Heterocyclic compounds, pharmaceutical compositions comprising the same, and methods of making and using the same

Abstract

This invention relates to heterocyclic compounds, pharmaceutical compositions comprising the same, methods of preparation thereof, and uses thereof. Specifically, the compounds of this invention are represented by formula (I) and are used for the prevention or treatment of diseases or conditions associated with RET activity.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202080009954.2, filed on February 11, 2020, entitled "Heterocyclic Compounds, Pharmaceutical Compositions Containing the Same, Preparation Methods and Uses Thereof Thereof". Technical Field

[0002] This invention relates to novel heterocyclic compounds, pharmaceutical compositions comprising the same, methods for their preparation, and their use in the prevention or treatment of diseases or conditions associated with RET (Rearranged during transfection) activity. Background Technology

[0003] Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins. Through mediating cell signaling processes, protein phosphorylation regulates cellular physiological activities, such as cell survival, proliferation, differentiation, apoptosis, and metabolism. Dysfunction of protein kinases is closely related to many diseases, including tumors, autoimmune diseases, inflammatory responses, central nervous system diseases, cardiovascular diseases, and diabetes.

[0004] RET is a proto-oncogene that encodes the RET protein, a transmembrane receptor-type tyrosine protein kinase. It consists of a cysteine-rich cadherin-like extracellular region (for ligand binding), a transmembrane region, and an intracellular structural region with tyrosine kinase activity. Activated RET protein can activate multiple downstream signaling pathways, including the RAS / RAF / ERK pathway, the PI3K / Akt pathway, and the JNK pathway, leading to cell proliferation, migration, and differentiation. Alterations in the RET gene (mutations or fusions) and aberrant expression of the wild-type RET gene result in abnormal activation of the RET protein, leading to overactivity of signaling pathways, which is one of the main mechanisms of carcinogenesis. Abnormally activated RET protein participates in the proliferation and invasion of different tumor cells through multiple signaling pathways, thus affecting tumor development and progression. Alterations in the RET gene have a more significant effect on downstream cascade reactions; RET gene mutations are mainly associated with medullary thyroid carcinoma and papillary thyroid carcinoma, while RET gene fusions are mainly associated with non-small cell lung cancer and chronic myeloid leukemia. Therefore, inhibiting RET activity has significant medical value (Nature Reviews Cancer, 2014, 14(3):173-86).

[0005] RET inhibitors possess significant potential for treating and preventing various diseases, such as cancer and irritable bowel syndrome. Currently, five compounds are in clinical trials, and compounds from several other companies are in preclinical research. However, no RET-targeting inhibitors are currently on the market. Therefore, there is a need to develop new, highly effective, and low-toxicity RET inhibitors to meet clinical needs. Summary of the Invention

[0006] This invention provides novel heterocyclic compounds that exhibit good inhibitory effects on RET and possess favorable pharmacokinetic and safety properties.

[0007] One aspect of the invention provides a compound of formula I, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0008]

[0009] in:

[0010] Ring A is selected from C 6-10 Aromatic rings and 5-6 quinary heterocyclic aromatic rings;

[0011] Ring B is selected from C 3-8 Cycloalkyl and 4-11 membered heterocyclic groups;

[0012] X 1 Selected from CH and N;

[0013] R 1 Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy), C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups and -NR 20a R 20b The alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, and heterocyclic groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl (e.g., C10) 1-4 Alkyl groups);

[0014] R 2 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl and -C(=O)R 21 The alkyl, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0015] R 3 and R 4 It either does not exist or, each time it appears, is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy) and C 3-6 The cycloalkyl group, wherein the alkyl group, heteroalkyl group (e.g., alkoxy group), and cycloalkyl group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy groups; when m is greater than 1, the two R groups... 3 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups; and / or when n is greater than 1, two R groups. 4 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups;

[0016] L is selected from -O-, -S-, -S(O)-, -S(O)2-, -N=CR 21 -、-N(R 23a )-C(O)-、C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 imidene group, C 2-6 Ethyne-1,

[0017] The alkylene, heteroalkylene, alkenylene, and ynylene groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy) and C 3-8 cycloalkyl; or L is -N(R) 23a )-;

[0018] R 5 Selected from hydroxyl, halogen, CN, NO2, C 1-6 Alkyl, C1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -S(=O)NR 20a R 20b -S(=O)2NR 20a R 20b -NR 20a S(=O)R 20b -NR 20a S(=O)2R 20b -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30aR 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups;

[0019] R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each is independently selected from H, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; or R 20a With R 20b R 23a With R 23b Or R 25a With R 25b Together with the atoms to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0020] R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0021] R 21 R 22 R 31 and R 32 Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, halogen, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups;

[0022] m can be 0, 1, 2, 3, or 4;

[0023] n can be 0, 1, 2, 3, or 4;

[0024] t is 0, 1, 2, 3, or 4; and

[0025] u can be 0, 1, 2, 3 or 4;

[0026] The condition is that ring B is a piperazine ring and X 1 When it is CH, R 2 It is not 4-CF3-pyridin-2-yl or 4-CN-pyridin-2-yl.

[0027] Another aspect of the invention provides a pharmaceutical composition comprising a preventatively or therapeutically effective amount of the compound of the invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, eutectic, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0028] Another aspect of the invention provides the use of the compounds of the invention, stereoisomers, tautomers or mixtures thereof, N-oxides of the compounds, pharmaceutically acceptable salts, eutectics, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, in the preparation of a medicament for the prevention or treatment of diseases or conditions associated with RET activity.

[0029] Another aspect of the invention provides compounds of the invention, stereoisomers, tautomers or mixtures thereof, N-oxides of the compounds, pharmaceutically acceptable salts, eutectics, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, for the prevention or treatment of diseases or conditions associated with RET activity.

[0030] Another aspect of the invention provides a method for preventing or treating diseases or conditions associated with RET activity, the method comprising administering to an individual in need an effective amount of a compound of the invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above.

[0031] Another aspect of the present invention provides a method for preparing the compounds of the present invention. Attached Figure Description

[0032] Figure 1 The results of in vivo efficacy tests of compound 17 and control compound BLU-667 in a subcutaneous xenograft model of medullary thyroid carcinoma TT cells are shown. Detailed Implementation

[0033] definition

[0034] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0035] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently made up of” and “composed of”).

[0036] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-6 "alkyl" and "C" 1-4 "Alkyl" refers to a linear or branched group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl) having 1-6 carbon atoms and 1-4 carbon atoms, respectively, optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" refers to a linear or branched group having 1-6 carbon atoms and 1-4 carbon atoms respectively. 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). The term "alkylene" indicates the corresponding divalent group, including, for example, "C..." 1-8 Alkylene, C 1-6 Alkylene, C 1-4 "alkylene", etc., specific examples include but are not limited to: methylene (-CH2-), ethylene (-CH2CH2- or -CH(CH3)-), propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), butylene, pentylene, hexylene, etc. The alkylene may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0037] As used herein, the term "heteroalkyl" refers to an optionally substituted alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges (e.g., C) may be given. 1-6 Heteroalkyl refers to the number of carbon atoms in the chain, in this example including 1-6 carbon atoms. For example, the -CH2OCH2CH3 group is called a C3 heteroalkyl. Connection to the rest of the molecule can be made by heteroatoms or carbon atoms in the heteroalkyl chain. The term "heteroalkylene" indicates the corresponding divalent group, including, for example, "C..." 1-6 "heteroalkyl", "C" 1-4 "Heteroalkyl" etc.

[0038] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms, and the term "C" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. 1-8 "Halogenated alkyl", "C" 1-6 "Halogenated alkyl" and "C" 1-4 "Halogenated alkyl" refers to alkyl haloatoms having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0039] As used herein, the term "hydroxyalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with hydroxyl groups, such as C10. 1-4 Hydroxyalkyl or C 1-3 Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, -C(CH3)2OH, etc.

[0040] As used herein, the term "alkoxy" means a group in which an oxygen atom is inserted at any reasonable position in an alkyl group (as defined above), preferably C. 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkyl group. C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, -CH2-OCH3, etc., wherein the alkoxy group is optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0041] As used herein, the term "alkeneoxy" refers to a divalent alkoxy group, such as -OCH2-, -OCH(CH3)CH2-, -OCH2CH2O-, -CH2CH2O-, etc., which is optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0042] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2–6 carbon atoms ("C"). 2-6The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side), pure Z (iso-side), or any mixture thereof. The term "alkenyl" refers to the corresponding divalent group, including, for example, "C..." 2-6 "Ideinyl", "C" 2-4 "Alkenyl", etc., specific examples of which include, but are not limited to: -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenyl, pentenyl, hexenyl, cyclopentenyl, cyclohexenyl, etc.

[0043] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group comprising one or more triple bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "ynynyl" refers to a corresponding divalent group, including, for example, "C..." 2-8 "Immyne", "C" 2-6 "Immyne", "C" 2-4 Examples include, but are not limited to, "ethynyl groups". The alkyne group is optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0044] As used herein, the term “fused ring” or “dense ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms.

[0045] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0046] As used in this article, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0047] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon cycloalkyl group, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl groups, including spirocyclic, fused-ring (fused-ring) or bridged-ring systems (i.e., spirocyclic alkyl, fused-ring (fused-ring) alkyl, and bridged-ring alkyl groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, etc.). In this invention, the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo group (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 cyclic carbon atoms, such as C10. 3-6 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be bicycloalkyl, such as C10, C20, C30, C40, C50, C60, C7 ...70, C60, C70, C70, C70, C70, C70, C70, C70, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0048] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, where the cycloalkyl group is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0049] As used herein, the term “heterocyclic group” or “heterocycle” refers to a monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, said heteroatoms including, but not limited to, oxygen, nitrogen, and sulfur atoms, wherein the carbon atoms and heteroatoms on said heterocyclic group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0050] As used herein, the term "4-11 membered heterocyclic group" refers to a heterocyclic group containing 4-11 ring atoms, including but not limited to 4-10 membered heterocyclic groups, 4-9 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the "nitrogen-containing heterocyclic group," "oxygen-containing heterocyclic group," and "sulfur-containing heterocyclic group" optionally also contains one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of 4-11 membered heterocyclic groups include, but are not limited to, ethylene oxide, aziridinyl, aziridine, oxobutyl, tetrahydrofuranyl, pyrrolylyl, pyrrolidone (e.g., ... ), imidazoalkyl, pyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazineyl, trithianyl.

[0051] As used herein, the term "heterocyclic group" encompasses fused ring structures, wherein the connection point between the fused ring structure and other groups can be on any ring of the fused ring structure. Therefore, the heterocyclic groups of the present invention also include, but are not limited to, heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, and monoheterocyclic fused monocycloalkyl groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C 4-6 (Mono)cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylazirylpropyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, and piperidinylmorpholinyl.

[0052] As used in this article, the term "heterocyclic group" encompasses both bridged heterocyclic groups and spirocyclic groups.

[0053] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two saturated rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, and 7-10 membered sulfur-containing bridged heterocycles, etc. The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" may optionally also contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.

[0054] As used herein, the term "spiroheterocycle" refers to a ring structure containing one or more heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing a single ring atom. This includes, but is not limited to, 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, and 6-10 membered sulfur-containing spiroheterocycles. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" may optionally also contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, of which at least one ring atom is a nitrogen atom.

[0055] In this invention, heterocyclic groups can fuse with aryl groups to form fused ring structures, examples of which include, but are not limited to:

[0056] As used herein, the term "aryl" or "aromatic ring" refers to a fully carbon monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. As used herein, the term "C" refers to a carbon monocyclic or fused polycyclic aromatic group. 6-12 "Aryl (aromatic ring)" refers to an aryl (aromatic ring) containing 6 to 12 carbon atoms, preferably C64-12 ... 6-10 Aryl (aromatic ring), preferably phenyl or naphthyl. The aryl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0057] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, for example, 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatom may be oxygen, nitrogen, or sulfur. The carbon atom and heteroatom on the heteroaryl group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0058] As used herein, the terms "5-10-membered heteroaryl" or "5-10-membered heteroaryl ring" refer to a heteroaryl (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6-membered nitrogen-containing heteroaryl, 5-6-membered oxygen-containing heteroaryl, 5-6-membered sulfur-containing heteroaryl, etc. The "nitrogen-containing heteroaryl," "oxygen-containing heteroaryl," and "sulfur-containing heteroaryl" may each optionally contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of these groups include, but are not limited to, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-10 fused cyclic groups containing these groups.

[0059] As used herein, the term "heteroaryl" encompasses a fused ring structure, wherein the connection point between the fused ring structure and other groups can be on any ring of the fused ring structure. Therefore, the heteroaryls of the present invention also include, but are not limited to, (mono)heteroaryl benzo(mono)heteroaryl, (mono)heteroaryl benzo(monocyclic)aryl, (mono)heteroaryl benzo(mono)heterocyclic, and (mono)heteroaryl benzo(mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl benzo5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl benzophenyl, 5-6 membered (mono)heteroaryl benzo5-6 membered (mono)heterocyclic, or 5-6 membered (mono)heteroaryl benzoC 4-6 (Mono)cycloalkyl groups (e.g., 5-6-membered heteroarylcyclobutyl, 5-6-membered heteroarylcyclopentyl, or 5-6-membered heteroarylcyclohexyl), examples of which include, but are not limited to, indole, isoindole, indazole, benzimidazole, quinolinyl, isoquinolinyl, wait.

[0060] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0061] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0062] If a substituent is described as "optionally...substituted", then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0063] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0064] As used herein, the term “one or more” means one or more under reasonable conditions, such as two, three, four, five or ten.

[0065] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0066] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0067] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g. 35S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0068] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, this can result in exo / meta-racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oximes can exist in equilibrium in solution in the following tautomeric forms:

[0069]

[0070] It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0071] Solid lines () and solid wedges can be used in this article. Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0072] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0073] Cocrystal refers to the combination of active pharmaceutical molecules and other physiologically acceptable acids, bases, salts, and nonionic compound molecules in the same crystal lattice via hydrogen bonds, π-π stacking interactions, van der Waals forces, and other non-covalent bonds.

[0074] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0075] Pharmaceutically acceptable salts of the compounds of this invention include their acid addition salts and base addition salts. Examples include hexafluorophosphate and meglumine salts. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0076] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0077] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0078] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized to oxides. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including but not limited to the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0079] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0080] This invention further includes, within its scope, prodrugs of the compounds of this invention, which are certain derivatives of the compounds of this invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of this invention can be prepared, for example, by replacing suitable functional groups present in the compounds of this invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0081] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P. ​​G. W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0082] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0083] compound

[0084] One aspect of the invention provides a compound of formula I, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0085]

[0086] in:

[0087] Ring A is selected from C 6-10 Aromatic rings and 5-6 quinary heterocyclic aromatic rings;

[0088] Ring B is selected from C 3-8 Cycloalkyl and 4-11 membered heterocyclic groups;

[0089] X 1 Selected from CH and N;

[0090] R 1 Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy), C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups and -NR 20a R 20b The alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, and heterocyclic groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl (e.g., C10) 1-4 Alkyl groups);

[0091] R 2 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic, 5-10 membered heteroaryl and -C(=O)R 21 The alkyl, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0092] R 3 and R 4 It either does not exist or, each time it appears, is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy) and C 3-6 The cycloalkyl group, wherein the alkyl group, heteroalkyl group (e.g., alkoxy group), and cycloalkyl group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4Haloalkoxy groups; when m is greater than 1, the two R groups... 3 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups; and / or when n is greater than 1, two R groups. 4 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups;

[0093] L is selected from -O-, -S-, -S(O)-, -S(O)2-, -N=CR 21 -、-N(R 23a )-C(O)-、C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 imidene group, C 2-6 Ethyne-1,

[0094] The alkylene, heteroalkylene, alkenylene, and ynylene groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy) and C 3-8 cycloalkyl; or L is -N(R) 23a )-;

[0095] R 5 Selected from hydroxyl, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -S(=O)NR 20a R 20b -S(=O)2NR 20a R 20b -NR 20aS(=O)R 20b -NR 20a S(=O)2R 20b -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35bThe cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups;

[0096] R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each is independently selected from H, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; or R 20a With R 20b R 23a With R 23b Or R 25a With R 25b Together with the atoms to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0097] R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0098] R 21 R 22 R 31 and R 32Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, halogen, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups;

[0099] m can be 0, 1, 2, 3, or 4;

[0100] n can be 0, 1, 2, 3, or 4;

[0101] t is 0, 1, 2, 3, or 4; and

[0102] u can be 0, 1, 2, 3 or 4;

[0103] The condition is that ring B is a piperazine ring and X 1 When it is CH, R 2 It is not 4-CF3-pyridin-2-yl or 4-CN-pyridin-2-yl.

[0104] In some embodiments, ring A is a benzene ring or a 5-6 membered heteroaromatic ring; preferably, ring A is a benzene ring, a thiazole ring, a pyridine ring, a pyrazine ring, or a pyrimidine ring; more preferably, ring A is... Its position marked by * is related to X 1 It is connected to the ring and connected to ring B through the position marked with **.

[0105] In some implementations, ring B is C. 3-6 Cycloalkyl or 5-7 membered heterocyclic group; preferably, ring B is a piperidine ring, piperazine ring, aziridine-heptane-bridged ring, or diazacyclic-heptane-bridged ring; more preferably, ring B is... It is connected to ring A by the position marked with * and to L by the position marked with **.

[0106] In some implementations, X 1 It is CH or N; preferably, X 1 Let N be the number of elements in the array.

[0107] In some implementations, R 1 Selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6Cycloalkyl and 4-10 membered heterocyclic groups, wherein the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, and heterocyclic groups are each optionally substituted by one or more substituents selected from: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl (e.g., C10) 1-4 Alkyl groups).

[0108] In some implementations, R 1 Selected from C 1-4 Alkyl groups, 5-membered nitrogen-containing heterocyclic groups and C 1-4 Heteroalkyl (e.g., C10) 1-4 Alkoxy), wherein the alkyl, heterocyclic and heteroalkyl (e.g. alkoxy) groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Heteroalkyl (e.g., C10) 1-4 Alkyl groups).

[0109] In some implementations, R 1 Selected from C 1-3 Alkyl (e.g., methyl), pyrrolyl (e.g., pyrrolidine-1-yl), and C 1-3 Alkoxy groups (e.g., ethoxy groups).

[0110] In some implementations, R 2 Selected from C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, 5-6 membered heteroaryl and -C(=O)R 21 The alkyl, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl and C 3-6 Cycloalkyl.

[0111] In some implementations, R 2 Selected from C 1-3Alkyl, 5-6-membered heteroaryl, and -C(=O)CH3, wherein each of the alkyl and heteroaryl groups is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl and C 3-6 Cycloalkyl.

[0112] In some implementations, R 2 Selected from C 1-3 Alkyl (e.g., methyl), -C(=O)CH3, thiophene, pyrrolyl, pyrazolyl, imidazole, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, and pyridyl, wherein each of the alkyl, thiophene, pyrrolyl, pyrrolyl, imidazole, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, and pyridyl groups is optionally substituted by one or more substituents selected from: hydroxyl, halogen, CN, C. 1-3 Alkyl (e.g., methyl), C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl (e.g., C10) 1-3 alkoxy) and C 3-6 cycloalkyl; preferably, R 2 It is a methyl-substituted pyrazolyl group (e.g., 5-methyl-1H-pyrazol-3-yl or 1-methyl-1H-pyrazol-4-yl), a cyclopropyl-substituted pyrazolyl group (e.g., 5-cyclopropyl-1H-pyrazol-3-yl) or -C(O)CH3.

[0113] In some implementations, R 3 and R 4 It either does not exist or is independently selected from hydroxyl, halogen, CN, C each time it appears. 1-4 Alkyl and C 1-4 The alkoxy group, wherein the alkyl group and the alkoxy group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy groups; when m is greater than 1, the two R groups... 3 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups; and / or when n is greater than 1, two R groups. 4 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups.

[0114] In some implementations, R 3 and R 4 It either does not exist or is independently selected from hydroxyl, halogen, CN, C each time it appears. 1-3 Alkyl and C 1-3 The alkoxy group, wherein the alkyl group and the alkoxy group are each optionally substituted by one or more substituents selected from the following: halogen, CN, and C. 1-3 Alkyl groups; when m is greater than 1, two R groups 3 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups; and / or when n is greater than 1, two R groups. 4 Optionally, it forms C together with the atoms it is attached to. 3-6 Cycloalkyl or 4-10 membered heterocyclic groups.

[0115] In some implementations, R 3 and R 4 The following are either absent or selected independently each time they appear: F, Cl, CN, OH, C 1-3 Alkyl and C 1-3 Alkoxy; preferably, R 3 and R 4 It does not exist.

[0116] In some implementations, L is selected from -O-, -S-, -C(O)-, -N(R)-. 23a -C(O)-、-C(O)-N(R) 23c )-、C 1-4 Alkylene, C 1-4 Heteroalkyl, The alkylene and heteroalkylene groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy) and C 3-6 Cycloalkyl.

[0117] In some embodiments, L is selected from -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-3 Alkylene, C 1-3 Heteroalkyl, The alkylene and heteroalkylene groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl (e.g., C10) 1-3 alkoxy) and C 3-6 cycloalkyl, wherein R 23a and R 23b H or C are preferred 1-3 alkyl.

[0118] In some embodiments, L is selected from -O-, -C(O)-, -NHC(O)-, -C(O)NH-, C 1-3 Alkylene The alkylene group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-3 Alkyl and C 1-3 Haloalkyl. Preferably, L is -CH2-, -CH(CH3)-, -O-, -C(O)-, -C(O)NH- or

[0119] In some implementations, R 5 Selected from hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -S(=O)NR 20a R 20b -S(=O)2NR 20a R 20b -NR 20a S(=O)R 20b -NR 20a S(=O)2R 20b -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR24a C(=O)NR 25a R 25b The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups.

[0120] In some implementations, R 5 Selected from C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group and 5-10 heteroaryl group, wherein each of the cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl, C3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups.

[0121] In some implementations, R 5 Selected from C 6-10 The aryl group and the 5-6 heteroaryl group, each of which is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl (e.g., C10) 1-3 alkoxy), C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -C(=O)R 31 -C(=O)NR 33a R 33b and -NR 33a C(=O)R 33b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-6 membered heterocyclic groups.

[0122] In some implementations, R 5 The group is selected from phenyl and 5-6-membered heteroaryl groups (e.g., pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, imidazolyl, or thiazolyl), wherein each of the phenyl and heteroaryl groups is optionally substituted by one or more substituents selected from: hydroxyl, halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl (e.g., C10) 1-3 alkoxy), C 3-6 cycloalkyl, C 3-6Cycloalkoxy, 4-6 membered heterocyclic groups, 5-8 membered heteroaryl groups (e.g., pyridyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, or cyclopentylpyrazolyl), -NR 30a R 30b -OR 31 -C(=O)R 31 -C(=O)NR 33a R 33b and -NR 33a C(=O)R 33b The cycloalkyl, cycloalkoxy, heterocyclic, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl (e.g., C10) 1-3 alkoxy), C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-6 membered heterocyclic groups.

[0123] In some implementations, R 5 The group is selected from phenyl, pyridyl, pyrazolyl, and thiazolyl, wherein each of the phenyl, pyridyl, pyrazolyl, and thiazolyl groups is optionally substituted by one or more substituents selected from: halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic groups, 5-8 membered heteroaryl groups (e.g., pyridyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, imidazolyl, thiazolyl, or cyclopentylpyrazolyl), -NR 30a R 30b and -OR 31 The heterocyclic group and the heteroaryl group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy and 4-6 membered heterocyclic groups. Preferably, R 5 Optionally, it is selected from one or more halogens (e.g., fluorine or chlorine), CN, C 1-3 Alkyl (e.g., methyl or ethyl), C1-3 Halogenated alkyl groups (e.g., trifluoromethyl), C 1-3 Alkyl groups (e.g., methoxy or ethoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 A phenyl, pyridyl, pyrazolyl, or thiazolyl group substituted with a cycloalkoxy group (e.g., cyclopropoxy) and a 5-6 membered heteroaryl group (e.g., pyridyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, imidazolyl, or thiazolyl), wherein the 5-6 membered heteroaryl group is optionally further substituted with one or more groups selected from halogens (e.g., fluorine or chlorine), C 1-3 Alkyl (e.g., methyl, ethyl, or isopropyl), C 1-3 Halogenated alkyl groups (e.g., fluoromethyl), C 1-3 Hydroxyalkyl (e.g., hydroxymethyl or hydroxypropyl), C 1-3 Alkoxy (e.g., methoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 Substituents of cycloalkoxy groups (e.g., cyclopropoxy or cyclobutoxy).

[0124] In some implementations, R 5 The group is selected from phenyl, pyridyl, pyrazolyl, and thiazolyl, wherein each of the phenyl, pyridyl, pyrazolyl, and thiazolyl groups is optionally substituted by one or more substituents selected from: halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic groups, 5-6 membered heteroaryl groups (e.g., pyridyl, pyrroleyl, furanyl, pyrazolyl, oxazolyl, imidazoleyl, or thiazolyl), -NR 30a R 30b and -OR 31 The heterocyclic group and the heteroaryl group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups. Preferably, R 5 Optionally, it is selected from one or more halogens (e.g., fluorine or chlorine), CN, C 1-3 Alkyl (e.g., methyl or ethyl), C 1-3 Halogenated alkyl groups (e.g., trifluoromethyl), C 1-3 Alkyl groups (e.g., methoxy or ethoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C3-6 A phenyl, pyridinyl, pyrazolyl, or thiazolyl group substituted with a cycloalkoxy group (e.g., cyclopropoxy) and a five-membered heteroaryl group (e.g., pyrazolyl, imidazolyl, or thiazolyl), wherein the five-membered heteroaryl group is optionally further substituted with one or more elements selected from halogens (e.g., fluorine or chlorine), C 1-3 Alkyl (e.g., methyl), C 1-3 Substituents of hydroxyalkyl groups (e.g., hydroxymethyl or hydroxypropyl).

[0125] In some implementations, R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each is independently selected from H and C. 1-4 Alkyl, C 1-4 Alkoxy and C 3-8 cycloalkyl; or R 20a With R 20b R 23a With R 23b Or R 25a With R 25b Together with the atoms to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0126] In some implementations, R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each independently represents H and C. 1-4 Alkyl or C 1-4 Alkyl group.

[0127] In some implementations, R 23a and R 23b Each is independently selected from H and C. 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl; or R 23a With R 23b Together with the C atoms it is attached to, it forms C3-6 Cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, and heterocyclic group are each optionally substituted by one or more substituents selected from the following: halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups.

[0128] In some implementations, R 21 R 22 R 31 and R 32 Each is independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclic groups, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, halogen, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups.

[0129] In some implementations, R 21 R 22 R 31 and R 32 Each is independently selected from C 1-4 alkyl.

[0130] In some implementations, R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups;

[0131] In some implementations, R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-4 alkyl.

[0132] In some implementations, m is 0.

[0133] In some implementations, n is 0, 1, or 2.

[0134] In some implementations, t is 0 or 1.

[0135] In some implementations, u is 0 or 1.

[0136] In some embodiments, the compounds of the present invention have the structure shown in Formula IA:

[0137]

[0138] in:

[0139] R 1 and R 2 As defined in Equation I above;

[0140] R 5 Selected from C 6-12 Aryl and 5-10 heteroaryl, wherein (1) the C 6-12 The aryl group may optionally be substituted by one or more substituents selected from the following: C 3-6 Cycloalkoxy, C 6-12 Aryl, 5-10 heteroaryl, -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkoxy, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 Cycloalkyl and 4-10 heterocyclic groups, and (2) the 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups; and

[0141] R23a R 30a R 30b R 31 R 32 R 33a R 33b R 34a R 35a and R 35b As defined in Equation I above, and R 23a H or C are preferred 1-3 alkyl.

[0142] In some implementation schemes, R 5 Selected from C 6-12 Aryl and 5-10 heteroaryl, wherein (1) the C 6-12 The aryl group may optionally be substituted by one or more substituents selected from the following: C 3-6 Cycloalkoxy, C 6-12 Aryl, 5-10 heteroaryl, -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkoxy, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 Cycloalkyl and 4-10 heterocyclic groups, and (2) the 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl groups and 4-10 membered heterocyclic groups; and

[0143] R 23a R 30a R 30b R 31 R 32 R 33a R 33b R 34a R 35a and R 35b As defined in Equation I above, and R23a H or C are preferred 1-3 alkyl.

[0144] In some embodiments, the compounds of the present invention have the structure shown in Formula IB:

[0145]

[0146] in:

[0147] R 1 R 2 R 5 and R 23a As defined in Equation I above, and R 23a H or C are preferred 1-3 alkyl.

[0148] In some embodiments, the compounds of the present invention have the structure shown in formula IC:

[0149]

[0150] in:

[0151] When X 1 When it is CH, R 1 R 2 R 5 and R 23a As defined in Equation I above, and R 23a H or C are preferred 1-3 Alkyl; and when X 1 When R is N, 1 R 2 R 5 and R 23a As defined in the formula IA above.

[0152] In some embodiments, the compounds of the present invention have the structure shown in Formula ID:

[0153]

[0154] in:

[0155] R 1 R 2 R 23a R 23b And t is as defined in equation I above;

[0156] When X 1 When it is CH, R 5 As defined in Equation I above; and

[0157] When X 1 When R is N, 5 C6-12 Aryl or 5-10 heteroaryl, among which

[0158] (i) When t is 0, the C 6-12 The aryl group and the 5-10 heteroaryl group are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups,

[0159] (ii) When t is 1, (1) the C 6-12 The aryl group may optionally be substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 Cycloalkyl and 4-10 heterocyclic groups, and (2) the 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the following: NO2, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6Cycloalkoxy, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The aryl and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl groups and 4-10 membered heterocyclic groups; and

[0160] R 30a R 30b R 31 R 32 R 33a R 33b R 34a R 35a and R 35b As defined in Formula I above.

[0161] In some embodiments, the compounds of the present invention have the structure shown in Formula IE:

[0162]

[0163] in:

[0164] R 1 R 2 R5 R 23a R 23b X 1 And t is defined as ID as above.

[0165] In some embodiments, the compounds of the present invention have the structure shown in Formula IF:

[0166]

[0167] in:

[0168] R 1 R 2 R 5 R 23a R 23b and X 1 As defined by the above-mentioned ID;

[0169] R 4 As defined in Equation I above, and preferably C 1-3 Alkyl or C 1-3 Alkoxy;

[0170] R 23c For H, C 1-3 Alkyl or C 1-3 The alkoxy group, wherein the alkyl group and the alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, C. 1-4 Alkoxy and C 1-4 Hydroxyalkyl;

[0171] u is 0 or 1; and

[0172] n is 0 or 1.

[0173] In some embodiments, the compounds of the present invention have the structure shown in formula IG:

[0174]

[0175] in:

[0176] X 1 For CH or N;

[0177] R 1 R 2 and R 4 As defined in Equation I above, and R 4 C is preferred 1-3 Alkyl or C 1-3 Alkoxy;

[0178] n is 0 or 1;

[0179] R 5 Selected from C6-12 Aryl and 5-10 heteroaryl, wherein (1) the C 6-12 The aryl group may optionally be substituted by one or more substituents selected from the following: C 3-6 Cycloalkoxy, C 6-12 Aryl, 5-10 heteroaryl, -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkoxy, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups; and (2) the 5-10 membered heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31-S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl (e.g., C10) 1-4 alkoxy), C 3-6 cycloalkyl groups and 4-10 membered heterocyclic groups; and

[0180] R 30a R 30b R 31 R 32 R 33a R 33b R 34a R 35a and R 35b As defined in Formula I above.

[0181] In some embodiments, the compounds of the present invention have the structure shown in Formula I, wherein:

[0182] Ring A is Its position marked by * is related to X 1 It is connected to the ring, and connected to ring B through the position marked with **.

[0183] Ring B is It is connected to ring A by the position marked with *, and to L by the position marked with **;

[0184] X 1 Let N be the number of people in the group.

[0185] R 1 Selected from C 1-3 Alkyl (e.g., methyl), pyrrolyl (e.g., pyrrolidine-1-yl), and C 1-3 Alkyl groups (e.g., ethoxy groups);

[0186] R 2 It is a methyl-substituted pyrazolyl group (e.g., 5-methyl-1H-pyrazol-3-yl or 1-methyl-1H-pyrazol-4-yl), a cyclopropyl-substituted pyrazolyl group (e.g., 5-cyclopropyl-1H-pyrazol-3-yl) or -C(O)CH3;

[0187] R 3 and R 4 It does not exist;

[0188] L represents -CH2-, -CH(CH3)-, -O-, -C(O)-, -C(O)NH- or and

[0189] R 5 Optionally, it is selected from one or more halogens (e.g., fluorine or chlorine), CN, C 1-3 Alkyl (e.g., methyl or ethyl), C 1-3 Halogenated alkyl groups (e.g., trifluoromethyl), C 1-3 Alkyl groups (e.g., methoxy or ethoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 3-6 A phenyl, pyridyl, pyrazolyl, or thiazolyl group substituted with a cycloalkoxy group (e.g., cyclopropoxy) and a 5-6 membered heteroaryl group (e.g., pyridyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, imidazolyl, or thiazolyl), wherein the 5-6 membered heteroaryl group is optionally further substituted with one or more groups selected from halogens (e.g., fluorine or chlorine), C 1-3 Alkyl (e.g., methyl, ethyl, or isopropyl), C 1-3 Halogenated alkyl groups (e.g., fluoromethyl), C 1-3 Hydroxyalkyl (e.g., hydroxymethyl or hydroxypropyl), C 1-3 Alkoxy (e.g., methoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl) and C 3-6 Substituents of cycloalkoxy groups (e.g., cyclopropoxy or cyclobutoxy).

[0190] This invention covers any combination of the above embodiments.

[0191] In some embodiments, the compounds of the present invention include, but are not limited to:

[0192]

[0193]

[0194]

[0195]

[0196]

[0197] Preparation method

[0198] In some embodiments, the compound of formula IA can be synthesized by the method shown in route A below:

[0199] Route A

[0200]

[0201] in:

[0202] Hal 1 and Hal 2 Each is independently F, Cl, Br, or I; preferably, Hal 1 It is F, Cl, Br or I, and Hal 2 It can be Cl, Br, or I;

[0203] R 1 Selected from H, cyano, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g., C10) 1-6 alkoxy), C 3-8 Cycloalkyl, 4-6 membered heterocyclic groups and -NR 20a R 20b The alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, and heterocyclic groups are each optionally substituted by one or more substituents selected from the following: halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl (e.g., C10) 1-4 Alkyl groups);

[0204] R 2 Selected from C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 4-6-membered heterocyclic and 5-6-membered heteroaryl groups, wherein each of the alkyl, heteroalkyl, cycloalkyl, heterocyclic and heteroaryl groups is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4Halogenated alkoxy groups, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0205] R 23a Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl group, wherein the alkyl group, alkoxy group, and cycloalkyl group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0206] R 20a and R 20b As defined in Equation I above; and

[0207] R 5 As defined in the formula IA above.

[0208] Step 1: Compound IA-1 and R 2 -NH2 reacts with a base in the presence of a base via substitution or coupling reactions (e.g., Buchwald reaction, Suzuki reaction, or Ullmann reaction) to form compound IA-2.

[0209] For substitution reactions, the base that can be used is, for example, [base name missing]. t BuONa t BuOK t BuOLi, Cs2CO3, DIPEA, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3, and solvents such as tert-butanol, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP can be used, and the reaction temperature is 40°C to 140°C.

[0210] For the Buchwald reaction, catalysts that can be used include, for example, Pd(OAc)₂, Pd₂(dba)₃, Pd(dba)₂, PdCl₂, Pd(PPh₃)₄, Pd(dppf)Cl₂, Pd(acac)₂, or Pd(allyl)₂. Ligands that can be used include PPh₃, XPhos, SPhos, RuPhos, XantPhos, Dppf, BINOL, BINAP, or Pcy₃. Bases that can be used include, for example, Pd(OAc)₂, Pd₂(dba)₃, Pd(dba)₂, PdCl₂, Pd(PPh₃)₄, Pd(dppf)Cl₂, Pd(acac)₂, or Pd(allyl)₂. t BuONa t BuOK tBuOLi, Cs2CO3, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3, and solvents such as toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP can be used, and the reaction temperature is 40°C to 140°C.

[0211] For the Suzuki reaction, catalysts such as Pd(PPh3)4 or Pd(dppf)Cl2 can be used, bases such as Cs2CO3, K3PO4, Na2CO3, AcOK, NaHCO3 or K2CO3 can be used, solvents such as 1,4-dioxane / H2O, DMF / H2O, DMSO / H2O or CH3CN / H2O can be used, and the reaction temperature is 60°C to 120°C.

[0212] For the Ullmann reaction, catalysts such as CuCl, CuBr, CuI, or Cu₂O can be used; ligands such as salicylaldehyde oxime, cyclohexanediamine, N,N'-dimethylethylenediamine, TMEDA, or ethylenediamine can be used; and bases such as... t BuONa t BuOK t BuOLi, Cs2CO3, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3, and solvents such as toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP can be used, and the reaction temperature is 40°C to 140°C.

[0213] Step 2: Compound IA-3 reacts with IA-4 in the presence of a base to form compound IA-5.

[0214] Usable bases include, for example: t BuONa t BuOK t BuOLi, Cs₂CO₃, DIPEA, LiHMDS, LDA, NaHMDS, KHMDS, K₃PO₄, Na₂CO₃, KOAc, NaHCO₃, or K₂CO₃. Suitable solvents include, for example, tert-butanol, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO, or NMP. The reaction temperature is 40°C to 140°C.

[0215] Step 3: Compound IA-5 reacts with a boron-containing reagent to generate compound IA-6.

[0216] Boron-containing reagents that can be used include, for example, B2(pin)2. Catalysts that can be used include, for example, Pd(PPh3)4, Pd(dppf)Cl2, or Pd(dppf)2Cl2·DCM. Bases that can be used include, for example, Cs2CO3, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3. Solvents that can be used include, for example, 1,4-dioxane, DMF, DMSO, or CH3CN. The reaction temperature is 50°C to 120°C.

[0217] Step 4: Compound IA-2 and IA-6 undergo a coupling reaction (e.g., the Suzuki reaction) to generate compound IA-7.

[0218] Suitable catalysts include, for example, Pd(PPh3)4, Pd(dppf)Cl2, or Pd(dppf)2Cl2·DCM. Suitable bases include, for example, Cs2CO3, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3. Suitable solvents include, for example, 1,4-dioxane, DMF, DMSO, or CH3CN, or any mixture of the above solvents with H2O. The reaction temperature is 50°C to 120°C.

[0219] Step 5: Compound IA-7 is deprotected under acidic conditions to generate compound IA-8.

[0220] Suitable acids include, for example, HCl in a 1,4-dioxane solution, HCl in an EA solution, or TFA in a DCM solution. The reaction temperature is from 0°C to 80°C.

[0221] Step 6: Compounds IA-8 and IA-9 undergo a reductive amination reaction to generate compound IA.

[0222] Suitable solvents include, for example, methanol, ethanol, THF, DCM, DCE, DMA, or mixtures thereof in any proportion with acetic acid. Suitable reducing agents include, for example, NaBH4, NaBH3CN, or NaBH(OAc)3. The reaction temperature is from 0°C to 80°C. In some embodiments, the reaction can be carried out in the presence of a base or acid, such as TEA or DIPEA, and such acid as AcOH, HCl, or Ti(O)2. i Pr)4.

[0223] In some embodiments, the compound of formula IA can be synthesized by the method shown in route B below:

[0224] Route B

[0225]

[0226] in:

[0227] Hal 2 R 1 R 2 R 5 and R 23a As defined in Route A above.

[0228] Step 1: Compound IA-5 is deprotected under acidic conditions to generate compound IA-10.

[0229] Suitable acids include, for example, HCl in a 1,4-dioxane solution, HCl in an EA solution, or TFA in a DCM solution. The reaction temperature is from 0°C to 80°C.

[0230] Step 2: Compound IA-10 and IA-9 undergo a reductive amination reaction to generate compound IA-11.

[0231] Suitable bases include, for example, DIPEA or TEA. Suitable reducing agents include, for example, NaBH3CN or NaBH(OAc)3. Suitable solvents include, for example, MeOH, EtOH, or DCE. The reaction temperature is from 0°C to 80°C.

[0232] Suitable solvents include, for example, methanol, ethanol, THF, DCM, DCE, DMA, or mixtures thereof in any proportion with acetic acid. Suitable reducing agents include, for example, NaBH4, NaBH3CN, or NaBH(OAc)3. The reaction temperature is from 0°C to 80°C. In some embodiments, the reaction can be carried out in the presence of a base or acid, such as TEA or DIPEA, and such acid as AcOH, HCl, or Ti(O)2. i Pr)4.

[0233] Step 3: Compound IA-11 reacts with a boron-containing reagent to generate compound IA-12.

[0234] Boron-containing reagents that can be used include, for example, B2(pin)2. Catalysts that can be used include, for example, Pd(PPh3)4, Pd(dppf)Cl2, or Pd(dppf)2Cl2·DCM. Bases that can be used include, for example, Cs2CO3, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3. Solvents that can be used include, for example, 1,4-dioxane, DMF, DMSO, or CH3CN. The reaction temperature is 50°C to 120°C.

[0235] Step 4: Compound IA-12 and IA-2 undergo a coupling reaction (e.g., the Suzuki reaction) to generate compound IA.

[0236] Suitable catalysts include, for example, Pd(PPh3)4, Pd(dppf)Cl2, or Pd(dppf)2Cl2·DCM. Suitable bases include, for example, Cs2CO3, K3PO4, Na2CO3, KOAc, NaHCO3, or K2CO3. Suitable solvents include, for example, 1,4-dioxane, DMF, DMSO, or CH3CN, or any mixture of the above solvents with H2O. The reaction temperature is 50°C to 120°C.

[0237] In some embodiments, compounds of formula IB can be synthesized by the method shown in route C below:

[0238] Route C

[0239]

[0240] in:

[0241] Hal 1 Hal 2 R 1 R 2 R 5 R 23a As defined in Route A above.

[0242] Step 1: Compound IB-1 and R 2 -NH2 reacts with a base in the presence of a base via substitution or coupling reactions (e.g., Buchwald reaction, Suzuki reaction, Ullmann reaction) to form compound IB-2.

[0243] The reaction conditions are as described in step A of route A for the preparation of compound IA.

[0244] Step 2: Compound IB-2 and IA-12 undergo a coupling reaction (e.g., the Suzuki reaction) to generate compound IB.

[0245] The reaction conditions are as described in step four of route A for the preparation of compound IA.

[0246] In some embodiments, compounds of formula IC can be synthesized by the method shown in route D below:

[0247] Route D

[0248]

[0249] in:

[0250] Hal 1 Hal 2 R 1 R 2 R5 and R 23a As defined in Route A above; and

[0251] X 1 Selected from CH and N.

[0252] Step 1: Compound IC-1 and R 2 -NH2 reacts with a base in the presence of a base via substitution or coupling reactions (e.g., Buchwald reaction, Suzuki reaction, or Ullmann reaction) to form compound IC-2.

[0253] The reaction conditions are as described in step A of route A for the preparation of compound IA.

[0254] Step 2: Compound IC-3 reacts with a boron-containing reagent to generate compound IC-4.

[0255] The reaction conditions are as described in step three of route A for the preparation of compound IA.

[0256] Step 3: Compound IC-2 and IC-4 undergo a coupling reaction (e.g., the Suzuki reaction) to generate compound IC-5.

[0257] The reaction conditions are as described in step four of route A for the preparation of compound IA.

[0258] Step 4: Compound IC-5 is deprotected under acidic conditions to generate compound IC-6.

[0259] The reaction conditions are as described in step 5 of route A for the preparation of compound IA.

[0260] Step 5: Compound IC-6 and IA-9 undergo a reductive amination reaction to generate compound IC.

[0261] The reaction conditions are as described in step six of route A for the preparation of compound IA.

[0262] In some embodiments, the compound of formula ID can be synthesized by the method shown in route E below:

[0263] Route E

[0264]

[0265] in:

[0266] R 1 and R 2 As defined in Route A above;

[0267] R 5 As defined by the above-mentioned ID;

[0268] R 23a and R 23b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; or R 23a With R 23b Together with the C atom to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic group is optionally substituted by one or more substituents selected from: CN, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0269] X 1 Selected from CH and N; and

[0270] t is 0 or 1.

[0271] Compound IC-6 and ID-1 undergo a condensation reaction to generate compound ID.

[0272] Suitable condensing agents include, for example, HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU, or PyBOP. Suitable bases include, for example, TEA, DIPEA, etc. t BuOK t BuONa t BuOLi, NaH, NaOH, Cs2CO3, K3PO4, or Na2CO3. Suitable solvents include, for example, THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH3CN, 1,4-dioxane, or toluene. The reaction temperature is from 0°C to 120°C, for example, room temperature.

[0273] Alternatively, compound ID-1 first reacts with an acylation reagent to form an acyl halide, and then optionally reacts with compound IC-6 in the presence of a base to form a compound of formula ID. Acylation reagents that can be used include, for example, thionyl chloride or oxalyl chloride. The reaction can also be carried out under the catalysis of a small amount of DMF. Bases that can be used include, for example, TEA or DIPEA. Solvents that can be used include, for example, THF, DCM, DCE, CH3CN, 1,4-dioxane, or toluene. The reaction temperature is from 0°C to 100°C.

[0274] In some embodiments, compounds of formula IE can be synthesized by the method shown in route F below:

[0275] Route F

[0276]

[0277] in:

[0278] R 1 R 2 R 5 R 23a R 23b And t is as defined in route E above;

[0279] X 1 Selected from CH and N; and

[0280] Hal 2 It is F, Cl, Br or I; preferably, Hal 2 It can be Cl, Br, or I.

[0281] Step 1: Compound IC-2 and IA-6 undergo a coupling reaction (e.g., the Suzuki reaction) to generate compound IE-1.

[0282] The reaction conditions are as described in step four of route A for the preparation of compound IA.

[0283] Step 2: Compound IE-1 is deprotected under acidic conditions to generate compound IE-2.

[0284] The reaction conditions are as described in step 5 of route A for the preparation of compound IA.

[0285] Step 3: Compound IE-2 and ID-1 undergo a condensation reaction to generate compound IE.

[0286] The reaction conditions are as described in route E for the preparation of compound ID.

[0287] In some embodiments, compounds of formula IF can be synthesized by the method shown in route G below:

[0288] Route G

[0289]

[0290] in:

[0291] R 1 R 2 R 23a R 23b and R 5 As defined in Route E above;

[0292] X 1 Selected from CH and N;

[0293] R 4It does not exist or is selected from hydroxyl, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Heteroalkyl (e.g., C10) 1-6 Alkyl groups);

[0294] R 23c For H, C 1-3 Alkyl or C 1-3 The alkoxy group, wherein the alkyl group and the alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, C. 1-4 Alkoxy and C 1-4 Hydroxyalkyl;

[0295] Hal 2 It is F, Cl, Br or I; preferably, Hal 2 It can be Cl, Br, or I;

[0296] u is 0 or 1; and

[0297] n is 0 or 1.

[0298] Step 1: Compound IC-2 and IF-1 undergo a coupling reaction (e.g., the Suzuki reaction) to generate compound IF-2.

[0299] The reaction conditions are as described in step four of route A for the preparation of compound IA.

[0300] Step 2: Compound IF-3 reacts with an amine via a condensation reaction to generate compound IF-4.

[0301] The reaction conditions are as described in route E for the preparation of compound ID.

[0302] Step 3: Compound IF-4 is deprotected under acidic conditions to generate compound IF-5.

[0303] The reaction conditions are as described in step 5 of route A for the preparation of compound IA.

[0304] Step 4: Compounds IF-2 and IF-5 undergo a nucleophilic substitution reaction in the presence of a base to generate compound IF.

[0305] The reaction conditions are as described in step two of route A for the preparation of compound IA.

[0306] In some embodiments, compounds of formula IG can be synthesized by the method shown in route H below:

[0307] Route H

[0308]

[0309] in:

[0310] R 1 and R 2 As defined in Route A above;

[0311] X 1 Selected from CH and N;

[0312] R 4 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Heteroalkyl;

[0313] R 5 As defined in the above formula IG; and

[0314] n is 0 or 1.

[0315] Step 1: Compound IG-1 and R 5 -OH undergoes the Mitsunobu reaction to generate compound IG-2.

[0316] Suitable reagents include, for example, PPh3, PMe3, DIAD, DEAD, or DBAD. Suitable solvents are aprotic solvents such as THF, diethyl ether, DCM, DMF, or toluene. The reaction temperature is from -20°C to 100°C, for example, room temperature.

[0317] Step 2: Compound IG-2 is deprotected under acidic conditions to generate compound IG-3.

[0318] The acid that can be used is, for example, a 1,4-dioxane solution of HCl, an EA solution of HCl, or a DCM solution of TFA, or the reaction can be carried out in a mixture of the aforementioned acid solution and any solvent selected from, for example, THF, MeOH, and EtOH. The reaction temperature is from 0°C to 80°C.

[0319] Step 3: Compound IF-2 and IG-3 undergo a nucleophilic substitution reaction in the presence of a base to generate compound IG.

[0320] The reaction conditions are as described in step two of route A for the preparation of compound IA.

[0321] Pharmaceutical compositions, formulations and treatments

[0322] In some embodiments, the present invention provides pharmaceutical compositions comprising a preventatively or therapeutically effective amount of the compound of the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, eutectic, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0323] In some embodiments, the present invention provides a pharmaceutical formulation, preferably a solid, semi-solid, liquid, or gaseous formulation. In some embodiments, the pharmaceutical composition may also contain one or more other therapeutic agents.

[0324] In some embodiments, the pharmaceutical composition or pharmaceutical preparation is preferably administered orally, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0325] In some embodiments, the present invention provides the use of the compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical preparations of the present invention in the preparation of medicaments for the prevention or treatment of diseases or conditions associated with RET activity.

[0326] In some embodiments, the present invention provides the use of the compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotopic derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical formulations of the present invention in the preparation of a medicament for modulating (e.g. reducing or inhibiting) the activity of RET.

[0327] In some embodiments, the present invention provides compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical preparations of the present invention, for the prevention or treatment of diseases or conditions associated with RET activity.

[0328] In some embodiments, the present invention provides a method for preventing or treating diseases or conditions associated with RET activity, the method comprising administering to an individual in need an effective amount of a compound of the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a pharmaceutical formulation of the present invention.

[0329] In some implementations, the disease or condition associated with RET activity is preferably cancer or tumor, or irritable bowel syndrome.

[0330] In some embodiments, the cancer or tumor is further preferably lung cancer (e.g., non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer (e.g., medullary thyroid carcinoma or papillary thyroid carcinoma), colon cancer, multiple myeloma, melanoma, glioma, brain tumor, or sarcoma.

[0331] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0332] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0333] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes.

[0334] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0335] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0336] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0337] The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0338] The content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.

[0339] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0340] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0341] In some embodiments, the pharmaceutical composition of the present invention may further comprise one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases). In some embodiments, the method of the present invention may further comprise administering one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases).

[0342] Example

[0343] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0344] The abbreviations used in this article have the following meanings:

[0345]

[0346]

[0347] The compounds of this invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or fast column chromatography (Flash column chromatography), and their structures are obtained by... 1 Confirmation was performed using 1H NMR and / or MS. Reaction monitoring was performed using TLC or LC-MS.

[0348] 1 The H NMR spectroscopy method was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400MHz).

[0349] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0350] TLC uses silica gel GF 254 as the stationary phase.

[0351] Column chromatography typically uses 200-300 mesh silica gel (Qingdao Marine) as the stationary phase.

[0352] Rapid column chromatography was performed using the Biotage rapid column chromatograph.

[0353] Prep-HPLC was performed using Agilent 1260, Waters 2489, and GeLai 3500 chromatographs.

[0354] The microwave reaction was carried out using the BiotageInitiator microwave reactor.

[0355] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0356] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or TEB Chemicals, etc.

[0357] Example 1: 2-(6-(6-benzyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 1)

[0358]

[0359] Step 1: Preparation of tert-butyl 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid (compound 1c)

[0360] Compounds 1a (1.50 g) and 1b (1.77 g) were added sequentially to a 100 mL single-necked flask, followed by DMSO (20.0 mL) and K₂CO₃ (5.83 g). The mixture was heated to 90 °C and stirred for 20 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with 100 mL of water, and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1) to give compound 1c (2.03 g). MS m / z (ESI): 354.1 [M+H] + .

[0361] Step 2: Preparation of 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (compound 1d)

[0362] Compound 1c (2.03 g), B2(pin)2 (4.01 g), KOAc (1.55 g), 1,4-dioxane (15.0 mL), and Pd(dppf)Cl2·DCM (644.67 mg) were added sequentially to a 100 mL single-necked flask and heated to 90 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 15:1) to give compound 1d (2.11 g). MS m / z (ESI): 402.3 [M+H] + .

[0363] Step 3: Preparation of 3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (compound 1f)

[0364] Compound 1e (950 mg) was dissolved in 1,4-dioxane (50.0 mL), followed by the addition of compound 1d (2.11 g), Cs₂CO₃ (3.15 g), and water (5.0 mL), and then Pd(dppf)Cl₂·DCM (477.83 mg). The mixture was heated to 90 °C for 14 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 1f (587.0 mg). MS m / z (ESI): 463.3 [M+H] + .

[0365] Step 4: Preparation of 2-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 1 g)

[0366] Compound 1f (1.36 g) was dissolved in DCM (20.0 mL), followed by the addition of TFA (20.0 mL). The reaction was carried out under nitrogen protection at room temperature. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain 1 g of trifluoroacetate (587.0 mg). MS m / z (ESI): 363.3 [M+H] + .

[0367] Step 5: Preparation of 2-(6-(6-benzyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 1)

[0368] 1 g of trifluoroacetate (31.58 mg) and compound 1h (27.74 mg) were dissolved in MeOH (0.5 mL), followed by the addition of TEA (8.46 mg) and sodium cyanoborohydride (26.27 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 1 (11.0 mg). MS m / z (ESI): 453.2 [M+H] + .

[0369] 1H NMR (400MHz, DMSO-d6) δ12.15(br,1H),9.67(s,1H),9.12(d,J=2.4Hz,1H),8.44(dd,J=8.8,2.4Hz,1H),7.43-7.21(m,5H) ,6.78(d,J=8.8Hz,2H),6.30(br,1H),3.98-3.57(m,8H),2.72-2.61(m,1H),2.33(s,3H),2.24(s,3H),1.72-1.64(m,1H).

[0370] Example 2: 2-(6-(6-(4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 2)

[0371]

[0372] 1 g of trifluoroacetate (30.0 mg) and compound 2a (33.81 mg) were dissolved in MeOH (0.5 mL), followed by the addition of TEA (8.12 mg) and sodium cyanoborohydride (25.21 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 2 (15.0 mg). MS m / z (ESI): 483.3 [M+H] + .

[0373] 1 H NMR (400MHz, DMSO-d6) δ12.14(br,1H),9.66(s,1H),9.12(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz,1H),7.26(d,J=8.8Hz,2H),6.88- 6.76(m,4H),6.30(br,1H),3.79-3.72(m,7H),3.58-3.53(m,4H),2.59-2.55(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0374] Example 3: 2-(6-(6-((6-chloropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 3)

[0375]

[0376] 1 g of trifluoroacetate (30.0 mg) and compound 3a (35.15 mg) were dissolved in MeOH (0.5 mL), followed by the addition of TEA (8.12 mg) and sodium cyanoborohydride (25.21 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 3 (20.0 mg). MS m / z (ESI): 488.2 [M+H] + .

[0377] 1 H NMR (400MHz, DMSO-d6) δ12.12(br,1H),9.67(s,1H),9.11(d,J=2.0Hz,1H),8.46-8.42(m,2H),7.87-7.80(m,1H),7.50-7.47 (m,1H),6.80-6.77(m,2H),6.31(br,1H),4.01-3.52(m,8H),2.66-2.57(m,1H),2.33(s,3H),2.26(s,3H),1.69-1.62(m,1H).

[0378] Example 4: 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 4)

[0379]

[0380] Step 1: Preparation of 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 4a)

[0381] Compound 1c (460.0 mg) was dissolved in DCM (5.0 mL) under nitrogen protection, and TFA (5.0 mL) was added. The reaction was carried out at room temperature for 2 h until the starting material was completely converted. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, washed with saturated sodium carbonate solution, extracted with DCM (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 4a (250.0 mg). MS m / z (ESI): 254.0 [M+H] + Step 2: Preparation of 3-(5-bromopyridin-2-yl)-6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (compound 4c).

[0382] Compounds 4a (250.0 mg) and 4b (275.0 mg) were dissolved in DCE (5.0 mL), and NaBH(OAc)3 (1.06 g) was added. The reaction mixture was reacted at room temperature for 10 h. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1-1:3) to give compound 4c (320.0 mg). MS m / z (ESI): 375.1 [M+H] + .

[0383] Step 3: Preparation of 6-((6-methoxypyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 4d)

[0384] Compound 4c (332.0 mg) was dissolved in 1,4-dioxane (5.0 mL), followed by the addition of B2(pin)2 (619.76 mg) and KOAc (237.11 mg). Under nitrogen protection, Pd(dppf)Cl2·DCM (99.65 mg) was added, and the mixture was heated to 90 °C for 4 h. After the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 4d (320.0 mg). MS m / z (ESI): 423.3 [M+H] + .

[0385] Step 4: Preparation of 2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 4)

[0386] Compound 4d (129.8 mg) was dissolved in 1,4-dioxane (5.0 mL), followed by the addition of compound 1e (55 mg), Cs₂CO₃ (149 mg), and water (5.0 mL). Under nitrogen protection, Pd(dppf)Cl₂·DCM (27.93 mg) was added, and the mixture was heated to 90 °C for 5 h. After the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by Prep-HPLC to obtain compound 4 (18.0 mg). MS m / z (ESI): 484.3 [M+H] + .

[0387] 1 H NMR (400MHz, DMSO-d6) δ11.97 (s, 1H), 9.65 (s, 1H), 9.12 (d, J = 2.4Hz, 1H), 8.43 (dd, J=8.8,2.4Hz,1H),8.07(d,J=2.0Hz,1H),7.68(dd,J=8.4,2.4Hz,1H),6.78-6.75(m ,3H),6.30(br,1H),3.82(s,3H),3.74(d,J=11.6Hz,2H),3.66(d,J=6.0Hz,2H),3.6 1-3.45(m,4H),2.53-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.57(d,J=8.0Hz,1H).

[0388] Example 5: 2-(6-(6-((5-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 18)

[0389]

[0390] 1 g of trifluoroacetate (35.00 mg) and compound 18a (27.75 mg) were added to methanol (1.0 mL), followed by the sequential addition of triethylamine (6.83 mg) and sodium cyanoborohydride (17.00 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 18 (6.0 mg). MS m / z (ESI): 484.3 [M+H] + .

[0391] 1H NMR (400MHz, DMSO-d6) δ12.13(br,1H),9.65(s,1H),9.12(d,J=2.2Hz,1H),8. 43(dd,J=8.92,2.32Hz,1H),8.21(s,1H),8.16-8.12(m,2H),7.35-7.31(m,1H ),6.77(d,J=9.0Hz,1H),6.31(br,1H),3.81(s,3H),3.78-3.69(m,4H),3.59( br,4H),2.59-2.52(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.36Hz,1H).

[0392] Example 6: 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 17)

[0393]

[0394] Step 1: Preparation of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinaldehyde (compound 17a)

[0395] Compound 8c (2.0 g), 91a hydrochloride (1.58 g), and potassium carbonate (4.45 g) were sequentially added to DMF (15 mL), and the mixture was heated to 80 °C and stirred for 14 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1) to give compound 17a (0.81 g). MS m / z (ESI): 192.1 [M+H] + .

[0396] Step 2: Preparation of 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 17)

[0397] 1 g of trifluoroacetate (22.82 mg) and compound 17a (27.47 mg) were added to methanol (1.0 mL), followed by the sequential addition of triethylamine (4.45 mg) and sodium cyanoborohydride (13.86 mg), and the reaction was carried out at room temperature for 14 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 17 (7.0 mg). MS m / z (ESI): 538.3 [M+H] + .

[0398] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.16Hz,1H),8.67(dd,J=4.54 ,0.64Hz,1H),8.43(dd,J=8.94,2.28Hz,1H),8.41(d,J=1.68,1H),7.98(dd,J=8.48Hz,2.12 1H),7.92(d,J=4.28,1H),7.87(d,J=8.4,1H),6.78(d,J=9.0Hz,2H),6.31(br,1H),3.78-3.71( m,4H),3.68-3.52(m,4H),2.59-2.52(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.36Hz,1H).

[0399] Example 7: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(((6-methylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 16)

[0400]

[0401] 1 g of trifluoroacetate (35.0 mg) and compound 16a (35.1 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (9.5 mg) and sodium cyanoborohydride (29.4 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 16 (15.0 mg). MS m / z (ESI): 468.2 [M+H] + .

[0402] 1H NMR (400MHz, DMSO-d6) δ11.97 (s, 1H), 9.66 (s, 1H), 9.12 (d, J = 2.4Hz, 1H), 8.43 ( dd,J=8.8,2.4Hz,1H),8.38(s,1H),7.63(dd,J=7.6,1.6Hz,1H),7.18(d,J=8.0Hz ,1H),6.77(d,J=8.8Hz,2H),6.29(br,1H),3.83-3.64(m,4H),3.63-3.45(m,4H), 2.57-2.52(m,1H),2.43(s,3H),2.33(s,3H),2.26(s,3H),1.58(d,J=8.0Hz,1H).

[0403] Example 8: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(((2-methylthiazolyl-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 15)

[0404]

[0405] 1 g of trifluoroacetate (35.0 mg) and compound 15a (36.8 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (9.5 mg) and sodium cyanoborohydride (29.4 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 15 (16.0 mg). MS m / z (ESI): 474.2 [M+H] + .

[0406] 1 H NMR (400MHz, DMSO-d6) δ12.19(br,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H),8.43(dd,J=8.8,2.4Hz,1H),8.17(s,1H),7.46(s,1H),6.76(d,J=8. 8Hz,1H),6.29(br,1H),3.78-3.66(m,6H),3.64-3.51(m,2H),2.59(s,3 H),2.49-2.44(m,1H),2.33(s,3H),2.25(s,3H),1.57(d,J=8.4Hz,1H).

[0407] Example 9: 2-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 49)

[0408]

[0409] Step 1: Preparation of 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (compound 49b)

[0410] Compound 49a (2.00 g), B2(pin)2 (4.09 g), KOAc (1.58 g), 1,4-dioxane (15.0 mL), and Pd(dppf)Cl2·DCM (657.43 mg) were added sequentially to a reaction flask, and the mixture was heated to 90 °C for 3 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain compound 49b (2.77 g). MS m / z (ESI): 390.3 [M+H] + .

[0411] Step 2: Preparation of 4-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (compound 49c)

[0412] Compound 1e (1.30 g) was dissolved in 1,4-dioxane (50.0 mL), followed by the addition of compound 49b (2.80 g), Cs₂CO₃ (3.44 g), and water (2.0 mL), and then Pd(dppf)Cl₂·DCM (647.3 mg). The mixture was heated to 90 °C for 4 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 49c (587.0 mg). MS m / z (ESI): 451.3 [M+H] + .

[0413] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(piperazin-1-yl)pyridin-3-yl)pyrimidine-4-amine (compound 49d)

[0414] Compound 49c (2.7 g) was dissolved in DCM (20.0 mL), followed by the addition of TFA (20.0 mL). The reaction was carried out under nitrogen protection at room temperature for 4 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain trifluoroacetate of compound 49d (761.0 mg). MS m / z (ESI): 351.2 [M+H] + .

[0415] Step 4: Preparation of 2-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 49)

[0416] The trifluoroacetate salt of compound 49d (35.0 mg) and compound 4b (38.9 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (9.3 mg) and sodium cyanoborohydride (28.8 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 49 (25.0 mg). MS m / z (ESI): 472.3 [M+H] + .

[0417] 1 H NMR (400MHz, DMSO-d6) δ12.20(br,1H),9.65(s,1H),9.03(d,J=2.4Hz,1H),8.36(dd,J=8.8,2.0Hz,1H),8.09(d,J=2.0Hz,1H),7.68(dd,J=8 .4,2.4Hz,1H),6.94-6.78(m,3H),6.29(br,1H),3.84(s,3H),3.64-3.56(m,4H),3.49(s,2H),2.49-2.44(m,4H),2.31(s,3H),2.24(s,3H).

[0418] Example 10: 2-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 23)

[0419]

[0420] The trifluoroacetate salt of compound 49d (35.0 mg) and compound 2a (38.9 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (9.3 mg) and sodium cyanoborohydride (28.8 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 23 (18.0 mg). MS m / z (ESI): 471.3 [M+H] + .

[0421] 1 H NMR(CD3OD,400MHz)δ9.07(d,J=2.4Hz,1H),8.45(dd,J=8.8,2.4Hz,1H),8.28(s,1H),7.42-7.35(m,2H),7.02- 6.92(m,3H),6.76(s,1H),6.26(s,1H),3.99(s,2H),3.82(s,7H),3.08-3.00(m,4H),2.40(s,3H),2.31(s,3H).

[0422] Example 11: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(((4-methylpyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (Compound 21)

[0423]

[0424] 1 g of trifluoroacetate (35.0 mg) and compound 21a (27.52 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (7.4 mg) and sodium cyanoborohydride (23.08 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 21 (10.0 mg). MS m / z (ESI): 468.3 [M+H] + .

[0425] 1H NMR (400MHz, DMSO-d6) δ11.93 (s, 1H), 9.61 (s, 1H), 9.07 (d, J = 1.2Hz, 1H), 8.39 (dd, J=8.8,2.2Hz,1H),8.35(s,1H),8.25(d,J=4.8Hz,1H),7.11(d,J=4.8Hz,1H),7.01-6 .63(m,2H),6.27(br,1H),3.82-3.69(m,2H),3.63(d,J=6.4Hz,2H),3.59-3.42(m,4 H),2.52-2.46(m,1H),2.28(s,3H),2.25(s,3H),2.21(s,3H),1.53(d,J=8.4Hz,1H).

[0426] Example 12: 2-(6-(6-(2-fluoro-5-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 96)

[0427]

[0428] 1 g of trifluoroacetate (30.0 mg) and compound 96a (19.41 mg) were dissolved in MeOH (0.5 mL), followed by the addition of TEA (6.37 mg) and sodium cyanoborohydride (19.78 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 96 (10.0 mg). MS m / z (ESI): 501.2 [M+H] + .

[0429] 1 H NMR(400MHz,DMSO-d6)δ11.97(br,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H), 8.43(dd,J=9.2,2.4Hz,1H),7.06(t,J=9.2Hz,1H),7.03-7.00(m,1H),6.83- 6.78(m,1H),7.03-6.64(m,2H),6.32(br,1H),3.77-3.71(m,7H),3.58-3.53 (m,4H),2.58-2.53(m,1H),2.33(s,3H),2.25(s,3H),1.58(d,J=8.4Hz,1H).

[0430] Example 13: (6-methoxypyridin-3-yl)(4-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)piperazin-1-yl)methyl ketone (compound 110)

[0431]

[0432] Compound 110a (16.5 mg), HATU (53.2 mg), and DIPEA (41.7 mg) were added to DMF (3.0 mL) and reacted at room temperature for 5 min. Then, trifluoroacetate of compound 49d (50.0 mg) was added, and the reaction was incubated at room temperature for 0.5 h. After the reaction was complete, the reaction solution was diluted with EA, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to obtain compound 110 (19.0 mg). MS m / z (ESI): 486.3 [M+H] + .

[0433] 1 H NMR (400MHz, DMSO-d6) δ12.01(br,1H),9.69(s,1H),9.08(d,J=2.2Hz,1H),8.41(dd,J=9.0,2.3Hz,1H),8.34(d,J=2.1H z,1H),7.84(dd,J=8.5,2.3Hz,1H),7.12-6.63(m,3H),6.30(s,1H),3.92(s,3H),3.72(s,8H),2.34(s,3H),2.26(s,3H).

[0434] Example 14: 2-(6-methoxypyridin-3-yl)-1-(4-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)piperazin-1-yl)acet-1-one (Compound 111)

[0435]

[0436] Compound 111a (18.0 mg), HATU (53.2 mg), and DIPEA (41.7 mg) were added to DMF (3.0 mL) and reacted at room temperature for 5 min. Then, trifluoroacetate of compound 49d (50.0 mg) was added, and the reaction was incubated at room temperature for 0.5 h. After the reaction was complete, the reaction solution was diluted with EA, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to obtain compound 111 (6.0 mg). MS m / z (ESI): 500.3 [M+H]+ .

[0437] 1 H NMR (400MHz, DMSO-d6) δ12.02(br,1H),9.68(s,1H),9.06(d,J=2.3Hz,1H),8.39(dd,J=9.0,2.3Hz,1H),8.02(d,J=2.2Hz,1H),7.56(dd,J=8. 5,2.4Hz,1H),6.94(d,J=9.0Hz,1H),6.90-6.69(m,2H),6.27(s,1H),3 .83(s,3H),3.74(s,2H),3.70-3.59(m,8H),2.32(s,3H),2.25(s,3H).

[0438] Example 15: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(4-methylbenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 80)

[0439]

[0440] 1 g of trifluoroacetate (30 mg) and compound 80a (22.70 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 80 (10.0 mg). MS m / z (ESI): 467.3 [M+H] + .

[0441] 1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),9.66(s,1H),9.11(d,J=2.2Hz,1H),8 .43(dd,J=8.9,2.3Hz,1H),7.22(d,J=7.9Hz,2H),7.11(d,J=7.9Hz,2H),6.7 6(d,J=9.0Hz,2H),6.31(br,1H),3.78-3.65(m,4H),3.64-3.49(m,4H),2.60 -2.49(m,1H),2.33(s,3H),2.27(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0442] Example 16: 5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]hept-6-yl)methyl)-2-cyanopyridine (compound 117)

[0443]

[0444] 1 g of trifluoroacetate (30 mg) and compound 117a (24.96 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 117 (2.0 mg). MS m / z (ESI): 479.2 [M+H] + .

[0445] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.65(s,1H),9.11(d,J=2.2Hz,1H),8.74(d,J=1.2Hz,1H),8.43(dd,J=8.9,2.3Hz,1H),8.01(dt,J=17.2,5.0Hz ,2H),6.77(d,J=9.0Hz,2H),6.32(br,1H),3.81-3.66(m,6H),3.65-3.52( m,2H),2.61-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.4Hz,1H).

[0446] Example 17: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 118)

[0447]

[0448] 1 g of trifluoroacetate (30 mg) and compound 118a (43.48 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 118 (6.0 mg). MS m / z (ESI): 522.3 [M+H] +.

[0449] 1 H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8 .74(s,1H),8.43(dd,J=8.9,2.3Hz,1H),8.06(d,J=7.1Hz,1H),7.84(d,J=8. 1Hz,1H),6.77(d,J=9.0Hz,2H),6.30(br,1H),3.84-3.65(m,6H),3.60-3.48 (m,2H),2.61-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.61(d,J=8.4Hz,1H).

[0450] Example 18: 6-Methyl-2-(6-(6-((6-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 62)

[0451]

[0452] 1 g of trifluoroacetate (30 mg) and compound 62a (46.49 mg, prepared according to the synthesis method of compound 17a in Example 6, except that 4-fluoropyrazole was replaced with 4-methylpyrazole) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 62 (6.0 mg). MS m / z (ESI): 534.2 [M+H] + .

[0453] 1H NMR (400MHz, DMSO-d6) δ11.97 (s, 1H), 9.65 (s, 1H), 9.12 (d, J = 2.2Hz, 1H), 8.44 (dd, J=8.9,2.3Hz,1H),8.37(m,2H),7.93(dd,J=8.5,2.2Hz,1H),7.82(d,J=8.4Hz,1H),7 .62(s,1H),6.78(d,J=9.0Hz,2H),6.30(br,1H),3.83-3.67(m,4H),3.66-3.50(m,4 H),2.60-2.52(m,1H),2.33(s,3H),2.26(s,3H),2.11(s,3H),1.59(d,J=8.4Hz,1H).

[0454] Example 19: 2-(6-(6-((6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 60)

[0455]

[0456] 1 g of trifluoroacetate (30 mg) and compound 60a (43.00 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 60 (11.0 mg). MS m / z (ESI): 520.2 [M+H] + .

[0457] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.65(s,1H),9.13(d,J=2.2Hz,1H),8.59(dd,J=2.6,0.5Hz,1H), 8.46-8.42(dd,J=8.8,2.4Hz,1H),8.41-8.39(d,J=2.0Hz,1H),7.97(dd,J=8.4,2.2Hz,1H),7.88(d,J= 8.4Hz,1H),7.81(d,J=1.0Hz,1H),6.78(d,J=9.0Hz,2H),6.56(dd,J=2.5,1.7Hz,1H),6.29(br,1H),3. 82-3.68(m,4H),3.67-3.52(m,4H),2.59-2.52(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0458] Example 20: 2-(6-(6-((5-fluoropyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 98)

[0459]

[0460] 1 g of trifluoroacetate (35.0 mg) and compound 98a (36.24 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (9.77 mg) and sodium cyanoborohydride (30.34 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 98 (15.0 mg). MS m / z (ESI): 472.3 [M+H] + .

[0461] 1 H NMR (400MHz, DMSO-d6) δ11.98(br,1H),9.66(s,1H),9.12(d,J=2.2Hz,1H),8.45-8.41(m,3H),7.73-7.65(m,1H),6.77(d,J=9.0Hz,2H),6. 29(br,1H),3.74(t,J=8.7Hz,4H),3.64(s,2H),3.58(d,J=6.5Hz,2H),2.55-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0462] Example 21: 2-(6-(6-((5-chloropyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 69)

[0463]

[0464] 1 g of trifluoroacetate (35.0 mg) and compound 69a (41.0 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (9.77 mg) and sodium cyanoborohydride (30.34 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 69 (16.0 mg). MS m / z (ESI): 488.2 [M+H] + .

[0465] 1 H NMR (400MHz, DMSO-d6) δ12.01(br,1H),9.66(s,1H),9.11(d,J=2.2Hz,1H),8.50(d,J=2.3H z,1H),8.43(dd,J=8.9,2.3Hz,1H),7.89(dd,J=8.4,2.5Hz,1H),7.52(d,J=8.4Hz,1H),6.76 (d,J=9.0Hz,2H),6.30(s,1H),3.79(d,J=11.7Hz,2H),3.73(d,J=5.9Hz,2H),3.65(s,2H), 3.57(d,J=10.0Hz,3H),2.55-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0466] Example 22: 2-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 67)

[0467]

[0468] 1 g of trifluoroacetate (30 mg) and compound 67a (25.90 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 67 (10.0 mg). MS m / z (ESI): 484.3 [M+H] + .

[0469] 1 H NMR (400MHz, DMSO-d6)) δ11.97(br,1H),9.65(s,1H),9.11(d,J=2.1Hz,1H),8.43(dd,J =8.9,2.3Hz,1H),8.16(dd,J=2.8,0.6Hz,1H),7.39(d,J=8.3Hz,1H),7.35(dd,J=8.6,2 .9Hz,1H),6.76(d,J=9.0Hz,2H),6.30(s,1H),3.85-3.77(m,5H),3.69(d,J=5.9Hz,2H) ,3.60-3.47(m,4H),2.55-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.58(d,J=8.4Hz,1H).

[0470] Example 23: 2-(6-(6-(4-ethoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 41)

[0471]

[0472] 1 g of trifluoroacetate (30 mg) and compound 41a (28.37 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 41 (15.0 mg). MS m / z (ESI): 497.3 [M+H] + .

[0473] 1H NMR (400MHz, DMSO-d6) δ11.97(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.43( dd,J=8.8,2.4Hz,1H),7.22(d,J=8.8Hz,2H),6.88-6.76(m,4H),6.32(br,1H),3.9 8(q,J=6.9Hz,2H),3.68(dd,J=30.7,8.6Hz,4H),3.51(d,J=30.4Hz,4H),2.59-2. 55(m,1H),2.33(s,3H),2.26(s,3H),1.56(d,J=8.3Hz,1H),1.31(t,J=7.0Hz,3H).

[0474] Example 24: 2-(6-(6-(1-(4-methoxyphenyl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 50)

[0475]

[0476] 1 g of trifluoroacetate (30 mg) and compound 50a (28.37 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 50 (15.0 mg). MS m / z (ESI): 497.3 [M+H] + .

[0477] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.63(s,1H),9.11(d,J=2.1Hz,1H),8.42( dd,J=8.9,2.2Hz,1H),7.25(d,J=8.6Hz,2H),7.02-6.57(m,4H),6.30(br,1H),3 .97-3.77(m,2H),3.72(s,3H),3.67-3.50(m,2H),3.50-3.36(m,2H),2.49-2.39 (m,2H),2.33(s,3H),2.26(s,3H),1.51(d,J=8.3Hz,1H),1.12(d,J=6.2Hz,3H).

[0478] Example 25: 2-(6-(6-(4-fluorobenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 83)

[0479]

[0480] 1 g of trifluoroacetate (35.0 mg) and compound 83a (18.2 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 83 (26.0 mg). MS m / z (ESI): 471.2 [M+H] + .

[0481] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.64(s,1H),9.11(d,J=2.4Hz,1H),8.42(dd,J=9.2,2.4Hz,1H),7.93-7.35(m,2H),7.13-7.09(m,2H),6.83(br ,1H),6.76(d,J=9.2Hz,1H),6.30(br,1H),3.74-3.66(m,4H),3.62-3.53( m,4H),2.55-2.52(m,1H),2.32(s,3H),2.25(s,3H),1.57(d,J=8.4Hz,1H).

[0482] Example 26: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-(4-(trifluoromethyl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 84)

[0483]

[0484] 1 g of trifluoroacetate (35.0 mg) and compound 84a (25.6 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 84 (17.0 mg). MS m / z (ESI): 521.2 [M+H] + .

[0485] 1 H NMR (400MHz, DMSO-d6) δ11.90(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.42(dd,J=8.8,2.4Hz,1H),7.66(d,J=8.0,2H),7.58(d,J=8.4,2 H),6.94(br,1H),6.76(d,J=9.2Hz,1H),6.30(br,1H),3.74-3.57(m,8H),2.57-2.55(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0486] Example 27: 4-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)benzonitrile (compound 85)

[0487]

[0488] 1 g of trifluoroacetate (35.0 mg) and compound 85a (19.3 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 85 (12.0 mg). MS m / z (ESI): 478.2 [M+H] + .

[0489] 1 H NMR (400MHz, DMSO-d6) δ12.08(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.42(dd,J=9.2,2.4Hz,1H),7.77(d,J=8.4,2H),7.56(d,J=8.0,2 H),6.89(br,1H),6.76(d,J=8.8Hz,1H),6.30(br,1H),3.74-3.56(m,8H),2.59-2.58(m,1H),2.33(s,3H),2.25(s,3H),1.61(d,J=8.4Hz,1H).

[0490] Example 28: 2-(6-(6-(4-(1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 86)

[0491]

[0492] Step 1: Preparation of 4-(1H-pyrazole-1-yl)benzaldehyde (compound 86b)

[0493] Compounds 83a (1.0 g) and 86a (0.8 g) were dissolved in DMF (10.0 mL), and anhydrous potassium carbonate (2.2 g) was added. The mixture was heated to 120 °C and reacted for 16 h until the starting materials were completely converted. After the reaction was complete, the reaction solution was washed with saturated sodium carbonate solution, extracted with EA (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 86b (1.1 g). MS m / z (ESI): 173.1 [M+H] + .

[0494] Step 2: Preparation of 2-(6-(6-(4-(1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methylN-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 86)

[0495] 1 g of trifluoroacetate (35.0 mg) and compound 86b (25.3 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 86 (12.0 mg). MS m / z (ESI): 519.2 [M+H] + .

[0496] 1H NMR(400MHz, DMSO-d6)11.97(s,1H),9.65(s,1H),9.12(d,J=2.4Hz,1H),8.46-8.42(m,2H),7.77-7.72(m,3H),7.45(d,J=8.8Hz,2H),6.89(br,1H) ,6.77(d,J=9.2Hz,1H),6.52(t,J=2.0Hz,1H),6.30(br,1H),3.77-3.59(m ,8H),2.56-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0497] Example 29: 2-(6-(6-(4-chlorobenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 82)

[0498]

[0499] 1 g of trifluoroacetate (35.0 mg) and compound 82a (20.6 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 82 (26.0 mg). MS m / z (ESI): 487.2 [M+H] + .

[0500] 1 H NMR (400MHz, DMSO-d6) δ12.21(br,1H),9.65(s,1H),9.11(d,J=2.4Hz,1H),8.43(dd,J=8.8,2.4Hz,1H),7.41-7.36(m,4H),6.86(b r,1H),6.76(d,J=9.2Hz,1H),6.30(br,1H),3.75-3.63(m,8H),2.60-2.56(m,1H),2.33(s,3H),2.25(s,3H),1.63(d,J=8.4Hz,1H).

[0501] Example 30: 2-(6-(6-(4-(4-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 91)

[0502]

[0503] Step 1: Preparation of 4-(4-fluoro-1H-pyrazole-1-yl)benzaldehyde (compound 91b)

[0504] Compounds 83a (0.1 g) and 91a (0.1 g) were dissolved in DMF (5.0 mL), potassium tert-butoxide (0.3 g) was added, and the mixture was heated to 120 °C for 16 h until the starting materials were completely converted. After the reaction was complete, the reaction solution was washed with saturated sodium carbonate solution, extracted with EA (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 91b (60 mg). MS m / z (ESI): 190.1 [M+H] + .

[0505] Step 2: Preparation of 2-(6-(6-(4-(4-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 91)

[0506] 1 g of trifluoroacetate (35.0 mg) and compound 91b (27.9 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (7.4 mg) and sodium cyanoborohydride (23.1 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 91 (23.0 mg). MS m / z (ESI): 537.3 [M+H] + .

[0507] 1 H NMR (400MHz, DMSO-d6)11.97(s,1H),9.63(s,1H),9.12(d,J=2.4Hz,1H),8.61(d,J =4.8Hz,1H),8.43(dd,J=8.8,2.0Hz,1H),7.80(d,J=4.0Hz,1H),7.71(d,J=8.8Hz, 2H),7.46(d,J=6.8Hz,2H),6.89(br,1H),6.77(d,J=8.8Hz,1H),6.30(br,1H),3.7 6-3.59(m,8H),2.56-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0508] Example 31: 6-Methyl-2-(6-(6-(4-(4-methyl-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 88)

[0509]

[0510] Step 1: Preparation of 1-(4-(1,3-dioxolane-2-yl)phenyl)-4-methyl-1H-pyrazole (compound 88c)

[0511] Compounds 88a (300 mg), 88b (161.3 mg), trans-N,N'-dimethyl-1,2-cyclohexanediamine (74.5 mg), CuI (50.0 mg), and cesium carbonate (1.71 g) were added to DMF (5.0 mL) and reacted at 115 °C for 7 h under nitrogen protection. The reaction was quenched with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 88c (120 mg) was purified by silica gel column chromatography (PE:EA = 3:1). MS m / z (ESI): 231.2 [M+H] + .

[0512] Step 2: Preparation of 4-(4-methyl-1H-pyrazole-1-yl)benzaldehyde (compound 88d)

[0513] Concentrated hydrochloric acid (1.5 mL) was added dropwise to a solution of compound 88c (120 mg) in THF (10 mL) and H₂O (8 mL), and the mixture was heated to 65 °C for 1.5 h. After the reaction was complete, the reaction solution was cooled in an ice bath, and then saturated sodium bicarbonate solution was slowly added dropwise to adjust the pH of the reaction solution to approximately 8. The THF solvent was removed under reduced pressure, and the solution was then extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 88d (90 mg). MS m / z (ESI): 187.1 [M+H] + .

[0514] Step 3: Preparation of 6-methyl-2-(6-(6-(4-(4-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 88)

[0515] 1 g of trifluoroacetate (35.0 mg) and compound 88d (54.0 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (9.8 mg) and sodium cyanoborohydride (30.3 mg), and the reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 88 (10.0 mg). MS m / z (ESI): 533.3 [M+H] + .

[0516] 1 H NMR (400MHz, DMSO) δ11.98(s,1H),9.66(s,1H),9.14(s,1H),8.45(d,J=8.4H z,1H),8.23(s,1H),7.71(d,J=8.0Hz,2H),7.54(s,1H),7.44(d,J=8.0Hz,2H) ,6.97-6.65(m,2H),6.32(br,1H),3.82-3.67(m,4H),3.65-3.50(m,4H),2.6 2-2.55(m,1H),2.35(s,3H),2.27(s,3H),2.11(s,3H),1.60(d,J=8.0Hz,1H).

[0517] Example 32: 2-(6-(6-((6-(3,4-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 121)

[0518]

[0519] Step 1: Preparation of 2-(3,4-dimethyl-1H-pyrazol-1-yl)-5-(1,3-dioxolane-2-yl)pyridine (compound 121c)

[0520] Compounds 121a (300 mg), 121b (188.0 mg), trans-N,N'-dimethyl-1,2-cyclohexanediamine (74.2 mg), CuI (49.7 mg), and cesium carbonate (1.70 g) were added to DMF (5.0 mL) and reacted at 120 °C for 5 h under nitrogen protection. The reaction was quenched with H₂O (10 mL) and extracted with EA (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 121c (305 mg) was purified by silica gel column chromatography (PE:EA = 4:1). MS m / z (ESI): 246.1 [M+H] + .

[0521] Step 2: Preparation of 6-(3,4-dimethyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 121d)

[0522] Concentrated hydrochloric acid (2.0 mL) was added dropwise to a THF (10 mL) solution of compound 121c (305 mg), and the mixture was heated to 65 °C for 1.5 h. After the reaction was complete, the reaction mixture was cooled in an ice bath, and potassium carbonate was slowly added to adjust the pH to approximately 8. The mixture was then extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 121d (200 mg) was purified by silica gel column chromatography (PE:EA = 4:1). MS m / z (ESI): 202.2 [M+H] + .

[0523] Step 3: Preparation of 2-(6-(6-((6-(3,4-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine (compound 121)

[0524] 1 g of trifluoroacetate (40.4 mg) and compound 121d (53.4 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (8.7 mg) and sodium cyanoborohydride (26.9 mg), and the reaction was carried out at 20 °C for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 121 (3.0 mg). MS m / z (ESI): 548.3 [M+H] + .

[0525] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),9.63(s,1H),9.12(d,J=2.4Hz,1H),8.43(dd,J=8 .8,2.4Hz,1H),8.32(d,J=1.6Hz,1H),8.27(s,1H),7.88(dd,J=8.4,2.4Hz,1H),7.79-7. 70(m,1H),7.03-6.60(m,2H),6.29(br,1H),3.83-3.70(m,4H),3.66-3.47(m,4H),2.58- 2.52(m,1H),2.33(s,3H),2.25(s,3H),2.19(s,3H),2.02(s,3H),1.58(d,J=8.4Hz,1H).

[0526] Example 33: 2-(6-(6-((5-fluoropyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 70)

[0527]

[0528] 1 g of trifluoroacetate (30 mg) and compound 70a (23.63 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (6.37 mg) and sodium cyanoborohydride (19.78 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 70 (12.0 mg). MS m / z (ESI): 472.3 [M+H] + .

[0529] 1 H NMR (400MHz, DMSO-d6)) δ11.97(br,1H),9.64(s,1H),9.11(d,J=2.2Hz,1H),8.43(dd,J =9.6,2.7Hz,2H),7.69(td,J=8.8,3.0Hz,1H),7.54(dd,J=8.7,4.7Hz,1H),6.77(d,J=9 .0Hz,2H),6.31(s,1H),3.80(d,J=11.9Hz,2H),3.72(d,J=5.9Hz,2H),3.64(s,2H),3.5 6(d,J=10.2Hz,2H),2.57-2.51(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0530] Example 34: 2-(6-(6-((6-(3-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 63)

[0531]

[0532] 1 g of trifluoroacetate (30 mg) and compound 63a (47.47 mg, prepared according to the synthesis method of compound 17a in Example 6, except that 4-fluoropyrazole was replaced with 3-fluoropyrazole) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg), and the mixture was stirred at 20 °C for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 63 (10.0 mg). MS m / z (ESI): 538.2 [M+H] + .

[0533] 1 H NMR (400MHz, DMSO-d6) δ11.97 (s, 1H), 9.65 (s, 1H), 9.12 (d, J = 2.1Hz, 1H), 8.55 (m,1H),8.47-8.38(m,2H),7.98(d,J=8.6Hz,1H),7.70(d,J=8.4Hz,1H),6.80(d ,J=8.0Hz,2H),6.56(dd,J=8,4Hz,1H),6.29(br,1H),3.84-3.68(m,4H),3.67-3 .47(m,4H),2.60-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.2Hz,1H).

[0534] Example 35: 2-(6-(6-((6-(4-fluoro-1H-imidazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 64)

[0535]

[0536] Step 1: Preparation of 5-(1,3-dioxolane-2-yl)-2-(4-fluoro-1H-imidazol-1-yl)pyridine (compound 64b)

[0537] Compounds 64a (230 mg), 121a (86 mg), N,N'-dimethylethylenediamine (38 mg), CuI (83 mg), and cesium carbonate (425 mg) were added to DMF (1 mL) and heated to 115 °C for 3 h under nitrogen protection. The reaction was quenched with water and extracted with EA. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 64b (120 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 236.1 [M+H] + .

[0538] Step 2: Preparation of 6-(4-fluoro-1H-imidazol-1-yl)nicotinaldehyde (compound 64c)

[0539] Concentrated hydrochloric acid (12N, 3.0 mL) was added dropwise to a solution of compound 64b (120 mg) in THF (10 mL) and water (10 mL), and the reaction was carried out at room temperature for 18 h. After the reaction was complete, the pH of the reaction solution was adjusted to approximately 8 with saturated sodium bicarbonate solution, then extracted with EA and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, crude product 64c (60 mg) was obtained, which was used directly in the next reaction without purification. MS m / z (ESI): 192.1 [M+H] + .

[0540] Step 3: Preparation of 2-(6-(6-((6-(4-fluoro-1H-imidazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 64)

[0541] 1 g of trifluoroacetate (30 mg) and compound 64c (47.47 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg). The mixture was stirred at 20 °C for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 64 (10.0 mg). MS m / z (ESI): 538.2 [M+H] + .

[0542] 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.64(s,1H),9.12(d,J=2.2Hz,1H),8.44(dd,J=9.1 ,2.4Hz,2H),8.28(m,1H),7.99(d,J=8.4Hz,1H),7.76-7.74(d,J=8.0Hz,1H),7.69-7.67( dd,J=8.4,1.6Hz,1H),6.86(br,1H),6.77(d,J=9.2Hz,1H),6.30(br,1H),3.78-3.71(m,4 H),3.67-3.51(m,4H),2.59-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0543] Example 36: 2-(6-(6-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 52)

[0544]

[0545] 1 g (320 mg) of compound 52a, 181.17 mg (prepared according to the synthesis method of compound 17a in Example 6, except that 6-bromonicoraldehyde was replaced with 1-(6-bromopyridin-3-yl)acetone), and tetraisopropyl titanate (752.81 mg) were added to 25 mL of dry THF. After purging with nitrogen three times, the mixture was stirred at 75 °C for 24 h. Then, sodium triacetoxyborohydride (935.64 mg) was added to the system in portions, followed by the addition of 15 mL of dry THF, and the mixture was stirred at 75 °C for another 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by rapid column chromatography (MeOH:DCM = 1:9) to obtain crude compound 52. This crude compound 52 was then purified by Prep-HPLC to obtain compound 52 (90.0 mg). MS m / z (ESI): 552.3 [M+H] + .

[0546] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),9.63(s,1H),9.12(d,J=2.1Hz,1H),8.66(d,J=4.4Hz,1H),8 .46-8.39(m,2H),8.01(dd,J=8.5,2.0Hz,1H),7.90(dd,J=14.7,6.2Hz,2H),6.82(br,1H),6.75(d ,J=12.0Hz,1H),6.27(br,1H),3.96-3.82(m,2H),3.77(q,J=6.1Hz,1H),3.63(m,1H),3.49-3.37( m,3H),2.55-2.51(m,1H),2.33(s,3H),2.25(s,3H),1.55(d,J=8.4Hz,1H),1.23(d,J=6.2Hz,3H).

[0547] Example 37: 2-(6-(6-((6-(3-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 120)

[0548]

[0549] 1 g of trifluoroacetate (30 mg) and compound 120a (22.95 mg, prepared according to the synthesis method of compound 64c in Example 35, except that the starting material 4-fluoroimidazole was replaced with 3-cyclopropylpyrazole) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (8.38 mg) and sodium cyanoborohydride (26.01 mg), and the mixture was stirred at 20 °C for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 120 (13.0 mg). MS m / z (ESI): 560.3 [M+H] + .

[0550] 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.64(s,1H),9.12(d,J=2.2Hz,1H),8.44(dd,J=8.9,2.4Hz,2H), 8.35(d,J=1.3Hz,1H),7.92(dd,J=8.5,1.8Hz,1H),7.78(d,J=8.4Hz,1H),6.8(br,1H),6.78(d,J=9.0Hz ,1H),6.28(br,1H),6.26(d,J=2.5Hz,1H),3.81-3.66(m,4H),3.67-3.52(m,4H),2.58-2.53(m,1H),2. 33(s,3H),2.26(s,3H),2.03-1.95(m,1H),1.59(d,J=8.4Hz,1H),0.98-0.91(m,2H),0.79-0.73(m,2H).

[0551] Example 38: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 119)

[0552]

[0553] Step 1: Preparation of 4-((6-methylpyridin-3-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (compound 119b)

[0554] Compound 119a (100 mg), N-Boc-4-hydroxypiperidine (276.65 mg), and triphenylphosphine (480.18 mg) were added to dry THF (5 mL), and the mixture was cooled to 0 °C. DIAD (370.21 mg) was added dropwise to the system, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the system was concentrated under reduced pressure and purified by rapid column chromatography (PE:EA = 1:1) to give compound 119b (65 mg). MS m / z (ESI): 293.2 [M+H] + .

[0555] Step 2: Preparation of 2-methyl-5-(piperidin-4-yloxy)pyridine (compound 119c)

[0556] Compound 119b (65 mg) was added to a mixture of 1,4-dioxane (4 N, 2 mL) hydrogen chloride solution and THF (1 mL), and stirred at room temperature for 2 h. The solution was concentrated to dryness under reduced pressure to give the hydrochloride salt of compound 119c (54 mg). MS m / z (ESI): 193.2 [M+H] + .

[0557] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrimidin-4-amine (compound 119)

[0558] Compound 119c hydrochloride (50 mg), compound 119d (50 mg), and potassium carbonate (73 mg) were added to DMF (2 mL) and heated to 100 °C with stirring for 16 h. After the reaction was complete, the reaction solution was cooled to room temperature. Water (30 mL) was added for dilution, and the solution was extracted with EA (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 119 (13 mg) was purified by Prep-HPLC. MS m / z (ESI): 457.3 [M+H] + .

[0559] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),9.63(s,1H),9.04(d,J=2.4Hz,1H),8.37(dd,J=9.0 ,2.4Hz,1H),8.19(d,J=2.9Hz,1H),7.38(dd,J=8.5,3.0Hz,1H),7.18(d,J=8.5Hz,1H),6.9 6(d,J=9.1Hz,1H),6.82(s,1H),6.28(s,1H),4.72-4.65(m,1H),4.13-4.01(m,2H),3.49- 3.40(m,2H),2.40(s,3H),2.32(s,3H),2.25(s,3H),2.06-1.98(m,2H),1.69-1.58(m,2H).

[0560] Example 39: 2-(6-(6-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 89)

[0561]

[0562] Step 1: Preparation of 1-(4-(1,3-dioxolane-2-yl)phenyl)-3-fluoro-1H-pyrazole (compound 89b)

[0563] Compounds 89a (80 mg), 88a (212.92 mg), N,N'-dimethylethylenediamine (81.94 mg), cesium carbonate (908.55 mg), and CuI (177.02 mg) were sequentially added to DMF (6 mL) and heated to 110 °C with stirring for 12 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid column chromatography (PE:EA = 63:37) to give compound 89b (35 mg). MS m / z (ESI): 235.1 [M+H] + .

[0564] Step 2: Preparation of 4-(3-fluoro-1H-pyrazole-1-yl)benzaldehyde (compound 89c)

[0565] Compound 89b (35 mg) was added to a mixture of 1,4-dioxane solution (4 N, 2 mL) and DCM (1 mL), and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to give compound 89c (28 mg). MS m / z (ESI): 191.1 [M+H] + .

[0566] Step 3: Preparation of 2-(6-(6-(4-(3-fluoro-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 89)

[0567] Compound 89c (14.37 mg), 1 g of trifluoroacetate of compound 89c (30 mg), triethylamine (6.37 mg), and sodium cyanoborohydride (19.78 mg) were sequentially added to methanol (0.5 mL), and stirred at room temperature for 36 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (0.1 mL). The reaction solution was concentrated and pre-purified by preparative TLC (DCM:MeOH = 10:1) to give 5 mg of crude product (R). f =0.15-0.25), and then purified by Prep-HPLC to obtain compound 89 (4 mg). MS m / z (ESI): 537.3 [M+H] + .

[0568] 1H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.64(s,1H),9.12(d,J=2.3Hz,1H),8.49-8.39(m,2H),7.68(d,J=8.6Hz,2H),7.46(d,J=8.5Hz,2H),6.78(d,J =9.0Hz,2H),6.31(dd,J=5.8,2.6Hz,2H),3.80-3.67(m,4H),3.64-3.48(m ,4H),2.59-2.54(m,1H),2.33(s,3H),2.25(s,3H),1.59(d,J=8.4Hz,1H).

[0569] Example 40: 6'-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)-[2,3'-bipyridine]-6-amine (Compound 6)

[0570]

[0571] Step 1: Preparation of tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylic acid (compound 6b)

[0572] Compound 6a (2.4 g) was dissolved in dry THF (50 mL), and NaH (988.39 mg, 60% purity) was added in portions, followed by stirring for 10 min. Di-tert-butyl dicarbonate (5.39 g) was added dropwise, and the mixture was stirred at 25 °C for 2 h under nitrogen protection. The reaction was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by silica gel column chromatography (PE:EA = 5:1) to give compound 6b (3.95 g).

[0573] Step 2: Preparation of 3-((6-bromo-4-methylpyridin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (compound 6d)

[0574] Compounds 6c (1.0 g), 6b (864.65 mg), palladium acetate (89.47 mg), Xantphos (461.20 mg), and cesium carbonate (2.60 g) were sequentially added to 1,4-dioxane (10 mL), and stirred at 95 °C for 2 h under nitrogen protection. LC-MS monitoring showed complete reaction of the starting materials and formation of the target product. The reaction solution was cooled to room temperature, filtered, and concentrated. Compound 6d (415 mg) was purified by silica gel column chromatography (PE:EA = 3:1). MS m / z (ESI): 367 [M+H]+ .

[0575] Step 3: Preparation of 6-bromo-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyridine-2-amine (compound 6e)

[0576] Compound 6d (300 mg) was added to a 1,4-dioxane solution of hydrogen chloride (4 N, 2 mL) and stirred at 25 °C for 1 h. The solution was concentrated directly to dryness, and the crude product was dissolved in methanol (5 mL). Then, triethylamine (1 mL) was added, and the mixture was stirred at room temperature for 15 min. The reaction solution was concentrated and purified by silica gel rapid column chromatography (DCM:MeOH = 97:3) to give compound 6e (145 mg). MS m / z (ESI): 267 [M+H] + Step 4: Preparation of 6'-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-4-methyl-N-(5-methyl-1H-pyrazol-3-yl)-[2,3'-bipyridine]-6-amine (compound 6)

[0577] Compound 6e (30 mg), 10f (85 mg), Na₂CO₃ (27.85 mg), Pd(PPh₃)₄ (12.98 mg), H₂O (1 mL), and 1,4-dioxane (5 mL) were added sequentially to the reaction flask. After purging with nitrogen three times, the mixture was stirred at 95 °C for 5 h. After the reaction was complete, the mixture was diluted with water and extracted with EA. The organic layer was collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, pre-purified by preparative TLC (DCM:MeOH = 9:1), and then purified by Prep-HPLC to obtain compound 6 (6 mg). MS m / z (ESI): 537.3 [M+H] + .

[0578] 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),9.02(s,1H),8.86(d,J=2.3Hz,1H),8.67(dd,J=4.5,0.6Hz,1 H),8.41(d,J=1.7Hz,1H),8.21(dd,J=8.9,2.4Hz,1H),7.98(dd,J=8.5,2.2Hz,1H),7.92(d,J=4.3H z,1H),7.86(d,J=8.4Hz,1H),7.03(s,1H),6.88(s,1H),6.77(d,J=9.0Hz,1H),6.22(s,1H),3.81-3 .69(m,4H),3.66-3.53(m,4H),2.58-2.53(m,1H),2.26(s,3H),2.22(s,3H),1.59(d,J=8.4Hz,1H).

[0579] Example 41: 2-(6-(6-((6'-methoxy-[2,3'-bipyridinyl]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 7)

[0580]

[0581] Step 1: Preparation of 5-(1,3-dioxolane-2-yl)-6'-methoxy-2,3'-bipyridine (compound 7b)

[0582] Compound 7a (499 mg), 121a (500 mg), Na₂CO₃ (691 mg), Pd(PPh₃)₄ (126 mg), H₂O (3 mL), and 1,4-dioxane (17 mL) were added sequentially to a reaction flask. After purging with nitrogen three times, the mixture was stirred at 95 °C for 5 h. After the reaction was completed, the mixture was concentrated to dryness. Compound 7b (350 mg) was purified by silica gel column chromatography (PE:EA = 1:1).

[0583] Step 2: Preparation of 6'-methoxy-[2,3'-bipyridine]-5-carboxaldehyde (compound 7c)

[0584] Concentrated hydrochloric acid (12N, 3.0 mL) was added dropwise to a solution of compound 7b (200 mg) in THF (11 mL) and water (9 mL), and the reaction was carried out at room temperature for 18 h. After the reaction was complete, the pH of the reaction solution was adjusted to approximately 10 with potassium carbonate solution, and then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (PE:EA = 2:1) to give compound 7c (60 mg). MS m / z (ESI): 215.1 [M+H] + .

[0585] Step 3: Preparation of 2-(6-(6-((6'-methoxy-[2,3'-bipyridinyl]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine (compound 7)

[0586] 1 g of trifluoroacetate (50 mg) and compound 7c (67.44 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (10.62 mg) and sodium cyanoborohydride (32.97 mg), and the reaction was carried out at room temperature for 20 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 7 (10.0 mg). MS m / z (ESI): 561.3 [M+H] + .

[0587] 1 H NMR (400MHz, DMSO-d6) δ11.98(br,1H),9.65(s,1H),9.13(d,J=2.2Hz,1H),8.86(d,J=2.2Hz,1H),8. 60(d,J=1.5Hz,1H),8.44(dd,J=8.9,2.3Hz,1H),8.36(dd,J=8.7,2.5Hz,1H),7.90(d,J=8.1Hz,1H), 7.83(dd,J=8.2,2.1Hz,1H),6.85(dd,J=56.9,8.8Hz,3H),6.33(s,1H),3.91(s,3H),3.75(dd,J=20. 2,8.9Hz,4H),3.65-3.49(m,4H),2.59-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0588] Example 42: 2-(6-(6-((5'-fluoro-2'-methyl-[2,3'-bipyridinyl]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 8)

[0589]

[0590] Step 1: Preparation of 5-fluoro-2-methylpyridine-3-boronic acid pinacol ester (compound 8b)

[0591] Pinaryl diboronate (1.20 g), compound 8a (300 mg), Pd(dppf)Cl2·DCM (128.93 mg), potassium acetate (464.85 mg), and dried 1,4-dioxane (10 mL) were added sequentially to the reaction flask. The mixture was heated to 100 °C and stirred for 4 h under nitrogen protection. After the reaction was complete, the mixture was filtered. The filtrate was diluted with water and extracted with EA. The organic phase was washed twice with water and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and purified by silica gel rapid column chromatography (PE:EA = 1:1) to obtain compound 8b (300 mg). MS m / z (ESI): 238.2 [M+H] + .

[0592] Step 2: Preparation of 2-(6-(6-((6-bromopyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 8d)

[0593] 1 g of trifluoroacetate (200 mg) and compound 8c (195.20 mg) were added to methanol (10 mL), and triethylamine (42.48 mg) was added with stirring at room temperature. After stirring for 30 min, sodium cyanoborohydride (131.89 mg) was added, and the mixture was stirred at 20 °C for 16 h. LC-MS monitoring showed a clear product peak. Compound 8d (220 mg) was purified by silica gel rapid column chromatography (DCM:MeOH = 10:1). MS m / z (ESI): 532.1 [M+H] + .

[0594] Step 3: Preparation of 2-(6-(6-((5'-fluoro-2'-methyl-[2,3'-bipyridinyl]-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine (compound 8)

[0595] Compounds 8b (222.63 mg), 8d (100 mg), Na₂CO₃ (69.87 mg), Pd(PPh₃)₄ (32.55 mg), water (1 mL), and 1,4-dioxane (5 mL) were added sequentially to a reaction flask, and the mixture was stirred at 95 °C for 5 h under nitrogen protection. After the reaction was complete, the solvent was removed by rotary evaporation, and the mixture was pre-purified by preparative TLC (DCM:MeOH = 9:1) followed by Prep-HPLC purification to obtain compound 8 (25 mg). MS m / z (ESI): 563.3 [M+H] + .

[0596] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.66(s,1H),9.13(d,J=2.2Hz,1H),8.66(d,J=1.5Hz,1H),8. 51(d,J=2.9Hz,1H),8.44(dd,J=8.9,2.3Hz,1H),7.90(dd,J=8.1,2.1Hz,1H),7.76(dd,J=9.5,2.8Hz ,1H),7.62(d,J=8.0Hz,1H),6.81(br,1H),6.79(d,J=9.0Hz,1H),6.32(br,1H),3.85-3.71(m,4H), 3.70-3.51(m,4H),2.61-2.53(m,1H),2.51(s,3H),2.33(s,3H),2.26(s,3H),1.61(d,J=8.4Hz,1H).

[0597] Example 43: 6-Methyl-2-(6-(6-((6-(5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 9)

[0598]

[0599] 1 g of trifluoroacetate (30 mg) and compound 9a (17.68 mg, prepared according to the synthesis method of compound 64c in Example 35, except that the starting material 4-fluoroimidazole was replaced with 5-methylpyrazole) were added to methanol (0.5 mL), followed by triethylamine (8.38 mg). After stirring for 30 min, sodium cyanoborohydride (19.78 mg) was added, and the mixture was stirred at 20 °C for 16 h. LC-MS analysis showed that the reaction proceeded completely and the product peak was distinct. Compound 9 (7 mg) was obtained by Prep-HPLC purification. MS m / z (ESI): 534.3 [M+H]+ .

[0600] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),9.67(s,1H),9.14(d,J=2.1Hz,1H),8.49(d,J=2.4Hz,1H),8 .45(dd,J=9.2,2.4Hz,1H),8.38(d,J=1.6Hz,1H),7.94(dd,J=8.5,2.1Hz,1H),7.81(d,J=8.4Hz,1 H),6.83(br,1H),6.79(d,J=9.2Hz,1H),6.38(d,J=2.4Hz,1H),6.33(br,1H),3.85-3.71(m,4H),3 .69-3.51(m,4H),2.61-2.55(m,1H),2.35(s,3H),2.30(s,3H),2.27(s,3H),1.61(d,J=8.4Hz,1H).

[0601] Example 44: N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methylpyrimidin-4-amine (Compound 10)

[0602]

[0603] Step 1: Preparation of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylpyrimidin-4-amine (compound 10c)

[0604] Compounds 10b (1.0 g) and 10a (755.53 mg) were dissolved in ethanol (20.00 mL), and then N,N-diisopropylethylamine (1590.00 mg) was added. The mixture was heated to 70 °C and stirred for 48 h under nitrogen protection. The reaction solution was concentrated under reduced pressure and diluted with EA (300.00 mL). The organic phase was washed three times with water, then washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by silica gel column chromatography (DCM:MeOH = 9:1) to give compound 10c (820.00 mg). MS m / z (ESI): 250.1 [M+H] + .

[0605] Step 2: Preparation of 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 10d)

[0606] Compound 1c (1180.00 mg) was dissolved in a mixed solvent of methanol (5.00 mL) and DCM (10.00 mL), and then a solution of 1,4-dioxane hydrogen chloride (4 N, 6.00 mL) was slowly added dropwise under ice bath conditions, and the mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated under reduced pressure to give the hydrochloride salt of compound 10d (1040.00 mg). MS m / z (ESI): 254.0 [M+H] + .

[0607] Step 3: Preparation of 3-(5-bromopyridin-2-yl)-6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (compound 10e)

[0608] Compound 10d hydrochloride (300.00 mg) and compound 17a (297.04 mg) were dissolved in 1,2-dichloroethane (10.00 mL), and triethylamine (104.82 mg) was slowly added dropwise. After stirring for 10 min, acetic acid (31.10 mg) was added dropwise, and stirring was continued for 30 min. Then, sodium triacetoxyborohydride (878.21 mg) was added, and the mixture was stirred at 25 °C for 20 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution, diluted with water, and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by silica gel column chromatography (PE:EA = 1:1) to give compound 10e (363.00 mg). MS m / z (ESI): 429.1 [M+H] + .

[0609] Step 4: Preparation of 6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (compound 10f)

[0610] Compound 10e (187.00 mg) and pinacol diboronate (221.23 mg) were dissolved in 1,4-dioxane (15.00 mL), followed by the addition of potassium acetate (106.88 mg) and Pd(dppf)Cl2·DCM (35.57 mg). The mixture was heated to 95 °C and stirred for 5 h under nitrogen protection. The reaction solution was diluted with EA (100.00 mL) and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 10f (100.00 mg). MS m / z (ESI): 477.3 [M+H] + .

[0611] Step 5: Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methylpyrimidin-4-amine (compound 10)

[0612] Compounds 10c (26.21 mg) and 10f (50.00 mg) were dissolved in 1,4-dioxane (4.00 mL), followed by the addition of Pd(PPh3)4 (18.19 mg) and an aqueous solution of sodium carbonate (33.38 mg dissolved in 1.00 mL of water). The mixture was heated to 95 °C and stirred for 12 h under nitrogen protection. After the reaction was complete, EA (20.00 mL) was added to the reaction solution for dilution, and the mixture was washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC to obtain compound 10 (9.00 mg). MS m / z (ESI): 564.3 [M+H] + .

[0613] 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),9.64(s,1H),9.11(d,J=2.4Hz,1H),8.67(dd,J=4.8,0.8Hz,1 H),8.42(dd,J=9.2,2.0Hz,2H),7.99(dd,J=8.4,2.0Hz,1H),7.92(dd,J=4.4,0.8Hz,1H),7.87(d,J= 8.4Hz,1H),6.78(d,J=9.2Hz,2H),6.18(br,1H),3.79-3.71(m,4H),3.64-3.53(m,4H),2.56-2.51( m,1H),2.33(s,3H),1.95-1.89(m,1H),1.60(d,J=8.4Hz,1H),0.97-0.92(m,2H),0.75-0.69(m,2H).

[0614] Example 45: 2-(6-(6-((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 11)

[0615]

[0616] Step 1: Preparation of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-(1,3-dioxolane-2-yl)pyridine (compound 11b)

[0617] Compounds 11a (1.0 g), 121a (1.74 g), N,N'-dimethylethylenediamine (664.83 mg), CuI (1.44 g), and cesium carbonate (7.37 g) were added to DMF (30 mL) and reacted at 98 °C for 16 h under nitrogen protection. The reaction mixture was quenched with water and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 11b (0.69 g) was purified by silica gel column chromatography (PE:EA = 3:1). MS m / z (ESI): 246.2 [M+H] + .

[0618] Step 2: Preparation of 6-(3,5-dimethyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 11c)

[0619] Hydrochloric acid (2N, 3.0 mL) was added dropwise to a THF (6 mL) solution of compound 11b (250 mg), and the reaction was carried out at room temperature for 3 h. After the reaction was complete, the reaction solution was cooled in an ice bath. Potassium carbonate was slowly added to adjust the pH to approximately 8, and then the solution was extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (PE:EA = 3:1) to give compound 11c (150 mg).

[0620] Step 3: Preparation of 2-(6-(6-((6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine (compound 11)

[0621] Compound 1 g (30 mg) and compound 11c (25 mg) were added to methanol (1 mL), followed by acetic acid (5 mg), and stirred at room temperature for 0.5 h. Sodium cyanoborohydride (15.6 mg) was then added, and the reaction was continued at room temperature for 20 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and pre-purified by preparative TLC (DCM:MeOH = 96:4) to obtain the crude product. This crude product was then purified by Prep-HPLC to obtain compound 11 (7 mg). MS m / z (ESI): 548.3 [M+H] + .

[0622] 1H NMR (400MHz, DMSO-d6)) δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8.44(dd,J= 8.9,2.2Hz,1H),8.37(d,J=1.8Hz,1H),7.91(dd,J=8.5,2.2Hz,1H),7.74(d,J=8.4Hz,1 H),6.96-6.67(m,2H),6.31(s,1H),6.09(s,1H),3.85-3.68(m,4H),3.66-3.49(m,4H), 2.56(s,3H),2.54(s,1H),2.33(s,3H),2.26(s,3H),2.19(s,3H),1.60(d,J=8.5Hz,1H).

[0623] Example 46: 2-(6-(6-((6-(5-isopropyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 12)

[0624]

[0625] Step 1: Preparation of 5-(1,3-dioxolane-2-yl)-2-(5-isopropyl-1H-pyrazol-1-yl)pyridine (compound 12b)

[0626] Compounds 12a (210.68 mg), 121a (400 mg), N,N'-dimethylethylenediamine (153.27 mg), cesium carbonate (1.13 g), and CuI (331.13 mg) were sequentially added to DMF (10 mL) and heated to 110 °C with stirring for 3 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 55:45) to give compound 12b (300 mg). MS m / z (ESI): 260.2 [M+H] + .

[0627] Step 2: Preparation of 6-(5-isopropyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 12c)

[0628] Compound 12b (300.00 mg) was added to a mixture of 1,4-dioxane solution (4 N, 6 mL) and DCM (4 mL), and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and purified by rapid column chromatography (PE:EA = 80:20) to give compound 12c (120 mg). MS m / z (ESI): 216.2 [M+H] + .

[0629] Step 3: Preparation of 2-(6-(6-((6-(5-isopropyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 12)

[0630] Compound 12c (26.73 mg), 1 g (30 mg), and sodium cyanoborohydride (26.01 mg) were sequentially added to a mixed solvent of methanol (1 mL) and acetic acid (0.1 mL), and the mixture was heated to 40 °C and stirred for 16 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (0.1 mL). The reaction solution was concentrated and purified by Prep-HPLC to obtain trifluoroacetate of compound 12 (15 mg), which was then separated by MPLC to obtain free compound 12 (8 mg). MS m / z (ESI): 562.3 [M+H] + .

[0631] MPLC conditions:

[0632] Instrument model: Biotage Isolera Prime 2.3.1; Column: Agela Technologies C18 spherical 20-35um 100A, 12g; Column temperature: 25℃; Flow rate: 15.0mL / min; Detection wavelength: 254nm; Elution gradient: (0min: 0% A, 100% B; 3.0min: 0% A, 100% B; 20min: 80% A, 20% B); Mobile phase A: 100% acetonitrile; Mobile phase B: 0.5% ammonium bicarbonate aqueous solution; Compound collection time: 10.4min-11.8min.

[0633] 1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.65(s,1H),9.16-9.09(m,1H),8.49-8.40(m,2H),8.36( d,J=1.9Hz,1H),7.93(dd,J=8.5,2.3Hz,1H),7.81(dd,J=8.4,0.7Hz,1H),6.78(d,J=9.0Hz,2H) ,6.42(d,J=2.5Hz,1H),6.33(s,1H),3.83-3.68(m,4H),3.66-3.50(m,4H),2.99(p,J=6.9Hz,1H ),2.59-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H),1.27(s,3H),1.25(s,3H).

[0634] Example 47: 2-(6-(6-(4-(5,6-dihydrocyclopentenano[c]pyrazol-2(4H)-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 25)

[0635]

[0636] Step 1: Preparation of 2-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenteneno[c]pyrazole (compound 25b)

[0637] Compound 25a (206.83 mg), compound 121a (400 mg), N,N'-dimethylethylenediamine (153.27 mg), cesium carbonate (1.13 g), and CuI (331.13 mg) were sequentially added to DMF (10 mL), and the mixture was heated to 110 °C and stirred for 12 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 25b (525 mg). MS (ESI, m / z): 258.2 [M+H] + .

[0638] Step 2: Preparation of 6-(5,6-dihydrocyclopenten[c]pyrazol-2(4H)-yl)nicotinaldehyde (compound 25c)

[0639] Compound 25b (315 mg) was added to a mixture of 1,4-dioxane solution (4 N, 10 mL) and DCM (10 mL), and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by rapid column chromatography (PE:EA = 80:20) to give compound 25c (200 mg). MS m / z (ESI): 214.2 [M+H] + .

[0640] Step 3: Preparation of 2-(6-(6-(4-(5,6-dihydrocyclopentenano[c]pyrazol-2(4H)-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 25)

[0641] Compound 25c (29.42 mg), 1 g (50 mg), and sodium cyanoborohydride (43.35 mg) were sequentially added to a mixed solvent of methanol (0.5 mL) and acetic acid (0.05 mL), and the mixture was heated to 40 °C and stirred for 16 h. The reaction was quenched by adding 0.1 mL of saturated ammonium chloride aqueous solution. The reaction solution was concentrated and purified by Prep-HPLC to obtain trifluoroacetate of compound 25 (25 mg), which was then separated by MPLC to obtain free compound 25 (15 mg). MS m / z (ESI): 560.3 [M+H] + .

[0642] MPLC conditions:

[0643] Instrument model: Biotage Isolera Prime 2.3.1; Column: Agela Technologies C18 spherical 20-35um 100A, 12g; Column temperature: 25℃; Flow rate: 15.0mL / min; Detection wavelength: 254nm; Elution gradient: (0min: 0% A, 100% B; 3.0min: 0% A, 100% B; 20min: 80% A, 20% B); Mobile phase A: 100% acetonitrile; Mobile phase B: 0.5% ammonium bicarbonate aqueous solution; Compound collection time: 11.4min-12.8min.

[0644] 1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.65(s,1H),9.15-9.10(m,1H),8.44(dd,J=8.9,2.3Hz,1 H),8.35-8.30(m,1H),8.19(d,J=1.2Hz,1H),7.89(dd,J=8.5,2.3Hz,1H),7.76(dd,J=8.4,0.7H z,1H),6.78(d,J=9.0Hz,2H),6.31(s,1H),3.82-3.69(m,4H),3.66-3.50(m,4H),2.74-2.62(m, 4H),2.57-2.54(m,2H),2.38(q,J=7.4Hz,2H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0645] Example 48: (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl) methyl ketone (compound 26)

[0646]

[0647] Step 1: Preparation of methyl 6-(4-fluoro-1H-pyrazol-1-yl)nicotinic acid (compound 26b)

[0648] Compounds 26a (1 g) and 91a (478.08 mg) were added to acetonitrile (20 mL), followed by salicylaldehyde oxime (129.96 mg), cesium carbonate (3.77 g), and cuprous oxide (132.47 mg) in sequence. The mixture was heated to 85 °C and stirred for 16 h under nitrogen protection. After the reaction was complete, dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 5. Silica gel was added and the mixture was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 26b (602 mg). MS m / z (ESI): 221.9 [M+H] + .

[0649] Step 2: Preparation of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinic acid (compound 26c)

[0650] Compound 26b (580 mg) was added to THF (10 mL) and H₂O (5 mL), followed by NaOH (314.66 mg), and stirred at 25 °C for 14 h. After the reaction was complete, dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 5, and the mixture was extracted with EA (80 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 26c (312 mg). MS m / z (ESI): 208.1 [M+H] + .

[0651] Step 3: Preparation of (6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)(3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl ketone (compound 26)

[0652] Compound 26c (20 mg) was added to DMF (5 mL), followed by the sequential addition of HBTU (29.41 mg), DIPEA (37.43 mg), and 1 g of trifluoroacetate (50.60 mg). The mixture was stirred at 25 °C for 1 h. The reaction was quenched by adding water (25 mL) and extracted with EA (80 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to obtain compound 26 (25 mg). MS m / z (ESI): 551.8 [M+H] + .

[0653] 1 H NMR (400MHz, DMSO) δ11.97(s,1H),9.65(s,1H),9.04(s,1H),8.77-8.73(m,2H),8.38(dd,J= 8.8,2.0Hz,1H),8.25(dd,J=8.4,2.0Hz,1H),8.03(d,J=4.4Hz,1H),7.97(d,J=8.8Hz,1H),7. 05-6.47(m,2H),6.27(br,1H),4.96(s,1H),4.67(s,1H),4.17(d,J=9.6Hz,1H),3.80-3.65(m ,2H),3.63-3.50(m,1H),2.92-2.82(m,1H),2.31(s,3H),2.24(s,3H),1.72(d,J=8.4Hz,1H).

[0654] Example 49: 2-(6-(6-((6-(5-cyclobutoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 27)

[0655]

[0656] Step 1: Preparation of tert-butyl 3-hydroxy-1H-pyrazole-1-carboxylic acid (compound 27b)

[0657] Compound 27a (500 mg), Boc₂O (1.30 g), TEA (1.81 g), and DMAP (145.31 mg) were added sequentially to a reaction flask, followed by THF (20 mL). The mixture was stirred at room temperature for 16 h, allowing the reaction solution to gradually clear from a yellow turbidity. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography (DCM:MeOH = 20:1) to obtain compound 27b (425 mg).

[0658] Step 2: Preparation of tert-butyl 3-cyclobutoxy-1H-pyrazole-1-carboxylic acid (compound 27d)

[0659] Compounds 27b (360 mg), 27c (215.71 mg), and PPh3 (776.71 mg) were dissolved in toluene (10 mL) and cooled in an ice-water bath. DIAD (628.74 mg) was added, and the mixture was heated to 110 °C for 6 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:20) to obtain compound 27d (374 mg).

[0660] Step 3: Preparation of 3-cyclobutoxy-1H-pyrazole (compound 27e)

[0661] Compound 27d (374 mg) was dissolved in methanol (3 mL), and then a solution of 1,4-dioxane hydrogen chloride (4 N, 3 mL) was added. The reaction was carried out at room temperature under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to give the hydrochloride salt of compound 27e (280 mg). MS m / z (ESI): 139.1 [M+H] + .

[0662] Step 4: Preparation of 2-(5-cyclobutoxy-1H-pyrazole-1-yl)-5-(1,3-dioxolane-2-yl)pyridine (compound 27f)

[0663] Compound 121a (315 mg), the hydrochloride salt of compound 27e (239 mg), Cs₂CO₃ (675.94 mg), and DMF (10 mL) were added to a reaction flask. After stirring until homogeneous, N,N'-dimethylethylenediamine (48.77 mg) and CuI (52.68 mg, 273.84 μmol) were added, and the mixture was heated to 100 °C for 14 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:1) to obtain compound 27f (300 mg). MS m / z (ESI): 287.9 ​​[M+H] + .

[0664] Step 5: Preparation of 6-(5-cyclobutoxy-1H-pyrazol-1-yl)nicotinaldehyde (compound 27g)

[0665] Compound 27f (300 mg) was dissolved in THF (5 mL), and hydrochloric acid (2 N, 5 mL) was added to the solution. The reaction was carried out at room temperature for 8 h. After the reaction was completed, the reaction solution was diluted with water (20 mL), the pH was adjusted to 7-8 with saturated NaHCO3 aqueous solution, and extracted with EA (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 1:15) to give compound 27 g (140 mg). MS m / z (ESI): 243.9 [M+H] + .

[0666] Step 6: Preparation of 2-(6-(6-((6-(5-cyclobutoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 27)

[0667] 1 g (65 mg), 27 g (50.66 mg), and tetraisopropyl titanate (195.65 mg) of compound were dissolved in dry THF (3 mL), and the mixture was heated to 75 °C for 1 h. Sodium triacetoxyborohydride (182.37 mg) was added to the reaction flask, and the reaction was maintained at 75 °C for 18 h. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by Prep-HPLC to give compound 27 (20 mg). MS m / z (ESI): 589.9 [M+H] + .

[0668] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.66(s,1H),9.13(d,J=2.4Hz,1H),8.44(dd,J=8.8,2.4Hz,1H),8.40(d,J=2 .4Hz,1H),8.33(d,J=2.0Hz,1H),7.91(dd,J=8.4,2.4Hz,1H),7.66(d,J=8.4Hz,1H),7.12-6.69(m,2H),6.49-6.14( m,1H),6.02(d,J=2.8Hz,1H),4.90(p,J=7.6Hz,1H),3.83-3.73(m,2H),3.73-3.66(m,2H),3.65-3.47(m,4H),2.60- 2.53(m,1H),2.46-2.38(m,2H),2.33(s,3H),2.26(s,3H),2.13-2.03(m,2H),1.82-1.73(m,1H),1.67-1.56(m,2H).

[0669] Example 50: 2-(6-(6-((6-(4-chloro-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-(6-(4-chloro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 28 / Compound 28')

[0670]

[0671] Step 1: Preparation of 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-5-(1,3-dioxolane-2-yl)pyridine and 2-(4-chloro-5-methyl-1H-pyrazol-1-yl)-5-(1,3-dioxolane-2-yl)pyridine (compound 28b / compound 28b')

[0672] Compounds 121a (202.0 mg), 28a (102.3 mg), CuI (167.2 mg), N,N'-dimethylethylenediamine (77.3 mg), and Cs₂CO₃ (856.1 mg) were dissolved in DMF (5.0 mL) under nitrogen protection and heated to 120 °C until the reactants were completely converted. After the reaction, the reaction solution was washed with saturated sodium carbonate aqueous solution and extracted with EA (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative TLC to give a mixture of compounds 28b and 28b' (230.0 mg). MS m / z (ESI): 266.0 [M+H] + .

[0673] Step 2: Preparation of 6-(4-chloro-3-methyl-1H-pyrazol-1-yl)nicotinaldehyde and 6-(4-chloro-5-methyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 28c / compound 28c')

[0674] A mixture of compounds 28b and 28b' (230.0 mg) was added to a mixed solvent of concentrated hydrochloric acid (3 mL), THF (10 mL), and water (10 mL), and reacted at 25 °C until the starting material was completely converted. The reaction solution was concentrated to dryness under reduced pressure to give a mixture of compounds 28c and 28c' (39.0 mg). MS m / z (ESI): 222.1 [M+H] + .

[0675] Step 3: Preparation of 2-(6-(6-((6-(4-chloro-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-(6-(4-chloro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 28 / compound 28')

[0676] A mixture of compounds 28c and 28c' (29.0 mg) and 1 g of the trifluoroacetate of compound 28 (30.0 mg) were added to methanol (0.5 mL), followed by the sequential addition of triethylamine (6.4 mg) and sodium cyanoborohydride (19.8 mg). The reaction was carried out at room temperature until all the starting materials were converted. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 28 (2.0 mg, collection time 5.6–6.0 min), MS m / z (ESI): 568.2 [M+H]. + Compound 28' (1.0 mg, collected in 5.0–5.4 min), MS m / z (ESI): 568.2 [M+H] + .

[0677] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.64(s,1H),9.13(d,J=2.0Hz,1H),8.69(s,1 H),8.45(d,J=8.0Hz,1H),8.40(s,1H),7.98(d,J=8.8Hz,1H),7.82(d,J=8.4Hz,1H), 6.89 (d, J = 8.8 Hz, 1H), 6.76–6.67 (m, 1H), 6.38–6.23 (m, 1H), 3.80–3.55 (m, 8H), 2.62–2.58 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H), 1.61 (d, J = 8.0 Hz, 1H) (Compound 28).

[0678] 1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),9.68(s,1H),9.18(d,J=2.4Hz,1H),8.51(d,J=2.4 Hz,1H),8.48(d,J=2.4Hz,1H),8.05(dd,J=8.4,2.4Hz,1H),7.90(s,1H),7.83(d,J=8.4H z, 1H), 6.85 (d, J = 9.2 Hz, 1H), 6.82–6.69 (m, 1H), 6.43–6.29 (m, 1H), 3.86–3.56 (m, 8H), 2.63 (s, 3H), 2.62–2.58 (m, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 1.66 (d, J = 8.4 Hz, 1H) (Compound 28').

[0679] Example 51: 2-(6-(4-((5-fluoropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 29)

[0680]

[0681] Step 1: Preparation of tert-butyl 4-((5-fluoropyridin-3-yl)oxy)piperidine-1-carboxylic acid (compound 29b)

[0682] Compound 29a (425.6 mg), N-Boc-4-hydroxypiperidine (505.0 mg), and PPh3 (1.3 g) were dissolved in dry THF (5.0 mL) under nitrogen protection. The solution was cooled to 0 °C, and DIAD (1.0 g) was added dropwise. The mixture was then slowly heated to 25 °C until the starting material was completely converted. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography to obtain compound 29b (736.2 mg). MS m / z (ESI): 297.1 [M+H] + .

[0683] Step 2: Preparation of 3-fluoro-5-(piperidin-4-yloxy)pyridine (compound 29c) hydrochloride

[0684] Compound 29b (555.5 mg) was added to a 1,4-dioxane solution of hydrogen chloride (4 N, 20 mL) and reacted at 25 °C until the starting material was completely converted. The reaction solution was concentrated to dryness under reduced pressure to give the hydrochloride salt of compound 29c (390.0 mg). MS m / z (ESI): 197.1 [M+H] + .

[0685] Step 3: Preparation of 2-(6-(4-((5-fluoropyridin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 29)

[0686] The hydrochloride salt of compound 29c (86.0 mg), compound 119d (55.5 mg), and K₂CO₃ (122.7 mg) were added to DMF (5 mL), and the mixture was heated to 125 °C until the starting material was completely converted. After the reaction, the reaction solution was washed with saturated sodium carbonate aqueous solution and extracted with EA (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to give compound 29 (17.0 mg). MS m / z (ESI): 460.9 [M+H] + .

[0687] 1 H NMR (400MHz, DMSO-d6) δ12.41 (s, 1H), 11.12 (s, 1H), 8.97 (d, J = 2.4Hz, 1H), 8.31 (dd, J=9.2,2.4Hz,1H),8.25(t,J=1.6Hz,1H),8.20(d,J=2.4Hz,1H),7.59(dt,J=11.6,2.4 Hz,1H),7.14(d,J=9.2Hz,1H),6.90-6.80(m,2H),4.87-4.81(m,1H),4.19-4.13(m,2H ),3.85-3.73(m,2H),2.47(s,3H),2.28(s,3H),2.11-2.05(m,2H),1.72-1.63(m,2H).

[0688] Example 52: 2-(6-(6-((R)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 52-1 / Compound 52-2)

[0689]

[0690] Compound 52 (100 mg) was resolved by chiral Prep-HPLC to yield compounds 52-1 (retention time 6.788 min) and 52-2 (retention time 10.115 min). The two compounds were distinguished based on the order of their chiral separation retention times. Compound 52-1 (14 mg, ee: 98.85%) was thus obtained, MS m / z (ESI): 552.3 [M+H]. + Compound 52-2 (20 mg, ee: 99.22%), MS m / z (ESI): 552.3 [M+H] + .

[0691] Chiral HPLC separation conditions:

[0692] Instrument model: Shimadzu LC-20AD; Column: CHIRALPAK IE (IE00CD-RH008), 0.46cm I.D. × 15cm L; Column temperature: 35℃; Flow rate: 1.0mL / min; Detection wavelength: 254nm; Mobile phase: MeOH:CAN:DEA=80:20:0.1(V / V / V); Elution time of compound 52-1 was 6.788min, and elution time of compound 52-2 was 10.115min.

[0693] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H),8.66(d,J=4.6Hz,1H),8.43(d,J =2Hz,1H), 8.41(d,J=2.4Hz,1H), 8.01(dd,J=8.5,1.9Hz,1H), 7.90(dd,J=16.8,6.4Hz,2H), 6.82(br,1H), 6.75 (d, J = 8.8 Hz, 1H), 6.29 (br, 1H), 3.95-3.81 (m, 2H), 3.77 (q, J = 6.1 Hz, 1H), 3.63 (s, 1H), 3.53-3.38 (m, 3H), 2.55-2.53 (m, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.55 (d, J = 8.4 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H). (Compound 52-1)

[0694] 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.65(s,1H),9.11(d,J=2.0Hz,1H),8.66(d,J=4.6Hz,1H),8.43(d,J =2Hz,1H), 8.41(d,J=2.4Hz,1H), 8.00(dd,J=8.5,1.9Hz,1H), 7.89(dd,J=16.8,6.4Hz,2H), 6.82(br,1H), 6.75 (d, J = 8.8 Hz, 1H), 6.27 (br, 1H), 3.95-3.81 (m, 2H), 3.76 (q, J = 6.1 Hz, 1H), 3.62 (s, 1H), 3.53-3.38 (m, 3H), 2.55-2.51 (m, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.54 (d, J = 8.4 Hz, 1H), 1.21 (d, J = 6.2 Hz, 3H). (Compound 52-2)

[0695] Example 53: 2-(6-(6-((6-(5-cyclopropoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 30)

[0696]

[0697] Step 1: Preparation of tert-butyl 3-cyclopropoxy-1H-pyrazole-1-carboxylic acid (compound 30b)

[0698] Compounds 27b (300 mg), 30a (141.89 mg), and triphenylphosphine (640.09 mg) were added to toluene (10 mL) and cooled to 0 °C. DIAD (493.51 mg) was added dropwise, and the mixture was heated to 110 °C for 6 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 23:77) to give compound 30b (60 mg).

[0699] Step 2: Preparation of 3-cyclopropoxy-1H-pyrazole (compound 30c)

[0700] Compound 30b (102 mg) was added to a mixed solution of 1,4-dioxane hydrogen chloride (4 N, 2 mL) and THF (2 mL), and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to give the hydrochloride salt of compound 30c (73 mg). MS m / z (ESI): 125.1 [M+H] + Step 3: Preparation of 2-(5-cyclopropoxy-1H-pyrazole-1-yl)-5-(1,3-dioxolane-2-yl)pyridine (compound 30d)

[0701] Compound 30c hydrochloride (69.81 mg), compound 121a (100 mg), N,N'-dimethylethylenediamine (38.32 mg), cesium carbonate (424.87 mg), and CuI (82.78 mg) were sequentially added to DMF (10 mL), and the mixture was heated to 110 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with DCM (50 mL x 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Prep-HPLC to obtain compound 30d (80 mg). MS m / z (ESI): 273.9 [M+H] + .

[0702] Step 4: Preparation of 6-(5-cyclopropoxy-1H-pyrazol-1-yl)nicotinaldehyde (compound 30e)

[0703] Compound 30d (80 mg) was added to a mixture of 1,4-dioxane (4 N, 3 mL) and EA (2 mL) solution of hydrogen chloride, and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and diluted with DCM (30 mL). The solution was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 30e (55 mg). MS m / z (ESI): 229.9 [M+H] + Step 5: Preparation of 2-(6-(6-((6-(5-cyclopropoxy-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine (compound 30)

[0704] Compound 30e (40 mg), 1 g (40 mg), and tetraisopropyl titanate (26.01 mg) were placed in a 5 mL reaction flask, and dry THF (2 mL) was added. The mixture was heated to 75 °C and stirred for 16 h. Then, sodium triacetoxyborohydride (26.01 mg) was added, and the mixture was stirred at 75 °C for 8 h. The reaction mixture was cooled to room temperature, and the reaction was quenched by adding 0.1 mL of saturated ammonium chloride aqueous solution. The reaction mixture was concentrated and pre-purified by preparative TLC (DCM:MeOH = 10:1) to give 25 mg (R) of crude product. f =0.35-0.45), and then purified by Prep-HPLC to obtain compound 30 (10 mg). MS m / z (ESI): 575.9 [M+H] + .

[0705] 1 H NMR (400MHz, DMSO-d6) δ11.95 (s, 1H), 9.62 (s, 1H), 9.12 (d, J = 2.3Hz, 1H), 8.46-8.41 (m, 2H), 8 .34(d,J=2.2Hz,1H),7.92(dd,J=8.4,2.2Hz,1H),7.67(d,J=8.4Hz,1H),6.78(d,J=9.0Hz,2H), 6.29(s,1H),6.17(d,J=2.7Hz,1H),4.10(tt,J=6.0,3.2Hz,1H),3.84-3.68(m,4H),3.66-3.48 (m,4H),2.60-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H),0.79-0.68(m,4H).

[0706] Example 54: 2-(6-(6-((6-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 31)

[0707]

[0708] Step 1: Preparation of methyl 1-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)-1H-pyrazole-3-carboxylic acid (compound 31b)

[0709] Compounds 121a (2.0 g), 31a (1.12 g), Cs₂CO₃ (5.72 g), trans-N,N'-dimethylcyclohexanediamine (504.72 mg), CuI (337.89 mg), and DMF (10 mL) were added to a reaction flask, and the mixture was heated to 90 °C for 2 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with EA (30 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 20:80) to give compound 31b (2.2 g). MS m / z (ESI): 276.0 [M+H] + .

[0710] Step 2: Preparation of (1-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)-1H-pyrazol-3-yl)methanol (compound 31c)

[0711] Compound 31b (2.2 g) was dissolved in THF (20 mL) and cooled to -20 °C. LiAlH4 (464.31 mg) was slowly added in portions to the reaction mixture, and the reaction was maintained at this temperature for 15 min. After the reaction was complete, EA (1 mL) was slowly added dropwise to consume excess LiAlH4. The reaction was then quenched by adding water (1 mL), diluted with water (20 mL), and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 50:50) to obtain compound 31c (1.24 g). MS m / z (ESI): 248.0 [M+H] + .

[0712] Step 3: Preparation of 5-(1,3-dioxolane-2-yl)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyridine (compound 31d)

[0713] Under nitrogen protection, 20 mL of dried DCM was cooled to -40 °C, and then 2.86 g of bis(2-methoxyethyl)aminosulfur trifluoride was slowly added dropwise. A 20 mL solution of 0.8 g of compound 31c in DCM was added dropwise to the reaction mixture, and the reaction mixture was then slowly heated to 25 °C and reacted for 20 h. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution. After the bubbles were released, the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 20:80) to obtain compound 31d (200 mg). MS m / z (ESI): 249.9 [M+H] + .

[0714] Step 4: Preparation of 6-(3-(fluoromethyl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 31e)

[0715] Compound 31d (200 mg) was dissolved in THF (5 mL), and hydrochloric acid (2 N, 2.3 mL) was added to the solution. The reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was diluted with water (20 mL), and the pH was adjusted to 7-8 with saturated NaHCO3 aqueous solution. The solution was directly concentrated and purified by silica gel rapid column chromatography (EA:PE = 15:85) to obtain compound 31e (110 mg). MS m / z (ESI): 206.0 [M+H] + .

[0716] Step 5: Preparation of 2-(6-(6-((6-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 31)

[0717] 1 g (87 mg) of compound 31e (110 mg) and tetraisopropyl titanate (278.46 mg) were dissolved in 10 mL of dry THF and heated to 75 °C for 8 h. The reaction solution was cooled to 25 °C, sodium triacetoxyborohydride (259.57 mg) was added to the reaction flask, and the reaction was maintained at 25 °C for 12 h. The reaction was quenched by adding 1 mL of water, concentrated, and pre-purified by silica gel column chromatography (DCM:MeOH = 90:10), followed by Prep-HPLC purification to obtain compound 31 (25 mg). MS m / z (ESI): 551.8 [M+H] + .

[0718] 1H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 9.13 (d, J = 2.0Hz, 1H), 8.62 (d, J = 2.4Hz, 1H), 8. 49-8.39(m,2H),8.15(s,1H),7.99(dd,J=8.4,1.6Hz,1H),7.90-7.84(m,1H),7.07-6. 74(m,2H),6.70(s,1H),6.30(br,1H),5.53(s,1H),5.41(s,1H),3.81-3.73(m,4H),3 .67-3.58(m,4H),2.63-2.53(m,1H),2.34(s,3H),2.26(s,3H),1.61(d,J=8.4Hz,1H).

[0719] Example 55: 2-(6-(6-((6-(5-ethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 46)

[0720]

[0721] Step 1: Preparation of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 46a)

[0722] Compound 86a (2 g) was added to 3,4-dihydropyran (6 mL), followed by TFA (334.97 mg), and the mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 60:1–10:1) to obtain compound 46a (2.4 g). MS m / z (ESI): 153.2 [M+H] + .

[0723] Step 2: Preparation of 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 46b)

[0724] Compound 46a (2 g) was added to dry THF (30 mL), followed by the addition of n-butyllithium (2.5 M, 6.31 mL) at -78 °C and stirring for 1 h. Iodoethane (3.07 g) was then slowly added at -78 °C, and the mixture was slowly heated to room temperature and stirred for 5 h. The reaction was quenched with methanol (50 mL), directly mixed with silica gel, and purified by column chromatography (PE:EA = 40:1–5:1) to obtain compound 46b (721 mg). MS m / z (ESI): 181.0 [M+H] + .

[0725] Step 3: Preparation of 5-ethyl-1H-pyrazole (compound 46c)

[0726] Compound 46b (721 mg) was added to MeOH (7 mL), followed by a 1,4-dioxane solution of hydrogen chloride (4 N, 1 mL), and stirred at 25 °C for 1 h. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution (50 mL) and extracted with EA (80 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to obtain compound 46c (185 mg). MS m / z (ESI): 97.1 [M+H] + .

[0727] Step 4: Preparation of 5-(1,3-dioxolane-2-yl)-2-(5-ethyl-1H-pyrazol-1-yl)pyridine (compound 46d)

[0728] Compounds 121a (401 mg) and 46c (184.31 mg) were added to DMF (15 mL), followed by N,N-dimethylethylenediamine (153.39 mg), cesium carbonate (1.7 g), and CuI (331.96 mg) in sequence. The mixture was heated to 110 °C and stirred for 10 h under nitrogen protection. The reaction was quenched with water (100 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 40:1–3:1) to obtain compound 46d (199 mg). MS m / z (ESI): 245.9 [M+H] + .

[0729] Step 5: Preparation of 6-(5-ethyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 46e)

[0730] Compound 46d (200 mg) was added to THF (4 mL) and H₂O (2 mL), followed by a 1,4-dioxane solution of hydrogen chloride (4 N, 1 mL) and stirring at 25 °C for 5 h. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (50 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 40:1–3:1) to obtain compound 46c (91 mg). MS m / z (ESI): 202.1 [M+H] + .

[0731] Step 6: Preparation of 2-(6-(6-((6-(5-ethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 46)

[0732] 1 g (40.93 mg) of compound 46, 25 mg of 46e, and tetraisopropyl titanate (128.41 mg) were added to 10 mL of dry THF. After purging with nitrogen three times, the mixture was stirred at 75 °C for 10 h. Then, sodium triacetoxyborohydride (119.69 mg) was added in portions, and the mixture was stirred at 75 °C for another 6 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 46 (8 mg). MS m / z (ESI): 547.9 [M+H] + .

[0733] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.65(s,1H),9.12(d,J=2.0Hz,1H),8.47(d,J=2.4Hz,1H),8.44 (dd,J=9.20,2.4Hz,1H),8.36(d,J=1.6Hz,1H),7.93(dd,J=8.4,2.0Hz,1H),7.81(d,J=8.4Hz,1H),7. 20-6.69(m,2H),6.40(d,J=2.8Hz,1H),6.32(s,1H),3.83-3.68(m,4H),3.66-3.53(m,4H),2.66(q,J= 7.6Hz,2H),2.61-2.53(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.4Hz,1H),1.23(t,J=7.6Hz,3H).

[0734] Example 56: 2-(6-(6-((6-(4-fluoro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 122)

[0735]

[0736] Step 1: Preparation of 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 122a)

[0737] Compound 91a (500 mg) was added to 3,4-dihydropyran (2.5 mL), followed by TFA (129.96 mg), and the mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 50:1–10:1) to obtain compound 122a (901 mg). MS m / z (ESI): 171.1 [M+H] + .

[0738] Step 2: Preparation of 4-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 122b)

[0739] Compound 122a (900 mg) was added to 10 mL of dry THF, followed by the addition of 2.33 mL of 2.5 M butyllithium at -78 °C and stirring for 1 h. Iodomethane (1.13 g) was then slowly added at -78 °C, and the mixture was slowly heated to room temperature and stirred for 3 h. The reaction was quenched with methanol and extracted with EA (80 x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 60:1–10:1) to obtain compound 122b (845 mg) as a pale yellow liquid. MS m / z (ESI): 185.0 [M+H] + .

[0740] Step 3: Preparation of 4-fluoro-5-methyl-1H-pyrazole (compound 122c)

[0741] Compound 122b (800 mg) was added to MeOH (7 mL), followed by a 1,4-dioxane solution of hydrogen chloride (4 N, 7 mL), and stirred at 25 °C for 1 h. The reaction was quenched by adding a saturated sodium bicarbonate aqueous solution (50 mL), and extracted with EA (80 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 122c (300 mg). MS m / z (ESI): 101.2 [M+H] + .

[0742] Step 4: Preparation of 5-(1,3-dioxolane-2-yl)-2-(4-fluoro-5-methyl-1H-pyrazol-1-yl)pyridine (compound 122d)

[0743] Compounds 121a (300 mg) and 122c (143.58 mg) were added to DMF (15 mL), followed by N,N-dimethylethylenediamine (114.75 mg), cesium carbonate (1.27 g), and CuI (248.35 mg) in sequence. The mixture was heated to 110 °C and stirred for 10 h under nitrogen protection. The reaction was quenched with water (100 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 50:1–10:1) to obtain compound 122d (254 mg). MS m / z (ESI): 249.9 [M+H] + .

[0744] Step 5: Preparation of 6-(4-fluoro-5-methyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 122e)

[0745] Compound 122d (240 mg) was added to THF (5 mL) and H₂O (2 mL), followed by a solution of 1,4-dioxane hydrogen chloride (4 N, 991.74 μL), and stirred at 25 °C for 5 h. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (50 mL) and extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 122e (55 mg). MS m / z (ESI): 205.9 [M+H] + .

[0746] Step 6: Preparation of 2-(6-(6-((6-(4-fluoro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 122)

[0747] 1 g (101 mg) of compound 122e (51.98 mg) and tetraisopropyl titanate (288.01 mg) were added to 25 mL of dry THF. After purging with nitrogen three times, the mixture was stirred at 75 °C for 10 h. Then, sodium triacetoxyborohydride (268.46 mg) was added in portions, and the mixture was stirred at 75 °C for another 6 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 122e (22 mg). MS m / z (ESI): 551.8 [M+H] + .

[0748] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),9.65(s,1H),9.13(d,J=4.0Hz,1H),8.57(d,J= 4.8Hz,1H),8.44(dd,J=8.8,2.0Hz,1H),8.37(s,1H),7.94(dd,J=8.4,1.6Hz,1H),7.8 0(d,J=8.4Hz,1H),6.97-6.74(m,2H),6.31(s,1H),3.81-3.69(m,4H),3.66-3.52(m, 4H),2.59-2.53(m,1H),2.33(s,3H),2.28(s,3H),2.24(s,3H),1.59(d,J=8.4Hz,1H).

[0749] Example 57: 2-(6-(6-((6-(1H-pyrrolo-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 123)

[0750]

[0751] Step 1: Preparation of tert-butyl 2-(5-formylpyridin-2-yl)-1H-pyrrole-1-carboxylic acid (compound 123b)

[0752] Compound 123a (1.13 g), 8c (1.0 g), tetrakis(triphenylphosphine)palladium (310.62 mg), and sodium carbonate (1.71 g) were added to 1,4-dioxane (60 mL) and water (15 mL), and the mixture was heated to 95 °C for 14 h under nitrogen protection. After the reaction was completed, the organic solvent was removed by concentration and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 123b (1.25 g).

[0753] Step 2: Preparation of 2-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)pyridin-2-yl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (compound 123c)

[0754] 1 g (50 mg) of compound 123b (37.57 mg) and tetraisopropyl titanate (156.84 mg) were added to 5 mL of dry THF and stirred at 72 °C for 18 h. Then, sodium triacetoxyborohydride (146.19 mg) was added, and the reaction was carried out at 72 °C for 4 h. After the reaction was complete, the mixture was purified by direct silica gel column chromatography (DCM:MeOH = 93:7) to give compound 123c (40 mg). MS m / z (ESI): 618.9 [M+H] + .

[0755] Step 3: Preparation of 2-(6-(6-((6-(1H-pyrrolo-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 123)

[0756] A 1,4-dioxane solution of hydrogen chloride (4N, 2.0 mL) was added dropwise to a methanol solution (2 mL) of compound 123c (40 mg), and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated to dryness. The crude product was dissolved in methanol, excess potassium carbonate was added, and the mixture was stirred at room temperature for 0.5 h to release the hydrochloride salt. After filtration and concentration under reduced pressure, the product was purified by Prep-HPLC to obtain compound 123 (22 mg). MS m / z (ESI): 518.9 [M+H] + .

[0757] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),11.43(s,1H),9.66(s,1H),9.12(d,J=2.1 Hz,1H),8.49-8.35(m,2H),7.70(d,J=7.9Hz,1H),7.61(d,J=8.2Hz,1H),6.93-6 .59(m,4H),6.31(s,1H),6.12(dd,J=5.7,2.5Hz,1H),3.85-3.68(m,4H),3.65-3 .49(m,4H),2.59-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.2Hz,1H).

[0758] Example 58: 2-(6-(6-((6-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 124)

[0759]

[0760] Step 1: Preparation of 4-fluoro-3-iodo-1H-pyrazole (compound 124a)

[0761] 4-Fluoropyrazole (1.5 g), NIS (4.31 g), and chloroform (30 mL) were added sequentially to the reaction flask, and the mixture was stirred at 80 °C for 7 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, directly mixed with silica gel, and purified by rapid silica gel column chromatography (PE:EA = 4:1) to obtain compound 124a (1.2 g). MS m / z (ESI): 213 [M+H] + .

[0762] Step 2: Preparation of 5-(1,3-dioxolane-2-yl)-2-(4-fluoro-3-iodo-1H-pyrazol-1-yl)pyridine (compound 124b)

[0763] Compounds 121a (576.33 mg), 124a (354 mg), cesium carbonate (1.63 g), and DMF (15 mL) were added sequentially to the reaction flask, and the mixture was stirred at 90 °C for 12 h. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with EA. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to C244-distillation. 18Column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 68:32) yielded compound 124b (300 mg). MS m / z (ESI): 362 [M+H] + .

[0764] Step 3: Preparation of 2-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)-5-(1,3-dioxolane-2-yl)pyridine (compound 124c)

[0765] Cyclopropylboronic acid (89.20 mg), compound 124b (125 mg), palladium acetate (15.54 mg), potassium phosphate (257.17 mg), tricyclohexylphosphine (9.71 mg), toluene (5 mL), and water (1 mL) were added sequentially to the reaction flask, and the mixture was stirred at 90 °C for 12 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, directly mixed with silica gel, and purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 124c (70 mg). MS m / z (ESI): 276 [M+H] + .

[0766] Step 4: Preparation of 6-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)nicotinaldehyde (compound 124d)

[0767] Compound 124c (70 mg) was dissolved in a mixed solution of THF (8 mL) and water (8 mL), and concentrated hydrochloric acid (5 mL, 37%) was added dropwise. The mixture was stirred at 25 °C for 18 h. After the reaction was complete, a portion of the solvent was evaporated, and the pH of the reaction solution was adjusted to approximately 9 with a saturated sodium bicarbonate aqueous solution, followed by extraction with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel rapid column chromatography (PE:EA = 3:1) to obtain compound 124d (18 mg). MS m / z (ESI): 232 [M+H] + .

[0768] Step 5: Preparation of 2-(6-(6-((6-(3-cyclopropyl-4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 124)

[0769] Compound 124d (18 mg), 1 g (31.04 mg), isopropyl titanate (88.50 mg), and dry THF (5 mL) were added sequentially to a reaction flask, and the mixture was stirred at 75 °C for 18 h under nitrogen protection. Then, sodium triacetoxyborohydride (82.49 mg) was added in portions, and the mixture was stirred at 75 °C for another 6 h. After the reaction was complete, a portion of the solvent was evaporated, the pH of the reaction solution was adjusted to approximately 9 with saturated sodium bicarbonate solution, and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and pre-purified by preparative TLC (DCM:MeOH = 9:1), followed by Prep-HPLC purification to obtain compound 124 (15 mg). MS m / z (ESI): 577.9 [M+H] + .

[0770] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.65(s,1H),9.12(d,J=2.1Hz,1H),8.55(d,J=4.6Hz,1H),8.44( dd,J=8.9,2.2Hz,1H),8.35(d,J=1.5Hz,1H),7.93(dd,J=8.5,2.0Hz,1H),7.76(d,J=8.5Hz,1H),6.82(b r,1H),6.79(d,J=12Hz,1H),6.30(br,1H),3.84-3.75(m,4H),3.73-3.49(m,4H),2.59-2.53(m,1H),2. 33(s,3H),2.26(s,3H),2.02-1.93(m,1H),1.59(d,J=8.4Hz,1H),1.03-0.95(m,2H),0.94-0.86(m,2H).

[0771] Example 59: 2-(6-(6-((R)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((S)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 125-1 / Compound 125-2)

[0772]

[0773] Step 1: Preparation of 1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)acetone (compound 125b)

[0774] Compounds 86a (328.18 mg), 125a (500 mg), and cesium carbonate (1.57 g) were sequentially added to DMSO (5 mL), and the mixture was heated to 100 °C and stirred for 2 h. The reaction solution was cooled to room temperature, diluted with water, and extracted with EA. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 50:50) to give compound 125b (364 mg). MS m / z (ESI): 188.1 [M+H] + .

[0775] Step 2: Preparation of 2-(6-(6-(1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine (compound 125)

[0776] Compound 125b (309.90 mg), 1 g (400 mg), and tetraisopropyl titanate (1.25 g) were placed in a 250 mL reaction flask, and 20 mL of dry THF was added. The mixture was heated to 75 °C and stirred for 16 h. Then, sodium triacetoxyborohydride (1.17 g) was added, and the mixture was stirred at 75 °C for 2 h. The reaction mixture was cooled to room temperature, and the reaction was quenched by adding 3 mL of saturated ammonium chloride aqueous solution. The reaction mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH = 9:1) to give compound 125 (270 mg). MS m / z (ESI): 533.9 [M+H] + .

[0777] Step 3: Preparation of 2-(6-(6-((R)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 2-(6-(6-((S)-1-(6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 125-1 / compound 125-2)

[0778] Compound 125 (250 mg) was resolved by chiral Prep-HPLC to yield compound 125-1 (retention time 7.647 min) and compound 125-2 (retention time 11.638 min). The two compounds were distinguished based on the order of their chiral resolution retention times; stereostructural identification was not performed. Compound 125-1 (101 mg, ee: 100%) was thus obtained, MS m / z (ESI): 533.9 [M+H]. + Compound 125-2 (100 mg, ee: 99.93%), MS m / z (ESI): 533.9 [M+H] + .

[0779] Chiral HPLC separation conditions:

[0780] Instrument model: Shimadzu LC-20AD; Column: CHIRALPAK IE-3 (IE30CD-UL006), 0.46cm I.D. × 15cm L; Column temperature: 25℃; Flow rate: 1.0mL / min; Detection wavelength: 254nm; Mobile phase: MeOH:ACN:DEA=70:30:0.1(V / V / V); Elution time of compound 125-1 was 7.647min, and that of compound 125-2 was 11.638min.

[0781] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.3Hz,1H),8.59(s,1H),8.47-8.3 9(m,2H),7.99(d,J=6.4Hz,1H),7.89(d,J=7.4Hz,1H),7.81(s,1H),6.75(d,J=9.0Hz,2H),6.56(s ,1H), 6.31(s,1H), 3.96-3.83(m,2H), 3.75(d,J=3.3Hz,1H), 3.63(s,1H), 3.54-3.36(m,3H), 2.57-2.53(m,1H), 2.33(s,3H), 2.25(s,3H), 1.54(d,J=6.9Hz,1H), 1.22(d,J=2.5Hz,3H). (Compound 125-1)

[0782] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.3Hz,1H),8.59(d,J=2.6Hz,1H),8.47-8.3 9(m,2H),8.00(dd,J=8.5,2.2Hz,1H),7.90(d,J=8.4Hz,1H),7.81(d,J=1.6Hz,1H),6.75(d,J=9.0Hz,2H), 6.57 (t, J = 2.1 Hz, 1H), 6.31 (s, 1H), 3.96–3.83 (m, 2H), 3.76 (q, J = 6.2 Hz, 1H), 3.63 (s, 1H), 3.54–3.36 (m, 3H), 2.57–2.53 (m, 1H), 2.33 (s, 3H), 2.25 (s, 3H), 1.55 (d, J = 8.4 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H). (Compound 125-2)

[0783] Example 60: 2-(6-(6-((6-(4-fluoromethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 126) and (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)methanol (compound 127)

[0784]

[0785] Step 1: Preparation of ethyl 1-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (compound 126b)

[0786] Compounds 121a (3.0 g), 126a (1.86 g), Cs₂CO₃ (8.67 g), trans-N,N'-dimethylcyclohexanediamine (757.08 mg), CuI (506.84 mg), and DMF (15 mL) were added to a reaction flask and heated to 90 °C for 2 h under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (30 mL x 3). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 20:80) to give compound 126b (3.31 g). MS m / z (ESI): 290.0 [M+H] + .

[0787] Step 2: Preparation of 1-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)-1H-pyrazol-4-yl)methanol (compound 126c)

[0788] Compound 126b (3.31 g) was dissolved in THF (30 mL) and cooled to -20 °C. LiAlH4 (651.40 mg, 16.99 mmol) was slowly added in portions to the reaction solution, and the reaction was maintained at this temperature for 15 min. After the reaction was complete, EA (2 mL) was slowly added dropwise to consume excess LiAlH4. The reaction was then quenched by adding water (1 mL), diluted with water (20 mL), and extracted with EA (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 50:50) to obtain compound 126c (2.30 g). MS m / z (ESI): 248.0 [M+H] + .

[0789] Step 3: Preparation of 5-(1,3-dioxolane-2-yl)-2-(4-(fluoromethyl)-1H-pyrazol-1-yl)pyridine (compound 126d)

[0790] Under nitrogen protection, 30 mL of dried DCM was cooled to -40 °C, and then 6.06 g of diethylaminotrifluoride was slowly added dropwise. A 30 mL solution of DCM containing 2.30 g of compound 126c was added dropwise to the reaction mixture, and the reaction mixture was then slowly heated to 25 °C and reacted for 20 h. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution. After the bubbles were released, it was extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (EA:PE = 20:80) to obtain compound 126d (684 mg). MS m / z (ESI): 249.9 [M+H]+ .

[0791] Step 4: Preparation of 6-(4-(fluoromethyl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 126e)

[0792] Compound 126d (684 mg) was dissolved in THF (10 mL), and hydrochloric acid (1 N, 5 mL) was added to the solution. The reaction was carried out at 25 °C for 16 h. After the reaction was completed, water (20 mL) was added to dilute the reaction solution, and the pH was adjusted to 7-8 with saturated NaHCO3 aqueous solution. THF was removed by direct concentration, followed by extraction with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 126e (460 mg). MS m / z (ESI): 206.0 [M+H] + .

[0793] Step 5: Preparation of 2-(6-(6-((6-(4-fluoromethyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 126) and (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)methanol (compound 127)

[0794] 1 g (200 mg) of compound 126, 182 mg of 126e, and 640 mg of tetraisopropyl titanate were dissolved in 40 mL of dry THF and heated to 75 °C for 8 h. The reaction solution was cooled to 25 °C, and 597 mg of sodium triacetoxyborohydride was added to the reaction flask. The reaction was maintained at 25 °C for 12 h. The reaction was quenched by adding 1 mL of water, concentrated, and pre-purified by silica gel column chromatography (DCM:MeOH = 90:10) to obtain the crude product (a mixture of compounds 126 and 127). This crude product was then purified by Prep-HPLC to obtain compound 126 (21 mg), MS m / z (ESI): 552.3 [M+H]. + Compound 127 (19 mg), MS m / z (ESI): 550.3 [M+H] + .

[0795] 1H NMR (400MHz, DMSO-d6) δ12.00(br,1H),9.65(s,1H),9.13(d,J=2.2Hz,1H),8.77(d,J=3.2H z,1H),8.44(dd,J=8.8,2.2Hz,2H),7.99(dd,J=8.4,2.0Hz,1H),7.94(s,1H),7.91-7.96(m ,1H), 6.95-6.69(m,2H), 6.30(br,1H), 5.46(s,1H), 5.34(s,1H), 3.82-3.70(m,4H), 3.68-3.52(m,4H), 2.59-2.54(m,1H), 2.33(s,3H), 2.26(s,3H), 1.60(d,J=8.4Hz,1H).(Compound 126)

[0796] 1 H NMR(400MHz,DMSO-d6)δ12.04(br,1H),9.66(s,1H),9.13(d,J=2.2Hz,1H),8.52-8 .35(m,3H),7.95(dd,J=8.4,1.6Hz,1H),7.88-7.81(m,1H),7.73(s,1H),6.99-6.64 (m, 2H), 6.31 (br, 1H), 5.05 (br, 1H), 4.45 (s, 2H), 3.93–3.70 (m, 4H), 3.67–3.51 (m, 4H), 2.59–2.53 (m, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.60 (d, J = 8.4 Hz, 1H). (Compound 127)

[0797] Example 61: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(1-methyl-1H-pyrrolo-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 128)

[0798]

[0799] Step 1: Preparation of 6-(1H-pyrrolo-2-yl)nicotinaldehyde (compound 128a)

[0800] A 1,4-dioxane solution of hydrogen chloride (4N, 6.0 mL) was added dropwise to a methanol solution (10 mL) of compound 123b (500 mg), and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated to dryness. The crude product was dissolved in methanol, excess potassium carbonate was added, and the mixture was stirred at room temperature for 0.5 h to release the hydrochloride salt. After filtration and concentration under reduced pressure, the product was purified by silica gel column chromatography (PE:EA = 4:1) to give compound 128a (250 mg). MS m / z (ESI): 173.0 [M+H] + .

[0801] Step 2: Preparation of 5-(1,3-dioxolane-2-yl)-2-(1H-pyrrolo-2-yl)pyridine (compound 128b)

[0802] Compound 128a (250 mg), ethylene glycol (180 mg), and p-toluenesulfonic acid (27.6 mg) were added to toluene (15 mL), and the mixture was refluxed to remove water for 18 h. After the reaction was complete, the reaction solution was diluted with EA and washed with saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 128b (290 mg). MS m / z (ESI): 217.0 [M+H] + .

[0803] Step 3: Preparation of 5-(1,3-dioxolane-2-yl)-2-(1-methyl-1H-pyrrolo-2-yl)pyridine (compound 128c)

[0804] Compound 128b (250 mg) was dissolved in 5 mL of dry DMF. NaH (138.7 mg, 60% purity) was added at 0 °C under nitrogen protection, and the mixture was stirred for 15 min. Iodomethane (820 mg) was then added, and the reaction was carried out at room temperature for 5 h. After the reaction was complete, the reaction solution was poured into saturated brine, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 128c (125 mg). MS m / z (ESI): 231.0 [M+H] + .

[0805] Step 4: Preparation of 6-(1-methyl-1H-pyrrole-2-yl)nicotinaldehyde (compound 128d)

[0806] Dilute hydrochloric acid (2N, 2.0 mL) was added dropwise to a THF (4.0 mL) solution of compound 128c (110 mg) and reacted at room temperature for 3 h. After the reaction was complete, the reaction solution was concentrated to dryness. The crude product was dissolved in methanol, excess potassium carbonate was added, and the mixture was stirred at room temperature for 0.5 h to release the hydrochloride salt. After filtration, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 128d (75 mg). Step 5: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(1-methyl-1H-pyrrolo-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (compound 128)

[0807] Compound 1 g (40 mg), 128d (25 mg), and tetraisopropyl titanate (125 mg) were added to dry THF (5 mL) and stirred at 72 °C for 10 h. Then, sodium triacetoxyborohydride (117 mg) was added, and the reaction was carried out at 72 °C for 6 h. After the reaction was complete, the mixture was pre-purified by silica gel column chromatography (DCM:MeOH = 93:7), followed by Prep-HPLC purification to obtain compound 128 (34 mg). MS m / z (ESI): 532.9 [M+H] + .

[0808] 1 H NMR(400MHz,CD3OD)δ9.14(d,J=2.1Hz,1H),8.59-8.43(m,2H),7.78(dd,J=8.2,2.2 Hz,1H),7.55(d,J=8.2Hz,1H),6.85(d,J=9.0Hz,1H),6.81-6.65(m,2H),6.50(dd,J= 3.7,1.8Hz,1H),6.35(s,1H),6.10(dd,J=3.7,2.7Hz,1H),4.02-3.77(m,7H),3.77- 3.59(m,4H),2.73(d,J=6.3Hz,1H),2.41(s,3H),2.32(s,3H),1.71(d,J=8.8Hz,1H).

[0809] Example 62: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(thiazol-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 129)

[0810]

[0811] Step 1: Preparation of 4-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)thiazole (compound 129b)

[0812] Compounds 129a (325 mg), 121a (200 mg), and tetra(triphenylphosphine-palladium) (50 mg) were added to toluene (10 mL) and reacted at 120 °C for 6 h. After the reaction was complete, the reaction solution was concentrated to dryness and purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 129b (115 mg). MS m / z (ESI): 235.1 [M+H] + .

[0813] Step 2: Preparation of 6-(thiazol-4-yl)nicotinaldehyde (compound 129c)

[0814] Dilute hydrochloric acid (2.0 mL, 3N) was added dropwise to a THF (3.0 mL) solution of compound 129b (115 mg), and the reaction was carried out at room temperature for 15 h. After the reaction was complete, saturated sodium bicarbonate solution was slowly added dropwise to adjust the pH of the solution to approximately 10, and then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 129c (83 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 191.1 [M+H] + .

[0815] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(thiazo-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (compound 129)

[0816] 1 g (50 mg) of compound 129, 26.2 mg of 129, and tetraisopropyl titanate (156.8 mg) were added to 5 mL of dry THF and reacted with stirring at 72 °C for 10 h. Then, sodium triacetoxyborohydride (146.2 mg) was added and the reaction was continued at 72 °C for 6 h. After the reaction was complete, the mixture was crudely purified by direct silica gel column chromatography (DCM:MeOH = 8:1), followed by Prep-HPLC purification to obtain compound 129 (51 mg). MS m / z (ESI): 537.3 [M+H] + .

[0817] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.66(s,1H),9.22(d,J=2.1Hz,1H),9.13(d,J= 2.1Hz,1H),8.58(d,J=1.6Hz,1H),8.44(dd,J=8.9,2.3Hz,1H),8.29(d,J=2.0Hz,1H), 8.06(d,J=8.0Hz,1H),7.88(dd,J=8.1,2.2Hz,1H),7.01–6.64(m,2H),6.33(s,1H),3 .87–3.49(m,8H),2.61–2.54(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0818] Example 63: 2-(6-(6-([[2,2'-bipyridine]-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 130)

[0819]

[0820] Step 1: Preparation of 5-(1,3-dioxolane-2-yl)-2,2'-bipyridine (compound 130b)

[0821] Compounds 130a (320 mg), 121a (200 mg), and tetra(triphenylphosphine)palladium (50 mg) were added to toluene (10 mL) and reacted by microwave at 120 °C for 4 h. After the reaction was complete, the reaction solution was concentrated to dryness and purified by silica gel column chromatography (PE:EA = 2:1) to obtain compound 130b (100 mg). MS m / z (ESI): 229.1 [M+H] + .

[0822] Step 2: Preparation of [2,2'-bipyridine]-5-carboxaldehyde (compound 130c)

[0823] Dilute hydrochloric acid (5.0 mL, 3N) was added dropwise to a THF (5.0 mL) solution of compound 130b (100 mg), and the reaction was carried out at room temperature for 15 h. After the reaction was complete, saturated sodium bicarbonate solution was slowly added dropwise to adjust the pH of the solution to approximately 10, and then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 130c (45 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 185.2 [M+H] + .

[0824] Step 3: Preparation of 2-(6-(6-([[2,2'-bipyridinyl]-5-ylmethyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 130)

[0825] 1 g (50 mg) of compound 130, 25.4 mg of 130, and tetraisopropyl titanate (156.8 mg) were added to 5 mL of dry THF and reacted with stirring at 72 °C for 10 h. Then, sodium triacetoxyborohydride (146.2 mg) was added and the reaction was continued at 72 °C for 6 h. After the reaction was complete, the mixture was crudely purified by direct silica gel column chromatography (DCM:MeOH = 10:1), followed by Prep-HPLC purification to obtain compound 130 (40 mg). MS m / z (ESI): 531.3 [M+H] + .

[0826] 1 H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.65(s,1H),9.13(d,J=2.2Hz,1H),8.75–8.57 (m,2H),8.44(dd,J=8.9,2.3Hz,1H),8.35(dd,J=9.7,8.2Hz,2H),7.93(ddd,J=8.3,5 .9,1.9Hz,2H),7.44(ddd,J=7.5,4.8,1.1Hz,1H),7.08–6.57(m,2H),6.31(s,1H),3. 82–3.57(m,8H),2.63–2.56(m,1H),2.33(s,3H),2.26(s,3H),1.61(d,J=8.4Hz,1H).

[0827] Example 64: 2-(6-(6-((6-(5-fluoro-1H-pyrrolo-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 131)

[0828]

[0829] Step 1: Preparation of 6-(5-fluoro-1H-pyrrole-2-yl)nicotinaldehyde (compound 131a)

[0830] Compound 128a (200 mg) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (432 mg, selective fluorine reagent) were added to acetonitrile (15 mL) and reacted by microwave at 70 °C for 10 min. After the reaction was complete, the reaction solution was concentrated to dryness and purified by silica gel column chromatography (PE:EA = 5:1) to obtain compound 131a (60 mg). MS m / z (ESI): 191.1 [M+H] + .

[0831] Step 2: Preparation of 2-(6-(6-((6-(5-fluoro-1H-pyrrolo-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 131)

[0832] 1 g (50 mg) of compound 131a (26.2 mg) and tetraisopropyl titanate (156.8 mg) were added to 5 mL of dry THF and reacted with stirring at 72 °C for 10 h. Then, sodium triacetoxyborohydride (146.2 mg) was added and reacted at 72 °C for 6 h. After the reaction was completed, the mixture was crudely purified by direct silica gel column chromatography (DCM:MeOH = 8:1), followed by Prep-HPLC purification to obtain compound 131 (9 mg). MS m / z (ESI): 537.3 [M+H] + .

[0833] 1 H NMR (400MHz, DMSO-d6) δ12.06 (s, 1H), 11.98 (s, 1H), 9.65 (s, 1H), 9.12 (d, J = 2.1Hz, 1H), 8.43 (dd, J=8.9,2.3Hz,1H),8.39(d,J=1.3Hz,1H),7.74–7.65(m,1H),7.57(d,J=8.2Hz,1H),6.92–6.72(m, 2H),6.57(t,J=4.2Hz,1H),6.31(s,1H),5.57(t,J=3.8Hz,1H),3.76(d,J=11.2Hz,2H),3.70(d,J= 5.7Hz,2H),3.63-3.52(m,4H),2.60-2.55(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.2Hz,1H).

[0834] Example 65: 2-(6-(6-((6-(1H-pyrazol-5-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 132)

[0835]

[0836] Step 1: Preparation of 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinaldehyde (compound 132b)

[0837] Compound 132a (2.24 g), 8c (1 g), tetrakis(triphenylphosphine)palladium (310.6 mg), and 1,4-dioxane (20 mL) were added sequentially to a reaction flask, followed by a 5 mL solution of sodium carbonate (1.71 g) in water. The mixture was stirred at 95 °C for 5 h under nitrogen protection. After the reaction was complete, the mixture was diluted with water and extracted with EA (20 mL × 3). The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid column chromatography (DCM:MeOH = 96:4) to obtain compound 132b (1.14 g).

[0838] Step 2: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-((6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (compound 132c)

[0839] 1 g (500 mg) of compound 132b (477.8 mg) was dissolved in DMA (10 mL), and the mixture was stirred at 25 °C for 2 h. Then, sodium triacetoxyborohydride (1.17 g) was added, and the mixture was stirred at 25 °C for another 16 h. After the reaction was complete, the mixture was quenched with water and then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 132c (697 mg). MS m / z (ESI): 604.3 [M+H] + .

[0840] Step 3: Preparation of 2-(6-(6-((6-(1H-pyrazol-5-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 132)

[0841] Compound 132c (697 mg) was dissolved in MeOH (15 mL), and then TFA (0.86 mL) was added dropwise. The reaction was carried out at 25 °C for 16 h. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction, and the pH of the solution was adjusted to approximately 9. The methanol was removed by concentration, diluted with water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to obtain compound 132 (279 mg). MS m / z (ESI): 521.3 [M+H] + .

[0842] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.48 (s, 0.3H, tautomer 1), 13.01 (s, 0.7H, tautomer 2), 11.98 (s, 1H), 9.66 (s, 1H), 9.13 (d, J = 2.2Hz, 1H), 8.52 (s, 1H), 8.44 (dd, J = 8.9, 2.3Hz, 1H), 8.01–7.64 (m, 3H), 7.01–6.59 (m, 3H), 6.32 (br, 1H), 3.85–3.68 (m, 4H), 3.68–3.45 (m, 4H), 2.60–2.53 (m, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.60 (d, J = 8.4Hz, 1H).

[0843] Example 66: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(5-methylfuran-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (Compound 133)

[0844]

[0845] Step 1: Preparation of 6-(5-methylfuran-2-yl)nicotinaldehyde (compound 133b)

[0846] Compound 133a (203.1 mg), 8c (200 mg), Na₂CO₃ (341.9 mg), tetrakis(triphenylphosphine)palladium (62.1 mg), water (2.5 mL), and 1,4-dioxane (10 mL) were added sequentially to the reaction flask, and the mixture was stirred at 95 °C for 2 h. After the reaction was complete, the reaction solution was cooled to room temperature and purified directly by silica gel column chromatography (PE:EA = 87:13) to obtain compound 133b (124 mg). MS m / z (ESI): 188.1 [M+H] + .

[0847] Step 2: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(5-methylfuran-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (compound 133)

[0848] Compound 133b (23.2 mg), 1 g (30 mg), and DMA (1 mL) were added sequentially to the reaction flask, and the mixture was stirred at 25 °C for 2 h. Then, sodium triacetoxyborohydride (70.2 mg) was added, and the reaction was continued at 25 °C for 16 h. After the reaction was complete, the reaction solution was purified by Prep-HPLC to obtain compound 133 (9 mg). MS m / z (ESI): 534.3 [M+H] + .

[0849] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.2Hz,1H),8.48(d,J=1.5Hz,1H),8. 44(dd,J=8.9,2.3Hz,1H),7.78(dd,J=8.2,2.1Hz,1H),7.60(d,J=8.1Hz,1H),6.96(d,J=4.5Hz,1H), 6.84(br,1H),6.78(d,J=9.0Hz,1H),6.31(br,1H),6.25(dd,J=3.2,1.0Hz,1H),3.82-3.68(m,4H), 3.68-3.45(m,4H),2.60-2.53(m,1H),2.36(s,3H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0850] Example 67: 6-Methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (Compound 134)

[0851]

[0852] Step 1: Preparation of 2-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)oxazole (compound 134b)

[0853] Compounds 121a (300.0 mg) and 134a (467.0 mg) were dissolved in toluene (15.0 mL), and then tetrakis(triphenylphosphine)palladium (75.3 mg) was added. The mixture was stirred at 120 °C for 12 h under nitrogen protection. The reaction solution was concentrated under reduced pressure and diluted with EA (200.0 mL). The organic phase was washed three times with water, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 7:3) to obtain compound 134b (78.0 mg). MS m / z (ESI): 219.1 [M+1] + .

[0854] Step 2: Preparation of 6-(oxazol-2-yl)nicotinaldehyde (compound 134c)

[0855] Compound 134b (78.0 mg) was dissolved in a mixed solvent of THF (2.0 mL) and water (2.0 mL), and then concentrated hydrochloric acid (1.0 mL, 12 N) was slowly added dropwise while stirring at 25 °C for 8 h. The reaction solution was adjusted to alkalinity with potassium carbonate aqueous solution and extracted with EA (100.0 mL). The organic phase was washed three times with water, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 9:1) to obtain compound 134c (51.0 mg). MS m / z (ESI): 175.1 [M+1] + .

[0856] Step 3: Preparation of 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(oxazol-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine-4-amine (compound 134)

[0857] Compound 134c (28.8 mg) and 1 g (30.0 mg) were dissolved in N,N-dimethylacetamide (1.0 mL) and stirred at 25 °C for 1 h. Then, sodium triacetoxyborohydride (70.2 mg) was added to the reaction mixture, and the mixture was stirred at 25 °C for 12 h. The reaction solution was diluted with EA (20 mL), washed three times with water, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This crude product was purified by Prep-HPLC to give compound 134 (17.0 mg). MS m / z (ESI): 521.3 [M+1] + .

[0858] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),9.68(s,1H),9.14(d,J=2.4Hz,1H),8.66(s,1H) ,8.45(dd,J=9.2,2.4Hz,1H),8.29(s,1H),8.06(d,J=8.4Hz,1H),7.95(d,J=8.0Hz,1H ),7.45(s,1H),6.79(br,1H),6.78(d,J=8.8Hz,1H),6.32(br,1H),3.79-3.75(m,4H), 3.67-3.60(m,4H),2.58-2.56(m,1H),2.34(s,3H),2.26(s,3H),1.61(d,J=8.0Hz,1H).

[0859] Example 68: 2-(6-(6-((6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 135)

[0860]

[0861] Step 1: Preparation of 5-(1,3-dioxolane-2-yl)-2-(1H-pyrazol-4-yl)pyridine (compound 135b)

[0862] Compounds 121a (1.0 g) and 135a (1.0 g) were dissolved in 1,4-dioxane (30 mL) and H₂O (6 mL), followed by the sequential addition of Pd(dppf)Cl₂ (130 mg) and K₂CO₃ (1.5 g). The mixture was stirred at 95 °C for 2 h under nitrogen protection. After the reaction was complete, the mixture was cooled in an ice-water bath and filtered through diatomaceous earth. The filtrate was concentrated to dryness and purified by MPLC to obtain compound 135b (452 ​​mg). MS m / z (ESI): 218.2 [M+H] + .

[0863] MPLC conditions:

[0864] Instrument model: Biotage Isolera Prime 2.3.1; Column: Agela Technologies C18 spherical 20-35um 100A, 120g; Column temperature: 25℃; Flow rate: 30.0mL / min; Detection wavelength: 254nm; Elution gradient: (0min: 20% A, 80% B; 3.0min: 20% A, 80% B; 25min: 90% A, 10% B); Mobile phase A: acetonitrile, Mobile phase B: 0.05% TFA aqueous solution.

[0865] Step 2: Preparation of 5-(1,3-dioxolane-2-yl)-2-(1-isopropyl-1H-pyrazol-4-yl)pyridine (compound 135d)

[0866] Compound 135b (100 mg) and Cs₂CO₃ (374.9 mg) were added to 10 mL of dry DMF, followed by compound 135c (195.6 mg). The mixture was stirred at 80 °C for 12 h. After the reaction was complete, water (100 mL) was added to quench the reaction mixture, and the solution was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain compound 135d (52 mg). MS m / z (ESI): 260.0 [M+H] + .

[0867] Step 3: Preparation of 6-(1-isopropyl-1H-pyrazol-4-yl)nicotinaldehyde (compound 135e)

[0868] Compound 135d (240 mg) was added to THF (4 mL) and H₂O (2 mL), followed by a 1,4-dioxane solution of HCl (4 N, 1 mL) and stirring at 25 °C for 5 h. After the reaction was complete, a saturated sodium bicarbonate aqueous solution (50 mL) was added to quench the reaction mixture, and the mixture was extracted with EA (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give compound 135e (40 mg). MS m / z (ESI): 216.1 [M + H].

[0869] Step 4: Preparation of 2-(6-(6-((6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 135)

[0870] 1 g (40 mg) of compound, 135e (26.1 mg), and tetraisopropyl titanate (31.4 mg) were added to 25 mL of dry THF and stirred at 75 °C for 10 h under nitrogen protection. Then, sodium triacetoxyborohydride (23.4 mg) was added to the reaction system, and stirring was continued at 75 °C for 6 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 135 (2.1 mg). MS m / z (ESI): 562.1 [M+H] + .

[0871] 1 H NMR (400MHz, DMSO-d6) δ11.98 (s, 1H), 9.67 (s, 1H), 9.12 (d, J = 2.0Hz, 1H), 8.56-8.39 (m ,2H),8.32(s,1H),7.97(s,1H),7.71(dd,J=8.0,2.0Hz,1H),7.59(d,J=8.0Hz,1H),7.05 -6.65(m,2H),6.33(s,1H),4.64-4.36(m,1H),3.94-3.63(m,4H),3.64-3.45(m,4H),2. 62-2.50(m,1H),2.31(s,3H),2.29(s,3H),1.56(d,J=8.0Hz,1H),1.45(d,J=6.4Hz,6H).

[0872] Example 69: 2-(1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-5-yl)prop-2-ol (compound 136)

[0873]

[0874] Step 1: Preparation of 2-(1-(5-(1,3-dioxolane-2-yl)pyridin-2-yl)-1H-pyrazol-3-yl)prop-2-ol (compound 136a)

[0875] Compound 31b (200 mg) was added to 10 mL of dry THF and cooled in a dry ice-ethanol bath for 15 min. Then, a solution of magnesium methyl bromide in diethyl ether (3 N, 0.65 mL) was slowly added dropwise, and the reaction was maintained at this temperature for 15 min. The reaction was then allowed to continue at room temperature for 4 h. The reaction was quenched by adding 1 mL of saturated ammonium chloride solution, followed by dilution with 30 mL of water and extraction with EA (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 136a (200 mg). MS m / z (ESI): 276.1 [M+H] + .

[0876] Step 2: Preparation of 6-(3-(2-hydroxypropyl-2-yl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 136b)

[0877] Compound 136a (200 mg) was added to THF (5 mL), followed by hydrochloric acid (2 N, 4.5 mL), and stirred at 25 °C for 12 h. The pH was adjusted to 7-8 by adding saturated sodium bicarbonate solution, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 136b (165 mg). MS m / z (ESI): 232.1 [M+H] + Step 3: Preparation of 2-(1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-5-yl)prop-2-ol (compound 136)

[0878] Compound 136b (50.5 mg) and compound 1 g (30 mg) were added to DMA (3 mL) and stirred at room temperature for 1 h under nitrogen protection. Then, sodium triacetoxyborohydride (101 mg) was added, and the reaction was allowed to continue overnight at room temperature. After the reaction was complete, water (60 mL) was added to quench the reaction mixture, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Pre-HPLC to obtain compound 136 (12 mg). MS m / z (ESI): 578.3 [M+H] + .

[0879] 1H NMR(400MHz,DMSO-d6)δ12.14(br,1H),9.67(s,1H),9.12(d,J=2.0Hz,1H),8.50-8.41 (m,2H),8.41-8.35(m,1H),7.99-7.92(m,1H),7.82(d,J=8.4Hz,1H),6.79(d,J=9.2Hz, 2H),6.52(d,J=2.4Hz,1H),6.31(br,1H),5.10(s,1H),3.82-3.70(m,4H),3.68-3.55(m ,4H),2.61-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H),1.49(s,6H).

[0880] Example 70: (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)methanol (compound 137)

[0881]

[0882] Step 1: Preparation of 6-(3-(hydroxymethyl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 137a)

[0883] Compound 31c (189 mg) was added to THF (5 mL), followed by dilute hydrochloric acid (2 N, 5 mL), and stirred at 25 °C for 2 h. The pH was adjusted to 7-8 by adding saturated sodium bicarbonate solution, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 137a (157 mg). MS m / z (ESI): 204.1 [M+H] + Step 2: Preparation of (1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)methanol (compound 137)

[0884] Compound 137a (50.5 mg) and compound 1 g (50 mg) were added to DMA (2 mL) and stirred at room temperature for 1 h under nitrogen protection. Then, sodium triacetoxyborohydride (159 mg) was added, and the reaction was allowed to continue overnight at room temperature. After the reaction was complete, water (60 mL) was added to quench the reaction mixture, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Pre-HPLC to give compound 137 (10 mg). MS m / z (ESI): 550.3 [M+H] + .

[0885] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),9.68(s,1H),9.13(d,J=2.0Hz,1H),8.52(d,J=2.4Hz,1H),8.44 (dd,J=8.8,2.4Hz,1H),8.38(d,J=2.4Hz,1H),7.94(dd,J=8.4,2.0Hz,1H),7.82(d,J=8.4Hz,1H),7.0 6-6.65(m,2H),6.51(d,J=2.4Hz,1H),6.29(br,1H),5.26(t,J=6.0Hz,1H),4.53(d,J=5.6Hz,2H),3.8 1-3.69(m,4H),3.67-3.49(m,4H),2.59-2.53(m,1H),2.34(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0886] Example 71: 2-(6-(6-((6-(4-fluoro-3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 138)

[0887]

[0888] Compound 138 was prepared according to the synthetic method described in Example 56. MS m / z (ESI): 551.8 [M+H] + .

[0889] Separation method:

[0890] Prep-HPLC purification of compounds in Examples 1-51, 53-58, and 60-71 was performed using an Aglient 1260, Waters 2489, or GeLai 3500 HPLC system. The column temperature was 25°C, and the detection wavelengths were 214 nm, 254 nm, or 280 nm. Other separation conditions are shown in the table below.

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898] The following intermediate compounds in the examples were purified using a GeLai 3500 HPLC system at a column temperature of 25°C and detection wavelengths of 214 nm, 254 nm, or 280 nm. Other separation conditions are shown in the table below.

[0899]

[0900] Biological evaluation

[0901] Experimental Example 1: RET Inhibition Experiment

[0902] Experimental Methods: The inhibitory effects of the compounds of this invention on the activities of wild-type RET enzymes, mutant RET enzymes (RET-V804M, RET-V804L, and RET-M918T), and fusion RET enzyme (RET-CCDC6) were determined according to the instructions of the HTRF KinEASE-TK kit (Cisbio). Different RET enzymes were pre-incubated with different concentrations of the test compounds at room temperature for 30 min, followed by the addition of substrate and adenosine triphosphate (ATP) to initiate the reaction. After incubation at room temperature for 40 min, the TK antibody-caecin compound and antibiotic streptavidin-XL665 were added, and the reaction was incubated at room temperature for 45 min before detection. The solvent group (DMSO) served as a negative control, and the buffer group (containing no RET enzyme) served as a blank control. The relative percentage of inhibitory activity (i.e., inhibition rate) of different concentrations of the compound was calculated using the following formula:

[0903] Relative inhibition percentage = 1 - (different concentrations of compound group - blank control) / (negative control - blank control) * 100%

[0904] The relative inhibitory activity percentage of different compound concentrations was plotted against the compound concentration. The curve was fitted using a four-parameter model, and the IC was calculated using the following formula. 50 value:

[0905] y = min + (max - min) / (1 + (x / IC) 50 )^(-Hillslope))

[0906] Where y is the relative inhibitory activity percentage, max and min are the maximum and minimum values ​​of the fitted curve, respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

[0907] Experiment Example 2: VEGFR2 Inhibition Experiment

[0908] Experimental Methods: The inhibitory effect of the compounds of this invention on VEGFR2 enzyme activity was determined according to the instructions of the HTRF KinEASE-TK kit (Cisbio). VEGFR2 enzyme was pre-incubated with different concentrations of the test compounds at room temperature for 30 min, followed by the addition of substrate and adenosine triphosphate (ATP) to initiate the reaction. After incubation at room temperature for 40 min, TK antibody-caecin compound and antibiotic streptavidin-XL665 were added, and the reaction was incubated at room temperature for 45 min before detection. The solvent group (DMSO) served as a negative control, and the buffer group (containing no VEGFR2 enzyme) served as a blank control. The relative percentage of inhibitory activity (i.e., inhibition rate) of different concentrations of the compound was calculated using the following formula:

[0909] Relative inhibition percentage = 1 - (different concentrations of compound group - blank control) / (negative control - blank control) * 100%

[0910] The relative inhibitory activity percentage of different compound concentrations was plotted against the compound concentration. The curves were fitted using a four-parameter model, and the IC was calculated using the following formula. 50 value:

[0911] y = min + (max - min) / (1 + (x / IC) 50 )^(-Hillslope))

[0912] Where y is the relative inhibitory activity percentage, max and min are the maximum and minimum values ​​of the fitted curve, respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

[0913] Experimental results:

[0914] The experimental results are shown in Table 1-4.

[0915] Table 1. Inhibition rate of the compounds of the present invention on the activity of mutant RET enzyme at a concentration of 100 nM

[0916] 1 86％ 33％ 2 93％ 51％ 3 86％ 34％ 4 N / A 69％

[0917] Note: N / A indicates not tested.

[0918] As can be seen from Table 1, the compounds of the present invention have a significant inhibitory effect on mutant RET enzymes.

[0919] Table 2. Inhibition rate of the compounds of the present invention against RET-V804M enzyme

[0920] 6 (10 nM) 83％ 84 (100 nM) 72％ 7 (10 nM) 46％ 85 (100 nM) 77％ 8 (10 nM) 46％ 86 (10 nM) 64％ 15 (100 nM) 91％ 88 (10 nM) 62％ 16 (100 nM) 92％ 89 (10 nM) 70％ 18 (100 nM) 70％ 91 (10 nM) 70％ 21 (100 nM) 49％ 96 (100 nM) 84％ 23 (10 nM) 47％ 98 (100 nM) 63％ 26 (10 nM) 83％ 110 (100 nM) 62％ 27 (10 nM) 87％ 111 (100 nM) 46％ 28'(10nM) 34％ 117 (100 nM) 76％ 29 (10 nM) 52％ 118 (100 nM) 74％ 30 (10 nM) 88％ 125-2(10nM) 82％ 31 (10 nM) 81％ 126 (100 nM) 82％ 41 (10 nM) 64％ 127 (100 nM) 84％ 46 (10 nM) 92％ 128 (10 nM) 48％ 49 (100 nM) 75％ 129 (10 nM) 84％ 50 (100 nM) 50％ 130 (10 nM) 44％ 63 (10 nM) 65％ 131 (10 nM) 72％ 64 (10 nM) 79％ 132 (10 nM) 84％ 67 (100 nM) 82％ 133 (10 nM) 82％ 69 (10 nM) 56％ 134 (10 nM) 50％ 80 (10 nM) 51％ 135 (10 nM) 65％ 82 (10 nM) 43％ 137 (10 nM) 93％ 83 (10 nM) 56％ - -

[0921] As can be seen from Table 2, the compounds of the present invention have a significant inhibitory effect on RET-V804M enzyme.

[0922] Table 3-1. Inhibition IC50 of the compounds of the present invention against RET-WT enzyme 50 (nM)

[0923] 17 1.32±0.31 60 2.70±0.69 120 7.33±1.19 122 2.35±0.24

[0924] Table 3-2. Inhibition IC50 of the compounds of the present invention against RET-CCDC6 enzyme 50 (nM)

[0925] 17 2.50±0.55 60 3.99±0.79 69 10.97±9.65 120 18.66±7.27 122 2.91±0.41

[0926] Table 3-3. Inhibition IC50 of the compounds of the present invention against RET-V804L enzyme 50 (nM)

[0927] 17 6.54±2.43 60 5.07±0.40 120 10.09±1.05 122 4.79±1.68

[0928] Table 3-4. Inhibition IC50 of the compounds of the present invention against RET-V804M enzyme 50 (nM)

[0929]

[0930] Table 3-5. Inhibition IC50 of the compounds of the present invention against RET-M918T enzyme 50 (nM)

[0931] 17 1.47±0.29 60 1.29±0.27 69 8.60±1.46 120 15.81±3.65 122 4.03±0.66

[0932] As can be seen from Tables 3-1 to 3-5, the compounds of the present invention have significant inhibitory effects on RET-CCDC6, RET-M918T, RET-V804M, RET-V804L and RET-WT enzymes.

[0933] Table 4. Inhibition rate of the compounds of this invention against VEGFR2

[0934]

[0935]

[0936] In addition, it was determined that compound 11 inhibits VEGFR2 by IC50. 50 The concentration was 158.02 ± 25.08 nM, and compound 17 inhibited VEGFR2 with an IC50 of 158.02 ± 25.08 nM. 50 The value was 62.97 ± 11.77 nM. These results, combined with the inhibition rate data in Table 4, indicate that the compound of this invention exhibits weak inhibition of VEGFR2 and better selective inhibition of RET enzymes compared to VEGFR2.

[0937] Experimental Example 3: Pharmacokinetics and Tissue Distribution of Compounds in Rats

[0938] Male SD rats were administered BLU-667 (prepared according to Example 5 of WO2017 / 079140A1) and compound 17 via oral gavage (PO). The plasma concentrations of BLU-667 and compound 17, as well as their concentrations in the brain, lung, and thyroid tissues, were determined to investigate pharmacokinetic characteristics. The PO dose was 5 mg / kg, and the solvent was 0.5% MC (methylcellulose). Blood samples were collected at different time points (0 h before administration, and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration). Blood samples were anticoagulated with dipotassium EDTA, centrifuged, and the resulting plasma samples were stored at -80°C. Rats were euthanized by exsanguination via the abdominal aorta at 0.5 h, 2 h, 8 h, and 24 h after PO administration. Brain, lung, and thyroid tissues were collected, washed, homogenized with physiological saline at a specific ratio, and stored at -80°C. Plasma and tissue samples were analyzed by LC-MS / MS after protein precipitation. Pharmacokinetic parameters were calculated using WinNonlin 6.3 software with a non-compartmental model; the results are shown in Table 5.

[0939] Table 5. Pharmacokinetic parameters of compounds administered via PO in rat plasma and tissues.

[0940]

[0941] The data in Table 5 show that after SD rats were administered 5 mg / kg of BLU-667 and compound 17 by gavage, the exposure of compound 17 in the brain, lungs and thyroid gland of each target organ tissue was better than that of BLU-667.

[0942] Experiment Example 4: Drug Efficacy Test of Compounds in Mice

[0943] Objective: To evaluate the in vivo efficacy of compounds 17 and BLU-667 in a Balb / c-nu mouse model with subcutaneous xenografts of human medullary thyroid carcinoma TT cells.

[0944] Drug preparation: Compound 17 and BLU-667 were dissolved in 0.1M H3PO4 aqueous solution and 0.1M HOAc aqueous solution, respectively, to prepare clear solutions (pH approximately 4.0). The solvent control group used H3PO4 aqueous solution with a pH of approximately 4.0. Administration was by PO, BID.

[0945] Tumor measurement: The tumor diameter was measured twice a week using calipers. The formula for calculating tumor volume is: V = 0.5 × a × b 2 Where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compound was evaluated using the tumor growth inhibition rate (TGI) (%): TGI (%) = [(1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%. Results are shown in […]. Figure 1 .

[0946] Statistical analysis: Based on the relative tumor volume at the end of the trial, statistical analysis was performed using Prism Graphpad 5.0 software. Two-way ANOVA was used for comparisons among multiple groups, and p < 0.05 was considered statistically significant.

[0947] Experimental Results: In a human medullary thyroid carcinoma TT nude mouse xenograft model, compound 17 exhibited significant antitumor activity at a dose of 5 mg / kg, and this antitumor activity showed a dose-dependent trend. The antitumor effect of compound 17 at a dose of 5 mg / kg (T / C = 17.44%, TGI = 131.36%, p < 0.05) was superior to that of BLU-667 at a dose of 5 mg / kg (T / C = 33.62%, TGI = 88.82%, p < 0.05). The relative tumor proliferation rate T / C (%) = T RTV / C RTV ×100%, where T RTV C represents the average relative tumor volume of the tested compound group. RTV The relative tumor volume is the solvent control group; and the relative tumor volume RTV = V t / V0, where V0 is the average tumor volume at the start of drug administration, V t The mean tumor volume is measured t days after drug administration.

[0948] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt of said compound, wherein said compound has the structure of formula I: ， in: Ring A is a pyridine ring; Ring B is , , , or Through The marked position is connected to ring A, and through The marked position is connected to L; X 1 is selected from CH and N; R 1 selected from H, halo, hydroxyl, cyano, C 1-6 alkyl and C 1-6 heteroalkyl, each of said alkyl and heteroalkyl optionally substituted with one or more substituents selected from hydroxyl, halo, CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 heteroalkyl; R 2 It is a 5-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl; R 3 and R 4 It either does not exist or, each time it appears, is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl and C 1-6 Heteroalkyl groups, wherein the alkyl group and the heteroalkyl group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; L is selected from -O-, -C(O)-, C 1-4 Alkylene and The alkylene group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Heteroalkyl; R 5 Selected from phenyl and 5-6-membered heteroaryl groups, wherein each of the phenyl and heteroaryl groups is optionally substituted by one or more substituents selected from: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, -NR 30a R 30b -OR 31 and substances selected from one or more of the following: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl, C 3-6 5-10-membered heteroaryl groups substituted with cycloalkoxy and 4-10-membered heterocyclic groups; R 23a and R 23b Each is independently selected from H and C. 1-6 alkyl; R 30a and R 30b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; R 31 C 1-6 alkyl; m is 0 or 1; n can be 0, 1, 2, 3, or 4.

2. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein: R 1 Selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl and C 1-4 Heteroalkyl groups, wherein each alkyl group and the heteroalkyl group are optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl; and / or R 2 It is a 5-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Heteroalkyl groups.

3. The compound of claim 2 or a pharmaceutically acceptable salt of the compound, wherein: R 1 Selected from C 1-4 Alkyl and C 1-4 Heteroalkyl groups, wherein the alkyl group and the heteroalkyl group are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Heteroalkyl groups.

4. The compound of claim 3 or a pharmaceutically acceptable salt of the compound, wherein: R 1 Selected from C 1-3 Alkyl and C 1-3 Alkyl group.

5. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: R 2 The group is selected from thienyl, pyrrolyl, pyrazolyl, imidazoleyl, thiazolyl, thiadiazoleyl, isothiazolyl, oxazolyl, oxadiazoleyl, and isoxazolyl, wherein each of the thienyl, pyrrolyl, pyrazolyl, imidazoleyl, thiazolyl, thiadiazoleyl, isothiazolyl, oxazolyl, oxadiazoleyl, and isoxazolyl groups is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Heteroalkyl groups.

6. The compound of claim 5 or a pharmaceutically acceptable salt of the compound, wherein: R 2 It is a methyl-substituted pyrazolyl group.

7. The compound of claim 6 or a pharmaceutically acceptable salt of said compound, wherein: R 2 It is 5-methyl-1H-pyrazole-3-yl or 1-methyl-1H-pyrazole-4-yl.

8. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: Ring A is Through The position of the marker and X 1 The ring is connected, and through The marked position is connected to ring B.

9. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: X 1 Let N be the number of elements in the array.

10. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: R 3 and R 4 It either does not exist or is independently selected from hydroxyl, halogen, CN, C each time it appears. 1-4 Alkyl and C 1-4 The alkoxy group, wherein the alkyl group and the alkoxy group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups.

11. The compound of claim 10 or a pharmaceutically acceptable salt of said compound, wherein: R 3 and R 4 It either does not exist or is independently selected from hydroxyl, halogen, CN, C each time it appears. 1-3 Alkyl and C 1-3 The alkoxy group, wherein the alkyl group and the alkoxy group are each optionally substituted by one or more substituents selected from the following: halogen, CN, and C. 1-3 alkyl.

12. The compound of claim 11 or a pharmaceutically acceptable salt of said compound, wherein: R 3 and R 4 The following do not exist or are selected independently each time they appear: F, Cl, CN, C 1-3 Alkyl and C 1-3 Alkyl group.

13. The compound of claim 12 or a pharmaceutically acceptable salt of said compound, wherein: R 3 and R 4 It does not exist.

14. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: R 5 The group is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, imidazoleyl, or thiazolyl, wherein each of the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, imidazoleyl, or thiazolyl groups is optionally substituted by one or more substituents selected from: hydroxyl, halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl, -NR 30a R 30b -OR 31 and optionally selected by one or more elements selected from hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Heteroalkyl, C 3-6 cycloalkyl, C 3-6 5-8-membered heteroaryl groups substituted with cycloalkoxy and 4-6-membered heterocyclic groups.

15. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: R 5 The group is selected from phenyl, pyridyl, pyrazolyl, and thiazolyl, wherein each of the phenyl, pyridyl, pyrazolyl, and thiazolyl groups is optionally substituted by one or more substituents selected from: halogen, CN, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, -NR 30a R 30b -OR 31 and optionally selected from one or more halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 5-8-membered heteroaryl groups substituted with cycloalkoxy and 4-6-membered heterocyclic groups.

16. The compound of claim 15 or a pharmaceutically acceptable salt of said compound, wherein: R 5 To be optionally selected by one or more halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 The alkoxy group and the 5-6 heteroaryl group are substituted with phenyl, pyridinyl, pyrazolyl, or thiazolyl groups, wherein the 5-6 heteroaryl group is optionally further substituted with one or more groups selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl and C 3-6 Substitution of cycloalkoxy groups.

17. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: R 23a and R 23b Each is independently selected from H and C. 1-4 alkyl; and / or R 31 C 1-4 alkyl; and / or R 30a and R 30b Each is independently selected from H and C. 1-4 Alkyl, C 1-4 Halogenated alkyl groups and C 1-4 Hydroxyalkyl.

18. The compound of claim 17 or a pharmaceutically acceptable salt of said compound, wherein: R 23a and R 23b Each is independently selected from H and C. 1-3 alkyl.

19. The compound of claim 17 or a pharmaceutically acceptable salt of said compound, wherein: R 30a and R 30b Each is independently selected from H and C. 1-4 alkyl.

20. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, wherein: L is selected from -O-, -C(O)-, and C. 1-4 Alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl groups.

21. The compound of claim 20 or a pharmaceutically acceptable salt of said compound, wherein: L is selected from -O-, -C(O)-, and C. 1-3 Alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Heteroalkyl groups.

22. The compound of claim 21 or a pharmaceutically acceptable salt of said compound, wherein: L is selected from -O-, -C(O)-, and C. 1-3 Alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

23. The compound of claim 22 or a pharmaceutically acceptable salt of said compound, wherein: L can be -CH2-, -CH(CH3)-, -O-, or -C(O)-.

24. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, The compound described thereof has a structure shown in one of formulas IA to IE and IG: ； in: R 5 Selected from phenyl and 5-6-membered heteroaryl, wherein (1) the phenyl is optionally substituted with one or more 5-10-membered heteroaryl groups, wherein the 5-10-membered heteroaryl groups are optionally substituted with one or more substituents selected from: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10-membered heterocyclic groups, and (2) the 5-6-membered heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, 5-10-membered heteroaryl, -NR 30a R 30b and -OR 31 The 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups; and R 1 R 2 R 23a R 30a R 30b and R 31 As defined in any one of claims 1-23; ， in: R 1 R 2 R 5 and R 23a As defined in any one of claims 1-23; ， in: When X 1 When it is CH, R 1 R 2 R 5 and R 23a As defined in any one of claims 1-23; and when X 1 When R is N, 1 R 2 R 5 and R 23a As defined for formula IA; ， in: R 1 R 2 R 23a R 23b As defined in any one of claims 1-23; t is 1; When X 1 When it is CH, R 5 As defined in any one of claims 1-23; and When X 1 When R is N, 5 It is a phenyl or a 5-6 membered heteroaryl group, wherein: (1) The phenyl group is optionally substituted with one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, 5-10-membered heteroaryl, -NR 30a R 30b and -OR 31 The 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 The cycloalkyl group and the 4-10-membered heterocyclic group, and (2) the 5-6-membered heteroaryl group is optionally substituted by one or more substituents selected from the following: NO2, 5-10-membered heteroaryl, -NR 30a R 30b and -OR 31 The 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl groups and 4-10 membered heterocyclic groups; and R 30a R 30b and R 31 As defined in any one of claims 1-23; ， in: R 1 R 2 R 5 R 23a R 23b X 1 and t are as defined for the formula ID; ， in: X 1 For CH or N; R 1 R 2 and R 4 As defined in any one of claims 1-23; n is 0 or 1; R 5 Selected from phenyl and 5-6-membered heteroaryl, wherein (1) the phenyl is optionally substituted with one or more 5-10-membered heteroaryl groups, wherein the 5-10-membered heteroaryl groups are optionally substituted with one or more substituents selected from: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups; and (2) the 5-6 membered heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl and 5-10 heteroaryl groups, wherein the 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups.

25. The compound of claim 24 or a pharmaceutically acceptable salt of said compound, in, R 23a For H or C 1-3 alkyl.

26. The compound of claim 1 or a pharmaceutically acceptable salt of said compound, The compounds mentioned therein are selected from: and .

27. A method for preparing a compound, the method comprising the following steps: Route A ， in: Hal 1 and Hal 2 Each can be independently F, Cl, Br, or I; R 1 Selected from H, cyano, C 1-6 Alkyl and C 1-6 Heteroalkyl groups, wherein the alkyl group and the heteroalkyl group are each optionally substituted by one or more substituents selected from the following: halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl; R 2 It is a 5-membered heteroaryl group, wherein the heteroaryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Heteroalkyl; R 23a Selected from H and C 1-6 Alkyl; and R 5 As defined in claim 24, formula IA; Step 1: Compound IA-1 and R 2 -NH2 reacts in the presence of a base to form compound IA-2; Step 2: Compound IA-3 and IA-4 react in the presence of a base to generate compound IA-5; Step 3: Compound IA-5 reacts with a boron-containing reagent to generate compound IA-6; Step 4: Compound IA-2 reacts with IA-6 to form compound IA-7; Step 5: Compound IA-7 undergoes deprotection under acidic conditions to generate compound IA-8; Step 6: Compound IA-8 reacts with IA-9 to form compound IA; or, The method includes the following steps: Route B ， in: Each group is as defined for route A; Step 1: Compound IA-5 is deprotected under acidic conditions to generate compound IA-10; Step 2: Compound IA-10 reacts with IA-9 to generate compound IA-11; Step 3: Compound IA-11 reacts with a boron-containing reagent to generate compound IA-12; Step 4: Compound IA-12 reacts with IA-2 to form compound IA; or, The method includes the following steps: Route C ， in: Each group is as defined for route A; Step 1: Compound IB-1 and R 2 -NH2 reacts in the presence of a base to form compound IB-2; Step 2: Compound IB-2 reacts with IA-12 to generate compound IB; or, The method includes the following steps: Route D ， in: Each group is as defined for route A; and X 1 Selected from CH and N; Step 1: Compound IC-1 and R 2 -NH2 reacts in the presence of a base to form compound IC-2; Step 2: Compound IC-3 reacts with a boron-containing reagent to generate compound IC-4; Step 3: Compound IC-2 reacts with IC-4 to generate compound IC-5; Step 4: Compound IC-5 is deprotected under acidic conditions to generate compound IC-6; Step 5: Compound IC-6 reacts with IA-9 to form compound IC; or, The method includes the following steps: Route E ， in: R 1 and R 2 As defined for route A; R 5 As defined by ID as in claim 24; R 23a and R 23b Each is independently selected from H and C. 1-6 alkyl; X 1 Selected from CH and N; and t is 0 or 1; or, The method includes the following steps: Route F ， in: R 1 R 2 R 5 R 23a R 23b And t is as defined for route E; X 1 Selected from CH and N; and Hal 2 It can be F, Cl, Br or I; Step 1: Compound IC-2 reacts with IA-6 to form compound IE-1; Step 2: Compound IE-1 is deprotected under acidic conditions to generate compound IE-2; Step 3: Compound IE-2 and ID-1 undergo a condensation reaction to generate compound IE; or, The method includes the following steps: Route H ， in: R 1 and R 2 As defined for route A; X 1 Selected from CH and N; R 4 Does not exist or selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Heteroalkyl; R 5 As defined in claim 24, IG; and n is 0 or 1; Step 1: Compound IG-1 and R 5 The -OH reaction produces compound IG-2; Step 2: Compound IG-2 is deprotected under acidic conditions to generate compound IG-3; Step 3: Compound IF-2 and IG-3 undergo a nucleophilic substitution reaction in the presence of a base to generate compound IG.

28. A pharmaceutical composition comprising a preventive or therapeutically effective amount of any one of the compounds of claims 1-26 or a pharmaceutically acceptable salt of said compound; Optionally, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers.

29. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt of the compound, or the pharmaceutical composition of claim 28, in the preparation of a medicament for the prevention or treatment of diseases or conditions associated with RET activity.

30. The use as described in claim 29, wherein: The diseases or conditions associated with RET activity are cancer or irritable bowel syndrome.

31. The use as described in claim 29, wherein: The disease or condition associated with RET activity is a tumor.

32. The use as described in claim 29, wherein: The diseases or conditions associated with RET activity are lung cancer, breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer, colon cancer, multiple myeloma, melanoma, glioma, brain tumor, sarcoma, or irritable bowel syndrome.

33. The use as described in claim 32, wherein: The lung cancer is non-small cell lung cancer; the thyroid cancer is medullary thyroid carcinoma or papillary thyroid carcinoma.

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