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 chemical 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] Q is

[0015] 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 chemical 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 chemical 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 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl and C2-6 alkynyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkylcarbonyloxy, 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 alkylcarbonyloxy, 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 is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkylcarbonyloxy, 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 alkylcarbonyloxy, 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 selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyloxy, halo, cyano, hydroxy and amino;

[0021] R 5A , R 5B , R 5C , R 5D , R 6A and R 6Bindependently H or C 1-6 alkyl;

[0022] 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.

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

[0032] 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, such as phenyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, isothiazolyl, more preferably from 5-membered heteroaryl, such as isoxazolyl, pyrazolyl and isothiazolyl, all of which are optionally substituted by one or more R 7 substituents;

[0033] L 2 is selected from a chemical bond, -O-, -S-, -C(R 5C )- or -N(R 5D )-, provided that L 6B and L 1 are not both a chemical bond, and 2 one of L 1 and L 2 is a chemical bond, or when L 1 and L 2 are both a chemical bond, Cy is selected from 5- to 8-membered spirocycloalkyl optionally substituted by one or more substituents (e.g. );

[0034] R 1 is H or C 1-6 alkyl;

[0035] 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 1-6 alkoxy, C 1-6 alkoxycarbonyl, halogen, cyano, hydroxy and amino;

[0036] R 3 and R 4 are independently selected from H, 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 halogen, cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, amino, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, wherein 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, halogen, cyano, hydroxy 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, wherein 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, halogen, cyano, hydroxy and amino;

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

[0039] R 7 is selected from the group consisting of 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 the group consisting of halogen, cyano, pyridyl, phenyl and hydroxy.

[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 the group consisting of C 1-6 alkyl, C 3-8cycloalkyl and 3- to 8-membered heterocyclyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens, the 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, optionally substituted with one or more halogens, e.g., 1, 2, or 3 halogens, e.g., 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 the C 1-6 alkyl is optionally substituted with one or more halogens, the 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, optionally substituted with one or more halogens, e.g., 1, 2, or 3 halogens, e.g., 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 3-8 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, the C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl is optionally substituted with one or more substituents selected from C1-6 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 a cyclopropyl, azetidinyl or oxetanyl group, 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 being optionally substituted with one or more halogen, for example F; preferably, Ar is phenyl optionally substituted with halogen, for example F, wherein Q and L 1 are in para position 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 being 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.

[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 L 1 and L 2 are not both a bond; preferably, L 2 is -C(R 5C R 5D )-, for example -CH2- or -CH(CH3)-, more preferably L 2 is -CH2-;

[0048] R 7 is selected from C1-6 alkyl, C 3-8 cycloalkyl and C 3-8 cycloalkyl-C 1-6 alkyl, wherein the C 1-6 alkyl and C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of 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 the 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 the C 3-6 alkyl is selected from optionally F-substituted isopropyl and tert-butyl, the 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 ortho 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 , the 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 bond, -C(R 5C R 5D )- or -N(R 6B )-, provided that one of L 1 and L 2 is a bond, or when both L 1 and L 2 are bonds, Cy is selected from 5- to 8-membered spirocycloalkyl optionally substituted with one or more substituents (for example ); preferably, L 2 is -C(R 5C R 5D )- or -N(R 6B)-, such as -CH2-, -CH(CH3)-, -NH-, more preferably L 2 is -CH2- or -NH-, particularly preferably L 2 is -CH2-;

[0053] 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, hydroxy, cyano, pyridinyl; 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, 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, R7is selected from -C(CH3)2CF3,

[0054] preferably, R 7 the ortho position to the N atom of the cyclic group to which it is attached.

[0055] 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,

[0056] wherein:

[0057] L 1 is selected from a bond, -O-, -S-, -C(R 5A R 5B )- and -N(R 6A )-;

[0058] Ar is selected from aryl and heteroaryl, preferably phenyl and 5- to 6-membered heteroaryl, for example phenyl, pyrrolyl, oxazolyl, pyridinyl, 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, hydroxyl, and amino;

[0059] Q is

[0060] 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 saturated spirocycloalkyl, such as phenyl, isoxazolyl, pyrazolyl, isothiazolyl, More preferably, it is selected from 5-membered heteroaryl, such as isoxazolyl, pyrazolyl and isothiazolyl, all of which are optionally substituted by one or more R 7 replace;

[0061] 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 is a chemical bond;

[0062] 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 heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally substituted by one or more radicals selected from halogen, cyano, hydroxy, C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, amino, C 3-8 Substituted by cycloalkyl and 3 to 8-membered heterocyclic substituents; the C 3-8 The cycloalkyl and 3 to 8 membered heterocyclic groups are optionally substituted by one or more selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 substituted by alkoxycarbonyl, halogen, cyano, hydroxyl and amino substituents;

[0063] R 5A 、R5B R 5C R 5D R 6A and R 6B are independently of each other H or C 1-6 alkyl;

[0064] 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.

[0065] In one embodiment, 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 are 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 are 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,

[0066] In one embodiment, the present application provides a compound represented by Formula I-1 or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof, wherein L 1 is a bond or -CH2-; preferably, L 1 is a bond.

[0067] In one embodiment, the present application provides a compound represented by Formula I-1 or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof, wherein Ar is phenyl or pyridyl, said phenyl and pyridyl are optionally substituted with one or more halogen, for example F; preferably, Ar is phenyl optionally substituted with halogen, for example F, wherein Q and L 1 are in para position to each other.

[0068] In one embodiment, the present application provides a compound represented by Formula I-1 or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a 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, C3-8 Cycloalkyl and 3- to 8-membered heterocyclyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogen, the 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, R2is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, azetidinyl and oxetanyl are optionally substituted with one or more halogen, e.g. 1, 2 or 3 halogen, e.g. F; for example, R2is selected from -CHF2, -CH(CH3)2, -CH(CF3)CH3,

[0075] In one embodiment, the present application provides a compound according to 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 according to Formula I-2, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Cy is phenyl, pyridyl, pyrimidyl, 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 para position to each other on Cy.

[0077] In one embodiment, the present application provides a compound according to 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, e.g. methyl, ethyl, n-propyl, i-propyl, preferably W is O;

[0079] L 2 is a bond, -C(R 5C R 5D )- or -N(R 6B )-, provided that one of L 1 and L 2 is a bond, or when both L 1 and L 2 are a bond, Cy is selected from 5- to 8-membered spirocycloalkyl 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-;

[0080] 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, hydroxy, cyano, 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 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 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, R7is selected from -C(CH3)2CF3,

[0081] preferably, R 7 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 1 , L 2 , 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 , Cy and R 2 are as defined above. 7

[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 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.

[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 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 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, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, cyano, hydroxy, and amino; preferably, R 8 is absent or selected from halogen, for example 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, solvate, or 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 pyridinyl; 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, cyano, pyridinyl, and hydroxyl, for example, wherein said C3-6 alkyl is selected from isopropyl and tert-butyl optionally substituted with F, CN, hydroxyl, or pyridyl, said C 3-6 cycloalkyl is selected from cyclobutyl and cyclopentyl optionally substituted with F and hydroxyl; 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 selected from halogen, e.g., 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 halogen; 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 said C 1-6 alkyl and C 3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and hydroxyl; for example, R 7 is selected from C 3-6 alkyl, C 3-6 cycloalkyl, and C 3-6cycloalkyl-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 is selected from the group consisting of -C(CH3)2CF3, wherein * indicates the point of attachment of the group to the isoxazole;

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

[0115] In one embodiment, the present application provides a compound selected from the group consisting of:

[0116] 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 a disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application as described above or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer thereof.

[0121] In one embodiment, the disease or disorder is selected from the group consisting of 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 neoplasia type 2A or 2B (MEN2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal stromal tumor, and cervical cancer; and the inflammation is ulcerative colitis.

[0123] In one embodiment, the cancer or inflammation is associated with or caused by a disorder in 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 terminology

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

[0127] "Alkyl" refers to a saturated aliphatic hydrocarbon group, the alkyl moiety can be straight chain alkyl or branched chain alkyl. For example, C1-C6alkyl refers to 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 refers to an alkyl group having 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] "Cyclo" 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 cyclo can be optionally substituted, and can be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic, tricyclic rings. Cyclo of the present application generally has 1-20 ring atoms, for example, 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" is the number of skeletal atoms that make up the 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 containing heteroatoms in the skeletal atoms are heterocyclic rings; aromatic groups containing heteroatoms are heteroaromatic groups; non-aromatic groups containing heteroatoms are heterocyclyl groups, which include heterocycloalkyl groups.

[0130] "Heteroatom" refers to an atom other than carbon or hydrogen. One or more 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 is saturated or partially unsaturated (containing one or more double bonds but no ring has a completely conjugated pi-electron system and is not aromatic) containing one or more rings. Cycloalkyl further includes monocycloalkyl and polycycloalkyl groups containing from 3 to 20 carbon atoms that can form a ring, preferably 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 containing 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] "Heterocyclyl," "heterocycloalkyl," and "cycloheteroalkyl" are used interchangeably and refer to saturated or non-aromatic unsaturated monocyclic, fused, bridged, and spiro rings containing one or more (e.g., 1, 2, 3, or 4) heteroatoms. The heteroatoms can be N, O, S, or SO2 preferably N, O, and / or S. The heterocycloalkyl group can be a 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 group. 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 manner generally understood for structural formulas, 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 formed from the above groups, e.g.

[0137] wherein 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" means a monocyclic or fused polycyclic (that is, rings that share pairs of adjacent carbon atoms) ring radical of six to fourteen carbon atoms having a conjugated pi-electron system (6- to 14-membered), preferably six to ten 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" means 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). The heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- 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 =O.

[0141] "Halo" or "halogen" means fluorine, chlorine, bromine, or iodine.

[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 group" refers to a chemical structure having the formula -COOR, where R can be an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. C1-C4 ester group refers to a chemical structure having the formula -COOR x1 The structure of R x1 It is a C1-C4 alkyl group.

[0144] "Amide" means an amino group having the formula "-CONR x1 R x2 ” or “-NR x3 COR x4 " chemical structure, where R x1 、R x2 、R x3 and R x4 are independently H or C 1-6 alkyl.

[0145] The term "C 1-6 "Alkoxy" refers to the following groups: R'-O-, where R' is C 1-6 alkyl.

[0146] “C 3-6 Cycloalkyloxy" refers to the following group: R"-O-, wherein R" is C 3-6 Cycloalkyl.

[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 (including multiple substitutions on the same moiety) is chemically permitted, and each substituent can be located at any available position on the group and can be attached through any available atom on the substituent. "Any available position" refers to any position on the group that is chemically accessible by methods known in the art or methods taught herein and does not produce an overly unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and can therefore be the same or different.

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

[0149] "RET selectivity" refers to the inhibitory activity of the compound selectively acting on RET kinase or RET-mediated proliferative cells, avoiding or reducing the inhibitory effect on other kinases or kinase-mediated proliferative cells. The "RET selectivity (compared to VEGFR2)" described herein refers to the inhibitory activity of the compound selectively acting on RET kinase (including RET wild type, RET-V804, RET-G810, etc., especially RET-V804, RET-G810 mutations) or the proliferative cells mediated by them, avoiding or reducing the inhibitory effect on VEGFR2 kinase or the proliferative cells mediated by it. The "RET selectivity (compared to VEGFR2)" can be measured in the form of, for example, multiples, for example, using the IC value of the compound acting on VEGFR2-mediated proliferative cells. 50 The value is divided by the IC value for RET-mediated proliferating cells (e.g., RET-V804 proliferating cells or RET-G810 proliferating cells). 50 The value is the multiple of "RET selectivity (over VEGFR2)". It is generally believed in the art that a multiple of less than 3-fold indicates no selectivity, while a multiple of more than 5-fold indicates significant selectivity. The higher the multiple of "RET selectivity (over VEGFR2)" described in the present invention, the stronger the selectivity of RET over VEGFR2.

[0150] "RET activity balance" refers to the difference in inhibitory activity of a compound when it acts on different mutant / rearranged RET kinases or RET-mediated proliferative cells. The "RET activity balance" can be measured in the form of multiples, for example, the IC value of the compound acting on RET-V804, RET-G810-mediated proliferative cells is 50 value, with relatively high IC 50 The value divided by the relatively low IC50 value is the fold value of "RET activity balance." It is generally believed in the field that a fold value of around 3-4 times indicates slight differences in activity and good activity balance; a fold value of less than 3 times indicates essentially no differences in activity, indicating a better activity balance; conversely, a fold value exceeding 5 times indicates significant differences in activity, indicating a poorer activity balance. The lower the fold value of "RET activity balance" as described in the present invention, the better the RET activity balance.

[0151] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted" means that the group may or may not be substituted; "heterocycloalkyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, including instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0152] The term "stereoisomers" as used herein refers to compounds which have a common molecular formula but differ in the spatial arrangement of their atoms. The term "enantiomers" refers to two stereoisomers of a compound, which are non-superimposable mirror images of each other. Stereoisomers also include "diastereomers" which have different spatial arrangements but are not mirror images of each other. Stereoisomers include enantiomers and diastereomers. The term "racemic mixture" refers to a mixture of D- and L-rotatory enantiomers in equal amounts. The term "scalemic mixture" refers to a mixture of D- and L-rotatory enantiomers in unequal amounts. The term "scalemic mixture" also refers to a mixture of diastereomers in unequal amounts. The term "geometric isomers" refers to compounds which have a common molecular formula but differ in the spatial arrangement of their atoms around a double bond, ring or ring system. The term "tautomer" refers to a pair of structural formulas which differ only in the arrangement of atoms in a ring structure or the position of a proton. The term "tautomers" also includes mixtures of tautomers. The term "mixtures of stereoisomers" refers to mixtures of enantiomers, mixtures of diastereomers, mixtures of geometric isomers, mixtures of tautomers, or mixtures of any combination thereof.

[0153] The compounds of the present application can also exist in tautomeric forms (one of the functional group isomers) which have different hydrogen attachment sites by virtue of the migration of one or more double bonds, for example, a ketone and his enol form are keto-enol tautomers. Each tautomer and mixtures thereof are within the scope of the present application.

[0154] In the present application, when referring to the compounds of the present application, all enantiomers, diastereomers, racemates, meso forms, cis and trans isomers, tautomers, geometric isomers, epimers, mixtures thereof, and the like of the compounds are included within the scope of the present application.

[0155] In the structural formulas of the present application, when a bond to a chiral carbon is depicted as a straight line, it is understood that the structural formula contains both the (R) and (S) configurations of the chiral carbon and thus also contains both enantiomers and mixtures thereof. Similarly, when a compound name is described without specifying the chirality of a chiral carbon, it is understood that the name includes both the (R) and (S) configurations of the chiral carbon and thus also contains both enantiomers and mixtures thereof. The production of a particular stereoisomer or mixtures thereof can be identified in the examples where such stereoisomer or mixture is obtained, but this is by no means a limitation that all stereoisomers and mixtures thereof are not included within the scope of the present application.

[0156] The present application includes all possible enantiomeric and diastereomeric forms and mixtures of two or more stereoisomers in all proportions, for example mixtures of enantiomers and / or diastereomers. Thus, enantiomers are subject of the present application in enantiomerically pure form (left- and right-handed enantiomers), in racemic form, and in mixtures of both enantiomers in all proportions. In the case of cis / trans isomers, the present application includes both the cis and trans forms as well as mixtures of these forms in all proportions. If desired, the preparation of individual stereoisomers can be achieved by separation of a mixture of the desired isomers, for example, by chromatography or crystallization techniques, by using stereospecific synthetic methods, or by stereoselective synthesis. Optionally, derivatization can be accomplished to enhance the separation of a stereoisomer. The separation of stereoisomers can be achieved by separation of the racemic mixture into individual enantiomers or diastereomers, or by using a final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of a crystalline product or crystalline intermediate which is derivatized, if necessary, to introduce a chiral center of known absolute configuration. When the compounds of the present application can exist in tautomeric forms, all such tautomers are embraced within the scope of the present application. Unless otherwise stated, a particular enantiomer, salt, solvate (including hydrate), or solvated salt of such enantiomer of a racemate, diastereomer, or racemic form is intended to encompass both the individual enantiomer, salt, solvate (including hydrate), or solvated salt of such enantiomer of a racemate, diastereomer, or racemic form, and mixtures with other enantiomers, salts, solvates (including hydrates), or solvated salts of such enantiomer of a racemate, diastereomer, or racemic form.

[0157] The term "fused ring" as used herein refers to a polycyclic structure in which each ring in the system shares an adjacent pair of ring atoms with other rings in the system, 5 to 20 membered, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 membered, more preferably 8 to 10 membered. Fused rings can be bi-, tri-, tetra- or more cyclic, preferably bi- or tri-cyclic, more preferably 5 / 5 or 5 / 6 bi-cyclic, depending on the number of constituent rings. The term "fused ring" as defined in the context of the present application includes fused carbocyclic and fused heterocyclic rings. The fused heterocyclic ring is a fused ring containing one or more heteroatoms in addition to carbon in the ring-forming atoms, selected from O, S, N, including, for example, fused aliphatic heterocyclic and fused heteroaromatic rings. Fused rings can be aromatic or non-aromatic, with common representative aromatic fused ring compounds including, but not limited to, naphthalene, anthracene, phenanthrene, and the like; fused ring heterocyclic compounds include, but are not limited to, indole, quinoline, purine, and the like.

[0158] The term "bridged ring" refers to a polycyclic structure of 5 to 20 members, any two rings of which share two non-adjacent (i.e., "not directly attached") ring atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings involved, the term "bridged ring" can refer to a bicyclic, tricyclic, tetracyclic or polycyclic bridged ring, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic. The term "bridged ring" as defined in the context of the present application includes bridged carbocyclic and bridged heterocyclic rings. The bridged heterocyclic ring, i.e., one in which the ring atoms include one or more heteroatoms in addition to carbon, are selected from O, S, and N. The term "bridged cycloalkyl" as defined in the context of the present application refers to a bridged carbocyclic ring which does not contain an unsaturated bond.

[0159] The term "spirocyclic" refers to a polycyclic structure of 5 to 20 members, any two rings of which share one carbon atom (referred to as a spiro atom), which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, 6 to 14 members, more preferably 7 to 10 members. The term "spirocyclic" as defined in the context of the present application includes spiro carbocyclic and spiro heterocyclic rings. The spiro heterocyclic ring, i.e., one in which the ring atoms include one or more heteroatoms in addition to carbon, are selected from O, S, and N. The term "spirocyclic cycloalkyl" as defined in the context of the present application refers to a spiro carbocyclic ring which does not contain an unsaturated bond.

[0160] The term "individual" as used herein includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) suffering from a disease (e.g., a disease described herein) or a normal individual. "Non-human animals" in the context of the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals, and / or laboratory models (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0161] A "pharmaceutical composition" as described herein refers to a composition comprising one or more compounds of Formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, and a carrier or excipient, which is generally accepted in the art for delivery of a biologically active compound to an organism (e.g., a human).

[0162] The term "pharmaceutical combination" as used herein means a combination of a compound of the present application with another active agent which is useful for the purposes of the present application. The other active agent can be one or more additional compounds of the present application, or can be a second or additional (e.g., third) compound that is compatible with the compound of the present application, i.e., does not adversely affect its performance or activity, or has complementary activity. Such active agents are present in effective amounts to achieve the intended purpose. The other active agent(s) can be co-administered with the compound of the present application in a single pharmaceutical composition, or in separate, discrete units from the compound of the present application, and when administered separately, can be administered simultaneously or sequentially. The sequential administration can be close in time or remote.

[0163] The term "effective amount" as used herein refers to an amount that is sufficient to achieve or at least partially achieve a desired effect. For example, a therapeutically effective amount refers to an amount that is sufficient to cure or at least partially arrest a disease and its complications in a patient already suffering from the disease. A prophylactically effective amount refers to an amount that is effective to prevent, arrest, or delay the onset of a disease. Determining such effective amounts is well within the capabilities of those skilled in the art. For example, an amount effective for therapeutic use will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient such as age, weight, and gender, the mode of administration of the drug, and other therapies that the patient may be undergoing, among other things.

[0164] The amount of a compound of the present application, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a prodrug, or a deuterated compound thereof, administered to an individual or subject depends on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs, as well as on the dosage form and mode of administration of the drug, and on the duration and interval of the administration, among other factors. One skilled in the art is able to determine an appropriate dosage based on these and other factors. Generally, a daily dose of a compound of the present application, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, a prodrug, or a deuterated compound thereof for therapeutic use is in the range of from about 0.0001 to 1000 mg / kg body weight per day, which can be given in a single dose or in divided doses.

[0165] According to certain embodiments of the application, the pharmaceutically acceptable salts of the application refer to salts of the compounds of the application that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic, can be inorganic or organic acid- addition salts and base salts. In particular, such salts include: (1) acid addition salts, formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids, e.g. 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-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when acidic protons present in the parent compound are replaced by a metal ion, e.g. alkali metal ions, alkaline earth metal ions or aluminum ions, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts also include, by way of example only, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, and the like; when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable positively charged counterion of an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0166] "Pharmaceutically acceptable excipient" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the application is administered.

[0167] "Solvate" refers to a form of a compound that is associated with a solvent by a solvating reaction, usually by a solvolysis reaction. This physical association involves hydrogen bonding. Common solvents that form solvates with compounds of the application include water, EtOH, acetic acid, and the like. The compounds of the application can be prepared, for example, as crystalline forms and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0168] The pharmaceutical compositions of the present application can be administered in standard fashion. For example, suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal, or pulmonary (inhalation) administration, with parenteral infusion including intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. For these purposes, the compounds of the present application can be formulated by means known in the art into the form of, 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 aqueous or oily solutions or suspensions for injectable administration.

[0169] Synthetic methods of the compounds of the present application

[0170] The present application also provides a synthetic method of the above-mentioned compounds, and the synthetic method of the present application is mainly based on the preparation methods reported in the chemical literature or related synthesis starting from commercially available chemical reagents.

[0171] The compounds of the present application can be prepared, for example, by the following routes,

[0172] Method 1

[0173] The steps are as follows:

[0174] a1) carrying out a nucleophilic substitution reaction between a compound represented by formula (i-1) and a compound represented by formula (i-a) to obtain a compound represented by formula (i-2);

[0175] b1) carrying out a ring-closing reaction of the compound represented by formula (i-2) under the action of a ring-closing urea reagent (such as carbonyldiimidazole, carbonylbis(triazole), etc.) to obtain a compound represented by formula (i-3);

[0176] c1) reacting the compound represented by formula (i-3) with an amine group reagent (such as 4-methoxybenzylamine) carrying an amino protecting group to obtain a compound represented by formula (i-4);

[0177] d1) carrying out a coupling reaction between the compound represented by formula (i-4) and a compound represented by formula (i-b) or carrying out a nucleophilic substitution reaction between the compound represented by formula (i-4) and a compound represented by formula (i-b') to obtain a compound represented by formula (i-5);

[0178] e1) carrying out an ester hydrolysis reaction of the compound represented by formula (i-5) under the action of a basic reagent, etc. to obtain a compound represented by formula (i-6);

[0179] f1) further carrying out an amide condensation reaction between the compound represented by formula (i-6) and a compound represented by formula (i-c) to obtain a compound represented by formula (i-7);

[0180] g1) finally removing the amino protecting group (e.g., 4-methoxybenzyl) from the compound represented by formula (i-7) to obtain the target compound of the present invention represented by formula (I-2);

[0181] Wherein, Hal is a halogen (such as Br or Cl), Z, R 2 , L 1 , L 2 、Cy、 Consistent with the above definition, the compound represented by formula (ib) can also be a pinacol boron ester compound When the compound represented by formula (i-1) is replaced by The target compound can be prepared by the same method as the above method 1. Or when the compound represented by formula (i-1) is replaced by or When the target compound is prepared according to the above method 1 and omitting step c1), Among them, Z, R 2 , L 1 , L 2 、Cy、 Consistent with the above definition. In the present invention, when R substituted by hydroxyl 7 When substituted, the compound represented by formula (ic) may also be a derivative containing a hydroxyl protecting group or a carbonyl protecting group (e.g. In step g1), the hydroxyl protecting group or the carbonyl protecting group can be removed simultaneously, and the carbonyl group can be further hydrogenated and reduced to make R 7 Substituted with hydroxyl groups.

[0182] In certain embodiments of the present invention, the compound represented by intermediate formula (i-4) can also be prepared by using method 1 through the following route 2:

[0183] The steps are as follows: a compound represented by formula (i') is subjected to a nucleophilic substitution reaction with a compound represented by formula (ia) to obtain a compound represented by formula (i'-1); then the compound is reacted with an aminating reagent with an amino protecting group (such as 4-methoxybenzylamine) to obtain a compound represented by formula (i'-2); then a hydrogenation reduction reaction is performed to obtain a compound represented by formula (i'-3); finally, a ring-closing reaction is performed under the action of a ring-closing urea reagent (such as carbonyldiimidazole, carbonylbis(triazole), etc.) to obtain a compound represented by formula (i-4); when the compound represented by formula (i') is replaced by When the intermediate is obtained, the method of the aforementioned route 2 can be used to prepare Among them, Z, R 2 Consistent with the above definition.

[0184] Method 2

[0185] The steps are as follows:

[0186] a2) carrying out nucleophilic substitution reaction of the compound shown as formula (ii-1) with the compound shown as formula (i-a) to obtain the compound shown as formula (ii-2);

[0187] b2) reacting the compound shown as formula (ii-2) with a protected amine-based reagent (such as bis(4-methoxybenzyl)amine, etc.) to obtain the compound shown as formula (ii-3);

[0188] c2) carrying out nucleophilic substitution reaction of the compound shown as formula (ii-3) with the compound shown as formula (i-b”) to obtain the compound shown as formula (ii-4);

[0189] d2) carrying out ring-closing reaction of the compound shown as formula (ii-4) under the action of a ring-closing urea reagent (such as carbonyldiimidazole, carbonylbis(triazole), etc.) to obtain the compound shown as formula (i-5);

[0190] Repeating steps e1) to g1) in Method 1 obtains the target compound shown as formula (I-2) of the present application; when the compound shown as formula (ii-1) is replaced by , the target compound shown as formula (I’-2) or formula (I”-2) is prepared by the same method as Method 2 described above; wherein Z, R 2 , L 1 , L 2 , Cy, are consistent with the definitions described above.

[0191] Method 3

[0192] The steps are as follows:

[0193] a3) carrying out coupling reaction of the compound shown as formula (iii-1) with the compound shown as formula (i-d) to obtain the compound shown as formula (iii-2);

[0194] b3) reacting the compound shown as formula (iii-2) with an amine-based reagent with an amino protecting group (such as 4-methoxybenzylamine) to obtain the compound shown as formula (iii-3);

[0195] c3) hydrogenation reduction of the compound shown as formula (iii-3) under the action of a reducing agent (such as iron powder, etc.), and then spontaneous ring-closing reaction or catalytic ring-closing reaction under the action of an alkaline reagent (such as potassium carbonate, etc.) to obtain the compound shown as formula (iii-4);

[0196] d3) removing the methylthio group of the compound of formula (iii-4) by a hydrogenation reduction reaction to obtain a compound of formula (iii-5);

[0197] e3) coupling the compound of formula (iii-5) with a compound of formula (i-b) or nucleophilic substitution reaction of the compound of formula (iii-5) with a compound of formula (i-b') to obtain a compound of formula (iii-6);

[0198] f3) hydrolyzing the ester of the compound of formula (iii-6) under the action of a basic reagent to obtain a compound of formula (iii-7);

[0199] g3) further acylating and condensing the compound of formula (iii-7) with a compound of formula (i-c) to obtain a compound of formula (iii-8);

[0200] h3) finally removing the amino protecting group (for example, 4-methoxybenzyl) of the compound of formula (iii-8) to obtain the target compound of formula (I') of the present application;

[0201] wherein Hal is halogen (for example, Br or Cl), Z, R 3 , R 4 , L 1 , L 2 , Cy, According to the foregoing definitions, the compound of formula (i-b) can also be a pinacol borate compound When the compound of formula (iii-1) is replaced by , the target compound can be prepared by the same method as the foregoing method 3, or when the compound of formula (iii-1) is replaced by or , the target compound can be prepared according to the foregoing method 3 and omitting step b3), wherein Z, R 3 , R 4 , L 1 , L 2 , Cy, According to the foregoing definitions.

[0202] In some embodiments of the present application, when L 1 , L 2 are both chemical bonds, and Cy is selected from 5- to 8-membered spirocycloalkyl 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 represented by formula (i'-3) is subjected to reductive amination reaction with a reducing agent (for example, sodium borohydride, sodium triacetyl borohydride, etc.) to obtain a compound represented by formula (i'-4); then ring closure reaction is carried out under the action of a ring closure urea reagent (for example, carbonyl diimidazole, carbonyl bis(triazole), etc.) to obtain a compound represented by formula (i'-5); ester hydrolysis reaction is carried out under the action of a basic reagent, etc. to obtain a compound represented by formula (i'-6); amide condensation reaction is carried out with a compound represented by formula (i-c) to obtain a compound represented by formula (i'-7); and finally the amino protecting group (for example, 4-methoxybenzyl) is removed to obtain the target compound represented by formula (I") of the present application; wherein, Z, R 2 、 According to the foregoing definitions, Cy is selected from 5- to 8-membered spirocycloalkyl optionally substituted with one or more substituents.

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

[0205] The steps are as follows: coupling reaction is carried out between a compound represented by formula (i-4) and a compound represented by formula (i-f) to obtain a compound represented by formula (i"-5); then the Boc protecting group is removed to obtain a compound represented by formula (i"-6); urea formation reaction is carried out with a compound represented by formula (i-c) under the action of a urea formation reagent (for example, carbonyl diimidazole, etc.) to obtain a compound represented by formula (i-7); and the target compound represented by formula (I-2) of the present application is obtained by repeating step g1) of Method 1; when the compound represented by formula (i-4) is replaced by a similar intermediate such as the compound represented by formula (iii-5) in Method 3, etc., the target compounds represented by formula (I'), formula (I'-2) or formula (I"-2) can be prepared by the same path as described above, wherein, L 2 is -N(R 6B )-, Z, R 2 , R 6B , L 1 , Cy, According to the foregoing definitions.

[0206] The aforementioned starting materials, the compounds represented by formula (i-a), formula (i-b), formula (i-b'), formula (i-b"), formula (i-c), formula (i-d), formula (i-e) can be commercially available products or can be prepared by the preparation methods disclosed in the prior art by those skilled in the art; for example, when is isoxazolyl, the compound represented by formula (i-c) can be obtained by the following method

[0207] The compound represented by formula (1c) is reacted with acetonitrile under the action of a strong base (e.g. LDA) to obtain a compound represented by formula (2c), which is then closed under basic conditions with hydroxylamine to obtain a compound represented by formula (1d). is substituted by R 7 is substituted by R

[0208] For example, 3-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-5-amine is commercially available or can be prepared by a method disclosed in the prior art, for example, Preparation Example 1.

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

[0210] Acetonitrile (1.44 g) was dissolved in a tetrahydrofuran solution, the reaction system was cooled to -78°C, then LDA (2.12 g) was added and stirred for 1 hour, finally methyl 2-(trifluoromethyl)-2-methylpropanoate (1 g) was added, after the completion of the addition, the reaction system was stirred at -78°C for 2 hours, then slowly warmed to room temperature and stirred for 16 hours, TLC showed that the raw material was completely reacted, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, the organic phase was concentrated under reduced pressure, and column chromatography was used for separation and purification to obtain 4-trifluoromethyl-4-methyl-3-oxopentanenitrile. 4-Trifluoromethyl-4-methyl-3-oxopentanenitrile (0.3 g) was dissolved in a water solution, then hydroxylamine hydrochloride (0.22 g) and sodium hydroxide (0.24 g) were added, after the completion of the addition, the reaction system was warmed to 100°C and stirred for 3 hours, LCMS showed that the raw material was completely reacted, extracted with ethyl acetate, the organic phases were combined, the organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 3-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-5-amine.

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

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

[0213] Methyl 2-(3,3-difluorocyclobutyl)-2-methylpropanoate (1 g) was added to the reaction system after stirring for 1 h at -78 °C after adding LDA (2.23 g) in tetrahydrofuran solution, and the reaction system was stirred at -78 °C for 2 h, then slowly warmed to room temperature and stirred for 16 h. TLC showed that the raw material was completely reacted, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was combined. The organic phase was concentrated under reduced pressure, and column chromatography was used for separation and purification to obtain 4-(3,3-difluorocyclobutyl)-4-methyl-3-oxovaleride. 4-(3,3-Difluorocyclobutyl)-4-methyl-3-oxovaleride (0.4 g) was dissolved in water solution, then hydroxylamine hydrochloride (0.24 g) and sodium hydroxide (0.26 g) were added, and the reaction system was stirred at 100 °C for 3 h after being added. LCMS showed that the raw material was completely reacted, ethyl acetate was added for extraction, and the organic phase was combined. The organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 3-(2-(3,3-difluorocyclobutyl)prop-2-yl)isoxazol-5-amine.

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

[0215] Methyl 2-(3,3-difluorocyclobutyl)-2-methylpropanoate (1 g) was added to the reaction system after stirring for 1 h at -78 °C after adding LDA (2.23 g) in tetrahydrofuran solution, and the reaction system was stirred at -78 °C for 2 h, then slowly warmed to room temperature and stirred for 16 h. TLC showed that the raw material was completely reacted, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was combined. The organic phase was concentrated under reduced pressure, and column chromatography was used for separation and purification to obtain 4-(3,3-difluorocyclobutyl)-4-methyl-3-oxovaleride. 4-(3,3-Difluorocyclobutyl)-4-methyl-3-oxovaleride (0.4 g) was dissolved in water solution, then hydroxylamine hydrochloride (0.24 g) and sodium hydroxide (0.26 g) were added, and the reaction system was stirred at 100 °C for 3 h after being added. LCMS showed that the raw material was completely reacted, ethyl acetate was added for extraction, and the organic phase was combined. The organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 3-(2-(3,3-difluorocyclobutyl)prop-2-yl)isoxazol-5-amine.

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

[0217] The acetonitrile (4.01 g) was dissolved in a tetrahydrofuran solution, the reaction system was cooled to -78°C, then LDA (4.18 g) was added and stirred for 1 hour, finally 2-(pyridin-4-yl)-2-methylpropionic acid methyl ester (3.5 g) was added, after the completion of the addition, the reaction system was stirred at -78°C for 2 hours, then slowly warmed to room temperature and stirred for 16 hours, TLC showed that the raw material was completely reacted, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, the organic phase was concentrated under reduced pressure, and column chromatography was used for separation and purification to obtain 4-(pyridin-4-yl)-4-methyl-3-oxovaleramide. 4-(pyridin-4-yl)-4-methyl-3-oxovaleramide (1.5 g) was dissolved in a water solution, then hydroxylamine hydrochloride (0.95 g) and sodium hydroxide (1.06 g) were added, after the completion of the addition, the reaction system was warmed to 100°C and stirred for 3 hours, LCMS showed that the raw material was completely reacted, extracted with ethyl acetate, the organic phases were combined, the organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 3-(2-(pyridin-4-yl)prop-2-yl)isoxazol-5-amine. DETAILED DESCRIPTION

[0218] In order to further illustrate the present application, the cyclin-dependent kinase inhibitory activity compound of the present application, the preparation method and application thereof are further described below in conjunction with specific examples, but the scope of protection of the present application is not limited thereto.

[0219] In the present application, for the same compound, the compound structure is used as the standard if the compound name and the structure formula are inconsistent.

[0220] Abbreviation term explanation: 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 (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methane sulfonate; K3PO4 represents anhydrous potassium phosphate; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; NaHMDS represents sodium hexamethyldisilazide; Xphos represents 2-dicyclohexylphospho-2,4,6-triisopropyl biphenyl; PMB- represents 4-methoxybenzyl; Boc represents tert-butoxycarbonyl; LDA represents lithium diisopropylamide; h represents hour.

[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)prop-2-yl)isoxazol-5-yl)acetamide (Compound 1)

[0222] Step 1: 6-chloro-N 4 Preparation of 6-amino-9-isopropyl-pyrimidine-4,5-diamine (Compound 1A)

[0223] Step 1: 6-chloro-N + = 187.2.

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

[0225] Step 1: 6-chloro-N 4 Preparation of 6-amino-9-isopropyl-pyrimidine-4,5-diamine (Compound 1A) + = 213.1.

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

[0227] Step 1: 6-chloro-N + = 187.2.

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

[0225] Step 1: 6-chloro-N 4 Preparation of 6-amino-9-isopropyl-pyrimidine-4,5-diamine (Compound 1A) + = 213.1.

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

[0227] Step 1: 6-chloro-N + = 187.2.+ = 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] Methyl 2-(4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7- yl)phenyl)acetate (Compound 1D) was prepared according to the following procedure. 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 completed, the reaction system was stirred at room temperature for 16 hours. LCMS showed that the starting material was substantially completely reacted. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to obtain 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 (Compound 1D) was prepared according to the following procedure. 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 completed, the reaction system was stirred at room temperature for 16 hours. LCMS showed that the starting material was substantially completely reacted. The reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was separated and purified by column chromatography to obtain Compound 1D. MS (ESI) m / z (M+H) + = 448.3.

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

[0233] To a solution of 3-(2-(3,3-difluorocyclobutyl)prop-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) in dichloromethane (5.0 mL) was added 1-propylphosphonic anhydride (220.7 mg, 0.35 mmol, 50%) dropwise. After the addition was complete, the reaction was stirred at room temperature for 2 h. LCMS showed the starting material was almost consumed. The reaction mixture was concentrated and the residue was purified by column chromatography to give 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)prop-2-yl)isoxazol-5-yl)acetamide (Compound 1)

[0236] To a solution of N-(3-(2-(3,3-difluorocyclobutyl)prop-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) in trifluoroacetic acid (5.0 mL). The reaction was stirred at 50 °C for 2 h. The reaction was complete. The reaction mixture was concentrated and adjusted to basic with ammonia water. The mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude was purified by preparative HPLC to give Compound 1.

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

[0238] 1 HNMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.14 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 6.24 (s, 1H), 5.59 (br s, 2H), 4.69 - 4.60 (m, 1H), 3.81 (s, 2H), 2.46 - 2.32 (m, 5H), 1.51 (d, J = 6.9 Hz, 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-methylpropan-2-yl)isoxazol-5-yl)acetamide (Compound 2)

[0240] Using 3-(1,1,1 -trifluoro-2-methylpropan-2-yl)isoxazol-5-amine instead of 3-(2-(3,3- difluorocyclobutyl)propan-2-yl)isoxazol-5-amine in Step 6 of Example 1, Compound 2 of Example 2 was obtained using the same preparation method as Example 1.

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

[0242] 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (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)propan-2-yl)isoxazol-5-yl)propanamide (Compound 3)

[0244] Using (4-(1-ethoxy-1-oxopropan-2-yl)phenyl)boronic acid instead of (4-(2-methoxy-2- oxoethyl)phenyl)boronic acid in Step 4 of Example 1, Compound 3 of Example 3 was obtained using the same preparation method as Example 1.

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

[0246] 1H NMR (400 MHz, DMSO-d6) δ 11.78 (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)propan-2-yl)isoxazol-5-yl)acetamide (Compound 4)

[0248] Using (4-(2-ethoxy-2-oxoethyl)-3-fluorophenyl)boronic acid instead of (4-(2-methoxy-2- oxoethyl)phenyl)boronic acid in Step 4 of Example 1, the compound 4 of Example 4 was obtained using the same preparation method as Example 1.

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

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.15 (s, 1H), 7.54 (t, J = 8.0 Hz, 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 = 8.0 Hz, 6H), 1.20 (s, 6H).

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

[0252] Step 1: Preparation of N-(3-(2-(1,4-dioxaspiro[4.4]nonan-7-yl)propan-2-yl)isoxazol-5-yl)-2-(4-(9- isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetamide (Compound 5A)

[0253] Dissolve 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) in dichloromethane, then add 3-(2-(1,4- dioxaspiro[4.4]nonan-7-yl)propan-2-yl)isoxazol-5-amine (0.067 g, 0.26 mmol), N,N- diisopropylethylamine (0.17 g, 1.32 mmol) and 1-propylphosphonic anhydride (0.28 g, 0.88 mmol), and stir the reaction at room temperature for 2 hours after the addition is complete. After the reaction is complete, concentrate the reaction under reduced pressure, and purify the residue by column chromatography on silica gel 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-hydroxycyclopentyl)propan-2-yl)isoxazol-5-yl)acetamide (Compound 5)

[0255] Dissolve N-(3-(2-(1,4-dioxaspiro[4.4]nonan-7-yl)propan-2-yl)isoxazol-5-yl)-2-(4-(9- isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)acetamide (0.08 g) in trifluoroacetic acid (5.0 mL), and stir the reaction at 70°C for 2 hours after the addition is complete. After the reaction is complete, concentrate the reaction, then add ammonia water dropwise to make the reaction basic, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate 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)propan-2-yl)isoxazol-5-yl)acetamide (Compound 5)

[0258] 2-(4-(6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(2-(3-oxocyclopentyl)propan-2-yl)isoxazol-5-yl)acetamide (0.07 g) was dissolved in methanol, and sodium borohydride (0.026 g) was added. After the addition, the reaction system 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 reaction was concentrated under reduced pressure to obtain a crude product, which 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]pyrimidin]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-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, sodium methoxide (0.59 g) was added at 0°C, and the reaction system was heated to room temperature and stirred for 2 hours. After the reaction was completed, water was added to the reaction solution, and ethyl acetate was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was 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)oxetane-3-carboxylate (Compound 6B)

[0265] Methyl 3-(6-methoxy-2-(methylthio)-5-nitropyrimidin-4-yl)oxetane-3-carboxylate (1.42 g) was dissolved in tetrahydrofuran solution, p-methoxybenzylamine (0.62 g) and N,N- diisopropylethylamine (1.74 g) were added, and the reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated by distillation under reduced pressure, and the obtained crude product was separated by column chromatography to obtain compound 6C. + = 316.3.

[0266] Step 3: Preparation of methyl 3-(6-((4-methoxybenzyl)amino)-2-(methylthio)-5- nitropyrimidin-4-yl)oxetane-3-carboxylate (Compound 6C)

[0267] Methyl 3-(6-methoxy-2-(methylthio)-5-nitropyrimidin-4-yl)oxetane-3-carboxylate (1.42 g) was dissolved in tetrahydrofuran solution, p-methoxybenzylamine (0.62 g) and N,N- diisopropylethylamine (1.74 g) were added, and the reaction system was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated by distillation under reduced pressure, and the obtained 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)oxetane-3-carboxylate (Compound 6D)

[0270] Methyl 3-(6-((4-methoxybenzyl)amino)-2-(methylthio)-5-nitropyrimidin-4-yl)oxetane-3-carboxylate (0.8 g) was dissolved in MeOH, ammonium chloride (0.61 g) and iron powder (0.64 g) were added, and the reaction system was stirred at 60°C for 1 hour. After the reaction was completed, water was added to the reaction solution, which was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure, and the obtained 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]pyrimidin]-6'(5'H)-one (Compound 6E)

[0273] Methyl 3-(5-amino-6-((4-methoxybenzyl)amino)-2-(methylthio)pyrimidin-4- yl)oxetane-3-carboxylate (0.6 g) was dissolved in methanol solution, potassium carbonate (0.64 g) was added, after the addition was completed, the reaction system was warmed to 60°C and stirred for 2 hours. After the reaction was completed, water was added to the reaction liquid and extracted with ethyl acetate, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, the organic phase was concentrated by reduced pressure distillation, the obtained 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]pyrimidin]- 6'(5'H)-one (Compound 6F)

[0276] 4'-((4-methoxybenzyl)amino)-2'-(methylthio)spiro[oxetane-3,7'-pyrrolo[3,2-d]pyrimidin]- 6'(5'H)-one (0.25 g) was dissolved in a mixed solution of methanol and 1,4-dioxane, then Raney nickel (0.0041 g) was added, after the addition was completed, hydrogen was introduced into the reaction system and stirred at 50°C for 1 hour. After the reaction was completed, the reaction liquid was filtered with diatomite, the filtrate was concentrated by reduced pressure distillation, the obtained 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 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'- pyrrolo[3,2-d]pyrimidin]-5'(6'H)-yl)phenyl)acetate (Compound 6G)

[0278] To a solution of 4'-((4-methoxybenzyl)amino)spiro[oxetane-3,7'-pyrrolo[3,2- d]pyrimidin]-6'(5'H)-one (0.14 g) in N,N-dimethylformamide was added (4-(2-ethoxy-2- oxoethyl)phenyl)boronic acid (0.11 g), triethylamine (0.14 g), copper acetate (0.098 g) and molecular sieves, and the reaction system was purged with oxygen and stirred at 80°C for 5 hours. After the completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The obtained crude product was separated by column chromatography to obtain 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]pyrimidin]-5'(6'H)-yl)phenyl)acetic acid (compound 6H)

[0280] To a solution of ethyl 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'- pyrrolo[3,2-d]pyrimidin]-5'(6'H)-yl)phenyl)acetate (0.15 g) in 1,2-dichloroethane was added trimethyltin hydroxide (0.58 g), and the reaction system was stirred at 80°C for 5 hours. After the completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The obtained crude product was separated by column chromatography to obtain 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]pyrimidin]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol- 5-yl)acetamide (compound 6I)

[0282] To a solution of 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'- pyrrolo[3,2-d]pyrimidin]-5'(6'H)-yl)phenyl)acetic acid (0.1 g) in dichloromethane was added 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-isoxazol-5-amine (0.0431 g), N,N- diisopropylethylamine (0.17 g) and 1-propylphosphonic anhydride (0.21 g) and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under reduced pressure and the crude product was purified 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]pyrimidin]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl) isoxazol-5-yl)acetamide (Compound 6)

[0284] To a solution of 2-(4-(4'-((4-methoxybenzyl)amino)-6'-oxospiro[oxetane-3,7'- pyrrolo[3,2-d]pyrimidin]-5'(6'H)-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl) isoxazol-5-yl)acetamide (90 mg) in 1,2-dichloroethane was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.032 g) and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure. 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] 1H NMR (400 MHz, 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). Reference Example 7: 4-((6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl)methyl)-N-(3-(2-(3,3-difluorocyclobutyl)prop-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-purin-7-yl)methyl)benzoate (Compound 7A)

[0288] Methyl 4-(bromomethyl)benzoate (1.0 g), 9-isopropyl-6-((4-methoxybenzyl)amino)-7,9-dihydro-8H-purin-8-one (1.37 g), potassium carbonate (1.81 g) were sequentially dissolved in N,N-dimethylformamide (20.0 mL), and then the system was warmed to 100 °C for 16 hours. After the reaction was completed, the reaction liquid was poured into ice water, and extracted with ethyl acetate three times, and the combined organic phase was dried over anhydrous sodium sulfate, and then the organic phase was concentrated by reduced pressure distillation, and the obtained crude product was purified by column chromatography to obtain 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-purin-7-yl)methyl)benzoic acid (Compound 7B)

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

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

[0292] N-(3-(2-(3,3-difluorocyclobutyl)propan-2-yl)isoxazol-5-yl)-4-((9-isopropyl-6-((4- methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)methyl)benzamide (250 mg) was dissolved in trifluoroacetic acid (20.0 mL), then the system was warmed to 80 °C for 1 hour. The reaction was complete, the reaction liquid was concentrated, then ammonia water was added to adjust to alkaline, after extraction with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was separated and purified by preparative HPLC to obtain Compound 7. + = 646.3.

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

[0294] N-(3-(2-(3,3-difluorocyclobutyl)propan-2-yl)isoxazol-5-yl)-4-((9-isopropyl-6-((4- methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)methyl)benzamide (250 mg) was dissolved in trifluoroacetic acid (20.0 mL), then the system was warmed to 80 °C for 1 hour. The reaction was complete, the reaction liquid was concentrated, then ammonia water was added to adjust to alkaline, after extraction with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was separated and purified by preparative HPLC to obtain Compound 7.

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

[0296] 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.05 (s, 1H), 8.00 - 7.89 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.49 (s, 2H), 6.41 (s, 1H), 5.32 (s, 2H), 4.69 - 4.62 (m, 1H), 2.50 - 2.31 (m, 5H), 1.49 (d, J = 4.0 Hz, 6H), 1.23 (s, 6H).

[0297] Example 30: 2-(4-(6-amino-8-oxo-9-(propan-2-yl)-8,9-dihydro-7H-purin-7-yl)phenyl)-N-(3-(1,1,1- trifluoro-2-methylpropan-2-yl)-isoxazol-5-yl)acetourea (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] tert-Butyl 4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7- yl)phenylcarbamate (1.0 g) was dissolved in methanol (30 mL). To the solution was added hydrochloric acid in 1,4-dioxane (5.0 mL). After the addition, the reaction mixture was stirred at room temperature overnight. The reaction was complete. The reaction mixture was concentrated and then adjusted to basic with sodium bicarbonate solution. The mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative HPLC to give 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- purin-7-yl)phenylamine

[0301] tert-Butyl 4-(9-isopropyl-6-((4-methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7- yl)phenylcarbamate (1.0 g) was dissolved in methanol (30 mL). To the solution was added hydrochloric acid in 1,4-dioxane (5.0 mL). After the addition, the reaction mixture was stirred at room temperature overnight. The reaction was complete. The reaction mixture was concentrated and then adjusted to basic with sodium bicarbonate solution. The mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by preparative HPLC to give the title compound. MS (ESI) m / z (M+H)

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

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

[0304] 3-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-5-amine (310 mg), 4-(9-isopropyl-6-((4- methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenylamine (644 mg) and triethylamine (323.2 mg) were dissolved in tetrahydrofuran (15 mL), carbonyldiimidazole (390 mg) was added under ice bath. After the addition was completed, the reaction system was stirred at room temperature for 16 hours. LCMS showed that the starting material was substantially completely reacted, the reaction solution was concentrated, and the residue was separated and 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)prop-2-yl)isoxazol-5-yl)urea (Compound 30)

[0307] 3-(3-(2-(trifluoromethyl)prop-2-yl)isoxazol-5-yl)-1-(4-(9-isopropyl-6-((4- methoxybenzyl)amino)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)urea (200 mg) was dissolved in trifluoroacetic acid (10 mL). The reaction system was stirred at 50°C for 2 hours. The reaction was complete, the reaction solution was concentrated, and ammonia was added to adjust to basicity. After extraction with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was separated and purified by preparative HPLC to obtain Compound 30.

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

[0309] 1H NMR (400 MHz, DMSO-d6) δ 9.77 (d, J = 1.8 Hz, 1H), 9.07 (d, J = 2.2 Hz, 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 = 6.9 Hz, 6H).

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

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

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

[0313] Step 2: Preparation of 5-bromo-N 4 -isopropyl-N 6 ,N 6 -dibenzylpyrimidine-4,6-diamine (Compound 32B)

[0314] 5-bromo-6-chloro-N-isopropylpyrimidin-4-amine (1 g), N,N-dibenzylamine (4.11 g), triethylamine (3.23 g) were sequentially dissolved in n-butanol (10 mL) at room temperature, and reacted at 120 °C for 48 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated by column chromatography to obtain Compound 32B. MS (ESI) m / z (M+H) + = 471.2.

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

[0316] Compound 32A (0.05 g), 6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl acetic acid ethyl ester (0.05 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g), tris(dibenzylideneacetone)dipalladium (0.29 g), cesium carbonate (1.04 g) were added into toluene (5 mL) under nitrogen, and the system was reacted at 110 °C overnight. After the reaction was completed, the system was cooled to room temperature, stirred with methanol for 2 h, concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated by column chromatography to obtain compound 32B. MS (ESI) m / z (M+H) 4 - isopropyl-N 6 ,N 6 - bis(4-methoxybenzyl)pyrimidine-4,6-diamine ((0.5 g), 6-amino spiro[3.3]heptane-2-acetic acid ethyl ester (0.027 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g), tris(dibenzylideneacetone)dipalladium (0.29 g), cesium carbonate (1.04 g) were added into toluene (5 mL) under nitrogen, and the system was reacted at 110 °C overnight. After the reaction was completed, the system was cooled to room temperature, stirred with methanol for 2 h, concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated by column chromatography to obtain compound 32C. MS (ESI) m / z (M+H) + = 546.3.

[0317] Step 4: 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 ethyl ester (compound 32D)

[0318] Compound 32A (0.05 g), 6-amino-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7-yl acetic acid ethyl ester (0.05 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g), tris(dibenzylideneacetone)dipalladium (0.29 g), cesium carbonate (1.04 g) were added into toluene (5 mL) under nitrogen, and the system was reacted at 110 °C overnight. After the reaction was completed, the system was cooled to room temperature, stirred with methanol for 2 h, concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated by column chromatography to obtain compound 32B. 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[l. l. l]pentan-l -yl)acetate (20 mg), lithium hydroxide (4.2 mg) were sequentially dissolved in water (0.5 mL), methanol (1.5 mL), tetrahydrofuran (0.5 mL) at room temperature, and reacted at room temperature for 1 hour. After completion of the reaction, the system was adjusted to be acidic with dilute hydrochloric acid in an ice bath, extracted with dichloromethane three times, and the organic phase was combined and dried and concentrated to obtain the crude compound 32E. The crude compound was used directly in the next step without purification. MS (ESI) m / z (M+H) + = 558.3.

[0321] Step 6: Preparation of 2-(3-(6-bis[(4-methoxyphenyl)methyl]amino)-8-oxo-9-(propan-2-yl)- 8,9-dihydro-7H-purin-7-yl)bicyclo[l. l. l]pent-l -yl)-N-(3-(l,l,l -trifluoro-2-methylpropan-2-yl)- isoxazol-5-yl)acetamide (Compound 32F)

[0322] Ethyl 2-(3-(6-(bis(4-methoxybenzyl)amino)-9-isopropyl-8-oxo-8,9-dihydro-7H-purin-7- yl)bicyclo[l. l. l]pentan-l -yl)acetate (20 mg), lithium hydroxide (4.2 mg) were sequentially dissolved in water (0.5 mL), methanol (1.5 mL), tetrahydrofuran (0.5 mL) at room temperature, and reacted at room temperature for 1 hour. After completion of the reaction, the system was adjusted to be acidic with dilute hydrochloric acid in an ice bath, extracted with dichloromethane three times, and the organic phase was combined and dried and concentrated to obtain the crude compound 32E. The crude compound was used directly in the next step without purification. MS (ESI) m / z (M+H) + = 558.3.

[0323] Step 7: Preparation of 2-(3-(6-amino-8-oxo-9-(propan-2-yl)-8,9-dihydro-7H-purin-7-yl)bicyclo[l. l. l]pent-l -yl)-N-(3-(l,l,l -trifluoro-2-methylpropan-2-yl)-isoxazol-5-yl)acetamide (Compound 32)

[0324] N-(3-(1,1,1-trifluoro-2-methylpropan-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 completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, and the obtained crude product was purified by preparative HPLC to obtain Example 32.

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

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (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 = 6.8 Hz, 6H).

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

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

[0329] 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 g) was dissolved in DMF, potassium carbonate (3.18 g) was added, the reaction system was cooled to 0 °C, 2-iodopropane (2.15 g) was added, the reaction system was naturally warmed to room temperature and stirred for 5 hours, after the reaction was completed, water was added to the reaction solution, extracted with ethyl acetate, the organic phase was combined, dried with anhydrous sodium sulfate, the organic phase was removed by reduced pressure distillation, and the obtained 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 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetate (Compound A-2)

[0332] To a solution of 3-iodo-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-4-amine (1.6 g) in a mixed solution of ethylene glycol dimethyl ether and water, ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acetate (1.84 g), Pd(dppf)Cl2(0.39 g) and sodium carbonate (1.68 g) were added, and the reaction system was warmed to 90°C and stirred for 16 hours. After the reaction was completed, water was added to the reaction solution, and extraction was performed with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and the organic phase was removed by distillation under reduced pressure. The obtained 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-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetic acid (Compound A-3)

[0334] To a solution of ethyl 2-(4-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetate (0.8 g) in a mixed solution of water, methanol and tetrahydrofuran, lithium hydroxide (0.28 g) was added, and after the completion of the addition, the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, 1M HCl was added to the reaction solution to adjust the pH to weakly acidic, and extraction was performed with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and the organic phase was removed by distillation under reduced pressure. The obtained 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-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(3-(2-(3-(benzyloxy)cyclobutyl)prop-2-yl)isoxazol-5-yl)acetamide (Compound A-4)

[0336] To a solution of 2-(4-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)acetic acid (0.1 g) in dichloromethane, 3-(2-(3-(benzyloxy)cyclobutyl)prop-2-yl)isoxazol-5-amine (0.092 g), DIPEA (0.25 g) and T3P (0.81 g) were sequentially added, and after the completion of the addition, the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained 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)prop-2-yl)isoxazol-5-yl)acetamide (Compound A)

[0338] 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(3-(2-(3- (benzyloxy)cyclobutyl)prop-2-yl)isoxazol-5-yl)acetamide (0.1 g) was dissolved in dichloromethane solution, the reaction system was cooled to 0 °C, trifluoromethanesulfonic acid (0.89 g) was added, after the addition was completed, the reaction system was stirred at 0 °C for 2 hours, LCMS showed that the raw material was completely reacted, triethylamine was added to the reaction liquid to adjust the pH to neutral, dichloromethane was added for extraction, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, the obtained crude product was separated and purified by preparative HPLC to obtain Compound A.

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

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.24 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 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 in a similar manner to the above examples, using the corresponding starting materials and reagents.

[0342] Biological Experimental Example 1: Cell proliferation inhibition test

[0343] 1. Materials and reagents:

[0344] 2. Experimental method:

[0345] Cell proliferation inhibition activity of the compounds was determined using CTG (CELLTITER-GLO) luminescence method. The starting concentration of the compounds used was 10 mM, 3-fold dilution, 10 concentrations, and duplicate wells were tested.

[0346] (1) Day 0: Cell plating

[0347] Ba / F3-TEL-VEGFR2, Ba / F3-KIF5B-RET-V804M, Ba / F3-KIF5B-RET-G810R cells were recovered with complete medium (RPMI 1640 + 10% FBS + 1% P / S). After two generations or so, the logarithmic growth phase cells were collected by centrifugation and counted, and the cells were resuspended to the appropriate concentration. The cell suspension was inoculated in a 96-well plate, 95 μL of cell suspension was added to each well, and the plating density was 2000 cells / well.

[0348] (2) Day 1: Drug treatment

[0349] The test compound was prepared as a stock solution with DMSO, and was diluted with DMSO in a 3-fold gradient to obtain 10 concentration gradients, with 10 mM as the highest concentration. The test compound was diluted 50 times with medium, and 5 μL was added to the 96-well cell plate containing 95 μL of cells. In the Min control wells, 5 μL of DMSO-cell culture medium mixture (DMSO final concentration 0.1%) was added, and in the Max control wells, 5 μL of DMSO-cell culture medium mixture (DMSO final concentration 0.1%) was added. The plates were incubated in a 37°C, 5% CO2, relative humidity above 90% incubator for 3 days.

[0350] (3) Day 4: Data detection

[0351] 50 μL / well of CellTiter Glo was added to terminate the reaction, and the plates were incubated at room temperature in the dark for 30 min. The RLU value of each well was read on a SpectraMax Paradigm microplate reader.

[0352] (4) Data analysis

[0353] The cell inhibition rate was calculated according to the formula: cell growth inhibition rate % = (1-As / Ac) x 100. Wherein As: RLU 样品 (cells + CTG + test compound) - RLU Min (no cells in the culture medium), Ac: RLU normal growth cell control (cells + CTG + DMSO) - RLU Min (no cells in the culture medium).

[0354] The inhibition rate Inh% (Y) corresponding to each concentration (X) was input into EXCEL, and the half-inhibitory concentration (IC 50 ) value of each compound was calculated according to the built-in four-parameter fitting formula Y = Bottom + (Top-Bottom) / (1+(IC50 / X)*HillSlope) in Graphpad Prism 8.0 software.

[0355] 3. Experimental results:

[0356] The compound in the application has obvious inhibitory activity on RET-mediated proliferative cells, especially good inhibitory activity on RET mutant-mediated proliferative cells. It is found that the IC 50 value of the inhibitory activity of the compound in the application on RET mutant proliferative cells (such as V804M, G810R) is less than or equal to 50nM, the IC 50 value of the inhibitory activity of some compounds in the application on RET mutant proliferative cells (such as V804M, G810R) is greater than or equal to 25nM and less than 50nM, the IC 50 value of the inhibitory activity of some compounds in the application on RET mutant proliferative cells (such as V804M, G810R) is greater than or equal to 10nM and less than 25nM, the IC 50 value of the inhibitory activity of some compounds in the application on RET mutant proliferative cells (such as V804M, G810R) is greater than or equal to 5nM and less than 10nM, and the IC50 value of the inhibitory activity of some compounds in the application on RET mutant proliferative cells (such as V804M, G810R) is less than 5nM.

[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, and " / " represents undetected or not applicable.

[0358] Biological experiment example 2: RET kinase inhibition test

[0359] 1. Materials and reagents:

[0360] 2. Experimental method:

[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 compounds were dissolved in 100% dimethyl sulfoxide (DMSO) system, prepared to 10 mM and stored in a nitrogen cabinet in the dark.

[0363] Reaction conditions:

[0364] Detection method:

[0365] 1. Add 2 μL of kinase and 1 μL of compound to the 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 5 μL ADP-Glo TM Reagent, incubate at room temperature for 40 minutes;

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

[0369] 5. Read the plate on a 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 the present invention have significant inhibitory activity against RET kinase, especially against RET kinase mutants. Experiments have found that the IC values ​​of the compounds of the present invention for the inhibitory activity against RET mutants (e.g., V804M, G810R) are 50 The IC value is less than or equal to 5 nM, and the inhibitory activity of certain compounds of the present invention on RET mutants (such as V804M, G810R) 50 The IC values ​​of some compounds of the present invention for the inhibitory activity against RET mutants (e.g., V804M, G810R) are greater than or equal to 3 nM and less than 5 nM. 50 The IC values ​​of some compounds of the present invention for the inhibitory activity against RET mutants (e.g., V804M, G810R) are greater than or equal to 1 nM and less than 3 nM. 50The IC50value of the inhibitory activity of certain compounds of the present application against RET mutant (e.g. V804M, G810R) is less than 0.5 nM.

[0374] The above examples, test examples are specific to illustrate the exemplary examples of the present application, and are not intended to limit the scope of the protection of the present application, any improvement, modification, equivalent structure or equivalent process transformation made by using the principles and contents of the present application, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present application.

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 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 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 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 optionally substituted by 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 spirocycloalkyl, for example selected from phenyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 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 groups are optionally substituted by 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 is a 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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