Indazole derivatives, their preparation methods, pharmaceutical compositions and applications

Abstract

This invention discloses an indazole derivative, its preparation method, pharmaceutical composition, and applications. Specifically, this invention discloses a compound as shown in Formula I, its solvate, its pharmaceutically acceptable salt, or a solvate of a pharmaceutically acceptable salt thereof. The compound as shown in Formula I has a novel structure and exhibits excellent inhibitory activity against wild-type ALK and TRKA.

Description

[0001] This application claims priority to Chinese patent application 2022103480471, filed on March 28, 2022. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to an indazole derivative, its preparation method, pharmaceutical composition, and its application. Background Technology

[0003] Lung cancer has the highest incidence and mortality rate among all malignant tumors, and there is a constant need to discover new compounds with better activity and higher selectivity in the field of targeted therapy for lung cancer. Non-small cell lung cancer (NSCLC) has the highest incidence rate among lung cancers, accounting for 80-85%. Genes mainly associated with NSCLC include NTRK (NeuroTrophin Receptor Kinase) and ALK (Anaplastic Lymphoma Kinase). The "golden mutation"—ALK gene—due to its mutual repulsion with other driver genes, shows that ALK inhibitors have higher efficacy and more significant cure rates compared to targeted therapy for EGFR gene mutations. Furthermore, NTRK gene fusions have been found in both common cancer tissues and rare tumors, thus NTRK achieves a truly "broad spectrum." Currently, there are marketed drugs targeting both ALK and NTRK, indicating their good drug-like properties. Therefore, designing and synthesizing dual-target drugs targeting ALK / TRK (tropomyosin receptor kinase) has significant theoretical and practical value.

[0004] Currently, there are three main generations of ALK inhibitors on the market: first-generation crizotinib; second-generation alectinib, ceritinib, and brigatinib; and third-generation lorlatinib. In 2011, the FDA approved crizotinib for the treatment of ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), filling a gap in targeted therapies for this disease at the time. In 2017, the FDA approved ceritinib and brigatinib for the treatment of ALK-positive NSCLC patients whose disease has progressed or who are intolerant to crizotinib. In 2018, the FDA approved lorlatinib for the treatment of progressive ALK-positive NSCLC, metastatic disease in patients who have received crizotinib and at least one other ALK inhibitor, or patients whose disease has progressed to metastasis after treatment with alectinib or ceritinib.

[0005] There are two main TRK inhibitors: larotrectinib and entrectinib, which were approved by the FDA in 2018 and 2019, respectively, for the treatment of adult and pediatric patients with solid tumors that have NTRK gene fusions rather than specific cancer types. Research on entrectinib targeting ALK is currently in the clinical phase. Summary of the Invention

[0006] The technical problem to be solved by this invention is to provide a novel indazole derivative, its preparation method, a pharmaceutical composition, and its application. The indazole derivative of this invention exhibits excellent inhibitory activity against wild-type ALK and TRKA (wherein, the IC50 value for wild-type ALK and TRKA is significantly higher). 50 The values ​​are all at the nanomolar level.

[0007] The present invention solves the above-mentioned technical problems by means of the following method.

[0008] The present invention provides a compound as shown in Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0009]

[0010] Among them, R 1 It is a 3- to 8-membered heterocyclic alkyl group, with one or more R 1-1 Substituted 3- to 8-membered heterocyclic alkyl groups, 5- to 8-membered heterocyclic alkenyl groups, or those with one or more R groups 1-2 Substituted 5-8 membered heterocyclic alkenyl groups, with one or more R 1-3 Substituted C1-C6 alkyl groups, -NR 1-4 R 1-5 or -(C=O)R 1-6 ;

[0011] R 1-3 and R 1-6 Each is independently a 3- to 8-membered heterocyclic alkyl group, and is surrounded by one or more R a Substituted 3- to 8-membered heterocyclic alkyl groups, -NR c R d 5-8 membered heterocyclic alkenyl groups, with one or more R groups b Substituted 5- to 8-membered heterocyclic alkenyl groups;

[0012] R 1-1 R 1-2 R a and R b Each is independently a C1 to C6 alkyl group or -NR e R f ;

[0013] R1-4 R 1-5 R c and R d Each is independently a C1 to C6 alkyl group or is composed of one or more R groups. g Substituted C1-C6 alkyl groups;

[0014] R g For -NR h R i ;

[0015] R e R f R h and R i Each is independently a C1 to C6 alkyl group;

[0016] R 2 It is H, C1-C6 alkyl, and is formed by one or more R 2-1 Substituted C1-C6 alkyl, 3-8 membered heterocyclic alkyl, or substituted with one or more R 2-2 Substituted 3- to 8-membered heterocyclic alkyl groups;

[0017] R 2-1 -OH, C1-C6 alkoxy, C6-C 14 Aryl, -(C=O)NR 2-1-1 R 2-1-2 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkyl substituted with one or more hydroxyl groups, 3- to 8-membered heterocycloalkyl, or substituted with one or more R groups j Substituted 3- to 8-membered heterocyclic alkyl groups; R 2-1-1 and R 2-1-2 Each is independently H or C1-C6 alkyl;

[0018] R 2-2 and R j Each is independently a C1-C6 alkyl group or -COOR 2-2-1 ;R 2-2-1 It is a C1 to C6 alkyl group;

[0019] X is -CR x1 R x2 -、-O- or -O-CR x3 R x4 -;R x1 R x2 R x3 and R x4 Each is independently H or C1-C6 alkyl;

[0020] R 3 C6~C 14 aryl groups or C6-C groups substituted with one or more halogens 14 Aryl;

[0021] In the 3- to 8-membered heterocyclic alkyl groups and 5- to 8-membered heterocyclic alkenyl groups, the types of heteroatoms are each independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3.

[0022] In one implementation scheme, R 1 R 1-3 and R 1-6 In the 3- to 8-membered heterocyclic alkyl group, the type of heteroatom can be independently N and / or O, preferably N, or N and O; the number of heteroatoms can be independently 1 or 2.

[0023] In one implementation scheme, R 1 R 1-3 and R 1-6 In this context, the 3- to 8-membered heterocyclic alkyl group can be independently a 5- to 7-membered heterocyclic alkyl group, such as tetrahydropyrrolyl, piperazinyl, piperidinyl, morpholinyl, or a 7-membered heterocyclic alkyl group containing 2 nitrogen atoms, more specifically...

[0024] In one implementation scheme, R 1 R 1-3 and R 1-6 In the 5- to 8-membered heterocyclic alkenyl group, the type of heteroatom can be N independently; the number of heteroatoms can be 1 independently.

[0025] In one implementation scheme, R 1 R 1-3 and R 1-6 In this context, the 5- to 8-membered heterocyclic alkenyl group can independently be a 6-membered heterocyclic alkenyl group, such as a 6-membered heterocyclic alkenyl group containing one N atom, or more specifically...

[0026] In one implementation scheme, R 1 In this context, the C1-C6 alkyl group can be a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0027] In one implementation scheme, R 1-1 R 1-2 R a and R b In this context, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0028] In one implementation scheme, R 1-4 R 1-5 R c and R dIn this context, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.

[0029] In one implementation scheme, R e R f R h and R i In this context, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0030] In one implementation scheme, R 1 This can be methyl-substituted piperazine, piperidinyl, morpholinyl, methyl-substituted morpholinyl, methyl-substituted 7-membered heterocyclic alkyl with 2 nitrogen atoms, methyl-substituted 6-membered heterocyclic alkenyl with 1 nitrogen atom, methyl-substituted piperidinyl, dimethylamino-substituted piperidinyl, dimethylamino-substituted tetrahydropyrrolyl, methyl and dimethylaminoethyl-substituted amino, methyl-substituted piperazine-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, methyl-substituted morpholinyl-CH2-, methyl-substituted 7-membered heterocyclic alkyl with 2 nitrogen atoms-CH2-, or methyl-substituted 6-membered heterocyclic alkenyl with 1 nitrogen atom. -CH2-, methyl-substituted piperidinyl-CH2-, dimethylamino-substituted piperidinyl-CH2-, dimethylamino-substituted tetrahydropyrrolyl-CH2-, methyl and dimethylaminoethyl-substituted amino-CH2-, methyl-substituted piperazine-(C=O)-, methyl-substituted morpholinyl-(C=O)-, methyl-substituted 7-membered heterocyclic alkyl-(C=O)- containing 2 N atoms, dimethylamino-substituted piperidinyl-(C=O)-, morpholinyl-(C=O)-, dimethylamino-substituted tetrahydropyrrolyl-(C=O)-, methyl and dimethylaminoethyl-substituted amino-(C=O)-, for example

[0031]

[0032] In one implementation scheme, R 2 In this context, the C1-C6 alkyl group can be independently C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, ethyl, n-propyl, isopropyl or isobutyl.

[0033] In one implementation scheme, R 2 and R 2-1 In the 3- to 8-membered heterocyclic alkyl group, the type of heteroatom can be independently selected from N or O; the number of heteroatoms can be independently 1.

[0034] In one implementation scheme, R 2 and R2-1 In this context, the 3- to 8-membered heterocyclic alkyl group can be independently a 4- to 6-membered heterocyclic alkyl group, such as oxobutyranyl, azirheptacyclic butyranyl, tetrahydropyranyl, or piperidinyl, more specifically...

[0035] In one implementation scheme, R 2-1 In this context, the C1-C6 alkoxy group can be independently a C1-C3 alkoxy group, such as methoxy, ethoxy, n-propoxy, or isopropoxy, preferably methoxy.

[0036] In one implementation scheme, R 2-1 In the context, C6 to C 14 Aryl groups can be C6-C6. 10 Aryl groups, such as phenyl groups.

[0037] In one implementation scheme, R 2-1-1 and R 2-1-2 In this context, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl.

[0038] In one implementation scheme, R 2-1 In this context, the 3- to 8-membered cycloalkyl group can be independently a 4- to 6-membered cycloalkyl group, such as cyclohexyl.

[0039] In one implementation scheme, R 2-2 and R j In this context, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0040] In one implementation scheme, R 2-2-1 In this context, the C1-C6 alkyl group can be independently C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably tert-butyl.

[0041] In one implementation scheme, R x1 R x2 R x3 and R x4 In this context, the C1-C6 alkyl group can be a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0042] In one implementation scheme, R x1 R x2 R x3 and R x4 Each can be either H or methyl.

[0043] In one implementation scheme, R 2It can be H, isopropyl, methoxy-substituted ethyl, methoxy-substituted propyl, hydroxy-substituted ethyl, phenyl-CH2-, carbamoyl-CH2-, methoxy-substituted isobutyl, hydroxy-substituted cyclohexyl-CH2-, oxetane, tetrahydropyranyl, tetrahydropyranyl-CH2-, aziridine-CH2-, piperidinyl, methyl-substituted piperidinyl-CH2-, tert-butoxycarbonyl-substituted aziridine-CH2-, tert-butoxycarbonyl-substituted piperidinyl, tert-butoxycarbonyl-substituted piperidinyl-CH2-, and more, for example, H,

[0044] In one embodiment, X can be -CH2-, -O-, or -O-CHCH3-, for example -CH2-, -O-, or

[0045] In one implementation scheme, R 3 In the context, C6 to C 14 Aryl groups can be C6-C6. 10 Aryl groups, such as phenyl groups.

[0046] In one implementation scheme, R 3 In this context, the number of halogens is denoted as n, which can be 2 or 3.

[0047] In one implementation scheme, R 3 In this context, the halogen is denoted as M, and M can be selected from one or more of F, Cl, Br and I, preferably F and / or Cl.

[0048] In one implementation scheme, R 3 It can be a fluorine-substituted phenyl, or a fluorine and chlorine-substituted phenyl, more for example

[0049] In one implementation scheme, R 1 For one or more R 1-1 The substituted 3- to 8-membered heterocyclic alkyl group is preferably replaced by one or more R 1-1 The substituted 6-membered heterocyclic alkyl group; preferably, in the 3- to 8-membered heterocyclic alkyl group, the type of heteroatom is N, and the number of heteroatoms is preferably 2; preferably, the 3- to 8-membered heterocyclic alkyl group is piperazine-based, for example...

[0050] In one implementation scheme, R 1-1 It is a C1 to C6 alkyl group.

[0051] In one implementation scheme, R 1 For example, piperazine groups substituted with methyl groups.

[0052] In one implementation scheme, R 2 It is a 3- to 8-membered heterocyclic alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl groups, or those with one or more R 2-2 Substituted 3- to 8-membered heterocyclic alkyl groups.

[0053] In one implementation scheme, R 2-1 It is a 3- to 8-membered heterocyclic alkyl group, preferably a 4- or 6-membered heterocyclic alkyl group; the type of heteroatom can be independently selected from N and O; the number of heteroatoms can be independently 1.

[0054] In one implementation scheme, R 2-1 It is a four-membered heterocyclic alkyl group containing one nitrogen atom or a six-membered heterocyclic alkyl group containing one oxygen atom, such as tetrahydropyranyl or aziridine, and more specifically...

[0055] In one implementation scheme, R 2 It is a 6-membered heterocyclic alkyl group, with one or more R 2-2 Substituted 6-membered heterocyclic alkyl groups, tetrahydropyranyl-substituted C1-C6 alkyl groups, or aziridine-substituted C1-C6 alkyl groups, such as tetrahydropyranyl, piperidinyl, tetrahydropyranyl-substituted methyl groups, or aziridine-substituted methyl groups, more specifically...

[0056] In one implementation scheme, R 1 For one or more R 1-1 The substituted 3- to 8-membered heterocyclic alkyl group is preferably replaced by one or more R 1-1 Substituted 6-membered heterocyclic alkyl; more preferably, a 6-membered heterocyclic alkyl containing 2 N atoms substituted with one or more C1-C6 alkyl groups, such as a methyl-substituted piperazine group, and more preferably...

[0057] R 2 It is a 3- to 8-membered heterocyclic alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl groups, or those with one or more R 2-2 The substituted 3- to 8-membered heterocyclic alkyl group, preferably a 6-membered heterocyclic alkyl group, a C1- to C6 alkyl group substituted with one or more (a four-membered heterocyclic alkyl group containing one N atom or a six-membered heterocyclic alkyl group containing one O atom), or a substituted alkyl group substituted with one or more R 2-2 The substituted 6-membered heterocyclic alkyl group, more preferably a 6-membered heterocyclic alkyl group, is substituted with one or more R groups. 2-2 Substituted 6-membered heterocyclic alkyl groups, tetrahydropyranyl-substituted C1-C6 alkyl groups, or aziridine-substituted C1-C6 alkyl groups, such as tetrahydropyranyl, piperidinyl, tetrahydropyranyl-substituted methyl groups, or aziridine-substituted methyl groups, more specifically...

[0058] In one implementation scheme, R 1 For one or more R 1-1 Substituted 3- to 8-membered heterocyclic alkyl groups, with one or more R 1 -3 Substituted C1-C6 alkyl groups or -(C=O)R 1-6 Preferably, in the 3- to 8-membered heterocyclic alkyl group, the heteroatoms are N and O, and the number of heteroatoms is preferably 2; preferably, the 3- to 8-membered heterocyclic alkyl group is morpholinyl, for example...

[0059] In one implementation scheme, R 1-3 It is a 5- to 8-membered heterocyclic alkenyl group, preferably a 6-membered heterocyclic alkenyl group, and more preferably a six-membered heterocyclic alkenyl group containing one nitrogen atom, for example...

[0060] In one implementation scheme, R 1-6 For one or more R a The substituted 3- to 8-membered heterocyclic alkyl group; preferably, the heteroatom in the 3- to 8-membered heterocyclic alkyl group is N and O, and the number of heteroatoms is preferably 2; preferably, the 3- to 8-membered heterocyclic alkyl group is morpholino, for example...

[0061] In one implementation scheme, R a It is a C1 to C6 alkyl group.

[0062] In one implementation scheme, R b It is a C1 to C6 alkyl group.

[0063] In one implementation scheme, R 1 For one or more R 1-1 Substituted 3- to 8-membered heterocyclic alkyl groups, with one or more R 1 -3 Substituted C1-C6 alkyl groups or -(C=O)R 1-6 Preferably, it is controlled by one or more R 1-1 Substituted 3- to 8-membered heterocyclic alkyl groups containing N and O atoms, and substituted with (one or more R) b ) substituted 5- to 8-membered heterocyclic alkenyl-substituted C1- to C6 alkyl groups, or -(C=O)- substituted with one or more R a Substituted 3- to 8-membered heterocyclic alkyl groups, such as morpholino groups substituted with one or more methyl groups, methyl groups substituted with (one or more methyl groups)-6-membered heterocyclic alkenyl groups, or -(C=O)-morpholino groups substituted with one or more methyl groups, more such as Among them, by (one or more R) bThe substituted 5- to 8-membered heterocyclic alkenyl group and the substituted C1- to C6 alkyl group refer to substituents in which the 5- to 8-membered heterocyclic alkenyl group is a C1- to C6 alkyl group, while R b Substituents are 5- to 8-membered heterocyclic alkenyl groups.

[0064] In one implementation scheme, R 1 For one or more R 1-3 Substituted C1-C6 alkyl groups or -(C=O)R 1-6 .

[0065] In one implementation scheme, R 1-3 For one or more R a The substituted 3- to 8-membered heterocyclic alkyl group, preferably, has N and O heteroatoms, and preferably has two heteroatoms; preferably, the 3- to 8-membered heterocyclic alkyl group is morpholino, for example...

[0066] In one implementation scheme, R 1-6 For one or more R a The substituted 3- to 8-membered heterocyclic alkyl group; preferably, the heteroatom in the 3- to 8-membered heterocyclic alkyl group is N, and the number of heteroatoms is preferably 2; preferably, the 3- to 8-membered heterocyclic alkyl group is piperazine-based, for example...

[0067] In one implementation scheme, X is CH2.

[0068] In one implementation scheme, R 1 For one or more R 1-3 Substituted C1-C6 alkyl groups or -(C=O)R 1-6 Preferably, it is controlled by (one or more R) a ) substituted methyl groups containing N and O atoms, or -(C=O)-substituted with one or more R a Substituted 3- to 8-membered heterocyclic alkyl groups containing two nitrogen atoms, such as morpholino-substituted methyl groups or piperazine-substituted -(C=O)- groups, more specifically...

[0069] X is CH2.

[0070] In one embodiment, the compound represented by Formula I may be any one of the following compounds:

[0071]

[0072] The definitions of each letter and group are as defined in this invention.

[0073] In one embodiment, the compound represented by Formula I is any one of the following compounds:

[0074]

[0075]

[0076] The present invention also provides a method for preparing a compound as shown in Formula I, comprising the following steps: in a solvent, a compound as shown in Formula 1 and a compound as shown in Formula 2 are reacted as shown below;

[0077]

[0078] Wherein, Y is a halogen, such as F, Cl, Br or I, preferably I; the definitions of the other substituents in the above formulas are as described above.

[0079] In one embodiment, the preparation method of the compound shown in Formula I includes the following steps: in a solvent, under the action of CuI, trans-1,2-cyclohexanediamine and a base, the compound shown in Formula 1 and the compound shown in Formula 2 are reacted.

[0080] In one embodiment, in the preparation of the compound as shown in Formula I, the solvent may be an ether solvent, such as dioxane.

[0081] In one embodiment, in the preparation scheme of the compound shown in Formula I, the base may be an alkali metal carbonate, such as cesium carbonate.

[0082] The present invention also provides a pharmaceutical composition comprising substance P and a pharmaceutically acceptable excipient; said substance P is a compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0083] The present invention also provides the use of the above-mentioned substance P or the above-mentioned pharmaceutical composition in the preparation of ALK and / or TRK inhibitors.

[0084] The present invention also provides the use of the above-mentioned substance P or the above-mentioned pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of diseases related to ALK and / or TRK.

[0085] In one implementation, the diseases associated with ALK and / or TRK may be cancer, pain, neurological disorders, autoimmune diseases, and inflammation.

[0086] In one implementation, the cancer may be lung cancer, such as non-small cell lung cancer.

[0087] In one implementation, TRK may be TRKA.

[0088] Unless otherwise specified, the terms used in this invention have the following meanings:

[0089] The term "heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 8), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatom (one or more of N, O and S), and each ring is saturated.

[0090] The term "heterocyclic alkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic group formed by a carbon atom and at least one heteroatom, wherein the heteroatom is independently selected from N, O, or S, examples including but not limited to...

[0091] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0092] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. The terms "C1-C6 alkyl", "C1-C4 alkyl", and "C1-C3 alkyl" refer to straight-chain or branched alkyl groups having 1 to 6 carbon atoms, 1 to 4 carbon atoms, and 1 to 3 carbon atoms, respectively, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl.

[0093] The term "cycloalkyl" refers to a saturated monocyclic carbocyclic substituent; for example, 3- to 8-membered cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0094] The term "alkoxy" refers to a group in which an oxygen atom is inserted at any reasonable position in an alkyl group (as defined above). Representative examples of C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, and -CH2-OCH3.

[0095] In this invention, "R-CH2-" means that one H in -CH3 is replaced by R to form an R-substituted methyl group. For example, morpholino-CH2- means a methyl group replaced by a morpholino group.

[0096] In this invention, "R-(C=O)-" means that one side of the carbonyl group is replaced by R. For example, methyl-substituted piperazine-(C=O)- means that one side of the carbonyl group is replaced by a methyl-substituted piperazine group, where R is a methyl-substituted piperazine group.

[0097] In structural fragments This refers to the connection between the structural segment and other segments in the molecule through this site.

[0098] The term "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0099] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive phrase “...independently” used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups.

[0100] The term "solvate" refers to a substance formed by the crystallization of a compound with a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0101] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0102] The term "pharmaceuticalally acceptable salt solvate" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol, etc.). The pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" mentioned above.

[0103] The term "pharmaceutical excipient" or "pharmaceuticalally acceptable carrier" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances contained in a pharmaceutical preparation, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition). Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition. They may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipient may be an inert filler or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0104] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the disease or one or more biological manifestations of the condition. “Treatment” can also mean prolonging survival compared to expected survival without treatment.

[0105] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0106] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0107] The reagents and raw materials used in this invention are all commercially available.

[0108] The positive and progressive effects of this invention are as follows: the compounds of this invention, as shown in Formula I, exhibit excellent inhibitory activity against ALK and TRKA, with IC50 values ​​higher than those against wild-type ALK and TRKA. 50 The values ​​are all at the nanomolar level. Detailed Implementation

[0109] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0110] In the following examples, the preparation methods of intermediates I-2 to I-45 are the same as those of intermediate I, and the preparation methods of intermediates D-1 and D-2 are the same as those of intermediate D.

[0111] Example 1: Synthesis of Compound 1

[0112]

[0113] Synthetic route

[0114]

[0115] 1) Compound B (7.1 g, 34.15 mmol), Pd(PPh3)4 (700 mg, 0.61 mmol), and potassium phosphate (13.2 g, 62.18 mmol) were added sequentially to a toluene solution of compound A (5.12 g, 31.04 mmol) under magnetic stirring. The mixture was refluxed at 105 °C under a nitrogen atmosphere for 4 h. After the reaction was completed by TLC monitoring, the reaction solution was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 40 / 1) to obtain intermediate C (light brown solid; 5.8 g; yield: 76%).

[0116] 2) Add 85% hydrazine hydrate (5.6 mL, 95.0 mmol) to a butanol solution of compound C (4.7 g, 19.0 mmol) under magnetic stirring. Reflux at 120 °C for 14 h. After the reaction is complete, the reaction solution is allowed to cool naturally to room temperature. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry it with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain the crude product. The crude product is purified by column chromatography (PE / EA = 40 / 1) to obtain intermediate D (white solid; 4.7 g; yield: 96%).

[0117] 3) A tetrahydrofuran solution containing compound E (5 g, 25.38 mmol) under magnetic stirring was cooled to 0 °C, sodium hydride (2.03 g, 84.58 mol) was added, and the mixture was stirred for 30 min. Then, compound methoxybenzyl bromide (5.17 g, 33.01 mmol) was added, the mixture was heated to 70 °C, and the reaction was carried out for 4 h. The mixture was washed three times with water, the organic layer was dried, and the mixture was concentrated to obtain intermediate F (a light yellow oily substance; 4.5 g; yield: 56%).

[0118] 4) Intermediate F (4 g, 12.62 mmol) was dissolved in 60 mL of toluene, and methylpiperazine (3.78 g, 37.80 mmol), palladium acetate (284 mg, 1.26 mmol), cesium carbonate (12.34 mg, 37.85 mmol), and BINAP (780 mg, 1.25 mmol) were added sequentially. The reaction was carried out at 105 °C for 10 h. The reaction solution was filtered through diatomaceous earth and subjected to column chromatography to obtain intermediate G (brown oil; 1.7 g; yield: 40%).

[0119] 5) Intermediate G (1.2 g, 18.89 mmol) was added to trifluoroacetic acid (20 mL) and reacted at 105 °C for 18 h. The reaction solution was concentrated, the pH was adjusted to neutral with sodium carbonate, the aqueous layer was extracted with ethyl acetate (3 x 100 mL), and the organic phase was separated by column chromatography to obtain intermediate H (light brown solid; 0.5 g; yield: 93%).

[0120] 6) Dissolve intermediate H (0.5 g, 2.3 mmol) in DMF solution, and after the temperature is reduced to 0 °C, add potassium tert-butoxide (194.6 mg, 3.45 mmol), stir for 5 min, add iodine (700.5 mg, 2.76 mmol), quench the reaction with sodium thiosulfate after 15 min, extract the aqueous layer with ethyl acetate (3 x 150 mL), dry the organic phase, and obtain intermediate I (light brown solid; 0.7 g; yield: 89%).

[0121] 7) Intermediate I (200 mg, 0.58 mmol) was dissolved in dioxane (5 mL) solution. Compound D (227 mg, 0.8 mmol), CuI (33 mg, 0.17 mmol), trans-1,2-cyclohexanediamine (20 mg, 0.17 mmol), and Cs₂CO₃ (0.4 g, 1.2 mmol) were added sequentially to the solution. The reaction solution was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction solution was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 1 (light brown solid; 0.19 g; yield: 69%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.56 (d, J = 8.0, 2H), 7.45-7.57 (m, 3H), 7.35 (d, J = 8.0Hz, 1H) ,7.12-7.17(m,4H),4.12(s,2H),3.27(s,4H),2.45(s,4H),2.26(s,3H).ES-API(m / z):[M+H]+ 474.5.

[0122] Example 2: Synthesis of Compound 2

[0123]

[0124] Synthetic route

[0125]

[0126] Under nitrogen protection, intermediate I-2 (460 mg, 1.2 mmol) (referring to Example 1, with intermediate I-2 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 2 (gray solid; 0.18 g; yield: 35%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.54 (d, J=8.0Hz, 2H), 7.45-7.54 (m, 3H), 7.40 ( s,1H),7.02-7.08(m,4H),4.05(s,2H),1.42(d,J=8.0,6H).ES-API(m / z):[M+H] + 516.3.

[0127] Example 3: Synthesis of Compound 3

[0128]

[0129] Synthetic route

[0130]

[0131] Under nitrogen protection, intermediate I-3 (480 mg, 1.2 mmol) (referring to Example 1, with intermediate I-3 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 3 (brown solid; 0.24 g; yield: 45%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J = 8.0, 2H), 7.45-7.57 (m, 3H), 7.35 (d, J = 8.0Hz, 1H), 7.12-7.17 (m, 4H), 4.12 (s, 2H),3.72(d,J=6.0Hz,2H),3.48(d,J=6.0Hz,2H),3.42(s,3H),3.25(s,4H),2.48(s,4H),2.24(s,3H).ES-API(m / z):[M+H] + 532.3.

[0132] Example 4: Synthesis of Compound 4

[0133]

[0134] Synthetic route

[0135]

[0136] Under nitrogen protection, intermediate I-4 (497 mg, 1.2 mmol) (referring to Example 1, with intermediate I-4 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 4 (grayish-white solid; 0.3 g; yield: 54%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J=8.0Hz, 2H), 7.45-7.57 (m, 3H), 7.35 (d, J=8.0Hz, 1H), 7.12-7.17 (m, 4H), 4 .12(s,2H),3.50(t,J=6.0,4H),3.35(s,3H),3.25(s,4H),2.48(s,4H),2.24(s,3H),2.10(m,2H).ES-API(m / z):[M+H] + 546.5.

[0137] Example 5: Synthesis of Compound 5

[0138]

[0139] Synthetic route

[0140]

[0141] Under nitrogen protection, intermediate I-5 (464 mg, 1.2 mmol) (referring to Example 1, with intermediate I-5 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (grayish-white solid; 0.23 g; yield: 44%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.35 (d, J = 8.0Hz, 2H), 7.44-7.50 (m, 3H), 7.35 (s, 1H), 7.12-7.17 (m, 4H), 4.96 (s, 1H), 4. 12(s,2H),4.29-4.34(m,2H),4.09(s,2H),3.27(s,4H),3.76-3.84(m,2H),2.45(s,4H),2.26(s,3H).ES-API(m / z):[M+H] + 518.3.

[0142] Example 6: Synthesis of Compound 6

[0143]

[0144] Synthetic route

[0145]

[0146] Under nitrogen protection, intermediate I-6 (518 mg, 1.2 mmol) (referring to Example 1, with intermediate I-6 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 6 (gray solid; 0.2 g; yield: 36%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.35 (d, J=8.0Hz, 2H), 7.47-7.53 (m, 3H), 7.35 (s, 1H), 7.23-7.32 (m, 5H) ,7.12-7.17(m,4H),4.56(s,2H),4.12(s,2H),3.27(s,4H),2.45(s,4H),2.26(s,3H).ES-API(m / z):[M+H] + 564.5.

[0147] Example 7 Synthesis of Compound 7

[0148]

[0149] Synthetic route

[0150]

[0151] Under nitrogen protection, intermediate I-7 (480 mg, 1.2 mmol) (referring to Example 1, with intermediate I-7 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 7 (grayish-white solid; 0.22 g; yield: 42%).1 H-NMR (400MHz, DMSO-d6, δppm): 8.45 (d, J = 8.0Hz, 2H), 7.45-7.52 (m, 3H), 7.34 (s, 1H), 7.68-7.75 (m, 4 H),7.21(s,2H),4.69(s,2H),4.05(s,2H),3.24(s,4H),2.46(s,4H),2.25(s,3H).ES-API(m / z):[M+H] + 530.9.

[0152] Example 8: Synthesis of Compound 8

[0153]

[0154] Synthetic route

[0155]

[0156] Under nitrogen protection, intermediate I-8 (550 mg, 1.2 mmol) (referring to Example 1, with intermediate I-8 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 8 (gray solid; 0.26 g; yield: 44%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55(d,J=8.0Hz,2H),7.45-7.57(m,3H),7.35(d,J=8.0Hz,1H),7.12-7.22(m,4H),4.36(d,J=6.0H z,2H),4.12(s,2H),3.89-3.93(m,1H),3.64-3.68(m,4H),3.27(s,4H),3.22(s,6H),2.45(s,4H),2.26(s,3H).ES-API(m / z):[M+H] + 589.8.

[0157] Example 9: Synthesis of Compound 9

[0158]

[0159] Synthetic route

[0160]

[0161] Under nitrogen protection, intermediate I-9 (545 mg, 1.2 mmol) (referring to Example 1, with intermediate I-9 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 9 (gray solid; 0.3 g; yield: 54%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.54 (d, J = 8.0, 2H), 7.43-7.58 (m, 3H), 7.37 (d, J = 8.0Hz, 1H), 7.14-7.24 (m, 4H), 4.11 (s, 2H), 3.65 (d, J = 3. 2Hz,2H),3.54(m,1H),3.26(s,4H),2.43(s,4H),2.24(s,3H),1.43-1.46(m,1H),1.37-1.42(m,4H),1.40-1.46(m,4H).ES-API(m / z):[M+H] + 586.4.

[0162] Example 10: Synthesis of Compound 10

[0163]

[0164] Synthetic route

[0165]

[0166] Under nitrogen protection, intermediate I-10 (460 mg, 1.2 mmol) (referring to Example 1, with intermediate I-10 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 10 (gray solid; 0.21 g; yield: 41%). 1 H-NMR (400MHz, DMSO-d6, δppm):8.53(d,J=8.0,2H),7.46-7.56(m,3H),7.33(d,J=8.0Hz,1H),7.13-7.27(m,4H) ,5.45-5.53(m,1H),5.16-5.23(m,4H),4.13(s,2H),3.24(s,4H),2.46(s,4H),2.24(s,3H).ES-API(m / z):[M+H] + 530.2.

[0167] Example 11 Synthesis of Compound 11

[0168]

[0169] Synthetic route

[0170]

[0171] Under nitrogen protection, intermediate I-11 (511 mg, 1.2 mmol) (referring to Example 1, where intermediate I-11 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 11 (gray solid; 0.28 g; yield: 51%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J = 8.0, 2H), 7.45-7.57 (m, 3H), 7.35 (d, J = 8.0Hz, 1H), 7.12-7.27 (m, 4H), 4.12 (s, 2H), 3 .64(m,1H),3.58-3.58(m,4H),3.25(s,4H),2.48(s,4H),2.24(s,3H)2.06-2.11(m,2H),1.72-1.79(m,2H).ES-API(m / z):[M+H] + 558.5.

[0172] Example 12 Synthesis of Compound 12

[0173]

[0174] Synthetic route

[0175]

[0176] Under nitrogen protection, intermediate I-12 (528 mg, 1.2 mmol) (referring to Example 1, with intermediate I-12 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 12 (gray solid; 0.21 g; yield: 37%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J = 8.0, 2H), 7.45-7.57 (m, 3H), 7.35 (d, J = 8.0Hz, 1H), 7.12-7.27 (m, 4H), 4.12 (s, 2H), 4.03-4.08 (m, 2H),3.57-3.62(m,4H),3.26(s,4H),2.54(s,4H),2.26(s,3H),1.65-1.69(m,2H),1.53-1.59(m,1H),1.24-1.28(m,2H).ES-API(m / z):[M+H] + 571.9.

[0177] Example 13 Synthesis of Compound 13

[0178]

[0179] Synthetic route

[0180]

[0181] Under nitrogen protection, intermediate I-13 (490 mg, 1.2 mmol) (referring to Example 1, with intermediate I-13 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 13 (gray solid; 0.29 g; yield: 54%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.56 (d, J = 8.0, 2H), 7.45-7.57 (m, 3H), 7.35 (d, J = 8.0Hz, 1H), 7.12-7.27 (m, 4H), 4.12 (s, 2H) ,3.63(d,J=6.4Hz,2H),3.58(d,J=10.8Hz,2H),3.34-3.42(m,3H),3.25(s,4H),2.48(s,4H),2.24(s,3H).ES-API(m / z):[M+H] + 542.8.

[0182] Example 14 Synthesis of Compound 14

[0183]

[0184] Synthetic route

[0185]

[0186] Under nitrogen protection, intermediate I-14 (510 mg, 1.2 mmol) (referring to Example 1, where intermediate I-14 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 14 (gray solid; 0.26 g; yield: 47%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.57 (d, J = 8.0, 2H), 7.41-7.52 (m, 3H), 7.36 (d, J = 8.0Hz, 1H), 7.02-7.14 (m, 4H), 4.15 (s, 2H), 3.25 (s, 4H), 3.14 (d,J=6.4Hz,2H),2.48(s,4H),2.37-2.41(m,2H),2.24(s,3H),1.48(d,J =12.3Hz,2H),1.36-1.44(m,1H),1.14-1.19(m,2H).ES-API(m / z):[M+H] + 557.5.

[0187] Example 15 Synthesis of Compound 15

[0188]

[0189] Synthetic route

[0190]

[0191] Under nitrogen protection, intermediate I-15 (526 mg, 1.2 mmol) (referring to Example 1, with intermediate I-15 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 15 (brown solid; 0.26 g; yield: 46%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.13-8.17 (q, J=4.0Hz, 2H), 7.70 (s, 1H), 7.40 (dd, J= 1.2Hz,1H),7.02-7.08(m,3H),6.89(s,1H),5.94(s,2H),4.09(s,2H),3.25(s,4H),3. 19(d,J=6.4Hz,2H),2.89(d,J=11.9Hz,2H),2.44(s,4H),2.39-2.45(m,2H),2.24(s,3 H),1.55(d,J=12.3Hz,2H),1.46-1.30(m,1H),1.16-1.22(m,2H).ES-API(m / z):[M+H] + 571.4.

[0192] Example 16 Synthesis of Compound 16

[0193]

[0194] Synthetic route

[0195]

[0196] Under nitrogen protection, intermediate I-16 (453 mg, 1.2 mmol) (referring to Example 1, where intermediate I-16 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 16 (brown solid; 0.3 g; yield: 52%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.24-8.27 (q, J=4.0Hz, 2H), 7.75 (s, 1H), 7.46 (dd, J=1.2Hz,1H),7.08-7.12(m,3H),6.82(s,1H),5.93(s,2H),4.12(s,2H),4.03(d,J=1 1.8,2H),3.25(s,4H),2.48(s,4H),2.53(d,J=10.4Hz,2H),2.42(d,J=10.4,2H),2. 24(s,3H),2.18(s,3H),1.54-1.64(m,3H),1.34(d,J=11.4,2H).ES-API(m / z):[M+H] + 585.5.

[0197] Example 17 Synthesis of Compound 17

[0198]

[0199] Synthetic route

[0200]

[0201] Under nitrogen protection, intermediate I-17 (613 mg, 1.2 mmol) (referring to Example 1, with intermediate I-17 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 17 (light brown solid; 0.19 g; yield: 31%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.13-8.17(q,J=4.0Hz,2H),7.70(s,1H),7.40(dd,J=1.2Hz,1H),7.02-7.08(m,3H),6.89(s,1H),5.94(s,2H),4.0 9(s,2H),3.63(d,J=6.4Hz,2H),3.58(d,J=10.8Hz,2H),3.34-3.42(m,3H) ,3.25(s,4H),2.48(s,4H),2.24(s,3H),1.34(s,9H).ES-API(m / z):[M+H] + 643.1.

[0202] Example 18 Synthesis of Compound 18

[0203]

[0204] Synthetic route

[0205]

[0206] Under nitrogen protection, intermediate I-18 (630 mg, 1.2 mmol) (referring to Example 1, with intermediate I-18 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 18 (light brown solid; 0.24 g; yield: 36%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.13-8.17 (q, J=4.0Hz, 2H), 7.70 (s, 1H), 7.40 (dd ,J=1.2Hz,1H),7.02-7.08(m,3H),6.89(s,1H),5.94(s,2H),4.09(s,2H),3.25(s,4 H),3.14(d,J=6.4Hz,2H),2.48(s,4H),2.37-2.41(m,2H),2.24(s,3H),1.48(d,J=1 2.3Hz,2H),1.36-1.44(m,1H),1.14-1.19(m,2H),1.48(s,9H).ES-API(m / z):[M+H] + 657.3.

[0207] Example 19 Synthesis of Compound 19

[0208]

[0209] Synthetic route

[0210]

[0211] Under nitrogen protection, intermediate I-19 (647 mg, 1.2 mmol) (referring to Example 1, where intermediate I-19 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 19 (brown solid; 0.19 g; yield: 29%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.13-8.17 (q, J=4.0Hz, 2H), 7.70 (s, 1H), 7.40 (dd, J=1. 2Hz,1H),7.02-7.08(m,3H),6.89(s,1H),5.94(s,2H),4.09(s,2H),3.25(s,4H),3.19(d, J=6.4Hz,2H),2.89(d,J=11.9Hz,2H),2.44(s,4H),2.39-2.45(m,2H),2.24(s,3H),1.55( d,J=12.3Hz,2H),1.46-1.30(m,1H),1.16-1.22(m,2H),1.43(s,9H).ES-API(m / z):[M+H] + 671.2.

[0212] Example 20 Synthesis of Compound 20

[0213]

[0214] Synthetic route

[0215]

[0216] Under nitrogen protection, intermediate I-20 (395 mg, 1.2 mmol) (referring to Example 1, with intermediate I-20 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 20 (brown solid; 0.19 g; yield: 42%). 1 H-NMR (400MHz, DMSO-d6, δppm): 13.10 (s, 1H), 8.55 (d, J = 8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J =8.0Hz,1H),6.97-6.99(m,4H),4.01(s,2H),3.56(s,4H),1.57-1.72(m,6H).ES-API(m / z):[M+H] + 458.9

[0217] Example 21 Synthesis of Compound 21

[0218]

[0219] Synthetic route

[0220]

[0221] Under nitrogen protection, intermediate I-21 (394 mg, 1.2 mmol) (referring to Example 1, with intermediate I-21 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 21 (brown solid; 0.23 g; yield: 52%).1 H-NMR (400MHz, DMSO-d6, δppm): 13.10 (s, 1H), 8.55 (d, J = 8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J = 8.0H z,1H),6.97-6.99(m,4H),4.01(s,2H),3.27(t,J=9.6Hz,4H),2.5(t,J=9.6Hz,4H).ES-API(m / z):[M+H] + 461.5.

[0222] Example 22 Synthesis of Compound 22

[0223]

[0224] Synthetic route

[0225]

[0226] Under nitrogen protection, intermediate I-22 (428 mg, 1.2 mmol) (referring to Example 1, with intermediate I-22 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 22 (light brown solid; 0.28 g; yield: 58%). 1 H-NMR (400MHz, DMSO-d6, δppm): 13.10 (s, 1H), 8.55 (d, J = 8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J = 8.0Hz, 1H), 6.97-6.99 (m, 4H), 4. 01(s,2H),3.27-3.57(m,2H),2.67(dd,J=12.4,2.0Hz,2H),2.17(dd,J=12.2,10.2Hz,2H),1.26(d,J=6.2Hz,6H).ES-API(m / z):[M+H] + 489.1.

[0227] Example 23 Synthesis of Compound 23

[0228]

[0229] Synthetic route

[0230]

[0231] Under nitrogen protection, intermediate I-23 (427 mg, 1.2 mmol) (referring to Example 1, with intermediate I-23 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 23 (light brown solid; 0.23 g; yield: 47%). 1 H-NMR (400MHz, DMSO-d6, δppm): 13.10 (s, 1H), 8.55 (d, J = 8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J = 8.0Hz, 1H), 6.97- 6.99(m,4H),4.01(s,2H),2.90-3.11(m,4H),2.58-2.65(m,4H),2.43(s,3H),1.74-1.85(m,2H).ES-API(m / z):[M+H] + 487.9.

[0232] Example 24 Synthesis of Compound 24

[0233]

[0234] Synthetic route

[0235]

[0236] Under nitrogen protection, intermediate I-24 (406 mg, 1.2 mmol) (referring to Example 1, where intermediate I-24 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 24 (brown solid; 0.24 g; yield: 51%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J=8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J=8.0Hz, 1H), 6.97-6.99 (m, 4H), 6.14 (t, J= 6.4Hz,1H),4.01(s,2H),3.32(t,J=4.0Hz,2H),2.57(t,J=4.0Hz,2H),2.26(s,3H),1.94(t,J=3.6Hz,2H).ES-API(m / z):[M+H] + 470.9.

[0237] Example 25 Synthesis of Compound 25

[0238]

[0239] Synthetic route

[0240]

[0241] Under nitrogen protection, intermediate I-26 (409 mg, 1.2 mmol) (referring to Example 1, where intermediate I-26 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 25 (light brown solid; 0.23 g; yield: 48%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J=8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J=8.0Hz, 1H), 6.97-6.99 (m, 4H), 4.0 1(s,2H),3.12-3.19(m,2H),2.41-2.51(m,3H),2.18(s,3H),1.74-1.78(m,2H),1.43-1.48(m,2H).ES-API(m / z):[M+H] + 473.2.

[0242] Example 26 Synthesis of Compound 26

[0243]

[0244] Synthetic route

[0245]

[0246] Under nitrogen protection, intermediate I-26 (444 mg, 1.2 mmol) (referring to Example 1, where intermediate I-26 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 26 (brown solid; 0.21 g; yield: 43%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J=8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J=8.0Hz, 1H), 6.97-6.99 (m, 4H), 4.01 (s, 2H), 3.25-3.35(m,2H),2.57-2.67(m,2H),2.33-2.50(m,1H),2.24(s,6H),1.86-1.97(m,2H),1.50-1.55(m,2H).ES-API(m / z):[M+H] + 502.5.

[0247] Example 27 Synthesis of Compound 27

[0248]

[0249] Synthetic route

[0250]

[0251] Under nitrogen protection, intermediate I-27 (427 mg, 1.2 mmol) (referring to Example 1, with intermediate I-27 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 27 (light brown solid; 0.24 g; yield: 51%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.33-8.37(q,J=4.0Hz,2H),7.65(s,1H),7.40(dd,J=1.2Hz,1H),7.22-7.28(m,3H),6.89(s,1H),5.94(s,2H) ,4.09(s,2H),3.15-3.24(m,2H),3.04-3.14(m,2H),2.71-2.79(m,1H), 2.26(s,6H),1.71-1.77(m,1H),1.51-1.58(m,1H).ES-API(m / z):[M+H] + 487.9.

[0252] Example 28 Synthesis of Compound 28

[0253]

[0254] Synthetic route

[0255]

[0256] Under nitrogen protection, intermediate I-28 (413 mg, 1.2 mmol) (referring to Example 1, with intermediate I-28 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 28 (light brown solid; 0.22 g; yield: 48%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.43-8.51 (q, J=4.0Hz, 2H), 7.54 (s, 1H), 7.30 (dd, J=1.2Hz, 1H), 7.02-7.08 (m, 3H), 6.8 9(s,1H),5.94(s,2H),4.09(s,2H),3.43(t,J=Hz,2H),2.41(t,J=Hz,2H),2.24(s,3H),2.19(s,6H).ES-API(m / z):[M+H] + 476.4.

[0257] Example 29 Synthesis of Compound 29

[0258]

[0259] Synthetic route

[0260]

[0261] Under nitrogen protection, intermediate I-29 (427 mg, 1.2 mmol) (referring to Example 1, with intermediate I-29 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 29 (brown solid; 0.23 g; yield: 47%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J = 8.0, 2H), 7.45-7.57 (m, 3H), 7.35 (d, J = 8.0Hz, 1H), 7.12-7. 17(m,4H),4.12(s,2H),3.89-3.96(s,2H),3.27(s,4H),2.45(s,4H),2.26(s,3H).ES-API(m / z):[M+H] + 487.9.

[0262] Example 30 Synthesis of Compound 30

[0263]

[0264] Synthetic route

[0265]

[0266] Under nitrogen protection, intermediate I-30 (409 mg, 1.2 mmol) (referring to Example 1, with intermediate I-30 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 30 (brown solid; 0.16 g; yield: 35%). 1 H-NMR (400MHz, DMSO-d6, δppm): 13.10 (s, 1H), 8.55 (d, J = 8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J = 8.0H z,1H),6.97-6.99(m,4H),4.34(s,2H),4.01(s,2H),3.56(s,4H),1.57-1.72(m,6H).ES-API(m / z):[M+H] + 473.2.

[0267] Example 31 Synthesis of Compound 31

[0268]

[0269] Synthetic route

[0270]

[0271] Under nitrogen protection, intermediate I-31 (411 mg, 1.2 mmol) (referring to Example 1, where intermediate I-31 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 31 (light brown solid; 0.18 g; yield: 38%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.38 (d, J = 8.0, 2H), 7.45-7.54 (m, 3H), 7.36 (d, J = 8.0Hz, 1H), 7.11 -7.16(m,4H),4.12(s,2H),3.42(s,2H),3.62-3.86(m,4H),2.39-2.71(m,4H),ES-API(m / z):[M+H] + 475.4.

[0272] Example 32 Synthesis of Compound 32

[0273]

[0274] Synthetic route

[0275]

[0276] Under nitrogen protection, intermediate I-32 (445 mg, 1.2 mmol) (referring to Example 1, with intermediate I-32 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 32 (light brown solid; 0.26 g; yield: 53%).1 H-NMR (400MHz, DMSO-d6, δppm): 13.10 (s, 1H), 8.55 (d, J = 8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J = 8.0Hz, 1H), 6.97-6.99 (m, 4H), 4.01 (s, 2 H),3.81(s,2H),3.27-3.57(m,2H),2.67(dd,J=12.4,2.0Hz,2H),2.17(dd,J=12.2,10.2Hz,2H),1.26(d,J=6.2Hz,6H).ES-API(m / z):[M+H] + 502.9.

[0277] Example 33 Synthesis of Compound 33

[0278]

[0279] Synthetic route

[0280]

[0281] Under nitrogen protection, intermediate I-33 (444 mg, 1.2 mmol) (referring to Example 1, with intermediate I-33 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 33 (light brown solid; 0.28 g; yield: 57%). 1 H-NMR (400MHz, DMSO-d6, δppm): 13.10 (s, 1H), 8.55 (d, J = 8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J = 8.0Hz, 1H), 6.97-6.99 ( m,4H),4.01(s,2H),3.44(s,2H),2.90-3.11(m,4H),2.58-2.65(m,4H),2.43(s,3H),1.74-1.85(m,2H).ES-API(m / z):[M+H] + 502.1.

[0282] Example 34 Synthesis of Compound 34

[0283]

[0284] Synthetic route

[0285]

[0286] Under nitrogen protection, intermediate I-34 (423 mg, 1.2 mmol) (referring to Example 1, where intermediate I-34 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 34 (brown solid; 0.16 g; yield: 35%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.54 (d, J = 8.0Hz, 2H), 7.47-7.57 (m, 3H), 7.32 (d, J = 8.0Hz, 1H), 6.90-6.99 (m, 4H), 6.14 (t, J = 6.4Hz, 1H ),4.09(s,2H),3.34(d,J=4.0Hz,2H),3.22-3.32(m,2H),2.54(t,J=4.0Hz,2H),2.26(s,3H),2.07(t,J=3.6Hz,2H).ES-API(m / z):[M+H] + 485.2.

[0287] Example 35 Synthesis of Compound 35

[0288]

[0289] Synthetic route

[0290]

[0291] Under nitrogen protection, intermediate I-35 (426 mg, 1.2 mmol) (referring to Example 1, with intermediate I-35 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 35 (brown solid; 0.25 g; yield: 52%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.55 (d, J=8.0Hz, 2H), 7.48-7.57 (m, 3H), 7.30 (d, J=8.0Hz, 1H), 6.97-6.99 (m, 4H), 4.01 (s, 2 H),3.46(s,2H),3.12-3.19(m,2H),2.41-2.51(m,3H),2.18(s,3H),1.74-1.78(m,2H),1.43-1.48(m,2H).ES-API(m / z):[M+H] + 487.3.

[0292] Example 36 Synthesis of Compound 36

[0293]

[0294] Synthetic route

[0295]

[0296] Under nitrogen protection, intermediate I-36 (460 mg, 1.2 mmol) (referring to Example 1, with intermediate I-36 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 36 (brown solid; 0.19 g; yield: 37%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.58 (d, J=8.0Hz, 2H), 7.44-7.54 (m, 3H), 7.37 (d, J=8.0Hz, 1H), 6.91-6.98 (m, 4H), 4.08 (s, 2H), 3.25-3.37(m,2H),2.54-2.63(m,2H),2.42-2.50(m,1H),2.26(s,6H),1.81-1.86(m,2H),1.52-1.62(m,2H).ES-API(m / z):[M+H] + 516.2.

[0297] Example 37 Synthesis of Compound 37

[0298]

[0299] Synthetic route

[0300]

[0301] Under nitrogen protection, intermediate I-37 (444 mg, 1.2 mmol) (referring to Example 1, where intermediate I-37 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 37 (brown solid; 0.2 g; yield: 40%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.13-8.17(q,J=4.0Hz,2H),7.70(s,1H),7.40(dd,J=1.2Hz,1H),7.02-7.08(m,3H),6.89(s,1H),5.94(s,2H),4.09( s,2H),3.35(s,2H),3.15-3.24(m,2H),3.04-3.14(m,2H),2.71-2.79(m,1 H),2.26(s,6H),1.71-1.77(m,1H),1.51-1.58(m,1H).ES-API(m / z):[M+H] + 502.4.

[0302] Example 38 Synthesis of Compound 38

[0303]

[0304] Synthetic route

[0305]

[0306] Under nitrogen protection, intermediate I-38 (430 mg, 1.2 mmol) (referring to Example 1, with intermediate I-38 replacing intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 38 (brown solid; 0.17 g; yield: 35%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.13-8.17 (q, J=4.0Hz, 2H), 7.70 (s, 1H), 7.40 (dd, J=1.2Hz, 1H), 7.02-7.08 (m, 3H), 6.89(s,1H),5.94(s,2H),4.09(s,2H),3.43(t,J=Hz,2H),3.34(s,2H),2.41(t,J=Hz,2H),2.24(s,3H),2.19(s,6H).

[0307] ES-API(m / z):[M+H] + 489.9

[0308] Example 39: Synthesis of Compound 39

[0309]

[0310] Synthetic route

[0311]

[0312] Under nitrogen protection, intermediate I-39 (444 mg, 1.2 mmol) (referring to Example 1, where intermediate I-39 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 39 (light brown solid; 0.18 g; yield: 36%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.65 (d, J = 8.0, 2H), 7.75-7.81 (m, 3H), 7.53 (d, J = 8.0Hz, 1H) ,7.24-7.32(m,4H),4.12(s,2H),3.27(s,4H),2.45(s,4H),2.26(s,3H).ES-API(m / z):[M+H] + 501.9.

[0313] Example 40 Synthesis of Compound 40

[0314]

[0315] Synthetic route

[0316]

[0317] Under nitrogen protection, intermediate I-40 (462 mg, 1.2 mmol) (referring to Example 1, where intermediate I-40 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 2 (light brown solid; 0.2 g; yield: 39%). 1H-NMR (400MHz, DMSO-d6, δppm): 8.64(d,J=8.0,2H),7.79-7.84(m,3H),7.56(d,J=8.0Hz,1H),7.26-7.37(m,4H),4.16(s,2H ),3.27-3.57(m,2H),2.67(dd,J=12.4,2.0Hz,2H),2.17(dd,J=12.2,10.2Hz,2H),1.26(d,J=6.2Hz,6H).ES-API(m / z):[M+H] + 517.2.

[0318] Example 41 Synthesis of Compound 41

[0319]

[0320] Synthetic route

[0321]

[0322] Under nitrogen protection, intermediate I-41 (460 mg, 1.2 mmol) (referring to Example 1, where intermediate I-41 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 41 (light brown solid; 0.19 g; yield: 37%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.67 (d, J = 8.0, 2H), 7.78-7.86 (m, 3H), 7.58 (d, J = 8.0Hz, 1H), 7.26-7.34 (m, 4H),4.14(s,2H),3.01-2.90(m,4H),2.66-2.57(m,4H),2.39(s,3H),1.85-1.776(m,2H).ES-API(m / z):[M+H] + 516.3.

[0323] Example 42 Synthesis of Compound 42

[0324]

[0325] Synthetic route

[0326]

[0327] Under nitrogen protection, intermediate I-42 (477 mg, 1.2 mmol) (referring to Example 1, where intermediate I-42 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 42 (brown solid; 0.21 g; yield: 37%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.64 (d, J = 8.0, 2H), 7.81-7.88 (m, 3H), 7.56 (d, J = 8.0Hz, 1H), 7.25-7.36 (m, 4H), 4.14 (s, 2H), 3 .25-3.35(m,2H),2.57-2.67(m,2H),2.33-2.50(m,1H),2.24(s,6H),1.86-1.97(m,2H),1.50-1.55(m,2H).ES-API(m / z):[M+H] + 529.9.

[0328] Example 43 Synthesis of Compound 43

[0329]

[0330] Synthetic route

[0331]

[0332] Under nitrogen protection, intermediate I-43 (428 mg, 1.2 mmol) (referring to Example 1, where intermediate I-43 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 432 (brown solid; 0.26 g; yield: 54%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.65 (d, J = 8.0, 2H), 7.75-7.81 (m, 3H), 7.53 (d, J = 8.0Hz, 1H), 7 .24-7.32(m,4H),4.12(s,2H),3.12(t,J=9.6Hz,4H),2.61(t,J=9.6Hz,4H).ES-API(m / z):[M+H] + 488.9.

[0333] Synthesis of compound 44 was carried out.

[0334]

[0335] Synthetic route

[0336]

[0337] Under nitrogen protection, intermediate I-44 (461 mg, 1.2 mmol) (referring to Example 1, where intermediate I-44 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 44 (brown solid; 0.23 g; yield: 44.6%).1 H-NMR (400MHz, DMSO-d6, δppm): 8.64 (d, J = 8.0, 2H), 7.78-7.84 (m, 3H), 7.58 (d, J = 8.0Hz, 1H), 7.24-7.32 (m, 4H), 4.12 (s, 2H), 3 .14-3.23(m,2H),3.02-3.12(m,2H),2.67-2.73(m,1H),2.25(s,6H),1.68-1.74(m,1H),1.56-1.65(m,1H).ES-API(m / z):[M+H] + 516.5.

[0338] Example 45 Synthesis of Compound 45

[0339]

[0340] Synthetic route

[0341]

[0342] Under nitrogen protection, intermediate I-45 (446 mg, 1.2 mmol) (referring to Example 1, where intermediate I-45 replaces intermediate I) was dissolved in dioxane (5 mL) solution. Compound D (260 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 45 (light brown solid; 0.22 g; yield: 43.8%). 1 H-NMR (400MHz, DMSO-d6, δppm): 8.58 (d, J = 8.0, 2H), 7.72-7.80 (m, 3H), 7.54 (d, J = 8.0Hz, 1H), 7.27-7.35 (m,4H),4.17(s,2H),3.43(t,J=Hz,2H),2.41(t,J=Hz,2H),2.24(s,3H),2.19(s,6H).ES-API(m / z):[M+H] + 504.5.

[0343] Example 46 Synthesis of Compound 46

[0344]

[0345] Synthetic route

[0346]

[0347] Under nitrogen protection, intermediate D-1 (340 mg, 1 mmol) (referring to Example 1, with intermediate D-1 replacing intermediate D) was dissolved in dioxane (5 mL) solution. Compound I (410 mg, 1.2 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 46 (light brown solid; 0.18 g; yield: 32.5%). 1H-NMR (400MHz, DMSO-d6, δppm): 8.65 (d, J = 8.0, 2H), 7.75-7.81 (m, 3H), 7.53 (d, J = 8.0Hz, 1H), 7.58 (dd, J = 8.8, 5.2Hz, 1H), 7.45- 7.51(m,1H),7.30(s,1H),6.19(q,J=6.8Hz,1H),1.75(d,J=6.4Hz,3H),3.25(s,4H),2.48(s,4H),2.24(s,3H).ES-API(m / z):[M+H] + :554.2.

[0348] Example 47 Synthesis of Compound 47

[0349]

[0350] Synthetic route

[0351]

[0352] Under nitrogen protection, intermediate D-2 (261 mg, 1 mmol) (referring to Example 1, with intermediate D-2 replacing intermediate D) was dissolved in dioxane (5 mL) solution. Compound I (410 mg, 1.2 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 47 (light brown solid; 0.15 g; yield: 32.6%). 1H-NMR (400MHz, DMSO-d6, δppm): 8.67 (d, J = 8.0, 2H), 7.63 (s, 1H), 7.54 (dd, J = 8.9, 0.49Hz, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.24 (dd, J = 8. 90,2.32Hz,1H),6.96(tt,J=9.31,2.27Hz,1H),6.67(dd,J=8.84,2.26Hz,2H),3.26(s,4H),2.41(s,4H),2.26(s,3H).ES-API(m / z):[M+H] + 475.9.

[0353] Example 48 Synthesis of Compound 48

[0354]

[0355] Synthetic route

[0356]

[0357] Under nitrogen protection, intermediate I-32 (445 mg, 1.2 mmol) (referring to Example 32, with intermediate D replacing intermediate D-1) was dissolved in dioxane (5 mL) solution. Compound D-1 (340 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed as monitored by TLC, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 48 (brown solid; 0.19 g; yield: 32.6%). 1H-NMR (400MHz, DMSO-d6, δppm): 8.68 (d, J = 8.0, 2H), 7.74-7.79 (m, 3H), 7.54 (d, J=8.0Hz,1H),7.57(dd,J=8.8,5.2Hz,1H),7.46-7.21(m,1H),7.32(s,1H),6.25( q,J=6.8Hz,1H),1.78(d,J=6.4Hz,3H),3.24-3.46(m,2H),2.65(dd,J=12.4,2.0H z,2H),2.15(dd,J=12.2,10.2Hz,2H),1.24(d,J=6.2Hz,6H).ES-API(m / z):[M+H] + 583.2.

[0358] Example 49 Synthesis of Compound 49

[0359]

[0360] Synthetic route

[0361]

[0362] Under nitrogen protection, intermediate I-32 (445 mg, 1.2 mmol) (referring to Example 32, with intermediate D replacing intermediate D-2) was dissolved in dioxane (5 mL) solution. Compound D-2 (261 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 49 (brown solid; 0.18 g; yield: 35.7%). 1H-NMR (400MHz, DMSO-d6, δppm): 8.64 (d, J=8.0, 2H), 7.68 (s, 1H), 7.59 (dd, J= 8.9,0.49Hz,1H),7.44(s,1H),7.35(s,1H),7.26(dd,J=8.90,2.32Hz,1H),6.98 (tt,J=9.31,2.27Hz,1H),6.63(dd,J=8.84,2.26Hz,2H),3.35-3.55(m,2H),2.6 1(dd,J=12.4,2.0Hz,2H),2.18(dd,J=12.2,10.2Hz,2H),1.24(d,J=6.2Hz,6H).

[0363] ES-API(m / z):[M+H] + :505.1.

[0364] Example 50 Synthesis of Compound 50

[0365]

[0366] Synthetic route

[0367]

[0368] Under nitrogen protection, intermediate I-39 (444 mg, 1.2 mmol) (referring to Example 39, with intermediate D-1 replacing intermediate D) was dissolved in dioxane (5 mL) solution. Compound D-1 (340 mg, 1 mmol), CuI (57 mg, 0.3 mmol), trans-1,2-cyclohexanediamine (34.3 mg, 0.3 mmol), and Cs₂CO₃ (0.65 g, 2.4 mmol) were added sequentially to the solution. The reaction mixture was heated to 110 °C and stirred at this temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction mixture was allowed to cool naturally to room temperature. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 50 (light brown solid; 0.16 g; yield: 27.5%). 1H-NMR (400MHz, DMSO-d6, δppm): 8.52 (d, J = 8.0, 2H), 7.72-7.82 (m, 3H), 7.54 (d, J = 8.0Hz, 1H), 7.64 (dd, J = 8.8, 5.2Hz, 1H), 7.45- 7.51(m,1H),7.38(s,1H),6.24(q,J=6.8Hz,1H),1.76(d,J=6.4Hz,3H),3.21(s,4H),2.45(s,4H),2.26(s,3H).ES-API(m / z):[M+H] + 582.3.

[0369] Example 1: In vitro kinase inhibitory activity

[0370] 1.1 Screening for ALK inhibitory activity

[0371] Dilute the 50 ng / μL ALK stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20). Add 6 μL of 1.67× 0.0668 ng / μL working solution to each well (final concentration 0.04 ng / μL). Add different compounds dissolved in DMSO to the wells using a nanoparticle pipette to achieve a final concentration gradient of 1000 nM to 0.244 nM, for a total of 7 concentrations. Also include blank control wells (without enzyme) and negative control wells (containing enzyme, with DMSO as solvent). After the enzyme reacts with the compound or solvent for 30 min, 50 μM ATP (final concentration 10 μM) prepared with kinase buffer and 0.5 μM substrate (final concentration 0.1 μM, U Light-poly GT) at a 1:1 ratio are mixed and added to each well at a concentration of 4 μL. The plate is sealed with a sealing film and incubated at room temperature for 2 h. Then, 5 μL of 40 mM EDTA (final concentration 10 mM) is added to each well and incubated at room temperature for 5 min. Finally, 5 μL of 8 nM PT66 (final concentration 2 nM) of 4× reagent is added to each well and incubated at room temperature for 1 h. The plate is read using a PE instrument (excitation 320 nm, emission 665 nm), and the IC50 is calculated using four-parameter fitting. 50 .

[0372] 1.2 Screening for TRKA inhibitory activity

[0373] TRK protein has three isoforms: TRKA, TRKB, and TRKC. TRKA is one of these isoforms.

[0374] The TRKA stock solution was diluted with 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 0.01% Tween-20, 0.01% BSA). The compound was diluted to 10 nM-1000 nM with 100% DMSO, and 100 μl of this diluted compound was transferred to the wells of a 96-well plate using a nanoparticle pipette. In the same 384-well Echo plate, 50 μl of 100% DMSO was added to two empty wells as a compound-free control and an enzyme-free control, respectively. The plate was labeled as the source plate. 100 nl was transferred from the 384-well Echo plate to the 384-well detection plate. To prepare a 2x substrate solution, add peptides and ATP to 1x kinase base buffer. Add 5 μl of the 2x substrate solution to each well to start the reaction and incubate at room temperature for 1 hour. To stop the reaction, prepare a 2x final concentration of detection solution in antibody dilution buffer and add 10 μl of the detection solution to each well. Incubate at room temperature for 1 hour. Use an Envision instrument to read the plate (excitation 340 nm, emission 520 nm and 495 nm), and calculate the IC50 using four-parameter fitting. 50 The results are shown in Table 1.

[0375] Table 1: Results of in vitro kinase inhibitory activity

[0376]

[0377]

Claims

1. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof; ； in, R 1 It is a 3- to 8-membered heterocyclic alkyl group, with one or two R atoms. 1-1 Substituted 3-8 membered heterocyclic alkyl groups, 5-8 membered heterocyclic alkenyl groups, and those with one or two R groups 1-2 The substituted 5-8 membered heterocyclic alkenyl group, with an R 1-3 Substituted C1~C6 alkyl groups, -NR 1-4 R 1-5 Or -(C=O)R 1-6 ; R 1-3 and R 1-6 Each is independently a 3- to 8-membered heterocyclic alkyl group, surrounded by one or two R groups. a Substituted 3- to 8-membered heterocyclic alkyl groups, -NR c R d 5-8 membered heterocyclic alkenyl groups, surrounded by 1 or 2 R groups b Substituted 5- to 8-membered heterocyclic alkenyl groups; R 1-1 R 1-2 R a and R b Each is independently a C1~C6 alkyl or -NR e R f ; R 1-4 R 1-5 R c and R d Each is independently a C1-C6 alkyl group or is surrounded by one or two R atoms. g Substituted C1~C6 alkyl groups; R g For -NR h R i ; R e R f R h and R i Each is independently a C1~C6 alkyl group; R 2 H, C1~C6 alkyl, with 1 R 2-1 Substituted C1~C6 alkyl groups, with two R atoms 2-1 Substituted C1-C6 alkyl groups, 3-8 membered heterocyclic alkyl groups, or substituted with one or two R groups 2-2 Substituted 3- to 8-membered heterocyclic alkyl groups; R 2 In the middle, the one R 2-1 In the substituted C1~C6 alkyl groups, R 2-1 -OH, C1~C6 alkoxy, C6~C 14 Aryl, -(C=O)NR 2 -1-1 R 2-1-2 3- to 8-membered cycloalkyl groups, 3- to 8-membered cycloalkyl groups substituted with one or two hydroxyl groups, 3- to 8-membered heterocycloalkyl groups, or alkyl groups substituted with one or two R groups. j Substituted 3- to 8-membered heterocyclic alkyl groups; R 2-1-1 and R 2-1-2 Each is independently H or C1~C6 alkyl; R 2 In the middle, the two R's 2-1 In the substituted C1~C6 alkyl groups, R 2-1 It is a C1~C6 alkoxy group; R 2-2 and R j Each is independently a C1~C6 alkyl group or -COOR 2-2-1 ;R 2-2-1 It is a C1~C6 alkyl group; X is -CR x1 R x2 -、-O- or -O-CR x3 R x4 -;R x1 R x2 R x3 and R x4 Each is independently H or C1~C6 alkyl; R 3 C6~C 14 The aryl group may be substituted by one, two, three, four, or five halogens in the C6~C region. 14 Aryl; In the 3-8 membered heterocyclic alkyl and 5-8 membered heterocyclic alkenyl groups, the types of heteroatoms are each independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 R 1-3 and R 1-6 In the 3-8 membered heterocyclic alkyl group, the heteroatom is independently N and / or O; (2) R 1 R 1-3 and R 1-6 In the 3-8 membered heterocyclic alkyl group, the number of heteroatoms is independently 1 or 2; (3) R 1 R 1-3 and R 1-6 In this context, the 3-8 membered heterocyclic alkyl group is independently a 5-7 membered heterocyclic alkyl group; (4) R 1 R 1-3 and R 1-6 In the 5-8 membered heterocyclic alkenyl group, the heteroatom is independently N; (5) R 1 R 1-3 and R 1-6 In the 5-8 membered heterocyclic alkenyl group, the number of heteroatoms is 1 independently; (6) R 1 R 1-3 and R 1-6 In this context, the 5-8 membered heterocyclic alkenyl group is independently a 6-membered heterocyclic alkenyl group; (7) R 1 In this context, the C1-C6 alkyl group is a C1-C3 alkyl group; (8) R 1-1 R 1-2 R a and R b In this context, the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (9) R 1-4 R 1-5 R c and R d In this context, the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (10) R e R f R h and R i In this context, the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (11) R 2 In this context, the C1-C6 alkyl groups are independently C1-C4 alkyl groups; (12) R 2 and R 2-1 In the 3-8 membered heterocyclic alkyl group, the type of heteroatom is independently selected from N and O; (13) R 2 and R 2-1 In the 3-8 membered heterocyclic alkyl group, the number of heteroatoms is 1 independently; (14) R 2 and R 2-1 In this context, the 3-8 membered heterocyclic alkyl group is independently a 4-6 membered heterocyclic alkyl group; (15) R 2-1 In this context, the C1-C6 alkoxy groups are independently C1-C3 alkoxy groups; (16) R 2-1 In the context, C6~C 14 The aryl group is C6~C 10 Aryl; (17) R 2-1-1 and R 2-1-2 In this context, the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (18)R 2-1 In this context, the 3- to 8-membered cycloalkyl groups are independently 4- to 6-membered cycloalkyl groups; (19) R 2-2 and R j In this context, the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (20)R 2-2-1 In this context, the C1-C6 alkyl groups are independently C1-C4 alkyl groups; (21) R x1 R x2 R x3 and R x4 In this context, the C1-C6 alkyl group is a C1-C3 alkyl group; (22)R 3 In the context, C6~C 14 The aryl group is C6~C 10 Aryl; (23)R 3 In this context, the halogen is selected from one or more of F, Cl, Br, and I; (24) R 3 In this context, the number of halogens is 2 or 3.

3. The compound of formula I as claimed in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 R 1-3 and R 1-6 In the 3-8 membered heterocyclic alkyl group, the heteroatom is independently N, or N and O.

4. The compound of formula I as claimed in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 R 1-3 and R 1-6 In this context, the 3- to 8-membered heterocyclic alkyl group is independently tetrahydropyrrolithyl, piperazineyl, piperidinyl, morpholinyl, or a 7-membered heterocyclic alkyl group containing 2 N atoms; (2) R 1 R 1-3 and R 1-6 In this context, the 5- to 8-membered heterocyclic alkenyl group is independently a 6-membered heterocyclic alkenyl group containing 1 N atom; (3) R 1 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl; (4) R 1-1 R 1-2 R a and R b In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, or isopropyl; (5) R 1-4 R 1-5 R c and R d In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, or isopropyl; (6) R e R f R h and R i In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, or isopropyl; (7) R 2 In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; (8) R 2 and R 2-1 In this context, the 3- to 8-membered heterocyclic alkyl group is independently an oxocyclic butyl group, an azacyclic butyl group, a tetrahydropyranyl group, or a piperidinyl group; (9) R 2-1 In this context, the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, or isopropoxy; (10) R 2-1 In the context, C6~C 14 The aryl group is phenyl; (11) R 2-1-1 and R 2-1-2 In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, or isopropyl; (12) R 2-1 In this context, the 3- to 8-membered cycloalkyl group is independently cyclohexyl; (13) R 2-2 and R j In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, or isopropyl; (14) R 2-2-1 In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; (15) R x1 R x2 R x3 and R x4 In this context, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl; (16) R 3 In the context, C6~C 14 The aryl group is phenyl; (17) R 3 In this context, the halogen is F and / or Cl.

5. The compound of formula I as claimed in claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 R 1-3 and R 1-6 In this context, the 3- to 8-membered heterocyclic alkyl groups are independently... , , , , or ; (2) R 1 R 1-3 and R 1-6 In this context, the 5-8 membered heterocyclic alkenyl group is independently... ; (3) R 1 In this context, the C1-C6 alkyl group is methyl; (4) R 1-1 R 1-2 R a and R b In this context, the C1-C6 alkyl group is independently methyl; (5) R 1-4 R 1-5 R c and R d In this context, the C1-C6 alkyl group is independently methyl or ethyl; (6) R e R f R h and R i In this context, the C1-C6 alkyl group is independently methyl; (7) R 2 In this context, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, or isobutyl; (8) R 2 and R 2-1 In this context, the 3- to 8-membered heterocyclic alkyl groups are independently... , , or ; (9) R 2-1 In this context, the C1-C6 alkoxy groups are independently methoxy groups; (10) R 2-2 and R j In this context, the C1-C6 alkyl group is independently methyl; (11) R 2-2-1 In this context, the C1-C6 alkyl groups are independently tert-butyl; (12) R x1 R x2 R x3 and R x4 In this context, the C1-C6 alkyl group is independently methyl; (13) R x1 R x2 R x3 and R x4 It can be H or methyl on its own.

6. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 The following are methyl-substituted piperazine, piperidinyl, morpholinyl, methyl-substituted morpholinyl, methyl-substituted 7-membered heterocyclic alkyl with 2 nitrogen atoms, methyl-substituted 6-membered heterocyclic alkenyl with 1 nitrogen atom, methyl-substituted piperidinyl, dimethylamino-substituted piperidinyl, dimethylamino-substituted tetrahydropyrrolyl, methyl and dimethylaminoethyl-substituted amino, methyl-substituted piperazine-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, methyl-substituted morpholinyl-CH2-, methyl-substituted 7-membered heterocyclic alkyl with 2 nitrogen atoms-CH2-, and methyl-substituted 6-membered heterocyclic alkenyl with 1 nitrogen atom. alkyl-CH2-, methyl-substituted piperidinyl-CH2-, dimethylamino-substituted piperidinyl-CH2-, dimethylamino-substituted tetrahydropyrrolyl-CH2-, methyl and dimethylaminoethyl-substituted amino-CH2-, methyl-substituted piperazine-(C=O)-, methyl-substituted morpholinyl-(C=O)-, methyl-substituted 7-membered heterocyclic alkyl-(C=O)- containing 2 N atoms, dimethylamino-substituted piperidinyl-(C=O)-, morpholinyl-(C=O)-, dimethylamino-substituted tetrahydropyrrolyl-(C=O)-, methyl and dimethylaminoethyl-substituted amino-(C=O)-; (2) R 2 H, isopropyl, methoxy-substituted ethyl, methoxy-substituted propyl, hydroxy-substituted ethyl, phenyl-CH2-, carbamoyl-CH2-, methoxy-substituted isobutyl, hydroxy-substituted cyclohexyl-CH2-, oxetane, tetrahydropyranyl, tetrahydropyranyl-CH2-, aziridine-CH2-, piperidinyl, methyl-substituted piperidinyl-CH2-, tert-butoxycarbonyl-substituted aziridine-CH2-, tert-butoxycarbonyl-substituted piperidinyl, tert-butoxycarbonyl-substituted piperidinyl-CH2-; (3) R 3 It is a fluorine-substituted phenyl or a fluorine and chlorine-substituted phenyl; (4) X is -CH2-, -O- or -O-CHCH3-.

7. The compound of formula I as claimed in claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , or ; (2) R 2 for , , , , , , , , , , , , , , , , or ; (3) R 3 for or ; (4) X is -CH2-, -O- or .

8. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It is any of the following schemes: Option 1: R 1 For one or two R 1-1 Substituted 3- to 8-membered heterocyclic alkyl groups; R 2 It is a 3- to 8-membered heterocyclic alkyl group, with one R 2-1 Substituted C1~C6 alkyl groups, with two R atoms 2-1 The substituted C1-C6 alkyl group or the group with one or two R atoms 2-2 Substituted 3- to 8-membered heterocyclic alkyl groups; Option 2: R 1 For one or two R 1-1 Substituted 3- to 8-membered heterocyclic alkyl groups, with an R 1-3 Substituted C1~C6 alkyl or -(C=O)R 1-6 ; Option 3: R 1 For being an R 1-3 Substituted C1~C6 alkyl or -(C=O)R 1-6 ; X is CH2.

9. The compound of formula I as claimed in claim 8, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In Scheme 1, R 1 For one or two R 1-1 Substituted 6-membered heterocyclic alkyl groups; (2) In the above scheme 1, R 2 A C1-C6 alkyl group that is a 6-membered heterocyclic alkyl group, a C1-C6 alkyl group substituted with a "four-membered heterocyclic alkyl group containing one nitrogen atom or a six-membered heterocyclic alkyl group containing one oxygen atom", or a C1-C6 alkyl group substituted with one or two R atoms. 2-2 Substituted 6-membered heterocyclic alkyl groups; (3) In Scheme 2, R 1 For one or two R 1-1 Substituted 3- to 8-membered heterocyclic alkyl groups containing N and O atoms, with one or two R atoms b "Substituted 5-8 membered heterocyclic alkenyl-substituted C1-C6 alkyl groups, or -(C=O)- substituted with one or two R groups." a Substituted 3- to 8-membered heterocyclic alkyl groups; (4) In the aforementioned scheme 3, R 1 For being "1 or 2 R" a "Substituted methyl groups or -(C=O)- with one or two R atoms in a 3- to 8-membered heterocyclic alkyl group containing N and O atoms" a Substituted 3- to 8-membered heterocyclic alkyl groups containing two nitrogen atoms.

10. The compound of formula I as claimed in claim 9, characterized in that, It meets one or more of the following conditions: (1) In Scheme 1, R 1 A six-membered heterocyclic alkyl group containing two nitrogen atoms that is substituted with one or two C1-C6 alkyl groups; (2) In the above scheme 1, R 2 It is a 6-membered heterocyclic alkyl group, surrounded by 1 or 2 R groups. 2-2 Substituted 6-membered heterocyclic alkyl, tetrahydropyranyl-substituted C1-C6 alkyl, or nitrogen-substituted heterocyclic butyl alkyl; (3) In Scheme 2, R 1 The morpholino group is substituted with one or two methyl groups, the methyl group is substituted with a 6-membered heterocyclic alkenyl group substituted with "one or two methyl groups", or the morpholino group substituted with one or two methyl groups (C=O). (4) In the aforementioned scheme 3, R 1 It is a morpholino-substituted methyl group or a piperazine group (-(C=O)-substituted with one or two methyl groups).

11. The compound of formula I as claimed in claim 10, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In Scheme 1, R 1 The piperazine group is methyl-substituted; (2) In the above scheme 1, R 2 Methyl groups substituted with tetrahydropyranyl, piperidinyl, tetrahydropyranyl, or aza-butyl substituted methyl groups; (3) In Scheme 2, R 1 for , ,or ; (4) In the aforementioned scheme 3, R 1 for or .

12. The compound of formula I as claimed in claim 11, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In Scheme 1, R 1 for ; (2) In Scheme 1, R 2 for , , , or .

13. The compound of formula I as claimed in any one of claims 1-12, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any one of the following compounds: , or ; Among them, R 1 R 2 X and R 3 The definitions are as described in any one of claims 1-12; M is selected from one or more of F, Cl, Br and I; n can be 2 or 3.

14. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any one of the following compounds: ； 。 15. A method for preparing a compound of formula I as described in any one of claims 1-14, characterized in that, It comprises the following steps: in a solvent, the compound shown in Formula 1 and the compound shown in Formula 2 undergo the reaction shown below; ； Wherein, Y is a halogen; the definitions of the other substituents in the above formulas are as described in any one of claims 1-14.

16. The method for preparing the compound of formula I as described in claim 15, characterized in that, Y can be F, Cl, Br, or I.

17. The method for preparing the compound of formula I as described in claim 16, characterized in that, Y is I.

18. The method for preparing the compound of formula I as described in claim 15, characterized in that, It includes the following steps: in a solvent, under the action of CuI, trans-1,2-cyclohexanediamine and a base, the compound shown in Formula 1 and the compound shown in Formula 2 are reacted.

19. The method for preparing the compound of formula I as described in claim 18, characterized in that, The solvent is an ether solvent.

20. The method for preparing the compound of formula I as described in claim 19, characterized in that, The solvent is dioxane.

21. The method for preparing the compound of formula I as described in claim 18, characterized in that, The alkali is an alkali metal carbonate.

22. The method for preparing the compound of formula I as described in claim 21, characterized in that, The alkali mentioned is cesium carbonate.

23. A pharmaceutical composition, characterized in that, It comprises substance P and pharmaceutically acceptable excipients; said substance P is a compound of formula I as described in any one of claims 1-14 or a pharmaceutically acceptable salt thereof.

24. The use of a compound of Formula I as described in any one of claims 1-14, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 23 in the preparation of ALK and / or TRK inhibitors, or in the preparation of medicaments for the prevention and / or treatment of diseases related to ALK and / or TRK.

25. The application as described in claim 24, characterized in that, The diseases associated with ALK and / or TRK include cancer, pain, neurological disorders, autoimmune diseases, and inflammation.

26. The application as described in claim 25, characterized in that, The disease associated with ALK and / or TRK is lung cancer.

27. The application as described in claim 26, characterized in that, The disease associated with ALK and / or TRK is non-small cell lung cancer.

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