Nitrogen-containing fused ring compound, pharmaceutical composition containing same, and use thereof

Abstract

Disclosed in the present invention are a nitrogen-containing fused ring compound, a pharmaceutical composition containing same, and the use thereof. Provided in the present application are a compound for restoring a wild-type function of a mutant p53, a pharmaceutical composition containing the compound, and a method for treating cell proliferative diseases, such as cancer, by means of using the compound of the present application. The compound has a structure as shown in formula (I). Further, the compound of the present application also has good selectivity for cells with the Y220C mutation. Furthermore, the compound of the present application shows a significant improvement in the inhibitory effect on CYP3A, that is, the compound of the present application provides higher medication safety, and / or the compound of the present application has excellent pharmacokinetic properties.

Description

Nitrogen-containing fused ring compounds, pharmaceutical compositions containing the same, and uses thereof

[0001] This application claims priority to Chinese Patent Application No. CN2024105858633, filed on May 11, 2024, Chinese Patent Application No. CN2024107066484, filed on May 31, 2024, Chinese Patent Application No. CN2024108350717, filed on June 25, 2024, Chinese Patent Application No. CN202411047593.7, filed on July 31, 2024, and Chinese Patent Application No. CN202510570801.X, filed on April 30, 2025. This application incorporates the entirety of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application is in the field of medicinal chemistry and relates specifically to compounds for restoring wild-type function of mutant p53, pharmaceutical compositions containing the compounds, and methods of using the compounds of the present application to treat cell proliferative diseases, such as cancer. BACKGROUND

[0003] Tumor suppressor protein p53 is a transcription factor composed of 393 amino acids, which exists in the form of a tetramer in vivo, and can inhibit tumor occurrence and development through multiple mechanisms such as initiation of apoptosis, maintenance of genome stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis in response to cell stress such as UV radiation, hypoxia, oncogene activation, and DNA damage. In normal cells, p53 is maintained at a low level by a series of regulatory factors. For example, MDM2 is a key negative regulator of p53 and can mediate the degradation of p53. Under various cell stress conditions such as DNA damage, oncogene activation, telomere erosion, and ribonucleotide depletion, the N-terminal domain of p53 is phosphorylated by protein kinases, leading to the activation of p53, which transduces upstream stress signals. Activation of p53 can induce endogenous and exogenous apoptosis pathways, cell cycle arrest, senescence, and DNA repair. Studies have found that the p53 tumor suppressor gene plays a crucial role in the occurrence and development of cancer. The p53 protein is encoded by the TP53 gene, which has a mutation rate as high as 50% in cancer patients. Mutations in this gene are an important driving force for cancer occurrence, development, treatment resistance, and poor prognosis.

[0004] The high frequency of TP53 mutations found in tumor cells can be caused by selective pressure favoring the survival of mutant cells that have evaded tumor suppression. Most TP53 cancer mutations occur in the DNA-binding core domain of the protein, which consists of a central β-sandwich of two anti-parallel β-sheets, serving as a basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two β-turn loops (L2 and L3) stabilized by zinc ions and a loop-helix-loop motif. These structural elements together form an extended DNA-binding surface that is rich in positively charged amino acids and makes specific contacts with various p53 response elements. p53 Y220C is one of the most common types of p53 mutations, in which the tyrosine (Tyr) at position 220 is changed to cysteine (Cys), causing a change in the overall conformation, a decrease in the thermal stability of the protein, and a loss of DNA binding ability, which in turn leads to the loss of normal transcriptional regulation function of p53. At the same time, the Y220C mutation causes a unique surface crack region to appear locally, and the binding and occupation of this region by a compound can stabilize the p53 structure and restore the wild-type conformation of p53, which provides the possibility for targeted drug development.

[0005] Although a large number of prior arts have disclosed compounds that can restore the wild-type p53 DNA binding activity, there are few molecules in the clinical stage, and all are in the early stage of clinical trials, therefore, it is of great significance to develop a new class of compounds for restoring the wild-type function of mutant p53. SUMMARY

[0006] The purpose of the present application is to overcome the defect of the existing structure of the compound for restoring the wild-type function of mutant p53, and the present application provides a class of nitrogen-containing fused ring compounds, a pharmaceutical composition containing the same and the application thereof, specifically, the nitrogen-containing fused ring compound of the present application can be used for restoring the wild-type function of mutant p53, and can be used for treating cancer. Further, the compound of the present application also has good selectivity for Y220C mutant cells. Still further, the inhibitory effect of the compound of the present application on CYP3A is significantly improved, that is, the drug safety is higher, and / or the compound of the present application has excellent pharmacokinetic properties.

[0007] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0008] wherein,

[0009] Z1, Z2, Z3, Z4 are each independently selected from N or CH;

[0010] R1 is selected from -S(=O)2R1a , -P(=O)R 1b R 1c , -C(=O)NR 1b R 1c , -S(=O)2NR 1b R 1c , R 1b N=S(=O)(R 1c )-, -N=S(=O)R 1b R 1c or optionally substituted 5-6 membered heteroaryl; wherein said R 1a , R 1b , R 1c are each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or optionally substituted 5-6 membered heteroaryl; or R 1b and R 1c together with the atom to which they are attached form an optionally substituted 5-8 membered heterocyclyl; wherein said C 1-4 alkyl, 5-6 membered heteroaryl, and 5-8 membered heterocyclyl can be optionally substituted with 1-3 groups selected from hydroxyl, cyano, amino, halogen, C 1-4 alkyl, C a alkoxy, -C 1-4 alkyl-OH, -C 1-4 alkyl-OC 1-4 alkyl, or C 1-4 haloalkyl; or two adjacent R 1-4 together with the atom to which they are attached form a C 1-4 cycloalkyl, wherein said C a cycloalkyl can be optionally substituted with p R 3-6 ; R 3-6 is selected from hydrogen, deuterium, hydroxyl, amino, halogen, C d alkyl, C d alkoxy, -C 1-4 alkyl-OH, -C 1-4 alkyl-OC 1-4 alkyl, or C 1-4 haloalkyl;

[0011] Ring A is selected from 5-6 membered heterocyclyl or 5-6 membered heteroaryl; R a are each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-4 alkyl, -C 1-4 alkyl-OH, C 1-4 alkoxy, -C 1-4 alkyl-OC 1-4 alkyl, or C 1-4 haloalkyl; or two adjacent R a together with the atom to which they are attached form a C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl can be optionally substituted with p R d ; R d is selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkyl-OH, -C 1-4 alkyl-OC 1-4 alkyl, or C 1-4 haloalkyl;

[0012] R2is selected from hydrogen, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4haloalkyl or C 1-4 alkoxy;

[0013] or R1, R2and the atoms to which they are attached cyclize to form an optionally substituted 5-6 membered heterocyclyl;

[0014] R3is selected from -CH2CF3, -OCF3, -SeCF3;

[0015] Ring B is selected from 5-8 membered heterocyclyl; R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkyl, C 3-6 cycloalkyl, -C(O)CH3or wherein said C 1-4 alkyl can be further optionally substituted with 1-3 groups selected from hydroxyl, halogen, C 1-4 alkoxy or a deuterium atom;

[0016] m, n, p are each independently selected from 0, 1, 2 or 3.

[0017] The present application provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

[0018] Z1, Z2, Z3, Z4are each independently selected from N or CH;

[0019] R1is selected from -S(=O)2R 1a , -P(=O)R 1b R 1c , -C(=O)NR 1b R 1c , -S(=O)2NR 1b R 1c , R 1b N=S(=O)(R 1c )-, -N=S(=O)R 1b R 1c or optionally substituted 5-6 membered heteroaryl; wherein said R 1a , R 1b , R 1c are each independently selected from hydrogen, deuterium, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or optionally substituted 5-6 membered heteroaryl; or R 1b and R 1c to which they are attached cyclize to form an optionally substituted 5-8 membered heterocyclyl;

[0020] Ring A is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; R a each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-4 alkyl, -C 1-4 alkyl-OH, C 1-4 alkoxy, -C 1-4 alkyl-OC 1-4 alkyl or C 1-4 haloalkyl; or two adjacent R a together with the atom to which they are attached form a C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is optionally substituted with p R d ; R d each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkyl-OH, -C 1-4 alkyl-OC 1-4 alkyl or C 1-4 haloalkyl;

[0021] R2is selected from hydrogen, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy;

[0022] or R1, R2and the atom to which they are attached cyclize together to form an optionally substituted 5-6 membered heterocyclyl;

[0023] R3is selected from -CH2CF3, -OCF3, -SeCF3;

[0024] Ring B is selected from a 5-8 membered heterocyclyl; R b each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy, C 3-6 cycloalkyl, -C(O)CH3or wherein said C 1-4 alkyl can be further optionally substituted with 1-3 groups selected from hydroxyl, halogen, C 1-4 alkoxy or a deuterium atom;

[0025] m, n, p are each independently selected from 0, 1, 2 or 3.

[0026] In some embodiments of the application, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, the definition of certain groups can be as follows, and the definition of other groups can be as described in any of the embodiments of the application (hereinafter "in some embodiments of the application") Z3is selected from N, Z1, Z2, Z4are selected from CH.

[0027] In some embodiments of the application, Z2, Z3are selected from N, Z1, Z4are selected from CH.

[0028] In some embodiments of the application, Z1, Z3are selected from N, Z2, Z4are selected from CH.

[0029] In some embodiments of the application, Z1, Z4are selected from N, Z2, Z3are selected from CH.

[0030] In some embodiments of the application, Z4is selected from N, Z1, Z2, Z3are selected from CH.

[0031] In some embodiments of the application, Z3is N, Z1and Z2are CH, Z4is C.

[0032] In some embodiments of the application, Z1and Z3are N, Z2is CH, Z4is C.

[0033] In some embodiments of the application, Z3and Z4are N, Z1is CH, Z4is C.

[0034] In some embodiments of the application, R 1b N=S(=O)(R 1c )-.

[0035] In some embodiments of the application, R1is -S(=O)2R 1a , -P(=O)R 1b R 1c , -C(=O)NR 1b R 1c , -S(=O)2NR 1b R 1c , or R 1b N=S(=O)(R 1c )-.

[0036] In some embodiments of the application, R 1a is C 1-4 alkyl.

[0037] In some embodiments of the application, R 1b and R 1c are H or C 1-4alkyl, said C 1-4 alkyl is optionally substituted with 1-3 groups selected from the group consisting of: hydroxy and cyano.

[0038] In some embodiments of the application, m is 0.

[0039] In some embodiments of the application, ring A is 5-6 membered heterocyclyl.

[0040] In some embodiments of the application, p is 0.

[0041] In some embodiments of the application, R2is hydrogen.

[0042] In some embodiments of the application, R1, R2, and the atoms to which they are attached cyclize to form wherein "1" indicates the point of attachment of R1to the phenyl ring, and "2" indicates the point of attachment of R2to the phenyl ring.

[0043] In some embodiments of the application, R3is -CH2CF3or -SeCF3; for example, -CH2CF3.

[0044] In some embodiments of the application, R b is halogen or C 1-4 alkyl.

[0045] In some embodiments of the application, n is 2.

[0046] In some embodiments of the application, said C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; for example, cyclopropyl.

[0047] In some embodiments of the application, said halogen is independently F, Cl, Br, or I; for example, F.

[0048] In some embodiments of the application, said C 1-4 alkyl is independently methyl, ethyl, n-propyl, or i-propyl; for example, methyl or ethyl; for example, methyl.

[0049] In some embodiments of the application, said 5-8 membered heterocyclyl is independently 5-6 membered heterocyclyl.

[0050] In some embodiments of the application, the heteroatoms in said 5-8 membered heterocyclyl are independently selected from N, O, P, and S, and the number of heteroatoms is independently 1, 2, or 3; for example, the heteroatoms are N, and the number of heteroatoms is 1; for example, the heteroatoms are P, and the number of heteroatoms is 1; for example, for example,

[0051] In some embodiments of the application, the heteroatoms in the 5-6 membered heterocyclyl group are independently selected from N, O and S, and the number of heteroatoms is independently 1, 2 or 3; for example the heteroatoms are O and the number of heteroatoms is 1.

[0052] In some embodiments of the application, the 5-8 membered heterocyclyl group is independently a 5-8 membered saturated heterocyclyl group.

[0053] In some embodiments of the application, the 5-6 membered heterocyclyl group is independently a 5-8 membered saturated heterocyclyl group.

[0054] In some embodiments of the application, the 5-8 membered heterocyclyl group is independently a monocyclic ring.

[0055] In some embodiments of the application, the 5-6 membered heterocyclyl group is independently a monocyclic ring.

[0056] In some embodiments of the application, R1is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0057] In some embodiments of the application, R1is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0058] In some embodiments of the application, R1is selected from

[0059] In some embodiments of the application, R1is selected from

[0060] In some embodiments of the application, R1is selected from -S(O)2CH3, for example is

[0061] In some embodiments of the application, ring A is selected from

[0062] In some embodiments of the application, ring A is selected from

[0063] In some embodiments of the application, the structural unit is selected from wherein R a , R d , m, p are as described in any embodiment of the application.

[0064] In some embodiments of the application, the structural unit is selected from

[0065] In some embodiments of the application, the structural unit is selected from wherein "*" indicates the carbon atom to which R1is attached is attached to the carbon atom adjacent to the carbon atom to which R1is attached.

[0066] In some embodiments of the application, R1, R2and the atoms to which they are attached cyclize to form

[0067] In some embodiments of the application, the structural unit is selected from

[0068] In some embodiments of the application, the structural unit is selected from

[0069] In some embodiments of the application, the structural unit is for example is for example is

[0070] In some embodiments of the application, the structural unit is selected from for example is selected from

[0071] In some embodiments of the application, the structural unit is selected from

[0072] In some embodiments of the application, the structural unit is selected from

[0073] In some embodiments of the application, the structural unit is

[0074] In some embodiments of the application, the structural unit is selected from

[0075] In some embodiments of the application, the structural unit is selected from

[0076] In some embodiments of the application, the structural unit is selected from

[0077] In some embodiments of the application, ring B is selected from wherein M is selected from NR c , R c is selected from C 1- 4alkyl, C 3-6 cycloalkyl, -C(O)CH3or wherein the C 1-4 alkyl group can be further optionally substituted with 1-3 groups selected from hydroxy, halogen, C 1-4 alkoxy or a deuterium atom.

[0078] In some embodiments of the application, R c is selected from methyl, ethyl, isopropyl, t-butyl,

[0079] In some embodiments of the application, the structural unit is selected from

[0080] In some embodiments of the application, the structural unit is selected from

[0081] In some embodiments of the application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0082] wherein Z1, Z2, Z3, Z4, R1, R3, ring B, R a , R b , R d , p, m, n are as described in any embodiment of the application.

[0083] In some embodiments of the application, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0084] wherein the structural unit is selected from the structural unit is selected from R a is selected from hydrogen, R1is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0085] In some embodiments of the application, the compound according to Formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0086] wherein the structural unit is selected from the structural unit is selected from R d is selected from hydrogen, R1is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0087] In some embodiments of the application, the compound according to Formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0088] wherein Z1, Z2, Z3, Z4, R1, R3, R a , R b , R d , p, m, n, R c are as described in any embodiment of the application.

[0089] In some embodiments of the application, the compound according to Formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0090] wherein R1, R3, R a , R b , R c , R d , m, n, p are as described in any embodiment of the application.

[0091] In some embodiments of the application, the compound according to Formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0092] wherein R1, R3, Ra , R b , R c , R d , m, n, p are as described in any embodiment of the present application.

[0093] In some embodiments of the present application, the compound according to formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0094] wherein R1is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0095] In some embodiments of the present application, the compound according to formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0096] wherein R1is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0097] The present application also provides the following compounds or a pharmaceutically acceptable salt thereof, which are selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0098] The present application also provides the following compounds or a pharmaceutically acceptable salt thereof, which are selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0099] The present application also provides the following compounds or a pharmaceutically acceptable salt thereof, which are selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0100] In some embodiments of the present application, the compound is selected from any one of the following compounds:

[0101] the compound eluting first under the following conditions: prep column: 25*250mm 10pm, mobile phase: MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), flow rate: 60 mL / min, gradient: 40%, detection wavelength: 214 nm; for example eluting at 4.162 min;

[0102] or, the compound eluting after the following conditions: preparative column: 25*250mm 10μm, mobile phase: MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), flow rate: 60 mL / min, gradient: 40%, detection wavelength: 214 nm; for example eluting at 5.186 min.

[0103] The present application also provides a pharmaceutical composition comprising (preferably in a therapeutically effective amount) the above-mentioned compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0104] In certain embodiments of the present application, the content of the compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 0.1 mg-1000 mg.

[0105] In certain embodiments of the present application, the pharmaceutically acceptable carrier in the pharmaceutical composition comprises one or more of a filler, a disintegrant, a binder, a glidant, a lubricant.

[0106] The present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating cancer.

[0107] In some embodiments of the present application, the cancer is selected from solid tumors, preferably the solid tumor is lung cancer, gastric cancer, liver cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer or endometrial cancer.

[0108] The present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating p53 mutation-mediated cancer.

[0109] The present application also provides the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for use in treating p53 mutation-mediated cancer.

[0110] The present application also provides a method for treating p53 mutation-mediated cancer, comprising administering to a patient a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.

[0111] In some embodiments of the present application, in the above-mentioned use and method, the p53 mutation is p53 Y220C mutation.

[0112] In some embodiments of the application, in the above-mentioned uses and methods, the cancer is selected from solid tumors, preferably the solid tumor is selected from lung cancer, gastric cancer, liver cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, endometrial cancer carrying p53 Y220C mutation.

[0113] Technical effects

[0114] The compounds of the present application have good DNA binding activity, and can be used to restore the wild-type function of mutant p53. Further, the compounds of the present application have good selectivity for cells with Y220C mutation, and further, the compounds of the present application have significantly improved inhibition of CYP3A, i.e. are safer in use, and / or, the compounds of the present application have excellent pharmacokinetic properties.

[0115] Explanation and definition

[0116] The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be considered indefinite or unclear if not specifically defined, but should be construed in accordance with the ordinary meaning.

[0117] The term "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0118] The term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present application prepared from a relatively non-toxic acid or base. These salts can be prepared during the final isolation and purification of the compound, or separately, by simply reacting the free form of the compound with a suitable acid or base.

[0119] The term "pharmaceutically acceptable carrier" means a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, and more specifically humans, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending upon the nature of the dosage form and the means of administration. Pharmaceutically acceptable carriers are formulated in accordance with routine procedures, such as those set forth in Remington: The Science and Practice of Pharmacy, 21stEd., 2005, incorporated herein by reference. The appropriate formulation is chosen to suit the mode of delivery and the nature of the active agent. In addition to the active agent, such carriers include a wide variety of different ingredients and additives, which are included in the formulation for a variety of reasons (e.g., to stabilize the active agent, to bind the active agent, etc.), and such additional ingredients are well known to those of ordinary skill in the art.

[0120] The term "effective prophylactic or therapeutic amount" means a sufficient amount of a compound of the application, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. It will be understood, however, that the total daily usage of the compounds of the application, of the pharmaceutically acceptable salts thereof, and compositions of the application will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0121] The compounds of the application, as well as stereoisomers thereof, are within the scope of the application, including enantiomers, diastereomers, racemic mixtures.

[0122] • a wedged solid line bond and a wedged dashed line bond represent the absolute configuration of a stereocenter, a straight solid line bond and a straight dashed line bond represent the relative configuration of a stereocenter.

[0123] Stereoisomers of the compounds of the application can be prepared using chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the application can be prepared by asymmetric catalytic techniques or chiral auxiliary derivatization techniques. Alternatively, a single stereoisomer can be obtained from a mixture by chiral resolution techniques. Or directly prepared using chiral starting materials. Isolation of optically pure compounds is typically accomplished using preparative chromatography on chiral columns to achieve separation of the chiral compounds.

[0124] The absolute stereochemistry is specified using the configuration of the compound of the application having the desired absolute stereochemistry. Enantiomers of the compounds of the application can be prepared using chiral syntheses or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the application can be prepared by asymmetric catalytic techniques or chiral auxiliary derivatization techniques. Alternatively, a single stereoisomer can be obtained from a mixture by chiral resolution techniques. Or directly prepared using chiral starting materials. Isolation of optically pure compounds is typically accomplished using preparative chromatography on chiral columns to achieve separation of the chiral compounds.

[0125] The term "optionally" means that the moiety can or can not be substituted and that the nature and number of the substituents can be any that are chemically possible, for example, the term "optionally substituted with one or more R d "means that the moiety can or can not be substituted with one or more R d "and that the nature and number of the substituents can be any that are chemically possible. d

[0126] When any variable (e.g. R d ) occurs more than one time in a compound or stereoisomer, its definition on each occurrence is independent of its definition at every other occurrence. For example, indicates that the cyclopentyl group is substituted with 3 R d groups and each R d group is independently selected.

[0127] When a bond to a substituent is cross-linked to two atoms of a ring, the substituent can be bonded to either atom of the ring. For example, the structural element indicates that the substituent R1may be bonded at any position on the phenyl ring.

[0128] When a substituent is recited as being "selected from the group consisting of" or "selected from the group including" particular naming of the group, the phrase "consisting of" or "including" is intended to use the disclaimer which recites that the substituent can be bonded to the chemical structure at any atom of the substituent, not just the atom explicitly named. For example, pyrazole as a substituent means that either carbon or nitrogen atom of the pyrazole ring is bonded to the group being substituted; when the structure is , the atom to which the group is bonded is the bonding atom, for example indicates that the N atom of the morpholine ring is the bonding atom.​

[0129] Unless otherwise specified, "ring" means saturated, partially saturated, or unsaturated monocyclic and polycyclic, "polycyclic" includes spiro, fused, or bridged. Representative "rings" include substituted or unsubstituted heterocyclyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "hetero" means substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, also known as heteroatom groups, which are generally selected from N, O, S, P, and oxidized forms generally include NO, P(O), SO, S(O)2; the number of atoms in a ring is generally defined as the ring member, for example, "3-6 membered heterocyclyl" means a ring of 3-6 atoms arranged in a ring, each ring optionally containing 1-3 heteroatoms and / or heteroatom groups, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR.

[0130] Unless otherwise specified, "cycloalkyl" means saturated monocyclic or polycyclic hydrocarbon groups. Cycloalkyl groups are preferably C 3-8 monocycloalkyl, more preferably C 3-6 monocycloalkyl, more preferably C

[0131] Unless otherwise specified, "heterocyclyl" means non-aromatic monocyclic or polycyclic rings containing a certain number of heteroatoms and / or heteroatom groups in the ring, which can be saturated or partially saturated. The heteroatoms and / or heteroatom groups are generally selected from N, O, S, NO, SO, S(O)2, and P(O), wherein the carbon atoms in the heterocycle are optionally oxidized, i.e., form -C(O)-. "Heterocyclyl" is preferably 3-8 membered monocyclic heterocyclyl, more preferably 5-6 membered monocyclic heterocyclyl, examples of which include, but are not limited to, oxiranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.

[0132] Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom or heteroatom group (N, O, S, NO, SO, S(O)2, or NR). Preferred are 5- or 6-membered monocyclic heteroaryls. Examples of heteroaryls include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyrimidinyl.

[0133] Unless otherwise specified, the term "alkyl" is used to denote straight-chain or branched-chain saturated hydrocarbon groups. Preferred are C 1-6 alkyl groups, more preferably C 1-4Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl, pentyl, i-pentyl, neopentyl, n-hexyl, and the like.

[0134] Unless otherwise specified, the term "alkoxy" means an alkyl group attached through an oxygen bridge, i.e., the group obtained by replacing a hydrogen atom in a hydroxyl group with an alkyl group. Preferably C 1-6 alkoxy, more preferably C 1-4 alkoxy. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl, pentyl, i-pentyl, neopentyl, n-hexyl, and the like.

[0135] Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine, or iodine atom.

[0136] Unless otherwise specified, the term "haloalkyl" means an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. Preferably C 1-6 haloalkyl, more preferably C 1-4 haloalkyl. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0137] It is specifically contemplated that all combinations of substituents and / or variables in the present disclosure are permissible unless such combinations result in unstable compounds.

[0138] The methods for preparing some of the compounds in the present application refer to the methods for preparing analogous compounds described above. Those skilled in the art should know that when using or referring to using the cited preparation methods, the feeding ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0139] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by the combination of the specific embodiments with other chemical synthetic methods well known to those skilled in the art, and equivalent replacements well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application. DETAILED DESCRIPTION

[0140] The structures of the compounds of the present application were determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured by Bruker Neo 400M or Bruker Ascend 400 NMR instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), heavy water (D2O) as the determination solvent, and tetramethylsilane (TMS) as the internal standard.

[0141] The starting materials in the examples of the present application are known and commercially available, or can be synthesized by or according to methods known in the art.

[0142] Unless otherwise specified, all reactions of the present application were carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature was in degrees Celsius.

[0143] I. Preparation Examples

[0144] Example 1:

[0145] 7-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizin-2-yl)propionic acid)-2-alkyn-1-yl)amino)-N-methyl-2,3- dihydrobenzofuran-4-formamide

[0146] Reaction Scheme:

[0147] Step A: 3-Bromopyridinecarboxaldehyde (5 g, 26.88 mmol) and methyl acrylate (2.78 g, 32.26 mmol) were dissolved in 1,4-dioxane (45 mL) and water (15 mL), and triethylenediamine (0.18 g, 1.61 mmol) was added, and stirred at room temperature overnight. TLC detection showed that the starting material disappeared, the reaction liquid was poured into water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 6.79 g of 2-((3-bromopyridin-2-yl)(hydroxy)methyl)methyl acrylate.

[0148] MS (ESI) M / Z: 271.9 [M+H] + .

[0149] Step B: Methyl 2-((3-bromopyridin-2-yl)(hydroxy)methyl)acrylate (6.59 g, 24.23 mmol) was dissolved in acetic anhydride (120 mL) and stirred at 100 °C for 16 h. TLC indicated the starting material was consumed. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification on silica gel column gave 4.5 g of 8-bromoindolin-2-yl acetate.

[0150] MS (ESI) M / Z: 254.0 [M+H] + .

[0151] Step C: 8-Bromoindolin-2-yl acetate (4.43 g, 17.44 mmol) was dissolved in 1,2-dichloroethane (40 mL). DMAP (0.23 g, 1.92 mmol) and triethylamine (2.12 g, 20.93 mmol) were added. Trifluoroacetic anhydride (4.03 g, 19.18 mmol) was added dropwise at ice water bath. After the addition was completed, the reaction was stirred at 60 °C for 5 h. TLC indicated the starting material was consumed. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification on silica gel column gave 5 g of 8-bromo-3-(2,2,2-trifluoroacetyl)indolin-2-yl acetate.

[0152] MS (ESI) M / Z: 349.9 [M+H] + .

[0153] Step D: 8-Bromo-3-(2,2,2-trifluoroacetyl)indolin-2-yl acetate (5 g, 14.28 mmol) was dissolved in super dry tetrahydrofuran (50 mL). Borane tetrahydrofuran complex (1 M, 21.4 mL, 21.4 mmol) was added. The reaction was stirred at 25 °C for 1 h. LCMS indicated the starting material was consumed. The reaction was quenched by pouring into methanol (30 mL). Concentration and purification on silica gel column gave 4.5 g of 8-bromo-3-(2,2,2-trifluoro-1-hydroxyethyl)indolin-2-yl acetate.

[0154] MS (ESI) M / Z: 335.9 [M-16+H] + .

[0155] Step E: 8-Bromo-3-(2,2,2-trifluoro-l-hydroxyethyl)indolizine-2-yl acetate (4.5 g, 12.78 mmol) was dissolved in trifluoroacetic acid (30 mL), then triethylsilane (15 mL) was added, and the reaction was stirred at 70 °C for 2 hours. LCMS showed the starting material was consumed. The reaction was diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give 4 g of 8-bromo-3-(2,2,2-trifluoroethyl)indolizine-2-yl acetate.

[0156] MS (ESI) M / Z: 336.0 [M+H] + .

[0157] Step F: 8-Bromo-3-(2,2,2-trifluoroethyl)indolizine-2-yl acetate (4 g, 11.9 mmol) was dissolved in tetrahydrofuran / methanol / water (20 mL / 20 mL / 10 mL), then sodium hydroxide (2.38 g, 59.5 mmol) was added, and the reaction was stirred at 80 °C for 1 hour. LCMS showed the reaction was completed. The reaction was adjusted to pH ~3 with 1 M hydrochloric acid, and extracted with dichloromethane three times. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to give 1.7 g of 8-bromo-3-(2,2,2-trifluoroethyl)indolizine-2-carboxylic acid. It was used in the next step without purification.

[0158] MS (ESI) M / Z: 321.9 [M+H] + .

[0159] Step G: 8-Bromo-3-(2,2,2-trifluoroethyl)indolizine-2-carboxylic acid (1 g, 3.1 mmol) was dissolved in dichloromethane (10 mL), then dimethylhydroxylamine hydrochloride (0.91 g, 9.3 mmol), N,N-diisopropylethylamine (2 g, 15.5 mmol), and HATU (1.77 g, 4.65 mmol) were added successively, and the reaction was stirred at 20 °C for 2 hours. LCMS showed the starting material was consumed. The reaction was diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give 968 mg of 8-bromo-N-methoxy-N-methyl-3-(2,2,2-trifluoroethyl)indolizine-2-carboxamide.

[0160] MS (ESI) M / Z: 364.9 [M+H] + .

[0161] Step H: Dissolve 8-bromo-N-methoxy-N-methyl-3-(2,2,2-trifluoroethyl)indolizine- 2-carboxamide (968 mg, 2.65 mmol) in super dry tetrahydrofuran (10 mL), add diisobutylaluminum hydride (1.5 M, 2.65 mL, 3.97 mmol) dropwise at 0 °C, and stir for 1 hour. TLC plate monitoring shows the disappearance of starting material. Pour the reaction into 5% aqueous potassium sodium tartrate solution, then add dichloromethane and stir for half an hour. After standing, separate the organic phase, extract the aqueous phase with dichloromethane three times, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain 600 mg of 8-bromo-3-(2,2,2-trifluoroethyl)indolizine-2-carboxaldehyde.

[0162] MS (ESI) M / Z: 305.9 [M+H] + .

[0163] Step I: Dissolve 8-bromo-3-(2,2,2-trifluoroethyl)indolizine-2-carboxaldehyde (600 mg, 1.96 mmol) in methanol (6 mL), add potassium carbonate (810 mg, 5.88 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (560 mg, 2.94 mmol) in sequence, and stir at 20 °C for 2 hours. LCMS monitoring shows the disappearance of starting material. Add water to the reaction, extract with ethyl acetate twice, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 535 mg of 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)indolizine.

[0164] MS (ESI) M / Z: 301.9 [M+H] + .

[0165] Step J: Dissolve 8-bromo-2-ethynyl-3-(2,2,2-trifluoroethyl)indolizine (535 mg, 1.77 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL), and stir at 100 °C for 18 hours. LCMS monitoring shows the disappearance of starting material. Add water to the reaction, extract with ethyl acetate twice, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 100 mg of 3-(8-bromo-3-(2,2,2-trifluoroethyl)indolizin-2-yl)propanal.

[0166] 1H NMR (400 MHz, CDC13) δ 9.46 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.92 (s, 1H), 6.59 (t, J = 7.1 Hz, 1H), 3.87 (q, J = 9.9 Hz, 2H).

[0167] Step K: 3-(8-bromo-3-(2,2,2-trifluoroethyl)indolizin-2-yl)propanal (100 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL), 7-amino-N-methyl-2,3-dihydrobenzofuran-4- carboxamide (100 mg, 0.52 mmol), 3A molecular sieves (500 mg), acetic acid (0.1 mL) were added, stirred at room temperature for 2 hours, then sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added, reacted at room temperature for 16 hours. LCMS monitoring showed that the raw material disappeared, the reaction liquid was added with water, extracted with ethyl acetate twice, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 90 mg of 7-((3-(8-bromo-3-(2,2,2-trifluoroethyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide.

[0168] MS (ESI) M / Z: 505.9 [M+H] + .

[0169] Step L: 7-((3-(8-bromo-3-(2,2,2-trifluoroethyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N- methyl-2,3-dihydrobenzofuran-4-carboxamide (90 mg, 0.18 mmol) was dissolved in 1,4- dioxane (3 mL), (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (59 mg, 0.27 mmol), cesium carbonate (174 mg, 0.53 mmol), 2-dicyclohexylphosphino-2',6'-d iisopropoxy-1,1'- biphenyl (17 mg, 0.036 mmol) and methane sulfonic acid (2-dicyclohexylphosphino-3,6- dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.02 mmol) were added, nitrogen was purged for three times, 95 °C for 16 h. LCMS monitoring showed the starting material was consumed, the reaction was diluted with water, extracted with ethyl acetate twice, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography to give 90 mg of (3S,4R)-3-fluoro-4-((2-(3-((4-(methylcarbamoyl)-2,3- dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)indolizin-8- yl)amino)piperidine-1-carboxylate.

[0170] MS (ESI) M / Z: 644.4 [M+H] + .

[0171] Step M: (3S,4R)-3-fluoro-4-((2-(3-((4-(methylcarbamoyl)-2,3-dihydrobenzofuran-7- yl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)indolizin-8-yl)amino)piperidine-1- carboxylate (90 mg, 0.14 mmol) was dissolved in hydrochloric acid (5 mL, 2M in EA), 25 °C for 1 h. LCMS monitoring showed the starting material was consumed, the reaction was diluted with saturated sodium bicarbonate to pH = 7, extracted with dichloromethane twice, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 70 mg of 7-((3-(8-((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- (2,2,2-trifluoroethyl)indolizin-2-yl)prop-2-yn-1-yl)amino, which was used in the next step without purification.

[0172] MS (ESI) M / Z: 544.3 [M+H] + .

[0173] Step N: 7-((3-(8-((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizin-2-yl)prop-2-yn-1-yl)amino (70 mg, 0.13 mmol) was dissolved in methanol (2 mL), added with paraformaldehyde (20 mg, 0.65 mmol), acetic acid (0.1 mL), then sodium cyanoborohydride (40 mg, 0.65 mmol), and reacted at 50 °C for 3 hours. LCMS monitoring showed that the starting material disappeared, the reaction solution was added with water, extracted with ethyl acetate twice, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (NH3H2O) to obtain 9.66 mg of 7-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizin-2-yl)propyl)-2-yn-1-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4- carboxamide (Compound 1).

[0174] Separation condition: Prep column: Waters Xbridge C18 19*250mm 10um, mobile phase: 0.1% NH3H2O in water / CH3CN, flow rate: 20 mL / min, gradient: 45%-60%, detection wavelength: 214nm / 254nm, retention time: 8.42 min.

[0175] MS (ESI) M / Z: 558.3 [M+H] + .

[0176] 1 H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 7.1 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.62 (s, 1H), 6.51 (t, J = 7.2 Hz, 1H), 5.88 (d, J = 7.4 Hz, 1H), 4.93 (s, 1H), 4.81 (s, 1H), 4.59 (t, J = 8.8 Hz, 2H), 4.25 (s, 2H), 3.75 (q, J = 10.4 Hz, 2H), 3.61 (dd, J = 28.7, 8.9 Hz, 1H), 3.47 (t, J = 8.8 Hz, 2H), 3.19 (t, J = 11.1 Hz, 1H), 2.93 (d, J = 11.0 Hz, 1H), 2.86 (s, 3H), 2.42 - 2.20 (m, 5H), 2.05 - 1.88 (m, 2H).

[0177] Example 2

[0178] 3-((3-(8-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1a,6b- dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide

[0179] Reaction Scheme:

[0180] Step A: 3-Bromopyridin-2-amine (6.0 g, 34.9 mmol) and 4,4,4-trifluorobutyric acid (5.94 g, 41.9 mmol) were dissolved in acetonitrile (120 mL), N-methylimidazole (10.0 g, 122.2 mmol) and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (11.8 g, 41.9 mmol) were added successively, replaced with nitrogen for three times, and the reaction was carried out at 25 °C for 16 hours. LCMS showed that the raw material disappeared, the reaction solution was added with saturated aqueous ammonium chloride solution, extracted with ethyl acetate for three times, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3 g of N-(3-bromopyridin-2-yl)-4,4,4-trifluorobutyramide.

[0181] MS (ESI) M / Z: 297.0 [M+H] + .

[0182] Step B: N-(3-bromopyridin-2-yl)-4,4,4-trifluorobutyramide (3.0 g, 10.1 mmol) was dissolved in chloroform (120 mL), triethylamine (2.16 g, 21.4 mmol) and sulfur monochloride (2.5 g, 21.4 mmol) were added successively, replaced with nitrogen for three times, and the reaction was carried out at 90 °C for 6 hours. LCMS showed that the raw material disappeared, the reaction solution was added with saturated aqueous sodium bicarbonate solution to adjust the pH to about 10, extracted with dichloromethane for three times, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.56 g of 8-bromo-2-chloro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine.

[0183] MS (ESI) M / Z: 312.9 [M+H] + .

[0184] Step C: Dissolve 8-bromo-2-chloro-3-(2,2,2-trifluoroethyl)imidazo[l,2- a]pyridine (600 mg, 1.92 mmol) in 1,4-dioxane (12 mL), add (3S,4R)-4-amino-3- fluoropiperidine- 1-carboxylic acid tert-butyl ester (629 mg, 2.88 mmol), cesium carbonate (1.25 g, 3.84 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (161 mg, 0.38 mmol) and palladium acetate (43 mg, 0.19 mmol) sequentially, replace with nitrogen for three times, then react at 110 °C for 16 h. LCMS monitoring shows the disappearance of starting material, add water to the reaction, extract with dichloromethane twice, combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the residue with silica gel column to get 220 mg of (3S,4R)-4-((2-chloro-3-(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-8-yl)amino)-3-fluoropiperidine- 1-carboxylic acid tert-butyl ester.

[0185] MS (ESI) M / Z: 451.0 [M+H] + .

[0186] Step D: Dissolve (3S,4R)-4-((2-chloro-3-(2,2,2-trifluoroethyl)imidazo[l,2- a]pyridin-8-yl)amino)-3-fluoropiperidine- 1-carboxylic acid tert-butyl ester (600 mg, 1.33 mmol) and N-methyl-3-(prop-2-en-l-ylamino)-l a,6b-dihydro-lH- cyclopropyl[b]benzofuran-6-carboxamide (390 mg, 1.60 mmol) in acetonitrile (12 mL), add cesium carbonate (1.13 g, 3.46 mmol), 2-biscyclohexylphosphino-2',4',6'- triisopropylbiphenyl (200 mg, 0.41 mmol) and palladium bis(acetonitrile) dichloride (30 mg, 0.12 mmol) sequentially, replace with nitrogen for three times, react at 95 °C for 1.5 h. LCMS shows the disappearance of starting material, add saturated ammonium chloride solution to the reaction, extract with ethyl acetate three times, combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the residue with silica gel column to get 220 mg of tert-butyl (3S,4R)-3-fluoro-4-((2-(3-((6-(methylcarbamoyl)- 1 a,6b-dihydro- 1 H-cyclopropyl[b]benzofuran-3-yl)amino)prop- 1 -yn- 1 -yl)-3-(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-8-yl)amino.

[0187] MS (ESI) M / Z: 657.4 [M+H] + .

[0188] Step E: tert-Butyl (3S,4R)-3-fluoro-4-((2-(3-((6-(methylcarbamoyl)- 1a,6b-dihydro-1H-cyclopropyl[b]benzofuran-3-yl)amino)prop-1-yn-1-yl)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-8-yl)amino)pyrrolidine-1-carboxylate (238 mg, 0.53 mmol) was dissolved in hydrochloric acid (2 M in EA, 5 mL, 10 mmol) and reacted at 25 °C for 1 h. LCMS monitoring showed that the starting material disappeared, the reaction solution was added with water, and the pH was adjusted to 10 with sodium hydroxide solution. The organic phase was extracted with ethyl acetate three times, combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 180 mg of 3-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino.

[0189] MS (ESI) M / Z: 557.3 [M+H] + .

[0190] Step F: 3-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)pyrrolidine-1-carboxylate (180 mg, 0.32 mmol) was dissolved in methanol (5 mL), and acetic acid (0.5 mL) was added dropwise. Sodium cyanoborohydride (102 mg, 1.62 mmol) and paraformaldehyde (49 mg, 1.62 mmol) were added, and the reaction was carried out at 50 °C for 7 h. LCMS monitoring showed that the starting material disappeared, the reaction solution was added with ammonia water to quench, and the organic phase was extracted with dichloromethane three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to obtain 40 mg of 3-((3-(8-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1a,6b-dihydro-1H- cyclopropyl[b]benzofuran-6-carboxamide (Compound 2).

[0191] Separation conditions: prep column: Welch Ultimate XB-C18 (filler 70 g) 10 um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 20%-30%, detection wavelength: 214 nm / 254 nm, retention time: 9.13 min.

[0192] The obtained product was separated by chiral HPLC, and the separation conditions were: prep column: Chiralpak IC (filler 50 g) 5 um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 20%-30%, detection wavelength: 214 nm / 254 nm, retention time: 9.13 min. 25*250mm 10pm, mobile phase: MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), flow rate: 70 mL / min, gradient: 40%, detection wavelength: 214 nm, to obtain 2-P1 (10.54 mg, elution time: 3.493 min) and 2-P2 (16.17 mg, elution time: 4.694 min).

[0193] 2-P1:

[0194] MS (ESI) M / Z: 571.2 [M+H] +

[0195] 1 H NMR (400 MHz, CD3OD) δ 7.63 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 4.95 - 4.86 (m, 2H), 4.29 (s, 2H), 3.90 - 3.66 (m, 3H), 3.23 - 3.03 (m, 2H), 2.90 (s, 4H), 2.48 - 2.23 (m, 5H), 2.01 - 1.91 (m, 2H), 1.10 - 1.05 (m, 1H), 0.24 - 0.21 (m, 1H).

[0196] 2-P2:

[0197] MS (ESI) M / Z: 571.2 [M+H] +

[0198] 1 H NMR (400 MHz, CD3OD) δ 7.64 (d, J = 6.7 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 4.97 - 4.86 (m, 2H), 4.29 (s, 2H), 3.89 - 3.71 (m, 3H), 3.20 (d, J = 12.2 Hz, 1H), 3.14 - 3.06 (m, 1H), 2.93 (d, J = 19.7 Hz, 4H), 2.52 - 2.34 (m, 1H), 2.34 (s, 4H), 2.05 - 2.01 (m, 1H), 1.99 - 1.96 (m, 1H), 1.10 - 1.05 (m, 1H), 0.24 - 0.21 (m, 1H).

[0199] Example 3:

[0200] (1aS,6bS)-3-((3-(8-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizin-2-yl)prop-2-yn-1 -yl)amino)-N-methyl-1 a,6b-dihydro-1 H- cyclopropa[b]benzofuran-6-carboxamide

[0201] (1aR,6bR)-3-((3-(8-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizin-2-yl)prop-2-yn-1 -yl)amino)-N-methyl-1 a,6b-dihydro-1 H- cyclopropa[b]benzofuran-6-carboxamide

[0202] Reaction Scheme:

[0203] Step A: 3-(8-Bromo-3-(2,2,2-trifluoroethyl)indolizin-2-yl)propanal (378 mg, 1.15 mmol) was dissolved in dichloromethane (5 mL), 3-amino-N-methyl-1 a,6b-dihydro-1 H- cyclopropa[b]benzofuran-6-carboxamide (1.17 g, 5.75 mmol), 3A molecular sieves (500 mg), acetic acid (0.4 mL) were added and stirred at room temperature for 8 hours, then sodium triacetoxyborohydride (731 mg, 3.45 mmol) was added and the reaction was stirred at room temperature for 16 hours. LCMS monitoring showed the disappearance of the starting material, the reaction was quenched with water, extracted with ethyl acetate twice, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography to give 370 mg of 3-((3-(8-bromo-3-(2,2,2-trifluoroethyl)indolizin-2-yl)prop-2-yn-1 - yl)amino)-N-methyl-1 a,6b-dihydro-1 H-cyclopropa[b]benzofuran-6-carboxamide.

[0204] MS (ESI) M / Z: 518.1 [M+H] + .

[0205] Step B: 3-((3-(8-bromo-3-(2,2,2-trifluoroethyl)indolizine-2-yl)prop-2-yn-1-yl)amino)-N- methyl-1a,6b-dihydro-1H-cyclopropyl[b]benzofuran-6-carboxamide (370 mg, 0.72 mmol) was dissolved in 1,4-dioxane (4 mL), added (3S,4R)-4-amino-3-fluoropiperidine-1- carboxylic acid tert-butyl ester (234 mg, 1.07 mmol), cesium carbonate (704 mg, 2.16 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (67 mg, 0.14 mmol) and methane sulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (63 mg, 0.07 mmol), replaced with nitrogen three times, reacted at 90 °C for 16 hours. LCMS monitoring showed that the starting material disappeared, the reaction liquid was added with water, extracted with ethyl acetate twice, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 370 mg of tert-butyl (3S,4R)-3-fluoro-4-((2-(3-((6-(methylcarbamoyl)-1a,6b-dihydro-1H- cyclopropyl[b]benzofuran-3-yl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)indolizidin-8- yl)amino.

[0206] MS (ESI) M / Z: 656.1 [M+H] + .

[0207] Step C: tert-butyl (3S,4R)-3-fluoro-4-((2-(3-((6-(methylcarbamoyl)-1a,6b-dihydro-1H- cyclopropyl[b]benzofuran-3-yl)amino)prop-1-yn-1-yl)-3-(2,2,2-trifluoroethyl)indolizidin-8- yl)amino) (370 mg, 0.56 mmol) was dissolved in hydrochloric acid (5 mL, 2M in EA), reacted at 25 °C for 1 hour. LCMS monitoring showed that the starting material disappeared, the reaction liquid was added with saturated sodium bicarbonate, extracted with dichloromethane twice, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain 310 mg of 3-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizidin-2-yl)prop-2-yn-1-yl)amino. It was directly used in the next step without purification.

[0208] MS (ESI) M / Z: 556.0 [M+H] + .

[0209] Step D: 3-((3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizin-2-yl)prop-2-yn-1-yl)amino)(310 mg, 0.56 mmol) was dissolved in methanol (3 mL), paraformaldehyde (84 mg, 2.8 mmol), acetic acid (0.3 mL) was added, followed by sodium cyanoborohydride (174 mg, 2.8 mmol) and the reaction was stirred at 50 °C for 2 h. LCMS monitoring showed the disappearance of starting material, the reaction was quenched with water, extracted with ethyl acetate twice, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by prep-HPLC (NH3H2O) to give 160 mg of 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1a,6b-dihydro-1H- cyclopropa[b]benzofuran-6-carboxamide.

[0210] Separation condition: Prep Column: Waters Xbridge C18 10um OBD 19*250mm, Mobile Phase: 0.1% NH3H2O in water / CH3CN, Flow Rate: 20 mL / min, Gradient: 40%-55%, Detection Wavelength: 214nm / 254nm, Retention Time: 11.31 min.

[0211] The obtained product was separated by chiral HPLC, separation condition: Prep Column: Chiralpak IC 25*250mm 10μm, Mobile Phase: MEOH(+0.1% 7.0 mol / l Ammonia in MEOH), Flow Rate: 60 mL / min, Gradient: 40%, Detection Wavelength: 214nm, 3-P1 (58.58 mg, peak time: 4.162 min); 3-P2 (61.42 mg, peak time: 5.186 min) were obtained. 25*250mm 10μm, Mobile Phase: MEOH(+0.1% 7.0 mol / l Ammonia in MEOH), Flow Rate: 60 mL / min, Gradient: 40%, Detection Wavelength: 214nm, 3-P1 (58.58 mg, peak time: 4.162 min); 3-P2 (61.42 mg, peak time: 5.186 min) were obtained.

[0212] 3-P1:

[0213] MS (ESI) M / Z: 570.3 [M+H] + .

[0214] 1H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 6.9 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.74 - 6.66 (m, 1H), 6.62 (d, J = 0.5 Hz, 1H), 6.50 (t, J = 7.2 Hz, 1H), 5.88 (d, J = 7.3 Hz, 1H), 4.93 (s, 1H), 4.88 (dd, J = 5.3, 1.9 Hz, 1H), 4.80 (s, 1H), 4.23 (s, 2H), 3.75 (q, J = 10.4 Hz, 2H), 3.61 (ddd, J = 15.6, 11.8, 3.0 Hz, 1H), 3.19 (dd, J = 12.4, 10.2 Hz, 1H), 3.08 (ddd, J = 9.1, 5.2, 4.0 Hz, 1H), 2.92 (d, J = 15.1 Hz, 4H), 2.41 - 2.21 (m, 5H), 1.99 (dddd, J = 21.1, 14.3, 8.5, 6.2 Hz, 2H), 1.07 (dt, J = 9.1, 6.2 Hz, 1H), 0.23 (ddd, J = 6.0, 3.9, 1.9 Hz, 1H).

[0215] 3-P2:

[0216] MS (ESI) M / Z: 570.3 [M+H] + .

[0217] 1 H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 6.9 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.74 - 6.66 (m, 1H), 6.62 (d, J = 0.5 Hz, 1H), 6.50 (t, J = 7.2 Hz, 1H), 5.88 (d, J = 7.3 Hz, 1H), 4.93 (s, 1H), 4.88 (dd, J = 5.3, 1.9 Hz, 1H), 4.80 (s, 1H), 4.23 (s, 2H), 3.75 (q, J = 10.4 Hz, 2H), 3.61 (ddd, J = 15.6, 11.8, 3.0 Hz, 1H), 3.19 (dd, J = 12.4, 10.2 Hz, 1H), 3.08 (ddd, J = 9.1, 5.2, 4.0 Hz, 1H), 2.92 (d, J = 15.1 Hz, 4H), 2.41 - 2.21 (m, 5H), 1.99 (dddd, J = 21.1, 14.3, 8.5, 6.2 Hz, 2H), 1.07 (dt, J = 9.1, 6.2 Hz, 1H), 0.23 (ddd, J = 6.0, 3.9, 1.9 Hz, 1H).

[0218] Example 4:

[0219] N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-7-(3-(((4-(methylsulfonyl)-2,3- dihydrobenzofuran-7-yl)amino)prop-1 -yn-1 -yl)-6-(2,2,2-trifluoroethyl)pyrrolo[1,2- a]pyrazin-1 -amine

[0220] Reaction Scheme:

[0221] Procedure:

[0222] Step A: To a solution of 1-chloro-7-iodo-6-(2,2,2-trifluoroethyl)pyrrolo[1,2- a]pyrazine (334 mg, 0.93 mmol), 4-(methylsulfonyl)-N-(prop-2-yn-1 -yl)-2,3- dihydrobenzofuran-7-amine (350 mg, 1.40 mmol) in DMF (10 mL) was added triethylamine (20 mL), bis(triphenylphosphine)palladium dichloride (65 mg, 0.093 mmol), tetrakis(triphenylphosphine)palladium (1 10 mg, 0.093 mmol), copper iodide (89 mg, 0.47 mmol). The air was replaced by argon three times. The reaction was stirred at 30 °C for 2 hours. LCMS detection showed the reaction was complete. The reaction was concentrated under reduced pressure, the residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude was purified by silica gel column chromatography to give 297 mg of N-(3-(1 -chloro-6-(2,2,2-trifluoroethyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1 -yl)-4- (methylsulfonyl)-2,3-dihydrobenzofuran-7-amine.

[0223] MS (ESI) M / Z: 484.1 [M+H] + .

[0224] Step B: To a solution of N-(3-(l-chloro-6-(2,2,2-trifluoroethyl)pyrrolo[l,2- a]pyrazin-7-yl)prop-2-yn-l-yl)-4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amme (150 mg, 0.31 mmol), (3S,4R)-4-amino-3-fluoropiperidine-l-carboxylic acid tert-butyl ester (140 mg, 0.62 mmol) in toluene (22 mL) was added palladium acetate (14 mg, 0.062 mmol), Ruphos (58 mg, 0.12 mmol) and cesium carbonate (300 mg, 0.93 mmol). The air was replaced by argon three times. The reaction was stirred at 100 °C for 18 h. LCMS indicated the reaction was complete. The reaction was poured into water (10 mL), extracted with ethyl acetate (10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by Flash (C18, 0.1% HCOOH in water / CH3CN) to give 41 mg of (3S,4R)-3-fluoro-4-((7-(3-((4-(methylsulfonyl)-2,3- dihydrobenzofuran-7-yl)amino)prop-l-yn-l-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[l,2- a]pyrazin-l-yl)amino]piperidine-l-carboxylic acid tert-butyl ester.

[0225] MS (ESI) M / Z: 666.3 [M+H] + .

[0226] Step C: To a solution of (3S,4R)-3-fluoro-4-((7-(3-((4-(methylsulfonyl)-2,3- dihydrobenzofuran-7-yl)amino)prop-l-yn-l-yl)-6-(2,2,2-trifluoroethyl)pyrrolo[l,2- a]pyrazin-l-yl)amino]piperidine-l-carboxylic acid tert-butyl ester (45 mg, 0.068 mmol) in dichloromethane (1.5 mL) was added hydrogen chloride in ethyl acetate (2 M, 4.5 mL, 9.0 mmol). The reaction was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure to give 38 mg of N-((3S,4R)-3-fluoropiperidin-4-yl)-7-(3-((4- (methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl-l-yn-l-yl)-6-(2,2,2- trifluoroethyl)pyrrolo[l,2-a]pyrazin-l-amine hydrochloride.

[0227] MS (ESI) M / Z: 566.1 [M+H] + .

[0228] Step D: To a solution of N-((3S,4R)-3-fluoropiperidin-4-yl)-7-(3-((4- (methylsulfonyl)-2,3-dihydrobenofuran-7-yl)amino)propyl-1-yn-1-yl)-6-(2,2,2- trifluoroethyl)pyrrolo[1,2-a]pyrazin-1-amine hydrochloride (38 mg, 0.063 mmol) in methanol (7.55 mL) was added triethylamine (34 mg, 0.34 mmol), paraformaldehyde (9 mg, 0.29 mmol), acetic acid (4 mg, 0.067 mmol). The reaction was stirred at room temperature for 10 minutes. To the reaction was added sodium cyanoborohydride (21 mg, 0.34 mmol). The reaction was stirred at 50 °C for 2 hours. The reaction was checked by LCMS and was complete. The reaction was quenched with ammonia (25%, 10 mL). The reaction was extracted with dichloromethane (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give 13 mg of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-(3-(((4- (methylsulfonyl)-2,3-dihydrobenofuran-7-yl)amino)prop-1-yn-1-yl)-6-(2,2,2- trifluoroethyl)pyrrolo[1,2-a]pyrazin-1-amine.

[0229] Separation conditions: Prep Column: Waters X bridge C18 10um OBD 19*250mm, Mobile Phase: 0.1% NH4HCO3 in water, Flow rate: 20 mL / min, Gradient: 5%-95%, Detection wavelength: 214nm / 254nm, Retention time: 7.90 min.

[0230] MS (ESI) M / Z: 580.3 [M+H] + .

[0231] 1 H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 5.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.05 (s, 1H), 7.03 (d, J = 5.1 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 4.68 (t, J = 8.9 Hz, 2H), 4.30 (s, 2H), 4.26 - 4.08 (m, 2H), 3.79 (q, J = 10.4 Hz, 2H), 3.51 (t, J = 8.8 Hz, 2H), 3.25 - 3.10 (m, 2H), 3.04 (s, 3H), 2.99 - 2.92 (m, 1H), 2.45 - 2.36 (m, 1H), 2.31 (s, 3H), 2.29 - 2.01 (m, 2H), 1.90 - 1.74 (m, 1H).

[0232] With reference to the above examples, the following molecules were prepared:

[0233] * The meaning of: Take 6-P1 and 6-P2 as an example, the absolute configuration is unknown, that is, the structure of 6-P1 is

[0234] 6-P2 is the other one of the two.

[0235] Example 15:

[0236] Method for preparing 7-((3-(8-(3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)seleno)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-2,3- dihydrobenzofuran-4-carboxamide

[0237] Reaction Scheme:

[0238] Step A: Dissolve potassium selenocyanate (3.6 g, 25.0 mmol) in water (120 mL), add silver nitrate (4.2 g, 25.0 mmol), replace with argon three times, and react at room temperature for 1 hour. After the reaction is completed, filter the reaction solution, and collect the filter cake to obtain 5.1 g of silver selenocyanate. Directly use for the next step.

[0239] Step B: Dissolve N-chlorophthalimide (1.06 g, 5.87 mmol) in dichloromethane (20 mL), add silver selenocyanate (1.5 g, 7.04 mmol), replace with argon three times, and react at room temperature for 16 hours. After the reaction is completed, filter the reaction solution, and concentrate the filtrate to obtain 720 mg of 2-selenocyanatoisoindoline-1,3-dione.

[0240] 1 H NMR (400 MHz, DMSO) δ 7.84 (s, 1H).

[0241] Step C: Put 2-selenocyanatoisoindoline-1,3-dione (590 mg, 2.36 mmol) and methyl 8- bromoindolizine-2-carboxylate (500 mg, 1.97 mmol) in a mortar, and grind for 1 hour. TLC detection shows that the raw material disappears, dilute the reaction mixture with water, and then extract with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography to obtain 560 mg of methyl 8-bromo-3-selenocyanatoindolizine-2-carboxylate.

[0242] MS (ESI) M / Z: 358.8 [M+H] + .

[0243] Step D: 8-Bromo-3-selenoformic acid indolizine-2-carboxylate (560 mg, 1.56 mmol) was dissolved in super dry acetonitrile (10 mL), then cesium carbonate (2.03 g, 6.24 mmol) was added, (trifluoromethyl)trimethylsilane (665 mg, 4.68 mmol) was added dropwise under ice bath, and the reaction was allowed to react at room temperature for 2 hours. LCMS detection showed that the starting material disappeared, the reaction liquid was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 395 mg of 8-bromo-3-((trifluoromethyl)selenyl)indolizine-2-carboxylic acid methyl ester.

[0244] MS (ESI) M / Z: 401.7 [M+H] + .

[0245] Step E: 8-Bromo-3-((trifluoromethyl)selenyl)indolizine-2-carboxylic acid methyl ester (395 mg, 0.99 mmol) was dissolved in tetrahydrofuran / methanol / water (2 mL / 2 mL / 2 mL), then sodium hydroxide (197 mg, 4.92 mmol) was added, and the reaction was allowed to react at 60°C for 1 hour. LCMS detection showed that the reaction was complete. The reaction liquid was adjusted to pH with 1M dilute hydrochloric acid, extracted with dichloromethane three times, the organic phase was combined, dried with anhydrous sodium sulfate, and concentrated to obtain 381 mg of 8-bromo-3-((trifluoromethyl)selenyl)indolizine-2-carboxylic acid. It was directly used in the next step without purification.

[0246] MS (ESI) M / Z: 387.7 [M+H] +

[0247] Step F: 8-Bromo-3-((trifluoromethyl)selenyl)indolizine-2-carboxylic acid (381 mg, 0.98 mmol) was dissolved in dichloromethane (5 mL), then dimethylhydroxylamine hydrochloride (288 mg, 2.94 mmol), N,N-diisopropylethylamine (632 mg, 4.9 mmol), HATU (558 mg, 1.47 mmol) were added in turn, and the reaction was allowed to react at 20°C for 2 hours. LCMS detection showed that the starting material disappeared, the reaction liquid was diluted with water, then extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 371 mg of 8-bromo-N-methoxy-N-methyl-3-((trifluoromethyl)selenyl)indolizine-2-carboxamide.

[0248] MS (ESI) M / Z: 430.8 [M+H] + .

[0249] Step G: Dissolve 8-bromo-N-methoxy-N-methyl-3-((trifluoromethyl)selenoI)indolizine- 2-carboxamide (371 mg, 0.86 mmol) in super dry tetrahydrofuran (5 mL), add diisobutylaluminum hydride (1.5 M, 1.72 mL, 2.58 mmol) dropwise at 0 °C, and stir for 1 hour. TLC plate monitoring shows the disappearance of starting material, pour the reaction into 5% aqueous potassium sodium tartrate solution, then add dichloromethane and stir for half an hour, separate the organic phase after standing, extract the aqueous phase with dichloromethane three times, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify on a silica gel column to give 162 mg of 8-bromo-3-((trifluoromethyl)selenyl)indolizine-2-carbaldehyde.

[0250] MS (ESI) M / Z: 372.0 [M+H] + .

[0251] Step H: Dissolve 8-bromo-3-((trifluoromethyl)selenyl)indolizine-2-carbaldehyde (162 mg, 0.44 mmol) in methanol (2 mL), add potassium carbonate (182 mg, 1.32 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (127 mg, 0.66 mmol) in sequence, and stir at 20 °C for 2 hours. LCMS monitoring shows the disappearance of starting material, add water to the reaction, extract with ethyl acetate twice, dry the combined organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue on a silica gel column to give 154 mg of 8-bromo-2-ethynyl-3-((trifluoromethyl)selenyl)indolizine.

[0252] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 7.1 Hz, 1H), 7.41 (d, J = 7.1 Hz, 1H), 6.93 - 6.75 (m, 2H), 4.43 (s, 1H).

[0253] Step I: Dissolve 8-bromo-2-ethynyl-3-((trifluoromethyl)selenyl)indolizine (154 mg, 0.42 mmol) in N,N-dimethylformamide dimethyl acetal (3 mL), and stir at 100 °C for 16 hours. LCMS monitoring shows the disappearance of starting material, cool the reaction to room temperature, filter, and purify the filtrate by flash (FA) to give 116 mg of 3-(8-bromo-3-((trifluoromethyl)selenyl)indolizin-2-yl)propynal.

[0254] 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.55 (d, J = 7.1 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.14 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H).

[0255] Step J: 3-(8-bromo-3-((trifluoromethyl)seleno)indolizin-2-yl)prop-2-ynal (116 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL), 7-amino-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (115 mg, 0.6 mmol), 3A molecular sieves, acetic acid (0.1 mL) were added, stirred at room temperature for 2 hours, then sodium triacetoxyborohydride (190 mg, 0.9 mmol) was added, reacted at room temperature for 18 hours. LCMS monitoring showed that the raw material disappeared, the reaction liquid was added with water, extracted with ethyl acetate twice, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 108 mg of 7-((3-(8-bromo-3-((trifluoromethyl)seleno)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide.

[0256] MS (ESI) M / Z: 571.7 [M+H] + .

[0257] Step K: 7-((3-(8-bromo-3-((trifluoromethyl)seleno)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (50 mg, 0.087 mmol) was dissolved in 1,4-dioxane (2 mL), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (36 mg, 0.174 mmol), cesium carbonate (170 mg, 0.52 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) (35 mg, 0.044 mmol) were added, replaced with nitrogen for three times, reacted at 100°C for 8 hours. LCMS monitoring showed that the raw material disappeared, the reaction liquid was added with water, extracted with ethyl acetate twice, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC (NH3H2O) to obtain 1.59 mg of 7-((3-(8-(3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)seleno)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide.

[0258] Separation conditions: Prep Column: Waters Xbridge C18 19*250mm 10um, mobile phase: 0.1% NH3H2O in water / CH3CN, flow rate: 20 mL / min, gradient: 50%-60%, detection wavelength: 214nm / 254nm, retention time: 9.38 min.

[0259] MS (ESI) M / Z: 624.2 [M+H] + .

[0260] 1 H NMR (400 MHz, CD3OD) δ 7.87 (d, J = 6.9 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.66 (t, J = 7.2 Hz, 1H), 6.07 (d, J = 7.5 Hz, 1H), 4.59 (t, J = 8.8 Hz, 2H), 4.27 (s, 2H), 3.75 - 3.59 (m, 2H), 3.53 - 3.41 (m, 2H), 3.06 - 2.94 (m, 1H), 2.86 (s, 3H), 2.36 (s, 3H), 2.27 - 2.14 (m, 1H), 2.11 - 1.89 (m, 5H).

[0261] The following compounds were synthesized according to the above method:

[0262] The control molecule PC14586 was synthesized, and its structure is as follows:

[0263] The control molecule B was synthesized, and its structure is as follows:

[0264] The control molecule C was synthesized, and its structure is as follows:

[0265] The control molecule D was synthesized, and its structure is as follows:

[0266] II. Biological activity experiments

[0267] (I) In vitro DNA binding experiment

[0268] The ability of p53 protein to bind to DNA was tested in vitro using the Homogeneous Time Resolved Fluorescence (HTRF) method and the half maximal effective concentration EC50 of the compound to restore the ability of p53 Y220C protein to bind to DNA was determined 50 .

[0269] 1. Experimental materials

[0270] 2. Experimental method

[0271] Compounds were gradient diluted in DMSO in 384PP Plate Compound Dilution Plate, 0.1 μL of compound was transferred to 384 Reaction Microplate (Greiner 784075) using Echo, ensuring the final DMSO content of 1% (duplicated). 2.5 μL of P53-Y220C enzyme solution was added to each well of 384 Reaction Microplate, incubated at 25°C for 10 minutes. 2.5 μL of MAb-Anti-His-Tb solution was added to each well, incubated at 30°C for 60 minutes. 5 μL of Streptavidin-d2 and dsDNA mixed solution was added to each well to continue incubation for 60 minutes (final concentration: 20 mM Hepes (PH 7.5), 75 mM KCl, 1 mM MgCl2, 0.1% BSA, 1 mM DTT, 50 nM P53-Y220C, 10 nM dsDNA, 1x MAb-Anti-His-Tb, 1x Streptavidin-d2). The wells containing 10 μM positive drug and enzyme were used as high control, and the wells containing the same amount of DMSO and enzyme were used as low control. The HTRF signal was read on the BMG (PHERAstar FSX) microplate reader, and the HTRF ratio of each well was calculated by the following formula: HTRF ratio = (signal F665 / signal F620) * 10000. The activation percentage of the compound treatment well was normalized between the high control and the low control (% activation = (HTRF ratio low control - HTRF ratio 化合物处理 ) / (HTRF ratio low control - HTRF ratio high control) * 100). Then the four-parameter EC 50 curve was fitted and analyzed by XLfit 5.5.0, and the EC 50 was the compound concentration corresponding to 50% activation degree on the curve.

[0272] 3. Experimental results

[0273] The DNA binding data of the compounds of the present application in vitro is shown in Table 1. It can be seen that the compounds of the present application have good DNA binding activity. The EC 50 Generally less than 500 nM, preferably, the EC 50 of some of the compounds is less than 200 nM, more preferably, the EC 50 of some of the compounds is less than 100 nM, further preferably, the EC 50 of some of the compounds is less than 50 nM.

[0274] Table 1

[0275] (ii) Cell proliferation inhibition experiment

[0276] The method of measuring the intracellular ATP content (CellTiter-Glo) was used to detect the inhibitory effect of the compounds on the proliferation of NUGC-3, HuH-7, BxPC-3, AGS, BT-549 and NCI-H1299 cell lines, and the half inhibitory concentration IC 50 .

[0277] 1. Experimental materials

[0278] RPMI-1640 medium, DMEM medium, fetal bovine serum (FBS), 100X Pen / Strep, GlutaMAX-I Supplement were purchased from GIBCO company; NUGC-3, AGS and BT-549 cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd., NCI-H1299 and BxPC-3 cell lines were purchased from the American ATCC cell library, HuH-7 cell line was purchased from the Chinese Academy of Sciences cell library; Cell Titer-Glo luminescent cell viability assay reagent was purchased from Promega company.

[0279] 2. Experimental method

[0280] 1) According to the density of 200 NUGC-3 cells per well or 200 HuH-7 cells per well or 300 BxPC-3 cells per well or 300 BT-549 cells per well or 200 NCI-H1299 cells per well or 100 AGS cells per well, the cells were inoculated in 384-well culture plates, 50 μL per well. According to the density of 500 NUGC-3 cells per well or 800 HuH-7 cells per well or 1000 BxPC-3 cells per well or 200 AGS cells per well, the cells were inoculated in 96-well culture plates, 100 μL per well. Incubated in an incubator (37℃, 5% CO2) overnight.

[0281] 2) Day 0: 200 nL (384-well) or 400 nL (96-well) of the test compound (10 mM initial concentration, 9 concentrations, 1:3 dilution ratio) were added into the cells in the culture plate using D300e (TECAN), and the final concentration of DMSO was 0.4%, and the culture plate was incubated in the cell incubator (37°C, 5% CO2) for 168 hours. Blank control: 200 nL (384-well) or 400 nL (96-well) of DMSO was added to each well.

[0282] 3) Day 7: 20 pL (384-well) or 50 pL (96-well) of Cell Titer-Glo reagent was added to each well, 500 rpm shaking for 10 minutes, and incubated at room temperature in the dark for 10 minutes to stabilize the luminescent signal.

[0283] 4) Envision microplate reader (PerkinElmer) was used to detect the luminescent signal.

[0284] 5) Data analysis was performed using GraphPad Prism software, and the IC 50 .

[0285] Table 2

[0286] The data in Table 2 shows that the compounds of the present application have good selectivity for cells with Y220C mutation.

[0287] III. CYP450 enzyme inhibition evaluation experiment

[0288] 1. Purpose of the experiment

[0289] The potential inhibition of the 3A4 subtype by the compounds of the present application was evaluated through an in vitro liver microsomal incubation system to predict the risk of drug-drug interactions (DDI) induced by the compounds.

[0290] 2. Materials and methods

[0291] 2.1 Experimental materials

[0292] • Human liver microsomes (HLM): purchased from BD Gentest company, protein concentration 20 mg / mL

[0293] • Specific probe substrates: midazolam and testosterone

[0294] 2.2 Experimental design

[0295] Pre-incubation stage

[0296] Incubate different concentrations of test compounds (0.1-30 μM) with HLM (0.2 mg / mL) and probe substrate at 37 °C water bath for 5 min, then add NADPH to start the reaction, 37 °C water bath for 5 min (midazolam) or 10 min (testosterone), add acetonitrile to terminate the reaction.

[0297] 2.3 Sample analysis

[0298] LC-MS / MS was used to quantify the amount of metabolite production:

[0299] Mass spectrometry conditions: ESI+ mode, MRM monitoring (example: midazolam 1'-hydroxyl metabolite m / z 342→203)

[0300] 3. Data processing

[0301] Remaining enzyme activity (%) = (test group metabolite / solvent control group) x 100

[0302] Non-linear regression analysis was performed using GraphPad Prism to obtain IC 50 values

[0303] 4. Experimental results

[0304] Table 3 Inhibition of CYP3A by test compounds

[0305] 5. Conclusion

[0306] The above data show that the inhibition of CYP3A by the compound of Example 1 is significantly improved compared with the control molecule.

[0307] Four, in vivo pharmacokinetic determination in mice

[0308] Mice were used as test animals, and after intravenous bolus and oral injection administration of the compound of the present disclosure, plasma samples were collected at specific time points, the concentration of the compound in the plasma was detected by LC-MS / MS, and the PK parameters were calculated to reflect the pharmacokinetic behavior of the compound of the present disclosure in the plasma of mice in vivo.

[0309] 1. Test scheme

[0310] 1.1 Test drug:

[0311] The compound of Example 1 of the present disclosure and the control molecule C.

[0312] 1.2 Test animals

[0313] Mice, balb / c nude, female, supplied by Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0314] The compound of Example 1 and the control molecule C are both self-prepared.

[0315] 1.3 Administration

[0316] The mouse administration information of the compound of Example 1 and the control molecule C: IV (intravenous injection), PO (oral administration). The experimental group is 3 mice. The mouse IV administration dose of the compound of Example 1 and the control molecule C is 2 mg / kg, the administration volume is 5 mL / kg, and the solvent is 5% DMSO + 10% Solutol + 85% Saline. The mouse PO administration dose is 100 mg / kg, the administration volume is 10 mL / kg, and the solvent is 10% DMSO + 20% Solutol + 70% water.

[0317] 1.4 Experimental apparatus

[0318] The centrifuge is purchased from Eppendorf Company, and the pipette is purchased from Eppendorf Company.

[0319] 1.5 Sample collection

[0320] After the mice are administered, at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hours, 0.025 mL and 0.2 mL of blood are respectively taken from the mice by intravenous blood collection, and placed in EDTA-K2 test tubes. The plasma is separated by centrifugation at 4°C and 2000g for 10 min, and stored at -80°C.

[0321] 1.6 Sample processing

[0322] Mouse plasma sample processing:

[0323] 1) 5 μL of the plasma sample is added to 10 μL of blank plasma matrix, and 200 μL of acetonitrile is added for precipitation. After vortex mixing, centrifugation is performed for 15 min.

[0324] 2) 90 μL of the supernatant is taken for LC / MS / MS analysis to determine the concentration of the test compound.

[0325] 2. Experimental results

[0326] The pharmacokinetic parameters are calculated using WinNonlin. The pharmacokinetic parameters of the mice after intravenous injection and oral administration are shown in Table 3, wherein Cmax represents the maximum plasma concentration, CL represents the clearance rate, Vss represents the steady-state distribution volume, T1 / 2 represents the terminal elimination half-life, and AUC represents the area under the plasma concentration-time curve. max 1 / 2

[0327] Table 4 Note: " / " represents not determined

[0328] ​​Results: As can be seen from Table 4, the compound of the present disclosure has good exposure and excellent pharmacokinetic properties.

Claims

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein, Z1, Z2, Z3, Z4are each independently selected from N or CH; R1is selected from -S(=O)2R 1a , -P(=O)R 1b R 1c , -C(=O)NR 1b R 1c , -S(=O)2NR 1b R 1c , R 1b N=S(=O)(R 1c )-, -N=S(=O)R 1b R 1c or optionally substituted 5-6 membered heteroaryl; wherein said R 1a , R 1b , R 1c are each independently selected from hydrogen, deuterium, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or optionally substituted 5-6 membered heteroaryl; or R 1b and R 1c cyclo with the atom to which they are attached to form an optionally substituted 5-8 membered heterocyclyl; wherein said C 1-4 alkyl, 5-6 membered heteroaryl and 5-8 membered heterocyclyl can be optionally substituted with 1-3 groups selected from hydroxy, cyano, amino, halogen, C 1-4 alkoxy; Ring A is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; R a each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-4 alkyl, -C 1-4 alkyl-OH, C 1-4 alkoxy, -C 1-4 alkyl-OC 1-4 alkyl or C 1-4 haloalkyl; or two adjacent R a together with the atom to which they are attached form a C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is optionally substituted with p R d ; R d each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkyl-OH, -C 1-4 alkyl-OC 1-4 alkyl or C 1-4 haloalkyl; R2is selected from hydrogen, hydroxy, amino, halogen, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy; or R1, R2and the atoms to which they are attached cyclize together to form an optionally substituted 5-6 membered heterocyclyl; R3is selected from -CH2CF3, -OCF3, -SeCF3; Ring B is selected from 5-8 membered heterocyclyl; R b selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, deuterated C 1-4 alkoxy, C 3-6 cycloalkyl, -C(O)CH3or wherein the C 1-4 alkyl can be further optionally substituted with 1-3 groups selected from hydroxy, halo, C 1-4 alkoxy, or a deuterium atom; m, n, p are each independently selected from 0, 1, 2 or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, which satisfies one or more of the following conditions: 1) R1is -S(=O)2R 1a , -P(=O)R 1b R 1c , -C(=O)NR 1b R 1c , -S(=O)2NR 1b R 1c , or R 1b N=S(=O)(R 1c )-; 2) R 1a is C 1-4 alkyl; 3) R 1b and R 1c is H or C 1-4 alkyl, said C 1-4 alkyl is optionally substituted with 1-3 groups selected from the group consisting of hydroxy and cyano; 4) m is 0; 5) ring A is 5-6 membered heterocyclyl; 6) p is 0; 7) R2is hydrogen; or, R1, R2and the atoms to which they are attached cyclize to form wherein "1" indicates the point of attachment of R1to the phenyl ring and "2" indicates the point of attachment of R2to the phenyl ring; 8) R3is -CH2CF3or -SeCF3; for example -CH2CF3; 9) R b halogen or C 1-4 alkyl; 10) n is 2.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein which satisfies one or more of the following conditions: 1) the C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; for example, cyclopropyl; 2) said halogen is independently F, Cl, Br or I; for example F; 3) said C 1-4 alkyl is independently methyl, ethyl, n-propyl or i-propyl; for example methyl or ethyl; for example again methyl; 4) said 5-8 membered heterocyclyl is independently 5-6 membered heterocyclyl; 5) the heteroatoms in the 5-8 membered heterocyclyl group are independently selected from N, O, P and S, and the number of heteroatoms is independently 1, 2 or 3; for example the heteroatoms are N and the number of heteroatoms is 1; for example the heteroatoms are P and the number of heteroatoms is 1; for example For example, 6) said heteroatom in said 5-6 membered heterocyclyl is independently selected from N, O and S, and the number of heteroatoms is independently 1, 2 or 3; for example the heteroatom is O and the number of heteroatoms is 1; 7) said 5-8 membered heterocyclyl is independently 5-8 membered saturated heterocyclyl; 8) said 5-6 membered heterocyclyl is independently 5-8 membered saturated heterocyclyl; 9) said 5-8 membered heterocyclyl is independently monocyclic; 10) said 5-6 membered heterocyclyl is independently monocyclic.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3, for example -S(O)2CH3, 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from wherein R a , R d , m, p are as described in any of claims 1-5.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Structural unit selected from 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Structural unit selected from wherein "*" indicates the carbon atom to which R1is attached adjacent to the carbon atom to which R1is attached.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, R1, R2and the atoms to which they are attached cyclize together to form 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein, structural unit selected from for example, the structural unit is for example, the structural unit for example, the structural unit 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein, structural unit selected from 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from wherein M is selected from NR c , R c is selected from C 1-4 alkyl, C 3-6 cycloalkyl, -C(O)CH3 or wherein said C 1-4 alkyl can be further optionally substituted with 1-3 groups selected from hydroxy, halogen, C 1-4 alkoxy or a deuterium atom.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein, R c selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein, structural unit selected from 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from 19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, selected from the compounds shown below, or a pharmaceutically acceptable salt thereof, wherein, Z1, Z2, Z3, Z4, R1, R3, ring B, R a , R b , R d , p, m, n are as defined in claims 1-18.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein, selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof, wherein, wherein, R1, R3, R a , R b , R c , R d , m, n, p are as defined in claim 19.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, selected from the compounds shown below, or a pharmaceutically acceptable salt thereof, wherein R1is as defined in claim 20.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein selected from the following compounds or a pharmaceutically acceptable salt thereof:

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from any one of the following compounds: The compounds eluting first under the following conditions: prep column: 25*250mm 10μm, mobile phase: MEOH (+0.1% 7.0mol / l Ammonia in MEOH), flow rate: 60 mL / min, gradient: 40%, detection wavelength: 214nm; for example it has a retention time of 4.162min; or, Compounds eluting later in the following conditions: Prep Column: 25*250mm 10μm, mobile phase: MEOH (+0.1% 7.0mol / l Ammonia in MEOH), flow rate: 60 mL / min, gradient: 40%, detection wavelength: 214nm; for example it has a retention time of 5.186min.

24. A pharmaceutical composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. Use of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 24, for the manufacture of a medicament for the treatment of cancer.

26. The use of claim 25, wherein the cancer is a solid tumor, for example lung cancer, gastric cancer, liver cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer or endometrial cancer.

27. Use of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 24, for the manufacture of a medicament for the treatment of a p53 mutation-mediated cancer.

28. The use of claim 27, wherein the p53 mutation is a p53 Y220C mutation.

29. The use of claim 27 or 28, wherein the cancer is selected from a solid tumor.

30. The use of claim 29, wherein the cancer is selected from lung cancer, gastric cancer, liver cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, or endometrial cancer harboring a p53 Y220C mutation.

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