ABL oncoprotein commonly found in chronic myeloid leukemia.

SOS1 is also a GEF for activating the GTPases RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1):125-36). Like RAS family proteins, RAC1 has been implicated in the pathogenesis of various human cancers and other diseases (Bid et al., Mol. Cancer Ther. 2013, 12(10):1925-34).

Herein, we describe novel SOS1 inhibitor compounds that bind to the SOS1 catalytic site and simultaneously prevent interaction with and activation of RAS family proteins. This resulted in a marked inhibition of the interaction of SOS1 with RAS family proteins, especially KRAS (with low single-digit nanomolar IC50 activity), and thus markedly reduced ERK phosphorylation in KRAS mutant cancer cell lines.

The selective SOS1 inhibitor compounds described herein are expected to provide pharmacological benefit to patients with cancers associated with a dependency on RAS family protein signaling. Such cancers expected to be targeted by SOS1 inhibitor compounds include those that exhibit alterations (mutations, gene amplification, overexpression) in components (proteins, genes) in the RAS family protein pathway, such as KRAS , NRAS, HRAS, receptor tyrosine kinases (eg, EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL), GAP (eg, NF1) and SOS1. Additionally, given the role of SOS1 in RAC1 activation, cancers that exhibit RAC1 dependence are expected to be targeted by SOS1 inhibitor compounds. Furthermore, SOS1 inhibitors are expected in other diseases associated with dysregulation of RAS family protein pathways such as neurofibromatosis, Noonan syndrome (NS), cardiofacial skin syndrome (CFC) and hereditary gingival fibromatosis type 1 Compounds will also provide pharmacological benefits.

In addition to inhibition and potency, the compounds disclosed herein show good solubility, excellent DMPK properties, and good selectivity for the kinases of the human kinome.

SUMMARY OF THE INVENTION

Invention to solve problem

The present invention aims to provide a class of tetracyclic compounds with novel structures used as SOS1 inhibitors, which exhibit good inhibitory activity on tumor cells, have good druggability, and have broad prospects for drug development.

solution to the problem

In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein

in,

A is selected from C ₆ -C ₁₀ aryl, 5- to 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, and wherein each of the aryl, monocyclic and bicyclic heteroaryl groups optionally substituted with m independent R ₄ , wherein m is independently any integer from 0 to 5;

X and Y are each independently selected from _CR or N;

Z ₁ and Z ₂ are each independently selected from -O-, -CR ₇ - or -NR ₇ -;

L ₁ , L ₂ and L ₃ are each independently selected from -(CH ₂ ) _n - or -(CH ₂ ) _n -O-(CH ₂ ) _p -O-(CH ₂ ) _o - or -O-( CH ₂ ) _q -, wherein each of n, o, p and q is independently any integer from 0 to 3;

R ₁ and R ₂ are each independently selected from hydrogen and C ₁ -C ₈ alkyl; or R ₁ and R ₂ together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl, said alkyl and cycloalkane Each group is optionally substituted by at least 1 R ₈ , and R ₁ or R ₂ and A ring form a 4-8 membered saturated carbocyclic or heterocyclic ring;

R ₃ is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R ₇ ), -C(=O)-NH(R ₇ ), C ₁ -C ₆ alkyl, C ₂ -C ₄ alkenyl , C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 8 membered heterocycloalkyl, C ₁ -C ₃ alkoxy and C ₁ -C ₆ haloalkyl, and wherein said alkyl , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl are each optionally substituted with at least 1 R ₈ ;

R ₄ is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R ₇ ), -C(=O)-NH(R ₇ ), C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkane alkyl, 3- to 8-membered heterocycloalkyl, C ₁ -C ₃ alkoxy and C ₁ -C ₆ haloalkyl, each of the alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl being any optionally substituted with at least 1 R ₈ ;

R ₅ and R ₆ are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N(R ₇ )(R ₈ ), C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3 to 8-membered heterocycloalkyl, C1 _- C3alkoxy, and _C1 _- _C6 haloalkyl, or _R7 and _R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, and wherein The alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1 R ₁₀ ;

R ₇ is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -N(R ₈ )(R ₉ ), -C(=O)-N(R ₈ )(R ₉ ), -C(= O)-R ₈ , -C(=O)-OR ₈ , -S(=O) ₂ -R ₈ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3- to 8-membered heterocycle Alkyl, 5-10-membered aryl or heteroaryl, _C1 _- C3 alkoxy or _C1 - _C6 haloalkyl, or _R8 and _R9 together with the nitrogen atom to which they are attached form a 5- to 6-membered heteroalkyl group cycloalkyl, and wherein said alkyl, cycloalkyl, heterocycloalkyl, alkoxy, and haloalkyl are each optionally substituted with at least ₁ R;

Each of R ₈ and R ₉ is independently selected from hydrogen, halogen, cyano, hydroxy, amino, carbamoyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₈ ring Alkyl, 3- to 14-membered heterocycloalkyl, _C1 _- C3alkoxy, _C1 _- _C3haloalkoxy , _C6 -C10aryl, 5- to 6-membered monocyclic heteroaryl or 9- to 10 membered bicyclic heteroaryl, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl and bicyclic heteroaryl each is optionally substituted with at least 1 R ₁₀ ;

The heteroatoms or heteroatomic groups contained in the heteroalkyl groups, heterocycloalkyl groups, heterocycloalkoxy groups, and heteroaryl groups described in R ₁ to R ₉ are each independently selected from -C(=O)N(R ₁₀ )-, -N(R ₁₀ )-, -NH-, -N=, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S) -, -S(=O)-, -S(=O) ₂ - and -N(R ₁₀ )C(=O)N(R ₁₀ )-, the number of said heteroatoms or heteroatoms is independently selected from 1, 2 and 3;

Each R ₁₀ is independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethyl oxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.

Preferably, it is a compound represented by any one of formulae I-1, I-2, I-3, I-4, I-5 or I-6,

More preferably, it is a compound represented by any one of formula I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1,

More preferably, the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I - A specific compound shown in 3-1, I-4-1, I-5-1 or I-6-1, which is:

In the second aspect, the present invention provides a pharmaceutical composition, which comprises formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1 , I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1 The compound or its pharmaceutically acceptable salt, hydrate, solvate, stereo One or more of an isomer, tautomer, metabolite or prodrug.

Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.

In the third aspect, the present invention provides formulas such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I- - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof The use of a body, metabolite or prodrug or a pharmaceutical composition comprising the same in the manufacture of a medicament for the prevention and/or treatment of diseases caused by overexpression of SOS1.

In the fourth aspect, the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I- - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof The use of a body, a metabolite or a prodrug or a pharmaceutical composition comprising the same in the preparation of a SOS1 inhibitor medicament.

The fifth aspect, the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof Use of a medicament, metabolite or prodrug, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer.

Preferably, the cancer is any one or more of pancreatic cancer, colorectal cancer and lung cancer.

In a sixth aspect, the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of SOS1, comprising preventing and/or treating an effective amount of such as formula I, formula I-1, I -2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I - The compound shown in 6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition comprising the same is administered to individuals in need.

In a seventh aspect, the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of SOS1, comprising adding a preventive and/or therapeutically effective amount of 94 compounds such as compound 1 to compound 94 in total or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, to be administered to an individual in need thereof.

effect of invention

The present invention provides a series of tetracyclic compounds with novel structures. It is proved by relevant enzyme and cell activity tests that the compounds of the present invention have excellent cell proliferation inhibitory activity. In vitro experiments, the IC ₅₀ value of cell proliferation reaches nM It can be applied well in a variety of tumors. At the same time, the compounds of the present invention have very good inhibitory effect on KRAS:SOS1 activation, which can reach nM level, and are suitable for being prepared as SOS1 inhibitors for preventing and/or treating diseases or conditions related to SOS1 activation, such as cancer ( including but not limited to pancreatic cancer, colorectal cancer and lung cancer).

Detailed ways

General terms and definitions

Unless stated to the contrary, terms used in the present invention have the following meanings.

"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, for example, may be 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms carbon atoms, straight and branched chain groups of 1 to 6 carbon atoms or 1 to 4 carbon atoms. In the present invention, "alkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl and various branched chain isomers, etc. Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, ethylene, propylene, propylene, butylene, butylene, and various branched chain isomers thereof. In addition, in the present invention, "alkyl" may be optionally substituted or unsubstituted.

"Alkoxy" refers to a "-O-alkyl" group, wherein "alkyl" is as defined above.

"Alkenyl" refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 1 to 20 carbon atoms and at least 1 carbon-carbon double bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkenyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, vinyl (-CH=CH ₂ ), propen-1-yl (-CH=CH-CH ₃ ), propen-2-yl (-C(CH ₃ )=CH ₂ ), Buten-1-yl (-CH=CH-CH ₂ -CH ₃ ), buten-2-yl (-C(C ₂ H ₅ )=CH ₂ ), 1-methylpropen-1-yl (- C(CH ₃ )=CH-CH ₃ ) and various branched chain isomers thereof. Non-limiting examples also include, but are not limited to, 1,1-ethenylene (=C=CH ₂ ), 1,2-ethenylene (-CH=CH-), 1,1-propenylene (=C= CH-CH ₃ ), 1,2-propenylene (-CH=C(CH ₃ )-), 1,3-propenylene (-CH=CH-CH ₂ -) and various branched isomers thereof body. In addition, in the present invention, "alkenyl" may be optionally substituted or unsubstituted.

"Alkynyl" refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 1 to 20 carbon atoms and at least 1 carbon-carbon triple bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkynyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡C- _CH3 ), butynyl

pentynyl

and various branched chain isomers. Non-limiting examples also include, but are not limited to, ethynylene (-C≡C-), propynylene

butynylene

and its various branched-chain isomers. In addition, in the present invention, "alkynyl" may be optionally substituted or unsubstituted.

"Heteroalkyl" means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 2 to 20 atoms, for example, may be 2 to 18 atoms, 2 to 12 atoms, 2 to 8 atoms, Linear and branched groups of 2 to 6 atoms or 2 to 4 atoms, wherein one or more atoms is a hetero group selected from nitrogen, oxygen or S(O) _m (wherein m is 0, 1 or 2) atoms, and the rest are carbon. In the present invention, "heteroalkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-azapropyl), and various Branched chain isomers, etc. In addition, in the present invention, "heteroalkyl" may be optionally substituted or unsubstituted.

"Cycloalkyl" means a saturated or partially unsaturated, monocyclic or polycyclic, aliphatic hydrocarbon group comprising 3 to 12 ring atoms, eg, 3 to 12, 3 to 10, or 3 to 6 Ring atoms (ie, 3 to 6 membered rings). Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclopentyl Heptatrienyl, cyclooctyl, etc. In the present invention, "cycloalkyl" may be optionally substituted or unsubstituted.

"Heterocycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 20 ring atoms, for example, may be 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is 0, 1 or 2) and the remaining ring atoms are carbon. Preferred heterocycloalkyl groups comprise 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 10 ring atoms, and most preferably 5 or 6 ring atoms, of which 1 to 4, Preferably 1 to 3, more preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyl groups include, but are not limited to, spirocyclic or bridged ring heterocycloalkyl groups.

"Halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

"Haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more identical or different halogen atoms. Examples of preferred alkyl or alkoxy groups include, but are not limited to: tris Fluoromethyl, trifluoroethyl, trifluoromethoxy.

"Cyano" refers to the "-CN" group.

"Hydroxy" refers to the "-OH" group.

"Amino" refers to the " _-NH2 " group.

"Carbamoyl" refers to a "-(C=O) _-NH2 " group.

"Aryl" means monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms A loop with one or more points of attachment to the rest of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6-10 or 6-7 ring atoms.

"Heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more selected from nitrogen, oxygen , Sulfur heteroatoms, where each ring system contains a ring of 5-7 atoms with one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl, quinolinyl. Preferably, the heteroaryl group is a ring system of 5-10 ring atoms.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not be, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted with a corresponding number of substituents.

"Pharmaceutically acceptable salts" refers to salts prepared from compounds of the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups (such as carboxyl or sulfonic acid groups), base addition salts can be obtained by contacting their free forms with a sufficient amount of base in neat solution or in a suitable inert solvent . Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts. When the compounds of the present invention contain relatively basic functional groups such as amino or guanidino groups, acid addition salts can be obtained by contacting their free forms with a sufficient amount of acid in neat solution or in a suitable inert solvent . Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (eg, hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate) , monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (such as acetate, propionate, isobutyrate, malonate, succinate , Suberate, Maleate, Fumarate, Citrate, Tartrate, Lactate, Mandelate, Benzoate, Phthalate, Mesylate, Benzene Sulfonate acid salts, p-toluenesulfonic acid salts, glucuronic acid, etc.) and amino acid salts (eg, arginine salts, etc.). See also Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66: 1-19) for specific forms of pharmaceutically acceptable salts. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of a compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents. According to embodiments of the present invention, preferably the pharmaceutically acceptable salt of the compound represented by formula I is an acid addition salt, preferably hydrochloride, hydrobromide, phosphate or sulfate, more preferably hydrochloride.

"Pharmaceutical composition" refers to a pharmaceutically acceptable composition comprising one or more compounds of Formula I or a pharmaceutically acceptable form thereof (eg, a salt, hydrate, solvate, stereoisomer isomers, tautomers, metabolites, prodrugs, etc.), and other components (eg, pharmaceutically acceptable excipients).

In the present invention, "pharmaceutically acceptable auxiliary materials" refer to auxiliary materials widely used in the field of pharmaceutical production. The main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in properties and/or has specific functionality, and also to provide a method so that after the drug is administered to a subject, the active ingredient can be The rate of dissolution, or the promotion of effective absorption of the active ingredient in the subject to which it is administered. Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (eg, stabilizing the overall pH of the composition or preventing the degradation of active ingredients in the composition). Non-limiting examples of pharmaceutically acceptable adjuvants include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, sizing agents, disintegrating agents, lubricants, anti-adhering agents , glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, sweeteners, etc.

The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping and/or lyophilizing processes.

In the present invention, the purpose of using the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient, and then exert biological activity. The pharmaceutical compositions of the present invention can be administered in any form, including injection (intraarterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid, oral liquid), rectal, inhalation, implant , topical (eg ocular) administration, etc. Non-limiting examples of oral solid formulations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like. Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like. Non-limiting examples of formulations for topical administration include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Non-limiting examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like. The pharmaceutical compositions of the present invention can also be formulated in controlled release or delayed release dosage forms (eg, liposomes or microspheres).

Preferably, a compound of the present invention or a pharmaceutical composition comprising the same is administered orally or intravenously to an individual in need thereof. Depending on the particular circumstances of the subject being administered, other modes of administration may also be employed or even preferred. For example, for patients who are forgetful or irritable with oral medications, transdermal administration would be a very important mode of administration. In the present invention, the administration channel can be varied or adjusted in any suitable manner to meet the needs of the nature of the drug, the convenience of the patient and medical staff, and other relevant factors.

The compounds of the present invention or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs or pharmaceutical compositions containing them have excellent SOS1 enzyme activity and cellular The proliferation inhibitory activity can be used as an SOS1 inhibitor for preventing and/or treating diseases or conditions caused by overexpression of SOS1, and has good clinical and medical applications. Preferably, a non-limiting example of a disease or disorder caused by overexpression of SOS1 is cancer, including but not limited to pancreatic cancer, colorectal cancer and lung cancer.

The technical solutions of the present invention will be described below with reference to specific embodiments. The following embodiments are provided to further illustrate the present invention, but not to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the invention.

The preparation of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention. The known starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means (for example, purchased from Shaoyuan Chemical Technology, Beijing Coupling Technology, etc.). Unless otherwise specified, the reactions were carried out in an argon atmosphere or a nitrogen atmosphere. The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times. The reaction temperature is room temperature, and the temperature range is 20°C-30°C. Monitoring the progress of the reaction can be accomplished by synthetic methods well known to those skilled in the art, including but not limited to thin layer chromatography (TLC). The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The developing solvent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent can be determined according to the polarity of the compound. adjust.

The separation and purification of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC) Wait. Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier, and the eluent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent can be based on the compound. The polarity can be adjusted, and a small amount of acidic or basic anti-tailing reagents can also be added for adjustment. The HPLC chromatogram was determined by Agilent1200DAD HPLC chromatograph (chromatographic column: Sunfire C18, 150×4.6mm, 5μm) or Waters 2695-2996 HPLC chromatograph (chromatographic column: Gimini C18, 150×4.6mm, 5μm).

Structural identification of the compounds of the present invention can be accomplished by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), and the like. The NMR spectrum was determined by Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDC1 ₃ ) or deuterated methanol (CD ₃ OD), The internal standard is tetramethylsilane (TMS), and the chemical shifts are in ^10-6 (ppm). MS spectra were determined using an Agilent SQD (ESI) mass spectrometer (model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (model: 2020).

Preparation of intermediates

Preparation of intermediate INT-1

Step 1: Synthesis of compound INT-1B

Compound INT-1A (25 g, 107 mmol) was dissolved in THF (250 mL), tert-butylsulfinamide (19.5 g, 161 mmol) was added at room temperature, followed by tetraethyl titanate (61 g, 267.5 mmol). After the addition, the temperature of the reaction solution was raised to 70°C, and the reaction was carried out for 4h. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was slowly added to ice water, and the aqueous phase was extracted with ethyl acetate (3×150 mL). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 (volume ratio)) , to obtain compound INT-1B (27.7 g, pale yellow solid, yield 77%).

MS(ESI): m/z 337[M+1] ⁺ .

Step 2: Synthesis of compound INT-1C

Compound INT-1B (27 g, 80 mmol) was dissolved in a mixed solvent of methanol (200 mL) and water (100 mL), cooled to -20 °C, then sodium borohydride (6 g, 160 mmol) was added in batches, and the reaction was maintained at -20 °C After 1 h, the temperature was naturally raised to room temperature, and the reaction was continued for 3 h at room temperature. After TLC showed that the reaction was complete, methanol was evaporated under reduced pressure, and the aqueous phase was extracted with ethyl acetate (3 x 150 mL). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 (volume ratio)) , to obtain compound INT-1C (22 g, pale yellow solid, yield 82%).

MS(ESI): m/z 339[M+1] ⁺ .

Step 3: Synthesis of compound INT-1

Compound INT-1C (20 g, 59 mmol) was added to 4N HCl-ethyl acetate solution (200 mL), and the reaction was carried out at room temperature for 2 h. TLC showed that after the completion of the reaction, a solid was precipitated, which was filtered, and the solid was washed with ethyl acetate and dried to obtain the hydrochloride salt of compound INT-1 (12.3 g, pale yellow solid, yield 89%). The product did not need to be purified and was directly used in the subsequent reaction.

MS(ESI): m/z 235[M+1] ⁺ .

Preparation of intermediate INT-2

The synthesis of intermediate INT-2 refers to the synthesis steps for the preparation of intermediate INT-1, wherein in the first step, S-tert-butylsulfinamide is used instead of tert-butylsulfinamide to synthesize compound intermediate INT-2.

MS(ESI): m/z 235[M+1] ⁺ .

Preparation and functional verification of target compounds

Example 1: Preparation of Compound 1

The synthetic route of compound 1 is:

The specific preparation method of compound 1 includes:

Step 1: Synthesis of Compound 1C

Compound 1A (4 g, 18.4 mmol) and DIPEA (4.8 g, 36.8 mmol) were dissolved in DMF (40 mL), and compound 1B 1-Boc-3-hydroxymethylpiperazine (4 g, 18.4 mmol) was added under ice bath, The reaction solution was then reacted at 80 degrees for 1 hour. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1 (volume ratio)) to obtain compound 1C (5.4 g, yellow oil, 71% yield).

MS(ESI): m/z 414[M+1] ⁺ .

Step 2: Synthesis of Compound 1D

Compound 1C (4.4 g, 10.6 mmol) was dissolved in DMF (40 mL), NaH (0.43 g, 12.7 mmol) was added under ice bath, and the temperature was raised to 30° C. to react for 1 h. After TLC showed that the reaction was completed, pour into ice water to quench, extract with ethyl acetate, wash with brine, dry the organic phase with anhydrous sodium sulfate, and spin dry to obtain compound 1D (4 g, yellow oil, yield 95%).

MS(ESI): m/z 394[M+1] ⁺ .

Step 3: Synthesis of Compound 1E

Compound 1D (1 g, 2.5 mmol) was added to EA (10 mL), 8% HCl-EA (10 mL) was added dropwise under ice bath, and the reaction was carried out at room temperature for 12 h. After TLC showed that the reaction was completed, the reaction solution was spin-dried to obtain compound 1E (0.7 g, yellow solid, yield 94%).

MS(ESI): m/z 294[M+1] ⁺ .

Step 4: Synthesis of Compound 1F

Compound 1E (700 mg, 2.4 mmol) was added to DCM (8 mL), then TEA (735 mg, 7.2 mmol) and Ac2O (290 mg, 2.9 mmol) were added, and the reaction solution was reacted at room temperature for 20 mins. After TLC showed that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:1 (volume ratio)) to obtain compound 1F (750 mg, pale yellow) solid, 93% yield).

MS(ESI): m/z 336[M+1] ⁺ .

Step 5: Synthesis of Compound 1G

At room temperature, compound 1F (750 mg, 2.2 mmol) was added to methanol (8 mL), and then 10% palladium on carbon (100 mg) was added. After the addition, the bottle mouth was covered with a hydrogen balloon, and after the gas was replaced three times, the reaction was maintained at room temperature for 12 hours in a hydrogen atmosphere. TLC showed that the reaction was completed, filtered, the solid was washed with methanol, the filtrate was collected, and the solvent was evaporated under reduced pressure to obtain compound 1G (600 mg, gray solid, yield 88%).

MS(ESI): m/z 306[M+1] ⁺ .

Step 6: Synthesis of Compound 1H

Compound 1G (500 mg, 1.6 mmol) was added to a stuffy tank containing acetonitrile (5 mL) at room temperature, and then 8% HCl-EA (5 mL) was added. Then heated to 100 degrees and reacted for 16h. After TLC showed that the reaction was complete, it was filtered, the solid was washed with EA, and the solid was collected to give compound 1H (500 mg, grey solid, 98% yield).

MS(ESI): m/z 273[M+1] ⁺ .

Step 7: Synthesis of Compound 1I

Compound 1H (550 mg, 2.2 mmol) was added to DCM (6 mL) at room temperature, then TEA (400 mg, 6.6 mmol) and Ac2O (150 mg, 2.6 mmol) were added, and the reaction solution was reacted at room temperature for 12 h. After TLC showed that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:2 (volume ratio)) to obtain compound 1I (400 mg, pale yellow solid) , the yield is 63%).

MS(ESI): m/z 315[M+1] ⁺ .

Step 8: Synthesis of Compound 1J

Compound II (100 mg, 0.3 mmol) was added to DMF (2 mL) at room temperature, followed by INT-1 (120 mg, 0.34 mmol) and DBU (150 mg, 0.9 mmol). Then heated to 60 degrees and reacted for 16h. After TLC showed that the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted with water, washed with brine, the organic phase was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=0: 1 (volume ratio)) to obtain compound 1J (40 mg, pale yellow solid, 34% yield).

MS(ESI): m/z 531[M+1] ⁺ .

Step 9: Synthesis of Compound 1

Compound 1J (40 mg, 0.07 mmol) was added to EtOH (6 mL) and water (1 mL) at room temperature, followed by iron powder (25 mg, 2.8 mmol) and ammonium chloride (30 mg, 5.6 mmol). Then heated to 80 degrees and reacted for 2h. After TLC showed that the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted with water, washed with brine, the organic phase was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=0: 1 (volume ratio)), reverse phase HPLC preparation (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile run for 1 min, 52%-52% acetonitrile run To 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 1 (7mg, pale yellow solid, yield 19%).

MS(ESI): m/z 501[M+1] ⁺ .

¹ H-NMR(400MHz,DMSO)δ(ppm)7.96(d,J=8Hz,1H),6.85-6.84(m,1H),6.69(s,1H),5.55(d,J=8Hz,2H) ,4.46-4.42(m,2H)4.06-3.97(m,3H),3.19-3.03(m,2H),2.94-2.74(m,2H),2.68-2.61(m,1H),2.33(s,3H ), 2.09 (d, J=8Hz, 3H), 1.54 (d, J=8Hz, 3H).

Example 2: Preparation of Compound 2

The synthesis of compound 2 refers to the synthesis procedure of compound 1 in example 1, wherein compound 1B is replaced by (R)-1-Boc-3-hydroxymethylpiperazine, and (1R)-1-[3-nitro-5 -(trifluoromethyl)phenyl]ethylamine was substituted for compound INT-1, and compound 2 was synthesized.

MS(ESI): m/z 501[M+1] ⁺ .

Example 3: Preparation of Compound 3

The synthesis of compound 3 refers to the synthesis procedure of compound 1 in Example 1, wherein compound 1B is replaced by (S)-1-Boc-3-hydroxymethylpiperazine, and (1R)-1-[3-nitro-5 -(trifluoromethyl)phenyl]ethanamine was substituted for compound INT-1, and compound 3 was synthesized.

MS(ESI): m/z 501[M+1] ⁺ .

Example 4: Preparation of Compound 4

The synthesis of compound 4 refers to the synthesis steps of compound 1 in Example 1, wherein in the first step, (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B, and in the eighth step, (R)-2-( 3-(1-Aminoethyl)-2-fluorophenyl)-2,2-difluoroethane-1-ol was used to replace compound INT-1, and compound 4 was synthesized.

MS(ESI): m/z 515[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ (ppm) 8.15 (s, 1H), 8.03 (d, J=6.7Hz, 1H), 7.62 (dd, J=13.7, 5.8Hz, 2H), 7.40 (t, J =7.2Hz,1H),7.23(dd,J=20.2,12.5Hz,1H),6.84(d,J=3.1Hz,1H),5.83-5.82(m,1H),5.78(brs,1H),4.50 –4.46(m, 2H), 4.08 – 3.95(m, 3H), 3.36(s, 1H), 3.20(s, 1H), 3.12 – 3.00(m, 1H), 2.89 – 2.85(m, 2H), 2.75 –2.62(m,1H),2.27(d,J＝1.8Hz,3H),2.09(d,J＝11.4Hz,3H),1.59(d,J＝6.9Hz,3H).

Example 5: Preparation of Compound 5

The synthesis of compound 5 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and (R)-1-(3 -(1-Aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol was substituted for compound INT-1, and compound 5 was synthesized.

MS(ESI): m/z 544[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO) δ (ppm) 8.10 (d, J=34.7 Hz, 1H), 7.77-7.73 (m, 1H), 7.37-7.33 (m, 1H), 7.26-7.04 (m, 1H) ,7.05(d,J＝8.0Hz,1H),5.97-5.91(m,1H),5.35(s,1H),4.56-4.52(m,2H),4.22(dd,J＝28.7,12.1Hz,1H ), 4.14–3.95 (m, 2H), 3.62–3.58 (m, 1H), 3.20–3.04 (m, 2H), 3.01–2.64 (m, 2H), 2.45 (d, J=7.5Hz, 3H), 2.08(s, 3H), 1.68(dd, J=6.7, 4.0Hz, 3H), 1.23–1.19(m, 6H)

Example 6: Preparation of Compound 6

The synthesis of compound 6 refers to the synthesis steps of compound 1 in Example 1, wherein the first step uses (R)-1-Boc-3-hydroxymethylpiperazine to replace compound 1B, and the eighth step uses (R)-1-( 3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 6 was synthesized.

MS(ESI): m/z 486[M+1] ⁺ .

1H NMR(400MHz,DMSO)δ(ppm)8.03(d,J=4.0Hz,1H),7.70-7.59(m,2H),7.49(t,J=6.9Hz,1H),7.29(t,J= 7.7Hz, 1H), 7.23 (t, J=56.0Hz, 1H), 6.84 (d, J=3.2Hz, 1H), 5.83-5.78 (m, 1H), 4.62–4.37 (m, 2H), 4.06– 3.98 (m, 3H), 3.23–3.02 (m, 1H), 2.95–2.85 (m, 1H), 2.68 (dd, J=10.0, 2.3Hz, 1H), 2.50–2.35 (m, 1H), 2.26 ( d, J=1.4Hz, 3H), 2.10 (d, J=11.3Hz, 3H), 1.60 (d, J=6.8Hz, 3H).

Example 7: Preparation of Compound 7

The synthesis of compound 7 refers to the synthesis steps of compound 1 in Example 1, wherein in the first step, (S)-1-Boc-3-hydroxymethylpiperazine is used instead of compound 1B, and in the eighth step, (R)-1-( 3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 7 was synthesized.

MS(ESI): m/z 486[M+1] ⁺ .

¹ H NMR(300MHz,DMSO)δ(ppm)8.00(d,J=7.4Hz,1H),7.65-7.61(m,2H),7.48(t,J=6.9Hz,1H),7.27(t,J =7.7Hz,1H),7.23(t,J=54.0Hz,1H),6.84(d,J=2.0Hz,1H),5.83-5.79(m,1H),4.59-4.43(m,2H),4.09 –3.96(m, 3H), 3.31-3.20(m, 1H), 2.90–2.86(m, 1H), 2.71-2.67(m, 1H), 2.48–2.35(m, 1H), 2.26(s, 3H), 2.10(d,J=8.5Hz,3H),1.60(d,J=7.1Hz,3H).

Example 8: Preparation of Compound 8

The synthesis of compound 8 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and cyclopropylcarbonyl chloride is used to replace ethyl acetate in the fourth step. Acid chloride, in the eighth step, ((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 8 was synthesized.

MS(ESI): m/z 512[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.03(d,J=8.0Hz,1H),7.66-7.63(m,2H),7.49(t,J=6.8Hz,1H),7.28(t,J =7.7Hz,1H),7.23(t,J=56.0Hz,1H),6.84(s,1H),5.84-5.76(m,1H),4.58-4.40(m,3H),4.05(s,2H) , 3.06–2.72 (m, 4H), 2.26 (s, 3H), 1.60 (d, J=7.0Hz, 3H), 1.54–1.42 (m, 1H), 0.78–0.76 (m, 4H).

Example 9: Preparation of Compound 9

The synthesis of compound 9 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and p-toluenesulfonyl chloride is used to replace acetyl chloride in the fourth step. In the eighth step, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine is used to replace compound INT-1, and compound 9 is synthesized.

MS(ESI): m/z 598[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ (ppm) 8.38 (s, 1H), 7.70–7.66 (m, 4H), 7.52–7.47 (m, 3H), 7.30 (t, J=7.7Hz, 1H), 7.23 (t, J=52.0Hz, 1H), 6.84 (s, 1H), 5.83–5.75 (m, 1H), 4.42 (dd, J=10.9, 2.7Hz, 1H), 4.15 (d, J=12.4Hz, 1H), 4.01–3.98 (m, 1H), 3.88–3.72 (m, 2H), 2.98–2.92 (m, 2H), 2.44 (d, J=2.6Hz, 1H), 2.41 (s, 3H), 2.35 –2.31(m, 1H), 2.28(s, 3H), 1.60(d, J=7.0Hz, 3H).

Example 10: Preparation of Compound 10

synthetic route:

Preparation:

Step 1: Synthesis of Compound 10A

Synthesis of compound 10A (1.0 g, 3.2 mmol, synthetic reference Example 1 for the synthesis of intermediate 1I, replace 1B (1-Boc-3-hydroxymethylpiperazine) with (R)-1-Boc-3-hydroxymethylpiperazine Piperazine) was synthesized to obtain 10A), which was dissolved in DCE (10 mL), triphenylphosphine (1.68 g, 6.4 mmol) and carbon tetrachloride (1.48 g, 9.6 mmol) were added to the reaction solution, and then under nitrogen protection, the The reaction was heated to 70°C and stirred for 2h. After TLC showed that the reaction was over, the reaction solution was cooled to room temperature, added to saturated sodium bicarbonate solution (100 mL), then extracted with dichloromethane (25 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, then Spin to dryness, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/isopropanol=10:1) to obtain compound 10A (0.5 g, yellow oil, yield 47.2%).

MS(ESI): m/z 333[M+1] ⁺ .

Step 2: Synthesis of compound 10C

Compound 10A (0.5 g, 1.5 mmol) was dissolved in DMF (125 mL), INT-2 (401 mg, 1.71 mmol) was added, then DIEA (580 mg, 5.155 mmol) was added, and the reaction solution was heated to reflux at 80 °C Overnight, after TLC showed that the reaction was over, the reaction solution was added to saturated NaCl solution (50 mL), then extracted with ethyl acetate (25 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and the residue was Purification by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1) gave compound 10C (0.5 g, off-white solid, 62.5%).

MS(ESI): m/z 531[M+1] ⁺ .

Step 3: Synthesis of Compound 10D

Compound 10C (0.5 g, 0.94 mmol) was dissolved in ethanol (5 mL), and concentrated hydrochloric acid (1 mL) was added. After the addition, the reaction solution was heated to 80 °C and stirred for 16 h. After TLC showed that the reaction was completed, the reaction solution was spun dry to obtain compound 10D (0.5 g off-white solid, yield 100.0%).

MS(ESI): m/z 489[M+1] ⁺ .

Step 4: Synthesis of Compound 10F

Compound 10D (200 mg, 0.41 mmol) was dissolved in DCE (2 ml), 10E (118 mg, 1.64 mmol) was added, 3 drops of AcOH were added, and the reaction solution was stirred at room temperature for 1 h, and then NaBH ₃ CN ( 38.7 mg, 0.614 mmol) and then the reaction solution was stirred at room temperature for 1 h. After TLC showed that the reaction was over, ammonia water was added to adjust the pH to 8-9, then spin-dried, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain compound 10F (130 mg, yield 58.41%).

MS(ESI): m/z 545[M+1] ⁺ .

Step 5: Synthesis of Compound 10

Compound 10F (130 mg, 0.24 mmol) was dissolved in ethanol/water (2 mL/0.5 mL), ammonium chloride (103.2 mg, 1.91 mmol) was added, and iron powder (53.5 mg, 0.995 mmol) was added, and the reaction was The solution was heated to 80°C and refluxed for 1 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, prepared by reverse-phase HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: Acetonitrile, gradient: 10% acetonitrile run for 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to obtain compound 10 (80 mg, pale yellow solid, yield 65.0%) ).

MS(ESI): m/z 515[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)7.90(d,J=7.9Hz,1H),7.55(s,1H),6.86(d,J=9.5Hz,2H),6.82(s,1H), 6.70(s,1H),5.61-5.55(m,1H),5.54(s,2H),4.64-4.44(m,4H),4.34(dd,J=10.7,2.7Hz,1H),4.01-3.96( m, 2H), 3.54–3.42 (m, 1H), 3.18 (t, J=9.8Hz, 1H), 3.01–2.71 (m, 3H), 2.31 (s, 3H), 2.17–2.01 (m, 1H) ,1.67(t,J=10.6Hz,1H),1.53(d,J=7.0Hz,3H).

Example 11: Preparation of Compound 11

The synthesis of compound 11 refers to the synthesis steps of compound 10 in Example 10, wherein in the fourth step, paraformaldehyde is used instead of 10E to synthesize compound 11.

MS(ESI): m/z 473[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)7.90(d,J=7.8Hz,1H),7.54(s,1H),6.89-6.79(m,3H),6.69(s,1H),5.59-5.54 (m, 3H), 4.33 (dd, J=10.7, 2.8Hz, 1H), 4.01-3.93 (m, 2H), 3.16 (dd, J=13.3, 6.4Hz, 1H), 2.98 (d, J=11.2 Hz, 1H), 2.84–2.77 (m, 2H), 2.35–2.28 (m, 3H), 2.24 (d, J=8.8Hz, 3H), 2.16–2.14 (m, 1H), 1.71 (t, J= 10.7Hz, 1H), 1.52(d, J=12.0Hz, 3H).

Example 12: Preparation of Compound 12

The synthesis of compound 12 refers to the synthesis steps of compound 10 in Example 10, wherein in the fourth step, tetrahydropyranone is used instead of 10E, and compound 12 is synthesized.

MS(ESI): m/z 543[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ(ppm) 7.92(d, J=7.3Hz, 1H), 7.54(s, 1H), 6.92-6.77(m, 3H), 6.69(s, 1H), 5.59-5.54 (m, 3H), 4.35 (dd, J=10.6, 2.7Hz, 1H), 4.04-3.95 (m, 2H), 3.91 (dd, J=11.0, 2.9Hz, 2H), 3.33-3.25 (m, 2H) ), 3.15–3.04 (m, 2H), 3.01 (d, J=10.4Hz, 1H), 2.78–2.66 (m, 1H), 2.46 (d, J=11.3Hz, 1H), 2.37–2.34 (m, 1H), 2.31(s, 3H), 1.91(t, J=10.6Hz, 1H), 1.76-1.72(m 2H), 1.51(dd, J=18.0, 5.4Hz, 3H), 1.49-1.37(m, 2H).

Example 13: Preparation of Compound 13

synthetic route:

Preparation:

Compound 13A (181 mg, 0.41 mmol, synthetic reference Example 10 for the synthesis of intermediate 10D was synthesized with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine Instead of INT-2, 13A was synthesized and dissolved in DCE (2ml), then 30% to 35% aqueous formaldehyde solution (150mg, 1.64mmol) was added, and 3 drops of AcOH were added, and then the reaction solution was stirred at room temperature for 1h , and then add NaBH3CN (38.7 mg, 0.614 mmol) and then the reaction solution was stirred at room temperature for 1 h. After TLC showed that the reaction was over, ammonia water was added to adjust the pH to 8-9, then concentrated and spin-dried, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain compound 13 (130 mg, yield 58.41%).

MS(ESI): m/z 458[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)7.97(d,J=7.2Hz,1H),7.65(t,J=7.2Hz,1H),7.58(s,1H),7.48(t,J=6.8 Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=56.0Hz, 1H), 6.81(s, 1H), 5.79(m, 1H), 4.33(dd, J=10.7 ,2.7Hz,1H),4.01-3.96(m,2H),3.17(t,J=9.9Hz,1H),2.99(d,J=10.8Hz,1H),2.90–2.71(m,2H),2.26 (d, J=3.9Hz, 6H), 2.22–2.13 (m, 1H), 1.72 (t, J=10.7Hz, 1H), 1.59 (d, J=7.1Hz, 3H).

Example 14: Preparation of Compound 14

The synthesis of compound 14 refers to the synthesis procedure of compound 13 in Example 13, wherein 3-oxetanone is used instead of formaldehyde, and compound 14 is synthesized.

MS(ESI): m/z 500[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 7.98 (d, J=7.2Hz, 1H), 7.65 (t, J=7.7Hz, 1H), 7.59 (s, 1H), 7.49 (t, J= 7.0Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=56.0Hz, 1H), 6.82(s, 1H), 5.86–5.73(m, 1H), 4.60(dd, J=15.8, 6.5Hz, 2H), 4.55–4.47 (m, 2H), 4.34 (d, J=8.1Hz, 1H), 4.00 (dd, J=18.7, 9.1Hz, 2H), 3.55–3.44 (m ,1H),3.25-3.13(m,1H),2.96(d,J=10.1Hz,1H),2.87-2.83(m,2H),2.25(s,3H),2.17-2.08(m,1H), 1.69(t, J=10.8Hz, 1H), 1.59(d, J=7.0Hz, 3H).

Example 15: Preparation of Compound 15

The synthesis of compound 15 refers to the synthesis procedure of compound 13 in Example 13, wherein tetrahydropyranone is used instead of formaldehyde to synthesize compound 15.

MS(ESI): m/z 528[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 7.97 (d, J=7.3Hz, 1H), 7.65 (t, J=7.3Hz, 1H), 7.57 (s, 1H), 7.48 (t, J= 6.5Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.23(t, J=56.0Hz, 1H), 6.81(s, 1H), 5.87–5.73(m, 1H), 4.35(dd, J=10.6, 2.5Hz, 1H), 4.12–3.86 (m, 5H), 3.14 (dd, J=20.8, 7.8Hz, 4H), 3.01 (d, J=10.8Hz, 1H), 2.75 (t, J ＝10.3Hz, 1H), 2.39(t, J＝9.9Hz, 1H), 2.25(s, 3H), 1.92(t, J＝10.7Hz, 1H), 1.75(d, J＝11.5Hz, 2H), 1.59(d, J=7.0Hz, 3H), 1.45(s, 2H).

Example 16: Preparation of Compound 16

The synthesis of compound 16 refers to the synthesis steps of compound 13 in Example 13, wherein (S)-1-Boc-3-hydroxymethylpiperazine replaces (R)-1-Boc-3 used in the synthesis of intermediate 13A -Hydroxymethylpiperazine, compound 16 was synthesized.

MS(ESI): m/z 458[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 7.98 (d, J=7.4Hz, 1H), 7.63 (t, J=7.4Hz, 1H), 7.58 (s, 1H), 7.48 (t, J= 7.0Hz, 1H), 7.27(t, J=7.6Hz, 1H), 7.23(t, J=54.0Hz, 1H), 6.81(s, 1H), 5.87–5.71(m, 1H), 4.34(dd, J=10.7, 2.5Hz, 1H), 3.99-3.94(m, 2H), 3.17(t, J=9.7Hz, 1H), 3.00(d, J=11.0Hz, 1H), 2.86(d, J=10.3 Hz, 1H), 2.78(t, J＝10.3Hz, 1H), 2.26(s, 3H), 2.25(s, 3H), 2.18(t, J＝10.2Hz, 1H), 1.71(t, J＝10.8 Hz,1H),1.60(d,J＝7.0Hz,3H).

Example 17: Preparation of Compound 17

The synthesis of compound 17 refers to the synthesis procedure of compound 13 in Example 13, wherein acetone is used instead of formaldehyde, and compound 17 is synthesized.

MS(ESI): m/z 486[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 7.99 (d, J=7.3Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 7.57 (s, 1H), 7.49 (t, J= 6.8Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.81(s, 1H), 5.87-5.71(m, 1H), 4.35(dd, J=10.6, 2.7Hz, 1H), 4.04-3.91(m, 2H), 3.090(t, J=9.8Hz, 1H), 3.00(d, J=10.7Hz, 1H), 2.90(d, J=10.5 Hz, 1H), 2.80-2.69(m, 2H), 2.41-2.40(m, 1H), 2.25(s, 3H), 1.92(t, J=10.6Hz, 1H), 1.59(d, J=7.1Hz ,3H),1.03(t,J＝6.5Hz,6H).

Example 18: Preparation of Compound 18

synthetic route:

Preparation:

Compound 13A (181 mg, 0.41 mmol) was dissolved in acetonitrile (2 ml), potassium carbonate (113 mg, 0.82 mmol) was added at room temperature, compound 18A (108 mg, 0.82 mmol) was added, and the reaction solution was heated to 60 °C and stirred 2h. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, then spin-dried, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain compound 18 (116 mg, yield 52.4 %).

MS(ESI): m/z 540[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 8.54 (s, 2H), 8.04 (d, J=7.2Hz, 1H), 7.69-7.63 (m, 2H), 7.49 (t, J=6.9Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.85(s, 1H), 5.83-5.76(m, 1H), 4.70(dd, J=36.1 ,12.3Hz,2H),4.51(dd,J=10.8,2.7Hz,1H),4.21-4.01(m,2H),3.26-3.18(m,2H),2.90-2.85(m,1H),2.80- 2.70(m, 1H), 2.26(s, 3H), 1.60(d, J=7.1Hz, 3H).

Example 19: Preparation of Compound 19

Synthesis of compound 19 Referring to the synthesis procedure of compound 18 in Example 18, wherein 2-bromoethyl methyl ether was used instead of 18A, compound 19 was synthesized.

MS(ESI): m/z 502[M+1] ⁺ .

¹ H-NMR (400MHz, DMSO): δ(ppm) 7.99(d, J=4.0Hz, 1H), 7.65(dd, J=14.4, 7.1Hz, 1H), 7.58(s, 1H), 7.49(t , J=6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.82(s, 1H), 5.81-5.78(m, 1H), 4.35 (dd,J＝10.7,2.7Hz,1H),4.01-3.96(m,2H),3.51-3.49(m,2H),3.3(s,3H),3.13-3.09(m,2H),2.97(d , J=6.0Hz, 1H), 2.80-2.76(m, 1H), 2.59-2.49(m, 2H), 2.29-2.25(m, 1H), 2.24(s, 3H), 1.82(t, J=6.0 Hz,1H),1.59(d,J=7.1Hz,3H).

Example 20: Preparation of Compound 20

Preparation:

Step 1: Synthesis of Compound 20B

Compound 20A (500 mg, 4.23 mmol) was dissolved in DCM (5 mL) solution, then pyridine (762 mg, 8.46 mmol) and DMAP (52 mg, 0.423 mmol) were added, followed by p-toluenesulfonyl chloride (1.2 g, 6.34 mmol), After the addition, the mixture was stirred at room temperature for 2 hours. After TLC showed that the reaction was over, the reaction solution was added to saturated aqueous sodium bicarbonate solution (50 mL), the organic layer was separated, and the aqueous phase was extracted with DCM (25 mL×3), and the organic phases were combined. , dried over anhydrous sodium sulfate, spin-dried the solvent, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1 (volume ratio)) to obtain compound 20B (1.1 g, pale yellow solid) , yield 93.2%).

Step 2: Synthesis of Compound 20

Compound 13A (181 mg, 0.41 mmol) was dissolved in acetonitrile (2 ml), potassium carbonate (113 mg, 0.82 mmol) was added at room temperature, compound 20B (155 mg, 0.82 mmol) was added, and the reaction solution was heated to 60 °C and stirred 2h. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, then spin-dried, and the residue was purified by pre-TLC (developing solvent: ethyl acetate/methanol = 10:1) to obtain compound 20 (106 mg).

MS(ESI): m/z 544[M+1] ⁺ .

¹ H NMR (400 MHz, DMSO): δ (ppm) 8.26 (d, J=19.0 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.64 (s, 1H), 7.50 (t, J= 6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=54.0Hz, 1H), 6.84(s, 1H), 5.86-5.78(m, 1H), 5.75(s, 1H), 4.37-4.32(m, 1H), 3.99-3.96(m, 2H), 3.81-3.69(m, 4H), 3.67-3.55(m, 4H), 3.27-2.91(m, 4H), 2.44- 2.32(m, 2H), 2.29(s, 3H), 1.61(d, J=7.0Hz, 3H).

Example 21: Preparation of Compound 21

The synthesis of compound 21 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, trifluoromethyl ethanol is used instead of 20A, and compound 21 is synthesized.

MS(ESI): m/z 526[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 8.00 (d, J=7.2Hz, 1H), 7.65-7.49 (m, 1H), 7.60 (s, 1H), 7.49 (t, J=6.9Hz, 1H), 7.29(t, J＝7.7Hz, 1H), 7.23(t, J＝52.0Hz, 1H), 6.82(s, 1H), 5.83-5.76(m, J＝7.0Hz, 1H), 4.35( dd,J＝10.7,2.7Hz,1H),3.98(dd,J＝12.5,7.0Hz,2H),3.31-3.10(m,5H),3.02(d,J＝10.6Hz,1H),2.84(dd , J=12.0, 9.2Hz, 1H), 2.67(t, J=10.5Hz, 1H), 2.26-2.20(m, 3H), 1.59(d, J=7.1Hz, 3H).

Example 22: Preparation of Compound 22

The synthesis of compound 22 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, oxetane-3-methanol is used to replace 20A, and compound 22 is synthesized.

MS(ESI): m/z 514[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 8.03 (d, J=7.3Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.60 (s, 1H), 7.48 (t, J= 6.8Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.81(s, 1H), 5.84-5.76(m, 1H), 4.69-4.65( m, 2H), 4.37-4.26(m, 3H), 4.05-3.96(m, 2H), 3.26-3.25(m, 1H), 3.18-3.06(m, 1H), 2.97(d, J=10.9Hz, 1H), 2.84(d, J＝10.2Hz, 1H), 2.79-2.64(m, 3H), 2.25(s, 3H), 2.21(d, J＝11.6Hz, 1H), 1.75(t, J＝10.6 Hz,1H),1.59(d,J=7.1Hz,3H).

Example 23: Preparation of Compound 23

The synthesis of compound 23 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, 3-tetrahydrofuran methanol replaces 20A, and compound 23 is synthesized.

MS(ESI): m/z 528[M+1] ⁺ .

¹ H-NMR (400MHz, DMSO): δ(ppm) 8.10(d, J=5.3Hz, 1H), 7.66(t, J=7.2Hz, 1H), 7.60(s, 1H), 7.49(t, J ＝6.9Hz,1H),7.28(dd,J＝16.5,8.9Hz,1H),7.23(t,J＝52.0Hz,1H),6.82(s,1H),5.85-5.77(m,1H),4.35 (dd,J=10.6,2.7Hz,1H),4.05-3.95(m,2H),3.81-3.69(m,2H),3.63(dd,J=15.4,7.5Hz,1H),3.43-3.40(m ,2H),3.13(d,J＝10.3Hz,1H),3.09-2.92(m,2H),2.83-2.74(m,1H),2.37-2.32(m,2H),2.26(s,3H), 2.23-2.18(m, 1H), 2.03-1.90(m, 1H), 1.77-1.70(m, 1H), 1.60(d, J=7.1Hz, 3H), 1.56-1.52(m, 1H).

Example 24: Preparation of Compound 24

The synthesis of compound 24 refers to the synthesis steps of compound 20 in Example 20, wherein in the second step, bromoacetonitrile replaces 20B, and compound 24 is synthesized.

MS(ESI): m/z 483[M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.51-7.46 (m, 2H), 7.26 (s, 1H), 7.18 (t, J=7.7Hz, 1H), 7.10 (s, 1H), 6.92 (t, J＝56.0Hz, 1H), 6.85(s, 1H), 5.85-5.66(m, 1H), 4.29(dd, J＝10.7, 2.7Hz, 1H), 4.12(t, J＝9.9Hz, 1H), 3.89(d, J=10.0Hz, 1H), 3.63(s, 2H), 3.32(dd, J=13.3, 6.4Hz, 1H), 3.00-2.97(m, 2H), 2.83-2.65(m , 2H), 2.49(s, 3H), 2.28(t, J=10.6Hz, 1H), 1.71(d, J=6.7Hz, 3H).

Example 25: Preparation of Compound 25

synthetic route:

Preparation:

Step 1: Synthesis of compound 25C

Compound 25A (12.5 g, 57.57 mmol) was dissolved in DMF (125 ml), 25B (7.42 g, 63.33 mmol) was added, DIEA (23.4 g, 181.4 mmol) was added dropwise, and the reaction solution was heated to 80 °C °C stirred for 16h. After TLC showed that the reaction was over, the reaction solution was poured into ethyl acetate (200ml) and saturated NaCl solution (500ml), the organic layer was separated, the aqueous phase was extracted with ethyl acetate (150ml×3), the organic phases were combined, and the Dry over anhydrous sodium sulfate, then spin dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain compound 25C (15.6 g, yellow liquid, yield 86.22%) .

MS(ESI): m/z 315.09[M+1] ⁺ .

Step 2: Synthesis of Compound 25D

Compound 25C (15.6 g, 49.64 mmol) was dissolved in DMF (125 mL), NaH (2 g, 49.64 mmol) was added in portions at 0 °C, and then the temperature was raised to 30 °C and stirred for 2 h. After TLC showed that the reaction was over, the reaction solution was added to saturated NaCl solution (500 mL), extracted with ethyl acetate (150 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried to obtain compound 25D ( 14.1 g, yellow oil, 96.53% yield). It was used directly in the next step without further purification.

MS(ESI): m/z 295[M+1] ⁺ .

Step 3: Synthesis of Compound 25E

Compound 25D (14.1 g, 47.92 mmol) was dissolved in methanol (140 mL), and Pb/C (1.4 g, 0.1 eq) with a mass fraction of 10% was added. After the addition, the bottle was covered with a hydrogen balloon and replaced three times. After degassing, keep the hydrogen atmosphere at room temperature for 5h. After TLC showed that the reaction was completed, the reaction solution was filtered, and the filtrate was spin-dried to obtain compound 25E (12 g, gray solid, yield 94.76%). It was used directly in the next step without further purification.

MS(ESI): m/z 265[M+1] ⁺ .

Step 4: Synthesis of Compound 25F

Compound 25E (5 g, 18.92 mmol) was dissolved in acetonitrile (5 ml), 4% HCl-MeCN (50 mL) was added, and the reaction solution was placed at 110° C. for overnight reaction. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of solid was precipitated. The solid was filtered, washed with ice-cold acetonitrile several times, and then dried to obtain compound 25F (3.6 g, white solid, yield 69.63%).

MS(ESI): m/z 274[M+1] ⁺ .

Step 5: Synthesis of Compound 25G

Compound 25F (2 g, 7.32 mmol) was dissolved in _POCl3 (23 mL), followed by DMF (3 drops), and the reaction was heated to 100 °C. After TLC showed that the reaction was completed, the reaction solution was spin-dried, and then adjusted to weakly alkaline (PH=8-9) with saturated aqueous sodium bicarbonate solution, and then diluted with water (100 mL), and the obtained aqueous phase was washed with ethyl acetate Extraction (150ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/isopropanol=10:1) to obtain the compound 25G (1.6 g, pale yellow powder, 74.94%).

MS(ESI): m/z 292[M+1] ⁺ .

Step 6: Synthesis of Compound 25I

Compound 25G (500 mg, 1.71 mmol) was dissolved in DMF (5 mL), 25H (401 mg, 1.71 mmol) was added, then DIEA (665 mg, 5.16 mmol) was added, and the reaction solution was heated to 80 °C for 16 h. TLC After the completion of the reaction, the reaction solution was spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3:1) to obtain compound 25I (200 mg, pale yellow oil, 23.84%)

MS(ESI): m/z 490[M+1] ⁺ .

Step 7: Synthesis of Compound 25

Compound 25I (200 mg, 408.62 mmol) was dissolved in ethanol/water (1.6 mL/0.4 mL), ammonium chloride (176.7 mg, 3.11 mmol) was added, and iron powder (91.6 mg, 1.636 mmol) was added to the reaction. The solution was heated to 80°C and refluxed for 1 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to obtain Compound 25 (325 mg, pale yellow solid).

MS(ESI): m/z 460[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)7.95(d,J=7.8Hz,1H),7.55(s,1H),6.87-6.84(m,3H),6.70(s,1H),5.61-5.55 (m,1H),5.54(s,2H),4.32(dd,J=10.7,2.0Hz,1H),4.08(dd,J=11.3,2.9Hz,1H),3.96–3.90(m,2H), 3.83(d,J=11.6Hz,1H),3.68-3.35(m,1H),3.24-3.17(m,2H),2.85-2.82(m,1H),2.32(s,3H),1.54(d, J=7.1Hz, 3H).

Example 26: Preparation of Compound 26

The synthesis of compound 26 refers to the synthesis procedure of compound 25 in Example 25, wherein in the sixth step, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine is used instead of 25H , compound 26 was synthesized.

MS(ESI): m/z 445[M+1] ⁺ .

¹ H-NMR(400MHz,DMSO)δ(ppm)7.99(d,J=7.2Hz,1H),7.65(t,J=7.3Hz,1H),7.59(s,1H),7.49(t,J= 6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.24(t, J=72Hz, 1H), 6.84(s, 1H), 5.80(m, 1H), 4.33(dd, J=10.8, 2.0Hz, 1H), 4.17–4.05 (m, 1H), 4.02–3.79 (m, 3H), 3.70 (dd, J=11.8, 9.3Hz, 1H), 3.26–3.18 (m, 2H), 2.86 (n ,1H),2.27(s,3H),1.60(d,J=7.1Hz,3H).

Example 27: Preparation of Compound 27

synthetic route:

Preparation:

Step 1: Synthesis of compound 27A

To compound 10A (4.42 g, 14.1 mmol) was added 1,2-dichloroethane (50 mL), followed by carbon tetrachloride (1.73 g, 11.3 mmol), followed by triphenylphosphine (1.48 g, 5.64 g) mmol, 4.0 eq), after the addition, the gas was replaced with nitrogen three times, and then the reaction solution was heated to 80° C. and stirred for 2 h under nitrogen protection. After TLC showed that the reaction was over, it was spin-dried to obtain the crude compound 27A (5.2 g, dark brown oil), which was used in the next step without further purification.

MS(ESI): m/z 333.3[M+1] ⁺ .

Step 2: Synthesis of Compound 27B

NMP (50 mL) was added to the crude compound 27A (5.2 g) obtained in the previous step, followed by (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (2.84 g). g, 15.0 mmol, 1.0 eq) and DIEA (3.8 g, 30.0 mmol), after the addition, the reaction solution was heated to 100 °C and stirred for 3 h. After TLC showed that the reaction was over, ethyl acetate (100 mL) and saturated brine (100 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (100 mL×2), the organic phases were combined and dried , spin dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1 (volume ratio)) to obtain compound 27B (5.5 g, pale yellow solid, two-step yield 80.2%) .

MS(ESI): m/z 486.2[M+1] ⁺ .

The third step: synthesis of compound 27C

Compound 27B (5.0 g, 10.3 mmol) was added to ethanol (50 mL), then concentrated hydrochloric acid (10 mL) was added, then the temperature was raised to 90 ° C, and the reaction was carried out for 12 hours. The crude product (5.7 g, white solid) was used in the next step without further purification.

Step 4: Synthesis of Compound 27

The crude hydrochloride of compound 27C (0.57 g) and compound 3-oxetane carboxylic acid (175 mg, 1.72 mmol) were added to DMF (5.5 mL), the reaction solution was cooled to 0° C., and added to the reaction solution. T3P (712 mg, 2.24 mmol) was added dropwise, and then triethylamine (0.52 g, 5.16 mmol) was added dropwise. After the dropwise addition was completed, the reaction solution was heated to 25° C. and reacted for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), and the organic phases were combined, Dry, spin dry, the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20:1 (volume ratio)), and the product purified by column chromatography is purified by HPLC preparative purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min to end ) to give compound 27 (0.34 g, off-white solid, 63.2% yield for two steps).

MS(ESI): m/z 528.2[M+1] ⁺ .

¹ H NMR (300MHz, DMSO): δ (ppm) 8.05-7.97 (m, 1H), 7.68-7.59 (m, 2H), 7.49 (t, J=7.2Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.24(d, J＝54.0Hz, 1H), 6.84(s, 1H), 5.85-5.74(m, 1H), 4.80-4.69(m, 3H), 4.68-4.36(m, 3H) ,4.30-4.15(m,1H),4.13-3.95(m,2H),3.64-3.50(m,1H),3.28-3.04(m,2H),2.94-2.83(m,1H),2.79-2.66( m, 1H), 2.26(s, 3H), 1.60(d, J=7.2Hz, 3H).

Example 28: Preparation of Compound 28

The synthesis of compound 28 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (R)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 28.

MS(ESI): m/z 542.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 9.62 (s, 1H), 7.83 (s, 1H), 7.71 (t, J=7.3Hz, 1H), 7.57 (t, J=7.1Hz, 1H) ,7.37(t,J＝7.7Hz,1H),7.23(t,J＝54.3Hz,1H),6.97(s,1H),5.98-5.87(m,1H),4.66-4.45(m,2H), 4.26-4.07(m, 2H), 4.01(d, J=12.1Hz, 1H), 3.96-3.87(m, 1H), 3.80-3.61(m, 3H), 3.55-3.38(m, 2H), 3.25- 3.12(m, 1H), 2.99-2.79(m, 2H), 2.52(s, 3H), 2.13-1.92(m, 2H), 1.69(d, J=6.8Hz, 3H).

Example 29: Preparation of Compound 29

The synthesis of compound 29 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (S)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 29.

MS(ESI): 542.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 9.69-9.57 (m, 1H), 7.83 (s, 1H), 7.72 (t, J=7.3Hz, 1H), 7.57 (t, J=6.9Hz, 1H), 7.37(t, J=7.7Hz, 1H), 7.23(t, J=54.2Hz, 1H), 6.97(s, 1H), 5.97-5.89(m, 1H), 4.64-4.53(m, 2H) ), 4.26-4.08(m, 2H), 4.01(d, J=11.9Hz, 1H), 3.96-3.88(m, 1H), 3.78-3.68(m, 3H), 3.56-3.38(m, 2H), 3.27-3.18(m, 1H), 3.01-2.76(m, 2H), 2.52(s, 3H), 2.15-1.91(m, 3H), 1.69(d, J=6.8Hz, 3H).

Example 30: Preparation of Compound 30

synthetic route:

Preparation:

Step 1: Synthesis of Compound 30

The crude hydrochloride of compound 27C (0.57 g, 1.03 mmol) was added to DMF (5.5 mL), the reaction solution was cooled to 0 °C, and triethylamine (0.52 g, 5.16 mmol) was added dropwise, followed by Then methyl chloroformate (162 mg, 1.72 mmol) was added dropwise, and the reaction solution was heated to 25 °C for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), and the organic phases were combined, Dry, spin dry, the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20:1 (volume ratio)), and the product purified by column chromatography is purified by HPLC preparative purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min to end ) to give compound 30 (142 mg, off-white solid, 28.2% yield).

MS(ESI): m/z 502.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 8.05 (d, J=7.2Hz, 1H), 7.71-7.62 (m, 2H), 7.49 (t, J=6.8Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 7.23(d, J=54.0Hz, 1H), 6.84(s, 1H), 5.80(q, J=7.2Hz, 1H), 4.44(dd, J=10.8, 2.4Hz, 1H), 4.14(d, J=12.8Hz, 1H), 4.07(d, J=12.0Hz, 2H), 4.03-3.95(m, 1H), 3.66(s, 3H), 3.20-3.11(m, 2H) ), 2.84-2.65(m, 2H), 2.26(s, 3H), 1.60(d, J=7.2Hz, 3H).

Example 31: Preparation of Compound 31

synthetic route:

Preparation:

Step 1: Synthesis of Compound 31

The crude hydrochloride of compound 27C (0.29 g, 0.5 mmol) was added to DCM (2 mL), then triethylamine (100 mg, 1.0 mmol) was added to the reaction solution, the reaction solution was cooled to 0 °C, and added in batches Triphosgene (296 mg, 1.0 mmol) was added and reacted at 0°C for 30 min. After TLC showed that the reaction was completed, dimethylamine hydrochloride (81.5 mg, 1.0 mmol) was added, and triethylamine (100 mg, 1.0 mmol) was added. After the addition, the reaction solution was warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was over, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (5 mL×2), the organic phases were combined, dried, and spun to dry, and the residue was prepared by HPLC Purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile was run to the end of 16 min) to give compound 31 (108 mg, white solid, 42.0% yield).

MS(ESI): m/z 515.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 9.97 (s, 1H), 8.10 (s, 1H), 7.87 (t, J=7.3Hz, 1H), 7.54 (t, J=6.9Hz, 1H) ,7.34(t,J=7.7Hz,1H),7.23(t,J=54.3Hz,1H),7.07(s,1H),6.01- 5.91(m,1H),4.53(dd,J=10.9,2.8 Hz, 1H), 4.16(d, J＝11.8Hz, 1H), 4.09(t, J＝10.0Hz, 1H), 3.70(d, J＝12.1Hz, 2H), 3.63(d, J＝12.3Hz, 1H), 3.26(dd, J＝13.1, 6.7Hz, 1H), 3.04-2.95(m, 2H), 2.93-2.84(m, 4H), 2.82(s, 6H), 2.61-2.54(m, 1H) ,2.49(s,3H),1.71(d,J=7.1Hz,3H).

Example 32: Preparation of Compound 32

The synthesis of compound 32 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methyl-3-azetidine carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 32.

MS(ESI): 541.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 8.19 (s, 1H), 8.02 (d, J=7.0Hz, 1H), 7.68-7.61 (m, 1H), 7.50 (t, J=7.1Hz, 1H), 7.28(t, J＝7.1Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 6.84(s, 1H), 5.85-5.75(m, 1H), 4.57-4.40(m, 3H) ), 4.10-3.97(m, 2H), 3.79-3.61(m, 4H), 3.43-3.25(m, 2H), 3.18-3.02(m, 1H), 2.96-2.81(m, 1H), 2.78-2.65 (m, 1H), 2.33(s, 3H), 2.26(s, 3H), 1.60(d, J=7.0Hz, 3H).

Example 33: Preparation of Compound 33

synthetic route:

Preparation:

Step 1: Synthesis of Compound 33

The crude hydrochloride salt of compound 27C (0.29 g, 0.5 mmol) and 2-bromo-N,N-dimethylacetamide (166 mg, 1.0 mmol) were added to DMF (5.0 mL) followed by potassium carbonate (138 mg) , 1.0mmol), reacted at room temperature overnight, TLC showed that some raw materials were not reacted, continued to add 2-bromo-N,N-dimethylacetamide (166mg, 1.0mmol) and potassium carbonate (138mg, 1.0mmol) , reacted for 3 hours, TLC showed that the reaction was over, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (15 mL×2), the organic phases were combined, dried, and spun to dry, the residual The compound was preparatively purified by HPLC (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile run for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile Run to 14min, 10% acetonitrile run to 16min end) to give compound 33 (87.3 mg, white solid, 33.0% yield).

MS(ESI): m/z 529.3[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 7.98 (d, J=7.2Hz, 1H), 7.65 (t, J=7.2Hz, 1H), 7.59 (s, 1H), 7.49 (t, J= 6.8Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.23(d, J=54.0Hz, 1H), 6.82(s, 1H), 5.80(q, J=6.8Hz, 1H), 4.34 (dd,J=10.8,2.8Hz,1H),4.03-3.91(m,2H),3.30(s,1H),3.21(d,J=14.4Hz,1H),3.15(d,J=9.6Hz, 1H), 3.08(d, J=10.8Hz, 1H), 3.03(s, 3H), 2.95(d, J=10.4Hz, 1H), 2.87-2.76(m, 4H), 2.47-2.38(m, 1H) ), 2.26(s, 3H), 1.97(t, J=10.8Hz, 1H), 1.59(d, J=7.2Hz, 3H).

Example 34: Preparation of Compound 34

The synthesis of compound 34 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-cyano-1-cyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 34.

MS(ESI): 537.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 8.04 (d, J=7.2Hz, 1H), 7.72-7.59 (m, 2H), 7.49 (t, J=6.8Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 7.24(d, J=54.0Hz, 1H), 6.86(s, 1H), 5.79(q, J=6.89Hz, 1H), 4.57-4.42(m, 2H), 4.37( d, J＝12.4Hz, 1H), 4.18-4.03(m, 2H), 3.32-3.13(m, 2H), 2.98-2.79(m, 2H), 2.26(s, 3H), 1.74-1.47(m, 7H).

Example 35: Preparation of Compound 35

The synthesis of compound 35 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, N-methyl-D-proline is used instead of 3-oxetane carboxylic acid to synthesize compound 35.

MS(ESI): 555.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO): δ (ppm) 8.02 (d, J=7.2Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 7.49 (t, J=6.9Hz, 1H), 7.28 (t, J=7.7Hz, 1H), 7.23 (t, J=52.0Hz, 1H), 6.85 (s, 1H), 5.86–5.75 (m, 1H), 4.66–4.28 (m, 5H), 4.10– 4.03(m, 2H), 3.51-3.49(m, 1H), 3.13-3.08(m, 1H), 2.95-2.92(m, 1H), 2.75-2.67(m, 1H), 2.33-2.31(m, 4H ), 2.26(s, 3H), 2.19-2.16(m, 1H), 1.86-1.73(m, 3H), 1.60(d, J=7.0Hz, 3H).

Example 36: Preparation of Compound 36

The synthesis of compound 36 refers to the synthesis steps of compound 30 in Example 30, wherein in the first step, methyl chloroformate is replaced by methylsulfonyl chloride, and compound 36 is synthesized.

MS(ESI): 522.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.04(d,J=7.2Hz,1H),7.69(s,1H),7.65(t,J=7.2Hz,1H),7.49(t,J=6.8 Hz, 1H), 7.29(t, J＝7.6Hz, 1H), 7.23(d, J＝54.0Hz, 1H), 6.86(s, 1H), 5.80(q, J＝6.8Hz, 1H), 4.46( dd,J＝10.8,2.4Hz,1H),4.20(d,J＝12.0Hz,1H),4.03(dd,J＝10.8,8.8Hz,1H),3.70(dd,J＝19.6,11.2Hz,2H) ),3.33-3.27(m,1H),3.10-2.87(m,5H),2.63(t,J=11.2Hz,1H),2.26(s,3H),1.60(d,J=7.2Hz,3H) .

Example 37: Preparation of Compound 37

The synthesis of compound 37 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 3-methoxypropionic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 37.

MS(ESI): 530.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.00(t,J=6.0Hz,1H),7.69-7.61(m,2H),7.49(t,J=6.8Hz,1H),7.28(t,J ＝7.67Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.84(s, 1H), 5.85-5.74(s, 1H), 4.54(dd, J＝35.2, 12.8Hz, 1H), 4.44 (d, J=10.4Hz, 1H), 4.19-3.96 (m, 3H), 3.59 (dd, J=10.4, 5.6Hz, 2H), 3.24 (s, 3H), 3.11 (dt, J=17.6, 9.6 Hz, 1H), 2.94-2.82(m, 1H), 2.82-2.58(m, 3H), 2.47-2.37(m, 1H), 2.26(s, 3H), 1.60(d, J=7.2Hz, 3H) .

Example 38: Preparation of Compound 38

The synthesis of compound 38 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, pivalic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 38.

MS(ESI): 528.2[M+1] ⁺ .

¹ H NMR(300MHz,DMSO)δ(ppm)8.02(d,J=7.3Hz,1H),7.69-7.58(m,2H),7.49(t,J=7.2Hz,1H),7.28(t,J ＝7.8Hz, 1H), 7.24(t, J＝54.3Hz, 1H), 6.84(s, 1H), 5.86-5.73(m, 1H), 4.59-4.47(m, 2H), 4.41(d, J＝ 13.4Hz, 1H), 4.09-3.94(m, 2H), 3.21-3.04(m, 2H), 2.73(dd, J=22.5, 10.3Hz, 2H), 2.26(s, 3H), 1.60(d, J =7.1Hz,3H),1.26(s,9H).

Example 39: Preparation of Compound 39

The synthesis of compound 39 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-fluorocyclopropane carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 39.

MS(ESI): 530.2[M+1] ⁺ .

¹ H NMR(300MHz,DMSO)δ(ppm)8.03(d,J=7.2Hz,1H),7.64(d,J=8.4Hz,2H),7.49(t,J=7.0Hz,1H),7.28( t, J＝7.7Hz, 1H), 7.24(t, J＝54.3Hz, 1H), 6.86(s, 1H), 5.88-5.72(m, 1H), 4.56-4.27(m, 3H), 4.08(dd , J=17.0, 8.1Hz, 2H), 3.28-3.12(m, 2H), 2.94-2.79(m, 2H), 2.26(s, 3H), 1.60(d, J=7.0Hz, 3H), 1.43- 1.14(m,4H).

Example 40: Preparation of Compound 40

The synthesis of compound 40 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, methoxyacetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 40.

MS(ESI): 516.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.01(d,J=7.3Hz,1H),7.65(d,J=7.7Hz,2H),7.49(t,J=6.9Hz,1H),7.28( t, J＝7.7Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 6.84(s, 1H), 5.80(q, J＝6.8Hz, 1H), 4.62-4.35(m, 2H), 4.31-3.85(m, 5H), 3.33(s, 3H), 3.15(d, J=42.7Hz, 1H), 3.00-2.69(m, 2H), 2.48-2.43(m, 1H), 2.26(s, 3H),1.60(d,J=7.0Hz,3H).

Example 41: Preparation of Compound 41

The synthesis of compound 41 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-(methoxymethyl)cyclopropylcarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 41.

MS(ESI): 556.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.15(s,1H),8.02(d,J=7.3Hz,1H),7.66(d,J=9.0Hz,2H),7.49(t,J=6.9Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.85(s, 1H), 5.87-5.73(m, 1H), 4.53-4.45(m, 2H) ), 4.39(d, J＝12.4Hz, 1H), 4.12-4.98(m, 2H), 3.38-3.28(m, 3H), 3.25(s, 3H), 3.17-3.06(m, 2H), 2.82- 2.70(m, 1H), 2.26(s, 3H), 1.60(d, J=7.0Hz, 3H), 0.90(t, J=6.1Hz, 2H), 0.76(t, J=5.2Hz, 2H).

Example 42: Preparation of Compound 42

The synthesis of compound 42 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, methylamine hydrochloride is used instead of dimethylamine hydrochloride to synthesize compound 42.

MS(ESI): 501.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.00(d,J=7.3Hz,1H),7.70-7.59(m,2H),7.49(t,J=6.9Hz,1H),7.29(t,J =7.7Hz,1H),7.23(t,J=54.4Hz,1H),6.83(s,1H),6.64(d,J=4.3Hz,1H),5.80(q,J=6.9Hz,1H), 4.37(dd,J＝10.8,2.7Hz,1H),4.12(d,J＝13.1Hz,1H),4.02(dd,J＝21.9,11.5Hz,3H),3.08(t,J＝9.9Hz,1H) ), 2.99(dd, J=12.4, 9.9Hz, 1H), 2.77-2.66(m, 1H), 2.62(d, J=4.2Hz, 3H), 2.63-2.46(m, 1H), 2.26(s, 3H),1.60(d,J=7.1Hz,3H).

Example 43: Preparation of Compound 43

The synthesis of compound 43 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, ethylamine hydrochloride is used instead of dimethylamine hydrochloride to synthesize compound 43.

MS(ESI): 515.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.00(d,J=7.3Hz,1H),7.70-7.57(m,2H),7.49(t,J=6.8Hz,1H),7.29(t,J ＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.83(s,1H),6.69(t,J＝5.2Hz,1H),5.80(q,J＝6.8Hz,1H), 4.37(dd,J＝10.8,2.7Hz,1H),4.15(d,J＝12.7Hz,1H),4.02(dd,J＝21.7,12.0Hz,3H),3.09(tt,J＝11.1,5.6Hz ,3H),2.98(dd,J=12.3,10.1Hz,1H),2.76-2.65(m,1H),2.58-2.54(m,1H),2.26(s,3H),1.60(d,J=7.1 Hz,3H),1.04(t,J=7.1Hz,3H).

Example 44: Preparation of Compound 44

synthetic route:

Preparation:

Step 1: Synthesis of compound 44B

Compound 44A (10.0 g, 46.0 mmol), (3S)-tert-butyl 3-(2-hydroxyethyl)-1-piperazinecarboxylate (10.6 g, 46.0 mmol) was dissolved in DMF (100 mL), followed by DIEA (7.13 g, 55.2 mmol) was weighed into the reaction flask, and then the reaction solution was heated to 80° C. and stirred for 16 h. After TLC showed that the reaction was completed (about 15% of SM1 raw material was not fully reacted), ethyl acetate (100 mL) and saturated brine (100 mL) were added to the reaction solution, the organic layer was separated, and the aqueous phase was washed with ethyl acetate (20 mL). ×2) Extracted twice, combined the organic phases, dried, spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 44B (11.0 g) , 25.8 mmol, pale yellow oil, 56.1% yield).

MS(ESI): m/z 428.2[M+1] ⁺ .

Step 2: Synthesis of compound 44C

Compound 44B (11.0 g, 25.8 mmol) was dissolved in DMF (110 mL), the reaction solution was cooled to 0 °C, 60% sodium hydride (1.24 g, 31.0 mmol) was added in portions at 0 °C, and then the temperature was raised to 45 °C The reaction was stirred for 1 h. After TLC showed that the reaction was completed, the reaction solution was cooled to 0°C, methanol (2 mL) was added dropwise to the reaction solution, stirred until no bubbles were generated, and then ethyl acetate (100 mL) and saturated brine were added to the reaction solution (100 mL), the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), the organic phases were combined, dried, and spin-dried to give compound 44C (9.1 g, 22.4 mmol, pale yellow oil, yield 87.0 %).

MS(ESI): m/z 408.2[M+1] ⁺ .

Step 3: Synthesis of Compound 44D

Compound 44C (9.1 g, 22.4 mmol) was dissolved in methanol (90 mL), and 10% wet Pb/C (0.91 g, 10%) was added to the reaction solution. After the hydrogen was replaced three times, the hydrogen pressure was kept at 50 psi, and the reaction was carried out at 25 °C for 5 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 44D (7.55 g) , pale yellow solid, yield 90.0%).

MS(ESI): m/z 378.2[M+1] ⁺ .

Step 4: Synthesis of Compound 44E

Compound 44D (7.55 g, 20.2 mmol) was dissolved in ethyl acetate (35 mL), the reaction solution was cooled to 0 °C, 8% HCl-EtOAc (105 mL) was added dropwise to the reaction solution, and then the reaction solution was heated to 40 Stir at ℃ for 2h. After TLC showed that the reaction was over, concentrate, and then add ethyl acetate (30 mL×2) to replace twice (remove part of hydrochloric acid to prevent moisture absorption), finally add ethyl acetate (35 mL) to make slurry, filter, and dry the filter cake to obtain compound 44E (7.2 g, off-white solid, 100.0% yield).

MS(ESI): m/z 278.2[M+1] ⁺ .

Step 5: Synthesis of compound 44F

Compound 44E (7.2 g, 20.2 mmol) was added to acetonitrile (80 mL), followed by 6N HCl-MeCN (10 mL, 60.6 mmol), the reaction solution was placed in a stuffy tank, then heated to 110 °C and stirred for 16 h. After TLC showed that the reaction was over, concentrate, and then add acetonitrile (30 mL×2) for replacement twice (remove part of hydrochloric acid to prevent moisture absorption), finally add acetonitrile (35 mL) to make slurry, filter, and wash the filter cake with a small amount of acetonitrile to obtain compound 44F (5.56 g, off-white solid, yield: 85.0%).

MS(ESI): m/z 287.1[M+1] ⁺ .

Step 6: Synthesis of compound 44G

Compound 44F (0.56 g, 1.72 mmol) and cyclopropanecarboxylic acid (0.16 g, 1.89 mmol) were added to DMF (55 mL), the reaction solution was cooled to 0 °C, and T ₃ P (1.42 mmol) was added dropwise to the reaction solution. g, 2.24 mmol), then triethylamine (0.52 g, 5.16 mmol) was added dropwise, the dropwise addition was completed, and the reaction solution was heated to 25° C. for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (4 mL×2), and the organic phases were combined, Dry, spin dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 (volume ratio)) to obtain compound 44G (0.5 g, khaki solid, yield 81.9%).

MS(ESI): m/z 355.2[M+1] ⁺ .

Step 7: Synthesis of compound 44H

To compound 44G (0.5 g, 1.41 mmol) was added 1,2-dichloroethane (5 mL), followed by carbon tetrachloride (1.73 g, 11.3 mmol), followed by triphenylphosphine (1.48 g, 5.64 g) mmol), after the addition, the gas was replaced three times with nitrogen, and then the reaction solution was heated to 80 °C under nitrogen protection and stirred for 2 h. After TLC showed that the reaction was complete, it was spin-dried to give crude compound 44H (0.52 g, 1.41 mmol, dark brown oil), which was used in the next step without purification.

MS(ESI): m/z 373.2[M+1] ⁺

Step 8: Synthesis of Compound 44

To compound 44H (0.26 g, 0.7 mmol) was added NMP (2.5 mL) followed by (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (0.14 g, 0.7 mmol, 1.0 eq) and DIEA (0.18 g, 1.4 mmol, 2.0 eq), after the addition, the reaction solution was heated to 100 °C and stirred for 3 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (4 mL×2), the organic phases were combined and dried , spin-dried, the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 (volume ratio)), and the chromatographically purified product was purified by HPLC preparation (Waters Sunfire OBD 100×30 mm, 5 μm, Mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile for 10 min, 95% acetonitrile for 14 min, 10% acetonitrile for 16 min), Compound 44 was obtained (0.1 g, white solid, 27.1% yield).

MS(ESI): m/z 526.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ (ppm) 8.14 (d, J=7.0Hz, 1H), 7.78 (s, 1H), 7.67 (t, J=7.2Hz, 1H), 7.49 (t, J=6.9 Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=52Hz, 1H), 6.90(s, 1H), 5.87–5.73(m, 1H), 4.61(m, 1H) ,4.22(m,2H),4.07-3.97(m,2H),3.63-3.51(m,2H),3.15-2.99(m,2H),2.27(s,3H),2.16-2.05(m,2H) ,1.98–1.79(m,1H),1.60(d,J=7.0Hz,3H),0.78(d,J=3.4Hz,4H).

Example 45: Preparation of Compound 45

synthetic route:

Preparation:

Step 1: Synthesis of compound 45B

Compound 45A (1 g, 5.79 mmol) was dissolved in DMF (15 mL), NBS (1.03 g, 5.79 mmol) was added in portions under ice bath, and the reaction was warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was completed, the reaction solution was poured into water, white solid was precipitated, filtered, and the filter cake was collected and spin-dried to obtain compound 45B (1.5 g, white solid, yield 96%).

MS (ESI): m/z 251.0 [M+H] ⁺ .

Step 2: Synthesis of compound 45C

Compound 45B (1.4 g, 5.57 mmol) was added to triethyl orthoacetate (8 mL), ammonium formate (1.76 g, 27.8 mmol) was added, and the mixture was heated to 100 degrees and stirred for 18 h. After TLC showed that the reaction was over, the reaction solution was slowly added to water: ethyl acetate (volume ratio 1:1, 40 mL), a gray solid was precipitated, filtered, the filter cake was collected, and spin-dried to obtain compound 45C (0.6 g, gray solid) , the yield is 39%).

MS (ESI): m/z 274.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 45D

Compound 45C (50 mg, 0.18 mmol) was added to dioxane dioxane (2 mL), triphenylphosphine (95 mg, 0.36 mmol) and carbon tetrachloride (84 mg, 0.55 mmol) were added, and it was raised to 70 under nitrogen protection Stir for 4h. After TLC showed that the reaction was over, spin to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2:1 (volume ratio)) to obtain compound 45D (30 mg, pale yellow oil, yield 56%).

MS(ESI): m/z 292.9 [M+H] ⁺ .

Step 4: Synthesis of Compound 45E

Compound 45D (30 mg, 0.1 mmol) was added to DMF (1 mL), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (23 mg, 0.12 mmol) and DIEA (40 mg, 0.31 mmol), raised to 50 degrees and stirred for 3 h. After TLC showed that the reaction was completed, water was slowly added, white solid was precipitated, filtered, and the filter cake was collected and spin-dried to obtain compound 45E (30 mg, white solid, yield 65%).

MS (ESI): m/z 445.0 [M+H] ⁺ .

Step 5: Synthesis of Compound 45G

Compound 45E (300 mg, 0.67 mmol) was added to DMSO (10 mL), compound 45F (230 mg, 0.81 mmol) and cesium fluoride (410 mg, 2.69 mmol) were added, and the mixture was heated to 90 degrees and stirred for 3 h. After TLC showed that the reaction was complete, ethyl acetate was diluted, added to water, extracted, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1: 1 (volume ratio)) to obtain compound 45G (400 mg, pale yellow solid, 85% yield).

MS(ESI): m/z 693.2 [M+H] ⁺ .

Step 6: Synthesis of compound 45H

Compound 45G (400 mg, 0.57 mmol) was added to ethyl acetate (4 mL), 8% HCl/ethyl acetate (5 mL) was added dropwise, and the mixture was warmed to room temperature and stirred for 12 h. After TLC showed that the reaction was over, spin to dryness, add aqueous sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, spin dry, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol) = 15:1 (volume ratio)) to obtain compound 45H (300 mg, pale yellow solid, yield 87%).

MS (ESI): m/z 593.2 [M+H] ⁺ .

Step 7: Synthesis of Compound 45

Compound 45H (0.11g, 0.19mmol) was dissolved in toluene (4mL), Xphos Pd G3 (15mg, 0.02mmol) and cesium carbonate (0.12g, 0.37mmol) were added, and the reaction solution was heated to 100°C under nitrogen protection Stir for 16h. After TLC showed that the reaction was over, water was added, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and the residue was purified by HPLC preparation (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA in water , mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile for 10 min, 95% acetonitrile for 14 min, 10% acetonitrile for 16 min) to obtain compound 45 (30 mg, white solid, Yield 31%)

MS(ESI): m/z 513.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm) 8.24-8.17(m, 2H), 7.64(t, J=7.2Hz, 1H), 7.50(t, J=6.8Hz, 1H), 7.29( t, J=7.7Hz, 1H), 7.23 (t, J=54.4Hz, 1H), 5.83-5.70 (m, 1H), 4.67-4.32 (m, 3H), 4.25-4.15 (m, 1H), 3.99 -3.80(m, 1H), 3.20-2.95(m, 2H), 2.95-2.70(m, 2H), 2.29(s, 3H), 2.17-2.04(m, 1H), 1.59(d, J=8.0Hz ,3H),0.90-0.60(m,4H).

Example 46: Preparation of Compound 46

The synthesis of compound 46 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (1S,2R)-2-fluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 46.

MS(ESI): 530.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.02(t,J=9.6Hz,1H),7.68-7.61(m,2H),7.49(t,J=7.2Hz,1H),7.28(t,J =7.7Hz,1H),7.23(t,J=54.4Hz,1H),6.85(d,J=4.5Hz,1H),5.80(q,J=7.0Hz,1H),5.00-4.69(m,1H) ), 4.58-4.40(m, 3H), 4.17-3.97(m, 2H), 3.08-2.71(m, 5H), 2.28(s, 3H), 1.60(d, J=7.0Hz, 3H), 1.52- 1.37(m,1H),1.28-1.12(m,1H).

Example 47: Preparation of Compound 47

The synthesis of compound 47 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (1S,2S)-2-fluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 47.

MS(ESI): 530.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ (ppm) 9.65-9.50 (m, 1H), 7.84 (s, 1H), 7.72 (t, J=7.5Hz, 1H), 7.57 (t, J=7.2Hz, 1H) ),7.41-7.35(m,1H),7.24(t,J＝54.4Hz,1H),6.97(s,1H),5.98-5.88(m,1H),5.09-4.81(m,1H),4.64– 4.35(m, 3H), 4.21-3.98(m, 2H), 3.54-3.43(m, 1H), 3.17-2.75(m, 3H), 2.48(s, 3H), 2.30-2.11(m, 1H), 1.69(d, J＝7.0Hz, 3H), 1.64-1, 48(m, 1H), 1.12-1.03(m, 1H).

Example 48: Preparation of Compound 48

The synthesis of compound 48 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2,2-difluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 48.

MS(ESI): 548.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.20(s,1H),8.14(s,1H),7.67(d,J=10.7Hz,2H),7.49(d,J=6.5Hz,1H), 7.29(t,J＝7.5Hz,1H),7.16(d,J＝54.3Hz,1H),6.88(d,J＝4.9Hz,1H),5.87-5.74(m,1H),4.49(t,J =16.8Hz,2H),4.13(ddd,J=31.0,24.7,7.6Hz,3H),3.45(d,J=13.9Hz,1H),3.32(d,J=8.3Hz,1H),3.12(d , J=12.9Hz, 1H), 3.01(d, J=11.6Hz, 1H), 2.84-2.67(m, 1H), 2.29(s, 3H), 2.00-1.86(m, 2H), 1.61(d, J=5.2Hz, 3H).

Example 49: Preparation of Compound 49

The synthesis of compound 49 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylcyclopropane-1-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 49.

MS(ESI): 526.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.87(s,1H),7.81(s,1H),7.72(t,J=7.1Hz,1H),7.52(t,J=6.7Hz,1H), 7.31(t,J＝7.6Hz,1H),7.23(t,J＝54.3Hz,1H),6.93(s,1H),5.93-5.80(m,1H),4.60-4.32(m,3H),4.20 -4.00(m, 2H), 3.66-3.58(m, 1H), 3.15-3.11(m, 2H), 2.85-2.80(m, 1H), 2.37(s, 3H), 1.65(d, J=6.9Hz ,3H),1.28(s,3H),0.86(s,2H),0.59(s,2H).

Example 50: Preparation of Compound 50

The synthesis of compound 50 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2,2,3,3-tetramethylcyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 50.

MS(ESI): 568.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.79(s,1H),7.77(s,1H),7.73-7.68(m,1H),7.51(t,J=7.0Hz,1H),7.30(t , J=7.6Hz, 1H), 7.16(t, J=54.3Hz, 1H), 6.97(s, 1H), 5.94-5.74(m, 1H), 4.69-4.38(m, 2H), 4.20-4.0( s,3H),3.26-3.17(m,2H),3.00-2.80(m,2H),2.73-2.67(m,1H),2.36(s,3H),1.64(d,J=6.9Hz,3H) ,1.21-1.12(m,12H).

Example 51: Preparation of Compound 51

Synthesis of compound 51 Referring to the synthesis procedure of compound 8 in Example 8, in the synthesis of the tricyclic intermediate, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 51.

MS(ESI): 512.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.15(s, 1H), 8.11(d, J=7.4Hz, 1H), 7.67-7.63(m, 2H), 7.49(t, J=7.1Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.86(s, 1H), 5.85-5.76(m, 1H), 4.59-4.42(m, 3H) ),4.13-3.98(m,2H),3.23-3.08(m,2H),2.99-2.91(m,1H),2.82-2.69(m,1H),2.27(s,3H),2.18-2.07(m ,1H),1.61(d,J＝7.1Hz,3H),0.87-0.70(m,4H).

Example 52: Preparation of Compound 52

Synthesis of compound 52 Referring to the synthetic procedure of compound 30 in Example 30, in the synthesis of the tricyclic intermediate, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 52.

MS(ESI): 512.2[M+1] ⁺ .

¹ H NMR (400MHz, Chloroform-d) δ(ppm) 9.14(br.s, 1H), 8.77(s, 1H), 7.70-7.56(m, 2H), 7.46(t, J=7.1Hz, 1H) ,7.19(t,J＝7.7Hz,1H),6.92(t,J＝55.0Hz,1H),6.80(s,1H),5.76-5.67(m,1H),4.35-4.12(m,3H), 4.07-4.01(m, 2H), 3.76(s, 3H), 3.25-3.18(m, 1H), 3.12-3.03(m, 1H), 2.94-2.85(m, 1H), 2.73-2.62(m, 1H) ), 2.44(s, 3H), 1.72(d, J=7.0Hz, 3H).

Example 53: Preparation of Compound 53

Synthesis of compound 53 Referring to the synthetic procedure of compound 37 in Example 37, in the synthesis of the tricyclic intermediate, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 53.

MS(ESI): 530.2[M+1] ⁺ .

¹ H NMR (400MHz, Chloroform-d) δ(ppm) 8.80(s, 1H), 7.75-7.50(m, 2H), 7.50-7.41(m, 1H), 7.24-7.16(m, 1H), 6.92( t, J＝55.0Hz, 1H), 6.89-6.80(m, 1H), 5.79-5.67(m, 1H), 4.81-4.64(m, 1H), 4.37-4.28(m, 1H), 4.14-3.88( m, 3H), 3.73(t, J=6.3Hz, 2H), 3.37(s, 3H), 3.35-3.28(m, 1H), 3.24-3.12(m, 1H), 3.00-2.82(m, 2H) ,2.76-2.55(m,2H),2.45(s,3H),1.73(d,J=7.0Hz,3H).

Example 54: Preparation of Compound 54

Synthesis of compound 54 Referring to the synthetic procedure of compound 40 in Example 40, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 54.

MS(ESI): 516.2[M+1] ⁺ .

¹ H NMR (400MHz, Chloroform-d)δ(ppm) 8.96(br.s,1H),8.79(s,1H),7.72-7.55(m,2H),7.47(d,J=7.1Hz,1H) ,7.21(t,J＝7.2Hz,1H),6.92(t,J＝55.0Hz,1H),6.89-6.81(m,1H),5.77-5.68(m,1H),4.74-4.56(m,1H) ), 4.37-4.29(m, 1H), 4.24-4.17(m, 1H), 4.15-4.03(m, 3H), 3.45(s, 3H), 3.37-3.15(m, 2H), 2.99-2.85(m ,2H),2.54-2.47(m,1H),2.46(s,3H),1.73(d,J=7.0Hz,3H).

Example 55: Preparation of Compound 55

Synthesis of compound 55 Referring to the synthetic procedure of compound 42 in Example 42, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 55.

MS(ESI): 501.2[M+1] ⁺ .

¹ H NMR (400MHz, Chloroform-d) δ(ppm) 9.21(br.s, 1H), 8.77(s, 1H), 7.66(t, J=7.5Hz, 1H), 7.59(s, 1H), 7.47 (t, J=7.1Hz, 1H), 7.19 (t, J=7.7Hz, 1H), 6.91 (t, J=55.0Hz, 1H), 6.77 (s, 1H), 5.87-5.77 (m, 1H) ,5.35(br.s,1H),4.25-4.11(m,2H),3.99-3.90(m,3H),3.19-3.07(m,2H),2.85(s,3H),2.82-2.79(m, 1H), 2.60-2.53(m, 1H), 2.51(s, 3H), 1.74(d, J=7.1Hz, 3H).

Example 56: Preparation of Compound 56

The synthesis of compound 56 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2-oxetanecarboxylate is used instead of 3-oxetanecarboxylate to synthesize compound 56.

MS(ESI): 528.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.12-8.00(m,1H),7.66(dt,J=12.5,5.2Hz,2H),7.49(t,J=6.8Hz,1H),7.29(t ,J=7.6Hz,1H),7.23(t,J=54.4Hz,1H),6.89-6.77(m,1H),5.80(q,J=6.6Hz,1H),5.57-5.43(m,1H) ,4.64-4.26(m,4H),4.19-3.91(m,3H),3.88-3.68(m,1H),3.40-3.05(m,2H),3.01-2.65(m,3H),2.27(s, 3H),1.60(d,J=7.0Hz,3H).

Example 57: Preparation of Compound 57

The synthesis of compound 57 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, cyclopropylamine is used instead of dimethylamine hydrochloride to synthesize compound 57.

MS(ESI): 527.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ (ppm) 8.44 (s, 1H), 7.74-7.63 (m, 2H), 7.51 (t, J=6.9Hz, 1H), 7.30 (t, J=7.7Hz, 1H) ), 7.23(t, J＝54.4Hz, 1H), 6.87(s, 1H), 6.81(s, 1H), 5.89-5.77(m, 1H), 4.39(dd, J＝10.8, 2.7Hz, 1H) ,4.13(d,J＝12.5Hz,1H),4.01(dd,J＝19.8,9.9Hz,3H),3.14-3.05(m,1H),3.01-2.92(m,1H),2.81-2.63(m ,2H),2.54(s,1H),2.32(s,3H),1.62(d,J=7.0Hz,3H),0.63-0.53(m,2H),0.45-0.36(m,2H).

Example 58: Preparation of Compound 58

The synthesis of compound 58 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, cyclopropanol is used instead of dimethylamine hydrochloride to synthesize compound 58.

MS(ESI): 528.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ (ppm) 8.40 (s, 1H), 8.04 (d, J=7.3Hz, 1H), 7.68-7.62 (m, 2H), 7.48 (t, J=6.8Hz, 1H) ), 7.28(t, J＝7.7Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.83(s, 1H), 5.87-5.73(m, 1H), 4.42(d, J＝9.0Hz ,1H),4.19-3.90(m,5H),3.18-3.04(m,2H),2.80-2.62(m,2H),2.25(s,3H),1.59(d,J=7.1Hz,3H), 0.69-0.62(m,4H).

Example 59: Preparation of Compound 59

The synthesis of compound 59 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, morpholine is used instead of dimethylamine hydrochloride to synthesize compound 59.

MS(ESI): 557.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ (ppm) 8.15 (s, 1H), 8.03 (d, J=7.2Hz, 1H), 7.69-7.58 (m, 2H), 7.49 (t, J=6.9Hz, 1H) ),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.84(s,1H),5.80(q,J＝6.9Hz,1H),4.44(dd,J ＝10.8,2.7Hz,1H),4.05-3.96(m,2H),3.76(d,J＝12.4Hz,1H),3.66(d,J＝12.4Hz,1H),3.60(t,J＝4.4Hz ,4H),3.25-3.20(m,5H),3.11-3.04(m,1H),2.87-2.77(m,1H),2.65-2.57(m,1H),2.26(s,3H),1.60(d ,J=7.1Hz,3H).

Example 60: Preparation of Compound 60

The synthesis of compound 60 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, tetrahydropyran-4-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 60.

MS(ESI): 556.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.07(d,J=6.8Hz,1H),7.73-7.60(m,2H),7.49(t,J=6.4Hz,1H),7.28(t,J ＝7.6Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.85(s, 1H), 5.89-5.75(m, 1H), 4.65-4.41(m, 2H), 4.29-4.15(m, 1H), 4.05(dd, J=18.6, 9.8Hz, 3H), 3.87(d, J=9.7Hz, 3H), 3.21-3.10(m, 1H), 3.10-2.64(m, 4H), 2.27(s ,3H),1.71-1.45(m,7H).

Example 61: Preparation of Compound 61

The synthesis of compound 61 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylpiperidine-4-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 61.

MS(ESI): 569.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm) 8.19(s, 2H), 8.03(d, J=7.3Hz, 1H), 7.67-7.63(m, 2H), 7.49(t, J=7.1 Hz, 1H), 7.28(t, J＝7.7Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 6.85-5.76(m, 1H), 5.79(d, J＝9.0Hz, 1H), 4.59(d,J=13.0Hz,1H),4.51-4.43(m,2H),4.19-4.14(m,1H),4.10-4.00(m,3H),3.37(t,J=12.6Hz,1H) ,3.21-3.13(m,1H),3.06-2.88(m,3H),2.82-2.69(m,2H),2.33(s,3H),2.26(s,3H),2.24-2.20(m,1H) ,1.73-1.66(m,3H),1.60(d,J=7.1Hz,3H).

Example 62: Preparation of Compound 62

The synthesis of compound 62 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, N-methylpiperazine is used instead of dimethylamine hydrochloride to synthesize compound 62.

MS(ESI): 570.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ(ppm)8.26(s,1H),7.72-7.61(m,2H),7.50(t,J=7.0Hz,1H),7.29(t,J=7.7Hz,1H) ), 7.23(t, J＝52.0Hz, 1H), 6.86(s, 1H), 5.82(p, J＝6.9Hz, 1H), 4.45(dd, J＝10.7, 2.6Hz, 1H), 4.05–4.00 (m, 2H), 3.74 (d, J=12.6Hz, 1H), 3.64 (d, J= 12.4Hz, 1H), 3.51–3.45 (m, 2H), 3.26–3.13 (m, 3H), 3.10– 3.02(m,1H), 2.86-2.81(m,1H), 2.66-2.57(m,1H), 2.50-2.46(m,4H), 2.29(s,6H), 1.61(d,J=7.0Hz, 3H).

Example 63: Preparation of Compound 63

The synthesis of compound 63 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylpyrazole-5-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 63.

MS(ESI): 552.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ8.15(s, 1H), 8.03(s, 1H), 7.80(s, 1H), 7.67-6.62(m, 2H), 7.49(t, J=6.6Hz, 1H) ),7.28(t,J＝7.7Hz,1H),7.17(t,J＝54.4Hz,1H),6.85(s,1H),6.64(s,1H),5.85-5.74(m,1H),5.26 -5.24(m,1H),4.68-4.62(m,1H),4.49-4.41(m,1H),4.12-4.06(m,2H),3.92(s,3H),3.25-3.16(m,2H) ,2.89-2.85(m,2H),2.26(s,3H),1.60(d,J=6.9Hz,3H).

Example 64: Preparation of Compound 64

The synthesis of compound 64 refers to the synthesis procedure of compound 27 in Example 27, wherein (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine is used in the second step Substitute (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, and in the fourth step, use cyclopropanecarboxylic acid instead of 3-oxetane carboxylic acid to synthesize Compound 64.

MS(ESI): 552.2[M+1]+.

¹ H NMR (400MHz, DMSO) δ8.15(s, 1H), 8.03(s, 1H), 7.80(s, 1H), 7.67-6.62(m, 2H), 7.49(t, J=6.6Hz, 1H) ), 7.28(t, J＝7.7Hz, 1H), 7.17(t, J＝54.4Hz, 1H), 6.85(s, 1H), 6.64(s, 1H), 5.85-5.74(m, 1H), 5.26 -5.24(m,1H),4.68-4.62(m,1H),4.49-4.41(m,1H),4.12-4.06(m,2H),3.92(s,3H),3.25-3.16(m,2H) ,2.89-2.85(m,2H),2.26(s,3H),1.60(d,J=6.9Hz,3H).

Example 65: Preparation of Compound 65

The synthesis of compound 65 refers to the synthesis procedure of compound 44 in Example 44, wherein the eighth step uses (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine In place of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, compound 65 was synthesized.

MS(ESI): 578.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.21-8.06(m,2H),7.78-7.70(m,1H),7.64-7.51(m,2H),7.41-7.31(m,2H),6.87(s, 1H), 5.70-5.50(m, 1H), 4.60(t, J=11.5Hz, 1H), 4.45-4.30(m, 1H), 4.28-4.10(m, 2H), 4.10-3.91(m, 1H) ,3.73-3.55(m,3H),3.53-3.47(m,2H),3.08-2.95(m,2H),2.33-2.25(m,3H),2.15-2.01(m,2H),1.97-1.66( m,4H),1.64-1.46(m,4H),0.87-0.63(m,4H).

Example 66: Preparation of Compound 66

synthetic route:

Preparation:

Step 1: Synthesis of compound 66A

Compound 44F (5.6 g, 17.2 mmol) and acetic acid (1.14 g, 18.9 mmol) were added to DMF (55 mL), the reaction solution was cooled to 0°C, and T ₃ P (14.2 g, 22.4 mmol), and then triethylamine (5.2 g, 51.6 mmol) was added dropwise, the dropwise addition was completed, and the reaction solution was heated to 25° C. and reacted for 1 h. After TLC showed that the reaction was over, ethyl acetate (200 mL) and saturated brine (200 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (40 mL×2), and the organic phases were combined, Dry, spin dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 (volume ratio)) to obtain compound 66A (5.1 g, khaki solid, yield 82.2%).

MS(ESI): m/z 329.2[M+1] ⁺ .

The second step: synthesis of compound 66B

To compound 66A (4.64 g, 14.1 mmol) was added 1,2-dichloroethane (50 mL), followed by carbon tetrachloride (1.73 g, 11.3 mmol), followed by triphenylphosphine (1.48 g, 5.64 g) mmol, 4.0 eq), after the addition, the gas was replaced three times with nitrogen, and then the reaction solution was heated to 80° C. and stirred for 2 h under nitrogen protection. After TLC showed that the reaction was complete, it was spin-dried to obtain the crude compound 66B (5.0 g, dark brown oil), which was directly used in the next step without further purification.

MS(ESI): m/z 347.1[M+1] ⁺ .

The third step: synthesis of compound 66C

To the crude compound 66B (5.0 g) obtained in the previous step was added NMP (50 mL), followed by (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (2.84 g) g, 15.0 mmol, 1.0 eq) and DIEA (3.8 g, 30.0 mmol), after the addition, the reaction solution was heated to 100 °C and stirred for 3 h. After TLC showed that the reaction was over, ethyl acetate (100 mL) and saturated brine (100 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (100 mL×2), the organic phases were combined and dried , spin to dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1 (volume ratio)) to obtain compound 66C (6.0 g, pale yellow solid, two-step yield 85.2%) .

MS(ESI): m/z 500.2[M+1] ⁺ .

Step 4: Synthesis of Compound 66D

Compound 66C (6.0 g, 12 mmol) was added to ethanol (60 mL), then concentrated hydrochloric acid (12 mL) was added, then the temperature was raised to 90° C., and the reaction was performed for 12 hours. TLC showed that the reaction was over, and spin-dried to obtain the crude hydrochloride of compound 66D. (5.8 g, white solid) was used in the next step without further purification.

Step 5: Synthesis of Compound 66

The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) was added to DCM (2 mL), then triethylamine (100 mg, 1.0 mmol) was added to the reaction solution, the reaction solution was cooled to 0 °C, and added in batches Triphosgene (296 mg, 1.0 mmol) was added and reacted at 0°C for 30 min. After TLC showed that the reaction was completed, dimethylamine hydrochloride (81.5 mg, 1.0 mmol) was added, and triethylamine (100 mg, 1.0 mmol) was added. After the addition, the reaction solution was warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was over, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (5 mL×2), the organic phases were combined, dried, and spun to dry, and the residue was prepared by HPLC Purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile was run to the end of 16 min) to give compound 66 (87 mg, white solid, 33.0% yield).

MS(ESI): 529.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ8.18(s, 2H), 7.80(s, 1H), 7.67(t, J=7.2Hz, 1H), 7.49(t, J=6.8Hz, 1H), 7.29( t, J＝7.6Hz, 1H), 7.23(t, J＝56Hz, 1H), 6.88(s, 1H), 5.87–5.68(m, 1H), 4.67(t, J＝10.8Hz, 1H), 4.19 (d, J＝10.8Hz, 1H), 3.62(d, J＝11.6Hz, 1H), 3.36(t, J＝11.2Hz, 2H), 3.15-3.08(m, 2H), 3.05-2.92(m, 2H), 2.80(s, 6H), 2.27(s, 3H), 2.15-2.05(m, 1H), 1.87(d, J=15.2Hz, 1H), 1.60(d, J=7.2Hz, 3H).

Example 67: Preparation of Compound 67

synthetic route:

Preparation:

Step 1: Synthesis of compound 67

The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) and compound 3-oxetane carboxylic acid (175 mg, 1.72 mmol) were added to DMF (5.5 mL), the reaction solution was cooled to 0 °C, and the mixture was added to DMF (5.5 mL). T3P (712 mg, 2.24 mmol) was added dropwise to the reaction solution, and then triethylamine (0.52 g, 5.16 mmol) was added dropwise. After the addition was completed, the reaction solution was heated to 25° C. and reacted for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), and the organic phases were combined, Dry, spin dry, the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20:1 (volume ratio)), and the product purified by column chromatography is purified by HPLC preparative purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min to end ) to give compound 67 (60 mg, off-white solid, 22.1% yield for two steps).

MS(ESI): m/z 542.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.17(d,J=7.3Hz,1H),7.77(d,J=5.3Hz,1H),7.66(t,J=7.3Hz,1H),7.49(t, J＝7.0Hz, 1H), 7.29(t, J＝7.7Hz, 1H), 7.23(t, J＝52.0Hz, 1H), 6.90(d, J＝4.5Hz, 1H), 5.82-5.77(m, 1H), 4.84-4.64(m, 4H), 4.61-4.49(m, 1H), 4.30-4.10 (m, 3H), 3.25-3.17(m, 3H), 3.06-3.02(m, 2H), 2.28( s, 3H), 2.11–2.07 (m, 1H), 1.92–1.85 (m, 1H), 1.60 (d, J=7.1Hz, 3H).

Example 68: Preparation of Compound 68

The synthesis of compound 68 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, (R)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 68.

MS(ESI): 556.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ9.83-9.69(m,1H),7.98(s,1H),7.79-7.70(m,1H),7.59(t,J=6.7Hz,1H),7.39(t , J=7.7Hz, 1H), 7.24(t, J=54.2Hz, 1H), 7.01(d, J=2.9Hz, 1H), 6.02-5.78(m, 1H), 4.80-4.59(m, 1H) ,4.38(dd,J＝6.7,4.0Hz,1H),4.21(d,J＝12.0Hz,1H),4.06-3.85(m,3H),3.81-3.64(m,3H),3.60-3.44(m ,2H),3.28-3.19(m,3H),2.51(s,3H),2.27-2.16(s,1H),2.12-1.96(m,3H),1.10(d,J=7.0Hz,3H).

Example 69: Preparation of Compound 69

The synthesis of compound 69 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, (S)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 69.

MS(ESI): 556.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ9.88-9.70(m,1H),7.95(s,1H),7.78-7.69(m,1H),7.58(t,J=6.7Hz,1H),7.38(t , J=7.7Hz, 1H), 7.25(t, J=54.2Hz, 1H), 7.00(d, J=2.9Hz, 1H), 6.01-5.78(m, 1H), 4.79-4.59(m, 1H) ,4.36(dd,J＝6.7,4.0Hz,1H),4.20(d,J＝12.0Hz,1H),4.05-3.83(m,3H),3.80-3.64(m,3H),3.59-3.44(m ,2H),3.28-3.18(m,3H),2.52(s,3H),2.25-2.14(s,1H),2.12-1.96(m,3H),1.69(d,J=7.0Hz,3H).

Example 70: Preparation of Compound 70

The synthesis of compound 70 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-cyano-1-cyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 70.

MS(ESI): 551.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.25-8.14(m,1H),7.80(s,1H),7.67(t,J=7.1Hz,1H),7.49(t,J=7.1Hz,1H), 7.29(t, J＝7.2Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.91(s, 1H), 5.87-5.74(m, 1H), 4.62(t, J＝11.2Hz, 1H) ), 4.30-4.14(m, 2H), 4.10-3.95(m, 1H), 3.72-3.53(m, 2H), 3.20-3.08(m, 3H), 2.28(s, 3H), 2.20-2.06(m ,1H),2.00-1.85(m,1H),1.75-1.40(m,7H).

Example 71: Preparation of Compound 71

The synthesis of compound 71 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-methoxycyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 71.

MS(ESI): 556.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.20(d,J=6.8Hz,1H),7.79(s,1H),7.67(t,J=7.2Hz,1H),7.49(t,J=6.9Hz, 1H), 7.29(t, J=7.2Hz, 1H), 7.23(t, J=56Hz, 1H), 6.91(s, 1H), 5.86–5.74(m, 1H), 4.64(t, J=10.8Hz) ,1H),4.21(d,J＝11.2Hz,1H),4.08(br.s,1H),3.32-3.25(m,7H),3.12-3.01(m,2H),2.28(s,3H), 2.18-2.02(m, 1H), 1.90(d, J=14.0Hz, 1H), 1.60(d, J=7.2Hz, 3H), 1.02-0.87(m, 4H).

Example 72: Preparation of Compound 72

The synthesis of compound 72 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, methyl chloroformate is used instead of dimethylamine hydrochloride to synthesize compound 72.

MS(ESI): 516.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.15(s,1H),7.79(s,1H),7.67(t,J=7.2Hz,1H),7.49(t,J=6.8Hz,1H),7.29( t, J＝7.2Hz, 1H), 7.23(t, J＝56Hz, 1H), 6.89(s, 1H), 5.86–5.73(m, 1H), 4.58(t, J＝10.6Hz, 1H), 4.20 (d, J=11.2Hz, 1H), 3.93 (d, J=7.2Hz, 1H), 3.74 (d, J=12.0Hz, 1H), 3.65 (s, 3H), 3.25-3.17 (m, 4H) ,3.05(s,1H),2.27(s,3H),2.15-2.05(m,1H),1.88(d,J=14Hz,1H),1.60(d,J=7.2Hz,3H).

Example 73: Preparation of Compound 73

The synthesis of compound 73 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, azetidine-1-acetic acid hydrochloride is used instead of 3-oxetane carboxylic acid to synthesize compound 73.

MS(ESI): 555.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ8.20(s, 1H), 7.78(s, 1H), 7.71-7.61(m, 1H), 7.50(t, J=4.0Hz, 1H), 7.29(t, J ＝4.0Hz, 1H), 7.24(t, J＝56Hz, 1H), 6.90(s, 1H), 5.85-5.73(m, 1H), 4.66-4.49(m, 1H), 4.25-4.10(m, 2H) ),3.97-3.85(m,1H),3.75-3.70(m,1H),3.47-3.40(m,2H),3.34-3.29(m,4H),3.27-3.22(m,1H),3.19-3.08 (m,3H),2.62-2.53(m,1H),2.28(s,3H),2.15-2.0(m,2H),1.93-1.78(s,1H),1.60(d,J=6.4Hz,3H ).

Example 74: Preparation of Compound 74

The synthesis of compound 74 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, methoxyacetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 74.

MS(ESI): 530.2[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.78 (s, 1H), 7.67 (t, J=7.5Hz, 1H), 7.49 (t, J=7.1Hz, 1H) ,7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.90(s,1H),5.85-5.75(m,1H),4.66-4.55(m,1H), 4.25-4.10(m, 3H), 3.97-3.85(m, 1H), 3.69-3.65(m, 1H), 3.34(s, 2H), 3.31(s, 3H), 3.26-3.14(m, 3H), 3.09-3.04(m, 1H), 2.27(s, 3H), 2.15-2.06(m, 1H), 1.93-1.84(m, 1H), 1.60(d, J=7.0Hz, 3H).

Example 75: Preparation of Compound 75

synthetic route:

Preparation:

Step 1: Synthesis of Compound 75

The crude hydrochloride salt of compound 66D (0.24 g, 0.5 mmol) was added to anhydrous acetonitrile (5 ml), then potassium carbonate (138 mg, 1.0 mmol) and tetrahydrofuran-3-yl methanesulfonate (166 mg, 1.0 mmol) were added sequentially mmol), and then the reaction solution was heated and reacted under reflux conditions for 12 hours. After TLC showed that the reaction was over, after rotating to dryness, water (20 mL) and ethyl acetate (20 mL) were added, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (5 mL×2), the organic phases were combined, dried, and rotated. Dry, the residue was purified by preparative HPLC (Waters Sunfire OBD 100x30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to give compound 75 (61 mg, white solid, 23.0% yield).

MS(ESI): 528[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.14(d,J=7.3Hz,1H),7.79(s,1H),7.65(t,J=7.4Hz,1H),7.47(d,J=7.2Hz, 1H), 7.28(t, J=7.5Hz, 1H), 7.23(t, J=53.8Hz, 1H), 6.84(s, 1H), 5.85-5.71(m, 1H), 4.65(t, J=11.1 Hz,1H),4.16(d,J＝8.4Hz,1H),3.85-3.74(m,2H),3.72-3.60(m,1H),3.53(t,J＝7.6Hz,1H),3.15-2.87 (m,4H),2.80-2.66(m,1H),2.60-2.52(m,1H),2.37-2.17(m,5H),2.15-1.93(m,2H),1.86-1.69(m,2H) ,1.58(d,J=6.7Hz,3H).

Example 76: Preparation of Compound 76

synthetic route:

Preparation:

Step 1: Synthesis of Compound 76

The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) was added to anhydrous THF (5 ml), then paraformaldehyde (225 mg, 2.5 mmol) was added, stirred at room temperature for 4 hours, and then sodium cyanoborohydride was added (157 mg, 2.5 mmol). The mixture was heated to 50°C overnight with stirring. After cooling, 25 mL of water was added, the aqueous phase was extracted twice with dichloromethane (10 mL×2), the organic phases were combined, dried, and spun to dry, and the residue was purified by HPLC preparation (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile for 10 min, 95% acetonitrile for 14 min, 10% acetonitrile for 16 min) to obtain compound 76 (61 mg, white solid, 26.0% yield).

MS(ESI): 472.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.23-8.12(m,2H),7.80(s,1H),7.67(t,J=7.2Hz,1H),7.49(t,J=6.9Hz,1H), 7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.87(s,1H),5.79(q,J＝6.9Hz,1H),4.62(t,J＝10.8 Hz,1H),4.18(dd,J=7.6,3.4Hz,1H),3.37(t,J=10.8Hz,2H),3.11(d,J=11.6Hz,1H),3.04-2.96(m,1H) ),2.84(d,J＝10.8Hz,1H),2.63(d,J＝9.8Hz,1H),2.28(s,3H),2.27(s,3H),2.23-2.01(m,2H),1.83 (d, J=15.5Hz, 1H), 1.60 (d, J=7.0Hz, 3H).

Example 77: Preparation of Compound 77

The synthesis of compound 77 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 1-bromo-2-methoxyethane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 77.

MS(ESI): 516.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.12(t,J=7.1Hz,1H),7.80(d,J=8.1Hz,1H),7.67(d,J=7.1Hz,1H),7.49(d, J＝6.7Hz,1H),7.29(dd,J＝15.5,7.8Hz,1H),7.25(td,J＝54.4,15.5Hz,1H),6.87(d,J＝8.8Hz,,1H),5.85 -5.71(m, 1H), 4.70-4.57(m, 1H), 4.17(s, 1H), 3.52-3.45(m, 2H), 3.40-3.35(m, 1H), 3.28(d, J=8.8Hz ,3H),3.13-3.04(m,1H),3.02-2.88(s,2H),2.75-2.65(m,1H),2.60-2.53(m,2H),2.36-2.28(m,1H),2.28 (d, J=7.1Hz, 3H), 2.25-2.18 (m, 1H), 2.15-2.02 (m, 1H), 1.86-1.77 (m, 1H), 1.60 (t, J=7.1Hz, 3H).

Example 78: Preparation of Compound 78

The synthesis of compound 78 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, azetidine is used instead of dimethylamine hydrochloride to synthesize compound 78.

MS(ESI): 541.2[M+1] ⁺ .

¹ H NMR(400MHz, DMSO)δ8.18(d,J=7.1Hz,2H),7.77(s,1H),7.67(t,J=7.3Hz,1H),7.49(t,J=6.7Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.88(s, 1H), 5.86-5.72(m, 1H), 4.62(t, J=10.7 Hz, 1H), 4.23-4.17(m, 1H), 4.01-3.89(m, 4H), 3.75(d, J=12.6Hz, 1H), 3.29-3.23(m, 2H), 3.22-3.05(m, 4H), 3.03-2.94(m, 1H), 2.27(s, 3H), 2.22-2.04(m, 3H), 1.89(d, J=15.0Hz, 1H), 1.60(d, J=7.0Hz, 3H ).

Example 79: Preparation of Compound 79

The synthesis of compound 79 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, nicotinic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 79.

MS(ESI): 563.2[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.76-8.60(m,2H),8.20(br.s,1H),8.01-7.74(m,2H),7.68(t,J=4.0,1H),7.58- 7.46(m, 2H), 7.30(t, J=8.0Hz, 1H), 7.24(t, J=56Hz, 1H), 6.90(s, 1H), 5.87-5.74(m, 1H), 4.73-4.52( m,1H),4.42-4.09(m,2H),3.72-3.58(m,1H),3.47-3.36(m,2H),3.25-3.18(m,1H),3.15-3.09(m,2H), 2.28(s, 3H), 2.21-1.75(m, 2H), 1.60(d, J=7.2Hz, 3H).

Example 80: Preparation of Compound 80

The synthesis of compound 80 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, acetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 80.

MS(ESI): 500.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.14(d,J=3.7Hz,1H),7.77(d,J=2.3Hz,1H),7.65(t,J=7.5Hz,1H),7.48(t, J=7.2Hz, 1H), 7.27(t, J=7.7Hz, 1H), 7.22(t, J=57.0Hz, 1H), 6.88(s, 1H), 5.86-5.70(m, 1H), 4.63- 4.52(m, 1H), 4.21-4.17(m, 2H), 3.95-3.84(m, 2H), 3.47-3.37(m, 2H), 3.14-2.98(m, 2H), 2.26(s, 3H), 2.08-2.02(m, 4H), 1.89-1.80(m, 1H), 1.57(d, J=7.1Hz, 3H).

Example 81: Preparation of Compound 81

The synthesis of compound 81 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, 3-azetidinol is used instead of dimethylamine hydrochloride to synthesize compound 81.

MS(ESI): 558.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.15(d,J=7.5Hz,1H),7.79(s,1H),7.65(t,J=7.4Hz,1H),7.48(t,J=7.2Hz, 1H), 7.28(t, J=7.5Hz, 1H), 7.23(t, J=54.3Hz, 1H), 6.88(s, 1H), 5.86-5.71(m, 1H), 5.39-5.27(m, 1H) ), 4.78(t, J＝6.7Hz, 2H), 4.64-4.45(m, 3H), 4.25-4.14(m, 1H), 4.07-3.67(m, 1H), 3.26-3.14(m, 4H), 3.10-3.04(m, 2H), 2.26(s, 3H), 2.18-2.01(m, 1H), 1.94-1.82(m, 1H), 1.58(d, J=7.0Hz, 3H).

Example 82: Preparation of Compound 82

The synthesis of compound 82 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 3-iodooxetane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 82.

MS(ESI): 514.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.15(d,J=7.2Hz,1H),7.81(s,1H),7.66(t,J=7.3Hz,1H),7.48(t,J=6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.85(s, 1H), 5.87-5.70(m, 1H), 4.72-4.53(m, 3H) ), 4.47(t, J＝5.3Hz, 2H), 4.21-4.09(m, 1H), 3.56-3.45(m, 1H), 3.29-3.22(m, 1H), 3.17-3.08(m, 1H), 3.05-2.95(m, 1H), 2.82-2.69(m, 1H), 2.62-2.51(m, 1H), 2.25(s, 3H), 2.25-2.20(m, 3H), 1.83(d, J=15.8 Hz,1H),1.58(d,J＝6.9Hz,3H).

Example 83: Preparation of Compound 83

synthetic route:

Preparation:

Step 1: Synthesis of compound 83

The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) was added to isopropanol (5 mL), then 5-iodo-1-methyl-pyrazole (208 mg, 1.0 mmol), ethylene glycol ( 0.33 g, 1.0 mmol), Cul (50 mg, 0.25 mmol mmol) and anhydrous potassium phosphate (633 mg, 3.0 mmol). The reaction mixture was heated to 100°C in a sealed tube under nitrogen protection for 16 hours. After TLC showed completion, the reaction mixture was filtered through celite, washed with EtOAc (100 mL) and the filtrate was concentrated in vacuo. The resulting residue was preparatively purified by HPLC (Waters Sunfire OBD 100x30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to give compound 83 (56 mg, white solid, 21.0% yield).

MS(ESI): 538.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.18(d,J=7.2Hz,1H),7.87(s,1H),7.67(t,J=7.2Hz,1H),7.47(d,J=6.6Hz, 1H), 7.34–7.25 (m, 2H), 7.23 (t, J=54Hz, 1H), 6.88 (s, 1H), 5.94 (d, J=1.8Hz, 1H), 5.83–5.73 (m, 1H) ,4.68(t,J＝11.1Hz,1H),4.24-4.16(m,1H),3.68(s,3H), 3.59-3.48(m,1H),3.27-3.13(m,3H),3.04-2.78 (m, 3H), 2.26 (s, 3H), 2.22–2.06 (m, 1H), 1.99–1.88 (m, 1H), 1.59 (d, J=7.2Hz, 3H).

Example 84: Preparation of Compound 84

The synthesis of compound 84 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, ammonia gas is used instead of dimethylamine hydrochloride to synthesize compound 84.

MS(ESI): 501.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.16(d,J=7.2Hz,1H),7.77(s,1H),7.65(t,J=7.2Hz,1H),7.48(t,J=6.9Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.86(s, 1H), 6.09(s, 2H), 5.80-5.75(m, 1H), 4.60(t,J＝10.5Hz,1H),4.19(d,J＝10.9Hz,1H),3.90(d,J＝12.9Hz,1H),3.66(s,1H),3.28-3.05(m,4H) ), 3.02-2.91(m, 1H), 2.25(s, 3H), 2.09(s, 1H), 1.80(d, J=15.5Hz, 1H), 1.58(d, J=7.0Hz, 3H).

Example 85: Preparation of Compound 85

The synthesis of compound 85 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-methylpyrazole-5-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 85.

MS(ESI): 566.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.17(s,1H),7.79(s,1H),7.65(t,J=7.2Hz,1H),7.55-7.44(m,2H),7.28(t,J =8.0Hz,1H),7.22(t,J=52Hz,2H),6.88(s,1H),6.59-6.44(m,1H),5.85- 5.71(m,1H),4.60(t,J=10.8 Hz,1H),4.41-4.05(m,2H),3.87(s,3H),3.83-3.68(m,1H),3.50-3.40(m,1H),3.31-3.23(m,2H),3.18- 3.09(m, 2H), 2.26(s, 3H), 2.10-1.93(m, 1H), 1.88-1.72(m, 1H), 1.58(d, J=7.2Hz, 3H).

Example 86: Preparation of Compound 86

The synthesis of compound 86 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 1-bromopropane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 86.

MS(ESI): 500.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.12(d,J=6.8Hz,1H),7.80(s,1H),7.66(t,J=7.6Hz,1H),7.55-7.43(m,1H), 7.34-7.25(m, 1H), 7.23(t, J=54.5Hz, 1H), 6.84(s, 1H), 5.89-5.68(m, 1H), 4.65(t, J=10.3Hz, 1H), 4.16 (d, J＝10.0Hz, 1H), 3.31-3.24(m, 1H), 3.14-3.01(m, 1H), 2.96-2.80(m, 2H), 2.78-2.56(m, 2H), 2.44-2.30 (m, 2H), 2.25(s, 3H), 2.16-1.97(m, 1H), 1.83(d, J=15.1Hz, 1H), 1.58(d, J=6.8Hz, 3H), 1.02(s, 6H).

Example 87: Preparation of Compound 87

The synthesis of compound 87 refers to the synthesis procedure of compound 75 in Example 75, wherein in the first step, 3-(bromomethyl)oxetane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 87.

MS(ESI): 528.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.11(d,J=7.5Hz,1H),7.80(s,1H),7.65(t,J=7.5Hz,1H),7.48(t,J=6.8Hz, 1H), 7.27(t, J=7.7Hz, 1H), 7.23(t, J=54.0Hz, 1H), 6.83(s, 1H), 5.81- 5.72(m, 1H), 4.67-4.59(m, 3H) ), 4.31-4.26(m, 2H), 4.18-4.11(m, 1H), 3.31-3.17(m, 2H), 3.03(d, J=11.4Hz, 1H), 2.96-2.89(m, 1H), 2.81(d,J＝11.1Hz,1H),2.69(d,J＝7.5Hz,2H),2.59(d,J＝9.6Hz,1H),2.28-2.23(m,4H),2.22-2.01(m ,2H),1.79(d,J＝16.0Hz,1H),1.57(d,J＝7.0Hz,3H).

Example 88: Preparation of Compound 88

The synthesis of compound 88 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, pivalic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 88.

MS(ESI): 542.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.17(d,J=7.6Hz,1H),7.76(s,1H),7.64(t,J=7.6Hz,1H),7.48(t,J=6.8Hz, 1H), 7.27(t, J=8.8Hz, 1H), 7.22(t, J=56Hz, 2H), 6.87(s, 1H), 5.82-5.70(m, 1H), 4.63(t, J=10.4Hz) ,1H),4.28-4.14(m,2H),4.00(d,J=12.4Hz,1H),3.34-3.25(m,3H),3.03-2.95(m,2H),2.25(s,3H), 2.18-2.05(m, 1H), 1.92(d, J=14.8Hz, 1H), 1.58(d, J=7.2Hz, 3H), 1.23(s, 9H).

Example 89: Preparation of Compound 89

The synthesis of compound 89 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 2-bromo-1,1,1-trifluoroethane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 89.

MS(ESI): 540.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.12(d,J=7.2Hz,1H),7.83(s,1H),7.65(t,J=7.2Hz,1H),7.48(t,J=6.6Hz, 1H), 7.28(t, J=7.5Hz, 1H), 7.23(t, J=54Hz, 1H), 6.85(s, 1H), 5.84–5.72(m, 1H), 4.62(t, J=10.8Hz) ,1H),4.17(d,J=10.5Hz,1H),3.48-3.35(m,1H),3.30-3.20(m,2H),3.13-2.92(m,3H),2.78(d,J=11.1 Hz, 1H), 2.65(t, J=10.2Hz, 1H), 2.57(d, J=10.5Hz, 1H), 2.25(s, 3H), 2.16–1.99(m, 1H), 1.81(d, J =15.6Hz,1H),1.58(d,J=6.9Hz,3H).

Example 90: Preparation of Compound 90

The synthesis of compound 90 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, bromoacetonitrile is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 90.

MS(ESI): 497.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.15(d,J=7.5Hz,1H),7.81(s,1H),7.66(t,J=7.2Hz,1H),7.48(t,J=6.9Hz, 1H), 7.28(t, J=7.8Hz, 1H), 7.23(t, J=54Hz, 1H), 6.87(s, 1H), 5.83-5.71(m, 1H), 4.57(t, J=11.1Hz) ,1H),4.19(d,J＝11.1Hz,1H),3.92–3.76(m,2H),3.38(d,J＝9.6Hz,1H),3.19(d,J＝11.1Hz,1H),3.09 -3.01(m, 1H), 2.90(d, J=10.8Hz, 1H), 2.68(d, J=9.9Hz, 1H), 2.56-2.50(m, 1H), 2.40(t, J=9.9Hz, 1H), 2.25(s, 3H), 2.15-2.02(m, 1H), 1.87(d, J=14.7Hz, 1H), 1.58(d, J=7.2Hz, 3H).

Example 91: Preparation of Compound 91

The synthesis of compound 91 refers to the synthesis steps of compound 44 in Example 44, wherein acetic acid is used instead of cyclopropanecarboxylic acid in the sixth step, and (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methane is used in the eighth step) (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was synthesized to give compound 91.

MS(ESI): 552.2[M+1] ⁺ .

¹ H NMR(300MHz,dmso)δ8.14-8.06(m,1H),7.76-7.70(m,1H),7.63-7.52(m,2H),7.42(t,J=7.6Hz,1H),7.34 (d, J=7.9Hz, 1H), 6.87(s, 1H), 5.67-5.52(m, 1H), 4.64-4.49(m, 1H), 4.44-4.27(m, 1H), 4.25-4.11(m ,2H),3.98-3.79(m,1H),3.75-3.55(m,4H),3.21-3.11(m,3H),3.07-2.94(m,2H),2.29(d,J=4.6Hz,3H ),2.14-2.00(m,4H),1.95-1.67(m,4H),1.63-1.44(m,4H).

Example 92: Preparation of Compound 92

The synthesis of compound 92 refers to the synthesis procedure of compound 44 in Example 44, wherein the eighth step uses (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro -2-Methylpropan-2-ol was substituted for (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, and compound 92 was synthesized.

MS(ESI): 584.2[M+1] ⁺ .

¹ H NMR(400MHz,dmso)δ8.12(d,J=7.3Hz,1H),7.78(s,1H),7.57(t,J=6.6Hz,1H),7.28(t,J=6.6Hz, 1H), 7.19(t, J＝7.7Hz, 1H), 6.87(s, 1H), 5.82–5.71(m, 1H), 5.30(s, 1H), 4.60(t, J＝10.2Hz, 1H), 4.26–4.14 (m, 2H), 4.06–3.96 (m, 1H), 3.66–3.47 (m, 1H), 3.27–2.99 (m, 4H), 2.24 (s, 3H), 2.16–1.99 (m, 2H) ), 1.97–1.82 (m, 1H), 1.55 (d, J=7.0Hz, 3H), 1.20 (d, J=12.3Hz, 6H), 0.81–0.68 (m, 4H).

Example 93: Preparation of Compound 93

Synthesis of compound 93 Refer to the synthetic procedure of compound 70 in Example 70, using (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methyl Substituting (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine with ylpropan-2-ol, compound 93 was synthesized.

MS(ESI): 609.2[M+1] ⁺ .

¹ H NMR(400MHz,dmso)δ8.15(d,J=5.5Hz,1H),7.79(s,1H),7.57(t,J=6.6Hz,1H),7.28(t,J=6.6Hz, 1H), 7.19(t, J=7.7Hz, 1H), 6.89(s, 1H), 5.82–5.74(m, 1H), 5.30(s, 1H), 4.60(t, J=10.6Hz, 1H), 4.26–4.14 (m, 2H), 4.06–3.96 (m, 1H), 3.73–3.33 (m, 4H), 3.19–3.06 (m, 1H), 2.24 (s, 3H), 2.17–2.06 (m, 1H) ), 1.99–1.89 (m, 1H), 1.67–1.49 (m, 7H), 1.20 (d, J=12.1Hz, 6H).

Example 94: Preparation of Compound 94

Synthesis of compound 94 Refer to the synthetic procedure of compound 89 in Example 89, using (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methyl Substituting (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine with ylpropan-2-ol, compound 94 was synthesized.

MS(ESI): 598.2[M+1] ⁺ .

¹ H NMR(400MHz,dmso)δ8.09(d,J=7.0Hz,1H),7.82(s,1H),7.57(t,J=6.5Hz,1H),7.29(t,J=6.6Hz, 1H), 7.20(t, J＝7.7Hz, 1H), 6.84(s, 1H), 5.80–5.73(m, 1H), 5.30(s, 1H), 4.61(t, J＝10.6Hz, 1H), 4.18–4.15 (m, 1H), 3.42–3.37 (m, 1H), 3.29–3.22 (m, 2H), 3.10–3.07 (m, 1H), 3.02–2.99 (m, 2H), 2.79–2.77 (m ,1H),2.68–2.64(m,1H),2.55(t,J=10.3Hz,1H),2.24(s,3H),2.12–2.03(m,1H),1.84–1.80(m,1H), 1.55(d,J=7.1Hz,3H),1.21(d,J=12.6Hz,6H).

Experimental Example 1: Binding Experiment of KRAS(G12C) and SOS1

This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12C. Lower _IC50 values indicate high potency of compounds as SOS1 inhibitors in the following assay setup.

1. Experimental materials:

KRAS(G12C) protein was synthesized by Pujian Biotechnology Co., Ltd.;

SOS1 protein exchange human recombinant domain protein (564-1049) was purchased from Cytoskeleton;

Anti-6-histidine-tagged monoclonal antibody XL665 (Mab Anti 6HIS-XL665) and anti-glutathione thioltransferase-tagged europium cryptate monoclonal antibody (Mab Anti GST-Eu cryptate) were purchased from Cisbio.

2. Experimental method:

1X buffer preparation (as is): Hepes: 5 mM; NaCl: 150 mM; EDTA: 10 mM; Igepal: 0.0025%; KF: 100 mM; DTT: 1 mM; BSA: 005%.

The compounds to be tested were diluted 3-fold to the 8th concentration, ie, from 100 μM to 45.7 nM, using a row gun.

Dilute each compound to be tested with 1X buffer into a working solution of 2% DMSO, add 5 μL/well to the corresponding well, and set up a double-well experiment. Centrifuge for 1 min at 1000 rpm.

A mixed working solution of KRAS(G12C) (200nM) and Mab Anti GST-Eu cryptate (1ng/μL) was prepared with 1X buffer, and the mixed working solution was placed at 25℃ for 5min, and 2.5μL/well was added to the corresponding well.

Prepare a mixed working solution of SOS1 (80nM) and Mab Anti 6HIS-XL665 (8g/μL) with 1X buffer, add 2.5μL/well to the corresponding well, and add 2.5μL Mab Anti 6HIS-XL665 (8g/μL) to the Blank well ) dilution solution, at this time, the final concentration of the compound was diluted from 1 μM to 0.457nM, KRAS(G12C)(500nM), MAb Anti GST-Eucryptate(0.25ng/μL), SOS1(20nM), Mab Anti 6HIS-XL665(2g /μL), the reaction system was placed at 25 °C for 60 min. After the reaction, the HTRF was read using a multi-label analyzer.

Max well: 1% DMSO, KRAS(G12C) (500nM), MAb Anti GST-Eu cryptate (0.25ng/μL), SOS1 (20nM), Mab Anti 6HIS-XL665 (2g/μL)

Min well: 1% DMSO, KRAS(G12C)(500nM), MAb Anti GST-Eu cryptate(0.25ng/μL), Mab Anti 6HIS-XL665(2g/μL)

3. Data analysis:

Using the equation (sample-Min)/(Max-Min)×100%, the raw data is converted into inhibition rate, and the IC ₅₀ value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).

The inhibitory activity of compound 1 prepared by the present invention and KRAS-SOS1 inhibitor BI-3406 commonly used in the art on the binding of KRAS (G12C) to SOS1 is shown in Table 1, wherein + represents >1uM, ++ represents 100nM-1uM , +++ stands for 10nM-100nM, ++++ stands for <10nM, ND stands for not tested.

Table 1. _IC50 data for inhibition of KRAS(G12C) and SOS1 binding by compounds of the invention

化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)
对照化合物BI-3406Control compound BI-3406	8.38.3
化合物1Compound 1	7.677.67
化合物2Compound 2	7.977.97
化合物3Compound 3	14.0314.03
化合物4Compound 4	3.953.95
化合物5Compound 5	27.2227.22
化合物6Compound 6	2.572.57
化合物7Compound 7	20.820.8
化合物10Compound 10	8.688.68
化合物11Compound 11	13.113.1
化合物12Compound 12	20.1420.14
化合物13Compound 13	39.639.6
化合物14Compound 14	24.124.1

化合物15Compound 15	48.948.9
化合物16Compound 16	20.7920.79
化合物44Compound 44	3.43.4
化合物70Compound 70	10.110.1
化合物89Compound 89	9.19.1

It can be seen from Table 1 that the compounds of the present invention have a good inhibitory effect on SOS1, and have a significant inhibitory effect on the combination of KRAS(G12C) and SOS1, and the inhibitory effect of some compounds is less than 10nM, which has a good clinical application prospect.

Experimental example 2: p-ERK experiment

Experimental Materials:

DLD-1 cells were purchased from Wuhan Prosser Life Technology Co., Ltd.; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio.

experimental method:

DLD-1 cells were seeded in a transparent 96-well cell culture plate, 80 μL of cell suspension per well, each well containing 8000 DLD-1 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37 degrees overnight;

Compounds to be tested were diluted with 100% DMSO to 2 mM as the first concentration, and then 5-fold diluted with a pipette to the eighth concentration, ie, from 2 mM to 0.026 [mu]M. Add 2 μL of compound to 78 μL of cell starvation medium, and after mixing, add 20 μL of compound solution to the corresponding cell plate wells, put the cell plate back into the carbon dioxide incubator and continue to incubate for 1 hour. is 0.5%;

After the incubation, discard the cell supernatant and add 50 μL of cell lysate to each well, and incubate with shaking at room temperature for 30 minutes;

Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody were diluted 20-fold with Detection buffer;

Take 16μL of cell lysate supernatant per well into a new 384 white microplate, add 2μL of Phospho-ERK1/2 Eu Cryptate antibody dilution and 2μL of Phospho-ERK1/2 d2 antibody dilution, and incubate at room temperature for 4 hours;

After the incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm.

data analysis:

Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into inhibition rate, the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived). Table 2 shows the inhibitory activity of compound 1 prepared by the present invention and KRAS-SOS1 inhibitor BI-3406 commonly used in the art on DLD-1 cell phosphorylation.

Table 2. Test results IC ₅₀ data of the compounds of the present invention on DLD-1 cell phosphorylation inhibitory activity

化合物编号Compound number	IC50(nM)IC50(nM)	化合物编号Compound number	IC50(nM)IC50(nM)
对照化合物BI-3406Control compound BI-3406	20.0720.07	化合物47Compound 47	7.337.33
化合物1Compound 1	97.5797.57	化合物48Compound 48	23.1223.12
化合物2Compound 2	23.1123.11	化合物49Compound 49	73.9773.97
化合物3Compound 3	48.048.0	化合物50Compound 50	367.10367.10
化合物4Compound 4	5.905.90	化合物51Compound 51	30.6330.63
化合物5Compound 5	20.1120.11	化合物52Compound 52	103.70103.70
化合物6Compound 6	2.572.57	化合物53Compound 53	79.6779.67
化合物7Compound 7	82.9282.92	化合物54Compound 54	31.2931.29
化合物8Compound 8	13.8113.81	化合物55Compound 55	19.6719.67
化合物9Compound 9	513.3513.3	化合物56Compound 56	6.026.02
化合物10Compound 10	25.1225.12	化合物57Compound 57	177.50177.50
化合物11Compound 11	63.0763.07	化合物58Compound 58	99.2899.28
化合物12Compound 12	31.2531.25	化合物59Compound 59	5.395.39
化合物13Compound 13	39.5939.59	化合物60Compound 60	18.0718.07
化合物14Compound 14	24.1524.15	化合物61Compound 61	918.4918.4
化合物15Compound 15	48.9248.92	化合物62Compound 62	99.9899.98
化合物16Compound 16	20.7920.79	化合物63Compound 63	69.1069.10
化合物17Compound 17	387.2387.2	化合物64Compound 64	16.5216.52
化合物18Compound 18	344.4344.4	化合物65Compound 65	78.278.2
化合物19Compound 19	97.3497.34	化合物66Compound 66	47.1047.10
化合物20Compound 20	94.2394.23	化合物67Compound 67	13.2113.21
化合物21Compound 21	467.8467.8	化合物68Compound 68	10.2810.28
化合物22Compound 22	92.8192.81	化合物69Compound 69	18.2918.29

化合物23Compound 23	76.4376.43	化合物70Compound 70	19.1719.17
化合物24Compound 24	89.9389.93	化合物71Compound 71	49.1549.15
化合物25Compound 25	46.2546.25	化合物72Compound 72	78.1478.14
化合物26Compound 26	20.1120.11	化合物73Compound 73	389.9389.9
化合物27Compound 27	1.791.79	化合物74Compound 74	28.4628.46
化合物28Compound 28	22.2322.23	化合物75Compound 75	31.9531.95
化合物29Compound 29	21.1521.15	化合物76Compound 76	30.3030.30
化合物30Compound 30	12.612.6	化合物77Compound 77	11.4811.48
化合物31Compound 31	2.932.93	化合物78Compound 78	43.5043.50
化合物32Compound 32	806.8806.8	化合物79Compound 79	40.6540.65
化合物33Compound 33	295.9295.9	化合物80Compound 80	12.2112.21
化合物34Compound 34	15.9315.93	化合物81Compound 81	78.1978.19
化合物35Compound 35	267.1267.1	化合物82Compound 82	35.7835.78
化合物36Compound 36	76.6776.67	化合物83Compound 83	24.1424.14
化合物37Compound 37	20.8920.89	化合物84Compound 84	88.1788.17
化合物38Compound 38	20.3920.39	化合物85Compound 85	51.5451.54
化合物39Compound 39	4.614.61	化合物86Compound 86	75.3475.34
化合物40Compound 40	3.713.71	化合物87Compound 87	27.3927.39
化合物41Compound 41	25.7825.78	化合物88Compound 88	49.1549.15
化合物42Compound 42	20.8420.84	化合物89Compound 89	16.7116.71
化合物43Compound 43	48.6548.65	化合物90Compound 90	70.8070.80
化合物44Compound 44	11.1011.10	化合物92Compound 92	2.402.40
化合物45Compound 45	186.1186.1	化合物93Compound 93	2.402.40
化合物46Compound 46	25.9825.98	化合物94Compound 94	10.9010.90

It can be seen from Table 2 that the compounds of the present invention, many of which are significantly better than the positive control BI-3406, have extremely excellent inhibitory effect on the phosphorylation of DLD-1 cells, and have good clinical application prospects.

Experimental example 3: In vivo pharmacodynamic experiment 2

1. Experimental purpose

To evaluate the in vivo efficacy of test compounds in human pancreatic cancer MIA-PaCa2 cell subcutaneous xenograft tumor model.

2. Experimental animals

BALB/nude mice, female, 6-8 weeks old, weighing 18-22 g, were provided by Beijing Weitong Lihua Technology Co., Ltd.

3. Experimental method

The MIA-PaCa2 tumor cells were resuspended in PBS to prepare a cell suspension with a density of 1×10 ⁷ cells/mL, and 0.2 mL of the cell suspension was subcutaneously inoculated on the right back of each mouse (Add Matrigel, volume ratio of 1:1), waiting for tumor growth. Randomization was initiated when the mean tumor volume reached approximately 150 ^mm3 . After administration, tumor diameters were measured with a vernier caliper twice a week, and the tumor volume was calculated as follows:

V=0.5a×b ² , where a and b represent the long and short diameters of the tumor, respectively.

The tumor-inhibitory efficacy of a compound was evaluated by TGI (%), which reflects the tumor growth inhibition rate and was calculated as follows:

TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group-at the beginning of treatment in the solvent control group Mean tumor volume)] × 100%.

4. Experimental results

The related results are shown in Table 9.

Table 9. In vivo efficacy test results

5. Experimental conclusion

22 days after the start of administration, under the same dose, the compound of the present invention has a more significant tumor inhibitory effect compared with the positive control BI-3406, and the TGI can reach 80% at the highest, indicating that the compound of the present invention is effective in human pancreas. The cancer MIA-PaCa2 subcutaneous xenograft tumor model showed good in vivo efficacy.

Although the embodiments of the present invention have been shown and described above, it is to be understood that the above-described embodiments are exemplary and should not be construed to limit the present invention. Without departing from the principles and spirit of the present invention, those of ordinary skill in the art can make changes, modifications, substitutions and alterations to the above-mentioned embodiments within the scope of the present invention, and these changes, modifications, substitutions and modifications are all included in the within the scope of the present invention.

Claims

A tetracyclic compound, characterized in that the compound is a compound represented by formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or pro- medicine,

in,

A is selected from C 6 -C 10 aryl, 5- to 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, and wherein each of the aryl, monocyclic and bicyclic heteroaryl groups optionally substituted with m independent R 4 , wherein m is independently any integer from 0 to 5;

X and Y are each independently selected from CR or N;

Z 1 and Z 2 are each independently selected from -O-, -CR 7 - or -NR 7 -;

L 1 , L 2 and L 3 are each independently independently selected from -(CH 2 ) n - or -(CH 2 ) n -O-(CH 2 ) p -O-(CH 2 ) o - or -O-( CH 2 ) q -, wherein each of n, o, p and q is independently any integer from 0 to 3;

R 1 and R 2 are each independently selected from hydrogen and C 1 -C 8 alkyl, or R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, said alkyl and cycloalkane Each group is optionally substituted by at least 1 R 8 , and R 1 or R 2 and A ring form a 4-8 membered saturated carbocyclic or heterocyclic ring;

R 3 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R 7 ), -C(=O)-NH(R 7 ), C 1 -C 6 alkyl, C 2 -C 4 alkenyl , C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 1 -C 3 alkoxy and C 1 -C 6 haloalkyl, and wherein said alkyl , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl are each optionally substituted with at least 1 R 8 ;

R 4 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R 7 ), -C(=O)-NH(R 7 ), C 1 -C 6 alkyl, C 3 -C 6 cycloalkane alkyl, 3- to 8-membered heterocycloalkyl, C 1 -C 3 alkoxy and C 1 -C 6 haloalkyl, and wherein said alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl each is optionally substituted with at least 1 R;

R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N(R 7 )(R 8 ), C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C1 - C3alkoxy, and C1 - C6 haloalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, and wherein The alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1 R 10 ;

R 7 is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -N(R 8 )(R 9 ), -C(=O)-N(R 8 )(R 9 ), -C(= O)-R 8 , -C(=O)-OR 8 , -S(=O) 2 -R 8 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocycle Alkyl, 5-10-membered aryl or heteroaryl, C1 - C3 alkoxy or C1 - C6 haloalkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 5- to 6-membered heteroalkyl group cycloalkyl, and wherein said alkyl, cycloalkyl, heterocycloalkyl, alkoxy, and haloalkyl are each optionally substituted with at least 1 R;

Each of R 8 and R 9 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 ring Alkyl, 3- to 14-membered heterocycloalkyl, C1 - C3alkoxy, C1 - C3haloalkoxy , C6 -C10aryl, 5- to 6-membered monocyclic heteroaryl or 9- to 10 membered bicyclic heteroaryl, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl and bicyclic heteroaryl each is optionally substituted with at least 1 R 10 ;

The heteroatom or heteroatom group contained in the heteroalkyl group, heterocycloalkyl group, heterocycloalkoxy group, heteroaryl group described in R 1 to R 9 are independently selected from -C(=O)N(R 10 )-, -N(R 10 )-, -NH-, -N=, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S) -, -S(=O)-, -S(=O) 2 - and -N(R 10 )C(=O)N(R 10 )-, the number of said heteroatoms or heteroatoms is independently selected from 1, 2 and 3;

Each R 10 is independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethyl oxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.
The compound according to claim 1, characterized in that it is a compound represented by any one of formula I-1, I-2, I-3, I-4, I-5 or I-6,
The compound according to claim 2, wherein it is of formula I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I-6 -1 any of the compounds shown,
The compound according to claim 3, characterized in that it is a compound represented by any one of Formula 1 to Formula 94,
A pharmaceutical composition, characterized in that it contains an effective dose of the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or its interconversion One or more of the isomers, or their hydrates, or their solvates, or their metabolites, or their prodrugs.
The pharmaceutical composition according to claim 5, characterized in that, the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer, or a hydrate thereof, or a solvate thereof , or a metabolite thereof, or a prodrug thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing and/or treating diseases caused by overexpression of SOS1.
A compound shown in formula I as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, Use of its solvate, or its metabolite, or its prodrug, or its pharmaceutical composition in the preparation of a SOS1 inhibitor medicine.
A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer, or a hydrate thereof, or a solvate thereof , or a metabolite thereof, or a prodrug thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating and/or preventing cancer.
The use according to claim 9, wherein the cancer is any one or more of pancreatic cancer, colorectal cancer and lung cancer.