Heterocyclic compound and use thereof as RET inhibitor

Abstract

The present disclosure relates to a novel heterocyclic compound for use as an RET (rearranged during transfection) inhibitor, a pharmaceutically acceptable salt thereof, a preparation method therefor, and the use thereof for regulating or inhibiting RET activity, for treating and preventing RET activity-related diseases and for preparing drugs for treating the diseases.

Description

Heterocyclic compounds and their use as ret inhibitors INVENTION

[0001] The present invention belongs to the technical field of medicine, in particular to a new heterocyclic compound as RET (rearranged during transfection) inhibitor, pharmaceutically acceptable salts thereof, a preparation method thereof, and a use thereof for regulating or inhibiting the activity of RET, for treating and preventing diseases related to the activity of RET, and for preparing drugs for treating the diseases. BACKGROUND

[0002] The RET (rearranged during transfection) proto-oncogene, located on chromosome 10, contains 21 exons and is 60 kb in length. The encoded RET protein is a receptor tyrosine kinase (RTK) that exists on the cell membrane and is composed of an extracellular domain, a transmembrane domain, and an intracellular tyrosine protein kinase domain [Altanerovd V. Cancers connected with mutations in Ret oncogene. Neoplasma. 2001; 48(5): 325-331; Takashi Kohno, Junya Tabata, Takashi Nakaoku, RET o ma: a cancer subtype with a shared driver oncogene, Carcinogenesis. 2020 Apr 22; 41(2): 123-129.]. Unlike other receptor tyrosine kinases, RET activation requires the interaction between a ligand (glial cell-derived neurotrophic factor family ligand, GFLS) and a co-receptor (GFLS family receptor-alpha), forming a GFLs-GFRa complex that binds to the extracellular domain of RET, and then completes the activation after phosphorylation through the intracellular domain. The activated RET protein can activate the signal transduction cascade pathway of cell proliferation, including the MAPK, PI3K, JAK-STAT, PKA, and PKC pathways, thereby regulating the normal physiological functions of cells [Calihno D, Rizzo C, D'Alessio A, et al. Signaling through Ras is essential for ret oncogene-induced cell differentiation in C12 cells. J Biol Chem. 2000; 275(25): 19297-19305.]. During embryonic development, RET plays an important role in the development of the kidney and enteric nervous system. In addition, RET is also very important for maintaining the homeostasis of tissues, including neural, neuroendocrine, hematopoietic, and male germ cell tissues [Jiang Q, Liu Q, Zuo WS. Recent progress in molecular biology of thyroid filter cell carcinoma. Guo Wai Yi Xue Zhong Liu Xue Fen Ce. 2000; 27(3): 162-165.].

[0003] RET has been confirmed to be closely related to the occurrence and development of various malignant tumors, the most important carcinogenic variation is RET gene fusion (also known as RET rearrangement) and RET gene mutation. In addition, in gastrointestinal diseases such as irritable bowel syndrome (IBS) [Schenck Eidam H, Russell J, Raha K, et al. Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS. ACS Med Chem Lett. 2018 May 24; 9(7): 623-628.], inflammatory bowel disease (IBD) [Meir M, Burkard N, Ungewiβ H, et al. Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease. J Clin Invest. 2019 Jun 17; 129(7): 2824-2840.], RET is also found to be related.

[0004] RET rearrangements produce chimeric proteins that fuse the RET kinase domain to a partner protein containing a dimerization domain. RET fusions are present in 5-10% of papillary thyroid cancers and 1-2% of lung cancer patients. In non-small cell lung cancer (NSCLC), at least 12 fusion RET partner genes have been found (KIF5B-RET, CCDC6-RET, NCOA4-RET, MYO5C-RET, EPHA5-RET, TRIM33-RET, CLIP1-RET, ERC1-RET, PICALM-RET, FRMD4A-RET, RUFY2-RET, TRIM24-RET RET), of which KIF5B-RET fusion is the most common. The activation mechanism of RET fusion proteins is similar to the oncogenic activation of ALK fusions in NSCLC, but is distinct from ROS1. In addition, RET fusions have also been found in malignancies such as MEN2A (multiple endocrine neoplasia type 2), ovarian cancer, salivary gland cancer, colorectal cancer, breast cancer, Spitz tumor and chronic myeloproliferative neoplasm [Takashi Kohno, Junya Tabata, Takashi Nakaoku, REToma: a cancer subtype with a shared driver oncogene, Carcinogenesis. 2020 Apr 22; 41(2): 123-129.; Zheng Y, Jiang W, Chen D, Li Y, Dai L, Huang L, Wang M. [Research Progress of Fusion Genes RET in Non-small Cell Lung Cancer]. Zhongguo Fei Ai Za Zhi. 2021 Aug 20; 24(8): 591-597.].

[0005] Another common oncogenic variation of RET is a genetic mutation, approximately 65% of sporadic medullary thyroid cancer (MTC) patients have RET mutations, accounting for 3 / 4 of all MTC, which is the main cancer type in MEN2 patients. Most are RET M918T mutations, other RET mutations include: E768D and A883, C634R, V804M / L, RET mutations can drive the occurrence of hereditary and sporadic thyroid cancer [Zheng Y, Jiang W, Chen D, Li Y, Dai L, Huang L, Wang M. [Research Progress of Fusion Genes RET in Non-small Cell Lung Cancer]. Zhongguo Fei Ai Za Zhi. 2021 Aug 20;24(8):591-597.; Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 2016 Apr;12(4):192-202.]. More and more studies have found that RET mutations occur in different tumors, including RET C634R in breast cancer, RET E511K in endometrial cancer and Merkel cell carcinoma, RET M918T in paraganglioma and atypical lung cancer, RET V804M mutation in colorectal cancer, meningioma, gastrointestinal stromal tumor and liver cancer, etc. [Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discov. 2020;10:498-505.; Iams WT, Lovly CM. Stop fRETting the target: next-generation RET inhibitors have arrived. Cancer Discov. 2018;8(7):797-799.].

[0006] Several multi-kinase inhibitors with RET inhibitory activity have been applied in clinical, such as Vandetanib (mainly used for treating unresectable, locally advanced or metastatic, symptomatic or progressive medullary thyroid cancer), Sorafenib (liver cancer, kidney cancer, local recurrence or metastasis, progression, differentiated thyroid cancer refractory to radioactive iodine), but the therapeutic effect is limited, and the toxic side effects are obvious. Targeted drugs for RET gene are constantly emerging, and two selective RET inhibitors Selpercatinib (LOXO-292) and Pralsetinib (BLU-667) have been approved for marketing, showing obvious anticancer activity. Selpercatinib is used for treating lung cancer and thyroid cancer with RET mutation or fusion, and shows unprecedented efficacy in RET fusion-driven lung cancer; Pralsetinib is used for treating advanced RET fusion-positive non-small cell lung cancer in adult patients. However, not all RET rearrangement / mutation patients respond to these drugs. The existing RET inhibitors (such as Selpercatinib, Pralsetinib, etc.) have weak or no inhibitory effect on some RET mutations (such as G810, A833, C634, etc.); or although some RET inhibitors can act on various RET rearrangements / mutations, the inhibitory activity is poor in balance (for example, Vandetanib, Selpercatinib, etc. for RET V804M, RET G810R, RET M918T mutations, the inhibitory activity difference is about 100 times), which leads to a large difference in the onset dose for some RET mutant types, and is easy to produce toxic effects; or some RET inhibitors (such as Vandetanib) still have high VEGFR2 (or KDR2) inhibitory activity, lack of selectivity for them, and produce off-target effects, leading to higher incidence of adverse events and drug toxicity limitations. Therefore, it is necessary to develop a targeted inhibitor with high activity, small side effects, strong specificity, and balanced and effective for RET mutations and rearrangements. SUMMARY

[0007] The compound provided by the present application has good inhibitory activity on RET wild type, RET V804 and RET G810, etc. RET kinases, and the inhibitory activity is strong and balanced; at the same time, the compound of the present application has good selectivity for RET.

[0008] In one aspect, the present application provides a compound represented by formula I or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof,

[0009] wherein:

[0010] X is N or CR 1 ;

[0011] Y is NR 2 or CR 3 R 4 ;

[0012] L 1 is selected from the group consisting of a bond, -O-, -S-, -C(R 5A R 5B )- and -N(R 6A )-;

[0013] Ar is selected from the group consisting of aryl and heteroaryl, preferably from the group consisting of phenyl and 5- to 6-membered heteroaryl, for example from the group consisting of phenyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl and pyridazinyl, optionally substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl and amino;

[0014] [Corrected according to Rule 91 30.12.2025] Q is

[0015] [Corrected according to Rule 91 30.12.2025] is selected from the group consisting of 6-membered aryl, 5- to 6-membered heteroaryl and 5- to 8-membered cycloalkyl, preferably from the group consisting of phenyl, 5-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl and 5- to 8-membered saturated spirocycloalkyl, for example phenyl, isoxazolyl, pyrazolyl, isothiazolyl, more preferably from the group consisting of 5-membered heteroaryl, for example isoxazolyl, pyrazolyl and isothiazolyl, all of which are optionally substituted by one or more R 7 ;

[0016] L 2 is selected from the group consisting of a bond, -O-, -S-, -C(R 5C R 5D )- or -N(R 6B )-, with the proviso that one of L 1 and L 2 is a bond;

[0017] R 1 is H or C 1-6 alkyl;

[0018] R 2 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halo, cyano, hydroxy and amino;

[0019] R 3 and R 4 are independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halo, cyano, hydroxy and amino;

[0020] or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halo, cyano, hydroxy and amino;

[0021] R 5A , R 5B , R5C R 5D R 6A R 6B are independently of each other H or C 1-6 alkyl;

[0022] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy.

[0023] In another aspect, the present application also provides a compound represented by Formula I' or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof,

[0024] wherein:

[0025] X is N or CR 1 ;

[0026] Y is NR 2 or CR 3 R 4 ;

[0027] Z is CH or N;

[0028] R A , R B are each independently NH2or H, and R A , R B are not simultaneously NH;

[0029] L 1 is selected from a bond, -O-, -S-, -C(R 5A R 5B )- and -N(R 6A )-;

[0030] Cy is selected from aryl, heteroaryl or cycloalkyl optionally substituted with one or more substituents, preferably selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl or 5- to 8-membered saturated spiro cycloalkyl, for example selected from phenyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, said substituents are selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxy and amino;

[0031] [Corrected according to detailed rule 91 30.12.2025] Q is

[0032] [Corrected according to Rule 91, December 2025] The group is selected from 6-membered aryl, 5- to 6-membered heteroaryl, and 5- to 8-membered cycloalkyl, preferably selected from phenyl, 5-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl, and 5- to 8-membered spirocycloalkyl, such as phenyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, and so on. More preferably, the group is selected from 5-membered heteroaryl groups, such as isoxazolyl, pyrazolyl, and isothiazolyl, all of which are optionally surrounded by one or more R groups. 7 replace;

[0033] L 2 Selected from chemical bonds, -O-, -S-, -C(R) 5C R 5D - or -N(R) 6B -, the condition is L 1 and L 2 One of them is a chemical bond, or when L 1 and L 2 When all are chemical bonds, Cy is selected from 5- to 8-membered spirocyclic alkyl groups optionally substituted with one or more substituents (e.g., );

[0034] R 1 Is it H or C? 1-6 alkyl;

[0035] R 2 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl and 3 to 8-membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 Substituents of cycloalkyl groups and 3 to 8-membered heterocyclic groups; the C 3-8 The cycloalkyl group and the 3 to 8-membered heterocyclic group are optionally separated by one or more groups selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituted by alkoxycarbonyl, halogen, cyano, hydroxyl and amino substituents;

[0036] R3 and R 4 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl and amino;

[0037] or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl and amino;

[0038] R 5A , R 5B , R 5C , R 5D , R 6A and R 6B are independently from each other H or C 1-6 alkyl;

[0039] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano, pyridyl, phenyl and hydroxyl.

[0040] In one embodiment, the present application provides a compound according to Formula I or Formula I', or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X is N and Y is NR 2 wherein R2is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogens, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl is optionally substituted with one or more halogens, for example, 1, 2, or 3 halogens, for example, F; for example, R2is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3,

[0041] In one embodiment, the present application provides a compound according to Formula I or Formula I', or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X is N and Y is NR 2 wherein R2is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogens, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl is optionally substituted with one or more halogens, for example, 1, 2, or 3 halogens, for example, F; for example, R2is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3,

[0042] In one embodiment, the present application provides a compound according to Formula I or Formula I', or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X is N and Y is CR 3 R 4 wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl, and C 3-8cycloalkyl, or R 3 and R 4 together with the carbon atom to which they are attached form C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from C 1-6 alkyl and halo; for example, R 3 and R 4 are independently selected from H, methyl and cyclopropyl, or R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl, azetidinyl and oxetanyl, optionally substituted with C 1-6 alkyl.

[0043] In one embodiment, the present application provides a compound according to Formula I or Formula I', or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein L 1 is a bond or -CH2-; preferably, L 1 is a bond.

[0044] In one embodiment, the present application provides a compound according to Formula I, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Ar is phenyl or pyridyl, said phenyl and pyridyl are optionally substituted with one or more halo, for example F; preferably, Ar is phenyl optionally substituted with halo, for example F, wherein Q and L 1 are in the para position relative to each other.

[0045] In one embodiment, the present application provides a compound according to Formula I', or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Cy is phenyl, pyridyl, pyrimidinyl, pyrazinyl, said Cy is optionally substituted with one or more halo, for example F; preferably, Cy is phenyl optionally substituted with halo, for example F, wherein Q and L 1 are in the para position relative to each other on Cy.

[0046] In one embodiment, the present application provides a compound according to Formula I or Formula I', or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q is wherein:

[0047] L 2 is a bond or -C(R 5C R 5D )-, provided that one of L 1 and L 2 is a bond; preferably, L 2 is -C(R5C R 5D )-, for example -CH2- or -CH(CH3)-, more preferably L 2 is -CH2-;

[0048] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 is selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from optionally F-substituted isopropyl and tert-butyl, and said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R7is selected from -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole;

[0049] preferably, R 7 is located in ortho position to the nitrogen atom of the isoxazolyl group.

[0050] In one embodiment, the present application provides a compound of formula I' or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q is wherein:

[0051] W is O or NR W , said R W is selected from H, C 1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, preferably W is O;

[0052] L 2 is a chemical bond, -C(R 5C R 5D )- or -N(R 6B )-, provided that one of L 1 and L 2 is a chemical bond, or when L 1 and L 2When all are chemical bonds, Cy is selected from 5- to 8-membered spirocyclic alkyl groups optionally substituted with one or more substituents (e.g., Preferably, L 2 It is -C(R) 5C R 5D - or -N(R) 6B -, for example -CH2-, -CH(CH3)-, -NH-, more preferably L 2 It is -CH2- or -NH-, with L being particularly preferred. 2 It is -CH2-;

[0053] R 7 Selected from C 1-6 Alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 3-8 The cycloalkyl group is optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano, and pyridyl groups; for example, R 7 Selected from C 3-6 Alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 Alkyl, wherein the C 3-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one or more substituents independently selected from halogen, cyano, pyridyl, and hydroxyl groups, for example, wherein the C... 3-6 The alkyl group is selected from isopropyl and tert-butyl, optionally substituted with F, CN, hydroxyl or pyridyl, wherein the C 3-6 The cycloalkyl group is selected from cyclobutyl and cyclopentyl groups optionally substituted with F and a hydroxyl group; preferably, R7 is selected from -C(CH3)2CF3, -C(CH3)2OH, -C(CH3)2CN, More preferably, R7 is selected from -C(CH3)2CF3,

[0054] Preferably, R 7 It is attached to the adjacent position of the N atom of the cyclic group to which it is attached.

[0055] In one embodiment, the present invention provides a compound of formula I-1 or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof.

[0056] in:

[0057] L 1 Selected from chemical bonds, -O-, -S-, -C(R) 5A R 5B)- and -N(R 6A )-;

[0058] Ar is selected from aryl and heteroaryl, preferably from phenyl and 5- to 6-membered heteroaryl, for example from phenyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl and pyridazinyl, optionally substituted by one or more substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxy and amino;

[0059] [Amended according to Rule 91 30.12.2025] Q is

[0060] [Amended according to Rule 91 30.12.2025] is selected from 6-membered aryl, 5- to 6-membered heteroaryl and 5- to 8-membered cycloalkyl, preferably from phenyl, 5-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl and 5- to 8-membered saturated spirocycloalkyl, for example phenyl, isoxazolyl, pyrazolyl, isothiazolyl, more preferably from 5-membered heteroaryl, for example isoxazolyl, pyrazolyl and isothiazolyl, all of which are optionally substituted by one or more R 7 substituents;

[0061] L 2 is selected from a chemical bond, -O-, -S-, -C(R 5C R 5D )- or -N(R 6B )-, provided that one of L 1 and L 2 is a chemical bond;

[0062] R 2 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted by one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6Alkoxy, C 1-6 Substituted by alkoxycarbonyl, halogen, cyano, hydroxyl and amino substituents;

[0063] R 5A R 5B R 5C R 5D R 6A and R 6B H or C are independent of each other. 1-6 alkyl;

[0064] R 7 Selected from C 1-6 Alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 Alkyl, wherein the C 1-6 Alkyl and C 3-8 The cycloalkyl group is optionally substituted by one or more substituents independently selected from halogen, cyano and hydroxyl groups.

[0065] In one implementation, R 2 Selected from C 1-6 Alkyl, C 3-8 cycloalkyl groups and 3 to 8-membered heterocyclic groups, wherein the C 1-6 The alkyl group is optionally substituted with one or more halogens, wherein the C 3-8 The cycloalkyl group and the 3 to 8-membered heterocyclic group are optionally separated by one or more groups selected from C 1-6 The alkyl group is substituted with a halogen substituent; for example, R2 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, aziridine, and oxetidine, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, aziridine, and oxetidine groups are optionally substituted with one or more halogens, such as one, two, or three halogens, such as F; for example, R2 is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3, ...

[0066] In one embodiment, the present invention provides a compound of formula I-1 or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof, wherein L 1 It is a chemical bond or -CH2-; preferably, L 1 It is a chemical bond.

[0067] In one embodiment, the present invention provides a compound of formula I-1 or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof, wherein Ar is a phenyl or pyridyl group, said phenyl and pyridyl group optionally substituted with one or more halogens, such as F; preferably, Ar is a phenyl group optionally substituted with a halogen, such as F, wherein Q and L 1 They are positioned opposite each other.

[0068] In one embodiment, the present application provides a compound represented by Formula I-1 or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q is wherein:

[0069] L 2 is a chemical bond or -C(R 5C R 5D )-; preferably, L 2 is -C(R 5C R 5D )-, for example -CH2- or -CH(CH3)-, more preferably L 2 is -CH2-;

[0070] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 is selected from C 3-6 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy, for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, and said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R7is selected from -C(CH3)2CF3, wherein * indicates the point of attachment of said group to the isoxazole;

[0071] preferably, R 7 is located at the ortho position of the nitrogen atom of said isoxazolyl group.

[0072] In one embodiment, the present application provides a compound represented by Formula I-2 or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof,

[0073] wherein Z, R 2 , L 1 , Cy, Q are as defined above.

[0074] In one embodiment, the present application provides a compound represented by Formula I-2, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogen, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl is optionally substituted with one or more halogen, for example 1, 2, or 3 halogen, for example F; for example, R2is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3,

[0075] In one embodiment, the present application provides a compound represented by Formula I-2, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein L 1 is a bond or -CH2-; preferably, L 1 is a bond.

[0076] In one embodiment, the present application provides a compound represented by Formula I-2, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Cy is phenyl, pyridyl, pyrimidinyl, pyrazinyl, said Cy is optionally substituted with one or more halogen, for example F; preferably, Cy is phenyl optionally substituted with halogen, for example F, wherein Q and L 1 are in para position to each other on Cy.

[0077] In one embodiment, the present application provides a compound represented by Formula I-2, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q is wherein:

[0078] W is O or NR W , said R W is selected from H, C 1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, preferably W is O;

[0079] L 2 is a bond, -C(R 5C R 5D )-, or -N(R 6B )-, provided that L 1and L 2 one of L 1 and L 2 is a chemical bond, or when L 2 and L 5C are both chemical bonds, Cy is selected from 5- to 8-membered spirocycloalkyl groups optionally substituted with one or more substituents; preferably, L 5D is -C(R 6B )- or -N(R 2 )-, for example -CH2-, -CH(CH3)-, -NH-, more preferably L 2 is -CH2- or -NH-, particularly preferably L 7 is -CH2-;

[0080] R 1-6 is selected from C 3-8 alkyl, C 3-8 cycloalkyl and C 1-6 cycloalkyl-C 1-6 alkyl, wherein said C 3-8 alkyl and C 7 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, pyridyl; for example, R 3-6 is selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano, pyridyl and hydroxy, for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, CN, hydroxy or pyridyl, and said C 7 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R7is selected from -C(CH3)2CF3, -C(CH3)2OH, -C(CH3)2CN,

[0081] preferably, R 1 is attached to the ortho position of the cyclic group N atom to which it is attached.

[0082] In one embodiment, the present application provides a compound represented by Formula (II-1) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof,

[0083] wherein X, Y, L 2 , L2 , Ar and R 7 are as defined above.

[0084] In one embodiment, the present application provides a compound represented by Formula (II-2) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof,

[0085] wherein X, Y, Z, W, L 1 , L 2 , Cy and R 7 are as defined above.

[0086] In one embodiment, the present application provides a compound represented by Formula (III) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof,

[0087] wherein R 8 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl, and amino; preferably, R 8 is selected from H and halogen, e.g., F; and

[0088] X, Y, L 2 and R 7 are as defined above.

[0089] In one embodiment, the present application provides a compound represented by Formula (III) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein:

[0090] X is N and Y is NR 2 , wherein R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogen, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl is optionally substituted with one or more halogen, e.g., 1, 2, or 3 halogen, e.g., F; for example, R 2 is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3,

[0091] L 2 is -CH2- or -CH(CH3)-, preferably -CH2-;

[0092] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 is selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl, optionally substituted with F, and said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl, optionally substituted with F and hydroxy; preferably, R 7 is selected from -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole;

[0093] R 8 is selected from H and halogen, for example F.

[0094] In one embodiment, the present application provides a compound represented by Formula (III) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein:

[0095] X is N and Y is CR3R4, wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl and C 3-8 cycloalkyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example R 3 and R 4is independently selected from H, methyl and cyclopropyl, or R3and R4together with the carbon atom to which they are attached form an optionally substituted C 1-6 alkyl-substituted cyclopropyl, azetidinyl and oxetanyl;

[0096] L 2 is -CH2-;

[0097] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 is selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, and said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R 7 is selected from -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole;

[0098] R 8 is selected from H and halogen, for example F.

[0099] In one embodiment, the present application provides a compound represented by Formula (IV) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof,

[0100] wherein V 1 , V 2 , V 3 , V 4 are each independently CH or N, and at most two are N; preferably, is selected from wherein * indicates the point of attachment to X;

[0101] R 8 is absent or selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl, and amino; preferably, R 8 is absent or selected from halogen, e.g., F; and

[0102] X, Y, Z, W, L 2 and R 7 are as defined above.

[0103] In one embodiment, the present application provides a compound represented by Formula (IV) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof, wherein:

[0104] X is N and Y is NR 2 wherein R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogen, said C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl is optionally substituted with one or more halogen, e.g., 1, 2, or 3 halogen, e.g., F; for example, R 2 is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3,

[0105] Z is CH or N;

[0106] L 2 is -CH2-, -CH(CH3)-, or -NH-, preferably -CH2- or -NH-, more preferably -CH2-;

[0107] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, and pyridyl; for example, R 7 is selected from C 3-6 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C3-6 alkyl and C 3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from halo, cyano, pyridyl, and hydroxy, for example, wherein the C 3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, CN, hydroxy, or pyridyl, and the C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R 7 is selected from -C(CH3)2CF3, -C(CH3)2OH, -C(CH3)2CN, More preferably, R7is selected from -C(CH3)2CF3,

[0108] R 8 is absent or is selected from halo, for example F.

[0109] In one embodiment, the present application provides a compound represented by Formula (IV) or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein:

[0110] X is N and Y is CR3R4, wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl and C 3-8 cycloalkyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halo; for example, R 3 and R 4 are independently selected from H, methyl and cyclopropyl, or R3and R4together with the carbon atom to which they are attached form cyclopropyl, azetidinyl, and oxetanyl optionally substituted with C 1-6 alkyl;

[0111] Z is CH or N;

[0112] L 2 is -CH2-;

[0113] R 7 is selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein the C 1-6 alkyl and C 3-8cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen and hydroxy; for example, R 7 selected from the group consisting of C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from the group consisting of isopropyl and tert-butyl optionally substituted with F, and said C 3-6 cycloalkyl is selected from the group consisting of cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R 7 selected from the group consisting of -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole;

[0114] R 8 selected from the group consisting of H and halogen, for example F.

[0115] [Corrected according to Rule 91 30.12.2025] In one embodiment, the present application provides a compound selected from the group consisting of:

[0116] [Corrected according to Rule 91 30.12.2025] In one embodiment, the present application provides a compound selected from the group consisting of:

[0117] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application as described above or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof and a pharmaceutically acceptable excipient.

[0118] In another aspect, the present application provides the use of a compound of the present application as described above or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof for the preparation of a medicament for the treatment of a disease or a disorder.

[0119] In another aspect, the present application provides a compound of the present application as described above or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof for use in the treatment of a disease or a disorder.

[0120] In another aspect, the present application provides a method of treating a disease or disorder, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present application as described above or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof.

[0121] In one embodiment, the disease or disorder is selected from cancer and inflammation.

[0122] In one embodiment, the cancer is lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasm type 2A or 2B (MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal stromal nerve cell tumor, and cervical cancer; the inflammation is ulcerative colitis.

[0123] In one embodiment, the cancer or inflammation is associated with or caused by a dysregulation of the RET gene and / or RET kinase expression or activity or level.

[0124] In one embodiment, the cancer is medullary thyroid cancer (MTC), non-small cell lung cancer (NSCLC), metastatic solid tumors with RET gene mutations / fusions, and advanced solid tumors.

[0125] Definitions and general terms

[0126] Unless otherwise indicated, the following terms have the meanings set forth below in the specification and claims:

[0127] "Alkyl" means a saturated aliphatic hydrocarbon group, the alkyl moiety can be straight-chain alkyl or branched-chain alkyl. For example, C1-C6alkyl means an alkyl group having from 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, and the like. The alkyl group can be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like. 1-6 Alkyl means an alkyl group having from 1 to 6 carbon atoms, for example, an alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, and the like. The alkyl group can be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.

[0128] "Ring" refers to any covalently closed structure, including, for example, carbocyclic (e.g., aryl or cycloalkyl), heterocyclic (e.g., heteroaryl or heterocycloalkyl), aromatic (e.g., aryl or heteroaryl), non-aromatic (e.g., cycloalkyl or heterocycloalkyl). The ring can be optionally substituted, and can be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic, tricyclic rings. The rings of the present application generally have from 1 to 20 ring atoms, e.g., 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms, 19 ring atoms, or 20 ring atoms.

[0129] "Member" refers to the number of skeletal atoms that make up a ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, for example, cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like. Of these, rings that contain heteroatoms in the skeletal atoms are heterocyclic rings; aromatic groups that contain heteroatoms are heteroaromatic groups; non-aromatic groups that contain heteroatoms are heterocycloalkyl groups, which include heterocycloalkyl groups.

[0130] "Heteroatom" refers to an atom other than carbon or hydrogen. One or more of the heteroatoms in the heterocyclic rings of the present application can be independently selected from O, S, N, Si, and P, but are not limited thereto.

[0131] "Cycloalkyl" refers to a cyclic hydrocarbon substituent that contains one or more rings which are saturated or partially unsaturated (containing one or more double bonds, but no ring has a completely conjugated pi-electron system and is not aromatic). Cycloalkyl further includes monocycloalkyl and polycycloalkyl groups, which contain from 3 to 20 carbon atoms that can form a ring, preferably from 3 to 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecane, cyclododecyl, cyclohexenyl, and the like; polycycloalkyl groups also include cycloalkyl groups that contain spiro, fused, and bridged ring structures. Typical cycloalkyl groups include, but are not limited to:

[0132]

[0133] It is understood that when a cycloalkyl group is attached to two groups according to the structure or context, the cycloalkyl group is a divalent group, i.e., has two points of attachment. In this case, it can also be referred to as a cycloalkylidene group. Examples of preferred cycloalkylidene groups include, but are not limited to, monocyclic structures such as cyclopropylidene, cyclobutylidene, cyclopentylidene (e.g., cyclopent-1,2-diyl, cyclopent-1,3-diyl), cyclohexylidene (e.g., cyclohex-1,2-diyl, cyclohex-1,3-diyl, cyclohex-1,4-diyl), cycloheptylidene, or cyclooctylidene, and the like.​

[0134] "Heterocycloalkyl" and "cycloheteroalkyl" are used interchangeably and refer to saturated or unsaturated, mono-, fused-, bridged-, and spiro-cyclic groups containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., N, O, S, or SO2). Preferably, the heteroatoms are N, O, and / or S. Heterocycloalkyl groups can be 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) monocyclic or bicyclic or tricyclic groups. Typical heterocycloalkyl groups include, but are not limited to, monovalent groups derived from the following rings: Preferably, the heteroatoms are N, O, and / or S. Heterocycloalkyl groups can be 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered, i.e., containing 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) monocyclic or bicyclic or tricyclic groups. Typical heterocycloalkyl groups include, but are not limited to, monovalent groups derived from the following rings:

[0135] These heterocycloalkyl groups can also be represented in the usual structural formulaic manner, e.g.,

[0136] It is understood that when a heterocycloalkyl group is connected to two groups according to the structure or context, the heterocycloalkyl group is a divalent group, i.e., has two points of attachment. In this case, it can also be referred to as a heterocycloalkylene group. Examples of heterocycloalkylene groups include, but are not limited to, divalent groups derived from the above groups, e.g.,

[0137] where R 10 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C(O)R f , R f is selected from hydrogen or C 1-3 alkyl; r, s, p, q are each independently selected from 0, 1, or 2.

[0138] "Aryl" refers to a monocyclic or fused polycyclic (that is, rings that share pairs of adjacent carbon atoms) ring system having 6 to 14 carbon atoms (6- to 14-membered), preferably having 6 to 10 atoms, e.g., phenyl and naphthyl. More preferably, aryl is phenyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring.

[0139] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms, 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 membered or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl, or pyrimidinyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring.

[0140] "Oxo" means a hydrogen on a carbon is replaced with =0.

[0141] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo.

[0142] "Haloalkyl" means an alkyl group as defined herein in which one or more hydrogens is replaced by the same or different halogen. Examples of haloalkyl include -CF3, -CH2Cl, -CH2CF3, -CH2CCl3, and the like.

[0143] "Ester" means a chemical group with the formula -COOR, where R can be an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, and the like. A C1-C4 ester group means a chemical group with the formula -COOR x1 , where R x1 is a C1-C4 alkyl group.

[0144] "Amido" means a chemical group with the formula "-CONR x1 R x2 " or "-NR x3 COR x4 ", where R x1 , R x2 , R x3 , and R x4 are independently H or a C 1-6 alkyl group.

[0145] The term "C 1-6 alkoxy" means a group R'-O-, where R' is a C 1-6 alkyl group.

[0146] "C 3-6 cycloalkyloxy" means a group R"-O-, where R" is a C 3-6 cycloalkyl group.

[0147] The term "substituted or unsubstituted" herein refers to any group that is monosubstituted or polysubstituted by a specified substituent to the extent that such monosubstituted or polysubstituted substitution (including multiple substitutions in the same moiety) is chemically permissible, each substituent may be located at any available position on the group and may be connected by any available atom on said substituent. "Any available position" means any position on said group that is chemically obtainable by methods known in the art or taught herein and does not produce excessively unstable molecules. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and may therefore be the same or different.

[0148] "Inhibitor" refers to a substance that reduces enzyme activity.

[0149] "RET selectivity" refers to the selective action of a compound on RET kinases or the inhibitory activity of RET-mediated proliferating cells, avoiding or minimizing inhibitory effects on other kinases or kinase-mediated proliferating cells. In this article, "RET selectivity (compared to VEGFR2)" refers to the selective action of a compound on RET kinases (including wild-type RET, RET-V804, RET-G810, etc., especially mutants such as RET-V804 and RET-G810) or their inhibitory activity on proliferating cells, avoiding or minimizing inhibitory effects on VEGFR2 kinase or its mediated proliferating cells. "RET selectivity (compared to VEGFR2)" can be measured, for example, by multiples, such as the IC50 of the compound on VEGFR2-mediated proliferating cells. 50 The value divided by its IC50 value for RET-mediated proliferative cells (e.g., RET-V804 proliferating cells or RET-G810 proliferating cells) 50 The value represents a multiple of "RET selectivity (compared to VEGFR2)". It is generally accepted in the art that a multiple less than 3 indicates no selectivity, while a multiple greater than 5 indicates significant selectivity. In this invention, the higher the multiple of "RET selectivity (compared to VEGFR2)", the stronger the selectivity of the RET relative to VEGFR2.

[0150] "RET activity uniformity" refers to the difference in inhibitory activity of a compound when it acts on different mutant / rearranged RET kinases or RET-mediated proliferating cells. This "RET activity uniformity" can be measured, for example, by measuring the IC50 of a compound on RET-V804 and RET-G810-mediated proliferating cells. 50 Value, with a relatively high IC 50Dividing the value by the relatively low IC50 value gives the multiple of "RET activity balance". In the art, it is generally considered that a multiple of 3 to 4 times indicates slight differences in activity and good activity balance; a multiple of less than 3 times indicates virtually no activity difference, i.e., even better activity balance; conversely, a multiple of more than 5 times indicates significant differences in activity, i.e., poor activity balance. In this invention, the lower the multiple of "RET activity balance", the better the RET activity balance.

[0151] "Optional" or "optionally" means that the event or environment described below may, but does not have to, occur, including the possibility that the event or environment may or may not occur. For example, "optionally substituted" means that it may or may not be substituted; "optionally alkyl-substituted heterocyclic alkyl" means that the alkyl group may, but does not have to, be present, including cases where the heterocyclic alkyl group is substituted by an alkyl group and cases where the heterocyclic alkyl group is not substituted by an alkyl group.

[0152] The term "stereoisomer" as used in this invention refers to the fact that when the compounds of this invention contain one or more asymmetric centers, they can exist as racemic mixtures and racemic mixtures, as single enantiomers, mixtures of diastereomers, and single diastereomers. The scope of this invention includes all possible optical isomers and mixtures thereof. Furthermore, if the compounds of this invention contain olefin double bonds, the scope of this invention includes cis and trans isomers unless otherwise specified.

[0153] The compounds of the present invention can also exist as tautomers (a type of functional group isomer) having different hydrogen connection sites through one or more double bond shifts; for example, ketones and their enol forms are keto-enol tautomers. All tautomers and mixtures thereof are within the scope of the present invention.

[0154] In this invention, when referring to the compounds of this invention, all enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof are included within the scope of this invention.

[0155] In the structural formulas of this invention, when the bonds connected to the chiral carbon are depicted as straight lines, it should be understood that the formula includes both (R) and (S) configurations of the chiral carbon, and therefore also includes both enantiomers and mixtures thereof. Similarly, when the chirality of the chiral carbon is not specified when describing a compound name, it should be understood that the name includes both (R) and (S) configurations of the chiral carbon, and thus also includes individual enantiomers and mixtures thereof. The generation of specific stereoisomers or mixtures thereof may be identified in examples of obtaining such stereoisomers or mixtures, but this is by no means a limitation to include all stereoisomers and mixtures thereof within the scope of this invention.

[0156] This invention encompasses all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers in all proportions, such as mixtures of enantiomers and / or diastereomers. Therefore, enantiomers are the subject of this invention in the following forms: enantiomerically pure forms (levorotatory and dextrorotatory enantiomers), racemic forms, and mixtures of two enantiomers in all proportions. In the case of cis / trans isomers, this invention encompasses both cis and trans forms, as well as mixtures of these forms in all proportions. If desired, the stereoisomers can be prepared individually by separating the mixture using conventional methods, such as chromatography or crystallization; by using stereochemically homogeneous starting materials for synthesis; or by stereoselective synthesis. Optionally, derivatization can be performed prior to the separation of stereoisomers. The separation of stereoisomer mixtures can be carried out as an intermediate step in the synthesis of the target compound, or using the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of the crystallized product or the derivatized crystallization intermediate, if desired, using reagents containing a stereoisomeric center with a known configuration. When the compounds of the present invention are capable of tautomerism, all individual tautomers and mixtures thereof are included within the scope of the present invention. Unless a specific isomer, salt, solvate (including hydrates), or solvated salt of such racemate, enantiomer, diastereomer, or tautomer is specified, the present invention includes all such isomers, salts, solvates (including hydrates), or solvated salts of such racemate, enantiomer, diastereomer, and tautomer, and mixtures thereof.

[0157] As used herein, the term "fused ring" refers to a 5- to 20-membered polycyclic structure in which each ring in the system shares a pair of adjacent ring atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 8- to 10-membered. Depending on the number of rings, fused rings can be classified as bicyclic, tricyclic, tetracyclic, or more rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic. The term "fused ring" as defined in the context of this invention includes fused carbon rings and fused heterocyclic rings. A fused heterocyclic ring is a fused ring in which the ring-forming atoms contain one or more heteroatoms selected from O, S, and N in addition to carbon, including, for example, fused aliphatic heterocyclic rings and fused heteroaromatic rings. Fused rings can be aromatic or non-aromatic; common typical fused ring aromatic compounds include, but are not limited to, naphthalene, anthracene, and phenanthrene; fused ring heterocyclic compounds include, but are not limited to, indole, quinoline, and purine.

[0158] The term "bridged ring" refers to a polycyclic structure with 5 to 20 rings, in which any two rings share two non-adjacent (i.e., "not directly connected") ring atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 rings, more preferably 7 to 10 rings. Bridged rings can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic based on the number of rings, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. The term "bridged ring" as defined in the context of this invention includes bridged carbocyclic rings and bridged heterocyclic rings. A bridged heterocyclic ring is one in which the ring-forming atoms contain one or more heteroatoms selected from O, S, and N in addition to carbon. The term "bridged cycloalkyl ring" as defined in the context of this invention refers to a bridged carbocyclic ring that does not contain unsaturated bonds.

[0159] The term "spirocyclic" refers to a polycyclic structure consisting of 5 to 20 cyclic rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 cyclic, more preferably 7 to 10 cyclic. The term "spirocyclic" as defined in the context of this invention includes spirocarbocyclic and spiroheterocyclic rings. A spiroheterocyclic ring contains one or more heteroatoms selected from O, S, and N in addition to carbon. The term "spirocycloalkyl" as defined in the context of this invention refers to a spirocarbocyclic ring that does not contain unsaturated bonds.

[0160] As used herein, the term "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.).

[0161] The “pharmaceutical composition” of this invention refers to a composition comprising one or more compounds of formula (I) or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, and a carrier or excipient generally accepted in the art for delivering a bioactive compound to an organism (e.g., a human).

[0162] As used herein, the term "pharmaceutical combination" refers to the combination of the compounds of the present invention with other active agents to achieve the objectives of the present invention. These other active agents may be one or more other compounds of the present invention, or may be a second or additional (e.g., a third) compound that is compatible with the compounds of the present invention, i.e., does not adversely affect each other, or has complementary activity. Such active agents are suitably combined in an effective amount to achieve the intended purpose. These other active agents may be administered co-administered with the compounds of the present invention in a single pharmaceutical composition, or separately administered in different discrete units, and when administered separately, may be simultaneously or sequentially. The sequential administration may be close in time or spaced apart.

[0163] As used in this invention, the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, the desired effect. For example, a therapeutically effective amount is an amount sufficient to cure or at least partially prevent the disease and its complications in a patient already suffering from the disease. A preventatively effective amount is an amount capable of effectively preventing, stopping, or delaying the onset of a disease. Determining such an effective amount is entirely within the capabilities of those skilled in the art. For example, an effective amount for therapeutic purposes will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general characteristics such as age, weight, and sex, the method of administration of the drug, and other concurrent treatments, etc.

[0164] The amount of the compound of the present invention, its stereoisomers, tautomers, or mixtures thereof, pharmaceutically acceptable salts, prodrugs, or deuterated compounds administered to an individual or subject depends on the type and severity of the disease or condition, as well as the characteristics of the subject, such as general health status, age, sex, weight, and tolerance to the drug. It also depends on the type of formulation and the route of administration, and factors such as the dosing cycle or time interval. Those skilled in the art can determine the appropriate dosage based on these and other factors. Generally, the daily dose of the compound of the present invention, its stereoisomers, tautomers, or mixtures thereof, pharmaceutically acceptable salts, prodrugs, or deuterated compounds for treatment can be approximately 0.0001 to 1000 mg / kg body weight / day, which can be administered once or in multiple divided doses as appropriate.

[0165] According to certain embodiments of the present invention, the pharmaceutically acceptable salts of the present invention refer to salts of compounds of the present invention that are pharmaceutically acceptable and have the expected pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chloro... Benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucohepanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions or aluminum ions) or coordinated with organic bases (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc.). Salts also include (by way of example) sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, etc.; when the compound contains basic functional groups, it also includes salts of non-toxic organic acids or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. The term "pharmaceutical-grade cation" refers to an acceptable positively charged counterion with an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium cations.

[0166] "Pharmaceutically acceptable excipients" refers to diluents, adjuvants, excipients, or carriers that are applied together with the compounds of this invention.

[0167] "Solvate" refers to a compound that associates with a solvent, typically through a solvation reaction. This physical association includes hydrogen bonding. Common solvents include water, EtOH, acetic acid, etc. The compounds of this invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include both stoichiometric and non-stoichiometric solvates. In some cases, solvates will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0168] The pharmaceutical compositions of the present invention can be administered in a standard manner. Suitable administration methods include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal, or pulmonary (inhalation) administration, wherein parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. For these purposes, the compounds of the present invention can be formulated by methods known in the art into, for example, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder formulations, and sterile injectable aqueous or oily solutions or suspensions.

[0169] Method for synthesizing the compounds of the present invention

[0170] The present invention also provides a method for synthesizing the above-mentioned compounds. The method of synthesis of the present invention mainly adopts the preparation methods reported in chemical literature or uses commercially available chemical reagents as starting materials for related synthesis.

[0171] The compounds of the present invention can be prepared by, for example, the following routes and methods.

[0172] Method 1

[0173] The steps are as follows:

[0174] a1) The compound shown in formula (i-1) is subjected to a nucleophilic substitution reaction with the compound shown in formula (ia) to obtain the compound shown in formula (i-2);

[0175] b1) The compound shown in formula (i-2) is subjected to a cyclization reaction in the presence of a cyclization urea-forming reagent (such as carbonyl diimidazole, carbonyl di(triazole) etc.) to obtain the compound shown in formula (i-3);

[0176] c1) The compound shown in formula (i-3) is reacted with an amino-protecting amino-containing ...

[0177] d1) The compound shown in formula (i-4) is coupled with the compound shown in formula (ib) or the compound shown in formula (i-4) is nucleophilically substituted with the compound shown in formula (i-b') to obtain the compound shown in formula (i-5).

[0178] e1) The compound shown in formula (i-5) is subjected to ester hydrolysis under the action of alkaline reagents to obtain the compound shown in formula (i-6);

[0179] f1) The compound shown in formula (i-6) is then subjected to an amidation condensation reaction with the compound shown in formula (ic) to obtain the compound shown in formula (i-7);

[0180] g1) Finally, the compound shown in formula (i-7) is deamino protecting group (e.g., 4-methoxybenzyl) to obtain the target compound of the present invention shown in formula (i-2);

[0181] Where Hal is a halogen (e.g., Br or Cl), Z and R 2 L 1 L 2 Cy Consistent with the foregoing definition, the compound represented by formula (ib) can also be a pinacol boron ester compound. When the compound shown in equation (i-1) is replaced with The target compound can be prepared using the same method as described in Method 1 above. Or when the compound shown in formula (i-1) is replaced with or Then, following the aforementioned method 1 (omitting step c1), the target compound was prepared. Among them, Z and R 2 L 1 L 2 Cy Consistent with the foregoing definition. In this invention, when R replaced by hydroxyl group 7 When substituted, the compound represented by formula (ic) can also be a derivative containing a hydroxyl protecting group or a carbonyl protecting group (e.g. In step g1), either the hydroxyl protecting group or the carbonyl protecting group can be removed simultaneously, and the carbonyl group can be further hydrogenated and reduced to R. 7 It is replaced by a hydroxyl group.

[0182] In some embodiments of the present invention, the compound of intermediate formula (i-4) can also be prepared by method 1 via the following path 2.

[0183] The steps are as follows: The compound shown in formula (i') undergoes a nucleophilic substitution reaction with the compound shown in formula (ia) to obtain the compound shown in formula (i'-1); then it reacts with an amino-protecting amino-containing ... At that time, the intermediate can be prepared using the method described in path 2 above. Among them, Z and R 2 Consistent with the aforementioned definition.

[0184] Method 2

[0185] The steps are as follows:

[0186] a2) The compound shown in formula (ii-1) is subjected to a nucleophilic substitution reaction with the compound shown in formula (ia) to obtain the compound shown in formula (ii-2);

[0187] b2) The compound shown in formula (ii-2) is reacted with a protected amination agent (e.g., bis(4-methoxybenzyl)amine) to give the compound shown in formula (ii-3);

[0188] c2) The compound shown in formula (ii-3) is subjected to a nucleophilic substitution reaction with the compound shown in formula (ib”) to obtain the compound shown in formula (ii-4);

[0189] d2) The compound shown in formula (ii-4) is subjected to a cyclization reaction in the presence of a cyclization urea-forming reagent (such as carbonyl diimidazole, carbonyl di(triazole) etc.) to obtain the compound shown in formula (i-5);

[0190] Repeating steps e1) to g1) of method 1 yields the target compound of the present invention shown in formula (I-2); when the compound shown in formula (ii-1) is replaced with Then, by using the same method as described in Method 2 above, the target compound shown in formula (I'-2) or formula (I”-2) above is prepared; wherein, Z, R 2 L 1 L 2 Cy Consistent with the aforementioned definition.

[0191] Method 3

[0192] The steps are as follows:

[0193] a3) The compound shown in formula (iii-1) is coupled with the compound shown in formula (id) to obtain the compound shown in formula (iii-2);

[0194] b3) Reaction of the compound shown in formula (iii-2) with an amino-protecting amino-containing amination reagent (e.g., 4-methoxybenzylamine) yields the compound shown in formula (iii-3);

[0195] c3) The compound shown in formula (iii-3) is hydrogenated and reduced in the presence of a reducing agent (such as iron powder), and then undergoes a ring-closure reaction spontaneously or under the catalysis of a basic reagent (such as potassium carbonate) to obtain the compound shown in formula (iii-4);

[0196] d3) The compound of formula (iii-4) is demethylated by hydrogenation reduction to obtain the compound shown in formula (iii-5);

[0197] e3) The compound shown in formula (iii-5) is coupled with the compound shown in formula (ib) or the compound shown in formula (iii-5) is nucleophilically substituted with the compound shown in formula (i-b') to obtain the compound shown in formula (iii-6);

[0198] f3) The compound shown in formula (iii-6) is subjected to ester hydrolysis under the action of alkaline reagents to obtain the compound shown in formula (iii-7);

[0199] g3) The compound shown in formula (iii-7) is then subjected to an amidation condensation reaction with the compound shown in formula (ic) to obtain the compound shown in formula (iii-8);

[0200] h3) Finally, the compound shown in formula (iii-8) is deamino protecting group (e.g., 4-methoxybenzyl) to obtain the target compound of the present invention shown in formula (I');

[0201] Where Hal is a halogen (e.g., Br or Cl), Z and R 3 R 4 L 1 L 2 Cy Consistent with the foregoing definition, the compound represented by formula (ib) can also be a pinacol boron ester compound. When the compound shown in formula (iii-1) is replaced with The target compound can be prepared using the same method as described in method 3 above. Or when the compound shown in formula (iii-1) is replaced with or Then, following method 3 described above (omitting step b3), the target compound was prepared. Among them, Z and R 3 R 4 L 1 L 2 Cy Consistent with the aforementioned definition.

[0202] In some embodiments of the present invention, when L 1 L 2 All are chemical bonds. When Cy is selected from 5- to 8-membered spirocycloalkyl groups optionally substituted with one or more substituents, the target compound (I”) can also be prepared by the following method.

[0203] The steps are as follows: The compound shown in formula (i'-3) and the compound shown in formula (ie) undergo a reductive amination reaction in the presence of a reducing agent (e.g., sodium borohydride, triacetylborohydride, etc.) to obtain the compound shown in formula (i'-4); then, a cyclization reaction is carried out in the presence of a urea-forming reagent (e.g., carbonyl diimidazole, carbonyl di(triazole) etc.) to obtain the compound shown in formula (i'-5); then, an ester hydrolysis reaction is carried out in the presence of a basic reagent to obtain the compound shown in formula (i'-6); then, an amidation condensation reaction is carried out with the compound shown in formula (ic) to obtain the compound shown in formula (i'-7); finally, the amino protecting group (e.g., 4-methoxybenzyl) is removed to obtain the target compound of the present invention shown in formula (I”); wherein, Z and R... 2 , Consistent with the foregoing definition, Cy is selected from 5- to 8-membered spirocyclic alkyl groups optionally substituted with one or more substituents.

[0204] In some embodiments of the present invention, when L 2 -N(R) 6B When )-, the target compound (I-2) can also be prepared by the following method,

[0205] The steps are as follows: The compound shown in formula (i-4) is coupled with the compound shown in formula (if) to obtain the compound shown in formula (i”-5); then the Boc protecting group is removed to obtain the compound shown in formula (i”-6); then, the compound shown in formula (ic) undergoes a urea-forming reaction with a urea-forming reagent (e.g., carbonyl diimidazole) to obtain the compound shown in formula (i-7); step g1) of method 1 is repeated to obtain the target compound of the present invention shown in formula (I-2); when the compound shown in formula (i-4) is replaced with an intermediate such as the compound shown in formula (iii-5) in method 3, the target compound shown in formula (I'), formula (I'-2), or formula (I”-2) can be prepared through the same path described above, wherein L 2 -N(R) 6B )-, Z, R 2 R 6B L 1 Cy Consistent with the aforementioned definition.

[0206] The compounds represented by the aforementioned starting materials (ia), (ib), (i-b'), (ib”), (ic), (id), and (ie) can be commercially available products or can be prepared by those skilled in the art using methods disclosed in the prior art; for example, when When the isoxazolyl group is present, the compound shown in formula (ic) can be obtained by the following methods.

[0207] The compound shown in formula (1c) is reacted with acetonitrile under strong base (e.g., LDA) to give the compound shown in formula (2c), which is then cyclized with hydroxylamine under alkaline conditions to give... For R 7 Compounds with substituted isoxazolyl groups as shown in formula (ic).

[0208] For example, 3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazole-5-amine is a commercially available product and can also be prepared by methods disclosed in the prior art, such as Preparation Example 1.

[0209] Preparation Example 1: Preparation of 3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazole-5-amine

[0210] Acetonitrile (1.44 g) was dissolved in tetrahydrofuran solution. The reaction system was cooled to -78 °C, and then LDA (2.12 g) was added and stirred for 1 hour. Finally, methyl 2-(trifluoromethyl)-2-methylpropionate (1 g) was added. After the addition was complete, the reaction system was stirred at -78 °C for 2 hours, and then slowly heated to room temperature and stirred for 16 hours. TLC showed that the reactants reacted completely. The reaction solution was quenched with saturated ammonium chloride solution, and ethyl acetate was added for extraction. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 4-trifluoromethyl-4-methyl-3-oxopentanilonitrile. 0.3 g of 4-trifluoromethyl-4-methyl-3-oxopentanilide was dissolved in an aqueous solution, followed by the addition of 0.22 g of hydroxylamine hydrochloride and 0.24 g of sodium hydroxide. After the addition was complete, the reaction system was heated to 100 °C and stirred for 3 hours. LC-MS showed that the reaction of the starting material was complete. Ethyl acetate was added for extraction, and the organic phases were combined. The organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-5-amine.

[0211] Similarly, 3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazole-5-amine, 3-(2-(1,4-dioxanespiro[4.4]non-7-yl)propyl-2-yl)isoxazole-5-amine, 3-(2-(pyridin-4-yl)propyl-2-yl)isoxazole-5-amine, and 3-(2-(3-(benzyloxy)cyclobutyl)propyl-2-yl)isoxazole-5-amine can also be prepared by Preparation 2, Preparation Example 3, Preparation Example 4, and Preparation Example 5, respectively.

[0212] Preparation Example 2: Preparation of 3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazole-5-amine

[0213] Acetonitrile (1.28 g) was dissolved in tetrahydrofuran solution. The reaction system was cooled to -78 °C, and then LDA (2.23 g) was added and stirred for 1 hour. Finally, methyl 2-(3,3-difluorocyclobutyl)-2-methylpropionate (1 g) was added. After the addition was complete, the reaction system was stirred at -78 °C for 2 hours, and then slowly heated to room temperature and stirred for 16 hours. TLC showed that the starting material reacted completely. The reaction solution was quenched with saturated ammonium chloride solution, and ethyl acetate was added for extraction. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 4-(3,3-difluorocyclobutyl)-4-methyl-3-oxopentanilonitrile. 4-(3,3-difluorocyclobutyl)-4-methyl-3-oxopentanilide (0.4 g) was dissolved in an aqueous solution, followed by the addition of hydroxylamine hydrochloride (0.24 g) and sodium hydroxide (0.26 g). After the addition was complete, the reaction system was heated to 100 °C and stirred for 3 hours. LCMS showed that the starting material reacted completely. Ethyl acetate was added for extraction, and the organic phases were combined. The organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-amine.

[0214] Preparation Example 3: Preparation of 3-(2-(1,4-dioxaspiro[4.4]non-7-yl)propyl-2-yl)isoxazole-5-amine

[0215] Acetonitrile (1.62 g) was dissolved in tetrahydrofuran solution. The reaction system was cooled to -78 °C, and then LDA (1.69 g) was added and stirred for 1 hour. Finally, methyl 2-(1,4-dioxolane[4,4]non-7-yl)-2-methylpropionate (1.8 g) was added. After the addition was complete, the reaction system was stirred at -78 °C for 2 hours, and then slowly heated to room temperature and stirred for 16 hours. TLC showed that the reactants were completely reacted. The reaction solution was quenched with saturated ammonium chloride solution, and ethyl acetate was added for extraction. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 4-(1,4-dioxolane[4,4]non-7-yl)-4-methyl-3-oxopentanilide. 1.2 g of 4-(1,4-dioxolane[4,4]non-7-yl)-4-methyl-3-oxopentanonitrile was dissolved in an aqueous solution, followed by the addition of hydroxylamine hydrochloride (0.6 g) and sodium hydroxide (0.67 g). After the addition was complete, the reaction system was heated to 100 °C and stirred for 3 hours. LCMS showed that the reaction of the starting material was complete. Ethyl acetate was added for extraction, and the organic phases were combined. The organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-(2-(1,4-dioxolane[4,4]non-7-yl)propyl-2-yl)isoxazol-5-amine.

[0216] Preparation Example 4: Preparation of 3-(2-(pyridin-4-yl)propyl-2-yl)isoxazole-5-amine

[0217] Acetonitrile (4.01 g) was dissolved in tetrahydrofuran solution. The reaction system was cooled to -78 °C, and then LDA (4.18 g) was added and stirred for 1 hour. Finally, methyl 2-(pyridin-4-yl)-2-methylpropionate (3.5 g) was added. After the addition was complete, the reaction system was stirred at -78 °C for 2 hours, and then slowly heated to room temperature and stirred for 16 hours. TLC showed that the starting material reacted completely. The reaction solution was quenched with saturated ammonium chloride solution, and ethyl acetate was added for extraction. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain 4-(pyridin-4-yl)-4-methyl-3-oxopentanilonitrile. 1.5 g of 4-(pyridin-4-yl)-4-methyl-3-oxopentanilide was dissolved in an aqueous solution, followed by the addition of 0.95 g of hydroxylamine hydrochloride and 1.06 g of sodium hydroxide. After the addition was complete, the reaction system was heated to 100 °C and stirred for 3 hours. LC-MS showed that the reaction of the starting material was complete. Ethyl acetate was added for extraction, and the organic phases were combined. The organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-(2-(pyridin-4-yl)propyl-2-yl)isoxazol-5-amine. Detailed Implementation

[0218] To further illustrate the present invention, the following detailed description, in conjunction with specific embodiments, provides further information on the cyclin-dependent kinase inhibitory compounds of the present invention, their preparation methods, and applications; however, the scope of protection of the present invention is not limited thereto.

[0219] In this invention, if the name and structural formula of the same compound are inconsistent, the structural formula shall prevail.

[0220] Abbreviations and their meanings: DMAP represents 4-dimethylaminopyridine; DCE represents 1,2-dichloroethane; DCM represents dichloromethane; THF represents tetrahydrofuran; TEA represents triethylamine; 1,4-dioxane represents 1,4-dioxane; H2O represents water; DIPEA represents N,N-diisopropylethylamine; LiOH represents lithium hydroxide; POCl3 represents phosphorus oxychloride; CDI represents N,N'-carbonyldiimidazole; Xphos Pd G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); K3PO4 represents anhydrous potassium phosphate; Pd(dppf)cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; NaHMDS represents sodium hexamethyldisilamide. Xphos represents 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl; PMB- represents 4-methoxybenzyl; Boc represents tert-butyloxycarbonyl; LDA represents lithium diisopropylamino; h represents hours.

[0221] Example 1: 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazo-5-yl)acetamide (Compound 1)

[0222] Step 1: 6-Chloro-N 4 Preparation of -isopropylpyrimidine-4,5-diamine (compound 1A)

[0223] 4,6-Dichloropyrimidin-5-amine (5.0 g, 30.49 mmol) was dissolved in n-butanol (50.0 mL) at room temperature, followed by the addition of isopropylamine (5.4 g, 91.47 mmol). After the addition was complete, the reaction mixture was stirred at 120 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 1A as a white solid. MS (ESI) m / z (M+H) + =187.2.

[0224] Step 2: Preparation of 6-chloro-9-isopropyl-7,9-dihydro-8H-purine-8-one (compound 1B)

[0225] 6-chloro-N 4 Isopropylpyrimidine-4,5-diamine (5.0 g, 26.79 mmol) was dissolved in tetrahydrofuran (100.0 mL), followed by the addition of carbonyl diimidazole (26.1 g, 160.74 mmol). After the addition was complete, the reaction mixture was stirred at 70 °C for 40 hours. After the reaction was nearly complete, the reaction solution was diluted with water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 1B. MS (ESI) m / z (M+H) + =213.1.

[0226] Step 3: Preparation of 9-isopropyl-6-((4-methoxybenzyl)amino)-7,9-dihydro-8H-purine-8-one (compound 1C)

[0227] 6-Chloro-9-isopropyl-7,9-dihydro-8H-purin-8-one (4.7 g, 22.10 mmol) was dissolved in n-butanol (55.0 mL), followed by the addition of 4-methoxybenzylamine (7.6 g, 55.26 mmol). After the addition was complete, the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by column chromatography to give compound 1C. MS (ESI) m / z (M+H)+ =314.2.

[0228] Step 4: Preparation of methyl 2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetate (compound 1D)

[0229] 9-Isopropyl-6-((4-methoxybenzyl)amino)-7,9-dihydro-8H-purin-8-one (1.0 g, 3.19 mmol) and (4-(2-methoxy-2-oxoethyl)phenyl)boronic acid (928.6 mg, 4.79 mmol) were dissolved in N,N-dimethylformamide (20.0 mL) and triethylamine (2.0 mL), followed by the addition of anhydrous copper acetate (695.6 mg, 3.83 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the starting materials had reacted substantially completely. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to give compound 1D. MS (ESI) m / z (M+H) + =462.3.

[0230] Step 5: Preparation of 2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetic acid (compound 1E)

[0231] Methyl 2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetate (600.0 mg, 1.3 mmol) was dissolved in tetrahydrofuran (10.0 mL) and water (10.0 mL), followed by the addition of lithium hydroxide monohydrate (109.1 mg, 2.60 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. LC-MS showed that the starting material reacted completely. The reaction solution was adjusted to pH 5 with 1 M hydrochloric acid, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give compound 1E. MS (ESI) m / z (M+H) + =448.3.

[0232] Step 6: Preparation of N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-yl)-2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)phenyl)acetamide (compound 1F)

[0233] 3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-amine (50.0 mg, 0.23 mmol), 2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetic acid (113.8 mg, 0.25 mmol), and N,N-diisopropylethylamine (89.66 mg, 0.69 mmol) were dissolved in dichloromethane (5.0 mL), followed by the addition of 1-propylphosphoric anhydride (220.7 mg, 0.35 mmol, 50%). After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the starting materials reacted substantially completely. The reaction mixture was concentrated, and the residue was purified by column chromatography to obtain compound 1F.

[0234] MS(ESI)m / z(M+H) + =646.3.

[0235] Step 7: Preparation of 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazo-5-yl)acetamide (compound 1)

[0236] N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-yl)-2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetamide (90.0 mg, 0.14 mmol) was dissolved in trifluoroacetic acid (5.0 mL). The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, adjusted to alkalinity with ammonia, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain compound 1.

[0237] MS(ESI)m / z(M+H) + =526.1.

[0238] 1 HNMR (400MHz, DMSO-d6) δ11.84(s,1H),8.14(s,1H),7.48(d,J=8.2Hz,2H),7.40(d,J=8.5Hz,2H),6.24(s, 1H), 5.59 (brs, 2H), 4.69-4.60 (m, 1H), 3.81 (s, 2H), 2.46-2.32 (m, 5H), 1.51 (d, J = 6.9Hz, 6H), 1.20 (s, 6H).

[0239] Example 2: Preparation of 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-5-yl)acetamide (compound 2):

[0240] Compound 2 of Example 2 was prepared by replacing 3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazole-5-amine in step 6 of Example 1 with 3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazole-5-amine using the same preparation method as in Example 1.

[0241] MS(ESI)m / z(M+H) + =504.2.

[0242] 1 H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.14(s,1H),7.52–7.44(m,2H),7.43–7.38(m,2H ),6.36–6.35(m,1H),5.59(s,2H),4.69–4.62(m,1H),3.82(s,2H),1.54–1.46(m,12H).

[0243] Example 3: Preparation of 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazo-5-yl)propionamide (compound 3)

[0244] Compound 3 of Example 3 was obtained by replacing (4-(2-methoxy-2-oxopropyl-2-yl)phenyl)boronic acid in step 4 of Example 1 with (4-(1-ethoxy-1-oxopropyl-2-yl)phenyl)boronic acid, using the same preparation method as in Example 1.

[0245] MS(ESI)m / z(M+H) + =540.2.

[0246] 1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.14(s,1H),7.54–7.47(m,2H),7.43–7.37(m,2H),6.27(s,1H), 5.62(s,2H),4.68–4.61(m,1H),4.00–3.95(m,1H),2.47–2.32(m,5H),1.52–1.47(m,9H),1.19(s,6H).

[0247] Example 4: Preparation of 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)-2-fluorophenyl)-N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazo-5-yl)acetamide (compound 4)

[0248] Compound 4 of Example 4 was obtained by replacing (4-(2-methoxy-2-oxyethyl)-3-fluorophenyl)boronic acid in step 4 of Example 1 with (4-(2-ethoxy-2-oxyethyl)-3-fluorophenyl)boronic acid and using the same preparation method as in Example 1.

[0249] MS(ESI)m / z(M+H) + =544.2.

[0250] 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.15(s,1H),7.54(t,J=8.0Hz,1H),7.37–7.34(m,1H),7.24–7.21(m,1H), 6.24(s,1H),5.78(s,2H),4.69–4.62(m,1H),3.87(s,2H),2.48–2.32(m,5H),1.51(d,J=8.0Hz,6H),1.20(s,6H).

[0251] Example 5: 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purine-7-yl)phenyl)-N-(3-(2-(3-hydroxycyclopentyl)propyl-2-yl)isoxazo-5-yl)acetamide (Compound 5)

[0252] Step 1: Preparation of N-(3-(2-(1,4-dioxaspiro[4.4]non-7-yl)propyl-2-yl)isoxazo-5-yl)-2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)phenyl)acetamide (compound 5A)

[0253] 2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetic acid (0.1 g, 0.22 mmol) was dissolved in dichloromethane, followed by the addition of 3-(2-(1,4-dioxaspiro[4.4]non-7-yl)propyl-2-yl)isoxazol-5-amine (0.067 g, 0.26 mmol), N,N-diisopropylethylamine (0.17 g, 1.32 mmol), and 1-propylphosphoric anhydride (0.28 g, 0.88 mmol). After the addition was complete, the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, the reaction system was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 5A. MS (ESI) m / z (M+H) + =682.2.

[0254] Step 2: Preparation of 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(2-(3-oxocyclopentyl)propyl-2-yl)isoxazol-5-yl)acetamide (compound 5B)

[0255] 0.08 g of N-(3-(2-(1,4-dioxaspiro[4.4]non-7-yl)propyl-2-yl)isoxazo-5-yl)-2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)phenyl)acetamide was dissolved in 5.0 mL of trifluoroacetic acid. After the addition was complete, the reaction system was heated to 70 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was concentrated and then ammonia was added dropwise to adjust to alkalinity. The solution was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 5B.

[0256] MS(ESI)m / z(M+H) + =518.2.

[0257] Step 3: Preparation of 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(2-(3-hydroxycyclopentyl)propyl-2-yl)isoxazo-5-yl)acetamide (compound 5)

[0258] 0.07 g of 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(2-(3-oxocyclopentyl)propyl-2-yl)isoxazo-5-yl)acetamide was dissolved in methanol, and 0.026 g of sodium borohydride was added. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution to quench the reaction, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 5 of Example 5.

[0259] MS(ESI)m / z(M+H) + =520.0.

[0260] 1 H NMR(400MHz, DMSO-d6)δ11.79(s,1H),8.14(s,1H),7.49–7.46(m,2H),7.42–7.38(m,2H),6.18–6.17(m,1H),5.59(s,2H),4.69–4.62(m, 1H),4.41–4.34(m,1H),4.01–3.98(m,1H),3.80(s,2H),2.12–1.57(m,3H),1.51(d,J=8.0Hz,6H),1.44–1.34(m,3H),1.19–1.09(m,7H).

[0261] Example 6: 2-(4-(4'-amino-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-5-yl)acetamide (Compound 6)

[0262] Step 1: Preparation of 4-chloro-6-methoxy-2-methylthio-5-nitropyrimidine (compound 6A)

[0263] 4,6-Dichloro-2-methylthio-5-nitropyrimidine (2.4 g) was dissolved in methanol, and sodium methoxide (0.59 g) was added at 0 °C. The reaction system was then heated and stirred for 2 hours. After the reaction was complete, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then separated by column chromatography to obtain compound 6A. MS (ESI) m / z (M+H) + =236.1.

[0264] Step 2: Preparation of methyl 3-(6-methoxy-2-(methylthio)-5-nitropyrimidin-4-yl)oxecyclobutane-3-carboxylic acid (compound 6B)

[0265] 1.5 g of 4-chloro-6-methoxy-2-methylthio-5-nitropyrimidine was dissolved in tetrahydrofuran solution, and 739.68 mg of methyl oxetane-3-carboxylate was added. The reaction system was cooled to -78 °C, and 2.13 g of bis(trimethylsilylamino)lithium was added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by vacuum distillation. The crude product was then separated by column chromatography to obtain compound 6B. MS (ESI) m / z (M+H) + =316.3.

[0266] Step 3: Preparation of methyl 3-(6-((4-methoxybenzyl)amino)-2-(methylthio)-5-nitropyrimidin-4-yl)oxecyclobutane-3-carboxylic acid (compound 6C)

[0267] Methyl 3-(6-methoxy-2-(methylthio)-5-nitropyrimidin-4-yl)oxetane-3-carboxylic acid (1.42 g) was dissolved in tetrahydrofuran solution, and p-methoxybenzylamine (0.62 g) and N,N-diisopropylethylamine (1.74 g) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated by vacuum distillation, and the crude product was separated by column chromatography to obtain compound 6C.

[0268] MS(ESI)m / z(M+H) + =421.4.

[0269] Step 4: Preparation of methyl 3-(5-amino-6-((4-methoxybenzyl)amino)-2-(methylthio)pyrimidin-4-yl)oxecyclobutane-3-carboxylic acid (compound 6D)

[0270] Methyl 3-(6-((4-methoxybenzyl)amino)-2-(methylthio)-5-nitropyrimidin-4-yl)oxetane-3-carboxylic acid (0.8 g) was dissolved in MeOH, and ammonium chloride (0.61 g) and iron powder (0.64 g) were added. The reaction system was heated to 60 °C and stirred for 1 hour. After the reaction was completed, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated by vacuum distillation, and the crude product was separated by column chromatography to obtain compound 6D.

[0271] MS(ESI)m / z(M+H)+ =391.4.

[0272] Step 5: Preparation of 4'-((4-methoxybenzyl)amino)-2'-(methylthio)spiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one (compound 6E)

[0273] Methyl 3-(5-amino-6-((4-methoxybenzyl)amino)-2-(methylthio)pyrimidin-4-yl)oxetane-3-carboxylic acid (0.6 g) was dissolved in methanol, and potassium carbonate (0.64 g) was added. After the addition was complete, the reaction system was heated to 60 °C and stirred for 2 hours. After the reaction was complete, water was added to the reaction solution and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated by vacuum distillation, and the crude product was separated by column chromatography to obtain compound 6E.

[0274] MS(ESI)m / z(M+H) + =359.4.

[0275] Step 6: Preparation of 4'-((4-methoxybenzyl)amino)spiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one (compound 6F)

[0276] 0.25 g of 4'-((4-methoxybenzyl)amino)-2'-(methylthio)spiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one was dissolved in a mixed solution of methanol and 1,4-dioxane, followed by the addition of Raney nickel (0.0041 g). After the addition was complete, hydrogen gas was introduced into the reaction system and the mixture was heated to 50 °C and stirred for 1 hour. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated by vacuum distillation. The crude product was separated by column chromatography to obtain compound 6F. MS (ESI) m / z (M+H) + =313.3.

[0277] Step 7: Preparation of ethyl acetate 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-5'(6'H)-yl)phenyl) (compound 6G)

[0278] 0.14 g of 4'-((4-methoxybenzyl)amino)spiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-6'(5'H)-one was dissolved in N,N-dimethylformamide, and 0.11 g of (4-(2-ethoxy-2-oxoethyl)phenyl)boronic acid, 0.14 g of triethylamine, 0.098 g of copper acetate, and molecular sieves were added. Oxygen was bubbled into the reaction system and the mixture was heated to 80 °C and stirred for 5 hours. After the reactants had reacted completely, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The crude product was separated by column chromatography to give compound 6G. MS (ESI) m / z (M+H) + =475.5.

[0279] Step 8: Preparation of 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-5'(6'H)-yl)phenyl)acetic acid (compound 6H)

[0280] Ethyl 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidin]-5'(6'H)-yl)phenyl)ethyl acetate (0.15 g) was dissolved in 1,2-dichloroethane solution, and trimethyltin hydroxide (0.58 g) was added. The reaction system was heated to 80 °C and stirred for 5 hours. After the reaction was completed, water was added to the reaction solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The crude product was separated by column chromatography to give compound 6H. MS(ESI) m / z(M+H) + =447.6.

[0281] Step 9: Preparation of 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-5-yl)acetamide (compound 6I)

[0282] 0.1 g of 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidin]-5'(6'H)-yl)phenyl)acetic acid was dissolved in dichloromethane, followed by the addition of 0.0431 g of 3-(1,1,1-trifluoro-2-methylpropyl-2-yl)-isoxazol-5-amine, 0.17 g of N,N-diisopropylethylamine, and 0.21 g of 1-propylphosphonic anhydride. The reaction mixture was stirred at room temperature for 2 hours after the addition was complete. After the reaction was complete, the reaction solution was concentrated by vacuum distillation, and the crude product was separated by column chromatography to obtain compound 6I. MS (ESI) m / z (M+H) + =623.6.

[0283] Step 10: Preparation of 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-5-yl)acetamide (compound 6)

[0284] 90 mg of 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidine]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-5-yl)acetamide was dissolved in 1,2-dichloroethane solution, and 0.032 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added. After the addition was complete, the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, a saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The crude product was purified by preparative HPLC to obtain compound 6 of Example 6.

[0285] MS(ESI)m / z(M+H) + =503.4.

[0286] 1¹H NMR (400MHz, DMSO-d6) δ 11.41 (s, 1H), 8.38 (s, 1H), 7.51–7.44 (m, 2H), 7.41–7.33 (m, 2H), 6.97 (s, 1H), 5.49 (s, 2H), 4.82–4.73 (m, 4H), 3.82–3.80 (m, 2H), 1.54–1.50 (m, 6H). Comparative Example 7: 4-((6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purine-7-yl)methyl)-N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-yl)benzamide (Compound 7)

[0287] Step 1: Preparation of methyl 4-((9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)methyl)benzoate (compound 7A)

[0288] 1.0 g of methyl 4-(bromomethyl)benzoate, 1.37 g of 9-isopropyl-6-((4-methoxybenzyl)amino)-7,9-dihydro-8H-purin-8-one, and 1.81 g of potassium carbonate were dissolved sequentially in 20.0 mL of N,N-dimethylformamide. The mixture was then heated to 100 °C and reacted for 16 hours. After the reaction was complete, the reaction solution was poured into ice water and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated by vacuum distillation. The crude product was purified by column chromatography to give compound 7A. MS (ESI) m / z (M+H) + =462.2.

[0289] Step 2: Preparation of 4-((9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)methyl)benzoic acid (compound 7B)

[0290] 1.5 g of methyl 4-((9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)methyl)benzoate was dissolved in a mixed solvent of tetrahydrofuran (40.0 mL), methanol (40.0 mL), and water (20.0 mL), and 0.39 g of lithium hydroxide was added. The system was then heated to 25 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was adjusted to pH 2–3 with 1 N hydrochloric acid in an ice bath, and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and the organic phase was concentrated by vacuum distillation. The crude product was purified by column chromatography to give compound 7B. MS (ESI) m / z (M+H) +=448.5.

[0291] Step 3: Preparation of N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-yl)-4-((9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)methyl)benzamide (compound 7C)

[0292] 3-(2-(3,3-difluorocyclobutyl)propan-2-yl)isoxazol-5-amine (0.1 g), 4-((9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)methyl)benzoic acid (0.21 g), and N,N-diisopropylethylamine (0.36 g) were dissolved in dichloromethane (15.0 mL), and 1-propylphosphoric anhydride (0.59 g) was slowly added dropwise. After the addition was complete, the system was heated to 80 °C and reacted for 36 hours. The reaction was complete. After the reaction was complete, the reaction solution was concentrated by vacuum distillation, and the crude product was separated by column chromatography to obtain compound 7C. MS (ESI) m / z (M+H) + =646.3.

[0293] Step 4: Preparation of 4-((6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purine-7-yl)methyl)-N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-yl)benzamide (compound 7)

[0294] N-(3-(2-(3,3-difluorocyclobutyl)propyl-2-yl)isoxazol-5-yl)-4-((9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)methyl)benzamide (250 mg) was dissolved in trifluoroacetic acid (20.0 mL), and the system was then heated to 80 °C and reacted for 1 hour. After the reaction was complete, the reaction solution was concentrated, adjusted to alkalinity with ammonia, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain compound 7.

[0295] MS(ESI)m / z(M+H) + =526.2.

[0296] 1H NMR (400MHz, DMSO-d6) δ10.67(s,1H),8.05(s,1H),8.00–7.89(m,2H),7.30(d,J=8.0Hz,2H),6.49(s,2 H), 6.41 (s, 1H), 5.32 (s, 2H), 4.69–4.62 (m, 1H), 2.50–2.31 (m, 5H), 1.49 (d, J = 4.0Hz, 6H), 1.23 (s, 6H).

[0297] Example 30: 2-(4-(6-amino-8-oxo-9-(propyl-2-yl)-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazo-5-yl)acetylurea (compound 30)

[0298] Step 1: Preparation of tert-butyl 4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenylcarbamate

[0299] 9-Isopropyl-6-((4-methoxybenzyl)amino)-7,9-dihydro-8H-purin-8-one (1.5 g) and 4-tert-butoxycarbonylaminophenylboronic acid (1.7 g) were dissolved in N,N-dimethylformamide (30.0 mL) and triethylamine (3.0 mL), followed by the addition of anhydrous copper acetate (1.1 g). After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the starting materials had reacted substantially completely. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =505.2.

[0300] Step 2: Preparation of 4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)phenylamine

[0301] 1.0 g of tert-butyl 4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenylcarbamate was dissolved in 30 mL of methanol. A solution of 1,4-dioxane in hydrochloric acid (5.0 mL) was added to the system. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was concentrated and adjusted to alkalinity with sodium bicarbonate solution. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain the title compound.

[0302] MS(ESI)m / z(M+H) + =405.2.

[0303] Step 3: Preparation of 3-(3-(2-(trifluoromethyl)propyl-2-yl)isoxazo-5-yl)-1-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)phenyl)urea

[0304] 3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazol-5-amine (310 mg), 4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)phenylamine (644 mg), and triethylamine (323.2 mg) were dissolved in tetrahydrofuran (15 mL), and carbonyl diimidazole (390 mg) was added under ice bath conditions. After the addition was complete, the reaction system was stirred at room temperature for 16 hours. LC-MS showed that the starting materials reacted substantially completely. After the reaction solution was concentrated, the residue was purified by column chromatography to obtain the title compound.

[0305] MS(ESI)m / z(M+H) + =625.2.

[0306] Step 4: Preparation of 1-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-3-(3-(2-(trifluoromethyl)propyl-2-yl)isoxazo-5-yl)urea (compound 30)

[0307] 200 mg of 3-(3-(2-(trifluoromethyl)propyl-2-yl)isoxazol-5-yl)-1-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purine-7-yl)phenyl)urea was dissolved in 10 mL of trifluoroacetic acid. The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, adjusted to alkalinity with ammonia, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain compound 30.

[0308] MS(ESI)m / z(M+H) + =504.9.

[0309] 1H NMR(400MHz, DMSO-d6)δ9.77(d,J=1.8Hz,1H),9.07(d,J=2.2Hz,1H),8.13(s,1H),7.66–7.58(m,2H) ,7.46–7.33(m,2H),6.92(s,1H),5.60(s,2H),4.70–4.60(m,1H),1.56(s,6H),1.51(d,J=6.9Hz,6H).

[0310] Example 32: 2-(3-(6-amino-8-oxo-9-(propyl-2-yl)-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pentan-1-yl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)-isoxazol-5-yl)acetamide (Compound 32)

[0311] Step 1: Preparation of 5-bromo-6-chloro-N-isopropylpyrimidine-4-amine (compound 32A)

[0312] 5-Bromo-4,6-dichloropyrimidine (1 g), isopropylamine (0.26 g), and triethylamine (0.89 g) were successively dissolved in n-butanol (5 mL) at room temperature, and reacted at 120 °C for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography to obtain compound 32A. MS (ESI) m / z (M+H) + =250.0.

[0313] Step 2: 5-Bromo-N 4 -Isopropyl-N 6 N 6 Preparation of bis(4-methoxybenzyl)pyrimidine-4,6-diamine (compound 32B)

[0314] 5-Bromo-6-chloro-N-isopropylpyrimidine-4-amine (1 g), N,N-bis(4-methoxybenzyl)amine (4.11 g), and triethylamine (3.23 g) were successively dissolved in n-butanol (10 mL) at room temperature and reacted at 120 °C for 48 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was then separated into compound 32B by column chromatography. MS (ESI) m / z (M+H) + =471.2.

[0315] Step 3: Preparation of ethyl acetate 2-(3-((4-(bis(4-methoxybenzyl)amino)-6-(isopropylamino)pyrimidin-5-yl)amino)bicyclo[1.1.1]pentan-1-yl) (compound 32C)

[0316] 5-Bromo-N at room temperature 4 -Isopropyl-N 6 N 6 Bis(4-methoxybenzyl)pyrimidine-4,6-diamine (0.5 g), 6-aminospiro[3.3]heptane-2-ethyl acetate (0.027 g), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.37 g), tris(dibenzylacetone)dipalladium (0.29 g), and cesium carbonate (1.04 g) were added to toluene (5 mL), purged with nitrogen, and the system was reacted overnight at 110 °C. After the reaction was complete, the system was cooled to room temperature, methanol was added, and the reaction was stirred for 2 h. The mixture was then concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain compound 32C. MS (ESI) m / z (M+H) + =546.3.

[0317] Step 4: Preparation of ethyl acetate 2-(3-(6-(bis(4-methoxybenzyl)amino)-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pentane-1-yl) (compound 32D)

[0318] At room temperature, 0.05 g of ethyl acetate (3-((4-(bis(4-methoxybenzyl)amino)-6-(isopropylamino)pyrimidin-5-yl)amino)bicyclo[1.1.1]pentan-1-yl), 0.030 g of N,N'-carbonylbis(1,2,4-triazole), and 0.014 g of triethylamine were successively dissolved in dichloromethane (5 mL), and the system was reacted at 80 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated by column chromatography to obtain compound 32D. MS (ESI) m / z (M+H) + =572.2.

[0319] Step 5: Preparation of 2-(3-(6-(bis(4-methoxybenzyl)amino)-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pentan-1-yl)acetic acid (compound 32E)

[0320] Ethyl 2-(3-(6-(bis(4-methoxybenzyl)amino)-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pentan-1-yl) (20 mg) and lithium hydroxide (4.2 mg) were dissolved sequentially in water (0.5 mL), methanol (1.5 mL), and tetrahydrofuran (0.5 mL) at room temperature, and reacted for 1 hour at room temperature. After the reaction was complete, the pH of the system was adjusted to acidic with dilute hydrochloric acid in an ice bath, and then extracted three times with dichloromethane. The organic phases were combined, dried, and concentrated to give crude compound 32E. No purification is required; it can be used directly in the next step. MS (ESI) m / z (M+H) + =558.3.

[0321] Step 6: Preparation of 2-(3-(6-bis[(4-methoxyphenyl)methyl]amino)-8-oxo-9-(propyl-2-yl)-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pent-1-yl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)-isoxazol-5-yl)acetamide (compound 32F)

[0322] At room temperature, 15 mg of 2-(3-(6-(bis(4-methoxybenzyl)amino)-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pentan-1-yl)acetic acid, 5.2 mg of 3-(1,1,1-trifluoro-2-methyl-2-propyl)-isoxazol-5-amine, and 35 mg of N,N-diisopropylethylamine were dissolved sequentially in dichloromethane (5 mL). 69 mg of 1-propylphosphonic anhydride was slowly added dropwise under ice bath conditions. After the addition was complete, the system was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was then separated by column chromatography to obtain compound 32F. MS (ESI) m / z (M+H) + =734.3.

[0323] Step 7: Preparation of 2-(3-(6-amino-8-oxo-9-(propyl-2-yl)-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pentan-1-yl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)isoxazo-5-yl)acetamide (compound 32)

[0324] 2-(3-(6-bis[(4-methoxyphenyl)methyl]amino)-8-oxo-9-(propyl-2-yl)-8,9-dihydro-7H-purin-7-yl)bicyclo[1.1.1]pent-1-yl)-N-(3-(1,1,1-trifluoro-2-methylpropyl-2-yl)-isoxazol-5-yl)acetamide (60 mg) was dissolved in trifluoroacetic acid (0.5 mL) at room temperature, and the system was stirred at 70 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain Example 32.

[0325] MS(ESI)m / z(M+H) + =494.2.

[0326] 1 H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.05(s,1H),6.44–6.35(m,1H),6.04(s, 2H), 4.56 (m, 1H), 2.73 (s, 2H), 2.37 (s, 6H), 1.51 (s, 6H), 1.43 (d, J = 6.8Hz, 6H).

[0327] Compound A: 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(3-(2-(3-hydroxycyclobutyl)propyl-2-yl)isoxazo-5-yl)acetamide

[0328] Step 1: Preparation of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine (compound A-1)

[0329] 3-Iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (3 g) was dissolved in DMF, and potassium carbonate (3.18 g) was added. The reaction system was cooled to 0 °C, and 2-iodopropane (2.15 g) was added. The reaction system was then naturally heated to room temperature and stirred for 5 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried with anhydrous sodium sulfate. The organic phase was removed by vacuum distillation, and the crude product was separated by column chromatography to obtain compound A-1.

[0330] MS(ESI)m / z(M+H) + =304.0.

[0331] Step 2: Preparation of ethyl acetate 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl) (compound A-2)

[0332] 1.6 g of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine was dissolved in a mixed solution of ethylene glycol dimethyl ether and water. Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)ethyl acetate (1.84 g), Pd(dppf)Cl2 (0.39 g), and sodium carbonate (1.68 g) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and removed by vacuum distillation. The crude product was separated by column chromatography to obtain compound A-2. MS(ESI) m / z(M+H) + =340.15.

[0333] Step 3: Preparation of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetic acid (compound A-3)

[0334] Ethyl 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)ethyl acetate (0.8 g) was dissolved in a mixed solution of water, methanol, and tetrahydrofuran. Lithium hydroxide (0.28 g) was added, and the reaction mixture was stirred at room temperature for 2 hours after the addition was complete. After the reaction was complete, 1 M HCl was added to the reaction solution to adjust the pH to weakly acidic. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and removed by vacuum distillation. The crude product was separated by column chromatography to obtain compound A-3. MS(ESI) m / z(M+H) + =312.1.

[0335] Step 4: Preparation of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(3-(2-(3-(benzyloxy)cyclobutyl)propyl-2-yl)isoxazo-5-yl)acetamide (compound A-4)

[0336] 0.1 g of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetic acid was dissolved in dichloromethane, followed by the addition of 0.092 g of 3-(2-(3-(benzyloxy)cyclobutyl)propyl-2-yl)isoxazol-5-amine, 0.25 g of DIPEA, and 0.81 g of T3P. The reaction mixture was stirred at room temperature for 2 hours after the addition was complete. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 0.1 g of the title compound. MS (ESI) m / z (M+H) +=580.9.

[0337] Step 5: Preparation of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(3-(2-(3-(benzyloxy)cyclobutyl)propyl-2-yl)isoxazo-5-yl)acetamide (compound A)

[0338] 0.1 g of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(3-(2-(3-(benzyloxy)cyclobutyl)propyl-2-yl)isoxazo-5-yl)acetamide was dissolved in dichloromethane solution. The reaction system was cooled to 0 °C, and 0.89 g of trifluoromethanesulfonic acid was added. After the addition was complete, the reaction system was stirred at 0 °C for 2 hours. LCMS showed that the starting material reacted completely. Triethylamine was added to the reaction solution to adjust the pH to neutral, and then dichloromethane was added for extraction. The organic phases were combined and dried with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain compound A.

[0339] MS(ESI)m / z(M+H) + =490.9.

[0340] 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.24(s,1H),7.64(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),6.14(s,1H),5.10– 5.03(m,1H),4.89–4.85(m,1H),3.78(s,3H),2.05–1.99(m,2H),1.89–1.79(m,1H),1.54–1.48(m,8H),1.14(s,6H).

[0341] The following compounds were prepared using appropriate raw materials and reagents in a manner similar to that described in the above embodiments.

[0342] Biological Experiment Example 1: Cell Proliferation Inhibition Test

[0343] 1. Materials and reagents:

[0344] 2. Experimental Methods:

[0345] The cell proliferation inhibitory activity of the compounds was determined using CTG (CELLTITER-GLO) luminescence assay. The compounds were initially used at a concentration of 10 μM, diluted 3-fold, and analyzed in replicates at 10 concentrations.

[0346] (1) Day 0: Cell plating

[0347] Ba / F3-TEL-VEGFR2, Ba / F3-KIF5B-RET-V804M, and Ba / F3-KIF5B-RET-G810R cells were revived using complete culture medium (RPMI 1640 + 10% FBS + 1% P / S). After approximately two passages, cells in the logarithmic growth phase were collected by centrifugation and counted. The cells were resuspended to an appropriate concentration, and the cell suspension was seeded into 96-well plates, with 95 μL of cell suspension added to each well, at a seeding density of 2000 cells / well.

[0348] (2) Day 1: Drug administration

[0349] The test compound was prepared into a stock solution using DMSO. It was serially diluted three times with DMSO at a maximum concentration of 10 mM to obtain 10 concentration gradients. The test compound was diluted 50 times with culture medium. 5 μL of each solution was added to a 96-well cell plate containing 95 μL of cells. Cell-free culture medium (containing 0.1% DMSO) was added to the Min control wells. 5 μL of DMSO-cell culture medium mixture (final DMSO concentration of 0.1%) was added to the Max control wells. The plates were incubated for 3 days in an incubator at 37°C, 5% CO2, and a relative humidity of 90% or higher.

[0350] (3) Day 4: Data Detection

[0351] Add 50 μL / well CellTiter Glo to stop the reaction, incubate at room temperature in the dark with shaking for 30 min, and read the RLU value of each well on a SpectraMax Paradigm microplate reader.

[0352] (4) Data Analysis

[0353] The cell growth inhibition rate is calculated using the formula: Cell growth inhibition rate % = (1 - As / Ac) × 100. Where As represents RLU. 样品 (Cells + CTG + Test Compound) - RLU Min (Cell-free culture medium), Ac:RLU normal growth cell control (cells + CTG + DMSO) -RLU Min (Cultural medium without cells)

[0354] Enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in Excel. Use Graphpad Prism 8.0 software to calculate the half-maximal inhibitory concentration (IC50) of each compound according to the built-in four-parameter fitting formula Y = Bottom + (Top - Bottom) / (1 + (IC50 / X) * HillSlope). 50 )value.

[0355] 3. Experimental Results:

[0356] The compounds of this invention exhibit significant inhibitory activity against RET-mediated proliferating cells, particularly against RET mutant-mediated proliferating cells. Experiments revealed that the IC50 of the compounds of this invention against RET mutant proliferating cells (e.g., V804M, G810R) is [value missing]. 50 The IC50 value is less than or equal to 50 nM. In this invention, certain compounds exhibit inhibitory activity against RET mutant proliferating cells (e.g., V804M, G810R). 50 The IC50 value of certain compounds in this invention is greater than or equal to 25 nM and less than 50 nM, indicating their inhibitory activity against RET mutant proliferating cells (e.g., V804M, G810R). 50 The IC50 value of certain compounds in this invention is greater than or equal to 10 nM and less than 25 nM, indicating their inhibitory activity against RET mutant proliferating cells (e.g., V804M, G810R). 50 The IC50 values ​​of certain compounds in this invention that inhibit RET mutant proliferating cells (e.g., V804M, G810R) are greater than or equal to 5 nM and less than 10 nM.

[0357] Table A In the table: A+: <5nM; A: ≥5nM and <10nM; B: ≥10nM and <25nM; C: ≥25nM and <50nM; D: ≥50nM and <200nM; E: ≥200nM and <500nM; F: ≥500nM and <1000nM; G: ≥1000nM and <5000nM; H: ≥5000nM. " / " indicates not detected or not applicable.

[0358] Biological Experiment Example 2: RET Kinase Inhibition Test

[0359] 1. Materials and reagents:

[0360] 2. Experimental Methods:

[0361] Preparation of kinase reaction buffer: Kinase Buffer: 40mM Tris-HCl, pH 7.5; 20mM MgCl2; 0.1mg / ml BSA; 50μM DTT.

[0362] Compounds: The test compound was dissolved in a 100% dimethyl sulfoxide (DMSO) system to prepare a 10 mM solution for later use, and stored in a nitrogen cabinet protected from light.

[0363] Reaction conditions:

[0364] Detection method:

[0365] 1. Add 2 μL of kinase and 1 μL of compound to a 384 plate and incubate at room temperature for 5 minutes;

[0366] 2. Add 2 μL of substrate / ATP mixture and incubate at room temperature for 60 minutes;

[0367] 3. Add 5μL of ADP-Glo TM Reagent, incubate at room temperature for 40 minutes;

[0368] 4. Add 10 μL of Kinase Detection Reagent and incubate at room temperature for 30 minutes;

[0369] 5. Read the plate on the microplate reader and record the luminescence (set the integration time to 0.50 seconds).

[0370] Data processing:

[0371] Inhibition rate calculation formula:

[0372] 3. Experimental Results:

[0373] The compounds of this invention exhibit significant inhibitory activity against RET kinase, particularly against RET kinase mutants. Experiments revealed that the IC50 of the compounds of this invention against RET mutants (e.g., V804M, G810R) is [value missing]. 50 The IC50 value is less than or equal to 5 nM. For certain compounds in this invention, the IC50 value indicates their inhibitory activity against RET mutants (e.g., V804M, G810R). 50 The IC50 value is greater than or equal to 3 nM and less than 5 nM. In this invention, certain compounds exhibit inhibitory activity against RET mutants (e.g., V804M, G810R) at IC50 values. 50 The IC50 value is greater than or equal to 1 nM and less than 3 nM. In this invention, certain compounds exhibit inhibitory activity against RET mutants (e.g., V804M, G810R) at IC50 values. 50The IC50 values ​​of the inhibitory activity of certain compounds in this invention, such as RET mutants (e.g., V804M, G810R), are greater than or equal to 0.5 nM and less than 1 nM.

[0374] The above embodiments and test examples are exemplary instances that specifically illustrate the present invention and are not intended to limit the scope of protection of the present invention. Any improvements, modifications, equivalent structural or procedural changes made based on the principles of the present invention and the contents of the specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A compound of Formula I ###0001### Formula I or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof. wherein: X is N or CR 1 ; Y is NR 2 or CR 3 R 4 ; L 1 is selected from a chemical bond, -0-, -S-, -C(R 5A R 5B )- and -N(R 6A )-; Ar is selected from aryl and heteroaryl, optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl, and amino; Q is The group is selected from 6-membered aryl, 5- to 6-membered heteroaryl, and 5- to 8-membered cycloalkyl, preferably selected from phenyl, 5-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl, and 5- to 8-membered spirocycloalkyl, such as phenyl, isoxazolyl, pyrazolyl, isothiazolyl, and others. More preferably selected from 5-membered heteroaryl, such as isoxazolyl, pyrazolyl and isothiazolyl, all of which are optionally substituted with one or more R 7 substituents; L 2 is selected from a chemical bond, -0-, -S-, -C(R 5C R 5D )- or -N(R 6B )-, provided that L 1 and L 2 one of L R 1 is H or C 1-6 alkyl; R 2 selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl and amino; R 3 and R 4 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl and amino; or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl, and amino; R 5A , R 5B , R 5C , R 5D , R 6A and R 6B are independently of each other H or C 1-6 alkyl; R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy.

2. A compound of Formula I' ###0002### I' or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: X is N or CR 1 ; Y is NR 2 or CR 3 R 4 ; Z is CH or N; R A , R B each independently NH2or H, and R A , R B are not simultaneously NH; L 1 selected from a chemical bond, -0-, -S-, -C(R 5A R 5B )- and -N(R 6A )-; Cy is selected from aryl, heteroaryl, or cycloalkyl groups optionally substituted with one or more substituents, preferably selected from phenyl, naphthyl, 5- to 6-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl, or 5- to 8-membered spirocycloalkyl, for example selected from phenyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and pyrazinyl groups. said substituents are selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl and amino; Q is selected from the group consisting of 6-membered aryl, 5- to 6-membered heteroaryl and 5- to 8-membered cycloalkyl, preferably selected from the group consisting of phenyl, 5-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl and 5- to 8-membered saturated spirocycloalkyl, such as phenyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, More preferably selected from 5-membered heteroaryl, such as isoxazolyl, pyrazolyl and isothiazolyl, all of which are optionally substituted with one or more R 7 substituents; L 2 is selected from a chemical bond, -O-, -S-, -C(R 5C R 5D )-, or -N(R 6B )-, provided that L 1 and L 2 is a chemical bond, or when both L 1 and L 2 are chemical bonds, Cy is selected from 5- to 8-membered spirocycloalkyl (e.g. )； R 1 is H or C 1-6 alkyl; R 2 selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl and amino; R 3 and R 4 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl and amino; or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl, and amino; R 5A , R 5B , R 5C , R 5D , R 6A and R 6B are independently of each other H or C 1-6 alkyl; R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano, pyridyl, phenyl and hydroxy.

3. The compound of claim 1 or 2, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: X is N and Y is NR 2 , wherein R2is selected from C 1-6 alkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogen, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl is optionally substituted with one or more halogen, for example 1, 2 or 3 halogen, for example F; for example, R2is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3, 4. The compound of claim 1 or 2, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: X is N and Y is CR 3 R 4 , wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl and C 3-8 cycloalkyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3- to 8-membered heterocyclyl, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl being optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example R 3 and R 4 are independently selected from H, methyl and cyclopropyl, or R 3 and R 4 together with the carbon atom to which they are attached form cyclopropyl, azetidinyl and oxetanyl, optionally substituted with C 1-6 alkyl.

5. The compound of any one of claims 1 to 4, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: L 1 is a chemical bond or -CH2-; preferably, L 1 is a chemical bond.

6. The compound of any one of claims 1, 3 to 5, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: Ar is phenyl or pyridyl, which phenyl and pyridyl are optionally substituted with one or more halogen, e.g. F; preferably, Ar is phenyl optionally substituted with halogen, e.g. F, wherein Q and L 1 are in para position to each other.

7. The compound of any one of claims 1 to 6, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: Q is wherein: L 2 is a chemical bond or -C(R 5C R 5D )-; preferably, L 2 is -C(R 5C R 5D )-, for example -CH2- or -CH(CH3)-, more preferably L 2 is -CH2-. R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl, optionally substituted with F, and said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl, optionally substituted with F and hydroxy; preferably, R7is selected from -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole; Preferably, R 7 the ortho position of the nitrogen atom of said isoxazolyl.

8. The compound of claim 1 having the structure of Formula I-1 or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: L 1 is selected from a chemical bond, -0-, -S-, -C(R 5A R 5B )- and -N(R 6A )-; Ar is selected from aryl and heteroaryl, optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl, and amino; Q is selected from the group consisting of 6-membered aryl, 5- to 6-membered heteroaryl and 5- to 8-membered cycloalkyl, preferably selected from the group consisting of phenyl, 5-membered heteroaryl, 5- to 8-membered saturated bridged cycloalkyl and 5- to 8-membered saturated spirocycloalkyl, such as phenyl, isoxazolyl, pyrazolyl, isothiazolyl, More preferably selected from 5-membered heteroaryl, such as isoxazolyl, pyrazolyl and isothiazolyl, all of which are optionally substituted with one or more R 7 substituents; L 2 Selected from chemical bonds, -O-, -S-, -C(R) 5C R 5D - or -N(R) 6B -, the condition is L 1 and L 2 One of them is the chemical bond; R 2 selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl; said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxyl and amino; R 5A , R 5B , R 5C , R 5D , R 6A and R 6B are independently of each other H or C 1-6 alkyl; R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy.

9. The compound of claim 2 having the structure of Formula I-2: ###00010### I-2 or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof. wherein, Z, R 2 , L 1 , Cy, Q are as defined in claim 2.

10. The compound of claim 8 or 9, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogen, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl, and oxetanyl is optionally substituted with one or more halogen, for example 1, 2, or 3 halogen, for example F; for example, R 2 is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3, 11. The compound of any one of claims 8-10, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein L 1 is a bond or -CH2-; preferably, L 1 is a bond.

12. The compound of any one of claims 8, 10-11 or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Ar is phenyl or pyridyl, which phenyl and pyridyl are optionally substituted with one or more halogen, e.g., F; preferably, Ar is phenyl optionally substituted with halogen, e.g., F, wherein Q and L 1 are para to each other.

13. The compound of any one of claims 9-11, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Cy is phenyl, pyridyl, pyrimidinyl, pyrazinyl, said Cy is optionally substituted with one or more halogen, e.g., F; preferably, Cy is phenyl optionally substituted with halogen, e.g., F, wherein Q and L 1 are in the para position relative to each other.

14. The compound of any one of claims 8-13, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q is wherein: L 2 is a chemical bond or -C(R 5C R 5D )-; preferably, L 2 is -C(R 5C R 5D )-, for example -CH2- or -CH(CH3)-, more preferably L 2 is -CH2-. R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, and said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R 7 selected from -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole; Preferably, R 7 the ortho position of the nitrogen atom of said isoxazolyl.

15. The compound of any one of claims 9-13, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q is wherein: W is O or NR W , said R W is selected from H, C 1-6 alkyl, such as methyl, ethyl, n-propyl, i-propyl, preferably W is O; L 2 is a chemical bond, -C(R 5C R 5D )- or -N(R 6B )-, provided that L 1 and L 2 are not both a chemical bond, or when L 1 and L 2 are both a chemical bond, Cy is selected from 5- to 8-membered spirocycloalkyl groups optionally substituted with one or more substituents (e.g. ) ; preferably, L 2 is -C(R 5C R 5D )- or -N(R 6B )-, for example -CH2-, -CH(CH3)-, -NH-, more preferably L 2 is -CH2- or -NH-, particularly preferably L 2 is -CH2-. R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, pyridinyl; for example, R 7 selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano, pyridinyl and hydroxy, for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, CN, hydroxy or pyridinyl, said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R7is selected from -C(CH3)2CF3, -C(CH3)2OH, -C(CH3)2CN, More preferably, R 7 selected from -C(CH3)2CF3, Preferably, R 7 the ortho position to the N atom of the cyclic group to which it is attached.

16. The compound of claim 1 having the structure of Formula (II-1) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X, Y, L 1 , L 2 , Ar and R 7 are as defined in claim 1.

17. The compound of claim 2 having the structure of Formula (II-2) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X, Y, Z, W, L 1 , L 2 , Cy and R 7 as defined in claim 2 18. The compound of claim 1 having a structure represented by Formula (III): ###0007### or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof. wherein R 8 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl, and amino; preferably, R 8 is selected from H and halogen, e.g. F; and X, Y, L 2 and R 7 as defined in claim 1.

19. The compound of claim 2 having a structure represented by Formula (IV): ###00010### or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof. wherein V 1 , V 2 , V 3 , V 4 are each independently CH or N, and at most two are N; preferably, selected from the group consisting of wherein * indicates the point of attachment to X; R 8 is absent or is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxyl, and amino; preferably, R 8 is absent or is halogen, e.g., F; and X, Y, Z, W, L 2 and R 7 as defined in claim 2.

20. The compound of any one of claims 16 to 19, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: X is N and Y is NR 2 , wherein R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl is optionally substituted with one or more halogen, said C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C 1-6 alkyl and halogen; for example, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl being optionally substituted with one or more halogen, for example 1, 2 or 3 halogen, for example F; for example, R 2 is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3, L 2 is -CH2- or -CH(CH3)-, preferably -CH2-; R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, and said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R 7 selected from -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole; R 8 selected from H and halogen, e.g. F.

21. The compound of any one of claims 16 to 19, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein: X is N and Y is CR3R4, wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl and C 3-8 cycloalkyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl being optionally substituted with one or more substituents selected from C 1-6 alkyl and halo; for example R 3 and R 4 are independently selected from H, methyl and cyclopropyl, or R3and R4together with the carbon atom to which they are attached form cyclopropyl, azetidinyl and oxetanyl, optionally substituted with C 1-6 alkyl; L 2 is -CH2-; R 7 selected from C 1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, R 7 selected from C 3-6 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 3-6 alkyl, wherein said C 3-6 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and hydroxy; for example, wherein said C 3-6 alkyl is selected from optionally F substituted isopropyl and tert-butyl, said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxy; preferably, R 7 is selected from -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole; R 8 selected from H and halogen, e.g. F.

22. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, selected from:

23. The compound of claim 2, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, selected from:

24. A pharmaceutical composition comprising a compound of any one of claims 1 to 23, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable excipient.

25. Use of a compound of any one of claims 1 to 23, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, for modulating or inhibiting the activity of RET.

26. Use of a compound of any one of claims 1 to 23, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, for the manufacture of a medicament for the treatment and prevention of a disease associated with a dysregulation of the RET gene and / or RET kinase, or caused by a dysregulation of the expression or activity or level of the RET gene and / or RET kinase.

27. The use of claim 26, wherein the disease or disorder is selected from the group consisting of cancer and inflammation.

28. The use of claim 27, wherein the cancer is lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal stromal ganglioneuroma, and cervical cancer; the inflammation is ulcerative colitis; for example, the cancer is medullary thyroid cancer (MTC), non-small cell lung cancer (NSCLC), metastatic solid tumors with RET gene mutations / fusions, and advanced solid tumors.

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